bluuebunny/crossref_metadata_2025 huggingface dataset:
Effectiveness of Routine Visits and Routine Tests in Detecting Isolated Locoregional Recurrences After Treatment for Early-Stage Invasive Breast Cancer: A Meta-Analysis and Systematic Review
Authors: de Bock G.H. , Bonnema J. , van Der Hage J. , Kievit J. , van de Velde C.J.H.
Published: September 2004

Purpose

To review the effectiveness of routine visits and routine tests in detecting isolated locoregional recurrences in asymptomatic patients after treatment for early-stage invasive breast cancer.

Methods

Systematic review and meta-analysis. The proportion of isolated locoregional recurrences diagnosed during routine visits or routine tests in asymptomatic patients was compared with the proportion of isolated locoregional recurrences in symptomatic patients.

Results

Twelve studies that involved a total of 5,045 patients and 378 isolated locoregional recurrences were identified. Pooling data showed an overall estimate of 40% of isolated locoregional recurrences diagnosed during routine visits or routine tests in asymptomatic patients (95% CI, 35 to 45). Of these, 47% (95% CI, 39 to 54) were diagnosed after mastectomy, and 36% (95% CI, 28 to 43) were diagnosed after breast-conserving therapy (relative risk, 1.327; 95% CI, 1.014 to 1.738). Apart from differences in therapy, we have not been able to discern subgroups of patients for whom results were different.

Conclusion

Approximately 40% of isolated locoregional recurrences are diagnosed during routine visits and routine tests in asymptomatic patients treated for early-stage invasive breast cancer. We could not assess whether these were detected by either physical examination or other tests, nor if the detection of asymptomatic isolated recurrences had any influence on potential for cure or quality of life. As the overall quality of the included studies and the overall incidence of isolated locoregional recurrences are low, this systematic review highlights the need for prospective comparative studies on cost-effective strategies for the follow-up of patients after a diagnosis of breast cancer.
Is Baseline Quality of Life Useful for Predicting Survival With Hormone-Refractory Prostate Cancer? A Pooled Analysis of Three Studies of the European Organisation for Research and Treatment of Cancer Genitourinary Group
Authors: Collette Laurence , van Andel George , Bottomley Andrew , Oosterhof Gosse O.N. , Albrecht Walter , de Reijke Theo M. , Fossà Sophie D.
Published: September 2004

Purpose

Patients with symptomatic metastatic hormone-resistant prostate cancer (HRPC) survive a median of 10 months and are often regarded as a homogeneous group. Few prognostic factors have been identified so far. We examined whether baseline health-related quality of life (HRQOL) parameters assessed by the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire C30 (EORTC QLQ-C30) were independent prognostic factors of survival and whether they bring extra precision to the predictions achievable with models based on clinical and biochemical factors only.

Patients and Methods

Data of 391 symptomatic (bone) metastatic HRPC patients from three randomized EORTC trials were used in multivariate Cox proportional hazards models. The significance level was set at α = .05.

Results

Of the 391 patients, 371 died, most of prostate cancer. Bone scan result, performance status, hemoglobin level, and insomnia and appetite loss as measured by the EORTC QLQ-C30 were independent predictors of survival. This model's area under the receiver operating curve was 0.65 compared with 0.63 without the two HRQOL factors.

Conclusion

Certain HRQOL sores, at baseline, seem to be predictors for duration of survival in HRPC. However, such measurements do not add to the predictive ability of models based only on clinical and biochemical factors.
Scintigraphic Response by 123I-Metaiodobenzylguanidine Scan Correlates With Event-Free Survival in High-Risk Neuroblastoma
Authors: Katzenstein Howard M. , Cohn Susan L. , Shore Richard M. , Bardo Dianna M.E. , Haut Paul R. , Olszewski Marie , Schmoldt Jennifer , Liu Dachao , Rademaker Alfred W. , Kletzel Morris
Published: September 2004

Purpose

To investigate whether response to induction therapy, evaluated by metaiodobenzylguanadine (MIBG) and bone scintigraphy, correlates with event-free survival (EFS) in children with high-risk neuroblastoma (NB).

Patients and Methods

Twenty-nine high-risk NB patients were treated prospectively with an intensive induction regimen and consolidated with three cycles of high-dose therapy with peripheral blood stem-cell rescue. The scintigraphic response was evaluated by MIBG and bone scans using a semi-quantitative scoring system. The prognostic significance of the imaging scores at diagnosis and following induction therapy was evaluated.

Results

A trend associating worse 4-year EFS rates for patients with versus without osteomedullary uptake on MIBG scintigraphs at diagnosis was seen (35% ± 11% v 80% ± 18%, respectively; P = .13). Similarly, patients with positive bone scans at diagnosis had worse EFS than those with negative scans, although the difference did not receive statistical significance (34% ± 10% v 83% ± 15%, respectively; P = .06). However, significantly worse EFS was observed in patients with a postinduction MIBG score of ≥ 3 compared to those with scores of less than 3 (0% v 58% ± 11%; P = .002). There was no correlation between bone scan scores and outcome following induction therapy.

Conclusion

MIBG scores ≥ 3 following induction therapy identifies a subset of NB patients who are likely to relapse following three cycles of high-dose therapy with peripheral blood stem-cell rescue, local radiotherapy, and 13-cis-retinoic acid. Alternative therapeutic strategies should be considered for patients with a poor response to induction therapy.
Pharmacogenetic Risk Factors for Osteonecrosis of the Hip Among Children With Leukemia
Authors: Relling Mary V. , Yang Wenjian , Das Soma , Cook Edwin H. , Rosner Gary L. , Neel Michael , Howard Scott , Ribeiro Raul , Sandlund John T. , Pui Ching-Hon , Kaste Sue C.
Published: September 2004

Purpose

One of the adverse effects of therapy for acute lymphoblastic leukemia (ALL) is osteonecrosis of the hip. Putative risk factors for osteonecrosis have included being female, white race, and older age. Our goal was to define possible genetic risk factors for osteonecrosis among children treated for newly diagnosed ALL.

