gebhart/patrepeval huggingface dataset:
The Hepatic First‐Pass Metabolism of Problematic Drugs (1993)

The first-pass hepatic metabolism of a number of important therapeutic agents is inconsistent with traditional models that assume that the hepatic extraction ratio of a drug is constant in each individual (independent of the concentration of drug in the hepatic sinusoidal blood and also independent of the history of exposure to the drug). In this review, the authors examine the first-pass metabolism of five "problematic drugs" (propranolol, lidocaine, propafenone, verapamil, and nitroglycerin). Each of these compounds has unique facets to its hepatic clearance and pharmacokinetics as well as striking similarities. Selected aspects of first-pass metabolism are reviewed, and a theory that may explain some of the unusual behavior of the four lipophilic bases (propranolol, lidocaine, propafenone, and verapamil) is presented. Finally, the unusual and variable clearance of nitroglycerin is discussed.
Brief communication Condition code predictor for fixed-point arithmetic units (1989)

Abstract This paper presents a method for determining the ‘results equals zero’ condition code and, by extension, all other related condition codes for arithmetic operations. The ‘result equals zero’ condition is predicted for all arithmetic operations computed by a typical hardwired adder, and can be implemented in hardware in parallel with such an adder without implicit or explicit use of the carries.
Synthesis of Yokonoside and Its Related Compounds (1976)

Total synthesis of yokonoside, 2'-carboxy-4', 5-dihydroxy-2-β-D-glucopyranosyloxybenzanilide (1b), isolated from Aconitum japonicum THUNB., was carried out by two different routes. The 4'-deoxy analog (1a) was also synthesized. The Koenigs-Knorr reaction of 5-benzyloxy-2-hydroxy-2'-methoxycarbonylbenzanilide (5a) with silver carbonate gave a dimer, 2, 3'-bis (2-methoxycarbonylphenylcarbamoyl)-4, 5'-dibenzyloxy-2'-hydroxydiphenyl ether (7a), as a by-product.
Electron microscopy of the sequence of events in the atheroembolic occlusion of cerebral arteries in an animal model. (1975)

Atheromatous material was removed from human atheromas, suspended in sterile saline in the ratio of 1 g to 5 ml and ground to allow passage through a needle; 0-5 ml of this suspension was injected into the left common carotid artery of 16 rabbits. Six animals died after the injection. The remaining animals were killed after various time intervals and the occluded arteries studied by electron microscopy. The general pattern of the embolic event in the cerebral arteries was that there were 3 groups of changes. Firstly, an immediate period of atherothrombotic occlusion occurred, which was followed by some resolution of the obstruction so as to leave the cholesterol crystals of the embolus stuck in the vessel walls as the only remaining element of the embolus in some cases. Finally, there was a late period in which the cholesterol crystals were isolated from the lumen of the vessel and surrounded by macrophages, fibroblastic cells and collagen. Endothelial lined channels developed in the original obstruction.
Sub-Lethal Effects of Pesticide Residues in Brood Comb on Worker Honey Bee (Apis mellifera) Development and Longevity (2011)

This study is the first to demonstrate sub-lethal effects on worker honey bees from pesticide residue exposure from contaminated brood comb. Sub-lethal effects, including delayed larval development and adult emergence or shortened adult longevity, can have indirect effects on the colony such as premature shifts in hive roles and foraging activity. In addition, longer development time for bees may provide a reproductive advantage for parasitic Varroa destructor mites. The impact of delayed development in bees on Varroa mite fecundity should be examined further.
Prediction of sensitivity of advanced non-small cell lung cancers to gefitinib (Iressa, ZD1839) (2004)

