gebhart/patrepeval huggingface dataset:
In Vitro Study of 6-mercaptopurine Oxidation Catalysed by Aldehyde Oxidase and Xanthine Oxidase (2007)

In spite of over 40 years of clinical use of 6-mercaptopurine, many aspects of complex pharmacology and metabolism of this drug remain unclear. It is thought that 6-mercaptopurine is oxidized to 6-thiouric acid through 6-thioxanthine or 8-oxo-6-mercaptopurine by one of two molybdenum hydroxylases, xanthine oxidase (XO), however, the role of other molybdenum hydroxylase, aldehyde oxidase (AO), in the oxidation of 6-mercaptopurine and possible interactions of AO substrates and inhibitors has not been investigated in more details. In the present study, the role of AO and XO in the oxidation of 6- mercaptopurine has been investigated. 6-mercaptopurine was incubated with bovine milk xanthine oxidase or partially purified guinea pig liver molybdenum hydroxylase fractions in the absence and presence of XO and AO inhibitor/substrates, and the reactions were monitored by spectrophotometric and HPLC methods. According to the results obtained from the inhibition studies, it is more likely that 6- mercaptopurine is oxidized to 6-thiouric acid via 6-thioxanthine rather than 8-oxo-6-mercaptopurine. The first step which is the rate limiting step is catalyzed solely by XO, whereas both XO and AO are involved in the oxidation of 6-thioxanthine to 6-thiouric acid.
Autoimmunity and Anti-TNF-α Agents (2005)

Abstract: Treatment of rheumatoid arthritis (RA) patients with anti-tumor necrosis factor-alpha (anti-TNF-α) biologic agents has been associated with a reduction in the levels of specific autoantibodies, such as rheumatoid factor (RF) and anticyclic citrullinated peptide (anti-CCP), and the induction of non- organ-specific autoantibodies (antinuclear antibodies [ANAs], anti-dsDNA, and antiphospholipid antibodies [aPLs]). The mechanisms by which the blockade of anti-TNF-α decreases the generation of specific autoantibodies, such as anti-CCP and RF, are not yet known. However, it has been shown that these agents can downregulate the production of several inflammatory cytokines and mediators and that these anti-inflammatory effects may account for reduced autoantibody generation, particularly in the synovial compartment. Infliximab treatment leads to the induction of ANAs in 63.8% of RA patients and 49.1% of Crohn's disease (CD) patients, and anti-dsDNA antibodies in 13% of RA patients and 21.5% of CD patients, respectively. The development of ANAs and anti-dsDNA antibodies has also been described after etanercept therapy in 11% and 15% of RA patients, respectively. In the controlled trials, increases in ANA and anti-dsDNA titers were observed in 5.3% and in 12.9% of adalimumab-treated RA patients. Only limited data on the induction of aPL antibodies during TNF-α blocking treatment are available.
Conformational perturbation of the anticancer nucleoside arabinosylcytosine on Z‐DNA: Molecular structure of (araC‐dG)3 at 1.3 Å resolution (1992)

The left-handed Z-DNA structure of an araC-containing (where araC stands for arabinosylcytosine) hexamer, (araC-dG)3, has been solved by x-ray diffraction analysis at 1.3 A resolution. This hexamer was crystallized in the hexagonal P6(5)22 (a = b = 17.96 A, c = 43.22 A) space group in which the hexamers have statistically disordered packing arrangement along the 6(5) screw axis, yet the crystals diffract x-rays to high resolution. Its structure has been refined by the constrained least square refinement to a final R factor of 0.287 using 737 [> 3.0 sigma(F)] observed reflections. The asymmetric unit of the unit cell contains only a dinucleotide, 5'-p (araC)p(dG). The overall conformation resembles that of the canonical Z-DNA, but with some differences in details. The O2' hydroxyl groups of the araC residues form intramolecular hydrogen bonds with N2 of the 5'-guanine residues. In the deep groove of Z-DNA, these hydroxy groups replace the bridging water molecules that stabilize the guanine in the syn conformation. The results reinforce the earlier observation made by the structural analysis of another hexamer, d(CG[araC]GCG), with a mono-substitution of araC [M.-K. Teng, Y.-C. Liaw, G. A. van der Marel, J. H. van Boom, and A. H.-J. Wang (1989) Biochemistry, vol. 28, pp. 4923-4928]. These two structures show that araC residue can be incorporated readily into the Z structure and probably facilitates the B to Z transition, as supported by uv absorption spectroscopic studies in a number of araC-containing oligonucleotides. The potential biological roles of the araC-modified Z-DNA are discussed.
Molecular characterization of two Clostridium acetobutylicum ATCC 824 butanol dehydrogenase isozyme genes (1992)

