A Dual-Engine for Early Analysis of Critical Systems

This paper presents a framework for modeling, simulating, and checking properties of critical systems based on the Alloy language -- a declarative, first-order, relational logic with a built-in transitive closure operator. The paper introduces a new dual-analysis engine that is capable of providing both counterexamples and proofs. Counterexamples are found fully automatically using an SMT solver, which provides a better support for numerical expressions than the existing Alloy Analyzer. Proofs, however, cannot always be found automatically since the Alloy language is undecidable. Our engine offers an economical approach by first trying to prove properties using a fully-automatic, SMT-based analysis, and switches to an interactive theorem prover only if the first attempt fails. This paper also reports on applying our framework to Microsoft's COM standard and the mark-and-sweep garbage collection algorithm.Comment: Workshop on Dependable Software for Critical Infrastructures (DSCI), Berlin 201

Methylation Status of Imprinted Genes and Repetitive Elements in Sperm DNA from Infertile Males

Stochastic, environmentally and/or genetically induced disturbances in the genome-wide epigenetic reprogramming processes during male germ-cell development may contribute to male infertility. To test this hypothesis, we have studied the methylation levels of 2 paternally (H19 and GTL2) and 5 maternally methylated (LIT1, MEST, NESPAS, PEG3, and SNRPN) imprinted genes, as well as of ALU and LINE1 repetitive elements in 141 sperm samples, which were used for assisted reproductive technologies (ART), including 106 couples with strictly male-factor or combined male and female infertility and 28 couples with strictly female-factor infertility. Aberrant methylation imprints showed a significant association with abnormal semen parameters, but did not seem to influence ART outcome. Repeat methylation also differed significantly between sperm samples from infertile and presumably fertile males. However, in contrast to imprinted genes, ALU methylation had a significant impact on pregnancy and live-birth rate in couples with male-factor or combined infertility. ALU methylation was significantly high-er in sperm samples leading to pregnancy and live-birth than in those that did not. Sperm samples leading to abortions showed significantly lower ALU methylation levels than those leading to the birth of a baby. Copyright (C) 2011 S. Karger AG, Base

Speckle-tracking echocardiography combined with imaging mass spectrometry assesses region-dependent alterations

Left ventricular (LV) contraction is characterized by shortening and thickening of longitudinal and circumferential fibres. To date, it is poorly understood how LV deformation is altered in the pathogenesis of streptozotocin (STZ)-induced type 1 diabetes mellitus-associated diabetic cardiomyopathy and how this is associated with changes in cardiac structural composition. To gain further insights in these LV alterations, eight-week-old C57BL6/j mice were intraperitoneally injected with 50 mg/kg body weight STZ during 5 consecutive days. Six, 9, and 12 weeks (w) post injections, echocardiographic analysis was performed using a Vevo 3100 device coupled to a 30-MHz linear-frequency transducer. Speckle-tracking echocardiography (STE) demonstrated impaired global longitudinal peak strain (GLS) in STZ versus control mice at all time points. 9w STZ animals displayed an impaired global circumferential peak strain (GCS) versus 6w and 12w STZ mice. They further exhibited decreased myocardial deformation behaviour of the anterior and posterior base versus controls, which was paralleled with an elevated collagen I/III protein ratio. Additionally, hypothesis-free proteome analysis by imaging mass spectrometry (IMS) identified regional- and time-dependent changes of proteins affecting sarcomere mechanics between STZ and control mice. In conclusion, STZ-induced diabetic cardiomyopathy changes global cardiac deformation associated with alterations in cardiac sarcomere proteins

BET bromodomain protein inhibition is a therapeutic option for medulloblastoma

Medulloblastoma is the most common malignant brain tumor of childhood, and represents a significant clinical challenge in pediatric oncology, since overall survival currently remains under 70%. Patients with tumors overexpressing MYC or harboring a MYC oncogene amplification have an extremely poor prognosis. Pharmacologically inhibiting MYC expression may, thus, have clinical utility given its pathogenetic role in medulloblastoma. Recent studies using the selective small molecule BET inhibitor, JQ1, have identified BET bromodomain proteins, especially BRD4, as epigenetic regulatory factors for MYC and its targets. Targeting MYC expression by BET inhibition resulted in antitumoral effects in various cancers. Our aim here was to evaluate the efficacy of JQ1 against preclinical models for high-risk MYC-driven medulloblastoma. Treatment of medulloblastoma cell lines with JQ1 significantly reduced cell proliferation and preferentially induced apoptosis in cells expressing high levels of MYC. JQ1 treatment of medulloblastoma cell lines downregulated MYC expression and resulted in a transcriptional deregulation of MYC targets, and also significantly altered expression of genes involved in cell cycle progression and p53 signalling. JQ1 treatment prolonged the survival of mice harboring medulloblastoma xenografts and reduced the tumor burden in these mice. Our preclinical data provide evidence to pursue testing BET inhibitors, such as JQ1, as molecular targeted therapeutic options for patients with high-risk medulloblastomas overexpressing MYC or harboring MYC amplifications

Primary Signet Ring Cell Mucinous Ovarian Carcinoma: A Case Report and Literature Review

A 24-year-old female patient presented with an extremely rare primary signet cell carcinoma of the right ovary 1 year after surgery for a mucinous borderline tumour of the left ovary. Relaparotomy was carried out with right adnexectomy, appendectomy and partial omentectomy. Surgery was followed by 6 courses of paclitaxel/carboplatinum chemotherapy. After an initial response, the patient again developed increasing ascites. The patient was transferred to our hospital and a re-relaparotomy was carried out, completing the operation. After 3 courses of pegylated doxorubicin/trabectedin, the clinical course showed a positive response and a decline of the tumour marker CEA in peripheral blood. After 5 months, ascites developed in the retroperitoneum so that the chemotherapy had to be changed. In spite of a positive response with the new chemotherapy, the patient died of a very rare pulmonary complication after 1 month within 2 days