In light of the limited efficacy of current treatments for cardiac regeneration, tissue engineering approaches have been explored for their potential to provide mechanical support to injured cardiac ...tissues, deliver cardio‐protective molecules, and improve cell‐based therapeutic techniques. Injectable hydrogels are a particularly appealing system as they hold promise as a minimally invasive therapeutic approach. Moreover, injectable acellular alginate‐based hydrogels have been tested clinically in patients with myocardial infarction (MI) and show preservation of the left ventricular (LV) indices and left ventricular ejection fraction (LVEF). This review provides an overview of recent developments that have occurred in the design and engineering of various injectable hydrogel systems for cardiac tissue engineering efforts, including a comparison of natural versus synthetic systems with emphasis on the ideal characteristics for biomimetic cardiac materials.
Injectable hydrogels for cardiac tissue engineering can be used for in vitro models, in vivo preclinical purposes, and for clinical trials.
Genetics of Dilated Cardiomyopathy Eldemire, Ramone; Mestroni, Luisa; Taylor, Matthew R.G
Annual review of medicine,
01/2024, Letnik:
75, Številka:
1
Journal Article
Recenzirano
Odprti dostop
Dilated cardiomyopathy (DCM) is defined as dilation and or reduced function of one or both ventricles and remains a common disease worldwide. An estimated 40% of cases of familial DCM have an ...identifiable genetic cause. Accordingly, there is a fast-growing interest in the field of molecular genetics as it pertains to DCM. Many gene mutations have been identified that contribute to phenotypically significant cardiomyopathy. DCM genes can affect a variety of cardiomyocyte functions, and particular genes whose function affects the cell-cell junction and cytoskeleton are associated with increased risk of arrhythmias and sudden cardiac death. Through advancements in next-generation sequencing and cardiac imaging, identification of genetic DCM has improved over the past couple decades, and precision medicine is now at the forefront of treatment for these patients and their families. In addition to standard treatment of heart failure and prevention of arrhythmias and sudden cardiac death, patients with genetic cardiomyopathy stand to benefit from gene mechanism-specific therapies.
Deep reinforcement learning (RL) has achieved outstanding results in recent years. This has led to a dramatic increase in the number of applications and methods. Recent works have explored learning ...beyond single-agent scenarios and have considered multiagent learning (MAL) scenarios. Initial results report successes in complex multiagent domains, although there are several challenges to be addressed. The primary goal of this article is to provide a clear overview of current multiagent deep reinforcement learning (MDRL) literature. Additionally, we complement the overview with a broader analysis: (i) we revisit previous key components, originally presented in MAL and RL, and highlight how they have been adapted to multiagent deep reinforcement learning settings. (ii) We provide general guidelines to new practitioners in the area: describing lessons learned from MDRL works, pointing to recent benchmarks, and outlining open avenues of research. (iii) We take a more critical tone raising practical challenges of MDRL (e.g., implementation and computational demands). We expect this article will help unify and motivate future research to take advantage of the abundant literature that exists (e.g., RL and MAL) in a joint effort to promote fruitful research in the multiagent community.
RATIONALE:Mutations in the LMNA gene, encoding LMNA (lamin A/C), are responsible for laminopathies. Dilated cardiomyopathy (DCM) is a major cause of mortality and morbidity in laminopathies.
...OBJECTIVE:To gain insights into the molecular pathogenesis of DCM in laminopathies.
METHODS AND RESULTS:We generated a tet-off bigenic mice expressing either a WT (wild type) or a mutant LMNA (D300N) protein in cardiac myocytes. LMNA mutation is associated with DCM in progeroid syndromes. Expression of LMNA led to severe myocardial fibrosis, apoptosis, cardiac dysfunction, and premature death. Administration of doxycycline suppressed LMNA expression and prevented the phenotype. Whole-heart RNA sequencing in 2-week-old WT and LMNA mice led to identification of ≈6000 differentially expressed genes. Gene Set Enrichment and Hallmark Pathway analyses predicted activation of E2F (E2F transcription factor), DNA damage response, TP53 (tumor protein 53), NFκB (nuclear factor κB), and TGFβ (transforming growth factor-β) pathways, which were validated by Western blotting, quantitative polymerase chain reaction of selected targets, and immunofluorescence staining. Differentially expressed genes involved cell death, cell cycle regulation, inflammation, and epithelial-mesenchymal differentiation. RNA sequencing of human hearts with DCM associated with defined LMNA pathogenic variants corroborated activation of the DNA damage response/TP53 pathway in the heart. Increased expression of CDKN2A (cyclin-dependent kinase inhibitor 2A)—a downstream target of E2F pathway and an activator of TP53—provided a plausible mechanism for activation of the TP53 pathway. To determine pathogenic role of TP53 pathway in DCM, Tp53 gene was conditionally deleted in cardiac myocytes in mice expressing the LMNA protein. Deletion of Tp53 partially rescued myocardial fibrosis, apoptosis, proliferation of nonmyocyte cells, left ventricular dilatation and dysfunction, and slightly improved survival.
