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Introduction: This study aimed to explore the effect of activated T cells on breast cancer (BC) cells and provide a theoretical basis for the interaction mechanism studies between BC and immune cells.Methods: The microarray dataset GSE73527 was downloaded from the Gene Expression Omnibus database. The common differentially expressed mRNAs (co-DEMs) and the common differentially expressed long non-coding RNAs (co-DElncRNAs) were identified between MDA-MB-231 cells and MCF7 activated human T cells, respectively. The RNA–miRNA–lncRNA (ceRNA) network was constructed. Furthermore, the Kyoto encyclopedia of genes and genomes pathway and the gene ontology function analyses were performed on co-DEMs. The protein–protein interaction networks and modules were investigated.Results: A total of 639 co-DEMs (such as interleukin-6 [IL6] and signal transducer and activator of transcription 1 [STAT1]) were detected in this study. Defense response to other organisms and herpes simplex infection were the most outstanding function and pathway assembled with co-DEMs, respectively. One protein–protein interaction network and three modules were further constructed. A total of 88 mRNA–miRNA–lncRNA relationships such as BTN3A1-has-mir-20-b-5p-HCP5 were explored in the ceRNA network.Conclusion: Activated T cells may play a crucial role in the defense response to other organ-ism functions and herpes simplex infection pathways by upregulating IL6 and STAT1, which further affected the progression of BC. The BTN3A1-has-miR-20b-5p-HCP5 relationship may be the potential interaction mechanism between BC and immune cells. [ABSTRACT FROM AUTHOR]

Small-cell gallbladder neuroendocrine carcinoma (GB-SCNEC) is a relatively rare histological type of gallbladder cancer, and the genomic landscape of GB-SCNEC is rarely considered in treatment decisions. We performed whole-genome sequencing on an advanced case of GB-SCNEC. We identified approximately 900 high-quality somatic single nucleotide variants (SNVs) and small insertions and deletions (INDELs), 109 of which were shared by both the primary and metastatic tumor tissues. Somatic non-synonymous coding variations with damaging impact in HMCN1 and CDH10 were observed in both the primary and metastatic tissue specimens. A pathway analysis of the genes mapped to the SNVs and INDELs revealed gene enrichment associated with axon guidance, ERBB signaling et al. Furthermore, we identified 11 deletions, 4 tandem duplications and 5 inversions that mapped to known genes. Two gene fusions, NCAM2-SGCZ and BTG3-CCDC40 were also discovered and validated by Sanger sequencing. Additionally, we identified genome-wide copy number variations and microsatellite instability. In this study, we identified novel biological markers of GB-SCNEC that may serve as valuable prognostic factors or indicators of treatment response in patients with GB-SCNEC with lymphatic metastasis. [ABSTRACT FROM AUTHOR]

The transcriptional coactivator Yes-associated protein 1 (YAP1), a key regulator of cell proliferation and organ size in vertebrates, has been implicated in various malignancies. However, little is known about the expression and biological function of YAP1 in human gallbladder cancer (GBC). In this study we examined the clinical significance and biological functions of YAP1 in GBC and found that nuclear YAP1 and its target gene AXL were overexpressed in GBC tissues. We also observed a significant correlation between high YAP1 and AXL expression levels and worse prognosis. The depletion of YAP1 using lentivirus shRNAs significantly inhibited cell proliferation by inducing cell cycle arrest in S phase in concordance with the decrease of CDK2, CDC25A, and cyclin A, and resulted in increased cell apoptosis and invasive repression in GBC cell lines in vitro . Furthermore, knockdown of YAP1 also inhibited tumor growth in vivo . Additionally, we demonstrated that the activation of the AXL/MAPK pathway was involved in the oncogenic functions of YAP1 in GBC. These results demonstrated that YAP1 is a putative oncogene and represents a prognostic marker and potentially a novel therapeutic target for GBC. [ABSTRACT FROM AUTHOR]

Individuals with gallbladder carcinoma (GBC), the most aggressive malignancy of the biliary tract, have a poor prognosis. Here we report the identification of somatic mutations for GBC in 57 tumor-normal pairs through a combination of exome sequencing and ultra-deep sequencing of cancer-related genes. The mutation pattern is defined by a dominant prevalence of C>T mutations at TCN sites. Genes with a significant frequency (false discovery rate (FDR) < 0.05) of non-silent mutations include TP53 (47.1%), KRAS (7.8%) and ERBB3 (11.8%). Moreover, ErbB signaling (including EGFR, ERBB2, ERBB3, ERBB4 and their downstream genes) is the most extensively mutated pathway, affecting 36.8% (21/57) of the GBC samples. Multivariate analyses further show that cases with ErbB pathway mutations have a worse outcome (P = 0.001). These findings provide insight into the somatic mutational landscape in GBC and highlight the key role of the ErbB signaling pathway in GBC pathogenesis. [ABSTRACT FROM AUTHOR]

