Konzeption und Umsetzung eines Werkzeugs zur Definition von Navigationsflüssen mittels Dienstannotationen

Die Diplomarbeit stellt einen innovativen und leichtgewichtigen Modellierungsansatz zur Beschreibung interaktiver, dienstbasierter Anwendungen auf Basis von Dienstannotationen vor

Carrier-envelope phase stability of hollow-fibers used for high-energy, few-cycle pulse generation

We investigated the carrier-envelope phase (CEP) stability of a hollow-fiber setup used for high-energy, few-cycle pulse generation. Saturation of the output pulse energy is observed at 0.6 mJ for a 260 um inner-diameter, 1 m long fiber, statically filled with neon, with the pressure adjusted to achieve an output spectrum capable of supporting sub-4fs pulses. The maximum output pulse energy can be increased to 0.8mJ by using either differential pumping, or circularly polarized input pulses. We observe the onset of an ionization-induced CEP instability, which does not increase beyond an input pulse energy of 1.25 mJ due to losses in the fiber caused by ionization. There is no significant difference in the CEP stability with differential pumping compared to static-fill, demonstrating that gas flow in differentially pumped fibers does not degrade the CEP stabilization.Comment: 4 pages, 4 figure

Forschung und Schulentwicklung: Kollaboration von Schule und Universität am Beispiel der Helene-Lange-Schule und ihrer wissenschaftlichen Begleitung

In diesem Beitrag stellen wir die Helene-Lange-Schule als Versuchsschule des Landes Hessen und ihr Konzept der wissenschaftlichen Begleitung vor. Dabei gehen wir auf den Prozess der Institutionalisierung und die organisatorischen Bedingungen der Zusammenarbeit ein und skizzieren die Erträge der Zusammenarbeit zu ausgewählten Themen (Lernen mit digitalen Medien, Lernen außerhalb der Schule und Individualisierung im Unterricht). Die Verzahnung von Versuchsschulauftrag, Schul- und Unterrichtsentwicklungsprozessen sowie Rückmeldungen aus der wissenschaftlichen Begleitung stehen im Zentrum des Beitrags. Die wissenschaftliche Begleitung konzipieren wir als arbeitsteiligen Prozess, in dem die Partner*innen auf Augenhöhe zusammenarbeiten. Umgesetzt als dokumentarische Evaluationsforschung ergeben sich aus der wissenschaftlichen Begleitung fruchtbare Anschlüsse an die erziehungswissenschaftliche Grundlagenforschung und die Schul- und Unterrichtsentwicklung. This paper presents the Helene Lange School as an experimental school of the state of Hesse and its concept of scientific support. We look at the process of institutionalization and the organizational conditions of cooperation and outline the results of cooperation on selected topics (learning with digital media, learning outside of school, and individualization in the classroom). The interlocking of the experimental school mission, school and classroom development processes as well as feedback from the scientific support are the focus of the paper. We conceive the scientific support as a process based on the division of labor, in which the partners work together as equals. When implemented as documentary evaluation research, the scientific monitoring results in fruitful connections to basic educational research and school and classroom development

Intraoperative Changes in Cerebrospinal Fluid Gas Tensions Reflect Paraplegia During Thoracoabdominal Aortic Surgery

Background: In this study, gas tensions in cerebrospinal fluid (CSF) were prospectively evaluated as intraoperative markers for the detection of neurological deficits. Methods: Spinal fluid, serum, and heart lung machine (HLM) perfusate were monitored for gas tensions (po2/pCo2) and related parameters (pH, lactate, and glucose) during thoracoabdominal aortic repair and correlated with perioperative neurological examination and electrophysiological testing. Results: Forty-seven patients were assessed for the study, and 40 consecutive patients were finally included. The patients were divided into 3 groups: group A (23 patients, 57.5%): no clinical or laboratory signs of neurological damage; group B (14 patients, 35%) who developed subclinical deficits; and group C (3 patients, 7.5%) who had paraplegia. Significant intraoperative changes in CSF gas tensions were observed with postoperative paraplegia. Glucose ratio between serum and CSF showed higher variability in group C, confirming a damage of the blood–brain barrier (BBB). Conclusion: Major neurological damage is reflected by early changes in CSF gas tensions and glucose variability, suggesting damage of the BBB in these patients

The association between mitochondrial DNA abundance and stroke : A combination of multivariable-adjusted survival and Mendelian randomization analyses

Acknowledgements The authors are grateful to the UK Biobank for allowing us the use of their data. The analyses done in UK Biobank were done under project number 56340. Furthermore, the authors acknowledge the participants and investigators of the MEGASTROKE consortium and the FinnGen Biobank who contributed to the summary statistics data which are made available for further studies. Financial support This work was supported by the VELUX Stiftung [grant number 1156] to DvH and RN, and JL was supported by the China Scholarship Counsel [No.201808500155]. RN was supported by an innovation grant from the Dutch Heart Foundation [grant number 2019T103 to R.N.]. Parts of this work were funded by the Åke Wibergs Foundation (grant number M19-0294 to F.G).Peer reviewedPublisher PD

Prognostic Impact of HER2 and ER Status of Circulating Tumor Cells in Metastatic Breast Cancer Patients with a HER2-Negative Primary Tumor

