bluuebunny/crossref_metadata_2025_split huggingface dataset:
Molecular characterization of FRAXB and comparative common fragile site instability in cancer cells
Authors: Arlt Martin F. , Miller Diane E. , Beer David G. , Glover Thomas W. 
Published: September 2002

AbstractThe common fragile site, FRA3B, has been shown to be a site of frequent homozygous deletions in some cancers, resulting in loss of expression of the associated FHIT gene. It has been proposed that FHIT is a tumor suppressor gene that is inactivated as a result of the instability of FRA3B in tumorigenesis. More recently, deletions at other common fragile sites, FRA7G and FRA16D, have been identified in a small number of cancer cell lines. Here, we have mapped and molecularly characterized the frequently observed common fragile site FRAXB, located at Xp22.3. Like other common fragile sites, it spans a large genomic region of approximately 500 kb. Three known genes, including the microsomal steroid sulfatase locus (STS), map within the fragile site region. We examined FRAXB and four other fragile sites (FRA3B, FRA7G, FRA7H, FRA16D), and several associated genes, for deletions and aberrant transcripts in a panel of cancer cell lines and primary tumors. Deletions within FRAXB were seen in 4/27 (14.8%) of the primary tumors and cell lines examined. Three of the 21 (14.3%) cell lines examined were characterized by loss of expression of one or more FRAXB‐associated genes. Moreover, all of the fragile sites examined were characterized by genomic deletions within the fragile site regions in one or more tumors or cell lines, including FRAXB, which is not associated with any known tumor suppressor genes or activity. Our results further support the hypothesis that common fragile sites and their associated genes are, in general, unstable in some cancer cells.
Cytogenetic clues to breast carcinogenesis
Authors: Teixeira Manuel R. , Pandis Nikos , Heim Sverre 
Published: September 2002

AbstractThe somatic mutation theory of cancer maintains that tumorigenesis is driven by genetic alterations, many of which are visible cytogenetically. We have examined breast cancer by chromosome banding analysis after short‐term culturing of tumor cells and here review our findings in 322 karyotypically abnormal samples obtained since 1992 from 256 patients. The screening capabilities of this technique enabled us to identify several cytogenetic subgroups of breast cancer, to study the intratumor heterogeneity of breast carcinomas, and to compare primary tumors with their metastases. Using chromosome abnormalities as clonality markers, we could determine on an individual basis when multiple, ipsilateral or bilateral breast, tumors were independent de novo carcinomas and when they resulted from the spreading of a single malignant clone within one breast or from one breast to the other. The distribution of chromosomal breakpoints and genomic gains and losses is clearly nonrandom in breast cancer, something that can guide further investigations using molecular methods. Based on the total dataset, we propose a multipathway model of mammary carcinogenesis that takes into consideration the genetic heterogeneity revealed by the karyotypic findings and review the karyotypic‐pathologic correlations and the possible clinical applications of the cytogenetic knowledge.
Mutations of the CHK2 gene are found in some osteosarcomas, but are rare in breast, lung, and ovarian tumors
Authors: Miller Carl W. , Ikezoe Takayuki , Krug Utz , Hofmann Wolf‐K. , Tavor Sigal , Vegesna Vijaya , Tsukasaki Kunihiro , Takeuchi Seisho , Koeffler H. Phillip 
Published: September 2002

AbstractCheckpoint genes, activated in response to DNA damage and other stresses, are frequently targeted for alteration in cancer. Checkpoint kinase 2 (CHK2, CDS1, RAD53) is activated by ataxia telangiectasia mutated (ATM) in response to γ irradiation. Activated CHK2 stabilizes TP53, and acts on other cell cycle and stress regulators. These findings place CHK2 in the middle of a pathway frequently targeted in cancer. Because of this, and the observation that CHK2 mutations are inherited in some Li‐Fraumeni cancer syndrome families, we decided to examine the role of CHK2 mutations in sporadic cancers. Exploiting the genomic sequence of chromosome 22, we looked for mutations in the exons and intron junctions of the CHK2 gene in DNA samples from 170 patients (57 osteosarcomas, 25 other sarcomas, 35 nonsmall‐cell lung, 20 ovarian, and 33 breast cancers). Missense mutations affecting the forkhead and kinase domains were detected in four osteosarcomas and in one ovarian and one lung cancer. These findings of CHK2 gene mutations are consistent with osteosarcoma being a defining tumor of Li‐Fraumeni syndrome. The occurrence of CHK2 mutations in sporadic cancers emphasizes the importance of the stress pathway which includes TP53.
Recurrence of OTT–MAL fusion in t(1;22) of infant AML‐M7
Authors: Mercher Thomas , Busson‐Le Coniat Maryvonne , Khac Florence Nguyen , Ballerini Paola , Mauchauffé Martine , Bui Hung , Pellegrino Béatrice , Radford Isabelle , Valensi Françoise , Mugneret Francine , Dastugue Nicole , Bernard Olivier A. , Berger Roland 
Published: September 2002

