Underapproximation of Procedure Summaries for Integer Programs

We show how to underapproximate the procedure summaries of recursive programs over the integers using off-the-shelf analyzers for non-recursive programs. The novelty of our approach is that the non-recursive program we compute may capture unboundedly many behaviors of the original recursive program for which stack usage cannot be bounded. Moreover, we identify a class of recursive programs on which our method terminates and returns the precise summary relations without underapproximation. Doing so, we generalize a similar result for non-recursive programs to the recursive case. Finally, we present experimental results of an implementation of our method applied on a number of examples.Comment: 35 pages, 3 figures (this report supersedes the STTT version which in turn supersedes the TACAS'13 version

Deciding Conditional Termination

We address the problem of conditional termination, which is that of defining the set of initial configurations from which a given program always terminates. First we define the dual set, of initial configurations from which a non-terminating execution exists, as the greatest fixpoint of the function that maps a set of states into its pre-image with respect to the transition relation. This definition allows to compute the weakest non-termination precondition if at least one of the following holds: (i) the transition relation is deterministic, (ii) the descending Kleene sequence overapproximating the greatest fixpoint converges in finitely many steps, or (iii) the transition relation is well founded. We show that this is the case for two classes of relations, namely octagonal and finite monoid affine relations. Moreover, since the closed forms of these relations can be defined in Presburger arithmetic, we obtain the decidability of the termination problem for such loops.Comment: 61 pages, 6 figures, 2 table

Vérification relationnelle pour des programmes avec des données entières

Les travaux présentés dans cette thèse sont lies aux problèmes de vérification de l'atteignabilité et de la terminaison de programmes qui manipulent des données entières non-bornées. On décrit une nouvelle méthode de vérification basée sur une technique d'accélération de boucle, qui calcule, de manière exacte, la clôture transitive d'une relation arithmétique. D'abord, on introduit un algorithme d'accélération de boucle qui peut calculer, en quelques secondes, des clôtures transitives pour des relations de l'ordre d'une centaine de variables. Ensuite, on présente une méthode d'analyse de l'atteignabilité, qui manipule des relations entre les variables entières d'un programme, et applique l'accélération pour le calcul des relations entrée-sortie des procédures, de façon modulaire. Une approche alternative pour l'analyse de l'atteignabilité, présentée également dans cette thèse, intègre l'accélération avec l'abstraction par prédicats, afin de traiter le problème de divergence de cette dernière. Ces deux méthodes ont été évaluées de manière pratique, sur un nombre important d'exemples, qui étaient, jusqu'a présent, hors de la portée des outils d'analyse existants. Dernièrement, on a étudié le problème de la terminaison pour certaines classes de boucles de programme, et on a montré la décidabilité pour les relations étudiées. Pour ces classes de relations arithmétiques, on présente un algorithme qui s'exécute en temps au plus polynomial, et qui calcule l'ensemble d'états qui peuvent générer une exécution infinie. Ensuite on a intégré cet algorithme dans une méthode d'analyse de la terminaison pour des programmes qui manipulent des données entières.This work presents novel methods for verification of reachability and termination properties of programs that manipulate unbounded integer data. Most of these methods are based on acceleration techniques which compute transitive closures of program loops. We first present an algorithm that accelerates several classes of integer relations and show that the new method performs up to four orders of magnitude better than the previous ones. On the theoretical side, our framework provides a common solution to the acceleration problem by proving that the considered classes of relations are periodic. Subsequently, we introduce a semi-algorithmic reachability analysis technique that tracks relations between variables of integer programs and applies the proposed acceleration algorithm to compute summaries of procedures in a modular way. Next, we present an alternative approach to reachability analysis that integrates predicate abstraction with our acceleration techniques to increase the likelihood of convergence of the algorithm. We evaluate these algorithms and show that they can handle a number of complex integer programs where previous approaches failed. Finally, we study the termination problem for several classes of program loops and show that it is decidable. Moreover, for some of these classes, we design a polynomial time algorithm that computes the exact set of program configurations from which non-terminating runs exist. We further integrate this algorithm into a semi-algorithmic method that analyzes termination of integer programs, and show that the resulting technique can verify termination properties of several non-trivial integer programs.SAVOIE-SCD - Bib.électronique (730659901) / SudocGRENOBLE1/INP-Bib.électronique (384210012) / SudocGRENOBLE2/3-Bib.électronique (384219901) / SudocSudocFranceF

