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1.
J Oncol ; 2022: 4269733, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35571489

RESUMO

Objectives: Limited research on the role of membrane-bound O-acyltransferase domain-containing 2 (MBOAT2) in cancer biology exists. In particular, the underlying role of MBOAT2 and its potential mechanisms in pancreatic cancer have not yet been explored. Further study of MBOAT2 could provide new ideas about the carcinogenesis and treatment of pancreatic cancer (PC). Methods: In the current study, the potential biological and clinical significances of MBOAT2 were explored by bioinformatics analysis. Real-time quantitative polymerase chain reaction and western blot analysis were performed to determine the level of MBOAT2 in pancreatic ductal adenocarcinoma (PDAC) cell lines. MTT, colony formation, and Transwell assays and flow cytometry of cell cycle were performed to analyze PDAC cell proliferation, migration, and cycle progression. The potential relationship between MBOAT2 level and tumor immunity was analyzed using the ESTIMATE algorithm, CIBERSORT algorithm, and single-sample gene set enrichment analysis. Results: The level of MBOAT2 was remarkably upregulated in most tumors, especially pancreatic tumors, and was positively correlated with a greater rate of tumor recurrence, higher histologic grade, and worse overall survival. MBOAT2 overexpression was also closely correlated with the mutation status and expression level of driver genes, especially KRAS. Meanwhile, functional enrichment analysis demonstrated that MBOAT2 might be involved in cell-cell communication; cell cycling; the Ras signaling pathway; and immune-related biological functions such as the leukocyte activation involved in T-cell-receptor signaling pathway, the inflammatory response, and antigen processing and presentation. Furthermore, in vitro experiments demonstrated that MBOAT2 overexpression accelerated PC cell proliferation and migration. MBOAT2 overexpression also enhanced CDK2 and CCNA2 expression, leading to cell cycle progression from the G1 phase to the G2 phase. Lastly, MBOAT2 overexpression reduced the infiltration level of CD8+ T-cells, plasmacytoid dendritic cells, and activated dendritic cells but triggered a high type-2 T helper/type-1 T helper cell ration (Th2/Th1 ration) in PC. Conclusion: Our findings suggest that MBOAT2 is a potential protooncogene in PDAC that predicts a poor prognosis and is related to KRAS activation and inferior infiltration of CD8+ T-cells in PC.

2.
RSC Adv ; 12(19): 11722-11731, 2022 Apr 13.
Artigo em Inglês | MEDLINE | ID: mdl-35432946

RESUMO

We present results of an unbiased structure search for the lowest energy crystalline structures of various stoichiometric iridium borides, using first-principles calculations combined with particle swarm optimization algorithms. As a result, besides three stable phases of C2/m-Ir3B2, Fmm2-Ir4B3, and Cm-Ir4B5, three promising metastable phases, namely, P21/m-Ir2B, P21/m-IrB, and Pnma-Ir3B4, whose energies are within 20 meV per atom above the convex hull curve, are also identified at ambient pressure. The high bulk modulus of 301 GPa, highest shear modulus of 148 GPa, and smallest Poisson's ratio of 0.29 for C2/m-Ir3B2 make it a promising low compressible material. C2/m-Ir3B2 is predicted to possess the highest Vickers hardnesses, with a Vickers hardness of 13.1 GPa and 19.4 GPa based on Chen's model and Mazhnik-Oganov's model respectively, and a high fracture toughness of 5.17 MPa m0.5. The anisotropic indexes and the three-dimensional surface constructions of Young's modulus indicate that Ir-B compounds are anisotropic with the sequence of the elastic anisotropy of Ir2B > IrB > Ir4B5 > Ir3B4 > Ir4B3 > Ir3B2. Remarkably, these iridium borides are all ductile. We further find that the four Ir-B phases of P21/m-Ir2B, C2/m-Ir3B2, P21/m-IrB, and Fmm2-Ir4B3 possess dominant Ir-B covalent bonding character, while strong B-B and Ir-B covalent bonds are present in Cm-Ir4B5 and Pnma-Ir3B4, which are responsible for their excellent mechanical properties.

