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1.
Europace ; 26(9)2024 Aug 30.
Article in English | MEDLINE | ID: mdl-39226147

ABSTRACT

AIMS: Advanced atrial fibrillation (AF) is currently a dilemma for electrophysiologists when choosing a minimally invasive treatment strategy. Previous studies have demonstrated the outcome of either catheter ablation or thoracoscopic surgical ablation (SA) is unsatisfactory in these patients. Whether hybrid ablation (HA) could improve outcomes in these patients is unknown. The purpose of this study was to evaluate the clinical efficacy of HA for the treatment of advanced AF. METHODS AND RESULTS: A randomized controlled trial was designed to enrol patients with persistent AF (PerAF) and enlarged left atrium or long-standing persistent AF (LSPAF) who were randomized to HA or thoracoscopic SA at a 1:1 ratio. The primary endpoint was freedom from any recurrence of AF off antiarrhythmic drugs (AADs) 12 months after operation. The primary endpoint was monitored by 7-day electrocardiogram monitoring devices. One hundred patients were enrolled. The mean age was 58.5 ± 7.6 years, and the mean left atrial diameter (LAD) was 50.1 ± 6.1 mm. At 12 months, freedom from AF off AADs was recorded in 71.4% (35/49) of patients in HA group and 45.8% (22/48) in SA group [odds ratio 2.955, 95% confidence interval (1.275-6.848), P = 0.014]. HA significantly reduced patients' AF burden (30.2% in SA group and 14.8% in HA group, P = 0.048) and the LAD (mean differences: -5.53 ± 4.97 mm in HA group and -3.27 ± 5.20 mm in SA group, P = 0.037) at 12 months after operation. CONCLUSION: In patients with PerAF and enlarged left atrium or LSPAF, HA achieved better freedom from AF after 1 year of follow-up compared with thoracoscopic SA.


Subject(s)
Atrial Fibrillation , Catheter Ablation , Recurrence , Thoracoscopy , Humans , Atrial Fibrillation/surgery , Atrial Fibrillation/physiopathology , Atrial Fibrillation/diagnosis , Male , Female , Catheter Ablation/methods , Middle Aged , Prospective Studies , Thoracoscopy/methods , Treatment Outcome , Pulmonary Veins/surgery , Pulmonary Veins/physiopathology , Anti-Arrhythmia Agents/therapeutic use , Aged , Time Factors , Electrocardiography, Ambulatory
2.
Innovations (Phila) ; : 15569845241275161, 2024 Sep 21.
Article in English | MEDLINE | ID: mdl-39305170

ABSTRACT

OBJECTIVE: There is no consensus on the optimal ablation strategy for nonparoxysmal atrial fibrillation (NPAF) with enlarged left atrium. We aimed to explore whether hybrid ablation (HA) of combined thoracoscopic surgical ablation with catheter ablation (CA) was superior to CA alone in these patients. METHODS: Patients with NPAF and left atrial diameter (LAD) ≥45 mm who underwent hybrid biatrial ablation or CA procedure from June 2014 to July 2021 were included in this study. Propensity score matching was applied to select patients in each group. The primary endpoint was freedom from atrial tachyarrhythmias after procedures. RESULTS: After propensity score matching, 52 patients with enlarged left atrium (median LAD = 51 mm) were enrolled in each group. The median follow-up was 36 months. The probability of freedom from atrial tachyarrhythmias at 12, 24, and 36 months on antiarrhythmic drugs (AADs) was 70.1%, 65.4%, and 62.6% in the HA group and 34.3%, 29.4%, and 22.0% in the CA group, respectively (P < 0.001); off AADs was 57.1%, 52.7%, and 50.0% in the HA group and 25.0%, 16.2%, and 11.5% in the CA group (P < 0.001); on AADs after redo CA was 76.2%, 73.7%, and 73.7% in the HA group and 43.6%, 43.6%, and 38.2% in the CA group, respectively (P < 0.001); off AADs after redo CA was 62.5%, 60.1%, and 60.1% in the HA group and 30.4%, 25.1%, and 20.9% in the CA group, respectively (P < 0.001). CONCLUSIONS: For patients with NPAF and enlarged left atrium, hybrid biatrial ablation was superior to CA in sinus rhythm maintenance even if redo CA was performed.

