dataesr/scientific-paragraphs-categorization huggingface dataset:
Functional analyses of mutant BMPR1B receptors We performed a luciferase reporter gene assay using the SMAD dependent BRE reporter to determine the signal transduction capacity of the BMPR1B variant Arg31Cys, which is associated with ACD du Pan type in our patient (Fig. 3a ). We compared its activity to the previously described BMPR1B mutation Cys53Arg, which is associated with ACD Grebe type and to Arg31His, another allele listed in genomic databases  [9]. The WT receptor induced the luciferase expression approximately 8-fold compared to a control vector and was strongly stimulated by the presence of recombinant GDF5. BMPR1B Arg31Cys showed only moderate activity when no ligand was used for stimulation (less than 2-fold). Arg31His induced the SMAD signaling pathway approximately 5-fold, but remained significantly less active than the WT receptor.
BMPR1B Cys53Arg did not activate SMAD signaling at all. Data were tested for normal distribution (Kolmogorov-Smirnoff normality test) and analyzed using a One-Way-ANOVA with subsequent Bonferroni's Multiple Comparison Test (n = 8; ns not significant, *** p < 0. 001). b NIH/3 T3 cells were transfected with the indicated HA-tagged Bmpr1b variants. Using an anti-HA antibody the expression of BMPR1B could by visualized via confocal microscopy. DAPI was used for staining of cell nuclei. All BMPR1B variants were translocated to the cell membrane our results show that both Grebe and du Pan dysplasia can be caused by BMPR1B mutations in rare cases. While the number of affected individuals with ACD due to BMPR1B mutations is small, our previous  [9]  and present results indicate a possible genotype-phenotype correlation according to which BMPR1B mutations with a strong functional effect would cause Grebe syndrome, while milder mutations would result in the clinically and radiologically milder du Pan dysplasia.
1) expressing RLuc. Forty-eight hours post-infection, infectivity was determined by RLuc activity measurement. Cells treated with CD81 targeting or scrambled siRNAs served as controls. SRFBP1-targeting siRNA 394 was used in all experiments. Data from three to five biological replicates are displayed as mean + SD. See also Figure  S6. and disruption of cellular compartments, and thus, careful follow-up analysis is critical for the here-described methodology. Clearly, receptor interaction proteomics will not only allow the follow-up search for entry factors but can also reveal host factors involved in innate immune recognition or cellular perturbations triggered by the virus like, e. g. , apoptosis (Figure  S7 ). Given that co-IP proteomics reveals interconnectivity of pathogen receptors and host cofactors, we envision that the technique can spur the development of peptidomimetics or small molecules for therapeutic intervention of pathogen invasion  (de Chassey et al.
(C) SRFBP1-silenced cells (siRNA 394) express CD81, CLDN1, and SR-BI at the plasma membrane. Surface expression of CD81, CLDN1, and SR-BI on Huh-7. 5 cells was analyzed 48 hpt with the indicated siRNAs. Cells were stained with antibodies against HCV entry factors followed by flow cytometric analysis of 10,000 cells per sample. For quantification and additional controls, see FigureS4. Control is directly conjugated isotype antibody (histogram 1) or secondary antibody only (histograms 2 and 3). (D) OCLN expression levels are stable after SRFBP1 silencing (siRNA 394). Immunoblot analysis of OCLN (red) and SRFBP1 (green) after siRNA mediated silencing for 48 hr is shown. Actin served as loading control. Data are representative of at least three independent experiments. See also FigureS4.
ACKNOWLEDGMENTS We thank  Takaji Wakita  for the JFH1 isolate;  Jens Bukh  for intergenotypic chimeric HCV strains;  Marino Zerial  for Rab-GFP constructs;  Dirk Lindemann  for the pc. Z. VSV-G plasmid;  Gert Zimmer  for VSV*M Q ;  Volker Thiel  for coronavirus 229E-Luc;  Didier Trono  for pWPI and pCMVdeltaR8. 74constructs; and  Annie Cahour ,  Jean Dubuisson , and  Yves Rouille  for the pIRF construct. This work was supported by fellowships from the  Human Frontier Science Program  ( LT-000048-2009 ), the  German Academy of Science Leopoldina  ( LPDS 2009-9 ), the  German Research Foundation  (DFG;  GE 2145/3-1 ), and the  German Liver Foundation  ( S163/10073/2011 ; to G. G. ). Grants from the  Deutsche Forschungsgemeinschaft  ( SFB 900 ; project  A6 ) and the  Helmholtz Association   SO-024  funded T.
