gebhart/patrepeval huggingface dataset:
N-glucuronidation of drugs and other xenobiotics by human and animal UDP-glucuronosyltransferases (2011)

Metabolic disposition of drugs and other xenobiotics includes glucuronidation reactions that are catalyzed by the uridine diphosphate glucuronosyltransferases (UGTs). The most common glucuronidation reactions are O- and N-glucuronidation and in this review, we discuss both, while the emphasis is on N-glucuronidation. Interspecies difference in glucuronidation is another central issue in this review due to its importance in drug development. Accordingly, the available data on glucuronidation in different animals comes mainly from the species that are used in preclinical studies to assess the safety of drugs under development. Both O- and N-glucuronidation reactions are chemically diverse. Different O-glucuronidation reactions are described and discussed, and many drugs that undergo such reactions are indicated. The compounds that undergo N-glucuronidation include primary aromatic amines, hydroxylamines, amides, tertiary aliphatic amines, and aromatic N-heterocycles. The interspecies variability in N-glucuronidation is particularly high, above all when it comes to aliphatic tertiary amines and aromatic N-heterocycles. The N-glucuronidation rates in humans are typically much higher than in animals, largely due to the activity of two enzymes, the extensively studied UGT1A4, and the more recently identified as a main player in N-glucuronidation, UGT2B10. We discuss both enzymes and review the findings that revealed the role of UGT2B10 in N-glucuronidation.
Pentoxifylline Diminishes the Oxidative Damage to Renal Tissue Induced by Streptozotocin in the Rat (2004)

Oxidative damage has been suggested to be a contributing factor in the development to diabetic nephropathy (DN). Recently, there has been evidence that pentoxifylline (PTX) has free radical-scavenging properties; thus, its anti-inflammatory and renoprotective effects may be related to a reduction in reactive oxygen species production. It is likely that the pharmacological effects of PTX include an antioxidant mechanism as shown in in vitro assays. The aim of this study was to evaluate whether the reported renoprotective effects of PTX could be the result of its antioxidant actions in streptozotocin (STZ)-induced DN in rats. The administration of PTX over a period of 8 weeks, in addition to displaying renoprotective effects, caused a significant reduction in lipoperoxide levels (LPOS) in the diabetic kidney (P < 0.05), compared to untreated rats. These levels were comparable to those in the healthy kidney of experimental animals (P > 0.05). All untreated STZ rats exhibited an increase in LPOS as opposed to healthy controls (H) (P < 0.001). The total antioxidant activity (TAA) in plasma was increased significantly already after 2 days of STZ (P < 0.05). When we examined the progression of TAA in STZ rats, there was a significant decrease over 8 weeks (P < 0.05). PTX treatment caused an increase in TAA when compared to untreated STZ rats (P < 0.05). Renal hypertrophy was less evident in PTX-treated STZ than in untreated STZ rats, evaluated by kidney weight/body weight ratio. These results indicate that PTX decreases the oxidative damage induced by these experimental procedures and may increase antioxidant defense mechanisms in STZ-induced diabetes in rats.
Activation of Wnt/β‐catenin pathway mediates growth and survival in B‐cell progenitor acute lymphoblastic leukaemia (2007)

This study investigated the response of acute lymphoblastic leukaemia (ALL) cells to Wnt proteins. Accumulation of beta-catenin was measured by Western blotting and immunofluorescence microscopy. Reverse transcription polymerase chain reaction (RT-PCR) analysis of B-cell progenitor acute lymphoblastic leukaemia (ALL) cells revealed expression of Wnt genes, including WNT2B in 33%, WNT5A in 42%, WNT10B in 58% and WNT16B in 25% of cases. The Wnt receptors, (Frizzled) FZD7 and FZD8 were also expressed in most cases while FZD3, FZD4 and FZD9 were occasionally detected. Stimulation of ALL cells with Wnt-3a activated canonical Wnt signalling with increased expression and nuclear translocation of beta-catenin. This resulted in a 1.7- to 5.3-fold increase in cell proliferation, which was associated with enhanced cell cycle entry. A significant increase in the survival of ALL cells under conditions of serum deprivation was also observed. Microarray analysis and quantitative RT-PCR revealed that activation of the Wnt/beta-catenin pathway led to altered expression of genes involved in cell cycle regulation and apoptosis in normal and leukaemic B-cell progenitors. Our results demonstrate that Wnt-3a provides proliferative and survival cues in ALL cells. This data suggests that targeting the Wnt signalling pathway may be a useful therapeutic strategy in ALL.
Genetic evidence for two distinct transactivation functions of the herpes simplex virus alpha protein ICP27 (1990)

