Julio Vera

Friedrich-Alexander-University of Erlangen-Nürnberg | FAU · Department of Dermatology

Cancer is a disease of subverted regulatory pathways. In this paper, we reconstruct the regulatory network around E2F, a family of transcription factors whose deregulation has been associated to cancer progression, chemoresistance, invasiveness, and metastasis. We integrate gene expression profiles of cancer cell lines from two E2F1-driven highly a...

MicroRNAs (miRNAs) are short, noncoding RNAs that regulate gene expression by suppressing mRNA translation and reducing mRNA stability. A miRNA can potentially bind many mRNAs, thereby affecting the expression of oncogenes and tumor suppressor genes as well as the activity of whole pathways. The promise of miRNA therapeutics in cancer is to harness...

Therapeutic anticancer vaccination has been adapted as an immunotherapy in several solid tumors. However, the selection of promising candidates from the total quantity of possible epitopes poses a challenge to clinicians and bioinformaticians alike, and very few epitopes have been tested in experimental or clinical settings to validate their effica...

Dendritic cells (DCs) are professional antigen-presenting cells that induce and regulate adaptive immunity by presenting antigens to T cells. Due to their coordinative role in adaptive immune responses, DCs have been used as cell-based therapeutic vaccination against cancer. The capacity of DCs to induce a therapeutic immune response can be enhance...

Multiple types of genomic variations are present in cutaneous melanoma and some of the genomic features may have an impact on the prognosis of the disease. The access to genomics data via public repositories such as TCGA (The Cancer Genome Atlas) allows for a better understanding of melanoma at the molecular level, therefore making characterization...

Artificial intelligence is an advanced method to identify novel anticancer targets and discover novel drugs from biology networks because the networks can effectively preserve and quantify the interaction between components of cell systems underlying human diseases such as cancer. Here, we review and discuss how to employ artificial intelligence ap...

Background Plasma extracellular vesicles (pEV) can harbor a diverse array of factors including active proteases and the amyloid-precursor-protein (APP) cleavage product Aβ, involved in plaque formation in Alzheimer`s diseases (AD). A potential role of such vesicles in AD pathology is unexplored. Methods In a case-control study of randomly selected...

Dendritic cells (DCs) can be used for therapeutic vaccination against cancer. The success of this therapy depends on efficient tumor-antigen presentation to cytotoxic T lymphocytes (CTLs) and the induction of durable CTL responses by the DCs. Therefore, simulation of such a biological system by computational modeling is appealing because it can imp...

Merkel cell carcinoma (MCC) is a rare and highly aggressive cancer, which is mainly caused by genomic integration of the Merkel cell polyomavirus and subsequent expression of a truncated form of its large T antigen. The resulting primary tumor is known to be immunogenic and under constant pressure to escape immune surveillance. Because interferon g...

This study aimed to identify prognostic factors in patients with metastatic uveal melanoma (UM) that were associated with long-term survival in a real-world setting. A total of 94 patients with metastatic UM were included from German skin cancer centers and the German national skin cancer registry (ADOReg). Data were analyzed for the response to tr...

Alternatively activated macrophages (AAMs) contribute to the resolution of inflammation and tissue repair. However, molecular pathways that govern their differentiation have remained incompletely understood. Here, we show that uncoupling protein-2-mediated mitochondrial reprogramming and the transcription factor GATA3 specifically controlled the di...

Background Allergies are on the rise globally, with an enormous impact on affected individuals’ quality of life as well as health care resources. They cause a wide range of symptoms, from slightly inconvenient to potentially fatal immune reactions. While allergies have been described and classified phenomenologically, there is an unmet need for eas...

Skin melanoma presents increasing prevalence and poor outcomes. Progression to aggressive stages is characterized by overexpression of the transcription factor E2F1 and activation of downstream pro-metastatic gene regulatory networks (GRNs). Appropriate therapeutic manipulation of the E2F1-governed GRNs holds potential to prevent metastasis, howeve...

