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International audience; Tokamaks coils are wound with long lengths of cables including hundreds of superconducting and copper strands twisted together into multiple stages. They refer to Cable In Conduit Conductors (CICC). Coupling losses induced by magnetic field variations dissipate power in the coils during machine operation. For several years, the CEA has been developing the analytical model COLISEUM (COupling Losses analytIcal Staged cablEs Unified Model) aiming at predicting coupling losses at various conductor scales. Geometrical (cabling radii, twist pitches) and electrical (inter-strand and inter-bundle conductances) parameters of each stage constitute the model inputs. In this article, we first present the raw 3D tomographic image treatment method that will serve to generate COLISEUM inputs with high level of reliability. We then define and extract several relevant effective geometric cable parameters from images data. These inputs are used along with the COLISEUM model to improve coupling losses prediction. A systematic study of six JT-60SA TF type samples has been realized and a geometric parameters database is constructed. The COLISEUM model is used in a 2-stage configuration with the two highest stages of the cable. First results are presented and discussed.

Pediatric growth tracking has been identified as a top priority by international health agencies to assess the severity of malnutrition and stunting. However, remote low-resource settings often lack the necessary infrastructure for longitudinal analysis of growth for the purposes of early identification and immediate intervention of stunting.To address this gap, we developed a portable field unit (PFU) capable of identifying a child over the course of multiple visits, each time adding new anthropomorphic measurements. We conducted a preliminary field evaluation of the PFU by using the unit on two distinct visits to three schools in the area surrounding a medical clinic in rural San Jose, Honduras. The unit was used to assess children at each school as part of the community outreach.Community outreaches to three schools were conducted by two distinct teams, where they used the device to assess 210 children. Of the 180 children registered during the first visit, 112 were re-identified and assessed on the subsequent visit. Twenty-four instances of moderate-to-severe malnutrition were identified and referred for further evaluation to the central clinic.This initial assessment suggests that the PFU could be an effective means of identifying at-risk children.Les organismes internationaux de santé ont identifié le suivi de la croissance des enfants comme une priorité absolue pour évaluer la gravité de la malnutrition et les retards de croissance. Cependant, les zones reculées à faibles ressources n’ont souvent pas les infrastructures nécessaires à l’analyse longitudinale de la croissance à des fins d’identification précoce et d’intervention immédiate de lutte contre les retards de croissance.Pour combler ces lacunes, nous avons développé un appareil portatif de terrain (PFU) capable d’identifier un même enfant lors de plusieurs visites et d’ajouter les nouvelles mesures anthropomorphiques de chaque visite. Nous avons réalisé une évaluation de terrain préliminaire du PFU en utilisant l’appareil lors de deux visites différentes dans trois écoles de la zone rurale aux alentours d’une clinique médicale de San Jose, Honduras. L’appareil a été utilisé pour évaluer les enfants de chaque école dans le cadre d’un programme de sensibilisation communautaire.Des programmes de sensibilisation communautaire ont été menés dans trois écoles par deux équipes différentes, qui ont utilisé l’appareil pour évaluer 210 enfants. Sur les 180 enfants enregistrés lors de la première visite, 112 ont été de nouveau identifiés et évalués lors de la visite suivante. Vingt-quatre cas de malnutrition modérée à sévère ont été identifiés et adressés pour examen complémentaire à la clinique centrale.Cette évaluation initiale suggère que le PFU pourrait être un moyen efficace d’identification des enfants à risque.

