Interleukin-8 is the single most up-regulated gene in whole genome profiling of H. pylori exposed gastric epithelial cells

<p>Abstract</p> <p>Background</p> <p>The association between <it>Helicobacter pylori </it>infection and upper gastrointestinal disease is well established. However, only a small fraction of <it>H. pylori </it>carriers develop disease, and there are great geographical differences in disease penetrance. The explanation to this enigma lies in the interaction between the bacterium and the host. <it>H. pylori </it>Outer Membrane Phospholipase A (OMPLA) has been suggested to play a role in the virulence of this bacterium. The aim of this study was to profile the most significant cellular pathways and biological processes affected in gastric epithelial cells during 24 h of <it>H. pylori </it>exposure, and to study the inflammatory response to OMPLA⁺and OMPLA^-<it>H. pylori </it>variants.</p> <p>Results</p> <p>Interleukin-8 was the most significantly up-regulated gene and appears to play a paramount role in the epithelial cell response to <it>H. pylori </it>infection and in the pathological processes leading to gastric disease. MAPK and NF-kappaB cellular pathways were powerfully activated, but did not seem to explain the impressive <it>IL-8 </it>response. There was marked up-regulation of <it>TP53BP2</it>, whose corresponding protein ASPP2 may interact with <it>H. pylori </it>CagA and cause marked p53 suppression of apoptosis. Other regulators of apoptosis also showed abberant regulation. We also identified up-regulation of several oncogenes and down-regulation of tumor suppressor genes as early as during the first 24 h of infection. <it>H. pylori </it>OMPLA phase variation did not seem to influence the inflammatory epithelial cell gene response in this experiment.</p> <p>Conclusion</p> <p>In whole genome analysis of the epithelial response to <it>H. pylori </it>exposure, <it>IL-8 </it>demonstrated the most marked up-regulation, and was involved in many of the most important cellular response processes to the infection. There was dysregulation of apoptosis, tumor suppressor genes and oncogenes as early as in the first 24 h of <it>H. pylori </it>infection, which may represent early signs of gastric tumorigenesis. OMPLA^+/-did not affect the acute inflammatory response to <it>H. pylori</it>.</p

The Prognostic Impact of Protein Expression of E-Cadherin-Catenin Complexes Differs between Rectal and Colon Carcinoma

The E-cadherin-catenin complex provides cell-cell adhesion. In order for a carcinoma to metastasize, cancer cells must let go of their hold of neighboring cells in the primary tumor. The presence of components of the E-cadherin-catenin complex in 246 rectal adenocarcinomas was examined by immunohistochemistry and compared to their presence in 219 colon carcinomas. The expression data were correlated to clinical information from the patients' records. There were statistically significant differences in protein expression between the rectal and the colon carcinomas regarding membranous β-catenin, γ-catenin, p120-catenin, and E-cadherin, as well as nuclear β-catenin. In the rectal carcinomas, there was a significant inverse association between the expression of p120-catenin in cell membranes of the primary tumors and the occurrence of local recurrence, while membranous protein expression of β-catenin was inversely related to distant metastases

Differences in Protein Expression and Gene Amplification of Cyclins between Colon and Rectal Adenocarcinomas

Adenocarcinomas of rectum and colon may be different with regard to the cellular biological basis for cancer development. A material of 246 rectal cancers removed surgically at Akershus University Hospital in the years 1992–2000 was investigated and was compared to a material of 219 colon cancers operated on at Akershus University Hospital during the years 1988, 1990 and 1997–2000. There were highly significant differences between the rectal and the colon cancers in the protein expression of cyclin D1, cyclin D3, cyclin E, nuclear β-catenin, and c-Myc and in gene amplification of cyclin A2, cyclin B1, cyclin D1, and cyclin E. Gene amplification and protein expression in the rectal cancers correlated significantly for the cyclins B1, D3, and E. A statistically significant relation was observed between overexpression of cyclin A2 and local relapse of rectal carcinomas, as higher expression of cyclin A2 was associated with lower local recurrence rate

Compensation claims in pediatric orthopedics in Norway between 2012 and 2018: a nationwide study of 487 patients

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Patients Who Die by Suicide: A Study of Treatment Patterns and Patient Safety Incidents in Norway