Impact of the putative cancer stem cell markers and growth factor receptor expression on the sensitivity of ovarian cancer cells to treatment with various forms of the HER inhibitors and cytotoxic drugs

Increased expression and activation of human epidermal growth factor receptor (EGFR) and HER-2 have been reported in numerous cancers. The aim of this study was to determine the sensitivity of a large panel of human ovarian cancer cell lines (OCCLs) to treatment with various forms of small molecule tyrosine kinase inhibitors (TKIs) and cytotoxic drugs. The aim was to see if there was any association between the protein expression of various biomarkers including three putative ovarian cancer stem cell (CSC) markers (CD24, CD44, CD117/c-Kit), P-glycoprotein (P-gp), and HER family members and response to treatment with these agents. The sensitivity of 10 ovarian tumour cell lines to the treatment with various forms of HER TKIs (gefitinib, erlotinib, lapatinib, sapitinib, afatinib, canertinib, neratinib), as well as other TKIs (dasatinib, imatinib, NVP-AEW541, crizotinib) and cytotoxic agents (paclitaxel, cisplatin and doxorubicin), as single agents or in combination, was determined by SRB assay. The effect on these agents on the cell cycle distribution, and downstream signaling molecules and tumour migration were determined using flow cytometry, western blotting, and the IncuCyte Clear View cell migration assay respectively. Of the HER inhibitors, the irreversible pan-TKIs (canertinib, neratinib and afatinib) were the most effective TKIs for inhibiting the growth of all ovarian cancer cells, and for blocking the phosphorylation of EGFR, HER-2, AKT and MAPK in SKOV3 cells. Interestingly, while the majority of cancer cells were highly sensitive to treatment with dasatinib, they were relatively resistant to treatment with imatinib (i.e., IC50 >10 µM). Of the cytotoxic agents, paclitaxel was the most effective for inhibiting the growth of OCCLs, and of various combinations of these drugs, only treatment with a combination of NVP-AEW541 and paclitaxel produced a synergistic or additive anti-proliferative effect in all three cell lines examined (i.e., SKOV3, Caov3, ES2). Finally, of the TKIs, only treatment with afatinib, neratinib and dasatinib were able to reduce the migration of HER-2 overexpressing SKOV3 cells. We did not find any significant association between the expression of putative ovarian CSC marker, HER family members, c-MET, ALK, and IGF-IR and the response to the irreversible HER TKIs. Our results support the need for further investigations of the therapeutic potential of these irreversible HER family blockers in ovarian cancer, and the therapeutic potential of dasatinib when used in combination with the inhibitors of the HER family members in ovarian cancer

Inherited trombophilic states and pulmonary embolism

Pulmonary embolism (PE) and deep vein thrombosis (DVT) are associated with considerable morbidity and mortality, mostly, in case of PE for its lack of sensitivity of its early detection. For as much as twenty-five percent of PE patients the primary clinical appearance is unexpected death. While PE is one of the most avertable causes of hospital associated deaths, its diagnostics can be extremely difficult. Newly increased interest in an inherited thrombophilic states has been provoked by the discovery of several common inherited abnormalities, i.e. the prothrombin (PT) gene G20210A, Factor V Leiden (FVL) mutation (Arg506Gln), hyperhomocystenemia and homocysteiuria, Wein-Penzing defect, Sticky Platelet Syndrome (SPS), Quebec platelet disorder (QPD) and Sickle Cell Disease (SCD). PE incidence rates increase exponentially with age for both men and women, as they might harbor more than one thrombophilic state. Although the impact of genetic factors on PE is to some extent documented with lacking taxonomy, its genetic testing as its prevention strategy fall short