4.
iScience ; 27(7): 110276, 2024 Jul 19.
Article in English | MEDLINE | ID: mdl-39109172

ABSTRACT

Understanding the mechanism of cancer immune surveillance is crucial for precision medicine and effective immunotherapy. We report here that ZNF408, encoded by a gene linked to familial exudative vitreoretinopathy (FEVR) and autosomal recessive retinitis pigmentosa (RP), is physically associated with the SETD1A/COMPASS complex mediating histone H3 lysine 4 (H3K4) methylation in breast cancer cells. Integrative epigenomic and transcriptomic analyses reveal that ZNF408 and SETD1A share overlapped chromatin landscape and coordinately activate a cohort of genes, among which STING1 is critical in innate immune responses. ZNF408-SETD1A complex enhances STING1 expression and promotes STING-mediated anti-tumor immune responses both in vitro and in vivo. Importantly, ZNF408 expression is positively correlated with that of STING1 and negatively correlated with the histological grade of breast cancer. Our study uncovers a role for ZNF408 in cancer immune surveillance, supporting further investigations for therapeutic targeting of ZNF408-SETD1A-STING1 axis in breast carcinogenesis and other ZNF408-associated diseases including FEVR and RP.

5.
J Stroke Cerebrovasc Dis ; 33(8): 107813, 2024 Aug.
Article in English | MEDLINE | ID: mdl-38871261

ABSTRACT

OBJECTIVES: The genetic association of long non-coding RNAs (lncRNAs) polymorphism with ischemic stroke (IS) susceptibility is not fully understood. To explore whether lncRNA MIAT rs1894720 polymorphism can predict the susceptibility of IS in the Chinese Han population. MATERIALS AND METHODS: 200 IS cases and 200 healthy controls were enrolled. Serum MIAT levels were tested via qRT-PCR. Rs1894720 genotyping was accomplished through Sanger sequencing. RESULTS: MIAT rs1894720 genotypes were differentially distributed in IS and control groups. Rs1894720 TT genotype was considered to be a protective factor for IS risk in dominant model (GT + TT vs GG: OR = 0.630, 95 % CI = 0.412-0.962, P = 0.032). Further stratification results showed that individuals carrying the rs1894720 G allele in people older than 65 years, men, smokers, or those with hypertension had a higher risk of IS. MIAT rs1894720 GG genotype was positively related to the susceptibility to IS of LAA subtype compared with the healthy controls. GG genotype carriers had high serum MIAT levels compared to those with GT and TT genotypes. CONCLUSIONS: MIAT rs1894720 polymorphism was associated with the risk of IS in the Chinese Han population, especially for LAA subtype. Rs1894720 GG genotype carriers were at greater risk of developing IS.


Subject(s)
Asian People , Gene Frequency , Genetic Association Studies , Genetic Predisposition to Disease , Ischemic Stroke , Polymorphism, Single Nucleotide , RNA, Long Noncoding , Humans , RNA, Long Noncoding/genetics , Male , Female , Middle Aged , Aged , Ischemic Stroke/genetics , Ischemic Stroke/ethnology , Ischemic Stroke/diagnosis , Ischemic Stroke/epidemiology , Ischemic Stroke/blood , Case-Control Studies , China/epidemiology , Asian People/genetics , Risk Factors , Phenotype , East Asian People
6.
Article in English | MEDLINE | ID: mdl-38775401

