IMT030122, A novel engineered EpCAM/CD3/4-1BB tri-specific antibody, enhances T-cell recruitment and demonstrates anti-tumor activity in mouse models of colorectal cancer.

Colorectal cancer is a major global health burden, with limited efficacy of traditional treatment modalities in improving survival rates. However, recently advances in immunotherapy has improved treatment outcomes for patients with this cancer. To address the continuing need for improved treatment efficacy, this study introduced a novel tri-specific antibody, IMT030122, that targets EpCAM, 4-1BB, and CD3. We evaluated the pharmacological efficacy and mechanism of action of IMT030122 in vitro and in vivo. In in vitro studies, IMT030122 exhibited differential binding to antigens and cells expressing EpCAM, 4-1BB, and CD3. Moreover, IMT030122 relied on EpCAM-targeted activation of intracellular CD3 and 4-1BB signaling and mediated T cell cytotoxicity specific to HCT116 colorectal cancer cells. In vivo, IMT030122 demonstrated potent anti-tumor activity, significantly inhibiting the growth of colon cancer HCT116 and MC38-hEpCAM subcutaneous grafts. Further pharmacological analysis revealed that IMT030122 recruited lymphocytes from peripheral blood into colorectal cancer tissue and exerted durable anti-tumor activity, predominantly by promoting the activation, proliferation, and differentiation of CD8T cells. Notably, IMT030122 still exhibited anti-tumor efficacy even in the presence of significantly depleted lymphocytes in colorectal cancer tissue. The potent pharmacological activity and anti-tumor effects of IMT030122 suggest it may enhance treatment efficacy and substantially extend the survival of patients with colorectal cancer in the future.

Comparison of endovascular interventional embolization and microsurgical clipping for ruptured cerebral aneurysms: impact on patient outcomes.

OBJECTIVE: To compare the therapeutic efficacy of endovascular interventional embolization and microsurgical clipping in patients with ruptured cerebral aneurysms and investigate their subsequent influence on inflammatory indices, neurological function, prognosis, and recovery. METHODS: The two groups were compared in terms of surgery duration, hospital stay, Hunt-Hess classification, and inflammatory indices before and after the surgery, as well as National Institutes of Health Stroke Scale (NIHSS), Baethel Index (BI), and one-year prognosis of patients affected. RESULTS: The surgery duration and hospital stay of the intervention group were (116.27 ± 12.32) min and (19.82 ± 2.26) d, respectively, and those of the clipping group was (173.87 ± 10.39) min and (24.11 ± 2.33) d, respectively (both p < 0.05). Neither the intervention nor the microscopic approach had a significant impact on the severity of the patients' conditions in terms of Hunt-Hess classification (p > 0.05). In the intervention group, CRP was changed to (5.31 ± 1.22) mg/L and PCT decreased to (1.17 ± 0.39) µg/L after the surgery, while the corresponding values in clipping group were (9.78 ± 2.35) mg/L and (2.75 ± 0.81) µg/L (p > 0.05). After surgery, both groups' NIHSS scores declined dramatically, with the intervention group scoring lower than the microscopy group (6.81 ± 1.22 vs 8.72 ± 1.27) (p < 0.05). CONCLUSION: The findings of this study support the potential advantages of endovascular interventional embolization (coiling) over microsurgical clipping for the management of ruptured cerebral aneurysms. These advantages include shorter surgical duration, reduced hospital stay, lower inflammatory response, improved neurological and functional outcomes, and better long-term prognosis.

Association of ACP5 with the tumor immune microenvironment and its role in cell proliferation and metastasis in pancreatic cancer.

