bluuebunny/crossref_metadata_2025_split huggingface dataset:
Increased Serum Interleukin-8 in Patients with Early and Metastatic Breast Cancer Correlates with Early Dissemination and Survival
Authors: Benoy Ina H. , Salgado Roberto , Van Dam Peter , Geboers Katrien , Van Marck Eric , Scharpé Simon , Vermeulen Peter B. , Dirix Luc Y. 
Published: September 2005

AbstractPurpose: The prognostic significance of serum interleukin (IL)-8 was evaluated in patients with metastatic breast cancer. The predictive value of serum IL-8 for the presence of occult metastatic tumor cells in bone marrow aspirates was evaluated in patients with operable and metastatic breast cancer.Experimental Design: Serum IL-8 was measured in healthy controls, patients with operable breast cancer, and patients with untreated, progressive metastatic breast cancer. In 69 patients with either operable or advanced breast cancer, occult cytokeratin-positive cells were counted in bone marrow aspirates.Results: Serum IL-8 levels are increased in 67% (52 of 77) of patients with advanced breast cancer. Overall, these levels are significantly higher in patients with breast cancer compared with healthy volunteers (P &lt; 0.001). The IL-8 levels increase significantly in patients with more advanced disease. An elevated serum IL-8 is related to an accelerated clinical course, a higher tumor load, and the presence of liver or lymph node involvement. A multivariate analysis indicates that serum IL-8 is an independent significant factor for postrelapse survival. There was a significant difference between serum IL-8 levels in patients with or without occult cytokeratin-positive bone marrow cells (P &lt; 0.04). Serum IL-8 levels also showed an association with the number of these cells (P &lt; 0.01).Conclusions: Serum IL-8 is increased in patients with breast cancer and has an independent prognostic significance for postrelapse survival. The observations on the relationship between occult cytokeratin-positive bone marrow cells corroborate the concept of IL-8 acting as a contributor to the process of tumor cell dissemination. Similarly, the relationship between serum IL-8 and nodal stage at presentation deserves further study. These results further expand the concept that inflammation and inflammatory cytokines are critical components of tumor progression.
Detection of Neuroblastoma Cells in Bone Marrow and Peripheral Blood by Different Techniques
Authors: Corrias Maria Valeria , Faulkner Lawrence B. , Pistorio Angela , Rosanda Cristina , Callea Francesco , Piccolo Maria Serena Lo , Scaruffi Paola , Marchi Cinzia , Lacitignola Laura , Occhino Marzia , Gambini Claudio , Tonini Gian Paolo , Haupt Riccardo , De Bernardi Bruno , Pistoia Vito , Garaventa Alberto 
Published: September 2005

Abstract
Purpose: Detection of metastatic tumor cells in bone marrow (BM) and peripheral blood (PB) of children with neuroblastoma is crucial for prognosis and planning of therapy. Aims of this large descriptive repeated survey were to evaluate the diagnostic accuracy of different techniques in diagnostic samples obtained at several disease course time points and to correlate positive results with patient clinical features and outcome.
Experimental Design: BM aspirates, trephine biopsies, PB, and peripheral blood stem cell (PBSC) samples from Italian children with neuroblastoma were analyzed by morphological and histologic techniques, as well as by immunocytochemistry (IC) for disialoganglioside GD2 and reverse transcription-PCRs (RT-PCRs) for tyrosine hydroxylase (TH) and pgp9.5 genes. The diagnostic odd ratio (DOR) was used to measure the accuracy of the different techniques.
Results: A total of 2,247 evaluations were done on 561 BM, 265 PB, and 69 PBSC samples from 247 patients. IC showed the best accuracy. Whereas TH RT-PCR accuracy was satisfactory, that of pgp9.5 was very low. Positive results obtained by IC in BM and PB samples at diagnosis from stage 1, 2, and 3 patients correlated with unfavourable outcome. No correlation was found between positive results obtained by IC or TH RT-PCR in BM, PB, and PBSC samples from stage 4 patients and their outcome.
Conclusions: Because of its elevated diagnostic accuracy, IC may represent a useful adjunct to conventional morphological techniques, especially in view of its potential prognostic role in patients with localized disease. Longitudinal multicenter studies are warranted to definitely establish the clinical usefulness of TH RT-PCR.
Loss of Heterozygosity and Immunohistochemistry of Adenocarcinomas of the Esophagus and Gastric Cardia
Authors: Marsman Willem A. , Birjmohun Rakesh S. , van Rees Bastiaan P. , Caspers Eric , Johan G. , Offerhaus A. , Bosma Piter J. , Jan J. , van Lanschot B. 
Published: September 2005

