To determine whether gene expression profiling could improve risk classification and outcome prediction in older acute myeloid leukemia (AML) patients, expression profiles were obtained in pretreatment leukemic samples from 170 patients whose median age was 65 years. Unsupervised clustering methods were used to classify patients into 6 cluster groups (designated A to F) that varied significantly in rates of resistant disease (RD; P < .001), complete response (CR; P ‫؍‬ .023), and disease-free survival (DFS; P ‫؍‬ .023). Cluster A (n ‫؍‬ 24), dominated by NPM1 mutations (78%), normal karyotypes (75%), and genes associated with signaling and apoptosis, had the best DFS (27%) and overall survival (OS; 25% at 5 years). Patients in clusters B (n ‫؍‬ 22) and C (n ‫؍‬ 31) had the worst OS (5% and 6%, respectively); cluster B was distinguished by the highest rate of RD (77%) and multidrug resistant gene expression (ABCG2, MDR1). Cluster D was characterized by a "proliferative" gene signature with the highest proportion of detectable cytogenetic abnormalities (76%; including 83% of all favorable and 34% of unfavorable karyotypes). Cluster F (n ‫؍‬ 33) was dominated by monocytic leukemias (97% of cases), also showing increased NPM1 mutations (61%

Outcome for children with childhood acute lymphoblastic leukemia (ALL) who relapse is poor. To gain insight into the mechanisms of relapse, we analyzed gene-expression profiles in 35 matched diagnosis/relapse pairs as well as 60 uniformly treated children at relapse using the Affymetrix platform. Matched-pair analyses revealed significant differences in the expression of genes involved in cell-cycle regulation, DNA repair, and apoptosis between diagnostic and earlyrelapse samples. Many of these pathways have been implicated in tumorigenesis previously and are attractive targets for intervention strategies. In contrast, no common pattern of changes was observed among late-relapse pairs. Earlyrelapse samples were more likely to be similar to their respective diagnostic sample while we noted greater divergence in gene

Background Observational studies of patients with rheumatoid arthritis have suggested that racial and ethnic disparities exist for minority populations. We compared disease activity and clinical outcomes across racial and ethnic groups using data from a large, contemporary United States registry. Methods We analyzed data from two time periods (2005-2007 and 2010-2012). The Clinical Disease Activity Index was examined as both a continuous measure and as dichotomous measures of disease activity states. Outcomes were compared in unadjusted and a series of cross-sectional and longitudinal multivariable regression models. Results For 2005-2007, significant differences of mean disease activity level (p<0.001) were observed across racial and ethnic groups. Over the five-year period, modest improvements in disease activity were observed across all groups, including whites [3.7 (95% CI 3.2 - 4.1) compared with African Americans [4.3 (95% CI 2.7 – 5.8)] and Hispanics [2.7 (95% CI 1.2 – 4.3)]. For 2010-2012, significant differences of mean disease activity level persisted (p<0.046) across racial and ethnic groups, ranging from 11.6 (95% CI 10.4-12.8) in Hispanics to 10.7 (95% CI 9.6-11.7) in whites. Remission rates remained significantly different across racial/ethnic groups across all models for 2010-2012, ranging from 22.7 (95% CI 19.5-25.8) in African Americans to 27.4 (95% CI 24.9-29.8) in whites. Conclusions Despite improvements in disease activity across racial and ethnic groups over a 5-year period, disparities persist in disease activity and clinical outcomes for minority groups versus white patients.

While beta 2 integrin ligand-receptor recognition interactions are well characterized, less is known about how these events trigger signal transduction cascades to regulate the transition from tethering to firm adhesion, spreading, and transendothelial migration. We have identified critical positive and negative regulatory components of this cascade in monocytes. Whereas the Syk tyrosine kinase is essential for beta 2 integrin signaling and cell spreading, the Src family kinase Fgr is a negative regulator of this pathway. Fgr selectively inhibits beta 2 but not beta 1 integrin signaling and Syk kinase function via a direct association between the Fgr SH2 domain and Syk tyrosine Y342. The inhibitory effects of Fgr are independent of its kinase activity, are dose dependent, and can be overcome by chemokines and inflammatory mediators.