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Feuerhahn S.,French Institute of Health and Medical Research | Giraudon C.,French Institute of Health and Medical Research | Martinez-Diez M.,PharmaMar | Bueren-Calabuig J.A.,University of Alcalá | And 4 more authors.
Chemistry and Biology | Year: 2011

Trabectedin and Zalypsis are two potent anticancer tetrahydroisoquinoline alkaloids that can form a covalent bond with the amino group of a guanine in selected triplets of DNA duplexes and eventually give rise to double-strand breaks. Using well-defined in vitro and in vivo assays, we show that the resulting DNA adducts stimulate, in a concentration-dependent manner, cleavage by the XPF/ERCC1 nuclease on the strand opposite to that bonded by the drug. They also inhibit RNA synthesis by: (1) preventing binding of transcription factors like Sp1 to DNA, and (2) arresting elongating RNA polymerase II at the same nucleotide position regardless of the strand they are located on. Structural models provide a rationale for these findings and highlight the similarity between this type of DNA modification and an interstrand crosslink. © 2011 Elsevier Ltd All rights reserved.


Hostettler A.,University of Strasbourg | Hostettler A.,Institute Of Recherche Contre Les Cancers Of Lappareil Digestif | George D.,University of Strasbourg | Remond Y.,University of Strasbourg | And 3 more authors.
Computer Methods and Programs in Biomedicine | Year: 2010

This article presents a method of predictive simulation, patient-dependant, in real time of the abdominal organ positions during free breathing. The method, that considers both influence of the abdominal breathing and thoracic breathing, needs a tracking of the patient skin and a model of the patient-specific modification of the diaphragm shape. From a measurement of the abdomen viscera kinematic during free breathing, we evaluate through a finite element analysis, the stress field sustained by the organs for a hyperelastic mechanical behaviour using large strain theory. From this analysis, we deduce an in vivo Poisson's ratio and a homogeneous bulk modulus of the liver and kidneys, and compare it to the ones in vitro available in the literature. © 2010 Elsevier Ireland Ltd.


Chatelin S.,University of Strasbourg | Oudry J.,University of Strasbourg | Oudry J.,Echosens | Perichon N.,University of Strasbourg | And 4 more authors.
Biorheology | Year: 2011

Understanding the mechanical properties of human liver is one of the most critical aspects of its numerical modeling for medical applications or impact biomechanics. Generally, model constitutive laws come from in vitro data. However, the elastic properties of liver may change significantly after death and with time. Furthermore, in vitro liver elastic properties reported in the literature have often not been compared quantitatively with in vivo liver mechanical properties on the same organ. In this study, both steps are investigated on porcine liver. The elastic property of the porcine liver, given by the shear modulus G, was measured by both Transient Elastography (TE) and Dynamic Mechanical Analysis (DMA). Shear modulus measurements were realized on in vivo and in vitro liver to compare the TE and DMA methods and to study the influence of testing conditions on the liver viscoelastic properties. In vitro results show that elastic properties obtained by TE and DMA are in agreement. Liver tissue in the frequency range from 0.1 to 4 Hz can be modeled by a two-mode relaxation model. Furthermore, results show that the liver is homogeneous, isotropic and more elastic than viscous. Finally, it is shown in this study that viscoelastic properties obtained by TE and DMA change significantly with post mortem time and with the boundary conditions. © 2011 - IOS Press and the authors. All rights reserved.


Afors K.,King's College | Centini G.,Institute Of Recherche Contre Les Cancers Of Lappareil Digestif | Murtada R.,Institute Of Recherche Contre Les Cancers Of Lappareil Digestif | Castellano J.,Institute Of Recherche Contre Les Cancers Of Lappareil Digestif | And 2 more authors.
Best Practice and Research: Clinical Obstetrics and Gynaecology | Year: 2015

Since the 1980s, minimally invasive techniques have been applied to an increasing number and variety of surgical procedures with a gradual increase in the complexity of procedures being successfully performed laparoscopically. In the past, obesity was considered a contraindication to laparoscopy due to the higher risk of co-morbid conditions such as diabetes, hypertension, coronary artery disease and venous thromboembolism. Performing laparoscopic gynaecological procedures in morbidly obese patients is no longer a rare phenomenon; however, it does necessitate changes in clinical practice patterns. Understanding of the physiological changes induced by laparoscopy, particularly in obese patients, is important so that these may be counteracted and adverse outcomes avoided. Laparoscopy in obese patients confers certain advantages such as shorter hospital stay, less post-operative pain and fewer wound infections. In addition to these benefits, minimal-access surgery has been demonstrated as safe and effective in obese patients; however, specific surgical strategies and operative techniques may need to be adopted. © 2015 Elsevier Ltd. All rights reserved.


