Apport des technologies mobiles à l'amélioration des soins en cancérologie

Réalisé en cotutelle avec Claude Sicotte PhD Université de Montréal et le Pr. Étienne Minvielle École des Hautes Études en Santé Publique à Paris.L’amélioration de la prise en charge du cancer est un enjeu de santé publique important compte tenu des impacts de cette maladie pour la santé publique. Les technologies de l’information et de communication (TIC) sont perçues comme une solution pouvant contribuer à l’amélioration de cette prise en charge. Malgré cela, peu d’expériences évaluent leur utilisation dans un contexte de coordination des soins en cancérologie. Le but de ce mémoire est d’apprécier comment les TIC peuvent être utilisées pour améliorer la coordination des soins en cancérologie et de décrire quelles sont les stratégies pouvant permettre leur succès. Deux articles ont été rédigés avec chacun un objectif rattaché au but global du mémoire. L’objectif du premier article est de rassembler les connaissances existantes relatives aux usages des TIC pouvant être à même de fournir une amélioration de la coordination des soins en cancérologie. Il présente les résultats d’une revue de littérature ayant identifié six types d’usages des TIC pouvant être utilisés dans un parcours coordonné. Il propose six recommandations pouvant contribuer à la réussite de leur conception et de leur implantation. Les plus importantes sont la planification rigoureuse du design de l’intervention et l’amélioration des stratégies de gestion de projet. Le deuxième article a comme objectif de connaître la perception des professionnels de soins par rapport à l’utilisation des technologies mobiles. Il analyse les perceptions et les attentes de professionnels oeuvrant dans un centre de cancérologie spécialisé (France) à partir de 10 entretiens faits auprès d’individus rattachés à divers services. Leur analyse permet de constater l’attitude favorable à l’utilisation de TIC mobiles en cancérologie et le peu de craintes associées aux impacts néfastes qu’il pourrait avoir. Elle met en évidence l’importance des enjeux organisationnels nécessaire à la mise en place et au succès de cette intervention. Ces deux études permettent de constater les rapprochements et les écarts entre les usages et recommandations tirés de la littérature et les perceptions des répondants en cancérologie. Mots-clés : technologies de l’information, cancérologie, parcours coordonné, étude de cas, revue de littérature, coordination des soins, enjeux organisationnels, usages des TIC.The impact of cancer care is a major public health issue, mainly because of both its major health and economic impacts. The use of information technologies (IT) is seen as a solution that can contribute to reduce the load associated with cancer. Despite this, there are only few experiments evaluating their use in the cancer care. The purpose of this memoir is to find ways how IT can be used to improve this situation and describe what strategies can help them succeed. To do so, this memoir presents two articles each pursuing a goal related to that global objective. The first article aims to gather existing knowledge on how the use of IT may provide better coordination of cancer care. It presents the results of a literature review that built a typology of six uses in which IT can be used to provide better care coordination. It also offers six recommendations to insure the success of their design and their implementation. The two most important ones are rigorous planning and strong intervention design. The second article reports and analyse the perception of health professionals in relation to the use of mobile technologies in a cancer care setting. It presents data gathered from 10 interviews conducted a the cancer center (France). Their analysis shows that most of them have a positive attitude towards the use of IT in cancer care. It also denotes some of the fears associated with the adverse impacts it may bring. The results highlights the importance of considering organizational issues for the implementation of sucessful interventions. These two studies show that there are many similarities and few differences between the usages and recommendations from the literature and the perceptions of the professionnals working in a specialized cancer care center

A Tri-Marker Proliferation Index Predicts Biochemical Recurrence after Surgery for Prostate Cancer

Prostate cancer exhibits tremendous variability in clinical behavior, ranging from indolent to lethal disease. Better prognostic markers are needed to stratify patients for appropriately aggressive therapy. By expression profiling, we can identify a proliferation signature variably expressed in prostate cancers. Here, we asked whether one or more tissue biomarkers might capture that information, and provide prognostic utility. We assayed three proliferation signature genes: MKI67 (Ki-67; also a classic proliferation biomarker), TOP2A (DNA topoisomerase II, alpha), and E2F1 (E2F transcription factor 1). Immunohistochemical staining was evaluable on 139 radical prostatectomy cases (in tissue microarray format), with a median clinical follow-up of eight years. Each of the three proliferation markers was by itself prognostic. Notably, combining the three markers together as a “proliferation index” (0 or 1, vs. 2 or 3 positive markers) provided superior prognostic performance (hazard ratio = 2.6 (95% CI: 1.4–4.9); P = 0.001). In a multivariate analysis that included preoperative serum prostate specific antigen (PSA) levels, Gleason grade and pathologic tumor stage, the composite proliferation index remained a significant predictor (P = 0.005). Analysis of receiver-operating characteristic (ROC) curves confirmed the improved prognostication afforded by incorporating the proliferation index (compared to the clinicopathologic data alone). Our findings highlight the potential value of a multi-gene signature-based diagnostic, and define a tri-marker proliferation index with possible utility for improved prognostication and treatment stratification in prostate cancer