CONCLUSIONS:Cardiac myocyte-specific expression of LMNA, associated with DCM, led to pathogenic activation of the E2F/DNA damage response/TP53 pathway in the heart and induction of myocardial fibrosis, apoptosis, cardiac dysfunction, and premature death. The findings denote the E2F/DNA damage response/TP53 axis as a responsible mechanism for DCM in laminopathies and as a potential intervention target.
Current heart failure (HF) treatment is based on targeting symptoms and left ventricle dysfunction severity, relying on a common HF pathway paradigm to justify common treatments for HF patients. This ...common strategy may belie an incomplete understanding of heterogeneous underlying mechanisms and could be a barrier to more precise treatments. We hypothesized we could use RNA-sequencing (RNA-seq) in human heart tissue to delineate HF etiology-specific gene expression signatures.
RNA-seq from 64 human left ventricular samples: 37 dilated (DCM), 13 ischemic (ICM), and 14 non-failing (NF). Using a multi-analytic approach including covariate adjustment for age and sex, differentially expressed genes (DEGs) were identified characterizing HF and disease-specific expression. Pathway analysis investigated enrichment for biologically relevant pathways and functions. DCM vs NF and ICM vs NF had shared HF-DEGs that were enriched for the fetal gene program and mitochondrial dysfunction. DCM-specific DEGs were enriched for cell-cell and cell-matrix adhesion pathways. ICM-specific DEGs were enriched for cytoskeletal and immune pathway activation. Using the ICM and DCM DEG signatures from our data we were able to correctly classify the phenotypes of 24/31 ICM and 32/36 DCM samples from publicly available replication datasets.
Our results demonstrate the commonality of mitochondrial dysfunction in end-stage HF but more importantly reveal key etiology-specific signatures. Dysfunctional cell-cell and cell-matrix adhesion signatures typified DCM whereas signals related to immune and fibrotic responses were seen in ICM. These findings suggest that transcriptome signatures may distinguish end-stage heart failure, shedding light on underlying biological differences between ICM and DCM.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Genotype-phenotype correlations in dilated cardiomyopathy (DCM) and, in particular, the effects of gene variants on clinical outcomes remain poorly understood.
The purpose of this study was to ...investigate the prognostic role of genetic variant carrier status in a large cohort of DCM patients.
A total of 487 DCM patients were analyzed by next-generation sequencing and categorized the disease genes into functional gene groups. The following composite outcome measures were assessed: 1) all-cause mortality; 2) heart failure–related death, heart transplantation, or destination left ventricular assist device implantation (DHF/HTx/VAD); and 3) sudden cardiac death/sustained ventricular tachycardia/ventricular fibrillation (SCD/VT/VF).
A total of 183 pathogenic/likely pathogenic variants were found in 178 patients (37%): 54 (11%) Titin; 19 (4%) Lamin A/C (LMNA); 24 (5%) structural cytoskeleton-Z disk genes; 16 (3.5%) desmosomal genes; 46 (9.5%) sarcomeric genes; 8 (1.6%) ion channel genes; and 11 (2.5%) other genes. All-cause mortality was no different between variant carriers and noncarriers (p = 0.99). A trend toward worse SCD/VT/VF (p = 0.062) and DHF/HTx/VAD (p = 0.061) was found in carriers. Carriers of desmosomal and LMNA variants experienced the highest rate of SCD/VT/VF, which was independent of the left ventricular ejection fraction.
Desmosomal and LMNA gene variants identify the subset of DCM patients who are at greatest risk for SCD and life-threatening ventricular arrhythmias, regardless of the left ventricular ejection fraction.
