gebhart/patrepeval huggingface dataset:
Attenuated poxviruses generate clinically relevant frequencies of CMV-specific T cells (2004)

Immunotherapeutic approaches to limit cytomegalovirus (CMV) morbidity and mortality after hematopoietic stem cell transplants (HSCTs) are currently under investigation as alternatives to antiviral drugs. In this context, we have inserted full-length and ubiquitin-modified CMV phosphoprotein 65 (pp65), phosphoprotein 150 (pp150), and immediate early protein 1 (IE1) immunodominant antigens into the virulent Western Reserve strain of vaccinia virus (VV) and the highly attenuated strain, modified vaccinia Ankara (MVA). Recombinant (r) VV or rMVA stimulated vigorous expansion of CMV-specific CD8+ T cells in CMV-positive donor peripheral blood mononuclear cells (PBMCs), which showed minimal alloreactivity and high levels of HLA tetramer binding, cytokine production, and cytotoxicity. Ubiquitinated antigens had a profound effect when expressed in VV. Single antigen rMVA expressing pp65 or IE1, either ubiquitin-modified or native, stimulated both cytotoxic T lymphocyte (CTL) populations to be expanded up to 500-fold in a 60-mL blood draw from the same donor. This result demonstrates the clinical feasibility of simultaneously amplifying multiple CMV-CTL populations. Transgenic HLA A2.1 (HHD II) mice, immunized with the same rMVA as used with human PBMCs, produced a robust cytotoxic response to both CMV pp65 and IE1. The specificity of the vigorous immunologic response to rMVA, both in vitro and in vivo, makes them candidates for clinical evaluation in the context of adoptive immunotherapy for hematopoietic stem cell transplant (HSCT) recipients or donor vaccination.
Comparison of NucliSens and Roche Monitor Assays for Quantitation of Levels of Human Immunodeficiency Virus Type 1 RNA in Plasma (1999)

We compared the performance of Organon Teknika's NucliSens and Roche Diagnostic Systems' Monitor quantitative human immunodeficiency type 1 RNA assays. Both had similar linearity and sensitivity over most of the dynamic range of the assays, although the Monitor assay was superior at the low range of RNA values while the NucliSens assay was more consistent at higher RNA values. NucliSens generally showed less interassay variability.
Pulmonary surfactant in health and human lung diseases: state of the art (1999)

Pulmonary surfactant is a complex and highly surface active material composed of lipids and proteins which is found in the fluid lining the alveolar surface of the lungs. Surfactant prevents alveolar collapse at low lung volume, and preserves bronchiolar patency during normal and forced respiration (biophysical functions). In addition, it is involved in the protection of the lungs from injuries and infections caused by inhaled particles and micro-organisms (immunological, non-biophysical functions). Pulmonary surfactant can only be harvested by lavage procedures, which may disrupt its pre-existing biophysical and biochemical micro-organization. These limitations must always be considered when interpreting ex vivo studies of pulmonary surfactant. A pathophysiological role for surfactant was first appreciated in premature infants with respiratory distress syndrome and hyaline membrane disease, a condition which is nowadays routinely treated with exogenous surfactant replacement. Biochemical surfactant abnormalities of varying degrees have been described in obstructive lung diseases (asthma, bronchiolitis, chronic obstructive pulmonary disease, and following lung transplantation), infectious and suppurative lung diseases (cystic fibrosis, pneumonia, and human immunodeficiency virus), adult respiratory distress syndrome, pulmonary oedema, other diseases specific to infants (chronic lung disease of prematurity, and surfactant protein-B deficiency), interstitial lung diseases (sarcoidosis, idiopathic pulmonary fibrosis, and hypersensitivity pneumonitis), pulmonary alveolar proteinosis, following cardiopulmonary bypass, and in smokers. For some pulmonary conditions surfactant replacement therapy is on the horizon, but for the majority much more needs to be learnt about the pathophysiological role the observed surfactant abnormalities may have.
Dominant and recessive mutations define functional domains of Toll, a transmembrane protein required for dorsal-ventral polarity in the Drosophila embryo. (1991)

