Dynamic regulation of EXO1 promotes the progression from liver fibrosis to HCC through TGF-ß1/Smad signaling feedback loop.

BACKGROUND: HSCs are the main stromal cells in the process of liver fibrosis and accelerate HCC progression. Previous studies determined that highly expressed exonuclease 1 (EXO1) increases the malignant behavior of HCC cells and is closely related to liver cirrhosis. This study aimed to explore the roles and mechanisms of EXO1 in the development of liver cirrhosis and HCC. METHODS: We fully demonstrated that EXO1 expression was positively correlated with liver fibrosis and cirrhotic HCC by combining bioinformatics, hepatic fibrosis mouse models, and human HCC tissues. The role of EXO1 in a murine HCC model induced by activated forms of AKT and Ras oncogenes (AKT/Ras) was investigated by employing an adeno-associated virus-mediated EXO1 knockdown technique. RESULTS: The knockdown of EXO1 promoted a regression of HCC in AKT/Ras mice and reduced the degree of liver fibrosis. Downregulated EXO1 inhibited LX-2 cell activation and inhibited the proliferation and migration of HCC cells. Moreover, conditioned medium of LX-2 cells with EXO1 overexpression increased the proliferation and migration of HCC cells, which was attenuated after EXO1 knockout in LX-2 cells. EXO1 knockdown attenuated the role of LX-2 in promoting HepG2 xenograft growth in vivo. Mechanistically, EXO1 promotes the activation of the downstream TGF-ß-smad2/3 signaling in LX-2 and HCC cells. Interestingly, increased TGF-ß-smad2/3 signaling had a feedback effect on EXO1, which sustains EXO1 expression and continuously stimulates the activation of HSCs. CONCLUSIONS: EXO1 forms a positive feedback circuit with TGF-ß-Smad2/3 signaling and promotes the activation of HSCs, which accelerates HCC progression. Those findings indicate EXO1 may be a promising target for the diagnosis and treatment of cirrhotic HCC.

Effect of "Internet + tertiary hospital-primary hospital-family linkage home care" model on self-care ability and quality of life of discharged stroke patients.

OBJECTIVE: To investigate the intervention effect of an "Internet + tertiary hospital-primary hospital-family linkage home care" model on the quality of life and self-care abilities of discharged stroke patients. METHODS: The clinical data of 90 patients with stroke who were hospitalized and discharged from the Department of Neurology of the Affiliated Hospital of Youjiang Medical College for Nationalities from October 2020 to September 2021 were retrospectively analyzed. They were split into a control group (41 cases) and an intervention group (40 cases) based on different care modes. The intervention group was given the "Internet + tertiary hospital-primary hospital-family connection home care" paradigm, while the control group received normal nursing interventions. The degree of nerve defect, quality of life, anxiety and depression, self-care ability and exercise ability of the patients were evaluated by National Institutes of Health Stroke Scale (NIHSS), Stroke Specific Quality of Life Scale (SS-QOL), General Hospital Anxiety and Depression Scale (HADS), Self-care Ability Scale (ESCA), and Fugl-Meyer Motor Function Assessment (FMA) before discharge and at 3rd, 6th and 12th month after discharge, respectively. The re-hospitalization rate, treatment compliance and exercise ability of the two groups were compared within a year after discharge. RESULTS: The scores of SS-QOL, ESCA and FMA in the intervention group increased with time, and the scores of SS-QOL, ESCA and FMA at 3rd, 6th and 12th month after discharge were higher than those in the control group (all P<0.05). The NIHSS and HADS scores decreased over time, and the NIHSS and HADS scores were lower than the control group at 12th month after discharge (P<0.05). Within a year of discharge, the intervention group had a lower rehospitalization rate than the control group (P<0.05), and the treatment compliance score was higher in the intervention group than that in the control group (P<0.05). CONCLUSION: The "Internet + tertiary hospital-primary hospital-family nursing" model can improve self-care ability and treatment compliance of patients, improve their nerve defects and psychological status as well as quality of life, and reduce rehospitalization rate.

MAIT cells ameliorate liver fibrosis by enhancing the cytotoxicity of NK cells in cholestatic murine models.

