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BACKGROUND: In the ongoing, randomised, double-blind phase 3 TOPAZ-1 study, durvalumab, a PD-L1 inhibitor, plus gemcitabine and cisplatin was associated with significant improvements in overall survival compared with placebo, gemcitabine, and cisplatin in people with advanced biliary tract cancer at the pre-planned intermin analysis. In this paper, we present patient-reported outcomes from TOPAZ-1. METHODS: In TOPAZ-1 (NCT03875235), participants aged 18 years or older with previously untreated, unresectable, locally advanced, or metastatic biliary tract cancer with an Eastern Cooperative Oncology Group performance status of 0 or 1 and one or more measurable lesions per Response Evaluation Criteria in Solid Tumors (RECIST; version 1.1) were randomly assigned (1:1) to the durvalumab group or the placebo group using a computer-generated randomisation scheme. Participants received 1500 mg durvalumab or matched placebo intravenously every 3 weeks (on day 1 of the cycle) for up to eight cycles in combination with 1000 mg/m2 gemcitabine and 25 mg/m2 cisplatin intravenously on days 1 and 8 every 3 weeks for up to eight cycles. Thereafter, participants received either durvalumab (1500 mg) or placebo monotherapy intravenously every 4 weeks until disease progression or other discontinuation criteria were met. Randomisation was stratified by disease status (initially unresectable vs recurrent) and primary tumour location (intrahepatic cholangiocarcinoma vs extrahepatic cholangiocarcinoma vs gallbladder cancer). Patient-reported outcomes were assessed as a secondary outcome in all participants who completed the European Organisation for Research and Treatment of Cancer's 30-item Quality of Life of Cancer Patients questionnaire (QLQ-C30) and the 21-item Cholangiocarcinoma and Gallbladder Cancer Quality of Life Module (QLQ-BIL21). We calculated time to deterioration-ie, time from randomisation to an absolute decrease of at least 10 points in a patient-reported outcome that was confirmed at a subsequent visit or the date of death (by any cause) in the absence of deterioration-and adjusted mean change from baseline in patient-reported outcomes. FINDINGS: Between April 16, 2019, and Dec 11, 2020, 685 participants were enrolled and randomly assigned, 341 to the durvalumab group and 344 to the placebo group. Overall, 345 (50%) of participants were male and 340 (50%) were female. Data for the QLQ-C30 were available for 318 participants in the durvalumab group and 328 in the placebo group (median follow-up 9·9 months [IQR 6·7 to 14·1]). Data for the QLQ-BIL21 were available for 305 participants in the durvalumab group and 322 in the placebo group (median follow-up 10·2 months [IQR 6·7 to 14·3]). The proportions of participants in both groups who completed questionnaires were high and baseline scores were mostly similar across treatment groups. For global health status or quality of life, functioning, and symptoms, we noted no difference in time to deterioration or adjusted mean changes from baseline were observed between groups. Median time to deterioration of global health status or quality of life was 7·4 months (95% CI 5·6 to 8·9) in the durvalumab group and 6·7 months (5·6 to 7·9) in the placebo group (hazard ratio 0·87 [95% CI 0·69 to 1·12]). The adjusted mean change from baseline was 1·23 (95% CI -0·71 to 3·16) in the durvalumab group and 0·35 (-1·63 to 2·32) in the placebo group. INTERPRETATION: The addition of durvalumab to gemcitabine and cisplatin did not have a detrimental effect on patient-reported outcomes. These results suggest that durvalumab, gemcitabine, and cisplatin is a tolerable treatment regimen in patients with advanced biliary tract cancer. FUNDING: AstraZeneca.
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Anticuerpos Monoclonales , Protocolos de Quimioterapia Combinada Antineoplásica , Neoplasias del Sistema Biliar , Cisplatino , Desoxicitidina , Gemcitabina , Medición de Resultados Informados por el Paciente , Humanos , Cisplatino/administración & dosificación , Método Doble Ciego , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Masculino , Femenino , Neoplasias del Sistema Biliar/tratamiento farmacológico , Neoplasias del Sistema Biliar/patología , Neoplasias del Sistema Biliar/mortalidad , Desoxicitidina/análogos & derivados , Desoxicitidina/administración & dosificación , Persona de Mediana Edad , Anticuerpos Monoclonales/administración & dosificación , Anciano , Adulto , Calidad de VidaRESUMEN
BACKGROUND: Long non-coding RNAs (lncRNAs) regulate tumor development and metastasis in several types of cancers through various molecular mechanisms. However, the biological role of most lncRNAs in pancreatic cancer (PC) remains unclear. Here, we explored the expression, biological functions, and molecular mechanism of LINC01128 in PC. METHODS: Quantitive reverse transcription PCR was used to detect the expression level of LINC01128 in PC tissues and different PC cell lines. A loss-of-function and gain-of-function experiment was used to explore the biological effects of LINC01128 on PC carcinogenesis in vitro and in vivo. Western blot analysis, subcellular fractionation experiment, luciferase reporter gene assay, and MS2-RNA immunoprecipitation experiment were used to study the potential molecular mechanism of LINC01128 during carcinogenesis. RESULTS: The expression of LINC01128 was upregulated in PC tissues and cell lines, and overexpression of LINC01128 was significantly related to the poor prognosis of patients with PC. Furthermore, silencing LINC01128 significantly inhibited the proliferation, migration, invasion, and epithelial-mesenchymal transition (EMT) of PC cells in vitro and tumor growth in vivo, while LINC01128 overexpression promoted these processes. Further research showed that LINC01128 acted as a sponge for microRNA miR-561-5p, and lactate dehydrogenase A (LDHA) was the downstream target gene of miR-561-5p. It was also revealed that the expression of miR-561-5p in PC was decreased, and a negative correlation between miR-561-5p and LINC01128 was revealed. Based on rescue experiments, LDHA overexpression partially restored the inhibitory effect of LINC01128 knockdown on proliferation, migration, and invasion of PC cells. CONCLUSIONS: LINC01128 promotes the proliferation, migration, invasion, and EMT of PC by regulating the miR-561-5p/LDHA axis, suggesting LINC01128 may be a new prognostic marker and therapeutic target in PC.
