bluuebunny/crossref_metadata_2025_split huggingface dataset:
Phase I Trial of the Cyclin-Dependent Kinase Inhibitor and Protein Kinase C Inhibitor 7-Hydroxystaurosporine in Combination With Fluorouracil in Patients With Advanced Solid Tumors
Authors: Kortmansky Jeremy , Shah Manish A. , Kaubisch Andreas , Weyerbacher Amanda , Yi Sandy , Tong William , Sowers Rebecca , Gonen Mithat , O'Reilly Eileen , Kemeny Nancy , Ilson David I. , Saltz Leonard B. , Maki Robert G. , Kelsen David P. , Schwartz Gary K. 
Published: February 2005

Purpose Preclinical studies indicate that the cyclin-dependent kinase and protein kinase C inhibitor 7-hydroxystaurosporine (UCN-01) potentiates the cytotoxic effects of fluorouracil (FU). We designed a phase I clinical trial of FU in combination with UCN-01. Patients and Methods FU was administered as a weekly 24-hour infusion. Doses were escalated in successive cohorts according to a modified Fibonacci design. UCN-01 was administered once every 4 weeks, immediately after disconnection from FU, at a dose of 135 mg/m2 over 72 hours in cycle 1 and 67.5 mg/m2 over 36 hours in subsequent cycles. FU and UCN-01 pharmacokinetics were obtained on all patients, and thymidylate synthetase (TS) activity was measured in peripheral-blood mononuclear cells by reverse-transcriptase polymerase chain reaction. Results We escalated the weekly FU dose to 2,600 mg/m2 in combination with once a month infusions of UCN-01. Dose-limiting toxicity included arrhythmia and syncope. Other toxicities included hyperglycemia, headache, and nausea and vomiting. The mean maximal plasma concentration of UCN-01 was 33.5 μmol/L. There was significant interpatient variability, which correlated with plasma concentrations of alpha-1 acid glycoprotein. FU was rapidly cleared and the dose had no effect on the area under the curve of UCN-01. Changes in TS expression were detectable in peripheral-blood mononuclear cells after administration of UCN-01 but did not correlate with toxicity or activity. We observed no objective response, although seven patients had stable disease, six of whom had received prior fluoropyrimidines. Conclusion The combination of weekly infusions of FU and monthly UCN-01 can be administered safely and warrants further study in phase II trials. The recommended phase II dose of FU in combination with monthly UCN-01 is 2,600 mg/m2.
Genetic Variation at the Locus Encompassing 11-β Hydroxylase and Aldosterone Synthase Accounts for Heritability in Cortisol Precursor (11-Deoxycortisol) Urinary Metabolite Excretion
Authors: Keavney Bernard , Mayosi Bongani , Gaukrodger Nicole , Imrie Helen , Baker Michelle , Fraser Robert , Ingram Mary , Watkins Hugh , Farrall Martin , Davies Eleanor , Connell John 
Published: February 2005

Genetic variation in the gene encoding aldosterone synthase (CYP11B2) has previously been shown to be associated with hypertension and left ventricular hypertrophy. The intermediate phenotype most consistently associated with variation at this locus is that of elevated plasma 11-deoxycortisol (S). However, in normal subjects, aldosterone synthase does not metabolize S, which is converted to cortisol (F) by the enzyme 11β hydroxylase, encoded by the gene CYP11B1, which lies adjacent to CYP11B2 on chromosome 8. It is possible that the quantitative trait locus for the phenotype is within CYP11B1 and that linkage disequilibrium across the extended locus could account for these observations. However, variation across the whole CYP11B1/B2 locus had not been extensively characterized with respect to these phenotypes. We genotyped six polymorphisms in the CYP11B2 gene and three polymorphisms in the CYP11B1 gene in 248 Caucasian nuclear families comprising 1428 individuals. We measured plasma levels of S and F in 460 individuals from 86 families and urinary excretion rates of tetrahydrodeoxycortisol (THS) and tetrahydrodeoxycorticosterone in 573 individuals from 105 families. We examined heritability of the phenotypes and their association with genotypes and haplotypes at this locus.
All steroid phenotypes except urinary tetrahydrodeoxycorticosterone were highly heritable (P &lt; 0.00001). There was strong linkage disequilibrium across the CYP11B1/B2 locus. There was modest evidence for association between polymorphisms of CYP11B2 and plasma levels of S (P = 0.02 for T4986C polymorphism) and the plasma S to F ratio, reflecting the activity of 11-β hydroxylase (P = 0.01 for T4986C polymorphism). There was strong evidence for association between polymorphisms of both CYP11B1 and CYP11B2 and urinary THS, which was strongest for the CYP11B1 exon 1 polymorphism (P = 0.00002). Addition of other marker data to CYP11B1 exon 1 did not improve the fit of a log-linear model. Genotype at CYP11B1 explained approximately 5% of the variance in urinary THS excretion in the population. Thus, it is likely that linkage disequilibrium between causative CYP11B1 variants and CYP11B2 polymorphisms account for the previous observations. Further fine-mapping studies across the CYP11B1 locus are required to localize the causative variant(s) for the biochemical phenotype; this may also identify susceptibility alleles for hypertension and left ventricular hypertrophy.
Aurora B Overexpression Associates with the Thyroid Carcinoma Undifferentiated Phenotype and Is Required for Thyroid Carcinoma Cell Proliferation
Authors: Sorrentino Rosanna , Libertini Silvana , Pallante Pier Lorenzo , Troncone Giancarlo , Palombini Lucio , Bavetsias Vassilios , Spalletti-Cernia Daniela , Laccetti Paolo , Linardopoulos Spiros , Chieffi Paolo , Fusco Alfredo , Portella Giuseppe 
Published: February 2005

