dataesr/scientific-paragraphs-categorization huggingface dataset:
RNA Extraction and Real-Time Quantitative PCR (RT-qPCR) Total RNA was extracted from frozen biopsies using the RNeasy Mini Kit (Qiagen, Hilden, Germany). After checking RNA quality, 68 tumor samples were deemed suitable for expression analysis (59 responders and nine nonresponders) (Supplementary Table  1 ). Reverse-transcription and RT-qPCR measurements were performed as described in the Supplementary Material. A P-value of ≤0. 05 was considered to be statistically significant (Statgraphics TM Software). ROC-AUC was investigated using the SPSS TM Software.
The Kaplan-Meier Plotter (KMP) Breast Cancer Cohort The KMP cohort investigation resulted from a meta-analysis of gene-expression profiles from 2,978 primary breast cancer specimens who had not received any therapy before surgery and with known adjuvant therapy and clinical follow-up  (Gyorffy and Schafer, 2009). The SPSS TM Software was used to assess the prognostic value of ZNF217 or Ki-67 mRNA expression (univariate analysis). Data were divided into two groups with either high or low expression values according to the median value. Candidate prognostic factors for RFS with a 0. 1 significance level in univariate analysis were entered in a multivariate Cox model, and a backward selection procedure was used to determine independent prognostic markers.
The 68 patients were separated in two groups, based on the median ZNF217 expression value. The positive clinical response rate in the low ZNF217 expression level group was significantly higher (P = 0. 027) than that in the high ZNF217 expression level group, with high ZNF217 expression levels being associated with the absence of response to neoadjuvant ET (Supplementary Table  2 ). The ZNF217 low and high expression level groups were comparable in terms of Ki-67 values in the initial tumor (pre-treatment) (P = 0. 20, data not shown). Changes in Ki-67 for individual patients before and after neoadjuvant ET response are shown in Figure  1B. In the ZNF217 low expression levels group (Wilcoxon signed-rank test, P < 0. 00004), only one patient was ET-resistant (displaying increased Ki-67 level), while 33/34 patients were responders (Figure  1B ).
, 2007; Ellis et al. , 2008; Chia et al. , 2010). In posttreatment tumor samples, no differences in ZNF217 expression levels were observed between responders and non-responders (P = 0. 4, Mann-Whitney test, data not shown), suggesting that assessing ZNF217 expression levels in the initial tumor before ET is the most informative. To support our finding, we then hypothesized that if ZNF217 expression retains any predictive value for ET response in the neoadjuvant setting, then, the biomarker value of ZNF217 would be different between ER+ breast cancer patients treated with adjuvant ET only and patients who did not received any treatment. We thus performed a retrospective analysis of geneexpression array data from 2,978 breast cancer patients (KMP cohort). In this cohort, we have previously demonstrated that high levels of ZNF217 mRNA expression levels were strongly and significantly associated with shorter RFS (P < 10 -9 ,  Nguyen et al.
01, univariate analysis). Interestingly, this signature was identified as the best fit for predicting clinical outcome of ET-treated patients (likelihood = 741. 46), compared to the models integrating ZNF217 mRNA levels (likelihood = 746. 65, P = 0. 023) or Ki-67 mRNA levels (likelihood = 749. 24, P = 0. 005) only. Our data support that ZNF217 is a predictive biomarker for response to ET, and that, in the ER+/HER2-/LN0 cohort, the signature including both ZNF217/Ki-67 mRNA levels had the best predictive value.
, 2015). The genes that predicted response to ET included two pre-treatment genes associated with immune response and apoptosis and two genes measured after 2 weeks of treatment, which were associated with proliferation. Altogether, these data suggest that transcriptomic changes that develop during treatment are representative of the drug's mechanism of action, suggesting that suppression of proliferation is the main driver of response. In the present pilot study, the clinical sample size used is small and included only nine non-responders. Nevertheless, we found that ZNF217 expression levels are predictive of neoadjuvant ET response in ER+ breast cancer. ZNF217 expression levels are not associated with Ki-67 values, neither in the initial nor in the treated tumor, ruling out that ZNF217 could only be a surrogate marker of cell proliferation.
