bluuebunny/crossref_metadata_2025_split huggingface dataset:
Expression of Extracellular Matrix Components Versican, Chondroitin Sulfate, Tenascin, and Hyaluronan, and Their Association with Disease Outcome in Node-Negative Breast Cancer
Authors: Suwiwat Supaporn , Ricciardelli Carmela , Tammi Raija , Tammi Markku , Auvinen Paivi , Kosma Veli-Matti , LeBaron Richard G. , Raymond Wendy A. , Tilley Wayne D. , Horsfall David J. 
Published: September 2005

Abstract
Purpose: The purpose is to determine whether the levels of expression of extracellular matrix components in peritumoral stroma are predictive of disease outcome for women with node-negative breast cancer.
Experimental Design: Tumor tissue from 86 patients with node-negative breast cancer was examined by immunohistochemical staining for the expression of versican, chondroitin sulfate (CS), tenascin, and hyaluronan (HA). With the exception of HA, the expression of the extracellular matrix components was measured by video image analysis. Statistical correlation of the immunohistochemical data with clinicopathological characteristics and disease outcome was performed.
Results: All of the extracellular matrix components were present in the peritumoral stroma of the entire study cohort. In contrast, immunoreactivity within the cancer cell was observed in 82% of tumors for HA, 12% for CS, and 4% for tenascin; no immunostaining of cancer cells for versican was observed for any of the tumors. Cox regression and Kaplan-Meier analyses indicated that elevated expression of stromal versican predicted increased risk and rate of relapse in this cohort. Elevated expression of tenascin was predictive of increased risk and rate of death only. Although neither CS nor HA were predictive of disease outcome in this cohort, tumor size was predictive of increased risk and rate of both relapse and survival.
Conclusions: Elevated expression within peritumoral stromal matrix of versican and tenascin was predictive of relapse-free and overall survival, respectively, in women with node-negative breast cancer.
CCL21 Chemokine Regulates Chemokine Receptor CCR7 Bearing Malignant Melanoma Cells
Authors: Takeuchi Hiroya , Fujimoto Akihide , Tanaka Maki , Yamano Tomoki , Hsueh Eddy , Hoon Dave S. B. 
Published: September 2005

AbstractPurpose: The chemokine CC-ligand 21/secondary lymphoid tissue chemokine (CCL21/SLC) regulates the homing of naïve T cells and dendritic cells that express CC-chemokine receptor 7 (CCR7) from distant sites to lymphoid tissue such as lymph nodes. We hypothesized that CCL21/SLC regulates the migration of CCR7-bearing melanoma cells from a primary lesion to regional tumor-draining lymph nodes.Experimental Design: Quantitative real-time reverse transcriptase-PCR (qRT) assay and immunohistochemistry (IHC) were used to assess the level of CCR7 expression in melanoma cell lines and in primary and metastatic melanoma tumors. Cell migration assay using melanoma cell lines was performed under the induction of CCL21/SLC. The CCL21/SLC expression level in tumor-draining sentinel lymph nodes (SLNs) was assessed by both qRT assay and IHC.Results: Melanoma cell lines and tumors demonstrated heterogeneous expression of CCR7 mRNA by qRT assay. There was strong functional correlation between CCR7 mRNA expression and cell migration induced by CCL21/SLC. IHC evidence of CCR7 expression in primary melanomas significantly (P = 0.02) correlated with Breslow thickness. Assessment of SLN from 55 melanoma patients by qRT assay demonstrated that CCL21/SLC mRNA expression level was significantly (P = 0.008) higher in pathologically melanoma-negative SLNs than in melanoma-positive SLNs.Conclusions: This report demonstrates a potential mechanism for recruitment and homing of CCR7(+) metastatic melanoma cells to tumor-draining lymph nodes, which express CCL21/SLC. The study also suggests that lymph nodes bearing metastasis may suppress CCL21/SLC production.
Death-Associated Protein Kinase Loss of Expression Is a New Marker for Breast Cancer Prognosis
Authors: Lévy Delphine , Plu-Bureau Geneviève , Decroix Yves , Hugol Danielle , Rostène William , Kimchi Adi , Gompel Anne 
Published: September 2005

