Multidrug resistance proteins in rheumatoid arthritis, role in disease-modifying antirheumatic drug efficacy and inflammatory processes: an overview.

Drug resistance is generally accepted as an important cause of treatment failure for patients with neoplastic or infectious diseases. Molecular mechanisms underlying drug resistance include the action of drug efflux pumps belonging to the super-family of ATP binding cassette (ABC) proteins, which mediate the cellular extrusion of a large variety of therapeutic drugs, a phenotype that is referred to as multidrug resistance (MDR). Unlike neoplastic and infectious diseases, chronic inflammatory diseases have received little attention.

Folate deprivation results in the loss of breast cancer resistance protein (BCRP/ABCG2) expression. A role for BCRP in cellular folate homeostasis.

Breast cancer resistance protein (BCRP/ABCG2) is currently the only ABC transporter that exports mono- and polyglutamates of folates and methotrexate (MTX). Here we explored the relationship between cellular folate status and BCRP expression. Toward this end, MCF-7 breast cancer cells, with low BCRP and moderate multidrug resistance protein 1 (MRP1/ABCC1) levels, and their mitoxantrone (MR)-resistant MCF-7/MR subline, with BCRP overexpression and low MRP1 levels, were gradually deprived of folic acid from 2.

Folate concentration dependent transport activity of the Multidrug Resistance Protein 1 (ABCC1).

The Multidrug Resistance Protein MRP1 (ABCC1) can confer resistance to a variety of therapeutic drugs. In addition, MRP1/ABCC1 mediates cellular export of natural folates, such as folic acid and l-leucovorin. In this study we determined whether cellular folate status affected the functional activity of MRP1/ABCC1 mediated efflux of an established substrate, the anthracycline daunorubicin (DNR).

Progressive idiopathic axonal neuropathy--a comparative clinical and histopathological study with vasculitic neuropathy.

Patients with a progressive disabling idiopathic axonal neuropathy could have a potentially treatable immune mediated neuropathy. To evaluate whether progressive idiopathic axonal neuropathy could be a pathologically difficult to prove vasculitic neuropathy pathologically difficult to prove or if it could be a separate clinical entity (i. e.

Functional characteristics of photochemically treated platelets.

Background: A photochemical treatment (PCT) process using the psoralen compound amotosalen HCL (S59) and long wavelength UVA light was developed for inactivation of infectious pathogens and WBCs. In this study the effect of PCT on functional characteristics of the platelets was evaluated in vitro.

Study Design And Methods: Platelet concentrates were treated photochemically using the experimental clinical processing system T-bag S59 Reduction Device (SRD) (n = 4) or the commercially available integral processing system Wafer SRD (n = 4) and compared with control platelet concentrates in plasma/PAS III alone (n = 4).

Specific interaction of ERp57 and calnexin determined by NMR spectroscopy and an ER two-hybrid system.

Calnexin and ERp57 act cooperatively to ensure a proper folding of proteins in the endoplasmic reticulum (ER). Calnexin contains two domains: a lectin domain and an extended arm termed the P-domain. ERp57 is a protein disulfide isomerase composed of four thioredoxin-like repeats and a short basic C-terminal tail.

Molecular basis of Refsum disease: sequence variations in phytanoyl-CoA hydroxylase (PHYH) and the PTS2 receptor (PEX7).

Refsum disease has long been known to be an inherited disorder of lipid metabolism characterized by the accumulation of phytanic acid (3,7,11,15-tetramethylhexadecanoic acid) caused by an alpha-oxidation deficiency of this branched chain fatty acid in peroxisomes. The mechanism of phytanic acid alpha-oxidation and the enzymes involved had long remained mysterious, but they have been resolved in recent years. This has led to the resolution of the molecular basis of Refsum disease.

Reduced folate carrier mutations are not the mechanism underlying methotrexate resistance in childhood acute lymphoblastic leukemia.