Gefitinib (Iressa, ZD1839), an inhibitor of epidermal growth factor receptor-tyrosine kinase, has shown potent anti-tumor effects and improved symptoms and quality-of-life of a subset of patients with advanced non-small cell lung cancer (NSCLC). However, a large portion of the patients showed no effect to this agent. To establish a method to predict the response of NSCLC patients to gefitinib, we used a genome-wide cDNA microarray to analyze 33 biopsy samples of advanced NSCLC from patients who had been treated with an identical protocol of second to seventh line gefitinib monotherapy. We identified 51 genes whose expression differed significantly between seven responders and 10 non-responders to the drug. We selected the 12 genes that showed the most significant differences to establish a numerical scoring system (GRS, gefitinib response score), for predicting response to gefitinib treatment. The GRS system clearly separated the two groups without any overlap, and accurately predicted responses to the drug in 16 additional NSCLC cases. The system was further validated by the semi-quantitative RT-PCR, immunohistochemistry and ELISA for serological test. Moreover, we proved that the anti-apoptotic activity of amphiregulin, a protein that was significantly over-expressed in non-responders but undetectable in responders, leads to resistance of NSCLC cells to gefitinib in vitro. Our results suggested that sensitivity of a given NSCLC to gefitinib can be predicted according to expression levels of a defined set of genes that may biologically affect drug sensitivity and survival of lung cancer cells. Our scoring system might eventually lead to achievement of personalized therapy for NSCLC patients.
Solvent extraction and purification of sugars from hemicellulose hydrolysates using boronic acid carriers (2004)

Abstract Research was performed to determine whether it was technically feasible to use boronic acid extractants to purify and concentrate the sugars present in hemicellulose hydrolysates. Initially, five types of boronic acids (phenylboronic acid, 3,5‐dimethylphenylboronic acid, 4‐ tert ‐butylphenylboronic acid, trans ‐β‐styreneboronic acid or naphthalene‐2‐boronic acid) dissolved in an organic diluent (Shellsol ® 2046 or Exxal ® 10) containing the quaternary amine Aliquat ® 336 were tested for their ability to extract sugars (fructose, glucose, sucrose and xylose) from a buffered, immiscible aqueous solution. Naphthalene‐2‐boronic acid was found to give the greatest extraction of xylose regardless of which diluent was used. Trials were then conducted to extract xylose and glucose from solutions derived from the dilute acid hydrolysis of sugar cane bagasse and to then strip the loaded organic solutions using an aqueous solution containing hydrochloric acid. This produced a strip solution in which the xylose concentration had been increased over 7× that of the original hydrolysate while reducing the concentration of the undesirable acid‐soluble lignin by over 90%. Hence, this process can be exploited to produce high concentration xylose solutions suitable for direct fermentation. Copyright © 2004 Society of Chemical Industry
Semi‐automated flow cytometric analysis of CD34‐expressing hematopoietic cells in peripheral blood progenitor cell apheresis products (1999)

The ProCOUNT kit and software for semi-automated data acquisition and analysis represents a further step toward standardization of CD34 cell quantitation in peripheral blood progenitor cell apheresis products. However, the occurrence of software warnings is high, and analysis or data reevaluation by experienced staff is still mandatory. Therefore, currently there is no definite advantage of the kit and software over the existing guidelines for CD34+ analysis in peripheral blood progenitor cell grafts.
Osteoprotegerin (OPG)—a potential new role in the regulation of endothelialcell phenotype and tumour angiogenesis? (2005)

The progression of cancer depends on the establishment of a tumour blood supply, and therefore tumour angiogenesis has been identified as a major target for new anticancer agents. Recent reports have suggested that osteoprotegerin (OPG) is involved in the control of endothelial cell survival through the inhibition of the activity of tumour necrosis factor- (TNF) related apoptosis-inducing ligand (TRAIL). The role of OPG in human tumour development and angiogenesis is currently unknown. In the present study we demonstrate the ability of OPG to support endothelial cell survival, as well as the formation of cord-like structures in vitro using a matrigel tubule formation assay. Investigation of various human cancers demonstrated endothelial OPG expression in 59% of malignant tumours (n=512), but in contrast, OPG was absent in endothelial cells associated with benign tumours and normal tissues (n=178). In a series of 400 breast tumours, endothelial OPG expression was associated with high tumour grade and certain histological types. Our data show a clear separation in endothelial OPG expression between malignant tumours and nonmalignant tissues, supporting a potential biological role for this molecule in the development and/or maintenance of the tumour vasculature. This is the first study to report the proangiogenic effects of OPG in vitro, as well as correlating expression of OPG by tumour endothelial cells with clinicopathological data in human tumours.
Pathogen Inactivation of Platelet and Plasma Blood Components for Transfusion Using the INTERCEPT Blood System<sup>TM</sup> (2011)

