dataesr/scientific-paragraphs-categorization huggingface dataset:
Several studies are currently underway based on this scheme: for instance, NCT02897765 study adds a personalized vaccine after 3 months of nivolumab in different types of cancers. The advantage in this context of advanced disease is the possibility of performing sequential tumor biopsies to evaluate changes in the immune infiltrate following vaccination, in addition to demonstrate the induction of a specific immune response detected in blood. Furthermore, neoepitopes-based vaccines could be an interesting approach in combination with ICIs for diseases with low or no response to ICIs alone despite a significant mutational burden. This is the case for microsatellite stable colorectal cancer, where response to immunotherapeutic approaches (eg T-cell recruiting bispecific antibody with atezolizumab) have shown clinical responses in favor of a functional immune system  [39].
The risk of relapse is high and the vaccine is set up in a context of low tumoral mass after conventional treatment combining neoadjuvant chemotherapy, surgery and radiotherapy. Several phase I trials are underway in this context, such as NCT02348320 study. It will be necessary to set up control groups in this setting to demonstrate a benefit in terms of survival. Furthermore, the absence of biopsy-accessible tumors restrains the immunological analyses to the blood level. Nevertheless, it is likely that the adjuvant setting in pathologies at high risk of relapse represents a positioning of choice for vaccine approaches, used alone or in combination with an anti-PD-1/-L1.
Melanoma, Non-Small Cell RNA Advanced/ Lung, Bladder, Colorectal, metastatic Breast (TN), Renal, Head and Neck NCT03480152 National Cancer Melanoma, Colon, RNA Advanced/ Institute (NCI) Gastrointestinal, metastatic Genitourinary, Hepatocellular NCT03552718 NantBioScience, Inc. Colorectal, Breast, Head and DC Adjuvant Neck, Melanoma, Non-Small Cell Lung, Pancreatic, liver NCT03633110 Genocea Biosciences, Melanoma, Non-small cell Long Adjuvant Inc. Lung, Head and Neck, peptide Urothelial Carcinoma, Renal Cell Carcinoma NCT03558945 Changhai Hospital Pancreatic NA Adjuvant NCT03645148 Zhejiang Provincial Pancreatic Long Advanced/ People's Hospital & peptide metastatic Hangzhou Neoantigen Therapeutics Co. , Ltd.
Flow Cytometry Analysis of Tumor-Infiltrating Leukocytes in the MBT-Treated Tumors To identify immune cells infiltrating subcutaneous PHEO tumors during MBT therapy, we performed a flow cytometry analysis of tumor-infiltrating leukocytes. Since we limited the number of mice per group (n = 3/group), we decided to present tumor-infiltrating leukocytes data as individual values for each mouse, with a color legend based on the size of the analyzed tumors. The flow cytometry analysis of tumor-infiltrating leukocytes showed increased levels of CD45 + cells in the MBT-treated group. This trend culminated on the 15th day of therapy (Figure  5A ). T cells (CD3 + ) were the most common leukocytes in the MBT-treated tumors (Figure  5A ). The analysis of CD3 + subpopulations revealed increased levels of Th cells (CD4 + ) (Figure  S2A ) and Tc cells (CD8 + ) (Figure  S2B ) in the MBT-treated group.
Tumor Size Evaluation Subcutaneous tumor volume was measured every other day with a caliper and calculated as V = (π/6) AB 2 (A and B = the largest and the smallest dimension of the tumor, respectively)  [54]. Survival curves are based on the time of death caused by tumor growth or on the time of sacrifice of mice reaching the maximally allowed tumor size of 2 cm in diameter. In metastatic PHEO, mice were imaged by an IVIS system (Bruker, Billerica, MA, USA) once a week to detect a bioluminescence signal intensity of metastatic organ lesions, and the signal was evaluated using Bruker MI SE software.