Infected-cell protein 27 (ICP27) is a herpes simplex virus type 1 alpha, or immediate-early, protein involved in the regulation of viral gene expression. To better understand the function(s) of ICP27 in infected cells, we have isolated and characterized viral recombinants containing defined alterations in the ICP27 gene. The mutant virus d27-1 contains a 1.6-kilobase deletion which removes the ICP27 gene promoter and most of the coding sequences, while n59R, n263R, n406R, and n504R are mutants containing nonsense mutations which encode ICP27 molecules truncated at their carboxyl termini. All five mutants were defective for lytic replication in Vero cells. Analysis of the mutant phenotypes suggests that ICP27 has the following regulatory effects during the viral infection: (i) stimulation of expression of gamma-1 genes, (ii) induction of expression of gamma-2 genes, (iii) down regulation of expression of alpha and beta genes late in infection, and (iv) stimulation of viral DNA replication. Cells infected with the mutant n504R expressed wild-type levels of gamma-1 proteins but appeared to be unable to efficiently express gamma-2 mRNAs or proteins. This result suggests that ICP27 mediates two distinct transactivation functions, one which stimulates gamma-1 gene expression and a second one required for gamma-2 gene induction. Analysis of the mutant n406R suggested that a truncated ICP27 polypeptide can interfere with the expression of many viral beta genes. Our results demonstrate that ICP27 has a variety of positive and negative effects on the expression of viral genes during infection.
Synthesis and Characterization of Tris(trialkylphosphine)copper(I)trimethylsilylchalcogenolates (2000)

The copper−chalogenolates (R3P)3Cu−ESiMe3 (E = S, 1; Se, 2; Te, 3; R = Et, a; nPr, b) have been prepared in high yield from (R3P)3CuOAc and E(SiMe3)2 at low temperatures. Complexes 1−3 contain a pendant −SiMe3 moiety bonded to a chalcogen center. These copper−chalcogenolates are clear, colorless, low-melting-point solids and have been characterized by single-crystal crystallographic and spectroscopic methods.
Scalable Superconducting Architecture for Adiabatic Quantum Computation (2004)

A scalable superconducting architecture for adiabatic quantum computers is proposed. The architecture is based on time-independent, nearest-neighbor interqubit couplings: it can handle any problem in the class NP even in the presence of measurement errors, noise, and decoherence. The implementation of this architecture with superconducting persistent-current qubits and the natural robustness of such an implementation to manufacturing imprecision and decoherence are discussed.
The first 3,000 Non-Invasive Prenatal Tests (NIPT) with the Harmony test in Belgium and the Netherlands. (2014)

As the classical first trimester Down syndrome screening (FTS, combination test) has a false-negative rate of 20-25% and > 95% of the abnormal FTS results are false-positive, we evaluated the new Non-Invasive Prenatal Test (NIPT) in Belgium and the Netherlands. The study population consisted of 3000 consecutive pregnancies in Belgium and the Netherlands in which NIPT was performed using the Harmony test. In 57 (1.9%) of the 3000 pregnancies an abnormal NIPT result was found. This included 51 fetuses with trisomy 21, 4 fetuses with trisomy 18 and 2 fetuses with trisomy 13. In 47 of the 57 the NIPT result was confirmed by genetic testing of material obtained by amniocentesis or chorionic biopsy, and no false-positive results were recorded. The false-negative rate as determined on more than 2000 women that had delivered at the time of reporting was low, and so far only 2 false-negative results were reported (one trisomy 18 and one trisomy 21). The failure rate where no NIPT result could be obtained after repeated sampling was 0.90%. In this large clinical series, NIPT using the Harmony test proves to be a very reliable prenatal test to detect fetal trisomies 21, 18 and 13 in maternal blood in Belgium and the Netherlands.
The anti-tumor immune response induced by a combination of MAGE-3/MAGE-n-derived peptides (2008)

