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Endothelial cells represent major effectors in inflammation and angiogenesis, processes that drive a multitude of pathological states such as atherosclerosis and cancer. Both inflammation and angiogenesis are interconnected with each other in the sense that many pro-inflammatory proteins possess proangiogenic properties and vice versa. To elucidate this interplay further, we present a comparative proteome study of inflammatory and angiogenic activated endothelial cells. HUVEC were stimulated with interleukin 1-β and VEGF, respectively. Cultured primary cells were fractionated into secreted, cytoplasmic and nuclear protein fractions and processed for subsequent LC-MS/MS analysis. Obtained protein profiles were filtered for fraction-specific proteins to address potential cross fractional contamination, subjected to comparative computational biology analysis (GO-Term enrichment analysis, weighted gene co-expression analysis) and compared to published mRNA profiles of IL-1β respectively VEGF stimulated HUVEC. GO Term enrichment analysis and comparative pathway analysis revealed features such as NOD and NfkB signaling for inflammatory activated HUVEC and VEGF and ErB signaling for VEGF-activated HUVEC with potential crosstalk via map kinases MAP2K2. Weighted protein co-expression network analysis revealed several potential hub genes so far not associated with driver function in inflammation or angiogenesis such as HSPG2, ANXA3, and GPI. \"Classical\" inflammation or angiogenesis markers such as IL6, CXCL8 or CST1 were found in a less central position within the co-expression networks. In conclusion, this study reports a framework for the computational biology based analysis of proteomics data applied to cytoplasmic, nucleic and extracellular fractions of quiescent, inflammatory and angiogenic activated HUVEC. Novel potential hub genes relevant for these processes were successfully identified.

Besides human red blood cells (RBC), a standard model used in AFM-single cell force spectroscopy (SCFS), little is known about apparent Young’s modulus (Ea) or adhesion of animal RBCs displaying distinct cellular features. To close this knowledge gap, we probed chicken, horse, camel, and human fetal RBCs and compared data with human adults serving as a repository for future studies. Additionally, we assessed how measurements are affected under physiological conditions (species-specific temperature in autologous plasma vs. 25 °C in aqueous NaCl solution). In all RBC types, Ea decreased with increasing temperature irrespective of the suspension medium. In mammalian RBCs, adhesion increased with elevated temperatures and scaled with reported membrane sialic acid concentrations. In chicken only adhesion decreased with higher temperature, which we attribute to the lower AE-1 concentration allowing more membrane undulations. Ea decreased further in plasma at every test temperature, and adhesion was completely abolished, pointing to functional cell enlargement by adsorption of plasma components. This halo elevated RBC size by several hundreds of nanometers, blunted the thermal input, and will affect the coupling of RBCs with the flowing plasma. The study evidences the presence of a RBC surface layer and discusses the tremendous effects when RBCs are probed at physiological conditions.

Several pathways modulating longevity and stress resistance converge on translation by targeting ribosomal proteins or initiation factors, but whether this involves modifications of ribosomal RNA is unclear. Here, we show that reduced levels of the conserved RNA methyltransferase NSUN5 increase the lifespan and stress resistance in yeast, worms and flies. Rcm1, the yeast homologue of NSUN5, methylates C2278 within a conserved region of 25S rRNA. Loss of Rcm1 alters the structural conformation of the ribosome in close proximity to C2278, as well as translational fidelity, and favours recruitment of a distinct subset of oxidative stress-responsive mRNAs into polysomes. Thus, rather than merely being a static molecular machine executing translation, the ribosome exhibits functional diversity by modification of just a single rRNA nucleotide, resulting in an alteration of organismal physiological behaviour, and linking rRNA-mediated translational regulation to modulation of lifespan, and differential stress response. Cellular pathways modulating longevity and stress resistance are known to affect protein translation. Here the authors show that the RNA methyltransferase, Nsun5, or its yeast homologue Rcm1, regulates lifespan of three different model organisms by modifying ribosomal RNA at a specific cytosine residue.

