dataesr/scientific-paragraphs-categorization huggingface dataset:
The US Food and Drug Administration (FDA) granted an accelerated approval to dabrafenib (Tafinlar) plus trametinib (Mekinist) for the treatment of unresectable or metastatic solid tumors with a BRAFV600E mutation. The combination was approved for patients aged 6 years and older in whom the tumors progressed after prior treatment and who had no alternative treatment options. This approval was supported by the meaningful efficacy and safety for the combination in the Rare Oncology Agnostic Research (ROAR) and National Cancer Institute-Molecular Analysis for Therapy Choice (NCI-MATCH, NCT02465060) studies in adults and a study (NCT02124772) in pediatric patients with refractory or recurrent solid tumors. This was the first approval for a tumor-agnostic BRAF and MEK inhibitor combination approach and was a considerable advance in precision medicine.
The ROAR study was designed to assess the activity and safety of dabrafenib plus trametinib in patients with BRAFV600E-mutated rare cancers. Based on the discretion of the treating physician and according to the local available standards of care, these cancers did not have any satisfactory treatment options. Rare cancer types included in the study were ATC, biliary tract cancer (BTC), gastrointestinal stromal tumor (GIST), adenocarcinoma of the small intestine (ASI), low-grade (World Health Organization (WHO) grade 1 or grade 2) glioma (LGG), high-grade (WHO grade 3 or grade 4) glioma (HGG), non-seminomatous germ cell tumors (NSGCTs)/non-germinomatous germ cell tumors (NGGCTs), HCL and MM. We previously published interim results for the ATC  14  , BTC  16  , LGG and HGG  17  and HCL cohorts (data cutoff dates: 26 August 2016 to 25 July 2018)  18.
Results From 17 April 2014 to 25 July 2018, a total of 251 patients were screened and 206 patients were enrolled in the study across the ATC (n = 36), BTC (n = 43), GIST (n = 1), LGG (n = 13), HGG (n = 45), ASI (n = 3), NSGCT/ NGGCT (n = 0), HCL (n = 55) and MM (n = 10) cohorts. The primary analysis cohort included a total of 108 patients: ATC (n = 15), BTC (n = 18), GIST (n = 1), LGG (n = 13), HGG (n = 24), ASI (n = 3), HCL (n = 24) and MM (n = 10); the expansion cohort included 98 patients: ATC (n = 21), BTC (n = 25), GIST (n = 0), LGG (n = 0), HGG (n = 21), ASI (n = 0), HCL (n = 31) and MM (n = 0) (Extended Data Fig. 1 ). BRAFV600E mutation status was confirmed by a central laboratory in 92%, 91%, 62%, 93% and 91% of patients in the ATC, BTC, LGG, HGG and HCL cohorts, respectively, and all patients in the GIST, ASI and MM cohorts.
Article https://doi. org/10. 1038/s41591-023-02321-8 cell carcinoma, decreased neutrophil count, squamous cell carcinoma (n = 3, 1. 5%), squamous cell carcinoma of the skin (n = 3, 1. 5%) and chills, leukopenia, nausea and vomiting (n = 2, 1% each) (Extended Data Table  5 ). Fatal SAEs were reported in nine (4. 4%) patients. Fatal SAEs were seen in three (8. 3%) patients in the ATC (sepsis, pneumonia, diverticulitis, pleural effusion and pulmonary embolism) cohort and three (5. 5%) patients in the HCL (sepsis, pneumonia, adenocarcinoma of the pancreas and hemorrhagic stroke) cohort. In the BTC cohort, two (4. 7%) patients died due to sepsis, and one patient in the HGG cohort died due to general physical health deterioration. No fatal SAEs were reported in the LGG and MM cohorts. None of these fatal SAEs was related to the study drug.