Blocking lactate transport Lactate efflux plays a critical role in intracellular pH regulation and in tumor-stroma interactions contributing to cancer cell invasiveness and immune escape. Lactate transport occurs via monocarbonate transporters (MCT): MCT-4 for lactate efflux of highly glycolytic cells, and MCT-1 for lactate import into cells that use lactate as an oxidative combustible (e. g. heat, skeletal muscle, normoxic PDAC cells)  [34]. High levels of both MCT-1 and MCT-4 are associated with poor prognosis, and MCT-1 inhibition reduces growth and tumorigenicity of RAS-mutated fibroblasts  [59, 127]. AZD3965, a MCT-1 inhibitor, is currently being evaluated in a Phase I trial (NCT01791595). Both MCT-1 and MCT-4 are associated with CD147 (also known as EMMPRIN or basigin), an immunoglobulin-family chaperone.
www. impactjournals. com/oncotarget The classically formulated L-asparaginase is limited by toxicity and development of an immune response. A new formulation encapsulating L-asparaginase in erythrocytes has increased bioavailability and a better toxicity profile while retaining strong antitumor activity in leukemia  [137]. Based on preclinical data showing activity, a phase II clinical trial in PDAC with this formulation as second-line therapy is ongoing in the PDAC metastatic setting (NCT02195180).
Pinocytosis and autophagy inhibitors The finding that survival of RAS-transformed cells depends on autophagy offers a potential approach for inhibition. Hydroxychloroquine is a compound approved for malaria and several rheumatologic diseases that prevents lysosome acidification, thus inhibiting autophagy and macropinocytosis. Several trials testing hydroxychloroquine in patients with PDAC are ongoing (NCT01978184; NCT01128296; NCT01506973; NCT01494155; NCT01273805). Wolpin et al. [142]  reported the results of a phase II study evaluating hydroxychloroquine monotherapy in 20 patients with previously treated metastatic PDAC. Median progressionfree survival and OS were limited (46. 5 and 69. 0 days, respectively). In addition, recent data showed that autophagy inhibition in PDAC cells lacking p53 may result in increased anabolism and tumor progression  [113].
Name (mechanism of action) Trial identifier Phase Current status AZD3965 (MCT-1 inhibitor) NCT01791595 1 Recruiting ERY001 (L-asparaginase encapsulated in red blood cells) -Metastatic PDAC NCT02195180 2 Recruiting Hydroxychloroquine (autophagy inhibitor) -Neo-adjuvant setting NCT01978184 2 Recruiting (combined with Gem and nab-P) NCT01494155 2 Recruiting (combined with capecitabine and radiotherapy) NCT01128296 1/2 Active, not recruiting (combined with gemcitabine) -Locally advanced or metastatic PDAC NCT01506973 1/2 Status unknown (combined with Gem and nab-P) NCT01273805 2 Active, not recruiting (monotherapy) Metformin (non-specific inhibitor) -Neo-adjuvant setting NCT02153450 2 Recruiting (combined with stereotactic radiosurgery) -Adjuvant setting NCT02005419 2 Recruiting (combined with Gem) -Locally advanced or metastatic PDAC NCT01210911 2 Completed (combined with Gem and erlotinib) NCT01167738 2 Terminated (concern of detrimental effect) NCT01666730 2 Recruiting (combined with FOLFOX 6) NCT02336087 1 Not yet recruiting (combined with Gem, nab-P, and a standardized dietary supplement) NCT01488552 1/2 Recruiting (combined with Gem + nab-P or FOLFIRINOX) NCT02048384 1/2 Recruiting (combined with rapamycin) NCT01971034 2 Completed (combined with paclitaxel) Gem: gemcitabine; nab-P: nab-paclitaxel; PDAC: pancreatic ductal adenocarcinoma review,.
Routes of entry and dissemination for vertebral osteomyelitis were reviewed. We also recorded the location of infection and the presence of any orthopedic prostheses or devices. We reviewed the antimicrobial and/or surgical treatment approaches used in each case. Data analyses were performed using IBM ® SPSS ® Statistics software v. 20. 0. Proportions were compared using two-tailed chi-squared tests. A value of p < 0. 05 was considered statistically significant.