ABSTRACT

OBJECTIVES: To investigate the predictive values of surface electrocardiogram-derived parameters in patients with atrial fibrillation who underwent thoracoscopic epicardial ablation. METHODS: The present study included 102 patients with atrial fibrillation who underwent thoracoscopic epicardial ablation and whose baseline 12-lead electrocardiograms were available. Frequency domain analysis was performed to calculate the electrocardiogram-derived parameters. Cox proportional hazards regression was used to identify predictive risk factors for postoperative recurrence. RESULTS: At 36-month interval, the overall rate of freedom from atrial tachyarrhythmia without antiarrhythmic drugs was 58.5%. The results of the univariable and multivariable analyses showed that larger left atrial diameter (hazard ratio: 1.074, 95% confidence interval: 1.021-1.130, P = 0.006) was an independent risk factor for atrial fibrillation recurrence, while higher fibrillatory wave amplitude was a protective factor (hazard ratio: 0.292, 95% confidence interval: 0.157-0.542, P < 0.001). The associations were clarified by the restricted cubic splines. The dominant frequency and organization index were not identified as statistically significant parameters. CONCLUSIONS: The fibrillatory wave amplitude has the highest predictive value for atrial fibrillation recurrence in electrocardiogram-derived parameters. Together with left atrial diameter, it may help identify patients in whom thoracoscopic ablation is likely to be effective.

7.
Comput Biol Med ; 174: 108391, 2024 May.
Article in English | MEDLINE | ID: mdl-38613887

ABSTRACT

BACKGROUND: Liquid chromatography-mass spectrometry (LC-MS)-based quantitative phosphoproteomics has been widely used to detect thousands of protein phosphorylation modifications simultaneously from the biological specimens. However, the complicated procedures for analyzing phosphoproteomics data has become a bottleneck to widening its application. METHODS: Here, we develop PhosMap, a versatile and scalable tool to accomplish phosphoproteomics data analysis. A standardized phosphorylation data format was created for data analyses, from data preprocessing to downstream bioinformatic analyses such as dimension reduction, differential phosphorylation analysis, kinase activity, survival analysis, and so on. For better usability, we distribute PhosMap as a Docker image for easy local deployment upon any of Windows, Linux, and Mac system. RESULTS: The source code is deposited at https://github.com/BADD-XMU/PhosMap. A free PhosMap webserver (https://huggingface.co/spaces/Bio-Add/PhosMap), with easy-to-follow fashion of dashboards, is curated for interactive data analysis. CONCLUSIONS: PhosMap fills the technical gap of large-scale phosphorylation research by empowering researchers to process their own phosphoproteomics data expediently and efficiently, and facilitates better data interpretation.


Subject(s)
Computational Biology , Phosphoproteins , Proteomics , Software , Proteomics/methods , Phosphoproteins/analysis , Phosphoproteins/metabolism , Computational Biology/methods , Humans , Phosphorylation , Mass Spectrometry/methods , Chromatography, Liquid/methods
8.
Angew Chem Int Ed Engl ; 63(22): e202403695, 2024 May 27.
Article in English | MEDLINE | ID: mdl-38436549

ABSTRACT

Aqueous zinc ion batteries (AZIBs) show a great potential for next-generation energy storage due to their high safety and high energy density. However, the severe side reactions of zinc negative electrode largely hinder the further application of AZIBs. Herein, trace tris(hydroxymethyl)aminomethane (Tris) additive with rich lone-pair-electrons and zincophilic sites is firstly introduced to achieve long-term and highly reversible Zn plating/stripping. Specifically, Tris not only regulates the solvation structure of Zn2+, but is also adsorbed vertically on the Zn anode surface with a changed coordination intensity during the plating/stripping process of Zn to generate an in situ dynamic adsorption layer for the first time. The dynamic adsorption layer could successively attract the solvated Zn2+ and then promote the de-solvation of the solvated Zn2+ owing to the orientation polarization with regularly-changed applied electric field, the volume rejection effect, and strong intermolecular force towards H2O of the vertically-adsorbed Tris. Therefore, an improved Zn2+-transport kinetics as well as the inhibition of side reactions of Zn anode are successfully realized. Accordingly, the Zn||Zn symmetric cell provides an ultra-long cycle life of 2600 h. Furthermore, the Zn||MnO2 full cell with Tris could demonstrate a high capacity and structural stability for practical applications.