Vérification relationnelle pour des programmes avec des données entières

Tato pr´ace pˇredstavuje nov´e metody pro verifikaci program°u pracuj´ıc´ıch s neomezen´ymiceloˇc´ıslen´ymi promˇenn´ymi, konkr´etnˇe metody pro anal´yzu dosaˇzitelnosti a koneˇcnosti.Vˇetˇsina tˇechto metod je zaloˇzena na akceleraˇcn´ıch technik´ach, kter´e poˇc´ıtaj´ı tranzitivn´ıuz´avˇery cykl°u programu.V pr´aci je nejprve pˇredstaven algoritmus pro akceleraci nˇekolika tˇr´ıd celoˇc´ıseln´ychrelac´ı. Tento algoritmus je aˇz o ˇctyˇri ˇr´ady rychlejˇs´ı neˇz existuj´ıc´ı techniky. Z teoretick´ehohlediska pr´ace dokazuje, ˇze uvaˇzovan´e tˇr´ıdy relac´ı jsou periodick´e a poskytuje tud´ıˇzjednotn´e ˇreˇsen´ı prol´emu akcelerace.Pr´ace d´ale pˇredstavuje semi-algoritmus pro anal´yzu dosaˇzitelnosti celoˇc´ıseln´ych program°u, kter´y sleduje relace mezi promˇenn´ymi programu a aplikuje akceleraˇcn´ı technikyza ´uˇcelem modul´arn´ıho v´ypoˇctu souhrn°u procedur. D´ale je v pr´aci navrˇzen alternativn´ıalgoritmus pro anal´yzu dosaˇzitelnosti, kter´y integruje predik´atovou abstrakci s accelerac´ıs c´ılem zv´yˇsit pravdˇepodobnost konvergence v´ypoˇctu. Proveden´e experimenty ukazuj´ı, ˇzeoba algoritmy lze ´uspˇeˇsnˇe aplikovat k verifikaci program°u, na kter´ych pˇredchoz´ı metodyselh´avaly.Pr´ace se rovnˇeˇz zab´yv´a probl´emem koneˇcnosti bˇehu program°u a dokazuje, ˇze tentoprobl´em je rozhodnuteln´y pro nˇekolik tˇr´ıd celoˇc´ıseln´ych relac´ı. Pro nˇekter´e z tˇechto tˇr´ıdrelac´ı je v pr´aci navrˇzen algoritmus, kter´y v polynomi´aln´ım ˇcase vypoˇc´ıt´a mnoˇzinu vˇsechkonfigurac´ı programu, z nichˇz existuje nekoneˇcn´y bˇeh. Tento algoritmus je integrov´ando metody, kter´a analyzuje koneˇcnost bˇeh°u celoˇc´ıseln´ych program°u. Efektivnost t´etometody je demonstrov´ana na nˇekolika netrivi´aln´ıch celoˇc´ıseln´ych programech.This work presents novel methods for verification of reachability and termination properties of programs that manipulate unbounded integer data. Most of these methods are based on acceleration techniques which compute transitive closures of program loops. We first present an algorithm that accelerates several classes of integer relations and show that the new method performs up to four orders of magnitude better than the previous ones. On the theoretical side, our framework provides a common solution to the acceleration problem by proving that the considered classes of relations are periodic. Subsequently, we introduce a semi-algorithmic reachability analysis technique that tracks relations between variables of integer programs and applies the proposed acceleration algorithm to compute summaries of procedures in a modular way. Next, we present an alternative approach to reachability analysis that integrates predicate abstraction with our acceleration techniques to increase the likelihood of convergence of the algorithm. We evaluate these algorithms and show that they can handle a number of complex integer programs where previous approaches failed. Finally, we study the termination problem for several classes of program loops and show that it is decidable. Moreover, for some of these classes, we design a polynomial time algorithm that computes the exact set of program configurations from which non-terminating runs exist. We further integrate this algorithm into a semi-algorithmic method that analyzes termination of integer programs, and show that the resulting technique can verify termination properties of several non-trivial integer programs.Les travaux présentés dans cette thèse sont lies aux problèmes de vérification de l'atteignabilité et de la terminaison de programmes qui manipulent des données entières non-bornées. On décrit une nouvelle méthode de vérification basée sur une technique d'accélération de boucle, qui calcule, de manière exacte, la clôture transitive d'une relation arithmétique. D'abord, on introduit un algorithme d'accélération de boucle qui peut calculer, en quelques secondes, des clôtures transitives pour des relations de l'ordre d'une centaine de variables. Ensuite, on présente une méthode d'analyse de l'atteignabilité, qui manipule des relations entre les variables entières d'un programme, et applique l'accélération pour le calcul des relations entrée-sortie des procédures, de façon modulaire. Une approche alternative pour l'analyse de l'atteignabilité, présentée également dans cette thèse, intègre l'accélération avec l'abstraction par prédicats, afin de traiter le problème de divergence de cette dernière. Ces deux méthodes ont été évaluées de manière pratique, sur un nombre important d'exemples, qui étaient, jusqu'a présent, hors de la portée des outils d'analyse existants. Dernièrement, on a étudié le problème de la terminaison pour certaines classes de boucles de programme, et on a montré la décidabilité pour les relations étudiées. Pour ces classes de relations arithmétiques, on présente un algorithme qui s'exécute en temps au plus polynomial, et qui calcule l'ensemble d'états qui peuvent générer une exécution infinie. Ensuite on a intégré cet algorithme dans une méthode d'analyse de la terminaison pour des programmes qui manipulent des données entières

