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In this study, we provide critical evidence that STAT2 stability regulation plays an essential role in melanoma cell proliferation and colony growth. We found that the interaction of FBXW7 and STAT2 induced STAT2 destabilization via a ubiquitination-mediated proteasomal degradation pathway. Notably, GSK3ß-mediated STAT2 phosphorylation facilitated STAT2-FBXW7 interactions via the DNA binding domain of STAT2 and domains 1, 2, 6, and 7 of FBXW7 WD40. Importantly, the inverse correlation between protein levels of STAT2 and FBXW7 were observed not only in human melanoma cells but also in a human skin cancer tissue array. The relationship between protein levels of STAT2 and FBXW7, cell proliferation, and colony growth were similarly observed in the melanoma cell lines SK-MEL-2, -5, and -28. Moreover, STAT2 knockdown in melanoma cells suppressed melanoma cell proliferation and colony formation. These data demonstrated that FBXW7-mediated STAT2 stability regulation plays an essential role in melanoma cell proliferation and cancer growth.
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Proteína 7 que Contiene Repeticiones F-Box-WD/metabolismo , Melanoma/patología , Factor de Transcripción STAT2/metabolismo , Neoplasias Cutáneas/patología , Adulto , Anciano , Anciano de 80 o más Años , Línea Celular Tumoral , Proliferación Celular , Femenino , Regulación Neoplásica de la Expresión Génica , Técnicas de Silenciamiento del Gen , Glucógeno Sintasa Quinasa 3 beta/metabolismo , Humanos , Masculino , Persona de Mediana Edad , Fosforilación , Estabilidad Proteica , Proteolisis , Factor de Transcripción STAT2/química , Factor de Transcripción STAT2/genética , Serina/metabolismo , Transducción de Señal , Piel/patología , Treonina/metabolismo , Análisis de Matrices Tisulares , Ubiquitinación , Repeticiones WD40RESUMEN
Mammalian target of rapamycin (mTOR) has a pivotal role in carcinogenesis and cancer cell proliferation in diverse human cancers. In this study, we observed that epimagnolin, a natural compound abundantly found in Shin-Yi, suppressed cell proliferation by inhibition of epidermal growth factor (EGF)-induced G1/S cell-cycle phase transition in JB6 Cl41 cells. Interestingly, epimagnolin suppressed EGF-induced Akt phosphorylation strongly at Ser473 and weakly at Thr308 without alteration of phosphorylation of MAPK/ERK kinases (MEKs), extracellular signal-regulated kinase (ERKs), and RSK1, resulting in abrogation of the phosphorylation of GSK3ß at Ser9 and p70S6K at Thr389. Moreover, we found that epimagnolin suppressed c-Jun phosphorylation at Ser63/73, resulting in the inhibition of activator protein 1 (AP-1) transactivation activity. Computational docking indicated that epimagnolin targeted an active pocket of the mTOR kinase domain by forming three hydrogen bonds and three hydrophobic interactions. The prediction was confirmed by using in vitro kinase and adenosine triphosphate-bead competition assays. The inhibition of mTOR kinase activity resulted in the suppression of anchorage-independent cell transformation. Importantly, epimagnolin efficiently suppressed cell proliferation and anchorage-independent colony growth of H1650 rather than H460 lung cancer cells with dependency of total and phosphorylated protein levels of mTOR and Akt. Inhibitory signaling of epimagnolin on cell proliferation of lung cancer cells was observed mainly in mTOR-Akt-p70S6K and mTOR-Akt-GSK3ß-AP-1, which was similar to that shown in JB6 Cl41 cells. Taken together, our results indicate that epimagnolin potentiates as chemopreventive or therapeutic agents by direct active pocket targeting of mTOR kinase, resulting in sensitizing cancer cells harboring enhanced phosphorylation of the mTORC2-Akt-p70S6k signaling pathway.
