dataesr/scientific-paragraphs-categorization huggingface dataset:
22 Subsequently, results of the REVEL  trial (NCT01168973, study 13852) led to the US and EU approvals of ramucirumab (Cyramza; Eli Lilly, Indianapolis, USA) in combination with docetaxel for patients with metastatic NSCLC with disease progression on or after platinum-based chemotherapy. 22 23 ntedanib Nintedanib is an oral, triple angiokinase inhibitor that inhibits VEGFR-1-3, FGF receptors 1-3 and PDGF receptor-α and PDGF receptor-β. 24 Nintedanib also inhibits FLT3 and the Src kinase family. Two phase III trials assessed the efficacy and safety of nintedanib. 25 26 Both studies were similar in design: multinational, randomised, double-blind, placebocontrolled trials conducted in Eastern Cooperative Oncology Group performance score (ECOG PS) 0-1 patients with histologically or cytologically confirmed stage IIIB/IV or recurrent NSCLC after one previous platinum-based chemotherapy.
32 Phase III trials for nivolumab versus docetaxel in patients with squamous (CheckMate-017, NCT01642004) and nonsquamous (CheckMate-057, NCT01673867) histology after the failure of platinum-based doublet chemotherapy were stopped early following planned interim analyses and a DMC assessment that concluded that both studies met their primary end point, demonstrating superior OS in patients receiving nivolumab when compared to the control arm. 32 33 Nivolumab (Opdivo; Bristol-Myers Squibb, New York, USA) has received US and EU approval for the treatment of locally advanced or metastatic NSCLC with progression on or after chemotherapy. 34 n the CheckMate-017 study (n=272), patients with stage IIIB/IV, squamous NSCLC and ECOG 0-1 were randomised to receive nivolumab (3 mg/kg every 2 weeks) or docetaxel (75 mg/m 2 every 3 weeks); patients were required to submit pretreatment (archival or recent) tumour-tissue specimen for retrospective biomarker analyses.
Safety profiles were similar between the subgroups of patients with PD-L1 expression of <1% and ≥1%. Immune-modulating agents were administered to resolve AEs such as rash and pruritus. Safety profiles were comparable in the CheckMate-057 and CheckMate-017 studies. 32 33 mbrolizumab Pembrolizumab is a monoclonal IgG4 anti-PD-1 antibody that disrupts the engagement of PD-1 with its ligand. 35 The KEYNOTE-001 phase I study (NCT01295827) enrolled 495 patients of whom 101 were treatment-naïve and 394 previously treated for advanced or metastatic NSCLC and with ECOG status 0-1. Overall, 401 (81%) patients had nonsquamous histology, 85 (17%) had squamous NSCLC and 9 (2%) had adenosquamous or unknown histology. Treatment with pembrolizumab (2 mg/kg or 10 mg/kg every 3 weeks or 10 mg/kg every 2 weeks) demonstrated antitumour activity (objective response rate (ORR) 19.
4%, mean response duration: 12. 5 months) and an acceptable side-effect profile in the overall population. 35 Biomarker analysis was performed, with results being reported as the percentage of neoplastic cells showing PD-L1 staining (tumour proportion score (TPS)). The biomarkerevaluable population included 73 patients with TPS ≥50% and 131 patients with TPS <50%. ORR was significantly higher (43. 9% vs 14. 1%; p<0. 001) for previously treated patients with TPS ≥50% (n=57) than those with TPS <50% (n=99). Median PFS among patients with a TPS ≥50% was 6. 1 months for previously treated patients. At a follow-up analysis with a data cut-off 6 months after the primary data cut-off, among 124 previously treated patients with PD-L1 TPS ≥50%, median PFS was 5. 8 months and median OS was 14. 0 months (HR not reported).
