Die Effekte der Augmentationstherapie auf systemische sowie pulmonale Inflammationsmarker beim hereditären alpha1-Antitrypsinmangel

Hintergrund: α1-Antitrypsin (AAT), auch als α1-Proteinase-Inhibitor oder SERPINA1 bezeichnet, ist ein im menschlichen Blutplasma vorkommendes Protein, welches eine wichtige Funktion im Proteasen-Antiproteasen Verhältnis erfüllt. Bei entsprechender genetischer Voraussetzung kommt es zu verminderter AAT Sekretion der Leber und damit zu einem Mangel an AAT im Plasma. Der AAT-Mangel (AATM) prädisponiert zu einer früh einsetzenden und schnell voranschreitenden chronisch obstruktiven Lungenerkrankung (COPD) mit Lungenemphysem und entzündlichen Lebererkrankungen. Die einzige spezifische Therapie für den AATM stellt die Substitution mit humanem AAT dar. Der Nutzen der Substitutionstherapie ist mangels eindeutigen Nachweises der Wirksamkeit in prospektiv randomisierten Studien weiterhin Gegenstand der Diskussion. Sowohl die immunmodulatorische Funktion des AAT wie auch die Rolle der bei an AATM erkrankten Patienten vermehrt auftretenden AAT-Polymere sind bisher nur unzureichend verstanden. Ziel: Ziel dieser Arbeit war es systemische sowie lokale Inflammationsmarker bei Patienten mit hereditärem AATM in vivo als auch in vitro zu evaluieren und deren Reaktion auf die Substitution mit AAT zu untersuchen. Hierdurch sollten die antiinflammatorischen sowie die immunologischen Effekte des AAT untersucht werden. Zudem sollte der Einfluss der Substitutionstherapie mit der kommerziell erhältlichen Form Prolastin™ auf die Bildung von AAT-Polymeren erfasst und deren potentiell proinflammatorische Effekte in vitro evaluiert werden. Methoden: Es wurden 24 AATM Patienten mit nachgewiesenem PiZZ Genotyp in die Studie eingeschlossen. 12 Patienten erhielten eine wöchentliche Substitutionstherapie mit humanem AAT und 12 erhielten keine Substitution mit AAT. Serum und EBC Proben wurden vor Substitution, 2 Stunden danach und an Tag 3 nach Substitution mit AAT bei den augmentierten Patienten gewonnen. Es erfolgte die Bestimmung des totalen sowie polymeren AAT im Serum und der Zytokine/Chemokine und des C-reaktiven Proteins (CRP) im Serum und Atemwegskondensat (Exhaled Breath Condensate, EBC). Für die in vitro Versuche wurden neutrophile Granulozyten von 12 PiZZ homozygoten Spendern sowie primäre humane Bronchialepithelzellen mit den verschiedenen AAT-Fraktionen stimuliert und die Zytokine/Chemokine bestimmt. Ergebnisse: Die gemessenen AAT Spiegel sind nach Substitution von AAT signifikant höher als vor Substitution. Die AAT Konzentrationen fallen an Tag 3 nach Substitution, bleiben jedoch signifikant höher als vor Substitution. Nicht substituierte Patienten haben signifikant niedrigere AAT Spiegel als substituierte Patienten. Bei substituierten Patienten sind die Polymerkonzentrationen nach Substitution signifikant höher. IL-8 und MCP-1, aber auch IL-6, TNF und VEGF zeigen im Serum nach Substitution signifikante Schwankungen. Bei nicht augmentierten Patienten werden höhere IL-8 und niedrigere MCP-1 Werte beobachtet. Im EBC werden signifikant höhere CRP Konzentrationen bei den nicht substituierten Patienten gemessen. Im Zellversuch zeigt sich nach Stimulation mit Prolastin™ und Polymeren eine signifikant niedrigere IL-8 Sekretion der NG im Vergleich zu Monomeren. Die gemessenen IL-8 Konzentrationen nach Stimulation mit Monomer sind signifikant höher als die der Kontrolle. Bei der Stimulation der primären humanen Bronchialepithelzellen zeigen die verschiedenen Fraktionen des AAT keine unterschiedlichen Effekte auf die Sekretion von IL-6, IL-8 und MCP-1. Schlussfolgerung: Neben seiner Funktion im Proteasen-Antiproteasen Verhältnis zeigt AAT auch eine Funktion in der Regulation des Immunsystems. Der Einfluss des substituierten AAT auf die Zytokine IL-8 und MCP-1 lässt auf eine Funktion bei der Rekrutierung von neutrophilen Granulozyten und Monozyten schließen. Im Vergleich der nicht substituierten mit den substituierten Patienten deuten die gemessenen höheren CRP Spiegel im EBC als auch die IL-8 Konzentrationen im Serum auf einen antiinflammatorischen Effekt des augmentierten AAT hin. Im Zuge der Substitution kommt es zu einem Anstieg der AAT-Polymere im Serum. Bei Stimulation der NG mit den verschiedenen AAT-Fraktionen zeigen sich unterschiedliche Wirkungen, wobei sich die nachweisbare Wirkung der hochmolekularen AAT Fraktion ähnlich wie Prolastin™ verhält. Eine toxische Wirkung von nicht modifizierten AAT-Polymeren auf humane Bronchialepithelzellen konnte in dieser Arbeit nicht nachgewiesen werden

