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BACKGROUND: The effect of neoadjuvant chemotherapy (NACT) in gallbladder cancer (GBC) patients remains controversial. The aim of this study was to assess the impact of NACT on overall survival (OS) and cancer specific survival (CSS) in patients with localized or locoregionally advanced GBC, and to explore possible protective predictors for prognosis. METHODS: Data for patients with localized or locoregionally advanced GBC (i.e., categories cTx-cT4, cN0-2, and cM0) from 2004 to 2020 were collected from the Surveillance, Epidemiology, and End Results (SEER) database. Patients in the NACT and non-NACT groups were propensity score matched (PSM) 1:3, and the Kaplan-Meier method and log-rank test were performed to analyze the impact of NACT on OS and CSS. Univariable and multivariable Cox regression models were applied to identify the possible prognostic factors. Subgroup analysis was conducted to identify patients who would benefit from NACT. RESULTS: Of the 2676 cases included, 78 NACT and 234 non-NACT patients remained after PSM. In localized or locoregionally advanced GBC patients, the median OS of the NACT and non-NACT was 31 and 16 months (log-rank P < 0.01), and the median CSS of NACT and non-NACT was 32 and 17 months (log-rank P < 0.01), respectively. Longer median OS (31 vs 17 months, log-rank P < 0.01) and CSS (32 vs 20 months, log-rank P < 0.01) was associated with NACT compared with surgery alone. Multivariable Cox regression analysis showed that NACT, stage, and surgery type were prognostic factors for OS and CSS in GBC patients. Subgroup analysis revealed that the survival hazard ratios (HRs) of NACT vs non-NACT for localized or locoregionally advanced GBC patients were significant in most subgroups. CONCLUSIONS: NACT may provide therapeutic benefits for localized or locoregionally advanced GBC patients, especially for those with advanced stage, node-positive, poorly differentiated or undifferentiated disease. NACT combined with radical surgery was associated with a survival advantage. Therefore, NACT combined with surgery may provide a better treatment option for resectable GBC patients.
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Neoplasias de la Vesícula Biliar , Terapia Neoadyuvante , Puntaje de Propensión , Programa de VERF , Humanos , Neoplasias de la Vesícula Biliar/patología , Neoplasias de la Vesícula Biliar/mortalidad , Neoplasias de la Vesícula Biliar/tratamiento farmacológico , Neoplasias de la Vesícula Biliar/terapia , Femenino , Masculino , Terapia Neoadyuvante/métodos , Terapia Neoadyuvante/estadística & datos numéricos , Persona de Mediana Edad , Pronóstico , Anciano , Quimioterapia Adyuvante/estadística & datos numéricos , Quimioterapia Adyuvante/métodos , Estadificación de Neoplasias , Estimación de Kaplan-MeierRESUMEN
Liver metastasis is common in patients with gallbladder cancer (GBC), imposing a significant challenge in clinical management and serving as a poor prognostic indicator. However, the mechanisms underlying liver metastasis remain largely unknown. Here, we report a crucial role of tyrosine aminotransferase (TAT) in liver metastasis of GBC. TAT is frequently up-regulated in GBC tissues. Increased TAT expression is associated with frequent liver metastasis and poor prognosis of GBC patients. Overexpression of TAT promotes GBC cell migration and invasion in vitro, as well as liver metastasis in vivo. TAT knockdown has the opposite effects. Intriguingly, TAT promotes liver metastasis of GBC by potentiating cardiolipin-dependent mitophagy. Mechanistically, TAT directly binds to cardiolipin and leads to cardiolipin externalization and subsequent mitophagy. Moreover, TRIM21 (Tripartite Motif Containing 21), an E3 ubiquitin ligase, interacts with TAT. The histine residues 336 and 338 at TRIM21 are essential for this binding. TRIM21 preferentially adds the lysine 63 (K63)-linked ubiquitin chains on TAT principally at K136. TRIM21-mediated TAT ubiquitination impairs its dimerization and mitochondrial location, subsequently inhibiting tumor invasion and migration of GBC cells. Therefore, our study identifies TAT as a novel driver of GBC liver metastasis, emphasizing its potential as a therapeutic target.
