Orchestrated Cytosolic Delivery of Antigen and Adjuvant by Manganese Ion-Coordinated Nanovaccine for Enhanced Cancer Immunotherapy.

Cancer vaccines have received tremendous attention in cancer immunotherapy due to their capability to induce a tumor-specific immune response. However, their effectiveness is compromised by the insufficient spatiotemporal delivery of antigens and adjuvants in the subcellular level to induce a robust CD8+ T cell response. Herein, a cancer nanovaccine G5-pBA/OVA@Mn is prepared through multiple interactions of manganese ions (Mn2+), benzoic acid (BA)-modified fifth generation polyamidoamine (G5-PAMAM) dendrimer, and the model protein antigen ovalbumin (OVA). In the nanovaccine, Mn2+ not only exerts a structural function to assist OVA loading as well as its endosomal escape, but works as an adjuvant of stimulator of interferon genes (STING) pathway. These collaboratively facilitate the orchestrated codelivery of OVA antigen and Mn2+ into cell cytoplasm. Vaccination with G5-pBA/OVA@Mn not only shows a prophylactic effect, but also significantly inhibits growth against B16-OVA tumors, indicating its great potential for cancer immunotherapy.

Clinical efficacy evaluation of Erlotinib Combined with Concurrent Chemoradiotherapy in the treatment of locally advanced Pancreatic Cancer.

OBJECTIVE: To evaluate the clinical effects of erlotinib combined with concurrent chemoradiotherapy in the treatment of locally advanced pancreatic cancer. METHODS: Eighty patients with locally advanced pancreatic cancer who attended Shijiazhuang People's Hospital or Anhui Cancer Hospital between January 2018 and January 2020 were randomly divided into two groups, with 40 cases in each group. Patients in the control group were treated with concurrent chemoradiotherapy, while those in the experimental group were treated with erlotinib tablets based on the treatment regimen of the control group. Anti-tumor efficacy evaluation was conducted for all patients in both groups, and the adverse drug reactions, improvement of performance status after treatment were compared and analyzed between the two groups. RESULTS: The overall response rate of the experimental group was 47.5%, which was significantly better than the 25% of the control group (p=0.03). The incidence of adverse drug reactions in the experimental group was 40%, while that in the control group was 30%. The incidence of adverse drug reactions in the experimental group was higher than that in the control group, but there was no statistical significance (p=0.34). Moreover, the improvement rate of performance status score in the experimental group was significantly higher than that in the control group (p=0.00). CONCLUSION: Erlotinib combined with concurrent chemoradiotherapy has been preliminarily proved to be safe and effective in the treatment of locally advanced pancreatic cancer, which can improve the physical condition of patients to a certain extent without significantly increasing adverse reactions.

Prognostic value of peripheral naive CD8+ T cells in oligometastatic non-small-cell lung cancer.

Aim: This study aimed to investigate the prognostic value of peripheral naive and memory CD8+ and CD4+ T cells and other immune cells in patients with oligometastatic non-small-cell lung cancer (NSCLC) undergoing radiotherapy (RT). Methods: A total of 142 patients with oligometastatic NSCLC treated with RT were enrolled, and their blood samples were collected within 3 days before RT. Immune cells were identified by flow cytometry. Results: Patients with high levels of naive CD8+ T cells had longer overall survival (p = 0.004) and progression-free survival (p = 0.001) than those with low levels of naive CD8+ T cells. Multivariate analyses revealed that naive CD8+ T cells were independently correlated with overall survival (p = 0.019) and progression-free survival (p = 0.024). Conclusion: The results suggest that peripheral naive CD8+ T cells may be an independent prognostic indicator for patients with oligometastatic NSCLC undergoing RT.

ZEB1-activated LINC01123 accelerates the malignancy in lung adenocarcinoma through NOTCH signaling pathway.

