dataesr/scientific-paragraphs-categorization huggingface dataset:
Evidence before this study We searched PubMed for articles published from database inception to 5 April 2021. All fields were searched for "newly diagnosed" AND "multiple myeloma" AND "overall survival" AND "monoclonal antibody". Our search identified 100 articles published during this timeframe. Of those, 18 articles were published before the first patient was enrolled in the MAIA study in March 2015, with one describing a clinical trial of a monoclonal antibody. In that phase 2 trial, siltuximab, an interleukin-6 monoclonal antibody, in combination with bortezomib, melphalan, and prednisone did not demonstrate a clinical benefit over bortezomib, melphalan, and prednisone alone in transplant-ineligible, newly diagnosed multiple myeloma. Of the 82 articles published after MAIA was initiated, nine reported results of clinical trials with a monoclonal antibody; survival benefit was shown only in the phase 3 ALCYONE study of daratumumab in combination with bortezomib, melphalan, and prednisone versus bortezomib, melphalan, and prednisone alone.
Efficacy response was determined by IMWG criteria. 16, 17 Complete definitions of all efficacy endpoints are included in the appendix (p 4-5). Efficacy assessments were performed as previously described. 11 OS data and updated data on CR or better rate, VGPR or better rate, and ORR are provided in this manuscript; however, MRD data were not updated based on the clinical cutoff for the analyses presented in this manuscript. Updated MRD results based on a shorter duration of follow-up are provided in this manuscript. Cytogenetic risk was assessed locally (no standard cutoff for clonal size) by fluorescence in situ hybridisation or karyotype testing; a high-risk cytogenetic profile was defined by a deletion (del)17p and/or translocations t(14;16), or t(4;14).
All key secondary endpoints (CR or better rate, VGPR or better rate, MRD-negativity rate, ORR, and OS) were evaluated with a two-sided alpha level of 0. 05 and using a hierarchical testing procedure at the time of the primary PFS analysis; all key secondary endpoints, except for OS, had crossed the prespecified stopping boundaries. OS and Among the patients who were randomly assigned, 729 patients (364 [99%] in the D-Rd group and 365 [99%] in the Rd group) received at least one dose of study treatment (figure  1   13  MRD data were not updated based on the clinical cutoff for the OS and PFS analyses presented in this manuscript; however, a formal MRD analysis is planned for a future data cut. 114 (31%) of 364 patients in the D-Rd group and 186 (51%) of 365 patients in the Rd group had received subsequent therapy at the clinical cutoff date.
25 Despite the better median OS and PFS associated with Rd in MAIA, D-Rd still demonstrated a significant clinical benefit over Rd. Results from the phase 3 POLLUX study support the use of D-Rd after first relapse in patients with RRMM who are not refractory to lenalidomide  9, 26  ; results of the current MAIA OS analysis highlight the role of D-Rd as first-line treatment in transplant-ineligible patients with NDMM. Real-world data from Europe showed high attrition rates that increased with each subsequent line of therapy (95% of patients received first-line therapy, 61% of patients received second-line therapy, and 38% of patients received third-line therapy). 27 Similarly, a retrospective review of three US databases showed high attrition rates (approximately 50%) after the first and each subsequent line of therapy among non-transplant patients; factors associated with high attrition levels were older age and poor comorbidity status.
30, 31 rther analyses are also needed to determine the optimal duration of daratumumab treatment. In the phase 3 CASSIOPEIA study (NCT02541383), transplant-eligible patients with NDMM who received daratumumab in combination with bortezomib, thalidomide and dexamethasone (D-    *The intention-to-treat population included all patients who underwent randomization. Post hoc analyses showed no significant differences between the two groups in the characteristics evaluated at baseline. † Eastern Cooperative Oncology Group (ECOG) performance status is scored on a scale from 0 to 5, with 0 indicating no symptoms and higher scores indicating increasing disability. ‡ Two patients had a score of greater than 2 (one patient had a score of 3, and another patient had a score of 4). § The International Staging System (ISS) disease stage, which is derived on the basis of the combination of serum β2-microglobulin and albumin levels, consists of three stages.