Comparison of two devices and two breathing patterns for exhaled breath condensate sampling.

Analysis of exhaled breath condensate (EBC) is a noninvasive method to access the epithelial lining fluid of the lungs. Due to standardization problems the method has not entered clinical practice. The aim of the study was to assess the comparability for two commercially available devices in healthy controls. In addition, we assessed different breathing patterns in healthy controls with protein markers to analyze the source of the EBC. EBC was collected from ten subjects using the RTube and ECoScreen Turbo in a randomized crossover design, twice with every device--once in tidal breathing and once in hyperventilation. EBC conductivity, pH, surfactant protein A, Clara cell secretory protein and total protein were assessed. Bland-Altman plots were constructed to display the influence of different devices or breathing patterns and the intra-class correlation coefficient (ICC) was calculated. The volatile organic compound profile was measured using the electronic nose Cyranose 320. For the analysis of these data, the linear discriminant analysis, the Mahalanobis distances and the cross-validation values (CVV) were calculated. Neither the device nor the breathing pattern significantly altered EBC pH or conductivity. ICCs ranged from 0.61 to 0.92 demonstrating moderate to very good agreement. Protein measurements were greatly influenced by breathing pattern, the device used, and the way in which the results were reported. The electronic nose could distinguish between different breathing patterns and devices, resulting in Mahalanobis distances greater than 2 and CVVs ranging from 64% to 87%. EBC pH and (to a lesser extent) EBC conductivity are stable parameters that are not influenced by either the device or the breathing patterns. Protein measurements remain uncertain due to problems of standardization. We conclude that the influence of the breathing maneuver translates into the necessity to keep the volume of ventilated air constant in further studies

Study Protocol for a Randomised Controlled Trial on Pulmonary Metastasectomy vs. Standard of Care in Colorectal Cancer Patients With ≥ 3 Lung Metastases (PUCC-Trial)

