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In hepatocellular carcinoma (HCC), blood platelets have been linked to tumor growth, epithelial-to-mesenchymal transition (EMT), extrahepatic metastasis and a limited therapeutic response to the multikinase inhibitor (MKi) sorafenib, the standard of care in advanced HCC for the last decade. Recent clinical data indicated an improved overall survival for sorafenib in combination with the HDAC inhibitor resminostat in a platelet count dependent manner. Here, the impact of platelets on the sorafenib and resminostat drug effects in HCC cells was explored. In contrast to sorafenib, resminostat triggered an anti-proliferative response in HCC cell lines independent of platelets. As previously described, platelets induced invasive capabilities of HCC cells, a prerequisite for extravasation and metastasis. Importantly, the resminostat/sorafenib drug combination, but not the individual drugs, effectively blocked platelet-induced HCC cell invasion. Exploration of the molecular mechanism revealed that the combined drug action led to a reduction of platelet-induced CD44 expression and to the deregulation of several other epithelial and mesenchymal genes, suggesting interference with cell invasion via EMT. In addition, the drug combination decreased phosphorylated ERK level, indicating inhibition of the mitogenic signaling pathway MEK/ERK. Taken together, the resminostat plus sorafenib combination counteracts platelet-mediated cancer promoting effects in HCC cells.

9545 Background: Anti-PD-1 +/- anti-CTLA4 antibodies are the current standard of care immunotherapy for advanced melanoma. However, a significant proportion of patients do not achieve disease control. Epigenetic modulation, particularly histone deacetylase (HDAC) inhibition, can overcome tumor escape mechanisms and thus might increase the susceptibility to immunotherapy. Methods: Advanced unresectable/metastatic cutaneous melanoma patients primary refractory or non-responding to prior checkpoint inhibitor (CI) therapy were treated with domatinostat at 5 different dose levels (DL) (100 mg (QD), 200 (QD), and 200 mg (BID) using two different schedules (D1-14 and D1-21 q3w) in combination with pembrolizumab (2 mg/kg) q3w to evaluate safety and tolerability. Tumor assessments were performed every 12 weeks and assessed using irRECIST. Sequential tumor biopsies were taken for gene expression analysis and peripheral blood for pharmacokinetic (PK) analysis. Results: We report on preliminary results from the phase Ib part of the ongoing study, data cut-off Feb 1st, 2021 a total of 40 patients have been enrolled. Patient characteristics show that the median number of pretreatments at stage IV was 3, 65 % of patients stage M1c (AJCC 7 or 8) and 35 % with elevated LDH at trial inclusion. Treatment emergent adverse events (AEs) related to domatinostat reported in ≥ 10% of patients were: diarrhea (23%), nausea (20%), fatigue (20%), rash (15%), pyrexia (13%), blood alkaline phosphatase increased (13%), vomiting (10%), dyspnea (10%), all grade 1 and 2 - except one maculo-papular rash grade 3. In total, 8 patients (20 %) developed ≥ grade 3 AEs, with no treatment-related deaths. Patterns of AEs resembled the known safety profiles of domatinostat and pembrolizumab with no increase of immune related AEs for the combination. Maximum tolerated dose was not reached. Four patients discontinued treatment per protocol due to AEs grade 3. We observed clinical activity with 1 complete response, 2 confirmed partial responses and 9 stable diseases (6 confirmed), resulting in a disease control rate of 30% in highly pretreated patients throughout all DLs. Notably, 3 out of 7 patients achieved disease control in DL 3 (domatinostat 200 mg BID D1-14, q3w) and were on treatment ≥ 1.5 years, indicating a trend of dose-dependent clinical activity. Domatinostat treatment resulted in a trend to higher intra-tumoral expression of MHC/APM genes and a more inflamed tumor microenvironment reflecting enhanced T cell infiltration. Conclusions: The combination of domatinostat and pembrolizumab was safe and well tolerated. The observed clinical activity in advanced melanoma patients refractory to previous checkpoint inhibition and the favorable translational findings warrant further development of domatinostat in combination with CI in melanoma and beyond. Clinical trial information: NCT03278665.

