bluuebunny/crossref_metadata_2025_split huggingface dataset:
Menopausal status dependence of the timing of breast cancer recurrence after surgical removal of the primary tumour
Authors: Demicheli Romano , Bonadonna Gianni , Hrushesky William JM , Retsky Michael W , Valagussa Pinuccia 
Published: October 2004

Abstract
Introduction
Information on the metastasis process in breast cancer patients undergoing primary tumour removal may be extracted from an analysis of the timing of clinical recurrence.

Methods
The hazard rate for local-regional and/or distant recurrence as the first event during the first 4 years after surgery was studied in 1173 patients undergoing mastectomy alone as primary treatment for operable breast cancer. Subset analyses were performed according to tumour size, axillary nodal status and menopausal status.

Results
A sharp two-peaked hazard function was observed for node-positive pre-menopausal patients, whereas results from node-positive post-menopausal women always displayed a single broad peak. The first narrow peak among pre-menopausal women showed a very steep rise to a maximum about 8–10 months after mastectomy. The second peak was considerably broader, reaching its maximum at 28–30 months. Post-menopausal patients displayed a wide, nearly symmetrical peak with maximum risk at about 18–20 months. Peaks displayed increasing height with increasing axillary lymph node involvement. No multi-peaked pattern was evident for either pre-menopausal or post-menopausal node-negative patients; however, this finding should be considered cautiously because of the limited number of events. Tumour size influenced recurrence risk but not its timing. Findings resulting from the different subsets of patients were remarkably coherent and each observed peak maintained the same position on the time axis in all analysed subsets.

Conclusions
The risk of early recurrence for node positive patients is dependent on menopausal status. The amount of axillary nodal involvement and the tumour size modulate the risk value at any given time. For pre-menopausal node-positive patients, the abrupt increase of the first narrow peak of the recurrence risk suggests a triggering event that synchronises early risk. We suggest that this event is the surgical removal of the primary tumour. The later, broader, more symmetrical risk peaks indicate that some features of the corresponding metastatic development may present stochastic traits. A metastasis development model incorporating tumour dormancy in specific micro-metastatic phases, stochastic transitions between them and sudden acceleration of the metastatic process by surgery can explain these risk dynamics.
Evidence that an Isoform of Calpain-10 Is a Regulator of Exocytosis in Pancreatic β-Cells
Authors: Marshall Catriona , Hitman Graham A. , Partridge Christopher J. , Clark Anne , Ma Hong , Shearer Thomas R. , Turner Mark D. 
Published: October 2004

AbstractCalpain-10 (CAPN10) is the first type 2 diabetes susceptibility gene to be identified through a genome scan, with polymorphisms being associated with altered CAPN10 expression. Functional data have been hitherto elusive, but we report here a corresponding increase between CAPN10 expression level and regulated insulin secretion. Pancreatic β-cell secretory granule exocytosis is mediated by the soluble N-ethylmaleimide-sensitive fusion protein attachment receptor protein complex of synaptosomal-associated protein of 25 kDa (SNAP-25), syntaxin 1, and vesicle-associated membrane protein 2. We report, for the first time, direct binding of a calpain-10 isoform with members of this complex. Furthermore, SNAP-25 undergoes a Ca2+-dependent partial proteolysis during exocytosis, with calpain protease inhibitor similarly suppressing both insulin secretion and SNAP-25 proteolysis. Based upon these findings, we postulate that an isoform of calpain-10 is a Ca2+-sensor that functions to trigger exocytosis in pancreatic β-cells.
LBP Proteins Modulate SF1-Independent Expression of P450scc in Human Placental JEG-3 Cells
Authors: Huang Ningwu , Miller Walter L. 
Published: October 2004