The ROAR study included patients with advanced disease, and all patients had received pre-treatment with standard-of-care therapies. This reduced the risk of observing an inflated ORR. In this study, we deployed an adaptive design for ORR with a Bayesian hierarchical model to increase the power to identify clinically meaningful outcomes. This helped to identify cohorts that could be further expanded and allowed for multiple interim data evaluations to determine if a histologic cohort should discontinue enrollment early due to success or futility. The ATC, BTC, HGG and HCL cohorts were stopped early for efficacy, and an expansion cohort was opened for each of these cohorts. None of the cohorts was stopped early due to futility. Additional strengths of the study design included the analysis of ORR with standard frequentist estimates for each of the cohorts and an independent radiology review for solid tumor cohorts.
Some of the cancers reported here are ultra-rare cancers and have never been studied before with BRAFV600 inhibitors in clinical trials. In a phase 2 trial (ClinicalTrials. gov identifier: NCT02684058), dabrafenib plus trametinib improved the ORR and prolonged PFS compared to standard chemotherapy in 110 pediatric patients (aged 1-17 years) with BRAFV600-mutant LGG  31. There are also case reports of the pediatric population benefiting with dabrafenib plus trametinib in the treatment of BRAF mutation-positive glioblastoma and gliomas  [32] [33] [34]  , pancreatic acinar cell carcinoma  35  and Wilms tumor  36. Figure  2  presents the ORR from various studies that provide evidence of the tumor-agnostic efficacy of dabrafenib plus trametinib in BRAFV600-positive rare cancers  20, 31, [37] [38] [39] [40] [41] [42].
This approval opens up access to patients with rare cancers with BRAFV600E mutations who otherwise may not have access to this valuable treatment. This is key to advancing clinical research in rare cancers and enabling evidence-based clinical practice in the management of these cancers  45. Similarly to other studies, such as ProTarget (NCT04341181), IMPRESS (NCT04817956) and MEGALiT (NCT04185831), the ROAR study is an endeavor to define actionable genomic targets to help advance management and provide equal treatment opportunities in the management of cancers, including rare cancers  46, 47. Dabrafenib 150 mg twice daily plus trametinib 2 mg once daily was well tolerated in this study, with a clinically acceptable incidence of AEs, dose interruptions and treatment discontinuations. Across all cohorts, the observed safety profile of this combination was consistent with the known safety profile in approved indications of BRAFV600 mutation-positive unresectable or metastatic melanoma, NSCLC and ATC  [11] [12] [13] [14].
Besides the parameters described in the protocol, additional safety tests were to be performed by the investigators during the course of the study based on newly available data to ensure appropriate safety monitoring. Appropriate local regulatory and ethical approvals applied before any additional testing was performed. AE monitoring was done continuously from the time the first dose of study treatment was administered until 30 days after discontinuation of study treatment. AEs were graded according to CTCAE version 4. 0 (ref. 56).
The independent radiology review was done as a supportive analysis in the ATC, BTC, ASI, LGG and HGG cohorts. Primary and secondary efficacy endpoints based on independent reviewer assessment were summarized in the same way as the best response based on investigator assessment. An assessment of the concordance between the investigator-assessed response and independent reviewer-assessed response was performed. In addition, waterfall plots were generated for best confirmed response based on investigator and independent assessment. The safety population included all patients who received at least one dose of dabrafenib or trametinib. Safety data were summarized descriptively by histology and across all cohorts. Incidence of deaths and primary cause of death were summarized. An independent data monitoring committee reviewed safety and activity results from https://doi.
org/10. 1038/s41591-023-02321-8 interim analyses at regular intervals and provided recommendations to the sponsor. Statistical tools. SAS (version 9. 3, SAS Institute) was used for all statistical analysis except for the hierarchical Bayesian model, which used C++ and R version 2. 15. 2 to evaluate the performance of the design under various assumptions for the distribution of true ORRs across histological cohorts and accounting for anticipated small sample sizes.