As substantial constituents of the multiple myeloma (MM) microenvironment, pro-inflammatory macrophages have emerged as key promoters of disease progression, bone destruction, and immune impairment. We identify beta-2-microglobulin (β2m) as a driver in initiating inflammation in myeloma-associated macrophages (MAMs). Lysosomal accumulation of phago...

Studying of the gene regulatory architecture that controls region-independent dynamics of oligodendrocyte differentiation, Cantone and co-authors derived a kinetic model in 14 ordinary differential equations (ODEs) [Cantone, M. Kuspert, M., Reiprich, S., et al., Glia 67(5), 825-843, 2019]. In this paper, we investigate a reduced version of this mod...

The bone marrow niche has a pivotal role in progression, survival, and drug resistance of multiple myeloma cells. Therefore, it is important to develop means for targeting the multiple myeloma bone marrow microenvironment. Myeloma-associated macrophages (MAM) in the bone marrow niche are M2 like. They provide nurturing signals to multiple myeloma c...

In most disciplines of natural sciences and engineering, mathematical and computational modelling are mainstay methods which are usefulness beyond doubt. These disciplines would not have reached today’s level of sophistication without an intensive use of mathematical and computational models together with quantitative data. This approach has not be...

The subventricular zone (SVZ) is the largest neurogenic niche in the adult forebrain. Notably, neural stem cells (NSCs) of the SVZ generate not only neurons, but also oligodendrocytes, the myelin-forming cells of the central nervous system. Transcriptomic studies have provided detailed knowledge of the molecular events that regulate neurogenesis, b...

Background: Before and after surgery melanoma patients harbor elevated levels of extracellular vesicles in plasma (pEV), suppressing tumor cell activity. However, due to technical reasons and lack of cell-specific biomarkers, their cellular origin remains obscure. Methods: We mimicked the interaction of tumor cells with liver cells and PBMC in vit...

Bacterial pneumonia is one of the most prevalent infectious diseases and has high mortality in sensitive patients (children, elderly and immunocompromised). Although an infection, the disease alters the alveolar epithelium homeostasis and hinders normal breathing, often with fatal consequences. A special case is hospitalized aged patients, which pr...

Dendritic cells (DCs) are professional antigen-presenting cells that induce and regulate adaptive immunity by presenting antigens to T cells. Due to their coordinative role in adaptive immune responses, DCs have been used as cell-based therapeutic vaccination against cancer. The capacity of DCs to induce a therapeutic immune response can be enhance...

Mycobacteria survive in macrophages despite triggering pattern recognition receptors and T cell-derived IFN-γ production. Mycobacterial cord factor trehalose-6,6-dimycolate (TDM) binds the C-type lectin receptor MINCLE and induces inflammatory gene expression. However, the impact of TDM on IFN-γ-induced macrophage activation is not known. In this s...

Background: Melanoma phenotype and the dynamics underlying its progression are determined by a complex interplay between different types of regulatory molecules. In particular, transcription factors (TFs), microRNAs (miRNAs), and long non-coding RNAs (lncRNAs) interact in layers that coalesce into large molecular interaction networks. Our goal her...

The objective of this study is to evaluate the role of cooperativity, captured by the Hill coefficient, in a minimal mathematical model describing the interactions between p53 and miR-34a. The model equations are analyzed for negative, none and normal cooperativity using a specific version of bifurcation theory and they are solved numerically. Spec...

Epigenetic deregulation remarkably triggers mechanisms associated with tumor aggressiveness like epithelial–mesenchymal transition (EMT). Since EMT is a highly complex, but also reversible event, epigenetic processes such as DNA methylation or chromatin alterations must be involved in its regulation. It was recently described that loss of the cell...

Uveal melanoma (UM) represents the most common intraocular malignancy in adults and accounts for about 5% of all melanomas. Primary disease can be effectively controlled by several local therapy options, but UM has a high potential for metastatic spread, especially to the liver. Despite its clinical and genetic heterogeneity, therapy of metastatic...

Lower respiratory infections, such as community-acquired pneumonia (CAP), and chronic obstructive pulmonary disease (COPD) rank among the most frequent causes of death worldwide. Improved diagnostics and profound pathophysiological insights are urgent clinical needs. In our cohort, we analysed transcriptional networks of peripheral blood mononuclea...

