Galectin-3 and Myeloperoxidase May Monitor Cancer-Therapy-Related Cardiotoxicity? A Systematic Review and Meta-Analysis.

Galectin-3 and myeloperoxidase (MPO) are novel biomarkers in the field of cardio-oncology, but conflicting results have been reported. Hence, a meta-analysis was performed to assess the monitoring value of galectin-3 and MPO in cancer-therapy-related cardiotoxicity. PubMed, Cochrane, Web of Science, Embase, CNKI databases and ClinicalTrials.gov were queried. According to the predefined inclusion and exclusion criteria, eight studies with 1979 patients were included in this meta-analysis. The examination of the study's heterogeneity (I2), quality assessment and statistical analysis were performed by two reviewers. No significant differences in galectin-3 levels were noted before and after treatment (WMD = -0.10, 90% CI -6.06-5.85, I2: 99%), and a weaker relationship was observed between galectin-3 evaluations and cancer-therapy-related cardiotoxicity (HR = 1.39, 90% CI 0.97-1.98, I2: 0%). However, MPO levels were increased in patients post-treatment (SMD = 0.58, 90% CI 0.35-0.80, I2: 56%), and an increased risk of cardiotoxicity was associated with early pre-post MPO assessments (HR = 1.16, 90% CI 1.02-1.32, I2: 21%). Surprisingly, the MPO levels were a more effective indicator of the response to tumor treatment compared with the TnI (SMD = 2.46, 90% CI -0.26-5.19, I2: 96%) and NT-proBNP levels (SMD = 1.08, 90% CI -0.82-2.98, I2: 96%). In conclusion, our meta-analysis suggests that MPO may rep-resent a potential biomarker for the early detection of cardiotoxicity in current cardio-oncology practice, but the monitoring value of galectin-3 requires further study.

The CDK1-Related lncRNA and CXCL8 Mediated Immune Resistance in Lung Adenocarcinoma.

BACKGROUND: Limited therapeutic options are available for advanced LUAD without driver gene mutations. Anti-CDK therapy has shown effectiveness in several kind of cancers, however, the mechanisms still need to be elucidated. MATERIALS AND METHODS: The lncRNA associated with CDK1 and the immunomodulatory factors that regulate CDK1 were found by bioinformatics analysis and experimental verification. The prognostic model and immune resistance mechanism of lung adenocarcinoma were revealed by single cell analysis, immune infiltration analysis, and signal pathway analysis. RESULTS: LINC00261 was found to be an important CDK1-related lncRNA with a better prognosis in LUAD. In addition, high CDK1 expression indicates a poor immunotherapy response, which may be associated with overexpression of CXCL8. CXCL8 decreased in patients who were immunotherapy-responsive but increased in patients who were immunotherapy-resistant. Signaling pathway analysis suggested that increased CXCL8 and decreased LINC00261 may participate in hypoxia-induced tumor angiogenesis and cause a poor prognosis for the patients. CXCL8 and CDK1 may change G2-M transformation and EMT and promote tumor proliferation. CONCLUSION: This study explained that LINC00261, CDK1, and CXCL8 may have a mutual regulation relationship, which affects the occurrence of LUAD and the efficacy of immunotherapy.

Prognostic Prediction, Immune Microenvironment, and Drug Resistance Value of Collagen Type I Alpha 1 Chain: From Gastrointestinal Cancers to Pan-Cancer Analysis.