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Transformación Celular Neoplásica/efectos de los fármacos , Lignanos/farmacología , Neoplasias Pulmonares/tratamiento farmacológico , Serina-Treonina Quinasas TOR/antagonistas & inhibidores , Animales , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Transformación Celular Neoplásica/patología , Quimioprevención , Medicamentos Herbarios Chinos/farmacología , Factor de Crecimiento Epidérmico/antagonistas & inhibidores , Quinasas MAP Reguladas por Señal Extracelular/metabolismo , Puntos de Control de la Fase G1 del Ciclo Celular/efectos de los fármacos , Glucógeno Sintasa Quinasa 3 beta/metabolismo , Células HEK293 , Humanos , Proteínas Quinasas JNK Activadas por Mitógenos/metabolismo , Neoplasias Pulmonares/patología , Ratones , Simulación del Acoplamiento Molecular , Fosforilación/efectos de los fármacos , Conformación Proteica , Proteínas Proto-Oncogénicas c-akt/metabolismo , Interferencia de ARN , ARN Interferente Pequeño/genética , Proteínas Quinasas S6 Ribosómicas 70-kDa/metabolismo , Proteínas Quinasas S6 Ribosómicas 90-kDa/metabolismoRESUMEN
Ras/Raf/MEKs/ERKs and PI3 K/Akt/mTOR signaling pathways have key roles in cancer development and growth processes, as well as in cancer malignance and chemoresistance. In this study, we screened the therapeutic potential of magnolin using 15 human cancer cell lines and combined magnolin sensitivity with the CCLE mutaome analysis for relevant mutation information. The results showed that magnolin efficacy on cell proliferation inhibition were lower in TOV-112D ovarian cancer cells than that in SKOV3 cells by G1 and G2/M cell cycle phase accumulation. Notably, magnolin suppressed colony growth of TOV-112D cells in soft agar, whereas colony growth of SKOV3 cells in soft agar was not affected by magnolin treatment. Interestingly, phospho-protein profiles in the MAPK and PI3 K signaling pathways indicated that SKOV3 cells showed marked increase of Akt phosphorylation at Thr308 and Ser473 and very weak ERK1/2 phosphorylation levels by EGF stimulation. The phospho-protein profiles in TOV-112D cells were the opposite of those of SKOV3 cells. Importantly, magnolin treatment suppressed phosphorylation of RSKs in TOV-112D, but not in SKOV3 cells. Moreover, magnolin increased SA-ß-galactosidase-positive cells in a dose-dependent manner in TOV-112D cells, but not in SKOV3 cells. Notably, oral administration of Shin-Yi fraction 1, which contained magnolin approximately 53%, suppressed TOV-112D cell growth in athymic nude mice by induction of p16Ink4a and p27Kip1 . Taken together, targeting of ERK1 and ERK2 is suitable for the treatment of ovarian cancer cells that do not harbor the constitutive active P13 K mutation and the loss-of-function mutations of the p16 and/or p53 tumor suppressor proteins.
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Proliferación Celular/efectos de los fármacos , Senescencia Celular , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Lignanos/farmacología , Proteína Quinasa 1 Activada por Mitógenos/antagonistas & inhibidores , Proteína Quinasa 3 Activada por Mitógenos/antagonistas & inhibidores , Neoplasias Ováricas/patología , Animales , Apoptosis , Resistencia a Antineoplásicos , Femenino , Humanos , Masculino , Ratones , Ratones Desnudos , Neoplasias Ováricas/tratamiento farmacológico , Neoplasias Ováricas/metabolismo , Transducción de Señal , Células Tumorales Cultivadas , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Ribosomal S6 kinase 2 (RSK2), regulated by Ras/Raf/MEKs/ERKs, transmits upstream activation signals to downstream substrates including kinases and transcription and epigenetic factors. We observed that ELK members, including ELK1, 3, and 4, highly interacted with RSK2. We further observed that the RSK2-ELK3 interaction was mediated by N-terminal kinase and linker domains of RSK2, and the D and C domains of ELK3, resulting in the phosphorylation of ELK3. Importantly, RSK2-mediated ELK3 enhanced c-fos promoter activity. Notably, chemical inhibition of RSK2 signaling using kaempferol (a RSK2 inhibitor) or U0126 (a selective MEK inhibitor) suppressed EGF-induced c-fos promoter activity. Moreover, functional deletion of RSK2 by knockdown or knockout showed that RSK2 deficiency suppressed EGF-induced c-fos promoter activity, resulting in inhibition of AP-1 transactivation activity and Ras-mediated foci formation in NIH3T3 cells. Immunocytofluorescence assay demonstrated that RSK2 deficiency reduced ELK3 localization in the nucleus. In MDA-MB-231 breast cancer cells, knockdown of RSK2 or ELK3 suppressed cell proliferation with accumulation at the G1 cell cycle phase, resulting in inhibition of foci formation and anchorage-independent cancer colony growth in soft agar. Taken together, these results indicate that a novel RSK2/ELK3 signaling axis, by enhancing c-Fos-mediated AP-1 transactivation activity, has an essential role in cancer cell proliferation and colony growth.
