[Cluster Analysis and Ablation Success Rate in Atrial Fibrillation Patients Undergoing Catheter Ablation]. / æˆ¿é¢¤å°„é¢‘æ¶ˆèžæ‚£è€ çš„èšç±»åˆ†æžåŠæ¶ˆèžæˆåŠŸçŽ‡è¯„ä»·.

Objective: Atrial fibrillation (AF) is a disease of high heterogeneity, and the association between AF phenotypes and the outcome of different catheter ablation strategies remains unclear. Conventional classification of AF (e.g. according to duration, atrial size, and thromboembolism risk) fails to provide reference for the optimal stratification of the prognostic risks or to guide individualized treatment plan. In recent years, research on machine learning has found that cluster analysis, an unsupervised data-driven approach, can uncover the intrinsic structure of data and identify clusters of patients with pathophysiological similarity. It has been demonstrated that cluster analysis helps improve the characterization of AF phenotypes and provide valuable prognostic information. In our cohort of AF inpatients undergoing radiofrequency catheter ablation, we used unsupervised cluster analysis to identify patient subgroups, to compare them with previous studies, and to evaluate their association with different suitable ablation patterns and outcomes. Methods: The participants were AF patients undergoing radiofrequency catheter ablation at West China Hospital between October 2015 and December 2017. All participants were aged 18 years or older. They underwent radiofrequency catheter ablation during their hospitalization. They completed the follow-up process under explicit informed consent. Patients with AF of a reversible cause, severe mitral stenosis or prosthetic heart valve, congenital heart disease, new-onset acute coronary syndrome within three months prior to the surgery, or a life expectancy less than 12 months were excluded according to the exclusion criteria. The cohort consisted of 1102 participants with paroxysmal or persistent/long-standing persistent AF. Data on 59 variables representing demographics, AF type, comorbidities, therapeutic history, vital signs, electrocardiographic and echocardiographic findings, and laboratory findings were collected. Overall, data for the variables were rarely missing (<5%), and multiple imputation was used for correction of missing data. Follow-up surveys were conducted through outpatient clinic visits or by telephone. Patients were scheduled for follow-up with 12-lead resting electrocardiography and 24-hours Holter monitoring at 3 months and 6 months after the ablation procedure. Early ablation success was defined as the absence of documented AF, atrial flutter, or atrial tachycardia >30 seconds at 6-month follow-up. Hierarchical clustering was performed on the 59 baseline variables. All characteristic variables were standardized to have a mean of zero and a standard deviation of one. Initially, each patient was regarded as a separate cluster, and the distance between these clusters was calculated. Then, the Ward minimum variance method of clustering was used to merge the pair of clusters with the minimum total variance. This process continued until all patients formed one whole cluster. The "NbClust" package in R software, capable of calculating various statistical indices, including pseudo t2 index, cubic clustering criterion, silhouette index etc, was applied to determine the optimal number of clusters. The most frequently chosen number of clusters by these indices was selected. A heatmap was generated to illustrate the clinical features of clusters, while a tree diagram was used to depict the clustering process and the heterogeneity among clusters. Ablation strategies were compared within each cluster regarding ablation efficacy. Results: Five statistically driven clusters were identified: 1) the younger age cluster (n=404), characterized by the lowest prevalence of cardiovascular and cerebrovascular comorbidities but the highest prevalence of obstructive sleep apnea syndrome (14.4%); 2) a cluster of elderly adults with chronic diseases (n=438), the largest cluster, showing relatively higher rates of hypertension, diabetes, stroke, and chronic obstructive pulmonary disease; 3) a cluster with high prevalence of sinus node dysfunction (n=160), with patients showing the highest prevalence of sick sinus syndrome and pacemaker implantation; 4) the heart failure cluster (n=80), with the highest prevalence of heart failure (58.8%) and persistent/long-standing persistent AF (73.7%); 5) prior coronary artery revascularization cluster (n=20), with patients of the most advanced age (median: 69.0 years old) and predominantly male patients, all of whom had prior myocardial infarction and coronary artery revascularization. Patients in cluster 2 achieved higher early ablation success with pulmonary veins isolation alone compared to extensive ablation strategies (79.6% vs. 66.5%; odds ratio [OR]=1.97, 95% confidence interval [CI]: 1.28-3.03). Although extensive ablation strategies had a slightly higher success rate in the heart failure group, the difference was not statistically significant. Conclusions: This study provided a unique classification of AF patients undergoing catheter ablation by cluster analysis. Age, chronic disease, sinus node dysfunction, heart failure and history of coronary artery revascularization contributed to the formation of the five clinically relevant subtypes. These subtypes showed differences in ablation success rates, highlighting the potential of cluster analysis in guiding individualized risk stratification and treatment decisions for AF patients.

