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Adherence to medication plays a crucial role in the effective management of chronic diseases. However, patients often miss their scheduled drug administrations, resulting in suboptimal disease control. Therefore, we propose an implantable device enabled with automated and precisely timed drug administration. Our device incorporates a built-in mechanical clock movement to utilize a clockwork mechanism, i.e., a periodic turn of the hour axis, enabling automatic drug infusion at precise 12-h intervals. The actuation principle relies on the sophisticated design of the device, where the rotational movement of the hour axis is converted into potential mechanical energy and is abruptly released at the exact moment for drug administration. The clock movement can be charged either automatically by mechanical agitations or manually by winding the crown, while the device remains implanted, thereby enabling the device to be used permanently without the need for batteries. When tested using metoprolol, an antihypertensive drug, in a spontaneously hypertensive animal model, the implanted device can deliver drug automatically at precise 12-h intervals without the need for further attention, leading to similarly effective blood pressure control and ultimately, prevention of ventricular hypertrophy as compared with scheduled drug administrations. These findings suggest that our device is a promising alternative to conventional methods for complex drug administration.
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Fontes de Energia Elétrica , Animais , Humanos , Preparações FarmacêuticasRESUMO
Multinucleated microglia have been observed in contexts associated with infection, inflammation, and aging. Though commonly linked to pathological conditions, the larger cell size of multinucleated microglia might enhance their phagocytic functions, potentially aiding in the clearance of brain debris and suggesting a reassessment of their pathological significance. To assess the phagocytic capacity of multinucleated microglia and its implications for brain debris clearance, we induced their formation by inhibiting Pyk2 activity using the pharmacological inhibitor PF-431396, which triggers cytokinesis regression. Multinucleated microglia demonstrate enhanced phagocytic function, as evidenced by their increased capacity to engulf ß-amyloid (Aß) oligomers. Concurrently, the phosphorylation of Pyk2, induced by Aß peptide, was diminished upon treatment with a Pyk2 inhibitor (Pyk2-Inh, PF-431396). Furthermore, the increased expression of Lamp1, a lysosomal marker, with Pyk2-inh treatment, suggests an enhancement in proteolytic activity. In vivo, we generated an acute Alzheimer's disease (AD) model by infusing Aß into the brains of Iba-1 EGFP transgenic (Tg) mice. The administration of the Pyk2-Inh led to an increased migration of microglia toward amyloid deposits in the brains of Iba-1 EGFP Tg mice, accompanied by morphological activation, suggesting a heightened affinity for Aß. In human microglia, lipopolysaccharide (LPS)-induced inflammatory responses showed that inhibition of Pyk2 signaling significantly reduced the transcription and protein expression of pro-inflammatory markers. These results suggest that Pyk2 inhibition can modulate microglial functions, potentially reducing neuroinflammation and aiding in the clearance of neurodegenerative disease markers. This highlights Pyk2 as a promising target for therapeutic intervention in neurodegenerative diseases.
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Doença de Alzheimer , Peptídeos beta-Amiloides , Modelos Animais de Doenças , Quinase 2 de Adesão Focal , Camundongos Transgênicos , Microglia , Fagocitose , Quinase 2 de Adesão Focal/metabolismo , Quinase 2 de Adesão Focal/antagonistas & inibidores , Animais , Peptídeos beta-Amiloides/metabolismo , Microglia/efeitos dos fármacos , Microglia/metabolismo , Camundongos , Fagocitose/efeitos dos fármacos , Fagocitose/fisiologia , Doença de Alzheimer/patologia , Doença de Alzheimer/metabolismo , Humanos , Camundongos Endogâmicos C57BLRESUMO
BACKGROUNDS: Metabolic dysfunction-associated steatotic liver disease (MASLD) has gained attention owing to its severe complications. This study aimed to explore the interaction between Mediterranean-diet (MD) adherence, genetic factors, and MASLD risk in a Korean population. METHODS: In total, 33,133 individuals aged 40 years and older from the Korean Genome and Epidemiology Study (KoGES) were analyzed. Participants were assessed for MASLD based on criteria and MD adherence measured by the Korean version of the Mediterranean-Diet Adherence Screener (K-MEDAS). Individuals were categorized into two groups based on their MD adherence: high adherence (K-MEDAS > 6) and low adherence (K-MEDAS < 5). Single nucleotide polymorphism (SNP) genotypes were obtained using the Korea Biobank array. Logistic regression was used to examine the single-marker variants for genetic associations with MASLD prevalence. RESULTS: Individuals were categorized into MASLD (10,018 [30.2%]) and non-MASLD (23,115 [69.8%]) groups. A significant interaction was observed between the rs780094 glucokinase regulatory protein (GCKR) gene and K-MEDAS on MASLD (p < 10 - 2 ). Of individuals with K-MEDAS > 6, those carrying the minor allele (C) of the GCKR gene rs780094 exhibited a lower risk of MASLD compared to those without the allele (odds ratio [OR] = 0.88 [0.85-0.91], p-value = 5.54e-13). CONCLUSION: The study identified a significant interaction involving the rs780094 variant near the GCKR gene, with carriers of the minor allele exhibiting a lower MASLD risk among those adhering well to the MD. Dietary habits influence the MASLD risk associated with the rs780094 allele, emphasizing the need for personalized nutrition recommendations.
