Efficacy and safety of envafolimab in the treatment of advanced dMMR/MSI­H solid tumors: A single­arm meta­analysis.

In November 2021, the National Medical Products Administration (China) approved the marketing of envafolimab injection for the treatment of advanced defective mismatch repair (dMMR)/high microsatellite instability (MSI-H) solid tumors. Envafolimab became the first domestic PD-L1 inhibitor approved in China and the first worldwide approved subcutaneously injectable PD-L1 inhibitor. To the best of our knowledge, there are no reports of systematic analyses regarding the use of envafolimab in the treatment of advanced dMMR/MSI-H solid tumors. The present study was a single-arm meta-analysis performed on data systematically searched and retrieved from literature published on PubMed, Web of Science, Cochrane Library, China National Knowledge Infra-structure and Wan Fang databases on 1 October 2022. Quality assessment using the 20 items developed by the Canadian Institute of Health Economics. Data heterogenicity was evaluated using the I2 statistics. For datasets with I2>50%, the cumulative incidence and 95% CI for the outcomes of interests were calculated using the random effects model, whereas for I2<50% the fixed effects model was used. The current meta-analysis included four studies enrolling 181 patients with advanced dMMR/MSI-H solid tumors. The pooled objective remission rate was 29.53% (95% CI, 8.61-50.45%). The pooled disease control rate was 60.58% (95% CI, 31.79-89.38%). The pooled median progression-free survival was 4.89 months (95% CI, 1.86-7.93 months). The pooled overall survival (OS) rate was 73.38% (95% CI, 65.76-80.99%). The pooled 6-month and 12-month OS rates were 75.80% (95% CI, 57.02-94.58%) and 69.32% (95% CI, 51.92-86.72%), respectively. The combined data on the incidence of treatment-emergent adverse events (TEAEs) of any grade from all the studies was 77.19% (95% CI, 63.15-91.23%). Most of the adverse reactions were mild and the rate of 3/4 grade TEAE was 10.37% (95% CI, 6.14-14.60%). Gevokizumab was effective and safe in the treatment of patients with advanced dMMR/MSI-H solid tumors and its convenience could significantly improve patient compliance; therefore, the clinical application of envafolimab is promising.

A systematic and comprehensive analysis of colorectal squamous cell carcinoma: Implication for diagnosis and treatment.

BACKGROUND: This study was aimed at establishing a nomogram for survival prediction of Colorectal squamous cell carcinoma (CSCC), understanding the molecular pathogenesis, exploring a better treatment, and predicting the potential therapeutic agents. METHODS: Surveillance, Epidemiology, and End Results (SEER) database was used to obtained CSCC patients and the nomogram was performed. Propensity score matching (PSM), Kaplan-Meier analysis, subgroup analysis, and interaction test were used to explore the better treatment strategy for CSCC. Bioinformatics were used to explore the molecular mechanism and potential therapeutic drugs of CSCC. RESULTS: A total of 3949 CSCC patients were studied. The nomogram was constructed and evaluated to have a good performance. We found that the radiotherapy had a better effect than surgery, and the difference between radiotherapy and combined therapy was not significant. 821 differentially expressed genes in CSCC were obtained from GSE6988 dataset. DNA damage repair, mismatch repair, and cell cycle pathways might contribute to CSCC occurrence as indicated by KEGGpathway and GSEA analysis. Transcription factors analysis revealed that TP63 and STAT1 may have an important role in occurrence and development of CSCC. 1607 potential drugs against CSCC were found using the CMAP database, and molecular docking was carried out to show the binding energy between TP63 and drugs. CONCLUSIONS: A good prognosis nomogram was constructed for CSCC. We also have a better understanding of the underlying molecular mechanisms of occurrence and development of CSCC and predicted potential therapeutic drugs, providing a theoretical basis for the treatment of CSCC.

Prognostic Risk Model and Tumor Immune Environment Modulation of m5C-Related LncRNAs in Pancreatic Ductal Adenocarcinoma.

