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2.
Eur Respir J ; 52(1)2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-29853494

RESUMO

While targeted nonsmall cell lung cancer (NSCLC) therapies have improved the outcome of defined disease subtypes, prognosis for most patients remains poor. We found the AAA+ ATPase Reptin to be highly expressed in the vast majority of 278 NSCLC tumour samples. Thus, the objective of the study was to assess the role of Reptin in NSCLC.Survival analyses of 1145 NSCLC patients revealed that high RNA expression levels of Reptin are associated with adverse outcome. Knockdown of Reptin in human NSCLC cells impaired growth ex vivo and eliminated engraftment in a xenograft model. Reptin directly interacted with histone deacetylase 1 (HDAC1) as the critical mechanism driving NSCLC tumour progression. Pharmacological disruption of the Reptin/HDAC1 complex resulted in a substantial decrease in NSCLC cell proliferation and induced significant sensitisation to cisplatin.Our results identify Reptin as a novel independent prognostic factor and as a key regulator mediating proliferation and clonal growth of human NSCLC cells ex vivo and in vivo We unveil a Reptin/HDAC1 protein complex whose pharmacological disruption sensitises NSCLC cells to cisplatin, suggesting this approach for application in clinical trials.


Assuntos
ATPases Associadas a Diversas Atividades Celulares/metabolismo , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Proteínas de Transporte/metabolismo , DNA Helicases/metabolismo , Histona Desacetilase 1/metabolismo , Neoplasias Pulmonares/metabolismo , Idoso , Animais , Apoptose/efeitos dos fármacos , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/patologia , Proliferação de Células/efeitos dos fármacos , Cisplatino/uso terapêutico , Resistencia a Medicamentos Antineoplásicos , Feminino , Células HEK293 , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/patologia , Masculino , Camundongos , Camundongos Knockout , RNA Interferente Pequeno/genética , Ensaios Antitumorais Modelo de Xenoenxerto
4.
Acta Haematol ; 137(3): 163-172, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28399522

RESUMO

Within this retrospective single-center study, we analyzed the survival of 320 multiple myeloma (MM) patients receiving melphalan high-dose chemotherapy (HDCT) and either single (n = 286) or tandem (n = 34) autologous stem cell transplantation (ASCT) from 1996 to 2012. Additionally, the impact of novel induction regimens was assessed. Median follow-up was 67 months, median overall survival (OS) 62 months, median progression-free survival (PFS) 33 months (95% CI 27-39), and treatment-related death (TRD) 3%. Multivariate analysis revealed age ≥60 years (p = 0.03) and stage 3 according to the International Staging System (p = 0.006) as adverse risk factors regarding PFS. Median OS was significantly better in newly diagnosed MM patients receiving induction therapy with novel agents, e.g., bortezomib, thalidomide, or lenalidomide, compared with a traditional regimen (69 vs. 58 months; p = 0.01). More patients achieved at least a very good partial remission in the period from 2005 to 2012 than from 1996 to 2004 (65 vs. 30%; p < 0.001), with a longer median OS in the later period (71 vs. 52 months, p = 0.027). In conclusion, our analysis confirms HDCT-ASCT as an effective therapeutic strategy in an unselected large myeloma patient cohort with a low TRD rate and improved prognosis due to novel induction strategies.


Assuntos
Mieloma Múltiplo/tratamento farmacológico , Mieloma Múltiplo/terapia , Transplante de Células-Tronco , Adulto , Idoso , Antineoplásicos Alquilantes/administração & dosagem , Protocolos Antineoplásicos , Estudos de Coortes , Terapia Combinada , Intervalo Livre de Doença , Feminino , Humanos , Quimioterapia de Indução , Masculino , Melfalan/administração & dosagem , Pessoa de Meia-Idade , Prognóstico , Estudos Retrospectivos , Transplante Autólogo
5.
PLoS One ; 11(8): e0160871, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27575819

