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BACKGROUND: Fluorine 18 (18F) fluorodeoxyglucose (FDG) positron emission tomography/computed tomography (PET/CT) has limitations in staging hepatocellular carcinoma (HCC). The recently introduced 18F-labeled fibroblast-activation protein inhibitor (FAPI) has shown promising prospects in detection of HCC lesions. This study aimed to investigate the initial staging and restaging performance of 18F-FAPI PET/CT compared to 18F-FDG PET/CT in HCC. METHODS: This prospective study enrolled histologically confirmed HCC patients from March 2021 to September 2022. All patients were examined with 18F-FDG PET/CT and 18F-FAPI PET/CT within 1 week. The maximum standard uptake value (SUVmax), tumor-to-background ratio (TBR), and diagnostic accuracy were compared between the two modalities. RESULTS: A total of 67 patients (57 men; median age, 57 [range, 32-83] years old) were included. 18F-FAPI PET showed higher SUVmax and TBR values than 18F-FDG PET in the intrahepatic lesions (SUVmax: 6.7 vs. 4.3, P < 0.0001; TBR: 3.9 vs. 1.7, P < 0.0001). In diagnostic performance, 18F-FAPI PET/CT had higher detection rate than 18F-FDG PET/CT in intrahepatic lesions [92.2% (238/258) vs 41.1% (106/258), P < 0.0001] and lymph node metastases [97.9% (126/129) vs 89.1% (115/129), P = 0.01], comparable in distant metastases [63.6% (42/66) vs 69.7% (46/66), P > 0.05]. 18F-FAPI PET/CT detected primary tumors in 16 patients with negative 18F-FDG, upgraded T-stages in 12 patients and identified 4 true positive findings for local recurrence than 18F-FDG PET, leading to planning therapy changes in 47.8% (32/67) of patients. CONCLUSIONS: 18F-FAPI PET/CT identified more primary lesions, lymph node metastases than 18F-FDG PET/CT in HCC, which is helpful to improve the clinical management of HCC patients. TRIAL REGISTRATION: Clinical Trials, NCT05485792 . Registered 1 August 2022, Retrospectively registered.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , Adulto , Idoso , Idoso de 80 Anos ou mais , Humanos , Masculino , Pessoa de Meia-Idade , Carcinoma Hepatocelular/diagnóstico por imagem , Carcinoma Hepatocelular/terapia , Fluordesoxiglucose F18 , Radioisótopos de Gálio , Neoplasias Hepáticas/diagnóstico por imagem , Neoplasias Hepáticas/terapia , Metástase Linfática , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Estudos ProspectivosRESUMO
Hepatocellular carcinoma (HCC) is a highly prevalent and lethal tumor worldwide and its late discovery and lack of effective specific therapeutic agents necessitate further research into its pathogenesis and treatment. Organoids, a novel model that closely resembles native tumor tissue and can be cultured in vitro, have garnered significant interest in recent years, with numerous reports on the development of organoid models for liver cancer. In this study, we have successfully optimized the procedure and established a culture protocol that enables the formation of larger-sized HCC organoids with stable passaging and culture conditions. We have comprehensively outlined each step of the procedure, covering the entire process of HCC tissue dissociation, organoid plating, culture, passaging, cryopreservation, and resuscitation, and provided detailed precautions in this paper. These organoids exhibit genetic similarity to the original HCC tissues and can be utilized for diverse applications, including the identification of potential therapeutic targets for tumors and subsequent drug development.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , Humanos , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/genética , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/genética , Descoberta de Drogas , Desenvolvimento de Medicamentos , OrganoidesRESUMO
Background: Antibody-based cancer therapeutics is developing rapidly in recent years for its advantages in precisely targeting the tumor cells. However, tumor-specific cell surface antigens are still lacking, and the heterogeneity of tumor mass greatly impeded the development of effective drugs. Methods: In the present study, single-cell RNA sequencing was used to dissect tumor heterogeneity in human hepatocellular carcinoma (HCC). Tissues from different spatial regions including the tumor, para-tumor, and distant normal liver tissues were dissociated into single cells, and the gene expressions were compared in a different subpopulation of cells from these regions and validated in independent cohorts. Results: A total of 28 cell clusters with different distribution patterns and gene expression profiles were identified within a heterogenous tumor and its paired liver tissues. Differentially expressed genes encoding the plasma membrane in cells with hepatic lineage were further extracted from single-cell transcriptome sequencing and validated in TCGA database. A 3-gene signature was identified to be significantly upregulated in dominant HCC tumor cell subpopulations with prognostic significance and validated in multiple independent patient cohorts. Conclusion: The composition of the three plasma membrane proteins on the surface of HCC tumor cells within a heterogenous tumor might indicate poor prognostic tumor subpopulations during cancer evolution and potential therapeutic targets.
