Increased LACTB2 Expression Regulates Oxidative Phosphorylation and mTORC1 Signaling of Colorectal Cancer.

This study aimed to investigate the mechanisms of LACTB2 in colorectal cancer (CRC). Microarrays and sequencing data of CRC were acquired from UCSC Xena, GTEx, Gene Expression Omnibus, and TCGA. Pooled analysis of the mRNA expression of LACTB2 in CRC was performed using Stata software. The protein expression of LACTB2 in CRC tissues was evaluated by immunohistochemistry. The relationship between immune cell infiltration and LACTB2 expression was investigated using CIBERSORT. The potential signaling pathways and biological mechanisms of LACTB2 were explored using GSEA, KEGG, and GO. Subsequently, further screening of small molecular compounds with potential therapeutic effects on CRC was conducted through the HERB database, followed by molecular docking studies of these compounds with the LACTB2 protein. The integration and analysis of expression data obtained from 2294 CRC samples and 1286 noncancerous colorectal samples showed that LACTB2 was highly expressed in CRC. Immunohistochemistry performed on in-house tissue samples confirmed that LACTB2 protein expression was upregulated in CRC. CIBERSORT revealed lower B cell infiltration levels in the high LACTB2 expression group than in the low expression group. GO, KEGG, and GSEA analyses showed that LACTB2 expression and genes positively correlating with it were mainly related to DNA synthesis and repair, mitochondrial translational elongation and translational termination, phosphorylation, and mTORC1 signaling. Finally, molecular docking simulations confirmed the ability of quercitin to target and bind to LACTB2. This is the first study to demonstrate that LACTB2 is upregulated in CRC. LACTB2 promotes colorectal tumorigenesis and tumor progression.

Wogonin inhibits the migration and invasion of fibroblast-like synoviocytes by targeting PI3K/AKT/NF-κB pathway in rheumatoid arthritis.

BACKGROUND: Rheumatoid arthritis (RA) is currently an autoimmune inflammatory disease with an unclear pathogenesis. Fibroblast-like synoviocytes (FLSs) have tumor-like properties, and their activation and secretion of pro-inflammatory factors are important factors in joint destruction. Wogonin (5,7-dihydroxy-8-methoxyflavone), a natural flavonoid isolated from Scutellaria baicalensis root, has been shown to have significant anti-inflammatory, anti-oxidative stress, and anti-tumor effects in a variety of diseases. However, the role of wogonin in RA has not yet been demonstrated. PURPOSE: To investigate the inhibitory effect of wogonin on the invasive behavior of fibroblast-like synoviocytes and to explore the mechanism of action of wogonin in RA. METHODS: CCK-8, EdU, cell migration and invasion, immunofluorescence staining, RT-qPCR, and protein blot analysis were used to study the inhibitory effects of wogonin on migration, invasion, and pro-inflammatory cytokine overexpression in the immortalized rheumatoid synovial cell line MH7A. The therapeutic effects of wogonin were validated in vivo using arthritis scores and histopathological evaluation of collagen-induced arthritis mice. RESULTS: Wogonin inhibited the migration and invasion of MH7A cells, reduced the production of TNF-α, IL-1ß, IL-6, MMP-3 and MMP-9, and increased the expression of IL-10. Moreover, wogonin also inhibited the myofibrillar differentiation of MH7A cells, increased the expression of E-cadherin (E-Cad) and decreased the expression of α-smooth muscle actin (α-SMA). In addition, wogonin treatment effectively ameliorated joint destruction in CIA mice. Further molecular mechanism studies showed that wogonin treatment significantly inhibited the activation of PI3K/AKT/NF-κB signaling pathway in TNF-α-induced arthritic FLSs. CONCLUSION: Wogonin effectively inhibits migration, invasion and pro-inflammatory cytokine production of RA fibroblast-like synoviocytes through the PI3K/AKT/NF-κB pathway, and thus wogonin, as a natural flavonoid, has great potential for treating RA.

A retrospective cohort study on the efficacy and safety for combination therapy of immunotherapy, targeted agent, and chemotherapy versus immunochemotherapy or chemotherapy alone in the first-line treatment of advanced biliary tract carcinoma.

