Publications by authors named "Sophie Noël"

12 Publications

  • Page 1 of 1

Optimization of Novel Antagonists to the Neurokinin-3 Receptor for the Treatment of Sex-Hormone Disorders (Part II).

ACS Med Chem Lett 2015 Jul 19;6(7):736-40. Epub 2015 May 19.

Euroscreen SA , 47 rue Adrienne Bolland, 6041 Gosselies, Belgium.

Further lead optimization on N-acyl-triazolopiperazine antagonists to the neurokinin-3 receptor (NK3R) based on the concurrent improvement in bioactivity and ligand lipophilic efficiency (LLE) is reported. Overall, compound 3 (LLE > 6) emerged as the most efficacious in castrated rat and monkey to lower plasma LH, and it displayed the best off-target safety profile that led to its clinical candidate nomination for the treatment of sex-hormone disorders.
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http://dx.doi.org/10.1021/acsmedchemlett.5b00117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4499830PMC
July 2015

Discovery and optimization of novel antagonists to the human neurokinin-3 receptor for the treatment of sex-hormone disorders (Part I).

J Med Chem 2015 Apr 18;58(7):3060-82. Epub 2015 Mar 18.

Euroscreen SA, 47 Rue Adrienne Bolland, 6041 Gosselies, Belgium.

Neurokinin-3 receptor (NK3R) has recently emerged as important in modulating the tonic pulsatile gonadotropin-releasing hormone (GnRH) release. We therefore decided to explore NK3R antagonists as therapeutics for sex-hormone disorders that can potentially benefit from lowering GnRH pulsatility with consequent diminished levels of plasma luteinizing hormone (LH) and correspondingly attenuated levels of circulating androgens and estrogens. The discovery and lead optimization of a novel N-acyl-triazolopiperazine NK3R antagonist chemotype achieved through bioisosteric lead change from the high-throughput screening (HTS) hit is described. A concomitant improvement in the antagonist bioactivity and ligand lipophilic efficiency (LLE) parameter were the principal guidelines in the lead optimization efforts. Examples of advanced lead analogues to demonstrate the amenability of this chemotype to achieving a suitable pharmacokinetic (PK) profile are provided as well as pharmacokinetic-pharmacodynamic (PKPD) correlations to analyze the trends observed for LH inhibition in castrated rats and monkeys that served as preliminary in vivo efficacy models.
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http://dx.doi.org/10.1021/jm5017413DOI Listing
April 2015

Current state of medical thromboprophylaxis in Australia.

Australas Med J 2014 28;7(2):58-63. Epub 2014 Feb 28.

Department of Medicine, Albany Regional Hospital, Albany, Western Australia 6330, Australia.

Background: Australia has two published national guidelines for general medical thromboprophylaxis (MT), but the two differ in detail and the basis for patient selection remains uncertain. Several aspects of current guidelines are controversial, as is the proposed design of a dedicated prescribing box in the National Inpatient Medication Chart.

Aim: To discuss and comment on the current standing of medical thromboprophylaxis in Australia.

Method: We have marshalled literature known to us from our previous published research, and have applied this knowledge to discuss shortcomings, which, in our opinion, exist in current medical thromboprophylaxis practice, and to suggest solutions.

Conclusion: Australian guidelines are flawed because they are based on unsuitable evidence (incidence of subclinical thrombotic disease) and define eligibility broadly, such that about 80 per cent of patients are considered eligible. They urge that prescribers should "consider" prophylaxis without supplying an adequate basis for doing so. They do not provide grounds for assessing the balance between hazard (in the form of major bleeds) and benefit (thrombotic events avoided). Other clinical factors promoting unnecessary use of medical thromboprophylaxis include the use of age as a risk factor and proposed inclusion of a new DVT prophylaxis section in the National Inpatient Medication Chart (NIMC), which implicitly discourages non-prescription of prophylaxis.
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http://dx.doi.org/10.4066/AMJ.2014.1915DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3941577PMC
March 2014

Consumption of omega-3 fatty acids and the risk of skin cancers: a systematic review and meta-analysis.

