bluuebunny/crossref_metadata_2025_split huggingface dataset:
Hypermethylation of the tumor suppressor gene RASSFIA and frequent concomitant loss of heterozygosity at 3p21 in cervical cancers
Authors: Yu Mei Y. , Tong Joanna H.M. , Chan Paul K.S. , Lee Tin L. , Chan Michael W.Y. , Chan Anthony W.H. , Lo Kwok W. , To Kai F. 
Published: April 2003

AbstractLoss of heterozygosity (LOH) at chromosome 3p21 is frequent in cervical cancers. The candidate tumor suppressor gene, RASSF1A located at 3p21.3, is found to be inactivated in several major human cancers, implicating its significance in carcinogenesis. We aimed to investigate the status of RASSF1A in cervical cancers. The mutation and methylation status of RASSF1A were analysed in 4 cervical cancer cell lines, 50 primary cervical cancers including 33 squamous cell carcinoma (SCC), 17 adenocarcinoma (AC) and 11 normal controls. The primary cancer samples were also detected for LOH at 3p21 and human papillomavirus (HPV). Hypermethylation of RASSF1A was detected in 30% of SCC, 12% of AC and in 1 of the 4 cancer cell lines but was absent in all normal cases. Methylation of the cancer cell line was associated with loss of gene expression, which was restored by demethylation. About 67% (8 of 12) of hypermethylated primary cancers showed concomitant LOH at 3p21. No somatic mutation was found in all primary cancer samples or cell lines but 2 cases showed germline polymorphism at codon 133. Oncogenic HPV DNAs were found in most cancer samples. No correlation was detected between RASSF1A‐hypermethylation or LOH at 3p21 and age of patient, HPV genotype, tumor grade and stage. Hypermethylation of RASSF1A occurs in a subset of cervical cancers, among which concomitant LOH at 3p21 is common. The results supported that RASSF1A may be one of the cervical cancer‐related tumor suppressor genes located at 3p21 regions. © 2003 Wiley‐Liss, Inc.
Differences in T‐cell immunity toward tumor‐associated antigens in colorectal cancer and breast cancer patients
Authors: Nagorsen Dirk , Scheibenbogen Carmen , Schaller Gerhard , Leigh Binta , Schmittel Alexander , Letsch Anne , Thiel Eckhard , Keilholz Ulrich 
Published: April 2003

AbstractThere is increasing evidence that tumors elicit specific T‐cell responses in a substantial proportion of patients. Recently, we have shown that in patients with colorectal cancer specific T cells against the tumor‐associated antigens (TAA) Ep‐CAM, her‐2/neu or CEA can be detected in peripheral blood using IFNγ‐ELISPOT assay. In our study, we have analyzed T‐cell responses against HLA‐A*0201‐restricted epitopes of these TAA in peripheral blood of patients with breast cancer and colorectal cancer. Surprisingly, a complete absence of ex vivo T‐cell responses against these TAA was found in 20 patients with breast cancer. In contrast, specific T cells were detectable in 12 of 49 patients with colorectal cancer against at least 1 of these TAA, confirming our previous results. T‐cell responses against influenza‐derived peptides were similar in both malignancies. The results of our study indicate a difference either of tumor immunogenicity or of the migratory pattern of tumor‐specific T cells between breast cancer and colorectal cancer patients. The findings reported here have implications for the development of antigen‐specific T‐cell therapies. © 2003 Wiley‐Liss, Inc.
Atopic disease and childhood acute lymphoblastic leukemia
Authors: Schüz Joachim , Morgan Gareth , Böhler Eva , Kaatsch Peter , Michaelis Jörg 
Published: April 2003

