Tonsil and adenoid-tissue hypertrophy (AH) is the most common cause of pediatric sleep-disordered breathing (SDB), with AH possibly initiated by repeated exposure to infectious agents or allergens. ...Here, we evaluated IL-17A activity in adenoid tissue from children with SDB and its association with AH and pneumococcal carriage. Thirty-five children (aged 3-12 years) with SDB and receiving adenoidectomy and tonsillectomy were enrolled. During surgery, nasopharyngeal carriage was determined by bacterial culture and multiplex PCR via nasopharyngeal swab, and adenoid samples were collected. IL-17A and associated cytokine expression was evaluated by real-time PCR and western blotting. The mRNA analysis showed that IL-17A level, IL-17A:IL-10 ratio, and RAR-related orphan receptor-γt:forkhead box P3 ratio were significantly higher in adenoid tissues with AH, as were IL-17A level and IL-17A:IL-10 ratio in adenoid tissues with pneumococcal carriage. Additionally, pneumococcal carriage was more common in nasopharyngeal adenoids from patients without AH than those with AH. IL-17A was upregulated in adenoid tissues from patients with AH and with pneumococcal carriage. These results suggested that pneumococcal carriage initiates an IL-17A-mediated immune response in nasopharyngeal adenoids, which might be associated with AH in patients with SDB.
Streptococcus pneumonia, one of the major colonizers in nasopharyngeal adenoids, has been the predominant pathogen causing acute otitis media (AOM) in children. Recent evidence suggests an ...association between IL-17A-mediated immune response and the clearance of pneumococcal colonization in nasopharyngeal adenoids. Here, we evaluated the expressions of IL-17A and associated genes in hypertrophic adenoid tissues of children with sleep-disordered breathing (SDB) and otitis media with effusion (OME) and their association with pneumococcal carriage. Sixty-six pediatric patients with adenoid hypertrophy were enrolled. During adenoidectomy, nasopharyngeal swab and adenoid tissues were used to determine pneumococcal carriage and IL-17A expression. Our results revealed significantly higher levels of IL-17A and IL-17A:IL-10 mRNA in the SDB patients positive for nasopharyngeal pneumococcal carriage than those negative. However, these differences were not significant in the OME group. These results suggested, in OME patients, prolonged or chronic pneumococcal carriage may occur because of insufficient IL-17A-mediated mucosal clearance, and could further lead to AOM and OME development.
Stress-induced phosphoprotein 1 (STIP1), a cochaperone that organizes other chaperones, heat shock proteins (HSPs), was recently shown to be secreted by human ovarian cancer cells. In neuronal ...tissues, binding to prion protein was required for STIP1 to activate the ERK (extracellular-regulated MAP kinase) signaling pathways. However, we report that STIP1 binding to a bone morphogenetic protein (BMP) receptor, ALK2 (activin A receptor, type II-like kinase 2), was necessary and sufficient to stimulate proliferation of ovarian cancer cells. The binding of STIP1 to ALK2 activated the SMAD signaling pathway, leading to transcriptional activation of ID3 (inhibitor of DNA binding 3), promoting cell proliferation. In conclusion, ovarian-cancer-tissue-secreted STIP1 stimulates cancer cell proliferation by binding to ALK2 and activating the SMAD-ID3 signaling pathways. Although animal studies are needed to confirm these mechanisms in vivo, our results may pave the way for developing novel therapeutic strategies for ovarian cancer.
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► Ovarian cancer tissues secrete STIP1 into blood circulation ► rhSTIP1 may bind to BMP receptor ALK2 and activate the SMAD1/SMAD5-ID3 pathway ► The STIP1-ALK2 pathway stimulates cell proliferation in ovarian cancer cells
STIP1 is a cochaperone for heat shock proteins. When secreted by neuronal cells, STIP1 was shown to bind to prion membrane protein and activate ERK pathways. Herein, Chao, Wang, and colleagues report that the ovarian-cancer-tissue-secreted STIP1 binds to a BMP receptor, ALK2, to activate SMAD1/SMAD5 pathways and upregulate ID3 expression, leading to cancer cell proliferation. These results not only provide insights into the tumorigenesis of ovarian cancer but also pave the way for developing novel therapeutic strategies.
