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1.
Circulation ; 149(24): 1865-1874, 2024 06 11.
Artigo em Inglês | MEDLINE | ID: mdl-38690659

RESUMO

BACKGROUND: The morbidity and mortality rates of patients with heart failure (HF) and functional mitral regurgitation (MR) remain substantial despite guideline-directed medical therapy for HF. We evaluated the efficacy of ertugliflozin for reduction of functional MR associated with HF with mild to moderately reduced ejection fraction. METHODS: The EFFORT trial (Ertugliflozin for Functional Mitral Regurgitation) was a multicenter, double-blind, randomized trial to examine the hypothesis that the sodium-glucose cotransporter 2 inhibitor ertugliflozin is effective for improving MR in patients with HF with New York Heart Association functional class II or III, 35%≤ejection fraction<50%, and effective regurgitant orifice area of chronic functional MR >0.1 cm2 on baseline echocardiography. We randomly assigned 128 patients to receive either ertugliflozin or placebo in addition to guideline-directed medical therapy for HF. The primary end point was change in effective regurgitant orifice area of functional MR from baseline to the 12-month follow-up. Secondary end points included changes in regurgitant volume, left ventricular (LV) volume indices, left atrial volume index, LV global longitudinal strain, and NT-proBNP (N-terminal pro-B-type natriuretic peptide). RESULTS: The treatment groups were generally well-balanced with regard to baseline characteristics: mean age, 66±11 years; 61% men; 13% diabetes; 51% atrial fibrillation; 43% use of angiotensin receptor-neprilysin inhibitor; ejection fraction, 42±8%; and effective regurgitant orifice area, 0.20±0.12 cm2. The decrease in effective regurgitant orifice area was significantly greater in the ertugliflozin group than in the placebo group (-0.05±0.06 versus 0.03±0.12 cm2; P<0.001). Compared with placebo, ertugliflozin significantly reduced regurgitant volume by 11.2 mL (95% CI, -16.1 to -6.3; P=0.009), left atrial volume index by 6.0 mL/m2 (95% CI, -12.16 to 0.15; P=0.005), and LV global longitudinal strain by 1.44% (95% CI, -2.42% to -0.46%; P=0.004). There were no significant between-group differences regarding changes in LV volume indices, ejection fraction, or NT-proBNP levels. Serious adverse events occurred in one patient (1.6%) in the ertugliflozin group and 6 (9.2%) in the placebo group (P=0.12). CONCLUSIONS: Among patients with functional MR associated with HF, ertugliflozin significantly improved LV global longitudinal strain and left atrial remodeling, and reduced functional MR. Sodium-glucose cotransporter 2 inhibitors may be considered for patients with functional MR. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT04231331.


Assuntos
Compostos Bicíclicos Heterocíclicos com Pontes , Insuficiência Cardíaca , Insuficiência da Valva Mitral , Inibidores do Transportador 2 de Sódio-Glicose , Humanos , Insuficiência Cardíaca/tratamento farmacológico , Insuficiência Cardíaca/fisiopatologia , Insuficiência da Valva Mitral/tratamento farmacológico , Insuficiência da Valva Mitral/diagnóstico por imagem , Insuficiência da Valva Mitral/fisiopatologia , Masculino , Feminino , Idoso , Método Duplo-Cego , Pessoa de Meia-Idade , Inibidores do Transportador 2 de Sódio-Glicose/uso terapêutico , Compostos Bicíclicos Heterocíclicos com Pontes/uso terapêutico , Compostos Bicíclicos Heterocíclicos com Pontes/efeitos adversos , Volume Sistólico/efeitos dos fármacos , Resultado do Tratamento , Fragmentos de Peptídeos/sangue , Função Ventricular Esquerda/efeitos dos fármacos , Peptídeo Natriurético Encefálico
2.
Am J Physiol Renal Physiol ; 327(3): F363-F372, 2024 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-38961839

RESUMO

Epithelial-to-mesenchymal transition (EMT) is considered as one of the senescence processes; reportedly, antisenescence therapies effectively reduce EMT. Some models have shown antisenescence effects with the use of sodium-glucose cotransporter 2 (SGLT2) inhibitor. Therefore, our study investigated the antisenescence effects of empagliflozin as an SGLT2 inhibitor in a peritoneal fibrosis model and their impact on EMT inhibition. For in vitro study, human peritoneal mesothelial cells (HPMCs) were isolated and grown in a 96-well plate. The cell media were exchanged with serum-free M199 medium with d-glucose, with or without empagliflozin. All animal experiments were carried out in male mice. Mice were randomly classified into three treatment groups based on peritoneal dialysis (PD) or empagliflozin. We evaluated changes in senescence and EMT markers in HPMCs and PD model. HPMCs treated with glucose transformed from cobblestone to spindle shape, resulting in EMT. Empagliflozin attenuated these morphological changes. Reactive oxygen species production, DNA damage, senescence, and EMT markers were increased by glucose treatment; however, cotreatment with glucose and empagliflozin attenuated these changes. For the mice with PD, an increase in thickness, collagen deposition, staining for senescence, or EMT markers of the parietal peritoneum was observed, which, however, was attenuated by cotreatment with empagliflozin. p53, p21, and p16 increased in mice with PD compared with those in the control group; however, these changes were decreased by empagliflozin. In conclusion, empagliflozin effectively attenuated glucose-induced EMT in HPMCs through a decrease in senescence. Cotreatment with empagliflozin improved peritoneal thickness and fibrosis in PD.NEW & NOTEWORTHY Epithelial-to-mesenchymal transition (EMT) is considered one of the senescence processes. Antisenescence therapies may effectively reduce EMT in peritoneal dialysis models. Human peritoneal mesothelial cells treated with glucose show an increase in senescence and EMT markers; however, empagliflozin attenuates these changes. Mice undergoing peritoneal dialysis exhibit increased senescence and EMT markers, which are decreased by empagliflozin. These findings suggest that empagliflozin may emerge as a novel strategy for prevention or treatment of peritoneal fibrosis.


