bluuebunny/crossref_metadata_2025_split huggingface dataset:
Positive Correlation between Estradiol and Vascular Endothelial Growth Factor but not Fibroblast Growth Factor-2 in Normal Human Breast Tissue In vivo
Authors: Dabrosin Charlotta 
Published: March 2006

Abstract
Purpose: Angiogenesis is crucial in tumor development and progression. Ovarian hormones regulate angiogenesis in the reproductive tract but very little is known about its regulation in the normal breast. Sex steroids play an important role in breast cancer development by poorly understood mechanisms. Vascular endothelial growth factor (VEGF) and fibroblast growth factor-2 (FGF-2) are potent stimulators of angiogenesis. Both VEGF and FGF-2 function in autocrine/paracrine pathways and there is a major contribution of bioactive proteins by a posttranslational activation of sequestered molecules in the extracellular space. A direct measurement of these molecules in the extracellular compartment is, therefore, needed.
Experimental Design: In this study, microdialysis was used to measure extracellular VEGF and FGF-2 in normal human breast tissue in situ in 11 premenopausal and 5 postmenopausal women.
Results: Significantly higher level of VEGF in breast tissue of premenopausal women was found. Plasma as well as local estradiol and breast tissue VEGF exhibited significant correlations, whereas progesterone had no correlation with breast VEGF. FGF-2 did not correlate with either estradiol or progesterone.
Conclusion: The result suggests that estradiol is a more potent regulator of free VEGF levels than progesterone in the normal breast. The control of free FGF-2 seems to be independent of sex steroids in the breast. Estrogen induction of free extracellular VEGF may be one mechanism involved in sex steroid–dependent breast carcinogenesis.
Signal Pathway of Hypoxia-Inducible Factor-1α Phosphorylation and its Interaction with von Hippel-Lindau Tumor Suppressor Protein During Ischemia in MiaPaCa-2 Pancreatic Cancer Cells
Authors: Kwon Seok J. , Song Jae J. , Lee Yong J. 
Published: March 2006

Abstract
Purpose and Experimental Design: Previously, we observed that the activation of p38 mitogen-activated protein kinase (MAPK) and c-Jun NH2-terminal kinase (JNK1) is mediated through the activation of apoptosis signal–regulating kinase 1 (ASK1) as a result of the reactive oxygen species–mediated dissociation of glutaredoxin and thioredoxin from ASK1. In this study, we examined whether p38 MAPK and JNK1 are involved in the accumulation of hypoxia-inducible factor-1α (HIF-1α) during ischemia. Human pancreatic cancer MiaPaCa-2 cells were exposed to low glucose (0.1 mmol/L) with hypoxia (0.1% O2).
Results and Conclusions: During ischemia, p38 MAPK and JNK1 were activated in MiaPaCa-2 pancreatic cancer cells. The activated p38 MAPK, but not JNK1, phosphorylated HIF-1α. Data from in vivo binding assay of von Hippel-Lindau tumor suppressor protein with HIF-1α suggests that the p38-mediated phosphorylation of HIF-1α contributed to the inhibition of HIF-1α and von Hippel-Lindau tumor suppressor protein interaction during ischemia. SB203580, a specific inhibitor of p38 MAPK, inhibited HIF-1α accumulation during ischemia, probably resulting from the ubiquitination and degradation of HIF-1α.
[131I]meta-Iodobenzylguanidine and Topotecan Combination Treatment of Tumors Expressing the Noradrenaline Transporter
Authors: McCluskey Anthony G. , Boyd Marie , Ross Susan C. , Cosimo Emilio , Clark Anne Marie , Angerson Wilson J. , Gaze Mark N. , Mairs Robert J. 
Published: March 2006

