dataesr/scientific-paragraphs-categorization huggingface dataset:
Analysis with LINC00460 predicted an increased OS in the TNBC GEO derived cohort GSE16446 (using all TNBC samples; n= 107; HR = 0. 26; 95% CI [0. 09 -0. 72]; logrank p = 0. 0053) (Figure  5D ). To further characterize LINC00460 association with aggressive BRCA, we analyzed its expression in Lehman refined triple negative breast cancer classification (TNBCtype4) (Figure  6A ). We observed a significant LINC00460 enrichment in the Basal-like 2 (BL2) subtype (n= 135, Jonckheere-Terpstra test for ordered variables; p=0. 026) in a Chinese BRCA cohort (GSE76250). LINC00460 high expression level is also able to predict a favorable clinical response in BL2 triple negative BRCA GEO cohorts, both in OS (n=28; logrank, p=0. 0062; Figure  6B ) and RFS (n= 52; logrank, p=0. 04; Figure  6C ). Altogether, these observations suggest that LINC00460 expression is generally related to intrinsically aggressive tumor phenotypes, as shown for HNSC, LUSC, LUAD, KIRC and basallike BRCA (Figure  2  and Supplementary Figures  S3, 4 ).
Furthermore, Ingenuity Pathway Analysis revealed that the proliferation process was negatively enriched in the high LINC00460 group (z score= -0. 513). Cellular migration, adhesion, cell cycle progression and proliferation were also enriched in these BRCA samples, although no z-score enrichment was detected in these pathways (see Figure  7B ). This data pinpoints the role of LINC00460 as a potential regulator of transcripts and cellular cancer-related processes like proliferation, migration and cell proliferation in BRCA. 4 ). Some of these transcripts are classic cancer-related, such as WNT7A, SFRP5, FOSL1, IFNK, CSF2, DUSP7 and IL1A.
Differential expression analysis was performed in TCGA BRCA Overrepresentation Enrichment Analysis (ORA) showed that WNT signaling pathway, cytokine inflammatory response, fluoropyrimidine activity pathway and photodynamic therapyinduced NF-kB survival signaling are enriched in LINC00460 over-expressed BRCA samples (Figure  7C ). In addition, we observed that 73% (61/84) of the BRCA Mexican cohort samples displayed high levels of stromal TILs (see Table  1 ). Analyzing the LINC00460 co-expressed genes list, we observed that similar genes had been previously identified as enriched in Lehman's TNBC subtypes (77) (Supplementary Table  S3 ). Altogether, these enrichment data suggests that LINC00460 is potentially related with inflammatory pathways and might partially explain its effect in good prognosis prediction in BRCA.
In contrast, analysis with LINC00460:KRTAP11-1 ratio did not retrieve any significant survival effect (data not shown). Survival analysis using the mature sequence of miR-103-a-1 (hsa-miR-103a), showed a marginal, non-significant association between overexpression of the of miR-103-a-1 and decreased survival in TCGA TNBC cohort (n=97, logrank p=0. 059; Supplementary Figure  S7 ). Taken together, these data show that the expression ratio of two genes, LINC00460:WNT7A is a composite marker that accurately predicts Basal-like BRCA OS and DMFS. Furthermore, we identified that the combination of LINC00460 and WNT7A overexpression is significantly associated with pathological complete response (pCR) after anthracycline therapy in ER-BRCA patients (n= 665, Mann-Whitney U test p= 0. 0047) (Figure  8C ).
Finally, we sought to investigate if some of the potential candidate genes would have a combinatorial role for OS and therapy response in basal-like BRCA. We found that LINC00460 was deregulated in seven different tumor types in the TCGA database, including two not previously reported tumors, namely LGG and GBM. We have also confirmed LINC00460 deregulation in BRCA using two independent cohorts. Interestingly, LINC00460 expression is associated with clinically aggressive tumors, such advanced stage LUAD, LUSC and KIRC, high histology grade in KIRC, HPV-negative HNSC and basal-like BRCA, suggesting an important role of LINC00460 in the progression or intrinsically aggressiveness of these tumors. Indeed, it has been previously shown that LINC00460 expression can promote cancer progression  (34, 35, 38, 50) , metastasis  (36)  and influences therapy response  (79).
