An injectable and pH-responsive hyaluronic acid hydrogel as metformin carrier for prevention of breast cancer recurrence.

To achieve the pH-responsive release of metformin in tumor acidic microenvironment, we prepared OHA-Met by covalently grafting metformin (Met) onto oxidized hyaluronic acid (OHA) through imine bonds, and then prepared carboxymethyl chitosan (CMCS)/OHA-Met drug loaded hydrogels. The CMCS/OHA-Met hydrogels showed the in-situ injection performance. At pH = 7.4, the cumulative release rate of metformin from CMCS/OHA-Met20 hydrogel was 42.7 ± 2.6 % in 6 h, and the release tended to balance after 72 h. At pH = 5.5, the release kept constant and the cumulative release rate was 79.3 ± 4.7 % at 6 h, showing good pH-responsive behavior. Metformin induced apoptosis of MCF-7 cells through the caspase 3/PARP pathway. CMCS/OHA-Met20 hydrogel could effectively kill MCF-7 cells, while reducing the cytotoxicity of free metformin to L929 cells. In vivo breast cancer recurrence experiments showed CMCS/OHA-Met20 hydrogel could achieve local injection and pH-responsive smart drug delivery at the tumor resection site, inhibiting breast cancer recurrence. Compared with direct administration, CMCS/OHA-Met20 hydrogel reduced the metformin dosage, frequency of administration and systemic side effects.

Identification of necroptosis-related signature and tumor microenvironment infiltration characteristics in lung adenocarcinoma.

OBJECTIVES: Lung cancer remains the most common cancer and the leading cause of cancer deaths. However, the potential roles of necroptosis-related signature and tumor microenvironment (TME) in the lung adenocarcinoma (LUAD) still unknown. MATERIALS AND METHODS: Expression data and clinical information were obtained from the Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) database. In the TCGA dataset, necroptosis phenotype-related differentially expressed genes (DEGs) were identified. A necroticscore score was developed and validated by integrating GEO-meta datasets. The clinical value of the risk score was further evaluated using Kaplan-Meier and immunotherapeutic cohort (IMvigor210 cohort). RESULTS: Three necroptosis-related patterns and distinct necroptosis-related gene cluster were identified based on the abnormal expression of 14 necroptosis regulators. The necroptosis genomic phenotypes were obtained based on 117 necroptosis phenotype-related DEGs. A necroticscore were constructed to evaluate necroptosis pattern of each patient. Low necroticscore was linked with decreased immune check-point expression, enhanced immune check-point inhibitor response, and better clinical benefits. CONCLUSION: This study suggested that the crucial roles of necroptosis-related regulators in modeling the heterogeneity of TME characteristics. Thus, assessing necroptosis patterns provided us with a deeper understanding of TME and might guide the clinical immunotherapy treatment of lung cancer.

Molecular Characterization Clinical and Immunotherapeutic Characteristics of m5C Regulator NOP2 Across 33 Cancer Types.

Background: Recent studies have identified that RNA 5-methylcytosine (m5C) is a wide-spread epigenetic modification in tumorigenesis. However, the clinical and immunotherapeutic values of m5C regulator NOP2 in 33 cancers remain unclear. Methods: The mRNA expression data and clinical data of 33 cancers were downloaded from The Cancer Genome Atlas (TCGA) database. The immunotherapy data including GSE67501, GSE78220, GSE35640, and IMvigor210 were downloaded from the Gene Expression Omnibus (GEO) database and the website based on the Creative Commons 3.0 license (http://research-pub.Gene.com/imvigor210corebiologies). The expression, survival, clinical parameters, tumor mutation burden (TMB), microsatellite instability (MSI), and tumor microenvironment (TME) were evaluated. Finally, the relationship between NOP2 and immunotherapy response was further explored. Results: NOP2 was significantly upregulated in most cancers, and high NOP2 expression was associated with poor prognosis. TMB, MSI, and NOP2 activities were involved in the dysregulation of NOP2. NOP2 was closely associated with immune cell infiltration, immune modulators, and immunotherapeutic inactivation. Conclusions: We comprehensively explored the clinical and immunotherapeutic values of NOP2 in cancers, providing evidence regarding the function of NOP2 and its role in clinical treatment.