Tumor antigen-derived peptides have been widely used to elicit tumor-specific cytotoxic T lymphocytes (CTLs). MAGE gene products are of particular interest owing to their wide expression in many tumors and their potential to induce tumor-specific CTL responses. Antigen-specific CTLs induced by MAGE gene-derived peptides have proven to be highly efficacious in the prevention and treatment of various types of tumors. MAGE-3 has been used as a target for tumor immunotherapy. MAGE-n is a new member of the MAGE gene family and has been shown to be closely associated with hepatocellular carcinoma (HCC). However, the majority of previous investigations focused on the single MAGE antigen-derived peptides as a cancer vaccine which has many limitations. The tumor antigen expression is known to be heterogeneous and tumor cells can express multiple tumor antigens. Thus, vaccines incorporating single antigen-derived epitopes may be inadequate in generating a complete immune response against the tumor. Instead, a polyvalent vaccine incorporating epitopes derived from several tumor antigens may be more effective. Our study combined the MAGE-3 and MAGE-n-derived peptides as a cancer vaccine. The results showed that the combination of MAGE-3 and MAGE-n epitopes induced more effective anti-tumor immune responses than either of the peptides alone. In addition, the peptide-specific activity was observed to be in an MHC-restricted manner. Our study indicated that the combination of several tumor antigen-derived peptides may present a better peptide-based cancer immunotherapy.
Development of high amylose wheat through TILLING (2012)

We report the use of TILLING to develop new traits in crops with complex genomes without the use of transgenic modifications. Combined mutations in SBEIIa in durum and bread wheat varieties resulted in lines with significantly increased amylose and resistant starch contents.
Promotion of Angiogenesis by Low Energy Laser Irradiation (2002)

The effect of low energy laser (He-Ne) irradiation (LELI) on the process of angiogenesis in the infarcted rat heart and in the chick chorioallantoic membrane (CAM), as well as the proliferation of endothelial cells in tissue culture, was investigated. Formation of new blood vessels in the infarcted rat heart was monitored by counting proliferating endothelial cells in blood vessels. In the CAM model, defined areas were laser-irradiated or nonirradiated and blood vessel density was recorded in each site in the CAM at various time intervals. Laser irradiation caused a 3.1-fold significant increase in newly formed blood vessels 6 days post infarction, as compared with nonirradiated rats. In the CAM model, a slight inhibition of angiogenesis up to 2 days post irradiation and a significant enhancement of angiogenesis in the laser-irradiated foci as compared with control nonirradiated spots were evident. The LELI caused a 1.8-fold significant increase in the rate of proliferation in endothelial cells in culture over nonirradiated cells. It is concluded that LELI can promote the proliferation of endothelial cells in culture, which may partially explain the augmentation of angiogenesis in the CAM model and in the infarcted heart. These results may have clinical significance by offering therapeutic options to ameliorate angiogenesis in ischemic conditions.
veA‐dependent RNA‐pol II transcription elongation factor‐like protein, RtfA, is associated with secondary metabolism and morphological development in Aspergillus nidulans (2012)

In Aspergillus nidulans the global regulatory gene veA is necessary for the biosynthesis of several secondary metabolites, including the mycotoxin sterigmatocystin (ST). In order to identify additional veA-dependent genetic elements involved in regulating ST production, we performed a mutagenesis on a deletion veA (ΔveA) strain to obtain revertant mutants (RM) that regained the capability to produce toxin. Genetic analysis and molecular characterization of one of the revertant mutants, RM3, revealed that a point mutation occurred at the coding region of the rtfA gene, encoding a RNA-pol II transcription elongation factor-like protein, similar to Saccharomyces cerevisiae Rtf1. The A. nidulans rtfA gene product accumulates in nuclei. Deletion of rtfA gene in a ΔveA background restored mycotoxin production in a medium-dependent manner. rtfA also affects the production of other metabolites including penicillin. Biosynthesis of this antibiotic decreased in the absence of rtfA. Furthermore, rtfA is necessary for normal morphological development. Deletion of the rtfA gene in wild-type strains (veA+) resulted in a slight decrease in growth rate, drastic reduction in conidiation, and complete loss of sexual development. This is the first study of an Rtf1 like gene in filamentous fungi. We found rtfA putative orthologues extensively conserved in numerous fungal species.
Dr H.V. Evatt - Part One: A Question of Sanity (2007)

