dataesr/scientific-paragraphs-categorization huggingface dataset:
Treating hypertension is highly effective at delaying the onset of and perhaps preventing heart failure in older people  [35]. However, not all antihypertensive agents are similarly beneficial, but the number needed to treat is rather high  [36, 37]. Other preventive therapies targeting glycemic control and cholesterol have been disappointing. Many patients with heart failure have associated comorbidities such as hypertension, diabetes mellitus, ischemic heart disease, atrial fibrillation, chronic lung disease, renal dysfunction and anemia. Stratification beyond such gross phenotypes using 'omic' technologies may help target therapeutic intervention more safely and effectively. Candidate 'omics'-based biomarkers (Supplementary Table  3 , available online) relevant to heart fail- ure, processes of aging, inflammation, fibrosis or myocyte damage and related to main comorbid conditions of heart failure in elderly people have been selected after a systematic search of relevant scientific and patent databases after consulting experts within the present HOMAGE consortium.
All candidate biomarkers have passed the discovery and verification phase, are published or patented by SMEs or academic groups, including groups in the HOMAGE consortium and are readily measurable by available techniques. Emphasis is on validation of clinically useful biomarkers that can predict the risk of developing heart failure, help make an early diagnosis or help choose the right treatment, at the right time for the right patient. The consortium is also open for discovery of novel markers, novel insights into pathophysiology and identification of novel therapeutic targets. Each investigator of the HOMAGE consortium can propose analyses using the information available in the common database that eventually could lead to the discovery of new biomarkers, patents or publications. In conclusion, HOMAGE has assembled a very large set of international data and biological samples focusing on patients at risk of, or with heart failure, that will be an important platform for bio-marker discovery.
In recent years, the expansion of acquisition, storage and transmission techniques and the success of tablet computers facilitate the development of many large image databases as well as the interactions with the users. This thesis  [1]  deals with the problem of Content-Based Image Retrieval (CBIR) on these huge masses of data. Among three CBIR phases (feature extraction, feature space structuring and retrieval), we are particularly interested in the structuring phase (normally called indexing phase), which plays a very important role in finding information in large databases. This phase aims at organizing the visual feature descriptors of all images into an efficient data structure in order to facilitate, accelerate and improve further retrieval. Instead of traditional structuring methods, clustering methods which organize image descriptors into groups of similar objects (clusters), without any constraint on the cluster size, are studied.
Then, the user visualizes the clustering result and provides feedback for guiding the reclustering phase. The system then re-organizes the dataset by using not only the similarity between objects, but also the user feedback in order to reduce the semantic gap. The interactive loop can be iterated until the clustering result satisfies the user. In the case of large database indexing, we assume that the user has no prior knowledge about the image database. Therefore, an unsupervised clustering method is suitable to be used for the initial clustering, when no supervised information is available yet. Then, after receiving the user feedback in each interactive iteration, a semi-supervised clustering can be used for the re-clustering process. Based on a deep study of different unsupervised clustering methods [3] as well as semi-supervised clustering approaches [2], we propose in this thesis a new interactive semi-supervised clustering model  [2]  involving the.
user in the clustering phase. From the formal analysis of different unsupervised clustering methods  [3] , we chose to experiment some methods which appear to be the most suitable to be used in an incremental context involving the user. The hierarchical BIRCH unsupervised clustering  (Zhang et al. , 1996)  which gives the best performance from these experiments  [3]  is chosen to be used as the initial clustering in our model. Then, an interactive loop in which the user provides the feedback and the system re-organizes the database using the new semi-supervised clustering method proposed in this thesis is iterated until the clustering result satisfies the user. As the user has no prior knowledge about the image database, it is difficult for him/her to label the clusters or the images in the clusters using classes.
Neighbourhood information groups images according to the willingness of the user to classify them in the same clusters (via user feedback of all interactive iterations). This kind of information helps to maximize the supervised information gained from a same number of user clicks. In order to avoid the subjective dependence of the results on the human user, a software agent simulating the behaviour of the human user for providing feedback is used for the experimental analysis of our system using different image databases of increasing sizes (Wang, PascalVoc2006, Caltech101, Corel30k). Moreover, different strategies for deducing pairwise constraints from user feedback and neighbourhood information were investigated. Among these strategies, the strategy which keeps only the most "difficult" constraints (must-link between the most distant objects and cannot-links between the closest objects) was shown to give the best trade-off between the performance and the processing time.
