bluuebunny/crossref_metadata_2025 huggingface dataset:
Lysophosphatidic acid‐regulated mitogenic ERK signaling in androgen‐insensitive prostate cancer PC‐3 cells
Authors: Kue Pao F. , Taub Jason S. , Harrington Liza Barki , Polakiewicz Roberto D. , Ullrich Axel , Daaka Yehia
Published: November 2002

Advanced and recurrent prostate tumors contain elevated levels of activated extracellular signal‐regulated kinases 1 and 2 (ERK) in comparison to early‐stage or benign specimens, and inhibition of ERK activation attenuates growth factor‐dependent proliferation of prostate cells, suggesting a potential regulatory role for ERK in prostate tumorigenesis. Factors responsible for ERK activation in prostate cells are not well defined. Here, we show positive cooperative interaction between the G protein‐coupled lysophosphatidic acid (LPA) and tyrosine kinase epidermal growth factor (EGF) receptors in androgen‐insensitive prostate cancer PC‐3 cells. Pre‐treatment of the PC‐3 cells with LPA decreases the dose of EGF required to elicit maximal activation of EGFR. Furthermore, treatment with LPA alone induces the rapid (maximal signal within 2 min) tyrosine phosphorylation of EGFR, and subsequent (maximal signal after 5 min) activation of ERK, suggesting that EGFR activation precedes ERK phosphorylation and may constitute a required component for signal relay from the LPA receptor to ERK. Accordingly, we show that inhibition of EGFR kinase activity attenuates the LPA‐regulated ERK activation. In addition, we find that the LPA‐regulated tyrosine phosphorylation of EGFR and activation of ERK are attenuated by batimastat, a generic inhibitor of matrix metalloproteinases (MMP). However, unlike the situation in fibroblasts, we find that the LPA‐induced transactivation of EGFR in PC‐3 cells is not mediated by shedding of heparin‐binding EGF. Together, our data show that LPA and EGF cooperate to induce mitogenic signaling in prostate cancer cells in an MMP‐regulated activation of the ERK pathway. © 2002 Wiley‐Liss, Inc.
Elevated expression of p63 protein in human esophageal squamous cell carcinomas
Authors: Hu Hai , Xia Shu‐Hua , Li Ai‐Dong , Xu Xin , Cai Yan , Han Ya‐Ling , Wei Fang , Chen Bao‐Sheng , Huang Xiao‐Ping , Han Yu‐Sheng , Zhang Jian‐Wei , Zhang Xun , Wu Min , Wang Ming‐Rong
Published: November 2002

p63 is a recently identified homologue of the tumor suppressor gene TP53, which encodes multiple isotypes with transactivating, death‐inducing and dominant–negative activities. p63 is expressed in basal cells of squamous epithelia and many kinds of tumors. To explore the penetrance of p63 in esophageal cancer, we analyzed p63 expression in squamous cell carcinomas, adjacent dysplasia and histologically normal mucosa of the esophagus by combination of immunohistochemistry and reverse transcriptase‐polymerase chain reaction (RT‐PCR). The results showed that the ΔNp63 mRNA was easily detectable in all malignant and histologically normal tissues, whereas TAp63 presented extremely low or no expression. The p63 protein was highly expressed in 50 of 51 tumor tissues without significant difference in gender, age, stage and grade. Ten of 11 dysplasia exhibited strong p63 staining in all abnormal cells. Interestingly, p63 expression was observed in 96% (45/47) histologically normal epithelia adjacent to the cancerous tissues but only in 47% (14/30) mucosa far from tumors. Most of the epithelia far from tumors showed weaker staining than that adjacent to the cancerous tissues. In all the histologically normal epithelia with p63 expression, irrespective of the distance from the tumors, immunohistochemical reaction was restricted to the basal and suprabasal cell layers. Our data suggested that ΔNp63 is the major isotype expressed in epithelia and tumors of the esophagus. Elevated expression of p63 is probably an early event in esophageal squamous cell carcinomas, which may play a significant role in the development of the disease. © 2002 Wiley‐Liss, Inc.
Progression of microsatellite instability from premalignant lesions to tumors of the head and neck
Authors: Ha Patrick K. , Pilkington Thomas A. , Westra William H. , Sciubba James , Sidransky David , Califano Joseph A.
Published: November 2002

The role of microsatellite alterations other than loss of heterozygosity (LOH) in the progression of benign epithelium to head‐and‐neck squamous cell cancer (HNSCC) has not been previously described. As the severity of the dysplasia increases at the microscopic level, there is an increase in the prevalence of LOH as defined by microsatellite analysis. Other alterations have been detected in the form of microsatellite instability (MSI), represented by insertions or deletions of base pairs. It is unknown, however, whether the prevalence of these alterations likewise increases during these early stages of tumor progression. Using 6 selected markers that demonstrate a high rate of MSI and allelic imbalance in invasive head‐and‐neck cancer, we examined 111 lesions ranging from hyperplasia without atypia to invasive mucosal HNSCC. Two of 34 (5.9%) of the hyperplasias without atypia, 2/12 (16.7%) of the mild dysplasias, 2/21 (9.5%) of the moderate dysplasias, 7/26 (26.9%) of the high‐grade dysplasias/carcinomas in situ and 6/18 (33%) of the HNSCCs demonstrated microsatellite base pair length alterations. Our findings indicate that MSI becomes increasingly more common as early dysplastic lesions progress to fully malignant HNSCC and confirm this as a supplemental detection method in microsatellite analysis. © 2002 Wiley‐Liss, Inc.
Socio‐economic differences in incidence rates of cancers of the male genital organs in Finland, 1971–95
Authors: Pukkala Eero , Weiderpass Elisabete
Published: November 2002