36 ased on results from the KEYNOTE-001 study, pembrolizumab (Keytruda; Merck & Co, Kenilworth, USA) was granted accelerated approval in the USA for the treatment of patients with metastatic NSCLC whose tumours express PD-L1, as determined by a Food and Drug Administration (FDA)-approved test and who have disease progression on or after platinum-containing chemotherapy. 37 The PD-L1 immunohistochemistry (IHC) 22C3 pharmDx test is designed to detect PD-L1 expression, with tumour samples considered to be PD-L1-positive if ≥50% of viable cells exhibit membrane staining. Based on this cut-off, KEYNOTE-001 reported the estimated prevalence of PD-L1-positive patients as 22. 7% of the previously treated patient population. 35 n the KEYNOTE-010 phase II/III study (NCT01905657), previously treated PD-L1-positive (TPS ≥1%) patients with advanced NSCLC were randomised in a 1:1:1 ratio to receive either pembrolizumab 2 mg/kg every 3 weeks (n=344), pembrolizumab 10 mg/kg every 3 weeks (n=346) or docetaxel 75 mg/m 2 every 3 weeks (n=343).
52 The analysis also used data from patients in the LUME-Lung 2 trial. These analyses suggest that: (1) time since the start of first-line therapy was a prognostic and predictive clinical biomarker for the treatment effect of nintedanib, combined with either docetaxel or pemetrexed, for patients with advanced non-squamous NSCLC, progressing after platinum-based chemotherapy; and (2) a treatment benefit was evident in those non-squamous patients with a particularly poor prognosis who progressed during or shortly after first-line treatment. Results from the REVEL study also confirm time since the start of first-line therapy as a potential clinical marker for ramucirumab. 28 -1/PD-L1 inhibition PD-L1 is upregulated in many cancer types and contributes to malignancy by inhibiting T-cell activation, limiting tumour cell killing by the immune system; PD-L1 expression assessed by IHC is being investigated as a marker for many anti-PD-1/PD-L1 agents.
Microarray analysis Independent datasets on liver samples were collected from previous studies  [4, 20] : 15-day-old Csb m/m /Xpa -/-(n = 3), 16-week old Ercc1 -/Δ-7 (n = 3), and age-matched WT controls (n = 3), 13-week old and 130-week old mice (n = 3) (E-MEXP-835, E-MEXP-1503 and E-MEXP-1504 all based on Affymetrix Mouse Genome 430 2. 0 arrays) and euthyroid and hypothyroid WT mice (n = 3) (GSE10001, based on Affymetrix Mouse Gene 1. 0 ST arrays). CEL files from these experiments were processed independently using the Partek software and differential expression values and corresponding p-values were obtained using ANOVA. Since the type of arrays used in these studies were different, they were matched by their corresponding RefSeq transcripts IDs (18440 matches in total) using home-made programs (Python™).
The data was then filtered based on thresholds of 1. 2-fold change (up and down) and p-values0. 05. Venn diagrams were produced using the Venny online tool (http://bioinfogp. cnb. csic. es/ tools/venny/index. html) [21]. Significance of the overrepresentation of common and co-directionally regulated genes was approximated using Poisson and binomial distributions. To analyze for gene expression similarities, we subsequently filtered out genes that were not present in all four data sets. These groups were subsequently clustered based on co-directionality of expression changes and heatmaps were constructed using the MultiExperimentViewer software. All gene lists were also analysed using the Ingenuity Pathway Analysis software to look for dataset significant enrichment for specific pathways.
To obtain a complete overview, we explored if TH-dependent transcriptional programs are altered during aging by genome-wide expression profiling. To this aim we first determined the effect of thyroid state on the liver mRNA expression profile by comparing livers from young adult (9-week old) euthyroid WT mice and WT mice rendered hypothyroid using a low iodine diet supplemented with propylthiouracil  [26]. Using predefined criteria, we filtered out a set of 6897 genes which is differentially expressed under hypothyroid conditions (data not shown). In the same way, we compared the microarray datasets of liver samples from 15-day old XAA mice or 16-week old MAA mutants with age-matched WT animals, and from 130-week versus 13-week old WT mice, resulting in 3005, 3559 and 2536 differentially expressed genes, respectively.