Data abstraction The agency websites were used as the primary data source for the analysis. Consistent with the HTA agency's individual commitments to transparency, only data that were formally disclosed in the public domain and posted on the agencies' websites were included in the analysis. (Note: there was one exception -the review of bevacizumab for metastatic colorectal cancer in Québec was never published on the INESSS website but was included in the analysis because the information was in the public domain). Specifically, the documents retrieved for the analysis were:   10, 11  and the pCODR Expert Review Committee Final Recommendation (2011-2013) 12 • NICE: information from the Appraisal Committee only (not information from the Manufacturer's Submission). 13 Some drugs were reviewed for multiple indications.
If so, then all distinct indications were included in the analysis. Some drugs were reviewed multiple times for the same indication. If so, then only the most recent recommendation was included in the analysis. The following data were extracted for each recommendation: • efficacy: progression-free survival (PFS) gain • efficacy: overall survival (OS) gain • incremental cost-effectiveness ratio (ICER) • recommendation • reason for negative recommendation (if applicable) • arrangements between payers and manufacturers (if applicable: risk-sharing, price negotiation, access scheme). Note: NICE uses the terminology "pricing scheme" to denote any type of manufacturer agreement, including product discounts and rebates. It is recognized that clinical benefit goes well beyond PFS or OS, including quality of life and safety endpoints, among others.
). INESSS was established by legislation in 2011, succeeding the Conseil du Médicament and the Agence d'Évaluation des Technologies et Modes d'Interventions en santé in the province of Québec. The mission of INESSS is to prepare drug funding recommendations for the Minister of Health. Previous to INESSS, the Conseil performed this function; the legislation that established INESSS formalized this process by law within the institution. Recommendations from both agencies have been stored in the same database.
As such, RT can be regarded as a common therapeutic target, acting early in cancer onset and in an ample spectrum of cancers; 2. as summarized above, RT inhibition affects the cancer transcriptome globally, reduces proliferation of cancer cells and restores their "normal" phenotypes; 3. in ongoing phase II trials on metastatic prostate carcinoma patients, RT inhibitors exert a predominant cytostatic effect with low, or no, adverse effects on patients (clinicaltrials. gov/ct2/show/ NCT00964002?term=NCT00 964002&rank=1) (Piazza, unpublished results); 4. RT inhibition is sufficient to arrest, or significantly slow down, tumor progression and metastatic spreading, both in pre-clinical and small-size clinical trials, converting aggressive cancers into a chronic disease. The RT-based therapy might therefore be suited to fulfill the requirements for a unified therapeutic approach across a large spectrum of cancer types with otherwise diversified features.
ACKNOWLEDGEMENTS We acknowledge the skillful assistance of  Cosimo Curianò  with drawing preparation. Work in our laboratory was supported by  ISS-NIH  cooperation grants ("Endogenous Reverse Transcriptase activity and chromatin remodeling in normal and transformed cells and early embryos"),  Italian Ministry of Health  grants "New therapeutic strategies based on studies of tumor microenvironment and new targets identified through genomic profile analysis", "Endogenous Reverse Transcriptase as tumour marker and causative agent of tumour onset and progression", "Endogenous Reverse Transcriptase in tumour onset and progression and in tumour therapy" to CS.
Similarity analysis To substantiate the observation that the stimuli elicited consistent responses, we employed the two-sample Kolmogorov-Smirnov (KS) test to assess the response similarities for all stimuli and for all cells. This test takes a pair of data samples as input and tests the null hypothesis that they are drawn from an indentical, yet unknown, distribution. The samples comprised the time sequences, { i t 1 , i t 2 ,:::, i t N }, of the spike times measured from the beginning of the trial, where i t N is the time of the last spike, N, of trial i. Pairs of samples were produced by pooling sequences from two randomly selected but disjointed subsets of trials of cardinality 24 for the same neuron and the same stimulation condition, omitting the first trial. If a neuron had a reproducible response to a stimulus, then there should be no statistically significant difference between any two samples constructed this way.
