Screening and optimization of a water-soluble near-infrared fluorescent probe for drug-induced liver injury monitoring.

Peroxynitrite (ONOO-) is a potential biomarker of drug-induced liver injury (DILI) and is involved in the process of DILI. Therefore, developing a reliable detection method for ONOO- will greatly contribute to ensuring drug safety and improving treatment efficiency. Here, based on the previous work, two kinds of NIR fluorescence probes PN and SPN were developed with phenyl-hydrazine as the ONOO- recognition group, which based on two fluorophores RN and SRN that are stable to ONOO-. A sensitive NIR probe SPN with good water solubility, low detection limit and good biocompatibility was selected through in vitro spectral property screening. Further experimental results show that there is a good linear relationship between the response intensity of probe SPN to ONOO- and the concentration of ONOO-, and the detection limit can reach 19.7 nM. At the cellular level, probe SPN can achieve a good and specific response to endogenous and exogenous ONOO-. Also, the probe SPN can be used for imaging and detection of DILI in zebrafish level and small animal level, indicating that probe SPN can be used as a powerful tool for diagnosis of DILI and efficacy evaluation of therapeutic drugs.

Expression of pyroptosis-related genes are correlated with immune microenvironment and predict prognosis in ESCA.

OBJECTIVES: Pyroptosis-related genes (PRGs) are abnormally expressed in a variety of gastrointestinal tumors, this study aimed to investigate the role of pyroptosis genes in assessing the prognosis of esophageal cancer (ESCA). METHODS: Through consensus clustering, we identified two subtypes associated with PRGs. After Lasso regression and multivariate Cox regression analysis, a polygenic signature based on six prognostic PRGS was constructed. Afterwards, we combined the risk score with clinical predictors to construct and validate a PRGs-associated ESCA prognostic model. RESULTS: Through analysis, we Successfully constructed and validated a PRGs-associated ESCA prognostic model that predicts ESCA survival and correlates with the tumor immune microenvironment. CONCLUSION: Based on PRGs features, we established a new ESCA hierarchical model. This model has important clinical implications for ESCA patients, both in terms of assessing prognosis and in terms of targeted and immunotherapy.

Comprehensive Curative Effect of Targeting PD-1 or Traditional Single-Agent Chemotherapy in Second-Line Therapy for Terminal or Metastatic Esophageal Cancer: A Systematic Review and Meta-Analysis.

The number of programmed cell death protein 1 (PD-1) inhibitors is gradually increasing; this study aimed to comprehensively and systematically evaluate the impact of PD-1 inhibitors as second-line therapy for terminal or metastatic esophageal cancer (EC) on patient survival and the occurrence of adverse events. Suitable randomized controlled trials (RCTs) were retrieved from PubMed, Web of Science, Embase, and Cochrane Library databases. Moreover, we searched for conference abstracts from the American Society of Clinical Oncology (ASCO) and the European Society for Medical Oncology (ESMO) to compare the comprehensive curative effects of PD-1 inhibitors or single-agent therapy in terminal or metastatic EC. The primary outcome indicators were overall survival (OS), progression-free survival (PFS), objective response rate (ORR), and disease control rate (DCR). Treatment-related adverse events (TRAEs) were the secondary outcome indicators. We compared the previously mentioned indicators of the two treatment modalities using Stata software (version 12.0). We compared the long-term survival rates of both treatment groups and analyzed the possible factors affecting OS. We selected five RCTs with 2197 patients as study subjects. Compared with conventional single-agent chemotherapy, PD-1 inhibitors greatly improved the patients' OS (HR = 0.77, 95% CI 0.70-0.85, P < 0.001), but PFS (HR = 0.93, 95% CI 0.77-1.12, P=0.431) and DCR (RR = 0.93, 95% CI 0.71-1.22, P=0.609) were not greatly improved. Moreover, PD-1 inhibitors improved ORR (RR = 1.83, 95% CI 1.16-2.89, P=0.009) and decreased TRAEs (RR = 0.76, 95% CI 0.61-0.95, P < 0.001) and serious TRAEs (RR = 0.40, 95% CI 0.32-0.49, P < 0.001). Further analysis demonstrated that OS was affected by age, sex, region, smoking history, and the number of organ and lymph node metastases. Compared with the traditional single chemotherapy drugs, PD-1 inhibitors can achieve higher OS and ORR, fewer and more serious TRAEs, and better efficacy and safety for second-line therapy of terminal or metastatic EC.

Preoperative White Blood Cell-Related Indicators Can Predict the Prognosis of Patients with Transurethral Resection of Bladder Cancer.

