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The cellular origin of hepatocellular carcinomas (HCC) and the role of Notch1 signalling in HCC initiation are controversial. Herein, we establish Notch1 as a regulator of HCC development and progression. Clinically, high Notch1 expression correlates with enhanced cancer progression, elevated lung metastasis, increased cancer stem cell (CSC)-like cells' gene signature expression, and poor overall survival in HCC patients. Notch1 intracellular domain (N1ICD) overexpression spontaneously transforms rat liver progenitor cells (LPC) into CSC-like cells (WB

We read with great interest the recent article published in Gut in which Yeoh et al demonstrated that gut microbiota composition of recovered patients with COVID-19 remained significantly distinct from uninfected controls.1 Persisting symptoms, also known as ‘long COVID-19’, have been reported in a significant proportion of patients following hospital discharge.2 3 Gut dysbiosis might link to long COVID-19 risks.1 Few studies have focused on the recovery process of gut microbiota following SARS-CoV-2 infection. Here, we conducted a prospective study to longitudinally monitor alterations of gut microbiota in patients with COVID-19 using 16S rDNA sequencing (detailed methods in online supplementary materials). Faecal microbiota was monitored at three timepoints, acute phase (from illness onset to viral clearance), convalescence (from viral clearance to 2 weeks after hospital discharge), postconvalescence (6 months after hospital discharge).### Supplementary data [gutjnl-2021-324090supp001.pdf] The gut microbiota richness, measured by Chao 1 index, was obviously lower (p

Objective Hepatocellular carcinoma (HCC) is an intractable disease because patients with HCC frequently develop sorafenib resistance after long-term chemotherapy. Although studies has demonstrated the availability of cumulative information on drug-resistant patients, little is known about the strategies and molecular mechanisms to reverse sorafenib resistance. Here, the present study identified critical mRNAs and transcription factors (TFs) associated with sorafenib resistance of HCC and evaluated the significance correlation between drug-resistant genes and TFs in comprehensive network for HCC xenografts mice. Methods The expression profiles of mRNAs were compared between sorafenib-acquired resistant tissue and sorafenib sensitive tissue utilizing RNA-Seq data from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO). Gene Ontology and KEGG pathway analysis were performed to investigate the biological function of significantly dysregulated mRNA. Furthermore, the Kaplan-Meier survival analyses were performed to evaluate the effect of mRNA on over survival. Subsequently, TFs were predicted using TRANSFAC and TF-mRNA regulatory networks were visualized using cytoscape software. Results A total of 827 mRNAs were found to be differentially expressed in sorafenib-acquired resistant tissue compared with control. Thereafter, the results of functional enrichment analysis showed the dysregulated mRNAs involved in drug-resistant signaling pathway, including MAPK, JAK-STAT, TGF-β and drug-metabolism cytochrome P450 signaling pathway. CDK1, CDKN1A and TAPBP might serve as prognostic signature of resistance of HCC to sorafenib according to the survival analysis. Furthermore, TF-mRNA networks were constructed. There were 18 TFs were predicted to regulate differentially expressed mRNAs, which play an essential role in the regulation of dysfunctional gene networks. NFKB1 was presented in the TF-mRNA networks as the node with the highest degree and MYC was predicted as prognostic TF in drug resistance of HCC Conclusions Taken together, our findings showed that novel mRNAs and TFs, which served as critical biomarkers to predict survival and therapeutic targets of resistance to sorafenib in HCC. Furthermore, we constructed the TF-mRNA networks, which provides valuable theoretical references to further evaluate the molecular mechanisms of resistance to sorafenib in HCC.

In recent years, the deoxycytidine analogue gemcitabine (2′,2′,-difluorodeoxycytidine) has become the first-line chemotherapeutic agent for patients with pancreatic cancer. However, due to the intrinsic resistance of pancreatic cancer cells, gemcitabine-based chemotherapy yields limited disease control, with >85% disease progression at 6 months from diagnosis. Therefore, elucidating the mechanisms of chemoresistance is a critical step in improving cancer therapy, especially for the treatment of pancreatic cancer. We show PROM2, a transmembrane glycoprotein, is ubiquitously upregulated in pancreatic cancer cell. We also found higher PROM2 expression is associated with shortened overall and disease-free survival times in patients diagnosed with pancreatic cancer. We provide evidence that PROM2 promotes chemoresistance to gemcitabine both in vivo and in vitro. Mechanistically, we demonstrate that PROM2 could directly interacted with Akt and activates the Akt signaling pathway, which thus inhibiting gemcitabine-induced apoptosis. As further evidence, we show PROM2 expression and Akt phosphorylation both promote gemcitabine chemoresistance, and cause poorer survival in clinical samples with pancreatic cancer. Combining gemcitabine with the Akt inhibitor MK-2206 facilitated significant tumor shrinkage and dramatically elevated the survival status in mice xenografted with pancreatic cancer cells. Our findings not only establish PROM2 as a novel positive regulator of the Akt signaling pathway and a candidate prognostic indicator of gemcitabine response, but also provide a neo-therapeutic approach for patients resistant to gemcitabine treatment., Pancreatic cancer: Exploring a pathway to drug resistance A cell membrane protein called PROM2 promotes the resistance of pancreatic cancer to the anti-cancer drug gemcitabine, suggesting PROM2 and the molecular signaling pathway it stimulates could be targeted by new treatments. Researchers in China led by Jian Sun at Sun Yat-Sen University, Guangzhou, investigated the role of PROM2 in cultured human pancreatic cancer cells and in a mouse model of pancreatic cancer. Production and activity of PROM2 were increased in cancer cells, leading to increased resistance to gemcitabine. The researchers found that PROM2’s promotion of gemcitabine resistance was linked to its ability to bind to another protein called Akt. This interaction stimulates the Akt signaling pathway, sustaining cancer cells. Combining gemcitabine therapy with an Akt pathway inhibitor restored cancer cell sensitivity to gemcitabine, revealing a potential approach to developing drugs to overcome gemcitabine resistance.