Of utmost interest is that the predictive value of ZNF217 expression levels seems to reside in the initial tumor and is not the reflection of transcriptional changes following ET in the treated tumors. This is the first pilot prospective study conducted in the neoadjuvant setting to relate ZNF217 expression levels with treatment efficacy, thus suggesting that aside from its prognostic value in luminal breast cancers  (Vendrell et al. , 2012; Nguyen et al. , 2014) , ZNF217 expression may also be predictive of response to ET. In this exploratory study, it is difficult to estimate the accuracy of ZNF217 mRNA levels for predicting response to ET, due to the low numbers of non-responders (9 out of 68). However, while obtained in a small cohort, our preliminary data are encouraging and need to be extended to a larger cohort for validation.
Altogether, these data support the idea that in the luminal breast cancer subclass, ZNF217 expression levels relate to ET response and provide a novel candidate biomarker. Finally, there are several ongoing trials investigating the combination of ET and other targeted therapies to prevent/reverse endocrine resistance. The PI3K/mTOR pathway, CDK4/6, HDAC, and immune checkpoints are the most promising and widely investigated targets  (Rugo et al. , 2016). Further studies are needed to delineate whether the ER+/ZNF217 high breast cancer subpopulation might benefit from combining ET with another therapy.
Apart from demonstrating the industrial capacity to produce component parts, the other aim is to check that their properties are not too far from the existing mean values, coming from databases obtained on smaller sheets or tubes. This is the case in  [141]  or  [142] , where the variation of tube or forging thicknesses is negligible on tensile and creep properties. The mechanical performances of FM steels are also largely dependent on the final heat treatment conditions. The typical industrial treatments applied to these steels imply successive normalization / quenching / tempering steps. An example taken as a guide for the industrial practice is given in  [139]. Figure  1  shows the extent of grade 91 mechanical properties after tempering at different temperatures between 650 and 850°C. With an increase of tempering temperature up to Ac1, the yield strength, tensile strength and hardness decrease whereas the impact toughness increases.
All codes need to be improved in order to meet the requirements of future fission and fusion power plants. Some advanced design concepts, in particular for ITER and for other advanced fusion systems, are either not completely defined or they imply fabrication routes and operating conditions that are not yet incorporated in existing codes. TBM modules for example are geometrically complex, involving state-of-the-art joining technologies, together with relevant Non Destructive Examination techniques, that have not been nuclear qualified  [188]. The integration of a new material in a nuclear code may also constitute a key challenge. New materials must be licensed to be used in future fission and fusion reactors, which means that an extensive database needs to be built on appropriate products regarding relevant thermal and mechanical properties, for base metal and weldments (example of EUROFER97 in  [189] ).
The final qualification steps may go through the fabrication of well-conceived mock-ups and their test in operation conditions as close as possible to the in-service thermo-mechanical loadings and environments. In-service surveillance programs are also intended to validating the materials properties and following their ageing process in actual conditions. Hence the codification of FM steels requires material specifications, qualification of fabrication procedures, mechanical databases, assessment of allowable limits and adjustment of design rules. The major existing codes have implemented at least two FM steels. ASME Grade 91 is codified in the ASME Code Section III Division 5  [136]. T91 is also implemented in the JSME code and in the European RCC-MRx. EUROFER97 has recently been the second FM material to be included in the RCC-MRx code, under the Section III Tome 6 "Probationary Phase Rules", for the design and manufacturing of TBM concepts and, on a longer term, of the blankets for DEMO, the fusion Demonstration Power Plants  [190].
The estimation of hardening shift coefficient C defined as C=∆DBTT/∆σ at irradiation temperatures Tirr ≤350°C for a number of reduced activation FM steels yielded 0. 17 ≤C ≤0. 53 °C/MPa in  [208]  which was found to be in a good agreement with the analysis of larger database on 7-9% Cr RAFM steels yielding C = (0. 38 ± 0. 18) °C/MPa  [282]  and indicated that the embrittlement is dominated by a hardening mechanism. The hardening shift coefficient increased at Tirr = 400 °C which suggested a non-hardening embrittlement (NHE) mechanism that primarily occurs due to aging conditions  [208]. (a) Figure  7 : Neutron irradiation induced hardening of FM steels as a function of irradiation temperature (a), and as a function of irradiation dose at ~300°C (b) after neutron irradiation in different MTRs  [275] ,  [254] , ,  [263] ,  [277] , ,  [271] ,  [266] ,  [212] ,  [274] ,  [210] ,  [215] ,  [214] ,  [283] ,  [195] ,  [280] ,  [281].