Methods

Using a candidate gene approach, we determined the genotypes for 16 common polymorphisms in genes likely to affect the pharmacokinetics or pharmacodynamics of antileukemic medications in 64 children with ALL. Therapy included glucocorticoids and antifolates. Magnetic resonance imaging of both hips was used to diagnose osteonecrosis, and was performed at similar times from the start of ALL therapy (P = .61) in the 25 patients with and the 39 patients without osteonecrosis (median, 447 days and 443 days, respectively).

Results

In addition to age older than 10 years (odds ratio [OR], 24.2; P = .0001) and white race (OR, 11.1; P = .037), host factors for osteonecrosis included the vitamin D receptor FokI start site CC genotype (OR, 4.5; P = .045), and the thymidylate synthase low activity 2/2 enhancer repeat genotype (OR, 7.4; P = .049).

Conclusion

Because folate-related and vitamin D–receptor genetic variants have been associated with bone and vasculature morbidity, these pharmacogenetic associations likely reflect the interaction of antileukemic medications with germline sensitivity to drug actions, and might identify ALL patients at highest risk to develop osteonecrosis.
Microarray Gene Expression Profiling of B-Cell Chronic Lymphocytic Leukemia Subgroups Defined by Genomic Aberrations and VH Mutation Status
Authors: Haslinger Christian , Schweifer Norbert , Stilgenbauer Stephan , Döhner Hartmut , Lichter Peter , Kraut Norbert , Stratowa Christian , Abseher Roger
Published: September 2004

Purpose

Genomic aberrations and mutational status of the immunoglobulin variable heavy chain (VH) gene have been shown to be among the most important predictors for outcome in patients with B-cell chronic lymphocytic leukemia (B-CLL). In this study, we report on differential gene expression patterns that are characteristic for genetically defined B-CLL subtypes.

Materials and Methods

One hundred genetically well-characterized B-CLL samples, together with 11 healthy control samples, were analyzed using oligonucleotide arrays, which test for the expression of some 12,000 human genes.

Results

Aiming at microarray-based subclassification, class predictors were constructed using sets of differentially expressed genes, which yielded in zero or low misclassification rates. Furthermore, a significant number of the differentially expressed genes clustered in chromosomal regions affected by the respective genomic losses/gains. Deletions affecting chromosome bands 11q22-q23 and 17p13 led to a reduced expression of the corresponding genes, such as ATM and p53, while trisomy 12 resulted in the upregulation of genes mapping to chromosome arm 12q. Using an unsupervised analysis algorithm, expression profiling allowed partitioning into predominantly VH-mutated versus unmutated patient groups; however, association of the expression profile with the VH mutational status could only be detected in male patients.

Conclusion

The finding that the most significantly differentially expressed genes are located in the corresponding aberrant chromosomal regions indicates that a gene dosage effect may exert a pathogenic role in B-CLL. The significant difference in the partitioning of male and female B-CLL samples suggests that the genomic signature for the VH mutational status might be sex-related.
Transdifferentiation of the retina into pigmented cells in ocular retardation mice defines a new function of the homeodomain geneChx10
Authors: Rowan Sheldon , Chen C.-M. Amy , Young Tracy L. , Fisher David E. , Cepko Constance L.
Published: September 2004

The homeodomain transcription factor Chx10 is one of the earliest markers of the developing retina. It is required for retinal progenitor cell proliferation as well as formation of bipolar cells, a type of retinal interneuron. orJ (ocular retardation) mice, which are Chx10 null mutants, are microphthalmic and show expanded and abnormal peripheral structures, including the ciliary body. We show here, in a mixed genetic background, the progressive appearance of pigmented cells in the neural retina, concomitant with loss of expression of retinal markers. Fate mapping analysis using a multifunctional Chx10 BAC reporter mouse revealed this process to be direct transdifferentiation of retinal cells into pigmented cells. Microarray and in situ hybridization analyses revealed a complex program underlying the transdifferentiation. This program involved the expansion of expression of genes normally found only in the periphery into central regions of the eye. These genes included a transcription factor controlling pigmentation, Mitf, and the related factor Tfec(Tcfec – Mouse Genome Informatics), which can activate a melanogenic gene expression program. Misexpression of Chx10 in the developing retinal pigmented epithelium (RPE) caused downregulation of Mitf, Tfec, and associated pigment markers, leading to a nonpigmented RPE. These data link Chx10 and Mitf to maintenance of the neural retina and RPE fates respectively. Further, they suggest a new role for Chx10 in maintenance of compartment boundaries in the peripheral retina.
Wnt signals across the plasma membrane to activate the β-catenin pathway by forming oligomers containing its receptors, Frizzled and LRP
Authors: Cong Feng , Schweizer Liang , Varmus Harold
Published: September 2004

