bluuebunny/crossref_metadata_2025_split huggingface dataset:
Appearance of neurons and glia with respect to the wavefront during colonization of the avian gut by neural crest cells
Authors: Conner Paul J. , Focke Paul J. , Noden Drew M. , Epstein Miles L. 
Published: January 2003

AbstractThe enteric nervous system is formed by neural crest cells that migrate, proliferate, and differentiate into neurons and glia distributed in ganglia along the gastrointestinal tract. In the developing embryo some enteric crest cells cease their caudal movements, whereas others continue to migrate. Subsequently, the enteric neurons form a reticular network of ganglia interconnected by axonal projections. We studied the developing avian gut to characterize the pattern of migration of the crest cells, and the relationship between migration and differentiation. Crest cells at the leading edge of the migratory front appear as strands of cells; isolated individual crest cells are rarely seen. In the foregut and midgut, these strands are located immediately beneath the serosa. In contrast, crest cells entering the colon appear first in the deeper submucosal mesenchyme and later beneath the serosa. As the neural crest wavefront passes caudally, the crest cell cords become highly branched, forming a reticular lattice that presages the mature organization of the enteric nervous system. Neurons and glia first appear within the strands at the advancing wavefront. Later neurons are consistently located at the nodes where branches of the lattice intersect. In the most rostral foregut and in the colon, some neurons initially appear in close association with extrinsic nerve fibers from the vagus and Remak's nerve, respectively. We conclude that crest cells colonize the gut as chains of cells and that, within these chains, both neurons and glia appear close to the wavefront.© 2002 Wiley‐Liss, Inc.
Comparative genomic hybridization of 49 primary retinoblastoma tumors identifies chromosomal regions associated with histopathology, progression, and patient outcome
Authors: Lillington Debra M. , Kingston Judith E. , Coen Pietro G. , Price Elizabeth , Hungerford John , Domizio Paola , Young Bryan D. , Onadim Zerrin 
Published: January 2003

AbstractForty‐nine primary retinoblastoma (Rb) tumors were analyzed by the use of comparative genomic hybridization (CGH), and clinical/histological correlations were performed. Adverse histological factors were present in 13 patients. Chromosomal imbalance was a frequent phenomenon, seen in 96% of the tumors. Gain of 6p represented the most frequent event (69% of the tumors), whereas +1q was observed in 57%, confirming that these abnormalities are key secondary events in retinoblastoma tumor progression. Loss of 13q and 16 was significantly associated with tumors displaying adverse histo‐prognostic factors, whereas −16q was significantly associated with tumors without adverse features. In three patients who developed an extra‐ocular relapse, the tumors showed −13q and 2/3 had −5q, suggesting that these abnormalities may be associated with metastasis. Children ≥ 36 months of age at enucleation tended to have more CGH abnormalities per tumor than children < 12 months (median numbers 11 vs. 3). In addition, +1q, +13q, −16, and −16q were more frequent in children with an older age at enucleation. Identical CGH changes were found in both tumors from one patient with bilateral tumors, suggesting a common origin. It is possible that tumors displaying loss of 13q and 5q indicate those patients who may suffer an adverse outcome and who would require alternative or more intensive therapy. CGH analysis on larger cohorts and in prospective clinical trials will be invaluable in determining whether a genetic classification of retinoblastoma represents a reliable measure of prognosis. © 2003 Wiley‐Liss, Inc.
Hypermethylation‐mediated regulation of CD44 gene expression in human neuroblastoma
Authors: Yan Pu , Mühlethaler Annick , Bourloud Katia Balmas , Beck Maja Nenadov , Gross Nicole 
Published: January 2003