• SLE for systems KCl + PEG10000/20000 + H 2 O at 288.2 and 298.2 K were determined. • The effect of temperature, PEG molecular weight of the system were discussed. • The modified Pitzer model was used for correlating the experimental data. This work finished measuring the phase equilibria of ternary systems {KCl + polyethylene glycol (PEG) 10000/20000 + H 2 O} at 288.2 and 298.2 K. The solubility, density and refractive index were determined and corresponding diagrams were plotted in this work. There was only solid–liquid phase equilibrium existing in the ternary systems {KCl + PEG10000/20000 + H 2 O} at 288.2 K and 298.2 K. All of the phase diagrams of four systems are divided into three parts which respectively are the regions of unsaturated homogeneous liquid (L), one liquid and one solid KCl (L + S), and one liquid and two solids KCl and PEG (L + 2S). In addition, the effects of molar mass of PEG (PEG1000/4000/10000/20000) and temperature (288.2 K and 298.2 K) on phase equilibria were discussed. Results show that the sizes of regions of (L) and (L + S) increased and that of (L + 2S) decreased with the increase of temperature, and the regions of (L) and (L + S) decreased and that of (L + 2S) increased with the increase of the molar mass of PEG. The modified Pitzer model was adopted as the equilibrium thermodynamics model to correlate the experimental data. Comparing the experimental data and calculated dada, it can give a precise result with small error. [ABSTRACT FROM AUTHOR]

• SLE and LLE existing for system PEG4000-RbCl-H 2 O at 298.15 and 308.15 K. • The effects of temperature, salts on the size of two-phase region are discussed. • The modified Chen-NRTL model was used to correlate the tie-lines. The phase equilibria of ternary system polyethylene glycol with molar mass of 4000 g∙mol−1(PEG 4000), rubidium chloride (RbCl) and water (H 2 O) were determined at T =(288.15, 298.15, 308.15) K. Results show that there is only solid-liquid equilibrium (SLE) relationship in the system at 288.15 K, both of solid-liquid equilibrium (SLE) and liquid-liquid equilibrium (LLE) are found in the system at 298.15 K and 308.15 K. The phase diagram at 288.15 K was divided into 3 areas including the region L (unsaturated liquid phase), the region L + S (saturated solutions with a solid phase RbCl) and the region L + 2S (saturated liquid phase with two solid phases of PEG4000 and RbCl) and the solubility of RbCl decreased with PEG4000 increasing. The complete phase diagrams at 298.15 K and 308.15 K including 6 areas (L (unsaturated liquid phase), 2L (aqueous two-phase), L + 2S (saturated liquid phase with two solid phases of PEG4000 and RbCl), 2L + S (two liquids with one solid phase RbCl), and 2 areas of L + S (saturated solutions with one solid phase RbCl) were constructed. Furthermore, the binodal curves, compositions, length of the tie-line (TLL) and slope of tie-line (STL) were obtained for these mixed solvent systems at 298.15 K and 308.15 K. Three nonlinear expressions, proposed by Mistry, Hu, and Jayapal, were used to fit the binodal curves. The data of tie-line were correlated by using Othmer-Tobias equations, Bancroft equations, Hand equation, Bachman equations and the Chen-NRTL model. All the presented results, both the experimental and calculated data, show convincing values. [ABSTRACT FROM AUTHOR]

The solubilities, densities and refractive indices of the ternary KCl + PEG8000 + H2O system were determined at 288.2, 298.2, and 308.2 K. In terms of phase diagrams at 288.2, 298.2, and 308.2 K, they are all made up of three areas, where the homogeneous area (L) contains unsaturated liquid, area (L + S) contains one saturated liquid and one solid (KCl), and area (L + 2S) contains one saturated liquid and two solids (KCl and PEG8000). The results of these experiments showed that with an addition of PEG8000 to the liquid, the solubility of KCl and density of the liquid phase decreased, whereas the refractive index inceased. By comparing the phase diagrams at 288.2, 298.2, and 308.2 K, it is seen that with an increase of temperature, the areas of (L) and (L + S) enlarged, whereas the area of (L + 2S) reduced. The phase diagrams of the ternary systems KCl + PEG1000/4000/6000/8000 + H2O were also compared and showed that with an increase of the molar mass of PEG, the ovedrall phase diagrams did not change although the areas of each part varied in size. Also, a modified Pitzer model was adopted as the equilibrium thermodynamics model to correlate the experimental data. [ABSTRACT FROM AUTHOR]

