PTEN deficiency induces an extrahepatic cholangitis-cholangiocarcinoma continuum via aurora kinase A in mice.

BACKGROUND & AIMS: The PTEN-AKT pathway is frequently altered in extrahepatic cholangiocarcinoma (eCCA). We aimed to evaluate the role of PTEN in the pathogenesis of eCCA and identify novel therapeutic targets for this disease. METHODS: The Pten gene was genetically deleted using the Cre-loxp system in biliary epithelial cells. The pathologies were evaluated both macroscopically and histologically. The characteristics were further analyzed by immunohistochemistry, reverse-transcription PCR, cell culture, and RNA sequencing. Some features were compared to those in human eCCA samples. Further mechanistic studies utilized the conditional knockout of Trp53 and Aurora kinase A (Aurka) genes. We also tested the effectiveness of an Aurka inhibitor. RESULTS: We observed that genetic deletion of the Pten gene in the extrahepatic biliary epithelium and peri-ductal glands initiated sclerosing cholangitis-like lesions in mice, resulting in enlarged and distorted extrahepatic bile ducts in mice as early as 1 month after birth. Histologically, these lesions exhibited increased epithelial proliferation, inflammatory cell infiltration, and fibrosis. With aging, the lesions progressed from low-grade dysplasia to invasive carcinoma. Trp53 inactivation further accelerated disease progression, potentially by downregulating senescence. Further mechanistic studies showed that both human and mouse eCCA showed high expression of AURKA. Notably, the genetic deletion of Aurka completely eliminated Pten deficiency-induced extrahepatic bile duct lesions. Furthermore, pharmacological inhibition of Aurka alleviated disease progression. CONCLUSIONS: Pten deficiency in extrahepatic cholangiocytes and peribiliary glands led to a cholangitis-to-cholangiocarcinoma continuum that was dependent on Aurka. These findings offer new insights into preventive and therapeutic interventions for extrahepatic CCA. IMPACT AND IMPLICATIONS: The aberrant PTEN-PI3K-AKT signaling pathway is commonly observed in human extrahepatic cholangiocarcinoma (eCCA), a disease with a poor prognosis. In our study, we developed a mouse model mimicking cholangitis to eCCA progression by conditionally deleting the Pten gene via Pdx1-Cre in epithelial cells and peribiliary glands of the extrahepatic biliary duct. The conditional Pten deletion in these cells led to cholangitis, which gradually advanced to dysplasia, ultimately resulting in eCCA. The loss of Pten heightened Akt signaling, cell proliferation, inflammation, fibrosis, DNA damage, epigenetic signaling, epithelial-mesenchymal transition, cell dysplasia, and cellular senescence. Genetic deletion or pharmacological inhibition of Aurka successfully halted disease progression. This model will be valuable for testing novel therapies and unraveling the mechanisms of eCCA tumorigenesis.

Investigation of the prevalence and risk factors of Helicobacter pylori infection and the value of different gastric cancer screening methods in a low-risk region of gastric cancer in China.

BACKGROUND: The aim of this current study was to identify the prevalence and risk factors of H. pylori infection in the low-risk area of gastric cancer in China, and evaluate the value of different gastric cancer screening methods. METHODS: An epidemiological study was conducted in Yudu County, Jiangxi, China, and participants were followed up for 6 years. All participants completed a questionnaire, laboratory tests and endoscopy. Patients were divided into H. pylori positive and negative groups, and risk factors for H. pylori infection were identified using multivariate logistic regression analysis. RESULTS: A total of 1962 residents were included, the prevalence of H. pylori infection was 33.8%. Multivariate analysis showed that annual income ≤20,000 yuan (OR: 1.44, 95% CI: 1.18-1.77, p < 0.001), loss of appetite (OR: 1.71, 95% CI: 1.29-2.26, p < 0.001), PG II >37.23 ng/mL (OR: 2.11, 95% CI: 1.50-2.97, p < 0.001), G-17 > 1.5 and ≤5.7 pmol/L (OR: 2.52, 95% CI: 1.93-3.30, p < 0.001), and G-17 > 5.7 pmol/L (OR: 1.96, 95% CI: 1.48-2.60, p < 0.001) were risk factors of H. pylori infection, while alcohol consumption (OR: 0.70, 95% CI: 0.54-0.91, p = 0.006) was a protective factor. According to the new gastric cancer screening method, the prevalence of low-grade intraepithelial neoplasia in the low-risk group, medium-risk group and high-risk group was 4.4%, 7.7% and 12.5% respectively (p < 0.001). CONCLUSIONS: In a low-risk area of gastric cancer in China, the infection rate of H. pylori is relatively low. Low income, loss of appetite, high PG II, and high G-17 were risk factors for H. pylori infection, while alcohol consumption was a protective factor. Moreover, the new gastric cancer screening method better predicted low-grade intraepithelial neoplasia than the ABC method and the new ABC method.