BACKGROUND AND AIMS: Mucosal-associated invariant T (MAIT) cells are innate-like lymphocytes that display a critical role in various liver diseases. However, the role of MAIT cells in cholestatic liver fibrogenesis remains obscure. Our study aims to assess the contribution of MAIT cells and underlying mechanisms during this process. METHODS: Cholestatic murine models using MAIT cell-deficient (MR1- /- ) and wild-type (WT) mice were established by feeding a 0.1% 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC)-enriched diet or bile duct ligation (BDL). Liver samples were collected to determine the severity of fibrosis. Lymphocytes of the liver were isolated for analysing the phenotype and function of MAIT cells. Cell co-culture experiments were performed to investigate the cross-talk between MAIT and NK cells. RESULTS: Liver MAIT cells were more activated with increased cytokines in cholestatic mice models than in control mice, although their frequency was decreased. MAIT cell deficiency led to severe liver inflammation and fibrosis with more activated HSCs in cholestatic mice. In addition, MR1- /- mice had an increased frequency of NK cells with higher expression of stimulatory receptors relative to WT mice. Paradoxically, activated MAIT cells significantly promoted the anti-fibrotic ability of NK cells by enhancing their cytotoxicity against HSCs in co-culture experiments. Importantly, this effect depended on direct cell-cell contact and TNF-α produced by MAIT cells. CONCLUSION: Our findings indicate that MAIT cells ameliorate cholestatic liver fibrosis by enhancing the cytotoxicity of NK cells against HSCs. An in-depth understanding of the MAIT cell-mediated regulatory effect will provide more valuable immunotherapy strategies to treat liver fibrosis.

Clinical Study of Mobile Application- (App-) Based Family-Centered Care (FCC) Model Combined with Comprehensive Iron Removal Treatment in Children with Severe Beta Thalassemia.

Methods: A retrospective study was conducted on the clinical records of 148 children diagnosed with severe beta thalassemia who were admitted to our hospital between October 2018 and September 2021. The patients were separated into two groups, a control group and an intervention group, with 74 cases in each group, according to the various care approaches. The basic treatment regimen was given to all of the children: deferoxamine mesylate combined with deferiprone. During treatment, the control group received routine care, and the intervention group adopted the FCC model based on a mobile app. The quality of life scale for children and adolescents (QLSCA) score, the family assessment device (FAD) score, the exercise of self-care agency scale (ESCA) score, and the medication compliance scale score were compared between the two groups. Results: The QLSCA score, ESCA score, and medication compliance scale score of the intervention group were significantly higher than those of the control group and showed a significant difference (intergroup effect: F = 198.400, 259.200, and 129.800, all P < 0.001). Scores in both groups increased over time (time effect: F = 19.350, 40.830, and 12.130, all P < 0.001), and there was an interaction effect between grouping and time (interaction effect: F = 3.937, 12.020, and 5.028). The P values were 0.020, <0.001, and 0.007. The FAD score of the intervention group was significantly lower than that of the control group (intergroup effect: F = 177.200, P < 0.001). The FAD scores of both groups decreased over time (time effect: F = 7.921, P = 0.005). There was an interaction effect between groups and time (interaction effect: F = 5.206, P = 0.006). Conclusion: The application effect of the mobile app-based FCC model combined with the comprehensive iron removal treatment program in children with severe beta thalassemia is significant, which can significantly improve the quality of life, family function, self-care ability, and medication compliance of children, and has high clinical application value.

A deep learning network based on multi-scale and attention for the diagnosis of chronic atrophic gastritis.

BACKGROUND AND STUDY AIM: Chronic atrophic gastritis plays an important role in the process of gastric cancer. Deep learning is gradually introduced in the medical field, and how to better apply a convolutional neural network (CNN) to the diagnosis of chronic atrophic gastritis remains a research hotspot. This study was designed to improve the performance of CNN on diagnosing chronic atrophic gastritis by constructing and evaluating a network structure based on the characteristics of gastroscopic images. METHODS: Three endoscopists reviewed the endoscopic images of the gastric antrum from the Gastroscopy Image Database of Zhongnan Hospital and labelled available images according to pathological results. Two novel modules proposed recently were introduced to construct the Multi-scale with Attention net (MWA-net) considering the characters of similar medical images. After training the network using images of training sets, the diagnostic ability of the MWA-net was evaluated by comparing it with those of other deep learning models and endoscopists with varying degrees of expertise. RESULTS: As a result, 5,159 images of the gastric antrum from 2,240 patients were used to train and test the MWA-net. Compared with the direct application of famous networks, the MWA-net achieved the best performance (accuracy, 92.13%) with an increase of 1.80% compared to that of ResNet. The suspicious lesions indicated by the network are consistent with the conclusion of experts. The sensitivity and specificity of the convolutional network for gastric atrophy diagnosis are 90.19% and 94.51%, respectively, which are higher than those of experts. CONCLUSIONS: Highly similar images of chronic atrophic gastritis can be identified by the proposed MWA-net, which has a better performance than other well-known networks. This work can further reduce the workload of gastroscopists, simplify the diagnostic process and provide medical assistance to more residents.

Blockade of GCH1/BH4 Axis Activates Ferritinophagy to Mitigate the Resistance of Colorectal Cancer to Erastin-Induced Ferroptosis.