"Honeycomb" Photothermal Lubricated Porous Foam with Low-Temperature, Weak-Light, Anti-Icing/Deicing, and Long-Lasting Lubrication Properties.

The prevalence of icing in nature has become a significant threat to human work and life, prompting the development of more energy-efficient active/passive combination anti-icing/deicing technologies. In order to overcome the disadvantage of the poor durability of superhydrophobic surfaces, lubricated surfaces inspired by nepenthes have been preferred. In this study, a paraffin and silicone oil-infused photothermal foam (PSIPF) with excellent overall performance was prepared using polypyrrole (PPy) as a photothermal conversion material, a mixture of silicone oil and paraffin as a lubricating fluid, and melamine foam (MF) as a carrier. The surface adhesive strength is less than 20 kPa at -20 °C, the melting time is only 1018 s at an irradiance of 200 W/m2 and -20 °C (0.2 sun), and surface droplets do not freeze within 1 h at -10 °C. Furthermore, the surface exhibits excellent mechanical durability and stability, maintaining optimal lubrication properties following repeated cycles of icing/deicing, water rinsing, and immersion for 2 days in acid and alkaline conditions. This photothermal lubricated surface with excellent anti-icing/deicing properties at low temperatures and in weak-light environments provides a wider range of applications for equipment at high latitudes and high altitudes.

Quantitatively Lighting up the Spatial Organization of CD47/SIRPα Immune Checkpoints on the Cellular Membrane with Single-Molecule Localization Microscopy.

Immunotherapy including immune checkpoint inhibition has reinvigorated the current cancer treatment field. The development of efficient cancer immunotherapies depends on a thorough understanding of the status of immune checkpoints and how they interact. However, the distribution and spatial organization changes of immune checkpoints during their interactions at the single-molecule level remain difficult to directly visualize due to the lack of in situ imaging techniques with appropriate spatial and stoichiometric resolution. Herein, we report the direct visualization and quantification of the spatial distribution and organization of CD47 on the bladder tumor cell membrane and SIRPα on the macrophage membrane by using a single-molecule localization imaging technique called quantitative direct stochastic optical reconstruction microscopy (QdSTORM). Results showed that a portion of CD47 and SIRPα was present on cell membranes as heterogeneous clusters of varying sizes and densities prior to activation. Quantitative analyses of the reconstructed super-resolution images and theoretical simulation revealed that CD47 and SIRPα were reorganized into larger clusters upon binding to each other. Furthermore, we found that blocking the immune checkpoint interaction with small-molecule inhibitors or antibodies significantly impacted the spatial clustering behavior of CD47 on bladder tumor cells, demonstrating the promise of our QdSTORM strategy in elucidating the molecular mechanisms underlying immunotherapy. This work offers a promising strategy to advance our understanding of immune checkpoint state and interactions while also contributing to the fields including signal regulation and cancer therapy.

Columbianadin attenuates doxorubicin-induced cardiac injury, oxidative stress, and apoptosis via Sirt1/FOXO1 signaling pathway.