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Dieta Mediterrânea , Cooperação do Paciente , Polimorfismo de Nucleotídeo Único , Humanos , Masculino , Feminino , República da Coreia/epidemiologia , Polimorfismo de Nucleotídeo Único/genética , Pessoa de Meia-Idade , Fatores de Risco , Fígado Gorduroso/genética , Predisposição Genética para Doença , Adulto , Proteínas Adaptadoras de Transdução de Sinal/genética , Idoso , Doenças Metabólicas/genética , Doenças Metabólicas/epidemiologiaRESUMO
BACKGROUND: Paclitaxel is commonly used as a second-line therapy for advanced gastric cancer (AGC). The decision to proceed with second-line chemotherapy and select an appropriate regimen is critical for vulnerable patients with AGC progressing after first-line chemotherapy. However, no predictive biomarkers exist to identify patients with AGC who would benefit from paclitaxel-based chemotherapy. METHODS: This study included 288 patients with AGC receiving second-line paclitaxel-based chemotherapy between 2017 and 2022 as part of the K-MASTER project, a nationwide government-funded precision medicine initiative. The data included clinical (age [young-onset vs. others], sex, histology [intestinal vs. diffuse type], prior trastuzumab use, duration of first-line chemotherapy), and genomic factors (pathogenic or likely pathogenic variants). Data were randomly divided into training and validation sets (0.8:0.2). Four machine learning (ML) methods, namely random forest (RF), logistic regression (LR), artificial neural network (ANN), and ANN with genetic embedding (ANN with GE), were used to develop the prediction model and validated in the validation sets. RESULTS: The median patient age was 64 years (range 25-91), and 65.6% of those were male. A total of 288 patients were divided into the training (n = 230) and validation (n = 58) sets. No significant differences existed in baseline characteristics between the training and validation sets. In the training set, the areas under the ROC curves (AUROC) for predicting better progression-free survival (PFS) with paclitaxel-based chemotherapy were 0.499, 0.679, 0.618, and 0.732 in the RF, LR, ANN, and ANN with GE models, respectively. The ANN with the GE model that achieved the highest AUROC recorded accuracy, sensitivity, specificity, and F1-score performance of 0.458, 0.912, 0.724, and 0.579, respectively. In the validation set, the ANN with GE model predicted that paclitaxel-sensitive patients had significantly longer PFS (median PFS 7.59 vs. 2.07 months, P = 0.020) and overall survival (OS) (median OS 14.70 vs. 7.50 months, P = 0.008). The LR model predicted that paclitaxel-sensitive patients showed a trend for longer PFS (median PFS 6.48 vs. 2.33 months, P = 0.078) and OS (median OS 12.20 vs. 8.61 months, P = 0.099). CONCLUSIONS: These ML models, integrated with clinical and genomic factors, offer the possibility to help identify patients with AGC who may benefit from paclitaxel chemotherapy.
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Neoplasias Gástricas , Humanos , Masculino , Adulto , Pessoa de Meia-Idade , Idoso , Idoso de 80 Anos ou mais , Feminino , Neoplasias Gástricas/tratamento farmacológico , Neoplasias Gástricas/genética , Paclitaxel/uso terapêutico , Trastuzumab/uso terapêutico , Intervalo Livre de Progressão , Genômica , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêuticoRESUMO
BACKGROUND: Tandem high-dose chemotherapy and autologous stem cell transplantation (HDCT/auto-SCT) and incorporation of 131I-metaiodobenzylguanidine (131I-MIBG) treatment have shown positive outcomes in high-risk neuroblastoma. However, more optimized treatment strategies are still needed. PROCEDURE: The NB-2014 study was a nonrandomized, prospective trial that examined survival outcomes in metastatic high-risk neuroblastoma patients using response-adapted consolidation therapy. We used post-induction residual 123I-MIBG status at metastatic sites as a treatment response marker. Patients achieving complete resolution of MIBG uptake at metastatic sites underwent a reduced first HDCT/auto-SCT with a 20% dose reduction in HDCT. After the first HDCT/auto-SCT, patients with remaining MIBG uptake received dose-escalated (18 mCi/kg) 131I-MIBG treatment. In contrast, those with complete resolution of MIBG at metastatic sites received a standard dose (12 mCi/kg) of 131I-MIBG. We compared survival and toxicity outcomes with a historical control group from the NB-2009. RESULTS: Of 65 patients treated, 63% achieved complete resolution of MIBG uptake at metastatic sites following induction chemotherapy, while 29% of patients still had MIBG uptake at metastatic sites after the first HDCT/auto-SCT. The 3-year event-free survival (EFS) and overall survival (OS) rates were 68.2% ± 6.0% and 86.5% ± 4.5%, respectively. Compared to NB-2009, EFS was similar (p = .855); however, NB-2014 had a higher OS (p = .031), a lower cumulative incidence of treatment-related mortality (p = .036), and fewer acute and late toxicities. CONCLUSIONS: Our results suggest that response-adaptive consolidation therapy based on chemotherapy response at metastatic sites facilitates better treatment tailoring, and appears promising for patients with metastatic high-risk neuroblastoma.
