Silencing Rac1 and Prex1 Inhibit Epithelial-Mesenchymal Transition in Human Gastric Cancer Cells Induced by Transforming Growth Factor-ß1.

BACKGROUND/AIMS: Transforming growth factor-beta can influence tumor cells, causing epithelial-mesenchymal transition and enhancing their invasion and metastasis ability. Rac1 protein could be used as an independent tumor diagnostic marker and survival predictor. Prex1 is closely related to cell metastasis. In this study, the impact of silencing Rac1 and Prex1 on transforming growth factor-beta 1-induced epithelial-mesenchymal transition and apoptosis of human gastric cancer cells MGC-803 and MKN45 was investigated. MATERIALS AND METHODS: MGC-803 and MKN45 cells received recombinant transforming growth factor-beta 1 (rTGF-ß1) treatments at various concentrations. Cell Counting Kit-8 kit was used to determine cell viability. Rac1 and Prex1 interference vectors were transfected into the rTGF-ß1-treated MGC-803 and MKN45 cells. Cell apoptosis and migration were detected by flow cytometry and scratch test, respectively. Western blot was used to detect the epithelial-mesenchymal transition-related markers E-cadherin, N-cadherin, vimentin, and PDLIM2 expression levels. RESULTS: The rTGF-ß1 (10 ng/mL) could promote MGC-803 and MKN45 cell viability. Silencing Rac1 and Prex1 could increase E-cadherin and PDLIM2 expression, decrease N-cadherin and vimentin expression, inhibit cell viability and migration, and promote apoptosis in rTGF-ß1-treated MGC-803 and MKN45 cells. CONCLUSIONS: Silencing Rac1 and Prex1 could inhibit epithelial-mesenchymal transition, reduce cell viability and migration, and promote apoptosis in human gastric cancer cells.

Development a novel nomogram model for predicting significant hepatic histological changes in chronic hepatitis B virus carriers.

A proportion of chronic hepatitis B virus (HBV) carriers with normal alanine transaminase (ALT) present with significant liver histological changes (SLHC). To construct a noninvasive nomogram model to identify SLHC in chronic HBV carriers with different upper limits of normal (ULNs) for ALT. The training cohort consisted of 732 chronic HBV carriers who were stratified into four sets according to different ULNs for ALT: chronic HBV carriers I, II, III, and IV. The external validation cohort comprised 277 chronic HBV carriers. Logistic regression and least absolute shrinkage and selection operator analyses were applied to develop a nomogram model to predict SLHC. A nomogram model-HBGP (based on hepatitis B surface antigen, gamma-glutamyl transpeptidase, and platelet count) demonstrated good performance in diagnosing SLHC with area under the curve (AUCs) of 0.866 (95% confidence interval [CI]: 0.839-0.892) and 0.885 (95% CI: 0.845-0.925) in the training and validation cohorts, respectively. Furthermore, HBGP displayed high diagnostic values for SLHC with AUCs of 0.866 (95% CI: 0.839-0.892), 0.868 (95% CI: 0.838-0.898), 0.865 (95% CI: 0.828-0.901), and 0.853 (95% CI: 0.798-0.908) in chronic HBV carriers I, II, III, and IV, respectively. Additionally, HBGP showed greater ability in predicting SLHC compared with the existing predictors. HBGP has shown high predictive performance for SLHC, and thus may lead to an informed decision on the initiation of antiviral treatment.

IL2-inducible T-cell Kinase is Required for HBV-induced Type T Interferon Expression and Antiviral Response.

Background and Aims: Hepatitis B is a vaccine-preventable liver infection caused by the hepatitis B virus (HBV), and is seen as a serious global health problem. HBV infection induces the expression of type I interferon (IFN), including IFN-α and IFN-ß, which have anti-HBV activities, and have been used for HBV treatment. IL2-inducible T-cell kinase (ITK) is a tyrosine kinase, which regulates T-cell differentiation and activation, while its precise effects on type I IFN production during HBV infection remain unknown. Methods: We monitored the ITK expression in peripheral blood mononuclear cells (PBMCs) from healthy donors and patients with acute and chronic HBV infection. We used ITK inhibitor ibrutinib to treat hepatocytes and evaluated the type I IFN expression after HBV infection. We also administrated ibrutinib to mice and evaluated its effect on HBV infection in vivo. We generated ITK, suppressor of cytokine signaling 1 (SOCS1) knockout and ITK/SOCS1 double knockout cells using CRISPR, and monitored the HBV-induced type I IFN production. Results: ITK and type I IFN were upregulated in patients with acute HBV infection. Inhibition of ITK by ibrutinib suppressed HBV-induced expression of type I IFN mRNA in mice. ITK knockout cells had decreased IRF3 activation but promoted the expression of SOCS1. ITK negatively regulated SOSC1 expression. The down regulation of type I IFN in ITK knockout cells after HBV stimulation was abolished in the absence of SOCS1. Conclusions: ITK regulated HBV-induced expression of type I IFN mRNA by modulating SOCS1.

