The role of epigenetics in renal ageing

An ability to separate natural ageing processes from processes specific to morbidities is required to understand the heterogeneity of age-related organ dysfunction. Mechanistic insight into how epigenetic factors regulate ageing throughout the life course, linked to a decline in renal function with ageing, is already proving to be of value in the analyses of clinical and epidemiological cohorts. Noncoding RNAs provide epigenetic regulatory circuits within the kidney, which reciprocally interact with DNA methylation processes, histone modification and chromatin. These interactions have been demonstrated to reflect the biological age and function of renal allografts. Epigenetic factors control gene expression and activity in response to environmental perturbations. They also have roles in highly conserved signalling pathways that modulate ageing, including the mTOR and insulin/insulin-like growth factor signalling pathways, and regulation of sirtuin activity. Nutrition, the gut microbiota, inflammation and environmental factors, including psychosocial and lifestyle stresses, provide potential mechanistic links between the epigenetic landscape of ageing and renal dysfunction. Approaches to modify the renal epigenome via nutritional intervention, targeting the methylome or targeting chromatin seem eminently feasible, although caution is merited owing to the potential for intergenerational and transgenerational effects

Big science and big data in nephrology

There have been tremendous advances during the last decade in methods for large-scale, high-throughput data generation and in novel computational approaches to analyze these datasets. These advances have had a profound impact on biomedical research and clinical medicine. The field of genomics is rapidly developing toward single-cell analysis, and major advances in proteomics and metabolomics have been made in recent years. The developments on wearables and electronic health records are poised to change clinical trial design. This rise of ‘big data’ holds the promise to transform not only research progress, but also clinical decision making towards precision medicine. To have a true impact, it requires integrative and multi-disciplinary approaches that blend experimental, clinical and computational expertise across multiple institutions. Cancer research has been at the forefront of the progress in such large-scale initiatives, so-called ‘big science,’ with an emphasis on precision medicine, and various other areas are quickly catching up. Nephrology is arguably lagging behind, and hence these are exciting times to start (or redirect) a research career to leverage these developments in nephrology. In this review, we summarize advances in big data generation, computational analysis, and big science initiatives, with a special focus on applications to nephrology

Cardio-oncology: new insights into association and interaction between cardiovascular disease and cancer

Cardiovascular disease (CVD) and cancer stand as the top leading causes of morbidity and mortality. The emerging field of Cardio-Oncology has unveiled their intricate connection, which arises from the cardiotoxicity of cancer treatments, common risk factors, and the potential for cardiac dysfunction to accelerate cancer progression. Consequently, there's a growing academic interest and clinical importance to investigate the link between these conditions and the underlying mechanism. In this thesis, we studied the CVD-cancer association from various perspectives. We assessed tumour biomarkers in heart failure (HF) patients, revealing that several biomarkers significantly correlate with adverse HF outcomes, indicating shared pathophysiological processes.Additionally, our investigation into clonal haematopoiesis of indeterminate potential (CHIP) showed that CHIP primarily associates with incident HF in individuals < 65 years, which underscores the importance of early detection and prevention of CHIP. We also explored the impact of HF on tumour growth and could show that this varies among different cancer types. Notably, HF didn't promote renal cancer growth in our study, cautioning against broad generalizations about HF-cancer interaction.Furthermore, we provided multi-omics characterization of myocardial tissue in three different HF mouse models (MI, TAC and PLN-R14Δ/Δ), investigated myostatin inhibition in cardiac pressure-overloaded mice, and summarized findings on shared risk factors, mechanisms, and pathophysiological signalling pathways linking cancer with other multifactorial diseases (CVDs, CKD, COPD and MAFLD).In conclusion, this thesis contributes valuable insights to the Cardio-Oncology field, enhancing clinicians' awareness of the potential risks associated with co-morbid HF/cancer, and facilitating safe and efficacious medication use in clinical practice

