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Dutoit R.,Institute Of Recherches Microbiologiques Jm Wiame | Dubois E.,Institute Of Recherches Microbiologiques Jm Wiame | Dubois E.,Luniversite Libre Of Bruxelles | Jacobs E.,Institute Of Recherches Microbiologiques Jm Wiame
Nucleic Acids Research | Year: 2010

Diverse tools are available for performing genetic modifications of microorganisms. However, new methods still need to be developed for performing precise genomic engineering without introducing any undesirable side-alteration. Indeed for functional analyses of genomic elements, as well as for some industrial applications, only the desired mutation should be introduced at the locus considered. This article describes a new approach fulfilling these requirements, based on the use of selection systems consisting in truncated genes encoding dominant-negative transcription factors. We have demonstrated dominant-negative effects mediated by truncated Gal4p and Arg81p proteins in Saccharomyces cerevisiae, interfering with galactose and arginine metabolic pathways, respectively. These genes can be used as positive and negative markers, since they provoke both growth inhibition on substrates and resistance to specific drugs. These selection markers have been successfully used for precisely deleting HO and URA3 in wild yeasts. This genetic engineering approach could be extended to other microorganisms. © The Author(s) 2010. Published by Oxford University Press.


O'Sullivan C.C.,U.S. National Cancer Institute | Bradbury I.,Frontier Science | Campbell C.,Frontier Science | Spielmann M.,Institute Of Cancerologie Gustave Roussy | And 12 more authors.
Journal of Clinical Oncology | Year: 2015

Purpose: We compared efficacy of trastuzumab versus no trastuzumab in patients with small (≤ 2 cm) human epidermal growth factor receptor 2 (HER2) -positive breast cancer treated in randomized trials. Methods: A meta-analysis was conducted using data from five of the six adjuvant trastuzumab trials. Efficacy end points were disease-free survival (DFS) and overall survival (OS). Separate analyses were prospectively planned for hormone receptor (HR) -positive and HR-negative cohorts. Random effect models and Yusuf-Peto fixed effects models assessed the impact of heterogeneity on baseline hazards and treatment effects across studies. Peto-Pike cumulative incidence estimates were stratified by study and nodal status. Results: Median follow-up time was 8 years. For 2,263 patients with HR-positive disease, 8-year cumulative incidence rates comparing trastuzumab versus no trastuzumab were 17.3% versus 24.3% (P < .001) for DFS and 7.8% versus 11.6% (P = .005) for OS, respectively; for 1,092 HR-positive patients with zero or one positive lymph nodes, results were 12.7% versus 19.4% (P = .005) for DFS and 5.3% versus 7.4% (P = .12) for OS, respectively. For 1,957 patients with HR-negative disease, 8-year cumulative incidence rates were 24.0% versus 33.4% (P < .001) for DFS and 12.4% versus 21.2% (P < .001) for OS, respectively; for 1,040 HR-negative patients with zero or one positive lymph nodes, results were 20.4% versus 26.3% (P = .05) for DFS and 8.2% versus 12.2% (P = .084) for OS, respectively. Conclusion: Women with HER2-positive tumors ≤ 2 cm in the randomized trastuzumab trials derived substantial DFS and OS benefit from adjuvant trastuzumab. Trastuzumab-treated patients with HR-positive disease and ≤ one positive lymph node may be candidates for trials assessing less aggressive treatment approaches. © 2015 by American Society of Clinical Oncology.


Naslim N.,Armagh Observatory | Jeffery C.S.,Armagh Observatory | Ahmad A.,Armagh Observatory | Behara N.,Armagh Observatory | And 3 more authors.
Astrophysics and Space Science | Year: 2010

As part of an extended study of the surface abundances of extremely helium-rich hot subdwarfs, high-resolution optical échelle spectra of the three helium-rich subdwarf B stars LB 1766, SB 21 and BPS 22940-0009 are presented. Opacity-sampled line-blanketed model atmospheres have been used to derive atmospheric properties and surface abundances. All three stars are moderately metal-poor compared with the Sun ([Fe/H]≈-0. 4). The first two stars are nitrogen-rich He-sdBs, while the third is a carbon-rich He-sdB. The surface composition and locus of single N-rich He-sdBs are currently best explained by the merger of two helium white dwarfs. C-rich He-sdBs require further investigation. © 2010 Springer Science+Business Media B.V.


