dataesr/scientific-paragraphs-categorization huggingface dataset:
6 (95% CI 8. 2-22. 7) months. For SSA-naı ¨ve patients with midgut NET (nZ24), median PFS was 22. 2 (95% CI 8. 3-29. 5) months. For patients who had received SSA previously, the median PFS was 11. 1 (95% CI 8. 4-14. 3) months. Among the SSA-pretreated patients who had midgut NET (nZ119), the median PFS was 12. 0 (95% CI 8. 4-19. 3) months. Median OS was 35. 8 (95% CI 32. 5-48. 9) months for patients in the placebo plus octreotide LAR arm; 50. 6 (36. 4 -not reached) months for SSA-naı ¨ve patients and 33. 5 (95% CI 27. 5-44. 7) months for those who had received prior SSA. This post hoc analysis of the placebo arm of the large phase 3 RADIANT-2 study provides data on PFS and OS among patients with progressive NET treated with octreotide therapy.
Study design RADIANT-2 was a multinational, multicenter, randomized, double-blind, placebo-controlled phase 3 study (Clinical-Trials. gov number, NCT00412061; http://clinicaltrials. gov/show/NCT00412061); the detailed study design has been described earlier  (Pavel et al. 2011). Patients were randomly assigned (1:1) to receive everolimus (10 mg/day) plus octreotide LAR (30 mg intramuscularly every 28 days) or placebo plus octreotide LAR (30 mg intramuscularly every 28 days). The study treatment continued until disease progression, development of unacceptable adverse events, withdrawal of patient consent, or primary analysis (cutoff date, 2 April 2010). During the double-blind phase, patients were permitted to crossover from the placebo plus octreotide LAR arm to the open-label everolimus plus octreotide LAR arm upon disease progression according to the Response Evaluation Criteria in Solid Tumors (RECIST, version 1.
0;  Therasse et al. 2000). A blind was broken for these patients. At the end of the double-blind phase, all ongoing patients were unblinded and were allowed to transition to open-label everolimus plus octreotide LAR at the discretion of the treating physician. All patients who switched to the open-label everolimus plus octreotide LAR (during the double-blind phase or after unblinding) discontinued everolimus treatment upon disease progression. These patients were then followed up monthly for survival information (until 13 June 2013, data cutoff date for the overall survival (OS) analysis). The patients enrolled in the placebo plus octreotide LAR arm were the focus of the present post hoc analysis (Fig. 1 ).
Statistical analysis In the primary analysis of the RADIANT-2 study, the primary endpoint was PFS, assessed by an adjudicated central radiology review according to RECIST, version 1. 0  (Pavel et al. 2011). PFS (data cutoff date, 2 April 2010) was estimated using the Kaplan-Meier method and reported with corresponding 95% CIs. The median PFS was also assessed by local investigators. The secondary endpoint was OS (data cutoff date, 13 June 2013). For this post hoc analysis, patients were stratified based on previous SSA use and tumor location (foregut, midgut, or hindgut), and the median PFS and OS were calculated in these subgroups. In a multivariate analysis, HRs and 95% CIs were calculated with a Cox proportional hazards model using specified variables selected by stepwise regression. baseline 5-hydroxyindoleacetic acid level (elevated (greater than median) or normal (less than or equal to median)), and primary tumor site.
Conclusions The post hoc analysis of the placebo arm of large phase 3 RADIANT-2 study, for the first time, provides data on PFS and OS from a prospective study among patients with progressive NET treated with octreotide therapy. This post hoc analysis showed that SSA-naı ¨ve patients with progressive midgut NET treated with octreotide LAR had a relatively long median PFS of 22. 2 months, exceeding the time to tumor progression of 14. 3 months observed in the PROMID study. The median PFS assessed by RECIST criteria may represent a more accurate reflection of the true PFS associated with SSA use in midgut NET. Earlier presentations Presented at the Gastrointestinal Cancers Symposium (ASCO GI), January 16-18, 2014, San Francisco, California, and at the European Neuroendocrine Tumor Society (ENETS), March 5-7, 2014, Barcelona, Spain.