Several reports show that LINC00460 is a marker for poor OS prognosis across different tumors, such as CESC  (48) , HNSC  (80) , KIRC  (81) , LUAD  (49)  and PAAD  (82). In addition, we describe here that LINC00460 high expression is significantly associated with poor survival in three different tumors (GBM, LGG and SARC) but related with a favorable survival rate in BRCA, i. e. , its association to clinical outcome varies between tumors. This data suggests that the expression levels and its impact on OS, RFS or DMFS may be tissuespecific. Indeed, it has previously been shown that the same lncRNA may exert dual prognostic roles in distinct tumors. For example, high MALAT-1 expression has been reported as a marker for poor prognosis in various tumors, including COAD, NSCLC, STAD, PAAD, ESCA, among others  (83) , but also as a good prognosis factor for BRCA, acting as a metastasis suppressor  (84).
Altogether, these data suggest that of miR-103-a-1 is a marker for poor prognosis in several tumors, including BRCA. To the best of our knowledge, this is the first report that suggests a potential connection between LINC00460, WNT7A and miR-103-a-1. Future research must elucidate the exact mechanisms involved in this potential 3gene network, and its impact in basal-like BRCA biology. In conclusion, LINC00460 expression is a dual potential marker for aggressive phenotypes and poor clinical outcome in distinct tumors, including HNSC, KIRC LUSC and LUAD, that is also associated with increased prognosis in basal-like BRCA. LINC00460 is enriched in BL2 TNBC, and potentially regulates the WNT differentiation pathway. LINC00460 can also modulate a plethora of immunogenic related genes in BRCA, such as SFRP5, FOSL1, IFNK, CSF2, DUSP7 and IL1A and interacts with miR-103-a-1, in-silico, which, in turn, can no longer target WNT7A.
LINC00460:WNT7A ratio is a composite marker that can predict a favorable OS and DMFS in TNBC, and combination of LINC00460 and WNT7A over-expression is associated with complete pathological response (pCR) after anthracycline therapy in ER-BRCA patients. This data confirms that LINC00460 is a master regulator in BRCA molecular circuits and influences clinical outcome. Diseases, FUCAM (Registration number: CE2009/11). The patients/participants provided their written informed consent to participate in this study.
Imagining quantification Image analyzes were performed using the Fiji software. For Arabidopsis confocal imaging, different ratios were defined to characterize the subcellular localization of proteins according to the repartition of the fluorescent signal intensity in cells as previously described  (Platre et al, 2018). Fluorescent intensity of a region of interest (ROI) in pictures was evaluated by the measure of the mean gray value of pixels using the Mean Grey Value function of Fiji software. The ratio of fluorescence PM/cyto was measured on the root cells tips and corresponds to a ratio between the intensity of the fluorescent signal at the level of the plasma membrane (PM) and the intensity of the fluorescent signal at the level of the cytosol (cyto). Per cell, two linear ROI measurements were done (one per cell side) at the level of the plasma membrane and at the level of the cytosol, using the Measure function of software and mean between the both measurements was done.
For the transgenic line analyzes, the measurements were carried out on at least five independent lines with the measurement of twenty cells per root tip on at least three different roots per line. For the pharmacological analyzes, the measurements were carried out on three independent experiments, with the measurement of twenty cells per root tips on at least five roots per experiment. The fluorescence ratio endo-PM/PM were measured in mature pollen. It corresponds to a ratio between the intensity of fluorescent signal at the level of the endo-PM and the intensity of the fluorescent signal at the PM level. All pictures for a same experiment were acquired in same microscope setup. For the immunogold labelling quantifications, full sperm cell pictures were reconstituted using the Adobe® Photoshop® software.
Statistical analyzes Statistical analyzes were performed with the RStudio® software. Comparisons of the fluorescence intensity between different samples were performed using the non-parametric Wilcoxon-Mann-Whitney test. Comparison of two different proportions were performed using the chi-square test. Confocal imaging (Z-stack projection) of mature pollen expressing pNLD::NLD:mCitrine and pNLD::H2B5:mCherry constructs shows that NLD:mCitrine protein localizes at the MGU, whereas the promoter activity is found in the nucleus of the vegetative cell. D -G Following of sperm cells released from mature pollen of pTUBα::YFP:TUBα (D,F) and pNLD::NLD:mCitrine (E,G) lines after osmotic choc (D,E) and sperm cell isolation using Percoll gradient (F,G). YFP:TUBα fusion protein is localized inside the sperm cells, while NLD:mCitrine fusion protein is not detected inside isolated sperm cells.
