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PURPOSE: This study aimed to assess the prevalence and factors of physical, psychological, and social frailty among older adults in the emergency department, comparing these data with community population to understand emergency setting manifestations. METHODS: Conducted at the Emergency Department of National Taiwan University BioMedical Park Hospital, this prospective observational cohort study enrolled older adult patients over a three-month period. Frailty assessments included the Study of Osteoporotic Fractures scale for physical frailty, the Tilburg Frailty Indicator for psychological frailty, and the Makizako Social Frailty Index for social frailty. Data analysis involved a multivariable logistic model to determine the risk factors associated with each frailty type. RESULTS: Out of 991 older adult individuals seeking medical care, 207 participated in the study. The study found high prevalence rates of frailty: 46.38% for physical, 41.06% for psychological, and 48.79% for social frailty. Risk factors for frailty included older age and a history of falls. Interestingly, the prevalence of social frailty was notably higher than physical and psychological frailty. Gender and polypharmacy showed no significant association with any frailty type. CONCLUSION: This research reveals high physical, psychological, and social frailty among older ED patients, especially noting social frailty's prevalence. It highlights the importance for emergency care to adopt holistic care strategies that address older adults' multifaceted health challenges, suggesting a paradigm shift in current healthcare practices to better cater to the multifaceted needs of this vulnerable population.
RéSUMé: OBJECTIFS: Cette étude visait à évaluer la prévalence et les facteurs de la fragilité physique, psychologique et sociale chez les personnes âgées au service des urgences, en comparant ces données avec la population communautaire pour comprendre les manifestations en situation d'urgence. MéTHODES: Menée au service des urgences de l'hôpital BioMedical Park de l'Université nationale de Taiwan, cette étude prospective de cohorte observationnelle a recruté des patients adultes âgés sur une période de trois mois. Les évaluations de la fragilité comprenaient l'échelle de l'étude des fractures ostéoporotiques pour la fragilité physique, l'indicateur de la fragilité psychologique de Tilburg et l'indice de fragilité sociale de Makizako pour la fragilité sociale. L'analyse des données comportait un modèle logistique multivarié pour déterminer les facteurs de risque associés à chaque type de fragilité. RéSULTATS: Sur 991 personnes âgées ayant besoin de soins médicaux, 207 ont participé à l'étude. L'étude a révélé des taux de prévalence élevés de la fragilité : 46,38% pour le physique, 41,06% pour le psychologique et 48,79% pour la fragilité sociale. Les facteurs de risque de fragilité comprenaient un âge avancé et des antécédents de chute. Fait intéressant, la prévalence de la fragilité sociale était nettement plus élevée que la fragilité physique et psychologique. Le genre et la polypharmacie n'ont montré aucune association significative avec aucun type de fragilité. CONCLUSION: Cette recherche révèle une grande fragilité physique, psychologique et sociale chez les patients âgés aux urgences, en particulier la prévalence de la fragilité sociale. Il souligne l'importance pour les soins d'urgence d'adopter des stratégies de soins holistiques qui répondent aux défis de santé multiformes des personnes âgées, suggérant un changement de paradigme dans les pratiques de soins de santé actuelles pour mieux répondre aux besoins multiformes de cette population vulnérable.
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PURPOSE: Our previous study revealed that elevated C-C motif chemokine ligand 2 (CCL2) secretion by irradiated cancer cells recruited C-C motif chemokine receptor 2 (CCR2)-positive myeloid cells and polarized M2-type tumor-associated macrophages (TAMs), promoting lung metastasis in an established mouse model. This study investigated the impact of CCL2 and TAMs on adaptive immunity. METHODS: We assessed the influence of CCL2 and TAMs on adaptive immunity through two ectopic allograft mouse models constructed with MB49 bladder cancer cells and Lewis lung carcinoma cells. Both models exhibited delayed primary tumor growth following radiation therapy (RT), but RT promoted the development of pulmonary metastases in C57BL/6 mice. Additionally, we employed a direct coculture system to investigate the interaction between macrophages and target cells in the context of adaptive immunity. RESULTS: C-C motif chemokine receptor 4 (CCR4)-positive regulatory T cells (Tregs) were recruited to the postirradiated tumor microenvironment (TME). Utilizing a CCR4 antagonist to inhibit CCL2-CCR4 activation reversed the infiltration of CCR4 + Tregs and reduced the incidence of pulmonary metastases. In addition, a positive feedback loop between M2-type TAMs and Tregs was observed. The combined blockade of the CCL2-CCR4 and CCL2-CCR2 signaling pathways further decreased the risk of RT-promoted lung metastasis. CONCLUSION: The recruitment of CCR4 + Tregs to the postirradiated TME increases the metastatic potential of tumor cells through increased interactions with M2-type TAMs. A significant reduction in post-RT lung metastases in ectopic mouse models was achieved by disrupting the recruitment of both CCR4 + Tregs and CCR2 + myeloid cells, which are TAM precursors.