PURPOSE: Oxidative stress and apoptosis contribute to the pathological basis of doxorubicin (DOX)-induced cardiotoxicity. Columbianadin (CBN) is one of the main bioactive constituents isolated from the root of Angelica pubescens. Herein, we intended to explore the potential role and molecular basis of CBN in DOX-induced cardiotoxicity. METHODS: C57BL/6 mice were subjected to DOX (15 mg/kg/day, i.p.) to generate DOX-induced cardiotoxicity. CBN (10 mg/kg/day, i.p.) was administered for four week following DOX injection. RESULTS: DOX administered markedly dampened cardiac function, increased cardiac injury, excessive reactive oxygen species (ROS) production, and cardiomyocyte loss. These alterations induced by DOX significantly alleviated by CBN treatment. Mechanistically, our results demonstrated that the CBN exerts cardioprotection role against DOX by up-regulating silent information regulator 1 (Sirt1) and decreasing acetylation of forkhead box O1 (FOXO1). Moreover, Sirt1 inhibition with Ex-527 significantly blunt the beneficial effect of CBN on DOX-induced cardiotoxicity, including cardiac dysfunction, ROS, and apoptosis. CONCLUSION: Collectively, CBN attenuated oxidative stress and cardiomyocyte apoptosis in DOX-induced cardiotoxicity through maintaining Sirt1/FOXO1 signaling pathway. Our results demonstrated that CBN might be used to treat DOX-related cardiotoxicity.

Geranylated or prenylated flavonoids from Cajanus volubilis.

Five new flavonoid derivatives, cajavolubones A-E (1-5), along with six known analogues (6-11) were isolated from Cajanus volubilis, and their structures were elucidated by spectroscopic analysis and quantum chemical calculations. Cajavolubones A and B (1 and 2) were identified as two geranylated chalcones. Cajavolubone C (3) was a prenylated flavone, while cajavolubones D and E (4 and 5) were two prenylated isoflavanones. Compounds 3, 8, 9 and 11 displayed cytotoxicity against HCT-116 cancer cell line.

Dearomatization-Rearomatization Reaction of Metal-Polarized Aza-ortho-Quinone Methides.

Metal-polarized aza-ortho-quinone methides (aza-o-QMs) are a unique and efficient handle for azaheterocycle synthesis. Despite great achievements, the potential of these reactive intermediates has not yet been fully exploited, especially the new reaction modes. Herein, we disclosed an unprecedented dearomatization process of metal-polarized aza-o-QMs, affording transient dearomatized spiroaziridine intermediates. Based on this serendipity, we accomplished three sequential dearomatization-rearomatization reactions of benzimidazolines with aza-sulfur ylides, enabling the divergent synthesis of bis-nitrogen heterocycles with high efficiency and flexibility. Moreover, experimental and theoretical studies were performed to explain the proposed mechanisms and observed selectivity. Further cellular evaluation of the dibenzodiazepine products identified a hit compound for new antitumor drugs.

Amino-Ligand-Coordinated Dicopper Active Sites Enable Catechol Oxidase-Like Activity for Chiral Recognition and Catalysis.

Developing highly active and selective advanced nanozymes for enzyme-mimicking catalysis remains a long-standing challenge for basic research and practical applications. Herein, we grafted a chiral histidine- (His-) coordinated copper core onto Zr-based metal-organic framework (MOF) basic backbones to structurally mirror the bimetal active site of natural catechol oxidase. Such a biomimetic fabricated process affords MOF-His-Cu with catechol oxidase-like activity, which can catalyze dehydrogenation and oxidation of o-diphenols and then transfer electrons to O2 to generate H2O2 by the cyclic conversion of Cu(II) and Cu(I). Specifically, the elaborate incorporation of chiral His arms results in higher catalytic selectivity over the chiral catechol substrates than natural enzyme. Density functional theory calculations reveal that the binding energy and potential steric effect in active site-substrate interactions account for the high stereoselectivity. This work demonstrates efficient and selective enzyme-mimicking catalytic processes and deepens the understanding of the catalytic mechanism of nanozymes.

Unexpected assembly machinery for 4(3H)-quinazolinone scaffold synthesis.

