Biomechanical model of tumor growth: application to the European ContraCancrum project

This abstract presents the biomechanical model that is used in the European ContraCancrum project, aiming at simulating tumor evolution in the brain and lung. The construction of the finite element model as well as a simulation of tumor growth are shown. The construction of the mesh is fully automatic and is therefore compatible with a clinical application. This biomechanical model will be later combined to a cellular level simulator also developed in the project.

Atlas-based Segmentation of Tumor-bearing Brain Images

In diagnostic neuroradiology as well as in radiation oncology and neurosurgery, there is an increasing demand for accurate segmentation of tumor-bearing brain images. Atlas-based segmentation is an appealing automatic technique thanks to its robustness and versatility. However, atlas-based segmentation of tumor-bearing brain images is challenging due to the confounding effects of the tumor in the patient image. In this article, we provide a brief background on brain tumor imaging and introduce the clinical perspective, before we categorize and review the state of the art in the current literature on atlas-based segmentation for tumor-bearing brain images. We also present selected methods and results from our own research in more detail. Finally, we conclude with a short summary and look at new developments in the field, including requirements for future routine clinical use.

Silence That Can Be Dangerous: A Vignette Study to Assess Healthcare Professionals' Likelihood of Speaking up about Safety Concerns

PURPOSE To investigate the likelihood of speaking up about patient safety in oncology and to clarify the effect of clinical and situational context factors on the likelihood of voicing concerns. PATIENTS AND METHODS 1013 nurses and doctors in oncology rated four clinical vignettes describing coworkers' errors and rule violations in a self-administered factorial survey (65% response rate). Multiple regression analysis was used to model the likelihood of speaking up as outcome of vignette attributes, responder's evaluations of the situation and personal characteristics. RESULTS Respondents reported a high likelihood of speaking up about patient safety but the variation between and within types of errors and rule violations was substantial. Staff without managerial function provided significantly higher levels of decision difficulty and discomfort to speak up. Based on the information presented in the vignettes, 74%-96% would speak up towards a supervisor failing to check a prescription, 45%-81% would point a coworker to a missed hand disinfection, 82%-94% would speak up towards nurses who violate a safety rule in medication preparation, and 59%-92% would question a doctor violating a safety rule in lumbar puncture. Several vignette attributes predicted the likelihood of speaking up. Perceived potential harm, anticipated discomfort, and decision difficulty were significant predictors of the likelihood of speaking up. CONCLUSIONS Clinicians' willingness to speak up about patient safety is considerably affected by contextual factors. Physicians and nurses without managerial function report substantial discomfort with speaking up. Oncology departments should provide staff with clear guidance and trainings on when and how to voice safety concerns.

Hyperthermia-related clinical trials on cancer treatment within the ClinicalTrials.gov registry

PURPOSE Hyperthermia has been shown to improve the effectiveness of chemotherapy and radiotherapy in the treatment of cancer. This paper summarises all recent clinical trials registered in the ClinicalTrials.gov registry. MATERIALS AND METHODS The records of 175,538 clinical trials registered at ClinicalTrials.gov were downloaded on 29 September 2014 and a database was established. We searched this database for hyperthermia or equivalent words. RESULTS A total of 109 trials were identified in which hyperthermia was part of the treatment regimen. Of these, 49 trials (45%) had hyperthermic intraperitoneal chemotherapy after cytoreductive surgery (HIPEC) as the primary intervention, and 14 other trials (13%) were also testing some form of intraperitoneal hyperthermic chemoperfusion. Seven trials (6%) were testing perfusion attempts to other locations (thoracic/pleural n = 4, limb n = 2, hepatic n = 1). Sixteen trials (15%) were testing regional hyperthermia, 13 trials (12%) whole body hyperthermia, seven trials (6%) superficial hyperthermia and two trials (2%) interstitial hyperthermia. One remaining trial tested laser hyperthermia. CONCLUSIONS In contrast to the general opinion, this analysis shows continuous interest and ongoing clinical research in the field of hyperthermia. Interestingly, the majority of trials focused on some form of intraperitoneal hyperthermic chemoperfusion. Despite the high number of active clinical studies, HIPEC is a topic with limited attention at the annual meetings of the European Society for Hyperthermic Oncology and the Society of Thermal Medicine. The registration of on-going clinical trials is of paramount importance for the achievement of a comprehensive overview of available clinical research activities involving hyperthermia.

