bluuebunny/crossref_metadata_2025 huggingface dataset:
A three‐dimensional atlas of pituitary gland development in the zebrafish
Authors: Chapman Susan C. , Sawitzke Arleen L. , Campbell Douglas S. , Schoenwolf Gary C.
Published: May 2005

The pituitary gland is unique to Chordates, with significant variation within this group, offering an excellent opportunity to increase insight into phylogenetic relationships within this phylum. The structure of the pituitary in adult Teleosts (class: Osteichthyes) is quite different from that in other chordates and is also variable among members of the class. Therefore, a complete description of the structure and development of the pituitary in members of this class is a critical component to our overall understanding of this gland. An obvious teleost model organism is the zebrafish, Danio rerio, as a significant amount of work has been done on the molecular control of pituitary development in this fish. However, very little work has been published on the morphological development of the pituitary in the zebrafish; the present study aims to fill this void. The pituitary develops from cells on the rostrodorsal portion of the head and reaches its final position, ventral to the hypothalamus, as the cephalic flexure occurs and the jaws and mouth form. The pituitary placode is juxtaposed to cells that will form the olfactory vesicles, the stomodeum, and the hatching gland. The volume of the pituitary is greatest at 24 hours post fertilization (hpf). From 24 to 120 hpf, the pituitary decreases in height and width as it undergoes convergent extension, increasing in length with the axis. The adenohypophysis is a morphologically distinct structure by 24 hpf, whereas the neurohypophysis remains indistinct until 72 hpf. The findings of this study correlate well with the available molecular data. J. Comp. Neurol. 487:428–440, 2005. © 2005 Wiley‐Liss, Inc.
Chain formation and glial tube assembly in the shift from neonatal to adult subventricular zone of the rodent forebrain
Authors: Peretto Paolo , Giachino Claudio , Aimar Patrizia , Fasolo Aldo , Bonfanti Luca
Published: May 2005

The subventricular zone (SVZ) is regarded as an embryonic germinal layer persisting at the end of cerebral cortex neurogenesis and capable of generating neuronal precursors throughout life. The two distinct compartments of the adult rodent forebrain SVZ, astrocytic glial tubes and chains of migrating cells, are not distinguishable in the embryonic and early postnatal counterpart. In this study we analyzed the SVZ of mice and rats around birth and throughout different postnatal stages, describing molecular and morphological changes which lead to the typical structural arrangement of adult SVZ. In both species studied, most changes occurred during the first month of life, the transition being slightly delayed in mice, in spite of their earlier development. Important modifications affected the glial cells, eventually leading to glial tube assembly. These changes involved an overall reorganization of glial processes and their mutual relationships, as well as gliogenesis occurring within the SVZ which gives rise to glial cell subpopulations. The neuroblast cell population remained qualitatively quite homogeneous throughout all the stages investigated, changes being restricted to the relationships among cells and consequent formation of chains at about the third postnatal week. Electron microscopy showed that chain formation is not directly linked to glial tube assembly, generally preceding the occurrence of complete glial ensheathment. Moreover, chain and glial tube formation is asymmetric in the medial/lateral aspect of the SVZ, being inversely related. The attainment of an adult SVZ compartmentalization, on the other hand, seems linked to the pattern of expression of adhesion and extracellular matrix molecules. J. Comp. Neurol. 487:407–427, 2005. © 2005 Wiley‐Liss, Inc.
Functional organization and hemispheric comparison of primary auditory cortex in the common marmoset (Callithrix jacchus)
Authors: Philibert Bénédicte , Beitel Ralph E. , Nagarajan Srikantan S. , Bonham Ben H. , Schreiner Christoph E. , Cheung Steven W.
Published: May 2005

Hemispheric fine‐grain maps of primary auditory cortex (AI) were derived from microelectrode penetrations in the temporal gyrus of the common marmoset (Callithrix jacchus) to 1) compare the functional organization of AI in the marmoset with other mammalian species and 2) compare the right and left AI maps in individual monkeys. Frequency receptive fields (FRFs) were recorded with pure tones. Five FRF parameters were analyzed: characteristic frequency, threshold, sharpness of tuning 10 dB and 40 dB above threshold, and minimum response latency. The present study confirms that the functional organization of AI is characterized by a robust tonotopic frequency gradient overlaid with spatially clustered distributions of other FRF parameters. Globally, this functional organization of AI in the common marmoset is similar to that in other mammalian species. With respect to within‐subject hemispheric comparisons of the five FRF parameters, a coherent pattern of asymmetry is not evident in marmoset AI. The overall results indicate that the basic functional organization between hemispheres is similar but not identical. J. Comp. Neurol. 487:391–406, 2005. © 2005 Wiley‐Liss, Inc.
Distribution and cellular localization of insulin‐regulated aminopeptidase in the rat central nervous system
Authors: Fernando Ruani N. , Larm Jari , Albiston Anthony L. , Chai Siew Yeen
Published: May 2005

