Dissecting super-enhancer heterogeneity: time to re-examine cancer subtypes?

The heterogeneity of transcriptional regulations by super-enhancers (SEs) is poorly understood in human cancers. Herein, we summarize a bioinformatics workflow for genome-wide SE profiling and identification of subtype-specific SEs and regulatory networks. Dissecting SE heterogeneity provides new insights into cancer biology and alternative therapeutic strategies for cancer precision medicine.

Low-dose ionizing radiation promotes motor recovery and brain rewiring by resolving inflammatory response after brain injury and stroke.

Traumatic brain injury (TBI) and stroke share a common pathophysiology that worsens over time due to secondary tissue injury caused by sustained inflammatory response. However, studies on pharmacological interventions targeting the complex secondary injury cascade have failed to show efficacy. Here, we demonstrated that low-dose ionizing radiation (LDIR) reduced lesion size and reversed motor deficits after TBI and photothrombotic stroke. Magnetic resonance imaging demonstrated significant reduction of infarct volume in LDIR-treated mice after stroke. Systems-level transcriptomic analysis showed that genes upregulated in LDIR-treated stoke mice were enriched in pathways associated with inflammatory and immune response involving microglia. LDIR induced upregulation of anti-inflammatory- and phagocytosis-related genes, and downregulation of key pro-inflammatory cytokine production. These findings were validated by live-cell assays, in which microglia exhibited higher chemotactic and phagocytic capacities after LDIR. We observed substantial microglial clustering at the injury site, glial scar clearance and reversal of motor deficits after stroke. Cortical microglia/macrophages depletion completely abolished the beneficial effect of LDIR on motor function recovery in stroke mice. LDIR promoted axonal projections (brain rewiring) in motor cortex and recovery of brain activity detected by electroencephalography recordings months after stroke. LDIR treatment delayed by 8 h post-injury still maintained full therapeutic effects on motor recovery, indicating that LDIR is a promising therapeutic strategy for TBI and stroke.

An integrated workflow for biomarker development using microRNAs in extracellular vesicles for cancer precision medicine.

EV-miRNAs are microRNA (miRNA) molecules encapsulated in extracellular vesicles (EVs), which play crucial roles in tumor pathogenesis, progression, and metastasis. Recent studies about EV-miRNAs have gained novel insights into cancer biology and have demonstrated a great potential to develop novel liquid biopsy assays for various applications. Notably, compared to conventional liquid biomarkers, EV-miRNAs are more advantageous in representing host-cell molecular architecture and exhibiting higher stability and specificity. Despite various available techniques for EV-miRNA separation, concentration, profiling, and data analysis, a standardized approach for EV-miRNA biomarker development is yet lacking. In this review, we performed a substantial literature review and distilled an integrated workflow encompassing important steps for EV-miRNA biomarker development, including sample collection and EV isolation, EV-miRNA extraction and quantification, high-throughput data preprocessing, biomarker prioritization and model construction, functional analysis, as well as validation. With the rapid growth of "big data", we highlight the importance of efficient mining of high-throughput data for the discovery of EV-miRNA biomarkers and integrating multiple independent datasets for in silico and experimental validations to increase the robustness and reproducibility. Furthermore, as an efficient strategy in systems biology, network inference provides insights into the regulatory mechanisms and can be used to select functionally important EV-miRNAs to refine the biomarker candidates. Despite the encouraging development in the field, a number of challenges still hinder the clinical translation. We finally summarize several common challenges in various biomarker studies and discuss potential opportunities emerging in the related fields.

Identification and comprehensive characterization of lncRNAs with copy number variations and their driving transcriptional perturbed subpathways reveal functional significance for cancer.

Numerous studies have shown that copy number variation (CNV) in lncRNA regions play critical roles in the initiation and progression of cancer. However, our knowledge about their functionalities is still limited. Here, we firstly provided a computational method to identify lncRNAs with copy number variation (lncRNAs-CNV) and their driving transcriptional perturbed subpathways by integrating multidimensional omics data of cancer. The high reliability and accuracy of our method have been demonstrated. Then, the method was applied to 14 cancer types, and a comprehensive characterization and analysis was performed. LncRNAs-CNV had high specificity in cancers, and those with high CNV level may perturb broad biological functions. Some core subpathways and cancer hallmarks widely perturbed by lncRNAs-CNV were revealed. Moreover, subpathways highlighted the functional diversity of lncRNAs-CNV in various cancers. Survival analysis indicated that functional lncRNAs-CNV could be candidate prognostic biomarkers for clinical applications, such as ST7-AS1, CDKN2B-AS1 and EGFR-AS1. In addition, cascade responses and a functional crosstalk model among lncRNAs-CNV, impacted genes, driving subpathways and cancer hallmarks were proposed for understanding the driving mechanism of lncRNAs-CNV. Finally, we developed a user-friendly web interface-LncCASE (http://bio-bigdata.hrbmu.edu.cn/LncCASE/) for exploring lncRNAs-CNV and their driving subpathways in various cancer types. Our study identified and systematically characterized lncRNAs-CNV and their driving subpathways and presented valuable resources for investigating the functionalities of non-coding variations and the mechanisms of tumorigenesis.

