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Many tumors evolve sophisticated strategies to evade the immune system, and these represent major obstacles for efficient antitumor immune responses. Here we explored a molecular mechanism of metabolic communication deployed by highly glycolytic tumors for immunoevasion. In contrast to colon adenocarcinomas, melanomas showed comparatively high glycolytic activity, which resulted in high acidification of the tumor microenvironment. This tumor acidosis induced Gprotein–coupled receptor–dependent expression of the transcriptional repressor ICER in tumor-associated macrophages that led to their functional polarization toward a non-inflammatory phenotype and promoted tumor growth. Collectively, our findings identify a molecular mechanism of metabolic communication between non-lymphoid tissue and the immune system that was exploited by high-glycolytic-rate tumors for evasion of the immune system. Tumors can vary in both their control by immunosurveillance and their glycolytic activity. Bopp and colleagues demonstrate that highly glycolytic tumors acidify their microenvironment and use this to initiate a mechanism of localized immunosuppression.

Background Cardiovascular disease (CVD) is the leading cause of death worldwide and considered one of the most environmentally driven diseases. The role of DNA methylation in response to the individual exposure for the development and progression of CVD is still poorly understood and a synthesis of the evidence is lacking. Results A systematic review of articles examining measurements of DNA cytosine methylation in CVD was conducted in accordance with PRISMA (preferred reporting items for systematic reviews and meta-analyses) guidelines. The search yielded 5,563 articles from PubMed and CENTRAL databases. From 99 studies with a total of 87,827 individuals eligible for analysis, a database was created combining all CpG-, gene- and study-related information. It contains 74,580 unique CpG sites, of which 1452 CpG sites were mentioned in ≥ 2, and 441 CpG sites in ≥ 3 publications. Two sites were referenced in ≥ 6 publications: cg01656216 (near ZNF438 ) related to vascular disease and epigenetic age, and cg03636183 (near F2RL3 ) related to coronary heart disease, myocardial infarction, smoking and air pollution. Of 19,127 mapped genes, 5,807 were reported in ≥ 2 studies. Most frequently reported were TEAD1 (TEA Domain Transcription Factor 1) and PTPRN2 (Protein Tyrosine Phosphatase Receptor Type N2) in association with outcomes ranging from vascular to cardiac disease. Gene set enrichment analysis of 4,532 overlapping genes revealed enrichment for Gene Ontology molecular function “DNA-binding transcription activator activity” ( q  = 1.65 × 10 –11 ) and biological processes “skeletal system development” ( q  = 1.89 × 10 –23 ). Gene enrichment demonstrated that general CVD-related terms are shared, while “heart” and “vasculature” specific genes have more disease-specific terms as PR interval for “heart” or platelet distribution width for “vasculature.” STRING analysis revealed significant protein–protein interactions between the products of the differentially methylated genes ( p  = 0.003) suggesting that dysregulation of the protein interaction network could contribute to CVD. Overlaps with curated gene sets from the Molecular Signatures Database showed enrichment of genes in hemostasis ( p  = 2.9 × 10 –6 ) and atherosclerosis ( p  = 4.9 × 10 –4 ). Conclusion This review highlights the current state of knowledge on significant relationship between DNA methylation and CVD in humans. An open-access database has been compiled of reported CpG methylation sites, genes and pathways that may play an important role in this relationship.

Use of galectin-3 for assessing cardiac function in prediabetes and type 2 diabetes mellitus (T2DM) needs to be established. Within the Gutenberg Health Study cohort (N = 15,010, 35–74 years) patient characteristics were investigated regarding galectin-3 levels. Prognostic value of galectin-3 compared to NT-proBNP concerning cardiac function and mortality was assessed in individuals with euglycaemia, prediabetes and T2DM in 5 years follow-up. Higher galectin-3 levels related to older age, female sex and higher prevalence for prediabetes, T2DM, cardiovascular risk factors and comorbidities. Galectin-3 cross-sectionally was related to impaired systolic (β − 0.36, 95% CI − 0.63/− 0.09; P = 0.008) and diastolic function (β 0.014, 95% CI 0.001/0.03; P = 0.031) in T2DM and reduced systolic function in prediabetes (β − 0.34, 95% CI − 0.53/− 0.15; P = 0.00045). Galectin-3 prospectively related to systolic (β − 0.656, 95% CI − 1.07/− 0.24; P = 0.0021) and diastolic dysfunction (β 0.0179, 95% CI 0.0001/0.036; P = 0.049), cardiovascular (hazard ratio per standard deviation of galectin-3 (HR perSD ) 1.60, 95% CI 1.39–1.85; P < 0.0001) and all-cause mortality (HR perSD 1.36, 95% CI 1.25–1.47; P < 0.0001) in T2DM. No relationship between galectin-3 and cardiac function was found in euglycaemia, whereas NT-proBNP consistently related to reduced cardiac function. Prospective value of NT-proBNP on cardiovascular and all-cause mortality was higher. NT-proBNP was superior to galectin-3 to assess reduced systolic and diastolic function.