Background: Advanced malignant solitary fibrous tumors (SFTs) are rare soft-tissue sarcomas with a poor prognosis. Several treatment options have been reported, but with uncertain rates of efficacy. Our aim is to describe the activity of trabectedin in a retrospective, multi-center French series of patients with SFTs. Methods: Patients were mainly identified through the French RetrospectYon database and were treated between January 2008 and May 2013. Trabectedin was administered at an initial dose of 1. 5 mg/m 2 , q3 weeks. The best tumor response was assessed according to the Response Evaluation Criteria In Solid Tumors 1. 1. The Kaplan-Meier method was used to estimate median progression-free survival (PFS) and overall survival (OS). The growth-modulation index (GMI) was defined as the ratio between the time to progression with trabectedin (TTP n ) and the TTP with the immediately prior line of treatment (TTP n-1 ).
Patients Most patients were identified through the French Retro-spectYon database, which collected data from patients treated with trabectedin between January 2008 and December 2011 in French Sarcoma Group centers. Additional patients were identified through the electronic databases of certain French cancer centers between January 2012 and May 2013. We collected data on: patients' characteristics at diagnosis; disease characteristics including primary tumor site, extent of disease and pathological features; previous chemotherapy; and clinical outcomes with trabectedin therapy. This study was approved by the ethics committee of the French Sarcoma Group as well as the scientific board (which permitted access to the RestrospectYon database). Access to local databases was granted by the institutional scientific board of each participating center belonging to the French Sarcoma Group.
Statistical analyses The data are presented using frequency and percentage for categorical variables and median and range for continuous variables. All survival times were calculated from the date of first administration of trabectedin, and were estimated by the Kaplan-Meier method using the following first-event definitions: progression according to RECIST or death for progression-free survival (PFS) and death from any cause for overall survival (OS). Patients who were still progression-free were censored at the time of their last follow-up. All statistical analyses were conducted using STATA 13. 0 software.
Progression can be favored by a concomitant disease, such as hepatitis C  [22, 23] , HIV superinfection  [24, 25] , or the initiation of particular medications (e. g. immunosuppressive drugs following organ transplantation)  [26]. However, there are few data on the risk factors for immunologic and/or virologic progression in HICs. Understanding the mechanisms leading to disease progression in HICs could help to (i) identify the major determinants of HIV control and (ii) optimize care for these uncommon patients. To address these issues, we investigated the rate of immunologic and/or virologic progression and its determinants in the French CODEX cohort of HICs (the ANRS CO21 study). We focused on (i) clinical and biological events preceding the progression, and (ii) the ultrasensitive HIV VL, HIV DNA levels, T cell activation and plasma levels of inflammatory biomarkers at enrollment.
Data collection Clinical characteristics (age, gender, HCV co-infection, comorbidities, and HIV history (year of HIV diagnosis, CD4+ nadir, the number and intensity of transient detectable plasma VLs (blips), and the baseline CD4+ count and HIV RNA VL) were recorded. The parameters of interest (CD4+ and CD8+ T cell counts and the HIV VL before progression, at the time of the suspected progression, at the next visit, and at the last measurement) were documented. The cART regimen and initiation date were also noted. A standardized data collection form was provided for the investigation of any clinical events occurring in the three months prior to the suspected progression (e. g. unprotected sex intercourse, intravenous drug use, concurrent infectious events, vaccinations, treatment changes, etc.
Acknowledgments The authors thank the patients for their participation in this study, along with all the physicians and nurses involved in the cohort and the  ANRS C021 CODEX study group. Special thanks are also due to  Azeb Tadesse  and  Samia Hendou  for data monitoring, and to  Ludivine David  and  Adeline Mélard  for virologic analyses. The members of the  ANRS   CO21  CODEX study group are:  Henri Agut ,  Brigitte Autran ,  Francis Barin ,  Faroudy Boufassa ,  Dominique Costagliola ,  Olivier Lambotte ,  Laurence Meyer ,  Gianfranco Pancino ,  Christine Rouzioux ,  Assia Samri-Hassimi ,  Olivier Taulera ,  Ioannis Theodorou ,  Roland Tubiana ,  Alain Venet ,  Jean-Paul Viard ,  Yazdan Yazdanpanah.
Acknowledgments We thank the members of the  Gaël Adolescent Espoir Leucémie and Association des Greffés de Moelle Osseuse de Midi-Pyrénées  for their kind support to patients. Dr. Tavitian  is a hematologist at the  Institut Universitaire du Cancer de Toulouse. Her clinical research interests include infectious complications related to hematological malignancies, myeloproliferative neoplasia and acute lymphoblastic leukemia.
