bluuebunny/crossref_metadata_2025_split huggingface dataset:
Mutations of BRAF are associated with extensive hMLH1 promoter methylation in sporadic colorectal carcinomas
Authors: Koinuma Koji , Shitoh Kazuhisa , Miyakura Yasuyuki , Furukawa Taiji , Yamashita Yoshihiro , Ota Jun , Ohki Ruri , Choi Young Lim , Wada Tomoaki , Konishi Fumio , Nagai Hideo , Mano Hiroyuki 
Published: June 2004

AbstractActivating mutations of BRAF have been frequently observed in microsatellite unstable (MSI+) colorectal carcinomas (CRCs), in which mutations of BRAF and KRAS are mutually exclusive. Previously, we reported that hypermethylation of hMLH1 might play an important role in the tumorigenesis of right‐sided sporadic CRCs with MSI showing less frequency of KRAS/TP53 alteration. Therefore, we have assumed that BRAF mutations might be highly associated with hMLH1 methylation status rather than MSI status. In this study, mutations of BRAF and KRAS and their relationship with MSI and hMLH1 methylation status were examined in 140 resected specimens of CRC. The methylation status was classified into 3 types: full methylation (FM), partial methylation (PM) and nonmethylation (NM). Only FM closely linked to reduced expression of hMLH1 protein. BRAF mutations were found in 16 cases (11%), all leading to the production of BRAFV599E. As for MSI status, BRAF mutations were found in 43% of MSI+ and 4% of MSI− cases (p < 0.0001). Among the MSI+ individuals, BRAF mutations were more frequent in cases with hMLH1 deficiency (58%) than those with hMSH2 deficiency (0%; p = 0.02). Moreover, they were found in 69% of FM, 4% of PM and 4% of NM, revealing a striking difference between FM and the other 2 groups (FM vs. PM or NM; p < 0.0001). These findings suggest that BRAF activation may participate in the carcinogenesis of sporadic CRCs with hMLH1 hypermethylation in the proximal colon, independently of KRAS activation. © 2003 Wiley‐Liss, Inc.
Expression of PAX 3 alternatively spliced transcripts and identification of two new isoforms in human tumors of neural crest origin
Authors: Parker Craig J. , Shawcross Susan G. , Li Honggui , Wang Qui‐Yu , Herrington C. Simon , Kumar Shant , MacKie Rhona M. , Prime Wendy , Rennie Ian G. , Sisley Karen , Kumar Patricia 
Published: June 2004

AbstractThe developmental gene PAX 3 is expressed in the early embryo in developing muscle and elements of the nervous system, including the brain. Since no one has investigated the expression of the isoforms of PAX 3 in the neuroectodermal tumors melanoma and small cell lung cancer (SCLC), we have carried out a comprehensive screening for the expression of the isoforms PAX 3a–e using RT‐PCR in human melanoma cell lines, primary human ocular and secondary cutaneous melanomas. We have identified 2 new isoforms of PAX 3, g and h, which we have isolated, cloned and sequenced. Sets of primers for each isoform were designed and their specificity was confirmed by sequence analysis of the products. The isoforms PAX 3a–e were detected in all human cutaneous melanoma cell lines (8/8), but only PAX 3c (1/2) and PAX 3d (2/2) in ocular melanoma cell lines. The same PAX 3 isoforms were detected in more than 80% of human cutaneous melanomas: PAX 3a and b (15/17), PAX 3c (14/17), PAX 3d (16/17) and PAX 3e (15/17). In contrast the results for 7 SCLC cell lines were PAX 3a (0/7), PAX 3b (1/7), PAX 3c (3/7), PAX 3d (6/7), PAX 3e (2/7); 8/8 cutaneous melanoma cell lines and 8/8 ocular melanoma tissues, together with 14/17 cutaneous melanoma tissues screened, expressed the new isoform PAX 3g. All 8 cutaneous melanoma cell lines expressed PAX 3h, but it was not detectable in any of the tumor tissues (0/20). Neither of the 2 ocular melanoma cell lines expressed the 2 new isoforms. Comparison of the different amplicon staining intensities on a gel suggests that PAX 3c and PAX 3d are the predominant transcripts expressed, with relatively low expression of PAX 3e and PAX 3h. We propose that these and the 2 new isoforms we have discovered may be important in oncogenesis and differential diagnosis of melanomas or SCLC. © 2003 Wiley‐Liss, Inc.
An in vitro model to optimize dose scheduling of multimodal radioimmunotherapy and chemotherapy: Effects of p53 expression
Authors: Blumenthal Rosalyn D. , Leone Evelyn , Goldenberg David M. , Rodriguez Marisol , Modrak David 
Published: June 2004