5-methylcytosine RNA methylation regulators affect prognosis and tumor microenvironment in lung adenocarcinoma.

Background: Accumulating evidence has shown that 5-methylcytosinec (m5C) RNA methylation plays an essential role in tumorigenesis. However, the roles of m5C regulators in the prognosis, tumor microenvironment (TME), and immunotherapy responses of lung adenocarcinoma (LUAD) have not been fully analyzed. Methods: Based on 14 m5C RNA regulators, we evaluated the m5C RNA modification patterns in patients with LUAD (n=594) in The Cancer Genome Atlas (TCGA). Unsupervised clustering analysis was performed to confirm distinct m5C modification patterns. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were performed to investigate the biological functions of differentially expressed genes (DEGs) among different m5C RNA modification patterns. An m5C signature (m5Csig) was constructed using least absolute shrinkage and selection operator (LASSO) algorithms. The GSE72094 cohort (n=442) from the Gene Expression Omnibus (GEO) was used to validate m5Csig. A receiver operating characteristic (ROC) model was constructed to evaluate the sensitivity and specificity of m5Csig. Tumor-infiltrating immune cells (TIICs) between the high- and low-risk groups were estimated using the Cell Type Identification By Estimating Relative Subsets Of RNA Transcripts (CIBERSORT) algorithm. Results: We identified 3 m5C RNA modification clusters. Overall survival (OS) differed among the 3 clusters. The m5Csig, including TRDMT1, NSUN1, NSUN4, NSUN7, and ALYREF, was constructed to classify patients with LUAD into high- and low-risk groups. The high-risk group, with more immune cell infiltration, had a significantly poorer OS than that the low-risk group, which was associated with better response to immune checkpoint blockade therapy. Conclusions: The present study revealed that m5C RNA regulators play a significant role in TME regulation in LUAD. The m5Csig can predict the prognosis of patients with LUAD and might provide novel strategies for tumor immunotherapy.

Molecular Characterization of the Clinical and Tumor Immune Microenvironment Signature of 5-methylcytosine-Related Regulators in non-small Cell Lung Cancer.

Background: DNA methylation is an important epigenetic modification, among which 5-methylcytosine methylation (5mC) is generally associated with tumorigenesis. Nonetheless, the potential roles of 5mC regulators in the tumor microenvironment (TME) remain unclear. Methods: The 5mC modification patterns of 1,374 lung adenocarcinoma samples were analyzed systematically. The correlation between the 5mC modification and tumor microenvironment cell infiltration was further assessed. The 5mCscore was developed to evaluate tumor mutation burden, immune check-point inhibitor response, and the clinical prognosis of individual tumors. Results: Three 5mC modification patterns were established based on the clinical characteristics of 21 5mC regulators. According to the differential expression of 5mC regulators, three distinct 5mC gene cluster were also identified, which showed distinct TME immune cell infiltration patterns and clinical prognoses. The 5mCscore was constructed to evaluate the tumor mutation burden, immune check-point inhibitor response, and prognosis characteristics. We found that patients with a low 5mCscore had significant immune cell infiltration and increased clinical benefit. Conclusion: This study indicated that the 5mC modification is involved in regulating TME infiltration remodeling. Targeting 5mC modification regulators might be a novel strategy to treat lung cancer.

Identification of Clinical and Tumor Microenvironment Characteristics of Hypoxia-Related Risk Signature in Lung Adenocarcinoma.

