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Herein, we aimed to evaluate the efficacy and safety of camrelizumab combined with docetaxel and carboplatin as a neoadjuvant treatment for locally advanced oesophageal squamous cell carcinoma (OSCC). Fifty-one patients with OSCC, treated from July 2020 to October 2022, were analyzed. Of them, 41 patients underwent surgery 4-8 weeks after undergoing two cycles of camrelizumab (200 mg IV Q3W) combined with docetaxel (75 mg/m2 IV Q3W) and carboplatin (area under the curve = 5-6 IV Q3W). The primary endpoint was the pathological complete response rate. All 51 patients (100%) experienced treatment-related grades 1-2 adverse events, and 2 patients (3.9%) experienced grade 4 events (including elevated alanine transaminase/aspartate transferase levels and Guillain-Barre syndrome). Fifty patients were evaluated for the treatment efficacy. Of them, 13 achieved complete response, and the objective response rate was 74%. Only 41 patients underwent surgical treatment. The pathological complete response rate was 17.1%, the major pathological response rate was 63.4%, and the R0 resection rate was 100%. Approximately 22% of the patients had tumor regression grades 0. Eight patients (19.5%) developed surgery-related complications. The median follow-up time was 18 months (range: 3-29 months). Four patients experienced disease progression, while four died. The median disease-free survival and overall survival were not reached. Camrelizumab combined with docetaxel and carboplatin is an effective and safe neoadjuvant treatment for locally advanced OSCC. This regimen may afford a potential strategy to treat patients with locally advanced OSCC.
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Anticuerpos Monoclonales Humanizados , Neoplasias Esofágicas , Carcinoma de Células Escamosas de Esófago , Humanos , Docetaxel/uso terapéutico , Carboplatino , Carcinoma de Células Escamosas de Esófago/tratamiento farmacológico , Carcinoma de Células Escamosas de Esófago/patología , Terapia Neoadyuvante , Estadificación de Neoplasias , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias Esofágicas/patologíaRESUMEN
Although the importance of artificial intelligence (AI) has often been highlighted in strategic agility and decision outcomes, whether it helps firms strengthen their competitiveness and the means firms use to achieve such competitiveness are still under-researched. Our research thus joins the recent discussion on digitalization trends and strategic responses to COVID-19 to better understand how firms strengthen their competitiveness during such challenging times. Namely, this study incorporates the strategic responses to COVID-19 into the technology-organization-environment (TOE) framework by investigating the impacts of different configurations of TOE contexts and strategic responses on a firm's competitive advantage. We used fuzzy-set qualitative comparative analysis to investigate how TOE contexts and strategic responses integrate into configurations and impact a firm's competiveness. By applying a configurational approach with data from 514 exporting firms in China, we find a strong indication of the equifinality of different strategies, indicating that multiple strategic paths can be used to respond to crises. The adoption of AI, while important, is not sufficient to enhance a firm's competitiveness. Our results stress the significance of data quality, organizational resources and capabilities, and digital business model innovation for AI adoption. We also identify successful strategic paths of AI adoption aversion and ambidextrous strategies. The findings have practical implications for firms seeking effective strategies to respond to future crises and sustain their competitive advantages.
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Aim: To explore the prognostic value of the systemic inflammatory response index (SIRI) and peripheral blood T-cell subsets in patients with hepatocellular carcinoma (HCC) and the relationship between them. Materials & methods: We treated 352 patients with HCC with sorafenib and/or immune checkpoint inhibitors (ICIs) and analyzed SIRI and peripheral blood T cells. Results: SIRI was an independent prognostic factor for patients with HCC receiving systemic therapy. Patients with high SIRI and low baseline peripheral blood T-cell counts showed a poor response to ICIs. SIRI was significantly and negatively correlated with CD3+, CD4+ and CD8+ T-cell counts. Conclusion: SIRI markers can be employed to noninvasively assess the presence of cancer-promoting inflammation in the tumor microenvironment and predict the efficacy of targeted therapy and immunotherapy.