Background: A paucity of effective treatment for biliary tract carcinoma (BTC) has necessitated the investigation into new therapies. As combinations of targeted therapy with immunotherapy are well-established in hepatocellular carcinoma, the GEMOX chemotherapy (gemcitabine and oxaliplatin) is the standard treatment for BTC. This study aimed to evaluate the efficacy and safety of immunotherapy in combination with targeted agent and chemotherapy in advanced BTC. Methods: Patients who were pathologically identified advanced BTC and had received gemcitabine-based chemotherapy alone or in combination with anlotinib, and/or anti-programmed cell death protein-1 (PD-1)/programmed death ligand 1 (PD-L1) inhibitors such as camrelizumab as first-line treatment were retrospectively screened from The First Affiliated Hospital of Guangxi Medical University from February 2018 to August 2021. The outcomes included objective response rate (ORR), median overall survival (OS), and median progressive-free survival (PFS). Adverse events (AEs) were assessed according to the NCI-CTCAE v. 4.03. Patients were followed up weekly. Results: A total of 35 patients were enrolled in this study: 11 patients treated with PD-1/PD-L1 inhibitor plus anlotinib and gemcitabine (arm A), 12 patients with the GEMOX combined with PD-1/PD-L1 inhibitor (arm B), and 12 patients with GEMOX (arm C). With a median follow-up time of 31.9 months (range, 23.8-39.7 months), the median OS was 16.8 months [95% confidence interval (CI): 7.0-not reached], 11.8 months (95% CI: 7.2-31.7 months), and 11.6 months (95% CI: 7.3-18.0 months) in arms A, B, and C, respectively (P=0.298). The median PFS was 16.8 months (95% CI: 7.0-NR), 6.0 months (95% CI: 5.1-8.7 months), and 6.3 months (95% CI: 4.6-7.0 months) in arms A, B, and C, respectively. The ORR were 63.6% in arm A, 33.3% in arm B, and 25.0% in arm C. AEs of all grades occurred in 33 (94.3%) patients. Grade 3-4 AEs in all patients included neutrophil count decrease (14.3%), aspartate aminotransferase increase (8.6%), alanine aminotransferase increase (8.6%), fatigue (5.7%), and blood bilirubin increase (5.7%). Conclusions: Anti-PD-1/PD-L1 immunotherapy in combination with anlotinib and gemcitabine showed promising efficacy and an acceptable safety profile for the BTC patients included in this study.

A cohesin-associated gene score may predict immune checkpoint blockade in hepatocellular carcinoma.

Stromal antigen 1 (STAG1), a component of cohesion, is overexpressed in various cancers, but it is unclear whether it has a role in the transcriptional regulation of hepatocellular carcinoma (HCC). To test this hypothesis, here, we screened global HCC datasets and performed multiscale embedded gene co-expression network analysis to identify the potential functional modules of differentially expressed STAG1 co-expressed genes. The putative transcriptional targets of STAG1 were identified using chromatin immunoprecipitation followed by high-throughput DNA sequencing. The cohesin-associated gene score (CAGS) was quantified using the The Cancer Genome Atlas HCC cohort and single-sample gene set enrichment analysis. Distinct cohesin-associated gene patterns were identified by calculating the euclidean distance of each patient. We assessed the potential ability of the CAGS in predicting immune checkpoint blockade (ICB) treatment response using IMvigor210 and GSE78220 cohorts. STAG1 was upregulated in 3313 HCC tissue samples compared with 2692 normal liver tissue samples (standard mean difference = 0.54). A total of three cohesin-associated gene patterns were identified, where cluster 2 had a high TP53 mutated rate and a poor survival outcome. Low CAGS predicted a significant survival advantage but presaged poor immunotherapy response. Differentially expressed STAG1 co-expression genes were enriched in the mitotic cell cycle, lymphocyte activation, and blood vessel development. PDS5A and PDGFRA were predicted as the downstream transcriptional targets of STAG1. In summary, STAG1 is significantly upregulated in global HCC tissue samples and may participate in blood vessel development and the mitotic cell cycle. A cohesin-associated gene scoring system may have potential to predict the ICB response.

Efficacy and Safety of First-Line Chemotherapies for Patients With Advanced Biliary Tract Carcinoma: A Systematic Review and Network Meta-Analysis.