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3-Iodobenzilguanidina , Quimioterapia de Consolidação , Neuroblastoma , Humanos , Neuroblastoma/terapia , Neuroblastoma/mortalidade , Neuroblastoma/patologia , Neuroblastoma/tratamento farmacológico , Feminino , Masculino , Pré-Escolar , Lactente , Criança , 3-Iodobenzilguanidina/uso terapêutico , Estudos Prospectivos , Taxa de Sobrevida , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Adolescente , Seguimentos , Transplante Autólogo , Prognóstico , Transplante de Células-Tronco Hematopoéticas , Compostos RadiofarmacêuticosRESUMO
Although Argonaute (AGO) proteins have been the focus of microRNA (miRNA) studies, we observed AGO-free mature miRNAs directly interacting with RNA-binding proteins, implying the sophisticated nature of fine-tuning gene regulation by miRNAs. To investigate microRNA-binding proteins (miRBPs) globally, we analyzed PAR-CLIP data sets to identify RBP quaking (QKI) as a novel miRBP for let-7b. Potential existence of AGO-free miRNAs were further verified by measuring miRNA levels in genetically engineered AGO-depleted human and mouse cells. We have shown that QKI regulates miRNA-mediated gene silencing at multiple steps, and collectively serves as an auxiliary factor empowering AGO2/let-7b-mediated gene silencing. Depletion of QKI decreases interaction of AGO2 with let-7b and target mRNA, consequently controlling target mRNA decay. This finding indicates that QKI is a complementary factor in miRNA-mediated mRNA decay. QKI, however, also suppresses the dissociation of let-7b from AGO2, and slows the assembly of AGO2/miRNA/target mRNA complexes at the single-molecule level. We also revealed that QKI overexpression suppresses cMYC expression at post-transcriptional level, and decreases proliferation and migration of HeLa cells, demonstrating that QKI is a tumour suppressor gene by in part augmenting let-7b activity. Our data show that QKI is a new type of RBP implicated in the versatile regulation of miRNA-mediated gene silencing.
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MicroRNAs , Humanos , Animais , Camundongos , MicroRNAs/genética , MicroRNAs/metabolismo , Células HeLa , Inativação Gênica , Proteínas de Ligação a RNA/genética , Proteínas de Ligação a RNA/metabolismo , Proteínas Argonautas/genética , Proteínas Argonautas/metabolismo , RNA Mensageiro/genéticaRESUMO
BACKGROUND: Differences in clinical efficacy based on the fluence of fractional picosecond laser treatment for acne scars are unknown. OBJECTIVE: To compare the efficacy and safety of low-fluence versus high-fluence fractional picosecond Nd:YAG 1064-nm laser treatment in acne scar patients. METHODS: In this 12-week, investigator-blinded, randomized, split-face study, 25 patients with moderate-to-severe acne scars received three sessions of high-fluence laser treatment (1.0 J/cm2 ) on one side of their face and low-fluence (0.3 J/cm2 ) on the other side every 4 weeks. Patients were assessed using acne scar counts, the scar global assessment (SGA), and the ECCA scar grading scale every 4 weeks. The histological analysis compared the acne scars obtained before and 4 weeks after treatment. RESULTS: At their last visit, 88.00% and 92.00% of the subjects achieved >30% reduction in scar counts on the low- and high-fluence sides, respectively, without a significant difference between the two sides. On both sides, the scar counts, SGA, and ECCA score significantly improved 4 weeks after the last treatment. Although the high-fluence side showed a greater reduction in scar counts (-66.73%) than the low-fluence side (-62.13%), the two sides had no significant difference in the grading scores. The high-fluence side showed significantly more severe pain and higher side-effect scores immediately and 4 weeks after treatment. Histological analysis revealed a significantly increased collagen, elastin, and vimentin expression after treatment on the low-fluence side. CONCLUSIONS: The low-fluence setting demonstrated comparable efficacy and superior safety in treating acne scars compared with the high-fluence setting.