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Carcinoma Pulmonar de Lewis , Neoplasias Pulmonares , Animais , Camundongos , Humanos , Macrófagos Associados a Tumor , Quimiocinas CC , Linfócitos T Reguladores , Camundongos Endogâmicos C57BL , Carcinoma Pulmonar de Lewis/radioterapia , Receptores de Quimiocinas , Neoplasias Pulmonares/radioterapia , Microambiente Tumoral , Linhagem Celular Tumoral , Receptores CCR4RESUMO
Urothelial carcinoma (UC) is the 10th most common cancer globally with an almost 4 times higher prevalence in men. The main risk factors for development of urothelial carcinoma are advanced age, smoking, arsenic contamination, exposure to carcinogens. Metastatic urothelial carcinoma (mUC) has overall poor prognosis with a 5-year overall survival rate of only < 5%. The standard of care comprises of platinum-based chemotherapy, but the responses are often not sustained. A working group was established with an objective to discuss the most recent clinical data on the genitourinary tumors of interest and comprised of experts across Latin America, Emerging Asia (except China, Japan, and South Korea), Africa, and the Middle East (known as Emerging Markets or EM). There is an evident disparity in terms of uneven mortality and incidence rate distribution among various regions. There is a lack and/or insufficient data on epidemiology, treatment, and outcomes in the EM. The lack of registries impacts the healthcare decisions and the lower incidence from the region might not be reflective of the true disease burden. The treatment outcomes of mUC can be improved by understanding the current disease burden and treatment approach of mUC and identifying the gaps and challenges associated with management. Hence, a literature review was developed to summarize the current disease burden and treatment approach of mUC across EM. The review also highlights the unmet needs for mUC management in EM and suggests a way forward to improve the current situation in order to better serve the patients.
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Carcinoma de Células de Transição , Neoplasias da Bexiga Urinária , Masculino , Humanos , Carcinoma de Células de Transição/terapia , Carcinoma de Células de Transição/tratamento farmacológico , Neoplasias da Bexiga Urinária/patologia , Prova Pericial , Resultado do Tratamento , Efeitos Psicossociais da DoençaRESUMO
INTRODUCTION: The changes occurring in the liver in cases of outflow deprivation have rarely been investigated, and no measurements of this phenomenon are available. This investigation explored outflow occlusion in a pig model using a hyperspectral camera. METHODS: Six pigs were enrolled. The right hepatic vein was clamped for 30 min. The oxygen saturation (StO2%), deoxygenated hemoglobin level (de-Hb), near-infrared perfusion (NIR), and total hemoglobin index (THI) were investigated at different time points in four perfused lobes using a hyperspectral camera measuring light absorbance between 500 nm and 995 nm. Differences among lobes at different time points were estimated by mixed-effect linear regression. RESULTS: StO2% decreased over time in the right lateral lobe (RLL, totally occluded) when compared to the left lateral (LLL, outflow preserved) and the right medial (RML, partially occluded) lobes (p < 0.05). De-Hb significantly increased after clamping in RLL when compared to RML and LLL (p < 0.05). RML was further analyzed considering the right portion (totally occluded) and the left portion of the lobe (with an autonomous draining vein). StO2% decreased and de-Hb increased more smoothly when compared to the totally occluded RLL (p < 0.05). CONCLUSIONS: The variations of StO2% and deoxy-Hb could be considered good markers of venous liver congestion.
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Bladder cancer is the ninth most common cancer worldwide with a striking sex-based difference in incidence. Emerging evidence indicates that the androgen receptor (AR) might promote the development, progression and recurrence of bladder cancer, contributing to the observed sex differences. Targeting androgen-AR signalling has promise as potential therapy for bladder cancer and helps to suppress progression of this disease. In addition, the identification of a new membrane AR and AR-regulated non-coding RNAs has important implications for bladder cancer treatment. The success of human clinical trials of targeted-AR therapies will help in the development of improved treatments for patients with bladder cancer.
