gebhart/patrepeval huggingface dataset:
ZD6474 – a novel inhibitor of VEGFR and EGFR tyrosine kinase activity (2005)

Angiogenesis is crucial for maintaining the supply of oxygen and nutrients required to support solid tumour growth. Inhibitors of tumour blood vessel formation are therefore being sought, in particular, inhibitors of vascular endothelial growth factor-A (VEGF)-signalling, which has a pivotal role in stimulating neovascular growth and survival. ZD6474 is an orally bioavailable inhibitor of VEGF receptor-2 tyrosine kinase activity that in preclinical studies has been shown to inhibit both VEGF-induced signalling in endothelial cells and tumour-induced angiogenesis. Consistent with inhibition of angiogenesis, once-daily oral dosing of ZD6474 produced significant broad-spectrum antitumour activity in a panel of histologically diverse human tumour xenografts. In addition to its antiangiogenic properties, ZD6474 also has activity against the epidermal growth factor receptor (EGFR) tyrosine kinase, which could impart a direct inhibitory effect on tumour cell growth and survival. This may be particularly relevant in tumours with a dependency upon EGFR signalling, for example in certain tumours harbouring activating mutations in EGFR. RET kinase has also been identified as a third target for ZD6474. This review summarises preclinical studies with this unique agent and considers its future direction in cancer treatment.
Endoscope-assisted brachytherapy for pancreatic cancer: From tumor killing to pain relief and drainage (2011)

Locally advanced or metastatic pancreatic cancer has been a long-term challenge to clinicians, due to the poor overall survival rate compared with that of other gastrointestinal malignancies. Recently, with the emerging applications of therapeutic endoscopic ultrasonography (EUS), EUS- guided fine needle injection with antitumor agents is considered a promising modality. In this review, we summarize recently published data on the efficacy of endoscope guided interventional procedures with radioactive seeds. Firstly, EUS-guided iodine-125 seed implantation was reported to have a short-term efficacy on pancreatic cancer, with a three-month partial remission rate of 13.6% to 27%. Thereafter, feasibility of celiac ganglion radiation was tested in animal models to achieve pain relief. Recently, a seed-based stent has been introduced in the endoscopic retrograde cholangio-pancreatography (ERCP) drainage of biliary obstruction caused by pancreatic cancer, with a response rate of 72.7%. In addition, we discuss the potential of radioactive seed-based, endoscope-assisted interventional treatment of patients with locally advanced pancreatic cancer. Further studies should focus on the precise amount and distribution of seeds with the aim to improve the survival rate as well as the quality of life.
Belligerent Beginnings: JFK on the Opening Day (1996)

Dean Rusk has argued that John Kennedy “showed qualities of genuine greatness” during the Cuban missile crisis. Ted Sorensen has similarly extolled the virtues of his performance. Harold Macmillan, Sorensen wrote retrospectively, was right: the young president had “earned his place in history by this one act alone.” And JFK himself, according to Robert Kennedy, regarded his handling of the missile crisis as his finest accomplishment.1
Transactivation Domains Facilitate Promoter Occupancy for the Dioxin-Inducible CYP1A1 Gene In Vivo (1997)

We have studied the transcriptional regulation of the dioxin-inducible mouse CYP1A1 gene in its native chromosomal setting. We analyzed the ability of aromatic hydrocarbon receptor (AhR) mutants and AhR chimeras to restore dioxin responsiveness to the CYP1A1 gene in AhR-defective mouse hepatoma cells. Our data reveal that transactivation domains in AhR's C-terminal half mediate occupancy of the nuclear factor 1 site and TATA box for the CYP1A1 promoter in vivo. Transactivation domains of VP16 and AhR nuclear translocator, but not Sp1, can substitute for AhR's C-terminal half in facilitating protein binding at the promoter. Our data also reveal an apparent linear relationship between promoter occupancy and CYP1A1 gene expression in chromatin. These findings provide new insights into the in vivo mechanism of transcriptional activation for an interesting mammalian gene.
Thin-Film Transistor Integration for Biomedical Imaging and AMOLED Displays (2008)

