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BACKGROUND: S-Nitrosylation (SNO), a prototypic redox-based posttranslational modification, is involved in cardiovascular disease. Aortic aneurysm and dissection are high-risk cardiovascular diseases without an effective cure. The aim of this study was to determine the role of SNO of Septin2 in macrophages in aortic aneurysm and dissection. METHODS: Biotin-switch assay combined with liquid chromatography-tandem mass spectrometry was performed to identify the S-nitrosylated proteins in aortic tissue from both patients undergoing surgery for aortic dissection and Apoe-/- mice infused with angiotensin II. Angiotensin II-induced aortic aneurysm model and ß-aminopropionitrile-induced aortic aneurysm and dissection model were used to determine the role of SNO of Septin2 (SNO-Septin2) in aortic aneurysm and dissection development. RNA-sequencing analysis was performed to recapitulate possible changes in the transcriptome profile of SNO-Septin2 in macrophages in aortic aneurysm and dissection. Liquid chromatography-tandem mass spectrometry and coimmunoprecipitation were used to uncover the TIAM1-RAC1 (Ras-related C3 botulinum toxin substrate 1) axis as the downstream target of SNO-Septin2. Both R-Ketorolac and NSC23766 treatments were used to inhibit the TIAM1-RAC1 axis. RESULTS: Septin2 was identified S-nitrosylated at cysteine 111 (Cys111) in both aortic tissue from patients undergoing surgery for aortic dissection and Apoe-/- mice infused with Angiotensin II. SNO-Septin2 was demonstrated driving the development of aortic aneurysm and dissection. By RNA-sequencing, SNO-Septin2 in macrophages was demonstrated to exacerbate vascular inflammation and extracellular matrix degradation in aortic aneurysm. Next, TIAM1 (T lymphoma invasion and metastasis-inducing protein 1) was identified as a SNO-Septin2 target protein. Mechanistically, compared with unmodified Septin2, SNO-Septin2 reduced its interaction with TIAM1 and activated the TIAM1-RAC1 axis and consequent nuclear factor-κB signaling pathway, resulting in stronger inflammation and extracellular matrix degradation mediated by macrophages. Consistently, both R-Ketorolac and NSC23766 treatments protected against aortic aneurysm and dissection by inhibiting the TIAM1-RAC1 axis. CONCLUSIONS: SNO-Septin2 drives aortic aneurysm and dissection through coupling the TIAM1-RAC1 axis in macrophages and activating the nuclear factor-κB signaling pathway-dependent inflammation and extracellular matrix degradation. Pharmacological blockade of RAC1 by R-Ketorolac or NSC23766 may therefore represent a potential treatment against aortic aneurysm and dissection.
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Aneurisma Aórtico , Dissecção Aórtica , Macrófagos , Septinas , Proteína 1 Indutora de Invasão e Metástase de Linfoma de Células T , Proteínas rac1 de Ligação ao GTP , Animais , Humanos , Masculino , Camundongos , Angiotensina II/metabolismo , Aneurisma Aórtico/metabolismo , Aneurisma Aórtico/patologia , Aneurisma Aórtico/genética , Dissecção Aórtica/metabolismo , Dissecção Aórtica/patologia , Dissecção Aórtica/genética , Modelos Animais de Doenças , Macrófagos/metabolismo , Macrófagos/patologia , Camundongos Endogâmicos C57BL , Neuropeptídeos , Proteínas rac1 de Ligação ao GTP/metabolismo , Proteínas rac1 de Ligação ao GTP/genética , Septinas/metabolismo , Septinas/genética , Transdução de Sinais , Proteína 1 Indutora de Invasão e Metástase de Linfoma de Células T/metabolismo , Proteína 1 Indutora de Invasão e Metástase de Linfoma de Células T/genéticaRESUMO
ConspectusPhotocatalytic energy conversion is a pivotal process for harnessing solar energy to produce chemicals and presents a sustainable alternative to fossil fuels. Key strategies to enhance photocatalytic efficiency include facilitating mass transport and reactant adsorption, improving light absorption, and promoting electron and hole separation to suppress electron-hole recombination. This Account delves into the potential advantages of electrically conductive metal-organic frameworks (EC-MOFs) in photocatalytic energy conversion and examines how manipulating electronic structures and controlling morphology and defects affect their unique properties, potentially impacting photocatalytic efficiency and selectivity. Moreover, with a proof-of-concept study of photocatalytic hydrogen peroxide production by manipulating the EC-MOF's electronic structure, we highlight the potential of the strategies outlined in this Account.EC-MOFs not only possess porosity and surface areas like conventional MOFs, but exhibit electronic conductivity through d-p conjugation between ligands and metal nodes, enabling effective charge transport. Their narrow band gaps also allow for visible light absorption, making them promising candidates for efficient photocatalysts. In EC-MOFs, the modular design of metal nodes and ligands allows fine-tuning of both the electronic structure and physical properties, including controlling the particle morphology, which is essential for optimizing band positions and improving charge transport to achieve efficient and selective photocatalytic energy conversion.Despite their potential as photocatalysts, modulating the electronic structure or controlling the morphology of EC-MOFs is nontrivial, as their fast growth kinetics make them prone to defect formation, impacting mass and charge transport. To fully leverage the photocatalytic potential of EC-MOFs, we discuss our group's efforts to manipulate their electronic structures and develop effective synthetic strategies for morphology control and defect healing. For tuning electronic structures, diversifying the combinations of metals and linkers available for EC-MOF synthesis has been explored. Next, we suggest that synthesizing ligand-based solid solutions will enable continuous tuning of the band positions, demonstrating the potential to distinguish between photocatalytic reactions with similar redox potentials. Lastly, we present incorporating a donor-acceptor system in an EC-MOF to spatially separate photogenerated carriers, which could suppress electron-hole recombination. As a synthetic strategy for morphology control, we demonstrated that electrosynthesis can modify particle morphology, enhancing electrochemical surface area, which will be beneficial for