The experimental procedure was approved by the 'Comitede protection des personnes Ile-de-France II'. The experimental procedures were approved in advance by the Malmo ¨/Lund Animal Research Ethics Committee (permit number and approval-ID: M05-12). Funding statement. Supported by the European Research Council (FP7 program) ERC Advanced grant (PATCH) to V. H. (no. 247300) and by a European Commission grant 'THE Hand Embodied' (no. 248587) within the European FP7 programme.
Objective Evaluate ustekinumab, an anti-interleukin (IL)-12 and IL-23 antibody, effects on radiographic progression in psoriatic arthritis (PsA). Methods We conducted preplanned integrated analyses of combined radiographic data from PSUMMIT-1 and PSUMMIT-2 phase 3, randomised, controlled trials. Patients had active PsA despite prior conventional and/or biologic disease-modifying antirheumatic drugs (≥5/66 swollen, ≥5/68 tender joints, C-reactive protein ≥3. 0 mg/L, documented plaque psoriasis). Patients (PSUMMIT-1, n=615; PSUMMIT-2, n=312) were randomised to ustekinumab 45 mg, 90 mg, or placebo, at weeks (wk) 0, 4 and every (q) 12 wks. At wk 16, patients with <5% improvement in tender/swollen joint counts entered blinded early escape. All other placebo patients received ustekinumab 45 mg at wk 24 and wk 28, then q 12 wks.
Radiographs of hands/feet at wks 0/24/52 were assessed using PsA-modified van der Heijde-Sharp (vdH-S) scores; combined PSUMMIT-1 and PSUMMIT-2 changes in total vdH-S scores from wk 0 to wk 24 comprised the prespecified primary radiographic analysis. Treatment effects were assessed using analysis of variance on van der Waerden normal scores (factors=treatment, baseline methotrexate usage, and study). Results Integrated data analysis results indicated that ustekinumab-treated patients (regardless of dose) demonstrated significantly less radiographic progression at wk 24 than did placebo recipients (wk 0-24 total vdH-S score mean changes: 0. 4-combined/individual ustekinumab dose groups, 1. 0-placebo; all p<0. 02). From wk 24 to wk 52, inhibition of radiographic progression was maintained for ustekinumab-treated patients, and progression was substantially reduced among initial placebo recipients who started ustekinumab at wk 16 or wk 24 (wk 24wk 52, total vdH-S score mean change: 0.
INTRODUCTION Psoriatic arthritis (PsA) is an inflammatory arthropathy occurring in association with skin psoriasis. The PsA musculoskeletal presentation is heterogeneous, involving peripheral joints, entheses, other periarticular tissues, and/or axial spine. The PsA radiographic spectrum is highly variable and includes patients with mild, non-destructive joint inflammation and those with severe, debilitating joint pain and deformities resulting from progressive joint damage. Diverse radiographic findings are reported to include erosions and joint space narrowing, soft tissue changes, and new bone formation including juxta-articular periosteal reaction and ankylosis. 1 2 Recent data implicate T helper (Th)-17 cells, key effectors in inflammation and tissue damage in several immune-mediated diseases, as playing a role in the immunopathophysiology of PsA.
Change in radiographic progression from baseline at wk 24 using data combined from the two studies, assessed via PsA-modified van der Heijde-Sharp (vdH-S) scores, was a prespecified major secondary study endpoint for both studies. This approach was taken because of the similar trial designs and contemporaneous enrolment and reading of radiographs adopted in the programme, and because the initial power calculation indicated the need for a sample size larger than would be available from either study individually to detect a significant treatment effect (also see online supplementary text). These integrated radiographic analyses through 1 year of ustekinumab treatment in the combined phase 3 PSUMMIT-1 and PSUMMIT-2 trials are reported herein.
0 mg/L (modified to ≥3. 0 mg/L after study start; upper limit of normal 10 mg/L) at screening, and active or a documented history of plaque psoriasis. The PSUMMIT-1 (NCT01009086, EudraCT 2009-012264-14) and PSUMMIT-2 (NCT01077362, EudraCT 2009-012265-60) studies were conducted according to the Declaration of Helsinki and International Committee on Harmonisation good clinical practices. The protocols were reviewed and approved by each site's governing institutional review board/ethics committee, reflecting national requirements for study conduct approval. All patients provided written informed consent. In these phase 3, multicenter, placebo-controlled trials, patients were randomly assigned (1:1:1) to receive ustekinumab 45 mg, 90 mg, or placebo, at wk 0, wk 4 and every 12 wks (q12wks) thereafter.
