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1.
Exp Mol Med ; 2024 May 01.
Artículo en Inglés | MEDLINE | ID: mdl-38689086

RESUMEN

Tumor-associated macrophages (TAMs) are vital contributors to the growth, metastasis, and therapeutic resistance of various cancers, including hepatocellular carcinoma (HCC). However, the exact phenotype of TAMs and the mechanisms underlying their modulation for therapeutic purposes have not been determined. Here, we present compelling evidence that glutamine-derived aspartate in TAMs stimulates spermidine production through the polyamine synthesis pathway, thereby increasing the translation efficiency of HIF-1α via eIF5A hypusination. Consequently, augmented translation of HIF-1α drives TAMs to undergo an increase glycolysis and acquire a metabolic phenotype distinct from that of M2 macrophages. Finally, eIF5A levels in tumor stromal lesions were greater than those in nontumor stromal lesions. Additionally, a higher degree of tumor stromal eIF5A hypusination was significantly associated with a more advanced tumor stage. Taken together, these data highlight the potential of inhibiting hypusinated eIF5A by targeting glutamine metabolism in TAMs, thereby opening a promising avenue for the development of novel therapeutic approaches for HCC.

2.
Int J Mol Sci ; 25(6)2024 Mar 14.
Artículo en Inglés | MEDLINE | ID: mdl-38542291

RESUMEN

Because cancer is a leading cause of death and is thought to be caused by genetic errors or genomic instability in many circumstances, there have been studies exploring cancer's genetic basis using microarray and RNA-seq methods, linking gene expression data to patient survival. This research introduces a methodological framework, combining heterogeneous gene expression data, random forest selection, and pathway analysis, alongside clinical information and Cox regression analysis, to discover prognostic biomarkers. Heterogeneous gene expression data for colorectal cancer were collected from TCGA-COAD (RNA-seq), and GSE17536 and GSE39582 (microarray), and were integrated with Entrez Gene IDs. Using Cox regression analysis and random forest, genes with consistent hazard ratios and significantly affecting patient survivability were chosen. Predictive accuracy was evaluated using ROC curves. Pathway analysis identified potential RNA biomarkers. The authors identified 28 RNA biomarkers. Pathway analysis revealed enrichment in cancer-related pathways, notably EGFR downstream signaling and IGF1R signaling. Three RNA biomarkers (ZEB1-AS1, PI4K2A, and ITGB8-AS1) and two clinical biomarkers (stage and age) were chosen for a prognostic model, improving predictive performance compared to using clinical biomarkers alone. Despite biomarker identification challenges, this study underscores integration of heterogenous gene expression data for discovery.


Asunto(s)
Neoplasias Colorrectales , ARN , Humanos , Pronóstico , Estudios de Cohortes , Biomarcadores de Tumor/genética , Neoplasias Colorrectales/diagnóstico , Neoplasias Colorrectales/genética , Regulación Neoplásica de la Expresión Génica
3.
Int J Mol Sci ; 24(21)2023 Oct 31.
Artículo en Inglés | MEDLINE | ID: mdl-37958805

RESUMEN

Prostate cancer continues to pose a global health challenge as one of the most prevalent malignancies. Mutations of the Forkhead box A1 (FOXA1) gene have been linked to unique oncogenic features in prostate cancer. In this study, we aimed to unravel the intricate molecular characteristics of FOXA1 mutant prostate cancer through comprehensive in silico analysis of transcriptomic data from The Cancer Genome Atlas (TCGA). A comparison between FOXA1 mutant and control groups unearthed 1525 differentially expressed genes (DEGs), which map to eight intrinsic and six extrinsic signaling pathways. Interestingly, the majority of intrinsic pathways, but not extrinsic pathways, were validated using RNA-seq data of 22Rv1 cells from the GEO123619 dataset, suggesting complex biology in the tumor microenvironment. As a result of our in silico research, we identified novel therapeutic targets and potential drug candidates for FOXA1 mutant prostate cancer. KDM1A, MAOA, PDGFB, and HSP90AB1 emerged as druggable candidate targets, as we found that they have approved drugs throughout the drug database CADDIE. Notably, as most of the approved drugs targeting MAOA and KDM1A were monoamine inhibitors used for mental illness or diabetes, we suggest they have a potential to cure FOXA1 mutant primary prostate cancer without lethal side effects.


