gebhart/patrepeval huggingface dataset:
CD38-Mediated Immunosuppression as a Mechanism of Tumor Cell Escape from PD-1/PD-L1 Blockade (2018)

Although treatment with immune checkpoint inhibitors provides promising benefit for patients with cancer, optimal use is encumbered by high resistance rates and requires a thorough understanding of resistance mechanisms. We observed that tumors treated with PD-1/PD-L1 blocking antibodies develop resistance through the upregulation of CD38, which is induced by all-trans retinoic acid and IFNβ in the tumor microenvironment. <i>In vitro</i> and <i>in vivo</i> studies demonstrate that CD38 inhibits CD8<sup>+</sup> T-cell function via adenosine receptor signaling and that CD38 or adenosine receptor blockade are effective strategies to overcome the resistance. Large data sets of human tumors reveal expression of CD38 in a subset of tumors with high levels of basal or treatment-induced T-cell infiltration, where immune checkpoint therapies are thought to be most effective. These findings provide a novel mechanism of acquired resistance to immune checkpoint therapy and an opportunity to expand their efficacy in cancer treatment.<b>Significance:</b> CD38 is a major mechanism of acquired resistance to PD-1/PD-L1 blockade, causing CD8<sup>+</sup> T-cell suppression. Coinhibition of CD38 and PD-L1 improves antitumor immune response. Biomarker assessment in patient cohorts suggests that a combination strategy is applicable to a large percentage of patients in whom PD-1/PD-L1 blockade is currently indicated. <i>Cancer Discov; 8(9); 1156-75. ©2018 AACR.</i><i>See related commentary by Mittal et al., p. 1066</i><i>This article is highlighted in the In This Issue feature, p. 1047</i>.
Use of the valine biosynthetic pathway to convert glucose into isobutanol (2010)

Microbiological synthesis of higher alcohols (1-butanol, isobutanol, 2-methyl-1-butanol, etc.) from plant biomass is critically important due to their advantages over ethanol as a motor fuel. In recent years, the use of branched-chain amino acid (BCAA) biosynthesis pathways together with heterologous Ehrlich pathway enzyme system (Hazelwood et al. in Appl Environ Microbiol 74:2259-2266, 2008) has been proposed by the Liao group as an alternative approach to aerobic production of higher alcohols as new-generation biofuels (Atsumi et al. in Nature 451:86-90, 2008; Atsumi et al. in Appl Microbiol Biotechnol 85:651-657, 2010; Cann and Liao in Appl Microbiol Biotechnol 81:89-98, 2008; Connor and Liao in Appl Environ Microbiol 74:5769-5775, 2008; Shen and Liao in Metab Eng 10:312-320, 2008; Yan and Liao in J Ind Microbiol Biotechnol 36:471-479, 2009). On the basis of these remarkable investigations, we re-engineered Escherichia coli valine-producing strain H-81, which possess overexpressed ilvGMED operon, for the aerobic conversion of sugar into isobutanol. To redirect valine biosynthesis to the production of alcohol, we also--as has been demonstrated previously (Atsumi et al. in Nature 451:86-90, 2008; Atsumi et al. in Appl Microbiol Biotechnol 85:651-657, 2010; Cann and Liao in Appl Microbiol Biotechnol 81:89-98, 2008; Connor and Liao in Appl Environ Microbiol 74:5769-5775, 2008; Shen and Liao in Metab Eng 10:312-320, 2008; Yan and Liao in J Ind Microbiol Biotechnol 36:471-479, 2009)--used enzymes of Ehrlich pathway. In particular, in our study, the following heterologous proteins were exploited: branched-chain 2-keto acid decarboxylase (BCKAD) encoded by the kdcA gene from Lactococcus lactis with rare codons substituted, and alcohol dehydrogenase (ADH) encoded by the ADH2 gene from Saccharomyces cerevisiae. We show that expression of both of these genes in the valine-producing strain H-81 results in accumulation of isobutanol instead of valine. Expression of BCKAD alone also resulted in isobutanol accumulation in the culture broth, supporting earlier obtained data (Atsumi et al. in Appl Microbiol Biotechnol 85:651-657, 2010) that native ADHs of E. coli are also capable of isobutanol production. Thus, in this work, isobutanol synthesis by E. coli was achieved using enzymes similar to but somewhat different from those previously used.
T1R3 and gustducin in gut sense sugars to regulate expression of Na + -glucose cotransporter 1 (2007)