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Acne Vulgar , Lasers de Estado Sólido , Humanos , Cicatriz/etiologia , Cicatriz/radioterapia , Acne Vulgar/complicações , Acne Vulgar/radioterapia , Resultado do Tratamento , Lasers de Estado Sólido/efeitos adversos , ElastinaRESUMO
PURPOSE: We aimed to assess the effects of different exercise modalities on cardiometabolic risk factors within a comprehensive, representative sample of the Korean population. METHODS: We categorized 13,971 adult participants into aerobic exercise (AE), resistance exercise (RE), combined aerobic and resistance exercise (TE), insufficient exercise, and inactive groups. Multivariable regressions were conducted to compare the incidence of chronic diseases across the groups before and after propensity score matching (PSM). RESULTS: The TE and RE groups had significantly lower waist circumference (WC), mean blood pressure (BP), glucose and insulin-related indices, and white blood cell count (WBC) measures, with TE showing the most significant differences. The TE group had significantly lower triglyceride levels and higher high-density lipoprotein-cholesterol levels. Post-PSM, the TE group had the lowest risk for metabolic syndrome, hypertension, and diabetes, closely followed by the RE group when compared with the inactive group. In a subgroup analysis, RE consistently exhibited benefits including lower body mass index, WC, BP, total cholesterol, glucose and insulin-related indices, and WBC count when compared with AE. RE may be associated with reduced incidence of cardiometabolic diseases compared to AE alone. CONCLUSION: TE appears to be associated with significant reduction in cardiometabolic risk in Korean adults. RE possibly provides a more favorable cardiometabolic effect than AE.
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Fatores de Risco Cardiometabólico , Exercício Físico , Pontuação de Propensão , Humanos , República da Coreia/epidemiologia , Masculino , Feminino , Adulto , Pessoa de Meia-Idade , Doenças Cardiovasculares/epidemiologia , Doenças Cardiovasculares/prevenção & controle , Síndrome Metabólica/epidemiologia , Idoso , Fatores de RiscoRESUMO
BACKGROUND: To evaluate the effects of local radiotherapy (RT) on growth, we evaluated the chronological growth profiles and vertebral features of children with high-risk neuroblastoma. METHODS: Thirty-eight children who received local photon or proton beam therapy to the abdomen or retroperitoneum between January 2014 and September 2019 were included. Simple radiography of the thoracolumbar spine was performed before and every year after RT. The height and vertical length of the irradiated vertebral bodies (VBs) compared with the unirradiated VBs (vertebral body ratio, VBR) were analyzed using the linear mixed model. Shape feature analysis was performed to compare the irradiated and unirradiated vertebrae. RESULTS: The follow-up was a median of 53.5 months (range, 21-81 months) after RT. A decline in height z-scores was mainly found in the early phase after treatment. In the linear mixed model with height, the initial height (fixed, p < 0.001), sex (time interaction, p = 0.008), endocrine dysfunction (time interaction, 0.019), and age at diagnosis (fixed and time interaction, both p = 0.002) were significant. Unlike the trend in height, the change in VBR (ΔVBR) decreased gradually (p < 0.001). The ΔVBR in the group that received more than 30 Gy decreased more than in the group that received smaller doses. In the shape feature analysis, the irradiated VBs changed to a more irregular surface that were neither round nor rectangular. CONCLUSION: The irradiated VBs in children were gradually restricted compared to the unirradiated VBs in long-term follow-up, and higher RT doses were significantly affected. Radiation-induced irregular features of VBs were observed.
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Neuroblastoma , Humanos , Neuroblastoma/radioterapia , Neuroblastoma/diagnóstico por imagem , Masculino , Feminino , Pré-Escolar , Criança , Lactente , Seguimentos , Estudos Retrospectivos , Estatura/efeitos da radiação , Vértebras Torácicas/efeitos da radiação , Vértebras Torácicas/diagnóstico por imagem , Vértebras Lombares/efeitos da radiação , Vértebras Lombares/diagnóstico por imagem , Neoplasias Abdominais/radioterapia , Neoplasias Abdominais/diagnóstico por imagem , Corpo Vertebral/diagnóstico por imagem , Corpo Vertebral/efeitos da radiação , Terapia com Prótons/efeitos adversos , Neoplasias Retroperitoneais/radioterapia , Neoplasias Retroperitoneais/diagnóstico por imagemRESUMO
mRNA vaccines have emerged as a pivotal tool in combating COVID-19, offering an advanced approach to immunization. A key challenge with these vaccines is their need for extremely-low-temperature storage, which affects their stability and shelf life. Our research addresses this issue by enhancing the stability of mRNA vaccines through a novel cationic lipid, O,O'-dimyristyl-N-lysyl aspartate (DMKD). DMKD effectively binds with mRNA, improving vaccine stability. We also integrated phosphatidylserine (PS) into the formulation to boost immune response by promoting the uptake of these nanoparticles by immune cells. Our findings reveal that DMKD-PS nanoparticles maintain structural integrity under long-term refrigeration and effectively protect mRNA. When tested, these nanoparticles containing green fluorescent protein (GFP) mRNA outperformed other commercial lipid nanoparticles in protein expression, both in immune cells (RAW 264.7 mouse macrophage) and non-immune cells (CT26 mouse colorectal carcinoma cells). Importantly, in vivo studies show that DMKD-PS nanoparticles are safely eliminated from the body within 48 h. The results suggest that DMKD-PS nanoparticles present a promising alternative for mRNA vaccine delivery, enhancing both the stability and effectiveness of these vaccines.