RESUMO

BACKGROUND: This retrospective, multicenter study aimed to reveal risk predictors for mortality in the intensive care unit (ICU) as well as survival after ICU discharge in patients with acute myeloid leukemia (AML) requiring treatment in the ICU. METHODS AND RESULTS: Multivariate analysis of data for 187 adults with AML treated in the ICU in one institution revealed the following as independent prognostic factors for death in the ICU: arterial oxygen partial pressure below 72 mmHg, active AML and systemic inflammatory response syndrome upon ICU admission, and need for hemodialysis and mechanical ventilation in the ICU. Based on these variables, we developed an ICU mortality score and validated the score in an independent cohort of 264 patients treated in the ICU in three additional tertiary hospitals. Compared with the Simplified Acute Physiology Score (SAPS) II, the Logistic Organ Dysfunction (LOD) score, and the Sequential Organ Failure Assessment (SOFA) score, our score yielded a better prediction of ICU mortality in the receiver operator characteristics (ROC) analysis (AUC = 0.913 vs. AUC = 0.710 [SAPS II], AUC = 0.708 [LOD], and 0.770 [SOFA] in the training cohort; AUC = 0.841 for the developed score vs. AUC = 0.730 [SAPSII], AUC = 0.773 [LOD], and 0.783 [SOFA] in the validation cohort). Factors predicting decreased survival after ICU discharge were as follows: relapse or refractory disease, previous allogeneic stem cell transplantation, time between hospital admission and ICU admission, time spent in ICU, impaired diuresis, Glasgow Coma Scale <8 and hematocrit of ≥25% at ICU admission. Based on these factors, an ICU survival score was created and used for risk stratification into three risk groups. This stratification discriminated distinct survival rates after ICU discharge. CONCLUSIONS: Our data emphasize that although individual risks differ widely depending on the patient and disease status, a substantial portion of critically ill patients with AML benefit from intensive care.


Assuntos
Unidades de Terapia Intensiva/estatística & dados numéricos , Leucemia Mieloide Aguda/mortalidade , Síndrome de Resposta Inflamatória Sistêmica/epidemiologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Mortalidade Hospitalar , Humanos , Masculino , Pessoa de Meia-Idade , Mortalidade , Análise Multivariada , Escores de Disfunção Orgânica , Estudos Retrospectivos , Fatores de Risco , Centros de Atenção Terciária , Adulto Jovem
6.
Clin Sarcoma Res ; 5: 24, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26587222

RESUMO

BACKGROUND: Rhabdomyosarcoma (RMS), a malignant tumour of mesenchymal origin which can occur at various sites in the body, is one of the most common soft tissue sarcomas in both children and adolescents, but is rare in adults with a prevalence of less than 1 %. The alveolar subtype of rhabdomyosarcoma (ARMS) is typically characterized by a specific reciprocal chromosomal translocation involving the PAX3 and FKHR or PAX7 and FKHR genes, respectively. ARMS is most frequently seen in childhood, and typically affects the sinuses and soft tissue of the extremities, with approximately 23 % exhibiting metastasis to the marrow. Non-invasive F-18-fluorodeoxyglucose positron-emission tomography (FDG-PET) scans have a high ability to detect lymph nodes, bone, and bone marrow involvement in patients with metastatic RMS, often with higher sensitivity and specificity compared with conventional modalities. CASE PRESENTATION: Here, we report an unusual case of ARMS confined to the bone marrow in an older adult that lacked an identifiable primary tumour using FDG-PET/CT and mimicked a haematological disease with pancytopenia but without abnormal findings by FDG-PET/CT. The patient was initially treated with topotecan/cyclophosphamide and subsequently switched to vinorelbine. Due to severe toxicity the treatment was discontinued, however after 7-months follow-up, the patient is still alive with an improved general state of health and only a mild pancytopenia with no need for blood transfusions. CONCLUSION: Rhabdomyosarcoma can be limited to the bone marrow with no identifiable primary tumour. This case shows that the use of a bone marrow biopsy in suspected malignancies affecting the bone marrow is irreplaceable.

7.
Int J Cancer ; 137(6): 1306-17, 2015 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-25704182

RESUMO

Epigenomic changes are an important feature of malignant tumors. How tumor aggressiveness is affected by DNA methylation of specific loci is largely unexplored. In genome-wide DNA methylation analyses, we identified the KCa 3.1 channel gene (KCNN4) promoter to be hypomethylated in an aggressive non-small-cell lung carcinoma (NSCLC) cell line and in patient samples. Accordingly, KCa 3.1 expression was increased in more aggressive NSCLC cells. Both findings were strong predictors for poor prognosis in lung adenocarcinoma. Increased KCa 3.1 expression was associated with aggressive features of NSCLC cells. Proliferation and migration of pro-metastatic NSCLC cells depended on KCa 3.1 activity. Mechanistically, elevated KCa 3.1 expression hyperpolarized the membrane potential, thereby augmenting the driving force for Ca(2+) influx. KCa 3.1 blockade strongly reduced the growth of xenografted NSCLC cells in mice as measured by positron emission tomography-computed tomography. Thus, loss of DNA methylation of the KCNN4 promoter and increased KCa 3.1 channel expression and function are mechanistically linked to poor survival of NSCLC patients.