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Receptores Androgênicos , Neoplasias da Bexiga Urinária , Humanos , Masculino , Feminino , Receptores Androgênicos/genética , Neoplasias da Bexiga Urinária/terapia , Neoplasias da Bexiga Urinária/tratamento farmacológico , Transdução de SinaisRESUMO
BACKGROUND/PURPOSE: Thirty-day hospital readmission rate significantly raised with advanced age. The performance of existing predictive models for readmission risk remained uncertain in the oldest population. We aimed to examine the effect of geriatric conditions and multimorbidity on readmission risk among older adults aged 80 and over. METHODS: This prospective cohort study enrolled patients aged 80 and older discharged from a geriatric ward at a tertiary hospital, with phone follow-up for 12 months. Demographics, multimorbidity, and geriatric conditions were assessed before hospital discharge. Logistic regression models were conducted to analyse risk factors for 30-day readmission. RESULTS: Patients readmitted had higher Charlson comorbidity index scores, and were more likely to have falls, frailty, and longer hospital stay, compared to those without 30-day readmission. Multivariate analysis revealed that higher Charlson comorbidity index score was associated with readmission risk. Older patients with a fall history within 12 months had a near 4-fold increase in readmission risk. Severe frailty status before index admission was associated with a higher 30-day readmission risk. Functional status at discharge was not associated with readmission risk. CONCLUSION: In addition to multimorbidity, history of falls and frailty were associated with higher hospital readmission risk in the oldest.
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Fragilidade , Readmissão do Paciente , Humanos , Idoso de 80 Anos ou mais , Idoso , Multimorbidade , Fragilidade/epidemiologia , Estudos Prospectivos , Alta do Paciente , Fatores de Risco , Centros de Atenção Terciária , Estudos RetrospectivosRESUMO
BACKGROUND: Although trimodality therapy resecting tumours followed by chemoradiotherapy is emerged for muscle-invasive bladder cancer (MIBC), chemotherapy produces toxicities. Histone deacetylase inhibitors have been identified as an effective strategy to enhance cancer radiotherapy (RT). METHODS: We examined the role of HDAC6 and specific inhibition of HDAC6 on BC radiosensitivity by performing transcriptomic analysis and mechanism study. RESULTS: HDAC6 knockdown or HDAC6 inhibitor (HDAC6i) tubacin exerted a radiosensitizing effect, including decreased clonogenic survival, increased H3K9ac and α-tubulin acetylation, and accumulated γH2AX, which are similar to the effect of panobinostat, a pan-HDACi, on irradiated BC cells. Transcriptomics of shHDAC6-transduced T24 under irradiation showed that shHDAC6 counteracted RT-induced mRNA expression of CXCL1, SERPINE1, SDC1 and SDC2, which are linked to cell migration, angiogenesis and metastasis. Moreover, tubacin significantly suppressed RT-induced CXCL1 and radiation-enhanced invasion/migration, whereas panobinostat elevated RT-induced CXCL1 expression and invasion/migration abilities. This phenotype was significantly abrogated by anti-CXCL1 antibody, indicating the key regulator of CXCL1 contributing to BC malignancy. Immunohistochemical evaluation of tumours from urothelial carcinoma patients supported the correlation between high CXCL1 expression and reduced survival. CONCLUSION: Unlike pan-HDACi, the selective HDAC6i can enhance BC radiosensitization and effectively inhibit RT-induced oncogenic CXCL1-Snail-signalling, thus further advancing its therapeutic potential with RT.
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Carcinoma de Células de Transição , Desacetilase 6 de Histona , Tolerância a Radiação , Neoplasias da Bexiga Urinária , Humanos , Acetilação , Linhagem Celular Tumoral , Desacetilase 6 de Histona/genética , Inibidores de Histona Desacetilases/farmacologia , Ácidos Hidroxâmicos/farmacologia , Panobinostat/farmacologia , Tubulina (Proteína)/metabolismo , Neoplasias da Bexiga Urinária/tratamento farmacológico , Neoplasias da Bexiga Urinária/genética , Neoplasias da Bexiga Urinária/radioterapiaRESUMO
PURPOSE: Radiation therapy (RT) is mainly used for bladder preservation in patients with muscle-invasive bladder cancer. The response of urothelial tumors to RT remains unsatisfactory. We investigated the interaction of RT and tumor-associated macrophages (TAMs) in the context of bladder cancer radioresistance. METHODS AND MATERIALS: We evaluated the therapeutic effects of RT and TAM distribution by establishing an ectopic allograft mouse model. A Transwell coculture system was used to simulate the interaction between TAMs and MB49 bladder cancer cells in the tumor microenvironment. Cytokines and chemokines were analyzed in irradiated MB49 cells. Colony formation and Boyden chamber assays were used to assess the cytotoxic effects and the effects of TAMs on MB49 cell invasion, respectively. RESULTS: Local RT delayed primary tumor growth but promoted pulmonary metastases in C57BL/6 mice. Increased secretion of C-C motif chemokine ligand (CCL2) by irradiated MB49 cells, especially in the presence of M1-type TAMs, contributed to the infiltration of bone marrow-derived C-C motif chemokine receptor 2 (CCR2)-positive myeloid cells and the polarization of M1-type TAMs toward the M2 type to promote MB49 cell invasion. Blockade of CCL2-CCR2 activation by a CCR2 antagonist reversed the phenotypic TAM transformation and suppressed pulmonary metastases. CONCLUSIONS: Bladder cancer cells responded to RT by producing CCL2, which recruited TAM precursors from bone marrow and polarized M1-type TAMs toward the M2 type. This phenotypic TAM transformation promoted the pulmonary metastasis of bladder cancer cells after RT. Disrupting the CCL2-CCR2 signaling axis in combination with RT holds promise for improving RT efficacy in bladder cancer.