Interplay between inflammation and calcification in cardiovascular diseases

Cardiovascular calcification has been linked to all-cause mortality and is a broadly adopted predictor of cardiovascular (CV) events. Rather than a mere by-product of the changing disease environment, calcification impacts actively the disease progression and pathogenesis as it predominates both in early- and late-stages, through mediating tissue biomechanical destabilisation and directly impacting tissue inflammation. However, its clinical contribution to the fate of the disease remains to be elucidated. Emerging body of evidence from both basic and clinical research has demonstrated the significance of the innate immune system in cardiovascular diseases (CVDs). Here, inflammation and calcification are engaged in a vicious cycle particularly at early-stages, whereas in advanced-lesions, large calcifications linked with suppressed inflammation and plaque stability. However, this interaction during disease progression remains largely elusive. The aim of this thesis is to investigate the interplay between inflammation and calcification in advanced atherosclerosis and calcific aortic valve disease (CAVD). Study I explores gene and protein expression signatures and biological pathways of advanced CAVD lesions in order to characterise the underlining mechanisms associated with the disease pathology. Multi-omics integration of overlapping transcriptome/proteome molecules with miRNAs, identified a unique CAVD-related protein-protein 3D layered interaction network. After addition of a metabolite layer, Alzheimer's disease (AD) was identified in the core of the gene-disease network. This study suggests a novel molecular CAVD network potentially linked to amyloid-like structures formation. Study II characterises osteomodulin (OMD) in the context of atherosclerosis, chronic kidney disease (CKD) and CAVD. Plasma OMD levels were correlated with markers of inflammation and bone turnover, with the protein being present in the calcified arterial media of patients with CKD stage 5. Circulating OMD levels were also associated with cardiac valve calcification in the same patients and its positive signal was detected in calcified valve leaflets by immunohistochemistry. In patients with carotid atherosclerosis, plasma OMD levels were increased in association with plaque calcification as assessed by computed tomography. Transcriptomic and proteomic data analysis showed that OMD expression was upregulated in atherosclerotic compared to non-atherosclerotic control arteries, and particularly in highly calcified plaques, where its expression correlated positively with markers of vascular smooth muscle cells (VSMCs) and osteoblasts. In vivo, OMD was enriched in VSMCs around calcified nodules in aortic media of nephrectomised rats and in plaques from ApoE-/- mice on warfarin. In vitro experiments revealed that exogenous administration of recombinant human OMD protein repressed the calcification process of VSMCs treated with phosphate by maintaining the VSMC contractile phenotype along with enriched extracellular matrix (ECM) organisation, thereby attenuating VSMC osteoblastic transformation. Study III analyses OMD expression in human carotid plaques and particularly its link with future CV events. Transcriptomic analysis revealed that OMD levels were increased in plaques from asymptomatic patients compared to symptomatic ones, with high levels being associated with fewer CV events in a follow-up analysis. Study IV investigates the link between mast cell (MC) activation and key features of human plaque vulnerability, and the role of MC in VSMC-mediated calcification. Integrative analyses from a large biobank of human plaques showed that MC activation is inversely associated with macrocalcification and positively with morphological parameters of plaque vulnerability. Bioinformatic analyses revealed associations of MCs with NK cells and other immune cells in plaques. Mechanistic in vitro experiments showed that calcification attenuated MC activation, while both active and resting MCs induced VSMC calcification and triggered their dedifferentiation towards a pro-inflammatory- and osteochondrocyte-like phenotype. Overall, this thesis demonstrates that the underlying mechanisms of CVD related to inflammation and calcification can be comprehensively characterised by integration of largescale multi-omics datasets along with cellular and molecular assays on one side, and disease specific biomarkers and advanced diagnostic imaging tools on the other. In summary, these studies not only indicate that advanced-calcification is a stabilising factor for plaque and disease progression but also, unveil novel insights into the cardiovascular calcification pathobiology, and offer promising biomarkers and new therapeutic avenues for further exploration

From Mouse Models to Patients: A Comparative Bioinformatic Analysis of HFpEF and HFrEF

