dataesr/scientific-paragraphs-categorization huggingface dataset:
Ethical approval Ethical approval for this survey was obtained from the National Committee for Ethics and Research for Development for one year, under the protocol number SEN12/57 and from the International Food Policy Research Institute Institutional Review Board (IFPRI IRB). An amendment of the protocol was submitted to both the National Committee of Senegal and the IFPRI IRB to include an additional measure of hemoglobin in April 2013. The protocol was registered in the clinical trial. gov website (NCT02079961).
Acknowledgments We thank all pastoralists, mothers and children involved in this study, all the implementing partners  Laiterie du Berger, GRET, CLM , as well as partners for data collection UniversiteGaston Berger-Saint Louis. We greatly appreciate  Elodie Becquey  and  Ampa Diatta  ( International Food Policy Research Institute, Dakar ) for their valuable help with data collection in the field and  Dr Ndeye Khady Toure  and  Aminata Ndoye  ( CLM ) for their technical support. We also thank  Guillaume Bastard  and  Mamadou Bobo Sow (GRET)  for implementing the program and  Bagore Bathilly  and  Isabelle Sultan  ( Laiterie du Berger ) for their collaboration.
In this study, we provide first data reporting the link between the development of a specific immune response and clinical benefit for a viral-based immunotherapeutic in advanced NSCLC. TG4010 is a therapeutic cancer vaccine based on a modified vaccinia Ankara strain (MVA) encoding for the full-length cancer antigen Mucin 1 (MUC1) and human IL-2. Administration of TG4010 in combination with chemotherapy (CT) has resulted in improved clinical outcomes in several clinical studies over the standard chemotherapy regimen  [3, 4]. We used combinatorial two color encoding of MHC multimers  [5]  for the parallel detection of T-cell epitopes from TG4010 and other antigens reported to be prevalent in lung cancer  [6]. Interactions between the vaccine and the development of T cell responses against other neo-antigens was also evaluated to evaluate the possible development of further anti-tumor response through epitope spreading.
Patients and study design The TIME trial (NCT00415818) is a double-blind, placebo-controlled, randomized phase 2b/3 clinical study aimed at assessing the combination of TG4010 with firstline chemotherapy in advanced NSCLC. Inclusion criteria included age > 18 years, histology-confirmed diagnosis of previously untreated stage IV NSCLC, expression of MUC1 in at least 50% of tumor cells, Eastern Cooperative Oncology Group performance status of 0 or 1, and adequate hepatic, renal, and hematologic function. Patients were randomly allocated to receive subcutaneous injections of either 108 plaque-forming units of TG4010 or placebo, from the beginning of chemotherapy every week for 6 weeks and then every 3 weeks up to progression (Additional file 1: Figure  S1 ). Chemotherapy regimen were chosen by the investigator: paclitaxel and carboplatin, pemetrexed and cisplatin or gemcitabine and cisplatin.
Flu and CMV epitopes were added as controls. Operators during sample processing and flow cytometry data analysis were blinded to treatment arm. Prior to clinical sample analysis, this method was validated (Additional file 2: Validation method) with blood samples from healthy donors to determine the limit of blank and the limit of detection for each MHC multimer. This was based on the assumption that healthy donors have very low frequencies of circulating specific T cells against the antigens tested in this study with the exception of positive controls (hCMV and Flu). Hence, for any of the TIME trial sample, a response was considered positive as being below the limit of detection (LOD) prior to treatment and above LOD post treatment. For those patients who displayed a response to a given epitope that was above the corresponding LOD prior treatment, positivity of the response to treatment was determined by specific T CD8+ frequency increase of at least two times the corresponding standard deviation.
Statistical analysis Log-rank Mantel-Cox tests were used to compare survival between different groups. Hazard Ratios (HR) and corresponding 95% Confidence Interval (95% CI) were estimated using a Cox regression model. For comparisons on the number of responses between the two groups of response to MUC1, non-parametric Mann-Whitney U tests were used given the limited number of data. Prism (GraphPad Software Inc. , v5) was used for graphical representation of data, and both Prism and SAS (SAS Institute Inc. , Cary, NC, USA) were used for statistical testing. P values <0. 05 were considered statistically significant. Differences on continuous clinical and demographic baseline parameters between subgroups of patients were tested using the non-parametric Wilcoxon-Mann-Whitney test and Fisher exact test was used for categorical parameters.
