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Background: COPD causes substantial economic burden on healthcare. Alternative treatment strategies for COPD can be associated with different costs dependent upon their relative safety and effectiveness. We compared costs and healthcare resource utilization (HCRU) associated with LAMA or LABA/ICS initiation. Methods: Using the Korean National Health Insurance Service database, we enrolled COPD patients initiating treatment with LAMA or LABA/ICS between January 2005 and April 2015. Propensity score matched individuals were compared on all-cause and COPD-related medical costs and HCRU over a three-year follow-up period. Results: A total of 2444 patients were enrolled in each treatment group. LAMA group was associated with significantly lower costs than LABA/ICS group, both in all-cause (403.08 vs 474.50 USD per patient per month [PPPM], cost ratio 1.18, 95% confidence interval [CI]=1.10-1.26, p<0.0001) and COPD-related (216.37 vs 267.32 USD PPPM, cost ratio 1.24, 95% CI=1.13-1.35, p<0.0001) medical costs. All-cause HCRU was not significantly different between groups, while COPD-related HRCU was higher in LAMA group (0.66 vs 0.60 medical visits PPPM, p<0.0001). Conclusion: COPD patients initiating treatment with LAMA were associated with lower all-cause and COPD-related medical costs than those starting with LABA/ICS despite the similar all-cause HCRU and higher COPD-related HCRU. Initiation with LAMA is a cost-efficient option for the treatment of COPD.
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Agonistas de Receptores Adrenérgicos beta 2 , Broncodilatadores , Bases de Dados Factuais , Custos de Medicamentos , Doença Pulmonar Obstrutiva Crônica , Brometo de Tiotrópio , Humanos , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Doença Pulmonar Obstrutiva Crônica/economia , Doença Pulmonar Obstrutiva Crônica/diagnóstico , República da Coreia/epidemiologia , Masculino , Feminino , Idoso , Pessoa de Meia-Idade , Agonistas de Receptores Adrenérgicos beta 2/economia , Agonistas de Receptores Adrenérgicos beta 2/administração & dosagem , Brometo de Tiotrópio/administração & dosagem , Brometo de Tiotrópio/economia , Resultado do Tratamento , Broncodilatadores/economia , Broncodilatadores/administração & dosagem , Fatores de Tempo , Administração por Inalação , Antagonistas Muscarínicos/economia , Antagonistas Muscarínicos/administração & dosagem , Antagonistas Muscarínicos/efeitos adversos , Corticosteroides/administração & dosagem , Corticosteroides/economia , Combinação de Medicamentos , Análise Custo-Benefício , Estudos Retrospectivos , Redução de Custos , Recursos em Saúde/estatística & dados numéricos , Recursos em Saúde/economia , Pulmão/fisiopatologia , Pulmão/efeitos dos fármacosRESUMO
Inflammatory bowel disease (IBD) is characterized by abnormal immune responses, including elevated proinflammatory cytokines, such as tumor necrosis factor-α (TNFα) and interleukin-6 (IL-6) in the gastrointestinal (GI) tract. This study presents the synthesis and anti-inflammatory evaluation of 2,4,5-trimethylpyridin-3-ol analogues, which exhibit dual inhibition of TNFα- and IL-6-induced inflammation. Analysis using in silico methods, including 3D shape-based target identification, modeling, and docking, identified G protein-coupled estrogen receptor 1 (GPER) as the molecular target for the most effective analogue, 6-26, which exhibits remarkable efficacy in ameliorating inflammation and restoring colonic mucosal integrity. This was further validated by surface plasmon resonance (SPR) assay results, which showed direct binding to GPER, and by the results showing that GPER knockdown abolished the inhibitory effects of 6-26 on TNFα and IL-6 actions. Notably, 6-26 displayed no cytotoxicity, unlike G1 and G15, a well-known GPER agonist and an antagonist, respectively, which induced necroptosis independently of GPER. These findings suggest that the GPER-selective compound 6-26 holds promise as a therapeutic candidate for IBD.
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Doenças Inflamatórias Intestinais , Receptores de Estrogênio , Receptores Acoplados a Proteínas G , Receptores Acoplados a Proteínas G/antagonistas & inibidores , Receptores Acoplados a Proteínas G/metabolismo , Receptores Acoplados a Proteínas G/agonistas , Doenças Inflamatórias Intestinais/tratamento farmacológico , Doenças Inflamatórias Intestinais/metabolismo , Humanos , Animais , Receptores de Estrogênio/metabolismo , Receptores de Estrogênio/antagonistas & inibidores , Mucosa Intestinal/metabolismo , Mucosa Intestinal/efeitos dos fármacos , Mucosa Intestinal/patologia , Interleucina-6/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Camundongos , Simulação de Acoplamento Molecular , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/uso terapêutico , Anti-Inflamatórios/química , Anti-Inflamatórios/síntese química , Piridinas/farmacologia , Piridinas/síntese química , Piridinas/química , Piridinas/uso terapêutico , Camundongos Endogâmicos C57BL , Relação Estrutura-AtividadeRESUMO
BACKGROUND: Probiotics are beneficial for animal health and new potential probiotics need to be characterized for their prospective use in improving animal health. In this study, 32 bacterial strains were isolated from a Norwegian forest cat (castrated, 12 years old) and a Persian cat (castrated, 10 years old), which were privately owned and had indoor access. RESULTS: Lactobacillus rhamnosus CACC612 (CACC612) and Bifidobacterium animalis subsp. lactis CACC789 (CACC789) were selected as potential probiotics; characterization of the two strains showed equivalent acid tolerance, similar cell adhesion rates on the HT-29 monolayer cell line, and superior bile tolerance compared to Lactobacillus rhamnosus GG (LGG). Subsequently, they exhibited inhibitory effects against a broad spectrum of pathogenic bacteria, including E. coli (KCTC 2617), Salmonella Derby (NCCP 12,238), Salmonella Enteritidis (NCCP 14,546), Salmonella Typhimurium (NCCP 10,328), Clostridium difficile JCM 1296T. From evaluating host effects, the viability of the feline macrophage cell line (Fcwf-4) increased with the treatment of CACC612 or CACC789 (P < 0.05). The induced expression of immune-related genes such as IFN-γ, IL1ß, IL2, IL4, and TNF-α by immune stimulation was significantly attenuated by the treatment of CACC612 or CACC789 (P < 0.05). When 52 clinical factors of sera from 21 healthy cats were analyzed using partial least squares discriminant analysis (PLS-DA), the animals were obviously clustered before and after feeding with CACC612 or CACC789. In addition, hemoglobin and mean corpuscular hemoglobin concentration (MCHC) significantly increased after CACC612 feeding (P < 0.05). CONCLUSIONS: In this study, feline-originated probiotics were newly characterized and their potentially probiotic effects were evaluated. These results contribute to our understanding of the functional effects of feline-derived probiotics and support their industrial applications.
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Bifidobacterium animalis , Lacticaseibacillus rhamnosus , Probióticos , Gatos , Animais , Escherichia coli , Probióticos/farmacologia , Fator de Necrose Tumoral alfaRESUMO
BACKGROUND: Breast cancer, the most prevalent cancer in women worldwide, faces treatment challenges due to drug resistance, posing a serious threat to patient survival. The present study aimed to identify the key molecules that drive drug resistance and aggressiveness in breast cancer cells and validate them as therapeutic targets. METHODS: Transcriptome microarray and analysis using PANTHER pathway and StemChecker were performed to identify the most significantly expressed genes in tamoxifen-resistant and adriamycin-resistant MCF-7 breast cancer cells. Clinical relevance of the key genes was determined using Kaplan-Meier survival analyses on The Cancer Genome Atlas dataset of breast cancer patients. Gene overexpression/knockdown, spheroid formation, flow cytometric analysis, chromatin immunoprecipitation, immunocytochemistry, wound healing/transwell migration assays, and cancer stem cell transcription factor activation profiling array were used to elucidate the regulatory mechanism of integrin α11 expression. Tumour-bearing xenograft models were used to demonstrate integrin α11 is a potential therapeutic target. RESULTS: Integrin α11 was consistently upregulated in drug-resistant breast cancer cells, and its silencing inhibited cancer stem cells (CSCs) and epithelial-mesenchymal transition (EMT) while restoring sensitivity to anticancer drugs. HIF1α, GLI-1, and EZH2 contributed the most to the regulation of integrin α11 and EZH2 expression, with EZH2 being more necessary for EZH2 autoinduction than HIF1α and GLI-1. Additionally, unlike HIF1α or EZH2, GLI-1 was the sole transcription factor activated by integrin-linked focal adhesion kinase, indicating GLI-1 as a key driver of the EZH2-integrin α11 axis operating for cancer stem cell survival and EMT. Kaplan-Meier survival analysis using The Cancer Genome Atlas (TCGA) dataset also revealed both EZH2 and integrin α11 could be strong prognostic factors of relapse-free and overall survival in breast cancer patients. However, the superior efficacy of integrin α11 siRNA therapy over EZH2 siRNA treatment was demonstrated by enhanced inhibition of tumour growth and prolonged survival in murine models bearing tumours. CONCLUSION: Our findings elucidate that integrin α11 is upregulated by EZH2, forming a positive feedback circuit involving FAK-GLI-1 and contributing to drug resistance, cancer stem cell survival and EMT. Taken together, the results suggest integrin α11 as a promising prognostic marker and a powerful therapeutic target for drug-resistant breast cancer.
