gebhart/patrepeval huggingface dataset:
Pre-clinical investigation and clinical development of E7080, a multi-targeted tyrosine kinase inhibitor : implications for melanoma (2010)

The basis for this PhD project was to investigate E7080, a novel multi-targeted tyrosine kinase inhibitor, both pre-clinically and clinically. Traditional early clinical trials of cytotoxic agents in cancer patients may not be the optimal way to develop new targeted agents, whose mechanism of action often means they are cytostatic, rather than cytotoxic, and have much less in the way of toxicity. For this reason, the use of biomarkers to aid early clinical development is becoming increasingly popular. 
The initial aims of this PhD were to develop a pharmacodynamic biomarker of the activity of E7080 in patient peripheral blood mononuclear cells (PBMCs), and to gain a better understanding of its mechanism of action, while simultaneously performing a phase I clinical trial of E7080.
Two approaches were used to identify a pharmacodynamic biomarker of E7080’s activity, a candidate approach and a global phosphoproteomic approach. Neither approach was successful in identifying a biomarker in PBMCs, partly due to the finding that PBMCs were not an ideal candidate for a biomarker of E7080 activity as they lacked expression of some of the main receptor targets of E7080.
Inhibition of three of E7080’s main receptor targets, VEGFR-2, PDGFR-β and FGFR-1, was confirmed at concentrations of E7080 achieved in patients on the clinical trial. E7080 had no effect on basal proliferation of a number of different tumour cell lines, but caused a significant impairment of cellular migration and invasion in vitro, suggesting a potential role for E7080 in the adjuvant setting. 
As the clinical trial of E7080 progressed, it became clear that patients with advanced malignant melanoma were deriving an unexpectedly high benefit from treatment with E7080, and our hypothesis was that this benefit was due to the inhibition fibroblast growth factor receptor-1 (FGFR-1) signalling, which has been implicated in the progression of malignant melanoma in vitro, and in mouse models in vivo. Therefore, a further investigation was undertaken to explore the relationship of FGFR-1 expression in human melanoma, and its impact on patient outcome. FGFR-1 expression was examined in a large human melanoma tumour tissue microarray, and was found to increase significantly as lesions progressed from benign naevi to primary malignant melanomas. FGFR-1 expression also significantly correlated with patient outcome. In patients with non-metastatic melanoma, low expression of FGFR-1 was an independent prognostic factor for poorer progression free and overall survival.
In conclusion, very encouraging evidence of efficacy was observed in patients treated on the phase I clinical trial of E7080, most notably with metastatic melanoma, with implications for future treatment. While it was not possible to identify a PBMC pharmacodynamic biomarker for the activity of E7080, pre-clinical investigation into the mechanism of action of E7080 has suggested a further role for E7080 in the adjuvant setting.
Acute Kidney Injury: Lessons from Experimental Models (2011)

For decades severe tubular necrosis has been the hallmark of experimental models of acute renal failure (ARF), such as prolonged ischemia and reflow. This fits well with the still widely used traditional clinical term 'acute tubular necrosis'. Nevertheless, the rareness of tubular necrosis in human kidney biopsies in the background of hypoxic, toxic and septic AKI led to the adoption of a new term, 'acute kidney injury' (AKI), which refers to such clinical scenarios irrespective of the renal morphology. Indeed, experimental AKI models, which have more limited acute renal parenchymal compromise, underscore the focal and regional tissue injury patterns that range from adaptive stress response, through cellular dysfunction, apoptotic cell death and frank acute tubular necrosis. Such stress and injury patterns, short of necrosis, may go unnoticed morphologically and even functionally, and may even confer resistance to subsequent insults. Herein we describe the spectrum of what we call 'sublethal injury', referring to a condition, which by itself is insufficient to produce cellular death, but may or may not produce organ failure. Such sublethal injury can be detected by overt morphological changes, by the upregulation of cell survival factors, and by recently developed biomarkers and imaging techniques of organ physiology and dysfunction. The use of combined sublethal insults in animal models is an attempt to replicate the clinical situation of comorbidities, a circumstance which underlies most situations of AKI. This review will discuss the definition of such sublethal injury and the modes of its detection.
Harvesting Singlet and Triplet Energy in Polymer LEDs (1999)