Assuntos
Epigênese Genética/genética , Canais de Potássio Ativados por Cálcio de Condutância Intermediária/genética , Neoplasias Pulmonares/genética , Adenocarcinoma/genética , Adenocarcinoma/patologia , Adenocarcinoma de Pulmão , Animais , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/patologia , Linhagem Celular Tumoral , Metilação de DNA/genética , Epigenômica/métodos , Feminino , Xenoenxertos , Humanos , Neoplasias Pulmonares/patologia , Camundongos , Camundongos Nus , Prognóstico , Regiões Promotoras Genéticas/genética
8.
Exp Hematol ; 43(1): 32-43.e1-35, 2015 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-25450514

RESUMO

The use of genome-wide copy-number analysis and massive parallel sequencing has revolutionized the understanding of the clonal architecture of pediatric acute lymphoblastic leukemia (ALL) by demonstrating that this disease is composed of highly variable clonal ancestries following the rules of Darwinian selection. The current study aimed to analyze the molecular composition of childhood ALL biopsies and patient-derived xenografts with particular emphasis on mechanisms associated with acquired chemoresistance. Genomic DNA from seven primary pediatric ALL patient samples, 29 serially passaged xenografts, and six in vivo selected chemoresistant xenografts were analyzed with 250K single-nucleotide polymorphism arrays. Copy-number analysis of non-drug-selected xenografts confirmed a highly variable molecular pattern of variegated subclones. Whereas primary patient samples from initial diagnosis displayed a mean of 5.7 copy-number alterations per sample, serially passaged xenografts contained a mean of 8.2 and chemoresistant xenografts a mean of 10.5 copy-number alterations per sample, respectively. Resistance to cytarabine was explained by a new homozygous deletion of the DCK gene, whereas methotrexate resistance was associated with monoallelic deletion of FPGS and mutation of the remaining allele. This study demonstrates that selecting for chemoresistance in xenografted human ALL cells can reveal novel mechanisms associated with drug resistance.


Assuntos
Antineoplásicos/farmacologia , Células Clonais/patologia , Células-Tronco Neoplásicas/patologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/patologia , Animais , Antineoplásicos/uso terapêutico , Biópsia , Citarabina/farmacologia , Citarabina/uso terapêutico , DNA de Neoplasias/genética , Desoxicitidina Quinase/genética , Dexametasona/uso terapêutico , Progressão da Doença , Resistencia a Medicamentos Antineoplásicos/genética , Feminino , Dosagem de Genes , Xenoenxertos , Humanos , Masculino , Metotrexato/farmacologia , Metotrexato/uso terapêutico , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Mutação , Proteínas de Neoplasias/genética , Transplante de Neoplasias , Peptídeo Sintases/genética , Polimorfismo de Nucleotídeo Único , Leucemia-Linfoma Linfoblástico de Células Precursoras B/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras B/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras B/patologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Leucemia-Linfoma Linfoblástico de Células T Precursoras/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células T Precursoras/genética , Leucemia-Linfoma Linfoblástico de Células T Precursoras/patologia , Quimera por Radiação , Análise de Sequência de DNA , Vincristina/uso terapêutico
9.
Dig Dis Sci ; 60(2): 492-501, 2015 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-25280558

RESUMO

BACKGROUND AND AIM: Ulcerative colitis increases the risk of developing dysplasia and colitis-associated cancer (CAC). The purpose of this study was to determine the risk factors as well as protective measures for disease burden, need for colectomy and the development of CAC in ulcerative colitis (UC) patients. METHODS: A cohort of n = 434 UC patients was evaluated. Data analysis was performed by univariate and multivariate logistic regression. Odds ratios (OR) and 95 % confidence intervals (CI) were calculated, and significance was assessed by the likelihood ratio test. RESULTS: Mean patient age at UC diagnosis was 45.7 ± 15.1 years which manifested mainly as pancolitis (47 %) or left-sided colitis (45.2 %). CAC was detected in ten patients (2.3 %). UC disease duration was strongly associated with the risk of CAC (P < 0.0014); disease duration between 9 and 15 years: OR of 2.5 (95 % CI 0.2-41.1), more than 15 years: OR of 21.4 (95 % CI 2.6-173.6). The risk of developing dysplasia (low-grade intraepithelial neoplasia, LGIEN and high-grade intraepithelial neoplasia, HGIEN) or the need to undergo colectomy was also significantly related to disease duration (P = 0.006, P = 0.002, respectively). Established anti-inflammatory medication (e.g., 5-ASA, anti-TNF-α) significantly reduced the risk of both dysplasia and CAC (P = 0.02). CONCLUSIONS: Despite the use of modern therapies for UC, CAC rates remain high. In our study, risk factors included disease duration while anti-inflammatory therapies reduced the risk. Effective control of the intestinal inflammation also reduced the disease burden as indicated by decreased risk of requiring colectomy, underscoring the need for sufficient surveillance and anti-inflammatory therapies.