Asunto(s)
Neoplasias de la Próstata , Masculino , Humanos , Neoplasias de la Próstata/tratamiento farmacológico , Neoplasias de la Próstata/genética , Transducción de Señal , Regulación Neoplásica de la Expresión Génica , Microambiente Tumoral , Factor Nuclear 3-alfa del Hepatocito/genética , Factor Nuclear 3-alfa del Hepatocito/metabolismo , Histona Demetilasas/metabolismo
4.
Front Oncol ; 13: 1152991, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-37342190

RESUMEN

Background/objective: High-grade serous ovarian carcinoma (HGSOC) is the most common histologic type of epithelial ovarian cancer (EOC). Due to its poor survival outcomes, it is essential to identify novel biomarkers and therapeutic targets. The hippo pathway is crucial in various cancers, including gynaecological cancers. Herein, we examined the expression of the key genes of the hippo pathway and their relationship with clinicopathological significance, immune cells infiltration and the prognosis of HGSOC. Methods: The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) data were curated to analyse the mRNA expression as well as the clinicopathological association and correlation with immune cell infiltration in HGSOC. The protein levels of significant genes in the HGSOC tissue were analysed using Tissue Microarray (TMA)-based immunohistochemistry. Finally, DEGs pathway analysis was performed to find the signalling pathways associated with VGLL3. Results: VGLL3 mRNA expression was significantly correlated with both advanced tumor stage and poor overall survival (OS) (p=0.046 and p=0.003, respectively). The result of IHC analysis also supported the association of VGLL3 protein with poor OS. Further, VGLL3 expression was significantly associated with tumor infiltrating macrophages. VGLL3 expression and macrophages infiltration were both found to be independent prognostic factors (p=0.003 and p=0.024, respectively) for HGSOC. VGLL3 was associated with four known and three novel cancer-related signalling pathways, thus implying that VGLL3 is involved in the deregulation of many genes and pathways. Conclusion: Our study revealed that VGLL3 may play a distinct role in clinical outcomes and immune cell infiltration in patients with HGSOC and that it could potentially be a prognostic marker of EOC.

5.
J Korean Med Sci ; 38(15): e117, 2023 Apr 17.
Artículo en Inglés | MEDLINE | ID: mdl-37069811

RESUMEN

BACKGROUND: The largest outbreak of enterohemorrhagic Escherichia coli (EHEC) O157:H7 occurred at a preschool in South Korea from June 12 to 29, 2020. This study aimed to analyze the epidemiological and clinical characteristics of EHEC infection in this outbreak. METHODS: Epidemiological investigation was performed on all 184 children and 19 workers at the preschool using a standard questionnaire to assess symptoms, food intake, attendance, and special activity history. Pulsed-field gel electrophoresis analysis of confirmed cases was performed to determine genetic relevance. RESULTS: During this outbreak, 103 children were affected, whereas only one infection was identified in adults. Of the 103 pediatric patients, 85 had symptoms (82.5%), including diarrhea, abdominal pain, bloody stool, fever, and vomiting. Thirty-two patients (31.1%) were hospitalized, 15 (14.6%) were diagnosed with hemolytic uremic syndrome, and 4 (3.9%) received dialysis treatment. Pulsed-field gel electrophoresis analysis identified 4 genotypes with high genetic relevance (92.3%). Epidemiological investigation revealed that this outbreak might have occurred from ingesting foods stored in a refrigerator with a constant temperature above 10°C, which was conducive to bacterial growth. Despite several measures after outbreak recognition, new infections continued to appear. Therefore, the preschool was forced to close on June 19 to prevent further person-to-person transmission. CONCLUSION: Our findings from the response to the largest outbreak will help prepare countermeasures against future EHEC outbreak.


