bluuebunny/crossref_metadata_2025_split huggingface dataset:
Tissue-Engineered Bone Serves as a Target for Metastasis of Human Breast Cancer in a Mouse Model
Authors: Moreau Jodie E. , Anderson Kristen , Mauney Joshua R. , Nguyen Trang , Kaplan David L. , Rosenblatt Michael 
Published: November 2007

Abstract
The high frequency and mortality associated with breast cancer metastasis to bone has motivated efforts to elucidate tumor-stroma interactions in the bone microenvironment contributing to invasion and proliferation of metastatic cells. The development of engineered tissues has prompted the integration of engineered bone scaffolds into animal models as potential targets for metastatic spread. Silk scaffolds were coupled with bone morphogenetic protein-2 (BMP-2), seeded with bone marrow stromal cells (BMSC), and maintained in culture for 7 weeks, 4 weeks, and 1 day before s.c. implant in a mouse model of human breast cancer metastasis from the orthotopic site. Following injection of SUM1315 cells into mouse mammary fat pads, tumor burden of implanted tissues was observed only in 1-day scaffolds. Scaffold development and implantation was then reinitiated to identify the elements of the engineered bone that contribute to metastatic spread. Untreated scaffolds were compared with BMP-2–coupled, BMSC-seeded, or BMP-2/BMSC–combined treatment. Migration of SUM1315 cells was detected in four of four mice bearing scaffolds with BMP-2 treatment and with BMSC treatment, respectively, whereas only one of six mice of the BMP-2/BMSC combination showed evidence of metastatic spread. Histology confirmed active matrix modeling and stromal cell/fibroblast infiltration in scaffolds positive for the presence of metastasis. These results show the first successful integration of engineered tissues in a model system of human breast cancer metastasis. This novel platform now can be used in continued investigation of the bone environment and stem cell contributions to the process of breast cancer metastasis. [Cancer Res 2007;67(21):10304–8]
Night Shift Work and the Risk of Endometrial Cancer
Authors: Viswanathan Akila N. , Hankinson Susan E. , Schernhammer Eva S. 
Published: November 2007

Abstract
Melatonin has several oncostatic properties, including possible anti-estrogenic and anti-aromatase activity, and seems to be linked with fat metabolism. Night workers have lower levels of melatonin, which may predispose them to develop cancer. Endometrial cancer risk is influenced significantly by hormonal and metabolic factors; therefore, we hypothesize that night workers may have an increased risk of endometrial cancer. Of the 121,701 women enrolled in a prospective cohort study, 53,487 women provided data on rotating night shift work in 1988 and were followed through on June 1, 2004. A total of 515 women developed medical record–confirmed invasive endometrial cancer. We used Cox regression models to calculate multivariate relative risks (MVRRs), controlling for endometrial cancer risk factors. Women who worked 20+ years of rotating night shifts had a significantly increased risk of endometrial cancer [MVRR, 1.47; 95% confidence interval (95% CI), 1.03–1.14]. In stratified analyses, obese women working rotating night shifts doubled their baseline risk of endometrial cancer (MVRR, 2.09; 95% CI, 1.24–3.52) compared with obese women who did no night work, whereas a nonsignificant increase was seen among non-obese women (MVRR, 1.07; 95% CI, 0.60–1.92). Women working rotating night shifts for a long duration have a significantly increased risk of endometrial cancer, particularly if they are obese. We speculate that this increased risk is attributable to the effects of melatonin on hormonal and metabolic factors. Our results add to growing literature that suggests women who work at night may benefit from cancer prevention strategies. [Cancer Res 2007;67(21):10618–22]
Inhibition of Nuclear Factor-κB DNA Binding by Organoselenocyanates through Covalent Modification of the p50 Subunit
Authors: Chen Kun-Ming , Spratt Thomas E. , Stanley Bruce A. , De Cotiis Dan A. , Bewley Maria C. , Flanagan John M. , Desai Dhimant , Das Arunangshu , Fiala Emerich S. , Amin Shantu , El-Bayoumy Karam 
Published: November 2007

