gebhart/patrepeval huggingface dataset:
Up-regulation of LFA-3 and ICAM-1 on the surface of fibroblasts infected with cytomegalovirus. (1993)

The effect of cytomegalovirus (CMV) infection on the cell surface expression of the adhesion molecules LFA-3 and ICAM-1 was studied by flow cytometry using human embryo lung fibroblasts. Our results demonstrated a marked increase in the expression of these molecules from days 1 to 5 post-infection. Peak expression of LFA-3 and ICAM-1 on the surface of the infected cell occurred at 2 days post-infection, when LFA-3 was twofold, and ICAM-1 threefold, greater than the level observed on uninfected fibroblasts. In contrast, parallel studies on the expression of class I HLA confirmed our previous findings that CMV induces a down-regulation of this molecule on the surface of the infected cell, and further demonstrated that at the time of maximum increase in LFA-3 and ICAM-1 expression, class I HLA expression was only 46% of the uninfected cell level. Immunofluorescence and confocal scanning laser microscopy revealed markedly enhanced expression of LFA-3 in infected cells, with accumulations in discrete granules in the perinuclear area, contrasting with the diffuse cytoplasmic distribution of this molecule in uninfected fibroblasts. ICAM-1 was found to be highly localized at the cell membrane of infected cells, whereas a diffuse cytoplasmic distribution was observed in the uninfected cell. The mechanism of the up-regulation of adhesion molecule expression on the CMV-infected cells remains to be determined; however cytokines known to up-regulate ICAM-1 were not detected in the culture supernatant of infected cells. The effects of CMV infection on the adhesion of peripheral blood leucocytes to fibroblasts is described in the accompanying manuscript (p. 413).
Evolution of Hepatitis B Virus Polymerase Gene Sequence during Famciclovir Therapy for Chronic Hepatitis B (2000)

Prolonged administration of nucleoside analogues for chronic hepatitis B may result in the emergence of hepatitis B viral polymerase mutants. To gain insight into the mechanism involved in the virus's resistance to famciclovir, the amino acid sequences of the terminal protein and reverse-transcriptase (RT) domains of the viral polymerase were determined during therapy among 28 patients. The antiviral response was independent of viral genotypes, and nonresponse to famciclovir was associated with a complex variability of the RT domain. No mutation in the YMDD motif was observed, whereas an L528M mutation was clearly selected by famciclovir treatment in 2 patients, as well as 14 novel mutations in 7 patients. Clone sequence analysis of the RT domains of patients undergoing retreatment with famciclovir and/or lamivudine showed the selection of a preexisting drug-resistant mutant in one case and indicated that sequential antiviral therapy may allow the rapid selection of resistant strains.
Preliminary results of a phase I/IIa study of BMS-986156 (glucocorticoid-induced tumor necrosis factor receptor–related gene [GITR] agonist), alone and in combination with nivolumab in pts with advanced solid tumors. (2017)

104 Background: BMS-986156 is a fully human IgG1 agonist mAb that binds GITR and promotes T effector cell activation and possible reduction/inactivation of T regulatory cells. Preclinical data show enhanced antitumor T-cell activity with anti-GITR + anti–programmed death-1 (PD-1). Here we describe preliminary dose escalation data from a phase I/IIa study of BMS-986156 ± nivolumab (anti–PD-1 mAb) in pts with advanced solid tumors (NCT02598960). Methods: During dose escalation, pts received BMS-986156 (10–800 mg) or BMS-986156 (30–800 mg) + nivolumab (240 mg) every 2 weeks. Objectives included safety (primary), immunogenicity, pharmacokinetics (PK), pharmacodynamics (PD), and efficacy. Results: As of Dec 12, 2016, 66 pts were treated with BMS-986156 (n = 29) or BMS-986156 + nivolumab (n = 37).No dose-limiting toxicities (DLTs) were reported during dose escalation. The most common treatment-related adverse events reported with BMS-986156/BMS-986156 + nivolumab included pyrexia (21%/30%), chills (10%/16%), and fatigue (14%/14%); events were G1/2 in all pts except for 4 pts (6%) treated with the combination (G3 lipase [n = 1], G3 lung infection [n = 1], G3 fatigue [n = 1], and G3 aspartate aminotransferase with G4 creatine phosphokinase [n = 1; leading to discontinuation of treatment]). Preliminary data indicate that the incidence of immunogenicity to BMS-986156 was low when BMS-986156 ± nivolumab was administered. Preliminary data also indicate that BMS-986156 ± nivolumab exhibits linear PK with dose proportionality after a single dose, and BMS-986156 ± nivolumab is biologically active in PD analyses in peripheral blood. Initial antitumor activity has been observed in several pts treated with the combination; these data will be reported. Conclusions: This is the first report of clinical data with an anti-GITR mAb ± a PD-1 inhibitor.BMS-986156 ± nivolumab was well tolerated, with no DLTs and low immunogenicity. Antitumor activity was observed with BMS-986156 + nivolumab at doses predicted to be biologically active. Further evaluation of this combination in pts with advanced solid tumors is ongoing. Clinical trial information: NCT02598960.
Synthesis of four colors fluorescently labelled 3'-O-blocked nucleotides with fluoride cleavable blocking group and linker for array based Sequencing-by-Synthesis applications (2008)

