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Find video protocols related to scientific articles indexed in Pubmed.
Theoretical study on the chemical mechanism of enoyl-CoA hydratase and the form of inhibitor binding.
J Mol Model
PUBLISHED: 09-02-2014
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Enoyl-CoA hydratase (ECH) catalyzes the second step in the vital ?-oxidation pathway of fatty acid metabolism. This enzyme catalyzes the syn-addition of a water molecule across the double bond of 4-(N,N-dimethylamino) cinnamoyl-CoA (DAC-CoA). In this work, the reaction mechanisms of ECH were investigated using the density functional theory (DFT) methods. The different protonation states in which the important residues Glu164 and Glu144 are either neutral or ionized were considered. Four models of the active site were designed based on the X-ray crystal structure of the enzyme. The calculations gave strong support to the proposed mechanism and confirmed that both Glu164 and Glu144 are in a deprotonated state in the reaction mechanism of ECH. In addition, we constructed a model of the active site with the inhibitor acetoacetyl-CoA based on the crystal structure. Caomparison of the calculated energy barriers showed that binding of the keto-enol form of the inhibitor is more reasonable than that of the di-keto form in the inhibition process. Moreover, acetoacetyl-CoA was found to exhibit a keto-enol tautomerism when it acts as an inhibitor in the reaction. The present theoretical results indicated that both residues Glu164 and Glu144 are unprotonated in ECH with the substrate bound, while only Glu164 is unprotonated when the inhibitor binds ECH.
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Inactivation of miR-34a by aberrant CpG methylation in Kazakh patients with esophageal carcinoma.
J. Exp. Clin. Cancer Res.
PUBLISHED: 02-13-2014
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Esophageal squamous cell carcinoma (ESCC) is an aggressive tumor with dismal prognosis and high incidence and mortality in Kazakh population. MiR-34a, a direct p53 target gene, possesses tumor-suppressive properties as they mediate apoptosis, cell cycle arrest, and senescence. The reduced expression of miR-34a by methylation in various cancers has been reported.
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Absence of 19 known hotspot oncogenic mutations in soft tissue clear cell sarcoma: two cases report with review of the literature.
Int J Clin Exp Pathol
PUBLISHED: 01-01-2014
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Clear cell sarcoma (CCS) of the tendons and aponeuroses is a rare soft tissue sarcoma that morphologically resembles cutaneous malignant melanoma but exhibits a distinct molecular profile. Gastrointestinal (GI) CCS is extremely rare. In this study, two cases of CCS were presented: (1) left thumb and (2) jejunum. Case 1 manifested the characteristic CCS morphology. Case 2 was morphologically unusual and difficult to diagnose. Immunohistochemically, the two cases of tumor cells were diffusely positive for S100, vimentin, NSE protein, focal expression of CgA, and CAM2.5 protein. In case 1, the tumor cells were diffusely positive for HMB45, focal expression of CD56, and melan A antigen. Reverse transcriptase-polymerase chain reaction (RT-PCR) results confirmed the presence of the EWS/ATF1 translocation (type 1) in the two cases. Then, we detected 19 hotspot oncogenes in the two cases. To the best of our knowledge, this study is the first to apply a high-throughput OncoCarta panel 1.0 and MassARRAY system to detect 238 known mutations in 19 hotspot oncogenes in soft tissue clear cell sarcoma. In this study, no mutations were observed in these hotspot oncogenes in the two cases.
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Significance of elevated ERK expression and its positive correlation with EGFR in Kazakh patients with esophageal squamous cell carcinoma.
Int J Clin Exp Pathol
PUBLISHED: 01-01-2014
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Extracellular signal-regulated kinases (ERKs) are activated by the MAPK pathway. ERKs are downstream effectors of the epidermal growth factor receptor (EGFR), which belongs to the receptor tyrosine kinases family. Studies on the activation of the EGFR-ERK pathway in Kazakh patients with esophageal squamous cell carcinoma (ESCC) have not been reported. Using immunohistochemical staining on tissue microarrays, we investigated the protein expression of EGFR and ERK in 90 ethnic Kazakh patients with ESCC and 48 adjacent normal esophageal tissues (NETs). EGFR and ERK1 expression was localized in the cytoplasm, whereas ERK2 expression was localized in the nucleus. Both were more highly expression in the ESCC tissues than in the NETs, and the difference was considered significant (P=0.003, 0.002, and 0.005, respectively). ERK1 and EGFR expression was positively correlated with lymph nodes metastasis (P=0.011 and 0.013, respectively). ERK1 staining was also significantly associated with tumor-node-metastases stage of ESCC (P=0.044). ERK2 staining was significantly associated with Histological grade (P=0.012). Furthermore, ERK1 and EGFR expression in the ESCC tissues were positively correlated (r=0.413, P<0.001); EGFR was more highly expressed in the ESCC tissues with high ERK1 expression than in the ESCC tissues with low ERK1 expression (4.95±0.57 vs. 3.21±0.35, P=0.01). This study is thus far the first to demonstrate the correlation between EGFR overexpression and ERK overexpression in Kazakh patients with ESCC. This correlation suggests that the EGFR-ERK signaling pathway participates in ESCC progression and can thus be used as a prognostic marker.
