SIP1 is downregulated in hepatocellular carcinoma by promoter hypermethylation

Background: Smad interacting protein-1 is a transcription factor that is implicated in transforming growth factor-β/bone morphogenetic protein signaling and a repressor of E-cadherin and human telomerase reverse transcriptase. It is also involved in epithelial-mesenchymal transition and tumorigenesis. However, genetic and epigenetic alterations of SIP1 have not been fully elucidated in cancers. In this study, we investigated mutations and promoter hypermethylation of the SIP1 gene in human hepatocellular carcinomas.Methods: SIP1 expression was analyzed in HCC cell lines and primary tumors in comparison to normal and non-tumor liver tissues by using semi-quantitative RT-PCR, quantitative real-time RT-PCR and immunohistochemistry. Mutation and deletion screening of the SIP1 gene were performed by direct sequencing in HCC-derived cells. Restoration of SIP1 expression was sought by treating HCC cell lines with the DNA methyl transferase inhibitor, 5-AzaC, and the histone deacetylase inhibitor, TSA. SIP1 promoter methylation was analyzed by the combined bisulfite restriction analysis assay in in silico-predicted putative promoter and CpG island regions.Results: We found that the expression of SIP1 was completely lost or reduced in five of 14 (36%) HCC cell lines and 17 of 23 (74%) primary HCC tumors. Immunohistochemical analysis confirmed that SIP1 mRNA downregulation was associated with decreased expression of the SIP1 protein in HCC tissues (82.8%). No somatic mutation was observed in SIP1 exons in any of the 14 HCC cell lines. Combined treatment with DNA methyl transferase and histone deacetylase inhibitors synergistically restored SIP1 expression in SIP1-negative cell lines. Analysis of three putative gene regulatory regions revealed tumor-specific methylation in more than half of the HCC cases.Conclusions: Epigenetic mechanisms contribute significantly to the downregulation of SIP1 expression in HCC. This finding adds a new level of complexity to the role of SIP1 in hepatocarcinogenesis. © 2011 Acun et al; licensee BioMed Central Ltd

PTPRD is homozygously deleted and epigenetically downregulated in human hepatocellular carcinomas

PTPRD (protein tyrosine phosphatase, receptor type, D) is a tumor suppressor gene, frequently inactivated through deletions or epigenetic mechanisms in several cancers with importance for global health. In this study, we provide new and functionally integrated evidence on genetic and epigenetic alterations of PTPRD gene in hepatocellular carcinomas (HCCs). Importantly, HCC is the sixth most common malignancy and the third most common cause of cancer-related mortality worldwide. We used a high throughput single nucleotide polymorphism (SNP) microarray assay (Affymetrix, 10K2.0 Assay) covering the whole genome to screen an extensive panel of HCC cell lines (N=14 in total) to detect DNA copy number changes. PTPRD expression was determined in human HCCs by Q-RT-PCR and immunohistochemistry. Promoter hypermethylation was assessed by combined bisulfite restriction analysis (COBRA). DNA methyl transferase inhibitor 5-azacytidine (5-AzaC) and/or histone deacetylase inhibitor Trichostain A (TSA) were used to restore the expression. We identified homozygous deletions in Mahlavu and SNU475 cells, in the 5′UTR and coding regions, respectively. PTPRD mRNA expression was downregulated in 78.5% of cell lines and 82.6% of primary HCCs. PTPRD protein expression was also found to be lost or reduced in HCC tumor tissues. We found promoter hypermethylation in 22.2% of the paired HCC samples and restored PTPRD expression by 5-AzaC and/or TSA treatments. In conclusion, PTPRD is homozygously deleted and epigenetically downregulated in HCCs. We hypothesize PTPRD as a tumor suppressor candidate and potential cancer biomarker in human HCCs. This hypothesis is consistent with compelling evidences in other organ systems, as discussed in this article. Further functional assays in larger samples may ascertain the contribution of PTPRD to hepatocarcinogenesis in greater detail, not to forget its broader importance for diagnostic medicine and the emerging field of personalized medicine in oncology. © Copyright 2015, Mary Ann Liebert, Inc. 2015

Muscle Hemangiomatosis presenting as a severe feature in a patient with the pten mutation: Expanding the phenotype of vascular malformations in bannayan-riley-ruvalcaba syndrome

Bannayan-Riley-Ruvalcaba syndrome (BRRS) is a rare autosomal, dominantly-inherited, hamartoma syndrome with distinct phenotypic features. Mutations in the PTEN gene have been identified in PTEN hamartoma tumor syndromes. Our aim was to determine the correlation of phenotype-genotype relationships in a BRRS case. We have evaluated a PTEN mutation in a patient with vascular anomalies and the phenotypic findings of BRRS. We described an 8-year-old girl with the clinical features of BRRS, specifically with vascular anomalies. The mutation in the PTEN gene was identified by DNA sequencing. In our patient, we defined a de novo nonsense R335X (c.1003 C>T) mutation in exon 8, which results in a premature termination codon. Due to vascular anomalies and hemangioma, the patient's left leg was amputated 1 year after the hemangioma diagnosis. Bannayan - Riley - Ruvalcaba syndrome patients with macrocephaly and vascular anomalies should be considered for PTEN mutation analysis and special medical care

