bluuebunny/crossref_metadata_2025_split huggingface dataset:
Clonal variation of the immunogenotype in relapsed ETV6/RUNX1‐positive acute lymphoblastic leukemia indicates subclone formation during early stages of leukemia development
Authors: Peham Martina , Konrad Marianne , Harbott Jochen , König Margit , Haas Oskar A , Panzer‐Grümayer E. Renate 
Published: December 2003

AbstractRecent data suggest that late relapses evolve from an ancestral ETV6/RUNX1‐positive (also designated TEL/AML1‐positive) clone resulting from secondary changes (ETV6 deletion) that differ from those of the initial leukemia and, as a consequence, may also deviate in their clonotypic immunoglobulin/T‐cell receptor (IG/TCR) gene rearrangements. The aim of our study was to compare the immunogenotype and fluorescence in situ hybridization (FISH) patterns of the unrearranged ETV6 allele of matched diagnosis/relapse samples from 12 children with an early or late relapse. We identified varying degrees of differences in the IG/TCR in six of them. A clonal change or evolution of the unrearranged ETV6 allele was also observed in six children but remained unchanged in three. However, these two parameters were not in concordance, nor did the immunogenotype pattern correlate with the duration of the first remission. We therefore propose that the potential of the immunogenotype to diversify depends primarily on the stage of IG/TCR gene configuration of the cell in which the ETV6/RUNX1 gene fusion takes place. © 2003 Wiley‐Liss, Inc.
Mutational analysis of susceptibility genes RNASEL/HPC1, ELAC2/HPC2, and MSR1 in sporadic prostate cancer
Authors: Nupponen Nina N. , Wallén Mika J. , Ponciano Damaris , Robbins Christiane M. , Tammela Teuvo L.J. , Vessella Robert L. , Carpten John D. , Visakorpi Tapio 
Published: December 2003

AbstractThree putative prostate cancer–susceptibility genes, RNASEL/HPC1 at 1q24, MSR1 at 8p22, and ELAC2/HPC2 at 17p11, have recently been identified. Our objective was to investigate somatic mutations in these genes in sporadic prostate cancer. We analyzed 39 clinical prostate cancer specimens, 10 prostate cancer xenografts (LuCaP series), and 4 prostate cancer cell lines (LNCaP, DU145, PC‐3, and MPC‐3) for genetic changes using denaturing high‐performance liquid chromatography and direct sequencing in order to screen the whole coding regions of RNASEL and MSR1, as well as exons 7 and 17 of ELAC2. The known 471delAAAG truncating mutation was found in the RNASEL gene in cell line LNCaP. The only new missense variation in RNASEL, Gly296Val, was found in cell line DU145, but not in any other samples. RNASEL and ELAC2 also showed the common missense polymorphic changes. A previously reported truncating mutation (Arg293X) was found in MSR1 in the germ line of one individual. Our results indicate that inactivation of the RNASEL, ELAC2, or MSR1 genes by somatic mutation is a rare phenomenon in sporadic prostate cancer. © 2003 Wiley‐Liss, Inc.
Activated BRAF targets proximal colon tumors with mismatch repair deficiency and MLH1 inactivation
Authors: Domingo Enric , Espín Eloi , Armengol Manel , Oliveira Carla , Pinto Mafalda , Duval Alex , Brennetot Caroline , Seruca Raquel , Hamelin Richard , Yamamoto Hiroyuki , Schwartz Simó 
Published: December 2003

