bluuebunny/crossref_metadata_2025 huggingface dataset:
Topoisomerase II may be linked to the reduction of chromosome number in meiosis
Authors: Paliulis Leocadia V. , Nicklas R. Bruce
Published: March 2003

A reduction of chromosome number in meiosis is essential for genome transmission in diploid organisms. Reduction depends on a change in kinetochore configuration.1 A recent study2 connects changes in kinetochores with other changes in chromosome structure and raises the intriguing possibility that topoisomerase II, the DNA untangling enzyme, is involved. BioEssays 25:309–312, 2003. © 2003 Wiley Periodicals, Inc.
A small issue addressed
Authors: Gumienny Tina L. , Padgett Richard W.
Published: March 2003

Cell size is an important determinant of body size. While the genetic mechanisms of cell size regulation have been well studied in yeast, this process has only recently been addressed in multicellular organisms. One recent report by Wang et al. (2002) shows that in the nematode C. elegans, the TGFβ‐like pathway acts in the hypodermis to regulate cell size and consequently body size.1 This finding is an exciting step in discovering the molecular mechanisms that control cell and body size. BioEssays 25:305–308, 2003. © 2003 Wiley Periodicals, Inc.
Pre‐whitening of data by covariance‐weighted pre‐processing
Authors: Martens Harald , Høy Martin , Wise Barry M. , Bro Rasmus , Brockhoff Per B.
Published: March 2003

A data pre‐processing method is presented for multichannel ‘spectra’ from process spectrophotometers and other multichannel instruments. It may be seen as a ‘pre‐whitening’ of the spectra, and serves to make the instrument ‘blind’ to certain interferants while retaining its analyte sensitivity. Thereby the instrument selectivity may be improved already prior to multivariate calibration. The result is a reduced need for process perturbation or sample spiking just to generate calibration samples that span the unwanted interferants. The method consists of shrinking the multidimensional data space of the spectra in the off‐axis dimensions corresponding to the spectra of these interferants. A ‘nuisance’ covariance matrix Σ is first constructed, based on prior knowledge or estimates of the major interferants' spectra, and the scaling matrix G = Σ−1/2 is defined. The pre‐processing then consists of multiplying each input spectrum by G. When these scaled spectra are analysed in conventional chemometrics software by PCA, PCR, PLSR, curve resolution, etc., the modelling becomes simpler, because it does not have to account for variations in the unwanted interferants. The obtained model parameter may finally be descaled by G−1 for graphical interpretation. The pre‐processing method is illustrated by the use of prior spectroscopic knowledge to simplify the multivariate calibration of a fibre optical vis/NIR process analyser. The 48‐dimensional spectral space, corresponding to the 48 instrument wavelength channels used, is shrunk in two of its dimensions, defined by the known spectra of two major interferants. Successful multivariate calibration could then be obtained, based on a very small calibration sample set. Then the paper shows the pre‐whitening used for reducing the number of bilinear PLSR components in multivariate calibration models. Nuisance covariance Σ is either based on the prior knowledge of interferants' spectra or based on estimating the interferants' spectral subspace from the calibration data at hand. The relationship of the pre‐processing to weighted and generalized least squares from classical statistics is outlined. Copyright © 2003 John Wiley & Sons, Ltd.
Variable selection in random calibration of near‐infrared instruments: ridge regression and partial least squares regression settings
Authors: Gusnanto Arief , Pawitan Yudi , Huang Jian , Lane Bill
Published: March 2003

Standard methods for calibration of near‐infrared instruments, such as partial least‐squares (PLS) and ridge regression (RR), typically use the full set of wavelengths in the model. In this paper we investigate the effect of variable (wavelength) selection for these two methods on the model prediction. For RR the selection is optimized with respect to the ridge parameter, the number of variables and the configuration of the variables in the model. A fast iterative computational algorithm is developed for the purpose of this optimization. For PLS the selection is optimized with respect to the number of components, the number of variables and the configuration of the variables. We use three real data sets in this study: processed milk from the market, milk from a dairy farm and milk from the production line of a milk processing factory. The quantity of interest is the concentration of fat in the milk. The observations are randomly split into estimation and validation sets. Optimization is based on the mean square prediction error computed on the validation set. The results indicate that the wavelength selection will not always give better prediction than using all of the available wavelengths. Investigation of the information in the spectra is necessary to determine whether all of them are relevant to the objective of the model. Copyright © 2003 John Wiley & Sons, Ltd.
Macrocycles from Perhalogenated Heterocycles
Authors: Sandford Graham
Published: March 2003

Perhalogenated heteroaromatic systems, such as trichloro‐s‐triazine and pentafluoropyridine, are multifunctional “building blocks” that react with a number of appropriate difunctional nucleophiles to provide access to a variety of macrocyclic and even cage‐like molecular architectures. Unusual structural and complexation characteristics of the systems reported so far, such as the recognition of anions, provide a further stimulus for the development of this area.
High‐Pressure Structural Trends of Group 15 Elements: Simple Packed Structures versus Complex Host–Guest Arrangements
Authors: Häussermann Ulrich
Published: March 2003