Hepatocellular carcinoma (HCC) has high morbidity and mortality. MicroRNAs (miRNAs), which could be regulated by cancer-derived exosomes, play critical regulatory roles in the initiation and development of cancer. However, the expressions, effects, and mechanisms of abundant miRNAs regulated by HCC cancer-derived exosomes in HCC remain largely unclear. Exosomes of HepG2 cells under heat shock, TGF-β1, doxorubicin, acid and hypoxia/reoxygenation (H/R) conditions, and exosomes were successfully identified by transmission electron microscopy and Western blot analysis. The identified exosomes were then applied to evaluate the miRNA expression profiles by RNA sequencing. Mechanically, we discovered that doxorubicin was upregulated, TGF-β1 downregulated the expressions of Vps4A, Rab27A, Alix, and Hrs in HepG2 cells and exosomes, and Vps4A and Rab27A, as target genes for miR-4454, could also be downregulated by miR-4454. Functionally, we revealed that miR-4454 inhibitor and miR-4454 inhibitor-mediated exosomes could markedly suppress proliferation, migration, invasion, and vascularization and accelerate cycle arrest, apoptosis, and ROS of HepG2 cells. This study provided many potential HCC cancer-derived exosome-mediated miRNAs in HCC under 5 different stimulus conditions. Meanwhile, we certified that miR-4454 in exosomes could provide a novel and effective mechanism for HCC function.

Patients with persistent positive hepatitis B surface antigen (HBsAg), even with a low HBV-DNA load, have a higher risk of hepatocellular carcinoma (HCC) than those without HBV infection. Given that tumor stemness has a critical role in the occurrence and maintenance of neoplasms, this study aimed to explore whether HBsAg affects biological function and stemness of HCC by regulating microRNA, and to explore underlying mechanisms.We screened out miR-203a, the most significant down-regulated microRNA in the microarray analysis of HBsAg-positive samples and focused on that miRNA in the ensuing study.MiR-203a was significantly down-regulated in HBsAg-positive HCC with the sharpest decrease shown in microarray analysis. The negative correlation between miR-203a and HBsAg expression was confirmed by quantitative real-time PCR after stimulation or overexpression/knockdown of HBsAg in cells. We demonstrated the function of miR-203a in inhibiting HCC cell proliferation, migration, clonogenic capacity, and tumor developmentHBsAg may promote the development of HCC and tumor stemness by inhibiting miR-203a, resulting in poor prognosis. miR-203a may serve as a crucial treatment target in HBsAg-positive HCC. More explicit mechanistic studies and animal experiments need to be conducted as a next step.

BACKGROUND Diarrhea is a major infectious cause of childhood morbidity and mortality worldwide. In clinical trials, Lactobacillus rhamnosus GG ATCC 53013 (LGG) has been used to treat diarrhea. However, recent randomized controlled trials (RCTs) found no evidence of a beneficial effect of LGG treatment. AIM To evaluate the efficacy of LGG in treating acute diarrhea in children. METHODS The EMBASE, MEDLINE, PubMed, Web of Science databases, and the Cochrane Central Register of Controlled Trials were searched up to April 2019 for metaanalyses and RCTs. The Cochrane Review Manager was used to analyze the relevant data. RESULTS Nineteen RCTs met the inclusion criteria and showed that compared with the control group, LGG administration notably reduced the diarrhea duration [mean difference (MD) -24.02 h, 95% confidence interval (CI) (-36.58, -11.45)]. More effective results were detected at a high dose . 1010 CFU per day [MD -22.56 h, 95%CI (-36.41, -8.72)] vs a lower dose. A similar reduction was found in Asian and European patients [MD -24.42 h, 95%CI (-47.01, -1.82); MD -32.02 h, 95%CI (- 49.26, -14.79), respectively]. A reduced duration of diarrhea was confirmed in LGG participants with diarrhea for less than 3 d at enrollment [MD -15.83 h, 95%CI (-20.68, -10.98)]. High-dose LGG effectively reduced the duration of rotavirus-induced diarrhea [MD -31.05 h, 95%CI (-50.31, -11.80)] and the stool number per day [MD -1.08, 95%CI (-1.87, -0.28)]. CONCLUSION High-dose LGG therapy reduces the duration of diarrhea and the stool number per day. Intervention at the early stage is recommended. Future trials are expected to verify the effectiveness of LGG treatment. (Less)

