bluuebunny/crossref_metadata_2025 huggingface dataset:
A Synovial Sarcoma-Specific Preoperative Nomogram Supports a Survival Benefit to Ifosfamide-Based Chemotherapy and Improves Risk Stratification for Patients
Authors: Canter Robert J. , Qin Li-Xuan , Maki Robert G. , Brennan Murray F. , Ladanyi Marc , Singer Samuel
Published: December 2008

Purpose: To identify prognostic factors related to outcome in 255 patients with synovial sarcoma and to construct a preoperative nomogram to predict the risk of disease-specific death.

Design: Between July 1982 and June 2006, 301 patients underwent treatment at our institution for primary synovial sarcoma of all anatomic sites and 255 patients with localized disease at presentation were resected with curative intent. Data were collected prospectively and analyzed retrospectively.

Results: Five-, 10-, and 15-year disease-specific survival (DSS) was 72%, 60%, and 53%, respectively. Multivariate analysis revealed size and primary tumor site as the only independent adverse predictors of disease-specific death. A nomogram based on preoperative data for surgical patients not receiving anthracycline-ifosfamide (AI) chemotherapy (n = 196) estimates 3- and 5-year DSS with a concordance index of 77.3%. For the first 3 years following diagnosis, the observed DSS for patients treated with AI chemotherapy (n = 59) was greater than that predicted by the preoperative nomogram based on patients not receiving AI chemotherapy. SYT-SSX fusion transcript data were available for 132 patients. Multivariate analysis of this subset showed that SYT-SSX1 fusion type was predictive of early, but not late, distant recurrence.

Conclusion: Size and location govern prognosis in primary synovial sarcoma resected with curative intent. A nomogram based on preoperative variables provides individualized patient survival estimates and shows an early survival benefit to chemotherapy that may dissipate over time. This nomogram may improve decision-making with regards to selecting patients most likely to benefit from neoadjuvant/adjuvant chemotherapy.
Genetic Susceptibility Loci for Breast Cancer by Estrogen Receptor Status
Authors: Garcia-Closas Montserrat , Chanock Stephen
Published: December 2008

Breast cancer is a heterogeneous disease, and risk factors could be differentially associated with the development of distinct tumor subtypes that manifest different biological behavior and progression. In support of this view, there is growing evidence that known breast cancer risk factors vary by hormone receptor status and perhaps other pathologic characteristics of disease. Recent work from large consortial studies has led to the discovery of novel breast cancer susceptibility loci in genic (CASP8, FGFR2, TNRC9, MAP3K1, LSP1) and nongenic regions (8q24, 2q35, 5p12) of the genome, and to the finding of substantial heterogeneity by tumor characteristics. In particular, susceptibility loci in FGFR2, TNRC9, 8q24, 2q35, and 5p12 have stronger associations for estrogen receptor–positive (ER+) disease than estrogen receptor–negative (ER−) disease. These findings suggest that common genetic variants can influence the pathologic subtype of breast cancer, and provide further support for the hypothesis that ER+ and ER− disease result from different etiologic pathways. Current studies had limited power to detect susceptibility loci for less common tumor subtypes, such as ER− disease including triple-negative and basal-like tumors. Ongoing work targeting uncommon subtypes is likely to identify additional tumor-specific susceptibility loci in the near future. Characterization of etiologic heterogeneity of breast cancer may lead to improvements in the understanding of the biological mechanisms for breast cancer, and ultimately result in improvements in prevention, early detection, and treatment.
Allelic Imbalance Analysis Using a Single-Nucleotide Polymorphism Microarray for the Detection of Bladder Cancer Recurrence
Authors: Coenen Marieke J.H. , Ploeg Martine , Schijvenaars Mascha M.V.A.P. , Cornel Erik B. , Karthaus Herbert F.M. , Scheffer Hans , Witjes J. Alfred , Franke Barbara , Kiemeney Lambertus A.L.M.
Published: December 2008

Purpose: Non–muscle-invasive bladder cancer is a frequently occurring cancer, with an extremely high recurrence risk. Recurrence detection is based on cytology and urethrocystoscopy. A previous study suggested that a single-nucleotide polymorphism (SNP) array may be effective for noninvasive detection of allelic imbalances in urine. We investigated whether this method is suitable to detect allelic imbalance as an indicator of recurrences in non–muscle-invasive bladder cancer follow-up.

Experimental Design: DNA from blood and urine from 158 patients (113 with and 45 without recurrence) was hybridized to the Affymetrix GeneChip Mapping 10K 2.0. Allelic imbalance detection was based on SNPs showing changes from heterozygosity in blood to homozygosity in urine and on automatic analysis of copy number changes using Copy Number Analyser for GeneChip.

Results: Urine samples with tumor showed allelic imbalance at 0.4% of all informative SNPs. In samples without tumors, 0.04% of these SNPs were affected (P = 0.07). In addition, Copy Number Analyser for GeneChip analysis showed more copy number changes in samples with a tumor (P = 0.001). Losses and gains of chromosomal regions showed clustering, overlapping with known bladder cancer loci. However, 25 (22%) patients with a tumor recurrence did not display any regions with copy number changes, whereas 24 (53%) individuals without a recurrence did. Receiver operating characteristic curve analysis using the number of SNPs displaying copy number changes from the Copy Number Analyser for GeneChip analysis resulted in an area under the curve of only 0.67 (95% confidence interval, 0.58-0.76).

