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Horakova, D.

Publications and source records attributed to Horakova, D..

2 recordsLinked to original sources

Immunotherapy prevents long-term disability in relapsing multiple sclerosis over 15 years

ObjectiveWhether immunotherapy improves long-term disability in multiple sclerosis has not been satisfactorily demonstrated. This study examined the effect of immunotherapy on long-term disability outcomes in relapsing-remitting multiple sclerosis.\n\nMethodsWe studied patients from MSBase followed for [≥]1 year, with [≥]3 visits, [≥]1 visit per year and exposed to a multiple sclerosis therapy, and a subset of patients with [≥]15-year follow-up. Marginal structural models were used to compare the hazard of 12-month confirmed increase and decrease in disability, EDSS step 6 and the incidence of relapses between treated and untreated periods. Marginal structural models were continuously re-adjusted for patient age, sex, pregnancy, date, disease course, time from first symptom, prior relapse history, disability and MRI activity.\n\nResults14,717 patients were studied. During the treated periods, patients were less likely to experience relapses (hazard ratio 0.60, 95% confidence interval 0.43-0.82, p=0.0016), worsening of disability (0.56, 0.38-0.82, p=0.0026) and progress to EDSS step 6 (0.33, 0.19-0.59, p=0.00019). Among 1085 patients with [≥]15-year follow-up, the treated patients were less likely to experience relapses (0.59, 0.50-0.70, p=10-9) and worsening of disability (0.81, 0.67-0.99, p=0.043).\n\nConclusionsContinued treatment with multiple sclerosis immunotherapies reduces disability accrual (by 19-44%), the risk of need of a walking aid by 67% and the frequency of relapses (by 40-41%) over 15 years. A proof of long-term effect of immunomodulation on disability outcomes is the key to establishing its disease modifying properties.

neuroscience↗

Human telomere repeat binding factor TRF1 replaces TRF2 bound to shelterin core hub TIN2 when TPP1 is absent

Human telomeric repeat binding factors TRF1, TRF2 along with TIN2 form a core of shelterin complex that protects chromosome ends against unwanted end-joining and DNA repair. We applied a single-molecule approach to assess TRF1-TIN2-TRF2 complex formation in solution at physiological conditions. Fluorescence Cross-Correlation Spectroscopy (FCCS) was used to describe the complex formation by analyzing how coincident fluctuations of differently labeled TRF1 and TRF2 correlate when they move together through the confocal volume of the microscope. We observed, at the single-molecule level, that TRF1 effectively substituted TRF2 on TIN2. We assessed the effect of another telomeric factor TPP1 that recruits telomerase to telomeres. We found that TPP1 upon binding to TIN2 induces allosteric changes that expand TIN2 binding capacity, such that TIN2 can accommodate both TRF1 and TRF2 simultaneously. We suggest a molecular model that explains why TPP1 is essential for the stable formation of TRF1-TIN2-TRF2 core complex.

biochemistry↗