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Movimiento Celular , Neoplasias de la Vesícula Biliar , Neoplasias Hepáticas , Ribonucleoproteínas , Ubiquitinación , Animales , Humanos , Ratones , Línea Celular Tumoral , Neoplasias de la Vesícula Biliar/patología , Neoplasias de la Vesícula Biliar/genética , Neoplasias de la Vesícula Biliar/metabolismo , Regulación Neoplásica de la Expresión Génica , Neoplasias Hepáticas/secundario , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patología , Ratones Endogámicos BALB C , Ratones Desnudos , Mitofagia , Invasividad Neoplásica , Ribonucleoproteínas/metabolismo , Ribonucleoproteínas/genética , Tirosina TransaminasaRESUMEN
Ion migration activated by illumination is a critical factor responsible for the performance decline and stability degradation of perovskite solar cells (PSCs). While ion migration has been widely believed to be much slower than charge transport, recent research suggests that, despite the lack of understanding of the mechanism, it may also be involved in a series of rapid photoelectric responses of PSCs. Here, we report an improved circuit-switched transient photoelectric technique with nanosecond temporal resolution, which enables quantitative characterization of ion migration dynamics in PSCs across a fairly broad time window. Specifically, ion migration occurring within microseconds after illumination (corresponding to a diffusion length of â¼10-7 cm) is unambiguously identified. In conjunction with the composition engineering protocol, we justify that it arises from the short-range migration of halide anions and organic cations around the contact/perovskite interface. The rapid ion migration kinetics revealed in this work strongly complement the well-established ion migration model, which offers new insights into the mechanism of ion-carrier interaction in PSC devices.
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Gallbladder cancer (GBC) is a type of rare but highly aggressive cancer with a dismal prognosis. Runt-related transcription factor 3 (RUNX3), a member of the runt-domain family, and its promoter methylation have been widely observed in a variety of human malignancies. However, the biological function and underlying mechanism of RUNX3 in GBC remain elusive. In this study, bisulfate sequencing PCR (BSP), Western blot, and qPCR were applied to identify the expression level and DNA methylation level of RUNX3 in GBC tissues and cells. The transcriptional relationship between RUNX3 and Inhibitor of growth 1 (ING1) was validated by dual-luciferase reporter assay and ChIP assay. A series of gain-of-function and loss-of-function assays were performed to detect the function and the regulatory relationship of RUNX3 in vitro and in vivo. RUNX3 was aberrantly downregulated in GBC cells and tissues caused by DNA Methyltransferase 1 (DNMT1)-mediated methylation, and downregulation of RUNX3 is associated with poor prognosis of GBC patients. Functional experiments reveal that RUNX3 can induce ferroptosis of GBC cells in vitro and in vivo. Mechanistically, RUNX3 induces ferroptosis by activating ING1 transcription, thereby repressing SLC7A11 in a p53-dependent manner. In conclusion, the downregulation of RUNX3 is mediated by DNA methylation, which promotes the pathogenesis of gallbladder cancer through attenuating SLC7A11-mediated ferroptosis. This study gives novel insights into the role of RUNX3 in the ferroptosis of GBC cells, which may contribute to developing potential treatment targets for GBC.
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Ferroptosis , Neoplasias de la Vesícula Biliar , Humanos , Sistema de Transporte de Aminoácidos y+/genética , Línea Celular Tumoral , Metilación de ADN , Neoplasias de la Vesícula Biliar/metabolismo , Regulación Neoplásica de la Expresión Génica , Regiones Promotoras GenéticasRESUMEN
Objective: Gallbladder cancer (GBC) is highly malignant and is often diagnosed at the advanced stage. Lack of opportunity to surgery results in an unsatisfactory outcome. This pilot study employed gemcitabine combined with nab-paclitaxel (AG) as a conversion therapeutic measure for locally advanced GBC and successfully achieved conversion surgery in three initially unresectable GBC patients. We will introduce our experience on improving the outcome of this dismal disease. Methods: Radiology and nuclear medicine imaging were performed in each patient, and resectability was evaluated by joint consultation of our multi-disciplinary team (MDT). Patients evaluated as unresectable were treated with the AG regimen and re-evaluated for treatment response. When complete or partial response is achieved, MDT opinion would be required to assess the possibility of performing conversion surgery with R0 resection. Results: Three GBC patients who were initially evaluated as unresectable successfully underwent R0 resection after conversion therapy with the AG regimen. The first case was a recurrent GBC patient evaluated as locally advanced and eventually achieved pathological complete response. The second case was a GBC patient who underwent R1 resection with residual lesions in the gallbladder bed and isolated No. 16 lymph node metastasis and who had a pathologically complete response after treatment. The third case had multiple but resectable liver metastases; both objective response and partial pathologic response were achieved. None of the patients experienced serious treatment-related adverse events. All cases revealed no evidence of recurrence or metastasis after a median follow-up of 12 months. Conclusions: Conversion therapy shows a favorable efficacy in those unresectable GBC patients. Gemcitabine plus nab-paclitaxel has the potential to be used as a preoperative treatment option for GBC patients at the advanced stage. To further explore the efficacy of AG on conversion therapy for GBC patients, a prospective clinical trial has been registered (ChiCTR2200055698).