Conclusion: Single-nucleotide polymorphism microarray analysis of allelic imbalance in urine cannot replace urethrocystoscopy and cytology for the detection of recurrences in non–muscle-invasive bladder cancer follow-up.
Early Tumor Drug Pharmacokinetics Is Influenced by Tumor Perfusion but not Plasma Drug Exposure
Authors: Saleem Azeem , Price Pat M.
Published: December 2008

Purpose: Pharmacokinetic parameters derived from plasma sampling are used as a surrogate of tumor pharmacokinetics. However, pharmacokinetics-modulating strategies do not always result in increased therapeutic efficacy. Nonsurrogacy of plasma kinetics may be due to tissue-specific factors such as tumor perfusion.

Experimental Design: To assess the impact of tumor perfusion and plasma drug exposure on tumor pharmacokinetics, positron emission tomography studies were done with oxygen-15 radiolabeled water in 12 patients, with 6 patients undergoing positron emission tomography studies with carbon-11 radiolabeled N-[2-(dimethylamino)ethyl]acridine-4-carboxamide and the other 6 with fluorine-18 radiolabeled 5-fluorouracil.

Results: We found that tumor blood flow (mL blood/mL tissue/minute) was significantly correlated to early tumor radiotracer uptake between 4 and 6 minutes [standard uptake value (SUV)4-6; ρ = 0.79; P = 0.002], tumor radiotracer exposure over 10 minutes [area under the time-activity curve (AUC)0-10; predominantly parent drug; ρ = 0.86; P < 0.001], and tumor radiotracer exposure over 60 minutes (AUC0-60; predominantly radiolabeled metabolites; ρ = 0.80; P = 0.002). Similarly, fractional volume of distribution of radiolabeled water in tumor (Vd) was significantly correlated with SUV4-6 (ρ = 0.80; P = 0.002), AUC0-10 (ρ = 0.85; P < 0.001), and AUC0-60 (ρ = 0.66; P = 0.02). In contrast, no correlation was observed between plasma drug or total radiotracer exposure over 60 minutes and tumor drug uptake or exposure. Tumor blood flow was significantly correlated to Vd (ρ = 0.69; P = 0.014), underlying the interdependence of tumor perfusion and Vd.

Conclusions: Tumor perfusion is a key factor that influences tumor drug uptake/exposure. Tumor vasculature-targeting strategies may thus result in improved tumor drug exposure and therefore drug efficacy.
The Incidence, Correlation with Tumor-Infiltrating Inflammation, and Prognosis of Phosphorylated STAT3 Expression in Human Gliomas
Authors: Abou-Ghazal Mohamed , Yang David S. , Qiao Wei , Reina-Ortiz Chantal , Wei Jun , Kong Ling-Yuan , Fuller Gregory N. , Hiraoka Nobuyoshi , Priebe Waldemar , Sawaya Raymond , Heimberger Amy B.
Published: December 2008

Purpose: The signal transducer and activator of transcription 3 (STAT3) is frequently overexpressed in most cancers, propagates tumorigenesis, and is a key regulator of immune suppression in cancer patients. We sought to determine the incidence of phosphorylated STAT3 (p-STAT3) expression in malignant gliomas of different pathologic types, whether p-STAT3 expression is a negative prognostic factor, and whether p-STAT3 expression influences the inflammatory response within gliomas.

Methods: Using immunohistochemical analysis, we measured the incidence of p-STAT3 expression in 129 patients with gliomas of various pathologic types in a glioma tissue microarray. We categorized our results according to the total number of p-STAT3–expressing cells within the gliomas and correlated this number with the number of infiltrating T cells and T regulatory cells. We then evaluated the association between p-STAT3 expression and median survival time using univariate and multivariate analyses.

Results: We did not detect p-STAT3 expression in normal brain tissues or low-grade astrocytomas. We observed significant differences in the incidence of p-STAT3 expression between the different grades of astrocytomas and different pathologic glioma types. p-STAT3 expression was associated with the population of tumor-infiltrating immune cells but not with that of T regulatory cells. On univariate analysis, we found that p-STAT3 expression within anaplastic astrocytomas was a negative prognostic factor.

Conclusions: p-STAT3 expression is common within gliomas of both the astrocytic and oligodendroglial lineages and portends poor survival in patients with anaplastic astrocytomas. p-STAT3 expression differs significantly between gliomas of different pathologic types and grades and correlated with the degree of immune infiltration.
miR-192 Regulates Dihydrofolate Reductase and Cellular Proliferation through the p53-microRNA Circuit
Authors: Song Bo , Wang Yuan , Kudo Kenji , Gavin Elaine J. , Xi Yaguang , Ju Jingfang
Published: December 2008

Purpose: The purpose of this study is to investigate the molecular mechanism of miR-192 in colon cancer.

Experimental Design: Human colon cancer cell lines with different p53 status were used as our model system to study the effect of miR-192 on cell proliferation, cell cycle control, and mechanism of regulation.

Results: Our results show that one of the key miR-192 target genes is dihydrofolate reductase (DHFR). miR-192 affects cellular proliferation through the p53-miRNA circuit. Western immunoblot analyses indicated that the expression of DHFR was significantly decreased by miR-192. Further investigation revealed that such suppression was due to translational arrest rather than mRNA degradation. More profound inhibition of cellular proliferation was observed by ectopic expression of miR-192 in colon cancer cell lines containing wild-type p53 than cells containing mutant p53. Thus, the effect of miR-192 on cellular proliferation is mainly p53 dependent. Overexpression of miR-192 triggered both G1 and G2 arrest in HCT-116 (wt-p53) cells but not in HCT-116 (null-p53) cells. The cell cycle checkpoint control genes p53 and p21 were highly overexpressed in cells that overexpressed miR-192. Endogenous miR-192 expression was increased in HCT-116 (wt-p53) and RKO (wt-p53) cells treated with methotrexate, which caused an induction of p53 expression. Chromatin immunoprecipitation-quantitative reverse transcription-PCR analysis revealed that the p53 protein interacted with the miR-192 promoter sequence.