AbstractBRAF, a serine/threonine kinase of the RAF family, is a downstream transducer of the RAS‐regulated MAPK pathway and signals upstream of MEK1/2 kinases. Recently, activating mutations within BRAF have been reported in a high percentage of melanomas and colorectal carcinomas and shown to have oncogenic capabilities. Further, their association to mismatch‐repair‐deficient tumors has suggested the involvement of the RAS/RAF pathway in the tumorigenesis of microsatellite‐unstable colon cancers, and that RAS and RAF mutations are alternative genetic events. We determined whether colorectal mismatch‐repair‐deficient tumors with BRAF mutations show a specific genotype when compared with tumors with wild‐type BRAF, and whether they can be associated with a particular clinicopathological feature. Here, we report a striking association of BRAF, but not of APC, KRAS2, AXIN2, and TP53 mutations, with proximal mismatch‐repair‐deficient colon tumors and MLH1 hypermethylation. Our results support the hypothesis that proximal and distal colorectal tumors with mismatch repair deficiency harbor different genetic alterations, and we suggest that the involvement of the RAS/RAF pathway in colorectal tumorigenesis is differentially modulated according to tumor location and MLH1 inactivation. © 2003 Wiley‐Liss, Inc.
Expression of a naturally occurring constitutively active variant of the epidermal growth factor receptor in mouse fibroblasts increases motility
Authors: Pedersen Mikkel W. , Tkach Vadim , Pedersen Nina , Berezin Vladimir , Poulsen Hans S. 
Published: December 2003

AbstractTumor cell motility is one of the rate‐limiting steps of invasion, which defines progression toward a more malignant phenotype. Elevated expression of epidermal growth factor receptor (EGFR) in many cancers is associated with progression of superficial to invasive forms of the disease. The naturally occuring type III mutant epidermal growth factor receptor (EGFRvIII) is a tumor‐specific, ligand‐independent, constitutively active variant of the epidermal growth factor receptor. EGFRvIII is expressed frequently by a number of human solid tumours including those of the lung, breast, prostate, brain and ovary. Our study was designed to investigate the effect of EGFRvIII expression on cell motility and compare it to that of ligand‐activated EGFR using transfected fibroblasts. We show here using time‐lapse video recording that expression of EGFRvIII greatly enhances the motility of fibroblasts independently of ligand stimulation. In addition, expression of EGFRvIII caused a marked increase in the number of cellular protrusions (lamellipodia) and a reduction in the number of stress fibers and focal adhesions. The EGFR tyrosine kinase inhibitor, AG1478, and the MEK inhibitor, U0126, blocked these cellular effects of EGFRvIII. Two cell lines expressing different levels of EGFR were used for comparison. The low‐expressing cell line responded to EGF treatment by increasing motility in a manner very similar to the motility induced by EGFRvIII. In contrast, the high‐expressing cell line responded to EGF by detachment from the extracellular matrix and decreased motility. Cellular detachment was correlated to a high phosphorylation of PLC‐γ, whereas increased motility was correlated to a high level of ERK phosphorylation. Overall these results indicate that tumor‐associated EGFR mutations might be critical for tumor cell motility, invasion and thus progression of disease. © 2003 Wiley‐Liss, Inc.
Elevated levels and distinct patterns of expression of A‐type cyclins and their associated cyclin‐dependent kinases in male germ cell tumors
Authors: Liao Ching , Li Sherry Q. , Wang XiangYuan , Muhlrad Samantha , Bjartell Anders , Wolgemuth Debra J. 
Published: December 2003

