RESUMO
Calcium ions (Ca2+) play pivotal roles in regulating numerous cellular functions, including metabolism and growth, in normal and cancerous cells. Consequently, Ca2+ signaling is a vital determinant of cell fate and influences both cell survival and death. These intracellular signals are susceptible to modulation by various factors, including changes in the extracellular environment, which leads to mechanical alterations. However, the effect of extracellular matrix (ECM) stiffness variations on intracellular Ca2+ signaling remains underexplored. In this study, we aimed to elucidate the mechanisms of Ca2+ regulation through the mitochondria, which are crucial to Ca2+ homeostasis. We investigated how Ca2+ regulatory mechanisms adapt to different levels of ECM stiffness by simultaneously imaging the mitochondria and endoplasmic reticulum (ER) in live cells using genetically encoded biosensors. Our findings revealed that the uptake of mitochondrial Ca2+ through Voltage-Dependent Anion Channel 1 (VDAC1), facilitated by intracellular tubulin, is influenced by ECM stiffness. Unraveling these Ca2+ regulatory mechanisms under various conditions offers a novel perspective for advancing biomedical studies involving Ca2+ signaling.
RESUMO
BACKGROUND: Concomitant use of clopidogrel and proton pump inhibitor (PPI) is common, but PPI may reduce the antiplatelet effects of clopidogrel in patients undergoing percutaneous coronary intervention (PCI). We evaluated the impact of PPI use on clinical outcomes in post-PCI patients, by incorporating P2Y12 reaction unit (PRU) and CYP2C19 genotyping results. METHODS: From a multicenter registry of patients who underwent PCI with drug-eluting stent implantation and received clopidogrel-based dual antiplatelet therapy (DAPT), patients who were prescribed a PPI at the time of PCI (PPI users) were compared to those who were not (non-users). The primary outcome included all-cause death, myocardial infarction, stent thrombosis, or cerebrovascular accident at 12 months. Major bleeding (Bleeding Academic Research Consortium [BARC] types 3-5) and gastrointestinal (GI) bleeding (BARC types 3-5) were important secondary outcomes. The adjusted outcomes were compared using a 1:1 propensity-score (PS) matching and competing risk analysis. RESULTS: Of 13,160 patients, 2,235 (17.0%) were prescribed PPI, with an average age of 65.4 years. PPI users had higher on-treatment PRU levels than non-users. After PS matching, the primary outcome occurred in 51 patients who were PPI users (cumulative incidence, 4.7%) and 41 patients who were non-users (cumulative incidence, 3.7%; log-rank p = 0.27). In carriers of both CYP2C19 loss-of-function alleles, PPI use was linked to an increased risk of the primary outcome (hazard ratio, 3.22; 95% confidence interval, 1.18-8.78). The incidence of major bleeding and GI bleeding (BARC types 3-5) was comparable between PPI users and non-users in the PS-matched cohort. CONCLUSIONS: In post-PCI patients receiving clopidogrel-based DAPT, PPI use was not linked to an increased risk of adverse cardiac and cerebrovascular events, but there was a small but significant increase in on-treatment PRU. Future research using a more individualized approach would further elucidate these interactions and guide evidence-based clinical practices.