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Quimiocina CCL2 , Neoplasias Pulmonares , Microambiente Tumoral , Macrófagos Associados a Tumor , Neoplasias da Bexiga Urinária , Animais , Linhagem Celular Tumoral , Polaridade Celular , Quimiocina CCL2/metabolismo , Neoplasias Pulmonares/secundário , Camundongos , Camundongos Endogâmicos C57BL , Macrófagos Associados a Tumor/patologia , Neoplasias da Bexiga Urinária/patologia , Neoplasias da Bexiga Urinária/radioterapiaRESUMO
BACKGROUND: The albumin-bilirubin (ALBI) grade has been validated as a significant prognostic predictor for hepatocellular carcinoma (HCC). However, there is little information about the ALBI grade in patients with non-B non-C HCC (NBNC-HCC) receiving surgery. AIM: This study aimed to evaluate the prognostic significance of the ALBI grade in patients with NBNC-HCC after primary curative resection. METHOD: From January 2010 to April 2016, 2137 patients with HCC who received hepatectomy were screened for study eligibility. Finally, a total of 168 NBNC-HCC patients who received primary curative resection were analyzed. The impacts of the ALBI grade on disease-free survival (DFS) and overall survival (OS) were analyzed by multivariate analysis. RESULTS: There were 66 (39.3%), 98 (58.3%), and 4 (2.4%) patients with an ALBI grade of I, II, and III, respectively. Patients with an ALBI grade II/III were older (p = 0.002), more likely to have hypoalbuminemia (p < 0.001), and more commonly had Child-Pugh class B (p = 0.009) than patients with an ALBI grade I. After a median follow-up of 76 months, 74 (44%) patients experienced recurrence, and 72 (42.9%) patients died. Multivariate analysis revealed that alpha-fetoprotein (AFP) > 200 ng/mL (p = 0.021), number of tumors (p = 0.001), and tumor stage (p = 0.007) were independent prognostic factors for DFS. Additionally, AFP > 200 ng/mL (p = 0.002), ALBI grade II/III (p = 0.002), and tumor stage (p < 0.001) were independent risk factors for poor OS. CONCLUSION: The preoperative ALBI grade can be used to predict mortality in patients with NBNC-HCC after primary curative resection.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , Bilirrubina , Carcinoma Hepatocelular/cirurgia , Humanos , Neoplasias Hepáticas/cirurgia , Recidiva Local de Neoplasia , Prognóstico , Estudos Retrospectivos , Albumina Sérica/análiseRESUMO
BACKGROUND: The SmeVWX efflux pump of Stenotrophomonas maltophilia contributes to menadione (MD) tolerance and resistance to chloramphenicol, quinolones and tetracycline. The components of the SmeVWX efflux pump are encoded by a five-gene operon, smeU1VWU2X. We have previously demonstrated that the smeU1VWU2X operon is intrinsically unexpressed and inducibly expressed by MD via a SoxR- and SmeRv-involved regulatory circuit in S. maltophilia KJ. We also inferred that there should be other regulator(s) involved in MD-mediated smeU1VWU2X expression in addition to SoxR and SmeRv. OBJECTIVES: To identify novel regulator(s) involved in the regulation of MD-mediated smeU1VWU2X expression and elucidate the regulatory circuit. METHODS: A possible regulator candidate involved in the regulation of MD-mediated smeU1VWU2X expression was identified by a homologue search using the helix-turn-helix domain of SmeRv as a query. Gene expression was assessed using the promoter-xylE transcriptional fusion assay and quantitative RT-PCR. The impact of the regulator on SmeVWX pump-mediated functions was investigated via mutant construction and functional tests (antibiotic susceptibility and MD tolerance). RESULTS: AzoR (Smlt3089), a LysR-type transcriptional regulator, was investigated. In unstressed logarithmically grown cells, AzoR was abundantly expressed and functioned as a repressor, inhibiting the expression of the smeU1VWU2X operon. MD challenge attenuated azoR expression, thus derepressing the expression of the smeU1VWU2X operon in S. maltophilia KJ. AzoR down-regulation-mediated smeU1VWU2X expression was observed in quinolone-resistant and SmeVWX-overexpressing S. maltophilia clinical isolates. CONCLUSIONS: AzoR negatively regulates the expression of the smeU1VWU2X operon and SmeVWX pump-mediated antibiotic resistance in S. maltophilia.