AbstractOur objective was to test the hypothesis that the risk of childhood leukemia is associated with allergies or a family history of allergy. We used a German population‐based case‐control study with self‐reported information on allergies of the children and their first‐degree relatives. Our study included a total of 1,130 cases of acute lymphoblastic leukemia (ALL), 164 cases of acute myeloid leukemia (AML) and 2,957 controls. A major finding of our study is that hay fever, neurodermatitis and contact eczema are underrepresented within the group of children with ALL, with respective odds ratios (OR) of 0.45 (95% confidence interval [CI] 0.31–0.66) for hay fever, of 0.49 (CI 0.34–0.71) for neurodermatitis and of 0.62 (CI 0.39–0.99) for eczema, respectively. Atopic diseases, comprising hay fever, neurodermatitis and asthma, are much stronger related with a reduced risk of ALL than other allergies (OR 0.52, CI 0.40–0.67 vs. OR 0.89, CI 0.66–1.21). The strongest association is seen with an atopy in the index child; however, ALL risk is also reduced if one of the parents or a sibling had an atopic disease. No such consistent pattern is seen for AML. Our data suggest that atopy or a family history of atopy are associated with a reduced risk of childhood ALL. Recall bias remains a concern, but sensitivity analysis provided some evidence that the protective effect is unlikely to be attributable to this bias in its entirety. © 2003 Wiley‐Liss, Inc.
Targeting of cells expressing wild‐type EGFR and type‐III mutant EGFR (EGFRvIII) by anti‐EGFR MAb ICR62: A two‐pronged attack for tumour therapy
Authors: Modjtahedi Helmout , Moscatello David K. , Box Gary , Green Margaret , Shotton Christine , Lamb David J. , Reynolds Lesley J. , Wong Albert J. , Dean Christopher , Thomas Hilary , Eccles Suzanne 
Published: April 2003

AbstractWith a view to their use in cancer therapy, we have produced rat monoclonal antibodies (MAbs) directed against 5 distinct epitopes (A–E) on the external domain of the wild‐type human EGF receptor (EGFR). Here, we have investigated the relative binding and anti‐tumour activity of our anti‐EGFR MAbs against HC2 20d2/c cells, which have been engineered to overexpress the type‐III mutated form of the human EGFR (EGFRvIII). We found that anti‐EGFR MAbs that are the most effective antagonists of EGFR ligands (e.g., ICR16, ICR62 and ICR80) also bind to cells that overexpress the EGFRvIII. Although these antibodies are potent inhibitors of the growth of cells which express wild‐type EGFR, they did not directly inhibit the growth in vitro of EGFRvIII expressing HC2 20d2/c cells, or the constitutive tyrosine kinase activity of this receptor. However, in the presence of human peripheral blood mononuclear cells (PBMC), the rat IgG2b MAb ICR62 induced strong antibody‐dependent cell‐mediated cytotoxicity (ADCC) against HC2 20d2/c cells in culture. Interestingly, MAb ICR62 also inhibited very effectively experimental lung metastases of HC2 20d2/c cells in athymic nude mice. Our results suggest that anti‐EGFR MAb ICR62, which binds to the EGFRvIII, may have potential in the treatment of tumors which overexpress the EGFRvIII via immunological mechanisms such as ADCC. Since tumours that are EGFRvIII positive may also overexpress the wild‐type EGFR, the use of anti‐EGFR MAbs that target both wild‐type and mutant receptors may have advantages over those that target only1form. © 2003 Wiley‐Liss, Inc.
Immunization with tumor‐derived ER chaperone grp170 elicits tumor‐specific CD8+ T‐cell responses and reduces pulmonary metastatic disease
Authors: Wang Xiang‐Yang , Kazim Latif , Repasky Elizabeth A. , Subjeck John R. 
Published: April 2003

