dataesr/scientific-paragraphs-categorization huggingface dataset:
Procedures and Additional PNfS Implantation Eligible patients were randomly assigned to one of two parallel groups in a 1:1 ratio. Randomization was conducted through a clinical data collection website (https://www. dirc-hugo-online. org/csonline, accessed on 31 August 2021) designed for the purpose of this trial, accessible to the investigators through a personal identifier and password. Neither the study medical staff, nor the patients were blinded to the randomization. In addition to SCS device implantation, patients in the intervention group ("SCS+PNfS") were implanted with PNfS at baseline, whereas patients in the control group ("SCS only") were implanted with SCS alone for 4 months and then implanted with a PNfS device at the 4-month visit (Figure  1 ). PNfS implantation consisted in implanting patients with one Octad ® lead or two Quad ® subcutaneous peripheral stimulation leads (Medtronic, Inc.
Study Outcomes The primary objective of the study was to compare the percentage of decrease of back pain surface between baseline and 3 months between the "SCS only" group and "SCS+PNfS" group. For the purpose of the study, PRISMap software, specifically dedicated to assess pain surface changes objectively, was used to obtain quantitative and comparative metrics  [21]. This software has been designed and encapsulated into a tactile computerized interface, to assess patient painful area(s) in terms of intensity (mild, moderate, intense, very intense), real surface (available in cm²) and pain typology characterization (nociceptive/neuropathic pain), with objective, quantitative and reproducible measurements. From a clinical and research perspective, this allows robust comparisons between patients, neurostimulation devices, programs and waveforms, within time, by including a multidimensional composite pain assessment.
In this study, pain mapping was collected from a touch screen, where the patient could draw different painful zones, which were then represented as maps and diagrams. The pixels in the patient drawing were then converted into cm², using several anatomical landmarks, patient morphology and morphometry, to measure the pain surface optimally and accurately, using patented data processing system (Patent Applications n PCT/EP2014/067231  [22] , n PCT/FR 14/000 186  [23]  and n PCT/FR 14/000 187  [24] ). Secondary outcomes, collected at baseline and each visit, included back pain relief assessed with VAS; back pain paresthesia coverage corresponding to the percentage of.
Study Outcomes The primary objective of the study was to compare the percentage of decrease of back pain surface between baseline and 3 months between the "SCS only" group and "SCS + PNfS" group. For the purpose of the study, PRISMap software, specifically dedicated to assess pain surface changes objectively, was used to obtain quantitative and comparative metrics  [21]. This software has been designed and encapsulated into a tactile computerized interface, to assess patient painful area(s) in terms of intensity (mild, moderate, intense, very intense), real surface (available in cm 2 ) and pain typology characterization (nociceptive/neuropathic pain), with objective, quantitative and reproducible measurements. From a clinical and research perspective, this allows robust comparisons between patients, neurostimulation devices, programs and waveforms, within time, by including a multidimensional composite pain assessment.
In this study, pain mapping was collected from a touch screen, where the patient could draw different painful zones, which were then represented as maps and diagrams. The pixels in the patient drawing were then converted into cm 2 , using several anatomical landmarks, patient morphology and morphometry, to measure the pain surface optimally and accurately, using patented data processing system (Patent Applications n PCT/EP2014/067231  [22] , n PCT/FR 14/000 186  [23]  and n PCT/FR 14/000 187  [24] ). Secondary outcomes, collected at baseline and each visit, included back pain relief assessed with VAS; back pain paresthesia coverage corresponding to the percentage of pain surface covered (or not) by stimulation-generated paresthesia (using N-3D-L TM software/Please see previous publications mentioned above for further details); functional capacity measured with the Oswestry Disability Index (ODI) score  [25] ; health-related quality of life assessed with the EuroQuol-5Dimensions 3-level (EQ-5D-3L) index  [26] ; psychological state measured by the Hospital Anxiety and Depression Scales (HADS)  [27] ; medication intake measured by the third version of the Medication Quantification Scale (MQS-III)  [28].
| Study design The PROTECT VIII extension study was a multicentre, openlabel, uncontrolled, optional study for patients who completed the 36-week PROTECT VIII trial 11 (ClinicalTrials. gov identifier: NCT01580293), where they continued to receive BAY 94-9027 for ≥100 EDs (Figure  S1 ). The extension study was conducted at 53 study centres in 18 countries (Table  S1 ). Patients who decided to be treated on demand during the main study period had the option to either continue on-demand treatment in the extension The study was approved by the institutional review board at each site and was carried out in compliance with the protocol, the principles of the Declaration of Helsinki and Good Clinical Practice guidelines. All patients or their guardians gave written informed consent before initiation of any study-related procedures, before enrolment in the main study and at the end of the main study for continuation into the extension study.
