Model-Based Security Testing

Security testing aims at validating software system requirements related to security properties like confidentiality, integrity, authentication, authorization, availability, and non-repudiation. Although security testing techniques are available for many years, there has been little approaches that allow for specification of test cases at a higher level of abstraction, for enabling guidance on test identification and specification as well as for automated test generation. Model-based security testing (MBST) is a relatively new field and especially dedicated to the systematic and efficient specification and documentation of security test objectives, security test cases and test suites, as well as to their automated or semi-automated generation. In particular, the combination of security modelling and test generation approaches is still a challenge in research and of high interest for industrial applications. MBST includes e.g. security functional testing, model-based fuzzing, risk- and threat-oriented testing, and the usage of security test patterns. This paper provides a survey on MBST techniques and the related models as well as samples of new methods and tools that are under development in the European ITEA2-project DIAMONDS.Comment: In Proceedings MBT 2012, arXiv:1202.582

The PPARα agonist fenofibrate suppresses B-cell lymphoma in mice by modulating lipid metabolism

AbstractObesity is associated with an increased risk for malignant lymphoma development. We used Bcr/Abl transformed B cells to determine the impact of aggressive lymphoma formation on systemic lipid mobilization and turnover. In wild-type mice, tumor size significantly correlated with depletion of white adipose tissues (WAT), resulting in increased serum free fatty acid (FFA) concentrations which promote B-cell proliferation in vitro. Moreover, B-cell tumor development induced hepatic lipid accumulation due to enhanced hepatic fatty acid (FA) uptake and impaired FA oxidation. Serum triglyceride, FFA, phospholipid and cholesterol levels were significantly elevated. Consistently, serum VLDL/LDL-cholesterol and apolipoprotein B levels were drastically increased. These findings suggest that B-cell tumors trigger systemic lipid mobilization from WAT to the liver and increase VLDL/LDL release from the liver to promote tumor growth. Further support for this concept stems from experiments where we used the peroxisome proliferator-activated receptor α (PPARα) agonist and lipid-lowering drug fenofibrate that significantly suppressed tumor growth independent of angiogenesis and inflammation. In addition to WAT depletion, fenofibrate further stimulated FFA uptake by the liver and restored hepatic FA oxidation capacity, thereby accelerating the clearance of lipids released from WAT. Furthermore, fenofibrate blocked hepatic lipid release induced by the tumors. In contrast, lipid utilization in the tumor tissue itself was not increased by fenofibrate which correlates with extremely low expression levels of PPARα in B-cells. Our data show that fenofibrate associated effects on hepatic lipid metabolism and deprivation of serum lipids are capable to suppress B-cell lymphoma growth which may direct novel treatment strategies. This article is part of a Special Issue entitled Lipid Metabolism in Cancer

Interleukin‐6 initiates muscle‐ and adipose tissue wasting in a novel C57BL/6 model of cancer‐associated cachexia