We studied social class variation in the incidence of cancers of the prostate, testis, penis and scrotum among 1.1 million Finnish men (45–69 years of age) during 1971–95. The incidence of prostate cancer (6,972 cases) was increasing during the study period; the highest at all the times occurred in Social Class I (highest social class), 40–50% higher than in Social Class IV (lowest). The social class gradient was strongest in localized disease but there was some variation in incidence of non‐localized prostate cancer. A total of 174 testicular cancer cases were diagnosed during the study period. In the early 1970s, the incidence of testicular cancer in Social Class I was 5‐fold compared to Social Classes III and IV. Thereafter, the incidence rate decreased in Social Class I, but increased in the lower classes. The positive social class gradient was similar for seminomas and non‐seminomas. For penile cancer (n = 128), the incidence decreased over time and social class variation was small. Only 6 cases of scrotum cancer were observed. In testicular cancer the strong positive social class association in the early 1970s is disappearing along with converging incidence trend slopes in different social classes. The difference diminished to less than 2‐fold in the 1990s. Reasons for this observation remain open. © 2002 Wiley‐Liss, Inc.
Carcinogenesis modifier loci in rat tongue are subject to frequent loss of heterozygosity
Authors: Tanuma Jun‐ichi , Hiai Hiroshi , Shisa Hayase , Hirano Masato , Semba Ichiro , Nagaoka Shigetaka , Kitano Motoo
Published: November 2002

Rats of the DA strain are highly susceptible to 4NQO‐induced TCs, whereas WF rats are barely susceptible. In (DA × WF)F2 rats, 5 QTL, Tscc1–5, are responsible for most of the phenotypic variations, though they do not account for all of the phenotypic differences between WF and DA rats. Analysis of 40 tongue tumors >5 mm in diameter from (DA × WF)F1 rats for LOH at the Tscc loci revealed a high frequency of LOH in chromosomal regions where the Tscc2, ‐3 and ‐4 loci map. In most cases of LOH, the allele of the barely susceptible WF strain was lost, suggesting that these loci in the WF strain encode tumor‐suppressor genes. Analysis of the same tumors for somatic mutations in oncogenes indicated frequent alteration of Ha‐ras, which maps in the Tscc3 region, but rare mutation of the p15INK4B and p16INK4A genes or the p53 and Msh2 genes. Frequent LOH was also found on rat chromosomes 5 (RNO5) and 6 (RNO6). Tumors of large size accumulated LOH at multiple loci, suggesting the involvement of Tscc loci in tumor progression. © 2002 Wiley‐Liss, Inc.
Vascular endothelial growth factor mediated angiogenic potential of pancreatic ductal carcinomas enhanced by hypoxia: An in vitro and in vivo study
Authors: Sipos Bence , Weber Dirk , Ungefroren Hendrik , Kalthoff Holger , Zühlsdorff Andre , Luther Claudia , Török Virag , Klöppel Günter
Published: November 2002

Angiogenesis in pancreatic ductal adenocarcinomas depends on the presence of angiogenic factors such as vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) and is thought to be stimulated by hypoxia. We tested the angiogenic potential of 9 cell lines of pancreatic ductal carcinoma origin by screening mRNA and protein expression of VEGF and bFGF and the release of VEGF into culture medium under normoxic and hypoxic (5% or 0.2% O2) conditions. Angiogenic activity was determined using 2‐ and 3‐D endothelial cell assays. Furthermore, VEGF expression and tumor vascularization were studied in human pancreatic carcinoma tissues from orthotopic xenografts and resection specimens. All cell lines expressed (mRNA, protein) and secreted VEGF, whereas bFGF was only found in 3 cell lines and was secreted into the medium in low concentrations. In addition to the dominant isoforms VEGF121,VEGF165 and VEGF189, 2 isoforms described recently, VEGF145 and VEGF183, were detected. Severe hypoxia (0.2% O2), but not moderate hypoxia (5% O2) raised VEGF mRNA expression and protein secretion in 7/9 and 5/9 cell lines, respectively. Conditioned media from 7/9, 6/9, 8/9 and 7/9 cell lines stimulated endothelial cell proliferation under normoxic (24 and 48 hr) or hypoxic (24 hr, 0.2% and 48 hr 5% O2) conditions, respectively. Conditioned media from 4/9 cell lines also induced capillary‐like sprouting under normoxic conditions and from 6/9 under hypoxic (0.2% O2) conditions. In xenografted carcinoma tissues microvessel density was found not to be increased around areas of ischemic necrosis. In resected ductal carcinomas showing tumor necrosis VEGF expression and microvessel density were only increased in 3/12 and 2/13 cases, respectively. In conclusion, in vitro most pancreatic ductal carcinomas show a distinct VEGF related angiogenic potential, as demonstrated by 2‐ and 3‐D endothelial cell proliferation, which may be promoted by severe hypoxia. Surprisingly, perinecrotic tumor areas, which are supposed to be hypoxic, only rarely showed the expected increase in microvessel density and VEGF expression. © 2002 Wiley‐Liss, Inc.
Oxidative stress has a role in malignant transformation in Barrett's oesophagus
Authors: Sihvo Eero I.T. , Salminen Jukka T. , Rantanen Tuomo K. , Rämö O. Juhani , Ahotupa Markku , Färkkilä Martti , Auvinen Merja I. , Salo Jarmo A.
Published: November 2002