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The long non-coding RNAs (lncRNAs) have been implicated in multiple human cancers, which may offer great potential as putative targets for cancer diagnosis and treatment. However, the roles of most lncRNAs in gallbladder cancer (GBC) remain poorly understood. The objective of this research involves investigating the clinical implications and underlying mechanism of lncRNA motor neuron and pancreas homeobo×1 antisense RNA 1 (MNX1-AS1) in GBC. This study shows that MNX1-AS1 expression is elevated in the tissues of GBC patients, and is strongly associated with reduced patient survival. Functionally, MNX1-AS1 significantly stimulates the proliferation and metastasis of GBC cells in vitro and in vivo. Mechanistically, MNX1-AS1 is transcriptionally activated by TEA domain family member 4 (TEAD4), and suppresses insulin-like growing factor 2 mRNA-binding protein 3 (IGF2BP3) degradation by recruiting ubiquitin specific peptidase 16 (USP16). Furthermore, MNX1-AS1/IGF2BP3 axis inhibits the Hippo signaling pathway and subsequently activates TEAD4, thereby forming a positive feedback loop. According to our results, MNX1-AS1 facilitates tumorigenesis, progression and metastasis of GBC through a MNX1-AS1/IGF2BP3/Hippo pathway positive feedback loop, which could be both diagnostically and therapeutically helpful in GBC.
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Neoplasias de la Vesícula Biliar , MicroARNs , ARN Largo no Codificante , Línea Celular Tumoral , Movimiento Celular/genética , Proliferación Celular/genética , Retroalimentación , Neoplasias de la Vesícula Biliar/genética , Regulación Neoplásica de la Expresión Génica , Vía de Señalización Hippo , Proteínas de Homeodominio/genética , Humanos , Insulina/metabolismo , MicroARNs/genética , ARN Largo no Codificante/genética , ARN Mensajero , Proteínas de Unión al ARN/genética , Factores de Transcripción de Dominio TEA , Factores de Transcripción/genética , Factores de Transcripción/metabolismo , Ubiquitina TiolesterasaRESUMEN
Pancreatic cancer (PC) is one of the most fatal and chemoresistant malignancies with a poor prognosis. The current therapeutic options for PC have not achieved satisfactory results due to drug resistance. Therefore, it is urgent to develop novel treatment strategies with enhanced efficacy. This study sought to investigate the anticancer effect of gemcitabine and XCT790, an estrogen-related receptor alpha (ERRα) inverse agonist, as monotherapies or in combination for the treatment of PC. Here we demonstrated that the drug combination synergistically suppressed PC cell viability, its proliferative, migratory, invasive, apoptotic activities, and epithelial-to-mesenchymal transition (EMT), and it triggered G0/G1 cell cycle arrest and programmed cell death in vitro. In addition, in vivo assays using xenograft and mini-PDX (patient-derived xenograft) models further confirmed the synergistic antitumor effect between gemcitabine and XCT790 on PC. Mechanistically, gemcitabine and XCT790 suppressed PC by inhibiting ERRα and MEK/ERK signaling pathway. In conclusion, our current study demonstrated for the first time that gemcitabine combined with XCT790 displayed synergistic anticancer activities against PC, suggesting that their combination might be a promising treatment strategy for the therapy of PC.