A 4-kb segment of DNA containing two previously cloned butanol dehydrogenase (BDH) isozyme genes (D. Petersen, R. Welch, F. Rudolph, and G. Bennett, J. Bacteriol. 173:1831-1834, 1991) was sequenced. Two complete open reading frames (ORFs) were identified (bdhA and bdhB), along with a third truncated ORF (ORF1). The translation products of bdhA and bdhB corresponded to the N-terminal sequences of the purified BDH I and BDH II proteins, respectively. The two isozymes had a high amino acid identity (73%) and showed homology to a newly described class of alcohol dehydrogenases. Northern blots revealed that bdhA and bdhB did not form an operon. Primer extension experiments located single transcriptional start sites 37 and 58 bp upstream of the start codons of bdhA and bdhB, respectively. The -10 and -35 promoter regions for these genes were almost identical. bdhA and bdhB were found to be induced or derepressed immediately prior to significant butanol production in controlled pH 5.0 batch fermentations.
Assessing Susceptibility to Age-related Macular Degeneration with Proteomic and Genomic Biomarkers (2009)

Age-related macular degeneration (AMD) is a progressive disease and major cause of severe visual loss. Toward the discovery of tools for early identification of AMD susceptibility, we evaluated the combined predictive capability of proteomic and genomic AMD biomarkers. We quantified plasma carboxyethylpyrrole (CEP) oxidative protein modifications and CEP autoantibodies by ELISA in 916 AMD and 488 control donors. CEP adducts are uniquely generated from oxidation of docosahexaenoate-containing lipids that are abundant in the retina. Mean CEP adduct and autoantibody levels were found to be elevated in AMD plasma by approximately 60 and approximately 30%, respectively. The odds ratio for both CEP markers elevated was 3-fold greater or more in AMD than in control patients. Genotyping was performed for AMD risk polymorphisms associated with age-related maculopathy susceptibility 2 (ARMS2), high temperature requirement factor A1 (HTRA1), complement factor H, and complement C3, and the risk of AMD was predicted based on genotype alone or in combination with the CEP markers. The AMD risk predicted for those exhibiting elevated CEP markers and risk genotypes was 2-3-fold greater than the risk based on genotype alone. AMD donors carrying the ARMS2 and HTRA1 risk alleles were the most likely to exhibit elevated CEP markers. The results compellingly demonstrate higher mean CEP marker levels in AMD plasma over a broad age range. Receiver operating characteristic curves suggest that CEP markers alone can discriminate between AMD and control plasma donors with approximately 76% accuracy and in combination with genomic markers provide up to approximately 80% discrimination accuracy. Plasma CEP marker levels were altered slightly by several demographic and health factors that warrant further study. We conclude that CEP plasma biomarkers, particularly in combination with genomic markers, offer a potential early warning system for assessing susceptibility to this blinding, multifactorial disease.
The Biophysics of Radiofrequency Catheter Ablation in the Heart: The Importance of Temperature Monitoring (1993)

Radiofrequency (RF) catheter ablation is a technique whereby high frequency alternating electrical current with frequencies of 350 kHz to 1 MHz is delivered through electrode catheters to myocardial tissue creating a thermal lesion. The mechanism by which RF current heats tissue is resistive (or ohmic) heating of a narrow rim (< 1 mm) of tissue that is in direct contact with the electrode. Deeper tissue planes are then heated by conduction from the small region of volume heating. Heat is dissipated from the region by further heat conduction into normothermic tissue, and by heat convection via the circulating blood pool and larger coronary vessels. The lesion size is proportional to the temperature at the electrode-tissue interface (which is also a function of power level if electrical factors remain constant), and to the size of the electrode. At temperatures above 100 degrees C, boiling occurs at the electrode-tissue contact point resulting in a rapid rise in electrical impedance. Therefore, a theoretical maximum lesion size exists for any given electrode geometry. Other factors that are important for RF lesion formation include electrode-tissue contact pressure and duration of RF delivery. Temperature rises monoexponentially, and duration of energy delivery should be at least 35 to 45 seconds to approach steady state.
In the clinic: ongoing clinical trials evaluating c-MET-inhibiting drugs (2011)