Bakuchiol inhibits lung cancer by modulating tumor microenvironment and the expression of PD-L1.

Immune checkpoint therapy is an emerging frontier in cancer therapy. With the aim to develop an efficient herb derived compound to facilitate immune checkpoint therapy, here we investigate if a herb-derived compound, Bakuchiol (BAK), can be used to treat lung cancer and elucidate if BAK could serve as a PD-L1 regulator. To this end, a murine lung cancer model was established by subcutaneously inoculating murine Lewis lung carcinoma (LLC) cells. BAK of 5 to 40 mg/kg was used for treatment in vivo for 15 days. On Day 15, the population of CD4+ and CD8+ T cells, Treg cells. BAK could effectively inhibit tumor growth by starting treatment either on Day 0 or 6 after tumor inoculation at doses of 5-40 mg/kg. BAK treatment increased the population of cytotoxic immune cells (i.e., CD8+ T cells, and M1 macrophages), meanwhile decreasing pro-tumor immune cells (i.e., CD3+ T cells, Treg cells, and M2 macrophages). Anti-inflammatory cytokines, including IL1ß, IL2, IFNγ, TNF-α, IL4 and IL10 were upregulated by BAK. PD-L1 expression in the tumor was also lowered by BAK. AKT and STAT3 signaling were inhibited by BAK. BAK is an efficient agent in reducing LLC tumor growth. These data support the potential of BAK as a new drug for treating lung cancer by serving as a PD-L1 inhibitor that suppresses the activation of AKT and STAT3.

Association between physical activity and health-related quality of life: time to deterioration model analysis in lung adenocarcinoma.

BACKGROUND AND PURPOSE : Health-related quality of life (HRQoL) is a key aspect of care for cancer survivors that can be improved by physical activity. Our aim was to explore the relationship between physical activity and time to deterioration (TTD) of the HRQoL in patients with lung adenocarcinoma (LUAD). METHODS: We conducted a hospital-based prospective study. The International Physical Activity Questionnaire long-form (IPAQ-L) was used to investigate the pre-treatment physical activity levels, and the EORTC Quality of Life Questionnaire version 3.0 (EORTC QLQ-C30) and EORTC Quality of Life Questionnaire-Lung Cancer (EORTC QLQ-LC13) were used to assess HRQoL at baseline and during follow-up. The QoLR package was used to calculate the HRQoL scores and determine TTD events (minimal clinically important difference=5 points). The effect of physical activity on the HRQoL was assessed using Cox regression analysis. RESULTS: For EORTC QLQ-C30, TTD events of physical functioning (PF) and dyspnea (DY) in functional scales and symptom scales were the most common during follow-up. Pre-treatment physical activity was found to significantly delay TTD of insomnia (HR=0.635, 95%CI: 0.437-0.922, P=0.017) and diarrhea (HR=0.475, 95%CI: 0.291-0.774, P=0.003). For EORTC QLQ-LC13 scales, deterioration of dyspnea (LC-DY) was the most common event. Physical activity was found to delay the TTD of dyspnea (HR=0.654, 95%CI: 0.474-0.903, P=0.010), sore mouth (HR=0.457, 95%CI: 0.244-0.856, P=0.015), and dysphagia (HR=0.315, 95%CI: 0.172-0.580, P<0.001). CONCLUSIONS: Pre-treatment physical activity of LUAD patients may delay the TTD of multiple HRQoL indicators in EORTC QLQ-C30 and EORTC QLQ-LC13. IMPLICATION FOR CANCER SURVIVORS: Health-related quality of life (HRQoL) is a key aspect of care for cancer survivors (someone who is living with or beyond cancer), that can be improved by physical activity. Our aim was to explore the relationship between physical activity and time to deterioration (TTD) of the HRQoL in patients with lung adenocarcinoma (LUAD).