A modern nihilism

Presents the author's evolving views of the best current positions on certain core philosophical and psychological problems as they developed over time. These positions together suggest a skeptical or nihilist perspective modified by evolutionary psychology and contemporary philosophy that embraces our desire to live as best we can and the relative and psychological reality of values, free will and other phenomena while recognizing limitations on their foundations and our understanding. The below makes no claims to originality for most of the ideas expressed, drawing on a range of mostly unreferenced texts that will be familiar to philosophers and psychologists working in this area

The asparagine-transamidosome from Helicobacter pylori: a dual-kinetic mode in non-discriminating aspartyl-tRNA synthetase safeguards the genetic code

Helicobacter pylori catalyzes Asn-tRNAAsn formation by use of the indirect pathway that involves charging of Asp onto tRNAAsn by a non-discriminating aspartyl-tRNA synthetase (ND-AspRS), followed by conversion of the mischarged Asp into Asn by the GatCAB amidotransferase. We show that the partners of asparaginylation assemble into a dynamic Asn-transamidosome, which uses a different strategy than the Gln-transamidosome to prevent the release of the mischarged aminoacyl-tRNA intermediate. The complex is described by gel-filtration, dynamic light scattering and kinetic measurements. Two strategies for asparaginylation are shown: (i) tRNAAsn binds GatCAB first, allowing aminoacylation and immediate transamidation once ND-AspRS joins the complex; (ii) tRNAAsn is bound by ND-AspRS which releases the Asp-tRNAAsn product much slower than the cognate Asp-tRNAAsp; this kinetic peculiarity allows GatCAB to bind and transamidate Asp-tRNAAsn before its release by the ND-AspRS. These results are discussed in the context of the interrelation between the Asn and Gln-transamidosomes which use the same GatCAB in H. pylori, and shed light on a kinetic mechanism that ensures faithful codon reassignment for Asn

Helicobacter pylori CagA Disrupts Epithelial Patterning by Activating Myosin Light Chain

Helicobacter pylori infection is a leading cause of ulcers and gastric cancer. We show that expression of the H. pylori virulence factor CagA in a model Drosophila melanogaster epithelium induces morphological disruptions including ectopic furrowing. We find that CagA alters the distribution and increases the levels of activated myosin regulatory light chain (MLC), a key regulator of epithelial integrity. Reducing MLC activity suppresses CagA-induced disruptions. A CagA mutant lacking EPIYA motifs (CagAEPISA) induces less epithelial disruption and is not targeted to apical foci like wild-type CagA. In a cell culture model in which CagAEPISA and CagA have equivalent subcellular localization, CagAEPISA is equally potent in activating MLC. Therefore, in our transgenic system, CagA is targeted by EPIYA motifs to a specific apical region of the epithelium where it efficiently activates MLC to disrupt epithelial integrity

Genomic Profiling Identifies GATA6 as a Candidate Oncogene Amplified in Pancreatobiliary Cancer

Pancreatobiliary cancers have among the highest mortality rates of any cancer type. Discovering the full spectrum of molecular genetic alterations may suggest new avenues for therapy. To catalogue genomic alterations, we carried out array-based genomic profiling of 31 exocrine pancreatic cancers and 6 distal bile duct cancers, expanded as xenografts to enrich the tumor cell fraction. We identified numerous focal DNA amplifications and deletions, including in 19% of pancreatobiliary cases gain at cytoband 18q11.2, a locus uncommonly amplified in other tumor types. The smallest shared amplification at 18q11.2 included GATA6, a transcriptional regulator previously linked to normal pancreas development. When amplified, GATA6 was overexpressed at both the mRNA and protein levels, and strong immunostaining was observed in 25 of 54 (46%) primary pancreatic cancers compared to 0 of 33 normal pancreas specimens surveyed. GATA6 expression in xenografts was associated with specific microarray gene-expression patterns, enriched for GATA binding sites and mitochondrial oxidative phosphorylation activity. siRNA mediated knockdown of GATA6 in pancreatic cancer cell lines with amplification led to reduced cell proliferation, cell cycle progression, and colony formation. Our findings indicate that GATA6 amplification and overexpression contribute to the oncogenic phenotypes of pancreatic cancer cells, and identify GATA6 as a candidate lineage-specific oncogene in pancreatobiliary cancer, with implications for novel treatment strategies