Background: MP0274 is a four domain, trispecific, biparatopic, HER2-targeted Designed Ankyrin Repeat Protein (DARPin®) drug candidate. M0274 binds to domains II and IV of HER2 at different sites from trastuzumab and pertuzumab, and to human serum albumin for an extended half-life. MP0274 displays a unique mode of action in preclinical models by directly inducing apoptosis in HER2-addicted cancer cells. Compared to anti-HER2 monoclonal antibodies, preclinical studies revealed no additional safety signals and no maximum tolerated dose was reached. Trial Design: This is a first-in-human study with 2 parts. The dose escalation part of the study, follows a classical 3+3 dose escalation approach, including one extra cycle for exploration of specific PK characteristics, and will establish the recommended dose (RD) for further development based on safety, pharmacokinetics (PK), and preliminary efficacy. The extension part is designed to confirm safety and further estimate efficacy at the RD in additional patients. MP0274 monotherapy will be administered as infusion over one hour every 3 weeks until disease progression. Eligibility Criteria: The study population for this first-in-human study is HER2-positive cancer patients who have progressed after standard therapy for advanced disease. Inclusion/exclusion criteria are similar to those in studies with anti-HER2 antibodies. Specific Aims: The primary objective is to assess safety and tolerability. Secondary objectives are PK, preliminary anti-tumor efficacy (RECIST), and characterization of immunogenicity. Biomarker evaluation include exploratory markers such as PIK3CA, BCL2, p53, PTEN and p21 in both tissue or plasma (ctDNA), investigation of drug induced apoptotic markers as well as additional translational research. This may help get a deeper insight into MP0274's mode of action and into potential resistance mechanisms. MP0274 may have the potential to be active against all HER2-dependent tumors including those that are resistant to trastuzumab and pertuzumab due to incomplete signaling inhibition or inadequate ADCC functionality. MP0274 could be a valid treatment option for HER2 positive cancers. Statistical Methods: Due to being of non-comparative nature, no inferential statistical analysis will be applied in either the escalation or the expansion part of this study. Results will be listed and summarized by dose regimen using descriptive statistics. An interim evaluation of safety, tolerability and preliminary anti-tumor activity will be performed after 14 patients have been dosed at RD at least once and have completed end of Cycle 4. An interim analysis will be performed once all planned 29 patients have been dosed at RD at least once and completed end of Cycle 7 (pre-Cycle 8) tumor assessment. The final statistical analysis will occur after all patients have discontinued treatment for any reason and completed safety follow-up. Present Accrual and target accrual: Currently recruitment is planned in UK, Germany, and Switzerland. Target accrual is 36 evaluable patients. Citation Format: Baird R, Omlin A, Kiemle-Kallee J, Fiedler U, Zitt C, Feurstein D, Herbst J, Dawson K, vom Baur E, Stumpp M, Hermann F, Harstrick A, Schneeweiss A. MP0274-CP101: A phase 1, first-in-human, single-arm, multi-center, open-label, dose escalation study to assess safety, tolerability, and pharmacokinetics of MP0274 in patients with advanced HER2-positive solid tumors [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr OT1-03-02.

Background The efficacy of PD-(L)1 blockade depends on the composition of the tumor immune microenvironment (TIME) and is generally higher in tumors with pre-existing cytotoxic T cells (CTL) than in those with low CTL numbers. Nonetheless, a significant proportion of patients with pre-existing immunity fail to respond, indicating a therapeutic potential for combining PD-(L)1 blockade with additional immunomodulatory agents in both CTL-high and -low immune phenotypes. Here, we evaluated domatinostat (4SC-202), a class I-selective histone deacetylase (HDAC) inhibitor, for its effect on the TIME and its antitumoral efficacy using syngeneic mouse models with CTL-high or CTL-low tumors. Methods Domatinostat was evaluated in PD-1 blockade-insensitive CTL-low (CT26) and CTL-high (C38) syngeneic models alone and in combination with different immune-inhibitory and -stimulatory approaches. Effects on the immunophenotype were assessed via flow cytometry and RNA-seq analyses. The changes in RNA-seq-based immune signatures determined in a murine setting were investigated in patient samples from the first-dose cohort of the SENSITIZE trial (NCT03278665) evaluating domatinostat combined with pembrolizumab in advanced-stage melanoma patients refractory/nonresponding to PD-1 blockade. Results Domatinostat increased the expression of antigen-presenting machinery (APM) genes and MHC class I and II molecules, along with CTL infiltration, in tumors of both immune phenotypes. In combination with PD-(L)1 blockade, domatinostat augmented antitumor effects substantially above the effects of single-agent therapies, displaying greater benefit in tumors with pre-existing CTLs. In this setting, the combination of domatinostat with agonistic anti-4-1BB or both PD-1 and LAG3 blockade further increased the antitumor efficacy. In CTL-low tumors, domatinostat enhanced the expression of genes known to reinforce immune responses against tumors. Specifically, domatinostat increased the expression of Ifng and genes associated with responses to pembrolizumab and nivolumab. Clinically, these findings were confirmed in patients with advanced melanoma treated with domatinostat for 14 days, who demonstrated elevated expression of APM and MHC genes, the IFNG gene, and the IFN-γ and pembrolizumab response signatures in individual tumor samples. Conclusion In summary, these data suggest a promising potential of domatinostat in combination with immunotherapy to improve the outcome of refractory cancer patients.