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Combinação Besilato de Anlodipino e Olmesartana Medoxomila , Stenotrophomonas maltophilia , Antibacterianos/farmacologia , Proteínas de Bactérias/genética , Proteínas de Bactérias/metabolismo , Farmacorresistência Bacteriana Múltipla/genética , Proteínas de Membrana Transportadoras/genética , Testes de Sensibilidade Microbiana , Stenotrophomonas maltophilia/genética , Stenotrophomonas maltophilia/metabolismoRESUMO
BACKGROUND: Use of statins is associated with a reduced risk of hepatocellular carcinoma (HCC). However, the effect of statin use on HCC recurrence is unclear. This study aimed to evaluate the effect of statin use on recurrence after curative resection among patients with HCC. METHODS: We retrospectively assessed 820 patients with Barcelona Clinic Liver Cancer (BCLC) stage 0 or A HCC who underwent primary resection between January 2001 and June 2016 at Kaohsiung Chang Gung Memorial Hospital. Exposure to statins was defined as use of a statin for at least 3 months before HCC recurrence. Factors that influenced overall survival (OS) and recurrence-free survival (RFS) were analyzed using Cox proportional hazards models. RESULTS: Of the 820 patients, 46 (5.6%) used statins (statin group) and 774 (94.4%) did not (non-statin group). During the mean follow-up of 76.5 months, 440 (53.7%) patients experienced recurrence and 146 (17.8%) patients died. The cumulative incidence of HCC recurrence was significantly lower in the statin group than the non-statin group (p = 0.001); OS was not significantly different between groups. In multivariate analysis, age (hazard ratio [HR]: 1.291; p = 0.010), liver cirrhosis (HR: 1.743; p < 0.001), diabetes (HR:1.418; p = 0.001), number of tumors (HR: 1.750; p < 0.001), tumor size (HR: 1.406; p = 0.004) and vascular invasion (HR: 1.659; p < 0.001) were independent risk factors for HCC recurrence, whereas statin use (HR: 0.354; p < 0.001) and antiviral therapy (HR: 0.613; p < 0.001) significantly reduced the risk of HCC recurrence. The statin group still had lower RFS than the non-statin group after one-to-four propensity score matching. CONCLUSION: Statins may exert a chemo-preventive effect on HCC recurrence after curative resection.
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Carcinoma Hepatocelular/tratamento farmacológico , Hepatectomia/mortalidade , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Neoplasias Hepáticas/tratamento farmacológico , Recidiva Local de Neoplasia/prevenção & controle , Idoso , Carcinoma Hepatocelular/patologia , Carcinoma Hepatocelular/cirurgia , Feminino , Seguimentos , Humanos , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/cirurgia , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/epidemiologia , Estadiamento de Neoplasias , Pontuação de Propensão , Estudos Retrospectivos , Fatores de Risco , Taxa de Sobrevida , Taiwan/epidemiologiaRESUMO
The albumin-bilirubin (ALBI) grade has been validated as a significant predictor for hepatocellular carcinoma (HCC). However, there is little information about the impact of postoperative ALBI grade in patients with HCC who are undergoing liver resection. We enrolled 525 HCC patients who received primary resection from April 2001 to March 2017. The impact of the pre- and post-operative ALBI grades on overall survival (OS) and recurrence-free survival (RFS) were analyzed by multivariate analysis. During the follow-up period (mean, 65 months), 253 (48.1%) patients experienced recurrence, and 85 (16.2%) patients died. Multivariate analysis revealed that diabetes mellitus (DM) (p = 0.011), alpha-fetoprotein levels (AFP) (p < 0.001), low platelet count (p = 0.008), liver cirrhosis (p < 0.001), and the first year of ALBI grade after resection (p < 0.001) were independent predictors for RFS. Additionally, old age (p = 0.006), DM (p = 0.002), AFP (p = 0.027), and ALBI grade at the first year after resection (p < 0.001) were independent risk factors for poor liver-related survival. Patients with post-operative ALBI grades II/III had older age (p = 0.019), hypoalbuminemia (p = 0.038), DM (p = 0.043), and high stages of pTNM (p = 0.021). The post-operative ALBI grade is better for predicting the outcomes in HCC patients after curative hepatectomy than the pre-operative ALBI grade.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , Cuidados Pós-Operatórios , Adulto , Idoso , Carcinoma Hepatocelular/sangue , Carcinoma Hepatocelular/mortalidade , Carcinoma Hepatocelular/patologia , Carcinoma Hepatocelular/cirurgia , Intervalo Livre de Doença , Feminino , Seguimentos , Humanos , Neoplasias Hepáticas/sangue , Neoplasias Hepáticas/mortalidade , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/cirurgia , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , Fatores de Risco , Taxa de SobrevidaRESUMO