3.
J Exp Clin Cancer Res ; 41(1): 130, 2022 Apr 07.
Artigo em Inglês | MEDLINE | ID: mdl-35392973

RESUMO

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest cancer due to its highly aggressive phenotype and lack of effective biomarkers or treatment strategies. ZMAT1 belongs to the C2H2 type zinc finger family, but its biological function is rarely investigated, as well as its role in cancer development. METHODS: Multiple bioinformatics analyses were used to evaluate ZMAT1 expression and potential role in PDAC. Intro and vivo studies were performed to assess the effects of ZMAT1 on PDAC cells growth. Furthermore, CHIP-seq and luciferase reporter assay was conducted to identify its specific regulatory mechanism in PDAC. RESULTS: The current study identified the down-regulation of ZMAT1 and its associations with unfavorable clinicopathological characteristics and poor survival of PDAC. Further, we found overexpression of ZMAT1 inhibited pancreatic cancer cell proliferation by inducing p21, leading to impaired S/G2 cell cycle progression. Besides, over-expression of ZMAT1 led to decreased pancreatic cancer cell apoptosis. Mechanistically, ZMAT1 up-regulated p53 expression and inhibition of p53 abrogated the effect of ZMAT1 over-expression on pancreatic cancer cell, indicating the role of ZMAT1 in PDAC was dependent on p53. By performing CHIP-seq assay, we found ZMAT1 did not bind to P53 but bound to the promoter region of SIRT3, an upstream regulator for p53. Luciferase reporter assay showed transfection of ZMAT1 induced SIRT3 transcription, suggesting ZMAT1 was a transcriptional activator for SIRT3. CONCLUSION: Our findings indicated the role of ZMAT1-SIRT3-p53 signaling pathway during tumor growth, highlighting that ZMAT1 is a tumor suppressor and novel biomarker of PDAC.


Assuntos
Carcinoma Ductal Pancreático , Neoplasias Pancreáticas , Sirtuína 3 , Proteína Supressora de Tumor p53 , Carcinoma Ductal Pancreático/patologia , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células/genética , Regulação Neoplásica da Expressão Gênica , Genes Supressores de Tumor , Humanos , Neoplasias Pancreáticas/patologia , Transdução de Sinais , Sirtuína 3/genética , Sirtuína 3/metabolismo , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismo
4.
Cancer Biomark ; 2022 Mar 16.
Artigo em Inglês | MEDLINE | ID: mdl-35342079

RESUMO

OBJECTIVE: N6-methyladenosine (m6A) is a common RNA modification on eukaryotic mRNA and some of the m6a regulatory proteins play a crucial role in breast cancer. However, the copy number variations for m6a regulatory proteins and their role in clinicopathological characteristics and survival in breast cancer remain unclear. METHODS: In this study, we screened the m6A related genes alterations in breast cancer by analyzing the Molecular Taxonomy of Breast Cancer International Consortium and The Cancer Genome Atlas database, and further analyzed the clinical prognostic value of YTHDF1 amplification. RESULTS: The YTH domain family (YTHDF3 and YTHDF1) amplification exhibited higher alteration rates among 10 m6A regulatory genes. YTHDF1 and YTHDF3 amplification resulted in higher mRNA expression (P< 0.001). Protein expression of YTHDF1 and YTHDF3 were higher in breast cancer (P< 0.001). YTHDF1 amplification presented a high correlation with worse clinicopathological characteristics and overall survival in patients with breast cancer. COX regression analysis showed that YTHDF1 amplification was an independent risk factor for 10-year overall survival in breast cancer (hazard ratio: 1.549; 95% confidence interval: 1.408-1.705; P< 0.001). Gene set enrichment analysis revealed that the downstream target of YTHDF1 may be related to MYC signaling regulation and T cell differentiation. Moreover, YTHDF1 amplification and high expression resulted in lower immune cell infiltration. YTHDF1 knockdown retrained proliferation, migration and invasion in breast cancer cells in vitro. CONCLUSIONS: We found significant worse clinical characteristics and lower immune infiltrates in patients with YTHDF1 amplification. The findings indicate that YTHDF1 amplification may be a potential target for the treatment of breast cancer.