Supplementary Figure 8 shows the principal component analysis followed by k-means clustering to group xenografts based on their sensitivity to cisplatin, talazoparib and cisplatin-talazoparib

Purpose:Pancreatic ductal adenocarcinoma (PDAC) arising in patients with a germline BRCA1 or BRCA2 (gBRCA) mutation may be sensitive to platinum and PARP inhibitors (PARPi). However, treatment stratification based on gBRCA mutational status alone is associated with heterogeneous responses.Experimental Design:We performed a seven-arm preclinical trial consisting of 471 mice, representing 12 unique PDAC patient-derived xenografts, of which nine were gBRCA mutated. From 179 patients whose PDAC was whole-genome and transcriptome sequenced, we identified 21 cases with homologous recombination deficiency (HRD), and investigated prognostic biomarkers.Results:We found that biallelic inactivation of BRCA1/BRCA2 is associated with genomic hallmarks of HRD and required for cisplatin and talazoparib (PARPi) sensitivity. However, HRD genomic hallmarks persisted in xenografts despite the emergence of therapy resistance, indicating the presence of a genomic scar. We identified tumor polyploidy and a low Ki67 index as predictors of poor cisplatin and talazoparib response. In patients with HRD PDAC, tumor polyploidy and a basal-like transcriptomic subtype were independent predictors of shorter survival. To facilitate clinical assignment of transcriptomic subtype, we developed a novel pragmatic two-marker assay (GATA6:KRT17).Conclusions:In summary, we propose a predictive and prognostic model of gBRCA-mutated PDAC on the basis of HRD genomic hallmarks, Ki67 index, tumor ploidy, and transcriptomic subtype.

Supplementary Figure 1 shows the results of the Disambiguate algorithm used to assign the PDAC xenograft RNAseq reads to individual species

Supplementary Figure 3: Association of chemokine expression with a T cell-inflamed phenotype was validated in a second independent PDAC patient cohort

Supplementary Figure 9 shows the Cox proportional hazards model, integrating Moffitt transcriptomic subtype, tumour ploidy, stage and age

Supplementary Table 1: Top 99 genes associating with CD8+ TIL counts in primary resected cases

Purpose: To perform real-time whole genome sequencing (WGS) and RNA sequencing (RNASeq) of advanced pancreatic ductal adenocarcinoma (PDAC) to identify predictive mutational and transcriptional features for better treatment selection.Experimental Design: Patients with advanced PDAC were prospectively recruited prior to first-line combination chemotherapy. Fresh tumor tissue was acquired by image-guided percutaneous core biopsy for WGS and RNASeq. Laser capture microdissection was performed for all cases. Primary endpoint was feasibility to report WGS results prior to first disease assessment CT scan at 8 weeks. The main secondary endpoint was discovery of patient subsets with predictive mutational and transcriptional signatures.Results: Sixty-three patients underwent a tumor biopsy between December 2015 and June 2017. WGS and RNASeq were successful in 62 (98%) and 60 (95%), respectively. Genomic results were reported at a median of 35 days (range, 19–52 days) from biopsy, meeting the primary feasibility endpoint. Objective responses to first-line chemotherapy were significantly better in patients with the classical PDAC RNA subtype compared with those with the basal-like subtype (P = 0.004). The best progression-free survival was observed in those with classical subtype treated with m-FOLFIRINOX. GATA6 expression in tumor measured by RNA in situ hybridization was found to be a robust surrogate biomarker for differentiating classical and basal-like PDAC subtypes. Potentially actionable genetic alterations were found in 30% of patients.Conclusions: Prospective genomic profiling of advanced PDAC is feasible, and our early data indicate that chemotherapy response differs among patients with different genomic/transcriptomic subtypes. Clin Cancer Res; 24(6); 1344–54. ©2017 AACR.