9.
BMJ Open ; 14(3): e083153, 2024 Mar 05.
Article in English | MEDLINE | ID: mdl-38448081

ABSTRACT

INTRODUCTION: The prevalence of atrial fibrillation (AF) is increasing globally, and stroke prevention is the key to reduce the morbidity and mortality related to AF. Currently, direct oral anticoagulants (DOACs) are the primary options for stroke prevention, while it increases risk of bleeding. Left atrial appendage (LAA) is suspected as a vital source of cerebral emboli and may lead to ischaemic stroke, and thoracoscopic LAA clipping procedure provides an alternative option for stroke prevention in high-risk patients. However, high-quality evidence comparing LAA clipping to DOACs in terms of stroke prevention is lacking. This trial is designed to assess whether the efficacy of thoracoscopic LAA clipping is superior to DOACs for stroke prevention in AF patients at high risk of thrombosis (CHA2DS2-VASc≥2 in men and ≥3 in women)[CHA2DS2-VASc stands for "congestive heart failure, hypertension, age ≥75 (doubled), diabetes, stroke (doubled), vascular disease, age 65 to 74 and sex category (female)"]. METHODS AND ANALYSIS: This is a prospective, multicentre, open-labelled, randomised controlled study. This trial will randomly assign 290 patients with non-paroxysmal AF to thoracoscopic LAA clipping group or DOAC therapy group in a 1:1 randomisation. The primary endpoint is defined as a composite endpoint event consisting of stroke, systemic embolism, all-cause mortality, major bleeding events and clinically relevant non-major bleeding events at 24 months after randomisation. The secondary endpoints consist of the components of the primary composite endpoint, surgery-related adverse events and minor bleeding events. ETHICS AND DISSEMINATION: The central ethics committee at Fuwai Hospital approved the trial entitled "Epicardial left atrial appendage clipping versus direct oral anticoagulant to reduce stroke risk in non-paroxysmal atrial fibrillation (LAA-CLIP trial)". The results of this study will be disseminated through publications in peer-reviewed journals and conference presentations. TRIAL REGISTRATION NUMBER: NCT06021808.


Subject(s)
Atrial Appendage , Atrial Fibrillation , Brain Ischemia , Stroke , Male , Female , Humans , Aged , Atrial Fibrillation/complications , Atrial Fibrillation/surgery , Atrial Appendage/surgery , Prospective Studies , Stroke/etiology , Stroke/prevention & control , Anticoagulants/therapeutic use , Randomized Controlled Trials as Topic , Multicenter Studies as Topic
10.
J Chromatogr A ; 1719: 464774, 2024 Mar 29.
Article in English | MEDLINE | ID: mdl-38422707

ABSTRACT

Ginseng is beneficial in the prevention of many diseases and provides benefits for proper growth and development owing to the presence of various useful bioactive substances of diverse chemical heterogeneity (e.g., triterpenoid saponins, polysaccharides, volatile oils, and amino acids). As a result, understanding the therapeutic advantages of ginseng requires an in-depth compositional evaluation employing a simple and rapid analytical technique. In this work, three types of surface-activated carbon fibers (ACFs) were prepared by gas-phase oxidation, strong acid treatment, and Plasma treatment to obtain CO2-ACFs, acidified-ACFs, and plasma-ACFs, respectively. Three prepared ACFs were compared in terms of their physicochemical characterization (i.e., surface roughness and functional groups). A separation system was built using a column with modified ACFs, followed by mass spectrometry detection to investigate and determine substances of different polarities. Among the three columns, CO2-ACFs showed the optimum separation effect. 13 strong polar compounds (12 amino acids and1 oligosaccharide) and 15 lesser polar compounds (ginsenosides) were separated and identified successfully within 4 min in the ginseng sample. The data obtained by CO2-ACFs-TOF-MS/MS and UHPLC-TOF-MS/MS were compared. Our approach was found to be faster (4 min vs. 36 min) and greener, requiring much less solvent (1 mL vs. 10.8 mL), and power (0.06 vs. 0.6 kWh). The developed methodology can provide a faster, eco-friendly, and more reliable tool for the high-throughput screening of complex natural matrices and the simultaneous evaluation of several compounds in diverse samples.


