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1.  CDK/CK1 inhibitors roscovitine and CR8 down-regulate amplified MYCN in neuroblastoma cells 
Oncogene  2013;33(50):5675-5687.
To understand the mechanisms of action of (R)-roscovitine and (S)-CR8, two related pharmacological inhibitors of cyclin-dependent kinases (CDKs), we applied a variety of ‘-omics’ techniques to the human neuroblastoma SH-SY5Y and IMR32 cell lines: [1] kinase interaction assays, [2] affinity competition on immobilized broad-spectrum kinase inhibitors, [3] affinity chromatography on immobilized (R)-roscovitine and (S)-CR8, [4] whole genome transcriptomics analysis and specific quantitative PCR studies, [5] global quantitative proteomics approach and Western blot analysis of selected proteins. Altogether the results show that the major direct targets of these two molecules belong to the CDKs (1, 2, 5, 7, 9, 12), DYRKs, CLKs, CK1s families. By inhibiting CDK7, CDK9 and CDK12, these inhibitors transiently reduce RNA polymerase 2 activity, which results in down-regulation of a large set of genes. Global transcriptomics and proteomics analysis converge to a central role of MYC transcription factors down-regulation. Indeed CDK inhibitors trigger rapid and massive down-regulation of MYCN expression in MYCN amplified neuroblastoma cells as well as in nude mice xenografted IMR32 cells. Inhibition of casein kinase 1 may also contribute to the antitumoral activity of (R)-roscovitine and (S)-CR8. This dual mechanism of action may be crucial in the use of these kinase inhibitors for the treatment of MYC-dependent cancers, in particular neuroblastoma where MYCN amplification is a strong predictor factor for high-risk disease.
PMCID: PMC4087096  PMID: 24317512
cyclin-dependent kinase; CDK; casein kinase 1; CK1; kinase inhibitor; roscovitine; CR8; c-Myc; MYCN; neuroblastoma; medulloblastoma; interactomics; transcriptomics; proteomics
2.  Neutrophils scan for activated platelets to initiate inflammation 
Science (New York, N.Y.)  2014;346(6214):1234-1238.
Immune and inflammatory responses require leukocytes to migrate within and through the vasculature, a process that is facilitated by their capacity to switch to a polarized morphology with asymmetric distribution of receptors. We report that neutrophil polarization within activated venules served to organize a protruding domain that engaged activated platelets present in the bloodstream. The selectin ligand PSGL-1 transduced signals emanating from these interactions, resulting in redistribution of receptors that drive neutrophil migration. Consequently, neutrophils unable to polarize or to transduce signals through PSGL-1 displayed aberrant crawling, and blockade of this domain protected mice against thrombo-inflammatory injury. These results reveal that recruited neutrophils scan for activated platelets, and suggest that their bipolarity allows integration of signals present at both the endothelium and the circulation before inflammation proceeds.
PMCID: PMC4280847  PMID: 25477463
3.  A Structure-Based Classification and Analysis of Protein Domain Family Binding Sites and Their Interactions 
Biology  2015;4(2):327-343.
While the number of solved 3D protein structures continues to grow rapidly, the structural rules that distinguish protein-protein interactions between different structural families are still not clear. Here, we classify and analyse the secondary structural features and promiscuity of a comprehensive non-redundant set of domain family binding sites (DFBSs) and hetero domain-domain interactions (DDIs) extracted from our updated KBDOCK resource. We have partitioned 4001 DFBSs into five classes using their propensities for three types of secondary structural elements (“α” for helices, “β” for strands, and “γ” for irregular structure) and we have analysed how frequently these classes occur in DDIs. Our results show that β elements are not highly represented in DFBSs compared to α and γ elements. At the DDI level, all classes of binding sites tend to preferentially bind to the same class of binding sites and α/β contacts are significantly disfavored. Very few DFBSs are promiscuous: 80% of them interact with just one Pfam domain. About 50% of our Pfam domains bear only one single-partner DFBS and are therefore monogamous in their interactions with other domains. Conversely, promiscuous Pfam domains bear several DFBSs among which one or two are promiscuous, thereby multiplying the promiscuity of the concerned protein.