Thin film transistor (TFT) backplanes are being continuously researched for new applications such as active-matrix organic light emitting diode (AMOLED) displays, sensors, and x-ray imagers. However, the circuits implemented in presently available fabrication technologies including poly silicon (poly-Si), hydrogenated amorphous silicon (a-Si:H), and organic semiconductor, are prone to spatial and/or temporal non-uniformities.&#13;\nWhile current-programmed active matrix (AM) can tolerate mismatches and non-uniformity caused by aging, the long settling time is a significant limitation. Consequently, acceleration schemes are needed and are proposed to reduce the settling time to 20 µs. This technique is used in the development of a pixel circuit and system for biomedical imager and sensor. Here, a metal-insulator-semiconductor (MIS) capacitor is adopted for adjustment and boost of the circuit gain. Thus, the new pixel architecture supports multi-modality imaging for a wide range of applications with various input signal intensities. Also, for applications with lower current levels, a fast current-mode line driver is developed based on positive feedback which controls the effect of the parasitic capacitance. The measured settling time of a conventional current source is around 2 ms for a 100-nA input current and 200-pF parasitic capacitance whereas it is less than 4 μs for the driver presented here. &#13;\nFor displays needed in mobile devices such as cell phones and DVD players, another new driving scheme is devised that provides for a high temporal stability, low-power consumption, high tolerance of temperature variations, and high resolution. The performance of the new driving scheme is demonstrated in a 9-inch fabricated display intended for DVD players. Also, a multi-modal imager pixel circuit is developed using this technique to provide for gain-adjustment capability. Here, the readout operation is not destructive, enabling the use of low-cost readout circuitry and noise reduction techniques.&#13;\nIn addition, a highly stable and reliable driving scheme, based on step calibration is introduced for high precision displays and imagers. This scheme takes advantage of the slow aging of the electronics in the backplane to simplify the drive electronics. The other attractive features of this newly developed driving scheme are its simplicity, low-power consumption, and fast programming critical for implementation of large-area and high-resolution active matrix arrays for high precision.
Randomized study of biennial screening with a faecal occult blood test: results after nine screening rounds (2004)

The lesser reduction in mortality from CRC of 11% compared to 18% after 5 screening rounds may be explained by the decrease in the number screened. Efficacy in those screened supports the introduction of countrywide screening in Denmark, but it must be ascertained that acceptability, proportion of early CRC and logistics all reach the same standard as in the randomized trial.
Efficient Isothermal Titration Calorimetry Technique Identifies Direct Interaction of Small Molecule Inhibitors with the Target Protein (2016)

Protein-protein interactions (PPI) play a critical role in regulating many cellular processes. Finding novel PPI inhibitors that interfere with specific binding of two proteins is considered a great challenge, mainly due to the complexity involved in characterizing multi-molecular systems and limited understanding of the physical principles governing PPIs. Here we show that the combination of virtual screening techniques, which are capable of filtering a large library of potential small molecule inhibitors, and a unique secondary screening by isothermal titration calorimetry, a label-free method capable of observing direct interactions, is an efficient tool for finding such an inhibitor. In this study we applied this strategy in a search for a small molecule capable of interfering with the interaction of the tumor-suppressor p53 and the E3-ligase MDM2. We virtually screened a library of 15 million small molecules that were filtered to a final set of 80 virtual hits. Our in vitro experimental assay, designed to validate the activity of mixtures of compounds by isothermal titration calorimetry, was used to identify an active molecule against MDM2. At the end of the process the small molecule (4S,7R)-4-(4-chlorophenyl)-5-hydroxy-2,7-dimethyl-N-(6-methylpyridin-2-yl)-4,6,7,8 tetrahydrIoquinoline-3-carboxamide was found to bind MDM2 with a dissociation constant of ~2 µM. Following the identification of this single bioactive compound, spectroscopic measurements were used to further characterize the interaction of the small molecule with the target protein. 2D NMR spectroscopy was used to map the binding region of the small molecule, and fluorescence polarization measurement confirmed that it indeed competes with p53.
Regrowth of axons into the distal spinal cord through a Schwann‐cell‐seeded mini‐channel implanted into hemisected adult rat spinal cord (1999)