Alterations in chromosome number (aneuploidy) are common in human neoplasias. Loss of mitotic regulation is believed to induce aneuploidy in cancer cells and act as a driving force during the malignant progression. The serine/theronine protein kinases of aurora family genes play a critical role in the regulation of key cell cycle processes. Aurora B mediates chromosome segregation by ensuring orientation of sister chromatids and overexpression of Aurora B in diploid human cells NHDF (normal human diploid fibroblast) induces multinuclearity.
We analyzed Aurora B expression in human thyroid carcinomas. Cell lines originating from different histotypes showed an increase in Aurora B expression. Immunohistochemical analysis of archive samples showed a high expression of Aurora B in anaplastic thyroid carcinomas; conversely, Aurora B expression was not detectable in normal thyroid tissue. Real-time PCR analysis confirmed a strong expression of Aurora B in anaplastic thyroid carcinomas.
The block of Aurora B expression induced by RNA interference or by using an inhibitor of Aurora kinase activity significantly reduced the growth of thyroid anaplastic carcinoma cells.
Rigid-body modelling of shaken baby syndrome
Authors: Wolfson D R , McNally D S , Clifford M J , Vloeberghs M 
Published: February 2005

Recent reassessment of the literature on the shaken baby syndrome (SBS) has revealed a lack of scientific evidence and understanding of all aspects of the syndrome. In particular, studies have been unable to clarify the mechanisms of injury, indicating that impact, rather than shaking alone, is necessary to cause the type of brain damage observed. Rigid-body modelling (RBM) was used to investigate the effect of neck stiffness on head motion and head-torso impacts as a possible mechanism of injury. Realistic shaking data obtained from an anthropometric test dummy (ATD) was used to simulate shaking. In each study injury levels for concussion were exceeded, though impact-type characteristics were required to do so in the neck stiffness study. Levels for the type of injury associated with the syndrome were not exceeded. It is unlikely that further gross biomechanical investigation of the syndrome will be able to significantly contribute to the understanding of SBS. Current injury criteria are based on high-energy, single-impact studies. Since this is not the type of loading in SBS it is suggested that their application here is inappropriate and that future studies should focus on injury mechanisms in low-energy cyclic loading.
Impact of the new General Medical Services contract on the clinical laboratory
Authors: Smellie WSA , Roy DV 
Published: February 2005

The new General Medical Services contract that has been adopted in England and Wales, with similar contracts in Scotland and Northern Ireland, proposes far-reaching changes to the way in which general practitioners practise and are remunerated. This includes a range of quality indicators, which pay particular attention to chronic disease management. Among other things, the quality indicators require certain laboratory tests to be performed or result targets to be met in defined proportions of patients in particular disease categories in order to qualify for quality payments. This is a novel experiment, which may focus general practitioner activity on specific areas of patient management. It has significant potential impact on laboratories: testing activity in some areas may be boosted considerably; assay performance, notably bias, will have direct potential impact on practice earnings and any shift in clinical priorities may have future effects on assay development and repertoires as these become partly financially driven by practice income. The evidence base and research of the available guidance behind the indicators is sketchy in places and although there are 76 indicators several areas of practice are not addressed. The probable further increase in laboratory activity it may generate highlights the need for laboratories to continue to assist in promoting best practice in test requesting.
Lymphocyte PC-1 activity in patients on maintenance haemodialysis treated with human erythropoietin and 1-α-D3
Authors: Stefanovic V , Djordjevic V , Ivic M , Mitic-Zlatkovic M , Vlahovic P 
Published: February 2005