The FUT2 gene is a histo-blood group antigen (HBGA) that determines the susceptibility to Norovirus (NoV) infection. This study investigated the clinical significance of the FUT2 gene profile and ...HBGA expression in NoV infection.
Fecal specimens were collected from children in Chang-Gung Children's Hospital with acute gastroenteritis (AGE). The medical records were reviewed for clinical data. The viral etiology of gastroenteritis was validated using molecular methods. Genomic DNA was isolated from saliva or whole blood with the Puregene B Kit, according to the manufacturers' instructions. Single-nucleotide polymorphisms (SNPs) were determined by real-time PCR assays.
FUT2 gene DNA was examined in 98 children with AGE. NoV was detected by RT-PCR in 44 patients (44.8%), while 54 (55.2%) had non-NoV AGE. Of the 44 NoV patients, 38 (86.3%) were secretors (no G428A mutation) and six (13.7%) were non-secretors (G428A mutation). Of the 54 non-NoV AGE patients, 28 (51.9%) were secretors and 20 (48.1%) were non-secretors. NoV-infected patients who were secretors had more frequent vomiting (P < 0.001), longer duration of diarrhea (P < 0.001), and greater overall disease severity score (P < 0.001) compared with non-secretors. Non-NoV infection secretor AGE patients had a longer duration of diarrhea (P < 0.001) than non-secretors.
FUT2 secretor status affects NoV AGE in children. Secretor patients have prolonged diarrhea, more frequent vomiting, more severe disease, and greater infection transmissibility than non-secretors.
The latent membrane protein (LMP1) of Epstein-Barr virus (EBV) is expressed in EBV-associated nasopharyngeal carcinoma, which is notoriously metastatic. Although it is established that LMP1 represses ...E-cadherin expression and enhances the invasive ability of carcinoma cells, the mechanism underlying this repression remains to be elucidated. In this study, we demonstrate that LMP1 induces the expression and activity of the DNA methyltransferases 1, 3a, and 3b, using real-time reverse transcription-PCR and enzyme activity assay. This results in hypermethylation of the E-cadherin promoter and down-regulation of E-cadherin gene expression, as revealed by methylation-specific PCR, real-time reverse transcription-PCR and Western blotting data. The DNA methyltransferase inhibitor, 5′-Aza-2′dC, restores E-cadherin promoter activity and protein expression in LMP1-expressing cells, which in turn blocks cell migration ability, as demonstrated by the Transwell cell migration assay. Our findings suggest that LMP1 down-regulates E-cadherin gene expression and induces cell migration activity by using cellular DNA methylation machinery.
Abstract We compared microRNA profiles between choriocarcinoma and non-cancerous trophoblasts, and revealed that miR-199b was underexpressed in choriocarcinoma. By computational prediction and ...microarray studies, SET (protein phosphatase 2A inhibitor) was shown to be one of the target genes regulated by miR-199b. Ectopic expression of miR-199b inhibited endogenous SET protein levels and the activity of the luciferase reporter containing the 3′-UTR of SET. Further comparisons of formalin-fixed paraffin-embedded human choriocarcinoma, mole, and non-cancer trophoblast tissues confirmed the initial findings of low miR-199b expression and SET upregulation in choriocarcinomas, suggesting that microRNA-dysregulated SET protein may account for the rapid growth seen with choriocarcinomas.
Rotavirus vaccines were launched in Taiwan since early 2006. Our study was aimed to figure out long-term extended molecular epidemiology in acute gastroenteritis (AGE) in hospitalized young children ...after rotavirus vaccination in Taiwan.
During the 10-year period from January 2007 to December 2016, fecal samples from children under 5 years old with AGE hospitalized in Chang Gung Children's Hospital (CGCH) were examined for enteric pathogens and they were divided into two time intervals: early post-vaccine (Jan. 2007 to Dec. 2011; EPV) and late post-vaccine (Jan. 2012 to Dec. 2016; LPV).
In total, 837 patients with AGE were enrolled with complete study. In the EPV period, 106 (26.7%) rotavirus and 65 (16.4%) norovirus infections were identified as major pathogens. In the LPV period, 79 (17.9%) rotavirus and 98 (22.2%) norovirus infections were diagnosed. Statistical analyses showed a significantly decreased prevalence of rotavirus infection (P = 0.002) and a significantly increased prevalence of norovirus (P = 0.034) and enteric bacterial infections (P < 0.001). A substantial decrease of rotavirus G1 (P = 0.079) in the LPV period and norovirus GII.4 prevailed through the decade.
