We present in this article new strategies for selecting nodes in interval Branch and Bound algorithms for constrained global optimization. For a minimization problem the standard best-first strategy ...selects a node with the smallest lower bound of the objective function estimate. We first propose new node selection policies where an
upper bound
of each node/box is also taken into account. The good accuracy of this upper bound achieved by several contracting operators leads to a good performance of the node selection rule based on this criterion. We propose another strategy that also makes a tradeoff between diversification and intensification by greedily diving into potential feasible regions at each node of the best-first search. These new strategies obtain better experimental results than classical best-first search on difficult constrained global optimization instances.
Fungi belonging to the recently classified genus Pseudozyma possess some unique properties such as biocontrol activity, production of rare antimicrobial glycolipids and production of recombinant ...proteins. In this work, we report the first cloning of a promoter endogenous to the multi-faceted yeast-like Pseudozyma flocculosa, that of the actin gene. The promoter region lacked typical TATA or CAAT box but displayed three putative GC box and two CT-rich regions. As in other related basidiomycetes, only one copy of the actin gene was present in the genome of P. flocculosa. The activity of the actin promoter was compared to that of the HSP70 promoter from Ustilago maydis in two Pseudozyma species. In P. flocculosa, the actin promoter allowed the expression of a very high amount of GFP protein (27.8 mg g-¹ total protein) compared to those obtained with the HSP70 promoter in liquid culture. By contrast, the levels of GFP expression obtained in liquid culture were similar with the actin or the HSP70 promoter in Pseudozyma antarctica. A similar pattern of GFP expression was observed in solid culture. The cloning of this new promoter offers a unique genetic tool to further exploit and study the unusual properties of fungi from the Pseudozyma genus.
We present a hyper-heuristic approach to solve Orienteering Problem with Hotel Selection(OPHS). In practical applications, OPHS appears when a tourist is planning to visit various attractions and ...there is not enough time to reach all of them in a single day. Therefore, the tourist must build a tour within several days by selecting hotels, where each day has a different time budget. We propose a hyper-heuristic based on a Large Neighborhood Search, composed by a set of low-level heuristics that satisfy the different constraints associated with the problem. We put special emphasis on collaboration between low-level heuristics in order to guide the algorithm to more promising areas. We use 395 benchmark instances with known optimal solutions. This approach proves to be a more general method, with a simpler design compared to the literature, and is able to find 217 of the 395 known optimal solutions, in acceptable computational time.
In deterministic continuous constrained global optimization, upper bounding the objective function generally resorts to local minimization at several nodes/iterations of the branch and bound. We ...propose in this paper an alternative approach when the constraints are inequalities and the feasible space has a non-null volume. First, we extract an
inner region
, i.e., an entirely feasible convex polyhedron or box in which all points satisfy the constraints. Second, we select a point inside the extracted inner region and update the upper bound with its cost. We describe in this paper two original inner region extraction algorithms implemented in our interval B&B called IbexOpt (AAAI, pp 99–104,
2011
). They apply to nonconvex constraints involving mathematical operators like ,
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. This upper bounding shows very good performance obtained on medium-sized systems proposed in the
COCONUT
suite.
Metaheuristics are powerful techniques for solving hard real-world problems in many application domains. Their behavior and performance strongly depend on their ability to efficiently explore and ...exploit the search space. A well-known metaheuristic is Ant Colony Optimization which has been successfully applied to solve many engineering problems. In this paper, we focus on ACO that solves Constraint Satisfaction Problems. In this context ACO has already shown to be able to solve many difficult CSPs, however, some problems are still very hard for this kind of technique. We introduce two strategies that allow improving ACO intensification and diversification process: one for learning in a pre-processing step and a second strategy to focus the search to a feasible space. Our results suggest that both the learning phase as well as the strategy to focus the search allow improving the ACO performance especially to solve hard CSPs. Moreover, these strategies can be applied to ACO for other application domains.
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•We propose two strategies for ACO algorithms proposed for solving CSPs.•We use a strategy to define the initial pheromone matrix of ACO.•Another strategy to discriminate promising candidate instantiations.•Results show that both strategies allow to solve more hard problems.•We include an statistical analysis and fitness-distance plots.
