bluuebunny/crossref_metadata_2025 huggingface dataset:
ERBB2, TBX2, RPS6KB1, and MYC alterations in breast tissues of BRCA1 and BRCA2 mutation carriers
Authors: Adem Camilo , Soderberg Cheryl L. , Hafner Kari , Reynolds Carol , Slezak Jeffrey M. , Sinclair Colleen S. , Sellers Thomas A. , Schaid Daniel J. , Couch Fergus , Hartmann Lynn C. , Jenkins Robert B.
Published: June 2004

Breast cancer risk is greatly increased in women who carry mutations in the BRCA1 or BRCA2 genes. Because breast cancer initiation is different between BRCA1/2 mutation carriers and women who do not carry mutations, it is possible that the mechanism of breast cancer progression is also different. Histopathologic and genetic studies have supported this hypothesis. To test this hypothesis further, we utilized a large cohort of women who underwent therapeutic mastectomy (TM) and contralateral prophylactic mastectomy (PM). From this cohort, we developed case groups of women with a family history of breast cancer with BRCA1/2 deleterious mutations, with unclassified variant alterations, and with no detected mutation and matched these cases with sporadic controls from the same TM and PM cohort. Fluorescence in situ hybridization was performed on paraffin sections by use of dual‐color probes for ERBB2/CEP17, MYC/CEP8, TBX2/CEP17, and RPS6KB1/CEP17. All malignant and benign lesions, including putative precursor lesions, were studied. The invasive cancers from deleterious mutation carriers had a higher prevalence of duplication of MYC (P = 0.006) and TBX2 (P = 0.0008) compared to controls and a lower prevalence of ERBB2 amplification (P = 0.011). Coduplication of MYC and TBX2 was common in the in situ and invasive lesions from the deleterious mutation carriers. The odds ratio of having a BRCA1/2 mutation is 31.4 (95% CI = 1.7–569) when MYC and TBX2 are coduplicated but ERBB2 is normal. Unclassified variant carriers/no mutation detected and sporadic controls had a similar prevalence of alterations, suggesting that hereditary patients with no deleterious mutations follow a progression pathway similar to that of sporadic cases. With the exception of one atypical ductal hyperplasia lesion, no putative precursor lesion showed any detectable alteration of the probes tested. There was no significant intratumoral heterogeneity of genetic alterations. Our data confirm that a specific pattern of genomic instability characterizes BRCA1/2‐related cancers and that this pattern has implications for the biology of these cancers. Moreover, our current and previous results emphasize the interaction between phenotype and genotype in BRCA1/2‐related breast cancers and that a combination of morphologic features and alterations of ERBB2, MYC, and TBX2 may better define mechanisms of tumor progression, as well as determine which patients are more likely to carry BRCA1/2 mutations. © 2004 Wiley‐Liss, Inc.
Chromosomal instability and marker chromosome evolution in oral squamous cell carcinoma
Authors: Reshmi Shalini C. , Saunders William S. , Kudla Donna M. , Ragin Camille Rose , Gollin Susanne M.
Published: June 2004

Squamous cell carcinoma of the head and neck and its subset, oral squamous cell carcinoma (OSCC), arise through a multistep process of genetic alterations as a result of exposure to environmental agents, such as tobacco smoke, alcoholic beverages, and viruses, including human papillomavirus. We and others have shown that the karyotypes of OSCC are near‐triploid and contain multiple structural and numerical abnormalities. However, despite a background of clonal chromosomal aberrations, individual cells within a culture express many nonclonal numerical and structural abnormalities, termed chromosomal instability (CIN). To evaluate CIN in oral cancer cells, we isolated clones from two OSCC cell lines and carried out classical cytogenetic analysis, fluorescence in situ hybridization using centromere‐specific probes, and spectral karyotyping. We observed variation in chromosome number within clones and between clones of the same cell line. Although similar numbers of centromeric signals for a particular chromosome were present, “homologs” of a chromosome varied structurally from cell to cell (marker chromosome evolution) as documented by classical and spectral karyotyping. In addition to the numerical chromosome variations within a clone, we observed marker chromosome evolution by structural chromosome alterations. It appears that both intrinsic structural alterations and extrinsic cytoskeletal factors influence chromosome segregation, resulting in individual tumor cells that express unique karyotypes. We show that CIN and marker chromosome evolution are essential acquired features of neoplastic cells. Proliferation of this heterogeneous cell population may provide some cells with the ability to evade standard therapies. © 2004 Wiley‐Liss, Inc.
Willingness to pay for low‐lung‐cancer‐risk cigarettes in Taiwan
Authors: Jan Man‐Ser , Fu Tsu‐Tan , Huang Chung L.
Published: June 2004

This study develops a conceptual framework based on the random utility model to estimate smokers' willingness to pay (WTP) for the hypothetical low‐lung‐cancer‐risk cigarettes in Taiwan. Following the approach taken by Viscusi (J Polit Econ 1990; 98: 1253–1269), an individual's subjective risk perception on the probability of developing lung cancer from smoking cigarettes was measured and used in the estimation of demand for safer cigarettes. Other factors that may affect a smoker's purchase decision toward the hypothetically safer cigarettes are also identified. The average WTP for one pack of low‐lung‐cancer‐risk cigarettes is estimated to be NT$44.15, which represents a 152% price increase over the average price of cigarettes currently sold in the market. Copyright © 2004 John Wiley & Sons, Ltd.
Quality management and personnel participation: Improvement teams, a solution for ISO 9000 system maintenance problems in small to medium‐sized enterprises
Authors: Prado José Carlos Prado , Fernández‐González Arturo J. , García‐Lorenzo Antonio
Published: May 2004