reactant adsorption. Finally, we suggest a defect healing strategy that will enhance charge transport by reducing charge traps on defects, potentially improving the photocatalytic efficiency.Our vision in this Account is to introduce EC-MOFs as an efficient platform for photocatalytic energy conversion. Although EC-MOFs are a new class of semiconductor materials and have not been extensively studied for photocatalytic energy conversion, their inherent light absorption and electron transport properties indicate significant photocatalytic potential. We envision that employing modular molecular design to control electronic structures and applying effective synthetic strategies to customize morphology and defect repair can promote charge separation, electron transfer to potential reactants, and mass transport to realize high selectivity and efficiency in EC-MOF-based photocatalysts. This effort not only lays the foundation for the rational design and synthesis of EC-MOFs, but has the potential to advance their use in photocatalytic energy conversion.
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ConspectusElectrically conductive metal-organic frameworks (EC-MOFs) have emerged as a compelling class of materials, drawing increasing attention due to their unique properties facilitating charge transport within porous structures. The synergy between electrical conductivity and porosity has opened a wide range of applications, including electrocatalysis, energy storage, chemiresistive sensing, and electronic devices that have been underexplored for their insulating counterparts. Despite these promising prospects, a prevalent challenge arises from the predominant adoption of two-dimensional (2D) structures by most EC-MOFs. These 2D frameworks often show modest surface areas and short interlayer distances, hindering molecular accessibility, which deviates from the inherent characteristics of conventional MOFs. Furthermore, the quest for efficient charge transport imposes design constraints, leading to a restricted selection of functional building blocks. Additionally, there is a lack of established functionalization methods within EC-MOFs, limiting their functional diversity. Thus, these challenges have impeded EC-MOFs from reaching their full potential.In this Account, we summarize and discuss our group's efforts aimed at enhancing molecular accessibility and deploying the functional diversity of EC-MOFs. Our focus on enhancing molecular accessibility involves several strategies. First, we employed macrocyclic ligands with intrinsic pockets as the building blocks for EC-MOFs. The integrated intrinsic pockets in the frameworks supplement surface areas and additional pores to enhance molecular accessibility. The resulting macrocyclic ligand-based EC-MOFs exhibit exceptionally high surface areas and confer advantages in electrochemical performances. Second, our efforts extend to addressing the structural limitations, frequently associated with EC-MOFs' 2D structures. Through the pillar insertion strategy, we transformed a 2D EC-MOF platform into a three-dimensional (3D) structure, thereby achieving higher porosity and enhanced molecular accessibility. In pursuing functional diversity, we have delved into molecular-level tuning of EC-MOF building blocks. We demonstrated that electron-rich alkyne-based pockets in the macrocyclic ligands can host transition metals and alkali ions, enabling ion selectivity and showcasing diverse use of EC-MOFs. We utilized a postsynthetic approach to further functionalize metal nodes on the molecular level within an EC-MOF framework, introducing a proton-conducting pathway while preserving its electrical conductivity.We aspire for this Account to provide practical insights and strategies to surmount structural and functional diversity limitations in the realm of EC-MOFs. By integrating enhanced molecular accessibility and diverse functionality, our endeavor to propel the utility of these materials will inspire further rational development for future EC-MOFs and unlock their full potential.
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BACKGROUND: The cardiac-protective role of GSNOR (S-nitrosoglutathione reductase) in the cytoplasm, as a denitrosylase enzyme of S-nitrosylation, has been reported in cardiac remodeling, but whether GSNOR is localized in other organelles and exerts novel effects remains unknown. We aimed to elucidate the effects of mitochondrial GSNOR, a novel subcellular localization of GSNOR, on cardiac remodeling and heart failure (HF). METHODS: GSNOR subcellular localization was observed by cellular fractionation assay, immunofluorescent staining, and colloidal gold particle staining. Overexpression of GSNOR in mitochondria was achieved by mitochondria-targeting sequence-directed adeno-associated virus 9. Cardiac-specific knockout of GSNOR mice was used to examine the role of GSNOR in HF. S-nitrosylation sites of ANT1 (adenine nucleotide translocase 1) were identified using biotin-switch and liquid chromatography-tandem mass spectrometry. RESULTS: GSNOR expression was suppressed in cardiac tissues of patients with HF. Consistently, cardiac-specific knockout mice showed aggravated pathological remodeling induced by transverse aortic constriction. We found that GSNOR is also localized in mitochondria. In the angiotensin II-induced hypertrophic cardiomyocytes, mitochondrial GSNOR levels significantly decreased along with mitochondrial functional impairment. Restoration of mitochondrial GSNOR levels in cardiac-specific knockout mice significantly improved mitochondrial function and cardiac performance in transverse aortic constriction-induced HF mice. Mechanistically, we identified ANT1 as a direct target of GSNOR. A decrease in mitochondrial GSNOR under HF leads to an elevation of S-nitrosylation ANT1 at cysteine 160 (C160). In accordance with these findings, overexpression of either mitochondrial GSNOR or ANT1 C160A, non-nitrosylated mutant, significantly improved mitochondrial function, maintained the mitochondrial membrane potential, and upregulated mitophagy. CONCLUSIONS: We identified a novel species of GSNOR localized in mitochondria and found mitochondrial GSNOR plays an essential role in maintaining mitochondrial homeostasis through ANT1 denitrosylation, which provides a potential novel therapeutic target for HF.