The Group 15 elements P, As, Sb, and Bi all have layered structures consisting of six‐membered rings under ambient conditions and attain the body‐centered cubic (bcc) structure at the highest pressures applied. In the intermediate pressure region, however, phosphorus and its heavier congeners behave profoundly differently. In this region P first attains the open packed simple cubic (sc) structure for a wide range of pressures and then transforms into the rarely observed simple hexagonal (sh) structure. For the heavier congeners complex, incommensurately modulated host–guest structures emerge as intermediate pressure structures. We investigated the high‐pressure behavior of P and As by ab initio density functional calculations in which pseudopotentials and a plane wave basis set were employed. The incommensurately modulated high‐pressure structure of As was approximated by a supercell. Our calculations reproduced the experimentally established pressure stability ranges of the sc and sh structures for P and the host–guest structure for As very well. We found that the sc and especially the sh structure are decisively stabilized by the admixture of d states in the occupied levels of the electronic structure. This admixture releases s–s antibonding states above the Fermi level (s–d mixing). With pressure, s–d mixing increases rapidly for P, whereas it remains at a low level for As. As a consequence, the band energy contribution to the total energy determines the structural stability for P in the intermediate pressure region, giving rise to simple packed structures. On the other hand, in the intermediate pressure region of the heavier Group 15 elements, a delicate interplay between the electrostatic Madelung energy and the band energy leads to the formation of complex structures.
A Novel Design Method of Ratiometric Fluorescent Probes Based on Fluorescence Resonance Energy Transfer Switching by Spectral Overlap Integral
Authors: Takakusa Hideo , Kikuchi Kazuya , Urano Yasuteru , Kojima Hirotatsu , Nagano Tetsuo
Published: March 2003

A ratiometric measurement, namely, simultaneous recording of the fluorescence intensities at two wavelengths and calculation of their ratio, allows greater precision than measurements at a single wavelength, and is suitable for cellular imaging studies. Here we describe a novel method of designing probes for ratiometric measurement of hydrolytic enzyme activity based on switching of fluorescence resonance energy transfer (FRET). This method employs fluorescent probes with a 3′‐O,6′‐O‐protected fluorescein acceptor linked to a coumarin donor through a linker moiety. As there is no spectral overlap integral between the coumarin emission and fluorescein absorption, the fluorescein moiety cannot accept the excitation energy of the donor moiety and the donor fluorescence can be observed. After cleavage of the protective groups by hydrolytic enzymes, the fluorescein moiety shows a strong absorption in the coumarin emission region, and then acceptor fluorescence due to FRET is observed. Based on this mechanism, we have developed novel ratiometric fluorescent probes (1–3) for protein tyrosine phosphatase (PTP) activity. They exhibit a large shift in their emission wavelength after reaction with PTPs. The fluorescence quenching problem that usually occurs with FRET probes is overcome by using the coumarin–cyclohexane–fluorescein FRET cassette moiety, in which close contact of the two dyes is hindered. After study of their chemical and kinetic properties, we have concluded that compounds 1 and 2 bearing a rigid cyclohexane linker are practically useful for the ratiometric measurement of PTPs activity. The design concept described in this paper, using FRET switching by spectral overlap integral and a rigid link that prevents close contact of the two dyes, should also be applicable to other hydrolytic enzymes by introducing other appropriate enzyme‐cleavable groups into the fluorescein acceptor.
Cover Picture: Synthesis, Structure, and Properties of Novel Open‐Cage Fullerenes Having Heteroatom(s) on the Rim of the Orifice (Chem. Eur. J. 7/2003)
Authors: Murata Yasujiro , Murata Michihisa , Komatsu Koichi
Published: March 2003

The cover picture shows a newly developed synthetic route to an open‐cage fullerene derivative with a 13‐membered ring orifice and its X‐ray crystallographic structure. The open‐cage fullerene is a key compound for the organic synthesis of endohedral fullerene complexes. Heating a solution of C60 with 3‐(2‐pyridyl)‐5,6‐diphenyl‐1,2,4‐triazine afforded an open‐cage derivative of C60 with an eight‐membered ring orifice, in 85% yield. The orifice was enlarged to a 12‐membered ring by photo‐oxidative cleavage of a double bond at the rim, and further to a 13‐membered ring by insertion of a sulfur atom into the rim by heating with elemental sulfur in the presence of tetrakis(dimethylamino)ethylene (TDAE). An overall yield of the final product based on C60 was 40%. X‐ray crystallography indicated that the final product has a circlular‐shaped orifice, which would probably be the biggest hole opened on the fullerene cage so far. A detailed description of this study is reported by K. Komatsu et al. on p. 1600 ff.
Adjustment of Twist Angles in Pseudo‐Helical Lanthanide Complexes by the Size of Metal Ions
Authors: Mizukami Shin , Houjou Hirohiko , Kanesato Masatoshi , Hiratani Kazuhisa
Published: March 2003

Control of self‐assembled nanostructures is a promising technique for nanotechnology. We have examined as to whether nanostructures could be controlled by the size of the central metal ion. Lanthanides are a natural choice for such a study as the size of their trivalent ions changes with atomic number gradually. For this investigation, a series of rare earth complexes ([LaL1], [CeL1], [SmL1], [TbL1], [YL1], and [LuL1]) with a tripodal heptadentate ligand L1 were synthesized, and their X‐ray crystallographic analysis was performed. Although the structures of the ligand (H3L1) and of the metal complex ([ML1]) were quite different, all complexes were almost isostructural pseudohelices. The result of the crystallographic studies demonstrated that the twist angles of helices in the complexes depend on the ionic size of the central metal. A detailed analysis helped determine which portion of the helical strand contributed to the total helicity, and the major cause for the difference in helicity among the lanthanides is discussed. Moreover, this result is the first example showing that LaIII and LuIII complexes with the same tripodal heptadentate ligand are isostractural.
Large Enhancement of the Nonlinear Optical Response of Reduced Fullerene Derivatives
Authors: Koudoumas Emmanuil , Konstantaki Maria , Mavromanolakis Antonis , Couris Stelios , Fanti Marianna , Zerbetto Francesco , Kordatos Konstantinos , Prato Maurizio
Published: March 2003