Hepatocellular carcinoma (HCC) is one of the most common malignant tumors. The change of immune microenvironment plays an important role in the occurrence and development of HCC. Recently, targeted therapy and immunotherapy have brought new hope to patients with advanced HCC. However, owing to the complexity of the immune microenvironment, not all patients can benefit from it. This study explores a simple, non-invasive method based on blood cell count to assess the immune microenvironment of HCC and predict the efficacy of treatment.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , Carcinoma Hepatocelular/patología , Humanos , Inhibidores de Puntos de Control Inmunológico , Neoplasias Hepáticas/patología , Pronóstico , Síndrome de Respuesta Inflamatoria Sistémica/diagnóstico , Síndrome de Respuesta Inflamatoria Sistémica/etiología , Microambiente TumoralRESUMEN
OBJECTIVE: To explore whether the distance of rectal neuroendocrine neoplasms from the anal margin has an impact on the prognosis of patients and evaluate lymphatic metastases risk score for colorectal neuroendocrine neoplasms (NENs). METHODS: Clinical pathological and follow-up data of 71 patients identified as colorectal neuroendocrine neoplasms by pathology from July 2011 to July 2019 were carefully collected. RESULTS: Among 71 patients with colorectal NENs, most of the tumors were rectal NENs (62 cases). A total of 26 patients were in the presence of lymph node metastasis, and 44 patients had negative lymph nodes. Patients with lesions from the anal margin > 5 cm in rectum have a better prognosis (P = 0.022). Tumor stage (P = 0.034) and grade (P = 0.001) were independent risk predictors of lymphatic metastases. We developed a lymphatic metastasis risk score for rectal NENs, and patients with the score ≥ 7.5 were more likely to develop lymph node metastases (area 0.958, 95% CI 0.903-1.000, P = 0.000) with a sensitivity of 72.2% and a specificity of 97.3%. CONCLUSION: Patients with lesions from the anal margin > 5 cm and lymphatic metastasis risk score ≥ 7.5 should be treated actively.
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Tumores Neuroendocrinos , Neoplasias del Recto , Humanos , Metástasis Linfática , Estadificación de Neoplasias , Tumores Neuroendocrinos/patología , Pronóstico , Neoplasias del Recto/patología , Estudios Retrospectivos , Factores de RiesgoRESUMEN
Aim: To compare the performance of first-line paclitaxel liposome + oxaliplatin and SOX (tegafur/gimeracil/oteracil + oxaliplatin) in advanced gastric cancer patients. Materials & methods: Stage IIb-IV gastric cancer patients underwent either first-line paclitaxel liposome + oxaliplatin (n = 52) or SOX (n = 69) between 2010-2013, and followed up until 2015 or death. Results: Both groups had similar objective response rate (p = 0.48) and disease control rate (p = 0.992) after two chemotherapy cycles, median progression-free survival (p = 0.495) and median overall survival (p = 0.208). Liposome group had significantly lower rate of grade I-II platelet decline and liver function damage (p = 0.04 and 0.019). Multivariate COX regression identified pre-treatment neutrophil-to-lymphocyte ratio as an independent prognostic factor. Conclusion: First-line paclitaxel liposome + oxaliplatin has comparable efficacy, but causes reduced adverse reactions in advanced gastric cancer as compared with SOX.
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Antineoplásicos Fitogénicos/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Liposomas , Paclitaxel/administración & dosificación , Neoplasias Gástricas/tratamiento farmacológico , Neoplasias Gástricas/patología , Anciano , Anciano de 80 o más Años , Antineoplásicos Fitogénicos/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Biomarcadores , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Metástasis de la Neoplasia , Estadificación de Neoplasias , Paclitaxel/efectos adversos , Pronóstico , Estudios Retrospectivos , Neoplasias Gástricas/mortalidad , Resultado del TratamientoRESUMEN
Dysregulation of apoptosis occurs in different types of malignant tumors and is likely to influence the tumor evolution, as well as clinical prognosis. However, the limited number of studies investigating the predictive power of apoptosis-related genes (ARGs) in gastric cancer indicates a gap in the current research. 174 ARGs who differentially expressed were screened using public databases, including the Gene Expression Omnibus and the Molecular Signatures Database. Univariate and LASSO regression analyses were rigorous approaches to recognize the 12 optimal genes (CTHRC1, PDGFRL, VCAN, GJA1, LOX, UPP1, ANGPT2, CRIM1, HIF1A, APOD, RNase1, and ID1) that make up the prognostic risk model. Molecular mutations, related signaling pathways, and immune system characteristics in different subgroups defined by the risk model were analyzed using different R packages. Moreover, based on the database of Genomics of Drug Sensitivity in Cancer, chemotherapy sensitivity was predicted among the risk subgroups. As a result, there were differences in mutation profiles, signaling pathways, and infiltrated immune cells between patients in various risk groups. Moreover, the low-risk group displayed greater sensitivity to chemotherapy than the high-risk group. Risk model provided a better prognostic value than the T, N, and M stages, according to the receiver operating characteristic curve. Finally, in a nomogram, the risk model and clinical factors were combined to visualize the survival rates of patients with GC. In response to the differential expression of apoptosis-related genes, a novel model for predicting the prognosis of GC patients was developed. This model may be highly valuable for guiding doctors to deliver treatment plans tailored to the need of patients with GC.