PMCID: PMC4498303  PMID: 25860777
protein secondary structure; protein domain; protein binding sites; protein-protein interactions; domain-domain interactions; interaction promiscuity
4.  A process-based framework to guide nurse practitioners integration into primary healthcare teams: results from a logic analysis 
Integrating Nurse Practitioners into primary care teams is a process that involves significant challenges. To be successful, nurse practitioner integration into primary care teams requires, among other things, a redefinition of professional boundaries, in particular those of medicine and nursing, a coherent model of inter- and intra- professional collaboration, and team-based work processes that make the best use of the subsidiarity principle. There have been numerous studies on nurse practitioner integration, and the literature provides a comprehensive list of barriers to, and facilitators of, integration. However, this literature is much less prolific in discussing the operational level implications of those barriers and facilitators and in offering practical recommendations.
In the context of a large-scale research project on the introduction of nurse practitioners in Quebec (Canada) we relied on a logic-analysis approach based, on the one hand on a realist review of the literature and, on the other hand, on qualitative case-studies in 6 primary healthcare teams in rural and urban area of Quebec.
Five core themes that need to be taken into account when integrating nurse practitioners into primary care teams were identified. Those themes are: planning, role definition, practice model, collaboration, and team support.
The present paper has two objectives: to present the methods used to develop the themes, and to discuss an integrative model of nurse practitioner integration support centered around these themes.
It concludes with a discussion of how this framework contributes to existing knowledge and some ideas for future avenues of study.
PMCID: PMC4349481  PMID: 25889415
Collaboration; Delivery of health care; Integrating process; Logic evaluation; Nurse practitioners; Practice model; Primary health care; Role definition; Team support
5.  The small GTPase Rap1b negatively regulates neutrophil chemotaxis and transcellular diapedesis by inhibiting Akt activation 
The Journal of Experimental Medicine  2014;211(9):1741-1758.
Mice lacking the small GTPase Rap1b exhibit enhanced neutrophil recruitment to inflamed lungs and susceptibility to endotoxin shock via enhance PI3K-Akt activation.
Neutrophils are the first line of cellular defense in response to infections and inflammatory injuries. However, neutrophil activation and accumulation into tissues trigger tissue damage due to release of a plethora of toxic oxidants and proteases, a cause of acute lung injury (ALI). Despite its clinical importance, the molecular regulation of neutrophil migration is poorly understood. The small GTPase Rap1b is generally viewed as a positive regulator of immune cell functions by controlling bidirectional integrin signaling. However, we found that Rap1b-deficient mice exhibited enhanced neutrophil recruitment to inflamed lungs and enhanced susceptibility to endotoxin shock. Unexpectedly, Rap1b deficiency promoted the transcellular route of diapedesis through endothelial cell. Increased transcellular migration of Rap1b-deficient neutrophils in vitro was selectively mediated by enhanced PI3K-Akt activation and invadopodia-like protrusions. Akt inhibition in vivo suppressed excessive Rap1b-deficient neutrophil migration and associated endotoxin shock. The inhibitory action of Rap1b on PI3K signaling may be mediated by activation of phosphatase SHP-1. Thus, this study reveals an unexpected role for Rap1b as a key suppressor of neutrophil migration and lung inflammation.
PMCID: PMC4144729  PMID: 25092872
6.  Blood Thixotropy in Patients with Sickle Cell Anaemia: Role of Haematocrit and Red Blood Cell Rheological Properties 
PLoS ONE  2014;9(12):e114412.