Statistical analysis The sample size of 50 patients (plus 20% to anticipate losses due to exclusions, withdrawals, and lost-to-followup), i. e. a minimum of 60 patients, was calculated on the basis of an expected failure rate of 5%, 10% precision, and a confidence level of 95%  [12]. As recommended in the WHO protocol  [12] , per protocol analysis of the percentage of ACPR and Kaplan-Meier survival analysis were performed to calculate the probability of the time to treatment failure during the 28-day followup period. Data were entered into the standard pre-programmed Excel worksheet provided by the Global Malaria Programme, WHO, for per protocol analysis. Survival curves were plotted and analyzed using Prism 4. 0 (GraphPad Software, Inc. , La Jolla, CA) software. Quantitative variables were compared between the patient population in Nouakchott and Atar using the unpaired t-test.
Acknowledgements We would like to thank  Dr Mohamed Ould Weddady  (Teyarett health centre, Nouakchott),  Dr Abdoulah Ould Ehmeyada  and  Dr Sidatti Ould Sidi Elemine  (Atar health centre), and their medical staff for facilitating our studies. This work was supported by  Bill and Melinda Gates Foundation through Global Malaria Programme ,  World Health Organization, Geneva, Switzerland.
Microscopy and Quantitative Analyses Unbiased counts of TLR3-immunopositive, glial fibrillary acidic protein (GFAP)Yimmunopositive, and ionized calciumbinding adaptor molecule-1 (Iba-1)Yimmunopositive cells and the averaged cell density (hematoxylin positive nuclei/mm 2 ) were obtained using the CM1 and CM2 modules for virtual tissue scan (MicroBrightfield Inc, Colchester, VT) using stereology software (Stereo Investigator version 8. 27; MicroBrightfield Inc). The average area of each contour was encompassed by a 2. 1-mm 2 region, which was made using a 5Â objective microscope, to provide an average of 40 high-power field images per scan collected using a 40Â objective microscope (0. 0426 mm 2 ); counts were automated using the program Image Pro Premier (Media Cybernetics, Warrendale, PA).
After the nuclei had been counted, the cellular densities of GFAP-immunopositive and Iba-1Y immunopositive cells were quantified by the first author (Regina Vontell) and a student volunteer (Megan Holly Atkins) who were blinded to case data. Tissue scans were reviewed (by Regina Vontell) to ensure that the glia had met the criteria (e. g. hematoxylin-positive nucleus [G10 Km 2 ] and GFAPpositive cytoplasm) to avoid duplicate counts. Neuronal counts were performed using track-and-trace morphometry data analysis. In brief, after the cells had been counted, we identified those cells that were HuC/HuD-immunopositive using tracking data analysis (Image Pro Premier; Media Cybernetics). For glial and neuronal investigations, data were normalized by using the ratio of immunopositive cells to the entire population (hematoxylin-positive).
The area of TLR3 immunoreactivity was determined by dividing each TLR3 scan into 4 equal quadrants (500 Km 2 ) using the Image Pro Premier parentchild application (Image Pro Premier; Media Cybernetics). We defined the nucleus and the cytoplasm (''parent'') and averaged the measured area (Km 2 ) of TLR3 immunoreactivity (''child'') detected per cell for each of the thalamic and PLIC regions  (33). Data were analyzed using 1-way analysis of variance followed by the Tukey multiple comparison test to compare ratios in different thalamic nuclei and different regions of PLIC between groups (WMI compared with controls). Data are presented as mean T SE; significance was set at p G 0. 05. All statistical analyses were performed using GraphPad Prism 6. 0 (GraphPad Software, San Diego, CA). Cellular localization of TLR3 was performed via semiquantitative analysis through the center of the contour of the VLp region (Fig.
We continued with the Mander's correlation analysis. Data were analyzed with Student t-test using a Mann-Whitney post hoc test between groups (WMI compared with controls) in the VLp thalamus. Data are presented as mean T SD; significance was set at p G 0. 05. All statistical analyses were performed using GraphPad Prism 6. 0. Translocation of IRF-3 signal from the cytoplasm to the nucleus was determined using the Image Pro Premier parentchild application (Image Pro Premier; Media Cybernetics). In brief, each case had an average of 50 nuclei (obtained using a 63Â objective on the confocal microscope) in the VLp region of the thalamus (Fig. 1A ). The nuclear boundary was determined by DAPI staining, and the threshold was maximized to achieve a solid object (''parent''). Next, IRF-3 intensity was averaged using Leica-LAS Lite report for each stack in all of the cases (i.