Advantages of a Novel Model for Predicting Hepatic Fibrosis in Chronic Hepatitis B Virus Carriers Compared with APRI and FIB-4 Scores.

Background and Aims: Aspartate aminotransferase-to-platelet ratio index (APRI) and fibrosis-4 index (FIB-4) are widely used to assess liver fibrosis in chronic hepatitis B virus (HBV) infection. Currently, the definition of normal alanine aminotransferase (ALT) is controversial. We aimed to examine the diagnostic value of APRI and FIB-4 in chronic HBV carriers with different upper limits of normal (ULNs) for ALT. Methods: 581 chronic HBV carriers were divided into the following four groups based on different ULNs for ALT: chronic HBV carriers I, II, III, and IV. Furthermore, 106 chronic HBV carriers formed an external validation group. Predictive values of APRI and FIB-4 were elucidated using the area under the curve (AUC). A liver fibrosis-predictive model-GPSA (named for its measure of gamma glutamyl transpeptidase, platelet count, HBsAg and albumin) was developed using multivariate logistic regression analysis. Results: In chronic HBV carriers I, the AUCs of APRI and FIB-4 were 0.680 and 0.609 for significant fibrosis and 0.678 and 0.661 for cirrhosis, respectively. The AUCs of GPSA for significant fibrosis in the training group, internal group, and external validation group were 0.877, 0.837, and 0.871, respectively. The diagnostic value of GPSA differed among chronic HBV carriers I, II, III, and IV, with AUCs for significant fibrosis being 0.857, 0.853, 0.868, and 0.905 and AUCs for cirrhosis being 0.901, 0.905, 0.886, and 0.913, respectively. GPSA showed a higher diagnostic value than APRI and FIB-4 for predicting significant fibrosis in the four groups. Conclusions: The GPSA model allows for accurate diagnosis of liver fibrosis in chronic HBV carriers with different ULN for ALT.

The Bioinformatics-Based Analysis Identifies 7 Immune-Related Genes as Prognostic Biomarkers for Colon Cancer.

Colon cancer poses a great threat to human health. Currently, there is no effective treatment for colon cancer due to its complex causative factors. Immunotherapy has now become a new method for tumor treatment. In this study, 487 DEGs were screened from The Cancer Genome Atlas (TCGA) database and ImmPort database, and GeneOntology (GO) functional enrichment and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis was performed. Hierarchical clustering of all samples revealed a significant correlation between colon cancer and immunity. The weighted gene co-expression network analysis (WGCNA) algorithm was used to identify key gene modules associated with immunity in colon cancer, here, module grey60 showed the highest correlation. A protein-protein interaction (PPI) network was constructed using the STRING database to screen hub genes, and subsequently, 7 immune-related genes the most closely associated with colon cancer were identified by differential expression in cancer and paracancer. Finally, a risk prediction model was developed using least absolute shrinkage and selection operator (LASSO) COX analysis, and the accuracy of the model was validated by GSE14333. This study determined that IRF4 and TNFRSF17 were immune-related genes in colon cancer, providing immune-related prognostic biomarkers for colon cancer.

CDKN2B antisense RNA 1 suppresses tumor growth in human colorectal cancer by targeting MAPK inactivator dual-specificity phosphatase 1.