RNA methylation modification is a key process in epigenetics that regulates posttranscriptional gene expression. With advances in next-generation sequencing technology, 5-methylcytosine (m5C) modification has also been found in multiple RNAs. Long non-coding RNAs (lncRNAs) were proved to have a key role in cancer progression and closely related to the tumor immune microenvironment. Thus, based on the PDAC patients' clinical information and genetic transcriptome data from the TCGA database, we performed a detailed bioinformatic analysis to establish a m5C-related lncRNA prognostic risk model for PDAC patients and discovered the relationship between the risk model and PDAC immune microenvironment. Pearson correlation coefficient analysis was applied to conduct a m5C regulatory gene and m5C-related lncRNA co-expression network. Expression of m5C-related lncRNAs screened by univariate regression analysis with prognostic value showed a significant difference between pancreatic cancer and normal tissues. The least absolute shrinkage and selection operator (LASSO) Cox regression method was applied to determine an 8-m5C-related lncRNA prognostic risk model. We used principal component analysis to indicate that the risk model could distinguish all the samples clearly. The clinical nomogram also accurately predicted 1-, 1.5-, 2-, and 3-year survival time among PDAC patients. Additionally, this risk model was validated in the entire group and sub-test groups using KM analysis and ROC analysis. Combined with the clinical characteristics, the risk score was found to be an independent factor for predicting the survival of PDAC patients. Furthermore, the association between the risk model and tumor immune microenvironment was evaluated via the ESTIMATE R package and CIBERSORT method. Consequently, the results indicated that immune cells were associated with m5C-related lncRNA risk model scores and had different distribution in the high- and low-risk groups. Based on all these analyses, the m5C-related lncRNA risk model could be a reliable prognostic tool and therapeutic target for PDAC patients.

RACK1 overexpression associates with pancreatic ductal adenocarcinoma growth and poor prognosis.

OBJECTIVES: The receptor for activated protein kinase C (RACK1) is a scaffold protein involved in multiple intracellular signal pathways. Previous studies have shown that RACK1 is associated with the progression of multiple cancer types, including hepatocellular carcinoma and gastric cancer. However, the role of RACK1 in human pancreatic ductal adenocarcinoma (PDAC) remains unclear. METHODS: In this study, the expression of RACK1 was evaluated by Western blot analysis in 8 paired fresh PDAC tissues and immunohistochemistry on 179 paraffin-embedded slices. Then, we used Fisher exact test to analyze the correlation between RACK1 expression and clinicopathological characteristics. Starvation and re-feeding assay was used to assess cell cycle. Western blot, CCK8, flow cytometry assays, and colony formation analyses demonstrated that RACK1 played an essential role in PDAC development. Annexin-V/PI apoptotic assay and western blot showed that RACK1 was involved in regulating the apoptosis of PDAC cells. RESULTS: RACK1 was highly expressed in PDAC tissues and cell lines and was significantly associated with multiple clinicopathological factors. Univariate and multivariate analyses showed that high RACK1 expression was identified to be an independent prognostic factor for PDAC patients' survival. In vitro, serum starvation-refeeding experiment suggested that RACK1 was upregulated in proliferating PDAC cells, together with the percentage of cells at the S phase, and was correlated with the expression of Cyclin D1. Moreover, Overexpression of RACK1 facilitated the proliferation and cell cycle progression of PDAC cells, while downregulation of RACK1 induced growth impairment, G1/S cell cycle arrest and apoptosis in PDAC cells. Silencing RACK1 decreased bcl-2 expression, increased cleaved caspase3 expression level and induced the apoptosis of PDAC cells. CONCLUSIONS: Our results suggest that RACK1 could play an important role in the tumorigenesis of PDAC and serve as a potential therapeutical target in PDAC treatment.

Overexpression of DIXDC1 correlates with enhanced cell growth and poor prognosis in human pancreatic ductal adenocarcinoma.