AbstractSeveral reports have appeared on the use of combined radioimmunotherapy (RAIT) and chemotherapy. The choice of drug to use with RAIT and how to space the two treatments has not been completely addressed. Because every patient's cancer presents with a specific molecular phenotype, we hypothesized that it may be necessary to tailor therapy based on specific gene expression. We addressed how the form of expression of a single gene, the p53 tumor suppressor, would impact the choice of agents, as well as sequence and spacing of agents. p53 regulates cell cycle arrest to allow for DNA repair after therapy‐induced small DNA damage or induction of apoptosis if damage is great and has been shown to affect chemo‐ and radiosensitivity of cancer cells. We established 3 stable p53 transfectants of the SKOV‐3 p53null parental line (p53wt, p53143mut or p53273mut). p53 expression was confirmed using flow cytometry, using the DO1 pan‐p53 Ab and the PAb240 anti‐p53mut Ab. The colorimetric MTT assay was then used to measure dose‐dependent growth inhibition from single modality chemotherapy (doxorubicin, carboplatin, paclitaxel or topotecan) or radioimmunotherapy (90Y‐RS‐7 IgG anti‐EGP1). The % survival vs. log [drug] were plotted to obtain the IC50. We then used a matrix design in which we varied the sequence of the first and second modality of treatment and the spacing between the 2 treatments to determine the most synergistic and antagonistic combinations for the parental SKOV‐3 and each of the 3 transfectants. The IC50 for each therapeutic agent varied as a function of the form of p53 expressed. For example, of the 4 lines, the p53wt transfectant was the most resistant to topotecan and the 143mut was the most resistant to carboplatin. The 273mut was quite sensitive to both doxorubicin and paclitaxel, whereas the p53null and wt were not. For multimodal treatments, most combinations of RAIT and chemotherapy resulted in a 30–40% growth inhibition (GI) and were either additive or moderately antagonistic. The 3 best (>60% GI) and 3 worst (<25% GI) combinations were identified and were unique to the parental p53null and to the 3 transfectants. Certain combinations showed clear synergy and others were antagonistic, with the first treatment modality blocking the growth inhibitory effects of the second treatment modality. The form of p53 expressed affects chemosensitivity and radiosensitivity and will influence optimal multimodal therapy with RAIT and chemotherapy and the dose‐schedule (sequential with RAIT first or with drug first) when more than 1 agent is used. © 2003 Wiley‐Liss, Inc.
Suppression of 6A8 α‐mannosidase gene expression reduced the potentiality of growth and metastasis of human nasopharyngeal carcinoma
Authors: Yue Wei , Jin Yu Lan , Shi Geng Xian , Liu Yin , Gao Yang , Zhao Fang Tao , Zhu Ling Ping 
Published: June 2004