Acknowledgements We thank  Y. Jaillais  and  M. Platre  for discussions and comments,  G. Brunoud ,  T. Dresselhaus  and  Y. Jaillais  for providing transgenic lines,  O. Hamant  and  Y. Jaillais  for critical reading of the manuscript. We are grateful to  G. Gendrot ,  M. -F. Gérentes  and  J. Laplaige  for maize transformation, to  J. Berger ,  P. Bolland  and  A. Lacroix  for maize culture, to  I. Desbouchages  and  H. Leyral  for buffer and media preparation, and to  J. Guichard  for technical assistance. Sample preparation, immuno-electron microscopy experiments as well as transmission electron microscopy observations were performed at the  Centre Technologique des Microstructures (CTµ). We acknowledge the contribution of  SFR Biosciences  ( UMS3444/CNRS ,  US8/Inserm ,  ENS de Lyon, UCBL)  facilities, and in particular  C.
Lionnet  at the  LBI-PLATIM-MICROSCOPY  for assistance with imaging. This research was supported by the  ANR  grant ( ANR-19-CE20-0012 , "Not -Like-Dad ") to T. W. , and by the "pack ambition recherche" from the  Région Auvergne-Rhone-Alpes  (" DH-INNOV ") to T. W. N. M. A. J. and L. M. G. were supported by  CIFRE PhD fellowships  from  ANRT  funding agency (grant #  2019/0771  and  2015/0777 , respectively).
Background In 40-65% of patients presenting with acute ST-segment elevation myocardial infarction (STEMI), additional angiographic significant lesions (i. e. > 50% diameter stenosis) may exist in non-culprit vessels  [1] [2] [3] [4] [5]. The presence of multivessel disease (MVD) in these patients is an important predictor of short-term as well as long-term mortality after primary percutaneous coronary intervention (PCI) compared with patients with single-vessel disease (1-VD)  [1] [2] [3] [4] [5]. Several sources, including registries specific to acute myocardial infarction (AMI) and large administrative or billing databases, have shown a decrease in mortality in patients with STEMI over the last 20 years  [6] [7] [8] [9] [10] [11] [12] [13] [14] [15]. The decline in short-and long-term mortality in these patients is explained by several factors, including: increased use and improved delivery of reperfusion therapy, particularly primary PCI; temporal changes in patient population characteristics; and increased use and improved delivery of recommended secondary prevention  [6] [7] [8] [9] [10] [11] [12] [13] [14] [15].
FAST-MI registries Three nationwide French registries were conducted 5 years apart over a 10-year period  (2005) (2006) (2007) (2008) (2009) (2010) (2011) (2012) (2013) (2014) (2015) : French registry of Acute ST-elevation or non-ST-elevation Myocardial Infarction (FAST-MI) 2005 (ClinicalTrials. gov identifier: NCT00673036)  [16] , FAST-MI 2010 (ClinicalTrials. gov identifier: NCT01237418)  [17]  and FAST-MI 2015 (ClinicalTrials. gov identifier: NCT02566200)  [18]  (Appendix). The methods used for these registries have been detailed previously  [16] [17] [18] ; briefly, their primary objectives were to evaluate the characteristics, management and outcomes of patients with AMI, as seen in routine clinical practice, on a countrywide scale. All registries consecutively included patients with STEMI or non-ST-segment elevation myocardial infarction admitted to cardiac intensive care units within 48 hours of symptom onset, during a specified 1-month period (October to December 2005, 2010, and 2015).
e. 1-VD versus two-vessel disease [2-VD] versus three-vessel disease ). Multivessel CAD was defined as 2-VD or 3-VD. Procedural success for the culprit lesion was defined as a final Thrombolysis In Myocardial Infarction (TIMI) flow of 2 or 3 after PCI, whereas failure was defined as a final TIMI flow of 0 or 1 (data available in 3576/3907 patients). Finally, complete myocardial revascularization was defined by successful PCI of the culprit lesion and all non-culprit lesions (i. e. restoration of blood supply to the myocardium), achieved before discharge. Patient characteristics, management and outcomes were analysed according to coronary status (i. e. 1-VD versus 2-VD versus 3-VD). The primary endpoint of the study was survival at 3 years.