The asymmetry of the dorsal-ventral pattern of the Drosophila embryo appears to depend on the ventral activation of the transmembrane Toll protein. The Toll protein is found around the entire dorsal-ventral circumference of the embryo, and it appears to act as a receptor for a ventral, extracellular signal and to then relay that signal to the cytoplasm in ventral regions of the embryo. Three of five recessive loss-of-function alleles of Toll are caused by point mutations in the region of the cytoplasmic domain of Toll that is similar to the mammalian interleukin-1 receptor, supporting the hypothesis that Toll acts as a signal-transducing receptor. Nine dominant gain-of-function alleles that cause Toll to be active in dorsal, as well as ventral, regions of the embryo are caused by mutations in the extracellular domain. Three of the dominant alleles appear to cause the protein to be constitutively active and are caused by cysteine-to-tyrosine changes immediately outside the transmembrane domain. All six of the remaining dominant alleles require the presence of a wild-type transmembrane Toll protein for their ventralizing effect and all encode truncated proteins that lack the transmembrane and cytoplasmic domains.
Dose modifications of liposomal irinotecan (nal-IRI) + 5-fluorouracil/leucovorin (5-FU/LV) in NAPOLI-1: Impact on efficacy. (2018)

388 Background: In NAPOLI-1 (NCT01494506), a randomized phase 3 study in patients with metastatic pancreatic cancer previously treated with gemcitabine-based therapy, nal-IRI+5-FU/LV improved overall survival (OS; primary endpoint) vs 5-FU/LV (6.1 mos vs 4.2 mos; HR = 0·67, 95% CI 0.490.92; P = 0.012). This exploratory analysis examined the impact of dose modifications or delays used to manage adverse events (AEs) on OS. The study protocol allowed ≤2 dose reductions for nal-IRI and 5-FU and for up to 3 weeks. Methods: Patient who had a dose delay or reduction within the planned first 6 weeks of the study were included. Delays were defined as any delay in dosing &gt; 3 days from target dosing date and dose reductions were defined as any reduction in dose from initial administered dose. OS was compared within the nal-IRI+5-FU/LV arm and with the 5-FU/LV arm. Comparisons were made using the cohort of 5-FU/LV and nal-IRI+5-FU/LV patients enrolled under protocol version 2. Median OS was based on Kaplan-Meier estimates and Cox regression analysis was used to calculate HRs. Results: More patients in the nal-IRI+5-FU/LV treatment group experienced AEs that required dose delay and/or reduction than in the 5-FU/LV treatment group (62% vs 33%). Within the nal-IRI+5-FU/LV arm, median OS was numerically but not significantly different between patients who did (n = 34) vs did not (n = 83) have a dose reduction (9.3 vs 5.4 mos; HR = 0.66 [95% CI 0.43, 1.01]) and for those who did (n = 49) vs did not (n = 68) have a dose delay (8.4 vs 5.6 mos; 0.82 [95% CI 0.56, 1.23]). Between treatment arms, OS was greater in the nal-IRI+5-FU/LV arm regardless of dose delay or reduction (Table). Conclusions: Dose modifications in the nal-IRI+5-FU/LV arm did not significantly impact OS compared with those who did not need a dose modification, and OS remained greater than in 5-FU/LV-treated patients. This suggests that appropriate dose modification of nal-IRI+5-FU/LV for AEs may not adversely affect outcomes. Clinical trial information: NCT01494506. [Table: see text]
Apparent Inhibition of β-Fructosidase Secretion by Tunicamycin May Be Explained by Breakdown of the Unglycosylated Protein during Secretion (1989)

Suspension-cultured carrot (Daucus carota) cells synthesize and secrete beta-fructosidase, a glycoprotein with asparagine-linked glycans. Treatment of the cells with tunicamycin completely inhibits the apparent secretion of beta-fructosidase as measured by the accumulation of the radioactive protein in the cell wall or the culture medium. In the past, such a result has been interpreted as an inhibition of secretion by tunicamycin, but we suggest another explanation based on the following results. In the presence of tunicamycin, unglycosylated beta-fructosidase is synthesized and is associated with an endoplasmic-reticulum-rich microsomal fraction. Pulse-chase experiments show that the unglycosylated beta-fructosidase does not remain in the cells and appears to be secreted in the same way as glycosylated beta-fructosidase; however, no radioactive, unglycosylated beta-fructosidase accumulates extracellularly (cell wall or medium). Protoplasts obtained from carrot cells secrete beta-fructosidase protein and activity, and treatment of the protoplasts with tunicamycin results in the synthesis of unglycosylated beta-fructosidase. In the presence of tunicamycin, there is no accumulation of beta-fructosidase activity or unglycosylated beta-fructosidase polypeptide in the protoplast incubation medium. These results are consistent with the interpretation that the glycans of beta-fructosidase are necessary for its stability, and that in these suspension-cultured cells, the unglycosylated enzyme is degraded during the last stage(s) of secretion, or immediately after its arrival in the wall.
Atomic layer controlled growth of SiO2 films using binary reaction sequence chemistry (1997)