Assuntos
Clopidogrel , Citocromo P-450 CYP2C19 , Stents Farmacológicos , Intervenção Coronária Percutânea , Inibidores da Agregação Plaquetária , Inibidores da Bomba de Prótons , Humanos , Clopidogrel/uso terapêutico , Clopidogrel/efeitos adversos , Clopidogrel/administração & dosagem , Inibidores da Bomba de Prótons/efeitos adversos , Inibidores da Bomba de Prótons/uso terapêutico , Inibidores da Bomba de Prótons/administração & dosagem , Masculino , Feminino , Stents Farmacológicos/efeitos adversos , Idoso , Pessoa de Meia-Idade , Inibidores da Agregação Plaquetária/uso terapêutico , Inibidores da Agregação Plaquetária/efeitos adversos , Inibidores da Agregação Plaquetária/administração & dosagem , Intervenção Coronária Percutânea/efeitos adversos , Citocromo P-450 CYP2C19/genética , Resultado do Tratamento , Sistema de Registros , População do Leste AsiáticoRESUMO
BACKGROUND: Hypertensive disorders of pregnancy (HDP) pose significant risks to both maternal and fetal health, contributing to global morbidity and mortality. Management of HDP is complex, particularly because of concerns regarding potential negative effects on utero-placental circulation and limited therapeutic options due to fetal safety. Our study investigates whether blood pressure monitoring through a mobile health (mHealth) application can aid in addressing the challenges of blood pressure management in pregnant individuals with HDP. Additionally, we aim to assess whether this intervention can improve short-term maternal and fetal outcomes and potentially mitigate long-term cardiovascular consequences. METHODS: This prospective, randomized, single-center trial will include 580 pregnant participants who meet the HDP criteria or who have a heightened risk of pregnancy-related hypertension due to factors such as multiple pregnancies, obesity, diabetes, or a history of HDP in prior pregnancies leading to preterm birth. Participants will be randomized to either the mHealth intervention group or the standard care group. The primary endpoint is the difference in systolic blood pressure from enrollment to 1 month after childbirth. The secondary endpoints include various blood pressure parameters, obstetric outcomes, body mass index trajectory, step counts, mood assessment, and drug adherence. CONCLUSIONS: This study emphasizes the potential of mHealth interventions, such as the Heart4U application, to improve blood pressure management in pregnant individuals with HDP. By leveraging technology to enhance engagement, communication, and monitoring, this study aims to positively impact maternal, fetal, and postpartum outcomes associated with HDP. This innovative approach demonstrates the potential of personalized technology-driven solutions for managing complex health conditions. TRIAL REGISTRATION: ClinicalTrials.gov NCT05995106. Registered on 16 August 2023.
Assuntos
Pressão Sanguínea , Hipertensão Induzida pela Gravidez , Aplicativos Móveis , Ensaios Clínicos Controlados Aleatórios como Assunto , Telemedicina , Humanos , Gravidez , Feminino , Estudos Prospectivos , Hipertensão Induzida pela Gravidez/terapia , Hipertensão Induzida pela Gravidez/diagnóstico , Hipertensão Induzida pela Gravidez/fisiopatologia , Anti-Hipertensivos/uso terapêutico , Monitorização Ambulatorial da Pressão Arterial/métodos , Resultado do Tratamento , Adulto , Fatores de TempoRESUMO
Electrocardiogram (ECG) changes after primary percutaneous coronary intervention (PCI) in ST-segment elevation myocardial infarction (STEMI) patients are associated with prognosis. This study investigated the feasibility of predicting left ventricular (LV) dysfunction in STEMI patients using an artificial intelligence (AI)-enabled ECG algorithm developed to diagnose STEMI. Serial ECGs from 637 STEMI patients were analyzed with the AI algorithm, which quantified the probability of STEMI at various time points. The time points included pre-PCI, immediately post-PCI, 6 h post-PCI, 24 h post-PCI, at discharge, and one-month post-PCI. The prevalence of LV dysfunction was significantly associated with the AI-derived probability index. A high probability index was an independent predictor of LV dysfunction, with higher cardiac death and heart failure hospitalization rates observed in patients with higher indices. The study demonstrates that the AI-enabled ECG index effectively quantifies ECG changes post-PCI and serves as a digital biomarker capable of predicting post-STEMI LV dysfunction, heart failure, and mortality. These findings suggest that AI-enabled ECG analysis can be a valuable tool in the early identification of high-risk patients, enabling timely and targeted interventions to improve clinical outcomes in STEMI patients.
Assuntos
Inteligência Artificial , Eletrocardiografia , Infarto do Miocárdio com Supradesnível do Segmento ST , Disfunção Ventricular Esquerda , Humanos , Infarto do Miocárdio com Supradesnível do Segmento ST/complicações , Infarto do Miocárdio com Supradesnível do Segmento ST/fisiopatologia , Infarto do Miocárdio com Supradesnível do Segmento ST/diagnóstico , Infarto do Miocárdio com Supradesnível do Segmento ST/cirurgia , Masculino , Feminino , Disfunção Ventricular Esquerda/fisiopatologia , Disfunção Ventricular Esquerda/diagnóstico , Pessoa de Meia-Idade , Idoso , Prognóstico , Intervenção Coronária Percutânea , AlgoritmosRESUMO
AIM: The aim of this study was to compare the clinicopathological and oncological characteristics of sporadic colorectal cancer (CRC) between young and elderly patients without any genetic mutations that cause hereditary CRC. METHOD: In this cross-sectional, retrospective study conducted at three tertiary referral hospitals, we enrolled 1599 patients with CRC who underwent surgery between January 2010 and December 2017, including 157 young patients (age ≤ 40 years; yCRC) and 1442 elderly patients (age ≥ 70 years; eCRC). The clinicopathological and oncological outcomes were compared between the two groups. RESULTS: The median age at diagnosis was 37 years in the yCRC group (range 33.0-39.2 years) and 76 years in the eCRC group (range 72.0-79.0 years). The yCRC group did not present with advanced stages at diagnosis compared with the eCRC group, and the distribution of tumour stages was similar between the two groups. Microsatellite instability (MSI) testing revealed no difference in the frequency of tumours with high MSI (7.8% in yCRC, 5.8% in eCRC), and the frequency of mutations in the KRAS, NRAS and BRAF genes was also similar. The 3-year overall survival was better in the yCRC group than in the eCRC group (97.4% vs. 83.5%, p < 0.001); however, no such difference was observed in cancer-specific survival. CONCLUSION: Genetically proven sporadic CRCs did not differ significantly between young and elderly patients in terms of tumour stage, tumour location and various molecular features. CLINICAL TRIAL REGISTRATION NUMBER: The study was retrospectively registered with Clinical Trials.gov (no. NCT05601609).