An improved semantic segmentation model based on SVM for marine oil spill detection using SAR image.

In the oil industry, oil spills occur due to offshore rig explosions, ship collisions, and other reasons. It is crucial to accurately and rapidly identify oil spills to protect marine ecosystems. Synthetic aperture radar (SAR) can all-weather and all-time work and provide a wealth of polarization information for identification of oil spills based on semantic segmentation model. However, the performance of classifiers in the semantic segmentation model has become a significant challenge to improving recognition ability. To solve this problem, an improved semantic segmentation model named DRSNet was proposed, which uses ResNet-50 as the backbone in DeepLabv3+ and support vector machines (SVM) as the classifier. The experiment was conducted using ten polarimetric features from SAR images and results demonstrate that the DRSNet performs best compared to other semantic segmentation models. Current work provides a valuable tool to enhance maritime emergency management capabilities.

Multiple roles for cholinergic signaling in pancreatic diseases.

Cholinergic nerves are widely distributed throughout the human body and participate in various physiological activities, including sensory, motor, and visceral activities, through cholinergic signaling. Cholinergic signaling plays an important role in pancreatic exocrine secretion. A large number of studies have found that cholinergic signaling overstimulates pancreatic acinar cells through muscarinic receptors, participates in the onset of pancreatic diseases such as acute pancreatitis and chronic pancreatitis, and can also inhibit the progression of pancreatic cancer. However, cholinergic signaling plays a role in reducing pain and inflammation through nicotinic receptors, but enhances the proliferation and invasion of pancreatic tumor cells. This review focuses on the progression of cholinergic signaling and pancreatic diseases in recent years and reveals the role of cholinergic signaling in pancreatic diseases.

Removal of cadmium from rice grains by acid soaking and quality evaluation of decontaminated rice.

Contamination of rice by cadmium (Cd) is threatening a large population in China. In this study, we report that soaking rice grains in a hydrochloric acid (HCl) solution can remove Cd to a desirable extent. The results indicated that the degree of Cd removal was up to 45%∼85% at different soaking times and concentrations of HCl (0.06 M âˆ¼ 0.18 M), which was found to be logarithmically correlated with the reaction time at the optimized liquid-solid ratio of 1:2. Three HCl concentration-dependent mathematical models were established, which revealed various optimal soaking conditions depending on the initial Cd contamination. Four Cd-contaminated rice grain samples with different degrees of contamination were then tested based on the mathematical models, and the final Cd content was reduced to an acceptable extent. Moreover, the physicochemical and food properties of rice flours and rice grains after Cd removal were evaluated to highlight their potential applications.

MiR155 Disrupts the Intestinal Barrier by Inducing Intestinal Inflammation and Altering the Intestinal Microecology in Severe Acute Pancreatitis.