The third‐order nonlinear optical properties of fulleropyrrolidine and its salt as well as their reduced forms are investigated. Upon reduction, the response increases by up to, and sometimes more than, three orders of magnitude, giving values comparable to the largest ever reported. Calculations and experiments provide a coherent picture for the nonlinear optical properties of these new materials.
Photochemical Reaction of N,N‐Dimethyl‐4‐chloroaniline with Dienes: New Synthetic Paths via a Phenyl Cation
Authors: Guizzardi Benedetta , Mella Mariella , Fagnoni Maurizio , Albini Angelo
Published: March 2003

The irradiation of N,N‐dimethyl‐4‐chloroaniline in the presence of open‐chain dienes in acetonitrile leads to addition of the aminophenyl and chloro groups across one of the double bonds; transannular cyclization takes place with cyclic dienes, leading to an arylnortricyclene from norbornadiene and to 1‐arylbicyclo[3.3.0]octanes from 1,5‐cyclooctadiene. The reaction proceeds by photoheterolysis of the chloroaniline to yield the 4‐aminophenyl cation and addition to a CC double bond. The chemistry of the adduct cation depends on structure and medium, involving ion pairs in MeCN and solvated ions in CF3CH2OH. In the latter solvent, formation of ethers from open‐chain alkenes is accompanied by Wagner–Meerwein hydride shift. In acetonitrile, the cation from cyclooctadiene partitions between deprotonation and Ritter addition, while the one from norbornadiene is reduced; both cations undergo nucleophilic addition in trifluoroethanol. The relevance of these cationic reactions under unusually mild conditions is discussed.
Getting Closer to the Real Bacterial Cell Wall Target: Biomolecular Interactions of Water‐Soluble Lipid II with Glycopeptide Antibiotics
Authors: Vollmerhaus Pauline J. , Breukink Eefjan , Heck Albert J. R.
Published: March 2003

A novel synthesized water‐soluble variant of lipid II (LII) was used to evaluate the noncovalent interactions between a number of glycopeptide antibiotics and their receptor by bioaffinity electrospray ionization mass spectrometry (ESI‐MS). The water‐soluble variant of lipid II is an improved design, compared to the traditionally used tripeptide N,N′‐diacetyl‐L‐lysyl‐D‐alanyl‐D‐alanine (KAA), of the target molecule on the bacterial cell wall. A representative group of glycopeptide antibiotics was selected for this study to evaluate the validity of the novel cell‐wall‐mimicking target LII. Structure–function relationships of various glycopeptide antibiotics were investigated by means of 1) bioaffinity mass spectrometry to evaluate solution‐phase molecular interactions with both LII and KAA, 2) fluorescence leakage experiments to study the interactions with the membrane‐embedded lipid II, and 3) minimum inhibitory concentrations against the indicator strain Micrococcus flavus. Our results with the novel LII molecule reveal that some antibiotics interact differently with KAA and LII. Additionally, our data cast doubt on the hypothesis that antibiotic selfdimerization assists in the in‐vivo efficacy. Finally, the water‐soluble lipid II proved to be a better model of the bacterial cell wall.
Highly Stereoselective Radical Cyclization of Haloacetals Controlled by the Acetal Center
Authors: Villar Félix , Kolly‐Kovac Tanja , Equey Olivier , Renaud Philippe
Published: March 2003

A systematic investigation of radical haloacetal cyclizations (Ueno–Stork reaction) where the acetal center is the unique stereogenic element is reported. This highly diastereoselective reaction can be used for the preparation of polysubstituted tetrahydrofurans andγ‐lactones. We report herein the full experimental details of reactions where up to three new chiral centers are created. To demonstrate the potential of this approach, short syntheses of (+)‐eldanolide and of tricyclic acetals related to biologically active lignans have been achieved.
A Computational Study of Radical Haloacetal Cyclizations Controlled by the Acetal Center
Authors: Corminboeuf Olivier , Renaud Philippe , Schiesser Carl H.
Published: March 2003

The stereochemical outcome of the radical haloacetal cyclization reaction (Ueno–Stork reaction) has been examined by ab initio and other molecular orbital techniques. It was found that the stereochemistry of 5‐exo‐ and 6‐exo trig cyclizations can be accurately predicted from calculations using moderate levels of theory (UHF/6‐311G** or B3LYP/6‐311G**). A simplified computational procedure, easily run on a standard desktop computer, has been developed that provides excellent predictive ability for the stereochemical outcome for the reactions in question. Interestingly, a novel twist transition state has been identified for the first time in 5‐exo‐trig radical cyclization reactions.
Driving Force Dependence of Intermolecular Electron‐Transfer Reactions of Fullerenes
Authors: Fukuzumi Shunichi , Ohkubo Kei , Imahori Hiroshi , Guldi Dirk M.
Published: March 2003

Pulse‐radiolytic studies were performed to determine the rate constants of intermolecular electron transfer (ket) from fullerenes (C60, C76, and C78) to a series of arene radical cations in dichloromethane. The one‐electron oxidation potentials of the employed arenes—corresponding to the one‐electron reduction potentials of arene π‐radical cations—were determined in dichloromethane to evaluate the driving forces of electron‐transfer oxidation of fullerenes with arene π‐radical cations. The driving force dependence of log ket shows a pronounced decrease towards the highly exothermic region, representing the first definitive confirmation of the existence of the Marcus inverted region in a truly intermolecular electron transfer. Electron‐transfer reduction of fullerenes with anthracene radical anion was also examined by laser flash photolysis in benzonitrile. The anthracene radical anion was produced by photoinduced electron transfer from 10,10′‐dimethyl‐9,9′,10,10′‐tetrahydro‐9,9′‐biacridine [(AcrH)2] to the singlet excited state of anthracene in benzonitrile. The rate constants of electron transfer (ket) from anthracene radical anion to C60, C70, and a C60 derivative were determined from the decay of anthracene radical anion in the presence of various concentrations of the fullerene. Importantly, a significant decrease in the ket value was observed at large driving forces (1.50 eV) as compared to the diffusion‐limited value seen at smaller driving forces (0.96 eV). In conclusion, our study presents clear evidence for the Marcus inverted region in both the electron‐transfer reduction and oxidation of fullerenes.
A Quantum Chemical Study of Racemization Pathways in Substituted Chrysene Derivatives
Authors: Kind Carsten , Götz Andreas W. , Hess Bernd A.
Published: March 2003

