bluuebunny/crossref_metadata_2025_split huggingface dataset:
VEGF-Targeted Therapy Stably Modulates the Glycolytic Phenotype of Tumor Cells
Authors: Curtarello Matteo , Zulato Elisabetta , Nardo Giorgia , Valtorta Silvia , Guzzo Giulia , Rossi Elisabetta , Esposito Giovanni , Msaki Aichi , Pastò Anna , Rasola Andrea , Persano Luca , Ciccarese Francesco , Bertorelle Roberta , Todde Sergio , Plebani Mario , Schroer Henrike , Walenta Stefan , Mueller-Klieser Wolfgang , Amadori Alberto , Moresco Rosa Maria , Indraccolo Stefano 
Published: November 2014

Abstract
Anti-VEGF therapy perturbs tumor metabolism, severely impairing oxygen, glucose, and ATP levels. In this study, we investigated the effects of anti-VEGF therapy in multiple experimental tumor models that differ in their glycolytic phenotypes to gain insights into optimal modulation of the metabolic features of this therapy. Prolonged treatments induced vascular regression and necrosis in tumor xenograft models, with highly glycolytic tumors becoming treatment resistant more rapidly than poorly glycolytic tumors. By PET imaging, prolonged treatments yielded an increase in both hypoxic and proliferative regions of tumors. A selection for highly glycolytic cells was noted and this metabolic shift was stable and associated with increased tumor aggressiveness and resistance to VEGF blockade in serially transplanted mice. Our results support the hypothesis that the highly glycolytic phenotype of tumor cells studied in xenograft models, either primary or secondary, is a cell-autonomous trait conferring resistance to VEGF blockade. The finding that metabolic traits of tumors can be selected by antiangiogenic therapy suggests insights into the evolutionary dynamics of tumor metabolism. Cancer Res; 75(1); 120–33. ©2014 AACR.
The Cyclic AMP Pathway Is a Sex-Specific Modifier of Glioma Risk in Type I Neurofibromatosis Patients
Authors: Warrington Nicole M. , Sun Tao , Luo Jingqin , McKinstry Robert C. , Parkin Patricia C. , Ganzhorn Sara , Spoljaric Debra , Albers Anne C. , Merkelson Amanda , Stewart Douglas R. , Stevenson David A. , Viskochil David , Druley Todd E. , Forys Jason T. , Reilly Karlyne M. , Fisher Michael J. , Tabori Uri , Allen Jeffrey C. , Schiffman Joshua D. , Gutmann David H. , Rubin Joshua B. 
Published: November 2014

Abstract
Identifying modifiers of glioma risk in patients with type I neurofibromatosis (NF1) could help support personalized tumor surveillance, advance understanding of gliomagenesis, and potentially identify novel therapeutic targets. Here, we report genetic polymorphisms in the human adenylate cyclase gene adenylate cyclase 8 (ADCY8) that correlate with glioma risk in NF1 in a sex-specific manner, elevating risk in females while reducing risk in males. This finding extends earlier evidence of a role for cAMP in gliomagenesis based on results in a genetically engineered mouse model (Nf1 GEM). Thus, sexually dimorphic cAMP signaling might render males and females differentially sensitive to variation in cAMP levels. Using male and female Nf1 GEM, we found significant sex differences exist in cAMP regulation and in the growth-promoting effects of cAMP suppression. Overall, our results establish a sex-specific role for cAMP regulation in human gliomagenesis, specifically identifying ADCY8 as a modifier of glioma risk in NF1. Cancer Res; 75(1); 16–21. ©2014 AACR.
Change in Population Prevalences of Human Papillomavirus after Initiation of Vaccination: The High-Throughput HPV Monitoring Study
Authors: Söderlund-Strand Anna , Uhnoo Ingrid , Dillner Joakim 
Published: November 2014