That it is possible to surpass the 25 % limit set by spin statistics and achieve very efficient molecular light-emitting diodes (LEDs) is demonstrated by the experimental results presented here. It is shown that energy can be captured from both singlet and triplet excited states and transformed into emitted light. Studies of LEDs in which platinum octaethylporphyrin (PtOEP), an efficient triplet emitter, is used as a “dopant” in a semiconductor polymer host are described. Time-resolved measurements of light emission are used to determine the mechanism of excitation of PtOEP.
Structure-Function Analysis of Human 1,3-Fucosyltransferase (1996)

A series of molecular biology experiments were carried out to identify the catalytic domain of two human alpha1,3/4-fucosyltransferases (fucosyltransferases (FucTs) III and V), and to identify amino acids that function in acceptor substrate binding. Sixty-one and 75 amino acids could be eliminated from the N terminus of FucTs III and V, respectively, without a significant loss of enzyme activity. In contrast, the truncation of one or more amino acids from the C terminus of FucT V resulted in a dramatic or total loss of enzyme activity. Results from the truncation experiments demonstrate that FucT III62-361 (containing amino acids 62-361) and FucT V76-374 (containing amino acids 76-374) are active, whereas shorter forms of the enzymes were inactive. The shortest, active forms of the enzymes are more than 93% identical at the predicted amino acid level, but have distinct acceptor substrate specificities. Thus, FucT III is an alpha1,4-fucosyltransferase, whereas FucT V is an alpha1,3-fucosyltransferase with disaccharide substrates. All but one of the amino acid sequence differences between the two proteins occur near their N terminus. Results obtained from domain swapping experiments demonstrated that the single amino acid sequence difference near the C terminus of these enzymes did not alter the enzyme's substrate specificity. However, swapping a region near the N terminus of the truncated form of FucT III into an homologous region in FucT V produced a protein with both alpha1,3- and alpha1,4-fucosyltransferase activity. This region contains 8 of the amino acid sequence differences that occur between the two proteins.
Phenotypic Differentiation of TGF-β1-Responsive Pluripotent Premesenchymal Prehematopoietic Progenitor (P4 Stem) Cells from Murine Bone Marrow (2001)

On the horizon of modern molecular medicine is the requisite technology to capture multipotent human stem cells that are capable of self-renewal and to direct these stem cells along defined lineages for therapeutic purposes. In this article, we describe the hematopoietic and mesenchymal differentiation potential of a unique population of transforming growth factor-beta1 (TGF-beta1)-responsive stem cells derived from murine bone marrow. Stringent selection of the stem cells was accomplished under low serum conditions by virtue of an inherent survival response to a TGF-beta1-vWF fusion protein that was bound to collagen matrices. The TGF-beta1-responsive stem cells initially exhibited a non-adherent and uniformly blastoid morphology, underwent expansion into colonies upon serum reconstitution, and were capable of overt cytodifferentiation along fibrogenic, osteogenic, chondrogenic, or adipogenic lineages upon growth factor stimulation. Remarkably, these stem cells also underwent rapid expansion in the presence of either hematopoietic stem cell factor (SCF) or interleukin3 (IL-3), and differentiated into myeloid and lymphoid phenotypes upon exposure to the latter. Taken together, these results support the hypothesis that pluripotent premesenchymal prehematopoietic progenitor cells, designated P4 stem cells, are present postnatally in murine bone marrow and, thus, may be summarily isolated for various cell-based experimental therapies.
Equalization for orthogonal frequency division multiplexing system (2002)

Multipath distortion in a digital mobile channel can be alleviated by using the orthogonal frequency division multiplexing system in which the discrete Fourier transform is used for multiplexing N subchannels. Albeit every subchannel is subject to a flat fading, the difference in fading level results in intersymbol interference. Five equalization methods are studied, and their performance is compared. It is concluded that the minimum-mean-squared-error block linear equalizer is a good compromise between complexity and performance.
A preliminary study of etanercept in the treatment of severe, resistant psoriatic arthritis. (2001)