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Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Desoxicitidina/análogos & derivados , Nitrilos/farmacología , Neoplasias Pancreáticas/tratamiento farmacológico , Receptores de Estrógenos/efectos de los fármacos , Tiazoles/farmacología , Animales , Apoptosis/efectos de los fármacos , Ciclo Celular/efectos de los fármacos , Desoxicitidina/farmacología , Sinergismo Farmacológico , Transición Epitelial-Mesenquimal/efectos de los fármacos , Humanos , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Ensayos Antitumor por Modelo de Xenoinjerto , Gemcitabina , Receptor Relacionado con Estrógeno ERRalfaRESUMEN
BACKGROUND: Inflammation is often related to cancer, and several inflammatory scores have been established to predict the prognosis of various types of cancer. Our study aimed to determine the prognostic value of the preoperative lymphocyte to C-reactive protein ratio (LCR) for predicting postoperative outcomes in patients with resectable gallbladder cancer (GBC). METHODS: A retrospective analysis of 104 GBC patients who received curative surgery at Xinhua Hospital, Affiliated to Shanghai Jiao Tong University School of Medicine from January 2000 to December 2016 was performed. A time-dependent receiver operating characteristic curve was constructed to evaluate the accuracy of different markers. Univariate and multivariate Cox proportional hazard models were used to define factors associated with overall survival. RESULTS: Among the assessed variables, the preoperative LCR showed the highest accuracy in predicting the overall survival of GBC patients (AUC: 0.736). Decreased preoperative LCR was significantly associated with advanced tumor stage, including tumor invasion (P = 0.018), lymph node metastasis (P = 0.011) and TNM stage (P = 0.022). A low preoperative LCR (cutoff threshold = 145.5) was an independent risk factor for overall survival in patients with resectable GBC (P < 0.001). CONCLUSIONS: The preoperative LCR is a novel and valuable prognostic indicator of postoperative survival in patients with resectable GBC.
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Carcinoma in Situ , Neoplasias de la Vesícula Biliar , Proteína C-Reactiva/análisis , Carcinoma in Situ/patología , China , Neoplasias de la Vesícula Biliar/patología , Humanos , Linfocitos , Estadificación de Neoplasias , Neutrófilos/química , Neutrófilos/metabolismo , Neutrófilos/patología , Pronóstico , Estudios RetrospectivosRESUMEN
Dynamic mode decomposition (DMD) is a powerful tool for extracting spatial and temporal patterns from multi-dimensional time series, and it has been used successfully in a wide range of fields, including fluid mechanics, robotics and neuroscience. Two of the main challenges remaining in DMD research are noise sensitivity and issues related to Krylov space closure when modelling nonlinear systems. Here, we investigate the combination of noise and nonlinearity in a controlled setting, by studying a class of systems with linear latent dynamics which are observed via multinomial observables. Our numerical models include system and measurement noise. We explore the influences of dataset metrics, the spectrum of the latent dynamics, the normality of the system matrix and the geometry of the dynamics. Our results show that even for these very mildly nonlinear conditions, DMD methods often fail to recover the spectrum and can have poor predictive ability. Our work is motivated by our experience modelling multilegged robot data, where we have encountered great difficulty in reconstructing time series for oscillatory systems with intermediate transients, which decay only slightly faster than a period.
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Long noncoding RNA DiGeorge syndrome critical region gene 5 (DGCR5) has been shown to be highly associated with cancer development. However, the biological role and molecular mechanism of DGCR5 in pancreatic cancer (PC) remains largely unknown. This study aimed to explore the role of DGCR5 in PC. It was revealed that DGCR5 was highly expressed in PC tissues compared with adjacent normal tissues and was associated with poor prognosis in PC patients. Furthermore, DGCR5 depletion inhibited the proliferation, migration and invasion by increasing apoptosis and inducing G0/G1 cell cycle arrest in vitro. Moreover, xenograft assay validated that DGCR5 promotes PC tumor growth in vivo. Mechanistically, DGCR5 was found to act as a ceRNA by sponging miR-3163 to regulate DNA topoisomerase 2-alpha (TOP2A) and inhibit Wnt/ß-catenin pathway. In addition, it was found that DGCR5 downregulation could enhance the sensitivity of PC cells to gemcitabine, and ChIP assay showed that PAX5 (Paired Box 5) could bind to the promoter region of DGCR5 and increase its transcription. The results of the present study indicated that DGCR5 may be a potential diagnostic biomarker and therapeutic target for PC.