SiO 2 thin films were deposited with atomic layer control using binary reaction sequence chemistry. The SiO2 growth was accomplished by separating the binary reaction SiCl4+2H2O→SiO2+4HCl into two half-reactions. Successive application of the half-reactions in an ABAB… sequence produced SiO2 deposition at temperatures between 600 and 800 K and reactant pressures of 1–10 Torr. The SiO2 growth was monitored using ellipsometry versus substrate temperature and reactant exposure time. The maximum SiO2 deposition per AB cycle was 1.1 Å/AB cycle at 600 K. The surface topography measured using atomic force microscopy was extremely flat with a roughness nearly identical to the initial substrate.
Photo-oxidative Stability and its Correlation with Semi-empirical MO Calculations of Various Tetraazaporphyrin Derivatives in Solution (1997)

The photo-oxidative stability of various annelated and substituted tetraazaporphyrin derivatives were investigated in N , N -dimethylformamide by irradiation in the presence of air. First-order rate constants were calculated. In addition, the positions of the HOMO and LUMO energy levels of the compounds were calculated using a commercially available program. A linear correlation between the experimental values of the rate constants and the theoretical values of the HOMO position exists. The method described allows one to predict the photo-oxidative stability by calculating their HOMO levels, which is very important for the use of macrocyclic metal complexes in photo-oxidation reactions in solution. From the calculated triplet energies it is considered that the macrocyclic metal complexes can convert by photoinduced energy transfer triplet oxygen to singlet oxygen. Experimentally, tetraazaporphyrin derivatives show high quantum yields of singlet oxygen formation under irradiation. No correlations of the quantum yields with the position of the HOMOs or with the rate constants of decomposition was observed.
Bubble-Free Silicon Wafer Bonding in a Non-Cleanroom Environment (1988)

Bubble-free bonding of 4-inch silicon wafers on either silicon or quartz wafers is achieved outside a cleanroom. Two wafers are stacked horizontally in a rack with the two mirror-polished surfaces facing each other. In order to avoid wafer contact during hydrophilization, cleaning, and drying, the wafers are separated in the rack by teflon spacers introduced at the wafer edges. After drying the wafers by a spin dryer, the spacers are removed and bonding occurs. Using this procedure we are also able to monitor the bonding process between quartz and silicon wafers at different temperatures. We find that the initial wafer bonding process at room temperature stops operating at temperatures above 200°C.
Characterization of a New Animal Model for Evaluation of Persistent Postthoracotomy Pain (2004)

Chronic pain after thoracotomy is common, although its basis and therapy have not been well characterized. In this study we characterize the allodynic responses (mechanical and cold) as well as the histopathologic changes after thoracotomy and rib retraction in rats. The antinociceptive effect of systemic and intrathecal analgesics was also evaluated. Male Sprague-Dawley rats were anesthetized and the right 4th and 5th ribs surgically exposed. The pleura was opened between the ribs and a retractor placed under both ribs and opened 8 mm. Retraction was maintained for 5, 30, or 60 min. Control animals had pleural incision only. Beginning Day 2 postsurgery, animals were tested for mechanical allodynia using calibrated von Frey filaments and cold allodynia using acetone applied to the incision site. Two weeks after surgery, animals were tested for reduction of allodynia with intraperitoneal and intrathecal injections of analgesics. Intercostal nerve histology was examined at 14 days postsurgery. Allodynia developed in 50% of the animals with 60 min retraction but in only 11% and 10% of animals when the retraction time was 5 and 30 min, respectively, and in none of the control animals. Allodynic animals showed extensive axon loss in the intercostal nerves of the retracted ribs. Allodynia appeared by Day 10 in the rib-retraction model and lasted at least 40 days. Systemic morphine sulfate (50% effective dose [ED(50)], 1.06 mg/kg) and gabapentin (ED(50), 24.2 mg/kg), as well as intrathecal morphine (ED(50), 1.19 nmol), gabapentin (ED(50), 13.8 nmol), clonidine (ED(50), 72.7 nmol), and neostigmine (ED(50), 0.54 nmol) reduced allodynia. Rib-retraction in rats for 60 min produces allodynia that lasts more than 1 mo, and this allodynia is reduced by morphine, gabapentin, clonidine, and neostigmine. This new model may be useful for quantifying the efficacy of techniques to reduce the frequency and severity of long-term postthoracotomy pain.
An Efficient Method for Electroporation of Small Interfering RNAs into ENCODE Project Tier 1 GM12878 and K562 Cell Lines (2015)