Assuntos
Compostos Benzidrílicos , Senescência Celular , Transição Epitelial-Mesenquimal , Glucosídeos , Diálise Peritoneal , Fibrose Peritoneal , Inibidores do Transportador 2 de Sódio-Glicose , Animais , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Glucosídeos/farmacologia , Compostos Benzidrílicos/farmacologia , Diálise Peritoneal/efeitos adversos , Senescência Celular/efeitos dos fármacos , Masculino , Humanos , Inibidores do Transportador 2 de Sódio-Glicose/farmacologia , Fibrose Peritoneal/patologia , Fibrose Peritoneal/metabolismo , Fibrose Peritoneal/prevenção & controle , Peritônio/patologia , Peritônio/efeitos dos fármacos , Peritônio/metabolismo , Camundongos , Modelos Animais de Doenças , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/metabolismo , Células Epiteliais/patologia , Glucose/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Camundongos Endogâmicos C57BL , Células Cultivadas , Dano ao DNA/efeitos dos fármacos
3.
Neurobiol Dis ; 194: 106470, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38485094

RESUMO

Pathogenic variants in KCNB1 are associated with a neurodevelopmental disorder spectrum that includes global developmental delays, cognitive impairment, abnormal electroencephalogram (EEG) patterns, and epilepsy with variable age of onset and severity. Additionally, there are prominent behavioral disturbances, including hyperactivity, aggression, and features of autism spectrum disorder. The most frequently identified recurrent variant is KCNB1-p.R306C, a missense variant located within the S4 voltage-sensing transmembrane domain. Individuals with the R306C variant exhibit mild to severe developmental delays, behavioral disorders, and a diverse spectrum of seizures. Previous in vitro characterization of R306C described altered sensitivity and cooperativity of the voltage sensor and impaired capacity for repetitive firing of neurons. Existing Kcnb1 mouse models include dominant negative missense variants, as well as knockout and frameshifts alleles. While all models recapitulate key features of KCNB1 encephalopathy, mice with dominant negative alleles were more severely affected. In contrast to existing loss-of-function and dominant-negative variants, KCNB1-p.R306C does not affect channel expression, but rather affects voltage-sensing. Thus, modeling R306C in mice provides a novel opportunity to explore impacts of a voltage-sensing mutation in Kcnb1. Using CRISPR/Cas9 genome editing, we generated the Kcnb1R306C mouse model and characterized the molecular and phenotypic effects. Consistent with the in vitro studies, neurons from Kcnb1R306C mice showed altered excitability. Heterozygous and homozygous R306C mice exhibited hyperactivity, altered susceptibility to chemoconvulsant-induced seizures, and frequent, long runs of slow spike wave discharges on EEG, reminiscent of the slow spike and wave activity characteristic of Lennox Gastaut syndrome. This novel model of channel dysfunction in Kcnb1 provides an additional, valuable tool to study KCNB1 encephalopathies. Furthermore, this allelic series of Kcnb1 mouse models will provide a unique platform to evaluate targeted therapies.


Assuntos
Transtorno do Espectro Autista , Encefalopatias , Epilepsia , Animais , Camundongos , Transtorno do Espectro Autista/patologia , Encefalopatias/patologia , Epilepsia/patologia , Mutação , Fenótipo , Convulsões
4.
Cancer Immunol Immunother ; 73(8): 157, 2024 Jun 04.
Artigo em Inglês | MEDLINE | ID: mdl-38834889

RESUMO

Interleukin-2 (IL-2), a cytokine with pleiotropic immune effects, was the first approved cancer immunotherapy agent. However, IL-2 is associated with systemic toxicity due to binding with its ligand IL-2Rα, such as vascular leakage syndrome, limiting its clinical applications. Despite efforts to extend the half-life of IL-2 and abolish IL-2Rα interactions, the risk of toxicity remains unresolved. In this study, we developed the bispecific fusion protein MB2033, comprising a novel IL-2 variant (IL-2v) connected to anti-programmed death ligand 1 (PD-L1) via a silenced Fc domain. The IL-2v of MB2033 exhibits attenuated affinity for IL-2Rßγ without binding to IL-2Rα. The binding affinity of MB2033 for PD-L1 is greater than that for IL-2Rßγ, indicating its preferential targeting of PD-L1+ tumor cells to induce tumor-specific immune activation. Accordingly, MB2033 exhibited significantly reduced regulatory T cell activation, while inducing comparable CD8+ T cell activation to recombinant human IL-2 (rhIL-2). MB2033 induced lower immune cell expansion and reduced cytokine levels compared with rhIL-2 in human peripheral blood mononuclear cells, indicating a decreased risk of peripheral toxicity. MB2033 exhibited superior anti-tumor efficacy, including tumor growth inhibition and complete responses, compared with avelumab monotherapy in an MC38 syngeneic mouse model. In normal mice, MB2033 was safer than non-α IL-2v and tolerable up to 30 mg/kg. These preclinical results provide evidence of the dual advantages of MB2033 with an enhanced safety and potent clinical efficacy for cancer treatment.


