dataesr/scientific-paragraphs-categorization huggingface dataset:
Clinical Data for Epoetin Zeta in CIA The efficacy of epoetin zeta has also been demonstrated in CIA. In a phase III, open-label, multicentre international trial a total of 216 patients receiving chemotherapy in association with solid or non-myeloid haematological malignancies and at risk of transfusion were assessed over two treatment periods  [27]. The first was a 12-week treatment period in which patients received an anticipated 8 weeks of chemotherapy treatment, and epo etin zeta was started before (in week 0) or at the latest together with the new cycle of chemotherapy. The second treatment period included patients undergoing over 12 weeks of epoetin treatment, up to a possible 36 weeks. All patients continued to receive epoetin zeta until 1 month after their last chemotherapy dose. Therefore, treatment periods varied based on the duration of chemotherapy.
A rise in blood pressure was reported in 1. 3% of patients at 3 months. The same rate was reported at 6 months. The efficacy and tolerability results of this observational study were similar to those reported in the previous phase III open-label study for epoetin zeta in CIA  [27]. A second ORHEO study (NCT01626547) is currently underway in Germany on the use of epoetin zeta only in patients with CIA in association with solid tumours, lymphoma and myeloma. An estimated 300 patients were recruited and observed over a 6-month treatment period (the total study duration was 14 months)  [30]. In addition to the two mentioned ORHEO studies, a prospective study testing a minimum of 12 weeks of treatment with epoetin zeta in patients with low-risk myelodysplastic syndrome is ongoing in France in 15 centres (RCB 2012-A01395-38).
Acknowledgements The preparation of this manuscript was supported by  Hospira UK Ltd. All authors take full responsibility for the content of the article. The authors would like to thank  Andrew Buckley , an employee of Hospira Ltd at the time of preparation of the manuscript, for his critical review of the manuscript. The authors would like to thank  Dr. Marion James  and  Dr. Nason Maani Hessari  of apothecom scopemedical ltd (supported by  Hospira ) for assistance in preparing the manuscript.
All Ly6 family members contain one or more uPAR/Ly6 domains (Pfam identification code: PF00021;  [15] ), a 60-110 amino acid region that forms a characteristic "three-fingered protein domain" (TFPD) fold and contains eight or ten conserved cysteines  [16]. This TFPD fold places Ly6 proteins as part of the larger TFPD protein superfamily, which also includes the transforming growth factor beta receptor (TGFβR) family and the snake α-neurotoxins family  [16]. While each of these three protein families share the same core fold, they are differentiated by protein features (e. g. presence of Cterminal intracellular kinase domain in TGFβR family;  [17] ) and cysteine spacing (e. g. absolute conservation of C 1 -X-X-C 2 spacing in the Ly6 family;  [18] ). Unlike the restricted phylogenetic representation of the snake α-neurotoxins, Ly6 genes have been found across both vertebrate and invertebrate phyla (Homo sapiens CD59;  [19] , Drosophila melanogaster rtv;  [20]  and Caenorhadbditis elegans odr-2  [21] ).
Bioinformatic identification and characterisation of SmLy6 sequences PSI-BLAST  [30]  searches were performed with five separate representative Ly6 proteins obtained from NCBI-Homo sapiens CD59 ([AAA60957];  [24] ), H. sapiens uPAR ([Q03405. 1]; [25] ), C. elegans ODR-2 ([NP_001024089];  [21] ), D. melanogaster Boudin ([NP_572373];  [18] ) and D. melanogaster Rtv ([NP_572693];  [20] ) against the S. mansoni RefSeq database (genome version 5. 0)  [31]. Selection of potential S. mansoni Ly6 homologues during PSI-BLAST searches required the protein sequence to contain three characteristic features of uPAR/Ly6 domains used previously to identify Ly6 proteins  [18] : 1) presence of ten or more cysteine residues within a 60-110 aas region (lower and upper amino acid length defined using existing uPAR/Ly6 domains (Pfam domain: PF00021;  [15] )), 2) presence of an N-terminal motif C 1 -X-X-C 2 (where C 1 represents the first cysteine residue, X represents any amino acid and C 2 represents the second cysteine residue) and 3) presence of a C-terminal C 10 -N motif (where C 10 represents the tenth cysteine residue and N represents asparagine).
