Toward a rational design of combination therapy in cancer.

By merging computational systems modeling and experimental approaches, we have uncovered treatments reprogramming pro-angiogenic monocytes present in breast tumor into immunologically potent cells capable of mediating an anti-tumor immune response. The unraveled pathways and ligands which underlie monocyte pro-angiogenic activity have a strong predictive value for breast cancer patient relapse - free survival.

Effect of humeral stem design on humeral position and range of motion in reverse shoulder arthroplasty.

PURPOSE: The impacts of humeral offset and stem design after reverse shoulder arthroplasty (RSA) have not been well-studied, particularly with regard to newer stems which have a lower humeral inclination. The purpose of this study was to analyze the effect of different humeral stem designs on range of motion and humeral position following RSA. METHODS: Using a three-dimensional computer model of RSA, a traditional inlay Grammont stem was compared to a short curved onlay stem with different inclinations (155°, 145°, 135°) and offset (lateralised vs medialised). Humeral offset, the acromiohumeral distance (AHD), and range of motion were evaluated for each configuration. RESULTS: Altering stem design led to a nearly 7-mm change in humeral offset and 4 mm in the AHD. Different inclinations of the onlay stems had little influence on humeral offset and larger influence on decreasing the AHD. There was a 10° decrease in abduction and a 5° increase in adduction between an inlay Grammont design and an onlay design with the same inclination. Compared to the 155° model, the 135° model improved adduction by 28°, extension by 24° and external rotation of the elbow at the side by 15°, but led to a decrease in abduction of 9°. When the tray was placed medially, on the 145° model, a 9° loss of abduction was observed. CONCLUSIONS: With varus inclination prostheses (135° and 145°), elevation remains unchanged, abduction slightly decreases, but a dramatic improvement in adduction, extension and external rotation with the elbow at the side are observed.

High mobility group box 1 protein (HMGB1) : a pathogenic role in preeclampsia

Introduction : la Physiopathologie maternelle de la prééclampsie s'associe typiquement à un état inflammatoire systémique modéré. La protéine "high mobility group box 1" (HMGB-1) est une protéine nucléaire ubiquitaire. En cas de stress cellulaire, elle est relâchée dans le milieu extrace llua li re et peut ainsi exercer son activité pro-inflammatoire. En cas de prééclampsie, le liquide amniotique et le cytoplasme des cellules trophoblastiques contiennent des quantités anormalement élevées de HMGB-1, mais il n'est toujours pas universellement admis que ces concentrations se retrouvent dans le sang maternel. Méthodes : nous avons recruté 32 femmes au troisième trimestre de grossesse, 16 avec et 16 sans prééclampsie. Nous avons également observé 16 femmes non enceintes et en bonne santé, appariées selon l'âge avec les femmes enceintes. Nous avons mesuré la concentration sérique de HMGB-1 chez les femmes enceintes avant, puis 24-48 heures après leur accouchement, en utilisant un kit ELISA commercial. Le même dosage a été réalisé chez les femmes non enceintes, mais à une seule reprise, au moment de leur inclusion dans l'étude. Résultats : le jour de leur inclusion dans l'étude, la concentration médiane [intervalle interquartile] de HMGB-1 chez les femmes enceintes prééclamptiques était de 2.1 ng/ml [1.1 - 3.2], de 1.1 [1.0-1.2] chez les grossesses saines (p < 0.05 vs groupe prééclamptiques) et de 0.6 [0.5 - 0.8] chez les patientes non enceintes (p < 0.01 vs deux autres groupes). Pour les deux groupes de femmes enceintes, les concentrations mesurées en post-partum ne variaient pas significativement de celles mesurées avant l'accouchement. Conclusion : avec ou sans prééclampsie, le troisième triemstre de la grossesse est associé à une élévation des taux circulants de HMGB-1. Cette augmentation est exagérée en cas de prééclampsie. L'origine de ces concentrations élevées reste à déterminer, mais elle semble impliquer d'autres organes que le placenta lui-même.

Design and physicochemical stability studies of paediatric oral formulations of sildenafil

Abstract Personalized medicine is a challenging research area in paediatric treatments. Elaborating new paediatric formulations when no commercial forms are available is a common practice in pharmacy laboratories; among these, oral liquid formulations are the most common. But due to the lack of specialized equipment, frequently studies to assure the efficiency and safety of the final medicine cannot be carried out. Thus the purpose of this work was the development, characterization and stability evaluation of two oral formulations of sildenafil for the treatment of neonatal persistent pulmonary hypertension. After the establishment of a standard operating procedure (SOP) and elaboration, the physicochemical stability parameters appearance, pH, particle size, rheological behaviour and drug content of formulations were evaluated at three different temperatures for 90 days. Equally, prediction of long term stability, as well as, microbiological stability was performed. Formulations resulted in a suspension and a solution slightly coloured exhibiting fruity odour. Formulation I (suspension) exhibited the best physicochemical properties including Newtonian behaviour and uniformity of API content above 90% to assure an exact dosification process.