BACKGROUND: Intestinal dysfunction is a common complication of acute pancreatitis. MiR155 may be involved in the occurrence and development of intestinal dysfunction mediated by acute pancreatitis, but the specific mechanism is not clear. AIMS: To investigate the effect of miR155 on severe acute pancreatitis (SAP)-associated intestinal dysfunction and its possible mechanism in a mice model. METHODS: In this study, SAP mice model was induced by intraperitoneal injection of caerulein and LPS in combination. Adeno-associated virus (AAV) was given by tail vein injection before the SAP model. The pancreatic and intestinal histopathology changes were analyzed. Cecal tissue was collected for 16S rRNA Gene Sequencing. Intestinal barrier proteins ZO-1 and E-cad were measured by Immunohistochemistry Staining and Western Blot, respectively. Intestinal tissue miR155 and inflammatory factors TNF-α, IL-1ß, and IL-6 were detected by Q-PCR. The expression levels of protein associated with TNF-α and TLR4/MYD88 pathway in the intestinal were detected. RESULTS: In miR155 overexpression SAP group, the levels of tissue inflammatory factor were significantly increased, intestinal barrier proteins were significantly decreased, and the injury of intestinal was aggravated. Bacterial 16S rRNA sequencing was performed, showing miR155 promotes gut microbiota dysbiosis. The levels of TNF-α, TLR4, and MYD88 in the intestinal were detected, suggesting that miR155 may regulate gut microbiota and activate the TLR4/MYD88 pathway, thereby affecting the release of inflammatory mediators and regulating SAP-related intestinal injury. After application of miR155-sponge, imbalance of intestinal flora and destruction of intestinal barrier-related proteins have been alleviated. The release of inflammatory mediators decreased, and the histopathology injury of intestinal was improved obviously. CONCLUSION: MiR155 may play an important role in SAP-associated intestinal dysfunction. MiR155 can significantly alter the intestinal microecology, aggravated intestinal inflammation through TLR4/MYD88 pathway, and disrupts the intestinal barrier in SAP mice.

Pancreatic necrosis and severity are independent risk factors for pancreatic endocrine insufficiency after acute pancreatitis: A long-term follow-up study.

BACKGROUND: Pancreatic endocrine insufficiency after acute pancreatitis (AP) has drawn increasing attention in recent years. AIM: To assess the impact of risk factors on the development of pancreatic endocrine insufficiency after AP. METHODS: This retrospective observational long-term follow-up study was conducted in a tertiary hospital. Endocrine function was evaluated by the oral glucose tolerance test. The data, including age, sex, body mass index, APACHE II score, history of smoking and drinking, organ failure, pancreatic necrosis, debridement of necrosis (minimally invasive and/or open surgery), and time interval, were collected from the record database. RESULTS: A total of 361 patients were included in the study from January 1, 2012 to December 30, 2018. A total of 150 (41.6%) patients were diagnosed with dysglycemia (including diabetes mellitus and impaired glucose tolerance), while 211 (58.4%) patients had normal endocrine function. The time intervals (mo) of the above two groups were 18.73 ± 19.10 mo and 31.53 ± 27.27 mo, respectively (P = 0.001). The morbidity rates of pancreatic endocrine insufficiency were 46.7%, 28.0%, and 25.3%, respectively, in the groups with different follow-up times. The risk factors for pancreatic endocrine insufficiency after AP were severity (odds ratio [OR] = 3.489; 95% confidence interval [CI]: 1.501-8.111; P = 0.004) and pancreatic necrosis (OR = 4.152; 95%CI: 2.580-6.684; P = 0.001). CONCLUSION: Pancreatic necrosis and severity are independent risk factors for pancreatic endocrine insufficiency after AP. The area of pancreatic necrosis can affect pancreatic endocrine function.

Trypsin activity governs increased susceptibility to pancreatitis in mice expressing human PRSS1R122H.

