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2.
Eur J Haematol ; 107(5): 573-582, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34297437

RESUMO

We studied pretransplant minimal residual disease (MRD) in 224 patients (median age 44 years; range 17-65) with acute myeloid leukemia (AML) undergoing allogeneic stem cell transplant (HSCT) in complete remission. MRD was evaluated on marrow samples using multicolor flow cytometry and assessment of WT1 gene expression. Both methods showed a strong prognostic value and their combination allowed the identification of three groups of patients with different risk of relapse. In multivariate analysis, combined MRD was the only predictor of cumulative incidence of relapse, regardless of donor type, conditioning regimen, first or second CR at HSCT, HSCT year, and ELN risk group. Multivariate regression model showed that only negative combined MRD status (P < .001) and myeloablative conditioning (P = .004) were independently associated with better OS. Among MRD-positive patients, a reduced incidence of relapse was observed in patients receiving haplo transplant (P < .05) and in patients who showed grade II-IV aGVHD (P < .03). In patients with negative combined MRD, the intensity of conditioning regimen did not affect the overall favorable outcome. We suggest that pretransplant MRD evaluation combined with transplant-related factors can identify AML patients at higher risk for relapse and might help in defining the overall transplant strategy.


Assuntos
Transplante de Células-Tronco Hematopoéticas , Leucemia Mieloide Aguda/patologia , Leucemia Mieloide Aguda/terapia , Neoplasia Residual , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Transplante Homólogo , Resultado do Tratamento
5.
J Pharmacol Toxicol Methods ; 88(Pt 1): 7-18, 2017 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-28476566

RESUMO

BACKGROUND AND OBJECTIVE: Predicting blood-brain barrier permeability for novel compounds is an important goal for neurotherapeutics-focused drug discovery. It is impossible to determine experimentally the blood-brain barrier partitioning of all possible candidates. Consequently, alternative evaluation methods based on computational models are desirable or even necessary. The CORAL software (http://www.insilico.eu/coral) has been checked up as a tool to build up quantitative structure - activity relationships for blood-brain barrier permeation. METHODS: The Monte Carlo technique gives possibility to build up predictive model of an endpoint by means of selection of so-called correlation weights of various molecular features. Descriptors calculated with these weights are basis for correlations "structure-endpoint". RESULTS: The approach gives good models for three random splits into the training and validation sets. The best model characterized by the following statistics for the external validation set: the number of compounds is 41, determination coefficient is equal to 0.896, root mean squared error is equal to 0.175. CONCLUSIONS: The suggested approach can be applied as a tool for prediction of blood-brain barrier permeation.


Assuntos
Barreira Hematoencefálica/metabolismo , Simulação por Computador , Descoberta de Drogas/métodos , Modelos Moleculares , Relação Quantitativa Estrutura-Atividade , Permeabilidade Capilar , Estrutura Molecular , Método de Monte Carlo , Software
6.
Curr Drug Discov Technol ; 14(4): 229-243, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28545350

RESUMO

BACKGROUND: Traditional quantitative structure - property / activity relationships (QSPRs/QSARs) are based on representation of molecular structure by molecular graph or simplified molecular input-line entry system (SMILES). It is an attractive idea to develop predictive models for large molecules in general and for peptides in particular. However, the representation of these molecules by molecular graph or SMILES is problematic owing to large size of these molecules. A possible alternative of SMILES is the representation of peptides via sequence of abbreviations of amino acids. METHOD: Models for hemolysis and cytotoxicity of peptides are suggested. These models are based on representation of the peptides by sequences of amino acids. Correlation weights, which are calculated for each amino acid using the Monte Carlo method are basis for quantitative sequence - activity relationships (QSAR) for antimicrobial peptides. The correlation weights are the basis for optimal descriptors, which are correlated with experimental data for hemolysis and cytotoxicity. The basic hypothesis is that if optimal descriptors are correlated with endpoints of peptides for the training set, they should also correlate with the endpoints for validation set. RESULTS: Checking up of correlations between the above-mentioned descriptors and antimicrobial activity of peptides (cytotoxicity or hemolysis) has shown that these models have good predictive potential. CONCLUSION: Suggested approach can be used as a tool to develop predictive models of biological activity of peptides as a mathematical function of sequences of amino acids.