AbstractTranslocation t(1;22)(p13;q13) is associated with a peculiar subtype of acute megakaryocytic leukemia (M7) occurring in infants. We have recently characterized a fusion gene, OTT–MAL, resulting from this translocation. We now report three additional cases and show that this gene fusion is present in all five t(1;22) cases studied to date. Nucleotide sequence analysis of two translocation breakpoints suggests a nonhomologous end joining mechanism in the genesis of this translocation and reveals a noncanonical topoisomerase II‐like consensus sequence within the OTT gene. FISH and PCR techniques described in this work are useful for identifying t(1;22) associated with M7.
Identification of candidate liver tumor suppressor genes from human 11p11.2‐p12
Authors: Ricketts Sharon L. , Garcia Nicole F. , Betz Bryan L. , Coleman William B. 
Published: September 2002

AbstractWe have previously described a functional model for identification of human liver tumor suppressor genes in which human chromosome 11 was introduced into rat liver epithelial tumor cell lines via microcell‐mediated chromosome transfer, producing microcell hybrid (MCH) cell lines that exhibit suppression of tumorigenicity in vivo. Chromosome deletion mapping studies identified a 950‐kb region of 11p11.2‐p12 that was retained in all suppressed MCH cell lines, suggesting that this region may harbor one or more genes with liver tumor suppressor function. In this study, we generated a comprehensive transcription map of the 11p11.2‐p12 liver tumor suppressor region through examination of 142 expressed sequence tag (EST) markers among a group of suppressed MCH cell lines. Of 142 ESTs examined, 19 were localized within the 11p11.2‐p12 liver tumor suppressor region. RT‐PCR analysis of gene expression for these 19 ESTs among an index panel of suppressed MCH cell lines (n = 3) identified 11 potential candidate liver tumor suppressor genes. Examination of candidate gene expression among six additional suppressed MCH cell lines reduced the number of potential candidate genes to three (stSG30184, stSG10014, and stSG29748). Northern blot analysis of suppressed MCH cell lines and derived tumor cell lines suggested stSG30184 as the best candidate liver tumor suppressor gene. The 3.7 kb stSG30184 transcript was expressed by all suppressed MCH cell lines, but expression was extinguished coordinately with reexpression of tumorigenicity by these cells, consistent with a tumor suppressor gene. Subsequent characterization of this EST indicates that it is a novel transcript with expression in a broad range of tissue types. Further characterization of the genes identified in this study will provide a greater understanding of their role in the molecular pathogenesis of neoplastic liver disease.
Identification and functional characterization of the promoter region of the human MSH6 gene
Authors: Szadkowski Marta , Jiricny Josef 
Published: September 2002

AbstractPostreplicative mismatch repair (MMR) corrects polymerase errors arising during DNA replication. Consistent with this role, the Saccharomyces cerevisiae MMR genes MSH2, MSH6, and PMS1 were reported to be transcriptionally upregulated during late G1 phase of the cell cycle. Surprisingly, despite the high degree of conservation of the MMR system in evolution, the human MMR genes studied to date, MSH2, MLH1, and PMS2, appear to be transcribed from classical housekeeping promoters, and the amounts of the polypeptides encoded by them fluctuate little during the cell cycle. Only the amounts of the 160‐kDa MSH6 protein were reported to vary, both during development and following stimulation of cell growth. Moreover, transcription of this gene was found to be downregulated by CpG methylation of the promoter region in a subset of clones treated with alkylating agents. In an attempt to understand the molecular basis underlying these phenomena, we isolated the 5′ region of the MSH6 gene and subjected it to functional analysis. We now show that the MSH6 gene is also transcribed from a classical housekeeping gene promoter. Despite housing putative binding sites for the transcription factors AP1, NF‐κB, and MTF‐1, the MSH6 promoter failed to respond to ionizing radiation or heavy metals. Interestingly, MSH6 transcription was upregulated during late G1 phase, even though the levels of the protein remained essentially constant during the cell cycle.
Identification of cytogenetic subclasses and recurring chromosomal aberrations in AML and MDS with complex karyotypes using m‐FISH
Authors: Van Limbergen Heidi , Poppe Bruce , Michaux Lucienne , Herens Christian , Brown Jill , Noens Luc , Berneman Zwi , De Bock Robrecht , De Paepe Anne , Speleman Frank 
Published: September 2002