Wnt-induced signaling via β-catenin plays crucial roles in animal development and tumorigenesis. Both a seven-transmembrane protein in the Frizzled family and a single transmembrane protein in the LRP family(LDL-receptor-related protein 5/6 or Arrow) are essential for efficiently transducing a signal from Wnt, an extracellular ligand, to an intracellular pathway that stabilizes β-catenin by interfering with its rate of destruction. However, the molecular mechanism by which these two types of membrane receptors synergize to transmit the Wnt signal is not known. We have used mutant and chimeric forms of Frizzled, LRP and Wnt proteins, small inhibitory RNAs, and assays for β-catenin-mediated signaling and protein localization in Drosophila S2 cells and mammalian 293 cells to study transmission of a Wnt signal across the plasma membrane. Our findings are consistent with a mechanism by which Wnt protein binds to the extracellular domains of both LRP and Frizzled receptors, forming membrane-associated hetero-oligomers that interact with both Disheveled (via the intracellular portions of Frizzled) and Axin (via the intracellular domain of LRP). This model takes into account several observations reported here: the identification of intracellular residues of Frizzled required forβ-catenin signaling and for recruitment of Dvl to the plasma membrane;evidence that Wnt3A binds to the ectodomains of LRP and Frizzled; and demonstrations that a requirement for Wnt ligand can be abrogated by chimeric receptors that allow formation of Frizzled-LRP hetero-oligomers. In addition,the β-catenin signaling mediated by ectopic expression of LRP is not dependent on Disheveled or Wnt, but can also be augmented by oligomerization of LRP receptors.
Tbx2 is essential for patterning the atrioventricular canal and for morphogenesis of the outflow tract during heart development
Authors: Harrelson Zachary , Kelly Robert G. , Goldin Sarah N. , Gibson-Brown Jeremy J. , Bollag Roni J. , Silver Lee M. , Papaioannou Virginia E.
Published: September 2004

Tbx2 is a member of the T-box transcription factor gene family,and is expressed in a variety of tissues and organs during embryogenesis. In the developing heart, Tbx2 is expressed in the outflow tract, inner curvature, atrioventricular canal and inflow tract, corresponding to a myocardial zone that is excluded from chamber differentiation at 9.5 days post coitus (dpc). We have used targeted mutagenesis in mice to investigate Tbx2 function. Mice heterozygous for a Tbx2 null mutation appear normal but homozygous embryos reveal a crucial role for Tbx2 during cardiac development. Morphological defects are observed in development of the atrioventricular canal and septation of the outflow tract. Molecular analysis reveals that Tbx2 is required to repress chamber differentiation in the atrioventricular canal at 9.5 dpc. Analysis of homozygous mutants also highlights a role for Tbx2 during hindlimb digit development. Despite evidence that TBX2 negatively regulates the cell cycle control genes Cdkn2a, Cdkn2b and Cdkn1a in cultured cells, there is no evidence that loss of Tbx2 function during mouse development results in increased levels of p19ARF, p16INK4a,p15INK4b or p21 expression in vivo, nor is there evidence for a genetic interaction between Tbx2 and p53.
Reelin is a positional signal for the lamination of dentate granule cells
Authors: Zhao Shanting , Chai Xuejun , Förster Eckart , Frotscher Michael
Published: September 2004

Reelin is required for the proper positioning of neurons in the cerebral cortex. In the reeler mutant lacking reelin, the granule cells of the dentate gyrus fail to form a regular, densely packed cell layer. Recent evidence suggests that this defect is due to the malformation of radial glial processes required for granule cell migration. Here, we show that recombinant reelin in the medium significantly increases the length of GFAP-positive radial glial fibers in slice cultures of reeler hippocampus, but does not rescue either radial glial fiber orientation or granule cell lamination. However, rescue of radial glial fiber orientation and granule cell lamination was achieved when reelin was present in the normotopic position provided by wild-type co-culture, an effect that is blocked by the CR-50 antibody against reelin. These results indicate a dual function of reelin in the dentate gyrus,as a differentiation factor for radial glial cells and as a positional cue for radial fiber orientation and granule cell migration.
A phylogenetically conserved cis-regulatory module in theMsx2promoter is sufficient for BMP-dependent transcription in murine andDrosophilaembryos
Authors: Brugger Sean M. , Merrill Amy E. , Torres-Vazquez Jesus , Wu Nancy , Ting Man-Chun , Cho Jane Y.-M. , Dobias Sonia L. , Yi Soyun E. , Lyons Karen , Bell Jeffery R. , Arora Kavita , Warrior Rahul , Maxson Robert
Published: September 2004

To understand the actions of morphogens, it is crucial to determine how they elicit different transcriptional responses in different cell types. Here,we identify a BMP-responsive enhancer of Msx2, an immediate early target of bone morphogenetic protein (BMP) signaling. We show that the BMP-responsive region of Msx2 consists of a core element, required generally for BMP-dependent expression, and ancillary elements that mediate signaling in diverse developmental settings. Analysis of the core element identified two classes of functional sites: GCCG sequences related to the consensus binding site of Mad/Smad-related BMP signal transducers; and a single TTAATT sequence, matching the consensus site for Antennapedia superclass homeodomain proteins. Chromatin immunoprecipitation and mutagenesis experiments indicate that the GCCG sites are direct targets of BMP restricted Smads. Intriguingly, however, these sites are not sufficient for BMP responsiveness in mouse embryos; the TTAATT sequence is also required. DNA sequence comparisons reveal this element is highly conserved in Msx2promoters from mammalian orders but is not detectable in other vertebrates or non-vertebrates. Despite this lack of conservation outside mammals, the Msx2 BMP-responsive element serves as an accurate readout of Dpp signaling in a distantly related bilaterian – Drosophila. Strikingly, in Drosophila embryos, as in mice, both TTAATT and GCCG sequences are required for Dpp responsiveness, showing that a common cis-regulatory apparatus can mediate the transcriptional activation of BMP-regulated genes in widely divergent bilaterians.
Germline stem cells in theDrosophilaovary descend from pole cells in the anterior region of the embryonic gonad
Authors: Asaoka Miho , Lin Haifan
Published: September 2004