Newly identified Ly6 homologues were incorporated into the search matrix until no more members could be identified, typically after five to six rounds of iterative searching. Then, these sequences were used as novel queries to identify any further homologues remaining in the S. mansoni genome. To identify putative orthologues for SmLy6A-K in the S. haematobium and S. japonicum genomes, tBLASTn searches using each of the SmLy6 family members was performed against the latest publically available gene predictions (searches performed 17-08-2013) from those genomes (downloaded from SchistoDB. net and GeneDB. org respectively). Alignment of the SmLy6 family members and HsCD59 protein sequences was performed using MUSCLE software  [32]  with additional manual editing based on canonical residues implemented as necessary.
The prediction of signal peptides was performed using the software SignalP 3. 0  [33]  and presence/absence of signal peptides was defined by the default Neural Network Dscore threshold of 0. 43. Predicted hydrophobic regions in SmLy6 proteins were assessed using TMpred software  [34]  and potential GPI anchor sites were determined using the BIGPI server  [35]  with the site possessing the lowest e-value indicated.
Cloning of SmLy6 sequences S. mansoni total RNA was isolated  [10]  and used as templates to synthesise cDNA by reverse transcription as previously described  [36]. SmLy6 sequences were confirmed by PCR amplification of cDNA obtained from either 7-week adult mixed-sex worms (SmLy6A-I) or miracidia (SmLy6J, SmLy6K) using Phusion proof-reading polymerase (Finnzymes). Nucleotide sequences for each SmLy6 family member are deposited in Genbank (accession numbers provided in Table  1 ) and primers used to amplify SmLy6 sequences by PCR are listed in S1 Table.
Tertiary structure modeling Tertiary structural modeling of SmLy6 family members was performed using the predicted mature protein sequences of SmLy6A-K produced by translating the sequenced transcripts and removing the amino acids encoding signal peptides and regions C-terminal to the GPI anchor. Given the lack of significant sequence identity to any known structure and the small size, the structure of the protein was predicted using Rosetta  [37]  following the protocol described elsewhere  [38]  with the modification that only 1000 models were taken forward for full-atom minimization. Structural models were ranked using Rosetta's energy function and the top 20 models were visually inspected to assess the convergence of the models towards a similar fold. Models were visualized using PyMOL (DeLano Scientific LLC).
Expression profiles and recombinant production of SmLy6A and B Using information available from a DNA microarray database  [10] , the mRNA abundance for 8 of the 11 SmLy6 genes (SmLy6A-D and F-I) across 14 different schistosome life-stages was   ). Similarly, pre-treatment IgG 4 responses in the cohort also showed that responses to SmLy6A and SmLy6B are both abundantly expressed in adult schistosomes but only SmLy6B is detectable in schistosomula. SmLy6A and SmLy6B mRNA and protein abundances were elucidated as described in the Materials and Methods. Transcription profiles of SmLy6A (A) and SmLy6B (B) were derived from the S. mansoni lifecycle microarray data available via Array express  [10]  under the experimental accession number E-MEXP-2094. Values are mean normalized fluorescence units ± sem (standard error of the mean).
Acknowledgments We thank  Dr. Samirah Perally  and  Mr. Shawn Phillips  for initial work on identifying Ly6 family members. We also thank current and past members of the  Hoffmann group, Khalife group and Dunne group  for assistance in laboratory work and S. mansoni lifecycle maintenance. We acknowledge  Dr. Cornelis Hokke  for the proteomics confirmation of rSmLy6A and rSmLy6B and are also very grateful to the people of  Musoli  for the help and cooperation during the cohort study.