Defining the Critical Hurdles in Cancer Immunotherapy

ABSTRACT: Scientific discoveries that provide strong evidence of antitumor effects in preclinical models often encounter significant delays before being tested in patients with cancer. While some of these delays have a scientific basis, others do not. We need to do better. Innovative strategies need to move into early stage clinical trials as quickly as it is safe, and if successful, these therapies should efficiently obtain regulatory approval and widespread clinical application. In late 2009 and 2010 the Society for Immunotherapy of Cancer (SITC), convened an "Immunotherapy Summit" with representatives from immunotherapy organizations representing Europe, Japan, China and North America to discuss collaborations to improve development and delivery of cancer immunotherapy. One of the concepts raised by SITC and defined as critical by all parties was the need to identify hurdles that impede effective translation of cancer immunotherapy. With consensus on these hurdles, international working groups could be developed to make recommendations vetted by the participating organizations. These recommendations could then be considered by regulatory bodies, governmental and private funding agencies, pharmaceutical companies and academic institutions to facilitate changes necessary to accelerate clinical translation of novel immune-based cancer therapies. The critical hurdles identified by representatives of the collaborating organizations, now organized as the World Immunotherapy Council, are presented and discussed in this report. Some of the identified hurdles impede all investigators, others hinder investigators only in certain regions or institutions or are more relevant to specific types of immunotherapy or first-in-humans studies. Each of these hurdles can significantly delay clinical translation of promising advances in immunotherapy yet be overcome to improve outcomes of patients with cancer

Defining the critical hurdles in cancer immunotherapy

Scientific discoveries that provide strong evidence of antitumor effects in preclinical models often encounter significant delays before being tested in patients with cancer. While some of these delays have a scientific basis, others do not. We need to do better. Innovative strategies need to move into early stage clinical trials as quickly as it is safe, and if successful, these therapies should efficiently obtain regulatory approval and widespread clinical application. In late 2009 and 2010 the Society for Immunotherapy of Cancer (SITC), convened an "Immunotherapy Summit" with representatives from immunotherapy organizations representing Europe, Japan, China and North America to discuss collaborations to improve development and delivery of cancer immunotherapy. One of the concepts raised by SITC and defined as critical by all parties was the need to identify hurdles that impede effective translation of cancer immunotherapy. With consensus on these hurdles, international working groups could be developed to make recommendations vetted by the participating organizations. These recommendations could then be considered by regulatory bodies, governmental and private funding agencies, pharmaceutical companies and academic institutions to facilitate changes necessary to accelerate clinical translation of novel immune-based cancer therapies. The critical hurdles identified by representatives of the collaborating organizations, now organized as the World Immunotherapy Council, are presented and discussed in this report. Some of the identified hurdles impede all investigators; others hinder investigators only in certain regions or institutions or are more relevant to specific types of immunotherapy or first-in-humans studies. Each of these hurdles can significantly delay clinical translation of promising advances in immunotherapy yet if overcome, have the potential to improve outcomes of patients with cancer

The regional species richness and genetic diversity of Arctic vegetation reflect both past glaciations and current climate

AIM : The Arctic has experienced marked climatic differences between glacial and interglacial periods and is now subject to a rapidly warming climate. Knowledge of the effects of historical processes on current patterns of diversity may aid predictions of the responses of vegetation to future climate change. We aim to test whether plant species and genetic diversity patterns are correlated with time since deglaciation at regional and local scales. We also investigate whether species richness is correlated with genetic diversity in vascular plants. LOCATION : Circumarctic. METHODS : We investigated species richness of the vascular plant flora of 21 floristic provinces and examined local species richness in 6215 vegetation plots distributed across the Arctic. We assessed levels of genetic diversity inferred from amplified fragment length polymorphism variation across populations of 23 common Arctic species. Correlations between diversity measures and landscape age (time since deglaciation) as well as variables characterizing current climate were analysed using spatially explicit simultaneous autoregressive models. RESULTS : lts Regional species richness of vascular plants and genetic diversity were correlated with each other, and both showed a positive relationship with landscape age. Plot species richness showed differing responses for vascular plants, bryophytes and lichens. At this finer scale, the richness of vascular plants was not significantly related to landscape age, which had a small effect size compared to the models of bryophyte and lichen richness. MAIN CONCLUSION : Our study suggests that imprints of past glaciations in Arctic vegetation diversity patterns at the regional scale are still detectable today. Since Arctic vegetation is still limited by post-glacial migration lag, it will most probably also exhibit lags in response to current and future climate change. Our results also suggest that local species richness at the plot scale is more determined by local habitat factors.Compilation of the species richness data was made possible through the TFI Networks grant to CD, “Effect Studies and Adaptation to Climate Change,” under the Norforsk initiative (2011 – 2014) which supported two CBIONET-AVA workshops held in Denmark during 2013. The genetic studies were funded by the Research Council of Norway (grant nos. 150322/720 and 170952/V40 to CB).http://http://onlinelibrary.wiley.com/journal/10.1111/(ISSN)1466-82382017-04-30hb2016Plant Production and Soil Scienc