Immune signatures predict development of autoimmune toxicity in patients with cancer treated with immune checkpoint inhibitors.

BACKGROUND Immune checkpoint inhibitors (ICIs) are among the most promising treatment options for melanoma and non-small cell lung cancer (NSCLC). While ICIs can induce effective anti-tumor responses, they may also drive serious immune-related adverse events (irAEs). Identifying biomarkers to predict which patients will suffer from irAEs would enable more accurate clinical risk-benefit analysis for ICI treatment and may also shed light on common or distinct mechanisms underpinning treatment success and irAEs. METHODS In this prospective multi-center study, we combined a multi-omics approach including unbiased single-cell profiling of over 300 peripheral blood mononuclear cell (PBMC) samples and high-throughput proteomics analysis of over 500 serum samples to characterize the systemic immune compartment of patients with melanoma or NSCLC before and during treatment with ICIs. FINDINGS When we combined the parameters obtained from the multi-omics profiling of patient blood and serum, we identified potential predictive biomarkers for ICI-induced irAEs. Specifically, an early increase in CXCL9/CXCL10/CXCL11 and interferon-γ (IFN-γ) 1 to 2 weeks after the start of therapy are likely indicators of heightened risk of developing irAEs. In addition, an early expansion of Ki-67+ regulatory T cells (Tregs) and Ki-67+ CD8+ T cells is also likely to be associated with increased risk of irAEs. CONCLUSIONS We suggest that the combination of these cellular and proteomic biomarkers may help to predict which patients are likely to benefit most from ICI therapy and those requiring intensive monitoring for irAEs. FUNDING This work was primarily funded by the European Research Council, the Swiss National Science Foundation, the Swiss Cancer League, and the Forschungsförderung of the Kantonsspital St. Gallen

Disorders of sex development : insights from targeted gene sequencing of a large international patient cohort

Background: Disorders of sex development (DSD) are congenital conditions in which chromosomal, gonadal, or phenotypic sex is atypical. Clinical management of DSD is often difficult and currently only 13% of patients receive an accurate clinical genetic diagnosis. To address this we have developed a massively parallel sequencing targeted DSD gene panel which allows us to sequence all 64 known diagnostic DSD genes and candidate genes simultaneously. Results: We analyzed DNA from the largest reported international cohort of patients with DSD (278 patients with 46, XY DSD and 48 with 46, XX DSD). Our targeted gene panel compares favorably with other sequencing platforms. We found a total of 28 diagnostic genes that are implicated in DSD, highlighting the genetic spectrum of this disorder. Sequencing revealed 93 previously unreported DSD gene variants. Overall, we identified a likely genetic diagnosis in 43% of patients with 46, XY DSD. In patients with 46, XY disorders of androgen synthesis and action the genetic diagnosis rate reached 60%. Surprisingly, little difference in diagnostic rate was observed between singletons and trios. In many cases our findings are informative as to the likely cause of the DSD, which will facilitate clinical management. Conclusions: Our massively parallel sequencing targeted DSD gene panel represents an economical means of improving the genetic diagnostic capability for patients affected by DSD. Implementation of this panel in a large cohort of patients has expanded our understanding of the underlying genetic etiology of DSD. The inclusion of research candidate genes also provides an invaluable resource for future identification of novel genes

'Les Indes africaines' versus 'Le Congo minotaure' : debatten over klimaat, acclimatisatie, hygiëne en de idealisering van het imperiaal project van Leopold II in Congo, 1876-1908

Dit artikel is een onderzoek naar de relatie tussen debatten in België over het klimaat van Congo en de daaraan verbonden vermeende gezondheid of ongezondheid van het gebied, en de politieke agenda’s van de bijdragers aan dit debat voor de periode vanaf het begin van de Leopoldiaanse exploratie van Midden-Afrika in 1876 tot aan de overdracht van de Onafhankelijke Congostaat aan België in 1908. Vanaf het begin van die exploratie was er aandacht voor het klimaat. Zo werden er meteorologische gegevens over de verkende en geannexeerde gebieden verzameld en werd het klimaat vaak afgeschilderd als een onbekend kwaad : het werd als uiterst ongezond beschouwd. Zowel gruwelijke als fortuinlijke verhalen afkomstig van andere imperiale mogendheden over soortgelijke gebieden waren van invloed op het denken over het klimaat. Om Congo te promoten als lucratief en niet ongezond gebied, iets wat de voorstanders van het imperiale project graag deden, was het belangrijk om het kwade beeld over het klimaat te bevechten. De mening over het klimaat, en of de witte man kon acclimatiseren in Congo, werd dus niet enkel beïnvloed door de daadwerkelijke omstandigheden aldaar, maar in grote mate door de vraag of men Congo als een goed exploitatieterrein voor de Belgen zag. In dit artikel wordt behalve het geven van een algemene analyse van de debatten en hoe zij zich verhouden tot internationale ontwikkelingen op het gebied van bijvoorbeeld de koloniale hygiëne, ook ingezoomd op het discours van opponenten in een aantal uitgelichte discussies

Social Reform International Congresses and Organizations (1846–1914): From Sources to Data

TIC-Collaborative was a collaborative digital humanities project that focused on transnational intellectual cooperation (TIC) in the long nineteenth century, in particular on transnational connections in the field of social reform. The dataset contains information on over 1650 international congresses and 450 organizations and conference series related to the social question. The project focussed on the Low Countries and a selection of reform areas

Additional file 2: Figure S1. of Disorders of sex development: insights from targeted gene sequencing of a large international patient cohort

DSD gene variants in different global regions. DSD gene variants among the international cohort of 46,XY DSD patients. For ease of analysis, countries were grouped together into regions: Asia comprises Indonesia (97), Pakistan (25), Vietnam (35), Cambodia (16), India (1), a total of 174 patients ; Europe comprises the Netherlands (38), Austria (15), Belgium (6), and Italy (2), a total of 61 patients; and AUS & NZL comprises Australia (83) and New Zealand (7), a total of 90 patients. All curated variants are shown; those which have been curated and called pathogenic, likely pathogenic, and VUS. In the cohort from Asia, 35% of the patients were found to have a diagnostic variant (pathogenic or likely pathogenic), while this was 44% for Europe and 45% for AUS/NZL. Two patients from Canada were not included in the diagram. (PPTX 158 kb