Abstract
Purpose: Death-associated protein (DAP)-kinase is a new Ser/Thr kinase involved in cell apoptosis and tumor suppression, the expression of which has been correlated to invasive potential and metastasis in several human neoplastic tissues. We analyzed the level of DAP-kinase expression in breast cancer specimens and its correlation with survival.
Experimental Design: One hundred twenty-eight breast cancer specimens were analyzed by immunohistochemistry. Patient records were studied retrospectively for demographic characteristics, clinical data, hormonal treatment, outcome, and survival. DAP-kinase protein expression was also studied in normal breast cells primary cultures under estrogen and antiestrogen treatment.
Results: Among the 128 patients, 30 showed a DAP-kinase staining ≤ 20%, whereas 98 had a staining over 20%. Mean follow-up time was 62 months. The association between tumor Scarff-Bloom and Richardson grade (P = 0.009), estrogen receptor and progesterone receptor expression (P = 0.002 and 0.001, respectively), tumor size (P = 0.05), Bcl-2 expression (P = 0.004), and DAP-kinase immunostaining in the ductal carcinoma group was highly significant. Overall (64 months) and disease-free (63 months) survival in the high DAP-kinase expression group were significantly longer compared with the women whose tumors showed a loss of DAP-kinase expression (51 and 43 months, respectively). DAP-kinase protein was strongly expressed in normal breast tissue and in human breast epithelial cells primary cultures. Estradiol decreased DAP-kinase expression in these cells, arguing for hormonal regulation of the protein.
Conclusions: Loss of DAP-kinase expression negatively correlates to survival and positively correlates to the probability of recurrence in a very significant manner. DAP-kinase thus constitutes a novel and independent prognosis marker for breast cancer.
Characterization of Effusion-Infiltrating T Cells
Authors: Atanackovic Djordje , Block Andreas , de Weerth Andreas , Faltz Christiane , Hossfeld Dieter Kurt , Hegewisch-Becker Susanna 
Published: September 2005

Abstract
Purpose: While naïve T cells circulate between peripheral blood and lymph nodes, memory effector T cells acquire certain surface molecules that enable them to travel to peripheral tissues and exert their effector function. We analyzed whether deficient numbers of effector-type T cells within the malignant effusion might contribute to tumor escape from immunosurveillance.
Experimental Design: We analyzed the expression of a broad range of adhesion molecules and chemokine receptors (CD62L, CD56, CCR4, CCR5, CCR7, CXCR3, CLA, and integrin α4β7) on tumor-associated lymphocytes in effusions and peripheral blood lymphocytes of patients with malignant ascites (n = 11) or malignant pleural effusion (n = 16). A tumor-associated lymphocyte:peripheral blood lymphocyte ratio was calculated as an indicator for homing of lymphocytes into the effusions and was compared with patients with nonmalignant ascites (n = 17).
Results: Patients with malignancies show an increased enrichment of T cells expressing the phenotype of “naïve” (CD62L+ and CD45RA+CCR7+), “central memory” (CD45RA-CCR7+), and type 2-polarized (CCR4+) T cells within their effusions. In contrast, enrichment of “effector”-type (CD45RA-CCR7− or CD45RA+CCR7−) and presumably type 1-polarized T cells (CCR5+) at the tumor site is deficient. The same is true for natural killer cells and potentially cytotoxic CD56+ T cells.
Conclusions: Here we show for the first time that patients with malignant effusions show a deficient enrichment of T cells expressing the phenotype of type-1-polarized effector T cells at the tumor site. This mechanism is likely to contribute to the escape of tumor cells from immunosurveillance.
Persistent Activation of the Akt Pathway in Head and Neck Squamous Cell Carcinoma
Authors: Amornphimoltham Panomwat , Sriuranpong Virote , Patel Vyomesh , Benavides Fernando , Conti Claudio J. , Sauk John , Sausville Edward A. , Molinolo Alfredo A. , Gutkind J. Silvio 
Published: September 2005