AbstractThe CD44 adhesion receptor is silenced in highly malignant neuroblastomas (NBs) with MYCN amplification. Because its functional expression is associated with decreased tumorigenic properties, CD44 behaves as a tumor suppressor gene in NB and other cancers. Given that the precise mechanisms responsible for CD44 silencing are not elucidated, we investigated whether CD44 expression could be regulated by DNA hypermethylation. The methylation status of CD44 gene promoter and exon 1 regions was analyzed in 12 NB cell lines and 21 clinical samples after bisulfite genomic modification, followed by PCR and single‐strand conformation polymorphism analysis and genomic sequencing. The results showed that almost all CD44‐negative cell lines displayed hypermethylation in both regions, whereas all CD44‐expressing cell lines were unmethylated. These observations correlated with the ability to restore CD44 mRNA and protein expression by treatment of CD44‐negative cells with the 5‐aza‐2′‐deoxycytidine demethylating agent. In contrast, no CD44 gene hypermethylation could be detected in 21 NB clinical samples of different stages, irrespective of CD44 expression. Although our results suggest that aberrant methylation of promoter and exon 1 regions is involved in CD44 silencing in NB cell lines, they also indicate that methylation of unidentified regulatory sequences or methylation‐independent mechanisms also control the expression of CD44 in primary NB tumors and cell lines. We therefore conclude that CD44 silencing is controlled by complex and tumor cell–specific processes, including gene hypermethylation. Further investigation of other mechanisms and genes involved in CD44 regulation will be needed before demethylation‐mediated reactivation of the CD44 gene can be considered as therapeutic strategy for neuroblastoma and perhaps other related cancers. © 2003 Wiley‐Liss, Inc.
Chromosomes that show partial loss or gain in near‐diploid tumors coincide with chromosomes that show whole loss or gain in near‐triploid tumors: Evidence suggesting the involvement of the same genes in the tumorigenesis of high‐ and low‐risk neuroblastomas
Authors: Tomioka Nobumoto , Kobayashi Hirofumi , Kageyama Hajime , Ohira Miki , Nakamura Yohko , Sasaki Fumiaki , Todo Satoru , Nakagawara Akira , Kaneko Yasuhiko 
Published: January 2003

AbstractWe performed two‐color fluorescence in situ hybridization analysis to detect the numbers of chromosomes 1 and 17, 1p deletion, and 17q gain in 177 neuroblastomas, including 101 tumors that were found by a mass‐screening program for infants. Sixty‐eight tumors with disomy 1 or tetrasomy 1 were classified as the Dis1 group, and 109 tumors with trisomy 1, pentasomy 1, or a mixed population of cells with trisomy 1 and cells with tetrasomy 1 were classified as the Tris1 group. 17q gain was the most frequent genetic event, followed by 1p deletion, and MYCN amplification in both Dis1 and Tris1 tumors. However, the incidence of all the genetic events was higher in Dis1 tumors than in Tris1 tumors. These findings suggest that Tris1 tumors are more resistant to acquiring the genetic events than are Dis1 tumors. In addition, there was an accumulation of genetic events in more advanced stages, with the exception of a high incidence of 17q gain in the stage IVS Tris1 tumors. Comparative genomic hybridization analysis, which was performed in 59 of the 177 tumors, showed that chromosomes partially lost or gained in Dis1 tumors coincided with chromosomes totally lost or gained in Tris1 tumors. Dis1 and Tris1 tumors were considered to have near‐diploid/tetraploid and near‐triploid/pentaploid chromosome numbers, respectively. These findings suggest that the same tumor‐suppressor genes or oncogenes may be involved in the development and progression of both high‐ and low‐risk neuroblastomas, and that the ploidy state of the tumor plays a fundamental role in the heterogeneous behavior. © 2003 Wiley‐Liss, Inc.
Genomic anatomy of the specific reciprocal translocation t(15;17) in acute promyelocytic leukemia
Authors: Reiter Andreas , Sauβele Susanne , Grimwade David , Wiemels Joseph L. , Segal Mark R. , Lafage‐Pochitaloff Marina , Walz Christoph , Weisser Andreas , Hochhaus Andreas , Willer Andreas , Reichert Anja , Büchner Thomas , Lengfelder Eva , Hehlmann Rüdiger , Cross Nicholas C.P. 
Published: January 2003