A comprehensive overview of oncogenic pathways in human cancer.

Alterations of biological pathways can lead to oncogenesis. An overview of these oncogenic pathways would be highly valuable for researchers to reveal the pathogenic mechanism and develop novel therapeutic approaches for cancers. Here, we reviewed approximately 8500 literatures and documented experimentally validated cancer-pathway associations as benchmarking data set. This data resource includes 4709 manually curated relationships between 1557 paths and 49 cancers with 2427 upstream regulators in 7 species. Based on this resource, we first summarized the cancer-pathway associations and revealed some commonly deregulated pathways across tumor types. Then, we systematically analyzed these oncogenic pathways by integrating TCGA pan-cancer data sets. Multi-omics analysis showed oncogenic pathways may play different roles across tumor types under different omics contexts. We also charted the survival relevance landscape of oncogenic pathways in 26 tumor types, identified dominant omics features and found survival relevance for oncogenic pathways varied in tumor types and omics levels. Moreover, we predicted upstream regulators and constructed a hierarchical network model to understand the pathogenic mechanism of human cancers underlying oncogenic pathway context. Finally, we developed `CPAD' (freely available at http://bio-bigdata.hrbmu.edu.cn/CPAD/), an online resource for exploring oncogenic pathways in human cancers, that integrated manually curated cancer-pathway associations, TCGA pan-cancer multi-omics data sets, drug-target data, drug sensitivity and multi-omics data for cancer cell lines. In summary, our study provides a comprehensive characterization of oncogenic pathways and also presents a valuable resource for investigating the pathogenesis of human cancer.

[Improvement in compatibility of hot melt pressure-sensitive adhesive with cinnamon volatile oil and in vitro transdermal property by physical blending].

Hot melt pressure-sensitive adhesive(HMPSA) has broad application potential in the field of traditional Chinese medicine(TCM) plasters due to its high drug loading, weak skin irritation, satisfactory adhesion, etc. compared with rubber plasters.However, the structure of HMPSA is prone to suffer from the damage caused by volatile oils in TCM plasters. In view of this, a kind of HMPSA with a stable structure was prepared by physical blending of DINCH, polypropylene wax and liquid rubber(LIR) in the present study, which is denoted as DPL. The dosage of cinnamon volatile oil(CVO), the model drug, was selected with viscosity, softening point and cohesion as evaluation indexes. The interaction between DPL and HMPSA was investigated by Fourier transform infrared spectroscopy(FT-IR) and differential scanning calorimetry(DSC). The compatibility of HMPSA with CVO and its transdermal ability were studied by in vitro transdermal test, adhesion, scanning electron microscopy( SEM) and rheological evaluation. The results showed that 5% CVO began to damage the structure of HMPSA. The initial adhesion and holding adhesion of DPL-modified HMPSA(DPL-HMPSA) were not significantly changed compared with those of HMPSA, whereas the 180° peel strength was decreased. FI-IR unraveled that DPL formed the n-π conjugated system with styrene-isoprene-styrene block copolymer(SIS), and there was no significant difference in the glass transition temperature according to DSC results, which indicated the good compatibility of DPL with HMPSA. With 5% CVO loaded, the drug content of DPL-HMPSA was 1. 14 times higher than that of HMPSA, and the decrease rate of drug content in DPL-HMPSA was 16% lower than that in HMPSA after 3 months. SEM demonstrated that CVO did not cause obvious structural damage to DPL-HMPSA. Rheological evaluation revealed that the storage modulus and loss factor of DPL-HMPSA were higher than those of HMPSA, and the cohesion was also stronger. The percutaneous penetration rate of cinnamaldehyde in DPL-HMPSA was 2. 25 times that of HMPSA. In conclusion, DPL-HMPSA had more stable structure, better compatibility with CVO, and higher in vitro transdermal efficiency of cinnamaldehyde than before the modification. This study can provide reference for the mitigation of the matrix structure damage caused by volatile oil components in TCM plasters and the enhancement of the content and in vitro transdermal rate of drug.