Conclusion: These results indicate that miR-192 may be another miRNA candidate that is involved in the p53 tumor suppressor network with significant effect on cell cycle control and cell proliferation.
Inhibition of Melanoma Growth by Targeting of Antigen to Dendritic Cells via an Anti-DEC-205 Single-Chain Fragment Variable Molecule
Authors: Johnson Theron S. , Mahnke Karsten , Storn Volker , Schönfeld Kurt , Ring Sabine , Nettelbeck Dirk M. , Haisma Hidde J. , Le Gall Fabrice , Kontermann Roland E. , Enk Alexander H.
Published: December 2008

Purpose: Our goal was to target melanoma antigens to the dendritic cell-specific receptor DEC-205. DEC-205 is an antigen receptor expressed on dendritic cells and has been shown to guide antigens to MHC class I and II compartments for processing and presentation to T cells.

Experimental Design: The melanoma tumor-associated antigen (TAA), gp100, was fused to the single-chain fragment variable (scFv) specific for DEC-205. The binding capacity of the scFv was tested on lymph node-isolated CD11c+ cells. Mixed lymphocyte reactions were carried out to show an increased proliferative capacity of gp100 antigen-specific CD4 and CD8 T cells. Furthermore the scFv-TAA was used in a therapeutic setting using two different melanoma mouse models.

Results: C57Bl/6 mice were injected with scFv-DEC-205-gp100, monoclonal antibody anti-DEC-205, or PBS. Using fluorescence-activated cell sorting, we showed that lymph node CD11c+ dendritic cells stained positive for the binding of the scFv-mDEC-205-gp100 and the anti-DEC-205 monoclonal antibody, whereas the PBS-injected animals were negative. In mixed lymphocyte reactions, bone marrow-derived dendritic cells pulsed with scFv-mDEC-205-gp100 significantly increased proliferation of gp100-specific CD8+ and CD4+ T cells beyond gp100 peptide-pulsed or nonpulsed bone marrow-derived dendritic cells. Finally, in B16/F10 and RET models, a concentration-dependent suppression of tumor growth using scFv-mDEC-205-gp100 (66% reduction of tumor volume), in comparison with gp100 peptide vaccination, was observed.

Conclusions: Our results indicate that the scFv-mDEC-205-gp100 targets TAA to dendritic cells in vivo for presentation on both MHC class I and II molecules. In vivo, this leads to an improved immune response and a decrease in tumor growth rate.
Impact of Abcc2 (Mrp2) and Abcc3 (Mrp3) on the In vivo Elimination of Methotrexate and its Main Toxic Metabolite 7-hydroxymethotrexate
Authors: Vlaming Maria L.H. , Pala Zeliha , van Esch Anita , Wagenaar Els , van Tellingen Olaf , de Waart Dirk R. , Oude Elferink Ronald P.J. , van de Wetering Koen , Schinkel Alfred H.
Published: December 2008

Purpose: ATP-binding cassette sub-family C member 2 [ABCC2; multidrug resistance–associated protein 2 (MRP2)] and ABCC3 (MRP3) mediate the elimination of toxic compounds, such as drugs and carcinogens, and have a large overlap in substrate specificity. We investigated the roles of Abcc2 and Abcc3 in the elimination of the anticancer drug methotrexate (MTX) and its toxic metabolite 7-hydroxymethotrexate (7OH-MTX) in vivo.

Experimental Design: Abcc2;Abcc3 −/− mice were generated, characterized, and used to investigate possibly overlapping or complementary roles of Abcc2 and Abcc3 in the elimination of MTX and 7OH-MTX after i.v. administration of 50 mg/kg MTX.

Results: Abcc2;Abcc3 −/− mice were viable and fertile. In Abcc2−/− mice, the plasma area under the curve (AUCi.v.) for MTX was 2.0-fold increased compared with wild type, leading to 1.6-fold increased urinary excretion, which was not seen in Abcc2;Abcc3−/− mice. Biliary excretion of MTX was 3.7-fold reduced in Abcc2−/− but unchanged in Abcc2;Abcc3−/− mice. The plasma AUCi.v.s of 7OH-MTX were 6.0-fold and 4.3-fold increased in Abcc2−/− and Abcc2;Abcc3−/− mice, respectively, leading to increased urinary excretion. The biliary excretion of 7OH-MTX was 5.8-fold reduced in Abcc2−/− but unchanged in Abcc2;Abcc3−/− mice. 7OH-MTX accumulated substantially in the liver of Abcc2−/− and especially Abcc2;Abcc3−/− mice.

Conclusions: Abcc2 is important for (biliary) excretion of MTX and its toxic metabolite 7OH-MTX. When Abcc2 is absent, Abcc3 transports MTX and 7OH-MTX back from the liver into the circulation, leading to increased plasma levels and urinary excretion. Variation in ABCC2 and/or ABCC3 activity may therefore have profound effects on the elimination and severity of toxicity of MTX and 7OH-MTX after MTX treatment of patients.
The Novel Nuclear Factor-κB Inhibitor LC-1 Is Equipotent in Poor Prognostic Subsets of Chronic Lymphocytic Leukemia and Shows Strong Synergy with Fludarabine
Authors: Hewamana Saman , Lin Thet Thet , Jenkins Chris , Burnett Alan K. , Jordan Craig T. , Fegan Chris , Brennan Paul , Rowntree Clare , Pepper Chris
Published: December 2008

Purpose: We have recently shown that the novel nuclear factor-κB (NF-κB) inhibitor LC-1 is effective in primary chronic lymphocytic leukemia (CLL) cells. Here we elucidated the mechanism of action of LC-1, evaluated its relative cytotoxicity in prognostic subsets, and investigated its potential synergistic interaction with fludarabine.