BACKGROUND: Cancer‐associated cachexia (CAC) is a wasting syndrome drastically reducing efficacy of chemotherapy and life expectancy of patients. CAC affects up to 80% of cancer patients, yet the mechanisms underlying the disease are not well understood and no approved disease‐specific medication exists. As a multiorgan disorder, CAC can only be studied on an organismal level. To cover the diverse aetiologies of CAC, researchers rely on the availability of a multifaceted pool of cancer models with varying degrees of cachexia symptoms. So far, no tumour model syngeneic to C57BL/6 mice exists that allows direct comparison between cachexigenic‐ and non‐cachexigenic tumours. METHODS: MCA207 and CHX207 fibrosarcoma cells were intramuscularly implanted into male or female, 10–11‐week‐old C57BL/6J mice. Tumour tissues were subjected to magnetic resonance imaging, immunohistochemical‐, and transcriptomic analysis. Mice were analysed for tumour growth, body weight and ‐composition, food‐ and water intake, locomotor activity, O(2) consumption, CO(2) production, circulating blood cells, metabolites, and tumourkines. Mice were sacrificed with same tumour weights in all groups. Adipose tissues were examined using high‐resolution respirometry, lipolysis measurements in vitro and ex vivo, and radioactive tracer studies in vivo. Gene expression was determined in adipose‐ and muscle tissues by quantitative PCR and Western blotting analyses. Muscles and cultured myotubes were analysed histologically and by immunofluorescence microscopy for myofibre cross sectional area and myofibre diameter, respectively. Interleukin‐6 (Il‐6) was deleted from cancer cells using CRISPR/Cas9 mediated gene editing. RESULTS: CHX207, but not MCA207‐tumour‐bearing mice exhibited major clinical features of CAC, including systemic inflammation, increased plasma IL‐6 concentrations (190 pg/mL, P ≤ 0.0001), increased energy expenditure (+28%, P ≤ 0.01), adipose tissue loss (−47%, P ≤ 0.0001), skeletal muscle wasting (−18%, P ≤ 0.001), and body weight reduction (−13%, P ≤ 0.01) 13 days after cancer cell inoculation. Adipose tissue loss resulted from reduced lipid uptake and ‐synthesis combined with increased lipolysis but was not associated with elevated beta‐adrenergic signalling or adipose tissue browning. Muscle atrophy was evident by reduced myofibre cross sectional area (−21.8%, P ≤ 0.001), increased catabolic‐ and reduced anabolic signalling. Deletion of IL‐6 from CHX207 cancer cells completely protected CHX207(IL6KO)‐tumour‐bearing mice from CAC. CONCLUSIONS: In this study, we present CHX207 fibrosarcoma cells as a novel tool to investigate the mediators and metabolic consequences of CAC in C57BL/6 mice in comparison to non‐cachectic MCA207‐tumour‐bearing mice. IL‐6 represents an essential trigger for CAC development in CHX207‐tumour‐bearing mice

Loss of adipose triglyceride lipase is associated with human cancer and induces mouse pulmonary neoplasia

Metabolic reprogramming is a hallmark of cancer. Understanding cancer metabolism is instrumental to devise innovative therapeutic approaches. Anabolic metabolism, including the induction of lipogenic enzymes, is a key feature of proliferating cells. Here, we report a novel tumor suppressive function for adipose triglyceride lipase (ATGL), the rate limiting enzyme in the triglyceride hydrolysis cascade. In immunohistochemical analysis, non-small cell lung cancers, pancreatic adenocarcinoma as well as leiomyosarcoma showed significantly reduced levels of ATGL protein compared to corresponding normal tissues. The ATGL gene was frequently deleted in various forms of cancers. Low levels of ATGL mRNA correlated with significantly reduced survival in patients with ovarian, breast, gastric and non-small cell lung cancers. Remarkably, pulmonary neoplasia including invasive adenocarcinoma developed spontaneously in mice lacking ATGL pointing to an important role for this lipase in controlling tumor development. Loss of ATGL, as detected in several forms of human cancer, induces spontaneous development of pulmonary neoplasia in a mouse model. Our results, therefore, suggest a novel tumor suppressor function for ATGL and contribute to the understanding of cancer metabolism. We propose to evaluate loss of ATGL protein expression for the diagnosis of malignant tumors. Finally, modulation of the lipolytic pathway may represent a novel therapeutic approach in the treatment of human cancer

Gravothermal collapse of isolated self-interacting dark matter haloes: N-body simulation versus the fluid model

