Introduction

Hepatocellular carcinoma (HCC) is the leading cause of death in patients with cirrhosis. Indeed, several risk stratification scores have been developed to anticipate early detection in order to better codify their management, including the Toronto Hepatocellular Carcinoma Risk Index (THRI). It is a simple and validated tool that has been developed to predict the risk of HCC in patients with cirrhosis and is mainly based on the following parameters: etiology, age, sex and platelet count.
The objective of this study was to evaluate the reliability of the THRI score in predicting the occurrence of hepatocellular carcinoma.

Aims & Methods

We conducted a monocentric retrospective study collecting all cirrhotic patients over an 8-year period [2008-2015]. Clinico-biological data, disease severity, and long-term outcomes were collected.
THRI was calculated for all patients, and were classified according to HCC risk into three levels : low HCC risk (<120), intermediate HCC risk (between 120 and 240), and those with high HCC risk (>240).
A statistical study using the SPSS tool was carried out. The performance of this score was evaluated with the area under the receiver operating characteristics curve (AUROC).

Results

We included 120 cirrhotic patients with an M/F sex ratio equal to 0.5. The mean age was 57 years [14-85]. The most frequent aetiology of cirrhosis were viral C (49%) and viral B (31%). The mean overall survival was approximately 6 years after diagnosis.
Twenty-five patients developed HCC during follow-up (20.8%). Patients who developed HCC had a higher THRI score than those who did not develop HCC : 264.8 ± 48.6 versus 232.3 ± 64.8, respectively with p-value = 0.008
Patients with a low risk of HCC were 5 (4.2%), none of whom had developed HCC. Fifty-eight patients (48.3%) were at intermediate risk, 12% of them (N=7) had developed HCC. The remaining 57 patients (47.5%) were at a high risk and 31.6% of them (N=18) developed HCC during their follow-up.
The AUROC for the THRI to predict HCC was 0.649 ([95% CI 0.533–0.765]. The cutoff THRI value in predicting the occurrence of HCC was 235.5 with a sensitivity of 72% and a specificity of 50%.

Conclusion

According to our study, the THRI score appears to be an effective tool for predicting the occurrence of HCC in cirrhotic patients. Its good sensitivity allows to identify the high-risk HCC population for early screening.

Introduction

Aims & Methods

Results

Conclusion

Introduction

Gastric cancer is one of the most common malignant tumors with high morbidity, and Helicobacter pylori (H. pylori) infection is the predominant risk factor for gastric cancer. In our previous study, we performed proteomic analysis and compared the differentially expressed RNA-binding proteins between the two groups after H. pylori infection, which led us to focus on Insulin-like growth factor-2 mRNA-binding protein1 (IGF2BP1). As an RNA-binding protein, IGF2BP1 plays an increasingly important role in tumorigenesis, but its mechanism in the pathogenesis of H. pylori infection remains unclear. Therefore, we investigated the role of IGF2BP1 in response to H. pylori infection and gastric tumorigenesis in this study.

Aims & Methods

In vitro cell culture, patient-derived organoids, and in vivo mouse models were used. RT-qPCR and Western blot were used to verify the phenomena in cellular level, mouse model and patient samples. Bioinformatics analyses of local and public databases were applied to analyze IGF2BP1 expression, signaling pathways, and clinical significance. The IGF2BP1 over-expressed stable cell line and stable knockout cell line were constructed by lentiviral infection. Cell proliferation was verified by CCK8 and cell apoptosis assay and the reactive oxygen species (ROS) production was detected by DCFH-DA probe assay. Further mechanisms were explored by RNA Immunoprecipitation (RIP) and RNA turnover experiments. Validated IGF2BP1 as a potential therapeutic target was accomplished by patient-derived organoids culture and xenograft in nude mice with intratumoral injection of BTYNB, a small molecule compound, which was identified as a potent and selective inhibitor of IMP1 binding to c-Myc mRNA.

Results

We found that the expression of IGF2BP1 was significantly up-regulated when H. pylori infected in cell lines, mouse model and patient samples. Cell proliferation induced by IGF2BP1 up-regulated was verified by CCK8 and cell apoptosis assay and ROS production was significantly inhibited after overexpression of IGF2BP1 and up-regulated after knockout of IGF2BP1, suggesting that IGF2BP1 promoted cell proliferation and inhibit ROS production and thus facilitated the survival of malignant cells. Further, transcriptome sequencing revealed that the relevant differentially expressed genes were mainly enriched in the endoplasmic reticulum stress-related pathway, suggesting that IGF2BP1 might influence the occurrence of oxidative stress via ferroptosis. Then we found that IGF2BP1 could inhibit ferroptosis by up-regulating the SLC7A11, which is an important molecule of ferroptosis pathway. Mechanismly, IGF2BP1 acted as an RNA m6A methylation reader to recognize and bind to SLC7A11 mRNA, and promoted the expression level of SLC7A11 after increasing its mRNA stability thereby inhibiting ferroptosis. Taken together, IGF2BP1 could inhibit ferroptosis and promote cell proliferation, thus promoting the development of gastritis and gastric cancer associated with H. pylori infection. Intratumoral injection of BTYNB into xenograft in nude mice significantly inhibited the proliferation of tumors with high IGF2BP1 expression, which indicated that IGF2BP1 was a potential therapeutic target in gastric cancer.The same result was likewise demonstrated in patient-derived organoids culture system.
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Conclusion

Our results clarified the important role of IGF2BP1 in gastric mucosal diseases associated with H. pylori infection, and identified IGF2BP1 was a potential therapeutic target in gastric mucosal diseases through cellular experiments, mouse model and clinical patient samples.

