Role of interleukin-7 in degenerative and inflammatory joint diseases

IL-7 is known foremost for its immunostimulatory capacities, including potent T cell-dependent catabolic effects on bone. In joint diseases like rheumatoid arthritis and osteoarthritis, IL-7, via immune activation, can induce joint destruction. Now it has been demonstrated that increased IL-7 levels are produced by human articular chondrocytes of older individuals and osteoarthritis patients. IL-7 stimulates production of proteases by IL-7 receptor-expressing chondrocytes and enhances cartilage matrix degradation. This indicates that IL-7, indirectly via immune activation, but also by a direct action on cartilage, contributes to joint destruction in rheumatic diseases

MMsPred: a bioactivity and toxicology predictive system

In the last decade, the development and use of new methods in combinatorial chemistry and high-throughput screening has dramatically increased the number of known biologically active compounds. Paradoxically, the number of drugs reaching the market has not followed the same trend, often because many of the candidate drugs present poor qualities in absorption, distribution, metabolism, excretion, and toxicological properties (ADME-Tox). The ability to recognize and discard bad candidates early in the drug discovery steps would save lost investments in time and money. Machine learning techniques could provide solutions to this problem.
The goal of my research is to develop classifiers that accurately discriminate between active and inactive molecules for a specific target. To this end, I am comparing the effectiveness of the application of different machine learning techniques to this problem.	As a source of data we have selected a set of PubChem's public BioAssays1. In addition, with the objective of realizing a real-time query service with our predictors, we aim to keep the features describing the chemical compounds relatively simple.
At the end of this process, we should better understand how to build statistical models that are able to recognize molecules active in a specific bioassay, including how to select the most appropriate classification technique, and how to describe compounds in such a way that is not excessively resource-consuming to generate, yet contains sufficient information for the classification. We see immediate applications of such technology to recognize compounds with high-risk of toxicity, and also to suggest likely metabolic pathways that would process it

Body height among adult male and female Swiss Health Survey participants in 2017: Trends by birth years and associations with self-reported health status and life satisfaction

The increase in adult height for 150 years is linked to overall improvements in nutrition, hygiene, and living standards. Height is positively associated with general health and success on various levels (e.g. quality of life, earnings or happiness). The aim of this study was to investigate whether different subgroups show different trends across birth cohorts. We wanted to know whether taller individuals considered themselves as healthier and their quality of life as better than shorter individuals. We included 19,435 participants from the Swiss population-based Health Survey 2017. GAM were used to assess nonlinear associations between height and birth year. Multinomial logistic regression was used to predict probabilities of self-rated health in relation to height. The increase in average height slows down from the 1970s birth cohorts. Participants with parents from Central/Northern/Western Europe (men 177.9 cm, women: 165.1 cm) or Eastern Europe (men 178.7 cm, women: 165.7 cm) were taller than participants with parents from South America (men 174.3 cm, women: 161. cm) and Asia (men 173.2 cm, women: 160.1 cm). Participants with tertiary education were taller than participants from education levels (mean difference men: 4.5 cm, women: 5.0 cm). Height was positively associated with self-declared aspects of health and life satisfaction. These results support the conclusion that body height as a co-factor of health aspects should be considered in public health research. Although adult body height can no longer be influenced, nutritional status and thus also healthy growth can be influenced in childhood by public health programs, by eliminating social inequalities, and by strengthen healthy living conditions

Reinfections and Cross-Protection in the 1918/19 Influenza Pandemic: Revisiting a Survey Among Male and Female Factory Workers