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Insuficiência Cardíaca , Remodelação Ventricular , Animais , Humanos , Camundongos , Coração , Insuficiência Cardíaca/metabolismo , Camundongos Knockout , Mitocôndrias/metabolismoRESUMO
BACKGROUND AND AIMS: Vascular smooth muscle cell (VSMC) senescence is crucial for the development of atherosclerosis, characterized by metabolic abnormalities. Tumour necrosis factor receptor-associated protein 1 (TRAP1), a metabolic regulator associated with ageing, might be implicated in atherosclerosis. As the role of TRAP1 in atherosclerosis remains elusive, this study aimed to examine the function of TRAP1 in VSMC senescence and atherosclerosis. METHODS: TRAP1 expression was measured in the aortic tissues of patients and mice with atherosclerosis using western blot and RT-qPCR. Senescent VSMC models were established by oncogenic Ras, and cellular senescence was evaluated by measuring senescence-associated ß-galactosidase expression and other senescence markers. Chromatin immunoprecipitation (ChIP) analysis was performed to explore the potential role of TRAP1 in atherosclerosis. RESULTS: VSMC-specific TRAP1 deficiency mitigated VSMC senescence and atherosclerosis via metabolic reprogramming. Mechanistically, TRAP1 significantly increased aerobic glycolysis, leading to elevated lactate production. Accumulated lactate promoted histone H4 lysine 12 lactylation (H4K12la) by down-regulating the unique histone lysine delactylase HDAC3. H4K12la was enriched in the senescence-associated secretory phenotype (SASP) promoter, activating SASP transcription and exacerbating VSMC senescence. In VSMC-specific Trap1 knockout ApoeKO mice (ApoeKOTrap1SMCKO), the plaque area, senescence markers, H4K12la, and SASP were reduced. Additionally, pharmacological inhibition and proteolysis-targeting chimera (PROTAC)-mediated TRAP1 degradation effectively attenuated atherosclerosis in vivo. CONCLUSIONS: This study reveals a novel mechanism by which mitonuclear communication orchestrates gene expression in VSMC senescence and atherosclerosis. TRAP1-mediated metabolic reprogramming increases lactate-dependent H4K12la via HDAC3, promoting SASP expression and offering a new therapeutic direction for VSMC senescence and atherosclerosis.
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BACKGROUND AND AIMS: Drug-coated balloons (DCBs) have demonstrated favourable outcomes following endovascular therapy for femoropopliteal artery (FPA) disease. However, uncertainty remains whether the use of intravascular ultrasound (IVUS) can improve the outcomes of DCBs. METHODS: This prospective, multicentre, randomized trial, conducted at seven centres in South Korea, compared the outcomes of IVUS-guided vs. angiography-guided angioplasty for treating FPA disease with DCBs. Patients were assigned to receive IVUS-guided (n = 119) or angiography-guided (n = 118) angioplasty using DCBs. The primary endpoint was 12-month primary patency. RESULTS: Between May 2016 and August 2022, 237 patients were enrolled and 204 (86.0%) completed the trial (median follow-up; 363 days). The IVUS guidance group showed significantly higher primary patency [83.8% vs. 70.1%; cumulative difference 19.6% (95% confidence interval 6.8 to 32.3); P = .01] and increased freedom from clinically driven target lesion revascularization [92.4% vs. 83.0%; difference 11.6% (95% confidence interval 3.1 to 20.1); P = .02], sustained clinical improvement (89.1% vs. 76.3%, P = .01), and haemodynamic improvement (82.4% vs. 66.9%, P = .01) at 12 months compared with the angiography guidance group. The IVUS group utilized larger balloon diameters and pressures for pre-dilation, more frequent post-dilation, and higher pressures for post-dilation, resulting in a greater post-procedural minimum lumen diameter (3.90 ± 0.59 vs. 3.71 ± 0.73 mm, P = .03). CONCLUSIONS: Intravascular ultrasound guidance significantly improved the outcomes of DCBs for FPA disease in terms of primary patency, freedom from clinically driven target lesion revascularization, and sustained clinical and haemodynamic improvement at 12 months. These benefits may be attributed to IVUS-guided optimization of the lesion before and after DCB treatment.