Background: Although the majority of children with acute lymphoblastic leukemia (ALL) are cured with combination chemotherapy containing methotrexate (MTX), drug resistance contributes to treatment failure for a substantial fraction of patients. The primary transporter for folates and MTX is the reduced folate carrier (RFC). Impaired drug transport is a documented mechanism of MTX resistance in patients with ALL; however, to the authors' knowledge it is not known whether inactivating RFC mutations are a contributing factor.

Quantitative trait loci mapping for dairy cattle production traits using a maximum likelihood method.

A maximum likelihood method was developed for QTL mapping in half-sib designs and compared to the regression method in analyses of both field and simulated data. The field data consisted of milk production evaluations of 433 progeny tested sons of 6 sires and 64 microsatellite markers distributed over 12 chromosomes. Based on permutation tests, 5 significant QTL were detected in the field data by the regression method compared with 10 by the maximum likelihood method (P < 0.

Effectiveness of a physiotherapeutic exercise programme for chronic heart failure patients.

Background: This pilot study was conducted to evaluate the design and effects of a physiotherapeutic exercise programme on exercise capacity, muscle strength and quality of life in patients with chronic heart failure.

Methods: Eighteen patients with chronic heart failure were randomly assigned to either a training group (n=9) participating in a physiotherapeutic exercise programme or a regular care control group (n=9). At baseline and after three months patients underwent a maximal bicycle test, a six-minute walk test, a respiratory test, three muscle strength tests and a number of questionnaires pertaining to quality of life.

Development of sulfasalazine resistance in human T cells induces expression of the multidrug resistance transporter ABCG2 (BCRP) and augmented production of TNFalpha.

Objective: To determine whether overexpression of cell membrane associated drug efflux pumps belonging to the family of ATP binding cassette (ABC) proteins contributes to a diminished efficacy of sulfasalazine (SSZ) after prolonged cellular exposure to this disease modifying antirheumatic drug (DMARD).

Methods: A model system of human T cells (CEM) was used to expose cells in vitro to increasing concentrations of SSZ for a period of six months. Cells were then characterised for the expression of drug efflux pumps: P-glycoprotein (Pgp, ABCB1), multidrug resistance protein 1 (MRP1, ABCC1), and breast cancer resistance protein (BCRP, ABCG2).

Acquired resistance of human T cells to sulfasalazine: stability of the resistant phenotype and sensitivity to non-related DMARDs.

Background: A recent study from our laboratory showed that induction of the multidrug resistance related drug efflux pump ABCG2 contributed to acquired resistance of human T cells to the disease modifying antirheumatic drug (DMARD) sulfasalazine (SSZ).

Objectives: To investigate the duration of SSZ resistance and ABCG2 expression after withdrawal of SSZ and rechallenging with SSZ, and to assess the impact of SSZ resistance on responsiveness to other DMARDs.

Methods: Human CEM cells (T cell origin) with acquired resistance to SSZ (CEM/SSZ) were characterised for (a) SSZ sensitivity and ABCG2 expression during withdrawal and rechallenge of SSZ, and (b) antiproliferative efficacy of other DMARDs.

Evaluation criteria for aircraft noise.

Based on extensive and detailed reviews the present paper suggests evaluation limits for aircraft noise for the prediction of noise effects and for the protection of residents living in the vicinity of (newly constructed or extended) civil airports. The protection concept provides graded assessment values: Critical Limits indicate noise loads that shall be tolerated only exceptionally during a limited time. Protection Guides are central assessment values for taking actions to reduce noise imission.

The diagnostic difficulties of meningeal and intracerebral plasma cell granulomas--presentation of three cases.

Meningeal and intracerebral plasma cell granulomas are uncommon inflammatory lesions of unknown etiology. In this paper the diagnostic difficulties in two patients with meningeal plasma cell granuloma and one patient with intracerebral plasma cell granuloma are described. The first patient had an intracranial extra-axial lesion, which was first diagnosed as a meningioma.

Phosphorylation of the MAPKKK regulator Ste50p in Saccharomyces cerevisiae: a casein kinase I phosphorylation site is required for proper mating function.