Organizational models play a key role in today’s enterprise modeling. They usually show up as partial models produced in a distributed and non-synchronized fashion by people with different conceptual understandings. For this reason, there is a major need to organize partial organizational models within a suitable modeling framework, and, moreover, to check their mutual conformance. This builds the basis to integrate the partial organizational models later on into one holistic model of the organization and for model checking certain security, risk, and compliance constraints. In order to attain this goal, the authors present two mutually aligned contributions. The first one is a new enterprise modeling framework—the EM-Cube. The second one is a new approach for checking conformance of models based on the suggested formal modeling technique associated with the proposed framework. They evaluate the potential solution against concrete requirements derived from a real-world scenario coming out of the finance industry.

Colorectal cancer is the third most common cancer worldwide. A significant proportion of patients presents with unresectable metastatic disease or develops metachronous metastases following surgical resection of the primary tumor. The prognosis of the disease has improved over the past two decades, with extended multimodality treatment options and the development of increasingly intensified chemotherapy regimens that now typically include targeted biologics. A recent advance in therapy is a treatment regimen composed of three chemotherapeutic agents (i.e., triplet chemotherapy: 5-fluorouracil [5-FU]/leucovorin [LV], oxaliplatin, and irinotecan; FOLFOXIRI) in combination with the vascular endothelial growth factor inhibitor bevacizumab. This regimen has been shown to elicit significantly improved objective response rates and median progression-free survival compared with 5-FU/LV and irinotecan in combination with bevacizumab. However, triplet chemotherapy has been associated with increased rates of chemotherapy-related adverse events, and treatment-emergent adverse events should be properly managed to minimize treatment interruption or discontinuation. We present herein a review of clinical studies evaluating the safety and efficacy of FOLFOXIRI with bevacizumab in metastatic colorectal cancer, and propose a practical guide for the management of adverse events associated with the regimen. Support for third-party medical writing assistance was provided by Genentech, Inc.

Application conditions for rules and constraints for graphs are well-known in the theory of graph transformation and have been extended already to M-adhesive transformation systems. According to the literature we distinguish between two kinds of satisfaction for constraints, called general and initial satisfaction of constraints, where initial satisfaction is defined for constraints over an initial object of the base category. Unfortunately, the standard definition of general satisfaction is not compatible with negation in contrast to initial satisfaction. Based on the well-known restriction of objects along type morphisms, we study in this paper restriction and amalgamation of application conditions and constraints together with their solutions. In our main result, we show compatibility of initial satisfaction for positive constraints with restriction and amalgamation, while general satisfaction fails in general. Our main result is based on the compatibility of composition via pushouts with restriction, which is ensured by the horizontal van Kampen property in addition to the vertical one that is generally satisfied in M-adhesive categories., In Proceedings ACCAT 2012, arXiv:1208.4301