Data collection Data on baseline characteristics, including demographics, risk factors and medical history, were collected as described previously  [16] [17] [18]. Information on the use of cardiac procedures, including the use of PCI and the use of medications (anticoagulants, antiplatelet agents, diuretics, beta-blockers, angiotensin-converting enzyme inhibitors or angiotensin receptor blockers and lipid-lowering agents) in the first 48 hours and at hospital discharge, was collected. For all surveys, follow-up was centralized at the French Society of Cardiology. Three-year mortality follow-up was > 97% complete.
Procedural success and complete myocardial revascularization were added in a second model, including four groups: 1-VD with successful PCI; MVD with complete revascularization before discharge; MVD without complete revascularization before discharge; and primary PCI failure. A sensitivity analysis was performed in the population surviving the index hospitalization. Analyses were repeated using forward stepwise analysis to check the consistency of the results. Statistical analyses were performed using IBM SPSS Statistics, version 26. 0 (IBM SPSS Inc. , Chicago, IL, USA). For all analyses, two-sided P values < 0. 05 were considered significant. Briefly, out of 13,130 patients enrolled in the FAST-MI registries, 3907 patients with STEMI undergoing PCI within 24 hours of symptoms onset with available medical information were enrolled for the present analysis.
Improvement in survival among patients with STEMI Over the last 25 years, several registries specific to AMI and large administrative or billing databases have shown a decrease in mortality in patients with STEMI  [6] [7] [8] [9] [10] [11] [12] [13] [14] [15]. Most benefits in short-and long-term outcomes in patients with STEMI were related to the uptake and increased use of new and, in time, established interventional and medical treatments  [5]. Improvement in hospital survival was mainly related to the increased use of reperfusion treatment, including primary PCI, although the reduction in mortality was also associated with a substantial change in the patient risk profile  [10]. Improved survival among patients with STEMI has been reported in all categories of patients over the last 25 years  [6] [7] [8] [9] [10] [11] [12] [13] [14] [15].
Our observational data suggest that complete revascularization performed before discharge is probably preferable to subsequent scheduled PCI of significantly narrowed nonculprit lesions. On the other hand, the International Study of Comparative Health Effectiveness with Medical and Invasive Approaches (ISCHEMIA) did not find evidence that the initial invasive strategy reduced the risk of ischaemic cardiovascular events or death from any cause  [25]. These data were obtained in patients with coronary chronic syndrome and moderate or severe ischaemia (i. e. not in patients with recent myocardial infarction).
Fluoroquinolones efficacy depend on both the drug exposure and the level of drug resistance of the bacteria responsible for the infection. Specifically for the Staphylococcus species, which is the microorganism mainly involved in osteoarticular infections (OAI), in-vitro data reported that an AUC/MIC ratio above 115 h maximizes drug efficacy. However, data on OAI patients are lacking and a simple approach to access AUCs is still a clinical issue. We conducted a prospective, single-center study in 30 OAI patients hospitalized in the Rennes University Hospital to model ofloxacin pharmacokinetics and to define a limited sampling strategy (LSS) suitable for ofloxacin and levofloxacin treatments. Modeling was conducted with the Monolix software. The final model was externally validated using levofloxacin data.
Study population and design This prospective, single-center study included 30 patients hospitalized in Rennes University Hospital between June 2015 and December 2016. The inclusion criteria were an age over 18 years and a Staphylococcus sp. OAI treated with oral ofloxacin in line with French recommendations  [8, 9] , 200 mg twice daily (BID) or 200 mg three times daily (TID). All patients gave written informed consent. The FLUO-POP study (NCT02357407) was approved by the regulatory and ethics committee (ANSM 141294A-41 and CPP Ouest V 2014-004193-41) and was conducted in accordance with the declaration of Helsinki.
For the residual error model, additive, proportional and mixed additive-proportional models were investigated. For the structural model, one-and two-compartment models were investigated, with first-order elimination or nonlinear elimination process (Michaelis-Menten). Various absorption models were tested. Complex absorption models, including first-order absorption followed by zero-order absorption and zero-order absorption followed by firstorder absorption, were also tested. Parameters were estimated using the Stochastic Approximation Expectation Maximization (SAEM) algorithm implemented in the Monolix software (Monolix 2019R1)  [11].
External evaluation The final model was then externally evaluated using 211 additional samples of levofloxacin from the BDDLEVO study (Local ethics committee AP-HP. 5, IRB registration # 00011928). Plasma concentrations were predicted by fixing the population parameters in the structural and variance model to the estimates in the final model and using Monolix to estimate the individual parameters. Goodness of fit was verified by plotting the IPREDs against the observed concentrations and evaluating the residuals as described above. The relative bias and precision were also computed for the external dataset.