Enzyme-like biomimetic oral-agent enabling modulating gut microbiota and restoring redox homeostasis to treat inflammatory bowel disease.

Reactive oxygen species (ROS), immune dysregulation-induced inflammatory outbreaks and microbial imbalance play critical roles in the development of inflammatory bowel disease (IBD). Herein, a novel enzyme-like biomimetic oral-agent ZnPBA@YCW has been developed, using yeast cell wall (YCW) as the outer shell and zinc-doped Prussian blue analogue (ZnPBA) nanozyme inside. When orally administered, the ZnPBA@YCW is able to adhere to Escherichia coli occupying the ecological niche in IBD and subsequently release the ZnPBA nanozyme for removal of E. coli, meanwhile exhibiting improved intestinal epithelial barrier repair. Moreover, it is found that the ZnPBA nanozyme exhibits remarkable capability in restoring redox homeostasis by scavenging ROS and inhibiting NF-κB signaling pathway. More importantly, the 16S ribosomal RNA gene sequencing results indicate that post-oral of ZnPBA@YCW can effectively regulate gut microbiota by enhancing the bacterial richness and diversity, significantly increasing the abundance of probiotics with anti-inflammatory phenotype while downgrading pathogenic E. coli to the same level as normal mice. Such a novel nanomedicine provides a new idea for efficient treating those ROS-mediated diseases accompanying with flora disorders.

Comparison between cryotherapy and radiofrequency energy sources for parahisian accessory pathway percutaneous ablation.

BACKGROUND: Catheter ablation of parahisian accessory pathways (PHAP) are challenging due to their proximity to the normal conduction system. Retrospective studies suggest that cryoablation has a better safety profile but a higher recurrence rate when compared to radiofrequency ablation (RFCA). The objective of this study was to compare the results of parahisian AP ablation performed by electrophysiologists with experience in both technologies. METHODS: Prospective single-center, non-blinded and 1:1 model was used. Patients included had parahisian AP confirmed by an electrophysiological study and referred for radiofrequency or cryotherapy ablation according to current guidelines, under fluoroscopic guidance. No electroanatomic mapping was used. RESULTS: A total of 30 patients (mean age of 25±9.4 years; 90% male) were enrolled between Oct/2018 to Feb/2020. Acute success rate between RFCA and CRYO were similar (93% vs. 87%, p = 0.54). A nonsignificant reduction in short-term recurrence rate for RFCA (14% vs. 30%, p = 0.3) and mechanical trauma (6% vs. 20%; p = 0.28) was observed. Long-term recurrence rate and event-free survival time were similar in both groups after 1-year follow-up (p = 0.286). No persistent complete AV block or conduction disturbance was also observed. CONCLUSION: Considering the limitation of a small sample size and the lack of use of electroanatomic mapping for RFCA, the efficacy and safety profile of parahisian AP ablation with RFCA was not different from CRYO, when performed by experienced electrophysiologists. No cases of permanent complete AV block were reported with either energy modalities.

A consensus molecular subtypes classification strategy for clinical colorectal cancer tissues.

Consensus Molecular Subtype (CMS) classification of colorectal cancer (CRC) tissues is complicated by RNA degradation upon formalin-fixed paraffin-embedded (FFPE) preservation. Here, we present an FFPE-curated CMS classifier. The CMSFFPE classifier was developed using genes with a high transcript integrity in FFPE-derived RNA. We evaluated the classification accuracy in two FFPE-RNA datasets with matched fresh-frozen (FF) RNA data, and an FF-derived RNA set. An FFPE-RNA application cohort of metastatic CRC patients was established, partly treated with anti-EGFR therapy. Key characteristics per CMS were assessed. Cross-referenced with matched benchmark FF CMS calls, the CMSFFPE classifier strongly improved classification accuracy in two FFPE datasets compared with the original CMSClassifier (63.6% versus 40.9% and 83.3% versus 66.7%, respectively). We recovered CMS-specific recurrence-free survival patterns (CMS4 versus CMS2: hazard ratio 1.75, 95% CI 1.24-2.46). Key molecular and clinical associations of the CMSs were confirmed. In particular, we demonstrated the predictive value of CMS2 and CMS3 for anti-EGFR therapy response (CMS2&3: odds ratio 5.48, 95% CI 1.10-27.27). The CMSFFPE classifier is an optimized FFPE-curated research tool for CMS classification of clinical CRC samples.