Introduction: Numerous studies, including bladder cancer (BLCA), have confirmed the relationship between conventional systemic inflammatory biomarkers and the prognosis of tumors. Leukocytes, as the most common factor in inflammatory indicators, have been reported to predict prognosis in other tumors. However, we have not seen this research in BLCA. Therefore, we aim to find new blood markers to predict the prognosis of patients with transurethral resection of bladder tumor (TURBT). Methods: Two cohorts from the two different hospitals were used for the specific study. The best cutoff values of leukocytes-related indicators were determined according to the ROC curve. Univariate and multivariate Cox regression analysis were used to explore the impact of indicators and clinical features on prognosis for patients with TURBT. The KM curve was used to show the impact of indicators on the prognosis. According to the consequence of multivariate method, a risk model was established to evaluate the prognosis of patients with bladder cancer. Results: The white blood cell-to-lymphocyte ratio (WLR), the white blood cell-to-hemoglobin ratio (WHR), the white blood cell-to-neutrophil ratio (WNR), the white blood cell-to-monocyte ratio (WMR) and the white blood cell-to-erythrocyte ratio (WRR) are related to the prognosis of BLCA. The new risk model consisted of WHR, WMR and platelet-to-lymphocyte ratio (PLR), and patients with TURBT in the high-risk group had a worse prognosis. Conclusions: Leukocyte-related preoperative indicators could predict the prognosis of the patients with TURBT and provided some guidance for clinical workers.

Low expression of PRDM5 predicts poor prognosis of esophageal squamous cell carcinoma.

BACKGROUND: The role of the PRDM5 in esophageal squamous cell carcinoma (ESCC) has not been revealed. This study investigated the relationship between PRDM5 expression and survival outcome in esophageal squamous cell carcinoma and explored the mechanism in tumor development. METHODS: In present study, expression of PRDM5 mRNA in esophageal squamous cell carcinoma patients was conducted using the Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) database. The expression of PRDM5 was assessed by immunohistochemical staining. Kaplan-Meier curve and Cox regression analysis was performed to analyze the survival outcome and independent predictive factors. qRT-PCR and Methylation-specific PCR were performed to identify the mRNA level of PRDM5 and Methylation rate. Cibersort algorithm to analyze the relationship between PRDM5 expression and immune cell invasion. Western-blot was performed to confirm the expression of esophageal tumor tissues and adjacent tissues. RESULTS: The TCGA database and GEO database show that PRDM5 mRNA level in esophageal squamous cell carcinoma adjacent tissues was higher than that of cancer tissues, and ESCC patients with high expression of PRDM5 mRNA had better overall survival. Tissue microarray showed that the protein level of PRDM5 in the adjacent tissues of patients with ESCC was higher than that in cancer tissues, and the expression level of PRDM5 was significantly correlated with the grade of clinicopathological characteristics (P < 0.001). Patients with high expression of PRDM5 displayed a better OS and DFS. Cox regression analysis showed that PRDM5 was an independent risk factor and prognostic factor for ESCC patients (HR: 2.626, 95%CI: 1.824-3.781; P < 0.001). The protein level of PRDM5 matched with the transcriptional level, whereas the DNA methylation affected the transcriptional level. Cibersort showed that T cells CD4 memory resting, mast cells resting, eosinophils, M2 macrophages and mast cells activated were significantly positively correlated with PRDM5 expression (P < 0.05), while regulatory T cells, monocytes and dendritic cells negatively correlated with PRDM5 expression (P < 0.05). CONCLUSION: PRDM5 can be used as a biomarker to predict the survival of ESCC patients. Furthermore, PRDM5 expression in ESCC cells may affect WNT/ß-catenin signaling pathways, thus further affect the ESCC cell proliferation, migration, and invasion capacity.

Clinical Significance of Nutrition and Inflammation in Esophageal Cancer Patients with Surgery: A Meta-Analysis.

