Smear-based variable selection strategies are well-known and commonly used by branch-and-prune interval-based solvers. They estimate the impact of the variables on each constraint of the system by ...using the partial derivatives and the sizes of the variable domains. Then they aggregate these values, in some way, to estimate the impact of each variable on the whole system. The variable with the greatest impact is then selected. A problem of these strategies is that they, generally, consider all constraints equally important. In this work, we propose a new variable selection strategy which first weights the constraints by using the optimal Lagrangian multipliers of a linearization of the original problem. Then, the impact of the variables is computed with a typical smear-based function but taking into account the weights of the constraints. The strategy isg tested on a set of well-known benchmark instances outperforming significantly the classical variable selection strategies.
Chronic inflammation is believed to be a major factor in prostate cancer initiation and promotion and has been studied using prostate cancer cells and immortalized cell lines. However, little is ...known about the contribution of normal cells to the prostatic microenvironment and inflammation. We aim to study the contribution of normal prostate epithelial cells to prostate inflammation and to link the inflammatory status of normal cells to prostate cancer aggressiveness.
Short-term primary cell cultures of normal epithelial prostate cells were derived from prostate biopsies from 25 men undergoing radical prostatectomy, cystoprostatectomy, or organ donation. Cells were treated with polyinosinic:polycytidylic acid, a mimic of double-stranded viral RNA and a potent inducer of the inflammatory response. Secretion of interleukin (IL)-8 in the cell culture medium by untreated and treated cells was measured and we determined the association between IL-8 levels in these primary cell cultures and prostate cancer characteristics. The Fligner-Policello test was used to compare the groups.
Baseline and induced IL-8 secretion were highly variable between cultured cells from different patients. This variation was not related to drug use, past medical history, age, or preoperative prostate-specific antigen value. Nonetheless, an elevated secretion of IL-8 from normal cultured epithelial cells was associated with prostate cancer aggressiveness (P=0.0005).
The baseline secretion of IL-8 from normal prostate epithelial cells in culture is strongly correlated with cancer aggressiveness and may drive prostate cancer carcinogenesis. A better characterization of individual prostate microenvironment may provide a basis for personalized treatment and for monitoring the effects of strategies aimed at preventing aggressive prostate cancer.
Interval branch-and-bound solvers provide reliable algorithms for handling non-convex optimization problems by ensuring the feasibility and the optimality of the computed solutions, i.e. ...independently from the floating-point rounding errors. Moreover, these solvers deal with a wide variety of mathematical operators. However, these solvers are not dedicated to quadratic optimization and do not exploit nonlinear convex relaxations in their framework. We present an interval branch-andbound method that can efficiently solve quadratic optimization problems. At each node explored by the algorithm, our solver uses a quadratic convex relaxation which is as strong as a semi-definite programming relaxation, and a variable selection strategy dedicated to quadratic problems. The interval features can then propagate efficiently this information for contracting all variable domains. We also propose to make our algorithm rigorous by certifying firstly the convexity of the objective function of our relaxation, and secondly the validity of the lower bound calculated at each node. In the non-rigorous case, our experiments show significant speedups on general integer quadratic instances, and when reliability is required, our first results show that we are able to handle medium-sized instances in a reasonable running time.
Abstract
Background: In the past decade, the therapeutic landscape of metastatic castration resistant prostate cancer (mCRPC) has been transformed with the introduction of novel pharmaceutical agents ...including novel antiandrogens (nAA) such as darolutamide, enzalutamide or apalutamide. Currently, the management of mCRPC is mainly based on biomarkers obtained from the patient's blood or bulk tumor samples, which do not take into account for prostate cancer (PCa) cell heterogeneity.
Objectives: To develop a bioluminescence imaging technology enabling: 1) the detection of PCa single cells from dissociated biopsies and 2) single cell nAA sensitivity assessment.
Methods: The PCA3 promoter (PCa specific) and PSEBC promoter (androgen receptor-driven to monitor response to nAA therapy) have been incorporated in the non-replicating adenoviral multi-promoter integrated two-step transcriptional amplification system (MP-ITSTA) that allows imaging of complementary activities of two different promoters by a single output reporter gene. Thus, PCA3/PSEBC-ITSTA system was designed to monitor androgen receptor (AR) activity specifically within each single PCa cell by bioluminescence microscopy. Prostatic biopsies were dissociated in the presence of collagenase II and DNase for 18h. PCa cell lines or fresh biopsies-dissociated cancer cells were transduced for 72h and then covered with an extracellular matrix gel. Single cell bioluminescence microscopy images were done before and after exposure to DHT or DHT+AA to specifically monitoring therapy response. Changes in cell number and luminescence intensity after AA were normalized to the DHT group to exclude non-specific cell-death due to infection or time spent in culture.