BACKGROUND: The transmission of pathogens via blood transfusion is still a major threat. Expert conferences established the need for a pro-active approach and concluded that the introduction of a pathogen inactivation/reduction technology requires a thorough safety profile, a comprehensive pre-clinical and clinical development and an ongoing hemovigilance program. MATERIAL AND METHODS: The INTERCEPT Blood System utilizes amotosalen and UVA light and enables for the treatment of platelets and plasma in the same device. Preclinical studies of pathogen inactivation and toxicology and a thorough program of clinical studies have been conducted and an active he-movigilance-program established. RESULTS: INTERCEPT shows robust efficacy of inactivation for viruses, bacteria (including spirochetes), protozoa and leukocytes as well as large safety margins. Furthermore, it integrates well into routine blood center operations. The clinical study program demonstrates the successful use for very diverse patient groups. The hemovigilance program shows safety and tolerability in routine use. Approximately 700,000 INTERCEPT-treated products have been transfused worldwide. The system is in clinical use since class III CE-mark registration in 2002. The safety and efficacy has been shown in routine use and during an epidemic. CONCLUSION: The INTERCEPT Blood System for platelets and plasma offers enhanced safety for the patient and protection against transfusion-transmitted infections.
Nanophotonic phased array for visible light image projection (2016)

We demonstrate the first large-scale integrated nanophotonic phased array for visible wavelengths in a silicon nitride platform. The array consists of 32×32 optical antenna elements designed to project complex intensity patterns in the far field at a wavelength of λ = 635 nm.
CLDN3 inhibits cancer aggressiveness via Wnt-EMT signaling and is a potential prognostic biomarker for hepatocellular carcinoma (2014)

Hepatocellular carcinoma (HCC) is one of the most common fatal malignancies but the molecular genetic basis of this disease remains unclear. By using genome-wide methylation profiling analysis, we identified CLDN3 as an epigenetically regulated gene in cancer. Here, we investigated its function and clinical relevance in human HCC. CLDN3 downregulation occurred in 87/114 (76.3%) of primary HCCs, where it was correlated significantly with shorter survival of HCC patients (P=0.021). Moreover, multivariate cyclooxygenase regression analysis showed that CLDN3 was an independent prognostic factor for overall survival (P=0.014). Absent expression of CLDN3 was also detected in 67% of HCC cell lines, which was significantly associated with its promoter hypermethylation. Ectopic expression of CLDN3 in HCC cells could inhibit cell motility, cell invasiveness, and tumor formation in nude mice. Mechanistic investigations suggested through downregulation of GSK3B, CTNNB1, SNAI2, and CDH2, CLDN3 could significantly suppress metastasis by inactivating the Wnt/β-catenin-epithelial mesenchymal transition (EMT) axis in HCC cells. Collectively, our findings demonstrated that CLDN3 is an epigenetically silenced metastasis suppressor gene in HCC. A better understanding of the molecular mechanism of CLDN3 in inhibiting liver cancer cell metastasis may lead to a more effective management of HCC patients with the inactivation of CLDN3.
Engineering of blended nanoparticle platform for delivery of mitochondria-acting therapeutics (2012)

Mitochondrial dysfunctions cause numerous human disorders. A platform technology based on biodegradable polymers for carrying bioactive molecules to the mitochondrial matrix could be of enormous potential benefit in treating mitochondrial diseases. Here we report a rationally designed mitochondria-targeted polymeric nanoparticle (NP) system and its optimization for efficient delivery of various mitochondria-acting therapeutics by blending a targeted poly(d,l-lactic-co-glycolic acid)-block (PLGA-b)-poly(ethylene glycol) (PEG)-triphenylphosphonium (TPP) polymer (PLGA-b-PEG-TPP) with either nontargeted PLGA-b-PEG-OH or PLGA-COOH. An optimized formulation was identified through in vitro screening of a library of charge- and size-varied NPs, and mitochondrial uptake was studied by qualitative and quantitative investigations of cytosolic and mitochondrial fractions of cells treated with blended NPs composed of PLGA-b-PEG-TPP and a triblock copolymer containing a fluorescent quantum dot, PLGA-b-PEG-QD. The versatility of this platform was demonstrated by studying various mitochondria-acting therapeutics for different applications, including the mitochondria-targeting chemotherapeutics lonidamine and α-tocopheryl succinate for cancer, the mitochondrial antioxidant curcumin for Alzheimer's disease, and the mitochondrial uncoupler 2,4-dinitrophenol for obesity. These biomolecules were loaded into blended NPs with high loading efficiencies. Considering efficacy, the targeted PLGA-b-PEG-TPP NP provides a remarkable improvement in the drug therapeutic index for cancer, Alzheimer's disease, and obesity compared with the nontargeted construct or the therapeutics in their free form. This work represents the potential of a single, programmable NP platform for the diagnosis and targeted delivery of therapeutics for mitochondrial dysfunction-related diseases.
Modulation and induction of eosinophil chemotaxis by granulocyte- macrophage colony-stimulating factor and interleukin-3 (1991)

