Current and novel therapeutic opportunities for systemic therapy in biliary cancer

none24Biliary tract cancers (BTCs) are a group of rare and aggressive malignancies that arise in the biliary tree within and outside the liver. Beyond surgical resection, which is beneficial for only a small proportion of patients, current strategies for treating patients with BTCs include chemotherapy, as a single agent or combination regimens, in the adjuvant and palliative setting. Increased characterisation of the molecular landscape of these tumours has facilitated the identification of molecular vulnerabilities, such as IDH mutations and FGFR fusions, that can be exploited for the treatment of BTC patients. Beyond targeted therapies, active research avenues explore the development of novel therapeutics that target the crosstalk between cancer and stroma, the cellular pathways involved in the regulation of cell death, the chemoresistance phenotype and the dysregulation of RNA. In this review, we discuss the therapeutic opportunities currently available in the management of BTC patients, and explore the strategies that can support the implementation of precision oncology in BTCs, including novel molecular targets, liquid biopsies and patient-derived predictive tools.openMarin J.J.G.; Prete M.G.; Lamarca A.; Tavolari S.; Landa-Magdalena A.; Brandi G.; Segatto O.; Vogel A.; Macias R.I.R.; Rodrigues P.M.; Casta A.L.; Mertens J.; Rodrigues C.M.P.; Fernandez-Barrena M.G.; Da Silva Ruivo A.; Marzioni M.; Mentrasti G.; Acedo P.; Munoz-Garrido P.; Cardinale V.; Banales J.M.; Valle J.W.; Bridgewater J.; Braconi C.Marin, J. J. G.; Prete, M. G.; Lamarca, A.; Tavolari, S.; Landa-Magdalena, A.; Brandi, G.; Segatto, O.; Vogel, A.; Macias, R. I. R.; Rodrigues, P. M.; Casta, A. L.; Mertens, J.; Rodrigues, C. M. P.; Fernandez-Barrena, M. G.; Da Silva Ruivo, A.; Marzioni, M.; Mentrasti, G.; Acedo, P.; Munoz-Garrido, P.; Cardinale, V.; Banales, J. M.; Valle, J. W.; Bridgewater, J.; Braconi, C

Interatomic potentials for atomistic simulations of the Ti-Al system

Semi-empirical interatomic potentials have been developed for Al, alpha-Ti, and gamma-TiAl within the embedded atomic method (EAM) by fitting to a large database of experimental as well as ab-initio data. The ab-initio calculations were performed by the linear augmented plane wave (LAPW) method within the density functional theory to obtain the equations of state for a number of crystal structures of the Ti-Al system. Some of the calculated LAPW energies were used for fitting the potentials while others for examining their quality. The potentials correctly predict the equilibrium crystal structures of the phases and accurately reproduce their basic lattice properties. The potentials are applied to calculate the energies of point defects, surfaces, planar faults in the equilibrium structures. Unlike earlier EAM potentials for the Ti-Al system, the proposed potentials provide reasonable description of the lattice thermal expansion, demonstrating their usefulness in the molecular dynamics or Monte Carlo studies at high temperatures. The energy along the tetragonal deformation path (Bain transformation) in gamma-TiAl calculated with the EAM potential is in a fairly good agreement with LAPW calculations. Equilibrium point defect concentrations in gamma-TiAl are studied using the EAM potential. It is found that antisite defects strongly dominate over vacancies at all compositions around stoichiometry, indicating that gamm-TiAl is an antisite disorder compound in agreement with experimental data.Comment: 46 pages, 6 figures (Physical Review B, in press

Peabody Picture Vocabulary Test-III: Normative data for Spanish-speaking pediatric population

OBJECTIVE: To generate normative data for the Peabody Picture Vocabulary Test-III (PPVT-III) in Spanish-speaking pediatric populations. METHOD: The sample consisted of 4,373 healthy children from nine countries in Latin America (Chile, Cuba, Ecuador, Honduras, Guatemala, Mexico, Paraguay, Peru, and Puerto Rico) and Spain. Each participant was administered the PPVT-III as part of a larger neuropsychological battery. PPVT-III scores were normed using multiple linear regressions and standard deviations of residual values. Age, age2, sex, and mean level of parental education (MLPE) were included as predictors in the analyses. RESULTS: The final multiple linear regression models showed main effects for age in all countries, such that scores increased linearly as a function of age. In addition, age2 had a significant effect in all countries, except Guatemala and Paraguay. Models showed that children whose parent(s) had a MLPE >12 years obtained higher scores compared to children whose parent(s) had a MLPE ≤12 years in all countries, except for Cuba, Peru, and Puerto Rico. Sex affected scores for Chile, Ecuador, Guatemala, Mexico, and Spain. CONCLUSIONS: This is the largest Spanish-speaking pediatric normative study in the world, and it will allow neuropsychologists from these countries to have a more accurate interpretation of the PPVT-III when used in pediatric populations