4(3H)-quinazolinone is the core scaffold in more than 200 natural alkaloids and numerous drugs. Many chemosynthetic methodologies have been developed to generate it; however, investigation of its native enzymatic formation mechanism in fungi has been largely limited to fumiquinazolines, where the two nitrogen atoms come from anthranilate (N-1) and the α-NH2 of amino acids (N-3). Here, via biochemical investigation of the chrysogine pathway, unexpected assembly machinery for 4(3H)-quinazolinone is unveiled, which involves a fungal two-module nonribosomal peptide synthase ftChyA with an unusual terminal condensation domain catalysing tripeptide formation; reveals that N-3 originates from the inorganic ammonium ions or the amide of L-Gln; demonstrates an unusual α-ketoglutarate-dependent dioxygenase ftChyM catalysis of the C-N bond oxidative cleavage of a tripeptide to form a dipeptide. Our study uncovers a unique release and tailoring mechanism for nonribosomal peptides and an alternative route for the synthesis of 4(3H)-quinazolinone scaffolds.

N-Acylamino Saccharin as an Emerging Cysteine-Directed Covalent Warhead and Its Application in the Identification of Novel FBPase Inhibitors toward Glucose Reduction.

With a resurgence of covalent drugs, there is an urgent need for the identification of new moieties capable of cysteine bond formation. Herein, we report on the N-acylamino saccharin moieties capable of novel covalent reactions with cysteine. Their utility as alternative electrophilic warheads was demonstrated through the covalent modification of fructose-1,6-bisphosphatase (FBPase), a promising target associated with cancer and type 2 diabetes. The cocrystal structure of title compound W8 bound with FBPase unexpectedly revealed that the N-acylamino saccharin moiety worked as an electrophile warhead that covalently modified the noncatalytic C128 site in FBPase while releasing saccharin, suggesting a previously undiscovered covalent reaction mechanism of saccharin derivatives with cysteine. Treatment of title compound W8 displayed potent inhibition of glucose production in vitro and in vivo. This newly discovered reactive warhead supplements the current repertoire of cysteine covalent modifiers while avoiding some of the limitations generally associated with established moieties.

Complex Flavanones from Cryptocarya metcalfiana and Structural Revision of Oboflavanone A.

Nine new complex flavanones, cryptometcones A-I (1-9), along with four known analogues, were isolated from Cryptocarya metcalfiana. The structures of 1-9 including their absolute configurations were elucidated by spectroscopic data analysis and electronic circular dichroism (ECD) calculations. In addition, the structure of oboflavanone A was revised, while the absolute configurations of oboflavanone B, cryptoflavanone C, and cryptoflavanone D were determined, according to their spectroscopic data. Compounds 3-5, 8, and 9 exhibited cytotoxicity against the HCT-116 cancer cell line.

Cardiac echinococcosis secondary to hepatic echinococcosis: a rare case report.

Cystic echinococcosis (CE) is a zoonotic parasitic infection, which is very rare in developed countries. It can affect all internal organs, while cardiac echinococcosis is extremely rare, especially in children. Slowly enlarging hydatid cyst usually remains asymptomatic until the size or space occupying effects the involved organ and induces symptoms. The progression of cardiac echinococcosis can be very hidden, and the symptoms are similar to that of other cardiovascular diseases, which raises the difficulty in accurate diagnosis. We present a 13-year-old young girl with a history of hepatic echinococcosis who developed a huge cardiac hydatid cyst, but her symptoms were not specific, while the physical tests and biochemical examinations were unremarkable. Her residential area in Tibet and previous medical history of hepatic echinococcosis gave us clues in the diagnosis of cardiac echinococcosis. Combined with computed tomography (CT) and magnetic resonance imaging (MRI), the cardiac echinococcosis was finally confirmed, and the cardiac symptoms were relieved after surgical removal of the cardiac hydatid cyst. This is the first report of children's cardiac echinococcosis secondary to hepatic echinococcosis, and it remarks on the importance of rapid consideration of cardiac echinococcosis even if no remarkable symptoms or indexes are present. Moreover, the combination of previous history and imaging techniques are indispensable for obtaining a definite diagnosis.

Cytotoxic α-pyrone derivatives from Cryptocarya yunnanensis.