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ADN-Topoisomerasas de Tipo II/metabolismo , MicroARNs/metabolismo , Factor de Transcripción PAX5/metabolismo , Neoplasias Pancreáticas/metabolismo , ARN Largo no Codificante/metabolismo , Vía de Señalización Wnt , beta Catenina/metabolismo , Apoptosis/genética , Puntos de Control del Ciclo Celular/genética , Línea Celular Tumoral , Proliferación Celular , Transición Epitelial-Mesenquimal , Femenino , Técnicas de Silenciamiento del Gen , Humanos , Masculino , Persona de Mediana Edad , Invasividad Neoplásica , Neoplasias Pancreáticas/patología , ARN Largo no Codificante/genéticaRESUMEN
Estrogen-related receptor alpha (ERRα), an orphan nuclear receptor, was reported to be highly associated with the progression and tumorigenesis of several human malignancies. However, the biological role and underlying molecular mechanisms of ERRα in pancreatic cancer (PC) remain unknown. The present study demonstrated that ERRα was significantly overexpressed in PC tissues and cell lines. Its high expression was correlated with tumor size, distant metastasis, TNM stage, tumor differentiation and poor prognosis of PC. Subsequent functional assays showed that ERRα promoted PC cell proliferation, tumor growth, as well as migration and invasion via activating the epithelial-mesenchymal transition. In addition, knockdown of ERRα induced apoptosis and G0/G1 cell cycle arrest in PC cells. Plasminogen activator inhibitor 1 (PAI1) was identified by RNA sequencing, knockdown of which could suppress the cell proliferation, migration and invasion that promoted by ERRα overexpression. Further mechanistic investigation using chromatin immunoprecipitation and dual-luciferase reporter assays revealed that ERRα could bind to the PAI1 promoter region and transcriptionally enhance PAI1 expression. Moreover, our data indicated that ERRα played its oncogenic role in PC via activating the MEK/ERK pathway. Taken together, our study demonstrates that ERRα promotes PC progression by enhancing the transcription of PAI1 and activation of the MEK/ERK pathway, pointing to ERRα as a novel diagnostic and therapeutic target for PC.
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PURPOSE: The aim of this study was to determine the Immunoscore as an independent prognostic factor for cholangiocarcinoma and establish a useful prognostic model for postoperative patients. METHODS: This retrospective study was performed to assess the correlation between the clinicopathological features, tumor immune microenvironment, and prognosis of 76 patients with cholangiocarcinoma. Multivariate analysis was used to identify independent factors significantly associated with local recurrence-free survival (LRFS) and overall survival (OS). Finally, we constructed a nomogram combining the Immunoscore with clinicopathologic features to predict postoperative recurrence and OS. RESULTS: The present study showed that immune cell infiltration was negatively correlated with tumor size, peripheral vascular invasion, lymph node metastasis, and tumor staging. Kaplan-Meier curves indicated that a decreased Immunoscore was associated with poor prognosis. Multivariate analysis demonstrated that resection type, number of tumors, lymph node metastasis, TNM staging, and the Immunoscore were significantly associated with LRFS. For OS, the significantly correlated factors included resection type, peripheral vascular invasion, TNM staging, and the Immunoscore. Immunoscore was superior to TNM staging in predicting both LRFS and OS according to the receiver operating characteristic analysis. Based on the results of the Cox regression analysis, a prognostic nomogram for the postoperative recurrence of cholangiocarcinoma and OS of patients was established. CONCLUSION: The results of this study suggest that the Immunoscore may be used as an independent predictor of postoperative recurrence and OS of patients with cholangiocarcinoma. The Immunoscore appears to offer distinct advantages over the TNM staging system. By combining the Immunoscore and clinicopathological features, the proposed nomogram provides a more accurate predictive tool for postoperative patients with cholangiocarcinoma.
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Gallbladder cancer (GBC) is a highly aggressive malignant cancer with poor prognosis. Long noncoding RNA (lncRNA) DiGeorge syndrome critical region gene (DGCR5) has been reported to participate in various types of cancers, but its role in GBC remains largely unknown. This study aimed to explore the functions and mechanisms of DGCR5 in GBC. Here, we found that DGCR5 was upregulated in GBC tissues and cell lines. Through functional experiments, it was demonstrated that silence of DGCR5 significantly suppressed the cell proliferation, migration, invasion, and induced apoptosis and cell cycle arrest in GBC cells. In addition, miR-3619-5p was predicted and further verified as the target of DGCR5. Moreover, miR-3619-5p was observed downregulated in GBC tissues and cell lines, and miR-3619-5p mimics repressed the GBC cell proliferation, migration, invasion and could be rescued by DGCR5 overexpression. Mechanistically, it was found that DGCR5 knockdown and miR-3619-5p mimics inactivated the MEK/ERK1/2 and JNK/p38 MAPK pathways. In addition, rescue experiments indicated that inhibition of MEK/ERK1/2 and JNK/p38 MAPK pathways could reverse the effects of DGCR5 overexpression on cell proliferation, migration and invasion. Finally, xenograft model assay was used to validate that knockdown of DGCR5 suppressed GBC via regulating MEK/ERK1/2 and JNK/p38 MAPK pathways in vivo. Taken together, it was uncovered in our study that DGCR5 exerts an oncogenic role by sponging miR-3619-5p and activating MEK/ERK1/2 and JNK/p38 MAPK pathways in GBC progression.