Reversible terminators having a fluoride cleavable 3'-O-blocking group are presented. Each nucleotide triphosphate is labelled by a fluorescent dye cleavable by the same reagent. We present here their synthesis, cleavage experiments and polymerase incorporation tests for a possible use in a process of Sequencing-by-Synthesis.
Identification of antigens of Mycobacterium tuberculosis using human monoclonal antibodies. (1989)

Pleural tuberculosis constitutes a human model of local pro- tective immunity to mycobacterial infection as the disease is usually self-limited and recurrent pleurisy is rare. To identify potentially protective antigens of Mycobacterium tuberculosis, 37 human pleural fluid B cell clones were established using EBV and their supernatants assayed by ELISA and Western blot for antibody reactivity with M. tuberculosis sonicate and culture filtrate. One antibody identified 29,000, 31,000, and 33,000 bands in culture filtrate, and 31,000, 33,000, and 47,000 bands in sonicate; its species reactivity by ELISA was limited to M. tuberculosis. Eight antibodies identified a 31,000 band in culture filtrate and a 68,000 band in M. tuberculosis sonicate, suggesting recognition of a secreted antigen. The species crossreactivity of these eight antibodies extended to M. avium. Six antibodies identified multiple bands and had crossreactivity that included M. avium and M. kansasii. There was no reactivity with recombinant M. tuberculosis 65,000 antigen. Tuberculous pleurisy may prove useful in the identifi- cation of potentially protective mycobacterial antigens, particularly those secreted during active infection, and thus accessi- ble to the human immune response.
Cell Growth Transformation by Epstein Barr Virus (1991)

Epstein-Barr Virus (EBV) was discovered 25 years ago during a search for an etiologic agent in human Burkitt lymphoma (BL), a remarkably unusual, geographically restricted, tumor. In vitro infection of primary B lymphocytes acutely and efficiently resulted in persistent latent infection and lymphocyte growth transformation (for a review of biological properties and for relevant references prior to 1989 see 1). The latently infected, growth transformed, lymphocytes are not only immortal in culture, but also are tumorigenic when inoculated into the brain of nude mice or into the peritoneum of SCID mice. Large virus innocula also induce rapidly fatal lymphoproliferative disease in cotton top tamarinds. In some genetically predisposed or severely immune deficient humans, EBV infection can also evolve into rapidly fatal lymphoproliferative disease.Aside from these direct effects on cell proliferation, EBV infection is also closely associated with nasopharyngeal carcinoma (NPC) and African BL, tumors which occur long after primary EBV infection; even among populations with a relatively high incidence of these tumors. The uniform presence of EBV in all malignant cells of endemic BL or NPC and the molecular biologic evidence that these tumors grow from an EBV infected cell, link EBV etiologically to these late onset malignancies.
A phase 1 dose-escalation study of veliparib with bimonthly FOLFIRI in patients with advanced solid tumors. (2014)