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Neoplasias da Mama , Resistencia a Medicamentos Antineoplásicos , Proteína Potenciadora do Homólogo 2 de Zeste , Transição Epitelial-Mesenquimal , Regulação Neoplásica da Expressão Gênica , Células-Tronco Neoplásicas , RNA Interferente Pequeno , Ensaios Antitumorais Modelo de Xenoenxerto , Humanos , Resistencia a Medicamentos Antineoplásicos/genética , Feminino , Neoplasias da Mama/patologia , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/mortalidade , Neoplasias da Mama/terapia , Proteína Potenciadora do Homólogo 2 de Zeste/metabolismo , Proteína Potenciadora do Homólogo 2 de Zeste/genética , Animais , Camundongos , Transição Epitelial-Mesenquimal/genética , Células-Tronco Neoplásicas/metabolismo , Células-Tronco Neoplásicas/patologia , RNA Interferente Pequeno/genética , Linhagem Celular Tumoral , Progressão da Doença , Células MCF-7 , Proliferação de Células , Perfilação da Expressão GênicaRESUMO
Objective: This study aimed to assess the treatment compliance, patterns, healthcare resource utilization (HCRU), and costs of anti-epilepsy drugs (AEDs) as the first add-on therapy in patients with epilepsy. Methods: We conducted a retrospective population-based cohort study using Korean National Health Insurance claims data from 2016 to 2020. Patients with epilepsy who newly received AED add-on therapy were identified and followed for up to 12 months to evaluate persistence, adherence, treatment patterns, HCRU, and costs. Results: Among 6,746 patients who initiated AED add-on therapy, 65.5% were persistent on their index AED add-on from the index date until the end of the follow-up period, and the mean persistent time on the index add-on was 307.3 ± 92.3 days. A total of 76.8% patients were adherent, with a medication possession ratio (MPR) ≥80%, and the mean MPR was 88.9 ± 25.4%. Persistence and adherence to the index AED add-on were relatively higher among patients prescribed lamotrigine, levetiracetam, oxcarbazepine, and perampanel than those prescribed carbamazepine, topiramate, or valproate. A total of 41.0% of the patients changed their index AED add-on during the follow-up period. The carbamazepine, topiramate, and valproate groups had higher rates of change than the other AED groups. HCRU and costs tended to be lower in the lamotrigine, levetiracetam, oxcarbazepine, and perampanel groups. Furthermore, perampanel showed the lowest HCRU and costs for all-cause cases as well as the lowest length of stay and outpatient visits for epilepsy-related cases. Conclusion: In this population-based study, the use of lamotrigine, levetiracetam, oxcarbazepine, or perampanel as the first add-on therapy in patients with epilepsy contributed to better treatment compliance and lower HCRU and costs than that of carbamazepine, topiramate, or valproate.
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Importance: Valuable evidence regarding clinical characteristics, treatments, and outcomes for non-small cell lung cancer (NSCLC) is limited to individual hospital databases or national-level registries. The common data and federated analysis framework developed through the Extensible Platform for Observational Research in Lung Cancer (EXPLORE-LC) initiative allows for research across multiple high-quality data sources, which may provide a deeper understanding of the NSCLC landscape and identification of unmet needs of subpopulations. Objective: To describe clinical characteristics, initial treatment patterns, subsequent treatment, and overall survival (OS) of patients with NSCLC in South Korea. Design, Setting, and Participants: This multicenter cohort study included patients aged 18 years and older who were diagnosed with NSCLC between 2014 and 2019 and followed up until March 2020 at 3 tertiary hospitals in South Korea. Clinical data were collected using a common data model and clinical data warehouse. Patients who had an initial diagnosis of nonsquamous (NSQ) or squamous (SQ) NSCLC and who had received at least 1 treatment for NSCLC were included in the study. Data were analyzed from June through November 2022. Main Outcomes and Measures: The primary outcome was clinical OS for patients with NSCLC. Secondary outcomes were clinical characteristics and treatment patterns subsequent to the diagnosis of NSCLC. Results: Among 22â¯101 patients with NSCLC who received anticancer treatment analyzed in this study, 17â¯350 patients (78.5%) had NSQ and 4751 patients (21.5%) had SQ NSCLC. Clinical characteristics and outcomes and treatment patterns were assessed for 13â¯084 patients with NSQ cancer who had known EGFR and ALK status (75.4%; mean [SD] 62.2 [10.5] years; 6552 males [50.1%]) and all 4751 patients with SQ cancer (mean [SD] age, 67.1 [8.6] years; 4427 males [93.2%]). More than half of patients with NSQ cancer were never smokers (7399 patients [56.6%]). Patients with SQ cancer were mostly males and former or current smokers (4235 patients [89.1%]) and were diagnosed at a later clinical stage than patients with NSQ cancer (eg, stage I: 1165 patients [24.5%] vs 5388 patients [41.2%]). Patients with EGFR-positive and ALK-positive NSQ cancer diagnosed between 2017 and 2019 had better median OS than similar patients diagnosed between 2014 and 2016 (EGFR-positive: not reached [95% CI, 35.9 months to not reached] vs 28.4 months [95% CI, 25.8 to 30.0 months]; P < .001; ALK-positive: not reached [95% CI, not reached] vs 49.5 months [95% CI, 35.1 months to not reached]; P < .001). No significant difference was observed in OS from first-line treatment for patients with SQ cancer. Conclusions and Relevance: This study, which pooled medical data from multiple clinical data warehouses to produce a large study cohort, may provide meaningful insights into the clinical practice of NSCLC and underscores the value of a common data model approach. The analyzable dataset may hold great promise for future comprehensive identification of subpopulations and unmet needs.