Asunto(s)
Escherichia coli Enterohemorrágica , Infecciones por Escherichia coli , Escherichia coli O157 , Adulto , Niño , Humanos , Preescolar , Escherichia coli Enterohemorrágica/genética , Infecciones por Escherichia coli/diagnóstico , Infecciones por Escherichia coli/epidemiología , Infecciones por Escherichia coli/microbiología , Diarrea/epidemiología , Escherichia coli O157/genética , Brotes de Enfermedades , República de Corea/epidemiología
6.
Medicina (Kaunas) ; 59(2)2023 Feb 09.
Artículo en Inglés | MEDLINE | ID: mdl-36837526

RESUMEN

In patients with renal failure and hemodialysis, there are difficulties in drug selection and dose adjustment for cancer treatment. The use of immune checkpoint inhibitors (ICIs), including pembrolizumab, approved by the U.S. Food and Drug Administration (FDA) for patients with metastatic non-small cell lung cancer (NSCLC) in 2015, has become an important option for the treatment of metastatic NSCLC. However, data regarding the dosage and schedule for long-term use of ICIs, especially pembrolizumab, in hemodialysis patients are limited. We present the case of a patient with metastatic squamous NSCLC who demonstrated a long-term partial response to pembrolizumab monotherapy for 45 months during hemodialysis and showed no immune-related adverse events (irAEs). To our knowledge, this is the longest remission to be reported without irAEs after discontinuation of pembrolizumab in a NSCLC patient undergoing HD. In addition, we reviewed previously reported lung cancer patients who used ICI during dialysis, comparing them with our case in clinical aspect. We believe that this report will provide clinical insights into the long-term efficacy and safety of pembrolizumab in lung cancer patients undergoing hemodialysis.


Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas , Carcinoma de Células Escamosas , Neoplasias Pulmonares , Humanos , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Neoplasias Pulmonares/tratamiento farmacológico , Diálisis Renal
7.
Eur J Contracept Reprod Health Care ; 28(1): 65-71, 2023 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-36053277

RESUMEN

PURPOSE: To assess the association between abnormal timing of menarche among adolescent girls and neighbourhood socioeconomic status of their school area. MATERIALS AND METHODS: Our analysis included 187,024 girls aged 15-18 years from the Korea Youth Risk Behaviour Web-Based Survey (KYRBS) from 2007 to 2015. Early and late menarche were defined as menarche before 11 years and no menarche by age 14 years, respectively. The deprivation index values for the areas where the schools were located were used as an indicator of neighbourhood socioeconomic status based on the 2005 national census data. We calculated odds ratios (OR) for early and late menarche using a multinomial logistic regression model. Covariates included body mass index, parental education, single or stepparents, siblings, household wealth, year of birth, survey year, and urbanisation. RESULTS: Mean age at menarche was 12 years. The overall proportions of early and late menarche were 11.3% and 3.3%, respectively. When divided into four quartile groups based on the socioeconomic deprivation index, 11.3% of girls in the most deprived quartile and 10.6% in the least deprived area showed early menarche. The prevalence of late menarche did not differ across the deprivation index quartiles of school area. Attendance at schools located in highly deprived areas was associated with up to 10% higher risk of early menarche. This positive association was not evident for late menarche. CONCLUSION: Among contemporary Korean girls, socioeconomic deprivation of the school area was associated with earlier puberty. This finding highlights the potential role of the socioeconomic environment of schools in women's lifetime health.


Asunto(s)
Menarquia , Clase Social , Adolescente , Femenino , Humanos , Niño , Índice de Masa Corporal , Factores Socioeconómicos , Instituciones Académicas
8.
Sci Rep ; 12(1): 21241, 2022 12 08.
Artículo en Inglés | MEDLINE | ID: mdl-36481792