Int J Cancer 2014 Jul 18;135(1):149-56. Epub 2013 Dec 18.

Albany Health Campus, Warden Avenue, Albany, WA, Australia.

Skin cancers have a higher incidence than all other cancers combined and are a major cause of morbidity worldwide. Laboratory data suggest certain dietary constituents, notably omega-3 polyunsaturated fatty acids (n-3 PUFAs), could potentially protect against skin malignancy, although no large-scale review has been conducted in humans. The objective of this review and meta-analysis was to determine the relationship between dietary n-3 PUFAs and skin cancer incidence. It considered all published randomized controlled trials and observational studies up to March 2013. Five studies (two case-control and three cohort) were identified pertaining to oral n-3 PUFA consumption and incidence of basal cell carcinoma (BCC), squamous cell carcinoma (SCC), melanoma (or a combination) and were included in a random-effects meta-analysis. A further six studies considering nondietary n-3 PUFA exposure (e.g., by tissue analysis) and/or recognized biological markers of skin cancer risk (e.g., p53 expression) were analyzed qualitatively. Dietary n-3 PUFAs were not associated with BCC (pooled OR 1.05, 95% CIs 0.86-1.28). Consumption of high levels of n-3 PUFAs were inversely associated with melanoma, although with only one estimate available (OR 0.52, 95% CI 0.34-0.78), and SCC, although nonsignificantly (pooled OR 0.86, 95% CIs 0.59-1.23). Available evidence is suggestive, but currently inadequate, to support the hypothesis that n-3 PUFAs protect against skin malignancy.
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http://dx.doi.org/10.1002/ijc.28630DOI Listing
July 2014

An 81 year old man with a blistering rash.

BMJ 2013 Jan 31;346:f522. Epub 2013 Jan 31.

Department of Dermatology, Royal Berkshire Hospital, Reading RG1 5AN, UK.

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http://dx.doi.org/10.1136/bmj.f522DOI Listing
January 2013

Oxysterols direct immune cell migration via EBI2.

Nature 2011 Jul 27;475(7357):524-7. Epub 2011 Jul 27.

Euroscreen S.A., 6041 Gosselies, Belgium.

Epstein-Barr virus-induced gene 2 (EBI2, also known as GPR183) is a G-protein-coupled receptor that is required for humoral immune responses; polymorphisms in the receptor have been associated with inflammatory autoimmune diseases. The natural ligand for EBI2 has been unknown. Here we describe the identification of 7α,25-dihydroxycholesterol (also called 7α,25-OHC or 5-cholesten-3β,7α,25-triol) as a potent and selective agonist of EBI2. Functional activation of human EBI2 by 7α,25-OHC and closely related oxysterols was verified by monitoring second messenger readouts and saturable, high-affinity radioligand binding. Furthermore, we find that 7α,25-OHC and closely related oxysterols act as chemoattractants for immune cells expressing EBI2 by directing cell migration in vitro and in vivo. A critical enzyme required for the generation of 7α,25-OHC is cholesterol 25-hydroxylase (CH25H). Similar to EBI2 receptor knockout mice, mice deficient in CH25H fail to position activated B cells within the spleen to the outer follicle and mount a reduced plasma cell response after an immune challenge. This demonstrates that CH25H generates EBI2 biological activity in vivo and indicates that the EBI2-oxysterol signalling pathway has an important role in the adaptive immune response.
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http://dx.doi.org/10.1038/nature10280DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4297623PMC
July 2011

Evaluation of the nanotube intrinsic resistance across the tip-carbon nanotube-metal substrate junction by Atomic Force Microscopy.

Nanoscale Res Lett 2011 Apr 14;6(1):335. Epub 2011 Apr 14.

Lab, MSSMat, UMR CNRS 8579, Ecole Centrale Paris, Grande Voie des Vignes, Châtenay-Malabry 92290, France.