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Background: Lenvatinib is in a first-line therapy for advanced hepatocellular carcinoma (HCC). However, drug resistance is one of the principal obstacles for treatment failure. The molecular mechanism of Lenvatinib resistance has not been well investigated. Materials and methods: A genome-wide CRISPR/Cas9 knockout screening system was established and bioinformatic analysis was used to identify critical genes associated with Lenvatinib resistance. Cell proliferation assays, colony formation assays and cell migration assays were performed to investigate the effect of drug resistance associated genes, particularly DUSP4, on cancer cell malignant behavior during Lenvatinib treatment. In vivo experiments were conducted by using a xenograft mouse model. Results: We identified six genes that were associated with Lenvatinib resistance in HCC, including DUSP4, CCBL1, DHDH, CNTN2, NOS3 and TNF. DUSP4 was found to be significantly decreased at the mRNA and protein levels in Lenvatinib resistant HCC cells. DUSP4 knockout enhanced HCC cell survival, cell proliferation and migration during Lenvatinib treatment in vitro and in vivo, accompanied by regulation of p-ERK and p-MEK levels. This finding implied that DUSP4 deficiency induced Lenvatinib resistance. Interestingly, DUSP4 deficiency induced Lenvatinib resistance was abrogated by the MEK inhibitor Selumetinib, implying that MEK phosphorylation and DUSP4-inhibition dependent ERK activation were required for drug resistance. Finally, we found that DUSP4 deficiency was associated with HCC prognosis and response to Lenvatinib based on clinical data. Conclusions: DUSP4 deficiency mediates Lenvatinib resistance by activating MAPK/ERK signaling and combination therapy using Lenvatinib and MEK inhibitors may be a promising therapeutic strategy for overcoming Lenvatinib resistance.
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Carcinoma Hepatocelular , Resistencia a Medicamentos Antineoplásicos , Fosfatases de Especificidade Dupla , Neoplasias Hepáticas , Quinolinas , Animais , Sistemas CRISPR-Cas/genética , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/metabolismo , Linhagem Celular Tumoral , Resistencia a Medicamentos Antineoplásicos/genética , Fosfatases de Especificidade Dupla/genética , Fosfatases de Especificidade Dupla/metabolismo , Humanos , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/metabolismo , Camundongos , Quinases de Proteína Quinase Ativadas por Mitógeno/genética , Quinases de Proteína Quinase Ativadas por Mitógeno/metabolismo , Compostos de Fenilureia , Inibidores de Proteínas Quinases/farmacologia , Quinolinas/farmacologia , Quinolinas/uso terapêuticoRESUMO
Tumour lineage plasticity is an emerging hallmark of aggressive tumours. Tumour cells usually hijack developmental signalling pathways to gain cellular plasticity and evade therapeutic targeting. In the present study, the secreted protein growth and differentiation factor 1 (GDF1) is found to be closely associated with poor tumour differentiation. Overexpression of GDF1 suppresses cell proliferation but strongly enhances tumour dissemination and metastasis. Ectopic expression of GDF1 can induce the dedifferentiation of hepatocellular carcinoma (HCC) cells into their ancestral lineages and reactivate a broad panel of cancer testis antigens (CTAs), which further stimulate the immunogenicity of HCC cells to immune-based therapies. Mechanistic studies reveal that GDF1 functions through the Activin receptor-like kinase 7 (ALK7)-Mothers against decapentaplegic homolog 2/3 (SMAD2/3) signalling cascade and suppresses the epigenetic regulator Lysine specific demethylase 1 (LSD1) to boost CTA expression. GDF1-induced tumour lineage plasticity might be an Achilles heel for HCC immunotherapy. Inhibition of LSD1 based on GDF1 biomarker prescreening might widen the therapeutic window for immune checkpoint inhibitors in the clinic.