Abstract
Squamous carcinomas of the head and neck (HNSCC) represent the sixth most common cancer among men worldwide and a major cause of morbidity and mortality due to its relatively poor prognosis. As part of ongoing studies addressing the molecular events underlying tumor progression in HNSCC, we have explored the nature of the proliferative pathways in which dysregulation may promote aberrant cell growth in this tumor type. The serine/threonine protein kinase Akt is a downstream target of phosphatidylinositol 3-kinase and a key regulator of normal and cancerous growth and cell fate decisions. Therefore, in this study, we have examined the status of activation of Akt in different stages of squamous cell carcinoma development in mice and in clinical samples from HNSCC patients. By immunohistochemical analysis, using a recently developed phosphorylation state-specific antibody, we demonstrated that Akt activation correlates closely with the progression of mouse skin squamous cell carcinoma. We also observed that activation of Akt is a frequent event in human HNSCC because active Akt can be detected in these tumors with a pattern of expression and localization correlating with the progression of the lesions. In line with these observations, Akt was constitutively activated in a large fraction of HNSCC-derived cell lines. We also provide evidence that the Akt signaling pathway may represent a biologically relevant target for a novel antineoplastic agent, UCN-01, which recently has been shown to be active in cellular and xenograft models for HNSCC at concentrations safely achievable in clinically relevant situations.
Comparative Study between DNA Copy Number Aberrations Determined by Quantitative Microsatellite Analysis and Clinical Outcome in Patients with Stomach Cancer
Authors: Suzuki Seiji , Egami Kaku , Sasajima Koji , Ghazizadeh Mohammad , Shimizu Hajime , Watanabe Hidehiro , Hasegawa Hirokazu , Iida Shinya , Matsuda Takeshi , Okihama Yuji , Hosone Masaru , Shimizu Kazuo , Kawanami Oichi , Tajiri Takashi 
Published: September 2005

Abstract
Purpose: We detected the relative DNA copy numbers (RCNs) at target loci in patients with stomach cancer with quantitative microsatellite analysis. We additionally clarified the relationship between DNA copy number aberrations and the clinical outcome of the patients.
Experimental Design: Fresh frozen samples were obtained from 30 patients who had undergone surgery for stomach cancer. Seven microsatellite loci in chromosomes 8q, 16q, and 20q and one gene-specific locus (ZNF217) were selected as the target loci. The DNA copy number was obtained relatively to a pooled reference consisting of six microsatellite primer sets selected from the regions where few aberrations have been reported in comparative genomic hybridization analysis. On the basis of the TaqMan PCR system, the internal probes used were carrying donor (6-carboxyfluorescein) and acceptor (6-carboxytetramethylrhodamine) fluorescent molecules complementary to CA repeats in the microsatellite markers and to one gene-specific oligomer in the gene-specific marker.
Results: Chromosome 8q gain, 20q gain, and 16q loss were detected in 18 (60.0%), 8 (26.7%), and 13 (43.3%) cases, respectively. Gains in the RCNs of D8S1801 and D8S1724 were most frequently found (36.7%). There was a significant correlation between the loss of D16S3026 and reduced survival duration (P = 0.0158), and the simultaneous aberrations of D8S1801 gain and D16S3026 loss (double marker positive) was significantly associated with reduced survival duration (P = 0.0008). According to Cox proportional hazards model, the double marker positive was a significant and independent factor indicating an unfavorable prognostic factor (relative risk, 17.176; 95% confidence interval, 2.782–106.026; P = 0.0022).
Conclusion: RCN aberrations in tumor tissues determined by quantitative microsatellite analysis enable identification of the prognostic factors that correlate with clinical outcome of the patients with stomach cancer.
Selective Modulation of the Therapeutic Efficacy of Anticancer Drugs by Selenium Containing Compounds against Human Tumor Xenografts
Authors: Cao Shousong , Durrani Farukh A. , Rustum Youcef M. 
Published: September 2005