Enhancing Arrhythmogenic Right Ventricular Cardiomyopathy Detection and Risk Stratification: Insights from Advanced Echocardiographic Techniques.

INTRODUCTION: The echocardiographic diagnosis criteria for arrhythmogenic right ventricular cardiomyopathy (ARVC) are highly specific but sensitivity is low, especially in the early stages of the disease. The role of echocardiographic strain in ARVC has not been fully elucidated, although prior studies suggest that it can improve the detection of subtle functional abnormalities. The purposes of the study were to determine whether these advanced measures of right ventricular (RV) dysfunction on echocardiogram, including RV strain, increase diagnostic value for ARVC disease detection and to evaluate the association of echocardiographic parameters with arrhythmic outcomes. METHODS: The study included 28 patients from the Heart Institute of São Paulo ARVC cohort with a definite diagnosis of ARVC established according to the 2010 Task Force Criteria. All patients were submitted to ECHO's advanced techniques including RV strain, and the parameters were compared to prior conventional visual ECHO and CMR. RESULTS: In total, 28 patients were enrolled in order to perform ECHO's advanced techniques. A total of 2/28 (7%) patients died due to a cardiovascular cause, 2/28 (7%) underwent heart transplantation, and 14/28 (50%) patients developed sustained ventricular arrhythmic events. Among ECHO's parameters, RV dilatation, measured by RVDd (p = 0.018) and RVOT PSAX (p = 0.044), was significantly associated with arrhythmic outcomes. RV free wall longitudinal strain < 14.35% in absolute value was associated with arrhythmic outcomes (p = 0.033). CONCLUSION: Our data suggest that ECHO's advanced techniques improve ARVC detection and that abnormal RV strain can be associated with arrhythmic risk stratification. Further studies are necessary to better demonstrate these findings and contribute to risk stratification in ARVC, in addition to other well-known risk markers.

Randomized Study Comparing Radiofrequency Ablation with the PVAC Gold System vs. Antiarrhythmic Drugs in Elderly Patients with Symptomatic Atrial Fibrillation. / Estudo Randomizado Comparando a Ablação por Cateter com o PVAC Gold vs. Tratamento com Fármacos Antiarrítmicos em Pacientes Idosos com Fibrilação Atrial Sintomática.

BACKGROUND: There are no randomized studies comparing the maintenance of sinus rhythm after catheter ablation (CA) concerning treatment with antiarrhythmic drugs (AA) in elderly patients with paroxysmal atrial fibrillation (AF). OBJECTIVES: To compare the clinical results of pulmonary vein (PV) isolation with the second-generation PVAC Gold catheter against AA treatment in elderly people with recurrent symptomatic paroxysmal AF, refractory to at least one AA, and without structural heart disease. METHODS: Sixty patients with paroxysmal AF ≥ 65 years old were randomized to two forms of treatment: group 1: CA and group 2: AA drugs. The primary outcome was the AF recurrence-free rate after at least one year of follow-up. Secondary outcomes were: progression to persistent forms of AF, impact on quality of life (QOLF), and complications. The significance level adopted in the statistical analysis was 5% (p<0.05). RESULTS: The AF recurrence-free rate was 80% (10% with amiodarone) in the CA group, after 1.3 procedures per patient and 65% in the AA group (60% with amiodarone), (p = 0.119) in an average follow-up of 719 days (Q1: 566; Q3: 730). The persistent AF free rate was 83.4% in the AC group and 67.7% in the AA group (p = 0.073) Both strategies showed an improvement in the AFQoL score during follow-up (p < 0.001), with no difference between the groups. Although without clinical repercussions or impact on the intellectual assessment test, 25% of patients in the CA group showed signs of cerebral embolization on brain MRI. CONCLUSIONS: Both strategies for maintaining sinus rhythm promoted an improvement in the quality of life of elderly patients with symptomatic AF, with no statistical difference in the clinical outcomes. Additional studies using technologies with a better safety profile are needed to evaluate the benefits of CA in elderly patients with AF.

