In higher eukaryotic cells, mitochondria are essential subcellular organelles for energy production, cell signaling, and the biosynthesis of biomolecules. The mitochondrial DNA (mtDNA) genome is indispensable for mitochondrial function because it encodes protein subunits of the electron transport chain and a full set of transfer and ribosomal RNAs. MtDNA degradation has emerged as an essential quality control measure to maintain mtDNA and to cope with mtDNA damage resulting from endogenous and environmental factors. Among all types of DNA damage known, abasic (AP) sites, sourced from base excision repair and spontaneous base loss, are the most abundant endogenous DNA lesions in cells. In mitochondria, AP sites trigger rapid DNA loss; however, the mechanism and molecular factors involved in the process remain elusive. Herein, we demonstrate that the stability of AP sites is reduced dramatically upon binding to a major mtDNA packaging protein, mitochondrial transcription factor A (TFAM). The half-life of AP lesions within TFAM–DNA complexes is 2 to 3 orders of magnitude shorter than that in free DNA, depending on their position. The TFAM-catalyzed AP-DNA destabilization occurs with nonspecific DNA or mitochondrial light-strand promoter sequence, yielding DNA single-strand breaks and DNA–TFAM cross-links. TFAM–DNA cross-link intermediates prior to the strand scission were also observed upon treating AP-DNA with mitochondrial extracts of human cells. In situ trapping of the reaction intermediates (DNA–TFAM cross-links) revealed that the reaction proceeds via Schiff base chemistry facilitated by lysine residues. Collectively, our data suggest a novel role of TFAM in facilitating the turnover of abasic DNA.

ocial media platforms such as Facebook, Instagram, and Twitter are examples of a new generation of powerful online tools that enable people to communicate and interact instantly with a potentially limitless audience. These online networks began as a medium for social connection; in recent years, however, social media platforms have been recognized as effective and inexpensive ways to reach a wide variety of target audiences. Social media platforms have since found their way into the toolboxes of medical students, residents, physicians, and medical professionals worldwide. 1 Plastic surgeons in particular embraced creating and implementing social media, and use them to enhance their clinical practice through advertising, marketing, and sharing education-related information. The use of social media in plastic surgery is not limited to individuals; both the American Society for Aesthetic Plastic Surgery and the American Society of Plastic Surgeons 2 have endorsed social media by incorporating Twitter, Facebook, and YouTube applications into their websites and national meetings.The most recent U.S. Census reveals that the racial composition of the majority of Americans is white. African Americans are the largest racial minority, accounting for an estimated 13.4 percent of the population. Hispanics and Latino Americans are the largest ethnic minority,

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Background and Aims Hypoplastic left heart syndrome (HLHS) survival relies on surgical reconstruction for the right ventricle (RV) to provide systemic circulation. This substantially increases the RV load, wall stress, maladaptive remodeling, and dysfunction, which in turn increases the risk of death or transplantation. Methods We conducted a phase 1 open-label multicenter trial to assess the safety and feasibility of Lomecel-B as an adjunct to second stage HLHS surgical palliation. Lomecel-B, an investigational cell therapy consisting of allogeneic medicinal signaling cells (MSCs), was delivered via intramyocardial injections. The primary endpoint was safety, and measures of RV function for potential efficacy were obtained. Results Ten patients were treated. None experienced major adverse cardiac events (MACE). All were alive and transplant-free at 1-year post-treatment, and experienced growth comparable to healthy historical data. Cardiac magnetic resonance imaging (CMR) suggested improved tricuspid regurgitant fraction (TR RF) via qualitative rater assessment, and via significant quantitative improvements from baseline at 6 and 12 months post-treatment (p < 0.05). Global longitudinal strain (GLS) and RV ejection fraction (EF) showed no declines. To understand potential mechanisms of action, circulating exosomes from intramyocardially transplanted MSCs were examined. Computational modeling identified 54 MSC-specific exosome RNAs corresponding to changes in TR RF, including miR-215-3p, miR-374b-3p, and RNAs related to cell metabolism and MAPK signaling. Conclusions Intramyocardially-delivered Lomecel-B appears safe in HLHS patients and may favorably affect RV performance. Circulating exosomes of transplanted MSC-specific provide novel insight into bioactivity. Conduct of a controlled phase trial is warranted and is underway.