RESUMEN

Seborrheic dermatitis (SD) is one of the most common skin diseases characterized by inflammatory symptoms and cell proliferation, which has increased incidence in patients older than 50 years. Although the roles of microRNAs (miRNAs) have been investigated in several diseases, miRNA profiles of patients with SD remain unknown. This study aimed to identify differentially expressed miRNAs (DEMs) in lesions of elderly male patients with SD. We used a microarray-based approach to identify DEMs in lesions compared to those in non-lesions of patients with SD. Furthermore, Gene Ontology and pathway enrichment analysis were performed using bioinformatics tools to elucidate the functional significance of the target mRNAs of DEMs in lesions of patients with SD. Expression levels of two miRNAs-hsa-miR-6831-5p and hsa-miR-7107-5p-were downregulated, whereas those of six miRNAs-hsa-miR-20a-5p, hsa-miR-191-5p, hsa-miR-127-3p, hsa-miR-106b-5p, hsa-miR-342-3p, and hsa-miR-6824-5p-were upregulated. Functions of the SD-related miRNAs were predicted to be significantly associated with typical dermatological pathogenesis, such as cell proliferation, cell cycle, apoptosis, and immune regulation. In summary, SD alters the miRNA profile, and target mRNAs of the DEMs are related to immune responses and cell proliferation, which are the two main processes in SD pathogenesis.


Asunto(s)
Dermatitis Seborreica , MicroARNs , Humanos , Masculino , Anciano , Dermatitis Seborreica/genética , Ontología de Genes , MicroARNs/genética
9.
Biomedicines ; 10(10)2022 Oct 20.
Artículo en Inglés | MEDLINE | ID: mdl-36289913

RESUMEN

Gene fusion between androgen receptor (AR) response genes and E26 transformation-specific (ETS) family members increases the gene expression of ETS family members, and promotes tumorigenesis in prostate cancer. However, the molecular features of ETV4 fusion in prostate cancer are not fully understood, and drugs targeting ETV4 fusion have not been developed. To examine key cellular signaling pathways and explore therapeutic targets and drugs for ETV4-fusion-positive prostate cancer, we analyzed RNA sequencing data and clinical information for prostate cancer. The ETV4-fusion-positive group was selected through prior study and analysis comparing ETV4-fusion-positive and -negative groups was conducted using a Pearson correlation test. We obtained 393 genes correlated with ETV4 expression. Pathway analysis was performed using over-representation analysis (ORA), and six cancer-specific molecular signaling pathways (the irinotecan pathway, metabolism, androgen receptor signaling, interferon signaling, MAPK/NF-kB signaling, and the tamoxifen pathway) were altered in the ETV4-fusion-positive group. Furthermore, a gene-drug database was used to find an actionable drug and therapeutic target for the ETV4-fusion-positive group. Here, we have identified significantly altered genes and oncogenic signaling pathways in ETV4-fusion-positive prostate cancer, and we suggest therapeutic targets and potential drugs for ETV4-fusion-positive prostate patients.

10.
PLoS One ; 17(9): e0274555, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-36129915

RESUMEN

INTRODUCTION: Colorectal cancer (CRC) is one of the most deadly and common diseases in the world, accounting for over 881,000 casualties in 2018. The PTPRK-RSPO3 (P:R) fusion is a structural variation in CRC and well known for its ability to activate WNT signaling and tumorigenesis. However, till now, therapeutic targets and actionable drugs are limited in this subtype of cancer. MATERIALS AND METHOD: The purpose of this study is to identify key genes and cancer-related pathways specific for P:R fusion-positive CRC. In addition, we also inferred the actionable drugs in bioinformatics analysis using the Cancer Genome Atlas (TCGA) data. RESULTS: 2,505 genes were altered in RNA expression specific for P:R fusion-positive CRC. By pathway analysis based on the altered genes, ten major cancer-related signaling pathways (Apoptosis, Direct p53, EGFR, ErbB, JAK-STAT, tyrosine kinases, Pathways in Cancer, SCF-KIT, VEGFR, and WNT-related Pathway) were significantly altered in P:R fusion-positive CRC. Among these pathways, the most altered cancer genes (ALK, ACSL3, AXIN, MYC, TP53, GNAQ, ACVR2A, and FAS) specific for P:R fusion and involved in multiple cancer pathways were considered to have a key role in P:R fusion-positive CRC. Based on the drug-target network analysis, crizotinib, alectinib, lorlatinib, brigatinib, ceritinib, erdafitinib, infigratinib and pemigatinib were selected as putative therapeutic candidates, since they were already used in routine clinical practice in other cancer types and target genes of the drugs were involved in multiple cancer-pathways.