AbstractGlucose‐regulated protein (grp) 170 is a molecular chaperone localized in endoplasmic reticulum (ER), which has been demonstrated to interact with the peptides translocated by transporter associated with antigen presentation (TAP). In our study, we have evaluated the therapeutic efficacy of tumor‐derived grp170 against the highly metastatic and poorly immunogenic murine melanoma B16F10. Immunization of mice with grp170 preparations from autologous tumor significantly delayed progression of the primary cancer and reduced established pulmonary metastases, which was associated with the prolonged survival of metastases‐bearing mice. However, grp170 from normal liver or antigenically distinct tumor failed to exhibit therapeutic effect. In addition, tumor‐derived grp170 elicited a potent cytotoxic T‐lymphocyte response specific for B16F10 tumor, which correlates with in vivo protective effects. Adoptive transfer of splenocytes obtained from B16F10‐grp170‐primed animals remarkably suppressed pulmonary metastases. Depletion of either CD4+ or CD8+ T cells in priming phase significantly abrogated the tumor immunity induced by the B16F10‐grp170. However, the vaccine activity was intact when CD4+, not CD8+, T cells were depleted in effector phase. It suggests that CD4+ T helper cells play an important role in the generation of effective antitumor response, whereas CD8+ T cells are predominantly involved in direct killing of tumor cells. These observations have strong clinical implications for using tumor‐derived grp170 as a therapeutic vaccine against metastatic diseases. © 2003 Wiley‐Liss, Inc.
Altered tumor vessel maturation and proliferation in placenta growth factor‐producing tumors: Potential relationship to post‐therapy tumor angiogenesis and recurrence
Authors: Taylor Alice P. , Rodriguez Marisol , Adams Kelly , Goldenberg David M. , Blumenthal Rosalyn D. 
Published: April 2003

AbstractCells in human tumor xenografts express similar levels of angiogenic growth factors before treatment. After radioimmunotherapy (RAIT) surviving tumor cells upregulate angiogenic growth factors, including placenta growth factor (PlGF), in a tumor‐specific pattern. To determine the role of post‐treatment PlGF expression on blood vessel recovery, tumor xenografts were assayed for post‐RAIT vessel density (CD34+), proliferation (PCNA+) and maturity (SMA+ pericytes/mural cells). To further analyze the role of PlGF in blood vessel formation, PlGF‐containing Matrigel implants were also assessed in a similar manner. The xenografts producing post‐treatment PlGF increased CD34+ microvessel density 2‐ to 4‐fold over untreated controls (p < 0.05) within 3 weeks of RAIT treatment. The proportion of mature microvessels (SMA+) decreased. Pericyte coverage and density of microvessels remained stable in the tumor that expressed neither PlGF nor VEGF after treatment. Hemoglobin content of PlGF‐containing Matrigel implants was 5.7‐fold that of anti‐PlGF/anti‐VEGF treated controls (Day 6, p < 0.03). The vessel density in PlGF‐implants averaged 36.8 ± 10.6/mm compared to 4.9 ± 6.5/mm2 in controls (p < 0.001). Vessels of PlGF‐implants were lined by vWF+ cells, which were mostly flt‐1+. These findings point to a role for PlGF in rapid restoration of tumor blood supply after treatment and thus, to enhanced likelihood of tumor regrowth. Likewise, the cells of primary human tumors that upregulate PlGF after treatment may be more likely to survive and form recurring tumors. Prevention of this angiogenic response to treatment may require administration of anti‐angiogenic therapy during, rather than after, treatment. © 2003 Wiley‐Liss, Inc.
Von Hippel‐Lindau gene alterations in sporadic benign and malignant pheochromocytomas
Authors: Dannenberg Hilde , De Krijger Ronald R. , van der Harst Erwin , Abbou Mustaffa , IJzendoorn Ynske , Komminoth Paul , Dinjens Winand N.M. 
Published: April 2003