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Limonoids are considered the effective part in Meliaceae plants that exert anti-inflammatory effects. Gedunin-type limonoids specifically have anti-inflammatory effects. However, the role of gedunin-type limonoids in the inflammatory diseases mediated by NLRP3 inflammasome remains to be explored. We found that deacetylgudunin (DAG), a gedunin-type limonoid from Toona sinensis, had similar anti-inflammatory effects and lower toxicity than gedunin. Further studies showed that DAG down-regulated the NF-κB pathway, inhibited K+ efflux and ROS release, inhibited ASC oligomerization, and significantly weakened the interaction of NLRP3 with ASC and NEK7. Furthermore, DAG could not further inhibit IL-1ß secretion and K+ efflux when combined with the P2X7 inhibitor A438079. In conclusion, our research revealed that DAG exerted an anti-inflammatory effect by inhibiting the P2X7/NLRP3 signaling pathway and enriched the application of gedunin-type limonoids in inflammatory diseases driven by the NLRP3 inflammasome.
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Inflamasomas , Limoninas , Antiinflamatorios/farmacología , Inflamasomas/metabolismo , Interleucina-1beta/metabolismo , Limoninas/farmacología , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Transducción de Señal , ToonaRESUMEN
Long non-coding RNAs (lncRNAs) are a novel class of regulators in multiple cancer biological processes. However, the functions of lncRNAs in pancreatic ductal adenocarcinoma (PDAC) remain largely unknown. In this study, we identified PWAR6 as a frequently down-regulated lncRNA in PDAC samples as well as a panel of pancreatic cancer cell lines. Down-regulated PWAR6 was associated with multiple clinical outcomes, including advanced tumour stage, distant metastasis, and overall survival of PDAC patients. In our cell-based assays, ectopic expression of PWAR6 dramatically repressed PDAC cells proliferation, invasion and migration, accelerated apoptosis, and induced cell cycle arrest at G0/G1 phase. In contrast, depletion of PWAR6 mediated by siRNA exhibited opposite effects on PDAC cell behaviours. In vivo study further validated the anti-tumour role of PWAR6 in PDAC. By taking advantage of available online sources, we also identified YAP1 as a potential PWAR6 target gene. Negative correlation between YAP1 and PWAR6 expressions were observed in both online database and our PDAC samples. Notably, rescue experiments further indicated that YAP1 is an important downstream effector involved in PWAR6-mediated functions. Mechanistically, PWAR6 could bind to methyltransferase EZH2, a core component of Polycomb Repressive Complex 2 (PRC2) in regulating gene expression, and scaffold EZH2 to the promoter region of YAP1, resulting in epigenetic repression of YAP1. In conclusion, our data manifest the vital roles of PWAR6 in PDAC tumorigenesis and underscore the potential of PWAR6 as a promising target for PDAC diagnosis and therapy.
