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  • 1
    Publication Date: 2018-04-07
    Description: Objective Myeloid-derived suppressor cells (MDSCs) contribute to tumour immunosuppressive microenvironment and immune-checkpoint blockade resistance. Emerging evidence highlights the pivotal functions of cyclin-dependent kinases (CDKs) in tumour immunity. Here we elucidated the role of tumour-intrinsic CDK20, or cell cycle-related kinase (CCRK) on immunosuppression in hepatocellular carcinoma (HCC). Design Immunosuppression of MDSCs derived from patients with HCC and relationship with CCRK were determined by flow cytometry, expression analyses and co-culture systems. Mechanistic studies were also conducted in liver-specific CCRK -inducible transgenic (TG) mice and Hepa1–6 orthotopic HCC models using CRISPR/Cas9-mediated Ccrk depletion and liver-targeted nanoparticles for interleukin (IL) 6 trapping. Tumorigenicity and immunophenotype were assessed on single or combined antiprogrammed death-1-ligand 1 (PD-L1) therapy. Results Tumour-infiltrating CD11b + CD33 + HLA-DR – MDSCs from patients with HCC potently inhibited autologous CD8 + T cell proliferation. Concordant overexpression of CCRK and MDSC markers (CD11b/CD33) positively correlated with poorer survival rates. Hepatocellular CCRK stimulated immunosuppressive CD11b + CD33 + HLA-DR – MDSC expansion from human peripheral blood mononuclear cells through upregulating IL-6. Mechanistically, CCRK activated nuclear factor-B (NF-B) via enhancer of zeste homolog 2 (EZH2) and facilitated NF-B-EZH2 co-binding to IL-6 promoter. Hepatic CCRK induction in TG mice activated the EZH2/NF-B/IL-6 cascade, leading to accumulation of polymorphonuclear (PMN) MDSCs with potent T cell suppressive activity. In contrast, inhibiting tumorous Ccrk or hepatic IL-6 increased interferon + tumour necrosis factor-α + CD8 + T cell infiltration and impaired tumorigenicity, which was rescued by restoring PMN-MDSCs. Notably, tumorous Ccrk depletion upregulated PD-L1 expression and increased intratumorous CD8 + T cells, thus enhancing PD-L1 blockade efficacy to eradicate HCC. Conclusion Our results delineate an immunosuppressive mechanism of the hepatoma-intrinsic CCRK signalling and highlight an overexpressed kinase target whose inhibition might empower HCC immunotherapy.
    Keywords: Gut
    Print ISSN: 0017-5749
    Electronic ISSN: 1468-3288
    Topics: Medicine
    Published by BMJ Publishing Group
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  • 2
    Publication Date: 2018-01-03
    Description: Autophagic impairment is implicated in nonalcoholic fatty liver disease (NAFLD), but the molecular mechanism is unclear. We found that autophagic flux was significantly inhibited in 3 murine models of NAFLD. Interestingly, the number of acidic organelles and the level of mature cathepsin D were reduced, suggesting defective lysosome acidification. Asparagine synthetase (ASNS) was induced by endoplasmic reticulum stress, leading to the generation of asparagine, which inhibited lysosome acidification. Both steatotic- and asparagine-treated hepatocytes showed reduced lysosomal acidity and retention of lysosomal calcium. Knockdown of ASNS in steatotic hepatocytes restored autophagic flux. As a potential biomarker, increased serum p62/sequestosome 1 (SQSTM1) level was an independent risk factor for patients with steatosis and lobular inflammation. Impaired autophagy in NAFLD is elicited by defective lysosome acidification, which is caused by ASNS-induced asparagine synthesis under endoplasmic reticulum stress and subsequent retention of lysosomal calcium. p62/SQSTM1 could be used as a noninvasive biomarker in the diagnosis of NAFLD patients.—Wang, X., Zhang, X., Chu, E. S. H., Chen, X., Kang, W., Wu, F., To, K.-F., Wong, V. W. S., Chan, H. L. Y., Chan, M. T. V., Sung, J. J. Y., Wu, W. K. K., Yu, J. Defective lysosomal clearance of autophagosomes and its clinical implications in nonalcoholic steatohepatitis.
