ABSTRACT
BACKGROUND: Challenges accessing nearby health facilities may be a barrier to initiating and completing tuberculosis (TB) treatment. We aimed to evaluate whether distance from residence to health facility chosen for treatment is associated with TB treatment outcomes. METHODS: We conducted a retrospective cohort study of all patients initiating TB treatment at six health facilities in Kampala from 2014 to 2016. We investigated associations between distance to treating facility and unfavorable TB treatment outcomes (death, loss to follow up, or treatment failure) using multivariable Poisson regression. RESULTS: Unfavorable treatment outcomes occurred in 20% (339/1691) of TB patients. The adjusted relative risk (aRR) for unfavorable treatment outcomes (compared to treatment success) was 0.87 (95% confidence interval [CI] 0.70, 1.07) for patients living ≥2 km from the facility compared to those living closer. When we separately compared each type of unfavorable treatment outcome to favorable outcomes, those living ≥2 km from the facility had increased risk of death (aRR 1.42 [95%CI 0.99, 2.03]) but decreased risk for loss to follow-up (aRR 0.57 [95%CI 0.41, 0.78]) than those living within 2 km. CONCLUSIONS: Distance from home residence to TB treatment facility is associated with increased risk of death but decreased risk of loss to follow up. Those who seek care further from home may have advanced disease, but once enrolled may be more likely to remain in treatment.
Subject(s)
Antitubercular Agents/therapeutic use , Health Facilities/supply & distribution , Tuberculosis/drug therapy , Female , Health Facilities/statistics & numerical data , Health Services Accessibility , Humans , Male , Retrospective Studies , Risk , Treatment Outcome , Tuberculosis/epidemiology , Uganda/epidemiologyABSTRACT
: Mutations in the colony-stimulating factor 3 receptor (CSF3R) have been identified in the vast majority of patients with chronic neutrophilic leukemia and are present in other kinds of leukemia, such as acute myeloid leukemia. Here, we studied the function of novel germline variants in CSF3R at amino acid N610. These N610 substitutions were potently oncogenic and activated the receptor independently of its ligand GCSF. These mutations activated the JAK-STAT signaling pathway and conferred sensitivity to JAK inhibitors. Mass spectrometry revealed that the N610 residue is part of a consensus N-linked glycosylation motif in the receptor, usually linked to complex glycans. N610 was also the primary site of sialylation of the receptor. Membrane-proximal N-linked glycosylation was critical for maintaining the ligand dependence of the receptor. Mutation of the N610 site prevented membrane-proximal N-glycosylation of CSF3R, which then drove ligand-independent cellular expansion. Kinase inhibitors blocked growth of cells with an N610 mutation. This study expands the repertoire of oncogenic mutations in CSF3R that are therapeutically targetable and provides insight into the function of glycans in receptor regulation. SIGNIFICANCE: This study reveals the critical importance of membrane-proximal N-linked glycosylation of CSF3R for the maintenance of ligand dependency in leukemia.
Subject(s)
Carcinogenesis , Germ-Line Mutation , Leukemia/genetics , Mutation , Receptors, Colony-Stimulating Factor/genetics , Amino Acid Motifs , Animals , Binding Sites , Cell Membrane/metabolism , Disease Progression , Female , Gene Expression Regulation, Leukemic , Glycosylation , HEK293 Cells , Humans , Janus Kinases/metabolism , Leukemia/metabolism , Leukemia, Myeloid, Acute/genetics , Leukemia, Neutrophilic, Chronic/genetics , Ligands , Mass Spectrometry , Mice , Mice, Inbred C57BL , Middle Aged , Proteomics , Receptors, Colony-Stimulating Factor/metabolism , STAT Transcription Factors/metabolism , Sequence Analysis, DNA , Signal Transduction , Spectrometry, Mass, Matrix-Assisted Laser Desorption-IonizationABSTRACT
The amount of genomic information about leukemia cells currently far exceeds our overall understanding of the precise genetic events that ultimately drive disease development and progression. Effective implementation of personalized medicine will require tools to distinguish actionable genetic alterations within the complex genetic landscape of leukemia. In this study, we performed kinase inhibitor screens to predict functional gene targets in primary specimens from patients with acute myeloid leukemia and chronic myelomonocytic leukemia. Deep sequencing of the same patient specimens identified genetic alterations that were then integrated with the functionally important targets using the HitWalker algorithm to prioritize the mutant genes that most likely explain the observed drug sensitivity patterns. Through this process, we identified tyrosine kinase nonreceptor 2 (TNK2) point mutations that exhibited oncogenic capacity. Importantly, the integration of functional and genomic data using HitWalker allowed for prioritization of rare oncogenic mutations that may have been missed through genomic analysis alone. These mutations were sensitive to the multikinase inhibitor dasatinib, which antagonizes TNK2 kinase activity, as well as novel TNK2 inhibitors, XMD8-87 and XMD16-5, with greater target specificity. We also identified activating truncation mutations in other tumor types that were sensitive to XMD8-87 and XMD16-5, exemplifying the potential utility of these compounds across tumor types dependent on TNK2. Collectively, our findings highlight a more sensitive approach for identifying actionable genomic lesions that may be infrequently mutated or overlooked and provide a new method for the prioritization of candidate genetic mutations.