Objectives: The COVID-19 pandemic highlights questions regarding reinfections and immunity resulting from vaccination and/or previous illness. Studies addressing related questions for historical pandemics are limited.Methods: We revisit an unnoticed archival source on the 1918/19 influenza pandemic. We analysed individual responses to a medical survey completed by an entire factory workforce in Western Switzerland in 1919.Results: Among the total of n = 820 factory workers, 50.2% reported influenza-related illness during the pandemic, the majority of whom reported severe illness. Among male workers 47.4% reported an illness vs. 58.5% of female workers, although this might be explained by varied age distribution for each sex (median age was 31 years old for men, vs. 22 years old for females). Among those who reported illness, 15.3% reported reinfections. Reinfection rates increased across the three pandemic waves. The majority of subsequent infections were reported to be as severe as the first infection, if not more. Illness during the first wave, in the summer of 1918, was associated with a 35.9% (95%CI, 15.7–51.1) protective effect against reinfections during later waves.Conclusion: Our study draws attention to a forgotten constant between multi-wave pandemics triggered by respiratory viruses: Reinfection and cross-protection have been and continue to be a key topic for health authorities and physicians in pandemics, becoming increasingly important as the number of waves increases

Short-termed changes in quantitative ultrasound estimated bone density among young men in an 18-weeks follow-up during their basic training for the Swiss Armed Forces

Background Quantitative Ultrasound (QUS) methods have been widely used to assess estimated bone density. This study aimed to assess changes in estimated bone density in association with changes in body composition, physical activity, and anthropometry. Methods We examined changes in anthropometry, body composition, and physical activity associated with changes in estimated bone mineral density (measured using quantitative ultrasound with a heel ultrasound device indicating broadband ultrasound attenuation BUA and speed of sound SOS) in a follow-up sample of n = 73 young men at the beginning and again 18 weeks later at the end of basic military training. Results At the end of the basic training, the subjects were on average significantly heavier (+1.0%), slightly taller (+0.5%) and had a higher fat mass (+6.6%) and grip strength (+8.6%). A significant decrease in mean physical activity (−49.5%) and mean estimated bone density calculated with BUA (−7.5%) was observed in the paired t-test. The results of the multivariable linear regressions (backward selection) show that changes in skeletal muscle mass (delta = 2nd measurement minus 1st measurement) have negative and body weight (delta) have positive association with the speed of sound SOS (delta), while fat mass (delta) and physical activity (delta) had the strongest negative associations with estimated bone mineral density (delta). In particular, we found a negative association between fat mass (delta) and estimated bone mineral density (delta, estimated with BUA). Conclusion Our study suggests that estimated bone density from the calcaneus can change within a few months even in young and mostly healthy individuals, depending upon physical activity levels and other co-factors. Further studies including other troop types as control groups as well as on women should follow in order to investigate this public health relevant topic in more depth. To what extent the estimated bone density measurement with quantitative ultrasound is clinically relevant needs to be investigated in further studies

MMsINC: a large-scale chemoinformatics database

MMsINC (http://mms.dsfarm.unipd.it/MMsINC/search) is a database of non-redundant, richly annotated and biomedically relevant chemical structures. A primary goal of MMsINC is to guarantee the highest quality and the uniqueness of each entry. MMsINC then adds value to these entries by including the analysis of crucial chemical properties, such as ionization and tautomerization processes, and the in silico prediction of 24 important molecular properties in the biochemical profile of each structure. MMsINC is consequently a natural input for different chemoinformatics and virtual screening applications. In addition, MMsINC supports various types of queries, including substructure queries and the novel ‘molecular scissoring’ query. MMsINC is interfaced with other primary data collectors, such as PubChem, Protein Data Bank (PDB), the Food and Drug Administration database of approved drugs and ZINC

Das Gewicht der Schweiz: Eine quantitative Synthesestudie zum Body Mass Index und Bauchumfang sowie den damit verbundenen Kofaktoren bei erwachsenen Männern und Frauen in der Schweiz