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Background: Elevated level of interleukin-8 (IL-8) promotes hepatocellular carcinoma (HCC) development and contributes to poor prognosis. Previously, we have proved that Dicer inhibits HCC progression. In this study, we evaluated the potential interaction between IL-8 and Dicer as well as their influence on HCC. Methods: Hepatocellular carcinoma cells of SMMC-7721 were divided into 2 groups for subsequent analysis: pCMV-Dicer group for Dicer-overexpressing lentivirus transfected cells (pCMV-Dicer cells) and pCMV-NC group for empty lentivirus transfected cells (pCMV-NC cells). Cell Counting kit-8 (CCK8), wound healing, and transwell were used to evaluate the inhibitory effect of Dicer overexpression on proliferation, migration, and invasion of HCC cells. The level of IL-8 was measured by flow cytometry bead-based immunoassays. Male nude BALB/c mice injected with pCMV-Dicer or pCMV-NC cell suspensions was used for transplant of HCC tumor. Results: We found that the secretion of IL-8 was reduced in the medium of pCMV-Dicer cells (P = .027). Recombinant human IL-8 (rhIL-8) reversed the inhibitory effect of Dicer on proliferation (P < .01), migration (P = .003), and invasion (P = .001), whereas IL-8 inhibitor of reparixin enhanced inhibitory effect of Dicer on proliferation (P < .05), migration (P = .008), and invasion (P = .000). Lenvatinib downregulated the IL-8 level of HCC cells (P = .000) as well as promote Dicer-induced inhibition for HCC cells referring to proliferation (P < .05), migration (P = .000), and invasion (P = .000). Animal experiments also demonstrated that Dicer cooperated with lenvatinib to inhibit the growth of HCC tumors (P < .05). Conclusions: Dicer cooperated with lenvatinib to inhibit HCC growth via downregulating IL-8, and Dicer displayed its potential capability to enhance the anti-tumor effect of lenvatinib.
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Background: Programmed cell death protein-1 inhibitors combined with lenvatinib have become a popular treatment option for patients with unresectable hepatocellular carcinoma. Transarterial chemoembolization combined with programmed cell death protein-1 inhibitors and lenvatinib has also shown preliminary efficacy in the unresectable hepatocellular carcinoma. We conducted this observational, retrospective, cohort study to compare the clinical outcomes and safety of transarterial chemoembolization combined with programmed cell death protein-1 inhibitors plus lenvatinib versus programmed cell death protein-1 inhibitors plus lenvatinib in patients with unresectable hepatocellular carcinoma. Methods: Between November 2019 and November 2021, patients who were diagnosed with unresectable hepatocellular carcinoma and received transarterial chemoembolization combined with programmed cell death protein-1 inhibitors plus lenvatinib or programmed cell death protein-1 inhibitors plus lenvatinib treatment were reviewed for eligibility. The primary endpoints included objective response rate, overall survival, and progression-free survival. The secondary endpoint was the frequency of key adverse events. Results: In total, 105 patients were eligible for the present study, and they were divided into the transarterial chemoembolization combined with programmed cell death protein-1 inhibitors plus lenvatinib group (n = 46) and the programmed cell death protein-1 inhibitors plus lenvatinib group (n = 59). The patient cohort after a one-to-one propensity score matching (n = 86) was also analyzed. The transarterial chemoembolization combined with programmed cell death protein-1 inhibitors plus lenvatinib group had a higher objective response rate both in the patient cohort before propensity score matching (54.3% vs 25.4%, P = .002) and after propensity score matching (55.8% vs 30.2%, P = .017). The patients in the transarterial chemoembolization