This is a multicentre prospective randomised controlled trial for patients with 3 or more resectable pulmonary metastases from colorectal carcinoma. The study investigates the effects of pulmonary metastasectomy in addition to standard medical treatment in comparison to standard medical treatment plus possible local ablative measures such as SBRT. This trial is intended to demonstrate an overall survival difference in the group undergoing pulmonary metastasectomy. Further secondary and exploratory endpoints include quality of life (EORTC QLQ-C30, QLQ-CR29 and QLQ-LC29 questionnaires), progression-free survival and impact of mutational status. Due to the heterogeneity and complexity of the disease and treatment trajectories in metastasised colorectal cancer, well powered trials have been very challenging to design and execute. The goal of this study is to create a setting which allows treatment as close to the real life conditions as possible but under well standardised conditions. Based on previous trials, in which patient recruitment in the given setting hindered successful study completion, we decided to (1) restrict inclusion to patients with 3 or more metastases (since in case of lesser, surgery will probably be the preferred option) and (2) allow for real world standard of care (SOC) treatment options before and after randomisation including watchful waiting (as opposed to a predefined treatment protocol) and (3) possibility that patient can receive SOC externally (to reduce patient burden). Moreover, we chose to stipulate 12 weeks of systemic treatment prior to possible resection to further standardize treatment response and disease course over a certain period of time. Hence, included patients will be in the disease state of oligopersistence rather than primary oligometastatic. The trial was registered in the German Clinical Trials Register (DRKS-No.: DRKS00024727)

MPromDb update 2010: an integrated resource for annotation and visualization of mammalian gene promoters and ChIP-seq experimental data

MPromDb (Mammalian Promoter Database) is a curated database that strives to annotate gene promoters identified from ChIP-seq results with the goal of providing an integrated resource for mammalian transcriptional regulation and epigenetics. We analyzed 507 million uniquely aligned RNAP-II ChIP-seq reads from 26 different data sets that include six human cell-types and 10 distinct mouse cell/tissues. The updated MPromDb version consists of computationally predicted (novel) and known active RNAP-II promoters (42 893 human and 48 366 mouse promoters) from various data sets freely available at NCBI GEO database. We found that 36% and 40% of protein-coding genes have alternative promoters in human and mouse genomes and ∼40% of promoters are tissue/cell specific. The identified RNAP-II promoters were annotated using various known and novel gene models. Additionally, for novel promoters we looked into other evidences—GenBank mRNAs, spliced ESTs, CAGE promoter tags and mRNA-seq reads. Users can search the database based on gene id/symbol, or by specific tissue/cell type and filter results based on any combination of tissue/cell specificity, Known/Novel, CpG/NonCpG, and protein-coding/non-coding gene promoters. We have also integrated GBrowse genome browser with MPromDb for visualization of ChIP-seq profiles and to display the annotations. The current release of MPromDb can be accessed at http://bioinformatics.wistar.upenn.edu/MPromDb/

Development of an updated, standardized, patient-centered outcome set for lung cancer

BACKGROUND: In 2016, the International Consortium for Health Outcomes Measurement (ICHOM) defined an international consensus recommendation of the most important outcomes for lung cancer patients. The European Health Outcomes Observatory (H2O) initiative aimed to develop an updated patient-centered core outcome set (COS) for lung cancer, to capture the patient perspective of the impact of lung cancer and (novel) treatments using a combination of patient-reported outcome (PRO) instruments and clinical data as a means to drive value-based health-care. MATERIAL AND METHODS: An international, expert team of patient representatives, multidisciplinary healthcare professionals, academic researchers and pharmaceutical industry representatives (n = 17) reviewed potential outcomes generated through literature review. A broader group of patients/patient representatives (n = 31), healthcare professionals / academic researchers (n = 83), pharmaceutical industry representatives (n = 26), and health authority representatives (n = 6) participated in a Delphi study. In two survey rounds, participants scored the relevance of outcomes from a preliminary list. The threshold for consensus was defined as ≥ 70 % of participants scoring an outcome as 'highly relevant'. In concluding consensus-meeting rounds, the expert multidisciplinary team finalized the COS. RESULTS: The preliminary list defined by the core group consisted of 102 outcomes and was prioritized in the Delphi procedure to 64. The final lung cancer COS includes: 1) case-mix factors (n = 27); 2) PROs related to health-related quality of life (HRQoL) (n = 25); 3) clinical outcomes (n = 12). Patient-reported symptoms beyond domains included in the ICHOM lung cancer set in 2016 were insomnia, nausea, vomiting, anxiety, depression, lack of appetite, gastric problems, constipation, diarrhoea, dysphagia, and haemoptysis. CONCLUSIONS: We will implement the lung cancer COS in Europe within the H2O initiative by collecting the outcomes through a combination of clinician-reported measures and PRO measures. The COS will support the adoption and reporting of lung cancer measures in a standardized way across Europe and empower patients with lung cancer to better manage their health care