FAM3C/ILEI is an important cytokine for tumor progression and metastasis. However, its involvement in inflammation remains elusive. Here, we show that ILEI protein is highly expressed in psoriatic lesions. Inducible keratinocyte‐specific ILEI overexpression in mice ( K5‐ILEI ind ) recapitulates many aspects of psoriasis following TPA challenge, primarily manifested by impaired epidermal differentiation and increased neutrophil recruitment. Mechanistically, ILEI triggers Erk and Akt signaling, which then activates STAT3 via Ser727 phosphorylation. Keratinocyte‐specific ILEI deletion ameliorates TPA‐induced skin inflammation. A transcriptomic ILEI signature obtained from the K5 ‐ ILEI ind model shows enrichment in several signaling pathways also found in psoriasis and identifies urokinase as a targetable enzyme to counteract ILEI activity. Pharmacological inhibition of urokinase in TPA‐induced K5‐ILEI ind mice results in significant improvement of psoriasiform symptoms by reducing ILEI secretion. The ILEI signature distinguishes psoriasis from healthy skin with uPA ranking among the top “separator” genes. Our study identifies ILEI as a key driver in psoriasis, indicates the relevance of ILEI‐regulated genes for disease manifestation, and shows the clinical impact of ILEI and urokinase as novel potential therapeutic targets in psoriasis. Synopsis Analyses of human psoriatic skin and studies in genetically engineered mouse models revealed that FAM3C/ILEI contributes to psoriasis by controlling keratinocyte hyperproliferation, differentiation and neutrophil recruitment and identifies uPA, a regulator of ILEI secretion, as a druggable target. ILEI protein expression and regulators of its translation and activation were upregulated in psoriatic skin lesions. Mice with keratinocyte‐specific ILEI overexpression ( K5‐ILEI ind ) developed psoriasis‐like skin symptoms following TPA challenge. Keratinocyte‐specific ILEI overexpression contributed to impaired differentiation, increased hyperproliferation, and transcriptional upregulation of neutrophil‐recruiting factors in a cell‐intrinsic manner. Upon inflammation, keratinocyte‐specific ILEI expression generated a feed‐forward loop on the own secretion by the autocrine upregulation of uPA transcription. uPA was validated as therapeutic target in K5‐ILEI ind transgenic mice and proposed as being part of a “psoriasis ILEI gene signature” with strong relevance in human disease manifestation. Graphical Abstract Analyses of human psoriatic skin and studies in genetically engineered mouse models revealed that FAM3C/ILEI contributes to psoriasis by controlling keratinocyte hyperproliferation, differentiation, and neutrophil recruitment and identifies uPA, a regulator of ILEI secretion, as a druggable target.

The enactment of the Statute of Westminster in 1931 represents one of the most significant events in the history of the British Empire. The very name of this historic piece of legislation, with its medieval antecedents, epitomizes a sense of enduring grandeur and dignity. The Statute of Westminster recognized significant advances in the evolution of the self-governing Dominions into fully sovereign states. The term “Dominion” was initially adopted in relation to Canada, but was extended in 1907 to refer to all self-governing colonies of white settlement that had been evolving in the direction of greater autonomy since the middle of the nineteenth century. By the early 1930s, the Dominions included Canada, Australia, New Zealand, South Africa, Newfoundland, and the Irish Free State.