A model of massive pulmonary embolism, development and characterization The pre-clinical steps forward and details of the progress

<ul> <li><strong>BACKGROUND</strong>: Massive pulmonary embolism (MPE) is in most cases an unpredictable, life-threatening lung injury. In order to test this shock and its natural sequence, MPE animal model was established. Based on previous models, discussed within the article framework, this model was designed to closely narrate clinical pulmonary embolism.</li> <li><strong>METHODS</strong>: MPE was induced by a single injection of minced radioactive blood thrombi into an internal jugular vein. Thrombi were prepared from the autologous blood of each animal. Using rabbit model allowed sampling and recording additional data necessary for better analysis. Clotting additives were used for rapid clot stabilization. Clot was stabilized at room temperature for one hour and separated into micro-emboli of comparable size prior to the intravenous injection. A radioactive tracer, I-125 labeled rabbit fibrinogen, was added into thrombi to measure dynamic lung thrombiturnover.</li> <li><strong>RESULTS</strong>: Thrombolysis dynamic efficacy was characterized by presence of high statistical significant difference (P < 0.001) found between released radioactive I-125 fibrin degradation products (FDPs) at 10 minutes and all others FDP time points until 60 minutes. Pulmonary thrombolysis was characterized by measuring residual radioactivity of the lungs at 10 and 60 minutes and was found statistically significant (P < 0.05) during the period of 50 minutes. For the purpose of model validation, systemic blood pressure, measured in carotid artery, significantly increased from the baseline point 47 mmHg to 80 mmHg at the first 10 minutes. Enormous mechanical thrombus injury of lung vasculature was depicted by MSB staining.</li> <li><strong>CONCLUSIONS</strong>: This MPE model contains a set of important and original patho-physiological data mimicking the fundamental characteristics of this shock situation in humans, which enhances the understanding of MPE, and leads to better characterization of this critical clinical condition.</li> <li><strong>KEYWORDS</strong>: Massive pulmonary embolism, animal model, thrombolysis dynamic efficacy.</li> </ul&gt