Search

Background: There is evidence of pre-established vulnerability in individuals that increases the risk of their progression to severe disease or death, although the mechanisms causing this are still not fully understood. Previous research has demonstrated that a urinary peptide classifier (COV50) predicts disease progression and death from SARS-CoV-2 at an early stage, indicating that the outcome prediction may be partly due to vulnerabilities that are already present. The aim of this study is to examine the ability of COV50 to predict future non-COVID-19-related mortality, and evaluate whether the pre-established vulnerability can be generic and explained on a molecular level by urinary peptides., Methods: Urinary proteomic data from 9193 patients (1719 patients sampled at intensive care unit (ICU) admission and 7474 patients with other diseases (non-ICU)) were extracted from the Human Urinary Proteome Database. The previously developed COV50 classifier, a urinary proteomics biomarker panel consisting of 50 peptides, was applied to all datasets. The association of COV50 scoring with mortality was evaluated., Results: In the ICU group, an increase in the COV50 score of one unit resulted in a 20% higher relative risk of death [adjusted HR 1.2 (95% CI 1.17-1.24)]. The same increase in COV50 in non-ICU patients resulted in a higher relative risk of 61% [adjusted HR 1.61 (95% CI 1.47-1.76)], consistent with adjusted meta-analytic HR estimate of 1.55 [95% CI 1.39-1.73]. The most notable and significant changes associated with future fatal events were reductions of specific collagen fragments, most of collagen alpha I (I)., Conclusion: The COV50 classifier is predictive of death in the absence of SARS-CoV-2 infection, suggesting that it detects pre-existing vulnerability. This prediction is mainly based on collagen fragments, possibly reflecting disturbances in the integrity of the extracellular matrix. These data may serve as a basis for proteomics-guided intervention aiming towards manipulating/ improving collagen turnover, thereby reducing the risk of death., (© 2023. BioMed Central Ltd., part of Springer Nature.)

(1) Background: Prostate cancer (PCa) is the most frequently diagnosed cancer in men. Wide application of prostate specific antigen test has historically led to over-treatment, starting from excessive biopsies. Risk calculators based on molecular and clinical variables can be of value to determine the risk of PCa and as such, reduce unnecessary and invasive biopsies. Urinary molecular studies have been mostly focusing on sampling after initial intervention (digital rectal examination and/or prostate massage). (2) Methods: Building on previous proteomics studies, in this manuscript, we aimed at developing a biomarker model for PCa detection based on urine sampling without prior intervention. Capillary electrophoresis coupled to mass spectrometry was applied to acquire proteomics profiles from 970 patients from two different clinical centers. (3) Results: A case-control comparison was performed in a training set of 413 patients and 181 significant peptides were subsequently combined by a support vector machine algorithm. Independent validation was initially performed in 272 negative for PCa and 138 biopsy-confirmed PCa, resulting in an AUC of 0.81, outperforming current standards, while a second validation phase included 147 PCa patients. (4) Conclusions: This multi-dimensional biomarker model holds promise to improve the current diagnosis of PCa, by guiding invasive biopsies.

Delivering better care for patients with bladder cancer (BC) necessitates the development of novel therapeutic strategies that address both the high disease heterogeneity and the limitations of the current therapeutic modalities, such as drug low efficacy and patient resistance acquisition. Drug repurposing is a cost-effective strategy that targets the reuse of existing drugs for new therapeutic purposes. Such a strategy could open new avenues toward more effective BC treatment. BC patients' multi-omics signatures can be used to guide the investigation of existing drugs that show an effective therapeutic potential through drug repurposing. In this book chapter, we present an integrated multilayer approach that includes cross-omics analyses from publicly available transcriptomics and proteomics data derived from BC tissues and cell lines that were investigated for the development of disease-specific signatures. These signatures are subsequently used as input for a signature-based repurposing approach using the Connectivity Map (CMap) tool. We further explain the steps that may be followed to identify and select existing drugs of increased potential for repurposing in BC patients., (© 2023. The Author(s), under exclusive license to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Non-invasive urine-based biomarkers can potentially improve current diagnostic and monitoring protocols for bladder cancer (BC). Here we assess the performance of earlier published biomarker panels for BC detection (BC-116) and monitoring of recurrence (BC-106) in combination with cytology, in two prospectively collected patient cohorts., Methods: Of the 602 patients screened for BC, 551 were found eligible. For the primary setting, 73 patients diagnosed with primary BC (n = 27) and benign urological disorders, including patients with macroscopic haematuria, cystitis and/or nephrolithiasis (n = 46) were included. In total, 478 patients under surveillance were additionally considered (83 BC recurrences; 395 negative for recurrence). Urine samples were analysed with capillary electrophoresis-mass spectrometry. The biomarker score was estimated via support vector machine-based software., Results: Validation of BC-116 biomarker panel resulted in 89% sensitivity and 67% specificity (AUC BC-116  = 0.82). A diagnostic score based on cytology and BC-116 resulted in good (AUC Nom116  = 0.85) but not significantly better performance (P = 0.5672). A diagnostic score including BC-106 and cytology was evaluated (AUC Nom106  = 0.82), significantly outperforming both cytology (AUC cyt  = 0.72; P = 0.0022) and BC-106 (AUC BC-106  = 0.67; P = 0.0012)., Conclusions: BC-116 biomarker panel is a useful test for detecting primary BC. BC-106 classifier integrated with cytology showing >95% negative predictive value, might be useful for decreasing the number of cystoscopies during surveillance., (© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)