combined with programmed cell death protein-1 inhibitors plus lenvatinib group had prolonged overall survival (median, 20.5 vs 12.6 months, P = .015) and progression-free survival (median, 10.2 vs 7.4 months, P = .035). For patient cohort- propensity score matching, the overall survival (20.5 vs 12.8 months, P = .013) and progression-free survival (12.1 vs 7.8 months, P = .030) were also significantly better in the transarterial chemoembolization combined with programmed cell death protein-1 inhibitors plus lenvatinib group than in the programmed cell death protein-1 inhibitors plus lenvatinib group. There were no significant differences between the 2 groups concerning adverse reactions caused by immunotherapy and lenvatinib. The adverse reactions caused by transarterial chemoembolization were transient and were quickly reversed. Conclusions: Compared to programmed cell death protein-1 inhibitors plus lenvatinib, transarterial chemoembolization combined with programmed cell death protein-1 inhibitors plus lenvatinib may provide better treatment response and survival benefits for patients with unresectable hepatocellular carcinoma, and the adverse events were manageable.
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Carcinoma Hepatocelular , Quimioembolización Terapéutica , Neoplasias Hepáticas , Humanos , Carcinoma Hepatocelular/terapia , Inhibidores de Puntos de Control Inmunológico , Estudios de Cohortes , Estudios Retrospectivos , Quimioembolización Terapéutica/efectos adversos , Neoplasias Hepáticas/terapia , Proteínas Reguladoras de la ApoptosisRESUMEN
BACKGROUND: Rectal neuroendocrine neoplasms (NENs) are rare neoplasms with limited understanding of its genomic alterations and molecular typing. METHODS: The paraffin-embedded tissue specimens of 38 patients with rectal NENs after surgery were subjected to whole gene sequencing (WGS), and mutation profilings were drawn to identify high-frequency mutation genes, copy-number variations (CNVs), tumor mutation burden (TMB), signal pathways, mutation signatures, DNA damage repair (DDR) genes, and molecular types. The differences of mutated genes and signaling pathways in different pathological grades and metastatic/non-metastatic groups were compared. It helped to search for potential targets. RESULTS: C > T and T > C transitions are the most common base substitutions in rectal NENs. DNA mismatch repair deficiency, DNA base modifications, smoking and exposure to ultraviolet light might play a role in the occurrence of rectal NENs. DAXX, KMT2C, BCL2L1, LTK, MERTK, SPEN, PKN1, FAT3, and LRP2 mutations were found in only low-grade rectal NETs, whereas APC, TP53, NF1, SOX9, and BRCA1 mutations were common in high-grade rectal NECs/MiNENs. These genes helped in distinguishing poorly-differentiated or well-differentiated rectal NENs. Alterations in P53, Wnt and TGFß signaling pathways were more pronounced in rectal NECs and MiNENs. Alterations in Wnt, MAPK and PI3K/AKT signaling pathways promoted metastases. Rectal NENs were classified into two molecular subtypes by cluster analysis based on the mutant genes and signaling pathways combined with clinicopathological features. Patients with mutations in the LRP2, DAXX, and PKN1 gene showed a trend of well-differentiated and early-stage tumors with less metastasis (p = 0.000). CONCLUSIONS: This study evaluated risk factors for regional lymphatic and/or distant metastases, identified high-frequency mutated genes, mutation signatures, altered signaling pathways through NGS. Rectal NENs were divided into two molecular types. This helps to evaluate the likelihood of metastasis, formulate follow-up strategies for patients and provide a target for future research on precision treatment of rectal NENs. PARP inhibitors, MEK inhibitors, mTOR/AKT/PI3K and Wnt signaling pathway inhibitors may be effective drugs for the treatment of metastatic rectal NENs.