Extended Data Fig. 3  | Progression free survival by investigator and independent radiology assessment across tumor cohorts. Efficacy evaluable population: Primary and expansion cohorts in all except low grade glioma and MM which is primary analysis cohort; (A) Investigator assessment (B) Independent radiology assessment. ATC: By investigator assessment in 36 patients, 21 (58%) patients had disease progression and six (17%) had died without disease progression. Nine (25%) patients were censored due to end of follow-up. By independent radiology review, progression of disease was observed in 26 (72%) patients and three (8%) patients died without disease progression. Seven (19%) patients were censored due to end of follow-up. BTC: By investigator assessment in 43 patients, 33 (77%) patients had disease progression and six (14%) patients had died without disease progression.
Acknowledgements The ROAR study was designed and data were analyzed by the sponsor (Novartis) in collaboration with the trial steering committee. Study funding was provided by  Novartis. Writing and editorial assistance was provided by  T. Jandoo ,  Novartis Healthcare Pvt. Ltd. , India. The authors thank  G. Gao  for supporting data analysis for the manuscript. V. S. , an  Andrew Sabin Family Foundation Fellow at The University of Texas MD Anderson Cancer Center , acknowledges support from the  Jacquelyn A. Brady Fund  and is supported by  National Institutes of Health  grants  R01CA242845  and  R01CA273168. The  MD Anderson Cancer Center Department of Investigational Cancer Therapeutics  is supported by the  Cancer Prevention and Research Institute of Texas  ( RP1100584 ), the  Sheikh Khalifa Bin Zayed Al Nahyan Institute for Personalized Cancer Therapy  ( 1U01 CA180964 ),  National Center for Clinical and Translational Sciences  grant  UL1 TR000371  and the  MD Anderson Cancer Center Support Grant  ( P30 CA016672 ).
Extended Data Table 2 | AEs (≥10% in all cohorts) suspected to be study treatment related Values are number of patients, n (%). Preferred terms by MedDRA version 23. 0 and CTCAE version 4. 0. All treated patients (primary and expansion cohorts). ALP, alkaline phosphatase; ALT, alanine aminotransferase; AST, aspartate aminotransferase; G, grade; MedDRA, Medical Dictionary for Regulatory Activities; WBC, white blood cell.
The CORIMUNO-19 cohort We set up a national cohort of COVID-19 patients with moderate, severe, or critical pneumonia (CORIMUNO-19 Cohort, NCT04324047). This cohort was used to perform a series of randomized controlled trials testing different therapeutic regimens in COVID-19 patients. Two separate populations were recruited: group 1: patients with moderate-to-severe pneumonia with WHO 10-points Clinical Progression Scale [WHO-CPS] score 5 receiving at least 3L/min O 2 but without high flow oxygen (HFO), noninvasive ventilation (NIV), or mechanical ventilation (MV) and group 2: patients with critical pneumonia defined as WHO-CPS score 6 or more (i. e. , with HFO, NIV or MV) in intensive care unit (ICU). All patients included in the ancillary study presented in this work were included in the CORIMUNO-19 cohort in three randomized trials evaluating the efficacy of tocilizumab, sarilumab  (25)  and anakinra  (26).
IFN-a quantification in plasma samples Plasma and/or serum samples were collected from 84 COVID-19 patients, and 20 healthy donors from a single hospital (Hopital Bicetre, Assistance Publique-Hopitaux de Paris), and 56 COVID-19 patients included in other hospitals participating in the CORIMUNO-19 trials. These samples are part of the French-COVID collection. Plasma and sera were analyzed using the Simoa technology with the Quanterix SIMOA HD-X analyzer (Quanterix Corporation, Lexington, MA, USA). The levels of plasma IFN-a2 were measured using the commercial kit for IFN-a2 quantifications according to the manufacturer's instructions (Simoa® IFN-a Advantage Kit, reference 100860; Quanterix). The plasma and serum IFN-a2 levels were expressed in femtogramme per milliliters (fg/mL). We had both sera and plasma available from 12 additional patients (not included in the analysis since we do not yet have definitive data on the clinical evolution).
