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Therapy resistance in leukemia may be due to cancer cell-intrinsic and/or -extrinsic mechanisms. Mutations within BCR-ABL1, the oncogene giving rise to chronic myeloid leukemia (CML), lead to resistance to tyrosine kinase inhibitors (TKI), and some are associated with clinically more aggressive disease and worse outcome. Using the retroviral transduction/transplantation model of CML and human cell lines we faithfully recapitulate accelerated disease course in TKI resistance. We show in various models, that murine and human imatinib-resistant leukemia cells positive for the oncogene BCR-ABL1T315I differ from BCR-ABL1 native (BCR-ABL1) cells with regards to niche location and specific niche interactions. We implicate a pathway via integrin β3, integrin-linked kinase (ILK) and its role in deposition of the extracellular matrix (ECM) protein fibronectin as causative of these differences. We demonstrate a trend towards a reduced BCR-ABL1T315I+ tumor burden and significantly prolonged survival of mice with BCR-ABL1T315I+ CML treated with fibronectin or an ILK inhibitor in xenogeneic and syngeneic murine transplantation models, respectively. These data suggest that interactions with ECM proteins via the integrin β3/ILK-mediated signaling pathway in BCR-ABL1T315I+ cells differentially and specifically influence leukemia progression. Niche targeting via modulation of the ECM may be a feasible therapeutic approach to consider in this setting.
Aim: Pharmacoresistance is a major burden in epilepsy treatment. We aimed to identify genetic biomarkers in response to specific antiepileptic drugs (AEDs) in genetic generalized epilepsies (GGE). Materials & methods: We conducted a genome-wide association study (GWAS) of 3.3 million autosomal SNPs in 893 European subjects with GGE – responsive or nonresponsive to lamotrigine, levetiracetam and valproic acid. Results: Our GWAS of AED response revealed suggestive evidence for association at 29 genomic loci (p <10-5) but no significant association reflecting its limited power. The suggestive associations highlight candidate genes that are implicated in epileptogenesis and neurodevelopment. Conclusion: This first GWAS of AED response in GGE provides a comprehensive reference of SNP associations for hypothesis-driven candidate gene analyses in upcoming pharmacogenetic studies.
Background: The increasing number of cases and hospital admissions due to COVID-19 created an urgent need for rapid, reliable testing procedures for SARS-CoV-2 in Emergency Departments (ED) in order to effectively manage hospital resources, allocate beds and prevent nosocomial spread of infection. The ID NOW™ COVID-19 assay is a simple, user-friendly, rapid molecular test run on an instrument with a small footprint enabling point-of-care diagnostics.
Methods: In the first wave, outsourced RT-PCR testing regularly required 36-48 hours before results were available. This prospective study was conducted in the second wave (October 2020-April 2021) and evaluated the impact the implementation of the ID NOW™ COVID-19 test in the ED had on clinical care processes and patient pathways. 710 patients were recruited upon arrival at the ED which included those presenting clinical symptoms, asymptomatic individuals or persons fulfilling epidemiological criteria. The first anterior nasal swab was taken by trained nurses in the ambulance or a separate consultation room. The ID NOW™ COVID-19 test was performed in the ED in strict compliance with the manufacturer’s instructions and positive or suspected cases were additionally tested with RT_PCR (cobas SARS-COV-2 RT-PCR, Roche) following collection of a second nasopharyngeal NP specimen.
Results: Swabs directly tested with the ID NOW™ COVID-19 test showed a diagnostic concordance of 98 % (sensitivity 99.59 %, specificity 94.55 %, PPV 97.6 %, NPV 99.05 %) compared to RT-PCR as reference. The 488 patients that tested positive with the ID NOW™ COVID-19 had a Ct range in RT-PCR results between 7.94 to 37.42 (in 23.2 % > 30). Two false negative results (0.28%) were recorded from patients with Ct values > 30. 14 (1.69%) discordant results were reviewed case-by-case and usually associated with either very early or very advanced stages of infection. Furthermore, patients initially negative with the ID NOW™ COVID-19 test and admitted to the hospital were tested again on days 5 and 12: no patient became positive.
Discussion: The ID NOW™ COVID-19 test for detection of SARS-CoV-2 demonstrated excellent diagnostic agreement with RT-PCR under the above-mentioned patients pathways implemented during the second wave. The main advantage of the system was the provision of reliable results within a few minutes. This not only allowed immediate initiative of appropriate therapy and care for COVID-19 (patient benefit) but provided essential information on isolation and thus available beds. This drastically helped the overall finances of the department and additionally allowed more patients to be admitted including those requiring immediate attention; this was not possible during the first wave since beds were blocked waiting for diagnostic confirmation. Our findings also show that when interpreting the results, the clinical condition and epidemiological history of the patient must be taken into account, as with any test procedure. Overall, the ID NOW™ COVID-19 test for SARS-CoV-2 provided a rapid and reliable alternative to laboratory-based RT-PCR in the real clinical setting which became an acceptable part of the daily routine within the ED and demonstrated that early patient management can mitigate the impact of the pandemic on the hospital.