The epicardium is an essential cell population during cardiac development. It contributes different cell types to the developing heart through epithelial-to-mesenchymal transition (EMT) and it... Show moreThe epicardium is an essential cell population during cardiac development. It contributes different cell types to the developing heart through epithelial-to-mesenchymal transition (EMT) and it secretes paracrine factors that support cardiac tissue formation. In the adult heart the epicardium is a quiescent layer of cells which can be reactivated upon ischemic injury, initiating an embryonic-like response in the epicardium that contributes to post-injury repair processes. Therefore, the epicardial layer is considered an interesting target population to stimulate endogenous repair mechanisms. To date it is still not clear whether there are distinct cell populations in the epicardium that contribute to specific lineages or aid in cardiac repair, or that the epicardium functions as a whole. To address this putative heterogeneity, novel techniques such as single cell RNA sequencing (scRNA seq) are being applied. In this review, we summarize the role of the epicardium during development and after injury and provide an overview of the most recent insights into the cellular composition and diversity of the epicardium. Show less
Blankenstein, N.E.; Rooij, M. de; Ginkel, J. van; Wilderjans, T.F.; Ruigh, E.L. de; Oldenhof, H.C.; ... ; Jansen, L.M.C. 2021
Background Antisociality across adolescence and young adulthood puts individuals at high risk of developing a variety of problems. Prior research has linked antisociality to autonomic nervous... Show moreBackground Antisociality across adolescence and young adulthood puts individuals at high risk of developing a variety of problems. Prior research has linked antisociality to autonomic nervous system and endocrinological functioning. However, there is large heterogeneity in antisocial behaviors, and these neurobiological measures are rarely studied conjointly, limited to small specific studies with narrow age ranges, and yield mixed findings due to the type of behavior examined. Methods We harmonized data from 1489 participants (9-27 years, 67% male), from six heterogeneous samples. In the resulting dataset, we tested relations between distinct dimensions of antisociality and heart rate, pre-ejection period (PEP), respiratory sinus arrhythmia, respiration rate, skin conductance levels, testosterone, basal cortisol, and the cortisol awakening response (CAR), and test the role of age throughout adolescence and young adulthood. Results Three dimensions of antisociality were uncovered: 'callous-unemotional (CU)/manipulative traits', 'intentional aggression/conduct', and 'reactivity/impulsivity/irritability'. Shorter PEPs and higher testosterone were related to CU/manipulative traits, and a higher CAR is related to both CU/manipulative traits and intentional aggression/conduct. These effects were stable across age. Conclusions Across a heterogeneous sample and consistent across development, the CAR may be a valuable measure to link to CU/manipulative traits and intentional aggression, while sympathetic arousal and testosterone are additionally valuable to understand CU/manipulative traits. Together, these findings deepen our understanding of the fundamental mechanisms underlying different components of antisociality. Finally, we illustrate the potential of using current statistical techniques for combining multiple datasets to draw robust conclusions about biobehavioral associations. Show less
Oost, S. van; Meijer, D.M.; Kuijjer, M.L.; Bovee, J.V.M.G.; Miranda, N.F.C.C. de 2021
Sarcomas comprise a collection of highly heterogeneous malignancies that can be grossly grouped in the categories of sarcomas with simple or complex genomes. Since the outcome for most sarcoma... Show moreSarcomas comprise a collection of highly heterogeneous malignancies that can be grossly grouped in the categories of sarcomas with simple or complex genomes. Since the outcome for most sarcoma patients has barely improved in the last decades, there is an urgent need for improved therapies. Immunotherapy, and especially T cell checkpoint blockade, has recently been a game-changer in cancer therapy as it produced significant and durable treatment responses in several cancer types. Currently, only a small fraction of sarcoma patients benefit from immunotherapy, supposedly due to a general lack of somatically mutated antigens (neoantigens) and spontaneous T cell immunity in most cancers. However, genomic events resulting from chromosomal instability are frequent in sarcomas with complex genomes and could drive immunity in those tumors. Improving our understanding of the mechanisms that shape the immune landscape of sarcomas will be crucial to overcoming the current challenges of sarcoma immunotherapy. This review focuses on what is currently known about the tumor microenvironment in sarcomas and how this relates to their genomic features. Moreover, we discuss novel therapeutic strategies that leverage the tumor microenvironment to increase the clinical efficacy of immunotherapy, and which could provide new avenues for the treatment of sarcomas. Show less