Procedures Acute encephalitis syndrome and meningitis were defi ned according to WHO 2003 guidelines. 17 Acute encephalitis syndrome was defi ned as the acute onset of fever and either a change in mental status (including symptoms such as confusion, disorientation, coma, or inability to talk) and new onset of seizures (excluding simple febrile seizures) in a person of any age. Meningitis was defi ned as a sudden onset of fever (>38•5°C rectal or 38•0°C axillary) with one of the following signs: neck stiff ness, altered consciousness, or other meningeal signs. If a patient fulfi lled criteria for both disorders, we used the term meningoencephalitis. We recorded demographic and clinical data on standardised forms and grouped data according to guidelines. 17, 18 Occupations were classifi ed as farmer, housewife, teacher, government offi cial, driver, building worker, merchant, health worker, police, monk, mechanic, soldier, child (<5 years), schoolboy or girl (5-15 years), student (>15 years), or unemployed.
Of 446 patients with data available for both direct and serological results, we detected evidence of scrub typhus, Rickettsia spp or murine typhus, or leptospirosis in 59 (13%) of 446 patients. Leptospira interrogans was the most commonly identifi ed Leptospira species by microscopic agglutination test or sequencing (GenBank KJ150298-KJ150302; appendix p 3). We identifi ed Rickettsia spp as R typhi for 16 (84%) of 19 patients who were qPCR positive, but for three patients the Rickettsia species could not be established because no template remained. In addition to the 90 patients with O tsutsugamushi, R typhi/ Rickettsia spp and Leptospira spp monoinfections, we recorded grade 1 and grade 2 multiple infections in an additional 14 patients (appendix p 4). 24  More than half of all patients met the WHO criteria for meningitis (709/1093 [65%]) or acute encephalitis syndrome (610 [56%]), 84 (74%) met either criteria, and 521 (48%) fulfi lled both criteria (table 1 and fi gure 2).
Acknowledgments This study was funded by the  Wellcome Trust UK. We thank all the doctors and nursing staff of  Mahosot Hospital , the staff of the microbiology laboratory, especially  Rattanaphone Phetsouvanh ; the  Directors of Mahosot Hospital , the  Minister of Health  and the Director of the  Curative Department, Ministry of Health , for their support for this study;  Ampai Tanganuchitcharnchai  and  Suthatip Jintaworn  for the work on the immunofl uorescence assays;  Janjira Thaipadungpanit ,  Andrew Duggins ,  Gareth Turner , and  Paul Turner  for fruitful discussions and for the assistance of anonymous reviewers.
Acknowledgements We are grateful to: -Doctor Viviane Guerin (now retired) who developed ADAMTS-13 analysis in Bordeaux. Professor Dominique Dallay of the obstetrical unit of Bordeaux university hospital who provided access to patient data. Professor Marie-Edith Lafon  from the  Laboratory of Virology  for providing historic sera for analysis. - Hélène Fraisse , for her valuable help. -All of the nurses at the  Hôpital de Jour de Néphrologie.
Indeed, the guidelines stated that amoxicillin was the most active agent for pneumococci with decreased susceptibility to penicillin and was active for more than 85 % of nontypable Hi according to microbiologic data at the time  [3]. Since 2011, 2 major changes have occurred: the implementation of 13-valent PCV (PCV13) and the shift in antibiotic prescription for AOM, with decreased use of third-generation cephalosporins and amoxicillin-clavulanate replaced by amoxicillin  [14, 15]. A rapid change in resistance of Pnc and Hi to the commonly used antimicrobials prompts a reevaluation of the treatment strategies  [8]. To assess this question, we measured NP carriage and antibiotic susceptibility of these 2 otopathogens in young children with AOM in the PCV13 era in France.
Statistical analysis Data were double-entered by using 4D software 6. 4 and analyzed by using Stata SE 13. 1 (Stata Corp. , College Station, TX, USA) for univariate analysis and multivariate logistic regression (odds ratios [ORs] and 95 % confidence intervals [95 % CI]). Chi-square test was used to compare NP carriage of pneumococci and Hi before and after PCV13 implementation. Factors related to NP carriage were identified on univariate analysis (p < 0. 20, chisquare test). Multivariate logistic regression analysis was performed to identify the main factors associated with carriage of Pnc, Pnc strains with reduced susceptibility to penicillin (RSP), Hi carriage, and ß-lactamase-producing Hi strains. For these models, factors had to be determined by the physician during the visits. When different factors were highly correlated, such as recent antibiotic use, history of AOM and otitis-prone children, we retained the most relevant factor.