Abstract
Most known chemopreventive agents including certain selenium compounds suppress the activation of the nuclear factor κB (NF-κB), but the mechanisms remain largely elusive. Toward this end, we initially showed that the inhibition of NF-κB DNA binding by benzyl selenocyanate (BSC) and 1,4-phenylenebis(methylene)selenocyanate (p-XSC) was reversed by the addition of DTT; this suggests the formation of DTT-reducible selenium-sulfur bonds between selenocyanate moieties and cysteine residues in NF-κB (p50) protein. Furthermore, the inhibitory effect of selenocyanates on NF-κB was not altered in the presence of physiologic level of reduced glutathione (1 mmol/L), suggesting that selenocyanates can also inhibit NF-κB in vivo. Using both matrix-assisted laser desorption/ionization-time of flight and tandem mass spectrometry fragmentation, we showed for the first time that the Cys62 residue in the active site of NF-κB (p50) protein was modified by BSC through the formation of a selenium-sulfur bond. In addition, p-XSC–bound NF-κB (p50) protein was also detected by a radiotracer method. To provide further support, molecular models of both BSC and p-XSC positioned in the DNA binding pocket of the p50 were constructed through the covalent modification of Cys62; the models reveal that DNA substrate could be hindered to enter its DNA binding region. This study shows for the first time that BSC and p-XSC may exert their chemopreventive activity, at least in part, by inhibiting NF-κB through covalent modification of Cys62 of the p50 subunit of NF-κB. [Cancer Res 2007;67(21):10475–83]
Hypermethylation of let-7a-3 in Epithelial Ovarian Cancer Is Associated with Low Insulin-like Growth Factor-II Expression and Favorable Prognosis
Authors: Lu Lingeng , Katsaros Dionyssios , Rigault de la Longrais Irene A. , Sochirca Olga , Yu Herbert 
Published: November 2007

Abstract
MicroRNAs (miRNA) are endogenous noncoding small RNAs that regulate the activity of mRNAs. Many miRNA genes, including let-7a-3, are located in CpG islands, suggesting possible epigenetic regulation of their expression. Promoter CpG island methylation of tumor suppressor genes is involved in cancer development and progression. Using real-time methylation-specific PCR and real-time reverse transcription-PCR, we analyzed DNA methylation in the let-7a-3 gene and miRNA expression of let-7a in 214 patients with epithelial ovarian cancer to assess the effect of let-7a-3 methylation on the expressions of let-7a as well as a possible target of let-7 regulation, insulin-like growth factor-II (IGF-II). The association of let-7a-3 methylation with patient survival outcomes was also evaluated. let-7a-3 methylation was detected in epithelial ovarian cancer, and the expression of let-7a was slightly affected by the methylation, but the effect was not substantial. The methylation of let-7a-3, however, was inversely correlated with IGF-II expression and positively with insulin-like growth factor binding protein-3 (IGFBP-3) expression. Patients with methylated let-7a-3 seemed to have reduced risk for death compared with those without, and the association was independent of patient age at surgery, tumor grade, disease stage, and IGF-II or IGFBP-3 expression. No association was found for let-7a-3 methylation and disease progression. These results suggest that the let-7a-3 gene is methylated and the methylation may affect IGF-II expression and the survival of ovarian cancer patients. Further investigation of the role of miRNAs and their regulation in cancer is warranted. [Cancer Res 2007;67(21):10117–22]
Degradation of Lung Adenoma Susceptibility 1, a Major Candidate Mouse Lung Tumor Modifier, Is Required for Cell Cycle Progression
Authors: Liu Yan , Vikis Haris G. , Yi Yijun , Futamura Manabu , Wang Yian , You Ming 
Published: November 2007

Abstract
We have previously identified murine lung adenoma susceptibility 1 (Las1) as the pulmonary adenoma susceptibility 1 candidate gene. Las1 has two natural alleles, Las1-A/J and Las1-B6. Las1 encodes an 85-kDa protein with uncharacterized biological function. In the present study, we report that Las1 is an unstable protein and the rapid destruction of Las1 depends on the ubiquitin-proteasome pathway. Las1 is a new microtubule-binding protein and Las1 associated with tubulin is not ubiquitinated. We further show that Las1-A/J is a more stable protein than Las1-B6. Las1 is expressed in the G2 phase of the cell cycle and that ubiquitin-proteasome–mediated Las1 destruction occurs in mitosis. Overexpression of Las1-A/J inhibits normal E10 cell proliferation and induces a defective cytokinesis. The differential degradation of Las1-A/J and Las-B6 has important implications for its intracellular function and may eventually explain Las1-A/J in lung tumorigenesis. [Cancer Res 2007;67(21):10207–13]
Aromatase Expression Predicts Survival in Women with Early-Stage Non–Small Cell Lung Cancer
Authors: Mah Vei , Seligson David B. , Li Ai , Márquez Diana C. , Wistuba Ignacio I. , Elshimali Yahya , Fishbein Michael C. , Chia David , Pietras Richard J. , Goodglick Lee 
Published: November 2007