AbstractThe genomic breakpoints in the t(15;17)(q22;q21), associated with acute promyelocytic leukemia (APL), are known to occur within three different PML breakpoint cluster regions (bcr) on chromosome 15 and within RARA intron 2 on chromosome 17; however, the precise mechanism by which this translocation arises is unclear. To clarify this mechanism, we (i) assembled the sequence of RARA intron 2, (ii) amplified and sequenced the genomic PML‐RARA junction sequences from 37 APL patients, and (iii) amplified and sequenced the reverse RARA‐PML genomic fusion in 29 of these cases. Three significant breakpoint microclusters within RARA intron 2 were identified, suggesting that sequence‐associated or structural factors play a role in the formation of the t(15;17). There was no evidence that the location of a breakpoint in PML had any relationship to the location of the corresponding breakpoint in RARA. Although some sequence motifs previously implicated in illegitimate recombinations were found in the microcluster regions, these associations were not significant. Comparison of forward and reverse genomic junctions revealed microhomologies, deletions, and/or duplications of either gene in all but one case, in which a complex rearrangement with inversion of the PML‐derived sequence was found. These findings are consistent with the hypothesis that the t(15;17) occurs by nonhomologous recombination of DNA after processing of the double‐strand breaks by a dysfunctional DNA damage‐repair mechanism. © 2003 Wiley‐Liss, Inc.
Distinct chromosomal aberrations in sinonasal mucosal melanoma as detected by comparative genomic hybridization
Authors: van Dijk Marcory , Sprenger Sandra , Rombout Paul , Marres Henri , Kaanders Johannes , Jeuken Judith , Ruiter Dirk 
Published: January 2003

AbstractSinonasal mucosal melanomas are the most frequent mucosal melanomas and arise from melanocytes located in the nasal cavity and the paranasal sinuses. The melanoma types, cutaneous melanoma, uveal melanoma, and mucosal melanoma, differ in etiology, geographic distribution, and clinical behavior. Genetic alterations have been previously studied in cutaneous and uveal melanomas but, to the best of our knowledge, not in mucosal melanomas. Comparative genomic hybridization (CGH) was performed on 14 routinely processed sinonasal mucosal melanomas. Furthermore, ploidy analysis was performed on 11 tumors to provide complementary data on the DNA index. The CGH profiles of sinonasal mucosal melanomas show remarkably consistent alterations: chromosome arm 1q is gained in all tumors and gains of 6p and 8q are present in 93 and 57%, respectively. Comparison of CGH data with both the common variants of cutaneous melanoma and uveal melanoma revealed that sinonasal mucosal melanomas harbor a distinct pattern of chromosomal abnormalities. Ploidy analysis also showed that diploid tumors exhibit gains of 1q and alterations of chromosome 6 (3 of 3 cases tested), whereas clear‐copy gains and high‐copy gains were seen only in triploid and tetraploid tumors (6 of 8 cases tested). This indicates that alteration of chromosomes 1 and 6 may precede polyploidization and formation of clear‐copy gains and high‐copy gains. © 2003 Wiley‐Liss, Inc.
The IGFI receptor gene: A molecular target for disrupted transcription factors
Authors: Werner Haim , Roberts Charles T. 
Published: January 2003

AbstractThe biological actions of the insulin‐like growth factors, IGFI and IGFII, are mediated by their activation of the IGFI receptor (IGFIR), a transmembrane heterotetramer linked to the RAS‐RAF‐MAPK and PI3K‐PKB/AKT signal transduction cascades. The IGFIR displays potent mitogenic, antiapoptotic, and transforming activities, and is a prerequisite for oncogenic transformation. A number of transcription factors have been identified that control the expression of this gene and therefore determine, to a significant extent, the proliferative status of the cell. The purpose of this review is to summarize data showing that, under normal physiological conditions, expression of the IGFIR is under inhibitory control by a family of negative growth regulators or tumor suppressors. Cells with a reduced number of cell‐surface receptors are unable to progress through the cell cycle and remain in a postmitotic state. Loss‐of‐function mutation of tumor suppressors in certain cancers results in transcriptional derepression of the IGFIR gene, with ensuing increases in the levels of IGFIR and increased proliferative capacity. Understanding the molecular mechanisms responsible for transcriptional regulation of the IGFIR gene will prove important in designing novel therapies aimed at targeting the IGF axis. © 2003 Wiley‐Liss, Inc.
High‐resolution genomic profiling of occult micrometastatic tumor cells
Authors: Kraus Jürgen , Pantel Klaus , Pinkel Daniel , Albertson Donna G. , Speicher Michael R. 
Published: January 2003

