Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 9 de 9
Filtrar
Mais filtros










Base de dados
Intervalo de ano de publicação
1.
Br J Haematol ; 195(3): 378-387, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-34340254

RESUMO

Programmed cell death protein 1 (PD-1) and PD-ligand 1 (PD-L1) expression is upregulated in cluster of differentiation 34 (CD34)+ bone marrow cells from patients with myelodysplastic syndromes (MDS). Hypomethylating agent (HMA) treatment results in further increased expression of these immune checkpoints. We hypothesised that combining an anti-PD-1 antibody with HMAs may have efficacy in patients with MDS. To test this concept, we designed a phase II trial of the combination of azacitidine and pembrolizumab with two cohorts. In the 17 previously untreated patients, the overall response rate (ORR) was 76%, with a complete response (CR) rate of 18% and median overall survival (mOS) not reached after a median follow-up of 12·8 months. For the HMA-failure cohort (n = 20), the ORR was 25% and CR rate was 5%; with a median follow-up of 6·0 months, the mOS was 5·8 months. The most observed toxicities were pneumonia (32%), arthralgias (24%) and constipation (24%). Immune-related adverse events requiring corticosteroids were required in 43%. Overall, this phase II trial suggests that azacitidine and pembrolizumab is safe with manageable toxicities in patients with higher-risk MDS. This combined therapy may have anti-tumour activity in a subset of patients and merits further studies in the front-line setting.


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Antimetabólitos/uso terapêutico , Azacitidina/uso terapêutico , Síndromes Mielodisplásicas/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais Humanizados/efeitos adversos , Antimetabólitos/efeitos adversos , Antimetabólitos/farmacologia , Artralgia/induzido quimicamente , Azacitidina/efeitos adversos , Azacitidina/farmacologia , Constipação Intestinal/induzido quimicamente , Metilação de DNA/efeitos dos fármacos , Feminino , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Pneumonia/induzido quimicamente , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Receptor de Morte Celular Programada 1/imunologia , Intervalo Livre de Progressão , Risco
2.
Medicine (Baltimore) ; 98(52): e18313, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31876706

RESUMO

BACKGROUND: Glucocorticoid as the standard treatment of autoimmune hepatitis has been recommended with different doses. The purpose of this study is to compare the efficacy and safety of high and low doses for clinical practice. METHODS: Medline, Embase, and Cochrane Library were searched until January 16th, 2019 for cohort studies or randomized controlled trials in patients with autoimmune hepatitis. Glucocorticoid 60 mg/d or 1 mg/kg/d was defined as high dose and 40 to 50 mg/d or 0.5 mg/d as low dose. Outcome of interests includes the incidence of the biochemical remission, adverse event, and endpoint events. Double arcsine method with a random-effect model was used to combine the incidence. Potential heterogeneity was explored by meta-regression and subgroup analysis. RESULTS: Overall, 25 studies (3305 patients) were included, with 10 studies in the high dose group and 15 in low dose group. The biochemical remission rate in the high and low dose group was 0.79 (95% confidence interval [CI] [0.72, 0.85]) and 0.72 (95% CI [0.65, 0.78]), respectively. The incidence of endpoint events and adverse event in the high were slightly higher (0.03, 95% CI [0.02, 0.04]; 0.42, 95% CI [0.30, 0.53]) than that of the low dose group (0.01, 95% CI [0.00, 0.01]; 0.39, 95% CI [0.15, 0.63]). CONCLUSIONS: For autoimmune hepatitis patients, 60 mg/d or 1 mg/kg/d of glucocorticoid gives higher biochemical remission rate and higher incidence of endpoint events and adverse events.


Assuntos
Glucocorticoides/uso terapêutico , Hepatite Autoimune/tratamento farmacológico , Relação Dose-Resposta a Droga , Glucocorticoides/administração & dosagem , Glucocorticoides/efeitos adversos , Humanos , Resultado do Tratamento
3.
Chin Med J (Engl) ; 132(22): 2647-2656, 2019 Nov 20.
Artigo em Inglês | MEDLINE | ID: mdl-31725459

