The IL1-IL1RAP axis plays an important role in the inflammatory leukemic niche that favors acute myeloid leukemia proliferation over normal hematopoiesis.

Upregulation of the plasma membrane receptor IL1RAP in Acute Myeloid Leukemia (AML) has been reported but its role in the context of the leukemic bone marrow niche is unclear. Here, we studied the signaling events downstream of IL1RAP in relation to leukemogenesis and normal hematopoiesis. High IL1RAP expression was associated with a leukemic GMP-like state, and knockdown of IL1RAP in AML reduced colony-forming capacity. Stimulation with IL1β resulted in the induction of multiple chemokines and an inflammatory secretome via the p38 MAPK and NFκB signaling pathways in IL1RAP-expressing AML cells, but IL1β-induced signaling was dispensable for AML cell proliferation and NFκB-driven survival. IL1RAP was also expressed in stromal cells where IL1β induced expression of inflammatory chemokines and cytokines as well. Intriguingly, the IL1β-induced inflammatory secretome of IL1RAPexpressing AML cells grown on a stromal layer of mesenchymal stem cells affected normal hematopoiesis including hematopoietic stem/progenitor cells while AML cell proliferation was not affected. The addition of Anakinra, an FDA-approved IL1 receptor antagonist, could reverse this effect. Therefore, blocking the IL1-IL1RAP signaling axis might be a good therapeutic approach to reduce inflammation in the bone marrow niche and thereby promote normal hematopoietic recovery over AML proliferation after chemotherapy

Biocompatibility and Bone Formation of Flexible, Cotton Wool-like PLGA/Calcium Phosphate Nanocomposites in Sheep

BACKGROUND: The purpose of this preliminary study was to assess the in vivo performance of synthetic, cotton wool-like nanocomposites consisting of a biodegradable poly(lactide-co-glycolide) fibrous matrix and containing either calcium phosphate nanoparticles (PLGA/CaP 60:40) or silver doped CaP nanoparticles (PLGA/Ag-CaP 60:40). Besides its extraordinary in vitro bioactivity the latter biomaterial (0.4 wt% total silver concentration) provides additional antimicrobial properties for treating bone defects exposed to microorganisms. MATERIALS AND METHODS: Both flexible artificial bone substitutes were implanted into totally 16 epiphyseal and metaphyseal drill hole defects of long bone in sheep and followed for 8 weeks. Histological and histomorphological analyses were conducted to evaluate the biocompatibility and bone formation applying a score system. The influence of silver on the in vivo performance was further investigated. RESULTS: Semi-quantitative evaluation of histology sections showed for both implant materials an excellent biocompatibility and bone healing with no resorption in the adjacent bone. No signs of inflammation were detectable, either macroscopically or microscopically, as was evident in 5 µm plastic sections by the minimal amount of inflammatory cells. The fibrous biomaterials enabled bone formation directly in the centre of the former defect. The area fraction of new bone formation as determined histomorphometrically after 8 weeks implantation was very similar with 20.5 ± 11.2 % and 22.5 ± 9.2 % for PLGA/CaP and PLGA/Ag-CaP, respectively. CONCLUSIONS: The cotton wool-like bone substitute material is easily applicable, biocompatible and might be beneficial in minimal invasive surgery for treating bone defects

Supporting Information for A disease-associated XPA allele interferes with TFIIH binding and primarily affects transcription-coupled nucleotide excision repair

Supporting Text: Extended Methods Figures S1 to S6 Tables S1 to S4 SI References (16) Other supporting materials for this manuscript include the following: Datasets / spreadsheet S1Peer reviewe

Nucleotide excision repair leaves a mark on chromatin: DNA damage detection in nucleosomes

Global genome nucleotide excision repair (GG-NER) eliminates a broad spectrum of DNA lesions from genomic DNA. Genomic DNA is tightly wrapped around histones creating a barrier for DNA repair proteins to access DNA lesions buried in nucleosomal DNA. The DNA-damage sensors XPC and DDB2 recognize DNA lesions in nucleosomal DNA and initiate repair. The emerging view is that a tight interplay between XPC and DDB2 is regulated by post-translational modifications on the damage sensors themselves as well as on chromatin containing DNA lesions. The choreography between XPC and DDB2, their interconnection with post-translational modifications such as ubiquitylation, SUMOylation, methylation, poly(ADP-ribos)ylation, acetylation, and the functional links with chromatin remodelling activities regulate not only the initial recognition of DNA lesions in nucleosomes, but also the downstream recruitment and necessary displacement of GG-NER factors as repair progresses. In this review, we highlight how nucleotide excision repair leaves a mark on chromatin to enable DNA damage detection in nucleosomes

