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Meeting confidentiality requirements in software systems is vital for organizations. Considering confidentiality in early development phases such as the architectural design phase is beneficial compared to late phases such as the implementation because fixing design issues is more cost-efficient in early phases. This tutorial introduces an approach for modeling and statically analyzing confidentiality in software architectures within the Palladio tool suite. Besides foundational knowledge, the tutorial provides a practical hands-on session using the tool. The goal is to show that it is already possible to consider confidentiality in the early design process and that this consideration can be integrated into existing architectural design tools.

A b s t r ac t Background Adrenocortical carcinoma is a rare cancer that has a poor response to cytotoxic treatment. Methods We randomly assigned 304 patients with advanced adrenocortical carcinoma to re ceive mitotane plus either a combination of etoposide (100 mg per square meter of body-surface area on days 2 to 4), doxorubicin (40 mg per square meter on day 1), and cisplatin (40 mg per square meter on days 3 and 4) (EDP) every 4 weeks or streptozocin (streptozotocin) (1 g on days 1 to 5 in cycle 1; 2 g on day 1 in subsequent cycles) every 3 weeks. Patients with disease progression received the alternative regimen as second-line therapy. The primary end point was overall survival. Results For first-line therapy, patients in the EDP–mitotane group had a significantly higher response rate than those in the streptozocin–mitotane group (23.2% vs. 9.2%, P

Context: Quality of life (QoL) has been variously reported as normal or impaired in adults with\ud congenital adrenal hyperplasia (CAH). To explore the reasons for this discrepancy we investigated\ud the relationship between QoL, glucocorticoid treatment and other health outcomes in CAH adults.\ud Methods: Cross-sectional analysis of 151 adults with 21-hydroxylase deficiency aged 18–69 years in\ud whom QoL (assessed using the Short Form Health Survey), glucocorticoid regimen, anthropometric\ud and metabolic measures were recorded. Relationships were examined between QoL, type of\ud glucocorticoid (hydrocortisone, prednisolone and dexamethasone) and dose of glucocorticoid\ud expressed as prednisolone dose equivalent (PreDEq). QoL was expressed as z-scores calculated from\ud matched controls (14 430 subjects from UK population). Principal components analysis (PCA) was\ud undertaken to identify clusters of associated clinical and biochemical features and the principal\ud component (PC) scores used in regression analysis as predictor of QoL.\ud Results: QoL scores were associated with type of glucocorticoid treatment for vitality (PZ0.002) and\ud mental health (PZ0.011), with higher z-scores indicating better QoL in patients on hydrocortisone\ud monotherapy (P!0.05). QoL did not relate to PreDEq or mutation severity. PCA identified three PCs\ud (PC1, disease control; PC2, adiposity and insulin resistance and PC3, blood pressure and mutations)\ud that explained 61% of the variance in observed variables. Stepwise multiple regression analysis\ud demonstrated that PC2, reflecting adiposity and insulin resistance (waist circumference, serum\ud triglycerides, homeostasis model assessment of insulin resistance and HDL-cholesterol), related to QoL\ud scores, specifically impaired physical functioning, bodily pain, general health, Physical Component\ud Summary Score (P!0.001) and vitality (PZ0.002).\ud Conclusions: Increased adiposity, insulin resistance and use of prednisolone or dexamethasone are\ud associated with impaired QoL in adults with CAH. Intervention trials are required to establish whether\ud choice of glucocorticoid treatment and/or weight loss can improve QoL in CAH adults.

In comparison with essential hypertension, primary aldosteronism (PA) is associated with an increased risk of cardiovascular morbidity. To date, no data on mortality have been published. We assessed mortality of patients treated for PA within the German Conn's registry and identified risk factors for adverse outcome in a case-control study. Patients with confirmed PA treated in 3 university centers in Germany since 1994 were included in the analysis. All of the patients were contacted in 2009 and 2010 to verify life status. Subjects from the population-based F3 survey of the Cooperative Health Research in the Region of Augsburg served as controls. Final analyses were based on 600 normotensive controls, 600 hypertensive controls, and 300 patients with PA. Kaplan-Meyer survival curves were calculated for both cohorts. Ten-year overall survival was 95% in normotensive controls, 90% in hypertensive controls, and 90% in patients with PA (P value not significant). In multivariate analysis, age (hazard ratio, 1.09 per year [95% CI, 1.03-1.14]), angina pectoris (hazard ratio, 3.6 [95% CI, 1.04 -12.04]), and diabetes mellitus (hazard ratio, 2.55 [95% CI, 1.07-6.09]) were associated with an increase in all-cause mortality, whereas hypokalemia (hazard ratio, 0.41 per mmol/ L [95% CI, 0.17-0.99]) was associated with reduced mortality. Cardiovascular mortality was the main cause of death in PA (50% versus 34% in hypertensive controls; P < 0.05). These data indicate that cardiovascular mortality is increased in patients treated for PA, whereas all-cause mortality is not different from matched hypertensive controls. (Hypertension. 2012; 60: 618-624.). Online Data Supplement