We compared the blood thixotropic/shear-thinning properties and the red blood cells’ (RBC) rheological properties between a group of patients with sickle cell anaemia (SS) and healthy individuals (AA). Blood thixotropy was determined by measuring blood viscosity with a capillary viscometer using a “loop” protocol: the shear rate started at 1 s−1 and increased progressively to 922 s−1 and then re-decreased to the initial shear rate. Measurements were performed at native haematocrit for the two groups and at 25% and 40% haematocrit for the AA and SS individuals, respectively. RBC deformability was determined by ektacytometry and RBC aggregation properties by laser backscatter versus time. AA at native haematocrit had higher blood thixotropic index than SS at native haematocrit and AA at 25% haematocrit. At 40% haematocrit, SS had higher blood thixotropic index than AA. While RBC deformability and aggregation were lower in SS than in AA, the strength of RBC aggregates was higher in the former population. Our results showed that 1) anaemia is the main modulator of blood thixtropy and 2) the low RBC deformability and high RBC aggregates strength cause higher blood thixotropy in SS patients than in AA individuals at 40% haematocrit, which could impact blood flow in certain vascular compartments.
PMCID: PMC4263608  PMID: 25502228
7.  Extended spectrum of MBD5 mutations in neurodevelopmental disorders 
European Journal of Human Genetics  2013;21(12):1457-1461.
Intellectual disability (ID) is a clinical sign reflecting diverse neurodevelopmental disorders that are genetically and phenotypically heterogeneous. Just recently, partial or complete deletion of methyl-CpG-binding domain 5 (MBD5) gene has been implicated as causative in the phenotype associated with 2q23.1 microdeletion syndrome. In the course of systematic whole-genome screening of individuals with unexplained ID by array-based comparative genomic hybridization, we identified de novo intragenic deletions of MBD5 in three patients leading, as previously documented, to haploinsufficiency of MBD5. In addition, we described a patient with an unreported de novo MBD5 intragenic duplication. Reverse transcriptase-PCR and sequencing analyses showed the presence of numerous aberrant transcripts leading to premature termination codon. To further elucidate the involvement of MBD5 in ID, we sequenced ten coding, five non-coding exons and an evolutionary conserved region in intron 2, in a selected cohort of 78 subjects with a phenotype reminiscent of 2q23.1 microdeletion syndrome. Besides variants most often inherited from an healthy parent, we identified for the first time a de novo nonsense mutation associated with a much more damaging phenotype. Taken together, these results extend the mutation spectrum in MBD5 gene and contribute to refine the associated phenotype of neurodevelopmental disorder.
PMCID: PMC3831065  PMID: 23422940
MBD5; nonsense mutation; intragenic duplication; intellectual disability
8.  Role Clarification Processes for Better Integration of Nurse Practitioners into Primary Healthcare Teams: A Multiple-Case Study 
Nursing Research and Practice  2014;2014:170514.
Role clarity is a crucial issue for effective interprofessional collaboration. Poorly defined roles can become a source of conflict in clinical teams and reduce the effectiveness of care and services delivered to the population. Our objective in this paper is to outline processes for clarifying professional roles when a new role is introduced into clinical teams, that of the primary healthcare nurse practitioner (PHCNP). To support our empirical analysis we used the Canadian National Interprofessional Competency Framework, which defines the essential components for role clarification among professionals. A qualitative multiple-case study was conducted on six cases in which the PHCNP role was introduced into primary care teams. Data collection included 34 semistructured interviews with key informants involved in the implementation of the PHCNP role. Our results revealed that the best performing primary care teams were those that used a variety of organizational and individual strategies to carry out role clarification processes. From this study, we conclude that role clarification is both an organizational process to be developed and a competency that each member of the primary care team must mobilize to ensure effective interprofessional collaboration.
PMCID: PMC4322308  PMID: 25692039
10.  Pharmaceutical Sales Representatives and Patient Safety: A Comparative Prospective Study of Information Quality in Canada, France and the United States 
Journal of General Internal Medicine  2013;28(10):1368-1375.
The information provided by pharmaceutical sales representatives has been shown to influence prescribing. To enable safe prescribing, medicines information must include harm as well as benefits. Regulation supports this aim, but relative effectiveness of different approaches is not known. The United States (US) and France directly regulate drug promotion; Canada relies on industry self-regulation. France has the strictest information standards.
This is a prospective cohort study in Montreal, Vancouver, Sacramento and Toulouse. We recruited random samples of primary care physicians from May 2009 to June 2010 to report on consecutive sales visits. The primary outcome measure was “minimally adequate safety information” (mention of at least one indication, serious adverse event, common adverse event, and contraindication, and no unqualified safety claims or unapproved indications).