Following incubation with the antibodies, the lysis of red blood cells (RBC) was performed using 1X FACS Lysing Solution (BD Biosciences), and the samples were fixed with 1% PFA. Flow cytometry was performed on a BD LSRFortessa instrument using FACSDiva software (BD Biosciences), and the data were analyzed using FlowJo software (Treestar, San Carlos, CA). DC populations were defined as follows: pDC (CD14 -CD16 -CD123 + CD11c -), cDC1 (CD14 -CD16 -CD11c low , CD141 + CD1c + ), and cDC2 (CD14 -CD16 -CD11c + , CD141 -CD1c + ). The flow cytometry strategy is indicated in Figure  S2.
RNAseP positivity was necessary to validate the RT-PCR assay prior to any further analysis. Briefly, 9. 9 mL of extracted RNA was diluted in a 22 mL final reaction volume containing 5. 5 mL of One Step SuperMix, 2. 2 mL of Reverse Transcriptase, 1. 1 mL of 300mM DTT (One-Step RT-ddPCR Advanced Kit for Probes, Bio-Rad), 1. 1 mL of primers and probes mix (final probe concentration: 200 nM each, final primer concentration: 600 nM each) and 2. 2 µL (QS) of nuclease-free water. Then, each sample was primarily partitioned into 13000 to 20,000 droplets using the QX200 ™ Droplet Generator ™ (Bio-Rad). PCR amplification was then performed on a C1000 Touch ™ thermal cycler (Bio-Rad). The droplet reading and quantification were performed using the QX200 ™ Droplet Reader ™ , and data analysis was performed using the QuantaSoft ™ Analysis Pro software (Bio-Rad).
Study approval All methods were performed in accordance with the relevant guidelines and regulations. The trial was approved nationally by the ethics committee on March 23, 2020 (file #20. 03. 20. 56342, CPP I ̂le De France VI, EudraCT: 2020-001246-18), by the French Medical Products Agency and by the Commission Nationale Informatique et Liberte. Written informed consent was obtained from all patients or from the patient's legal representative if the patient was too unwell to consent to enter the CORIMUNO Cohort.
Results Baseline levels of plasma IFN-a2, anti-IFNa auto-Abs, and dendritic cells in patients with severe and critical COVID-19 To better understand the role of type I IFN in the evolution of COVID-19, we performed a longitudinal study of blood IFN-a2 levels in 140 patients from the CORIMUNO-19 cohort (NCT04324047) divided into two groups, group 1: patients with severe COVID-19 requiring at least 3L/min of oxygen (n=81) and group 2: patients with critical COVID-19, requiring high-flow, noninvasive (NIV) or mechanical ventilation (MV) in intensive care unit (ICU) (n=59)  (25). Twenty healthy blood donors were used as controls. The patients' and controls' baseline characteristics are indicated in Table  1. The baseline (at entry in the hospital [D1]) blood level of IFN-a2 was elevated in both groups compared to controls with higher levels in severe patients compared to critical patients (Figure  1 ).
Longitudinal follow-up of plasma IFN-a2 in relation to mortality in patients with severe and critical COVID-19 In order to determine whether IFN-a2 variation during disease evolution may have a predictive value, we collected samples over time to assess blood IFN-a2. Blood IFN-a2 levels decreased in both groups of COVID-19 patients over time (Figures  3A, S6 ) and did so regardless of the treatment group (usual care (UC), sarilumab, tocilizumab, or anakinra) (Figure  3B ). Baseline (D1) IFN-a2 was not different between groups and treatment did not induce different changes in IFN-a2 between groups (data not shown). Thus, we merged the treatments group and analyzed the severe and critical groups. The magnitude of the decrease measured by the D6/D1 blood IFN-a2 ratio was significantly higher in severe patients who subsequently died than in patients who survived (p=0.