Dietary sugars are transported from the intestinal lumen into absorptive enterocytes by the sodium-dependent glucose transporter isoform 1 (SGLT1). Regulation of this protein is important for the provision of glucose to the body and avoidance of intestinal malabsorption. Although expression of SGLT1 is regulated by luminal monosaccharides, the luminal glucose sensor mediating this process was unknown. Here, we show that the sweet taste receptor subunit T1R3 and the taste G protein gustducin, expressed in enteroendocrine cells, underlie intestinal sugar sensing and regulation of SGLT1 mRNA and protein. Dietary sugar and artificial sweeteners increased SGLT1 mRNA and protein expression, and glucose absorptive capacity in wild-type mice, but not in knockout mice lacking T1R3 or alpha-gustducin. Artificial sweeteners, acting on sweet taste receptors expressed on enteroendocrine GLUTag cells, stimulated secretion of gut hormones implicated in SGLT1 up-regulation. Gut-expressed taste signaling elements involved in regulating SGLT1 expression could provide novel therapeutic targets for modulating the gut's capacity to absorb sugars, with implications for the prevention and/or treatment of malabsorption syndromes and diet-related disorders including diabetes and obesity.
CW diode-pumped optical parametric oscillator inbulk periodically poled LiNbO 3 (1995)

The authors report a 1.96 µm doubly resonant optical parametric oscillator using bulk periodically poled LiNbO3 directly pumped by a commercial 980 nm CW diode laser.
Linear and proximal benzo-separated alkylated xanthines as adenosine-receptor antagonists (1989)

The linear and proximal benzo-separated derivatives of 8-phenyltheophylline, 1,3-diethyl-8-phenylxanthine, 1,3-dipropylxanthine, 1,3-dibutylxanthine, 3-isobutyl-1-methylxanthine, theophylline, caffeine, and isocaffeine have been synthesized and evaluated for affinity at the A1 and A2 adenosine receptors. Although structure-activity relationships in the benzo-separated series differed from the relationships in the simple xanthines, the most potent of the benzo-separated xanthines were about equal in affinity to the most potent of the corresponding xanthines. On the basis of the present results and the diverse structures reported in the literature as non-xanthine adenosine antagonists, it appears that the primary requirement for adenosine-receptor affinity in nonnucleosides is a flat, neutral, fused-ring heterocycle and that once this requirement is met there are numerous potential binding modes.
The Proapoptotic Activities of Bax and Bak Limit the Size of the Neural Stem Cell Pool (2003)

The proapoptotic Bcl-2 family members Bak and Bax play central and redundant roles in the regulation of apoptosis. In this study, we investigated the effect of loss of Bax and Bak in the CNS. The adult bax-/-bak-/- mice display masses of densely staining cells in the proliferative zones of the brain. These cells are shown to be a mix of neural progenitor cells and postmitotic cells at different stages of neural and glial differentiation. Both neural progenitor cells and mature neurons derived from bax-/-bak-/- mice were resistant to various apoptotic stimuli. Despite this resistance, postmitotic mature bax-/-bak-/- neurons remain as sensitive to excitoxic death as wild-type neurons. Thus, Bax and Bak play a critical role in regulating the number of neural progenitor cells in the adult brain but are not absolutely required for the initiation of neuronal cell death after neurotoxic injury.
Boosting in the presence of label noise (2013)

Boosting is known to be sensitive to label noise. We studied two approaches to improve AdaBoost's robustness against labelling errors. One is to employ a label-noise robust classifier as a base learner, while the other is to modify the AdaBoost algorithm to be more robust. Empirical evaluation shows that a committee of robust classifiers, although converges faster than non label-noise aware AdaBoost, is still susceptible to label noise. However, pairing it with the new robust Boosting algorithm we propose here results in a more resilient algorithm under mislabelling.
Tumor-Derived Tissue Factor Aberrantly Activates Complement and Facilitates Lung Tumor Progression via Recruitment of Myeloid-Derived Suppressor Cells (2017)

The initiator of extrinsic coagulation, tissue factor (TF), and its non-coagulant isoform alternatively spliced TF (asTF) are closely associated with tumor development. In the tumor microenvironment, the role of TF-induced coagulation in tumor progression remains to be fully elucidated. Using TF-knockdown lung tumor cells, we showed that TF is the dominant component of procoagulant activity but is dispensable in the cellular biology of tumor cells. In a xenograft model, using immunohistochemical analysis and flow cytometry analysis of the tumor microenvironment, we demonstrated that TF-induced fibrin deposition, which is correlated with complement activation and myeloid-derived suppressor cell (MDSC) recruitment, is positively associated with tumor progression. C5aR antagonism blunted the effect of TF on tumor progression and decreased MDSC recruitment. In conclusion, our data suggested that in tumor microenvironment, TF-induced coagulation activated the complement system and subsequently recruited myeloid-derived suppressor cells to promote tumor growth, which brings new insights into the coagulation-induced complement activation within the tumor microenvironment during tumor progression.
Progress toward high-performance infrared imaging systems-on-a-chip (2000)

