Ductile‐brittle‐transition of flash annealed Fe‐based metallic glass ribbons

Fe-based metallic glasses show a ductile-brittle-transition (DBT) after annealing above a critical temperature, which makes the further processing of annealed ribbons complicated. However, the annealing step is necessary to improve the soft magnetic properties of these materials for industrial applications. For the future development of ductile (partial-) nanocrystalline Fe-based ribbons with excellent soft magnetic properties, it is important to understand the mechanisms behind the DBT. Therefore, tensile and bending tests were performed to determine the DBT of 15-20 µm thin, flash annealed Fe85.2B9.5P4Cu0.8Si0.5 ribbons in terms of critical stress intensity factor and bending ductility. Microstructure analysis has been done via X-ray diffraction (XRD), differential scanning calorimetry (DSC) and atom probe tomography (ATP). Please click Additional Files below to see the full abstract

Kern-, Eineltern- und Stieffamilien in Europa: eine Analyse ihrer Häufigkeiten und Einbindung in haushaltsübergreifende Strukturen

Die vorliegende Studie befasst sich mit den Anteilen von Eineltern- und Stieffamilien sowie haushaltsübergreifenden Familienstrukturen in verschiedenen europäischen Ländern. Die Frage, wie viele Eineltern- und Stieffamilien es in den verschiedenen Ländern Europas tatsächlich gibt, konnte bislang nicht zufriedenstellend beantwortet werden. Für viele Länder existieren lediglich Schätzungen unter Rückgriff auf Scheidungsraten. Analysen auf Basis der Surveys des 'Generations and Gender Programme' (GGP), die mittlerweile für 16 Staaten Europas (Belgien, Bulgarien, Deutschland, Estland, Frankreich, Georgien, Italien, Litauen, Niederlande, Norwegen, Österreich, Polen, Rumänien, Tschechische Republik, Ungarn, inklusive Russland) verfügbar sind, ermöglichen es allerdings, komplexe Familienstrukturen, wie sie bei Scheidungs- und Trennungsfamilien vorliegen, zu analysieren. Insgesamt werden 55.350 Familienhaushalte berücksichtigt, in denen minderjährige Kinder leben. Die Ergebnisse zeigen, dass die Anteile von Scheidungs- und Trennungsfamilien in den vorliegenden Ländern zwischen 7 und 30 Prozent variieren. Dabei wird ein Nord-Süd-Gefälle deutlich: Während der Anteil an Scheidungs- und Trennungsfamilien in den nordeuropäischen Ländern eher hoch ausfällt, ist er in den südeuropäischen Ländern deutlich geringer. Darüber hinaus ist der Anteil an Scheidungs- und Trennungsfamilien in einigen osteuropäischen Ländern besonders niedrig, in anderen jedoch außerordentlich hoch. Neben der Verteilung von Eineltern- und Stieffamilien hinweg, werden auch haushaltsübergreifende Konstellationen berücksichtigt. Die Analysen zeigen, dass man die Diversität von Familien deutlich unterschätzt, wenn auf der Haushaltsebene verharrt wird.This study deals with the prevalence of single-parent- and stepfamilies in Europe and their linkages in cross-household constellations. The question about the prevalence of these family constellations could not be answered satisfactory in the past. Noumerous studies revert to rough estimations based on crude divorce rates. The analysis presents color-coded descriptive statistics from official sources as well as from the surveys of the "Generations and Gender Program" (GGP), allowing visual comparisons of the prevalence of complex family structures that emerge from divorce and separation as predicted by crude divorce rates and as present in nationally representative survey samples. Data are now available for 16 European states (Austria, Belgium, Bulgaria, the Czech Republic, Estonia, France, Georgia, Germany, Hungary, Italy, Lithuania, the Netherlands, Norway, Poland, Romania, and Russia) and include a total of 55,350 family households with non-adult children. Single-parent families and stepfamilies constituted between 7 and 30 percent of the national samples. A north-south divide is clearly evident such that the share of single-parent families and stepfamilies is much higher in Europe's northern countries. Eastern Europe, however, includes countries in which the share of single-parent- and stepfamilies was extraordinarily high and countries in which the share was extraordinarily low. Beside the prevalence of single-parent- and stepfamilies cross-household constellations are considered. Analyes emphasize an underestimation of complex family structures because of the persistent neclection of crosshousehold constellations

Functional Contribution and Targeted Migration of Group-2 Innate Lymphoid Cells in Inflammatory Lung Diseases: Being at the Right Place at the Right Time