Background: Relapse of patients with EGFR-mutated NSCLC treated with TKI regimens is most often due to TK mutation but also in a significant number of cases due to upregulation of bypass pathways, the most common being the HGF/cMET signaling pathway. Osimertinib, a third generation TKI, is currently approved for T790M-mutated NSCLC but options for treatment following relapse are unsatisfactory. Hence, there is a high medical need for therapies overcoming EGFR-TKI resistance, including inhibition of bypass mechanisms. In this respect, we are investigating combination of HGF/cMET pathway inhibition with EGFR-TKI therapy. MP0250 is a multi-DARPin drug candidate, specifically neutralizing HGF and VEGF, with the potential to block HGF-mediated bypass of EGFR-TKI inhibition in addition to exerting EGFR-independent antitumor activity via dual HGF and VEGF inhibition. We have shown that HGF expression is upregulated in most human tumors including in 4 of 5 NSCLC samples. In contrast, cMET was not highly overexpressed. MP0250 showed single-agent activity in 3 HGF-autocrine NSCLC PDX-models and an additive/synergistic effect in combination with erlotinib in an erlotinib-resistant model. These preclinical data support the reported observation that the HGF/cMET signaling pathway can confer resistance to EGFR-TKI therapy and that sensitivity to EGFR-TKIs can be restored by blocking HGF. Consequently, we have initiated a phase 1b/2 study for MP0250 in combination with osimertinib in the treatment of EGFR-mutated NSCLC patients. Trial Design: This is a phase Ib/II, single-arm, open-label, multi-center study of MP0250 in combination with osimertinib in patients with EGFR-mutated non-squamous non-small cell lung cancer (NSCLC) pretreated with osimertinib.The primary objective is to estimate the antitumor efficacy, as measured by Objective Response Rate (ORR) after 8 cycles of treatment with MP0250 i.v. every 3 weeks in combination with osimertinib orally once daily, when administered to patients with EGFR-mutated, advanced, non-squamous NSCLC after tumor progression on osimertinib and on or after the most recent therapy. Secondary and exploratory objectives are to determine safety, tolerability, progression-free survival, pharmacokinetics, immunogenicity and biomarkers. An initial dose escalation safety lead-in part, Part A, is intended to establish a safe recommended dose (RD) of MP0250 in combination with osimertinib. The cohort at RD from Part A will be expanded in order to confirm the tolerability and to further estimate the efficacy of MP0250 in combination with osimertinib. A total of 40 patients will be enrolled, 12 in part A and an additional 28 in part B at RD. Further details will be shown in the poster. Citation Format: Joachim Kiemle-Kallee, Ulrike Fiedler, Keith M. Dawson, Jutta Haunschild, Sandra Dietschy, Michael T. Stumpp, Frank Hermann, Andreas Harstrick. MP0250, a VEGF- and HGF-blocking multi-DARPin drug candidate, in combination with tyrosine-kinase-inhibitors targeting EGFR-mutated NSCLC: Preclinical rationale and phase Ib/II study outline [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr CT149.

Subobject transformation systems STS are proposed as a novel formal framework for the analysis of derivations of transformation systems based on the algebraic, double-pushout (DPO) approach. They can be considered as a simplified variant of DPO rewriting, acting in the distributive lattice of subobjects of a given object of an adhesive category. This setting allows a direct analysis of all possible notions of dependency between any two productions without requiring an explicit match. In particular, several equivalent characterizations of independence of productions are proposed, as well as a local Church–Rosser theorem in the setting of STS. Finally, we show how any derivation tree in an ordinary DPO grammar leads to an STS via a suitable construction and show that relational reasoning in the resulting STS is sound and complete with respect to the independence in the original derivation tree.

The vascular endothelium synthesizes and releases a spectrum of vasoactive substances and therefore plays a fundamental role in the basal and dynamic regulation of the circulation. Nitric oxide (NO)-originally described as endothelium-derived relaxing factor-is released from endothelial cells in response to shear stress produced by blood flow, and in response to activation of a variety of receptors. After diffusion from endothelial to vascular smooth muscle cells, NO increases intracellular cyclic guanosine-monophosphate concentrations by activation of the enzyme guanylate cyclase leading to relaxation of the smooth muscle cells. NO has also antithrombogenic, antiproliferative, leukocyte-adhesion inhibiting effects, and influences myocardial contractility. Endothelium-derived NO-mediated vascular relaxation is impaired in spontaneously hypertensive animals. NO decomposition by free oxygen radicals is a major mechanism of impaired NO bioavailability. The resulting imbalance of endothelium-derived relaxing and contracting substances disturbs the normal function of the vascular endothelium. Endothelin acts as the natural counterpart to endothelium-derived NO. Besides its arterial blood pressure rising effect in humans, endothelin-1 induces vascular and myocardial hypertrophy, which are independent risk factors for cardiovascular morbidity and mortality. Current therapeutic strategies concentrate mainly on lowering low-density lipoprotein cholesterol and an impressive reduction in the risk for cardiovascular morbidity and mortality has been achieved. Inflammatory mechanisms play an important role in vascular disease and inflammatory plasma markers correlate with prognosis. The production of reactive oxygen species under pathological conditions may represent an important inflammatory trigger. Novel therapeutic strategies specifically targeting inflammation thus bear great potential for the prevention and treatment of atherosclerotic vascular disease. In this context, the vascular actions of flavanol-rich cocoa, particularly with regard to enhanced NO synthesis and endothelial function observed in humans following consumption, warrants further attention. This review discusses pharmacological and dietary intervention.