Patients with poliomyelitis underwent total hip arthroplasty (THA) are known to be at higher risk of dislocation on account of muscular atrophy. This study aimed to investigate clinical outcomes, radiographic outcomes, complication rates, and survivorship of dual mobility THA in displaced femoral neck fractures of elderly with poliomyelitis.We retrospectively included 17 patients (17 hips) with residual poliomyelitis who underwent THA with dual mobility articulation. Clinical outcomes were assessed with the visual analog scale (VAS) pain score, Oxford hip score, and University of California Los Angeles activity (UCLA) score. Radiographic outcomes were examined by radiographs. Complications and re-operations following THA were recorded.The mean follow-up period was 77.05 months. The mean VAS, Oxford hip score, and UCLA score were improved significantly. In all but one patient, no complications were occurred. Re-operation was carried out in one patient due to posterior dislocation. The Kaplan-Meier survivorship with an end point of re-operation for any reason was 94.1%.THA with dual mobility system is proved to be effective in strengthening stability and reducing the risk of dislocation, which is suitable for patients with neuromuscular disease. Hence, in elderly with residual poliomyelitis, dual mobility THA is a valid choice as a treatment for displaced femoral neck fractures.

BACKGROUND Intestinal dysbiosis has been shown to be associated with the pathogenesis of alcoholic liver disease (ALD), which includes changes in the microbiota composition and bacterial overgrowth, but an effective microbe-based therapy is lacking. Pediococcus pentosaceus (P. pentosaceus) CGMCC 7049 is a newly isolated strain of probiotic that has been shown to be resistant to ethanol and bile salts. However, further studies are needed to determine whether P. pentosaceus exerts a protective effect on ALD and to elucidate the potential mechanism. AIM To evaluate the protective effect of the probiotic P. pentosaceus on ethanol-induced liver injury in mice. METHODS A new ethanol-resistant strain of P. pentosaceus CGMCC 7049 was isolated from healthy adults in our laboratory. The chronic plus binge model of experimental ALD was established to evaluate the protective effects. Twenty-eight C57BL/6 mice were randomly divided into three groups: The control group received a pair-fed control diet and oral gavage with sterile phosphate buffered saline, the EtOH group received a ten-day Lieber-DeCarli diet containing 5% ethanol and oral gavage with phosphate buffered saline, and the P. pentosaceus group received a 5% ethanol Lieber-DeCarli diet but was treated with P. pentosaceus. One dose of isocaloric maltose dextrin or ethanol was administered by oral gavage on day 11, and the mice were sacrificed nine hours later. Blood and tissue samples (liver and gut) were harvested to evaluate gut barrier function and liver injury-related parameters. Fresh cecal contents were collected, gas chromatography–mass spectrometry was used to measure short-chain fatty acid (SCFA) concentrations, and the microbiota composition was analyzed using 16S rRNA gene sequencing. RESULTS The P. pentosaceus treatment improved ethanol-induced liver injury, with lower alanine aminotransferase, aspartate transaminase and triglyceride levels and decreased neutrophil infiltration. These changes were accompanied by decreased levels of endotoxin and inflammatory cytokines, including interleukin-5, tumor necrosis factor-α, granulocyte colony-stimulating factor, keratinocyte-derived protein chemokine, macrophage inflammatory protein-1α and monocyte chemoattractant protein-1. Ethanol feeding resulted in intestinal dysbiosis and gut barrier disruption, increased relative abundance of potentially pathogenic Escherichia and Staphylococcus, and the depletion of SCFA-producing bacteria, such as Prevotella, Faecalibacterium, and Clostridium. In contrast, P. pentosaceus administration increased the microbial diversity, restored the relative abundance of Lactobacillus, Pediococcus, Prevotella, Clostridium and Akkermansia and increased propionic acid and butyric acid production by modifying SCFA-producing bacteria. Furthermore, the levels of the tight junction protein ZO-1, mucin proteins (mucin [MUC]-1, MUC-2 and MUC-4) and the antimicrobial peptide Reg3β were increased after probiotic supplementation. CONCLUSION Based on these results, the new strain of P. pentosaceus alleviated ethanol-induced liver injury by reversing gut microbiota dysbiosis, regulating intestinal SCFA metabolism, improving intestinal barrier function, and reducing circulating levels of endotoxin and proinflammatory cytokines and chemokines. Thus, this strain is a potential probiotic treatment for ALD.

