A New p53 Target Gene, RKIP, Is Essential for DNA Damage-Induced Cellular Senescence and Suppression of ERK Activation

Abstractp53, a strong tumor suppressor protein, is known to be involved in cellular senescence, particularly premature cellular senescence. Oncogenic stresses, such as Ras activation, can initiate p53-mediated senescence, whereas activation of the Ras-mitogen-activated protein kinase (MAPK) pathway can promote cell proliferation. These conflicting facts imply that there is a regulatory mechanism for balancing p53 and Ras-MAPK signaling. To address this, we evaluated the effects of p53 on the extracellular signal-regulated kinase (ERK) activation and found that p53 could suppress ERK activation through de novo synthesis. Through several molecular biologic analyses, we found that RKIP, an inhibitor of Raf kinase, is responsible for p53-mediated ERK suppression and senescence. Overexpression of RKIP can induce cellular senescence in several types of cell lines, including p53-deficient cells, whereas the elimination of RKIP by siRNA or forced expression of ERK blocks p53-mediated cellular senescence. These results suggested that RKIP is an essential protein for cellular senescence. Moreover, modification of the p53 serine 46 residue was critical for RKIP induction and ERK suppression as well as cellular senescence. These results indicated that RKIP is a novel p53 target gene that is responsible for p53-mediated cellular senescence and tumor suppressor protein expression

Orthogonal Stability of an Additive-quartic Functional Equation in Non-Archimedean Spaces

Using fixed point method, we prove the Hyers-Ulam stability of the orthogonally additive-quartic functional equation f(2x+y)+ f(2x-y)=4 f(x+y)+ 4 f(x-y) + 10 f(x) + 14f(-x) - 3 f(y)-3f(-y) for all $x, y$ with $xperp y$, in non-Archimedean Banach spaces. Here $perp$ is the orthogonality in the sense of Rätz

Arrhythmia surgery for atrial fibrillation associated with atrial septal defect: Right-sided maze versus biatrial maze

BackgroundAlthough it has been inferred that a biatrial maze procedure for atrial fibrillation in left-sided heart lesions may lead to better outcomes compared with a limited left atrial lesion set, it remains controversial whether the biatrial maze procedure is superior to the right atrial maze procedure in right-sided heart lesions.MethodsA retrospective review was performed for 56 adults who underwent surgical closure of atrial septal defect and various maze procedures for atrial fibrillation between June 1998 and February 2011. The median age at operation was 59 years (range, 34-79 years). Clinical manifestations of atrial fibrillation were paroxysmal in 8 patients, persistent in 15 patients, and long-standing persistent in 33 patients. A right atrial maze procedure was performed in 23 patients (group 1), and a biatrial maze procedure was performed in 33 patients (group 2). Treatment failure was defined as atrial fibrillation recurrence, development of atrial flutter or other types of atrial tachyarrhythmia, or implantation of a permanent pacemaker. The Cox proportional hazards model was used to identify risk factors for decreased time to treatment failure.ResultsDuring the median follow-up period of 49 months (range, 5-149 months), there was no early death and 1 late noncardiac death. On Cox survival model, group 1 showed a significantly decreased time to treatment failure in comparison with group 2 (hazard ratio, 5.11; 95% confidence interval, 1.59-16.44; P = .006). Maintenance of normal sinus rhythm without any episode of atrial fibrillation recurrence at 2 and 5 years postoperatively was 57% and 45% in group 1, respectively, and 82% and 69% in group 2, respectively.ConclusionsLeft-sided ablation in addition to a right atrial maze procedure leads to better electrophysiologic outcome in atrial fibrillation associated with atrial septal defect

Identification of DNA methylation changes associated with human gastric cancer

<p>Abstract</p> <p>Background</p> <p>Epigenetic alteration of gene expression is a common event in human cancer. DNA methylation is a well-known epigenetic process, but verifying the exact nature of epigenetic changes associated with cancer remains difficult.</p> <p>Methods</p> <p>We profiled the methylome of human gastric cancer tissue at 50-bp resolution using a methylated DNA enrichment technique (methylated CpG island recovery assay) in combination with a genome analyzer and a new normalization algorithm.</p> <p>Results</p> <p>We were able to gain a comprehensive view of promoters with various CpG densities, including CpG Islands (CGIs), transcript bodies, and various repeat classes. We found that gastric cancer was associated with hypermethylation of 5' CGIs and the 5'-end of coding exons as well as hypomethylation of repeat elements, such as short interspersed nuclear elements and the composite element SVA. Hypermethylation of 5' CGIs was significantly correlated with downregulation of associated genes, such as those in the <it>HOX </it>and histone gene families. We also discovered long-range epigenetic silencing (LRES) regions in gastric cancer tissue and identified several hypermethylated genes (<it>MDM2</it>, <it>DYRK2</it>, and <it>LYZ</it>) within these regions. The methylation status of CGIs and gene annotation elements in metastatic lymph nodes was intermediate between normal and cancerous tissue, indicating that methylation of specific genes is gradually increased in cancerous tissue.</p> <p>Conclusions</p> <p>Our findings will provide valuable data for future analysis of CpG methylation patterns, useful markers for the diagnosis of stomach cancer, as well as a new analysis method for clinical epigenomics investigations.</p

Clarithromycin Susceptibility Testing of Mycobacterium avium Complex Using 2,3-Diphenyl-5-thienyl-(2)-tetrazolium Chloride Microplate Assay with Middlebrook 7H9 Broth