Heart failure (HF) represents an immense health burden with currently no curative therapeutic strategies. Study of HF patient heterogeneity has led to the recognition of HF with preserved (HFpEF) and reduced ejection fraction (HFrEF) as distinct syndromes regarding molecular characteristics and clinical presentation. Until the recent past, HFrEF represented the focus of research, reflected in the development of a number of therapeutic strategies. However, the pathophysiological concepts applicable to HFrEF may not be necessarily applicable to HFpEF. HF induces a series of ventricular modeling processes that involve, among others, hallmarks of hypertrophy, fibrosis, inflammation, all of which can be observed to some extent in HFpEF and HFrEF. Thus, by direct comparative analysis between HFpEF and HFrEF, distinctive features can be uncovered, possibly leading to improved pathophysiological understanding and opportunities for therapeutic intervention. Moreover, recent advances in biotechnologies, animal models, and digital infrastructure have enabled large-scale collection of molecular and clinical data, making it possible to conduct a bioinformatic comparative analysis of HFpEF and HFrEF. Here, I first evaluated the field of HF transcriptome research by revisiting published studies and data sets to provide a consensus gene expression reference. I discussed the patient clientele that was captured, revealing that HFpEF patients were not represented. Thus, I applied alternative approaches to study HFpEF. I utilized a mouse surrogate model of HFpEF and analyzed single cell transcriptomics to gain insights into the interstitial tissue remodeling. I contrasted this analysis by comparison of fibroblast activation patterns found in mouse models resembling HFrEF. The human reference was used to further demonstrate similarities between models and patients and a novel possible biomarker for HFpEF was introduced. Mouse models only capture selected aspects of HFpEF but largely fail to imitate the complex multi-factor and multi-organ syndrome present in humans. To account for this complexity, I performed a top-down analysis in HF patients by analyzing phenome-wide comorbidity patterns. I derived clinical insights by contrasting HFpEF and HFrEF patients and their comorbidity profiles. These profiles were then used to predict associated genetic profiles, which could be also recovered in the HFpEF mouse model, providing hypotheses about the molecular links of comorbidity profiles. My work provided novel insights into HFpEF and HFrEF syndromes and exemplified an interdisciplinary bioinformatic approach for a comparative analysis of both syndromes using different data modalities

The European Hematology Association Roadmap for European Hematology Research: a consensus document

The European Hematology Association (EHA) Roadmap for European Hematology Research highlights major achievements in diagnosis and treatment of blood disorders and identifies the greatest unmet clinical and scientific needs in those areas to enable better funded, more focused European hematology research. Initiated by the EHA, around 300 experts contributed to the consensus document, which will help European policy makers, research funders, research organizations, researchers, and patient groups make better informed decisions on hematology research. It also aims to raise public awareness of the burden of blood disorders on European society, which purely in economic terms is estimated at €23 billion per year, a level of cost that is not matched in current European hematology research funding. In recent decades, hematology research has improved our fundamental understanding of the biology of blood disorders, and has improved diagnostics and treatments, sometimes in revolutionary ways. This progress highlights the potential of focused basic research programs such as this EHA Roadmap. The EHA Roadmap identifies nine ‘sections’ in hematology: normal hematopoiesis, malignant lymphoid and myeloid diseases, anemias and related diseases, platelet disorders, blood coagulation and hemostatic disorders, transfusion medicine, infections in hematology, and hematopoietic stem cell transplantation. These sections span 60 smaller groups of diseases or disorders. The EHA Roadmap identifies priorities and needs across the field of hematology, including those to develop targeted therapies based on genomic profiling and chemical biology, to eradicate minimal residual malignant disease, and to develop cellular immunotherapies, combination treatments, gene therapies, hematopoietic stem cell treatments, and treatments that are better tolerated by elderly patients

The European Hematology Association Roadmap for European Hematology Research. A Consensus Document

Abstract The European Hematology Association (EHA) Roadmap for European Hematology Research highlights major achievements in diagnosis and treatment of blood disorders and identifies the greatest unmet clinical and scientific needs in those areas to enable better funded, more focused European hematology research. Initiated by the EHA, around 300 experts contributed to the consensus document, which will help European policy makers, research funders, research organizations, researchers, and patient groups make better informed decisions on hematology research. It also aims to raise public awareness of the burden of blood disorders on European society, which purely in economic terms is estimated at Euro 23 billion per year, a level of cost that is not matched in current European hematology research funding. In recent decades, hematology research has improved our fundamental understanding of the biology of blood disorders, and has improved diagnostics and treatments, sometimes in revolutionary ways. This progress highlights the potential of focused basic research programs such as this EHA Roadmap. The EHA Roadmap identifies nine sections in hematology: normal hematopoiesis, malignant lymphoid and myeloid diseases, anemias and related diseases, platelet disorders, blood coagulation and hemostatic disorders, transfusion medicine, infections in hematology, and hematopoietic stem cell transplantation. These sections span 60 smaller groups of diseases or disorders. The EHA Roadmap identifies priorities and needs across the field of hematology, including those to develop targeted therapies based on genomic profiling and chemical biology, to eradicate minimal residual malignant disease, and to develop cellular immunotherapies, combination treatments, gene therapies, hematopoietic stem cell treatments, and treatments that are better tolerated by elderly patients. Received December 15, 2015. Accepted January 27, 2016. Copyright © 2016, Ferrata Storti Foundatio