Fragmented QRS complex could predict all-cause mortality in patients with connective tissue disease-associated pulmonary arterial hypertension.

OBJECTIVES: To investigate the prognostic impact and pathophysiological characteristics of fragmented QRS complex (fQRS) on patients with connective tissue disease-associated pulmonary arterial hypertension (CTD-PAH). METHODS: This was a multicentre retrospective study recruiting 141 patients with CTD-PAH diagnosed by right heart catheterization (114 cases in the discovery cohort and 27 cases in the validation cohort). fQRS and ST-T change were detected on conventional 12-lead electrocardiogram (ECG). Patients were followed up every 3 months to update their status and the primary end point was all-cause death. Clinical information and ECG characteristics were compared between survival and death groups and Kaplan-Meier curve was used for survival analysis. RESULTS: There were significant differences in age, gender, 6-min walk distance, NT-proBNP, WHO class, presence of fQRS and presence of ST-T change in inferior leads between survival group and death group. Inferior fQRS and ST-T change were significantly associated with right ventricular (RV) dilatation and reduced RV ejection fraction (RVEF). Kaplan-Meier curve showed that all-cause mortality was higher in CTD-PAH with fQRS (p= 0.003) and inferior ST-T change (p= 0.012). Low- and intermediate-risk CTD-PAH with inferior ST-T change had higher all-cause mortality (p= 0.005). The prognostic value of fQRS and inferior ST-T change was validated in external validation cohort. CONCLUSION: The presence of inferior fQRS and ST-T change could predict poor prognosis in CTD-PAH. CLINICAL TRIAL REGISTRATION NUMBER: NCT05980728, https://clinicaltrials.gov.

Identification of key biomarkers associated with immune cells infiltration for myocardial injury in dermatomyositis by integrated bioinformatics analysis.

BACKGROUND: Dermatomyositis (DM) is an acquired autoimmune disease that can cause damage to various organs, including the heart muscle. However, the mechanisms underlying myocardial injury in DM are not yet fully understood. METHODS: In this study, we utilized publicly available datasets from the Gene Expression Omnibus (GEO) database to identify hub-genes that are enriched in the immune system process in DM and myocarditis. Weighted gene co-expression network analysis (WGCNA), differentially expressed genes (DEGs) analysis, protein-protein interaction (PPI), and gene ontology (GO) analysis were employed to identify these hub-genes. We then used the CIBERSORT method to analyze immune cell infiltration in skeletal muscle specimens of DM and myocardium specimens of myocarditis respectively. Correlation analysis was performed to investigate the relationship between key genes and infiltrating immune cells. Finally, we predicted regulatory miRNAs of hub-genes through miRNet and validated their expression in online datasets and clinical samples. RESULTS: Using integrated bioinformatics analysis, we identified 10 and 5 hub-genes that were enriched in the immune system process in the database of DM and myocarditis respectively. The subsequent intersections between hub-genes were IFIT3, OAS3, ISG15, and RSAD2. We found M2 macrophages increased in DM and myocarditis compared to the healthy control, associating with the expression of IFIT3, OAS3, ISG15, and RSAD2 in DM and myocarditis positively. Gene function enrichment analysis (GSEA) showed that IFIT3, OAS3, ISG15, and RSAD2 were mainly enriched in type I interferon (IFN) signaling pathway, cellular response to type I interferon, and response to type I interferon. Finally, we verified that the expression of miR-146a-5p was significantly higher in the DM with myocardial injury than those without myocardial injury (p = 0.0009). CONCLUSION: Our findings suggest that IFIT3, OAS3, ISG15, and RSAD2 may play crucial roles in the underlying mechanism of myocardial injury in DM. Serum miR-146a-5p could be a potential biomarker for myocardial injury in DM.

Black phosphorus nanosheets-based platform for targeted chemo-photothermal synergistic cancer therapy.

As a new member of two-dimensional (2D) nanomaterials, black phosphorus (BP) has been considered as efficient photothermal therapy (PTT) agents owing to its excellent photothermal efficiency and biodegradability. Herein, a multifunctional nanoplatform based on black phosphorus nanosheets (BP NSs) was developed for chemo-photothermal synergistic cancer therapy. The BP NSs were successfully prepared by a liquid exfoliation technique. Doxorubicin (DOX), as a model drug, was loaded into the cavity of poly (amidoamine) (PAMAM) dendrimer using thin film hydration method. Then, PAMAM@DOX was coated on the surface of BP NSs using an electrostatic adsorption method that combined bath sonication with magnetic stirring. Hyaluronic acid (HA) was also modified onto the BP NS-PAMAM@DOX through electrostatic adsorption. PAMAM and HA layer could effectively isolate BP NSs from water and air to improve physiological stability. BP NSs and BP NS-PAMAM@DOX-HA were characterized by particle size, zeta potential, morphology, UV-vis-NIR absorption spectra, stability, photothermal performance and photothermal stability. This nanosystem exhibited a good pH and near infrared (NIR) dual-responsive drug release property. In addition, the obtained BP NS-PAMAM@D OX-HA nanocomposites possessed excellent PTT efficiency both in vitro and in vivo. The in vitro cell experiments suggested that the targeted BP NS-PAMAM@DOX-HA presented greater cytotoxicity and higher cellular uptake efficiency. Tumor xenograft model was established in BALB/C mice. The therapeutic effect of BP NS-PAMAM@DOX-HA was further augmented under 808 nm laser irradiation, displaying superior antitumor effect in comparison with chemotherapy or PTT alone. Such a biodegradable BP NS-based platform provide new insights for the rational design of PTT-based combinational cancer therapy.

Black phosphorus nanosheets and docetaxel micelles co-incorporated thermoreversible hydrogel for combination chemo-photodynamic therapy.

The platform of the combination chemo-photodynamic therapy has received widespread attention for enhancing anticancer efficacy and inhibiting tumor growth, which supports thermosensitive and controlled drug release. Here, an injectable thermoreversible hydrogel (BPNSs/DTX-M-hydrogel) co-encapsulating black phosphorus nanosheets (BPNSs) and docetaxel (DTX) micelles was prepared to increase drug accumulation in tumor tissue and improve anticancer efficacy. BPNSs were prepared by liquid exfoliation method with a simple and rapid preparation, and DTX micelles were prepared by the thin film dispersion method. Hydrogel was prepared with F127 as hydrogel matrix for intratumoral injection. BPNSs, DTX micelles, and BPNSs/DTX-M-hydrogel were characterized by particle size, morphology, stability and degradation, phase transition feature, and photodynamic performance. And the in vivo anticancer efficacy was evaluated in 4T1 tumor-bearing Balb/c mice. The results showed that the particle size of DTX micelles and BPNSs were about 16 and 180 nm, respectively. The hydrogel with the transformation temperature at near body exhibited great photodynamic efficacy and good biodegradability. Moreover, BPNSs/DTX-M-hydrogel with the combination of chemotherapy and photodynamic therapy exhibited unique anticancer efficacy with low toxicity. In conclusion, the combination platform of chemo-photodynamic therapy based on BPNSs could be a prospective strategy in antitumor research. Graphical abstract.