bluuebunny/crossref_metadata_2025_split huggingface dataset:
TRPC1 is regulated by caveolin‐1 and is involved in oxidized LDL‐induced apoptosis of vascular smooth muscle cells
Authors: Ingueneau Cécile , Huynh‐Do Uyen , Marcheix Bertrand , Athias Anne , Gambert Philippe , Nègre‐Salvayre Anne , Salvayre Robert , Vindis Cécile 
Published: November 2008

AbstractOxidized low‐density lipoprotein (oxLDL) induced‐apoptosis of vascular cells may participate in plaque instability and rupture. We have previously shown that vascular smooth muscle cells (VSMC) stably expressing caveolin‐1 were more susceptible to oxLDL‐induced apoptosis than VSMC expressing lower level of caveolin‐1, and this was correlated with enhanced Ca2+ entry and pro‐apoptotic events. In this study, we aimed to identify the molecular events involved in oxLDL‐induced Ca2+ influx and their regulation by the structural protein caveolin‐1. In VSMC, transient receptor potential canonical‐1 (TRPC1) silencing by ARN interference prevents the Ca2+ influx and reduces the toxicity induced by oxLDL. Moreover, caveolin‐1 silencing induces concomitant decrease of TRPC1 expression and reduces oxLDL‐induced apoptosis of VSMC. OxLDL enhanced the cell surface expression of TRPC1, as shown by biotinylation of cell surface proteins, and induced TRPC1 translocation into caveolar compartment, as assessed by subcellular fractionation. OxLDL‐induced TRPC1 translocation was dependent on actin cytoskeleton and associated with a dramatic rise of 7‐ketocholesterol (a major oxysterol in oxLDL) into caveolar membranes, whereas the caveolar content of cholesterol was unchanged. Altogether, the reported results show that TRPC1 channels play a role in Ca2+ influx and Ca2+ homeostasis deregulation that mediate apoptosis induced by oxLDL. These data also shed new light on the role of caveolin‐1 and caveolar compartment as important regulators of TRPC1 trafficking to the plasma membrane and apoptotic processes that play a major role in atherosclerosis.
Clinical significance of TTF‐1 protein expression and TTF‐1 gene amplification in lung adenocarcinoma
Authors: Barletta Justine A. , Perner Sven , Iafrate A. John , Yeap Beow Y. , Weir Barbara A. , Johnson Laura A. , Johnson Bruce E. , Meyerson Matthew , Rubin Mark A. , Travis William D. , Loda Massimo , Chirieac Lucian R. 
Published: November 2008

AbstractThe majority of lung adenocarcinomas express the lineage‐specific thyroid transcription factor‐1 (TTF‐1). We recently reported that in a subset of lung adenocarcinomas the TTF‐1 gene is amplified. Although the prognostic significance of TTF‐1 expression has been previously investigated, the significance of TTF‐1 amplification has not been established. We studied 89 consecutive patients with lung adenocarcinomas treated by surgery at Brigham and Women’s Hospital between 1997 and 1999 and performed immunohistochemical analysis for TTF‐1 expression and fluorescence in situ hybridization for TTF‐1 amplification. We investigated associations between clinical–pathological characteristics, TTF‐1 expression, TTF‐1 amplification and overall survival. TTF‐1 expression was categorized as high (48%), low (24%) or absent (28%). TTF‐1 was amplified in 7% of cases. Patients with adenocarcinomas with low or high TTF‐1 expression had a significantly better outcome than those with absent TTF‐1 expression (median overall survival times of 72.4, 77.8 and 30.5 months, respectively, P= 0.002). In contrast, patients with adenocarcinomas with TTF‐1 expression had a worse outcome if TTF‐1 was amplified (median overall survival time 39.5 versus 87.5 months). In multivariate analysis, improved overall survival was independently predicted by TTF‐1 expression in combination with no TTF‐1 amplification (P < 0.001). In patients with lung adenocarcinoma, TTF‐1 expression is a predictor of good outcome. Patients with no TTF‐1 expression or TTF‐1 expression and TTF‐1 gene amplification tend to have a significantly worse prognosis than patients with TTF‐1 expression and no TTF‐1 gene amplification.
Pharmacotherapeutic targets in Alzheimer's disease
Authors: Biran Yif'at , Masters Colin L. , Barnham Kevin J. , Bush Ashley I. , Adlard Paul A. 
Published: November 2008