During the last decade, group-2 innate lymphoid cells (ILC2s) have been discovered and successfully established as crucial mediators of lung allergy, airway inflammation and fibrosis, thus affecting the pathogenesis and clinical course of many respiratory diseases, like for instance asthma, cystic fibrosis and chronic rhinosinusitis. As an important regulatory component in this context, the local pulmonary milieu at inflammatory tissue sites does not only determine the activation status of lung-infiltrating ILC2s, but also influences their motility and migratory behavior. In general, many data collected in recent murine and human studies argued against the former concept of a very strict tissue residency of innate lymphoid cells (ILCs) and instead pointed to a context-dependent homing capacity of peripheral blood ILC precursors and the inflammation-dependent capacity of specific ILC subsets for interorgan trafficking. In this review article, we provide a comprehensive overview of the so far described molecular mechanisms underlying the pulmonary migration of ILC2s and thereby the numeric regulation of local ILC2 pools at inflamed or fibrotic pulmonary tissue sites and discuss their potential to serve as innovative therapeutic targets in the treatment of inflammatory lung diseases

Innate Lymphoid Cells as Regulators of Epithelial Integrity: Therapeutic Implications for Inflammatory Bowel Diseases

The occurrence of epithelial defects in the gut relevantly contributes to the pathogenesis of inflammatory bowel diseases (IBD), whereby the impairment of intestinal epithelial barrier integrity seems to represent a primary trigger as well as a disease amplifying consequence of the chronic inflammatory process. Besides epithelial cell intrinsic factors, accumulated and overwhelmingly activated immune cells and their secretome have been identified as critical modulators of the pathologically altered intestinal epithelial cell (IEC) function in IBD. In this context, over the last 10 years increasing levels of attention have been paid to the group of innate lymphoid cells (ILCs). This is in particular due to a preferential location of these rather newly described innate immune cells in close proximity to mucosal barriers, their profound capacity to secrete effector cytokines and their numerical and functional alteration under chronic inflammatory conditions. Aiming on a comprehensive and updated summary of our current understanding of the bidirectional mucosal crosstalk between ILCs and IECs, this review article will in particular focus on the potential capacity of gut infiltrating type-1, type-2, and type-3 helper ILCs (ILC1s, ILC2s, and ILC3s, respectively) to impact on the survival, differentiation, and barrier function of IECs. Based on data acquired in IBD patients or in experimental models of colitis, we will discuss whether the different ILC subgroups could serve as potential therapeutic targets for maintenance of epithelial integrity and/or mucosal healing in IBD

Regulation of Human Innate Lymphoid Cells in the Context of Mucosal Inflammation

Since their identification as a unique cell population, innate lymphoid cells (ILCs) have revolutionized our understanding of immune responses, leaving their impact on multiple inflammatory and fibrotic pathologies without doubt. Thus, a tightly controlled regulation of local ILC numbers and their activity is of crucial importance. Even though this has been extensively studied in murine ILCs in the last few years, our knowledge of human ILCs is still lagging behind. Our review article will therefore summarize recent insights into the function of human ILCs and will particularly focus on their regulation under inflammatory conditions. The quality and intensity of ILC involvement into local immune responses at mucosal sites of the human body can potentially be modulated via three different axes: (1) activation of tissue-resident mature ILCs, (2) plasticity and local transdifferentiation of specific ILC subsets, and (3) tissue migration and accumulation of peripheral ILCs. Despite a still ongoing scientific effort in this field, already existing data on the fate of human ILCs under different pathologic conditions clearly indicate that all three of these mechanisms are of relevance for the clinical course of chronic inflammatory and autoimmune diseases and might likewise provide new target structures for future therapeutic strategies

Total Neoadjuvant Therapy for Rectal Cancer in the CAO/ARO/AIO-12 Randomized Phase 2 Trial: Early Surrogate Endpoints Revisited

Background: Early efficacy outcome measures in rectal cancer after total neoadjuvant treatment are increasingly investigated. We examined the prognostic role of pathological complete response (pCR), tumor regression grading (TRG) and neoadjuvant rectal (NAR) score for disease-free survival (DFS) in patients with rectal carcinoma treated within the CAO/ARO/AIO-12 randomized phase 2 trial. Methods: Distribution of pCR, TRG and NAR score was analyzed using the Pearson’s chi-squared test. Univariable analyses were performed using the log-rank test, stratified by treatment arm. Discrimination ability of non-pCR for DFS was assessed by analyzing the ROC curve as a function of time. Results: Of the 311 patients enrolled, 306 patients were evaluable (Arm A:156, ArmB:150). After a median follow-up of 43 months, the 3-year DFS was 73% in both groups (HR, 0.95, 95% CI, 0.63–1.45, p = 0.82). pCR tended to be higher in Arm B (17% vs. 25%, p = 0.086). In both treatment arms, pCR, TRG and NAR were significant prognostic factors for DFS, whereas survival in subgroups defined by pCR, TRG or NAR did not significantly differ between the treatment arms. The discrimination ability of non-pCR for DFS remained constant over time (C-Index 0.58) but was slightly better in Arm B (0.61 vs. 0.56). Conclusion: Although pCR, TRG and NAR were strong prognostic factors for DFS in the CAO/ARO/AIO-12 trial, their value in selecting one TNT approach over another could not be confirmed. Hence, the conclusion of a long-term survival benefit of one treatment arm based on early surrogate endpoints should be stated with caution