Experimental Design: Ninety-six fully characterized CLL cases were assessed for in vitro sensitivity to LC-1 and fludarabine. In selected cases, caspase activation, inhibition of Rel A DNA binding, and the transcription of CFLAR, BIRC5, and BCL2 were measured before and after exposure to LC-1. In addition, the efficacy of LC-1 was assessed in the presence of the survival factors CD154 and interleukin-4, and the potential synergistic interaction between LC-1 and fludarabine was evaluated.

Results: Cell death was associated with caspase-3 activation mediated via activation of both caspase-8 and caspase-9. Apoptosis was preceded by a reduction of nuclear Rel A DNA binding and inhibition of CFLAR, BIRC5, and BCL2 transcription. Importantly, LC-1 overcame the cytoprotective effects by interleukin-4 and CD40 ligand and was equipotent in CLL cells derived from good and bad prognostic subsets. LC-1 exhibited strong synergy with fludarabine, and the combination produced a highly significant mean dose reduction index for fludarabine of >1,000.

Conclusions: In view of imminent first-in-man study of LC-1 in Cardiff, these data show an important mechanistic rationale for the use of LC-1 in this disease. Furthermore, it validates the concept of targeting nuclear factor-κB in CLL and identifies the therapeutic potential of LC-1 in combination with fludarabine even in patients with fludarabine resistance.
Does Loss of CD151 Expression Promote the Metastasis of Hypoxic Colon Cancer Cells?
Authors: Semenza Gregg L.
Published: December 2008

Intratumoral hypoxia increases invasion and metastasis through multiple mechanisms, including changes in gene expression that are mediated by hypoxia-inducible factor 1. In hypoxic colon cancer cells, hypoxia-inducible factor 1 inhibits the expression of CD151, a cell surface molecule that normally tethers epithelial cells to the basement membrane, which may promote metastasis.
Microsomal antiestrogen-binding site ligands induce growth control and differentiation of human breast cancer cells through the modulation of cholesterol metabolism
Authors: Payré Bruno , de Medina Philippe , Boubekeur Nadia , Mhamdi Loubna , Bertrand-Michel Justine , Tercé François , Fourquaux Isabelle , Goudounèche Dominique , Record Michel , Poirot Marc , Silvente-Poirot Sandrine
Published: December 2008

The microsomal antiestrogen-binding site (AEBS) is a high-affinity membranous binding site for the antitumor drug tamoxifen that selectively binds diphenylmethane derivatives of tamoxifen such as PBPE and mediates their antiproliferative properties. The AEBS is a hetero-oligomeric complex consisting of 3β-hydroxysterol-Δ8-Δ7-isomerase and 3β-hydroxysterol-Δ7-reductase. High-affinity AEBS ligands inhibit these enzymes leading to the massive intracellular accumulation of zymostenol or 7-dehydrocholesterol (DHC), thus linking AEBS binding to the modulation of cholesterol metabolism and growth control. The aim of the present study was to gain more insight into the control of breast cancer cell growth by AEBS ligands. We report that PBPE and tamoxifen treatment induced differentiation in human breast adenocarcinoma cells MCF-7 as indicated by the arrest of cells in the G0-G1 phase of the cell cycle, the increase in the cell volume, the accumulation and secretion of lipids, and a milk fat globule protein found in milk. These effects were observed with other AEBS ligands and with zymostenol and DHC. Vitamin E abrogates the induction of differentiation and reverses the control of cell growth produced by AEBS ligands, zymostenol, and DHC, showing the importance of the oxidative processes in this effect. AEBS ligands induced differentiation in estrogen receptor-negative mammary tumor cell lines SKBr-3 and MDA-MB-468 but with a lower efficiency than observed with MCF-7. Together, these data show that AEBS ligands exert an antiproliferative effect on mammary cancer cells by inducing cell differentiation and growth arrest and highlight the importance of cholesterol metabolism in these effects. [Mol Cancer Ther 2008;7(12):3707–18]
Kinin B2 Receptor Mediates Induction of Cyclooxygenase-2 and Is Overexpressed in Head and Neck Squamous Cell Carcinomas
Authors: Zhang Weiping , Bhola Neil , Kalyankrishna Shailaja , Gooding William , Hunt Jennifer , Seethala Raja , Grandis Jennifer R. , Siegfried Jill M.
Published: December 2008

Bradykinin has been shown to promote growth and migration of head and neck squamous cell carcinoma (HNSCC) cells via epidermal growth factor receptor (EGFR) transactivation. It has also been reported that bradykinin can cause the induction of cyclooxygenase-2 (COX-2), a protumorigenic enzyme, via the mitogen-activated protein kinase (MAPK) pathway in human airway cells. To determine whether COX-2 is up-regulated by bradykinin in HNSCC, the current study investigated bradykinin-induced EGFR transactivation, MAPK activation, and COX-2 expression in human HNSCC cells. Bradykinin induced a concentration- and time-dependent induction of COX-2 protein in HNSCC, which was preceded by phosphorylation of EGFR and MAPK. These effects were abolished by the B2 receptor (B2R) antagonist HOE140 but not by the B1 receptor (B1R) antagonist Lys-[Leu8]des-Arg9-bradykinin. COX-2 induction was accompanied by increased release of prostaglandin E2. No effect of a B1R agonist (des-Arg9-bradykinin) on p-MAPK or COX-2 expression was observed. B2R protein was found to be expressed in all four head and neck cell lines tested. Immunohistochemical analysis and immunoblot analysis revealed that B2R, but not B1R, was significantly overexpressed in HNSCC tumors compared with levels in normal mucosa from the same patient. In HNSCC cells, the bradykinin-induced expression of COX-2 was inhibited by the EGFR kinase inhibitor gefitinib or mitogen-activated protein kinase kinase inhibitors (PD98059 or U0126). These results suggest that EGFR and MAPK are required for COX-2 induction by bradykinin. Up-regulation of the B2R in head and neck cancers suggests that this pathway is involved in HNSCC tumorigenesis. (Mol Cancer Res 2008;6(12):1946–56)
Notch Inhibits Expression of the Krüppel-Like Factor 4 Tumor Suppressor in the Intestinal Epithelium
Authors: Ghaleb Amr M. , Aggarwal Gaurav , Bialkowska Agnieszka B. , Nandan Mandayam O. , Yang Vincent W.
Published: December 2008