    Print ISSN: 0892-6638
    Electronic ISSN: 1530-6860
    Topics: Biology
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  • 3
    ISSN: 1573-2665
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Type of Medium: Electronic Resource
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  • 4
    ISSN: 1434-4726
    Keywords: Key words Nucleolar organizer region ; Nasopharyngeal carcinoma ; Silver-staining ; Prognosis ; Outcome
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Increased expression of argyrophilic nucleolar organizer regions (AgNORs) has been identified in certain malignant tumors including nasopharyngeal carcinoma (NPC). However, its prognostic significance in NPC is uncertain and remains to be evaluated. To address this we silver-stained 63 paraffin sections of NPC cases, and examined the correlation between AgNOR count and area, calculated by the CAS 200 image analysis system, and tumor behavior, locoregional control, and survival of patients. The mean AgNOR count and area were 1.62 ± 0.31 and 3.98 ± 11.4 μm2, respectively. The AgNOR area was positively associated with T stage (r = 0.26, P = 0.04). The Mann-Whitney test confirmed no significant difference in AgNOR area and count between patients with different outcomes. Multivariate analysis using the Cox proportional hazard model showed neither AgNOR count nor area to be significant predictors of actuarial survival or disease-free survival. It is concluded that AgNOR does not have an independent and significant prognostic value in NPC. AgNOR expression may be merely a reflection of malignant phenotype as well as cellular activity but not necessarily the ultimate behavior of the tumor.
    Type of Medium: Electronic Resource
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  • 5
    ISSN: 1365-2036
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: There are conflicting reports on the expression of cyclooxygenase in Helicobacter pylori infection.〈section xml:id="abs1-2"〉〈title type="main"〉Aim:To evaluate the expression of COX-1 and COX-2 in H. pylori gastritis at messenger RNA (mRNA) and protein levels.〈section xml:id="abs1-3"〉〈title type="main"〉Methods:Endoscopic gastric biopsies were obtained from patients with non-ulcer dyspepsia. The levels of COX-1 and COX-2 mRNA were compared between H. pylori-infected and uninfected specimens using reverse transcription-polymerase chain reaction. The immunohistochemical findings were correlated with the cellular localization of cyclooxygenase mRNA using in situ hybridization.〈section xml:id="abs1-4"〉〈title type="main"〉Results:A total of 40 H. pylori-infected and 40 uninfected specimens were studied. mRNA of COX-2 but not COX-1 was elevated in H. pylori-infected mucosa. COX-1 was localized to the mononuclear inflammatory, endothelial and smooth muscle cells in the lamina propria. COX-2 was barely detectable in uninfected mucosa but was strongly expressed in the foveolar and glandular epithelia in H. pylori gastritis.〈section xml:id="abs1-5"〉〈title type="main"〉Conclusion:Cyclooxygenase-1 is expressed in the mononuclear inflammatory, endothelial and smooth muscle cells in the lamina propria irrespective of the H. pylori status. By contrast, H. pylori induces COX-2 expression in the foveolar and glandular epithelia.