Background: Lung cancer is the leading cause of cancer-related death globally. Hypoxia can suppress the activation of the tumor microenvironment (TME), which contributes to distant metastasis. However, the role of hypoxia-mediated TME in predicting the diagnosis and prognosis of lung adenocarcinoma (LUAD) patients remains unclear. Methods: Both RNA and clinical data from the LUAD cohort were downloaded from the Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases. Both univariate and multivariate Cox regression analyses were used to further screen prognosis-related hypoxia gene clusters. Time-dependent receiver operation characteristic (ROC) curves were established to evaluate the predictive sensitivity and specificity of the hypoxia-related risk signature. The characterization of gene set enrichment analysis (GSEA) and TME immune cell infiltration were further explored to identify hypoxia-related immune infiltration. Results: Eight hypoxia-related genes (LDHA, DCN, PGK1, PFKP, FBP1, LOX, ENO3, and CXCR4) were identified and established to construct a hypoxia-related risk signature. The high-risk group showed a poor overall survival compared to that of the low-risk group in the TCGA and GSE68465 cohorts (p < 0.0001). The AUCs for 1-, 3-, and 5-year overall survival were 0.736 vs. 0.741, 0.656 vs. 0.737, and 0.628 vs. 0.649, respectively. The high-risk group was associated with immunosuppression in the TME. Conclusion: The hypoxia-related risk signature may represent an independent biomarker that can differentiate the characteristics of TME immune cell infiltration and predict the prognosis of LUAD.

LKB1 expression and the prognosis of lung cancer: A meta-analysis.

BACKGROUND: In the past few decades, many lines of evidence implicate the importance of liver kinase B1 (LKB1) as a tumor suppressor gene in the development and progression of solid tumours. However, the prognostic and clinicopathological value of LKB1 in patients with lung cancer are controversial. This article aimed to investigate the latest evidence on this question. METHODS: A systematic literature searched in the PubMed, Web of Science, Embase, Cochrane library, Scopus until September 20, 2020. The association between overall survival (OS), relapse-free survival (RFS), progression-free survival (PFS), clinicopathological features and LKB1 were analysed by meta-analysis. RESULTS: Eleven studies including 1507 patients were included in this meta-analysis. The pooled results revealed that low LKB1 expression was significantly associated with poor overall survival (OS) (HR = 1.67, 95% CI: 1.07-2.60, P = .024) in lung cancer. However, no association was found between LKB1 expression and DFS/PFS (HR = 1.29, 95% CI: 0.70-2.39, P = .410). Pooled results showed that low LKB1 expression was associated with histological differentiation (poor vs moderate or well, OR = 4.135, 95% CI:2.524-6.774, P < .001), nodal metastasis (absent vs present, OR = 0.503, 95% CI: 0.303-0.835, P = .008) and smoking (yes vs no, OR = 1.765, 95% CI: 1.120-2.782, P = .014). CONCLUSION: These results suggest that low expression of LKB1 can be considered as a unfavorable prognostic biomarker for human lung cancer, which should be further researched.

Molecular identification of an immunity- and Ferroptosis-related gene signature in non-small cell lung Cancer.

BACKGROUND: Lung cancer is one of the dominant causes of cancer-related deaths worldwide. Ferroptosis, an iron-dependent form of programmed cell death, plays a key role in cancer immunotherapy. However, the role of immunity- and ferroptosis-related gene signatures in non-small cell lung cancer (NSCLC) remain unclear. METHODS: RNA-seq data and clinical information pertaining to NSCLC were collected from The Cancer Genome Atlas dataset. Univariate and multivariate Cox regression analyses were performed to identify ferroptosis-related genes. A receiver operating characteristic (ROC) model was established for sensitivity and specificity evaluation. Gene ontology enrichment and Kyoto Encyclopedia of Genes and Genomes pathway analyses were performed to explore the function roles of differentially expressed genes. RESULTS: A signature composed of five ferroptosis-related genes was established to stratify patients into high- and low-risk subgroups. In comparison with patients in the low-risk group, those in the high-risk one showed significantly poor overall survival in the training and validation cohorts (P < 0.05). Multivariate Cox regression analysis indicated risk score to be an independent predictor of overall survival (P < 0.01). Further, the 1-, 2-, and 3-year ROCs were 0.623 vs. 0.792 vs. 0.635, 0.644 vs. 0.792 vs. 0.634, and 0.631 vs. 0.641 vs. 0.666 in one training and two validation cohorts, respectively. Functional analysis revealed that immune-related pathways were enriched and associated with abnormal activation of immune cells. CONCLUSIONS: We identified five immunity- and ferroptosis-related genes that may be involved in NSCLC progression and prognosis. Targeting ferroptosis-related genes seems to be an alternative to clinical therapy for NSCLC.