The zinc finger-containing transcription factor, Krüppel-like factor 4 (KLF4), inhibits cell proliferation. An in vivo tumor-suppressive role for KLF4 is shown by the recent finding that Klf4 haploinsufficiency in ApcMin/+ mice promotes intestinal tumorigenesis. Studies also show that KLF4 is required for the terminal differentiation of goblet cells in the mouse intestine. The Notch signaling pathway suppresses goblet cell formation and is up-regulated in intestinal tumors. Here, we investigated the relationship between Notch signaling and KLF4 expression in intestinal epithelial cells. The rate of proliferation of HT29 human colon cancer cells was reduced when treated with the γ-secretase inhibitor dibenzazepine to inhibit Notch signaling or small interfering RNA directed against Notch. KLF4 levels were increased in dibenzazepine-treated or Notch small interfering RNA-treated cells. Conversely, overexpression of Notch in HT29 cells reduced KLF4 levels, suppressed KLF4 promoter activity, and increased proliferation rate. Treatment of ApcMin/+ mice with dibenzazepine resulted in a 50% reduction in the number of intestinal adenomas compared with the vehicle-treated group (P < 0.001). Both the normal-appearing intestinal mucosa and adenomas obtained from dibenzazepine-treated ApcMin/+ mice had increased goblet cell numbers and Klf4 staining accompanied by reduced cyclin D1 and Ki-67 staining when compared with those from vehicle-treated mice. Results of these studies indicate that Notch signaling suppresses KLF4 expression in intestinal tumors and colorectal cancer cells. Inhibition of Notch signaling increases KLF4 expression and goblet cell differentiation and reduces proliferation and tumor formation. KLF4 is therefore a potential mediator for the antitumor effect of Notch inhibitors such as dibenzazepine. (Mol Cancer Res 2008;6(12):1920–7)
TRAIL Resistance of Breast Cancer Cells Is Associated with Constitutive Endocytosis of Death Receptors 4 and 5
Authors: Zhang Yaqin , Zhang Baolin
Published: December 2008

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and its agnostic antibodies, which are being evaluated clinically as anticancer therapies, selectively kill cancer cells through the death receptors DR4 and DR5. However, their therapeutic potential is limited by occurring resistance in tumor cells. Here, we compared the apoptotic response of a panel of six human breast cancer cell lines with recombinant human TRAIL and antibodies to DR4 or DR5. Despite their total mRNA and protein expression, TRAIL death receptors, with a higher frequency in DR4, are absent on cell surface in some cell lines. Loss of cell surface expression of DR4 or DR5 accounts for resistance to their corresponding antibody and, importantly, correlates with a decreased sensitivity to TRAIL. TRAIL resistance occurs when both receptors are absent on cell surface regardless of alterations in Bcl-2 family proteins or caspases. Furthermore, inhibition of endocytosis by pharmacologic inhibitors or disruption of clathrin-dependent endocytosis signaling components (adaptor protein 2 and clathrin) restores cell surface expression of the death receptors and sensitize TRAIL-resistant cells to TRAIL-induced apoptosis. DR4 endocytosis appears to be mediated by its cytoplasmic domain EAQC337LL. The results show that TRAIL death receptors undergo constitutive endocytosis in some breast cancer cells. Loss of cell surface expression of DR4 and DR5 could be evaluated as a biomarker for TRAIL resistance in breast tumors. Moreover, the clathrin-mediated endocytosis pathway could be a potential target for therapeutics to overcome tumor resistance to TRAIL receptor-targeted therapies. (Mol Cancer Res 2008;6(12):1861–71)
Why Might People Donate Tissue for Cancer Research? Insights from Organ/Tissue/Blood Donation and Clinical Research
Authors: Axler Renata E. , Irvine Rob , Lipworth Wendy , Morrell Bronwen , Kerridge Ian H.
Published: December 2008

Little is known about why patients with cancer do or do not donate their biopsied/cancerous tissue to research. A review of the literature on motivations to participate in clinical research and to donate tissues/organs for therapeutic use may provide some insights relevant to tumour banking research. While more research is necessary, a better understanding of the factors that motivate patients to give or refuse consent to tumour banking may ultimately improve consent practices, public trust and donation rates.
Specific Induction of Tumor Neovasculature Death by Modified Murine PPE-1 Promoter Armed with HSV-TK
Authors: Varda-Bloom N. , Hodish I. , Shaish A. , Greenberger S. , Tal R. , Feder B. , Roitelman J. , Breitbart E. , Bangio L. , Barshack I. , Pfeffer R. , Harats D.
Published: December 2008