Aberrant expression of long noncoding RNA cyclin-dependent kinase inhibitor 2B antisense RNA 1 (CDKN2B-AS1) has been detected in human colorectal cancer (CRC). This study aimed to investigate the role of CDKN2B-AS1 and the underlying mechanism in human CRC. Gain- and loss-of-function assays were performed to explore the role of CDKN2B-AS1 in the malignant behavior of HCT116 and SW480 CRC cells in vitro and in vivo. RNA pull-down assay was conducted to identify the target of CDKN2B-AS1 in CRC cells. The physical and functional interactions between CDKN2B-AS1 and the target were examined. CDKN2B-AS1 inhibited CRC cell proliferation and migration while promoting apoptosis in vitro via activation of mitogen-activated protein kinase kinases (MEK)/extracellular signal-regulated kinase (ERK)/p38 signaling. CDKN2B-AS1 bound to mitogen-activated protein kinase (MAPK) inactivator dual-specificity phosphatase 1 (DUSP1) in CRC cells. In contrast to CDKN2B-AS1, DUSP1 promoted CRC cell proliferation, suppressed apoptosis and inactivated MEK/ERK/p38 signaling in CRC cells. Furthermore, CDKN2B-AS1 overexpression attenuated DUSP1 expression in normal colonic myofibroblasts and CRC cells. Overexpression of DUSP1 effectively countered the activation of MEK/ERK/p38 signaling induced by CDKN2B-AS1 overexpression or further blocked MEK/ERK/p38 signaling suppressed by CDKN2B-AS1 silencing. In the mouse xenograft model, CDKN2B-AS1 suppressed CRC growth, whereas DUSP1 promoted CRC growth. CDKN2B-AS1 induced cell apoptosis while suppressing EMT (epithelial-mesenchymal transition), whereas DUSP1 suppressed cell apoptosis while inducing EMT in CRC, as evidenced by the alterations in the protein levels of apoptosis and EMT markers in tumor tissue samples. CDKN2B-AS1 regulates CRC cell growth and survival by targeting MAPK inactivator DUSP1.

A novel HBsAg-based model for predicting significant liver fibrosis among Chinese patients with immune-tolerant phase chronic hepatitis B: a multicenter retrospective study.

BACKGROUND: Hepatitis B e antigen (HBeAg)-positive chronic hepatitis B (CHB) in the immune-tolerant (IT) phase is significantly associated with high risk for hepatocellular carcinoma, suggesting requirement for antiviral therapy, particularly for those with histological liver injury. This study aimed to establish a non-invasive panel to assess significant liver fibrosis in IT chronic hepatitis B. PATIENTS AND METHODS: One hundred and thirteen IT-phase CHB patients were retrospectively recruited and divided into two histopathological groups according to their histological profiles: necroinflammatory score <4 (N <4)/fibrosis score ⩽1 (F0-1), and necroinflammatory score ⩾4 (N ⩾4)/fibrosis score ⩾2 (F2-4). Multivariate analysis was conducted to assess the predictive value of the non-invasive model for significant liver fibrosis. RESULTS: IT-phase CHB patients with N <4/F0-1 had significantly higher HBsAg levels than those with N ⩾4/F2-4. The optimal HBsAg level of log 4.44 IU/mL for significant liver fibrosis (F ⩾2) gave an area under the curve (AUC) of 0.83, sensitivity of 81.1%, specificity of 81.6%, positive predictive value (PPV) of 68.2%, and negative predictive value (NPV) of 89.9%. An IT model with HBsAg and gamma glutamyl transpeptidase (GGT) in combination was established, and it had an AUC of 0.86, sensitivity of 86.5%, specificity of 81.6%, PPV of 69.6, NPV of 92.5, and accuracy of 83.2% to predict F ⩾2 in the IT-phase CHB patients. Notably, the IT model exhibited higher predictive value than the existing aspartate aminotransferase-to-platelet ratio index, Fibrosis-4 score, and GGT to platelet ratio. CONCLUSION: The established IT model combining HBsAg and GGT has good performance in predicting significant liver fibrosis in IT-phase CHB patients.

LINC00200 contributes to the chemoresistance to oxaliplatin of gastric cancer cells via regulating E2F1/RAD51 axis.

The goal of this research was to decipher the biological functions and mechanism of long intergenic non-protein coding RNA 200 (LINC00200) in gastric cancer (GC). In this study, our data confirmed that LINC00200 expression was up-regulated in GC tissues and its high expression was correlated with the poor differentiation of GC tissues and lymph node metastasis of the patients. In vitro experiments indicated that, the overexpression of LINC00200 facilitated the proliferation of GC cells, constrained their apoptosis, and increased the IC50 of oxaliplatin (Oxa), whereas knockdown of LINC00200 exhibited the opposite effects. Additionally, we demonstrated that LINC00200 could bind to E2F transcription factor 1 (E2F1), and the up-regulation of LINC00200 expression enhanced the binding between E2F1 and RAD51 promoter, hence promoting RAD51 transcription, while knockdown of LINC00200 inhibited the transcription of RAD51. In conclusion, LINC00200 may recruit E2F1 to the RAD51 recombinase (RAD51) promoter region, thereby up-regulating the expression of RAD51 and enhancing the chemoresistance of GC cells to Oxa. Our data suggested that LINC00200 could probably be a promising target for treating GC.