| Statistical analyses Statistical analysis was performed using SAS ® software 9. 2 (SAS Institute Inc. ). Summary statistics were calculated for continuous data, and frequencies were calculated for categorical data. The intent-to-treat (ITT) population (all patients who received ≥1 infusion of BAY 94-9027 for whom infusion and bleeding data were available) was used in the primary efficacy analysis. All patients who received ≥1 dose of study drug were included in the safety analysis. No formal statistics were performed to determine the sample size. The analysis was descriptive and based on extension data. Exposure data including total time and total EDs were based on total time in study (main and extension periods). Treatment groups were based on the treatment at the start of extension except for the VAR group, which included all patients who switched regimen at least once.
Statistical analysis Statistical analyses were conducted using Statistical Package for the Social Sciences (SPSS for Windows, version 21, SPSS Inc. , Chicago, IL, USA). The normal distribution was verified according to the Shapiro Wilk test. One-way ANOVA statistical analysis and Tukey's post-hoc test was used for means comparison, the significant difference was considered at P<0. 05 and correlation test was determined by Pearson's coefficient.
1B )  45. Each sample contained equal amounts of proteins originating from isogenic arginine and lysine E. coli auxotroph strains grown in the presence of the stable isotopelabeled ( 13 C 15 N) L-arginine and L-lysine forms. In addition to the labeling of S-NO cysteines with IAM-biotin, reversibly oxidized cysteines (S-OX), including disulfide bridges and sulfenic acids, were labeled with biotin-HPDP. Hence, three peptide fractions were obtained after affinity enrichment: (1) the unbound (reduced cysteines and cysteine-free peptides), (2) the DTT fraction (S-OX), and (3) the guanidine fraction (S-NO) (Fig. 1A bottom ). The overall results of the redox proteomics analysis are summed up in Table  1 , while the detailed datasets are reported in Supplementary Tables S1-S3. Volcano plot visualization of the data showed that the distributions of proteins and reduced cysteine fold changes were symmetric and overlapped between the two studied bacterial lifestyles (Supplementary Fig.
Data analysis Database search using MaxQuant (version 1. 3. 0. 5) on SwissProt database (2017_05) was performed with methionine oxidation, cysteine carbamidomethylation (IAM), and biotinylation (iodoacetyl-PEG2-biotin, IAMbiotin) as variable modifications, with the following conditions: first search error tolerance 20 ppm, main error tolerance 6 ppm, MS/MS error tolerance 20 ppm, FDR 1%. A fold change was calculated for each condition: internal standard/aerobic biofilm, internal standard/aerobic planktonic. Quantitative profiles. Quantitative profiles were generated by reprocessing the data from MaxQuant evidence file. Protein expression profiles were estimated using cysteine-free peptides only. We considered peptides carrying only one cysteine. Cysteine-containing peptides were classified according to their oxidation state (IAM labeled for reduced, IAM-biotin for S-NO, unmodified for S-OX).
When a given cysteine residue was detected in different peptide forms (miss cleavages or oxidized methionine containing peptides), the features were aggregated using the median value of the ratios. The fold changes of cysteine-containing peptide were normalized to the related protein fold changes in order to avoid quantification bias induced by the differential protein expression. The randomness of the datasets was tested by the non-parametric Wald-Wolfowitz runs test (p value threshold 0. 05) using the software SPSS 26 IBM (Supplementary Table  S6 ). The null hypothesis tests were performed by comparing the modified peptide fold change to the associated protein fold change. The normalized ratios (cysteine fold changes and protein fold changes) with the corresponding calculated variances were used to perform Student's test between biofilm and planktonic conditions.
Adjusted p values < 0. 05 (Benjamini-Hochberg FDR correction) and fold changes >1. 75 were chosen as significant thresholds. Proteins detected in four or five replicates and absent in the other conditions were labeled as "biofilm only" or "planktonic only". The same procedure was used for the cysteine-containing peptides, considering only species associated to proteins detected in both conditions. Proteins with significant fold changes were used to create a dataset of "upregulated" and "downregulated" entries. The datasets were uploaded in STRING  72  to perform protein network analyses and gene ontology enrichments, using K-means clustering, which produced six clusters.