Background: One strategy to increase tissue specificity of gene therapy is to use promoters or enhancers. Objectives: (1) To enhance the selectivity of a murine preproendothelin-1 (PPE-1) promoter in tumor angiogenesis by using a positive endothelial transcription-binding element. (2) To test the specificity and efficiency of the modified PPE-1 promoter [PPE-1(3X)] in vitro and in vivo by using reporter genes, and the therapeutic gene herpes simplex virus-thymidine kinase (HSV-TK) in a mouse model of Lewis lung carcinoma (LLC). Results: The modified PPE-1 promoter specifically induced expression in the tumor angiogenic vascular bed with a 35-fold higher expression compared to the normal vasculare bed of the lung. Thus, when the HSV-TK gene controlled by the modified PPE-1 promoter was used systemically, it induced tumor-specific necrosis, apoptosis and mononuclear infiltrates, leading to massive destruction of the neovasculature of the pulmonary metastasis, which suppressed metastasis development. Conclusions: These results show that an adenoviral vector armed with HSV-TK controlled by the endothelial-selective murine PPE-1(3X) promoter is efficient and safe to target tumor neovasculature.
Susceptibility of XRCC3, XPD, and XPG Genetic Variants to Cervical Carcinoma
Authors: He Xiaohong , Ye Feng , Zhang Jing , Cheng Qi , Shen Jiajie , Chen Huaizeng
Published: December 2008

Objective: DNA repair genes play a key role in maintaining genomic stability and integrity. DNA repair gene polymorphisms, such as those of XRCC3 and xeroderma pigmentosum, complementation group D and G (XPD, XPG), contribute to carcinogenesis. In this study, we investigated the correlation between cervical carcinoma risk and XRCC3, XPD, XPG genetic variants. Methods: A case-control study of 400 cases including 200 carcinoma, 200 cervical intraepithelial neoplasia (CIN) and 200 normal women was performed. Four single nucleotide polymorphisms (SNPs) (XRCC3 Thr241Met, XPG His1104Asp, XPD Asp312Asn, and XPD Lys751Gln) were genotyped by mismatch amplification polymerase chain reaction. Results: Women carrying homozygous Asp1104Asp genotypes had a significantly decreased risk of cervical or cervical squamous cell carcinoma compared to His1104Asp or His1104His genotypes. Similarly, XPD Asn312Asn (AA) reduced the risk of cervical or cervical squamous cell carcinoma. No association of XRCC3 Thr241Met or XPD Lys751Gln and cervical carcinoma was found. None of the 4 SNPs influenced the risk of CIN in our study. Conclusion: Our results support the hypothesis that genetic variations in DNA repair genes may contribute to an inherited genetic susceptibility to cervical carcinoma.
Effects of Various Dietary Arginine and Lysine Concentrations on Plasma and Liver Cholesterol Concentrations in Rats
Authors: Spielmann Julia , Noatsch Anne , Brandsch Corinna , Stangl Gabriele I. , Eder Klaus
Published: December 2008

Background: It has been hypothesized that the arginine:lysine ratio of dietary proteins influences cholesterol concentrations in plasma and liver of men and animals. This study was performed to test this hypothesis in rats by using diets with various concentrations of arginine and lysine, differing in their arginine:lysine ratios. Methods: Two experiments with growing rats were performed, some of which received diets containing 4.5, 9 or 18 g arginine/kg and 9 or 18 g lysine/kg, respectively, for a period of 21 days. In the first experiment, a cholesterol-free diet was used; in the second experiment, a diet supplemented with cholesterol and sodium cholate as hypercholesterolaemic compounds was used. Results: In experiment 1, increasing the arginine concentration lowered HDL and plasma cholesterol concentration; however, cholesterol concentrations in liver, LDL and VLDL remained unchanged. In experiment 2, increasing the arginine concentration lowered HDL cholesterol and increased liver cholesterol (p < 0.05); cholesterol concentrations in plasma, LDL and VLDL remained unchanged. The only effect of the dietary lysine concentration concerned the effect on VLDL and liver cholesterol concentration, which were both lower in rats fed the diets with 18 g lysine/kg than in those fed the diets with 9 g lysine/kg (p < 0.05). Varying the dietary arginine:lysine ratio between 0.25 and 2.0 had no influence on cholesterol concentration in LDL and VLDL in both experiments; HDL cholesterol concentration was lowered by increasing this ratio (p < 0.05). Conclusion: The present study does not support the hypothesis that an increase in the dietary arginine:lysine ratio causes hypocholesterolaemic effects in rats.
The Role of the Dorsal Anterior Cingulate in Evaluating Behavior for Achieving Gains and Avoiding Losses
Authors: Magno Elena , Simões-Franklin Cristina , Robertson Ian H. , Garavan Hugh
Published: December 2008

Effective goal-directed behavior relies on a network of regions including anterior cingulate cortex and ventral striatum to learn from negative outcomes in order to improve performance. We employed fMRI to determine if this frontal–striatal system is also involved in instances of behavior that do not presume negative circumstances. Participants performed a visual target/nontarget search game in which they could optionally abort a trial to avoid errors or receive extra reward for highly confident responses. Anterior cingulate and prefrontal cortex were equally activated for error avoidance and high reward trials but were not active on error trials, demonstrating their primary involvement in self-initiated behavioral adjustment and not error detection or prediction. In contrast, the insula and the ventral striatum were responsive to the high reward trials. Differential activation patterns across conditions for the nucleus accumbens, insula, and prefrontal cortex suggest distinct roles for these structures in the control of reward-related behavior.
Now You'll Feel It, Now You Won't: EEG Rhythms Predict the Effectiveness of Perceptual Masking
Authors: Schubert Ruth , Haufe Stefan , Blankenburg Felix , Villringer Arno , Curio Gabriel
Published: December 2008