BACKGROUND: Sublethal radiation induces matrix metalloproteinase 9 (MMP-9)-mediated radioresistance in Lewis lung carcinoma (LLC) cells and their metastatic dissemination. We aim to determine if EGFR/HER2 activation associates with MMP-9-mediated radioresistance and invasiveness in irradiated LLC cells. METHODS: LLC cells were treated with erlotinib or afatinib followed by sublethal radiation. After irradiation, we examined the phosphorylation of EGFR/HER2 and MMP-9 expression. Colony formation assay determined if the kinase inhibitors sensitize LLC cells to radiation. Matrigel-coated Boyden chamber assay assessed cellular invasiveness. Resulting tumors of wild-type LLC cells or HER2 knock-down mutant cells were irradiated to induce pulmonary metastases. RESULTS: Afatinib more effectively sensitized LLC cells to radiation and decreased invasiveness by inhibiting phosphorylation of EGFR, HER2, Akt, ERK, and p38, and down-regulating MMP-9 when compared to erlotinib. Afatinib abolished radiation-induced lung metastases in vivo. Furthermore, LLC HER2 knock-down cells treated with radiation had growth inhibition. CONCLUSION: Dual inhibition of radiation-activated EGFR and HER2 signaling by afatinib suppressed the proliferation and invasion of irradiated LLC cells. Increased radiosensitivity and decreased metastatic dissemination were observed by pharmacological or genetic HER2 inhibition in vivo. These findings indicate that HER2 plays a pivotal role in enhancing radioresistance and reducing metastatic potential of LLC cells.
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Carcinoma Pulmonar de Lewis/radioterapia , Tolerância a Radiação/efeitos dos fármacos , Receptor ErbB-2/antagonistas & inibidores , Afatinib/farmacologia , Animais , Carcinoma Pulmonar de Lewis/patologia , Linhagem Celular Tumoral , Receptores ErbB/antagonistas & inibidores , Humanos , Masculino , Metaloproteinase 9 da Matriz/fisiologia , Camundongos , Camundongos Endogâmicos C57BL , Invasividade Neoplásica , Metástase Neoplásica , Fosforilação , Receptor ErbB-2/fisiologia , Transdução de SinaisRESUMO
The androgen receptor (AR) has been linked to bladder cancer (BCa) progression, but if this involves circular RNAs (circRNAs) remains unclear. Here, we find that AR alters the levels of circRNA-FNTA (circFNTA) to increase BCa cell invasion and chemo-resistance. Mechanistically, AR represses the RNA editing gene ADAR2 via direct binding to its 5' promoter region to increase circFNTA levels, which then sponges the microRNA miR-370-3p to increase the expression of its host gene FNTA. This AR-mediated ADAR2/circFNTA/miR-370-3p/FNTA pathway then activates KRAS signaling to alter BCa cell invasion and chemo-sensitivity to cisplatin. A clinical BCa sample survey shows that circFNTA expression is elevated in BCa tissues, and results from a BCa mouse model indicate that depletion of circFNTA leads to the suppression of BCa metastases and increased cisplatin chemo-sensitivity. Together, based on our results using multiple BCa cell lines and an in vivo mouse model we suggest that targeting this newly identified AR/ADAR2/circFNTA/miR-370-3p/FNTA/KRAS axis may lead to the development of therapies to suppress BCa metastasis and to increase its chemo-sensitivity.
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Alquil e Aril Transferases/genética , Proteínas Proto-Oncogênicas p21(ras)/metabolismo , RNA Circular/genética , Receptores Androgênicos/metabolismo , Neoplasias da Bexiga Urinária , Animais , Linhagem Celular Tumoral , Proliferação de Células , Regulação Neoplásica da Expressão Gênica , Camundongos , Proteínas Proto-Oncogênicas p21(ras)/genética , Receptores Androgênicos/genética , Neoplasias da Bexiga Urinária/genéticaRESUMO
BACKGROUND: Aerobically-grown bacteria can be challenged by hydrogen peroxide stress from endogenous aerobic metabolism and exogenously generated reactive oxygen species. Catalase (Kat), alkyl hydroperoxidase (Ahp), and glutathione peroxidase (Gpx) systems are major adaptive responses to H2O2 stress in bacteria. Stenotrophomonas maltophilia is a ubiquitous Gram-negative bacterium equipped with four Kats (KatA1, KatA2, KatMn, and KatE), one Ahp (AhpCF), and three Gpxs (Gpx1, Gpx2, and Gpx3). Here, we systematically investigated how the eight H2O2 scavenging genes differentially contribute to the low-micromolar levels of H2O2 generated from aerobic metabolism and high-millimolar levels of H2O2 from exogenous sources. METHODS: Gene expression was assessed and quantified by reverse transcription-PCR (RT-PCR) and real time quantitative PCR (qRT-PCR), respectively. The contribution of these enzymes to H2O2 stress was assessed using mutant construction and functional investigation. RESULTS: Of the eight genes, katA2, ahpCF, and gpx3 were intrinsically expressed in response to low-micromolar levels of H2O2 from aerobic metabolism, and the expression of katA2 and ahpCF was regulated by OxyR. AhpCF and KatA2 were responsible for alleviating aerobic growth-mediated low concentration H2O2 stress and AhpCF played a critical role for stationary-phase cells. KatA2 was upregulated to compensate for AhpCF in the case of ahpCF inactivation. After exposure to millimolar levels of H2O2, katA2 and ahpCF were upregulated in an OxyR-dependent manner. KatA2 was the critical enzyme for dealing with high concentration H2O2. Loss-of-function of KatA2 increased bacterial susceptibility to high concentration H2O2. CONCLUSIONS: AhpCF and KatA2 are key enzymes protecting S. maltophilia from hydrogen peroxide stress.