Assuntos
Antígeno B7-H1 , Interleucina-2 , Proteínas Recombinantes de Fusão , Animais , Camundongos , Humanos , Proteínas Recombinantes de Fusão/farmacologia , Proteínas Recombinantes de Fusão/genética , Antígeno B7-H1/metabolismo , Antígeno B7-H1/antagonistas & inibidores , Feminino , Camundongos Endogâmicos C57BL , Imunoterapia/métodos , Linhagem Celular Tumoral , Melanoma Experimental/tratamento farmacológico , Melanoma Experimental/imunologia
5.
Small ; 20(22): e2307346, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38213011

RESUMO

α-In2Se3 semiconductor crystals realize artificial synapses by tuning in-plane and out-of-plane ferroelectricity with diverse avenues of electrical and optical pulses. While the electrically induced ferroelectricity of α-In2Se3 shows synaptic memory operation, the optically assisted synaptic plasticity in α-In2Se3 has also been preferred for polarization flipping enhancement. Here, the synaptic memory behavior of α-In2Se3 is demonstrated by applying electrical gate voltages under white light. As a result, the induced internal electric field is identified at a polarization flipped conductance channel in α-In2Se3/hexagonal boron nitride (hBN) heterostructure ferroelectric field effect transistors (FeFETs) under white light and discuss the contribution of this built-in electric field on synapse characterization. The biased dipoles in α-In2Se3 toward potentiation polarization direction by an enhanced internal built-in electric field under illumination of white light lead to improvement of linearity for long-term depression curves with proper electric spikes. Consequently, upon applying appropriate electric spikes to α-In2Se3/hBN FeFETs with illuminating white light, the recognition accuracy values significantly through the artificial learning simulation is elevated for discriminating hand-written digit number images.

6.
Ann Surg Oncol ; 31(9): 5785-5793, 2024 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-38802711

RESUMO

PURPOSE: Robot-assisted radical cystectomy (RARC) has gained traction in the management of muscle invasive bladder cancer. Urinary diversion for RARC was achieved with orthotopic neobladder and ileal conduit. Evidence on the optimal method of urinary diversion was limited. Long-term outcomes were not reported before. This study was designed to compare the perioperative and oncological outcomes of ileal conduit versus orthotopic neobladder cases of nonmetastatic bladder cancer treated with RARC. PATIENTS AND METHODS: The Asian RARC consortium was a multicenter registry involving nine Asian centers. Consecutive patients receiving RARC were included. Cases were divided into the ileal conduit and neobladder groups. Background characteristics, operative details, perioperative outcomes, recurrence information, and survival outcomes were reviewed and compared. Primary outcomes include disease-free and overall survival. Secondary outcomes were perioperative results. Multivariate regression analyses were performed. RESULTS: From 2007 to 2020, 521 patients who underwent radical cystectomy were analyzed. Overall, 314 (60.3%) had ileal conduit and 207 (39.7%) had neobladder. The use of neobladder was found to be protective in terms of disease-free survival [Hazard ratio (HR) = 0.870, p = 0.037] and overall survival (HR = 0.670, p = 0.044) compared with ileal conduit. The difference became statistically nonsignificant after being adjusted in multivariate cox-regression analysis. Moreover, neobladder reconstruction was not associated with increased blood loss, nor additional risk of major complications. CONCLUSIONS: Orthotopic neobladder urinary diversion is not inferior to ileal conduit in terms of perioperative safety profile and long-term oncological outcomes. Further prospective studies are warranted for further investigation.


Assuntos
Cistectomia , Procedimentos Cirúrgicos Robóticos , Neoplasias da Bexiga Urinária , Derivação Urinária , Humanos , Cistectomia/métodos , Masculino , Derivação Urinária/métodos , Feminino , Neoplasias da Bexiga Urinária/cirurgia , Neoplasias da Bexiga Urinária/patologia , Procedimentos Cirúrgicos Robóticos/métodos , Pessoa de Meia-Idade , Taxa de Sobrevida , Seguimentos , Idoso , Prognóstico , Coletores de Urina , Estudos Retrospectivos , Complicações Pós-Operatórias
7.
BMC Cancer ; 24(1): 70, 2024 Jan 12.
Artigo em Inglês | MEDLINE | ID: mdl-38216948

RESUMO

BACKGROUND: Both first and second-generation EGFR-TKIs are recommended in advanced NSCLC with common EGFR mutations. However, there are few data on the difference in efficacy of EGFR-TKIs based on the type of EGFR mutation and agents. METHODS: This retrospective real-world study evaluated the outcomes and clinicopathologic characteristics, including the type of EGFR mutations, of 237 advanced NSCLC patients treated with first- or second-generation (afatinib) EGFR-TKIs as first-line therapy. RESULTS: The median progression-free survival (PFS) and overall survival (OS) of all patients were 11 months (M) and 25M, respectively. In the univariate analysis, patients with exon 19 deletion (del) (n=130) had significantly longer median OS compared to those with other mutations (L858R: 84, others: 23) (30 vs. 22 M, p=0.047), without a difference in PFS (p=0.138). Patients treated with afatinib (n=60) showed significantly longer median OS compared to those treated with first-generation TKIs (gefitinib: 159, erlotinib: 18) (30 vs. 23 M, p=0.037), without a difference in PFS (p=0.179). In patients with exon 19 del, there was no significant difference in median PFS (p=0.868) or OS (p=0.361) between patients treated with afatinib and those treated with first-generation TKIs, while significantly better PFS (p=0.042) and trend in OS (p=0.069) were observed in patients receiving afatinib in other mutations. Exon 19 del was independently associated with favorable OS (p=0.028), while age >70 years (p=0.017), ECOG performance status ≥2 (p=0.001), primary metastatic disease (p=0.007), and synchronous brain metastasis (p=0.026) were independent prognostic factors of poor OS. CONCLUSIONS: The EGFR exon 19 del was associated with favorable OS in advanced NSCLC patients receiving first-line EGFR-TKIs. Moreover, in patients with exon 19 del, first-generation TKIs seem to be a reasonable treatment option if osimertinib is unavailable.


Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Humanos , Idoso , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Afatinib/uso terapêutico , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Estudos Retrospectivos , Inibidores de Proteínas Quinases/uso terapêutico , Receptores ErbB/genética , Mutação
8.
Transpl Int ; 37: 11878, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38644935

RESUMO

The effect of changes in immunosuppressive therapy during the acute phase post-heart transplantation (HTx) on clinical outcomes remains unclear. This study aimed to investigate the effects of changes in immunosuppressive therapy by corticosteroid (CS) weaning and everolimus (EVR) initiation during the first year post-HTx on clinical outcomes. We analyzed 622 recipients registered in the Korean Organ Transplant Registry (KOTRY) between January 2014 and December 2021. The median age at HTx was 56 years (interquartile range [IQR], 45-62), and the median follow-up time was 3.9 years (IQR 2.0-5.1). The early EVR initiation within the first year post-HTx and maintenance during the follow-up is associated with reduced the risk of primary composite outcome (all-cause mortality or re-transplantation) (HR, 0.24; 95% CI 0.09-0.68; p < 0.001) and cardiac allograft vasculopathy (CAV) (HR, 0.39; 95% CI 0.19-0.79; p = 0.009) compared with EVR-free or EVR intermittent treatment regimen, regardless of CS weaning. However, the early EVR initiation tends to increase the risk of acute allograft rejection compared with EVR-free or EVR intermittent treatment.


Assuntos
Corticosteroides , Everolimo , Rejeição de Enxerto , Transplante de Coração , Imunossupressores , Sistema de Registros , Humanos , Everolimo/administração & dosagem , Everolimo/uso terapêutico , Transplante de Coração/efeitos adversos , Pessoa de Meia-Idade , Masculino , Feminino , Imunossupressores/uso terapêutico , Imunossupressores/administração & dosagem , República da Coreia/epidemiologia , Rejeição de Enxerto/prevenção & controle , Corticosteroides/administração & dosagem , Corticosteroides/uso terapêutico , Resultado do Tratamento , Sobrevivência de Enxerto , Estudos Retrospectivos
9.
Semin Dial ; 37(3): 220-227, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38140722

RESUMO

INTRODUCTION: Results on the association between the use of renin-angiotensin system blockades (RASBs) and vascular access-related outcomes are inconsistent. We aimed to compare vascular access-related outcomes according to the use of RASBs in hemodialysis patients. METHODS: This study used data from a national hemodialysis quality assessment program of the Republic of Korea (n = 54,903). Group 1 was not prescribed any blood pressure-lowering drugs (n = 28,521). Group 2 was prescribed other blood pressure-lowering agents except for RASBs (n = 9571). Group 3 was prescribed RASBs (n = 16,811). Vascular access-related outcomes were classified into intervention-free survival (IFS), thrombosis-free survival (TFS), and vascular access survival (VAS). RESULTS: No significant difference in the three access survival rates was identified among the three groups. The multivariate Cox regression analyses indicated that Group 3 had better outcomes in IFS and TFS than Group 1. The numbers of angioplasties performed were significantly greater in Group 1 than in the other two groups. The numbers of thrombectomies performed were significantly the lowest in Group 3 among all the groups. CONCLUSIONS: Our study revealed different results according to types of access survival in univariate or multivariate analyses. The association of RASBs with favorable outcomes in vascular access remains unclear.


Assuntos
Antagonistas de Receptores de Angiotensina , Inibidores da Enzima Conversora de Angiotensina , Anti-Hipertensivos , Diálise Renal , Insuficiência Renal Crônica , Estudos Retrospectivos , Humanos , Sistema Renina-Angiotensina/efeitos dos fármacos , Anti-Hipertensivos/administração & dosagem , Inibidores da Enzima Conversora de Angiotensina/administração & dosagem , Antagonistas de Receptores de Angiotensina/administração & dosagem , Pessoa de Meia-Idade , Idoso , Masculino , Feminino , Análise de Sobrevida , Antagonistas Adrenérgicos beta/administração & dosagem , Insuficiência Renal Crônica/mortalidade , Insuficiência Renal Crônica/terapia
10.
Arch Toxicol ; 98(5): 1485-1498, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38483585