Handbook of life design : from practice to theory and from theory to practice

Our lives and careers are becoming ever more unpredictable. The "life-design paradigm" described in detail in this ground-breaking handbook helps counselors and others meet people's increasing need to develop and manage their own lives and careers. Life-design interventions, suited to a wide variety of cultural settings, help individuals become actors in their own lives and careers by activating, stimulating, and developing their personal resources. This handbook first addresses life-design theory, then shows how to apply life designing to different age groups and with more at-risk people, and looks at how to train life-design counselors

The octagon, the hendecagon and the approximation of pi: the geometric design of the clypeus in the enclosure of Imperial cult in Tarraco

The ancient temple dedicated to the Roman Emperor Augustus on the hilltop of Tarraco (today’s Tarragona), was the main element of the sacred precinct of the Imperial cult. It was a two hectare square, bordered by a portico with an attic decorated with a sequence of clypeus (i.e. monumental shields) made with marble plates from the Luni-Carrara’s quarries. This contribution presents the results of the analysis of a three-dimensional photogrammetric survey of one of these clipeus, partially restored and exhibited at the National Archaeological Museum of Tarragona. The perimeter ring was bounded by a sequence of meanders inscribed in a polygon of 11 sides, a hendecagon. Moreover, a closer geometric analysis suggests that the relationship between the outer meander rim and the oval pearl ring that delimited the divinity of Jupiter Ammon can be accurately determined by the diagonals of an octagon inscribed in the perimeter of the clypeus. This double evidence suggests a combined layout, in the same design, of an octagon and a hendecagon. Hypothetically, this could be achieved by combining the octagon with the approximation to Pi used in antiquity: 22/7 of the circle’s diameter. This method allows the drawing of a hendecagon with a clearly higher precision than with other ancient methods. Even the modelling of the motifs that separate the different decorative stripes corroborates the geometric scheme that we propose.

Structure-Based, Rational Design of T Cell Receptors.

Adoptive cell transfer using engineered T cells is emerging as a promising treatment for metastatic melanoma. Such an approach allows one to introduce T cell receptor (TCR) modifications that, while maintaining the specificity for the targeted antigen, can enhance the binding and kinetic parameters for the interaction with peptides (p) bound to major histocompatibility complexes (MHC). Using the well-characterized 2C TCR/SIYR/H-2K(b) structure as a model system, we demonstrated that a binding free energy decomposition based on the MM-GBSA approach provides a detailed and reliable description of the TCR/pMHC interactions at the structural and thermodynamic levels. Starting from this result, we developed a new structure-based approach, to rationally design new TCR sequences, and applied it to the BC1 TCR targeting the HLA-A2 restricted NY-ESO-1157-165 cancer-testis epitope. Fifty-four percent of the designed sequence replacements exhibited improved pMHC binding as compared to the native TCR, with up to 150-fold increase in affinity, while preserving specificity. Genetically engineered CD8(+) T cells expressing these modified TCRs showed an improved functional activity compared to those expressing BC1 TCR. We measured maximum levels of activities for TCRs within the upper limit of natural affinity, K D = ∼1 - 5 μM. Beyond the affinity threshold at K D < 1 μM we observed an attenuation in cellular function, in line with the "half-life" model of T cell activation. Our computer-aided protein-engineering approach requires the 3D-structure of the TCR-pMHC complex of interest, which can be obtained from X-ray crystallography. We have also developed a homology modeling-based approach, TCRep 3D, to obtain accurate structural models of any TCR-pMHC complexes when experimental data is not available. Since the accuracy of the models depends on the prediction of the TCR orientation over pMHC, we have complemented the approach with a simplified rigid method to predict this orientation and successfully assessed it using all non-redundant TCR-pMHC crystal structures available. These methods potentially extend the use of our TCR engineering method to entire TCR repertoires for which no X-ray structure is available. We have also performed a steered molecular dynamics study of the unbinding of the TCR-pMHC complex to get a better understanding of how TCRs interact with pMHCs. This entire rational TCR design pipeline is now being used to produce rationally optimized TCRs for adoptive cell therapies of stage IV melanoma.