Continuing advances in CMOS technology including finer lithography, the addition of dense planarized interconnect layers, concomitant improvements in transistor performance, and the availability of design tools that facilitate large- scale circuit integration, are now enabling the development of systems on a chip. While the first such imaging systems- on-a-chip supported detection of radiation at visible wavelengths, recent imaging systems-on-a-chip extend into the infrared. The result is high-performance infrared FPAs with high functionality. We report our progress at Rockwell Science Center in exploiting submicron CMOS to produce such infrared imaging systems-on-a-chip while overcoming accompanying challenges such as lower operating voltage. Our goal is to develop third-generation infrared imagers with compelling performance and functionality advantages that not only provide high sensitivity and resolution, but also facilitate on-demand sensor selection to adeptly match each mission without need for extensive support logistics including extensive cooling and elaborate camera electronics.
Basic and Clinical Neurocardiology (2004)

Abstract The progression of heart disease is associated with changes in the neurohumoral mechanisms that control cardiac function. The degree to which this neurohumoral remodelling occurs, even before overt signs of cardiac disease become manifest, is important for prognosis. To determine why some patients experience sudden death while others sustain life in the presence of severely compromised cardiac function, the neuronal control of cardiac electrical and mechanical events must be considered. Starting at the level of individual neurons and building upwards, this book describes the synergistic interactions that occur among intrathoracic and CNS feedback loops to permit precise control of regional cardiac behaviour. On this basic science foundation, subsequent clinical chapters explore the remodelling that occurs in this system with ageing, with the evolution of specific cardiac pathologies, and with the psychological concomitants of heart disease. Most importantly, these chapters provide unique insights into how specific therapies like beta-andrenergic receptor blockade not only affect cardiomyocytes directly but also mitigate the adverse neurohumoral changes that accompany disease processes, such as heart failure and essential hypertension. The paradigm advanced in this volume is that heart disease is a multifaceted phenomenon involving the interplay of neurohumoral, cardiomyocyte and structural elements, each of which depends on the other. With our cumulative understanding of these interdependent processes, new avenues for time-appropriate, targeted methods of treating heart diseases can be developed.
Androgens Stimulate Myogenic Differentiation and Inhibit Adipogenesis in C3H 10T1/2 Pluripotent Cells through an Androgen Receptor-Mediated Pathway (2003)

Testosterone supplementation increases skeletal muscle mass and decreases fat mass; however, the underlying mechanisms are unknown. We hypothesized that testosterone regulates body composition by promoting the commitment of mesenchymal pluripotent cells into myogenic lineage and inhibiting their differentiation into adipogenic lineage. Mouse C3H 10T1/2 pluripotent cells were treated with testosterone (0-300 nM) or dihydrotestosterone (DHT, 0-30 nM) for 0-14 d, and myogenic conversion was evaluated by immunocytochemical staining for early (MyoD) and late (myosin heavy chain II; MHC) myogenic markers and by measurements of MyoD and MHC mRNA and protein. Adipogenic differentiation was assessed by adipocyte counting and by measurements of peroxisomal proliferator-activated receptor gamma 2 (PPAR gamma 2) mRNA and PPAR gamma 2 protein and CCAAT/enhancer binding protein alpha. The number of MyoD+ myogenic cells and MHC+ myotubes and MyoD and MHC mRNA and protein levels increased dose dependently in response to testosterone and DHT treatment. Both testosterone and DHT decreased the number of adipocytes and down-regulated the expression of PPAR gamma 2 mRNA and PPAR gamma 2 protein and CCAAT/enhancer binding protein alpha. Androgen receptor mRNA and protein levels were low at baseline but increased after testosterone or DHT treatment. The effects of testosterone and DHT on myogenesis and adipogenesis were blocked by bicalutamide. Therefore, testosterone and DHT regulate lineage determination in mesenchymal pluripotent cells by promoting their commitment to the myogenic lineage and inhibiting their differentiation into the adipogenic lineage through an androgen receptor-mediated pathway. The observation that differentiation of pluripotent cells is androgen dependent provides a unifying explanation for the reciprocal effects of androgens on muscle and fat mass in men.
Dose-dependent effects of leucine supplementation on preservation of muscle mass in cancer cachectic mice (2011)