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Proteínas de Bactérias/genética , Peróxido de Hidrogênio/metabolismo , Estresse Oxidativo/genética , Espécies Reativas de Oxigênio/metabolismo , Stenotrophomonas maltophilia/genética , Proteínas de Bactérias/metabolismo , Stenotrophomonas maltophilia/metabolismoRESUMO
The aim of this study was to investigate prognostic molecular targets for selecting patients with muscle-invasive bladder cancer undergoing bladder-preserving therapy. Pretreatment biopsy samples from patients with muscle-invasive bladder cancer receiving trimodality bladder-preserving therapy were analyzed for expression levels of p53, p16, human epidermal growth factor receptor-2 (Her-2), epidermal growth factor receptor (EGFR), nuclear factor-kappa B (NFκB; p65), E-cadherin, matrix metalloproteinase-9 (MMP9), meiotic recombination 11 homolog (MRE11), programmed death-1 ligand (PD-L1), and mismatch repair proteins (MLH1, PMS2, MSH2, and MSH6) by immunohistochemical (IHC) staining. The correlations between these molecular markers with local progression-free survival (LPFS), distant metastasis-free survival (DMFS), and overall survival (OS) were explored. Biopsy samples from 41 out of 60 patients were evaluated using IHC. Univariate analysis revealed that the high expression of NFκB is associated with significantly worse LPFS, DMFS, and OS, and low expression of p16 is associated with significantly lower LPFS. Upon further multivariate analysis including sex, age, stage, and selected unfavorable factors in the model, NFκB and p16 independently remained significant. The investigational in vitro study demonstrated that irradiation induces up-regulation of NFκB signaling. Irradiated bladder cancer cells showed increased invasion capability and clonogenic survival; inhibition of NFκB signaling by an NFκB inhibitor, SC75741, or RNA interference reversed the observed increases. NFκB expression (p65) is associated with prognostic significance for both LPFS and DMFS in patients treated with bladder-preserving therapy, with consistent impact on cell viability of bladder cancer cells. NFκB may be a putative molecular target to help with outcome stratification.
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Genetic profiling studies on muscle-invasive bladder cancers (MIBCs) have discovered molecular subtypes with different biological characteristics. Immunohistochemical (IHC) markers such as GATA3, cytokeratin (CK) 20, CK5/6, and p53 are associated with these subtypes. In this study, we investigated the biological and prognostic significance of these IHC markers in MIBCs from 91 patients who underwent radical cystectomy. High Ki-67 indices were associated with negative CK20 (p = 0.002) and diffuse CK5/6 (p = 0.001) staining. By contrast, tumors with diffuse GATA3 expression had low Ki-67 index (p = 0.006). Regarding p53, three staining patterns were associated with a high Ki-67 index: (1) complete absence, (2) diffusely strong nuclear reactivity, and (3) diffusely strong cytoplasmic staining (p < 0.001 compared with other patterns). CK5/6 and CK20 expression was typically present in a reciprocal fashion; however, diffuse GATA3 and CK5/6 coexpression was observed in 13 (14.29%) cases. Among 78 chemotherapy-naïve patients, low GATA3 staining was associated with worse recurrence-free survival in both univariate (p = 0.008) and multivariate analyses (p = 0.002). CK20, CK5/6, or p53 expression was not associated with clinical outcome. Based on our results, IHC staining for GATA3 may help risk stratification in patients with MIBC receiving radical cystectomy. In addition, the differences in Ki-67 indices suggested that aberrant p53 expression was better defined by the three aforementioned patterns, rather than percentage of nuclear staining alone.