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Carcinoma Pulmonar de Células não Pequenas , Carcinoma de Células Escamosas , Neoplasias Pulmonares , Masculino , Humanos , Idoso , Feminino , Carcinoma Pulmonar de Células não Pequenas/terapia , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/epidemiologia , Neoplasias Pulmonares/terapia , Neoplasias Pulmonares/diagnóstico , Estudos de Coortes , Estudos Retrospectivos , Receptores Proteína Tirosina Quinases/uso terapêutico , Receptores ErbBRESUMO
Pedi coccus acidilactici CACC 537 was isolated from canine feces and reported to have probiotic properties. We aimed to characterize the potential probiotic properties of this strain by functional genomic analysis. Complete genome sequencing of P. acidilactici CACC 537 was performed using a PacBio RSII and Illumina platform, and contained one circular chromosome (2.0 Mb) with a 42% G + C content. The sequences were annotation revealed 1,897 protein-coding sequences, 15 rRNAs, and 56 tRNAs. It was determined that P. acidilactici CACC 537 genome carries genes known to be involved in the immune system, defense mechanisms, restriction-modification (R-M), and the CRISPR system. CACC 537 was shown to be beneficial in preventing pathogen infection during the fermentation process, help host immunity, and maintain intestinal health. These results provide for a comprehensive understanding of P. acidilactici and the development of industrial probiotic feed additives that can help improve host immunity and intestinal health.
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The stereoselective total synthesis of dechlorotrichotoxin A, alongside the synthesis of a 1:1 10E/Z mixture of trichotoxin A, was successfully achieved, commencing from the natural monoterpenoid (-)-citronellal. Key steps in the synthesis involved introducing three alkenes and establishing a stereogenic secondary alcohol center. These transformations were accomplished through olefin cross-metathesis, Tebbe olefination, and enantioselective allylation using a chiral phosphoric acid. A comparison of the spectroscopic data between the synthetic dechlorotrichotoxin A and the reported spectra confirmed that the polyketide isolated from a Smenospongia species corresponds to trichotoxin A rather than dechlorotrichotoxin A.
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Policetídeos , Poríferos , Animais , Estereoisomerismo , Alcenos/química , Etanol , Estrutura MolecularRESUMO
Von Hippel-Lindau (VHL) is a tumor suppressor that functions as the substrate recognition subunit of the CRL2VHL E3 complex. While substrates of VHL have been identified, its tumor suppressive role remains to be fully understood. For further determination of VHL substrates, we analyzed the physical interactome of VHL and identified the histone H3K9 methyltransferase SETBD1 as a novel target. SETDB1 undergoes oxygen-dependent hydroxylation by prolyl hydroxylase domain proteins and the CRL2VHL complex recognizes hydroxylated SETDB1 for ubiquitin-mediated degradation. Under hypoxic conditions, SETDB1 accumulates by escaping CRL2VHL activity. Loss of SETDB1 in hypoxia compared with that in normoxia escalates the production of transposable element-derived double-stranded RNAs, thereby hyperactivating the immune-inflammatory response. In addition, strong derepression of TEs in hypoxic cells lacking SETDB1 triggers DNA damage-induced death. Our collective results support a molecular mechanism of oxygen-dependent SETDB1 degradation by the CRL2VHL E3 complex and reveal a role of SETDB1 in genome stability under hypoxia.
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Instabilidade Genômica , Histona-Lisina N-Metiltransferase , Hipóxia , Humanos , Genes Supressores de Tumor , Histona-Lisina N-Metiltransferase/metabolismo , Hipóxia/genética , Hipóxia/metabolismo , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Oxigênio/metabolismo , Ubiquitina-Proteína Ligases/genética , Proteína Supressora de Tumor Von Hippel-Lindau/genética , Proteína Supressora de Tumor Von Hippel-Lindau/metabolismoRESUMO
BACKGROUND: Lysosomes are closely linked to autophagic activity, which plays a vital role in pancreatic ductal adenocarcinoma (PDAC) biology. The survival of PDAC patients is still poor, and the identification of novel genetic factors for prognosis and treatment is highly required to prevent PDAC-related deaths. This study investigated the germline variants related to lysosomal dysfunction in patients with PDAC and to analyze whether they contribute to the development of PDAC. METHODS: The germline putative pathogenic variants (PPV) in genes involved in lysosomal storage disease (LSD) was compared between patients with PDAC (n = 418) and healthy controls (n = 845) using targeted panel and whole-exome sequencing. Furthermore, pancreatic organoids from wild-type and KrasG12D mice were used to evaluate the effect of lysosomal dysfunction on PDAC development. RNA sequencing (RNA-seq) analysis was performed with established PDAC patient-derived organoids (PDOs) according to the PPV status. RESULTS: The PPV in LSD-related genes was higher in patients with PDAC than in healthy controls (8.13 vs. 4.26%, Log2 OR = 1.65, P = 3.08 × 10-3). The PPV carriers of LSD-related genes with PDAC were significantly younger than the non-carriers (mean age 61.5 vs. 65.3 years, P = 0.031). We further studied a variant of the lysosomal enzyme, galactosylceramidase (GALC), which was the most frequently detected LSD variant in our cohort. Autophagolysosomal activity was hampered when GALC was downregulated, which was accompanied by paradoxically elevated autophagic flux. Furthermore, the number of proliferating Ki-67+ cells increased significantly in pancreatic organoids derived from Galc knockout KrasG12D mice. Moreover, GALC PPV carriers tended to show drug resistance in both PDAC cell line and PDAC PDO, and RNA-seq analysis revealed that various metabolism and gene repair pathways were upregulated in PDAC PDOs harboring a GALC variant. CONCLUSIONS: Genetically defined lysosomal dysfunction is frequently observed in patients with young-onset PDAC. This might contribute to PDAC development by altering metabolism and impairing autophagolysosomal activity, which could be potentially implicated in therapeutic applications for PDAC.