Paclitaxel is a microtubule-stabilizing drug that has therapeutic effect on breast cancer. However, the molecular mechanism of paclitaxel on breast cancer has not been elucidated. Microarray data of GSE114403, including 50 pretreatment and 50 posttreatment samples, were downloaded from public database. The differentially expressed genes (DEGs) between pretreatment and posttreatment were identified, followed by functional enrichment analysis. Then, protein–protein interaction (PPI) network and transcription factor (TF)–miRNA–mRNA network were constructed. Finally, the survival analysis of hub genes was performed. A total of 107 DEGs were screened from pretreatment versus posttreatment. Genes were significantly enriched in GO terms such as inflammatory response, and pathways like cytokine–cytokine receptor interaction pathway. CXCL2, PTGS2, and ATF3 were considered as hub genes in PPI network. TFs such as FOXA2, NFE2L2, as well as miRNAs like has-miR-508-3p and has-miR-584 also played role in the paclitaxel treatment. Additionally, survival analysis revealed that breast cancer patients with high expression level of CXCL2, PTGS2, and ATF3 had longer survival time. In summary, we demonstrated that CXCL2, PTGS2, and ATF3 might be diagnostic and therapeutic molecular biomarkers for breast cancer. These findings might provide further insights into the pathophysiology of breast cancer, as well as enhance our understanding of the anticancer effects of paclitaxel. [ABSTRACT FROM AUTHOR]

Breast cancer is one of the most common cancers causing a high mortality worldwide. This study aimed to identify differential methylation and expression genes with prognostic value in breast cancer. DNA methylation and gene expression profiles (GSE60185, GSE42568, GSE21653, GSE58812, and GSE52865) were downloaded from TCGA (The Cancer Genome Atlas) and GEO (Gene Expression Omnibus) databases. The differentially expressed genes (DEGs) and differential methylation genes were identified between breast cancer samples and normal samples. Functional analysis was performed using DAVID (Database for Annotation, Visualization, and Integrated Discovery) tool. Furthermore, functional epigenetic modules (FEM) were analyzed to identify critical genes with prognostic values. A large amount of DEGs and aberrant methylation genes were identified between breast cancer samples and normal samples. These genes were mainly associated with several GO (Gene Ontology) terms and KEGG (Kyoto Encyclopedia of Genes and Genomes) pathways, such as neuroactive ligand–receptor interaction, alcoholism, gamma-aminobutyric acid signaling pathway, and G-protein-coupled receptor signaling pathway. Additionally, 10 DEGs with differential methylation levels were significantly correlated with survival outcomes in breast cancer patients. FEM analysis revealed that several DEGs (e.g., GABRA4, GABRG1, and GABRA1) in module GABRA4 were identified as potential biomarkers in breast cancer patients. Several DEGs identified were associated with breast cancer prognosis. These DEGs might act as prognostic and diagnostic markers in breast cancer. [ABSTRACT FROM AUTHOR]

• SLE data for CsCl-PEG1000-H 2 O, SLE and LLE data for CsCl-PEG4000/6000-H 2 O were determined at 298.15 K. • Salting out effect is greater with larger molecular mass of PEG as the EEV of PEG 6000 is larger than PEG 4000. • Three nonlinear expressions were used to correlate the experimental binodal data. • The tie-line data were related with Othmer-Tobias and Bancroft equations. The phase equilibrium of CsCl-polyethylene glycol (PEG) 1000 – H 2 O, solid-liquid equilibria (SLE), and liquid-liquid equilibria (LLE) data for aqueous two – phase system (ATPS) containing CsCl and PEG4000/6000 was determined at 298.15 K. The equilibrium phase compositions, binodal curves, tie-line length (TLL), and slope of tie-line (STL) for the aqueous two phase systems were determined. Furthermore, three non-linear expressions developed by Mistry, Hu, and Jayapal were used to correlate the binodal data, the effective excluded volumes (EEV) were calculated from binodal curve data, the tie-line data were correlated with Othmer-Tobias and Bancroft equations. It was found that the salting out effect is greater with larger molecular mass of PEG as the EEV of PEG6000 is larger than PEG4000. As the molecular mass of PEG increased, the binodal curve shifted toward the origin, which increased the liquid-liquid biphase region. [ABSTRACT FROM AUTHOR]