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Proteínas Adaptadoras Transductoras de Señales/antagonistas & inhibidores , Biomarcadores de Tumor/metabolismo , Carcinoma Ductal Pancreático/patología , Epigénesis Genética , Regulación Neoplásica de la Expresión Génica , Neoplasias Pancreáticas/patología , ARN Largo no Codificante/genética , Factores de Transcripción/antagonistas & inhibidores , Proteínas Adaptadoras Transductoras de Señales/genética , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Animales , Apoptosis , Biomarcadores de Tumor/genética , Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/metabolismo , Movimiento Celular , Proliferación Celular , Femenino , Humanos , Masculino , Ratones , Ratones Endogámicos NOD , Ratones SCID , Persona de Mediana Edad , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/metabolismo , Pronóstico , Tasa de Supervivencia , Factores de Transcripción/genética , Factores de Transcripción/metabolismo , Células Tumorales Cultivadas , Ensayos Antitumor por Modelo de Xenoinjerto , Proteínas Señalizadoras YAPRESUMEN
BACKGROUND: Monoclonal antibodies that target the PD-1 receptor are emerging as promising therapeutic candidates for the treatment of biliary tract cancers (BTCs). The purpose of the current study was to assess the combination of the camrelizumab with chemotherapy as a first-line treatment for metastatic BTCs. METHODS: We conducted a prospective single-arm pilot study of PD-1 antibody (camrelizumab 3 mg/kg d1, Q2 W or Q3 W) combined with different chemotherapy regimens as first-line treatment for BTCs. Efficacy endpoints were objective response rate (ORR), disease control rate (DCR), progression free survival (PFS), and overall survival (OS). Treatment-related adverse events (TRAEs) were also evaluated. RESULTS: Fourteen patients with histologically confirmed BTCs were evaluated. The ORR was 14.3% (95% CI: 1.8 to 42.8) and the DCR was 64.3% (95%CI: 41.7 to 86.9). The median PFS was 6.5 months (95% CI: 3.8 to 9.2), and the 6- and 12-month PFS rates were 61.6% and 12.3%, respectively. The median OS was 9.9 months (95% CI: 7.6 to 12.2), and the 6-and 12-month OS rates were 74.5% and 26.6%, respectively. All patients displayed at least 1 TRAE., and Grade 3 or 4 TRAEs occurred in 6 (42.86%) patients. CONCLUSIONS: Camrelizumab combined with chemotherapy as first-line treatment for metastatic BTCs demonstrated acceptable safety and efficacy in our pilot study. These findings warrant prospective controlled clinical trials comparing combinations of camrelizumab and chemotherapy to standard regimens.
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Anticuerpos Monoclonales Humanizados/uso terapéutico , Neoplasias del Sistema Biliar/tratamiento farmacológico , Receptor de Muerte Celular Programada 1/uso terapéutico , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias del Sistema Biliar/patología , Supervivencia sin Enfermedad , Humanos , Masculino , Persona de Mediana Edad , Proyectos Piloto , Estudios Prospectivos , Resultado del TratamientoRESUMEN
Copious evidence reveals that long non-coding RNAs (lncRNAs) exert great regulatory functions in various human cancers. LINC01224 is a novel lncRNA, identified as a cancer regulator of HCC. However, the underlying mechanisms and clinical significance of LINC01224 in other types of cancers need further researches to explore. In this study, we aimed to elucidate the biological role of LINC01224 in NSCLC progression. Presently, LINNC01224 expression was elevated and miR-2467 expression was down-regulated in NSCLC, compared with standard control. Then we described the reciprocal correlation between LINC01224 and miR 2467. Afterward, the dual-luciferase reporter assay, RIP assay and RNA pull-down assay validated the base-pair interaction between LINC01224 and miR-2467. Moreover, our findings demonstrated that the silence of LINC01224 inhibited cell proliferation and invasion in NSCLC and enhanced cisplatin (CDDP) sensitivity in vitro. Besides, rescue assays verified that miR-2467 inhibitor could reverse the effects on cell biological activities and CDDP resistance caused by knockdown of LINC01224. Finally, in vivo experiments implicated that knockdown of LINC01224 could inhibit NSCLC tumor growth. To sum up, LINC01224 can promote tumor progression and CDDP resistance in NSCLC via sponging miR-2467, suggesting a promising therapeutic target for better diagnosis and prognosis of NSCLC patients.
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Resistencia a Antineoplásicos , Neoplasias Pulmonares , MicroARNs , ARN Largo no Codificante , Carcinoma de Pulmón de Células no Pequeñas , Proliferación Celular , Cisplatino/farmacología , Resistencia a Antineoplásicos/genética , Humanos , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/genética , MicroARNs/genética , ARN Largo no Codificante/genéticaRESUMEN
Acylglycerol kinase (AGK) uses adenosine triphosphate (ATP) and acylglycerol to generate adenosine diphosphate (ADP) and acyl-sn-glycerol 3-phosphate in cells. Recent evidence has demonstrated that dysregulated AGK expression is associated with the development of various human cancers. This study investigated the effects of AGK on gastric cancer cell proliferation and carcinogenesis and explored the underlying molecular events. AGK expression was up-regulated in gastric cancer and was associated with poor prognosis in gastric cancer patients. AGK overexpression increased gastric cancer proliferation, invasion capacity and the expression of the epithelial-mesenchymal transition markers in vitro. Conversely, the knockdown of AGK expression reduced gastric cancer cell proliferation in vitro and in nude mouse tumour cell xenografts. Importantly, AGK expression was associated with the YAP1 expression in gastric cancer cells and tissues. YAP1 expression also transcriptionally induced AGK expression through the binding of TEAD to the AGK gene promoter. However, AGK expression inhibited the activation of the Hippo pathway proteins and induced YAP1 nuclear localization to enhance the transcription activity of YAP1/TEADs. In conclusion, the study demonstrates that AGK is not only a novel target of the Hippo-YAP1 pathway, but that it also positively regulates YAP1 expression, thus forming a YAP1-AGK-positive feedback loop.
