Sex-biased genetic regulation of inflammatory proteins in the Dutch population.

BACKGROUND: Significant differences in immune responses, prevalence or susceptibility of diseases and treatment responses have been described between males and females. Despite this, sex-differentiation analysis of the genetic architecture of inflammatory proteins is largely unexplored. We performed sex-stratified meta-analysis after protein quantitative trait loci (pQTL) mapping using inflammatory biomarkers profiled using targeted proteomics (Olink inflammatory panel) of two population-based cohorts of Europeans. RESULTS: Even though, around 67% of the pQTLs demonstrated shared effect between sexes, colocalization analysis identified two loci in the males (LINC01135 and ITGAV) and three loci (CNOT10, SRD5A2, and LILRB5) in the females with evidence of sex-dependent modulation by pQTL variants. Furthermore, we identified pathways with relevant functions in the sex-biased pQTL variants. We also showed through cross-validation that the sex-specific pQTLs are linked with sex-specific phenotypic traits. CONCLUSION: Our study demonstrates the relevance of genetic sex-stratified analysis in the context of genetic dissection of protein abundances among individuals and reveals that, sex-specific pQTLs might mediate sex-linked phenotypes. Identification of sex-specific pQTLs associated with sex-biased diseases can help realize the promise of individualized treatment.

Impact of variant histology on upstaging and survival in patients with nonmuscle invasive bladder cancer undergoing radical cystectomy.

INTRODUCTION: Variant histology (VH) of urothelial carcinoma is uncommon and frequently presents at the muscle-invasive stage. VH is considering a significant risk factor for progression among patients with nonmuscle invasive bladder cancer (NMIBC). While there is some debate, expert opinion is generally that upfront radical cystectomy (RC) should be consider for these patients. Limited data exists to support this position. In this study, we sought to examine the rate of upstaging and overall survival for patients with VH NMIBC against patients with pure urothelial NMIBC who underwent RC, to help clarify the optimal treatment strategy for these patients. METHODS: The institutional REDCap database was utilized to identify all patients with T1 and Ta bladder cancer that underwent RC over the study period (2004-2022). Matched-pair analysis was performed between patients with VH and pure urothelial NMIBC; 42 pairs were matched on prior intravesical therapy, presence of muscularis propria on transurethral resection of bladder tumor (TURBT), any carcinoma in situ presence on prior TURBTs, and final tumor staging on TURBT. The primary outcomes of interest were pathologic tumor upstaging rate at RC and overall survival. Secondary outcomes of interest included association of demographic or pretreatment variables with upstaging, and upstaging rates for specific variant histologies. RESULTS: Patients with VH NMIBC undergoing RC were upstaged at a significantly higher rate than a matched cohort of patients with pure urothelial NMIBC (73.8% vs. 52.4%, P = 0.0244) and among those upstaged, had significantly higher rates of pT3 to pT4 (54.7% vs. 23.8%, P = 0.0088). Rate of node positivity at RC for VH NMIBC was also higher compared to pure urothelial NMIBC (40.5% vs. 21.4%, P = 0.0389). Among histologic variants, patients with plasmacytoid and sarcomatoid subtypes demonstrated the highest rates of upstaging; differences were not statistically significant. The overall median survival was 28.4 months for patients with VH after RC compared to 155.1 months for patients with pure urothelial NMIBC (P = 0.009). CONCLUSION: Patients with VH NMIBC undergoing RC are at significantly higher risk of upstaging at RC when compared to patients with pure urothelial NMIBC and have worse overall survival. While this study supports the concept of an aggressive treatment approach for patients with VH NMIBC, improvements in understanding of the disease are necessary to improve outcomes.

Candida albicans extracellular vesicles trigger type I IFN signalling via cGAS and STING.

The host type I interferon (IFN) pathway is a major signature of inflammation induced by the human fungal pathogen, Candida albicans. However, the molecular mechanism for activating this pathway in the host defence against C. albicans remains unknown. Here we reveal that mice lacking cyclic GMP-AMP synthase (cGAS)-stimulator of IFN genes (STING) pathway components had improved survival following an intravenous challenge by C. albicans. Biofilm-associated C. albicans DNA packaged in extracellular vesicles triggers the cGAS-STING pathway as determined by induction of interferon-stimulated genes, IFNß production, and phosphorylation of IFN regulatory factor 3 and TANK-binding kinase 1. Extracellular vesicle-induced activation of type I IFNs was independent of the Dectin-1/Card9 pathway and did not require toll-like receptor 9. Single nucleotide polymorphisms in cGAS and STING potently altered inflammatory cytokine production in human monocytes challenged by C. albicans. These studies provide insights into the early innate immune response induced by a clinically significant fungal pathogen.

A systems approach to inflammation identifies therapeutic targets in SARS-CoV-2 infection

BackgroundInfection with SARS-CoV-2 manifests itself as a mild respiratory tract infection in the majority of individuals, which progresses to a severe pneumonia and acute respiratory distress syndrome (ARDS) in 10-15% of patients. Inflammation plays a crucial role in the pathogenesis of ARDS, with immune dysregulation in severe COVID-19 leading to a hyperinflammatory response. A comprehensive understanding of the inflammatory process in COVID-19 is lacking. MethodsIn this prospective, multicenter observational study, patients with PCR-proven or clinically presumed COVID-19 admitted to the intensive care unit (ICU) or clinical wards were included. Demographic and clinical data were obtained and plasma was serially collected. Concentrations of IL-6, TNF-, complement components C3a, C3c and the terminal complement complex (TCC) were determined in plasma by ELISA. Additionally, 269 circulating biomarkers were assessed using targeted proteomics. Results were compared between ICU and non ICU patients. FindingsA total of 119 (38 ICU and 91 non ICU) patients were included. IL-6 plasma concentrations were elevated in COVID-19 (ICU vs. non ICU, median 174.5 pg/ml [IQR 94.5-376.3] vs. 40.0 pg/ml [16.5-81.0]), whereas TNF- concentrations were relatively low and not different between ICU and non ICU patients (median 24.0 pg/ml [IQR 16.5-33.5] and 21.5 pg/ml [IQR 16.0-33.5], respectively). C3a and terminal complement complex (TCC) concentrations were significantly higher in ICU vs. non ICU patients (median 556.0 ng/ml [IQR 333.3-712.5]) vs. 266.5 ng/ml [IQR 191.5-384.0] for C3a and 4506 mAU/ml [IQR 3661-6595] vs. 3582 mAU/ml [IQR 2947-4300] for TCC) on the first day of blood sampling. Targeted proteomics demonstrated that IL-6 (logFC 2.2), several chemokines and hepatocyte growth factor (logFC 1.4) were significantly upregulated in ICU vs. non ICU patients. In contrast, stem cell factor was significantly downregulated (logFC -1.3) in ICU vs. non ICU patients, as were DPP4 (logFC -0.4) and protein C inhibitor (log FC -1.0), the latter two factors also being involved in the regulation of the kinin-kallikrein pathway. Unsupervised clustering pointed towards a homogeneous pathogenetic mechanism in the majority of patients infected with SARS-CoV-2, with patient clustering mainly based on disease severity. InterpretationWe identified important pathways involved in dysregulation of inflammation in patients with severe COVID-19, including the IL-6, complement system and kinin-kallikrein pathways. Our findings may aid the development of new approaches to host-directed therapy. FundingVidi grant (F.L.v.d.V.) and Spinoza grant (M.G.N.) from the Netherlands Organization for Scientific Research, and ERC Advanced Grant (#833247 to M.G.N.).