Abstract
Purpose: Adenocarcinomas of the distal esophagus and gastric cardia are two tumors that have many features in common. They have similar prognoses, treatment modalities, and patterns of dissemination. The etiology is different, with gastroesophageal reflux disease playing a major role for esophageal adenocarcinoma, in contrast to adenocarcinoma of the gastric cardia. In the present study, we investigated several genetic and immunohistochemical features of adenocarcinomas of the distal esophagus and gastric cardia.
Experimental Design: Sixty-two resection specimens of either adenocarcinoma of the esophagus or adenocarcinoma of the gastric cardia were carefully selected. The genetic analysis included loss of heterozygosity of several tumor suppressor genes known to be involved in esophagogastric carcinogenesis. Immunohistochemical studies included the analysis of p53, c-Met, c-erbB-2, β-catenin, and cyclooxygenase-2. In addition, a mutation analysis of the Tcf1 gene was done by direct sequencing.
Results: Patients with cardiac carcinoma had a significantly worse tumor stage and poorer differentiation on histology. Loss of heterozygosity analysis did not reveal significant differences between esophageal adenocarcinoma and cardiac adenocarcinoma. Immunohistochemical analysis revealed significantly more nuclear accumulation of β-catenin and overexpression of cyclooxygenase-2 in patients with esophageal adenocarcinoma, compared with patients with cardiac carcinoma. No mutation was found in the Tcf1 gene in either tumor type.
Conclusions: Although adenocarcinomas of the distal esophagus and gastric cardia have many features in common, we have found some evidence that they might form two different entities.
Coexpression of Matrix Metalloproteinase-7 (MMP-7) and Epidermal Growth Factor (EGF) Receptor in Colorectal Cancer
Authors: Mimori Koshi , Yamashita Keishi , Ohta Mitsuhiko , Yoshinaga Keiji , Ishikawa Kenji , Ishii Hideshi , Utsunomiya Tohru , Barnard Graham F. , Inoue Hiroshi , Mori Masaki 
Published: September 2005

Abstract
Purpose: Matrix metalloproteinase-7 (MMP-7) plays an important role in carcinoma invasion and metastasis of cancer. Recent studies focus on diverse roles of MMP-7, other than as a protease, during cancer progression. MMP-7 activates the epidermal growth factor (EGF) receptor by releasing an EGF ligand, tumor growth factor (TGF)-α.
Experimental Design: We examined expression of MMP-7 and EGF receptor in an immunohistochemical study of 40 colorectal cancer (CRC) cases. To determine the relationship between the EGF receptor and MMP-7, with a potential curative application, we compared the antitumor activity of the EGF receptor tyrosine kinase inhibitor (gefitinib) between MMP-7 transfectant, KYSE150 and HT29, and control cells.
Results: We found a statistically significant correlation (P = 0.04) between MMP-7 and activated (phosphorylated) EGF receptor expression, both being positive in six (15%) cases. Gefitinib reduced the cell number ratio more for MMP-7 transfectant than mock cells, and the proportion of apoptotic cells was 1.5 times higher in MMP-7 transfectant than mock cells by annexin/propidium iodide staining. This was mediated by activation of a TGF-β signal as confirmed by the abundant expression of TGF-β protein, the cytoplasmic to nuclear translocation of Smad4 protein by the administration of gefitinib, and the quantitative assay of the plasminogen activator inhibitor-1 promoter/luciferase construction.
Conclusions: We propose that there are some cancers with up-regulated MMP-7 expression that leads to the activation of apoptotic activity of TGF-β, which is susceptible to treatment with EGF receptor tyrosine kinase inhibitor.
Interplay of Insulin-Like Growth Factor-II, Insulin-Like Growth Factor-I, Insulin-Like Growth Factor-I Receptor, COX-2, and Matrix Metalloproteinase-7, Play Key Roles in the Early Stage of Colorectal Carcinogenesis
Authors: Nosho Katsuhiko , Yamamoto Hiroyuki , Taniguchi Hiroaki , Adachi Yasushi , Yoshida Yukinari , Arimura Yoshiaki , Endo Takao , Hinoda Yuji , Imai Kohzoh 
Published: September 2005