AbstractThe Von Hippel‐Lindau (VHL) gene product has a wide spectrum of tissue‐specific functions, and specific germline mutations are associated with clinical phenotypes in VHL disease. In particular, missense mutations are correlated with the susceptibility to pheochromocytomas. An association between VHL aberrations and prognosis has been suggested in renal clear cell carcinoma but has not been studied in pheochromocytomas. We studied the frequency and spectrum of VHL alterations in apparently sporadic pheochromocytomas in relation to the clinical behavior in 72 patients, including 48 patients with clinically benign and 24 patients with malignant pheochromocytomas. Single‐strand conformation polymorphism (SSCP) analysis followed by DNA sequencing, loss of heterozygosity analysis of the VHL locus and immunohistochemistry for VHL protein expression were used to investigate somatic VHL gene alterations. In 2 patients, 1 with a malignant tumor, germline mutations were identified in the stop codon. Tumor‐specific intragenic VHL mutations and accompanying loss of heterozygosity were identified in 2 (4.3%) of 47 sporadic benign pheochromocytomas compared to 4 (17.4%) of 23 malignant tumors (p = 0.064). Only one of these mutations has been previously described, in a renal clear cell carcinoma. Expression of the VHL protein was observed in all pheochromocytomas. No distinction in the nature of VHL alterations between benign and malignant pheochromocytomas and no correlation with histopathologic or clinical features was observed. We report novel VHL mutations in sporadic pheochromocytomas, which are slightly correlated with malignancy. VHL mutations may have some impact on the malignant transformation of pheochromocytomas. © 2003 Wiley‐Liss, Inc.
TP53, p14ARF, p16INK4a and H‐ras gene molecular analysis in intestinal‐type adenocarcinoma of the nasal cavity and paranasal sinuses
Authors: Perrone Federica , Oggionni Maria , Birindelli Sarah , Suardi Simona , Tabano Silvia , Romano Roberta , Moiraghi Maria Luisa , Bimbi Gabriella , Quattrone Pasquale , Cantu Giulio , Pierotti Marco A. , Licitra Lisa , Pilotti Silvana 
Published: April 2003

AbstractIntestinal‐type adenocarcinoma (ITAC) of the nasal cavity and paranasal sinuses is an uncommon tumor associated with occupational exposure to dusts of different origin. Few investigations addressed molecular alterations in ITAC mainly focused on TP53, K‐ras and H‐ras gene mutations. The occurrence of TP53, p14ARF and p16INK4a deregulation and H‐ras mutations was investigated in 21 consecutive and untreated ITACs cases, 17 with known professional exposure. No H‐ras mutations were found. In patients with known exposure, cumulative evidence of TP53 or p14ARF alterations accounted for 88% and the evidence of p16INK4a alterations for 65%, respectively. TP53 mutations were present in 44% of the ITACs, consisted of G:C→A:T transitions in 86%, and involved the CpG dinucleotides in 50% of the cases. LOH at the locus 17p13 and an uncommon high rate of p53 stabilization were detected in 58% and 59% of the cases, respectively. p14ARFand p16INK4a promoter methylation accounted for 80% and 67% respectively, and LOH at the locus 9p21 occurred in 45% of the cases. Interestingly, all dust‐exposed tumors with p16INK4a alterations shared TP53 or p14ARF deregulation. The present results show a close association of this occupational tumor with TP53, p14ARF and p16INK4a gene deregulation. Given the important role that these genes play in cell growth control and apoptosis, the knowledge of ITAC genetic profile may be helpful in selecting more tailored treatments. © 2003 Wiley‐Liss, Inc.
Overexpression of CCR7 mRNA in nonsmall cell lung cancer: Correlation with lymph node metastasis
Authors: Takanami Iwao 
Published: April 2003