Nowadays, companies have not only the challenge of developing systems for quality management, but also others of promoting and assuring the improvement of quality. Personnel participation becomes the key for quality system survival and improvement in the long term. This article contains the basis of a methodology that, within the framework of the ISO 9001:2000 standard and based on an Improvement Teams Program, contributes to quality management system maintenance on the way to excellence. The main target of this methodology is the small to medium‐sized enterprise. This methodology is illustrated with a brief description of its application in a leading Spanish company in the textile‐fashion‐clothing industry. © 2004 Wiley Periodicals, Inc. Hum Factors Man 14: 221–237, 2004.
Three‐dimensional analysis of a driver‐passenger vehicle interface
Authors: Chung Sung‐Jae , Park Min‐Yong
Published: May 2004

This article presents a method of analyzing how drivers' anthropometric data are best accommodated by a specific driver‐vehicle interface. Three‐dimensional (3‐D) manikins with 18 links were developed using anthropometric data for the U.S. 95th percentile male and 5th percentile female. In addition, an adjustable seating buck was constructed to control 7 package variables. After the manikins were positioned in each driving environment, 3‐D Cartesian coordinates for the manikins' articulations were determined using a coordinate measuring machine. The data were then converted into joint angles to suggest suitable driving environments that consider appropriate driving postures. © 2004 Wiley Periodicals, Inc. Hum Factors Man 14: 269–284, 2004.
Development of a knowledge‐based system for nonpowered hand tools (Tool Expert): Part I—The scientific basis
Authors: Kayis Berman , Charoenchai Nivit
Published: May 2004

The need for developing a clear and concise guide for designing, selecting, and using hand tools would minimize if not eliminate acute–chronic trauma exposure factors and help improve efficiency, well‐being, and morale. Despite several research efforts devoted to the exploration and understanding of the interrelation between human capabilities, task requirements, nature of tasks, and ergonomically designed hand tools, there appear to be several problems in utilizing existing knowledge in practical use. One of the most important barriers is the lack of interaction of several specialists from different backgrounds. In this article, TOOL‐EXPERT, a knowledge‐based system developed to assert the ergonomical nonpowered hand tool design, selection, and use, is explained, which will provide a guideline to several users from various backgrounds. The system is designed to run in any IBM‐compatible personal computer system. Knowledge from several domains was included. The type of knowledge used in the research was selected to be a declarative knowledge. Altogether it includes 423 goals, 35 questions, and 40 rules. © 2004 Wiley Periodicals, Inc. Hum Factors Man 14: 257–268, 2004.
The lean manufacturing enterprise: An emerging sociotechnological system integration
Authors: Paez O. , Dewees J. , Genaidy A. , Tuncel S. , Karwowski W. , Zurada J.
Published: May 2004

Lean production represents a change in production system paradigm that calls for integration of the human and technological practices. This article reviews previous models of lean production that concentrated mainly on some distinct features of its philosophy, organization, and techniques and presents a framework of lean production as a sociotechnological system. The proposed framework provides an integrated view based on the interactions of human and technological elements. The lean enterprise is viewed as a dynamic process that translates its goals (zero waste, flow, and pull) into combined techniques that should be implemented throughout the entire organization. © 2004 Wiley Periodicals, Inc. Hum Factors Man 14: 285–306, 2004.
Learning modulation by endogenous hippocampal IL‐1: Blockade of endogenous IL‐1 facilitates memory formation
Authors: Depino Amaicha M. , Alonso Mariana , Ferrari Carina , del Rey Adriana , Anthony Daniel , Besedovsky Hugo , Medina Jorge H. , Pitossi Fernando
Published: May 2004

The interleukin‐1 (IL‐1) cytokine family (IL‐1α, IL‐β, and the IL‐1 receptor antagonist) is involved in immune and inflammatory responses both in the brain and in the periphery. Recently, it has also been shown to influence behavior and memory consolidation. However, within the experimental systems studied, it has remained unclear whether the role of IL‐1β is associated solely with a pathophysiological process or whether it is a neuromodulator in normal adult brain. To evaluate the involvement of the nonpathological endogenous IL‐1 system in learning, we studied the expression of IL‐1α, IL‐1β, and IL‐1ra during memory consolidation. We observed a learning‐specific hippocampal IL‐1α mRNA induction, but not that of IL‐1β or IL‐1ra mRNAs, after inhibitory avoidance training. Moreover, when IL‐1 receptor activity was inhibited using an adenoviral vector that expresses the IL‐1 receptor antagonist (IL‐1ra) in the hippocampus, both short‐term and long‐term memory retention scores were facilitated. In contrast, endogenous hippocampal IL‐1 played no role in the habituation to a novel environment. These results demonstrate that endogenous hippocampal IL‐1 specifically modulates a fear‐motivated learning task, and suggest that IL‐1α activity in the CNS is part of the hippocampal memory processing. © 2003 Wiley‐Liss, Inc.
Intrinsic vesicular glutamate transporter 2‐immunoreactive input to septohippocampal parvalbumin‐containing neurons: Novel glutamatergic local circuit cells
Authors: Hajszan Tibor , Alreja Meenakshi , Leranth Csaba
Published: May 2004