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Tumores Neuroendocrinos , Neoplasias del Recto , Tumores Neuroendocrinos/clasificación , Tumores Neuroendocrinos/genética , Tumores Neuroendocrinos/patología , Neoplasias del Recto/clasificación , Neoplasias del Recto/genética , Neoplasias del Recto/patología , Adhesión en Parafina , Mutación , Tipificación Molecular , Análisis Mutacional de ADN , Estadificación de Neoplasias , Humanos , Masculino , Femenino , Adulto , Persona de Mediana Edad , Anciano , Anciano de 80 o más AñosRESUMEN
OBJECTIVE: Hepatocellular carcinoma (HCC) is a malignant tumor with high morbidity and mortality. Despite rapid progress in targeted therapy and immunotherapy for HCC over the past 10 years, the overall efficacy remains unsatisfactory. This is mainly due to the presence of an intrahepatic microenvironment of cirrhosis in HCC patients, leading to cancer recurrence and drug resistance. METHODS: In this study, we investigated the correlations between the Wnt-1/ß-catenin signaling pathway and the prognosis as well as liver function of HCC patients. Additionally, we conducted in vitro experiments using different concentrations of matrine on HuH-7 cells. Furthermore, we verified the associations between the Wnt-1/ß-catenin signaling pathway, inflammation, and epithelial-mesenchymal transition (EMT) in a rat model of pre-hepatocellular carcinoma. Finally, matrine was employed to treat pre-hepatocellular carcinoma in rats and patients with advanced hepatocellular carcinoma. RESULTS: The results demonstrated the activation of the Wnt-1/ß-catenin signaling pathway, the occurrence of EMT, and exacerbated inflammation in human HCC tissues. In HuH-7 cell experiments, matrine effectively downregulated the Wnt-1/ß-catenin pathway, reversed EMT, and suppressed migration and invasion of HCC cells. In the rat model of pre-hepatocellular carcinoma, matrine dose-dependently inhibited the activation of the Wnt-1/ß-catenin signaling pathway, reversed the occurrence of EMT, and alleviated liver inflammation. Matrine analogues exhibited promising hepatoprotective effects in patients with advanced HCC. CONCLUSIONS: Matrine can reverse EMT, alleviate intrahepatic inflammation, and counteract immune depletion by inhibiting the Wnt-1/ß-catenin signaling pathway in HCC.
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Background: Systemic therapies, including immune checkpoint inhibitors (ICIs) and tyrosine kinase inhibitors (TKIs), have challenged the use of conventional therapies for hepatocellular carcinoma (HCC). It is crucial to determine which patients could benefit most from combination therapy. This study aims to examine the associations of sarcopenia and systemic inflammation response index (SIRI) with the treatment responses and efficacies in patients with HCC treated with ICIs and tyrosine kinase inhibitors TKIs, as well as investigate the correlation between sarcopenia and inflammatory or immune states. Methods: We reviewed 160 patients with HCC treated with TKIs and ICIs. The patients' psoas muscle size was measured on axial computed tomography scans and normalized for the patients' height squared. This value was referred to as the psoas muscle index (PMI). Sarcopenia was determined from PMI and their relationships with patients' clinicopathological characteristics, inflammation indexes, peripheral blood T-cell subsets and survival were evaluated. Results: Sarcopenia and systemic inflammation response index (SIRI) were independent predictors for overall survival and progression-free survival. Patients with high PMI and low SIRI demonstrated significantly better median overall survival and progression-free survival (36.0 months and 9.6 months, respectively) than those with either low PMI or high SIRI (20.8 months and 6.0 months, respectively) and those with both high SIRI and low PMI (18.6 months and 3.0 months, respectively). Portal vein tumor thrombus (P=0.003), eastern cooperative oncology group performance status score of 1 (P=0.048), high alkaline phosphatase (P=0.037), high neutrophil-to-lymphocyte ratio (NLR) (P=0.012), low lymphocyte-to-monocyte ratio (LMR) (P=0.031), high platelet-to-lymphocyte ratio (PLR) (P=0.022) and high SIRI (P=0.012) were closely associated with an increased incidence of sarcopenia. PMI was negatively correlated with SIRI (r = -0.175, P=0.003), NLR (r = -0.169, P=0.036), and PLR (r = -0.328, P=0.000) and was significantly positively correlated with LMR (r = 0.232, P=0.004). The CD3+ and CD4+ T-cell counts of the high PMI group were significantly higher than those of the low PMI group. Conclusion: Sarcopenia and high SIRI were associated with reduced survival in patients with HCC treated with ICIs and TKIs. Sarcopenia could affect inflammatory states and the immune microenvironment.