Current pharmacotherapies for the treatment of ADAD pharmacotherapies targeting τAD pharmacotherapies targeting AβThe metal hypothesis of ADAD pharmacotherapies targeting metal ionsAbstractAlzheimer's disease (AD) is a progressive neurodegenerative disorder which is characterized by an increasing impairment in normal memory and cognitive processes that significantly diminishes a person's daily functioning. Despite decades of research and advances in our understanding of disease aetiology and pathogenesis, there are still no effective disease‐modifying drugs available for the treatment of AD. However, numerous compounds are currently undergoing pre‐clinical and clinical evaluations. These candidate pharma‐cotherapeutics are aimed at various aspects of the disease, such as the microtubule‐associated τ‐protein, the amyloid‐β (Aβ) peptide and metal ion dyshomeostasis – all of which are involved in the development and progression of AD. We will review the way these pharmacological strategies target the biochemical and clinical features of the disease and the investigational drugs for each category.
Hypothalamic sensing of circulating lactate regulates glucose production
Authors: Kokorovic Andrea , Cheung Grace W.C. , Rossetti Luciano , Lam Tony K.T. 
Published: November 2008

AbstractEmerging studies indicate that hypothalamic hormonal signalling pathways and nutrient metabolism regulate glucose homeostasis in rodents. Although hypothalamic lactate‐sensing mechanisms have been described to lower glucose production (GP), it is currently unknown whether the hypothalamus senses lactate in the blood circulation to regulate GP and maintain glucose homeostasis in vivo. To examine whether hypothalamic sensing of circulating lactate is required to regulate GP, we infused intravenous (i.v.) lactate in the absence or presence of inhibition of central/hypothalamic lactate‐sensing mechanisms in normal rodents. Inhibition of central/hypothalamic lactate‐sensing mechanisms was achieved by three independent approaches. Tracer‐dilution methodology in combination with the pancreatic clamp technique was used to assess the effect of i.v. and central/hypothalamic administrations on glucose metabolism in vivo. In the presence of physiologically relevant increases in the levels of plasma lactate, inhibition of central lactate‐sensing mechanisms by lactate dehydrogenase inhibitor oxamate (OXA) or ATP‐sensitive potassium channels blocker glibenclamide increased GP. Furthermore, direct administration of OXA into the mediobasal hypothalamus increased GP in the presence of similar elevation of circulating lactate. Together, these data indicate that hypothalamic sensing of circulating lactate regulates GP and is required to maintain glucose homeostasis.
Improving performance targets for flood defence assets
Authors: Flikweert J. , Simm J. 
Published: November 2008

AbstractThe Environment Agency manage over 10 000 km of raised flood defence assets (embankments, walls and structures) in England and Wales. These assets are managed to minimum targets that are expressed as a condition grade: a number between 1 (Very Good) and 5 (Very Poor) that is determined by visual inspection according to the Condition Assessment Manual. This paper discusses the good performance of the defences during the flood events of summer 2007: 1000 km of defences were tested, about 500 km was overtopped, but only four breaches occurred. The events have also shown that breaches can have various causes and that condition grade is only one indicator of performance. The paper then presents an analysis of the fragility of defences leading to the conclusion that in most cases, lower minimum condition grades are acceptable. This should enable more effective use of limited available funds, for example for data collection, analysis or improvement works.
Best Practices for Serving Traumatized Children and Families
Authors: Igelman Robyn S. , Ryan Barbara E. , Gilbert Alicia M. , Bashant Judge Cynthia , North Katherine 
Published: November 2008

ABSTRACTThis paper highlights the traumatic impact of child abuse and neglect upon children and adolescents who are commonly seen in court systems. In addition to describing prevalence rates of trauma exposure and psychological reactions among traumatized children, it addresses the need for judges and court personnel to work with children and families in a manner that is sensitive to their traumatic experiences and emphasizes the need for these children to receive the very best evidence‐based care available in order to help them more effectively cope and recover from trauma exposure. Cultural issues and model adaptations are covered in relation to the use of evidence‐based practices with children from various cultural and ethnic backgrounds. Specific recommendations are given to help judges and court personnel become better informed about the use of evidence‐based practices for treating child trauma, enabling them to respond more sensitively and appropriately in these cases.
Obtaining Information from Children in the Justice System
Authors: Olafson Erna , Kenniston Julie 
Published: November 2008

ABSTRACTEven young children can provide accurate accounts of experienced events if adults question them skillfully. However, most justice system personnel receive little training in evidence‐based methods to question children non‐suggestively and with developmental sensitivity. This paper summarizes key research findings about child forensic interviewing. It concludes with recommendations for judges and other justice system personnel who must engage in age‐appropriate consultation with children and outlines steps judges can take to establish evidence‐based interviewing practices by court personnel in their jurisdictions.
How to Maintain Emotional Health When Working with Trauma
Authors: Osofsky Joy D. , Putnam Frank W. , Lederman Judge Cindy S. 
Published: November 2008

