dataesr/scientific-paragraphs-categorization huggingface dataset:
Future work includes the overall validation of the integrated InDeal system following the aforementioned 5-step methodology (as presented in Section 3). The consortium also plans to validate the robustness of the proposed approach over a number of uncertainties associated with exogenous factors. To achieve this, the effect of the weather and energy demand forecasting error on the control performance will be assessed through the use of stochastic controllers' variants. The AI-based energy storage modeling module will be integrated within the controller as a means to capture the current storage capacity of the DH network. Future directions also include the application of the energy storage modelling not only to quantify the current capacity of the energy storage tank but also predict its future capacity within a time horizon of a few days.
Recruitment Volunteer competitive squash players were recruited with a study flyer posted on a local Web-based squash association newsletter. The inclusion criteria were as follows: (1) male, (2) aged 18 years or older, (3) no prior wrist surgery or injury, (4) English-speaking, and (5) a minimum of 5 years of playing experience. Only male subjects were recruited to reduce the risk of data variability, as previous work had demonstrated a difference in the magnitude and direction of wrist quasi-stiffness between the male and female sex  [14] [15] [16] [17]. Subjects were asked not to participate in any upper limb exercise in the 24 hours preceding their evaluation session to decrease the risk of reduced wrist ROM because of muscle swelling  [11]  and muscle thixotropic behavior  [23]  associated with eccentric wrist exercise.
The sample subject group had a mean of 20. 6 years of squash playing experience (range 10-53 years, SD 13. 85), a USRSL of 4. 2 (range 3-5. 5, SD 0. 94-possible ranking ranges from 2 to 6, with 6 being the highest ranking), and reported playing between 2 and 5 times per week (median=4, mode=4). A total of 4 subjects were enrolled in the young squash group (mean age 30. 75, SD 8. 06 years), and 3 subjects were enrolled in the older squash group (mean age 64. 67, SD 6. 35 years). The Massachusetts Institute of Technology Committee on the Use of Humans as Experimental Subjects approved the study, with all volunteers providing written informed consent before participation. Data from 7 right-hand dominant males (mean age 28. 57, SD 12. 11, range 19-55 years) reported in the study by Durand et al  [17]  (using the same experimental set-up) were used to compare wrist quasi-stiffness of unskilled subjects with the subjects participating in this trial who participate in regular, intensive, unilateral upper limb activity.
The fitting ellipse method (Figure  2 ) calculates the torque and angular displacement parallel and perpendicular to the direction of each of the 36 perturbations. Stiffness was then estimated (separately for outbound and inbound movements) by running a linear regression of the torque and the angle parallel to the perturbation direction. The mean stiffness values for the estimates of each of the outbound and inbound 36 perturbation directions were then used to fit a stiffness ellipse. Previous research indicates that the major weakness of the fitting ellipse approach is that it only considers the components of torque and angle parallel to the perturbation direction and does not include stiffness effects perpendicular to the perturbation direction. Of note, the fitting ellipse method allows for asymmetry of the elastic field with respect to the neutral position and is susceptible to data noise  [17].
Although we fitted the stiffness values with a least square condition to keep consistent ellipse shapes, an excessive stiffness value along 1 direction will tend to stretch the ellipse and increase the size of the ellipse. The MR method (Figure  2 ) determines the 4 elements of the stiffness matrix by multiple linear regression (using MATLAB's regress function  [26] ). Separate stiffness matrices were estimated for the inbound, outbound, and the composite of both movements. Each matrix was separated into the symmetric and asymmetric parts. Only the symmetric part of each stiffness matrix was displayed as a stiffness ellipse  [28]. A 1-sample Kolmogorov-Smirnov test was used to confirm the normal distribution of the data. A 1-way analysis of variance was calculated to determine the statistical difference between the wrist quasi-stiffness of the left and the right arm in the young and older squash player groups and to compare the magnitude of the wrist quasi-stiffness and orientation of the 4 young squash players with the results of the 7 young right-handed dominant, unskilled male subjects  [17].
Experimental Procedure Subject demographics were collected in the form of an interview (Table  1 ). The experiment commenced randomly with the left or right upper limb (using the MATLAB randi X function, MathWorks, Natick, 2016, MA)  [26]. The reference position for the upper limb was in keeping with the set-up of Durand et al  [17]  and Drake and Charles  [14]  to allow accurate analysis and comparison of study results; the elbow was flexed to 30°, the third metacarpal was aligned with the forearm, and the wrist was positioned in 0° wrist extension and 7° of ulnar deviation (UD). Although previous studies have used an almost neutral RUD wrist position (0° along wrist UD), this study and Durand et al  [17]  deliberately selected 7° of wrist UD as this initial wrist position was more comfortable, allowing subjects to remain in a passive muscle state and avoid unwanted muscle activity.