Also, the irradiation with spallation protons and neutrons has some limitations. Particularly, very high helium to dpa ratio of about 70appm/dpa and variations of the irradiation temperature due to the periodic variations of intensity of the proton beam have to be emphasized. Alternative techniques, such as the He injection technique during neutron irradiation utilizing Ni(n,α) reactions by plating NiAl on specimen surfaces may solve some of the above issues  [322]. The key issues with this technique are associated with the limited injected zone of He which is just a few μm from the specimen surface. Though the above mentioned simulation techniques do help to better understand helium effects and provide valuable input for the modelling activities, the availability of a FNS with fusion reactor relevant neutron spectra is mandatory for the detailed investigation of synergetic effects of displacement damage and transmutation gases at fusion relevant dpa and gas production rates and for the generation of the mechanical properties database for DEMO design criteria development.
Although gtk-fortran development is mainly focused on Linux, it can also be built under Windows, Mac OS X… It is licensed under the GNU General Public License version 3. It offers interfaces to around 10000 GTK+ and GLib functions  (GTK+ team, 1998 (GTK+ team, -2018)) , and also to the PLplot library. A higher-level interface (at a level comparable to the widget routines available in IDL  (Harris Geospatial Solutions, 1977 -2018) ) has been developed to offer an easier access to the main GTK+ widgets. The gtkf-sketcher tool even makes easier the design of a complex GTK+3 GUI by automatically generating the Fortran code from the XML files created by the user interface designer software Glade  (Glade team, 1998 (Glade team, -2018)). Moreover, even though gtk-fortran was mainly developed to visualise computing results and build GUIs, Fortran developers can also access the large set of utility functions offered by the GLib library.
They can for example implement visual management of tree-like data structures for handling of complex data projects. Along the wiki documentation of the project, the user can learn to use gtk-fortran thanks to tens of various example programs available in the repository. Among the publicly available research softwares using gtk-fortran, we can cite for example UncertRadio  (Kanisch, 2016) , designed for a generalized evaluation of environmental radioactivity measurements, and the gene network editor NetworkMaker (Roland Zimm, 2015) software. Coupling a modelling code with gtk-fortran can also be useful for teaching at the college level, for instance to simulate interactively the behaviour of a nuclear power plant  (Tincher et al. , 2017). The GTK+ and GLib libraries being in constant development, gtk-fortran is maintained to stay in tune with their evolutions.
Dietary Biomarker Discovery Using Cohort Studies Large-scale cohort studies are also valuable tools to discover dietary biomarkers. Dietary data may be collected using traditional methods to identify consumer profiles related to specific food (e. g. , low and high consumers, consumers, and nonconsumers). In this case, metabolomic profiles are compared between these subgroups to unveil potential dietary biomarkers. Given their practicability, Self-reported dietary assessment methods are often used in large-scale studies tend to rely on which are known to be notoriously prone to error. It is worth noting these studies are mainly association studies and don't allow causal inference (55). Intervention studies are, therefore, needed to validate the potential metabolite as a specific food intake biomarker.
So, innovative systematic strategies are urgently needed to unveil the role of food types in disease pathogenesis for, ultimately, design dietary recommendation to promote health and wellbeing or to cure diseases. Some efforts are already promising. For example, Zheng et al. proposed a computational framework for establishing diet-disease associations and additional information on the role of diet in disease development. The authors used large-scale gene expression datasets and network-based analyses to identify diet-disease relationships that could be used to build dietary recommendations tools  (118). Jensen et al. proposed a platform to explore dietary recommendations in association with drugs by building food-drug association database  (119). Zeevi et al. proposed an appealing and actionable integration of microbiome, clinical, and dietary data to customize dietary recommendations to tightly monitor glycemia (18).