Supplementary Figure 7 shows the comparison of COSMIC SBS mutational signatures between untreated parent xenografts vs. xenografts treated with gemcitabine-cisplatin

Supplementary Figure 5 shows the immunohistochemical analysis of apoptotic activity in xenografts treated with gemcitabine mono- and combination therapies

Supplementary Figure 3 shows the histological analysis of the xenografts evaluated in the preclinical trial

Supplementary Methods, Tables and Figures Supplementary Table 1: Summary of whole genome sequencing results including performance metrics and time to reporting (N=62). Supplementary Table 2: Summary of GATA6 RNA in situ results and its correlation with RNA subtype and histologic grade. Supplementary Figure 1: WGS Performance Characteristics. Supplementary Figure 2: Both COMP-0037 and COMP-0057 had germline BRCA2 p.S1982fs mutations but only COMP-0037 had a second hit (somatic LOH of wild type allele) and showed hallmarks of double strand break repair deficiency. Supplementary Figure 3: BRCA2 mutation status of COMP-0057. Supplementary Figure 4: Subtypes of advanced PDAC by Moffitt tumour classification Supplementary Figure 5: Correlation between Moffitt tumor RNA subtypes and GATA6 gene expression. Supplementary Figure 6: Correlation between GATA6 expression measured by RNASeq and RNA in situ hybridization. Supplementary Figure 7: Differentially expressed pathways between Moffitt's basal like and classical RNA subtypes Supplementary Figure 8: CDK4 amplification identified in COMP-0008 (A) and CDK6 amplification identified in COMP-0010 (B) validated by fluorescence in-situ hybridization.

Supplementary Figure 6 shows the tumour ploidy analysis of xenografts evaluated in the preclinical trial that were not whole genome sequenced

Supplementary Figure 2 shows the results of a pilot monotherapy trial to evaluate regimen-related toxicity

Supplementary Table 3 shows the establishment of primary cell cultures from HRD PDAC xenografts

Supplementary Table 1 shows the clinical characteristics of the patients from whom patient-derived xenografts were generated and evaluated in the preclinical trial

Purpose:The molecular drivers of antitumor immunity in pancreatic ductal adenocarcinoma (PDAC) are poorly understood, posing a major obstacle for the identification of patients potentially amenable for immune-checkpoint blockade or other novel strategies. Here, we explore the association of chemokine expression with effector T-cell infiltration in PDAC.Experimental Design:Discovery cohorts comprised 113 primary resected PDAC and 107 PDAC liver metastases. Validation cohorts comprised 182 PDAC from The Cancer Genome Atlas and 92 PDACs from the Australian International Cancer Genome Consortium. We explored associations between immune cell counts by immunohistochemistry, chemokine expression, and transcriptional hallmarks of antitumor immunity by RNA sequencing (RNA-seq), and mutational burden by whole-genome sequencing.Results:Among all known human chemokines, a coregulated set of four (CCL4, CCL5, CXCL9, and CXCL10) was strongly associated with CD8+ T-cell infiltration (P < 0.001). Expression of this “4-chemokine signature” positively correlated with transcriptional metrics of T-cell activation (ZAP70, ITK, and IL2RB), cytolytic activity (GZMA and PRF1), and immunosuppression (PDL1, PD1, CTLA4, TIM3, TIGIT, LAG3, FASLG, and IDO1). Furthermore, the 4-chemokine signature marked tumors with increased T-cell activation scores (MHC I presentation, T-cell/APC costimulation) and elevated expression of innate immune sensing pathways involved in T-cell priming (STING and NLRP3 inflammasome pathways, BATF3-driven dendritic cells). Importantly, expression of this 4-chemokine signature was consistently indicative of a T-cell–inflamed phenotype across primary PDAC and PDAC liver metastases.Conclusions:A conserved 4-chemokine signature marks resectable and metastatic PDAC tumors with an active antitumor phenotype. This could have implications for the appropriate selection of PDAC patients in immunotherapy trials.