The wrist and forearm position was verified with goniometry  [27]. Hand grip remained relaxed and the forearm in a neutral position by wrapping a strap over the fingers, securing the hand to the Wrist Robot handle. Subjects were instructed to remain relaxed throughout the experiment, which was monitored by palpating the muscle groups responsible for wrist FE-RUD and checking the data collected between trials. The robot applied a torque of up to 1. 95 Nm to reach a predefined target (from 0-20° along each direction defined through the 2D FE-RUD space) at a predefined speed (between 0. 1 and 0. 2 rad/s to inhibit muscle reflexes). Data were collected at a rate of 200 Hz. Each trial consisted of 36 movements (inbound and outbound movements) along 12 equally spaced directions through the space defined by FE-RUD.
Statistical Analysis Torque and displacement data were processed using a customized program in MATLAB 2016b  [26]. Data collected before commencing each trial of 36 movements were removed, knowing the time to complete each movement, the number of movements, and the acquisition frequency. The processed data were then applied to 2 different estimation methods, the fitting ellipse  [16]  and the multiple regression (MR) method  [28] , to obtain wrist stiffness magnitude and orientation among the 4 parameters commonly used (listed below) to characterize a stiffness ellipse  [16, 28]  Figure  2. (a) The fitting ellipse method, where variable τ represents torque, 'j' corresponds to 1 of the 12 directions considered through the FE-RUD plane, || means parallel to the wrist movement direction, and ⊥ means perpendicular to this direction.
Concomitant use of therapeutic anticoagulation with a vitamin K antagonist or with heparin, potent CYP3A4 inducers, and aspirin >100mg daily were prohibited. Patients were recruited at the Dana Farber/Harvard Cancer Center, and the protocol was approved by the Partners Institutional Review Board. The trial was conducted in accordance to the ethical guidelines of the Declaration of Helsinki. All patients provided written informed consent before study participation (NCT01775501).
Response was determined by an independent radiologic review using Response Evaluation Criteria in Solid Tumor (RECIST) version 1. 1 and modified RECIST (mRECIST), and patients continued treatment until disease progression, unacceptable toxicity, withdrawal of consent, or physician decision to discontinue. Patients were monitored for safety weekly for the first 7 weeks and then every other week thereafter. Safety evaluations included vital signs, physical exam, performance status evaluation, complete blood count, blood chemistries, coagulation studies, amylase, lipase, uric acid, lactate dehydrogenase, urinalyses, and electrocardiograms. Adverse events (AEs) were assessed according to the National Cancer Institute Common Toxicity Criteria for Adverse Events (NCI CTCAE) Version 4. 0. Safety data were monitored on an ongoing basis by an independent Data and Safety Monitoring Board (DSMB).
Patients with incomplete follow up or without adequate disease evaluations were censored at date last documented to be progression free. Kaplan-Meier estimates of median TTP and OS were calculated along with their corresponding 95% confidence intervals. For biomarker changes over time, we used the Wilcoxon signed rank test. Given the exploratory nature of these analyses, we did not correct for multiple comparisons. Cox proportional hazards regression model was used to assess the association of biomarkers with TTP and OS. The point estimates in the Cox regression model with a 95% confidence interval are presented. All analyses were performed using SAS 9. 4 (SAS Institute, Cary, NC).
In the current single arm, phase II trial, sorafenib+mFOLFOX demonstrated promising activity with a TTP of 7. 7 months and ORR of 18% in the first-line systemic treatment of advanced HCC. No unexpected toxicities emerged, but multiple patients discontinued treatment or withdrew consent due to toxicity and continued with either sorafenib or mFOLFOX alone off trial. Notably, sorafenib combined with capecitabine and oxaliplatin (SECOX) demonstrated a similar ORR of 16% in the preliminary report of a phase II trial in the first line treatment of advanced HCC, but the safety profile was deemed sufficiently manageable to proceed with a randomized phase II trial against sorafenib (NCT02716766). This in part may be due to stricter eligibility criteria in the SECOX trial on three accounts: 1) AST and ALT had to be ≤ 2.