Two hundred and fifty-five physicians reported on 1,692 drug-specific promotions. “Minimally adequate safety information” did not differ: 1.7 % of promotions; range 0.9–3.0 % per site. Sales representatives provided some vs. no information on harm more often in Toulouse than in Montreal and Vancouver: 61 % vs. 34 %, OR = 4.0; 95 % CI 2.8–5.6, or Sacramento (39 %), OR = 2.4; 95 % CI 1.7–3.6. Serious adverse events were rarely mentioned (5–6 % of promotions in all four sites), although 45 % of promotions were for drugs with US Food and Drug Administration (FDA) “black box” warnings of serious risks. Nevertheless, physicians judged the quality of scientific information to be good or excellent in 901 (54 %) of promotions, and indicated readiness to prescribe 64 % of the time.
“Minimally adequate safety information” did not differ in the US and Canadian sites, despite regulatory differences. In Toulouse, consistent with stricter standards, more harm information was provided. However, in all sites, physicians were rarely informed about serious adverse events, raising questions about whether current approaches to regulation of sales representatives adequately protect patient health.
Electronic supplementary material
The online version of this article (doi:10.1007/s11606-013-2411-7) contains supplementary material, which is available to authorized users.
PMCID: PMC3785667  PMID: 23558775
health policy; patient safety; primary care; health services research
11.  Climate and Leishmaniasis in French Guiana 
To study the link between climatic variables and the incidence of leishmaniasis a study was conducted in Cayenne, French Guiana. Patients infected between January 1994 and December 2010. Meteorological data were studied in relation to the incidence of leishmaniasis using an ARIMA model. In the final model, the infections were negatively correlated with rainfall (with a 2-month lag) and with the number of days with rainfall > 50 mm (lags of 4 and 7 months). The variables that were positively correlated were temperature and the Multivariate El Niño Southern Oscillation Index with lags of 8 and 4 months, respectively. Significantly greater correlations were observed in March for rainfall and in November for the Multivariate El Niño/Southern Oscillation Index. Climate thus seems to be a non-negligible explanatory variable for the fluctuations of leishmaniasis. A decrease in rainfall is linked to increased cases 2 months later. This easily perceptible point could lead to an interesting prevention message.
PMCID: PMC3771301  PMID: 23939706
12.  ECCB 2014: The 13th European Conference on Computational Biology 
Bioinformatics  2014;30(17):i345-i348.
PMCID: PMC4147932  PMID: 25161218
13.  Periaortic Brown Adipose Tissue as a Major Determinant of [18F]-Fluorodeoxyglucose Vascular Uptake in Atherosclerosis-Prone, ApoE−/− Mice 
PLoS ONE  2014;9(7):e99441.
[18F]-fluorodeoxyglucose (FDG) has been suggested for the clinical and experimental imaging of inflammatory atherosclerotic lesions. Significant FDG uptake in brown adipose tissue (BAT) has been observed both in humans and mice. The objective of the present study was to investigate the influence of periaortic BAT on apolipoprotein E-deficient (apoE−/−) mouse atherosclerotic lesion imaging with FDG.
ApoE−/− mice (36±2 weeks-old) were injected with FDG (12±2 MBq). Control animals (Group A, n = 7) were injected conscious and kept awake at room temperature (24°C) throughout the accumulation period. In order to minimize tracer activity in periaortic BAT, Group B (n = 7) and C (n = 6) animals were injected under anaesthesia at 37°C and Group C animals were additionally pre-treated with propranolol. PET/CT acquisitions were performed prior to animal euthanasia and ex vivo analysis of FDG biodistribution.
Autoradiographic imaging indicated higher FDG uptake in atherosclerotic lesions than in the normal aortic wall (all groups, P<0.05) and the blood (all groups, P<0.01) which correlated with macrophage infiltration (R = 0.47; P<0.001). However, periaortic BAT uptake was either significantly higher (Group A, P<0.05) or similar (Group B and C, P = NS) to that observed in atherosclerotic lesions and was shown to correlate with in vivo quantified aortic FDG activity.