Assuntos
Peptídeos Catiônicos Antimicrobianos/toxicidade , Modelos Moleculares , Relação Quantitativa Estrutura-Atividade , Células Epiteliais/efeitos dos fármacos , Eritrócitos/efeitos dos fármacos , Hemólise/efeitos dos fármacos , Método de Monte Carlo
7.
Toxicol Lett ; 250-251: 42-6, 2016 May 27.
Artigo em Inglês | MEDLINE | ID: mdl-27067105

RESUMO

The estimation of the cardiotoxicity of compounds is an important task for the drug discovery as well as for the risk assessment in ecological aspect. The experimental estimation of the above endpoint is complex and expensive. Hence, the theoretical computational methods are very attractive alternative of the direct experiment. A model for cardiac toxicity of 400 hERG blocker compounds (pIC50) is built up using the Monte Carlo method. Three different splits into the visible training set (in fact, the training set plus the calibration set) and invisible validation sets examined. The predictive potential is very good for all examined splits. The statistical characteristics for the external validation set are (i) the coefficient of determination r(2)=(0.90-0.93); and (ii) root-mean squared error s=(0.30-0.40).


Assuntos
Simulação por Computador , Canal de Potássio ERG1/antagonistas & inibidores , Cardiopatias/induzido quimicamente , Modelos Biológicos , Método de Monte Carlo , Bloqueadores dos Canais de Potássio/toxicidade , Cardiotoxicidade , Relação Dose-Resposta a Droga , Canal de Potássio ERG1/metabolismo , Cardiopatias/metabolismo , Humanos , Modelos Estatísticos , Estrutura Molecular , Bloqueadores dos Canais de Potássio/química , Relação Quantitativa Estrutura-Atividade , Reprodutibilidade dos Testes , Medição de Risco , Software
8.
Leuk Res ; 39(8): 866-73, 2015 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-26012361

RESUMO

Several genes with relevant pathogenetic and prognostic value have been identified in patients with myelodysplastic syndromes. Overexpression of WT1 at diagnosis has been associated with increased progression to acute myeloid leukemia and reduced leukemia free survival. Conversely, few data are available on the prognostic value of BAALC gene overexpression in AML and MDS patients. We evaluated the prognostic value of the combined expression of WT1 and BAALC genes at diagnosis in 86 MDS patients who had been stratified according to IPSS and R-IPSS scoring systems. Our results suggest that in the whole group of patients, low levels of both WT1 and BAALC were associated with a favorable outcome (3-year LFS 74.5%, median not reached), whereas patients presenting high expression levels of both genes had the worst prognosis (3-year LFS 0%, median 12 months, p<0.001). More specifically, molecular profiling was especially useful for intermediate 1 and intermediate-2/high risk groups. This study suggests that evaluating WT1 and BAALC gene expression at diagnosis may improve standard risk stratification and possibly refine the therapeutic approach for MDS patients.


Assuntos
Biomarcadores Tumorais/genética , Leucemia Mieloide Aguda/diagnóstico , Síndromes Mielodisplásicas/diagnóstico , Proteínas de Neoplasias/genética , Proteínas WT1/genética , Adulto , Progressão da Doença , Intervalo Livre de Doença , Feminino , Humanos , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/mortalidade , Leucemia Mieloide Aguda/terapia , Masculino , Síndromes Mielodisplásicas/genética , Síndromes Mielodisplásicas/patologia , Síndromes Mielodisplásicas/terapia , Prognóstico , Estudos Retrospectivos , Análise de Sobrevida , Transcriptoma
9.
Ann Hematol ; 91(7): 1013-22, 2012 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-22349722

RESUMO

Bendamustine is an alkylating agent with a nitrogen mustard group and a purine-like benzimidazole group. The aim of this study was to collect all the Italian experiences with this drug in order to evaluate the results in term of response to therapy and toxicities. We analyzed lymphoma patients treated in 24 Italian haematological centres with bendamustine alone or in combination with anti-CD20 antibody. One hundred seventy-five relapsed or refractory lymphoma patients were enrolled. The median age was 69 years (range 26-87). Seventy-nine patients were relapsed, 35 were refractory and 61 presented a progressive disease after partial response. The diagnoses were 60 indolent non-follicular lymphomas, 34 diffuse large B-cell lymphomas, 48 follicular lymphomas, 30 mantle cell lymphomas and three peripheral T-cell lymphomas. All patients were evaluable for response: 52 (29%) with complete remission, 72 (43%) with partial response with an overall response rate of 71%, and 51 non-responders. With a median observation period of 10 months (1-43), 70% of patients are alive. In summary, this retrospective study shows that treatment with bendamustine alone or in combination with rituximab is a safe and effective regimen in a subset of multi-resistant patients.