Abstract
Purpose: The aim of this study was to characterize the relationship of insulin-like growth factor (IGF)-II expression with IGF-I, IGF-I receptor (IGF-IR), cyclooxygenase-2 (COX-2), and matrix metalloproteinase (MMP)-7 in early colorectal carcinogenesis.
Experimental Design: With the semiquantitative reverse transcriptase-PCR, 90 human colorectal tumor tissues (63 adenomas and 27 submucosal pT1 cancers) were analyzed for IGF-II, IGF-IR, IGF-I, COX-2, and MMP-7 expression. Ninety-nine adenoma tissues and 60 pT1 cancer tissues were also analyzed immunohistochemically for IGF-II expression. Loss of imprinting of the IGF-II gene was analyzed. Paired carcinoma and adenoma tissues obtained from a carcinoma in adenoma lesion was analyzed by a cDNA array.
Results: IGF-II mRNA expression was detected in 37.8% of the 90 colorectal tumor tissues. The frequency of IGF-II mRNA expression was significantly higher in pT1 cancer (70.4%) than in adenoma (23.8%). Immunohistochemical IGF-II expression was also more frequently detected in pT1 cancer (58.3%) than in adenoma (25.3%). Loss of imprinting of the IGF-II gene was observed in 15 (44.1%) of the 34 colorectal tumors in which IGF-II was overexpressed. IGF-II expression was positively correlated with the expression of IGF-IR and IGF-I. COX-2 and MMP-7 mRNA expression was detected in 42.2% and 77.8% of the tumor tissues, respectively, and both were positively correlated with IGF-I, IGF-II, and IGF-IR expression. IGF-II was the most differentially expressed gene between carcinoma and adenoma lesions.
Conclusions: IGF-II, in conjunction with IGF-IR, IGF-I, COX-2, and MMP-7, seems to play a key role in the early stage of colorectal carcinogenesis.
Cell Cycle Genes in Ovarian Cancer
Authors: D’Andrilli Giuseppina , Kumar Christine , Scambia Giovanni , Giordano Antonio 
Published: September 2005

Abstract
Human malignant tumors are characterized by abnormal proliferation resulting from alterations in cell cycle-regulatory mechanisms. The regulatory pathways controlling cell cycle phases include several oncogenes and tumor suppressor genes that display a range of abnormalities with potential usefulness as markers of evolution or treatment response in ovarian cancer. This review summarizes the current knowledge about these aberrations in malignant tumors of the ovary. We sought to divide cell cycle-regulatory genes into four subgroups on the basis of their predominant role in a specific phase or during the transition between two phases of the cell cycle.
A Quantitative Promoter Methylation Profile of Prostate Cancer
Authors: Jerónimo Carmen , Henrique Rui , Hoque Mohammad O. , Mambo Elizabeth , Ribeiro Franclim R. , Varzim Graça , Oliveira Jorge , Teixeira Manuel R. , Lopes Carlos , Sidransky David 
Published: September 2005