Asunto(s)
Neoplasias Colorrectales , Proteína p53 Supresora de Tumor , Proteína Axina/metabolismo , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/genética , Crizotinib , Receptores ErbB/metabolismo , Humanos , ARN , Proteínas Tirosina Quinasas Receptoras/metabolismo , Proteínas Tirosina Fosfatasas Clase 2 Similares a Receptores/metabolismo , Transducción de Señal , Trombospondinas/metabolismo , Proteína p53 Supresora de Tumor/metabolismo , Tirosina
11.
Sci Rep ; 12(1): 15298, 2022 Sep 12.
Artículo en Inglés | MEDLINE | ID: mdl-36097042

RESUMEN

Existing data for the association between late-life body mass index (BMI) and the risk of Alzheimer's disease (AD) in the underweight population are limited with conflicting results. A large population-based cohort study of 148,534 individuals aged ≥ 65 years who participated in the national health screening program from 2002 to 2005 was performed using the Korean National Health Insurance Service-Senior cohort database 2006-2015. The risk of AD according to BMI category (kg/m2) in Asians was evaluated using a multivariable Cox regression model, after adjustments for age, sex, lifestyle, low-income status, and comorbidities. To evaluate the association between BMI and AD risk, the underweight population was further subdivided according to the degree of thinness. During the 10-year follow-up period, 22,279 individuals developed AD. Relative to the normal-weight population, the estimated adjusted hazard ratio (HR) for incident AD in the underweight, overweight, and obese populations was 1.17 (95% confidence interval [CI], 1.09-1.24), 0.90 (0.87-0.93), and 0.83 (0.80-0.85), respectively. In the underweight population, AD risk increased as the degree of thinness increased (p for the trend, < .001). Late-life BMI showed a significant inverse relationship with AD risk, especially in the underweight population. Public health strategies to screen for AD more actively in the underweight population and improve their weight status may help reduce the burden of AD.


Asunto(s)
Enfermedad de Alzheimer , Enfermedad de Alzheimer/complicaciones , Enfermedad de Alzheimer/etiología , Índice de Masa Corporal , Estudios de Cohortes , Humanos , Factores de Riesgo , Delgadez/complicaciones , Delgadez/epidemiología
12.
Vaccines (Basel) ; 10(9)2022 Aug 25.
Artículo en Inglés | MEDLINE | ID: mdl-36146465

RESUMEN

Influenza affects all age groups, but the risk of hospitalization and death due to influenza is strongly age-related and is at its highest among the elderly aged 65 years and older. The objective of this study is to compare the differences in influenza-associated disease burden under three different influenza vaccination strategies-the standard-dose quadrivalent influenza vaccine (QIV), high-dose QIV (HD-QIV), and MF59®-adjuvanted QIV (aQIV)-for the elderly population aged 65 years and older in South Korea. A one-year decision-tree model was developed to compare influenza disease burdens. The input data for the model were obtained from published literature reviews and surveillance data from the Korea Disease Control and Prevention Agency (KDCA). The analysis indicated that aQIV is more effective than QIV, preventing 35,390 influenza cases, 1602 influenza-associated complications, 709 influenza-associated hospitalizations, and 145 influenza-associated deaths annually. Additionally, aQIV, when compared to HD-QIV, also reduced the influenza-associated burden of disease, preventing 7247 influenza cases, 328 influenza-associated complications, 145 influenza-associated hospitalizations, and 30 influenza-associated deaths annually. Switching the vaccination strategy from QIV to aQIV is predicted to reduce the influenza-associated disease burden for the elderly in South Korea. The public health gains from aQIV and HD-QIV are expected to be comparable. Future studies comparing the effectiveness of the vaccines will further inform future vaccination strategies for the elderly in South Korea.