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Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/terapia , Plasticidade Celular/efeitos dos fármacos , Fator 1 de Diferenciação de Crescimento/metabolismo , Fator 1 de Diferenciação de Crescimento/farmacologia , Imunoterapia , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/patologia , Diferenciação Celular , Linhagem Celular Tumoral , Proliferação de Células , Humanos , Neoplasias Hepáticas/metabolismo , Masculino , Transdução de Sinais , Proteína Smad2/metabolismo , Proteína Smad3/metabolismo , Neoplasias Testiculares/metabolismoRESUMO
Pancreatic ductal adenocarcinoma (PDAC) has a hypoxic and desmoplastic tumor microenvironment (TME), leading to treatment failure. We aimed to develop a prognostic classifier to evaluate hypoxia status and hypoxia-related molecular characteristics of PDAC. In this study, we classified PDAC into three clusters based on 16 known hypoxia-inducible factor 1 (HIF-1)-related genes. Nine differentially expressed genes were identified to construct an HIF-1 score system, whose predictive efficacy was evaluated. Furthermore, we investigated oncogenic pathways and immune-cell infiltration status of PDAC with different scores. The C-index of the HIF-1score system for OS prediction in the meta-PDAC cohort and the other two validation cohorts were 0.67, 0.63, and 0.65, respectively, indicating that it had a good predictive value for patient survival. Furthermore, the area under the curve (AUC) of the receiver operating characteristic (ROC) curve of the HIF-1α score system for predicting 1-, 3-, and 4-year OS indicated the HIF-1α score system had an optimal discrimination of prognostic prediction for PDAC. Importantly, our model showed superior predictive ability compared to previous hypoxia signatures. We also classified PDAC into HIF-1 scores of low, medium, and high groups. Then, we found high enrichment of glycolysis, mTORC1 signaling, and MYC signaling in the HIF-1 score high group, whereas the cGMP metabolic process was activated in the low score group. Of note, analysis of public datasets and our own dataset showed a high HIF-1 score was associated with high immunosuppressive TME, evidenced by fewer infiltrated CD8+ T cells, B cells, and type 1 T-helper cells and reduced cytolytic activity of CD8+ T cells. In summary, we established a specific HIF-1 score system to discriminate PDAC with various hypoxia statuses and immune microenvironments. For highly hypoxic and immunosuppressive tumors, a combination treatment strategy should be considered in the future.
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Biomarcadores Tumorais/genética , Carcinoma Ductal Pancreático/genética , Perfilação da Expressão Gênica , Fator 1 Induzível por Hipóxia/genética , Neoplasias Pancreáticas/genética , Transcriptoma , Hipóxia Tumoral , Microambiente Tumoral/imunologia , Biomarcadores Tumorais/metabolismo , Carcinoma Ductal Pancreático/imunologia , Carcinoma Ductal Pancreático/metabolismo , Carcinoma Ductal Pancreático/terapia , Tomada de Decisão Clínica , Regulação Neoplásica da Expressão Gênica , Humanos , Fator 1 Induzível por Hipóxia/metabolismo , Linfócitos do Interstício Tumoral/imunologia , Neoplasias Pancreáticas/imunologia , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/terapia , Valor Preditivo dos Testes , Prognóstico , Reprodutibilidade dos Testes , Transdução de Sinais , Evasão TumoralRESUMO
Hepatic impairment in coronavirus disease 2019 (COVID-19) may derive from cholangiocyte damage in the beginning, but not from direct infection of hepatocytes. Chronic liver disease patients co-infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) exhibited overexpression of angiotensin-converting enzyme 2 receptors and overwhelming cytokine storm. Consensus has been reached that we should encourage as many people as possible to be vaccinated in order to achieve herd immunity. SARS-CoV-2 vaccines can prevent or alleviate severe infection and cytokine storm. It is recommended that all adult patients with chronic liver diseases and liver transplant recipients should receive COVID-19 vaccines using the standard dose and schedule. Data is not yet sufficient to compare the efficacy of different types of vaccines used in chronic liver disease patients.
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BACKGROUND: KRAS was reported to affect some metabolic genes and promote metabolic reprogramming in solid tumors. However, there was no comprehensive analysis to explore KRAS-associated metabolic signature or risk model for pancreatic cancer (PC). METHODS: In the current study, multiple bioinformatics analyses were used to identify differentially expressed metabolic genes based on KRAS mutation status in PC. Then, we developed and validated a prognostic risk model based on the selected KRAS-associated metabolic genes. Besides, we explored the association between the risk model and the metabolic characteristics as well as gemcitabine-associated chemoresistance in PC. RESULTS: 6 KRAS-associated metabolic genes (i.e., CYP2S1, GPX3, FTCD, ENPP2, UGT1A10, and XDH) were selected and enrolled to establish a prognostic risk model. The prognostic model had a high C-index of 0.733 for overall survival (OS) in TCGA pancreatic cancer database. The area under the curve (AUC) values of 1- and 3-year survival were both greater than 0.70. Then, the risk model was validated in two GEO datasets and also presented a satisfactory discrimination and calibration performance. Further, we found that the expression of some KRAS-driven glycolysis-associated genes (PKM, GLUT1, HK2, and LDHA) and gemcitabine-associated chemoresistance genes (i.e., CDA and RMM2) was significantly upregulated in high-risk PC patients evaluated by the risk model. CONCLUSIONS: We constructed a risk model based on 6 KRAS-associated metabolic genes, which predicted patients' survival with high accuracy and reflected tumor metabolic characteristics and gemcitabine-associated chemoresistance in PC.