Statistical analysis Progression of structural damage was measured by change from baseline in total PsA-modified vdH-S scores of the hands and feet at wk 24. As prespecified, this major secondary study endpoint was analysed based on an integrated data analysis combining data from the PSUMMIT-1 and PSUMMIT-2 studies with all randomised patients included. Patients were analysed according to randomised treatment group, irrespective of early escape. Analysis of variance on the van der Waerden normal scores, that is, ranktransformed scores based on normal distribution,  12  with treatment, patients' baseline MTX usage (yes/no), and study indicator (PSUMMIT-1 or PSUMMIT-2) as factors in the model was employed to test the treatment difference. To control for multiplicity, the initial analysis tested the difference between the combined ustekinumab groups (45 mg and 90 mg combined) and the placebo group.
Patient disposition and baseline radiographic characteristics Patient screening began in November 2009, and the wk 52 clinical database locks occurred in July (PSUMMIT-1) and December (PSUMMIT-2) of 2012; the radiographic database was locked in January 2013. Overall, 1771 patients were screened for the PSUMMIT-1 and PSUMMIT-2 trials, of whom 927 patients (747 anti-TNF-naive, 180 anti-TNF-experienced) were randomised to treatment. A majority of the anti-TNFexperienced subgroup had been exposed to ≥2 anti-TNF agents (55% of patients) and had previously demonstrated lack of efficacy or intolerance to anti-TNF-therapy (>70% of patients). The trials were conducted at 189 sites in European (565 patients), North American (319 patients), and Asia-Pacific (43 patients) countries. Patient disposition through 1 year has been previously described for each trial.
8 9 issing data were imputed via linear extrapolation or assignment of the median of change scores within the same MTX stratification. For the integrated dataset, the overall rates of missing radiographic data at wk 24 were low in all groups (ie, 2. 3-10. 3%) and would not be expected to impact the interpretability of the integrated analyses of the effect of ustekinumab on structural damage. Across both studies, median imputation was the predominant means of replacing missing data. However, the PSUMMIT-1 and PSUMMIT-2 studies differed in terms of the amount and pattern of missing radiographic data. The highest rate of missing data was observed in the anti-TNF-experienced population in the PSUMMIT-2 study, mainly resulting from early (within initial 8 wks) study agent discontinuation, and was more than twofold higher among placebo-treated than ustekinumab-treated patients for anti-TNF-experienced (24.
Primary radiographic analysis: integrated data analysis of change from baseline to wk 24 in the total vdH-S score (major secondary study endpoint) The study achieved the prespecified major secondary endpoint, that is, integrated analysis of change in the total modified vdH-S score at wk 24, such that patients in both ustekinumab dose groups demonstrated significantly less radiographic progression at wk 24 versus patients in the placebo group (table  2 , figures 1 and 2). Results of all sensitivity analyses conducted (see online supplementary text) support the robustness of these findings (data not shown). Inhibition of radiographic progression was observed for ustekinumab doses versus placebo, regardless of concomitant MTX status at baseline. In the ∼75% of patients weighing ≤100 kg, less radiographic progression was observed in ustekinumab-treated than placebo-treated patients; no treatment effect was observed in patients weighing >100 kg, although the number of patients in this subgroup was smaller, and the magnitude of radiographic progression was low in the placebo group.
While differences in treatment effect between the two studies may derive from the smaller size and heterogeneity of the PSUMMIT-2 population, the two studies also differed in terms of missing data. The highest rate was observed in anti-TNF-experienced, placebotreated patients within the PSUMMIT-2 study that included substantial numbers of anti-TNF-refractory patients, which then translated into higher rates of mandated data extrapolation. The higher rate of missing data in PSUMMIT-2 (table  1 ) was mainly a result of early (within the first 8 wks) discontinuations from the trial, with the majority occurring in the placebo arm. Per protocol, such patients did not qualify for radiographs upon discontinuation due to concerns related to excessive short-term radiation exposure. By contrast, the rate of missing data was generally low and consistent across the treatment groups in PSUMMIT-1 (table  1 ).