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Neoplasias de la Mama/genética , Transformación Celular Neoplásica/genética , Regulación Neoplásica de la Expresión Génica , Proteínas Proto-Oncogénicas c-fos/genética , Proteínas Proto-Oncogénicas/metabolismo , Proteínas Quinasas S6 Ribosómicas 90-kDa/metabolismo , Factores de Transcripción/metabolismo , Animales , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/patología , Línea Celular Tumoral , Proliferación Celular , Transformación Celular Neoplásica/metabolismo , Transformación Celular Neoplásica/patología , Femenino , Técnicas de Silenciamiento del Gen , Células HEK293 , Humanos , Ratones , Células 3T3 NIH , Regiones Promotoras Genéticas , Proteínas Proto-Oncogénicas/genética , Proteínas Proto-Oncogénicas c-ets , Proteínas Quinasas S6 Ribosómicas 90-kDa/genética , Factores de Transcripción/genéticaRESUMEN
Importance: The optimal treatment for Gleason score 9-10 prostate cancer is unknown. Objective: To compare clinical outcomes of patients with Gleason score 9-10 prostate cancer after definitive treatment. Design, Setting, and Participants: Retrospective cohort study in 12 tertiary centers (11 in the United States, 1 in Norway), with 1809 patients treated between 2000 and 2013. Exposures: Radical prostatectomy (RP), external beam radiotherapy (EBRT) with androgen deprivation therapy, or EBRT plus brachytherapy boost (EBRT+BT) with androgen deprivation therapy. Main Outcomes and Measures: The primary outcome was prostate cancer-specific mortality; distant metastasis-free survival and overall survival were secondary outcomes. Results: Of 1809 men, 639 underwent RP, 734 EBRT, and 436 EBRT+BT. Median ages were 61, 67.7, and 67.5 years; median follow-up was 4.2, 5.1, and 6.3 years, respectively. By 10 years, 91 RP, 186 EBRT, and 90 EBRT+BT patients had died. Adjusted 5-year prostate cancer-specific mortality rates were RP, 12% (95% CI, 8%-17%); EBRT, 13% (95% CI, 8%-19%); and EBRT+BT, 3% (95% CI, 1%-5%). EBRT+BT was associated with significantly lower prostate cancer-specific mortality than either RP or EBRT (cause-specific HRs of 0.38 [95% CI, 0.21-0.68] and 0.41 [95% CI, 0.24-0.71]). Adjusted 5-year incidence rates of distant metastasis were RP, 24% (95% CI, 19%-30%); EBRT, 24% (95% CI, 20%-28%); and EBRT+BT, 8% (95% CI, 5%-11%). EBRT+BT was associated with a significantly lower rate of distant metastasis (propensity-score-adjusted cause-specific HRs of 0.27 [95% CI, 0.17-0.43] for RP and 0.30 [95% CI, 0.19-0.47] for EBRT). Adjusted 7.5-year all-cause mortality rates were RP, 17% (95% CI, 11%-23%); EBRT, 18% (95% CI, 14%-24%); and EBRT+BT, 10% (95% CI, 7%-13%). Within the first 7.5 years of follow-up, EBRT+BT was associated with significantly lower all-cause mortality (cause-specific HRs of 0.66 [95% CI, 0.46-0.96] for RP and 0.61 [95% CI, 0.45-0.84] for EBRT). After the first 7.5 years, the corresponding HRs were 1.16 (95% CI, 0.70-1.92) and 0.87 (95% CI, 0.57-1.32). No significant differences in prostate cancer-specific mortality, distant metastasis, or all-cause mortality (≤7.5 and >7.5 years) were found between men treated with EBRT or RP (cause-specific HRs of 0.92 [95% CI, 0.67-1.26], 0.90 [95% CI, 0.70-1.14], 1.07 [95% CI, 0.80-1.44], and 1.34 [95% CI, 0.85-2.11]). Conclusions and Relevance: Among patients with Gleason score 9-10 prostate cancer, treatment with EBRT+BT with androgen deprivation therapy was associated with significantly better prostate cancer-specific mortality and longer time to distant metastasis compared with EBRT with androgen deprivation therapy or with RP.
