Targeting specifically primary prostate cancer (PCa) cells for immune therapy, gene therapy or molecular imaging is of high importance. The PCA3 long non-coding RNA is a unique PCa biomarker and ...oncogene that has been widely studied. This gene has been mainly exploited as an accurate diagnostic urine biomarker for PCa detection. In this study, the PCA3 promoter was introduced into a new transcriptional amplification system named the 3-Step Transcriptional Amplification System (PCA3-3STA) and cloned into type 5 adenovirus. PCA3-3STA activity was highly specific for PCa cells, ranging between 98.7- and 108.0-fold higher than that for benign primary prostate epithelial or non-PCa cells, respectively. In human PCa xenografts, PCA3-3STA displayed robust bioluminescent signals at levels that are sufficient to translate to positron emission tomography (PET)-based reporter imaging. Remarkably, when freshly isolated benign or cancerous prostate biopsies were infected with PCA3-3STA, the optical signal produced from primary PCa biopsies was significantly higher than from benign prostate biopsies (4.4-fold, p < 0.0001). PCA3-3STA therefore represents a PCa-specific expression system with the potential to target, with high accuracy, primary or metastatic PCa epithelial cells for imaging, vaccines, or gene therapy.
•Proposed algorithm to generate schedules for radiotherapy treatments.•Generated schedules take into account updated patients waiting time.•On-the-fly generated schedules reduce significantly the ...patients waiting time.
Scheduling Radiotherapy treatments for cancer patient is a major concern for hospital and clinics. The main problem consists in minimizing the patient waiting time in order to maximize the treatment effectiveness. Most of the modern scheduling approaches use expert systems based on scheduling heuristics and algorithms to develop detailed schedules, in order to efficiently map the patients requirements to the treatment capacity of the health center. In this paper, we propose RASON, a new heuristic based scheduling algorithm for radiotherapy treatments, which main objective is to minimize the average waiting time for each patient. In contrast to well-known existing approaches, our solution manages a priority list that can be dynamically updated according to both the patient category and his/her current waiting time. The generated schedule also impacts the minimization of the average tardiness of the first treatment sessions for each patient. We have evaluated our algorithm using both real data from the Institute of Radiotherapy in Santiago, Chilean and artificial cases generated with a self-developed generator called GeneRa. GeneRa is able to generate cases according to particular constraints inherent to several countries like UK, France and Italy. We show in our proposal evaluation that an on-the-fly scheduling has a great positive impact, allowing to reduce the average waiting time and tardiness for all patients categories. Our algorithm outperforms the JIT and ASAP well-known approaches, with a 95% statistical significance. Our scheduling algorithm allows to significantly reduce the treatment waiting time for different categories of patients. This is a major improvement for the patients as time and delays are crucial parameters to achieve the best effectiveness in cancer treatments.
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Background: Tumour FDG-uptake is of prognostic value in high-risk and metastatic prostate cancer (PCa). The aim of this study is to investigate the underlying glucose metabolism ...mechanisms of 18F-FDG-uptake on PET/CT imaging in PCa. Methods: Retrospective analysis was conducted for 94 patients diagnosed with a Gleason sum ≥8 at biopsy who underwent 18F-FDG-PET/CT imaging before radical prostatectomy. GLUT1, GLUT12 and HK2 expression were blindly scored after immunohistochemistry on radical prostatectomy specimens by 3 pathologists. 18F-FDG-uptake in primary lesion was measured by a blinded reader using maximum standardized uptake value (SUVmax). Correlations between GLUT1, GLUT12 and HK2 and SUVmax were assessed using Spearman’s rank correlation test. Survival probabilities were based on the Kaplan-Meier method. Results: With a median follow-up of 4.5 years, 56% (n=53) of patients had biochemical recurrence, 7% (n=7) progressed to castration-resistant PCa (CRPC) disease, 13% (n=12) developed metastasis and 6% (n=6) died. Correlation was found between GLUT1 expression and SUVmax level (r=0.2512, p=0.0182). In addition, SUVmax was significantly higher in tumours with high GLUT1 expression (n=17, 5.74±1.67) than tumours with low GLUT1 expression (n=71, 2.68±0.31, P=0.0037). Also, contrary to GLUT12 and HEX2 expression, a significant association was found between GLUT-1 expression levels and SUVmax index (p=0.004), lymph node status (p=0.046), volume of cancer (P=0.013), CRPC-free survival (p=0.02) and metastasis-free survival (p=0.04). Conclusions: GLUT1 expression in PCa tumours correlates with 18F-FDG-uptake and poor prognostic factors. These results suggest that this transporter is involved in the molecular mechanism of 18F-FDG-uptake in high-risk PCa and raise interest in targeting metabolic dependencies of PCa cells as a selective anticancer strategy.