The c-MET (mesenchymal-epithelial transition factor) pathway is dysregulated in many human cancers and promotes tumor growth, invasion and dissemination. The c-MET receptor tyrosine kinase can be activated via gene mutation, gene amplification, protein overexpression and/or a ligand-dependent autocrine/paracrine loop. Abnormalities in c-MET signaling have been reported to correlate with poor clinical outcomes and drug resistance in patients with cancer. Significant progress has been made in advancement of c-MET pathway inhibitors through to clinical trials. A robust pipeline of high-quality inhibitors targeting different aspects of c-MET activation is currently being explored in phase I, II and III clinical trials across multiple tumor types. Preliminary data demonstrate promising clinical activity with these agents, along with an acceptable toxicity profile. In this manuscript, the pharmacological profile of drugs targeting the c-MET pathway and available data from ongoing clinical trials of these drugs are discussed.
Cytotoxic onconase and ribonuclease a chimeras: comparison andin vitrocharacterization (1993)

AbstractOnconase, a protein isolated from fertilized Rana pipiens eggs, has antineoplastic properties both in vitro (Z. Darzynkiewicz, S. P. Carter, S. M. Mikulski, W. Ardelt, and K. Shogen, 1988, Cell Tissue Kinet. 21, 169–182) and in vivo (S. M. Mikulski, W. Ardelt, K. Shogen, E. H. Bernstein, and H. Menduke, 1990, J. Natl. Cancer Inst. 82, 151–153). The protein is a member of the pancreatic ribonuclease A superfamily and exhibits ribonuclease activity toward highly polymerized RNA (W. Ardelt, S. M. Mikulski, and K. Shogen, 1991, J. Biol. Chem. 266, 245–251). Previous work has demonstrated that bovine pancreatic ribonuclease A conjugated to transferrin (S. Rybak, S. Saxena, E. Ackerman, and R. Youle, 1991, J. Biol. Chem. 266, 21202–21207) or antibodies to the human transferrin receptor (D. Newton, O. Ilercil, D. Laske, E. Oldfield, S. Rybak, and R. Youle, 1992, J. Biol. Chem. 267, 169–182), acted like a class of reagents called immunotoxins to specifically inhibit protein synthesis in ligand-positive cells and prevent the growth of human glioblastoma tumors in vivo. To explore the properties of Onconase as an immunotoxin, this ribonuclease A homolog was conjugated to transferrin or an antibody (5E-9) to the human transferrin receptor and compared to bovine pancreatic ribonuclease A conjugates. The IC50's of both the Onconase and the ribonuclease A conjugates as inhibitors of protein synthesis in K562 human erythroleukemia cells were in the nano-molar range. Unconjugated Onconase also inhibited protein synthesis in K562 cells but was 20- to 100-fold less toxic on a molar basis than the Onconase conjugates. The time course profiles of Onconase and Onconase conjugates in affecting protein and RNA synthesis were very similar. Inhibition of protein synthesis was preceded by a decrease in RNA synthesis that subsequently increased relative to control values before it decreased again with time. Conjugated Onconase entered cells via a route mediated by transferrin or 5E-9 since excess of either ligand blocked toxicity of the conjugate but not the toxicity of unconjugated Onconase. Conjugated Onconase could also enter cells via the Onconase portion of the conjugate since it inhibited protein synthesis in cells that are not recognized by anti-human transferrin receptor antibody. ASPC-1 pancreatic carcinoma cells are essentially resistant to Onconase alone as measured by cell viability; however, when conjugated to antibody, Onconase did decrease the viability of ASPC-1 cells. This effect was markedly increased when the Onconase conjugate was combined with tamoxifen. These results demonstrate that the cytotoxic properties of a member of the ribonuclease A superfamily with inherent anti-tumor effects can be enhanced by conjugation to ligands capable of internalization. Therefore Onconase coupled to such ligands may have increased clinical relevance for some types of human cancer.
Expression of Tissue factor in Adenocarcinoma and Squamous Cell Carcinoma of the Uterine Cervix: Implications for immunotherapy with hI-con1, a factor VII-IgGFcchimeric protein targeting tissue factor (2011)

