gebhart/patrepeval huggingface dataset:
Phase 1 results of PTC596, a novel small molecule targeting cancer stem cells (CSCs) by reducing levels of BMI1 protein. (2017)

2574 Background: PTC596 is an oral investigational new drug that reduces levels of BMI1, a protein required for CSC survival. PTC596 reduced the number of CSCs in preclinical models and slowed growth rates of tumor xenografts in rodent models. The primary objectives of this first-in-human trial of PTC596 were to determine safety, dose-limiting toxicities (DLTs), maximum tolerated dose (MTD), and pharmacokinetics (PK). Secondary objectives included exploratory assessments of biological efficacy, pharmacodynamic changes and anti-tumor activity. Methods: A Phase I multi-center, open-label study was conducted in patients with advanced solid tumors using a modified 3+3 design, followed by a dose-confirmatory 10-patient expansion. PTC596 was administered using bodyweight-adjusted twice-per-week (biw) oral dosing in 4 week cycles. Dose escalation and MTD were based on observed cycle 1 DLTs. Anti-tumor activity was assessed by RECIST 1.1. Results: A total of 31 patients with a broad range of tumor types were enrolled at dose levels of 0.65 (N = 3), 1.3 (N = 3), 2.6 (N = 3), 5.2 (N = 11), 7 (N = 8) and 10 mg/kg (N = 3). Nausea, vomiting, and diarrhea were the most common all grade adverse events, though usually mild and manageable. At 10 mg/kg one patient experienced DLTs of neutropenia, mucositis, and thrombocytopenia. The other two patients at this dose level also experienced poor tolerability with Grade 2 nausea, vomiting, and diarrhea that may be partially due to the overall pill burden and excipients. The recommended dose for the expansion and further study was 7 mg/kg. Over the dosing range, plasma concentrations of PTC596 increased in an approximately dose-proportional manner and at doses of 2.6 mg/kg and above exceeded those associated with activity in vitro and in vivo models. Best response was stable disease in 5 patients including two with minor radiographic reductions in tumor volume. Conclusions: PTC596 is tolerable with manageable gastrointestinal side effects. At 7 mg/kg biw exposures exceeded those associated with preclinical activity and future clinical studies are planned for this first-in class molecule that targets CSCs. Clinical trial information: NCT02404480.
Ultra low-loss high power AlGaN/GaN HFET switches (2008)

Novel design concepts and cutting edge results are presented for high-power AlGaN/GaN Heterostructure Field-Effect Transistor switches for power converters, control and radio-frequency applications. For power switching, the HFET design has to be different from that of power amplifiers in order to minimize the contact resistance and avoid current crowding in the metal electrodes of large-periphery devices. Developed high-power III-Nitride HFET switches have the ON-resistance less than 1.25 Ω for a 3-mm wide multi-finger device, equivalent to less then 0.4 mΩcm <sup xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">2</sup> specific ON-resistance. New design and technology allows for low-loss power switching with above 1kV operating voltages, sub-nanosecond switching times, operating temperatures ranging from cryogenic up to 300°C and even higher.
Fiber Reinforced Metal Matrix Composite by a High Deformation Consolidation Process (1997)

Abstract Reinforcement geometry affects strengthening significantly for metal matrix composites. Using rule of mixtures, which assumes perfect stress transfer from matrix to reinforcement, as well as a differential CTE mechanism, which assumes a dislocation generation effect to strengthen the matrix, it can be shown that particulate reinforcement types are inherently inefficient for strengthening. As an alternative, a Ni pre-form fiber system has been used in this work as the reinforcement. The preform type eliminates the mixing problems inherent for a particulate system, but itself also introduces an additional binder burn-off step. Subsequent compaction was done using a cold isostatic press up to 3000 bars (−300 MPa), with the consolidation achieved by means of a hot extrusion / hot pressing method.
Tumor Necrosis Factor-α Regulates Cyclin-dependent Kinase 5 Activity during Pain Signaling through Transcriptional Activation of p35 (2008)