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Prostatectomía , Neoplasias de la Próstata/terapia , Radioterapia , Adulto , Anciano , Anciano de 80 o más Años , Antagonistas de Andrógenos/uso terapéutico , Braquiterapia , Causas de Muerte , Terapia Combinada , Progresión de la Enfermedad , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Clasificación del Tumor , Metástasis de la Neoplasia , Estadificación de Neoplasias , Puntaje de Propensión , Neoplasias de la Próstata/mortalidad , Neoplasias de la Próstata/patología , Radioterapia/métodos , Estudios Retrospectivos , Análisis de SupervivenciaRESUMEN
BACKGROUND: Magnolin is a natural compound abundantly found in Magnolia flos, which has been traditionally used in oriental medicine to treat headaches, nasal congestion and anti-inflammatory reactions. Our recent results have demonstrated that magnolin targets the active pockets of ERK1 and ERK2, which are important signaling molecules in cancer cell metastasis. The aim of this study is to evaluate the effects of magnolin on cell migration and to further explore the molecular mechanisms involved. METHODS: Magnolin-mediated signaling inhibition was confirmed by Western blotting using RSK2(+/+) and RSK2(-/-) MEFs, A549 and NCI-H1975 lung cancer cells, and by NF-κB and Cox-2 promoter luciferase reporter assays. Inhibition of cell migration by magnolin was examined by wound healing and/or Boyden Chamber assays using JB6 Cl41 and A549 human lung cancer cells. The molecular mechanisms involved in cell migration and epithelial-to-mesenchymal transition were determined by zymography, Western blotting, real-time PCR and immunocytofluorescence. RESULTS: Magnolin inhibited NF-κB transactivation activity by suppressing the ERKs/RSK2 signaling pathway. Moreover, magnolin abrogated the increase in EGF-induced COX-2 protein levels and wound healing. In human lung cancer cells such as A549 and NCI-H1975, which harbor constitutive active Ras and EGFR mutants, respectively, magnolin suppressed wound healing and cell invasion as seen by a Boyden chamber assay. In addition, it was observed that magnolin inhibited MMP-2 and -9 gene expression and activity. The knockdown or knockout of RSK2 in A549 lung cancer cells or MEFs revealed that magnolin targeting ERKs/RSK2 signaling suppressed epithelial-to-mesenchymal transition by modulating EMT marker proteins such as N-cadherin, E-cadherin, Snail, Vimentin and MMPs. CONCLUSIONS: These results demonstrate that magnolin inhibits cell migration and invasion by targeting the ERKs/RSK2 signaling pathway.
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Movimiento Celular/efectos de los fármacos , Quinasas MAP Reguladas por Señal Extracelular/metabolismo , Lignanos/farmacología , Proteínas Quinasas S6 Ribosómicas 90-kDa/metabolismo , Transducción de Señal/efectos de los fármacos , Animales , Línea Celular Tumoral , Factor de Crecimiento Epidérmico/farmacología , Transición Epitelial-Mesenquimal/efectos de los fármacos , Humanos , Ratones , FN-kappa B/metabolismo , Activación Transcripcional/efectos de los fármacosRESUMEN
Bruton tyrosine kinase (BTK) is an important signaling hub that activates the B-cell receptor (BCR) signaling cascade. BCR activation can contribute to the growth and survival of B-cell lymphoma or leukemia. The inhibition of the BCR signaling pathway is critical for blocking downstream events and treating B-cell lymphomas. Herein, we report potent and orally available proteolysis-targeting chimeras (PROTACs) that target BTK to inactivate BCR signaling. Of the PROTACs tested, UBX-382 showed superior degradation activity for wild-type (WT) and mutant BTK proteins in a single-digit nanomolar range of half-maximal degradation concentration in diffuse large B-cell lymphoma cell line. UBX-382 was effective on 7 out of 8 known BTK mutants in in vitro experiments and was highly effective in inhibiting tumor growth in murine xenograft models harboring WT or C481S mutant BTK-expressing TMD-8 cells over ibrutinib, ARQ-531, and MT-802. Remarkably, oral dosing of UBX-382 for <2 weeks led to complete tumor regression in 3 and 10 mg/kg groups in murine xenograft models. UBX-382 also provoked the cell type-dependent and selective degradation of cereblon neosubstrates in various hematological cancer cells. These results suggest that UBX-382 treatment is a promising therapeutic strategy for B-cell-related blood cancers with improved efficacy and diverse applicability.