Currently, an effective targeted therapy for pancreatitis is lacking. Hereditary pancreatitis (HP) is a heritable, autosomal-dominant disorder with recurrent acute pancreatitis (AP) progressing to chronic pancreatitis (CP) and a markedly increased risk of pancreatic cancer. In 1996, mutations in PRSS1 were linked to the development of HP. Here, we developed a mouse model by inserting a full-length human PRSS1R122H gene, the most commonly mutated gene in human HP, into mice. Expression of PRSS1R122H protein in the pancreas markedly increased stress signaling pathways and exacerbated AP. After the attack of AP, all PRSS1R122H mice had disease progression to CP, with similar histologic features as those observed in human HP. By comparing PRSS1R122H mice with PRSS1WT mice, as well as enzymatically inactivated Dead-PRSS1R122H mice, we unraveled that increased trypsin activity is the mechanism for R122H mutation to sensitize mice to the development of pancreatitis. We further discovered that trypsin inhibition, in combination with anticoagulation therapy, synergistically prevented progression to CP in PRSS1R122H mice. These animal models help us better understand the complex nature of this disease and provide powerful tools for developing and testing novel therapeutics for human pancreatitis.

Elevated arterial lactate level as an independent risk factor for pancreatic infection in moderately severe acute pancreatitis.

PURPOSE: The present study aimed to research the relationships between arterial lactate levels and pancreatic infection in moderately severe acute pancreatitis. METHODS: This study retrospectively analyzed data from 503 patients with moderately severe acute pancreatitis from January 1, 2013, to March 31, 2018. The baseline characteristics on admission were compared between patients with and without elevated arterial lactate levels. The parameters and laboratory data were compared between patients with and without pancreatic infections at admission. Univariate and multivariate logistic regression analyses were used to assess the value of elevated arterial lactate levels for identifying high-risk patients. P ≤ 0.05 was considered statistically significant. RESULTS: A total of 49 (9.2%) patients were diagnosed with pancreatic infections. Compared with patients without pancreatic infections, pancreatic infection patients had significantly increased arterial lactate levels at admission (1.5 ±â€¯0.7 vs. 2.5 ±â€¯0.9; P < 0.01). Multivariate logic analysis still showed that higher arterial lactate levels in moderately severe acute pancreatitis was an independent risk factor for developing pancreatic infections (hazard ratio: 6.31, 95% CI 3.01-13.24; P < 0.01). Arterial lactate level ≥2.1 mmol/L and procalcitonin level ≥0.5 ng/mL at admission had area under the receiver operating characteristic curves of 0.83 and 0.72, with sensitivity of 67.2% and 87%, and specificity of 82.0% and 60%, respectively, for the prediction of pancreatic infection in moderately severe acute pancreatitis. CONCLUSIONS: Our results indicate that a higher arterial lactate level is independently associated with pancreatic infection in patients with moderately severe acute pancreatitis and may be used as a tool to identify high-risk patients.

RACK1 Acts as a Potential Tumor Promoter in Colorectal Cancer.

BACKGROUND: The receptor of activated protein kinase C 1 (RACK1) promotes the progression and invasion of several cancers. However, the role of RACK1 in the pathogenesis of colorectal cancer (CRC) has not been clearly defined. Herein, we aimed to investigate the biological role of RACK1 in CRC. MATERIALS AND METHODS: The Cancer Genome Atlas (TCGA) and the Gene Expression Omnibus (GEO) dataset were searched, and the expression of RACK1 in CRC tissues and adjacent normal tissues was evaluated. Immunohistochemical staining was performed to detect the expression of RACK1 in human CRC, adenoma, and normal tissues. Western blotting was used to detect the expression of RACK1 in human CRC cell lines. Functional assays, such as BrdU, colony formation, and wound healing and transwell invasion assays, were used to explore the biological role of RACK1 in CRC. RESULTS: RACK1 was upregulated in CRC tissues compared with its expression in adjacent normal tissues in TCGA and the GEO dataset (P < 0.05). Moreover, RACK1 was significantly overexpressed in CRC and adenoma tissues compared with its expression in normal tissues (P < 0.05). Loss-of-function experiments showed that RACK1 promoted cell proliferation, migration, and invasion in vitro. CONCLUSIONS: Our data indicated that RACK1, as an oncogene, markedly promoted the progression of CRC, which suggested that RACK1 is a potential therapeutic target for CRC management.