Cyclin-dependent kinase 5 (Cdk5) is a proline-directed serine/threonine kinase. We have previously reported that Cdk5 participates in the regulation of nociceptive signaling, and the expression of Cdk5 and its activator, p35, are up-regulated in nociceptive neurons during peripheral inflammation. The aim of our current study was to identify the proinflammatory molecules that regulate Cdk5/p35 activity in response to inflammation. We constructed a vector that contains the mouse p35 promoter driving luciferase expression. We transiently transfected this vector in PC12 cells to test the effect of several cytokines on p35 transcriptional activity and Cdk5 activity. Our results indicate that tumor necrosis factor-alpha (TNF-alpha) activates p35 promoter activity in a dose- and time-dependent manner and concomitantly up-regulates Cdk5 activity. Because TNF-alpha is known to activate ERK1/2, p38 MAPK, JNK, and NF-kappaB signaling pathways, we examined their involvement in the activation of p35 promoter activity. MEK inhibitor, which inhibits ERK activation, decreased p35 promoter activity, whereas the inhibitors of p38 MAPK, JNK, and NF-kappaB increased p35 promoter activity, indicating that these pathways regulate p35 expression differently. The mRNA and protein levels of Egr-1, a transcription factor, were increased by TNF-alpha treatment, and this increase was dependent on ERK signaling. In a mouse model of inflammation-induced pain in which carrageenan injection into the hind paw causes hypersensitivity to heat stimuli, TNF-alpha mRNA was increased at the site of injection. These findings suggest that TNF-alpha-mediated regulation of Cdk5 activity plays an important role in inflammation-induced pain signaling.
Transduction Efficiencies of Novel AAV Vectors in Mouse Airway Epithelium In Vivo and Human Ciliated Airway Epithelium In Vitro (2020)

We have characterized the ability of adeno-associated virus (AAV) serotypes 1–9 in addition to nineteen novel vectors isolated from various tissues, to transduce mouse and human ciliated airway epithelium (HAE). Vectors expressing α-1-antitrypsin (AAT) and β-galactosidase were co-instilled into the mouse lung. Of all the vectors tested rh.64R1, AAV5 and AAV6 were the most efficient. The high transduction observed in mouse was reproduced in HAE cell cultures for both rh.64R1 and AAV6 but not for AAV5. Since AAV6 was the most efficient vector in mouse and HAE we also tested the transduction efficiencies of the AAV6 singleton vectors (i.e., AAV6 variants with targeted mutations) in these models. Of these, AAV6.2 transduced mouse airway epithelium and HAE with greater efficiency than all other AAV vectors tested. We demonstrated that AAV6.2 exhibits improved transduction efficiency compared to previously reported AAVs in mouse airways and in culture models of human airway epithelium and that this vector requires further development for preclinical and clinical testing.
Parallel Synthesis of Benzoxazoles via Microwave‐Assisted Dielectric Heating. (2003)

Abstract For Abstract see ChemInform Abstract in Full Text.
Stopping Criterion for Complexity Reduction of Sphere Decoding (2009)

Maximum-likelihood detection in MIMO communications amounts to solving a least-squares problem with a constellation (alphabet) constraint. One popular method that can be used to solve this problem is sphere decoding. We show in this letter that by employing a simple stopping criterion, it is possible to significantly reduce the complexity of sphere decoding over a wide range of SNRs, without a noticeable performance degradation. Specifically, simulation results demonstrate that a 10%-90% reduction of the average complexity could be achieved.
Triple‐quantum‐filtered sodium imaging at 9.4 Tesla (2015)

Conventional TQF in combination with flip angle apodization permits to exploit more efficiently the increased sensitivity available at 9.4T.
Identification and Preclinical Pharmacology of ((1R,3S)-1-Amino-3-((S)-6-(2-methoxyphenethyl)-5,6,7,8-tetrahydronaphthalen-2-yl)cyclopentyl)methanol (BMS-986166): A Differentiated Sphingosine-1-phosphate Receptor 1 (S1P1) Modulator Advanced into Clinical Trials (2019)