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Angioplastia com Balão , Artéria Femoral , Doença Arterial Periférica , Artéria Poplítea , Ultrassonografia de Intervenção , Grau de Desobstrução Vascular , Humanos , Ultrassonografia de Intervenção/métodos , Masculino , Angioplastia com Balão/métodos , Artéria Femoral/diagnóstico por imagem , Feminino , Artéria Poplítea/diagnóstico por imagem , Doença Arterial Periférica/terapia , Doença Arterial Periférica/diagnóstico por imagem , Estudos Prospectivos , Idoso , Pessoa de Meia-Idade , Materiais Revestidos Biocompatíveis , Resultado do Tratamento , AngiografiaRESUMO
BACKGROUND: Aortic aneurysm and aortic dissection (AAD) are life-threatening vascular diseases, with endothelium being the primary target for AAD treatment. Protein S-sulfhydration is a newly discovered posttranslational modification whose role in AAD has not yet been defined. This study aims to investigate whether protein S-sulfhydration in the endothelium regulates AAD and its underlying mechanism. METHODS: Protein S-sulfhydration in endothelial cells (ECs) during AAD was detected and hub genes regulating homeostasis of the endothelium were identified. Clinical data of patients with AAD and healthy controls were collected, and the level of the cystathionine γ lyase (CSE)/hydrogen sulfide (H2S) system in plasma and aortic tissue were determined. Mice with EC-specific CSE deletion or overexpression were generated, and the progression of AAD was determined. Unbiased proteomics and coimmunoprecipitation combined with mass spectrometry analysis were conducted to determine the upstream regulators of the CSE/H2S system and the findings were confirmed in transgenic mice. RESULTS: Higher plasma H2S levels were associated with a lower risk of AAD, after adjustment for common risk factors. CSE was reduced in the endothelium of AAD mouse and aorta of patients with AAD. Protein S-sulfhydration was reduced in the endothelium during AAD and protein disulfide isomerase (PDI) was the main target. S-sulfhydration of PDI at Cys343 and Cys400 enhanced PDI activity and mitigated endoplasmic reticulum stress. EC-specific CSE deletion was exacerbated, and EC-specific overexpression of CSE alleviated the progression of AAD through regulating the S-sulfhydration of PDI. ZEB2 (zinc finger E-box binding homeobox 2) recruited the HDAC1-NuRD complex (histone deacetylase 1-nucleosome remodeling and deacetylase) to repress the transcription of CTH, the gene encoding CSE, and inhibited PDI S-sulfhydration. EC-specific HDAC1 deletion increased PDI S-sulfhydration and alleviated AAD. Increasing PDI S-sulfhydration with the H2S donor GYY4137 or pharmacologically inhibiting HDAC1 activity with entinostat alleviated the progression of AAD. CONCLUSIONS: Decreased plasma H2S levels are associated with an increased risk of aortic dissection. The endothelial ZEB2-HDAC1-NuRD complex transcriptionally represses CTH, impairs PDI S-sulfhydration, and drives AAD. The regulation of this pathway effectively prevents AAD progression.
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Aneurisma Aórtico , Dissecção Aórtica , Animais , Camundongos , Cistationina gama-Liase/genética , Células Endoteliais/metabolismo , Endotélio/metabolismo , Histona Desacetilase 1 , Sulfeto de Hidrogênio/metabolismo , Complexo Mi-2 de Remodelação de Nucleossomo e Desacetilase , Proteína S , Homeobox 2 de Ligação a E-box com Dedos de ZincoRESUMO
Hydrogen peroxide (H2O2) holds significance as a vital chemical with the potential to serve as an energy carrier. Compared with the conventional anthraquinone process, photocatalytic H2O2 production has emerged as an appealing alternative because of its energy efficiency and environmental sustainability. However, the existing photocatalysts suffer from low catalytic efficiency, limited tunability of optical properties, and reliance on sacrificial agents due to high energy loss caused by inefficient charge separation. Therefore, developing catalysts with tunable optical properties and efficient charge separation is desirable. In this work, we introduce postsynthetic functionalization into an electrically conductive metal-organic framework, namely, DPT-MOF. Leveraging DPT (3,6-di(4-pyridyl)-1,2,4,5-tetrazine) as a pillar ligand, we exploited click-type chemistry to manipulate band position and charge separation efficiency, allowing for photocatalytic nonsacrificial H2O2 production. Notably, the fluorine-functionalized MOF exhibited the highest H2O2 production rate of 1676 µmol g-1 h-1 under visible light in O2-saturated water among our other samples. This high production rate is attributed to the tuned electronic structure and prolonged charge lifetime facilitated by the fluorine groups. This work highlights the effectiveness of postsynthetic methodology in tuning optical properties, opening a promising avenue for advancing the field of semiconductive MOF-based photocatalysis.