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Proteínas Adaptadoras Transductoras de Señales/metabolismo , Progresión de la Enfermedad , Regulación Neoplásica de la Expresión Génica , Fosfotransferasas (Aceptor de Grupo Alcohol)/genética , Neoplasias Gástricas/enzimología , Neoplasias Gástricas/genética , Factores de Transcripción/metabolismo , Regulación hacia Arriba/genética , Animales , Línea Celular Tumoral , Proliferación Celular/genética , Transición Epitelial-Mesenquimal/genética , Regulación Enzimológica de la Expresión Génica , Células HEK293 , Humanos , Ratones Desnudos , Invasividad Neoplásica , Fosfotransferasas (Aceptor de Grupo Alcohol)/metabolismo , Neoplasias Gástricas/patología , Transcripción Genética , Proteínas Señalizadoras YAPRESUMEN
BACKGROUND: Glucagon-like peptide 1 (GLP-1) and its analogs are first-line choices for the treatment of type 2 diabetes mellitus. Recent studies have shown that they exhibit antitumor properties in some tumors. We previously found that a GLP-1 analog, exendin-4 (Ex-4), inhibited the growth of prostate cancer cells through suppressing the PI3K/Akt/mTOR pathway, which is activated in response to enzalutamide treatment and reported to be closely related to resistance to enzalutamide. So we speculated that exendin-4 may enhance the sensitivity of prostate cancer to enzalutamide through inhibiting Akt activation. METHODS: LNCap and CWR22RV1 cell lines, as well as mice bearing xenografts formed from the two cells, were used. RESULTS: Exendin-4 in combination with enzalutamide dramatically suppressed tumor growth of prostate cancer cells compared to enzalutamide alone; exendin-4 is capable of antagonizing enzalutamide-induced invasion and migration of both prostate cancer cells (P < .05). Furthermore, the combination treatment significantly reduced Akt and mTOR levels that were triggered by enzalutamide administration, caused a further decrease in nuclear AR localization compared with the enzalutamide as a monotherapy (P < .5), though exendin-4 treatment alone showed no effect on nuclear AR. CONCLUSION: Our study demonstrated that exendin-4 alleviated resistance to enzalutamide, and suggested that exendin-4 combined with enzalutamide may be a more efficacious treatment for patients with advanced prostate cancer.
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Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Exenatida/farmacología , Feniltiohidantoína/análogos & derivados , Neoplasias de la Próstata/tratamiento farmacológico , Proteínas Proto-Oncogénicas c-akt/metabolismo , Animales , Benzamidas , Procesos de Crecimiento Celular/efectos de los fármacos , Línea Celular Tumoral , Movimiento Celular/efectos de los fármacos , Núcleo Celular/metabolismo , Sinergismo Farmacológico , Activación Enzimática/efectos de los fármacos , Exenatida/administración & dosificación , Receptor del Péptido 1 Similar al Glucagón/biosíntesis , Humanos , Masculino , Ratones Endogámicos BALB C , Ratones Desnudos , Invasividad Neoplásica , Nitrilos , Feniltiohidantoína/administración & dosificación , Feniltiohidantoína/farmacología , Neoplasias de la Próstata/enzimología , Neoplasias de la Próstata/patología , Distribución Aleatoria , Receptores Androgénicos/metabolismo , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
BACKGROUND: Follistatin-like 1 (FSTL1) plays a central role in the progression of tumor and tumor immunity. However, the effect of FSTL1 on the prognosis and immune infiltration of gastric cancer (GC) remains to be elucidated. METHODS: The expression of FSTL1 data was analyzed in Oncomine and TIMER databases. Analyses of clinical parameters and survival data were conducted by Kaplan-Meier plotter and immunohistochemistry. Western blot assay and real-time quantitative PCR (RT-qPCR) were used to analyze protein and mRNA expression, respectively. The correlations between FSTL1 and cancer immune infiltrates were analyzed by Tumor Immune Estimation Resource (TIME), Gene Expression Profiling Interactive Analysis (GEPIA), and LinkedOmics database. RESULTS: The expression of FSTL1 was significantly higher in GC tissues than in normal tissues, and bioinformatic analysis and immunohistochemistry (IHC) indicated that high FSTL1 expression significantly correlated with poor prognosis in GC. Moreover, FSTL1 was predicted as an independent prognostic factor in GC patients. Bioinformatics analysis results suggested that FSTL1 mainly involved in tumor progression and tumor immunity. And significant correlations were found between FSTL1 expression and immune cell infiltration in GC. CONCLUSIONS: The study effectively revealed useful information about FSTL1 expression, prognostic values, potential functional networks, and impact of tumor immune infiltration in GC. In summary, FSTL1 can be used as a biomarker for prognosis and evaluating immune cell infiltration in GC.