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Objective: To explore the value of 18F-fluorodeoxyglucose positron emission tomography-computed tomography (18F-FDG PET/CT) metabolic parameters before and after neoadjuvant chemotherapy in predicting histopathological response and prognosis of locally advanced gastric cancer. Materials and Methods: A total of 56 patients with locally advanced gastric cancer underwent 18F-FDG PET/CT before and after neoadjuvant chemotherapy. The maximum standardized uptake value (SUVmax), mean standardized uptake value (SUVmean), metabolic tumor volume (MTV), and total lesion glycolysis (TLG) of the lesions were measured before and after neoadjuvant chemotherapy. The percentage changes in the maximum standardized uptake value (ΔSUVmax%), mean standardized uptake value (ΔSUVmean%), metabolic tumor volume (ΔMTV%), and total lesion glycolysis (ΔTLG%), which were derived from 18F-FDG PET/CT, were calculated, and the cutoff values were determined by receiver operating characteristic curve analysis. Differences in progression-free survival (PFS) and overall survival (OS) between groups dichotomized by these cutoffs were analyzed using the Kaplan-Meier method and Cox proportional hazards regression model. Results: The patients were divided into histopathological responders and nonresponders according to the following cutoff values: 58.8% SUVmax reduction, 45.8% SUVmean reduction, 36.9% MTV reduction, and 57.8% TLG reduction. The differences in PFS and OS between groups dichotomized by these cutoffs were significant (all p < 0.01). Multivariate analysis suggested that a ΔTLG% > 57.8% was an independent postoperative risk factor for PFS (hazard ratio [HR] 0.348, 95% confidence interval [CI] 0.131-0.926, p = 0.035) and OS (HR 0.107, 95% CI 0.023-0.498, p = 0.004). Conclusions: The metabolic parameters before and after neoadjuvant chemotherapy of 18F-FDG PET/CT accurately reflected the chemotherapy effect, and ΔTLG% was the only independent postoperative predictive factor of PFS and OS for locally advanced gastric cancer.
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Antineoplásicos/farmacología , Fluorodesoxiglucosa F18/farmacología , Tomografía Computarizada por Tomografía de Emisión de Positrones/métodos , Complicaciones Posoperatorias/diagnóstico , Neoplasias Gástricas , Monitoreo de Drogas/métodos , Femenino , Gastrectomía/efectos adversos , Gastrectomía/métodos , Humanos , Masculino , Persona de Mediana Edad , Terapia Neoadyuvante/métodos , Valor Predictivo de las Pruebas , Pronóstico , Radiofármacos/farmacología , Neoplasias Gástricas/diagnóstico por imagen , Neoplasias Gástricas/metabolismo , Neoplasias Gástricas/patología , Neoplasias Gástricas/terapia , Resultado del Tratamiento , Carga TumoralRESUMEN
AIMS: Recent studies have shown that the hyperactive Notch pathway is involved in cirrhosis and hepatocellular carcinoma (HCC) development by regulating differentiation of hepatic oval cells (HOCs) into cancer cells. The aim of this study was to investigate whether matrine can alleviate liver injury and promote HOC differentiation into hepatocytes by suppression of Notch pathway. MAIN METHODS: We evaluated the expression of Notch-1, Jagged-1, and Hes-1 in HCC tissue by immunohistochemistry. Stem cell characteristics of HOCs were evaluated by CCK-8, cell cycle, and apoptosis. The expression of Notch pathway, HOC markers and albumin (ALB) was detected by immunohistochemistry, QRT-PCR and western blotting. The effects of matrine in protecting liver in vivo were investigated in a rat Solt-Farber precancerous model. KEY FINDINGS: We found an abnormal activated Notch pathway in HCC tissue, and the hyperactive Notch pathway was strongly associated with poor liver function in patients with cirrhosis with HCC. Using siNotch-1 to inhibit Notch pathway confirmed that Notch pathway could maintain stem cell characteristics of HOCs. Matrine inhibited stem cell characteristics of HOCs, the expression of Notch pathway and HOC markers but upregulated ALB. Matrine in combined with siNotch-1 RNA decreased the more potently inhibited HOC markers and Notch pathway. In rat Solt-Farber precancerous model, prophylactic application of matrine alleviated liver injury, downregulated Notch pathway and HOC markers, and upregulated ALB in a dose-dependent manner. SIGNIFICANCE: Matrine could promote the differentiation of HOCs into hepatocytes by inhibiting the Notch signalling pathway and alleviate liver injury.
