PRIMAGE project : predictive in silico multiscale analytics to support childhood cancer personalised evaluation empowered by imaging biomarkers

PRIMAGE is one of the largest and more ambitious research projects dealing with medical imaging, artificial intelligence and cancer treatment in children. It is a 4-year European Commission-financed project that has 16 European partners in the consortium, including the European Society for Paediatric Oncology, two imaging biobanks, and three prominent European paediatric oncology units. The project is constructed as an observational in silico study involving high-quality anonymised datasets (imaging, clinical, molecular, and genetics) for the training and validation of machine learning and multiscale algorithms. The open cloud-based platform will offer precise clinical assistance for phenotyping (diagnosis), treatment allocation (prediction), and patient endpoints (prognosis), based on the use of imaging biomarkers, tumour growth simulation, advanced visualisation of confidence scores, and machine-learning approaches. The decision support prototype will be constructed and validated on two paediatric cancers: neuroblastoma and diffuse intrinsic pontine glioma. External validation will be performed on data recruited from independent collaborative centres. Final results will be available for the scientific community at the end of the project, and ready for translation to other malignant solid tumours

Primeros episodios psicóticos: características clínicas y patrones de consumo de sustancias en pacientes ingresados en una unidad de agudos

Objetivo: observar y describir las características sociodemográficas, clínicas y patrones de consumo de sustancias que presentan los pacientes ingresados por primer episodio psicótico. Método: se incluyeron todos los ingresos realizados de primeros episodios psicóticos entre enero de 2000 y setiembre de 2003. La muestra final estuvo formada por 82 pacientes que ingresaron en la unidad de agudos del servicio de psiquiatría del Hospital de Mataró. Resultados: Del total de la muestra, un 56% de pacientes presentaron abuso de sustancias tóxicas en los últimos años de entre los cuales un 23.2% manifestó un aumento de dicho consumo durante las últimas tres semanas anteriores al ingreso psiquiátrico. Se observa una correlación significativa entre el aumento del consumo de sustancias en las tres últimas semanas y la duración del ingreso psiquiátrico (p=.043, r de Pearson). También entre los antecedentes de consumo de drogas y un debut más temprano del trastorno psicótico (p=.02). Conclusiones: El consumo de drogas en los trastornos psicóticos nos conduce directamente a la eterna reflexión de si la correlación que encontramos entre ambas variables podría ir más allá de una mera asociación y que el consumo fuese un factor predictivo del inicio o de la transición al primer episodio psicótico

A combined transcriptomic and genomic analysis identifies a gene signature associated with the response to anti-TNF therapy in rheumatoid arthritis

Background: Rheumatoid arthritis (RA) is the most frequent autoimmune disease involving the joints. Although anti-TNF therapies have proven effective in the management of RA, approximately one third of patients do not show a significant clinical response. The objective of this study was to identify new genetic variation associated with the clinical response to anti-TNF therapy in RA. Methods: We performed a sequential multi-omic analysis integrating different sources of molecular information. First, we extracted the RNA from synovial biopsies of 11 RA patients starting anti-TNF therapy to identify gene coexpression modules (GCMs) in the RA synovium. Second, we analyzed the transcriptomic association between each GCM and the clinical response to anti-TNF therapy. The clinical response was determined at week 14 using the EULAR criteria. Third, we analyzed the association between the GCMs and anti-TNF response at the genetic level. For this objective, we used genome-wide data from a cohort of 348 anti-TNF treated patients from Spain. The GCMs that were significantly associated with the anti-TNF response were then tested for validation in an independent cohort of 2,706 anti-TNF treated patients. Finally, the functional implication of the validated GCMs was evaluated via pathway and cell type epigenetic enrichment analyses. Results: A total of 149 GCMs were identified in the RA synovium. From these, 13 GCMs were found to be significantly associated with anti-TNF response (P < 0.05). At the genetic level, we detected two of the 13 GCMs to be significantly associated with the response to adalimumab (P = 0.0015) and infliximab (P = 0.021) in the Spain cohort. Using the independent cohort of RA patients, we replicated the association of the GCM associated with the response to adalimumab (P = 0.0019). The validated module was found to be significantly enriched for genes involved in the nucleotide metabolism (P = 2.41e-5) and epigenetic marks from immune cells, including CD4+ regulatory T cells (P = 0.041). Conclusions: These findings show the existence of a drug-specific genetic basis for anti-TNF response, thereby supporting treatment stratification in the search for response biomarkers in RA

Evaluation of 12 GWAS-drawn SNPs as biomarkers of rheumatoid arthritis response to TNF inhibitors. A potential SNP association with response to etanercept