RESUMO

Accumulating evidence indicates that chronic circadian rhythm disruption is associated with the development of neurodegenerative diseases induced by exposure to neurotoxic chemicals. Herein, we examined the relationship between cellular circadian rhythm disruption and cytotoxicity in neural cells. Moreover, we evaluated the potential application of an in vitro cellular circadian rhythm assay in determining circadian rhythm disruption as a sensitive and early marker of neurotoxicant-induced adverse effects. To explore these objectives, we established an in vitro cellular circadian rhythm assay using human glioblastoma (U87 MG) cells stably transfected with a circadian reporter vector (PER2-dLuc) and determined the lowest-observed-adverse-effect levels (LOAELs) of several common neurotoxicants. Additionally, we determined the LOAEL of each compound on multiple cytotoxicity endpoints (nuclear size [NC], mitochondrial membrane potential [MMP], calcium ions, or lipid peroxidation) using a multiparametric high-content screening (HCS) assay using transfected U87 MG cells treated with the same neurotoxicants for 24 and 72 h. Based on our findings, the LOAEL for cellular circadian rhythm disruption for most chemicals was slightly higher than that for most cytotoxicity indicators detected using HCS, and the LOAEL for MMP in the first 24 h was the closest to that for cellular circadian rhythm disruption. Dietary antioxidants (methylselenocysteine and N-acetyl-l-cysteine) prevented or restored neurotoxicant-induced cellular circadian rhythm disruption. Our results suggest that cellular circadian rhythm disruption is as sensitive as cytotoxicity indicators and occurs early as much as cytotoxic events during disease development. Moreover, the in vitro cellular circadian rhythm assay warrants further evaluation as an early screening tool for neurotoxicants.


Assuntos
Ritmo Circadiano , Neurônios , Humanos
11.
Biotechnol Lett ; 46(4): 521-530, 2024 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-38872071

RESUMO

Blood coagulation mediated by pig tissue factor (TF), which is expressed in pig tissues, causes an instant blood-mediated inflammatory reaction during pig-to-human xenotransplantation. Previously, we generated a soluble pig tissue factor pathway inhibitor α fusion immunoglobulin (TFPI-Ig) which inhibits pig TF activity more efficiently than human TFPI-Ig in human plasma. In this study, we generated several pig TFPI-Ig mutants and tested the efficacy of these mutants in preventing pig-to-human xenogeneic blood coagulation. Structurally important amino acid residues of pig TFPI-Ig were changed into different residues by site-directed mutagenesis. Subsequently, a retroviral vector encoding each cDNA of several pig TFPI-Ig mutants was cloned and transduced into CHO-K1 cells. After establishing stable cell lines expressing each of the pig TFPI-Ig mutants, soluble proteins were produced and purified for evaluating their inhibitory effects on pig TF-mediated blood coagulation in human plasma. The replacement of K36 and K257 with R36 and H257, respectively, in pig TFPI-Ig more efficiently blocked pig TF activity in human plasma when compared with the wild-type pig TFPI-Ig. These results may provide additional information to understand the structure of pig TFPIα, and an improved pig TFPI-Ig variant that more efficiently blocks pig TF-mediated blood coagulation during pig-to-human xenotransplantation.


Assuntos
Coagulação Sanguínea , Lipoproteínas , Transplante Heterólogo , Animais , Humanos , Suínos , Lipoproteínas/genética , Lipoproteínas/metabolismo , Coagulação Sanguínea/genética , Células CHO , Cricetulus , Tromboplastina/genética , Tromboplastina/metabolismo , Mutagênese Sítio-Dirigida , Análise Mutacional de DNA
12.
J Med Internet Res ; 26: e52139, 2024 Jul 03.
Artigo em Inglês | MEDLINE | ID: mdl-38959500

RESUMO

BACKGROUND: Although several biomarkers exist for patients with heart failure (HF), their use in routine clinical practice is often constrained by high costs and limited availability. OBJECTIVE: We examined the utility of an artificial intelligence (AI) algorithm that analyzes printed electrocardiograms (ECGs) for outcome prediction in patients with acute HF. METHODS: We retrospectively analyzed prospectively collected data of patients with acute HF at two tertiary centers in Korea. Baseline ECGs were analyzed using a deep-learning system called Quantitative ECG (QCG), which was trained to detect several urgent clinical conditions, including shock, cardiac arrest, and reduced left ventricular ejection fraction (LVEF). RESULTS: Among the 1254 patients enrolled, in-hospital cardiac death occurred in 53 (4.2%) patients, and the QCG score for critical events (QCG-Critical) was significantly higher in these patients than in survivors (mean 0.57, SD 0.23 vs mean 0.29, SD 0.20; P<.001). The QCG-Critical score was an independent predictor of in-hospital cardiac death after adjustment for age, sex, comorbidities, HF etiology/type, atrial fibrillation, and QRS widening (adjusted odds ratio [OR] 1.68, 95% CI 1.47-1.92 per 0.1 increase; P<.001), and remained a significant predictor after additional adjustments for echocardiographic LVEF and N-terminal prohormone of brain natriuretic peptide level (adjusted OR 1.59, 95% CI 1.36-1.87 per 0.1 increase; P<.001). During long-term follow-up, patients with higher QCG-Critical scores (>0.5) had higher mortality rates than those with low QCG-Critical scores (<0.25) (adjusted hazard ratio 2.69, 95% CI 2.14-3.38; P<.001). CONCLUSIONS: Predicting outcomes in patients with acute HF using the QCG-Critical score is feasible, indicating that this AI-based ECG score may be a novel biomarker for these patients. TRIAL REGISTRATION: ClinicalTrials.gov NCT01389843; https://clinicaltrials.gov/study/NCT01389843.