Seizure-related 6 homolog like 2 autoimmunity Neurologic syndrome and antibody effects

Objective To describe the clinical syndrome of 4 new patients with seizure-related 6 homolog like 2 antibodies (SEZ6L2-abs), study the antibody characteristics, and evaluate their effects on neuronal cultures. Methods SEZ6L2-abs were initially identified in serum and CSF of a patient with cerebellar ataxia by immunohistochemistry on rat brain sections and immunoprecipitation from rat cerebellar neurons. We used a cell-based assay (CBA) of HEK293 cells transfected with SEZ6L2 to test the serum of 95 patients with unclassified neuropil antibodies, 331 with different neurologic disorders, and 10 healthy subjects. Additional studies included characterization of immunoglobulin G (IgG) subclasses and the effects of SEZ6L2-abs on cultures of rat hippocampal neurons. Results In addition to the index patient, SEZ6L2-abs were identified by CBA in 3/95 patients with unclassified neuropil antibodies but in none of the 341 controls. The median age of the 4 patients was 62 years (range: 54-69 years), and 2 were female. Patients presented with subacute gait ataxia, dysarthria, and mild extrapyramidal symptoms. Initial brain MRI was normal, and CSF pleocytosis was found in only 1 patient. None improved with immunotherapy. SEZ6L2-abs recognized conformational epitopes. IgG4 SEZ6L2-abs were found in all 4 patients, and it was the predominant subclass in 2. SEZ6L2-abs did not alter the number of total or synaptic SEZ6L2 or the AMPA glutamate receptor 1 (GluA1) clusters on the surface of hippocampal neurons. Conclusions SEZ6L2-abs associate with a subacute cerebellar syndrome with frequent extrapyramidal symptoms. The potential pathogenic effect of the antibodies is not mediated by internalization of the antigen.Neurological Motor Disorder

Figurative language processing in atypical populations: the ASD perspective

This document is protected by copyright and was first published by Frontiers. All rights reserved. It is reproduced with permissionThis paper is intended to provide a critical overview of experimental and clinical research documenting problems in figurative language processing in atypical populations with a focus on the Autistic Spectrum. Research in the comprehension and processing of figurative language in autism invariably documents problems in this area. The greater paradox is that even at the higher end of the spectrum or in the cases of linguistically talented individuals with Asperger syndrome, where structural language competence is intact, problems with extended language persist. If we assume that figurative and extended uses of language essentially depend on the perception and processing of more concrete core concepts and phenomena, the commonly observed failure in atypical populations to understand figurative language remains a puzzle. Various accounts have been offered to explain this issue, ranging from linking potential failure directly to overall structural language competence (Norbury, 2005; Brock et al., 2008) to right-hemispheric involvement (Gold and Faust, 2010). We argue that the dissociation between structural language and figurative language competence in autism should be sought in more general cognitive mechanisms and traits in the autistic phenotype (e.g., in terms of weak central coherence, Vulchanova et al., 2012b), as well as failure at on-line semantic integration with increased complexity and diversity of the stimuli (Coulson and Van Petten, 2002). This perspective is even more compelling in light of similar problems in a number of conditions, including both acquired (e.g., Aphasia) and developmental disorders (Williams Syndrome). This dissociation argues against a simple continuity view of language interpretation

Newly developed Learning and Verbal Memory Test (TAMV-I): Normative data for Spanish-speaking pediatric population