Research in rheumatoid arthritis (RA) is increasingly focused on the discovery of biomarkers that could enable personalized treatments. The genetic biomarkers associated with the response to TNF inhibitors (TNFi) are among the most studied. They include 12 SNPs exhibiting promising results in the three largest genome-wide association studies (GWAS). However, they still require further validation. With this aim, we assessed their association with response to TNFi in a replication study, and a meta-analysis summarizing all nonredundant data. The replication involved 755 patients with RA that were treated for the first time with a biologic drug, which was either infliximab (n = 397), etanercept (n = 155) or adalimumab (n = 203). Their DNA samples were successfully genotyped with a single-base extension multiplex method. Lamentably, none of the 12 SNPs was associated with response to the TNFi in the replication study (p > 0.05). However, a drug-stratified exploratory analysis revealed a significant association of the NUBPL rs2378945 SNP with a poor response to etanercept (B = -0.50, 95% CI = -0.82, -0.17, p = 0.003). In addition, the metaanalysis reinforced the previous association of three SNPs: Rs2378945, rs12142623, and rs4651370. In contrast, five of the remaining SNPs were less associated than before, and the other four SNPs were no longer associated with the response to treatment. In summary, our results highlight the complexity of the pharmacogenetics of TNFi in RA showing that it could involve a drug-specific component and clarifying the status of the 12 GWAS-drawn SNPs. © 2019 Ferreiro-Iglesias et al.This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited

Validation study of genetic biomarkers of response to TNF inhibitors in rheumatoid arthritis

Genetic biomarkers are sought to personalize treatment of patients with rheumatoid arthritis (RA), given their variable response to TNF inhibitors (TNFi). However, no genetic biomaker is yet sufficiently validated. Here, we report a validation study of 18 previously reported genetic biomarkers, including 11 from GWAS of response to TNFi. The validation was attempted in 581 patients with RA that had not been treated with biologic antirheumatic drugs previously. Their response to TNFi was evaluated at 3, 6 and 12 months in two ways: change in the DAS28 measure of disease activity, and according to the EULAR criteria for response to antirheumatic drugs. Association of these parameters with the genotypes, obtained by PCR amplification followed by single-base extension, was tested with regression analysis. These analyses were adjusted for baseline DAS28, sex, and the specific TNFi. However, none of the proposed biomarkers was validated, as none showed association with response to TNFi in our study, even at the time of assessment and with the outcome that showed the most significant result in previous studies. These negative results are notable because this was the first independent validation study for 12 of the biomarkers, and because they indicate that prudence is needed in the interpretation of the proposed biomarkers of response to TNFi even when they are supported by very low p values. The results also emphasize the requirement of independent replication for validation, and the need to search protocols that could increase reproducibility of the biomarkers of response to TNFi. © 2018 Lopez-Rodriguez et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited

Replication of PTPRC as genetic biomarker of response to TNF inhibitors in patients with rheumatoid arthritis

Genetic biomarkers could be useful for orienting treatment of patients with rheumatoid arthritis (RA), but none has been convincingly validated yet. Putative biomarkers include 14 single nucleotide polymorphisms that have shown association with response to TNF inhibitors (TNFi) in candidate gene studies and that we assayed here in 755 RA patients. Three of them, in the PTPRC, IL10 and CHUK genes, were significantly associated with response to TNFi. The most significant result was obtained with rs10919563 in PTPRC, which is a confirmed RA susceptibility locus. Its RA risk allele was associated with improved response (B=0.33, P=0.006). This is the second independent replication of this biomarker (P=9.08 × 10 -8 in the combined 3003 RA patients). In this way, PTPRC has become the most replicated genetic biomarker of response to TNFi. In addition, the positive but weaker replication of IL10 and CHUK should stimulate further validation studies. © 2016 Macmillan Publishers Limited

High-precision mass measurements of neutron deficient silver isotopes probe the robustness of the NN = 50 shell closure

International audienceHigh-precision mass measurements of exotic $^{95-97}$Ag isotopes close to the $N = Z$ line have been conducted with the JYFLTRAP double Penning trap mass spectrometer, with the silver ions produced using the recently commissioned inductively-heated hot cavity catcher laser ion source at the Ion Guide Isotope Separator On-Line facility. The atomic mass of $^{95}$Ag was directly determined for the first time. In addition, the atomic masses of $\beta$-decaying 2$^+$ and 8$^+$ states in $^{96}$Ag have been identified and measured for the first time, and the precision of the $^{97}$Ag mass has been improved. The newly measured masses, with a precision of $\approx$ 1 keV/c$^2$, have been used to investigate the $N =$ 50 neutron shell closure confirming it to be robust. Precise empirical shell-gap and pairing energies determined with the new ground-state mass data are used to benchmark state-of-the-art \textit{ab initio} calculations with various chiral effective field theory Hamiltonians. In addition, density functional theory (DFT) calculations and configuration-interaction shell-model (CISM) calculations are compared with the experimental results. All theoretical approaches face challenges to reproduce the trend of nuclear ground-state properties in the silver isotopic chain across the $N =$50 neutron shell and toward the proton drip-line. Furthermore, the precise determination of the isomeric excitation energy of $^{96m}$Ag serves as a benchmark for \textit{ab initio} predictions of nuclear properties beyond the ground state, specifically for odd-odd nuclei situated in proximity to the proton dripline below $^{100}$Sn