    Type of Medium: Electronic Resource
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  • 6
    Electronic Resource
    Electronic Resource
    Oxford, UK : Blackwell Science Ltd
    ISSN: 1365-2230
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Type of Medium: Electronic Resource
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  • 7
    ISSN: 1365-2036
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Cyclooxygenase-2 may play a role in the development of hepatocellular carcinoma, but the relationship between cyclooxygenase-2 and chronic hepatitis B is unknown.〈section xml:id="abs1-2"〉〈title type="main"〉Aim:To investigate the expression and cellular localization of cyclooxygenase-2 in chronic hepatitis B patients and the effects of anti-viral therapy.〈section xml:id="abs1-3"〉〈title type="main"〉Methods:Using immunohistochemistry, in situ hybridization, Western blot and reverse transcription polymerase chain reaction, protein and messenger RNA expression and cellular localization of cyclooxygenase-2 in 35 chronic hepatitis B patients were assessed. Fourteen histologically normal and non-viral-infected livers were used as controls. The cyclooxygenase-2 immunoreactivities of paired liver biopsies from 12 patients receiving anti-viral therapy were compared.〈section xml:id="abs1-4"〉〈title type="main"〉Results:Immunohistochemistry and in situ hybridization revealed that cyclooxygenase-2 expression was confined to hepatocytes. Patients with chronic hepatitis B had significantly higher cyclooxygenase-2 expression compared with controls. The cyclooxygenase-2 expression of hepatitis B e antigen-positive and -negative chronic hepatitis B patients was not significantly different, although the necro-inflammatory activity of the latter group was significantly lower. Over-expression of cyclooxygenase-2 in patients with chronic hepatitis B was further confirmed by Western blot and reverse transcription polymerase chain reaction. Twelve hepatitis B e antigen-positive chronic hepatitis B patients received anti-viral therapy: lamivudine in seven and interferon in five. Despite hepatitis B e antigen seroconversion, disappearance of hepatitis B virus DNA in serum, normalization of liver enzymes and a significant reduction in necro-inflammatory activity in all 12 patients, no significant change in cyclooxygenase-2 expression was found.〈section xml:id="abs1-5"〉〈title type="main"〉Conclusions:Chronic hepatitis B is associated with elevated cyclooxygenase-2 levels in hepatocytes, and the over-expression of this enzyme does not reflect inflammatory activity. Up-regulation of cyclooxygenase-2 persists after successful anti-viral therapy.
    Type of Medium: Electronic Resource
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  • 8
    ISSN: 1365-2036
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Imbalance between apoptosis and proliferation may be one of the mechanisms underlying H. pylori associated gastric carcinogenesis.〈section xml:id="abs1-2"〉〈title type="main"〉Aim:To examine the cell kinetics of gastric intestinal metaplasia and the effect of H. pylori eradication.〈section xml:id="abs1-3"〉〈title type="main"〉Methods:Endoscopic gastric biopsies were obtained from 100 H. pylori-infected patients. Apoptosis was determined by triphosphate nick-end labelling (TUNEL) and apoptotic nuclei counting, whereas proliferation was assessed by Ki67 immunostaining. Gastric biopsies were repeated in a sub-group of intestinal metaplasia patients after H. pylori eradication.〈section xml:id="abs1-4"〉〈title type="main"〉Results:Antral apoptotic index was significantly lower in intestinal metaplasia than in non-intestinal metaplasia (0.19% vs. 0.51%; P 〈 0.0001) whereas the level of proliferation was comparable (28% vs. 22%, P=0.15). Serial antral biopsies taken from 14 intestinal metaplasia patients before and 1 year after H. pylori eradication showed a significant drop in proliferation in both intestinal metaplasia (50% vs. 12%, P 〈 0.001) and non-intestinal metaplasia area (47% vs. 9%, P 〈 0.001). A similar fall in apoptosis was detected in non-metaplastic region (0.58% vs. 0.38%, P 〈 0.001) but not in intestinal metaplasia (0.24% vs. 0.27%, P=0.56), resulting in a significant increase in the apoptosis/proliferation ratio (0.005–0.021; P=0.03).〈section xml:id="abs1-5"〉〈title type="main"〉Conclusions:Dysregulation in apoptosis control of gastric intestinal metaplasia may contribute to gastric carcinogenesis, which may be retarded by clearance of H. pylori.