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Carcinoma Ductal Pancreático , Neoplasias Pancreáticas , Humanos , Camundongos , Animais , Pessoa de Meia-Idade , Proteínas Proto-Oncogênicas p21(ras) , Neoplasias Pancreáticas/patologia , Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/patologia , Células Germinativas/metabolismo , Lisossomos/metabolismo , Lisossomos/patologia , Neoplasias PancreáticasRESUMO
BACKGROUND: Conducting a distinct comparison between the life expectancy (LE) and healthy life expectancy (HALE) of people with disabilities (PWDs) and the general population is necessary due to the various environmental and health conditions they encounter. Therefore, this study aimed to develop the life table for PWDs and calculate those of LE and HALE based on sex, severity, and disability types among the registered Korean PWDs. METHODS: We used aggregated data of registered PWDs from the Korea National Rehabilitation Center database between 2014 and 2018. Overall, 345,595 deaths were included among 12,627,428 registered PWDs. First, we calculated the LE for total PWDs and non-disabled people using a standard life table, extending the old age mortality among nine models. Subsequently, we calculated the LE for each type of disability using the relationship between the mortality of total PWDs and those of each type of disability. Finally, HALE was calculated using the Sullivan method for three types as follows: disability-free and perceived health (PH) using the National Survey, and hospitalized for ≥ 7 days using the Korea National Health Insurance System (NHIS) database. RESULTS: The calculated LE/HALE-NHIS (years) at registration in males and females were 81.32/73.32 and 87.38/75.58, 68.54/58.98 and 71.43/59.24, 73.87/65.43 and 78.25/67.51, and 61.53/50.48 and 62.41/49.72 years among non-disabled, total PWDs, mild disabled, and severe disabled, respectively. LE/HALE-NHIS was lowest and highest in respiratory dysfunction and hearing disabilities, respectively. CONCLUSIONS: Males with disabilities had shorter LE and HALE at registration than females, except for those with severe disabilities, and there were variabilities in the LE based on the disability types.
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Pessoas com Deficiência , Expectativa de Vida Saudável , Feminino , Masculino , Humanos , Expectativa de Vida , Centros de Reabilitação , República da Coreia/epidemiologiaRESUMO
OBJECTIVES: We estimated the population prevalence of antibodies to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), including unreported infections, through a Korea Seroprevalence Study of Monitoring of SARS-CoV-2 Antibody Retention and Transmission (K-SEROSMART) in 258 communities throughout Korea. METHODS: In August 2022, a survey was conducted among 10,000 household members aged 5 years and older, in households selected through two stage probability random sampling. During face-to-face household interviews, participants self-reported their health status, COVID-19 diagnosis and vaccination history, and general characteristics. Subsequently, participants visited a community health center or medical clinic for blood sampling. Blood samples were analyzed for the presence of antibodies to spike proteins (anti-S) and antibodies to nucleocapsid proteins (anti-N) SARS-CoV-2 proteins using an electrochemiluminescence immunoassay. To estimate the population prevalence, the PROC SURVEYMEANS statistical procedure was employed, with weighting to reflect demographic data from July 2022. RESULTS: In total, 9,945 individuals from 5,041 households were surveyed across 258 communities, representing all basic local governments in Korea. The overall population-adjusted prevalence rates of anti-S and anti-N were 97.6% and 57.1%, respectively. Since the Korea Disease Control and Prevention Agency has reported a cumulative incidence of confirmed cases of 37.8% through July 31, 2022, the proportion of unreported infections among all COVID-19 infection was suggested to be 33.9%. CONCLUSIONS: The K-SEROSMART represents the first nationwide, community-based seroepidemiologic survey of COVID-19, confirming that most individuals possess antibodies to SARS-CoV-2 and that a significant number of unreported cases existed. Furthermore, this study lays the foundation for a surveillance system to continuously monitor transmission at the community level and the response to COVID-19.