Preoperative pectoralis muscle radiodensity as a risk factor for postoperative complications after thoracoscopic lobectomy for non-small cell lung cancer.

BACKGROUND: Skeletal muscle radiodensity is associated with postoperative complications in cancer. However, data on skeletal muscle radiodensity and postoperative complication risk in patients with non-small cell lung cancer (NSCLC) are scarce, and this study investigated the relationship between skeletal muscle radiodensity and postoperative complication risk in patients with NSCLC treated by thoracoscopic lobectomy. METHODS: Quantitative and qualitative measurements of the pectoralis muscle were performed on a single axial slice above the aortic arch in the precontrast computed tomography (CT) scan performed before surgery. Sex-specific cutoffs for the pectoralis muscle mass index (PMI) and pectoralis muscle radiodensity (PMD) were set at the lowest tertile. A Clavien-Dindo grade ≥ III within 30 days of the operation was considered as a major complication, and logistic regression analysis was performed to identify risk factors for postoperative complications. RESULTS: The records of 163 consecutive patients with NSCLC receiving first-line thoracoscopic lobectomy between March 2016 and October 2019 were retrospectively reviewed and the PMI was found to be positively correlated with PMD (P<0.001). The PMI and PMD were significantly higher in men than in women (both P<0.001), and 23 (14.1%) patients experienced major postoperative complications. The multivariate analysis showed that male sex (P=0.032), lower body mass index (BMI) (P=0.016), and low PMD (P=0.012) before surgery, but not low PMI, were independent risk factors for major postoperative complications. CONCLUSIONS: Skeletal muscle quality but not muscle mass predicts major complications after thoracoscopic lobectomy for NSCLC. Skeletal muscle measures from the preoperative CT scan may be used to stratify patients with NSCLC into risk categories that can guide clinical decision-making.

Prognostic and clinicopathological value of PD-L2 in lung cancer: A meta-analysis.

OBJECTIVE: The prognostic role of programmed death ligand-2 (PD-L2) expression in lung cancer has been widely studied, however, the results are controversial. Accordingly, we investigated the prognostic and clinicopathological value of PD-L2 in patients with lung cancer in this meta-analysis. METHODS: Relevant studies were systematically searched in the PubMed, Web of Science, EMBASE, ClinicalTrials.gov., Scopus, and Cochrane Library until July 10, 2020. The hazard ratio (HR), odds ratio (OR), and their corresponding 95% confidence intervals (CIs) were calculated. RESULTS: Thirteen studies with 3107 participants were included. High PD-L2 expression was associated with poor overall survival (OS) (HR 1.248, 95% CI: 1.071-1.455, p = 0.004) and worse disease-free survival (DFS)/progression-free survival (PFS)/relapse-free survival (RFS) (HR 1.224, 95% CI: 1.058-1.417, p = 0.007) in lung cancer. Furthermore, unfavorable OS was found in lung adenocarcinoma (HR 1.349, 95% CI: 1.051-1.731, p = 0.019), but not in other pathological types (HR 1.192, 95% CI: 0.982-1.447 p = 0.076) with higher PD-L2 expression in our subgroup analysis. Concerning the clinicopathological characteristics, high PD-L2 expression was associated with smoking (OR 0.725, 95% CI: 0.591-0.890, p = 0.002) and PD-L1 (OR 1.607, 95% CI:1.115-2.314, p = 0.011) and vascular invasion (OR 1.500, 95% CI: 1.022-2.203, p = 0.039). CONCLUSION: PD-L2 overexpression might predict a poor prognosis in lung cancer patients after surgery. PD-L2 expression might be a potential biomarker for PD-1/PD-L1-targeted immunotherapy in lung cancer, which should be investigated in future studies.

MicroRNA-550a is associated with muscle system conferring poorer survival for esophageal cancer.

