Endocrine and inflammatory markers as predictors of frailty

OBJECTIVE: To examine the association of serum concentrations of 25-hydroxyvitamin D [25(OH)D], interleukin-6 (IL-6), C-reactive protein (CRP) and IGF-1 with prevalent and incident frailty. DESIGN: The Longitudinal Aging Study Amsterdam (LASA), a prospective cohort study with 3-yearly measurement cycles. Setting General population-based sample. PARTICIPANTS: The respondents were men and women aged 65 and over, who participated at T1 (1995/1996, N = 1720) and T2 (1998/1999, N = 1509). Blood samples were obtained at T1 (N = 1271). Measurements The presence of frailty at T1 and 3-year incidence of frailty. Frailty is defined as the presence of three out of nine frailty indicators. RESULTS: At T1, 242 (19.0%) of all respondents were frail. Those who were frail at T1 had higher CRP and lower 25(OH)D levels. Serum 25(OH)D remained associated with frailty after adjustment for potential confounders with an odd ratios (OR) of 2.60 [95% confidence interval (95% CI) 1.60-4.21] for 25(OH)D < 25 nmol/l and 1.72 (95% CI 1.19-2.47) for 25(OH)D 25-50 nmol/l vs. high levels of 25(OH)D. Of the nonfrail at T1, 125 respondents (14.1%) became frail at T2. After adjustment, moderately elevated CRP levels (3-10 microg/ml) (OR 1.69, 95% CI 1.09-2.63) and low 25(OH)D (OR 2.04, 95% CI 1.01-4.13) were associated with incident frailty. No consistent associations were observed for IL-6 and IGF-1. CONCLUSION: Low 25(OH)D levels were strongly associated with prevalent and incident frailty; moderately elevated levels of CRP were associated with incident frailty.     

Differential responses of FLIPLong and FLIPShort-overexpressing human myeloid leukemia cells to TNF-alpha and TRAIL-initiated apoptotic signals

OBJECTIVE: Clonal marrow cells from patients with early myelodysplastic syndrome (MDS) undergo apoptosis in response to tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL). Cells from advanced MDS are resistant to TRAIL. Two isoforms of the Flice inhibitory protein (FLIP) short (FLIPS) and FLIP long (FLIPL), which modulate TRAIL signals, showed disease-stage-dependent differential regulation. Therefore, we aimed at characterizing potential differential effects of FLIPL and FLIPS, on TRAIL and TNF-alpha-induced apoptosis in model leukemic cell lines. MATERIALS AND METHODS: Using lentiviral constructs, FLIPL and FLIPS, as well as a green fluorescent protein control were overexpressed in ML-1 cells, which constitutively express very low levels of FLIP and are highly sensitive to apoptosis induction. Cells were then exposed to TRAIL or TNF-alpha, and effects on the extrinsic and intrinsic pathways of apoptosis induction were assessed. RESULTS: Overexpression of FLIP reduced TRAIL and TNF-alpha-induced apoptosis in ML-1 cells. However, while FLIPL completely abrogated apoptosis, FLIPS allowed for BID cleavage and caspase-3 activation. Concurrently, there was a decline of Bcl-xL and X-linked inhibitor of apoptosis protein (XIAP) in FLIPS cells followed by apoptosis. Further, inhibition of nuclear factor-kappaB (NF-kappaB) activation in TNF-alpha-treated cells resulted in profound apoptosis in FLIPS, but not in FLIPL-overexpressing cells, consistent with the observations in patients with early stage MDS. Inhibition of NF-kappaB had only minimal effects on TRAIL signaling. CONCLUSION: Thus, FLIPL and FLIPS exerted differential effects in myeloid leukemic cell lines in response to TRAIL and TNF-alpha. It might be possible to therapeutically exploit those differences with effector molecules specific for the FLIP isoforms.     

A novel retroviral mutagenesis screen identifies prognostic genes in RUNX1 mediated myeloid leukemogenesis

Using a novel retroviral shuttle vector approach we identified genes that collaborate with a patient derived RUNX1 (AML1) mutant. RUNX1 mutations occurs in 40% of myelodysplastic syndromes (MDS). MDS are a group of hematopoietic stem cell disorders that are characterized by dysplasia that often progress to acute myeloid leukemia (AML). Our goal was to identify genes dysregulated by vector-mediated genotoxicity that may collaborate with the RUNX1 mutant (D171N). D171N expressing cells have a survival and engraftment disadvantage and require additional genetic lesions to survive and persist. By dysregulating genes near the integrated vector provirus, the shuttle vector can promote transformation of D171N cells and tag the nearby genes that collaborate with D171N. In our approach, a gammaretroviral shuttle vector that expresses D171N is used to transduce CD105⁺, Sca-1⁺ mouse bone marrow. Mutagenized cells are expanded in liquid culture and vector integration sites from surviving cells are then identified using a retroviral shuttle vector approach. We repeatedly recovered integrated vector proviruses near genes (Itpkb, Ccdc12, and Nbeal2). To assess the prognostic significance of the genes identified we examined differential expression, overall survival, and relapse free survival of AML patients with alteration in the genes identified using The Cancer Genome Atlas (TCGA) AML data set. We found that ITPKB functions as an independent factor for poor prognoses and RUNX1 mutations in conjunction with ITPKB, CCDC12, and NBEAL2 have prognostic potential in AML.     

High prevalence of undernutrition in Dutch community-dwelling older individuals

ObjectiveTo examine the prevalence of undernutrition in community-dwelling older individuals (≥65 y) using data from various settings.MethodsA cross-sectional observational study was performed to examine the prevalence of undernutrition in three samples (all ≥65 y): 1) 1267 community-dwelling individuals participating in a large prospective population-based study, the Longitudinal Aging Study Amsterdam (LASA) in 1998/99; 2) 814 patients receiving home care in 2009/10; and 3) 1878 patients from general practices during the annual influenza vaccination in 2009/10. Undernutrition was assessed by the Short Nutritional Assessment Questionnaire 65+.ResultsMean age was 77.3 y (SD 6.7) in the LASA sample, 81.6 y (SD 7.4) in the home care sample, and 75.3 y (SD 6.5) in the general practice sample. The prevalence of undernutrition was highest in the home care sample (35%), followed by the general practice (12%) and LASA (11%) samples. The prevalence of undernutrition increased significantly with age in the general practice and LASA samples. Gender differences were observed in the general practice and home care samples; women were more likely to be undernourished in the general practice sample and men were more likely to be undernourished in the home care sample.ConclusionThe prevalence of undernutrition in Dutch community-dwelling older individuals was relatively high, especially in home care patients.