In embryonic stem (ES) cells, bivalent chromatin domains with overlapping repressive (H3 lysine 27 tri-methylation) and activating (H3 lysine 4 tri-methylation) histone modifications mark the ...promoters of more than 2,000 genes. To gain insight into the structure and function of bivalent domains, we mapped key histone modifications and subunits of Polycomb-repressive complexes 1 and 2 (PRC1 and PRC2) genomewide in human and mouse ES cells by chromatin immunoprecipitation, followed by ultra high-throughput sequencing. We find that bivalent domains can be segregated into two classes -- the first occupied by both PRC2 and PRC1 (PRC1-positive) and the second specifically bound by PRC2 (PRC2-only). PRC1-positive bivalent domains appear functionally distinct as they more efficiently retain lysine 27 tri-methylation upon differentiation, show stringent conservation of chromatin state, and associate with an overwhelming number of developmental regulator gene promoters. We also used computational genomics to search for sequence determinants of Polycomb binding. This analysis revealed that the genomewide locations of PRC2 and PRC1 can be largely predicted from the locations, sizes, and underlying motif contents of CpG islands. We propose that large CpG islands depleted of activating motifs confer epigenetic memory by recruiting the full repertoire of Polycomb complexes in pluripotent cells.
In a cell-free approach to regenerative therapeutics, transient application of paracrine factors in vivo could be used to alter the behavior and fate of progenitor cells to achieve sustained clinical ...benefits. Here we show that intramyocardial injection of synthetic modified RNA (modRNA) encoding human vascular endothelial growth factor-A (VEGF-A) results in the expansion and directed differentiation of endogenous heart progenitors in a mouse myocardial infarction model. VEGF-A modRNA markedly improved heart function and enhanced long-term survival of recipients. This improvement was in part due to mobilization of epicardial progenitor cells and redirection of their differentiation toward cardiovascular cell types. Direct in vivo comparison with DNA vectors and temporal control with VEGF inhibitors revealed the greatly increased efficacy of pulse-like delivery of VEGF-A. Our results suggest that modRNA is a versatile approach for expressing paracrine factors as cell fate switches to control progenitor cell fate and thereby enhance long-term organ repair.
Lyme carditis, defined as direct infection of cardiac tissue by Borrelia bacteria, affects up to 10% of patients with Lyme disease. The most frequently reported clinical manifestation of Lyme ...carditis is cardiac conduction system disease. The goal of this study was to identify the incidence and predictors of permanent pacemaker implantation in patients hospitalized with Lyme disease.
A retrospective cohort analysis of the Nationwide Inpatient sample was performed to identify patients hospitalized with Lyme disease in the US between 2003 and 2014. Patients with Lyme carditis were defined as those hospitalized with Lyme disease who also had cardiac conduction disease, acute myocarditis, or acute pericarditis. Patients who already had pacemaker implants at the time of hospitalization (N = 310) were excluded from the Lyme carditis subgroup. The primary study outcome was permanent pacemaker implantation. Secondary outcomes included temporary cardiac pacing, permanent pacemaker implant, and in-hospital mortality.
Of the 96,140 patients hospitalized with Lyme disease during the study period, 10,465 (11%) presented with Lyme carditis. Cardiac conduction system disease was present in 9,729 (93%) of patients with Lyme carditis. Permanent pacemaker implantation was performed in 1,033 patients (1% of all Lyme hospitalizations and 11% of patients with Lyme carditis-associated conduction system disease). Predictors of permanent pacemaker implantation included older age (OR: 1.06 per 1 year; 95% CI:1.05-1.07; P<0.001), complete heart block (OR: 21.5; 95% CI: 12.9-35.7; P<0.001), and sinoatrial node dysfunction (OR: 16.8; 95% CI: 8.7-32.6; P<0.001). In-hospital mortality rate was higher in patients with Lyme carditis (1.5%) than in patients without Lyme carditis (0.5%).
Approximately 11% of patients hospitalized with Lyme disease present with carditis, primarily in the form of cardiac conduction system disease. In this 12-year study, 1% of all hospitalized patients and 11% of those with Lyme-associated cardiac conduction system disease underwent permanent pacemaker implantation.