Abstract
Estrogen signaling is critical in the progression of tumors that bear estrogen receptors. In most patients with breast cancer, inhibitors that block interactions of estrogen with its receptors or suppress the production of endogenous estrogens are important interventions in the clinic. Recent evidence now suggests that estrogen also contributes to the pathogenesis of non–small cell lung cancer (NSCLC). We used a human lung cancer xenograph model system to analyze the effect of aromatase or estradiol on tumor growth. We further examined the level of protein expression of aromatase in 422 patients with NSCLC using a high-density tissue microarray. Results were confirmed and validated on an independent patient cohort (n = 337). Lower levels of aromatase predicted a greater chance of survival in women 65 years and older. Within this population, the prognostic value of aromatase was greatest in earlier stage lung cancer (stage I/II). In addition, for women with no history of smoking, lower aromatase levels were a strong predictor of survival. Our findings implicate aromatase as an early-stage predictor of survival in some women with NSCLC. We predict that women whose lung cancers have higher levels of aromatase might be good candidates for targeted treatment with aromatase inhibitors. [Cancer Res 2007;67(21):10484–90]
Hepatocyte Growth Factor–Mediated Cell Invasion in Pancreatic Cancer Cells Is Dependent on Neuropilin-1
Authors: Matsushita Arikira , Götze Tobias , Korc Murray 
Published: November 2007

Abstract
Neuropilin-1 (Np-1), a receptor for semaphorin 3A and vascular endothelial growth factor, is expressed at high levels in pancreatic ductal adenocarcinoma (PDAC). To assess the potential role of Np-1 in PDAC, COLO-357 pancreatic cancer cells, which express relatively low levels of Np-1, were stably transfected with the Np-1 cDNA. Np-1 overexpression was associated with enhanced cell invasiveness in response to hepatocyte growth factor (HGF), and this effect was abolished by small interfering RNA–mediated down-regulation of c-Met. Conversely, in PANC-1 pancreatic cancer cells, which express relatively high levels of Np-1, suppression of endogenous Np-1 completely abolished HGF-mediated cell invasion. To determine which pathways are involved in Np-1–mediated facilitation of c-Met–dependent cell invasiveness, the effects of HGF on signaling were examined next in sham-transfected and Np-1–overexpressing COLO-357 cells. HGF actions on c-Met tyrosine phosphorylation and p38 mitogen-activated protein kinase (MAPK) activation were increased in Np-1–overexpressing COLO-357 cells by comparison with HGF effects in sham-transfected cells. SB203580, an inhibitor of p38 MAPK, suppressed HGF-induced invasion in Np-1–overexpressing cells, whereas U0126, a MAP/extracellular signal-regulated kinase kinase inhibitor, was without effect. PP2, a Src inhibitor, and LY294002, a phosphatidylinositol 3-kinase inhibitor, also suppressed HGF-induced invasion in these cells. Immunoprecipitation studies revealed that Np-1 associated with c-Met, but not with epidermal growth factor receptor, family members. Confocal microscopy indicated that this association occurred on the plasma membrane and that HGF promoted the internalization of Np-1–c-Met complex, leading to its perinuclear localization. These findings indicate that Np-1 is required for efficient activation of c-Met–dependent pathways that promote cell invasiveness. [Cancer Res 2007;67(21):10309–16]
Identification and Validation of a Novel Gene Signature Associated with the Recurrence of Human Hepatocellular Carcinoma
Authors: Wang Suk Mei , Ooi London Lucien P.J. , Hui Kam M. 
Published: November 2007

Abstract
Purpose: To improve the clinical management of human hepatocellular carcinoma (HCC) by accurate identification, at diagnosis, of patients at risk of recurrence after primary treatment for HCC.
Experimental Design: Two clinicopathologic variables available at diagnosis, vascular invasion and cirrhosis, together with molecular profiling using Affymetrix human HG-U133A and HG-U133B oligonucleotide probe arrays, were used to identify recurrent HCC disease.
Results: HCC patients presented clinically at diagnosis with vascular invasion and cirrhosis showed a high rate (78-83%) of developing recurrent disease within 6 to 35 months. In comparison, most of the HCC patients (80-100%) without vascular invasion and cirrhosis remained disease-free. However, the risk of recurrent disease for HCC patients with either vascular invasion or cirrhosis could not be accurately ascertained. Using a pool of 23 HCC patients with either vascular invasion or cirrhosis as training set, a 57-gene signature was derived and could predict recurrent disease at diagnosis, with 84% (sensitivity 86%, specificity 82%) accuracy, for a totally independent test set of 25 HCC patients with either vascular invasion or cirrhosis. On further analysis, the disease-free rate was significantly different between patients that were predicted to recur or not to recur in the test group (P = 0.002).
Conclusion: We have presented data to show that by incorporating the status of vascular invasion and cirrhosis available at diagnosis for patients with HCC after partial curative hepatectomy and a novel 57-member gene signature, we could accurately stratify HCC patients with different risks of recurrence.
Pathologic Complete Response to Trastuzumab-Based Neoadjuvant Therapy Is Related to the Level of HER-2 Amplification
Authors: Arnould Laurent , Arveux Patrick , Couturier Jerome , Gelly-Marty Marion , Loustalot Catherine , Ettore Francette , Sagan Christine , Antoine Martine , Penault-Llorca Frederique , Vasseur Berangere , Fumoleau Pierre , Coudert Bruno P. 
Published: November 2007