Since D3 activity may also affect local TH availability, we investigated if the larger decrease in liver T3 than in serum T3 levels is explained by an increased D3 activity. Interestingly, a large induction of D3 activity was observed in XAA mice (Fig  4D ). D3 activity was already stimulated at day 12, preceding the drop in liver T3 content at day 15, suggesting that the  Similar to serum concentrations, T4 and T3 levels in liver were unaffected in MAA mice compared to WT mice at both 4 and 18 weeks of age (Fig 4E  and 4F ). However, D1 activity was strongly decreased in 18-week old MAA mice (Fig  4G ). D3 activities were hardly detectable in MAA mice and littermates (data not shown). To investigate at which level the changes in deiodinase activities originate, we measured mRNA levels of Dio1 and Dio3 in the progeroid models using RT-qPCR.
Acknowledgments We acknowledge financial support of the European commission  FP7 Markage  ( FP7-Health-2008-200880 ),  DNA Repair  ( LSHG-CT-2005-512113 ) and LifeSpan ( LSHG-CT-2007-036894 ),  National Institute of Health (NIH)/National Institute of Ageing (NIA)  ( 1PO1 AG-17242-02 ),  NIEHS  ( 1UO1 ES011044 ), and the  Royal Academy of Arts and Sciences of the Netherlands  (academia professorship to JHJH) and a  European Research Council  Advanced Grant DamAge to JHJH. The research leading to these results has received funding from the  European Community 's  Seventh Framework Programme  ( FP7/2007-2013)  under grant agreement No. HEALTH-F2-2010-259893. WEV is supported by an  Erasmus University Fellowship  and a  Research fellowship  from the  American Thyroid Association.
This work was supported by the European commission  FP7 Markage  ( FP7-Health-2008-200880 ),  DNA Repair  ( LSHG-CT-2005-512113 ) and LifeSpan (LSHG-CT-2007-036894),  National Institutes of Health (NIH)/National Institute of Ageing (NIA ;  1PO1 AG-17242-02 ),  NIEHS  ( 1UO1 ES011044 ), and the  Royal Academy of Arts and Sciences of the Netherlands  (academia professorship to JHJH) and a  European Research Council  Advanced Grant DamAge to JHJH. The research ensuring diminished TH signaling, may contribute importantly to the protective metabolic response in aging. leading to these results has received funding from the  European Community 's  Seventh Framework Programme  ( FP7/2007-2013)  under grant agreement No. HEALTH-F2-2010-259893. WEV is supported by an  Erasmus University Fellowship  and a  Research fellowship  from the  American Thyroid Association.
Acknowledgments Work partially supported by grants  06/C441  from  SECTyP-Univ. Nac. Cuyo , and  PICT 2012-0770  from  FONCyT. D. G. F. thanks  CON-ICET  for support through a posdoctoral scholarship. N. S. acknowledges financial support from the  ExploAE'ra Sup program  of the  Rhône-Alpes region, France.
Background and purpose Flow diversion is an established technique to treat unruptured intracranial aneurysms not amenable to standard endovascular or microsurgical techniques. The suitability of flow diverting devices (FDD) to treat ruptured aneurysms is less clear. Materials and methods An in-depth search of multiple electronic publication databases was performed for reports describing ruptured intracranial aneurysms treated by flow diversion. Clinical and radiological characteristics, interventional details, and outcomes were pooled and analyzed in aggregate.
5 Prospective series (10+ pts) 7 3. 4 Retrospective series (10+ pts) 91 44. 2 Case report 35 17. 0 Case series (2-9 pts) 23 11. 2 Animalstudy 9 4. 4 Non-humanor imaging study 21 10. 2 Systematic reviewor meta-analysis 7 3. 4 National or state database analysis or literature review 12 5. 8.