Mechanisms underlying the development of oesophageal adenocarcinoma are poorly understood. To discover the role of oxidative stress and radical scavenger capacity in the malignant transformation of Barrett's oesophagus, we measured myeloperoxidase activity, superoxide dismutase activity, glutathione content and total aromatic DNA adducts. Mucosal specimens came from 52 patients in 6 groups: symptomatic gastro‐oesophageal reflux disease (GORD) without and with endoscopic oesophagitis, Barrett's epithelium without and with dysplasia, adenocarcinoma in the oesophagus and controls. In the GORD‐oesophagitis‐metaplasia‐dysplasia‐adenocarcinoma sequence, glutathione content was progressively lower and myeloperoxidase activity higher than in controls, plateauing at Barrett's epithelium without dysplasia. Only in Barrett's epithelium with dysplasia was SOD activity significantly increased. In all patient groups, DNA adduct levels were significantly higher than the control level. Though these levels between patient groups did not differ significantly, the level was highest in Barrett's epithelium without dysplasia and progressively lower in Barrett's with dysplasia and adenocarcinoma. Pooled data showed a negative correlation between glutathione content and DNA adducts (−0.28, p = 0.05). Simultaneous formation of DNA adducts, increased myeloperoxidase‐related oxidative stress, decreased antioxidant capacity (glutathione content) and the negative correlation between glutathione content and DNA adducts in the GORD–oesophagitis–metaplasia–dysplasia–adenocarcinoma sequence of Barrett's oesophagus indicate a role in the pathogenesis and malignant transformation related to oxidative stress. © 2002 Wiley‐Liss, Inc.
Oral vaccination with recombinant Listeria monocytogenes expressing human papillomavirus type 16 E7 can cause tumor growth in mice to regress
Authors: Lin Chih‐Wei , Lee Jen‐Yi , Tsao Yeou‐Ping , Shen Che‐Piao , Lai Hung‐Cheng , Chen Show‐Li
Published: November 2002

Listeria monocytogenes is a Gram‐positive, facultative intracellular bacterium with the ability to present secreted proteins to the major histocompatibility complex class I pathway to stimulate cell‐mediated immune response. In our study, we constructed the recombinant L. monocytogenes encoding human papillomavirus type 16 E7 gene (rLM‐E7). When orally administered to syngeneic mice, rLM‐E7 could induce a cytotoxic T‐lymphocyte (CTL) response. Furthermore, in vitro flow cytometric assay and in vivo immune deficiency assays showed that rLM‐E7 could prevent and eradicate tumor growth via CD8+‐dependent CTLs. Hence, the potency of rLM‐E7 as a therapeutic vaccine for cervical cancer is the result of the induction E7‐specific cell‐mediated immunity by L. monocytogenes. In addition to potency, this vaccine also offers ease of administration and reduced cost of production compared with other vaccines formulated for injection. Thus, L. monocytogenes encoding HPV‐16 E7 may be a useful oral vaccine for cervical cancer treatment. © 2002 Wiley‐Liss, Inc.
Trend of cervical cancer mortality in Belgium (1954–1994): Tentative solution for the certification problem of unspecified uterine cancer
Authors: Arbyn Marc , Geys Helena
Published: November 2002

We investigated the evolution of mortality from cervical cancer in Belgium between 1954 and 1994 in terms of absolute number of deaths, and standardised and age‐specific mortality rates. Changes over generations were summarised using the standardised cohort mortality ratio. Trend studies of cervical cancer mortality were hampered by certification problems. The number of deaths due to cancer of the uterine cervix is not known exactly since a substantial proportion of death causes are coded as cancer of the uterus without specifying the anatomic site: cervix or corpus uteri. This inaccuracy in codification has been corrected using distribution tables derived from countries where this certification problem is minimal. Trends in mortality from certified and corrected cervical cancers were compared. The corrected age‐standardised mortality rate decreased continuously over the last 4 decades, from over 14 to 5 per 100,000 woman‐years (slope −0.26/100,000 woman‐years, 95% CI −0.28 to −0.24). Its slope is 3.1 times (95% CI 2.9–3.5) more important than for the rate of mortality from certified cervical cancer. In addition to the almost linear decrease, substantial nonlinear cohort influences were observed in certified and corrected mortality rates. The tendency of increasing mortality in women born after 1935 required particular attention. Nevertheless, the slope of the corrected recent cohort effect remained limited in Belgium, probably as a consequence of screening. © 2002 Wiley‐Liss, Inc.
Cyclin E and p27 protein content in human renal cell carcinoma: Clinical outcome and associations with cyclin D
Authors: Hedberg Ylva , Davoodi Estela , Ljungberg Börje , Roos Göran , Landberg Göran
Published: November 2002

Aberrations in the G1‐S transition have been observed in several malignancies, suggesting that cell cycle defects are linked to the activation of oncogenes and inactivation of suppressor genes involved in the transformation process. The frequency of G1/S aberrations in human renal cell carcinoma (RCC) has not been fully clarified. We have therefore analyzed the cyclin E content, using Western blotting, in 79 RCC and 12 corresponding kidney cortex tissues as well as the fraction of p27‐positive cells in 73 RCCs, using immunohistochemistry. Most of the tumors (65%) exhibited higher cyclin E levels than corresponding normal kidney cortex tissues. However, only a small fraction of the tumors (3 of 80) had excessive levels of cyclin E when cyclin E levels were compared with proliferation. Cyclin E levels higher than the median value were associated with aneuploidy (p = 0.025), high stage (p = 0.027), high grade (p = 0.013) and high erythrocyte sedimentation rate (ESR; p = 0.005). Cyclin E was further inversely correlated with cyclin D1 (p = 0.023) and positively correlated with cyclin D3 (p = 0.003). Most tumors (76%) demonstrated a normal fraction of p27‐positive cells. There was an inverse correlation between p27 positivity and tumor size (p = 0.007), despite a lack of correlation between p27 and proliferation. Patients with p27 low tumors had a poor survival (p = 0.002). There was no correlation between p27 and cyclin E levels. In summary, the results suggest that protein expression of cyclin E and/or p27 is linked to tumor behavior. © 2002 Wiley‐Liss, Inc.
MYEOV: A candidate gene for DNA amplification events occurring centromeric to CCND1 in breast cancer
Authors: Janssen Johannes W.G. , Cuny Marguerite , Orsetti Béatrice , Rodriguez Carmen , Vallés Hélène , Bartram Claus R. , Schuuring Ed , Theillet Charles
Published: November 2002