2574 Background: Veliparib (V; ABT-888), a potent, competitive poly (ADP-ribose) polymerase (PARP)-1 and -2 inhibitor enhances the activity of irrinotecan (IRI). This study seeks to establish the maximum tolerated dose (MTD) and recommended Phase 2 dose (RPTD) of V in combination with bimonthly FOLFIRI. Methods: Solid tumorpatients (pts; ≤3 prior DNA-damaging regimens) were administered V BID (days 1-5; 15–19) and FOLFIRI in three parts (P) : (P1) IRI 150 mg/m2; (P2) IRI 180 mg/m2 with 5-FU 400 mg/m2 bolus; or (P3) IRI 180mg/m2. All regimens included folinic acid 400 mg/m2, immediately followed by 5-FU 46-hour continuous infusion. Dose escalation began with V 10 mg BID in P1 and 100 mg BID in P2 and P3. Two expansion cohorts were evaluated in gastric or colorectal cancer pts with no prior PARP inhibitor therapy. Results: 96 pts (median age 54.5 years; range, 24–77) were enrolled in cohorts from 10–300 mg BID V. Tumor types were: other (n=30); gastric (n=20); pancreatic (n=14); ovarian, breast, and colorectal (each, n=9). 88 pts discontinued: 83 due to progressive disease; 2 withdrew consent; and 3 other. Most common AEs (>40% pts) were diarrhea (61%), nausea (60%), neutropenia (59%), vomiting (48%), fatigue (47%), anemia and alopecia (each, 41%). Grade 3/4 AEs (>30 pts) were neutropenia (47%), nausea (38%), and diarrhea (34%). Four DLTs occurred: neutropenia (n=3; P1, 160 mg and 270 mg BID V; P2, 100 mg BID V); and gastritis and vomiting (P1, 270 mg BID V). 12 pts (gastric, n=3; ovarian, breast, pancreatic, and other, each n=2; colorectal, n=1) achieved a partial response and 1 (ovarian) a complete response. V exposure was approximately dose-proportional in combination with FOLFIRI. FOLFIRI PKs were comparable with or without V administration, indicating the lack of drug-drug interaction. Conclusions: V in combination with chemotherapy was generally well-tolerated without drug-drug interactions. Ovarian and breast cancer pts experienced the greatest anti-tumor activity with an objective response rate of 33% and 22%, respectively. The RPTD was 200 mg BID V with bimonthly FOLFIRI (IRI 150 or 180 mg/m2 without 5-FU bolus). This study supports further evaluation of V in combination with FOLFIRI in specific tumor types. Clinical trial information: NCT01123876.
Deconstructing Race in Family Therapy (1994)

Despite the pervasive significance of race in society, attention devoted to racial issues in family therapy has been minimal. This paper explores the ways in which family therapy has relegated racial issues to a position of insignificance through a process of marginalization. Recommendations for recognizing the saliency of race within family therapy theory, practice, and training are described.
Specific activation of mammalian Hox promoters in mosaic transgenic zebrafish. (1992)

Homeo box-containing genes (Hox) are expressed in restricted regions of vertebrate embryos and may specify positional information. The organization and expression patterns of these genes are highly conserved among different species, suggesting that their regulation may also have been conserved. We developed a transient expression system, using mosaically transgenic zebrafish, which allows rapid analysis of transgene expression, and examined the activities of two mammalian Hox genes, mouse Hox-1.1 and human HOX-3.3. We found that these Hox promoters are activated in specific regions and tissues of developing zebrafish embryos and that this specificity depends upon the same regulatory elements within the promoters that specify the spatial expression of these genes in mice. Our results suggest that the promoter activities have been remarkably conserved from fish to mammals. To study the regulation of Hox expression in the developing nervous system, we analyzed the promoter activities in spt-1 mutants that have a mesodermal deficiency. Our results suggest that interactions, probably with the paraxial mesoderm, differentially regulate the activities of Hox promoters in the developing nervous system.
Negative Regulation of NK Cell Activities by Inhibitory Receptor CD94/NKG2A Leads to Altered NK Cell-Induced Modulation of Dendritic Cell Functions in Chronic Hepatitis C Virus Infection (2004)

NK cells are potent activators of dendritic cells (DCs), but it remains obscure how third-party cells affect the ability of NK cells to modulate DC functions. We show here that NK cells derived from healthy donors (N-NK), when cocultured with human liver epithelial cells, induced maturation as well as activation of DCs, such as increased migratory capacity as well as T cell stimulatory activity. In contrast, NK cells from chronic hepatitis C virus-infected donors (HCV-NK) were not capable of activating DCs under the same conditions. In comparison to N-NK, HCV-NK showed higher expression of CD94/NKG2A and produced IL-10 and TGFbeta when cultured with hepatic cells, most of which express HLA-E, a ligand for CD94/NKG2A. Blockade of NKG2A restored the ability of HCV-NK to activate DCs, which appeared to result from the reduced NK cell production of IL-10 and TGFbeta. The blockade also endowed HCV-NK with an ability to drive DCs to generate Th1-polarized CD4+ T cells. These findings show that NK cell modulation of DCs is regulated by third-party cells through NK receptor and its ligand interaction. Aberrant expression of NK receptors may have an impact on the magnitude and direction of DC activation of T cells under pathological conditions, such as chronic viral infection.
Modulation of excitatory amino acid receptors by group IIB metal cations in cultured mouse hippocampal neurones. (1989)