Towards regenerative therapy for cardiac disease Ptaszek, Leon M, MD; Mansour, Moussa, MD; Ruskin, Jeremy N, MD ...
The Lancet (British edition),
03/2012, Volume:
379, Issue:
9819
Journal Article
Peer reviewed
Summary Development of regenerative therapeutic strategies to reverse the progression of advanced heart failure is one of the most urgent clinical needs of this century. Insights gained from clinical ...trials of adult stem cells, together with fundamental scientific advances in cardiac stem cell and regenerative biology, are beginning to yield potential new targets and strategies for regenerative therapies. Of particular importance are new scientific discoveries related to intrinsic cardiac regeneration, renewal factors that can trigger regeneration, and tissue-engineering technology, which are beginning to change the way investigators view the scientific and clinical position of cardiovascular regenerative therapy.
Chikungunya virus (CHIKV) infection causes acute disease characterized by fever, rash and arthralgia, which progresses to severe and chronic arthritis in up to 50% of patients. Moreover, CHIKV ...infection can be fatal in infants or immunocompromised individuals and has no approved therapy or prevention. This phase 1, first-in-human, randomized, placebo-controlled, proof-of-concept trial conducted from January 2019 to June 2020 evaluated the safety and pharmacology of mRNA-1944, a lipid nanoparticle-encapsulated messenger RNA encoding the heavy and light chains of a CHIKV-specific monoclonal neutralizing antibody, CHKV-24 ( NCT03829384 ). The primary outcome was to evaluate the safety and tolerability of escalating doses of mRNA-1944 administered via intravenous infusion in healthy participants aged 18-50 years. The secondary objectives included determination of the pharmacokinetics of mRNA encoding for CHKV-24 immunoglobulin heavy and light chains and ionizable amino lipid component and the pharmacodynamics of mRNA-1944 as assessed by serum concentrations of mRNA encoding for CHKV-24 immunoglobulin G (IgG), plasma concentrations of ionizable amino lipid and serum concentrations of CHKV-24 IgG. Here we report the results of a prespecified interim analysis of 38 healthy participants who received intravenous single doses of mRNA-1944 or placebo at 0.1, 0.3 and 0.6 mg kg
, or two weekly doses at 0.3 mg kg
. At 12, 24 and 48 h after single infusions, dose-dependent levels of CHKV-24 IgG with neutralizing activity were observed at titers predicted to be therapeutically relevant concentrations (≥1 µg ml
) across doses that persisted for ≥16 weeks at 0.3 and 0.6 mg kg
(mean t
approximately 69 d). A second 0.3 mg kg
dose 1 week after the first increased CHKV-24 IgG levels 1.8-fold. Adverse effects were mild to moderate in severity, did not worsen with a second mRNA-1944 dose and none were serious. To our knowledge, mRNA-1944 is the first mRNA-encoded monoclonal antibody showing in vivo expression and detectable ex vivo neutralizing activity in a clinical trial and may offer a treatment option for CHIKV infection. Further evaluation of the potential therapeutic use of mRNA-1944 in clinical trials for the treatment of CHIKV infection is warranted.
Purpose of Review
Atrial fibrillation (AF) is the most common arrhythmia in adults and is responsible for 600,000 emergency department (ED) visits each year in the USA. Over 60% of these patients are ...admitted to inpatient units. The prevalence of AF is increasing, resulting in higher numbers of AF-related ED visits and inpatient admissions. These trends underscore the need for improvements in the efficiency of AF management in the ED.
Recent Findings
Several treatment protocols have been developed to address challenges associated with AF management in the ED, including: initiation of oral anticoagulant (OAC) therapy, cardioversion, and arranging for outpatient follow-up. Studies of these protocols have demonstrated that they can be utilized safely and effectively.
Summary
Published treatment protocols for AF in the ED have been shown to reduce unnecessary hospital admissions and improve adherence to guideline-directed OAC therapy. Widespread adoption of AF treatment protocols could improve patient outcomes and reduce the costs associated with inpatient AF treatment.