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Fabricating nanoscale metal carbides is a great challenge due to them having higher Gibbs free energy of formation (ΔG°) values than other metal compounds; additionally, these carbides have harsh calcination conditions, in which metal oxidation is preferred in the atmosphere. Herein, we report oxocarbon-mediated calcination for the predictive synthesis of nanoscale metal carbides. The thermochemical oxocarbon equilibrium of CO-CO2 reactions was utilized to control the selective redox reactions in multiatomic systems of Mo-C-O, contributing to the phase-forming and structuring of Mo compounds. By harnessing the thermodynamically predicted processing window, we controlled a wide range of Mo phases (MoO2, α-MoC1-x, and ß-Mo2C) and nanostructures (nanoparticle, spike, stain, and core/shell) in the Mo compounds/C nanofibers. By inducing simultaneous reactions of C-O (selective C combustion) and Mo-C (Mo carbide formation) in the nanofibers, Mo diffusion was controlled in C nanofibers, acting as a template for the nucleation and growth of Mo carbides and resulting in precise control of the phases and structures of Mo compounds. The formation mechanism of nanostructured Mo carbides was elucidated according to the CO fractions of CO-CO2 calcination. Moreover, tungsten (W) and niobium (Nb) carbides/C nanofibers have been successfully synthesized by CO-CO2 calcination. We constructed the thermodynamic map for the predictive synthesis of transition metal carbides to provide universal guideline via thermochemical oxocarbon equilibrium. We revealed that our thermochemical oxocarbon-mediated gas-solid reaction enabled the structure and phase control of nanoscale transition metal compounds to optimize the material-property relationship accordingly.
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Site-specific recombinase-mediated genetic technology, such as inducible Cre-loxP recombination (CreER), is widely used for in vivo genetic manipulation with temporal control. The Cre-loxP technology improves our understanding on the in vivo function of specific genes in organ development, tissue regeneration, and disease progression. However, inducible CreER often remains inefficient in gene deletion. In order to improve the efficiency of gene manipulation, we generated a self-cleaved inducible CreER (sCreER) that switches inducible CreER into a constitutively active Cre by itself. We generated endocardial driver Npr3-sCreER and fibroblast driver Col1a2-sCreER, and compared them with conventional Npr3-CreER and Col1a2-CreER, respectively. For easy-to-recombine alleles such as R26-tdTomato, there was no significant difference in recombination efficiency between sCreER and the conventional CreER. However, for alleles that were relatively inert for recombination such as R26-Confetti, R26-LZLT, R26-GFP, or VEGFR2flox/flox alleles, sCreER showed a significantly higher efficiency in recombination compared with conventional CreER in endocardial cells or fibroblasts. Compared with conventional CreER, sCreER significantly enhances the efficiency of recombination to induce gene expression or gene deletion, allowing temporal yet effective in vivo genomic modification for studying gene function in specific cell lineages.
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Integrases/genética , Recombinação Genética , Alelos , Animais , Linhagem da Célula , Feminino , Fibroblastos , Deleção de Genes , Expressão Gênica , Integrases/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos TransgênicosRESUMO
The lithium deposited via the complex electrochemical heterogeneous lithium deposition reaction (LDR) process on a lithium foil-based anode (LFA) forms a high-aspect-ratio shape whenever the reaction kinetics reach its limit, threatening battery safety. Thereby, a research strategy that boosts the LDR kinetics is needed to construct a high-power and safe lithium metal anode. In this study, the kinetic limitations of the LDR process on LFA are elucidated through operando and ex situ observations using in-depth electrochemical analyses. In addition, ultra-thin (≈0.5 µm) and high modulus (≥19 GPa) double-walled carbon nanotube (DWNT) membranes with different surface properties are designed to catalyze high-safety LDRs. The oxygen-functionalized DWNT membranes introduced on the LFA top surface simultaneously induce multitudinous lithium nuclei, leading to film-like lithium deposition even at a high current density of 20 mA cm-2. More importantly, the layer-by-layer assembly of the oxygen-functionalized and pristine DWNT membranes results in different surface energies between the top and bottom surfaces, enabling selective surface LDRs underneath the high-modulus bilayer membranes. The protective LDR on the bilayer-covered LFA guarantees an invulnerable cycling process in large-area pouch cells at high current densities for more than 1000 cycles, demonstrating the practicability of LFA in a conventional liquid electrolyte system.
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BACKGROUND: Patients achieving pathological complete response (pCR) post-neoadjuvant chemoradiotherapy (nCRT) and surgery for locally advanced esophageal squamous cell carcinoma (ESCC) have a favorable prognosis. However, recurrence occurs in approximately 20-30% of all patients, with few studies evaluating their prognostic factors. We identified these prognostic factors, including inflammation-based markers, in patients with ESCC showing pCR after nCRT and surgery. PATIENTS AND METHODS: Patients with ESCC undergoing esophagectomy post-nCRT (January 2007-August 2017) were studied. Survival analysis evaluated 5-year overall (OS) and recurrence-free survival (RFS). Risk factors, including inflammation factors, neutrophil-to-lymphocyte ratio, and platelet-to-lymphocyte ratio (PLR), were analyzed using Cox-proportional hazards model. RESULTS: Overall, 123patients participated herein. After a median follow-up duration of 67 months (44-86 months), 17 patients (12.3%) had recurrent disease. The 5-year OS and RFS rates were 71.6% and 68.0%, respectively. In the multivariable analysis, older age ( ≥ 60 years) [hazard ratio (HR) 3.228, 95% confidence interval (CI) 1.478-7.048, p = 0.003], higher pretreatment T stage (≥ T3; HR 2.563, 95% CI 1.335-4.922, p = 0.005), nonapplication of induction chemotherapy (HR 2.389, 95% CI 1.184-4.824, p = 0.015), and higher post-nCRT PLR (≥ 184.2; HR 2.896, 95% CI 1.547-5.420, p = 0.001) were poor independent prognostic factors for 5-year RFS. The patient group with three to four identified factors with poor outcomes exhibited a 5-year RFS rate of 46.2%. CONCLUSIONS: Significant prognostic factors include higher post-nCRT PLR, older age, higher clinical T stage, and nonapplication of induction chemotherapy. Identifying higher recurrence risk patients is crucial for tailored follow-up and treatment.