As a consequence, the burden of TSC and its impact on the use of healthcare resources required for its management remain unknown. The TuberOus SClerosis registry to increase disease Awareness (TOSCA) was a large scale non-interventional study in patients with TSC, started in 2012 and was conducted at 170 sites in 31 countries. TOSCA registry was totally founded by Novartis AG and its related clinical study protocol and final study results are disclosed on the ENCePP portal at http://www. encepp. eu/ (EU PAS Register Number EUPAS324) (17). The design and methodology of TOSCA were published previously  (8). In short, patients of any age with TSC were enrolled and followed-up for up to 5 years. Patient data including demographics and information related to clinical features of TSC across all organ systems, comorbidities, and rare manifestations, were collected at baseline and at regular visits scheduled at a maximum interval of 1 year.
The registry consisted of a "core" part and six associated research projects focusing on: epilepsy, subependymal giant cell astrocytomas (SEGA), renal angiomyolipoma (rAML)/lymphangioleiomyomatosis (LAM), genetics, quality of life (QoL), and TSC-associated neuropsychiatric disorders (TAND); the "core" part collected demographic data, family history, prenatal history, disease features, and information on treatments, whereas the research projects recorded in-depth data related to specific disease manifestations or to specific aspects of the disease  (8). One of the research projects (research project on QoL) recorded data on the use of medical and non-medical resources for seven European countries (Belgium, Germany, Italy, Spain, Sweden, France, and the UK). Due to its long-term follow-up (up to 5 years) and to the inclusion of patients of any age from different countries from all over the world, the TOSCA registry offered a unique opportunity to observe how treatment patterns for the manifestations of TSC changed over time, and to evaluate differences in disease management depending on the age of the patients or their country of residence.
METHODS This study was based on data obtained from the TOSCA registry. The TOSCA registry was a non-interventional clinical study founded by Novartis AG, designed and conducted according to the Guidelines for Good Clinical Practice and ethical principles outlined in the Declaration of Helsinki  (18, 19). After appropriate approval by central and local research ethics committees, written informed consent was obtained from all patients, parents, or guardians, prior to enrollment. The first step for the present manuscript was a search for variables that could be of interest for the purpose of a study on the use of TSC-related resources (including medical and nonmedical resources), and an exhaustive analysis of all the listings and tables produced as part of the final analysis of the TOSCA registry, in order to identify relevant outcomes and analyses for each variable.
The variables and potential analyses are detailed in the Tables  S1, S2. Data on use of treatments (proportion of treated patients and types of treatment) were available for the overall population of patients included in the core registry. Data on the use of other medical resources (hospitalizations, primary, and secondary care visits) and on the use of non-medical resources (variables related to education needs, patient or caregiver employment situation and patient support/social services needs) were available for a subset of 143 patients included in the QoL research project, which was carried out in 7 European countries (Belgium, Germany, Italy, Spain, Sweden, France, and the UK). Treatment patterns were analyzed using the core registry data according to 4 clinical manifestations (epilepsy, SEGA, LAM, and rAML), the number of visits [baseline or follow-ups (FU1 to FU5), where FUs were conducted at intervals not longer than 12 months apart], the age group (≤2, >2 to ≤5, >5 to ≤9, >9 to ≤14, >14 to <18, ≥18 to ≤40, and >40 years), and the country of residence (for those countries included in the QoL research project; i.
Baseline Characteristics of Patients The baseline characteristics of patients enrolled in TOSCA registry were analyzed in detail. In brief, a total of 2,214 patients from 31 countries worldwide were enrolled into the study. Data from 2,211 eligible patients were analyzed as part of the TOSCA clinical study report delivered to Health Authorities by Novartis AG. Data of 3 patients were excluded from the analysis because of major protocol deviations. Of the analyzed patients, 1,152 (52. 1%) were female. The median age at enrolment was 13 years (range <1-71), and the median age at first TSC diagnosis was 1 year (range <1-69 years). The most common manifestation was epilepsy occurring in 1,879 (85. 0%) of patients. Among patients with epilepsy, 1,343 (71. 5%) had focal seizures (FS) and 735 (39.