Periaortic BAT FDG uptake was identified as a confounding factor while using FDG for the non-invasive imaging of mouse atherosclerotic lesions.
PMCID: PMC4108473  PMID: 25054923
15.  Study of inter- and intra-observer reproducibility in the interpretation of [18F]choline PET/CT examinations in patients suffering from biochemically recurrent prostate cancer following curative treatment 
EJNMMI Research  2014;4:25.
The aim of this study was to investigate the reproducibility of intra- and inter-observer interpretation of [18F]choline positron emission tomography/computed tomography examinations in patients suffering from biochemically recurrent prostate cancer following curative treatment.
A total of 60 patients with biochemical recurrence after curative treatment were included in this bicentric study. The interpretations were based on a systematic analysis of several anatomic regions and all the four nuclear medicine physicians used identical result consoles. The examinations were interpreted with no knowledge of the patients' clinical context. Two months later, a second interpretation of all these examinations was performed using the same method, in random order.
To evaluate local recurrences, when the prostate is in place, the results showed moderate inter- and intra-observer reproducibility: concordance of all 4 physicians has a Fleiss' kappa coefficient of 0.553 with a confidence interval of (0.425 to 0.693). For patients who had had a prostatectomy, there was excellent concordance for the negative examinations. For the lymphatic basin, inter- and intra-observer reproducibility was excellent with a Fleiss' kappa coefficient of 0.892 with a confidence interval of (0.788 to 0.975). The lymphatic sub-group analysis was also good. For the lymphatic groups in the right or left hemi-pelves, all Fleiss' kappa and Cohen's kappa coefficients are varying from 0.760 to 1 with narrow confidence intervals from (0.536 to 0.984) to (1 to 1) in favour of good/excellent inter-observer reproducibility. To evaluate bone metastasis, inter-observer reproducibility was good with a Fleiss' kappa coefficient of 0.703 and a confidence interval of (0.407 to 0.881).
Our study is at time the only one on the reproducibility of interpretation of [18F]choline positron emission tomography/computed tomography examinations, which is a key examination for the treatment of patients suffering biochemical recurrence of prostate cancer. Interpretation of the [18F]choline positron emission tomography/computed tomography examination is not so useful at prostate level in patients not previously treated with prostatectomy but has a great interest on patients treated by prostatectomy. It showed good concordance in the interpretation of sub-diaphragmatic lymphatic recurrences as well as in bone metastasis.
PMCID: PMC4077623  PMID: 25006544
18F; choline positron emission tomography; Computed tomography; Prostate cancer; Biochemical recurrence; Inter- and intra-observer reproducibility
16.  p53 Requires the Stress Sensor USF1 to Direct Appropriate Cell Fate Decision 
PLoS Genetics  2014;10(5):e1004309.
Genomic instability is a major hallmark of cancer. To maintain genomic integrity, cells are equipped with dedicated sensors to monitor DNA repair or to force damaged cells into death programs. The tumor suppressor p53 is central in this process. Here, we report that the ubiquitous transcription factor Upstream Stimulatory factor 1 (USF1) coordinates p53 function in making proper cell fate decisions. USF1 stabilizes the p53 protein and promotes a transient cell cycle arrest, in the presence of DNA damage. Thus, cell proliferation is maintained inappropriately in Usf1 KO mice and in USF1-deficient melanoma cells challenged by genotoxic stress. We further demonstrate that the loss of USF1 compromises p53 stability by enhancing p53-MDM2 complex formation and MDM2-mediated degradation of p53. In USF1-deficient cells, the level of p53 can be restored by the re-expression of full-length USF1 protein similarly to what is observed using Nutlin-3, a specific inhibitor that prevents p53-MDM2 interaction. Consistent with a new function for USF1, a USF1 truncated protein lacking its DNA-binding and transactivation domains can also restore the induction and activity of p53. These findings establish that p53 function requires the ubiquitous stress sensor USF1 for appropriate cell fate decisions in response to DNA-damage. They underscore the new role of USF1 and give new clues of how p53 loss of function can occur in any cell type. Finally, these findings are of clinical relevance because they provide new therapeutic prospects in stabilizing and reactivating the p53 pathway.