Acknowledgments We thank all pediatricians who participated in the study:  C Abt-Nord ,  M-J Aim-Mille ,  D Allain ,  M Amzallag ,  I Aubier ,  P Bakhache ,  J Baron ,  B Baszanger ,  G Beley ,  M Benani ,  C Bensoussan-Ambacher ,  E Billard ,  L Billet ,  J-P Blanc ,  M-J Bodin ,  E Boez ,  B Bohe ,  J Bouglé ,  F Bouillot ,  J-L Cabos ,  P Camier ,  F Ceccato ,  D Clavel ,  C Claverie ,  R Cohen ,  L Coicadan ,  F Corrard ,  L Cret ,  B de Brito ,  F De Grenier ,  P Deberdt ,  I Defives ,  A Delatour ,  V Derkx ,  V Desvignes ,  M Dogneton ,  I Donikian-Pujol ,  M Dubosc ,  C Dumont ,  A Elbez ,  J Elbhar ,  N Elkhoury ,  C Ferte-Devin ,  J-M Fiorini ,  D Garel ,  J-L Gasnier ,  A Gasser ,  B Gaudin ,  N Gelbert-Baudino ,  C Georgeot ,  M Gerardin ,  M Giorno ,  R Gorge ,  J-L Guillon ,  J-F Hassan ,  A Hayat ,  P Huguet ,  M Hunin ,  A Kalindjian ,  K Kassmann ,  Z Klink ,  M Koskas ,  C Lastman-Lahmi ,  M-C Lemarchand ,  J-C Lévêque ,  J Levy ,  D Livon ,  N Maamri ,  M-O Mercier-Oger ,  C Messica ,  A-S Michot ,  J Miclot ,  P Migault ,  I Nave ,  M Navel ,  J-F Nicolas ,  A Pappo ,  J Peguet ,  C Perrin ,  C Petit ,  O Pinard ,  A Piollet ,  J-F Pujol ,  M-T Pujol ,  Y Regnard ,  M Robert ,  C Turberg-Romain ,  O Romain ,  M-C Rondeau ,  C Schlemmer ,  G Sivelle ,  D Somerville ,  N Temam-Basse ,  J-M Thiron ,  F Thollot ,  J Vaugeois ,  F Vie Le Sage ,  J-L Vuillemin ,  A Werner ,  R Wisnewsky ,  A Wollner ,  C Wollner ,  C Ythier.
In the Pipeline Driven by these successes, several other bispecific formats targeting CD3 have been generated and most of them have already been demonstrated activity in preclinical studies. Two others Triomabs are currently in clinical investigations (Figure  1 ): ertumaxomab (Rexomum ) is in a phase 2 for the treatment of metastatic breast cancer (NCT01569412) and Lymphomum (FBTA05) is in a phase 1 for BCL therapy (NCT01138579). Three other BiTEs are also in phase 1 clinical investigations: (i) an anti-CEA ˆCD3 (AMG 211, MT111, MEDI-565) for gastrointestinal adenocarcinoma treatment (NCT01284231), developed in collaboration with Medimmune; (ii) an anti-PSMA ˆCD3 (MT112 BAY 2010112, NCT01723475), for prostate cancer developed by Bayer; and (iii) Solitomab, an anti-EpCAM ˆCD3 (AMG 110, MT110) for colorectal, lung and gastrointestinal cancer (NCT00635596)  [100].