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Proteínas Relacionadas con la Folistatina , Neoplasias Gástricas , Biomarcadores , Proteínas Relacionadas con la Folistatina/genética , Humanos , Pronóstico , Neoplasias Gástricas/genética , Neoplasias Gástricas/inmunologíaRESUMEN
Interferon regulatory factor 2 binding protein 2 (IRF2BP2) is a transcriptional repressor involved in regulating gene expression and other biological processes, including tumorigenesis. However, the clinical significance and roles of IRF2BP2 in human gastric cancer (GC) remain uncertain. Clinical GC tissues were obtained from GC patients at the First Affiliated Hospital of Nanchang University. Immunohistochemistry (IHC) was conducted to detect the IRF2BP2 protein in clinical paraffin specimens. Cell proliferation, migration and invasion were evaluated by MTT, colony formation assays and transwell assays. Co-immunoprecipitation was conducted to detect the interaction between TEA domain family members 4 (TEAD4) and vestigial-like family member 4 (VGLL4) or Yes-associated protein 1 (YAP1). Dual-luciferase reporter assay was used to confirm the binding of miR-101-3p to the 3'-UTR. The expression of IRF2BP2 was significantly higher in GC tissues than in normal tissues. Patients with higher IRF2BP2 protein expression had lower survival. IRF2BP2 knockdown inhibited proliferation, migration, invasion and epithelial-mesenchymal transition in GC cells. IRF2BP2 knockdown decreased the mRNA and protein levels of connective tissue growth factor (CTGF). The interaction between IRF2BP2 and VGLL4 increased the binding of TEAD4 to YAP1, resulting in the transcriptional coactivation of CTGF. In addition, miR-101-3p suppressed the expression of CTGF by directly targeting the 3'-UTR of IRF2BP2. Taken together, these findings provide a model for the role of miR-101-3p-IRF2BP2-CTGF signalling axis in GC and a novel insight into the mechanism of GC progression and metastasis.
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Factor de Crecimiento del Tejido Conjuntivo/metabolismo , Proteínas de Unión al ADN/metabolismo , Regulación Neoplásica de la Expresión Génica/genética , Neoplasias Gástricas/metabolismo , Factores de Transcripción/metabolismo , Regiones no Traducidas 3' , Proteínas Adaptadoras Transductoras de Señales/genética , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Animales , Línea Celular Tumoral , Movimiento Celular/genética , Proliferación Celular/genética , Factor de Crecimiento del Tejido Conjuntivo/genética , Proteínas de Unión al ADN/genética , Bases de Datos Genéticas , Progresión de la Enfermedad , Transición Epitelial-Mesenquimal/genética , Femenino , Humanos , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , MicroARNs/genética , MicroARNs/metabolismo , Persona de Mediana Edad , Proteínas Musculares/genética , Proteínas Musculares/metabolismo , Neoplasias Gástricas/genética , Neoplasias Gástricas/mortalidad , Neoplasias Gástricas/patología , Factores de Transcripción de Dominio TEA , Factores de Transcripción/genética , Trasplante Heterólogo , Proteínas Señalizadoras YAPRESUMEN
BACKGROUND: Exendin-4, one of the most widely used antidiabetic drugs, has recently been reported to have potential antitumor effects in cancers. Prostate cancer (PC) is one of the most common cancers in male patients with type 2 diabetes mellitus, and radiotherapy plays a vital role in the therapy of PC. Whether exendin-4 has the potential to enhance PC response to ionizing radiation (IR) remains unknown. We aimed to explore whether exendin-4 radiosensitizes PC cells. METHODS: GLP-1 receptor (GLP-1R) expression in PC tissue samples and cell lines were analyzed, Human prostate cancer cells (PC3 and LNCap) were treated with IR and exendin-4, and subjected to proliferation, clone formation, cell cycle, immunoblotting, and immunohistochemical analysis. An in situ prostate tumor of animal model was established. RESULTS: We found that GLP-1R was expressed in human PC tissues and cell lines. 1-100 nM exendin-4 promoted the anti-proliferation effects of IR in vitro and in vivo, and enhanced radiation-induced G2/M cycle arrest in PC cells in a dose-dependent manner. Furthermore, Ex-4 increased AMPK phosphorylation, decrease the levels of p-mTOR, cyclin B, and p34cdc2 . CONCLUSIONS: Our study suggested exendin-4 radiosensitizes PC cells via activation of AMPK A and subsequent inhibition of p-mTOR, cyclin B, and p34cdc2 activation.
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Exenatida/farmacología , Fármacos Sensibilizantes a Radiaciones/farmacología , Quinasas de la Proteína-Quinasa Activada por el AMP , Animales , Ciclo Celular/efectos de los fármacos , Procesos de Crecimiento Celular/efectos de los fármacos , Línea Celular Tumoral , Interacciones Farmacológicas , Receptor del Péptido 1 Similar al Glucagón/biosíntesis , Humanos , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Neoplasias de la Próstata/tratamiento farmacológico , Neoplasias de la Próstata/metabolismo , Neoplasias de la Próstata/radioterapia , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Quinasas/metabolismo , Distribución Aleatoria , Serina-Treonina Quinasas TOR/antagonistas & inhibidores , Serina-Treonina Quinasas TOR/metabolismo , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
YAP1, a vital effector of Hippo pathway, promotes cancer development via transcriptionally regulating a batch of target genes involved in various signaling pathways, including proliferation, apoptosis, and cell drug sensitivity. Recently, circular RNAs (circRNAs) have been shown to control gene expression post-transcriptionally and become a new layer of gene regulation. However, whether circRNAs play roles in YAP1-induced tumorigenesis is still largely elusive. Here, we identify circRNA-000425 as a new inhibitory target of YAP1, and also find that it binds to miR-17/miR-106b, and thus suppresses cancer cell growth induced by these miRNAs. circRNA-000425 is revealed as a YAP1 target through circRNA microarray analysis of RNAs extracted from cells treated with or without YAP1 siRNAs, and further confirmed by RT-q-PCR and ChIP assays. Interestingly, bioinformatics analysis, luciferase assay, and RT-q-PCR results showed that circRNA-000425 binds to miR-17 and miR-106b, but not let-7a, and rescues the inhibitory effect of miR-17/miR-106 on the expressions of both p21 and BIM. In addition, colony formation and MTT assay showed that circRNA-000425 inhibits cancer cell growth induced by miR-17. These findings reveal a mechanism by which YAP1 promotes oncogenic activities of miR-17 and miR-106b through transcriptionally inhibiting circRNA-000425 expression.