Coulomb drag in anisotropic systems: a theoretical study on a double-layer phosphorene

We theoretically study the Coulomb drag resistivity in a double-layer electron system with highly anisotropic parabolic band structure using Boltzmann transport theory. As an example, we consider a double-layer phosphorene on which we apply our formalism. This approach, in principle, can be tuned for other double-layered systems with paraboloidal band structures. Our calculations show the rotation of one layer with respect to another layer can be considered a way of controlling the drag resistivity in such systems. As a result of rotation, the off-diagonal elements of drag resistivity tensor have non-zero values at any temperature. In addition, we show that the anisotropic drag resistivity is very sensitive to the direction of momentum transfer between two layers due to highly anisotropic inter-layer electron-electron interaction and also the plasmon modes. In particular, the drag anisotropy ratio, \r{ho}yy/\r{ho}xx, can reach up to ~ 3 by changing the temperature. Furthermore,our calculations suggest that including the local field correction in dielectric function changes the results significantly. Finally, We examine the dependence of drag resistivity and its anisotropy ratio on various parameters like inter-layer separation, electron density, short-range interaction and insulating substrate/spacer.Comment: 10 pages, 9 figure

Overexpression of ZEB2 in Peritumoral Liver Tissue Correlates with Favorable Survival after Curative Resection of Hepatocellular Carcinoma

BACKGROUND: ZEB2 has been suggested to mediate EMT and disease aggressiveness in several types of human cancers. However, the expression patterns of ZEB2 in hepatocellular carcinoma (HCC) and its effect on prognosis of HCC patients treated with hepatectomy are unclear. METHODOLOGY/PRINCIPAL FINDINGS: In this study, the methods of tissue microarray and immunohistochemistry (IHC) were utilized to investigate ZEB2 expression in HCC and peritumoral liver tissue (PLT). Receiver operating characteristic (ROC), spearman's rank correlation, Kaplan-Meier plots and Cox proportional hazards regression model were used to analyze the data. Up-regulated expression of cytoplasmic/nuclear ZEB2 protein was observed in the majority of PLTs, when compared to HCCs. Further analysis showed that overexpression of cytoplasmic ZEB2 in HCCs was inversely correlated with AFP level, tumor size and differentiation (P<0.05). Also, overexpression of cytoplasmic ZEB2 in PLTs correlated with lower AFP level (P<0.05). In univariate survival analysis, a significant association between overexpression of cytoplasmic ZEB2 by HCCs/PLTs and longer patients' survival was found (P<0.05). Importantly, cytoplasmic ZEB2 expression in PLTs was evaluated as an independent prognostic factor in multivariate analysis (P<0.05). Consequently, a new clinicopathologic prognostic model with cytoplasmic ZEB2 expression (including HCCs and PLTs) was constructed. The model could significantly stratify risk (low, intermediate and high) for overall survival (P = 0.002). CONCLUSIONS/SIGNIFICANCE: Our findings provide a basis for the concept that cytoplasmic ZEB2 expressed by PLTs can predict the postoperative survival of patients with HCC. The combined cytoplasmic ZEB2 prognostic model may become a useful tool for identifying patients with different clinical outcomes

A systematic review of the effects of residency training on patient outcomes

<p>Abstract</p> <p>Background</p> <p>Residents are vital to the clinical workforce of today and tomorrow. Although in training to become specialists, they also provide much of the daily patient care. Residency training aims to prepare residents to provide a high quality of care. It is essential to assess the patient outcome aspects of residency training, to evaluate the effect or impact of global investments made in training programs. Therefore, we conducted a systematic review to evaluate the effects of relevant aspects of residency training on patient outcomes.</p> <p>Methods</p> <p>The literature was searched from December 2004 to February 2011 using MEDLINE, Cochrane, Embase and the Education Resources Information Center databases with terms related to residency training and (post) graduate medical education and patient outcomes, including mortality, morbidity, complications, length of stay and patient satisfaction. Included studies evaluated the impact of residency training on patient outcomes.</p> <p>Results</p> <p>Ninety-seven articles were included from 182 full-text articles of the initial 2,001 hits. All studies were of average or good quality and the majority had an observational study design.Ninety-six studies provided insight into the effect of 'the level of experience of residents' on patient outcomes during residency training. Within these studies, the start of the academic year was not without risk (five out of 19 studies), but individual progression of residents (seven studies) as well as progression through residency training (nine out of 10 studies) had a positive effect on patient outcomes. Compared with faculty, residents' care resulted mostly in similar patient outcomes when dedicated supervision and additional operation time were arranged for (34 out of 43 studies). After new, modified or improved training programs, patient outcomes remained unchanged or improved (16 out of 17 studies). Only one study focused on physicians' prior training site when assessing the quality of patient care. In this study, training programs were ranked by complication rates of their graduates, thus linking patient outcomes back to where physicians were trained.</p> <p>Conclusions</p> <p>The majority of studies included in this systematic review drew attention to the fact that patient care appears safe and of equal quality when delivered by residents. A minority of results pointed to some negative patient outcomes from the involvement of residents. Adequate supervision, room for extra operation time, and evaluation of and attention to the individual competence of residents throughout residency training could positively serve patient outcomes. Limited evidence is available on the effect of residency training on later practice. Both qualitative and quantitative research designs are needed to clarify which aspects of residency training best prepare doctors to deliver high quality care.</p