Nivolumab recently gained accelerated FDA approval for the treatment of advanced refractory HCC  14  and is currently being tested in the first line setting. Given the toxicity profile of sorafenib and the disappointing results of previous trials of sorafenib combinations, immune checkpoint inhibitors are increasingly being used as the backbone for combination regimens. Chemotherapy may potentially lead to release of tumor antigens and thus increase tumor immunogenicity and response to PD-1 blockade, a hypothesis supported by the efficacy of this combination strategy in non-small cell lung cancer. However, with the unclear role of chemotherapy in HCC, the utility of this approach remains untested in HCC. On the other hand, PD-1 blockade is currently being tested in combination with several multikinase inhibitors that have demonstrated efficacy in HCC such as sorafenib (NCT03211416), lenvatinib (NCT03006926), regorafenib.
Funding This study was funded by  Bayer. L. G. received the  NIH Loan Repayment Program Award  and the  NIH GI SPORE Award. R. K. J. and D. G. D. were supported by  NIH   P01-CA080124. KS was supported by a fellowship from  Uehara Foundation. EM received a grant from the  Philippe Foundation  and  Canceropole PACA.
At the chronic phase, recent data have underlined that balloon pulmonary angioplasty has multiple beneficial effects including kidney function improvement  [11]. On the other hand, several registries have underlined a higher prevalence of PE or venous thromboembolism in chronic kidney disease (CKD) patients [9,  12, 13]. In the present study, we sought to determine whether RD assessed by estimated glomerular filtration rate (eGFR) at diagnosis improves the sPESI score for risk stratification in patients with APE. In addition the impact of acute kidney injury defined as a > 25% increase in creatinine levels during hospital stay on adverse outcome was investigated.
Methods This study retrospectively included all eligible patients diagnosed as having APE who were consecutively admitted to the cardiology department of a university hospital (Nouvel Hôpital Civil, University of Strasbourg) from 1 April 2008 to 31 December 2013. The hospital database was analyzed using the International Classification of Diseases codes (126. 0 for acute pulmonary embolism with heart failure, 126. 9 for acute pulmonary embolism). Among 797 patients with APE as a primary or secondary diagnosis, 119 patients with APE considered as the secondary diagnosis were excluded. A total of 678 consecutive patients were hospitalized for PE, with the diagnosis confirmed mainly by computed tomographic (CT) pulmonary angiography. Baseline demographics and clinical characteristics were obtained from the medical records.
Twelve-lead electrocardiogram (ECG) and routine laboratory data including quantitative Troponin I (TN-I), BNP, C-reactive protein, urea, creatinine, eGFR, pH, PaO 2 , PaCO 2 , D-dimer and leukocyte levels were obtained serially. For each patient, the sPESI at the time of hospital admission was calculated based on the clinical and demographic characteristics of each patient. The flow chart is shown in Figure  1.
Pre-existing chronic kidney disease (CKD) was determined at the time of enrolment for each patient: (i) according to current KDIGO definitions: kidney damage or glomerular filtration rate (GFR) < 60 mL/min/1. 73 m 2 for 3 months or more, (ii) by evaluating available clinical and laboratory data from the patient or surrogate, (iii) using serum levels of calcium, phosphate, parathormone, alkaline phosphatase activity and albuminuria when available. A diagnosis of APE was confirmed by a high-probability ventilation-perfusion scan result (according to the criteria of the Prospective Investigation of the Pulmonary Embolism Diagnosis), or APE diagnosed on contrast-enhanced PE-protocol helical computed tomography of the chest. In some patients, APE diagnosis was based on clinical examination and biological data compatible with APE diagnosis (D-dimers elevation, hypoxemia, hypocapnia.
Renal Dysfunction and Simplified Pulmonary Embolism Severity Index (sPESI) for Prognostic Assessment of Acute Pulmonary Embolism (APE) Patients Data was further analyzed to investigate the relationship between renal dysfunction and sPESI in APE patients. Group 1 comprised 271 patients with preserved eGFR at diagnosis and sPESI at 0, Group 2 comprised 285 patients with either eGFR <60 mL/min/1. 73 m 2 or sPESI ≥1, Group 3 comprised 121 patients with eGFR <60 mL/min/1. 73 m 2 and sPESI ≥1. A significant stepwise increase in AKI, 30-day mortality, one-year mortality, all-cause mortality and cardiovascular mortality was observed between these groups (Table  7 , Figure  3A, B ), with the highest mortality noted in the group with RD and elevated sPESI.