Grant
Agency: Cordis | Branch: FP7 | Program: CP | Phase: ICT-2007.5.3 | Award Amount: 5.46M | Year: 2008

In 2006, over 45.000 European citizens died of cirrhosis of the liver and 44,000 additional citizens of liver cancer, knowing that the same year 48,700 new liver cancer cases were declared. Surgical procedures remain the options that offer the foremost success rate against such pathologies. Regretfully, surgery is not so frequent due to several limitations. Indeed, eligibility for liver surgery is based on the minimum safety liver volume remaining after resection (standardized FLR), but this minimum value varies over time and from one patient to another according to biological and mechanical properties of the liver. Since 1996, a large set of preoperative planning software has been developed, but all of them provide only the volume of the liver before and after resection. However interesting, this limited information is not sufficient to improve the rate of surgical eligibility. PASSPORT for Liver Surgery aims at overcoming these limitations by offering a patient-specific modelling that combines anatomical, mechanical, appearance and biological preoperative modelled information in a unified model of the patient. This first complete Virtual liver will be developed in an Open Source Framework allowing vertical integration of biomedical data, from macroscopic to microscopic patient information. From these models, a dynamic liver modelling will provide the patient-specific minimum safety standardized FLR in an educative and preoperative planning simulator allowing to predict the feasibility of the gesture and surgeons ability to realise it. Thus, any patient will be able to know the risk level of a proposed therapy. Finally, we expect to increase the rate of surgical treatment so as to save patients with a liver pathology. To reach these purposes, PASSPORT is composed of a high level partnership between internationally renowned surgical teams, leading European research teams in surgical simulation and an international leading company in surgical instrumentation.


PubMed | Institute Of Recherche Contre Les Cancers Of Lappareil Digestif, University of Strasbourg and King's College
Type: Journal Article | Journal: Best practice & research. Clinical obstetrics & gynaecology | Year: 2015

Since the 1980s, minimally invasive techniques have been applied to an increasing number and variety of surgical procedures with a gradual increase in the complexity of procedures being successfully performed laparoscopically. In the past, obesity was considered a contraindication to laparoscopy due to the higher risk of co-morbid conditions such as diabetes, hypertension, coronary artery disease and venous thromboembolism. Performing laparoscopic gynaecological procedures in morbidly obese patients is no longer a rare phenomenon; however, it does necessitate changes in clinical practice patterns. Understanding of the physiological changes induced by laparoscopy, particularly in obese patients, is important so that these may be counteracted and adverse outcomes avoided. Laparoscopy in obese patients confers certain advantages such as shorter hospital stay, less post-operative pain and fewer wound infections. In addition to these benefits, minimal-access surgery has been demonstrated as safe and effective in obese patients; however, specific surgical strategies and operative techniques may need to be adopted.


Grekova S.P.,German Cancer Research Center | Aprahamian M.,Institute Of Recherche Contre Les Cancers Of Lappareil Digestif | Daeffler L.,German Cancer Research Center | Leuchs B.,German Cancer Research Center | And 7 more authors.
Cancer Biology and Therapy | Year: 2011

Oncolytic viruses with their capacity to specifically replicate in and kill tumor cells emerged as a novel class of cancer therapeutics. Rat oncolytic parvovirus (H-1PV) was used to treat different types of cancer in preclinical settings and was lately successfully combined with standard gemcitabine chemotherapy in treating pancreatic ductal adenocarcinoma (PDAC) in rats. Our previous work showed that the immune system and particularly the release of interferon-gamma (IFNγ) seem to mediate the anticancer effect of H-1PV in that model. Therefore, we reasoned that the therapeutic properties of H-1PV can be boosted with IFNγ for the treatment of late incurable stages of PDAC like peritoneal carcinomatosis. Rats bearing established orthotopic pancreatic carcinomas with peritoneal metastases were treated with a single intratumoral (i.t.) or intraperitoneal (i.p.) injection of 5×10 8 plaque forming units of H-1PV with or without concomitant IFNγ application. Intratumoral injection proved to be more effective than the intraperitoneal route in controlling the growth of both the primary pancreatic tumors and peritoneal carcinomatosis, accompanied by migration of virus from primary to metastatic deposits. Concomitant i.p. treatment of H-1PV with recIFNγ resulted in improved therapeutic effect yielding an extended animal survival, compared with i.p. treatment with H-1PV alone. IFNγ application enhanced the H-1PV-induced peritoneal macrophage and splenocyte responses against tumor cells while causing a significant reduction in the titers of H1-PV-neutralising antibodies in ascitic fluid. Thus, IFNγ co-application together with H-1PV might be considered as a novel therapeutic option to improve the survival of PDAC patients with peritoneal carcinomatosis. © 2011 Landes Bioscience.