Subject(s)
Ginsenosides , Panax , Ginsenosides/analysis , Tandem Mass Spectrometry/methods , Charcoal , Carbon Fiber , Carbon Dioxide/analysis , Plant Extracts/chemistry , Amino Acids , Panax/chemistry , Chromatography, High Pressure Liquid/methods
11.
RSC Adv ; 13(51): 36382-36391, 2023 Dec 08.
Article in English | MEDLINE | ID: mdl-38099253

ABSTRACT

Traditional alkali degumming (TAL) has been widely used for hemp degumming; however, the produced degumming waste liquid pollutes the environment. For this phenomenon, an improved Fenton oxidation degumming process was developed in this study, that is, MnFe2O4 (Fenton-MnFe2O4) was added to the Fenton system. The purpose was to reduce the reaction time and the addition of chemical reagents, and reuse the added MnFe2O4. The effects of the Fenton-MnFe2O4 system on fiber properties (such as residual gum rate, and breaking strength) and the recyclability of MnFe2O4 were studied. The results indicated that the hemp fiber could be separated by Fenton-MnFe2O4 treatment (5.30% H2O2 (w/w), 0.310% FeSO4·7H2O (w/w), 0.040% MnFe2O4 (w/w), 40.0 °C, 40.0 min). The breaking strength of the refined fiber was 18.22 cN per dtex, and the residual gum rate was 5.47%. Compared with the TAL system, the time was shorter, energy consumption was less and pollution was smaller. In addition, the fiber treated with MnFe2O4 after five cycles still showed excellent properties, namely, 15.76 cN per dtex breaking strength and 7.79% residual gum rate, which met the needs of the spinning process. Therefore, Fenton-MnFe2O4 show great development potential in hemp fiber degumming.

12.
Anal Chim Acta ; 1283: 341907, 2023 Dec 01.
Article in English | MEDLINE | ID: mdl-37977798

ABSTRACT

BACKGROUND: As a vital energy source, light is one of the most significant environmental signals for plants' growth and development. The crosstalk amongst phytohormones regulated by light exhibits quantitative dynamic changes, but methodologies to analyze their distribution during plant growth are still limited. Rapid, highly sensitive, low-invasive detection and simultaneous assessment of the levels of multiple classes of phytohormones have important phytology applications, however the existing sample pretreatment strategies remain intricate, laborious, and far from being developed for in vivo high-sensitivity testing. (81) RESULTS: We applied a nanoconfined liquid phase nanoextraction (NLPNE) technique based on acidified carbon nanofibers (ACNFs) in combination with LC-ESI-MS/MS for highly sensitive analysis of acidic phytohormones' photoregulation and dynamic distribution. In this system, the mass transfer ability of analytes entering the nanoconfined space is significantly improved given the nanoconfined effect. In particular, the accelerated and strong adsorption of alkaline compounds to the ACNFs surface provide minimum interference for acidic compounds (photosensitive phytohormones), which facilitates their simple, fast, and selective quantification with improved sensitivity. The ACNFs-NLPNE strategy achieved quantitative enrichment of multi-class phytohormones in less than 5 min, and detection limits down to 0.49 fg mL-1. Moreover, we monitored the phytohormone changes under red and blue monochromatic light with relative standard deviations <13.4 %. The results further indicated that short-time red light regulation promoted Lepidium sativum L. growth while blue light inhibited it. (141) SIGNIFICANCE: A nanoconfinement effect-based sample pretreatment platform was developed for monitoring photoregulation phytohormones dynamic distribution with higher sensitivity and stability. Our findings highlighted the importance of the NLPNE approach in providing an accurate plant crosstalk information at the molecular level, which opens a promising avenue for investigating internal hormonal responses to external stimuli. (52).