Manganese Breaks the Immune Tolerance of HBs-Ag.

BACKGROUND: Manganese (Mn2+) has been shown to promote type I interferon (IFN) production and activate the cyclic GMP-AMP synthase (cGAS)/Stimulator of Interferon Genes (STING) signaling pathway, suggesting that Mn2+ could be used as an adjuvant for vaccination. METHODS: In present study, the effects of Mn2+ on vaccination against hepatitis B virus (HBV) were evaluated. We treated mouse hepatocytes and kuppfer cells with Mn2+ with or without adeno-associated virus (AAV)-HBV infection. Expression of IFN-α and IFN-ß and activation of TBK1 and IRF3 were monitored. Wild-type and STING-/- mice were treated with Mn2+ and then infected with AAV-HBV. Serum levels of HBV surface antigen (HBsAg), alanine aminotransferase (ALT) activity, IFN-α, and IFN-ß were detected. Lymphocyte infiltration in the liver was evaluated. HBsAg-Tg mice were vaccinated with Mn2+ and HBsAg. The serum levels of HBsAg antibody, alanine transaminase activity, and IFN-ß were monitored after vaccination. RESULTS: Mn2+ promoted IFN-α and IFN-ß production in mouse hepatocytes and kuppfer cells. Mn2+ failed to promote IFN-α and IFN-ß production in kuppfer cells deficient in STING. Mn2+ promoted activation/phosphorylation of TBK1 and IRF3 during AAV-HBV infection. Mn2+ decreased serum levels of HBsAG, increased serum levels of alanine aminotransferase (ALT), IFN-α and IFN-ß, and enhanced lymphocyte infiltration and the percentage of IFN-γ-producing CD8+ T cells in the liver of AAV-HBV-infected mice. In contrast, Mn2+ treatment did not affect serum levels of HBsAG, ALT, IFN-α, or IFN-ß in STING-deficient mice. CONCLUSIONS: Mn2 + promoted HBsAG antibody, ALT, and IFN-ß production after HBsAG immunization. Mn2+ promoted type I IFN production in AAV-HBV infection and HBsAG immunization and could be used as an adjuvant for vaccination.

Knockdown of Forkhead box A1 suppresses the tumorigenesis and progression of human colon cancer cells through regulating the phosphatase and tensin homolog/Akt pathway.

BACKGROUND: This study aimed to evaluate the role and the underlying mechanisms of Forkhead box A1 (encoded by FOXA1) in colon cancer. METHODS: We analyzed FOXA1 mRNA and protein expression in colon cancer tissues and cell lines. We also silenced FOXA1 expression in HCT116 and SW480 cells to evaluate the effects on cell proliferation, cell cycle, migration, and invasion by using MTT, colony formation, flow cytometry, and the Transwell assay, respectively. RESULTS: FOXA1 immunostaining was higher in colon cancer tissues than adjacent healthy tissues. FOXA1 mRNA and protein expression was significantly increased in human colon cancer cells compared with a normal colonic cell line. FOXA1 expression was also significantly higher in colorectal cancer tissues from TCGA data sets and was associated with worse prognosis in the R2 database. FOXA1 expression was negatively correlated with the extent of its methylation, and its knockdown reduced proliferation, migration, and invasion, and induced G2/M phase arrest in HCT116 and SW480 cells by suppressing the phosphatase and tensin homolog/Akt signaling pathway and inhibiting epithelial-mesenchymal transition. CONCLUSION: FOXA1 may act as an oncogene in colon cancer tumorigenesis and development.

Serum ceruloplasmin can predict liver fibrosis in hepatitis B virus-infected patients.