Background: Gastrointestinal cancers patients might experience multiple primary tumors in the digestive tract. Therefore, identifying potential biomarkers can help us better understand the underlying mechanism. From the GEO database, four profiles of gastrointestinal cancers were gathered for the screening process, and six hub genes were found by bioinformatics analysis. Collagen type I alpha 1 chain (COL1A1), one of the hub genes, is a component of the extracellular matrix and is critical for tumor microenvironment. However, the expression level, signaling pathway, prognostic prediction, and immunological value of COL1A1 in different cancers remain unclear. Methods: We comprehensively analyzed gene expression and genetic alteration patterns of COL1A1 among 33 types of malignancies from The Cancer Genome Atlas (TCGA) and the Genotype-Tissue Expression projects. Besides, we explored the correlation of COL1A1 with cancer prognosis, immune infiltrates, PD-L1, tumor mutational burden (TMB)/microsatellite instability status (MSI), and the pathway and drug sensitivity of co-expressed genes. Results: The results showed that COL1A1 was highly expressed and associated with poor prognosis in the majority of cancers. The most common alteration type of COL1A1 was missense mutation, and COL1A1 was associated with poor prognosis in KIRP, LGG, MESO, SKCM, and STAD. For the immunologic significance, COL1A1 expression was closely related to high TMB in THYM, LAML, ACC, KICH, PRAD, and LGG, and high MSI in TGCT, MESO, PRAD, COAD, SARC, and CESC. In addition, COL1A1 was positively correlated with the abundance of CAFs, macrophages, and tumor-infiltrating lymphocytes. However, it was negatively correlated with CD8+ T cells mainly in CESC, HNSC-HPV+, and SKCM. Besides, as a component of the extracellular matrix, COL1A1 was involved in the activation of epithelial-mesenchymal transition (EMT), and high expression of HTRA1 was resistant to multiple drugs. Conclusion: COL1A1 can serve as a prognostic and immunological biomarker in different cancers.

Combination of the EP and Anti-PD-1 Pathway or Anti-CTLA-4 for the Phase III Trial of Small-Cell Lung Cancer: A Meta-Analysis.

The morbidity and mortality of lung cancer remain one of the highest among multiple cancers, respectively. Small-Cell Lung Cancer (SCLC) accounts for around 10%-15% of all lung cancers. Approximately two-thirds of the diagnosed SCLCs are in extensive stage (ES). Decades later, we still rely on the same traditional regimen with etoposide and platinum (EP) as the mainstay of treatment with poor prognosis. This meta-analysis aims to assess the effect of adding Immune Checkpoint Inhibitors (CPIs) such as (ipilimumab, atezolizumab, pembrolizumab, and durvalumab) to the traditional EP regimen for small-cell lung cancer extensive stage (ES-SCLC). We searched through PubMed looking for studies that compare between EP and CPIs, with EP alone, and only Phase III randomized controlled trials were considered eligible for this study. A total of 3645 papers were the results of the initial search, and only 4 studies met our criteria. Each investigator extracted the data independently using the PRISMA MODEL (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guideline. Each author used a prespecified sheet. The primary endpoint was to calculate OS (overall survival) and PFS (progression-free survival) hazard ratios for both arms. We found that adding EP plus CPIs increased both OS (HR, 95% CI 0.80 [0.70, 0.93], P = 0.0001, I 2 = 49%) and PFS (HR95% CI 0.81 [0.74, 0.88], P < 0.00001, I 2 = 0%). On the other hand, ORR (overall response rate) was not affected by the addition of CPIs to EP compared to EP alone, and the same was true for adverse events. To conclude, CTLA-4 alone is not encouraging, but PD-1/PD-L1 adds survival benefits. A combined treatment regimen shows to be more effective, improving overall survival rate Durvalumab and atezolizumab showed improvement for OS, but pembrolizumab and ipilimumab did not show a significant increase of OS over EP; however, pembrolizumab showed significant prolongation of the disease-free period.

Effect of low dose of berberine on the radioresistance of cervical cancer cells via a PI3K/HIF-1 pathway under nutrient-deprived conditions.