Ferroptosis, a type of cell death triggered by excessive accumulation of iron-dependent lipid peroxidation, possesses an excellent potential in cancer treatment. However, many colorectal cancer (CRC) cell lines are resistant to ferroptosis induced by erastin and RSL3, the classical ferroptotic inducers. Moreover, the underlying mechanism of resistance remains poorly elucidated. This study sought to discover the major factor contributing to ferroptosis resistance in CRC. The study findings will help design strategies for triggering ferroptosis for application in individualized tumor therapy. Here, we show that tetrahydrobiopterin (BH4) determines the sensitivity of CRC cells to ferroptosis induced by erastin. GTP cyclohydrolase-1 (GCH1) is the first rate-limiting enzyme of BH4. Genetic or pharmacological inhibition of GCH1 decreased BH4 and assisted erastin in cell death induction, lipid peroxidation enhancement, and ferrous iron accumulation. BH4 supplementation completely inhibited ferroptotic features resulting from GCH1 knockdown. Unexpectedly, GCH1 knockdown failed to enhance RSL3-induced cell death in CRC. Mechanistically, GCH1 knockdown drastically activated ferritinophagy during erastin treatment rather than RSL3 treatment. Administration of an autophagy inhibitor reversed erastin resistance in GCH1-knockdown cells. GCH1 inhibitor and erastin co-treatment in vivo synergistically inhibited tumor growth in CRC. Overall, our results identified GCH1/BH4 metabolism as a burgeoning ferroptosis defense mechanism in CRC. Inhibiting GCH1/BH4 metabolism promoted erastin-induced ferroptosis by activating ferritinophagy, suggesting that combining GCH1 inhibitors with erastin in the treatment of CRC is a novel therapeutic strategy.

Identification of Vitamin D-related gene signature to predict colorectal cancer prognosis.

Colorectal cancer (CRC) is one of the most common malignant carcinomas worldwide with poor prognosis, imposing an increasingly heavy burden on patients. Previous experiments and epidemiological studies have shown that vitamin D and vitamin D-related genes play a vital role in CRC. Therefore, we aimed to construct a vitamin D-related gene signature to predict prognosis in CRC. The CRC data from The Cancer Genome Atlas (TCGA) was performed as the training set. A total of 173 vitamin D-related genes in the TCGA CRC dataset were screened, and 17 genes associated with CRC prognosis were identified from them. Then, a vitamin D-related gene signature consisting of those 17 genes was established by univariate and multivariate Cox analyses. Moreover, four external datasets (GSE17536, GSE103479, GSE39582, and GSE17537) were used as testing set to validate the stability of this signature. The high-risk group presented a significantly poorer overall survival than low-risk group in both of training set and testing sets. Besides, the areas under the curve (AUCs) for signature on OS in training set at 1, 3, and 5 years were 0.710, 0.708, 0.710 respectively. The AUCs of the ROC curve in GSE17536 for 1, 3, and 5 years were 0.649, 0.654, and 0.694. These results indicated the vitamin D-related gene signature model could effectively predict the survival status of CRC patients. This vitamin D-related gene signature was also correlated with TNM stage in CRC clinical parameters, and the higher risk score from this model was companied with higher clinical stage. Furthermore, the high accuracy of this prognostic signature was validated and confirmed by nomogram model. In conclusion, we have proposed a novel vitamin D-related gene model to predict the prognosis of CRC, which will help provide new therapeutic targets and act as potential prognostic biomarkers for CRC.

Clinical and Endoscopic Characteristics of Chinese Cronkhite-Canada Syndrome Patients: A Retrospective Study of 103 Cases.

INTRODUCTION: Cronkhite-Canada syndrome (CCS) is a rare non-inherited disease characterized by extensive gastrointestinal (GI) polyposis and ectodermal dysplasia. So far, most of CCS related literatures are published as single case report or reviewed with limited case numbers. Our study was to update the clinical and endoscopic characteristics of Chinese CCS patients. METHODS: This retrospective study was conducted in 103 Chinese CCS patients (102 cases from literatures and 1 case from our department). Their clinical and endoscopic data were collected, and statistical analyses were performed. RESULTS: (1) In Chinese population, people aged 50-70 years (62.62%) had a high incidence of CCS, and the ratio of male-to-female was 2.68:1. (2) The diverse range of GI manifestations was observed in all the patients, and almost all the patients had at least 1 symptom of ectodermal dysplasias. (3) All CCS patients presented multiple polyps in the GI tract except esophagus, and the size and appearance of polyps were diverse. Congestion, edema, and erosion were very common on the surface of polyps (96.83%) and the surrounding mucosa (85.71%). (4) The common pathological features of polyps were hyperplastic polyps (49.25%) and tubular adenomatous polyps (44.78%). The prevalence of cancer was 5.97% in Chinese CCS patients. CONCLUSIONS: Middle-aged and elderly people are the high-risk group. Various GI symptoms are observed in Chinese patients; the typical endoscopic finding is multiple small sessile polyps. These GI polyps have a chance of malignant potential. Long-term endoscopic surveillance and follow-up are recommended for the Chinese CCS patients.