Despite advancements in molecular classification, tumor stage and grade still remain the most relevant prognosticators used by clinicians to decide on patient management. Here, we leverage publicly available data to characterize bladder cancer (BLCA)'s stage biology based on increased sample sizes, identify potential therapeutic targets, and extract putative biomarkers. A total of 1135 primary BLCA transcriptomes from 12 microarray studies were compiled in a meta-cohort and analyzed for monotonal alterations in pathway activities, gene expression, and co-expression patterns with increasing stage (Ta-T1-T2-T3-T4), starting from the non-malignant tumor-adjacent urothelium. The TCGA-2017 and IMvigor-210 RNA-Seq data were used to validate our findings. Wnt, MTORC1 signaling, and MYC activity were monotonically increased with increasing stage, while an opposite trend was detected for the catabolism of fatty acids, circadian clock genes, and the metabolism of heme. Co-expression network analysis highlighted stage- and cell-type-specific genes of potentially synergistic therapeutic value. An eight-gene signature, consisting of the genes AKAP7 , ANLN , CBX7 , CDC14B , ENO1 , GTPBP4 , MED19 , and ZFP2 , had independent prognostic value in both the discovery and validation sets. This novel eight-gene signature may increase the granularity of current risk-to-progression estimators.

Prostate cancer (PCa) carries a growing burden on society. Lack of curative treatment and poor prognosis among patients with advanced PCa imply an urgent need for novel and improved drug identification. This is hampered by the disease's high molecular heterogeneity and complex molecular pathophysiology, resulting in drugs being efficient in a few patients and cancer developing resistance to treatment. De novo drug discovery has proven to be complex and challenging. Along with technological advancements (mainly linked to -omics approaches) that allow for comprehensive characterization of the molecular changes underlying disease, and considering respective developments in bioinformatics, computational drug repurposing has emerged as a promising approach to shorten the way from discovery to clinical application and address the disease molecular complexity. With this article, we aimed at reviewing recent studies in which drugs/ compounds for PCa were defined through the investigation of molecular profiling (-omics) data and the application of drug repurposing strategies. A brief overview of the technical requirements and associated challenges with the latter are also provided. For that purpose, a literature search was conducted using the PubMed database. Numerous drugs/ compounds have been proposed as potential PCa therapeutics, mostly based on the investigation of genomics and transcriptomics data. In most cases, further assessment in disease models is required. Since ultimately proteins are targeted by drugs, expanding on the use of proteomics profiling data (alone or in combination with other -omics) is expected to advance further defining new/repurposed drugs for PCa., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Background and Aims: Follistatin-like protein-1 (FSTL-1) is considered to be an adipokine or myokine that could be a potential regulator of metabolism. Our purpose is to investigate the relationship between circulating FSTL-1 levels and insulin resistance (IR) in type 2 diabetes mellitus (T2DM) and to identify the regulatory factors., Methods: FSTL-1 expression in C57BL/6J and db/db mice was examined by quantitative reverse transcriptase-polymerase chain reaction (qRT-PCR) and Western blots. Serum FSTL-1 levels were measured by enzyme-linked immunosorbent assay in 298 T2DM patients and 202 healthy controls. Changes in the circulating FSTL-1 level were observed during the oral glucose tolerance test, EHC (euglycemic-hyperinsulinemic clamp), lipid infusion, acute exercise, and cold-exposure test., Results: We found that FSTL-1 protein expression in the adipose tissue of db/db mice was significantly higher than that of wild-type mice. Importantly, circulating FSTL-1 levels in T2DM and overweight/obese participants were higher than those in healthy and lean individuals, and was related to HOMA-IR, adiponectin, and obesity- and metabolism-related parameters. In the intervention study, 45 minutes of physical activity was found to significantly increase the circulating FSTL-1 concentration in young, healthy participants. Further, FSTL-1 protein expression in adipose tissue rose dramatically in response to physical activity in mice. Hyperinsulinemia during EHC and acute elevated FFA induced by lipid infusion resulted in a significant decrease in the circulating FSTL-1 levels. However, no change was found in the circulating FSTL-1 levels in response to the oral glucose challenge or cold-exposure test., Conclusions: FSTL-1 may be an adipomyokine associated with insulin resistance and physical activity, and circulating FSTL-1 levels are increased in patients with T2DM., (© Endocrine Society 2020. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Multi-omics signatures of patients with bladder cancer (BC) can guide the identification of known de-risked therapeutic compounds through drug repurposing, an approach not extensively explored yet. In this study, we target drug repurposing in the context of BC, driven by tissue omics signatures. To identify compounds that can reverse aggressive high-risk Non-Muscle Invasive BC (NMIBC) to less aggressive low-risk molecular subtypes, the next generation Connectivity Map (CMap) was employed using as input previously published proteomics and transcriptomics respective signatures. Among the identified compounds, the ATP-competitive inhibitor of mTOR, WYE-354, showed a consistently very high score for reversing the aggressive BC molecular signatures. WYE-354 impact was assessed in a panel of eight multi-origin BC cell lines and included impaired colony growth and proliferation rate without any impact on apoptosis. Overall, with this study we introduce a promising pipeline for the repurposing of drugs for BC treatment, based on patients' omics signatures.