Using an atomic force microscope (AFM) at a controlled contact force, we report the electrical signal response of multi-walled carbon nanotubes (MWCNTs) disposed on a golden thin film. In this investigation, we highlight first the theoretical calculation of the contact resistance between two types of conductive tips (metal-coated and doped diamond-coated), individual MWCNTs and golden substrate. We also propose a circuit analysis model to schematize the «tip-CNT-substrate» junction by means of a series-parallel resistance network. We estimate the contact resistance R of each contribution of the junction such as Rtip-CNT, RCNT-substrate and Rtip-substrate by using the Sharvin resistance model. Our final objective is thus to deduce the CNT intrinsic radial resistance taking into account the calculated electrical resistance values with the global resistance measured experimentally. An unwished electrochemical phenomenon at the tip apex has also been evidenced by performing measurements at different bias voltages with diamond tips. For negative tip-substrate bias, a systematic degradation in color and contrast of the electrical cartography occurs, consisting of an important and non-reversible increase of the measured resistance. This effect is attributed to the oxidation of some amorphous carbon areas scattered over the diamond layer covering the tip. For a direct polarization, the CNT and substrate surface can in turn be modified by an oxidation mechanism.
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http://dx.doi.org/10.1186/1556-276X-6-335DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3211423PMC
April 2011

Discovery of 3-aryl-5-acylpiperazinyl-pyrazoles as antagonists to the NK3 receptor.

Bioorg Med Chem Lett 2011 Apr 13;21(7):1991-6. Epub 2011 Feb 13.

Euroscreen SA, 47 rue Adrienne Bolland, Gosselies, Belgium.

A series of 3-aryl-5-acylpiperazinyl-pyrazoles (e.g., 3a-b) initially identified through a high-throughput screening campaign using the aequorin Ca(2+) bioluminescence assay as novel, potent small molecule antagonists of the G protein-coupled human tachykinin NK(3) receptor (hNK3-R) is described. Preliminary profiling revealed poor plasma and metabolic stability for these structures in rodents. Further optimization efforts resulted in analogs with improved potency, stability, and pharmacokinetic properties as well as good brain permeability, for example, compounds 26 and 42. Unexpected cytotoxicity was observed in such N-Me pyrazole structures as compounds 41-42.
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http://dx.doi.org/10.1016/j.bmcl.2011.02.033DOI Listing
April 2011

Formyl peptide receptor-like 2 is expressed and functional in plasmacytoid dendritic cells, tissue-specific macrophage subpopulations, and eosinophils.

J Immunol 2009 Apr;182(8):4974-84

Institut de Recherche Interdisciplinaire en Biologie Humaine et Moléculaire, Université Libre de Bruxelles, Brussels, Belgium.

The formyl peptide receptor (FPR) is a key player in innate immunity and host defense mechanisms. In humans and other primates, a cluster of genes encodes two related receptors, FPR-like 1 and FPR-like 2 (FPRL1 and FPRL2). Despite their high sequence similarity, the three receptors respond to different sets of ligands and display a different expression pattern in leukocyte populations. Unlike FPR and FPRL1, FPRL2 is absent from neutrophils, and two endogenous peptide agonists, F2L and humanin, were recently described. In the present work, we investigated the detailed functional distribution of FPRL2 in leukocytes by quantitative PCR, flow cytometry, immunohistochemistry, and chemotaxis assays, with the aim of raising hypotheses regarding its potential functions in the human body. We describe that FPRL2 is highly expressed and functional in plasmacytoid dendritic cells and up-regulated upon their maturation. FPRL2 is also expressed in eosinophils, which are recruited but do not degranulate in response to F2L. FPRL2 is expressed and functional in macrophages differentiated from monocytes in vitro in different conditions. However, in vivo, only specific subsets of macrophages express the receptor, particularly in the lung, colon, and skin, three organs chronically exposed to pathogens and exogenous aggressions. This distribution and the demonstration of the production of the F2L peptide in mice underline the potential role of FPRL2 in innate immunity and possibly in immune regulation and allergic diseases.
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http://dx.doi.org/10.4049/jimmunol.0803128DOI Listing
April 2009

Linac stereotactic radiosurgery: an effective and safe treatment for elderly patients with brain metastases.