This preliminary and rather favorable experience with etanercept suggests that properly controlled trials of this agent in psoriatic arthritis are needed.
Performance of multi-level QAM with post-detection maximal ratio combining space diversity for digital land-mobile radio communications (1993)

A new type of post-detection maximal ratio combining for space diversity receivers in digital land-mobile communications is proposed. The combining scheme is designed for multilevel quadrature amplitude modulation (QAM) and employs a pilot-symbol-aided fading estimator. It is realized at baseband using a digital signal processing (DSP) technique to simplify the receiver hardware. Computer simulation and laboratory experiments confirm that the proposed diversity scheme achieves a performance very close to that of ideal maximal ratio combining.< <ETX xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">&gt;</ETX>
Biochemistry and Cell Biology of Tau Protein in Neurofibrillary Degeneration (2012)

Tau represents the subunit protein of one of the major hallmarks of Alzheimer disease (AD), the neurofibrillary tangles, and is therefore of major interest as an indicator of disease mechanisms. Many of the unusual properties of Tau can be explained by its nature as a natively unfolded protein. Examples are the large number of structural conformations and biochemical modifications (phosphorylation, proteolysis, glycosylation, and others), the multitude of interaction partners (mainly microtubules, but also other cytoskeletal proteins, kinases, and phosphatases, motor proteins, chaperones, and membrane proteins). The pathological aggregation of Tau is counterintuitive, given its high solubility, but can be rationalized by short hydrophobic motifs forming β structures. The aggregation of Tau is toxic in cell and animal models, but can be reversed by suppressing expression or by aggregation inhibitors. This review summarizes some of the structural, biochemical, and cell biological properties of Tau and Tau fibers. Further aspects of Tau as a diagnostic marker and therapeutic target, its involvement in other Tau-based diseases, and its histopathology are covered by other chapters in this volume.
Ribbon Growth on Substrate and Molded Wafer-Two Low Cost Silicon Ribbon Materials for PV (2006)

This paper focuses on two very promising silicon ribbon materials currently produced for research: ribbon growth on substrate (RGS) by ECN solar energy and molded wafer (MW) by GE Energy. Both materials are investigated in terms of solar cell processing and characterisation. First cell results of large area 10times10 cm <sup xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">2</sup> RGS cells are presented as well as results from 5times5 cm <sup xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">2</sup> cells processed from 8times12 cm <sup xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">2</sup> RGS and 12.5times12.5 cm <sup xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">2</sup> MW wafers
T1 and t2 of ferritin at different field strengths: effect on mri (1992)

Nuclear magnetic relaxation times T1 and T2 were measured in ferritin solutions at field strengths from 0.04 to 1.5 T. T1 was relatively constant, but 1/T2 increased linearly with field strength, in agreement with earlier MRI observations in the monkey brain. This finding supports the theory that ferritin is responsible for T2 shortening in brain nuclei containing iron. The linear dependence of 1/T2 on magnetic field is unique and not explained by present theories of the magnetic properties of ferritin.
The insulin gene contains multiple transcriptional elements that respond to glucose. (1994)

The beta cells in the pancreatic islets of Langerhans increase insulin gene transcription in response to increased glucose concentration. We have mapped sequences within the rat insulin I gene 5'-flanking DNA (rInsI promoter) that direct this transcriptional response to glucose. When linked to chloramphenicol acetyltransferase and expressed in cultured beta cells, no single mutation of the rInsI promoter removes its ability to respond to glucose, although several mutations cause marked reductions in basal chloramphenicol acetyltransferase expression. A 50-bp sequence isolated from the rInsI promoter, the Far-FLAT minienhancer, can confer glucose responsiveness to nonresponsive promoters. Fine mapping of this minienhancer further localizes a glucose response to the sequence GGCCATCTGGCC, or the Far element. Nuclear extracts from islets grown in various glucose concentrations demonstrate a glucose-stimulated increase in a protein complex that binds the Far element and contains the transcription factors Pan-1 and Pan-2. Overexpression of intact or partially deleted Pan-1 ablates the Far-directed transcriptional response to glucose. We conclude that the full glucose response of the insulin promoter involves the interaction of multiple sequence elements. Part of this response, however, results from activation of a complex binding at the Far element.
Excitons in carbon nanotubes: Diameter and chirality trends (2007)