AbstractAberrant expression of several key regulators controlling the G1/S phase of the cell cycle has been implicated in human male germ cell tumorigenesis. Given the critical role of cyclin A2 at both the G1/S and G2/M transitions and the essential role for cyclin A1 in male germ cell development, our present study focused on the involvement of the A‐type cyclins in the transformation and progression of male germ cell tumors (GCTs). The expression of the A‐type cyclins and their catalytic partners Cdk1 and Cdk2 was examined in all types and stages of human male GCTs, including carcinoma in situ(CIS), seminoma and non‐seminoma GCTs, along with normal testis samples. Elevated levels of cyclin A2, Cdk1 and Cdk2 were detected in the majority of GCTs and were correlated with the invasiveness of the tumors (p < 0.05). Cyclin A1 expression was virtually undetectable in CIS and seminoma, but was aberrantly expressed in all non‐seminomatous GCTs. Cyclin A2 expression was strongly correlated with that of its catalytic partners Cdk1 and Cdk2 in all types of testicular tumors examined (p < 0.05), whereas a strong correlation between cyclin A1 and Cdk1 or Cdk2 was only seen in non‐seminomatous GCTs (p < 0.05). Histone kinase activities of cyclin A1/Cdks and cyclin A2/Cdks were found to be elevated in tumors. Our data suggest that aberrant expression of A‐type cyclins and their Cdks is a significant factor in male germ cell tumorigenesis. The abundant ectopic expression of cyclin A1 in non‐seminomatous GCTs and its absence in CIS and seminomas is likely linked to the tumor transformation and progression and may be relevant to clinical prognosis. Supplementary material for this article can be found on the International Journal of Cancer website at http://www.interscience.wiley.com/jpages/0020‐7136/suppmat/index.html.© 2003 Wiley‐Liss, Inc.
hnRNP L enhances sensitivity of the cells to KW‐2189
Authors: Taguchi Fumiko , Kusaba Hitoshi , Asai Akira , Iwamoto Yasuo , Yano Keiichi , Nakano Hirofumi , Mizukami Tamio , Saijo Nagahiro , Kato Harubumi , Nishio Kazuto 
Published: December 2003

AbstractHeterogeneous nuclear ribonucleoproteins (hnRNPs) are involved in several RNA‐related biological processes. We demonstrated hnRNP L as a candidate protein of DARP (duocarmycin‐DNA adduct recognizing protein) by gel shift assay and amino acid sequencing. Stable transfectants of hnRNP L showed high sensitivity of the cells to the growth inhibitory effect of KW‐2189, a duocarmycin derivative in vitro. Immunostaining of hnRNP L demonstrated differential intracellular localization of hnRNP L among human lung cancer cell lines. A transfection study using a series of deletion mutants of hnRNP L fused to indicated that the N‐terminal portions of RRM(RNA recognition motif)1, RRM3 and RRM2 are involved in localization of hnRNP L. We identified sequences in these portions that have high homology with the sequences of known NLS (nuclear localization signal) and NES (nuclear export signal). hnRNP L is a factor that determines the sensitivities of cancer cells to the minor groove binder, and overexpression and differential intracellular localization of hnRNP L are involved in its function in lung cancer. © 2003 Wiley‐Liss, Inc.
Stat5a is tyrosine phosphorylated and nuclear localized in a high proportion of human breast cancers
Authors: Cotarla Ion , Ren Shuxun , Zhang Ying , Gehan Edmund , Singh Baljit , Furth Priscilla A. 
Published: December 2003

AbstractSignal transducers and activators of transcription (STATs) are latent cytoplasmic transcription factors that are activated and translocated into the nucleus after phosphorylation at a conserved tyrosine residue. Mouse model studies have demonstrated that activated Stat5a acts as a critical survival factor for normal, preneoplastic and malignant mammary epithelial cells. Very limited information is available, however, on the expression, tyrosine phosphorylation status and nuclear localization of Stat5a in human breast cancers. In our study, the pattern of Stat5a cellular localization was analyzed by immunohistochemistry in a series of 83 randomly selected primary human breast adenocarcinomas. Immunoprecipitation/Western blotting and immunohistochemistry assays employing different phospho‐specific antibodies verified Stat5a tyrosine phosphorylation status. Stat5a was nuclear localized and tyrosine phosphorylated in 59 of 78 (76%) breast cancers examined; 38 of 78 (49%) demonstrated Stat5a nuclear localization in more than 25% of the breast cancer cells within the adenocarcinomas. Nuclear localized Stat5a was associated positively with increased levels of histologic differentiation (p = 0.03). A statistically significant positive association with p27 nuclear localization also was identified (p = 0.05). No relationship was found between nuclear localized Stat5a and menopausal status, tumor size, ploidy, percentage of cells in S‐phase, lymph node metastases, ER, ErbB2, nuclear localized p21 or nuclear localized Stat5b/Stat3. As its role in human breast cancer progression and response to therapy is defined, Stat5a could become a new molecular target for breast cancer therapy. © 2003 Wiley‐Liss, Inc.
p66Shc protein is upregulated by steroid hormones in hormone‐sensitive cancer cells and in primary prostate carcinomas
Authors: Lee Ming‐Shyue , Igawa Tsukasa , Chen Siu‐Ju , Van Bemmel Dana , Lin Jamie S. , Lin Fen‐Fen , Johansson Sonny L. , Christman Judith K. , Lin Ming‐Fong 
Published: December 2003

