Airway inflammation is an important component of cystic fibrosis (CF) lung disease. We sought to determine whether alveolar macrophages were involved in early CF lung disease.Children with CF (median age 3.1 yrs) participated in a surveillance programme that included annual bronchoalveolar lavage (BAL). Control samples were obtained from non-CF children (median age 3.1 yrs; n524) investigated for persistent respiratory symptoms.Pulmonary infection was detected in 31% (16 out of 51) and 38% (nine out of 24) of children from the CF and non-CF groups, respectively. Alveolar macrophages in BAL were increased in CF compared with non-CF in the absence of infection (223610 3 versus 85610 3 cells?mL ; p,0.001)). Total cell counts and neutrophil numbers increased in the presence of infection; however, there was no additional effect of CF.Alveolar macrophages and CC chemokines are elevated in the lungs in young children with CF even in the absence of pulmonary infection. Longitudinal studies are required to determine the clinical relevance of these findings.
BackgroundContinuous complete clinical remission in T-cell acute lymphoblastic leukemia (T-ALL) is now approaching 80% due to the implementation of aggressive chemotherapy protocols but patients that relapse continue to have a poor prognosis. Such patients could benefit from augmented therapy if their clinical outcome could be more accurately predicted at the time of diagnosis. Gene expression profiling offers the potential to identify additional prognostic markers but has had limited success in generating robust signatures that predict outcome across multiple patient cohorts. This study aimed to identify robust gene classifiers that could be used for the accurate prediction of relapse in independent cohorts and across different experimental platforms.ResultsUsing HG-U133Plus2 microarrays we modeled a five-gene classifier (5-GC) that accurately predicted clinical outcome in a cohort of 50 T-ALL patients. The 5-GC was further tested against three independent cohorts of T-ALL patients, using either qRT-PCR or microarray gene expression, and could predict patients with significantly adverse clinical outcome in each. The 5-GC featured the interleukin-7 receptor (IL-7R), low-expression of which was independently predictive of relapse in T-ALL patients. In T-ALL cell lines, low IL-7R expression was correlated with diminished growth response to IL-7 and enhanced glucocorticoid resistance. Analysis of biological pathways identified the NF-κB and Wnt pathways, and the cell adhesion receptor family (particularly integrins) as being predictive of relapse. Outcome modeling using genes from these pathways identified patients with significantly worse relapse-free survival in each T-ALL cohort.ConclusionsWe have used two different approaches to identify, for the first time, robust gene signatures that can successfully discriminate relapse and CCR patients at the time of diagnosis across multiple patient cohorts and platforms. Such genes and pathways represent markers for improved patient risk stratification and potential targets for novel T-ALL therapies.
Lung disease in patients with cystic fibrosis (CF) is characterized by recurrent bacterial respiratory infections and intense airway inflammation. Pattern recognition receptors such as Toll-like receptor 2 (TLR2) and TLR4 identify bacterial pathogens and activate the innate immune response. We therefore hypothesized that increased expression of these receptors would be found on circulating immune cells from children with CF. A cohort of 66 young children (median age 3 years) with CF was studied and compared to both healthy controls (n = 14) and children without CF who were being investigated for recurrent respiratory infections (non-CF disease controls; n = 17) of a similar age. Surface expression of TLR2 and TLR4 on peripheral blood monocytes was analyzed using flow cytometry. TLR4 expression was significantly higher in patients with CF compared to healthy controls (P = 0.017) and non-CF disease controls (P = 0.025) but did not vary according to the presence or absence of pulmonary infection with Gram-negative or Gram-positive bacteria (P = 0.387) in the CF group. In contrast, TLR2 expression was similar across all three study groups (P = 0.930). The increased surface expression of TLR4 seen in young children with CF appears to be related to having CF per se and not related to current pulmonary infection.
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