Underlying patterns and factors behind suicides of patients in treatment are still unclear and there is a pressing need for more studies to address this knowledge gap. We analysed 278 cases of suicide reported to The Norwegian System of Patient Injury Compensation, drawing on anonymised data, i.e., age group, gender, diagnostic category, type of treatment provided, inpatient vs. outpatient status, type of treatment facility, and expert assessments of medical errors. The data originated from compensation claim forms, expert assessments, and medical records. Chi-square tests for independence, multinominal logistic regression, and Bayes factors for independence were used to analyse whether the age group, gender, diagnostic category, inpatient/outpatient status, type of institution, and type of treatment received by patients that had died by suicide were associated with different types of medical errors. Patients who received medication tended to be proportionally more exposed to an insufficient level of observation. Those who received medication and psychotherapy tended to be proportionally more exposed to inadequate treatment, including inadequate medication. Inpatients were more likely to be exposed to inappropriate diagnostics and inadequate treatment and follow up while outpatients to insufficient level of observation and inadequate suicide risk assessment. We conclude that the patients who had received medication as their main treatment tended to have been insufficiently observed, while patients who had received psychotherapy and medication tended to have been provided insufficient treatment, including inadequate medication. These observations may be used as learning points for the suicide prevention of patients in treatment in Norwegian psychiatric services

Pasientskader hos fastleger meldt til Norsk pasientskadeerstatning 2011–17

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Intratumoural mRNA expression of genes from the oestradiol metabolic pathway and clinical and histopathological parameters of breast cancer

INTRODUCTION: The expression of the oestrogen receptor (ER) is one of the more important clinical parameters of breast cancer. However, the relationship between the ER and its ligand, oestradiol, and the enzymes that synthesise it are not well understood. The expression of mRNA transcripts of members of the oestradiol metabolic and signalling pathways including the ER was studied in detail. METHOD: mRNA transcripts for aromatase (CYP19), 17-β-hydroxysteroid dehydrogenase I, 17-β-hydroxysteroid dehydrogenase II, ERα, ERβ, steroid sulfatase (STS), oestradiol sulfotransferase (EST), cyclin D(1 )(CYCLD1) and ERBB2 were fluorometrically quantified by competitive RT-PCR using an internal standard in 155 breast carcinomas. In addition, the transcripts of CYP19 were analysed for alternative splicing/usage of exon 1 and an alternative poly A tail. RESULTS: A great variability of expression was observed, ranging from 0 to 2376 amol/mg RNA. The highest levels were observed for STS and EST, and the lowest levels (close to zero) were observed for the 17-β-hydroxysteroid dehydrogenase isoenzymes. The levels of mRNA expression were analysed with respect to clinical and histopathological parameters as well as for disease-free survival. High correlation of the mRNA expression of STS, EST and 17-β-hydroxysteroid dehydrogenase in the tumours suggested a common regulation, possibly by their common metabolite (oestradiol). Hierarchical clustering analysis in the 155 patients resulted in two main clusters, representing the ERα-negative and ERα-positive breast cancer cases. The mRNA expression of the oestradiol metabolising enzymes did not follow the expression of the ERα in all cases, leading to the formation of several subclasses of tumours. Patients with no expression of CYP19 and patients with high levels of expression of STS had significantly shorter disease-free survival time (P > 0.0005 and P < 0.03, respectively). Expression of ERβ mRNA was a better prognostic factor than that of ERα in this material. CONCLUSION: Our results indicate the importance of CYP19 and the enzymes regulating the oestrone sulfate metabolism as factors of disease-free survival in breast cancer, in addition to the well-known factors ER and ERBB2

Overall survival after resection for colon cancer in a national cohort study was adversely affected by TNM stage, lymph node ratio, gender, and old age

Background A national surveillance program of colon cancer treatment was introduced in 2007. We examined prognostic factors for colon cancer operated in 2000 with an aim of improving survival in the new program and a special focus on the merit of lymph node yield. Methods A cohort of 269 patients, 152 women (56.5%), with a mean age of 71 years, was operated for colon cancer in 2000 at three teaching hospitals and followed up for 7 years. Results Overall 5-year survival was 58.0%, and overall hospital mortality was 5.2%, with 4.5% in elective cases and 12.5% after urgent surgery. In only 41.1% of the specimens were 12 or more lymph nodes retrieved, but this did not affect survival in the combined cohort, although one of the hospitals achieved a significantly better result with a harvest of 12 or more lymph nodes. In a multivariate analysis, old age, gender, a high lymph node ratio (LNR) at stage III, and tumor–node–metastasis stage were adverse factors for survival. Conclusions The operative mortality was high and should be reassessed. The lymph node count did not have a significant impact on outcome overall, whereas the LNR proved significant for stage III. A prospective protocol using overall lymph node yield as a surrogate measure for more radical surgery, nevertheless, seems warranted to improve the lymph node harvest according to international recommendations

DNA methylation profiling in doxorubicin treated primary locally advanced breast tumours identifies novel genes associated with survival and treatment response