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Linfoma de Células B Grandes Difuso , Pirimidinas , Humanos , Animales , Ratones , Agammaglobulinemia Tirosina Quinasa , Pirimidinas/farmacología , Pirimidinas/uso terapéutico , Transducción de Señal , Modelos Animales de Enfermedad , Linfoma de Células B Grandes Difuso/tratamiento farmacológico , Linfoma de Células B Grandes Difuso/genéticaRESUMEN
BACKGROUND: This study aimed to investigate trends in the prevalence of current smokers and motivation to quit among Korean male cancer survivors. METHODS: Out of 20,012 men who participated in the Korea National Health and Nutrition Examination Survey V (2010-2012), VI (2013-2015), and VII (2016-2017), 742 cancer survivors were included. A cancer survivor was defined as a person who concurred to the item, "The cancer has been diagnosed by a doctor" in the health questionnaire. Smoking status was classified as current, former, and never smokers. Regarding motivation to quit smoking, we defined those who had a willingness to quit within 6 months as the willing group. Logistic regression analysis was conducted to examine trends in the prevalence of current smokers and the proportion of the willing group among current smokers. RESULTS: Overall, 3.7% of Korean men who participated in the study were cancer survivors. Current smokers constituted 19.5%, 19.1%, and 15.3% of cancer survivors in phases V, VI, and VII respectively which did not show significant changes (P for trend=0.33). However, the proportion of current smokers in the non-cancer group was significantly reduced to 46.6%, 41.2%, and 38.9% in phases V, VI, and VII, respectively (P for trend <0.001). The proportion of those with a motivation to quit smoking did not show a significant trend in the cancer survivors (P for trend=0.964) and non-cancer group (P for trend=0.884). CONCLUSION: Prevalence of current smokers and motivation to quit in Korean male cancer survivors did not show significant trends.
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BACKGROUND: The role of elective whole-pelvis radiotherapy (WPRT) remains controversial. Few studies have investigated it in Gleason grade group (GG) 5 prostate cancer (PCa), known to have a high risk of nodal metastases. OBJECTIVE: To assess the impact of WPRT on patients with GG 5 PCa treated with external-beam radiotherapy (EBRT) or EBRT with a brachytherapy boost (EBRT+BT). DESIGN, SETTING, AND PARTICIPANTS: We identified 1170 patients with biopsy-proven GG 5 PCa from 11 centers in the United States and one in Norway treated between 2000 and 2013 (734 with EBRT and 436 with EBRT+BT). OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Biochemical recurrence-free survival (bRFS), distant metastasis-free survival (DMFS), and prostate cancer-specific survival (PCSS) were compared using Cox proportional hazards models with propensity score adjustment. RESULTS AND LIMITATIONS: A total of 299 EBRT patients (41%) and 320 EBRT+BT patients (73%) received WPRT. The adjusted 5-yr bRFS rates with WPRT in the EBRT and EBRT+BT groups were 66% and 88%, respectively. Without WPRT, these rates for the EBRT and EBRT+BT groups were 58% and 78%, respectively. The median follow-up was 5.6yr. WPRT was associated with improved bRFS among patients treated with EBRT+BT (hazard ratio [HR] 0.5, 95% confidence interval [CI] 0.2-0.9, p=0.02), but no evidence for improvement was found in those treated with EBRT (HR 0.8, 95% CI 0.6-1.2, p=0.4). WPRT was not significantly associated with improved DMFS or PCSS in the EBRT group (HR 1.1, 95% CI 0.7-1.7, p=0.8 for DMFS and HR 0.7, 95% CI 0.4-1.1, p=0.1 for PCSS), or in the EBRT+BT group (HR 0.6, 95% CI 0.3-1.4, p=0.2 for DMFS and HR 0.5 95% CI 0.2-1.2, p=0.1 for PCSS). CONCLUSIONS: WPRT was not associated with improved PCSS or DMFS in patients with GG 5 PCa who received either EBRT or EBRT+BT. However, WPRT was associated with a significant improvement in bRFS among patients receiving EBRT+BT. Strategies to optimize WPRT, potentially with the use of advanced imaging techniques to identify occult nodal disease, are warranted. PATIENT SUMMARY: When men with a high Gleason grade prostate cancer receive radiation with external radiation and brachytherapy, the addition of radiation to the pelvis results in a longer duration of prostate-specific antigen control. However, we did not find a difference in their survival from prostate cancer or in their survival without metastatic disease. We also did not find a benefit for radiation to the pelvis in men who received radiation without brachytherapy.