As of Apr. 22, 2020, the World Health Organization (2020) has reported over 2.4 million confirmed coronavirus disease 2019 (COVID-19) patients and 169 151 deaths. Recent articles have uncovered genomic characteristics and clinical features of COVID-19 (Chan et al., 2020; Chang et al., 2020; Guan et al., 2020; Zhu et al., 2020), while our understanding of COVID-19 is still limited. As suggested by guidelines promoted by the General Office of National Health Commission of the People's Republic of China (2020) (from Versions 1 to 6), discharged standards for COVID-19 were still dependent on viral real-time polymerase chain reaction (RT-PCR) tests of respiratory specimens, showing that recovered COVID-19 patients with twice negative RT-PCR could meet discharge criteria. Here, we examined two cases in which nucleic acid test results were inconsistent with clinical and radiological findings, leading to suboptimal care.

Dysregulation of dickkopf-related protein 1 (DKK1) expression has been reported in a variety of human cancers. We previously reported that DKK1 was upregulated in hepatocellular carcinoma (HCC). However, the role of DKK1 in HCC remains unclear. This study aimed to investigate the clinical significance and biological functions of DKK1 in HCC. The expression of DKK1 was examined in cirrhotic and HCC tissues by immunohistochemistry and quantitative real-time polymerase chain reaction (qRT-PCR). DKK1 was silenced or overexpressed in HCC cell lines, and in vitro and in vivo studies were performed. Immunohistochemistry revealed that DKK1 was weakly expressed in cirrhotic tissues (8/22, 36.4%) but upregulated in HCC tissues (48/53, 90.6%, cohort 1). Significant upregulation of DKK1 was observed in 57.6% (19/33, cohort 2) of HCC tissues by qRT-PCR, and the expression of DKK1 was associated with tumor size (P = 0.024) and tumor number (P = 0.019). Genetic depletion of DKK1 impaired the proliferation, colony-forming ability, invasion, and tumor formation of HCC cells (HepG2 and HUH-7). Conversely, forced expression of DKK1 increased the proliferation, colony-forming ability, and invasion of HepG2 and HUH-7 cells in vitro and enhanced tumor formation in vivo. Subsequent investigation revealed that the DKK1-mediated proliferation and tumorigenicity of HepG2 and HUH-7 cells is dependent on the Wnt/β-catenin signaling pathway. These findings indicate that DKK1 plays an oncogenic role in HCC by activating the Wnt/β-catenin signaling pathway.

Bacillus cereus (B. cereus) functions as a probiotic in animals, but the underlying mechanisms remain unclear. We aim to evaluate the protective effects and definite mechanism by which orally administered B. cereus prevents D-galactosamine (D-GalN)-induced liver injury in rats. Twenty-one Sprague–Dawley rats were equally assigned into three groups (N = 7 animals per group). B. cereus ATCC11778 (2 × 109 colony-forming units/ml) was administered to the B. cereus group via gavage, and phosphate-buffered saline was administered to the positive control (PC) and negative control (NC) groups for 2 weeks. The PC and B. cereus groups received 1.1 g/kg D-GalN via an intraperitoneal injection to induce liver injury. The blood, terminal ileum, liver, kidney and mesenteric lymph nodes (MLNs) were collected for histological examinations and to evaluate bacterial translocation. Liver function was also determined. Fecal samples were collected for deep sequencing of the 16S rRNA on an Illumina MiSeq platform. B. cereus significantly attenuated D-GalN-induced liver injury and improved serum alanine aminotransferase (ALT) and serum cholinesterase levels (P < 0.05 and P < 0.01, respectively). B. cereus modulated cytokine secretion, as indicated by the elevated levels of the anti-inflammatory cytokine interleukin-10 (IL-10) in both the liver and plasma (P < 0.05 and P < 0.01, respectively) and the substantially decreased levels of the cytokine IL-13 in the liver (P < 0.05). Pretreatment with B. cereus attenuated anoxygenic bacterial translocation in the veins (P < 0.05) and liver (P < 0.05) and upregulated the expression of the tight junction protein 1. The gut microbiota from the B. cereus group clustered separately from that of the PC group, with an increase in species of the Ruminococcaceae and Peptococcaceae families and a decrease in those of the Parabacteroides, Paraprevotella, and Desulfovibrio families. The potential probiotic B. cereus attenuated liver injury by restoring the gut flora balance and enhancing the intestinal barrier function.