Abstract
Purpose: Studies were carried out in athymic nude mice bearing human squamous cell carcinoma of the head and neck (FaDu and A253) and colon carcinoma (HCT-8 and HT-29) xenografts to evaluate the potential role of selenium-containing compounds as selective modulators of the toxicity and antitumor activity of selected anticancer drugs with particular emphasis on irinotecan, a topoisomerase I poison.
Experimental Design: Antitumor activity and toxicity were evaluated using nontoxic doses (0.2 mg/mouse/day) and schedule (14–28 days) of the selenium-containing compounds, 5-methylselenocysteine and seleno-l-methionine, administered orally to nude mice daily for 7 days before i.v. administration of anticancer drugs, with continued selenium treatment for 7–21 days, depending on anticancer drugs under evaluation. Several doses of anticancer drugs were used, including the maximum tolerated dose (MTD) and toxic doses. Although many chemotherapeutic agents were evaluated for toxicity protection by selenium, data on antitumor activity were primarily obtained using the MTD, 2 × MTD, and 3 × MTD of weekly ×4 schedule of irinotecan.
Results: Selenium was highly protective against toxicity induced by a variety of chemotherapeutic agents. Furthermore, selenium increased significantly the cure rate of xenografts bearing human tumors that are sensitive (HCT-8 and FaDu) and resistant (HT-29 and A253) to irinotecan. The high cure rate (100%) was achieved in nude mice bearing HCT-8 and FaDu xenografts treated with the MTD of irinotecan (100 mg/kg/week × 4) when combined with selenium. Administration of higher doses of irinotecan (200 and 300 mg/kg/week × 4) was required to achieve high cure rate for HT-29 and A253 xenografts. Administration of these higher doses was possible due to selective protection of normal tissues by selenium. Thus, the use of selenium as selective modulator of the therapeutic efficacy of anticancer drugs is new and novel.
Conclusions: We demonstrated that selenium is a highly effective modulator of the therapeutic efficacy and selectivity of anticancer drugs in nude mice bearing human tumor xenografts of colon carcinoma and squamous cell carcinoma of the head and neck. The observed in vivo synergic interaction is highly dependent on the schedule of selenium.
Zoledronic Acid Inhibits Visceral Metastases in the 4T1/luc Mouse Breast Cancer Model
Authors: Hiraga Toru , Williams Paul J. , Ueda Akimi , Tamura Daisuke , Yoneda Toshiyuki 
Published: September 2005

Abstract
Purpose: It is established that bisphosphonates (BPs), specific inhibitors of osteoclasts, have beneficial effects on bone metastases of breast cancer. In addition, recent studies have reported that BPs have anticancer effects and suppress visceral metastases, too. However, the results of clinical studies are still conflicting. In the present study, we examined the effects of the BP zoledronic acid (ZOL), one of the most potent BPs currently available, on visceral metastases of breast cancer using an animal model in which mouse breast cancer cells 4T1/luc implanted at the orthotopic mammary fat pad spontaneously metastasize to multiple organs including bone, lung, and liver in female BALB/c mice.
Experimental Design and Results: The 4T1/luc-bearing mice received single or four i.v. injections of ZOL (0.5 or 5 μg/mouse) during the whole experimental period. Bone metastases were reduced by the ZOL treatment. More importantly, ZOL significantly suppressed lung and liver metastases. Furthermore, ZOL prolonged overall survival of the tumor-bearing mice. Of interest, apoptosis in 4T1/luc cells colonized in bone was increased by ZOL; however, those in lung were not changed. In vitro studies demonstrated that ZOL inhibited cell migration and invasion and promoted apoptosis of 4T1/luc cells.
Conclusions: These results are consistent with the notion that ZOL affects breast cancer metastasis to visceral organs as well as bone. These effects of ZOL may be attributable to inhibition of migration and invasion of breast cancer cells. Clinical relevance of our experimental results needs to be determined in breast cancer patients with visceral metastases.
Gene Expression Profiling of Early- and Late-Relapse Nonseminomatous Germ Cell Tumor and Primitive Neuroectodermal Tumor of the Testis
Authors: Sugimura Jun , Foster Richard S. , Cummings Oscar W. , Kort Eric J. , Takahashi Masayuki , Lavery Todd T. , Furge Kyle A. , Einhorn Lawrence H. , Teh Bin Tean 
Published: September 2005