5.
J Mater Chem B ; 10(15): 2828-2843, 2022 Apr 13.
Artigo em Inglês | MEDLINE | ID: mdl-35316319

RESUMO

Multi-drug resistance (MDR) is a complicated cellular defense mechanism for tumor cells to resist chemotherapy drugs, which is also the main cause of chemotherapy failure. In this study, a local injectable hydrogel delivery system was used to construct an on-demand sustained-release platform with the advantages of chemotherapy, photothermal therapy (PTT), and magnetic resonance imaging (MRI). It could achieve synergistic chemo-photothermal therapy and real-time evaluation of the therapeutic effects (via MRI) for MDR hepatocellular carcinoma (HCC). Furthermore, after a single administration, the prepared hydrogel with a theranostic nanoprobe could release the therapeutic agents on demand for up to 14 d. Firstly, doxorubicin (DOX) and gold-manganese oxide (Au-MnO) nanoparticles (NPs) were incorporated into liposome-based self-assembled micelles, then loaded into the thermosensitive hydrogel (F127) to form DOX@Au-MnO-L NPs/F127 hydrogel (DAML/H). The prepared NP complex showed a spherical morphology with a narrow size distribution. The prepared hydrogel drug delivery system had injectable properties and stable photothermal conversion. Both the DOX@Au-MnO-L NPs and DAML/H showed controlled drug release under near infrared (NIR) laser irradiation. The in vitro MRI studies indicated that the prepared DAML/H had a high relaxation rate (14.38 mM-1 s-1) and good MRI scanning sensitivity conditions. The in vitro and in vivo results suggested the synergistic chemo-photothermal therapy of DAML/H with NIR irradiation (808 nm, 1 W cm-2, 10 min) improved the antitumor efficacy for MDR HCC. The in vivo retention experiment of Au in tumors indicated that the prepared hydrogel drug delivery system (DAML/H) had a good ability to retain Au in the tumor for a long time (at least 14 d). The western blotting results revealed that DAML/H with laser treatment could effectively downregulate P-glycoprotein (P-gp), p53 and antiapoptotic protein (Bcl-2), whereas the expression level of proapoptotic protein (Bax) and caspase-3 were increased. Therefore, DAML/H could serve as a promising synergistic chemo-photothermal therapy for MDR HCC, and a single administration might achieve long-term (14 d), on-demand, sustained-release treatment of tumors.


Assuntos
Carcinoma Hepatocelular , Neoplasias Hepáticas , Carcinoma Hepatocelular/diagnóstico por imagem , Carcinoma Hepatocelular/tratamento farmacológico , Preparações de Ação Retardada/uso terapêutico , Doxorrubicina , Humanos , Hidrogéis/uso terapêutico , Neoplasias Hepáticas/diagnóstico por imagem , Neoplasias Hepáticas/tratamento farmacológico , Fototerapia/métodos , Terapia Fototérmica , Nanomedicina Teranóstica
6.
Langmuir ; 38(9): 2751-2762, 2022 Mar 08.
Artigo em Inglês | MEDLINE | ID: mdl-35192347