13.
BMB Rep ; 55(11): 547-552, 2022 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-36016501

RESUMEN

Sorafenib, originally identified as an inhibitor of multiple oncogenic kinases, induces ferroptosis in hepatocellular carcinoma (HCC) cells. Several pathways that mitigate sorafenib-induced ferroptosis confer drug resistance; thus strategies that enhance ferroptosis increase sorafenib efficacy. Orphan nuclear receptor estrogen-related receptor γ (ERRγ) is upregulated in human HCC tissues and plays a role in cancer cell proliferation. The aim of this study was to determine whether inhibition of ERRγ with DN200434, an orally available inverse agonist, can overcome resistance to sorafenib through induction of ferroptosis. Sorafenib-resistant HCC cells were less sensitive to sorafenibinduced ferroptosis and showed significantly higher ERRγ levels than sorafenib-sensitive HCC cells. DN200434 induced lipid peroxidation and ferroptosis in sorafenib-resistant HCC cells. Mechanistically, DN200434 increased mitochondrial ROS generation by reducing glutathione/glutathione disulfide levels, which subsequently reduced mTOR activity and GPX4 levels. DN200434 induced amplification of the antitumor effects of sorafenib was confirmed in a tumor xenograft model. The present results indicate that DN200434 may be a novel therapeutic strategy to re-sensitize HCC cells to sorafenib. [BMB Reports 2022; 55(11): 547-552].


Asunto(s)
Antineoplásicos , Carcinoma Hepatocelular , Ferroptosis , Neoplasias Hepáticas , Humanos , Carcinoma Hepatocelular/metabolismo , Sorafenib/farmacología , Sorafenib/uso terapéutico , Neoplasias Hepáticas/metabolismo , Estrógenos , Línea Celular Tumoral , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Resistencia a Antineoplásicos
14.
Int J Mol Sci ; 23(14)2022 Jul 14.
Artículo en Inglés | MEDLINE | ID: mdl-35887121

RESUMEN

Acute myeloid leukemia (AML) patients are at risk of bleeding due to disease-related lack of platelets and systemic coagulopathy. Platelets play a role in hemostasis. Leukemic blasts have been shown to alter platelet activation in vitro. Here we investigated biomarkers associated with thrombocytopenia in normal karyotype AML (NK-AML). From The Cancer Genome Atlas database, case-control study was performed between normal karyotype (NK) platelet-decreased AML (PD-AML, platelet count < 100 × 109/L, n = 24) and NK platelet-not-decreased AML (PND-AML, with platelet count ≥ 100 × 109/L, n = 13). Differentially expressed gene analysis, pathway analysis and modelling for predicting platelet decrease in AML were performed. DEG analysis and pathway analysis revealed 157 genes and eight pathways specific for PD-AML, respectively. Most of the eight pathways were significantly involved in G-protein-coupled receptor-related pathway, cytokine-related pathway, and bone remodeling pathway. Among the key genes involved in at least one pathway, three genes including CSF1R, TNFSF15 and CLEC10A were selected as promising biomarkers for predicting PD-AML (0.847 of AUC in support vector machine model). This is the first study that identified biomarkers using RNA expression data analysis and could help understand the pathophysiology in AML with low platelet count.


Asunto(s)
Leucemia Mieloide Aguda , Biomarcadores , Estudios de Casos y Controles , Humanos , Cariotipo , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/metabolismo , Recuento de Plaquetas , Miembro 15 de la Superfamilia de Ligandos de Factores de Necrosis Tumoral/genética
15.
J Exp Clin Cancer Res ; 41(1): 98, 2022 Mar 14.
Artículo en Inglés | MEDLINE | ID: mdl-35287706