AbstractComplex chromosomal aberrations (CCAs) can be detected in a substantial proportion of AML and MDS patients, de novo as well as secondary or therapy‐related, and are associated with an adverse prognosis. Comprehensive analysis of the chromosomal rearrangements in these complex karyotypes has been hampered by the limitations of conventional cytogenetics. As a result, our knowledge concerning the cytogenetics of these malignancies is sparse. Here we describe a multiplex‐FISH (M‐FISH) study of CCAs in 36 patients with AML and MDS. M‐FISH generated a genome‐wide analysis of chromosomal aberrations in CCAs, establishing several cytogenetic subgroups. ‐5/5q‐ was demonstrated in the majority of patients (86%). Other rearrangements (present with or without ‐5/5q‐) included: deletion of 7q (47%), 3q rearrangements (19%), and MLL copy gain or amplification (17%). These genetic subgroups seem to display biological heterogeneity: MLL copy gain or amplification in association with 5q‐ was detected only in AML patients and was significantly associated with extremely short survival (median overall survival: 30 days, P = 0.0102). A partially cryptic t(4;5)(q31;q31), a balanced t(1;8)(p31;q22), and an unbalanced der(7)t(7;14)(q21;q13) were detected as possible new recurrent rearrangements in association with CCAs. Novel reciprocal translocations included t(5;11)(q33;p15)del(5)(q13q31) and t(3;6)(q26;q25). We conclude that AML and MDS with CCAs can be subdivided into molecular cytogenetic subclasses, which could reflect different clinical behavior and prognosis, and that three recurrent chromosomal aberrations are associated with karyotype complexity. © 2002 Wiley‐Liss, Inc.
Trisomy 8 in myelodysplasia and acute leukemia is constitutional in 15–20% of cases
Authors: Maserati Emanuela , Aprili Fiorenza , Vinante Fabrizio , Locatelli Franco , Amendola Giovanni , Zatterale Adriana , Milone Giuseppe , Minelli Antonella , Bernardi Franca , Lo Curto Francesco , Pasquali Francesco 
Published: September 2002

AbstractThe trisomy 8 found in malignancies may derive from a constitutional trisomy 8 mosaicism (CT8M), and in these cases the trisomy itself may be regarded as the first mutation in a multistep carcinogenetic process. To assess the frequency of CT8M in hematological dysplastic and neoplastic disorders with trisomy 8, an informative sample of 14 patients was collected. The data ascertained included chromosome analyses of fibroblast cultures and of PHA‐stimulated blood cultures in patients with normal blood differential count, as well as possible CT8M clinical signs. One patient showed trisomy 8 in all cell types analyzed and undoubtedly has a CT8M; a second patient consistently showed trisomy 8 in PHA‐stimulated blood cultures when no immature myeloid cells were present in blood and should be considered as having CT8M; a third patient, with Philadelphia‐positive chronic myelocytic leukemia, was more difficult to interpret, but the possibility that she had CT8M is likely. A few clinical signs of CT8M were also present in these three patients. Our data indicate that the frequency of CT8M in hematological dysplastic and neoplastic disorders with trisomy 8 is approximately 15–20%.
Comparative genomic hybridization detects genetic alterations during early stages of cervical cancer progression
Authors: Umayahara Kenji , Numa Fumitaka , Suehiro Yutaka , Sakata Aki , Nawata Shugo , Ogata Hidenobu , Suminami Yoshinori , Sakamoto Masaru , Sasaki Kohsuke , Kato Hiroshi 
Published: September 2002