Assuntos
Neoplasias Colorretais , Instabilidade de Microssatélites , Mutação , Proteínas Proto-Oncogênicas B-raf , Adulto , Idoso , Feminino , Humanos , Masculino , Fatores Etários , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Neoplasias Colorretais/mortalidade , Estudos Transversais , GTP Fosfo-Hidrolases/genética , Proteínas de Membrana/genética , Estadiamento de Neoplasias , Proteínas Proto-Oncogênicas B-raf/genética , Proteínas Proto-Oncogênicas p21(ras)/genética , Estudos RetrospectivosRESUMO
Importance: The appropriate follow-up surveillance strategy for patients with acute coronary syndrome (ACS) who have undergone percutaneous coronary intervention (PCI) remains unknown. Objective: To assess clinical outcomes in patients with and without ACS who have undergone high-risk PCI according to a follow-up strategy of routine stress testing at 12 months after PCI vs standard care alone. Design, Setting, and Participants: The POST-PCI (Pragmatic Trial Comparing Symptom-Oriented vs Routine Stress Testing in High-Risk Patients Undergoing Percutaneous Coronary Intervention) trial was a randomized clinical trial that compared follow-up strategies of routine functional testing vs standard care alone 12 months after high-risk PCI. Patients were categorized as presenting with or without ACS. Patients were enrolled in the trial from November 2017 through September 2019, and patients were randomized from 11 sites in South Korea; data analysis was performed in 2022. Intervention: Patients categorized as presenting with or without ACS were randomized to either a routine functional testing or standard care alone follow-up strategy 12 months after high-risk PCI. Main Outcomes and Measures: The primary outcome was a composite of death from any cause, myocardial infarction, or hospitalization for unstable angina at 2 years following randomization. Kaplan-Meier event rates through 2 years and Cox model hazard ratios (HRs) were generated, and interactions were tested. Results: Of 1706 included patients, 350 patients (20.5%) were female, and the mean (SD) patient age was 64.7 (10.3) years. In total, 526 patients (30.8%) presented with ACS. Compared with those without ACS, patients with ACS had a 55% greater risk of the primary outcome (HR, 1.55; 95% CI, 1.03-2.33; P = .03) due to higher event rates in the first year. The 2-year incidences of the primary outcome were similar between strategies of routine functional testing or standard care alone in patients with ACS (functional testing: 16 of 251 [6.6%]; standard care: 23 of 275 [8.5%]; HR, 0.76; 95% CI, 0.40-1.44; P = .39) and in patients without ACS (functional testing: 30 of 598 [5.1%]; standard care: 28 of 582 [4.9%]; HR, 1.04; 95% CI, 0.62-1.74; P = .88) (P for interaction for ACS = .45). Although a landmark analysis suggested that the rates of invasive angiography and repeat revascularization were higher after 1 year in the routine functional testing group, the formal interactions between ACS status and either invasive angiography or repeat revascularization were not significant. Conclusion and Relevance: Despite being at higher risk for adverse clinical events in the first year after PCI than patients without ACS, patients with ACS who had undergone high-risk PCI did not derive incremental benefit from routine surveillance stress testing at 12 months compared with standard care alone during follow-up. Trial Registration: ClinicalTrials.gov Identifier: NCT03217877.