The potential‐energy surfaces of 5,11‐disubstituted 6,12‐dimethoxychrysene and chrysene‐6,12‐dione derivatives were investigated by means of density functional calculations. We report relative energies of all conformers and an identification of the racemisation pathways of the chiral equilibrium structures. By analysis of homodesmotic reactions we were able to obtain an estimate for the strain energy of the substituted compounds. This strain energy can be used as a means of measuring the steric effects exerted by the substituents.
Sequence‐Selective Metalation of Double‐Helical Oligodeoxyribonucleotides with PtII, MnII, and ZnII Ions
Authors: Vinje J. , Parkinson J. A. , Sadler P. J. , Brown T. , Sletten E.
Published: March 2003

Reactions of [PtCl(dien)]+ (dien=diethylenetriamine), Mn2+ and Zn2+ ions with three different double‐helical oligodeoxyribonucleotides, which contain the central sequence GGXY (XY=AT, TA or CC) have been monitored by NMR spectroscopy. 2 D [1H, 15N] HSQC/HMQC NMR spectroscopy using 15N‐labeled Pt(dien) shows that the rate of formation of 3′‐G‐N 7 and 5′‐G‐N 7 platinated adducts is highly sequence dependent. The relative rates of platination of 5′‐G versus 3′‐G are largest for the sequence ‐GGCC‐, for which only a small fraction of the 3′‐G adduct is formed; for ‐GGTA‐, the rate of 5′‐G platination is about eight times that of 3′‐G, and for ‐GGAT‐ the ratio is 1.2. These values are in qualitative agreement with those obtained for G‐N 7/Mn2+ selectivity as determined by paramagnetic line broadening of the adjacent G‐H 8, and also G‐N 7/Zn2+ selectivity as determined by G‐H 8 chemical shift changes. Fluctuation in the nucleophilicity of G‐N 7 may be explained by variation of the π‐stacking interaction between base residues along the double helix. The reaction mixtures containing platinated 3′‐G and 5′‐G fractions were separated by HPLC. Since the duplexes are self‐complementary, the platinated single strands were readily annealed to duplexes with twofold symmetry and analyzed by 2 D [1H, 1H] NOESY NMR spectroscopy. Unexpectedly, the 5′‐G‐H 8 resonance signals of both 5′‐G and 3′‐G platinated duplexes showed large downfield shifts in the range δ=0.3–0.6 ppm, while the 3′‐G‐H 8 resonance signals in both cases exhibited no, or only slight, upfield shifts. Resonance signals for several other protons in the central region undergo large chemical shift variations induced by platination, indicating that monofunctional binding to DNA leads to appreciable conformational changes.
Photochemical and Thermal Transformations of 1‐Aryloxy‐2‐ and 4‐Azidoanthraquinones
Authors: Klimenko Lubov S. , Pritchina Elena A. , Gritsan Nina P.
Published: March 2003

The photolysis of 1‐aryloxy‐2‐azidoanthraquinones (3) in benzene is described herein which gave 1‐hydroxy‐2‐arylaminoanthraquinones (4) and two types of 5H‐naphtho[2,3‐c]phenoxazine‐8,13‐diones (5 and 6). Thermolysis of 3 yielded only one of phenoxazines 5 and small amount of 4. On the other hand thermolysis of 3 in the presence of phenols gave phenoxazine 6 as a major product. The mechanism of the photolysis and thermolysis of 2‐azido‐1‐aryloxyanthraquinones (3) is proposed and supported by the results from semiempirical calculations. A relative contribution of the primary photoreactions—azido group dissociation and aryl group migration was estimated to be 3:1. Photolysis and thermolysis of 4‐azido‐1‐(p‐tert‐butylphenoxy)‐9,10‐anthraquinone (8) gave 3‐(p‐tert‐butylphenoxy)‐anthra[1,9‐cd]‐izoxazole‐6‐one (9) as the only product.
Growth of Well‐Aligned γ‐MnO2 Monocrystalline Nanowires through a Coordination‐Polymer‐Precursor Route
Authors: Xiong Yujie , Xie Yi , Li Zhengquan , Wu Changzheng
Published: March 2003

A new coordination‐polymer‐precursor route has been developed to synthesize nanowires under hydrothermal conditions. In the present work, well‐aligned γ‐MnO2 nanowires, growing along the [0 0 2] axis, have successfully been prepared by selecting an appropriate coordination polymer [{Mn(SO4)(4,4′‐bpy)(H2O)2}n] as precursor. In comparison with the experimental results from other coordination‐polymer precursors, it is found that only [{Mn(SO4)(4,4′‐bpy)(H2O)2}n] is appropriate for the formation of γ‐MnO2 crystal lattices during the process of oxidization. The IR absorption spectra of as‐obtained precipitates at different reaction intervals minutely describe the reaction process, due to the different coordination abilities of ligands in the coordination polymer. More evidence about the mechanism will be further explored in the future study. Further observations show the ordered alignment of nanowires' tops and such well‐aligned nanowires provide more possible applications in lithium batteries.
Epithelial lesions in prophylactic mastectomy specimens from women with BRCA mutations
Authors: Kauff Noah D. , Brogi Edi , Scheuer Lauren , Pathak Dorothy R. , Borgen Patrick I. , Hudis Clifford A. , Offit Kenneth , Robson Mark E.
Published: March 2003

BACKGROUND

It has been suggested that BRCA‐associated breast carcinoma may often lack a detectable preinvasive phase. To investigate this hypothesis, the authors compared the prevalence of histopathologic lesions in prophylactic mastectomy (PM) specimens from women with BRCA mutations and in mastectomy specimens obtained at autopsy from an age and race‐matched comparison group without a known cancer predisposition.