Patient-derived organoids (PDOs) are now used to study many diseases, including prostate cancer. Here, we present a protocol for the transduction of human epithelial prostate cells and PDOs. We ...describe the steps for producing lentiviruses and transducing PDOs with high efficiency to obtain either overexpression or knockdown of specific genes. More generally, this protocol represents an efficient lentiviral transduction technique to study cell biology using various organoid models.
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•Lentiviral production in Lenti-X 293T cells for transducing epithelial cells•Tips to ensure high-efficiency transduction of mouse or human organoids•Suitable for use with prostate and other types of organoids
Publisher’s note: Undertaking any experimental protocol requires adherence to local institutional guidelines for laboratory safety and ethics.
Patient-derived organoids (PDOs) are now used to study many diseases, including prostate cancer. Here, we present a protocol for the transduction of human epithelial prostate cells and PDOs. We describe the steps for producing lentiviruses and transducing PDOs with high efficiency to obtain either overexpression or knockdown of specific genes. More generally, this protocol represents an efficient lentiviral transduction technique to study cell biology using various organoid models.
Proving that the state of a controlled nonlinear system always stays inside a time moving bubble (or capture tube) amounts to proving the inconsistency of a set of nonlinear inequalities in the ...time-state space. In practice however, even with a good intuition, it is difficult for a human to find such a capture tube except for simple examples. In 2014, Jaulin et al. established properties that support a new interval approach for validating a quasi capture tube, i.e. a candidate tube (with a simple form) from which the mobile system can escape, but into which it enters again before a given time. A quasi capture tube is easy to find in practice for a controlled system. Merging the trajectories originated from the candidate tube yields the smallest capture tube enclosing it. This paper proposes an interval constraint programming solver dedicated to the quasi capture tube validation. The problem is viewed as a differential CSP where the functional variables correspond to the state variables of the system and the constraints define system trajectories that escape from the candidate tube "for ever". The solver performs a branch and contract procedure for computing the trajectories that escape from the candidate tube. If no solution is found, the quasi capture tube is validated and, as a side effect, a corrected smallest capture tube enclosing the quasi one is computed. The approach is experimentally validated on several examples having 2 to 5 degrees of freedom. 2012 ACM Subject Classification Applied computing → Operations research; Mathematics of computing → Ordinary differential equations; Mathematics of computing → Differential algebraic equations; Mathematics of computing → Interval arithmetic; Theory of computation → Constraint and logic programming
In this paper, we present a review of the recent approaches proposed in the literature for strip-packing problems. Many of them have been concurrently published, given some similar results for the ...same set of benchmarks. Due to the quantity of published papers, it is difficult to ascertain the level of current research in this area.