Enrichment for murine keratinocyte stem cells based on cell surface phenotype

The identification and physical isolation of epithelial stem cells is critical to our understanding of their growth regulation during homeostasis, wound healing, and carcinogenesis. These stem cells remain poorly characterized because of the absence of specific molecular markers that permit us to distinguish them from their progeny, the transit amplifying (TA) cells, which have a more restricted proliferative potential. Cell kinetic analyses have permitted the identification of murine keratinocyte stem cells (KSCs) as slowly cycling cells that retain [3H]thymidine ([3H]Tdr) label, termed label-retaining cells (LRCs), whereas TA cells are visualized as rapidly cycling cells after a single pulse of [3H]Tdr, termed pulse-labeled cells (PLCs). Here, we report on the successful separation of KSCs from TA cells through the combined use of in vivo cell kinetic analysis and fluorescence-activated cell sorting. Specifically, we demonstrate that murine dorsal keratinocytes characterized by their high levels of α6 integrin and low to undetectable expression of the transferrin receptor (CD71) termed α6briCD71dim cells, are enriched for epithelial stem cells because they represent a minor (≈8%) and quiescent subpopulation of small blast-like cells, with a high nuclear:cytoplasmic ratio, containing ≈70% of label-retaining cells, the latter being a well documented characteristic of stem cells. Conversely, TA cells could be enriched in a phenotypically distinct subpopulation termed α6briCD71bri, representing the majority (≈60%) of basal keratinocytes that are actively cycling, and importantly contain ≈70% of [3H]Tdr pulse-labeled cells. Importantly, immunostaining of dorsal skin revealed the presence of CD71dim cells in the hair follicle bulge region, a well documented location for KSCs.

Mannose-6-phosphate/insulin-like growth factor-II receptor is a receptor for retinoic acid

Retinoic acid (RA) exerts diverse biological effects in the control of cell growth in embryogenesis and oncogenesis. These effects of RA are thought to be mediated by the nuclear retinoid receptors. Mannose-6-phosphate (M6P)/insulin-like growth factor-II (IGF-II) receptor is a multifunctional membrane glycoprotein that is known to bind both M6P and IGF-II and function primarily in the binding and trafficking of lysosomal enzymes, the activation of transforming growth factor-β, and the degradation of IGF-II. M6P/IGF-II receptor has recently been implicated in fetal development and carcinogenesis. Despite the functional similarities between RA and the M6P/IGF-II receptor, no direct biochemical link has been established. Here, we show that the M6P/IGF-II receptor also binds RA with high affinity at a site that is distinct from those for M6P and IGF-II, as identified by a photoaffinity labeling technique. We also show that the binding of RA to the M6P/IGF-II receptor enhances the primary functions of this receptor. The biological consequence of the interaction appears to be the suppression of cell proliferation and/or induction of apoptosis. These findings suggest that the M6P/IGF-II receptor mediates a RA response pathway that is important in cell growth regulation. This discovery of the interaction of RA with the M6P/IGF-II receptor may have important implications for our understanding of the roles of RA and the M6P/IGF-II receptor in development, carcinogenesis, and lysosomal enzyme-related diseases.

Amino-terminal Polypeptides of Vimentin Are Responsible for the Changes in Nuclear Architecture Associated with Human Immunodeficiency Virus Type 1 Protease Activity in Tissue Culture Cells

Electron microscopy of human skin fibroblasts syringe-loaded with human immunodeficiency virus type 1 protease (HIV-1 PR) revealed several effects on nuclear architecture. The most dramatic is a change from a spherical nuclear morphology to one with multiple lobes or deep invaginations. The nuclear matrix collapses or remains only as a peripheral rudiment, with individual elements thicker than in control cells. Chromatin organization and distribution is also perturbed. Attempts to identify a major nuclear protein whose cleavage by the protease might be responsible for these alterations were unsuccessful. Similar changes were observed in SW 13 T3 M [vimentin+] cells, whereas no changes were observed in SW 13 [vimentin−] cells after microinjection of protease. Treatment of SW 13 [vimentin−] cells, preinjected with vimentin to establish an intermediate filament network, with HIV-1 PR resulted in alterations in chromatin staining and distribution, but not in nuclear shape. These same changes were produced in SW 13 [vimentin−] cells after the injection of a mixture of vimentin peptides, produced by the cleavage of vimentin to completion by HIV-1 PR in vitro. Similar experiments with 16 purified peptides derived from wild-type or mutant vimentin proteins and five synthetic peptides demonstrated that exclusively N-terminal peptides were capable of altering chromatin distribution. Furthermore, two separate regions of the N-terminal head domain are primarily responsible for perturbing nuclear architecture. The ability of HIV-1 to affect nuclear organization via the liberation of vimentin peptides may play an important role in HIV-1-associated cytopathogenesis and carcinogenesis.