RESUMO

BACKGROUND: Few data are available regarding the progression of liver disease and therapeutic efficacy in chronic hepatitis B virus (HBV) carriers infected by mother-to-child transmission (MTCT). This study aimed to investigate these two aspects by comparing the adult chronic HBV carriers in MTCT group with those in horizontal transmission group. METHODS: The 683 adult chronic HBV patients qualified for liver biopsy including 191 with MTCT and 492 with horizontal transmission entered the multi-center prospective study from October 2013 to May 2016. Biopsy results from 217 patients at baseline and 78 weeks post antiviral therapy were collected. RESULTS: Patients infected by MTCT were more likely to have e antigen positive (68.6% vs. 58.2%, χ = -2.491, P = 0.012) than those with horizontal transmission. However, in patients with MTCT, levels of alkaline phosphatase (ALP) (P = 0.031), Fibroscan (P = 0.013), N-terminal propeptide of Type III procollagen (PIIINP) (P = 0.014), and Laminin (LN) (P = 0.006) were high, in contrast to the patients with horizontal transmission for whom the levels of albumin (ALB) (P = 0.041), matrix metalloproteinase-3 (MMP-3) (P = 0.001) were high. The 47.2% of patients with MTCT and 36.8% of those with horizontal transmission had significant liver fibrosis (P = 0.013). Following antiviral therapy for 78 weeks, 21.2% and 38.0% patients with MTCT and horizontal transmission acquired hepatitis B e antigen (HBeAg) clearance, respectively (P = 0.043), and the virological response rates were 54.7% and 74.1% in the MTCT and horizontal groups, respectively (P = 0.005). MTCT was a risk factor for HBeAg clearance and virological response. CONCLUSION: Adult patients with MTCT were more prone to severe liver diseases, and the therapeutic efficacy was relatively poor, which underlined the importance of earlier, long-term treatment and interrupting perinatal transmission. TRIAL REGISTRATION: NCT01962155; https://clinicaltrials.gov.


Assuntos
Hepatite B Crônica/prevenção & controle , Transmissão Vertical de Doenças Infecciosas/prevenção & controle , Adulto , Fosfatase Alcalina/metabolismo , Feminino , Antígenos E da Hepatite B/metabolismo , Hepatite B Crônica/imunologia , Hepatite B Crônica/metabolismo , Humanos , Laminina/metabolismo , Fígado/efeitos dos fármacos , Fígado/metabolismo , Fígado/patologia , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos
4.
J Gastroenterol Hepatol ; 34(4): 755-763, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30290019

RESUMO

BACKGROUND AND AIM: Little reliable data are available about the liver stiffness measurement (LSM) for fibrosis monitoring in chronic hepatitis B (CHB) patients on antiviral therapy. We aimed to assess the accuracy of LSM in fibrosis monitoring during 78-week antiviral therapy in CHB patients. METHODS: Five hundred fifty-six treatment-naïve CHB patients with qualified LSM and liver biopsy at baseline were analyzed. Patients receiving entecavir-based therapy were prospectively followed to 78 weeks for second LSM and liver biopsy. Serologic detection, LSM, and liver biopsy were performed on the same day. Necro-inflammatory activity was also evaluated. RESULTS: Areas under receiver operating characteristics curves of LSM at baseline and week 78 for significant fibrosis (≥ F3), advanced fibrosis (≥ F4), and liver cirrhosis (≥ F5) was 0.84, 0.87, 0.83 and 0.76, 0.85, 0.88, respectively. Patients with the same fibrosis stage but higher histology activity index score tend to have higher LSM at baseline. Liver stiffness decreased rapidly (3.8 [1.6-8.6] kPa) in parallel with baseline histology activity index scores from 11.3 (7.8-16.7) kPa at baseline to 6.4 (5.1-8.8) kPa at week 78. Greater decline of LSM in patients with only inflammation improvement was observed as compared with those without inflammation improvement (5.2 [2.5-9.7] vs 1.8 [0.2-8.1] kPa, P = 0.013). Baseline Ishak fibrosis score was the only predictor of 78-week fibrosis improvement (odds ratio, 1.859; P = 0.000). CONCLUSIONS: In CHB patients receiving 78-week antiviral treatment, LSM could diagnosis different liver fibrosis stages, decrease in absolute LSM value could reflect the remission of liver inflammation, and baseline Ishak fibrosis score was the only predictor for 78-week fibrosis reversion.