BACKGROUND: Tartrate-resistant acid phosphatase (ACP5) has been implicated in the progression of most malignant tumors, but its role in pancreatic cancer (PC) remained unclear. Thus, this study aimed to elucidate the role and function of ACP5 in PC progression. METHODS: The expression of ACP5 in PC samples was assessed via R programming, TNM plot, and Gene Expression Profiling Interactive Analysis (GEPIA). Western blotting and immunohistochemistry (IHC) were performed to detect ACP5 expression in cells and tissues. The correlation between ACP5 and methylation was analyzed using the University of ALabama at Birmingham Cancer data analysis Portal (UALCAN) and cBio Cancer Genomics Portal (cBioPortal). The Database for Annotation, Visualization and Integrated Discovery (DAVID) and Gene Set Enrichment Analysis (GSEA) were used for the enrichment of ACP5 in PC. Subsequently, Cell Counting Kit-8 (CCK8), clonogenic, and wound healing assays were used to investigate the role of ACP5 in PC. Finally, Tumor Immune Estimation Resource (TIMER) and R programming was utilized in evaluating the association between ACP5 and immune cell infiltration in PC. RESULTS: The analyses confirmed that ACP5 was highly expressed in PC samples. According to UALCAN and cBioPortal analysis, ACP5 expression, and methylation levels were negatively correlated in PC. The enrichment analysis also revealed that ACP5 was enriched in the proliferation and migration pathways. Meanwhile, ACP5 knockout reduced PC cell proliferation and migration and impaired the cells' independent viability. This gene also positively correlated with immune cell infiltration in PC, particularly regulatory T cells (Tregs). CONCLUSION: ACP5 is crucial for proliferation, migration, and immune cell infiltration in PC. Therefore, ACP5 may be a valuable target for future PC treatment.

RBM12 regulates the progression of hepatocellular cancer via miR-497-5p/CPNE1 Axis.

BACKGROUND: Hepatocellular Carcinoma (HCC), also called hepatocellular cancer, has emerged as a highly prevalent malignancy globally. By binding to specific RNA via one or more spherical RNA Domains (RBDs) or RNA Motifs (RBMs), RNA Binding Proteins (RBPs) can affect RNA modification, splicing, localization, translation, and stability. METHODS: This paper builds on previous research by further investigating the impact of RBM12 on LC progression. In order to determine the effect of RBM12 expression on the prognosis of patients with hepatocellular cancer, we first investigated its expression in liver cancer cells (LCC) and tissues. The effect of RBM12 on the malignant biological behavior of LCC was subsequently detected using cytological experiments. To explore the upstream mechanism affecting RBM12, we predicted the miRNA targeting RBM12. According to the database, miR-497-5p was the best candidate gene. The double Luciferase reporter gene experiment was executed to validate the bounding of miR-497-5p with RBM12. RESULTS: According to the cytological experiments, a high RBM12 expression promoted the propagation, migration, and invasion of LCC and impeded liver cancer cell apoptosis. By secreting TGF-ß1, RBM12 could induce the EMT process. The miR-497-5p expression is suppressed in hepatocellular cancer. As shown by the CCK8, plate cloning, Transwell, EDU, and other experiments, miR-497-5p suppressed RBM12 expression and tumor growth. The double Luciferase reporter gene system was utilized to verify the combination of miR-497-5p and RBM12. The CPNE1 is a downstream gene regulated by RBM12. A high CPNE1 expression was exhibited in LCC and tissues. The CPNE1 is essential in the process where RBM12 promotes the incidence and progression of liver cancer. CONCLUSIONS: By elucidating the exact molecular mechanism through which RBM12 promotes the initiation and progression of LC, thus, the current investigation provides some reference for the clinical management of LC.

A Retrospective Trail Investigating Temozolomide Neoadjuvant Chemotherapy Combined with Radiotherapy in Low-Grade Pituitary Tumors.

