dataesr/scientific-paragraphs-categorization huggingface dataset:
Statistical methods Descriptive analyses were obtained for age, index year, and health insurance coverage using paired t-tests, Wilcoxon-tests for paired samples or McNemar's tests. A logistic regression model was used to estimate the association between vulvar cancer and pre-defined diagnoses (diseases of Bartholin's gland, inflammation of vagina and vulva, or other specified noninflammatory disorders of vulva including atrophy, hypertrophy, and cyst). The following diagnoses known to be associated with a higher risk of vulvar cancer were included as covariables: vulva dysplasia (N90. 0-90. 3), leukoplakia of vulva (N90. 4) and benign neoplasm of vagina (D28. 1). P-values < 0. 05 were considered statistically significant. The analyses were carried out using SAS version 9. 3.
An interesting finding of this retrospective analysis is that such delay varied with the initial diagnosis given by gynecologists, with A delay in vulvar cancer diagnosis may also be caused by other reasons, such as physical disability of some patients, fear of special exams, or reluctance to get gynecological exams. Patients may also fail to recognize cancer symptoms or act on them. Furthermore, diagnostic delay may also occur if several invasive procedures are needed to confirm the diagnosis  [20]. Retrospective primary care database analyses are generally limited by the validity and completeness of the data on which they are based. The present study was subject to several limitations, such as the assessment of vulvar cancer and co-morbidities, which relied solely on ICD codes entered by gynecologists.
Furthermore, data pertaining to socioeconomic status (e. g. , education and income) and lifestyle-related risk factors (e. g. , physical activity) were also lacking. Furthermore, no documentation is provided on how the cancer diagnoses were made; however, in Germany, cancer diagnoses are usually confirmed by hospitals. Finally, the database is representative of resident physicians and does not include data from hospitals. The study also had several strengths. More than 1,000 women from several gynecological practices were included. Another strength was the use of real-time treatment data in gynecological practices where diagnoses were continuously documented, allowing for unbiased exposure assessment (no recall bias). Overall, potential mean delay of vulvar cancer diagnosis ranged from 186 to 328 days.
RNA 142 preparation was performed using Qiagen Rneasy protect animal blood kits ® and cDNA were 143 then obtained from those samples. We sponsored Beckman GATC Biotec (Konstanz, 144 Germany) to perform transcriptomic analysis and gene expression profiling by RNAseq with 145 Genome Sequencer Illumina HiSeq2500 ®. The raw RNA-Seq reads were analyzed using tools 146 that were previously reported  [23]. The reads were aligned to the reference genome or 147 reference transcriptome, assembled and annotates. And finally, merged transcripts from two 148 or more samples / conditions are compared to determine the differential expression levels 149 including a measure of significance between samples/conditions. All combinations were 150 compared together. Data are available on NCBI under the accession number PRJNA412849.
Data from paediatric patients with IMD 157 To explore the reliability of the impact of monocyte-macrophage in the evolution of IMD, we 158 reviewed retrospectively the files of pediatric patients who were admitted to the Robert-Debré 159 University Hospital in Paris for IMD between 1999 and 2016. Data regarding age, sex, 160 serogroup of meningococcal strain, biological parameters on hospital admission (CRP, PCT, 161 FG, Leucocytes, PMN, lymphocytes, monocytes, platelets, hemoglobin) and evolution data 162 (death or sequelae) were collected as a part of routine management of cases. 163 164.
Differentially expressed genes in mice during experimental meningococcal infection 239 Differentially expressed transcripts (DETs) in the blood were determined for all 240 combinations (blood from mice that were: non-infected, non-infected but treated with AMX, 241 or treated with AMX and DXM, infected non-treated, infected but treated with AMX or 242 treated with AMX and DXM). After 6 hours of infection with 24198LUX strain in transgenic 243 mice expressing the human transferrin, a large number DETs was observed. Among those 244 DETs, 231 were significantly up-regulated and 61 were significantly down-regulated 245 (p<0. 002) in infected mice compared to non-infected mice. Using PANTHER and DAVID 246 databases (See the Methods section), we were able to cluster the DETs into several ontology 247 pathways related to the immune process (innate immunity response, neutrophil chemotaxis, 248 monocyte chemotaxis, monocyte and neutrophil chemotaxis and cytokine response 249 (Supplementary Tables  1  and 2 ).