Abstract
Purpose: Both [131I]meta-iodobenzylguanidine ([131I]MIBG) and the topoisomerase I inhibitor topotecan are effective as single-agent treatments of neuroblastoma. The aim of this study was to investigate the efficacy of [131I]MIBG in combination with topotecan in vitro and in vivo.
Experimental Design: The cell lines used were SK-N-BE(2c) (human neuroblastoma) and UVW/NAT (glioma cell line transfected with the noradrenaline transporter gene). Three different treatment schedules were assessed: topotecan given before (schedule 1), after (schedule 2), or simultaneously (schedule 3) with [131I]MIBG. DNA strand breakage was evaluated by comet assay, and cytotoxicity was determined by clonogenic survival. Efficacy was also measured by growth delay of tumor xenografts in nude mice.
Results: Combination schedules 2 and 3 caused more cytotoxicity than schedule 1. Similarly, significant DNA damage was observed following treatment schedules 2 and 3 (P &lt; 0.005) but not schedule 1. The mean number of days for a doubling in volume of SK-N-BE(2c) tumors and a 10-fold increase in volume of UVW/NAT tumors were 10.4 and 18.6 (untreated), 19.7 and 25.3 (topotecan alone), 22.8 and 31.9 ([131I]MIBG alone), 26.3 and 37.1 (combination schedule 1), 34.3 and 49.7 (combination schedule 2), and 53.2 and &gt;71 (combination schedule 3), respectively. The highest rate of cure of both xenografts was observed following treatment with combination schedule 3.
Conclusions: The combination of topotecan and [131I]MIBG compared with either treatment alone gave rise to greater than additive DNA damage, clonogenic cell kill, and tumor growth delay. These effects were dependent on the scheduling of the two agents.
The Septin-Binding Protein Anillin Is Overexpressed in Diverse Human Tumors
Authors: Hall Peter A. , Todd Christopher B. , Hyland Paula L. , McDade Simon S. , Grabsch Heike , Dattani Mit , Hillan Kenneth J. , Russell S.E. Hilary 
Published: March 2006

Abstract
Anillin is an actin-binding protein that can bind septins and is a component of the cytokinetic ring. We assessed the anillin expression in 7,579 human tissue samples and cell lines by DNA microarray analysis. Anillin is expressed ubiquitously but with variable levels of expression, being highest in the central nervous system. The median level of anillin mRNA expression was higher in tumors than normal tissues (median fold increase 2.58; 95% confidence intervals, 2.19-5.68, P &lt; 0.0001) except in the central nervous system where anillin mRNA levels were lower in tumors. We developed a sensitive reverse transcription-PCR strategy to show that anillin mRNA is expressed in cell lines and in cDNA panels derived from fetal and adult tissues, thus validating the microarray data. We compared anillin with Ki67 mRNA expression and found a significant linear relationship between anillin and Ki67 mRNA expression (Spearmann r ∼ 0.6, P &lt; 0.0001). Anillin mRNA expression was analyzed during tumor progression in breast, ovarian, kidney, colorectal, hepatic, lung, endometrial, and pancreatic tumors and in all tissues there was progressive increase in anillin mRNA expression from normal to benign to malignant to metastatic disease. Finally, we used anti-anillin sera and found nuclear anillin immunoreactivity to be widespread in normal tissues, often not correlating with proliferative compartments. These data provide insight into the existence of nonproliferation-associated activities of anillin and roles in interphase nuclei. Thus, anillin is overexpressed in diverse common human tumors, but not simply as a consequence of being a proliferation marker. Anillin may have potential as a novel biomarker.
Tumor β-1,4-Galactosyltransferase IV Overexpression Is Closely Associated with Colorectal Cancer Metastasis and Poor Prognosis
Authors: Chen Wei-Shone , Chang Hong-Yi , Li Chung-Pin , Liu Jacqueline Ming , Huang Tze-Sing 
Published: March 2006