Cancer cachexia, which is characterized by muscle wasting, is associated with increased morbidity and mortality. Because muscle protein synthesis may be increased and protein breakdown reduced by leucine supplementation, we used the C26 tumor-bearing cachectic mouse model to assess the effects of dietary supplementation with leucine on muscle weight and the markers of muscle protein breakdown (mRNA of atrogin and murf). Male CD2F1 mice were subcutaneously inoculated with tumor cells (tumor-bearing mice; TB) or were sham injected (control; C). They were fed standard diets or diets supplemented with leucine [1 gr (TB1Leu) or 8 gr (TB8Leu) supplemented leucine per kg feed]; TB and C received 8.7% Leu/g protein, TB1Leu received 9.6% Leu/g protein and TB8Leu received 14.6 Leu/g protein. After 21 days, the following were determined: body weights, plasma amino-acid concentrations, tumor size and muscle mass of the gastrocnemius (mG), tibialis anterior (mTA), extensor digitorum longus (mEDL) and soleus (mS) muscles. In tumor-bearing (TB) mice, carcass and skeletal muscle masses decreased, and levels of atrogin and murf mRNA in the mEDL increased. Muscle-mass loss was counteracted dose-dependently by leucine supplementation: relative to TB, the mass of the mG was +23% in TB8Leu, and +22% in mTA (p<0.05). However, leucine supplementation did not change atrogin and murf mRNA levels. Total plasma amino acid concentrations increased in TB, especially for taurine, lysine, arginine and alanine (p<0.05). Leucine supplementation attenuated the increase in total plasma amino-acid concentrations (p<0.05). Irrespective of changes in muscle protein breakdown markers, leucine supplementation reduced muscle wasting in tumor-bearing cachectic mice and attenuated changes in plasma amino acids.
Extension and complexity reduction of TwinVQ audio coder (2002)

This paper proposes two novel techniques for twinVQ (transform domain weighted interleave VQ) high-quality audio coding scheme for rates lower than 64 kbit/s. One is an extension of the weighted interleave technique to the time and input channel domains as well as the frequency domain. The other is an efficient representation scheme of the spectral envelope by means of a interpolated square root LPC (linear predictive coding) spectrum.
Oocyte Galα1,3Gal Epitopes Implicated in Sperm Adhesion to the Zona Pellucida Glycoprotein ZP3 Are Not Required for Fertilization in the Mouse (1995)

The Gal alpha 1-->3Gal structure is displayed on the zona pellucida glycoprotein ZP3 on murine oocytes. This trisaccharide has been implicated in sperm-zona pellucida adhesive events thought to be essential to fertilization in the mouse. To determine directly if this molecule is required for fertilization, we have generated mice that are deficient in a gene (alpha 1,3GT) encoding the UDP-Gal:beta-D-Gal-alpha 1-->3Gal-galactosyltransferase enzyme responsible for Gal alpha 1-->3Gal synthesis and expression. These mice develop normally and exhibit no gross phenotypic abnormalities. The Gal alpha 1-->3Gal epitope is absent from the vascular endothelium and other tissues in alpha 1,3GT (-/-) adult mice. By contrast, alpha 1,3GT (-/-) mice, like humans, develop naturally occurring anti-alpha-galactoside antibodies normally absent in wild type mice. Female alpha 1,3GT (-/-) mice yield oocytes that are devoid of the Gal alpha 1-->3Gal epitope; however, these mice are fully fertile. These observations indicate that the Gal alpha 1-->3Gal moiety is not essential to sperm-oocyte interactions leading to fertilization or to essentially normal development. They further suggest that alpha 1,3GT (-/-) mice will find utility for exploring approaches to diminish anti-Gal-dependent hyperacute xenograft rejection, which presents a major barrier to the use of porcine and other non-primate organs for xenotransplantation in humans.
Structure/Function Analysis of Pasteurella multocida Heparosan Synthases (2012)