AbstractTumor cell migration into the lymph nodes is an important aspect of cancer, yet little is known about the processes involved. CCR7 has been shown to play an important role in tumor cell migration and lymph node metastasis. The aim of our study was to evaluate the expression of CCR7 in nonsmall cell lung cancers (NSCLCs). We investigated CCR7 expression in 71 patients with NSCLC who underwent curative tumor resection by means of reverse transcription‐polymerase chain reaction (RT‐PCR) and immunohistochemistry. CCR7 mRNA was expressed in 45 cases (63.3%). The CCR7 mRNA expression was significantly associated with lymph node metastasis, stage, lymphatic invasion, CCR7 protein and CXCR4 protein (p = 0.0001 for lymph node metastasis; p < 0.0001 for stage; p = 0.0454 for lymphatic invasion; p < 0.0001 for CCR7 protein; p = 0.0013 for CXCR4 protein). Twenty‐six (57.8%) of 45 cases with CCR7 mRNA expression in their cancer tissues were node‐positive, whereas only 3 (11.5%) of 26 cases without CCR7 mRNA expression were node‐positive. Furthermore, expression of CCR7 mRNA was shown to be an independent predictor of lymph node metastasis by multivariate analysis (p = 0.0117). Our study demonstrates that CCR7 might be related to the development of lymph node metastasis in NSCLC. The expression of CCR7 mRNA could open up a new window for the diagnostic staging and treatment of NSCLC. © 2003 Wiley‐Liss, Inc.
Persistence of xenogenized vaccine cells in vivo
Authors: Graf Nicolas , Adam Christian , Mocikat Ralph 
Published: April 2003

AbstractTrioma cell vaccination is a potent new immunotherapeutic strategy for the treatment of B cell neoplasias. It is based on the specific redirection of tumor antigens against surface receptors on professional antigen‐presenting cells (APC) that internalize antigens and present immunogenic peptides to T‐lymphocytes. Tumor cells are converted to trioma cells by fusion with xenogeneic hybridomas expressing an anti‐APC specificity. The trioma cell is a polyvalent vaccine that contains potentially all lymphoma‐derived antigens. Apart from the expression of the APC‐binding arm by the trioma cell, another requirement for successful tumor protection is the xenogeneic moiety of the trioma cells. We show that, despite their xenogenicity, trioma cells persist for extended periods in vaccinated animals. Trioma cells could be identified in spleens as long as about 12 weeks post vaccination. By using a suicide gene approach, trioma cells could partly be eliminated from immunized mice, whereby the antitumor effect was partly abrogated. We argue that not all trioma cells are immediately lysed in vivo and that the cell cycle of the remaining cells is arrested after having undergone few divisions. Trioma cells surviving in vivo may be instrumental for efficient induction of tumor immunity. © 2003 Wiley‐Liss, Inc.
Expression of hypoxia‐inducible factor‐1α is associated with tumor vascularization in human colorectal carcinoma
Authors: Kuwai Toshio , Kitadai Yasuhiko , Tanaka Shinji , Onogawa Seiji , Matsutani Norimasa , Kaio Eijiro , Ito Masanori , Chayama Kazuaki 
Published: April 2003

AbstractHIF‐1 is reported to transactivate expression of VEGF, which is an important angiogenic factor. To determine whether HIF‐1α plays a role in angiogenesis through its regulation of VEGF, we examined expression of HIF‐1α and its relation to clinicopathologic features, VEGF expression and prognosis of patients with colorectal carcinoma. Expression of HIF‐1α and VEGF was examined in 4 colorectal carcinoma cell lines (COLO320DM, COLO201, DLD‐1, WiDr) and 149 colorectal carcinoma tissues (10 fresh specimens, 139 archival, paraffin‐embedded specimens). HIF‐1α protein levels were increased by hypoxia in 3 of 4 colorectal carcinoma cell lines (COLO201, DLD‐1, WiDr), and VEGF mRNA levels were also increased by hypoxia in the same cell lines. In 8 of 10 patients with colorectal cancer, expression of HIF‐1α and VEGF was increased in tumor tissues compared to corresponding normal mucosa. Of 139 archival specimens of colorectal carcinoma, 81 (58.3%) expressed HIF‐1α protein at a high level. HIF‐1α expression was correlated with tumor invasion, tumor stage, lymphatic invasion, venous invasion and liver metastasis. Moreover, HIF‐1α expression was correlated significantly with VEGF expression and microvessel density. Although there was a tendency for poorer prognosis in patients with high HIF‐1α‐expressing tumors, this correlation was not statistically significant. These findings suggest that HIF‐1α may play a role in angiogenesis and tumor progression via regulation of VEGF in human colorectal carcinoma. © 2003 Wiley‐Liss, Inc.
Children, family and cancer survival in Norway
Authors: Kravdal Øystein 
Published: April 2003