Pedagogy, empowerment and discipline: Comparative perspectives of novice teachers in England and Turkey reflecting on 'the other'

This article discusses the views of Turkish and British novice teachers on pedagogy and pedagogical relationships with school students when confronted with the pedagogical practices of the 'Other' in particular policy contexts. Experiences of those practices were gained by novice teachers during an exchange visit for British and Turkish university students in the period 2008-2009. Data was collected through questionnaires and focus group interviews. Findings suggest that Turkish and British novice teachers initially constructed the 'Other' as very different from themselves. The views of members of both groups were heavily influenced by the cultural contexts in which they trained and worked. British novice teachers tended to take as axiomatic constructivist and inclusive approaches to pedagogy and the relevance to successful pedagogy of listening to students' voices. Turkish novice teachers questioned both, many seeing control and dissemination of knowledge as central to pedagogy and student teacher relationships. © 2011 British Association for International and Comparative Education.University of Leicester European CommissionThe data for this essay arises from a postgraduate student teacher exchange programme (jointly funded by the European Union and the Turkish government) between three universities in Turkey, led by Us¸]csel[di ak University and the University of Leicester in the UK. The programme focused on participants’ understandings of European citizenship, Citizenship Education and pedagogy. This article focuses on the last aspect

A model to explore Turkish teachers' ICT integration stages

The aim of the study is to determine teachers' ICT integration stages according to CEO Forum's standards and factors affecting their integration. Teachers are expected to use ICT in their teaching practice. Hence, it is crucial that their integration stages and factors affecting it are examined. A survey method was employed for this study. A sample of 200 teachers was selected randomly out of 460 teachers working in primary schools in Uşak, Turkey. Researchers of this study developed an ICT integration questionnaire. Analysis of the data reveals that the teachers are in three different stages in ICT integration. A significant relationship is discovered between feelings of inadequacy in using ICT and exhibiting stage 1 behaviors. It is also clear that the ICT knowledge of teachers is the most important variable for the teachers who were at the third (the highest) stage of ICT integration. A model showing interrelations among factors influencing ICT integration behaviors were drawn for further studies to be tested. © The Turkish Online Journal of Educational Technology

Genetic and Epigenetic Alterations of PTPRD in Hepatocellular Carcinoma

22nd Biennial Congress of the European-Association-for-Cancer-Research -- JUL 07-10, 2012 -- Barcelona, SPAINWOS: 000313036501024European Assoc Canc Re

PTPRD is homozygously deleted and epigenetically downregulated in human hepatocellular carcinomas

PTPRD (protein tyrosine phosphatase, receptor type, D) is a tumor suppressor gene, frequently inactivated through deletions or epigenetic mechanisms in several cancers with importance for global health. In this study, we provide new and functionally integrated evidence on genetic and epigenetic alterations of PTPRD gene in hepatocellular carcinomas (HCCs). Importantly, HCC is the sixth most common malignancy and the third most common cause of cancer-related mortality worldwide. We used a high throughput single nucleotide polymorphism (SNP) microarray assay (Affymetrix, 10K2.0 Assay) covering the whole genome to screen an extensive panel of HCC cell lines (N=14 in total) to detect DNA copy number changes. PTPRD expression was determined in human HCCs by Q-RT-PCR and immunohistochemistry. Promoter hypermethylation was assessed by combined bisulfite restriction analysis (COBRA). DNA methyl transferase inhibitor 5-azacytidine (5-AzaC) and/or histone deacetylase inhibitor Trichostain A (TSA) were used to restore the expression. We identified homozygous deletions in Mahlavu and SNU475 cells, in the 5'UTR and coding regions, respectively. PTPRD mRNA expression was downregulated in 78.5% of cell lines and 82.6% of primary HCCs. PTPRD protein expression was also found to be lost or reduced in HCC tumor tissues. We found promoter hypermethylation in 22.2% of the paired HCC samples and restored PTPRD expression by 5-AzaC and/or TSA treatments. In conclusion, PTPRD is homozygously deleted and epigenetically downregulated in HCCs. We hypothesize PTPRD as a tumor suppressor candidate and potential cancer biomarker in human HCCs. This hypothesis is consistent with compelling evidences in other organ systems, as discussed in this article. Further functional assays in larger samples may ascertain the contribution of PTPRD to hepatocarcinogenesis in greater detail, not to forget its broader importance for diagnostic medicine and the emerging field of personalized medicine in oncology. © Copyright 2015, Mary Ann Liebert, Inc. 2015