Central infusions of angiotensin IV enhance spatial learning, memory retention and retrieval, neurotransmitter release, and long‐term potentiation via interaction with a specific, high‐affinity binding site. This site was recently purified and identified as the insulin‐regulated aminopeptidase (IRAP). This enzyme was previously characterized as the marker protein of specialized insulin‐responsive vesicles containing GLUT4 in muscle and adipose tissue. The present study provides the first comprehensive description of IRAP distribution in the adult rat brain. By using immunohistochemistry, IRAP was found to be highly expressed in selected olfactory regions, in septal and hypothalamic nuclei, throughout the hippocampal formation and cerebral cortex, and in motor and motor associated nuclei. IRAP was expressed exclusively in neurons in these regions. At the cellular level, IRAP was localized within cell bodies, excluding the nucleus, in a punctate vesicular pattern of expression. IRAP‐positive immunoreactivity was also found in some proximal processes but was not detected in synaptic nerve terminals. The neurochemical composition of IRAP‐containing neurons was further characterized by dual‐label immunohistochemistry. IRAP was expressed in cholinergic cell bodies of the medial septum, a source of cholinergic projections to the hippocampus and cerebral cortex. The distribution of IRAP in motor and motor‐associated nuclei; the colocalization of the enzyme with potential in vivo substrates, oxytocin and vasopressin in the hypothalamus; and the colocalization with GLUT4 in selected nuclei all suggest diverse physiological roles for IRAP in the rat central nervous system. J. Comp. Neurol. 487:372–390, 2005. © 2005 Wiley‐Liss, Inc.
Serotonergic reticular formation cells in Rana pipiens: Categorization, development, and tectal projections
Authors: Zhao Bing , Debski Elizabeth A.
Published: May 2005

The reticular formation contributes serotonin to many brain regions, including the optic tectum. We examined the organization and development of its serotonergic neurons in the leopard frog. Serotonin‐immunoreactive (5‐HT‐ir) cells in adult frogs were organized into 10 distinct populations that were identified on the basis of their location and cellular morphology. Populations ranged in size from 16 to 2,066 cells and sometimes spanned more than one previously identified nuclear region. Four of the ten populations were absent in tadpoles. The remaining populations, though present, had two contrasting patterns of development. Half of the populations were established early and showed little change in numbers during tadpole stages but increased in size in juvenile and adult frogs. The other half increased dramatically during tadpole stages but failed to add many more cells in juveniles and adults. Three populations provided 90% of the serotonergic projections from the reticular region to the adult optic tectum. These projections were established early in development and likely originated from the dorsal raphe, median raphe, raphe pontis, raphe magnus, and reticularis pontis oralis. Termination sites were located in midtectal layers and were not topographically organized. We conclude that serotonergic cells within the reticular formation of the leopard frog have an organization similar to that found in mammals, that the overall increase in numbers of these cells is attributable to growth in different cell populations at different stages, and that input from this region changes activity levels in the optic tectum in a global rather than a site‐specific manner. J. Comp. Neurol. 487:441–456, 2005. © 2005 Wiley‐Liss, Inc.
Edge‐based adaptive implicit/explicit finite element procedures for three‐dimensional transport problems
Authors: Souza D. A. F. , Martins M. A. D. , Coutinho A. L. G. A.
Published: May 2005

We present an implementation of an edge‐based strategy together with an iterative adaptive implicit/explicit (AIE) time marching scheme for three‐dimensional transport problems. The AIE algorithm treats part of the mesh as implicit and part as explicit, based on some stability and accuracy criteria. The solution of the implicit partition has its speed increased and memory requirements reduced by performing the matrix–vector products, within the iterative solver, edge‐by‐edge. Numerical examples show that the combined procedures can achieve significantly faster solutions than the usual fully implicit element‐by‐element approach. Copyright © 2005 John Wiley & Sons, Ltd.
Degenerate Two‐Photon Absorption Spectra in Azoaromatic Compounds
Authors: De Boni Leonardo , Misoguti Lino , Zílio Sergio C. , Mendonça Cleber R.
Published: May 2005

A systematic study of the degenerate two‐photon absorption (2PA) spectra of seven azoaromatic compounds in dimethyl sulfoxide solution is reported, which employed the Z‐scan technique with femtosecond laser pulses from the bottom of the azo compound absorption bands up to 1100 nm. The 2PA peaks for pseudostilbene‐type azo compounds (Disperse Orange (DO) 3, Disperse Red (DR) 13, DR1, DR19, and DR19‐Cl) were observed at twice the peak wavelength of the linear absorption. However, such peaks were not observed for other azo compounds (PAMINO and DIAMINO) because of the symmetry of these molecules. A resonance enhancement of the 2PA cross‐section was observed for all compounds. The 2PA peak and the nonlinear resonance enhancement behavior could be adjusted with a model based on perturbation theory. Such knowledge can be a guideline to the understanding of the 2PA process in azoaromatic compounds.
Sonic hedgehog signaling regulates the expression of insulin‐like growth factor binding protein‐6 during fetal prostate development
Authors: Lipinski Robert J. , Cook Crist H. , Barnett Daniel H. , Gipp Jerry J. , Peterson Richard E. , Bushman Wade
Published: May 2005

At the onset of ductal morphogenesis in the developing prostate, Shh expression condenses at evaginations of urogenital sinus epithelium and activates Gli transcription factors in the adjacent mesenchyme. Abrogation of Hedgehog signaling disrupts proper prostatic budding, ductal growth, and branching. We now show that Hedgehog signaling regulates the expression of insulin‐like growth factor binding protein‐6 (Igfbp‐6) in the developing mouse prostate. Igfbp‐6 is a secreted factor that specifically binds insulin‐like growth factor‐II (IGF‐II), prevents its binding to the IGF‐I receptor, and is thought to regulate the activity of IGF‐II in growth and differentiation. Igfbp‐6 is expressed in both the developing and adult prostate. In the urogenital sinus, Igfbp‐6 mRNA colocalized with Ptc1 and Gli1 mRNA in the mesenchyme, while Igfbp‐6 protein was found in both the mesenchymal and epithelial layers. Exogenous Shh peptide induced expression of Igfbp‐6 in the developing prostate while the chemical inhibitor of Hedgehog signaling, cyclopamine, reduced its expression. These studies show that Igfbp‐6 is an actual target of Shh signaling in the urogenital sinus and provide the first evidence for a linkage between the Hedgehog and IGF signaling pathways in prostate development. Developmental Dynamics 233:829–836, 2005. © 2005 Wiley‐Liss, Inc.
Expression of rck/p54, a DEAD‐box RNA helicase, in gametogenesis and early embryogenesis of mice
Authors: Matsumoto Kenji , Kwon Oh‐Yong , Kim Hyungtae , Akao Yukihiro
Published: May 2005