BACKGROUND: The presence of significant liver fibrosis in hepatitis B virus (HBV)-infected individuals with persistently normal serum alanine aminotransferase (PNALT) levels is a strong indicator for initiating antiviral therapy. Serum ceruloplasmin (CP) is negatively correlated with liver fibrosis in HBV-infected individuals. AIM: To examine the potential value of serum CP and develop a noninvasive index including CP to assess significant fibrosis among HBV-infected individuals with PNALT. METHODS: Two hundred and seventy-five HBV-infected individuals with PNALT were retrospectively evaluated. The association between CP and fibrotic stages was statistically analyzed. A predictive index including CP [Ceruloplasmin hepatitis B virus (CPHBV)] was constructed to predict significant fibrosis and compared to previously reported models. RESULTS: Serum CP had an inverse correlation with liver fibrosis (r = -0.600). Using CP, the areas under the curves (AUCs) to predict significant fibrosis, advanced fibrosis, and cirrhosis were 0.774, 0.812, and 0.853, respectively. The CPHBV model was developed using CP, platelets (PLT), and HBsAg levels to predict significant fibrosis. The AUCs of this model to predict significant fibrosis, advanced fibrosis, and cirrhosis were 0.842, 0.920, and 0.904, respectively. CPHBV was superior to previous models like the aspartate aminotransferase (AST)-to-PLT ratio index, Fibrosis-4 score, gamma-glutamyl transpeptidase-to-PLT ratio, Forn's score, and S-index in predicting significant fibrosis in HBV-infected individuals with PNALT. CONCLUSION: CPHBV could accurately predict liver fibrosis in HBV-infected individuals with PNALT. Therefore, CPHBV can be a valuable tool for antiviral treatment decisions.

Gemcitabine and checkpoint blockade exhibit synergistic anti-tumor effects in a model of murine lung carcinoma.

Lung cancer is leading cause of cancer death in the world. Chemotherapy is currently one of the standard treatments for lung cancer. Gemcitabine is a pyrimidine nucleoside drug which has been approved by FDA to treat lung cancer. However, acquired resistance inevitable develops after Gemcitabine treatment, limiting clinical efficacy. Lewis lung carcinoma (LLC) cells were treated with Gemcitabine and cell apoptosis and programmed cell death-ligand 1 (PD-L1) expression were analyzed by flow cytometry. LLC mouse model was established to analysis the proportion and programmed cell death-1 (PD-1) expression of CD8 + T cells. Anti-tumor effect by treating with Gemcitabine and anti-PD-1 antibody was measured through in vivo LLC mouse model. Gemcitabine treatment induces tumor cell apoptosis and PD-L1 expression. Further study showed that Gemcitabine treatment also increases CD8+ and CD4+ T cells proportion, PD-1 and PD-L1 expression in LLC mouse model. Combination therapy with Gemcitabine and αPD-1 not only has strong anti-tumor effect, but also could inhibit postsurgical recurrence of LLC. Our findings demonstrated that the combination therapy of Gemcitabine and αPD-1 is an effective therapeutic strategy for lung cancer.

Cetuximab Maintenance Therapy in Patients with Unresectable Wild-Type RAS and BRAF Metastatic Colorectal Cancer: A Single-Institute Prospective Study.

INTRODUCTION: Cetuximab plus FOLFIRI (leucovorin, fluorouracil, and irinotecan) is the preferred first-line therapy for RAS and BRAF wild-type (RBWT) metastatic colorectal cancer (mCRC). To counter chemotherapy-induced side effects, use of maintenance therapy is suggested. Therefore, we evaluated the efficacy and safety of cetuximab maintenance therapy in patients after effective completion of first-line induction therapy. METHODS: This prospective study enrolled untreated patients with mCRC RBWT who received first-line cetuximab plus FOLFIRI therapy. Following this, patients with treatment response either entered observation (stop treatment) or maintenance treatment 1 (cetuximab plus irinotecan) groups. After 6-12 cycles of maintenance treatment 1, patients entered maintenance treatment 2 (cetuximab only). If a patient progressed on maintenance 2, cetuximab plus FOLFIRI was reintroduced. The primary end point was failure-free survival (FFS), whereas the secondary end points included disease control rate (DCR), objective remission rate (ORR), and progression-free survival (PFS). Safety events were also evaluated. RESULTS: Among 79 enrolled patients, 72 completed first-line treatment effectively (DCR 91.1%, ORR 63.9%) and 44 entered maintenance 1 [median PFS 1 (mPFS, maintenance 1) 6.1 months, 95% confidence interval (CI) 6.0-6.2; DCR 56.8%; ORR 22.7%]. Of them, 21 entered maintenance treatment 2 (mPFS2 8.7 months, 95% CI 3.3-14.1; DCR 28.6%; ORR 4.8%). Median FFS (mFFS) was significantly longer in the maintenance 1 group compared with the observation group [12.7 vs. 3.0 months; hazard ratio (HR) 0.202, 95% CI 0.111-0.369; P < 0.001]. Overall, mFFS was 19.0 and 9.3 months in maintenance and observation groups, respectively (HR 0.211, 95% CI 0.117-0.380; P < 0.001). Rash acneiform, mucositis, and asthenia were commonly observed adverse events during maintenance treatment. CONCLUSION: Maintenance treatment with cetuximab after first-line therapy significantly improved FFS, with an acceptable safety profile in untreated patients with mCRC RBWT. TRIAL REGISTRATION: Retrospectively registered, 2019/10/02, Chinese Clinical Trial Registry, ChiCTR number 1900026360.