BACKGROUND: At present, chemotherapy is still the primary treatment for advanced biliary tract carcinoma, but it is challenging to balance the efficacy and side effects. Network meta-analysis (NMA) is a better way to identify the protocol, and the advantage is that it can be combined with direct and indirect evidence to judge the best treatment regimens. Therefore, we conducted NMA on the searched randomized controlled trials (RCTs). METHODS: NMA was conducted regarding the searched RCTs by comparing progression-free survival (PFS), overall survival (OS), objective remission rates (ORRs), and adverse events (AEs) of different chemotherapy protocols. RESULTS: We screened 24 studies that met the inclusion criteria for further analysis. Compared with other regimens, the best supportive care (BSC) or FUFA protocol has a worse OS. Folfox4, GEMOX+erlotinib, and C+GEMOX can improve patients' PFS compared with BSC. Patients receiving GP+cediranib protocol have higher ORRs. There was reduced neutropenia grade ≥3 when adopting GP+cediranib, GS, C+GEMOX, RAM+GP, and MER+GP than when using FUFA protocol. The probability of vomiting of XELOX is lower than that of GEM+XELOX. There is a lower diarrhea incidence of XELOX than that of GEMOX+erlotinib. The results of cluster grade analysis illustrated that GEMOX+erlotinib owned a higher ORR and a higher surface under the cumulative ranking (SUCRA) of neutropenia and vomiting but also had a lower SUCRA of diarrhea and fatigue. Meanwhile, both GEMOX and C+GEMOX have a better ORR and a higher AE SUCRA. CONCLUSION: The NMA demonstrated that chemotherapy combined with targeted therapy has better efficacy and lower incidence of AEs than chemotherapy alone.

Efficacy and biomarker exploration of camrelizumab combined with apatinib in the treatment of advanced primary liver cancer: a retrospective study.

This study was to explore the efficacy and safety of camrelizumab combined with apatinib in patients with advanced liver cancer. Moreover, the relationship between peripheral blood parameters and tumor response rate was also investigated. Patients with unresectable or recurrent primary liver cancer (PLC) who received treatment from July 2019 to July 2020 in the First Affiliated Hospital of Guangxi Medical University were included in this single-center retrospective study. The patients were treated with camrelizumab (200 mg, intravenous q2w) plus apatinib (250 mg, oral qd) until the occurrence of disease progression or unbearable toxicity. All the patients underwent blood routine test and detection of lactate dehydrogenase and serum albumin levels before treatment. The primary endpoints were objective response rate (ORR) and disease control rate (DCR). This study included a total of 45 patients. The overall ORR was 33.3% [95% confidence interval (CI),19.0-47.7] and the overall DCR was 57.8% (95% CI, 42.8-72.8). The ORR and DCR were higher in the first-line treatment than those in the second-line treatment (ORR: 45.5% vs. 21.7%, DCR: 63.6% vs. 52.3%). Median progression-free survival in the second-line treatment was 10.5 months (95% CI, 7.9-13.1, P = 0.022). Adverse events occurred in 39 (86.7%) patients. Grade 3/4 adverse reactions occurred in 7 (15.6%) patients. One patient (4.3%) was terminated from treatment due to adverse events. One patient (4.3%) died, which was potentially associated with adverse events. Subgroup analysis indicated that the remission rate in patients with high lymphocyte to monocyte ratio (H-LMR) was higher than that in patients with low lymphocyte to monocyte ratio (L-LMR) (56.25% vs. 25.93%, P = 0.047), and the remission rate in patients with high Prognostic Nutritional Index (H-PNI) was higher than that in patients with low Prognostic Nutritional Index (L-PNI) (66.7% vs. 26.5%, P = 0.046). Camrelizumab combined with apatinib in the treatment of PLC showed encouraging clinical efficacy, with tolerable toxicities. Levels of PNI and LMR may serve as predictors of the prognosis of advanced PLC patients who receive immunotherapy combined with targeted therapy.

Clinical significance of CCNE2 protein and mRNA expression in thyroid cancer tissues.