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Proteínas Adaptadoras Transductoras de Señales/genética , Carcinogénesis/genética , Regulación Neoplásica de la Expresión Génica , MicroARNs/genética , Fosfoproteínas/genética , ARN/genética , Proliferación Celular , Humanos , Interferencia de ARN , ARN Circular , ARN Interferente Pequeño/genética , Factores de Transcripción , Proteínas Señalizadoras YAPRESUMEN
Three new meliacarpinin-type limonoids, toosendanes Aâ»C (1â»3), along with three, known meliacarpinins (4â»6) were isolated from the bark of Melia toosendan. Their structures, along with their absolute configurations, were elucidated, based on detailed analyses. These included HRESIMS and 1D/2D-NMR, modified Mosher's method, and electronic circular dichroism (ECD). Limonoids 2 and 3 showed moderate inhibitory activity on LPS-activated, RAW 264.7 macrophages.
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Limoninas/aislamiento & purificación , Melia/química , Corteza de la Planta/química , Animales , Antiinflamatorios/química , Antiinflamatorios/farmacología , Espectroscopía de Resonancia Magnética con Carbono-13 , Limoninas/química , Limoninas/farmacología , Ratones , Espectroscopía de Protones por Resonancia Magnética , Células RAW 264.7RESUMEN
5-Fluorouracil (5-FU) is a classic chemotherapeutic drug that has been widely used for colorectal cancer treatment, but colorectal cancer cells are often resistant to primary or acquired 5-FU therapy. Several studies have shown that miR-21 is significantly elevated in colorectal cancer. This suggests that this miRNA might play a role in this resistance. In this study, we investigated this possibility and the possible mechanism underlying this role. We showed that forced expression of miR-21 significantly inhibited apoptosis, enhanced cell proliferation, invasion, and colony formation ability, promoted G1/S cell cycle transition and increased the resistance of tumor cells to 5-FU and X radiation in HT-29 colon cancer cells. Furthermore, knockdown of miR-21 reversed these effects on HT-29 cells and increased the sensitivity of HT-29/5-FU to 5-FU chemotherapy. Finally, we showed that miR-21 targeted the human mutS homolog2 (hMSH2), and indirectly regulated the expression of thymidine phosphorylase (TP) and dihydropyrimidine dehydrogenase (DPD). These results demonstrate that miR-21 may play an important role in the 5-FU resistance of colon cancer cells.
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Quimioradioterapia , Neoplasias del Colon/genética , Neoplasias del Colon/terapia , MicroARNs/metabolismo , Terapia Molecular Dirigida , Regiones no Traducidas 3'/genética , Apoptosis/genética , Apoptosis/efectos de la radiación , Secuencia de Bases , Ciclo Celular/efectos de los fármacos , Ciclo Celular/efectos de la radiación , Proliferación Celular/efectos de los fármacos , Proliferación Celular/efectos de la radiación , Neoplasias del Colon/enzimología , Neoplasias del Colon/patología , Dihidrouracilo Deshidrogenasa (NADP)/genética , Dihidrouracilo Deshidrogenasa (NADP)/metabolismo , Ensayos de Selección de Medicamentos Antitumorales , Fluorouracilo/farmacología , Fluorouracilo/uso terapéutico , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Células HT29 , Humanos , MicroARNs/genética , Datos de Secuencia Molecular , Proteína 2 Homóloga a MutS/genética , Invasividad Neoplásica , Timidina Fosforilasa/genética , Timidina Fosforilasa/metabolismo , Ensayo de Tumor de Célula MadreRESUMEN
Background: Neoadjuvant therapy has become a mainstay of treatment for locally advanced resectable esophageal cancer. The objective of this research was to investigate the effectiveness and safety of neoadjuvant immunotherapy combined with chemotherapy in treating surgically removable esophageal squamous cell carcinoma (ESCC). Methods: From January 1, 2016 to April 1, 2023, we conducted a retrospective analysis of patients diagnosed with resectable esophageal cancer who underwent neoadjuvant immunotherapy combined with chemotherapy at The First Affiliated Hospital of Nanchang University. The primary endpoints of this study were pathologic complete response (pCR), major pathologic response (MPR) and disease-free survival (DFS). The secondary endpoints of this study were overall survival (OS), objective response rate (ORR) and safety. Results: A total of 122 patients with ESCC receiving neoadjuvant immune-chemotherapy (nICT) were included. Fifty-four patients achieved partial response (PR) and two patients achieved complete response (CR), with an ORR of 45.9%. Of the 106 patients who underwent surgery, a total of 28 patients achieved pCR (26.4%) and a total of 37 patients achieved MPR (34.9%). Grade 3 or higher adverse events occurred in 26 patients (21.3%). The most common postoperative complication was pneumonitis (25.5%). Conclusions: Neoadjuvant immunotherapy combined with chemotherapy demonstrates satisfactory efficacy in the treatment of locally advanced ESCC, with manageable treatment-related adverse events and postoperative complications.