METHODS

All specimens from women with a deleterious BRCA1 or BRCA2 mutation who participated in an ongoing follow‐up study and underwent PM at Memorial Sloan‐Kettering Cancer Center between November 1, 1987 and May 31, 2001 were reviewed. For each case, breast tissue from two age and race‐matched women without a known cancer predisposition was also reviewed. The prevalence of benign, premalignant, and cancerous lesions was compared.

RESULTS

Mastectomy specimens from 24 cases and 48 comparison subjects were reviewed. Ductal carcinoma in situ (DCIS), atypical ductal hyperplasia (ADH), and atypical lobular hyperplasia (ALH) were all more common in PM specimens from women with BRCA mutations than in those from the comparison group. The odds ratio for the detection of any high‐risk lesion (DCIS, lobular carcinoma in situ, ADH, or ALH) in specimens from BRCA mutation carriers was 12.7 (95% confidence interval, 3.1–52.4; P < 0.001).

CONCLUSIONS

Lesions associated with an increased risk of subsequent malignancy are more common in PM specimens from women with BRCA mutations than in breast tissue obtained at autopsy from unaffected women without a known predisposition. This finding suggests that hereditary breast carcinoma has a preinvasive phase that may be detectable with aggressive surveillance. Cancer 2003;97:1601–8. © 2003 American Cancer Society.

DOI 10.1002/cncr.11225
Carcinoid heart disease
Authors: Zuetenhorst Johanna M. , Bonfrer Johannes M. G. M. , Korse Catharina M. , Bakker Rob , van Tinteren Harm , Taal Babs G.
Published: March 2003

BACKGROUND

Serotonin excretion plays a role in the development of carcinoid heart disease (CHD), but the exact pathogenesis is not known. In the current study, the authors evaluated 24‐hour urinary 5‐hydroxyindoleacetic acid (5‐HIAA) excretion, as well as plasma levels of transforming growth factor‐β (TGF‐β), fibroblast growth factor (FGF), and atrial natriuretic peptide (ANP) in patients with and without CHD determined by ultrasound examination.

METHODS

Urine and plasma samples were obtained for 37 patients and cardiac ultrasound was performed during follow‐up in 1999 and 2000. Median 5‐HIAA excretion was calculated for the period between diagnosis and ultrasound examination. CHD was defined as the thickening of the tricuspid valve with additional III–IV/IV tricuspid valve regurgitation.

RESULTS

CHD was found in 9 of 37 patients (24%). No significant differences were found for age, gender, presence, and duration of liver metastases. All CHD patients had symptoms of the carcinoid syndrome compared with 71% of the non‐CHD patients (P = 0.159). Median 5‐HIAA excretion was significantly higher in the CHD group compared with the non‐CHD group: 576 μmol/24 hours versus 233 μmol/24 hours (P = 0.02). No difference in TGF‐β and FGF plasma levels was observed between both groups (P = 0.139 and P = 0.985, respectively), nor was there a correlation with morphology of the tricuspid valve or degree of dilatation of the right atrium/ventricle. However, the CHD group had higher median ANP levels than the non‐CHD group: 48 ng/L and 25 ng/L, respectively (P = 0.026).

CONCLUSIONS

High levels of 5‐HIAA excretion and plasma ANP were found to be associated with CHD. No significant relation with TGF‐β or FGF was been found. Cancer 2003;97:1609–15. © 2003 American Cancer Society.

DOI 10.1002/cncr.11226
Physical activity levels before and after a diagnosis of breast carcinoma
Authors: Irwin Melinda L. , Crumley Diane , McTiernan Anne , Bernstein Leslie , Baumgartner Richard , Gilliland Frank D. , Kriska Andrea , Ballard‐Barbash Rachel
Published: March 2003

BACKGROUND

Increased body weight at the time patients are diagnosed with breast carcinoma has been associated with an increased risk of recurrence and reduced survival. Weight gain also is common after diagnosis. Increasing physical activity (PA) after diagnosis may minimize these adverse outcomes. In this population‐based study, the authors investigated whether PA levels after diagnosis declined from prediagnosis levels and whether any changes in PA varied by disease stage, adjuvant treatment, patient age, or body mass index (BMI) in 812 patients with incident breast carcinoma (from in situ to Stage IIIa).

METHODS

Types of sports and household activities and their frequency and duration for the year prior to diagnosis and for the month prior to the interview (i.e., 4–12 months postdiagnosis) were assessed during a baseline interview.

RESULTS

Patients decreased their total PA by an estimated 2.0 hours per week from prediagnosis to postdiagnosis, an 11% decrease (P < 0.05). Greater decreases in sports PA were observed among women who were treated with radiation and chemotherapy (50% decrease) compared with women who underwent surgery only (24% decrease) or who were treated with radiation only (23%; (P < 0.05). Greater decreases in sports PA were observed among obese patients (41% decrease) compared with patients of normal weight (24% decrease; P < 0.05).

CONCLUSIONS

PA levels were reduced significantly after patients were diagnosed with breast carcinoma. Greater decreases in PA observed among heavier patients implied a potential for greater weight gain among women who already were overweight. Randomized, controlled trials are needed to evaluate how PA may improve the prognosis for patients with breast carcinoma. Cancer 2003;97:1746–57. © 2003 American Cancer Society.