Abstract
Purpose: To elucidate the significance of β-1,4-galactosyltransferase IV (β-1,4-GT-IV) in the clinical presentation and prognostication of colorectal cancer.
Experimental Design: Tissue lysates from paired tumor and nontumor tissues of a colon cancer patient were labeled separately with fluorescent dyes Cy5 and Cy3 for two-dimensional difference in-gel electrophoresis. Subsequent matrix-assisted laser desorption/ionization time-of-flight mass spectrometry and immunoblot analyses identified a down-regulated level of β-1,4-GT-IV in the tumor tissue. In the follow-up study, paired tissue lysates were obtained from 100 colorectal cancer patients with immunoblot analyses done to compare the levels of β-1,4-GT-IV expression in these patients.
Results: Of 100 colorectal patients studied, 48% had down-regulated expression of β-1,4-GT-IV in the tumor tissue but 28% of patients exhibited elevated β-1,4-GT-IV levels. Increased β-1,4-GT-IV in the tumor tissue was significantly coexistent with raised serum level of CA-199 and the presence of tumor metastasis (P = 0.006 and P &lt; 0.001, respectively) but was independent of age and gender of patient, tumor site, tumor size, serum level of carcinoembryonic antigen, grade of tumor cell differentiation, and depth of tumor invasion. The results of logistic regression analyses suggested that tumor β-1,4-GT-IV overexpression and tumor invasion, but not other patient variables such as tumor size and serum levels of carcinoembryonic antigen and CA19-9, were significantly correlated with the occurrence of metastases (P &lt; 0.05). In a multivariate regression analysis, the patient group with tumor β-1,4-GT-IV overexpression strongly predicted for tumor metastasis (odds ratio, 10.009; 95% confidence interval, 2.992-33.484; P &lt; 0.001). Likewise, tumor β-1,4-GT-IV overexpression was significantly associated with poor overall survival (P &lt; 0.01). By Cox regression analysis, this association remained significant even after adjustment for tumor metastasis (P = 0.048).
Conclusion: Increased β-1,4-GT-IV expression in tumor tissue was strongly associated with tumor metastases and poor prognosis in colorectal cancer.
Identification ofCCND3andBYSLas Candidate Targets for the 6p21 Amplification in Diffuse Large B-Cell Lymphoma
Authors: Kasugai Yumiko , Tagawa Hiroyuki , Kameoka Yoshihiro , Morishima Yasuo , Nakamura Shigeo , Seto Masao 
Published: March 2006

AbstractPurpose: Increases in gene dosage through DNA amplification represents a common feature of many tumors and can result in the up-regulation of tumor-promoting genes. Our recent genome-wide, array-based comparative genomic hybridization analysis of 66 cases of diffuse large B-cell lymphoma found that genomic gain of 6p21 was observed in as many as 17 cases, including 14 cases with low-level copy number gain and three cases with high-level copy number gains (amplifications).Experimental Design and Results: To identify the target gene(s) for 6p21 amplification, we constructed a detailed amplicon map at the region of genomic amplification with the aid of high-resolution contig array-based comparative genomic hybridization glass slides, consisting of contiguously ordered bacterial artificial chromosome/P1-derived artificial chromosome clones covering 3 Mb throughout the 6p21 amplification region. Alignment of the amplifications identified a minimally overlapping 800 kb segment containing 15 genes. Quantitative expression analysis of the genes from both patient samples and the SUDHL9 cell line revealed that CCND3 and BYSL (1.9 kb telomeric to the CCND3 gene locus) are the targets of 6p21 genomic gain/amplification.Conclusions: Although it is known that t(6;14)(p21;q32) induces aberrant overexpression of CCND3 in B-cell malignancies, we were able to show that CCND3, which encodes the cyclin D family member protein that controls the G1-S phase of cell cycle regulation, can also be a target of genomic gain/amplification. Overexpression of CCND3 through genomic amplification is likely to lead to aberrant cell cycle control, although the precise biological role of BYSL with respect to tumorigenesis remains to be determined.
The clinical value of somatic TP53 gene mutations in 1,794 patients with breast cancer.
Authors: Olivier Magali , Langer√∏d Anita , Carrieri Patrizia , Bergh Jonas , Klaar Sigrid , Eyfjord Jorunn , Theillet Charles , Rodriguez Carmen , Lidereau Rosette , Bi√®che Ivan , Varley Jennifer , Bignon Yves , Uhrhammer Nancy , Winqvist Robert , Jukkola-Vuorinen Arja , Niederacher Dieter , Kato Shunsuke , Ishioka Chikashi , Hainaut Pierre , B√∏rresen-Dale Anne-Lise 
Published: March 2006