RESUMO
BACKGROUND: Although organs are preserved and quality of life is improved, insufficient evidence is available for the oncologic safety of partial cystectomy in patients with colorectal cancer with suspected bladder invasion. Therefore, we aimed to compare partial and total cystectomy outcomes in patients with pathologically confirmed or clinically suspected bladder invasion. METHODS: Patients with colorectal cancer with suspected bladder invasion who underwent R0 resection from 2000 to 2020 were evaluated. Long-term outcomes were determined in patients with histologically confirmed bladder invasion. RESULTS: Of the 151 consecutive patients, 96 (64.6%) had histologically confirmed bladder involvement, and 105 (69.5%) underwent partial cystectomy. Operative time, estimated blood loss, and reoperation rate in ≤30 days were significantly worse in the total cystectomy group than in the partial cystectomy group. The overall recurrence rate was significantly higher in the total cystectomy group than in the partial cystectomy group (39.1% vs 21.9%; P = .046). Five-year overall survival (75.8% vs 53.2%; P = .006) rates were higher in the partial cystectomy group than in the total cystectomy group; however, disease-free survival (60.8% vs 41.6%; P = .088) rates were similar in patients with suspected bladder invasion. In patients with histologically confirmed bladder invasion, 5-year overall survival rates (78.1% vs 52.1%; P = .017) were higher in the partial cystectomy group than in the total cystectomy group; however, disease-free survival rates (53.4% vs 41.2%; P = .220) did not differ significantly. CONCLUSION: R0 resection is associated with favorable long-term outcomes in patients with locally advanced colorectal cancer. If R0 resection is possible, partial cystectomy is considered safe.
Assuntos
Neoplasias Colorretais , Cistectomia , Invasividade Neoplásica , Neoplasias da Bexiga Urinária , Humanos , Cistectomia/métodos , Masculino , Feminino , Neoplasias Colorretais/cirurgia , Neoplasias Colorretais/patologia , Neoplasias Colorretais/mortalidade , Neoplasias da Bexiga Urinária/cirurgia , Neoplasias da Bexiga Urinária/patologia , Neoplasias da Bexiga Urinária/mortalidade , Pessoa de Meia-Idade , Idoso , Invasividade Neoplásica/patologia , Estudos Retrospectivos , Recidiva Local de Neoplasia/epidemiologia , Recidiva Local de Neoplasia/patologia , Bexiga Urinária/patologia , Bexiga Urinária/cirurgia , Resultado do Tratamento , Intervalo Livre de Doença , Idoso de 80 Anos ou mais , AdultoRESUMO
Rice blast is a destructive fungal disease affecting rice plants at various growth stages, significantly threatening global yield stability. Development of resistant rice cultivars stands as a practical means of disease control. Generally, association mapping with a diversity panel powerfully identifies new alleles controlling trait of interest. On the other hand, utilization of a breeding panel has its advantage that can be directly applied in a breeding program. In this study, we conducted a genome-wide association study (GWAS) for blast resistance using 296 commercial rice cultivars with low population structure but large phenotypic diversity. We attempt to answer the genetic basis behind rice blast resistance among early maturing cultivars by subdividing the population based on its Heading date 1 (Hd1) functionality. Subpopulation-specific GWAS using the mixed linear model (MLM) based on blast nursery screening conducted in three years revealed a total of 26 significant signals, including three nucleotide-binding site leucine-rich repeat (NBS-LRR) genes (Os06g0286500, Os06g0286700, and Os06g0287500) located at Piz locus on chromosome 6, and one at the Pi-ta locus (Os12g0281300) on chromosome 12. Haplotype analysis revealed blast resistance associated with Piz locus was exclusively specific to Type 14 hd1 among japonica rice. Our findings provide valuable insights for breeding blast resistant rice and highlight the applicability of our elite cultivar panel to detect superior alleles associated with important agronomic traits.