ABSTRACTVicarious traumatization, compassion fatigue, or secondary traumatization refers to the cumulative effect of working with survivors of traumatic life events as part of everyday work. Although this issue has been acknowledged and addressed among professionals such as police officers and medical professionals, it has been discussed less among juvenile and family court judges who also experience secondary traumatic stress. In fact, in one recent study, a majority of judges reported one or more symptoms of secondary traumatization. This article describes the common signs and symptoms of secondary trauma, job‐related factors that contribute to secondary trauma among judges, and the potential negative impact on organizational performance. The authors conclude with specific recommendations tailored for juvenile and family court judges.
Antileishmanial Activity of 1,3,4-Thiadiazolium-2-Aminide in Mice Infected withLeishmania amazonensis
Authors: Rodrigues Raquel F. , Charret Karen S. , da Silva Edson F. , Echevarria Áurea , Amaral Verônica F. , Leon Leonor L. , Canto-Cavalheiro Marilene M. 
Published: November 2008

ABSTRACTThe efficacy of two mesoionic derivatives (MI-H-H and MI-4-OCH3) was evaluated in CBA/J mice infected withLeishmania amazonensis. Treatment with these compounds demonstrated that the MI-4-OCH3derivative and the reference drug meglumine antimoniate (Glucantime) presented significant activity relative to an untreated control. No apparent hepatic or renal toxicity due to these mesoionic compounds was found.
Inhibition of Methionyl-tRNA Synthetase by REP8839 and Effects of Resistance Mutations on Enzyme Activity
Authors: Green Louis S. , Bullard James M. , Ribble Wendy , Dean Frank , Ayers David F. , Ochsner Urs A. , Janjic Nebojsa , Jarvis Thale C. 
Published: November 2008

ABSTRACT

REP8839 is a selective inhibitor of methionyl-tRNA synthetase (MetRS) with antibacterial activity against a variety of gram-positive organisms. We determined REP8839 potency against
Staphylococcus aureus
MetRS and assessed its selectivity for bacterial versus human orthologs of MetRS. The inhibition constant (

K
i

) of REP8839 was 10 pM for
Staphylococcus aureus
MetRS. Inhibition of MetRS by REP8839 was competitive with methionine and uncompetitive with ATP. Thus, high physiological ATP levels would actually facilitate optimal binding of the inhibitor. While many gram-positive bacteria, such as
Staphylococcus aureus
, express exclusively the MetRS1 subtype, many gram-negative bacteria express an alternative homolog called MetRS2. Some gram-positive bacteria, such as
Streptococcus pneumoniae
and
Bacillus anthracis
, express both MetRS1 and MetRS2. MetRS2 orthologs were considerably less susceptible to REP8839 inhibition. REP8839 inhibition of human mitochondrial MetRS was 1,000-fold weaker than inhibition of
Staphylococcus aureus
MetRS; inhibition of human cytoplasmic MetRS was not detectable, corresponding to >1,000,000-fold selectivity for the bacterial target relative to its cytoplasmic counterpart. Mutations in MetRS that confer reduced susceptibility to REP8839 were examined. The mutant MetRS enzymes generally exhibited substantially impaired catalytic activity, particularly in aminoacylation turnover rates. REP8839

K
i

values ranged from 4- to 190,000-fold higher for the mutant enzymes than for wild-type MetRS. These observations provide a potential mechanistic explanation for the reduced growth fitness observed with MetRS mutant strains relative to that with wild-type
Staphylococcus aureus
.
Interaction Studies of Tipranavir-Ritonavir with Clarithromycin, Fluconazole, and Rifabutin in Healthy Volunteers
Authors: la Porte Charles J. L. , Sabo John P. , Elgadi Mabrouk , Cameron D. William 
Published: November 2008