Objective: To study and analyze the clinical application of temozolomide (TMZ) combined with radiotherapy in the treatment of low-grade pituitary tumors. Methods: A retrospective trail was conducted among 67 patients with low-grade pituitary tumors who were treated in our hospital from March 2018 to June 2020. According to different treatment methods, they were assigned into a combined group (37 cases, temozolomide capsules and radiotherapy) and a control group (30 cases, radiotherapy). The changes of serum prolactin (PRL), insulin-like growth factor-1 (IGF-1), GH levels, thyroid-stimulating hormone (TSH), serum free thyroxine (FT4), and adrenocorticotropic hormone (ACTH) were compared. Results: The chi-square test reports a significantly higher total effective rate in the combined group vs. control group (91.89% vs. 70.00%). Significant reductions in serum levels of PRL, IGF-1, and GH were observed in both groups after treatment, whereas the combined group treated with radiotherapy and TMZ resulted in significantly lower levels compared with the control group (p < 0.05). After treatment, TSH decreased, and FT4 and ACTH increased in both groups, and the treatment with radiotherapy and TMZ in the combined group led to a significantly greater amplitude of variation (p < 0.05). Conclusion: The combination of temozolomide and radiotherapy might be a promising technique for the treatment of pituitary tumors, thereby meriting promotion.

The expression and prognostic value of REXO4 in hepatocellular carcinoma.

BACKGROUND: Globally, one of the dominant causes of cancer-related mortality is liver cancer. Identification of potent biomarkers for initial stage diagnosis and prognosis is a key factor to ensure efficient therapy and reduce the mortality rate in liver cancer patients. REXO4 has been reported in neuropathic pain and familial isolated pituitary adenoma (FIPA), however, its relationship with liver cancer is still elusive. METHODS: In an attempt to scrutinize the expression of REXO4 in liver cancer, the Oncomine, and TCGA databases were analyzed. Real-time PCR was employed to identify the REXO4 mRNA levels in 45 patient tissue samples and western blot was used to detect the REXO4 protein levels in hepatocellular carcinoma (HCC) cells. Evaluation of the prognostic value of REXO4 in liver cancer was made using Univariate and multivariate Cox proportional hazards regression models and Kaplan-Meier plots. Tumor-associated biological processes related to REXO4 were revealed by LinkedOmics. The correlation of REXO4 and immune infiltration was evaluated using the TIMER database. RESULTS: REXO4 is significantly up-regulated in liver cancer in comparison with the nontumor controls. Moreover, poor progression-free survival and overall survival is a frequent outcome related to high expression of REXO4, highlighting it as a risk factor in case of liver cancer. Additionally, the plausible role of REXO4 in tumor-immune interactions was also investigated and it was revealed that the immune infiltration and immune activation of liver cancer might have an association with REXO4. CONCLUSIONS: REXO4 has a significant expression in liver cancer and could potentially become a predictor for the prognosis of liver cancers and a biomarker for targeted therapeutic regimens. Significant overexpression of REXO4 in HCC was revealed by the bioinformatics analysis, with REXO4 overexpression being related to a negative outcome in HCC patients, in addition, REXO4 might be associated with the immune infiltration in liver cancer. Such a vital understanding of the functioning of REXO4 may furnish a foundation for new targeted drug therapy as well as a new direction for additional investigation into the underlying mechanisms of REXO4 carcinogenesis in liver cancer.

Increased RBM12 expression predicts poor prognosis in hepatocellular carcinoma based on bioinformatics.