AbstractMetastasis is responsible for most deaths from cancer. Currently, little is known about the early genetic events in the metastatic evolution. Here we describe the application of a newly developed strategy for an in‐depth characterization of genomic changes in micrometastatic cells. Unique tumor cell lines were established from bone marrow of patients with cancer of the prostate and analyzed by multiplex‐FISH (M‐FISH) and array CGH. M‐FISH revealed that the occult disseminated cells were characterized by very complex numerical and structural aberrations. Many of these aberrations resulted in chromosomal gains and losses, such as losses of 8p, 13q, and 18q and gains of 8q, 9q, 20, and the X chromosome, which are typically observed in prostate cancer. Array CGH allowed an unprecedented high‐resolution assessment of copy number changes, pinpointing commonly gained or lost regions, which should narrow down the identification of regions critically involved in metastasis. Thus, occult micrometastatic cells are now amenable to detailed analyses of their genome. Markers for prognosis and treatment decisions can now be established. © 2003 Wiley‐Liss, Inc.
Establishment of the acute myeloid leukemia cell line Kasumi‐6 from a patient with a dominant‐negative mutation in the DNA‐binding region of the C/EBPα gene
Authors: Asou Hiroya , Gombart Adrian F. , Takeuchi Seisho , Tanaka Hideo , Tanioka Maki , Matsui Hirotaka , Kimura Akiro , Inaba Toshiya , Koeffler H. Phillip 
Published: January 2003

AbstractA myeloid leukemia cell line designated Kasumi‐6 was established from the bone marrow cells of an individual with acute myeloid leukemia, subtype M2. Both the original leukemic cells and the Kasumi‐6 cell line harbor a hemizygous point mutation in the gene encoding the CCAAT/enhancer binding protein alpha (C/EBPα), a critical myeloid transcriptional factor. The C to G transition at nucleotide 1063 of the C/EBPα gene results in amino acid transition R305P in the fork or hinge region between the DNA‐binding basic region and the leucine zipper dimerization domain of the C/EBPα protein. The Kasumi‐6 cells expressed both the p42 and p30 isoforms of the C/EBPα protein endogenously, but electrophoretic mobility shift assays demonstrated an absence of C/EBPα binding to its respective site. Exogenous expression of the mutant form of C/EBPα demonstrated that it was unable to bind DNA and activate transcription from a G‐CSF receptor–luciferase reporter construct. Furthermore, coexpression of the wild‐type and mutant forms revealed that the mutant form repressed reporter gene activation by the wild type in a dose‐responsive manner. This was concomitant with a dose‐responsive decrease in wild‐type protein binding to the G‐CSF receptor C/EBP site. The data suggest that the R305P alteration confers a dominant‐negative property on the mutant C/EBPα protein whereby the mutant polypeptide heterodimerizes with the wild‐type polypeptide and prevents it from binding to DNA, thus blocking transcriptional activation. The Kasumi‐6 cell line can serve as a model to study the cellular and molecular biology of the non‐t(8;21) M2 type of myeloid leukemia and can elucidate the role of mutated C/EBPα in leukemogenesis. © 2003 Wiley‐Liss, Inc.
Robustness of inference on measured covariates to misspecification of genetic random effects in family studies
Authors: M.Pfeiffer Ruth , Hildesheim Allan , H. Gail Mitchell , Pee David , Chen Chien‐Jen , M. Goldstein Alisa , R. Diehl Scott 
Published: January 2003

AbstractFamily studies to identify disease‐related genes frequently collect only families with multiple cases. It is often desirable to determine if risk factors that are known to influence disease risk in the general population also play a role in the study families. If so, these factors should be incorporated into the genetic analysis to control for confounding. Pfeiffer et al. [2001 Biometrika 88: 933–948] proposed a variance components or random effects model to account for common familial effects and for different genetic correlations among family members. After adjusting for ascertainment, they found maximum likelihood estimates of the measured exposure effects. Although it is appealing that this model accounts for genetic correlations as well as for the ascertainment of families, in order to perform an analysis one needs to specify the distribution of random genetic effects. The current work investigates the robustness of the proposed model with respect to various misspecifications of genetic random effects in simulations. When the true underlying genetic mechanism is polygenic with a small dominant component, or Mendelian with low allele frequency and penetrance, the effects of misspecification on the estimation of fixed effects in the model are negligible. The model is applied to data from a family study on nasopharyngeal carcinoma in Taiwan. Genet Epidemiol 24:14–23, 2003. © 2003 Wiley‐Liss, Inc.
On the use of DNA pooling to estimate haplotype frequencies
Authors: Wang Shuang , Kidd Kenneth K. , Zhao Hongyu 
Published: January 2003