Abstract We provide a closer look into the diameter and chirality dependences of exciton properties in carbon nanotubes, using a variational methodology based on the effective mass and envelope function approximations, supported by ab initio parameters. Experimental measurements of the binding energy are reproduced within 0.02 eV for a large variety of tubes. We also report on the singlet‐triplet energy splittings, which show a 1/ d 2 diameter dependence. (© 2007 WILEY‐VCH Verlag GmbH &amp; Co. KGaA, Weinheim)
Hi-C: A Method to Study the Three-dimensional Architecture of Genomes. (2010)

The three-dimensional folding of chromosomes compartmentalizes the genome and and can bring distant functional elements, such as promoters and enhancers, into close spatial proximity (2-6). Deciphering the relationship between chromosome organization and genome activity will aid in understanding genomic processes, like transcription and replication. However, little is known about how chromosomes fold. Microscopy is unable to distinguish large numbers of loci simultaneously or at high resolution. To date, the detection of chromosomal interactions using chromosome conformation capture (3C) and its subsequent adaptations required the choice of a set of target loci, making genome-wide studies impossible (7-10). We developed Hi-C, an extension of 3C that is capable of identifying long range interactions in an unbiased, genome-wide fashion. In Hi-C, cells are fixed with formaldehyde, causing interacting loci to be bound to one another by means of covalent DNA-protein cross-links. When the DNA is subsequently fragmented with a restriction enzyme, these loci remain linked. A biotinylated residue is incorporated as the 5' overhangs are filled in. Next, blunt-end ligation is performed under dilute conditions that favor ligation events between cross-linked DNA fragments. This results in a genome-wide library of ligation products, corresponding to pairs of fragments that were originally in close proximity to each other in the nucleus. Each ligation product is marked with biotin at the site of the junction. The library is sheared, and the junctions are pulled-down with streptavidin beads. The purified junctions can subsequently be analyzed using a high-throughput sequencer, resulting in a catalog of interacting fragments. Direct analysis of the resulting contact matrix reveals numerous features of genomic organization, such as the presence of chromosome territories and the preferential association of small gene-rich chromosomes. Correlation analysis can be applied to the contact matrix, demonstrating that the human genome is segregated into two compartments: a less densely packed compartment containing open, accessible, and active chromatin and a more dense compartment containing closed, inaccessible, and inactive chromatin regions. Finally, ensemble analysis of the contact matrix, coupled with theoretical derivations and computational simulations, revealed that at the megabase scale Hi-C reveals features consistent with a fractal globule conformation.
Perils of Dominance (2005)

Perils of Dominance is the first completely new interpretation of how and why the United States went to war in Vietnam. It provides an authoritative challenge to the prevailing explanation that U.S. officials adhered blindly to a Cold War doctrine that loss of Vietnam would cause a "domino effect" leading to communist domination of the area. Gareth Porter presents compelling evidence that U.S. policy decisions on Vietnam from 1954 to mid-1965 were shaped by an overwhelming imbalance of military power favoring the United States over the Soviet Union and China. He demonstrates how the slide into war in Vietnam is relevant to understanding why the United States went to war in Iraq, and why such wars are likely as long as U.S. military power is overwhelmingly dominant in the world. Challenging conventional wisdom about the origins of the war, Porter argues that the main impetus for military intervention in Vietnam came not from presidents Kennedy and Johnson but from high-ranking national security officials in their administrations who were heavily influenced by U.S. dominance over its Cold War foes. Porter argues that presidents Eisenhower, Kennedy, and Johnson were all strongly opposed to sending combat forces to Vietnam, but that both Kennedy and Johnson were strongly pressured by their national security advisers to undertake military intervention. Porter reveals for the first time that Kennedy attempted to open a diplomatic track for peace negotiations with North Vietnam in 1962 but was frustrated by bureaucratic resistance. Significantly revising the historical account of a major turning point, Porter describes how Secretary of Defense Robert McNamara deliberately misled Johnson in the Gulf of Tonkin crisis, effectively taking the decision to bomb North Vietnam out of the president's hands.
Finger loop inhibitors of the HCV NS5B polymerase: discovery and prospects for new HCV therapy. (2006)