Assuntos
Fator de Transcrição GATA3/metabolismo , Queratinas/metabolismo , Proteína Supressora de Tumor p53/genética , Neoplasias da Bexiga Urinária/genética , Neoplasias da Bexiga Urinária/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais , Feminino , Humanos , Imuno-Histoquímica , Masculino , Pessoa de Meia-Idade , Invasividade Neoplásica , Estadiamento de Neoplasias , Prognóstico , Modelos de Riscos Proporcionais , Proteína Supressora de Tumor p53/metabolismo , Neoplasias da Bexiga Urinária/mortalidade , Neoplasias da Bexiga Urinária/patologiaRESUMO
In Fig. 1b, upper part, the cell viability counts after treatment with cisplatin and TSA in T24 cells was by mistake a duplication of the image for NTUB1 on the left. In the corrected version of Fig. 1, the image was replaced appropriately.
RESUMO
In this study, we aimed to investigate the antitumor effects of trichostatin A (TSA), an antifungal antibiotic that inhibits histone deacetylase (HDAC) family of enzymes, alone or in combination with anyone of the three chemotherapeutic agents (cisplatin, gemcitabine, and doxorubicin) for the treatment of human urothelial carcinoma (UC). Two high-grade human UC cell lines (T24 and NTUB1) were used. Cytotoxicity and apoptosis were assessed by MTT assay and flow cytometry, respectively. The expression of phospho-c-Raf, phospho-MEK1/2, and phospho-ERK1/2 was measured by western blotting. ERK siRNA knockdown and the specific MEK inhibitor U0126 were used to examine the role of Raf/MEK/ERK signaling pathway in combined cytotoxicity of TSA and chemotherapy. TSA co-treatment with any one of the three chemotherapeutic agents induced synergistic cytotoxicity (combination index < 1) and concomitantly suppressed chemotherapeutic drug-induced activation of Raf-MEK-ERK pathway. Combination of ERK siRNA knockdown and treatment with the specific MEK inhibitor (U0126) enhanced the cytotoxic effects of the chemotherapy on UC cells. These observations were confirmed in a xenograft nude mouse model. Moreover, activated Raf/MEK/ERK pathway was observed in human bladder UC specimens from patients with chemoresistant status. In conclusion, TSA elicits a synergistic cytotoxic response in combination with chemotherapy via targeting the Raf/MEK/ERK pathway. TSA elicits synergistic cytotoxic response in combination with three DNA-damaging drugs (cisplatin, gemcitabine, and doxorubicin). Activated Raf/MEK/ERK pathway is involved in chemoresistant mechanism of UC. Combining chemotherapeutic agents with HDAC inhibitor (TSA) or with targeting Raf/MEK/ERK pathway is promising to circumvent chemoresistance in UCs.
Assuntos
Inibidores de Histona Desacetilases/farmacologia , Ácidos Hidroxâmicos/farmacologia , Neoplasias Urológicas/metabolismo , Animais , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Cisplatino/farmacologia , Cisplatino/uso terapêutico , Desoxicitidina/análogos & derivados , Desoxicitidina/farmacologia , Desoxicitidina/uso terapêutico , Doxorrubicina/farmacologia , Doxorrubicina/uso terapêutico , Sinergismo Farmacológico , Inibidores de Histona Desacetilases/uso terapêutico , Humanos , Ácidos Hidroxâmicos/uso terapêutico , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Camundongos Nus , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Quinases/genética , Proteínas Quinases/metabolismo , RNA Interferente Pequeno/administração & dosagem , Neoplasias Urológicas/genética , GencitabinaRESUMO
Epithelial-mesenchymal transition (EMT) has received considerable attention as a conceptual paradigm for explaining metastatic behavior during cancer progression. NOV/CCN3 is a matrix-associated protein involved in many cellular functions. Previous studies have shown that CCN3 expression is upregulated in prostate cancer (PCa) cells and in PCa patients. In this study, we have provided evidence of tumor promoting effects of CCN3, which includes induction of epithelial-to-mesenchymal transition (EMT) and tumor metastasis. We used an orthotopic in vivo model to demonstrate the prometastatic effects of CCN3. Overexpression or knockdown of CCN3 changed the EMT phenotype in PCa cells. Moreover, treatment with recombinant CCN3 promoted EMT in PCa cells. We also found that CCN3 may promote EMT by activating the FAK/Akt/HIF-1α pathway and this activation is responsible for Twist expression. IHC staining confirmed a positive correlation between the expression of CCN3, Twist, and tumor stage in PCa tissue. Our findings provide insight into the involvement of CCN3 in the EMT regulation of prostate cancer. CCN3 is a promising molecular target that may contribute to a novel therapeutic strategy against metastatic PCa.