PURPOSE: Thyroid carcinoma (TC) is the most common endocrinal malignancy worldwide. Cyclin E2 (CCNE2), a member of the cyclin family, acts as a regulatory subunit of cyclin-dependent kinases (CDKs). It controls the transition of quiescent cells into the cell cycle, regulates the G1/S transition, promotes DNA replication, and activates CDK2. This study explored the role and potential molecular mechanisms of CCNE2 expression in TC tissues. MATERIAL/METHODS: Immunohistochemistry was used to evaluate the CCNE2 protein expression levels in TC. High-throughput data on CCNE2 in TC were obtained from RNA sequencing (RNA-seq), microarray, and literature data. The CCNE2 expression levels in TC were comprehensively assessed through an integrated analysis. Analyses of Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and protein-protein interaction (PPIs) data facilitated the investigation of the relative molecular mechanisms of CCNE2 in TC. RESULTS: The immunohistochemical experiment showed a significant increase in the expression of CCNE2 in the TC tissues. For 505 TC and 59 non-cancerous samples from RNA-seq data, the area under the curve (AUC) was 0.8016 (95% confidence interval [CI] 0.742-0.8612; p<0.001). With another 14 microarrays, the pool standard mean difference [SMD] was 1.01 (95% CI [0.82-1.19]). The pooled SMD of CCNE2 was 1.12 (95% CI [0.60-1.64]), and the AUC was 0.87 (95% CI [0.84-0.90]) for 1157 TC samples and 366 non-cancerous thyroid samples from all possible sources. Nine hub genes were upregulated in TC. CONCLUSIONS: A high expression of CCNE2 may lead to carcinogenesis and the development of TC.

A qRT-PCR and Gene Functional Enrichment Study Focused on Downregulation of miR-141-3p in Hepatocellular Carcinoma and Its Clinicopathological Significance.

BACKGROUND: The clinical significance of miR-141-3p in hepatocellular carcinoma has not been verified. Therefore, we conducted this study to examine miR-141-3p expression and its clinical significance in hepatocellular carcinoma and to investigate the functions of its potential targets. METHODS: The Cancer Genome Atlas database and the Gene Expression Omnibus database were used to explore the aberrant expression of miR-141-3p in hepatocellular carcinoma. Furthermore, we assessed the miR-141-3p levels in 95 hepatocellular carcinoma tissues with 95 matched adjacent tissues using real-time quantitative polymerase chain reaction. Moreover, a target gene prediction analysis of miR-141-3p, a natural language processing analysis for hepatocellular carcinoma using PubMed, and a gene functional enrichment analysis were conducted to search the potential function of miR-141-3p in the pathogenesis of hepatocellular carcinoma. RESULTS: Regarding The Cancer Genome Atlas data, miR-141-3p levels were markedly downregulated in hepatocellular carcinoma tissue compared to para- or nontumor tissue (4.6112 [1.7096] vs 5.3053 [1.4254], P = .045). MiR-141-3p expression was reduced in patients with hepatocellular carcinoma with a low pathologic T stage (P = .006), a low grade (P = .01), elderly hepatocellular carcinoma patients (P = .001), and male patients with hepatocellular carcinoma (P = .01) compared with that in patients with hepatocellular carcinoma with high pathologic T stages, high grades, young patients with hepatocellular carcinoma, and female patients with hepatocellular carcinoma. However, according to the Gene Expression Omnibus database, no significant differences in the expression of miR-141-3p were observed between hepatocellular carcinoma tissue and normal liver tissue (P = .984). Real-time quantitative polymerase chain reaction confirmed a similar trend of decreased miR-141-3p in hepatocellular carcinoma tissue (1.7542 [0.8663] vs 2.5562 [1.7913], P = .001) as observed in The Cancer Genome Atlas. In addition, decreased miR-141-3p levels were detected in the multiple tumor nodes group (P = .004), the metastasis group (P < .001), and the advanced TNM stage group (P = .01), compared to the single tumor nodes group, the nonmetastasis group, and the early TNM stage group. Two hundred eighty-two genes were identified from the overlap between the predicted targets and the natural language processing analysis. Gene ontology and Kyoto Encyclopedia of Genes and Genomes pathway analyses revealed several significant biological functions and pathways related to the pathogenesis of cancers, including hepatocellular carcinoma. CONCLUSION: Downregulation of miR-141-3p might be responsible for the carcinogenesis and aggressiveness of hepatocellular carcinoma. MiR-141-3p may act as an antitumor microRNA, which is essential for hepatocellular carcinoma progression through the regulation of various signaling pathways. Thus, interactions with miR-141-3p may provide a novel strategy for hepatocellular carcinoma treatment in the future.