Distinct patterns of circulating microRNAs (miRNAs) were found to be involved in misguided thrombus resolution. Thus, we aimed to investigate dysregulated miRNA signatures during the acute phase of pulmonary embolism (PE) and test their diagnostic and predictive value for future diagnosis of chronic thromboembolic pulmonary hypertension (CTEPH). Microarray screening and subsequent validation in a large patient cohort (n = 177) identified three dysregulated miRNAs as potential biomarkers: circulating miR-29a and miR-720 were significantly upregulated and miR-let7a was significantly downregulated in plasma of patients with PE. In a second validation study equal expression patterns for miR-29a and miR-let7a regarding an acute event of recurrent venous thromboembolism (VTE) or deaths were found. MiR-let7a concentrations significantly correlated with echocardiographic and laboratory parameters indicating right ventricular (RV) dysfunction. Additionally, circulating miR-let7a levels were associated with diagnosis of CTEPH during follow-up. Regarding CTEPH diagnosis, ROC analysis illustrated an AUC of 0.767 (95% CI 0.54–0.99) for miR-let7a. Using logistic regression analysis, a calculated patient-cohort optimized miR-let7a cut-off value derived from ROC analysis of ≥ 11.92 was associated with a 12.8-fold increased risk for CTEPH. Therefore, miR-let7a might serve as a novel biomarker to identify patients with haemodynamic impairment and as a novel predictor for patients at risk for CTEPH.

Background The role of the BARD1 gene in breast cancer (BC) and ovarian cancer (OC) predisposition remains elusive, as published case-control investigations have revealed controversial results. We aimed to assess the role of deleterious BARD1 germline variants in BC/OC predisposition in a sample of 4920 BRCA1/2 -negative female BC/OC index patients of the German Consortium for Hereditary Breast and Ovarian Cancer (GC-HBOC). Methods A total of 4469 female index patients with BC, 451 index patients with OC, and 2767 geographically matched female control individuals were screened for loss-of-function (LoF) mutations and potentially damaging rare missense variants in BARD1 . All patients met the inclusion criteria of the GC-HBOC for germline testing and reported at least one relative with BC or OC. Additional control datasets (Exome Aggregation Consortium, ExAC; Fabulous Ladies Over Seventy, FLOSSIES) were included for the calculation of odds ratios (ORs). Results We identified LoF variants in 23 of 4469 BC index patients (0.51%) and in 36 of 37,265 control individuals (0.10%), resulting in an OR of 5.35 (95% confidence interval [CI] = 3.17–9.04; P  < 0.00001). BARD1- mutated BC index patients showed a significantly younger mean age at first diagnosis (AAD; 42.3 years, range 24–60 years) compared with the overall study sample (48.6 years, range 17–92 years; P  = 0.00347). In the subgroup of BC index patients with an AAD < 40 years, an OR of 12.04 (95% CI = 5.78–25.08; P  < 0.00001) was observed. An OR of 7.43 (95% CI = 4.26–12.98; P  < 0.00001) was observed when stratified for an AAD < 50 years. LoF variants in BARD1 were not significantly associated with BC in the subgroup of index patients with an AAD ≥ 50 years (OR = 2.29; 95% CI = 0.82–6.45; P  = 0.11217). Overall, rare and predicted damaging BARD1 missense variants were significantly more prevalent in BC index patients compared with control individuals (OR = 2.15; 95% CI = 1.26–3.67; P  = 0.00723). Neither LoF variants nor predicted damaging rare missense variants in BARD1 were identified in 451 familial index patients with OC. Conclusions Due to the significant association of germline LoF variants in BARD1 with early-onset BC, we suggest that intensified BC surveillance programs should be offered to women carrying pathogenic BARD1 gene variants.

Animal experiments and early phase human trials suggest that inhibition of factor XIa (FXIa) safely prevents venous thromboembolism (VTE), and specific murine models of sepsis have shown potential efficacy in alleviating cytokine storm. These latter findings support the role of FXI beyond coagulation. Here, we combine targeted proteomics, machine learning and bioinformatics, to discover associations between FXI activity (FXI:C) and the plasma protein profile of patients with VTE. FXI:C was measured with a modified activated partial prothrombin time (APTT) clotting time assay. Proximity extension assay-based protein profiling was performed on plasma collected from subjects from the Genotyping and Molecular Phenotyping of Venous Thromboembolism (GMP-VTE) Project, collected during an acute VTE event ( n  = 549) and 12-months after ( n  = 187). Among 444 proteins investigated, N  = 21 and N  = 66 were associated with FXI:C during the acute VTE event and at 12 months follow-up, respectively. Seven proteins were identified as FXI:C-associated at both time points. These FXI-related proteins were enriched in immune pathways related to causes of thrombo-inflammation, extracellular matrix interaction, lipid metabolism, and apoptosis. The results of this study offer important new avenues for future research into the multiple properties of FXI, which are of high clinical interest given the current development of FXI inhibitors.