Rd) versus SWOG S0777 (HR 0•71 with VRd vs Rd). For patients in SWOG S0777 aged >75 years, median PFS was around 3 years (39 months) in the VRd group (approximately 2 years less than the expected median PFS of 5 years in MAIA) versus 20 months in the Rd group. With a longer (84-month) median follow-up, median OS was NR with VRd versus 69 months with Rd (HR 0•709; 95% Wald CI 0•543-0•926; stratified two-sided p=0•0114); a median OS of greater than 84 months with VRd is anticipated. 15 A significant OS benefit was not observed with VRd versus Rd for patients aged ≥65 years (median, 65 vs 56 months, respectively; HR 0•769; stratified two-sided p=0•168). In the PEGASUS study, an anchored indirect treatment comparison leveraging individual-level patient data was performed between patients treated with D-Rd in MAIA and patients treated with VRd from the Flatiron Health electronic health record-derived database.
Acknowledgments This study was sponsored by  Janssen Research & Development. We thank the patients who volunteered to participate in this trial, their families, and the staff members at the trial sites who cared for them; the members of the data and safety monitoring committee ( Nikhil C. Munshi, MD  [chair],  Mario DiCato, MD , and  Weichung Shih, PhD ); representatives of the sponsor who were involved in data collection and analyses;  Intergroupe Francophone du Myélome  for their strong support and guidance during the trial start-up; and  Grace Wang, PharmD , and  Kimberly Carmony, PhD , of  Cello Health Communications/MedErgy , for medical writing and editorial assistance.
CEPHEUS (NCT03652064) is an ongoing phase 3 study evaluating D-Rd maintenance following induction with daratumumab in combination with VRd in patients with NDMM for whom transplant is not planned as initial therapy. 33 Further analyses of MAIA are ongoing to investigate the efficacy of daratumumab retreatment and the timing of neutropenia and infections in relation to daratumumab treatment. In transplant-ineligible patients with NDMM, treatment until disease progression with D-Rd resulted in a significant OS benefit compared with Rd. With longer follow-up, D-Rd is expected to demonstrate an unprecedented median PFS. These results strongly support the frontline use of D-Rd to maximise PFS for optimal long-term outcomes. Overall, daratumumab-based regimens have set new PFS and OS benchmarks for transplant-ineligible patients with NDMM.
Next, they sought understanding of cell-level tness e ects. Ideally, such assays would have been performed over an entire collective-level life cycle, but for practical reasons this is nigh impossible. Instead, various cell-level assays were conducted, including assessment of competitive ability in broth culture. Data from these experiments showed cell-level tness to have declined in derived populations (Figure  1b ), at least for the regime in which lineages passaged through soma-like and germ-like phases, thus giving the impression that the tness of cells had decoupled from the tness of collectives (Figure  1 ). Figure  1  Fitness-decoupling observation in the Pseudomonas system. Comparison of collective-level persistence (measured as the proportion of collective persistence after one generation when competed against an ancestral reference strain) and cell (particle) fitness (measured as the number of cells comprising a collective) for ancestral (blue) and derived (orange) populations under a regime designed to promote an ETI.
Error bars represent standard errors of the mean (based on n=15 ancestral and n=14 derived lineages respectively). Redrawn from  Hammerschmidt et al. (2014, Fig. 2 ) for ease of comparison with Figure  5. Protocol described and statistical analysis performed in  Hammerschmidt et al. (2014)  showing statistical significance between ancestral and derived collective persistence/cell fitness. Dataset published as  Rose et al. (2018). While tness decoupling and the export-of-tness model might seem useful concepts for understanding ETIs, we argue here that commensurably computed tnesses cannot be decoupled. Central to our argument (detailed in Section 2, and Box 1) is the need for measures of cell and collective tness to derive from analyses performed in the same reference environment and over precisely the same timescale  (Black et al.
e. the initial condition of the evolutionary trajectory will be taken to be , the optimal trait value for the ancestral unicellular organism. Thus , where is the value of for an organism with trait. Similarly, let be the optimal trait value for the collective, The code implementing this model and drawing the gures presented here is available as supplementary material (doi: 10. 5281/zenodo. 5352208). It makes use of the Matpopmod library  (Bienvenu & Doulcier, 2021). 3. 2 Conditions for " tness-decoupling" observations between or and 𝑓 1 𝑓 2 𝐹 Once a mutation (or change in the environment) makes the rst multi-particle collective possible, the process that drives population dynamics is one associated with F. A su cient condition for " tness decoupling" observations to be possible would be that the trait values that are optimal for single-particle collectives ( ) are not optimal for multi-particle collectives ( ), provided the tness landscape is smooth enough (and both F and are continuous functions of with a single maximum value).