Supplementary Table 2 shows the clinical characteristics of 21 HRD PDAC patients whose tumours were whole genome and whole transcriptome sequenced

Purpose:To determine the impact of basal-like and classical subtypes in advanced pancreatic ductal adenocarcinoma (PDAC) and to explore GATA6 expression as a surrogate biomarker.Experimental Design:Within the COMPASS trial, patients proceeding to chemotherapy for advanced PDAC undergo tumor biopsy for RNA-sequencing (RNA-seq). Overall response rate (ORR) and overall survival (OS) were stratified by subtypes and according to chemotherapy received. Correlation of GATA6 with the subtypes using gene expression profiling, in situ hybridization (ISH) was explored.Results:Between December 2015 and May 2019, 195 patients (95%) had enough tissue for RNA-seq; 39 (20%) were classified as basal-like and 156 (80%) as classical. RECIST response data were available for 157 patients; 29 basal-like and 128 classical where the ORR was 10% versus 33%, respectively (P = 0.02). In patients with basal-like tumors treated with modified FOLFIRINOX (n = 22), the progression rate was 60% compared with 15% in classical PDAC (P = 0.0002). Median OS in the intention-to-treat population (n = 195) was 9.3 months for classical versus 5.9 months for basal-like PDAC (HR, 0.47; 95% confidence interval, 0.32–0.69; P = 0.0001). GATA6 expression by RNA-seq highly correlated with the classifier (P < 0.001) and ISH predicted the subtypes with sensitivity of 89% and specificity of 83%. In a multivariate analysis, GATA6 expression was prognostic (P = 0.02). In exploratory analyses, basal-like tumors, could be identified by keratin 5, were more hypoxic and enriched for a T-cell–inflamed gene expression signature.Conclusions:The basal-like subtype is chemoresistant and can be distinguished from classical PDAC by GATA6 expression.See related commentary by Collisson, p. 4715

Kaposi Sarcoma (KS) is the most common AIDS-defining cancer, even as HIV-positive people live longer. Like other herpesviruses, human herpesvirus-8 (HHV-8) establishes a lifelong infection of the host that in association with HIV infection may develop at any time during the illness. With the increasing global incidence of KS, there is an urgent need of designing optimal therapeutic strategies for HHV-8-related infections. Here we formulate two models with innate and adaptive immune mechanisms, relevant for non-AIDS KS (NAKS) and AIDS-KS, where the initial condition of the second model is given by the equilibrium state of the first one. For the model with innate mechanism (MIM), we define an infectivity resistance threshold that will determine whether the primary HHV-8 infection of B-cells will progress to secondary infection of progenitor cells, a concept relevant for viral carriers in the asymptomatic phase. The optimal control strategy has been employed to obtain treatment efficacy in case of a combined antiretroviral therapy (cART). For the MIM we have shown that KS therapy alone is capable of reducing the HHV-8 load. In the model with adaptive mechanism (MAM), we show that if cART is administered at optimal levels, that is, 0.48 for protease inhibitors, 0.79 for reverse transcriptase inhibitors and 0.25 for KS therapy, both HIV-1 and HHV-8 can be reduced. The predictions of these mathematical models have the potential to offer more effective therapeutic interventions in the treatment of NAKS and AIDS-KS.

In this paper, we have investigated how an investor’s income, who is rewarded by managing dual company stocks and additionally receives stochastic income, grows. We have calculated the optimal stock price and the optimal stock output that maximize his returns. We have shown that the best strategy is to choose from the set of prices .

Compact and defect-free high melting point oxide strengthened metallic matrix configurations are promising to resolve the hydrogen permeation and brittleness issues relevant to the fusion research community. Previous studies on oxide addition to metallic matrix demonstrated a mitigation in brittleness behavior, while deposition techniques and material configurations are still to be investigated. Thus, here, we report the structural, morphological, and mechanical characterization of metal-oxides thin layers co-deposited by radio frequency (RF)and direct current (DC) magnetron sputtering. A total of six configurations were deposited such as single thin layers of oxides (Al2O3, Er2O3) and co-deposition configurations as metal-oxides (W, Be)—(Al2O3, Er2O3). The study of films roughness by atomic force microscopy (AFM) method show that for Al2O3 metallic-oxides is increased to an extent that could favor gaseous trapping, while co-depositions with Be seem to promote an increased roughness and defects formation probability compared to W co-depositions. Lower elastic modulus on metal-oxide co-depositions was observed, while the indentation hardness increased for Be and decreased for W matrix configurations. These outputs are highly relevant for choosing the proper compact and trap-free configuration that could be categorized as a permeation barrier for hydrogen and furtherly studied in laborious permeation yield campaigns.