Conclusion Finally, this work demonstrates that the viral vaccine TG4010 modulates the CD8+ T cell response and that changes induced by the vaccine are associated with improvements of clinical outcome. Monitoring of specific CD8+ T cells functionality induced by TG4010 (both toward MUC1 and other TAA), should be included in future clinical trials concerning this immunotherapeutic to allow confirmation in an independent cohort, as a predictor of treatment outcome and thus, as a biomarker to support the treatment of patients with TG4010. From the results of this trial and those of pre-clinical observations (Remy-Ziller et al. , in revision), TG4010 is now pursuing its clinical development in combination with Nivolumab (NCT02823990) in second line treatment for advanced NSCLC patients and soon in combination with Nivolumab + standard chemotherapy in first line treatment for advanced NSCLC patients.
Study Population Between 2000 and 2015, patients aged ≥18 years diagnosed with ≥ mild AS (aortic valve calcification with restricted systolic motion and AVA <2 cm 2 ) and LVEF ≥50% were prospectively identified and included in an electronic database. The following patients were excluded: (1) patients with more than mild aortic and/or mitral regurgitation; (2) patients with prosthetic valves, congenital heart disease (with the exception of bicuspid aortic valves), supravalvular or subvalvular AS, or dynamic LV outflow tract obstruction; and (3) patients who refused to participate in the study. The present analysis focused on 1143 patients with severe AS defined by AVA ≤1 cm 2 and/or AVA normalized to body surface area (BSA) ≤0. 6 cm 2 /m 2 and MTPG ≥40 mm Hg. Patients were retrospectively divided into 3 groups according to their baseline MTPG: Group 1 included patients with MTPG between 40 and 49 mm Hg; group 2 included patients with MTPG between 50 and 59 mm Hg; and group 3 included patients with MTPG ≥60 mm Hg.
Statistical Analysis SPSS software (v 18. 0; IBM Corp, Armonk, NY) was used for statistical analysis. Continuous variables are expressed as mean value AE1 SD or median and interquartile range, and categorical variables are expressed as percentages and counts. The relationship between baseline continuous variables and the various groups was explored using 1-way ANOVA tests (for normally distributed variables) or Kruskal-Wallis tests (for non-normally distributed variables). Pearson's chi-square statistic or Fisher's exact test were used to examine the association between the various groups and baseline categorical variables. The significance between the referent group and the other groups was examined when a significant difference across categories was observed. Individual differences were compared with Mann-Whitney U tests (with Bonferroni correction for multiple comparisons) and Tukey tests for normally distributed data.
Strengths and Limitations Because follow-up data were obtained retrospectively, our study therefore presents inherent limitations of this type of analysis. The specific indications for surgery during follow-up were not recorded in our database. However, diagnosis and follow-up were performed by cardiologists with expertise in valvular heart disease, and surgical decisions were taken by the heart team with the approval of the patient's physician in accord with current practice guidelines. We analyzed the subgroup of patients with no or minimal symptoms, because we consider that, in elderly patients with AS, it is often very difficult to differentiate asymptomatic individuals from patients with minimal symptoms. The mean pulmonary pressure observed in the study groups was lower than previously reported,  28, 29  presumably because of exclusion of patients with LV dysfunction and with significant associated mitral regurgitation, which accounted for 27% to 53% in other studies.
We therefore developed and validated a new model to predict outcome of patients after HMAF  6  that includes six clinical variables: age; performance status; complex cytogenetics (>4 abnormalities); marrow blast percentage >20%; platelet count; and red cell transfusion dependency  6. This model separates patients into two risk categories: lower-risk, with a median OS of 11. 0 months (95% confidence interval (CI) 8. 8-13. 6); and higher-risk disease, with median OS of 4. 5 months (95% CI 3. 9-5. 3)  6. The model was subsequently validated in an independent cohort of 223 MDS patients derived from the Groupe Francophone des Myélodysplasies database  7. In the validation cohort, 82 patients were classified in the lower-risk category and they had a median OS of 13 months compared to 141 higher-risk category patients with a median OS of 5 months (p < 0.
001)  7. In this analysis, we validate the model in a cohort of MDS patients treated prospectively on the ONTIME trial, a phase III, randomized clinical trial that evaluated the efficacy of rigosertib vs. best supportive care (BSC) in patients with IPSS intermediate-2 and high-risk MDS assessed after HMAF  8. Primary clinical data were obtained from MDS patients who enrolled on the trial. The ONTIME trial is a randomized, controlled phase III trial that enrolled patients with refractory anemia with excess blasts (RAEB)-1, RAEB-2, RAEB-t, and chronic myelomonocytic leukemia who failed treatment with HMA. Patients were randomly assigned (2:1) to receive rigosertib 1800 mg per 24 h via 72-h continuous intravenous infusion administered every other week or BSC with or without low-dose cytarabine  8.