FUNDAMENTO: Não existem estudos randomizados comparando a manutenção do ritmo sinusal após ablação por cateter (AC) em relação ao tratamento com fármacos antiarrítmicos (AA) em pacientes idosos portadores fibrilação atrial (FA) paroxística. OBJETIVOS: Comparar os resultados clínicos do isolamento das veias pulmonares (VPs) com o cateter PVAC Gold de segunda geração com o uso de AA em idosos com FA paroxística sintomática, recorrente, apesar do uso de fármacos AA. MÉTODOS: Sessenta pacientes com FA paroxística ≥ 65 anos e sem cardiopatias estruturais foram randomizados para duas formas de tratamento: grupo 1: AC e grupo 2: AA. O desfecho primário foi a taxa livre de recorrência de FA após pelo menos um ano de seguimento. Os desfechos secundários foram: progressão para formas persistentes de FA, impacto na qualidade de vida (QVFA) e complicações. O nível de significância adotado na análise estatística foi de 5% (p<0,05). RESULTADOS: A taxa livre de recorrência de FA foi de 80% (10% com amiodarona) no grupo AC, após 1,3 procedimentos por paciente e de 65% no grupo AA (60% com amiodarona), (p = 0,119) num seguimento médio de 719 dias (Q1: 566; Q3: 730). A taxa livre de FA persistente foi de 83,4% no grupo AC e de 67,7% no grupo AA (p = 0,073). Ambas as estratégias apresentaram melhora no escore de QVFA durante o seguimento (p < 0,001), sem diferença entre os grupos. Embora sem repercussão clínica ou impacto no teste de avaliação intelectual, 25% dos pacientes do grupo PVAC apresentou sinais de embolização cerebral na RNM cerebral. CONCLUSÕES: Ambas as estratégias para manutenção do ritmo sinusal promoveram melhora na qualidade de vida de pacientes idosos com FA sintomática, sem diferença estatística nos desfechos clínicos preconizados. Estudos adicionais usando tecnologias com melhor perfil de segurança são necessários para avaliar os benefícios da AC em pacientes idosos com FA.

Integrative network analysis reveals subtype-specific long non-coding RNA regulatory mechanisms in head and neck squamous cell carcinoma.

Head and neck squamous cell carcinoma (HNSC) is one of most common malignancies with high mortality worldwide. Importantly, the molecular heterogeneity of HNSC complicates the clinical diagnosis and treatment, leading to poor overall survival outcomes. To dissect the complex heterogeneity, recent studies have reported multiple molecular subtyping systems. For instance, HNSC can be subdivided to four distinct molecular subtypes: atypical, basal, classical, and mesenchymal, of which the mesenchymal subtype is characterized by upregulated epithelial-mesenchymal transition (EMT) and associated with poorer survival outcomes. Despite a wealth of studies into the complex molecular heterogeneity, the regulatory mechanism specific to this aggressive subtype remain largely unclear. Herein, we developed a network-based bioinformatics framework that integrates lncRNA and mRNA expression profiles to elucidate the subtype-specific regulatory mechanisms. Applying the framework to HNSC, we identified a clinically relevant lncRNA LNCOG as a key master regulator mediating EMT underlying the mesenchymal subtype. Five genes with strong prognostic values, namely ANXA5, ITGA5, CCBE1, P4HA2, and EPHX3, were predicted to be the putative targets of LNCOG and subsequently validated in other independent datasets. By integrative analysis of the miRNA expression profiles, we found that LNCOG may act as a ceRNA to sponge miR-148a-3p thereby upregulating ITGA5 to promote HNSC progression. Furthermore, our drug sensitivity analysis demonstrated that the five putative targets of LNCOG were also predictive of the sensitivities of multiple FDA-approved drugs. In summary, our bioinformatics framework facilitates the dissection of cancer subtype-specific lncRNA regulatory mechanisms, providing potential novel biomarkers for more optimized treatment of HNSC.

Long-Term Outcome of Cardiac Denervation Procedures: The Anatomically Guided Septal Approach.

BACKGROUND: Functional bradycardia is a challenging condition that affects a healthy population. Ganglionated plexus ablation has emerged as a therapeutic alternative to avoid a pacemaker. OBJECTIVES: The purpose of this study is to evaluate long-term effects of anatomically guided cardiac denervation. METHODS: This is a prospective longitudinal study that included 36 patients with symptomatic functional bradycardia. Electroanatomic reconstruction of both atria was carried out, and the main septal ganglionated plexi were anatomically located and targeted. RESULTS: Ablation endpoints were: 1) heart rate increment; 2) Wenckebach cycle length shortening; and 3) atrio-Hisian (AH) interval shortening. A sinus node denervation was obtained in all patients with an increment of 21.6% in the mean heart rate. All patients presented a negative atropine test after ablation. Twenty-eight (77.7%) patients presented immediate sings of atrioventricular node denervation, with a shortening of 15.6% of mean Wenckebach cycle length and 15.9% of the mean AH interval. All heart rate variability parameters showed a significant reduction after 12 months, enduring after 18 months. Thirty (83.3%) patients remained free of events after a mean follow-up of 52.1 ± 35.2 months. One patient (2.77%) presented acute sinus node artery occlusion during ablation with persistent sinus dysfunction and had a pacemaker implantation; 3 (8.3%) other patients evolved with sinus tachycardia, and 4 (11.1%) patients presented syncope recurrence during follow-up, 3 (8.3%) of them requiring a pacemaker implantation. No other tachyarrhythmia was observed. CONCLUSIONS: The anatomically guided septal approach is an effective technique for syncope prevention, promoting long-lasting autonomic changes. No significant proarrhythmia effect has been observed during the long-term follow-up.