RESUMO

NO2 and SO2, as valuable chemical feedstock, are worth being recycled from flue gases. The separation of NO2 and SO2 is a key process step to enable practical deployment. This work proposes SO2 separation from NO2 using chabazite zeolite (SSZ-13) membranes and provides insights into the feasibility and advantages of this process using molecular simulation. Grand canonical ensemble Monte Carlo and equilibrium molecular dynamics methods were respectively adopted to simulate the adsorption equilibria and diffusion of SO2, NO2, and N2O4 on SSZ-13 at varying Si/Al (1, 5, 11, 71, +∞), temperatures (248-348 K), and pressures (0-100 kPa). The adsorption capacity and affinity (SO2 > N2O4 > NO2) demonstrated strong competitive adsorption of SO2 based on dual-site interactions and significant reduction in NO2 adsorption due to dimerization in the ternary gas mixture. The simulated order of diffusivity (NO2 > SO2 > N2O4) on SSZ-13 demonstrated rapid transport of NO2, strong temperature dependence of SO2 diffusion, and the impermeability of SSZ-13 to N2O4. The membrane permeability of each component was simulated, rendering a SO2/NO2 membrane separation factor of 26.34 which is much higher than adsorption equilibrium (6.9) and kinetic (2.2) counterparts. The key role of NO2-N2O4 dimerization in molecular sieving of SO2 from NO2 was addressed, providing a facile membrane separation strategy at room temperature.

7.
Cancer Immunol Immunother ; 71(3): 601-612, 2022 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-34279685

RESUMO

BACKGROUND: It is widely considered that pancreatic cancer (PC) is an immunosuppressive cancer. Immune-based therapies remain promising therapeutic strategies for PC. Overexpression of lipase H (LIPH) was reported to be related to immunity in cattle and has also been demonstrated to promote tumor progression in several tumors, but its role in pancreatic carcinogenesis remains unclear. Study on LIPH in PC might provide a new insight into the immunosuppression in PC. METHODS: The potential biological and clinical significance of LIPH was evaluated by bioinformatics analysis. We further investigated potential associations between the expression of LIPH and tumor immune infiltration using the CIBERSORT algorithm, the ESTIMAT algorithm, and single sample gene set enrichment analysis (ssGSEA). RESULTS: LIPH was significantly overexpressed in tumor tissues compared with normal tissues. LIPH overexpression correlated with tumor recurrence, advanced histologic grade, and poorer overall survival (OS). Four of the most common somatic mutation, including KRAS, TP53, CDKN2A, and SMAD4, in PC were all correlated with high LIPH expression. And high LIPH expression was significantly correlated with KRAS activation and SMAD4 inactivation. Besides, LIPH expression was involved in various biological pathways such as negative regulation of cell-cell adhesion, actin cytoskeleton, EMT, angiogenesis, and signaling by MST1. And LIPH overexpression caused high infiltration of TAMs, Treg cells, and Th2/Th1, but reduced the infiltration of CD8+ T cells and Th1 cells. CONCLUSIONS: Our findings demonstrated that LIPH correlated with immune suppression or evasion and may function as a novel unfavorable prognostic biomarker in PC.


Assuntos
Biomarcadores Tumorais , Tolerância Imunológica , Lipase/genética , Neoplasias Pancreáticas/etiologia , Neoplasias Pancreáticas/mortalidade , Evasão Tumoral , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/metabolismo , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Humanos , Lipase/metabolismo , Mutação , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/patologia , Prognóstico , Evasão Tumoral/genética , Microambiente Tumoral/genética , Microambiente Tumoral/imunologia
8.
Front Immunol ; 12: 790661, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34925373

RESUMO

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.


Assuntos
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 Tumoral
9.
Biomed Res Int ; 2021: 9949272, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34660806

RESUMO

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.


Assuntos
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
10.
J Cancer ; 12(19): 5797-5806, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34475993

RESUMO

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.