Assuntos
Inteligência Artificial , Biomarcadores , Eletrocardiografia , Insuficiência Cardíaca , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Doença Aguda , Biomarcadores/sangue , Eletrocardiografia/métodos , Insuficiência Cardíaca/fisiopatologia , Insuficiência Cardíaca/mortalidade , Prognóstico , Estudos Prospectivos , República da Coreia , Estudos Retrospectivos
13.
BMC Med Inform Decis Mak ; 24(1): 85, 2024 Mar 22.
Artigo em Inglês | MEDLINE | ID: mdl-38519947

RESUMO

BACKGROUND: Patients with renal cell carcinoma (RCC) have an elevated risk of chronic kidney disease (CKD) following nephrectomy. Therefore, continuous monitoring and subsequent interventions are necessary. It is recommended to evaluate renal function postoperatively. Therefore, a tool to predict CKD onset is essential for postoperative follow-up and management. METHODS: We constructed a cohort using data from eight tertiary hospitals from the Korean Renal Cell Carcinoma (KORCC) database. A dataset of 4389 patients with RCC was constructed for analysis from the collected data. Nine machine learning (ML) models were used to classify the occurrence and nonoccurrence of CKD after surgery. The final model was selected based on the area under the receiver operating characteristic (AUROC), and the importance of the variables constituting the model was confirmed using the shapley additive explanation (SHAP) value and Kaplan-Meier survival analyses. RESULTS: The gradient boost algorithm was the most effective among the various ML models tested. The gradient boost model demonstrated superior performance with an AUROC of 0.826. The SHAP value confirmed that preoperative eGFR, albumin level, and tumor size had a significant impact on the occurrence of CKD after surgery. CONCLUSIONS: We developed a model to predict CKD onset after surgery in patients with RCC. This predictive model is a quantitative approach to evaluate post-surgical CKD risk in patients with RCC, facilitating improved prognosis through personalized postoperative care.


Assuntos
Carcinoma de Células Renais , Neoplasias Renais , Insuficiência Renal Crônica , Humanos , Carcinoma de Células Renais/cirurgia , Carcinoma de Células Renais/patologia , Neoplasias Renais/cirurgia , Neoplasias Renais/patologia , Taxa de Filtração Glomerular , Insuficiência Renal Crônica/diagnóstico , Insuficiência Renal Crônica/epidemiologia , Insuficiência Renal Crônica/etiologia , Nefrectomia/efeitos adversos , Estudos Retrospectivos
14.
J Korean Med Sci ; 39(1): e8, 2024 Jan 08.
Artigo em Inglês | MEDLINE | ID: mdl-38193327

RESUMO

BACKGROUND: The US Food and Drug Administration (FDA) and European Medicines Agency (EMA) approved empagliflozin for reducing cardiovascular mortality and heart failure (HF) hospitalization in patients with both HF with reduced ejection fraction (HFrEF) and HF with preserved ejection fraction (HFpEF). However, limited data are available on the generalizability of empagliflozin to clinical practice. Therefore, we evaluated real-world eligibility and potential cost-effectiveness based on a nationwide prospective HF registry. METHODS: A total of 3,108 HFrEF and 2,070 HFpEF patients from the Korean Acute Heart Failure (KorAHF) registry were analyzed. Eligibility was estimated by inclusion and exclusion criteria of EMPagliflozin outcomE tRial in Patients With chrOnic heaRt Failure With Reduced Ejection Fraction (EMPEROR-Reduced) and EMPagliflozin outcomE tRial in Patients With chrOnic heaRt Failure With Preserved Ejection Fraction (EMPEROR-Preserved) trials and by FDA & EMA label criteria. The cost-utility analysis was done using a Markov model to project the lifetime medical cost and quality-adjusted life year (QALY). RESULTS: Among the KorAHF patients, 91.4% met FDA & EMA label criteria, while 44.7% met the clinical trial criteria. The incremental cost-effectiveness ratio of empagliflozin was calculated at US$6,764 per QALY in the overall population, which is far below a threshold of US$18,182 per QALY. The cost-effectiveness benefit was more evident in patients with HFrEF (US$5,012 per QALY) than HFpEF (US$8,971 per QALY). CONCLUSION: There is a large discrepancy in real-world eligibility for empagliflozin between FDA & EMA labels and clinical trial criteria. Empagliflozin is cost-effective in HF patients regardless of ejection fraction in South Korea health care setting. The efficacy and safety of empagliflozin in real-world HF patients should be further investigated for a broader range of clinical applications. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01389843.


Assuntos
Insuficiência Cardíaca , Estados Unidos , Humanos , Insuficiência Cardíaca/tratamento farmacológico , Análise de Custo-Efetividade , Estudos Prospectivos , Volume Sistólico , República da Coreia
15.
Ren Fail ; 46(1): 2313173, 2024 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-38522955

RESUMO

BACKGROUND: This study aimed to evaluate the patient survival rates based on the use of angiotensin-converting enzyme inhibitor (ACEI) or angiotensin II receptor blocker (ARB) in a large cohort of patients undergoing maintenance hemodialysis (HD). METHODS: Data from a national HD quality assessment program were used in this retrospective study. The patients were classified into four groups based on the use of renin-angiotensin system blockers (RASBs) as follows: No group, patients without a prescription of any anti-hypertensive drugs including RASBs; Other group, patients with a prescription of anti-hypertensive drugs excluding RASBs; ACEI group, patients with a prescription of an ACEI; and ARB group, patients with a prescription of an ARB. RESULTS: The 5-year survival rates in the no, other, ACEI, and ARB groups were 68.6%, 67.8%, 70.6%, and 69.2%, respectively. The ACEI group had the best patient survival trend among the four groups. In multivariable Cox regression analyses, no differences were observed between the ACEI and ARB groups. Among young patients and patients without diabetes or heart disease, the ACEI group had the best patient survival among the four groups. However, among patients with DM or heart disease, the ARB group had the best patient survival. CONCLUSIONS: Our study found that patients receiving ACEI and ARB had comparable survival. However, patients receiving ARB had better survival in the subgroups of patients with DM or heart disease, and patients receiving ACEI had better survival in the subgroup of young patients or patients without diabetes or heart disease.