Five new α-pyrone derivatives, cryptoyunnanes A - E (1 - 5), together with four known analogues, were isolated from the leaves and twigs of Cryptocarya yunnanensis. Their structures including absolute configurations were elucidated by extensive spectroscopic data and electronic circular dichroism (ECD) analyses. Compounds 4 and 6 showed significant cytotoxicity against A549, HCT-116, MDA-MB-231, PC-3 and HeLa with IC50 values from 2.25 to 8.97 µM. Compounds 1, 2 and 7 also displayed good cytotoxicity against HCT-116, MDA-MB-231 and PC-3 with IC50 values from 1.26 to 8.32 µM. This is the first time to report the isolation and bioactivity evaluation of chemical constituents from C. yunnanensis.

Neolignans and Sesquiterpenoid from Piper yunnanense.

Two biphenyl-type neolignans with a rare dibenzofuran skeleton, including a new one piyunneolignan A (1) and a known one piperneolignan D (2), together with a new sesquiterpenoid piyunin A (3), were isolated from the leaves and twigs of Piper yunnanense. Their structures were established on the basis of comprehensive spectroscopic data analysis and electronic circular dichroism (ECD) calculation. Piyunneolignan A (1) featured a rare C-2-C-2'/C-3-O-C-3' linkage. Compounds 1-3 were evaluated for their antimicrobial and cytotoxic activities against a panel of bacteria, fungi, and human cancer cell lines, respectively.

Cryptoyunnanones A-H, Complex Flavanones from Cryptocarya yunnanensis.

Eight new complex flavanones with a novel linkage, cryptoyunnanones A-H (1-8), together with four known α-pyrones, were isolated from the leaves and twigs of Cryptocarya yunnanensis. The structures of 1-8 including their absolute configurations were characterized by spectroscopic data analysis and single-crystal X-ray crystallography. Plausible biosynthetic pathways for the formation of compounds 1-8 were proposed. Compounds 1-4 exhibited cytotoxicity against HCT-116, MDA-MB-231, and PC-3 cancer cells with IC50 values from 6.4 to 9.1 µM.

Iridoid Constituents of Viburnum brachybotryum.

Eleven new iridoids, brachybones A-K (1-11), were isolated from the twigs of Viburnum brachybotryum. Their structures including absolute configurations were determined by spectroscopic data analysis and from the electronic circular dichroism (ECD) spectra. All of the compounds 1-11 possess one or two acetoxysenecioate substituents. Furthermore, compounds 5-7 and 11 feature a Cl atom in the molecule, while compounds 9-11 exhibit a cagelike rigid skeleton through an unusual oxo bridge from C-3 to C-8 or C-10. The isolates were evaluated for cytotoxic activity against the HCT-116, A549, and Hela cell lines, and the results showed compounds 10 and 11 to be active against HCT-116 cells.

Impact of concomitant tricuspid annuloplasty on right ventricular remodeling in patients with rheumatic mitral valve disease.

BACKGROUND: Studies on the management of functional tricuspid regurgitation (TR) during mitral valve operations have drawn inconsistent conclusions. This study was designed to compare the treatment strategy of concomitant tricuspid annuloplasty (TAP) against isolated mitral valve replacement (MVR) in rheumatic mitral valve disease patients, and to assess the effect of concomitant TAP on postoperative right ventricular (RV) remodeling and function. METHODS: One hundred-seventy patients with rheumatic mitral valve disease receiving MVR were categorized into TAP group (n = 124) and non-TAP group (n = 46). Clinical and echocardiographic data were collected preoperatively and at 1-year follow-up. Three-dimensional echocardiographic indices of RV geometry and function were analyzed. RESULTS: At baseline, concomitant TAP group had larger RV end-diastolic volume, more decreased RV ejection fraction and RV longitudinal strain than non-TAP group (all P <  0.001). At 1-year follow-up, TAP group had improved RV geometry and function. While adverse changes were observed in non-TAP group. In analysis of variance, the above indices demonstrated significant interaction with different treatment group (all P <  0.001). In multivariate regression analysis, independent of age and Maze procedure, concomitant TAP was associated with postoperative RV volume reduction (P <  0.001), improvement of RV ejection fraction (P <  0.001), and relieved postoperative functional TR severity (P = 0.025). CONCLUSIONS: Our results suggest that concomitant TAP could improve RV remodeling and function for rheumatic mitral valve disease patients, while those with mild preoperative functional TR who had isolated MVR might experience RV dilation and deterioration of RV function at follow-up. Concomitant surgery for functional TR could be considered for patients undergoing MVR with rheumatic mitral valve disease.