Assuntos
Colite Ulcerativa/complicações , Neoplasias Colorretais/etiologia , Adulto , Idoso , Anti-Inflamatórios/uso terapêutico , Colectomia , Colite Ulcerativa/diagnóstico , Colite Ulcerativa/terapia , Neoplasias Colorretais/diagnóstico , Neoplasias Colorretais/prevenção & controle , Progressão da Doença , Feminino , Fármacos Gastrointestinais/uso terapêutico , Humanos , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Razão de Chances , Fatores de Proteção , Estudos Retrospectivos , Fatores de Risco , Centros de Atenção Terciária , Fatores de Tempo , Resultado do Tratamento
10.
Clin Exp Nephrol ; 19(1): 99-106, 2015 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-24599361

RESUMO

BACKGROUND: Lipocalin 2 (LCN2 or neutrophil gelatinase-associated lipocalin) is a secretory protein discovered from neutrophils, which accumulates in the blood and urine during acute kidney injury (AKI) and in the blood by bacterial infection. Little is known about the tissue source and molecular forms of this protein under normal and pathophysiologic conditions. METHODS: By sandwich ELISA, serum and urinary LCN2 levels were measured in 36 patients with hematologic malignancies who transiently became neutropenic by stem cell transplantation (SCT). To evaluate contribution of neutrophil-derived LCN2 in the physiologic blood LCN2 concentrations, we examined CCAAT/enhancer-binding protein ε (C/EBPε) knockout mice, which lack mature neutrophils. RESULTS: In patients without AKI and bacterial infection, at 1 week after SCT, the median blood neutrophil counts became zero and serum LCN2 levels were decreased by 76 ± 6 % (p < 0.01), but urinary LCN2 levels were not altered. During neutropenic conditions, bacterial infection caused only a modest rise of serum LCN2 but AKI produced a marked rise of serum and urinary LCN2 levels. Serum LCN2 concentrations in C/EBPε knockout mice were reduced by 66 ± 11 % compared to wild-type mice (p < 0.05). Blood LCN2 existed predominantly in high molecular weight forms (>100 kDa), while urinary LCN2 was mainly in low molecular weight forms. CONCLUSION: Our findings suggest that neutrophils are the major source of circulating LCN2 in normal and infected conditions, whereas blood and urinary LCN2 mainly derive from the kidney during AKI, and that the molecular forms and regulation of blood and urinary LCN2 are clearly distinct.


Assuntos
Injúria Renal Aguda/sangue , Rim/metabolismo , Lipocalinas/sangue , Neutrófilos/metabolismo , Proteínas Oncogênicas/sangue , Proteínas de Fase Aguda/urina , Animais , Infecções Bacterianas/sangue , Infecções Bacterianas/urina , Biomarcadores/sangue , Biomarcadores/urina , Proteínas Estimuladoras de Ligação a CCAAT/genética , Proteínas Estimuladoras de Ligação a CCAAT/fisiologia , Neoplasias Hematológicas/complicações , Neoplasias Hematológicas/terapia , Transplante de Células-Tronco Hematopoéticas , Humanos , Lipocalina-2 , Lipocalinas/urina , Camundongos , Camundongos Knockout , Peso Molecular , Proteínas Oncogênicas/urina
11.
Mol Nutr Food Res ; 58(7): 1474-90, 2014 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-24764203