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Modelos Biológicos , Neoplasias Pancreáticas/metabolismo , Proteínas Proto-Oncogênicas p21(ras)/metabolismo , Linhagem Celular Tumoral , Desoxicitidina/análogos & derivados , Desoxicitidina/farmacologia , Desoxicitidina/uso terapêutico , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Mutação/genética , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/patologia , Fenótipo , Prognóstico , Proteínas Proto-Oncogênicas p21(ras)/genética , Curva ROC , Reprodutibilidade dos Testes , Fatores de Risco , Análise de Sobrevida , GencitabinaRESUMO
Background: Recent evidence has shown that CKLF-like MARVEL transmembrane domain containing 3 (CMTM3) promoted carcinogenesis and tumor progression in a variety of cancer types. The goal of our study is to investigate the association between CMTM3 and pancreatic cancer (PC). Materials and Methods: In current study, data from public databases was used to analyze CMTM3 expression in PC. Quantitative real-time polymerase chain reaction (qRT-PCR) and immunohistochemistry (IHC) were used to investigate CMTM3 expression and determine its clinical significance in PC. Then CMTM3 promoting PC aggressiveness was demonstrated in vitro experiments by cell proliferation and migration assay. Functional and pathway enrichment analyses were performed to evaluate the potential role of CMTM3 in PC. Results: Results of qRT-PCR and IHC revealed that CMTM3 was significantly overexpressed in PC tissues. High CMTM3 expression was an independent risk factor for poor prognosis of PC patients. Overexpression of CMTM3 was associated with poor overall survival (P-value =0.031) and disease-free survival (P-value =0.0047) in the TCGA cohort. Functional and pathway enrichment analyses showed that CMTM3 were enriched in "Regulation of cell proliferation and regulation of cell differentiation, cell morphogenesis, regulation of cell differentiation, Hedgehog signaling pathway, Wnt signaling pathway, ECM-receptor interaction and pathways in cancer". In PC cell lines, CCK8, clone formation and transwell assays showed that CMTM3 knockdown inhibited cells proliferation and migration. Conclusion: CMTM3 was overexpressed and promotes tumor aggressiveness in PC. Our findings provided a novel therapeutic target for PC.
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BACKGROUND: Hyperthermic intraperitoneal chemotherapy (HIPEC) has been reported to effectively control peritoneal carcinomatosis (PC) in various patient populations, but there is a lack of real-world data. This study aimed to examine the safety and effectiveness of HIPEC in patients with PC in a real-world setting. METHODS: This was a retrospective study of patients with PC treated with the high-precision BR-TRG-I type HIPEC device between December 2006 and December 2016. Vital signs during HIPEC and adverse events were recorded. Effectiveness was evaluated by total objective remission rate (ORR), which was based on ascites' remission 4 weeks after HIPEC. RESULTS: A total of 1,200 patients were included. There were 518 males and 682 females, with a mean age of 58.6 ± 6.5 years (range, 32-76 years). Among the patients, 93.6% of the patients (1123/1200) successfully received the three sessions of HIPEC, 158 had massive ascites. The changes of vital signs during HIPEC were within acceptable ranges, and patients only had a transient fever and abdominal distension. Regarding the HIPEC-related complications, hemorrhage was observed in seven (0.6%) patients, anastomotic leakage in four (0.5%), and intestinal obstruction in eight (0.7%). Nine (0.8%, 9/1200) patients had CTCAE grade IV bone marrow suppression, and three (0.3%, 3/1200) patients had severe renal failure (SRF), which were considered to be drug-related. The ORR of malignant ascites was 95.6% (151/158). CONCLUSION: This real-world study strongly suggests that HIPEC was safe in treating PC patients with a low rate of adverse events and leads to benefits in PC patients with massive malignant ascites.
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BACKGROUND: Gallbladder cancer (GBC), which accounts for more than 80% of biliary tract malignancies, has a poor prognosis with an overall 5-year survival less than 10%. The study aimed to identify risk factors and develop a predictive model for GBC following surgical resection. METHODS: 98 GBC patients who underwent surgical resection from Guangdong Provincial People's Hospital were enrolled in the study. Cox-regression analysis was performed to identify significant prognostic factors. A nomogram was constructed and Harrell's concordance index, calibration plot, and decision cure analysis were used to evaluate the discrimination and calibration of the nomogram. RESULTS: Liver resection, tumor size, perineural invasion, surgical margin, and liver invasion were identified as independent risk factors for overall survival (OS) in GBC patients who underwent surgical resection. Based on the selected risk factors, a novel nomogram was constructed. The C-index of the nomogram was 0.777, which was higher than the American Joint Committee on Cancer (AJCC) staging system (0.724) and Nevin staging system (0.659). Decision cure analysis revealed that the nomogram had a better net benefit and the calibration curves for the 1-, 3-, and 5-year survival probabilities were also well matched with the actual survival rates. Lastly, high-risk GBC were stratified based on the scores of the nomogram and we found high-risk GBC were associated with both worse OS and disease-free survival (DFS). CONCLUSION: We developed a nomogram showing a better predictive capacity for patients' survival of resected GBC than the AJCC staging systems. The established model may help to stratify high-risk GBC and facilitate decision-making in the clinic.