ACKNOWLEDGEMENTS We thank  Rebecca Stevick  for discussion and critical reading of the manuscript. This work was supported by the  Institut Pasteur , the  French Government 's  Investissement d'Avenir program :  Laboratoire d'Excellence Integrative Biology of Emerging Infectious Diseases (LabEx IBEID)  (grant no. ANR-10-LABX-62-IBEID  to J. M. G. ), the  Fondation pour la Recherche Médicale  (grant no. DEQ20180339185  to J. M. G. ). Mass spectrometry equipment was subsidized by  Conseil Régional d'Île-de-France  (Sesame 2010 No. 10022268 ). N. B. was the recipient of a  LabEx IBEID post-doctoral fellowship.
Nasopharyngeal cancer (NPC), endemic in Southeast Asia, lacks effective diagnostic and therapeutic strategies. Even in high-income countries the 5-year survival rate for stage IV NPC is less than 40%. Here we report high somatostatin receptor 2 (SSTR2) expression in multiple clinical cohorts comprising 402 primary, locally recurrent and metastatic NPCs. We show that SSTR2 expression is induced by the Epstein-Barr virus (EBV) latent membrane protein 1 (LMP1) via the NF-κB pathway. Using cell-based and preclinical rodent models, we demonstrate the therapeutic potential of SSTR2 targeting using a cytotoxic drug conjugate, PEN-221, which is found to be superior to FDA-approved SSTR2-binding cytostatic agents. Furthermore, we reveal significant correlation of SSTR expression with increased rates of survival and report in vivo uptake of the SSTR2-binding 68 Ga-DOTA-peptide radioconjugate in PET-CT scanning in a clinical trial of NPC patients (NCT03670342).
EBV-driven signalling pathways involved in SSTR2 expression. To validate our finding of an association between SSTR2 expression and EBV infection, we analyzed an independent NPC cohort where gene expression data were available for 113 samples  16. Unsupervised hierarchical clustering and principal component analysis (PCA) based on gene expression revealed two groups of samples in this dataset (Fig. 2j , left panel). Differential gene expression analysis between these groups revealed overexpression of SSTR2 in group 1 tumors (Fig. 2j , middle panel). Furthermore, geneset enrichment analysis (GSEA) revealed an upregulation of pathways related to viral infection in group 1 samples compared to the other group (Fig. 2j , right panel). Further, a supervised analysis on another dataset where both EBV gene expression (Fig.
3e  shows data for lanreotide, data for octreotide not shown), but no changes in cell death/apoptotic pathways. In contrast, 72-h treatment with PEN-221 led to significant downregulation of SSTR2 expression (Fig. 3f ) as well as upregulation of pathways related to apoptotic signaling and mitotic spindle formation dysregulation, the latter in keeping with the mechanism of the cytotoxic payload of PEN-221  24. SSTR2 as a diagnostic NPC biomarker in the clinic. In a clinical trial of NPC patients (NCT03670342) we show the use of SSTR2 as a potential noninvasive biomarker in NPC and integrated SSTR2 protein expression data with 68 Ga-DOTA-peptide imaging data on 12 patients. We found a significant correlation of SSTR2 expression levels with in vivo uptake of 68 Ga-DOTApeptides (Fig. 4a, b ), indicating the potential of this imaging modality as a noninvasive marker to monitor SSTR2 expression and as a target for SSTR2 receptor-targeted radionuclide therapy (Lutetium-177, Ytrium-90).
2  EBV infection is associated with SSTR2 upregulation in NPC-in vitro experiments and external validation dataset. a Immunofluorescence analysis of EBNA1 (red) and SSTR2 (green) expression in two representative examples of cultured primary respiratory epithelial cells before and after infection with the epitheliotropic M81 EBV strain. Nuclei are counterstained with DAPI (blue); Replication (n = 5). b Percentages of cells positive for EBNA1 or co-expression of SSTR2 and EBNA1 c LMP1 induces SSTR2 expression in NP69, an immortalized normal nasopharyngeal epithelial cell line (relative quantities of SSTR2 were calculated using the comparative threshold cycle method and normalized using human beta-actin as endogenous control. Data is presented as a ratio relative to vector control). d LMP1-mediated SSTR2 induction in NP69 cells is inhibited by ectopic expression of TRAF3, a negative regulator of NF-κB.