Initial experience on cardiac magnetic resonance-aided VT ablation in South America.

BACKGROUND: Cardiac magnetic resonance (CMR) allowed to precisely identify the substrate in scar-related ventricular tachycardia (VT). New software has been developed to define the 3D scar and corridors to help VT ablation by integrating the scar and electroanatomical mapping (EAM). The objective of this study is to evaluate the results of VT ablation aided by the integration of EAM and CMR software processed scar. METHODS: We selected patients that underwent VT ablation with the integration of EAM and CMR processed using ADAS software and imported to the CARTO system using VTK file format. RESULTS: From 2019 to 2021, eight patients (mean age 63 ± 4.4, 62.5% male; EF 47 ± 12%) underwent CMR-aided VT ablation. Mean procedural time was 281 ± 77 min. There was of 9 ± 4.4 epicardial and 7.9 ± 4.3 endocardial bulls eye segments with at least 2 g of border zone or core scar. In a median follow-up time of 532 days (Q1: 284, Q3: 688), three patients (37.5%) presented VT recurrence, all three underwent a second procedure, with no VT recurrence on the follow-up. No patient died in the follow-up. CONCLUSION: CMR aided is ablation is feasible and effective in patients with scar related VT.

Genome-wide study reveals novel roles for formin-2 in axon regeneration as a microtubule dynamics regulator and therapeutic target for nerve repair.

Peripheral nerves regenerate successfully; however, clinical outcome after injury is poor. We demonstrated that low-dose ionizing radiation (LDIR) promoted axon regeneration and function recovery after peripheral nerve injury (PNI). Genome-wide CpG methylation profiling identified LDIR-induced hypermethylation of the Fmn2 promoter, exhibiting injury-induced Fmn2 downregulation in dorsal root ganglia (DRGs). Constitutive knockout or neuronal Fmn2 knockdown accelerated nerve repair and function recovery. Mechanistically, increased microtubule dynamics at growth cones was observed in time-lapse imaging of Fmn2-deficient DRG neurons. Increased HDAC5 phosphorylation and rapid tubulin deacetylation were found in regenerating axons of neuronal Fmn2-knockdown mice after injury. Growth-promoting effect of neuronal Fmn2 knockdown was eliminated by pharmaceutical blockade of HDAC5 or neuronal Hdac5 knockdown, suggesting that Fmn2deletion promotes axon regeneration via microtubule post-translational modification. In silico screening of FDA-approved drugs identified metaxalone, administered either immediately or 24-h post-injury, accelerating function recovery. This work uncovers a novel axon regeneration function of Fmn2 and a small-molecule strategy for PNI.

Clinical Features, Genetic Findings, and Risk Stratification in Arrhythmogenic Right Ventricular Cardiomyopathy: Data From a Brazilian Cohort.

BACKGROUND: Arrhythmogenic right ventricular cardiomyopathy (ARVC), a rare inherited disease, causes ventricular tachycardia, sudden cardiac death, and heart failure (HF). We investigated ARVC clinical features, genetic findings, natural history, and the occurrence of life-threatening arrhythmic events (LTAEs), HF death, or heart transplantation (HF-death/HTx) to identify risk factors. METHODS: The clinical course of 111 consecutive patients with definite ARVC, predictors of LTAE, HF-death/HTx, and combined events were analyzed in the entire cohort and in a subgroup of 40 patients without sustained ventricular arrhythmia before diagnosis. RESULTS: The 5-year cumulative probability of LTAE was 30% and HF-death/HTx was 10%. Predictors of HF-death/HTx were reduced right ventricle ejection fraction (HR: 0.93; P=0.010), HF symptoms (HR: 4.37; P=0.010), epsilon wave (HR: 4.99; P=0.015), and number of leads with low QRS voltage (HR: 1.28; P=0.001). Each additional lead with low QRS voltage increased the risk of HF-death/HTx by 28%. Predictors of LTAE were prior syncope (HR: 1.81; P=0.040), number of leads with T wave inversion (HR: 1.17; P=0.039), low QRS voltage (HR: 1.12; P=0.021), younger age (HR: 0.97; P=0.006), and prior ventricular arrhythmia/ventricular fibrillation (HR: 2.45; P=0.012). Each additional lead with low QRS voltage increased the risk of LTAE by 17%. In patients without ventricular arrhythmia before clinical diagnosis of ARVC, the number of leads with low QRS voltage (HR: 1.68; P=0.023) was independently associated with HF-death/HTx. CONCLUSIONS: Our study demonstrated the characteristics of a specific cohort with a high prevalence of arrhythmic burden at presentation, male predominance, younger age and HF severe outcomes. Our main results suggest that the presence and extension of low QRS voltage can be a risk predictor for HF-death/HTx in ARVC patients, regardless of the arrhythmic risk. This study can contribute to the global ARVC risk stratification, adding new insights to the international current scientific knowledge.