Telomerase inhibitors based on quadruplex ligands selected by a fluorescence assay

The reactivation of telomerase activity in most cancer cells supports the concept that telomerase is a relevant target in oncology, and telomerase inhibitors have been proposed as new potential anticancer agents. The telomeric G-rich single-stranded DNA can adopt in vitro an intramolecular quadruplex structure, which has been shown to inhibit telomerase activity. We used a fluorescence assay to identify molecules that stabilize G-quadruplexes. Intramolecular folding of an oligonucleotide with four repeats of the human telomeric sequence into a G-quadruplex structure led to fluorescence excitation energy transfer between a donor (fluorescein) and an acceptor (tetramethylrhodamine) covalently attached to the 5′ and 3′ ends of the oligonucleotide, respectively. The melting of the G-quadruplex was monitored in the presence of putative G-quadruplex-binding molecules by measuring the fluorescence emission of the donor. A series of compounds (pentacyclic crescent-shaped dibenzophenanthroline derivatives) was shown to increase the melting temperature of the G-quadruplex by 2–20°C at 1 μM dye concentration. This increase in Tm value was well correlated with an increase in the efficiency of telomerase inhibition in vitro. The best telomerase inhibitor showed an IC50 value of 28 nM in a standard telomerase repeat amplification protocol assay. Fluorescence energy transfer can thus be used to reveal the formation of four-stranded DNA structures, and its stabilization by quadruplex-binding agents, in an effort to discover new potent telomerase inhibitors.

A yeast gene, MGS1, encoding a DNA-dependent AAA+ ATPase is required to maintain genome stability

Changes in DNA superhelicity during DNA replication are mediated primarily by the activities of DNA helicases and topoisomerases. If these activities are defective, the progression of the replication fork can be hindered or blocked, which can lead to double-strand breaks, elevated recombination in regions of repeated DNA, and genome instability. Hereditary diseases like Werner's and Bloom's Syndromes are caused by defects in DNA helicases, and these diseases are associated with genome instability and carcinogenesis in humans. Here we report a Saccharomyces cerevisiae gene, MGS1 (Maintenance of Genome Stability 1), which encodes a protein belonging to the AAA+ class of ATPases, and whose central region is similar to Escherichia coli RuvB, a Holliday junction branch migration motor protein. The Mgs1 orthologues are highly conserved in prokaryotes and eukaryotes. The Mgs1 protein possesses DNA-dependent ATPase and single-strand DNA annealing activities. An mgs1 deletion mutant has an elevated rate of mitotic recombination, which causes genome instability. The mgs1 mutation is synergistic with a mutation in top3 (encoding topoisomerase III), and the double mutant exhibits severe growth defects and markedly increased genome instability. In contrast to the mgs1 mutation, a mutation in the sgs1 gene encoding a DNA helicase homologous to the Werner and Bloom helicases suppresses both the growth defect and the increased genome instability of the top3 mutant. Therefore, evolutionarily conserved Mgs1 may play a role together with RecQ family helicases and DNA topoisomerases in maintaining proper DNA topology, which is essential for genome stability.

Interacção mente-matéria com intenção terapêutica : breve revisão sobre imunologia, oncologia e dor moduladas pela hipnose

Trabalho Final do Curso de Mestrado Integrado em Medicina, Faculdade de Medicina, Universidade de Lisboa, 2014

Émergence et développement de l’oncologie au Québec : collaboration, compétition et défis organisationnels, 1900-2005