High Prevalence of Renal Dysfunction in APE Patients Recent findings from a large nationwide dataset have underlined an increased incidence of APE with declining renal function. In 32,616,411 adult discharges from hospitals covered by the NIS (Nationwide Inpatient Sample) 2007 database in the Unites States [9], the annual frequency of PE was 527 per 100,000, 204 per 100,000, and 66 per 100,000 persons with end stage renal disease, CKD, and normal renal function, respectively. In accordance with this finding, other studies have reported a high proportion (up to 48%) of renal dysfunction as defined by eGFR <60 mL/min/1. 73 m 2 in patients with APE  [7, 8]. In comparison, the proportion of patients with eGFR <60 mL/min/1. 73 m 2 appears to be lower in the present study (26. 9%). Additionally, the 30-day mortality rate observed in our cohort was lower than those reported in previous studies  [7, 14].
Impact of Renal Dysfunction on Mortality in APE Patients In our study, the increase in 30-day mortality, overall and cardiovascular mortality in patients with RD is in line with previous studies that have reported a negative association between previous RD or AKI and adverse outcomes  [7, 9, [15] [16] [17] [18]. In the International Cooperative Pulmonary Embolism Registry (ICOPER), elevated creatinine concentration (>177 mol/L) was found to be a predictor of mortality at 3 months  [15]. Likewise, in the large NIS database [9], in-hospital mortality was doubled in CKD patients or patients with end stage renal failure compared to patients with normal renal function. Other studies have highlighted the accuracy of eGFR in predicting mortality when coupled together with troponin elevation, heart rate, and the presence of congestive heart failure  [7].
This analysis revealed the existence of two populations of patients displaying either high or low IRE1 activity, respectively  (Fig 1C and Appendix Fig S2). Tumors exhibiting high IRE1 activity also correlated with shorter survival of the corresponding patients (Fig  1D ). We then tested the impact of IRE1 signaling on the expression levels of IBA1, CD14, and CD163 as markers of the inflammatory/immune response in the tumors  (Fig 1E) , the levels of CD31 and vWF to monitor angiogenesis  (Fig 1F) , or RHOA, CYR61, and CTGF expression as indicators of tumoral invasion  (Fig 1G). This revealed that tumors exhibiting high IRE1 activity also presented markers of massive infiltration of macrophages, with high vascularization and invasive properties. Similar observations were also obtained when analyzing the GBMmark dataset.
EtBr-stained agarose gel of XBP1 cDNA amplicons corresponding to unspliced (XBP1u) and spliced (XBP1s) forms of XBP1 mRNA revealed XBP1 splicing in basal conditions due to overexpression of WT, S769F, P336L and A414T but not Q780* forms of IRE1. B Bar graph representing the quantification of three levels of IRE1/XBP1 activation: IRE1 phosphorylation (p-IRE1/IRE1) and XBP1 mRNA splicing (XBP1s/ (XBP1u + XBP1s)) measured as indicated in (A). Three independent biological samples were used. Data from five independent experiments are presented as means AE SD. P-values are indicated. Student's t-test was used. C Heat-map representation of RIDD of mRNA target expression (normalized to 18S) after 2-h Actinomycin D (ActD) treatment. Three independent biological samples were used. D Analysis of miR-17-5p expression by RT-qPCR in IRE1 variant expressing cells under basal conditions.
Data from three independent experiments are presented as means AE SD. Student's t-test was used. E Recapitulative table of the signaling properties of IRE1 WT, DN, P336L, and A414T variants. F Phenotypic characterization of U87 cells expressing the different IRE1 variants and imaged by phase contrast microscopy. Scale bar = 100 lm. G Heat-map representation of the transcriptomes of U87-expressing variants upon basal conditions or ER stress (induction by tunicamycin). H Schematic representation of the signaling pathway enrichment based on the transcriptome data. Appendix Table  S2 ). We then used the XBP1s signature to classify tumors from the GBMmark cohort (Appendix Fig S6A ) and analyzed the expression of IBA1, CD31, and RHOA in tumors exhibiting high or low expression of XBP1s target genes  (Fig 4C).
We therefore applied the same clustering method as in Fig  6  on the transcriptome datasets from 12 primary GBM lines. This revealed that the 12 lines clustered into the same four groups as observed for the tumors (Fig  7A ). These tumor lines exhibited various phenotypes in culture, notably regarding adhesion/protrusion/migration (Fig  7B ). Interestingly, high adhesion/ migration also correlated with the XBP1 + status. This was confirmed using RT-qPCR with lines belonging to the XBP1 + group exhibiting the highest XBP1s levels (Fig  7C ). This information however was not further correlated with the in vitro migration properties of the primary lines (. These data show that primary GBM lines recapitulate, at least partially, the IRE1 signaling properties observed in human tumors and maintain the expected biological outputs even in vivo.