High SPRR1A expression is associated with poor survival in patients with colon cancer.

High expression of small proline-rich protein 1A (SPRR1A) has been shown to be associated with tumor prognosis; however, the association between SPRR1A expression and colon cancer prognosis remains unclear. The present study sought to evaluate the association between SPRR1A expression and the clinicopathological characteristics of colon cancer, and to examine its potential prognostic value. A total of 114 patients with colon cancer were included. SPRR1A expression was evaluated by immunohistochemical staining, and the association between SPRR1A expression and clinicopathological parameters was analyzed. The prognostic value of SPRR1A was analyzed by Cox regression analysis, the Oncomine database and the R2 platform. SPRR1A expression was significantly increased in cancerous tissues compared with that in adjacent non-cancerous tissues. SPPRR1A expression was significantly associated with lymph node invasion. High SPRR1A expression was significantly associated with worse overall and disease-free survival rate. Cox regression analysis revealed that T stage, pathological N stage and high SPRR1A expression remained independent predictors for overall survival rate. The Oncomine database analysis demonstrated that SPRR1A mRNA expression levels were significantly increased in colorectal cancer tissues compared with those in adjacent non-cancerous tissues, and high SPRR1A expression was associated with a significantly worse event- and relapse-free survival time in the R2 platform. The data indicate that SPRR1A may serve as a potential biomarker for the prognosis of colon cancer.

AT-rich interactive domain1A determines sensitivity to oxaliplatin in gastric cancer cells.

BACKGROUND: Gastric cancer is a highly heterogeneous disease and its traditional histopathological classification is difficult to meet clinical needs. Oxaliplatin is an antitumor drug with high efficiency and low toxicity. Therefore, the insensitivity or secondary drug resistance of oxaliplatin to gastric cancer is vital for tumor progression. The aim of this study was to investigate the sensitivity of gastric cancer cells to oxaliplatin after ARID1A (AT-rich interactive domain1A gene) gene silencing. METHODS: MGC-803 and AGS cells were selected as gastric cancer cells for study. ARID1A protein and mRNA expression was detected by Western blot and quantitative reverse-transcription PCR (qRT-PCR). The short hairpin RNA (shRNA) fragment of ARID1A gene silencing was constructed and introduced into gastric cancer cells. The cell proliferation activity was calculated using CCK8 and the IC50 was calculated. The flow cytometry was used to detect the cell cycle and apoptosis rate. The ability of cell invasion was detected by transwell method. Cells were treated with different concentrations of oxaliplatin. RESULTS: The proliferation of gastric cancer cells was promoted by ARID1A gene silencing (P<0.01), the quantity of cells in S phase increased (P<0.05), and the invasive ability increased (P<0.05). After treatment with oxaliplatin at different concentrations, ARID1A gene silencing reduced the inhibition rate of oxaliplatin on gastric cancer cells and apoptosis rate (P<0.05), and increased IC 50 (P<0.01). CONCLUSIONS: ARID1A gene silencing, a factor promoting proliferation of gastric cancer cells, would reduce the sensitivity of gastric cancer cells to oxaliplatin, which can provide a basis for the exploration of targeted drugs for individualized treatment of gastric cancer.

Overexpression of FZD7 is associated with poor survival in patients with colon cancer.