BACKGROUND: Liver cancer is one of the major causes of cancer death worldwide, incurring high mortality and a significant financial burden on the healthcare system. Abnormal RNA-binding proteins (RBPs) have been found to be associated with carcinogenesis in liver cancer. Among these, RNA-binding motif protein 12 (RBM12) is located in the exon junction complex (EJC). The goal of this study was to determine what role RBM12 plays in hepatocellular carcinoma (HCC) from a biological perspective. METHODS: The Tumor IMmune Estimation Resource (TIMER) and the Human Protein Atlas database were used to examine the expression level of RBM12, with the UALCAN and Gene Expression Profiling Interactive Analysis (GEPIA) databases used to investigate the relationship between RBM12 and other noteworthy clinical features. RBM12 expression in cells and tissue samples was detected using quantitative real-time polymerase chain reaction (qRT-PCR) and western blot analysis. The functional network of RBM12 in HCC was studied using LinkedOmics and gene set enrichment analysis (GSEA), while the effects of hypomethylation on the expression of RBM12 in HCC was investigated using methylation databases. Finally, we used TIMER and CIBERSORT to investigate the relationship between immune cell infiltration and RBM12 in HCC. RESULTS: RBM12 is highly elevated in HCC tissues and cells, and it can be used to predict the prognosis of patients with HCC. Analysis with LinkedOmics and GSEA revealed RBM12 to be closely linked with tumor progression. Furthermore, hypomethylation was linked to an increase in RBM12 expression in HCC, while RBM12 was associated with immune cell infiltration. CONCLUSIONS: This study shows that an elevated level of RBM12 in HCC indicates a poor patient prognosis. Furthermore, according to LinkedOmics and GSEA analyses, RBM12 was implicated in the most important hallmark pathways. Our findings suggest that RBM12 overexpression is caused by hypomethylation and that RBM12 plays a key role in liver cancer tumor immunity.

Supplementation With Dexmedetomidine for Transsphenoidal Resection of Pituitary Adenoma: A Meta-Analysis of Randomized Controlled Trials.

INTRODUCTION: The effect of dexmedetomidine supplementation on hemodynamic stability for transsphenoidal resection of pituitary adenoma remains controversial. We conduct a systematic review and meta-analysis to explore the influence of dexmedetomidine supplementation on hemodynamic stability for transsphenoidal resection of pituitary adenoma. METHODS: We have searched PubMed, EMbase, Web of science, EBSCO, and Cochrane library databases through August 2020 for randomized controlled trials assessing the effect of dexmedetomidine supplementation on transsphenoidal resection of pituitary adenoma. RESULTS: Four randomized controlled trials involving 160 patients were included in the meta-analysis. Overall, compared with the control group for transsphenoidal resection of pituitary adenoma, dexmedetomidine supplementation resulted in significantly reduced mean arterial pressure at 30 minutes [mean difference (MD), -26.62; 95% confidence interval (CI), -36.71 to -16.53; P < 0.00001], heart rate at 30 minutes (MD, -16.50; 95% CI, -32.48 to -0.53; P = 0.04), blood loss (MD, -112.57; 95% CI, -165.12 to -60.01; P < 0.0001), and fentanyl (MD, -154.13; 95% CI, -303.97 to -4.29; P = 0.04), but demonstrated similar incidence of nausea and vomiting (odds ratio, 0.37; 95% CI, 0.13-1.03; P = 0.06), and hypotension (odds ratio, 2.11; 95% CI, 0.49-9.22; P = 0.32). CONCLUSIONS: Dexmedetomidine supplementation was effective in improving hemodynamic stability for transsphenoidal resection of pituitary adenoma.

Low expression of AQP9 and its value in hepatocellular carcinoma.