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COVID-19 , SARS-CoV-2 , Humanos , Estudos Soroepidemiológicos , Teste para COVID-19 , COVID-19/epidemiologia , Anticorpos Antivirais , República da Coreia/epidemiologiaRESUMO
BACKGROUND: Although poor oral health is a common comorbidity in individuals with airflow limitation (AFL), few studies have comprehensively evaluated this association. Furthermore, the association between oral health and the severity of AFL has not been well elucidated. METHODS: Using a population-based nationwide survey, we classified individuals according to the presence or absence of AFL defined as pre-bronchodilator forced expiratory volume in 1 second/forced vital capacity < 0.7. Using multivariable logistic regression analyses, we evaluated the association between AFL severity and the number of remaining teeth; the presence of periodontitis; the Decayed, Missing, and Filled Teeth (DMFT) index; and denture wearing. RESULTS: Among the 31,839 participants, 14% had AFL. Compared with the control group, the AFL group had a higher proportion of periodontitis (88.8% vs. 79.4%), complete denture (6.2% vs. 1.6%), and high DMFT index (37.3% vs. 27.8%) (P < 0.001 for all). In multivariable analyses, denture status: removable partial denture (adjusted odds ratio [aOR], 1.12; 95% confidence interval [95% CI], 1.04-1.20) and complete denture (aOR, 1.52; 95% CI, 1.01-2.05), high DMFT index (aOR, 1.13; 95% CI, 1.02-1.24), and fewer permanent teeth (0-19; aOR, 1.32; 95% CI, 1.12-1.52) were significantly associated with AFL. Furthermore, those with severe to very severe AFL had a significantly higher proportion of complete denture (aOR, 2.41; 95% CI, 1.11-3.71) and fewer remaining teeth (0-19; aOR, 2.29; 95% CI, 1.57-3.01). CONCLUSION: Denture wearing, high DMFT index, and fewer permanent teeth are significantly associated with AFL. Furthermore, a reduced number of permanent teeth (0-19) was significantly related to the severity of AFL. Therefore, physicians should pay attention to oral health in managing patients with AFL, such as chronic obstructive pulmonary disease.
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Saúde Bucal , Doença Pulmonar Obstrutiva Crônica , Humanos , Fatores de Risco , Pulmão , Doença Pulmonar Obstrutiva Crônica/epidemiologia , República da Coreia/epidemiologiaRESUMO
Ankylosing spondylitis (AS) is a chronic inflammatory arthritis which causes potentially debilitating pain and loss of mobility. Biologics represent a highly effective treatment option in AS. Nonetheless, the choice of biologics often involves complex decision-making. A web-based medical communication aid (MCA) was designed to support information exchange and shared decision-making process between physicians and biologics naïve AS patients. This study aimed to assess the usability of the MCA prototype and the understandability of the MCA contents among rheumatologists and AS patients in South Korea. This was a cross-sectional study using a mixed-methods approach. Treating rheumatologists from major hospitals and their AS patients were recruited in this study. Participants navigated through the MCA and provided feedbacks, guided by interviewers using the think-aloud (TA) method. Participants were then asked to complete a set of surveys. The qualitative and quantitative data were analyzed to determine the usability of the MCA prototype and the understandability of the MCA contents. The MCA prototype received above average rating for usability and high rating for the understandability of its contents. Additionally, participants rated that the quality of information presented in the MCA as high. Analysis of the qualitative data highlighted three key aspects of the MCA; the usefulness of the MCA, the need to present concise and relevant content; and the importance of an intuitively designed tool. Overall, participants found the MCA to be potentially valuable in supporting the current unmet needs in clinical care and had expressed a willingness to use the MCA. The MCA had great potential in supporting shared decision-making by improving patients' knowledge on disease and treatment options, as well as clarifying patients' personal preferences and values in the management of AS.
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Espondilite Anquilosante , Humanos , Espondilite Anquilosante/terapia , Estudos Transversais , Resultado do Tratamento , Comunicação , InternetRESUMO
Lactobacillus amylovorus CACC736 was originated from swine feces in Korea. The complete genome sequences of the strain contained one circular chromosome (2,057,809 base pair [bp]) with 38.2% guanine-cytosine (GC) content and two circular plasmids, namely, pCACC736-1 and pCACC736-2. The predicted protein-coding genes, which are encoding the clustered regularly interspaced short palindromic repeats (CRISPR)-associated proteins, biosynthesis of bacteriocin (helveticin J), and the related proteins of the bile, acid tolerance. Notably, the genes related to vitamin B-group biosynthesis (riboflavin and cobalamin) were also found in L. amylovorus CACC736. Collectively, the complete genome sequence of the L. amylovorus CACC736 will aid in the development of functional probiotics in the animal industry.