Hyperthermic Intrathoracic Chemotherapy (HITOC) after Cytoreductive Surgery for Pleural Malignancies—A Retrospective, Multicentre Study

In the context of quality assurance, the objectives were to describe the surgical treatment and postoperative morbidity (particularly renal insufficiency). A retrospective, multicentre study of patients who underwent cytoreductive surgery (CRS) with cisplatin-based HITOC was performed. The study was funded by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation (GZ: RI 2905/3-1)). Patients (n = 350) with malignant pleural mesothelioma (n = 261; 75%) and thymic tumours with pleural spread (n = 58; 17%) or pleural metastases (n = 31; 9%) were analyzed. CRS was accomplished by pleurectomy/decortication (P/D: n = 77; 22%), extended P/D (eP/D: n = 263; 75%) or extrapleural pneumonectomy (EPP: n = 10; 3%). Patients received cisplatin alone (n = 212; 61%) or cisplatin plus doxorubicin (n = 138; 39%). Low-dose cisplatin (≤125 mg/m2 BSA) was given in 67% of patients (n = 234), and high-dose cisplatin (>125 mg/m2 BSA) was given in 33% of patients (n = 116). Postoperative renal insufficiency appeared in 12% of the patients (n = 41), and 1.4% (n = 5) required temporary dialysis. Surgical revision was necessary in 51 patients (15%). In-hospital mortality was 3.7% (n = 13). Patients receiving high-dose cisplatin were 2.7 times more likely to suffer from renal insufficiency than patients receiving low-dose cisplatin (p = 0.006). The risk for postoperative renal failure is dependent on the intrathoracic cisplatin dosage but was within an acceptable range

Zur Anwendung der statistischen Prozesskontrolle in der Wertpapieranalyse

Summary in EnglishAvailable from Bibliothek des Instituts fuer Weltwirtschaft, ZBW, Duesternbrook Weg 120, D-24105 Kiel W 1160 (102) / FIZ - Fachinformationszzentrum Karlsruhe / TIB - Technische InformationsbibliothekSIGLEDEGerman

Statistical process control and its application in finance

SIGLEAvailable from Bibliothek des Instituts fuer Weltwirtschaft, ZBW, Duesternbrook Weg 120, D-24105 Kiel W 1160 (80) / FIZ - Fachinformationszzentrum Karlsruhe / TIB - Technische InformationsbibliothekDEGerman

Predictors of adolescent smoking cessation and smoking reduction

OBJECTIVE: To investigate the processes of change, demographic, health- and smoking-related predictors of both smoking cessation and smoking reduction in adolescents. METHODS: Data were drawn from a sample of 755 adolescent smokers who participated in a study testing the efficacy of a text messaging-based intervention for smoking cessation. Demographic, health- and smoking-related variables were assessed at baseline. Five processes of smoking cessation, derived from the Transtheoretical Model and the Social Cognitive Theory, as well as outcome measures were assessed at 6-month follow up. Univariate and multivariate regression analyses were conducted to identify baseline and process variables to predict smoking abstinence and smoking reduction. RESULTS: Male gender (OR=0.43, p<.01), lower alcohol consumption (OR=0.90, p=.05) and a lower number of cigarettes smoked per day at baseline (OR=0.87, p<.01) predicted smoking abstinence. Baseline physical activity predicted smoking reduction (OR=1.04, p=.03). None of the examined process variables significantly predicted smoking abstinence. The process variable "counter-conditioning" predicted smoking reduction (OR=1.46, p=.03). CONCLUSIONS: Baseline predictors of smoking cessation differ from predictors of smoking reduction. Dynamic or modifiable variables play an important role in predicting adolescent smoking cessation. PRACTICE IMPLICATIONS: Counter-conditioning might be an important element in adolescent smoking cessation interventions