RESUMEN
PURPOSE: This study aims to determine the clinical features and outcomes of PD-1 inhibitor therapy as the initial treatment in patients aged 65 years or older with locally advanced or metastatic esophageal squamous cell carcinoma (ESCC). MATERIALS AND METHODS: The retrospective study conducted a comprehensive analysis of elder patients diagnosed with locally advanced or metastatic ESCC who underwent combined immunochemotherapy in the first affiliated hospital of Nanchang University from January 2019 to January 2023. The main efficacy measures were the objective response rate (ORR) and progression-free survival (PFS). The secondary endpoints were disease control rate (DCR) and overall survival (OS). The evaluation of safety was based on the assessment of adverse events (AEs). RESULTS: A total of 88 patients were enrolled in the study. All patients received PD-1 inhibitors combined with chemotherapy including taxane and platinum as the first-line treatment. The median PFS was 6.2 months (95% CI: 5.1-7.3), and the median OS was 15.3 months (95% CI: 12.9-17.7). The ORR and DCR were 42.0% and 72.7%, correspondingly. 68 (77.3%) patients experienced treatment-related adverse events (TRAEs) of various degrees, with neutrophil count decreased (21, 23.9%) being the most frequent. TRAEs of grade 3 or 4 occurred in 13 (14.8%) patients. CONCLUSION: The study demonstrated that individuals older than 65 years with locally advanced or metastatic ESCC have a survival benefit from the first-line treatment of PD-1 inhibitors combined therapy, with a manageable safety profile.
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Protocolos de Quimioterapia Combinada Antineoplásica , Neoplasias Esofágicas , Carcinoma de Células Escamosas de Esófago , Inhibidores de Puntos de Control Inmunológico , Supervivencia sin Progresión , Humanos , Anciano , Masculino , Femenino , Estudios Retrospectivos , Neoplasias Esofágicas/tratamiento farmacológico , Neoplasias Esofágicas/patología , Neoplasias Esofágicas/mortalidad , Carcinoma de Células Escamosas de Esófago/tratamiento farmacológico , Carcinoma de Células Escamosas de Esófago/mortalidad , Carcinoma de Células Escamosas de Esófago/patología , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Inhibidores de Puntos de Control Inmunológico/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Anciano de 80 o más Años , Resultado del Tratamiento , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Tasa de SupervivenciaRESUMEN
To explore the clinicopathological characteristics, survival outcomes, and prognosis of very young gastric cancer (GC). From January 1, 2011 to January 1, 2021, GC patients under 30 years old treated in three tertiary hospitals were enrolled. Clinicopathological characteristics were summarized, prognostic factors and survival outcomes including overall survival (OS), disease-free survival (DFS), and progression-free survival (PFS) were retrospectively analyzed. One hundred patients were finally included, with a median age of 23 years.73 (73.0%) were female. Most patients had initial symptoms of abdominal pain (66.0%). The most common tumor locations were gastric antrum (38.0%) and gastric body (37.0%). The main histological types were diffuse (81.0%) and poorly differentiated (91.0%). Most patients presented with stage III-IV disease (82.0%) at diagnosis and the common sites of metastasis were ovary (39.5%) and peritoneum (27.6%). The mOS of the whole group was 23.3 months (95% CI 17.2-29.4). Moreover, the mOS of patients at stage I-II was not reached. The mOS of patients at stage III and stage IV was 40.6 months (95% CI 10.2-70.9) and 10.3 months (95% CI 8.9-11.6), respectively. The mDFS of stage I-III patients was 28.5 months (95% CI 14.7-42.3), and the mPFS of the metastatic patients was 4.5 months (95% CI 4.0-5.0). TNM stage (P = 0.005) and radical surgery (P = 0.001) were independent prognostic factors of overall survival. The very young GC were predominantly female, diffuse type, and advanced diagnosis. TNM stage and radical surgery were independent prognosis factors for overall survival.
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Neoplasias Gástricas , Humanos , Femenino , Adulto Joven , Adulto , Masculino , Pronóstico , Neoplasias Gástricas/patología , Estadificación de Neoplasias , Estudios Retrospectivos , GastrectomíaRESUMEN
OBJECTIVE: The study aimed to explore the clinical and pathological characteristics, survival outcomes, and prognostic factors of colorectal hepatoid adenocarcinoma. METHODS: We performed two cases of colorectal hepatoid adenocarcinoma treated at the Oncology Department of the First Affiliated Hospital of Nanchang University. We also reviewed literature up to the present and performed a retrospective study of colorectal hepatoid adenocarcinoma. RESULTS: Among the 39 patients included in this study, 28 had primary tumors in the colon, 9 in the rectum, and 2 in the rectosigmoid junction. The median age was 52 years (range 31-75 years); 28 patients (71.8%) were male. Out of the 32 patients for whom survival data were available, 24 patients succumbed to disease-related causes. The median overall survival of 32 patients was 8 months, with 1-year and 2-year overall survival rates of 31.0% and 16.0%, respectively. Univariate analysis revealed that depth of infiltration, presence of liver metastases, TNM stage, and the completeness of surgical resection were significantly associated with the overall survival period of colorectal hepatoid adenocarcinoma. CONCLUSION: Colorectal hepatoid adenocarcinoma exhibits a high degree of aggressiveness and poor prognosis. The major strategy for early-stage HAC was radical surgery and chemoradiotherapy demonstrates limited efficacy for extending survival.