Many studies have reported that the geriatric nutritional risk index (GNRI) and C-reactive protein to albumin ratio (CAR) may be associated with prognosis of esophageal cancer (EC); however, the results are inconsistent. Therefore, we performed a meta-analysis to evaluate the effect of preoperative GNRI and CAR on the prognosis of EC. PubMed, Embase, Cochrane Library, and Web of Science databases were searched. Pooled hazard ratios (HRs) and 95% confidence intervals (CIs) were used to analyze the relationship between GNRI/CAR and prognosis. Publication bias was estimated using Begg's funnel plot asymmetry test and Egger's test. A total of 21 studies comprising 5,018 patients were included in the meta-analysis. A decreased GNRI was significantly associated with poorer overall survival (OS) (HR = 1.808, 95% CI: 1.489-2.196, P < 0.001) and cancer-specific survival (CSS) (HR = 1.769, 95% CI: 1.193-2.624, P = 0.005), and an increased CAR was significantly associated with lower OS (HR = 2.179, 95% CI: 1.587-2.992, P < 0.001), CSS (HR = 1.733, 95% CI: 1.333-2.253, P < 0.001), and recurrence-free survival (HR = 2.178, 95% CI: 1.328-3.573, P = 0.002). Thus, preoperative GNRI and CAR may be noninvasive and powerful tools for predicting survival outcomes in patients with EC.

Computed tomography-based radiomics analysis to predict lymphovascular invasion in esophageal squamous cell carcinoma.

OBJECTIVE: The present study explored the value of preoperative CT radiomics in predicting lymphovascular invasion (LVI) in esophageal squamous cell carcinoma (ESCC). METHODS: A retrospective analysis of 294 pathologically confirmed ESCC patients undergoing surgical resection and their preoperative chest-enhanced CT arterial images were used to delineate the target area of the lesion. All patients were randomly divided into a training cohort and a validation cohort at a ratio of 7:3. Radiomics features were extracted from single-slice, three-slice, and full-volume regions of interest (ROIs). The least absolute shrinkage and selection operator (LASSO) regression method was applied to select valuable radiomics features. Radiomics models were constructed using logistic regression method and were validated using leave group out cross-validation (LGOCV) method. The performance of the three models was evaluated using the receiver characteristic curve (ROC) and decision curve analysis (DCA). RESULTS: A total of 1218 radiomics features were separately extracted from single-slice ROIs, three-slice ROIs, and full-volume ROIs, and 16, 13 and 18 features, respectively, were retained after optimization and screening to construct a radiomics prediction model. The results showed that the AUC of the full-volume model was higher than that of the single-slice and three-slice models. According to LGOCV, the full-volume model showed the highest mean AUC for the training cohort and the validation cohort. CONCLUSION: The full-volume radiomics model has the best predictive performance and thus can be used as an auxiliary method for clinical treatment decision making. ADVANCES IN KNOWLEDGE: LVI is considered to be an important initial step for tumor dissemination. CT radiomics features correlate with LVI in ESCC and can be used as potential biomarkers for predicting LVI in ESCC.

Pyk2 level is a novel prognostic marker for patients with esophageal squamous cell carcinoma after radical surgery.

Esophageal squamous cell carcinoma (ESCC) is one of the most common malignant tumors in East Asia. Surgical resection is currently the typical treatment. However, due to the highly invasive and metastatic characteristic of the disease, the mortality rate is still high. A search for potential prognostic biomarkers and therapeutic targets is very necessary. Here, we studied the expression of proline-rich tyrosine kinase 2 (Pyk2), a non-receptor tyrosine protein kinase, in ESCC and its influence on prognosis. A total of 112 cases of ESCC and paired adjacent normal tissues (NT) were organized in tissue microarray (TMA) from the Nantong First People's Hospital. Our analysis of TMA revealed that Pyk2 levels were higher in ESCC than in paired adjacent NT by immunohistochemistry (p<0.001). Western blot and real-time quantitative PCR analysis (p=0.0359) also reached similar conclusions. To further explore the significance of Pyk2 in ESCC, another set of tissue microarrays was collected from the Affiliated Hospital of Nantong University, which includes 241 consecutive patients undergoing radical surgery for ESCC, to perform IHC scores. We demonstrated that the expression level of Pyk2 was positively correlated with N stage (node negative versus node positive, p=0.02) and clinical stage (I + II versus III + IV, p=0.042). Univariate and multivariate analyses suggested that high Pyk2 expression was an independent prognostic factor for overall survival with ESCC. Cell function studies found that Pyk2 promoted tumor proliferation and migration and reduced apoptosis. Pyk2 knockdown enhanced the sensitivity to cisplatin in ESCC cells. Western blot analysis confirmed that Pyk2 may promote tumor progression by activating the Akt signaling pathway.

Development of novel amino-quinoline-5,8-dione derivatives as NAD(P)H:quinone oxidoreductase 1 (NQO1) inhibitors with potent antiproliferative activities.