    Type of Medium: Electronic Resource
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  • 9
    ISSN: 1365-2036
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Cyclins and cyclin-dependent kinase inhibitors play a crucial role in the control of cell cycle transitions. Enhanced expression of cyclin D2 and reduced expression of p27kip1 (p27) have been implicated in the pathogenesis of cancer. Because intestinal metaplasia has been regarded as a pre-malignant lesion, we investigated the expression of cyclin D2 and p27 in Helicobacter pylori-associated chronic gastritis with and without intestinal metaplasia, and followed the changes after H. pylori eradication.〈section xml:id="abs1-2"〉〈title type="main"〉Methods:Expression of cyclin D2 and p27 was studied by immunohistochemistry in 59 patients (including 35 patients with intestinal metaplasia) and in 10 gastric cancer patients. Among them, 29 H. pylori-infected patients had serial gastric biopsies taken before and at 1-year after eradication of H. pylori.〈section xml:id="abs1-3"〉〈title type="main"〉Results:Expression of cyclin D2 was significantly higher in gastric cancers when compared to their adjacent non-tumour tissues (median score 3 vs. 1, P=0.015). Over-expression of cyclin D2 was detected in H. pylori-associated chronic gastritis and intestinal metaplasia, which was reduced after eradication of the organism (median score 2 vs. 1, P=0.037 in chronic gastritis; median score 2 vs. 0, P=0.008 in intestinal metaplasia). While the normal gastric mucosa showed strong p27 expression, five of the 10 gastric cancer tissues exhibited reduced p27 expression (P=0.039). Diminished p27 expression was also seen in intestinal metaplasia, which was restored 1-year after H. pylori eradication (eight out of 16 vs. one out of 16, P=0.018). Reduced expression of p27 was frequently associated with increased cyclin D2 expression in H. pylori-associated intestinal metaplasia (P=0.02).〈section xml:id="abs1-4"〉〈title type="main"〉Conclusion:Over-expression of cyclin D2 and reduced expression of p27 are closely linked to H. pylori-associated intestinal metaplasia. Eradication of H. pylori infection reverses the aberrant expression of cyclin D2 and p27 in intestinal metaplasia.
    Type of Medium: Electronic Resource
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  • 10
    ISSN: 1365-2036
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: The expression of cyclooxygenase (COX) in human gastric ulcers is unknown.〈section xml:id="abs1-2"〉〈title type="main"〉Aim:To study the expression and cellular localization of cyclooxygenase in human gastric ulcers.〈section xml:id="abs1-3"〉〈title type="main"〉Methods:A total of 38 surgical gastric ulcer specimens were studied; 20 were Helicobacter pylori-positive and 18 were associated with NSAID use. Twenty non-ulcerated, histologically normal gastric specimens were used as controls. The cellular localization of COX-1 and COX-2 were determined by immunohistochemistry and double immunofluorescence. Cyclooxygenase messenger RNA (mRNA) was measured by reverse transcription-polymerase chain reaction and localized by in situ hybridization.〈section xml:id="abs1-4"〉〈title type="main"〉Results:In control specimens, COX-1 was detected in stromal cells in the lamina propria. There was focal and weak immunostaining for COX-2 in the foveolar epithelium. At the ulcer edge, COX-1 was significantly increased in lamina propria cells whereas COX-2 was strongly expressed in the hyperplastic foveolar epithelium in H. pylori- and non-steroidal anti-inflammatory drugs (NSAID)-associated ulcers. At the ulcer base, there was strong expression of COX-1 and COX-2 in myofibroblasts, macrophages and endothelial cells in the granulation tissue, irrespective of H. pylori status or NSAID use. Messenger RNA of COX-1 and COX-2 were demonstrated by reverse transcription-polymerase chain reaction. Double immunofluorescence and in situ hybridization confirmed the cellular localization of cyclooxygenase at protein and mRNA levels, respectively.〈section xml:id="abs1-5"〉〈title type="main"〉Conclusion:Both COX-1 and COX-2 are up-regulated in human gastric ulcers.
    Type of Medium: Electronic Resource
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