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This study explores the optimal morphology of photochemical hydrogen evolution catalysts in a one-dimensional system. Systematic engineering of metal tips on precisely defined CdSe@CdS dot-in-rods is conducted to exert control over morphology, composition, and both factors. The outcome yields an optimized configuration, a Au-Pt core-shell structure with a rough Pt surface (Au@r-Pt), which exhibits a remarkable fivefold increase in quantum efficiency, reaching 86% at 455 nm and superior hydrogen evolution rates under visible and AM1.5G irradiation conditions with prolonged stability. Kinetic investigations using photoelectrochemical and time-resolved measurements demonstrate a greater extent and extended lifetime of the charge-separated state on the tips as well as rapid water reduction kinetics on high-energy surfaces. This approach sheds light on the critical role of cocatalysts in hybrid photocatalytic systems for achieving high performance.
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BACKGROUND: Tar is the main toxic of cigarettes, and its effect on atherosclerosis progression and the underlying mechanisms remain largely unknown. Vascular smooth muscle cells (VSMCs) play a key role in atherogenesis and plaque vulnerability. The present study sought to investigate the mechanism of atherosclerosis progression through tar-induced VSMC necroptosis, a recently described form of necrosis. METHODS: The effect of tar on atherosclerosis progression and VSMC necroptosis was examined in ApoE-/- mice and cultured VSMCs. The role of necroptosis in tar-induced plaque development was evaluated in RIPK3-deletion mice (ApoE-/-RIPK3-/-). The key proteins of necroptosis in carotid plaques of smokers and non-smokers were also examined. Quantitative proteomics of mice aortas was conducted to further investigate the underlying mechanism. Pharmacological approaches were then applied to modulate the expression of targets to verify the regulatory process of tar-induced necroptosis. RESULTS: Tar administration led to increased atherosclerotic plaque area and reduced collagen and VSMCs in ApoE-/- mice. The expression of RIPK1ãRIPK3ãand MLKL in VSMCs of plaques were all increased in tar-exposed mice and smokers. RIPK3 deletion protected against VSMC loss and plaque progression stimulated by tar. In mechanistic studies, quantitative proteomics analysis of ApoE-/- mice aortas suggested that tar triggered endoplasmic reticulum (ER) stress. PERK-eIF2α-CHOP axis was activated in tar-treated VSMCs and atherosclerotic plaque. Inhibition of ER stress using 4PBA significantly reduced plaque progression and VSMC necroptosis. Further study revealed that ER stress resulted in calcium (Ca2+) release into mitochondria and cytoplasm. Elevated Ca2+ levels lead to mitochondrial dysfunction and excessive reactive oxygen species (ROS) production, which consequently promote RIPK3-dependent necroptosis. In addition, Ca2+/calmodulin-dependent protein kinase II (CaMKII) activated by cytosolic Ca2+ overload binds to RIPK3, accounting for necroptosis. CONCLUSION: The findings revealed that cigarette tar promoted atherosclerosis progression by inducing RIPK3-dependent VSMC necroptosis and identified novel avenues of ER stress and Ca2+ overload.
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Aterosclerose , Placa Aterosclerótica , Alcatrões , Camundongos , Animais , Placa Aterosclerótica/metabolismo , Músculo Liso Vascular , Necroptose , Aterosclerose/metabolismo , Estresse do Retículo Endoplasmático , Apolipoproteínas E/metabolismo , Miócitos de Músculo Liso/metabolismoRESUMO
BACKGROUND AND AIMS: Argon plasma coagulation (APC) could be considered a treatment modality for small gastric low-grade dysplasia (LGD) instead of endoscopic resection. Our study investigated the clinical outcomes of APC for treating gastric LGD and associated variables with local recurrence. METHODS: This study included 911 patients who underwent APC for gastric neoplasms at the tertiary hospital from July 2007 to March 2022 with a minimal follow-up of 12 months. Of these patients, 112 without any information about Helicobacter pylori infection status, 164 who underwent APC for salvage therapy, 5 with high-grade dysplasia, and 12 with cancer were excluded. Through a retrospective review of medical data, the clinical outcomes and variables associated with the local recurrence were analyzed. RESULTS: A total of 618 patients with LGD (median age, 64 years) were followed up for a median of 30 months, and local recurrence has happened in 21 (3.4%) patients. Multivariate analysis showed that lesion size (hazard ratio, 1.06; 95% confidential interval, 1.01-1.12) was associated with the local recurrence. Among 557 lesions smaller than 10 mm, local recurrence was found in 14 (2.6%) cases, and local recurrence was found in 7 (9.5%) cases of 109 tumors larger than 10 mm (P < .004). CONCLUSIONS: In gastric LGD smaller than 10 mm without scars, APC is a good treatment modality in place of endoscopic resection. However, when a lesion is larger, APC should be selected carefully with close monitoring.