Abstract
Purpose: Promoter hypermethylation is an alternative pathway for gene silencing in neoplastic cells and a promising cancer detection marker. Although quantitative methylation-specific PCR (QMSP) of the GSTP1 promoter has demonstrated near perfect specificity for cancer detection in prostate biopsies, we postulated that identification and characterization of additional methylation markers might further improve its high (80–90%) sensitivity.
Experimental Design: We surveyed nine gene promoters (GSTP1, MGMT, p14/ARF, p16/CDKN2A, RASSF1A, APC, TIMP3, S100A2, and CRBP1) by QMSP in tissue DNA from 118 prostate carcinomas, 38 paired high-grade prostatic intraepithelial neoplasias (HGPIN), and 30 benign prostatic hyperplasias (BPH). The methylation levels were calculated and were correlated with clinical and pathologic indicators.
Results: Only the methylation frequencies of GSTP1 and APC were significantly higher in prostate carcinoma compared with BPH (P &lt; 0.001). Methylation levels of GSTP1, APC, RASSF1A, and CRBP1, differed significantly between prostate carcinoma and HGPIN, and/or HGPIN or BPH (P &lt; 0.0001).With QMSP and empirically defined cutoff values, the combined use of GSTP1 and APC demonstrated a theoretical sensitivity of 98.3% for prostate carcinoma, with 100% specificity. Methylation levels were found to correlate with tumor grade (GSTP1 and APC) and stage (GSTP1, RASSF1A, and APC).
Conclusions: Our data demonstrate the existence of a progressive increase of promoter methylation levels of several cancer-related genes in prostate carcinogenesis, providing additional markers to augment molecular detection of prostate carcinoma. Because methylation levels of GSTP1, APC, and RASSF1A are associated with advanced grade and stage, QMSP might augment the pathologic indicators currently used to predict tumor aggressiveness.
The Selective Cyclooxygenase-2 Inhibitor Nimesulide Prevents
Helicobacter pylori
-Associated Gastric Cancer Development in a Mouse Model
Authors: Nam Ki Taek , Hahm Ki-Baik , Oh Sang-Yeon , Yeo Marie , Han Sang-Uk , Ahn Byeongwoo , Kim Young-Bae , Kang Jin Seok , Jang Dong Deuk , Yang Ki-Hwa , Kim Dae-Yong 
Published: September 2005

Abstract
Purpose: Helicobacter pylori infection can lead to gastric cancer, and cyclooxygenase-2 (COX-2) is overexpressed in the stomach during H. pylori infection. Therefore, we investigated whether nonsteroidal anti-inflammatory drugs might protect against this form of cancer. Specifically, we examined the chemopreventive effect of the COX-2 inhibitor nimesulide on H. pylori-associated gastric carcinogenesis in mice.
Experimental Design: C57BL/6 mice were treated with the carcinogen N-methyl-N-nitrosourea (MNU) and/or H. pylori. To determine the effect of COX-2 inhibition, nimesulide was mixed with feed pellets and administered for the duration of the experiment. All of the mice were sacrificed 50 weeks after the start of the experiment. Histopathology, immunohistochemistry, and Western blotting for COX-2, Bax and Bcl-2 were performed in stomach tissues. In vitro experiments with the human gastric cancer cell line AGS were also performed to identify mechanisms underlying cancer chemoprevention by nimesulide.
Results: Gastric tumors developed in 68.8% of mice that were given both MNU and H. pylori, whereas less than 10% developed gastric tumors when given either MNU or H. pylori alone. These findings indicate that H. pylori promotes carcinogen-induced gastric tumorigenesis. In mice treated with both MNU and H. pylori, nimesulide administration substantially reduced H. pylori-associated gastric tumorigenesis, whereas substantial inductions of apoptosis were observed. In vitro studies demonstrated that nimesulide and H. pylori when combined acted synergistically to induce more apoptosis than either alone.
Conclusions: Our data show that nimesulide prevents H. pylori-associated gastric carcinogenesis, and suggest that COX-2 may be a target for chemoprevention of gastric cancer.
Trastuzumab Down-Regulates Bcl-2 Expression and Potentiates Apoptosis Induction by Bcl-2/Bcl-XL Bispecific Antisense Oligonucleotides in
HER-2
Gene–Amplified Breast Cancer Cells
Authors: Milella Michele , Trisciuoglio Daniela , Bruno Tiziana , Ciuffreda Ludovica , Mottolese Marcella , Cianciulli Anna , Cognetti Francesco , Zangemeister-Wittke Uwe , Del Bufalo Donatella , Zupi Gabriella 
Published: September 2005