The high sensitive dosage of IFN was performed thanks to Fondation DORMEUR. The study was in part supported by the mećeńat GHU Paris-Centre from AP-HP (to Heĺène Peŕe), grants from the Fondation pour la Recherche Medicale (FRM) (REA202010012514) and Agence Nationale de Recherches sur le Sida and emerging infectious diseases (ANRS) (ANRS0147) from the VINTED sponsorship to Pierre-Louis Tharaux, and grants from UniversitéParis-Saclay, DIM « One Health » and IDMIT (ANR-11-INBS-0008) to Roger Le Grand.
Isolation and Identification of Termite Mutualistic Microorganisms The strain was isolated from Nasutitermes similis termite aerial nest sampled in Piste de Saint-Elie (N 05 • 01,838' W 052 • 44,606') in French Guiana. The strain SNB-CN111 from the strain library collection at ICSN was identified as Penicillium sclerotiorum. The taxonomic marker analyses were externally performed by BACTUP Saint-Priest, France). The identification of the fungi was conducted by amplification of the ITS4 region of ribosomal. The sequences were aligned with DNA sequences from GenBank, NCBI (http://www. ncbi. nlm. nih. gov, accessed on 7 June 2021), using BLASTN 2. 2. 28. The sequence has been registered in the NCBI GenBank database (http://www. ncbi. nlm. nih. gov, accessed on 7 June 2021) under registry number KJ023726.
Data Processing and Analysis The data files were converted from the. d standard data format (Agilent Technologies) to. mzXML format using the MSConvert software, part of the ProteoWizard package 3. 0 [30]. All. mzxml were processed using MZmine2v51 as previously described  [31]. The mass detection was realized with MS1 noise level at 1000 and MS/MS noise level at 0. The ADAP chromatogram builder was employed with a minimum group size of scans of 3, a group intensity threshold of 1000, a minimum highest intensity of 1000, and m/z tolerance of 0. 008 (or 20 ppm). Deconvolution was performed with the ADAP wavelets algorithm according to the following settings: S/N threshold = 10, minimum features height = 1000, coefficient/area threshold = 10, peak duration range 0. 01-1. 5 min, t R wavelet range 0.
00-0. 05 min. MS/MS scans were paired using an m/z tolerance range of 0. 05 Da and t R tolerance range of 0. 5 min. Isotopologues were grouped using the isotopic peak grouper algorithm with an m/z tolerance of 0. 008 (or 20 ppm) and a t R tolerance of 0. 2 min. Peaks were filtered using Feature list row filter, keeping only peaks with MS/MS scans (GNPS). Peak alignment was performed using the join aligner with an m/z tolerance of 0. 008 (or 20 ppm), a weight for m/z at 20, a t R tolerance of 0. 2 min, and weight for t R at 50. The MGF file and the metadata were generated using the export/submit to GNPS option. Molecular networks were calculated and visualized using MetGem 1. 3 software [26-28], MS/MS spectra were window-filtered by choosing only the top 6 peaks in the ±50 Da window throughout the spectrum.
The data were filtered by removing all peaks in the ±17 Da range around the precursor m/z. The m/z tolerance windows used to find the matching peaks were set to 0. 02 Da, and cosine scores were kept in consideration for spectra sharing 2 matching peaks at least. The number of iterations, perplexity, learning-rate, and early exaggeration parameters were set to 5000, 25, 200, and 12 for t-SNE view. Figures were generated using R and related packages (ggplot2, Rcolorbrewer, Ven-nDiagram and gridextra), MetGem export function, and ChemDraw Professional 16. 0 (PerkinElmer). NMR spectra were processed and analyzed using TopSpin 3. 6. 2 (Bruker, Rheinstetten, Germany).