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Alcaloides/farmacología , Diferenciación Celular , Hepatocitos/patología , Hígado/lesiones , Hígado/patología , Quinolizinas/farmacología , Receptores Notch/metabolismo , Transducción de Señal , Animales , Apoptosis/efectos de los fármacos , Diferenciación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Modelos Animales de Enfermedad , Hígado Graso/patología , Hígado Graso/fisiopatología , Femenino , Hepatocitos/efectos de los fármacos , Hepatocitos/metabolismo , Humanos , Estimación de Kaplan-Meier , Hígado/efectos de los fármacos , Hígado/fisiopatología , Pruebas de Función Hepática , Masculino , Persona de Mediana Edad , Pronóstico , Modelos de Riesgos Proporcionales , ARN Interferente Pequeño/metabolismo , Ratas Sprague-Dawley , MatrinasRESUMEN
BACKGROUND: Gastric cancer (GC) remains one of the most common malignancies worldwide. Increasing evidence has demonstrated that circRNAs serve as critical roles in human cancer, including GC. In the present study, we focused on the detailed function and mechanism of circ_0000144 on GC progression. METHODS: The levels of circ_0000144, miR-623 and G-protein-coupled receptor, family C, group 5, member A (GPRC5A) were determined by quantitative real-time polymerase chain reaction (qRT-PCR). Targeted relationships among circ_0000144, miR-623 and GPRC5A were confirmed using dual-luciferase reporter and RNA immunoprecipitation (RIP) assays. Cell proliferation, colony formation, apoptosis, migration and invasion were evaluated by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), colony formation, flow cytometry and transwell assays. Measurement of glutamine and α-ketoglutarate (α-KG) levels was performed using a corresponding assay kit. GPRC5A protein expression was detected using Western blot. In vivo assays were used to explore the impact of circ_0000144 on tumor growth. RESULTS: Our data indicated that circ_0000144 was up-regulated and miR-623 was down-regulated in GC tissues and cells. Circ_0000144 interacted with miR-623 through directly binding to miR-623. Moreover, the knockdown of circ_0000144 weakened GC cell proliferation, colony formation, migration, invasion and glutaminolysis and accelerated cell apoptosis by up-regulating miR-623. GPRC5A was a direct target of miR-623 and circ_0000144 protected against GPRC5A repression through sponging miR-623. Furthermore, miR-623-mediated regulation on GC cell progression was reversed by the stored expression of GPRC5A. Additionally, circ_0000144 depletion inhibited tumor growth in vivo. CONCLUSION: Our study indicated that circ-0000144 knockdown repressed GC progression at least partly by regulating GPRC5A expression via sponging miR-623, illumining a novel therapeutic target for GC treatment.
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MicroARNs/metabolismo , ARN Circular/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Neoplasias Gástricas/metabolismo , Animales , Apoptosis , Línea Celular Tumoral , Movimiento Celular , Proliferación Celular , Progresión de la Enfermedad , Regulación Neoplásica de la Expresión Génica , Humanos , Masculino , Ratones Endogámicos BALB C , Ratones Desnudos , MicroARNs/genética , Invasividad Neoplásica , ARN Circular/genética , Receptores Acoplados a Proteínas G/genética , Transducción de Señal , Neoplasias Gástricas/genética , Neoplasias Gástricas/patología , Carga TumoralRESUMEN
Matrine (C15H24N2O) is an alkaloid extracted from the Chinese herb Sophora flavescens that has anti-fibrotic and anti-cancer properties. The aim of the present study was to determine the chemopreventive effect of matrine on the development of primary hepatocellular carcinoma (HCC) and its possible association with the suppression of the Notch signaling pathway. The rats were randomly divided into four groups: Control, model, low-dose matrine and high-dose matrine groups. The model was established by combining a partial hepatectomy with diethylnitrosamine (DEN) + 2-acetylaminofluorene (2-AAF). Low- and high-dose matrine groups received intragastric administration of matrine (0.25 and 2.5 g/l of matrine, respectively). DEN + 2-AAF injections and hepatectomy were not performed in the control group. All rats were sacrificed 2, 4 and 7 weeks after hepatectomy. HCC-like histopathological lesions were detected using hematoxylin and eosin staining. The expression levels of α-1-fetoprotein (AFP), albumin (ALB), Notch1 and Hes1 were analyzed using immunohistochemistry. Hepatic lobule structure loss, liver tissue necrosis and inflammatory cell infiltration, and edema degeneration were observed in the model group. By contrast, hepatocyte cord structure was restored and hepatocyte edema degeneration was significantly reduced after 7 weeks of treatment with matrine. In addition, compared with the model group, matrine reduced the expression of AFP, increased the expression of ALB and reduced the expression of Notch1 and Hes1 (only for high-dose matrine; all P<0.05). The findings suggested that matrine could prevent the early development of HCC-like lesions in a rat model, possibly by modulating Notch pathway activation.