A fundamental yet unexplored question in stem cell biology is how the fate of tissue stem cells is initially determined during development. In Drosophila, germline stem cells (GSCs) descend from a subset of primordial germ cells (PGCs) at the onset of oogenesis. GSC determination may occur at the onset of oogenesis when a subset of PGCs is induced to become GSCs by contacting niche cells. Alternatively, the GSC fate could be predetermined for a subset of PGCs before oogenesis, due to either their interaction with specific somatic cells in the embryonic/larval gonads, or their inherently heterogeneous potential in becoming GSCs, or both. Here, we show that anterior somatic cells in the embryonic gonad already differ from posterior somatic cells and are likely to be the precursors of niche cells in the adult ovary. Furthermore, only pole cells in the anterior half of the embryonic gonad give rise to the PGCs that frequently acquire contact with nascent niche cells in the late larval ovary. Eventually, only these contacting PGCs become GSCs, whereas non-contacting PGCs directly differentiate into cystoblasts. The strong preference of these `anterior PGCs'towards contacting niche cells does not require DE-cadherin-mediated adhesion and is not correlated with either orientation or rate of their divisions. These data suggest that the GSC fate is predetermined before oogenesis. The predetermination probably involves soma/pole-cell interaction in the anterior half of the embryonic gonad, followed by an active homing mechanism during PGC proliferation to maintain the contact between the `anterior PGCs' and anterior somatic cells.
Drosophilahomeodomain protein Nkx6 coordinates motoneuron subtype identity and axonogenesis
Authors: Broihier Heather T. , Kuzin Alexander , Zhu Yi , Odenwald Ward , Skeath James B.
Published: September 2004

The regulatory networks acting in individual neurons to control their stereotyped differentiation, connectivity, and function are not well understood. Here, we demonstrate that homeodomain protein Nkx6 is a key member of the genetic network of transcription factors that specifies neuronal fates in Drosophila. Nkx6 collaborates with the homeodomain protein Hb9 to specify ventrally projecting motoneuron fate and to repress dorsally projecting motoneuron fate. While Nkx6 acts in parallel with hb9 to regulate motoneuron fate, we find that Nkx6 plays a distinct role to promote axonogenesis, as axon growth of Nkx6-positive motoneurons is severely compromised in Nkx6 mutant embryos. Furthermore, Nkx6 is necessary for the expression of the neural adhesion molecule Fasciclin III in Nkx6-positive motoneurons. Thus, this work demonstrates that Nkx6 acts in a specific neuronal population to link neuronal subtype identity to neuronal morphology and connectivity.
Zebrafish and fly Nkx6 proteins have similar CNS expression patterns and regulate motoneuron formation
Authors: Cheesman Sarah E. , Layden Michael J. , Von Ohlen Tonia , Doe Chris Q. , Eisen Judith S.
Published: September 2004

Genes belonging to the Nkx, Gsh and Msx families are expressed in similar dorsovental spatial domains of the insect and vertebrate central nervous system (CNS), suggesting the bilaterian ancestor used this genetic program during CNS development. We have investigated the significance of these similar expression patterns by testing whether Nkx6 proteins expressed in ventral CNS of zebrafish and flies have similar functions. In zebrafish, Nkx6.1 is expressed in early-born primary and later-born secondary motoneurons. In the absence of Nkx6.1, there are fewer secondary motoneurons and supernumerary ventral interneurons, suggesting Nkx6.1 promotes motoneuron and suppresses interneuron formation. Overexpression of fish or fly Nkx6 is sufficient to generate supernumerary motoneurons in both zebrafish and flies. These results suggest that one ancestral function of Nkx6 proteins was to promote motoneuron development.
Time-lapse and cell ablation reveal the role of cell interactions in fly glia migration and proliferation
Authors: Aigouy Benoît , Van de Bor Véronique , Boeglin Marcel , Giangrande Angela
Published: September 2004

Migration and proliferation have been mostly explored in culture systems or fixed preparations. We present a simple genetic model, the chains of glia moving along fly wing nerves, to follow such dynamic processes by time-lapse in the whole animal. We show that glia undergo extensive cytoskeleton and mitotic apparatus rearrangements during division and migration. Single cell labelling identifies different glia: pioneers with high filopodial,exploratory, activity and, less active followers. In combination with time-lapse, altering this cellular environment by genetic means or cell ablation has allowed to us define the role of specific cell-cell interactions. First, neurone-glia interactions are not necessary for glia motility but do affect the direction of migration. Second, repulsive interactions between glia control the extent of movement. Finally, autonomous cues control proliferation.
Interaction of Polycomb-group proteins controlling flowering inArabidopsis
Authors: Chanvivattana Yindee , Bishopp Anthony , Schubert Daniel , Stock Christine , Moon Yong-Hwan , Sung Z. Renee , Goodrich Justin
Published: September 2004