RESUMO
BACKGROUND AND PURPOSE: In young patients (aged 18-60 years) with patent foramen ovale (PFO)-associated stroke, percutaneous closure has been found to be useful for preventing recurrent ischemic stroke or transient ischemic attack (TIA). However, it remains unknown whether PFO closure is also beneficial in older patients. METHODS: Patients aged ≥60 years who had a cryptogenic stroke and PFO from ten hospitals in South Korea were included. The effect of PFO closure plus medical therapy over medical therapy alone was assessed by a propensity-score matching method in the overall cohort and in those with a high-risk PFO, characterized by the presence of an atrial septal aneurysm or a large shunt. RESULTS: Out of the 437 patients (mean age, 68.1), 303 (69%) had a high-risk PFO and 161 (37%) patients underwent PFO closure. Over a median follow-up of 3.9 years, recurrent ischemic stroke or TIA developed in 64 (14.6%) patients. In the propensity score-matched cohort of the overall patients (130 pairs), PFO closure was associated with a significantly lower risk of a composite of ischemic stroke or TIA (hazard ratio [HR]: 0.45; 95% confidence interval [CI]: 0.24-0.84; P=0.012), but not for ischemic stroke. In a subgroup analysis of confined to the high-risk PFO patients (116 pairs), PFO closure was associated with significantly lower risks of both the composite of ischemic stroke or TIA (HR: 0.40; 95% CI: 0.21-0.77; P=0.006) and ischemic stroke (HR: 0.47; 95% CI: 0.23-0.95; P=0.035). CONCLUSION: Elderly patients with cryptogenic stroke and PFO have a high recurrence rate of ischemic stroke or TIA, which may be significantly reduced by device closure.
RESUMO
Progranulin (PGRN) haploinsufficiency is a major risk factor for frontotemporal lobar degeneration with TAR DNA-binding protein 43 (TDP-43) pathology (FTLD-GRN). Multiple therapeutic strategies are in clinical development to restore PGRN in the CNS, including gene therapy. However, a limitation of current gene therapy approaches aimed to alleviate FTLD-associated pathologies may be their inefficient brain exposure and biodistribution. We therefore developed an adeno-associated virus (AAV) targeting the liver (L) to achieve sustained peripheral expression of a transferrin receptor (TfR) binding, brain-penetrant (b) PGRN variant [AAV(L):bPGRN] in two mouse models of FTLD-GRN, namely, Grn knockout and GrnxTmem106b double knockout mice. This therapeutic strategy avoids potential safety and biodistribution issues of CNS-administered AAVs and maintains sustained concentrations of PGRN in the brain after a single dose. AAV(L):bPGRN treatment reduced several FTLD-GRN-associated pathologies including severe motor function deficits, aberrant TDP-43 phosphorylation, dysfunctional protein degradation, lipid metabolism, gliosis, and neurodegeneration in the brain. The potential translatability of our findings was tested in an in vitro model using cocultured human induced pluripotent stem cell (hiPSC)-derived microglia lacking PGRN and TMEM106B and wild-type hiPSC-derived neurons. As in mice, aberrant TDP-43, lysosomal dysfunction, and neuronal loss were ameliorated after treatment with exogenous TfR-binding protein transport vehicle fused to PGRN (PTV:PGRN). Together, our studies suggest that peripherally administered brain-penetrant PGRN replacement strategies ameliorate FTLD-GRN relevant phenotypes including TDP-43 pathology, neurodegeneration, and behavioral deficits. Our data provide preclinical proof of concept for the use of this AAV platform for treatment of FTLD-GRN and potentially other CNS disorders.
Assuntos
Encéfalo , Dependovirus , Modelos Animais de Doenças , Degeneração Lobar Frontotemporal , Camundongos Knockout , Progranulinas , Animais , Humanos , Camundongos , Encéfalo/metabolismo , Encéfalo/patologia , Dependovirus/metabolismo , Proteínas de Ligação a DNA/metabolismo , Proteínas de Ligação a DNA/genética , Degeneração Lobar Frontotemporal/metabolismo , Degeneração Lobar Frontotemporal/patologia , Terapia Genética , Fosforilação , Progranulinas/metabolismo , Progranulinas/genética , Receptores da Transferrina/metabolismoRESUMO
BACKGROUND: Carriers of CYP2C19 loss-of-function alleles have increased adverse events after percutaneous coronary intervention, but limited data are available for older patients. We aimed to evaluate the prognostic impact of CYP2C19 genotypes on clinical outcomes in older patients after percutaneous coronary intervention. METHODS AND RESULTS: The study included 1201 older patients (aged ≥75 years) who underwent percutaneous coronary intervention and received clopidogrel-based dual antiplatelet therapy in South Korea. Patients were grouped on the basis of CYP2C19 genotypes. The primary outcome was 3-year major adverse cardiac events, defined as a composite of cardiac death, myocardial infarction, and stent thrombosis. Older patients were grouped into 3 groups: normal metabolizer (36.6%), intermediate metabolizer (48.1%), and poor metabolizer (15.2%). The occurrence of the primary outcome was significantly different among the groups (3.1, 7.0, and 6.2% in the normal metabolizer, intermediate metabolizer, and poor metabolizer groups, respectively; P=0.02). The incidence rate of all-cause death at 3 years was greater in the intermediate metabolizer and poor metabolizer groups (8.1% and 9.2%, respectively) compared with that in the normal metabolizer group (3.5%, P=0.03) without significant differences in major bleeding. In the multivariable analysis, the intermediate metabolizer and poor metabolizer groups were independent predictors of 3-year clinical outcomes. CONCLUSIONS: In older patients, the presence of any CYP2C19 loss-of-function allele was found to be predictive of a higher incidence of major adverse cardiac events within 3 years following percutaneous coronary intervention. This finding suggests a need for further investigation into an optimal antiplatelet strategy for older patients. REGISTRATION: URL: https://clinicaltrials.gov. Identifier: NCT04734028.
