Visual impairments in children with cerebral palsy

Background: Visual impairments are associated with cerebral palsy (CP). They enhance functional limitations in children with CP. Objective: The objective of the study was to determine the types of visual impairments in children with CP, and thus the importance of early evaluation and intervention to improve the quality of life. Materials and Methods: Children with CP (n=775) attending the child development clinic from 2012 to 2017 were included in the study. Thorough antenatal, natal, postnatal, and developmental history were recorded. Complete demographic data, anthropometry and general physical, and neurological examination findings were recorded. All patients were advised neuroimaging (computed tomography/magnetic resonance imaging) and hearing and ophthalmological assessment. Results: Of the 775 patients, 270 (34.8%) patients had squint (including convergent and divergent). Detailed fundoscopic and visual evoked potentials (VEP) examination was done in 382 patients. Non-apparent abnormalities (VEP and fundus changes) were seen in 121 patients (31.7%) among 382 tested. Of those 121 patients, VEP changes and fundus changes were seen in 62 and 41 patients, respectively. Refractive errors were detected in 25 patients. Of the total patients assessed for ophthalmological ailments, 129 (33.7%) patients were completely normal. Conclusion: Visual impairments are associated in large percentage of CP patients. Early evaluation and intervention are emphasized to improve the quality of life in these patients

Oncogenic deubiquitination controls tyrosine kinase signaling and therapy response in acute lymphoblastic leukemia

Dysregulation of kinase signaling pathways favors tumor cell survival and therapy resistance in cancer. Here, we reveal a posttranslational regulation of kinase signaling and nuclear receptor activity via deubiquitination in T cell acute lymphoblastic leukemia (T-ALL). We observed that the ubiquitin-specific protease 11 (USP11) is highly expressed and associates with poor prognosis in T-ALL. USP11 ablation inhibits leukemia progression in vivo, sparing normal hematopoiesis. USP11 forms a complex with USP7 to deubiquitinate the oncogenic lymphocyte cell-specific protein-tyrosine kinase (LCK) and enhance its activity. Impairment of LCK activity leads to increased glucocorticoid receptor (GR) expression and glucocorticoids sensitivity. Genetic knockout of USP7 improved the antileukemic efficacy of glucocorticoids in vivo. The transcriptional activation of GR target genes is orchestrated by the deubiquitinase activity and mediated via an increase in enhancer-promoter interaction intensity. Our data unveil how dysregulated deubiquitination controls leukemia survival and drug resistance, suggesting previously unidentified therapeutic combinations toward targeting leukemia

Oncogenic deubiquitination controls tyrosine kinase signaling and therapy response in acute lymphoblastic leukemia

Dysregulation of kinase signaling pathways favors tumor cell survival and therapy resistance in cancer. Here, we reveal a posttranslational regulation of kinase signaling and nuclear receptor activity via deubiquitination in T cell acute lymphoblastic leukemia (T-ALL).We observed that the ubiquitin-specific protease 11 (USP11) is highly expressed and associates with poor prognosis in T-ALL. USP11 ablation inhibits leukemia progression in vivo, sparing normal hematopoiesis. USP11 forms a complex with USP7 to deubiquitinate the oncogenic lymphocyte cell-specific protein-tyrosine kinase (LCK) and enhance its activity. Impairment of LCK activity leads to increased glucocorticoid receptor (GR) expression and glucocorticoids sensitivity. Genetic knockout of USP7 improved the antileukemic efficacy of glucocorticoids in vivo. The transcriptional activation of GR target genes is orchestrated by the deubiquitinase activity and mediated via an increase in enhancer-promoter interaction intensity. Our data unveil how dysregulated deubiquitination controls leukemia survival and drug resistance, suggesting previously unidentified therapeutic combinations toward targeting leukemia