The Pasteurella multocida heparosan synthases, PmHS1 and PmHS2, are homologous (∼65% identical) bifunctional glycosyltransferase proteins found in Type D Pasteurella. These unique enzymes are able to generate the glycosaminoglycan heparosan by polymerizing sugars to form repeating disaccharide units from the donor molecules UDP-glucuronic acid (UDP-GlcUA) and UDP-N-acetylglucosamine (UDP-GlcNAc). Although these isozymes both generate heparosan, the catalytic phenotypes of these isozymes are quite different. Specifically, during in vitro synthesis, PmHS2 is better able to generate polysaccharide in the absence of exogenous acceptor (de novo synthesis) than PmHS1. Additionally, each of these enzymes is able to generate polysaccharide using unnatural sugar analogs in vitro, but they exhibit differences in the substitution patterns of the analogs they will employ. A series of chimeric enzymes has been generated consisting of various portions of both of the Pasteurella heparosan synthases in a single polypeptide chain. In vitro radiochemical sugar incorporation assays using these purified chimeric enzymes have shown that most of the constructs are enzymatically active, and some possess novel characteristics including the ability to produce nearly monodisperse polysaccharides with an expanded range of sugar analogs. Comparison of the kinetic properties and the sequences of the wild-type enzymes with the chimeric enzymes has enabled us to identify regions that may be responsible for some aspects of both donor binding specificity and acceptor usage. In combination with previous work, these approaches have enabled us to better understand the structure/function relationship of this unique family of glycosyltransferases.
Outline of a Theory of Statistical Estimation Based on the Classical Theory of Probability (1937)

Abstract We shall distinguish two aspects of the problems of estimation . (i) the practical and (ii) the theoretical. The practical aspect may be described as follows: (ia) The statistician is concerned with a population, π, which for some reason or other cannot be studied exhaustively. It is only possible to draw a sample from this population which may be studied in detail and used to form an opinion the values of certain constants describing the properties of the population π. For example, it may be desired to calculate approximately the mean of a certain character possessed by the individuals forming the population π, etc.
CALMODULIN AND CALBINDIN D28K IN ALZHEIMER DISEASE (1987)

The calcium binding proteins, calmodulin and calbindin D28K, were measured by radioimmunoassay in cerebral cortex from brains with degenerative brain diseases associated with dementia. Samples were obtained from 17 normal control brains, 18 Alzheimer affected brains, and 15 brains of patients who died of a dementia process other than Alzheimer disease. Calmodulin content in the non-Alzheimer group was not significantly different from control. However, in the Alzheimer group, frontal, temporal, parietal cortex, and subjacent white matter calmodulin content was significantly reduced (66% of that found in the other 2 groups). Calmodulin extracted from temporal cortex also demonstrated reduced efficacy as an activator of 3',5' cyclic nucleotide phosphodiesterase. Calbindin D28K was reduced both in Alzheimer and non-Alzheimer dementia brains. Reduced concentrations of these important proteins may affect calcium homeostasis and the regulation of a large number of calcium mediated brain functions.
cDNA Microarray Analysis of Gene Expression in Ovarian Cancer Cells After Treatment with Carboplatin and Paclitaxel (2006)

Background: Tumor resistance to chemotherapy results in ovarian cancer treatment failures. To understand the role of DNA damage, expression profiling was performed in ovarian cancer cells following suboptimal carboplatin (Carbo) and paclitaxel (Tax) treatments. Materials and Methods: Cell lines isolated from one patient were used. UL-3A was isolated at initial diagnosis, UL-3B after failure to cisplatin and Tax, and UL-3C at the final stages of the disease. Five clones isolated from UL-3A were also included. Sulforhodamine B assay was used to determine drug sensitivities. Gene expression was studied by DNA repair pathway specific microarray. Results: The cytotoxic phase was induced in all cells with Carbo and/or Tax treatments. Some cells recovered after individual drug treatments with the UL-3B cells surviving all modalities. Significant changes in the sensitivity of some surviving cells to chemotherapeutic agents were demonstrated. Carbo or Tax treatments resulted in significantly increased MDM2 and MSH6 and decreased 53BP1, EXT1, H2AFL and UNG expression. Combined Carbo and Tax treatment resulted in decreased ATR, CHEK1, PPM1D and PRKDC and increased RAD1, CDS1 and ATRX expression. Conclusion: Differential gene expression patterns were identified in cells that survived Carbo and Tax treatment that may be involved in ovarian cancer drug resistance.
High-Speed Multiprocessors and Compilation Techniques (1980)

The purpose of this paper is to present some ideas on multiprocessor design and on automatic translation of sequential programs into parallel programs for multiprocessors. With respect to machine design, two subjects are discussed. First, a multiprocessor allowing parallelism at a very low level is sketched and then, a brief discussion on the interconnection network is presented.