gebhart/patrepeval huggingface dataset:
Drug-drug interactions: An important negative attribute in drugs (2003)

Drug-drug interactions that arise by the alteration of the pharmacokinetics of one drug by another are of concern to the pharmaceutical industry, drug regulatory agencies, health-care professionals and patients. However, distinction needs to be made between interactions that only result in alterations in exposure levels and interactions that truly have an impact on efficacy and patient safety. To make this distinction, both the magnitude of the pharmacokinetic interaction and the therapeutic index of the affected drug must be taken into account. In this review, a description of the mechanistic underpinnings of drug interactions that has been developed over the past two decades is presented, with particular emphasis on drug-metabolizing enzymes and clearance concepts. The research approaches used to study drug interactions in vitro and in vivo are described. Finally, an accounting of major pharmacokinetic drug-drug interactions is made, organized by the drug-metabolizing enzyme or transporter protein affected. For each drug-metabolizing enzyme and transporter discussed, a position is offered on the severity of the issue of whether a new drug were to affect, or be affected by, a drug interaction through alteration of the activity of that enzyme.
A Cloned Human DNA Restriction Fragment Determines Expression of a GDP-L-fucose:β-D-Galactoside 2-α-L-fucosytransferase in Transfected Cells (1989)

We have described previously a gene transfer system for the isolation of human DNA sequences that determine expression of a mammalian GDP-fucose: beta-D-galactoside-2-alpha-L-fucosyltransferase (alpha-(1,2)-fucosyltransferase) (Ernst, L. K., Rajan, V. P., Larsen, R. D., Ruff, M. M., and Lowe, J. B. (1989) J. Biol. Chem. 264, 3436-3447). With this system, we found that de novo expression of the fucosyltransferase in mouse recipient cells was associated with the transfer and stable genomic integration of characteristic human DNA restriction fragments. We report here the results of experiments designed to determine the genetic origin of the fucosyltransferase determined by these sequences. First, we characterize the fucosyltransferases found in these mouse transfectants and in the human cell line used as a DNA donor. We compare their properties to those displayed by the human H and Secretor blood group fucosyltransferases. We find that the enzymes in the transfected cells have properties similar or identical to those of the human H alpha-(1,2)-fucosyltransferase. However, their properties differ significantly from the properties of the human Secretor alpha-(1,2)-fucosyltransferase and are also distinct from the properties of a murine alpha-(1,2)-fucosyltransferase. To confirm further that these transfected human sequences determine the H phenotype of the transfectants, we cloned the two human EcoRI restriction fragments common to each H-expressing secondary transfectant. The larger of these two fragments directs de novo expression of an alpha-(1,2)-fucosyltransferase when transfected into COS-1 cells. The pH activity profile of this alpha-(1,2)-fucosyltransferase and its apparent Michaelis constants for substrate and acceptor mirror those we determined for the human H alpha-(1,2)-fucosyltransferase. We conclude that genetic information sufficient to determine expression of this alpha-(1,2)-fucosyltransferase resides within the 3.4-kilobase pair human EcoRI restriction fragment and that this most likely represents the human H blood group locus.
Immunohistochemical Reactions for Fibroblast Growth Factor Receptor in Arteries of Patients with Moyamoya Disease (1994)

The cause of moyamoya disease remains unknown, and pathophysiological mechanisms remain uncertain. Basic fibroblast growth factor (FGF) is a pluripotent polypeptide that has been shown to play roles in angiogenesis, tumorigenesis and many other processes. In a previous study, we demonstrated immunohistochemically that the amount of basic FGF was increased above normal in the superficial temporal artery (STA) of patients with moyamoya disease. To clarify the function of basic FGF in moyamoya disease, we have performed an immunohistochemical study of the STA using a polyclonal antihuman FGF receptor antibody and also have tested immunohistochemical reactions for basic FGF. Twelve surgical specimens of the STA from patients with moyamoya disease were studied. Twelve specimens of the STA from skin flaps of patients with other neurological diseases were also investigated for comparison. The sections of the STA from patients with moyamoya disease showed dense and strong FGF receptor and basic FGF immunoreactivity in endothelial cells, in cells scattered in the thickened intima, and in smooth muscle cells in the media. In contrast, the sections of the STA of control patients showed faint basic FGF immunoreactivity. The statistical analysis revealed a significant difference of basic FGF immunoreactivity between moyamoya disease and other neurological diseases (chi 2 = 23; P = 0.0001). Moderately intense FGF receptor immunoreactivity was observed in most control patients. However, the statistical analysis revealed a significant difference of FGF receptor immunoreactivity between moyamoya disease and other neurological diseases (chi 2 = 13.382; P = 0.0012).(ABSTRACT TRUNCATED AT 250 WORDS)
Touring protein fold space with Dali/FSSP (1998)