The Ste50 protein of Saccharomyces cerevisiae is a regulator of the Ste11p protein kinase. Ste11p is a member of the MAP3K (or MEKK) family, which is conserved from yeast to mammals. Ste50p is involved in all the signaling pathways that require Ste11p function, yet little is known about the regulation of Ste50p itself.

Bright stable luminescent yeast using bacterial luciferase as a sensor.

Bright luminescent yeast cells with light intensities similar to bacteria containing luciferase (LuxAB) were generated by providing saturating nontoxic levels of the substrates for the bioluminescence reaction (FMNH(2)+O(2) and fatty aldehyde-->light). Z-9-Tetradecenal added to yeast (+luxAB) gave a luminescent signal close to that with decanal with the signal remaining strong for >24h while luminescence of yeast with decanal decayed to less than 0.01% of that with Z-9-tetradecenal after 2min.

Induction of resistance to the multitargeted antifolate Pemetrexed (ALIMTA) in WiDr human colon cancer cells is associated with thymidylate synthase overexpression.

Pemetrexed (ALIMTA, MTA) is a novel thymidylate synthase (TS) inhibitor and has shown activity against colon cancer, mesothelioma and nonsmall-cell lung cancer. We induced resistance to Pemetrexed in the human colon cancer cell line WiDr by using a continuous exposure to stepwise increasing Pemetrexed concentrations (up to 20 microM) as well as a more clinically relevant schedule with intermittent exposure (up to 50 microM) for 4 hr every 7 days, resulting in WiDr variants WiDr-cPEM and WiDr-4PEM, respectively. However, using the same conditions, it was not possible to induce resistance in the WiDr/F cell line, a variant adapted to growth under low folate conditions.

Estimation of genetic parameters for concentrations of milk urea nitrogen.

The objective of this study was to use field data collected by dairy herd improvement programs to estimate genetic parameters for concentrations of milk urea nitrogen (MUN). Edited data were 36,074 test-day records of MUN and yields of milk, fat, and protein obtained from 6102 cows in Holstein herds in Ontario, Canada. Data were divided into three sets, for the first three lactations.

Antifolate resistance associated with loss of MRP1 expression and function in Chinese hamster ovary cells with markedly impaired export of folate and cholate.

Export of folates from a Chinese hamster ovary PyrR100 cell line is markedly impaired, resulting in expansion of cellular folate pools and high-level antifolate resistance. We now report that MRP1 expression is absent in PyrR100 cells along with a marked decrease in MRP5 expression with 3-fold cross-resistance to thiopurines. PyrR100 and wild-type cells had comparable low levels of MRP2 expression; both lacked the breast cancer resistance protein.

Selective delivery of CB300638, a cyclopenta[g]quinazoline-based thymidylate synthase inhibitor into human tumor cell lines overexpressing the alpha-isoform of the folate receptor.

The alpha-isoform of the glycosylphosphatidylinositol cell membrane tethered folate receptor (alpha-FR) is overexpressed in some carcinomas (notably ovarian carcinomas) relative to normal tissues. The nonpolyglutamatable folate-based thymidylate synthase (TS) inhibitor, CB300638 (TS K(i) = 0.24 nM) displayed an IC(50) of 0.

The chemical biology of branched-chain lipid metabolism.

Mammalian metabolism of some lipids including 3-methyl and 2-methyl branched-chain fatty acids occurs within peroxisomes. Such lipids, including phytanic and pristanic acids, are commonly found within the human diet and may be derived from chlorophyll in plant extracts. Due to the presence of a methyl group at its beta-carbon, the well-characterised beta-oxidation pathway cannot degrade phytanic acid.

Expression and cell distribution of group I and group II metabotropic glutamate receptor subtypes in taylor-type focal cortical dysplasia.

Purpose: Focal cortical dysplasia (FCD) is known to be a major cause of intractable epilepsy. The cellular mechanism(s) underlying the epileptogenicity of FCD remain largely unknown. Because recent studies indicate that metabotropic glutamate receptor subtypes (mGluRs) play a role in epileptogenesis, we investigated the expression and cellular distribution pattern of mGluRs in FCD specimens.