We next focused on the comparison of infected mice that 250 were treated with AMX alone or with AMX and DXM as these conditions are relevant to the 251 medical management of IMD (but all combinations of comparison of DETs are available on 252 NCBI under the accession number PRJNA412849). Transcriptomic analysis in the blood of 253 mice treated with both AMX and DXM showed that 14 DETs showed significant changes 254 (Table  1 ). Four of those genes were up-regulated and 10 were down-regulated. Two were 255 involved in the immune system process: the up-regulated Schlafen 8 protein that is implicated 256 in regulation of LPS-and IFN-γ activated macrophages and in the differentiation of 257 monocytes and macrophages  [32, 33]  as well as the down-regulated Bpifa6 (of the family 258 PLUNC that is expressed in the respiratory pathway and that shows similarity to LPS-binding 259 protein which is involved in the response of monocytes to LPS  [34] [35] [36] ).
However, only Daple-V1 is increased in invasive tumor margins and in CTCs disseminated during CRCs progression. We next chose to study the role of Daple in melanoma, which, like colorectal cancers, is another cancer that is characterized by dysregulation of heterotrimeric G-protein as well as Wnt signaling; prior studies have implicated both pathways in the metastatic progression of melanomas  24, 25. When we analyzed the RNA sequencing dataset from The Cancer Genome Atlas (TCGA) for dysregulation of Daple/CCDC88C expression (CNVs, deletions or mutations) and the frequently mutated heterotrimeric G-protein GNAQ  26  , we found that mutations have been identified in patients with cutaneous, but not uveal melanomas for Daple/CCDC88C. For GNAQ, on the other hand, although mutations have been identified in both cutaneous and uveal melanomas, these are predominantly found in uveal melanomas (Fig  1A-B  We recently showed that the expression of Daple full-length (henceforth, Daple-V1) was elevated in EpCAM-immuno-isolated CTCs of colorectal cancer patients, and that Daple promotes epithelial-to-mesenchymal transition (EMT) during progression  18, 22.
Statistical analyses Statistical evaluation was performed using the GraphPad prism v5 software. Statistical significance of differences in marker expression among the patients with early vs. late stages of melanoma and normal healthy controls was analyzed using unpaired t-test. Optimal cut-off values for gene expression levels were derived by maximally selected log-rank statistics performed using R Software v2. 15. 0  37. The relationship between high vs. low levels of gene expression and incidence of metastatic progression was investigated by Fisher's exact test. To assess the relationship between gene expression and patient's age, clinical stage of disease, Clark level, Breslow thickness and ulceration, we used parametric Pearson's correlation and nonparametric Spearman's correlation analyses.
ACKNOWLEDGMENTS This work was funded by  NIH  ( R01CA160911  and  R01CA100768 ) and a  Translation and Clinical Research Award  from the  Moores Cancer Center  to PG. J. E was supported by a  NCI/NIH-funded Cancer Biology, Informatics & Omics  ( CBIO) Training Program  ( T32 CA067754 ) and a  Postdoctoral Fellowship  from the  American Cancer Society  ( PF-18-101-01-CSM ). Other funding support to MZ includes: NHMRC application number  1013349 ;  Cancer and Palliative Care Research and Evaluation Unit WAPCN Small Grants   2010/11 ; and  Cancer Council of WA Research Grants  (to M. Z).