Recently, our research group reported the identification of BMS-986104 (2) as a differentiated S1P<sub>1</sub> receptor modulator. In comparison to fingolimod (1), a full agonist of S1P<sub>1</sub> currently marketed for the treatment of relapse remitting multiple sclerosis (RRMS), 2 offers several potential advantages having demonstrated improved safety multiples in preclinical evaluations against undesired pulmonary and cardiovascular effects. In clinical trials, 2 was found to exhibit a pharmacokinetic half-life ( T<sub>1/2</sub>) longer than that of 1, as well as a reduced formation of the phosphate metabolite that is required for activity against S1P<sub>1</sub>. Herein, we describe our efforts to discover highly potent, partial agonists of S1P<sub>1</sub> with a shorter T<sub>1/2</sub> and increased in vivo phosphate metabolite formation. These efforts culminated in the discovery of BMS-986166 (14a), which was advanced to human clinical evaluation. The pharmacokinetic/pharmacodynamic (PK/PD) relationship as well as pulmonary and cardiovascular safety assessments are discussed. Furthermore, efficacy of 14a in multiple preclinical models of autoimmune diseases are presented.
Implementation Issues and Performance Evaluation of Sinusoidal, Surface-Mounted PM Machine Drives With Hall-Effect Position Sensors and a Vector-Tracking Observer (2008)

<para xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink"> This paper presents the implementation and evaluation of a high-resolution position estimation system for sinusoidal, surface phase modulation machines based on Hall-effect sensors and a vector-tracking observer. First, the tuning of the observer is presented and a speed-dependent gain scheduling strategy is proposed. Then various harmonic decoupling strategies are investigated to improve the performance of the observer, particularly at low speeds. Stability analysis is performed leading to the definition of local stability limits, within which the actual position is tracked with bounded estimation error. Both simulation and experimental testing illustrate the performance and limitations of the proposed observer topology and of the drive when this observer is used for state feedback. </para>
Hierarchical aqueous self-assembly of C60 nano-whiskers and C60–silver nano-hybrids under continuous flow (2007)

The ubiquitous starch-iodine complex can be used to organize hydrophobic fullerene C(60) in water into nano-whiskers shrouded by the biopolymer, and are approximately 5-8 nm in cross section, and 250-350 nm in length, as a hierarchical self assembly process. The preformed starch-iodine complex reacts with solid pristine C(60) affording nano-whiskers with iodine surrounding the fullerene array, the iodine then being removed on treatment with ascorbic acid. The hydrophobic surface of the nano-whiskers of C(60) can be coated with silver metal in a controlled way using 'soft energy' spinning disc processing.
Nucleofection of Human Embryonic Stem Cells (2005)

Human embryonic stem (hES) cells provide an important tool for the study of human development, disease, and tissue regeneration. Technologies for efficient genetic modification are required to exploit hES cells fully for these applications. Here we present a customized protocol for the transfection of hES cells with the Nucleofector technology and compare its efficiency with conventional electroporation and lipofection. Cell survival and transfection efficiency were quantified using an enhanced green fluorescent protein (EGFP) reporter construct. Our optimized nucleofection parameters yielded survival rates >70%. Under these conditions, 66% of the surviving cells showed transgene expression 24 h after nucleofection. Transfected cells maintained expression of the pluripotency- associated markers Tra-1-60, Tra-1-81, and Oct4 and could be expanded to stably transgene-expressing clones. The low quantities of hES cells and DNA required for nucleofection could make this method an attractive tool for miniaturized high throughput screening (HTS) applications.
Capillary and microelectrophoretic separations of ligase detection reaction products produced from low‐abundant point mutations in genomic DNA (2004)

Capillary gel electrophoresis (CGE) and polymer-based microelectrophoretic platforms were investigated to analyze low-abundant point mutations in certain gene fragments with high diagnostic value for colorectal cancers. The electrophoretic separations were carried out on single-stranded DNA (ssDNA) products generated from an allele-specific ligation assay (ligase detection reaction, LDR), which was used to screen for a single base mutation at codon 12 in the K-ras oncogene. The presence of the mutation generated a ssDNA fragment that was >40 base pairs (bp) in length, while the primers used for the ligation assay were <30 bp in length. Various separation matrices were investigated, with the success of the matrix assessed by its ability to resolve the ligation product from the large molar excess of unligated primers when the mutant allele was lower in copy number compared to the wild-type allele. Using CGE, LDR product models (44 and 51 bp) could be analyzed in a cross-linked polyacrylamide gel with a 1000-fold molar excess of LDR primers (25 bp) in approximately 45 min. However, when using linear polyacrylamide gels, these same fragments could not be detected due to significant electrokinetic biasing during injection. A poly(methylmethacrylate) (PMMA) microchip of 3.5 cm effective column length was used with a 4% linear polyacrylamide gel to analyze the products generated from an LDR. When the reaction contained a 100-fold molar excess of wild-type DNA compared to a G12.2D mutant allele, the 44 bp ligation product could be effectively resolved from unligated primers in under 120 s, nearly 17 times faster than the CGE format. In addition, sample cleanup was simplified using the microchip format by not requiring desalting of the LDR prior to loading.
Dexamethasone differentiates NG108-15 cells through cyclooxygenase 1 induction (2003)