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OBJECTIVE: We aimed to analyze the phosphatases of regenerating liver 1 (PTP4A1) expression and its relationship with tumor invasion, metastasis, and prognosis of non-small cell lung cancer (NSCLC). METHODS: The retrospective study enrolled 150 cases who underwent radical resection for primary NSCLC during the period from January 2006 to January 2014. Baseline characteristics of patients included age, gender, smoking history, pathological type, histological grade, clinical stage, and lymphatic metastasis. Lung cancer tissues collected from 150 cases and precancerous tissues, and normal lung tissues collected from 20 cases were used for PTP4A1 detection by immunohistochemistry. RESULTS: The expression of PTP4A1 was significantly different in different tissue samples (P = 0.025). The expression level of PTP4A1 was associated with clinical stage (P = 0.022), and lymphatic metastasis (P = 0.011). Survival analysis showed the total survival rate of overexpressed PTP4A1 group was significantly lower than that of the low expressed PTP4A1 group (P = 0.006), while the recurrence rate of overexpressed PTP4A1 was significantly higher than that of the low expressed PTP4A1 group (P = 0.014). In addition, the OS was affected by lymphatic metastasis, and disease-free survival was influenced by pathological type and lymphatic metastasis. CONCLUSION: The PTP4A1 expression level is a potential prognostic biomarker for NSCLC, and overexpression of PTP4A1 suggested a high risk of poor DFS during follow-up. Also, lymphatic metastasis had an adverse effect on survival time.
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The aim of the present study was to evaluate the efficacy and safety of a combination of intra-arterial and intravenous chemotherapy in the treatment of unresectable, advanced gastric cancer, and assess which patients are likely to benefit from combined treatment. The clinical data of 128 patients diagnosed with unresectable, advanced gastric cancer at The Fourth Hospital of Hebei Medical University (Shijiazhuang, China) from January 2009 to September 2012 were retrospectively analyzed. The patients were divided into two groups as follows: Those who received regional intra-arterial chemoembolization plus systemic chemotherapy (combined group; n=62) and those who received systemic chemotherapy only (venous group; n=66). The clinical response, overall survival (OS) and toxic effects in the two groups were compared. Univariate and multivariate analyses were performed to identify the primary factors affecting the survival time of patients in the combined group. The overall response rate was significantly increased (35.5%) in the combined group compared with the venous group (19.7%; P=0.045). The median OS was 14 months in the combined group and 13 months in the venous group, and the 1-year and 2-year survival rates in the two groups were 45.2 and 9.7%, and 40.9 and 6.1%, respectively. There were significant differences between the survival curves (P=0.044). The median time to progression in the combined group and the venous group was 10 months and 6 months, respectively, and the difference was statistically significant (P=0.003). Multivariate analysis revealed that tumor-node-metastasis (TNM)-stage and the degree of tumor staining were independent factors affecting OS. No differences in adverse reactions between the two groups were observed (P>0.05). The combination of intra-arterial and intravenous chemotherapy may effectively improve the rate of clinical response, prolong OS and time to symptomatic progression in patients with unresectable, advanced gastric cancer, in particular those with an earlier TNM stage and distinct tumor staining.