85 research outputs found
Cardiac innervation in acute myocardial ischaemia/reperfusion injury and cardioprotection
Acute myocardial infarction (AMI) and the heart failure (HF) that often complicates this condition, are among the leading causes of death and disability worldwide. To reduce myocardial infarct (MI) size and prevent heart failure, novel therapies are required to protect the heart against the detrimental effects of acute ischaemia/reperfusion injury (IRI). In this regard, targeting cardiac innervation may provide a novel therapeutic strategy for cardioprotection. A number of cardiac neural pathways mediate the beneficial effects of cardioprotective strategies such as ischaemic preconditioning and remote ischaemic conditioning, and nerve stimulation may therefore provide a novel therapeutic strategy for cardioprotection. In this article, we provide an overview of cardiac innervation and its impact on acute myocardial IRI, the role of extrinsic and intrinsic cardiac neural pathways in cardioprotection, and highlight peripheral and central nerve stimulation as a cardioprotective strategy with therapeutic potential for reducing MI size and preventing HF following AMI. This article is part of a Cardiovascular Research Spotlight Issue entitled 'Cardioprotection Beyond the Cardiomyocyte', and emerged as part of the discussions of the European Union (EU)-CARDIOPROTECTION Cooperation in Science and Technology (COST) Action, CA16225
Prognostic benefit of surgical management in renal cell carcinoma patients with thrombus extending to the renal vein and inferior vena cava: 17-year experience at a single center
Many LINE1 elements contribute to the transcriptome of human somatic cells
Over 600 LINE 1 elements are shown to be transcribed in humans; 400 of these are full-length elements in the reference genome
Engineering selection stringency on expression vector for the production of recombinant human alpha1-antitrypsin using Chinese Hamster ovary cells
Burden of disease attributable to risk factors in European countries: a scoping literature review
Objectives: Within the framework of the burden of disease (BoD) approach, disease, and injury burden estimates attributable to risk factors are a useful guide for policy formulation and priority setting in disease prevention. Considering the important differences in methods, and their impact on burden estimates, we conducted a scoping literature review to: (1) map the BoD assessments including risk factors performed across Europe, and (2) identify the methodological choices in comparative risk assessment (CRA) and risk assessment methods. Methods: We searched multiple literature databases, including grey literature websites, and targeted public health agencies' websites. Results: A total of 113 studies were included in the synthesis and further divided into independent BoD assessments (54 studies) and studies linked to the Global Burden of Disease (59 papers). Our results showed that the methods used to perform CRA varied substantially across independent European BoD studies. While there were some methodological choices that were more common than others, we did not observe patterns in terms of country, year, or risk factor. Each methodological choice can affect the comparability of estimates between and within countries and/or risk factors since they might significantly influence the quantification of the attributable burden. From our analysis, we observed that the use of CRA was less common for some types of risk factors and outcomes. These included environmental and occupational risk factors, which are more likely to use bottom-up approaches for health outcomes where disease envelopes may not be available. Conclusions: Our review also highlighted misreporting, the lack of uncertainty analysis, and the under-investigation of causal relationships in BoD studies. Development and use of guidelines for performing and reporting BoD studies will help understand differences, and avoid misinterpretations thus improving comparability among estimates.info:eu-repo/semantics/publishedVersio
Reprogramming triggers endogenous L1 and Alu retrotransposition in human induced pluripotent stem cells
Human induced pluripotent stem cells (hiPSCs) are capable of unlimited proliferation and can differentiate in vitro to generate derivatives of the three primary germ layers. Genetic and epigenetic abnormalities have been reported by Wissing and colleagues to occur during hiPSC derivation, including mobilization of engineered LINE-1 (L1) retrotransposons. However, incidence and functional impact of endogenous retrotransposition in hiPSCs are yet to be established. Here we apply retrotransposon capture sequencing to eight hiPSC lines and three human embryonic stem cell (hESC) lines, revealing endogenous L1, Alu and SINE-VNTR-Alu (SVA) mobilization during reprogramming and pluripotent stem cell cultivation. Surprisingly, 4/7 de novo L1 insertions are full length and 6/11 retrotransposition events occurred in protein-coding genes expressed in pluripotent stem cells. We further demonstrate that an intronic L1 insertion in the CADPS2 gene is acquired during hiPSC cultivation and disrupts CADPS2 expression. These experiments elucidate endogenous retrotransposition, and its potential consequences, in hiPSCs and hESCs
The impact of transposable element activity on therapeutically relevant human stem cells
Human stem cells harbor significant potential for basic and clinical translational research as well as regenerative
medicine. Currently ~ 3000 adult and ~ 30 pluripotent stem cell-based, interventional clinical trials are ongoing
worldwide, and numbers are increasing continuously. Although stem cells are promising cell sources to treat a
wide range of human diseases, there are also concerns regarding potential risks associated with their clinical use,
including genomic instability and tumorigenesis concerns. Thus, a deeper understanding of the factors and
molecular mechanisms contributing to stem cell genome stability are a prerequisite to harnessing their therapeutic
potential for degenerative diseases. Chemical and physical factors are known to influence the stability of stem cell
genomes, together with random mutations and Copy Number Variants (CNVs) that accumulated in cultured human
stem cells. Here we review the activity of endogenous transposable elements (TEs) in human multipotent and
pluripotent stem cells, and the consequences of their mobility for genomic integrity and host gene expression. We
describe transcriptional and post-transcriptional mechanisms antagonizing the spread of TEs in the human genome,
and highlight those that are more prevalent in multipotent and pluripotent stem cells. Notably, TEs do not only
represent a source of mutations/CNVs in genomes, but are also often harnessed as tools to engineer the stem cell
genome; thus, we also describe and discuss the most widely applied transposon-based tools and highlight the
most relevant areas of their biomedical applications in stem cells. Taken together, this review will contribute to the
assessment of the risk that endogenous TE activity and the application of genetically engineered TEs constitute for
the biosafety of stem cells to be used for substitutive and regenerative cell therapiesS.R.H. and P.T.R. are funded by the Government of Spain (MINECO, RYC-2016-
21395 and SAF2015–71589-P [S.R.H.]; PEJ-2014-A-31985 and SAF2015–71589-
P [P.T.R.]). GGS is supported by a grant from the Ministry of Health of the
Federal Republic of Germany (FKZ2518FSB403)
Somatic retrotransposition alters the genetic landscape of the human brain
Retrotransposons are mobile genetic elements that use a germline 'copy-and-paste' mechanism to spread throughout metazoan genomes. At least 50 per cent of the human genome is derived from retrotransposons, with three active families (L1, Alu and SVA) associated with insertional mutagenesis and disease. Epigenetic and post-transcriptional suppression block retrotransposition in somatic cells, excluding early embryo development and some malignancies. Recent reports of L1 expression and copy number variation in the human brain suggest that L1 mobilization may also occur during later development. However, the corresponding integration sites have not been mapped. Here we apply a high-throughput method to identify numerous L1, Alu and SVA germline mutations, as well as 7,743 putative somatic L1 insertions, in the hippocampus and caudate nucleus of three individuals. Surprisingly, we also found 13,692 somatic Alu insertions and 1,350 SVA insertions. Our results demonstrate that retrotransposons mobilize to protein-coding genes differentially expressed and active in the brain. Thus, somatic genome mosaicism driven by retrotransposition may reshape the genetic circuitry that underpins normal and abnormal neurobiological processes
Cytokine serum levels during post-transplant adverse events in 61 pediatric patients after hematopoietic stem cell transplantation
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