AbstractThe cholesterol side-chain cleavage enzyme, P450scc, initiates biosynthesis of all steroid hormones. Adrenal and gonadal P450scc expression requires steroidogenic factor-1 (SF1), but P450scc expression in human placental JEG-3 cells utilizes an SF1-independent element at −155/−131 that is inactive in adrenals and gonads. We previously cloned two transcription factors, long terminal repeat binding protein (LBP)-1b and LBP-9, from JEG-3 cells. In transient transfection assays, LBP-1b activated the −155/−131 element whereas LBP-9 suppressed its LBP-1b-stimulated expression. To assess the roles of these factors on the intact P450scc gene, we stably expressed LBP-1b or LBP-9 in JEG-3 cells. All cell lines stably expressing a fusion protein of LBP-1b and enhanced green fluorescent protein increased P450scc expression, but cell lines stably expressing LBP-9 fused to enhanced green fluorescent protein either increased or decreased P450scc expression. 8-Br-cAMP induced endogenous LBP-9, but not LBP-1b expression. Glutathione-S-transferase pull-down assays showed that LBP-1b and LBP-9 can dimerize with themselves and with each other; LBP-1b residues 300–540 and LBP-9 residues 300–479 were required for dimer formation. Glutathione-S-transferase pull-down assays, bandshifts, and transient transfection assays showed that TReP-132 (another factor that can bind to −155/−131) does not interact with either LBP-1b or LBP-9, or influence their ability to induce or suppress transcription from the −155/−131 element. Gal4 transactivation assays showed that transcriptional repression activity by LBP-9 requires residues 100–200. RNAi interference of either LBP-1b or LBP-9 mRNAs decreased P450scc expression. LBP-1b is an important SF1-independent transcriptional activator stimulating P450scc expression in human placental JEG-3 cells, whereas LBP-9 modulates the action of LBP-1b, exerting both positive and negative effects.
The HeLa Cell Glucagon-Like Peptide-2 Receptor Is Coupled to Regulation of Apoptosis and ERK1/2 Activation through Divergent Signaling Pathways
Authors: Koehler J. A. , Yusta B. , Drucker D. J. 
Published: October 2004

AbstractGlucagon-like peptide-2 (GLP-2) regulates proliferative and cytoprotective pathways in the intestine; however GLP-2 receptor (GLP-2R) signal transduction remains poorly understood, and cell lines that express the endogenous GLP-2R have not yet been isolated. We have now identified several expressed sequence tags from human cervical carcinoma cDNA libraries that correspond to GLP-2R nucleotide sequences. GLP-2R mRNA transcripts were detected by RT-PCR in two human cervical carcinoma cell lines, including HeLa cells. GLP-2 increased cAMP accumulation and activated ERK1/2 in HeLa cells transiently expressing the cloned human HeLa cell GLP-2R cDNA. However, the GLP-2R-induced activation of ERK1/2 was not mediated through Gαs, adenylyl cyclase, or transactivation of the epidermal growth factor receptor, but was pertussis toxin sensitive, inhibited by dominant negative Ras, and dependent on βγ-subunits. GLP-2 also induced a significant increase in bromodeoxyuridine incorporation that was blocked by dominant negative Ras. Furthermore, GLP-2 inhibited HeLa cell apoptosis induced by LY294002 in a protein kinase A-dependent, but ERK-independent, manner. These findings demonstrate that the HeLa cell GLP-2R differentially signals through both Gαs/cAMP- and Gi/Go-dependent pathways, illustrating for the first time that the GLP-2R is capable of coupling to multiple heterotrimeric G proteins defining distinct GLP-2R-dependent biological actions.
Assessment of Urinary Bone Markers for Monitoring Treatment of Osteoporosis
Authors: Worsfold Michael , Powell Diane E , Jones Teresa J W , Davie Michael W J 
Published: October 2004

AbstractBackground: The usefulness of urinary markers of bone turnover in monitoring therapy depends on their within-person variability compared with their responses to therapy. The aim of this study was to assess the performance of two such markers on this basis.Methods: We measured variation, during a whole year, of cross-linked N-terminal telopeptide of collagen I (NTx) and urinary deoxypyridinoline (DPD) as ratios to creatinine concentration and after log-transformation of the ratios in untreated women stratified into three bone density classes, of which the lowest was osteoporotic. We also measured changes in bone mineral density at the lumbar spine (LSBMD) and hip (FNBMD) in untreated women with normal bones and in those with moderate osteopenia and calculated the reference change value (RCV; or least significant change) at P &lt;0.05 for all of these measures. We made the same measurements on women treated with bisphosphonates, estrogen replacement (HRT), or calcium and examined their individual responses to treatment compared with RCV.Results: After 12 months on bisphosphonates, LSBMD changed more than RCV (2.55%) in 47% of women compared with 44% of those on HRT and 13% of those on calcium. Response of FNBMD was less. Log NTx (RCV= −28%) responded to bisphosphonates in 78%, regardless of BMD, but less often to HRT (67%). Log DPD (RCV= −30%) responded to bisphosphonates less frequently (31% at 12 months).Conclusions: NTx has advantages over DPD in monitoring therapy for osteoporosis when mailed urine samples are used.
Simultaneous and Sensitive Measurement of Anabasine, Nicotine, and Nicotine Metabolites in Human Urine by Liquid Chromatography–Tandem Mass Spectrometry
Authors: Xu Xu , Iba Michael M , Weisel Clifford P 
Published: October 2004