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Braquiterapia , Irradiación de Hemicuerpo , Neoplasias de la Próstata/radioterapia , Anciano , Humanos , Masculino , Clasificación del Tumor , Pelvis , Próstata , Neoplasias de la Próstata/mortalidad , Neoplasias de la Próstata/patología , Estudios Retrospectivos , Tasa de SupervivenciaRESUMEN
BACKGROUND: Dry eye syndrome is a common health problem in the adult population. Many risk factors including age, sex, prior eye surgery, various chronic diseases, and lifestyle factors can affect its development. We have evaluated the risk of dry eye syndrome based on the frequency of coffee consumption among Korean adult population. METHODS: A total of 9,752 adults with age 19 years and older were randomly selected between 2010 and 2012. They have all participated in the National Health and Nutrition Examination Survey V of Korea. Dry eye syndrome was being diagnosed by the physicians at some points in the participant's lifetime. The average daily coffee intake was divided into the following: less than 1 cup, 1 to 2 cups, and 3 cups or more. Various physio-environmental factors and medical conditions were used as correction variables to assess the risk of dry eye syndrome in relation to the frequency of coffee consumption. RESULTS: The prevalence of dry eye syndrome decreased to 9.2%, 8.8%, and 6.3% as coffee consumption increased from less than 1 cup to 1-2 cups and more than 3 cups, respectively. However, there was no significant relationship between the frequency of coffee consumption and the risk of dry eye syndrome after adjusting various risk factors. CONCLUSION: There is no relationship between the frequency of coffee consumption and risk of dry eye syndrome.
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BACKGROUND: Early menarche may be associated with increased risk of cardiovascular disease. The aim of this study was to evaluate the relationship between age at menarche and metabolic syndrome (MetS) in Korean premenopausal women. METHODS: We used nationally representative data from the Korea National Health and Nutrition Examination Survey from 2013 to 2014, and 3,023 premenopausal women aged 20-55 years were our subjects. We defined early menarche as age at first menstrual period less than 12 years. Multivariable logistic regression analysis was used to evaluate the relationship between age at menarche and MetS after adjusting for current age, and socioeconomic, lifestyle, and reproductive variables. RESULTS: MetS was much more common in women aged 40-55 years than in women aged 20-39 years (4.1% vs. 15.1%). Compared with women who experienced menarche at age 12-15 years, the risk of MetS in the early menarche group was not higher in either age group, after adjusting for current age, and socioeconomic, lifestyle, and reproductive variables (odds ratio [OR], 1.767; 95% confidence interval [CI], 0.718-4.351 in those aged 20-39 years; OR, 1.780; 95% CI, 0.775-4.085 in those aged 40-55 years). The risk of MetS in women with menarche at age ≥16 years was not higher than in women with menarche at age 12-15 years. CONCLUSION: Early or late menarche was not associated with an increased risk of MetS in premenopausal Korean women. Even before menopause, current age has a major influence on the development of MetS.