Subsequent incubation of the sections with secondary antibodies conjugated with Alexa Fluor 488 or 594 (1:400; Invitrogen) was performed at room temperature (RT) for 1 h. The slides were mounted using ProLong Gold Slowfade media with DAPI (Invitrogen). Immunofluorescence signals were examined under an IX73 microscope interfaced with an XM10 CCD camera and cellSens Digital Imaging Software (Olympus). For immunohistochemical analysis, sections following antigen retrieval were treated with 3% H 2 O 2 to quench endogenous peroxidase activity. Then, the sections were blocked with 5% non-immune serum and sequentially incubated with primary antibodies including rat anti-KRT8 (1:200; TROMA-I; Developmental Studies Hybridoma Bank), rabbit anti-estrogen receptor α (ERα; sc-542; 1:1000; Santa Cruz), rabbit anti-PGR (1:50; MA5-14505; Thermo Scientific), rabbit anti-calponin (CNN1; 1:500; #04589; EMD Millipore), rabbit anti-vimentin (VIM; 1:200; #5741; Cell Signaling Technology) and rabbit anti-collagen I (COL-1; 1:200; ab34710; Abcam), secondary antibody and Avidin/Biotin Complex (ABC; Vector Laboratories).
These observations strongly suggested that the immunodeficiency in the two patients mostly resulted from a T-cell immunodeficiency. We performed whole-exome sequencing (WES) that identified 20 homozygous variations in patient P1. 1. Only one of them appeared to be deleterious and was not found in public databases ExAc, 1000 genomes and in the database of our institute containing 10,432 exomes. The mutation corresponds to a two nucleotides insertion in the exon 16 of the RASGRP1 gene (c. 1910_1911insAG) leading to a frameshift that resulted in a premature stop codon p. Ala638GlyfsX16 (or A638GfsX16)  (Fig 1C). The mutation was then verified by Sanger sequencing in the family (Fig  1D ). Both patients were homozygous for the mutation, while parents were heterozygous and healthy siblings were heterozygous or wild-type carriers, confirming the autosomal recessive inheritance mode of the mutation  (Fig 1D).
Exome sequencing and analysis Exome capture and analysis were performed as previously described  (Martin et al, 2014; Izawa et al, 2017). The RASGRP1 variation identified in the patient (15:38786930 C/CCT), an homozygous frameshift insertion c. 1910_1911insAG p. Ala638GlyfsStop16 was not reported in the exome and genome aggregation consortium (ExAC and gnomAD) databases (http://exac. broadinstitute. org and http://gnomad. broadinstitute. org) nor in available exome public databases (dbSNP, the 1000 Genomes, the NHLBI Exome Sequencing Project) including our institute database containing 10,432 exomes.
Acknowledgements We acknowledge the patient, his family, and the healthy donors for cooperation and blood gifts. S. L. is a senior scientist at the  Centre National de la Recherche Scientifique-CNRS (France). We thank the  Tumor bank of Tenon Hospital (Paris, France ) and  Amélie Trinquand  et  Julie Bruneau  from the  Department of Pathology at Necker-Enfants Malades Hospital (Paris, France)  for providing with tissues of P1. 2 and for extraction of DNA. Sylvie Fabrega  from the  Plateform of Viral Vector and Gene Transfert at Necker-Enfants Malades Hospital (Paris, France)  for lentiviral productions. S. W. is supported by  Institut IMAGINE , and D. B. is supported by the  Agence Nationale de la Recherche  ( ANR-14-CE14-0028-01 (SL) ). This work was supported by grants from  Ligue Contre le Cancer-Equipe Labellisée (France)  (SL),  INSERM (France) , the  Agence Nationale de la Recherche ,  France  ( ANR-14-CE14-0028-01  ( SL ) and  ANR-10-IAHU-01  ( Imagine Institut )), and the  European Research Council (AF)  ( ERC-2009-AdG_20090506 n°FP7-249816 ).
5, 6 ertolizumab pegol (CZP) is the only Fc-free, PEGylated, antietumor necrosis factor (TNF) biologic. Because the drug lacks an IgG Fc region, CZP does not bind the neonatal Fc receptor (FcRn) for IgG and is consequently not expected to undergo FcRn-mediated transfer across the placenta,  7  showing minimal placental transfer of CZP from mothers to infants. 8 PEGylation increases the half-life of CZP to 14 days. 9 CZP is approved for the treatment of adults with rheumatoid arthritis, psoriatic arthritis, Crohn disease (United States), ankylosing spondylitis, and nonradiographic axial spondyloarthritis (European Union). CZP is currently under investigation for the treatment of moderate-tosevere plaque psoriasis, with promising results in 2 phase 2 studies. 10 In this phase 3 trial (CIMPACT; NCT02346240), the efficacy of CZP compared with placebo and etanercept and the safety of CZP were assessed in adults with moderate-to-severe chronic plaque psoriasis.