AbstractSuppression of α‐mannosidases by chemicals has been shown to reduce the potentiality of growth and metastasis of various tumors. In our study, the effect of 6A8 α‐mannosidase (MAN 6A8), recently discovered in our laboratory, on malignant behaviors of tumor cells was examined. Since the suppressive effect of chemicals on α‐mannosidase is not specific, antisense technique was used to specifically inhibit expression of the MAN 6A8 in human nasopharyngeal carcinoma cells, CNE‐2L2. Two cell clones, AS1 and AS2, with pronounced suppression of MAN 6A8 expression were developed. Wild‐type (W), mock‐transduced (M) and irrelevant DNA‐transduced (IR) CNE‐2L2 cells with normal expression of the enzyme were used as controls. Malignant behaviors of the cells were examined. Significant inhibition of growth of AS cells in vitro measured by MTT assay, colony formation and anchorage‐independent colony formation was found. Pronounced inhibition of formation of tumors from AS cells inoculated into nude mice and metastasis was also observed. W, M and IR cells cultured in plate wells appeared dispersed with a fibroblastic or epithelial morphology, whereas AS cells were in compact sheets with an epithelioid organization. Since E‐cadherin is the key factor in homophilic adhesion of epithelial cells, its expression on the surface of CNE‐2L2 cells was determined. E‐cadherin expression on AS cells was enhanced, whereas it was markedly diminished on W, M and IR cells. In addition, lamellipodia, which play an important role in cell spreading and mobility, almost disappeared on AS cells. The results demonstrate a significant suppressive effect of reduced expression of MAN 6A8 on malignant behaviors of CNE‐2L2 cells. © 2003 Wiley‐Liss, Inc.
Medication use and risk of ovarian carcinoma: A prospective study
Authors: Lacey James V. , Sherman Mark E. , Hartge Patricia , Schatzkin Arthur , Schairer Catherine 
Published: June 2004

AbstractInflammation and gonadotropins are hypothesized to influence ovarian carcinogenesis. In a prospective study, we evaluated ovarian cancer risk associated with self‐reported use of medications that influence inflammation or gonadotropin levels. The Breast Cancer Detection Demonstration Project Follow‐Up Study enrolled 61,431 women in 1979 and used telephone interviews and 3 mailed questionnaires through 1998 to update risk factor information and identify incident ovarian cancers. The 1992–95 questionnaire ascertained medication use, including duration and frequency of use for aspirin, acetaminophen, other nonsteroidal anti‐inflammatory drugs (NSAIDs), tranquilizers and histamine‐receptor antagonists. A Poisson regression analysis generated rate ratios (RRs) and 95% confidence intervals (CIs) for the 31,364 women who were at risk of ovarian cancer and responded to the questionnaire that queried regular medication use. One hundred sixteen women developed ovarian cancer during follow‐up. None of the anti‐inflammatory medications was associated with ovarian cancer, but the RR for more than 1 aspirin per day for 1 year or longer was 0.56 (95% CI 0.20–1.5) and the RR for more than 5 years of regular “other NSAID” use was 2.0 (95% CI 0.95–4.2). Regular tranquilizer use was not associated with ovarian cancer, but histamine‐receptor antagonists used regularly for more than 5 years (RR = 3.6, 95% CI 1.4–9.1) or more than once daily (RR = 3.1, 95% CI 1.5–6.5) appeared to increase risk. In our study, neither anti‐inflammatory medications nor anti‐psychotic medications were associated with ovarian cancer. Potential associations with histamine‐receptor antagonists may warrant further study. © 2003 Wiley‐Liss, Inc.
nm23‐H1 reduces in vitro cell migration and the liver metastatic potential of colon cancer cells by regulating myosin light chain phosphorylation
Authors: Suzuki Eiji , Ota Tetsuya , Tsukuda Kazunori , Okita Atsushi , Matsuoka Kinya , Murakami Masakazu , Doihara Hiroyoshi , Shimizu Nobuyoshi 
Published: June 2004

AbstractThe nm23‐H1 gene is known as a potential metastasis suppressor gene in various types of carcinomas. However, the role of nm23‐H1 in colorectal carcinoma still remains controversial and the cellular mechanisms by which its protein may modulate the metastatic phenotype are not yet known. We transfected nm23‐H1 cDNA into the human colon cancer cell line, HT‐29, to test the effects and cellular biological mechanism of nm23 protein in colon cancer. We found that nm23‐H1 strongly inhibited the liver metastasis of HT‐29 cells in nude mice and inhibited the epidermal growth factor (EGF)‐induced cell migration in vitro. Furthermore, we clarified the regulation of the myosin light chain (MLC) phosphorylation by nm23‐H1, which has been demonstrated as having potential role in cell migration. © 2003 Wiley‐Liss, Inc.
Quantitative real‐time RT‐PCR for detection of disseminated tumor cells in peripheral blood of patients with colorectal cancer using different mRNA markers
Authors: Schuster Ronny , Max Nicole , Mann Benno , Heufelder Karin , Thilo Florian , Gröne Jörn , Rokos Franziska , Buhr Heinz‐Johannes , Thiel Eckhard , Keilholz Ulrich 
Published: June 2004