Thus, the application of data-handling rules impacted PSUMMIT-2 more than PSUMMIT-1. Specifically, since most missing data required median imputation, the prespecified median imputation rules can be considered to have conservatively favoured the placebo group due to a higher proportion of placebo patients having a score of 0 applied to missing data. Although the treatment effect was not demonstrated in the anti-TNF-naive population in PSUMMIT-2 (unlike PSUMMIT-1), comparison of radiographic findings between these two trial populations is limited by the low progression rate seen across all randomised groups (including placebo) of the PSUMMIT-2 trial relative to placebo-treated patients in PSUMMIT-1. Thus, ustekinumab 45 mg and 90 mg through 1 year afforded significant and sustained inhibition of radiographic progression in active PsA, supporting the role of IL-23 and the Th17 pathway in the radiographic damage of PsA.
Acknowledgements The authors thank  Michelle Perate MS , a paid consultant for  Janssen Biotech, Inc. , and  Mary Whitman PhD , an employee of  Janssen Biotech, Inc. , for writing and editorial support;  Lisa T Dooley PhD , an employee of  Janssen Research & Development, LLC , for statistical support; and  Bruce Randazzo MD PhD  and  Philippe Szapary MD , employees of  Janssen Research & Development, LLC , for assistance with critical review of the manuscript contents. The authors also thank  Mittie K Doyle MD , currently an employee of  Alexion Pharmaceuticals , for her role in executing the PSUMMIT-1 and PSUMMIT-2 trials, as well as the PSUMMIT-1 8 and PSUMMIT-2 9 study investigators.
Alteration of neddylation levels is associated with liver malignancy in clinical HCC Dysregulated neddylation pathway was previously described in many types of cancer  [16]. Immunohistochemistry (IHC) analyses revealed significantly higher levels of global neddylation and of the Nedd8 activating enzyme E1 (NAE1) in malignant tissues from a cohort of human HCC (Fig. 1A ). Additionally, gene expression levels of Nedd8 and NAE1, examined by analysis of published microarrays obtained from an ONCOMINE search (http://www. ncbi. nlm. nih. gov/geo/ query/acc. cgi?acc=GSE14520), were increased in a cohort of 225 HCC human samples versus 200 controls  [17]  (Fig. 1B ). Neddylation activity increase is more specific of tumoral areas as can be observed in the IHC of a tumor with respective surrounding tissue in Suppl.
2C-D ). As expected, neddylation inhibition with MLN4924 promoted an upregulation of the cullin-targets c-Jun and Nrf2 (Suppl. Fig. 2B ), as detected by Western blot analysis. In addition, neddylation inhibition in Phb1-KO mice reduced liver fibrosis (Suppl. Fig. 2A ), further supporting the beneficial role of MLN4924-treatment without the appearance of secondary complications. High-throughput metabolomic analysis on liver samples was performed to highlight some of the mechanisms underlying tumor regression as a consequence of neddylation inhibition. Wide targeted metabolomics data revealed a strong reduction of sphigomyelins (SM), SM(d18:0/22:0) (90%, p<0. 05) together with decreased diacylglycerols (DAG) levels [DAG(32:1), DAG(32:2), DAG(34:2)] (~30% p<0. 05) in MLN4924-treated Phb1-KO mice (Suppl.
Human Samples Surgically resected liver specimens of 22 patients with HCC (10 Hepatitis C, 10 ASH and 2 NASH) were examined. The Basque Research Biobank (http:// www. biobasque. org) provided the data and type of biospecimen. For the bad and better prognosis analyses we used samples from 47 patients with liver cirrhosis and HCC detected during surveillance. They had preserved liver function and corresponded to BCLC stage A (n=34) and B (n=13). These patients are part of another study, reported elsewhere (Gut, submitted). All tissues samples from this study were from US-guided liver biopsy of HCC lesions. In brief, compensated patients with liver cirrhosis under ultrasonographic surveillance for HCC, when first identified as having developed a HCC lesion underwent a dedicated imaging protocol (2 computed tomography exams 6-weeks apart in a absence of any other therapy to evaluate growth speed) and an US-guided liver biopsy (to define transcriptomic characteristics of tumor).