RP-109

Analysis of complex proteomes often results in long protein lists, but falls short in measuring the validity of identification and quantification results on a greater number of proteins. Biological and technical replicates are mandatory, as is the combination of the MS data from various workflows (gels, 1D-LC, 2D-LC), instruments (TOF/TOF, trap, qTOF or FTMS), and search engines.

Methods based on isotope labeling and LC-MS/MS analysis are becoming a standard approach for the simultaneous identification and quantification of proteins on the proteomic scale, as they provide high accuracy, precision, sensitivity, speed, and compatibility with protein pre-fractionation. However, due to the high complexity of these experiments, a software platform is required that allows for efficient data acquisition, interpretation, and validation.

The search for new and validated biomarkers is of particular interest in clinical areas such as oncology, neurology, toxicology, and pharmacology. One of the challenges in finding the right technology for biomarker research is to combine a statistically reasonable throughput—hundreds of samples like serum, plasma, cell lysate, and urine—with an in-depth proteome technology. As proteolytic events play a significant role, in particular in disease-related events, biomarker discovery approaches may benefit from a top-down profiling approach, as proteolytic isoforms remain intact during the analysis.

The isotope-coded protein label (ICPL) technology has shown to be efficient for comparative quantification of proteins. A major aspect of this chemistry is the labeling of all free amino groups on the protein level. This allows for the application of protein fraction technologies such as 2D gel electrophoresis, liquid chromatography, or free-flow electrophoresis of the labeled protein sample under retention of the dynamic range in the sample. In addition, labeled free amino groups, which are sufficiently available in proteins, result in a high number of representative labeled peptides after protein digest. This is of high importance because at least five labeled peptide pairs are required for a reliable determination of regulation in proteins.

A variety of transcription factors including Wilms tumor gene (Wt-1), steroidogenic factor 1 (Sf-1), dosage-sensitive sex reversal, adrenal hypoplasia congenita on the X-chromosome, Gene 1 (Dax-1), and pre-B-cell transcription factor 1 (Pbx1) have been defined as necessary for regular adrenocortical development. However, the role of Pbx1 for adrenal growth and function in the adult organism together with the molecular relationship between Pbx1 and these other transcription factors have not been characterized. We demonstrate that Pbx haploinsufficiency (Pbx1+/–) in mice is accompanied by a significant lower adrenal weight in adult animals compared with wild-type controls. Accordingly, baseline proliferating cell nuclear antigen levels are lower in Pbx1+/– mice, and unilateral adrenalectomy results in impaired contralateral compensatory adrenal growth, indicating a lower proliferative potential in the context of Pbx1 haploinsufficiency. In accordance with the key role of IGFs in adrenocortical proliferation and development, real-time RT-PCR demonstrates significant lower expression levels of the IGF-I receptor, and up-regulation of IGF binding protein-2. Functionally, Pbx1+/– mice display a blunted corticosterone response after ACTH stimulation coincident with lower adrenal expression of the ACTH receptor (melanocortin 2 receptor, Mc2-r). Mechanistically, in vitro studies reveal that Pbx1 and Sf-1 synergistically stimulates Mc2-r promoter activity. Moreover, Sf-1 directly activates the Pbx1 promoter activity in vitro and in vivo. Taken together, these studies provide evidence for a role of Pbx1 in the maintenance of a functional adrenal cortex mediated by synergistic actions of Pbx1 and Sf-1 in the transcriptional regulation of the critical effector of adrenocortical differentiation, the ACTH receptor.