Subject(s)
Plant Growth Regulators , Tandem Mass Spectrometry , Plant Growth Regulators/analysis , Tandem Mass Spectrometry/methods , Chromatography, Liquid/methods , Plants , Light , Acids , Chromatography, High Pressure Liquid/methods
13.
Mol Cell ; 83(22): 4000-4016.e6, 2023 Nov 16.
Article in English | MEDLINE | ID: mdl-37935198

ABSTRACT

While 19S proteasome regulatory particle (RP) inhibition is a promising new avenue for treating bortezomib-resistant myeloma, the anti-tumor impact of inhibiting 19S RP component PSMD14 could not be explained by a selective inhibition of proteasomal activity. Here, we report that PSMD14 interacts with NSD2 on chromatin, independent of 19S RP. Functionally, PSMD14 acts as a histone H2AK119 deubiquitinase, facilitating NSD2-directed H3K36 dimethylation. Integrative genomic and epigenomic analyses revealed the functional coordination of PSMD14 and NSD2 in transcriptional activation of target genes (e.g., RELA) linked to myelomagenesis. Reciprocally, RELA transactivates PSMD14, forming a PSMD14/NSD2-RELA positive feedback loop. Remarkably, PSMD14 inhibitors enhance bortezomib sensitivity and fosters anti-myeloma synergy. PSMD14 expression is elevated in myeloma and inversely correlated with overall survival. Our study uncovers an unappreciated function of PSMD14 as an epigenetic regulator and a myeloma driver, supporting the pursuit of PSMD14 as a therapeutic target to overcome the treatment limitation of myeloma.


Subject(s)
Histones , Multiple Myeloma , Humans , Histones/genetics , Proteasome Endopeptidase Complex/genetics , Proteasome Endopeptidase Complex/metabolism , Bortezomib/pharmacology , Bortezomib/metabolism , Multiple Myeloma/drug therapy , Multiple Myeloma/genetics , Multiple Myeloma/pathology , Cell Line, Tumor , Deubiquitinating Enzymes/metabolism , Proteasome Inhibitors/pharmacology , Trans-Activators/metabolism
14.
Cell Rep ; 42(11): 113343, 2023 11 28.
Article in English | MEDLINE | ID: mdl-37906592

ABSTRACT

The intrinsic regulation of programmed death ligand-1 (PD-L1) expression remains unclear. Here, we report that zinc-finger protein 652 (ZNF652) is a potent transcription repressor of PD-L1. ZNF652 frequently experiences loss of heterozygosity (LOH) in various cancers. Higher LOH rate and lack of estrogen-inducible transcription lead to suppressed expression of ZNF652 in triple-negative breast cancer (TNBC). Mechanistically, ZNF652 is physically associated with the NuRD transcription co-repressor complex to repress a cohort of genes, including PD-L1. Overexpression of ZNF652 inhibits PD-L1 transcription, whereas depletion of ZNF652 upregulates PD-L1. Loss of ZNF652 in TNBC unleashes PD-L1-mediated immune evasion both in vitro and in vivo. Significantly, ZNF652 expression is progressively lost during breast cancer progression, and a low ZNF652 level is correlated with elevated PD-L1 expression, less infiltrated CD8+ T cells, and poor prognosis in TNBC. Our study provides insights into PD-L1 regulation and supports the pursuit of ZNF652 as a potential biomarker and drug target for breast cancer immunotherapy.


Subject(s)
Triple Negative Breast Neoplasms , Humans , Triple Negative Breast Neoplasms/metabolism , B7-H1 Antigen/genetics , B7-H1 Antigen/metabolism , Immune Evasion , CD8-Positive T-Lymphocytes/metabolism , Transcription Factors/genetics , Transcription Factors/metabolism
15.
Invest Ophthalmol Vis Sci ; 64(13): 43, 2023 10 03.
Article in English | MEDLINE | ID: mdl-37883092