AbstractPurpose: Fluorescence in situ hybridization (FISH) and immunohistochemistry (IHC) are used to determine human epidermal growth factor receptor-2 (HER-2) status and patient eligibility for trastuzumab therapy. Using FISH and IHC, we analyzed the relationship between pathologic complete response to trastuzumab-based neoadjuvant therapy and level of HER-2 amplification in locally advanced breast cancer.Experimental Design: Breast biopsies from 93 HER-2–positive patients treated with trastuzumab-based neoadjuvant therapy were centrally collected and analyzed retrospectively for HER-2 amplification using FISH and HER-2 overexpression using IHC. Tumors were classified by FISH as no, low, or high amplification. Biopsies were reassessed centrally by IHC and graded 0, 1+, 2+, or 3+.Results: HER-2 status of tumor samples as assessed by FISH and IHC correlated: 16 no amplification (11 IHC 1+ and 5 IHC 2+), 27 low amplification (26 IHC 3+ and 1 IHC 2+), and 50 high amplification (all IHC 3+). Trastuzumab-based neoadjuvant therapy achieved pathologic complete response in 35 of 93 (37.6%) tumors. Pathologic complete response rate in low- and high-amplification tumors was significantly higher than in no-amplification tumors (44% versus 6%; P &lt; 0.004). Pathologic complete response rate in high-amplification tumors was significantly higher compared with low-amplification tumors (56% versus 22%; P &lt; 0.005). In the subgroup of low- plus high-amplification tumors, no correlation was found between pathologic complete response rate and IHC score, treatment regimen, T or N stage, tumor grade, or hormonal receptors.Conclusions: This is the first study to show positive correlation between level of HER-2 amplification assessed by FISH and rate of pathologic complete response to trastuzumab-based neoadjuvant treatment.
Population Pharmacokinetics and Pharmacodynamics of Paclitaxel and Carboplatin in Ovarian Cancer Patients: A Study by the European Organization for Research and Treatment of Cancer-Pharmacology and Molecular Mechanisms Group and New Drug Development Group
Authors: Joerger Markus , Huitema Alwin D.R. , Richel Dick J. , Dittrich Christian , Pavlidis Nikolas , Briasoulis Evangelos , Vermorken Jan B. , Strocchi Elena , Martoni Andrea , Sorio Roberto , Sleeboom Henk P. , Izquierdo Miguel A. , Jodrell Duncan I. , Calvert Hilary , Boddy Alan V. , Hollema Harry , Féty Regine , Van der Vijgh Wjf J.F. , Hempel Georg , Chatelut Etienne , Karlsson Mats , Wilkins Justin , Tranchand Brigitte , Schrijvers Ad H.G.J. , Twelves Christian , Beijnen Jos H. , Schellens Jan H.M. 
Published: November 2007