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BACKGROUND: The prognosis of patients with pancreatic ductal adenocarcinoma (PDAC) of pancreatic head remains poor, even after potentially curative R0 resection. The aim of this study was to develop an accurate model to predict patients' prognosis for PDAC of pancreatic head following pancreaticoduodenectomy. METHODS: We retrospectively reviewed 112 patients with PDAC of pancreatic head after pancreaticoduodenectomy in Guangdong Provincial People's Hospital between 2014 and 2018. RESULTS: Five prognostic factors were identified using univariate Cox regression analysis, including age, histologic grade, American Joint Committee on Cancer (AJCC) Stage 8th, total bilirubin (TBIL), CA19-9. Using all subset analysis and multivariate Cox regression analysis, we developed a nomogram consisted of age, AJCC Stage 8th, perineural invasion, TBIL, and CA19-9, which had higher C-indexes for OS (0.73) and RFS (0.69) compared with AJCC Stage 8th alone (OS: 0.66; RFS: 0.67). The area under the curve (AUC) values of the receiver operating characteristic (ROC) curve for the nomogram for OS and RFS were significantly higher than other single parameter, which are AJCC Stage 8th, age, perineural invasion, TBIL, and CA19-9. Importantly, our nomogram displayed higher C-index for OS than previous reported models, indicating a better predictive value of our model. CONCLUSIONS: A simple and practical nomogram for patient prognosis in PDAC of pancreatic head following pancreaticoduodenectomy was established, which shows satisfactory predictive efficacy and deserves further evaluation in the future.
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LncRNAs play an important role in a variety of biological processes, such as cancer pathogenesis. The lncRNA zinc ribbon domain containing 1 antisense RNA 1 (ZNRD1-AS1) is a natural antisense transcript of ZNRD1. In this study, we found that ZNRD1-AS1 levels were significantly upregulated in gastric cancer tissues compared to those in adjacent healthy gastric tissues. ZNRD1-AS1 levels were correlated with lymph node metastasis, distal metastasis, and TNM stage, but were not correlated with age and sex. ZNRD1-AS1 knockdown suppressed cell proliferation, migration, and invasion, and promoted apoptosis. ZNRD1-AS1 overexpression had the opposite effect. ZNRD1-AS1 knockdown suppressed tumor growth and pulmonary metastasis in a nude mouse model ZNRD1-AS1 can bind to miR-9-5p and ZNRD1-AS1 knockdown can decrease the protein level of heat shock protein 90 alpha family class A member 1 (HSP90AA1), which is the target of miR-9-5p. The miR-9-5p inhibitor rescued the effect of ZNRD1-AS1 knockdown, and the mutant of miR-9-5p binding site on ZNRD1-AS1 sequence blocked the effect of ZNRD1-AS1 overexpression. In conclusion, ZNRD1-AS1 levels were upregulated in gastric cancer tissues, and knockdown of ZNRD1-AS1 suppressed gastric cancer cell proliferation and metastasis by targeting the miR-9-5p/HSP90AA1 axis. Our findings provide novel insights into the mechanism underlying the role of ZNRD1-AS1 in gastric cancer.