Cyclooxygenase (COX) is a key enzyme in the conversion of arachidonic acid into prostanoids which participate in various cellular functions including apoptosis, mitogenesis, inflammation, immune modulation and differentiation. Moreover, the synthetic glucocorticoid, dexamethasone has immune modulating and anti-inflammatory effects in vivo. Recently, dexamethasone was found to enhance retinoic acid-induced neuronal differentiation. In this study, we investigated the mechanisms of dexamethasone-mediated neuronal differentiation. Immunoblotting and morphological analysis demonstrated that dexamethasone induced neuronal differentiation through COX 1 induction. This phenomenon was inhibited by indomethacin, a COX inhibitor. In addition, the addition of exogenous prostaglandin E2 (PGE2), a substance produced by the COX-mediated pathway, triggered neurite outgrowth of cells treated with COX inhibitor. Taken together, COX 1 appears to play an important role in dexamethasone-mediated neuronal differentiation.
Issues related to the constitutive modeling of Ni-based single crystal superalloys under aeroengine certification conditions (2015)

This paper presents a constitutive modeling approach (the Polystar model) used to compute the viscoplastic behavior and the durability of high pressure turbine blades and vanes of aeroengines during complex thermomechanical histories typically encountered during certification procedures. This model is based on internal variables representing explicitly the microstructure evolutions occurring during very high temperature non-isothermal loading (e.g., dissolution/re-precipitation of the strengthening phase, dislocation recovery mechanisms, etc.) in a crystal viscoplasticity modeling framework. This article shows that the development of such a modeling tool requires a good characterization of fast microstructure evolutions, as well as in-service-type experiments (using burner rigs) able to reproduce the complex thermomechanical loading spectra. The capabilities of the model are illustrated, as well as its potential industrial applications and further developments are commented.
The generation of T‐cell memory to protect against tuberculosis (2019)

Tuberculosis (TB) kills more individuals each year than any other single pathogen and a more effective vaccine is critical for the global control of the disease. Although there has been recent progress in the clinical testing of candidates, no new vaccine has been licensed for use and correlates of protective immunity in humans have not been defined. Prior Mycobacterium tuberculosis infection does not appear to confer long-term protective immunity in humans; thus mimicking the natural immune response to infection may not be a suitable approach to develop improved TB vaccines. Data from animal testing are used to progress vaccines through the "vaccine pipeline", but studies in animals have not been able to predict efficacy in humans. Furthermore, although the generation of conventional CD4<sup>+</sup> T-cell responses are considered necessary to control infection with M. tuberculosis, these do not necessarily correlate with protection induced by candidate vaccines and other immune components may play a role, including donor unrestricted T cells, tissue-resident memory T cells and anti-M. tuberculosis antibodies. This review will summarize the current understanding of the protective immune responses following M. tuberculosis infection or vaccination, with a particular focus on vaccines that have recently entered clinical trials.
State-plane approach for the analysis of half-bridge parallel resonant converters (1995)

Generalised state-plane analysis for a half-bridge parallel resonant converter (PRC) operating in continuous conduction mode is presented. It is shown that a PRC circuit of any order can be analysed in terms of simple two-dimensional state-plane diagrams, without having to use any sinusoidal approximation. The approach presented makes use of the state-variable transformation technique previously used for the analysis of second- and third-order resonant converters. This method is applied to a specific example of a sixth-order parallel resonant converter operated in the continuous conduction mode.
Loss of 14-3-3σ in Prostate Cancer and Its Precursors (2004)

Our data suggest that loss of 14-3-3sigma contributes to the development of prostate adenocarcinoma. 14-3-3sigma expression is significantly decreased during the progression of normal prostatic epithelium to prostatic intraepithelial neoplasia and invasive cancer.
Effect of a Buttiauxella phytase on production performance in growing/finishing pigs fed a European-type diet without inclusion of inorganic phosphorus (2017)

Summary The effect of a Buttiauxella phytase, in a dose range of 0-1000 FTU/kg in feed, on production performance in growing/finishing pigs fed European type wheat, corn, barley and SBM based diet was determined. Five dietary treatments were tested including a positive control (PC), a negative control (NC) without inorganic P and with reduced Ca (–0.12%) and metabolisable energy content (–0.14 MJ ME/kg) or NC supplemented with Buttiauxella phytase (Axtra ® PHY, Danisco Animal Nutrition, DuPont Industrial Biosciences, Marlborough, UK) at 250, 500 or 1000 FTU/kg respectively. A total of 100 pigs (mean initial BW of 30 kg, Topig x Pi, 10 weeks of age) were used, with 20 replicates per treatment (50% gilts and 50% barrows). Pigs were individually housed in pens and randomly allocated on the basis of body weight (BW) and gender to the five treatments. Feed, in mash form, and water were offered ad libitum . Basal diets had an intrinsic phytase level of approximately 300 and 440 FTU/kg in NC grower and NC finisher diets respectively. Mean average daily gain (ADG), average daily feed intake (ADFI) and feed conversion ratio (FCR) were calculated for the feeding phases of 30–85 kg (grower), 85–125 kg (finisher) on trial and for overall period. During the grower phase, increasing phytase dose resulted in a linear increase in ADG. Phytase inclusion at 250, 500 and 1000 FTU/kg improved ADG by 3.5, 7.2 and 8.1% respectively compared to NC and by 0.8, 4.5 and 5.3% respectively compared to those fed the PC. Performance in the finisher phase, overall period and slaughter parameters were not different between dietary treatments. The data showed that it was beneficial to increase phytase dose up to 1000 FTU/kg in grower pigs up to 85 kg BW. In the finisher phase, in pigs with BW above 85 kg, 500 FTU/kg was sufficient to replace inorganic P and maintain performance and carcass characteristics comparable to pigs fed the PC.
The VTR project (2012)

To facilitate the development of future FPGA architectures and CAD tools -- both embedded programmable fabrics and pure-play FPGAs -- there is a need for a large scale, publicly available software suite that can synthesize circuits into easily-described hypothetical FPGA architectures. These circuits should be captured at the HDL level, or higher, and pass through logical and physical synthesis. Such a tool must provide detailed modelling of area, performance and energy to enable architecture exploration. As software flows themselves evolve to permit design capture at ever higher levels of abstraction, this downstream full-implementation flow will always be required. This paper describes the current status and new release of an ongoing effort to create such a flow - the 'Verilog to Routing' (VTR) project, which is a broad collaboration of researchers. There are three core tools: ODIN II for Verilog Elaboration and front-end hard-block synthesis, ABC for logic synthesis, and VPR for physical synthesis and analysis. ODIN II now has a simulation capability to help verify that its output is correct, as well as specialized synthesis at the elaboration step for multipliers and memories. ABC is used to optimize the 'soft' logic of the FPGA. The VPR-based packing, placement and routing is now fully timing-driven (the previous release was not) and includes new capability to target complex logic blocks. In addition we have added a set of four large benchmark circuits to a suite of previously-released Verilog HDL circuits. Finally, we illustrate the use of the new flow by using it to help architect a floating-point unit in an FPGA, and contrast it with a prior, much longer effort that was required to do the same thing.
Dynamic modeling of losses in electrical machines for active loss control (2012)

This paper presents a dynamic core loss model for active loss control of permanent magnet synchronous machines. Deadbeat-direct torque and flux control (DB-DTFC) enables direct control of torque and stator flux linkage over each switching period. Total machine loss can be minimized by selecting the optimal flux level in every sampled time instant. Reliable models for dynamic copper and core loss are an essential requirement for this optimizing task. This paper presents an analytical dynamic core loss model in switching period time-domain, using stator flux linkage as the manipulated input variable. Combining numerical and analytical calculation methods is used to create an easy and practical approach to estimate core loss components based on stator flux linkage without running FEA calculations for every time instant. Additional effects like high frequency eddy current loss in electrically conducting permanent magnets as well as spatial harmonic content are taken into account.