Abstract
Background: Determination of nicotine metabolism/pharmacokinetics provides a useful tool for estimating uptake of nicotine and tobacco-related toxicants, for understanding the pharmacologic effects of nicotine and nicotine addiction, and for optimizing nicotine dependency treatment.
Methods: We developed a sensitive method for analysis of nicotine and five major nicotine metabolites, including cotinine, trans-3′-hydroxycotinine, nicotine-N′-oxide, cotinine-N-oxide, and nornicotine, in human urine by liquid chromatography coupled with a TSQ Quantum triple quadrupole tandem mass spectrometer (LC/MS/MS). Urine samples to which deuterium-labeled internal standards had been added were extracted with a simple solid-phase extraction procedure. Anabasine, a minor tobacco alkaloid, was also included.
Results: The quantification limits of the method were 0.1–0.2 μg/L, except for nicotine (1 μg/L). Cotinine-N-oxide, trans-3′-hydroxycotinine, nicotine, and anabasine in urine were almost completely recovered by the solid-phase extraction, whereas the mean extraction recoveries of nicotine-N′-oxide, cotinine, and nornicotine were 51.4%, 78.6%, and 78.8%, respectively. This procedure provided a linearity of three to four orders of magnitude for the target analytes: 0.2–400 μg/L for nicotine-N′-oxide, cotinine-N-oxide, and anabasine; 0.2–4000 μg/L for cotinine, nornicotine, and trans-3′-hydroxycotinine; and 1.0–4000 μg/L for nicotine. The overall interday method imprecision and recovery were 2.5–18% and 92–109%, respectively.
Conclusions: This sensitive LC/MS/MS procedure can be used to determine nicotine metabolism profiles of smokers, people during nicotine replacement therapy, and passively exposed nonsmokers. This method avoids the need for a time-consuming and labor-intensive sample enrichment step and thus allows for high-throughput sample preparation and automation.
Folate Deficiencies and Cardiovascular Pathologies
Authors: Durand Philippe , Prost Michel , Blache Denis 
Published: October 2004

Abstract
Although folates are widely distributed in foods, folate deficiencies may be more frequent than expected because their true availability may be impaired due to their lability under various food cooking and processing conditions. Folate deficiency is frequently observed in elderly people, smokers, alcoholics and oral contraceptive users. It is also associated with the mutation leading to the thermolabile variant of N5, 10-methylenetetrahydrofolate reductase which is observed in about 10 % of the population. In addition to the essential role of the intracellular pool of polyglutamates in de novo biosynthesis of deoxyribonucleotides which allow cell growth and division, the reduced and methylated form of folate, N5-methyltetrahydrofolate, is required for the remethylation of homocysteine to methionine. By inhibiting this remethylation pathway, folate deficiency induces homocysteine efflux into the circulation. Many studies have shown a negative correlation between plasma folate, particularly N5-methyltetrahydrofolate, and circulating homocysteine levels. In addition, folate deficiency is a major cause of hyperhomocysteinemia which is fully recognised as an independent risk factor for atherothrombosis. Epidemiological and recent experimental studies have demonstrated that folate deficiency might increase the risk of cardiovascular disease by increasing circulating homocysteine levels. Thus, the clinical efficiency of folate supplementation, especially N5-methyltetrahydrofolate, in reducing homocysteine-dependent cardiovascular risk should be evaluated.
Molecular Diagnosis of Lecithin: Cholesterol Acyltransferase Deficiency in a Presymptomatic Proband
Authors: Cirera Susanna , Julve Josep , Ferrer Immaculada , Mainou Carles , Bonet Rosa , Martín-Campos Jesús M. , González-Sastre Francesc , Blanco-Vaca Francisco 
Published: October 2004