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Rheumatoid arthritis (RA) is a systemic inflammatory disease that mainly affects the synovial joints. Although involvement of the fibroblast growth factor (FGF) signaling pathway has been suggested as an important modulator in RA development, no clear evidence has been provided. In this study, we found that synovial fluid basic FGF (bFGF) concentration was significantly higher in RA than in osteoarthritis (OA) patients. bFGF stimulates proliferation and migration of human fibroblast-like synoviocytes (FLSs) by activation of the bFGF-FGF receptor 3 (FGFR3)-ribosomal S6 kinase 2 (RSK2) signaling axis. Moreover, a molecular docking study revealed that kaempferol inhibited FGFR3 activity by binding to the active pocket of the FGFR3 kinase domain. Kaempferol forms hydrogen bonds with the FGFR3 backbone oxygen of Glu555 and Ala558 and the side chain of Lys508. Notably, the inhibition of bFGF-FGFR3-RSK2 signaling by kaempferol suppresses the proliferation and migration of RA FLSs and the release of activated T-cell-mediated inflammatory cytokines, such as IL-17, IL-21, and TNF-α. We further found that activated phospho-FGFR3 and -RSK2 were more highly observed in RA than in OA synovium. The hyperplastic lining and sublining lymphoid aggregate layers of RA synovium showed p-RSK2-expressing CD68+ macrophages with high frequency, while pRSK2-expressing CD4+ T-cells was observed at a lower frequency. Notably, kaempferol administration in collagen-induced arthritis mice relieved the frequency and severity of arthritis. Kaempferol reduced osteoclast differentiation in vitro and in vivo relative to the controls and was associated with the inhibition of osteoclast markers, such as tartrate-resistant acid phosphatase, integrin ß3, and MMP9. Conclusively, our data suggest that bFGF-induced FGFR3-RSK2 signaling may play a critical role during the initiation and progression of RA in terms of FLS proliferation and enhanced osteoclastogenesis, and that kaempferol may be effective as a new treatment for RA.
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Artritis Reumatoide/prevención & control , Quempferoles/administración & dosificación , Receptor Tipo 3 de Factor de Crecimiento de Fibroblastos/metabolismo , Proteínas Quinasas S6 Ribosómicas 90-kDa/metabolismo , Animales , Artritis Reumatoide/genética , Artritis Reumatoide/metabolismo , Artritis Reumatoide/fisiopatología , Movimiento Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Factor 2 de Crecimiento de Fibroblastos/metabolismo , Humanos , Interleucina-17/genética , Interleucina-17/metabolismo , Interleucinas/genética , Interleucinas/metabolismo , Quempferoles/química , Masculino , Ratones , Ratones Endogámicos DBA , Simulación del Acoplamiento Molecular , Receptor Tipo 3 de Factor de Crecimiento de Fibroblastos/antagonistas & inhibidores , Receptor Tipo 3 de Factor de Crecimiento de Fibroblastos/química , Receptor Tipo 3 de Factor de Crecimiento de Fibroblastos/genética , Proteínas Quinasas S6 Ribosómicas 90-kDa/genética , Transducción de Señal/efectos de los fármacos , Sinoviocitos/citología , Sinoviocitos/metabolismoRESUMEN
PURPOSE: Gleason score (GS) 10 disease is the most aggressive form of clinically localized prostate adenocarcinoma (PCa). The long-term clinical outcomes and overall prognosis of patients presenting with GS 10 PCa are largely unknown because of its rarity. METHODS AND MATERIALS: The study included 112 patients with biopsy-determined GS 10 PCa who received treatment with radical prostatectomy (RP, n = 26), external beam radiation therapy (EBRT, n = 48), or EBRT with a brachytherapy boost (EBRT-BT, n = 38) between 2000 and 2013. Propensity scores were included as covariates for comparative analysis. Overall survival, prostate cancer-specific survival, and distant metastasis-free survival (DMFS) were estimated by the Kaplan-Meier method with inverse probability of treatment weighting to control for confounding. RESULTS: The median follow-up period was 4.9 years overall (3.9 years for RP, 4.8 years for EBRT, and 5.7 years for EBRT-BT). Significantly more EBRT patients than EBRT-BT patients received upfront androgen deprivation therapy (98% vs 79%, P < .01 by χ2 test), though the durations were similar (median, 24 months vs 22.5 months). Of the RP patients, 34% received postoperative EBRT, and 35% received neoadjuvant systemic therapy. The propensity score-adjusted 5-year overall survival rate was 80% for the RP group, 73% for the EBRT group, and 83% for the EBRT-BT group. The corresponding adjusted 5-year prostate cancer-specific survival rates were 87%, 75%, and 94%, respectively. The EBRT-BT group trended toward superior DMFS when compared with the RP group (hazard ratio, 0.3; 95% confidence interval 0.1-1.06; P = .06) and had superior DMFS when compared with the EBRT group (hazard ratio, 0.4; 95% confidence interval 0.1-0.99; P = .048). CONCLUSIONS: To our knowledge, this is the largest series ever reported on the clinical outcomes of patients with biopsy-determined GS 10 PCa. These data provide useful prognostic benchmark information for physicians and patients. Aggressive therapy with curative intent is warranted, as >50% of patients remain free of systemic disease 5 years after treatment.
