An unusual presentation of metastatic adenocarcinoma of lung: a case report

We report an unusual patient with primary adenocarcinoma of lung causing malignant pleural and pericardial effusions. The diagnosis was made only at autopsy as his staging computed tomography scan of chest was negative for an obvious mass lesion within the lung or pleura. Prior to his death, his symptoms were erroneously managed as left ventricular failure and community-acquired pneumonia

Revisiting the technical validation of tumour biomarker assays: how to open a Pandora's box

A tumour biomarker is a characteristic that is objectively measured and evaluated in tumour samples as an indicator of normal biological processes, pathogenic processes, or pharmacologic responses to a therapeutic intervention. The development of a biomarker contemplates distinct phases, including discovery by hypothesis-generating preclinical or exploratory studies, development and qualification of the assay for the identification of the biomarker in clinical samples, and validation of its clinical significance. Although guidelines for the development and validation of biomarkers are available, their implementation is challenging, owing to the diversity of biomarkers being developed. The term 'validation' undoubtedly has several meanings; however, in the context of biomarker research, a test may be considered valid if it is 'fit for purpose'. In the process of validation of a biomarker assay, a key point is the validation of the methodology. Here we discuss the challenges for the technical validation of immunohistochemical and gene expression assays to detect tumour biomarkers and provide suggestions of pragmatic solutions to address these challenges

Case–control study of lifetime total physical activity and endometrial cancer risk

A population-based case–control study of physical activity and endometrial cancer risk was conducted in Alberta between 2002 and 2006. Incident, histologically confirmed cases of endometrial cancer (n = 542) were frequency age-matched to controls (n = 1,032). The Lifetime Total Physical Activity Questionnaire was used to measure occupational, household, and recreational activity levels. Multivariable logistic regression analyses were conducted. Total lifetime physical activity reduced endometrial cancer risk (odds ratio [OR] for >129 vs. <82 MET-h/week/year = 0.86, 95% confidence interval [95% CI]: 0.63, 1.18). By type of activity, the risks were significantly decreased for greater recreational activity (OR = 0.64, 95% CI: 0.47, 0.87), but not for household activity (OR = 1.09, 95% CI: 0.75, 1.58) and/or occupational activity (OR = 0.90, 95% CI: 0.67, 1.20) when comparing the highest to lowest quartiles. For activity performed at different biologically defined life periods, some indication of reduced risks with activity done between menarche and full-term pregnancy and after menarche was observed. When examining the activity by intensity of activity (i.e., light <3, moderate 3–6, and vigorous >6 METs), light activity slightly decreased endometrial cancer risk (OR = 0.68, 95% CI: 0.48, 0.97) but no association with moderate or vigorous intensity activity was found. Endometrial cancer risk was increased with sedentary occupational activity by 28% (95 CI%: 0.89, 1.83) for >11.3 h/week/year versus ≤2.4 h/week/year or by 11% for every 5 h/week/year spent in sedentary behavior. This study provides evidence for a decreased risk between lifetime physical activity and endometrial cancer risk and a possible increased risk associated with sedentary behavior

Tumor markers in breast cancer - European Group on Tumor Markers recommendations

Recommendations are presented for the routine clinical use of serum and tissue-based markers in the diagnosis and management of patients with breast cancer. Their low sensitivity and specificity preclude the use of serum markers such as the MUC-1 mucin glycoproteins ( CA 15.3, BR 27.29) and carcinoembryonic antigen in the diagnosis of early breast cancer. However, serial measurement of these markers can result in the early detection of recurrent disease as well as indicate the efficacy of therapy. Of the tissue-based markers, measurement of estrogen and progesterone receptors is mandatory in the selection of patients for treatment with hormone therapy, while HER-2 is essential in selecting patients with advanced breast cancer for treatment with Herceptin ( trastuzumab). Urokinase plasminogen activator and plasminogen activator inhibitor 1 are recently validated prognostic markers for lymph node-negative breast cancer patients and thus may be of value in selecting node-negative patients that do not require adjuvant chemotherapy. Copyright (C) 2005 S. Karger AG, Basel

