Schriftinterpretation in der Septuaginta

Schriftinterpretation in der LXX geschah also nicht als Selbstzweck oder als quasi-akademisches, exegetisches Glasperlenspiel. Vielmehr zeigt sich, wie die Übersetzer und ihre Gemeinden die Schrift verstanden haben bzw. wie sie ihrer Meinung nach zu verstehen ist. Die griechische Übersetzung ist daher ein unverzichtbarer Bestandteil der frühen Rezeptions- und Wirkungsgeschichte der hebräischen Bibel

Mittelfristige Ergebnisse nach arthroskopischer Resektion des Schultereckgelenkes

27 Patienten, die sich einer arthroskopischen Resektion des Acromioclavicular-gelenkes unterzogen hatten, wurden nachuntersucht. Indikationen zur Operation waren die Osteolyse der lateralen Clavicula, die primäre Arthrose des AC-Gelenkes und die posttraumatische Schultereckgelenkarthrose. Die postoperativen Ergebnisse wurden mit dem Constant-Score und dem ASES-Score erhoben. Zur Untersuchung der Lebensqualität wurde der SF-36 Health Survey angewandt. Patienten mit einer Osteolyse zeigten in allen Scores die besten Resultate. Ein Zusammenhang zwischen dem Resektionsausmaß und dem Operationserfolg konnte nicht festgestellt werden. Nach den Ergebnissen dieser Arbeit und denen anderer Studien ist die arthroskopische AC-Gelenkresektion als ein geeignetes Verfahren bei isolierter AC-Gelenkarthrose anzusehen. Wichtig ist die strenge Indikationsstellung. Bei begleitender Instabilität des Gelenkes ist die offene Operation mit zusätzlichen stabilisierenden Maßnahmen notwendig

HnRNP L and L-like cooperate in multiple-exon regulation of CD45 alternative splicing

CD45 encodes a trans-membrane protein-tyrosine phosphatase expressed in diverse cells of the immune system. By combinatorial use of three variable exons 4–6, isoforms are generated that differ in their extracellular domain, thereby modulating phosphatase activity and immune response. Alternative splicing of these CD45 exons involves two heterogeneous ribonucleoproteins, hnRNP L and its cell-type specific paralog hnRNP L-like (LL). To address the complex combinatorial splicing of exons 4–6, we investigated hnRNP L/LL protein expression in human B-cells in relation to CD45 splicing patterns, applying RNA-Seq. In addition, mutational and RNA-binding analyses were carried out in HeLa cells. We conclude that hnRNP LL functions as the major CD45 splicing repressor, with two CA elements in exon 6 as its primary target. In exon 4, one element is targeted by both hnRNP L and LL. In contrast, exon 5 was never repressed on its own and only co-regulated with exons 4 and 6. Stable L/LL interaction requires CD45 RNA, specifically exons 4 and 6. We propose a novel model of combinatorial alternative splicing: HnRNP L and LL cooperate on the CD45 pre-mRNA, bridging exons 4 and 6 and looping out exon 5, thereby achieving full repression of the three variable exons

Transdiagnostic efficacy of a group exercise intervention for outpatients with heterogenous psychiatric disorders: a randomized controlled trial

Abstract Background Exercise efficaciously reduces disorder-specific symptoms of psychiatric disorders. The current study aimed to examine the efficacy of a group exercise intervention on global symptom severity and disorder-specific symptoms among a mixed outpatient sample. Methods Groups of inactive outpatients, waiting for psychotherapy, with depressive disorders, anxiety disorders, insomnia, and attention-deficit/hyperactivity disorders were randomized to a manualized 12-week exercise intervention, combining moderate to vigorous aerobic exercise with techniques for sustainable exercise behaviour change (n = 38, female = 71.1% (n = 27), M age  = 36.66), or a passive control group (n = 36, female = 75.0% (n = 27), M age  = 34.33). Primary outcomes were global symptom severity and disorder-specific symptoms, measured with the Symptom Checklist-90-Revised and Pittsburgh Sleep Quality Index pre- and post-treatment. Secondary outcome was the self-reported amount of exercise (Physical Activity, Exercise, and Sport Questionnaire), measured pre-treatment, intermediate-, and post-treatment. Intention-to-treat analyses were conducted using linear mixed models. Linear regressions were conducted to examine the effect of the change of exercise behaviour on the change of symptoms. Results The intervention significantly improved global symptom severity (d = 0.77, p = .007), depression (d = 0.68, p = .015), anxiety (d = 0.87, p = .002), sleep quality (d = 0.88, p = .001), and increased the amount of exercise (d = 0.82, p < .001), compared to the control group. Post-treatment differences between groups were significant for depression (d = 0.63, p = .031), sleep quality (d = 0.61, p = .035) and the amount of exercise (d = 1.45, p < .001). Across both groups, the reduction of global symptom severity was significantly predicted by an increase of exercise (b = .35, p = .012). Conclusions The exercise intervention showed transdiagnostic efficacy among a heterogeneous clinical sample in a realistic outpatient setting and led to sustained exercise behaviour change. Exercise may serve as an efficacious and feasible transdiagnostic treatment option improving the existing treatment gap within outpatient mental health care settings. Trial registration The study was registered on ClinicalTrials.gov (ID: NCT03542396 , 25/04/2018)