Rearrangements of chromosome 11q13 are frequently observed in human cancer. The 11q13 region harbors several chromosomal breakpoint clusters found in hematologic malignancies and exhibits frequent DNA amplification in carcinomas. DNA amplification patterns in breast tumors are consistent with the existence of at least 4 individual amplification units, suggesting the activation of more than 1 gene in this region. Two candidate oncogenes have been identified, CCND1 and EMS1/CORTACTIN, representing centrally localized amplification units. Genes involved in the proximal and distal amplicons remain to be identified. Recently we reported on a putative transforming gene, MYEOV, mapping 360 kb centromeric to CCND1. This gene was found to be rearranged and activated concomitantly with CCND1 in a subset of t(11;14)(q13;q32)‐positive multiple myeloma (MM) cell lines. To evaluate the role of the MYEOV gene in the proximal amplification core, we tested 946 breast tumors for copy number increase of MYEOV relative to neighboring genes or markers. RNA expression levels were studied in a subset of 72 tumors for which both RNA and DNA were available. Data presented here show that the MYEOV gene is amplified in 9.5% (90/946) and abnormally expressed in 16.6% (12/72) of breast tumors. Amplification patterns showed that MYEOV was most frequently coamplified with CCND1 (74/90), although independent amplification of MYEOV could also be detected (16/90). Abnormal expression levels correlated only partially with DNA amplification. MYEOV DNA amplification correlated with estrogen and progesterone receptor‐positive cancer, invasive lobular carcinoma type and axillary nodal involvement. In contrast to CCND1 amplification, no association with disease outcome could be found. Our data suggest that MYEOV is a candidate oncogene activated in the amplification core located proximal to CCND1. © 2002 Wiley‐Liss, Inc.
Both u‐PA inhibition and vitronectin binding by plasminogen activator inhibitor 1 regulate HT1080 fibrosarcoma cell metastasis
Authors: Praus Michael , Collen Désiré , Gerard Robert D.
Published: November 2002

Overexpression of plasminogen activator inhibitor 1 (PAI‐1) reduces tumor cell migration in vitro and metastasis in mice in vivo by mechanisms involving either inhibition of urokinase plasminogen activator (u‐PA) activity or competition for an integrin binding site on vitronectin. To analyze the effects of PAI‐1 on tumor cell migration in vitro and metastasis in vivo, recombinant adenoviral vectors expressing wild‐type or mutant PAI‐1 proteins were constructed. The mutant PAI‐1 proteins were defective in either vitronectin binding (PAI‐1VN−), plasminogen activator inhibition (PAI‐1INH−) or both (PAI‐1VN−,INH−). In vitro, migration of HT1080 human fibrosarcoma cells through a reconstituted extracellular matrix (ECM) was reduced 73% by overexpression of wild‐type PAI‐1 and 65% by PAI‐1VN− compared with control virus‐infected cells. Migration of cells infected by virus expressing either PAI‐1INH− or PAI‐1VN−,INH− was unaffected, indicating a requirement for plasminogen activator inhibitory activity. In vivo, however, only overexpression of wild‐type PAI‐1 reduced the burden of metastasis by 68% compared with the control group. This indicates that both u‐PA inhibition and PAI‐1 ECM interactions contribute to the mechanism of PAI‐1‐mediated regulation of cell migration. © 2002 Wiley‐Liss, Inc.
Possible transient adaptive response to mitomycin C in peripheral lymphocytes from thyroid cancer patients after iodine‐131 therapy
Authors: Monteiro Gil Octávia , Oliveira Nuno Guerreiro , Rodrigues António Sebastião , Laires António , Ferreira Teresa Cruz , Limbert Edward , Rueff José
Published: November 2002

Our study attempted to assess the possible induction and persistence of an adaptive response in lymphocytes of thyroidectomized thyroid cancer patients treated with 131I (2,590 MBq, corresponding to whole body doses in the range of 200–300 mGy), to a testing dose of mitomycin C (MMC) in vitro. The cytogenetic endpoint studied was the induction of micronuclei in cytokinesis‐blocked peripheral blood lymphocytes, immediately before treatment and 1, 6 and 24 months after therapy. One month after therapy, induction of micronucleated cytokinesis‐blocked lymphocytes (‰) by MMC was lower (34.6 ± 7.7) than before therapy (52.1 ± 5.0). In 7 of 11 patients this reduction was significant. However, at 6 months, induction of micronuclei was markedly higher (133.1 ± 13.6). This significant increase was observed regardless of the decrease at 1 month. At 24 months, the frequency of micronucleated cells decreased (84.8 ± 5.5), but remained higher than before treatment. The results obtained 1 month after therapy could reflect adaptation due to radiation, or a higher rate of early apoptosis or cell death, with bone marrow suppression, visible as a lower response in vitro towards MMC. At 6 months, recovery of the lymphocyte population may occur, and higher responses to MMC in vitro could reflect higher chromosomal instability in the previously irradiated stem cells with a concomitant disappearance of adaptation, whereas at 24 months the results show a tendency to return to pretherapy values. © 2002 Wiley‐Liss, Inc.
Very low incidence of microsatellite instability in intraductal papillary‐mucinous neoplasm of the pancreas
Authors: Nakata Bunzo , Yashiro Masakazu , Nishioka Nobuaki , Aya Makoto , Yamada Shinobu , Takenaka Chiemi , Ohira Masaichi , Ishikawa Tetsuro , Nishino Hiroji , Wakasa Kenichi , Seki Shuichi , Hirakawa Kosei
Published: November 2002