DISCUSSION The efficacy and safety of CZP, an Fc-free, PEGylated anti-TNF biologic, in adult patients with moderate-to-severe chronic plaque psoriasis have been previously studied in phase 2 trials. 10 In this phase 3 trial of adult patients with moderate-tosevere chronic plaque psoriasis, treatment with CZP 400 mg or 200 mg resulted in statistically significant and clinically meaningful improvements in signs and symptoms of psoriasis at weeks 12 and 16 in comparison with treatment with placebo, with clinically meaningful differences in PASI 75 responses observed as early as week 4. At week 12, CZP 400 mg was superior and CZP 200 mg was noninferior to etanercept for PASI 75 responder rate. During the maintenance period, efficacy and safety data were collected to assess the durability of treatment effects beyond the initial period; rerandomization also allowed for assessment of alternative dosing regimens.
Overall, treatment with either dose of CZP was associated with significant, clinically meaningful and sustained improvements in signs and symptoms of moderate-to-severe chronic plaque psoriasis. Generally, greater improvements in efficacy outcome measures were recorded with the higher dose. No new safety signals occurred at either dose over 48 weeks of treatment. These results support x Reported as fungal infection, preferred term in the database. k Pneumonia. that CZP, a unique anti-TNF biologic, affords a novel treatment option for psoriasis patients. Medical writing support was provided by Krystina Neuman, PhD, and Ashley A. Skorusa, PhD, of Prescott Medical Communications Group (Chicago, IL). All costs associated with the development of this manuscript were funded by Dermira Inc and UCB Inc.
In Silico Analysis of BSHs Bile salt hydrolases amino acid sequences from different bacterial species were retrieved from databases using BLASTP program from the National Center for Biotechnology Information (NCBI, http://www. ncbi. nlm. nih. gov/) and analyzed in silico. Multiple sequence alignments of BSH amino acid sequences were performed using CLUSTALO 1. 2. 1 (http://www. ebi. ac. uk/Tools/ msa/clustalo/) to identify the conserved motifs between the different enzymes. Phylogenetic relationships and phylogenic clustering of BSHs from different species were established by neighbor-joining methods using MEGA5 software (http://www. megasoftware. net/; Tamura et al. , 2011). Three-dimensional modeling of L. johnsonii La1-BSHs was performed using I-TASSER from University of Michigan (http://zhanglab.
amylovorus, and L. johnsonii, respectively. Finally, L. johnsonii-BSH56 showed 94 and 99% identity with BSHs from L. gasseri and both L. acidophilus and L. johnsonii, respectively. The 3D structures of CBAH-1 from C. perfringens  (Rossocha et al. , 2005)  and BlBSH from B. longum  (Kumar et al. , 2006)  have been determined (PDB: 2BJF and PDB: 2RF8, respectively), revealing the presence of key residues in the enzymatic active site (Cys-2, Arg-18, Asp-21, Asn-82, Asn-172, and Arg-225; numbering referring to CBAH-1). In addition, experimental studies validated the importance of Arg-18 in the catalytic site  (Fang et al. , 2009; Lin, 2014; Lin et al. , 2014). Therefore, multiple amino acid sequence alignments of BSH12, BSH47, and BSH56 with CBAH-1 and BlBSH were performed using ClustalO program (GONNET PAM 250 matrix), thereby indicating that these key residues were indeed highly conserved in all three L.
johnsonii La1-BSHs (Figure  1 ). Moreover, motifs surrounding these key amino acid positions were also found to be well conserved such as 16 FGRNXD, 72 NEXGLXXAGLNF, 170 VXXLTNXPXF, and 213 GXGXGXXGXPGD, a point that has been also reported in other studies  (Elkins et al. , 2001; Kim and Lee, 2008). However, residues, which are predicted to be involved in the substrate-binding site based on the 3D structure of C. perfringens, did not appear to be conserved in either L. johnsonii BSH enzyme  (Ridlon et al. , 2006). Predicted tridimensional structures of L. johnsonii BSH12, BSH47, and BSH56 were modeled with I-TASSER software, using existing 3D structures (Figure  S1 , BSH47 and BSH56 and Figure  S2, BSH12 ). Clostridium perfringens CBAH-1 was used as a template for BSH47 modeling (RMSD: 0. 64; TMscore: 0.