Hospitalizations and Visits The frequency of hospitalizations was analyzed in the subset of patients of the TOSCA registry included in the QoL research project (N = 143). Regarding visits to the specialist, the same subset was analyzed. Subjects from Spain (N = 11) were excluded from the analysis because of data inconsistencies in these patients. As a result, healthcare visits were analyzed in 132 patients. A total of 88 visits to the specialists were reported over 12 months during the last year. Half of the patients (69/132; 52. 3%) visited the specialist due to TSC at least once during the last year, and a quarter (29/132; 22. 0%) had 3 or more visits. Visits to the specialist for reasons other than TSC were reported for 34 patients (25. 8%), and 14 of them (10. 6%) reported 3 or more visits during the last year (Table  S3 ).
e. , after baseline). In line with the current guidelines  (21, 22) , which recommend the use of vigabatrin as a first-line antiepileptic drug treatment in patients with TSC and either IS or FS before the age of 1 year, the most prescribed drugs were GABAergics. In any case, these results must be interpreted with caution due to the large proportion of treatments included in the category "others" (at baseline, 44. 4% for IS and 66. 5% for FS) and to the fact that the category "GABAergics" included a large number of different AEDs. In future studies, more attention should therefore be paid to the definition of treatment variables. Besides, one has to take into consideration, that TOSCA enrollment started in August 2012, and last data entry was in August 2017. Everolimus, was approved by European Medicines Agency (EMA) for the treatment of drug-resistant epilepsy as late as in January 2017.
The exact economic cost of these changes was not possible to evaluate from this dataset. However, the potential reductions and delays in the use of surgery may have economic implications not only at the time of treatment initiation, but also in the followup of the patients. In this regard, a study comparing pre-surgery and post-surgery costs in TSC patients with SEGA surgery carried out in the US  (24)  found that medication and total costs in the post-surgery year were 1. 6-4. 3 times the costs in the pre-surgery year. Unfortunately, no formal economic evaluations comparing surgery and mTOR inhibitors in patients with SEGA have been carried out. Interestingly, the use of surgery in patients with SEGA was lower in the TOSCA registry (Figure  5 ) than in a previous survey study carried out by  Rentz et al.
A strength of the TOSCA registry was the prospective followup of patients, which allowed to trace changes in treatment patterns over time. However, data from the two last follow-up visits (after 4 and 5 years) were available, for only 764 and 147 patients out of 2,211, respectively. Hence, caution is required when drawing conclusions from the last two visits. Although the number of patients in the last follow-up is relatively low compared to the patients for whom data was available at baseline, other studies on use of resources in patients with TSC have been carried out in patient cohorts with a smaller sample size. For instance, a study carried out by Skalicky et al. (20)  included 116 patients and another study carried out by Lennert et al. (12)  included only 95 patients. The present study has some limitations.
The main caveat was that data relating resource use from the QoL research project was collected for <10% of the patients included in the registry, which is in contrast with excellent data quality for the medical aspects of TSC recorded in the core study. This might be due to the fact that data collection of data into the QoL research study was not mandatory, due to the observative nature of the registry, or might be due to the absence of site monitoring review of the QoL research project data collection. Carrying out specific studies to broaden the evidence on the use of medical resources in patients with TSC remains an interesting topic for future research. Also, the observational nature of the TOSCA registry meant that only available data from standard clinical practice was supposed to collected.
INTRODUCTION All areas of health care stand to benefit from data sharing, but no group perhaps more so than patients with rare disorders affecting facial morphology and their families  (Boycott et al. , 2017). This paper presents the Minerva Initiative, a global initiative to enable integration of facial photographs and medical information across health care systems and for research. The purpose of this initiative is to empower global research into rare diseases through computational phenotyping from personally identifiable data. New machine learning approaches hold great promise for transforming health care. By interrogating vast amounts of rich data, they can develop tools that empower clinical care. Making personal data available to researchers across the world raises a number of ethical, legal, data security, and societal challenges.