Small-cell gallbladder neuroendocrine carcinoma (GB-SCNEC) is a relatively rare histological type of gallbladder cancer, and the genomic landscape of GB-SCNEC is rarely considered in treatment decisions. We performed whole-genome sequencing on an advanced case of GB-SCNEC. We identified approximately 900 high-quality somatic single nucleotide variants (SNVs) and small insertions and deletions (INDELs), 109 of which were shared by both the primary and metastatic tumor tissues. Somatic non-synonymous coding variations with damaging impact in HMCN1 and CDH10 were observed in both the primary and metastatic tissue specimens. A pathway analysis of the genes mapped to the SNVs and INDELs revealed gene enrichment associated with axon guidance, ERBB signaling et al. Furthermore, we identified 11 deletions, 4 tandem duplications and 5 inversions that mapped to known genes. Two gene fusions, NCAM2-SGCZ and BTG3-CCDC40 were also discovered and validated by Sanger sequencing. Additionally, we identified genome-wide copy number variations and microsatellite instability. In this study, we identified novel biological markers of GB-SCNEC that may serve as valuable prognostic factors or indicators of treatment response in patients with GB-SCNEC with lymphatic metastasis. [ABSTRACT FROM AUTHOR]

Abstract: Gallbladder carcinoma (GBC) is one of the mostly aggressive and fatal malignancies. However, little is known about the oncogenic genes that contributed to the development of GBC. Zinc finger X-chromosomal protein (ZFX) was a novel member of the Krueppel C2H2-type zinc-finger protein family and its down-regulation led to impaired cell growth in human laryngeal squamous cell carcinoma. Here, we aim to investigate the function of ZFX in GBC cell proliferation and migration. Loss of function analysis was performed on GBC cell line (GBC-SD) using lentivirus-mediated siRNA against ZFX. The proliferation, in vitro tumorigenesis (colony-formation) ability as well as cell migration was significantly suppressed after GBC-SD cells which were infected with ZFX-siRNA-expressing lentivirus (Lv-shZFX). Our finding suggested that ZFX promoted the growth and migration of GBC cells and could present a potential molecular target for gene therapy of GBC. [Copyright &y& Elsevier]

p21-activated kinase (PAK)7 (also known as PAK5) is a member of the group B PAK family of serine/threonine protein kinases, which are effectors of the small GTPases Rac and CDC42. PAK7 can promote neurite outgrowth, induce microtubule stabilization, and activate cell survival signaling pathways. However, the role of PAK7 in cancer is still poorly understood. Here, we showed that PAK7 expression was upregulated in different gastric cancer cell lines and gastric cancer tissues, as compared with human embryonic kidney 293 cells and adjacent normal tissues, respectively. The results suggested that PAK7 expression was related to gastric cancer progression. Thus, we employed lentivirus-mediated small interfering RNA to inhibit PAK7 expression, to investigate the role of PAK7 in human gastric carcinogenesis. RNA interference efficiently downregulated expression of PAK7 in SGC-7901 and MGC-803 cells at both mRNA and protein levels. Knockdown of PAK7 inhibited human gastric cancer cell proliferation by inducing cell cycle arrest in G0/G1 phase, in concordance with the downregulation of CDK2, CDC25A, and cyclin D1. Our data suggest that PAK7 is a new hallmark of gastric cancer, in which PAK7 might contribute to gain of tumor growth potential, acting by affecting the expression of cell cycle regulators. Therefore, PAK7 may be an attractive candidate as a therapeutic target in gastric cancer. [ABSTRACT FROM AUTHOR]

Background: Gemcitabine plus platinum as the first-line chemotherapy for cholangiocarcinoma (CCA) has limited efficacy. The aim of this study was to evaluate the effectiveness of modified FOLFIRINOX (mFOLFIRINOX) compared to that of gemcitabine plus oxaliplatin (Gemox) for patients with locally advanced or metastatic CCA.Methods: From January 2016 to December 2019, consecutive patients who were diagnosed with locally advanced or metastatic CCA were treated with either mFOLFIRINOX or Gemox as a first-line chemotherapy. The main endpoint was Progression free survival (PFS). The second endpoints were Overall survival (OS), Disease control rate (DCR) and incidence of severe toxicity (grade 3-4). Tumors were evaluated at baseline and thence every 4-6 weeks. The study was designed and carried out in accordance with the principles of the declaration of Helsinki, approved by the Ethics Committee of Xinhua Hospital Affiliated to Shanghai Jiaotong University School of Medicine (XHEC-D-2020-154) and registered with ClinicalTrials.gov , number NCT04305288 (registration date: 12/03/2020).Results: Of 49 patients in this study, 27 were in the FOLFIRINOX regimen group and 22 in the Gemox regimen group. There were no significant differences between groups in baseline characteristics. The DCR was 77.8% in the mFOLFIRINOX group and 63.5% in the Gemox group. The corresponding median PFS was 9.9 months (95% confidence interval [CI], 7.3-12.4) in the mFOLFIRINOX group versus 6.4 months (95% CI,3.6-9.2, p = 0.040) in the Gemox group. The corresponding median OS was 15.7 months (95% CI, 12.5-19.0) versus 12.0 months (95% CI, 9.3-14.8, p = 0.099). Significantly more grade 3-4 vomiting occurred in the mFOLFIRINOX than the Gemox groups (7 (25.9%) vs 1 (4.5%), p = 0.044).Conclusions: First-line mFOLFIRINOX offered more promising results in patients with advanced or metastatic CCA. [ABSTRACT FROM AUTHOR]