Results: PCA3/PSEBC-ITSTA was specific to PCa cell lines. By determining the ratio of AR active cells before and after DHT or DHT+AA treatment in culture, PCA3-Cre-PSEBC-ITSTA was able to determine the AA sensitivity of LNCaP (sensitive), LAPC4 (moderately resistant) and 22Rv1 (resistant) PCa cell lines. Also, our method could detect and monitor AA sensitivity of primary PCa cells harvested from eight radical prostatectomy specimens. PCA3/PSEBC-ITSTA could dynamically quantify AR transcriptional activity during enzalutamide or bicalutamide treatments, in a dose dependent manner, and could unveil tumor AA response heterogeneity. As expected, inhibition of AR activity was stronger with enzalutamide than with bicalutamide.
Conclusions: Our bioluminescence microscopy-based biosensor could detect primary PCa cells in culture and it allows dynamic evaluation of AA sensitivity at a single-cell level in a heterogeneous cell population harvested from radical prostatectomy biopsies. We believe our approach opens to a novel field of treatment response predictive tools for cancer treatment decision-making.
Citation Format: Audrey Champagne, Pallavi Jain, Bertrand Neveu, Frédéric Pouliot. A transcriptionally enhanced biosensor to detect and monitor biopsy-dissociated primary prostate cancer single cell drug responses by bioluminescence microscopy abstract. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2015.
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.
The basidiomycetous fungus Pseudozyma flocculosa represents a promising new host for the expression of complex recombinant proteins. Two novel heterologous promoter sequences, the Ustilago maydis ...glyceraldehyde-3-phosphate dehydrogenase (GPD) and Pseudozyma tsukubaensis alpha-glucosidase promoters, were tested for their ability to provide expression in P. flocculosa. In liquid medium, these two promoters produced lower levels of intracellular green fluorescent protein (GFP) as compared to the U. maydis hsp70 promoter. However, GPD and alpha-glucosidase sequences behaved as constitutive promoters whereas the hsp70 promoter appeared to be morphology-dependent. When using the hsp70 promoter, the expression of GFP increased proportionally to the concentration of hygromycin in the culture medium, indicating possible induction of the promoter by the antibiotic. Optimal solid-state culture conditions were designed for high throughput screening of hygromycin-resistant transformants with the hsp70 promoter in P. flocculosa.
PURPOSEDihydrotestosterone and testosterone are thought to be major contributors of prostate cancer progression and resistance. We studied the modulation of 15 circulating steroids by castration and ...their association with dihydrotestosterone and testosterone levels. MATERIALS METHODSA total of 116 serum samples were collected from 99 prostate cancer patients and categorized as eugonadal, castration-sensitive prostate cancer, castration-resistant prostate cancer, or castration-resistant prostate cancer under abiraterone acetate. Serum levels of 15 steroids were measured using mass spectrometry and compared between groups using analysis of variance. Intrapatient association of steroid levels and the androgens testosterone and dihydrotestosterone were assessed using Pearson correlation and linear regression. RESULTSTestosterone, dihydrotestosterone, androstenedione, dehydroepiandrosterone, dehydroepiandrosterone-sulfate, androsterone, androstenediol, estrone, estrone-sulfate, estradiol, and androsterone/3α-diol-3/3α-diol-17-glucuronide levels were significantly decreased in castration-sensitive prostate cancer (castrated) compared to eugonadal patients. Testosterone levels were strongly associated with multiple steroids under eugonadal conditions, whereas they were weakly affected by precursor steroids in castrated patients. By contrast, dihydrotestosterone levels under androgen deprivation therapy were associated with testosterone and the backdoor pathway metabolite androsterone. In castration-resistant prostate cancer patients, levels of androstenedione were significantly associated with testosterone level, while testosterone was the only steroid associated with dihydrotestosterone levels. CONCLUSIONSAndrogen deprivation therapy significantly reduces the levels of 13 circulating steroids. Upon androgen deprivation therapy initiation, the backdoor pathway metabolite androsterone are strongly associated with dihydrotestosterone levels. Under castration-resistant prostate cancer conditions, androstenedione was significantly associated with testosterone levels, suggesting the presence of tumor-related circulating androgens in these patients. These results provide further rationale to intensify treatments with androgen receptor axis signaling pathway inhibitors in patients with prostate cancer.
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