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Proteínas de Choque Térmico HSP90/genética , Antígenos de Histocompatibilidade Classe I/genética , MicroRNAs/genética , Metástase Neoplásica/genética , RNA Antissenso/genética , Transdução de Sinais/genética , Neoplasias Gástricas/genética , Animais , Apoptose/genética , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células , Regulação Neoplásica da Expressão Gênica/genética , Técnicas de Silenciamento de Genes , Humanos , Camundongos , Camundongos Nus , Neoplasias Gástricas/patologia , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Family with sequence similarity 83 (FAM83) members were shown recently to have oncogenic effect in a variety of cancer types, but the biological roles and prognostic value of FAM83 family in pancreatic ductal adenocarcinoma remain unknown. In the current study, the clinical significance and molecular function of the FAM83 family were assessed by multiple bioinformatics analysis. Besides, potential associations between differentially expressed genes (DEGs) of FAM83 family and antitumor immunity were evaluated using TIMER and TISIDB analyses. As the results show, FAM83A, FAM83D, FAM83E, and FAM83H were significantly upregulated in PDAC and were identified as DEGs. Higher expression of FAM83A, FAM83B, FAM83D, FAM83E, and FAM83H were associated with advanced tumor stage or worse patient prognosis. Importantly, the overexpression of DEGs was found to be significantly correlated with activated KRAS and loss of SMAD4, which are important drivers for PDAC. Further, FAM83A, FAM83D, and FAM83H were associated with CD8+ T cell, Gamma Delta T cell, and CD4+ T cell infiltration in PDAC and FAM83H was found closely correlated with some immunomodulators including immunoinhibitors, immunostimulators, and MHC molecules. In conclusion, FAM83A, FAM83D, FAM83E, and FAM83H have significant prognostic value in PDAC and they may play important roles in regulating tumor progression and the immune cell infiltration.
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Biomarcadores Tumorais/genética , Carcinoma Ductal Pancreático/metabolismo , Proteínas de Ciclo Celular/genética , Proteínas Associadas aos Microtúbulos/genética , Proteínas de Neoplasias/genética , Neoplasias Pancreáticas/metabolismo , Proteínas/genética , Biomarcadores Tumorais/metabolismo , Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/patologia , Proteínas de Ciclo Celular/metabolismo , Movimento Celular , Humanos , Proteínas Associadas aos Microtúbulos/metabolismo , Invasividade Neoplásica , Proteínas de Neoplasias/metabolismo , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/patologia , Proteínas/metabolismo , Proteínas Proto-Oncogênicas p21(ras)/genética , Proteínas Proto-Oncogênicas p21(ras)/metabolismo , Proteína Smad4/genética , Proteína Smad4/metabolismo , Linfócitos T/fisiologia , Regulação para CimaRESUMO
Tumor lineage plasticity is emerging as a critical mechanism of therapeutic resistance and tumor relapse. Highly plastic tumor cells can undergo phenotypic switching to a drug-tolerant state to avoid drug toxicity. Here, we investigate the transmembrane tight junction protein Claudin6 (CLDN6) as a therapeutic target related to lineage plasticity for hepatocellular carcinoma (HCC). CLDN6 was highly expressed in embryonic stem cells but markedly decreased in normal tissues. Reactivation of CLDN6 was frequently observed in HCC tumor tissues as well as in premalignant lesions. Functional assays indicated that CLDN6 is not only a tumor-associated antigen but also conferred strong oncogenic effects in HCC. Overexpression of CLDN6 induced phenotypic shift of HCC cells from hepatic lineage to biliary lineage, which was more refractory to sorafenib treatment. The enhanced tumor lineage plasticity and cellular identity change were potentially induced by the CLDN6/TJP2 (tight junction protein 2)/YAP1 (Yes-associated protein 1) interacting axis and further activation of the Hippo signaling pathway. A de novo anti-CLDN6 monoclonal antibody conjugated with cytotoxic agent (Mertansine) DM1 (CLDN6-DM1) was developed. Preclinical data on both HCC cell lines and primary tumors showed the potent antitumor efficiency of CLDN6-DM1 as a single agent or in combination with sorafenib in HCC treatment.
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Antineoplásicos , Carcinoma Hepatocelular , Imunoconjugados , Neoplasias Hepáticas , Antineoplásicos/farmacologia , Carcinoma Hepatocelular/tratamento farmacológico , Linhagem Celular Tumoral , Proliferação de Células , Resistencia a Medicamentos Antineoplásicos , Humanos , Imunoconjugados/uso terapêutico , Neoplasias Hepáticas/tratamento farmacológico , Recidiva Local de Neoplasia , Sorafenibe/farmacologia , Sorafenibe/uso terapêuticoRESUMO
Beta-1,3-N-acetylglucosaminyltransferase 3 (B3GNT3) has been associated with tumor progression in several solid tumors, and inhibits CD8+ T cell-mediated anti-tumor immunity in breast cancer. However, little is known about the potential functions of B3GNT3 in immunosuppression in pancreatic cancer (PC). This study on B3GNT3 aims to provide novel insights into the mechanisms of immune suppression or evasion in PC. To this end, the clinical significance and oncologic roles of B3GNT3 were investigated through bioinformatic analysis and in vitro studies. Potential associations between the expression of B3GNT3 and tumor immunity were mainly analyzed by single-sample gene set enrichment analysis (ssGSEA) and immunofluorescence in tissue microarray (TMA). B3GNT3 overexpression was observed in PC tissue and was associated with larger tumor sizes, higher histologic grades, and poorer overall survival (OS). B3GNT3 overexpression was associated with the mutation status and expression of driver genes, especially for KRAS and SMAD4. B3GNT3 knockdown inhibited the proliferation, invasion, and epithelial-mesenchymal transition (EMT) of PC cells. B3GNT3 overexpression significantly correlated with decreased infiltration of tumor infiltrating lymphocytes (TILs), especially CD8+ T cells. Overall, our results indicate that B3GTN3 plays a novel role in tumor progression and immunosuppression, thus serving as a potential therapeutic target in PC.