DOI 10.1002/cncr.11227
Pattern of recurrence following complete resection of esophageal carcinoma and factors predictive of recurrent disease
Authors: Mariette Christophe , Balon Jean‐Michel , Piessen Guillaune , Fabre Sylvain , Van Seuningen Isabelle , Triboulet Jean‐Pierre
Published: March 2003

BACKGROUND

Despite increasingly radical surgery for esophageal carcinoma, a large number of patients still experience recurrent disease soon after operation. The current study was undertaken to evaluate the pattern of recurrence after curative esophagectomy for cancer of the thoracic esophagus and to identify factors predictive of recurrent disease.

METHODS

A total of 439 consecutive patients discharged from the authors' institution following R0 resection between January 1982 and July 2002 were followed for evidence of recurrence over a mean interval of 37.3 (range, 1–207) months.

RESULTS

Overall 1‐, 3‐ and 5‐years survival rates were 91%, 54%, and 41%, respectively. Some 230 patients (52.4%) developed proven recurrence, of whom 24 were alive and 206 were dead at the time of writing. The median time to recurrence was 12.0 (range, 6–96) months, with a median survival thereafter of 7.0 (range, 0–83) months. The pattern of recurrence was local in 12.1%, regional in 20.5% (cervical 3.6%, mediastinal 14.8%, and abdominal 2.1%), and distant in 19.8%, respectively. The overall pattern of dissemination was significantly different according to the histologic subtype (P = 0.021). One hundred five (45.7%) of all recurrences occurred within 12 months of surgery, with local, regional, and distant recurrence occurring at a median of 14.0 (range, 6–77), 13.5 (range, 6–73), and 11.0 (range, 6–96) months, respectively; A factor predictive of recurrent disease was histologic tumor depth invasion (P = 0.001).

CONCLUSIONS

Depth of tumor invasion should be used to identify patients who will have recurrence within 12 months of operation, so that these patients may be either entered into trials of multimodality treatment or offered nonsurgical palliation. Cancer 2003;97:1616–23. © 2003 American Cancer Society.

DOI 10.1002/cncr.11228
Sperm banking and rate of assisted reproduction treatment
Authors: Ragni Guido , Somigliana Edgardo , Restelli Liliana , Salvi Roberta , Arnoldi Mariangela , Paffoni Alessio
Published: March 2003

BACKGROUND

Semen cryostorage remains the only proven method to preserve fertility in men with cancer. However, the necessity and the justification of banking spermatozoa have been questioned because it has been reported that only a small percentage of patients are referred for assisted reproductive technologies using frozen semen.

METHODS

A 15‐year cryopreservation program involving 776 men with malignant diseases who were referred to the study institution for semen cryopreservation before proceeding with chemotherapy and/or radiotherapy was reviewed. Data regarding cancer diagnosis, age, semen quality, and use of frozen semen were analyzed.

RESULTS

Sperm banking was not performed for 90 of the 776 subjects (11.6%) because of azoospermia. Sperm quality was reduced in men with testicular carcinoma. To date, 36 of the 686 patients who had banked spermatozoa (5.2%) have attended the clinic for assisted conception treatments using frozen spermatozoa. Cumulative rates related to the use of frozen semen at 4, 8, and 12 years were 4.5%, 8.7%, and 11.8%, respectively. Relevant factors demonstrated to be significantly associated with a lower probability of using frozen material were a younger age at the time of cryostorage and a diagnosis of testicular carcinoma.

CONCLUSIONS

The rate of referral for assisted reproductive techniques in patients who have banked their semen is low but tends to rapidly increase extending the length of follow‐up. The cumulative percentage of use is at least above 10% but a longer follow‐up is required to draw definitive conclusions. A diagnosis of testicular carcinoma is associated with a lower rate of use when compared with other cancers. Cancer 2003;97:1624–9. © 2003 American Cancer Society.

DOI 10.1002/cncr.11229
Molecular markers of outcome after radiotherapy in patients with prostate carcinoma
Authors: Pollack Alan , Cowen Didier , Troncoso Patricia , Zagars Gunar K. , von Eschenbach Andrew C. , Meistrich Marvin L. , McDonnell Timothy
Published: March 2003

BACKGROUND

Abnormal expression of key proteins of the apoptotic pathway has been associated with poor prognosis, although there have been few studies of these correlations in patients with prostate carcinoma who are treated with radiotherapy. The current study examined the association between expression levels of Ki‐67, bcl‐2, bax, and bcl‐x in pretreatment biopsy specimens and patient outcome after definitive radiotherapy alone.

METHODS

Archival pretreatment prostate biopsy tumor tissue was retrieved from 106 patients with Stage T1–T3 prostate carcinoma who were treated at the University of Texas M. D. Anderson Cancer Center with external beam radiotherapy between 1987 and 1993. Expression levels of Ki‐67 (MIB‐1 staining; n = 106 patients), bcl‐2 (n = 77 patients), bax (n = 70 patients), and bcl‐x (both long and short splice variants; n = 72 patients) were determined by immunohistochemical staining. The Ki‐67 labeling index (Ki67‐LI) was available for all patients and was derived from the percentage of Ki‐67 positive cells. Biochemical failure after radiotherapy was defined as three consecutive rises in prostate specific antigen level on follow‐up. The median follow‐up was 62 months.

RESULTS

High Ki67‐LI (> 3.5%) expression was observed in 33% of patients, overexpression of bcl‐2 was observed in 16% of patients, altered bax expression was observed in 23% of patients, and altered bcl‐x expression was observed in 53% of patients. There was no correlation found between the biomarkers. Kaplan–Meier survival estimates of freedom from biochemical failure (bNED) and the log‐rank test revealed significantly lower rates in association with high Ki67‐LI, positive bcl‐2, and altered bax staining. No correlation was observed between bcl‐x staining and bNED. Cox proportional hazards multivariate analysis confirmed that bcl‐2 and bax were independent of pretreatment PSA level, Gleason score, disease stage, and Ki67‐LI in predicting bNED.