Die Versorgungspraxis der Substitutionstherapie Opiatabhängiger (COBRA)

Hintergrund: Die Datenlage zur Substitutionstherapie Opiatabhängiger ist defizitär. Vor diesem markant defizitären Erkenntnishintergrund erscheint es sinnvoll und notwendig, eine versorgungsepidemiologische Studie zur aktuellen Versorgungslage opiatabhängiger Substitutionspatienten durchzuführen, um offene Fragen zu klären. Hierfür haben wir ein mehrstufiges Forschungsprojekt unter dem Akronym COBRA initiiert. COBRA steht für "Cost-Benefit and Risk Appraisal of Substitution Treatments" und signalisiert, dass wir uns in umfassender Weise um eine Evaluation der Risiken, Vor- und Nachteile verschiedener Interventionsstrategien und Modalitäten in der Substitutions- und Versorgungspraxis Opiatabhängiger in Deutschland bemühen. Zielsetzungen des COBRA-Projekts sind: • Die Charakterisierung von bestehenden Einrichtungsformen und -modellen; • Die Charakterisierung von: – Merkmalen opiatabhängiger Patienten in diesen Einrichtungen (Schwere, Dauer/ Stadium, Komorbidität, Delinquenz, Desintegration etc.), – der Diagnostik sowie den Indikations- und Allokationsentscheidungen in der Versorgungsrealität sowie – den eingesetzten Interventionsmethoden (Substitutionsmittel, Therapie komorbider Störungen, psychotherapeutische und soziale Interventionen) • Die Ermittlung von Problemen der Substitutionstherapie bei verschiedenen Risikogruppen (z.B. Hepatitis-C- und HIVPatienten) • Die Beschreibung des Kurzzeitverlaufs und Outcomes hinsichtlich verschiedener klinischer und sozialer Kriterien Methodik: Die Studie teilt sich in einen deskriptiv-klinisch-epidemiologischen und einen analytisch-evaluativen Teil. Der deskriptive Teil soll zunächst darüber Auskunft geben, wie viele und welche Arten von Substitutionseinrichtungen in Deutschland wie viele Opiatabhängige erreichen und behandeln. Auf dieser Grundlage soll dann im evaluativen Teil an möglichst repräsentativen Einrichtungen und Patienten beurteilt werden, wie und mit welchen Methoden welche Arten von Patienten und Problemlagen versorgt werden. Durch Abgleich mit den wissenschaftlichen Bewertungsmaßstäben können daraus Defizite, Probleme und mögliche verbesserte Allokationsstrategien abgeleitet werden. Ergebnisse: Es werden erste Vorstudienbefunde und Ihre Design- Konsequenzen vorgestellt und diskutiert.In the present paper, we will describe aims, methods, and design along with selected pre-study findings of an epidemiological study in a nationally representative sample of substitution doctors (N = 381) and their patients (n = 2500) in Germany. The project has three major components: (a) Pre-study: We sent mailed questionnaires to a sample of over 1000 substitution doctors to describe qualification and setting characteristics, treatment profiles and attitudes of substitution doctors in Germany. (b) Cross-sectional study: With a two-step epidemiological design (target day assessment of the patients, clinical appraisals by the doctors), our main aims were (1) to determine the number of opiate addicts treated by methadone or buprenorphine or other substitution drugs; (2) to find predictors and correlates for treatment, taking into account doctors, patients, and system variables; and (3) to evaluate cross-sectional differences between groups with regard to clinical presentation (comorbidity), clinical course, acceptance/compliance, critical incidences, and social integration. (c) Furthermore, the study includes a prospective-longitudinal cohort study of a total of 1000 patients sampled from this data base. The cohort will be followed-up over a period of three months to investigate whether buprenorphine patients have a more favorable course and outcome in terms of clinical, psychosocial, pharmaco-economic, and related measures. Selected pre-study findings are summarized, highlightening that current registers include a considerable proportion of doctors and a considerable heterogeneity of setting characteristics in terms of the number of patients, choice of substitution drugs and involvement in hepatitis- C treatment