ABSTRACT

Three separate controlled, two-period studies with healthy volunteers assessed the pharmacokinetic interactions between tipranavir-ritonavir (TPV/r) in a 500/200-mg dose and 500 mg of clarithromycin (CLR), 100 mg of fluconazole (FCZ), or 150 mg of rifabutin (RFB). The CLR study was conducted with 24 subjects. The geometric mean ratios (GMR) and 90% confidence intervals (90% CI; given in parentheses) of the areas under the concentration-time curve (AUC), the maximum concentrations of the drugs in serum (
C
max
), and the concentrations in serum at 12 h postdose (Cp12h) for multiple-dose TPV/r and multiple-dose CLR, indicating the effect of TPV/r on the CLR parameters, were 1.19 (1.04-1.37), 0.95 (0.83-1.09), and 1.68 (1.42-1.98), respectively. The formation of the metabolite 14-OH-CLR was decreased by 95% in the presence of TPV, and the TPV AUC increased 66% compared to that for human immunodeficiency virus (HIV)-negative historical controls. The FCZ study was conducted with 20 subjects. The GMR (and 90% CI) of the AUC,
C
max
, and Cp24h, indicating the effect of multiple-dose TPV/r on the multiple-dose FCZ parameters, were 0.92 (0.88-0.95), 0.94 (0.91-0.98), and 0.89 (0.85-0.92), respectively. The TPV AUC increased by 50% compared to that for HIV-negative historical controls. The RFB study was conducted with 24 subjects. The GMR (and 90% CI) of the AUC,
C
max
, and Cp12h for multiple-dose TPV/r and single-dose RFB, indicating the effect of TPV/r on the RFB parameters, were 2.90 (2.59-3.26), 1.70 (1.49-1.94), and 2.14 (1.90-2.41), respectively. The GMR (and 90% CI) of the AUC,
C
max
, and Cp12h of TPV/r and RFB with 25-
O
-desacetyl-RFB were 4.33 (3.86-4.86), 1.86 (1.63-2.12), and 2.76 (2.44-3.12), respectively. Coadministration of TPV with a single dose of RFB resulted in a 16% increase in the TPV Cp12h compared to that for TPV alone. In the general population, no dose adjustments are necessary for the combination of TPV/r and CLR or FCZ. Combining TPV/r with RFB should be done with caution, while toxicity and RFB drug levels should be monitored. Study medications were generally well-tolerated in these studies.
Compounds Structurally Related to Ellagic Acid Show Improved Antiplasmodial Activity
Authors: Sturm Nicole , Hu Ying , Zimmermann Herbert , Fritz-Wolf Karin , Wittlin Sergio , Rahlfs Stefan , Becker Katja 
Published: November 2008

ABSTRACT

The cancer chemopreventive agent ellagic acid (EA) is a known inhibitor of glutathione
S
-transferases (GSTs) and possesses antiplasmodial activities in the upper-nanomolar range. In the recent drug development approach, the properties of the active site of
Plasmodium falciparum
GST were exploited for inhibitor design by introducing one or two additional hydroxyl groups into EA, yielding flavellagic acid (FEA) and coruleoellagic acid (CEA), respectively. Indeed, the inhibition of
P. falciparum
GST was improved with the increasing hydrophilicity of the planar polyaromatic ring system. Studying the effects of the two compounds on the central redox enzymes of
Plasmodium
revealed that glutathione reductase and thioredoxin reductase also are inhibited in the lower-micromolar range. Both compounds had strong antiplasmodial activity in the lower-nanomolar range and were particularly effective against chloroquine (CQ)-resistant
P. falciparum
strains. Neither FEA nor CEA showed cytotoxic effects on human cells. This was supported by negligible changes in transcript levels and enzyme activities of redox enzymes in human A549 cells upon treatment with the compounds. In
Plasmodium
, however, CEA treatment resulted in a marked downregulation of most antioxidant genes studied and impaired mainly the trophozoite stage of the parasites. In addition, EA, CEA, and FEA were found to strongly inhibit in vitro heme aggregation. In vitro and preliminary in vivo studies indicated that, compared to CQ, CEA is a slowly acting compound and is able to significantly improve the survival of
Plasmodium berghei
-infected mice. We conclude that FEA and CEA are promising antimalarial compounds that deserve to be studied further.
Statistical Model To Evaluate In Vivo Activities of Antimalarial Drugs in a
Plasmodium cynomolgi
-Macaque Model for
Plasmodium vivax
Malaria
Authors: Kocken Clemens H. M. , Remarque Edmond J. , Dubbeld Martin A. , Wein Sharon , van der Wel Annemarie , Verburgh R. Joyce , Vial Henri J. , Thomas Alan W. 
Published: November 2008

ABSTRACT

Preclinical animal models informing antimalarial drug development are scarce. We have used asexual erythrocytic
Plasmodium cynomolgi
infections of rhesus macaques to model
Plasmodium vivax
during preclinical development of compounds targeting parasite phospholipid synthesis. Using this malaria model, we accumulated data confirming highly reproducible infection patterns, with self-curing parasite peaks reproducibly preceding recrudescence peaks. We applied nonlinear mixed-effect (NLME) models, estimating treatment effects in three drug studies: G25 (injected) and the bisthiazolium prodrugs TE4gt and TE3 (oral). All compounds fully cured
P. cynomolgi
-infected macaques, with significant effects on parasitemia height and time of peak. Although all three TE3 doses tested were fully curative, NLME models discriminated dose-dependent differential pharmacological antimalarial activity. By applying NLME modeling treatment effects are readily quantified. Such drug development studies are more informative and contribute to reduction and refinement in animal experimentation.
A Small-Molecule Screen Identifies the Antipsychotic Drug Pimozide as an Inhibitor ofListeria monocytogenesInfection
Authors: Lieberman Linda A. , Higgins Darren E. 
Published: November 2008