The FSSP database and its new supplement, the Dali Domain Dictionary, present a continuously updated classification of all known 3D protein structures. The classification is derived using an automatic structure alignment program (Dali) for the all-against-all comparison of structures in the Protein Data Bank. From the resulting enumeration of structural neighbours (which form a surprisingly continuous distribution in fold space) we derive a discrete fold classification in three steps: (i) sequence-related families are covered by a representative set of protein chains; (ii) protein chains are decomposed into structural domains based on the recurrence of structural motifs; (iii) folds are defined as tight clusters of domains in fold space. The fold classification, domain definitions and test sets for sequence-structure alignment (threading) are accessible on the web at www.embl-ebi.ac.uk/dali . The web interface provides a rich network of links between neighbours in fold space, between domains and proteins, and between structures and sequences leading, for example, to a database of explicit multiple alignments of protein families in the twilight zone of sequence similarity. The Dali/FSSP organization of protein structures provides a map of the currently known regions of the protein universe that is useful for the analysis of folding principles, for the evolutionary unification of protein families and for maximizing the information return from experimental structure determination.
Ultrasound-mediated disruption of cell membranes. I. Quantification of molecular uptake and cell viability (2001)

Ultrasound-mediated drug delivery is a nonchemical, nonviral, and noninvasive method for targeted transport of drugs and genes into cells. Molecules can be delivered into cells when ultrasound disrupts the cell membrane by a mechanism believed to involve cavitation. This study examined molecular uptake and cell viability in cell suspensions (DU145 prostate cancer and aortic smooth muscle cells) exposed to varying peak negative acoustic pressures (0.6-3.0 MPa), exposure times (120-2000 ms), and pulse lengths (0.02-60 ms) in the presence of Optison (1.7% v/v) contrast agent. With increasing pressure and exposure time, molecular uptake of a marker compound, a calcein, increased and approached equilibrium with the extra cellular solution, while cell viability decreased. Varying pulse length produced no significant effect. All viability and molecular uptake measurements collected over the broad range of ultrasound conditions studied correlated with acoustic energy exposure. This suggests that acoustic energy exposure may be predictive of ultrasound's nonthermal bioeffects.
Critical Literacy and the Case for it in the Early Years of School (1998)

Debate continues about literacy: how to teach it, how to measure it, whether standards of it are falling, whether we are better or worse at it than our neighbours in other parts of the world. Less debated is what counts as literacy, whom it serves, and whether we encourage the best literacy for the age we live in. Often the assumption is that everyone shares the same meaning of the word 'literacy', that it is a unitary phenomenon, a neutral skill that is quantifiable. The notion that there are different and diverse literacies is rarely considered by policy makers or in media reports though it is increasingly acknowledged in the theoretical literature. This paper explores the relatively new concept of critical literacy and seeks, in particular, to assess its validity for the early years of the primary school. The theoretical research base for the paper is largely that associated with post-structuralism, it sees consciousness as socially produced in language and sees language and consciousness as sites of struggle and potential change (Weedon, 1987). The paper is an exploratory, theoretical study that reaches tentative, rather than conclusive, answers, and it beckons a theme that is ready for debate and ripe for research.
Mineralization of Individual Congeners of Linear Alkylbenzenesulfonate by Defined Pairs of Heterotrophic Bacteria (2004)