Dieser Beitrag ist mit Zustimmung des Rechteinhabers aufgrund einer (DFG geförderten) Allianz- bzw. Nationallizenz frei zugänglich., This publication is with permission of the rights owner freely accessible due to an Alliance licence and a national licence (funded by the DFG, German Research Foundation) respectively., M-adhesive categories provide an abstract framework for a large variety of specification frameworks for modelling distributed and concurrent systems. They extend the well-known frameworks of adhesive and weak adhesive HLR categories and integrate high-level constructs such as attribution as in the case of typed attributed graphs. In the current paper, we investigate M-adhesive transformation systems including negative application conditions (NACs) for transformation rules, which are often used in applications. For such systems, we propose an original equivalence on transformation sequences, called permutation equivalence, that is coarser than the classical switch equivalence. We also present a general construction of deterministic processes for M-adhesive transformation systems based on subobject transformation systems. As a main result, we show that the process obtained from a transformation sequence identifies its equivalence class of permutation-equivalent transformation sequences. Moreover, we show how the analysis of this process can be reduced to the analysis of the reachability graph of a generated Place/Transition Petri net. This net encodes the dependencies between rule applications of the transformation sequence, including the inhibiting effects of the NACs.

Dieser Beitrag ist mit Zustimmung des Rechteinhabers aufgrund einer (DFG geförderten) Allianz- bzw. Nationallizenz frei zugänglich. This publication is with permission of the rights owner freely accessible due to an Alliance licence and a national licence (funded by the DFG, German Research Foundation) respectively. Triple graph grammars (TGGs) are a well-established concept for the specification and execution of bidirectional model transformations within model driven software engineering. Their main advantage is an automatic generation of operational rules for forward and backward model transformations, which simplifies specification and enhances usability as well as consistency. In this paper we present several important results for analysing model transformations based on the formal categorical foundation of TGGs within the framework of attributed graph transformation systems. Our first main result shows that the crucial properties of correctness and completeness are ensured for model transformations. In order to analyse functional behaviour, we generate a new kind of operational rule, called a forward translation rule. We apply existing results for the analysis of local confluence for attributed graph transformation systems. As additional main results, we provide sufficient criteria for the verification of functional behaviour as well as a necessary and sufficient condition for strong functional behaviour. In fact, these conditions imply polynomial complexity for the execution of the model transformation. We also analyse information and complete information preservation of model transformations, that is, whether a source model can be reconstructed (uniquely) from the target model computed by the model transformation. We illustrate the results for the well-known model transformation example from class diagrams to relational database models.

Eine zellulosebasierte, technisch vergleichbare Alternative zur Bierfiltration mit Kieselgur wurde erforscht. Dazu wurden reine Zellulosefasern und mögliche zusätzliche Hilfsstoffe untersucht. Eine Technologie für Anschwemmfilter, einschließlich Filterhilfsmittelregeneration wurde entwickelt bzw. adaptiert und im Pilot-Maßstab systematisch überprüft und untersucht. Mehrfache Regeneration sowie der Einsatz von Kieselsol bei der laufenden Dosage senkten die Filtrattrübung und führten zu höherer Druckdifferenz. Die Faserzusammensetzung zeigte diesbezüglich ein Optimum bei 20 % Fibrillen. Die Trübungsretention konnte gegenüber frühreren Veröffentlichungen deutlich gesteigert werden. Eine speziell für Zellulosefasern ausgelegte Labormethode als günstige und einfache Alternative zu Versuchen im Pilotmaßstab wurde entwickelt, eingeführt und untersucht. Der neue Test erlaubt die Vorhersage der Auswirkungen von Variation bei Filtrationsparametern oder Filterhilfsmitteln. Pre-coat beer filtration using cellulose was investigated as an alternative to kieselguhr. Pure cellulose fibres and possible filter aid additions were examined. Filtration technology for pre-coat filter plants including regeneration of used filter aids was developed and systematically checked in large scale trials. Multiple regeneration of cellulose fibres as well as the addition of silica sol reduced filtered beer haze and increased pressure differential. With respect to the composition of the fibres, an optimum fibril share was found at 20 %. Haze reduction went significantly further than previously reported. A laboratory scale test minimizing time and effort for pilot scale trials was designed for cellulose fibres, introduced and checked. The new test method allows for predicting resulting tendencies by either filtration parameter or filter aid variation.

