The genetics behind the progression of myelodysplasia to secondary acute myeloid leukemia (sAML) is poorly understood. In this study, we profiled somatic mutations and their dynamics using next generation sequencing on serial samples from a total of 124 patients, consisting of a 31 patient discovery cohort and 93 patients from two validation cohorts. Whole-exome analysis on the discovery cohort revealed that 29 of 31 patients carry mutations related to at least one of eight commonly mutated pathways in AML. Mutations in genes related to DNA methylation and splicing machinery were found in T-cell samples, which expand at the initial diagnosis of the myelodysplasia, suggesting their importance as early disease events. On the other hand, somatic variants associated with signaling pathways arise or their allelic burdens expand significantly during progression. Our results indicate a strong association between mutations in activated signaling pathways and sAML progression. Overall, we demonstrate that distinct categories of genetic lesions play roles at different stages of sAML in a generally fixed order.
Introduction The Bone and Joint Monitor Project was developed to quantify the global burden of musculoskeletal conditions and develop strategies for their prevention. Experts within the Monitor Project have worked previously with officers at the World Health Organization (WHO) to estimate morbidity and mortality associated with rheumatic conditions. The present collaboration seeks means of providing additional and more current burden data. Objective To develop recommendations for performing epidemiological studies in sample populations with musculoskeletal conditions and problems, accounting for determinants and consequences to the individual and society. Methods Recommendations have been developed identifying the most relevant domains for measuring and monitoring the various musculoskeletal conditions by review of epidemiological data on occurrence, determinants and outcomes, and by expert opinion. Instruments that measure these domains were reviewed. Results The domains recommended follow the principles of the WHO International Classification of Functioning, Disability and Health [1,2], and consider: health condition; body function and structure; activity limitation; participation restriction; personal and environmental contextual factors; and, in addition, the resource utilisation and social consequences. The musculoskeletal conditions and problems considered were osteoarthitis, inflammatory arthritis, osteoporosis, spinal problems, musculoskeletal trauma and injuries, and musculoskeletal pain with restricted activity. The selection of indicators for each domain considered the feasibility of their use in a health interview survey (HIS), a health examination survey (HES), a register or a clinical study. Consensus on case definition was reached depending on the study methodology. For example, osteoporosis defined by bone densitometry cannot be ascertained in an HIS, whereas the outcome of osteoporosis (i.e. fragility fracture) can be. Osteoarthitis can be identified as joint pain in an HIS but the preferred definition is pain with X-ray changes and can only be ascertained in an HES. Previously validated generic and disease-specific instruments have been identified that include indicators for all or most of the recommended domains for the consequences of the different conditions and problems. The indicators of the domains for resource utilisation and social consequences and feasibility for collection will vary in different socioeconomic and geographic areas. Guidance on sampling methods is also being developed. Conclusions The comparability of data collected across the globe will improve by the application of agreed upon indicators that consider key domains for the different musculoskeletal conditions and problems in epidemiological studies conducted in different populations.
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