7 (BioLegend); PE/Cy7 anti-mouse Ly-6G/Ly-6C (GR-1), clone: RB6-8C5 (BioLegend); PE anti-mouse NK-1. 1, clone: PK136 (BioLegend); and Brilliant Violet 421 anti-mouse F4/80, clone: BM8 (BioLegend). LIVE/DEAD ® fixable yellow dead cell stain (Invitrogen, Carlsbad, CA, USA) was used to eliminate dead cells. Samples were measured using a BD Fortessa analyzer (San Jose, CA, USA) and evaluated with FlowJo software (Ashland, OR, USA). CountBright absolute counting beads (Invitrogen) were used to count absolute numbers of individual CD45 + cells.
02 mM mannan-BAM in culture medium for 30 min in 37 • C. After incubation and washing by centrifugation, mouse MTT-luciferase cells were co-cultured with activated or non-activated murine neutrophils and human hPheo1 cells with activated or non-inactivated human neutrophils for 2 h in 37 • C. The tumor cell/neutrophil ratio was 1:5 (50,000 tumor cells to 250,000 neutrophils). Dead cells were stained with DAPI (1 µM) (Invitrogen). APC anti-mouse CD45 antibody, clone 30-F11 (BioLegend), and APC anti-human CD45 antibody, clone H130 (BioLegend), were used to stain leukocytes (in this specific case neutrophils). CountBright absolute counting beads (Invitrogen) were used to count absolute numbers of live tumor cells in the samples. Samples were measured by FACSCantoII. FlowJo software was used for analysis.
Imaging of PHEO Cell-Neutrophil Interactions Adhered hPheo1 or MTT-luciferase cells were incubated with 0. 02 mM mannan-BAM in culture medium for 30 min in 37 • C. Following incubation, unbound mannan-BAM was washed by centrifugation and human neutrophils were added to the hPheo1 cells and mouse neutrophils to the MTT-luciferase cells (the ratio of tumor cells to neutrophils was 1:2 (50,000 tumor cells:100,000 neutrophils). Neutrophils and hPheo1/MTT-luciferase cell interactions were documented after 2 h of co-culturing in 37 • C. A Leica DMRB microscope and Leica LAS AF software were used for analysis.
Depletions Cellular subsets were depleted by administering 300 µg of depleting antibody intraperitoneally twice weekly starting one day prior to immunotherapy: CD8 + T-cells with anti-CD8α, clone 2. 43 (BioXCell), and CD4 + T-cells with anti-CD4, clone GK1. 5 (BioXCell). Cellular depletion of CD8 + and CD4 + T-cells were confirmed by flow cytometry of PBMC blood levels (Figure  S3 ). Samples were measured by FACSCantoII. FlowJo software was used for analysis.
Statistical Analysis Data were analyzed using STATISTICA 12 (StatSoft, Tulsa, OK, USA) or Prism 7 (GraphPad Software, San Diego, CA, USA). Individual data sets were compared using a dependent/independent Student's t-test. Analyses across multiple groups and times were performed using repeated measures ANOVA (for data with normal distribution) with individual groups assessed using Tukey's multiple comparison. For data without normal distribution, non-parametric ANOVA was used with individual groups were assessed by Kruskal-Wallis test. Kaplan-Meier survival curves were compared using a log-rank test. Error bars indicate the standard error of the mean (SEM). * p < 0. 05; ** p < 0. 01; *** p < 0. 001; **** p < 0. 0001. # p < 0. 05; ## p < 0. 01.
Acknowledgments: The authors would like to thank  Pradeep K. Dagur , and  Ankit Saxena , for their technical assistance during flow cytometry analyses, as well as the staff of the  Flow Cytometry Core ,  National Heart, Lung, and Blood Institute ,  NIH ,  MD 20892. The authors would also like to thank  Dale Kiesewetter ,  Laboratory of Molecular Imaging and Nanomedicine, National Institute of Biomedical Imaging and Bioengineering, National Institutes of Health, Bethesda, Maryland, MD, USA , for his assistance during the bioluminescence imaging of experimental mice.
