Development of a first-in-class unimolecular dual GIP/GLP-2 analogue, GL-0001, for the treatment of bone fragility

ABSTRACT Due to ageing of the population, bone frailty is dramatically increasing worldwide. Although some therapeutic options exist, they do not fully protect or prevent against the occurrence of new fractures. All current drugs approved for the treatment of bone fragility target bone mass. However, bone resistance to fracture is not solely due to bone mass but relies also on bone ECM material properties, i.e. the quality of the bone matrix component. Here, we introduce the first-in-class unimolecular dual GIP/GLP-2 analogues, GL-0001, that activate simultaneously the glucose-dependent insulinotropic polypeptide receptor (GIPr) and the glucagon-like peptide-2 receptor (GLP-2r). GL-0001 acts synergistically through a cAMP-LOX pathway to enhance collagen maturity. Furthermore, in mice with ovariectomy-induced bone fragility, GL-0001 prevented excess trabecular bone degradation at the appendicular skeleton and also enhanced bone ECM material properties through reduction of the degree of mineralization and augmentation in enzymatic collagen crosslinking. These results demonstrate that targeting bone ECM material properties is a viable option to enhance bone strength and opens an innovative pathway for the treatment of patients suffering of bone fragility

Studying the Hurdles of Insulin Prescription (SHIP©): development, scoring and initial validation of a new self-administered questionnaire

<p>Abstract</p> <p>Background</p> <p>Although insulin therapy is well-accepted by symptomatic diabetic patients, it is still often delayed in less severe patients, in whom injectable insulin remains under-used. A better understanding of patients' perception of insulin would eventually help physicians to adopt the most appropriate dialogue when having to motivate patients to initiate or to intensify insulin injection.</p> <p>Methods</p> <p>The 'Studying the Hurdles of Insulin Prescription' (SHIP) questionnaire was developed based on a list of concepts derived from three diabetic patients' focus groups, and was included into two cross-sectional studies with similar design: SHIP Oral study and SHIP Premix study. Diabetic patients treated with oral hypoglycaemic agents (OHA; n = 1,494) and patients already treated with insulin (n = 1,150) completed the questionnaire at baseline, 6- and 12 months. Psychometric properties were assessed: 1) structure analysis by Principal Component Analysis (PCA) with Varimax rotation, 2) internal consistency reliability (Cronbach's alpha), and 3) concurrent validity (Spearman correlation coefficients with the Fear of Self-Injecting (FSI) score of the Diabetes Fear of Injecting and Self-testing Questionnaire. Reluctance/motivation towards insulin was assessed. Scores' ability to predict patients' insulin injection reluctance/motivation and initiation/intensification was evaluated with the Area Under the Receiver Operating Characteristic (ROC) Curve (AUC).</p> <p>Results</p> <p>PCA analysis confirmed the structure of the 14 items grouped into 3 dimensions: 'acceptance and motivation', 'fear and constraints', and 'restraints and barriers' towards insulin injection. Internal consistency reliability was excellent (Cronbach's alpha > 0.70); concurrent validity was good. The three scores were significantly predictive of patients' reluctance/motivation towards insulin injection initiation, as they were of patients' actual switch, except for the 'restraints and barriers' dimension. 'Acceptance and motivation' and 'fears and constraints' dimensions were also significantly predictive of patients' reluctance/motivation towards insulin intensification. By the end of the 12-month study, 179 of the initially OHA-treated patients had started insulin injections; 186 of the patients already treated with insulin had increased their injections.</p> <p>Conclusion</p> <p>The SHIP questionnaire provides reliable and valid assessment of diabetic patients' attitude towards insulin and injections. The predictive power of scores for patients' reluctance/motivation and actual treatment decisions demonstrates encouraging potential for further application in clinical practice.</p

Diagnóstico de las nuevas tecnologías empleadas para el diseño de mezclas asfálticas densas en caliente MDC-2

El presente trabajo pretende brindar alternativas de modificación de las Mezclas Asfálticas Densas en Caliente, empleadas para la pavimentación de las vías en Colombia, mecanismos que actualmente generan un impacto ambiental negativo debido a la utilización de los materiales pétreos, los cuales debido a su ubicación no cumplen con las especificaciones técnicas o son de difícil acceso en algunas zonas de nuestro país. Es por ello que estudios realizados han demostrado que la fabricación de mezclas con asfalto convencional no han sido suficientes para soportar la acción del tránsito y el clima, por lo tanto se ha recomendado emplear modificadores o aditivos en las mezclas, con el fin de mejorar las características o propiedades geológicas tanto del cemento asfáltico como de las mezclas asfálticas, así como emplear desechos de materiales que generan un alto impacto en el ambiente