In Arabidopsis, the EMBYRONIC FLOWER2 (EMF2), VERNALISATION2 (VRN2) and FERTILISATION INDEPENDENT ENDOSPERM2 (FIS2) genes encode related Polycomb-group (Pc-G)proteins. Their homologues in animals act together with other Pc-G proteins as part of a multimeric complex, Polycomb Repressive Complex 2 (PRC2), which functions as a histone methyltransferase. Despite similarities between the fis2 mutant phenotype and those of some other plant Pc-G members, it has remained unclear how the FIS2/EMF2/VRN2 class Pc-G genes interact with the others. We have identified a weak emf2 allele that reveals a novel phenotype with striking similarity to that of severe mutations in another Pc-G gene, CURLY LEAF (CLF), suggesting that the two genes may act in a common pathway. Consistent with this, we demonstrate that EMF2 and CLF interact genetically and that this reflects interaction of their protein products through two conserved motifs, the VEFS domain and the C5 domain. We show that the full function of CLF is masked by partial redundancy with a closely related gene, SWINGER(SWN), so that null clf mutants have a much less severe phenotype than emf2 mutants. Analysis in yeast further indicates a potential for the CLF and SWN proteins to interact with the other VEFS domain proteins VRN2 and FIS2. The functions of individual Pc-G members may therefore be broader than single mutant phenotypes reveal. We suggest that plants have Pc-G protein complexes similar to the Polycomb Repressive Complex2 (PRC2) of animals, but the duplication and subsequent diversification of components has given rise to different complexes with partially discrete functions.
Hedgehog and Decapentaplegic instruct polarized growth of cell extensions in theDrosophilatrachea
Authors: Kato Kagayaki , Chihara Takahiro , Hayashi Shigeo
Published: September 2004

The migration of cellular extensions is guided by signals from tissues with which they contact. Many axon guidance molecules regulate growth cone migration by directly regulating actin cytoskeletal dynamics. Secreted morphogens control global patterns of cell fate decisions during organogenesis through transcriptional regulation, and constitute another class of guidance molecules. We have investigated the guidance roles of the morphogens Hedgehog and Decapentaplegic during directed outgrowth of cytoplasmic extensions in the Drosophila trachea. A subset of tracheal terminal cells adheres to the internal surface of the epidermis and elongates cytoplasmic processes called terminal branches. Hedgehog promotes terminal branch spreading and its extension over the posterior compartment of the epidermis. Decapentaplegic,which is expressed at the onset of terminal branching, restricts dorsal extension of the terminal branch and ensures its monopolar growth. Orthogonal expression of Hedgehog and Decapentaplegic in the epidermis instructs monopolar extension of the terminal branch along the posterior compartment,thereby matching the pattern of airway growth with that of the epidermis.
The receptor tyrosine kinase Off-track is required for layer-specific neuronal connectivity inDrosophila
Authors: Cafferty Patrick , Yu Li , Rao Yong
Published: September 2004

The nervous system in many species consists of multiple neuronal cell layers, each forming specific connections with neurons in other layers or other regions of the brain. How layer-specific connectivity is established during development remains largely unknown. In the Drosophila adult visual system, photoreceptor (R cell) axons innervate one of two optic ganglia layers; R1-R6 axons connect to the lamina layer, while R7 and R8 axons project through the lamina into the deeper medulla layer. Here, we show that the receptor tyrosine kinase Off-track (Otk) is specifically required for lamina-specific targeting of R1-R6 axons. Otk is highly expressed on R1-R6 growth cones. In the absence of otk, many R1-R6 axons connect abnormally to medulla instead of innervating lamina. We propose that Otk is a receptor or a component of a receptor complex that recognizes a target-derived signal for R1-R6 axons to innervate the lamina layer.
Requirement for Par-6 and Bazooka inDrosophilaborder cell migration
Authors: Pinheiro Elaine M. , Montell Denise J.
Published: September 2004

Polarized epithelial cells convert into migratory invasive cells during a number of developmental processes, as well as when tumors metastasize. Much has been learned recently concerning the molecules and mechanisms that are responsible for generating and maintaining epithelial cell polarity. However,less is known about what becomes of epithelial polarity proteins when various cell types become migratory and invasive. Here, we report the localization of several apical epithelial proteins, Par-6, Par-3/Bazooka and aPKC, during border cell migration in the Drosophila ovary. All of these proteins remained asymmetrically distributed throughout migration. Moreover, depletion of either Par-6 or Par-3/Bazooka by RNAi resulted in disorganization of the border cell cluster and impaired migration. The distributions of several transmembrane proteins required for migration were abnormal following Par-6 or Par-3/Bazooka downregulation, possibly accounting for the migration defects. Taken together, these results indicate that cells need not lose apical/basal polarity in order to invade neighboring tissues and in some cases even require such polarity for proper motility.
Distinct GATA6- and laminin-dependent mechanisms regulate endodermal and ectodermal embryonic stem cell fates
Authors: Li Li , Arman Esther , Ekblom Peter , Edgar David , Murray Patricia , Lonai Peter
Published: September 2004

This study investigates the establishment of alternative cell fates during embryoid body differentiation when ES cells diverge into two epithelia simulating the pre-gastrulation endoderm and ectoderm. We report that endoderm differentiation and endoderm-specific gene expression, such as expression of laminin 1 subunits, is controlled by GATA6 induced by FGF. Subsequently,differentiation of the non-polar primitive ectoderm into columnar epithelium of the epiblast is induced by laminin 1. Using GATA6 transformed Lamc1-null endoderm-like cells, we demonstrate that laminin 1 exhibited by the basement membrane induces epiblast differentiation and cavitation by cell-to-matrix/matrix-to-cell interactions that are similar to the in vivo crosstalk in the early embryo. Pharmacological and dominant-negative inhibitors reveal that the cell shape change of epiblast differentiation requires ROCK, the Rho kinase. We also show that pluripotent ES cells display laminin receptors; hence, these stem cells may serve as target for columnar ectoderm differentiation. Laminin is not bound by endoderm derivatives; therefore, the sub-endodermal basement membrane is anchored selectively to the ectoderm, conveying polarity to its assembly and to the differentiation induced by it. Unique to these interactions is their flow through two cell layers connected by laminin 1 and their involvement in the differentiation of two epithelia from the same stem cell pool: one into endoderm controlled by FGF and GATA6; and the other into epiblast regulated by laminin 1 and Rho kinase.
A vertebrate crossveinless 2 homologue modulates BMP activity and neural crest cell migration
Authors: Coles Edward , Christiansen Jeff , Economou Androulla , Bronner-Fraser Marianne , Wilkinson David G.
Published: September 2004