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Lipossomos , Nanopartículas , Vacinas , Animais , Camundongos , RNA Mensageiro/química , Vacinas de mRNA , Transfecção , Células Apresentadoras de Antígenos , Nanopartículas/químicaRESUMO
We reviewed the medical records of five patients with T-B+NK- severe combined immunodeficiency (SCID) who received minimal dose allogeneic hematopoietic cell transplantation (HCT) (total nucleated cell count (TNC) lower than 1.0 × 108/kg). Patients were administered a median of 5.0 mL of bone marrow or peripheral blood without conditioning (in four) or with anti-thymocyte globulin alone (in one). Three patients received HCT from a matched sibling donor, one from unrelated donor, and one from familial mismatched donor. The median TNC and CD34+ cells were 0.54 (0.29-0.84) × 108/kg and 0.61 (0.35-0.84) × 106/kg, respectively. Engraftment was achieved in all. Total T cell, CD4+ cell, and CD8+ cell recovery was obtained within a year in four, and immunoglobulin replacement was discontinued in all. All patients survived, exhibiting stable donor chimerism. We obtained sufficient therapeutic effects with minimal dose transplantation without intensive conditioning in patients with T-B+NK- SCID.
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Doença Enxerto-Hospedeiro , Transplante de Células-Tronco Hematopoéticas , Imunodeficiência Combinada Severa , Humanos , Imunodeficiência Combinada Severa/terapia , Condicionamento Pré-Transplante , Linfócitos T CD4-Positivos , Células Matadoras NaturaisRESUMO
INTRODUCTION: Lung cancer is one of the most malignant cancers and the leading cause of cancer-related deaths worldwide, while acquired chemoresistance would represent a major problem in the treatment of non-small cell lung cancer (NSCLC) because of the reduced treatment effect and increased rates of recurrence. METHODS: To establish the chemoresistant NSCLC cells, doxorubicin was treated to A549 cells over 3 months at gradually increasing concentrations from 0.03 to 0.5 µM. Real-time PCR and Western blotting were employed for investigating mRNA and protein expression of the glutathione peroxidase (GPX) protein family and multidrug resistance protein 1 (MRP1) in A549 and A549/CR cells. We also employed gas chromatography mass-spectrometry and nano electrospray ionization mass-spectrometry coupled with multivariate statistical analysis to characterize the unique metabolic and lipidomic profiles of chemoresistant NSCLC cells in order to identify potential therapeutic targets. RESULTS: Reactive oxygen species levels were decreased, and mRNA and protein levels of GPX2 and multidrug resistance protein 1 (MRP1) were increased in A549/CR. We identified 87 metabolites and intact lipid species in A549 and A549/CR. Among these metabolites, lactic acid, glutamic acid, glycine, proline, aspartic acid, succinic acid, and ceramide, alongside the PC to PE ratio, and arachidonic acid-containing phospholipids were suggested as characteristic features of chemoresistant NSCLC cells (A549/CR). CONCLUSIONS: This study reveals characteristic feature differences between drug-resistance NSCLC cells and their parental cells. We suggest potential therapeutic targets in chemoresistant NSCLC. Our results provide new insight into metabolic and lipidomic alterations in chemoresistant NSCLC. This could be used as fundamental information to develop therapeutic strategies for the treatment of chemoresistant NSCLC patients.
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Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Humanos , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Membro 1 da Subfamília B de Cassetes de Ligação de ATP , Lipidômica , MetabolômicaRESUMO
BACKGROUND: Patients with breast cancer undergo various treatments according to their tumor subtype and cancer stages within 1 year after being diagnosed. Each treatment may cause treatment-related symptoms that have negative impacts on patients' health and quality of life (QoL) The symptoms can be mitigated when exercise interventions are appropriately applied to patients' physical and mental conditions. Although many exercise programs were developed and implemented during this period, the effects of tailored exercise programs according to symptoms and cancer trajectories on patients' long-term health outcomes have not yet been fully elucidated. Therefore, this randomized controlled trial (RCT) aims to investigate the effect of tailored home-based exercise programs on short-term and long-term physiological outcomes in patients with breast cancer. METHODS: This 12-month RCT includes 96 patients with (stages 1-3) breast cancer randomly assigned to the exercise or control groups. Participants in the exercise group will receive an exercise program tailored to their phase of treatment, type of surgery, and physical function. During post-operative recovery, exercise interventions will be emphasized to improve shoulder range of motion (ROM) and strength. During chemoradiation therapy, exercise intervention will focus on improving physical function and preventing loss of muscle mass. Once chemoradiation therapy is completed, exercise intervention will focus on improving cardiopulmonary fitness and insulin resistance. All interventions will be home-based exercise programs supplemented with once-monthly exercise education and counseling sessions. The main outcome of the study is fasting insulin level at baseline, 6 months, and 1 year post-intervention. Our secondary outcomes include shoulder ROM and strength at 1 month and 3 months, body composition, inflammatory markers, microbiome, QoL, and physical activity levels at 1 month, 6 months, and 1 year post-intervention. CONCLUSION: This trial is the first tailored home-based exercise oncology trial to better understand the comprehensive phase-dependent short- and long-term effects of exercise on shoulder function, body composition, fasting insulin, biomarkers, and microbiome. The results of this study will inform the development of effective exercise programs tailored to the needs of patients with breast cancer post-operatively. TRIAL REGISTRATION: The protocol for this study is registered with the Korean Clinical Trials Registry (KCT0007853).