Int J Radiat Oncol Biol Phys 2005 Dec 18;63(5):1555-61. Epub 2005 Jul 18.

Department of Radiotherapy, Groupe Pitié-Salpêtrière, Assistance Publique-Hôpitaux de Paris, Paris, France.

Purpose: To evaluate the outcomes of radiosurgery for brain metastases in patients 65 years or older.

Patients And Methods: Between January 1994 and January 2003, 117 patients (47 women, 70 men), median age 71 years (range, 65-86 years), received radiosurgery for 227 metastases. Sixty-one patients (55%) presented symptoms in relation to the brain metastases. Thirty-eight patients (32%) received whole-brain radiotherapy. Median metastasis diameter and volume were 21 mm (range, 0.5-75 mm) and 1.7 cc (range, 0.02-71 cc), respectively.

Results: Median follow-up was 7 months (range, 1-45 months), 9.5 months for alive patients (range, 1-45 months). Median minimum and maximum doses were 14.5 Gy (6.5 Gy, 19.5 Gy), and 20.4 Gy (13.2 Gy, 41.9 Gy), respectively. Median survival was 8 months from the date of radiosurgery. Overall survival rates at 6 and 24 months were 58% +/- 5% and 13% +/- 4%, respectively. According to multivariate analysis, a low Karnofsky performance status was an independent unfavorable prognostic factor for overall survival (p = 0.003; odds ratio [OR] = 0.28; 95% confidence interval [CI], 0.14-0.56). Median brain disease-free survival was 10 months. Brain disease-free survival rates at 6 and 24 months were 67% +/- 6% and 40% +/- 7%, respectively. According to multivariate analysis, a radiosensitive lesion was an independent favorable factor (p = 0.038; OR = 0.42; 95% CI, 0.18-0.95); more than two metastases and a low Karnofsky performance status were independent unfavorable factors for brain disease-free survival (p = 0.046; OR = 2.15; 95% CI, 1.01-4.58 and p = 0.003; OR = 30.4; 95% CI, 3.1-296, respectively). Local control rates were 98% +/- 2% and 91% +/- 8.5% at 6 and 24 months. Out of the 61 patients presenting symptoms before radiosurgery, complete symptomatic response was achieved in 12 patients (20%), partial improvement in 25 (41%), stabilization in 7 (11%), and worsening in 4 (6%) related to a progression of the irradiated metastasis. Seven cases of radionecrosis were described and were related to the margin dose (p = 0.03).

Conclusion: Radiosurgery for elderly patients was effective and safe. Age alone should not be a criterion for denying radiosurgery to any patient with brain metastases.
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http://dx.doi.org/10.1016/j.ijrobp.2005.04.037DOI Listing
December 2005

Is there a relationship between c-erbB-1 and c-erbB-2 amplification and protein overexpression in NSCLC?

Lung Cancer 2005 Mar;47(3):325-36

Service des Soins Intensifs et Cancérologie Pulmonaire et Laboratoire d'Investigation Clinique et d'Oncologie Expérimentale HJ Tagnon, Institut Jules Bordet, 1 rue Héger Bordet, Bruxelles, Belgique.