The prevalence of human T-cell leukemia virus in blood donors in China.

BACKGROUND: China has not yet incorporated routine human T-lymphotropic virus (HTLV)-1/2 blood donor screening, even though HTLV has been reported in the southeastern coastal region. This study was conducted to investigate the prevalence of HTLV in five major regions across of China. METHODS: From January 2016 to December 2017, blood samples were collected in 20 blood centers located in different regions of China. These samples were screened for HTLV-1/2 antibodies using enzyme-linked immunosorbent assay (ELISA). If the test samples were reactive, the samples were confirmed with a western blot (WB) assay. If the results of WB were indeterminate, the donor was interviewed after a minimum lapse of 8 weeks. All follow-up samples from donors were tested for anti-HTLV-1/2 with ELISA and WB. RESULTS: There were 875,453 donor samples tested for anti-HTLV-1/2 by ELISA. In all, 365 samples tested negative, 22 samples tested positive by WB, and 14 samples with HTLV status undetermined due to being lost to follow-up. The prevalences were 11.09, 5.96, 3.16, 2.88 and 0.98 per 100,000 in Xiamen, Changsha, Beijing, Shenzhen, and Nanjing blood center, respectively. The prevalences were 0 per 100,000 for all 15 other blood centers. There was significant differences in the prevalence of HTLV in different regions of China (p = 0.0011). CONCLUSION: In China, HTLV-1 confirmed positive donors are mainly from southeastern coastal areas. It may be necessary to conduct HTLV screening in these areas to reduce the risk of transfusion-transmitted HTLV.

Inhibition of miR-155 reduces impaired autophagy and improves prognosis in an experimental pancreatitis mouse model.

Acute pancreatitis (AP) is a common digestive disease characterized by inflammation of the pancreas. MiR-155 plays a role in promoting inflammation and inhibiting the activation of anti-inflammatory pathways. Impaired autophagy could promote zymogen activation, abnormal acinar cell secretion, cell death, and the inflammatory response to aggravate AP. The aim of this study was to ascertain the effect of silencing miR-155 on AP through its effects on inflammation and impaired autophagy in vivo. In this study, AAV(adeno-associated virus)-mediated miR-155 and miR-155 sponge were injected through the tail vein of mice. After 3 weeks, AP was induced by intraperitoneal (IP) injections of cerulein. Pancreatic and pulmonary tissues were analyzed after 24 h. Silencing of miR-155 ameliorated pancreas and lung damage in three AP models of mice by preventing accumulation of autophagosomes that are unable to fuse with lysosomes and decreasing pancreatic inflammation by targeting TAB2. 3-MA could reduce the aberrant accumulation of autophagosomes, which alleviates the pancreas damage that was aggravated by increasing miR-155 levels. These findings demonstrate that the inhibition of miR-155 holds promise for limiting pancreatitis.

Expression and Function of miR-155 in Diseases of the Gastrointestinal Tract.

MicroRNAs (miRNAs) are a type of small noncoding RNA that can regulate the expression of target genes under physiological and pathophysiological conditions. miR-155 is a multifunctional miRNA with inflammation-related and oncogenic roles. In particular, the dysregulation of miR-155 has been strongly implicated in Helicobacter pylori-related gastric disease, inflammatory bowel disease, and colorectal cancer in addition to being involved in molecular changes of important targets and signaling pathways. This review focuses on the expression and function of miR-155 during inflammation and carcinogenesis and its potential use as an effective therapeutic target for certain gastrointestinal diseases.

Oil Adulteration Identification by Hyperspectral Imaging Using QHM and ICA.