Parvibaculum lavamentivorans DS-1(T) utilized the commercial surfactant linear alkylbenzenesulfonate (LAS) (20 congeners with C(10) to C(13) side chains) as a carbon and energy source by shortening the side chain, and sulfophenylcarboxylates (SPCs) and similar compounds (e.g., alpha,beta-unsaturated SPCs [SPC-2Hs]) were excreted with quantitative recovery of the sulfophenyl moiety. 2-(4-Sulfophenyl)decane (2-C10-LAS) was converted largely to 3-(4-sulfophenyl)butyrate (3-C4-SPC), as were 2-C12-LAS and 2-C14-LAS; the other products were 5-C6-SPC (SPC+2C) and 3-C4-SPC-2H. 2-C11-LAS was converted largely to 4-C5-SPC with the corresponding SPC+2C and SPC-2H; similarly, 3-C12-LAS yielded 4-C6-SPC with the corresponding SPC+2C and SPC-2H. This pattern of products confirmed that LAS is degraded by omega-oxygenation and chain shortening through beta-oxidation. At least nine major SPCs were formed from commercial LAS. The novel isolates Comamonas testosteroni SPB-2 and KF-1 utilized 3-C4-SPC; Delftia acidovorans SPH-1 utilized 4-C6-SPC enantioselectively. The substrate-dependent oxygen uptake of whole cells of strain SPB-2 indicated that there was inducible oxygenation of 3-C4-SPC and of 4-sulfophenol in whole cells of the strains of C. testosteroni during growth with 3-C4-SPC or 4-sulfophenol. The degradative pathways apparently involved 4-sulfocatechol and 4-sulfocatechol 1,2-dioxygenase. Strain SPB-2 and strain DS-1(T) grew together in LAS-salts medium, and only seven of the nine major SPCs were recovered. Strain SPB-2 utilized 3-C4-SPC, 3-C5-SPC, and 3-C4-SPC-2H. Strain SPH-1 grew together with strain DS-1(T) in LAS-salts medium, and a different set of seven major SPCs was recovered. Strain SPH-1 utilized 4-C6-SPC, 4-C5-SPC, 4-C6-SPC-2H, and 4-C5-SPC-2H. A three-member community consisting of strains DS-1(T), SPB-2, and SPH-1 utilized four major SPCs. We inferred that this community mineralized the major SPCs derived from 8 of the 20 LAS congeners.
Enticing Students to Careers in Gerontology (2005)

Recognition of the increasing demand for gerontologically trained social work professionals prompted an investigation of the factors that attract undergraduate students to a career of working with older adults. Faculty (n = 10) and students (n = 10) from the disciplines of social work, nursing, consumer and family sciences, psychology, recreation, and business participated in focus groups addressing such topics as the inclusion of content on aging, influences on choice of major, perceptions of aging, and personal experience with older adults. Respondents perceived (a) limited course content on older adulthood, (b) existing course content focused on frailty and aging, (c) a pervasive lack of awareness of the aging of the population, and (d) the essential contribution of positive intergenerational contact from early childhood through the college years. The results suggest the need for increasing efforts to enhance awareness and to integrate comprehensive content on aging throughout the curriculum in higher education. The essential role of intergenerational contact identifies a role for higher education in supporting current programs, such as the Foster Grandparent Program, while developing additional innovative means of promoting and nurturing intergenerational relationships.
TP53 mutation, allelism and survival in non-small cell lung cancer (2005)

TP53 is well-recognized as a mutational target in cancers and common variation in the TP53 gene has been investigated as potentially contributing to cancer susceptibility. The codon 72 polymorphism has been proposed to alter the phenotype of TP53 mutations, and TP53 mutations have been reported to occur preferentially on the arginine allele. Using a consecutive case series of non-small cell lung cancer we have investigated whether TP53 mutations occur preferentially on the arginine or proline allele, and whether the combination of mutation and allelism confers differences in the clinical phenotype. The overall prevalence of TP53 mutation was 26% (76/293). The majority of mutations occurred on the arginine allele (51/60, 85%), and there was corresponding strong selection for loss of the proline allele [87% of loss of heterozygosity (LOH) events were loss of proline]. However, there was no statistically significant difference in the prevalence of mutation by constitutional genotype and among heterozygotes with LOH, TP53 mutation prevalence did not differ by the codon 72 polymorphism (48% on arginine versus 40% on proline). Importantly, patient survival did significantly differ: those patients having a TP53 mutation on the proline allele had the worst survival outcomes (hazards ratio = 2.6, P < 0.03). Further, this phenotype was limited to those patients with advanced disease, where mutation on the proline allele was associated with a significantly worse outcome compared with those without mutation or with mutation on the arginine allele (P < 0.001). Our data suggest that there are selective pressures for loss of the TP53 proline allele in non-small cell lung cancer. Further, the combination of mutation with the codon 72 proline variant predicts poorer patient survival, particularly in a disease that has progressed outside the lung, a finding that warrants further investigation.
Anti–Glypican 3 Antibody as a Potential Antitumor Agent for Human Liver Cancer (2008)