In order to analyse the genetic abnormalities and protein expression of c-erbB-1 and -2, we have performed fluorescence in situ hybridisation (FISH) and immunohistochemistry (IHC) in resected non-small cell lung carcinoma (NSCLC). By IHC (106 patients), 11% of the patients were positive both for c-erbB-1 and -2 protein expression and 47% negative for both proteins. FISH (69 patients) showed a balanced disomy for both c-erbB-1 and -2 in 38%, all other cases had genetic abnormalities in at least one of both genes. c-erbB-2 gene was amplified in less than 10% of the tumours and c-erbB-1 gene was never amplified. c-erbB-2 protein overexpression was observed in only three out of the six cases showing c-erbB-2 amplification. The negative predictive value (NPV) of IHC for gene abnormalities was high for both markers. Median survival time (MST) was respectively of 76 and 174 weeks for patients with or without c-erbB-2 overexpression. Patients with c-erbB-2 amplification had a shorter survival: 125 weeks versus 165 weeks. MST was respectively of 109 and 196 weeks for patients with or without EGFR overexpression and patients with EGFR gene abnormalities had also a shorter survival with MST 136 weeks versus 189 weeks. These differences were not significant. In conclusion, if the majority of NSCLC showed genetic abnormalities in the c-erbB-1 and/or c-erbB-2 gene receptor, amplification could be observed only in a few tumours and was not strictly correlated with protein expression. Finally, survival of patients expressing EGFR and/or c-erbB-2 was slightly shorter.
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http://dx.doi.org/10.1016/j.lungcan.2004.07.047DOI Listing
March 2005

[Stereotaxic irradiation of brain metastasis in elderly patients].

Bull Cancer 2003 Oct;90(10):896-904

Service des tumeurs, Groupe Pitié-Salpêtrière, AP-HP, 47-83, bd de l'hôpital, 75651 Paris.

Aims: Analysis of results of stereotactic irradiation for brain metastases for patients older than 70 years.

Patients And Methods: From January 1994 to January 2002, 53 patients received stereotactic irradiation for a total of 105 brain metastases. There were 26 females and 27 males. Median age was 73 years (70-86). Median interval between cancer diagnosis and brain metastases was 18 months (0-216). Metastases were diagnosed after development of related clinical symptoms in 34 patients (64.1%). Patients were irradiated for one to 6 metastases. Twenty-nine patients (54.7%) were treated for only one metastasis. Median metastasis diameter and volume were respectively 24 mm (5-74.9 mm) and 2.1 cc (0.02-71.3). Eighty-three metastases were supratentorial (79%), and 22 subtentorial (21%). Forty-five underwent only one procedure (85%) and 8 patients underwent a second procedure for one or several new metastases. Three patients were irradiated with whole brain radiotherapy (WBRT) concomitantly of radiosurgery and three patients received WBRT after radiosurgery for development of more than four metastases or for carcinomatous meningitis.

Results: The median follow-up was 8 months (1-33). Median minimum and maximum doses delivered to the metastases were respectively, 16.42 Gy (6.5-20.5) and 20.36 Gy (13.2-41.9). The median overall survival duration was 9 months. Three-, 6-, 12- and 18-month overall survival rates were respectively, 85.6% +/- 5, 65.2% +/- 7.1, 35.5% +/- 7.8 and 26.6% +/- 8. According to unifactorial analysis, two prognostic factors of overall survival were retrieved, extra-cranial disease status and RPAa (Recursive Partitioning Analysis for aged patients) separated in three classes including Karnofsky index performance status and extra-cranial disease status, respectively p = 0.043 et p = 0.016. According to multifactorial analysis only RPAa was an independent prognostic factor of overall survival (p = 0.019, RR: 0.89, 95% confidence interval [0.017-0.47]). Median brain disease-free survival was 12 months. Three-, 6-, 12- and 18-month free-brain disease survival rates were, 81.5% +/- 6.4, 68.7% +/- 8, 47.2% +/- 9.9 and 35.4% +/- 12.6, respectively. No prognostic factor of free-brain disease survival was retrieved. Crude local control rate was 97%. Only three metastases relapsed. Six and 12-month local control rates were 98.6% +/- 1.4 and 88.5% +/- 7.6. Among 34 patients with initial clinical symptoms, one patient presented an aggravation, 9 improved up to complete response (26.5%), 13 patients presented a partial remission (38.2%) and 5 were stabilized (14.7%). For 6 patients, data were not available. We observed 3 radionecroses and 1 hemorrhage of the metastases.

Conclusion: Radiosurgery in the elderly was efficient and well tolerated. Age alone should not be used to deny potentially beneficial radiosurgery to any patient with brain metastases.
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October 2003