Abstract
Purpose: To investigate the possible existence of an antiapoptotic cross-talk between HER-2 and antiapoptotic Bcl-2 family members.
Experimental Design: Bcl-2 and Bcl-XL expression and apoptosis induction were analyzed in HER-2gene–amplified (BT474) and nonamplified (ZR 75-1) breast cancer cell lines exposed to trastuzumab, alone or in combination with either Bcl-2/Bcl-XL bispecific antisense oligonucleotides (AS-4625) or the small-molecule Bcl-2 antagonist HA14-1.
Results: In addition to HER-2 and epidermal growth factor receptor, trastuzumab down-regulated Bcl-2, but not Bcl-XL, protein, and mRNA expression in BT474 cells. Interestingly, trastuzumab-induced down-regulation of HER-2 and Bcl-2 was also observed in three of five and two of three breast cancer patients undergoing trastuzumab treatment, respectively. Despite Bcl-2 down-regulation, however, trastuzumab only marginally increased the rate of apoptosis (7.3 ± 3.5%). We therefore investigated whether a combination of AS-4625 and trastuzumab might increase proapoptotic efficiency. AS-4625 treatment of BT474 cells decreased both Bcl-2 and Bcl-XL expression, resulting in a 21 ± 7% net apoptosis induction; the combination of AS-4625 followed by trastuzumab resulted in a significantly stronger induction of apoptosis (37 ± 6%, P &lt; 0.01) that was not observed with the reverse treatment sequence (trastuzumab followed by AS-4625). Similar results were obtained with the Bcl-2 antagonist HA14-1; indeed, exposure of BT474 cells to HA14-1 followed by trastuzumab resulted in a striking proapoptotic synergism (combination index = 0.58 ± 0.18), as assessed by isobologram analysis.
Conclusions: Altogether our findings suggest that combined targeting of HER-2 and Bcl-2 may represent a novel, rational approach to more effective breast cancer therapy.
Efficacy and Safety Evaluation of Human Reovirus Type 3 in Immunocompetent Animals
Authors: Yang Wen Qing , Lun Xueqing , Palmer Cheryl Ann , Wilcox M. Elizabeth , Muzik Huong , Shi Zhong Qiao , Dyck Richard , Coffey Matt , Thompson Brad , Hamilton Mark , Nishikawa Sandra G. , Brasher Penny M. A. , Fonseca Kevin , George David , Rewcastle N. Berry , Johnston Randal N. , Stewart Doug , Lee Patrick W. K. , Senger Donna L. , Forsyth Peter A. 
Published: September 2005