Author Summary
Cancer is a complex disease that is characterized by the sequential accumulation of genetic mutations. Exposure to environmental agents, such as solar ultraviolet, induces such alterations and thus contributes to the development of genomic instability. The tumor suppressor p53 has a central role in orchestrating cellular responses to genotoxic stress. In response to DNA-damage, p53 is stabilized and activated to direct cell fate decisions. Cells in which p53 stabilization is compromised become more vulnerable to mutagenic agents and hence the mutation rate increases, which promotes tumor development. Stabilization of p53 is thus a critical step towards cancer prevention. Using a genetic approach, we demonstrate that the ubiquitous transcription factor Upstream Stimulatory factor 1 (USF1) is required for immediate p53 stabilization and appropriate cell fate decisions following genotoxic stress. Furthermore, we show that this involves a novel function of USF1 that underscores its critical role as a stress sensor. The loss of USF1 expression should thus be considered as a potential initiator of tumorigenesis in the context of environmental insults.
PMCID: PMC4022457  PMID: 24831529
17.  p190-B RhoGAP regulates the functional composition of the mesenchymal microenvironment 
Leukemia  2013;27(11):2209-2219.
Hematopoiesis is regulated by components of the microenvironment, so-called niche. Here, we show that p190-B GTPase Activating Protein (p190-B) deletion in mice causes hematopoietic failure during ontogeny, in p190-B−/− fetal liver and bones, and in p190-B+/− adult bones and spleen. These defects are non-cell autonomous, since we previously showed that transplantation of p190-B−/− hematopoietic cells into wild-type hosts leads to normal hematopoiesis. Coculture of mesenchymal stem/progenitor cells (MSC) and wild-type bone marrow cells reveals that p190-B−/− MSCs are dysfunctional in supporting hematopoiesis due to impaired Wnt signaling. Furthermore, p190-B loss causes alteration in bone marrow niche composition, including abnormal CFU-fibroblast, CFU-adipocyte and CFU-osteoblast numbers. This is due to altered MSC lineage fate specification to osteoblast and adipocyte lineages. Thus, p190-B organizes a functional mesenchymal/microenvironment for normal hematopoiesis during development.
PMCID: PMC3919554  PMID: 23563238
mesenchymal stem cell; p190-B RhoGAP; hematopoiesis; microenvironment; Wnt3a
18.  Providing high-quality care in primary care settings 
Canadian Family Physician  2014;60(5):e281-e289.
To gain a deeper understanding of how primary care (PC) practices belonging to different models manage resources to provide high-quality care.
Multiple-case study embedded in a cross-sectional study of a random sample of 37 practices.
Three regions of Quebec.
Health care professionals and staff of 5 PC practices.
Five cases showing above-average results on quality-of-care indicators were purposefully selected to contrast on region, practice size, and PC model. Data were collected using an organizational questionnaire; the Team Climate Inventory, which was completed by health care professionals and staff; and 33 individual interviews. Detailed case histories were written and thematic analysis was performed.
Main findings
The core common feature of these practices was their ongoing effort to make trade-offs to deliver services that met their vision of high-quality care. These compromises involved the same 3 areas, but to varying degrees depending on clinic characteristics: developing a shared vision of high-quality care; aligning resource use with that vision; and balancing professional aspirations and population needs. The leadership of the physician lead was crucial. The external environment was perceived as a source of pressure and dilemmas rather than as a source of support in these matters.
Irrespective of their models, PC practices’ pursuit of high-quality care is based on a vision in which accessibility is a key component, balanced by appropriate management of available resources and of external environment expectations. Current PC reforms often create tensions rather than support PC practices in their pursuit of high-quality care.
PMCID: PMC4020666  PMID: 24829023
19.  Does increased red blood cell deformability raise the risk for osteonecrosis in sickle cell anemia? 
Blood  2013;121(15):3054-3056.