Biomedical research is nowadays concerned with the investigation of complex biological networks, in which dozens to thousands of proteins, genes, and miRNAs interact to control cellular or tissue-level phenotypes. Investigation of these complex biological networks requires the use of various experimental methodologies that generate massive amounts...

Autism Spectrum Disorders (ASDs) stand out as a relevant example where omics-data approaches have been extensively and successfully employed. For instance, an outstanding outcome of the Autism Genome Project relies in the identification of biomarkers and the mapping of biological processes potentially implicated in ASDs’ pathogenesis. Several of th...

A current option for anti-cancer immunotherapy is to make use of epitopes which can guide cytotoxic T cells to destroy the tumor. It is however difficult to find immunogenic epitopes which engage the T cells sufficiently to fight cancer effectively. Additionally, cancer heterogeneity makes the development of such epitopes even more difficult since...

The central nervous system (CNS) is composed of many populations of functionally specialized, spatially organized and highly interacting cells, including neurons, astrocytes, oligodendrocytes and microglia. The ability of these cell populations to sustain their physiological functions is regulated by complex molecular networks. Experimental techniq...

Pathologic conditions in which the body's own response to an insult is the most damaging aspect of the disease, such as in auto-immunity and sepsis, have seen researchers and clinicians struggle to find therapeutic targets for decades. Large clinical cohorts and advanced molecular biology are key elements in the search for new medications. Methodol...

Glaucoma is an eye disease characterized by progressive damage to the optic nerve, often associated to high intraocular pressure, which causes vision impairment and vision loss in long term at the terminal phase. Glaucoma is a multifactorial disease because polymorphisms and deregulation of multiple genes are involved in the onset and development o...

Collecting duct carcinoma (CDC) is a rare renal cell carcinoma subtype with a very poor prognosis. There have been only a few studies on gene expression analysis in CDCs. We compared the gene expression profiles of two CDC cases with those of eight normal tissues of renal cell carcinoma patients. At a threshold of |log2fold-change| ≥ 1, 3349 genes...

Before and after surgery melanoma patients harbor elevated levels of extracellular vesicles in plasma (pEV), but their cellular origin is obscure. Here we suggest that these pEV are secreted in part by tumor cells, but particularly by liver and peripheral blood mononuclear cells (PBMC), which strongly suppressed tumor cell activity. As the cellular...

Apart from dedicated oligodendroglial progenitor cells, adult neural stem cells (aNSCs) can also give rise to new oligodendrocytes in the adult central nervous system (CNS). This process mainly confers myelinating glial cell replacement in pathological situations and can hence contribute to glial heterogeneity. Our previous studies demonstrated tha...

Macrophages are considered to contribute to chronic inflammatory diseases such as rheumatoid arthritis¹. However, both the exact origin and the role of macrophages in inflammatory joint disease remain unclear. Here we use fate-mapping approaches in conjunction with three-dimensional light-sheet fluorescence microscopy and single-cell RNA sequencing...

INTRODUCTION • E2F1 overexpression across high-grade tumors culminates in unfavorable prognosis and chemoresistance in patients. METHODS • We integrated bioinformatics, structural and kinetic modelling, and experiments to study regulation of E2F1 by cooperative microRNAs (miRNAs) in the context of anticancer chemotherapy resistance. RESULTS • We us...

The development of new theories, mathematical methods and models for effective control of complex systems is one of the main problems for modern science. Biological systems are complex and hierarchically organized, with the behaviour of higher levels influencing the dynamics of the lower ones and vice versa. Hierarchical organization can be observe...

We simulated all possible initial states of the network (2 29) and have obtained 72 attractors using a synchronous simulation. Over the 72 attractors, 40 were classified as fixed-point attractors and 32 as cyclic attractors. The latter ones can be further distinguished in bi-stable states (25 %) and tetra-stable states (75 %). In these cyclic attra...

The polarization of macrophages is regulated by transcription factors such as nuclear factor kappa B (NF-κB) and activator protein 1 (AP-1). In this manuscript, we delineated the role of the transcription factor Fos-related antigen 1 (Fra-1) during macrophage activation and development of arthritis. Network level interaction analysis of microarray...