Tumor volume was then estimated by measuring the length (L) and width (W) of each tumor and was calculated using the following formula (L × W 2 × 0. 5). CD31-positive vessels were numerated after immunohistologic staining of the vascular bed using rat antibodies against CD31 (PharMingen) and fluorescent secondary antibodies (Interchim). Imaging was carried out using a Axioplan 2 epifluorescence microscope (Zeiss) equipped with a digital camera Axiocam (Zeiss). Blood vessels were quantified by two independent investigators using a blinded approach. Vessel number was measured in 12-20 images per condition using ImageJ software. This quantification was made three times for each image, and three vessel sizes (surface) were reported: between 100 pixel² and 500 pixels², more than 500 pixel², or more than 5,000 pixel² (1 pixel = 0.
67 lm). The average of vessel number of each size was calculated per brain. Experiments were repeated at least on five Rag-c2 mice for each condition (up to 15). For GBM primary cell-line implantation, 5 × 10 5 cells/ mice were injected in immunocompromised nude mice as described  (Avril et al, 2017)  and above with U87 cells. Mice were daily clinically monitored and sacrificed at the first clinical signs. Mouse brains were collected, fixed in formaldehyde solution 4%, and paraffin-embedded for histological analysis after H&E staining. Tumor burden was compared in the different groups of mice and analyzed using ImageJ software. Furthermore, vascularization of the tumors (CD31), macrophage infiltration (IBA1), and invasion tumor (vimentin) were monitored using immunohistochemistry (Appendix Table  S8 ).
FACS analyses Glioblastoma multiform specimens were dissociated using the gentleMACS dissociator  (Miltenyi Biotec, Paris, France)   immunoglobulins and fluorescent-labelled primary antibodies for 30 min at 4°C. Cells were then washed with PBS 2% FBS and analyzed by flow cytometry using a FACSCanto II flow cytometer (BD Biosciences). The population of interest was gating according to its FSC/SSC criteria. The dead cell population was excluded using 7amino-actinomycin D (7AAD) staining (BD Biosciences). Data were analyzed with the FACSDiva (BD Biosciences). The paper explained Problem Glioblastoma multiform (GBM) is the most lethal primary brain cancer with an overall survival of 15 months and no effective treatment. The endoplasmic reticulum stress sensor IRE1 contributes to GBM progression, impacting tissue invasion and tumor vascularization.
Acknowledgements We thank  Drs S. Manié  (Lyon) and  R. Pedeux  ( Rennes ) for critical reading of the manuscript, the  CRB Santé of Rennes   BB-0033-00056  for patient samples, the  BIOSIT High Precision histopathology  platform  H2P2  ( A. Fautrel  and P. Bellaud; https://biosit. univ-rennes1. fr/?q=en/corefacilities /02/05 ) for their remarkable work, Biotrial (https://www. biotrial. com/)for help with some animal models and  R. Fronzes  ( IECB, Bordeaux ) for help with IRE1 3D models. Affymetrix microarrays were processed in the  Microarray Core Facility of the Institute in Regenerative Medicine and Biotherapy, CHU-INSERM-UM Montpellier  (http://irmb. chu-montpellier. fr/). This work was funded by grants from  Institut National du Cancer (INCa ; PLBIO:  2017-148 , PLBIO:  2015-111 ,  INCA_7981 ),  La Ligue Contre le Cancer (Comité des Landes ,  LARGE  project), and  PHC Maimonide  to EC;  EU H2020 MSCA ITN-675448  (TRAINERS) and  MSCA RISE-734749 (INSPIRED)  to EC and AS and from  Région Bretagne «AAP  CRITT santé 2013» to VQ.
SL was funded by a PhD scholarship from the  French government  and by a scholarship from the  Fondation pour la Recherche Médicale. ND was funded by a post-doctoral fellowship from the  Fondation de France. M. McMahon  was funded by an ARED PhD scholarship from the  Région Bretagne. This work was carried out under the auspices of  REACT (REnnes brAin Cancer Team).
Data availability The data from this publication have been deposited to the Array-Express database (https://www. ebi. ac. uk/; tumor transcriptomes GBMmark) with the accession number E-MTAB-6326 and GEO database (https://www. ncbi. nlm. nih. gov/geo/; cell-line transcriptomes) with the accession number GSE107859. Expanded View for this article is available online.