AbstractThe detection of disseminated tumor cells in peripheral blood from colorectal cancer patients by RT‐PCR could be an attractive method for selecting patients for adjuvant therapy. We here report on real‐time RT‐PCR assays (LightCycler) to quantitate potential mRNA markers. We investigated specimens from colon carcinoma and normal colon mucosa tissues, cell lines, blood samples from 129 patients with colorectal cancer (all stages) and 58 reference blood samples (healthy donors, persons suffering from inflammatory bowel or infectious diseases). The expression profile in tissues showed high values for CEA and CK20, whereas in cell lines ProtM was predominant. All markers were detected in reference and patient blood samples (ProtM, 22, 17%; CEA, 84, 86%; CK20, 85, 88%). After quantitative analysis, the definition of cutoff values for each marker and the combination of markers, 13% of patients were judged to have elevated marker concentrations in their blood, from which only 6 had values significantly differing from cutoff value. There were no differences between stages of disease. In the case of 19 patients, investigated prior to and 1 week after surgery, 2 samples revealed a significant postoperative increase in CEA or CK20 mRNA concentration. In spite of high expression levels in tissues and cell lines, we were not able to differentiate satisfyingly mRNA markers originating from tumor cells and those from illegitimate transcription in hematopoetic cells in blood. We conclude that either copy numbers of analyzed markers in circulating tumor cells are not sufficient for detection or, more probably, peripheral blood is not a suitable compartment for detection of tumor cells in colorectal cancer. © 2003 Wiley‐Liss, Inc.
Fruits and vegetables and lung cancer: Findings from the European prospective investigation into cancer and nutrition
Authors: Miller Anthony B. , Altenburg Hans‐Peter , Bueno‐de‐Mesquita Bas , Boshuizen Hendriek C. , Agudo Antonio , Berrino Franco , Gram Inger Torhild , Janson Lars , Linseisen Jacob , Overvad Kim , Rasmuson Torgney , Vineis Paolo , Lukanova Annekatrin , Allen Naomi , Amiano Pilar , Barricarte Aurelio , Berglund Göran , Boeing Heiner , Clavel‐Chapelon Françoise , Day Nicholas E. , Hallmans Göran , Lund Eiliv , Martinez Carmen , Navarro Carmen , Palli Dominico , Panico Salvatore , Peeters Petra H.M. , Quirós José Ramón , Tjønneland Anne , Tumino Rosario , Trichopoulou Antonia , Trichopoulos Dimitrios , Slimani Nadia , Riboli Elio 
Published: June 2004