Schwann cells (SCs) have been shown to be a key element in promoting axonal regeneration after being grafted into the central nervous system (CNS). In the present study, SC-supported axonal regrowth was tested in an adult rat spinal cord implantation model. This model is characterized by a right spinal cord hemisection at the eighth thoracic segment, implantation of a SC-containing mini-channel and restoration of cerebrospinal fluid circulation by suturing the dura. We demonstrate that a tissue cable containing grafted SCs formed an effective bridge between the two stumps of the hemicord 1 month after transplantation. Approximately 10 000 myelinated and unmyelinated axons (1 : 9) per cable were found at its midpoint. In addition to propriospinal axons and axons of peripheral nervous system (PNS) origin, axons from as many as 19 brainstem regions also grew into the graft without additional treatments. Most significantly, some regenerating axons in the SC grafts were able to penetrate through the distal graft-host interface to re-enter the host environment, as demonstrated by anterograde axonal labelling. These axons coursed toward, and then entered the grey matter where terminal bouton-like structures were observed. In channels containing no SCs, limited axonal growth was seen within the graft and no axons penetrated the distal interface. These findings further support the notion that SCs are strong promotors of axonal regeneration and that the mini-channel model may be appropriate for further investigation of axonal re-entry, synaptic reconnection and functional recovery following spinal cord injury.
A pathologic study of photoreceptor cell death in retinal photic injury (1991)

In the studies of retinal photic injury in the rat model, about 14-47% of the photoreceptor cell loss occurs in the first 24 hours. To understand the mechanism of this massive cell death and subsequent dissolution, we studied the early morphologic changes and examined the effect of cycloheximide, a protein synthesis inhibitor, on photic injury in rats. Groups of 2 dark-adapted albino Lewis rats were sacrificed immediately after 8, 16 or 24 hr of continuous exposure to green fluorescent light (intensity, 160-180 foot-candles; wavelength, 490-560 nm). An additional 2 rats were sacrificed 8 hr after a 24 hr light exposure, and 2 animals served as unexposed controls. The morphologic findings of the degenerating photoreceptor cells were assessed by light and electron microscopy. The integrity of the nuclear chromatin was investigated using a monoclonal anti-DNA antibody. Most of the photoreceptor cell loss was observed between 16 and 24 hr of exposure. No inflammatory or macrophagic cells were seen. Different stages of nuclear condensation and chromatin margination could be defined. The chromatin showed a progressive decrease in DNA labelling density. Scattered photoreceptor cells showed early cytoplasmic densification. To study the effect of cycloheximide, 4 rats were treated with 5 mg/kg subcutaneously at the start of a 24 hr exposure period and were sacrificed 6 hr after the exposure. Four untreated animals served as exposed controls for morphometric comparison of the outer nuclear layer (ONL). The control rats showed a 24% decrease in the thickness of the ONL when compared to cycloheximide-treated rats (p less than 0.001). The observations of mitochondrial changes and early DNA digestion were consistent with necrosis as the mechanism of cell death. However, in scattered photoreceptor cells, cytoplasmic densification, margination of nuclear chromatin, the lack of associated inflammation and the protective effect of cycloheximide were suggestive of apoptosis as another mechanism of cell death.
A non-peptide CCR5 antagonist inhibits collagen-induced arthritis by modulating T cell migration without affecting anti-collagen T cell responses (2002)

The chemokine receptors CCR5 and CXCR3 have been implicated as playing a central role in directing a Th1 inflammatory response. Here, we investigated whether a synthetic CCR5 antagonist affects the process of T cell migration to sites of inflammation. Immunization of DBA/1 mice with type II collagen resulted in typical arthritis, which is associated with cellular infiltration. Treatment with a CCR5 antagonist strikingly affected the development of arthritis by reducing both incidence and severity of disease. There was no substantial difference between collagen-immunized mice with and without antagonist treatment in the induction of anti-collagen T cell responses and the capacity to produce IL-12. This endogenous IL-12 functioned to induce comparable levels of CCR5 in these two immunized groups of T cells. Whereas a massive infiltration of inflammatory cells including CCR5(+) T cells occurred in the joints of mice immunized without antagonist, cellular infiltration in the antagonist-treated group was only marginal. These results indicate that administration of a CCR5 antagonist inhibits the development of arthritis not by affecting the generation of collagen-sensitized T cells but by interfering with their migration to joint lesions.
Atrial effects of the novel K+-channel-blocker AVE0118 in anesthetized pigs (2003)

The novel K(+) channel blocker AVE0118 prolonged atrial ERP and showed strong atrial antiarrhythmic efficacy with no apparent effect on ventricular repolarization in pigs in vivo.
ArF Chemically Amplified Negative Resist Using Alicyclic Epoxy Polymer. (1998)

