Collagen XVII (ColXVII) is an important epithelial anchorage molecule in the skin that is highly upregulated in several epithelial cancers during dysplasia-to-cancer transformation. Since ColXVII ectodomain is proteolytically released from the cell surface, we employed ectodomain selective antibodies to visualize ColXVII shedding in human squamous cell carcinomas (SCCs). ColXVII ectodomain was mainly located at the invasive front of SCCs, suggesting important functions in tumor progression. To investigate the role of ColXVII expression and shedding in skin carcinogenesis, we knocked down ColXVII in SCC-cell lines (Kd) using a viral shRNA approach. Loss of ColXVII in these cells resulted in dramatically decreased clonal growth capacity and invasiveness in vitro, as well as significantly reduced growth of SCC-25 xenografts in immunodeficient mice. Re-expression of wild-type full-length ColXVII in Kd cells fully restored matrix independent cell growth and matrigel invasion, while re-expression of a non-sheddable ColXVII mutant did not, indicating that both processes are modulated by ColXVII shedding. Moreover, specific blockage of shedding by monoclonal ColXVII antibodies repressed matrix-independent growth and invasion of SCC cells in organotypic co-cultures. Besides releasing an ectodomain, ColXVII shedding also generates a membrane-anchored endodomain. To explore their functions in cancer growth and invasion we either introduced the ectodomain (Ecto) or the endodomain (Endo) in Kd cells via retroviral transduction. Our data suggest that both domains have distinct functions during tumor progression: Endo selectively promotes clonal growth capacity, while Ecto mainly supports invasiveness. These results indicate that ColXVII shedding promotes proliferation and motility in SCCs. Thus, selective inhibition of ColXVII shedding may offer a therapeutic strategy to delay carcinoma progression.

Abstract: Objectives: We analyze whether the prevalence of depressive symptoms differs among various migrant and non-migrant populations in Germany and to what extent these differences can be attributed to socioeconomic position (SEP) and social relations. Methods: The German National Cohort health study (NAKO) is a prospective multicenter cohort study (N = 204,878). Migration background (assessed based on citizenship and country of birth of both participant and parents) was used as independent variable, age, sex, Social Network Index, the availability of emotional support, SEP (relative income position and educational status) and employment status were introduced as covariates and depressive symptoms (PHQ-9) as dependent variable in logistic regression models. Results: Increased odds ratios of depressive symptoms were found in all migrant subgroups compared to non-migrants and varied regarding regions of origins. Elevated odds ratios decreased when SEP and social relations were included. Attenuations varied across migrant subgroups. Conclusion: The gap in depressive symptoms can partly be attributed to SEP and social relations, with variations between migrant subgroups. The integration paradox is likely to contribute to the explanation of the results. Future studies need to consider heterogeneity among migrant subgroups whenever possible

Abstract: The German National Cohort (NAKO) is a multidisciplinary, population-based prospective cohort study that aims to investigate the causes of widespread diseases, identify risk factors and improve early detection and prevention of disease. Specifically, NAKO is designed to identify novel and better characterize established risk and protection factors for the development of cardiovascular diseases, cancer, diabetes, neurodegenerative and psychiatric diseases, musculoskeletal diseases, respiratory and infectious diseases in a random sample of the general population. Between 2014 and 2019, a total of 205,415 men and women aged 19-74 years were recruited and examined in 18 study centres in Germany. The baseline assessment included a face-to-face interview, self-administered questionnaires and a wide range of biomedical examinations. Biomaterials were collected from all participants including serum, EDTA plasma, buffy coats, RNA and erythrocytes, urine, saliva, nasal swabs and stool. In 56,971 participants, an intensified examination programme was implemented. Whole-body 3T magnetic resonance imaging was performed in 30,861 participants on dedicated scanners. NAKO collects follow-up information on incident diseases through a combination of active follow-up using self-report via written questionnaires at 2-3 year intervals and passive follow-up via record linkages. All study participants are invited for re-examinations at the study centres in 4-5 year intervals. Thereby, longitudinal information on changes in risk factor profiles and in vascular, cardiac, metabolic, neurocognitive, pulmonary and sensory function is collected. NAKO is a major resource for population-based epidemiology to identify new and tailored strategies for early detection, prediction, prevention and treatment of major diseases for the next 30 years

Abstract: Introduction: Family history of depression and childhood maltreatment are established risk factors for depression. However, how these factors are interrelated and jointly influence depression risk is not well understood. The present study investigated (i) if childhood maltreatment is associated with a family history of depression (ii) if family history and childhood maltreatment are associated with increased lifetime and current depression, and whether both factors interact beyond their main effects, and (iii) if family history affects lifetime and current depression via childhood maltreatment. Methods: Analyses were based on a subgroup of the first 100,000 participants of the German National Cohort (NAKO), with complete information (58,703 participants, mean age = 51.2 years, 53% female). Parental family history of depression was assessed via self-report, childhood maltreatment with the Childhood Trauma Screener (CTS), lifetime depression with self-reported physician's diagnosis and the Mini-International Neuropsychiatric Interview (MINI), and current depressive symptoms with the depression scale of the Patient Health Questionnaire (PHQ-9). Generalized linear models were used to test main and interaction effects. Mediation was tested using causal mediation analyses. Results: Higher frequencies of the childhood maltreatment measures were found in subjects reporting a positive family history of depression. Family history and childhood maltreatment were independently associated with increased depression. No statistical interactions of family history and childhood maltreatment were found for the lifetime depression measures. For current depressive symptoms (PHQ-9 sum score), an interaction was found, with stronger associations of childhood maltreatment and depression in subjects with a positive family history. Childhood maltreatment was estimated to mediate 7%-12% of the effect of family history on depression, with higher mediated proportions in subjects whose parents had a depression onset below 40 years. Abuse showed stronger associations with family history and depression, and higher mediated proportions of family history effects on depression than neglect. Discussion: The present study confirms the association of childhood maltreatment and family history with depression in a large population-based cohort. While analyses provide little evidence for the joint effects of both risk factors on depression beyond their individual effects, results are consistent with family history affecting depression via childhood maltreatment to a small extent