Asunto(s)
Adenocarcinoma/patología , Adenocarcinoma/terapia , Neoplasias de la Próstata/patología , Neoplasias de la Próstata/terapia , Adenocarcinoma/mortalidad , Adulto , Anciano , Anciano de 80 o más Años , Antagonistas de Andrógenos/uso terapéutico , Benchmarking , Braquiterapia , Distribución de Chi-Cuadrado , Supervivencia sin Enfermedad , Humanos , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Clasificación del Tumor , Puntaje de Propensión , Prostatectomía/métodos , Neoplasias de la Próstata/mortalidad , Tasa de Supervivencia , Resultado del TratamientoRESUMEN
PURPOSE: Internists and primary care providers play a growing role in cancer care. We therefore evaluated the awareness of radiation therapy in general and specifically the clinical utility of stereotactic body radiation therapy (SBRT) for early-stage non-small cell lung cancer (NSCLC) among current US internal medicine residents. METHODS AND MATERIALS: A web-based institutional review board-approved multi-institutional survey was distributed to US internal medicine residency programs. The survey evaluated trainee demographic characteristics, baseline radiation oncology awareness, knowledge of the role of SBRT for early-stage NSCLC, and whether the survey successfully improved awareness. RESULTS: Thirty US internal medicine programs participated, with an overall participant response rate of 46% (1177 of 2551). Of the trainees, 93% (n=1076) reported no radiation oncology education in their residency, 39% (n=452) reported confidence in knowing when to consult radiation oncology in an oncologic emergency, and 26% (n=293) reported confidence in knowing when to consult radiation oncology in the setting of a newly diagnosed cancer. Of the participants, 76% (n=850) correctly identified that surgical resection is the standard treatment in operable early-stage NSCLC, but only 50% (n=559) of participants would recommend SBRT to a medically inoperable patient, followed by 31% of participants (n=347) who were unsure of the most appropriate treatment, and 10% (n=117) who recommended waiting to offer palliative therapy. Ninety percent of participants (n=1029) agreed that they would benefit from further training on when to consult radiation oncology. Overall, 96% (n=1072) indicated that the survey increased their knowledge and awareness of the role of SBRT. CONCLUSIONS: The majority of participating trainees received no education in radiation oncology in their residency, reported a lack of confidence regarding when to consult radiation oncology, and overwhelmingly agreed that they would benefit from further training. These findings should serve as a call to increase the educational collaboration between internal medicine and radiation oncology departments to ensure optimal cancer care.
Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas/radioterapia , Conocimientos, Actitudes y Práctica en Salud , Medicina Interna/educación , Internado y Residencia , Neoplasias Pulmonares/radioterapia , Oncología Médica/educación , Radiocirugia/educación , Encuestas y Cuestionarios , Carcinoma de Pulmón de Células no Pequeñas/cirugía , Humanos , Medicina Interna/estadística & datos numéricos , Internado y Residencia/estadística & datos numéricos , Neoplasias Pulmonares/cirugía , Oncología Médica/estadística & datos numéricos , Evaluación de Programas y Proyectos de Salud , Derivación y Consulta , Estados UnidosRESUMEN
RSK2 is a downstream signaling protein of ERK1 and ERK2 and plays a key role in physiological homeostasis. For this reason, RSK2 is a highly conserved protein among the p90RSK family members. In its location in the signaling pathway, RSK2 is a kinase just upstream of transcription and epigenetic factors, and a few kinases involved in cell cycle regulation and protein synthesis. Moreover, activation of RSK2 by growth factors is directly involved in cell proliferation, anchorage-independent cell transformation and cancer development. Direct evidences regarding the etiological roles of RSK2 in cancer development in humans have been published by our research group illustrating that elevated total- and phospho-RSK2 protein levels mediated by ERK1 and ERK2 are higher in skin cancer tissues compared to normal skin tissues. Notably, it has been shown that RSK2 ectopic expression in JB6 Cl41 cells induces cell proliferation and anchorage- independent cell transformation. Importantly, knockdown of RSK2 suppresses Ras-mediated foci formation and anchorage-independent colony growth of cancer cells. Kaempferol is a one of the natural compounds showing selectivity in inhibiting RSK2 activity in epidermal growth factor-induced G1/S cell cycle transition and cell transformation. Thus, ERKs/RSK2 signaling axis is an important target signaling molecule in chemoprevention.