Assuntos
Anticorpos Monoclonais Murinos/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Linfoma não Hodgkin/tratamento farmacológico , Compostos de Mostarda Nitrogenada/administração & dosagem , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais Murinos/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Cloridrato de Bendamustina , Quimioterapia Adjuvante , Feminino , Fundações , Humanos , Itália/epidemiologia , Linfoma não Hodgkin/diagnóstico , Linfoma não Hodgkin/epidemiologia , Linfoma não Hodgkin/mortalidade , Masculino , Oncologia/organização & administração , Pessoa de Meia-Idade , Estudos Multicêntricos como Assunto , Compostos de Mostarda Nitrogenada/efeitos adversos , Recidiva , Estudos Retrospectivos , Rituximab , Sociedades Médicas , Análise de Sobrevida , Falha de Tratamento
10.
Ann Hematol ; 87(1): 49-55, 2008 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-17710398

RESUMO

To evaluate the safety and efficacy of pegfilgrastim administered as haematological support after autologous peripheral blood stem cell transplantation, we compared 44 patients with solid tumours and lymphomas receiving a 6-mg single dose of pegfilgrastim on day +5 after transplantation to a historical control group of 25 patients receiving filgrastim 5 microg kg(-1) day(-1) starting on day +5. There were no significant differences in haematological recovery nor in the incidence and duration of neutropenic fever. Median duration of grade 4 neutropenia in the pegfilgrastim and filgrastim group was similar. The incidence of grade III-IV mucositis was lower in pegfilgrastim than in filgrastim group due to the significant difference observed among the patients with solid tumours (p = 0.00). The only adverse event considered to be cytokine related was mild to moderate bone pain occurring during haematological recovery. According to the present study design and taking into account the current prices in our institution, the cost of the two drugs was similar in both treatment groups. In conclusion, a single injection of pegfilgrastim administered at day +5 post-transplantation shows comparable safety and efficacy profiles to daily injections of filgrastim and may be cost effective.


Assuntos
Fator Estimulador de Colônias de Granulócitos/química , Fator Estimulador de Colônias de Granulócitos/uso terapêutico , Neoplasias/tratamento farmacológico , Transplante de Células-Tronco de Sangue Periférico , Análise Custo-Benefício , Filgrastim , Fator Estimulador de Colônias de Granulócitos/efeitos adversos , Fator Estimulador de Colônias de Granulócitos/economia , Humanos , Proteínas Recombinantes , Transplante Autólogo
11.
Proc Natl Acad Sci U S A ; 102(28): 9830-5, 2005 Jul 12.
Artigo em Inglês | MEDLINE | ID: mdl-15998734

RESUMO

An important step toward improving the annotation of the human genome is to identify cis-acting regulatory elements from primary DNA sequence. One approach is to compare sequences from multiple, divergent species. This approach distinguishes multispecies conserved sequences (MCS) in noncoding regions from more rapidly evolving neutral DNA. Here, we have analyzed a region of approximately 238kb containing the human alpha globin cluster that was sequenced and/or annotated across the syntenic region in 22 species spanning 500 million years of evolution. Using a variety of bioinformatic approaches and correlating the results with many aspects of chromosome structure and function in this region, we were able to identify and evaluate the importance of 24 individual MCSs. This approach sensitively and accurately identified previously characterized regulatory elements but also discovered unidentified promoters, exons, splicing, and transcriptional regulatory elements. Together, these studies demonstrate an integrated approach by which to identify, subclassify, and predict the potential importance of MCSs.


Assuntos
Sequência Conservada/genética , Componentes do Gene/genética , Genoma Humano , Globinas/genética , Sequências Reguladoras de Ácido Nucleico/genética , Animais , Sequência de Bases , Biologia Computacional/métodos , Genômica/métodos , Humanos , Dados de Sequência Molecular , Alinhamento de Sequência , Análise de Sequência de DNA , Especificidade da Espécie
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