This work was supported by the  UK Medical Research Council strategic award  (Grant No. P19381 ), the  Wellcome Trust  (Grant No. WT094823 ),  Leducq Foundation ,  Swedish Medical Research Council  (Grant No. VR 2012-3500 ), the  Wilhelm and Martina Lundgren Foundation , the  Åhlen Foundation , the  Frimurare Barnhus Foundation , the  Byggma ¨stare Olle Engqvist Foundation ,  The Brain Foundation  (Grant No. 2013-0035 ), and  Governmental Grants for University Hospitals in Sweden  (Grant No. ALFGBG-137601 ). The authors acknowledge financial support from the  Department of Health  via the  National Institute for Health Research Comprehensive Biomedical Research Center award to Guy's and St Thomas' NHS Foundation Trust  in partnership with  King's College London and King's College Hospital NHS Foundation Trust.
Background: The most advanced dengue vaccine candidate is a live-attenuated recombinant vaccine containing the four dengue viruses on the yellow fever vaccine backbone (CYD-TDV) developed by Sanofi Pasteur. Several analyses have been published on the safety and immunogenicity of the CYD-TDV vaccine from single trials but none modelled the heterogeneity observed in the antibody responses elicited by the vaccine. Methods: We analyse the immunogenicity data collected in five phase-2 trials of the CYD-TDV vaccine. We provide a descriptive analysis of the aggregated datasets and fit the observed post-vaccination PRNT50 titres against the four dengue (DENV) serotypes using multivariate regression models. Results: We find that the responses to CYD-TDV are principally predicted by the baseline immunological status against DENV, but the trial is also a significant predictor.
Data We analyse the immunogenicity data collected in the vaccine arm of five phase-2, randomised, observer-blind, controlled trials of CYD-TDV conducted in the Philippines  [10] , Latin America  [12] , Vietnam  [6] , Thailand  [9]  and Brazil  [11]. The subjects enrolled in the trials were randomized with a 2:1 ratio to receive vaccine or placebo, respectively. Vaccine was delivered as three subcutaneous injections at months 0, 6 and 12. Blood samples for the assessment of the immunogenicity properties of CYD-TDV were obtained before the first dose and 28 days after each dose from all subjects in the Philippines, Latin America, Vietnam and Brazil and on a subset of 300 subjects in Thailand. Serum levels of neutralizing antibodies against each of the four CYD-TDV's dengue parental strains were determined using the 50% plaque reduction neutralizing test (PRNT50)  [13].
Models 6-11 extend models 1-5 by including interactions between different serotype titres. We then progressively build on the two best fitting of these 11 model variants and increase complexity by successively adding each one of the remaining covariates (baseline immunological status to DENV and JEV; gender; age; trial code; trial location; baseline titre against JEV). All model variants are described in the SI (Section 1. 4). Moreover, we tested the predictive power of the best models using cross-validation (Section 2. 3 of the SI). The analysis was performed using MATLAB (release R2013b) and R (version 3. 0. 2).
Acknowledgements This work was conducted within the  Dengue Modelling Consortium , which was established in 2013 between  Imperial College London, Fred Hutchinson Cancer Research Centre, Johns Hopkins University, University of Florida  and  Sanofi Pasteur  to improve understanding of the effectiveness and potential public health impact of CYD-TDV. The authors thank  Dr Mark Boaz  for the valuable comments on this manuscript. The authors also express their gratitude to the investigators and subjects that participated to the five clinical trials which results have been used in this manuscript.
We have shown that Pim2 was constantly expressed in primary blasts from AML. In these cells, Pim2 is involved in protein translation by controlling 4E-BP1 phosphorylation. Pim1 that is less frequently expressed than Pim2 in AML cells does not correct Pim2 knockdown in these cells  [8]. Several clinical trials are currently ongoing to test the potential of Pim kinase inhibitors in multiple myeloma, AML and myelodysplastic syndromes (https://clinicaltrials. gov). Thus, the understanding of the mechanisms that control the activity of Pim2 kinase is of utmost importance for cancer therapy. The overall structure of the Pim kinases is simple since these proteins are almost restricted to the kinase domain with short sequences both before and after this domain. Moreover, in contrast with most other kinases that need to be phosphorylated in the activation loop (A-loop) to be active, Pim kinases constitutively adopt an active conformation due to the presence of an acidic residue in the A-loop (Asp 200 in Pim1, Asp 196 and possibly Asp 198 in Pim2) that forms a salt bridge with basic residues of the catalytic loop (C-loop) and thus mimics the phosphorylable serine or threonine residue that is present in other kinases  [9, 10].