Objectifs : le principal objectif de notre projet doctoral consiste à mettre en relief les transformations qui ont marqué le développement de l’oncologie et de la lutte contre le cancer au Québec au 20e siècle. Pour ce faire, nous nous sommes penchées sur trois niveaux d’analyse : 1) le niveau micro aborde l’organisation des services médicaux au sein d’une organisation hospitalière, soit l’Hôtel-Dieu de Québec. 2) Le niveau méso analyse une lutte professionnelle, soit la lutte entre les hématologues et les oncologues médicaux pour la reconnaissance de l’oncologie médicale. 3) Le niveau macro s’intéresse à l’organisation de la lutte contre le cancer à travers la province de Québec et aux différents modèles organisationnels créés. Principale hypothèse : l’émergence et la transformation de l’oncologie et de la lutte contre le cancer ont été influencées des rapports de collaboration et de compétition entre les acteurs impliqués en oncologie. En effet, il apparaît que ce champ se trouve en tension entre l’obligation de collaborer pour offrir des services de qualité aux patients et les dynamiques professionnelles et/ou organisationnelles. Cadre théorique : un cadre théorique a été développé pour chacun des niveaux d’analyse. Le niveau micro s’inspire des travaux de Frickel, Abbott et Strauss et s’intéresse plus particulièrement aux négociations entourant l’ordre social au sein d’un hôpital universitaire; le niveau méso emploie les travaux de Bourdieu et Abbott pour analyser la lutte entre deux spécialités médicales pour le contrôle des agents de chimiothérapie; et le niveau macro, de la sociologie des organisations et de la théorie néo-institutionnaliste pour mettre en relief l’émergence et la transformation de la lutte contre le cancer au Québec au 20e siècle. Méthodologie : l’approche de l’étude de cas a été adoptée et chaque niveau d’analyse constitue une étude de cas à part entière. Le corpus de données se compose de données archivistiques recueillies dans 10 centres d’archives canadiens, et de données d’entrevues. Une soixantaine d’entrevues avec des oncologues, des professionnels de la santé, des gestionnaires, des chercheurs et des fonctionnaires ont été réalisées. Conclusion : les différents niveaux d’analyse offrent différentes contributions qui leurs sont propres, mais l’ensemble de la thèse tend à mettre en relief la complexité du changement organisationnel à travers un perpétuel processus de définition et de redéfinition des frontières professionnelles et des organisations en raison du développement des connaissances scientifiques, des technologies, des expertises professionnelles et de l’environnement social, politique et économique.

Émergence et développement de l’oncologie au Québec : collaboration, compétition et défis organisationnels, 1900-2005

Objectifs : le principal objectif de notre projet doctoral consiste à mettre en relief les transformations qui ont marqué le développement de l’oncologie et de la lutte contre le cancer au Québec au 20e siècle. Pour ce faire, nous nous sommes penchées sur trois niveaux d’analyse : 1) le niveau micro aborde l’organisation des services médicaux au sein d’une organisation hospitalière, soit l’Hôtel-Dieu de Québec. 2) Le niveau méso analyse une lutte professionnelle, soit la lutte entre les hématologues et les oncologues médicaux pour la reconnaissance de l’oncologie médicale. 3) Le niveau macro s’intéresse à l’organisation de la lutte contre le cancer à travers la province de Québec et aux différents modèles organisationnels créés. Principale hypothèse : l’émergence et la transformation de l’oncologie et de la lutte contre le cancer ont été influencées des rapports de collaboration et de compétition entre les acteurs impliqués en oncologie. En effet, il apparaît que ce champ se trouve en tension entre l’obligation de collaborer pour offrir des services de qualité aux patients et les dynamiques professionnelles et/ou organisationnelles. Cadre théorique : un cadre théorique a été développé pour chacun des niveaux d’analyse. Le niveau micro s’inspire des travaux de Frickel, Abbott et Strauss et s’intéresse plus particulièrement aux négociations entourant l’ordre social au sein d’un hôpital universitaire; le niveau méso emploie les travaux de Bourdieu et Abbott pour analyser la lutte entre deux spécialités médicales pour le contrôle des agents de chimiothérapie; et le niveau macro, de la sociologie des organisations et de la théorie néo-institutionnaliste pour mettre en relief l’émergence et la transformation de la lutte contre le cancer au Québec au 20e siècle. Méthodologie : l’approche de l’étude de cas a été adoptée et chaque niveau d’analyse constitue une étude de cas à part entière. Le corpus de données se compose de données archivistiques recueillies dans 10 centres d’archives canadiens, et de données d’entrevues. Une soixantaine d’entrevues avec des oncologues, des professionnels de la santé, des gestionnaires, des chercheurs et des fonctionnaires ont été réalisées. Conclusion : les différents niveaux d’analyse offrent différentes contributions qui leurs sont propres, mais l’ensemble de la thèse tend à mettre en relief la complexité du changement organisationnel à travers un perpétuel processus de définition et de redéfinition des frontières professionnelles et des organisations en raison du développement des connaissances scientifiques, des technologies, des expertises professionnelles et de l’environnement social, politique et économique.