CONCLUSIONS

Abnormalities in the expression levels of bcl‐2 and bax were associated with increased failure after patients were treated for prostate carcinoma with external beam radiotherapy. These biomarkers appeared to be useful in categorizing patient risk further, beyond Ki‐67 staining and conventional clinical prognostic factors. Cancer 2003;97:1630–8. © 2003 American Cancer Society.

DOI 10.1002/cncr.11230
Anatomic distribution of periprostatic adipose tissue
Authors: Hong Heng , Koch Michael O. , Foster Richard S. , Bihrle Richard , Gardner Thomas A. , Fyffe Joanne , Ulbright Thomas M. , Eble John N. , Cheng Liang
Published: March 2003

BACKGROUND

Because the prostatic capsule is often indistinct, recognition of extraprostatic extension by carcinoma depends heavily on the identification of carcinoma cells in the periprostatic adipose tissue. However, the distribution of adipose tissue along the prostatic surfaces has not been studied extensively.

METHODS

The authors analyzed the periprostatic adipose tissue in specimens from 100 patients treated with radical retropubic prostatectomy and bilateral pelvic lymphadenectomy for prostatecarcinoma. Each specimen was totally embedded and examined by the whole mount method. The presence or absence of adipose tissue on the anterior, posterior, right, and left surfaces of the prostate was determined and analyzed.

RESULTS

Periprostatic adipose tissue was present on 48% of all prostatic surfaces examined. The distribution of periprostatic adipose tissue varied among the different surfaces of the prostate, with the anterior, posterior, right, and left surfaces showing 44%, 36%, 59%, and 57% adipose tissue, respectively. The amount of periprostatic adipose tissue was similar among specimens from operations performed by different surgeons (P = 0.72). However, nerve‐sparing procedures resulted in less adipose tissue (46%) than non‐nerve‐sparing procedures (54%) (P = 0.01).

CONCLUSIONS

Less than half of the prostatic surfaces examined were covered by adipose tissue. The absence of adipose tissue over large areas of the prostatic surface, especially the posterior surface, makes the evaluation of extraprostatic extension difficult and unreliable. Further refinement of the prostate carcinoma staging system is needed. Cancer 2003;97:1639–43. © 2003 American Cancer Society.

DOI 10.1002/cncr.11231
Prediction of progression after radical nephrectomy for patients with clear cell renal cell carcinoma
Authors: Leibovich Bradley C. , Blute Michael L. , Cheville John C. , Lohse Christine M. , Frank Igor , Kwon Eugene D. , Weaver Amy L. , Parker Alexander S. , Zincke Horst
Published: March 2003

BACKGROUND

The objective of the current study was to develop an algorithm to predict progression to metastases after radical nephrectomy for patients with clinically localized renal cell carcinoma (RCC) to allow stratification of patients for potential adjuvant therapy trials.

METHODS

The authors identified 1671 sporadic patients with clinically localized, unilateral clear cell RCC who underwent radical nephrectomy between 1970 and 2000. The clinical features examined included age, gender, smoking history, recent onset hypertension, performance status, and presenting symptoms. The pathologic features examined included surgical margins, tumor stage, regional lymph node status, tumor size, nuclear grade, histologic tumor necrosis, sarcomatoid component, cystic architecture, and multifocality. Metastases free survival was estimated using the Kaplan–Meier method. A multivariate Cox proportional hazards regression model was fit to determine associations between the clinical and pathologic features and distant metastases.

RESULTS

The median follow‐up was 5.4 years (range, 0–31 years). Metastases occurred in 479 patients at a median of 1.3 years (range, 0–25 years) after nephrectomy. The estimated metastases free survival rates were 86.9% at 1 year, 77.8% at 3 years, 74.1% at 5 years, 70.8% at 7 years, and 67.1% at 10 years. Multivariate analysis showed that the following features were associated with progression to metastases: tumor stage, regional lymph node status, tumor size, nuclear grade, and histologic tumor necrosis (P < 0.001 for all).

CONCLUSIONS

In patients with clear cell RCC, tumor stage, regional lymph node status, tumor size, nuclear grade, and histologic tumor necrosis showed statistically significant associations with progression to metastatic RCC. The authors present a scoring algorithm based on these features that can be used to predict disease progression after patients undergo radical nephrectomy for clinically localized clear cell RCC. Cancer 2003;97:1663–71. © 2003 American Cancer Society.

DOI 10.1002/cncr.11234
Defects in the opioid growth factor receptor in human squamous cell carcinoma of the head and neck
Authors: McLaughlin Patricia J. , Stack Brendan C. , Levin Roger J. , Fedok Fred , Zagon Ian S.
Published: March 2003

BACKGROUND

The endogenous opioid peptide, [Met5]‐enkephalin, termed opioid growth factor (OGF), interacts with its receptor (OGFr) to play a role as a constitutively expressed inhibitory growth factor in the proliferation of epithelial cells. This study compared protein and gene expression of OGFr in surgical specimens of human squamous cell carcinoma of the head and neck (SCCHN) with normal epithelium.

METHODS

Tissues from 64 patients with SCCHN and from 49 patients undergoing uvulapalatoplasty or tonsillectomy were utilized. Binding affinity and capacity were assessed by receptor binding assays and the levels of OGFr protein were determined by quantitative Western blot analysis. Immunohistochemistry assessed the presence and distribution of OGFr. Levels of OGFr mRNA were quantitated by Northern blot analysis. Protein and gene expressions of OGFr also were evaluated in the margins of SCCHN.