Glutamatergic influence on the medial septum diagonal band of Broca complex (MSDB) is a crucial and powerful driver of hippocampal theta rhythm and associated memory processes, in the rat. The recent discovery of vesicular glutamate transporters (VGLUT) provided a specific marker for glutamatergic neuronal elements. Therefore, this study aimed to address two specific questions: (1) do glutamatergic axons innervate MSDB γ‐aminobutyric acid (GABA)ergic, parvalbumin (PV)‐containing septohippocampal neurons that are known to have a great influence on the electric activity of the hippocampus; and (2) is the origin of these glutamatergic axons extrinsic and/or intrinsic to the septum. The results of the correlated light and electron microscopic double‐labeling immunohistochemistry for VGLUT2 and PV, and single immunostaining for VGLUT2 in colchicine‐treated animals, showed that (1) VGLUT2‐containing boutons establish asymmetric synaptic contacts with PV‐positive perikarya and dendrites; (2) a large population of VGLUT2‐immunoreactive neurons is located primarily in the posterior division of the septum; and (3) following surgical fimbria/fornix transection and septal undercut, most VGLUT2‐containing axons, including those terminating on MSDB PV cells, remains intact. The latter two observations suggest that the major portion of MSDB glutamate axons have an intraseptal origin and raise a novel functional aspect of glutamatergic cells as local circuit neurons. A constant impulse flow in the septohippocampal GABA pathway is essential for the generation of theta rhythm. Thus, the heavy glutamatergic innervation of these septohippocampal GABA cells establishes the morphological basis for the powerful glutamatergic influence upon theta rhythm and hippocampus‐associated memory processes. © 2004 Wiley‐Liss, Inc.
In support of universalistic models of managerial and leadership effectiveness: Implications for HRD research and practice
Authors: Hamlin Robert G.
Published: June 2004

Various researchers have recently challenged “contingent” models of managerial and leadership effectiveness, arguing that logic suggesting the universality of manager and supervisory leader behaviors is compelling, although there is sparse empirical evidence to support this view. A comparative study of the findings from three previous empirical factor analytic studies into the criteria of managerial effectiveness, carried out in three different types of public sector organizations in the United Kingdom, support the view that “universalistic” as opposed to “contingent” models are more consistent with the facts. A generic model of managerial and leadership effectiveness is presented, and the implications for HRD research and practice are discussed.
Fat, fiber, fruits, vegetables, and risk of colorectal adenomas
Authors: Mathew Aleyamma , Peters Ulrike , Chatterjee Nilanjan , Kulldorff Martin , Sinha Rashmi
Published: June 2004

A case‐control study was conducted at the National Naval Medical Center (Maryland, USA) from 1994 to 1996 to investigate the possible association between dietary factors and colorectal adenomas. Cases (n = 239) were subjects diagnosed with adenomas (146 new and 93 recurrent) by sigmoidoscopy or colonoscopy. Those with no evidence of adenomas found by sigmoidoscopy were recruited as controls (n = 228). Dietary variables, assessed by a 100‐item food frequency questionnaire, were analyzed by the logistic regression model, which was adjusted for age, gender and total energy intake. Variables of fat intake were further adjusted for red meat intake. An increased risk of 7% [odds ratio (OR): 1.07; 95% confidence interval (95% CI): 0.94–1.22] per 5% energy/day from total fat was observed. Every additional 5% unit of oleic acid intake/day significantly increased the adenoma risk by 115% (OR: 2.15; 95% CI: 1.05–4.39). Red meat fat increased the risk by 20% (OR: 1.20; 95% CI: 0.71–2.04), and white meat fat decreased the risk by 67% (OR: 0.33; 95% CI: 0.19–0.95) for every additional 5% unit of respective intake/day. Risk decreased by 41% (OR: 0.59; 95% CI: 0.41–0.86) for every additional 5% unit of fiber intake/day. Vegetable [OR per 100 g of vegetable intake/day: 0.83, 95% CI: 0.67–1.04] and fruit (OR per 100 g of fruit intake/day: 0.92, 95% CI: 0.82–1.03) intake showed an inverse association, and the results are suggestive of an association with the risk for adenomas. In conclusion, a strong positive association between oleic acid intake and colorectal adenoma risk was observed. This is likely to be an indicator of “unhealthy” food (meat, dairy, margarine, mayonnaise, sweet baked food) consumption in this population. Increased intake of dietary fiber was associated with a moderately decreased risk of adenomas. © 2003 Wiley‐Liss, Inc.
Serum enterolactone concentration is not associated with breast cancer risk in a nested case‐control study
Authors: Kilkkinen Annamari , Virtamo Jarmo , Vartiainen Erkki , Sankila Risto , Virtanen Mikko J. , Adlercreutz Herman , Pietinen Pirjo
Published: June 2004

The lignan enterolactone produced by the intestinal microflora from dietary precursors has been hypothesized to protect against hormone‐dependent cancers. We conducted a nested case‐control study to examine the relationship between serum enterolactone concentration and risk of breast cancer. Enterolactone concentrations were measured by time‐resolved fluoroimmunoassay in serum collected at 4 independent cross‐sectional population surveys from 206 women with breast cancer diagnosed during follow‐up (mean 8.0 years) and from 215 controls frequency‐matched to cases by study cohort, 5‐year age group and study area. Mean serum enterolactone concentration (nmol/l) did not significantly differ between case and control subjects [25.2 (SD 22.2) vs. 24.0 (SD 21.3), respectively]. Odds ratios for breast cancer risk estimated by conditional logistic regression for increasing concentration of enterolactone in quartiles were 1.00 (referent), 1.67 (95% CI 0.95–2.95), 1.71 (95% CI 0.96–3.06) and 1.30 (95% CI 0.73–2.31), and p for trend was 0.48. Our findings do not support the hypothesis that high serum enterolactone concentration is associated with reduced risk of breast cancer. © 2003 Wiley‐Liss, Inc.
Anti‐neovascular therapy by liposomal drug targeted to membrane type‐1 matrix metalloproteinase
Authors: Kondo Masami , Asai Tomohiro , Katanasaka Yasufumi , Sadzuka Yasuyuki , Tsukada Hideo , Ogino Koichi , Taki Takao , Baba Kazuhiko , Oku Naoto
Published: June 2004