Background: Gallbladder cancer (GBC) is the most common cancer type of the biliary tract, and an association has been found between chronic calculous cholecystitis (CCC) and an increased incidence of GBC mortality. An understanding of the relationship between CCC and its carcinogenesis may enable us to prevent and cure GBC. In this study, we attempted to explore changes in the microbiome profile that take place during the transition from chronic cholecystitis mucosa to malignant lesions. Results: Seven paired human GBC and CCC samples were provided by patients who had undergone laparoscopic cholecystectomy or radical cholecystectomy. Mucosal DNA extraction and metagenomic sequencing were performed to evaluate changes in the microbiota between the two groups. We found that GBC patients and CCC patients shared similar stable and permanent dominant species and showed apparent differences in their biliary microbial composition and gene function. Peptostreptococcus stomatis and Enterococcus faecium may potentially play a role in GBC progression. In addition, the metagenomic species profiles, co‐abundance and co‐exclusion correlations, and CAZyme prevalence showed significant differences between the CCC and GBC groups. Conclusion: Our data suggested that changes in the microbiota between CCC and GBC may help deepen our understanding of the complex spectrum of different microbiotas involved in the development of GBC. Although the cohort size was small, this study has presented the first evidence of the existence of an altered biliary microbiota in GBC, which is clearly different from that in CCC patients. [ABSTRACT FROM AUTHOR]

Gallbladder carcinoma (GBC) is the most common malignancy of the biliary tract, and its molecular pathogenesis remains unclear. Here we explore the functional roles of epithelial membrane protein 3 (EMP3) in GBC progression, which is aberrantly expressed in various types of cancers. The results showed that the expression level of EMP3 was reduced in human GBC tissues compared with non-malignant tissues. Further, the low expression of EMP3 was associated with the poor prognosis of GBC patients by Kaplan-Meier analysis. The ectopic expression of EMP3 inhibited GBC cell proliferation, migration and invasion in vitro and in vivo. Conversely, the depletion of EMP3 promoted GBC cell growth and metastasis. In addition, we found that EMP3 was a target gene of miR-663a, and the downregulation of EMP3 in GBC was attributed to the overexpression of miR-663a. MiR-663a was also shown to be a tumor-promoting factor mediating GBC development. In this study, we demonstrate that downregulation of EMP3 activates MAPK/ERK signaling, which regulates GBC progression. These data reveal the mechanism by which EMP3 inhibits the progression of GBC, suggesting that the miR-663a/EMP3/MAPK/ERK axis may be a new therapeutic target for GBC treatment. • Low EMP3 expression was associated with poor prognosis of GBC patients. • EMP3 suppressed GBC cell growth and metastasis both in vitro and in vivo. • EMP3 was targeted and regulated by miR-663a which was proven to be a tumor-promoting factor. • EMP3 modulated GBC progression by inactivating MAPK/ERK signaling. [ABSTRACT FROM AUTHOR]

Gallbladder cancer (GBC) is the most common malignancy of the biliary tract and its molecular pathogenesis is poorly understood. Aberrant expression of epithelial membrane protein-3 (EMP3) was reported in different kinds of cancers. Our study aimed to explore the elusive functional roles and the underlying molecular mechanisms of EMP3 with respect to GBC progression. The results showed that human GBC tissues exhibited decreased levels of EMP3 compared with non-malignant tissues. Kaplan-Meier analysis indicated that low expression of EMP3 was associated with poor prognosis of GBC patients. Upregulation of EMP3 repressed GBC cell proliferation, migration and invasion both in vitro and in vivo. Conversely, EMP3 silencing promoted GBC cell growth and metastasis. Additionally, we found that EMP3 was a target gene of miR-663a, and downregulation of EMP3 in GBC was attributed to the overexpression of miR-663a. Furthermore, miR-663a was proven to be a tumor-promoting factor mediating GBC development. Finally, we demonstrated that downregulation of EMP3 activated MAPK/ERK signaling, which modulated GBC progression. These data showed the mechanism by which EMP3 suppresses GBC progression, suggesting that the miR-663a/EMP3/MAPK/ERK axis may be a novel therapeutic target for GBC treatment. [ABSTRACT FROM AUTHOR]