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Neoplasias da Mama , Insulinas , Humanos , Feminino , Neoplasias da Mama/terapia , Exercício Físico , Terapia por Exercício , Oncologia , Ensaios Clínicos Controlados Aleatórios como AssuntoRESUMO
In this study we observed that human GD1c/GT1a/GQ1b synthase (hST8Sia V) is particularly expressed in human glioblastoma cells. To address the mechanism regulating human glioblastoma-specific gene expression of the hST8Sia V, after the transcription start site (TSS) was identified by the 5'-rapid amplification of cDNA end with total RNA from human glioblastoma U87MG cells, the 5'-flanking region (2.5 kb) of the hST8Sia V gene was isolated and its promoter activity was examined. By luciferase reporter assay, this 5'-flanking region revealed strong promoter activity in only U-87MG cells, but not in other tissue-derived cancer cells. 5'-deletion mutant analysis showed that the region from -1140 to -494 is crucial for transcription of the hST8Sia V gene in U87MG cells. This region contains the activator protein-1 (AP-1) binding site, the main target of the c-Jun N-terminal kinase (JNK) downstream. The AP-1 binding site at -1043/-1037 was proved to be indispensable for the hST8Sia V gene-specific expression in U87MG cells by site-directed mutagenesis. Moreover, the transcriptional activation of hST8Sia V gene in U87MG cells was strongly inhibited by a specific JNK inhibitor, SP600125. These results suggest that the hST8Sia V gene-specific expression in U87MG cells is controlled by JNK/AP-1 signaling pathway.
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Glioblastoma , Humanos , Glioblastoma/genética , Fator de Transcrição AP-1/genética , Regiões Promotoras Genéticas/genética , Ativação TranscricionalRESUMO
OBJECTIVES: To investigate the incidence, risk factors, and clinical outcomes of pleuroparenchymal fibroelastosis (PPFE) in pediatric hematopoietic stem cell transplantation (HSCT) recipients. METHODS: This single-center, retrospective, case-control study included 738 consecutive patients who underwent chest CT more than 3 months after HSCT. We identified patients who fulfilled the diagnostic criteria for PPFE and assessed their clinical characteristics and radiologic findings. Propensity score-matched analysis was performed using four covariates (age, sex, HSCT type, and primary disease). The risk factors and clinical outcomes of PPFE were analyzed using the Fine and Gray regression model and stratified log-rank test in the matched groups. RESULTS: PPFE was identified in 4% (31/738, 8.3 ± 3.1 years, 15 males) of the pediatric HSCT recipients with a median time of 2.7 years after HSCT, and it occurred following allogeneic (5%, 15/317), autologous (4%, 15/379), or both (2%, 1/42). Matching yielded 30 and 130 cases in the PPFE and control groups, respectively. The PPFE group showed more frequent late-onset noninfectious pulmonary complications (LONIPCs) and pneumonia more than 3 months after HSCT (p < 0.05). Multivariable analysis showed a significantly higher risk of PPFE in HSCT recipients who had pneumonia more than 3 months after HSCT (hazard ratio = 10.78 [95% confidence interval: 4.29, 27.13], p < 0.001). The PPFE group showed higher mortality (73%, 22/30) and poorer median overall survival (6.8 years [95% confidence interval: 4.1, 9.5]) than the control group (p < 0.001). CONCLUSIONS: PPFE represents a severe type of LONIPC after HSCT. HSCT recipients with pneumonia after HSCT may have an increased risk of PPFE. KEY POINTS: ⢠The incidence of pleuroparenchymal fibroelastosis is not negligible (4%), and it can occur after either allogeneic or autologous hematopoietic stem cell transplantation. ⢠Pleuroparenchymal fibroelastosis after hematopoietic stem cell transplantation showed poor outcome with a high mortality rate of 73% and median overall survival of 6.8 years. ⢠After hematopoietic stem cell transplantation, pneumonia may increase the risk of pleuroparenchymal fibroelastosis development in children. ⢠Lung biopsy should not be indicated in patients with pleuroparenchymal fibroelastosis findings on chest CT as it can cause refractory pneumothorax without helping the diagnosis.