Because membrane type‐1 matrix metalloproteinase (MT1‐MMP) is expressed specifically on the angiogenic endothelium as well as tumor cells, an agent possessing the ability to bind to this molecule might be useful as a tool for active targeting of tumor angiogenic vessels. Based on the sequences of peptide substrates of MT1‐MMP, which had been determined by using a phage‐displayed peptide library, we examined the binding ability of peptide‐modified liposomes for endothelial cells and targeting ability for tumor tissues by positron emission tomography (PET). Liposomes modified with stearoyl‐Gly‐Pro‐Leu‐Pro‐Leu‐Arg (GPLPLR‐Lip) showed high binding ability to human umbilical vein endothelial cells and accumulated in the tumor about 4‐fold more than did the unmodified liposomes. Because we reported previously that liposomalized 5′‐O‐dipalmitoylphosphatidyl 2′‐C‐cyano‐2′‐deoxy‐1‐β‐D‐arabino‐pentofuranosylcytosine (DPP‐CNDAC), a hydrophobized derivative of the novel antitumor nucleoside CNDAC, strongly suppressed tumor growth when delivered in liposomes modified with another angiogenic homing peptide, we examined the antitumor activity of DPP‐CNDAC entrapped in GPLPLR‐Lip. DPP‐CNDAC/GPLPLR‐Lip showed significant tumor growth suppression compared to DPP‐CNDAC/unmodified liposomes. These results suggest that DPP‐CNDAC‐liposomes modified with MT1‐MMP‐targeted peptide are useful for cancer anti‐neovascular therapy (ANET), namely, tumor growth suppression by damage to angiogenic endothelial cells. © 2003 Wiley‐Liss, Inc.
Humoral immune response against melanoma antigens induced by vaccination with cytokine gene‐modified autologous tumor cells
Authors: Ehlken Hanno , Schadendorf Dirk , Eichmüller Stefan
Published: June 2004

Although the existence of a humoral response against tumor‐associated antigens is well appreciated, a systematic analysis of its possible induction by the tumor remains missing. We compared the specific IgG response of Stage IV melanoma patients during vaccination. Patients had been treated within 2 clinical trials with autologous tumor cells gene‐modified for IL‐7 or IL‐12. A panel of 27 tumor‐associated antigens (HD‐MM‐01 to HD‐MM‐27) was isolated by a SEREX screening of a testis cDNA library using a pool of 5 sera from patients after vaccination. All antigens were retested with individual sera of 12 patients both pre‐ and post‐vaccination. A serological response was induced during vaccination against 18 antigens. Remarkably, induction was detected only in patients included in the screening pool. The low overlap between sero‐reactivity of the 12 patients suggested a very individualized immunological reaction. Two of 5 sera included in the screening pool exhibited a high frequency of induced humoral responses. The same patients had been shown to have a high Karnovsky index and had generated lytic cytotoxic T cells against the tumor. Besides 2 known cancer‐germline genes (SCP‐1 and PLU‐1), the other isolated antigens were expressed in a non‐tumor‐specific fashion as analyzed by virtual Northern blot or RT‐PCR. The properties of homologues to several of the identified tumor‐antigens, especially PLU‐1, SCP‐1, DNEL2, CLOCK, and PIASx‐α, suggest further investigation of their possible function in malignant melanoma. We conclude that a strong humoral response against tumor‐associated antigens is inducible by tumor cells and that this response is very individual. © 2003 Wiley‐Liss, Inc.
Can cervical cancer screening be stopped at 50? The prevalence of HPV in elderly women
Authors: Baay Marc F.D. , Smits Evelien , Tjalma Wiebren A.A. , Lardon Filip , Weyler Joost , Van Royen Paul , Van Marck Eric A.E. , Vermorken Jan B.
Published: June 2004

Although the relation between cervical cancer and the human papillomavirus (HPV) has been established beyond doubt, the introduction of HPV detection in cervical cancer screening is halted, primarily by the high rate of false positivity in relation to morbidity, since the majority of women infected with HPV will not develop lesions. To counteract overconsumption of cervical cancer screening in elderly women, we wanted to test the hypothesis that women of 50 years or older who are HPV‐negative and have a cytologically normal smear might be encouraged to refrain from further screening. As a first step, the prevalence of high‐risk HPV in a population of 1,936 women of 50 years and older was investigated. After an initial decline, a slightly higher prevalence can be seen with increasing age. There is a decrease in the prevalence of multiple infections with age, paralleled by an increase in single infections, especially of HPV type 16 in the eldest‐age group. However, neither the decrease in multiple infections nor the increase in single infections is statistically significant. The data obtained in this study show that, even in the presence of a slight increase in the HPV prevalence in elderly women, approximately 94% of the elderly women can be withdrawn from the cervical cancer screening. However, a follow‐up study will be necessary to determine the frequency of (re)infection as well as the course of an HPV infection in elderly women. © 2003 Wiley‐Liss, Inc.
Prediagnostic levels of C‐peptide, IGF‐I, IGFBP ‐1, ‐2 and ‐3 and risk of endometrial cancer
Authors: Lukanova Annekatrin , Zeleniuch‐Jacquotte Anne , Lundin Eva , Micheli Andrea , Arslan Alan A. , Rinaldi Sabina , Muti Paola , Lenner Per , Koenig Karen L. , Biessy Carine , Krogh Vittorio , Riboli Elio , Shore Roy E. , Stattin Par , Berrino Franco , Hallmans Göran , Toniolo Paolo , Kaaks Rudolf
Published: June 2004