Improved survival of locoregional-advanced larynx and hypopharynx cancer patients treated according to the DeLOS-II protocol

IntroductionLarynx organ preservation (LOP) in locoregional-advanced laryngeal and hypopharyngeal squamous cell carcinoma (LA-LHSCC) being only R0-resectable (clear margins > 5 mm) by total laryngectomy (TL) is desirable. Based on tumor-specific survival (TSS) and overall survival (OS) data from the RTOG 91-11 trial and meta-analyses of randomized clinical trials (RCTs), cisplatin-based concurrent radiochemotherapy (CRT) is discussed being superior to cisplatin-based induction chemotherapy followed by radiotherapy (IC+RT) and TL followed by postoperative RT (TL+PORT) or radiochemotherapy (TL+PORCT). Outside of RCTs, T4 LHSCC treated with TL+PORCT demonstrated improved OS and TSS compared to CRT alone; comparisons with docetaxel plus cisplatin (TP)-based IC+RT are unpublished. Head-to-head comparisons in RCTs of these four alternatives are missing.Materials and methodsWe utilized monocentric registry data to compare the outcome in the LOP trial DeLOS-II (NCT00508664) and propensity score (PS)–matched LHSCC patients. DeLOS-II utilized endoscopic tumor staging after one cycle of TP-based IC for selecting TL+R(C)T for non-responders versus IC+RT for responders. Main risk factors for survival (localization hypopharynx, T4, N+, tobacco smoking >30 pack years, alcohol consumption >60 g/day, age, sex) were used to calculate the individual PS for each DeLOS-II patient and 330 LHSCC patients suitable for DeLOS-II according to eligibility criteria in Leipzig by CRT (78), TL+PORT (148), and TL+PORCT (104). We performed PS matching with caliper width 0.2.ResultsThe 52 DeLOS-II patients (whole intent-to-treat cohort) and three PS-matched cohorts (52 LHSCC patients each) had equal distribution regarding risk factors including Charlson comorbidity score (CS; all p > 0.05) but differed in outcome. During 12,498.6 months of follow-up, 162 deaths (36/41/43/42 in DeLOS-II/TL+PORCT/TL+PORT/CRT, p = 0.356) occurred; DeLOS-II patients had superior OS and TSS. Compared to DeLOS-II, the HR (95% CI) observed in TL+PORCT, TL+PORT, and CRT for OS and TSS were 1.49 (0.92–2.43), 1.49 (1.15–3.18), and 1.81 (1.11–2.96) for OS; and 2.07 (0.944–4.58), 3.02 (1.32–6.89), and 3.40 (1.58–7.31) for TSS.ConclusionIn addition potential LOP, LA-LHSCC suitable for LOP according the DeLOS-II protocol may achieve improved survival

Radiochemotherapy with or without cetuximab for unresectable esophageal cancer: final results of a randomized phase 2 trial (LEOPARD-2)

Abstract Purpose To investigate the efficacy and toxicity of cetuximab when added to radiochemotherapy for unresectable esophageal cancer. Methods This randomized phase 2 trial (clinicaltrials.gov, identifier NCT01787006) compared radiochemotherapy plus cetuximab (arm A) to radiochemotherapy (arm B) for unresectable esophageal cancer. Primary objective was 2‑year overall survival (OS). Arm A was considered insufficiently active if 2‑year OS was ≤40% (null hypothesis = H0), and promising if the lower limit of the 95% confidence interval was >45%. If that lower limit was >40%, H0 was rejected. Secondary objectives included progression-free survival (PFS), locoregional control (LC), metastases-free survival (MFS), response, and toxicity. The study was terminated early after 74 patients; 68 patients were evaluable. Results Two-year OS was 71% in arm A (95% CI: 55–87%) vs. 53% in arm B (95% CI: 36–71%); H0 was rejected. Median OS was 49.1 vs. 24.1 months (p = 0.147). Hazard ratio (HR) for death was 0.60 (95% CI: 0.30–1.21). At 2 years, PFS was 56% vs. 44%, LC 84% vs. 72%, and MFS 74% vs. 54%. HRs were 0.51 (0.25–1.04) for progression, 0.43 (0.13–1.40) for locoregional failure, and 0.43 (0.17–1.05) for distant metastasis. Overall response was 81% vs. 69% (p = 0.262). Twenty-six and 27 patients, respectively, experienced at least one toxicity grade ≥3 (p = 0.573). A significant difference was found for grade ≥3 allergic reactions (12.5% vs. 0%, p = 0.044). Conclusion Given the limitations of this trial, radiochemotherapy plus cetuximab was feasible. There was a trend towards improved PFS and MFS. Larger studies are required to better define the role of cetuximab for unresectable esophageal cancer