Loi S.,Institute Jules Bordet | Loi S.,Breast International Group BIG Headquarters | De Azambuja E.,Data Center | Pugliano L.,Breast International Group BIG Headquarters | And 4 more authors.
Current Opinion in Oncology | Year: 2011

Purpose of Review: There have been recent new developments in the treatment of breast cancer that over-expresses HER2 (ERRB2/HER2 positive) and the mechanistic understanding of trastuzumab response. We review these findings and reflect on how they may influence the next generation of clinical trials in this breast cancer subtype. Recent Findings: Two recent trials in the neoadjuvant setting report that treatment with dual anti-HER2 agents was superior, in terms of rates of pathological complete response, to trastuzumab alone. Recent data also highlight that HER2 positive disease is biologically different according to estrogen receptor status and for long lasting clinical remissions, anti-HER2 therapy also seems to require an effective adaptive immune response. Summary: We are currently in a very exciting era for therapeutic approaches in HER2 positive disease. Recent data suggest that intensive chemotherapy regimens may not be required for some women if we can determine the most potent combinations of signal inhibitors. We also propose that different clinical trials may need to be designed for HER2 positive breast cancer according to estrogen receptor status and consider incorporating immunotherapeutic approaches. © 2011 Wolters Kluwer Health | Lippincott Williams & Wilkins.


Zardavas D.,Luniversite Libre Of Bruxelles | Bozovic-Spasojevic I.,Luniversite Libre Of Bruxelles | De Azambuja E.,Luniversite Libre Of Bruxelles
Current Opinion in Oncology | Year: 2012

Purpose of Review: Many antihuman epidermal growth factor receptor (anti-HER2)-targeted agents, covering a broad spectrum of mechanisms of action, have been recently developed. The concept of dual anti-HER2 blockade has been preclinically and clinically assessed with positive results. In this article, the authors review the biologic rationale for dual HER2 blockade, along with the clinical findings. Recent Findings: Dual anti-HER2 blockade has been assessed in the metastatic setting, including with chemotherapy-free regimens, leading to impressive responses, even in heavily pretreated patients. In the neoadjuvant setting, dual anti-HER2 blockade combinations and chemotherapy have almost doubled the rates of pathologic complete response compared to single anti-HER2 therapy. Similar strategies are now actively being pursued in the adjuvant setting and, it is hoped, will improve the outcome of many patients with HER2-positive breast cancer. Summary: Combining different anti-HER2-targeted agents represents a promising therapeutic strategy, now reaching clinical practice. There are major clinical challenges yet to be resolved, rising from the increasing number of potential combinations and their mechanisms of resistance. Smartly designed clinical trials are required to address these challenges and perhaps to define a subset of patients that can be spared chemotherapy. © 2012 Wolters Kluwer Health | Lippincott Williams & Wilkins.


Pirson M.,Luniversite Libre Of Bruxelles | Delo C.,Luniversite Libre Of Bruxelles | Martins D.,Luniversite Libre Of Bruxelles | Leclercq P.,Luniversite Libre Of Bruxelles
European Journal of Health Economics | Year: 2011

Objectives: Objectives of this article are to evaluate the possibility to create a CW scale by pathology on the basis of cost data from Belgian hospitals, to compare several methodologies to create this CW scale, and to evaluate the financial impact of a modification of the financing system on hospitals' income. Methods: CW scales were elaborated according to various methodologies in order to isolate the scale allowing the most adequate financing system, i.e. approaching the real costs as much as possible. Twelve scales were created. They vary according to the type of data used, according to DRGs and severities of illness included within the scale, and according to the variable used in order to isolate outliers. Results: For a similar case-mix, Hospitals H2 and H5 would see their financing increased through a prospective system based on the selected CW scale (No. 6). This modification would generate a reduction in financing going from -1 to -9% according to hospitals. Conclusions: The cost database created made it possible to create a CW scale according to a technique which could constitute the first step of a PPS if advantages of a such financing system were established. In the Belgian context, it would be probably judicious to envisage regional databases allowing diversified methodological approaches whose results would be confronted, discussed, and coordinated at the federal level. © 2010 Springer-Verlag.