Abstract
Purpose: To better understand the molecular mechanisms that underlay the development and progression of nonseminomatous germ cell tumor of testis (NSGCTT) as well as malignant transformation of teratoma and primitive neuroectodermal tumor (PNET).
Experimental Design: We studied the gene expression profiles of 17 retroperitoneal NSGCTTs (10 yolk sac tumors, 3 embryonal carcinomas, 4 teratomas) and 2 PNETs obtained from patients with two clinical outcomes. Tissue samples were obtained from the Indiana University. One group of NSGCTT and PNET patients developed metastases within 2 years (early-relapse) of initial successful treatment, and the other group developed metastases after 2 years (late-relapse). Gene expression in these groups of patients was quantified using cDNA microarrays and real-time relative quantitative PCR.
Results: We demonstrate that the gene expression profiles of these tumors correlate with histological type. In addition, we identify type-specific genes that may serve as novel diagnostic markers. We also identify a gene set that can distinguish between early-relapse and late-relapse yolk sac tumors. The expression differences of these genes may underlie the differences in clinical outcome and drug response of these tumors.
Conclusion: This is the first study that used gene expression profiling to examine the molecular characteristics of the NSGCTTs and drug response in early- and late-relapse tumors. These results suggest that two molecularly distinct forms of NSGCTTs exist and that the integration of expression profile data with clinical parameters could enhance the diagnosis and prognosis of NSGCTTs. More importantly, the identified genes provide insight into the molecular mechanisms of aggressive NSGCTTs and suggest intervention strategies.
First 18F-Labeled Tracer Suitable for Routine Clinical Imaging of sst Receptor-Expressing Tumors Using Positron Emission Tomography
Authors: Schottelius Margret , Poethko Thorsten , Herz Michael , Reubi Jean-Claude , Kessler Horst , Schwaiger Markus , Wester Hans-Jürgen 
Published: September 2005