Background: Previous studies have suggested that Fetuin-B seems to be a secreted adipokine related to metabolic diseases. However, the results have been inconsistent. Here, our objective is to investigate the changes in circulating Fetuin-B levels in women with polycystic ovary syndrome (PCOS) and analyze the association of Fetuin-B and insulin resistance (IR)., Methods: The current study is comprised of a cross-sectional study and a series of interventional studies. Oral glucose tolerance test (OGTT) and euglycemic-hyperinsulinemic clamp (EHC) were engaged to assess glucose tolerance and insulin sensitivity. Serum Fetuin-B levels were determined by ELISA., Results: Serum Fetuin-B and TNF- α levels were markedly increased in women with PCOS compared to healthy women. Circulating Fetuin-B was positively associated with body mass index, waist-to-hip ratio, the percentage of body fat (FAT%), systolic blood pressure, triglyceride, low-density lipoprotein cholesterol, fasting blood glucose, 2 h blood glucose after glucose overload, fasting insulin, 2 h insulin after glucose overload, HOMA-insulin resistance index (HOMA-IR), the area under the curve for insulin (AUCi), AUCg, and TNF- α , while negatively associated with M value and follicular stimulating hormone (FSH). During the EHC, Fetuin-B levels were found to be significantly increased in PCOS women. After a glucose challenge, serum Fetuin-B levels in healthy women were significantly increased. Lipid infusion reduced serum Fetuin-B levels in 30 healthy subjects. After six months of glucagon-like peptide-1 receptor agonist (GLP-1RA) intervention, serum Fetuin-B concentrations in PCOS women markedly decreased following ameliorated IR., Conclusion: Our results indicate that Fetuin-B may be a biomarker of IR in individuals with PCOS. This trial is registered with ChiCTR-IIR-16007901., Competing Interests: The authors declare that there is no conflict of interest regarding the publication of this paper., (Copyright © 2020 Mani Mokou et al.)