Purpose: Radiotherapy (RT) is one of the major treatments of cervical cancer. Although the prognosis of clinical cervical cancer becomes better in recent years, some patients still suffer from the recurrence and metastasis. Insufficiency of glucose and oxygen supply could increase the radioresistance of cervical cancer cells through regulating hypoxia-inducible factor 1 (HIF-1) in tumor microenvironment and glucose metabolism. And, berberine can regulate HIF-1. However, how berberine regulates tumor microenvironment and radioresistance through HIF-1 remains to be elucidated.Materials and methods: The human HeLa cervical cancer cells were treated with berberine and radiation under the high and low concentrations of glucose and oxygen, respectively. The survival of cells was tested by CCK-8 assay and colony formation assay. We investigated the PI3K- and IDH3α-related pathway molecules that may regulate HIF-1α by qPCR and western blot. Differentially expressed genes (DEGs) were identified by integrating five related cohort profile datasets. Protein-protein interaction (PPI) network analyses of DEGs related to HIF-1α were conducted by using the STRING database and Cytoscape software.Results: Berberine dramatically damaged HeLa cells under hypoxic and low-glucose conditions compared with the normoxic and high-glucose conditions. The clonogenic assay indicated that the application of berberine decreased the number of colony counts compared to the negative control. Low doses of berberine might decrease the level of phospho-PI3K and HIF-1α under the nutrient-deprived conditions. Moreover, we found that most of the differentially expressed genes which were related to CDKN1B were the downstream molecules regulated by HIF-1α.Conclusion: The results indicated that berberine could dramatically overcome the low-glucose and hypoxia-induced radioresistance. And the regulation berberine on nutrition-deficient conditions might involve in PI3K/HIF-1 pathway. Thus, the interference of glucose metabolism by berberine might be an attractive method to eliminate radioresistant cells and improve radiotherapy efficacy.

Identification of key genes and pathways of diagnosis and prognosis in cervical cancer by bioinformatics analysis.

BACKGROUND: Cervical cancer as one of the most common malignant tumors lead to bad prognosis among women. Some researches already focus on the carcinogenesis and pathogenesis of cervical cancer, but it is still necessary to identify more key genes and pathways. METHODS: Differentially expressed genes were identified by GEO2R from the gene expression omnibus (GEO) website, then gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyzed by DAVID. Meanwhile, protein-protein interaction network was constructed by STRING, and both key genes and modules were found in visualizing network through Cytoscape. Besides, GEPIA did the differential expression of key genes and survival analysis. Finally, the expression of genes related to prognosis was further explored by UNLCAN, oncomine, and the human protein atlas. RESULTS: Totally 57 differentially expressed genes were founded, not only enriched in G1/S transition of mitotic cell cycle, mitotic nuclear division, and cell division but also participated in cytokine-cytokine receptor interaction, toll-like receptor signaling pathway, and amoebiasis. Additionally, 12 hub genes and 3 key modules were screened in the Cytoscape visualization network. Further survival analysis showed that TYMS (OMIM accession number 188350), MCM2 (OMIM accession number 116945), HELLS (OMIM accession number 603946), TOP2A (OMIM accession number 126430), and CXCL8 (OMIM accession number 146930) were associated with the prognosis of cervical cancer. CONCLUSION: This study aim to better understand the characteristics of some genes and signaling pathways about cervical cancer by bioinformatics, and could provide further research ideas to find new mechanism, more prognostic factors, and potential therapeutic targets for cervical cancer.

Comprehensive Analysis of Differential Gene Expression to Identify Common Gene Signatures in Multiple Cancers.

BACKGROUND With the development of research on cancer genomics and microenvironment, a new era of oncology focusing on the complicated gene regulation of pan-cancer research and cancer immunotherapy is emerging. This study aimed to identify the common gene expression characteristics of multiple cancers - lung cancer, liver cancer, kidney cancer, cervical cancer, and breast cancer - and the potential therapeutic targets in public databases. MATERIAL AND METHODS Gene expression analysis of GSE42568, GSE19188, GSE121248, GSE63514, and GSE66272 in the GEO database of multitype cancers revealed differentially expressed genes (DEGs). Then, GO analysis, KEGG function, and path enrichment analyses were performed. Hub-genes were identified by using the degree of association of protein interaction networks. Moreover, the expression of hub-genes in cancers was verified, and hub-gene-related survival analysis was conducted. Finally, infiltration levels of tumor immune cells with related genes were explored. RESULTS We found 12 cross DEGs in the 5 databases (screening conditions: "adj p<0.05" and "logFC>2 or logFC<-2"). The biological processes of DEGs were mainly concentrated in cell division, regulation of chromosome segregation, nuclear division, cell cycle checkpoint, and mitotic nuclear division. Furthermore, 10 hub-genes were obtained using Cytoscape: TOP2A, ECT2, RRM2, ANLN, NEK2, ASPM, BUB1B, CDK1, DTL, and PRC1. The high expression levels of the 10 genes were associated with the poor survival of these multiple cancers, as well as ASPM, may be associated with immune cell infiltration. CONCLUSIONS Analysis of the common DEGs of multiple cancers showed that 10 hub-genes, especially ASPM and CDK1, can become potential therapeutic targets. This study can serve as a reference to understand the characteristics of different cancers, design basket clinical trials, and create personalized treatments.