Background Esophageal cancer (ESCA) is one of the most common cancers in the digestive tract. Approximately 300000 people on an average die of ESCA per year worldwide. The determination of key microRNAs for the prognosis of ESCA is of indispensable significance in the clinical treatment. Methods The differentially expressed microRNAs were screened by analyzing The Cancer Genome Atlas (TCGA) database. By using the survival data of the database, we analyzed correlation between patients' survival time and miR-550a expression levels. Differential expression analysis and gene set enrichment analysis were performed using the targeted data. Results It was found that patients with high miR-550a expression levels had shorter survival time. Data mining and signal pathway enrichment analysis of TCGA database showed that abnormal miR-550a expressions affected the recurrence of tumors by the muscle system regulation. Conclusions Through the proposed investigation, miR-550a is found to be a potential biomarker as well as non-coding therapeutic target for esophagus cancer. These results suggest that miR-550a may serve as a therapeutic target and predictor for ESCA survival.

Vitamin D deficiency and the risk of anemia: a meta-analysis of observational studies.

AIMS: Anemia and vitamin D deficiency (VDD) are both very important health issues, recent accumulating evidence shows that VDD is prevalent in individuals with anemia. This meta-analysis aimed to detect a relationship between VDD and anemia. METHODS: We identified eligible studies by searching the Pub Med, Embase and Cochrane Library before October 2014. Quality assessments were performed with the Newcastle-Ottawa Scale. Heterogeneity was evaluated by Cochran's Q test and source of heterogeneity was detected by subgroup analysis and sensitivity analysis. RESULTS: A total of seven studies involving 5183 participants were included in the meta-analysis. VDD was associated with an increased incidence of anemia (OR = 2.25, 95% CI = 1.47-3.44), with significant evidence of heterogeneity among these studies (p for heterogeneity < 0.001, I(2) = 84.0%). The subgroup and sensitivity analysis confirmed the stability of the results and no publication bias was detected. CONCLUSION: Our outcomes showed that VDD increased the risk of developing anemia. More researches are warranted to clarify an understanding of the association between VDD and risk of anemia.

A Meta-Analysis of the Relationship between Testicular Microlithiasis and Incidence of Testicular Cancer.

PURPOSE: There are many recent observational studies on testicular microlithiasis (TM) and risk of testicular cancer. Whether TM increases the risk of testicular cancer is still inconclusive. The objective of this updated meta-analysis was to synthesize evidence from clinical observational studies that evaluated the association between TM and testicular cancer. MATERIALS AND METHODS: We identified eligible studies by searching the PubMed, Embase and Cochrane Library before March 2014. Adjusted relative risks (RR) with 95% confidence interval (CI) were calculated using random-or fixed-model. RESULTS: A total of 14 studies involving 35,578 participants were included in the meta-analysis. On the basis of the Newcastle Ottawa Scale systematic review, eleven studies were identified as relatively high-quality. TM was strong association with an increased incidence of testicular cancer (RR = 12.70, 95% CI: 8.18-19.71, P < .001), with significant evidence of heterogeneity among these studies (P for heterogeneity < .001, I2 = 82.1%). The subgroup and sensitivity analysis confirmed the stability of the results and no publication bias was detected. CONCLUSION: The present meta-analysis suggests that TM is significantly associated with risk of testicular cancer. More researches are warranted to clarify an understanding of the association between TM and risk of testicular cancer.

[A meta-analysis of platinum plus docetaxel or vinorelbine in the first-line treatment of advanced non-small cell lung cancer].