RESUMEN

BACKGROUND: Macropinocytosis, an important nutrient-scavenging pathway in certain cancer cells, allows cells to compensate for intracellular amino acid deficiency under nutrient-poor conditions. Ferroptosis caused by cysteine depletion plays a pivotal role in sorafenib responses during hepatocellular carcinoma (HCC) therapy. However, it is not known whether macropinocytosis functions as an alternative pathway to acquire cysteine in sorafenib-treated HCC, and whether it subsequently mitigates sorafenib-induced ferroptosis. This study aimed to investigate whether sorafenib drives macropinocytosis induction, and how macropinocytosis confers ferroptosis resistance on HCC cells. METHODS: Macropinocytosis, both in HCC cells and HCC tissues, was evaluated by measuring TMR-dextran uptake or lysosomal degradation of DQ-BSA, and ferroptosis was evaluated via C11-BODIPY fluorescence and 4-HNE staining. Sorafenib-induced ferroptosis and macropinocytosis were validated in tumor tissues taken from HCC patients who underwent ultrasound-guided needle biopsy. RESULTS: Sorafenib increased macropinocytosis in human HCC specimens and xenografted HCC tissues. Sorafenib-induced mitochondrial dysfunction was responsible for activation of PI3K-RAC1-PAK1 signaling, and amplified macropinocytosis in HCC. Importantly, macropinocytosis prevented sorafenib-induced ferroptosis by replenishing intracellular cysteine that was depleted by sorafenib treatment; this rendered HCC cells resistant to sorafenib. Finally, inhibition of macropinocytosis by amiloride markedly enhanced the anti-tumor effect of sorafenib, and sensitized resistant tumors to sorafenib. CONCLUSION: In summary, sorafenib induced macropinocytosis, which conferred drug resistance by mitigating sorafenib-induced ferroptosis. Thus, targeting macropinocytosis is a promising therapeutic strategy to facilitate ferroptosis-based therapy for HCC.


Asunto(s)
Carcinoma Hepatocelular/complicaciones , Carcinoma Hepatocelular/tratamiento farmacológico , Cisteína/uso terapéutico , Ferroptosis/efectos de los fármacos , Neoplasias Hepáticas/complicaciones , Neoplasias Hepáticas/tratamiento farmacológico , Pinocitosis/efectos de los fármacos , Inhibidores de Proteínas Quinasas/uso terapéutico , Sorafenib/uso terapéutico , Animales , Carcinoma Hepatocelular/patología , Cisteína/farmacología , Femenino , Humanos , Neoplasias Hepáticas/patología , Masculino , Ratones , Inhibidores de Proteínas Quinasas/farmacología , Sorafenib/farmacología
16.
Vaccines (Basel) ; 10(3)2022 Mar 14.
Artículo en Inglés | MEDLINE | ID: mdl-35335077

RESUMEN

The high disease burden of influenza in elderly and chronically ill adults may be due to the suboptimal effectiveness and mismatch of the conventional trivalent influenza vaccine (TIV). This study evaluated the cost-effectiveness of quadrivalent (QIV), adjuvanted trivalent (ATIV), and high-dose quadrivalent (HD-QIV) vaccines versus TIV used under the current Korean National Immunization Program (NIP) in older adults aged ≥65 years. We also evaluated the cost-effectiveness of programs for at-risk adults aged 19-64 and adults aged 50-64. A one-year static population model was used to compare the costs and outcomes of alternative vaccination programs in each targeted group. Influenza-related parameters were derived from the National Health Insurance System claims database; other inputs were extracted from the published literature. Incremental cost-effectiveness ratios (ICERs) were assessed from a societal perspective. In the base case analysis (older adults aged ≥65 years), HD-QIV was superior, with the lowest cost and highest utility. Compared with TIV, ATIV was cost-effective (ICER $34,314/quality-adjusted life-year [QALY]), and QIV was not cost-effective (ICER $46,486/QALY). The cost-effectiveness of HD-QIV was robust for all parameters except for vaccine cost. The introduction of the influenza NIP was cost-effective or even cost-saving for the remaining targeted gr3oups, regardless of TIV or QIV.