Sinus Node Artery Occlusion During Cardiac Denervation Procedures.

Cardioneural ablation is a novel treatment for functional bradycardia. However, the risk of acute complications is still unknown. The aim of this case report is to describe acute occlusion of the sinus node artery after cardiac denervation procedures in 2 patients and to encourage measures to prevent it, such as evaluating the aortic angulation in older patients before the procedure and by monitoring signs of sinus failure during ablation in patients with electroanatomical maps showing a constricted aspect of the right atrium. (Level of Difficulty: Advanced.).

Effect of Occurrence of Lamin A/C (LMNA) Genetic Variants in a Cohort of 101 Consecutive Apparent "Lone AF" Patients: Results and Insights.

Objective: Mutations in the Lamin A/C (LMNA) gene are commonly associated with cardiac manifestations, such as dilated cardiomyopathy (DCM) and conduction system disease. However, the overall spectrum and penetrance of rare LMNA variants are unknown. The present study described the presence of LMNA variants in patients with "lone atrial fibrillation (AF)" as their sole clinical presentation. Methods: One-hundred and one consecutive patients with "lone AF" criteria were initially screened by genetic testing. Genetic variants were classified according to the American College of Genetic and Genomic criteria. All subjects were evaluated through clinical and familial history, ECG, 24-h Holter monitoring, echocardiogram, cardiac magnetic resonance, treatment response, and the present relatives of LMNA carriers. In addition, whole-exome data from 49,960 UK Biobank (UKB) participants were analyzed to describe the overall penetrance of rare LMNA missense and loss of function (LOF) variants. Results: Three missense variants in LMNA were identified in probands with AF as their first and unique clinical manifestation. Other five first-degree relatives, after the screening, also presented LMNA gene variants. Among 49,960 analyzed UKB participants, 331 carried rare LMNA missense or LOF variant. Participants who carried a rare LMNA variant were significantly associated with higher odds of arrhythmic events and of an abnormal ECG in the per-protocol ECG exam (p = 0.03 and p = 0.05, respectively). Conclusion: Although a rare occurrence, our findings emphasize the possibility of an initial presentation of apparently "lone AF" in LMNA gene variant carriers.

Left Atrial Thrombus and Dense Spontaneous Contrast in Direct Oral Anticoagulant Therapy of Atrial Fibrillation: Insights from a Reference Center. / Trombo Atrial Esquerdo e Contraste Espontâneo Denso no Uso de Anticoagulante Oral de Ação Direta em Fibrilação Atrial: Visão de Centro Referenciado.

BACKGROUND: In the treatment of atrial fibrillation (AF), the most frequently sustained arrhythmia, with catheter ablation (CA) or electrical cardioversion (ECV), the periprocedural period is one of the most critical phases. Currently, the use of new direct action oral anticoagulants (DOAC) is increasingly frequent; however, in the real world, there are still few data on studies on the thrombus incidence in the left atrium (TrLA) or dense spontaneous contrast (DSC) on transesophageal echocardiogram (TEE). OBJECTIVE: To evaluate the prevalence of events and association with risk factors in patients using DOACs. Primary objective: to analyze the prevalence of thrombus in the LA by TEE in patients using DOAC undergoing ECV/CA. Second, evaluate the association of comorbidities with the presence of thrombi and DSC. METHODS: Retrospective cohort, single-center study with patients followed at the Arrhythmia Outpatient Unit (InCor-HCFMUSP). Patients indicated for procedures and using DOACs were selected, and their clinical/echocardiographic data were analyzed. A significance level of 5% was considered. RESULTS: 354 patients were included, a total of 400 procedures, from March 2012-March 2018. Thrombus in the LA was found in 11 patients (2.8%), associated with advanced age (p=0.007) and higher CHA2DS2-VASc (p<0.001) score. DSC in the LA before TEE was found in 29 patients (7.3%), with lower LVEF (p<0.038) and greater LA dimension (p<0.0001). CONCLUSION: The incidence of LA thrombus and DSC in patients using DOC in the context of AF ECV/CA, although small, is not negligible. Patients with higher CHA2DS2-VASc scores, especially older and with larger LA diameter, are more prone to these echocardiographic findings.