Growing incidence of lung adenocarcinoma (LUAD) has been detected recently. Multiple long non-coding RNAs (lncRNAs) have been proven as tumor facilitators or inhibitors by extensive works. Present study concentrated on characterizing the potential role of LINC01123 in LUAD. We explored the differential expression of LINC01123 through qRT-PCR and found the amplification of LINC01123 in LUAD cell lines. It was ascertained that LINC01123 was definitely responsible for the malignant processes of LUAD cells. Further, we validated the ceRNA network of LINC01123/miR-449b-5p/NOTCH1 in LUAD via mechanical experiments. As a transcriptional factor related to epithelial mesenchymal transition (EMT), ZEB1 was responsible for the transcriptional activation of both LINC01123 and NOTCH1. The involvement of NOTCH signaling in LUAD was interrogated through evaluating functional changes after treating with FLI-06 (NOTCH pathway suppressor). It showed that FLI-06-caused NOTCH signaling inactivation suppressed malignant functions in LUAD cells. Additionally, LINC01123 facilitated NOTCH1-dependent NOTCH signaling activation. Rescue experiments probed the modulatory function of LINC01123/miR-449b-5p/NOTCH1 in LUAD cellular processes. Altogether, ZEB1-activated LINC01123 accelerates the malignancy in LUAD through miR-449b-5p/NOTCH1 axis-mediated NOTCH signaling pathway, while NOTCH1 boosts ZEB1 in return. These observations suggest the huge potential of LINC01123 as a new target for LUAD therapy.

Application of circulating tumor DNA for dynamic monitoring of advanced non-small cell lung cancer treatment response: An open-label, multicenter, prospective, observational study protocol.

Response Evaluation Criteria in Solid Tumors version 1.1 is currently considered the indicator to assess the curative effect of cancer. However, radiographic measurements often fail to detect tiny lesions or changes in the tumor burden, while tumor biomarkers possess low sensitivity and stability. Circulating tumor DNA (ctDNA) is a potential noninvasive approach that can be used to make an earlier diagnosis, monitor disease progress, and determine treatment efficacy. Previous studies of non-small cell lung cancer (NSCLC) have not clearly determined the optimum time to monitor ctDNA. Hence, the appropriate time to evaluate ctDNA to determine the curative effects of treatment in advanced NSCLC compared to conventional imaging and tumor markers should be explored in order to prevent unnecessary side effects and to avoid continuing ineffective therapies. This protocol outlines a prospective clinical trial in which advanced NSCLC patients will be recruited and longitudinal changes in ctDNA levels with changes in radiographic tumor size or tumor biomarkers will be assessed. ctDNA will be quantified by determining the allele fraction of cancer-associated somatic mutations in plasma using multigene next-generation sequencing assay. Conclusions will be drawn from data collection and analysis.

Combination of stromal vascular fraction and Ad-COMP-Ang1 gene therapy improves long-term therapeutic efficacy for diabetes-induced erectile dysfunction.

Men with diabetic erectile dysfunction (ED) respond poorly to the currently available oral phosphodiesterase-5 inhibitors. Therefore, functional therapies for diabetic ED are needed. Stromal vascular fraction (SVF) and the adenovirus-mediated cartilage oligomeric matrix angiopoietin-1 (Ad-COMP-Ang1) gene are known to play critical roles in penile erection. We previously reported that SVF and Ad-COMP-Ang1 have only a short-term effect in restoring erectile function. Further improvements to ED therapy are needed for long-lasting effects. In the present study, we aimed to test if the combination of SVF and Ad-COMP-Ang1 could extend the erection effect in diabetic ED. We found that the combination therapy showed a long-term effect in restoring erectile function through enhanced penile endothelial and neural cell regeneration. Combination therapy with SVF and Ad-COMP-Ang1 notably restored cavernous endothelial cell numbers, pericyte numbers, endothelial cell-cell junctions, decreased cavernous endothelial cell permeability, and promoted neural regeneration for at least 4 weeks in diabetic mice. In summary, this is an initial description of the long-term effect of combination therapy with SVF and Ad-COMP-Ang1 in restoring erectile function through a dual effect on endothelial and neural cell regeneration. Such combination therapy may have therapeutic potential for the treatment of diabetic ED.

Snail interacts with Id2 in the regulation of TNF-α-induced cancer cell invasion and migration in OSCC.

The inflammatory tumor microenvironment has been identified to play a pivotal role in tumor development and metastasis. Tumor necrosis factor-α (TNF-α) is one of the key cytokines that regulate the inflammatory processes in tumor promotion. In the current study, we treated three oral squamous cell carcinoma (OSCC) cell lines with TNF-α to study its role in inflammation-induced tumor progression. Here we show that TNF-α induces stabilization of the transcriptional repressor Snail and activates NF-κB pathway in the three OSCC cell lines. These activities resulted in the increased motility and invasiveness of three OSCC cell lines. In addition, upon dealing with TNF-α for the indicated time, three OSCC cell lines underwent epithelial-to-mesenchymal transition (EMT), in which they presented a fibroblast-like phenotype and had a decreased expression of epithelial marker (E-cadherin) and an increased expression of mesenchymal marker (vimentin). We further demonstrated that TNF-α can up-regulate the expression of Id2 while inducing an EMT in oral cancer cells. Finally, we showed that Id2 interacted with Snail which may constrain Snail-dependent suppression of E-cadherin. In conclusion, our study indicates that TNF-α induces Snail stabilization is dependent on the activation of NF-κB pathway and results in increasing cell invasion and migration in OSCC cells. Id2 may contribute to regulate the function of Snail during TNF-α-mediated EMT in OSCC. These findings have significant implications for inflammation-induced tumor promotion in OSCC.

Expression of E-cadherin and vimentin in oral squamous cell carcinoma.

The aim of the study is to determine the levels of E-cadherin, vimentin expression in tumor tissues from patients with oral squamous cell carcinoma (OSCC), and the relationship between the expression of E-cadherin, vimentin and epithelial-mesenchymal transition, in order to explore its values for predicting the invasion and metastasis of oral squamous cell carcinoma, short survival of patients in many types of cancer. E-cadherin and vimentin expression of 10 benign and 42 OSCC tumor tissues was examined by immunohistochemical staining. E-cadherin is positively expressed in normal oral mucosa epithelium, but vimentin expression is not found in normal oral mucosa epithelia; the E-cadherin and vimentin were expressed in 26 of 42 (61.9%) and 16 of 42 (38.1%), respectively. No statistically difference was found for E-cadherin and vimentin expression in patients with different age, gender and tumor location, E-cadherin and vimentin expression was significantly associated with lymph node metastasis and tissue location (P<0.05); E-cadherin expression was also significantly associated with tumor stage (P<0.05); there are significantly difference between infiltrative margin and central area in patients with oral squamous cell carcinoma for E-cadherin and vimentin positive expression (P<0.05). E-cadherin and vimentin positive expression was associated with tumor metastasis of oral squamous cell carcinoma. Our study preliminarily confirmed that EMT phenomenon is existed during the development of oral squamous cell carcinoma. Co-evaluation of E-cadherin and vimentin might be a valuable tool for predicting OSCC patient outcome.

Correlation of human papilloma virus with oral squamous cell carcinoma in Chinese population.

Previous studies indicated that oral squamous cell carcinomas (OSCC) might be related to human papilloma virus (HPV) infection. However, the relationship between OSCC in a Chinese population and oral HPV infection is still unclear. In this study, we evaluate the relationship of OSCC with HPV infection in a Chinese population via a meta-analysis. The reports on HPV and OSCC in a Chinese population published between January, 1994, and October, 2015 were retrieved via CNKI/WANFANG/pubmed databases. According to the inclusion criteria, we selected 26 eligible case-control studies. After testing the heterogeneity of the studies by the Cochran Q test, the meta-analyses for HPV and HPV16 were performed using the random effects model. Quantitative meta-analyses showed that, compared with normal oral mucosa the combined odds ratio of OSCC with HPV infection were 1.98 (95% CI: 1.34-2.92). The test for overall effect showed that the P value was less than 0.05 (Z = 3.46). Forest plot analyses were seen in Figures 2 and 3. Publication bias and bias risk analysis using RevMan 5.3 software were measured indicators of the graphics of the basic symmetry. High incidences of HPV infection were found in the samples of Chinese OSCC. For the Chinese population, HPV infection elevates the risk of OSCC tumorigenesis.

Zinc dependent endopeptidases of matrix metalloproteinases-9 expressions is associated with tumor metastases of oral squamous cell carcinoma in Chinese population: a meta-analysis.

Matrix metalloproteinase-9 (MMP-9) is an important member of zinc dependent endopeptidases family and is considered to be involved in the invasion and metastasis of cancer cells. Many studies were published to assess the prognostic role of MMP-9 expression in patients with oral squamous cell Carcinoma, but the findings from those studies were inconsistent in Chinese population. We searched eligible studies in Pubmed, Embase, and Web of Science databases. Six studies with a total of 556 patients were finally included into the meta-analysis. The pooled odds ratios (OR) with the corresponding 95% confidence interval (95% CIs) for positive rate of MMP-9 were calculated by using meta-analysis. Overall, MMP-9 positive expression was associated with tumor metastases in patients with oral squamous cell Carcinoma (fixed-effects OR 4.24, 95% CI 2.25-7.99, P < 0.001; random-effects OR 4.35, 95% CI 2.31-8.21, P < 0.001). Our results indicated that MMP-9 expression is associated with tumor metastases in patients with oral squamous cell carcinoma, and patients with higher MMP-9 expression have less tumor metastases.