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In this study, a new series of 3-arylidene-4,6-dimethyl-5-hydroxy-7-azaoxindole compounds with a wide range of functional groups were designed, synthesized, and evaluated for their antitumor activity. Among the 35 compounds, compound 6-15, with a quinoline moiety, showed cytotoxic IC50 values superior to those of sunitinib against the seven cancer cell lines (MCF-7, MDA-MB-231, HT-29, DU145, U937, A549, and PANC-1). However, its inhibitory activity against receptor tyrosine kinases (VEGFR2, PDGFRß, c-KIT, FGFR1, FLT3, CSF1R, EGFR, Axl, and Axl mutant) was 100 -3000-fold weaker than that of sunitinib. Interestingly, compound 6-15 exerted a 3.6-fold stronger cytotoxicity than sunitinib in the gemcitabine-resistant PANC-1 cell line and significantly inhibited Axl, which was in contrast with the effect of sunitinib. Nonetheless, both compounds suppressed the expression of growth arrest-specific 6 (Gas6), the ligand of Axl. The inhibitory effect of compound 6-15 on the Gas6-Axl axis was similar to that of Gas6 knockdown by siRNA in PANC-1 cells in terms of apoptosis induction, increase in Bax/Bcl-2 ratio, Axl down-regulation, and PI3K/Akt inhibition. The inhibitory effect of compound 6-15 on tumor growth in mouse tumor models with A549 and PANC-1 xenografts was much greater than that of cisplatin or gemcitabine. Taken together, the current findings demonstrate that compound 6-15 is a promising anticancer drug candidate that acts by inhibiting the Gas6-Axl axis.
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Antineoplásicos , Transdução de Sinais , Animais , Camundongos , Humanos , Proteínas Proto-Oncogênicas/metabolismo , Sunitinibe/farmacologia , Fosfatidilinositol 3-Quinases/metabolismo , Linhagem Celular Tumoral , Receptores Proteína Tirosina Quinases/metabolismo , Antineoplásicos/farmacologiaRESUMO
PURPOSE: Androgen-refractory prostate cancer (ARPC) is one of the aggressive human cancers with metastatic capacity and resistance to androgen deprivation therapy (ADT). The present study investigated the genes responsible for ARPC progression and ADT resistance, and their regulatory mechanisms. METHODS: Transcriptome analysis, co-immunoprecipitation, confocal microscopy, and FACS analysis were performed to determine differentially-expressed genes, integrin α3ß4 heterodimer, and cancer stem cell (CSC) population. miRNA array, 3'-UTR reporter assay, ChIP assay, qPCR, and immunoblotting were used to determine differentially-expressed microRNAs, their binding to integrin transcripts, and gene expressions. A xenograft tumor model was used to assess tumor growth and metastasis. RESULTS: Metastatic ARPC cell lines (PC-3 and DU145) exhibiting significant downregulation of ZBTB16 and AR showed significantly upregulated ITGA3 and ITGB4. Silencing either one of the integrin α3ß4 heterodimer significantly suppressed ARPC survival and CSC population. miRNA array and 3'-UTR reporter assay revealed that miR-200c-3p, the most strongly downregulated miRNA in ARPCs, directly bound to 3'-UTR of ITGA3 and ITGB4 to inhibit the gene expression. Concurrently, miR-200c-3p also increased PLZF expression, which, in turn, inhibited integrin α3ß4 expression. Combination treatment with miR-200c-3p mimic and AR inhibitor enzalutamide showed synergistic inhibitory effects on ARPC cell survival in vitro and tumour growth and metastasis of ARPC xenografts in vivo, and the combination effect was greater than the mimic alone. CONCLUSION: This study demonstrated that miR-200c-3p treatment of ARPC is a promising therapeutic approach to restore the sensitivity to anti-androgen therapy and inhibit tumor growth and metastasis.
Assuntos
MicroRNAs , Neoplasias da Próstata , Masculino , Humanos , Regulação para Baixo/genética , Neoplasias da Próstata/patologia , Androgênios , Proteína com Dedos de Zinco da Leucemia Promielocítica/genética , Proteína com Dedos de Zinco da Leucemia Promielocítica/metabolismo , Antagonistas de Androgênios , Linhagem Celular Tumoral , MicroRNAs/genética , MicroRNAs/metabolismo , Regulação Neoplásica da Expressão Gênica , Proliferação de Células/genéticaRESUMO
Prostate cancer is the fifth leading cause of cancer-related mortality in men, primarily because of treatment resistance, recurrence, and metastasis. In the present study, we investigated the role of paracrine interleukin-8 (IL-8) in the antagonistic expression of IL-8 and androgen receptor (AR), and the contribution of IL-8 to prostate cancer aggressiveness. In hormone-responsive LNCaP cells that do not express IL-8, recombinant IL-8 treatment significantly increased expressions of IL-8, CXC chemokine receptor 2 (CXCR2), matrix metalloproteinase (MMP)-2/9, Snail, and vimentin. IL-8 treatment significantly decreased AR and E-cadherin expression. IL-8-induced gene expression changes were suppressed by navarixin, a CXCR1/2 inhibitor, and gallein, a Gßγ inhibitor. In PC-3 androgen-refractory prostate cancer cells, IL-8 knockdown reduced expressions of CXCR2, MMP-2/9, Snail, and vimentin, and increased AR and E-cadherin expressions at the mRNA and protein levels. Co-culture with MEG-01 human megakaryocytic cells secreting high levels of IL-8 induced gene expression changes in both LNCaP and PC-3 cells, similar to those induced by IL-8 treatment. The altered gene expressions were accompanied by significant activation of transcription factor Snail in LNCaP and PC-3 cells. Treatment with the CXCR blocker navarixin inhibited the invasion of PC-3 cells but not LNCaP cells. However, invasion induced by MEG-01 was inhibited by navarixin in both LNCaP and PC-3 cells. The collective findings demonstrate that IL-8 enhances CXCR2 expression, which antagonistically regulates AR expression. More importantly, through changes in IL-8/CXCR2-regulated gene expression, IL-8 induces antiandrogen therapy resistance and epithelial-mesenchymal transition in prostate cancer.