MS/MS data were then extracted to generate molecular networks by MetGem software  [26] [27] [28]. In a molecular network, specialized metabolites of the same family cluster according to their fragmentation similarity, facilitating the annotation of metabolites in complex mixtures. The advantage of t-SNE molecular networks over regular molecular network is that datasets are represented as a whole, preserving the structural relationship between distinct clusters. This methodology has already been successfully applied to extracts of Penicillium sclerotiorum SNB-CN111 on solid PD conditions to decipher the chemical diversity of produced azaphilones  [24, 25]. Cultivation on solid CZK medium, PD medium, and solid YE medium generated 255, 620 and 1069 distinct metabolic features, respectively, indicating that the chemical diversity is increasing with the complexity and concentration of the organic nitrogen sources (Figure  1b ).
Increasing the complexity of the organic nitrogen source also affected the production of unique metabolites. In fact, cultivation on YE led to the production of 716 unique features, accounting for 67% of YE produced metabolites. On the other hand, 29% and 35% of compounds produced by cultivation on CZK and PD were specific to these conditions, respectively. of t-SNE molecular networks over regular molecular network is that datasets are represented as a whole, preserving the structural relationship between distinct clusters. This methodology has already been successfully applied to extracts of Penicillium sclerotiorum SNB-CN111 on solid PD conditions to decipher the chemical diversity of produced azaphilones  [24, 25]. Cultivation on solid CZK medium, PD medium, and solid YE medium generated 255, 620 and 1069 distinct metabolic features, respectively, indicating that the chemical diversity is increasing with the complexity and concentration of the organic nitrogen sources (Figure  1b ).
Increasing the complexity of the organic nitrogen source also affected the production of unique metabolites. In fact, cultivation on YE led to the production of 716 unique features, accounting for 67% of YE produced metabolites. On the other hand, 29% and 35% of compounds produced by cultivation on CZK and PD were specific to these conditions, respectively. previously isolated  [25]  are circled in gold. To explore the t-SNE molecular network, a MS/MS database built from a previous work  [25]  was used leading to the annotation of 39 azaphilones distributed in five clusters (Figure  1c ). Yellow and orange azaphilones with pyran ring were annotated in clusters A and B. Cluster A displays the analogous metabolites of sclerotiorin (1) and cluster B the ochrephilone ones (2) (Tables  S1  and S2 , Figures  S1  and S2 ).
Indeed, out of the 174 azaphilones constituting cluster D, only 1 is produced from CZK medium, 28 are produced from PD and 162 azaphilones are produced from YE medium. As the organic nitrogen in YE results from protein digestion and amino acid metabolism, MS and MS/MS data of protonated species corresponding to putative analogs of sclerotiorin (1) with integrated amino acids or their metabolic derivatives were scrutinized. The molecular formula of the functionalized nitrogen chain was calculated and queried in the KEGG compound database  [32]  in order to annotate metabolites (Tables  S6-8 ). Cluster D was subdivided into three clusters (D-I, D-II and D-III) to facilitate the annotation in the t-SNE molecular network (Figure  S6 ). Fourteen azaphilones are bearing an amino acid as a nitrogen side chain, some over can be related to amino acid derivatives such as ethanolamine or tyramine (6-50) (Figure  2 ).
Methods: We conducted Mendelian randomization (MR) analyses to investigate potential causal relationships between self-perceived body size (thinner, plumper, or about average) in early life (age 10) and measured body mass index in adulthood (mean age 56. 5) with risk of colorectal cancer. The total and independent effects of body size exposures were estimated using univariable and multivariable MR, respectively. Summary data were obtained from a genome-wide association study of 453,169 participants in UK Biobank for body size and from a genome-wide association study meta-analysis of three colorectal cancer consortia of 125,478 participants. Results: Genetically predicted early life body size was estimated to increase odds of colorectal cancer (odds ratio [OR] per category change: 1. 12, 95% confidence interval [CI]: 0.