Cellular senescence throws new insights into patient classification and pharmacological interventions for clinical management of hepatocellular carcinoma.

BACKGROUND: Cellular senescence, a state of stable growth arrest, is intertwined with human cancers. However, characterization of cellular senescence-associated phenotypes in hepatocellular carcinoma (HCC) remains unexplored. AIM: To address this issue, we delineated cellular senescence landscape across HCC. METHODS: We enrolled two HCC datasets, TCGA-LIHC and International Cancer Genome Consortium (ICGC). Unsupervised clustering was executed to probe tumor heterogeneity based upon cellular senescence genes. Least absolute shrinkage and selection operator algorithm were utilized to define a cellular senescence-relevant scoring system. TRNP1 expression was measured in HCCs and normal tissues through immunohistochemistry, immunoblotting and quantitative real-time polymerase chain reaction. The influence of TMF-regulated nuclear protein (TRNP)1 on HCC senescence and growth was proven via a series of experiments. RESULTS: TCGA-LIHC patients were classified as three cellular senescence subtypes, named C1-3. The robustness and reproducibility of these subtypes were proven in the ICGC cohort. C2 had the worst overall survival, C1 the next, and C3 the best. C2 presented the highest levels of immune checkpoints, abundance of immune cells, and immunogenetic indicators. Thus, C2 might possibly respond to immunotherapy. C2 had the lowest somatic mutation rate, while C1 presented the highest copy number variations. A cellular senescence-relevant gene signature was generated, which can predict patient survival, and chemo- or immunotherapeutic response. Experimentally, it was proven that TRNP1 presented the remarkable upregulation in HCCs. TRNP1 knockdown induced apoptosis and senescence of HCC cells and attenuated tumor growth. CONCLUSION: These findings provide a systematic framework for assessing cellular senescence in HCC, which decode the tumor heterogeneity and tailor the pharmacological interventions to improve clinical management.

Menetrier's disease and differential diagnosis: A case report.

BACKGROUND: Gastric mucosal hypertrophy, also known as Menetrier's disease (MD), is more common in men over 50 years of age, and the cause is unknown. The symptoms of the disease are atypical, mostly accompanied by hypoproteinemia and edema, and sometimes accompanied by symptoms such as epigastric pain, weight loss, and diarrhea. Most experts believe that the site of the disease is mainly located in the fundus of the stomach and the body of the stomach. We found that the site of the disease in this patient involved the antrum of the stomach. CASE SUMMARY: We introduced the case of a 24-year-old woman who had repeated vomiting for 5 d and was admitted to our hospital. After various examinations such as computed tomography and pathology in our hospital, the final diagnosis of the presented case is MD. The salient feature is that the mucosal folds in the fundus and body of the stomach are huge and present in the shape of gyrus. The greater curvature is more prominent, and there are multiple erosions or ulcers on the folds. The patient did not undergo gastric surgery and did not undergo re-examination. She is drinking Chinese medicine for treatment, and her vomiting and abdominal pain symptoms have improved. This disease is relatively rare in clinical practice, and it is easy to be misdiagnosed as gastric cancer, chronic gastritis and gastric lymphoma, etc. CONCLUSION: MD can occur in the antrum, it is necessary to raise awareness of the disease and reduce misdiagnosis.

CD97 promotes gastric cancer cell proliferation and invasion through exosome-mediated MAPK signaling pathway.