1. Responses to the excitatory amino acids kainate, quisqualate, N‐methyl‐D‐aspartate (NMDA), L‐glutamate and L‐aspartate were recorded in mouse hippocampal neurones in cell culture, using the whole‐cell configuration of the patch clamp technique. Agonists were applied rapidly from an array of flow pipes each of 250 microns diameter, positioned within 100 microns of the nerve cell body. 2. Responses to NMDA, L‐aspartate and to low concentrations of L‐glutamate, recorded with glycine in the extracellular fluid, were strongly antagonized by 50 microM‐zinc. Responses to kainate, quisqualate, and in glycine‐free solution, responses to L‐glutamate, were potentiated by 50 microM‐zinc, but partially antagonized by 1 mM‐zinc. On average, with 50 microM‐zinc, responses to NMDA were reduced to 0.19 times control, while responses to kainate and quisqualate were increased to 1.09 and 1.14 times control. With 1 mM‐zinc responses to kainate and quisqualate were reduced to 0.54 and 0.42 times control. 3. Cadmium had a similar, though less potent action, and at 50 microM antagonized responses to NMDA but potentiated responses to kainate and quisqualate. On average, with 50 microM‐cadmium, responses to NMDA were reduced to 0.39 times control, while responses to kainate and quisqualate were increased to 1.08 and 1.15 times control. With 1 mM‐cadmium responses to NMDA were reduced to 0.04 times control while responses to kainate and quisqualate were reduced to 0.79 and 0.60 times control. Mercury was neurotoxic and increased the leakage current; however, no reduction of the response to NMDA was produced by 5 microM‐mercury. 4. The equilibrium dissociation constant (Kd) for zinc antagonism of responses to NMDA, estimated from fit of a single binding site adsorption isotherm, was 13 microM; cadmium was about 4 times less potent than zinc. These effects of zinc and cadmium were nearly voltage independent. In contrast the antagonism of responses to NMDA by 150 microM‐magnesium was highly voltage dependent, such that the Kd for magnesium increased e‐fold per 17.6 mV depolarization. 5. The potency of zinc as an NMDA antagonist did not vary with the concentration of NMDA, and was not greatly influenced by a 1000‐fold variation in the concentration of the NMDA‐modulator glycine. This suggests that zinc acts as a non‐competitive antagonist, and does not directly interfere with the binding of NMDA to the agonist recognition site nor with the binding of glycine to an allosteric site on the NMDA receptor complex.(ABSTRACT TRUNCATED AT 400 WORDS)
Ultra long-duration Local Anesthesia Produced by Injection of Lecithin-coated Methoxyflurane Microdroplets (1985)

This study was designed to evaluate a new drug delivery system. The authors undertook to determine if microdroplets prepared by encapsulating volatile anesthetics with a membrane of lecithin could be used for local anesthesia. Local anesthesia was determined by monitoring the response of the rat to tail clamping and electrical stimulation of the skin following the intradermal injection of the microdroplets. Microdroplets were prepared from isoflurane, enflurane, halothane, methoxyflurane, diethyl ether, chloroform, and heptane. Although all microdroplet preparations produced local anesthesia, only methoxyflurane microdroplets produced an ultra-long duration of local anesthesia (approximately 24 h). Further characterization of the methoxyflurane microdroplets revealed two important differences from conventional local anesthetics. First, the local anesthetic effect of methoxyflurane reached a plateau that did not change significantly for 20 h while the injection of lidocaine and bupivacaine resulted in a peak effect that returned to baseline within 1 and 3 h, respectively. Second, the anesthetic effect of methoxyflurane remained essentially localized to the site of injection, while the anesthetic effect of lidocaine and bupivacaine migrated 15 cm in less than 1 h. The toxicity and safety of methoxyflurane were evaluated. When administered over the dosage range 1-16% (v/v) intradermally, or by injections into muscle, or by repeat injections every 4 days for 16 days, all animals regained their pretreatment response to painful stimulations, and there was no evidence of gross injury to tissue. Deliberate intravenous injection of 0.8 ml of 6.7% (v/v) methoxyflurane microdroplets had no apparent anesthetic or toxic effect. The present study demonstrates that methoxyflurane microdroplets produce an anesthetic effect that is highly localized, stable in intensity, ultra-long in duration, and reversible.
Genome-Scale Reconstruction of the Saccharomyces cerevisiae Metabolic Network (2003)

