Arenobufagin increases the sensitivity of gastric cancer to cisplatin via alkaliptosis.

Background: Gastric cancer is the third leading cause of cancer-related death worldwide, for which several novel therapeutic strategies have been developed. Cisplatin (CDDP) mainly exerts its anti-gastric cancer effects; however, drug resistance limits its use. Thus, the development of drugs that can augment their antitumor effects is necessary. Arenobufagin (ArBu) is a novel anticancer drug, and the effects of ArBu in combination with CDDP on gastric cancer have not yet been studied. Aims: To identify a possible synergistic effect between ArBu and CDDP in gastric cancer and investigate the underlying mechanism. Methods: Cell viability, colony formation, migration, apoptosis, cell cycle, western blotting, immunofluorescence, and reverse-transcription polymerase chain reaction (RT-PCR) were analyzed in vitro. Western blotting, RT-PCR, hematoxylin and eosin (H&E) staining and blood biochemistry were carried out to examine in vivo. Results: We found that ArBu, in combination with CDDP, effectively inhibited the proliferation and migration of gastric cancer cells, promoted apoptosis, and downregulated the expression of carbonic anhydrase 9 (CA9), matrix metalloproteinase-2 (MMP-2), and matrix metalloproteinase-9 (MMP-9). In addition, treatment with ArBu in combination with CDDP increased the level of inhibitor of nuclear factor kappa B kinase subunit beta (IKBKB), E-cadherin, and nuclear factor kappa-B/p65 (NF-κB/p65). Furthermore, the combination of ArBu and CDDP inhibited tumor growth in xenograft nude mice with no obvious side effects. Conclusions: ArBu synergizes with CDDP to inhibit tumor growth both in vivo and in vitro by inducing alkaliptosis. This indicated that ArBu combined with CDDP may serve as a potential agent for the treatment of gastric cancer.

Arenobufagin causes ferroptosis in human gastric cancer cells by increasing rev-erbα expression.

Background and aims: Gastric cancer is the fifth most diagnosed malignant tumor worldwide with limited effective chemotherapy. Ferroptosis is a new type of programmed cell death, which is becoming as a novel therapeutic target for tumors. Arenobufagin (ArBu) is a bufadienolide isolated from toad skin and venom, which exhibits broad-spectrum anti-tumor activity. It is unclear whether ArBu causes ferroptosis, thereby exhibiting anti-tumor activity in gastric cancer. We aimed to determine whether ArBu causes ferroptosis in cultured human gastric cancer cells. Experimental procedure: Different human gastric cancer cells were treated with ArBu (5-20 µM, 48 h). Indicators of apoptosis and ferroptosis were measured. CRISPR/Cas-9 system was employed to delete Nr1d1 gene. Results: ArBu incubation reduced cell viability in a concentration-dependent manner. ArBu caused ferroptosis but not apoptosis at a lower concentration (10 µM), despite it caused both of them at a higher concentration (20 µM). Cotreatment with a selective ferroptosis inhibitor ferrostatin-1 protected against ArBu (10 µM)-induced reduction in cell viability. ArBu-mediated ferroptosis was associated with abnormal expression of genes involved in iron uptake, lipid peroxidation, and antioxidants. Particularly, Nr1d1 gene expression was most significantly increased after ArBu treatment. Furthermore, activating Rev-erbα encoded by Nr1d1 by a selective agonist GSK4112 (1 and 2 µM, 48 h) caused ferroptosis. In contrast, Rev-erbα knockout using the CRISPR/Cas-9 system diminished ArBu-induced ferroptosis in cultured human gastric cancer cells. Conclusion: ArBu causes ferroptosis by increasing Rev-erbα expression in human gastric cancer cells. This has implications of ArBu as a promising therapy for gastric cancer. Section: 1. Natural Products. Taxonomy classification by EVISE: Traditional medicine, pharmacology, gastric cancer, signal pathway.

Risk and Prognostic Factors for Small Bowel Adenocarcinoma: A Multicenter Retrospective Observational Study in China.

Background: Small bowel adenocarcinoma (SBA) is a rare malignancy that accounts for 3% of all gastrointestinal tumors. We evaluated the clinical characteristics, outcomes, and prognostic factors of primary SBAs. Methods: We retrospectively analyzed the clinicopathological features and clinical outcomes of 300 patients with SBA from three institutions in China between January 2003 and July 2020. Overall survival (OS) was analyzed using the Kaplan-Meier method and it was statistically compared using the log-rank test. Single-variable and multivariate analyses were used to identify the significant correlates of OS. Results: The primary tumor was on the duodenal papilla in 156 patients (52%), in the duodenum in 60 patients (20%), and in the jejunum-ileum in 84 patients (28%). The median OS of the entire cohort was 32.5 months (range, 0-213 months), with a 1-year OS rate of 78.0%. For jejunoileal adenocarcinoma, advanced age, advanced T stage, advanced N stage, more positive lymph nodes, distant metastasis, high carcinoembryonic antigen (CEA), and lymphocyte-to-monocyte ratio < 2.32 predicted worse survival on single-variable analysis. Multivariate analysis showed that advanced age, advanced tumor node metastases (TNM) stage, high CEA level, high alpha fetoprotein (AFP) level, and low prealbumin level were independent prognostic factors for non-ampullary SBA. The independent prognostic factors for duodenal papilla adenocarcinoma included TNM Stage III, nerve invasion, low platelet/lymphocyte ratio, and high CA19-9. Conclusion: We found different independent prognostic factors for tumors at different locations. This finding warrants further investigation to ensure more effective management strategies for SBA.