To investigate the feasibility of identification of qualified and adulterated oil product using hyperspectral imaging(HIS) technique, a novel feature set based on quantized histogram matrix (QHM) and feature selection method using improved kernel independent component analysis (iKICA) is proposed for HSI. We use UV and Halogen excitations in this study. Region of interest(ROI) of hyperspectral images of 256 oil samples from four varieties are obtained within the spectral region of 400-720nm. Radiation indexes extracted from each ROI are used as feature vectors. These indexes are individual band radiation index (RI), difference of consecutive spectral band radiation index (DRI), ratio of consecutive spectral band radiation index (RRI) and normalized DRI (NDRI). Another set of features called quantized histogram matrix (QHM) are extracted by applying quantization on the image histogram from these features. Based on these feature sets, improved kernel independent component analysis (iKICA) is used to select significant features. For comparison, algorithms such as plus L reduce R (plusLrR), Fisher, multidimensional scaling (MDS), independent component analysis (ICA), and principle component analysis (PCA) are also used to select the most significant wavelengths or features. Support vector machine (SVM) is used as the classifier. Experimental results show that the proposed methods are able to obtain robust and better classification performance with fewer number of spectral bands and simplify the design of computer vision systems.

Sonic hedgehog pathway contributes to gastric cancer cell growth and proliferation.

The Sonic Hedgehog (Shh) signaling pathway is commonly activated in gastrointestinal cancer. However, our understanding of the Shh pathway in gastric cancer remains limited. Here we examined the effects of cyclopamine, a specific inhibitor of the Shh signaling pathway, on cell growth and proliferation in gastric primary cancer cells GAM-016 and the MKN-45 cell line. The results showed that the Shh signaling molecules SHH, PTCH, SMO, GLI1, and GLI2 were intact and activated in both types of cells. Furthermore, we observed that cyclopamine inhibited gastric cancer cell proliferation through cell cycle arrest and apoptosis. An in vivo study using NOD/SCID mouse xenografts demonstrated that cyclopamine significantly prevented tumor growth and development. Our study indicated that Shh signaling pathway could promote gastric cancer cell proliferation and tumor development, and blocking this pathway may be a potential strategy in gastric cancer treatment.

Sonic Hedgehog pathway is essential for neuroblastoma cell proliferation and tumor growth.

Accumulated evidence suggests a major role for the activation of the Sonic Hedgehog (SHH) signaling pathway in the development of neural crest stem cells that give rise to the sympathetic nervous system. We therefore investigated the involvement of SHH signaling in the pathogenesis of neuroblastoma (NB), a common childhood malignant tumor of the sympathetic nervous system. Inhibition of SHH signaling by cyclopamine induced apoptosis and blocked proliferation in all major types of NB cells, and abrogated the tumorigenicity of NB cells. Our study has revealed a molecular mechanism for the persistent activation of the SHH pathway which promotes the development of NB, and suggests a new approach for the treatment of this childhood malignant tumor.

DNA-damaging drug-induced apoptosis sensitized by N-myc in neuroblastoma cells.

Neuroblastoma is one of the most common solid tumours in children (8-10% of all malignancies). Over 22% of cases have N-myc amplification associated with aggressively growing neuroblastomas. Oncogene-induced sensitization of cells to apoptosis is an important mechanism for suppression of tumorigenesis. Tumour suppressors often play a critical role in linking oncogenes to apoptotic machinery. For example, activated p53 then targets both intrinsic and extrinsic pathways to promote apoptosis through transcription-dependent and -independent mechanisms. Understanding of the involved mechanisms has important clinical implications. We have employed DNA-damaging drug-induced apoptosis sensitized by oncogene N-myc as a model. DNA damaging drugs trigger high levels of p53, leading to caspase-9 activation in neuroblastoma cells. Inactivation of p53 protects cells from drug-triggered apoptosis sensitized by N-myc. These findings thus define a molecular pathway for mediating DNA-damaging drug-induced apoptosis sensitized by oncogene, and suggest that inactivation of p53 or other components of this apoptotic pathway may confer drug resistance in neuroblastoma cells. The data also suggests that inactivation of apoptotic pathways through co-operating oncogenes may be necessary for the pathogenesis of neuroblastoma with N-myc amplification.