Discovery of microRNAs and other small RNAs in solid tumors

MicroRNAs (miRNAs) are ∼22-nt long, non-coding RNAs that regulate gene silencing. It is known that many human miRNAs are deregulated in numerous types of tumors. Here we report the sequencing of small RNAs (17–25 nt) from 23 breast, bladder, colon and lung tumor samples using high throughput sequencing. We identified 49 novel miRNA and miR-sized small RNAs. We further validated the expression of 10 novel small RNAs in 31 different types of blood, normal and tumor tissue samples using two independent platforms, namely microarray and RT–PCR. Some of the novel sequences show a large difference in expression between tumor and tumor-adjacent tissues, between different tumor stages, or between different tumor types. We also report the identification of novel small RNA classes in human: highly expressed small RNA derived from Y-RNA and endogenous siRNA. Finally, we identified dozens of new miRNA sequence variants that demonstrate the existence of miRNA-related SNP or post-transcriptional modifications. Our work extends the current knowledge of the tumor small RNA transcriptome and provides novel candidates for molecular biomarkers and drug targets

Development and validation of risk stratification trees for incident slow gait speed in persons at high risk for knee osteoarthritis

OBJECTIVES:Disability prevention strategies are more achievable before osteoarthritis disease drives impairment. It is critical to identify high-risk groups, for strategy implementation and trial eligibility. An established measure, gait speed is associated with disability and mortality. We sought to develop and validate risk stratification trees for incident slow gait in persons at high risk for knee osteoarthritis, feasible in community and clinical settings. METHODS:Osteoarthritis Initiative (derivation cohort) and Multicenter Osteoarthritis Study (validation cohort) participants at high risk for knee osteoarthritis were included. Outcome was incident slow gait over up to 10-year follow-up. Derivation cohort classification and regression tree analysis identified predictors from easily assessed variables and developed risk stratification models, then applied to the validation cohort. Logistic regression compared risk group predictive values; area under the receiver operating characteristic curves (AUCs) summarised discrimination ability. RESULTS:1870 (derivation) and 1279 (validation) persons were included. The most parsimonious tree identified three risk groups, from stratification based on age and WOMAC Function. A 7-risk-group tree also included education, strenuous sport/recreational activity, obesity and depressive symptoms; outcome occurred in 11%, varying 0%-29 % (derivation) and 2%-23 % (validation) depending on risk group. AUCs were comparable in the two cohorts (7-risk-group tree, 0.75, 95% CI 0.72 to 0.78 (derivation); 0.72, 95% CI 0.68 to 0.76 (validation)). CONCLUSIONS:In persons at high risk for knee osteoarthritis, easily acquired data can be used to identify those at high risk of incident functional impairment. Outcome risk varied greatly depending on tree-based risk group membership. These trees can inform individual awareness of risk for impaired function and define eligibility for prevention trials

Clinical significance of worsening versus stable preradiographic MRI lesions in a cohort study of persons at higher risk for knee osteoarthritis

Background Whether preradiographic lesions in knees at risk for osteoarthritis are incidental versus disease is unclear. We hypothesised, in persons without but at higher risk for knee osteoarthritis, that: 12–48 month MRI lesion status worsening is associated with 12–48 month incident radiographic osteoarthritis (objective component of clinical definition of knee osteoarthritis) and 48–84 month persistent symptoms. Methods In 849 Osteoarthritis Initiative participants Kellgren/Lawrence (KL) 0 in both knees, we assessed cartilage damage, bone marrow lesions (BMLs), and menisci on 12 month (baseline) and 48 month MRIs. Multivariable logistic regression was used to evaluate associations between 12–48 month worsening versus stable status and outcome (12–48 month incident KL ≥1 and KL ≥2, and 48–84 month persistent symptoms defined as frequent symptoms or medication use most days of ≥1 month in past 12 month, at consecutive visits 48–84 months), adjusting for age, gender, body mass index (BMI), injury and surgery. Results Mean age was 59.6 (8.8), BMI 26.7 (4.2) and 55.9% were women. 12–48 month status worsening of cartilage damage, meniscal tear, meniscal extrusion, and BMLs was associated with 12–48 month incident radiographic outcomes, and worsening of cartilage damage and BMLs with 48–84 month persistent symptoms. There was a dose-response association for magnitude of worsening of cartilage damage, meniscal tear, meniscal extrusion, and BMLs and radiographic outcomes, and cartilage damage and BMLs and persistent symptoms. Conclusions In persons at higher risk, worsening MRI lesion status was associated with concurrent incident radiographic osteoarthritis and subsequent persistent symptoms. These findings suggest that such lesions represent early osteoarthritis, and add support for a paradigm shift towards investigation of intervention effectiveness at this stage