<p>Abstract</p> <p>Background</p> <p>Breast cancer is the most frequent cancer in women and consists of a heterogeneous collection of diseases with distinct histopathological, genetic and epigenetic characteristics. In this study, we aimed to identify DNA methylation based biomarkers to distinguish patients with locally advanced breast cancer who may benefit from neoadjuvant doxorubicin treatment.</p> <p>Results</p> <p>We investigated quantitatively the methylation patterns in the promoter regions of 14 genes (<it>ABCB1</it>, <it>ATM</it>, <it>BRCA1</it>, <it>CDH3</it>, <it>CDKN2A</it>, <it>CXCR4</it>, <it>ESR1</it>, <it>FBXW7</it>, <it>FOXC</it>1, <it>GSTP1</it>, <it>IGF2</it>, <it>HMLH1</it>, <it>PPP2R2B</it>, and <it>PTEN</it>) in 75 well-described pre-treatment samples from locally advanced breast cancer and correlated the results to the available clinical and molecular parameters. Six normal breast tissues were used as controls and 163 unselected breast cancer cases were used to validate associations with histopathological and clinical parameters.</p> <p>Aberrant methylation was detected in 9 out of the 14 genes including the discovery of methylation at the <it>FOXC1 </it>promoter. Absence of methylation at the <it>ABCB1 </it>promoter correlated with progressive disease during doxorubicin treatment. Most importantly, the DNA methylation status at the promoters of <it>GSTP1</it>, <it>FOXC1 </it>and <it>ABCB1 </it>correlated with survival, whereby the combination of methylated genes improved the subdivision with respect to the survival of the patients. In multivariate analysis <it>GSTP1 </it>and <it>FOXC1 </it>methylation status proved to be independent prognostic markers associated with survival.</p> <p>Conclusions</p> <p>Quantitative DNA methylation profiling is a powerful tool to identify molecular changes associated with specific phenotypes. Methylation at the <it>ABCB1 </it>or <it>GSTP1 </it>promoter improved overall survival probably due to prolonged availability and activity of the drug in the cell while <it>FOXC1 </it>methylation might be a protective factor against tumour invasiveness. <it>FOXC1 </it>proved to be general prognostic factor, while <it>ABCB1 </it>and <it>GSTP1 </it>might be predictive factors for the response to and efficacy of doxorubicin treatment. Pharmacoepigenetic effects such as the reported associations in this study provide molecular explanations for differential responses to chemotherapy and it might prove valuable to take the methylation status of selected genes into account for patient management and treatment decisions.</p

Subtype-specific micro-RNA expression signatures in breast cancer progression.

Robust markers of invasiveness may help reduce the overtreatment of in situ carcinomas. Breast cancer is a heterogeneous disease and biological mechanisms for carcinogenesis vary between subtypes. Stratification by subtype is therefore necessary to identify relevant and robust signatures of invasive disease. We have identified microRNA (miRNA) alterations during breast cancer progression in two separate datasets and used stratification and external validation to strengthen the findings. We analyzed two separate datasets (METABRIC and AHUS) consisting of a total of 186 normal breast tissue samples, 18 ductal carcinoma in situ (DCIS) and 1,338 invasive breast carcinomas. Validation in a separate dataset and stratification by molecular subtypes based on immunohistochemistry, PAM50 and integrated cluster classifications were performed. We propose subtype-specific miRNA signatures of invasive carcinoma and a validated signature of DCIS. miRNAs included in the invasive signatures include downregulation of miR-139-5p in aggressive subtypes and upregulation of miR-29c-5p expression in the luminal subtypes. No miRNAs were differentially expressed in the transition from DCIS to invasive carcinomas on the whole, indicating the need for subtype stratification. A total of 27 miRNAs were included in our proposed DCIS signature. Significant alterations of expression included upregulation of miR-21-5p and the miR-200 family and downregulation of let-7 family members in DCIS samples. The signatures proposed here can form the basis for studies exploring DCIS samples with increased invasive potential and serum biomarkers for in situ and invasive breast cancer.This work was performed as part of the EurocanPlatform which has received funding from the European Community's Seventh Framework Programme (FP7/2007-2013) under grant agreement No. 260791. Portions of this research (Venn diagram creator) were supported by the W.R. Wiley Environmental Molecular Science Laboratory, a national scientific user facility sponsored by the U.S. Department of Energy's Office of Biological and Environmental Research and located at PNNL. PNNL is operated by Battelle Memorial Institute for the U.S. Department of Energy under contract DE-AC05-76RL0 1830.This is the author accepted manuscript. The final version is available from Wiley via http://dx.doi.org/10.1002/ijc.3014