Conditions related to chronic hyperinsulinemia, such as obesity, noninsulin dependent diabetes mellitus and polycystic ovary syndrome, are associated with an increased risk of endometrial cancer. Elevated plasma IGF‐I and decreased levels of IGF‐binding proteins have been shown to be associated with increased risk of several cancer types that are frequent in affluent societies. We investigated for the first time in a prospective study the association of pre‐diagnostic blood concentrations of C‐peptide (a marker of pancreatic insulin production), IGF‐I, IGFBP‐1, ‐2 and ‐3 with endometrial cancer risk. A case‐control study was nested within 3 cohorts in New York (USA), Umeå (Sweden) and Milan (Italy). It included 166 women with primary invasive endometrial cancer and 315 matched controls, of which 44 case and 78 control subjects were premenopausal at recruitment. Endometrial cancer risk increased with increasing levels of C‐peptide (ptrend = 0.0002), up to an odds ratio (OR) of 4.76 [95% confidence interval (CI) = 1.91–11.8] for the highest quintile. This association remained after adjustment for BMI and other confounders [OR for the top quintile = 4.40 (1.65–11.7)]. IGFBP‐1 levels were inversely related to endometrial cancer [ptrend = 0.002; OR in the upper quintile = 0.30 (0.15–0.62)], but the association was weakened and lost statistical significance after adjustment for confounders [ptrend = 0.06; OR in the upper quintile = 0.49 (0.22–1.07)]. Risk was unrelated to levels of IGF‐I, IGFBP‐2 and IGFBP‐3. Chronic hyperinsulinemia, as reflected by increased circulating C‐peptide, is associated with increased endometrial cancer risk. Decrease in the prevalence of chronic hyperinsulinemia, through changes in lifestyle or medication, is expected to prevent endometrial cancer. © 2003 Wiley‐Liss, Inc.
p53 polymorphic variants at codon 72 exert different effects on cell cycle progression
Authors: Pim David , Banks Lawrence
Published: June 2004

Two common polymorphic forms of the p53 tumor suppressor protein are widely distributed throughout the human population. These encode either proline or arginine at position 72, and this difference results in a marked alteration in the primary structure of the protein. A number of previous studies have shown significant differences in the biochemical properties of the p53 protein, depending on the particular polymorphic form. There is little information, however, on their respective biologic activities. In this study, we have used an inducible switch system for expressing both polymorphic forms of p53 within Saos‐2 cells. Cell cycle analysis postinduction of p53 function reveals striking differences in how the 2 forms of p53 bring about a cessation of cell growth. Thus, the Arg72 form of p53 is significantly more efficient than the Pro72 form at inducing apoptosis. In contrast, the Pro72 form appears to induce a higher level of G1 arrest than the Arg72 form. These results demonstrate significant differences in how the codon 72 polymorphism affects the biological activity of p53. © 2003 Wiley‐Liss, Inc.
Short tandem repeat polymorphism in a novel esophageal cancer‐related gene (ECRG2) implicates susceptibility to esophageal cancer in Chinese population
Authors: Yue Chun‐mei , Bi Mei‐xia , Tan Wen , Deng Da‐jun , Zhang Xin‐yu , Guo Li‐ping , Lin Dong‐xin , Lu Shih‐Hsin
Published: June 2004

We have previously cloned and identified a novel esophageal cancer related gene 2 (ECRG2; GenBank Accession Number AF268198), which is down‐regulated in esophageal squamous cell carcinoma (ESCC) and involved in the induction of the apoptosis in esophageal cancer cell lines. In the present study, we have found a short tandem repeat (STR) polymorphism in the noncoding region of the exon 4 of the ECRG2 gene by using PCR‐denaturing high‐performance liquid chromatography (DHPLC). Three STR genotypes, TCA3/TCA3, TCA3/TCA4 and TCA4/TCA4 were revealed and confirmed by DNA sequencing analysis. A total of 661 objects including 228 patients with ESCC and 373 normal controls were analyzed to investigate the impact of this ECRG2 STR polymorphism on risk of ESCC in case‐control studies. Genotypes were determined in 231 controls and 162 cases from Beijing, which is a low risk area of ESCC, and in 142 controls and 126 cases from Linxian, a well‐known high‐risk area of ESCC. In both of the Beijing and Linxian population, subjects who carried the TCA3/TCA3 genotype were at an increased risk of ESCC compared to those carrying the TCA4/TCA4 genotype, with the adjusted odds ratios (ORs) being 2.05 [95% confidence interval (CI), 1.02–4.06] for the subjects from Beijing and 4.40 (95% CI, 1.93–10.01) for the subjects from Linxian. Furthermore, comparison of the genotype distributions among other cancer sites might suggest that risk of the ECRG2 STR polymorphism might be specific to the esophagus. These findings indicate for the first time that the ECRG2 STR is a genetic susceptibility factor for ESCC and the TCA3/TCA3 allele might play a role in the development of this cancer. © 2003 Wiley‐Liss, Inc.
Cyclin D3 immunoreactivity in follicular lymphoma is independent of the t(6;14)(p21.1;q32.3) translocation or cyclin D3 gene amplification and is correlated with histologic grade and Ki‐67 labeling index
Authors: Pruneri Giancarlo , Valentini Stefano , Fabris Sonia , Del Curto Barbara , Laszlo Daniele , Bertolini Francesco , Martinelli Giovanni , Leocata Pietro , Viale Giuseppe , Neri Antonino
Published: June 2004