AbstractModels for all‐cause mortality among 45,000 men and women with cancer in 12 different sites were estimated, using register and census data for complete Norwegian birth cohorts. This observed‐survival method appeared to be an adequate approach. The results support the idea that women who were pregnant shortly before a breast cancer diagnosis may have a poorer prognosis than others. In principle, such an effect may also reflect that these women have a young child during the follow‐up period and are burdened by that. However, this social explanation can hardly be very important, given the absence of a corresponding significant effect in men and for other cancer sites in women. Breast cancer is different from other malignancies also with respect to the effect of parenthood more generally, regardless of the timing of the pregnancies. On the whole, male and female cancer patients with children experience lower mortality than the childless, though without a special advantage associated with adult children. This suggests a social effect, perhaps operating through a link between parenthood, lifestyle and general health. No parity effect was seen for breast cancer, however, which may signal that the social effect is set off against an adverse physiologic effect of motherhood for this particular cancer. Among men, both marriage and parenthood were associated with a good prognosis. Married male cancer patients with children had mortality one‐third lower than that among the childless and never‐married. Women who had never married did not have the same disadvantage. © 2003 Wiley‐Liss, Inc.
Frequent downregulation of DMBT1 and galectin‐3 in epithelial skin cancer
Authors: Mollenhauer Jan , Deichmann Martin , Helmke Burkhard , Müller Hanna , Kollender Gaby , Holmskov Uffe , Ligtenberg Toon , Krebs Inge , Wiemann Stefan , Bantel‐Schaal Ursula , Madsen Jens , Bikker Floris , Klauck Sabine M. , Otto Herwart F. , Moldenhauer Gerd , Poustka Annemarie 
Published: April 2003

AbstractDMBT1 and galectin‐3 are potential interacting proteins with presumably complex roles in tumorigenesis. While at present a variety of mechanisms are discussed for DMBT1 and its participation in cancer, galectin‐3 is commonly known to exert tumor‐promoting effects. However, in vitro studies in a rodent system have suggested that DMBT1/galectin‐3 interaction in the ECM triggers epithelial differentiation, which would point to tumor‐suppressive properties. To improve the understanding of DMBT1/galectin‐3 action in cancer, we carried out studies in skin cancer of different origins. Mutational analyses of DMBT1 identified a missense mutation in 1 of 13 melanoma cell lines. It led to an exchange of an evolutionary conserved proline residue for serine and located within the second CUB domain of DMBT1. Immunohistochemical analyses demonstrated absence of DMBT1/galectin‐3 expression from melanocytes but induction of DMBT1 expression in 1 of 8 nevi and 1 of 11 melanomas and of galectin‐3 expression in 3 of 8 nevi and 4 of 8 melanomas. These data suggest that DMBT1 and galectin‐3 are unlikely to act as classical tumor suppressors in melanomas. DMBT1 and galectin‐3 appear to be secreted to the ECM by epithelial cells within the epidermis and the hair follicle. Compared to the flanking normal epidermis, skin tumors of epithelial origin frequently displayed downregulation of DMBT1 (18 of 19 cases) and galectin‐3 (12 of 12 cases). Thus, loss of DMBT1/galectin‐3 expression may play a role in the genesis of epithelial skin cancer. This would support the view that galectin‐3 can exert tumor‐suppressive effects in certain scenarios, and DMBT1/galectin‐3‐mediated differentiation represents a candidate mechanism for this effect. © 2003 Wiley‐Liss, Inc.