Project description:Currently, several ?-synuclein immunotherapies are being tested in experimental Parkinson's disease models and in clinical trials. Recent research has revealed that ?-synuclein is not just an intracellular synaptic protein but also exists extracellularly. Moreover, the transfer of misfolded ?-synuclein between cells might be a crucial step in the process leading to a progressive increase in deposition of ?-synuclein aggregates throughout the Parkinson's disease brain. The revelation that ?-synuclein is present outside cells has increased the interest in antibody-based therapies and opens up for the notion that microglia might play a key role in retarding Parkinson's disease progression. The objectives of this review are to describe and contrast the use of active and passive immunotherapy in treating ?-synucleinopathies and highlight the likely important role of microglia in clearing misfolded ?-synuclein from the extracellular space.
Project description:BackgroundCancer cells possess a common metabolic phenotype, rewiring their metabolic pathways from mitochondrial oxidative phosphorylation to aerobic glycolysis and anabolic circuits, to support the energetic and biosynthetic requirements of continuous proliferation and migration. While, over the past decade, molecular and cellular studies have clearly highlighted the association of oncogenes and tumor suppressors with cancer-associated glycolysis, more recent attention has focused on the role of microRNAs (miRNAs) in mediating this metabolic shift. Accumulating studies have connected aberrant expression of miRNAs with direct and indirect regulation of aerobic glycolysis and associated pathways.Scope of reviewThis review discusses the underlying mechanisms of metabolic reprogramming in cancer cells and provides arguments that the earlier paradigm of cancer glycolysis needs to be updated to a broader concept, which involves interconnecting biological pathways that include miRNA-mediated regulation of metabolism. For these reasons and in light of recent knowledge, we illustrate the relationships between metabolic pathways in cancer cells. We further summarize our current understanding of the interplay between miRNAs and these metabolic pathways. This review aims to highlight important metabolism-associated molecular components in the hunt for selective preventive and therapeutic treatments.Major conclusionsMetabolism in cancer cells is influenced by driver mutations but is also regulated by posttranscriptional gene silencing. Understanding the nuanced regulation of gene expression in these cells and distinguishing rapid cellular responses from chronic adaptive mechanisms provides a basis for rational drug design and novel therapeutic strategies.
Project description:MicroRNAs (miRNAs) are short, non-protein-encoding RNAs that effect post-transcriptional gene regulation by targeting messenger RNAs. miRNAs are associated with specific human diseases and help regulate development. Here we review recent advances in understanding the roles of miRNAs in skeletal malformations, including cleft palate, and in the evolution of skeletal morphologies. We propose the hypothesis that evolutionary variation in miRNA expression patterns or structural variation in miRNA binding sites in messenger RNAs can help explain the evolution of craniofacial variation among species, the development of human craniofacial disease and physiological changes leading to osteopenia that increases with ageing.
Project description:What will be the role of the intensivist when computer-assisted decision support reaches maturity? Celi's group reports that Bayesian theory can predict a patient's fluid requirement on day 2 in 78% of cases, based on data collected on day 1 and the known associations between those data, based on observations in previous patients in their unit. There are both advantages and limitations to the Bayesian approach, and this test study identifies areas for improvement in future models. Although such models have the potential to improve diagnostic and therapeutic accuracy, they must be introduced judiciously and locally to maximize their effect on patient outcome. Efficacy is thus far undetermined, and these novel approaches to patient management raise new challenges, not least medicolegal ones.
Project description:MicroRNAs are implicated in many biological and pathological processes and are emerging as key actors in lung health and disease. Specific patterns of dysregulated microRNAs have been found in idiopathic pulmonary fibrosis (IPF), an untreatable interstitial lung disease of unknown etiology. IPF is characterized by dramatic and extensive phenotypic changes in the lung that include alveolar cell hyperplasia, fibroblast proliferation and formation of myofibroblast foci, deposition of extracellular matrix, and changes in lung transcriptional programming. Here, we discuss the latest insights about the role of microRNAs in lung fibrosis with a focus on the contribution of animal models of disease to the derivation of these insights.
Project description:Pediatric cardiac arrests carry significant morbidity and mortality. With increasing rates of return of spontaneous circulation, it is vital to optimize recovery conditions to decrease morbidity.MethodsWe evaluated all patients who presented to a large quaternary pediatric intensive care unit with return of spontaneous circulation. We compared patient-specific postcardiac arrest care preimplementation and postimplementation of a standardized postcardiac arrest resuscitation pathway. We implemented evidence-based best practices using the Translating Research into Practice framework and Plan-Do-Study-Act cycles. Our primary aim was to increase the percent of postcardiac arrest care events meeting guideline targets for blood pressure and temperature within the first 12 hours by 50% within 18 months.ResultsEighty-one events occurred in the preintervention group (August 1, 2016-April 30, 2018) and 64 in the postintervention group (May 1, 2018-December 1, 2019). The percent of postcardiac arrest events meeting guideline targets for the entirety of their postarrest period improved from 10.9% for goal mean arterial blood pressure to 26.3%, P = 0.03, and increased from 23.4% for temperature to 71.9%, P < 0.0001.ConclusionsImplementing a postcardiac arrest standardized care plan improved adherence to evidence-based postcardiac arrest care metrics, specifically preventing hypotension and hyperthermia. Future multicenter research is needed to link guideline adherence to patient outcomes.
Project description:Healthcare workers (HCWs) are a high-risk group for hepatitis B virus (HBV) infection. Notably, about 5–10% of the general population does not respond to the HBV vaccination. In this study, we aimed to investigate DNA methylation (DNAm) in order to estimate the biological age of B cells from HCW of both sexes, either responder (R) or non-responder (NR), to HBV vaccination. We used genome-wide DNA methylation data to calculate a set of biomarkers in B cells collected from 41 Rs and 30 NRs between 22 and 62 years old. Unresponsiveness to HBV vaccination was associated with accelerated epigenetic aging (DNAmAge, AltumAge, DunedinPoAm) and was accompanied by epigenetic drift. Female non-responders had higher estimates of telomere length and lower CRP inflammation risk score when compared to responders. Overall, epigenetic differences between responders and non-responders were more evident in females than males. In this study we demonstrated that several methylation DNAm-based clocks and biomarkers are associated with an increased risk of non-response to HBV vaccination, particularly in females. Based on these results, we propose that accelerated epigenetic age could contribute to vaccine unresponsiveness. These insights may help improve the evaluation of the effectiveness of vaccination strategies, especially among HCWs and vulnerable patients.