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Overexpression of GEFT, a Rho family guanine nucleotide exchange factor, predicts poor prognosis in patients with rhabdomyosarcoma.
Int J Clin Exp Pathol
PUBLISHED: 01-01-2014
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Rhabdomyosarcoma (RMS) is one of the most common soft-tissue sarcomas in children and adolescents with poor prognosis. Yet, there is lack of effective prognostic biomarkers for RMS. The present study, therefore, aimed to explore potential biomarkers for RMS based on our previous findings using array comparative genomic hybridization. We investigated guanine nucleotide exchange factor, GEFT, at expression level in 45 RMS patients and 36 normal striated muscle controls using immunohistochemistry using tissue microarrays. The expression rate of GEFT in RMS samples (42/45, 93.33%) was significantly higher (P<0.05) than that in normal controls (5/36, 13.89%). Moreover, the overexpression rate of GEFT in RMS (31/45, 68.89%) was also significantly higher (P<0.05) than that in normal controls (0/36, 0.00%). Increased expression of GEFT correlated significantly with advanced disease stages (stages III/IV) (P=0.001), lymph node metastasis (P=0.019), and distant metastasis (P=0.004), respectively, in RMS patients. In addition, RMS patients having overexpressed GEFT experienced worse overall survival (OS) than those having low levels of GEFT (P=0.001). GEFT overexpression was determined to be an independent prognostic factor for poor OS in RMS patients (hazard ratio: 3.491, 95% confidence interval: 1.121-10.871, P=0.004). In conclusion, these observations provide the first evidence of GEFT overexpression in RMS and its correlations with disease aggressiveness and metastasis. These findings suggest that GEFT may serve as a promising biomarker predicting poor prognosis in RMS patients, thus implying its potential as a therapeutic target.
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Analysis of molecular cytogenetic alteration in rhabdomyosarcoma by array comparative genomic hybridization.
PLoS ONE
PUBLISHED: 01-01-2014
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Rhabdomyosarcoma (RMS) is the most common pediatric soft tissue sarcoma with poor prognosis. The genetic etiology of RMS remains largely unclear underlying its development and progression. To reveal novel genes more precisely and new therapeutic targets associated with RMS, we used high-resolution array comparative genomic hybridization (aCGH) to explore tumor-associated copy number variations (CNVs) and genes in RMS. We confirmed several important genes by quantitative real-time polymerase chain reaction (QRT-PCR). We then performed bioinformatics-based functional enrichment analysis for genes located in the genomic regions with CNVs. In addition, we identified miRNAs located in the corresponding amplification and deletion regions and performed miRNA functional enrichment analysis. aCGH analyses revealed that all RMS showed specific gains and losses. The amplification regions were 12q13.12, 12q13.3, and 12q13.3-q14.1. The deletion regions were 1p21.1, 2q14.1, 5q13.2, 9p12, and 9q12. The recurrent regions with gains were 12q13.3, 12q13.3-q14.1, 12q14.1, and 17q25.1. The recurrent regions with losses were 9p12-p11.2, 10q11.21-q11.22, 14q32.33, 16p11.2, and 22q11.1. The mean mRNA level of GLI1 in RMS was 6.61-fold higher than that in controls (p?=?0.0477) by QRT-PCR. Meanwhile, the mean mRNA level of GEFT in RMS samples was 3.92-fold higher than that in controls (p?=?0.0354). Bioinformatic analysis showed that genes were enriched in functions such as immunoglobulin domain, induction of apoptosis, and defensin. Proto-oncogene functions were involved in alveolar RMS. miRNAs that located in the amplified regions in RMS tend to be enriched in oncogenic activity (miR-24 and miR-27a). In conclusion, this study identified a number of CNVs in RMS and functional analyses showed enrichment for genes and miRNAs located in these CNVs regions. These findings may potentially help the identification of novel biomarkers and/or drug targets implicated in diagnosis of and targeted therapy for RMS.