Assuntos
Clopidogrel , Citocromo P-450 CYP2C19 , Genótipo , Intervenção Coronária Percutânea , Inibidores da Agregação Plaquetária , Humanos , Citocromo P-450 CYP2C19/genética , Citocromo P-450 CYP2C19/metabolismo , Intervenção Coronária Percutânea/efeitos adversos , Masculino , Feminino , Idoso , Inibidores da Agregação Plaquetária/farmacocinética , Inibidores da Agregação Plaquetária/uso terapêutico , Inibidores da Agregação Plaquetária/efeitos adversos , República da Coreia/epidemiologia , Clopidogrel/farmacocinética , Clopidogrel/uso terapêutico , Clopidogrel/efeitos adversos , Idoso de 80 Anos ou mais , Prognóstico , Resultado do Tratamento , Fatores de Tempo , Doença da Artéria Coronariana/genética , Doença da Artéria Coronariana/cirurgia , Doença da Artéria Coronariana/mortalidade , Doença da Artéria Coronariana/terapia , Fatores de Risco , Terapia Antiplaquetária Dupla/efeitos adversos , Medição de Risco , Fatores Etários , Infarto do Miocárdio/genética , Infarto do Miocárdio/epidemiologia , Variantes FarmacogenômicosRESUMO
This study evaluated the association of atherogenic index of plasma (AIP) with platelet reactivity and clinical outcomes according to acute myocardial infarction (AMI). The composite of 3-year adverse outcomes of all-cause death, myocardial infarction, and cerebrovascular accident was evaluated in 10,735 patients after successful percutaneous coronary intervention with drug-eluting stents. AIP was defined as the base 10 logarithm of the ratio of triglyceride to high-density lipoprotein cholesterol concentration. High platelet reactivity (HPR) was defined as ≥ 252 P2Y12 reactivity unit. An increase of AIP (per-0.1 unit) was related to the decreased risk of HPR [odds ratio (OR) 0.97, 95% confidence interval (CI) 0.96-0.99; P = 0.001] in non-AMI patients, not in AMI patients (OR 0.98, 95% CI 0.96-1.01; P = 0.138). The HPR was associated with the increased risk of composite outcomes in both non-AMI and AMI patients (all-P < 0.05). AIP levels were not independently associated with the risk of composite outcomes in both patients with non-AMI and AMI. In conclusion, an inverse association between AIP and the risk of HPR was observed in patients with non-AMI. This suggests that the association between plasma atherogenicity and platelet reactivity may play a substantial role in the development of AMI.Trial registration: NCT04734028.
Assuntos
Aterosclerose , Plaquetas , Infarto do Miocárdio , Humanos , Infarto do Miocárdio/sangue , Masculino , Feminino , Pessoa de Meia-Idade , Idoso , Plaquetas/metabolismo , Aterosclerose/sangue , Intervenção Coronária Percutânea , Fatores de Risco , Triglicerídeos/sangue , HDL-Colesterol/sangue , Stents Farmacológicos , Ativação PlaquetáriaRESUMO
This study aimed to examine the differences in physical activity (PA) level, fundamental movement skill (FMS), and obesity-related factors in preschoolers. A cross-sectional study was conducted in 426 preschool children aged 3-5 years. Participants were assigned to the low PA group (LPAG), moderate PA group (MPAG), and high PA group (HPAG) according to the total score obtained in the PA questionnaire for young children. FMS and obesity-related factors were also analyzed. PA was compared by age and sex, and FMS and obesity-related factors were compared between groups. Significant differences were found according to sex. Boys were more active than girls in the 3-4 years age group, but no significant differences were observed at the age of 5 years. LPAG showed lower FMS than MPAG and HPAG, although this was not statistically significant. However, body mass index (BMI), BMI z-score, body fat, and muscle mass showed significant differences in terms of PA levels. Consideration of age and sex is crucial in promoting PA among preschoolers. Additionally, better obesity-related factors are associated with higher PA levels, and FMS may be a useful tool in evaluating health and fitness.