Intraductal papillary‐mucinous carcinoma (IPMC) of the pancreas, a new entity of pancreatic cancer with a favorable prognosis, has shown a gradual increase in the number of reported cases. Patients with high‐frequency microsatellite instability (MSI‐H) tumors have been shown to survive longer than those with low‐frequency MSI (MSI‐L) or microsatellite stable (MSS) tumors in colorectal and gastric cancer. We investigated whether MSI‐H in patients with IPMC can contribute to a good prognosis. The formalin‐fixed paraffin‐embedded tumors and surrounding normal pancreatic tissues from 10 patients with IPMCs and 16 with intraductal papillary‐mucinous adenomas (IPMAs) were provided for DNA extraction after microdissection. Polymerase chain reaction (PCR) was carried out using 8 microsatellite primer marker sets. The mixed PCR samples were analyzed using a genetic analyzer. MSI‐H was determined by assessment of microsatellite variations in 3 or more of the 8 tested markers. Immunohistochemical staining of the MSI‐responsible proteins hMLH1 and hMSH2 was conducted for both the IPMC and IPMA samples. Ten percent of IPMC harbored MSI‐H tumors, whereas no MSI‐H tumors were detected in the IPMAs. Thirty percent of IPMC tumors and 25% of IPMA tumors showed MSI‐L. All IPMCs and IPMAs showed normal expression of both hMLH1 and hMSH2. MSI‐H and loss of hMLH1 and hMSH2 are very rare events in both IPMCs and IPMAs. We conclude that a good prognosis for patients with IPMC is not associated with MSI‐H. © 2002 Wiley‐Liss, Inc.
Promoter hypermethylation of tumor‐related genes in gastric intestinal metaplasia of patients with and without gastric cancer
Authors: To Ka‐Fai , Leung Wai K. , Lee Tin‐Lap , Yu Jun , Tong Joanna H.M. , Chan Michael W.Y. , Ng Enders K.W. , Chung S.C. Sydney , Sung Joseph J.Y.
Published: November 2002

Promoter hypermethylation is an alternative mechanism of gene silencing in human cancers including gastric cancer. While intestinal metaplasia (IM) is generally regarded as a precancerous lesion of the stomach, our study examines the presence of gene promoter hypermethylation in IM of patients with and without gastric cancer. We examined 31 samples of gastric cancer, 36 gastric IM (21 associated with gastric cancer and 15 from noncancer patients) and 10 normal gastric biopsies. Tissues containing foci of IM were carefully microdissected from paraffin‐embedded section. Bisulfite‐modifiedDNA was examined for gene promoter hypermethylation in DAP‐kinase, E‐cadherin, GSTP1, p14, p15, p16, RASSF1A and hMLH1 by methylation‐specific‐PCR. None of the control gastric tissues had hypermethylation detected, but gene promoter hypermethylation was frequently detected in gastric cancer and IM. The mean number of methylated genes in cancer and IM was 3.0 and 1.4, respectively (p < 0.0001). Methylation in IM from cancer patients was all associated with concurrent methylation in the corresponding tumor samples. The numbers of methylated genes were similar in IM obtained from cancer and noncancer patients. By examining the methylation patterns of these genes, 3 differential methylation patterns were recognized: hypermethylation was more frequent in cancer than in IM (DAP‐kinase, p14, p15 and p16); comparable frequencies of methylation in cancer and IM (E‐cadherin and hMLH1); and no methylation (GSTP1). Aberrant methylation in tumor‐related genes is frequently detected in gastric IM of both cancer and noncancer patients, suggesting their early involvement in the multistep progression of gastric carcinogenesis. © 2002 Wiley‐Liss, Inc.
Antitumor vaccination with HER‐2‐derived recombinant antigens
Authors: Vidovic Damir , Graddis Thomas , Chen Feng , Slagle Paul , Diegel Michael , Stepan Lara , Laus Reiner
Published: November 2002

Certain types of malignant tumors overexpress HER‐2, a transmembrane glycoprotein of the class I receptor tyrosine kinase erbB family. To develop an effective HER‐2 vaccine for the selective immunotherapy of these malignancies, we have genetically engineered fusion proteins containing portions of extra‐ and intracellular HER‐2 domains. Activated dendritic cells (DC) cocultured with these novel antigens (Ag) could induce potent responses of Ag‐specific T‐cell lines in vitro and a protection against HER‐2‐expressing tumor in vivo. The protective capabilities of HER‐2‐derived fusion proteins correlated with the efficiency of their presentation to Ag‐specific T‐cell hybridomas. The most effective Ag contained GM‐CSF, the presence of which facilitated their internalization by antigen‐presenting cells (APC) in a receptor‐mediated manner. © 2002 Wiley‐Liss, Inc.
Cancer and other causes of mortality among radiologic technologists in the United States
Authors: Mohan Aparna K. , Hauptmann Michael , Freedman D. Michal , Ron Elaine , Matanoski Genevieve M. , Lubin Jay H. , Alexander Bruce H. , Boice John D. , Morin Doody Michele , Linet Martha S.
Published: December 2002