AbstractMembers of Shc family conventionally serve as critical adaptors in tyrosine phosphorylation signal transduction pathways. p66Shc protein, a member of Shc family, is predominantly expressed in epithelial cells, whereas the regulation of its expression remains an enigma. We describe the effect of steroid hormones on the protein level of p66Shc and growth stimulation in hormone‐sensitive human prostate, testicular and breast cancer cells. In DHT‐treated androgen‐sensitive prostate cancer LNCaP C‐33 cells, the protein level of p66Shc was elevated by approximately 3‐fold, correlating with increased cell growth. This DHT effect on p66Shc protein level and growth regulation was also observed in another androgen‐sensitive prostate cancer cell line MDA PCa2b as well as 2 testicular cancer cell lines, Tera‐1 and Tera‐2 cells. Similarly, the female sex hormone estrogen had a stimulating effect on p66Shc protein level and proliferation in estrogen‐sensitive MCF‐7 breast cancer cells. The upregulation of p66Shc protein level by DHT was competitively abolished by Casodex, an androgen antagonist used to treat prostate cancer. Moreover, immunohistochemical analyses showed that the p66Shc protein level was significantly higher in primary prostate tumors than in adjacent non‐cancerous cells (p < 0.05). The data collectively indicate that p66Shc protein levels correlate with steroid hormone‐stimulated cell growth and prostate carcinogenesis. © 2003 Wiley‐Liss, Inc.
mRNA expression of leukemia‐associated antigens in patients with acute myeloid leukemia for the development of specific immunotherapies
Authors: Greiner Jochen , Ringhoffer Mark , Taniguchi Masanori , Li Li , Schmitt Anita , Shiku Hiroshi , Döhner Hartmut , Schmitt Michael 
Published: December 2003

AbstractSpecific immunotherapies for patients with acute myeloid leukemia (AML) using leukemia‐associated antigens (LAA) as target structures might be a therapeutic option to enhance the graft‐vs.‐leukemia effect observed after allogeneic stem cell transplantation or to prolong a complete remission (CR) achieved by chemotherapy. Significant mRNA expression of LAA is a prerequisite for such immunotherapies. Here, previously characterized antigens associated with solid tumors (TAA) and newly characterized LAA were investigated for their expression in up to 60 AML patients and in leukemia cell lines. To investigate their specificity for leukemic blasts, the mRNA expression was also characterized in PBMN and CD34 positive cells of healthy volunteers and in a panel of normal tissues. The following antigens showed high mRNA expression in AML patients: MPP11 was detected in 43/50 (86%), RHAMM in 35/50 (70%), WT1 in 40/60 (67%), PRAME in 32/50 (64%), G250 in 18/35 (51%), hTERT in 7/25 (28%) and BAGE in 8/30 (27%) of AML patients. Real‐time RT‐PCR showed a tumor‐specific expression of the antigens BAGE, G250 and hTERT, as well as highly tumor‐restricted expression for RHAMM, PRAME and WT1. The antigen MPP11 was overexpressed. These antigens might be candidates for immunotherapies of leukemia patients and, because of their simultaneous expression, also for polyvalent vaccines. © 2003 Wiley‐Liss, Inc.
Serum concentrations of IGF‐I, IGFBP‐3 and c‐peptide and risk of hyperplasia and cancer of the breast in postmenopausal women
Authors: Schairer Catherine , Hill Deirdre , Sturgeon Susan R. , Fears Thomas , Pollak Michael , Mies Carolyn , Ziegler Regina G. , Hoover Robert N. , Sherman Mark E. 
Published: December 2003