BACKGROUND AND OBJECTIVE: Platinum plus a third-generation agent doublet chemotherapy is the standard regimen and first-line chemotherapy for the treatment of advanced non-small cell lung cancer (NSCLC). The aim of this study is to evaluate the efficacy and safety of docetaxel plus platinum (DP) compared with vinorelbine plus platinum (VP) regimens in patients with advanced NSCLC. METHODS: We searched the PubMed, EMBASE, Cochrane Library, CNKI, CBM, VIP, and WanFang databases for randomized controlled trials (RCTs), in which DP regimen was compared with VP regimen. A quality assessment of qualified RCTs was performed according to Cochrane Handbook 5.1.0, and Stata 12.0 was used to perform meta-analysis. RESULTS: Seven RCTs involving 2,318 patients were included. Meta-analysis results indicated that the DP regimen increased the two-year survival rate (HR=0.887, 95%CI: 0.810-0.972, P=0.010), response rate (RR=1.276, 95%CI: 1.107 -1.450, P=0.001), and diarrhea rate (RR=3.134, 95%CI: 1.918-5.121, P<0.001) compared with the VP regimen. Anemia rate was also reduced (RR=0.386, 95%CI: 0.311-0.478, P<0.001). No statistical differences were observed between DP and VP regimens in terms of one-year survival rate, leukopenia, neutropenia, thrombocytopenia, anorexia, nausea, and vomiting. CONCLUSIONS: DP regimen reduced the rate of anemia and increased the rate of diarrhea, two-year survival rate, and response rate. Therefore, DP regimen may be a more effective option as a first-line treatment for advanced NSCLC compared with VP regimen.

[Using the lower medial leg fasciocutaneous flap to repair soft tissue defects at root of tongue].

OBJECTIVE: To investigate the clinical value of lower medial leg fasciocutaneous flap for the repair of soft tissue defects at root of tongue. METHODS: 4 cases of soft tissue defects at root of tongue were underwent surgery with lower medial leg fasciocutaneous flaps. This paper describes in detail the anatomy of the flap, technique of make up the flap, advantages and disadvantages, and its clinical applications. RESULTS: All the 4 flaps were got successfully one stage repair. A satisfied reconstruction were attained, the transplanted skin grafts on the defect regions of lower medial leg survived without necrosis. CONCLUSIONS: The lower medial leg fasciocutaneous flaps is a good method for the repair of the defect reconstruction at the root of tongue. The soft tissue defects at root of tongue can be used the flap combined with partial soleus. The flaps not only has thin fat and soft quality, but also is far away from the region of head and neck. The donor site is blanket with less damage.

[Changes of masticatory muscles after occlusal recovery in rats with unilateral chew].

PURPOSE: To study the effect of occlusal recovery on masticatory muscles in rats with unilateral chew. METHODS: 40 white rats were divided into two experimental groups and two control groups. The right upper and lower posterior teeth of all the rats were ground to the gingival level without occlusal contact. The rats of the first experimental and control group were killed 10 weeks late,those of the second groups were killed 16 weeks late. The pathological changes of masticatory muscles were studied. SPSS 10.0 software package was used for statistical analysis. RESULTS: There was significant correlation between the first experimental group and control group in the damage of masticatory muscles (Chi(2)=40, P<0.01). However,there was no significant correlation between the second experimental group and control group in the damage of masticatory muscles (Chi(2)=3.66, P>0.05). CONCLUSION: Early occlusal recovery can rehabilitate the damage of masticatory muscles in rats with unilateral chew.

[Significance of VEGF expression and microvessel count in oral carcinoma].

OBJECTIVE: To evaluate the clinical significance of vascular endothelial growth factor(VEGF) expression in oral carcinomas. METHODS: Immunohistochemical staining(SABC) was used to quantify VEGF expression in specimens from 56 patients with oral carcinomas. SPSS statistical software was used for analysis. RESULTS: VEGF expression was observed in 29 of the patients(51.8%). The microvessel count was significantly higher (P < 0.05) in the oral carcinomas with VEGF expression than in the oral carcinomas without it. In the clinicopathologic factors, lymph node metastasis(P < 0.05) and differentiated degree (P < 0.05) were significantly correlated with VEGF expression, but there was no significantly correlation between the clinicopathologic stage and VEGF positive expression. The 5-year survival rate after curative surgery was better in the patients without VEGF expression (P < 0.05). CONCLUSION: This study indicates that VEGF expression is associated with angiogenesis, VEGF is one of the main angiogenic factors for oral carcinomas. Quantification of VEGF in oral tissues may provide a valuable marker for the prognosis of patients with oral carcinomas.