Data are limited on the role of chronic exposure to low‐dose ionizing radiation in the etiology of cancer. In a nationwide cohort of 146,022 U.S. radiologic technologists (73% female), we evaluated mortality risks in relation to work characteristics. Standardized mortality ratios (SMRs) were computed to compare mortality in the total cohort vs. the general population of the United States. Mortality risks were low for all causes (SMR = 0.76) and for all cancers (SMR = 0.82) among the radiologic technologists. We also calculated relative risks (RR) for the 90,305 technologists who responded to a baseline mailed questionnaire, using Poisson regression models, adjusted for known risk factors. Risks were higher for all cancers (RR = 1.28, 95% confidence interval [CI] = 0.93–1.69) and breast cancer (RR = 2.92, 95% CI = 1.22–7.00) among radiologic technologists first employed prior to 1940 compared to those first employed in 1960 or later, and risks declined with more recent calendar year of first employment (p‐trend = 0.04 and 0.002, respectively), irrespective of employment duration. Risk for the combined category of acute lymphocytic, acute myeloid and chronic myeloid leukemias was increased among those first employed prior to 1950 (RR = 1.64, 95% CI = 0.42–6.31) compared to those first employed in 1950 or later. Risks rose for breast cancer (p‐trend = 0.018) and for acute lymphocytic, acute myeloid and chronic myeloid leukemias (p‐trend = 0.05) with increasing duration of employment as a radiologic technologist prior to 1950. The elevated mortality risks for breast cancer and for the combined group of acute lymphocytic, acute myeloid and chronic myeloid leukemias are consistent with a radiation etiology given greater occupational exposures to ionizing radiation prior to 1950 than in more recent times. © 2002 Wiley‐Liss, Inc.
Past and future directions in x‐ray computed tomography (CT)
Authors: Natterer Frank , Ritman Erik L.
Published: November 2002

We give a short account of the history of CT from motion tomography in the early 1930's to sprial CT. We discuss the physical and the mathematical background. Finally we give an outlook on possible future developments of CT and related techniques. © 2002 Wiley Periodicals, Inc. Int J Imaging Syst Technol 12, 175–187, 2002; Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/ima.10021
Image indexing by Color Plane Moment
Authors: Lin Shinfeng D. , Chen Kuo‐Hae , Yang Xin‐Lun
Published: November 2002

Among the features of content‐based image retrieval, color features provide important clues to search similar image contents. In addition to color, there exists more information in the image. In this article, we propose a new method for content‐based image retrieval: Color Plane Moment (CPM). This method combines colors' content and their spatial distribution to improve image query results. It integrates the ideas of color histogram, backprojection, and moments. The CPM uses backprojection as one of the image preprocessing methods and computes the invariant moments with those dominant color plane images after preprocessing. There are several dominant colors chosen by color histogram in an image, and each can be expressed by seven invariant moment values that represent spatial distribution of those dominant color planes, respectively. Simulation results demonstrate that the proposed technique outperforms the other techniques. © 2002 Wiley Periodicals, Inc. Int J Imaging Syst Technol 12, 139–148, 2002; Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/ima.10022
Multifoveal imager for stereo applications
Authors: Camacho P. , Coslado F. , González M. , Sandoval F.
Published: November 2002

A multiresolution imager based on adaptive retinal structures, with data compressions above 85%, is presented in this article. The main goal of the imager platform is to speed up image processing with the use of selective data reductions to shorten the vision systems' tasks in stereo applications. Implemented on a field‐programmable gate array, the platform can be configured as the front end of active vision systems, with use of adaptive foveal sensing on uniresolution images to cover wide fields of view, being also a development tool for multiresolution applications with different image formats and interfaces. The multifoveal imager provides the hierarchical data structures related to multiresolution levels, following instructions to control sensor parameters or to perform adaptive fovea fixations in real time, adapting its operation to the constraints of the active vision systems. It also uses intermediate resolution data to implement in hardware an efficient background extractor to cooperate with image processors in motion detection tasks and attention mechanisms. Some platform configurations are explained and experimental results are discussed in relation to the advantages of the adaptive retinal structures. © 2002 Wiley Periodicals, Inc. Int J Imaging Syst Technol 12, 149–165, 2002; Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/ima.10023
Wavelet‐based adaptive vector quantization for still‐image coding
Authors: Chen Wen‐Shiung , Hsieh Lili
Published: November 2002

Wavelet transform coding (WTC) with vector quantization (VQ) has been shown to be efficient in the application of image compression. An adaptive vector quantization coding scheme with the Gold‐Washing dynamic codebook‐refining mechanism in the wavelet domain, called symmetric wavelet transform‐based adaptive vector quantization (SWT‐GW‐AVQ), is proposed for still‐image coding in this article. The experimental results show that the GW codebook‐refining mechanism working in the wavelet domain rather than the spatial domain is very efficient, and the SWT‐GW‐AVQ coding scheme may improve the peak signal‐to‐noise ratio (PSNR) of the reconstructed images with a lower encoding time. © 2002 Wiley Periodicals, Inc. Int J Imaging Syst Technol 12, 166–174, 2002; Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/ima.10024
Role of ERK and calcium in the hypoxia‐induced activation of HIF‐1
Authors: Mottet Denis , Michel Gaetan , Renard Patricia , Ninane Noelle , Raes Martine , Michiels Carine
Published: November 2002