AbstractExperimental evidence suggests that insulin and insulin‐related growth factors may play a role in breast pathology through their mitogenic and anti‐apoptotic effects on breast cells. Our objective was to assess the relationship between serum concentrations of insulin‐like growth factor‐I (IGF‐I), its major binding protein (IGFBP‐3), the ratio IGF‐I:IGFBP‐3, c‐peptide (a marker of insulin secretion) and the ratio c‐peptide:fructosamine (a marker of insulin resistance) and the risk of epithelial hyperplasia (an established breast cancer risk factor) and localized breast cancer among postmenopausal women. Study subjects were patients who provided serum before breast biopsy or mastectomy in 3 hospitals in Grand Rapids, MI between 1977 and 1987. Two case groups, 186 subjects with epithelial hyperplasia of the breast and 185 subjects with localized breast cancer, were compared to 159 subjects with nonproliferative breast changes that have not been associated with increased breast cancer risk. Serum concentrations of IGF‐I, IGFBP‐3 and the ratio IGF‐I:IGFBP‐3 were not related to risk of either hyperplasia or breast cancer. For women in the highest quartile of c‐peptide or of c‐peptide:fructosamine compared to those in the lowest quartile, the odds ratios (ORs) for hyperplasia were 3.0 (95% confidence interval [CI] 1.4–6.5) and 3.3 (95% CI 1.5–7.3), respectively (p trend = 0.02 and 0.02, respectively). The corresponding ORs for breast cancer were 1.5 (95% CI 0.7–3.0) and 1.6 (95% CI 0.8–3.2), respectively (p trend = 0.35 and 0.25, respectively). Our results suggest that insulin and insulin resistance may play a role in breast pathology in postmenopausal women. © 2003 Wiley‐Liss, Inc.
Identification of bladder cancer antigens recognized by IgG antibodies of a patient with metastatic bladder cancer
Authors: Ito Keiichi , Fujita Tomonobu , Akada Masanori , Kiniwa Yukiko , Tsukamoto Makoto , Yamamoto Aiko , Matsuzaki Yuriko , Matsushita Maiko , Asano Takako , Nakashima Jun , Tachibana Masaaki , Hayakawa Masamichi , Ikeda Hideyuki , Murai Masaru , Kawakami Yutaka 
Published: December 2003

AbstractTo identify tumor antigens useful for the diagnosis and treatment of patients with bladder cancer, a lambda phage cDNA library constructed from a high‐grade bladder cancer cell line was screened with autologous serum from a patient with metastatic bladder cancer. Forty‐eight distinct antigens were isolated. By evaluating the immunogenicity and the tissue‐specific expression, KU‐BL‐1 and KU‐BL‐2 were identified as immunogenic antigens with restricted tissue expression. KU‐BL‐1 was found to be a putative human lipoic acid synthetase with a metal‐binding site, CXXXCXXC, that was expressed in bladder cancer cell lines and most bladder cancer tissues, as well as normal bladder mucosa and testis tissues. Immunoglobulin (Ig)G antibody to KU‐BL‐1 was detected in 2 of 28 patients with bladder cancer, but not in 30 healthy individuals. KU‐BL‐2 was found to be a putative human kelch‐like protein that was homologous to Drosophila
kelch, with a BTB/POZ domain and kelch repeats. KU‐BL‐2 was expressed in bladder cancer cell lines, most bladder cancer tissues, testis and heart, but not in normal bladder mucosa. IgG antibody to KU‐BL‐2 was detected in 8 of 28 patients with bladder cancer, but not in 16 healthy individuals. Tumor reactive T cells were induced from peripheral blood mononuclear cells (PBMC) by stimulation with one of the HLA–A24 binding KU‐BL‐2 peptides. Therefore, KU‐BL‐1 and KU‐BL‐2, which showed preferential expression in bladder cancer with restricted expression in normal tissues, as well as immunogenicity in multiple patients with bladder cancer, may be useful for the development of diagnostic and therapeutic methods for patients with bladder cancer. © 2003 Wiley‐Liss, Inc.
The role of type of tobacco and type of alcoholic beverage in oral carcinogenesis
Authors: Castellsagué Xavier , Quintana Maria Jesús , Martínez Maria Carmen , Nieto Adoración , Sánchez Maria José , Juan Amparo , Monner Antoni , Carrera Marta , Agudo Antoni , Quer Miquel , Muñoz Nubia , Herrero Rolando , Franceschi Silvia , Bosch F. Xavier 
Published: December 2003