PubMed | Luniversite Libre Of Bruxelles
Type: Journal Article | Journal: Current opinion in oncology | Year: 2011

There have been recent new developments in the treatment of breast cancer that over-expresses HER2 (ERRB2/HER2 positive) and the mechanistic understanding of trastuzumab response. We review these findings and reflect on how they may influence the next generation of clinical trials in this breast cancer subtype.Two recent trials in the neoadjuvant setting report that treatment with dual anti-HER2 agents was superior, in terms of rates of pathological complete response, to trastuzumab alone. Recent data also highlight that HER2 positive disease is biologically different according to estrogen receptor status and for long lasting clinical remissions, anti-HER2 therapy also seems to require an effective adaptive immune response.We are currently in a very exciting era for therapeutic approaches in HER2 positive disease. Recent data suggest that intensive chemotherapy regimens may not be required for some women if we can determine the most potent combinations of signal inhibitors. We also propose that different clinical trials may need to be designed for HER2 positive breast cancer according to estrogen receptor status and consider incorporating immunotherapeutic approaches.


PubMed | Luniversite Libre Of Bruxelles
Type: Journal Article | Journal: Current opinion in oncology | Year: 2012

Many antihuman epidermal growth factor receptor (anti-HER2)-targeted agents, covering a broad spectrum of mechanisms of action, have been recently developed. The concept of dual anti-HER2 blockade has been preclinically and clinically assessed with positive results. In this article, the authors review the biologic rationale for dual HER2 blockade, along with the clinical findings.Dual anti-HER2 blockade has been assessed in the metastatic setting, including with chemotherapy-free regimens, leading to impressive responses, even in heavily pretreated patients. In the neoadjuvant setting, dual anti-HER2 blockade combinations and chemotherapy have almost doubled the rates of pathologic complete response compared to single anti-HER2 therapy. Similar strategies are now actively being pursued in the adjuvant setting and, it is hoped, will improve the outcome of many patients with HER2-positive breast cancer.Combining different anti-HER2-targeted agents represents a promising therapeutic strategy, now reaching clinical practice. There are major clinical challenges yet to be resolved, rising from the increasing number of potential combinations and their mechanisms of resistance. Smartly designed clinical trials are required to address these challenges and perhaps to define a subset of patients that can be spared chemotherapy.


PubMed | Luniversite Libre Of Bruxelles
Type: Journal Article | Journal: Annals of oncology : official journal of the European Society for Medical Oncology | Year: 2013

Human epidermal growth factor receptor 2 (HER2) overexpression is detected in approximately 15% to 20% of all breast cancers (BCs). A revolutionary change in the prognosis of this subgroup of patients has occurred since trastuzumab therapy was introduced into daily clinical practice. However, because trastuzumab resistance is common, new molecules with complementary and/or synergistic mechanisms of action have been developed. Pertuzumab is a new anti-HER2 humanized monoclonal antibody that prevents the formation of HER2 dimers.A computer-based literature search was carried out using PubMed (keywords: breast neoplasm, dimerization, HER-2, pertuzumab); data reported at international meetings are included.This paper describes pertuzumabs mechanism of action, safety, and role in HER2-positive BCs. It also explores the role of pertuzumab as a single agent or combined with trastuzumab by reviewing data from preclinical research to ongoing clinical trials. Recently published trials, particularly the CLEOPATRA study, highlight the efficacy, tolerability, and increase in disease-free survival associated with this novel agent when combined with trastuzumab.The pertuzumab and trastuzumab anti-HER2 dual blockade is likely to represent a substantial advance for patients with HER2-positive BCs and a new milestone on the way to personalized medicine.

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