ABSTRACTWe developed a screening procedure to identify small-molecule compounds that altered infection byListeria monocytogenesto gain insights into bacterial/host cellular processes required for intracellular pathogenesis. A small-molecule library of 480 compounds with known biological functions was screened, and 21 compounds that altered theL. monocytogenesinfection of murine bone marrow-derived macrophages (BMM) were identified. The identified compounds affected various cellular functions, such as actin polymerization, kinase/phosphatase activity, calcium signaling, and apoptosis. Pimozide, an FDA-approved drug used to treat severe Tourette's syndrome and schizophrenia, was further examined and shown to decrease the bacterial uptake and vacuole escape ofL. monocytogenesin BMM. The inhibitory effect of pimozide on internalization was not specific forL. monocytogenes, as the phagocytosis of other bacterial species (Bacillus subtilis,Salmonella entericaserovar Typhimurium, andEscherichia coliK12) was significantly inhibited in the presence of pimozide. The invasion and cell-to-cell spread ofL. monocytogenesduring the infection of nonprofessional phagocytic cells also was decreased by pimozide treatment. Although pimozide has been reported to be an antagonist of mammalian cell calcium channels, the infection of BMM in a calcium-free medium did not relieve the inhibitory effects of pimozide onL. monocytogenesinfection. Our results provide a generalizable screening approach for identifying small-molecule compounds that affect cellular pathways that are required for intracellular bacterial pathogenesis. We also have identified pimozide, a clinically approved antipsychotic drug, as a compound that may be suitable for further development as a therapeutic for intracellular bacterial infections.
Phenotypic and Enzymatic Comparative Analysis of the Novel KPC Variant KPC-5 and Its Evolutionary Variants, KPC-2 and KPC-4
Authors: Wolter Daniel J. , Kurpiel Philip M. , Woodford Neil , Palepou Marie-France I. , Goering Richard V. , Hanson Nancy D. 
Published: November 2008

ABSTRACT

A novel
Klebsiella pneumoniae
carbapenemase (KPC) variant, designated
bla
KPC-5
, was discovered in a carbapenem-resistant
Pseudomonas aeruginosa
clinical isolate from Puerto Rico. Characterization of the upstream region of
bla
KPC-5
showed significant differences from the flanking regions of other
bla
KPC
variants. Comparison of amino acid sequences with those of other KPC enzymes revealed that KPC-5 was an intermediate between KPC-2 and KPC-4, differing from KPC-2 by a single amino acid substitution (Pro
103
→Arg), while KPC-4 contained Pro
103
→Arg plus an additional amino acid change (Val
239
→Gly). Transformation studies with an
Escherichia coli
recipient strain showed differences in the properties of the KPC variants. KPC-4 and KPC-5 both had pIs of 7.65, in contrast with the pI of 6.7 for KPC-2. KPC-2 transformants were less susceptible to the carbapenems than KPC-4 and KPC-5 transformants. These data correlated with higher rates of imipenem hydrolysis for KPC-2 than for KPC-4 and KPC-5. However, KPC-4 and KPC-5 transformants had higher ceftazidime MICs, and the enzymes from these transformants had slightly better hydrolysis of this drug than KPC-2. KPC-4 and KPC-5 were more sensitive than KPC-2 to inhibition by clavulanic acid in both susceptibility testing and hydrolysis assays. Thus, KPC enzymes may be evolving through stepwise mutations to alter their spectra of activity.
International Interlaboratory Proficiency Testing Program for Measurement of Azole Antifungal Plasma Concentrations
Authors: Brüggemann Roger J. M. , Touw Daan J. , Aarnoutse Rob E. , Verweij Paul E. , Burger David M. 
Published: November 2008

ABSTRACT
An international interlaboratory proficiency testing program for the measurement of antifungal drugs was initiated in 2007. This first round was limited to azole antifungals: fluconazole, itraconazole and hydroxyitraconazole, voriconazole, and posaconazole. The results demonstrate the need for and utility of an ongoing proficiency testing program to further improve the analytical methods for routine patient management and clinical research.