BACKGROUND: Overexpression of Frizzled-7 (FZD7) has been associated with tumor invasion and distant metastases, but little is known about the relationship between FZD7 expression and prognosis in colon cancer. PATIENTS AND METHODS: A total of 114 patients with colon cancer between June 2010 and December 2010 were enrolled in this study. The expression of FZD7 in cancerous and adjacent non-cancerous tissues was determined by immunohistochemistry, and the association between FZD7 expression and patient's clinicopathological characteristics was explored. The correlation between FZD7 expression and prognosis of colon cancer patients was analyzed using the Oncomine database and R2. RESULTS: FZD7 expression levels were significantly higher in colon cancer tissues compared with adjacent non-cancerous tissues (P < 0.001). High expression of FZD7 was significantly associated with metastatic or recurrent disease in colon cancer (P = 0.010). Kaplan-Meier survival analysis demonstrated that colon cancer patients with high expression of FZD7 had a significantly poorer OS (P = 0.013) and DFS (P = 0.010). Cox regression demonstrated that the expression of FZD7 was an independent prognostic factor for DFS (HR = 6.647, P = 0.023). A meta-analysis from the Oncomine database demonstrated that FZD7 mRNA levels were significantly higher in colorectal cancer tissues than in normal colorectal tissues, and FZD7 high expression was associated with a significantly poorer event and relapse-free survival time by analyzing the data from the R2: Genomics Analysis and Visualization Platform. CONCLUSIONS: Overexpression of FZD7 was associated with poor survival in patients with colon cancer. Our data suggest that FZD7 expression could be an effective prognostic biomarker for colon cancer.

Combination leflunomide and methotrexate impedes the recovery of liver fibrosis, partly through inhibition of myeloid cell admittance.

The process of liver fibrosis is reversible and involves a recovery phase. In the present study, the potential side effects of combination leflunomide and methotrexate (LEF+MTX), a conventional rheumatoid arthritis therapy used in the resolution of liver fibrosis, was investigated. In a carbon tetrachloride­induced liver fibrosis model, the results of hepatic pathology demonstrated that the LEF+MTX combination delayed the recovery of fibrosis, although the activation of hepatic stellate cells in vitro was inhibited. A total of four liver fibrosis­associated indicators, hyaluronic acid, laminin, procollagen type III and collagen IV, maintained high levels in the serum of LEF+MTX­treated mice, while detection of bone marrow­driven monocytes in the blood by flow cytometry indicated that they were significantly decreased. Notably, the results of immunofluorescence staining of hepatic myeloid cells and detection of vascular growth factor A (VEGF­A) in blood and liver suggested that the reduced degeneration of collagen in liver sinusoids was associated with decreased myeloid cell adhesion and the downregulation of VEGF­A in the liver. The present results suggested that in certain cases, treatment with LEF+MTX may impede the recovery of hepatic fibrosis­associated diseases in mice.

Demethylation and Overexpression of CSF2 are Involved in Immune Response, Chemotherapy Resistance, and Poor Prognosis in Colorectal Cancer.

PURPOSE: This study aimed to evaluate the role of colony-stimulating factor 2 (CSF2) in chemotherapy resistance, prognosis, and immune response and to identify its possible mechanisms underlying drug resistance. METHODS: Drug-resistant cell lines were obtained by successively increasing drug concentration. RNA-Seq was performed to screen hub genes. CSF2 expression was analyzed via immunohistochemistry. Moreover, The Cancer Genome Atlas (TCGA), Tumor Immune Estimation Resource (TIMER) dataset, and R2 platform were used to explore the correlations among CSF2 expression, prognosis, and immune response. RESULTS: RNA-Seq indicated that microRNAs in cancer, P53 signaling pathway, and cell cycle were associated with FOLFOX chemotherapy resistance. Protein-protein interaction (PPI), molecular complex detection (MOCDE), and qRT-PCR analysis verified CSF2 as the hub gene in chemotherapy resistance. Moreover, CSF2 expression was lower in the normal tissue than in the cancerous tissue (P<0.05). Higher expression of CSF2 was associated with poor OS and DFS in colon cancer patients (P<0.05). We further found similar results in the Oncomine database and R2 platform (P<0.05). A higher expression of CSF2 in the CRC tissue may be caused by demethylation, which was verified using the TCGA datasets. Moreover, GSEA demonstrated that CSF2 was associated with immune response, which was consistent with results reported using TIMER datasets. CONCLUSION: CSF2 is a novel biomarker and a prognostic factor for the survival of CRC patients affecting the immune response, and an overexpression of CSF2 in CRC patients may be caused by DNA demethylation.