Acknowledgements The scientific assessment summarised in this report is based on important contributions from the rapporteur and corapporteur assessment teams, Committee for Human Medicinal Products (CHMP) members and additional experts following the application for a marketing authorisation from the company. Contributors Data analysis and interpretation: YY, DM, CH, PH, RV, TW, GDH, TK, MD and BB. Manuscript writing: KT, YY, DM, CH, PH, RV, TW, GDH, TK, MD, BB and FP. Final approval of manuscript: all authors. Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
P Mangeat CNRS, UMR5539, Montpellier, France) and cells were stained using phalloidin. Bacteria were analyzed using an Incucyte S3 analysis system (Sartorius). Four images were acquired per IBIDI channel (×20 magnification). Surface of colonizing bacteria was determined using the Incucyte S3 software and expressed as median of colonization index with interquartile range (total surface of bacteria in μm 2 over total surface occupied by cells in μm 2 ). Immunofluorescence on Nm-infected cells. After infection, cells were washed three times and fixed for 20 min in PBS containing 4% PFA and permeabilized for 5 min in PBS containing 0. 1% Triton X-100. Cells were incubated in PBS containing 0. 1% bovin serum albumin (BSA) for 30 min and then with polyclonal antiezrin rabbit antibody (1:1000) in PBS containing 0.
1% BSA for 1 h. After three washings in the same buffer, DAPI (4′,6-diamidino-2-phenylindole; 0. 5 μg/ml) was added to Alexa-conjugated secondary antibodies for 1 h (A-11003 and A-11035, Thermo Fisher Scientific, 1:200). After additional washings, coverslips were mounted in Mowiol. Image acquisition was performed on a laser-scanning confocal microscope (Leica TCS SP5). Images were collected and processed using the Leica Application Suite AF lite (Leica) software. Expression and purification of pilin recombinant proteins. Recombinant His-tag pilin fusion proteins were produced as perisplam-directed proteins as described before  51. Fragments of pilE, pilV, and comP genes lacking the region coding for the amino-acid residues 1 to 28 of the full-length proteins were amplified by PCR from the existing plasmids pmal-PilE, pmal-PilV, and pmal-ComP 9 and subcloned in pET22b (Novagen) between BamHI and XhoI restriction sites.
At least 50 colonies were observed per coverslip. Each experiment was repeated several times in triplicate. Data were examined for significance using the Prism GraphPad software. Quantification of ezrin recruitment below colonies was also performed by measuring the intensity of fluorescence signals (as in Fig. 6b ): 10 fields per slides were acquired with a Zeiss Apotome 2. 0. Each colony was analyzed using the ImageJ software. Briefly, the DAPI layer and ezrin staining layer were extracted and a threshold mask was applied on the ezrin staining layer to suppress the background staining (normal ezrin staining at the plasma membrane) and to transform the layer into a black and white image. The mean value of pixel intensity below colonies reflects the total area covered by ezrin staining and is expressed as Arbitrary Intensity of ezrin recruitment.
Higher energy collisional dissociation (HCD) fragmentations were performed on the 10 most abundant ions with a dynamic exclusion time of 30 s. Precursor selection window was set at 4 Th. HCD normalized collision energy was set at 30% and MS/MS scan resolution was set at 17,500 with AGC target 1 × 10 5 within 100 ms MIIT. Spectra were recorded in profile mode. MS data were analyzed using Mascot 2. 5. 1 (www. matrixscience. com). The database used was a concatenation of human sequences from the Uniprot-Swissprot database (release 2019-02, 20492 sequences) and a customized database of 70 modified sequences including the four ADRB2-mutated HA-tagged sequences (WT, N6A, +11, and N15A), and a list of in-house and common contaminant sequences (292 sequences). Cysteine carbamidomethylation was set as constant modification; asparagine deamidation was set as variable modification to allow detection of peptide modified by PNGase F enzymatic deglycosylation.