Human glypican 3 (GPC3) is preferentially expressed in the tumor tissues of liver cancer patients. In this study, we obtained a monoclonal antibody (mAb) against the COOH-terminal part of GPC3, which induced antibody-dependent cellular cytotoxicity (ADCC). The mAb, designated GC33, exhibited marked tumor growth inhibition of s.c. transplanted Hep G2 and HuH-7 xenografts that expressed GPC3 but did not inhibit growth of the SK-HEP-1 that was negative for GPC3. GC33 was efficacious even in an orthotopic model; it markedly reduced the blood alpha-fetoprotein levels of mice intrahepatically transplanted with Hep G2 cells. Humanized GC33 (hGC33) was as efficacious as GC33 against the Hep G2 xenograft, but hGC33 lacking carbohydrate moieties caused neither ADCC nor tumor growth inhibition. Depletion of CD56+ cells from human peripheral blood mononuclear cells markedly abrogated the ADCC caused by hGC33. The results show that the antitumor activity of hGC33 is mainly attributable to ADCC, and in human, natural killer cell-mediated ADCC is one possible mechanism of the antitumor effects by GC33. hGC33 will provide a novel treatment option for liver cancer patients with GPC3-positive tumors.
Long-Term Treatment with Slow Release Oxprenolol Alone, or in Combination with other Drugs: Effects on Blood Pressure, Lipoproteins and Exercise Performance (1982)

Twenty-eight patients with mild essential hypertension were treated with placebo for six weeks and then with active medication for a further 32 weeks. Twelve patients were well-controlled with 160-320 mg/day of slow release oxprenolol alone, 12 required oxprenolol and chlorthalidone, and four also required hydrallazine. beta-adrenergic blockade reduced the basal level of plasma free fatty acid (FFA) by 41%. A sub-maximal exercise test reduced the level of FFA by 34% during placebo treatment. The same exercise test during beta-blockade reduced the already lowered basal FFA level by a further 45%. Only female subjects experienced exercise-induced leg fatigue during beta-blockade. They always had higher FFA levels than males, but the relative changes in FFA concentration were similar in both sexes. Exercise testing induced a 52 mmHg rise in systolic blood pressure, but this was reduced to only 14 mmHg during treatment. Patients controlled on oxprenolol alone showed no significant change in plasma lipid and lipoprotein levels. Those patients ultimately requiring combination drug therapy experienced a statistically significant rise in plasma triglycerides and a significant fall in high density lipoprotein cholesterol. The biological importance of these changes is uncertain.
A Cluster of Basic Repeats in the Dystrophin Rod Domain Binds F-actin through an Electrostatic Interaction (1998)

The dystrophin rod domain is composed of 24 spectrin-like repeats and was thought to act mainly as a flexible spacer between the amino-terminal actin binding domain and carboxyl-terminal membrane-associated domains. We previously demonstrated that a fragment of the dystrophin rod domain also binds F-actin. However, the nature and extent of rod domain association with F-actin is presently unclear. To begin addressing these questions, we characterized two recombinant proteins representing adjacent regions of the dystrophin rod. DYS1416 (amino acids 1416-1880) bound F-actin with a Kd of 14.2 +/- 5.2 microM and a stoichiometry of 1 mol:mol of actin. However, DYS1030 (amino acids 1030-1494) failed to bind F-actin, suggesting that not all rod domain repeats are capable of binding F-actin. Interestingly, DYS1416 corresponds to a unique region of the dystrophin rod rich in basic amino acids, whereas DYS1030 is composed mainly of acidic repeats. This observation suggested that DYS1416 may interact with acidic actin filaments through an electrostatic interaction. Supporting this hypothesis, actin binding by DYS1416 was dramatically inhibited by increasing ionic strength. We suggest that electrostatic interactions between basic spectrin-like repeats and actin filaments may contribute to the actin binding activity of other members of the actin cross-linking protein family.
Equine Infectious Anemia Viral Vector-Mediated Codelivery of Endostatin and Angiostatin Driven by Retinal Pigmented Epithelium-Specific VMD2 Promoter Inhibits Choroidal Neovascularization (2009)

