Gold nanoparticles enhance the effect of tyrosine kinase inhibitors in acute myeloid leukemia therapy.

BACKGROUND AND AIMS: Every year, in Europe, acute myeloid leukemia (AML) is diagnosed in thousands of adults. For most subtypes of AML, the backbone of treatment was introduced nearly 40 years ago as a combination of cytosine arabinoside with an anthracycline. This therapy is still the worldwide standard of care. Two-thirds of patients achieve complete remission, although most of them ultimately relapse. Since the FLT3 mutation is the most frequent, it serves as a key molecular target for tyrosine kinase inhibitors (TKIs) that inhibit FLT3 kinase. In this study, we report the conjugation of TKIs onto spherical gold nanoparticles. MATERIALS AND METHODS: The internalization of TKI-nanocarriers was proved by the strongly scattered light from gold nanoparticles and was correlated with the results obtained by transmission electron microscopy and dark-field microscopy. The therapeutic effect of the newly designed drugs was investigated by several methods including cell counting assay as well as the MTT assay. RESULTS: We report the newly described bioconjugates to be superior when compared with the drug alone, with data confirmed by state-of-the-art analyses of internalization, cell biology, gene analysis for FLT3-IDT gene, and Western blotting to assess degradation of the FLT3 protein. CONCLUSION: The effective transmembrane delivery and increased efficacy validate its use as a potential therapeutic.

Antisynthetase syndrome with anti-Jo1 antibodies in 48 patients: pulmonary involvement predicts disease-modifying antirheumatic drug use.

OBJECTIVE: To analyze the characteristics, outcomes, and predictive factors of disease-modifying antirheumatic drug (DMARD) use in 48 patients with antisynthetase syndrome [characterized by myositis, interstitial lung disease (ILD), arthritis, Raynaud's phenomenon (RP), and/or mechanic's hands] and the presence of anti-histidyl-transfer RNA synthetase (anti-Jo1) autoantibodies. METHODS: Forty-eight patients (33 women, 15 men) who were anti-Jo1-positive referred to one center between 1998 and 2008 were analyzed retrospectively. RESULTS: The median age of disease onset was 43 years [interquartile range (IQR) 33-53 yrs]. The median followup was 5 years (IQR 2-8 yrs). At diagnosis, 81% of patients presented with myositis, 80% ILD, 77% arthralgia, 48% RP, and 21% mechanic's hands. During the followup, 14 patients (29%) had no need for DMARD, while 34 (71%) required DMARD. Patients with mechanic's hands (p=0.02) and higher creatine phosphokinase at diagnosis (median 6070 IU/l vs 1121 IU/l; p=0.002) were more likely to need DMARD. ILD, noted on computed tomography scan by a nonspecific interstitial pneumonia score, was lower in the group of patients with no DMARD need (4 vs 7; p=0.04). Twenty patients (44%) presented with a pulmonary aggravation (worsening of radiologic score of ILD and/or pulmonary function test results) leading to DMARD use. Nonspecific interstitial pneumonia score (7 vs 5; p=0.05) and total lung volume (57.5% vs 70%; p=0.02) values predicted pulmonary aggravation. CONCLUSION: Our study outlines the burden of chest involvement for the prognosis of antisynthetase syndrome in terms of patients' requirement for DMARD therapy.

Hierarchical cluster and survival analyses of antisynthetase syndrome: phenotype and outcome are correlated with anti-tRNA synthetase antibody specificity.

The clinical phenotype and evolution of antisynthetase syndrome (ASS) are heterogeneous. This study was therefore undertaken to identify subgroups of ASS patients with similar clinico-biological features and outcomes. This retrospective multicentric study included 233 consecutive patients with three different anti-aminoacyl-tRNA-synthetase antibodies (anti-ARS): anti-Jo1 (n=160), anti-PL7 (n=25) and anti-PL12 (n=48). To characterise ASS patients, bivariate, multiple correspondence (MCA), cluster and survival analyses were performed. Interstitial lung disease (ILD) and myositis were the most common ASS manifestations. However, their respective frequencies were correlated to anti-ARS specificity: ILD was more frequent (80% and 88% vs 67%, p=0.014) whereas myositis was less common (44% and 47% vs 74%, p<0.001) in patients with anti-PL7 and anti-PL12 compared to anti-Jo1. The MCA suggested that anti-PL7 and anti-PL12 phenotypes were close to one another and distinct from anti-Jo1. The clustering analysis confirmed these data, identifying subgroups strongly defined by the anti-ARS specificity and other clinical features. Cluster 1 (n=175, 86% of anti-Jo1) defined patients with the most diffuse phenotype, whereas patients from cluster 2 (n=48, 96% of anti-PL12 and anti-PL7) exhibited a disease more restricted to the lung. Patient survival was also conditioned by the anti-ARS specificity, and was significantly lower in patients with anti-PL7/12 rather than anti-Jo1 (p=0.012). Other factors associated with poor survival were mostly related to pulmonary involvement, including severe dyspnea (p=0.003) and isolated ILD (p=0.009) at diagnosis. In patients with ASS, the phenotype and the survival were correlated with the anti-ARS specificity.