Using DNA methylation biomarkers in cancer detection is a potential direction in clinical testing. Some methylated genes have been proposed for cervical cancer detection; however, more reliable ...methylation markers are needed. To identify new hypermethylated genes in the discovery phase, we compared the methylome between a pool of DNA from normal cervical epithelium (n = 19) and a pool of DNA from cervical cancer tissues (n = 38) using a methylation bead array. We integrated the differentially methylated genes with public gene expression databases, which resulted in 91 candidate genes. Based on gene expression after demethylation treatment in cell lines, we confirmed 61 genes for further validation. In the validation phase, quantitative MSP and bisulfite pyrosequencing were used to examine their methylation level in an independent set of clinical samples. Fourteen genes, including ADRA1D, AJAP1, COL6A2, EDN3, EPO, HS3ST2, MAGI2, POU4F3, PTGDR, SOX8, SOX17, ST6GAL2, SYT9, and ZNF614, were significantly hypermethylated in CIN3+ lesions. The sensitivity, specificity, and accuracy of POU4F3 for detecting CIN3+ lesions were 0.88, 0.82, and 0.85, respectively. A bioinformatics function analysis revealed that AJAP1, EDN3, EPO, MAGI2, and SOX17 were potentially implicated in β‐catenin signaling, suggesting the epigenetic dysregulation of this signaling pathway during cervical cancer development. The concurrent methylation of multiple genes in cancers and in subsets of precancerous lesions suggests the presence of a driver of methylation phenotype in cervical carcinogenesis. Further validation of these new genes as biomarkers for cervical cancer screening in a larger population‐based study is warranted.
What's New?
The identification of novel genes that are hypermethylated in cancer and precancerous lesions is needed in order to achieve a better sensitivity and specificity in cervical cancer screening. Using a genome‐wide approach, here the authors identified 14 genes that were frequently hypermethylated in CIN3+ and might thus become useful biomarkers in future molecular cervical cancer screening. A bioinformatics function analysis revealed that five of these genes were potentially implicated in β‐catenin signaling, suggesting the epigenetic dysregulation of Wnt signaling during cervical cancer development. The concurrent hypermethylation of multiple genes also suggests the involvement of a CpG island methylator phenotype.
Fucosylation is one of the most common modifications of oligo‐N‐acetyllactosamine (oligo‐LacNAc) glycans. However, none of known fucosyltransferases (FucTs) could install the α1,3‐linked fucose to ...the oligo‐LacNAc substrates in a site‐specific manner. Here, we report a facile and general redox‐controlled substrate engineering strategy for the site‐specific α1,3‐fucosylation of complex glycans containing multiple LacNAc units. This strategy takes advantage of an operationally simple oxidation enzyme module by using galactose oxidase (GOase) to convert the LacNAc unit into oxidized C6′‐aldehyde LacNAc sequence, which is not a good substrate for recombinant α1,3‐FucT from Helicobacter pylori strain 26695 (Hpα1,3FucT), enabling the site‐specific α1,3‐fucosylation at intact LacNAc sites. The general applicability and robustness of this strategy were demonstrated by the synthesis of a variety of structurally well‐defined fucosides of linear and branched O‐ and N‐linked glycans.
A galactose oxidase‐mediated redox system was coupled with enzymatic modular assembly strategy to control the site‐selectivity of α1,3‐fucosylation. This redox‐controlled site‐specific fucosylation strategy provides a general and operational simple approach for the precisely enzymatic synthesis of various complex fucosylated oligo‐N‐acetyllactosamine (oligo‐LacNAc) containing O‐ and N‐glycans with defined fucosylation patterns.
Compounds displaying delayed fluorescence (DF), from severe concentration quenching, have limited applications as nondoped organic light‐emitting diodes and material sciences. As a nondoped ...fluorescent emitter, aggregation‐induced emission (AIE) materials show high emission efficiency in their aggregated states. Reported herein is an AIE‐active, DF compound in which the molecular interaction is modulated, thereby promoting triplet harvesting in the solid state with a high photoluminescence quantum yield of 93.3 %, which is the highest quantum yield, to the best of our knowledge, for long‐lifetime emitters. Simultaneously, the compound with asymmetric molecular structure exhibited strong mechanoluminescence (ML) without pretreatment in the solid state, thus exploiting a design and synthetic strategy to integrate the features of DF, AIE, and ML into one compound.
In a “scense”: A novel compound having an asymmetric structure exhibited aggregation‐induced emission, delayed fluorescence, and mechanoluminescence simultaneously.