An abnormal expression of cyclin D3, a key regulator of the cell cycle, has been documented in a variety of human malignancies, and the cyclin D3 gene, mapping to 6p21, may be deregulated in plasma cell myeloma and non‐Hodgkin's lymphoma as a result of the t(6;14)(p21.1;q32.3) translocation and/or gene amplification. In the current study, we for the first time investigated by immunohistochemistry and fluorescence in situ hybridization (FISH) the prevalence of cyclin D3 abnormalities in follicular lymphomas (FLs), comparing the results with traditional clinicopathologic characteristics, p27 and skp2 immunoreactivity (IR) and Ki‐67 labeling index (LI). Cyclin D3, skp2 and Ki‐67 IR significantly increased from grade I to grade III FL (p = 0.0003, p = 0.0001 and p < 0.0001, respectively), while p27 IR was significantly (p < 0.0001) more prevalent in low‐grade tumors. Cyclin D3 IR was directly correlated with the Ki‐67 LI (p < 0.0001) and inversely correlated with p27 IR (p = 0.050). None of the 13 cases analyzed by FISH showed the t(6;14) translocation, but in 2 (15.3%) grade I FLs 3 cyclin D3 signals were detected. Cohybridization with probes specific for the centromeric region and the long arm of the chromosome 6 indicated trisomy in one case and a pattern highly suggestive for the presence of an isochromosome 6p in the other case. Our data suggest that the t(6;14) translocation may be extremely uncommon in FL and that a deregulated expression of cyclin D3, possibly due to epigenetic mechanisms, may be involved in the pathogenesis of high‐grade tumors. © 2004 Wiley‐Liss, Inc.
EGF receptor (EGFR) signaling promoting invasion is disrupted in androgen‐sensitive prostate cancer cells by an interaction between EGFR and androgen receptor (AR)
Authors: Bonaccorsi Lorella , Carloni Vinicio , Muratori Monica , Formigli Lucia , Zecchi Sandra , Forti Gianni , Baldi Elisabetta
Published: June 2004

We previously demonstrated that expression of androgen receptor (AR) by transfection of the androgen‐independent prostate cancer cell line PC3 decreases invasion and adhesion of these cells (PC3‐AR) through modulation of α6β4 integrin expression. The treatment with androgens further reduced invasion of the cells without modifying α6β4 expression, suggesting an interference with the invasion process by androgens. Here, we investigated EGF‐mediated signal transduction processes that lead to invasion in PC3‐AR cells. We show that EGF‐induced EGFR autotransphosphorylation is reduced in PC3‐AR cells compared to PC3 cells transfected only with the vector (PC3‐Neo). EGF‐stimulated PI3K activity, a key signaling pathway for invasion of these cells, and EGF‐PI3K interaction are also decreased in PC3‐AR cells and further reduced by treatment with androgen. Finally, we show that EGFR internalization process was reduced in PC3‐AR and LNCaP cells compared to PC3‐Neo. Investigations on the location of AR in PC3‐AR transfected cells were also conducted. Immunoconfocal microscopy and coimminoprecipitation studies demonstrated the presence of an interaction between EGFR and AR at membrane level in PC3‐AR and LNCaP cells. In conclusion, our results suggest that the expression of AR by transfection in PC3 cells confers a less‐malignant phenotype by interfering with EGFR signaling leading to invasion through a mechanism involving an interaction between AR and EGFR. © 2004 Wiley‐Liss, Inc.
Comparison of the prognostic potential of hyaluronic acid, hyaluronidase (HYAL‐1), CD44v6 and microvessel density for prostate cancer
Authors: Ekici Sinan , Cerwinka Wolfgang H. , Duncan Robert , Gomez Pablo , Civantos Francisco , Soloway Mark S. , Lokeshwar Vinata B.
Published: June 2004

Despite the development of nomograms designed to evaluate a prostate cancer (PCa) patient's prognosis, the information has been limited to PSA, clinical stage, Gleason score and tumor volume estimates. We compared the prognostic potential of 4 histologic markers, hyaluronic acid (HA), HYAL‐1‐type hyaluronidase (HAase), CD44v6 and microvessel density (MVD) using immunohistochemistry. HA is a glycosaminoglycan that promotes tumor metastasis. CD44 glycoproteins serve as cell surface receptors for HA, and the CD44v6 isoform is associated with tumor metastasis. HYAL‐1‐type HAase is expressed in tumor cells and, like other HAases, degrades HA into angiogenic fragments. Archival PCa specimens (n = 66) were obtained from patients who underwent radical prostatectomy for clinically localized PCa and had a minimum follow‐up of 72 months (range 72–131 months, mean 103 months). For HA, HYAL‐1 and CD44v6 staining and MVD determination, a biotinylated HA‐binding protein, an anti‐HYAL‐1 IgG, an anti‐CD44v6 IgG and an anti‐CD34 IgG were used, respectively. HA and HYAL‐1 staining was classified as either low‐ or high‐grade. CD44v6 staining and MVD were evaluated quantitatively and then grouped as either low‐ or high‐grade. Using 72 months as the cut‐off limit for evaluating biochemical recurrence, HA, HYAL‐1, combined HA–HYAL‐1, CD44v6 and MVD staining predicted progression with 96%, 84%, 84%, 68% and 76% sensitivity, respectively. Specificity was, 61% (HA), 80.5% (HYAL‐1), 87.8% (HA–HYAL‐1), 56.1% (CD44v6) and 61% (MVD). Sensitivity and specificity values for each marker did not change significantly in a subset of 45 patients for whom follow‐up of longer than 112 months was available. In univariate analysis using the Cox proportional hazards model, preoperative PSA, Gleason sum, margin status, seminal vesicle, extraprostatic extension (EPE), HA, HYAL‐1, HA–HYAL‐1 and MVD, but not CD44v6, age and clinical stage, were significant in predicting biochemical recurrence (p < 0.05). In multivariate analysis using stepwise selection, only preoperative PSA (hazard ratio/unit PSA change = 1.086, p < 0.0001), EPE (hazard ratio = 6.22, p = 0.0016) and HYAL‐1 (hazard ratio = 8.196, p = 0.0009)/HA–HYAL‐1 (hazard ratio = 5.191, p = 0.0021) were independent predictors of biochemical recurrence. HA was an independent predictor of prognosis if HYAL‐1 staining inference was not included in the multivariate model. In our retrospective study with 72‐ to 131‐month follow‐up, EPE, preoperative PSA and HYAL‐1 either alone or together with HA (i.e., combined HA–HYAL‐1) were independent prognostic indicators for PCa. © 2004 Wiley‐Liss, Inc.
Polymorphisms and haplotype structures in genes for transforming growth factor β1 and its receptors in familial and unselected breast cancers
Authors: Jin Qianren , Hemminki Kari , Grzybowska Ewa , Klaes Rüdiger , Söderberg Magnus , Zientek Helena , Rogozinska‐Szczepka Jadwiga , Utracka‐Hutka. Beata , Pamula Jolanta , Pekala Wioletta , Försti Asta
Published: June 2004