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Objectives The aim of this study was to discern the role of the cardiac voltage-gated sodium ion channel SCN5A in the etiology of dilated cardiomyopathy (DCM). Background Dilated cardiomyopathy ...associates with mutations in the SCN5A gene, but the frequency, phenotype, and causative nature of these associations remain the focus of ongoing investigation. Methods Since 1991, DCM probands and family members have been enrolled in the Familial Cardiomyopathy Registry and extensively evaluated by clinical phenotype. Genomic deoxyribonucleic acid samples from 338 individuals among 289 DCM families were obtained and screened for SCN5A mutations by denaturing high-performance liquid chromatography and sequence analysis. Results We identified 5 missense SCN5A mutations among our DCM families, including novel mutations E446K, F1520L, and V1279I, as well as previously reported mutations D1275N and R222Q. Of 15 SCN5A mutation carriers in our study, 14 (93%) manifested arrhythmia: supraventricular arrhythmia (13 of 15), including sick sinus syndrome (5 of 15) and atrial fibrillation (9 of 15), ventricular tachycardia (5 of 15), and conduction disease (9 of 15). Conclusions Mutations in SCN5A were detected in 1.7% of DCM families. Two-thirds (6 of 9) of all reported DCM mutations in SCN5A localize to the highly conserved homologous S3 and S4 transmembrane segments, suggesting a shared mechanism of disruption of the voltage-sensing mechanism of this channel leading to DCM. Not surprisingly, SCN5A mutation carriers show a strong arrhythmic pattern that has clinical and diagnostic implications.
In crabs, metal concentrations differ among tissues, but may also differ in edible white meat (muscle) in different parts of the body. This case study compared metal contaminants in the claw and body ...muscle for a popular crab species (Giant Mud Crab, Scylla serrata). For lead and nickel, body muscle concentrations were generally lower than claw concentrations, while the converse was true for arsenic, cadmium and mercury. When body and appendage meat proportions were used to weight body and claw metal concentrations the estimated concentration in total edible muscle closely reflected the claw muscle for zinc, but remained elevated relative to claw muscle (to varying degrees) for arsenic, cadmium and mercury. Linear models for these relationships allowed the total edible muscle concentration to be estimated from measured claw muscle concentrations. The relationships reported are useful for modelling exposure risk, and in crab ecotoxicology more broadly.
Off-label drug use in children is common and potentially harmful. In most previous off-label use research, authors studied hospitalized children, specific drug classes, or non-US settings. We ...characterized frequencies, trends, and reasons for off-label systemic drug orders for children in ambulatory US settings.
Using nationally representative surveys of office-based physicians (National Ambulatory Medical Care Surveys, 2006-2015), we studied off-label orders of systemic drugs for children age <18 based on US Food and Drug Administration-approved labeling for age, weight, and indication. We characterized the top classes and diagnoses with off-label orders and analyzed factors and trends of off-label orders using logistic regression.
Physicians ordered ≥1 off-label systemic drug at 18.5% (95% confidence interval: 17.7%-19.3%) of visits, usually (74.6%) because of unapproved conditions. Off-label ordering was most common proportionally in neonates (83%) and in absolute terms among adolescents (322 orders out of 1000 visits). Off-label ordering was associated with female sex, subspecialists, polypharmacy, and chronic conditions. Rates and reasons for off-label orders varied considerably by age. Relative and absolute rates of off-label orders rose over time. Among common classes, off-label orders for antihistamines and several psychotropics increased over time, whereas off-label orders for several classes of antibiotics were stable or declined.
US office-based physicians have ordered systemic drugs off label for children at increasing rates, most often for unapproved conditions, despite recent efforts to increase evidence and drug approvals for children. These findings can help inform education, research, and policies around effective, safe use of medications in children.
Environmental emissions of perfluoroalkyl acids (PFAAs) impact estuarine species and the fisheries that rely on them. Migratory estuarine fishes may be captured for consumption in areas distant to ...known contaminant sources, but exposure risk depends on how quickly contaminants are depurated. This baseline presents the outcomes from a novel experiment simulating the migration of a popular recreational fish species (Dusky Flathead, Platycephalus fuscus) following environmental exposure to PFAAs, and assessing depuration from edible muscle tissues. Over the 33-day experiment, perfluorooctane sulfonate (PFOS) concentrations declined slowly, with modelling suggesting that concentrations fell below the relevant screening value (5.2 μg kg−1) within ∼558 h (285–1372 h; 90 % CI). Low concentrations (<1.2 μg kg−1) of perfluorohexane sulfonate also depurated rapidly. This study provides useful information for assessing potential exposure risk posed by recreationally targeted fish migrating away from contaminated areas. The experimental design employed has a real-world context that is relevant for future studies.
•Depuration of perfluoroalkyl acids was assessed for a recreationally fished species.•Perfluorooctane sulfonate concentration in edible tissue declined slowly with time.•Perfluorohexane sulfonate concentration in edible tissue declined rapidly with time.•The experimental design has a real-world context that is relevant for future studies.
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