Background Exposure to ionizing radiation induces complex stress responses in cells, which can lead to adverse health effects such as cancer. Although a variety of studies investigated gene expression and affected pathways in human fibroblasts after exposure to ionizing radiation, the understanding of underlying mechanisms and biological effects is still incomplete due to different experimental settings and small sample sizes. Therefore, this study aims to identify the time point with the highest number of differentially expressed genes and corresponding pathways in primary human fibroblasts after irradiation at two preselected time points. Methods Fibroblasts from skin biopsies of 15 cell donors were exposed to a high (2Gy) and a low (0.05Gy) dose of X-rays. RNA was extracted and sequenced 2 h and 4 h after exposure. Differentially expressed genes with an adjusted p -value < 0.05 were flagged and used for pathway analyses including prediction of upstream and downstream effects. Principal component analyses were used to examine the effect of two different sequencing runs on quality metrics and variation in expression and alignment and for explorative analysis of the radiation dose and time point of analysis. Results More genes were differentially expressed 4 h after exposure to low and high doses of radiation than after 2 h. In experiments with high dose irradiation and RNA sequencing after 4 h, inactivation of the FAT10 cancer signaling pathway and activation of gluconeogenesis I , glycolysis I, and prostanoid biosynthesis was observed taking p -value (< 0.05) and (in) activating z-score (≥2.00 or ≤ − 2.00) into account. Two hours after high dose irradiation, inactivation of small cell lung cancer signaling was observed. For low dose irradiation experiments, we did not detect any significant ( p  < 0.05 and z-score ≥ 2.00 or ≤ − 2.00) activated or inactivated pathways for both time points. Conclusions Compared to 2 h after irradiation, a higher number of differentially expressed genes were found 4 h after exposure to low and high dose ionizing radiation. Differences in gene expression were related to signal transduction pathways of the DNA damage response after 2 h and to metabolic pathways, that might implicate cellular senescence, after 4 h. The time point 4 h will be used to conduct further irradiation experiments in a larger sample.

Targeted proteomics utilizing antibody-based proximity extension assays provides sensitive and highly specific quantifications of plasma protein levels. Multivariate analysis of this data is hampered by frequent missing values (random or left censored), calling for imputation approaches. While appropriate missing-value imputation methods exist, benchmarks of their performance in targeted proteomics data are lacking. Here, we assessed the performance of two methods for imputation of values missing completely at random, the previously top-benchmarked ‘missForest’ and the recently published ‘GSimp’ method. Evaluation was accomplished by comparing imputed with remeasured relative concentrations of 91 inflammation related circulating proteins in 86 samples from a cohort of 645 patients with venous thromboembolism. The median Pearson correlation between imputed and remeasured protein expression values was 69.0% for missForest and 71.6% for GSimp (p = 5.8e-4). Imputation with missForest resulted in stronger reduction of variance compared to GSimp (median relative variance of 25.3% vs. 68.6%, p = 2.4e-16) and undesired larger bias in downstream analyses. Irrespective of the imputation method used, the 91 imputed proteins revealed large variations in imputation accuracy, driven by differences in signal to noise ratio and information overlap between proteins. In summary, GSimp outperformed missForest, while both methods show good overall imputation accuracy with large variations between proteins.

The correct Author names are presented in this paper.

The genetic etiology of sporadic childhood cancer cases remains unclear. We recruited a cohort of 20 patients who survived a childhood malignancy and then developed a second primary cancer (2N), and 20 carefully matched patients who survived a childhood cancer without developing a second malignancy (1N). Twenty matched cancer-free (0N) and additional 1000 (0N) GHS participants served as controls. Aiming to identify new candidate loci for cancer predisposition, we compared the genome-wide DNA copy number variations (CNV) with the RNA-expression data obtained after in vitro irradiation of primary fibroblasts. In 2N patients, we detected a total of 142 genes affected by CNV. A total of 53 genes of these were not altered in controls. Six genes (POLR3F, SEC23B, ZNF133, C16orf45, RRN3, and NTAN1) that we found to be overexpressed after irradiation were also duplicated in the genome of the 2N patients. For the 1N collective, 185 genes were affected by CNV and 38 of these genes were not altered in controls. Five genes (ZCWPW2, SYNCRIP, DHX30, DHRS4L2, and THSD1) were located in duplicated genomic regions and exhibited altered RNA expression after irradiation. One gene (ABCC6) was partially duplicated in one 1N and one 2N patient. Analysis of methylation levels of THSD1 and GSTT2 genes which were detected in duplicated regions and are frequently aberrantly methylated in cancer showed no changes in patient’s fibroblasts. In summary, we describe rare and radiation-sensitive genes affected by CNV in childhood sporadic cancer cases, which may have an impact on cancer development.Key messages• Rare CNV’s may have an impact on cancer development in sporadic, non-familial, non-syndromic childhood cancer cases.• In our cohort, each patient displayed a unique pattern of cancer-related gene CNVs, and only few cases shared similar CNV.• Genes that are transcriptionally regulated after radiation can be located in CNVs in cancer patients and controls.• THSD1 and GSTT2 methylation is not altered by CNV.