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Transplante de Células-Tronco Hematopoéticas , Doenças Pulmonares Intersticiais , Masculino , Humanos , Criança , Doenças Pulmonares Intersticiais/epidemiologia , Doenças Pulmonares Intersticiais/etiologia , Estudos Retrospectivos , Estudos de Casos e Controles , Pontuação de Propensão , Transplante de Células-Tronco Hematopoéticas/efeitos adversosRESUMO
BACKGROUND: Patients with relapsed osteosarcoma have poor treatment outcomes. High-dose chemotherapy with autologous stem cell transplantation (HDCT/ASCT) has been used in several high-risk malignant solid tumors; however, few studies have evaluated their role in treating osteosarcoma. We evaluated the effectiveness of HDCT/ASCT in relapsed pediatric osteosarcoma cases. PROCEDURE: We retrospectively reviewed the medical records of 40 patients diagnosed with and treated for relapsed osteosarcoma at Asan Medical Center and Samsung Medical Center from January 1996 to July 2019. RESULTS: The median age of this cohort was 13.4 years (range: 6.1-18.2). The cohort's 5-year overall survival (OS) was 51.0% ± 0.1% during a median follow-up period of 67.5 months. Twenty-five patients (62.5%) achieved complete remission (CR) with salvage treatment, and the 5-year OS was 82.4% ± 0.1%, whereas none of the remaining 15 patients who did not achieve CR survived (p < .0001). Of the 25 CR cases, 15 underwent subsequent HDCT/ASCT. We compared the effect of HDCT/ASCT among patients who achieved CR. There were no significant differences in the 5-year OS outcomes between patients who did and did not receive HDCT/ASCT (83.9% ± 0.1%, 13/15 vs. 80.0% ± 0.1%, 8/10, respectively; p = .923). CONCLUSION: To our knowledge, we report the first comparative cohort study that proved HDCT/ASCT does not significantly improve survival outcomes in relapsed osteosarcoma. Achievement of CR remains the most crucial factor for good survival outcomes.
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Transplante de Células-Tronco Hematopoéticas , Osteossarcoma , Humanos , Criança , Adolescente , Estudos Retrospectivos , Estudos de Coortes , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Transplante Autólogo , Intervalo Livre de Doença , Transplante de Células-TroncoRESUMO
BACKGROUND: Periodontal diseases are closely connected with insulin resistance (IR) and metabolic syndrome. The Triglyceride Glucose Index (TyG) assesses IR, and recently, a few indices combining TyG and body composition have emerged with higher IR predictive performance than TyG alone. We aimed to examine which TyG-related parameters are most helpful in predicting the risk of periodontal disease. METHODS: From 2013 to 2015, data were collected through the Korean National Health and Nutrition Examination Survey. Periodontitis was defined using the Community Periodontal Index. TyG-body mass index (BMI), TyG-waist circumference (WC), and TyG-waist-to-height ratio (WHtR) were calculated by multiplying TyG index score by BMI, WC, and WHtR, respectively. Multiple logistic regression analysis was used to calculate odds ratio (OR) and 95% confidence intervals (CI). Receiver operating characteristic curves were used to estimate areas under the curve (AUC). RESULTS: Compared to each reference quartile (Q)1, Q4 of the TyG index, TyG-BMI, TyG-WC, and TyG-WHtR were significantly associated with a higher risk of periodontitis after adjusting for confounders (OR, 95% CI; 1.23, 1.01-1.49 for TyG; 1.63, 1.22-2.17 for TyG-BMI; 1.37, 1.04-1.81 for TyG-WC; and 1.53, 1.16-2.02 for TyG-WHtR). The AUC and 95% CIs of TyG, TyG-BMI, TyG-WC, and TyG-WHtR in predicting periodontitis were 0.609 (0.600-0.617), 0.605 (0.596-0.617), 0.629 (0.621-0.637), and 0.636 (0.628-0.644), respectively (all p < .001). CONCLUSIONS: TyG, TyG-BMI, TyG-WC, and TyG-WHtR appear to be significantly associated with the prevalence of periodontitis. Among the TyG and modified TyG indices, TyG-WHtR exhibited the highest predictive performance for periodontitis.
Assuntos
Resistência à Insulina , Periodontite , Adulto , Humanos , Glucose , Triglicerídeos , Fatores de Risco , Inquéritos Nutricionais , Índice de Massa Corporal , Periodontite/epidemiologia , República da Coreia/epidemiologiaRESUMO
BACKGROUND: Although the atherogenic index of plasma (AIP) based on a single measurement is a known risk factor for cardiovascular disease (CVD), little is known about whether changes in AIP over time are related to incident CVD. We aimed to determine whether AIP trajectory, which reflects homogenous AIP trends for a particular period, is associated with CVD risk. METHODS: Data from 5,843 participants of the Korean Genome and Epidemiology Study (KoGES) were analyzed. The KoGES had been conducted biennially from the baseline survey (2001-2002) to the eighth follow-up survey (2017-2018). The research design specifies the exposure period from baseline to the third follow-up, designates the latent period at the fourth follow-up, and establishes the event accrual period from the fifth to the eighth follow-up. During the exposure period, we identified two trajectories: a decreasing (n = 3,036) and an increasing group (n = 2,807) using latent variable mixture modeling. Information on CVD was collected initially through the self-reporting, followed by in depth person-to-person interview conducted by a well-trained examiner. During the event accrual period, the cumulative incidence rates of CVD between the two AIP trajectory groups were estimated using Kaplan-Meier analysis with the log-rank test. Multiple Cox proportional hazard models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs). RESULTS: The increasing AIP trajectory group had a significantly higher cumulative incidence rate of CVD than the decreasing AIP trajectory group. Compared to the decreasing AIP trajectory group, the increasing AIP trajectory group had a higher risk of incident CVD (HR: 1.31, 95% CI: 1.02-1.69) after adjusting for confounders. CONCLUSIONS: The risk of incident CVD increased when the AIP level showed an increasing trend and remained high over a long period. This suggests that checking and managing the trajectory of the AIP can be a preventive strategy for incident CVD.