Acknowledgements We wish to thank all the patients as well as all clinical and virological investigators of the  HIV-2 Cohort Study  ( ANRS CO5 VIH-2 ). We thank  Dr. Didier Negre  for the pAd-SIV4 and GAE-SFFV-GFP-WPRE plasmids and  Dr. Greg Towers  for the Mafa-TRIMCyp and Mamu-TRIMCyp plasmids. pMIG-TRIMCyp plasmid ( Dr. David Sayah  and  Dr. Jeremy Luban ) and pLPCX-TRIM5arh plasmid ( Drs. Joseph Sodroski  and  Matt Stremlau ) were obtained through the  NIH AIDS Research and Reference Reagent Program, Division of AIDS, NIAID ,  NIH. This work was supported by the  Agence Nationale de Recherche sur le   SIDA 13  , the  Fondation pour la Recherche Médicale (FRM)  and the  Portuguese Foundation for Science and Technology (FCT)  with co-financing from the  European Social Fund  (fellowship # SFRH/BD/45053/2008 ).
Safety data sheets At the time of purchase, safety data sheets were obtained as far as available at the retail outlet or subsequently from the producer's or retailer's website. The sheets were meticulously searched for any information, warnings or listings referring to isothiazolinones or for warnings concerning allergy risks. The paint cans were inspected for information on isothiazolinone content and environmental labelling. The environmental labels found consisted of 'EU Ecolabel' ('European Flower'; EU)  (17) , 'Svanen' (The Nordic Swan label; Denmark and Sweden) (18), 'Der Blaue Engel' (The Blue Angel; Germany)  (19) , 'Svalanmärkt' (Asthma and Allergy Association; Sweden) (20), 'TÜV NORD: Für Allergiker geeignet, Freiwillife Materialprüfung' (optional material testing; Germany) and volatile organic compound (VOC) labelling (low VOC content, minimal VOC content).
Statistics The data were processed with SPSS TM (SPSS TM Statistics, Chicago, IL, USA; IBM PASW Statistics) for Windows TM , edition 22. 0, and R statistical software (www. r-project. org), version 3. 2. 0. The Mann-Whitney U-test was applied for (i) analysis of differences in MI, MCI and BIT concentrations found in the previously tested paints  (12)  and the newly found MI, MCI and BIT concentrations, (ii) analysis of differences between the MI, MCI, BIT, OIT and DCOIT concentrations in paints with environmental labels and paints with no environmental labelling and (iii) analysis of differences between the MI, MCI, BIT, OIT and DCOIT concentrations in wet room paints and white wall paints. The distribution of the measured values for MI and BIT were graphically represented by a strip chart with an overlay box plot.
Results Sixty paints were analyzed for their contents of five isothiazolinones. MI was identified in 91. 7% (n = 55) of the purchased paints, with concentrations ranging from 1. 1 to 142. 7 ppm. MCI was in 20. 0% (n = 12) of the paints, ranging from 0. 5 to 3. 5 ppm. BIT was in 88. 3% (n = 53) of the paints, ranging from 0. 4 to 331. 0 ppm. OIT was in 26. 7% (n = 16) of the paints, ranging from 0. 03 to 16. 01 ppm. DCOIT was identified in 50. 0% (n = 30) of the purchased paints, ranging from 0. 01 to 156. 2 ppm. Concomitant presence of MI, MCI and BIT is visualized in Fig. 1B. Supplemental Table  S1  shows a detailed description of the sixty paints with regards to product names, analysis results, environmental labelling and safety data sheet information. As in the previous study, samples were taken from a thin layer of surface liquid when obviously present (seven paints).
Lumican is a small leucine-rich proteoglycan (SLRP) being known as a key regulator of collagen fibrillogenesis. However, little attention has been given so far in studying its influence on tumorassociated matrix architecture. Here, we investigate the role of host lumican on tumor matrix organization as well as on disease progression considering an immunocompetent model of melanoma implanted in Lum -/-vs. wild type syngeneic mice. Conjointly, lumican impact on tumor response to matrix-targeted therapy was evaluated considering a previously validated peptide, namely TAX2, that targets matricellular thrombospondin-1. Analysis of available genomics and proteomics databases for melanoma first established a correlation between lumican expression and patient outcome. In the B16 melanoma allograft model, endogenous lumican inhibits tumor growth and modulates response to TAX2 peptide.