A randomized phase II study of paclitaxel alone versus paclitaxel plus sorafenib in second- and third-line treatment of patients with HER2-negative metastatic breast cancer (PASO)

Abstract Background We conducted an open-label, randomized, two-arm multi-center study to assess the efficacy and safety of paclitaxel versus paclitaxel + sorafenib in patients with locally advanced or metastatic HER2-negative breast cancer. Methods Patients were randomly assigned to receive either paclitaxel monotherapy (80 mg/m2) weekly (3 weeks on, 1 week off) plus sorafenib 400 mg orally, twice a day taken continuously throughout 28 day cycles. Sorafenib dose was gradually escalated from a starting dose of 200 mg twice a day. The primary endpoint was progression free survival (PFS). Results A pre-planned efficacy interim analysis was performed on the data of 60 patients, 30 patients in each treatment arm. Median PFS was estimated at 6.6 months (95% CI: 5.1 to 9.0) in patients randomized to single-agent paclitaxel (Arm A) and 5.6 months (95% CI: 3.8 to 6.5) in patients randomized to paclitaxel-sorafenib combination (Arm B) therapy. Contrary to the hypothesis, the treatment effect was statistically significant in favor of paclitaxel monotherapy (hazard ratio 1.80, 95% CI: 1.02 to 3.20; log-rank test P = 0.0409). It was decided to stop the trial early for futility. Median OS was also in favor of Arm A (20.7 months (95% CI: 16.4 to 26.7) versus 12.1 months (95% CI: 5.8 to 20.4) in Arm B. Clinical control was achieved in 28 patients (93.3%) in Arm A and in 21 patients 70.0% in Arm B. Overall response rate was met in 43.3% of patients in Arm A and in 40.0% in Arm B. Toxicities were increased in Arm B with higher rates of diarrhea, nausea, neutropenia, hand-foot skin reaction (HFSR) and anorexia, Grad 3 and 4 toxicities were rare. Conclusions In this pre-planned interim analysis, paclitaxel-sorafenib combination therapy was not found to be superior to paclitaxel monotherapy with regard to the primary end point, progression-free survival. The trial was therefore discontinued early. There was no indication of more favorable outcomes for combination therapy in secondary efficacy end points. As expected, the safety and toxicity profile of the combination therapy was less favorable compared to monotherapy. Overall, this trial did not demonstrate that adding sorafenib to second- or third-line paclitaxel provides any clinical benefit to patients with HER2-negative advanced or metastatic breast cancer. Cautious dosing using a sorafenib ramp up schedule might have contributed to negative results. Trial registration The study was registered at EudraCT (No 2009–018025-73) and retrospectively registered at Clinical trials.gov on March 17, 2011 ( NCT01320111 )

The effect of exercise and affect regulation skills on mental health during the COVID-19 pandemic: A cross-sectional survey

Background: COVID-19-related confinements pose a threat to mental health. We investigated prevalence rates of symptoms of depression, generalized anxiety and insomnia in German adults. Furthermore, we explored associations of exercise behavior with disorder-specific symptoms and assessed whether specific affect regulation skills enhance the effect of exercise on symptom alleviation. Methods: Cross-sectional survey-based data collected during the first lockdown is presented: 4268 adults completed questionnaires on mental health, exercise behavior and Covid-related lifestyle factors. Primary outcome was depression (PHQ-9), secondary outcomes generalized anxiety (PHQ-D) and sleep quality (PSQI). Multiple linear regression analyses were performed to examine the association of exercise behavior with the outcomes. Results: Analyses resulted in elevated symptoms of psychological distress (probable cases of depressive disorder: 31.2%, anxiety disorder: 7.5%, sleeping disorder: 43.0%). A change towards less exercise during the lockdown was significantly associated with higher levels of depression (t=5.269; β=0.077, p<.001), anxiety (t=3.397; β=0.055, p<.001) and insomnia (t=3.466; β=0.058; p<.001). Physical activity (PA)-related affect regulation enhanced the effect of exercise on mental health. Conclusions: Results suggest a demand for measures which promote the maintenance of exercise during a pandemic and improve PA-related affect regulation to optimize effects of exercise on mental health

Phosphorylation of tyrosine 90 in SH3 domain is a new regulatory switch controlling Src kinase

The activation of Src kinase in cells is strictly controlled by intramolecular inhibitory interactions mediated by SH3 and SH2 domains. They impose structural constraints on the kinase domain holding it in a catalytically non-permissive state. The transition between inactive and active conformation is known to be largely regulated by the phosphorylation state of key tyrosines 416 and 527. Here, we identified that phosphorylation of tyrosine 90 reduces binding affinity of the SH3 domain to its interacting partners, opens the Src structure, and renders Src catalytically active. This is accompanied by an increased affinity to the plasma membrane, decreased membrane motility, and slower diffusion from focal adhesions. Phosphorylation of tyrosine 90 controlling SH3-medited intramolecular inhibitory interaction, analogical to tyrosine 527 regulating SH2-C-terminus bond, enables SH3 and SH2 domains to serve as cooperative but independent regulatory elements. This mechanism allows Src to adopt several distinct conformations of varying catalytic activities and interacting properties, enabling it to operate not as a simple switch but as a tunable regulator functioning as a signalling hub in a variety of cellular processes