The tumour microenvironment is critical to both the initiation and maintenance of tumorigenesis. Reconstitution of the microenvironment is a major challenge for in vitro cancer models. Indeed, ...conventional 2D culture systems cannot replicate the complexity, diversity and dynamic nature of the tumour microenvironment. In this study, we have developed a 3D endotheliazed vesical equivalent by using tissue engineering from primary human cells in which non-invasive or invasive bladder cancer (BCa) cell lines, cultured as compact spheroids, were incorporated. Invasive BCa cells cross the basement membrane and invade the stromal compartment whereas non-invasive BCa cells are confined to the urothelium. Our 3D BCa model could be used as a reliable model for assessing drug responses, potentially reducing or partially replacing animal experiments, and thus should have applications in the identification of novel targets as well as toxicological evaluation of anti-cancer therapies.
Prostate cancer is well known to be dependent on the androgen receptor (AR) for growth and survival. Thus, AR is the main pharmacological target to treat this disease. However, after an initially ...positive response to AR-targeting therapies, prostate cancer will eventually evolve to castration-resistant prostate cancer, which is often lethal. Tumour growth was initially thought to become androgen-independent following treatments; however, results from molecular studies have shown that most resistance mechanisms involve the reactivation of AR. Consequently, tumour cells become resistant to castration - the blockade of testicular androgens - and not independent of AR per se. However, confusion still remains on how to properly define preclinical models of prostate cancer, including cell lines. Most cell lines were isolated from patients for cell culture after evolution of the tumour to castration-resistant prostate cancer, but not all of these cell lines are described as castration resistant. Moreover, castration refers to the blockade of testosterone production by the testes; thus, even the concept of "castration" in vitro is questionable. To ensure maximal transfer of knowledge from scientific research to the clinic, understanding the limitations and advantages of preclinical models, as well as how these models recapitulate cancer cell androgen dependency and can be used to study castration resistance mechanisms, is essential.
Abstract
BACKGROUND
Currently, liquid biposies for imaging single cancer cell to provide personalised medicine is gaining importance. In the last years, molecular imaging techniques using ...transcriptional amplification systems have been developed but a system enabling both PCa cell detection and treatment response assessment is lacking. PCA3 RNA is a unique PCa biomarker that has been widely studied for PCa screening and detection while the PSA gene is another biomarker of high clinical significance as it gives an account of response to androgen deprivation treatments (ADT). In this study, we have developed and studied an imaging system based on the combined transcriptional activities of the PCA3 and PSA gene promoters for single PCa cell detection and ADT response assessment from patients body fluids.
METHODS
Adenoviruses (Ad) were constructed utilizing the ability of site-specific recombination of the Cre-Lox system. The PCA3 and PSA promoters were integrated into a single Ad backbone with one promoter driving the expression of CRE recombinase and the other driving the Two Step Transcriptional Amplification system and the Firefly luciferase gene (fl) to generate a new system that we named the Multigenic Integrative Transcriptional Amplification System (MP-ITSTA). PCa cells specificity and ADT response was tested by transient infection. To detect cells in body fluid, 22Rv1-GFP cells were spiked in urine or blood of healthy control, infected with MP-ITSTA after purification and single cell imaging was done using the LV200 bioluminescence microscope.
RESULTS
We show that the PCA3-TSTA driven fl expression is specific to PCa cells (22Rv1, LAPC4, PC3, DU145) giving 8.5-108.4 fold higher expression when compared to SW780 bladder cancer cells. Contrary to PCA3-TSTA, the PSA-TSTA activity is regulated by androgen treatment but is not prostate cancer-specific as it is active in AR responsive breast cancer cells (CAMA-1 and ZR-75). We show that MP-ITSTA reporter expression is dependent on the combined activation of two promoters (PCA3 and PSA promoter) in a DHT dependent manner. MP-ITSTA could therefore also give an account of responsiveness to bicalutamide or enzalutamide treatments PCa cells. The signal obtained by MP-ITSTA system is 2.3 and 1.6 times higher than PCA3-TSTA in 22Rv1 and LAPC4, respectively proving that MP-ITSTA has the ability to enhance the reporter gene expression from a weak but PCa specific PCA3 promoter. Finally, MP-ITSTA could specifically target spiked 22Rv1-mcherry cells isolated from urine while no signal was found in non-spiked samples.