RESUMO

SCOPE: In previous studies, we could show that the B vitamin nicotinamide (NAM) enhanced antimicrobial activity of neutrophils. Here, we assessed the effects of NAM in two models of experimental colitis. METHODS AND RESULTS: Colitis was induced in C57BL/6 mice either by oral infection with Citrobacter rodentium or by DSS (dextran sodium sulphate) administration, and animals were systemically treated with NAM. Ex vivo bacterial clearance was assessed in murine and human whole blood, as well as isolated human neutrophils. In C. rodentium-induced colitis, NAM treatment resulted in markedly decreased systemic bacterial invasion, histological damage and increased fecal clearance of C. rodentium by up to 600-fold. In contrast, NAM had no effect when administered to neutrophil-depleted mice. Ex vivo stimulation of isolated human neutrophils, as well as murine and human whole blood with NAM led to increased clearance of C. rodentium and enhanced expression of antimicrobial peptides in neutrophils. Moreover, NAM treatment significantly ameliorated the course of DSS colitis, as assessed by body weight, histological damage and myeloperoxidase activity. CONCLUSION: Pharmacological application of NAM mediates beneficial effects in bacterial and chemically induced colitis. Future studies are needed to explore the clinical potential of NAM in the context of intestinal bacterial infections and human inflammatory bowel disease (IBD).


Assuntos
Antibacterianos/farmacologia , Colite/tratamento farmacológico , Neutrófilos/efeitos dos fármacos , Niacinamida/farmacologia , Animais , Proteínas Estimuladoras de Ligação a CCAAT/genética , Proteínas Estimuladoras de Ligação a CCAAT/metabolismo , Citrobacter rodentium/efeitos dos fármacos , Colite/induzido quimicamente , Sulfato de Dextrana , Modelos Animais de Doenças , Infecções por Enterobacteriaceae/tratamento farmacológico , Fezes/microbiologia , Feminino , Regulação da Expressão Gênica , Humanos , Intestinos/efeitos dos fármacos , Intestinos/microbiologia , Complexo Antígeno L1 Leucocitário/sangue , Camundongos , Camundongos Endogâmicos C57BL , Viabilidade Microbiana/efeitos dos fármacos , Neutrófilos/metabolismo
12.
Clin Cancer Res ; 20(4): 814-26, 2014 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-24334763

RESUMO

PURPOSE: Cancer cell phenotypes are partially determined by epigenetic specifications, such as DNA methylation. Metastasis development is a late event in cancerogenesis and might be associated with epigenetic alterations. EXPERIMENTAL DESIGN: An in vivo selection approach was used to generate highly aggressive non-small cell lung cancer (NSCLC) cell lines (A549 and HTB56) followed by genome-wide DNA methylation analysis. Furthermore, the therapeutic effects of the epigenetic agent azacytidine on DNA methylation patterns and the in vivo phenotypes were explored. RESULTS: Widespread changes of DNA methylation were observed during development of highly aggressive cell lines. Up to 2.5% of the CpG-rich region was differentially methylated as identified by reduced representation bisulfite sequencing compared with the less aggressive parental cell lines. DNA methyltransferase inhibition by azacytidine reversed the prometastatic phenotype; this was highly associated with the preferential loss of DNA methylation at sites that were hypermethylated during the in vivo selection. Of note, polycomb (PRC2) binding sites were particularly affected by DNA methylation changes after azacytidine exposure that persisted over time. CONCLUSIONS: We could show that metastatic capability of NSCLC is closely associated with DNA methylome alterations. Because inhibition of DNA methyltransferase reversed metastasis-prone phenotype, epigenetic modulation seems to be a potential therapeutic approach to prevent metastasis formation.


Assuntos
Adenocarcinoma/genética , DNA-Citosina Metilases/antagonistas & inibidores , Epigênese Genética , Neoplasias Pulmonares/genética , Proteínas do Grupo Polycomb/fisiologia , Adenocarcinoma/tratamento farmacológico , Adenocarcinoma/enzimologia , Adenocarcinoma/secundário , Animais , Antimetabólitos Antineoplásicos/farmacologia , Azacitidina/farmacologia , Sítios de Ligação , Linhagem Celular Tumoral , Metilação de DNA , DNA-Citosina Metilases/metabolismo , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/enzimologia , Neoplasias Pulmonares/patologia , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Transplante de Neoplasias , Fenótipo
14.
Ann Hematol ; 92(8): 1041-8, 2013 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-23532626