In Taiwan, under a suboptimal rotavirus vaccination policy, there was a marked decrease in the rate of rotavirus AGE of hospitalized young children. Significantly increased norovirus infection has replaced rotavirus as the leading cause. Expansion of rotavirus vaccine coverage, development of a norovirus prevention strategy, and sustained bacterial infection control are important for AGE containment in children in Taiwan.
IntroductionTherapeutic efficiency of glucagon-like peptide-1 (GLP-1) analog is about 50%–70% in type 2 diabetes mellitus (T2DM). Discovery of potential genetic biomarkers for prediction of treatment ...efficiency of GLP-1 analog before therapy is still necessary. We assess whether DNA methylation was associated with glycemic response to GLP-1 analog therapy in patients with poorly controlled T2DM.Research design and methodsGenomic DNA was extracted from the peripheral blood of training (n=10) and validation (n=128) groups of patients with T2DM receiving GLP-1 analogs. DNA methylome was analyzed using Infinium Human Methylation EPIC Bead Chip in the training group. The candidate genes were examined using a pyrosequencing platform in the validation group. The association between DNA methylation status and glycemic response to GLP-1 was analyzed in these patients.ResultsThe most differential methylation region between those with a good (responsive) and poor (unresponsive) glycemic response to GLP-1 analog therapy was located on chromosome 5q31.1 (135415693 to 135416613), the promoter of VTRNA2-1 in the training group. The methylation status of the VTRNA2-1 promoter was examined in the validation group via pyrosequencing reaction, and the hypomethylation of VTRNA2-1 (<40% methylation) was significantly associated with poor glycemic response to GLP-1 treatment (OR 2.757, 95% CI 1.240 to 6.130, p=0.011). Since the VTRNA2-1 promoter region was previously reported maternal imprinting extended to the adjacent centromeric CCCTC-binding factor site that contained an A/C polymorphism (rs2346018), which was associated with methylation density of VTRNA2-1, this A/C polymorphism was also integrated to analyze association with glycemic response to GLP-1 analog therapy. In patients with the A allele of rs2346018 and hypomethylation (<40%) on the VTRNA2-1 promoter, the OR increased to 4.048 (95% CI 1.438 to 11.389, p=0.007).ConclusionsThe glycemic response to GLP-1 analog treatment is associated with the methylation status of the VTRNA2-1 promoter and polymorphism of rs2346018.
Estrogens can elicit rapid cellular responses via the G-protein-coupled receptor 30 (GPR30), followed by estrogen receptor α (ERα/ESR1)-mediated genomic effects. Here, we investigated whether rapid ...estrogen signaling via GRP30 may affect ESR1 expression, and we examined the underlying molecular mechanisms. The exposure of human endometrial cancer cells to 17β-estradiol promoted p62 phosphorylation and increased ESR1 protein expression. However, both a GPR30 antagonist and GPR30 silencing abrogated this phenomenon. GPR30 activation by 17β-estradiol elicited the SRC/EGFR/PI3K/Akt/mTOR signaling pathway. Intriguingly, unphosphorylated p62 and ESR1 were found to form an intracellular complex with the substrate adaptor protein KEAP1. Upon phosphorylation, p62 promoted ESR1 release from the complex, to increase its protein expression. Given the critical role played by p62 in autophagy, we also examined how this process affected ESR1 expression. The activation of autophagy by everolimus decreased ESR1 by promoting p62 degradation, whereas autophagy inhibition with chloroquine increased ESR1 expression. The treatment of female C57BL/6 mice with the autophagy inhibitor hydroxychloroquine—which promotes p62 expression—increased both phosphorylated p62 and ESR1 expression in uterine epithelial cells. Collectively, our results indicate that 17β-estradiol-mediated GPR30 activation elicits the SRC/EGFR/PI3K/Akt/mTOR signaling pathway and promotes p62 phosphorylation. In turn, phosphorylated p62 increased ESR1 expression by inducing its release from complexes that included KEAP1. Our findings may lead to novel pharmacological strategies aimed at decreasing ESR1 expression in estrogen-sensitive cells.
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