DNA/RNA-based classification of bladder cancer (BC) supports the existence of multiple molecular subtypes, while investigations at the protein level are scarce. Here, we aimed to investigate if Nonmuscle Invasive Bladder Cancer (NMIBC) can be stratified to biologically meaningful groups based on the proteome. Tissue specimens from 117 patients at primary diagnosis (98 with NMIBC and 19 with MIBC), were processed for high-resolution proteomics analysis by liquid chromatography-tandem mass spectrometry (LC-MS/MS). The proteomics output was subjected to unsupervised consensus clustering, principal component analysis (PCA) and investigation of subtype-specific features, pathways, and gene sets. NMIBC patients were optimally stratified to three NMIBC proteomic subtypes (NPS), differing in size, clinicopathologic and molecular backgrounds: NPS1 (mostly high stage/grade/risk samples) was the smallest in size (17/98) and overexpressed proteins reflective of an immune/inflammatory phenotype, involved in cell proliferation, unfolded protein response and DNA damage response, whereas NPS2 (mixed stage/grade/risk composition) presented with an infiltrated/mesenchymal profile. NPS3 was rich in luminal/differentiation markers, in line with its pathological composition (mostly low stage/grade/risk samples). PCA revealed a close proximity of NPS1 and conversely, remoteness of NPS3 to the proteome of MIBC. Proteins distinguishing these two extreme subtypes were also found to consistently differ at the mRNA levels between high and low-risk subtypes of the UROMOL and LUND cohorts. Collectively, our study identifies three proteomic NMIBC subtypes and following a cross-omics validation in two independent cohorts, shortlists molecular features meriting further investigation for their biomarker or potentially therapeutic value., (© 2019 UICC.)

Background: Human mesenchymal stem/stromal cells (MSCs) and their secreted molecules exert beneficial effects in injured tissues by promoting tissue regeneration and angiogenesis and by inhibiting inflammation and fibrosis. We have previously demonstrated that the therapeutic activity of fetal MSCs derived from amniotic fluid (AF-MSCs) and their hepatic progenitor-like cells (HPL) is mediated by paracrine effects in a mouse model of acute hepatic failure (AHF)., Methods: Herein, we have combined proteomic profiling of the AF-MSCs and HPL cell secretome with ex vivo and in vivo functional studies to identify specific soluble factors, which underpin tissue regeneration in AHF., Findings: The anti-inflammatory molecule Annexin-A1 (ANXA1) was detected at high levels in both AF-MSC and HPL cell secretome. Further functional analyses revealed that the shRNA-mediated knock-down of ANXA1 in MSCs (shANXA1-MSCs) decreased their proliferative, clonogenic and migratory potential, as well as their ability to differentiate into HPL cells. Liver progenitors (oval cells) from AHF mice displayed reduced proliferation when cultured ex vivo in the presence of conditioned media from shANXA1-MSCs compared to control MSCs secretome. Intra-hepatic delivery of conditioned media from control MSCs but not shANXA1-MSCs reduced liver damage and circulating levels of pro-inflammatory cytokines in AHF., Interpretation: Collectively, our study uncovers secreted Annexin-A1 as a novel effector of MSCs in liver regeneration and further underscores the potential of cell-free therapeutic strategies for liver diseases. FUND: Fondation Santé, GILEAD Asklipeios Grant, Fellowships of Excellence - Siemens, IKY, Reinforcement of Postdoctoral Researchers, IKY., (Copyright © 2019 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: The increased prevalence of cardiovascular disease (CVD) indicates a demand for novel therapeutic approaches. Proteome analysis of vascular tissues from animal models and humans with CVD could lead to the identification of novel druggable targets., Methods: LC-MS/MS analysis of thoracic aortas from three mouse models of non-diabetic and diabetic (streptozotocin (STZ)-induced) atherosclerosis followed by bioinformatics/pathway analysis was performed. Selected findings were confirmed by proteomics analysis of human vessels from patients with CVD as well as in vitro studies (migration, proliferation, angiogenesis assays) using endothelial (HUVEC) cells., Findings: Comparative tissue proteomics of low density lipoprotein receptor deficient (Ldlr-/-) and diabetic Ldlr-/- (Ldlr-/-STZ) with wild type (WT) animals led to the identification of 284 differentially expressed proteins in both models. Among them, 177 proteins were also differentially expressed in diabetic apolipoprotein E deficient (ApoE-/-STZ) mice, suggesting expression changes associated with atherosclerosis independent of the model used. These proteins recapitulated the hallmarks of atherosclerosis. Comparison of these findings with differentially expressed proteins in human vessels with CVD enabled shortlisting of six commonly dysregulated proteins. Among them, lysine-specific demethylase 5D (KDM5D) exhibited pronounced overexpression accompanied by a reduction in the protein levels of its substrate, the trimethylated lysine 4 of histone H3 (H3K4me3), in patients with CVD. Functional interference studies applying a KDM5 inhibitor on HUVEC reduced cell proliferation, migration and tube-forming ability in vitro., Interpretation: This high-throughput proteomics strategy identified KDM5 histone demethylases being potentially involved in CVD, possibly by affecting H3K4 methylation. FUND: [SysVasc, HEALTH-2013 603288], [ERA-CVD PROACT: ANR-17-ECVD-0006, 01KL1805], [FRM, DEQ20170336759]., (Copyright © 2019. Published by Elsevier B.V.)