ABSTRACT

Purpose: This study aimed to establish an image-based classification that can reveal the clinical characteristics of patients with dry eye using unsupervised learning methods. Methods: In this study, we analyzed 82,236 meibography images from 20,559 subjects. Using the SimCLR neural network, the images were categorized. Data for each patient were averaged and subjected to mini-batch k-means clustering, and validated through consensus clustering. Statistical metrics determined optimal category numbers. Using a UNet model, images were segmented to identify meibomian gland (MG) areas. Clinical features were assessed, including tear breakup time (BUT), tear meniscus height (TMH), and gland atrophy. A thorough ocular surface evaluation was conducted on 280 cooperative patients. Results: SimCLR neural network achieved clustering patients with dry eye into six image-based subtypes. Patients in different subtypes harbored significantly different noninvasive BUT, significantly correlated with TMH. Subtypes 1 and 5 had the most severe MG atrophy. Subtype 2 had the highest corneal fluorescent staining (CFS). Subtype 4 had the lowest TMH, whereas subtype 5 had the highest. Subtypes 3 and 6 had the largest MG areas, and the upper MG areas of a person's bilateral eyes were highly correlated. Image-based subtypes are related to meibum quality, CFS, and morphological characteristics of MG. Conclusions: In this study, we developed an unsupervised neural network model to cluster patients with dry eye into image-based subtypes using meibography images. We annotated these subtypes with functional and morphological clinical characteristics.


Subject(s)
Dry Eye Syndromes , Unsupervised Machine Learning , Humans , Dry Eye Syndromes/diagnostic imaging , Dry Eye Syndromes/pathology , Meibomian Glands/pathology , Tears , Atrophy/pathology
16.
Nat Chem Biol ; 19(10): 1223-1234, 2023 10.
Article in English | MEDLINE | ID: mdl-37400539

ABSTRACT

Cancer-associated chromosomal rearrangements can result in the expression of numerous pathogenic fusion proteins. The mechanisms by which fusion proteins contribute to oncogenesis are largely unknown, and effective therapies for fusion-associated cancers are lacking. Here we comprehensively scrutinized fusion proteins found in various cancers. We found that many fusion proteins are composed of phase separation-prone domains (PSs) and DNA-binding domains (DBDs), and these fusions have strong correlations with aberrant gene expression patterns. Furthermore, we established a high-throughput screening method, named DropScan, to screen drugs capable of modulating aberrant condensates. One of the drugs identified via DropScan, LY2835219, effectively dissolved condensates in reporter cell lines expressing Ewing sarcoma fusions and partially rescued the abnormal expression of target genes. Our results indicate that aberrant phase separation is likely a common mechanism for these PS-DBD fusion-related cancers and suggest that modulating aberrant phase separation is a potential route to treat these diseases.


Subject(s)
Proto-Oncogene Protein c-fli-1 , Sarcoma, Ewing , Humans , Solubility , RNA-Binding Protein EWS/genetics , RNA-Binding Protein EWS/metabolism , Proto-Oncogene Protein c-fli-1/genetics , Proto-Oncogene Protein c-fli-1/metabolism , Sarcoma, Ewing/drug therapy , Sarcoma, Ewing/genetics , Sarcoma, Ewing/metabolism , Cell Line
18.
Angew Chem Int Ed Engl ; 62(11): e202217458, 2023 Mar 06.
Article in English | MEDLINE | ID: mdl-36640120

ABSTRACT

Constructing efficient artificial solid electrolyte interface (SEI) film is extremely vital for the practical application of lithium metal batteries. Herein, a dense artificial SEI film, in which lithiophilic Zn/Lix Zny are uniformly but nonconsecutively dispersed in the consecutive Li+ -conductors of Lix SiOy , Li2 O and LiOH, is constructed via the in situ reaction of layered zinc silicate nanosheets and Li. The consecutive Li+ -conductors can promote the desolvation process of solvated-Li+ and regulate the transfer of lithium ions. The nonconsecutive lithiophilic metals are polarized by the internal electric field to boost the transfer of lithium ions, and lower the nucleation barrier. Therefore, a low polarization of ≈50 mV for 750 h at 2.0 mA cm-2 in symmetric cells, and a high capacity retention of 99.2 % in full cells with a high lithium iron phosphate areal loading of ≈13 mg cm-2 are achieved. This work offers new sights to develop advanced alkali metal anodes for efficient energy storage.