PMCID: PMC3988032  PMID: 23580637
Aged; Anemia, Sickle Cell; blood; drug therapy; Antisickling Agents; therapeutic use; Erythrocyte Deformability; Female; Humans; Hydroxyurea; therapeutic use; Logistic Models; Male; Middle Aged; Multivariate Analysis; Osteonecrosis; blood; Risk Assessment; Risk Factors; Young Adult
20.  Acute Moderate Exercise Does Not Further Alter the Autonomic Nervous System Activity in Patients with Sickle Cell Anemia 
PLoS ONE  2014;9(4):e95563.
A decreased global autonomic nervous system (ANS) activity and increased sympathetic activation in patients with sickle cell anemia (SCA) seem to worsen the clinical severity and could play a role in the pathophysiology of the disease, notably by triggering vaso-occlusive crises. Because exercise challenges the ANS activity in the general population, we sought to determine whether a short (<15 min) and progressive moderate exercise session conducted until the first ventilatory threshold had an effect on the ANS activity of a group of SCA patients and a group of healthy individuals (CONT group). Temporal and spectral analyses of the nocturnal heart rate variability were performed before and on the 3 nights following the exercise session. Standard deviation of all normal RR intervals (SDNN), total power, low frequencies (LF) and high frequencies powers (HF) were lower but LF/HF was higher in SCA patients than in the CONT group. Moderate exercise did not modify ANS activity in both groups. In addition, no adverse clinical events occurred during the entire protocol. These results imply that this kind of short and moderate exercise is not detrimental for SCA patients.
PMCID: PMC3989338  PMID: 24740295
21.  High Dose Thiotepa in Patients with Relapsed or Refractory Osteosarcomas: Experience of the SFCE Group 
Sarcoma  2014;2014:475067.
Introduction. Osteosarcoma relapse has a poor prognosis, with less than 25% survival at 5 years. We describe the experience of the French Society of Paediatric Oncology (SFCE) with high dose (HD) thiotepa and autologous stem cell transplantation (ASCT) in 45 children with relapsed osteosarcoma. Patients and Methods. Between 1992 and 2004, 53 patients received HD thiotepa (900 mg/m2) followed by ASCT in 6 centres. Eight patients were excluded from analysis, and we retrospectively reviewed the clinical radiological and anatomopathological patterns of the 45 remaining patients. Results. Sixteen girls and 29 boys (median age, 15.9 years) received HD thiotepa after initial progression of metastatic disease (2), first relapse (26), and second or third relapse (17). We report 12 radiological partial responses and 9 of 31 histological complete responses. Thirty-two patients experienced further relapses, and 13 continued in complete remission after surgical resection of the residual disease. Three-year overall survival was 40%, and 3-year progression-free survival was 24%. Delay of relapse (+/− 2 years from diagnosis) was a prognostic factor (P = 0.011). No acute toxic serious adverse event occurred. Conclusion. The use of HD thiotepa and ASCT is feasible in patients with relapsed osteosarcoma. A randomized study for recurrent osteosarcoma between standard salvage chemotherapy and high dose thiotepa with stem cell rescue is ongoing.
PMCID: PMC3941142  PMID: 24672280
22.  Core Competencies for Shared Decision Making Training Programs: Insights From an International, Interdisciplinary Working Group 
Shared decision making is now making inroads in health care professionals’ continuing education curriculum, but there is no consensus on what core competencies are required by clinicians for effectively involving patients in health-related decisions. Ready-made programs for training clinicians in shared decision making are in high demand, but existing programs vary widely in their theoretical foundations, length, and content. An international, interdisciplinary group of 25 individuals met in 2012 to discuss theoretical approaches to making health-related decisions, compare notes on existing programs, take stock of stakeholders concerns, and deliberate on core competencies. This article summarizes the results of those discussions. Some participants believed that existing models already provide a sufficient conceptual basis for developing and implementing shared decision making competency-based training programs on a wide scale. Others argued that this would be premature as there is still no consensus on the definition of shared decision making or sufficient evidence to recommend specific competencies for implementing shared decision making. However, all participants agreed that there were 2 broad types of competencies that clinicians need for implementing shared decision making: relational competencies and risk communication competencies. Further multidisciplinary research could broaden and deepen our understanding of core competencies for shared decision making training.