Background/Aims: The role of ZFX in tumourigenesis is unclear. We aimed to study ZFX expression, regulation, and function and the clinical implications of this protein in human pancreatic cancer (PCa). Methods: One hundred and twenty patients with histologically confirmed PCa who underwent surgery were recruited for this study. Tumour samples and PCa cell lines were used to examine ZFX. Various cell functions related to tumourigenesis were assessed. In vivo mouse tumour xenografts were used to confirm the in vitro results. Results: Patients with ZFX-positive tumours had worse overall survival than patients with ZFX-negative tumours. The depletion of ZFX using lentiviral shRNAs significantly inhibited cell proliferation by inducing cell cycle arrest in G0/G1 phase and resulted in increased cell apoptosis and invasive repression. In vivo studies confirmed that ZFX promoted tumour growth. Mechanistically, MAPK pathway activation was involved in the oncogenic functions of ZFX. Conclusions: ZFX acts as a putative oncogene in PCa and could be a novel therapeutic target for this disease. [ABSTRACT FROM AUTHOR]

Despite of the high lethality of gallbladder cancer (GBC), little is known regarding molecular regulation of the tumor immunosuppressive microenvironment. Here, we determined tumor expression levels of YKL-40 and the molecular mechanisms by which YKL-40 regulates escape of anti-tumor immune surveillance. We found that elevated expression levels of YKL-40 in plasma and tissue were correlated with tumor size, stage IV and lymph node metastasis. Single cell transcriptome analysis revealed that YKL-40 was predominantly derived from M2-like subtype of infiltrating macrophages. Blockade of M2–like macrophage differentiation of THP-1 cells with YKL-40 shRNA resulted in reprogramming to M1-like macrophages and restricting tumor development. YKL-40 induced tumor cell expression and secretion of growth differentiation factor 15 (GDF15), thus coordinating to promote PD-L1 expression mediated by PI3K, AKT and/or Erk activation. Interestingly, extracellular GDF15 inhibited intracellular expression of GDF15 that suppressed PD-L1 expression. Thus, YKL-40 disrupted the balance of pro- and anti-PD-L1 regulation to enhance expression of PD-L1 and inhibition of T cell cytotoxicity, leading to tumor immune evasion. The data suggest that YKL-40 and GDF15 could serve as diagnostic biomarkers and immunotherapeutic targets for GBC. • Increased YKL-40 in plasma were correlated with tissue expression of YKL-40 and GBC progression. • Blockade of YKL-40 in M2-like macrophages resulted in M1-like macrophage reprogramming. • YKL-40 promoted GDF15 secretion, which in turn inhibited intracellular GDF15 function that suppressed PD-L1 expression. • YKL-40 and GDF15 induced PD-L1 expression and abrogated cytotoxicity of infiltrating CD8+ T lymphocytes. [ABSTRACT FROM AUTHOR]

The long non-coding RNAs (lncRNAs) have been implicated in multiple human cancers, which may offer great potential as putative targets for cancer diagnosis and treatment. However, the roles of most lncRNAs in gallbladder cancer (GBC) remain poorly understood. The objective of this research involves investigating the clinical implications and underlying mechanism of lncRNA motor neuron and pancreas homeobo×1 antisense RNA 1 (MNX1-AS1) in GBC. This study shows that MNX1-AS1 expression is elevated in the tissues of GBC patients, and is strongly associated with reduced patient survival. Functionally, MNX1-AS1 significantly stimulates the proliferation and metastasis of GBC cells in vitro and in vivo. Mechanistically, MNX1-AS1 is transcriptionally activated by TEA domain family member 4 (TEAD4), and suppresses insulin-like growing factor 2 mRNA-binding protein 3 (IGF2BP3) degradation by recruiting ubiquitin specific peptidase 16 (USP16). Furthermore, MNX1-AS1/IGF2BP3 axis inhibits the Hippo signaling pathway and subsequently activates TEAD4, thereby forming a positive feedback loop. According to our results, MNX1-AS1 facilitates tumorigenesis, progression and metastasis of GBC through a MNX1-AS1/IGF2BP3/Hippo pathway positive feedback loop, which could be both diagnostically and therapeutically helpful in GBC. [ABSTRACT FROM AUTHOR]