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Linfócitos T CD8-Positivos/metabolismo , Proliferação de Células/genética , Linfócitos do Interstício Tumoral/metabolismo , N-Acetilglucosaminiltransferases/genética , Neoplasias Pancreáticas/genética , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Linfócitos T CD8-Positivos/patologia , Linhagem Celular Tumoral , Movimento Celular/genética , Biologia Computacional , Bases de Dados Genéticas , Progressão da Doença , Transição Epitelial-Mesenquimal/genética , Feminino , Técnicas de Silenciamento de Genes , Humanos , Linfócitos do Interstício Tumoral/patologia , Masculino , Pessoa de Meia-Idade , N-Acetilglucosaminiltransferases/metabolismo , Invasividade Neoplásica/genética , Invasividade Neoplásica/patologia , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/mortalidade , Neoplasias Pancreáticas/patologia , Prognóstico , Proteínas Proto-Oncogênicas p21(ras)/genética , Proteínas Proto-Oncogênicas p21(ras)/metabolismo , Proteína Smad4/genética , Proteína Smad4/metabolismo , Taxa de SobrevidaRESUMO
Solitary large hepatocellular carcinoma (SLHCC) is a specific subtype of HCC with unique characteristics. It is of great interest to assess and stratify the prognosis of SLHCCs after curative resection. In this study, we tried to construct a prognostic nomogram for SLHCC following curative resection through a retrospective analysis of 202 SLHCC cases. Seven prognostic factors were identified and integrated to establish a novel prognostic nomogram, which included tumor size, microvascular invasion, tumor differentiation, Ki67 (%), α-fetoprotein (AFP), carbohydrate antigen 125 (CA125), and HBsAg status. The Harrell's concordance index (C-index) of the nomogram for overall survival (OS) in the training, validation, and whole sets was 0.752, 0.703, and 0.733, respectively. Furthermore, the area under the curve (AUC) of the receiver operating characteristic (ROC) curve of the nomogram for predicting 1-, 3-, and 5-year OS indicated that the nomogram had an optimal discrimination of the prognostic prediction for SLHCC. The total score of each patient was calculated based on the nomogram, and patients were divided into three subgroups: low-risk group (total score ⦠107), medium-risk group (107 < total score ≤ 125), and high-risk group (total score > 125). The 1-, 3-, and 5-year OS rates of the low-risk, medium-risk, and high-risk groups in the whole set were 89.3 vs. 70.1 vs. 33.3%, 76.6 vs. 37.8 vs. 14.5%, and 69.8 vs. 25.1 vs. 12.5%, respectively (P < 0.001). Similar results were shown in terms of the recurrence-free survival (RFS) rate. By analyzing 101 cases of recurrent tumors, transarterial chemoembolization (TACE) plus radiofrequency ablation (RFA)/surgery was found to prolong patient survival when compared to TACE alone in the low-risk group, but not in the medium/high-risk group. In conclusion, our prognostic nomogram successfully stratifies the prognosis for SLHCC after curative resection, which deserves further study in future clinical practice.
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INTRODUCTION: The efficacy of different timings of cytoreductive surgery (CRS) with hyperthermic intraperitoneal chemotherapy (HIPEC) in controlling malignant ascites caused by peritoneal carcinomatosis of colorectal cancer (CRC) is not well defined. The study aims to investigate the clinical efficacy and safety of different timings of CRS with HIPEC for malignant ascites caused by peritoneal carcinomatosis from CRC. MATERIALS AND METHODS: This was a preliminary randomized controlled study performed at the Intracelom Hyperthermic Perfusion Therapy Center of the Cancer Hospital of Guangzhou Medical University (China) from December 2008 to December 2016. The patients were randomized to: CRS, followed by HIPEC (CRS+HIPEC; nâ=â14), and ultrasound-guided HIPEC, followed by CRS 1 to 2 weeks later (HIPEC+ delayed cytoreductive surgery (dCRS) group, nâ=â14). The endpoints were complete remission rate of ascites, successful complete CRS rate, and overall survival. RESULTS: Malignant ascites in all patients showed complete remission; the total effective rate was 100%. Complete CRS was not feasible in any patient. The median follow-up of the 2 groups was 41.9 and 42.3 months in the CRS+HIPEC and HIPEC+dCRS groups, respectively. Overall survival was 14.5 (95%CI: 7-19 months) and 14.3 months (95%CI: 4-21 months) (Pâ>â.05). The adverse effects of HIPEC were manageable. CONCLUSIONS: CRS+HIPEC and HIPEC+dCRS have the same efficacy in controlling malignant ascites caused by CRC and peritoneal carcinomatosis. The timing of CRS and HIPEC does not prolong the survival of patients with peritoneal carcinomatosis from CRC, even when a complete CRS is not feasible.