HIV-1 Matrix Dependent Membrane Targeting Is Regulated by Gag mRNA Trafficking

Retroviral Gag polyproteins are necessary and sufficient for virus budding. Productive HIV-1 Gag assembly takes place at the plasma membrane. However, little is known about the mechanisms by which thousands of Gag molecules are targeted to the plasma membrane. Using a bimolecular fluorescence complementation (BiFC) assay, we recently reported that the cellular sites and efficiency of HIV-1 Gag assembly depend on the precise pathway of Gag mRNA export from the nucleus, known to be mediated by Rev. Here we describe an assembly deficiency in human cells for HIV Gag whose expression depends on hepatitis B virus (HBV) post-transcriptional regulatory element (PRE) mediated-mRNA nuclear export. PRE-dependent HIV Gag expressed well in human cells, but assembled with slower kinetics, accumulated intracellularly, and failed to associate with a lipid raft compartment where the wild-type Rev-dependent HIV-1 Gag efficiently assembles. Surprisingly, assembly and budding of PRE-dependent HIV Gag in human cells could be rescued in trans by co-expression of Rev-dependent Gag that provides correct membrane targeting signals, or in cis by replacing HIV matrix (MA) with other membrane targeting domains. Taken together, our results demonstrate deficient membrane targeting of PRE-dependent HIV-1 Gag and suggest that HIV MA function is regulated by the trafficking pathway of the encoding mRNA

Off-Target Effects of Psychoactive Drugs Revealed by Genome-Wide Assays in Yeast

To better understand off-target effects of widely prescribed psychoactive drugs, we performed a comprehensive series of chemogenomic screens using the budding yeast Saccharomyces cerevisiae as a model system. Because the known human targets of these drugs do not exist in yeast, we could employ the yeast gene deletion collections and parallel fitness profiling to explore potential off-target effects in a genome-wide manner. Among 214 tested, documented psychoactive drugs, we identified 81 compounds that inhibited wild-type yeast growth and were thus selected for genome-wide fitness profiling. Many of these drugs had a propensity to affect multiple cellular functions. The sensitivity profiles of half of the analyzed drugs were enriched for core cellular processes such as secretion, protein folding, RNA processing, and chromatin structure. Interestingly, fluoxetine (Prozac) interfered with establishment of cell polarity, cyproheptadine (Periactin) targeted essential genes with chromatin-remodeling roles, while paroxetine (Paxil) interfered with essential RNA metabolism genes, suggesting potential secondary drug targets. We also found that the more recently developed atypical antipsychotic clozapine (Clozaril) had no fewer off-target effects in yeast than the typical antipsychotics haloperidol (Haldol) and pimozide (Orap). Our results suggest that model organism pharmacogenetic studies provide a rational foundation for understanding the off-target effects of clinically important psychoactive agents and suggest a rational means both for devising compound derivatives with fewer side effects and for tailoring drug treatment to individual patient genotypes

Levels of DNA methylation vary at CpG sites across the BRCA1 promoter, and differ according to triple negative and "BRCA-like" status, in both blood and tumour DNA

Triple negative breast cancer is typically an aggressive and difficult to treat subtype. It is often associated with loss of function of the BRCA1 gene, either through mutation, loss of heterozygosity or methylation. This study aimed to measure methylation of the BRCA1 gene promoter at individual CpG sites in blood, tumour and normal breast tissue, to assess whether levels were correlated between different tissues, and with triple negative receptor status, histopathological scoring for BRCA-like features and BRCA1 protein expression. Blood DNA methylation levels were significantly correlated with tumour methylation at 9 of 11 CpG sites examined (p<0.0007). The levels of tumour DNA methylation were significantly higher in triple negative tumours, and in tumours with high BRCA-like histopathological scores (10 of 11 CpG sites; p<0.01 and p<0.007 respectively). Similar results were observed in blood DNA (6 of 11 CpG sites; p<0.03 and 7 of 11 CpG sites; p<0.02 respectively). This study provides insight into the pattern of CpG methylation across the BRCA1 promoter, and supports previous studies suggesting that tumours with BRCA1 promoter methylation have similar features to those with BRCA1 mutations, and therefore may be suitable for the same targeted therapies

Genetic interactions between a phospholipase A2 and the Rim101 pathway components in S. cerevisiae reveal a role for this pathway in response to changes in membrane composition and shape

Modulating composition and shape of biological membranes is an emerging mode of regulation of cellular processes. We investigated the global effects that such perturbations have on a model eukaryotic cell. Phospholipases A2 (PLA2s), enzymes that cleave one fatty acid molecule from membrane phospholipids, exert their biological activities through affecting both membrane composition and shape. We have conducted a genome-wide analysis of cellular effects of a PLA2 in the yeast Saccharomyces cerevisiae as a model system. We demonstrate functional genetic and biochemical interactions between PLA2 activity and the Rim101 signaling pathway in S. cerevisiae. Our results suggest that the composition and/or the shape of the endosomal membrane affect the Rim101 pathway. We describe a genetically and functionally related network, consisting of components of the Rim101 pathway and the prefoldin, retromer and SWR1 complexes, and predict its functional relation to PLA2 activity in a model eukaryotic cell. This study provides a list of the players involved in the global response to changes in membrane composition and shape in a model eukaryotic cell, and further studies are needed to understand the precise molecular mechanisms connecting them