Fourteen novel amino-quinoline-5,8-dione derivatives (6a-h and 7a-h) were designed and synthesized by coupling different alkyl- or aryl-amino fragments at the C6- or C7-position of quinoline-5,8-dione. All target compounds showed antiproliferative potency in the low micromolar range in both drug sensitive HeLaS3 and multidrug resistant KB-vin cell lines. Compounds 6h, 6d, 7a, and 7d exhibited more potent antiproliferative effects than the other compounds. Especially, compounds 6d and 7d displayed NQO1-dependent cytotoxicity and competitive NQO1 inhibitory effects in both drug sensitive HeLaS3 and multidrug resistant KB-vin cell lines. Furthermore, compounds 6h, 6d, 7a, and 7d induced a dose-dependent lethal mitochondrial dysfunction in both drug sensitive HeLaS3 and multidrug resistant KB-vin cells by increasing intracellular reactive oxygen species (ROS) levels. Notably, compound 7d selectively inhibited cancer cells, but not non-tumor liver cell proliferation in vitro, and significantly triggered HeLaS3 cell apoptosis by regulating apoptotic proteins of Bcl-2, Bax, and cleaved caspase-3 in a dose-dependent manner. Our findings suggest that these novel C6- or C7-substituted amino-quinoline-5,8-dione derivatives, such as 7d, could be further developed in the future as potent and selective antitumor agents to potentially circumvent multi-drug resistance (MDR).

A novel harmine derivative, N-(4-(hydroxycarbamoyl)benzyl)-1-(4- methoxyphenyl)-9H-pyrido[3,4-b]indole-3-carboxamide (HBC), as histone deacetylase inhibitor: in vitro antiproliferation, apoptosis induction, cell cycle arrest, and antimetastatic effects.

This study aims to design and synthesize a novel harmine derivative N-(4-(hydroxycarbamoyl) benzyl)-1-(4-methoxyphenyl)-9H-pyrido [3,4-b]indole-3-carboxamide (HBC) as histone deacetylase (HDAC) inhibitor, and evaluate its antitumor activities and anti-metastasis mechanism. HBC not only exerted significant ant-proliferation activity against five human cancer cell lines, especially for HepG2 cell with an IC50 value of 2.21 µM, which is nearly three-fold lower than SAHA (IC50 = 6.26 µM), but also showed selective HDAC1/6 inhibitory effects in vitro. However, HBC had little effect on normal hepatic cells LO2. Furthermore, HBC simultaneously increased the acetylation of histone H3, H4, and α-tubulin, induced hypochromism by electrostatical interaction with CT-DNA, triggered more significant cancer cell apoptosis and cell cycle arrest at G2/M than SAHA by inhibition of both CDK1 and cyclin B in a concentration dependent manner. In addition, scratch and invasion assay showed that HBC also dose-dependently suppressed migration and invasion capacities of highly metastatic HCC HepG2 cells through down-regulated the expression of tumor metastasis related proteins MMP-2 and MMP-9, significantly better than SAHA. Finally, HBC showed low acute toxicity to mice and significant growth inhibition of the hepatoma tumor in vivo. These results demonstrate that novel harmine-based HDAC inhibitor HBC not only exhibited selective HDAC1/6 inhibitory activity and significant in vitro and in vivo antitumor activity, but also possessed DNA binding effect, apoptosis induction, cell cycle arrest effects, and potent anti-metastasis mechanisms, which may hold great promise as therapeutic agent targeting HDAC1/6 for the intervention of human cancers.

Development of novel ß-carboline-based hydroxamate derivatives as HDAC inhibitors with antiproliferative and antimetastatic activities in human cancer cells.

A series of novel ß-carboline-based hydroxamate derivatives 12a-k were designed and synthesized, and their biological activities in a series of in vitro assays were evaluated. Several of these ß-carboline derivatives not only showed excellent HDAC1/3/6 inhibitory effects, but also displayed significant antitumor activities against five human cancer cells. The most potent compound 12f demonstrated the highest anticancer potency against cancer cell lines with IC50 values of 0.53-1.56 µM, which was considerably more potent than harmine (IC50 = 46.7-55.3 µM) and also three-to ten-fold lower than that of SAHA (IC50 = 4.48-6.26 µM). Immunoblot analysis revealed that 12f dose-dependently inhibited histone H3 and α-tubulin acetylation, confirming its HDAC inhibitory effects. Moreover, 12f significantly arrested HepG2 cells at G2/M phase through inhibiting cell cycle related protein CDK1 and cyclin B in a concentration dependent manner. Interestingly, 12f also exerted strong anti-metastasis activity by simultaneously reducing the protein level of MMP2 and MMP9 and inhibiting MAPK signaling pathway.