FUNDAMENTO: No tratamento da fibrilação atrial (FA), a arritmia sustentada mais frequente, com ablação por cateter (ABL) ou cardioversão elétrica (CVE), o período periprocedimento é uma das fases mais críticas. Atualmente, o uso de novos anticoagulantes orais de ação direta (DOAC) é cada vez mais frequente, no entanto, no mundo real, ainda existem poucos dados de estudos sobre a incidência de trombo no átrio esquerdo (TrAE) ou contraste espontâneo denso (CE) no ecocardiograma transesofágico (ETE). OBJETIVO: Analisar a prevalência de TrAE, por ETE, em pacientes em uso de DOAC submetidos à CVE/ABL. Secundariamente: avaliar a associação de comorbidades com a presença de trombos e CE. MÉTODOS: Estudo de coorte retrospectivo, unicêntrico, com pacientes do Ambulatório de Arritmia (InCor-HCFMUSP). Foram selecionados e analisados dados clínicos e ecocardiográficos no prontuário da instituição de pacientes com indicação de procedimentos e em uso de DOACs. Considerado um nível de significância de 5%. RESULTADOS: Foram incluídos 354 pacientes, no total de 400 procedimentos, de março de 2012-março de 2018. TrAE foi encontrado em 11 pacientes (2,8%), associado com idade avançada (p=0,007) e CHA2DS2-VASc maior (p<0,001). Foi encontrado CE no AE no procedimento antes da ETE em 29 pacientes (7,3%), com menor FEVE (p <0,038) e maior dimensão do AE (p <0,0001). CONCLUSÃO: A incidência de TrAE e CE em pacientes em uso de DOAC no contexto de CVE/ABL de FA, embora pequena, não é desprezível. Pacientes com escore CHA2DS2-VASc maior, principalmente mais idosos e com diâmetro do AE maior, são mais propensos a esses achados ecocardiográficos.

Multi-Omics Data Fusion for Cancer Molecular Subtyping Using Sparse Canonical Correlation Analysis.

It is now clear that major malignancies are heterogeneous diseases associated with diverse molecular properties and clinical outcomes, posing a great challenge for more individualized therapy. In the last decade, cancer molecular subtyping studies were mostly based on transcriptomic profiles, ignoring heterogeneity at other (epi-)genetic levels of gene regulation. Integrating multiple types of (epi)genomic data generates a more comprehensive landscape of biological processes, providing an opportunity to better dissect cancer heterogeneity. Here, we propose sparse canonical correlation analysis for cancer classification (SCCA-CC), which projects each type of single-omics data onto a unified space for data fusion, followed by clustering and classification analysis. Without loss of generality, as case studies, we integrated two types of omics data, mRNA and miRNA profiles, for molecular classification of ovarian cancer (n = 462), and breast cancer (n = 451). The two types of omics data were projected onto a unified space using SCCA, followed by data fusion to identify cancer subtypes. The subtypes we identified recapitulated subtypes previously recognized by other groups (all P- values < 0.001), but display more significant clinical associations. Especially in ovarian cancer, the four subtypes we identified were significantly associated with overall survival, while the taxonomy previously established by TCGA did not (P- values: 0.039 vs. 0.12). The multi-omics classifiers we established can not only classify individual types of data but also demonstrated higher accuracies on the fused data. Compared with iCluster, SCCA-CC demonstrated its superiority by identifying subtypes of higher coherence, clinical relevance, and time efficiency. In conclusion, we developed an integrated bioinformatic framework SCCA-CC for cancer molecular subtyping. Using two case studies in breast and ovarian cancer, we demonstrated its effectiveness in identifying biologically meaningful and clinically relevant subtypes. SCCA-CC presented a unique advantage in its ability to classify both single-omics data and multi-omics data, which significantly extends the applicability to various data types, and making more efficient use of published omics resources.