Assuntos
Elasticidade , Hepatite B Crônica/patologia , Cirrose Hepática/diagnóstico , Cirrose Hepática/patologia , Fígado/patologia , Fígado/fisiopatologia , Adulto , Antivirais/uso terapêutico , Biópsia , Feminino , Guanina/análogos & derivados , Guanina/uso terapêutico , Hepatite B Crônica/complicações , Hepatite B Crônica/tratamento farmacológico , Hepatite B Crônica/fisiopatologia , Humanos , Cirrose Hepática/etiologia , Cirrose Hepática/fisiopatologia , Masculino , Monitorização Fisiológica , Estudos Prospectivos , Curva ROC , Fatores de Tempo
5.
J Viral Hepat ; 26(2): 297-307, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30380170

RESUMO

The limitations of liver biopsy have led to the development of indirect noninvasive models for liver fibrosis assessment. We aimed to evaluate and compare the performance of 30 noninvasive models to predict fibrosis stage in treatment-naïve and treated chronic hepatitis B (CHB) patients. A total of 576 Chinese treatment-naïve CHB patients and 236 treated CHB patients who had undergone percutaneous liver biopsy were included in the analysis. Histological grading and staging was assessed by the Ishak scoring system. The diagnostic accuracies of 30 noninvasive models were assessed by area under the receiver operating characteristic curves (AUROCs). In treatment-naïve CHB patients, the AUROCs of the 30 noninvasive models for discriminating significant fibrosis (SF) were less than 0.800, and only the AUROC of the PP score for diagnosing advanced fibrosis (AF) was more than 0.800, while the AUROCs of FIB-4, FibroQ, HB-F, Lok index, PHP score and PP score for predicting cirrhosis were greater than 0.800. In treated CHB patients, only the AUROCs of APRI, GUCI, King's score and Wang I for identifying cirrhosis were more than 0.800. The Spearman correlation analysis identified that only the changes in FCI and Virahep-C model values were weakly correlated with changes in Ishak fibrosis scores before and after treatment (r = 0.206, p = 0.008; r = 0.187, p = 0.016, respectively). In conclusion, in Chinese CHB patients, the 30 existing noninvasive models were not suitable for assessing each stage of fibrosis except cirrhosis before and after antiviral therapy, especially in gauging progression and regression of liver fibrosis following therapy.


Assuntos
Hepatite B Crônica/complicações , Cirrose Hepática/sangue , Cirrose Hepática/diagnóstico , Modelos Estatísticos , Adulto , Antivirais/uso terapêutico , Biomarcadores/sangue , Biópsia , China , Feminino , Hepatite B Crônica/tratamento farmacológico , Humanos , Fígado/patologia , Cirrose Hepática/classificação , Masculino , Pessoa de Meia-Idade , Curva ROC , Estudos Retrospectivos , Índice de Gravidade de Doença , Estatísticas não Paramétricas
6.
Cancer ; 123(24): 4851-4859, 2017 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-28841236

RESUMO

BACKGROUND: Pracinostat is a potent histone deacetylase inhibitor with antitumor activity in both solid tumor and acute myeloid leukemia (AML) cell lines. Pracinostat is reported to have modest clinical activity in patients with advanced solid tumors. Given the higher preclinical sensitivity of hematologic malignancies to pracinostat, the authors conducted a phase 1 study to assess the safety, maximum tolerated dose, recommended phase 2 dose, efficacy, pharmacokinetics, and pharmacodynamics of pracinostat in patients with advanced hematological malignancies. METHODS: Pracinostat was administered orally 3 times a week for 3 weeks on a 28-day cycle. Patients were assigned to 7 dose levels using a 3 + 3 dose escalation design. RESULTS: A total of 44 patients were enrolled, 25 of whom had AML and 14 of whom had myelodysplastic syndrome. The maximum tolerated dose was 120 mg and the recommended phase 2 dose was 60 mg. Two patients with AML achieved a response: 1 complete remission (CR) and 1 complete cytogenetic response. Despite a dose-dependent increase in the plasma concentration of pracinostat, a similar increase in histone acetylation was not observed. As an extension, 10 additional patients with myelodysplastic syndrome were enrolled to assess the safety and efficacy of pracinostat in combination with azacitidine. Six patients achieved a CR and 3 achieved a CR without platelet recovery with no added toxicity. CONCLUSIONS: The results of the current study demonstrate that pracinostat is safe, with modest single-agent activity in patients with hematological malignancies. Cancer 2017;123:4851-9. © 2017 American Cancer Society.