The Encyclopedia of DNA Elements (ENCODE) Project aims to identify all functional sequence elements in the human genome sequence by use of high-throughput DNA/cDNA sequencing approaches. To aid the standardization, comparison, and integration of data sets produced from different technologies and platforms, the ENCODE Consortium selected several standard human cell lines to be used by the ENCODE Projects. The Tier 1 ENCODE cell lines include GM12878, K562, and H1 human embryonic stem cell lines. GM12878 is a lymphoblastoid cell line, transformed with the Epstein-Barr virus, that was selected by the International HapMap Project for whole genome and transcriptome sequencing by use of the Illumina platform. K562 is an immortalized myelogenous leukemia cell line. The GM12878 cell line is attractive for the ENCODE Projects, as it offers potential synergy with the International HapMap Project. Despite the vast amount of sequencing data available on the GM12878 cell line through the ENCODE Project, including transcriptome, chromatin immunoprecipitation-sequencing for histone marks, and transcription factors, no small interfering siRNA-mediated knockdown studies have been performed in the GM12878 cell line, as cationic lipid-mediated transfection methods are inefficient for lymphoid cell lines. Here, we present an efficient and reproducible method for transfection of a variety of siRNAs into the GM12878 and K562 cell lines, which subsequently results in targeted protein depletion.
Dopamine Neuron Agenesis in Nurr1-Deficient Mice (1997)

Dopamine neurons of the substantia nigra and ventral tegmental area regulate movement and affective behavior and degenerate in Parkinson's disease. The orphan nuclear receptor Nurr1 was shown to be expressed in developing dopamine neurons before the appearance of known phenotypic markers for these cells. Mice lacking Nurr1 failed to generate midbrain dopaminergic neurons, were hypoactive, and died soon after birth. Nurr1 expression continued into adulthood, and brains of heterozygous animals, otherwise apparently healthy, contained reduced dopamine levels. These results suggest that putative Nurr1 ligands may be useful for treatment of Parkinson's disease and other disorders of midbrain dopamine circuitry.
Emergency Department Crowding: Time for Interventions and Policy Evaluations (2012)

This paper summarises the consequences of emergency department crowding. It provides a comparison of the scales used to measure emergency department crowding. We discuss the multiple causes of crowding and present an up-to-date literature review of the interventions that reduce the adverse consequences of crowding. We consider interventions at the level of an individual hospital and a policy level.
Mutations in the EGFR kinase domain mediate STAT3 activation via IL-6 production in human lung adenocarcinomas (2007)

Persistently activated or tyrosine-phosphorylated STAT3 (pSTAT3) is found in 50% of lung adenocarcinomas. pSTAT3 is found in primary adenocarcinomas and cell lines harboring somatic-activating mutations in the tyrosine kinase domain of EGFR. Treatment of cell lines with either an EGFR inhibitor or an src kinase inhibitor had no effect on pSTAT3 levels, whereas a pan-JAK inhibitor (P6) blocked activation of STAT3 and inhibited tumorigenesis. Cell lines expressing these persistently activated mutant EGFRs also produced high IL-6 levels, and blockade of the IL-6/gp130/JAK pathway led to a decrease in pSTAT3 levels. In addition, reduction of IL-6 levels by RNA interference led to a decrease in tumorigenesis. Introduction of persistently activated EGFR into immortalized breast epithelial cells led to tumorigenesis, IL-6 expression, and STAT3 activation, all of which could be inhibited with P6 or gp130 blockade. Furthermore, inhibition of EGFR activity in multiple cell lines partially blocked transcription of IL-6 and concurrently decreased production and release of IL-6. Finally, immunohistochemical analysis revealed a positive correlation between pSTAT3 and IL-6 positivity in primary lung adenocarcinomas. Therefore, mutant EGFR could activate the gp130/JAK/STAT3 pathway by means of IL-6 upregulation in primary human lung adenocarcinomas, making this pathway a potential target for cancer treatment.
Use of Bacteriophage-resistant Mutants to Study the Nature of the Bacteriophage Receptor Site of Staphylococcus aureus (1969)