rck/p54 is a DEAD‐box RNA helicase protein with ATP‐dependent RNA‐unwinding activity. Its ortholog is required for sexual reproduction in yeast and for oocyte survival and sperm fertility in Caenorhabditis elegans. In the current study, we investigated the expression of rck/p54 in mouse gametogenesis and early embryogenesis. Western blot analysis revealed that rck/p54 was highly expressed in both the ovary and testis. In the ovary, maturing oocytes strongly expressed rck/p54 in their cytoplasm. In contrast, in the testis, spermatogonia and primary spermatocytes highly expressed rck/p54 in their cytoplasm, but its expression decreased in the spermatids. Interestingly, rck/p54 was concentrated in the heads of spermatozoa; and then its expression gradually decreased as these cells matured along the epididymal duct. After fertilization, rck/p54 protein and its mRNA remained present in the pronucleus phase; and then their expression levels slightly but definitely decreased in morulae and blastocytes. The injection of a CMV‐based rck/p54 expression vector into the pronuclei of fertilized eggs caused a delay in early embryogenesis. In generating RCK transgenic mice, the birth rate of the mice was significantly lower than those of other gene transgenic mice. These findings indicate that rck/p54 may play an important role in gametogenesis and early embryogenesis in mammals. Developmental Dynamics 233:1149–1156, 2005. © 2005 Wiley‐Liss, Inc.
Foxc1 integrates Fgf and Bmp signalling independently of twist or noggin during calvarial bone development
Authors: Rice Ritva , Rice David P.C. , Thesleff Irma
Published: May 2005

Calvarial bone and suture development is under complex regulation where bone morphogenetic protein (Bmp) and fibroblast growth factor (Fgf) signalling interact with Msx2/Twist and Noggin and regulate frontal bone primordia proliferation and suture fusion, respectively. We have shown previously that the winged helix transcription factor Foxc1, which is necessary for calvarial bone development, is required for the Bmp regulation of Msx2. We now show that FGF2 regulates the expression of Foxc1, indicating that Foxc1 integrates Bmp and Fgf signalling pathways. We also show that Foxc1 is not needed for the acquisition of osteogenic potential or for the differentiation of osteoblasts. The expression of Fgf receptors and Twist were normal in Foxc1‐deficient calvarial mesenchyme, and ectopic FGF2 was able to induce the expression Osteopontin. Furthermore, we demonstrate that Foxc1 does not participate in the regulation of Noggin expression. Our findings indicate that Foxc1 integrates the Bmp and Fgf signalling pathways independently of Twist or Noggin. This signalling network is essential for the correct patterning and growth of calvarial bones. Developmental Dynamics 233:847–852, 2005. © 2005 Wiley‐Liss, Inc.
Restoration of DSCR1 to disomy in the trisomy 16 mouse model of Down syndrome does not correct cardiac or craniofacial development anomalies
Authors: Lange Alexander W. , Rothermel Beverly A. , Yutzey Katherine E.
Published: May 2005

The Down syndrome critical region 1 (DSCR1) gene is located in syntenic regions of human chromosome 21 and mouse chromosome 16 and encodes a regulatory protein in the calcineurin/NFAT pathway. DSCR1 expression in the embryonic brain, craniofacial structures, and heart is consistent with a role in contributing to Down syndrome developmental anomalies. In the trisomy 16 (Ts16) murine model of Down syndrome, expression of DSCR1 isoforms is elevated and NFAT transcriptional activity is decreased in the developing heart and brain. The individual contribution of DSCR1 to Down syndrome‐related anomalies was examined by specific restoration of DSCR1 to disomic levels in Ts16 embryos. However, genetic restoration of DSCR1 did not rescue major morphological abnormalities in cardiac or craniofacial development. These data demonstrate that trisomy of DSCR1 alone does not significantly contribute to developmental defects in Ts16 mice and underscore the complexity of developmental anomalies associated with Down syndrome. Developmental Dynamics 233:954–963, 2005. © 2005 Wiley‐Liss, Inc.
Specification of dorsoventral polarity in the embryonic chick mesencephalon and its presumptive role in midbrain morphogenesis
Authors: Li Naixin , Hornbruch Amata , Klafke Ruth , Katzenberger Barbara , Wizenmann Andrea
Published: May 2005

The chick midbrain is subdivided into functionally distinct ventral and dorsal domains, tegmentum and optic tectum. In the mature tectum, neurons are organized in layers, while they form discrete nuclei in the tegmentum. Dorsoventral (DV) specification of the early midbrain should thus play a crucial role for the organization of the neuronal circuitry in optic tectum and tegmentum. To investigate regional commitment and establishment of cellular differences along the midbrain DV axis, we examined the commitment of gene expression patterns in isolated ventral and dorsal tissue in vivo and in vitro, and studied their cell mixing properties. Use of explant cultures, and grafting of dorsal midbrain into a ventral environment or vice versa, revealed a gradual increase in the autonomy of region‐specific gene regulation between stages 12 and 18 (embryonic day 2 to 3). This process becomes independent of the activity of midline organizers, such as floor and roof plate, by stage 16. Once the DV axis polarity is fixed, cells from dorsal and ventral midbrain adopt differential adhesive properties. Thus between stages 18 to 23 (embryonic day 3 and 4), cells of dorsal and ventral origin start to separate from each other, at a time‐point when the majority of midbrain cells is not yet differentiated. Hence, our results suggest that progressive specification of the midbrain DV axis is accompanied by progressively reduced cell mixing between dorsal and ventral precursors, leading to a partial regionalization of midbrain tissue into autonomous units of precursor cell populations. Developmental Dynamics 233:907–920, 2005. © 2005 Wiley‐Liss, Inc.
Expression of Xenopus suppressor of cytokine signaling 3 (xSOCS3) is induced by epithelial wounding
Authors: Kuliyev Emin , Doherty Joanne R. , Mead Paul E.
Published: May 2005