AIM: To investigate the mechanism underlying the promoting role of CD97 in gastric cancer cell proliferation and invasion. METHODS: Two types of exosomes released by gastric cancer cells with high (SGC/wt) or low (SGC/kd) CD97 expression were isolated by ultracentrifugation and identified by electron microscopy and western blot analysis. The influences of the two exosomes on gastric cancer cell proliferation and invasion were investigated by proliferation and Matrigel invasion assays. Exosomal miRNAs were subsequently isolated from the two samples and their miRNA profiles were compared via microarray assay analysis. Reverse transcription-quantitative real-time polymerase chain reaction was used to validate the microarray assay. Target genes of the differently expressed microRNAs were predicted based on five independent algorithms and were then subjected to gene oncology enrichment and Kyoto encyclopedia of genes and genomes (KEGG) pathway analysis. After identifying the pathway that was the most likely altered, tumor cells were treated with the two exosomes at different concentrations, and the pathway activation was identified through western blot analysis. RESULTS: Exosomes isolated from SGC/wt cells significantly promoted tumor cell proliferation in a dose-dependent manner in vitro. SGC/wt exosomes also significantly elevated the invasiveness of both SGC/wt (129.67 ± 8.327 vs 76.00 ± 5.292, P < 0.001) and SGC/kd (114.52 ± 9.814 vs 45.73 ± 4.835, P < 0.001) cells as compared to the exosomes released by SGC/kd cells. Microarray assay of the two exosomes revealed that 62 miRNAs were differently regulated with a signal intensity of > 500 and a false discovery rate < 0.05. The following KEGG analysis defined the MAPK signaling pathway as the most likely candidate pathway that regulated tumor cell proliferation and invasion. Through western blot analysis, significant up-regulations of phosphorylated MAPKs, including extracellular signal-regulated kinase, Jun NH2-terminal kinase, and p38 mitogen-activated protein kinase, were detected in a dose-dependent manner in the SGC/wt exosomes treated groups, confirming activation of the MAPK signaling pathway stimulated by SGC/wt exosomes. CONCLUSION: CD97 promotes gastric cancer cell proliferation and invasion in vitro through exosome-mediated MAPK signaling pathway, and exosomal miRNAs are probably involved in activation of the CD97-associated pathway.

HER-2 overexpression and survival in colorectal cancer: a meta-analysis.

OBJECTIVE: Numerous studies examining the relationship between human epidermal growth factor receptor 2 (HER-2) overexpression and survival in patients with colorectal cancer (CRC) have yielded controversial results. We therefore performed a meta-analysis more precisely to estimate its prognostic value. METHODS: Published studies investigating the effect of HER-2 overexpression on CRC survival were identified; the hazard ratios (HRs) and their corresponding 95% confidence intervals (95% CIs) were pooled in terms of disease-specific or overall survival. RESULTS: Eleven studies were included in the meta-analysis. The pooled data showed that HER-2 overexpression was negatively related to CRC survival (HR=1.10, 95% CI: 0.77-1.44). Subgroup analyses regarding test method and study quality also demonstrated little association between HER-2 overexpression and CRC survival (HR=0.89, 95% CI: 0.50-1.29; HR=0.90, 95% CI: 0.43-1.37, respectively). CONCLUSIONS: Regardless of several limitations, our study suggested that HER-2 overexpression probably had little impact on CRC survival.

Potential of sivelestat in protection against severe acute pancreatitis-associated lung injury in rats.

The incidence of acute pancreatitis has been rising worldwide in the past few decades. Despite extensive research efforts, the population-based mortality from acute pancreatitis remains high. Since dysfunction of multiple vital organs, most importantly the lungs, is the major cause of early death in acute pancreatitis patients, developing effective strategies to manage lung injury has become one of the focuses of recent research efforts aiming at improving the outcome of patients with acute pancreatitis. In this study, we attempted to create a rat model of acute pancreatitis through intraductal infusion of taurocholate and to evaluate the potential of sivelestat, a synthetic neutrophil elastase inhibitor, in protection against acute pancreatitis-associated lung injury using this rat model. The results demonstrated that: (1) 5% sodium taurocholate successfully induced histopathologic and biochemical abnormalities in the circulation, lung and pancreas characteristic of human acute pancreatitis, including an increase in amylase concentration and a decrease in partial arterial oxygen pressure (PaO2) in the blood, increases in activities of myeloperoxidase (MPO) (a lung injury marker) and neutrophil elastase (a quantitative indicator of neutrophil infiltration), and levels of malondialdehyde (an indicator of lipid peroxidation) and tumor necrosis factor-alpha (a major inflammatory mediator) in the lung; (2) intravenous administration of sivelestat effectively attenuated the taurocholate-induced abnormalities in all parameters analyzed except for serum amylase concentration. Our findings have validated the taurocholate model of acute pancreatitis and demonstrated great therapeutic potential for sivelestat in managing acute pancreatitis-associated lung injury.