LASP-1 is an actin-binding protein that regulates cytoskeletal dynamics and cell migration. LASP-1 was previously identified in a cDNA library from metastatic breast cancer samples. This protein has since been detected in multiple human cancers, including liver cancer, gastric cancer and pancreatic cancer. S100P is a small calcium-binding protein in the S100 protein family that regulates cellular, physiological and pathological processes in various cancers. However, the clinical significance of LASP-1 and S100P expression in gallbladder cancer (GBC) is not yet clear. In our study, we focused on the clinical significance, biological function and mechanism of LASP-1 in gallbladder cancer and detected LASP-1 and S100P overexpression in GBC tissues. The expression of LASP-1 was significantly correlated with poor prognosis in GBC patients (P < 0.05). Furthermore, down-regulation of LASP-1 expression resulted in the obvious inhibition of proliferation and migration and caused cell cycle arrest by down-regulating S100P via the PI3K/AKT pathway; in mice, tumor volume was significantly decreased. In conclusion, LASP-1 may act as an oncogene to regulate the expression of S100P to influence cellular functions in GBC. LASP-1 could serve as a genetic treatment target in GBC patients. [ABSTRACT FROM AUTHOR]

Hilar cholangiocarcinoma (HCC) remains one of the most difficult tumors to stage and treat. The aim of the study was to assess the diagnostic efficiency of computed tomography (CT), magnetic resonance imaging (MRI), and positron emission tomography/computer tomography (PET/CT) in evaluating the resectability of HCC. A systematic search was performed of the PubMed, EMBASE, and Cochrane databases. Sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and diagnostic accuracy were calculated for individual studies and pooled data as well as test for heterogeneity and public bias. Our data showed that CT had the highest pooled sensitivity at 95% (95% CI: 91-97), whereas PET/CT had the highest pooled specificity at 81% (95% CI: 69-90). The area under the curve (AUC) of CT, MRI, and PET/CT was 0.9269, 0.9194, and 0.9218, respectively. In conclusion, CT is the most frequently used imaging modality to assess HCC resectability with a good sensitivity and specificity. MRI was generally comparable with that of CT and can be used as an alternative imaging technique. PET/CT appears to be the best technique in detecting lymph node and distant metastasis in HCC but has no clear role in helping to evaluate issues of local resectability. [ABSTRACT FROM AUTHOR]

Fibronectin (FN), a heterodimeric glycoprotein overexpressed in several types of tumors, has been implicated in cancer progression via the activation of integrin-mediated pro-oncogenic pathways. The FN level in human bile fluid is dramatically increased in malignant biliary diseases; however, FN expression and its biological functions in gallbladder cancer (GBC) remain unknown. In this study, we found that FN was overexpressed in GBC tissues and was associated with a worse prognosis in GBC patients. In vitro experimental studies indicated that exogenous FN significantly enhanced cell proliferation, invasion and active MMP-9 secretion in human GBC cell lines (GBC-SD and NOZ). Moreover, the key kinases of the mTOR signaling pathway, including FAK, Akt, mTOR and 4E-BP1, were markedly activated in a time-dependent manner in FN-treated GBC-SD and NOZ cells. The IHC statistical analyses validated that FN expression was positively correlated with the phosphorylation levels of the 4E-BP1 protein in GBC tissues. Furthermore, rapamycin, a specific inhibitor of mTOR, almost completely blocked FN-induced phosphorylation of 4E-BP1 and also partially abrogated the stimulatory effects of FN on GBC cell proliferation and invasion. In vivo , FN treatment significantly promoted the proliferation and metastasis of GBC cells and markedly activated Akt/mTOR/4E-BP1 signaling cascade. These findings demonstrate that FN may play a critical role in the modulation of cell proliferation and invasion via mTOR signaling pathway activation during GBC progression. [ABSTRACT FROM AUTHOR]

Purpose: To compare the safety and effectiveness of primary closure with those of T-tube drainage in laparoscopic common bile duct exploration (LCBDE) for choledocholithiasis. Methods: A comprehensive search was performed in the PubMed, EmBase, and Cochrane Library databases. Only randomized controlled trials comparing primary closure with T-tube drainage in LCBDE were considered eligible for this meta-analysis. The analyzed outcome variables included postoperative mortality, overall morbidity, biliary complication rate, biliary leak rate, reoperation, operating time, postoperative hospital stay, time to abdominal drain removal, and retained stone. All calculations and statistical tests were performed using ReviewerManager 5.1.2 software. Results: A total of 295 patients (148 patients with primary closure and 147 patients with T-tube drainage) from three trials were identified and analyzed. No deaths occurred in any of the trials. Primary closure showed significantly better results in terms of morbidity (risk ratio (RR), 0.51; 95% confidence interval (CI), 0.30 to 0.88), biliary complication without a combination of retained stone (RR, 0.44; 95% CI, 0.20 to 0.97), reoperation (RR, 0.16; 95% CI, 0.03 to 0.87), operating time (mean difference (MD), −20.72; 95% CI, −29.59 to −11.85), postoperative hospital stay (MD, −3.24; 95% CI, −3.96 to −2.52), and time to abdominal drainage removal (MD, −0.45; 95% CI, −0.86 to −0.04). Statistically significant differences were not found between the two methods in terms of biliary leak, biliary complication, and retained stones. Conclusion: The current meta-analysis indicates that primary closure of the common bile duct is safer and more effective than T-tube drainage for LCBDE. Therefore, we do not recommend routine performance of T-tube drainage in LCBDE. [ABSTRACT FROM AUTHOR]