(1999b). All successfully amplified products were cleaned using an ExoSAP-IT (USB, Cleveland, Ohio) before being sequenced commercially (Macrogen Inc. , Korea) Sequences were edited, assembled and aligned using the Geneious software package version 7 (Biomatters, available from http://www. geneious. com/). Alignment was straight forward as no gaps were found in the rbcL data set. Alignment for the RuBisCo spacer used MAFFT  (Katoh et al. 2002)  as implemented in Geneious and visually refined. LSU alignment used the online version of MAFFT v7 and the Q-INS-I algorithm that takes into account RNA secondary structure  (Katoh & Standley 2013)  and visually refined. Cox2-3 spacer sequences were difficult to align, and thus we aligned using a posteriori lineages (block alignment). The 5-prime end of cox2 was alignable between all samples, and produced a phylogeny consistent with the other genes (not shown), the spacer was then aligned as blocks between samples from the different lineages.
For the rbcL and LSU analyses the outgroup used was Bostrychia kelanensis a species with cladohaptera, in a group that is shown to be distinct from species with peripherohaptera in the tribe Bostrychieae  (Zuccarello & West 2006). The program Modeltest version 3. 7  (Posada & Crandall 1998)  was used to find the model of sequence evolution that best fit the data set by a Akaike Information Criterion (AIC)  (Posada & Crandall 2001). Maximum likelihood was performed with RAxML 7. 2. 8  (Stamatakis 2006). RAxML was performed, with all three codons partitioned (where appropriate) and the GTR+gamma model and 500 non-parametric bootstrap replicates  (Felsenstein 1985). Bayesian inference was performed with MrBayes v3. 2  (Ronquist et al. 2012). Analyses consisted of two independent simultaneous runs of one cold and three incrementally heated chains, and 3 x 10 6 generations with sampling every 1000 generations.
Log files were visualized in Tracers v1. 5  (Rambaut & Drummond 2009)  for assessing the stationary state of parameters based on the value of estimate effective sample size. After removing 25% of trees as burn-in, the remaining trees were used to generate a single summarized tree in TreeAnnotator v2. 0. 2 (BEAST v2. 0. 2 package) as an input file for GMYC. The GMYC analyses with a single-and multiple-threshold model were performed in R (R Core Team, 2013) under "splits" package using the 'GMYC' function (R -Forge, http://r-forge. rproject. org/projects/splits/). The ABGD method was tested via a web interface (ABGD web, http://wwwabi. snv. jussieu. fr/public/abgd/ abgdweb. html).
RESULTS The rbcL data set consisted of 1163 basepairs (bp) and 58 specimens. The sister relationships to the B. tenella species complex are not well resolved, nor is the B. tenella species complex strongly supported with this data set (73% ML bootstrap support, 1. 0 Bayesian posterior probabilities; Fig. 1 ). Within the B. tenella species complex three major clades are evident. One clade is sister to the other two, designated lineage A, consisting of samples from around the world (e. g. Brazil, Indonesia, Australia; Fig. 1. , Supplementary Table  1 ). Within lineage A, a single sample is genetically distinct, sublineage A1. Samples identified as B. montagnei also form a well supported clade and are exclusively from tropical America. The clade sister to B. montagnei is composed of two sublineages with high support.
Bostrychia montagnei makes a supported clade with the RuBisCo spacer data with two haplotypes. Haplotype M1 is exclusive to the American Atlantic (USA, Brazil) and M2 is found in both the Atlantic and Pacific (e. g. Belize, El Salvador; Fig. 2 , Supplementary Table  1 ). The third clade is again divided into two sublineages, B and C, that are well supported. Sublineage B has seven haplotypes with the putative ancestral one found throughout the world (B1; n=39, e. g. Cuba, Panama, South Africa, Australia, Papua New Guinea, Korea; Fig. 2 ). The other six haplotypes are found only in the western Pacific (e. g. the Philippines, Palau). Sublineage C consists of 6 haplotypes with the putative ancestral haplotype, C1 (n=17), again found throughout the world (e. g. Brazil, Madagascar, Papua New Guinea).
ACKNOWLEDGEMENTS We thank staff of the  Royal Botanical Garden Melbourne herbarium  for help with Bostrychia binderi type specimens. The following people were helpful in collections: Rosario Braga  (Brazil),  Nida Calumpong  (Philippines),  Judy Connor  (Panama),  John Huisman  (Australia),  Jhoana Larrea  (Cuba),  Chris Lobban (Guam) , and  Laurie Sullivan  (Belize). Long-term financing for this work was provided through personal funds of JAW and from the  Australian Research Council ,  Australian Biological Resources Study and Hermon Slade Foundation  grants to JAW/GCZ.