In LD, the daily rhythm in the vigilance states did not significantly change over the 14 days period (Fig. 1 ). Total 24 h sleep time was not significantly affected by LDim (LD: 43. 8 ± 1. 7%, 14 days LDim: 47. 2 ± 1. 0%, P = 0. 293). In order to investigate homeostatic sleep drive, we analyzed the rhythm of slow wave activity (SWA, EEG power density between 0. 75-4. 0 Hz). SWA showed a clear day/night rhythm with a peak at the beginning and a trough at the end of the light phase. LDim gradually decreased the amplitude of the SWA rhythm (Day P = 0. 001; Fig. 2a ). Registrations on day 0 and day 1 started at ZT12, recordings on day 7 and day 14 started at ZT0, but all data are plotted from ZT0 for convenience. Data are represented as mean ± SEM. If a significant main effect was detected, post hoc tests for differences from baseline were performed with student's t-test and indicated by asterisks (P < 0.
Between 0. 25 and 5. 0 Hz, values were collapsed into 0. 5 Hz bins, between 5. 25-25. 0 Hz in 1-Hz bins. Average values of the amount of each vigilance state and the corresponding spectra, and changes over the day in vigilance states and EEG power density, were computed for each vigilance state and for each recording day. EEG power density data were standardized relative to the individual 24-h mean baseline value in NREM sleep (=100%) and subsequently averaged over all animals. Circadian experiments. Rats (n = 8, bodyweight 254 ± 1 g) were individually housed in transparent plastic cages and locomotor activity was monitored by passive infrared detectors using Actimetrics software (Wilmette, Il, USA). In circadian experiment A, animals were first exposed to 10 days LD and subsequently to 30 days LDim, 20 days constant darkness (DD), re-entrainment during 30 days LD and finally 10 days DD.
In situ hybridization of Per1 and Arntl (Bmal1) were performed using riboprobes of rPer1 (kindly provided by Dr. H. Okamura, Kyoto University, Japan) and mArntl (mBmal1)  65  genes. Antisense RNA probes were generated with an in vitro transcription kit (Maxiscript; Ambion, Austin, TX, USA). Hybridization was carried out as described previously  66. Slices and radioactive standards were exposed to an autoradiographic film (Biomax MS-1 Kodak, Sigma-Aldrich, St Louis, MO, USA). Quantitative analysis of the autoradiograms was performed using the ImageJ software (W. Rasband, National Institutes of Health, Bethesda, MD, USA). A Nissl staining was performed on the same slides and the section containing the mid SCN was selected. The optical density of the whole SCN, the ventromedial SCN and the dorsolateral SCN were measured by a researcher (JMen) who was blind for treatment, Relative optical density was determined by subtracting the background intensity (measured in the anterior hypothalamic area) from the signal for each animal.
Statistical analysis. Normally distributed variables are expressed as mean and standard error of the mean (SEM). Vigilance state and EEG data were analyzed with repeated measures ANOVA with the factors Phase (Light, Dark/Dim), Day (0, 1, 7, 14) and their Interaction. Power density spectra of NREM sleep were analyzed with ANOVA with the factors Frequency (0. 25-25. 0 Hz), Day (0, 1, 7, 14) and their Interaction. For circadian locomotor activity data, the rhythm period and strength were determined with F-periodogram analysis  63  as previously described  64. Rhythm strengths were analyzed by ANOVA with the factor Light schedule (LD, LDim, DD). SCN gene expression data were analyzed with ANOVA using the factors Time (ZT6, ZT18), Group (LD, LDim-aligned, LDim-misaligned) and their Interaction.