The Notch pathway plays an important role in both stem cell biology and cancer. Notch2 was reported to be upregulated in human hepatocellular carcinoma (HCC) tissues. However, the biological function of Notch2 in human HCC cells has not yet been documented. The aim of this study was to investigate its possible function on the progression of human HCC cells. The expression of Notch2 was detected in four human HCC cell lines by western blotting. Next, Notch2 was knocked down by small interference RNA (siRNA) in human HCC cells. The role of Notch2 in human HCC cells was investigated by cell proliferation assay, colony formation assay, chemoresistance and xenograft formation assay. In the present study, western blotting revealed that the expression of Notch2 was upregulated in human HCC cell lines. Genetic depletion of Notch2 in HCC cells not only resulted in significantly inhibited proliferation, cell cycle progression and colony formation ability but also increased its sensitivity to 5-fluorouracil (5-FU) compared with controls. In addition, upregulation of Notch2 was discovered in CD90 positive HCC cells, CD90 is a marker of hepatic stem cells. Most importantly, knockdown of Notch2 in HCC cells impaired the tumor formation in vivo. Taken together, our findings indicate that Notch2 may confer stemness properties in HCC; downregulation of Notch2 inhibited the proliferation and tumor formation of HCC cells and increase their sensitivity to 5-FU, suggesting Notch2 as a potential therapeutic target for HCC.

// Wen-rui Wu 1, 2, * , Hong Sun 3, * , Rui Zhang 1, 2, * , Xian-huan Yu 1, 2 , Xiang-de Shi 1, 2 , Man-sheng Zhu 1, 2, 4 , Hong Zeng 5 , Li-xu Yan 6 , Lei-bo Xu 1, 2 , Chao Liu 1, 2 1 Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, 510120, China 2 Department of Biliary-Pancreatic Surgery, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, 510120, China 3 Department of Respiratory, The First Affiliated Hospital/School of Clinical Medical, Guangdong Pharmaceutical University, Guangzhou, 510080, China 4 Department of Thoracic Surgery, Cancer Center of Guangzhou Medical University, Guangzhou, 510095, China 5 Department of Pathology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, 510120, China 6 Department of Pathology, Guangdong General Hospital, Guangdong Academy of Medical Science, Guangdong, 510080, China * These authors have contributed equally to this work Correspondence to: Lei-bo Xu, email: mdxuleibo@hotmail.com Chao Liu, email: mdliuchao@hotmail.com Keywords: hepatocellular carcinoma, progression, microRNA-200b, methylation, BMI1 Received: November 09, 2015 Accepted: February 09, 2016 Published: February 23, 2016 ABSTRACT This study aims to investigate the biological function of microRNA-200b and BMI1 , predicted target of microRNA-200b in human hepatocellular carcinoma (HCC). MicroRNA-200b and BMI1 expression in HCC tissues were evaluated by qPCR. A luciferase reporter assay was used to validate BMI1 as a direct target of microRNA-200b. The effect of microRNA-200b on HCC progression was studied in vitro and in vivo . Methylation specific PCR (MSP) and bisulfite sequencing PCR (BSP) were used to detect the methylation status of the microRNA-200b promoter. Significant downregulation of microRNA-200b was observed in 83.3% of HCC tissues. By contrast, BMI1 was significantly overexpressed in 66.7% of HCC tissues. The results of the luciferase assay confirmed BMI1 as a direct target gene of microRNA-200b. Forced expression of microRNA-200b in HCC cells dramatically repressed proliferation, colony formation, cell cycle progression, and invasion. Moreover, microRNA-200b synergized with 5-fluorouracil to induce apoptosis in vitro and suppressed tumorigenicity in vivo . In addition, MSP analysis and BSP revealed that CpG sites in the promoter region of microRNA-200b were extensively methylated in HCC, with concomitant downregulation of microRNA-200b expression. Furthermore, microRNA-200b was activated in HCC cells after treatment with 5-azacytidine, whereas BMI1 expression was clearly downregulated. Our results indicate that microRNA-200b is partially silenced by DNA hypermethylation and that it can repress tumor progression by directly targeting BMI1 in HCC.

CA extern Dysregulation of dickkopf-related protein 1 (DKK1) expression has been reported in a variety of human cancers. We previously reported that DKK1 was upregulated in hepatocellular carcinoma (HCC). However, the role of DKK1 in HCC remains unclear. This study aimed to investigate the clinical significance and biological functions of DKK1 in HCC. The expression of DKK1 was examined in cirrhotic and HCC tissues by immunohistochemistry and quantitative real-time polymerase chain reaction (qRT-PCR). DKK1 was silenced or overexpressed in HCC cell lines, and in vitro and in vivo studies were performed. Immunohistochemistry revealed that DKK1 was weakly expressed in cirrhotic tissues (8/22, 36.4%) but upregulated in HCC tissues (48/53, 90.6%, cohort 1). Significant upregulation of DKK1 was observed in 57.6% (19/33, cohort 2) of HCC tissues by qRT-PCR, and the expression of DKK1 was associated with tumor size (P = 0.024) and tumor number (P = 0.019). Genetic depletion of DKK1 impaired the proliferation, colony-forming ability, invasion, and tumor formation of HCC cells (HepG2 and HUH-7). Conversely, forced expression of DKK1 increased the proliferation, colony-forming ability, and invasion of HepG2 and HUH-7 cells in vitro and enhanced tumor formation in vivo. Subsequent investigation revealed that the DKK1-mediated proliferation and tumorigenicity of HepG2 and HUH-7 cells is dependent on the Wnt/β-catenin signaling pathway. These findings indicate that DKK1 plays an oncogenic role in HCC by activating the Wnt/β-catenin signaling pathway.