Abstract
We report the molecular diagnosis of a lecithin : cholesterol acyltransferase deficiency in a 12-year old proband with a high-density lipoprotein deficiency. The increased percentage of free cholesterol in plasma and high-density lipoprotein indicated an inherited lecithin : cholesterol acyltransferase deficiency as the underlying cause. This diagnosis was confirmed by a low plasma lecithin : cholesterol acyltransferase activity and a combination of genetic analyses which demonstrated compound heterozygosity for two mutations in the lecithin : cholesterol acyltransferase gene of the proband. One was a previously unreported 2 bp deletion leading to a stop signal in codon 77 and the other a point mutation causing Arg 135 → Gln transition. To our knowledge, this is the first diagnosis of lecithin : cholesterol acyltransferase deficiency in a pre-symptomatic patient. Whether the proband will develop signs of complete lecithin : cholesterol acyltransferase deficiency or the milder form (Fish Eye Disease) is uncertain, although the former possibility is more likely. The risk of premature atherosclerosis conferred by lecithin : cholesterol acyltransferase deficiency is not well established. The proband will need to be carefully monitored in the future.
Cathepsin D and Cathepsin L Activities in Aortic Aneurysm Wall and Parietal Thrombus
Authors: Gacko Marek , Glowiński Stanislav 
Published: October 2004

Abstract
Deterioration of the aortic wall resulting in formation of aneurysms may be caused by increased activity of metalloproteases and lysosomal proteases. The aim of this work was the evaluation of cathepsin D and cathepsin L activities, and activities of inhibitors of cysteine cathepsins in the wall of aortic aneurysms and in parietal thrombus. Aortic aneurysms were obtained during operation. Aortas taken from organ donors and blood clots were used as control material. Activities of cathepsin D and cathepsin L in the aortic aneurysm wall and parietal thrombus were higher than in the control groups. The aneurysm wall showed lower activity of inhibitors of cysteine proteases than the normal aorta. Parietal thrombus had a higher level of cysteine protease inhibitor activity than blood clot. Cathepsin D and cathepsin L present in the aneuerysm wall and in the parietal thrombus filling the aneurysm may act on proteins determining elasticity and mechanical resistance of arteries.
The Diagnostic Value of Serum Homocysteine Concentration as a Risk Factor for Coronary Artery Disease
Authors: Dierkes Jutta , Bissé Emmanuel , Nauck Matthias , Orth Matthias , Mayer Horst , Luley Claus , Wieland Heinrich 
Published: October 2004

Abstract
Hyperhomocysteinemia is now regarded as an established risk factor for coronary artery disease and is present frequently in the general population. However, the diagnostic value of this risk factor relative to others has only occasionally been investigated. We compared the diagnostic value of classic risk factors and of homocysteine in a retrospective case-control study in 191 cases with angiographically established coronary artery disease and 231 healthy controls. Life style habits were assessed by a detailed questionnaire. Laboratory parameters including lipoproteins and blood lipids, homocysteine, folate, and vitamin B12 were measured and their diagnostic value compared with each other by use of receiver-operator characteristic analysis. Comparison of the receiver-operator characteristic curves revealed that homocysteine significantly discriminated between cases and control subjects. High-density-lipoprotein cholesterol, triglycerides and non-esterified fatty acids also had an area under the curve significantly different from 0.5 (the area under the curve representing no discrimination). Homocysteine was weakly related to folate, vitamin B12, age and serum creatinine concentration. We conclude that hyperhomocysteinemia is at least as important as conventional risk factors for coronary artery disease and that receiver operator characteristic analysis of homocysteine is suitable to determine patients at the highest risk for coronary artery disease. Clinical trials testing the effect of homocysteine lowering by vitamin supplementation in the prevention of coronary artery disease are needed.
The Uncertainty Associated with the Predictive Value of Test Results
Authors: Malvano Renzo , Chiecchio Andrea , Borsa Margherita , Messeri Gianni 
Published: October 2004

Abstract
The uncertainty associated with predictive value of test results was taken into consideration, as concerns both sampling error (related to the size of the statistical reference samples) and analytical imprecision (unavoidably involved by the measurement itself). A software package, developed for the statistical calculations, was used for the treatment of the results obtained for serum free thyroxin in euthyroid and dysthyroid subjects, assumed as an experimental model. Examples are shown for the obtainable functions predictive value vs. estimate and the related uncertainy regions. These data could help in comparing test results and, in particular, in preparing fully informative laboratory reports. The difficulties involved by an extensive application of the procedure are discussed.
Clinical Evaluation of the CARDIAC STATus™, a Rapid Immunochromatographic Assay for Simultaneous Detection of Elevated Concentrations of CK-MB and Myoglobin in Whole Blood
Authors: Schouten Yvonne , de Winter Robbert J. , Gorgels Jozef P. M. C. , Koster Rudolph W. , Adams Rob , Sanders Gerard T. 
Published: October 2004