We designed novel alicyclic epoxy polymers, poly(carboxy- tetracyclo[4.4.0.12, 5.17, 10]dodecyl (meth)acrylate-co-epoxyalicyclic acrylate) (poly(CTCDD(M)Ax-EPAAy)) for an ArF single-layer negative resist. These polymers became insoluble in a TMAH solution by an acid-catalyzed crosslinking reaction of the epoxy groups. A chemically amplified negative resist (consisting of the polymer having a 3, 4-epoxytricyclo [5.2.1.02, 6]decyl group and photoacid generator (PAG)) exhibited a resolution of 0.3 0-μm L/S using a 0.238% TMAH developer and an ArF exposure system (NA=0.55). We also investigated the influence of the polymer structures and additives on the lithographic characteristics. We found that the addition of alicyclic polyalcohol improved the resolution. The three-component resist system composed of the polymer which has 64% of the 2- epoxyethylnorbornyl group, 2, 3-dihydroxy-5-hydroxymethylnorbornane, and PAG resolved a 0.225-μm L/S pattern at 6.8mJ/cm2 with a 2.38% TMAH solution.
A silicon micromachined device for use in blood cell deformability studies (1995)

An application of silicon micromachining to the analysis of blood cell rheology is described. The system, based upon a micromachined flow cell, provides a specific measurement of each cell in a statistically significant population in terms of both flow velocity profile and an index of cell volume while the cells flow through an array of microchannels. The rationale, design, and fabrication of the silicon micromachined flow cell is discussed. Interrelated considerations determining the design of the associated fluidic, mechanical, imaging, and real-time image analysis subsystems are examined. Sample data comparing normal and iron deficiency anaemic blood are presented to illustrate the potential of this technique.
Drug Discovery Approaches to Target Wnt Signaling in Cancer Stem Cells (2010)

Cancer stem cells (CSCs) represent a unique subset of cells within a tumor that possess self-renewal capacity and pluripotency, and can drive tumor initiation and maintenance. First identified in hematological malignancies, CSCs are now thought to play an important role in a wide variety of solid tumors such as NSCLC, breast and colorectal cancer. The role of CSCs in driving tumor formation illustrates the dysregulation of differentiation in tumorigenesis. The Wnt, Notch and Hedgehog (HH) pathways are developmental pathways that are commonly activated in many types of cancer. While substantial progress has been made in developing therapeutics targeting Notch and HH, the Wnt pathway has remained an elusive therapeutic target. This review will focus on the clinical relevance of the Wnt pathway in CSCs and tumor cell biology, as well as points of therapeutic intervention and recent advances in targeting Wnt/β-catenin signaling.
Polymerase chain reaction amplification products separated on rehydratable polyacrylamide gels and stained with silver. (1989)

Separation of polymerase chain reaction (PCR) amplification of specific fragment length polymorphisms was carried out on rehydratable polyacrylamide gels on a horizontal flat slab system. A discontinuous sulfate-borate buffer system was employed on 5-8% T gels crosslinked with 3.5% C. Samples were diluted in leading sulfate ion buffer at 1/10 the ionic strength of the separating gel buffer and placed directly onto the surface of the rehydrated gels in 0.5-10 microliters volumes. The trailing ion and counterion were contained in a gel plug and placed directly onto the anodal and cathodal ends of the gel, and the electrodes placed directly onto the surface of the gel plugs. Filter paper wicks, soaked in diluted leading ion buffer, were placed along each side to lower the ionic strength of the edges, thereby increasing mobility at the edge and thus preventing smile effects. The gel-gel contact of the plug and separating gel prevent the production of a junction potential which occurs between dissimilar materials such as a paper wick and the gel. Ten- to 20-cm separations were carried out from 2-5 h, respectively, and resolution in the 20 cm system was 1.6-4 bp (base pairs) between 100 and 500 bp, 4-7 bp between 500 and 1000 bp, 12-20 bp between 1000 and 2000 bp and about 50 bp between 2000 and 3000 bp. Between 3000 and 4000 bp, resolution fell off to +/- 100 bp. Sensitivity, using a silver stain, indicated that one could readily distinguish less than 10 pg of DNA per mm width on the gels.(ABSTRACT TRUNCATED AT 250 WORDS)
Proteasomes: protein and gene structures. (1992)