Übergewicht wird multifaktoriell verursacht und hat in der Schweiz seit den 1990er Jahren stark zugenommen. Eine breit abgestützte Untersuchung der involvierten Kofaktoren würde es ermöglichen, Risikofaktoren und damit auch Interventionsprogramme präziser als bisher zu definieren. Für die erwachsene Bevölkerung in der Schweiz wurden bisher die bestehenden gesamtschweizerischen bevölkerungsweiten Studien zu Übergewicht noch nie zusammengefasst in einer Synthesestudie ausgewertet. Wir haben alle uns bekannten gesamtschweizerischen und bevölkerungsbezogenen Studien aus den Bereichen Gesundheit, Ernährung und Wirtschaft zusammengetragen, die auch Informationen über den Body Mass Index (BMI) sowie wenn möglich auch zu Bauchumfang/Taillenumfang (Waist Circumference, WC) und Waist-to-Height-Ratio (WHtR) enthielten. Eingeschlossen wurden die Nationale Ernährungserhebung Schweiz (menuCH, 2014/2015), die Schweizerischen Gesundheitsbefragungen 2012 und 2017, das Swiss Household Panel 2013-2017, die Schweizer Erhebung über Einkommen & Lebensbedingungen (SILC, 2017), das Swiss Food Panel (2010 und 2017) sowie der Swiss Survey on Salt Intake (2010/2011). Wir haben die mehrheitlich repräsentativen Datensätze nicht gepoolt, sondern mittels mixed multinomial logistic Regressionsanalysen übergreifende Gesamteffekte geschätzt. Zusätzlich haben wir die anthropometrischen Monitoring-Daten der Stellungspflichtigen 2019 vergleichend hinzugezogen. Grundsätzlich sind von zehn erwachsenen Menschen in der Schweiz rund drei Personen (31.7 %) von Übergewicht und rund eine Person (11.2 %) von Adipositas betroffen. Die Analyse der acht bevölkerungsbasierten Studien zeigt, dass die Kofaktoren Geschlecht, Alter, Bildung, Körperhöhe, Sprachregion und körperliche Aktivität signifikant mit dem BMI zusammenhängen. Betrachtet man auch die Kofaktoren, welche nicht in allen Studien erhoben worden sind, dann finden sich weitere signifikante Assoziationen zu Stadt/Land, Nationalität, Fleischkonsum, Konsum von Süssgetränken, Einhalt der Empfehlungen zu körperlicher Aktivität, selbsteingeschätztem Gesundheitszustand und Schlafstörungen. Die Daten der Stellungspflichtigen für die Armee decken sich in der Aussagerichtung weitgehend mit diesem Bild: Der BMI der jungen Schweizer Männer 2019 ist assoziiert mit Alter, Körperhöhe, Sprachregionen, Stadt/Land, sozioökonomischem Berufsstatus, sozioökonomischem Nachbarschaftsindex, Blutdruck und Leistung im Sporttest. Die vergleichende Analyse zwischen BMI, WC und WHtR in den beiden populationsbasierten Studien menuCH und Swiss Salt Survey sowie bei den Stellungspflichtigen zeigt einerseits eine weitgehende Kongruenz zwischen den anthropometrischen Massen auf, anderseits aber auch den Mehrwert des WHtR, welcher den WC relativiert zur Körperhöhe und zu mehr akzentuierten Koeffizienten führt. Unsere Resultate zur Bedeutung der Körperhöhe als relevanter Kofaktor bestätigen, dass es sich beider Prävention von Übergewicht gleich mehrfach lohnt, bereits im Kindesalter anzusetzen: Einerseits wird dadurch ein günstiger kindlicher Gesundheitsstatus (Balance zwischen Ernährung, Bewegung und Gesundheit) gefördert, welcher sich auch auf das Wachstum auswirkt, andererseits werden damit früh gesundheitsrelevante Verhaltensmuster erlernt (Ernährung, Schlaf, Bewegung), was ebenfalls bis ins Erwachsenenleben nachwirkt. Dieser Ansatz ist ganz im Sinne des Life Course Approach to Health, wie er beispielweise auch in der NCD-Strategie des Bundesrates eingeflossen ist. Weiter haben sich in unseren Modellen die soziodemografischen Faktoren als besonders wichtig herausgestellt. Zukünftige Studien sollten Interaktionen zwischen soziodemografischen Faktoren, Lebensstilfaktoren und Gesundheitsfaktoren, welche für einzelne Datensätze gut dokumentiert sind, ebenfalls im Sinne einer Synthese über verschiedene Datensätze hinweg untersuchen. Unsere Ergebnisse schlagen vor, dabei ein besonderes Augenmerk auf Süssgetränke, Schlafstörungen und den selbsteingeschätzten Gesundheitszustand zu legen