Abstract
To investigate the clinical value of somatic TP53 mutations in breast cancer, we assembled clinical and molecular data on 1,794 women with primary breast cancer with long-term follow-up and whose tumor has been screened for mutation in exons 5 to 8 of TP53 by gene sequencing. TP53 mutations were more frequent in tumors of ductal and medullar types, aggressive phenotype (high grade, large size, node positive cases, and low hormone receptor content) and in women &lt;60 years old. TP53 mutations within exons 5 to 8 conferred an elevated risk of breast cancer-specific death of 2.27 (relative risk &gt;10 years; P &lt; 0.0001) compared with patients with no such mutation. The prognostic value of TP53 mutation was independent of tumor size, node status, and hormone receptor content, confirming and reconciling previous findings in smaller series. Moreover, an interaction between TP53 mutation and progesterone receptor (PR) status was revealed, TP53 mutation combined with the absence of progesterone receptor being associated with the worst prognosis. Whereas previous studies have emphasized the fact that missense mutations in the DNA-binding motifs have a worse prognosis than missense mutations outside these motifs, we show that non-missense mutations have prognostic value similar to missense mutations in DNA-binding motifs. Nonetheless, specific missense mutants (codon 179 and R248W) seem to be associated with an even worse prognosis. These results, obtained on the largest series analyzed thus far, show that TP53 mutations identified by gene sequencing have an independent prognostic value in breast cancer and could have potential uses in clinical practice.
Tumor Necrosis Factor α and Adiponectin in Bone Marrow Interstitial Fluid from Patients with Acute Myeloid Leukemia Inhibit Normal Hematopoiesis
Authors: Iversen Per Ole , Wiig Helge 
Published: March 2006

AbstractPurpose: Locally residing cytokines may inhibit bone marrow hematopoiesis in acute myeloid leukemia (AML). Using a novel method to isolate bone marrow interstitial fluid, we examined if this fluid from 10 adult AML patients could affect normal bone marrow hematopoiesis.Experimental Design: Bone marrow interstitial fluid was isolated by centrifugation of bone marrow biopsies obtained at time of diagnosis and 2 to 4 weeks after start of induction therapy. The isolated fluid was added to normal bone marrow CD34 hematopoietic progenitor cells sampled from five healthy subjects.Results: Unlike plasma, AML-derived bone marrow interstitial fluid clearly repressed hematopoietic progenitor cell growth as determined by an in vitro colony assay, an effect that was lost after successful induction treatment. Antibodies against tumor necrosis factor α (TNFα) and adiponectin abolished growth inhibition by bone marrow interstitial fluid, suggesting a mechanistic role of these cytokines in impairing normal hematopoiesis in AML. The plasma levels of adiponectin and TNFα were unaffected by therapy whereas bone marrow interstitial fluid levels of both cytokines fell significantly in patients entering remission. Transcripts for TNFα, but not for adiponectin, were found in AML blast cells. Neither the plasma levels nor the bone marrow interstitial fluid levels of the proangiogenic factors vascular endothelial growth factor or basic fibroblast growth factor were appreciably elevated in the patients nor did they change with treatment.Conclusions: Specific analyses of bone marrow interstitial fluid may give novel information on normal and malignant hematopoietic activity and thus form the basis for mechanism-based therapy.
In vitro and In vivo Clinical Pharmacology of Dimethyl Benzoylphenylurea, a Novel Oral Tubulin-Interactive Agent
Authors: Rudek Michelle A. , Zhao Ming , Smith Nicola F. , Robey Robert W. , He Ping , Hallur Gurulingappa , Khan Saeed , Hidalgo Manuel , Jimeno Antonio , Colevas A. Dimitrios , Messersmith Wells A. , Wolff Antonio C. , Baker Sharyn D. 
Published: March 2006