TF is highly expressed in squamous and adenocarcinoma of the uterine cervix. hI-con1 induces strong cytotoxicity against primary cervical cancer cell lines overexpressing TF and may represent a novel therapeutic agent for the treatment of cervical cancer refractory to standard treatment modalities.
A Preliminary Investigation of Shape Memory Alloys in the Surgical Correction of Scoliosis (1993)

Nitinol, a shape memory alloy, is flexible at low temperatures but retains its original shape when heated. This offers interesting possibilities for scoliosis correction. Of the shape memory alloys, nitinol is the most promising medically because of biocompatibility and the ability to control transition temperature. In vivo: Six goats with experimental scoliosis were instrumented with 6-mm nitinol rods. The rods were transformed, and the scoliosis corrected, in the awakened goats by 450-kHz radio frequency induction heating. The curves averaged 41 degrees before instrumentation, 33 degrees after instrumentation, and 11 degrees after rod transformation. The animals tolerated the heating without discomfort, neurologic injury, or evidence of thermal injury to the tissues or the spinal cord. In vitro: Nitinol rods were tested under both constant deflection and constant loading conditions and plotted temperature versus either force or displacement. The 6-mm rod generated forces of 200 N. The 9-mm rod generated up to 500 N. We safely coupled shape memory alloy transformation to the spine and corrected an experimental spinal deformity in awake animals. The forces generated can be estimated by the rod's curvature and temperature. The use of shape memory alloys allows continuous neurologic monitoring during awake correction, true rotational correction by rod torsion, and the potential option of periodic correction to take advantage of spinal viscoelasticity and the potential of true rotational correction by rod torsion.
Proteinticle/Gold Core/Shell Nanoparticles for Targeted Cancer Therapy without Nanotoxicity (2014)

PGCS-NPs (40 nm) with excellent photo-thermal activity are developed, on the surface of which affibody peptides with specific affinity for EGFR and many small gold dots (1-3 nm) are densely presented. The IV-injected PGCS-NPs into EGFR-expressing tumor-bearing mice successfully perform targeted and photothermal therapy of cancer. It seems that the small gold dots released from disassembled PGCS-NPs are easily removed and never cause in vivo toxicity problems.
Selective Electrical Stimulation of Postganglionic Cerebrovascular Parasympathetic Nerve Fibers Originating from the Sphenopalatine Ganglion Enhances Cortical Blood Flow in the Rat (1990)

Recently, the origins and pathways of cerebrovascular acetylcholine- and vasoactive intestinal polypeptide-containing nerves have been elucidated in detail in the rat: The sphenopalatine ganglion is the major source for postganglionic parasympathetic fibers to the vascular beds of the cerebral hemispheres. To clarify the functional role of the nerves on cerebral blood vessels in vivo, brain cortical microvascular blood flow was measured in rats during electrical stimulation of these particular postganglionic fibers. Animals were subjected to transection of the right nasociliary nerve 2 weeks before the flow measurements to eliminate activation of peptidergic sensory fibers. Relative change in microvascular blood flow was continuously recorded by a laser-Doppler flowmeter system under alpha-chloralose anesthesia. The postganglionic fibers were electrically stimulated just proximal to the ethmoidal foramen by a bipolar platinum electrode (5 V; 0.5 ms; 3, 10, 30, 60 Hz; as a continuous stimulation for 90 s). Stimulation at 10 Hz induced a marked increase of the cortical blood flow (CoBF) on the ipsilateral side, whereas no change was observed on the contralateral side. It reached a maximum mean value of 42.5% at 46 s, and then slightly declined during the remaining stimulation period. No significant changes were observed in the mean arterial blood pressure or blood gases during or after stimulation. Both atropine and scopolamine failed to alter this flow increase. Electrical stimulation of the postganglionic fibers at different frequencies revealed a maximal increase in the CoBF at 30 Hz in the control situation (47.2%), but at 10 Hz after scopolamine administration (51.6%).(ABSTRACT TRUNCATED AT 250 WORDS)
Resettlement action plan (2004)

