Whiteheadkorsholm9690

Bladder cancer (BCa) is one of the most common urinary malignancies in the world. Growing evidence suggests that epithelial-to-mesenchymal transition (EMT) is a major contributor for BCa metastasis. lncRNA small nucleolar RNA host gene 16 (SNHG16) has been reported as a tumor promoter in many cancers. This study aims to investigate the function and mechanism of SNHG16 on EMT in BCa. Quantitative RT-PCR (qRT-PCR) was used to determine the expression of SNHG16 in human BCa tissues and TGF-β-induced cells. Western blot (WB) was performed to evaluate the expression of EMT-related proteins. Transwell assay was exerted to assess the migration and invasion ability of SNHG16 in BCa. RNA pull-down assay was conducted to confirm the RNA-RNA interaction. The precise mechanism by which SNHG16 regulated EMT process in BCa was also explored. SNHG16 was found up-regulated in TGF-β-induced BCa cells and BCa tissues. Transwell assay showed that overexpression of SNHG16 significantly promoted the migration and invasion of BCa cells, whereas knock-down of SNHG16 caused the opposite effects. Then, the interaction between SNHG16 and miR-200a-3p was verified by dual-luciferase reporter assay and RNA pull-down assay. And the effects of knock-down or overexpression of SNHG16 on migration and invasion were reversed by co-transfecting miR-200a-3p inhibitors or mimics. This study first demonstrated that SNHG16 was responsible for EMT of BCa cells via miR-200a-3p/ ZEB1/ZEB2 axis. These results provided a potential therapeutic strategy for BCa treatment, especially in metastatic BCa.Three cholangiocarcinoma (CCA) cell line-formerly named, M156, M213 and M214 have been intensively used with discrepancy of their tumor origins. They were assumed to be originated from three different donors without authentication. To verify the origins of these cell lines, the short tandem repeat (STR) analysis of the currently used cell lines, the cell stocks from the establisher and the primary tumor of a CCA patient were performed. Their phenotypic and genotypic originality were compared. The currently used 3 CCA cell lines exhibited similar STR as CCA patient ID-M213 indicating the same origin of these cells. The cell stocks from the establisher, however, revealed the same STR of M213 and M214 cells, but not M156. The misidentification of M214 and M156 is probably due to the mislabeling and cross-contamination of M213 cells during culture. These currently used cell lines were renamed as KKU-213A, -213B and -213C, for the formerly M213, M214 and M156 cells, respectively. These cell lines were established from a male with an intrahepatic mass-forming CCA stage-4B. The tumor was an adenosquamous carcinoma with the liver fluke ova granuloma in evidence. All cell lines had positive CK19 with differential CA19-9 expression. They exhibited aneuploidy karyotypes, distinct cell morphology, cell growth, cytogenetic characteristic and progressive phenotypes. KKU-213C formed a adenosquamous carcinoma, whereas KKU-213A and KKU-213B formed poorly- and well-differentiated squamous cell carcinomas in xenografted mice. mRNA microarray revealed different expression profiles among these three cell lines. The three cell lines have unique characteristics and may resemble the heterogeneity of tumor origin.Certolizumab pegol (Cimzia®) is a PEGylated, Fab'-only, recombinant humanized antibody against TNF-α. Subcutaneous certolizumab pegol is indicated for the treatment of various immune-mediated inflammatory diseases (IMIDs), including moderate to severe plaque psoriasis. In pivotal phase III trials in adults with moderate to severe plaque psoriasis, significantly more patients receiving certolizumab pegol 200 mg or 400 mg once every 2 weeks than placebo recipients achieved a ≥ 75% reduction in PASI score (PASI75 responder) and a PGA score of clear/mostly clear with a ≥ 2 point improvement from baseline (PGA0/1 responder) at week 12 (CIMPACT) or 16 (CIMPASI-1 and -2). In CIMPACT, certolizumab pegol 400 mg once every 2 weeks was superior to etanercept (highest recommended dosage) at 12 weeks, with certolizumab pegol 200 mg once every 2 weeks demonstrating non-inferiority, but not superiority, to etanercept. The clinical benefits of certolizumab pegol were maintained during the maintenance phase (to week 48) and the open-label extension phase of these trials. Certolizumab pegol is unique among the biologics, with the absence of an Fc fragment conferring pharmacokinetic advantages; most notably, its minimal transfer across the placenta, and low relative infant dose during breastfeeding in conjunction with its low oral bioavailability. Certolizumab pegol was generally well tolerated and no new safety signals were identified in these phase III trials, which complements its established safety profile in other IMIDs. Certolizumab pegol is a useful option for the treatment of moderate to severe plaque psoriasis and provides an important treatment option for women of childbearing age, for whom there are limited options available.BACKGROUND Using the Faroese Septuagenarian cohort, we aimed to describe the incidence of dementia and assess the validity of neurocognitive tests to predict subsequent dementia diagnosis. METHODS In this population-based cohort, 713 Faroese septuagenarians aged 70-74 years without dementia, underwent clinical and neuropsychological examinations. After 10-years of follow-up, information was collected on all participants referred for cognitive evaluations and diagnosed with dementia. Incidence rates were calculated and presented with 95% confidence intervals (CIs), assuming a Poisson distribution. We then performed discriminant analysis to determine the best set of neuropsychological tests to identify