Abstract
Purpose: Despite excellent radionuclide characteristics, no 18F-labeled peptides are available for quantitative peptide receptor mapping using positron emission tomography (PET) so far, mainly due to time-consuming multistep radiosyntheses with limited overall yields. A newly developed two-step chemoselective conjugation method allows rapid and high-yield [18F]fluorination of peptides via oxime formation and was applied for the synthesis of new 18F-labeled carbohydrated Tyr3-octreotate (TOCA) analogs with optimized pharmacokinetics suitable for clinical routine somatostatin-receptor (sst) imaging.
Experimental Design: 18F-labeled glucose (Gluc-S-) and cellobiose (Cel-S-) derivatives of aminooxy-functionalized TOCA were synthesized via oxime formation with 4-[18F]fluorobenzaldehyde ([18F]FBOA-peptides). Both the in vitro internalization profile of Gluc-S-Dpr([18F]FBOA)TOCA and Cel-S-Dpr([18F]FBOA)TOCA in hsst2-expressing Chinese hamster ovary cells (dual tracer protocol) and their biodistribution in AR42J tumor-bearing mice were investigated and compared with two [18F]fluoropropionylated ([18F]FP) analogs, Gluc-Lys([18F]FP)TOCA and Gluc-S-Dpr([18F]FP)TOCA.
Results: In contrast to [18F]FP-labeling (3 h), chemo-selective [18F]FBOA-formation (50 min) afforded the respective radiopeptides in high yields (65–85%). In vitro, Gluc-S-Dpr([18F]FBOA)TOCA and Cel-S-Dpr([18F]FBOA)-TOCA showed high internalization (139 ± 2 and 163 ± 8 of the reference [125I]Tyr3-octreotide, respectively), which was reflected by high tumor accumulation in vivo [21.8 ± 1.4 and 24.0 ± 2.5% of injected dose/g (1 h), respectively]. How-ever, only Cel-S-Dpr([18F]FBOA)TOCA and Gluc-S-Dpr([18F]FP)TOCA (tumor: 15.1 ± 1.5% of injected dose/g) with its very low accumulation in all of the nontarget organs showed improved tumor:organ ratios compared with Gluc-Lys([18F]FP)TOCA. For Cel-S-Dpr([18F]FBOA)TOCA,tumor:organ ratios (1 h) were 42:1, 27:1, 15:1, 3:1, and 208:1 for blood, liver, intestine, kidney, and muscle, respectively.
Conclusion: Due to the fast and high-yield chemoselective radiofluorination strategy and to its excellent pharmacokinetics, Cel-S-Dpr([18F]FBOA)TOCA represents the first tracer suitable for routine clinical application in PET somatostatin receptor imaging.
Characterization of p53 Wild-Type and Null Isogenic Colorectal Cancer Cell Lines Resistant to 5-Fluorouracil, Oxaliplatin, and Irinotecan
Authors: Boyer John , McLean Estelle G. , Aroori Somaiah , Wilson Peter , McCulla Andrea , Carey P. Declan , Longley Daniel B. , Johnston Patrick G. 
Published: September 2005

Abstract
To elucidate mechanisms of resistance to chemotherapies currently used in the first-line treatment of advanced colorectal cancer, we have developed a panel of HCT116 p53 wild-type (p53+/+) and null (p53−/−) isogenic colorectal cancer cell lines resistant to the antimetabolite 5-fluorouracil (5-FU), topoisomerase I inhibitor irinotecan (CPT-11), and DNA-damaging agent oxaliplatin. These cell lines were generated by repeated exposure to stepwise increasing concentrations of each drug over a period of several months. We have demonstrated a significant decrease in sensitivity to 5-FU, CPT-11, and oxaliplatin in each respective resistant cell line relative to the parental line as determined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide analysis, with increases in IC50 (72 h) concentrations ranging from 3- to 65-fold. Using flow cytometry, we have also demonstrated compromised apoptosis and cell cycle arrest in 5-FU-, oxaliplatin-, and CPT-11-resistant cell lines compared with the parental lines after exposure to each drug. In addition, we found that resistance to 5-FU and oxaliplatin was higher in parental p53−/− cells compared with parental p53+/+ cells, with an ∼5-fold increase in IC50 (72 h) for each drug. In contrast, the IC50 (72 h) doses for CPT-11 were identical in the p53 wild-type and null cell lines. Furthermore, apoptosis after treatment with 5-FU and oxaliplatin, but not CPT-11, was significantly reduced in parental p53−/− cells compared with parental p53+/+ cells. These data suggest that p53 may be an important determinant of sensitivity to 5-FU and oxaliplatin but not CPT-11. Using semiquantitative reverse transcription-PCR, we have demonstrated down-regulation of thymidine phosphorylase mRNA in both p53+/+ and p53−/− 5-FU-resistant cells, suggesting that decreased production of 5-FU active metabolites may be an important resistance mechanism in these lines. In oxaliplatin-resistant cells, we noted increased mRNA levels of the nucleotide excision repair gene ERCC1 and ATP-binding cassette transporter breast cancer resistance protein. In CPT-11-resistant cells, we found reduced mRNA levels of carboxylesterase, the enzyme responsible for converting CPT-11 to its active metabolite SN-38, and topoisomerase I, the SN-38 target enzyme. In addition, we noted overexpression of breast cancer resistance protein in the CPT-11-resistant lines. These cell lines are ideal tools with which to identify novel determinants of drug resistance in both the presence and absence of wild-type p53.