AbstractIntake of fruits and vegetables is thought to protect against the development of lung cancer. However, some recent cohort and case‐control studies have shown no protective effect. We have assessed the relation between fruit and vegetable intake and lung cancer incidence in the large prospective investigation on diet and cancer, the European Prospective Investigation Into Cancer and Nutrition (EPIC). We studied data from 478,021 individuals that took part in the EPIC study, who were recruited from 10 European countries and who completed a dietary questionnaire during 1992–1998. Follow‐up was to December 1998 or 1999, but for some centres with active follow‐up to June 2002. During follow‐up, 1,074 participants were reported to have developed lung cancer, of whom 860 were eligible for our analysis. We used the Cox proportional hazard model to determine the effect of fruit and vegetable intake on the incidence of lung cancer. We paid particular attention to adjustment for smoking. Relative risk estimates were obtained using fruit and vegetable intake categorised by sex‐specific, cohort‐wide quintiles. After adjustment for age, smoking, height, weight and gender, there was a significant inverse association between fruit consumption and lung cancer risk: the hazard ratio for the highest quintile of consumption relative to the lowest being 0.60 (95% Confidence Interval 0.46–0.78), p for trend 0.0099. The association was strongest in the Northern Europe centres, and among current smokers at baseline, and was strengthened when the 293 lung cancers diagnosed in the first 2 years of follow‐up were excluded from the analysis. There was no association between vegetable consumption or vegetable subtypes and lung cancer risk. The findings from this analysis can be regarded as re‐enforcing recommendations with regard to enhanced fruit consumption for populations. However, the effect is likely to be small compared to smoking cessation. © 2003 Wiley‐Liss, Inc.
NF‐κB activity blockade impairs the angiogenic potential of human pancreatic cancer cells
Authors: Xiong Henry Q. , Abbruzzese James L. , Lin Edward , Wang Liwei , Zheng Leizhen , Xie Keping 
Published: June 2004

AbstractThe effect of blockade of NF‐κB activity on human pancreatic cancer angiogenesis was determined in an orthotopic xenograft model. Highly metastatic L3.3 human pancreatic cancer cells, which expressed an elevated level of constitutive NF‐κB activity, were transfected with a mutated IκBα (IκBαM). After implantation in the pancreas of nude mice, parental (L3.3) and control vector‐transfected (L3.3‐Neo) cells produced rapidly growing tumors and liver metastases, whereas IκBαM‐transfected (L3.3‐IκBαM) cells had decreased tumorigenicity and metastatic potential. NF‐κB signaling blockade significantly inhibited the in vitro and in vivo expression of the major proangiogenic molecules vascular endothelial growth factor and interleukin‐8 and decreased tumor vascular formation. These events were correlated with retarded tumor growth and suppression of metastasis. Collectively, these data suggest that suppression of tumorigenicity and metastasis by NF‐κB blockade is due to impaired angiogenic potential of tumor cells. © 2003 Wiley‐Liss, Inc.
Frequent somatic mutations of mitochondrial DNA in esophageal squamous cell carcinoma
Authors: Kumimoto Hiroshi , Yamane Yoshihiro , Nishimoto Yoshio , Fukami Hiroko , Shinoda Masayuki , Hatooka Shunzo , Ishizaki Kanji 
Published: June 2004

AbstractRecent studies of various cancers, such as those of the breast, head and neck, bladder and lung, reported that 46–64% of somatic mutations in the D‐loop region of mitochondrial DNA (mtDNA) are observed. However, in esophageal cancer, only a low rate (5%) of somatic mutations has so far been reported in one article (Hibi, K. et al., Int J Cancer 2001;92:319–321). Thus, to confirm this we analyzed the somatic mutations for hypervariable regions (HVR‐I and HVR‐II) in the D‐loop of mtDNA to reevaluate the possibility of mitochondrial genetic instability in this cancer. We amplified both HVRs by PCR and DNA samples obtained from 38 esophageal tumors and matched normal tissues, and then sequenced them. Comparing the sequences of tumors to those of normal tissues, we found 14 somatic mutations in 13 patients (34.2%). Eleven mutations were at the C consecutive stretch from position 303 to 309 of MITOMAP in the mitochondria databank (http://www.mitomap.org/), 1 at position 215 in HVR‐II and 2 at positions 16,304 and 16,324 in HVR‐I. There were 41 types of germ line variations in HVR‐I including 2 not so far recorded in the mtDNA databank and 17 in HVR‐II including 1 not yet recorded. We also determined nuclear genome instability of these 38 specimens by analyzing 3 independent microsatellite sequences. While 4 specimens showed a single microsatellite change, which is tumor specific, we did not find any co‐relation between a somatic mtDNA mutation and microsatellite instability of nuclear genome DNA. These results suggest that mtDNA mutations might show a genetic instability in esophageal cancer independently from a nuclear genome instability. © 2003 Wiley‐Liss, Inc.
Induction of apoptosis and tumor regression by vesicular stomatitis virus in the presence of gemcitabine in lung cancer
Authors: Li Qiu , Wei Yu‐Quan , Wen Yan‐Jun , Zhao Xia , Tian Ling , Yang Li , Mao Yong‐Qiu , Kan Bing , Wu Yang , Ding Zhen‐Yu , Deng Hong‐Xin , Li Jiong , Luo Yan , Li Hong‐Li , He Qiu‐Ming , Su Jing‐Mei , Xiao Fei , Zou Chun‐Hua , Fu Chun‐Hua , Xie Xing‐Jiang , Yi Tao , Tan Guang‐Hong , Wang Lian , Chen Jing , Liu Jian , Gao Zhen‐Nan 
Published: June 2004