Autoimmune pancreatitis (AIP) is a rare type of chronic pancreatitis that is often misdiagnosed as pancreatic cancer (PaC). This study was undertaken to investigate the clinicopathological characteristics of AIP, in order to improve the diagnosis and treatment of the disease. Among the 271 patients with PaC who underwent pancreatoduodenectomy between January 2003 and December 2012 at the Sun Yat-Sen Memorial Hospital, chronic pancreatitis was identified and tissue samples obtained from 16 patients. The clinicopathological and imaging characteristics of 16 of the patients with chronic pancreatitis were analyzed retrospectively. The expression of immunoglobulin G4 (IgG4) in the pancreas tissue was detected by immunohistochemistry. Immunohistochemistry showed that IgG4 was highly expressed in 12 out of the 16 patients, and those 12 patients were diagnosed with AIP. Among those 12 patients, 6 presented with emaciation and 7 with jaundice and abdominal pain, respectively. Among the 16 included patients, 12 had an elevated level of serum γ-glutamyltransferase and 9 had an elevated level of serum carbohydrate antigen 19-9. The imaging features were as follows: Pancreatic enlargement in 11 patients (particularly pancreatic head enlargement), pancreatic miniature in 1, 'sausage-like' pancreatic changes in 4 and 'halo' sign pancreatic changes in 5. Massive plasma cell infiltration (11/12) and parenchymal fibrosis (8/12) were observed in the pancreatic tissues through pathology. These results suggest that combining imaging with IgG4 expression for the purpose of diagnosis can enhance the preoperative diagnostic value and reduce the rate of AIP misdiagnosis.

Fowl adenovirus (FAdV) has caused significant losses in chicken flocks throughout China in recent years. However, the current understanding of the genetic and pathogenic characteristics of the FAdV epidemic in southwestern China remains poorly understood. In this study, a total of 22 strains were isolated from liver samples of diseased chickens from farms in southwestern China. Phylogenetic analysis based on the hexon loop-1 gene showed that the 22 isolates were clustered into four distinct serotypes: FAdV serotype 4 (FAdV-4) (86.4%, 19/22), FAdV-2 (4.5%, 1/22), FAdV-8a (4.5%, 1/22), and FAdV-8b (4.5%, 1/22). FAdV-4 was the predominant serotype in southwestern China. Pathogenicity testing showed that the FAdV-4 serotype strain CH/GZXF/1602 and FAdV-8a strain CH/CQBS/1504 were pathogenic to chickens, with mortality rates reaching as high as 80% and 20%, respectively. The primary clinical feature observed following infection with strain CH/GZXF/1602 (FAdV-4) was hepatitis-hydropericardium syndrome, and that of strain CH/CQBS/1504 (FAdV-8a) was inclusion body hepatitis. Conversely, the FAdV-2 serotype strain CH/GZXF/1511 and FAdV-8b serotype strain CH/CQBS/1512 was not observed to be pathogenic in chickens. Then, CH/GZXF/1602 (FAdV-4) was selected for the preparation of an inactivated oil-emulsion vaccine. Immune studies on Partridge Shank broilers showed that a single dose immunization at 17 days of age could not only protect against homologous challenge with virulent FAdV-4 but also provided protection against clinical disease following challenge with the heterologous FAdV-8b virulent strain until 70 days of age. The characterization of newly prevalent FAdV strains provides a valuable reference for the development of an efficacious control strategy.

In order to have an effective induction and treatment about the various uncertain factors in the process of Job Shop manufacturing shop re- scheduling under the uncertain environment, Through the description of all kinds of uncertainties and disturbances during the workshop production process, here put forward a way to divide these uncertain factors into different types, such as type A uncertain factors which can cause scheduling scheme invalid, type B uncertain factors which have an uncertain impact on scheduling scheme and type C uncertain factors which may lead the schedule partial failure.

Satellite system design is a process involving various branches of knowledge, in which the designer usually needs to tradeoff many essentials and takes remarkable time. While multidisciplinary design optimization (MDO) method provides an effective approach for complicated system design, it seems especially suitable for such kind design purpose. By applying MDO in satellite system design, the efficiency of design can be expected to be improved and powerful technical supports can be obtained, which means better performance, faster design process and lower cost. According to the Resource satellite mission, width of ground cover and ground resolution are taken as the performance measurement, which combined with total mass of satellite is accounted in the optimization objective in system level. The design variables and constraints of the problem are dealt with disciplines or subsystems such as GNC, power, structure and thermal control. Corresponding analysis modules close to practical engineering are modeled. A MDO program system is developed by integrating collaborative optimization (CO) methods in iSIGHT. The result shows that the comprehensive objective can be improved, which also indicates MDO is feasible and efficient to solve the spacecraft design problem. The technology can be consulted for further research work.