The suppressor of cytokine signaling (SOCS) family of proteins are intracellular mediators of cytokine signaling. These proteins are induced rapidly by cytokine stimulation and act in a classic negative‐feedback loop to attenuate the cellular response to the cytokine signal. In this study, we present the cloning and initial characterization of the Xenopus SOCS3 gene. We show that xSOCS3 is rapidly induced in response to epithelial wounding in the tadpole. The induction of xSOCS3 in response to trauma is transient with maximal expression being reached 1 hr after the injury and diminishing after that. Unlike other genes known to be responsive to wound‐induced activation of the mitogen‐activated protein (MAP) kinase pathway, such as Egr1, SOCS3 expression in response to trauma is unaffected by blockade of the MAP kinase pathway by chemical inhibitors. Developmental Dynamics 233:1123–1130, 2005. © 2005 Wiley‐Liss, Inc.
Characterization and expression pattern of two zebrafish atf7 genes
Authors: Zhao Chengtian , Qi Jingjing , Meng Anming
Published: May 2005

Members of the ATF/CREB (activating transcription factor/cAMP‐responsive element binding protein) transcription factor family play diverse roles in controlling cell proliferation, apoptosis, and oncogenesis, as well as in embryonic development of vertebrates. We identified two zebrafish orthologs of human ATF7 gene: atf7a and atf7b. Whole‐mount in situ hybridization shows that zebrafish atf7a is first expressed in the notochord precursors at 80% epiboly stage and then in the developing notochord during segmentation. The expression of atf7a is positively regulated by ntl, flh, and spr2, which are involved in development of the notochord. In contrast, atf7b is maternally expressed and during embryogenesis its mRNA is ubiquitously distributed, showing an expression pattern similar to that of mammalian Atf7. Developmental Dynamics 233:1157–1162, 2005. © 2005 Wiley‐Liss, Inc.
DNA damage in mice treated with sulfur dioxide by inhalation
Authors: Meng Ziqiang , Qin Guohua , Zhang Bo
Published: May 2005

Sulfur dioxide (SO2) is a ubiquitous air pollutant produced by the burning of fossil fuels. In this study, single‐cell gel electrophoresis (the Comet assay) was used to evaluate the DNA damage produced by inhalation exposure of mice to SO2. Male and female mice were housed in exposure chambers and treated with 14.00 ± 1.25, 28.00 ± 1.98, 56.00 ± 3.11, and 112.00 ± 3.69 mg/m3 SO2 for 6 hr/day for 7 days, while control groups were exposed to filtered air. Comet assays were performed on blood lymphocytes and cells from the brain, lung, liver, spleen, kidney, intestine, and testicles of the animals. SO2 caused significant, dose‐dependent increases in DNA damage, as measured by Olive tail moment, in all the cell types analyzed from both sexes of mice. The results indicate that inhalation exposure to SO2 damages the DNA of multiple organs in addition to the lung, and suggests that this damage could result in mutation, cancer, and other diseases related to DNA damage. Further work will be required to understand the ultimate toxicological significance of this damage. These data also suggest that detecting DNA damage in blood lymphocytes, using the Comet assay, may serve as a useful tool for evaluating the impact of pulmonary SO2 exposure in human biomonitoring studies. Environ. Mol. Mutagen., 2005. © 2005 Wiley‐Liss, Inc.
New species of the genus Astragalus L. (Fabaceae), mainly from the “Flora Iranica” area
Authors: Zarre Sh. , Podlech D. , Taeb Fatimeh
Published: May 2005

During the work on the genus Astragalus for the “Flora Iranica” and a planned revision of the whole genus in the Old World several new species (35) could be discovered among the material recently investigated. They are described here: Sect. Aegacantha: A. vallis‐astoris; Sect. Alopecuroidei: A. ebrahimabadensis; Sect. Ammodendron: A. harirudensis; Sect. Brachycarpus: A. ohbaensis, A. pishanxianensis; Sect. Craccina: A. tenuissimus; Sect. Dissitiflori: A. ahangarensis, A. capitis‐regni, A. sessiliflorus, A. shogotensis; Sect. Erioceras: A. hecatae; Sect. Hololeuce: A. repentinus; Sect. Hymenostegis: A. qorvehensis; Sect. Hypoglottidei: A.nezva‐montis; Sect. Incani: A. dorudensis, A. hamadryadis, A. harazensis, A. innotabilis; Sect. Malacothrix: A. absconditus, A. anodiophilus, A. khunsarensis, A. meshkinensis, A. segregatus, A. shehbazii, A. taebiae; A. tahbaziae, A. vicinalis; Sect. Onobrychoidei: A. affinis, A. dysbatophilus; A. ignotus; Sect. Ornithopodium: A. zourabadensis; Sect. Platyglottis: A. semitarius; Sect. Polycladus: A. swatensis; Sect. Stereothrix: A. bavanatensis, A. damghanensis. (© 2005 WILEY‐VCH Verlag GmbH & Co. KGaA, Weinheim)
A new species of Anthurium (Araceae) from Espírito Santo State, eastern Brazil
Authors: Gonçalves E. G.
Published: May 2005

A new species of Anthurium (A. viridispathum E.G.Gonç., sp. nova) is described and illustrated. It occurs in rocky outcrops in Espírito Santo state, eastern Brazil. It seems to be closer to Anthurium validinervium Engl., but differs in the primary lateral veins departing from the midrib in a more obtuse angle (45–55° not 30°), much wider spathe (2–2.3 times longer than broad, not 5–6) and inflorescenes longer than leaves (much shorter in A. validinervium).