AbstractIncidence rates of oral and oropharyngeal cancers (oral cancer) in Spain are among the highest in Europe. Spain has a population heavily exposed to various types of tobacco and alcoholic beverages but the role and impact of tobacco type and beverage type in oral carcinogenesis remain controversial. To estimate the independent and joint effects of tobacco smoking and alcohol drinking habits on the risk of developing oral cancer, we carried out a multicenter, hospital‐based, case‐control study in Spain. Data from 375 patients newly diagnosed with cancer of the oral cavity or oropharynx and 375 matched control subjects were analyzed using multivariate logistic regression procedures. All exposure characteristics of amount, duration and cessation of both tobacco smoking and alcohol drinking were strongly associated with cancer risk following a dose‐dependent relationship. At equal intake or duration levels, black‐tobacco smoking and drinking of spirits were both associated with a 2‐ to 4‐fold increase in cancer risk compared to blond tobacco smoking or drinking of wine or beer, respectively. While ever exposure to smoking only or drinking only was associated with a moderate and nonsignificant increase in cancer risk, a history of simultaneous exposure to both habits was associated with a 13‐fold increase that was compatible with a synergistic effect model (p‐value for interaction: 0.008). Exposure to black tobacco smoking and/or drinking of spirits may account for up to 77% of oral cancer occurrence in Spain. Both black tobacco smoking and drinking of spirits place individuals at a very high risk of developing oral cancer. Simultaneous exposure to tobacco and alcohol consumption increases oral cancer risk in a synergistic fashion, even when consumption levels are moderate. These results underline the importance of type of tobacco and alcohol concentration in oral carcinogenesis. © 2003 Wiley‐Liss, Inc.
Two new trifunctional antibodies for the therapy of human malignant melanoma
Authors: Ruf Peter , Jäger Michael , Ellwart Joachim , Wosch Susanne , Kusterer Elisabeth , Lindhofer Horst 
Published: December 2003

AbstractTrifunctional antibodies are able to redirect T cells and Fcγ receptor+ accessory immune cells to tumor targets. The simultaneous activation of these different classes of effector cells results in efficient killing of the tumor cells by different mechanisms such as phagocytosis and perforin‐mediated cytotoxicity. Here, we introduce 2 new trifunctional antibodies specific for human melanoma. These trifunctional antibodies recognize with one binding arm CD3 on human T cells. The other binding arm is directed against melanoma‐associated proteoglycans or melanoma‐associated gangliosides (GD2 as well as GD3). They mediate specific lysis of various melanoma cell lines in correlation with the level of antigen expression in short‐term cytotoxicity experiments. A combination of the 2 trifunctional antibodies was equally or even more efficient. Moreover, they induced a strong Th1 cytokine pattern with high amounts of IFN‐γ and low or no IL‐4. Accordingly, CD4+ and especially CD8+ T cells expanded, whereas B cells, NK cells and monocytes decreased. The cytokine response was up to 16‐fold higher when tumor cells were present. IFN‐γ reached cytotoxic concentrations for SK‐MEL‐23 melanoma cells. The induction of a T‐cell‐activatory and melanoma cell‐inhibitory cytokine milieu together with the redirection of T‐cell‐ and accessory cell‐mediated cytotoxicity are interesting features of these trifunctional antibodies. They may be a new option for the therapy of human malignant melanoma. © 2003 Wiley‐Liss, Inc.