Acknowledgements We thank  N. Goudin  of the  Necker Institute Imaging Facility ,  S. Fabrega ,  L. Nay , and  S. Hadj Hamou  of the Viral Vectors and  Genes Transfer facility (VVTG)  for their technical support. This work was supported by  ANR-14-IFEC-0006-01 ,  ANR-15-CE15-0002 , and  ANR  MECAD-R 2019 grants. S. M. and X. N. are supported by  INSERM ,  CNRS ,  Université Paris Descartes , and the  Fondation pour la Recherche Médicale.
Acknowledgements We thank all the members of the  Microenvironment & Immunity Unit , as well as from the  Stroma, Inflammation & Tissue Repair Unit , for support and discussion and the members of  Gnotobiology Platform of the Institut Pasteur  for technical support with GF mice. Funding: J. H. P. was supported by the  Agence Nationale de la Recherche , and S. C. by grants from the  European Molecular Biology Organization  and the  Human Frontiers Science Program.
Cell debris and doublets were excluded on the basis of side versus forward scatter. Cells were analysed on a FACS CANTO II cytometer (BD Biosciences) using FACS Diva (BD Biosciences) software. Recent thymic emigrants (RTE) were defined as CD45RA + CD31 + CD4 + T cells  (12). Data were analysed by considering the percentage of RTE among CD4 + T cells (RTE frequency or RTE%) and the absolute numbers of circulating RTE/mm 3 (Figure  S2 , supplementary data).
Acknowledgements We acknowledge  Pr Bruno Moulin  ( CHU Strasbourg ),  Pr Luc Frimat  ( CHU Nancy ),  Pr Christiane Mousson  ( CHU Dijon ),  Pr Philippe Rieu  ( CHU Reims ),  Pr Anne-Elisabeth Heng  ( CHU Clermont-Ferrand ), and  Pr Antoine Durrbach  ( CHU Kremlin-Bicêtre ) for participation in the ORLY-EST study Acknowledgments Supported by grants from the  Fondation Transplantation , the PHRC 2005 and 2011 (to DD), the  Fondation de France  ( Appel d'offre "Maladies Cardiovasculaires " 2007 # 2007 001859  to PS), the  DHOS/INSERM/INCa  (Appel d'offre Recherche Translationnelle 2008 to DD and PS) and the  APICHU 2010  (to JB), from the  Agence Nationale de la Recherche  ( Labex LipSTIC ,  ANR-11-LABX-0021 ) and the  Région de Franche-Comté  (support to  Labex LipSTIC  to PS). JB, CC, TC, and CR received financial support from the  Fondation Transplantation  (# ET-031211  and # ET-050320 , respectively).
Study Design In this retrospective EBMT registry-based analysis, all patients age 18 years who had undergone alloHCT from a matched sibling or unrelated donor for FL, DLBCL, MCL, or PTCL between 2003 and 2013 and were registered with the EBMT were eligible. Patients allografted with a cord blood or haploidentical transplant were excluded. All patient-, disease-, and transplantation-related data used in this study were collected from EBMT MED-A standard forms. Because comorbidity information was not a compulsory item on the MED-A versions used during the study period, it was available for only a subset of the entire patient sample. Therefore, the study was split into an analysis of the entire sample and a second analysis of the subset with comorbidity information available ,including this variable as covariate in multivariable risk factor assessments.
Discussion The aim of this observational survey was to investigate how French health professionals working in vaccination centers used the JE vaccination. The response rate of 38. 5% was satisfactory and close to those obtained in other studies based on sending questionnaires by regular mail to family physicians  [6] [7] [8]. The use of questionnaires sent by email offered the opportunity to easily target all regions of France, including the overseas regions. Few significant statistical differences in practice were observed in the present study. One of them was the higher proportion of health professionals prescribing the JE vaccination in mainland France as compared with the overseas regions. Little data on the size and number of vaccination centers in mainland France is available to accurately interpret this result.