In several application areas, Graph Transformation Systems (GTSs) are equipped with Negative Application Conditions (NACs) that specify “forbidden contexts”, in which the rules shall not be applied. The extension to NACs, however, introduces inhibiting effects among transformation steps that are not local in general, causing a severe problem for a concurrent semantics. In fact, the relation of sequential independence among derivation steps is not invariant under switching, as we illustrate with an example. We first show that this problem disappears if the NACs are restricted to be incremental. Next we present an algorithm that transforms a GTS with arbitrary NACs into one with incremental NACs only, able to simulate the original GTS. We also show that the two systems are actually equivalent, under certain assumptions on NACs.

Triple graph grammars (TGGs) have been used successfully to analyse correctness of bidirectional model transformations. Recently, also a corresponding formal approach to model synchronization has been presented, where updates on a given domain (either source or target) can be correctly (forward or backward) propagated to the other model. However, a corresponding formal approach of concurrent model synchronization, where a source and a target modification have to be synchronized simultaneously, has not yet been presented and analysed. This paper closes this gap taking into account that the given and propagated source or target model modifications are in conflict with each other. Our conflict resolution strategy is semi-automatic, where a formal resolution strategy --- known from previous work --- can be combined with a user-specific strategy. As first result, we show correctness of concurrent model synchronization, that is, each result of our nondeterministic concurrent update leads to a consistent correspondence between source and target models, where consistency is defined by the TGG. As second result, we show compatibility of concurrent with basic model synchronization: concurrent model synchronization can realize both forward and backward propagation. The results are illustrated by a running example on updating organizational models.

Services provide access to software components that can be discovered dynamically via the Internet. The increasing number of services a requester may be able to use demand support for finding and selecting services. In particular, it is unrealistic to expect that a single service will satisfy complex requirements, so services will have to be combined to match clients’ requests. In this paper, we propose a visual, incremental approach for the composition of services, in which we describe the requirements of a requester as a goal which is matched against multiple provider offers. After every match with an offer we decompose the goal into satisfied and remainder parts. We iterate the decomposition until the goal is satisfied or we run out of offers, leading to a resolution-like matching strategy. Finally, the individual offers can be composed into a single combined offer and shown to the requester for feedback. Our approach is based on visual specifications of pre- and postconditions by graph transformation systems with loose semantics, where a symbolic approach based on constraints is used to represent attributes and their computation in graphs.

Triple Graph Grammars (TGGs) are a well-established concept for the specification of model transformations. In previous work we have formalized and analyzed already crucial properties of model transformations like termination, correctness and completeness, but functional behaviour is missing up to now. In order to close this gap we generate forward translation rules, which extend standard forward rules by translation attributes keeping track of the elements which have been translated already. In the first main result we show the equivalence of model transformations based on forward resp. forward translation rules. This way, an additional control structure for the forward transformation is not needed. This allows to apply critical pair analysis and corresponding tool support by the tool AGG. However, we do not need general local confluence, because confluence for source graphs not belonging to the source language is not relevant for the functional behaviour of a model transformation. For this reason we only have to analyze a weaker property, called translation confluence. This leads to our second main result, the functional behaviour of model transformations, which is applied to our running example, the model transformation from class diagrams to database models.

Triple graph grammars (TGGs) are a formal and intuitive concept for the specification of model transformations. Their main advantage is an automatic derivation of operational rules for bidirectional model transformations, which simplifies specification and enhances usability as well as consistency. In this paper we continue previous work on the formal definition of model transformations based on triple graph rules with negative application conditions (NACs). The new notion of partial source consistency enables us to construct consistent model transformations on-the-fly instead of analyzing consistency of completed model transformations. We show the crucial properties termination, correctness and completeness (including NAC-consistency) for the model transformations resulting from our construction. Moreover, we define parallel independence for model transformation steps which allows us to perform partial-order reduction in order to improve efficiency. The results are applicable to several relevant model transformations and in particular to our example transformation from class diagrams to database models.

