Beyond testosterone, several steroids contribute to the activation of the androgen receptor pathway, but their relative contributions to the activation of the androgen receptor signaling axis in ...patients with castrated prostate cancer remain unknown.
Serum levels of 9 steroids were measured by mass spectrometry from continuously castrated patients of the PR.7 study (219) and from the PCA24 cohort (116). For each steroid standard curves for dose dependent prostate specific antigen promoter activation were built in castration sensitive (LAPC4) and resistant (VCaP) prostate cancer models. Standard curves were used to determine the androgen receptor activation potency for each steroid measurement from patients in these trials.
In LAPC4 and VCaP cells testosterone, dihydrotestosterone and androstenedione induced androgen receptor transcriptional activity, while dehydroepiandrosterone, 5alpha-androstan-3beta,17beta-diol, androstenediol and androsterone stimulated androgen receptor only in VCaP cells. Extragonadal steroids were responsible for 34% (LAPC4) and 88% (VCaP) of the serum total androgen receptor transcriptional activity found in castrated cases. The total androgen receptor transcriptional activity secondary to testosterone, dihydrotestosterone and androstenedione was associated with time to castration resistance in patients from the PR.7 study (HR 2.17, 95% CI 1.12-4.23, p=0.02) in multivariate analysis using the castration sensitive model (LAPC4). Androgen receptor transcriptional activity of extragonadal androstenedione was the only steroid statistically associated with time to castration resistance in univariate analysis (HR 1.89, 95% CI 1.04-3.44, p=0.036).
Extragonadal steroids contribute significantly to the androgen receptor axis activation at castration levels of testosterone in recurrent nonmetastatic prostate cancer and these sustain the development of castration resistance after primary local treatment.
One the way to improve the self-repair properties of sol–gel films on aluminium alloy is the addition of corrosion inhibitors which could be released from the coating, minimising the corrosion of the ...unprotected area. Environmentally friendly corrosion inhibitors are studied (chromium III, molybdate, permanganate and cerium III) and compared to the standard corrosion inhibitor, i.e. hexavalent chromium.
Corrosion performances are studied by polarisation resistance (Rp) in chloride medium. Evolution of composition of sol–gel coatings, during the corrosion test, is examined by GDOES (glow discharge optical emission spectroscopy).
The results show that the morphology of sol–gel and the solubility of the additive play a role in the effectiveness of corrosion protection for a long term. Additives such as molybdate and permanganate ions decrease the sol–gel network stability and are too soluble (they are rapidly lost from the sol–gel films, in an aggressive medium), decreasing the power to prevent corrosion. Incorporation of Ce III is not efficient for a long time due to its high solubility. Sol–gel films containing Cr VI and Cr III provide adequate corrosion protection, due to the sol–gel stability and their low solubility.
Objective
To determine the prevalence of intra‐patient inter‐metastatic heterogeneity based on positron emission tomography (PET)/computed tomography (CT) in patients with metastatic ...castration‐resistant prostate cancer (mCRPC) and to determine the prevalence of neuroendocrine disease in these patients and their eligibility for radioligand therapies (RLTs).
Patients and Methods
This multicentre observational prospective clinical study will include 100 patients with mCRPC from five Canadian academic centres. Patients with radiological or biochemical progression and harbouring at least three metastases by conventional imaging will be accrued. Intra‐patient inter‐metastatic heterogeneity will be determined with triple‐tracer imaging using fluorine‐18 fluorodeoxyglucose (18F‐FDG), gallium‐68‐(68Ga)‐prostate‐specific membrane antigen (PSMA)‐617 and 68Ga‐DOTATATE, which are a glucose analogue, a PSMA receptor ligand and a somatostatin receptor ligand, respectively. The 68Ga‐PSMA‐617 and 18F‐FDG PET/CT scans will be performed first. If at least one PSMA‐negative/FDG‐positive lesion is observed, an additional PET/CT scan with 68Ga‐DOTATATE will be performed. The tracer uptake of individual lesions will be assessed for each PET tracer and patients with lesions presenting discordant uptake profiles will be considered as having inter‐metastatic heterogeneous disease and may be offered a biopsy.