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Coagulação com Plasma de Argônio , Recidiva Local de Neoplasia , Neoplasias Gástricas , Humanos , Coagulação com Plasma de Argônio/métodos , Masculino , Pessoa de Meia-Idade , Feminino , Neoplasias Gástricas/cirurgia , Neoplasias Gástricas/patologia , Estudos Retrospectivos , Idoso , Adulto , Resultado do Tratamento , Carga Tumoral , Gastroscopia/métodos , Idoso de 80 Anos ou mais , Gradação de TumoresRESUMO
BACKGROUND: Although albuminuria is the gold standard for defining chronic kidney disease (CKD), total proteinuria has also been widely used in real-world clinical practice. Moreover, the superiority of the prognostic performance of albuminuria over proteinuria in patients with CKD remains inconclusive. Therefore, we aimed to compare the predictive performances of albuminuria and proteinuria in these patients. METHODS: From the Korean Cohort Study for Outcome in Patients with CKD we included 2099 patients diagnosed with CKD grades 1-5 who did not require kidney replacement therapy. We measured the spot urine albumin:creatinine ratio (mACR) and protein:creatinine ratio (PCR) and estimated the ACR (eACR) using the PCR. Kidney failure risk equation (KFRE) scores were calculated using the mACR, PCR and eACR. The primary outcome was the 5-year risk of kidney failure with replacement therapy (KFRT). RESULTS: The eACR significantly underestimated mACR in patients with low albuminuria levels. The time-dependent area under the receiver operating characteristics curve showed excellent predictive performance for all KFRE scores from the mACR, PCR and eACR. However, eACR was inferior to mACR based on the continuous net reclassification index (cNRI) and integrated discrimination improvement index (IDI) in all CKD cause groups, except for the group with an unclassified aetiology. Moreover, the cNRI and IDI statistics indicated that both eACR and PCR were inferior to mACR in patients with low albuminuria (<30 mg/g). Conversely, the predictive performance of PCR was superior in severe albuminuria and nephrotic-range proteinuria, in which the IDI and cNRI of the PCR were greater than those of the mACR. CONCLUSIONS: The mACR, eACR and PCR showed excellent performance in predicting KFRT in patients with CKD. However, eACR was inferior to mACR in patients with low albuminuria, indicating that measuring rather than estimating albuminuria is preferred for these patients.
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Albuminúria , Insuficiência Renal Crônica , Humanos , Albuminúria/diagnóstico , Albuminúria/etiologia , Albuminúria/urina , Estudos de Coortes , Creatinina/urina , Proteinúria/diagnóstico , Proteinúria/etiologia , Proteinúria/urina , Insuficiência Renal Crônica/complicações , Insuficiência Renal Crônica/diagnóstico , Insuficiência Renal Crônica/urina , Taxa de Filtração GlomerularRESUMO
BACKGROUND: A suboptimal peak inspiratory flow rate (PIFR) in dry-powder inhaler (DPI) users can lead to insufficient therapeutic effects in the treatment of chronic obstructive pulmonary disease (COPD). However, few data on the prevalence of and factors associated with suboptimal PIFR in Korean patients with COPD are available. METHODS: We conducted a cross-sectional study of patients with COPD who had been using DPIs for more than three months. PIFR was measured using an In-Check DIAL G16 device. Suboptimal PIFR was defined as below the resistance-matched threshold. Multivariable logistic regression analysis was used to determine factors associated with suboptimal PIFR. RESULTS: Of 444 DPI users with COPD, the rate of suboptimal PIFR was 22.0 % (98/444). In a multivariable analysis, significant factors associated with suboptimal PIFR were age (adjusted odds ratio [aOR] = 1.06 by 1-year increase; 95 % confidence interval [CI] = 1.02-1.09), male sex (aOR = 0.28; 95 % CI = 0.11-0.73), body mass index (BMI) (aOR = 0.91 by 1 kg/m2 increase; 95 % CI = 0.85-0.99), post-bronchodilator forced vital capacity (FVC) %pred (aOR = 0.97 by 1%pred increase; 95 % CI = 0.95-0.99), and In-Check DIAL R2-type inhaler [medium-low resistance] use (aOR = 3.70 compared with R1-type inhalers [low resistance]; 95 % CI = 2.03-7.03). CONCLUSIONS: In Korea, more than one-fifth of DPI users with COPD had a suboptimal PIFR. The factors associated with suboptimal PIFR were age, female gender, low BMI, low FVC, and R2-type inhaler use. Therefore, clinicians should carefully evaluate the possibility of suboptimal PIFR when prescribing DPIs.