CONCLUSIONS
MP-ITSTA therefore represents a prostate cancer specific and non-invasive tool to target with high accuracy PCa cells and to detect their response to ADT cell per cell from body fluids.
Citation Format: Pallavi Jain, Bertrand Neveu, Yves Fradet, Frédéric Pouliot. Development of a multigenic bioluminescence imaging system to detect prostate cancer cells and assess their response to therapy. abstract. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4764.
How to assign colors to the occurrences of cars in a car factory? How to divide fairly a necklace between thieves who have stolen it? These two questions are addressed in two combinatorial problems ...that have attracted attention from a theoretical point of view these last years, the first one more by people from the combinatorial optimization community, the second more from the topological combinatorics and computer science point of view.
The first problem is the paint shop problem, defined by Epping et al. (2004) 11. Given a sequence of cars where repetition can occur, and for each car a multiset of colors where the sum of the multiplicities is equal to the number of repetitions of the car in the sequence, decide the color to be applied for each occurrence of each car so that each color occurs with the multiplicity that has been assigned. The goal is to minimize the number of color changes in the sequence.
The second problem, highly related to the first one, takes its origin in a famous theorem found by Alon (1987) 1 stating that a necklace with t types of beads and qau occurrences of each type u (au is a positive integer) can always be fairly split between q thieves with at most t(q−1) cuts. An intriguing aspect of this theorem lies in the fact that its classical proof is completely non-constructive. Designing an algorithm that computes theses cuts is not an easy task, and remains mostly open.
The main purpose of the present paper is to make a step in a more operational direction for these two problems by discussing practical ways to compute solutions for instances of various sizes. Moreover, it starts with an exhaustive survey on the algorithmic aspects of them, and some new results are proved.
When several life-prolonging drugs are indicated for cancer treatment, predictive drug-response tumor biomarkers are essential to guide management. Most conventional biomarkers are based on bulk ...tissue analysis, which cannot address the complexity of single-cell heterogeneity responsible for drug resistance. Therefore, there is a need to develop alternative drug response predictive biomarker approaches that could directly interrogate single-cell and whole population cancer cell drug sensitivity. In this study, we report a novel method exploiting bioluminescence microscopy to detect single prostate cancer (PCa) cell response to androgen receptor (AR)-axis-targeted therapies (ARAT) and predict cell population sensitivity.
We have generated a new adenovirus-delivered biosensor,
-Cre-
-ITSTA, which combines an integrated two-step transcriptional amplification system (ITSTA) and the activities of the prostate cancer antigen 3 (
) and modified prostate-specific antigen (
) gene promoters as a single output driving the firefly luciferase reporter gene. This system was tested on PCa cell lines and on primary PCa cells. Single cells, exposed or not to ARAT, were dynamically imaged by bioluminescence microscopy. A linear discriminant analysis (LDA)-based method was used to determine cell population sensitivities to ARAT.
We show that the
-Cre-
-ITSTA biosensor is PCa-specific and can dynamically monitor single-cell AR transcriptional activity before and after ARAT by bioluminescence microscopy. After biosensor transduction and bioluminescence microscopy single-cell luminescence dynamic quantification, LDA analysis could discriminate the cell populations overall ARAT sensitivity despite heterogeneous single-cell responses. Indeed, the biosensor could detect a significant decrease in AR activity following exposure to conventional ARAT in hormone-naive primary PCa cells, while in castration-resistant PCa patients, treatment response correlated with the observed clinical ARAT resistance.
The exploitation of bioluminescence microscopy and multi-promoter transcriptionally-regulated biosensors can aptly define the overall treatment response of patients by monitoring live single cell drug response from primary cancer tissue. This approach can be used to develop predictive biomarkers for drug response in order to help clinicians select the best drug combinations or sequences for each patient.
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