MATERIALS AND METHODS Individual calf PK data from three different sources (A = 10, B = 32, C = 8) were used for the POP PK analysis (see Supplementary Material, giving raw data). Source A consisted of 10 calves from a published study  (Sidhu et al. , 2014). Source B was a drug company (Norbrook Laboratories Limited); it comprised 16 calves enrolled in a cross-over bioequivalence study (MSD Nuflor R and Norbrook Norfenicol R formulations) Norfenicol R being a FDA and EMA approved generic product  (Anonymous, 2018a). The 32 data sets were provided by 16 sets for each product, so that for this analysis each of these calves provided two data sets. The third source comprised data from 8 calves in an unpublished study. All calves were in good health and all received a subcutaneous florfenicol dose of 40 mg/kg.
Assuming that the residual mainly reflects variability of the analytical technique, we explored, as a part of the quality control of the merged data sets, what might be the precision of the three analytical techniques used to generate the data i. e. , included in the error model was the source of the data as a covariate. It was concluded that differences were not sufficiently large to retain this covariate. Therefore, in the final model, a single residual without covariate was used. The residual error model without covariate was of the form (Equation  4 ): Y = f (θ , Time) × (1 + ε 1 ) + ε 2 (4) with ε1 the multiplicative error term having a mean of 0 and a variance of σ1 ε1 ≈ N (0, σ 1 2 ) and ε2 the common additive error term having a mean of 0 and a variance noted σ2 ε2 ≈ N (0, σ 2 2 ) Sigma1 and Sigma2 were estimated by Phoenix and reported as a CV% for sigma1 and as a STDV for sigma2.
, 2008). For the two-compartment model, when the BLQ incidence was <5%, it was shown that omission of the BLQ data generally did not inflate the bias in the fixed-effect parameters  (Xu et al. , 2011). The shrinkage for the etas was estimated by the equation  (Karlsson and Savic, 2007) : Eta shrinkage = 1- SD (EBE η ) ω ( 5 ) where ω is the estimated variability for the population and SD is the SD of the individual values of the Empirical Bayesian Estimates (EBE) of η. Different diagnostic plots were reviewed to determine whether or not a model was adequate. These included PRED (Population Predicted Value based on population parameter estimates) and IPRED (Individual Predicted value based on individual's ETAs) vs. the DV (Dependent variable) (with and without a log scale) Conditional weighted residuals (CWRES) and individual fitting.
The overall adequacy of the 2-compartment PK model was established by plotting the Visual Predictive Check (VPC) i. e. , a graphical comparison between the observed data and prediction intervals derived from the simulated data. Secondary parameters were also computed (terminal halflives for the first and second phases of drug disposition and contribution of the first and second phases to drug absorption). Monte Carlo simulations (MCS) of the predicted concentration (IPRED) from the model i. e. , simulation of concentration without the error term from 0 to 96 h post administration, with a step of 1 h, were used to generate a meta-population of 5,000 calves. These curves were analyzed using the Non-Compartmental tool of Phoenix to compute the areas under the curve and the time above selected MICs from 0 to 96 h, 96 h being the claimed duration of florfenicol activity after a single SC administration of Nuflor R (Anonymous, 2018b).
This is unfortunately not the case for veterinary medicine, where CBPs can also be "formulationdependent. " The formulations, Nuflor R from MSD and its generics, evaluated in this study were all administered by the subcutaneous route, these being the most extensively used formulations and route of administration for florfenicol in cattle. However, other florfenicol formulations and other routes of administration are used in cattle, so that VetCAST CBP is not guaranteed to be applicable to other formulations and/or other routes of administration. These issues are discussed in the VetCAST position paper  (Toutain et al. , 2017). Finally from a pooled raw data analysis, using a NLME and MCS for florfenicol, a PK/PD CO of 1 mg/L is proposed for the extensively used LA florfenicol formulations investigated.