Introduction

Gastric cancer is a malignant tumor that seriously endangers human physical and mental health worldwide. H. pylori infection is considered to be the major cause of gastric cancer. Differences in clinical outcomes after H. pylori infection may be related to bacterial virulence. Thioredoxin-1 (Trx1) and Arginase (RocF) expressed by H. pylori were found to be closely related to its pathogenicity and promoted gastric cancer pathogenesis in our previous study.

Aims & Methods

To explore whether Helicobacter pylori Trx1 and RocF can be used as a marker of highly pathogenic Helicobacter pylori and its pathogenesis. We investigated the expression level of H. pylori trx1 and H. pylori rocF in human gastric antrum tissues using reverse transcription and quantitative real-time PCR (RT-qPCR) and clarified the clinical application value of trx1 and rocF for screening highly pathogenic H. pylori. The pathogenic mechanism of Trx1 were further explored by RNA-seq of GES-1 cells co-cultured with trx1 high or low expressing H. pylori. Differentially expressed genes and signaling pathways were validated by RT-qPCR, Enzyme-linked immunosorbent assay (ELISA), western blot, immunohistochemistry and immunofluorescence. We also assessed the adherence of trx1 high and low expressing H. pylori to GES-1 cells.

Results

We found that H. pylori trx1 and H. pylori rocF were more significantly expressed in the gastric cancer and peptic ulcer group than that in the gastritis group and the parallel diagnosis of H. pylori trx1 and H. pylori rocF had high sensitivity. Trx1 high expressing H. pylori had stronger adhesion ability to GES-1 cells and upregulated the interleukin (IL) 23A/Nuclear factor κappaB (NF-κB)/IL17A, IL6,IL8 pathway.

Conclusion

In conclusion, H. pylori trx1 and H. pylori rocF can be used in clinical screening of highly pathogenic H. pylori and predicting the outcome of H. pylori infection. trx1 high expressing H. pylori enhances the adhesion capacity and promotes the development of gastric diseases by upregulating the NF-κB signaling pathway and related inflammatory cytokines.

References

1. Sung H.,Ferlay J.,Siegel R.L.,Laversanne M.,Soerjomataram I.,Jemal A., et al. (2021) Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA Cancer J Clin.71, 209-249.
2. Schottker B., Adamu M.A., Weck M.N. and Brenner H. (2012) Helicobacter pylori infection is strongly associated with gastric and duodenal ulcers in a large prospective study. Clin Gastroenterol Hepatol.10, 487-493.

Disclosure

The authors declare that there is no competing interests associated with the manuscript.

Introduction

A few studies have suggested the association between Helicobacter pylori (HP) infection and atherosclerosis including coronary heart disease and ischemic stroke. However, the effect of HP eradication on ischemic stroke has not been well evaluated, so far.

Aims & Methods

The objective of this study was twofold: (1) to compare the risks of ischemic stroke and cerebral atherosclerosis as a pre-clinical stage of ischemic stroke according to HP eradication status among HP-infected patients (HP-eradicated vs. HP-non-eradicated), and (2) to compare these risks in HP-eradicated patients to those in HP-naive subjects. We conducted a prospective observational cohort study. HP tests with gastroscopy were performed in Seoul National University Bundang Hospital from May 2003 to February 2023. HP infection was diagnosed through ≥1 findings of histopathology, rapid urease test or culture. Propensity score matching for each group was calculated with relevant covariates, including age, sex, alcohol, smoking, hypertension, diabetes mellitus, dyslipidemia, atrial fibrillation, and aspirin intake. Patients in HP-eradicated group were matched in a 2:1 and 1:1 ratio with patients in HP-non-eradicated and HP-naive groups, respectively. Ischemic stroke and cerebral atherosclerosis were confirmed by brain MRI. The risk of ischemic stroke and cerebral atherosclerosis was analyzed using Cox-proportional hazard regression analysis.

Results

A total of 8,025 patients were included. After 2:1 matching, HP-eradicated group comprised 2,030 patients and HP-non-eradicated group comprised 1,015 patients(Figure). In a Cox-proportional hazard analysis, HP-eradicated group was associated with a significantly lower risk of ischemic stroke and cerebral atherosclerosis (hazard ratio [HR] 0.651, 95% confidence interval [CI] 0.451-0.941, p=0.026) (Table). In a second analysis, we included 2,064 patients with HP-eradicated and 2,064 HP-naive subjects, after PSM at a 1:1 ratio. In a Cox-proportional hazard analysis, the risk of ischemic stroke and cerebral atherosclerosis was not significantly different between the two groups (HR 1.109, 95% CI 0.777-1.584, p=0.569).

Conclusion

This large prospective observational cohort study suggested that HP eradication has preventive effect on the ischemic stroke and cerebral atherosclerosis.