Alterations in TGF‐β signaling appear to be associated with an altered risk of developing cancer, including breast cancer. We carried out a case‐control study on 8 polymorphisms, including 5 in the TGF‐β1 gene (G‐800A, C‐509T, Leu10→Pro, Arg25→Pro and Thr263→Ile), a polyalanine polymorphism (9A→6A) in the TGF‐βRI gene and 2 (G‐875A and A‐364G) in the TGF‐βRII gene, using samples from 2 different populations, Polish familial and Finnish unselected breast cancer cases, together with ethnically and geographically matched controls. Additionally, familial breast cancer cases with respective controls from Sweden and Germany were studied in the Leu10→Pro polymorphism, making the total number of familial cases 659. Allele, genotype and haplotype analysis on the TGF‐β1 gene as well as an analysis of the combinations of genotypes of the TGF‐β1 and its receptor genes in each individual were performed. Population differences in the allele and genotype distributions were found from 5 of the polymorphisms and 3 common haplotypes from the TGF‐β1 gene between the Finnish and other populations. However, no statistically significant difference between the breast cancer and healthy control groups was found for any of the 8 polymorphisms nor did the haplotype or genotype combination analysis reach statistical significance. Thus, none of the studied polymorphisms from the TGF‐β1 and its receptor genes was found to influence significantly susceptibility to breast cancer. The possible contribution of 6A/6A homozygosity in the TGF‐βRI gene to breast cancer needs to be confirmed in an independent study. © 2004 Wiley‐Liss, Inc.
Analysis of gene expression in cancer cell lines identifies candidate markers for pancreatic tumorigenesis and metastasis
Authors: Missiaglia Edoardo , Blaveri Ekaterini , Terris Benoit , Wang Yao‐He , Costello Eithne , Neoptolemos John P. , Crnogorac‐Jurcevic Tatjana , Lemoine Nicholas R.
Published: June 2004

Pancreatic cancer is a highly aggressive type of malignancy and the prognosis for disease presenting typically at a late stage is extremely poor. A comprehensive understanding of its molecular genetics is required in order to develop new approaches to clinical management. To date, serial analysis of gene expression and more recently oligo/cDNA microarray technologies have been employed in order to identify genes involved in pancreatic neoplasia that can be developed as diagnostic markers and drug targets for this dismal disease. This study describes the expression profile obtained from 20 pancreatic cell lines using cDNA microarrays containing 9,932 human gene elements. Numerous genes were identified as being differentially expressed, some of which have been previously implicated in pancreatic adenocarcinoma (S100P, S100A4, prostate stem cell antigen, lipocalin 2, claudins 3 and 4, trefoil factors 1 and 2) as well as several novel genes. The differentially expressed genes identified are involved in a variety of cellular functions, including control of transcription, regulation of the cell cycle, proteolysis, cell adhesion and signaling. Validation of our array results was performed by exploring the SAGEmap database and by immunohistochemistry for a selection of 4 genes that have not previously been studied in pancreatic cancer: anterior gradient 2 homologue (Xenopus laevis), insulin‐like growth factor binding protein 3 and 4 and Forkhead box J1. Immunostaining was performed using pancreas‐specific tissue microarrays containing core biopsies from 305 clinical specimens. In addition, using statistical group comparison and hierarchical clustering, a selection of genes was identified that may be linked to the site of metastasis from which these cell lines were isolated. © 2004 Wiley‐Liss, Inc.
Tumor‐specific exon creation of the HELLS/SMARCA6 gene in non‐small cell lung cancer
Authors: Yano Masaaki , Ouchida Mamoru , Shigematsu Hisayuki , Tanaka Noriyoshi , Ichimura Koichi , Kobayashi Kazuyasu , Inaki Yasuhiko , Toyooka Shinichi , Tsukuda Kazunori , Shimizu Nobuyoshi , Shimizu Kenji
Published: June 2004

To identify tumor‐suppressor genes on chromosome 10 in non‐small cell lung cancers, we isolated 10 types of splicing variant of the HELLS/SMARCA6 gene transcripts. HELLS/SMARCA6 is a novel member of SNF2 family, which is implicated in cellular functions like chromatin remodeling. Variant 1 was an alternatively spliced isoform containing an insertion of a 44 ntd intronic sequence between exons 3 and 4, giving rise to a premature termination of translation. Expression of variant 1 was detected exclusively in lung cancer specimens (11 of 43 cases, 26%) but was not detected in corresponding normal tissues. The D10S520 marker in the proximity of the HELLS/SMARCA6 gene showed prevalent allelic loss (41%) compared to flanking markers (25–31%). These results suggest that loss of function of HELLS/SMARCA6 by allelic loss and aberrant proteins by tumor‐specific exon creation may result in epigenetic deregulation, leading lung cells to malignancy or its progression. © 2004 Wiley‐Liss, Inc.
Use of sol–gel‐derived titania coating for direct soft tissue attachment
Authors: Areva Sami , Paldan Hannu , Peltola Timo , Närhi Timo , Jokinen Mika , Lindén Mika
Published: June 2004