Assuntos
Ascite/etiologia , Ascite/terapia , Neoplasias Colorretais/complicações , Procedimentos Cirúrgicos de Citorredução , Hipertermia Induzida , Adulto , Idoso , Ascite/mortalidade , China , Neoplasias Colorretais/mortalidade , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Taxa de Sobrevida , Ultrassonografia de IntervençãoRESUMO
Pancreatic neuroendocrine tumors (pNETs) are a heterogeneous group of tumors with complicated treatment options that depend on pathological grading, clinical staging, and presence of symptoms related to hormonal secretion. With regard to diagnosis, remarkable advances have been made: Chromogranin A is recommended as a general marker for pNETs. But other new biomarker modalities, like circulating tumor cells, multiple transcript analysis, microRNA profile, and cytokines, should be clarified in future investigations before clinical application. Therefore, the currently available serum biomarkers are insufficient for diagnosis, but reasonably acceptable in evaluating the prognosis of and response to treatments during follow-up of pNETs. Surgical resection is still the only curative therapeutic option for localized pNETs. However, a debulking operation has also been proven to be effective for controlling the disease. As for drug therapy, steroids and somatostatin analogues are the first-line therapy for those with positive expression of somatostatin receptor, while everolimus and sunitinib represent important progress for the treatment of patients with advanced pNETs. Great progress has been achieved in the combination of systematic therapy with local control treatments. The optimal timing of local control intervention, planning of sequential therapies, and implementation of multidisciplinary care remain pending.
Assuntos
Técnicas de Ablação/métodos , Antineoplásicos/uso terapêutico , Biomarcadores Tumorais/sangue , Tumores Neuroendócrinos/diagnóstico , Pancreatectomia/métodos , Neoplasias Pancreáticas/diagnóstico , Antineoplásicos/farmacologia , Quimioterapia Adjuvante/métodos , Terapia Combinada , Procedimentos Cirúrgicos de Citorredução , Intervalo Livre de Doença , Humanos , Excisão de Linfonodo , Terapia de Alvo Molecular/métodos , Gradação de Tumores , Estadiamento de Neoplasias , Tumores Neuroendócrinos/sangue , Tumores Neuroendócrinos/mortalidade , Tumores Neuroendócrinos/terapia , Pâncreas/patologia , Pâncreas/cirurgia , Neoplasias Pancreáticas/sangue , Neoplasias Pancreáticas/mortalidade , Neoplasias Pancreáticas/terapia , Equipe de Assistência ao Paciente , Prognóstico , Intervalo Livre de Progressão , Somatostatina/análogos & derivados , Somatostatina/uso terapêutico , Resultado do TratamentoRESUMO
BACKGROUND: Loss of terminal differentiation markers and gain of stem cell-like properties are a major hallmark of cancer malignant progression. Identification of novel biomarkers representing tumor developmental progeny and predictive of patients' prognosis would greatly benefit clinical cancer management. METHODS: Human embryonic stem cells were induced to differentiate into hepatocytes along hepatic lineages. Transcriptomic data from different liver developmental stages were analyzed combining with the RNA-seq data from The Cancer Genome Atlas (TCGA) project. Kaplan-Meier survival analysis and Cox regression analyses were used to analyze the clinical significance in HCC patients. RESULTS: A shifted expression pattern of claudin (CLDN) family genes were identified to be closely associated with liver development and tumor progression. Claudins with hepatic features were found to be significantly down-regulated and predicted better prognosis in HCC patients. Conversely, another set of claudins with embryonic stem cell features were found to be significantly up-regulated and predicted worse prognosis in HCC patients. A claudin signature score system was further established by combining the two sets of claudin genes. The newly established claudins signature could robustly predict HCC patients' prognosis in the training, testing, and independent validation cohorts. CONCLUSIONS: In the present study, we developed a novel embryonic developmental claudins signature to monitor the extent of tumor dedifferentiation in HCC from an in vitro hepatocyte differentiation model. The claudins signature might present a great potential in predicting prognostic significance in HCC as cell surface biomarkers, and provide novel therapeutic targets for precision oncology further in the clinic.