Negative pressure wound therapy (NPWT) decreases postoperative complications of various surgeries. However, the use of NPWT for oncological surgical wounds remains controversial. To evaluate the ...association of NPWT with oncologic recurrence in surgical wounds without residual malignancy, we analysed studies that compared NPWT with conventional non‐pressure dressings for cancer surgical wounds without residual tumour by August 12, 2020. We compared tumour recurrence rates and postoperative complications between the two procedures. The six studies included 118 patients who received NPWT, and 149 patients who received conventional non‐pressure wound care. The overall quality of the included studies was high based on the Newcastle–Ottawa scale score of 7.5. Tumour recurrence after NPWT was not significantly different compared with conventional non‐negative pressure wound care (9.3% versus 11.4%, P = 0.40). There was no significant heterogeneity between the studies (I2 = 3%). Although NTWT was associated with a lower complication rate compared with the control group, the result was non‐significant (P = 0.15). Application of NPWT in oncologic resection wounds without residual malignancy revealed no difference in local recurrence and may reduce the risk of postoperative complications compared with conventional non‐negative pressure dressings. NPWT can be considered an alternative method for reconstruction in challenging cases.
Serous carcinoma (SC) is the most common and lethal subtype of epithelial ovarian carcinoma; immunotherapy is a potential treatment for SC, however, the global immunological functions of SC as well ...as their change during the progression of SC have not been investigated in detail till now. We conducted a genome-wide integrative analysis to investigate the immunofunctionomes of SC at four tumor stages by quantifying the immunological functions defined by the Gene Ontology gene sets. DNA microarray gene expression profiles of 1100 SCs and 136 normal ovarian tissue controls were downloaded from the Gene Expression Omnibus database and converted to the functionome. Then the immunofunctionomes were reconstructed by extracting the offspring from the functionome for the four SC staging groups. The key immunological functions extracted from immunofunctionomes with a series of filters revealed that the immunopathy of SC consisted of a group of deregulated functions with the core members including B cell activation and differentiation, regulation of leukocyte chemotaxis/cellular extravasation, antigen receptor mediated signaling pathway, T helper mediated immunity and macrophage activation; and the auxiliary elements included leukocyte mediated immunity, regulation of inflammatory response, T cell differentiation, mononuclear cell migration, megakaryocyte differentiation, complement activation and cytokine production. These deregulated immunological functions reveal the candidates to target in the immunotherapy.
Fatal hepatitis B virus (HBV) reactivation in lymphoma patients with “resolved” HBV infection (hepatitis B surface antigen HBsAg negative and hepatitis B core antibody anti‐HBc positive) can occur, ...but the true incidence and severity remain unclear. From June 2009 to December 2011, 150 newly diagnosed lymphoma patients with resolved HBV infection who were to receive rituximab‐CHOP (cyclophosphamide, doxorubicin, vincristine, prednisolone)‐based chemotherapy were prospectively followed. HBV DNA was checked at baseline, at the start of each cycle of chemotherapy, and every 4 weeks for 1 year after completion of rituximab‐CHOP chemotherapy. Patients with documented HBV reactivation were treated with entecavir at a dosage of 0.5 mg/day for 48 weeks. HBV reactivation was defined as a greater than 10‐fold increase in HBV DNA, compared with previous nadir levels, and hepatitis flare was defined as a greater than 3‐fold increase in alanine aminotransferase (ALT) that exceeded 100 IU/L. Incidence of HBV reactivation and HBV‐related hepatitis flares was 10.4 and 6.4 per 100 person‐year, respectively. Severe HBV‐related hepatitis (ALT >10‐fold of upper limit of normal) occurred in 4 patients, despite entecavir treatment. Patients with hepatitis flare exhibited significantly higher incidence of reappearance of HBsAg after HBV reactivation (100% vs. 28.5%; P = 0.003). Conclusion: In lymphoma patients with resolved HBV infections, chemotherapy‐induced HBV reactivation is not uncommon, but can be managed with regular monitoring of HBV DNA and prompt antiviral therapy. Serological breakthrough (i.e., reappearance of HBsAg) is the most important predictor of HBV‐related hepatitis flare. (Hepatology 2014;59:2092–2100)
Fungi represent a significant proportion of the gut microbiota. Aberrant immune responses to fungi are frequently observed in inflammatory bowel diseases (IBD) and colorectal cancer (CRC), and ...mutations in the fungal-sensing pathways are associated with the pathogenesis of IBD. Fungal recognition receptors trigger downstream signaling via the common adaptor protein CARD9 and the kinase SYK. Here we found that commensal gut fungi promoted inflammasome activation during AOM-DSS-induced colitis. Myeloid cell-specific deletion of Card9 or Syk reduced inflammasome activation and interleukin (IL)-18 maturation and increased susceptibility to colitis and CRC. IL-18 promoted epithelial barrier restitution and interferon-γ production by intestinal CD8+ T cells. Supplementation of IL-18 or transfer of wild-type myeloid cells reduced tumor burden in AOM-DSS-treated Card9−/− and Sykfl/flLysMCre/+ mice, whereas treatment with anti-fungal agents exacerbated colitis and CRC. CARD9 deletion changes the gut microbial landscape, suggesting that SYK-CARD9 signaling maintains a microbial ecology that promotes inflammasome activation and thereby restrains colitis and colon tumorigenesis.