The hepatitis C virus (HCV) infects millions of people wzorldwzide and currently available therapies suffer from limited efficacy and severe side effects. This review describes the discovery of a novel class of non-nucleoside HCV non-structural protein 5B (NS5B) polymerase inhibitors that inhibit the replication of viral RNA by binding to an allosteric site on the enzyme. Initial lead compounds based on a benzimidazole scaffold were optimized yielding novel indole derivatives with sub-micromolar activity in a cell-based replicon assay. X-ray crystallographic studies suggest that inhibitor binding interferes with the conformational movements of the protein that are necessary for enzyme activity. Finger loop inhibitors of HCV NS5B show potential for the development of novel anti-HCV therapeutics.
Temperature‐sensitive polymer‐conjugated IFN‐γ induces the expression of IDO mRNA and activity by fibroblasts populated in collagen gel (FPCG) (2004)

Indoleamine 2,3-dioxygenase (IDO) is an intracellular tryptophan-catabolizing enzyme possessing various immunosuppressive properties. Here, we report the use of this enzyme to suppress the proliferation of peripheral blood mononuclear cells (PBMC) co-cultured with IDO-expressing fibroblasts of an allogeneic skin substitute in vitro. Fetal foreskin fibroblasts populated within collagen gel (FPCG) were treated with interferon-gamma (IFN-gamma) conjugated with a temperature-sensitive polymer to induce the expression of IDO mRNA and protein. SDS-PAGE showed successful conjugation of IFN-gamma with the temperature-sensitive polymer. Expression of IDO mRNA was evaluated by Northern analysis. IDO enzyme activity was evaluated by the measurement of kynurenine levels. The results of Northern blot analysis showed an induction of IDO mRNA expression when treated with polymer-conjugated IFN-gamma. Kynurenine levels, as a measure of IDO bioactivity, were significantly higher in IFN-gamma-treated fibroblasts than in controls (P < 0.001). In a lasting effect experiment, the expression of IDO mRNA in FPCG treated with polymer-conjugated IFN-gamma was significantly longer than in those treated with free (non-conjugated) IFN-gamma (P < 0.001). IFN-gamma radiolabeling showed a prolonged retention of IFN-gamma within collagen gel in its polymer-conjugated form, compared to its free form. Presence of IDO protein in FPCG was demonstrated by Western analysis even 16 days after removal of the conditioned medium (containing released IFN-gamma). To demonstrate the immunosuppressive effects of IDO on the proliferation of PBMC, IDO-expressing FPCG treated with polymer-conjugated IFN-gamma were co-cultured with PBMC for a period of 5 days. The results showed a significant reduction in proliferation of PBMC co-cultured with IFN-gamma-treated IDO-expressing fibroblasts, compared to those co-cultured with non-IDO-expressing fibroblasts (P < 0.001). The addition of an IDO inhibitor (1-methyl-D-tryptophan) reversed the suppressive effects of IDO on PBMC proliferation. In conclusion, IDO expression in FPCG suppresses the proliferation of immune cells in vitro. The use of a temperature-sensitive polymer further prolongs the effect of IFN-gamma on the expression of IDO. Therefore, modulating IDO levels in situ might be an alternative for prolonging the survival of skin allografts.
Pb Introduction to the High-Tc Superconductor Bi-Sr-Ca-Cu-O (1988)

The effect of Pb substitution has been studied for the new high-Tc superconductor Bi-Sr-Ca-Cu-O. The zero resistivity temperature Tc(offset) was increased with increasing Pb content. A maximum Tc(offset) value of 85.5 K was obtained for the composition Bi0.5Pb0.5SrCaCu2Oy: an enhancement of 10 K compared with a non-Pb-additive sample. Further introduction of Pb caused a decrease in Tc, and finally an insulator phase transition occurred due to a second phase formation.