AbstractVesicular stomatitis virus (VSV) has been shown to replicate rapidly in vitro and kill selectively a variety of tumor cell lines. The present study was designed to determine whether gemcitabine potentiates the antitumor activity of VSV in vitro and in vivo. A549 human lung adenocarcinoma cells and LLC Lewis lung carcinoma cells were treated with VSV (0.1–10 plaque‐forming units per cell) plus gemcitabine (20 nM to 20 μM). Mice bearing A549 or LLC were treated with VSV (5 × 104 to 1 × 108 plaque‐forming units) daily for 5 days plus gemcitabine (5–125 mg/kg/day) once every 3 days for 4 times. Induction of apoptosis and effects on growth inhibition were assessed. The lung cancer cells treated with VSV plus gemcitabine displayed the apparently increased apoptotic cells compared with treatment with VSV or gemcitabine alone. The combined treatment with VSV plus gemcitabine induced the apparent antitumor activity with complete regression of the established lung cancer in both A549 and LLC lung cancer models and augmented the induction of apoptosis in lung cancer cells in vivo as well. This study suggests that the combined treatment with VSV plus gemcitabine may augment the induction of apoptosis in lung cancer cells in vitro and in vivo, and that the augmented antitumor activity in vivo may result from the increased induction of apoptosis in lung cancer cells. The present findings may be of importance to the further exploration of the potential application of this combined approach in the treatment of lung cancer. © 2004 Wiley‐Liss, Inc.
Reduced expression of MYO18B, a candidate tumor‐suppressor gene on chromosome arm 22q, in ovarian cancer
Authors: Yanaihara Nozomu , Nishioka Michiho , Kohno Takashi , Otsuka Ayaka , Okamoto Aikou , Ochiai Kazunori , Tanaka Tadao , Yokota Jun 
Published: June 2004

AbstractAllelic imbalance on chromosome arm 22q has been detected in 50–70% of ovarian cancers, suggesting the presence of a tumor‐suppressor gene on this chromosome arm that is involved in ovarian carcinogenesis. Recently, we isolated a candidate tumor‐suppressor gene, MYO18B, at 22q12.1, which is deleted, mutated and hypermethylated in approximately 50% of lung cancers. In our study, we analyzed genetic and epigenetic alterations of the MYO18B gene in ovarian cancers. Missense MYO18B mutations were detected in 1 of 4 (25%) ovarian cancer cell lines and in 1 of 17 (5.9%) primary ovarian cancers. MYO18B expression was reduced in all 4 ovarian cancer cell lines and in 12 of 17 (71%) of primary ovarian cancers. MYO18B expression was restored by treatment with 5‐aza‐2′‐deoxycytidine and/or trichostatin A in 3 of 4 cell lines with reduced MYO18B expression, and hypermethylation of the promoter CpG island for MYO18B was observed in 2 of these 3 cell lines. Its hypermethylation was also observed in 2 of 15 (13%) primary ovarian cancers. Thus, it was indicated that MYO18B expression is reduced in a considerable fraction of ovarian cancers by several mechanisms, including hypermethylation, while the MYO18B gene is mutated in a small subset of ovarian cancers. The present results suggest that MYO18B alterations, including both epigenetic and genetic alterations, play an important role in ovarian carcinogenesis. © 2004 Wiley‐Liss, Inc.