RESUMO

High-dose chemotherapy (HDT) followed by autologous stem cell transplantation (ASCT) is considered standard in the treatment of patients with relapsed or refractory aggressive peripheral T cell lymphoma (PTCL). However, the optimal salvage regimen before ASCT has not yet been established. We retrospectively analyzed 31 patients with relapsed or refractory aggressive PTCL after anthracycline-based first-line chemotherapy who received either DexaBEAM (dexamethasone, carmustine, etoposide, cytarabine, and melphalan; n = 16) or ICE (ifosfamide, carboplatin, and etoposide; n = 15) regimen as first salvage chemotherapy followed by HDT/ASCT. The overall response rate (OR) was significantly higher for patients treated with DexaBEAM (69 %; 95 % confidence interval 46.0-91.5 %) as compared to the ICE group (20 %; 95 % confidence interval -0.2-40.2 %; P = 0.01), with higher complete response (CR; 38 %; 95 % confidence interval 13.8-61.2 %; vs. 7 %; 95 % confidence interval -6.0-19.6 %) as well as partial response (PR; 31 vs. 13 %) rate. Changing regimen due to failure of first salvage therapy, 12 patients initially receiving ICE still achieved an OR of 58 % (33 % CR, 25 % PR) with DexaBEAM as second salvage therapy, whereas in three patients receiving ICE after DexaBEAM failure, only one achieved an OR (1 PR). Median progression-free survival was significantly higher in the DexaBEAM group (6.4 vs. 2 months; P = 0.01). Major adverse event in both groups was myelosuppression with higher but tolerable treatment-related toxicity for patients in the DexaBEAM group. For all patients proceeding to HDT/ASCT, a 3-year overall survival was 50 %. Together, considering the limitations of the retrospective design of the evaluation and the small sample size, our data suggest that DexaBEAM salvage chemotherapy is superior to ICE for patients with relapsed or refractory aggressive PTCL for remission induction prior to autologous transplantation, with higher but manageable treatment-related toxicity.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Linfoma de Células T Periférico/tratamento farmacológico , Transplante de Células-Tronco de Sangue Periférico , Terapia de Salvação , Adolescente , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Carboplatina/administração & dosagem , Carboplatina/efeitos adversos , Carmustina/administração & dosagem , Carmustina/efeitos adversos , Terapia Combinada , Citarabina/administração & dosagem , Citarabina/efeitos adversos , Dexametasona/administração & dosagem , Dexametasona/efeitos adversos , Intervalo Livre de Doença , Avaliação de Medicamentos , Etoposídeo/administração & dosagem , Etoposídeo/efeitos adversos , Feminino , Fator Estimulador de Colônias de Granulócitos/uso terapêutico , Doenças Hematológicas/induzido quimicamente , Mobilização de Células-Tronco Hematopoéticas , Humanos , Ifosfamida/administração & dosagem , Ifosfamida/efeitos adversos , Estimativa de Kaplan-Meier , Linfoma de Células T Periférico/cirurgia , Masculino , Melfalan/administração & dosagem , Melfalan/efeitos adversos , Pessoa de Meia-Idade , Mucosite/induzido quimicamente , Cuidados Pré-Operatórios , Estudos Retrospectivos , Transplante Autólogo , Resultado do Tratamento , Adulto Jovem
15.
Int J Cancer ; 132(12): 2730-7, 2013 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-23165325

RESUMO

Despite recent advances in therapy, breast cancer remains the second most common cause of death from malignancy in women. Chemotherapy plays a major role in breast cancer management, and combining chemotherapeutic agents with nonchemotherapeutic agents is of considerable clinical interest. Cucurbitacins are triterpenes compounds found in plants of the Cucurbitaceae family, reported to have anticancer and anti-inflammatory activities. Previously, we have shown antiproliferative activity of cucurbitacin B (CuB) in breast cancer, and we hypothesized that combining CuB with chemotherapeutic agents can augment their antitumor effect. Here, we show that a combination of CuB with either docetaxel (DOC) or gemcitabine (GEM) synergistically inhibited the proliferation of MDA-MB-231 breast cancer cells in vitro. This antiproliferative effect was accompanied by an increase in apoptosis rates. Furthermore, in vivo treatment of human breast cancer orthotopic xenografts in immunodeficient mice with CuB at either low (0.5 mg/kg) or high (1 mg/kg) doses in combination with either DOC (20 mg/kg) or GEM (12.5mg/kg) significantly reduced tumor volume as compared with monotherapy of each drug. Importantly, no significant toxicity was noted with low-dose CuB in combination with either DOC or GEM. In conclusion, combination of CuB at a relatively low concentration with either of the chemotherapeutic agents, DOC or GEM, shows prominent antiproliferative activity against breast cancer cells without increased toxicity. This promising combination should be examined in therapeutic trials of breast cancer.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Neoplasias da Mama/patologia , Triterpenos/farmacologia , Animais , Antineoplásicos Fitogênicos/toxicidade , Apoptose/efeitos dos fármacos , Células da Medula Óssea/efeitos dos fármacos , Neoplasias da Mama/tratamento farmacológico , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Desoxicitidina/análogos & derivados , Desoxicitidina/farmacologia , Docetaxel , Sinergismo Farmacológico , Feminino , Humanos , Camundongos , Taxoides/farmacologia , Triterpenos/toxicidade , Carga Tumoral/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto , Gencitabina
16.
J Clin Invest ; 122(9): 3316-29, 2012 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-22922257