MBD2 serves as a viable target against pulmonary fibrosis by inhibiting macrophage M2 program.

Despite past extensive studies, the mechanisms underlying pulmonary fibrosis (PF) still remain poorly understood. Here, we demonstrated that lungs originating from different types of patients with PF, including coronavirus disease 2019, systemic sclerosis-associated interstitial lung disease, and idiopathic PF, and from mice following bleomycin (BLM)-induced PF are characterized by the altered methyl-CpG-binding domain 2 (MBD2) expression in macrophages. Depletion of Mbd2 in macrophages protected mice against BLM-induced PF. Mbd2 deficiency significantly attenuated transforming growth factor-ß1 (TGF-ß1) production and reduced M2 macrophage accumulation in the lung following BLM induction. Mechanistically, Mbd2 selectively bound to the Ship promoter in macrophages, by which it repressed Ship expression and enhanced PI3K/Akt signaling to promote the macrophage M2 program. Therefore, intratracheal administration of liposomes loaded with Mbd2 siRNA protected mice from BLM-induced lung injuries and fibrosis. Together, our data support the possibility that MBD2 could be a viable target against PF in clinical settings.

IL-24 deficiency protects mice against bleomycin-induced pulmonary fibrosis by repressing IL-4-induced M2 program in macrophages.

Idiopathic pulmonary fibrosis (IPF) is the most common type of idiopathic interstitial pneumonia and has one of the poorest prognosis. However, the molecular mechanisms underlying IPF progression remain largely unknown. In this study, we determined that IL-24, an IL-20 subfamily cytokine member, was increased both in the serum of IPF patients and the bronchoalveolar lavage fluid (BALF) of mice following bleomycin (BLM)-induced pulmonary fibrosis. As a result, IL-24 deficiency protected mice from BLM-induced lung injury and fibrosis. Specifically, loss of IL-24 significantly attenuated transforming growth factor ß1 (TGF-ß1) production and reduced M2 macrophage infiltration in the lung of BLM-induced mice. Mechanistically, IL-24 alone did not show a perceptible impact on the induction of M2 macrophages, but it synergized with IL-4 to promote M2 program in macrophages. IL-24 suppressed IL-4-induced expression of suppressor of cytokine signaling 1 (SOCS1) and SOCS3, through which it enhanced signal transducer and activator of transcription 6/peroxisome proliferator-activated receptor gamma (STAT6/PPARγ) signaling, thereby promoting IL-4-induced production of M2 macrophages. Collectively, our data support that IL-24 synergizes with IL-4 to promote macrophage M2 program contributing to the development of pulmonary fibrosis.

Relationship between ABO blood group and risk of venous thrombosis in cancer patients with peripherally inserted central catheters: A protocol for systematic review and meta-analysis.

BACKGROUND: Peripherally inserted central catheter (PICC) is closely related to venous thromboembolism (VTE). It is a common complication of hospitalized patients, and its etiology is complex. How to prevent the occurrence of VTE is the focus of clinical work. In order to provide basis for individual prevention and accurate treatment of VTE, the purpose of this study was to explore the relationship between ABO blood group and the risk of VTE in cancer patients associated with PICC through meta-analysis. METHODS: Electronic databases, including Embase, Cochrane Library, Pubmed, Chinese databases SinoMed, Chinese National Knowledge Infrastructure (CNKI), Chinese Scientific Journals Database (VIP), and Wanfang Data, were searched for case-control studies of ABO blood group and PICC-related VTE in cancer patients. The languages were limited to Chinese and English. Two reviewers were responsible for the selection of the study, the extraction of data and the evaluation of the quality of the research. All statistical analyses were carried out with Review Manager 5.3 and Stata 14.0. RESULTS: The results of this meta-analysis would be published in peer-reviewed journals. CONCLUSION: This study provided evidence to support the relationship between ABO blood group and the risk of PICC-related VTE in cancer patients. OSF REGISTRATION NUMBER: DOI 10.17605/OSF.IO/6DPFG.