Assuntos
Diabetes Mellitus , Cardiopatias , Humanos , Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Antagonistas de Receptores de Angiotensina/uso terapêutico , Estudos Retrospectivos , Anti-Hipertensivos , Estudos de Coortes , Diálise Renal , Diabetes Mellitus/induzido quimicamente , Cardiopatias/induzido quimicamente
16.
Curr Ther Res Clin Exp ; 100: 100735, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38380420

RESUMO

Background: Hypertension and dyslipidemia significantly contribute to cardiovascular disease development. Their coexistence poses challenges in managing multiple medications, influencing treatment adherence. Objective: This study aimed to assess the efficacy and safety of a combined treatment approach using a fixed-dose combination therapy. Methods: This multicenter, 8-week, randomized, double-blind, Phase IV trial was named Telmisartan/Amlodipine/Rosuvastatin from Samjin Pharmaceuticals and evaluated the efficacy and safety of fixed-dose combination treatment in patients with essential hypertension and dyslipidemia. They were randomly assigned to 2 fixed-dose combination therapy groups, telmisartan 40 mg/amlodipine 5 mg/rosuvastatin 10 mg (TEL/ALD/RSV) or amlodipine 5 mg/atorvastatin 10 mg (ALD/ATV) after washout/run-in period. The primary outcomes were the change in mean sitting systolic blood pressure and the percentage change of LDL-C after 8 weeks of medical treatment. Adverse drug reactions and events were assessed. Results: Of a total of 304 patients who underwent screening, 252 were randomized to the TEL/ALD/RSV group (125 patients) and the ALD/ATV group (127 patients). The mean (SD) ages of the TEL/ALD/RSV group and the ALD/ATV group were 67.4 (11.3) and 68.2 (10.6) years, respectively (P = 0.563). The least-squares mean (SE) in mean sitting systolic blood pressure changes between the 2 groups were -16.27 (0.93) mm Hg in the TEL/ALD/RSV group, -6.85 (0.92) mm Hg in the ALD/ATV group (LSM difference = -9.42 mm Hg; 95% CI, -11.99 to -6.84; P < .001). For LDL-C level changes, a significant difference was noted between the 2 groups: -50.03% (1.18%) in the TEL/ALD/RSV group, -39.60% (1.17%) in the ALD/ATV group (LSM difference = -10.43%; 95% CI, -13.70 to -7.16; P < .001). No severe adverse events were observed. Conclusions: TEL/ALD/RSV proved to be more efficient than ALD/ATV in lowering blood pressure and reducing LDL-C levels among patients with hypertension and dyslipidemia, with no notable safety concerns. (Curr Ther Res Clin Exp. 2024; XX:XXX-XXX). ClinicalTrials.gov identifier: NCT03860220.

17.
Medicina (Kaunas) ; 60(1)2024 Jan 22.
Artigo em Inglês | MEDLINE | ID: mdl-38276067

RESUMO

Acute disseminated encephalomyelitis (ADEM) is an inflammatory demyelinating disorder that typically follows an infection or recent vaccination. Symptoms such as encephalopathy and focal neurological deficits appear weeks after the initial illness, leading to swift and progressive neurological decline. While ADEM in the brain has been well documented, reports of ADEM, specifically in the spinal cord, are relatively limited. A 58-year-old male presented with rapidly progressive bilateral lower extremity tingling, numbness, and mild gait disturbance approximately two days prior to visiting the emergency room. Spinal magnetic resonance imaging revealed a diffuse, longitudinal, high-signal lesion with mild enlargement of the conus and proximal cauda equina. The lesions were predominantly localized in the distal conus and cauda equina, and serial electrodiagnostic studies showed that the lesions progressed toward the proximal conus in tandem with symptom evolution and lacked clear lateralization. The patient was subsequently treated with high-dose steroids for seven days (intravenous methylprednisolone, 1 mg/kg). The patient's lower extremity weakness gradually improved and he was able to walk independently under supervision three weeks after symptom onset. In this case of spinal ADEM in a middle-aged adult, high-dose steroid treatment led to outstanding neurological recovery from both the initial occurrence and subsequent attacks.


Assuntos
Encefalomielite Aguda Disseminada , Compressão da Medula Espinal , Masculino , Pessoa de Meia-Idade , Adulto , Humanos , Encefalomielite Aguda Disseminada/diagnóstico , Encefalomielite Aguda Disseminada/tratamento farmacológico , Compressão da Medula Espinal/complicações , Compressão da Medula Espinal/patologia , Encéfalo/patologia , Imageamento por Ressonância Magnética/efeitos adversos , Dano Encefálico Crônico
18.
Medicina (Kaunas) ; 60(1)2024 Jan 10.
Artigo em Inglês | MEDLINE | ID: mdl-38256393