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Adenocarcinoma , Neoplasias Colorrectales , Neoplasias Hepáticas , Humanos , Masculino , Adulto , Persona de Mediana Edad , Anciano , Femenino , Estudios Retrospectivos , Adenocarcinoma/patología , Neoplasias Hepáticas/secundario , Recto/patologíaRESUMEN
The effects of over-expression of ANXA10 gene on proliferation and apoptosis of hepato-cellular carcinoma cell line HepG2 were elucidated. The human ANXA10 gene was subcloned into the lentiviral vector, PGC-FU, to generate the lentiviral expression vector, PGC-FU-ANXA10. The corrected ANXA10 was confirmed by endoenzyme digestion, and sequencing. Recombinant lentiviruses were produced by 293T cells following the co-transfection of PGC-FU-ANXA10 with the packaging plasmids pHelper1.0 and pHelper2.0. The resulting recombinant lentiviruses carrying ANXA10 were then used to infect human embryonic kidney epithelial cells, and lentiviral particles were produced. The ANXA10 expression in 293T cells was detected by using fluorescent microscope and Western blotting. HepG2 cells were infected, and divided into PGC-Fu-ANXA10 group, PGC-Fu group and HepG2 cell group. The changes of ANXA10 mRNA and protein expression were detected by using RT-PCR and Western blotting respectively. Flow cytometry and MTT assay were performed to examine the changes in cell apoptosis and proliferation respectively. The recombinant PGC-FU-ANXA10 vector was successfully constructed, the ANXA10 protein was detected by using Western blotting, and virus titer was 2×10(8) TU/mL. The recombinant lentiviruses were effectively infected into HepG2 cells in vitro and the infection efficiency was 70%. At 72 h after infection, the ANXA10 mRNA and protein expression levels in PGC-Fu-ANXA10 group were significantly higher than in PGC-Fu group and HepG2 cell group (P<0.05); the in vitro growth inhibition rate of HepG2 cells in PGC-Fu-ANXA10 group was 24.65%, significantly higher than that in PGC-Fu group and HepG2 cell group (P<0.05), but there was no significant difference between PGC-Fu group and HepG2 cell group; the apoptosis rate in PGC-Fu-ANXA10 group, PGC-Fu group and HepG2 cell group was (51.92±1.41)%, (19.00±1.12)% and (3.59±0.89)% respectively. The apoptosis rate in PGC-Fu-ANXA10 group was significantly higher than in PGC-Fu group and HepG2 cell group (P<0.05). The recombinant lentiviruses PGC-FU-ANXA10 were constructed successfully and infected into HepG2 cells. The overexpression of ANXA10 gene can significantly inhibit proliferation and promote apoptosis of HepG2 cells in vitro.
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Anexinas/genética , Apoptosis/genética , Carcinoma Hepatocelular/genética , Neoplasias Hepáticas/genética , Línea Celular Tumoral , Proliferación Celular , Células Hep G2 , HumanosRESUMEN
F-box and WD repeat domain-containing 5 (FBXW5), with WD40 repeats, can bind to the PPxY sequence of the large tumor suppressor kinases 1/2 (LATS1/2) kinase domain, resulting in ubiquitination. Ubiquitination and the subsequent degradation of LATS1/2 abrogate the Hippo pathway and worsen gastric cancer (GC). However, the effects and molecular mechanisms of FBXW5 in GC remain unexplored. To elucidate the clinical significance of FBXW5, immunohistochemistry was conducted to reveal the positive correlation between FBXW5 expression and lymph node metastasis (p < 0.001) and TNM stage (training cohort: p = 0.018; validation cohort: p = 0.001). Further, patients with high FBXW5 expression were found to have poor prognosis (training cohort: log-rank p = 0.020; validation cohort: log-rank p = 0.025). Cell experiments revealed the promoting effects of FBXW5 on the proliferation, invasion, metastasis, and chemoresistance of GC cells. Blocking LATS1-YAP1 leads to the loss of FBXW5-mediated regulation of the Hippo pathway and partial functions. Further, co-immunoprecipitation and in vivo ubiquitination assays revealed the interaction between FBXW5 and LATS1, which promoted the ubiquitination and degradation of LATS1. Based on mouse xenograft assays, FBXW5 silencing attenuated the growth of subcutaneous tumor xenografts. Altogether, FBXW5 was found to inactivate the Hippo signaling pathway by enhancing LATS1 ubiquitination and degradation, which promoted the invasion, metastasis, and drug resistance of GC cells.