AbstractPurpose: Paclitaxel and carboplatin are frequently used in advanced ovarian cancer following cytoreductive surgery. Threshold models have been used to predict paclitaxel pharmacokinetic-pharmacodynamics, whereas the time above paclitaxel plasma concentration of 0.05 to 0.2 μmol/L (tC &gt; 0.05−0.2) predicts neutropenia. The objective of this study was to build a population pharmacokinetic-pharmacodynamic model of paclitaxel/carboplatin in ovarian cancer patients.Experimental Design: One hundred thirty-nine ovarian cancer patients received paclitaxel (175 mg/m2) over 3 h followed by carboplatin area under the concentration-time curve 5 mg/mL*min over 30 min. Plasma concentration-time data were measured, and data were processed using nonlinear mixed-effect modeling. Semiphysiologic models with linear or sigmoidal maximum response and threshold models were adapted to the data.Results: One hundred five patients had complete pharmacokinetic and toxicity data. In 34 patients with measurable disease, objective response rate was 76%. Neutrophil and thrombocyte counts were adequately described by an inhibitory linear response model. Paclitaxel tC &gt; 0.05 was significantly higher in patients with a complete (91.8 h) or partial (76.3 h) response compared with patients with progressive disease (31.5 h; P = 0.02 and 0.05, respectively). Patients with paclitaxel tC &gt; 0.05 &gt; 61.4 h (mean value) had a longer time to disease progression compared with patients with paclitaxel tC &gt; 0.05 &lt; 61.4 h (89.0 versus 61.9 weeks; P = 0.05). Paclitaxel tC &gt; 0.05 was a good predictor for severe neutropenia (P = 0.01), whereas carboplatin exposure (Cmax and area under the concentration-time curve) was the best predictor for thrombocytopenia (P &lt; 10−4).Conclusions: In this group of patients, paclitaxel tC &gt; 0.05 is a good predictive marker for severe neutropenia and clinical outcome, whereas carboplatin exposure is a good predictive marker for thrombocytopenia.
The Prognostic Biomarkers HOXB13, IL17BR, and CHDH Are Regulated by Estrogen in Breast Cancer
Authors: Wang Zuncai , Dahiya Sonika , Provencher Heather , Muir Beth , Carney Erin , Coser Kathryn , Shioda Toshi , Ma Xiao-Jun , Sgroi Dennis C. 
Published: November 2007

Abstract
Purpose: We previously identified three genes, HOXB13, IL17BR, and CHDH, that strongly predict clinical outcome in estrogen receptor (ER)–positive breast cancer patients receiving tamoxifen monotherapy. The biological mechanisms linking these genes to estrogen signaling and tamoxifen response in breast cancer remain to be determined.
Experimental Design: In a consecutive series of 148 ER-positive and ER-negative breast cancers, HOXB13, IL17BR, and CHDH gene expression was measured by quantitative real-time PCR and correlated with ER, PR, and HER2 expression. The role of estrogen and ER in the regulation of these three genes was assessed in several ER-positive and ER-negative breast cancer cell lines.
Results: In primary breast tumors, HOXB13 expression correlated negatively, and IL17BR and CHDH expression correlated positively, with ER status, and all three genes exhibited an ER-dependent correlation pattern with HER2 status that differs from PR and PS2, two canonical estrogen-regulated genes. Results using breast cancer cell lines show that these genes are regulated by estradiol in an ER-dependent manner, and that this regulation is abrogated by tamoxifen.
Conclusions: HOXB13, IL17BR, and CHDH are estrogen-regulated genes, but their pattern of correlation with known positive (ER, PR) and negative (HER2) predictors of tamoxifen response differs from canonical ER signature genes. These results provide a biological rationale for the prognostic utility of these three genes in early-stage ER-positive breast cancer and for their potential to predict anti-estrogen resistance.
Immunologic and Clinical Outcomes of a Randomized Phase II Trial of Two Multipeptide Vaccines for Melanoma in the Adjuvant Setting
Authors: Slingluff Craig L. , Petroni Gina R. , Chianese-Bullock Kimberly A. , Smolkin Mark E. , Hibbitts Sarah , Murphy Cheryl , Johansen Naomi , Grosh William W. , Yamshchikov Galina V. , Neese Patrice Y. , Patterson James W. , Fink Robyn , Rehm Patrice K. 
Published: November 2007

AbstractPurpose: Human melanoma cells express shared antigens recognized by CD8+ T lymphocytes, the most common of which are melanocytic differentiation proteins and cancer-testis antigens. However, peptide vaccines for melanoma usually target only one or two MHC class I–associated peptide antigens. Because melanomas commonly evade immune recognition by selective antigen loss, optimization of melanoma vaccines may require development of more complex multipeptide vaccines.Experimental Design: In a prospective randomized clinical trial, we have evaluated the safety and immunogenicity of a vaccine containing a mixture of 12 peptides from melanocytic differentiation proteins and cancer-testis antigens, designed for human leukocyte antigen types that represent 80% of the melanoma patient population. This was compared with a four-peptide vaccine with only melanocytic differentiation peptides. Immune responses were assessed in peripheral blood and in vaccine-draining lymph nodes.Results: These data show that (a) the 12-peptide mixture is immunogenic in all treated patients; (b) immunogenicity of individual peptides is maintained despite competition with additional peptides for binding to MHC molecules; (c) a broader and more robust immune response is induced by vaccination with the more complex 12-peptide mixture; and (d) clinical outcome in this peptide vaccine trial correlates with immune responses measured in the peripheral blood lymphocytes.Conclusions: These data support continued investigation of complex multipeptide vaccines for melanoma.