Expected Results
The proposed triple‐tracer approach will allow whole‐body mCRPC characterisation, investigating the inter‐metastatic heterogeneity in order to better understand the phenotypic plasticity of prostate cancer, including the neuroendocrine transdifferentiation that occurs during mCRPC progression. Based on 68Ga‐PSMA‐617 or 68Ga‐DOTATATE PET positivity, the potential eligibility of patients for PSMA and DOTATATE‐based RLT will be assessed. Non‐invasive whole‐body determination of mCRPC heterogeneity and transdifferentiation is highly innovative and might establish the basis for new therapeutic strategies. Comparison of molecular imaging findings with biopsies will also link metastasis biology to radiomic features.
Conclusion
This study will add novel, biologically relevant dimensions to molecular imaging: the non‐invasive detection of inter‐metastatic heterogeneity and transdifferentiation to neuroendocrine prostate cancer by using a multi‐tracer PET/CT strategy to further personalise the care of patients with mCRPC.
An operator called
CID
and an efficient variant
3BCID
were proposed in 2007. For the numerical CSP handled by interval methods, these operators compute a partial consistency equivalent to ...Partition-1-AC for the discrete CSP. In addition to the constraint propagation procedure used to refute a given subproblem, the main two parameters of
CID
are the number of times the main
CID
procedure is called and the maximum number of sub-intervals treated by the procedure. The
3BCID
operator is state-of-the-art in numerical CSP, but not in constrained global optimization, for which it is generally too costly. This paper proposes an adaptive variant of
3BCID
called
ACID
. The number of variables handled is auto-adapted during the search, the other parameters are fixed and robust to modifications. On a representative sample of instances,
ACID
appears to work efficiently, both with the
HC4
constraint propagation algorithm and with the state-of-the-art
Mohc
algorithm. Experiments also highlight that it is relevant to auto-adapt only a number of handled variables, instead of a specific set of selected variables. Finally,
ACID
appears to be the best interval constraint programming operator for solving and optimization, and has been therefore added to the default strategies of the
Ibex
interval solver.
Abstract
Development of a molecular imaging system based on the transcriptional activity of the DD3/PCA3 non-coding RNA for imaging specifically the prostate cancer cells
OBJECTIVE: Molecular imaging ...plays an important role in oncology for staging of tumors. Unfortunately, the specificity and sensitivity of current techniques remains low. This study aims to improve the existing imaging system based on transcriptional activation, named as “Two -Step- Transcriptional Amplification (TSTA) system”, with the goal to precisely image in vivo prostate cancer cells (PCa) by Positron Emission Tomography (PET). We have studied the potential of DD3/PCA3 promoter, a gene specifically expressed in PCa, to achieve this goal.
METHODS: Various adenovirus constructs incorporating the DD3 promoter, the TSTA system and the Firefly luciferase reporter gene were generated and their specificity for PCa cells was tested in transient infection. By molecular engineering, we have improved the TSTA system and generated the 3STA. The luciferase activities of DD3-TSTA, DD3-3STA and PSA-TSTA (Prostate Specific Antigen) were compared in vivo by bioluminescence in xenograft mouse models. Ex vivo prostate biopsy from RP (radical prostatectomy) specimen were exposed to DD3-3STA and luciferase expression was evaluated using bioluminescence and Immunohistochemistry.
RESULTS: The DD3 promoter activity is both specific to prostate and cancer cells. When DD3 promoter is incorporated in the amplification systems TSTA and 3STA, it is specific to PCa cells and its activity is amplified 32 and 95 times, respectively, when compared to the activity of the DD3 promoter alone. Moreover, activity of DD3-TSTA and DD3-3STA is androgen-independent. In vivo, DD3-3STA activity is comparable to that obtained with the PSA-TSTA whose activity can be imaged by PET. DD3-3STA could detect primary prostate cancer cells ex vivo in prostate biopsy obtained from RP specimen (Figure 1).
CONCLUSIONS: The new system DD3-3STA allows specific and sensitive imaging of PCa cells. The new amplification system 3STA allows the DD3 promoter to produce reporter signal high enough to be detected by PET, a technology available in the clinic.