We selected 42 early-stage primary biliary cirrhosis (PBC) patients and 30 healthy controls (HC). Metagenomic sequencing of the 16S rRNA gene was used to characterize the fecal microbiome. UPLC-MS/MS assaying of small molecules was used to characterize the metabolomes of the serum, urine and feces. Liquid chip assaying of serum cytokines was used to characterize the immune profiles. The gut of PBC patients were depleted of some potentially beneficial bacteria, such as Acidobacteria, Lachnobacterium sp., Bacteroides eggerthii and Ruminococcus bromii, but were enriched in some bacterial taxa containing opportunistic pathogens, such as γ-Proteobacteria, Enterobacteriaceae, Neisseriaceae, Spirochaetaceae, Veillonella, Streptococcus, Klebsiella, Actinobacillus pleuropneumoniae, Anaeroglobus geminatus, Enterobacter asburiae, Haemophilus parainfluenzae, Megasphaera micronuciformis and Paraprevotella clara. Several altered gut bacterial taxa exhibited potential interactions with PBC through their associations with altered metabolism, immunity and liver function indicators, such as those of Klebsiella with IL-2A and Neisseriaceae with urinary indoleacrylate. Many gut bacteria, such as some members of Bacteroides, were altered in their associations with the immunity and metabolism of PBC patients, although their relative abundances were unchanged. Consequently, the gut microbiome is altered and may be critical for the onset or development of PBC by interacting with metabolism and immunity.

Notch signaling has been reported to be activated to promote biliary epithelial cell differentiation and tubulogenesis during bile duct development. In this study, clinicopathological significance of aberrant expression of Notch receptors in intrahepatic cholangiocarcinoma (ICC) was investigated. Thus, forty-one ICC specimens were examined by immunohistochemistry using anti-Notch1-4 antibodies, respectively. Expression of Notch receptors was scored by percentage of positive tumor cells and intensity of immunostaining. Clinicopathological parameters and survival data were compared with the expression of Notch receptors, respectively. Expression of Notch receptors was identified in cancer cells, as well as in non-neoplastic cells. Compared with adjacent non-tumor liver tissues, Notch1 and 4 were up regulated, and Notch2 and 3 were relatively weaker. Positive immunostaining of Notch1 in ICC cells was detected in 34 cases (82.9%), Notch2 in 23 (56.1%), Notch3 in 16 (39.0%) and Notch4 in 14 (34.1%). Notch1 was overexpressed in cases with tumor size > 5 cm (P = 0.036). Expression of Notch2 was correlated inversely with histological grade (P = 0.016). Overexpression of Notch4 was more common in cases with serum CA125 > 35 U/ml than cases with CA125 ≤ 35 U/ml (P = 0.048). Expression of Notch3 was not correlated with any other clinicopathological parameters. Moreover, Notch4 was related to poor survival (P < 0.001). To conclude, this study reveals that aberrant expression of Notch receptors 1 and 4 might play important roles during ICC progression.

The Notch signaling pathway has been reported to play crucial roles in inhibiting hepatocyte differentiation and allowing formation of intrahepatic bile ducts. However, little is known about its significance in intrahepatic cholangiocarcinoma (ICC). The aim of the present study was to investigate the effects of Notch1 expression in ICC tissues and cells. The expression of Notch1 was examined in paraffin-embedded sections of ICC (n=44) by immunohistochemistry. Notch1 was knocked down by RNA interference (RNAi) in cultured ICC cells (RBE and HCCC-9810). The proliferation, invasiveness and sensitivity to 5-fluorouracil (5-FU) were detected by Cell Counting Kit-8 (CCK-8), colony formation assays, Transwell assays and flow cytometry, respectively. The expression levels of several multidrug resistance (MDR)-related genes, MDR1-P-glycoprotein (ABCB‑1), breast cancer resistance protein (ABCG‑2) and the multidrug resistance protein isoform 1 (MRP‑1), were examined by quantitative real-time polymerase chain reaction (qRT-PCR) and western blotting. Notch1 was overexpressed in cell membranes and cytoplasm of ICC compared with the adjacent liver tissue (35/44, 79.5%) and this was more common in cases with tumor size≥5 cm (p=0.021) and HBs-Ag positive (p=0.018). By silencing Notch1, the proliferation and invasiveness of ICC cells were inhibited and the inhibition rate of 5-FU was markedly increased. In addition, IC50 values of 5-FU in RBE cells were decreased from 148.74±0.72 to 5.37±0.28 µg/ml and the corresponding values for HCCC-9810 cells were 326.92±0.87 to 42.60±0.35 µg/ml, respectively. Furthermore, Notch1 silencing clearly increased the percentage of apoptotic cells treated by 5-FU compared with the control. Notch1 knockdown led to diminished expression levels of ABCB‑1 and MRP‑1. Therefore, Notch may play important roles in the development of ICC. Silencing Notch1 can inhibit the proliferation and invasiveness of ICC cells and increase their sensitivity to 5-FU in vitro.