those who would develop dementia. RESULTS Over the 10-years, 65 participants (9.1%) were diagnosed with dementia, with a 10-year incidence rate of 1063 cases per 100,000 person years (95% CI 825, 1343). Women had a greater incidence than men (incidence rate ratio (IRR) = 1.58; 95% CI 0.93, 2.71). After stepwise selection, gender and six neuropsychological measures were selected to discriminate between those who would and would not develop dementia. Overall, the model was able to correctly identify 82% of those who would not develop dementia (specificity) and 71% of those who would (sensitivity). CONCLUSIONS These results indicate that among a greater number of tests covering a broad range of cognitive abilities, tests reflecting verbal and visual learning and recall, visuospatial function, attention, and encoding into and retrieval from long-term memory may be helpful in identifying patients in the pre-symptomatic phase of dementia. Thus, helping care-givers identify patients at a higher risk of developing dementia and adjusting management of care accordingly.BACKGROUND Metformin, a widely prescribed antidiabetic drug, has been suggested to have a neuroprotective effect on 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced neurotoxicity in mice. In this study, we investigated the neuroprotective potential of metformin against rotenone-induced dopaminergic neuron damage and its underlying mechanisms. METHODS C57BL/6 mice were given saline or rotenone (2.5 mg/kg/day, ip) injection for 10 days. Metformin treatment (300 mg/kg/day, ip) was started concurrently with rotenone administration and continued for 10 days. The neuroprotective effect of metformin on rotenone-induced dopaminergic toxicity was assessed by tyrosine hydroxylase (TH), cleaved caspase-3 and α-synuclein immunohistochemistry in substantia nigra (SN). SN tissues were extracted for biochemical analysis. Malondialdehyde (MDA) and 4-hydroxynonenal (4-HNE) protein levels were measured by spectrophotometric assay. RESULTS We found that metformin treatment attenuated the rotenone-induced loss of TH+ neurons in the SN. Additionally, metformin significantly decreased the rotenone-induced increase of cleaved caspase-3 and α-synuclein accumulation in the SN; however, there was no difference in motor behaviours between the experimental groups. Meanwhile, the levels of MDA and 4-HNE in SN were significantly reduced in the rotenone-metformin group compared to the rotenone group. CONCLUSIONS Results showed that metformin treatment attenuated dopaminergic neuron loss in SN induced by rotenone by decreasing lipid peroxidation.RATIONALE The α4β2 nicotinic acetylcholine receptors (α4β2-nAChRs) may represent useful targets for cognitive improvement. It has been recently proposed that a strategy based on positive allosteric modulation of α4β2-nAChRs reveals several advantages over the direct agonist approach. Nevertheless, the procognitive effects of α4β2-nAChR positive allosteric modulators (PAMs) have not been extensively characterized. OBJECTIVES The aim of the present study was to evaluate the procognitive efficacy of desformylflustrabromine (dFBr), a selective α4β2-nAChR PAM. METHODS Cognitive effects were investigated in the novel object recognition task (NORT) and the attentional set-shifting task (ASST) in rats. RESULTS The results demonstrate that dFBr attenuated the delay-induced impairment in NORT performance and facilitated cognitive flexibility in the ASST. The beneficial effects of dFBr were inhibited by dihydro-β-erythroidine, a relatively selective α4β2-nAChR antagonist, indicating the involvement of α4β2-nAChRs in cognitive processes. The tested α4β2-PAM was also effective against ketamine- and scopolamine-induced deficits of object recognition memory. Moreover, procognitive effects were also observed after combined treatment with inactive doses of dFBr and TC-2403, a selective α4β2-nAChR agonist. CONCLUSIONS These findings indicate that dFBr presents procognitive activity, supporting the strategy based on α4β2-nAChR potentiation as a plausible therapy for cognitive impairment.BACKGROUND Telomerase plays an essential role in cancer cell proliferation. In this study, we investigated inhibition mechanism of aloe emodin (AE) on three different types of breast cancer cell lines, MDA-MB-453, MDA-MB-231 and MCF-7. METHODS The cells were treated with different concentrations of AE. Relative length of telomere and human telomerase reverse-transcriptase (hTERT) mRNA level was analyzed by quantitative PCR (qPCR). Protein level was assayed by Western blot. Sodium bisulfite methylation sequencing was performed to assess the methylation status of gene promoter. Enzymology kinetics was applied to reveal the interaction between AE and telomerase. Ultraviolet-visible titration and fluorescence resonance energy transfer (FRET) melting experiment were carried out to study the interaction between AE and telomeric DNA. RESULTS Continuous AE exposure of these cells for 48 h results in shortening of telomeres and inhibition of telomerase. The transcription of hTERT was repressed by activation of E2F1 and inactivation of c-myc proteins. Significant demethylation of CpG islands in hTERT gene promoter was observed in MDA-MB-453 and MCF-7 cells. AE competed with dNTP for occupation of the enzyme active site. AE was a telomeric G-quadruplex structure stabilizer as indicated by titration test and FRET experiments. CONCLUSIONS AE was a competitive inhibitor of telomerase and a G-quadruplex structure stabilizer. AE decreased the transcription of hTERT gene in the three breast cancer cell lines via up-regulation E2F1 and down-regulation c-myc expressions. The suppressed transcription was also related to the demethylation of the gene promoter.