Anthurium viridispathum is tentavely placed in the section Urospadix Engl. subsection Obscureviridia Engl. (© 2005 WILEY‐VCH Verlag GmbH & Co. KGaA, Weinheim)
Identification key to the Cypress family (Cupressaceae)
Authors: Schulz C. , Knopf P. , Stützel Th.
Published: May 2005

The identification of Cupressaceae taxa, except for some local and easily distinguishable taxa, is difficult even for specialists. One reason for this is the lack of a complete key including all Cupressaceae taxa, another reason is that diagnoses and descriptions are spread over several hundred publications which are sometimes difficult to access. Based on morphological studies of about 3/4 of the species and a careful compilation of the most important descriptions of Cupressaceae, a first identification key for the entire Cypress family (Cupressaceae) could be set up. The key comprises any of the 30 genera, 134 species, 7 subspecies, 38 varieties, one form and thus all 180 taxa recognized byFarjon(2001). The key uses mainly features of adult leaves, female cones and other characters which are all relatively easy to be used. (© 2005 WILEY‐VCH Verlag GmbH & Co. KGaA, Weinheim)
Pressure relaxation procedures for multiphase compressible flows
Authors: Lallemand M.‐H. , Chinnayya A. , Le Metayer O.
Published: May 2005

This paper deals with pressure relaxation procedures for multiphase compressible flow models. Such models have nice mathematical properties (hyperbolicity) and are able to solve a wide range of applications: interface problems, detonation physics, shock waves in mixtures, cavitating flows, etc. The numerical solution of such models involves several ingredients. One of those ingredients is the instantaneous pressure relaxation process and is of particular importance.

In this article, we present and compare existing and new pressure relaxation procedures in terms of both accuracy and computational efficiency. Among these procedures we enhance an exact one in the particular case of fluids governed by the stiffened gas equation of state, and approximate procedures for general equations of state, which are particularly well suited for problems with large pressure variations. We also present some generalizations of these procedures in the context of multiphase flows with an arbitrary number of fluids. Some tests are provided to illustrate these comparisons. Copyright © 2005 John Wiley & Sons, Ltd.
Contrasting a novel temporally orientated Hamilton–Jacobi‐equation‐based ILES method with other approaches for a complex geometry flow
Authors: Tucker P. G. , Liu Y.
Published: May 2005

Flow and heat transfer inside an idealized electronics system is simulated using large‐eddy simulation (LES)‐related approaches that have been validated for simpler canonical flows. These include: Yoshizawa LES, detached eddy simulation (DES), limited numerical scales (LNS) and other hybrid LES–RANS (Reynolds‐averaged Navier–Stokes) approaches including a new ILES (implicit LES)–RANS method. For the ILES, dissipation from the one legged temporal discretization is used to drain turbulence. The use of differential equations, including the Hamilton–Jacobi and Eikonal, to model turbulence distance functions is explored. The Hamilton–Jacobi is shown to be especially compatible with the zonal RANS–ILES approach and the Eikonal with DES. Performances of the LES‐related methods are compared with explicit algebraic stress unsteady RANS (URANS) results and also measurements. Considering the problem complexity, generally, for all methods, predicted mean velocities and turbulence intensities are in a reasonable agreement with measurements. Average errors are 15 and 25%, respectively. With the exception of the zonal ILES–RANS method, turbulence intensities are under‐predicted. For heat transfer, none of the models performs well giving circa 100% errors. Notably, the LNS performs poorly for both the flow field and heat transfer giving a highly complex RANS–LES interface with inappropriate upstream LES boundary conditions. DES is found impossible to converge. This is partly attributed to the irregular LES–RANS interface arising with the method. All the LES approaches significantly underpredict heat transfer and the URANS over‐predicts. Even the increased flow activity arising from use of the less dissipative ILES element does not prevent the significant heat transfer under‐prediction. Copyright © 2005 John Wiley & Sons, Ltd.
Increased chromosome instability but not cancer predisposition in haploinsufficient Bub3 mice
Authors: Kalitsis Paul , Fowler Kerry J. , Griffiths Belinda , Earle Elizabeth , Chow C. W. , Jamsen Kris , Choo K. H. Andy
Published: May 2005

Mitotic spindle checkpoint proteins have been shown to play a crucial role in the accurate segregation of chromosomes during cell division. Bub3 is a member of a group of mitotic checkpoint proteins that are essential for this process. To investigate the role of Bub3 in chromosome segregation and cancer development, we analyzed haploinsufficient cells in mice. Heterozygous Bub3 embryonic fibroblasts displayed increased aneuploidy and premature sister‐chromatid separation. In addition, when challenged with the microtubule disruptor nocodazole, the cells showed a slight increase in chromatid breakage and a decrease in the mitotic index. No substantial differences were observed between wild‐type and Bub3 heterozygous mice in the frequency or the rate at which tumors appeared. Crossing Bub3+/− mice onto a heterozygous tumor‐suppressor background of Trp53 or Rb1 similarly revealed no substantial differences in either the number or the rate at which tumors appeared. These results suggest that haploinsufficiency of Bub3 causes a slight increase in chromosome instability but is not clearly associated with a noticeable rise in the probability of tumor formation in the animal, possibly because of a partially functional mitotic checkpoint, or cells exhibiting chromosome instability could have activated the apoptosis pathway and thus escaped tumor induction and detection. © 2005 Wiley‐Liss, Inc.
Statistical modeling and projections of lung cancer mortality in 4 industrialized countries
Authors: Shibuya Kenji , Inoue Mie , Lopez Alan D.
Published: May 2005