In addition, two anti-CD19 ˆCD3 are currently developed for the treatment of hematologic malignancies. The more advanced is AFM11, a TandAb by Affimed GmbH which is in phase 1 (NCT02106091). Interestingly, a side by side comparison between AFM11 and a BiTE-blinatumomab construct was made by Reusch et al. [101]. AFM11 possesses the same target specificities as blinatumomab but it is bivalent for both CD19 and CD3. AFM11 which has a 100-fold higher affinity for CD3, exhibited a more potent anti-tumor activity in vitro, in vivo and ex vivo, using realistic settings in term of effector to target ratio. The second one is an anti-CD19 ˆCD3 DART developed by MacroGenics. Preclinical data revealed an enhanced redirected T-cell killing against CD19 + cells by this bsAb compared to anti-CD19 ˆCD3 BiTE and a potent antitumor activity in mice and chimpanzees  [95, 102, 103].
Deriving from this DART, a CD19 ˆCD3 DART-Fc (MGD011) is currently developed by MacroGenics in collaboration with Jansen Biotech Inc. (Horsham, PA, USA) in which a Fc moiety has been added for extending its pharmacokinetic properties  [104]. To our knowledge, there is no bibliographic data available on this format, yet. An anti-CD19 ˆTCR DART targeting an invariable region of TCRαβ has also shown high killing properties against CD19 + cells in vitro and potent antitumor activity in mice  [105] , demonstrating an alternative to target T-cells. Two other DART molecules targeting T-cells and different TAA are currently evaluated by MacroGenics in collaboration with Servier (Suresnes, France), MGD006 (also encoded as S80880 by Servier), an anti-CD123 ˆCD3 in phase 1 (NCT02152956) for the treatment of acute myeloid leukemia (AML) and myelodysplatic syndrome and MGD007, an anti-gpA33 ˆCD3, in phase 1 for primary and metastatic human colorectal cancers (NCT02248805) (Figure  1 ).
Besides AFM11 described above, two TandAbs are in the pipeline of Affimed: an anti-EGFRvIIIxCD3/CD16A (AFM21) for solid tumor and an anti-CD33 ˆCD3 for acute myeloid leukemia  [106]. RO6958688, also called CEA-TCB for CEA T-cell bispecific format, is a 2:1 CrossMab format bivalent for CEA and monovalent for CD3. Moreover, mutations have been introduced in the Fc fragment to suppress its effector function  [71]. It is currently being investigated in a dose-escalation phase 1 clinical study by Roche for the treatment of CEA positive solid tumors (clinical trial NCT02324257). Of note, bsAbs of the most basic format, i. e. , chemical cross-linking of full size monoclonal antibodies, yielded some interesting results in clinical studies. These types of constructs are being used to "arm" patient's T cells that have been massively expanded and IL-2 activated prior to re-injection.
Several lines of evidence support ADCC as a pivotal mechanism underlying the anti-tumor efficacy of several therapeutic mAbs such as rituximab, trastuzumab or even checkpoint inhibitor ipilimumab which exerts its efficacy through both immune check point inhibition and ADCC  [132, 138]. As a result, tremendous efforts have been made to enhance the effector function of therapeutic mAb using different approaches such as fucose removal and Fc mutations  [45, 46]. Another attractive approach is the design of bispecific antibodies that aim at recruiting and activating NK cells to tumor site via the potent CD16A receptor (Figure  2 ). 4. 1. 1. From Bench to Clinic: Only One Bispecific Antibody Up to now, only one bispecific antibody, with ADCC as unique mode of action, is currently in clinical trial (NCT02321592) (Figure  1 ).
Indeed, AFM13, an anti-CD30 ˆCD16A TandAb developed by Affimed, represents the first-in-class tetravalent bsAb for the treatment of Hodgkin's disease  [139]. Preclinical studies showed a very efficient anti-tumor activity of AFM13 with no off-target NK cell activation despite the bivalent binding to CD16A. A phase1 dose-escalation study (NCT01221571) involving 28 patients has demonstrated that AFM13 has an acceptable safety profile  [139]  and a phase 2 clinical investigation (NCT02321592) is ongoing to evaluate the efficiency of AFM13 for the treatment of patients with relapsed or refractory Hodgkin lymphoma. On the same model, an anti-EGFRvIII ânti-CD16A TandAb, recruiting NK cells is currently in the pipeline of Affimed.