17.
Endocrinol Metab (Seoul) ; 36(6): 1189-1200, 2021 12.
Artículo en Inglés | MEDLINE | ID: mdl-34852423

RESUMEN

BACKGROUND: Epidemiological data have shown that vitamin D deficiency is highly prevalent in Korea. Genetic factors influencing vitamin D deficiency in humans have been studied in Europe but are less known in East Asian countries, including Korea. We aimed to investigate the genetic factors related to vitamin D levels in Korean people using a genome-wide association study (GWAS). METHODS: We included 12,642 subjects from three different genetic cohorts consisting of Korean participants. The GWAS was performed on 7,590 individuals using linear or logistic regression meta- and mega-analyses. After identifying significant single nucleotide polymorphisms (SNPs), we calculated heritability and performed replication and rare variant analyses. In addition, expression quantitative trait locus (eQTL) analysis for significant SNPs was performed. RESULTS: rs12803256, in the actin epsilon 1, pseudogene (ACTE1P) gene, was identified as a novel polymorphism associated with vitamin D deficiency. SNPs, such as rs11723621 and rs7041, in the group-specific component gene (GC) and rs11023332 in the phosphodiesterase 3B (PDE3B) gene were significantly associated with vitamin D deficiency in both meta- and mega-analyses. The SNP heritability of the vitamin D concentration was estimated to be 7.23%. eQTL analysis for rs12803256 for the genes related to vitamin D metabolism, including glutamine-dependent NAD(+) synthetase (NADSYN1) and 7-dehydrocholesterol reductase (DHCR7), showed significantly different expression according to alleles. CONCLUSION: The genetic factors underlying vitamin D deficiency in Korea included polymorphisms in the GC, PDE3B, NADSYN1, and ACTE1P genes. The biological mechanism of a non-coding SNP (rs12803256) for DHCR7/NADSYN1 on vitamin D concentrations is unclear, warranting further investigations.


Asunto(s)
Estudio de Asociación del Genoma Completo , Deficiencia de Vitamina D , Pueblo Asiatico , Humanos , Polimorfismo de Nucleótido Simple , Vitamina D/genética , Deficiencia de Vitamina D/epidemiología , Deficiencia de Vitamina D/genética
19.
Osong Public Health Res Perspect ; 12(2): 73-79, 2021 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-33979997

RESUMEN

OBJECTIVE: This study analyzed trends in foodborne and waterborne diseases in South Korea between 2015 and 2019. METHODS: The data consisted of information on outbreaks of waterborne and foodborne infectious diseases reported through the Korea Centers for Disease Control and Prevention (KCDC) system. We analyzed the trends and epidemiological aspects of outbreaks by month, place of occurrence, and causative pathogens in this observational study. RESULTS: The number of outbreaks has steadily increased over the last 5 years, but the number of cases per outbreak has followed a decreasing trend. Incidence at daycare centers and preschools has been steadily increasing over consecutive years. CONCLUSION: The steady number of patients and decreasing number of cases per outbreak, even as the number of outbreaks has been increasing, suggest that the KCDC's professional management system is operating effectively. It is necessary to continue improving the objectivity and efficiency of the management system and to carefully examine the increasing number of outbreaks in smaller-scale group catering facilities, such as daycare centers and preschools. Outbreaks can be prevented by closely examining those caused by unidentified pathogens and group outbreaks caused by other diseases, identifying problems, and supplementing the management system.

20.
Vaccines (Basel) ; 9(4)2021 Apr 10.
Artículo en Inglés | MEDLINE | ID: mdl-33920117

RESUMEN

Increased awareness of adverse events following immunization (AEFI) can disrupt vaccination programs. In South Korea, a report of alleged influenza vaccine-related deaths attracted significant media attention in 2020. We retrieved the vaccination coverage and AEFI data to determine their association with media coverage. Between 2015 and 2019, the vaccination coverage rate ranged between 80.5% and 83.3%; however, the vaccination coverage rate declined significantly from 2020 to 2021 to 73.6% (p < 0.0001). During the 43rd week of 2020, following a large amount of media coverage on vaccine safety issues, the number of cases with AEFI reached 60. Between 2015 and 2020, the mortality rate ratios for influenza vaccines and non-vaccines ranged between 0.1296 (95% confidence interval (CI), 0.1262-0.1331, p < 0.0001) and 0.1608 (95% CI, 0.1572-0.1644, p < 0.0001). Vaccine safety surveillance should be continued in conjunction with investigation and transparent risk communication to maintain public trust in vaccines and vaccinations.

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