Background: Plasma cell differentiation antigen 1 (PC-1) is an inhibitor of insulinreceptor tyrosine-kinase. PC-1 content is elevated in muscle and adipose tissue from insulin-resistant subjects and its elevation correlates with in vivo insulin resistance. It is known that insulin resistance in uraemia may be improved with erythropoietin (EPO) and vitamin D therapy. Therefore, in this study the effects of human recombinant EPO and 1-alpha-D3 treatments on lymphocyte PC-1 expression in patients with end-stage renal failure on haemodialysis (HD) were investigated. Methods: Lymphocyte basal, concanavalin A (Con A), and phorbol-12-myristate13-acetate (PMA)-stimulated PC-1 activity were investigated in HD patients before and after a two-month treatment with subcutaneous EPO (15 patients, 2000-3000 U thrice weekly) or oral 1-α-D3 (14 patients, 2 μg thrice weekly). Twenty-nine patients (16 men and 13 women), aged 22-68 years (49 ± 7 years), on HD from 13 to 112 months, and 30 healthy controls participated in the study. None was obese and all had normal fasting plasma glucose. Results: A two-month EPO treatment produced a 41% haematocrit increase, with a rise in haemoglobin from 6.51 ± 0.18 g/dL to 9.69 ± 0.14 g/dL. Basal lymphocyte PC-1 activity in HD patients was found to be significantly increased ( P < 0.005) over the level in healthy controls. Treatment of patients with EPO decreased unstimulated lymphocyte PC-1 activity to values significantly lower than before the treatment ( P < 0.001). Lymphocyte Con A and PMA-stimulated PC-1 activity in patients on HD was found to be slightly increased over the level in healthy controls, but significantly reduced ( P < 0.005 and 0.05, respectively) after the EPO treatment. A two-month pulse oral 1-α-D3 treatment increased haematocrit by 21% and raised haemoglobin from 7.11 ± 0.32 g/dL to 8.80 ± 0.39 g/dL. This treatment normalized serum alkaline phosphatase activity and slightly reduced serum parathyroid hormone concentration. PC-1 in unstimulated and PMA-stimulated lymphocytes was unchanged, but significantly decreased ( P < 0.05) in Con A-stimulated lymphocytes after 1-α-D3 treatment. Fasting plasma glucose was not changed by the treatment. Conclusion: An increased lymphocyte PC-1 activity over control was found in HD patients. A two-month EPO therapy significantly decreased PC-1 activity to the control values, suggesting that an effect on PC-1 expression could be implicated in the amelioration of insulin resistance in uraemic patients treated with EPO. Treatment with pulse oral 1-α-D3 had an effect only on PC-1 of Con A-transformed lymphocytes of haemodialysed patients and requires further investigation.
Japanese standard reference material for JDS Lot 2 haemoglobin A1c. I: comparison of Japan Diabetes Society-assigned values to those obtained by the Japanese and USA domestic standardization programmes and by the International Federation of Clinical Chemistry reference laboratories
Authors: Tominaga Makoto , Makino Hideichi , Yoshino Gen , Kuwa Katsuhiko , Takei Izumi , Aono Yukuko , Hoshino Tadao , Umemoto Masao , Shimatsu Akira , Sanke Tokio , Kuwashima Masamichi , Taminato Tomohiko , Ono Junko 
Published: February 2005