RESULTS

Binding analyses indicated nearly ninefold fewer OGFr binding sites in tumor tissue in comparison with normal samples. The OGFr protein levels were reduced fivefold in tumor tissues relative to normal epithelium. Values of OGFr mRNA were comparable in tumors and normal epithelium. Tumor margins had intermediate levels of protein and binding, but OGFr mRNA values were similar to those of normal specimens.

CONCLUSIONS

These data demonstrate that OGFr is defective in SCCHN and that translation/posttranslation of OGFr protein, but not transcriptional levels of the OGFr gene, is involved. In addition, the attenuated levels of OGFr binding capacity may serve as a marker for SCCHN. These subnormal levels of OGFr may be responsible in part for tumor progression, diminishing the interaction of OGF with OGFr that aids in stabilizing cell replication by an inhibitory mechanism. Gene therapy to reinstate OGFr and/or function could provide a useful treatment for inhibiting tumor progression. Cancer 2003;97:1701–10. © 2003 American Cancer Society.

DOI 10.1002/cncr.11237
Fractionated cyclophosphamide, vincristine, liposomal daunorubicin, and dexamethasone plus rituximab and granulocyte‐macrophage–colony stimulating factor (GM‐CSF) alternating with methotrexate and cytarabine plus rituximab and GM‐CSF in patients with Richter syndrome or fludarabine‐refractory chronic lymphocytic leukemia
Authors: Tsimberidou Apostolia M. , Kantarjian Hagop M. , Cortes Jorge , Thomas Deborah A. , Faderl Stefan , Garcia‐Manero Guillermo , Verstovsek Srdan , Ferrajoli Alessandra , Wierda William , Alvarado Yesid , O'Brien Susan M. , Albitar Maher , Keating Michael J. , Giles Francis J.
Published: March 2003

BACKGROUND

Therapy for patients with Richter syndrome (RS) or fludarabine‐refractory chronic lymphocytic leukemia (CLL) is unsatisfactory. A Phase II study was conducted to evaluate an alternating combination cytotoxic regimen given with rituximab and granulocyte‐macrophage–colony stimulating factor (GM‐CSF) in these patients.

METHODS

Fludarabine‐refractory CLL was defined as failure to respond to most recent prior fludarabine‐containing regimen. Patients received up to six cycles of fractionated cyclophosphamide, vincristine, liposomal daunorubicin, and dexamethasone (hyper‐CVXD) plus rituximab and GM‐CSF alternating with methotrexate and cytarabine plus rituximab and GM‐CSF. Response, toxicity, and survival data were compared with data from prior therapy with hyper‐CVXD alone in this patient group.

RESULTS

Forty‐nine patients with RS (n = 30 patients) or refractory CLL (n = 19 patients) were treated on study. Nine patients (18%) achieved a complete remission, and 11 patients achieved a partial remission (22%), for an overall objective response (OR) rate of 41%. With a median follow‐up of 7.5 months and a maximum follow‐up of 15.2 months, the 12‐month failure free survival (FFS) rate was 27%, and the overall survival (OS) rate was 39%. Nine patients (18%) died during the first cycle of therapy, and two patients (4%) died during the second cycle. There were no significant differences between the rates of OR, OS, and FFS in the current study and those obtained with hyper‐CVXD alone on a prior study.

CONCLUSIONS

The study regimen had activity and significant toxicity in patients with RS or fludarabine‐refractory CLL. It was not clearly better compared with hyper‐CVXD alone in this patient population. Cancer 2003;97:1711–20. © 2003 American Cancer Society.

DOI 10.1002/cncr.11238
Comparison of allogeneic stem cell transplantation, high‐dose cytarabine, and autologous peripheral stem cell transplantation as postremission treatment in patients with de novo acute myelogenous leukemia
Authors: Tsimberidou Apostolia‐Maria , Stavroyianni Niki , Viniou Nora , Papaioannou Maria , Tiniakou Maria , Marinakis Theodoros , Skandali Anastasia , Sakellari Ioanna , Yataganas Xenophon
Published: March 2003

BACKGROUND

Postremission therapy is critical in maintaining complete remission (CR) in patients with de novo acute myelogenous leukemia (AML). The aim of this trial was to compare allogeneic stem cell transplantation (SCT), high‐dose cytarabine (ara‐C; HiDAC), and autologous SCT as postremission therapy in patients with de novo AML.

METHODS

One hundred twenty patients age ≤ 60 years with previously untreated AML (non‐M3) and a performance status score of ≤ 2 received induction therapy with 3 days of idarubicin and 7 days of ara‐C (IA). Patients in CR received one course of HiDAC. Subsequently, patients age ≤ 50 years with available HLA‐compatible donors were assigned to receive allogeneic SCT; patients with “favorable” cytogenetics received a second course of HiDAC; and all others were randomized to a second course of HiDAC or autologous SCT.

RESULTS

The IA combination induced CR in 99 patients (82.5%). With a median follow‐up of 43 months (range, 18–64 years), the 3‐year survival and failure‐free survival (FFS) rates were 47% and 45%, respectively. The factors associated with longer survival were those identified for CR (i.e., age and cytogenetics). Forty‐nine patients (49%) received the assigned postremission therapy. Fifteen patients underwent allogeneic SCT. Nineteen patients underwent autologous SCT and 15 patients received a second course of HiDAC, after randomization. In the allogeneic SCT group, both the 3‐year survival and the FFS rates were 73%. In the autologous SCT and HiDAC groups, the 3‐year survival rates were 58% and 46%, respectively (P = 0.80), and the 3‐year FFS rates were 42% and 33%, respectively (P = 0.83).

CONCLUSIONS

The three postremission treatment groups had comparable survival. Allogeneic SCT is associated with a prolonged FFS. Cancer 2003;97:1721–31. © 2003 American Cancer Society.

DOI 10.1002/cncr.11240