Do ongoing brain states determine conscious perception of an upcoming stimulus? Using the high temporal resolution of EEG, we investigated the relationship between prestimulus neuronal oscillations and the perceptibility of two competing somatosensory stimuli embedded in a backward masking paradigm. We identified two prestimulus EEG signatures predictive for a suprathreshold yet weak target stimulus to become perceptually resistant against masking by a stronger distractor stimulus: (i) over left frontal cortex a desynchronization of the regional beta rhythm (∼20 Hz) 500 msec prior to a perceived target, and (ii) a subsequent additional attenuation of both mu (∼10 Hz) and beta “idling” rhythms over those pericentral sensorimotor cortices which are going to process the upcoming target stimulus. Furthermore, across subjects the probability for target perception strongly correlates with the individual absolute level of pre-target amplitudes in these frequency bands and locations. These signatures significantly differed from the EEG characteristics preceding detected and undetected single stimuli. We suggest that the early activation of left frontal areas involved in top–down attentional control is critical for preventing backward masking and leads the preparation of primary sensory cortices: The ensuing prestimulus suppression of sensory idling rhythms warrants an intensified poststimulus processing, and thus, effectively promotes conscious perception of suprathreshold target stimuli embedded into an ecologically relevant condition featuring competing environmental stimuli.
The Timing of Neural Activity during Shifts of Spatial Attention
Authors: Brignani Debora , Lepsien Jöran , Rushworth Matthew F. S. , Nobre Anna Christina
Published: December 2008

We developed a new experimental task to investigate the relative timing of neural activity during shifts of spatial attention with event-related potentials. The task enabled the investigation of nonlateralized as well as lateralized neural activity associated with spatial shifts. Participants detected target stimuli within one of two peripheral streams of visual letters. Colored letters embedded within the streams indicated which stream was to be used for target detection, signaling that participants should “hold” or “shift” their current focus of spatial attention. A behavioral experiment comparing performance in these focused-attention conditions with performance in a divided-attention condition confirmed the efficacy of the spatial cues. Another behavioral experiment showed that overt shifts of spatial attention were mainly complete by around 400 msec, placing an upper boundary for isolating neural activity that was instrumental in controlling spatial shifts. Event-related potentials recorded during a covert version of the focused-attention task showed a large amount of nonlateralized neural activity associated with spatial shifts, with significant effects starting around 330 msec. The effects started over posterior scalp regions, where they remained pronounced. Transient effects were also observed over frontal scalp regions. The results are compatible with a pivotal role of posterior parietal areas in initiating shifts of spatial attention.
Neural Correlates of Cross-modally Induced Changes in Tactile Awareness
Authors: Hötting Kirsten , Friedrich Claudia K. , Röder Brigitte
Published: December 2008

When a single tactile stimulus is presented together with two tones, participants often report perceiving two touches. It is a matter of debate whether this cross-modal effect of audition on touch reflects the interplay between modalities at early perceptual or at later processing stages, and which brain processes determine what in the end is consciously perceived. Event-related brain potentials (ERPs) were recorded while rare single tactile stimuli accompanied by two tones (1T2A) were presented among frequent tactile double stimuli accompanied by two tones (2T2A). Although participants were instructed to ignore the tones and to respond to single tactile stimuli only, they often failed to respond to 1T2A stimuli (“illusory double touches,” 1T2A(i)). ERPs to “illusory double touches” versus “real double touches” (2T2A) differed 50 msec after the (missing) second touch. This suggests that at an early sensory stage, illusory and real touches are processed differently. On the other hand, although similar stimuli elicited a tactile mismatch negativity (MMN) between 100 and 200 msec in a unisensory tactile experiment, no MMN was observed for the 1T2A(i) stimuli in the multisensory experiment. “Tactile awareness” was associated with a negativity at 250 msec, which was enhanced in response to correctly identified deviants as compared to physically identical deviants that elicited an illusion. Thus, auditory stimuli seem to alter neural mechanisms associated with automatic tactile deviant detection. The present findings contribute to the debate of which processing step in the brain determines what is consciously perceived.
Interactions between Voluntary and Stimulus-driven Spatial Attention Mechanisms across Sensory Modalities
Authors: Santangelo Valerio , Belardinelli Marta Olivetti , Spence Charles , Macaluso Emiliano
Published: December 2008

In everyday life, the allocation of spatial attention typically entails the interplay between voluntary (endogenous) and stimulus-driven (exogenous) attention. Furthermore, stimuli in different sensory modalities can jointly influence the direction of spatial attention, due to the existence of cross-sensory links in attentional control. Using fMRI, we examined the physiological basis of these interactions. We induced exogenous shifts of auditory spatial attention while participants engaged in an endogenous visuospatial cueing task. Participants discriminated visual targets in the left or right hemifield. A central visual cue preceded the visual targets, predicting the target location on 75% of the trials (endogenous visual attention). In the interval between the endogenous cue and the visual target, task-irrelevant nonpredictive auditory stimuli were briefly presented either in the left or right hemifield (exogenous auditory attention). Consistent with previous unisensory visual studies, activation of the ventral fronto-parietal attentional network was observed when the visual targets were presented at the uncued side (endogenous invalid trials, requiring visuospatial reorienting), as compared with validly cued targets. Critically, we found that the side of the task-irrelevant auditory stimulus modulated these activations, reducing spatial reorienting effects when the auditory stimulus was presented on the same side as the upcoming (invalid) visual target. These results demonstrate that multisensory mechanisms of attentional control can integrate endogenous and exogenous spatial information, jointly determining attentional orienting toward the most relevant spatial location.
ERP Evidence for Rapid Hedonic Evaluation of Logos
Authors: Handy Todd C. , Smilek Daniel , Geiger Lena , Liu Cindy , Schooler Jonathan W.
Published: December 2008