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Parachordoma/myoepithelioma of the kidney: first report of a myxoid mimicry in an unusual location.
Int J Clin Exp Pathol
PUBLISHED: 01-01-2014
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We report a case of parachordoma (or myoepithelioma) of the right upper kidney in a 56 year-old male patient. Light microscopic features of the tumor exhibited epithelioid, glomoid, and spindle cells with eosinophilic and vacuolated cytoplasm as well as round to oval nuclei. These cells were embedded in a myxoid and hyaline stroma separated by a fibrous tissue with minimal cellular atypia and a few small nucleoli. Immunohistochemically, the tumor cells were immunoreactive for epithelial membrane antigen, calponin, vimentin, S-100, and type-IV collagen. All kidney and adrenal were resected, and the patient was carefully followed up. During the 11 months follow-up, recurrence and metastases were not observed. To our knowledge, this study is the first to document a case of parachordoma/myoepithelioma of the kidney. We add this new case to existing tumors and discuss its distinction from other types.
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Chromosomal and genetic imbalances in Chinese patients with rhabdomyosarcoma detected by high-resolution array comparative genomic hybridization.
Int J Clin Exp Pathol
PUBLISHED: 01-01-2014
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Rhabdomyosarcoma (RMS) is the most common soft-tissue sarcoma in children. Although associations between ARMS tumorigenesis and PAX3, PAX7, and FKHR are well recognized, the complete genetic etiology underlying RMS pathogenesis and progression remains unclear. Chromosomal copy number variations (CNVs) and the involved genes may play important roles in the pathogenesis and progression of human malignancies. Using high-resolution array comparative genomic hybridization (aCGH), we examined 20 formalin-fixed, paraffin-embedded (FFPE) RMS tumors to explore the involvement of the relevant chromosomal regions with resident genes in RMS tumorigenesis. In RMS, frequent gains were identified on chromosome regions 12q13.3-q14.1, 12q24.31, 17q25.1, 1q21.1, and 7q11.23, whereas frequent losses were observed on chromosome regions 5q13.2, 14q32.33, and 15q11.2. Amplifications were observed on chromosome regions 9p13.3, 12q13.3-q14.1, 12q15, and 16p13.11, whereas deletions were detected on chromosome regions 1p36.33, 1p13.1, 2q11.1, 5q13.2, 8p23.1, 9p24.3, and 16p11.2. Frequent gains were detected in GLI1, GEFT, OS9, and CDK4 (12q13.3-q14.1), being 60% in embryonal rhabdomyosarcoma (ERMS) and 66.67% in alveolar rhabdomyosarcoma (ARMS), respectively. However, frequent losses were detected in IGHG1, IGHM, IGHG3, and IGHG4 (14q32.33), being 70% in ERMS and 55.56% in and ARMS, respectively. Frequent gains were detected in TYROBP, HCST, LRFN3, and ALKBH6 (19q13.12) in ERMS but not in ARMS. The frequency of TYROBP, HCST, LRFN3, and ALKBH6 gains is significantly different in ERMS versus ARMS (P=0.011). The results suggest that novel TYROBP, HCST, LRFN3, and ALKBH6 genes may play important roles in ERMS. The technique used is a feasible approach for array comparative genomic hybridization analysis in archival tumor samples.
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Heterozygote of PLCE1 rs2274223 increases susceptibility to human papillomavirus infection in patients with esophageal carcinoma among the Kazakh populations.
J. Med. Virol.
PUBLISHED: 08-13-2013
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The involvement of human papillomavirus (HPV) in the carcinogenesis of esophageal squamous carcinoma remains undetermined. However, three genome-wide association studies of esophageal cancer have identified a shared susceptibility locus at 10q23 (rs2274223: A5780G) in phospholipase C epsilon 1 (PLCE1). The current study aims to present a comprehensive and novel spectrum about the HPV genotype distribution of esophageal carcinoma in Kazakhs and assess its association with PLCE1 polymorphisms. The HPV genotypes in 183 patients with esophageal cancer and 89 controls selected from the Kazakh population were evaluated using the HPV gene chip. The PLCE1 rs2274223 variant was genotyped in esophageal carcinoma patients by MALDI-ToF Mass Spectrometry. The presence of seven HPV genotypes in esophageal carcinoma tissues-including HPV 16, 18, 35, 52, 6, 11, 43-was significantly higher at 31.7% than those in controls at 9.0% (P?
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