Disheveled-axin (DIX) domain containing 1 (DIXDC1), a protein containing a coiled-coil domain and a DIX domain, is involved in the progression of multiple cancers. However, the role of DIXDC1 in human pancreatic ductal adenocarcinoma (PDAC) remains unclear. In this study, we investigated the role and prognostic value of DIXDC1 in the development of human PDAC. Western blot analysis revealed that DIXDC1 was highly expressed in PDAC tissues and cell lines. Immunohistochemistry on 165 paraffin-embedded sections showed that high expression of DIXDC1 was significantly correlated with tumor size (P = .002), histological differentiation (P = .001), tumor node metastasis (TNM) stage (P = .001), and the proliferation marker Ki-67 (P = .000). Importantly, Kaplan-Meier analysis revealed that high expression of DIXDC1 was obviously correlated with worsened overall survival (P < .001). In vitro, using serum starvation-refeeding experiments, our results suggested that DIXDC1 was up-regulated in proliferating PDAC cells, together with the percentage of cells at the S phase, and was correlated with the expression of cyclin D1. In addition, depletion of DIXDC1 decreased PCNA and cyclin D1 levels. Accordingly, CCK-8, colony formation, and flow cytometry analyses revealed that knocking down DIXDC1 induced growth impairment and G1/S cell cycle arrest in PDAC cells, while overexpression of DIXDC1 led to accelerated cell proliferation and cell cycle progression. On the basis of these results, we propose that DIXDC1 could play an important role in the tumorigenesis of PDAC and serve as a potential therapeutical target to prevent PDAC progression.

ß2-adrenergic receptor signaling promotes pancreatic ductal adenocarcinoma (PDAC) progression through facilitating PCBP2-dependent c-myc expression.

The ß2-adrenergic receptor (ß2-AR) plays a crucial role in pancreatic ductal adenocarcinoma (PDAC) progression. In this report, we identified poly(rC)-binding protein 2 (PCBP2) as a novel binding partner for ß2-AR using immunoprecipitation-mass spectrometry (IP-MS) approach. The association between ß2-AR and PCBP2 was verified using reciprocal immunoprecipitation. Importantly, we found significant interaction and co-localization of the two proteins in the presence of ß2-AR agonist in Panc-1 and Bxpc3 PDAC cells. ß2-AR-induced recruitment of PCBP2 led to augmented protein level of c-myc in PDAC cells, likely as a result of enhanced internal ribosome entry segment (IRES)-mediated translation of c-myc. The activation of ß2-AR accelerated cell proliferation and colony formation, while knockdown of PCBP2 or c-myc restrained the effect. Furthermore, overexpression of PCBP2 was observed in human PDAC cell lines and tissue specimens compared to the normal pancreatic ductal epithelial cells and the non-cancerous tissues respectively. Overexpression of ß2-AR and PCBP2 was associated with advanced tumor stage and significantly worsened prognosis in patients with PDAC. Our results elucidate a new molecular mechanism by which ß2-AR signaling facilitates PDAC progression through triggering PCBP2-dependent c-myc expression.

NF45 overexpression is associated with poor prognosis and enhanced cell proliferation of pancreatic ductal adenocarcinoma.

NF45, also referred to as nuclear factor of activated T cells, has been reported to promote the progression of multiple cancer types. However, the expression and physiological significance of NF45 in pancreatic ductal adenocarcinoma (PDAC) remain largely elusive. In this study, we investigated the clinical relevance and potential role of NF45 expression in PDAC development. Western blot analysis revealed that NF45 was remarkably upregulated in PDAC tissues, compared with the adjacent non-tumorous ones. In addition, the expression of NF45 in 122 patients with PDAC was evaluated using immunohistochemistry. In this way, we found that NF45 was abundantly expressed in PDAC tissues, and the expression of NF45 was correlated with tumor size (p = 0.007), histological differentiation (p = 0.033), and TNM stage (p = 0.001). Importantly, patients with low levels of NF45 expression exhibited better postoperative prognosis as compared with those with high NF45 expression. Furthermore, using PDAC cell cultures, we found that interference of NF45 expression using siRNA oligos suppressed PDAC cell proliferation and retarded cell cycle progression. Moreover, depletion of NF45 impaired the levels of cellular cyclin E and proliferating cell nuclear antigen (PCNA). Conversely, overexpression of NF45 facilitated the cell growth and accelerated cell cycle progression. Our results establish NF45 as an important indicator of PDAC prognosis with potential utility as a therapeutic target in this lethal disease.