Eosinophilia and eosinophil function are regulated by cytokines such as granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin-3 (IL-3), and IL-5. We have investigated the modulatory role of GM-CSF and IL-3 on the platelet-activating factor (PAF)-, neutrophil-activating factor (NAF/IL-8)-, leukotriene B4 (LTB4)-, N-formyl-methionyl-leucyl-phenylalanine (FMLP)-, and human complement factor C5a-induced chemotaxis of eosinophils from normal individuals. These eosinophils show a chemotactic response toward PAF, LTB4, and C5a, but not to NAF/IL-8 and FMLP. Preincubation of the eosinophils with picomolar concentrations of GM-CSF caused a significant increase in the response toward LTB4 and induced a significant chemotactic response toward NAF/IL-8 and FMLP. Preincubation of the eosinophils with picomolar concentrations of IL-3 also induced a chemotactic response toward NAF/IL-8 and FMLP, and enhanced the PAF-induced chemotaxis response toward C5a was not influenced by both cytokines. Nanomolar concentrations of GM-CSF or IL-3 caused a significant inhibition of the C5a-induced chemotaxis. The LTB4-induced chemotaxis was also significantly inhibited in case of GM-CSF. At these concentrations both GM-CSF and IL-3 acted as chemotaxins for eosinophils were washed after pretreatment with GM-CSF and IL-3 the potentiation of the chemotactic response remained, whereas the inhibitory mode of action disappeared. Our data indicate that at picomolar concentrations the cytokines GM-CSF and IL-3 can modulate eosinophil chemotaxis and at nanomolar concentrations these cytokines can act as chemotaxins for eosinophils.
H2O2 and Tumor Necrosis Factor-α Activate Intercellular Adhesion Molecule 1 (ICAM-1) Gene Transcription through Distinct cis-Regulatory Elements within the ICAM-1 Promoter (1995)

We investigated the mechanisms by which H2O2 increases intercellular adhesion molecule 1 (ICAM-1; CD54) expression in endothelial cells. The H2O2-induced increase in ICAM-1 mRNA was inhibited by actinomycin D, by the antioxidant N-acetylcysteine, and by 3-amino-benzamide (which blocks oxidant-induced AP-1 activity), but not by pyrrolidine dithiocarbamate (which blocks oxidant-induced NF-kappa B activity). Nuclear run-on and transient transfections of ICAM-1 promoter constructs indicated that H2O2 stimulated ICAM-1 gene transcription by activation of a distinct region of the ICAM-1 promoter. The H2O2-responsive element was localized to sequences between -981 and -769 (relative to start codon). Located within this region are two 16-base pair repeats, each containing binding sites for the transcription factors AP-1 and Ets. A similar composite AP-1/Ets element isolated from the macrophage scavenger receptor gene conferred H2O2 responsiveness to a minimal promoter. Mutation of the 16-base pair repeats within the ICAM-1 promoter prevented H2O2-induced DNA binding activity, and their deletion abrogated the H2O2-induced transcriptional activity. In contrast, TNF alpha induced ICAM-1 transcription via activation of promoter sequences between -393 and -176, a region with C/EBP and NF-kappa B binding sites. The results indicate that H2O2 activates ICAM-1 transcription through AP-1/Ets elements within the ICAM-1 promoter, which are distinct from NF-kappa B-mediated ICAM-1 expression induced by TNF alpha.
THE IMMUNOTHERAPY OF SOLID CANCERS BASED ON CLONING THE GENES ENCODING TUMOR-REJECTION ANTIGENS (1996)