Data from the calorimetric cages were analyzed with a linear mixed model in order to correctly incorporate missing data, with Light schedule (LD, LDim), Week (week 0-9) and their Interaction as fixed effects. The covariance structure 'Compound Symmetry' was selected based on the Akaike's Information Criterion (AIC). If a significant main effect was detected in ANOVA or linear mixed model analyses, post hoc tests were performed with an independent samples two-tailed student's t-test (for 2 groups with independent samples), a related samples two-tailed student's t-test (for 2 groups with related samples) or Duncan's test (for > 2 groups). For glucose tolerance data, the iAUC was calculated for individual animals as described previously  67. The effect of LDim exposure on body weight, organ weight and glucose tolerance was assessed with a student's independent samples two-tailed t-test or a student's related samples two-tailed t-test where appropriate.
Acknowledgements We are grateful to  M. Stok  for assistance with animal experiments,  Dr. J. W. Stenvers  and  Dr. R. de Roode  for technical assistance,  Dr. N. van Geloven  for statistical advice,  Dr. H. Okamura  for providing the Per1 plasmid and  Dr. H. Dardente  for providing the Arntl clone. D. J. S. is supported by  ZonMW Agiko stipend 92003592. J. M. is supported by the  Agence National de la Recherche  ( ANR-14-CE13-0002-01 ADDiCLOCK JCJC ). A. L. O. is supported by  STW  grant " OnTime " (# 12195 ).
No intravenous contrast agent was administrated. Immediately after completion of WB acquisition and patient repositioning (i. e. , 6 ± 5 min after the end of the WB PET images), an HN PET/CT data set was acquired from the base of the skull to the upper thorax, with arms positioned along the body using one bed position of 8 min. CT scan of the HN PET/CT protocol was acquired with the following parameters: 100 mAs; 130 kV; slice thickness, 2. 5 mm; and pitch, 1. All PET data sets were reconstructed with a PSF reconstruction algorithm (HD; TrueX, Siemens Medical Solutions; 3 iterations and 21 subsets), using a 168×168 matrix and a 256×256 matrix for WB PET and HN PET, respectively. No post-filtering was used, as modelling the PSF during iterative reconstruction introduces correlations between neighbouring voxels in a manner similar to smoothing filters and has thus been shown to achieve maximal performance with little or no filtering  [20].
PET/CT interpretation Overall, 170 anonymized PET/CT data sets (85 WB PET/CT images and 85 HN PET/CT images) were reviewed after randomisation (Prism random number generator, GraphPad software) by two board-certified nuclear medicine physicians (S. B. and R. C. ) during separate reading sessions on a digital workstation (Siemens Medical Solutions). Each reviewer independently and blindly reviewed the 170 PET/CT studies in a random order. WB and HN PET/CT images were not paired together during interpretation. For each study, the reviewer had only knowledge of the pathology, the side and the TNM classification (7 th edition) of the primary thyroid tumor. PET images (with and without attenuation correction), CT images and fused PET/CT images were available for interpretation. WB PET/CT images were reviewed from the base of the skull to the upper thorax region.
Node/background (N/B) ratios were computed as the ratio between the SUVmax in the node and the SUVmean in the background (muscle and vascular background, respectively). The presence of lesions on co-registered CT image sets in front of each FDG focus was also reported. When a LN or a mass in the thyroid bed was measurable, its short-axis dimension and shape were reported. CT data were interpreted according to Choi et al. [22] , i. e. a LN visible on co-registered CT images was scored benign if it did not have a round shape, its small axis < 10 mm, there was no calcification, and there were no cystic features. Otherwise, it was scored malignant. At patient level, the PET/CT images data set was scored negative if the foci were all scored 1 or 2, indeterminate if no foci scored higher than score 3, and positive if at least one score 4 or 5.
Statistical analysis Quantitative data are presented as mean ± standard deviation (SD) or median (min-max) if necessary. Weighted kappa was used for inter-observer agreement and agreement between PET data sets. The node/background ratios were compared using the non-parametric Mann-Whitney test for paired samples. The sizes of the largest metastasis depending on the status for WB PET and HN PET were compared using the Kruskal-Wallis rank sum test. Statistical significance was defined as P<0. 05. Prism (GraphPad software) and Vassar University clinical research calculators were used for graphs and statistics (http://vassarstats. net/). Receiver-Operating Characteristic (ROC) curve analysis was performed with Medcalc (version 11. 6. 1). The areas under the curve (AUC) were compared using the Hanley test.