Assuntos
Azacitidina/administração & dosagem , Benzimidazóis/administração & dosagem , Neoplasias Hematológicas/tratamento farmacológico , Neoplasias Hematológicas/mortalidade , Leucemia Mieloide Aguda/tratamento farmacológico , Síndromes Mielodisplásicas/tratamento farmacológico , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Azacitidina/efeitos adversos , Benzimidazóis/efeitos adversos , Intervalo Livre de Doença , Relação Dose-Resposta a Droga , Esquema de Medicação , Quimioterapia Combinada , Feminino , Seguimentos , Neoplasias Hematológicas/patologia , Humanos , Estimativa de Kaplan-Meier , Leucemia Mieloide Aguda/mortalidade , Leucemia Mieloide Aguda/patologia , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade , Síndromes Mielodisplásicas/mortalidade , Síndromes Mielodisplásicas/patologia , Invasividade Neoplásica/patologia , Estadiamento de Neoplasias , Segurança do Paciente , Medição de Risco , Fatores Sexuais , Análise de Sobrevida , Resultado do Tratamento
7.
J Mol Cell Biol ; 3(4): 250-9, 2011 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-21377978

RESUMO

Acetylcholinesterase (AChE) is emerging as an important contributor to apoptosis in various cell types. However, overexpression of AChE does not initiate apoptosis, and cells which express AChE at basal levels grow normally, suggesting that AChE may function differently between normal and apoptotic conditions. In this study, we determined that an AChE-derived protein (∼55 kDa) positively correlated with cellular apoptotic levels. The 55 kDa AChE protein was not a result of a novel splice variant of the AChE primary transcript. Instead, it was determined to be a cleaved fragment of the full-length 68 kDa AChE protein that could not be inhibited by cycloheximide (CHX) but could be suppressed by caspase inhibitors in apoptotic PC-12 cells. Furthermore, activation of the Akt cascade abolished the 55 kDa protein, and both AChE protein forms (68 and 55 kDa) accumulated in the nucleus during apoptosis. In a mouse model for ischemia/reperfusion (I/R)-induced acute renal failure, the 55 kDa AChE protein was detected in the impaired organs but not in the normal ones, and its levels correlated with the genotype of the mice. In summary, a 55 kDa AChE protein resulting from the cleavage of 68 kDa AChE is induced during apoptosis, and it is negatively regulated by the Akt pathway. This study suggests that an alternative form of AChE may play a role in apoptosis.


Assuntos
Acetilcolinesterase/metabolismo , Apoptose , Regulação Enzimológica da Expressão Gênica , Proteínas Proto-Oncogênicas c-akt/metabolismo , Acetilcolinesterase/química , Acetilcolinesterase/genética , Animais , Linhagem Celular , Cicloeximida/farmacologia , Modelos Animais de Doenças , Ativação Enzimática , Humanos , Camundongos , Interferência de RNA , RNA Interferente Pequeno/metabolismo , Ratos , Proteínas Recombinantes de Fusão/antagonistas & inibidores , Proteínas Recombinantes de Fusão/genética , Proteínas Recombinantes de Fusão/metabolismo , Traumatismo por Reperfusão/metabolismo , Transdução de Sinais
9.
Zhonghua Er Bi Yan Hou Ke Za Zhi ; 39(3): 139-42, 2004 Mar.
Artigo em Chinês | MEDLINE | ID: mdl-15283291

RESUMO

OBJECTIVES: To explore the effect of endoscopic sinus surgery (ESS) in patients with chronic rhinosinusitis and asthma. METHODS: Forty-two patients with asthma who underwent ESS and control group were investigated. Interleukin-4 (IL-4), interferon-gamma (IFN-gamma), soluble interleukin-2 receptor (sIL-2R) and soluble CD23 (sCD23) levels in culture supernatant of peripheral blood mononuclear cell (PBMC) were determined by enzyme-linked immunosorbent assay (ELISA). RESULTS: Of these 42 patients 32 (76%), their asthma was relieved greatly after ESS comparing with that before ESS. 14 of 21 patients (67%) taken regular medication for asthma before ESS reported that less medicine was used after operation. CONCLUSION: This study demonstrates that ESS has a favorable effect on asthma in patients with symptomatic chronic sinusitis.


Assuntos
Asma/cirurgia , Endoscopia , Pólipos Nasais/cirurgia , Sinusite/cirurgia , Adolescente , Adulto , Asma/sangue , Asma/complicações , Doença Crônica , Feminino , Seguimentos , Humanos , Interferon gama/sangue , Interleucina-4/sangue , Masculino , Pessoa de Meia-Idade , Pólipos Nasais/complicações , Receptores de Interleucina-2/sangue , Sinusite/complicações
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...