E-government services usually process large amounts of confidential data. Therefore, security requirements for the communication between components have to be adhered in a strict way. Hence, it is of main interest that developers can analyze their modularized models of actual systems and that they can detect critical patterns. For this purpose, we present a general and formal framework for critical pattern detection and user-driven correction as well as possibilities for automatic analysis and verification at meta-model level. The technique is based on the formal theory of graph transformation, which we extend to transformations of type graphs with inheritance within a type graph hierarchy. We apply the framework to specify relevant security requirements. The extended theory is shown to fulfil the conditions of a weak adhesive HLR category allowing us to transfer analysis techniques and results shown for this abstract framework of graph transformation. In particular, we discuss how confluence analysis and parallelization can be used to enable parallel critical pattern detection and elimination.

We would like to thank Drs Popa and Netea for their interest in our study1 and their comments. It is a prerequisite of clinical studies investigating endothelial function that patients remain clinically stable throughout the course of the study to allow the assessment of the potential impact of the study drug. Clinically stable patients, however, present with low disease activity and demonstrate low markers of inflammation, thus explaining the relatively low …

Impaired endothelial function was demonstrated in HIV-infected persons on protease inhibitor (PI)-containing antiretroviral therapy, probably due to altered lipid metabolism. Atazanavir is a PI causing less atherogenic lipoprotein changes. This study determined whether endothelial function improves after switching from other PI to atazanavir.Randomised, observer-blind, treatment-controlled trial.Three university-based outpatient clinics.39 HIV-infected persons with suppressed viral replication on PI-containing regimens and fasting low-density lipoprotein (LDL)-cholesterol greater than 3 mmol/l.Patients were randomly assigned to continue the current PI or change to unboosted atazanavir.Endpoints at week 24 were endothelial function assessed by flow-mediated dilation (FMD) of the brachial artery, lipid profiles and serum inflammation and oxidative stress parameters.Baseline characteristics and mean FMD values of the two treatment groups were comparable (3.9% (SD 1.8) on atazanavir versus 4.0% (SD 1.5) in controls). After 24 weeks' treatment, FMD decreased to 3.3% (SD 1.4) and 3.4% (SD 1.7), respectively (all p = ns). Total cholesterol improved in both groups (p0.0001 and p = 0.01, respectively) but changes were more pronounced on atazanavir (p = 0.05, changes between groups). High-density lipoprotein and triglyceride levels improved on atazanavir (p = 0.03 and p = 0.003, respectively) but not in controls. Serum inflammatory and oxidative stress parameters did not change; oxidised LDL improved significantly in the atazanavir group.The switch from another PI to atazanavir in treatment-experienced patients did not result in improvement of endothelial function despite significantly improved serum lipids. Atherogenic lipid profiles and direct effects of antiretroviral drugs on the endothelium may affect vascular function.NCT00447070.

Triple graph grammars have been applied and implemented as a formal basis for model transformations in a variety of application areas. They convince by special abilities in automatic derivation of forward, backward and several other transformations out of just one specified set of rules for the integrated model defined by a triple of graphs. While many case studies and all implementations, which state that they are using triple graph grammars, do not use triples of graphs, this paper presents the justification for many of them. It shows a one to one correspondence between triple graph grammars and suitable plain graph grammars, thus results and benefits of the triple case can be transferred to the plain case.Main results show the relationship between both graph transformation approaches, syntactical correctness of model transformations based on triple graph grammars and a sound and complete condition for functional behaviour. Theoretical results are elaborated on an intuitive case study for a model transformation from class diagrams to database models.