3%) acids. A white and iridescent precipitate around colonies is indicative of BSH hydrolytic activity. E. coli SE1 strain expressing rBSH47 efficiently hydrolyzed tauroconjugated bile salts, whereas no BSH activity was detected for glyco-conjugated bile salts (Figure  3A ). E. coli SE1 strain expressing rBSH56 efficiently hydrolyzed both tauro-and glycolconjugated bile salts (data not shown). A slight deconjugation FIGURE 1 | L. johnsonii La1 BSH possess conserved key amino acids in their predicted active sites. Multiple sequence alignments of BSH were performed with the ClustalO program (http://www. ebi. ac. uk/Tools/msa/clustalo/) using GONNET 250 matrix. An "*" (asterisk) indicates positions of fully conserved residues in all five sequences; a ":" (colon) indicates conservation of amino acid with strongly similar chemical properties (Gonnet PAM 250 matrix score > 0.
5); a ". " indicates conservation of amino acid with similar chemical properties (Gonnet PAM 250 matrix score ≤ 0. 5). Residues highlighted in light gray correspond to the predicted key active site amino acids, based on the 3D structures of BSHs from both C. perfringens (CBAH-1, PDB: 2BJF)  (Rossocha et al. , 2005)  and B. longum (BlBSH, PDB: 2RF8)  (Kumar et al. , 2006). Residues highlighted in dark gray indicate amino acids putatively involved in substrate binding based on CBAH-1 3D structure  (Rossocha et al. , 2005; Ridlon et al. , 2006). Boxes indicate conserved signatures, i. e. , 16 FGRNXD, 72 NEXGLXXAGLNF, 170 VXXLTNXPXF, and 213 GXGXGXXGXPGD (CBAH-1 numbering). was observed with E. coli strain producing rBSH12 against glycoconjugated bile salts. However, BSH12 was not further tested in this study.
Phylogenetic relationship among selected BSH sequences and related substrate predictions were represented on a neighborjoining tree, constructed using amino acid sequences of BSHs whose substrate specificities have been previously characterized, with 500 bootstrap replications using MEGA5 software (http:// www. megasoftware. net/). Such a phylogenetic analysis showed that L. johnsonii La1-BSH12 is more closely related to L. johnsonii 100-100-BSH-α (Figure  3B ), an enzyme which is able to hydrolyze both tauro-and glyco-conjugated bile salts. The L. johnsonii La1-BSH56 is phylogenetically related to a compact cluster including L. johnsonii PF01-BSHB (LjBSHB), L. acidophilus PF01-BSH (LaBSH), and L. johnsonii 100-100-BSH-β (LjBSH-β). Both BSH56 and LjBSH-β display broad substrate specificity, with a slight preference for tauro-conjugated over glyco-conjugated bile salts, whereas LaBSH and LjBSHB exclusively hydrolyze tauro-conjugated bile salts  (Chae et al.
, 2013). Finally, L. johnsonii La1-BSH47 was more closely related to L. johnsonii PF01-BSHC (LjBSHC) hydrolyzing only glycoconjugated bile acids, whereas BSH47 displays a preference for tauro-conjugated substrates. These observations suggest that substrate specificities are not systematically conserved among lactobacilli BSHs, despite a good conservation of their 3D-structures and of key amino acids in their active sites, which makes substrate specificity prediction based on phylogenetic analysis not straightforward for the moment. coli by Western Blotting using anti-His tag antibody. Production of BSH was done under the control of pStaby system in E. coli (induced with 1 mM IPTG). Cytoplasmic fractions were extracted from E. coli SE1 harboring pLB490 plasmid (E. coli BSH12), pLB491 plasmid (E.