This article is the first of a two-part study looking into the public career of Dr Evatt. The first part, entitled 'A Question of Sanity', analyses the synergy between Evatt's personal and political pathology from the perspectives of forensic psychology and historical-political analysis and the second part 'The Question of Loyalty' assesses whether his aberrant destructive behaviour was caused solely by his unstable mental state or whether there was a more sinister explanation of his motives. Part two of this article is: Andrew Campbell, 'Dr H.V. Evatt: The Question of Loyalty', National Observer, No. 76, Autumn 2008, pp. 33-55.
Systemic Adenovirus Infection Associated with High Mortality in Mule Deer (Odocoileus hemionus) in California (1996)

Seventeen counties in northern California experienced epizootics of high mortality in the mule deer (Odocoileus hemionus) population during the latter half of 1993. Thirteen deer submitted to the California Veterinary Diagnostic Laboratory System as part of this natural die-off had systemic adenovirus infection. Pulmonary edema was present in all 13 deer. Erosions, ulceration, and abscessation of the upper alimentary tract occurred in 7/13 deer. Four of 13 deer had hemorrhagic enteritis. All 13 deer had widespread systemic vasculitis with endothelial intranuclear inclusions. Fluorescein isothiocyanate-labeled antibody directed against bovine adenovirus type 5 bound to antigen in endothelial cells. Adenovirus was identified by transmission electron microscopy within the nuclei of endothelial cells in 6/6 deer examined. An adenovirus was isolated from lung homogenates of one deer that were cultured on black-tailed deer pulmonary artery endothelial cells. With the exception of the intranuclear inclusions evident on histologic evaluation, gross and histologic changes were similar to those described for bluetongue virus infection and epizootic hemorrhagic disease virus infection in white-tailed deer. Nine additional deer were emaciated and had pharyngeal abscesses with focal vasculitis, which may represent the chronic affects of previous nonfatal adenovirus infection.
Basaloid bronchial carcinoma. A histologic group with a poor prognosis (1994)

This subset of non-small cell lung cancer (NSCLC) has a worse prognosis than other NSCLC, and this should be considered in survival studies and new treatment trials.
Lymphoma Regression Induced by Ganciclovir in Mice Bearing a Herpes Thymidine Kinase Transgene (1990)

The dose limitations imposed on cancer chemotherapeutic agents by their lack of selectivity can, in theory, be circumvented by a strategy entailing the prophylactic insertion into hosts of drug-sensitivity genes that are acquired or expressed in some but not all cells. This strategy predicts that neoplasms arising from drug-sensitive cells might be safely treatable with tumor-eradicative drug doses because the presence of a modicum of drug-insensitive stem cells will protect vital tissues from lethal depopulation. To test this prediction, lymphomas were induced with Abelson leukemia virus in mice bearing a herpes simplex virus thymidine kinase (HSV-TK) transgene selectively expressed in lymphoid cells. Of 12 transgenic mice treated with the HSV-TK-specific substrate ganciclovir (GCV), 11 exhibited complete tumor regressions; 5 of these mice remained tumor-free over observation periods that exceeded 100 days. Among the lymphomas that recurred, most appeared to represent mutant subpopulations that were GCV-insensitive because they had lost HSV-TK, implying that independent insertion of multiple HSV-TK gene copies might provide a means of preventing recurrences. The results of this study demonstrate that chemosensitivity genes can enhance the efficacy of treatment in hosts who subsequently develop a neoplasm. While the use of a germ-line gene insertion model precludes direct human application, the results also imply the merits of exploring an alternative version of the strategy in which somatic insertion of chemosensitivity genes in mosaic fashion is used prophylactically to enhance the prospect that a subsequent tumor will respond to therapy.
Regulation of fibroblast functions by lysophospholipid mediators: Potential roles in wound healing (2007)