We know that human neurocognitive systems rapidly and implicitly evaluate emotionally charged stimuli. But what about more everyday, frequently encountered kinds of objects, such as computer desktop icons and business logos? Do we rapidly and implicitly evaluate these more prosaic visual images, attitude objects that might only engender a mild sense of liking or disliking, if at all? To address this question, we asked participants to view a set of unfamiliar commercial logos in the context of a target identification task as brain electrical responses to these objects were recorded via event-related potentials (ERPs). Following this task, participants individually identified those logos that were most liked or disliked, allowing us to then compare how ERP responses to logos varied as a function of hedonic evaluation—a procedure decoupling evaluative responses from any normative classification of the logos themselves. In Experiment 1, we found that visuocortical processing manifest a specific bias for disliked logos that emerged within the first 200 msec of stimulus onset. In Experiment 2, we replicated this effect while dissociating normative- and novelty-related influences. Taken together, our results provide direct electrophysiological evidence suggesting that we rapidly and implicitly evaluate commercial branding images at a hedonic level.
Order and Magnitude Share a Common Representation in Parietal Cortex
Authors: Franklin Michael S. , Jonides John
Published: December 2008

The role of the intraparietal sulcus (IPS) in the representation of numerical magnitude is well established. Recently, there has also been speculation that the IPS is involved in the representation of ordinal information as well. These claims, however, overlook the fact that all neuroimaging paradigms in which participants make judgments about either magnitude and/or order result in a behavioral distance effect (i.e., the comparison is easier when the stimuli span a greater distance). This leaves open two possibilities: It may be that activation of the IPS is due to the mechanism that yields distance effects, or it may be that the IPS is involved in the representation of information about both magnitude and order. The current study used fMRI to compare a magnitude task in which participants show distance effects to an order-judgment task that yields reverse-distance effects. The results reveal activation of the IPS for both the magnitude and order tasks that is based on participants' strategies as opposed to the actual distance between the numbers. This leads to the conclusion that the IPS represents a mental number line, and that accessing this line can lead to distance effects when participants compare magnitudes and to reverse-distance effects when participants check for order.
Coordination Dynamics of Large-scale Neural Circuitry Underlying Rhythmic Sensorimotor Behavior
Authors: Jantzen Kelly J. , Steinberg Fred L. , Kelso J. A. Scott
Published: December 2008

In coordination dynamics, rate is a nonspecific control parameter that alters the stability of behavioral patterns and leads to spontaneous pattern switching. We used fMRI in conjunction with measures of effective connectivity to investigate the neural basis of behavioral dynamics by examining two coordination patterns known to be differentially stable (synchronization and syncopation) across a range of rates (0.75 to 1.75 Hz). Activity in primary auditory and motor cortices increased linearly with rate, independent of coordination pattern. On the contrary, activity in a premotor–cerebellar circuit varied directly with the stability of the collective variable (relative phase) that specifies coordinated behavioral patterns. Connectivity between premotor and motor cortices was also modulated by the stability of the behavioral pattern indicative of greater reliance on sensorimotor integration as action becomes more variable. By establishing a critical connection between behavioral and large scale brain dynamics, these findings reveal a basic principle for the neural organization underlying coordinated action.
Simulated WSR-88D Velocity and Reflectivity Signatures of Numerically Modeled Tornadoes
Authors: Wood Vincent T. , Brown Rodger A. , Dowell David C.
Published: December 2008

Low-altitude radar reflectivity measurements of tornadoes sometimes reveal a donut-shaped signature (low-reflectivity eye surrounded by a high-reflectivity annulus) and at other times reveal a high-reflectivity knob associated with the tornado. The differences appear to be due to such factors as (i) the radar’s sampling resolution, (ii) the presence or absence of lofted debris and a low-reflectivity eye, (iii) whether measurements were made within the lowest few hundred meters where centrifuged hydrometeors and smaller debris particles were recycled back into the tornadic circulation, and (iv) the presence or absence of multiple vortices in the parent tornado.

To explore the influences of some of these various factors on radar reflectivity and Doppler velocity signatures, a high-resolution tornado numerical model was used that incorporated the centrifuging of hydrometeors. A model reflectivity field was computed from the resulting concentration of hydrometeors. Then, the model reflectivity and velocity fields were scanned by a simulated Weather Surveillance Radar-1988 Doppler (WSR-88D) using both the legacy resolution and the new super-resolution sampling. Super-resolution reflectivity and Doppler velocity data are displayed at 0.5° instead of 1.0° azimuthal sampling intervals and reflectivity data are displayed at 0.25-km instead of 1.0-km range intervals.

Since a mean Doppler velocity value is the reflectivity-weighted mean of the radial motion of all the radar scatterers within a radar beam, a nonuniform distribution of scatterers produces a different mean Doppler velocity value than does a uniform distribution of scatterers. Nonuniform reflectivities within the effective resolution volume of the radar beam can bias the indicated size and strength of the tornado’s core region within the radius of the peak tangential velocities. As shown in the simulation results, the Doppler-indicated radius of the peak wind underestimates the true radius and true peak tangential velocity when the effective beamwidth is less than the tornado’s core diameter and there is a weak-reflectivity eye at the center of the tornado. As the beam becomes significantly wider than the tornado’s core diameter with increasing range, the peaks of the Doppler velocity profiles continue to decrease in magnitude but overestimate the tornado’s true radius. With increasing range from the radar, the prominence of the weak-reflectivity eye at the center of the tornado is progressively lessened until it finally disappears. As to be expected, the Doppler velocity signatures and reflectivity eye signatures were more prominent and stronger with super-resolution sampling than those with legacy-resolution sampling.