Previous work has revealed that proteins that bind to bone morphogenetic proteins (BMPs) and inhibit their signalling have a crucial role in the spatial and temporal regulation of cell differentiation and cell migration by BMPs. We have identified a chick homologue of crossveinless 2, a Drosophila gene that was identified in genetic studies as a promoter of BMP-like signalling. Chick Cv-2 has a conserved structure of five cysteine-rich repeats similar to those found in several BMP antagonists, and a C-terminal Von Willebrand type D domain. Cv-2 is expressed in the chick embryo in a number of tissues at sites at which elevated BMP signalling is required. One such site of expression is premigratory neural crest, in which at trunk levels threshold levels of BMP activity are required to initiate cell migration. We show that, when overexpressed, Cv-2 can weakly antagonise BMP4 activity in Xenopus embryos, but that in other in vitro assays Cv-2 can increase the activity of co-expressed BMP4. Furthermore, we find that increased expression of Cv-2 causes premature onset of trunk neural crest cell migration in the chick embryo, indicative of Cv-2 acting to promote BMP activity at an endogenous site of expression. We therefore propose that BMP signalling is modulated both by antagonists and by Cv-2 that acts to elevate BMP activity.
Canonical Wnt activity regulates trunk neural crest delamination linking BMP/noggin signaling with G1/S transition
Authors: Burstyn-Cohen Tal , Stanleigh Jonathan , Sela-Donenfeld Dalit , Kalcheim Chaya
Published: September 2004

Delamination of premigratory neural crest cells depends on a balance between BMP/noggin and on successful G1/S transition. Here, we report that BMP regulates G1/S transition and consequent crest delamination through canonical Wnt signaling. Noggin overexpression inhibits G1/S transition and blocking G1/S abrogates BMP-induced delamination; moreover, transcription of Wnt1 is stimulated by BMP and by the developing somites, which concomitantly inhibit noggin production. Interfering with β-catenin and LEF/TCF inhibits G1/S transition, neural crest delamination and transcription of various BMP-dependent genes, which include Cad6B, Pax3 and Msx1, but not that of Slug,Sox9 or FoxD3. Hence, we propose that developing somites inhibit noggin transcription in the dorsal tube, resulting in activation of BMP and consequent Wnt1 production. Canonical Wnt signaling in turn stimulates G1/S transition and generation of neural crest cell motility independently of its proposed role in earlier neural crest specification.
Book Reviews
Authors: Redouane Rabia , Ringrose Priscilla , Redouane Rabia , Yee Jennifer , Waters Julia , Vogl Mary B. , Sellin Eric , Saidi Redouan , Poole Sara , Mitchell Samia , Magedera-Hofhansl Hanna D. , Langford Rachael , Fiorito Giulio , Brüning Angela
Published: September 2004

L’Année de l’éclipse, Latifa Ben Mansour (2001). Paris: Calman-Lévy, 273 pp.

Women, Immigration and Identities in France, Jane Freedman and Carrie Tarr, (eds.) (2000). Oxford: Berg, 256 pp.

Une adoration, Nancy
Houston (2003). Paris: Actes Sud, 400 pp.

France in Indochina: Colonial Encounters, Nicola Cooper (2001). Oxford/New York: Berg, 240 pp.

East-West Encounters: Franco-Asian Cinema and Literature, Sylvie Blum-Reid (2003). London and New York, Wallflower
Press, 179 pp.

Francophone Post-colonial Cultures, Kamal Salhi (ed.), (2003). Lanham, MD: Lexington Books, 471 pp., pbk and hbk.

Disenchanting Les Bons Temps: Identity and Authenticity in Cajun Music and Dance, Charles J. Stivale (2003). Durham, NC and London:
Duke University Press, 217 pp.

French in and out of France: Language Policies, Intercultural Antagonisms and Dialogue, Kamal Salhi (ed.), (2002). Oxford, Bern, Berlin, Brussels, New York and Vienna: Peter Lang, 487 pp.

Experimental Nations, Réda Bensmaïa
(2003). Princeton: Princeton University Press, 215 pp.

The Politics of Frenchness in Colonial Algeria, 1930–1954, Jonathan K. Gosnell, (2002). Rochester, NY: University of Rochester Press, 234 pp.

Albert Memmi, autobiographie et autographie, Joëlle
Strike (2003). Paris: L’Harmattan, 225 pp.

Écritures Littéraires: Dictionnaire critique des oeuvres africaines de langue française, 2 vols. (vol. I, A–L; vol. II, M–Z), Pius Ngandu Nkashama (2002). New Orleans: Presses Universitaires
du Nouveau Monde, 1060 pp., Vol. I, $59.95/60 euros. Vol. II, $59.95/60 euros.