Oxygen‐dependent regulation of HIF‐1 activity occurs at multiple levels in vivo. The mechanisms regulating HIF‐1α protein expression have been most extensively analyzed but the ones modulating HIF‐1 transcriptional activity remain unclear. Changes in the phosphorylation and/or redox status of HIF‐1α certainly play a role. Here, we show that ionomycin could activate HIF‐1 transcriptional activity in a way that was additive to the effect of hypoxia without affecting HIF‐1α protein level. In addition, a calmodulin dominant negative mutant and W7, a calmodulin antagonist, as well as BAPTA, an intracellular calcium chelator, inhibited the hypoxia‐induced HIF‐1 activation. These results indicate that elevated calcium in hypoxia could participate in HIF‐1 activation. Furthermore, ERK but not JNK phosphorylation was evidenced in both conditions, ionomycin and hypoxia. PD98059, an inhibitor of the ERK pathway as well as a ERK1 dominant negative mutant also blocked HIF‐1 activation by hypoxia and by ionomycin. A MEKK1 (a kinase upstream of JNK) dominant negative mutant had no effect. In addition, BAPTA, calmidazolium, a calmodulin antagonist and PD98059 inhibited VEGF secretion by hypoxic HepG2. All together, these results suggest that calcium and calmodulin would act upstream of ERK in the hypoxia signal transduction pathway. © 2002 Wiley‐Liss, Inc.
Cytoplasmic bacterial lipopolysaccharide does not induce NFκB activation or NFκB mediated activation signals in human macrophages and an LPS reporter cell line
Authors: Seitzer Ulrike , Gerdes Johannes
Published: November 2002

Although many membrane components have been described to be involved in the activation of cells by bacterial lipopolysaccharide (LPS), the question remains whether LPS, once internalized by target cells, is also capable of interacting with cytoplasmic elements in such a way that activation of cells results independently of receptor engagement. This is an important aspect to consider with respect to the development of strategies aimed at attenuating adverse effects of LPS in the framework of bacterial infections. In this study, human monocyte derived macrophages as representatives of one of the primary target cells activated by LPS, were microinjected with LPS to circumvent exogenous LPS stimulation. Parameters correlating to cytoplasmic activation of the nuclear transcription factor NFκB (intracellular calcium mobilization), to nuclear translocation of the NFκB p65 subunit and to mRNA‐transcription of inflammatory cytokines known to be expressed upon exogenous LPS‐stimulation and to require NFκB activation (interleukin‐1beta, interleukin‐6, tumor necrosis factor alpha) were investigated. In addition, the LPS‐reporter cell line 3E10, which contains a reporter gene under the control of an NFκB‐inducible promoter was analyzed with respect to NFκB nuclear translocation and reporter gene expression. None of the cellular systems used and none of the parameters investigated led to the observation that intracellular LPS leads to activation of the cells in comparison to external LPS stimulation. These experiments allow the conclusion that LPS in the cytoplasmic compartment does not lead to NFκB translocation, cytokine mRNA transcription, and NFκB dependent protein expression and suggest that these activation parameters require the interaction of LPS with external membrane components. © 2002 Wiley‐Liss, Inc.
Use of isolated mature osteoblasts in abundance acts as desired‐shaped bone regeneration in combination with a modified poly‐DL‐lactic‐co‐glycolic acid (PLGA)‐collagen sponge
Authors: Ochi Kensuke , Chen Gouping , Ushida Takashi , Gojo Satoshi , Segawa Kaoru , Tai Hitoshi , Ueno Kenju , Ohkawa Hiroyuki , Mori Taisuke , Yamaguchi Akira , Toyama Yoshiaki , Hata Jun‐ichi , Umezawa Akihiro
Published: November 2002

Controlled regeneration of bone or cartilage has recently begun to facilitate a host of novel clinical treatments. An osteoblast line, which we isolated is able to form new bone matrix in vivo within 2 days and exhibits a mature osteoblast phenotype both in vitro and in vivo. Using these cells, we show that cuboidal bones can be generated into a predesigned shaped‐bone with high‐density bone trabeculae when used in combination with a modified poly‐DL‐lactic‐co‐glycolic acid (PLGA)‐collagen sponge. PLGA coated with collagen gel serves as a good scaffold for osteoblasts. These results indicate that mature osteoblasts, in combination with a scaffold such as PLGA‐collagen sponge, show promise for use in a custom‐shaped bone regeneration tool for both basic research into osteogenesis and for development of therapeutic applications. © 2002 Wiley‐Liss, Inc.
Inhibition of growth and sensitization to cisplatin‐mediated killing of ovarian cancer cells by polyphenolic chemopreventive agents
Authors: Chan Marion M. , Fong Dunne , Soprano Kenneth J. , Holmes William F. , Heverling Harry
Published: November 2002

The polyphenolic compounds curcumin and quercetin increased sensitivity of ovarian cancer cells (CAOV3 and SKOV3) to cisplatin. The effect was obtained when the compounds were added simultaneously with cisplatin, as well as when they were added 24 h before. High serum levels of certain cytokines, for example interleukin‐6 (IL‐6), have been associated with poor prognosis and cisplatin resistance in various forms of cancer. Furthermore, it has been hypothesized that cytokines may increase proliferation, metastasis, and stimulate production of detoxification enzymes and multi‐drug resistant proteins. Curcumin inhibits the production of many cytokines. The two ovarian cell lines differ significantly in IL‐6 production, and correspondingly the high producer, CAOV3, was less susceptible to cisplatin. Curcumin inhibited the production of IL‐6 in this cell suggesting that one of the mechanisms for synergy between cisplatin and curcumin was by reducing the autologous production of IL‐6. However, the synergy was also observed in the low IL‐6 producer, SKOV3, indicating that the action was most probably a result of multiple targeting. In sum, this study suggests that the compounds, curcumin and quercetin, potentially may be useful for enhancing drug sensitivity in certain cancer. J. Cell. Physiol. 194: 63–70, 2002. © 2002 Wiley‐Liss, Inc.
Pleiotropic effects of fatty acids on pancreatic β‐cells
Authors: Haber E.P. , Ximenes H.M.A. , Procópio J. , Carvalho C.R.O. , Curi R. , Carpinelli A.R.
Published: November 2002