Tumor mutation burden predicts response and survival to immune checkpoint inhibitors: a meta-analysis.

BACKGROUND: Cancer is one of the world's top three causes of death now. Immune checkpoint inhibitors (ICIs) show encouraging ability to treat some malignancies due to its long-term efficacy and low side effects. However, the predictive biomarker of the immunotherapy efficacy has been inconclusive. Thus, exploring new biomarkers is important. METHODS: A meta-analysis was conducted to evaluate whether tumor mutation burden (TMB) could be a predictive biomarker of the efficacy of ICIs. Using the PubMed and Cochrane Library databases, we searched for articles about TMB and the prognosis of patients with multiple malignancies conducted from 1984 to May 22, 2020. We identified the relationship between TMB and the clinical efficacy of ICIs by using Stata 12.1 software. RESULTS: Eighteen articles with a total of 4,535 patients were included in this meta-analysis. Results showed that high-TMB patients had better progression-free survival (PFS) than low-TMB patients with cancer treated with ICIs (HR =0.45; 95% CI: 0.36-0.56, P=0.002). Moreover, high-TMB patients had longer overall survival (OS) than low-TMB patients. However, the heterogeneity was extremely high, so the result regarding OS was meaningless (HR =0.56; 95% CI: 0.44-0.70, P=0.000, I-squares: 72.6%). CONCLUSIONS: Our study indicates that high TMB is associated with better PFS. Thus, TMB can be considered as a predictive marker of PFS of patients treated with ICIs in the future.

Efficacy and safety of apatinib treatment for gastric cancer, hepatocellular carcinoma and non-small cell lung cancer: a meta-analysis.

Apatinib (Aitan®, brand name in China) is a new anti-antiangiogenic agent that has recently been approved for the treatment of advanced gastric cancer (GC) in China. Nevertheless, its therapeutic efficacy against other types of advanced solid tumors remains unclear. This meta-analysis examines the short-term efficacy and safety of apatinib or combination therapy for GC, hepatocellular carcinoma (HCC) and non-small-cell lung cancer (NSCLC); and provides a discussion of its anti-angiogenesis therapy applications. Seven clinical studies met the inclusion criteria. The treatment of cancers using apatinib was more successful compared to therapy without apatinib. Both objective response rates (ORRs) and disease control rates (DCRs) were significantly improved in the apatinib group compared to those in the control group (RR=2.18, 95% CI 1.30-3.65; RR=2.09, 95% CI 1.21-3.60). The DCR of 850 mg qd and 750 mg qd were higher than those in the control group (P<0.05). Based on the short-term acute adverse reactions of apatinib, significant differences between groups were found for hypertension, urine protein, hand foot syndrome, and gastrointestinal reactions (diarrhea), while no significant differences were found for myelosuppression, nausea and vomiting. Moreover, the results showed that apatinib prolonged patient survival (HR=0.38, 95% CI: 0.28-0.52), and the effect was more pronounced in patients treated with 750 mg qd or 850 mg qd of apatinib than in those treated with a dose of ≤500 mg qd. Additionally, compared to its second-line application, the third-line application was shown to further reduce the risk ratio in patients. Furthermore, overall survival was longer in patients treated with apatinib. Apatinib was shown to have certain short-term effects and survival benefits on GC, HCC, and NSCLC with controllable adverse effects.