Animals Eye position was recorded monocularly at 1000 Hz with a scleral search coil  [16] [17] [18]  Recordings included data from five awake rhesus macaques (Macaca mulatta). Three monkeys were studied at Harvard Medical School (eye-tracking equipment by Remmel Labs, Inc) and two monkeys were studied at the Barrow Neurological Institute (eye-tracking equipment by Riverbend Instruments, Inc). Standard sterile surgical techniques, recording procedures, and animal care methods were approved by the Harvard Medical School Standing Committee on Animals and the Institutional Animal Care and Use Committee at Barrow Neurological Institute. Monkeys fixated their gaze on a small fixation target (0. 5 degrees of visual angle [deg], with a luminance of 24. 3 cd per m 2 ) on a video monitor (Reference Calibrator V, 60-120 Hz refresh rate; Barco) placed at a distance of 57 cm.
e. weekends, data analysis and manuscript writing periods, etc. ), they had free access to water in the vivarium. Cranial head-post and scleral search-coil implantation surgeries were conducted previous to the eye movement recordings, under general anesthesia using aseptic techniques, and with full post-operative analgesia and antibiotic therapy. No animals were sacrificed at the end of the experiments. We followed the ARRIVE (Animal Research: Reporting of In Vivo Experiments) guidelines and the ARRIVE Checklist is available as supporting information (S1 Checklist).
After some time, the centrifuge was stopped, and the cells retrieved and fixed. They were analyzed for cell height. From these experiments, we initially concluded that cell heights increased with increasing g-levels. However, we expected cell heights to decrease with increasing g. To verify this hypothesis, we also conducted a more sophisticated experiment where we measured cell height by means of an atomic force microscope (AFM) accommodated inside a centrifuge. Cell heights were measured while going through three g-levels, 1, 2, and 3g  [35]. The AFM data showed that the cells were indeed flattened at higher g-levels, verifying our initial hypothesis. However, this did not explain the initial increase in cell heights from the first experiments. What might have happened is that the cells in the initial study were indeed flattened at high g but displayed a kind of overshoot recovery after stopping the centrifuge and before fixation.
The IAAStudy Group has started writing guidelines for the standardization of bed-rest studies. The length of bed rest will be categorized into 3 different durations with associated pre-and post-bed-rest phases. The table below describes these categories. The bed-rest studies are divided into three phases: (1) a pre-bed-rest phase for acclimation and baseline data collection, (2) a bed rest phase, and (3) a Obviously, the standardization of the bed-rest experiment is of major importance both for the bed-rest phase and for the control phase (i. e. preand post-bed-rest phases). The pre-bed-rest phase to collect baseline data is of particular importance because the deconditioning of the subjects can start during the pre-bed-rest phase. Indeed, keeping the subjects in normal daily life condition is really challenging, and significant changes can occur among subjects if habits are changed too much (mainly in term of exercise level and diet).
Number of Volunteers Determining the optimal sample size for a study assures an adequate power to detect statistical significance. Hence, it is a critical step in the design of a planned research protocol. Using too many participants in a study is expensive and exposes more number of subjects to the procedure. Similarly, if the study is underpowered, it will be statistically inconclusive and may make the whole protocol a failure. In addition, even in well-designed and well-conducted studies, it is unusual to finish with a dataset, which is complete for all the subjects recruited, in a usable format. The reason could be subject factors like subjects may fail to particular questions, physical measurements may suffer from technical problems, and in high-demanding studies dropouts before the study ends are not unlikely.
Acknowledgment The authors are grateful for the bilateral  PROCOPE program. The " GeoFlow " project is funded by  ESA  (Grant No. AO-99-049 ) and by the  German Aerospace Center DLR  (Grant No. 50WM0122  and  50WM0822 ). The authors would also like to thank  ESA  for funding the " GeoFlow" Topical Team  (Grant No. 18950/05/NL/VJ ). B. F. thanks the financial support by the  Brandenburg Ministry of Science, Research and Culture (MWFK)  as part of the  International Graduate School at Brandenburg University of Technology (BTU)  and the funding at the  Otto von Guericke Universität Magdeburg  through the  Saxony-Anhalt Ministry of Culture  ( MK HGB/BFP ). I. M thanks the financial support from  CNES (French Space Agency)  and the  CPER-Haute Normandie  under the program THETE. H. Y and I. M. acknowledge the financial support by  References 101 the french Agence Nationale de la Recherche (ANR) , through the program " Investissements d'Avenir"  ( ANR-10 LABX-09-01 ),  LABEX EMC 3.