Self-Interacting Dark Matter (SIDM) is a collisional form of cold dark matter (CDM), originally proposed to solve problems that arose when the collisionless CDM theory of structure formation was compared with observations of galaxies on small scales. The quantitative impact of the proposed elastic collisions on structure formation has been estimated previously by Monte Carlo N-body simulations and by a conducting fluid model, with apparently diverging results. To improve this situation, we make direct comparisons between new Monte Carlo N-body simulations and solutions of the conducting fluid model, for isolated SIDM haloes of fixed mass. This allows us to separate cleanly the effects of gravothermal relaxation from those of continuous mass accretion in an expanding background universe. When these two methods were previously applied to halo formation with cosmological boundary conditions, they disagreed by an order of magnitude about the size of the scattering cross section required to solve the so-called 'cusp-core problem.' We show here, however, that the methods agree with each other within 20 per cent for isolated haloes. This suggests that the two methods are consistent, and that their disagreement for cosmological haloes is not caused by a breakdown of their validity. The isolated haloes studied here undergo gravothermal collapse. We compare the solutions calculated by these two methods for gravothermal collapse starting from several initial conditions. This allows us to calibrate the heat conduction which accounts for the effect of elastic hard-sphere scattering in the fluid model. The amount of tuning of the thermal conductivity parameters required to bring the two methods into close agreement for isolated haloes, however, is too small to explain the discrepancy found previously in the cosmological context.Comment: 14 pages, 10 figures, accepted for publication on MNRA

The RNA-Editing Enzyme ADAR1 Controls Innate Immune Responses to RNA

The ADAR RNA-editing enzymes deaminate adenosine bases to inosines in cellular RNAs. Aberrant interferon expression occurs in patients in whom ADAR1 mutations cause Aicardi-Goutières syndrome (AGS) or dystonia arising from striatal neurodegeneration. Adar1 mutant mouse embryos show aberrant interferon induction and die by embryonic day E12.5. We demonstrate that Adar1 embryonic lethality is rescued to live birth in Adar1; Mavs double mutants in which the antiviral interferon induction response to cytoplasmic double-stranded RNA (dsRNA) is prevented. Aberrant immune responses in Adar1 mutant mouse embryo fibroblasts are dramatically reduced by restoring the expression of editing-active cytoplasmic ADARs. We propose that inosine in cellular RNA inhibits antiviral inflammatory and interferon responses by altering RLR interactions. Transfecting dsRNA oligonucleotides containing inosine-uracil base pairs into Adar1 mutant mouse embryo fibroblasts reduces the aberrant innate immune response. ADAR1 mutations causing AGS affect the activity of the interferon-inducible cytoplasmic isoform more severely than the nuclear isoform

Eosinophils in glioblastoma biology

Glioblastoma multiforme (GBM) is the most common primary brain tumor in adults. The development of this malignant glial lesion involves a multi-faceted process that results in a loss of genetic or epigenetic gene control, un-regulated cell growth, and immune tolerance. Of interest, atopic diseases are characterized by a lack of immune tolerance and are inversely associated with glioma risk. One cell type that is an established effector cell in the pathobiology of atopic disease is the eosinophil. In response to various stimuli, the eosinophil is able to produce cytotoxic granules, neuromediators, and pro-inflammatory cytokines as well as pro-fibrotic and angiogenic factors involved in pathogen clearance and tissue remodeling and repair. These various biological properties reveal that the eosinophil is a key immunoregulatory cell capable of influencing the activity of both innate and adaptive immune responses. Of central importance to this report is the observation that eosinophil migration to the brain occurs in response to traumatic brain injury and following certain immunotherapeutic treatments for GBM. Although eosinophils have been identified in various central nervous system pathologies, and are known to operate in wound/repair and tumorstatic models, the potential roles of eosinophils in GBM development and the tumor immunological response are only beginning to be recognized and are therefore the subject of the present review

Addressing climate change with behavioral science: a global intervention tournament in 63 countries

Effectively reducing climate change requires marked, global behavior change. However, it is unclear which strategies are most likely to motivate people to change their climate beliefs and behaviors. Here, we tested 11 expert-crowdsourced interventions on four climate mitigation outcomes: beliefs, policy support, information sharing intention, and an effortful tree-planting behavioral task. Across 59,440 participants from 63 countries, the interventions’ effectiveness was small, largely limited to nonclimate skeptics, and differed across outcomes: Beliefs were strengthened mostly by decreasing psychological distance (by 2.3%), policy support by writing a letter to a future-generation member (2.6%), information sharing by negative emotion induction (12.1%), and no intervention increased the more effortful behavior—several interventions even reduced tree planting. Last, the effects of each intervention differed depending on people’s initial climate beliefs. These findings suggest that the impact of behavioral climate interventions varies across audiences and target behaviors