, 2014, asterisks indicate  tradeoff-breaking observations in two lineages). Dataset published as  Rose et al. (2018). To illustrate this point, we provide two examples from biology. The rst one is the well-understood tradeo between photosynthesis and nitrogen xation --from dinitrogen gas (N 2 ) --in cyanobacteria. The tradeo is caused by the oxygen sensitivity of the enzyme nitrogenase, which catalyses the process of reducing N 2 to ammonia (NH 3 ). This prevents cells from performing both functions simultaneously and has resulted in several morphological and physiological adaptations (Figure  6a ). In the unicellular species, Cyanothece sp. ATCC 51142 and Crocosphaera watsonii WH8501, and the undi erentiated lamentous Plectonema boryanum UTEX 594, the two functions are temporally separated by a circadian rhythm: the oxygen-sensitive N 2 xation is performed during the night, unhindered by the oxygen-producing photosynthesis during the day.
In addition, a large likelihood ratio would favor the more complex model while a small likelihood ratio would favor the simpler model. For this specific dataset, model 2 was favored over model 1 by both the above criteria. The model was able to capture accurately the global parasite dynamics across the blood and adipose tissue over 28 days (Fig. 2B  and Supplementary Model Information). Further adding an extra layer of complexity, by allowing variation of the differentiation parameter across the two compartments (model 3), produced largely overlapping estimates for these infection traits in blood and adipose tissue and did not significantly improve the model fit (Supplementary Table  S3 ). The key parameter change between the null model 1 and favored model 2 is the difference in parasite growth rates between the two compartments.
Proteome analysis suggests downregulated protein translation in ATFs To experimentally validate the model prediction that slender forms in the adipose tissue grow twice longer than in the blood, we started by comparing the proteome of slender forms isolated from blood and gonadal adipose tissue. Given that the proteome of stumpy and slender forms is different  17  , and stumpy forms are present in unequal amounts in the two tissues, we chose to infect mice with a monomorphic strain, which does not form stumpy forms. Five days post-infection, parasites were isolated from blood and adipose tissue and processed for proteome analysis. We identified a total of 2693 protein groups among ATF and BSF parasites (Supplementary Dataset S1), from which 6% were differentially expressed, namely, 54 protein groups were upregulated and 112 protein groups were downregulated in the ATFs (Fig.
3A ). The relative abundances of the differentially expressed protein groups showed high consistency between replicates (Fig. 3B ), suggesting that the differences detected between ATF and BSF parasites are reproducible between infections in different animals. To identify which processes may be downregulated in ATFs, we performed a Gene Ontology (GO) term enrichment analysis of the downregulated proteins (Fisher's exact test, p≤0. 05). The biological process ontology showed significant depletion of two GO terms, namely, translation and ribosome biogenesis (Supplementary Table  S4 ). Among those, the most significant alteration that took place in ATFs was the down-regulation of proteins involved in translation (Fig. 3C  and Supplementary Dataset S1 and Table  S4 ). 96 ribosomal proteins of 208 annotated protein groups within this GO term were down-regulated in the ATF proteome.
Ribosome biogenesis, a pivotal process for protein translation was also diminished. A curated analysis of the proteins revealed that multiple ribosomal proteins of both 40S and 60S ribosomal subunits were downregulated. Interestingly, despite not annotated to any of the obtained GO terms, the second largest subunit of the RNA polymerase I was also downregulated (Tb927. 11. 630, fold change of 0. 5) suggesting a lower transcription of ribosomal gene units (Supplementary Dataset S1 and Table  S4 ). These data strongly suggest that ATFs undergo a generalized reduction in the machinery responsible for synthesizing proteins. GO term analysis of the proteins upregulated in ATFs (Supplementary Table  S4 ) suggests that these parasites are metabolically distinct from BSFs, which is consistent with our previous transcriptomic and biochemical characterization 8.