RESUMO

The myeloid-specific transcription factor, CCAAT/enhancer-binding protein ε (C/EBPε) is a critical mediator of myelopoiesis. Mutation of this gene is responsible for neutrophil-specific granule deficiency in humans, a condition that confers susceptibility to Staphylococcus aureus infection. We found that C/EBPε-deficient mice are severely affected by infection with S. aureus, and C/EBPε deficiency in neutrophils contributes to the infectious phenotype. Conversely, exposure to the epigenetic modulator nicotinamide (vitamin B3) increased expression of C/EBPε in WT myeloid cells. Further, nicotinamide increased the activity of C/EBPε and select downstream antimicrobial targets, particularly in neutrophils. In a systemic murine infection model as well as in murine and human peripheral blood, nicotinamide enhanced killing of S. aureus by up to 1,000 fold but had no effect when administered to either C/EBPε-deficient mice or mice depleted of neutrophils. Nicotinamide was efficacious in both prophylactic and therapeutic settings. Our findings suggest that C/EBPε is an important target to boost killing of bacteria by the innate immune system.


Assuntos
Proteínas Estimuladoras de Ligação a CCAAT/metabolismo , Niacinamida/farmacologia , Infecções Cutâneas Estafilocócicas/tratamento farmacológico , Staphylococcus aureus/fisiologia , Acetilação , Animais , Antibacterianos/farmacologia , Proteínas Estimuladoras de Ligação a CCAAT/genética , Células Cultivadas , Expressão Gênica/efeitos dos fármacos , Regulação da Expressão Gênica , Histonas/metabolismo , Humanos , Imunidade Inata , Macrófagos/efeitos dos fármacos , Macrófagos/microbiologia , Camundongos , Camundongos Knockout , Viabilidade Microbiana , Neutrófilos/efeitos dos fármacos , Neutrófilos/imunologia , Neutrófilos/microbiologia , Niacinamida/fisiologia , Regiões Promotoras Genéticas , Infecções Cutâneas Estafilocócicas/imunologia , Infecções Cutâneas Estafilocócicas/patologia
17.
Ann Hematol ; 91(9): 1419-25, 2012 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-22543828

RESUMO

The acronym POEMS syndrome stands for a rare multi-system disorder, comprised of polyneuropathy, organomegaly, endocrinopathy, M protein, and skin changes. Here, we present a single-center report of a series of five POEMS patients treated with melphalan high-dose therapy (HDT) with subsequent autologous blood stem cell transplantation (ABSCT). After a median follow-up of 52 months from time of diagnosis (range, 15-192) and a median follow-up of 18 months after ABSCT (range, 11-120), all patients were alive. Overall, no severe transplantation-associated complications such as engraftment syndrome or peri- or post-transplant death were noted. In two cases, HDT followed by ABSCT resulted in a complete hematologic response; in the additional three cases, partial responses (PR) were achieved including one very good hematologic PR. Only one patient with initial PR developed progressive disease nearly 2.5 years after transplantation. Consequently, a second HDT with ABSCT was successfully applied resulting in clinical improvement and hematologic PR. In line with previous single-center reports, melphalan HDT followed by ABSCT proved to be a first-line treatment option with tolerable side effects in severely affected POEMS patients with progressing symptoms.