Abstract
We studied the performance of the CARDIAC STATusTM, a new rapid, easy to perform qualitative whole blood bedside test for detection of elevated CK-MB and myoglobin in the emergency room. Blood samples from 182 consecutive patients with chest pain were drawn on admission and at five and seven hours after the onset of symptoms. The CARDIAC STATusTM tests were performed by coronary care unit nurses and, independently, by a trained laboratory technician. The results were compared with quantitative assays for CK-MB mass and myoglobin. At the end of the study, a second test series using a new lot number of cartridges was performed on the same blood samples because of possible elution buffer contamination. Nurses produced more false negative results than the technician (CK-MB 43 vs. 27 %, p=0.01, myoglobin 31 vs. 13 %, p<0.0001), but the technician produced more false positive myoglobin results (9.3 vs. 5.5 %, p=0.0001). In the second test series, the nurses produced significantly fewer false negative tests both for CK-MB (19 %, p<0.0001) and myoglobin (13 %, p=0.0002). The false negative rate for the technician was not different between the first and the second test series. The CARDIAC STATusTM yields a substantial number of false negative results both for CK-MB and myoglobin when compared to a quantitative assay, and therefore at present has limited value for ruling out an acute myocardial infarction.
Multicentre Evaluation of KONE Optima Analysis System
Authors: Ferrero Carlo , Modenese Annalisa , Bonini Pier Angelo , Ceriotti Ferruccio , Carobene Anna , Franzin Michela , Guder Walter G. , Hofmann Walter , Puukka Matti , Laitinen Harri , Makarovsky Vladimir , Gaidukova Natalia , Lampinen Hannu 
Published: October 2004

Abstract

Optima from KONE Instruments Corporation is a new selective laboratory analyzer for turbidimetric, colorimetric and ion selective electrode measurements. Overall analytical performance of Optima and reagents provided by KONE was evaluated according to ECCLS guidelines, in a multicentre study involving four different laboratories, including substrates (cholesterol, high-density lipoprotein-cholesterol, creatinine), specific proteins (transferrin, IgG), enzyme activities (γ-glutamyltransferase, alanine aminotransferase) and electrolytes (sodium, potassium, chloride).
The results obtained attest good precision of the system for all the analytes tested: the range of withinrun CV is 0.5%–4.3%, and range of between-day CV% is 0.8%–7.9% (median of four laboratories). Except for total cholesterol (5 % overestimation compared to the reference method) accuracy of measurement is adequate. Creatinine and uric acid assays were subjects of interference (defined as deviation > 10% from target value) by bilirubin and haemoglobin respectively.
Qualitative Immunoglobulin Abnormalities in HIV-Positive Patients: Long-Term Follow-Up
Authors: Pontet Françoise , Gué Xavier , Mazeron Marie-Christine , Alain Sophie , Sanson-Le Pors Marie-José 
Published: October 2004

Abstract
We studied the immunoglobulins of a cohort of 212 HIV-positive patients followed-up for 13 years. The qualitative study of immunoglobulins by immunoelectrophoresis and immunofixation distinguished three groups of patients: those with monoclonal immunoglobulins, those with minor abnormalities of immunoglobulins and those with polyclonal immunoglobulins. We characterized these groups according to age, sex, immunoglobulin isotypes, and survival curves. The results show that this population of immunoglobulinopathies has distinctive characteristics. In particular, the presence of immunoglobulin abnormalities has no significant prognostic value.
The Human Genome Project: From Mapping to Sequencing
Authors: Weissenbach Jean 
Published: October 2004

Abstract
Until recently, the “human genome” programs were mainly directed towards the development of maps to identify disease genes. The genetic map comprises about 8000 highly informative second generation markers of the microsatellite type. The density of markers is now sufficient to localize a gene for a monogenic disease with a precision of 1 to 2 million base pairs easily, and to define intervals which contain susceptibility genes for multifactorial disorders. A third generation map based on single nucleotide polymorphisms that can be genotyped using DNA chip technology is in progress. The physical map, based on sets of overlapping yeast artificial chromosomes ordered using sequence-tagged sites, covers over 90 % of the genome. However, this physical map cannot serve as a support for sequencing because of the numerous rearrangements that occur in yeast artificial chromosomes. An international network of laboratories has mapped a set of more than 30000 expressed sequences from cDNAs using whole genome radiation hybrids that enable integration of genes within existing maps. The human genome program is now progressively shifting to massive sequencing, although sequence ready maps are not available for the major part of the human genome. Similarly, our capacity to interpret the available genomic sequence remains limited.