The purpose of this work was to model lung cancer mortality as a function of past exposure to tobacco and to forecast age‐sex‐specific lung cancer mortality rates. A 3‐factor age‐period‐cohort (APC) model, in which the period variable is replaced by the product of average tar content and adult tobacco consumption per capita, was estimated for the US, UK, Canada and Australia by the maximum likelihood method. Age‐ and sex‐specific tobacco consumption was estimated from historical data on smoking prevalence and total tobacco consumption. Lung cancer mortality was derived from vital registration records. Future tobacco consumption, tar content and the cohort parameter were projected by autoregressive moving average (ARIMA) estimation. The optimal exposure variable was found to be the product of average tar content and adult cigarette consumption per capita, lagged for 25–30 years for both males and females in all 4 countries. The coefficient of the product of average tar content and tobacco consumption per capita differs by age and sex. In all models, there was a statistically significant difference in the coefficient of the period variable by sex. In all countries, male age‐standardized lung cancer mortality rates peaked in the 1980s and declined thereafter. Female mortality rates are projected to peak in the first decade of this century. The multiplicative models of age, tobacco exposure and cohort fit the observed data between 1950 and 1999 reasonably well, and time‐series models yield plausible past trends of relevant variables. Despite a significant reduction in tobacco consumption and average tar content of cigarettes sold over the past few decades, the effect on lung cancer mortality is affected by the time lag between exposure and established disease. As a result, the burden of lung cancer among females is only just reaching, or soon will reach, its peak but has been declining for 1 to 2 decades in men. Future sex differences in lung cancer mortality are likely to be greater in North America than Australia and the UK due to differences in exposure patterns between the sexes. © 2005 Wiley‐Liss, Inc.
Physical activity and the risk of ovarian cancer: A case‐control study in Canada
Authors: Pan Sai Yi , Ugnat Anne‐Marie , Mao Yang ,   The Canadian Cancer Registries Epidemiology Research Group
Published: May 2005

We evaluated the impact of recreational and occupational physical activity on ovarian cancer risk using data from a population‐based case‐control study of 442 cases with histologically confirmed incident ovarian cancer and 2,135 controls aged 20–76 years, conducted in 1994–1997 in Canada. Frequency and intensity of physical activity were collected through self‐administered questionnaires. Compared to women in the lowest tertiles of moderate, vigorous and total recreational activity, those in the highest tertiles had multivariable‐adjusted odds ratios (and 95% confidence intervals) of 0.67 (0.50–0.88), 0.93 (0.70–1.24) and 0.73 (0.58–0.98), respectively. There were statistically significant trends of decreasing risk with increasing levels of moderate and total recreational activity, with similar patterns for premenopausal and postmenopausal women. A significant reduction in risk associated with higher level of moderate recreational activity was observed for serous, endometrioid and other but not mucinous types of tumors. The analyses in one province with the largest number of cases and controls indicated that occupational activity was associated with reduced ovarian cancer risk by lifetime activity and by various life periods (early 20s, early 30s, early 50s and 2 years before interview). Our study suggests that occupational and regular moderate recreational physical activity reduce ovarian cancer risk. © 2005 Wiley‐Liss, Inc.
Immunotherapy of malignant ascites with trifunctional antibodies
Authors: Heiss Markus M. , Ströhlein Michael A. , Jäger Michael , Kimmig Rainer , Burges Alexander , Schoberth Alexandra , Jauch Karl‐Walter , Schildberg Friedrich‐Wilhelm , Lindhofer Horst
Published: May 2005

A new class of intact bispecific antibodies shows unmet effector qualities by activation of not only T cells but also simultaneous activation of Fcγ receptor type I/III+ cells (macrophages, NK‐cells and DC). These trifunctional antibodies (trAb) lead to efficient specific killing of targeted tumor cells without any pre‐ or co‐stimulation. This concept was investigated in vivo in patients with malignant ascites in a clinical situation that allowed monitoring of tumor cell elimination and correlation with clinical effects. In a prospective study, 8 patients with malignant ascites due to peritoneal carcinomatosis were treated with intraperitoneal application of trAb, which bound either the EpCAM‐ or Her2/neu‐antigen on tumor cells. Treatment consisted of 4–6 applications within 9–23 days with a total amount of 145–940 μg. Seven of eight patients required no further paracentesis during follow‐up or until death with a mean paracentesis‐free interval of 38 weeks (median = 21.5, range = 4–136). Tumor cell monitoring showed a complete elimination of tumor cells in ascites already at total doses as low as 40–140 μg. Clinical response with disappearance of ascites accumulation was seen in all patients, which was correlated with elimination of tumor cells (p = 0.0014). Severe adverse events were not observed. Clinically relevant side effects were fever, moderate abdominal pain and skin reactions. Intraperitoneal immunotherapy with trAb showed convincing efficacy in patients with malignant ascites. This treatment offers new therapeutic options for patients with peritoneal carcinomatosis. © 2005 Wiley‐Liss, Inc.
Association of the BCRP C421A polymorphism with nonpapillary renal cell carcinoma
Authors: Korenaga Yoshihito , Naito Katsusuke , Okayama Naoko , Hirata Hiroshi , Suehiro Yutaka , Hamanaka Yuichiro , Matsuyama Hideyasu , Hinoda Yuji
Published: May 2005