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PURPOSE: Adequate physical activity (PA) can significantly contribute to the prevention of undesirable health outcomes in childhood cancer survivors (CCS). This study aimed to identify the patterns of PA and related factors in Korean CCS. METHODS: Study subjects were 184 adolescents selected from an ongoing cohort study of Korean CCS and 1,840 sex- and school grade-matched controls randomly selected from the participants of the 2019 Korea Youth Risk Behavior Web-based Survey. Information on PA and sedentary behaviors was collected by self-administered questionnaire. We estimated body mass index (BMI)-adjusted odds ratio (OR) and 95% confidence interval (CI) for the advisable healthy behaviors of CCS compared with healthy controls using conditional logistic regression analysis. In addition, the associations of advisable healthy behaviors of CCS with sociodemographic and clinical factors were estimated using multiple logistic regression analysis. RESULTS: CCS were less likely to be physically active than controls, but this finding was evident only in males. The ORs (95% CIs) for regular exercise, moderate intensity PA, vigorous intensity PA, and walking were 0.42 (0.27-0.65), 0.39 (0.24-0.63), 0.53 (0.33-0.84), and 0.64 (0.42-0.98), respectively, in male CCS compared with same-sex controls. Compared with same-sex controls, male CCS were 4.60 times and female survivors were 15.19 times more likely to sleep longer than 8 h a day. Among CCS, males were 2.92 times and 3.07 times more likely to perform moderate intensity PA and muscle-strengthening exercise, respectively, than female. Higher BMI (OR: 1.16), highest family income (OR: 3.98), and a caregiver who performed regular exercise (OR: 2.08) were positively associated with vigorous intensity PA of CCS. With increasing time after treatment completion, the probability of engaging in sedentary activity for less than 6 h per day decreased (OR = 0.89, 95% CI 0.79-1.00). CONCLUSION: Korean adolescent CCS were physically inactive compared with control adolescents. Several sociodemographic factors such as sex, family income, caregiver PA, and obesity level were associated with PA behaviors of CCS. IMPLICATIONS: Strategic effort would be needed to increase physical activity of childhood cancer survivors in adolescent period with consideration of various sociodemographic factors found in this study.
Assuntos
Sobreviventes de Câncer , Neoplasias , Adolescente , Criança , Feminino , Humanos , Masculino , Estudos de Coortes , Exercício Físico , Neoplasias/terapia , República da Coreia , Autorrelato , Estudos de Casos e ControlesRESUMO
The aim of this study was to examine trends in serum uric acid (SUA) levels over a recent 5-year period according to age, sex, obesity, and abdominal obesity among Korean children and adolescents. We conducted a serial cross-sectional analysis using nationally representative data from the Korea National Health and Nutritional Examination Survey from 2016 to 2020. The study outcome was trends in SUA levels. SUA trends were analyzed by survey-weighted linear regression analysis considering the survey year as a continuous variable. SUA trends were also analyzed for subgroups based on age, sex, abdominal obesity, or obesity. This study included 3,554 children and adolescents aged 10-18 years. SUA increased significantly over the study period in boys (p for trend = 0.043), but not in girls (p for trend = 0.300). In age-specific analyses, SUA increased significantly in the 10-12 years group (p for trend = 0.029). After adjusting for age, SUA increased significantly in the obese group of both boys (p for trend = 0.026) and girls (p for trend = 0.023), but not in the overweight, normal, or under-weight groups of either sex. After adjusting for age, SUA increased significantly in the abdominal obesity group of boys (p for trend = 0.017) and girls (p for trend = 0.014), but not in the non-abdominal obesity group of either sex. Conclusion: In the current study, SUA levels significantly increased in both boys and girls with obesity or abdominal obesity. Further studies of the effect of SUA on health outcomes in boys and girls with obesity or abdominal obesity are needed. What is Known: ⢠High serum uric acid (SUA) is a risk factor for various metabolic diseases, including gout, hypertension, and type 2 diabetes. What is New: ⢠SUA levels increased in boys and the 10-12 years group of Korean children and adolescents. ⢠SUA levels increased significantly in Korean children and adolescents with obesity or central obesity.