RESUMO
BACKGROUND: Although age and body mass index (BMI) significantly affect platelet reactivity units and clinical outcomes after percutaneous coronary intervention, there are limited data on the relationship between high on-treatment platelet reactivity (HPR) and clinical outcomes on age and BMI differences. Thus, we investigated the association of HPR with clinical outcomes according to age and BMI. METHODS AND RESULTS: The study analyzed 11 714 patients who underwent platelet function tests after percutaneous coronary intervention. The primary end point was the occurrence of major adverse cardiac and cerebrovascular events (MACCEs), whereas the secondary end point was major bleeding. HPR was defined as platelet reactivity units ≥252. Patients were categorized by age (<67 years of age or ≥67 years of age) and BMI (≤22.6 kg/m2 or >22.6 kg/m2). Patients <67 years of age with HPR had increases in both MACCEs (adjusted hazard ratio [HR], 1.436 [95% CI, 1.106-1.867]; P=0.007) and major bleeding (adjusted HR, 1.584 [95% CI, 1.095-2.290]; P=0.015) compared with the those with non-HPR, respectively. In patients ≥67 years of age with HPR, there were no differences in MACCEs, but there was a decrease in major bleeding (adjusted HR, 0.721 [95% CI, 0.542-0.959]; P=0.024). Meanwhile, patients with HPR with BMI >22.6 kg/m2 had increases in MACCEs (adjusted HR, 1.387 [95% CI, 1.140-1.688]; P=0.001). No differences were shown in major bleeding. CONCLUSIONS: HPR was linked to an increase in MACCEs or a decrease in major bleeding in patients after percutaneous coronary intervention, depending on age and BMI. This study is the first to observe that clinical outcomes in patients with HPR after percutaneous coronary intervention may vary based on age and BMI. Because the study is observational, the results should be viewed as hypothesis generating and emphasize the need for randomized clinical trials.
Assuntos
Índice de Massa Corporal , Intervenção Coronária Percutânea , Inibidores da Agregação Plaquetária , Testes de Função Plaquetária , Humanos , Masculino , Feminino , Idoso , Pessoa de Meia-Idade , Fatores Etários , Inibidores da Agregação Plaquetária/uso terapêutico , Resultado do Tratamento , Doença da Artéria Coronariana/sangue , Doença da Artéria Coronariana/terapia , Fatores de Risco , Hemorragia/induzido quimicamente , Hemorragia/epidemiologia , Estudos Retrospectivos , Plaquetas/metabolismo , Medição de Risco , População do Leste AsiáticoRESUMO
From extrachromosomal DNA to neo-peptides, the broad reprogramming of the cancer genome leads to the emergence of molecules that are specific to the cancer state. We recently described orphan non-coding RNAs (oncRNAs) as a class of cancer-specific small RNAs with the potential to play functional roles in breast cancer progression1. Here, we report a systematic and comprehensive search to identify, annotate, and characterize cancer-emergent oncRNAs across 32 tumor types. We also leverage large-scale in vivo genetic screens in xenografted mice to functionally identify driver oncRNAs in multiple tumor types. We have not only discovered a large repertoire of oncRNAs, but also found that their presence and absence represent a digital molecular barcode that faithfully captures the types and subtypes of cancer. Importantly, we discovered that this molecular barcode is partially accessible from the cell-free space as some oncRNAs are secreted by cancer cells. In a large retrospective study across 192 breast cancer patients, we showed that oncRNAs can be reliably detected in the blood and that changes in the cell-free oncRNA burden captures both short-term and long-term clinical outcomes upon completion of a neoadjuvant chemotherapy regimen. Together, our findings establish oncRNAs as an emergent class of cancer-specific non-coding RNAs with potential roles in tumor progression and clinical utility in liquid biopsies and disease monitoring.