Abstract
Dimethyl benzoylphenylurea (BPU) is a novel tubulin-interactive agent with poor and highly variable oral bioavailability. In a phase I clinical trial of BPU, higher plasma exposure to BPU and metabolites was observed in patients who experienced dose-limiting toxicity. The elucidation of the clinical pharmacology of BPU was sought. BPU, monomethylBPU, and aminoBPU were metabolized by human liver microsomes. Studies with cDNA-expressed human cytochrome P450 enzymes revealed that BPU was metabolized predominantly by CYP3A4 and CYP1A1 but was also a substrate for CYP2C8, CYP2D6, CYP3A5, and CYP3A7. BPU was not a substrate for the efflux transporter ABCG2. Using simultaneous high-performance liquid chromatography/diode array and tandem mass spectrometry detection, we identified six metabolites in human liver microsomes, plasma, or urine: monomethylBPU, aminoBPU, G280, G308, G322, and G373. In patient urine, aminoBPU, G280, G308, and G322 collectively represented &lt;2% of the given BPU dose. G280, G308, G322, and G373 showed minimal cytotoxicity. When BPU was given p.o. to mice in the presence and absence of the CYP3A and ABCG2 inhibitor, ritonavir, there was an increase in BPU plasma exposure and decrease in metabolite exposure but no overall change in cumulative exposure to BPU and the cytotoxic metabolites. Thus, we conclude that (a) CYP3A4 and CYP1A1 are the predominant cytochrome P450 enzymes that catalyze BPU metabolism, (b) BPU is metabolized to two cytotoxic and four noncytotoxic metabolites, and (c) ritonavir inhibits BPU metabolism to improve the systemic exposure to BPU without altering cumulative exposure to BPU and the cytotoxic metabolites.
In vitro and In vivo Effects and Mechanisms of Celecoxib-Induced Growth Inhibition of Human Hepatocellular Carcinoma Cells
Authors: Cui Wei , Yu Chang-Hong , Hu Ke-Qin 
Published: March 2006

Abstract
Purpose: Cyclooxygenase-2 (COX-2) inhibitors cause growth inhibition of human hepatocellular carcinoma cells but it remains unclear whether this is both COX-2 dependent and independent. The related mechanisms remain to be determined. The present study was aimed to determine the effect of celecoxib on growth of hepatocellular carcinoma cells and xenografts and the related mechanisms.
Experimental Design: Both low COX-2 expressing PLC/PRF/5 and high COX-2 expressing HuH7 cells, and nude mice bearing hepatocellular carcinoma xenografts were used to study the effect and mechanisms of celecoxib on hepatocellular carcinoma cell growth.
Results: Celecoxib resulted in a comparable growth inhibition of both hepatocellular carcinoma cells that was associated with decreased production of prostaglandin E2 and increased peroxisome proliferator-activated receptor γ in both cells. Addition of prostaglandin E2 only partially counteracted the effect of celecoxib on both cells. Celecoxib resulted in a significant reduction of retinoblastoma phosphorylation and DP1/E2F1 complex in both cells. Celecoxib caused a significant increase of apoptosis and activation of caspase-3 and caspase-9 in both cells. In nude mice inoculated with HuH7 cells, celecoxib resulted in decreased frequency and mean weight of hepatocellular carcinoma xenografts.
Conclusion: The present study showed that celecoxib causes COX-2-dependent and COX-2-independent growth inhibition of hepatocellular carcinoma cells and xenografts by (a) decreased retinoblastoma phosphorylation and DP1/E2F1 complex; (b) increased activation of caspase-3 and caspase-9; and (c) increased expression of proliferator-activated receptor γ. The present study significantly extended our knowledge on the effect and mechanisms of celecoxib-induced inhibition of hepatocellular carcinoma cell growth.
A Simple and Fast Method for the Simultaneous Detection of Nine Fibroblast Growth Factor Receptor 3 Mutations in Bladder Cancer and Voided Urine
Authors: van Oers Johanna M.M. , Lurkin Irene , van Exsel Antonius J.A. , Nijsen Yvette , van Rhijn Bas W.G. , van der Aa Madelon N.M. , Zwarthoff Ellen C. 
Published: March 2006