Citation Format: Pallavi Jain, Bertrand Neveu, Yves Fradet, Frederic Pouliot. Development of a molecular imaging system based on the transcriptional activity of the DD3/PCA3 non-coding RNA for imaging specifically the prostate cancer cells. abstract. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 206. doi:10.1158/1538-7445.AM2015-206
Abstract only
148
Background: Beyond testosterone, several steroids contribute to the activation of the androgen receptor (AR) pathway, but their relative contributions in castrated prostate cancer ...(PCa) patients remain unknown. Methods: Serum levels of nine steroids were measured by mass spectrometry from continuously castrated patients of the PR.7 study (n=219) and from the PCA24 cohort (n=116). For each steroid, standard curves for dose-dependent prostate-specific antigen promoter activation were built in castration-sensitive (LAPC4) and resistant (VCaP) PCa models. Standard curves were used to determine the AR activation potency for each steroid measurement from patients. Results: In LAPC4 and VCaP cells, testosterone, dihydrotestosterone and androstenedione induced AR transcriptional activity, while dehydroepiandrosterone, 5alpha-androstan-3beta,17beta-diol, androstenediol, androsterone stimulated AR only in VCaP cells. Extragonadal steroids were responsible for 34% (LAPC4) and 88% (VCaP) of the serum total AR transcriptional activity found in castrated patients. The total AR transcriptional activity secondary to testosterone, dihydrotestosterone and androstenedione was associated with time to castration resistance in patients from the PR.7 study (HR=2.17; 95% CI: 1.12-4.23; p=0.02) in multivariate analysis using the castration-sensitive model (LAPC4). AR transcriptional activity of extragonadal androstenedione was the only steroid statistically associated with time to castration resistance in univariate analysis (HR=1.89; 95% CI: 1.04-3.44; p=0.036). Conclusions: Extragonadal steroids contribute significantly to the AR axis activation at testosterone castration levels in recurrent non-metastatic PCa and these sustain the development of castration resistance after primary local treatment.
Prostate cancer (PCa) is the most frequently diagnosed cancer in men and the third cause of cancer mortality. PCa initiation and growth are driven by the androgen receptor (AR). The AR is activated ...by androgens such as testosterone and controls prostatic cell proliferation and survival. Here, we report an AR signaling network generated using BioID proximity labeling proteomics in androgen-dependent LAPC4 cells. We identified 31 AR-associated proteins in nonstimulated cells. Strikingly, the AR signaling network increased to 182 and 200 proteins, upon 24 h or 72 h of androgenic stimulation, respectively, for a total of 267 nonredundant AR-associated candidates. Among the latter group, we identified 213 proteins that were not previously reported in databases. Many of these new AR-associated proteins are involved in DNA metabolism, RNA processing, and RNA polymerase II transcription. Moreover, we identified 44 transcription factors, including the Kru¨ppel-like factor 4 (KLF4), which were found interacting in androgen-stimulated cells. Interestingly, KLF4 repressed the well-characterized AR-dependent transcription of the KLK3 (PSA) gene; AR and KLF4 also colocalized genome-wide. Taken together, our data report an expanded high-confidence proximity network for AR, which will be instrumental to further dissect the molecular mechanisms underlying androgen signaling in PCa cells.
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•BioID proteomics identifies 267 androgen receptor (AR)-associated candidates•Krüppel-like factor 4 (KLF4) is a new AR interaction partner•AR and KLF4 colocalize genome-wide on >4000 genes, including KLK3 (PSA)•KLF4 acts as a repressor for the AR target gene KLK3 (PSA)
A proximity interaction network for the androgen receptor (AR) was obtained from androgen-responsive prostate cancer cells. A total of 267 candidates were identified, most associating following ligand stimulation, including Krüppel-like factor 4 (KLF4). KLF4 and AR were found to colocalize genome-wide on 4097 genes including PSA (KLK3), for which KLF4 acts as a repressor, without regulating the expression of AR. These results are instrumental to further dissect the molecular mechanisms underlying androgen signaling in prostate cells.
In engineering sciences, parameter estimation is a challenging problem consisting in computing the parameters of a parametric model that fit observed data. The system is defined by unknown parameters ...and sometimes internal constraints. The observed data provide constraints on the parameters. This problem is particularly difficult when some observation constraints correspond to outliers and/or the constraints are non convex. The
ransac
randomized algorithm can efficiently handle it, but is non deterministic and must be specialized for every problem. This paper presents the first generic interval branch and bound algorithm that produces a model maximizing the number of observation constraints satisfied within a given tolerance. This tool is inspired by the IbexOpt branch and bound algorithm for constrained global optimization (NLP) and is endowed with an improved version of a relaxed intersection operator applied to observations. Experiments have been carried out on two different computer vision problems. They highlight a significant speedup w.r.t. Jaulin et al.’s interval method in 2D and 3D shape recognition problems (having three parameters). We have also obtained promising results on a stereo vision problem where the
essential matrix
(five parameters) is estimated exactly at a good accuracy in hours for models having a thousand points, a typical size for such problems.
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