Pitfalls in assessing stromal tumor infiltrating lymphocytes (sTILs) in breast cancer

Stromal tumor-infiltrating lymphocytes (sTILs) are important prognostic and predictive biomarkers in triple-negative (TNBC) and HER2-positive breast cancer. Incorporating sTILs into clinical practice necessitates reproducible assessment. Previously developed standardized scoring guidelines have been widely embraced by the clinical and research communities. We evaluated sources of variability in sTIL assessment by pathologists in three previous sTIL ring studies. We identify common challenges and evaluate impact of discrepancies on outcome estimates in early TNBC using a newly-developed prognostic tool. Discordant sTIL assessment is driven by heterogeneity in lymphocyte distribution. Additional factors include: technical slide-related issues; scoring outside the tumor boundary; tumors with minimal assessable stroma; including lymphocytes associated with other structures; and including other inflammatory cells. Small variations in sTIL assessment modestly alter risk estimation in early TNBC but have the potential to affect treatment selection if cutpoints are employed. Scoring and averaging multiple areas, as well as use of reference images, improve consistency of sTIL evaluation. Moreover, to assist in avoiding the pitfalls identified in this analysis, we developed an educational resource available at www.tilsinbreastcancer.org/pitfalls.Stromal tumor-infiltrating lymphocytes (sTILs) are important prognostic and predictive biomarkers in triple-negative (TNBC) and HER2-positive breast cancer. Incorporating sTILs into clinical practice necessitates reproducible assessment. Previously developed standardized scoring guidelines have been widely embraced by the clinical and research communities. We evaluated sources of variability in sTIL assessment by pathologists in three previous sTIL ring studies. We identify common challenges and evaluate impact of discrepancies on outcome estimates in early TNBC using a newly-developed prognostic tool. Discordant sTIL assessment is driven by heterogeneity in lymphocyte distribution. Additional factors include: technical slide-related issues; scoring outside the tumor boundary; tumors with minimal assessable stroma; including lymphocytes associated with other structures; and including other inflammatory cells. Small variations in sTIL assessment modestly alter risk estimation in early TNBC but have the potential to affect treatment selection if cutpoints are employed. Scoring and averaging multiple areas, as well as use of reference images, improve consistency of sTIL evaluation. Moreover, to assist in avoiding the pitfalls identified in this analysis, we developed an educational resource available at www.tilsinbreastcancer.org/pitfalls.Peer reviewe

Comprehensive and Integrated Genomic Characterization of Adult Soft Tissue Sarcomas

Sarcomas are a broad family of mesenchymal malignancies exhibiting remarkable histologic diversity. We describe the multi-platform molecular landscape of 206 adult soft tissue sarcomas representing 6 major types. Along with novel insights into the biology of individual sarcoma types, we report three overarching findings: (1) unlike most epithelial malignancies, these sarcomas (excepting synovial sarcoma) are characterized predominantly by copy-number changes, with low mutational loads and only a few genes (, , ) highly recurrently mutated across sarcoma types; (2) within sarcoma types, genomic and regulomic diversity of driver pathways defines molecular subtypes associated with patient outcome; and (3) the immune microenvironment, inferred from DNA methylation and mRNA profiles, associates with outcome and may inform clinical trials of immune checkpoint inhibitors. Overall, this large-scale analysis reveals previously unappreciated sarcoma-type-specific changes in copy number, methylation, RNA, and protein, providing insights into refining sarcoma therapy and relationships to other cancer types