AbstractInvasive cervical carcinoma is thought to arise from cervical intraepithelial neoplasm (CIN). Genetic changes that occur during progression of CIN to cervical carcinoma are poorly understood, although they appear to be directly involved in this process. We used comparative genomic hybridization (CGH) with precise microdissection and degenerate oligonucleotide primed‐polymerase chain reaction (DOP‐PCR) to detect genetic alterations in normal epithelial, CIN, and invasive carcinoma tissues colocalized in tumors from 18 patients with squamous cell carcinoma of the uterine cervix. Gains on chromosome 1 and on 3q and losses on 2q, 3p, 4, 6p, 11q, and 17p were frequent alterations found in CIN and invasive carcinoma lesions. Interestingly, several of these genetic changes were observed in preinvasive carcinoma lesions. The frequency and average number of genetic alterations corresponded directly to the extent to which the cervical carcinoma had progressed. Frequent alterations were found in more than 90% of CIN III lesions. Gains on 3q and losses on 11q were the most prevalent genetic alterations found in association with uterine cervix carcinogenesis. The common regions of alteration were 3q26.1‐q28 and 11q23‐qter. The majority of tumor samples showed variability in genetic alterations across lesion types within a single specimen.
Frequent alterations in the Wnt signaling pathway in colorectal cancer with microsatellite instability
Authors: Shimizu Yosuke , Ikeda Satoshi , Fujimori Masahiko , Kodama Shinya , Nakahara Masahiro , Okajima Masazumi , Asahara Toshimasa 
Published: September 2002

AbstractIt is generally accepted that both dysfunction of the Wnt signaling pathway, including mutations in the adenomatous polyposis coli (APC) and β‐catenin genes, and genetic instability play important roles in colorectal carcinogenesis. However, alteration of the components in the Wnt signaling pathway in colorectal cancer (CRC) with microsatellite instability (MSI) has not been elucidated. In order to assess the status of the Wnt signaling components in CRC with MSI, mutational analyses of the β‐catenin, APC, Axin 1, and T cell factor 4 (TCF4) genes were performed. Three of 33 samples had mutations in exon 3 of the β‐catenin gene and two in the APC gene. Eight mutations in seven samples were detected by single‐strand conformation polymorphism and subsequent direct sequence analysis of the entire coding region of the Axin 1 gene. Furthermore, TCF4, which is one of the transcriptional factors in the Wnt signaling pathway and has a mononucleotide repeat sequence (a nine‐ adenine repeat, (A)9) in its C‐terminal region, was mutated in 13 of the 33 samples. Thus, alteration in the Wnt signaling pathway is frequently observed in CRC with MSI, including hereditary nonpolyposis colorectal cancer, as well as in familial adenomatous polyposis and sporadic CRC without MSI. © 2002 Wiley‐Liss, Inc.
A framework for continuous design of production systems and its application in collective redesign of production line equipment
Authors: Darses Françoise 
Published: September 2002

AbstractThe continuous design of production systems is a major challenge facing companies, and one that requires organization and systematization. This article describes one of the continuous design endeavors implemented in a factory manufacturing steel tubes. We have studied the collective redesign of production line equipment. For 2 years, we followed the operations of a multioccupational group composed of the various actors involved in manufacturing (including the operators). Their task was to redesign the tools used in their production line.Our analysis is focused on the cognitive side of the activity and especially on the collective redesign processes. From the transcripts of the meetings, we have examined how the codesigners come to an agreement about the redesigned equipment. We show that the criteria spontaneously used for the evaluation of the solution are far wider (quantitatively and qualitatively) than the list of functional criteria prescribed to the codesigners for the decision‐making process. This analysis leads us to propose three conditions that have to be met to guarantee success: (a) a true systemic view of the production system must be developed by all the continuous design actors, (b) there must be support for the collective decision‐making process, and (c) new forms of knowledge must be institutionalized. © 2002 John Wiley & Sons, Inc.
Effects of the work environment and safety activities on occupational accidents in eight wood‐processing companies
Authors: Varonen Unto , Mattila Markku 
Published: September 2002