Assuntos
Inaladores de Pó Seco , Doença Pulmonar Obstrutiva Crônica , Humanos , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Doença Pulmonar Obstrutiva Crônica/fisiopatologia , Masculino , Feminino , Estudos Transversais , República da Coreia , Pessoa de Meia-Idade , Idoso , Administração por Inalação , Broncodilatadores/administração & dosagem , Broncodilatadores/uso terapêutico , Índice de Massa Corporal , Fatores Sexuais , Fatores EtáriosRESUMO
Although the cardiovascular benefits of an increased urinary potassium excretion have been suggested, little is known about the potential cardiac association of urinary potassium excretion in patients with chronic kidney disease. In addition, whether the cardiac association of urinary potassium excretion was mediated by serum potassium levels has not been studied yet. We reviewed the data of 1633 patients from a large-scale multicentre prospective Korean study (2011-2016). Spot urinary potassium to creatinine ratio was used as a surrogate for urinary potassium excretion. Cardiac injury was defined as a high-sensitivity troponin T ≥ 14 ng/l. OR and 95 % (CI for cardiac injury were calculated using logistic regression analyses. Of 1633 patients, the mean spot urinary potassium to creatinine ratio was 49·5 (sd 22·6) mmol/g Cr and the overall prevalence of cardiac injury was 33·9 %. Although serum potassium levels were not associated with cardiac injury, per 10 mmol/g Cr increase in the spot urinary potassium to creatinine ratio was associated with decreased odds of cardiac injury: OR 0·917 (95 % CI 0·841, 0·998), P = 0·047) in multivariate logistic regression analysis. In mediation analysis, approximately 6·4 % of the relationship between spot urinary potassium to creatinine ratio and cardiac injury was mediated by serum potassium levels, which was not statistically significant (P = 0·368). Higher urinary potassium excretion was associated with lower odds of cardiac injury, which was not mediated by serum potassium levels.
Assuntos
Potássio , Insuficiência Renal Crônica , Humanos , Estudos de Coortes , Potássio/urina , Creatinina/urina , Estudos Prospectivos , Insuficiência Renal Crônica/complicações , República da Coreia/epidemiologiaRESUMO
BACKGROUND: The Leicester Cough Questionnaire (LCQ) is a reliable tool for measuring the multidimensional impact of cough on patients' quality of life; however, its scoring algorithm is lengthy and complex for routine clinical use. OBJECTIVE: The study aimed to develop a simplified version of the LCQ, the Rapid Cough Questionnaire (RCQ), as a substitue in clinical practice and validate the RCQ using an independent cohort. METHODS: To select items for the RCQ score, a correlation network was used to determine the items from each domain that were strongly correlated with the total LCQ score. The final items for the RCQ were selected on the basis of the centrality of the node degree, betweenness, and closeness in the correlation network. RESULTS: The RCQ score was derived from 3 items: tiredness (LCQ3) in the physical domain, the feeling of being fed up (LCQ13) in the psychological domain, and annoyance with partner/family/friends (LCQ19) in the social domain. The correlation between the LCQ and RCQ was high, with a coefficient of 0.93 (P < .001). The mean score of the RCQ was 11.2 ± 3.2, with scores ranging from 5.15 to 19.55. The minimal clinically important difference in the RCQ score was calculated to be 1.6 using a distribution-based method. The concurrent validity of the LCQ and the RCQ with cough numeric rating scale was similar. In the validation cohort, the correlation between the LCQ and RCQ scores was consistent regardless of sex and etiology. CONCLUSION: The RCQ score, which is concise, reliable, and valid, can be a valuable tool for patient assessment, particularly in clinical practice.
Assuntos
Tosse , Qualidade de Vida , Humanos , Inquéritos e Questionários , Tosse/diagnóstico , Tosse/etiologia , Emoções , FadigaRESUMO
BACKGROUND: Although various monoclonal antibodies have been used as add-on therapy for severe eosinophilic asthma (SEA), to the best of our knowledge, no direct head-to-head comparative study has evaluated their efficacy. OBJECTIVE: To compare the efficacy of reslizumab, mepolizumab, and dupilumab in patients with SEA. METHODS: This was a multicenter, prospective observational study in patients with SEA who had received 1 of these biologic agents for at least 6 months. Cox proportional hazard models were used to compare the risk of the first exacerbation event, adjusting for sputum or blood eosinophils and common asthma-related covariates. The annual exacerbation rate was analyzed using a negative binomial model, and a mixed-effect model was used to analyze changes in forced expiratory volume in 1 second and asthma control test score over time. RESULTS: A total of 141 patients with SEA were included in the analysis; 71 (50%) received dupilumab; 40 (28%) received reslizumab, and 30 (21%) received mepolizumab. During the 12-month follow-up, 27.5%, 43.3%, and 38.0% of patients in the reslizumab, mepolizumab, and dupilumab groups, respectively, experienced at least 1 exacerbation. However, after adjusting for confounding factors, the dupilumab and mepolizumab groups showed similar outcomes in time-to-first exacerbation, exacerbation rate, forced expiratory volume in 1 second, and asthma control test score to those of the reslizumab group. CONCLUSION: In patients with SEA, treatment with reslizumab, mepolizumab, and dupilumab resulted in comparable clinical outcomes within a 12-month period. TRIAL REGISTRATION: The cohort protocol was sanctioned by the Institutional Review Board of each study center (clinicaltrial.gov identifier NCT05164939).