Abstract
Purpose: Human reovirus type 3 has been proposed to kill cancer cells with an activated Ras signaling pathway. The purpose of this study was to investigate the efficacy of reovirus in immunocompetent glioma animal models and safety/toxicity in immunocompetent animals, including nonhuman primates.
Experimental Design: Racine glioma cells 9L and RG2 were implanted s.c. or intracranially in Fisher 344 rats with or without reovirus antibodies, followed by treatment of reovirus. To study whether reovirus kills contralateral tumors in the brain and to determine viral distribution, we established an in situ dual tumor model followed by reovirus intratumoral inoculation only into the ipsilateral tumor. To evaluate neurotoxicity/safety of reovirus, Cynomolgus monkeys and immunocompetent rats were given intracranially with reovirus, and pathological examination and/or behavioral studies were done. Viral shedding and clinical biochemistry were systematically studied in monkeys.
Results: Intratumorally given reovirus significantly suppressed the growth of both s.c. and intracranially tumors and significantly prolonged survival. The presence of reovirus-neutralizing antibodies did not abort the reovirus’ antitumor effect. Reovirus inhibited glioma growth intracranially in the ipsilateral but not the contralateral tumors; viral load in ipsilateral tumors was 15 to 330-fold higher than the contralateral tumors. No encephalitis or behavioral abnormalities were found in monkeys and rats given reovirus intracranially. No treatment-related clinical biochemistry changes or diffuse histopathological abnormality were found in monkeys inoculated intracranially with Good Manufacturing Practice prepared reovirus. Microscopic changes were confined to the region of viral inoculation and were dose related, suggesting reovirus intracranially was well tolerated in nonhuman primates.
Conclusions: These data show the efficacy and safety of reovirus when it is used in the treatment of gliomas in immunocompetent hosts. Inoculation of reovirus into the brain of nonhuman primates did not produce significant toxicities.
Pseudolaric Acid B Inhibits Angiogenesis and Reduces Hypoxia-Inducible Factor 1α by Promoting Proteasome-Mediated Degradation
Authors: Li Mei-Hong , Miao Ze-Hong , Tan Wen-Fu , Yue Jian-Min , Zhang Chao , Lin Li-Ping , Zhang Xiong-Wen , Ding Jian 
Published: September 2005

Abstract
Purpose: Pseudolaric acid B (PAB), the naturally occurring diterpenoid isolated from the root bark of Pseudolarix kaempferi Gordon tree (Pinaceae), possesses potent antifungal and pregnancy-terminating effects that may be tightly associated with angiogenesis. This study was to examine its angiogenic inhibition, impact on vascular endothelial growth factor (VEGF) secretion from tumor cells and the possible mechanism of action.
Experimental Design: Angiogenesis inhibition was assessed by the human umbilical vascular endothelial cell proliferation, migration, and tube-formation assays, as well as the chorioallantoic membrane assay. ELISA, reverse transcription-PCR, and Western blotting analyses were performed to examine VEGF protein secretion, mRNA expression, and the possible mechanism in hypoxic MDA-MB-468 cells.
Results: PAB displayed potent in vitro antiangiogenic activity shown by inhibiting VEGF-stimulated proliferation and migration and fetal bovine serum-stimulated tube formation of human umbilical vascular endothelial cells in a concentration-dependent manner. Moreover, PAB (10 nmol per egg) significantly suppressed in vivo angiogenesis in the chorioallantoic membrane assay. On the other hand, PAB abrogated hypoxia-induced VEGF secretion from MDA-MB-468 cells via reducing HIF-1α protein. Additional analyses using LY294002 and U0126 indicated that the increase in hypoxia-inducible factor 1 (HIF-1)α protein level was highly dependent on phosphatidylinositol 3′-kinase and p42/p44 mitogen-activated protein kinase activities in hypoxic MDA-MB-468 cells. However, PAB treatment did not affect the active (phosphorylated) forms of Akt and Erk. Interestingly, the selective proteasome inhibitor MG-132 completely reversed the reduction of HIF-1α protein in the PAB-treated MDA-MB-468 cells.
Conclusions: PAB displays the dual antiangiogenic activities of directly inhibiting endothelial cells and abrogating paracrine stimulation of VEGF from tumor cells due to reducing HIF-1α protein by promoting its proteasome-mediated degradation in MDA-MB-468 cells, which has potential clinical relevance.