johnsonii 100-100, respectively  (Elkins and Savage, 1998; Elkins et al. , 2001; Pridmore et al. , 2004). A  neighbor-joining tree of various BSHs protein sequences from several lactic acid bacteria confirmed that L. johnsonii La1-BSH enzymes are phylogenetically related to BSHs from other species. In addition, they share a high degree of similarity to various subgroups of BSHs; for instance, BSH12 shares 99% identity with L. johnsonii 100-100 cbsHα and L. johnsonii PF01 BSHA at amino acid level, and BSH56 shares 99% identity with L. johnsonii 100-100 cbsHβ and 98% with L. johnsonii PF01 BSHB at amino acid level. L. johnsonii La1 and L. johnsonii PF01 both possess a third BSH gene, bsh47 and bshC, respectively, which is absent from L. johnsonii 100-100. Besides, the close relationship among L.
johnsonii La1 BSH47, L. johnsonii PF01 BSHC, and L. acidophilus NCFM BSHB, at amino acid level, suggests that these enzymes likely share a common ancestor. These observations contribute to the idea that BSH might have been acquired through horizontal gene transfer from microorganisms sharing the same intestinal environment  (Corzo and Gilliland, 1999; Franz et al. , 2001; McAuliffe et al. , 2005; Begley et al. , 2006) , although this latter hypothesis remains to be tested. Multiple amino acid sequence alignment of L. johnsonii La1 BSHs indicated a high variability among characterized BSHs; however, well-conserved motifs were observed around residues involved in the active site. These observations are in agreement with previous studies  (Rossocha et al. , 2005; Fang et al. , 2009; Lin et al.
johnsonii La1 (Q74LX7_LACJO); CBAH-1, C. perfringens strain 13 (P54965. 3); BSHA, L. acidophilus LA4 (ACL98173. 1); BSHB, L. acidophilus LA4 (ACL98173. 1); BSHA, L. acidophilus LA11 (ACL98175. 1); BSHB, L. acidophilus LA11 (ACL98176. 1); BSHA, L. acidophilus NCFM (YP_193782. 1); BSHB, L. acidophilus NCFM (AAV42923. 1); BSH, L. gasseri AM1 (ACL98172. 1); BSH-α, L. johnsonii 100-100 (AAG22541. 1); BSH-β, L. johnsonii 100-100 (AAC34381. 1); BSHA, L. johnsonii pf01 (EGP12224. 1); BSHB, L. johnsonii pf01 (EGP13287. 1); BSHC, L. johnsonii pf01 (EGP12391. 1); pCBH1, L. plantarum 80 (AAB24746. 1); BSH1, L. plantarum WCSF (CCC80500. 1); BlBSH, B. longum subsp. longum (2HF0); BSH, L. acidophilus PF01 (ABQ01980. 1); BSH, L. plantarum CK 102 (Ha et al. , 2006) ; Penicillin V Acylase (PVA), Bacillus sphaericus (3PVA).
FigureS1| Protein structure prediction of L. johnsonii La1 BSHs. Protein structures were modeled for L. johnsonii BSH56 (a) and BSH47 (b) using I-TASSER software (http://zhanglab. ccmb. med. umich. edu/I-TASSER/). CBAH-1 (PDB: 2BJF) from C. perfringens (Rossocha et al. , 2005)  and BlBSH from B. longum (Kumar et al. , 2006)  (PDB: 2HF0) were used as templates for modeling BSH47 and BSH56, respectively. Best values of the C-score were chosen for model structure prediction. Visualization of predicted structures for BSH47 (red, a) and BSH56 (blue, b) and superimposition (c,d) were performed using Pymol software (https://www. pymol. org/).
FigureS2| Protein structure prediction of L. johnsonii La1 BSH12. Protein structure was modeled for L. johnsonii BSH12 using I-TASSER software (http:// zhanglab. ccmb. med. umich. edu/I-TASSER/). Bile salt hydrolase (PDB: 2RF8) from C. perfringens was used as a template for modeling. Best value of the C-score was chosen for model structure prediction. Visualization of predicted structure was performed using Pymol software (https://www. pymol. org/).