The permafrost mineral reserve: identify potential mineral nutrient hotspots upon thawing

The thawing of permafrost exposes organic matter to decomposition but also mineral constituents to water. To evaluate the potential to create mineral nutrients hotspots upon thawing, an inventory of the mineral element content and its local variability in permafrost terrain is needed. Based on measurements from major Arctic regions (Alaska, Greenland, Svalbard and Siberia), it is suggested that the mineral reserve in permafrost is firstly controlled by the local lithology. More specifically, the data highlight the potential for mineral nutrient hotspots to be generated upon thawing in soils derived from deltaic deposits, but not in thermokarst deposits. Finally, we suggest that portable X-ray fluorescence (pXRF) may present a quick and low-cost alternative to total digestion and ICP-AES measurements to build a mineral element inventory in permafrost terrain at a large spatial scale

Enhancing tumor specific immune responses by transcutaneous vaccination.

Our understanding of the involvement of the immune system in cancer control has increased over recent years. However, the development of cancer vaccines intended to reverse tumor-induced immune tolerance remains slow as most current vaccine candidates exhibit limited clinical efficacy. The skin is particularly rich with multiple subsets of dendritic cells (DCs) that are involved to varying degrees in the induction of robust immune responses. Transcutaneous administration of cancer vaccines may therefore harness the immune potential of these DCs, however, this approach is hampered by the impermeability of the stratum corneum. Innovative vaccine formulations including various nanoparticles, such as liposomes, are therefore needed to properly deliver cancer vaccine components to skin DCs. Areas covered: The recent insights into skin DC subsets and their functional specialization, the potential of nanoparticle-based vaccines in transcutaneous cancer vaccination and, finally, the most relevant clinical trial advances in liposomal and in cutaneous cancer vaccines will be discussed. Expert commentary: To define the optimal conditions for mounting protective skin DC-induced anti-tumor immune responses, investigation of the cellular and molecular interplay that controls tumor progression should be pursued in parallel with clinical development. The resulting knowledge will then be translated into improved cancer vaccines that better target the most appropriate immune players.journal articlereviewresearch support, non-u.s. gov't2017 11importe

Genome analysis of the necrotrophic fungal pathogens Sclerotinia sclerotiorum and Botrytis cinerea

Sclerotinia sclerotiorum and Botrytis cinerea are closely related necrotrophic plant pathogenic fungi notable for their wide host ranges and environmental persistence. These attributes have made these species models for understanding the complexity of necrotrophic, broad host-range pathogenicity. Despite their similarities, the two species differ in mating behaviour and the ability to produce asexual spores. We have sequenced the genomes of one strain of S. sclerotiorum and two strains of B. cinerea. The comparative analysis of these genomes relative to one another and to other sequenced fungal genomes is provided here. Their 38–39 Mb genomes include 11,860–14,270 predicted genes, which share 83% amino acid identity on average between the two species. We have mapped the S. sclerotiorum assembly to 16 chromosomes and found large-scale co-linearity with the B. cinerea genomes. Seven percent of the S. sclerotiorum genome comprises transposable elements compared t

Development of the SPUR tool : a profiling instrument for patient treatment behavior

International audienceBackground: Long-term treatment adherence is a worldwide concern, with nonadherence resulting from a complex interplay of behaviors and health beliefs. Determining an individual’s risk of nonadherence and identifying the drivers of that risk are crucial for the development of successful interventions for improving adherence. Here, we describe the development of a new tool assessing a comprehensive set of characteristics predictive of patients’ treatment adherence based on the Social, Psychological, Usage and Rational (SPUR) adherence framework. Concepts from existing self-reporting tools of adherence-related behaviors were identified following a targeted MEDLINE literature review and a subset of these concepts were then selected for inclusion in the new tool. SPUR tool items, simultaneously generated in US English and in French, were tested iteratively through two rounds of cognitive interviews with US and French patients taking long-term treatments for chronic diseases. The pilot SPUR tool, resulting from the qualitative analysis of patients’ responses, was then adapted to other cultural settings (China and the UK) and subjected to further rounds of cognitive testing. Results: The literature review identified 27 relevant instruments, from which 49 concepts were included in the SPUR tool (Social: 6, Psychological: 13, Usage: 11, Rational: 19). Feedback from US and French patients suffering from diabetes, multiple sclerosis, or breast cancer (n = 14 for the first round; n = 16 for the second round) indicated that the SPUR tool was well accepted and consistently understood. Minor modifications were implemented, resulting in the retention of 45 items (Social: 5, Psychological: 14, Usage: 10, Rational: 16). Results from the cognitive interviews conducted in China (15 patients per round suffering from diabetes, breast cancer or chronic obstructive pulmonary disease) and the UK (15 patients suffering from diabetes) confirmed the validity of the tool content, with no notable differences being identified across countries or chronic conditions. Conclusion Our qualitative analyses indicated that the pilot SPUR tool is a promising model that may help clinicians and health systems to predict patient treatment behavior. Further steps using quantitative methods are needed to confirm its predictive validity and other psychometric properties