A series of 119 Mycobacterium avium complex isolates were subjected to clarithromycin susceptibility testing using microplates containing 2,3-diphenyl-5-thienyl-(2)-tetrazolium chloride (STC). Among 119 isolates, 114 (95.8%) were susceptible to clarithromycin and 5 were resistant according to the new and the standard method. STC counts the low cost and reduces the number of procedures needed for susceptibility testing

Association between Workplace Risk Factor Exposure and Sleep Disturbance: Analysis of the 2nd Korean Working Conditions Survey

OBJECTIVES: Sleep is essential for human beings to live and work properly. This study was conducted to investigate the relationship between occupational exposures to workplace risk factors and sleep disturbance in Korean workers. METHODS: The data were drawn from the second Korean Working Conditions Survey (KWCS); a total of 7,112 paid workers were analyzed. The independent variables were occupational exposures such as physical, chemical, biological, and psychosocial risk factor in the workplace, and psychosocial risk factor was divided into five categories (job demand, job control, social support, job insecurity, lack of reward). We estimated the relationship between various occupational exposures and sleep disturbance using multivariate logistic regression analysis. RESULTS: The results showed that people who exposed to physical, chemical, biological, and psychosocial (high job demand, inadequate social support, lack of reward) risk factors were more likely to increase the risk of sleep disturbance. Furthermore, after adjusting for general and occupational characteristics, we found significant positive associations between exposures to physical (odds ratios [OR] 1.47, 95% confidence interval [CI] 1.05-2.07) and psychosocial (high job demand (OR 2.93, 95% CI 2.16-3.98), inadequate social support (OR 1.57, 95% CI 1.14-2.15), lack of reward (OR 1.45, 95% CI 1.08-1.96)) risk factors and sleep disturbance. CONCLUSION: These results suggest that occupational exposures to physical and psychosocial workplace risk factors are significantly related to sleep disturbance

Systems analysis reveals a transcriptional reversal of the mesenchymal phenotype induced by SNAIL-inhibitor GN-25

Abstract Background HMLEs (HMLE-SNAIL and Kras-HMLE, Kras-HMLE-SNAIL pairs) serve as excellent model system to interrogate the effect of SNAIL targeted agents that reverse epithelial-to-mesenchymal transition (EMT). We had earlier developed a SNAIL-p53 interaction inhibitor (GN-25) that was shown to suppress SNAIL function. In this report, using systems biology and pathway network analysis, we show that GN-25 could cause reversal of EMT leading to mesenchymal-to-epithelial transition (MET) in a well-recognized HMLE-SNAIL and Kras-HMLE-SNAIL models. Results GN-25 induced MET was found to be consistent with growth inhibition, suppression of spheroid forming capacity and induction of apoptosis. Pathway network analysis of mRNA expression using microarrays from GN-25 treated Kras-HMLE-SNAIL cells showed an orchestrated global re-organization of EMT network genes. The expression signatures were validated at the protein level (down-regulation of mesenchymal markers such as TWIST1 and TWIST2 that was concurrent with up-regulation of epithelial marker E-Cadherin), and RNAi studies validated SNAIL dependent mechanism of action of the drug. Most importantly, GN-25 modulated many major transcription factors (TFs) such as inhibition of oncogenic TFs Myc, TBX2, NR3C1 and led to enhancement in the expression of tumor suppressor TFs such as SMAD7, DD1T3, CEBPA, HOXA5, TFEB, IRF1, IRF7 and XBP1, resulting in MET as well as cell death. Conclusions Our systems and network investigations provide convincing pre-clinical evidence in support of the clinical application of GN-25 for the reversal of EMT and thereby reducing cancer cell aggressiveness

Isolation and characterization of equine amniotic membrane-derived mesenchymal stem cells

Recent studies have shown that mesenchymal stem cells (MSCs) are able to differentiate into multi-lineage cells such as adipocytes, chondroblasts, and osteoblasts. Amniotic membrane from whole placenta is a good source of stem cells in humans. This membrane can potentially be used for wound healing and corneal surface reconstruction. Moreover, it can be easily obtained after delivery and is usually discarded as classified waste. In the present study, we successfully isolated and characterized equine amniotic membrane-derived mesenchymal stem cells (eAM-MSCs) that were cultured and maintained in low glucose Dulbeccos modified Eagles medium. The proliferation of eAM-MSCs was measured based on the cumulative population doubling level (CPDL). Immunophenotyping of eAM-MSCs by flow cytometry showed that the major population was of mesenchymal origin. To confirm differentiation potential, a multi-lineage differentiation assay was conducted. We found that under appropriate conditions, eAM-MSCs are capable of multi-lineage differentiation. Our results indicated that eAM-MSCs may be a good source of stem cells, making them potentially useful for veterinary regenerative medicine and cell-based therapy.This work was supported by a National Research Foundation of Korea (NRF) grant funded by the Korean government (MEST, 2010-0020265).OAIID:oai:osos.snu.ac.kr:snu2013-01/102/0000051105/4SEQ:4PERF_CD:SNU2013-01EVAL_ITEM_CD:102USER_ID:0000051105ADJUST_YN:NEMP_ID:A077262DEPT_CD:551CITE_RATE:1.161FILENAME:2013 jvs 14(2)151-159-equine stem cell.pdfDEPT_NM:수의학과EMAIL:[email protected]_YN:YCONFIRM: