gebhart/patrepeval huggingface dataset:
Abstract 4134: Reversal of adenosine-mediated immune suppression by CB-708, an orally bioavailable and potent small molecule inhibitor of CD73 (2019)

Introduction: High adenosine (ADO) in the tumor microenvironment suppresses the immune response against cancer cells by inhibiting immune effector functions and promoting the development of immunosuppressive cells. Extracellular ADO can be generated from ATP released by cells undergoing stress or death through the combined actions of the ecto-nucleotidases CD39 (ATP to AMP) and CD73 (AMP to ADO). Inhibition of ADO production via CD73 is a promising therapeutic approach for the treatment of cancer.Methods: The potency of CB-708 was evaluated against recombinant CD73 and CD73-expressing cells using a malachite green assay. Selectivity against related ecto-nucleotidases was also assessed. Inhibition of CD73 in plasma was measured using LC/MS to assess conversion of 15N5-AMP into 15N5-ADO. The ability to reverse AMP-mediated immune suppression of human CD8+ T cells was determined by adding exogenous AMP during T cell activation. T cell proliferation was assayed by flow cytometry and cytokine levels were measured by ELISA. The EG7 syngeneic tumor model was used to assess the therapeutic effect of CB-708.Results: CB-708 is an orally bioavailable small molecule inhibitor that can potently inhibit both soluble human CD73 (IC50 = 170 pM) and cell-bound human CD73 (IC50 = 210 pM), but does not inhibit human CD39 (IC50>10 µM), ENTPD2 (IC50>10 µM), nor ENTPD3 (IC50>10 µM). CB-708 retained high potency in the presence of plasma and reversed AMP-mediated suppression of human CD8+ T cell proliferation and production of IFNγ (EC50 = 4.5 nM) and granzyme B (EC50 = 5.6 nM) in vitro. Orally administered CB-708 had dose-dependent single-agent tumor growth inhibition in the EG7 mouse syngeneic tumor model and that was associated with pharmacodynamic inhibition of plasma CD73. Enhanced tumor growth inhibition was observed when anti-PD-L1 was combined with a highly related analog of CB-708 in the EG7 model.Conclusion: CB-708 is an orally bioavailable and highly potent small molecule inhibitor of CD73. CB-708 reverses the immunosuppressive effects of AMP-derived ADO in vitro and in vivo and leads to anti-tumor activity as a monotherapy. CB-708 is expected to enter clinical development in 2019.Citation Format: Clarissa C. Lee, Deepthi Bhupathi, Roland J. Billedeau, Jason Chen, Lijing Chen, Ethan D. Emberley, Matthew I. Gross, Tony Huang, Weiqun Li, Yong Ma, Andrew L. Mackinnon, Amani Makkouk, Gisele M. Marguier, Silinda Neou, Francesco Parlati, Natalija Sotirovska, Timothy F. Stanton, Susanne M. Steggerda, Jing Zhang, Winter Zhang, Jim Li. Reversal of adenosine-mediated immune suppression by CB-708, an orally bioavailable and potent small molecule inhibitor of CD73 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4134.
Evaluating Common Electronic Components and GaN HEMTs Under Cryogenic Conditions (2021)

Superconducting motors are a solution to electrifying large scale transport (aviation, rail, shipping) due to their superior power density over conventional electric motors. Cooling a superconducting motor and its power converter using the same cryogenic system provides a unique opportunity to increase the converter’s power density. This paper evaluates how conventional power converter components and emerging Gallium Nitride (GaN) technologies would fare at cryogenic temperatures. It is shown that GaN devices have a significant reduction in conduction losses at cryogenic temperatures. The behaviour of integrated circuits varies depending on device technology (CMOS, BJT, JFET), while temperature variation in capacitors depends on their dielectric material.
A Gja1 missense mutation in a mouse model of oculodentodigital dysplasia (2005)

Oculodentodigital dysplasia (ODDD) is an autosomal dominant disorder characterized by pleiotropic developmental anomalies of the limbs, teeth, face and eyes that was shown recently to be caused by mutations in the gap junction protein alpha 1 gene (GJA1), encoding connexin 43 (Cx43). In the course of performing an N-ethyl-N-nitrosourea mutagenesis screen, we identified a dominant mouse mutation that exhibits many classic symptoms of ODDD, including syndactyly, enamel hypoplasia, craniofacial anomalies and cardiac dysfunction. Positional cloning revealed that these mice carry a point mutation in Gja1 leading to the substitution of a highly conserved amino acid (G60S) in Cx43. In vivo and in vitro studies revealed that the mutant Cx43 protein acts in a dominant-negative fashion to disrupt gap junction assembly and function. In addition to the classic features of ODDD, these mutant mice also showed decreased bone mass and mechanical strength, as well as altered hematopoietic stem cell and progenitor populations. Thus, these mice represent an experimental model with which to explore the clinical manifestations of ODDD and to evaluate potential intervention strategies.
Generation of CD8+T-Cell Responses by a Recombinant NonpathogenicMycobacterium smegmatisVaccine Vector Expressing Human Immunodeficiency Virus Type 1 Env (2006)

Because the vaccine vectors currently being evaluated in human populations all have significant limitations in their immunogenicity, novel vaccine strategies are needed for the elicitation of cell-mediated immunity. The nonpathogenic, rapidly growing mycobacterium Mycobacterium smegmatis was engineered as a vector expressing full-length human immunodeficiency virus type 1 (HIV-1) HXBc2 envelope protein. Immunization of mice with recombinant M. smegmatis led to the expansion of major histocompatibility complex class I-restricted HIV-1 epitope-specific CD8(+) T cells that were cytolytic and secreted gamma interferon. Effector and memory T lymphocytes were elicited, and repeated immunization generated a stable central memory pool of virus-specific cells. Importantly, preexisting immunity to Mycobacterium bovis BCG had only a marginal effect on the immunogenicity of recombinant M. smegmatis. This mycobacterium may therefore be a useful vaccine vector.
Febuxostat, But Not Allopurinol, Markedly Raises the Plasma Concentrations of the Breast Cancer Resistance Protein Substrate Rosuvastatin (2020)

Xanthine oxidase inhibitors febuxostat and allopurinol are commonly used in the treatment of gout. Febuxostat inhibits the breast cancer resistance protein (BCRP) in vitro. Rosuvastatin is a BCRP substrate and genetic variability in BCRP markedly affects rosuvastatin pharmacokinetics. In this study, we investigated possible effects of febuxostat and allopurinol on rosuvastatin pharmacokinetics. In a randomized crossover study with 3 phases, 10 healthy volunteers ingested once daily placebo for 7 days, 300 mg allopurinol for 7 days, or placebo for 3 days, followed by 120 mg febuxostat for 4 days, and a single 10 mg dose of rosuvastatin on day 6. Febuxostat increased the peak plasma concentration and area under the plasma concentration-time curve of rosuvastatin 2.1-fold (90% confidence interval 1.8-2.6; P = 5 × 10<sup>-5</sup> ) and 1.9-fold (1.5-2.5; P = 0.001), but had no effect on rosuvastatin half-life or renal clearance. Allopurinol, on the other hand, did not affect rosuvastatin pharmacokinetics. In vitro, febuxostat inhibited the ATP-dependent uptake of rosuvastatin into BCRP-overexpressing membrane vesicles with a half-maximal inhibitory concentration of 0.35 µM, whereas allopurinol showed no inhibition with concentrations up to 200 µM. Taken together, the results suggest that febuxostat increases rosuvastatin exposure by inhibiting its BCRP-mediated efflux in the small intestine. Febuxostat may, therefore, serve as a useful index inhibitor of BCRP in drug-drug interaction studies in humans. Moreover, concomitant use of febuxostat may increase the exposure to BCRP substrate drugs and, thus, the risk of dose-dependent adverse effects.
SPEED (2009)

This paper describes an inter-procedural technique for computing symbolic bounds on the number of statements a procedure executes in terms of its scalar inputs and user-defined quantitative functions of input data-structures. Such computational complexity bounds for even simple programs are usually disjunctive, non-linear, and involve numerical properties of heaps. We address the challenges of generating these bounds using two novel ideas. We introduce a proof methodology based on multiple counter instrumentation (each counter can be initialized and incremented at potentially multiple program locations) that allows a given linear invariant generation tool to compute linear bounds individually on these counter variables. The bounds on these counters are then composed together to generate total bounds that are non-linear and disjunctive. We also give an algorithm for automating this proof methodology. Our algorithm generates complexity bounds that are usually precise not only in terms of the computational complexity, but also in terms of the constant factors. Next, we introduce the notion of user-defined quantitative functions that can be associated with abstract data-structures, e.g., length of a list, height of a tree, etc. We show how to compute bounds in terms of these quantitative functions using a linear invariant generation tool that has support for handling uninterpreted functions. We show application of this methodology to commonly used data-structures (namely lists, list of lists, trees, bit-vectors) using examples from Microsoft product code. We observe that a few quantitative functions for each data-structure are usually sufficient to allow generation of symbolic complexity bounds of a variety of loops that iterate over these data-structures, and that it is straightforward to define these quantitative functions. The combination of these techniques enables generation of precise computational complexity bounds for real-world examples (drawn from Microsoft product code and C++ STL library code) for some of which it is non-trivial to even prove termination. Such automatically generated bounds are very useful for early detection of egregious performance problems in large modular codebases that are constantly being changed by multiple developers who make heavy use of code written by others without a good understanding of their implementation complexity.
Low loss amorphous silicon photonic wire and ring resonator fabricated by CMOS process (2007)

We report low loss amorphous photonic wire loss of 3.5dB/cm. We also report compact racetrack ring resonators with Q factor greater than 20,000. The photonic circuit is fabricated with standard CMOS production
Closed-loop congestion control for mixed responsive and non-responsive traffic (2004)

Today's known and widely used active queue management (AQM) schemes do not differentiate between packets from responsive (e.g., TCP sessions) and non-responsive traffic (e.g., UDP). This results in further widening the gap of unfair advantage already inherent to non-responsive traffic, as the responsive sender can significantly reduce its future transmit rate as a result of the congestion signals. As a simple work-around, responsive and non-responsive traffic are often assigned distinct AQM parameters. This approach, however, requires tuning for each traffic class that potentially depends on the current or expected offered load. In other words, responsiveness and TCP friendliness cannot be estimated easily - not at least due to short-lived TCP sessions. We propose a closed-loop congestion control (CLCC) scheme on top of an existing AQM scheme to achieve fair bandwidth distribution among concurrent responsive and non-responsive traffic. The new scheme has the advantage that it does not need to estimate the level of responsiveness of traffic. We analyze our scheme on top of an existing rate-based AQM scheme known to approximate max-min fairness, and, by means of simulations, show that our extension significantly improves fair bandwidth allocation for responsive and non-responsive traffic. The simulation results have been verified with a prototype implementation on the IBM PowerNP 4GS3 network processor.
Comparison of Adsorption Conformation of Comb‐Shaped Polycarboxylate on Tricalcium Aluminate (100) and Ettringite (100) Surfaces: A Molecular Dynamics Study (2021)

Abstract The adsorption conformations of three comb‐shaped polycarboxylate (PCE) with different numbers of grafted side‐chains on the tricalcium aluminate (C3A) and ettringite surface is studied by all‐atom molecular dynamics (MD) simulations with INTERFACE‐PCFF forcefield. The similarity of absorbed PCEs on both surfaces is backbones of PCEs absorbed on the surface and the side‐chains extended to liquid phase. The difference is that side‐chains of PCEs keep a tilt angle with the C3A crystal but maintain parallel and closer to ettringite crystals. The absolute value of adsorption energy of PCEs on C3A surface is greater than that on ettringite surface, which indicate the stronger interaction between PCEs and C3A than ettringite. PCE with less side chains is favorable for the adsorption due to stronger electrostatic interaction with surface. Adsorption capacity and water‐reducing ability of PCEs are contradictory. Density of water near the solid–liquid interface is more severely decreased by PCE with more side chains. Correlation of the adsorption conformation of PCEs with the flow behaviors of fresh cement paste is summarized.
Nondegenerate optical Kerr effect in semiconductors (1994)

We calculate the nondegenerate bound electronic nonlinear refractive index n/sub 2/(/spl omega//sub 1/;/spl omega//sub 2/) (i.e., an index change at frequency /spl omega//sub 1/ due to the presence of a beam at frequency /spl omega//sub 2/) in semiconductors. We calculate this nonlinearity and its dispersion using a Kramers-Kronig transformation on the calculated nondegenerate nonlinear absorption spectrum due to two-photon absorption, electronic Raman and optical Stark effects. The calculated n/sub 2/ values and their dispersion are compared to new experimental values for ZnSe and ZnS obtained using a 2-color Z-scan.< <ETX xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">&gt;</ETX>
A Dual-Core Multi-Threaded Xeon Processor with 16MB L3 Cache (2006)

A dual-core 64b Xeonreg MP processor is implemented in a 65nm 8M process. The 435mm <sup xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">2</sup> die has 1.328B transistors. Each core has two threads and a unified 1MB L2 cache. The 16MB unified, 16-way set-associative L3 cache implements both sleep and shut-off leakage reduction modes
Posttreatment interleukin‐2 in patients with acute myeloid leukemia: The end of a long road for patients and clinical trials? (2013)

For over 2 decades, a series of clinical trials has tested the efficacy of interleukin‐2 as postremission therapy for patients with acute myeloid leukemia. In this issue, Kolitz et al describe a large clinical trial testing this hypothesis that ultimately failed to answer the question because of patients failing to complete the prescribed therapy.
Upfront autologous stem cell transplantation (ASCT) versus carfilzomib-cyclophosphamide-dexamethasone (KCd) consolidation with K maintenance in transplant-eligible, newly diagnosed (NDTE) multiple myeloma (MM). (2021)

8000 Background: Upfront ASCT for NDTE MM remains under evaluation with high MRD rates following novel induction and consolidation (cons) strategies. Current phase 3 trials support ASCT, however these employ lenalidomide maintenance which predominantly benefits standard risk (SR) patients (pts). The CARDAMON trial investigated the role of ASCT using K based induction and maintenance. Methods: NDTE pts received 4 x KCd induction (K 20/56 mg/m 2 biweekly, C 500 mg D 1,8,15, d 40mg weekly) before 1:1 randomisation to ASCT or 4 x KCd cons. All received 18 months K maintenance (56mg/m 2 D1,8,15). Flow cytometric MRD (10 -5 ) was assessed post induction, pre-maintenance and at 6 months maintenance. Primary endpoints were ≥VGPR post induction and 2-year PFS from randomisation. 210 randomised pts were needed to exclude a 10% non-inferiority margin with 15% 1-sided alpha, 80% power. Results: 281 pts were registered, median age 59y (33–74), 24% high risk [t(4;14), t(14;16), t(14;20) or del(17p)]. Post induction, ≥VGPR rate was 58.5%, ORR was 87% with similar responses for high risk vs SR. 52 pts did not proceed to PBSCH (6 MR, 16 PD, 19 toxicity, 4 deaths: 3 infection, 1 cardiac event, 7 other). 109 were randomised to ASCT, 109 to KCd cons. ≥VGPR rate was 78.5% after cons and 80.0% after ASCT (p = 0.8). Median KCd cons dose was 55.5 mg/m 2 , 99 (90.8%) pts completed 4 cycles, 104 (95.4%) pts received ASCT. After 2.6 years follow-up, median PFS was not reached for ASCT vs 3.8 years for cons (HR: 0.82 (70% CI 0.65, 1.05, p = 0.4). Observed 2-year PFS for ASCT was 75.5% vs 70.7% for cons; calculated difference in 2-year PFS rate (cons vs ASCT) was -4.5% (70% CI -9.2%, +1.1%, non-inferior). High risk pts had inferior outcomes to SR overall regardless of randomisation (2-year PFS ASCT: 52% vs 82% (HR 4.09); cons 48% vs 77% (HR 2.83)). 2 year PFS did not differ according to randomisation: SR 82% (ASCT) vs 77% (cons) HR: 1.29 (0.71-2.35); high risk: 52% (ASCT) vs 48% (cons) HR: 1.06 (0.50-2.23). MRD negativity post induction was 24.3% and similar by genetic risk. MRD negative rates were higher post ASCT (53.1%) than cons (35.8%) (p = 0.02) independent of genetics: SR 49% (ASCT) vs 36% (cons); high risk: 57% (ASCT) vs 32% (cons). G3+ adverse events to induction were infections (18.7%), hypertension (11.2%), anaemia (10.4%), cardiac disorders (3.6%), vomiting (2.2%), fatigue (2.2%), diarrhoea (1.8%). Conclusions: In NDMM receiving KCd induction and K maintenance, KCd cons was non-inferior to ASCT. High risk pts had inferior outcomes, that were not influenced by ASCT or cons randomisation. Clinical trial information: NCT02315716. [Table: see text]
LASER MICROMACHINING OF SILICON: A NEW TECHNIQUE FOR FABRICATING HIGH QUALITY TERAHERTZ WAVEGUIDE COMPONENTS' (1997)

One of the main obstacles encountered in designing low noise, high efficiency, heterodyne receivers and local oscillator sources at submillimeter wavelengths is the quality and cost of waveguide structures. At wavelengths shorter than 400 micrometers, rectangular waveguide structures, feedhorns, and backshorts become extremely difficult to fabricate using standard machining techniques. We have used a new laser milling technique to fabricate high quality, THz waveguide components and feedhorns. Once metallized, the structures have the properties of standard waveguide components. Unlike waveguide components made using silicon wet-etching techniques, laser-etched components can have almost any cross section, from rectangular to circular. Under computer control, the entire waveguide structure (including the corrugated feedhorn!) of a submillimeter-wave mixer or multiplier can be fabricated to micrometer tolerances in a few hours. Laser etching permits the direct scaling of successful waveguide multiplier and mixer designs to THz frequencies. Since the entire process is computer controlled, the cost of fabricating submillimeter waveguide components is significantly reduced. With this new laser etching process, the construction of high ' The Lincoln Laboratory portion of this work was performed under a cooperative research and development agreement (CRDA) with the University of Arizona. Opinions, interpretations, conclusions, and recommendations are those of the author and are not necessarily endorsed by the United States Government.
Confined Dynamics of Grafted Polymer Chains in Solutions of Linear Polymer (2017)

We measure the dynamics of high molecular weight polystyrene grafted to silica nanoparticles dispersed in semidilute solutions of linear polymer. Structurally, the linear free chains do not penetrate the grafted corona but increase the osmotic pressure of the solution, collapsing the grafted polymer and leading to eventual aggregation of the grafted particles at high matrix concentrations. Dynamically, the relaxations of the grafted polymer are controlled by the solvent viscosity according to the Zimm model on short time scales. On longer time scales, the grafted chains are confined by neighboring grafted chains, preventing full relaxation over the experimental time scale. Adding free linear polymer to the solution does not affect the initial Zimm relaxations of the grafted polymer but does increase the confinement of the grafted chains. Our results elucidate the physics underlying the slow relaxations of grafted polymer.
Growth inhibition of U937 leukemia cells by aqueous extract of Cordyceps militaris through induction of apoptosis (2005)

Cordyceps militaris is a traditional herbal ingredient, which has been used for patients suffering from cancer in Oriental medicine. In the present study, we investigated the biochemical mechanisms of anti-proliferative effects by aqueous extract of C. militaris (AECM) in human leukemia U937 cells. It was found that AECM could inhibit cell growth of U937 cells in a dose-dependent manner, which was associated with morphological change and apoptotic cell death such as formation of apoptotic bodies and DNA fragmentation. We observed the down-regulation of anti-apoptotic Bcl-2 expression and proteolytic activation of caspase-3 in AECM-treated U937 cells. However, AECM did not affect the pro-apoptotic Bax expression and activity of caspase-9. Furthermore, Western blotting and RT-PCR revealed that AECM treatment caused a dose-dependent inhibition of cyclooxygenase-2 and prostaglandin E2 accumulation. Taken together, these results indicated that the anti-proliferative effects of AECM were associated with the induction of apoptotic cell death through regulation of several major growth regulatory gene products such as Bcl-2 family expression and caspase protease activity, and AECM may have therapeutic potential in human leukemia treatment.
Signal dependent noise removal from a single image (2014)

State-of-the-art image denoising algorithms usually assume additive white Gaussian noise (AWGN), although they have achieved outstanding performance, modeling and removing real signal dependent noise from a single image still remains a challenging problem. In this paper we propose a segmentation-based image denoising algorithm for signal dependent noise. Incorporating a noise identification algorithm, we integrate these two modules into a full blind, end-to-end denoising algorithm for signal dependent noise. First, we identify the noise level function for a given single noisy image. Then, after initial denoising, segmentation is applied to the pre-filtered image. Assuming the noise level of each segment is constant, we apply AWGN denoising algorithm to each segment. We obtain a final de-noised image by composing the denoised segments. Various experimental results on synthetic and real noisy images show that our algorithm outperforms state-of-the-art denoising algorithms in removing real signal dependent noise.