The Algerian War and the French Army: Experiences, Images, Testimonies, Martin Alexander, Martin Evans and J.F.V. Keiger (eds.), (2002). Basingstoke: Palgrave Macmillan

Soundings
in French Caribbean Writing Since 1950: The Shock of Space and Time, Mary Gallagher (2002). Oxford: Oxford University Press, 293 pp.
L’écriture de la mémoire chez Albert Bensoussan
Authors: Elbaz Robert
Published: September 2004

Les écrits autobiographiques d’Albert Bensoussan dépassent de loin les preoccupations solipsistes de l’autobiographie occidentale car ils relèvent d’une méditation ethno-historique et l’individu Bensoussan incorpore non seulement la
perte d’Alger, sa ville, mais aussi de son identité juive-berbère, et de son identité sépharade, dans le sens originel du terme, et encore plus loin dans le passé, à l’histoire du judaisme biblique. De là, la tâche acharnée
de sa mémoire répétitive obsédée par une récupération impossible qui, dans cette quête indéterminée, constitue une oeuvre multiple et variée.
El Maleh, un humaniste enraciné dans un unique paysage, le Maroc
Authors: Devergnas-Dieumegard Annie
Published: September 2004

Ce n’est qu’à l’âge de la maturité qu’Edmond Amran El Maleh publie son premier roman, Parcours immobile, qui fut immédiatement distingué au sein de la littérature maghrébine et francophone pour son originalité
et sa grande valeur littéraire. Ce premier roman jette les bases d’une oeuvre cohérente, au ton à la fois autobiographique et historique, qui constitue au fil des romans une fresque de la société juive marocaine de la première moitié du
XX° siècle. Au thème de la mort personnelle, hérité d’une enfance maladive, se superpose celui de la disparition progressive, vers le milieu du siècle, de cette communauté. Mais c’est surtout le style d’écriture d’Edmond
Amran El Maleh qui est remarquable; achronique, métaphorique, proche de l’oralité, à la ponctuation rare, il donne aux faits historiques relatés un caractère de déroutante subjectivité. Cette étude cherche à montrer comment
cet auteur singulier - dont la biographie ne peut se séparer de l’oeuvre - s’approprie l’écriture comme unique moyen de maintenir vivants tant son propre passé, que la mémoire de la communauté juive marocaine aujourd’hui disparue.
L’aventure collective des voix littéraires sépaharades au Canada
Authors: Redouane Najib
Published: September 2004

Le but de cette étude est de montrer que les deux textes examinés Le Goût des confitures by Bob Oré Abitbol et Tangers, les miens et les autres de Mary Abécassis Obadia, indépendamment des styles, d’intention identique, ont
pour source une mémoire collective, l’exil et le désir d’intégration dans un nouveau pays d’accueil. L’aventure de l’écriture devient ainsi partie d’une volonté plus vaste où ce qui est en jeu n’est rien d’autre
que l’affirmation d’une identité francophone et judéo-sépharade au sein d’un pays qui témoigne d’un pluralisme ethnique et culturel.
Jacob, Ménahem et Mimoun: une épopée familiale. Poétique de l’identité chez Marcel Bénabou
Authors: Bornier Evelyne M.
Published: September 2004

Homme des deux rives, Marcel Bénabou à un double devoir d’allégeance: aux origines marocaines et à son identité confessionnelle d’une part et à sa terre d’accueil, la France, d’autre part. Cette appartenance à
deux cultures distinctes et opposées est ce qui va, entre autres, devenir l’un des thèmes centraux des textes de l’auteur qui se trouve, comme il l’explique lui-même en ‘situation de décalage’. A travers le roman qui nous intéresse,
Jacob, Ménahem et Mimoun: une épopée familiale, nous étudierons comment Bénabou tente de rendre hommage aux Juifs marocains par le biais de l’écriture et dans quelle mesure cette écriture lui est impossible.
Judéités, à lire dans l’oeuvre d’Hélène Cixous
Authors: Stevens Christa
Published: September 2004

Dans ses publications récentes, Hélène Cixous, née en 1937 en Algérie coloniale, interroge le rôle destinal qu’ont joué ses origines juives, doublement séfarade et ashkénaze. Dans sa recherche autobiographique, elle
s’occupe certes de questions de l’histoire et de l’appartenance, mais elle s’intéresse surtout aux langages et aux discours qui constituent la judéité. La judéité étant dès lors un sujet à lire, cet article se
propose de suivre certains signifiants à partir desquels ou contre lesquels l’auteur énonce son identité juive.
Bisphosphonates: Preclinical Review
Authors: Green Jonathan R.
Published: September 2004

Learning Objectives

After completing this course, the reader will be able to:

Describe the mechanism of action of first-generation and nitrogen-containing bisphosphonates. Explain how the mechanism of action of the bisphosphonates might directly affect tumor growth. Discuss how the bisphosphonates might be incorporated into both the prevention and treatment of cancer.

Access and take the CME test online and receive 1 hour of AMA PRA category 1 credit at CME.TheOncologist.com

Bisphosphonates effectively inhibit osteoclast-mediated bone resorption and are integral in the treatment of benign and malignant bone diseases. The evolution of bisphosphonates over the past 30 years has led to the development of nitrogen-containing bisphosphonates (N-BPs), which have a mechanism of action different from that of the nonnitrogen-containing bisphosphonates. Studies conducted over the past decade have elucidated the mechanism of action and pharmacologic properties of the N-BPs. N-BPs exert their effects on osteoclasts and tumor cells by inhibiting a key enzyme in the mevalonate pathway, farnesyl diphosphate synthase, thus preventing protein prenylation and activation of intracellular signaling proteins such as Ras. Recent evidence suggests that N-BPs also induce production of a unique adenosine triphosphate analogue (Apppi) that can directly induce apoptosis. Our increased understanding of the pharmacologic effects of bisphosphonates is shedding light on the mechanisms by which they exert antitumor effects. As a result of their biochemical effects on protein prenylation, N-BPs induce caspase-dependent apoptosis, inhibit matrix metalloproteinase activity, and downregulate αvβ3 and αvβ5 integrins. In addition, zoledronic acid (Zometa®; Novartis Pharmaceuticals Corp.; East Hanover, NJ and Basel, Switzerland) exerts synergistic antitumor activity when combined with other anticancer agents. Zoledronic acid also inhibits tumor cell adhesion to the extracellular matrix and invasion through Matrigel™ and has antiangiogenic activity. A growing body of evidence from animal models demonstrates that zoledronic acid and other bisphosphonates can reduce skeletal tumor burden and prevent metastasis to bone. Further studies are needed to fully elucidate these biochemical mechanisms and to determine if the antitumor potential of bisphosphonates translates to the clinical setting.
Toward New Horizons: The Future of Bisphosphonate Therapy
Authors: Lipton Allan
Published: September 2004