Adult hepatic progenitor cells (HPCs) are involved in a wide range of human liver diseases, including hepatocellular carcinoma (HCC). Bmi1 has been reported to have vital roles in stem cell self-renewal and carcinogenesis. We have previously demonstrated that Bmi1 is upregulated in HCC with bile duct tumor thrombi, a subtype of HCC characterized by profuse expression of hepatic stem cell markers. However, the function of Bmi1 in HPCs has not yet been well elucidated. The current study was designed to investigate the effects of Bmi1 on the biological properties of rat HPCs. To accomplish this, Bmi1 was silenced or enhanced in two HPC cell lines (WB-F344 and OC3) by, respectively, using either small interfering RNA against Bmi1 or a forced Bmi1 expression retroviral vector. The biological functions of Bmi1 in HPCs were investigated through cell proliferation assays, colony-formation assays, cell cycle analysis and invasion assays, as well as through xenograft-formation assays. In this study, genetic depletion of Bmi1 repressed cell proliferation, colony formation and invasion in both assessed HPC cell lines relative to controls. Conversely, forced expression of Bmi1 in two HPCs cell lines promoted cell proliferation, colony formation and invasion in vitro. Aldehyde dehydrogenase (ALDH) assay revealed a significant increase in the number of ALDH-positive cells following the forced expression of Bmi1 in HPCs. Most importantly, transplantation of forced Bmi1 expression HPCs into nude mice resulted in the formation of tumors with histological features of poorly differentiated HCC. Taken together, our findings indicate that forced expression of Bmi1 promotes the malignant transformation of HPCs, suggesting Bmi1 might be a potential molecular target for the treatment of HCC.

Because of the intermittence of wind resource, as well as electricity quantity is determined by the local wind resource, it is difficult to compare the economic operation situations of wind farms of different wind resource and other conditions. Evaluation Indexes of economic operation for wind farms were discussed according to actual operation and monitoring situations of wind farms, as well as influencing factors for economic operation of wind farm. Available wind energy efficiency, earnings rate and maintenance coefficient were proposed as evaluation indexes. And through consistency processing, dimensionless processing and normalizing processing, a comprehensive evaluation system was established. The feasibility of the evaluation system was verified by comparison of three different wind farms. The evaluation indexes were also compared with thermal power, water power, nuclear power and other power industries, the results indicated system efficiency and earnings rate can be used in all power plants, and available wind energy efficiency and maintenance coefficient are of the wind farm's characteristics.

With the development of wind industry, influencing factors for economic operation of wind farm is attracting more and more attention. The internal and external factors during wind farm's life cycle are discussed. For external factors, wind electricity price, taxes, repayment load, tempo of wind power industry are analyzed; as to internal factors, evaluation of wind resource, site selection, feasibility study, project bidding, project design of wind farm, design and manufacture of wind power equipments, construction, operation and maintenance of wind farm are analyzed in this paper. According to the analysis, we can obtain the conclusion: the external factor, i.e. wind electricity price, taxes, repayment load, tempo of wind industry leave little selection room for wind power enterprise, as to internal factors, wind resource is the precondition, design and manufacture of wind power equipments, design and construction of wind farm are the pledge, operation and maintenance is the last stage but not the least important stage to achieve economic benefit.

As the leading cause of disease-related deaths, cancer is a major public health threat worldwide. Surgical resection is still the first-line therapy for patients with early-stage cancers. However, postoperative relapse and metastasis remain the cause of 90% of deaths of patients with solid organ malignancies, including hepatocellular carcinoma (HCC). With the rapid development of molecular biology techniques in recent years, molecularly targeted therapies using monoclonal antibodies, small molecules, and vaccines have become a milestone in cancer therapeutic by significantly improving the survival of cancer patients, and have opened a window of hope for patients with advanced cancer. Hypervascularization is a major characteristic of HCC. It has been reported that anti-angiogenic treatments, which inhibit blood vessel formation, are highly effective for treating HCC. However, the efficacy and safety of anti-angiogenesis therapies remain controversial. Sorafenib is an oral multikinase inhibitor with anti-proliferative and anti-angiogenic effects and is the first molecular target drug approved for the treatment of advanced HCC. While sorafenib has shown promising therapeutic effects, substantial evidence of primary and acquired resistance to sorafenib has been reported. Numerous clinical trials have been conducted to evaluate a large number of molecularly targeted drugs for treating HCC, but most drugs exhibited less efficacy and/or higher toxicity compared to sorafenib. Therefore, understanding the mechanism(s) underlying sorafenib resistance of cancer cells is highlighted for efficiently treating HCC. This concise review aims to provide an overview of anti-angiogenesis therapy in the management of HCC and to discuss the common mechanisms of resistance to anti-angiogenesis therapies.