AbstractBACKGROUND: Preclinical and clinical studies have reported that human epidermal growth factor receptor 2 (HER2) overexpression yields resistance to endocrine therapies. Here the prevalence and prognostic impact of HER2-positive circulating tumor cells (CTCs) were investigated retrospectively in metastatic breast cancer (MBC) patients with a HER2-negative primary tumor receiving endocrine therapy. Additionally, the prevalence and prognostic significance of HER2-positive CTCs were explored in a chemotherapy cohort, as well as the prognostic impact of the estrogen receptor (ER) CTC status in both cohorts. METHODS: Included were MBC patients with a HER2-negative primary tumor, with ≥1 detectable CTC, starting a new line of treatment. CTCs were enumerated using the CellSearch system, characterized for HER2 with the CellSearch anti-HER2 phenotyping reagent, and characterized for ER mRNA expression. Primary end point was progression-free rate after 6 months (PFR6months) of endocrine treatment in HER2-positive versus HER2-negative CTC patients. RESULTS: HER2-positive CTCs were present in 29% of all patients. In the endocrine cohort (n=72), the PFR6months was 53% for HER2-positive versus 68% for HER2-negative CTC patients (P=.23). In the chemotherapy cohort (n=82), no prognostic value of HER2-positive CTCs on PFR6months was observed either. Discordances in ER status between the primary tumor and CTCs occurred in 25% of all patients but had no prognostic value in exploratory survival analyses. CONCLUSION: Discordances regarding HER2 status and ER status between CTCs and the primary tumor occurred frequently but had no prognostic impact in our MBC patient cohorts

Prognostic Impact of HER2 and ER Status of Circulating Tumor Cells in Metastatic Breast Cancer Patients with a HER2-Negative Primary Tumor

BACKGROUND: Preclinical and clinical studies have reported that human epidermal growth factor receptor 2 (HER2) overexpression yields resistance to endocrine therapies. Here the prevalence and prognostic impact of HER2-positive circulating tumor cells (CTCs) were investigated retrospectively in metastatic breast cancer (MBC) patients with a HER2-negative primary tumor receiving endocrine therapy. Additionally, the prevalence and prognostic significance of HER2-positive CTCs were explored in a chemotherapy cohort, as well as the prognostic impact of the estrogen receptor (ER) CTC status in both cohorts. METHODS: Included were MBC patients with a HER2-negative primary tumor, with ≥1 detectable CTC, starting a new line of treatment. CTCs were enumerated using the CellSearch system, characterized for HER2 with the CellSearch anti-HER2 phenotyping reagent, and characterized for ER mRNA expression. Primary end point was pr

Estrogen receptor mutations and splice variants determined in liquid biopsies from metastatic breast cancer patients

Mutations and splice variants in the estrogen receptor (ER) gene, ESR1, may yield endocrine resistance in metastatic breast cancer (MBC) patients. These putative endocrine resistance markers are likely to emerge during treatment, and therefore, its detection in liquid biopsies, such as circulating tumor cells (CTCs) and cell-free DNA (cfDNA), is of great interest. This research aimed to determine whether ESR1 mutations and splice variants occur more frequently in CTCs of MBC patients progressing on endocrine treatment. In addition, the presence of ESR1 mutations was evaluated in matched cfDNA and compared to CTCs. CellSearch-enriched CTC fractions (≥5/7.5 mL) of two MBC cohorts were evaluated, namely (a) patients starting first-line endocrine therapy (n = 43, baseline cohort) and (b) patients progressing on any line of endocrine therapy (n = 40, progressing cohort). ESR1 hotspot mutations (D538G and Y537S/N/C) were evaluated in CTC-enriched DNA using digital PCR and compared with matched cfDNA (n = 18 baseline cohort; n = 26 progressing cohort). Expression of ESR1 full-length and 4 of its splice variants ((increment)5, (increment)7, 36 kDa, and 46 kDa) was evaluated in CTC-enriched mRNA. It was observed that in the CTCs, the ESR1 mutations were not enriched in the progressing cohort (8%), when compared with the baseline cohort (5%) (P = 0.66). In the cfDNA, however, ESR1 mutations were more prevalent in the progressing cohort (42%) than in the baseline cohort (11%) (P = 0.04). Three of the same mutations were observed in both CTCs and cfDNA, 1 mutation in CTCs only, and 11 in cfDNA only. Only the (increment)5 ESR1 splice variant was CTC-specific expressed, but was not enriched in the progressing cohort. In conclusion, sensitivity for detecting ESR1 mutations in CTC-enriched fractions was lower than for cfDNA. ESR1 mutations detected in cfDNA, rarely present at the start of first-line endocrine therapy, were enriched at progression, strongly suggesting a role in conferring endocrine resistance in MBC

Epithelial HMGB1 delays skin wound healing and drives tumor initiation by priming neutrophils for NET formation

Regenerative responses predispose tissues to tumor formation by largely unknown mechanisms. High-mobility group box 1 (HMGB1) is a danger-associated molecular pattern contributing to inflammatory pathologies. We show that HMGB1 derived from keratinocytes, but not myeloid cells, delays cutaneous wound healing and drives tumor formation. In wounds of mice lacking HMGB1 selectively in keratinocytes, a marked reduction in neutrophil extracellular trap (NET) formation is observed. Pharmacological targeting of HMGB1 or NETs prevents skin tumorigenesis and accelerates wound regeneration. HMGB1-dependent NET formation and skin tumorigenesis is orchestrated by tumor necrosis factor (TNF) and requires RIPK1 kinase activity. NETs are present in the microenvironment of keratinocyte-derived tumors in mice and lesional and tumor skin of patients suffering from recessive dystrophic epidermolysis bullosa, a disease in which skin blistering predisposes to tumorigenesis. We conclude that tumorigenicity of the wound microenvironment depends on epithelial-derived HMGB1 regulating NET formation, thereby establishing a mechanism linking reparative inflammation to tumor initiation