Abstract: Ethnopharmacological relevance: A traditional Chinese medicine Scutellaria baicalensis is prescribed for the treatment of a variety of inflammatory diseases and tumors in clinic in China. However, the detailed mechanism of anti-metastasis effect of wogonin, a main active ingredient of Scutellaria baicalensis, remains elusive. Aim of the study: The present study was designed to investigate the action and mechanism of wogonin on the mobility and invasion of human gallbladder carcinoma GBC-SD cells. Materials and methods: Viability, apoptosis, mRNA and protein expression of tumor cells were analyzed by MTT, Annexin V staining, real-time PCR and Western blot, respectively. The migration and invasion assay was used to evaluate the anti-metastasis effect of wogonin. Knockdown of maspin was performed by specific small interference RNA. Results: Wogonin at the dose of 1–10μM, which did not induce apoptosis, significantly inhibited the mobility and invasion activity of human gallbladder carcinoma GBC-SD cells. In addition, the expressions of matrix metalloproteinase (MMP)-2, MMP-9 and phosphorylated extracellular regulated protein kinase 1/2 (ERK1/2) but not phosphorylated Akt were dramatically suppressed by wogonin in a concentration-dependent manner. Furthermore, the metastasis suppressor maspin was confirmed as the downstream target of wogonin. Both maspin mRNA and protein were upregulated by wogonin. Interestingly, the knockdown of maspin resulted in almost completely blocking of wogonin-induced inhibition of MMP-2, MMP-9 and phosphorylated ERK1/2 as well as the mobility and invasion activity of GBC-SD cells. Conclusions: These findings suggest that wogonin inhibits cell mobility and invasion by upregulating the metastasis suppressor maspin. Together, these data provide novel insights into the chemoprotective effect of wogonin, a main active ingredient of Chinese medicine Scutellaria baicalensis. [Copyright &y& Elsevier]

Background: Gallbladder cancer is the most frequent malignancy of the bile duct with high aggressive and extremely poor prognosis. The main objective of the paper was to investigate the inhibitory effects of oridonin, a diterpenoid isolated from Rabdosia rubescens, on gallbladder cancer both in vitro and in vivo and to explore the mechanisms underlying oridonin-induced apoptosis and cell cycle arrest.Methods: The anti-tumor activity of oridonin on SGC996 and NOZ cells was assessed by the MTT and colony forming assays. Cell cycle changes were detected by flow cytometric analysis. Apoptosis was detected by annexin V/PI double-staining and Hoechst 33342 staining assays. Loss of mitochondrial membrane potential was observed by Rhodamine 123 staining. The in vivo efficacy of oridonin was evaluated using a NOZ xenograft model in athymic nude mice. The expression of cell cycle- and apoptosis-related proteins in vitro and in vivo was analyzed by western blot analysis. Activation of caspases (caspase-3, -8 and -9) was measured by caspases activity assay.Results: Oridonin induced potent growth inhibition, S-phase arrest, apoptosis, and colony-forming inhibition in SGC996 and NOZ cells in a dose-dependent manner. Intraperitoneal injection of oridonin (5, 10, or 15 mg/kg) for 3 weeks significantly inhibited the growth of NOZ xenografts in athymic nude mice. We demonstrated that oridonin regulated cell cycle-related proteins in response to S-phase arrest by western blot analysis. In contrast, we observed inhibition of NF-κB nuclear translocation and an increase Bax/Bcl-2 ratio accompanied by activated caspase-3, caspase-9 and PARP-1 cleavage after treatment with oridonin, which indicate that the mitochondrial pathway is involved in oridonin-mediated apoptosis.Conclusions: Oridonin possesses potent anti-gallbladder cancer activities that correlate with regulation of the mitochondrial pathway, which is critical for apoptosis and S-phase arrest. Therefore, oridonin has potential as a novel anti-tumor therapy for the treatment of gallbladder cancer. [ABSTRACT FROM AUTHOR]