A firm bond between an implant and the surrounding soft tissue is important for the performance of many medical devices (e.g., stents, canyls, and dental implants). In this study, the performance of nonresorbable and reactive sol–gel‐derived nano‐porous titania (TiO2) coatings in a soft tissue environment was investigated. A direct attachment between the soft tissue and the sol–gel‐derived titania coatings was found in vivo after 2 days of implantation, whereas the titanium control implants showed no evidence of soft tissue attachment. The coated implants were in immediate contact with the connective tissue, whereas the titanium controls formed a gap and a fibrous capsule on the implant‐tissue interface. The good soft tissue attachment of titania coatings may result from their ability to initiate calcium phosphate nucleation and growth on their surfaces (although the formation of poorly crystalline bonelike apatite does not occur). Thus, the formation of a bonelike CaP layer is not crucial for their integration in soft tissue. The formation of bonelike apatite was hindered by the adsorption of proteins onto the initially formed amorphous calcium phosphate growth centers, thus preventing the dissolution/reprecipitation processes required for the formation of poorly crystalline bonelike apatite. These findings might open novel application areas for sol–gel‐derived titania‐based coatings. © 2004 Wiley Periodicals, Inc. J Biomed Mater Res 70A: 169–178, 2004
Endothelial cell adhesion on RGD‐containing methacrylate terpolymers
Authors: Fussell Garland W. , Cooper Stuart L.
Published: June 2004

Hexyl methacrylate (HMA), methyl methacrylate (MMA), and methacrylic acid (MAA) were used as comonomers to produce a low glass transition temperature material, potentially useful in fabricating a small diameter vascular graft. Because it has been shown that grafts seeded with endothelial cells have better resistance to thrombosis, RGD‐based peptide sequences were incorporated into the terpolymer. The two methods used for incorporating peptide sequences were a chain transfer reaction during polymerization, and a coupling reaction between the amine terminus of the peptide and the carboxyl groups of the MAA. Polymers were synthesized using the chain transfer reaction with peptide concentrations ranging from 1.7 to 7.0 μmol/g. Weight‐average molecular weights decreased with increasing peptide concentration from 310,000 g/mol for the terpolymer without peptide, to 110,000 g/mol for a peptide concentration of 7.0 μmol/g. As a result, Young's modulus decreased with increasing peptide concentration. Terpolymers with peptides attached through a coupling reaction showed no decrease in molecular weight or mechanical properties. Confocal microscopy showed cells seeded on the RGD surfaces adhered and spread, while terpolymers with RGE sequences showed cells that were rounded and not spreading. Cell density on RGD surfaces increased with increasing peptide concentration up to a bulk peptide concentration of approximately 5 μmol/g and reached a plateau, which indicated the minimum peptide concentration necessary for maximum cell adhesion. © 2004 Wiley Periodicals, Inc. J Biomed Mater Res 70A: 265–273, 2004
The in vitro elution of gentamicin sulfate from a commercially available gentamicin‐loaded acrylic bone cement, VersaBond™ AB
Authors: Lewis Gladius , Janna Si
Published: May 2004

The present study was designed to yield results that would be used to contribute to the ongoing debate about the mechanism of the in vitro elution of an antibiotic from an antibiotic‐loaded acrylic bone cement. To this end, the elution rates (R) of gentamicin sulfate (expressed as a weight percentage of the initial mass of the antibiotic in the specimen, normalized with respect to the duration of the test) from statically loaded (STATIC) and dynamically loaded (±10 MPa; 2 Hz; until fracture; DYNAMIC) specimens fabricated from a commercially available acrylic bone cement (VersaBond™ AB), in phosphate‐buffered saline solution at 37°C, were obtained with the use of a spectrophotometric method. There was evidence of microcracking in the fracture surfaces of DYNAMIC specimens, but no such evidence in the case of STATIC specimens. The surface area of the DYNAMIC specimens, during the tensile phase of the cyclical loading, was estimated to be about 3% larger than for the STATIC specimens (1742 mm2 versus 1696 mm2). The bulk porosities P of the specimens in both sets were also determined and found to not be statistically different, with P for the STATIC and DYNAMIC specimens being 8.55 ± 0.10 and 8.88 ± 0.18%, respectively. At the end of the test period, R was found to be 0.36 ± 0.20 and 1.28 ± 0.14 wt %/day for the STATIC and DYNAMIC specimens, respectively. It is suggested that the present results provide support for the postulate that the elution mechanism of gentamicin in this cement is a surface phenomenon. © 2004 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater 71B: 77–83, 2004
Protein electrostatic self‐assembly on poly(DL‐lactide) scaffold to promote osteoblast growth
Authors: Zhu Huiguang , Ji Jian , Barbosa M. A. , Shen Jiacong
Published: May 2004

The development of protein coating on 3D biodegradable scaffold based on electrostatic self‐assembly (ESA) to promote osteoblast growth is reported. Poly (ethylenimine) (PEI) was employed to obtain a stable positively charged surface on poly(DL‐lactide) (PDL‐LA) substrate. An extracellular‐matrix (ECM)‐like biomacromolecule, gelatin, was chosen as the polyelectrolyte to deposit on the activated PDL‐LA substrate via ESA technique. Osteoblast (MC3T3) was then cultured on unmodified and gelatin‐modified PDL‐LA scaffolds. Osteoblast testing regarding total intracellular protein content, total DNA content, cell activity, and cell morphology on the ECM‐like multilayer‐modified PDL‐LA scaffold showed that osteoblast growth was promoted. It will be easy to replace the gelatin with osteoinductive proteins or other polyelectrolytes to promote specific osteoblast functions. In comparison with conventional coating methods, polyelectrolyte multilayers are easy and stable to prepare. They may be a good choice for the surface modification of complex biomedical devices, especially for the 3D tissue‐engineering scaffold. These very flexible systems allow broad medical applications for drug delivery and tissue engineering. © 2004 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater 71B: 159–165, 2004