Die Versorgungspraxis der Substitutionstherapie Opiatabhängiger (COBRA)

Hintergrund: Die Datenlage zur Substitutionstherapie Opiatabhängiger ist defizitär. Vor diesem markant defizitären Erkenntnishintergrund erscheint es sinnvoll und notwendig, eine versorgungsepidemiologische Studie zur aktuellen Versorgungslage opiatabhängiger Substitutionspatienten durchzuführen, um offene Fragen zu klären. Hierfür haben wir ein mehrstufiges Forschungsprojekt unter dem Akronym COBRA initiiert. COBRA steht für "Cost-Benefit and Risk Appraisal of Substitution Treatments" und signalisiert, dass wir uns in umfassender Weise um eine Evaluation der Risiken, Vor- und Nachteile verschiedener Interventionsstrategien und Modalitäten in der Substitutions- und Versorgungspraxis Opiatabhängiger in Deutschland bemühen. Zielsetzungen des COBRA-Projekts sind: • Die Charakterisierung von bestehenden Einrichtungsformen und -modellen; • Die Charakterisierung von: – Merkmalen opiatabhängiger Patienten in diesen Einrichtungen (Schwere, Dauer/ Stadium, Komorbidität, Delinquenz, Desintegration etc.), – der Diagnostik sowie den Indikations- und Allokationsentscheidungen in der Versorgungsrealität sowie – den eingesetzten Interventionsmethoden (Substitutionsmittel, Therapie komorbider Störungen, psychotherapeutische und soziale Interventionen) • Die Ermittlung von Problemen der Substitutionstherapie bei verschiedenen Risikogruppen (z.B. Hepatitis-C- und HIVPatienten) • Die Beschreibung des Kurzzeitverlaufs und Outcomes hinsichtlich verschiedener klinischer und sozialer Kriterien Methodik: Die Studie teilt sich in einen deskriptiv-klinisch-epidemiologischen und einen analytisch-evaluativen Teil. Der deskriptive Teil soll zunächst darüber Auskunft geben, wie viele und welche Arten von Substitutionseinrichtungen in Deutschland wie viele Opiatabhängige erreichen und behandeln. Auf dieser Grundlage soll dann im evaluativen Teil an möglichst repräsentativen Einrichtungen und Patienten beurteilt werden, wie und mit welchen Methoden welche Arten von Patienten und Problemlagen versorgt werden. Durch Abgleich mit den wissenschaftlichen Bewertungsmaßstäben können daraus Defizite, Probleme und mögliche verbesserte Allokationsstrategien abgeleitet werden. Ergebnisse: Es werden erste Vorstudienbefunde und Ihre Design- Konsequenzen vorgestellt und diskutiert.In the present paper, we will describe aims, methods, and design along with selected pre-study findings of an epidemiological study in a nationally representative sample of substitution doctors (N = 381) and their patients (n = 2500) in Germany. The project has three major components: (a) Pre-study: We sent mailed questionnaires to a sample of over 1000 substitution doctors to describe qualification and setting characteristics, treatment profiles and attitudes of substitution doctors in Germany. (b) Cross-sectional study: With a two-step epidemiological design (target day assessment of the patients, clinical appraisals by the doctors), our main aims were (1) to determine the number of opiate addicts treated by methadone or buprenorphine or other substitution drugs; (2) to find predictors and correlates for treatment, taking into account doctors, patients, and system variables; and (3) to evaluate cross-sectional differences between groups with regard to clinical presentation (comorbidity), clinical course, acceptance/compliance, critical incidences, and social integration. (c) Furthermore, the study includes a prospective-longitudinal cohort study of a total of 1000 patients sampled from this data base. The cohort will be followed-up over a period of three months to investigate whether buprenorphine patients have a more favorable course and outcome in terms of clinical, psychosocial, pharmaco-economic, and related measures. Selected pre-study findings are summarized, highlightening that current registers include a considerable proportion of doctors and a considerable heterogeneity of setting characteristics in terms of the number of patients, choice of substitution drugs and involvement in hepatitis- C treatment