4 results on '"Angehrn L"'
Search Results
2. Doxycycline-controlled splicing modulation by regulated antisense U7 snRNA expression cassettes
- Author
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Kampfer, S.S., Schümperli, Daniel, Angehrn, L., and Marquis, J.
- Subjects
570 Life sciences ,biology - Abstract
Many diseases affect pre-mRNA splicing, and alternative splicing is a major source of proteome diversity and an important mechanism for modulating gene expression. The ability to regulate a specific splicing event is therefore desirable; for example, to understand splicing-associated pathologies. We have developed methods based on modified U7 snRNAs, which allow us to induce efficient skipping or inclusion of selected exons. Here, we have adapted these U7 tools to a regulatable system that relies on a doxycycline-sensitive version of the Kruppel-associated box (KRAB)/KAP1 transcriptional silencing. Co-transduction of target cells with two lentiviral vectors, one carrying the KRAB protein and the other the regulatable U7 cassette, allows a tight regulation of the modified U7 snRNA. No leakage is observed in the repressed state, whereas full induction can be obtained with doxycycline in ng ml(-1) concentrations. Only a few days are necessary for a full switch, and the induction/repression can be repeated over several cycles without noticeable loss of control. Importantly, the U7 expression correlates with splicing correction, as shown for the skipping of an aberrant beta-globin exon created by a thalassaemic mutation and the promotion of exon 7 inclusion in the human SMN2 gene, an important therapeutic target for spinal muscular atrophy.
- Published
- 2009
- Full Text
- View/download PDF
3. Number of comorbidities and their impact on perioperative outcome and costs - a single centre cohort study.
- Author
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Cavalli L, Angehrn L, Schindler C, Orsini N, Grob C, Kaufmann M, Steiner LA, Schwenkglenks M, and Dell-Kuster S
- Subjects
- Cohort Studies, Comorbidity, Humans, Length of Stay, Postoperative Period, Retrospective Studies, Postoperative Complications epidemiology
- Abstract
Aims of the Study: Multimorbidity is a growing global health problem, resulting in an increased perioperative risk for surgical patients. Data on both the prevalence of multimorbidity and its impact on perioperative outcome are limited. The American Society of Anesthesiologists (ASA) classification uses only the single most severe systemic disease to define the ASA class and ignores multimorbidity. This study aimed to assess the number and type of all anaesthesia-relevant comorbidities and to analyse their impact on outcome and hospital costs., Methods: This cohort study is nested in the ClassIntra® validation study and includes only patients enrolled at the University Hospital of Basel. Approximately 30 patients per surgical discipline undergoing any type of in-hospital surgery were followed up until hospital discharge to record all intra- and postoperative adverse events. In addition, the type and severity of all perioperatively relevant comorbidities were extracted from the electronic medical record according to a predefined list. The primary endpoint was the number of all anaesthesia-relevant comorbidities by ASA class. Using structural equation models, the direct and indirect effects of comorbidities on costs were estimated after adjustment for the ASA class and further relevant confounders and mediators., Results: Of 320 enrolled patients, 27 were ASA I (8%), 150 ASA II (47%), 116 ASA III (36%) and 27 ASA IV (8%). The median number of comorbidities per patient was 5 (range 0-18), this number significantly increasing with higher ASA class: 1 comorbidity (95% CI 0.0-2.0) in ASA I, 4 comorbidities (3.8-4.2) in ASA II, 9 (8.1-9.9) in ASA III and 12 (10-14) in ASA IV patients. Independent of ASA class, each additional comorbidity increased hospital costs by EUR 1,198 (95% CI 288-2108) with almost identical proportions of direct and indirect effects. The number of anaesthesia-relevant comorbidities also increased postoperative complications and postoperative length of hospital stay., Conclusions: Multimorbidity in perioperative patients is highly prevalent and has a relevant impact on hospital costs, independent of the ASA class. Incorporating multimorbidity into the ASA classification might be warranted to improve its predictive ability and support adequate reimbursement.
- Published
- 2022
- Full Text
- View/download PDF
4. Spinal muscular atrophy: SMN2 pre-mRNA splicing corrected by a U7 snRNA derivative carrying a splicing enhancer sequence.
- Author
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Marquis J, Meyer K, Angehrn L, Kämpfer SS, Rothen-Rutishauser B, and Schümperli D
- Subjects
- Base Sequence, Cell Line, Cyclic AMP Response Element-Binding Protein genetics, DNA, Antisense genetics, Exons genetics, Fibroblasts, Humans, Molecular Sequence Data, Muscular Atrophy, Spinal pathology, Nerve Tissue Proteins genetics, RNA, Messenger genetics, RNA-Binding Proteins genetics, SMN Complex Proteins, Survival of Motor Neuron 1 Protein, Survival of Motor Neuron 2 Protein, Time Factors, Cyclic AMP Response Element-Binding Protein metabolism, Muscular Atrophy, Spinal genetics, Muscular Atrophy, Spinal metabolism, Nerve Tissue Proteins metabolism, RNA Splicing genetics, RNA, Small Nuclear genetics, RNA-Binding Proteins metabolism
- Abstract
Spinal muscular atrophy (SMA) is a lethal hereditary disease caused by homozygous deletion/inactivation of the survival of motoneuron 1 (SMN1) gene. The nearby SMN2 gene, despite its identical coding capacity, is only an incomplete substitute, because a single nucleotide difference impairs the inclusion of its seventh exon in the messenger RNA (mRNA). This splicing defect can be corrected (transiently) by specially designed oligonucleotides. Here we have developed a more permanent correction strategy based on bifunctional U7 small nuclear RNAs (snRNAs). These carry both an antisense sequence that allows specific binding to exon 7 and a splicing enhancer sequence that will improve the recognition of the targeted exon. When expression cassettes for these RNAs are stably introduced into cells, the U7 snRNAs become incorporated into small nuclear ribonucleoprotein (snRNP) particles that will induce a durable splicing correction. We have optimized this strategy to the point that virtually all SMN2 pre-mRNA becomes correctly spliced. In fibroblasts from an SMA patient, this approach induces a prolonged restoration of SMN protein and ensures its correct localization to discrete nuclear foci (gems).
- Published
- 2007
- Full Text
- View/download PDF
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