RESUMO
BACKGROUND: Elevated expression of Dickkopf-1 (DKK1) is frequently observed in hepatocellular carcinoma (HCC) patients with poor clinical outcomes. Several reports indicating the functional involvement of DKK1 in HCC progression have suggested DKK1 as a promising therapeutic target for HCC. OBJECTIVE: In this study, to develop an efficient way to target DKK1, we assessed the effect of CDK9 inhibitors on DKK1 expression linked to metastatic movement of HCC. METHODS: The expression of DKK1 in CDK9 inhibitor-treated HCC cells was measured by western blot, ELISA and quantitative real-time reverse transcription PCR. Wound healing assay, migration assay, invasion assay and western blot were examined to evaluate the functional role of DKK1 in CDK9 inhibitors-treated HCC. RESULTS: Inactivation of CDK9 either by a catalytic inhibitor being clinically evaluated or by a specific CDK9 protein degrader largely downregulated DKK1 expression at the transcript and protein levels. In addition, CDK9 inhibitors suppressed the migration and invasion of HCC cells. We observed that ectopic high expression of DKK1 at least partially reversed the defects in metastatic movement of HCC cells mediated by CDK9 inhibitors. We further discovered that the DKK1-nuclear ß-catenin axis associated with the metastatic potential of HCC cells was impaired by CDK9 inhibitors. CONCLUSION: Taken together, our findings suggest that CDK9 inhibitors are potent tools to target DKK1, which can suppress the metastatic progression of HCC.
Assuntos
Carcinoma Hepatocelular , Neoplasias Hepáticas , Humanos , Carcinoma Hepatocelular/patologia , Neoplasias Hepáticas/patologia , Linhagem Celular Tumoral , Movimento Celular , Peptídeos e Proteínas de Sinalização Intercelular , Quinase 9 Dependente de CiclinaRESUMO
Macrophage colony-stimulating factor (M-CSF, also known as CSF1) in tumor tissues stimulates tumor growth and tumor-induced angiogenesis through an autocrine and paracrine action on CSF1 receptor (CSF1R). In the present study, novel bioisosteres of pexidartinib (1) were synthesized and evaluated their inhibitory activities against CSF1R kinase and tumor growth. Among newly synthesized bioisosteres, compound 3 showed the highest inhibition (95.1%) against CSF1R tyrosine kinase at a fixed concentration (1 µM). The half maximal inhibitory concentration (IC50) of pexidartinib (1) and compound 3 was 2.7 and 57.8 nM, respectively. Unlike pexidartinib (1), which cross-reacts to three targets with structural homology, such as CSF1R, c-KIT, and FLT3, compound 3 inhibited CSF1R, c-KIT, but not FLT3, indicating compound 3 may be a more selective CSF1R inhibitor than pexidartinib (1). The inhibitory effect of compound 3 on the proliferation of various cancer cell lines was the strongest in U937 cells followed by THP-1 cells. In the case of cancer cell lines derived from solid tumors, the anti-proliferative activity of compound 3 was weaker than pexidartinib (1), except for Hep3B. However, compound 3 was safer than pexidartinib (1) in terminally differentiated normal cells such as macrophages. Pexidartinib (1) and compound 3 suppressed the production of CSF1 in Hep3B liver cancer cells as well as in the co-culture of Hep3B cells and macrophages. Also, pexidartinib (1) and compound 3 decreased the population ratio of the M2/M1 phenotype and inhibited their migration. Importantly, compound 3 preferentially inhibited M2 phenotype over M1, and the effect was about 4 times greater than that of pexidartinib (1). In addition, compound 3 inhibited maintenance of cancer stem cell population. In a chick chorioallantoic membrane (CAM) tumor model implanted with Hep3B cells, tumor growth and tumor-induced angiogenesis were significantly blocked by compound 3 to a similar extent as pexidartinib (1). Overall, compound 3, a bioisostere of pexidartinib, is an effective dual inhibitor to block CSF1R kinase and CSF1 production, resulting in significant inhibition of tumor growth.