Assuntos
Melfalan/uso terapêutico , Agonistas Mieloablativos/uso terapêutico , Síndrome POEMS/tratamento farmacológico , Transplante de Células-Tronco de Sangue Periférico , Adulto , Antraciclinas/uso terapêutico , Terapia Combinada , Dexametasona/uso terapêutico , Feminino , Humanos , Masculino , Melfalan/administração & dosagem , Pessoa de Meia-Idade , Agonistas Mieloablativos/administração & dosagem , Exame Neurológico , Síndrome POEMS/sangue , Síndrome POEMS/cirurgia , Transplante Autólogo , Resultado do Tratamento , Fator A de Crescimento do Endotélio Vascular/sangue
18.
Leuk Lymphoma ; 53(8): 1577-85, 2012 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-22260161

RESUMO

Disturbances of circadian rhythms and mammalian clock genes have been implicated in the etiologies of many chronic illnesses, including cancer. We show that transcription factor CCAAT/enhancer-binding protein alpha (C/EBPalpha)-regulated PER2 activation is a potential tumor suppressor pathway in diffuse large B-cell lymphoma (DLBCL), one of the commonest types of mature B-cell lymphoma. Expression analysis of human B-cell lymphoma samples including DLBCL (n = 50), mantle cell (n = 21), follicular (n = 25) and Burkitt (n = 18) lymphoma revealed markedly down-regulated CEBPA and PER2 mRNA levels exclusively in DLBCL samples compared to control lymphatic tissue. We demonstrated direct regulation of the circadian core clock gene PER2 by C/EBPalpha in the pro-B cell line Ba/F3, and forced expression of PER2 resulted in decreased proliferation, G0/G1 cell cycle arrest and increased rates of apoptosis. Interestingly, treatment of human DLBCL cell lines with the histone deacetylase-inhibitor suberoylanilide hydroxamic acid (SAHA) significantly increased the expression of C/EBPalpha and Per2, accompanied by cell growth inhibition; in contrast, siRNA knockdown of CEBPA reduced the anti-proliferative effect of SAHA treatment. Our results show for the first time that C/EBPalpha with its associated direct core clock gene target, PER2, are highly deregulated in DLBCL, suggesting an important tumor suppressive pathway in the pathogenesis of this lymphoma entity.


Assuntos
Proteína alfa Estimuladora de Ligação a CCAAT/biossíntese , Regulação Neoplásica da Expressão Gênica , Linfoma Difuso de Grandes Células B/genética , Linfoma Difuso de Grandes Células B/metabolismo , Proteínas Circadianas Period/biossíntese , Apoptose , Biópsia , Ciclo Celular , Linhagem Celular Tumoral , Proliferação de Células , Sobrevivência Celular , Ritmo Circadiano , Perfilação da Expressão Gênica , Genes Reporter , Humanos , Modelos Genéticos
19.
Blood ; 119(10): 2346-57, 2012 Mar 08.
Artigo em Inglês | MEDLINE | ID: mdl-22207736

RESUMO

With the use of ChIP on microarray assays in primary leukemia samples, we report that acute myeloid leukemia (AML) blasts exhibit significant alterations in histone H3 acetylation (H3Ac) levels at > 1000 genomic loci compared with CD34(+) progenitor cells. Importantly, core promoter regions tended to have lower H3Ac levels in AML compared with progenitor cells, which suggested that a large number of genes are epigenetically silenced in AML. Intriguingly, we identified peroxiredoxin 2 (PRDX2) as a novel potential tumor suppressor gene in AML. H3Ac was decreased at the PRDX2 gene promoter in AML, which correlated with low mRNA and protein expression. We also observed DNA hypermethylation at the PRDX2 promoter in AML. Low protein expression of the antioxidant PRDX2 gene was clinically associated with poor prognosis in patients with AML. Functionally, PRDX2 acted as inhibitor of myeloid cell growth by reducing levels of reactive oxygen species (ROS) generated in response to cytokines. Forced PRDX2 expression inhibited c-Myc-induced leukemogenesis in vivo on BM transplantation in mice. Taken together, epigenome-wide analyses of H3Ac in AML led to the identification of PRDX2 as an epigenetically silenced growth suppressor, suggesting a possible role of ROS in the malignant phenotype in AML.


Assuntos
Metilação de DNA , Histonas/metabolismo , Peroxirredoxinas/genética , Proteínas Supressoras de Tumor/genética , Acetilação , Doença Aguda , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Proliferação de Células , Células Cultivadas , Epigênese Genética , Feminino , Perfilação da Expressão Gênica/métodos , Estudo de Associação Genômica Ampla , Células HL-60 , Humanos , Masculino , Pessoa de Meia-Idade , Análise de Sequência com Séries de Oligonucleotídeos/métodos , Peroxirredoxinas/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Proteínas Supressoras de Tumor/metabolismo , Células U937 , Adulto Jovem
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