Geneset enrichment analysis was performed using the GSEA function from clusterProfiler  38  , with the reactome database  39  pathways on the gene DESeq2 Wald statistics and a minimum and maximum pathway size of 25 and 500, respectively. Pathways with a q-value <0. 05 were considered significantly enriched. For publicly-available NPC dataset where only FPKM values were available, differential expression analysis was performed using the limma package  40  with sample groups defined through hierarchical clustering of the log2(FPKM + 1) values. Adjusted p-values were computed using the eBayes function. GSEA was performed as for DESeq2 results, but with log2-fold change as the ranking score. In vivo mouse experiments. The experiments have been approved by the Animal Welfare and Ethical Review Body (AWERB) of University College London according to Animals (Scientific Procedures) Act 1986 under the project license of B.
C666-1 were xenografted and tumor specimens were stained on formalin-fixed paraffin-embedded slides as described above for SSTR2. Patient survival analysis. IBM SPSS Statistics software (version 24) and R was used to analyze the data. The likelihood of univariable independence between groups was performed using the Pearson X 2 test (and the Fisher's exact test when appropriate) for categorical variables. Rates of survival were calculated with the Kaplan-Meier method and comparison of survival by Log-rank test. SSTR2 positivity was compared using backward logistic regression analysis, also taking into account significant clinicopathological characteristics. The following clinicopathological characteristics were dichotomized: age (cutoff at 65 years), T-stage (T1/2 versus T3/4), N-stage (N0 versus N1/2/3), and M-stage (M0 versus M1).
Two-tailed p-values <0. 05 were considered statisticallysignificant. Multivariate cox regression survival analysis was performed with the R package survival, with center (dichotomized to Europe/Asia), SSTR2 status, EBV status, sex, and age as well as T (dichotomized to T1-2 and T3-4), N (dichotomized to N0-1 and N2-3), and M staging as covariates initially. Center and sex were removed from the final model as they were found to be nonsignificant (p < 0. 05). The proportional hazards assumption was tested using the cox. zph function; none of the covariates in the final model were found to violate the proportional hazards assumption (p < 0. 05). Concordance was calculated with Cohen's Kappa. 68 Ga-DOTATATE molecular Imaging. Patients were recruited prospectively under the Pilot study of Somatostatin Receptor Imaging in Nasopharyngeal carcinoma (ClinicalTrials.
gov: NCT03670342). Informed consent was obtained from all patients, and approval was obtained from the centralized institution review board (IRB protocol no. 2015/2482). Peptide labeling with 68 Ga in the Department of Nuclear Medicine and Molecular Imaging, Singapore General Hospital was performed using an automated synthesis module (Scintomics GmbH). In brief, 40 µg DOTA-[Tyr 3 ] Octreotate precursor (Auspep) was radiolabeled with Gallium-68 eluted from 68 Ge/ 68 Ga generator (iThemba, South Africa). The 68Ge/68Ga generator is eluted with 10 ml 0. 6 M hydrochloric acid. Gallium-68 was trapped using PS-H cartridge and eluted with 1. 7 ml 5 M sodium chloride solution into 3 ml of 1. 5 M HEPES buffer solution. The solution was heated at 125 °C for 6 min and purified using a Sep-Pak Light C18 cartridge and the final labelled product eluted with 2 ml of 50% Ethanol (v/v) into a product vial and diluted with 19 ml of phosphate buffered saline.
For SUVmax calculations volumes of interest of tumor lesions (nasopharyngeal tumor, nodes, and metastatic sites including lymph nodes, soft tissue, visceral, and osseous lesions) and reference tissue (liver and spleen) were drawn automatically and adjusted manually to lesion size, applying a commercially available software provided by the vendor of the PET/CT-scanner (GE AWS). available from the GEO website under accession GSE102349. All the other data supporting the findings of this study are available within the article and its supplementary information files and from the corresponding author upon reasonable request. Source data are provided with this paper.
Acknowledgements This research work was funded by the  Rhinology and Laryngology Research Fund, Royal College of Surgeons  ( Colledge Family Research Grant ),  UCL/UCLH Biomedical Research Centre (BRC) , the  Association for the Global Advancement of ENT Surgery and Head and Neck Cancer Research (AGA-ENT) , the  Austrian Science Foundation  ( FWF grant :  I 3976-B33 ) and the  Christian Doppler Research Association. Research reported in this publication was jointly supported by the  ASEAN-European Academic University Network (ASEA-UNINET) , the  Austrian Federal Ministry of Education, Science and Research and the Austrian Agency for International Cooperation in Education and Research (OeAD-GmbH). We would like to acknowledge the invaluable support from  Prof. Tariq Enver  via the  UCL Shenzhen collaboration  and the  UCL Cancer Institute.