Background: In Parkinson's disease (PD), there is heterogeneity in the clinical presentation and underlying biology. Research on PD subtypes aims to understand this heterogeneity with potential... Show moreBackground: In Parkinson's disease (PD), there is heterogeneity in the clinical presentation and underlying biology. Research on PD subtypes aims to understand this heterogeneity with potential contribution for the knowledge of disease pathophysiology, natural history and therapeutic development. There have been many studies of PD subtypes but their impact remains unclear with limited application in research or clinical practice.Objective: To critically evaluate PD subtyping systems.Methods: We conducted a systematic review of PD subtypes, assessing the characteristics of the studies reporting a subtyping system for the first time. We completed a critical appraisal of their methodologic quality and clinical applicability using standardized checklists.Results: We included 38 studies. The majority were cross-sectional (n = 26, 68.4%), used a data-driven approach (n = 25, 65.8%), and non-clinical biomarkers were rarely used (n = 5, 13.1%). Motor characteristics were the domain most commonly reported to differentiate PD subtypes. Most of the studies did not achieve the top rating across items of a Methodologic Quality checklist. In a Clinical Applicability Checklist, the clinical importance of differences between subtypes, potential treatment implications and applicability to the general population were rated poorly, and subtype stability over time and prognostic value were largely unknown.Conclusion: Subtyping studies undertaken to date have significant methodologic shortcomings and most have questionable clinical applicability and unknown biological relevance. The clinical and biological signature of PD may be unique to the individual, rendering PD resistant to meaningful cluster solutions. New approaches that acknowledge the individual-level heterogeneity and that are more aligned with personalized medicine are needed. Show less
Gracht, E.T.I. van der; Behr, F.M.; Arens, R. 2021
Tissue-resident memory T (T-RM) cells mediate potent local innate and adaptive immune responses and provide long-lasting protective immunity. T-RM cells localize to many different tissues,... Show moreTissue-resident memory T (T-RM) cells mediate potent local innate and adaptive immune responses and provide long-lasting protective immunity. T-RM cells localize to many different tissues, including barrier tissues, and play a crucial role in protection against infectious and malignant disease. The formation and maintenance of T-RM cells are influenced by numerous factors, including inflammation, antigen triggering, and tissue-specific cues. Emerging evidence suggests that these signals also contribute to heterogeneity within the T-RM cell compartment. Here, we review the phenotypic and functional heterogeneity of CD8(+) T-RM cells at different tissue sites and the molecular determinants defining CD8(+) T-RM cell subsets. We further discuss the possibilities of targeting the unique cell surface molecules, cytokine and chemokine receptors, transcription factors, and metabolic features of T-RM cells for therapeutic purposes. Their crucial role in immune protection and their location at the frontlines of the immune defense make T-RM cells attractive therapeutic targets. A better understanding of the possibilities to selectively modulate T-RM cell populations may thus improve vaccination and immunotherapeutic strategies employing these potent immune cells. Show less
Eekelen, R. van; Putter, H.; McLernon, D.J.; Eijkemans, M.J.; Geloven, N. van 2019
Clinical prediction models aim to provide estimates of absolute risk for a diagnostic or prognostic endpoint. Such models may be derived from data from various studies in the context of a meta... Show moreClinical prediction models aim to provide estimates of absolute risk for a diagnostic or prognostic endpoint. Such models may be derived from data from various studies in the context of a meta-analysis. We describe and propose approaches for assessing heterogeneity in predictor effects and predictions arising from models based on data from different sources. These methods are illustrated in a case study with patients suffering from traumatic brain injury, where we aim to predict 6-month mortality based on individual patient data using meta-analytic techniques (15 studies, n = 11 022 patients). The insights into various aspects of heterogeneity are important to develop better models and understand problems with the transportability of absolute risk predictions. Show less