PMCID: PMC3911960  PMID: 24347105 CAMSID: cams3819
shared decision making; education; patient-centered care; implementation science; theory; risk communication
23.  Plasma Concentration of Platelet-Derived Microparticles Is Related to Painful Vaso-Occlusive Phenotype Severity in Sickle Cell Anemia 
PLoS ONE  2014;9(1):e87243.
High plasma level of microparticles (MPs) deriving mainly from erythrocytes and platelets has been detected in sickle cell anemia (SCA) patients. Flow cytometry was used to determine the concentration of MPs in two groups of SCA patients exhibiting marked differences in painful vaso-occlusive crisis rates [a non-severe group (n = 17) and a severe group (n = 12)], and in a control group composed of healthy subjects (n = 20). A 3- to 4-fold increase of total MP plasma concentration was detected in SCA patients. Higher platelet-derived MPs concentration was detected in the severe SCA group while erythrocyte-derived MPs concentration was increased in the non-severe SCA patient group only. Our results suggest that plasma concentration of MPs shed by platelets is a biomarker of the vaso-occlusive phenotype-related severity.
PMCID: PMC3901744  PMID: 24475257
24.  Prediction of Monomer Isomery in Florine: A Workflow Dedicated to Nonribosomal Peptide Discovery 
PLoS ONE  2014;9(1):e85667.
Nonribosomal peptides represent a large variety of natural active compounds produced by microorganisms. Due to their specific biosynthesis pathway through large assembly lines called NonRibosomal Peptide Synthetases (NRPSs), they often display complex structures with cycles and branches. Moreover they often contain non proteogenic or modified monomers, such as the D-monomers produced by epimerization. We investigate here some sequence specificities of the condensation (C) and epimerization (E) domains of NRPS that can be used to predict the possible isomeric state (D or L) of each monomer in a putative peptide. We show that C- and E- domains can be divided into 2 sub-regions called Up-Seq and Down-Seq. The Up-Seq region corresponds to an InterPro domain (IPR001242) and is shared by C- and E-domains. The Down-Seq region is specific to the enzymatic activity of the domain. Amino-acid signatures (represented as sequence logos) previously described for complete C-and E-domains have been restricted to the Down-Seq region and amplified thanks to additional sequences. Moreover a new Down-Seq signature has been found for Ct-domains found in fungi and responsible for terminal cyclization of the peptides. The identification of these signatures has been included in a workflow named Florine, aimed to predict nonribosomal peptides from NRPS sequence analyses. In some cases, the prediction of isomery is guided by genus-specific rules. Florine was used on a Pseudomonas genome to allow the determination of the type of pyoverdin produced, the update of syringafactin structure and the identification of novel putative products.
PMCID: PMC3897469  PMID: 24465643
25.  Primary Healthcare Solo Practices: Homogeneous or Heterogeneous? 
Introduction. Solo practices have generally been viewed as forming a homogeneous group. However, they may differ on many characteristics. The objective of this paper is to identify different forms of solo practice and to determine the extent to which they are associated with patient experience of care. Methods. Two surveys were carried out in two regions of Quebec in 2010: a telephone survey of 9180 respondents from the general population and a postal survey of 606 primary healthcare (PHC) practices. Data from the two surveys were linked through the respondent's usual source of care. A taxonomy of solo practices was constructed (n = 213), using cluster analysis techniques. Bivariate and multilevel analyses were used to determine the relationship of the taxonomy with patient experience of care. Results. Four models were derived from the taxonomy. Practices in the “resourceful networked” model contrast with those of the “resourceless isolated” model to the extent that the experience of care reported by their patients is more favorable. Conclusion. Solo practice is not a homogeneous group. The four models identified have different organizational features and their patients' experience of care also differs. Some models seem to offer a better organizational potential in the context of current reforms.
PMCID: PMC3913485  PMID: 24523964

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