Results Low lumican expression correlates with poor outcome in human melanoma. Lumican was previously reported as being expressed within tumor stroma of malignant melanoma, while inversely correlating with malignancy according to Clark levels that reflect disease vertical progression  9. Consistently, the pattern of lumican immunohistochemistry (IHC) staining among the Human Protein Atlas cohort  25  shows differential protein expression ranging from total absence of lumican within dense tumor tissue to a moderate staining of both cancer and stromal cells (Fig. 1a  and b ). Analysis of lumican-encoding gene (LUM) expression among 44 cases of metastatic melanoma  26  confirmed such heterogeneity (Fig. 1c ). Among this cohort, LUM gene expression correlates with survival in patients with melanoma, with a 4-fold increase in median overall survival being observed in the high lumican-expressing group, as determined using the optimal cut-off (calculated using the R2 web tool) of LUM mRNA expression (Bhardwaj dataset, GEO accession number GSE19234, Fig.
1d ). Study was then extended to include data from The Cancer Genome Atlas (TCGA), among which separation was performed between risk groups characterized by differences in LUM gene expression. We found that LUM expression levels significantly correlate with a lower risk of poor prognosis for skin cutaneous melanoma patients (Fig. 1e ), and therefore confirmed that overall survival is longer in cases exhibiting higher LUM expression (Fig. 1f ). Interestingly, alterations in LUM gene sequence are found in about 5% of clinical samples in TCGA dataset as well as across 3 independent studies (Fig. 1g ), with highest mutation rates being observed in desmoplastic melanoma i. e. a deeply infiltrating subtype of melanoma with abundant stroma  27. A decrease in both overall and disease-free survival of TCGA patients is observed when mutations in LUM gene sequence are reported (Fig.
5d ). Analyses of relative pixel distribution further characterized the above-mentioned TAX2-related striking effect, which can only be observed in Lum -/-mice that display increased tumor tissue heterogeneity (Fig. 5e  and f ). Altogether, this FT-IR microspectroscopy approach coupled to unsupervised clustering allowed detection of slight structural from different cohorts. Data were obtained from the cBioPortal for cancer genomics. (h) Overall and (i) diseasefree survival curves of TCGA patients presenting skin cutaneous melanoma with (red) or without (blue) LUM mutations. (j) Histogram summarizes median overall survival values (months) in above-mentioned molecular subgroups across R2 (top) and TCGA (middle) datasets as well as median disease-free survival among TCGA patients (bottom). GEO, Gene Expression Omnibus; TCGA, The Cancer Genome Atlas.
Endogenous lumican deficiency decreases intratumoral collagen deposition. Lumican has long time been recognized as a regulator of collagenous matrix self-assembly  37, 38. Hence, we sought to determine whether the impact of lumican on tumor ECM topology may depend on collagen fibrillogenesis. Co-expression analyses were first performed among TCGA melanoma dataset, highlighting that human LUM mRNA levels correlate with expression of genes encoding for α chains of type I (Fig. 6a  and b ) and type III (Fig. 6c ) collagens, i. e. two of the most abundant matrix components within a tumor microenvironment  39. Then, a Fourier transform infrared (FT-IR) imaging spectroscopy methodology was used for detection and quantitative analyses of collagen deposition within B16F1 s. c. allografts. This alternative approach overcomes the variability experienced in conventional staining techniques  40  and allows high resolution and automated data collection without addition of any chemical or histology reagent to the tissue sample.
Discussion A comprehensive and large-scale mining of public microarray databases was first performed in this study, thus unambiguously demonstrating a correlation between altered lumican expression and poor outcome in human melanoma. Then, B16 melanoma allografts were transplanted in both WT and Lum KO mice in order to characterize the influence of host lumican on tumorigenesis. Taken together, the results obtained from this model indicate that (i) lumican acts as a potent endogenous inhibitor of tumor growth, while (ii) newly establishing lumican as a key driver of tumor matrix assembly. At the same time, a previously validated anticancer peptide targeting matricellular TSP-1  20, [22] [23] [24]  was considered so as to figure out lumican-related modulation of tumor response to ECM-targeted therapeutic strategies.