Prostate cancer (PCa) has a broad spectrum of clinical behavior; hence, biomarkers are urgently needed for risk stratification. Here, we aim to find potential biomarkers for risk stratification, by utilizing a gene co‐expression network of transcriptomics data in addition to laser‐microdissected proteomics from human and murine prostate FFPE samples. We show up‐regulation of oxidative phosphorylation (OXPHOS) in PCa on the transcriptomic level and up‐regulation of the TCA cycle/OXPHOS on the proteomic level, which is inversely correlated to STAT3 expression. We hereby identify gene expression of pyruvate dehydrogenase kinase 4 ( PDK4 ), a key regulator of the TCA cycle, as a promising independent prognostic marker in PCa. PDK4 predicts disease recurrence independent of diagnostic risk factors such as grading, staging, and PSA level. Therefore, low PDK4 is a promising marker for PCa with dismal prognosis. Synopsis Transcriptomic and proteomic analyses in prostate cancer (PCa) reveal high TCA/OXPHOS activity and low PDK4 expression in low STAT3 tumors. PDK4 is a promising independent predictor of biochemical recurrence in PCa. Low STAT3 tumors show enhanced TCA/OXPHOS and ribosome activity in a gene co‐expression network and in transcriptomic and proteomic analyses. Enhanced ribosome‐ and metabolic activity is found in mice with a deletion of Pten and Stat3 in the prostate epithelium. Low STAT3 is associated with low PDK4 expression. PDK4 is an important regulator of TCA/OXPHOS. Analysis of patient data indicates that low PDK4 correlates with earlier biochemical recurrence in PCa. Graphical Abstract Transcriptomic and proteomic analyses in prostate cancer (PCa) reveal high TCA/OXPHOS activity and low PDK4 expression in low STAT3 tumors. PDK4 is a promising independent predictor of biochemical recurrence in PCa.

Osteosarcoma (OS) is a rare tumor of the bone occurring mainly in young adults accounting for 5% of all childhood cancers. Because of the limited therapeutic options, there has been no survival improvement for OS patients in the past 40 years. The epidermal growth factor receptor (EGFR) is highly expressed in OS; however, its clinical relevance is unclear. Here, we employed an autochthonous c‐Fos‐dependent OS mouse model (H2 ‐c‐fos LTR) and human OS tumor biopsies for preclinical studies aimed at identifying novel biomarkers and therapeutic benefits of anti‐EGFR therapies. We show that EGFR deletion/inhibition results in reduced tumor formation in H2‐ c‐fos LTR mice by directly inhibiting the proliferation of cancer‐initiating osteoblastic cells by a mechanism involving RSK2/CREB‐dependent c‐Fos expression. Furthermore, OS patients with co‐expression of EGFR and c‐Fos exhibit reduced overall survival. Preclinical studies using human OS xenografts revealed that only tumors expressing both EGFR and c‐Fos responded to anti‐EGFR therapy demonstrating that c‐Fos can be considered as a novel biomarker predicting response to anti‐EGFR treatment in OS patients. Synopsis Epidermal growth factor receptor (EGFR) is frequently overexpressed in osteosarcomas (OSs). However, its clinical relevance is still under debate. In this study, the role of EGFR in OS development and progression is investigated in human OS biopsies and in genetic engineered mouse models (GEMMs) using PET/CT imaging. EGFR signalling in osteoblasts promotes OS development in GEMMs via RSK2/CREB‐dependent upregulation of the AP‐1 transcription factor c‐Fos. Patients suffering from EGFR and FOS double positive OSs exhibit reduced overall survival. In preclinical trials using orthotopic human xenografts, anti‐EGFR therapy is effective only in tumours expressing both EGFR and c‐Fos. Graphical Abstract Epidermal growth factor receptor (EGFR) is frequently overexpressed in osteosarcomas (OSs). However, its clinical relevance is still under debate. In this study, the role of EGFR in OS development and progression is investigated in human OS biopsies and in genetic engineered mouse models (GEMMs) using PET/CT imaging.

Induction therapy is widely used in lung transplantation to control the host alloresponse, reducing acute cellular rejection and improving graft survival. Despite its use, data on the biological effects of different induction agents remain limited. This study examines serum proteomics profiles in lung transplant patients receiving alemtuzumab, anti-thymocyte globulin (ATG), or no induction therapy. Adult lung transplant recipients who underwent transplantation between 2007 and 2013 at the Medical University of Vienna were included. Using mass spectrometry (MS), serum samples were examined before transplantation (T1) and 12 months post-transplant (T2). Among 102 patients (50 alemtuzumab, 34 ATG, 18 no induction), we identified significantly differentially expressed proteins over time and between groups at T2. In the alemtuzumab group, 40 proteins were differentially expressed (3 upregulated, 37 downregulated), in ATG, 22 proteins (3 upregulated, 19 downregulated), and none in the no-induction group. At T2, two proteins (fibulin-1 and fetuin-B) were downregulated between alemtuzumab and no induction, with no significant differences between alemtuzumab and ATG or ATG and no induction. Our findings suggest alemtuzumab may have a stronger effect on circulating proteome. Further studies are warranted to elucidate the underlying mechanisms and explore potential clinical implications.