11.
J Hepatocell Carcinoma ; 8: 899-912, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34395329

RESUMO

BACKGROUND: Recent evidence has shown that Solute Carrier Family 39 Member 10 (SLC39A10) promoted tumor progression in several cancer types. The study intended to explore the expression and function of SLC39A10 in hepatocellular carcinoma (HCC). METHODS: Multiple bioinformatics analyses were used to evaluate SLC39A10 expression and potential role in HCC. Quantitative real-time polymerase chain reaction and immunohistochemistry were used to confirm SLC39A10 expression. Intro studies were performed to assess the effects of SLC39A10 on HCC cells proliferation and migration. Furthermore, flow cytometry was conducted to identify its specific function in apoptosis of HCC. RESULTS: SLC39A10 was significantly over-expressed in HCC samples from both bioinformatic databases and our cohort. Survival analyses suggested patients with high expression of SLC39A10 had poor overall survival and disease-free survival (P-value <0.01). Further, the expression of SLC39A10 was positively correlated with tumor-infiltrating lymphocytes and some immune checkpoints like CTLA4, TIM3 and TGFB1. In HCC cell lines, SLC39A10 knockdown inhibited cells proliferation and migration, but promoted apoptosis. CONCLUSION: An increased SLC39A10 expression was found and served as an unfavorable indicator of survival in HCC. Further studies suggested SLC39A10 promotes tumor aggressiveness and may provide a novel target for HCC therapy.

12.
J Oncol ; 2021: 6619149, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34447433

RESUMO

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.

13.
Am J Cancer Res ; 11(6): 2754-2768, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34249426

RESUMO

Left-sided pancreatic adenocarcinoma (LPAC) has a poorer prognosis and has some distinct features compared to cancer of pancreatic head. A reliable model to predict the prognosis of LPAC following surgery is needed in clinical practice. Our study included 231 patients with resected LPAC from 3 Chinese pancreatic disease centers. Cox-regression analysis was conducted to identify independent risk factors of LAPC. Then we established a nomogram and performed C-index, receiver operating characteristic curve, calibration plot and decision curve analysis to assess its discrimination and calibration. As a result, CA19-9, surgical margin, tumor differentiation, lymph node metastasis, and postoperative adjuvant chemotherapy were identified as significant prognostic factors. Based on these predictors, a novel nomogram was constructed. The nomogram achieved high C-indexes in the training cohort (0.805) and validation cohort (0.719), which were superior than the AJCC-8 staging system and other nomograms. The area under curve of the nomogram for predicting patients survival at 1-, 2-, and 3-year in training cohort were more than 0.8. Kaplan-Meier survival curve for the subgroups stratified based on the nomogram showed a better separation than the AJCC-8 stage I, II, III, indicating a superior ability of risk stratification for our model. In summary, we constructed a nomogram which showed a better predictive ability for patients' survival with LPAC after surgical resection than the AJCC staging system and other predictive models. Our model would be helpful to discriminate high-risk LPAC and facilitate clinical decision making.

14.
Clin Med Insights Oncol ; 15: 11795549211024149, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34211308

RESUMO

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.

15.
Spectrochim Acta A Mol Biomol Spectrosc ; 261: 119991, 2021 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-34091359

RESUMO

In this work, we investigate the low-lying electronic states correlated to the first and the second dissociation channels of MgGa molecule, neglecting and including the spin-orbit coupling effect. High-level ab initio calculations have been performed by using the icMRCI + Q method. Potential energy curves, spectroscopic constants, electron configurations and dipole moments are derived and discussed. Molecular structures of several magnesium-group 13 diatomics have been probed and analyzed. Information associated with transition dipole moments, Franck-Condon factors, vibrational branching ratios and radiative lifetimes between the Ω states are also well characterized. It is anticipated this work will provide some inspiration for further studies on MgGa.

16.
Dis Markers ; 2021: 6682697, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33747255

RESUMO

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.