RESUMO
Background: Complex percutaneous coronary intervention (C-PCI) and high platelet reactivity (HPR) have been proposed as representative risk factors for the high ischemic phenotype. Uncertainty remains regarding the relative prognostic importance of these factors. Objectives: This study aimed to investigate the prognostic implication of HPR according to procedural complexity. Methods: Patients treated with drug-eluting stent implantation (PTRG-PFT cohort; N = 11,714) were classified according to procedural complexity. HPR criteria were determined using VerifyNow (≥252 P2Y12 reaction units). The major adverse cardiac and cerebrovascular events (MACCE) (the composite of all-cause death, myocardial infarction, definite stent thrombosis, or stroke) and major bleeding were assessed for up to 3 years. Results: C-PCI was performed in 3,152 patients (26.9%). C-PCI significantly increased the risk of MACCE (HRadjusted: 1.21; 95% CI: 1.01-1.44; P = 0.035), driven by a higher rate of all-cause death (HRadjusted: 1.45; 95% CI: 1.15-1.83; P = 0.002), although it did not increase the risk of major bleeding. Irrespective of procedural complexity, the HPR phenotype was significantly associated with MACCE (Pinteraction = 0.731) and all-cause mortality (Pinteraction = 0.978), in which the prognostic implication appeared prominent within 1 year. The HPR phenotype did not show a significant interaction with any type of C-PCI. In addition, the number of complexity features per procedure did not proportionally increase the risk of MACCE. Conclusions: C-PCI was significantly associated with 3-year risk of MACCE and all-cause death. The HPR phenotype appears to have a similar prognostic implication irrespective of the type and extent of procedural complexity. (Platelet Function and Genotype-Related Long-Term Prognosis in DES-Treated Patients [PTRG-DES]; NCT04734028).
RESUMO
The increasing prevalence of endocrine-disrupting chemicals (EDCs) in our environment is a growing concern, with numerous studies highlighting their adverse effects on the human endocrine system. Among the EDCs, estrogenic endocrine-disrupting chemicals (eEDCs) are exogenous compounds that perturb estrogenic hormone function by interfering with estrogen receptor (ER) homo (α/α, ß/ß) or hetero (α/ß) dimerization. To date, a comprehensive screening approach for eEDCs affecting all ER dimer forms in live cells is lacking. Here, we developed ER dimerization-detecting biosensors (ERDDBs), based on bioluminescence resonance energy transfer, for dimerization detection and rapid eEDC identification. To enhance the performance of these biosensors, we determined optimal donor and acceptor locations using computational analysis. Additionally, employing HaloTag as the acceptor and incorporating the P2A peptide as a linker yielded the highest sensitivity among the prototypes. We also established stable cell lines to screen potential ER dimerization inducers among estrogen analogs (EAs). The EAs were categorized through cross-comparison of ER dimer responses, utilizing EC values derived from a standard curve established with 17ß-estradiol. We successfully classified 26 of 72 EAs, identifying which ER dimerization types they induce. Overall, our study underscores the effectiveness of the optimized ERDDB for detecting ER dimerization and its applicability in screening and identifying eEDCs.
RESUMO
Purpose: Anal wounds following hemorrhoidectomy can lead to severe pain and postoperative bleeding, impacting patient recovery and quality of life. Hyaluronic acid (HA) stimulates tissue regeneration and wound healing by accelerating cell migration and proliferation. This study aimed to investigate the differences in wound healing rate and completeness of recovery of perianal wounds topically treated with HA-soaked cotton in a murine model. Methods: Forty-eight 8-week-old Sprague-Dawley rats with perianal wounds created using a biopsy punch were divided into 2 groups: simple dressing with gauze (control) and topical HA-soaked cotton. A single application of HA-soaked cotton was administered after surgery. Wound healing rate and completeness of recovery were evaluated by measuring the healed area and conducting histological analyses. Results: The HA-cotton group exhibited a shorter complete wound healing duration compared to the control group (13.9 days vs. 16.4 days, P = 0.031). Differences in wound healing area between the 2 groups were greatest on postoperative day 2 (51.6% vs. 28.8%, P < 0.001). The HA-cotton group exhibited fewer cases of granulation tissue (2 vs. 5) or redness (0 vs. 3) upon complete wound healing. Histologically, the HA-cotton group showed accelerated reepithelialization, rapid shift to lymphocyte-dominant inflammation, enhanced fibroblast proliferation, and increased collagen deposition compared to the control group. Conclusion: Herein, topical application of HA-soaked cotton on perianal wounds in rats resulted in accelerated wound healing, particularly in the initial stages, and improved completeness of recovery, underscoring the potential of the topical application of HA-soaked cotton on hemorrhoidectomy wounds in human patients to improve wound healing.