Limited sampling strategy (LSS) Developing a LSS using a Bayesian approach allows using the final model as a clinical tool to accurately predict AUC between doses through a limited number of samples. A Bayesian approach based on the final model was chosen because it allows a change in covariate values, dosing regimen and sampling times, which is essential in a clinical use. Using the final model, we used the Simulx package in R to simulate 1000 plasma concentrations profiles at 0, 0. 5, 1, 1. 5, 2, 2. 5, 3, 3. 5 and 4 h. The covariates entering the final model were simulated according to the distribution in the original dataset. Because our objective was to limit the number of samples to 3 samples or less, we then generated datasets including 1, 2 or 3 concentrations among these simulated profile, testing all possible combinations respecting clinical constraints.
For each combination of sampling times, we used the model and estimated population parameters to obtain individual Bayesian estimates for each individual in the simulated dataset by fixing the population estimates. We used the estimated clearance to predict the model-based AUC for each subject (AUC pred ) and compared it to the AUC computed using the true (simulated) parameters (AUC obs ), in both cases using the formula AUC=Dose/CL with the corresponding CL. We then selected the combination of times providing the best agreement between predicted and simulated AUC, as measured by the R 2 adjusted (with an objective of > 90%) and the lowest rate of outliers. The predictive performance of LSS was also evaluated using bias (MPE) and precision (RMSE). A plot of observed versus predicted concentrations was inspected and a Bland-Altman plot was used to compare AUC obs and AUC pred.
Model evaluation Graphically, the model appeared adequate with no trend in the distribution of the residuals (Fig. 1 ). Visual predictive checks for BID and TID regimens showed values within the prediction interval with a slight overestimation of the 10th percentile for the BID regimen (Fig. 2 ). Best and worst individual adjustments are presented in Fig. S1. We considered that the shrinkage was low enough (<40%) for graphs based on individual predictions to remain informative. The mean relative bias was -0. 12 and -1. 3% for the concentration and AUC values, respectively, and 2. 0% and 7. 1% for their accuracy. An external validation was conducted on the independent dataset composed of 211 levofloxacin plasma concentrations measured in OAI patients. Model performance for levofloxacin was good, with mean relative bias and precision for concentrations of -0.
The second study aimed at modeling levofloxacin in bone and joint infections to evaluate the current dosage recommendation of 750 mg QD  [19]. Glomerular filtration rate estimated through the CKD-EPI formula and age were the two covariates explaining drug clearance variability in that model. As ofloxacin and levofloxacin are mainly renally excreted, renal function is expected to impact drug clearance. Again, because routine data were used in that work, the pharmacokinetic sampling scheme was sparse with only 4 time-points, resulting in a one-compartment model selected, in line with the limited number of samples during the elimination phase. This model was not externally validated which is another difference with our work. Considering ofloxacin only, two models focused on the drug, both in   tuberculosis  [14, 20].
09 to 1. 8  [22]. We choose our bone:plasma diffusion ratios hypothesis based on concurring data reported for ofloxacin and levofloxacin with lower ratios found for cortical bone while diffusion in cancellous bone is reported to range from 50% to 100%  [12, 23, 24]. In absence of any definitive conclusion, the choice of target should be driven by infection location and according to the clinical settings. Finally, the complete sampling scheme while being limited to 3 h can be seen as a long stay in the outpatient phase of infection management but this relatively time-consuming approach has to be balanced with the benefit of maximizing efficacy and minimizing the risk of adverse events onset by individually adjusting FQs to AUC/MIC ratio. One important advantage of our model is its robustness, demonstrated by the external validation on a separate dataset, and its ability to offer a convenient tool for both ofloxacin and levofloxacin treatments.
Likewise, a large-scale untargeted quantitative and comprehensive analysis of the molecular alterations in the kidney proteome could provide a dataset of shared interest for understanding the mechanisms underlying the development of LBW-related nephropathy. However, the omics of LBW kidneys remain unknown, and no dataset is available for performing pathway and biomarker analyses. In particular, the bioinformatic study of proteome changes could allow for prediction of the putative transcription factors, kinases or microRNAs involved in the observed changes based on the detailed knowledge of their targets and directionality of the expected changes in target expression. We recently used this predictive strategy to discover the role of various genetic regulators in different disease contexts  [16] [17] [18] [19].