Acknowledgements We thank  Josep Calderón ,  Roger Prades , E mmanuel Sevin , and  Nuno Va  sconcelos for their help with the ICP-MS measurements,t he bovine BBB model, the human BBB model, and mice perfusion, respectively. W ea lso acknowledge the  NMR facility at CCiT UB. This study was funded by  MINECO-FEDER  ( Bio2013-40716-R ),  MICINN  ( SAF2013-46196 ), RecerCaixa-2014-Gate2Brain, and the  Generalitat de Catalunya  (X. R. B. ;  2009SGR-1005 ,  2014SGR-535 ,  PROVAT-2011-013 ). B. O. -S. a nd M. S. -N. h old " La Caixa"/IRB Barcelona  and  Juan de la Cierva  fellowships,r espectively.
ACKNOWLEDGMENTS We thank  J. Ewbank  for helpful discussions and reading the manuscript and  Moritz Schüssler  for help and discussions during an Erasmus Programme short stay. The  Institut National de la Santé et de la Recherche Médicale  and the  Centre National de la Recherche Scientifique  provided institutional support and the  Association pour la Recherche sur le Cancer  project support. Y. S. was supported by a grant from the  Government of China.
The purpose of this study was to describe the routine use of maraviroc in treatment-experienced HIV-infected individuals with treatment failure, and to assess its effectiveness in terms of durability, virological and immunological responses, and clinical outcome according to viral tropism. Funding: FHDH is supported by Agence Nationale de Recherches sur le Sida (ANRS), Institut National de la Santé et de la Recherche Médicale (INSERM) and the French Ministry of Health. This study was funded by ViiV Healthcare. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing Interests: The study was sponsored by Viiv Healthcare. The author LF is affiliated with ViiV as the funding organization and have had a role in the study design, preparation of the manuscript and decision to publish.
The author CA is affiliated with GSK and have had a role in the study design, preparation of the manuscript and decision to publish. Furthermore, CA and LF have an affiliation to the commercial funders of this research study "ViiV". This does not alter the authors' adherence to PLOS ONE policies on sharing data and materials. The French Hospital Database on HIV (FHDH) is a hospital-based multicentre open cohort in which inclusions have been ongoing since 1989  [14]. It includes data from 70 general or university hospitals distributed throughout France. Individuals are eligible if they have documented HIV-1 or HIV-2 infection and give their written informed consent to participate. Data are collected prospectively by trained research assistants using standardized forms and include demographic characteristics, biological markers such as the CD4 cell count and plasma HIV RNA level, the date and type of AIDS and non AIDS-defining events, antiretroviral treatments, and the date and causes of death.
Literature search To identify published studies on the association between toxoplasmosis and epilepsy, we conducted a systematic search of the literature published in English or French. The search was conducted on MEDLINE, INGENTACONNECT, REFDOC, SCIENCEDIRECT, GOOGLE, Médecine/Sciences, PLOS ONE and the database of the Institut d'Epidémiologie neurologique et Neurologie Tropicale (IENT): http://www. unilim. fr/IENT/recherche_bvna. phpbase. This database contains medical dissertations, theses, and articles on tropical neurology and parasitology. The keywords for epidemiological aspects were: "epilepsy, Toxoplasma, toxoplasmosis". Similar keywords were used in French. While searching, OR and/or AND were used for combination terms. We also searched the bibliographies of the articles retained after our database search.
Selection of studies Articles were selected based on their titles and then their abstracts. Those retained were read in full, but only those articles that met the inclusion-exclusion criteria were finally included. Inclusion criteria were: epilepsy as a disease and toxoplasmosis as an exposure, presence of a control group, sample sizes suitably estimated, details of techniques used to diagnose epilepsy and toxoplasmosis, and details on selection of participants, including socio-economic level. Data were then entered in a database covering: title, principal author, year of publication, type of study, objectives, methods, results, and any additional comments.