RESUMO

Background and Objectives: Urolithiasis occurrence is uncommon in kidney transplantation patients, though it has serious implications, including acute kidney injury in the transplanted kidney. This study investigates the leading causes of urolithiasis in kidney transplantation patients, the diagnostic process, and the outcomes of multimodal management. Materials and Methods: Data collection spanned from January 1997 to December 2021, involving kidney transplantation patients with urolithiasis from the database of the Korean Society of Endourology and Robotics (KSER) research committee. Analysis encompassed factors triggering urolithiasis, the diagnostic process, stone attributes, treatment methods, and outcomes. Results: Our analysis included 58 kidney transplantation patients with urolithiasis from eight medical centers. Of these patients, 37 were male and 4 had previous urolithiasis diagnoses. The mean age was 59.09 ± 10.70 years, with a mean duration from kidney transplantation to diagnosis of 76.26 ± 183.14 months. The most frequent method of stone detection was through asymptomatic routine check-ups (54.7%). Among the 58 patients, 51 underwent stone treatment. Notably, 95.3% of patients with ureter stones received treatment, a significantly higher rate than the 66.7% of patients with renal stones (p = 0.010). Success rates showed no significant differences between renal (70%) and ureter stone (78.0%) groups (p = 0.881). Conclusions: Urolithiasis in transplanted kidneys constitutes an acute condition requiring emergency intervention. Endo-urological interventions are effective for kidney transplantation patients with urolithiasis. To ensure prevention and early detection, diligent follow-up and routine imaging tests are necessary.


Assuntos
Cálculos Renais , Transplante de Rim , Urolitíase , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Povo Asiático , Rim , Transplante de Rim/efeitos adversos , Urolitíase/etiologia , República da Coreia
19.
Int J Mol Sci ; 25(1)2023 Dec 19.
Artigo em Inglês | MEDLINE | ID: mdl-38203215

RESUMO

Periodontitis is an oral infectious disease caused by various pathogenic bacteria, such as Porphyromonas gingivalis. Although probiotics and their cellular components have demonstrated positive effects on periodontitis, the beneficial impact of peptidoglycan (PGN) from probiotic Lactobacillus remains unclear. Therefore, our study sought to investigate the inhibitory effect of PGN isolated from L. reuteri (LrPGN) on P. gingivalis-induced inflammatory responses. Pretreatment with LrPGN significantly inhibited the production of interleukin (IL)-1ß, IL-6, and CCL20 in RAW 264.7 cells induced by P. gingivalis lipopolysaccharide (LPS). LrPGN reduced the phosphorylation of PI3K/Akt and MAPKs, as well as NF-κB activation, which were induced by P. gingivalis LPS. Furthermore, LrPGN dose-dependently reduced the expression of Toll-like receptor 4 (TLR4), indicating that LrPGN inhibits periodontal inflammation by regulating cellular signaling cascades through TLR4 suppression. Notably, LrPGN exhibited stronger inhibition of P. gingivalis LPS-induced production of inflammatory mediators compared to insoluble LrPGN and proteinase K-treated LrPGN. Moreover, MDP, a minimal bioactive PGN motif, also dose-dependently inhibited P. gingivalis LPS-induced inflammatory mediators, suggesting that MDP-like molecules present in the LrPGN structure may play a crucial role in the inhibition of inflammatory responses. Collectively, these findings suggest that LrPGN can mitigate periodontal inflammation and could be a useful agent for the prevention and treatment of periodontitis.


Assuntos
Endopeptidases , Limosilactobacillus reuteri , Periodontite , Humanos , Receptor 4 Toll-Like , Lipopolissacarídeos/toxicidade , Peptidoglicano/farmacologia , Porphyromonas gingivalis , Fosfatidilinositol 3-Quinases , Inflamação , Mediadores da Inflamação
20.
Medicina (Kaunas) ; 59(12)2023 Dec 11.
Artigo em Inglês | MEDLINE | ID: mdl-38138251

RESUMO

Background and Objectives: Hand grip strength (HGS) and osteoporosis are known to be closely related to the health condition of the elderly, respectively. Comprehensive studies including adults over middle age were insufficient. This study aimed to investigate the relationship between HGS with osteoporosis and health-related quality of life (HRQoL) in adults aged >40 years. Materials and Methods: This cross-sectional analysis included data from 13,966 people aged >40 years between 2015 to 2018 provided by the Korea National Health and Nutrition Examination Survey. The HGS was divided into strong and weak quartiles, defined as the highest and lowest quartiles, respectively. We used the European Quality of Life Scale-Five dimensions (EQ-5D) for HRQoL. We performed multiple logistic regression and post hoc analysis to confirm the relationship between the four groups and HRQoL. Results: Osteoporotic patients with weak HGS showed the lowest EQ-5D index (0.87 ± 0.01) among all groups and had a significantly impaired HRQoL in all EQ-5D dimensions, at least 1.75 times more than healthy individuals with strong HGS (0.95 ± 0.00). Osteoporotic patients with weak HGS showed, notably, 2.68 times more impaired mobility compared to healthy individuals with strong HGS among all five dimensions of the EQ-5D. In self-care, significant sex differences in impaired HRQoL were observed (males 6.03, 2.23-16.35; females 2.51, 1.70-3.71). Conclusions: Weak HGS and the presence of osteoporosis were associated with low HRQoL, respectively. Middle-aged and older adults with both weak HGS and osteoporosis showed poorer HRQoL compared to healthy middle-aged and older adults. This suggests that HGS is a possible factor for predicting poor HRQoL in adults aged >40 years with or without osteoporosis. It is necessary to assess the risk of low HRQoL by measuring HGS and confirming whether osteoporosis is accompanied in adults over middle age.


Assuntos
Osteoporose , Qualidade de Vida , Idoso , Pessoa de Meia-Idade , Humanos , Masculino , Feminino , Inquéritos Nutricionais , Força da Mão , Estudos Transversais , Osteoporose/complicações , Osteoporose/epidemiologia , Inquéritos e Questionários
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