Ultrasound (US) guidance has been shown to be a safe and effective option for gaining access to the axillary vein during implantation of cardiovascular implantable electronic devices (CIEDs). ...However, US-based technique has not been universally adopted in CIED implantations performed in cardiac electrophysiology (EP) laboratories, despite potential advantages over other vascular access techniques. For this reason, not all cardiac electrophysiologists have been trained to use US guidance during CIED implantation. This review is intended to provide a practical guide to the use of US guidance to obtain axillary vein access in the EP laboratory setting.
Bioprinting has emerged as a promising tool in tissue engineering and regenerative medicine. Various 3D printing strategies have been developed to enable bioprinting of various biopolymers and ...hydrogels. However, the incorporation of biological factors has not been well explored. As the importance of personalized medicine is becoming more clear, the need for the development of bioinks containing autologous/patient-specific biological factors for tissue engineering applications becomes more evident. Platelet-rich plasma (PRP) is used as a patient-specific source of autologous growth factors that can be easily incorporated to hydrogels and printed into 3D constructs. PRP contains a cocktail of growth factors enhancing angiogenesis, stem cell recruitment, and tissue regeneration. Here, the development of an alginate-based bioink that can be printed and crosslinked upon implantation through exposure to native calcium ions is reported. This platform can be used for the controlled release of PRP-associated growth factors which may ultimately enhance vascularization and stem cell migration.
Mammalian preimplantation embryonic development (PED) is thought to be governed by highly conserved processes. While it had been suggested that some plasticity of conserved signaling networks exists ...among different mammalian species, it was not known to what extent modulation of the genomes and the regulatory proteins could "rewire" the gene regulatory networks (GRN) that control PED. We therefore generated global transcriptional profiles from three mammalian species (human, mouse, and bovine) at representative stages of PED, including: zygote, two-cell, four-cell, eight-cell, 16-cell, morula and blastocyst. Coexpression network analysis suggested that 40.2% orthologous gene triplets exhibited different expression patterns among these species. Combining the expression data with genomic sequences and the ChIP-seq data of 16 transcription regulators, we observed two classes of genomic changes that contributed to interspecies expression difference, including single nucleotide mutations leading to turnover of transcription factor binding sites, and insertion of cis-regulatory modules (CRMs) by transposons. About 10% of transposons are estimated to carry CRMs, which may drive species-specific gene expression. The two classes of genomic changes act in concert to drive mouse-specific expression of MTF2, which links POU5F1/NANOG to NOTCH signaling. We reconstructed the transition of the GRN structures as a function of time during PED. A comparison of the GRN transition processes among the three species suggested that in the bovine system, POU5F1's interacting partner SOX2 may be replaced by HMGB1 (a TF sharing the same DNA binding domain with SOX2), resulting in rewiring of GRN by a trans change.
Delivery of comprehensive arrhythmia care requires the simultaneous presence of many resources. These include complex hospital infrastructure, expensive implantable equipment, and expert personnel. ...In many low- and middle-income countries (LMICs), at least 1 of these components is often missing, resulting in a gap between the demand for arrhythmia care and the capacity to supply care. In addition to this treatment gap, there exists a training gap, as many clinicians in LMICs have limited access to formal training in cardiac electrophysiology. Given the progressive increase in the burden of cardiovascular diseases in LMICs, these patient care and clinical training gaps will widen unless further actions are taken to build capacity. Several strategies for building arrhythmia care capacity in LMICs have been described. Medical missions can provide donations of both equipment and clinical expertise but are only intermittently present and therefore are not optimized to provide the longitudinal support needed to create self-sustaining infrastructure. Use of donated or reprocessed equipment (eg, cardiac implantable electronic devices) can reduce procedural costs but does not address the need for infrastructure, including diagnostics and expert personnel. Collaborative efforts involving multiple stakeholders (eg, professional organizations, government agencies, hospitals, and educational institutions) have the potential to provide longitudinal support of both patient care and clinician education in LMICs.
PDF