Abstract
Purpose: Mutations in the fibroblast growth factor receptor 3 (FGFR3) occur in 50% of primary bladder tumors. An FGFR3 mutation is associated with good prognosis, illustrated by significantly lower percentage of patients with progression and disease-specific mortality. FGFR3 mutations are especially prevalent in low grade/stage tumors, with pTa tumors harboring mutations in 85% of the cases. These tumors recur in 70% of patients. Efficient FGFR3 mutation detection for prognostic purposes and for detection of recurrences in urine is an important clinical issue. In this paper, we describe a simple assay for the simultaneous detection of nine different FGFR3 mutations.
Experimental Design: The assay consists of one multiplex PCR, followed by extension of primers for each mutation with a labeled dideoxynucleotide. The extended primers are separated by capillary electrophoresis, and the identity of the incorporated nucleotide indicates the presence or absence of a mutation.
Results: The assay was found to be more sensitive than single-strand conformation polymorphism analysis. Mutations could still be detected with an input of only 1 ng of genomic DNA and in a 20-fold excess of wild-type DNA. Moreover, in urine samples from patients with a mutant tumor, the sensitivity of mutation detection was 62%.
Conclusions: We have developed a fast, easy to use assay for the simultaneous detection of FGFR3 mutations, which can be of assistance in clinical decision-making and as an alternative for the follow-up of patients by invasive cystoscopy for the detection of recurrences in urine.
In vivoTherapeutic Responses Contingent on Fanconi Anemia/BRCA2 Status of the Tumor
Authors: van der Heijden Michiel S. , Brody Jonathan R. , Dezentje David A. , Gallmeier Eike , Cunningham Steven C. , Swartz Michael J. , DeMarzo Angelo M. , Offerhaus G. Johan A. , Isacoff William H. , Hruban Ralph H. , Kern Scott E. 
Published: March 2006

AbstractPurpose: BRCA2, FANCC, and FANCG gene mutations are present in a subset of pancreatic cancer. Defects in these genes could lead to hypersensitivity to interstrand cross-linkers in vivo and a more optimal treatment of pancreatic cancer patients based on the genetic profile of the tumor.Experimental Design: Two retrovirally complemented pancreatic cancer cell lines having defects in the Fanconi anemia pathway, PL11 (FANCC-mutated) and Hs766T (FANCG-mutated), as well as several parental pancreatic cancer cell lines with or without mutations in the Fanconi anemia/BRCA2 pathway, were assayed for in vitro and in vivo sensitivities to various chemotherapeutic agents.Results: A distinct dichotomy of drug responses was observed. Fanconi anemia–defective cancer cells were hypersensitive to the cross-linking agents mitomycin C (MMC), cisplatin, chlorambucil, and melphalan but not to 5-fluorouracil, gemcitabine, doxorubicin, etoposide, vinblastine, or paclitaxel. Hypersensitivity to cross-linking agents was confirmed in vivo; FANCC-deficient xenografts of PL11 and BRCA2-deficient xenografts of CAPAN1 regressed on treatment with two different regimens of MMC whereas Fanconi anemia–proficient xenografts did not. The MMC response comprised cell cycle arrest, apoptosis, and necrosis. Xenografts of PL11 also regressed after a single dose of cyclophosphamide whereas xenografts of genetically complemented PL11FANCC did not.Conclusions: MMC or other cross-linking agents as a clinical therapy for pancreatic cancer patients with tumors harboring defects in the Fanconi anemia/BRCA2 pathway should be specifically investigated.