Prognostic significance of metastatic lymph node ratio in patients with gastric cancer after curative gastrectomy: a single-center retrospective study.

BACKGROUND: The objective of this study was to evaluate the prognostic value of Metastatic lymph node ratio (MLNR) after curative gastrectomy in patients with gastric cancer (GC) and the potential for new indicators to strengthen the current guidelines. METHODS: We retrospectively researched 3864 GC patients with curative gastrectomy between February 2011 and February 2016. The following clinical data were collected from the included patients: gender, type of gastrectomy, tumor location, T stage, N stage, ELN, tumor size, age at surgery, perineural invasion, vascular invasion, TNM stage, survival time and survival status. Patients were divided into low-MLNR (L-MLNR), and high-MLNR (H-MLNR) groups based on adjusted the X-tile cutoff-value of 0.25 for MLNR, the survival rates and clinicopathological characteristics of each group were compared. For the assessment of significant associations between clinicopathological characteristics and patients' survival, univariate and multivariate analyses were performed using the Kaplan-Meier method and Cox proportional hazards analysis. The log-rank test was used to examine the statistical significance of differences among different survival curves. Clinicopathological features significantly associated with MLNR were assessed by the Chi-square test and multinomial logistic regression. The discriminative ability was measured by calculating the Bayesian Information Criterion (BIC) values for each category. Assessment of the effect of clinicopathological features on MLNR for predicting prognosis of GC patients used stratum analysis through Kaplan-Meier analysis and Cox proportional risk Analysis. RESULTS: Survival analysis indicated that MLNR was negatively associated with overall survival (OS) (p < .001) and was an independent prognostic predictor in 3864 GC patients (p < .001). MLNR had significant prognostic significance in various subgroups with clinicopathological characteristics (gender, type of gastrectomy, tumor location, T stage, N stage, ELN, tumor size, age at surgery, perineural invasion, vascular invasion, and TNM stage) (p < .001). CONCLUSIONS: The MLNR may become a new indicator to assess the prognosis of GC patients who underwent curative gastrectomy. The results may have potential clinical implications that should be considered when developing clinical practice guidelines or the design of the future investigation.

miR-140-3p is involved in the occurrence and metastasis of gastric cancer by regulating the stability of FAM83B.

BACKGROUND: Gastric cancer (GC) is a malignant tumor and microRNAs (miRNAs) are closely connected to GC development. The purpose of this study is to investigate the effect of miR-140-3p on the occurrence and metastasis of GC. METHODS: We detected miR-140-3p expression in GC cells and tissues. The correlation between miR-140-3p and prognosis and clinicopathological features in GC was analyzed. The role of miR-140-3p in GC cell migration, invasion, and proliferation was analyzed. The model of tumor transplantation and metastasis in nude mice was established, and the effect of miR-140-3p on the development and metastasis of GC was assessed. The relation between miR-140-3p and SNHG12 and the relations among HuR, SNHG12, and FAM83B were analyzed. RESULTS: miR-140-3p was poorly expressed in GC. GC patients with low miR-140-3p expression had a poor prognosis and unfavorable clinicopathologic features. Overexpression of miR-140-3p inhibited GC cell migration, invasion, and proliferation, and inhibited the development and metastasis of GC. miR-140-3p directly bound to SNHG12 in GC tissues and downregulated SNHG12 expression. SNHG12 overexpression induced HuR nuclear transportation. HuR can bind to FAM83B and up-regulate the mRNA level of FAM83B. Overexpression of SNHG12 or FAM83B reduced the inhibition of overexpression of miR-140-3p on GC. CONCLUSION: miR-140-3p directly bound to SNHG12 in GC and down-regulated the expression of SNHG12, reduced the binding of SNHG12 and HuR, thus inhibiting the nuclear transportation of HuR and the binding of HuR and FAM83B, and reducing the transcription of FAM83B, and finally inhibiting the growth and metastasis of GC.

Hybrid Fiber-Optic Sensing Integrating Brillouin Optical Time-Domain Analysis and Fiber Bragg Grating for Long-Range Two-Parameter Measurement.

Distributed fiber sensing (DFS) can provide real-time signals and warnings. The entire length of fiber optic cable can act as a sensing element, but the accuracy is sometimes limited. On the other hand, point-to-point fiber sensing (PPFS) is usually implemented using one or more fiber Bragg gratings (FBGs) at specific positions along with the fiber for the monitoring of specific parameters (temperature, strain, pressure, and so on). However, the cost becomes expensive when the number of FBGs increases. A hybrid fiber sensing scheme is thus proposed, combining the advantages of DFS and PPFS. It is based on a Brillouin optical time-domain analysis (BOTDA) fiber system with additional FBGs embedded at certain positions where it is necessary to detect specific parameters. The hybrid fiber sensing system has the advantages of full sensing coverage at essential locations that need to be carefully monitored. In our work, the test results showed that the proposed system could achieve a sensing distance of 16 km with the single-mode fiber with a 2 m spatial resolution. For FBG parameter measurements, the temperature variation was 52 °C, from 25 °C to 77 °C, with a temperature sensitivity of 23 pm/°C, and the strain was from 0 to 400 µÎµ, with a strain sensitivity of 0.975 pm/µÎµ, respectively, using two FBGs.