The bioactive lysophospholipids, primarily lysophosphatidic acid (LPA) and sphingosine-1-phosphate (S1P), are recent additions to the list of potent mediators of tissue repair and wound healing. In this review, we highlight the diverse actions of LPA and S1P on many types of cells involved in the wound healing process, with special emphasis on their regulation of fibroblasts. The effects of LPA and S1P are principally mediated via specific cell surface receptors. Important signaling pathways downstream of these receptors and the importance of TGFbeta and S1P cross-talk for wound healing are also discussed. Moreover, specific agonists and antagonists of the lysophospholipid receptors may be useful for the treatment of wounds and abnormal wound healing.
Compensation mechanism in tumor cell migration (2003)

Invasive tumor dissemination in vitro and in vivo involves the proteolytic degradation of ECM barriers. This process, however, is only incompletely attenuated by protease inhibitor-based treatment, suggesting the existence of migratory compensation strategies. In three-dimensional collagen matrices, spindle-shaped proteolytically potent HT-1080 fibrosarcoma and MDA-MB-231 carcinoma cells exhibited a constitutive mesenchymal-type movement including the coclustering of beta 1 integrins and MT1-matrix metalloproteinase (MMP) at fiber bindings sites and the generation of tube-like proteolytic degradation tracks. Near-total inhibition of MMPs, serine proteases, cathepsins, and other proteases, however, induced a conversion toward spherical morphology at near undiminished migration rates. Sustained protease-independent migration resulted from a flexible amoeba-like shape change, i.e., propulsive squeezing through preexisting matrix gaps and formation of constriction rings in the absence of matrix degradation, concomitant loss of clustered beta 1 integrins and MT1-MMP from fiber binding sites, and a diffuse cortical distribution of the actin cytoskeleton. Acquisition of protease-independent amoeboid dissemination was confirmed for HT-1080 cells injected into the mouse dermis monitored by intravital multiphoton microscopy. In conclusion, the transition from proteolytic mesenchymal toward nonproteolytic amoeboid movement highlights a supramolecular plasticity mechanism in cell migration and further represents a putative escape mechanism in tumor cell dissemination after abrogation of pericellular proteolysis.
Nanoparticle and Iron Chelators as a Potential Novel Alzheimer Therapy (2009)

Current therapies for Alzheimer disease (AD) such as the acetylcholinesterase inhibitors and the latest NMDA receptor inhibitor, Namenda, provide moderate symptomatic delay at various stages of the disease, but do not arrest the disease progression or bring in meaningful remission. New approaches to the disease management are urgently needed. Although the etiology of AD is largely unknown, oxidative damage mediated by metals is likely a significant contributor since metals such as iron, aluminum, zinc, and copper are dysregulated and/or increased in AD brain tissue and create a pro-oxidative environment. This role of metal ion-induced free radical formation in AD makes chelation therapy an attractive means of dampening the oxidative stress burden in neurons. The chelator desferrioxamine, FDA approved for iron overload, has shown some benefit in AD, but like many chelators, it has a host of adverse effects and substantial obstacles for tissue-specific targeting. Other chelators are under development and have shown various strengths and weaknesses. Here, we propose a novel system of chelation therapy through the use of nanoparticles. Nanoparticles conjugated to chelators show unique ability to cross the blood-brain barrier (BBB), chelate metals, and exit through the BBB with their corresponding complexed metal ions. This method may provide a safer and more effective means of reducing the metal load in neural tissue, thus attenuating the harmful effects of oxidative damage and its sequelae. Experimental procedures are presented in this chapter.
CpG ODN-mediated regulation of IL-12 p40 transcription (2000)

Oligodeoxynucleotides (ODN) containing CpG motifs activate RAW 264.7 mouse macrophages and RPMI 8226 human myeloma cells to produce IL-12 p40. Using deletion and site-directed mutagenesis, the nuclear factor (NF)-kappaB half-site and the CCAAT/enhancer binding protein (C/EBP) recognition site were identified as potent cis-acting elements in CpG ODN-mediated IL-12 p40 promoter activation. Several NF-kappaB/Rel proteins competed for binding to the NF-kappaB half-site. The p65/c-Rel and p65/p50 heterodimer occupied this site shortly after CpG ODN administration (0.5-2 h), while the p50/c-Rel heterodimer dominated binding in the late stage (8-12 h). The induction of p50/c-Rel heterodimer was associated with a significant expression of IL-12 p40 mRNA. C/EBPbeta also contributed to CpG ODN-mediated IL-12 p40 promoter activation.