Equine infectious anemia virus (EIAV) is a nonprimate lentivirus that does not cause human disease. Subretinal injection into mice of a recombinant EIAV lentiviral vector in which lacZ is driven by a CMV promoter (EIAV CMV LacZ) resulted in rapid and strong expression of LacZ in retinal pigmented epithelial (RPE) cells and some other cells including ganglion cells, resulting in the presence of 5-bromo-4-chloro-3-indolyl-beta-D-galactopyranoside within the optic nerve. Substitution of the RPE-specific promoter from the vitelliform macular dystrophy (VMD2) gene for the CMV promoter resulted in prolonged (at least 1 year) expression of LacZ that was restricted to RPE cells, albeit reduced 6- to 10-fold compared with the CMV promoter. Similarly, the amount of FLAG-tagged endostatin detected in eyes injected with the EIAV VMD2 Endo(FLAG) vector was similar to that seen in eyes injected with a vector that expressed both endostatin and angiostatin [EIAV VMD2 Endo(FLAG)/Angio]; expression was approximately 6-fold lower than with identical vectors in which the CMV promoter drove expression. Compared with murine eyes treated with a control EIAV vector, subretinal injection of EIAV vectors expressing murine endostatin alone or in combination with angiostatin driven by either the CMV or VMD2 promoter caused significant suppression of choroidal neovascularization (NV) at laser-induced rupture sites in Bruch's membrane. These data support proceeding toward clinical studies with EIAV-based gene therapy for choroidal NV, using the VMD2 promoter to selectively drive expression of a combination of endostatin and angiostatin in RPE cells.
Delivery of antisense oligodeoxyribonucleotides against the human epidermal growth factor receptor into cultured KB cells with liposomes conjugated to folate via polyethylene glycol. (1995)

Antisense oligodeoxyribonucleotides targeted to the epidermal growth factor (EGF) receptor were encapsulated into liposomes linked to folate via a polyethylene glycol spacer (folate-PEG-liposomes) and efficiently delivered into cultured KB cells via folate receptor-mediated endocytosis. The oligonucleotides were a phosphodiester 15-mer antisense to the EGF receptor (EGFR) gene stop codon (AEGFR2), the same sequence with three phosphorothioate linkages at each terminus (AEGFR2S), a randomized 15-mer control of similar base composition to AEGFR2 (RC15), a 14-mer control derived from a symmetrized Escherichia coli lac operator (LACM), and the 5'-fluorescein-labeled homologs of several of the above. Cellular uptake of AEGFR2 encapsulated in folate-PEG-liposomes was nine times higher than AEGFR2 encapsulated in nontargeted liposomes and 16 times higher than unencapsulated AEGFR2. Treatment of KB cells with AEGFR2 in folate-PEG-liposomes resulted in growth inhibition and significant morphological changes. Curiously, AEGFR2 and AEGFR2S encapsulated in folate-PEG-liposomes exhibited virtually identical growth inhibitory effects, reducing KB cell proliferation by > 90% 48 hr after the cells were treated for 4 hr with 3 microM oligonucleotide. Free AEGFR2 caused almost no growth inhibition, whereas free AEGFR2S was only one-fifth as potent as the folate-PEG-liposome-encapsulated oligonucleotide. Growth inhibition of the oligonucleotide-treated cells was probably due to reduced EGFR expression because indirect immunofluorescence staining of the cells with a monoclonal antibody against the EGFR showed an almost quantitative reduction of the EGFR in cells treated with folate-PEG-liposome-entrapped AEGFR2. These results suggest that antisense oligonucleotide encapsulation in folate-PEG-liposomes promise efficient and tumor-specific delivery and that phosphorothioate oligonucleotides appear to offer no major advantage over native phosphodiester DNA when delivered by this route.