Woodard G.,Stanford University | Ahmed S.,Stanford University | Podelski V.,Institute Of Recherche Contre Les Cancers Of Lappareil Digestif | Hernandez-Boussard T.,Stanford University | And 2 more authors.
British Journal of Surgery | Year: 2012

Background: Obese men have lower serum levels of testosterone, dehydroepiandrosterone (DHEA) and prostate-specific antigen (PSA), but an increased risk of dying from prostate cancer. The aim of this study was to examine the effect of surgically induced weight loss on serum testosterone, DHEA and PSA levels in obese men. Methods: Consecutive men undergoing Roux-en-Y gastric bypass (RYGB) participated in a prospective, longitudinal study. Main outcomes were changes were body mass index (BMI), percentage excess weight loss, serum levels of testosterone, DHEA and PSA, PSA mass and plasma volume, measured before operation and 3, 6 and 12 months later. Results: In 64 patients, mean BMI fell from 48.2 kg/m 2 before operation to 39.2, 35.6 and 32.4 kg/m 2 at 3, 6 and 12 months after RYGB. Testosterone levels rose significantly from 259 ng/dl to 386, 452 and 520 ng/dl respectively. Serum PSA levels increased significantly from 0.51 ng/ml to 0.67 ng/ml at 12 months. There were no significant changes in DHEA or PSA mass. Conclusion: RYGB normalizes the serum testosterone level. PSA levels increase with weight loss and may be inversely correlated with changes in plasma volume, indicating that PSA levels may be artificially low in obese men owing to haemodilution. Copyright © 2012 British Journal of Surgery Society Ltd. Published by John Wiley & Sons, Ltd.


Li J.,German Cancer Research Center | Bonifati S.,German Cancer Research Center | Hristov G.,German Cancer Research Center | Marttila T.,German Cancer Research Center | And 9 more authors.
EMBO Molecular Medicine | Year: 2013

The rat parvovirus H-1PV has oncolytic and tumour-suppressive properties potentially exploitable in cancer therapy. This possibility is being explored and results are encouraging, but it is necessary to improve the oncotoxicity of the virus. Here we show that this can be achieved by co-treating cancer cells with H-1PV and histone deacetylase inhibitors (HDACIs) such as valproic acid (VPA). We demonstrate that these agents act synergistically to kill a range of human cervical carcinoma and pancreatic carcinoma cell lines by inducing oxidative stress, DNA damage and apoptosis. Strikingly, in rat and mouse xenograft models, H-1PV/VPA co-treatment strongly inhibits tumour growth promoting complete tumour remission in all co-treated animals. At the molecular level, we found acetylation of the parvovirus nonstructural protein NS1 at residues K85 and K257 to modulate NS1-mediated transcription and cytotoxicity, both of which are enhanced by VPA treatment. These results warrant clinical evaluation of H-1PV/VPA co-treatment against cervical and pancreatic ductal carcinomas. © 2013 The Authors. Published by John Wiley and Sons, Ltd on behalf of EMBO.


Grant
Agency: Cordis | Branch: FP7 | Program: CP | Phase: ICT-2007.3.6 | Award Amount: 3.08M | Year: 2008

Miniaturized Stereoscopic Distal Imaging Sensor for Minimally Invasive Surgery (MiniSurg) is a project that aims to research and process converging of miniaturized imaging sensor technologies for the most advanced Minimally Invasive Surgery. It aims to overcome packaging, manufacture and potential distortions of CMOS based miniaturized unit. The integrated unit will be of the higher performances a low cost and disposable sensor. MiniSurgs goal is to provide beyond the present state-of-the-art of stereoscopic natural surgery visualization sensor of up to Euro 10 cost. The system on a chip of 7.5mm in diagonal will be designed for maximum area efficiency, by minimizing electrical contacts areas. The beyond the state of the art stereoscopic imaging performances will be achieved by the research and design of pixel array of 2300 horizontal over 1150 vertical and pixel aspect ratio of 2 width over 3 height, accompanied by significantly low cross talk level ( 10%). MiniSurg project will address unique packaging design and multilevel interfacing to accomplish the system performance goals. In particular MiniSurg will design chip package for the optic mounting. The high accuracy of this assembly (>>10m) will enable to shrink the chip for a minimum of pixel area due to the tolerances during optic assembly. MiniSurg incorporates micron sized lens array, an advanced image sensor module and supplementary software algorithm technologies. The Distal Stereoscopic imaging is achieved by collecting light through a pair of left and right pupils, focusing by the micro lens array, each side on a definite pixel column. The micro lenses are fabricated on the sensitive area of the sensor in a FAB, thus adding minimal cost.

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