AbstractThe study was conducted at 16 wood‐processing companies in southern Finland. The companies involved were selected according to the following criteria: (a) 8 companies were to have an accident rate that was clearly below the average rate for the wood‐processing industry in the period 1985–1989, and 8 companies a rate clearly higher than the average; and (b) the companies were to form pairs engaged in the same type of activity and exhibiting different rates.Companies were divided into 2 groups. Two sawmills, 1 parquet, and 1 plywood factory with a low accident rate and 4 similar factories with a high rate were selected as “experiment companies” and received advice aimed at improving their work environment and safety activities. Eight similar companies were selected as a control group and received no advice. This study attempted to ascertain the effects of such advice on the work environment, safety activities, and occupational accidents. In addition, differences in the safety of the work environment, in safety activities, and in occupational accidents were studied in companies with a low accident rate as compared with the situation in companies with a high rate.Work environment and safety activities showed a statistically significant correlation with accident rate. The better the situation, the lower the accident rate. In the companies with a low accident rate, the work environment and safety activities were also better than in the companies with a high rate.In the period 1989–1994, the drop in the accident rate at the experiment companies was greater—to a statistically significant extent—than it was in the control group or in the wood‐processing industry as a whole. In cases where advice was given to the experiment companies with the aim of preventing particular occupational accidents, the rate of such accidents declined; there was no such trend in the control companies. By contrast, trends for other types of accidents were similar in the experiment and control companies. Changes in the accident rates of the experiment or control companies could not be explained by economic cycles or by changes either in the employees' work experience or in the duration of absences.It is highly probable that the positive trend with regard to occupational accidents in the experiment companies was related to improvement in the work environment and safety activities and that this in turn was a result of the advice given to these companies in 1990. © 2002 John Wiley & Sons, Inc.
A comparative simulation study of work processes in autonomous production cells
Authors: Schlick Christopher , Reuth Ralph , Luczak Holger 
Published: September 2002

AbstractAn approach to human‐centered design and assessment of work processes in flexible manufacturing systems with the help of dynamic task networks is presented. To model and simulate the task networks, the method of timed colored Petri Nets is used. Two task networks are developed. The first task network is a model of work processes in Autonomous Production Cells (APCs). The second task network represents work processes in conventional Computer Numerically Controlled (CNC)‐based manufacturing systems. The material processing technology is associated with 5‐axis milling. The values of attributes of task elements were acquired empirically on a fine‐grained level with reference to a sample milling order. Comparative hypotheses regarding time‐on‐task, supervisory control functions, levels of cognitive control, human error (HE), and labor division were then formulated. To test these hypotheses, several simulation experiments were conducted. The results from inferential statistics show that single‐operator APCs have a 30% higher efficiency in relation to total time‐on‐task. Moreover, the level of cognitive control is significantly shifted toward rule‐ and knowledge‐based behavior. Surprisingly, the simulation of minor HE does not demonstrate a significantly worse performance from APCs. A simulated labor division among central process planner and production operator allows an additional efficiency improvement of approximately 15%. However, the labor division has two important drawbacks: first, a sequential incompleteness of operators' task spectrum occurs; second, the operator has to cope with hierarchical task incompleteness. Finally, a sensitivity analysis was carried out to investigate the effects of varying lot sizes and number of processed orders. © 2002 John Wiley & Sons, Inc.
The role of human factors in flexibility management: A survey
Authors: Kara Sami , Kayis Berman , O'Kane Shaun 
Published: September 2002

AbstractFlexibility can be defined as the ability to respond effectively to the ever‐changing and increasing needs of the customer. For this demand to be satisfied, flexibility should be built into the total chain of acquisition, processing, and distribution stages. As a result, there is an increasing interest in flexibility and flexibility enabling mechanisms/parameters to achieve the best strategy for obtaining the right and desired output. Although quite a number of flexibility definitions and mechanisms can be found in the literature, flexibility remains poorly understood and utilized in practice. That is due to the lack of standardization in the terminology about the flexibility definitions and mechanisms.This article presents the finding of an extensive literature survey to determine the Intra flexibility mechanisms/parameters. These mechanisms/parameters are then classified, according to their contribution to the supply chain stages and their interaction with Inter Flexibility mechanisms (e.g., Organizational structure flexibility, Technology flexibility, Information system flexibility, and Human resource flexibility). In addition, the crucial role of human factors and its relationship with flexibility mechanisms are investigated, and related flexibility mechanisms are identified. © 2002 John Wiley & Sons, Inc.