Acknowledgement The author would like to thank the  French Space Agency  for its financial support. 278  Index Inertial  and gravitational mass 186 Instrument field testing 165, 167 Instrument testing facilities 31, 38, 167 Interfaces 158, 196, 199 Interfacial transport 197 Interplanetary mission 173, 270 Interstellar medium 25 Ionizing radiation 221, 240, 247, 249 Isolation 7, 127, 174, 267 Isotope mixture 105, 110 282 Editor's Biographies for the science implementation in microgravity payloads, e. g. Microgravity Science Glovebox (MSG) ,  Life Sciences Glovebox (LSG)  and the  ESA  EMCS experiment container. Here he also initiated the  BioPack facility  which flew on STS-107. Besides flight instruments he also developed instruments and payloads for ground-based research. He manages the very first large and bench-top Random Positioning Machines (RPM).
Capillary electrophoresis. The CZE experiments were carried out on a P/ACE MDQ TM CE system from Sciex Separation (Brea, CA) equipped with a UV detection, a temperature controlled autosampler and a power supply able to deliver up to 30 kV. A 32 Karat TM 8. 0 (Sciex Separation, Brea, CA) was used for instrument control, data acquisition and data handling. Polymicro bare fused-silica capillaries of 75 µm i. d. , 375 o. d. (75. 5 cm effective length, 82 cm total length) were obtained from Photonlines (St-Germain-en-Laye, France). New capillaries were conditioned by successive flushes with 1. 00 M and 0. 10 M NaOH and then with water under a pressure of 30 psi for 10 min each. The temperature in the capillary cartridge and autosampler were set at 25 °C. The acquisition rate was 10 points / s. Capillaries were rinsed with water and dried by air when not in use.
MALDI-TOF-MS. The matrix was prepared by dissolving 2,5-dihydroxybenzoic acid (DHB) (2g/L) in 0. 1% trifluoroacetic acid/acetonitrile (TFA/ACN) (30/70)(v/v). Fraction collection was realized using Ground Steel MALDI target (Bruker Daltonics, Bremen, Germany). Mass spectra of the CZE fractions were recorded using an Autoflex II MALDI-TOF (Bruker Daltonics, Bremen, Germany), operating in reflector mode and with FlexControl software. Positively charged ions were detected and sums of 1500 single-shot spectra were acquired automatically from each sample by using the AutoXecute software. Data processing was performed with FlexAnalysis 3. 0 provided by the mass spectrometer manufacturer. All spectra were calibrated according an external calibration using Protein calibration standard I (Bruker Daltonics, Bremen, Germany) for intact protein separation.
ESI-TOF-MS. For sheathless CZE-ESI-MS experiments the CE system was coupled to a maxis 4G (Bruker Daltonics, Bremen, Germany). MS transfer parameters were optimized using the actual sample directly infused via the CE system using a pressure of 5 psi (340 mbar). MS parameters were optimized so that high m/z ions could be properly transferred to the TOF analyzer while avoiding fragmentation. In the case of the maxis 4G, ion funnels were set at values of 300 Vpp and 400 Vpp. The electrospray voltage (capillary voltage) was typically ranging from -1. 2 to -1. 8 kV. Dry gas was set at 1. 5 L/min and source temperature at 180°C. Data processing was performed with DataAnalysis 4. 0. Deconvolution of the mass spectra was performed based on maximum entropy analysis using ESI Compass 1. 3 Maximum Entropy Deconvolution Option in DataAnalysis 4.
In addition, to exclude carryover effect, we performed infusion of fractions corresponding to peak 4 and to a period of 2 min before detection of peak 1. No ESI-MS spectra have been detected corresponding to Fc/2 fragment (data not shown). Cetuximab, as other mAbs, is known to have a large number of microheterogeneities commonly found in proteins which are reflected by differences in mass, charge or conformation and then differences in effective mobilities. Moreover, it is plausible that several cumulative modifications could lead to a variation of conformation without mass shifts. Although further work is required to identify these modifications. An important class of modification that can significantly impact the immunogenic properties of cetuximab in terms of PK and PD is glycosylation  10.
Acknowledgments Authors would like to thank  Sciex separations Inc. for lending a CESI prototype and  Dr. M. Anselme  from  Sciex separations Inc. for his support. The authors would like also to express their gratitude to  Dr. E. Wagner-Rousset ,  Dr. D. Ayoub ,  MC. Janin-Bussat  and  O. Colas  ( Centre d'Immunologie Pierre Fabre, St Julien en Genevois, France ) for helpful discussions around antibody structural characterization.