Abstract: Hintergrund Die NAKO Gesundheitsstudie ist ein bundesweites interdisziplinäres Forschungsvorhaben mit dem Ziel, die Ursachen für chronische Krankheiten und deren vorklinische Stadien zu untersuchen. Der Artikel gibt einen Überblick über das Studiendesign, die Methoden, die Teilnahme an den Untersuchungen und ihre Qualitätssicherung zur Halbzeit der Basiserhebung. Methoden Für die Basiserhebung wurden mehr als 200.000 Frauen und Männer im Alter von 20-69 Jahren aus Zufallsstichproben der Allgemeinbevölkerung in 18 Studienzentren rekrutiert (2014-2019). Die Basiserhebung beinhaltet Untersuchungen, Befragungen und Biomaterialien für alle Teilnehmerinnen und Teilnehmer (Level 1), ein erweitertes Programm für mindestens 20 % (Level 2) und eine Magnetresonanztomografie (MRT) für 30.000 Teilnehmerinnen und Teilnehmer. Sekundär- und Registerdaten werden über Krankheitsregister, Kranken- und Rentenversicherungen erhoben. Die Auswertung bezieht die Datenbasis zur Halbzeit der Basiserhebung mit 101.839 Teilnehmerinnen und Teilnehmern ein, davon 11.371 mit einer MRT-Untersuchung. Ergebnisse Die mittlere Responsequote zur Halbzeit betrug insgesamt 18 %. Die Teilnahme an den Untersuchungen lag überwiegend bei mehr als 95 %. Bei 96 % der MRT-Teilnehmerinnen und Teilnehmer konnten alle 12 MRT-Sequenzen vollständig durchgeführt werden. Der Erschließung und wissenschaftlichen Nutzung ergänzender Sekundär- und Registerdaten stimmten mehr als 90 % der Teilnehmerinnen und Teilnehmer zu. Diskussion Die Bereitschaft, möglichst alle Untersuchungsmodule durchzuführen, war trotz des zeitlichen Aufwandes außerordentlich hoch. Dadurch wird die NAKO zu einer zentralen Ressource für die epidemiologische Forschung in Deutschland. Sie wird es ermöglichen, neue Strategien zur Früherkennung, Vorhersage und Primärprävention chronischer Krankheiten zu entwickeln

Abstract: Hintergrund Eine Erhebung des respiratorischen Gesundheitszustandes auf Grundlage bundesweit einheitlich durchgeführter Lungenfunktionsmessungen lag in Deutschland bislang nicht vor. Dieser Beitrag beschreibt das Vorgehen bei der Untersuchung der Lungenfunktion in der NAKO Gesundheitsstudie und stellt erste Ergebnisse auf der Datenbasis zur Halbzeit der Basiserhebung vor. Material und Methoden Es wurden eine Spirometrie (Level 1) und eine Messung des exhalierten Stickstoffmonoxids (FeNO, Level 2) durchgeführt. Das Qualitätssicherungskonzept beinhaltete regelmäßige Schulungen der Lungenfunktionsprüfung an verschiedenen NAKO-Standorten, Zwischenauswertungen zur Untersuchungsqualität und regelmäßige Kalibrations-/Messkontrollen der Untersuchungsgeräte. Für die Spirometrie wurde zudem ein stufenweises Vorgehen zur Offlinequalitätskontrolle auf Basis der Fluss-Volumen-Rohkurven etabliert. Ergebnisse In den betrachteten Daten (n = 101.734) lag eine Spirometrie bei 86.893 Teilnehmenden und eine FeNO-Messung bei 15.228 Teilnehmenden vor. Es fand sich im Mittel (±SD) für die Einsekundenkapazität (FEV1) ein Z-Score (gemäß GLI 2012) von −0,321 ± 1,047, für die forcierte Vitalkapazität (FVC) ein Z-Score von −0,153 ± 0,941 und für den Tiffeneau-Index (FEV1/FVC) ein Z-Score von −0,337 ± 0,901. Die Differenz in FEV1/FVC zwischen Rauchern und Nie-Rauchern stieg mit dem Alter an. FeNO lag im geometrischen Mittel bei 14,2 ÷ 2,0 ppb, bei aktiven Rauchern war FeNO um 43 % vermindert, bei Nie-/Ex-Rauchern mit respiratorischer Allergie um 16 % erhöht. Diskussion Die Ergebnisse der Spirometrie und FeNO-Messungen liegen bezüglich ihrer Verteilungen und bekannter Einflussgrößen im erwarteten Bereich. Die NAKO liefert damit die Datenbasis zur Untersuchung der Atemwegsgesundheit und ihrer Determinanten sowie zur Eruierung der Möglichkeiten zur Prävention respiratorischer Erkrankungen in Deutschland