Acknowledgements We would like to thank the  Vienna Drosophila Resource Centre , the  Bloomington Drosophila Stock Centre  and  Mirka Uhlirova  for fly stocks. We are thankful to  Core Services  and  Advanced Technologies at the Cancer Research UK Beatson Institute  ( C596/A17196 ), with particular thanks to  Beatson Advanced Imaging Resource. We are very grateful to  Dr. Dahua Chen  for sharing the anti-Defensin antibody, to  Dr. Sebastien Voisin  for his critical contribution in mass spectrometry analyses and to  Dr. Mate Naszai  for critical help in the quantification of staining co-localization. JPP and YY are supported by  Cancer Research UK  core funding through the  CRUK Beatson Institute  ( A17196 ). JBC is a  Sir Henry Dale Fellow jointly  funded by the  Wellcome Trust  and the  Royal Society  (grant number  104103/Z/14/Z ).
A phase IIIb study (post-HERCULES study) is currently ongoing in order to assess the long-term efficacy and tolerance of caplacizumab (NCT02878603); in the meantime, the drug was already approved by the European Medicines Agency for adult patients with iTTP as a frontline treatment in association with TPE/corticosteroids and rituximab. It is also under review by the Food and Drug Administration. Because ADAMTS13 deficiency is directly involved in the occurrence of the disease, a treatment based on a specific ADAMTS13 supply is an attractive perspective. This strategy has been highlighted in mice knock-out for adamts13 gene in which clinical and hematological features of TTP can be reproduced after the administration of human recombinant vWF. Interestingly, the features of the disease could be reverted by the administration of recombinant human (rh)ADAMTS13  (60) , opening the way to clinical trials in patients with cTTP.
A phase 3 study is now ongoing to assess rhADAMTS13 efficacy in cTTP (NCT03393975). As a perspective, such replacement strategy could significantly reduce the volume of plasma required to maintain patients in remission, or even replace plasmatherapy, allowing a decrease of plasma-related side effects: fluid overload, allergic reactions, transfusions-related acute lung injury and alloimmunisation. Lastly, the adaptation of rhADAMTS13 to patient weight, inhibitor titer and response to therapy would be part of a more personalized medicine. In the next future, the development of inhibitor-resistant recombinant ADAMTS13 proteins with enhanced vWFcleaving activity should still refine this new approach  (62). N-acetylcysteine (NAC) is a small molecule commonly used to treat acetaminophen poisoning or as a mucolytic agent.
Its ability to reduce disulfide bounds and thereby reducing the length of soluble ULvWF multimers raised interest for the treatment of TTP. Interestingly, it seems that NAC quite particularly disrupts the disulfide bound located in the A1 domain of vWF, preventing its binding to the platelets receptor Gp1b  (63). Despite a strong biologic rationale and an encouraging case report  (64) , definitive clinical evidence is still lacking, and its efficacy has been recently called into question in a mouse and baboon pre-clinical study  (65). In this work, albeit effective as a prophylaxis, high-dose NAC was unable to reverse established TTP manifestations despite a reduction in ULvWF multimers length. NAC is currently evaluated as an adjunction to initial therapy with TPE in a randomized pilot trial (NCT01808521).
Classification and features The ITS, ftsZ, rpoB and gltA genes as well as the 16S ribosomal RNA (rRNA) gene were amplified and sequenced to identify isolated Bartonella strains. After the sequences analysis, two strains, OS09 T and OS23 T , showed almost the same genetic similarity: they had 100% identity for the 16S rRNA and rpoB genes, 99. 8% for the ftsZ gene and 99. 9% for the gltA gene. No mutation was detected for the ITS gene, and only a 5 bp deletion was found for the OS23 T strain. The similarities of the sequences of the OS09 T and OS23 T strains with respect to the different species closest to the genus Bartonella for the 16S rRNA, ITS, ftsZ, rpoB and gltA genes were 99. 5%, 79. 5-81. 3%, 96. 8-96. 9%, 93. 2% and 94. 5-94. 6% respectively. According to La Scola et al. [8] , these data support the notion that strains OS09 T and OS23 T may be identified as a new and same species.