Patients with advanced bladder cancer have poor outcomes, indicating a need for more efficient therapeutic approaches. This study characterizes proteomic changes underlying bladder cancer invasion aiming for the better understanding of disease pathophysiology and identification of drug targets. High resolution liquid chromatography coupled to tandem mass spectrometry analysis of tissue specimens from patients with non-muscle invasive (NMIBC, stage pTa) and muscle invasive bladder cancer (MIBC, stages pT2+) was conducted. Comparative analysis identified 144 differentially expressed proteins between analyzed groups. These included proteins previously associated with bladder cancer and also additional novel such as PGRMC1, FUCA1, BROX and PSMD12, which were further confirmed by immunohistochemistry. Pathway and interactome analysis predicted strong activation in muscle invasive bladder cancer of pathways associated with protein synthesis e.g. eIF2 and mTOR signaling. Knock-down of eukaryotic translation initiation factor 3 subunit D (EIF3D) (overexpressed in muscle invasive disease) in metastatic T24M bladder cancer cells inhibited cell proliferation, migration, and colony formation in vitro and decreased tumor growth in xenograft models. By contrast, knocking down GTP-binding protein Rheb (which is upstream of EIF3D) recapitulated the effects of EIF3D knockdown in vitro , but not in vivo . Collectively, this study represents a comprehensive analysis of NMIBC and MIBC providing a resource for future studies. The results highlight EIF3D as a potential therapeutic target., Competing Interests: CONFLICTS OF INTEREST Harald Mischak is the founder and co-owner of Mosaiques Diagnostics. Dr. Maria Frantzi is employed by Mosaiques Diagnostics. Dr. Agnieszka Latosinska is also currently employed by Mosaiques Diagnostics.

Introduction: Although multiple efforts have been initiated to shed light into the molecular mechanisms underlying cardiovascular disease, it still remains one of the major causes of death worldwide. Proteomic approaches are unequivocally powerful tools that may provide deeper understanding into the molecular mechanisms associated with cardiovascular disease and improve its management. Areas covered: Cardiovascular proteomics is an emerging field and significant progress has been made during the past few years with the aim of defining novel candidate biomarkers and obtaining insight into molecular pathophysiology. To summarize the recent progress in the field, a literature search was conducted in PubMed and Web of Science. As a result, 704 studies from PubMed and 320 studies from Web of Science were retrieved. Findings from original research articles using proteomics technologies for the discovery of biomarkers for cardiovascular disease in human are summarized in this review. Expert commentary: Proteins associated with cardiovascular disease represent pathways in inflammation, wound healing and coagulation, proteolysis and extracellular matrix organization, handling of cholesterol and LDL. Future research in the field should target to increase proteome coverage as well as integrate proteomics with other omics data to facilitate both drug development as well as clinical implementation of findings.

Background: Bladder Cancer (BC) has two clearly distinct phenotypes. Non-muscle invasive BC has good prognosis and is treated with tumor resection and intravesical therapy whereas muscle invasive BC has poor prognosis and requires usually systemic cisplatin based chemotherapy either prior to or after radical cystectomy. Neoadjuvant chemotherapy is not often used for patients undergoing cystectomy. High-throughput analytical omics techniques are now available that allow the identification of individual molecular signatures to characterize the invasive phenotype. However, a large amount of data produced by omics experiments is not easily accessible since it is often scattered over many publications or stored in supplementary files., Objective: To develop a novel open-source database, BcCluster (http://www.bccluster.org/), dedicated to the comprehensive molecular characterization of muscle invasive bladder carcinoma., Materials: A database was created containing all reported molecular features significant in invasive BC. The query interface was developed in Ruby programming language (version 1.9.3) using the web-framework Rails (version 4.1.5) (http://rubyonrails.org/)., Results: BcCluster contains the data from 112 published references, providing 1,559 statistically significant features relative to BC invasion. The database also holds 435 protein-protein interaction data and 92 molecular pathways significant in BC invasion. The database can be used to retrieve binding partners and pathways for any protein of interest. We illustrate this possibility using survivin, a known BC biomarker., Conclusions: BcCluster is an online database for retrieving molecular signatures relative to BC invasion. This application offers a comprehensive view of BC invasiveness at the molecular level and allows formulation of research hypotheses relevant to this phenotype.