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•Commensal gut fungi contribute to inflammasome activation during experimental colitis•Microbial landscape is altered in Card9−/− mice•Defective inflammasome activation, IL-18 maturation in myeloid cells lacking CARD9 or SYK•Metronidazole treatment protects Card9−/− and SykLysM mice from colon tumorigenesis
Fungi represent a significant proportion of the gut microbiota, but how anti-fungal immunity contributes to tumor-promoting inflammatory responses is unclear. Malik et al. find that recognition of commensal gut fungi, sensed via the Card9-Syk signaling axis, is protective in the context of inflammation-associated cancer. IL-18 maturation downstream of inflammasome activation promotes epithelial barrier restitution and IFN-γ production by intestinal CD8+ T cells.
The exonuclease activity of Apurinic/apyrimidinic endonuclease 1 (APE1) is responsible for processing matched/mismatched terminus in various DNA repair pathways and for removing nucleoside analogs ...associated with drug resistance. To fill in the gap of structural basis for exonucleolytic cleavage, we determine the APE1-dsDNA complex structures displaying end-binding. As an exonuclease, APE1 does not show base preference but can distinguish dsDNAs with different structural features. Integration with assaying enzyme activity and binding affinity for a variety of substrates reveals for the first time that both endonucleolytic and exonucleolytic cleavage can be understood by an induced space-filling model. Binding dsDNA induces RM (Arg176 and Met269) bridge that defines a long and narrow product pocket for exquisite machinery of substrate selection. Our study paves the way to comprehend end-processing of dsDNA in the cell and the drug resistance relating to APE1.
Lung stem/progenitor cells are potentially useful for regenerative therapy, for example in repairing damaged or lost lung tissue in patients. Several optical imaging methods and probes have been used ...to track how stem cells incorporate and regenerate themselves in vivo over time. However, these approaches are limited by photobleaching, toxicity and interference from background tissue autofluorescence. Here we show that fluorescent nanodiamonds, in combination with fluorescence-activated cell sorting, fluorescence lifetime imaging microscopy and immunostaining, can identify transplanted CD45(-)CD54(+)CD157(+) lung stem/progenitor cells in vivo, and track their engraftment and regenerative capabilities with single-cell resolution. Fluorescent nanodiamond labelling did not eliminate the cells' properties of self-renewal and differentiation into type I and type II pneumocytes. Time-gated fluorescence imaging of tissue sections of naphthalene-injured mice indicates that the fluorescent nanodiamond-labelled lung stem/progenitor cells preferentially reside at terminal bronchioles of the lungs for 7 days after intravenous transplantation.
Amyloid precursor protein (APP) has been modified by β and γ-secretase that cause amyloid deposits (plaques) in neuronal cells. Glyceraldhyde-derived AGEs has been identified as a major source of ...neurotoxicity in Alzheimer's disease (AD). In a previous study, we demonstrated that glyceraldehyde-derived AGEs increase APP and Aβ via ROS. Furthermore, the combination of AGEs and Aβ has been shown to enhance neurotoxicity. In mice, APP expression is increased by tail vein injection of AGEs. This evidence suggests a correlation between AGEs and the development of AD. However, the role played by AGEs in the pathogenesis of AD remains unclear. In this report, we demonstrate that AGEs up-regulate APP processing protein (BACE and PS1) and Sirt1 expression via ROS, but do not affect the expression of downstream antioxidant genes HO-1 and NQO-1. Moreover, we found that AGEs increase GRP78 expression and enhance the cell death-related pathway p53, bcl-2/bax ratio, caspase 3. These results indicate that AGEs impair the neuroprotective effects of Sirt1 and lead to neuronal cell death via ER stress. Our findings suggest that AGEs increase ROS production, which stimulates downstream pathways related to APP processing, Aβ production, Sirt1, and GRP78, resulting in the up-regulation of cell death related pathway. This in-turn enhances neuronal cell death, which leads to the development of AD.
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