Dr. Wolfgang Freysinger  from the  Medical University of Innsbruck ,  Prof Dr. Felix Offner  from the  LKH Feldkirch. Dr. Charles Breeze  for his help with molecular data and Research Services at  UCL  and the  UCL Ethics Committee. Research in the laboratory of B. V. is supported by  Cancer Research UK  ( C23338/A25722 ) and the  UK NIHR University College London Hospitals Biomedical Research Centre. N. P. is funded through a  Cancer Research   UK clinician scientist fellowship  (Award reference:  18387 ). C. S. is funded by  Cancer Research UK. Dr. Kwok-Wai Lo  is supported by the  Research Grants Council (RGC) of Hong Kong  ( T1-2-401/13-R ;  C4001-18GF ;  C7027-16G ;  C5012-15E ;  14117316 ). M. L. K. C. is supported by the  National Medical Research Council   Singapore Clinician-Scientist Award -# NMRC/CSA/0027/2018 , the  Duke-NUS   Oncology Academic Program Proton Research Program , and the  National Research Foundation Clinical Research Program Grant  ( NRF-CRP17-2017-05 ).
Data availability The RNA sequencing data from untreated/treated NPC cell lines have been deposited in the GEO database under the accession code GSE160882. The expression array data referenced during the study are available in a public repository from the GEO website under accession GSE12452. The RNA sequencing data references during the study are Work in U. O. 's laboratory was supported by the LEAN Network from the Leducq Foundation, NIHR BRC Oxford, CRUK and from the People Programme (Marie Curie Actions) of the European Union's Seventh Framework Programme (FP7/2007-2013) under REA grant agreement no. [609305]. Q. L. E. is supported by R01 DE025227 (NIDCR/NIH). S. W. T. was supported by grants GRF 106180141, CRF C7027-16G, and HRF260870784 for the establishments of the NPC cell lines.
8 6 8 Fig. 2EBV infection is associated with SSTR2 upregulation in NPC-in vitro experiments and external validation dataset. a Immunofluorescence analysis of EBNA1 (red) and SSTR2 (green) expression in two representative examples of cultured primary respiratory epithelial cells before and after infection with the epitheliotropic M81 EBV strain. Nuclei are counterstained with DAPI (blue); Replication (n = 5). b Percentages of cells positive for EBNA1 or co-expression of SSTR2 and EBNA1 c LMP1 induces SSTR2 expression in NP69, an immortalized normal nasopharyngeal epithelial cell line (relative quantities of SSTR2 were calculated using the comparative threshold cycle method and normalized using human beta-actin as endogenous control. Data is presented as a ratio relative to vector control). d LMP1-mediated SSTR2 induction in NP69 cells is inhibited by ectopic expression of TRAF3, a negative regulator of NF-κB.
The recovery of the complex wavenumbers of the three modes is finally performed, frequency by frequency, by minimizing the following cost function: f opt (ω) = ∑ s r ∑ s i u(s, ω) -u th (s, ω) 2. ( 8 ) Note that the minimization is performed under constraints with the Nelder-Mead simplex algorithm and the use of the function fminsearchbnd in MATLAB. For details and other applications of the SLaTCoW method which are beyond the scope of this manuscript, the readers are referred to the works in  [27, 47, 48]. For the comparison with the experimental results, the complex Lamb wave spectrum is computed applying to elasticity equations a numerical spectral method, as proposed in  [49]. The attenuation used to plot the theoretical curves shown in Figure  4  is 0 and 0. 4 dB/cm/MHz for the cases without and with accounting for the attenuation, respectively, so that the reader can appreciate the necessity to account for the attenuation in order to retrieve the correct path of the complex branches.
Results More Tregs, More FoxP3 in Severe COVID-19 Patients. We performed a deep immunologic and transcriptional analysis of circulating blood Tregs across a cohort of confirmed COVID-19 patients (n = 57) (Fig. 1A  and Dataset S1): mild, outpatients; severe, hospitalized, 65% of which in intensive care (ICU), mostly sampled during the cytokine storm period; and recovered, virus-negative convalescents. Flow cytometry, with a multiparameter panel that parsed CD25 + FoxP3 + Tregs and their different phenotypes (gating strategies in SI Appendix, Fig. S1A ), revealed several perturbations (representative plots in Fig. 1B ). First, several severe patients showed increased Treg proportions among CD4 + T cells: for some as an increased proportion only (likely resulting from preferential.