The resettlement principles include replacing land for farmers, promoting employment opportunities and social assistance to help maintain or raise the standard of living, and setting up a grievance mechanism to resolve problems. Land replaced will be equivalent in both quantity and quality, or alternatively cash compensation will be paid according to set criteria based on land surveys and consultation with the affected populations. The resettlement plan also calls for offering technical and service training to raise their capability to do seasonal and temporary work, and to pay yearly subsidies to farmers. As part of the plan, the procedures covering land selection, information disclosure, and village consultation for land acquisition are outlined. Resettlement planning will be coordinated with local state land regulation, the social development plan, and the national economy.
Glucocorticoid-regulated gene in transformed to normal phenotypic reversion. (1994)

Glucocorticoid hormones modulate the actions of peptide growth factors and constitute important therapeutic tools as anti-inflammatory and anti-tumor agents. The C6 rat glioma cell line responds to glucocorticoids with changes in morphology and growth block. The hyper-responsive ST1 cell variant displays a dramatic phenotypic reversion under the influence of these hormones. Thus, the transformed and tumorigenic cells reversibly change to a normal and non-tumorigenic phenotype. In addition, the cells also produce a C-type retrovirus. We used poly A+ mRNA from ST1 cells that had been treated with hydrocortisone to generate a cDNA library that was then screened, by differential hybridization, for glucocorticoid-responsive cellular sequences. The retroviral genomic RNA was used to generate a viral-specific probe. Cross hybridization led to the isolation of at least 4 cDNA clones of which 3 are cellular sequences and one corresponds to a retroviral gene. These clones were characterized by DNA sequencing and Northern blot hybridization analysis.
Expression of the c-myc protooncogene in human prostatic carcinoma and benign prostatic hyperplasia. (1986)

We have examined the level of c-myc transcripts in prostate tissue obtained from patients with both benign prostatic hyperplasia and adenocarcinoma of the prostate. A significantly higher level of c-myc transcripts is observed in patients with adenocarcinoma (P less than 0.05). In addition, a subset of patients with adenocarcinoma had levels of c-myc transcripts 2-fold higher than the mean level for this group. These preliminary results indicate that the investigation of c-myc levels as a prognostic indicator in prostatic carcinoma is warranted.
Combinatorial Synthesis of Genetic Networks (2002)

A central problem in biology is determining how genes interact as parts of functional networks. Creation and analysis of synthetic networks, composed of well-characterized genetic elements, provide a framework for theoretical modeling. Here, with the use of a combinatorial method, a library of networks with varying connectivity was generated in Escherichia coli. These networks were composed of genes encoding the transcriptional regulators LacI, TetR, and lambda CI, as well as the corresponding promoters. They displayed phenotypic behaviors resembling binary logical circuits, with two chemical "inputs" and a fluorescent protein "output." Within this simple system, diverse computational functions arose through changes in network connectivity. Combinatorial synthesis provides an alternative approach for studying biological networks, as well as an efficient method for producing diverse phenotypes in vivo.
Noninvasive temperature estimation in tissue via ultrasound echo-shifts. Part I. Analytical model (1996)

Temperature changes in tissue, caused by high-intensity focused ultrasound, cause time shifts in the echoes that traverse the heated tissue. These time shifts are caused by thermally induced changes in the distribution of the velocity of sound and by thermal expansion within the tissue. Our analytical model relates these shifts to changes in temperature distribution. It is proposed that these relationships can be used as a method for the noninvasive estimation of temperature within the tissue. The model shows that the echo shifts depend mostly on changes in the mean velocity along the acoustical path of the echoes and that no explicit information about the shape of the velocity distribution is required. The effects of the tissue thermal expansion are small in comparison, but may be significant under certain conditions. The theory, as well as numerical simulations, also predicts that the time shifts have an approximately linear behavior as a function of temperature. This suggests that an empirical linear delay-temperature relationship can be determined for temperature prediction. It is also shown that, alternatively, the distribution of temperature in the tissue can be estimated from the distribution of echo delays along the acoustical path. In the proposed system, low-level pulse echoes are sampled during brief periods when the high-intensity ultrasonic irradiation is off, and thus linear acoustic behavior is assumed. The possibility of nonlinear aftereffects and other disturbances limiting this approach is discussed.