Learning Objectives

After completing this course, the reader will be able to:

Discuss the role of bisphosphonates in managing bone disease in the setting of cancer and its treatment. Describe differences in treatment paradigms for bone loss as a complication of cancer and its treatment versus benign bone loss. Explain the mechanism of action of bisphosphonates in the setting of malignant bone disease.

Access and take the CME test online and receive 1 hour of AMA PRA category 1 credit at CME.TheOncologist.com

Bisphosphonate therapy has become a standard of care for patients with malignant bone disease. In addition, preclinical and preliminary clinical data suggest that bisphosphonates may prevent cancer-treatment-induced bone loss (CTIBL) and the development of malignant bone disease in patients with early-stage cancer. Patients who receive adjuvant hormonal therapy for breast cancer or androgen-deprivation therapy for prostate cancer are at an especially high risk for CTIBL because of reduced estrogenic signaling. Oral clodronate (Bonefos®; Anthra Pharmaceuticals; Princeton, NJ), oral risedronate (Actonel®; Proctor and Gamble Pharmaceuticals, Inc.; Cincinnati, OH), and i.v. zoledronic acid (Zometa®; Novartis Pharmaceuticals Corp.; East Hanover, NJ) have all demonstrated promise in preventing CTIBL in patients receiving hormonal therapy for breast cancer. Zoledronic acid has demonstrated efficacy with the longest between-treatment interval (3–6 months) and is currently being investigated in the Zometa®/Femara® Adjuvant Synergy Trials (Z-FAST and ZO-FAST in the United States and Europe, respectively). In patients receiving androgen-deprivation therapy for prostate cancer, i.v. pamidronate (Aredia®; Novartis Pharmaceuticals Corp.) and i.v. zoledronic acid both have demonstrated significant benefits over placebo, but only zoledronic acid produced significant increases in bone mineral density compared with baseline values. Additionally, bisphosphonates have demonstrated antitumor activities in preclinical models, and clinical trials with oral clodronate suggest that bisphosphonates might prevent or delay bone metastasis in patients with early-stage breast cancer. Clinical trials are investigating the effect of zoledronic acid on disease progression in patients with breast cancer, prostate cancer, and non-small cell lung cancer. The results of these clinical trials should further define the clinical benefit of bisphosphonates in the oncology setting.
Dielectric Properties of Pure (BaSr)TiO3 and Composites with Different Grain Sizes Ranging from the Nanometer to the Micrometer
Authors: Hornebecq V. , Huber C. , Maglione M. , Antonietti M. , Elissalde C.
Published: September 2004

Starting with a BST (Ba0.6Sr0.4TiO3) nanopowder with a mean diameter of about 50 nm, the average grain size increases from the nanometer to the micrometer range (from 70 nm to 1–2 μm) by thermal annealing between 700 and 1400 °C. The dielectric properties of these pressed powders has been determined, showing that the temperature of transition decreases with grain size. In order to check this evolution in dense ceramics in which the grain size is conserved, composite materials based on ferroelectric nanograins and a non‐ferroelectric matrix have been prepared. Core–shell composites with different core sizes (150 and 50 nm) were synthesized in this way and the results obtained confirmed the decrease of the transition temperature with grain size, from 290 to 230 K respectively. Furthermore, dielectric losses are very weak in these core–shell composites—at between 0.1 and 1 % in the temperature range 150–450 K and the frequency range 1 × 103–1 × 105 Hz. Ferroelectric nanograins of BST were also incorporated into silica gel for comparison with the core–shell materials. Even for a high fraction of BST (approx. 75 %), the properties of the grains are masked by the presence of silica, which possesses a very low dielectric constant. This study has allowed the possible determination of the macroscopic dielectric properties in nanostructured ceramics.
A Ferroelectric Ferromagnetic Composite Material with Significant Permeability and Permittivity
Authors: Qi X. , Zhou J. , Yue Z. , Gui Z. , Li L. , Buddhudu S.
Published: September 2004

Composite materials containing both ferroelectric and ferromagnetic phases have been synthesized from nanometer‐sized powders of BaTiO3 (ferroelectric phase) and NiCuZn ferrite (ferromagnetic phase) by a standard ceramic method. The coexistence of magnetic and electric hysteresis in the composite material has been observed at room temperature. Upon the application of magnetic and electric fields, the magnetization and electric polarization of the composite material can easily be tuned based on the changing BaTiO3 content of the materials studied. These composite materials exhibit both excellent dielectric and soft‐magnetic properties with a variation of the frequency. Our results strongly suggest that this composite material may be the best candidate for the development of truly integrated passive filters. Due to the combination of both inductance and capacitance in one material, the adoption of an integrated passive filter could greatly reduce the size of printed circuit boards and could efficiently suppress electromagnetic interference, thereby enabling significant miniaturization of electronic elements and devices.