Comparative analysis of canine and human melanomas

This paper presents epidemiological and clinical data from 2350 cases of melanocytic tumours from dogs sampled in France. In addition, we present the histological and genetic characterization of subsets of melanoma cases (n=153 and n=100, respectively), with a comparative aspect to human melanomas. Dog melanomas occur at the same anatomical sites than human melanomas, but with different frequency and severity. We demonstrate that the specificities of dog melanomas make them good models to understand the non-UV pathways of human melanomas. Interestingly, somatic mutations in oral canine melanomas were detected in the NRAS and PTEN genes, precisely at the same hotspots as human mutations. In contrast, mutations in the BRAF gene were not detected. This paper highlights the similarities and differences of dog and human melanoma types and the strong potential of dog melanomas to decipher the non-UV light pathways in different melanoma types, especially mucosal and acral types.Cet article présente les données épidémiologiques et cliniques de 2350 cas de tumeurs mélanocytaires canines collectées en France. Nous avons réalisé la caractérisation histologique (n = 153) et génétique (n = 100) d'un sous-groupe de mélanomes dont les résultats ont été comparés aux données des mélanomes humains. Les mélanomes apparaissent aux mêmes sites anatomiques chez le chien et l'Homme, mais avec des fréquences et des sévérités différentes. Nous montrons les prédispositions raciales des mélanomes canins et l'intérêt de ce modèle pour rechercher les gènes prédisposant difficiles à identifier chez l'Homme. Des mutations somatiques dans les gènes NRAS et PTEN ont été détectées dans les mélanomes buccaux canins, précisément aux mêmes points chauds (hotspots) que les mutations de ces gènes chez l'homme. Au contraire, aucune mutation dans le gène BRAF n'a été retrouvée dans les échantillons canins analysés. Ce travail met en lumière les homologies et différences entre les types de mélanomes humains et canins et démontre la force du modèle canin pour analyser les voies de signalisation non UV-dépendantes des mélanomes humains, particulièrement dans les types muqueux et acraux

Genomic Analysis of the Necrotrophic Fungal Pathogens Sclerotinia sclerotiorum and Botrytis cinerea

Sclerotinia sclerotiorum and Botrytis cinerea are closely related necrotrophic plant pathogenic fungi notable for their wide host ranges and environmental persistence. These attributes have made these species models for understanding the complexity of necrotrophic, broad host-range pathogenicity. Despite their similarities, the two species differ in mating behaviour and the ability to produce asexual spores. We have sequenced the genomes of one strain of S. sclerotiorum and two strains of B. cinerea. The comparative analysis of these genomes relative to one another and to other sequenced fungal genomes is provided here. Their 38–39 Mb genomes include 11,860–14,270 predicted genes, which share 83% amino acid identity on average between the two species. We have mapped the S. sclerotiorum assembly to 16 chromosomes and found large-scale co-linearity with the B. cinerea genomes. Seven percent of the S. sclerotiorum genome comprises transposable elements compared to <1% of B. cinerea. The arsenal of genes associated with necrotrophic processes is similar between the species, including genes involved in plant cell wall degradation and oxalic acid production. Analysis of secondary metabolism gene clusters revealed an expansion in number and diversity of B. cinerea–specific secondary metabolites relative to S. sclerotiorum. The potential diversity in secondary metabolism might be involved in adaptation to specific ecological niches. Comparative genome analysis revealed the basis of differing sexual mating compatibility systems between S. sclerotiorum and B. cinerea. The organization of the mating-type loci differs, and their structures provide evidence for the evolution of heterothallism from homothallism. These data shed light on the evolutionary and mechanistic bases of the genetically complex traits of necrotrophic pathogenicity and sexual mating. This resource should facilitate the functional studies designed to better understand what makes these fungi such successful and persistent pathogens of agronomic crops