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Background: Hypoplastic left heart syndrome (HLHS) survival relies on surgical reconstruction for the right ventricle (RV) to provide systemic circulation. This leads to substantially increased loads on the RV, wall stress, maladaptive remodeling and dysfunction, which in turn can increase risk of death or transplantation. Objectives: We conducted a phase I multicenter trial to assess safety and feasibility of intra-operative MSC injection in HLHS patients to boost RV performance in the systemic position. Methods: Allogeneic MSCs were directly administered by intramyocardial injections during the second stage palliative operation. The primary endpoint was safety Results: Ten patients received intramyocardial injections of allogeneic MSCs (Lomecel-B). No patients experienced major adverse cardiac events (MACE). All subjects were alive and transplant-free at 1 year following, and experienced growth comparable to healthy control historical data. Cardiac magnetic resonance imaging (CMR) revealed improving tricuspid regurgitant fraction (Baseline: 0.45 ± 0.19; 6 mo.: 0.32 ± 0.06; 12 mo.: 0.06 ± 0.09), while global longitudinal strain (Baseline: -24.39 ± 6.99; 6 mo.: -20.55 ± 3.05, p > 0.05 vs baseline; 12 mo.: -23.88 ± 4.6, p>0.05 vs baseline) and RV ejection fraction (EF; baseline: 62.62 ± 5.99; 6 mo.: 53.69 ± 9.56; 12 mo.: 52.31 ± 5.63: p=NS for change over time) were unchanged. Computational modeling identified 167 derived RNAs specific to tcirculating exosomes originating from transplanted MSCs corresponding to RVEF changes and identifying potential mechanistic underpinnings. Conclusions: Intramyocardial MSCs appear safe in HLHS patients, and may favorably affect RV performance. Circulating exosomes of transplanted MSC-specific provide novel insight into bioactivity. Conduct of a controlled phase trial is warranted and is underway.

Introduction: Stem cells are an emerging therapy for cardiovascular disease. The immune system is modulated by stem cell administration, therefore we sought to characterize the immune environment following stem cell administration. Hypothesis: Neonatal cardiac mesenchymal stem cells (nMSC) improved heart function through an acute sterile immune response characterized by the temporal and regional of macrophages. Methods: nMSC were isolated from healthy neonatal myocardium. Brown Norway rats underwent ischemia-reperfusion injury (IRI) by temporary ligation of left anterior descending artery for 45 minutes. Following closure of the chest cavity, neonatal mesenchymal stem cells (nMSCs), dead nMSCs (dnMSCs), or placebo was administered by intra-coronary injection. At day five heart was collected for single cell suspensions. CD45 positive selection was performed and fed into the Chromium Single Cell Gene Expression workflow (Pleasanton, CA). Single cell sequencing analysis was completed using the Seurat package on RStudio v1.3.1093 (Boston, MA). Echocardiography was completed on post-operative days 7 and 28 for rats not sacrificed for single cell sequencing. Results: Our results demonstrate that nMSC treatment after IRI injury can significantly recover left ventricular ejection fraction. Single-cell sequencing analysis of CD45+ cells identified multiple unique CD68+ clusters. Notably, macrophage cluster 2 primarily consisted of cells from the nMSC treated group, whereas the macrophage cluster 1 was primarily cells from the dnMSC and placebo groups. Gene ontology analysis of macrophage cluster 2 demonstrated that this cluster primarily consisted of macrophages strongly associated with various aspects of the activated immune response, including lymphocyte activation and cytokine production. Conversely, macrophage cluster 1 gene ontology analysis revealed a weaker immune response signature. Conclusions: nMSCs are a promising therapeutic candidate for the treatment of myocardial infarction. The mechanism of this therapy is likely related to macrophage activation that further enhances the immune response in the impacted and at-risk myocardium following IRI injury.

Background Despite the possibility of using botulinum toxin to improve perfusion and prevent vasospasm, only a few studies have examined the use of botulinum toxin in the setting of flap surgery and thrombosis, and the mechanisms have not been fully explained. Objective The primary objective of this study was to provide a comprehensive review of the effectiveness of botulinum toxin in anastomotic thrombosis prevention and surgical flap survival to determine the value of conducting large-scale human trials. Methods Using the SYRCLE and CAMRADES criteria, a systematic review was performed. PubMed, Medline, EmBase, and the Cochrane Library were searched for studies that met our eligibility criteria. Results Twenty studies were included in the final selection. A total of 397 subjects were included. Eighteen studies used botulinum toxin type A alone, one used botulinum toxin type B alone, and only one used both botulinum toxin type A and botulinum toxin type B. The most commonly used injection technique was a preoperative intradermal injection. The most common procedure performed was a pedicled flap with random pattern skin flaps (65%). The mean injection dose was 28.17 ± 49.21 IU, whereas the mean reported injection time for studies using animal models was 7.4 ± 6.84 days. Conclusions Similar mechanisms demonstrated in animal models may be replicable in humans, allowing botulinum toxin to be used to prolong flap survival. However, many factors, such as optimal injection techniques, dosages, and long-term outcomes of botulinum use in flap surgery, need to be further assessed before applying this to clinical practice.