OBJECTIVE: To generate normative data for the Learning and Verbal Memory Test (TAMV-I) in Spanish-speaking pediatric populations. METHOD: The sample consisted of 4,373 healthy children from nine countries in Latin America (Chile, Cuba, Ecuador, Guatemala, Honduras, Mexico, Paraguay, Peru, and Puerto Rico) and Spain. Each participant was administered the TAMV-I as part of a larger neuropsychological battery. Free recall, memory delay and recognition scores were normed using multiple linear regressions and standard deviations of residual values. Age, age2, sex, and mean level of parental education (MLPE) were included as predictors in the analyses. RESULTS: The final multiple linear regression models indicated main effects for age on all scores, such that scores increased linearly as a function of age. Age2 had a significant effect in all countries except Cuba, and Puerto Rico for free recall score; a significant effect for memory delay score in all countries except Cuba and Puerto Rico; and a significant effect for recognition score in in all countries except Guatemala, Honduras, and Puerto Rico. Models showed an effect for MLPE in Chile (free recall), Honduras (free recall), Mexico (free recall), Puerto Rico (free recall, memory delay, and recognition), and Spain (free recall and memory delay). Sex affected free recall score for Cuba, Ecuador, Guatemala, Mexico, Paraguay, Peru, and Spain, memory delay score for all countries except Chile, Paraguay, and Puerto Rico, and recognition score for Ecuador, Mexico, Peru, and Spain, with girls scoring higher than boys. CONCLUSIONS: This is the largest Spanish-speaking pediatric normative study in the world, and it will allow neuropsychologists from these countries to have a more accurate way to interpret the TAMV-I with pediatric populations

Aboveground biomass density models for NASA's Global Ecosystem Dynamics Investigation (GEDI) lidar mission

NASA's Global Ecosystem Dynamics Investigation (GEDI) is collecting spaceborne full waveform lidar data with a primary science goal of producing accurate estimates of forest aboveground biomass density (AGBD). This paper presents the development of the models used to create GEDI's footprint-level (similar to 25 m) AGBD (GEDI04_A) product, including a description of the datasets used and the procedure for final model selection. The data used to fit our models are from a compilation of globally distributed spatially and temporally coincident field and airborne lidar datasets, whereby we simulated GEDI-like waveforms from airborne lidar to build a calibration database. We used this database to expand the geographic extent of past waveform lidar studies, and divided the globe into four broad strata by Plant Functional Type (PFT) and six geographic regions. GEDI's waveform-to-biomass models take the form of parametric Ordinary Least Squares (OLS) models with simulated Relative Height (RH) metrics as predictor variables. From an exhaustive set of candidate models, we selected the best input predictor variables, and data transformations for each geographic stratum in the GEDI domain to produce a set of comprehensive predictive footprint-level models. We found that model selection frequently favored combinations of RH metrics at the 98th, 90th, 50th, and 10th height above ground-level percentiles (RH98, RH90, RH50, and RH10, respectively), but that inclusion of lower RH metrics (e.g. RH10) did not markedly improve model performance. Second, forced inclusion of RH98 in all models was important and did not degrade model performance, and the best performing models were parsimonious, typically having only 1-3 predictors. Third, stratification by geographic domain (PFT, geographic region) improved model performance in comparison to global models without stratification. Fourth, for the vast majority of strata, the best performing models were fit using square root transformation of field AGBD and/or height metrics. There was considerable variability in model performance across geographic strata, and areas with sparse training data and/or high AGBD values had the poorest performance. These models are used to produce global predictions of AGBD, but will be improved in the future as more and better training data become available

Global patient outcomes after elective surgery: prospective cohort study in 27 low-, middle- and high-income countries.

BACKGROUND: As global initiatives increase patient access to surgical treatments, there remains a need to understand the adverse effects of surgery and define appropriate levels of perioperative care. METHODS: We designed a prospective international 7-day cohort study of outcomes following elective adult inpatient surgery in 27 countries. The primary outcome was in-hospital complications. Secondary outcomes were death following a complication (failure to rescue) and death in hospital. Process measures were admission to critical care immediately after surgery or to treat a complication and duration of hospital stay. A single definition of critical care was used for all countries. RESULTS: A total of 474 hospitals in 19 high-, 7 middle- and 1 low-income country were included in the primary analysis. Data included 44 814 patients with a median hospital stay of 4 (range 2-7) days. A total of 7508 patients (16.8%) developed one or more postoperative complication and 207 died (0.5%). The overall mortality among patients who developed complications was 2.8%. Mortality following complications ranged from 2.4% for pulmonary embolism to 43.9% for cardiac arrest. A total of 4360 (9.7%) patients were admitted to a critical care unit as routine immediately after surgery, of whom 2198 (50.4%) developed a complication, with 105 (2.4%) deaths. A total of 1233 patients (16.4%) were admitted to a critical care unit to treat complications, with 119 (9.7%) deaths. Despite lower baseline risk, outcomes were similar in low- and middle-income compared with high-income countries. CONCLUSIONS: Poor patient outcomes are common after inpatient surgery. Global initiatives to increase access to surgical treatments should also address the need for safe perioperative care. STUDY REGISTRATION: ISRCTN5181700