Interestingly, the most significant category of upregulated proteins comprised purine metabolism (5 of the 54 upregulated protein groups) (Fig. 3C ). The upregulation of the purine nucleoside transporter, with high affinity for adenosine, and adenosine transporter 2 ((Tb927. 9. 7470 and Tb927. 2. 6150, respectively, fold change 6. 8), together with inosine-adenosine-guanosine-nucleosidehydrolase (Tb927. 3. 2960, fold change 1. 8) and adenine phosphoribosyltransferase (Tb927. 7. 1780, fold change 2. 0) (Fig. 3C  and Supplementary, Dataset S1 and Table  S4 ), could culminate in increased cellular levels of adenosine monophosphate (AMP) and consequently stimulate the ATP production and/or affect the AMP/ATP ratio. Mitochondrial pathways involved in central metabolism are also upregulated in ATFs with evidence in the proteome of upregulated enzymatic reactions involved in ATP metabolism (13 of the 54 upregulated genes).
1, respectively) (Supplementary Dataset S1). It is noteworthy that the proline degradation pathway, which includes the upregulated delta-1-pyrroline-5-carboxylate dehydrogenase (Tb927. 10. 3210, fold change 1. 9), also produces glutamate that can then be converted into α-ketoglutarate as well. In addition, the proteome of ATFs suggested a concomitant expanded use by the mitochondrial F1/FO-ATP synthase of the ATP produced in the mitochondrion. Indeed, the absent expression of any component of the oxidative phosphorylation pathway together with the increased expression levels of four mitochondrial F1/FO-ATP-synthase subunits pointed towards a reverse mode of action with a concomitant ATP hydrolyzation in these parasite forms. Namely, the F1 complex subunit gamma (Tb927. 10. 180, fold change 1.
7), the FO complex subunit B (Tb927. 5. 1710, fold change of 1. 8), the subunit 5 (Tb927. 10. 8030, fold change 1. 6) and the putative ATP synthase subunit (Tb927. 5. 3090, fold change 2. 3) (Supplementary Dataset S1) of the mitochondrial F1/FO-ATP-synthase showed increased expression levels. Curiously, evidence for an increased oxidative stress response was also observed in the adipose tissue parasites (oxidation-reduction process group) (Fig. 3C ), with the upregulation of iron/ascorbate oxidoreductase family protein and iron superoxide dismutase A (Tb11. v5. 0215 and Tb927. 5. 3350, fold changes 6. 3 and 1. 8, respectively) (Supplementary Dataset S1), probably as part of the adaptation process to the new environment. In summary, the proteome analysis revealed that the slender forms that live in the adipose tissue and blood present significantly different proteomes.
Model 2, for instance, predicts a migration rate of about 0. 11 cells/mg/day suggesting that, per milligram of organ, each day about 11% of blood parasites leave to the adipose tissue and vice-versa (0. 005 per hour). This observation is in line with previously estimated migration rates between blood and organs of mice infected with Salmonella enterica (0. 005 per hour)  31. Similarly, the lower bound for the ratio between slender vs stumpy cells killing rates, estimated by the joint posterior of this model in the interval 6. 5-24, also falls within the reported estimated range 5-7  32  , although we find more uncertainty with this dataset. The remaining parameter estimates are similar between models and approximate existing values in the literature (e. g. antigen switching rate)  13, 30. Naturally, the space for modeling is infinite, but including additional complexity is a stepwise process, ideally backed by different and incremental sources of data.
Further, the two in-host compartments, blood and adipose tissue, were connected through migration, assumed to occur at the same rate in either direction and for all cells. All variants were assumed symmetric, in their parameters, including the switch rate to the next wave. The majority of parameters were estimated by fitting the model to the dynamic data; with exception of a few such as, the stumpy cell lifespan which was fixed at about 2 days  13  (Supplementary Model Information for detailed description on model structure and biological assumptions). Model fitting to data was performed under a Bayesian framework, using the adaptive Monte Carlo Markov chain mcmcstat package in Matlab 44. To compare hypotheses, Deviance Information Criterion (DIC)  14  , the posterior error distribution and marginal likelihood  15  were computed for each model, and the quality of fits to data and feasibility of parameters were inspected.