Melanoma is a highly aggressive tumor with a strong dependence on intracellular signaling pathways. Almost half of all melanomas are driven by mutations in the v-Raf murine sarcoma viral oncogene homolog B (BRAF) with BRAFV600E being the most prevalent mutation. Recently developed targeted treatment directed against mutant BRAF and downstream mitog...

Upon tumor development, new extracellular vesicles appear in circulation. Our knowledge of their relative abundance, function, and overall impact on cancer development is still preliminary. Here, we demonstrate that plasma extracellular vesicles (pEVs) of non-tumor origin are persistently increased in untreated and post-excision melanoma patients,...

Career situation of first and presenting author Student for a master or a PhD. Introduction The activator protein (AP)-1 transcription factor family, especially its subfamily of FOS proteins (cFos, FosB, Fra-1 and Fra-2) are associated to the regulatory network of macrophage responses. Moreover, it is well known that macrophages are central player...

Oligodendrocytes (OLs) facilitate information processing in the vertebrate central nervous system via axonal ensheathment. The structure and dynamics of the regulatory network that mediates oligodendrogenesis are poorly understood. We employed bioinformatics and meta‐analysis of high‐throughput datasets to reconstruct a regulatory network underpinn...

This volume details a collection of state-of-art methods including identification of novel ncRNAs and their targets, functional annotation and disease association in different biological contexts. Chapters guide readers through an overview of disease-specific ncRNAs, computational methods and workflows for ncRNA discovery, annotation based on high-...

Mathematical modeling of cell differentiated in colonic crypts can contribute to a better understanding of basic mechanisms underlying colonic tissue organization, but also its deregulation during carcinogenesis and tumor progression. Here, we combined bifurcation analysis to assess the effect that time delay has in the complex interplay of stem ce...

Background Community-acquired pneumonia (CAP) remains a major cause of death worldwide. Mechanisms underlying the detrimental outcome despite adequate antibiotic therapy and comorbidity management are still not fully understood. Methods To model timely versus delayed antibiotic therapy in patients, mice with pneumococcal pneumonia received ampicil...

Motivation Extracellular vesicles (EVs), including exosomes and microvesicles, are potent and clinically valuable tools for early diagnosis, prognosis and potentially the targeted treatment of cancer. The content of EVs is closely related to the type and status of the EV-secreting cell. Circulating exosomes are a source of stable RNAs including mRN...

Metastasis is one of the most challenging issues in cancer patient management, and effective therapies to specifically target disease progression are missing, emphasizing the urgent need for developing novel antimetastatic therapeutics. Cancer stem cells (CSCs) gained fast attention as a minor population of highly malignant cells within liquid and...

Pneumococcal infection is the most frequent cause of pneumonia, and one of the most prevalent diseases worldwide. The population groups at high risk of death from bacterial pneumonia are infants, elderly and immunosuppressed people. These groups are more vulnerable because they have immature or impaired immune systems, the efficacy of their respons...

A transcriptomic map of ligand expression in the choroid plexus. All transcripts enriched in the CP across multiple cell types presented as a heatmap. Red white and blue are relative intensity expression of 2, 0.5 and −1 respectively. CP, choroid plexus; aNSCs, active neural stem cells; qNSCs, quiescent neural stem cells; MGs, microglia; OPCs, olig...

A transcriptomic map of ligand expression in NSCs. All transcripts enriched in NSCs across multiple cell types presented as a heatmap. Red, white and blue are relative intensity expression of 2, 0.5, and −1 respectively. Gene symbols in red, light red and black show enrichment (≥1.8 fold change; ≤ 5% FDR) in qNSCs, aNSCs or homogenous expression to...

A transcriptomic map of ligand expression in adjacent glial cells. All transcripts enriched in glial cells across multiple cell types presented as a heatmap. Red, white and blue are relative intensity expression of 2, 0.5, and −1 respectively. CP, choroid plexus; aNSCs, active neural stem cells; qNSCs, quiescent neural stem cells; MGs, microglia; O...