Interestingly, our data show that lumican expression within host tissues affects both soluble factors as well as immune and endothelial cells intratumoral distribution, hence sharply modifying tumor response to TAX2 peptide. Bioinformatics analyses of both mRNA and protein levels of lumican among melanoma clinical cases highlighted much heterogeneity (Fig. 1a to c ), which is consistent with discrepancies that previously arose when looking at in vitro lumican expression depending on the cell line used  9, 42. A thorough screening of multiple melanoma clinical datasets further highlighted that both alterations in LUM gene sequence as well as lower mRNA expression are associated with decreased patient survival (Fig. 1d to j ). This should be put in perspective with previous work underlying decreased lumican expression within the most infiltrative melanoma lesions  9.
(j) Quantification of the number of collagen pixels relative to total tumor pixels (%) implanted in Lum +/+ (WT) vs. Lum -/-mice (mean ± SEM, t test, *p < 0. 05), as performed using ImageJ software. (e-g) Quantification of tumor ECM collagen organization from spectra derived from Gabor filtering and FFT. (e) Flowchart depicting the different stages of image analysis. From grey scale-converted picrosiriusstained images, a 3 × 3 median filter is applied before Gabor filtering and then FFT. After determining the elliptical shape of the scatter pattern (see red ellipses on right panel), measurements of the elliptical axes (black lines) generated from ω angle values n 1 to n 4 were performed so as to produce a collagen orientation be a positive regulator of angiogenesis in collagen-rich environments  45.
Materials and Methods Bioinformatics and clinical data mining. The pattern of LUM staining in melanoma clinical samples was characterized using the Human Protein Atlas web portal (available from www. proteinatlas. org)  25. Semiquantitative analysis was performed among 12 melanoma cases for classification of immunohistochemical outcome, including evaluation of staining intensity (negative, weak, moderate) and fraction of stained cells (negative, <25, 25-75 or >75%). Lumican-encoding gene (i. e. LUM) was assessed for mRNA expression among 44 patients with metastatic melanoma. Publicly available Bhardwaj gene expression dataset  26  was obtained from R2 microarray analysis and visualization platform (http://r2. amc. nl). Cut-off value for separating high and low LUM expression groups in survival analysis was determined by the online algorithm.
Among skin cutaneous melanoma dataset from The Cancer Genome Atlas (TCGA; https://tcga-data. nci. nih. gov/tcga), risk estimation was performed using SurvExpress biomarker validation tool  66. Risk groups were generated based on prognostic index (PI) calculations (higher values for higher risk), with PI being known as the linear component of the Cox model  67. Two groups were split from the ordered PI according to SurvExpress optimization algorithm, with chosen split point corresponding to the lowest logrank p-value. LUM gene mutation rate was also assessed in 4 datasets providing comprehensive profiling of melanoma clinical samples  27, 68, 69. The cBio Cancer Genomics Portal  70, 71  was used to investigate the impact of LUM somatic mutations on patients' overall and disease-free survival as well as to establish gene expression correlations among TCGA data.
The number of functional blood vessels (i. e. vessels displaying endothelial layer integrity) and their mean diameter as well as relative CD3-and CD31-positive areas were determined in five random ×100 fields. Tumor necrotic part as well as VEGF-positive area and intratumoral blood vessels positive for TSP-1 immunostaining were quantified across the whole s. c. allograft sections. All quantitative analyses were performed using ImageJ software binarization and thresholding tools. µCT tumor angiography. In vivo µCT was performed on isoflurane-anaesthetized tumor-bearing mice at days 9 and 14 after melanoma cell inoculation. CT images were acquired on a dedicated small animal µCT scanner (Skyscan 1076, Bruker, Kontich, Belgium) while continuously rotating the camera by 180° with the following parameters: 50 kV, 0.
5 mm Al filter, 200 µA source current, 35 µm isotropic resolution, 180 ms exposure time, 4 projection images per 0. 7° rotation step and a retrospective synchronization. Projections were reconstructed using Skyscan software (NRecon, Skyscan) filtered backprojection algorithm. Tumor angiography was performed after retro-orbital injection (5 ml/kg BW) of the alkaline-earth metal-based nanoparticulate CT imaging agent ExiTron TM nano 12000 (Viscover TM , nanoPET Pharma GmbH). Mice were imaged during the first 30 min post imaging agent application, a time period during which no reduction in contrast was observed  73. Analysis of reconstructed images was performed using Amira 5. 4. 3 software (Visualization Sciences Group, Burlington, MA).