Background: The Committee on Standardization of Laboratory Testing Related to Diabetes Mellitus of the Japan Diabetes Society (JDS) previously recommended use of the primary calibrator (JDS Lot 1) prepared by the former Committee for Standardization of Glycohemoglobin for standardizing the measurement of haemoglobin A1c (HbA1c). Owing to the depletion of vials of Lot 1 in March 2001, the present committee certified a new reference material, Lot 2, now distributed by the Health Care Technology Foundation (HECTEF). The standardization programme for HbA1c measurement in Japan is currently based on Lot 2, which has values assigned from within Lot 1; the Lot 1 values were consensus values based on assays by laboratories in the Japanese national quality control programme. In this study, for the purpose of international comparison and standardization, Lot 2 was assayed by the JDS reference laboratories, the National Glycoprotein Standardization Program (NGSP) in the USA, and by reference laboratories approved by the International Federation of Clinical Chemistry and Laboratory Medicine (IFCC). Method: The HbA1c values of JDS Lot 2 were transferred from those assigned to Lot 1 using KO500, a high-resolution HPLC method, at three laboratories approved by the JDS committee. Subsequently, vials of JDS Lot 2 were shipped to and assayed by the NGSP in the USA and 10 IFCC reference laboratories. Result: The JDS-assigned HbA1c values (from Lot 1) are 4.04 for Level 1, 5.38 for Level 2, 7.32 for Level 3, 9.88 for Level 4, and 12.63 for Level 5, all expressed as a percentage of total haemoglobin. The values obtained by NGSP and the IFCC laboratories gave the following formulas: NGSP value (%) = JDS value (%) + 0.3%; IFCC value (%) = 1.068 x JDS value (%) -1.741%. Conclusion: Although the values obtained by the IFCC laboratories are significantly lower than the values assigned to Lot 2 by the JDS, the relationship is linear. In addition, standardization of HbA1c based on JDS Lot 2 is currently at a satisfactory level in Japan. As a result, the reassignment of values for Lot 2 to agree with the IFCC values should be relatively easy and will be done after all relevant parties agree to the change.
Susceptibility of glomerular filtration rate estimations to variations in creatinine methodology: a study in older patients
Authors: Lamb Edmund J , Wood Joanna , Stowe Helen J , O'Riordan Shelagh E , Webb Michelle C , Dalton R Neil 
Published: February 2005

Background: It is recommended that measurement of serum creatinine should be supplemented with a creatinine-based estimation of glomerular filtration rate (GFR). The influence of creatinine methodology on these estimates is not always appreciated. We have studied differences in creatinine methods and their influence on GFR estimation specifically in older people. Methods: In all, 46 older patients (mean age 80 y, range 69-92 y) with predominantly mild or moderate kidney disease were studied. Serum creatinine was measured using a rate Jaffe method and two different enzymatic methods. Isotope dilution mass spectrometry served as the reference creatinine method. GFR was estimated using both the Modification of Diet in Renal Disease (MDRD) and Cockcroft and Gault formulae: a 51Cr-EDTA GFR estimation served as the reference GFR method. Results: Both enzymatic methods produced creatinine results that were significantly different ( P < 0.001) from the reference method. The Jaffe method over- and underestimated creatinine at low and high concentrations, respectively. The most likely explanation for these differences relates to standardization of the assays. Irrespective of creatinine method, the Cockroft and Gault formula tended to underestimate GFR, and the MDRD formula to overestimate GFR. Use of the differing creatinine methods to estimate GFR produced predictable biases of the estimate, with mean GFR estimates varying by 14% across the creatinine methods. Conclusion: Estimates of GFR depend critically upon the accuracy and precision of the creatinine measurement used in their calculation.
The comparative analytical performance of four troponin I assays at low concentration
Authors: Koerbin G , Tate JR , Potter JM , Hickman PE 
Published: February 2005

Background: Low troponin concentrations have been shown to be informative in the prognosis of acute coronary syndrome. We have investigated the analytical performance of four commonly used cardiac troponin I methods at concentrations approaching their analytical limit of detection. Method: We assayed 167 patient samples within 24 h of collection using the Beckman Coulter AccuTnI, Dade Behring Dimension, Abbott AxSYM and Bayer Centaur methods and compared their relative analytical performance. Results: Of the four assays compared, the AccuTnI was observed to have greater sensitivity at low concentrations. Using the limit of detection as the threshold, the Beckman assay showed superior performance at concentrations corresponding to a 20% coefficient of variation (CV), the Dade assay had a similar performance; and at concentrations corresponding to 10% CV most assays provide similar information. Conclusion: The newer or recently modified assays such as the Beckman Coulter AccuTnI and Dade Behring assays are best able to identify very low concentrations of troponin.
The Vinylcyclopropane–CyclopenteneRearrangement
Authors: Hudlický Tomáš , Kutchan Toni M. , Naqvi Saiyid M. 
Published: February 2005