Breast cancer resistance protein (BCRP), the second member of the ATP‐binding cassette membrane transporter family, has a single nucleotide polymorphism, C421A (resulting in Q141K), that is of functional importance. Our aim was to explore the relationship between this polymorphism of the BCRP gene and the risk of renal cell carcinoma (RCC) development. For a case‐control study, DNA samples from 200 nonpapillary RCC patients and 200 healthy control subjects were analyzed using the TaqMan technique. The genotypic frequencies of the BCRP C421A polymorphism were compared between RCC patients and control subjects. The frequency of the C/C genotype was significantly higher in RCC patients than in control subjects (age‐ and gender‐adjusted OR = 1.96, 95% CI 1.32–2.93). No associations were observed between the BCRP C421A polymorphism and clinicopathologic or epidemiologic factors, including age, gender, tumor grade, stage, cigarette smoking, family history of cancer and body mass index. Carriers with the C/C genotype of the BCRP C421A polymorphism are at risk of developing nonpapillary RCC. These data suggest that BCRP is a candidate RCC susceptibility gene. © 2005 Wiley‐Liss, Inc.
Efficient induction of T‐cell responses to carcinoembryonic antigen by a heterologous prime‐boost regimen using DNA and adenovirus vectors carrying a codon usage optimized cDNA
Authors: Mennuni Carmela , Calvaruso Francesco , Facciabene Andrea , Aurisicchio Luigi , Storto Mariangela , Scarselli Elisa , Ciliberto Gennaro , La Monica Nicola
Published: May 2005

The immunogenic properties of plasmid DNA and recombinant adenovirus (Ad) encoding the carcinoembryonic antigen (CEA) were examined in mice by measuring both the amplitude and type of immune response, and the immunogenicity of codon usage optimized cDNA encoding CEA (CEAopt) was assessed both in C57Bl/6 and CEA transgenic mice. Vectors were injected into quadriceps muscle either alone or in combination, and plasmid DNA was electroporated to enhance gene expression efficiency and immunogenicity. Injection of plasmid pVIJ/CEA followed by Ad‐CEA boost elicited the highest amplitude of both CD4+ and CD8+ T‐cell response to the target antigen, measured by both IFNγ‐ELIspot assay and intracellular staining. Vectors carrying cDNA of CEAopt expressed a greater amount of the CEA protein than their wild‐type counterparts, and this enhanced expression was associated with greater immunogenicity. Both CD4+ and CD8+ T‐cell epitopes were mapped in the C‐terminal portion of the protein. In CEA transgenic mice, only immunization based on repeated injections of pVIJ/CEAopt followed by Ad‐CEAopt was able to elicit a CEA‐specific CD8+ T‐cell response, whereas the wild‐type vectors did not break tolerance to this target antigen. MC38‐CEA tumor cells injected s.c. in CEA transgenic mice vaccinated with CEAopt vectors exhibited delayed growth kinetics. These studies demonstrate that this type of genetic vaccine is highly immunogenic and can break tolerance to CEA tumor antigen in CEA transgenic mice. © 2005 Wiley‐Liss, Inc.
SCCA antigen combined with alpha‐fetoprotein as serologic markers of HCC
Authors: Giannelli Gianluigi , Marinosci Felice , Trerotoli Paolo , Volpe Anna , Quaranta Michele , Dentico Pietro , Antonaci Salvatore
Published: May 2005

Hepatocellular carcinoma (HCC) is the fifth most common cancer in the world. Because of its increased incidence in the last decade and the estimated further increase in the next 2 decades, HCC is arousing great interest. In Europe and North America, it commonly develops on cirrhotic livers, and surveillance programs have therefore been suggested to identify early HCC, at a stage when it remains suitable for surgical therapy and has a better clinical outcome. The only serologic marker used in clinical practice is α‐fetoprotein (α‐FP), but its sensitivity is poor. In our study, 120 patients with HCC and 90 patients with liver cirrhosis were investigated. We report for the first time to our knowledge that as a marker of HCC, the squamous cell carcinoma (SCCA) antigen has high sensitivity (84.2%) but low specificity (48.9%). However, the combination of α‐FP and SCCA yielded a correct serologic diagnosis in 90.83% of the HCC patients. A small percentage of patients remain undetected, likely because of the low specificity of SCCA. In conclusion, the combined use of α‐FP and SCCA antigen represents a more powerful tool for the serologic detection of HCC. © 2005 Wiley‐Liss, Inc.
Modulation of hepatic cytochromes P450 and phase II enzymes by dietary doses of sulforaphane in rats: Implications for its chemopreventive activity
Authors: Yoxall Victoria , Kentish Peter , Coldham Nick , Kuhnert Nikolai , Sauer Maurice J. , Ioannides Costas
Published: May 2005

The principal objectives of our study were to ascertain whether sulforaphane, at dietary levels of intake, modulates rat hepatic cytochrome P450 and phase II enzyme systems and to evaluate the impact of such changes in the chemopreventive activity of this isothiocyanate. Animals were exposed to sulforaphane in their drinking water for 10 days, equivalent to daily doses of 3 and 12 mg/kg. Depentylation of pentoxyresorufin decreased and was paralleled by a decline in CYP2B apoprotein levels. At the higher dose, erythromycin N‐demethylase activity declined and was accompanied by a similar decrease in CYP3A2 apoprotein levels. However, sulforaphane treatment upregulated CYP1A2 levels, determined immunologically, but the dealkylations of methoxy‐ and ethoxyresorufin were not similarly increased. Hepatic S9 preparations from sulforaphane‐treated rats were less effective than control preparations in converting IQ (2‐amino‐3‐methylimidazo‐[4,5‐f]quinoline) to mutagenic intermediates in the Ames test. To clarify the underlying mechanism, in vitro studies were undertaken. In β‐naphthoflavone‐treated rats, the inhibition by sulforaphane of the O‐dealkylations of methoxy‐ and ethoxyresorufin was enhanced if the isothiocyanate was preincubated in the presence of NADPH. It may be inferred that sulforaphane induces hepatic CYP1A2 but the enzyme is not catalytically competent because of bound sulforaphane metabolite(s). Finally, sulforaphane stimulated, in a dose‐dependent fashion, quinone reductase but failed to influence glutathione S‐transferase, epoxide hydrolase and glucuronosyl transferase activities. It is concluded that, even at dietary doses, sulforaphane can modulate the xenobiotic‐metabolising enzyme systems, shifting the balance of carcinogen metabolism toward deactivation, and this may be an important mechanism of its chemopreventive activity. © 2005 Wiley‐Liss, Inc.
TP53 alterations and patterns of carcinogen exposure in a U.S. population‐based study of bladder cancer
Authors: Kelsey Karl T. , Hirao Tomoko , Hirao Shuya , Devi‐Ashok Tara , Nelson Heather H. , Andrew Angeline , Colt Joanne , Baris Dalsu , Morris J. Steven , Schned Alan , Karagas Margaret
Published: May 2005