Proteomics Mice infected for 5 days were sacrificed and parasite isolation from blood and adipose tissue was performed as described above. Parasites were washed in Creeks Minimal Medium depleted from Fetal Bovine Serum and lysed with 1X LDS Buffer supplemented with 100mM Dithiothreitol (DTT) by boiling at 80ºC for 15 minutes. Parasites isolated from up to 6 mice were pooled to obtain a minimum of 0. 32 million parasites. Protein samples were then separated, prepared and measured as in  45  except for the peptide elution. This step was performed with a 200 minutes optimized gradient from 2 to 40% acetonitrile with 0. 1% formic acid at a flow rate of 225nL/min. Protein quantification was processed in MaxQuant version 1. 6. 7. 0 46 using standard settings. The raw proteomics files were searched against the protein databases of T.
brucei TREU927 (TriTrypDB version 33), Mus musculus strain C57BL/6J (UniProt), the 14 VSGs of the Lister 427 T. brucei strain (UniProt) and the contaminants database included in MaxQuant. Contaminants, reverse Protein Groups (PGs) and PGs only identified by a modification site or by less than 2 peptides (of which 1 needed to be unique) were removed as well as M. musculus identified proteins. To assign a quantification to missing values, these were imputed 1000 times using a β-distribution with equal shape parameters (α=β=2) and a PG was only considered differentially regulated if it was found up or downregulated in at least 99% of times. For each individual replicate, the obtained distribution was scaled between 0. 1 and 1. 5 percentile of the log2 transformed measured label-free quantitation (LFQ) intensity values.
Finally, only the PGs that were quantified by LFQ intensity in at least 2 replicates of one condition (ATFs or BSFs) were considered for further analysis. Regulated PGs were determined if the relationship between the significance of the Welch's t-test and their fold-change was above a threshold defined by a reciprocal function (with limits p-value=0. 05 and fold change=1. 5). The GO term enrichment analysis was performed in R with GO. db annotation package  47  from Bioconductor and Fisher's Exact Test (p-value ≤ 0. 05) from stats package. T. brucei TREU927 GO term annotations were obtained from TriTrypDB and GO term enrichment was assessed. PGs were associated with the GO terms of the individual genes in the group and a GO term enrichment test was performed separately on upregulated and downregulated gene.
Acknowledgments The authors thank  Keith Matthews  ( University of Edinburgh ) for providing AnTat1. 1Eclone,  Christian Janzen  ( University of Wurzburg ) for the GFP::PAD1utr cell line,  Ruy M. Ribeiro  for useful discussions about the statistical analysis and  Helena Pinheiro  for drawing the diagram of the mathematical infection model. The authors would like to acknowledge the  Rodents, Bioimaging and Flow Citometry Units of the Instituto de Medicina Molecular  and all members of the L. M. F. lab. This work was supported by  IC&DT Programa de Actividades Conjuntas -ref. 016417 "Oneida", 771714 (ERC)  and  029161  (FCT),  SFRH/BPD/89833/2012  (FCT) to S. T,  LT000047/2019-L (HFSP)  and  ALTF 1048-2016  (EMBO) to M. D. N,  IMM/BI/83-2017  ( FCT individual fellowship , project number  PTDC/BIM-MET/4471/2014 ) to T.
Athletes' inclusion All athletes who underwent an MRI of the following peripheral joints during the 2016 Summer Olympic games were included in this study: shoulder, elbow, wrist, hip, knee, and ankle. Athletes were imaged for a multitude of reasons but had an MRI mainly for suspected structural damage following acute trauma or non-traumatic joint pain. MRIs were performed at the Polyclinic located within the IOC Olympic Village using two MR scanners (3. 0-T Discovery MR750w and 1. 5-T Optima 450 MRw; GE Healthcare, Brazil). Imaging data were collected retrospectively from the Centricity Radiological Information System and Picture Archiving and Communication System, both of which were provided by GE Healthcare. These data were stratified according to sex, age, type of sport, and peripheral joint.
The data remained confidential and were deidentified in the medical database after the games. Our study was approved by the medical research ethics committee of the South-Eastern Norway Regional Health Authority (S-07196C). Because the information in this study was anonymized and deidentified, the need for informed consent was waived. The International Olympic Committee granted approval to use the anonymized imaging and demographic data for publication. An additional institutional review board approval was obtained from Boston University (H-36593). The athletes' information was collected, stored, and analyzed in strict compliance with data protection and confidentiality.