Abstract
The vinylcyclopropane‐cyclopentene isomerization was discovered in 1959. After the mechanism was studied in detail, this rearrangement was incorporated into many useful synthetic schemes. Various heterocyclic permutations of the vinylcyclopropane system have also been investigated, yielding several synthetic methods based on the rearrangements of cyclopropyl ketones and cyclopropyl imines to dihydrofurans and dihydropyrroles, respectively. This chapter is concerned only with the rearrangements of vinylcyclopropanes to cyclopentenes. Excluded are Cope rearrangements of divinylcyclopropanes and rearrangements of cyclopropyl compounds not leading to cyclopentenes.
The isomerization of 2,2‐dichlorovinylcyclopropane was described in 1959. The rearrangement of the parent hydrocarbon was reported independently by two laboratories a year later. Although no prior mention of this rearrangement exists in the literature, it appears likely that it occured unobserved as early as 1922 during the preparation of vinylcyclopropane by drastic methods. The presence of cyclopentene in the reaction mixtures resulting from the Hofmann elimination of a β‐cyclopropylethylammonium salt is a likely possibility, considering the low temperature at which vinylcyclopropane rearranges. The detection and identification of reaction products by refractive indices only may have prevented recognition of the isomerization at that time.
During the decade following the discovery of the rearrangement, virtually every simple vinylcyclopropane was studied in an attempt to settle the question of biradical versus concerted mechanism. Later there was intense activity in the applications of this rearrangement and many of its analogs to organic synthesis. Studies have also emphasized transition‐metal‐catalyzed rearrangements of vinylcyclopropanes.
Tandem Vicinal Difunctionalization: β‐Addition to α,β‐Unsaturated Carbonyl Substrates Followed by α‐Functionalization
Authors: Chapdelaine Marc J. , Hulce Martin 
Published: February 2005

AbstractVicinal difunctionalization reactions play an important role in modern synthetic organic chemistry. They provide access to complex structures in a stereocontrolled fashion and act as powerful, attractive, convergent elements in synthetic strategy. Consequently, examples of these reactions are numerous. Among them may be cited the Diels–Alder reaction, which results in vicinal dialkylation of a dienophile; epoxidation–functionalization of alkenes which results in 2‐substituted alkanols carbenoid additions to alkenes resulting in cyclopropanes; organometalation–functionalization of alkynes giving vicinally disubstituted alkenes, and the additions of halides and acyl halides to alkenes using Friedel–Crafts catalysts. [2 + 2] Photocycloadditions and 1,3‐dipolar cycloadditions are but two of many more examples. New reactions are introduced regularly, such as radical cyclization–trapping, which recently has been applied to a synthesis of prostaglandin F2α.
TheBiginelli Dihydropyrimidine Synthesis
Authors: Kappe C. Oliver , Stadler Alexander 
Published: February 2005

AbstractThe cyclocondensation of suitable CH‐acidic carbonyl compounds, aldehydes, and urea‐type blocks under acidic conditions provides multifunctionalized derivatives. The discovery of this three‐component condensation process was made by Biginelli in 1893, therefore this reaction is called the “Biginelli reaction,” “Biginelli condensation,” or the “Biginelli dihydropyrimidine synthesis.” While the early examples of this cyclocondensation process typically involved a beta‐ketoester, aromatic aldehyde, and urea, the scope has now been extended considerably by variation of three building blocks, allowing access to a large number of multifunctionalized pyridmidine derivatives. The importance of multicomponent reactions in combinatorial chemistry has generated a renewed interest in the Biginelli reaction and the number of patents and publications on this subject is growing.In this chapter, all three‐component condensations involving suitable CH‐acidic carbonyl compounds, aldehydes, and urea‐type building blocks following the Biginelli concept are covered. Therefore, reactions involving 1,3‐diketones or nitroacetone as building blocks leading to dihydropyrimides that follow the discussed substitution pattern are included in contrast to earlier articles. Patents are only cited if they contain information not otherwise available.
Cu,Ni, andPdMediated Homocoupling Reactions in Biaryl Syntheses: TheUllmann Reaction
Authors: Nelson Todd D. , Crouch R. David 
Published: February 2005

AbstractThe traditional Ullman reaction is the homocoupling of aromatic halides mediated by copper at elevated temperatures. Ullman first reported this reaction in 1901. Although the coupling conditions first reported are still widely used, a host of modifications have been made to these reactions. Some of these modifications include the use of activated and alternative metals, often resulting in much lower coupling temperatures. Nickel and palladium are the most utilized source of alternative metals, Periodic reviews have been published. This chapter covers the literature on copper, nickel, and palladium mediated homocoupling reactions in biaryl synthesis from 1901 to 2000. The focus of this chapter is the scope and limitation of these processes, preparation of the activated metal, and mechanism of the homocoupling process