Proteasomes are ring- or cylinder-shaped particles that have a sedimentation coefficient of 20S and are composed of a characteristic set of small polypeptides. These particles have a latent multicatalytic proteinase activity. Recently, proteasomes were found to combine reversibly with multiple protein components to form 26S proteolytic complexes that catalyze ATP-dependent, selective breakdown of proteins ligated with ubiquitin. This suggests that the 26S complexes are a new type of ATP-requiring protease in eukaryotic cells. We have studied the structures of various eukaryotic proteasomes at the molecular level by physicochemical and recombinant DNA techniques and have proposed that the gross structures of proteasomes, such as their size and shape, have been highly conserved during evolution. Proteasome subunits appear to be encoded by a family of homologous genes named the "proteasome gene family," which may have evolved from a common ancestral gene. Evidence obtained by genetic analyses in yeast and studies on the levels of proteasome expression in various eukaryotic cells indicates that proteasomes have essential roles in the cell. In this review, we summarize available information on the protein and gene structures of proteasomes and discuss the biological functions of proteasomes.
Protein Kinase C Mediates the Mitogenic Action of Thrombopoietin in c-Mpl–Expressing UT-7 Cells (1998)

Protein kinase C (PKC) has been implicated in signal transduction events elicited by several hematopoietic growth factors. Thrombopoietin (TPO) is the major regulator of megakaryocytic lineage development, and its receptor, c-Mpl, transduces signals for the proliferation and differentiation of hematopoietic progenitors. In this study we have examined the effect of TPO on the subcellular distribution of PKC (a measure of enzyme activation) in a growth factor-dependent pluripotent hematopoietic cell line that was engineered to express the c-Mpl receptor (UT-7/mpl). In addition, we have assessed the significance of this activation for the induction of both mitogenesis and differentiation. Using a PKC translocation assay, TPO was found to stimulate a time- and dose-dependent increase in the total content of PKC activity present in the membrane fraction of UT-7/mpl cells (maximum increase = 2.3-fold above basal level after 15 minutes with 40 ng/mL TPO, EC50 = 7 ng/mL). Accordingly, a decrease of PKC content in the cytosolic fraction was observed. Immunoblot analysis using PKC isotype-specific antibodies showed that TPO treatment led to a marked increase of the Ca2+/diacylglycerol-sensitive PKC isoforms alpha and beta found in the membrane fraction. In contrast, the subcellular distribution of these isoforms did not change after treatment with granulocyte-macrophage colony-stimulating factor (GM-CSF). Exposure of UT-7/mpl cells to the selective PKC inhibitor GF109203X completely inhibited the PKC activity associated to the membrane fraction after TPO treatment, and blocked the mitogenic effect of TPO. In contrast, GF109203X had no effect on the TPO-induced expression of GpIIb, a megakaryocytic differentiation antigen. Downregulation of PKC isoforms alpha and beta to less than 25% of their initial level by treatment with phorbol 12,13-dibutyrate also abolished the TPO-induced mitogenic response, but had no significant effect when this response was induced by GM-CSF. Taken together, these findings suggest that (1) TPO stimulates the activation of PKC, (2) PKC activation mediates the mitogenic action of TPO, and (3) PKC activation is not required for TPO-induced expression of megakaryocytic surface markers.
Queuine analogs. Their synthesis and inhibition of growth of mouse L5178Y cells in vitro (1986)

A variety of analogues of queuine (7-[(3S,4R,5S)-4,5-dihydroxycyclopent-1-en-3-ylaminomethyl]- 7 -deazaguanine), i.e., those with 7-N-substituted aminomethyl side chains and those in which the oxygen function at the 6 position of the 7-deazaguanine ring was replaced by sulfur, were synthesized and tested for ability to act as substrates for tRNA-guanine transglycosylase and for inhibitory effects on growth of mouse L5178Y leukemic cells in vitro. Of the compounds tested, analogues with sulfur at the 6 position of the 7-deazaguanine ring in place of oxygen or with an N-o-hydroxyphenyl, N-m-hydroxyphenyl, or iodoacetyl group in the 7-aminomethyl side chain in place of the naturally occurring cyclopentene diol moiety markedly inhibited the growth of cells at concentrations of 1-10 micrograms/mL, although queuine itself had practically no effect at a concentration of 100 micrograms/mL.