Purpose: To determine the impact of basal-like and classical subtypes in advanced pancreatic ductal adenocarcinoma (PDAC) and to explore GATA6 expression as a surrogate biomarker. Experimental Design: Within the COMPASS trial, patients proceeding to chemotherapy for advanced PDAC undergo tumor biopsy for RNA-sequencing (RNA-seq). Overall response rate (ORR) and overall survival (OS) were stratified by subtypes and according to chemotherapy received. Correlation of GATA6 with the subtypes using gene expression profiling, in situ hybridization (ISH) was explored. Results: Between December 2015 and May 2019, 195 patients (95%) had enough tissue for RNA-seq; 39 (20%) were classified as basal-like and 156 (80%) as classical. RECIST response data were available for 157 patients; 29 basal-like and 128 classical where the ORR was 10% versus 33%, respectively (P = 0.02). In patients with basal-like tumors treated with modified FOLFIRINOX (n = 22), the progression rate was 60% compared with 15% in classical PDAC (P = 0.0002). Median OS in the intention-to-treat population (n = 195) was 9.3 months for classical versus 5.9 months for basal-like PDAC (HR, 0.47; 95% confidence interval, 0.32–0.69; P = 0.0001). GATA6 expression by RNA-seq highly correlated with the classifier (P < 0.001) and ISH predicted the subtypes with sensitivity of 89% and specificity of 83%. In a multivariate analysis, GATA6 expression was prognostic (P = 0.02). In exploratory analyses, basal-like tumors, could be identified by keratin 5, were more hypoxic and enriched for a T-cell–inflamed gene expression signature. Conclusions: The basal-like subtype is chemoresistant and can be distinguished from classical PDAC by GATA6 expression. See related commentary by Collisson, p. 4715

Environmental noises often affect population dynamics, and hence many benefits are gained in using stochastic models since real life is full of stochasticity and randomness. In this paper a stochastic extension of a model by Asfaw et al. (Int J Biomath 11:1850057, 2018) is considered. Due to the non-linearity of the model, first, a simplified stochastic plant-herbivore model is formulated and analyzed for its global Lipschitz continuity, positivity, existence and uniqueness of solutions. Second, the analysis is extended to a more complex and realistic model. Numerical simulations using Euler-Maruyama method are employed to demonstrate the long term dynamics. It was found that the noise added to the herbivore population resulted more change in the dynamics than the noise added to the plant population (food source). Ignoring the environmental noise could make the land management and wild life conservation not to maintain their goals.

In ecology, plant–herbivore relationships are the crucial link generating animal biomass from mere sunlight through photosynthesis. These interactions are basic in understanding ecology and evolution of virtually any ecosystem. The relationship depends also on environmental factors like rainfall, temperature and altitude. Understanding patterns of these environment-dependent interactions will help to make better predictions and recommend possible conservation strategies. Many of existing mathematical models for plant–herbivore interactions and their analysis do not include these environmental factors. In this study, a mathematical model that incorporates variations of some of the parameter values due to changes in temperature and rainfall is formulated and used to determine necessary threshold values for co-existence. To validate the results of the mathematical model, real data from the Genale-Dawa river basin in the southern part of Ethiopia, is collected and used. The river basin represents the three major climatic zones of the country, the cool zone, temperate zone and hot lowlands. Numerical simulations were done using the collected data and it is observed that coexistence is possible in all the three regions but it is sensitive to the change in rainfall and temperature. If the change is within 10% there is a possibility of population extinction. Hence this paper shows that co-existence of population is highly dependent on the environmental changes.