Hyperlipidemia is frequently associated with insulin resistance states as found in type 2 diabetes and obesity. Effects of free fatty acids (FFA) on pancreatic β‐cells have long been recognized. Acute exposure of the pancreatic β‐cell to FFA results in an increase of insulin release, whereas a chronic exposure results in desensitization and suppression of secretion. We recently showed that palmitate augments insulin release in the presence of non‐stimulatory concentrations of glucose. Reduction of plasma FFA levels in fasted rats or humans severely impairs glucose‐induced insulin release. These results imply that physiological plasma levels of FFA are important for β‐cell function. Although, it has been accepted that fatty acid oxidation is necessary for its stimulation of insulin secretion, the possible mechanisms by which fatty acids (FA) affect insulin secretion are discussed in this review. Long‐chain acyl‐CoA (LC‐CoA) controls several aspects of the β‐cell function including activation of certain types of protein kinase C (PKC), modulation of ion channels, protein acylation, ceramide‐ and/or nitric oxide (NO)‐mediated apoptosis, and binding to nuclear transcriptional factors. The present review also describes the possible effects of FA on insulin signaling. We showed for the first time that acute exposure of islets to palmitate upregulates the intracellular insulin‐signaling pathway in pancreatic islets. Another aspect considered in this review is the source of FA for pancreatic islets. In addition to be exported to the medium, lipids can be transferred from leukocytes (macrophages) to pancreatic islets in co‐culture. This process consists an additional source of FA that may plays a significant role to regulate insulin secretion. © 2002 Wiley‐Liss, Inc.
Human osteoblasts express functional CXC chemokine receptors 3 and 5: Activation by their ligands, CXCL10 and CXCL13, significantly induces alkaline phosphatase and β‐N‐acetylhexosaminidase release
Authors: Lisignoli Gina , Toneguzzi Stefania , Piacentini Anna , Cattini Luca , Lenti Anna , Tschon Matilde , Cristino Sandra , Grassi Francesco , Facchini Andrea
Published: November 2002

Osteoblasts (OBs) contribute to the maintenance of bone homeostasis and their activity can be influenced by immune cells localized in bone lacunae. We investigated the expression of the chemokine receptors in isolated human OBs by reverse transcriptase‐polymerase chain reaction (RT‐PCR) and flow cytometry, and report a novel finding, namely, that OBs express high levels of CXC chemokine receptor 3 (CXCR3) and 5 (CXCR5). Functional assays to evaluate CXCR3 and CXCR5 demonstrated that their ligands—CXCL10 and CXCL13, respectively—significantly induce the release of β‐N‐acetylhexosaminidase, an enzyme involved in endochondral ossification and bone remodeling able to degrade important extracellular matrix components. Alkaline phosphatase activity, a useful index of matrix formation was also up‐regulated by CXCL10 and CXCL13. However, OB activation by these ligands does not affect OB proliferation. Both Bordetella pertussis toxin and neutralizing anti‐CXCR3/anti‐CXCR5 monoclonal antibodies block CXCL10 and CXCL13 induction, respectively. We also demonstrated the expression of CXCL10 and CXCL13 in human bone tissue biopsies. These results indicate that both CXCR3/CXCL10 and CXCR5/CXCL13 receptor–ligand pairs may play an important role in OB activity through the specific up‐regulation of two enzymes, which are involved in the bone remodeling process. Moreover, our data suggest that OBs may play a role in the modulation of bone formation through the combined action of these two enzymes. © 2002 Wiley‐Liss, Inc.
Development of the fetal intestine in mice lacking the glucocorticoid receptor (GR)
Authors: Gartner Hans , Graul M. Colleen , Oesterreicher Thomas J. , Finegold Milton J. , Henning Susan J.
Published: November 2002

During rodent development there are two surges of circulating corticosterone: one just prior to birth and then one in the third postnatal week. Prior studies have shown that the latter controls the rate of intestinal development in the postnatal period. To date, a role for the earlier surge in the prenatal phase of intestinal development has not been investigated. We hypothesized that the late fetal surge of circulating corticosterone is involved in both morphologic and functional maturation of the intestinal epithelium, and thus that such maturation would be delayed if glucocorticoid action was abrogated. The hypothesis was tested by studying intestinal development in mice lacking a functional glucocorticoid receptor (GR). After GR+/− mice were bred onto a C57Bl/6 background, heterozygote matings yielded the expected ratios of −/−, +/−, and +/+ offspring. Analysis of GR mRNA in intestines of +/+ and −/− fetuses confirmed expression in wild‐type mice but not in the GR‐null mice. Intestinal histology of GR+/+ and −/− littermates at E13.5, E15.5, and E18.5 showed no effect of GR genotype on morphologic development. Further studies at E18.5 showed that GR−/− mice have normal functional maturation of the intestinal epithelium as assessed by: lactase activity in the enterocyte lineage, normal numbers of goblet and enteroendocrine cells, and normal numbers of proliferating cells in the intestinal crypts. Neither the minerolocorticoid receptor (MR) nor the pregnane X receptor (PXR) showed compensatory up‐regulation in GR−/− mice. We conclude that, in contrast to our original hypothesis, the rodent intestine passes through a phase of glucocorticoid independence (late fetal) prior to becoming responsive to glucocorticoids in the postnatal period. These findings have implications for the clinical use of corticosteroids to enhance intestinal maturation in preterm infants. © 2002 Wiley‐Liss, Inc.