19.
J Cardiovasc Electrophysiol ; 34(1): 62-70, 2023 01.
Article in English | MEDLINE | ID: mdl-36273409

ABSTRACT

INTRODUCTION: The necessity of complete bi-atrial lesion created by radiofrequency clamp and pen for nonparoxysmal atrial fibrillation (AF) in patients with rheumatic mitral valve disease (RMVD) remains unclear. METHODS: From January 2014 to December 2018, patients with RMVD concomitant with nonparoxysmal AF who underwent mitral valve surgery concomitant surgical ablation were retrospectively enrolled. We divided patients into Group A (complete bi-atrial lesion set created by radiofrequency clamp and pen) and Group B (simplified lesion sets created by radiofrequency clamp alone including bi-atrial ablation with incomplete mitral isthmus line and stand-alone left atrial ablation) according to the surgical ablation lesion sets. Propensity score matching was applied to analyze freedom from atrial tachyarrhythmias between the two groups. RESULTS: Two hundred eight (38.5%) and 332 (61.5%) patients were divided into Group A and Group B, respectively. In Group B, the proportion of patients with recurrent atrial flutter in the subgroup of bi-atrial ablation with incomplete mitral isthmus line was higher than that in Group A (p = .044). After propensity score matching, there were 203 patients in each group. Better freedom from atrial tachyarrhythmias without antiarrhythmic drugs was obtained in Group A (83.1%, 79.6%, and 65.4%) than Group B (73.1%, 68.4%, and 52.7%) at 12, 36, and 60 months after operation (p = .012). CONCLUSION: The application of radiofrequency clamp and pen to create complete bi-atrial lesion set in surgical ablation for nonparoxysmal AF in RMVD was associated with superior long-term efficacy.


Subject(s)
Atrial Fibrillation , Catheter Ablation , Heart Valve Diseases , Humans , Mitral Valve/diagnostic imaging , Mitral Valve/surgery , Atrial Fibrillation/diagnosis , Atrial Fibrillation/surgery , Atrial Fibrillation/complications , Retrospective Studies , Follow-Up Studies , Heart Valve Diseases/diagnosis , Heart Valve Diseases/diagnostic imaging , Catheter Ablation/adverse effects , Catheter Ablation/methods , Treatment Outcome
20.
Nat Commun ; 13(1): 7578, 2022 12 08.
Article in English | MEDLINE | ID: mdl-36481721

ABSTRACT

How the carbohydrate binding protein galectin-3 might act as a diabetogenic and tumorogenic factor remains to be investigated. Here we report that intracellular galectin-3 interacts with Rag GTPases and Ragulator on lysosomes. We show that galectin-3 senses lipopolysaccharide (LPS) to facilitate the interaction of Rag GTPases and Ragulator, leading to the activation of mTORC1. We find that the lipopolysaccharide/galectin-3-Rag GTPases/Ragulator-mTORC1 axis regulates a cohort of genes including GLUT1, and HK2, and PKM2 that are critically involved in glucose uptake and glycolysis. Indeed, galectin-3 deficiency severely compromises LPS-promoted glycolysis. Importantly, the expression of HK2 is significantly reduced in diabetes patients. In multiple types of cancer including hepatocellular carcinoma (HCC), galectin-3 is highly expressed, and its level of expression is positively correlated with that of HK2 and PKM2 and negatively correlated with the prognosis of HCC patients. Our study unravels that galectin-3 is a sensor of LPS, an important modulator of the mTORC1 signaling, and a critical regulator of glucose metabolism.


Subject(s)
Carcinoma, Hepatocellular , Liver Neoplasms , Humans , Galectin 3/genetics , Mechanistic Target of Rapamycin Complex 1/genetics , Lipopolysaccharides , Carcinoma, Hepatocellular/genetics , Liver Neoplasms/genetics
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