Assuntos
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 Cima
17.
J Cell Mol Med ; 25(6): 3006-3018, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33580614

RESUMO

S100 calcium-binding protein A (S100A) family members regulate multiple biological functions related to pancreatic cancer (PC) progression and metastasis. However, the prognostic and oncologic values of S100A family have not been systematically investigated in PC. In the present study, the mRNA expression and potential functions of S100A family were investigated by bioinformatic analysis. Our results demonstrated that overexpression of S100A2, S100A6, S100A10, S100A11, S100A14 and S100A16 was significantly associated with higher T stage, advanced histologic grade and worse prognosis in PC. Besides, one CpG of S100A2, three CpG of S100A6, four CpG of S100A10, four CpG of S100A11, two CpG of S100A14 and five CpG of S100A16 were negatively associated with corresponding S100A family members expression and positively associated with overall survival (OS). The signature based on four CpGs showed good prediction ability of OS. Besides, S100A2 overexpression took part in the regulation of mitotic cell cycle, ECM-receptor interaction and HIF-1α transcription factor network. Overexpression of S100A6, S100A10, S100A11, S100A14 and S100A16 may impair the infiltration and cytolytic activity of CD8+ T cells through focal adhesion-Ras-stimulating signalling pathway in PC. Overall, this study explores the multiple prognostic values and oncologic functions of the S100A family in PC.


Assuntos
Biomarcadores Tumorais , Imunomodulação/genética , Família Multigênica , Neoplasias Pancreáticas/etiologia , Neoplasias Pancreáticas/mortalidade , Proteínas S100/genética , Biologia Computacional/métodos , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Humanos , Estimativa de Kaplan-Meier , Gradação de Tumores , Estadiamento de Neoplasias , Neoplasias Pancreáticas/patologia , Prognóstico , Modelos de Riscos Proporcionais , Proteínas S100/metabolismo , Transdução de Sinais , Transcriptoma
19.
J Immunother Cancer ; 9(1)2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33472857

RESUMO

Exosomes, as the main group of extracellular vesicles, are biologically active lipid-bilayer vesicles that are naturally released from different types of normal or tumor cells. These vesicles play an important role in intercellular communication and influence the extracellular environment and the immune system. Emerging evidence demonstrates that cancer-derived exosomes are enriched in immunosuppressive proteins, such as the programmed death-ligand 1 (PD-L1). PD-L1 and its receptor programmed cell death protein 1 (PD-1) are the key immune checkpoint molecules that promote tumor progression via negative regulation of immune responses. PDL-1 is highly expressed on the surface of tumor cells and binds to PD-1 on the surface of activated T cells, leading to suppression of T cells, which consequently enables cancer cells to escape antitumor immunity. Currently, there are several Food and Drug Administration-approved monoclonal antibodies blocking PD-1/PD-L1 interaction, which are clinically used for cancer treatment. However, despite impressive treatment outcomes, some patients show poor response to PD-1/PD-L1 blockade. Of note, tumor-derived exosomes containing PD-L1 can recapitulate the effect of cell-surface PD-L1. There is evidence that reveals a significant association between levels of circulating exosomal PD-L1 and rate of response to anti-PD-1/PD-L1 antibody therapy. The present article reviews the role of exosomal PDL-1 in the therapeutic resistance to anti-PD-1/PD-L1 treatment. Importantly, it is suggested that the removal of exosomal PDL-1 could serve as a therapeutic adjuvant for enhancing the efficacy of anti-PD-1/PD-L1 therapy in patients with cancer.


Assuntos
Antígeno B7-H1/metabolismo , Resistencia a Medicamentos Antineoplásicos , Exossomos/metabolismo , Neoplasias/imunologia , Antígeno B7-H1/efeitos dos fármacos , Progressão da Doença , Exossomos/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Inibidores de Checkpoint Imunológico/farmacologia , Inibidores de Checkpoint Imunológico/uso terapêutico , Neoplasias/tratamento farmacológico , Receptor de Morte Celular Programada 1/efeitos dos fármacos , Receptor de Morte Celular Programada 1/metabolismo , Regulação para Cima/efeitos dos fármacos
20.
Aging (Albany NY) ; 13(2): 2310-2329, 2020 12 09.
Artigo em Inglês | MEDLINE | ID: mdl-33316775

RESUMO

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.


Assuntos
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 Sobrevida
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