Due to their high biological activity, thiosemicarbazones have been developed for treatment of diverse diseases, including cancer, resulting in multiple clinical trials especially of the lead compound Triapine. During the last years, a novel subclass of anticancer thiosemicarbazones has attracted substantial interest based on their enhanced cytotoxic activity. Increasing evidence suggests that the double-dimethylated Triapine derivative Me 2 NNMe 2 differs from Triapine not only in its efficacy but also in its mode of action. Here we show that Me 2 NNMe 2 - (but not Triapine)-treated cancer cells exhibit all hallmarks of paraptotic cell death including, besides the appearance of endoplasmic reticulum (ER)-derived vesicles, also mitochondrial swelling and caspase-independent cell death via the MAPK signaling pathway. Subsequently, we uncover that the copper complex of Me 2 NNMe 2 (a supposed intracellular metabolite) inhibits the ER-resident protein disulfide isomerase, resulting in a specific form of ER stress based on disruption of the Ca 2+ and ER thiol redox homeostasis. Our findings indicate that compounds like Me 2 NNMe 2 are of interest especially for the treatment of apoptosis-resistant cancer and provide new insights into mechanisms underlying drug-induced paraptosis.

Background Pleural mesothelioma (PM) is an aggressive malignancy with poor prognosis . Unlike many other cancers, PM is mostly characterized by inactivation of tumor suppressor genes. Its highly malignant nature in absence of tumor driving oncogene mutations indicates an extrinsic supply of stimulating signals by cells of the tumor microenvironment (TME). Cancer-associated fibroblasts (CAFs) are an abundant cell type of the TME and have been shown to drive the progression of several malignancies. The aim of the current study was to isolate and characterize patient-derived mesothelioma-associated fibroblasts (Meso-CAFs), and evaluate their impact on PM cells. Methods Meso-CAFs were isolated from surgical specimens of PM patients and analyzed by array comparative genomic hybridization, next generation sequencing, transcriptomics and proteomics. Human PM cell lines were retrovirally transduced with GFP. The impact of Meso-CAFs on tumor cell growth, migration, as well as the response to small molecule inhibitors, cisplatin and pemetrexed treatment was investigated in 2D and 3D co-culture models by videomicroscopy and automated image analysis. Results Meso-CAFs show a normal diploid genotype without gene copy number aberrations typical for PM cells. They express CAF markers and lack PM marker expression. Their proteome and secretome profiles clearly differ from normal lung fibroblasts with particularly strong differences in actively secreted proteins. The presence of Meso-CAFs in co-culture resulted in significantly increased proliferation and migration of PM cells. A similar effect on PM cell growth and migration was induced by Meso-CAF-conditioned medium. Inhibition of c-Met with crizotinib, PI3K with LY-2940002 or WNT signaling with WNT-C59 significantly impaired the Meso-CAF-mediated growth stimulation of PM cells in co-culture at concentrations not affecting the PM cells alone. Meso-CAFs did not provide protection of PM cells against cisplatin but showed significant protection against the EGFR inhibitor erlotinib. Conclusions Our study provides the first characterization of human patient-derived Meso-CAFs and demonstrates a strong impact of Meso-CAFs on PM cell growth and migration, two key characteristics of PM aggressiveness, indicating a major role of Meso-CAFs in driving PM progression. Moreover, we identify signaling pathways required for Meso-CAF-mediated growth stimulation. These data could be relevant for novel therapeutic strategies against PM.