The metabolic network in the yeast Saccharomyces cerevisiae was reconstructed using currently available genomic, biochemical, and physiological information. The metabolic reactions were compartmentalized between the cytosol and the mitochondria, and transport steps between the compartments and the environment were included. A total of 708 structural open reading frames (ORFs) were accounted for in the reconstructed network, corresponding to 1035 metabolic reactions. Further, 140 reactions were included on the basis of biochemical evidence resulting in a genome-scale reconstructed metabolic network containing 1175 metabolic reactions and 584 metabolites. The number of gene functions included in the reconstructed network corresponds to approximately 16% of all characterized ORFs in S. cerevisiae. Using the reconstructed network, the metabolic capabilities of S. cerevisiae were calculated and compared with Escherichia coli. The reconstructed metabolic network is the first comprehensive network for a eukaryotic organism, and it may be used as the basis for in silico analysis of phenotypic functions.
Secretion of Active Fc Fragments of Immunoglobulin E Directed by the Yeast Invertase Signal Sequence in Mammalian Cells. (1996)

The human Fc fragments of immunoglobulin E (IgE-Fc) expressed in the mammalian COS cells, those mainly consisting of C epsilon 3-C epsilon 4 chains with or without Cys-328 known to be responsible for interchain disulfide bonding, were secreted into the culture medium directed by the yeast Saccharomyces cerevisiae invertase (SUC2) signal sequence (SUC2/Ig2 or SUC2/Ig, respectively) as well as by the human interleukin 2 receptor alpha chain signal sequence (IL2R/Ig2 or IL2R/Ig, respectively). For the binding activity to the human soluble alpha chain of high affinity receptor for IgE, IgE-Fc with Cys328, SUC2/Ig2 and IL2R/Ig2, were active but had smaller activity than native IgE. By comparison IgE-Fc without Cys328, SUC2/Ig and IL2R/Ig, showed lower activity than SUC2/Ig2 and IL2R/Ig2. Immunoprecipitation analysis revealed both SUC2/Ig and SUC2/Ig2 had molecular weights (M(r)s) and degrees of glycosylation similar to IL2R/Ig and IL2R/Ig2, respectively. These results suggested that in mammalian cells the SUC2 signal sequence was functional in directing the heterologous multimeric proteins to the endoplasmic reticulum, resulting in secretion of the active proteins. This finding might show merits on heterologous protein secretion systems.
Plasma density measurement in an imperfect microwave cavity (1987)

The density of a plasma generated in a TM010/2.45 GHz microwave cavity has been measured from the shift of the TM110 mode excited at a higher frequency. Since the design was aimed at obtaining optimum power coupling, the cavity has several openings and is imperfect from the viewpoint of the density measurement. A technique based on the dipole resonance behavior of cavity modes with nonzero axial mode number has been utilized to calibrate the observed TM110 mode frequency shift, which is found to differ considerably from the ideal cavity formula. A new theoretical formula which accounts for the particular form of cavity imperfection used in the experiment, has been derived and verified. It is also shown that the cavity shift method is conveniently applicable to pulsed microwave discharges.
Activation of smooth muscle myosin Mg2+-ATPase by native thin filaments and actin/tropomyosin. (1987)

Application of the myosin competition test (Lehman, W., and Szent-Györgyi, A. G. (1975) J. Gen. Physiol. 66, 1-30) to chicken gizzard actomyosin indicated that this smooth muscle contains a thin filament-linked regulatory mechanism. Chicken gizzard thin filaments, isolated as described previously (Marston, S. B., and Lehman, W. (1985) Biochem. J. 231, 517-522), consisted almost exclusively of actin, tropomyosin, caldesmon, and an unidentified 32-kilodalton polypeptide in molar ratios of 1:1/6:1/26:1/17, respectively. When reconstituted with phosphorylated gizzard myosin, these thin filaments conferred Ca2+ sensitivity (67.8 +/- 2.1%; n = 5) on the myosin Mg2+-ATPase. On the other hand, no Ca2+ sensitivity of the myosin Mg2+-ATPase was observed when purified gizzard actin or actin plus tropomyosin was reconstituted with phosphorylated gizzard myosin. Native thin filaments were rendered essentially free of caldesmon and the 32-kilodalton polypeptide by extraction with 25 mM MgCl2. When reconstituted with phosphorylated gizzard myosin, caldesmon-free thin filaments and native thin filaments exhibited approximately the same Ca2+ sensitivity (45.1 and 42.7%, respectively). The observed Ca2+ sensitivity appears, therefore, not to be due to caldesmon. Only trace amounts of two Ca2+-binding proteins could be detected in native thin filaments. These were identified as calmodulin (present at a molar ratio to actin of 1:733) and the 20-kilodalton light chain of myosin (present at a molar ratio to actin of 1:270). The Ca2+ sensitivity observed in an in vitro system reconstituted from gizzard thin filaments and either skeletal myosin or phosphorylated gizzard myosin is due, therefore, to calmodulin and/or an unidentified minor protein component of the thin filaments which may be an actin-binding protein involved in regulating actin filament structure in a Ca2+-dependent manner.