In the fight against androgen-sensitive prostate cancer, the enzyme 17beta-hydroxysteroid dehydrogenase type 3 (17beta-HSD3) is an attractive therapeutic target considering its key role in the ...formation of androgenic steroids. In this study, we attempted to assess the in vivo efficacy of the compound RM-532-105, an androsterone derivative developed as an inhibitor of 17beta-HSD3, in the prostate cancer model of androgen-sensitive LAPC-4 cells xenografted in nude mice. RM-532-105 did not inhibit the tumor growth induced by 4-androstene-3,17-dione (4-dione); rather, the levels of the androgens testosterone (T) and dihydrotestosterone (DHT) increased within the tumors. In plasma, however, DHT levels increased but T levels did not. In troubleshooting experiments, the non-androgenic potential of RM-532-105 was confirmed by two different assays (LAPC-4 proliferation and androgen receptor transcriptional activity assays). The enzyme 5alpha-reductase was also revealed to be the predominant enzyme metabolizing 4-dione in LAPC-4 cells, yielding 5alpha-androstane-3,17-dione and not T. Other 17beta-HSDs than 17beta-HSD3 seem responsible in the androgen synthesis. From experiments with LAPC-4 cells, we fortuitously came across the interesting finding that 17beta-HSD3 inhibitor RM-532-105 is concentrated inside tumors.
In interval arithmetics, special care has been brought to the definition of interval extension functions that compute narrow interval images. In particular, when a function
f
is monotonic w.r.t. a ...variable in a given domain, it is well-known that the monotonicity-based interval extension of
f
computes a sharper image than the natural interval extension does. This paper presents a so-called “occurrence grouping” interval extension
f
og
of a function
f
. When
f
is
not
monotonic w.r.t. a variable
x
in a given domain, we try to transform
f
into a new function
f
og
that is monotonic w.r.t. two subsets
x
a
and
x
b
of the occurrences of
x
:
f
og
is increasing w.r.t.
x
a
and decreasing w.r.t.
x
b
.
f
og
is the interval extension by monotonicity of
f
og
and produces a sharper interval image than the natural extension does. For finding a good occurrence grouping, we propose a linear program and an algorithm that minimize a Taylor-based over-estimate of the image diameter of
f
og
. Experiments show the benefits of this new interval extension for solving systems of nonlinear equations.
Abstract
Background: The androgen receptor (AR) is an established orchestrator of cell metabolism in prostate cancer (PCa), notably by inducing an oxidative mitochondrial program. Intriguingly, AR ...regulates cytoplasmic isocitrate dehydrogenase 1 (IDH1) but not its mitochondrial counterparts IDH2 and IDH3. Here, we aimed to understand the functional role of IDH1 in PCa.
Methods: Mouse models, in vitro human PCa cell lines, and human prostate organoids were used to study the expression and activity of IDH enzymes in the normal prostate and PCa. Genetic and pharmacological inhibition of IDH1 was then combined with extracellular flux analysis and gas chromatography-mass spectrometry for metabolomic analyses and cancer cell proliferation in vitro and in vivo.
Results: In PCa cells, more than 90% of the total IDH activity is mediated through IDH1 rather than its mitochondrial counterparts. This profile seems to originate from the specialized prostate metabolic program, as observed using mouse prostate and human patient-derived organoids. Pharmacological and genetic inhibition of IDH1 impaired mitochondrial respiration, suggesting that this cytoplasmic enzyme contributes to the mitochondrial tricarboxylic acid cycle (TCA) in PCa. Mass spectrometry-based metabolomics confirmed this hypothesis, showing that inhibition of IDH1 impairs carbon flux into the TCA cycle. Consequently, inhibition of IDH1 decreased PCa cell proliferation in vitro and in vivo.
Conclusions: These results demonstrate that PCa cells have a hybrid cytoplasmic-mitochondrial TCA cycle that depends on IDH1. This metabolic enzyme represents a metabolic vulnerability of PCa cells and a potential new therapeutic target.
Citation Format: Kevin Gonthier, Cindy Weidmann, Line Berthiaume, Cynthia Jobin, Aurélie Lacouture, Camille Lafront, Mario Harvey, Bertrand Neveu, Jérémy Loehr, Alain Bergeron, Yves Fradet, Louis Lacombe, Julie Riopel, Éva Latulippe, Chantal Atallah, Michael Shum, Jean-Philippe Lambert, Frédéric Pouliot, Martin Pelletier, Étienne Audet-Walsh. Isocitrate dehydrogenase 1 sustains a hybrid cytoplasmic-mitochondrial tricarboxylic acid cycle in prostate cancer. abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3700.
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