Only two genetic studies have been carried out on this species  [14, 15] , but they did not investigate all subspecies, in the entire distributional range. Here, we carried out an extensive phylogeographic study based on mitochondrial DNA sequences (cytochrome b and ND2 genes) from samples covering the worldwide distribution of the Osprey. This exhaustive dataset allowed addressing specific questions. a) Does the Osprey show any phylogeographic structure in mitochondrial DNA at the continental level? b) How was such a specialized raptor able to colonize the entire world? We propose a hypothetical evolutionary scenario explaining how the species' distribution and differentiation took place in the past. In the light of these new genetic clarifications, we discuss the potential implications for revisions of the taxonomy and for conservation (e.
[17]. From each museum, we mainly choose museum study skins of various origins and collected during the breeding season, so excluding possible vagrants, wintering birds or dispersing animals. From both fresh and museum specimens DNA was extracted and amplified by PCR (see technical procedures below) for the mitochondrial Cytochrome b (cyt b) and NADH dehydrogenase subunit 2 (ND2). For the cyt b, five sequences from the GenBank database were also included, leading to a total of 209 sequences (see Additional file 1). For ND2 a subset of only 37 individuals returned high-quality PCR products to which we added one sequence from GenBank, thus leading to a dataset of 38 individuals (Additional file 1). Finally, four other raptor species were used as outgroups: White-tailed eagle (Haliaeetus albicilla), Tawny eagle (Aquila rapax), Blackbreasted buzzard (Hamirostra melanosternon) and Grayheaded kite (Leptodon cayanensis).
The choice of these outgroups was motivated because 1) both cyt b and ND2 sequences were available in GenBank (see  [11]  for outgroup accession numbers), and 2) they represent four lineages of the Accipitridae family, the sister taxa of Pandionidae (including only Pandion haliaetus;  [11] ). The number of individuals and the length of sequences used for each analysis are reported in supplementary information (Additional file 2). Total genomic DNA was extracted from fresh and historical samples using a Qiagen DNeasy Tissue kit, following the manufacturer's instructions (Qiagen, Hilden, Germany). To avoid contamination with contemporary DNA  [18] , all extractions from museum specimens were performed using the facilities of the platform "degraded DNA" (Labex CeMEB, Montpellier, France) dedicated to degraded DNA experiments, where we adopted the following specific safety measures.
A mitochondrial cytochrome b 1040 nucleotides fragment was amplified with PANHF1 and PANHR5 primers; F13 and PHND2-R1 primers were used to amplify a ND2 nucleotide fragment of 1100 bp. In case of degraded DNA, we used internal primers to amplify cyt b and ND2 in 300 to 500 nucleotides overlapping fragments (see Additional file 3). Screening of the PCR products was performed by running on a 1 % agarose gel using GelRed TM nucleic Acid gel stain (Biotium). Size products have been compared to long fragments ladder from Eurogentec, Smart LadderTM. After band sizes were determined, PCR products were sequenced at the Genoscope (Evry, France). Electrophoregrams were read using CodonCode Aligner 4. 0. 4 software and sequences were aligned by eye using Seaview 4 software  [19]. Sequences were also translated into amino acids to check for any stop codons and possible amplification of pseudo-genes.
Partitioning and phylogenetic analyses Phylogenetic relationships were inferred from the cyt b alone or from the concatenated cyt b + ND2 datasets. We determined both the best-fit partitioning scheme and the best models of sequence evolution using Parti-tionFinder 1. 0. 1  [20]. Phylogenetic trees were reconstructed using two probabilistic methods: Bayesian inference (BI) and maximum likelihood (ML). Bayesian analyses were performed with MrBayes 3. 2  [21]  using the partitioning strategy obtained with PartitionFinder (see also Results). Two separate runs of five million generations (sampled every 250 generations) were conducted simultaneously. Tracer 1. 5  [22]  was used to check the convergence between the two runs and to determine the burn-in period. On this basis, the first 2000 phylogenetic trees were discarded (10 %), and the remaining 18000 trees were used to estimate posterior parameters and probability distributions.
ML tree was constructed with RaxMl 8. 0. 17  [23]. As GTR is the only nucleotide substitution model available in RaxMl, GTR + G was applied to all partitions previously determined by PartitionFinder. The robustness of nodes was evaluated with 1000 bootstrap replicates with the option -b. The consensus tree was obtained using the program Consense of the Phylip 3. 69 package  [24]. Relationships between haplotypes were also visualized as a minimum spanning network, using the Median-Joining (MJ) network algorithm implemented in the program network 4. 1. 1. 0 [25]. In order to avoid artefactual groupings due to missing data, the MJ network was built considering the most complete dataset in terms of nucleotides and individuals, which is a fragment of 661 bp of the cyt b on 146 samples.