Background— The excess in cardiovascular risk in patients with rheumatoid arthritis provides a strong rationale for early therapeutical interventions. In view of the similarities between atherosclerosis and rheumatoid arthritis and the proven benefit of angiotensin-converting enzyme inhibitors in atherosclerotic vascular disease, it was the aim of the present study to delineate the impact of ramipril on endothelial function as well as on markers of inflammation and oxidative stress in patients with rheumatoid arthritis. Methods and Results— Eleven patients with rheumatoid arthritis were included in this randomized, double-blind, crossover study to receive ramipril in an uptitration design (2.5 to 10 mg) for 8 weeks followed by placebo, or vice versa, on top of standard antiinflammatory therapy. Endothelial function assessed by flow-mediated dilation of the brachial artery, markers of inflammation and oxidative stress, and disease activity were investigated at baseline and after each treatment period. Endothelial function assessed by flow-mediated dilation increased from 2.85±1.49% to 4.00±1.81% ( P =0.017) after 8 weeks of therapy with ramipril but did not change with placebo (from 2.85±1.49% to 2.84±2.47%; P =0.88). Although systolic blood pressure and heart rate remained unaltered, diastolic blood pressure decreased slightly from 78±7 to 74±6 mm Hg ( P =0.03). Tumor necrosis factor-α showed a significant inverse correlation with flow-mediated dilation ( r =−0.408, P =0.02), and CD40 significantly decreased after ramipril therapy ( P =0.049). Conclusions— Angiotensin-converting enzyme inhibition with 10 mg/d ramipril for 8 weeks on top of current antiinflammatory treatment markedly improved endothelial function in patients with rheumatoid arthritis. This finding suggests that angiotensin-converting enzyme inhibition may provide a novel strategy to prevent cardiovascular events in these patients.

Background— Dark chocolate has potent antioxidant properties. Coronary atherosclerosis is promoted by impaired endothelial function and increased platelet activation. Traditional risk factors, high oxidative stress, and reduced antioxidant defenses play a crucial role in the pathogenesis of atherosclerosis, particularly in transplanted hearts. Thus, flavonoid-rich dark chocolate holds the potential to have a beneficial impact on graft atherosclerosis. Methods and Results— We assessed the effect of flavonoid-rich dark chocolate compared with cocoa-free control chocolate on coronary vascular and platelet function in 22 heart transplant recipients in a double-blind, randomized study. Coronary vasomotion was assessed with quantitative coronary angiography and cold pressor testing before and 2 hours after ingestion of 40 g of dark (70% cocoa) chocolate or control chocolate, respectively. Two hours after ingestion of flavonoid-rich dark chocolate, coronary artery diameter was increased significantly (from 2.36±0.51 to 2.51±0.59 mm, P P =0.01). Platelet adhesion decreased from 4.9±1.1% to 3.8±0.8% ( P =0.04) in the dark chocolate group but remained unchanged in the control group. Conclusions— Dark chocolate induces coronary vasodilation, improves coronary vascular function, and decreases platelet adhesion 2 hours after consumption. These immediate beneficial effects were paralleled by a significant reduction of serum oxidative stress and were positively correlated with changes in serum epicatechin concentration.

Sesqui-pushout (SqPO) rewriting—“sesqui” means “one and a half” in Latin—is a new algebraic approach to abstract rewriting in any category. SqPO rewriting is a deterministic and conservative extension of double-pushout (dpo) rewriting, which allows to model “deletion in unknown context”, a typical feature of single-pushout (spo) rewriting, as well as cloning. After illustrating the expressiveness of the proposed approach through a case study modelling an access control system, we discuss sufficient conditions for the existence of final pullback complements and we analyze the relationship between SqPO and the classical dpo and spo approaches.

The effects of chocolate on cardiovascular health are still a matter of debate. Chocolate may adversely affect cardiovascular risk because of its effects on glucose, lipids, and body weight or potentially favour cardiovascular health through antioxidative effects of chocolate ingredients, such as flavonoids (present in dark but not white chocolate). Endothelial dysfunction and platelet activation are cornerstones in the pathogenesis of atherothrombosis, leading to vasoconstriction, thrombus formation, and inflammation. Smoking is a major cardiovascular risk factor. The mechanisms promoting atherothrombosis in smokers primarily include increased oxidative stress that enhances proatherogenic processes such as low density lipoprotein oxidation and inactivation of endothelium derived nitric oxide. Platelets contribute both to acute coronary syndromes and to the progression of atherothrombosis. Both active and passive cigarette smoking has consistently been shown to induce endothelial dysfunction. Therefore, smokers serve as an ideal model to study the beneficial vascular effects of antioxidant strategies such as dark chocolate.1 The goal of the present study was to investigate whether the beneficial antioxidant effect of polyphenol-rich dark chocolate can induce an improvement of endothelial and platelet function in healthy volunteers with known endothelial dysfunction and platelet hyperreactivity. Twenty five male smokers were enrolled in the study after giving written informed consent. Women were excluded for known sex hormone induced differences in vascular tone and reactivity. All study participants did not take any medication, including vitamins or dietary supplements. The local institutional ethical review board approved the protocol. To assess the effect of dark …