Bacteriophage-resistant strains of Staphylococcus aureus H were isolated after mutagenesis with N -methyl- N′ -nitro- N -nitrosoguanidine. Cell walls isolated from about half of these resistant strains were incapable of inactivating phages and were shown to lack N -acetyl- d -glucosamine (GlcNAc) in their cell wall teichoic acid. Apart from the lack of GlcNAc, two of these mutant strains were deficient in cell wall phosphorus and ester-linked d -alanine. These two strains were also found to be resistant to both phage K and a host-range mutant isolated from the parent phage. These two phages could lyse the other phage-resistant mutants which lacked GlcNAc in their teichoic acid. Cell walls from the remaining phage-resistant mutant strains did inactivate phages and were found to have normal cell wall teichoic acid. Although GlcNAc in teichoic acid was required for phage inactivation, no difference in phage inactivation ability was detected with cell walls isolated from strains of S. aureus having exclusively α- or exclusively β-linked GlcNAc in their cell wall teichoic acid.
Hypermethylated APC DNA in Plasma and Prognosis of Patients With Esophageal Adenocarcinoma (2000)

The APC promoter region was hypermethylated in tumors of the majority of patients with primary esophageal adenocarcinomas. Levels of hypermethylated APC gene DNA in the plasma may be a useful biomarker of biologically aggressive disease in esophageal adenocarcinoma patients and should be evaluated as a potential biomarker in additional tumor types.
Customizable Lipid Nanoparticle Materials for the Delivery of siRNAs and mRNAs (2018)

RNAs are a promising class of therapeutics given their ability to regulate protein concentrations at the cellular level. Developing safe and effective strategies to deliver RNAs remains important for realizing their full clinical potential. Here, we develop lipid nanoparticle formulations that can deliver short interfering RNAs (for gene silencing) or messenger RNAs (for gene upregulation). Specifically, we study how the tail length, tail geometry, and linker spacing in diketopiperazine lipid materials influences LNP potency with siRNAs and mRNAs. Eight lipid materials are synthesized, and 16 total formulations are screened for activity in vitro; the lead material is evaluated with mRNA for in vivo use and demonstrates luciferase protein expression in the spleen. In undertaking this approach, not only do we develop synthetic routes to delivery materials, but we also reveal structural criteria that could be useful for developing next-generation delivery materials for RNA therapeutics.
Oxygen Distribution in the Rabbit Eye and Oxygen Consumption by the Lens (2006)

Intraocular oxygen is mostly derived from the retinal and iris vasculature and by diffusion across the cornea. Freshly secreted aqueous humor and the aqueous humor in the anterior chamber angle are relatively depleted of oxygen. The marked increase in oxygen consumption that occurs when the lens is exposed to increased oxygen is likely to result in the production of higher levels of reactive oxygen species and may provide a link between elevated oxygen levels and the risk of nuclear cataracts.
APCSK9Missense Variant Associated with a Reduced Risk of Early-Onset Myocardial Infarction (2008)

Patients Controls % Finland FINRISK 209 210 1.3 4.1 0.30 (0.11-0.84) 0.02 Sweden Malm Diet and Cancer Study -cardiovascular cohort 150 149 0.7 2.0 0.32 (0.07-1.61) 0.17 Spain Registre Gironi del Cor (REGICOR) 361 361 1.0 2.8 0.35 (0.15-0.82) 0.02 Seattle Heart Attack Risk in Puget Sound 542 631 0.9 1.9 0.45 (0.21-0.98) 0.
Cellular eIF2B subunit localization: implications for the integrated stress response and its control by small molecule drugs (2019)

Eukaryotic initiation factor 2 (eIF2) is a G protein critical for translation. It is tightly regulated in the integrated stress response (ISR) via phosphorylation of eIF2α and the subsequent control of eukaryotic initiation factor 2B (eIF2B), a multisubunit guanine nucleotide exchange factor. Through studying the localization of eIF2B subunits, we identified cytoplasmic eIF2B bodies in mammalian cells. We highlight a relationship between body size and the eIF2B subunits localizing to them; larger bodies contain all subunits and smaller bodies contain predominantly catalytic subunits. eIF2 localizes to eIF2B bodies and shuttles within these bodies in a manner that correlates with eIF2B activity. On stress, eIF2α-P localizes predominately to larger bodies and results in a decreased shuttling of eIF2. Interestingly, drugs that inhibit the ISR can rescue eIF2 shuttling in a manner correlating to levels of eIF2α-P. In contrast, smaller bodies show increased eIF2 shuttling in response to stress, which is accompanied by the localization of eIF2Bδ to these bodies, suggesting the formation of a novel trimeric complex of eIF2B. This response is mimicked by ISR-inhibiting drugs, providing insight into their potential mechanism of action. This study provides evidence that the composition and function of mammalian eIF2B bodies are regulated by the ISR and the drugs that control it.