Cellular immune reactions play a major role in the host reaction to growing cancers. Tumor infiltrating lymphocytes (TIL) can be isolated from melanomas and can specifically recognize unique tumor antigens. The adoptive transfer of TIL plus interleukin-2 can mediate tumor regression in patients with metastatic melanoma. TIL capable of mediating tumor regression have been used to clone and sequence a variety of the genes that encode the tumor-regression antigens recognized by these TIL. This information has opened new opportunities for the development of cancer immunotherapies. These gene products can be used to generate lymphocytes, in vitro, with improved antitumor activity for use in adoptive transfer. Active immunization can be performed using either the immunodominant peptides present in these proteins or by incorporating the tumor antigen genes into recombinant viruses. Cancer vaccine trials using many of these approaches have recently begun. Attempts to apply a similar strategy to epithelial tumors such as breast and ovarian cancer are underway.
Effect of Amino-Terminal Processing by Staphylococcus aureus V-8 Protease on Activity and Structure of Recombinant Human Interferon-γ (1990)

Treatment of recombinant human interferon-gamma (rHuIFN-gamma) with Staphylococcus aureus V-8 protease generated a transiently stable species that lacks 10 amino-terminal residues. This protein showed distinct secondary and higher-order structures with an alpha-helical content of 31%, suggesting that the secondary and tertiary structure largely remain upon removal of 10 amino-terminal residues. The antiviral activity was abolished, or greatly reduced, for this species relative to the intact protein. These results suggest an important role for the amino-terminal portion in the activity of human interferon-gamma. Since the digested protein is difficult to refold from the acid-denatured state, it was concluded that, although not essential for maintaining the core structure of the protein, the amino-terminal portion is critical for refolding the protein from acid.
Discrete Variational Autoencoders (2016)

Probabilistic models with discrete latent variables naturally capture datasets composed of discrete classes. However, they are difficult to train efficiently, since backpropagation through discrete variables is generally not possible. We present a novel method to train a class of probabilistic models with discrete latent variables using the variational autoencoder framework, including backpropagation through the discrete latent variables. The associated class of probabilistic models comprises an undirected discrete component and a directed hierarchical continuous component. The discrete component captures the distribution over the disconnected smooth manifolds induced by the continuous component. As a result, this class of models efficiently learns both the class of objects in an image, and their specific realization in pixels, from unsupervised data, and outperforms state-of-the-art methods on the permutation-invariant MNIST, Omniglot, and Caltech-101 Silhouettes datasets.
Sensors and sensor arrays based on conjugated polymers and carbon nanotubes (2002)

Abstract The need for cheaper, faster, and more accurate measurements has been a driving force for the development of new sensing devices. As is well known, the electrical conductivity of conjugated polymers can be reliably regulated over a wide range through interactions with electron acceptors and donors. This, together with the fast optical dynamics (either in the ground or excited states) of most conjugated polymers, has made conjugated polymers very attractive as transducer-active materials. On the other hand, the unusual electronic, mechanical, and thermal properties of carbon nanotubes have also led to their potential use in a wide range of devices, including sensors. In particular, the ability of carbon nanotubes and their derivatives to operate as gas and glucose sensors has been recently demonstrated. This article provides a status review on the research and development of sensors and sensor arrays based on conjugated polymers and carbon nanotubes. The unique features characteristic of most reported sensing transduction modes related to conjugated polymers and carbon nanotubes are discussed, along with their pros and cons.
IL-10–producing and naturally occurring CD4+ Tregs: limiting collateral damage (2004)

Effective immune responses against pathogens are sometimes accompanied by strong inflammatory reactions. To minimize damage to self, the activation of the immune system also triggers anti-inflammatory circuits. Both inflammatory and anti-inflammatory reactions are normal components of the same immune response, which coordinately fight infections while preventing immune pathology. IL-10 is an important suppressive cytokine, produced by a large number of immune cells in addition to the antigen-driven IL-10-producing regulatory and the naturally occurring suppressor CD4+ T cells, which is a key player in anti-inflammatory immune responses. However, additional mechanisms have evolved to ensure that pathogen eradication is achieved with minimum damage to the host. Here we discuss those mechanisms that operate to regulate effector immune responses.
A micromachining post-process module for RF silicon technology (2002)

A bulk-micromachining post-process module, based on two-level structuring of RF silicon substrates and a 4-/spl mu/m thick one-level sub-surface metal pattern, is presented. This allows for fabricating three-dimensional structures for novel RF components and has potential in more compact integration. Next to a concise description of the relevant aspects of the fabrication process, mechanical stability of the postprocessed wafers is analyzed. Sub-surface spiral inductors with good quality and low coupling to inductors built at the wafer surface are presented, thus demonstrating the feasibility of three-dimensional integration of RF components.