The molecular pathology of bladder cancer has been the subject of considerable interest, and current efforts are targeted toward elucidating the interrelationships between individual somatic gene loss and both etiologic and prognostic factors. Mutation of theTP53gene has been associated with more invasive bladder cancer, and evidence suggests thatTP53mutation, independent of stage, may be predictive of outcome in this disease. However, there is no consensus in the literature that bladder carcinogen exposure is associated with inactivation of theTP53gene. Work to date has been primarily hospital based and, as such, subject to possible bias associated with selection of more advanced cases for study. We examined exposure relationships with bothTP53gene mutation and TP53 protein alterations in a population‐based study of 330 bladder cancer cases in New Hampshire. Tobacco smoking was not associated with TP53 alterations. We found a higher prevalence ofTP53inactivation (i.e.,mutation and nuclear accumulation) among hair dye users (odd ratio [OR] = 4.1; 95% confidence interval [CI] 1.2–14.7), and the majority of these mutations were transversions. Men who had “at risk” occupations were more likely to have mutatedTP53tumors (OR = 2.9; 95% CI 1.1–7.6). There also was a relative absence ofTP53mutation (OR = 0.4; 95% CI 0.0–2.9) and TP53 protein alterations (OR = 0.6; 95% CI 0.3–1.4) in bladder cancers from individuals with higher arsenic exposure. Our data suggest that there is exposure‐specific heterogeneity in inactivation of the TP53 pathway in bladder cancers and that integration of the spectrum of pathway alterations in population‐based approaches (capturing the full range of exposures to bladder carcinogens) may provide important insights into bladder tumorigenesis. © 2005 Wiley‐Liss, Inc.
Combination therapy with tumor‐lysate pulsed dendritic cells and antiangiogenic drug TNP‐470 for mouse pancreatic cancer
Authors: Miyazaki Junichi , Tsuzuki Yoshikazu , Matsuzaki Koji , Hokari Ryota , Okada Yoshikiyo , Kawaguchi Atsushi , Nagao Shigeaki , Itoh Kazuro , Miura Soichiro
Published: May 2005

Most cases of pancreatic cancer are inoperable when diagnosed. Since immunotherapy and antiangiogenic therapy have been reported to be promising for pancreatic cancer, we examined whether the combination of immunotherapy with dendritic cells (DCs) and the antiangiogenic drug TNP‐470 induces tumor regression. Syngeneic mouse pancreatic adenocarcinoma cells were orthotopically inoculated into C57/BL6 mice. DCs with or without tumor lysate (TL) were administered i.p. at 4 and 5 weeks. TNP‐470 was injected s.c. into tumor‐bearing mice every other day from 4 weeks to 6 weeks. We compared anticancer effects in 6 groups: NT (no treatment), DC/TL− (DCs without TL), DC/TL+ (DCs pulsed with TL), TNP (TNP‐470 alone), DC/TL–TNP (DC/TL− plus TNP‐470) and DC/TL+TNP (DC/TL+ plus TNP‐470). We measured tumor volume, mean vascular density (MVD) and vessel diameter by FITC‐dextran using an intravital microscope; degrees of proliferation and apoptosis of cancer cells by PCNA and TUNEL; infiltrating lymphocytes and expression levels of VEGF and MMP‐9 by immunohistochemistry and immunoblotting. Tumor volume and MVD were significantly suppressed in the treatment groups with prolonged survival rate, especially in the DC/TL+TNP group. There were no significant differences in apoptosis among the 6 groups except DC/TL+. The number of infiltrating CD4+ cells in the DC/TL+ group was higher than that in the NT group. VEGF expression was significantly suppressed in the treatment groups containing TNP‐470, and MMP‐9 was also suppressed in the groups containing DC/TL+. Our data suggested that TL‐pulsed DCs combined with TNP‐470 induced regression of mouse pancreatic cancer, possibly through induction of immune responses and suppression of angiogenesis. © 2005 Wiley‐Liss, Inc.
HLA class II allele control of HPV load in carcinoma in situ of the cervix uteri
Authors: Beskow Anna H. , Moberg Martin , Gyllensten Ulf B.
Published: May 2005

Human papillomavirus (HPV) infection is the most important risk factor for development of cervical carcinoma. Carriers of certain HLA class II alleles, e.g., DRB1*1501 and DQB1*0602, are more prone to HPV 16 infection and cervical carcinoma, whereas other alleles, e.g., DRB1*1301 and DQB1*0603, render carriers less susceptible to the disease. In our study comprising 484 cases and 601 controls, we examine the effect of HLA class II alleles on viral load of the oncogenic types HPV 18/45 and HPV 31 and risk of developing cervical carcinoma in situ. We find that carriers of the commonly reported protective DRB1*1301 and DQB1*0603 alleles have lower HPV 18/45 load compared to noncarriers and a lower risk of developing HPV 18/45‐positive cervical carcinoma. This provides further evidence that the HLA class II‐mediated immune response to HPV is important for controlling viral load and outcome of an infection. © 2005 Wiley‐Liss, Inc.