The improved performance of the complementary HN acquisition is related to several factors. Firstly, the 256×256 matrix of the HN PET together with the use of PSF modelling improves the detection of small lesions in comparison to the 168×168 matrix of the WB PET. Secondly, time acquisition per bed position is longer for HN PET than for WB PET. Also, arms are positioned along the body during HN PET. Lastly, HN PET examination was always performed after the WB PET scan and thus benefited from a slightly higher uptake time, which in turn may have increased tumor uptake, as reported in studies on delayed or dual time-point PET imaging. These factors contribute to increase node/background ratios as shown in the present study. Nevertheless, the difference in tumor uptake time between HN PET and WB PET was very low and is likely to have had a minimal influence on the difference between these two PET data sets.
Acknowledgment: The following persons contributed to data collection and/or analysis, or critical review of the manuscript: Regeneron:  W. J. Sasiela, PhD ,  M. Louie, MD, MPH, MSc , and  C. Hudson , BPharm; Sanofi:  J. Edelberg, MD, PhD ,  L. V. Lee, MD , and  M. Howard ,  MBA. Writing support was provided by  S. K. Rushton-Smith, PhD , funded by  Sanofi and Regeneron Pharmaceuticals, Inc.
Historical records include data from herbarium collections and trawling fishery expeditions in the mid-twentieth century, while recent data comprise records of the last 17 years from MEDITS expeditions, ROV surveys of historical kelp locations, benthic surveys and records by fishermen. Altogether, these findings demonstrate that the Adriatic population of L. rodriguezii has suffered a decline of more than 85 % of its historical range and is now present only around the small offshore island of Palagruža. Bottom trawling activities are presumably responsible for the disappearance elsewhere. et  al. 2002). Their distribution in lower latitudes is limited to waters rarely exceeding 20 °C; furthermore, many species require lower winter temperatures for gametogenesis  (Lüning 1980). In cases of strong stratification and high water transparency, kelp communities may occur in a coldwater layer receiving enough sunlight for photosynthesis beneath a constantly or seasonally warmer surface layer.
In the Adriatic Sea, L. rodriguezii is only reported from the Central Adriatic (mainly in Croatian, occasionally in international waters). First detailed knowledge of its distribution in the region was obtained during the Hvar fisheries biology expedition in  1948 -1949 (Ercegović 1960)) , which was conducted to gather data on commercial trawl resources after several years of suspension of fishing during the Second World War. This dataset is a baseline (zero state) dataset of trawling bottom species till 400 m depth  (Vrgoc ˇ et al. 2004). The expedition also collected data on bycatch including benthic seaweeds. L. rodriguezii was found in the areas of Jabuka Pit (henceforth referred to as "Jabuka"), Biševo Island ("Biševo") and Palagruža Island ("Palagruža"). Between 1956 and 1961, further fisheries expeditions also recorded data on deep-water algae  (Gamulin-Brida 1965).
During fisheries expeditions in the following three decades, data on L. rodriguezii were not collected. Since 1996, annual fishery surveys (Mediterranean International Bottom Trawl Suveys, MEDITS) using trawl nets have been conducted, covering transects similar to the Hvar expedition  (Bertrand et al. 2002). This allowed a comparison of historical fisheries data with new records. Within the framework of the project "Brown algal biodiversity and ecology in the Eastern Mediterranean Sea", we have recently conducted deep-water transects in the areas of the Adriatic Sea where L. rodriguezii was recorded in the 1950s and 1960s, using a ship-deployed remotely-operated vehicle (ROV). The results of these transects, together with the biological surveys performed from the mid-1990s, combined with information provided by professional fishermen, give an overview of the recent populations of L.