BACKGROUND: The mortality rate for liver cancer is high worldwide. The etiology of liver cancer has altered with the high incidence rate of non-alcoholic fatty liver disease (NAFLD) although effective vaccination strategies have been developed. Therefore, it is important to discover new biomarkers for diagnosis and prognosis. Aquaporin 9 (AQP9) has been reported in some cancers, especially in liver cancer, although its role in this malignancy remains to be clarified. In this study, we conducted a bioinformatics analysis to clarify the function of AQP9 in liver cancer. METHODS: Immunohistochemistry, real-time qPCR, western blot analysis were applied to detect AQP9 expression in tissue samples or cells. Online databases were used to analyze the correlation of AQP9 expression and clinical factors. LinkedOmics and gene set enrichment analysis (GSEA) were used to analyze the functional network of AQP9 in hepatocellular carcinoma (HCC). Four authoritative databases were used to predict the candidate microRNAs that bind to AQP9. Finally, we used the Tumor Immune Estimation Resource (TIMER) to assess the correlation of AQP9 and immune cell infiltration in HCC. RESULTS: All analysis were revealed AQP9 is significantly decreased in HCC tissues and cells. AQP9 was negatively correlated with different tumor stage, grade, and weight, as well as lymph node metastasis, sex, and histological subtypes. AQP9 can be used to predict the prognosis of HCC patients. GSEA revealed that AQP9 was significantly involved in most significant hallmark pathways. LinkedOmics was used to analyze the relationship of AQP9 with Gene Ontology and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways. Mechanistically, mir-23a-3p and mir-330-3p may downregulate AQP9 expression in HCC. AQP9 was found to be specifically correlated with immune cell infiltration and play a major role in the liver cancer microenvironment. CONCLUSIONS: In this study, we found that AQP9 was significantly decreased in HCC, with low AQP9 levels indicating a poor outcome. GSEA analysis and LinkedOmics revealed that AQP9 was significantly involved in the most significant hallmarks pathways. Mir-23a-3p and mir-330-3p may inhibit AQP9 expression in HCC. Our results also suggest that AQP9 is important in tumor immunity in the liver cancer.

A super-enhancer controls TGF- ß signaling in pancreatic cancer through downregulation of TGFBR2.

Pancreatic cancer is one of the most lethal malignant tumors due to a late diagnosis and highly invasion and metastasis. Transforming growth factor-ß (TGF-ß) signaling plays a vital role in the progression of pancreatic cancer. The delicate activity of TGF-ß signaling is particular important for the development of aggression and metastasis which must be fine-tuned. Here, we investigated the role of super-enhancers in regulating the expression of TGF-ß signaling pathway in pancreatic cancer. TGFBR2 owns the modification of H3K27Ac around the gene in pancreatic cancer cells. Inhibition of BRD4 by JQ1 robustly blocked the expression of TGFBR2 in a dose dependent manner. We successfully mapped a super-enhancer in TGFBR2 by sgRNA. Deletion of the super-enhancer in TGFBR2 (sgTGFBR2-SEΔ) significantly reduced the expression of TGFBR2 in pancreatic cancer cells. TGF-ß-induced p-SMAD2/3 was greatly impaired in TGFBR2 super-enhancer deleted cells. Both migration and EMT induced by TGF-ß in pancreatic cancer cells were impaired after deleting the super-enhancer of TGFBR2. Our data suggest a novel molecular mechanism by which a super-enhancer regulates TGFBR2, affecting the activity of TGF-ß as well as its function in pancreatic cancer progression.

A super-enhancer maintains homeostatic expression of Regnase-1.

Regnase-1 is not only a key component in maintaining intracellular homeostasis but also a critical negative regulator in preventing autoimmune diseases and cancer development. To keep homeostatic state, Regnase-1 has to be maintained at a desired level in multiple cell types. However, the molecular mechanism of keeping a certain transcriptional level of Reganase-1 is largely unknown. In this study, we found a super-enhancer (Reg-1-SE) around Regnase-1 gene is able to control the homeostatic expression of Regnase-1. Functional inhibition of super-enhancers through BRD4 inhibitors or genetic silence of key components such as BRD4 and MED1 significantly downregulates Regnase-1 expression at multiple cell types. Consistently, treatment of JQ1 or I-BET-762 dramatically decreases the protein level of Regnase-1. By analyzing Regnase-1 gene, the distribution of H3K27Ac is highly enriched at a 8 kb DNA region around the second intron. Several DNA elements at the second intron are highly conserved between different species. Deletion of the second intron by CRISPR-Cas9 technology significantly reduces the expression of Regnase-1. JQ1 or I-BET-762 failed to further downregulate the expression of Regnase-1 in cells without the second intron. Our result reveals a novel molecular mechanism by which a super-enhancer around the second intron regulates the expression of Regnase-1, and in turn maintains a desired level of Regnase-1.