AbstractGenome‐wide association studies may be necessary to identify genes underlying certain complex diseases. Because such studies can be extremely expensive, DNA pooling has been introduced, as it may greatly reduce the genotyping burden. Parallel to DNA pooling developments, the importance of haplotypes in genetic studies has been amply demonstrated in the literature. However, DNA pooling of a large number of samples may lose haplotype information among tightly linked genetic markers. Here, we examine the cost‐effectiveness of DNA pooling in the estimation of haplotype frequencies from population data. When the maximum likelihood estimates of haplotype frequencies are obtained from pooled samples, we compare the overall cost of the study, including both DNA collection and marker genotyping, between the individual genotyping strategy and the DNA pooling strategy. We find that the DNA pooling of two individuals can be more cost‐effective than individual genotypings, especially when a large number of haplotype systems are studied. Genet Epidemiol 24:74–82, 2003. © 2003 Wiley‐Liss, Inc.
On a semiparametric test to detect associations between quantitative traits and candidate genes using unrelated individuals
Authors: Zhang Shuanglin , Zhu Xiaofeng , Zhao Hongyu 
Published: January 2003

AbstractAlthough genetic association studies using unrelated individuals may be subject to bias caused by population stratification, alternative methods that are robust to population stratification such as family‐based association designs may be less powerful. Recently, various statistical methods robust to population stratification were proposed for association studies, using unrelated individuals to identify associations between candidate markers and traits of interest (both qualitative and quantitative). Here, we propose a semiparametric test for association (SPTA). SPTA controls for population stratification through a set of genomic markers by first deriving a genetic background variable for each sampled individual through his/her genotypes at a series of independent markers, and then modeling the relationship between trait values, genotypic scores at the candidate marker, and genetic background variables through a semiparametric model. We assume that the exact form of relationship between the trait value and the genetic background variable is unknown and estimated through smoothing techniques. We evaluate the performance of SPTA through simulations both with discrete subpopulation models and with continuous admixture population models. The simulation results suggest that our procedure has a correct type I error rate in the presence of population stratification and is more powerful than statistical association tests for family‐based association designs in all the cases considered. Moreover, SPTA is more powerful than the Quantitative Similarity‐Based Association Test (QSAT) developed by us under continuous admixture populations, and the number of independent markers needed by SPTA to control for population stratification is substantially fewer than that required by QSAT. Genet Epidemiol 24:44–56, 2003. © 2003 Wiley‐Liss, Inc.
Correcting for nonrandom ascertainment in generalized linear mixed models (GLMMs), fitted using Gibbs sampling
Authors: Burton Paul R. 
Published: January 2003

AbstractGibbs sampling‐based generalized linear mixed models (GLMMs) provide a convenient and flexible way to extend variance components models for multivariate normally distributed continuous traits to other classes of phenotype. This includes binary traits and right‐censored failure times such as age‐at‐onset data. The approach has applications in many areas of genetic epidemiology. However, the required GLMMs are sensitive to nonrandom ascertainment. In the absence of an appropriate correction for ascertainment, they can exhibit marked positive bias in the estimated grand mean and serious shrinkage in the estimated magnitude of variance components. To compound practical difficulties, it is currently difficult to implement a conventional adjustment for ascertainment because of the need to undertake repeated integration across the distribution of random effects. This is prohibitively slow when it must be repeated at every iteration of the Markov chain Monte Carlo (MCMC) procedure. This paper motivates a correction for ascertainment that is based on sampling random effects rather than integrating across them and can therefore be implemented in a general‐purpose Gibbs sampling environment such as WinBUGS. The approach has the characteristic that it returns ascertainment‐adjusted parameter estimates that pertain to the true distribution of determinants in the ascertained sample rather than in the general population. The implications of this characteristic are investigated and discussed. This paper extends the utility of Gibbs sampling‐based GLMMs to a variety of settings in which family data are ascertained nonrandomly. Genet Epidemiol 24:24–35, 2003. © 2003 Wiley‐Liss, Inc.