Abstract
Background: Organized human papillomavirus (HPV) vaccination was introduced in Sweden in 2012. On-demand vaccination was in effect from 2006 to 2011. We followed the HPV prevalences in Southern Sweden from 2008 to 2013.
Methods: Consecutive, anonymized samples from the Chlamydia trachomatis screening were analyzed for HPV DNA for two low-risk types and 14 high-risk types using PCR with genotyping using mass spectrometry. We analyzed 44,146 samples in 2008, 5,224 in 2012, and 5,815 in 2013.
Results: Registry-determined HPV vaccination coverages of the population in Southern Sweden increased mainly among 13- to 22-year-old women. Most analyzed samples contained genital swabs from women and the HPV6 prevalence in these samples decreased from 7.0% in 2008 to 4.2% in 2013 [−40.0%; P &lt; 0.0005 (χ2 test)]. HPV16 decreased from 14.9% to 8.7% (−41.6%; P &lt; 0.0005) and HPV18 decreased from 7.9% to 4.3% (−45.6%; P &lt; 0.0005) among 13- to 22-year-old women. There were only small changes in vaccination coverage among 23- to 40-year-old women. In this age group, HPV18 decreased marginally (−19.6%; P = 0.04) and there were no significant changes for HPV6 or HPV16. Two nonvaccine HPV types (HPV52 and HPV56) were increased among 13- to 22-year-old women, both in 2012 and 2013.
Conclusions: A major reduction of HPV6, 16, and 18 prevalences is seen in the age groups with a concomitant increase in HPV vaccination coverage. The minor changes seen for nonvaccine types will require further investigation.
Impact: Monitoring of type-specific HPV prevalences may detect early effects of HPV vaccination. Cancer Epidemiol Biomarkers Prev; 23(12); 2757–64. ©2014 AACR.
Biomarkers of Exposure among U.S. Cigar Smokers: An Analysis of 1999–2012 National Health and Nutrition Examination Survey (NHANES) Data
Authors: Chen Jiping , Kettermann Anna , Rostron Brian L. , Day Hannah R. 
Published: November 2014

Abstract
Background: Cigar consumption is increasing in the United States, but little information is available about exposure to toxic constituents from cigar smoking.
Methods: We conducted a cross-sectional analysis of biomarkers of tobacco exposure among 25,522 participants from the National Health and Nutrition Examination Survey (NHANES, 1999–2012). The biomarkers analyzed were serum cotinine, urinary 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL), blood lead, blood cadmium, and urinary arsenic. We calculated geometric mean concentrations for each biomarker by tobacco use category and geometric mean ratios controlling for demographic factors.
Results: Cigar smokers had higher cotinine, NNAL, and lead concentrations than nontobacco users. The geometric mean concentration [95% confidence interval (CI)] of cotinine for primary cigar smokers (i.e., current cigar/never cigarette smokers) was 6.2 (4.2–9.2) ng/mL versus 0.045 (0.043–0.048) ng/mL for nontobacco users, and the NNAL concentration was 19.1 (10.6–34.3) pg/mg creatinine for primary cigar smokers versus 1.01 (0.95–1.07) pg/mg creatinine for nontobacco users. Secondary cigar smokers (i.e., current cigar/former cigarette smokers) and dual cigar/cigarette smokers had higher cadmium concentrations than nontobacco users. Cigar smoking was associated with significantly higher concentrations of cotinine, NNAL, cadmium, and lead, after adjusting for demographic factors. Secondary cigar smokers had significantly higher cotinine and NNAL concentrations than primary cigar smokers. The NNAL concentrations in daily cigar smokers were comparable with those in daily cigarette smokers.
Conclusions: Cigar smokers have higher concentrations of several toxic and carcinogenic substances than nontobacco users.
Impact: Our results are consistent with epidemiologic evidence demonstrating cigar smoking as a cause of disease and premature death. Cancer Epidemiol Biomarkers Prev; 23(12); 2906–15. ©2014 AACR.
18F-FAZA PET Imaging Response Tracks the Reoxygenation of Tumors in Mice upon Treatment with the Mitochondrial Complex I Inhibitor BAY 87-2243
Authors: Chang Edwin , Liu Hongguang , Unterschemmann Kerstin , Ellinghaus Peter , Liu Shuanglong , Gekeler Volker , Cheng Zhen , Berndorff Dietmar , Gambhir Sanjiv S. 
Published: November 2014

Abstract
Purpose: We describe a noninvasive PET imaging method that monitors early therapeutic efficacy of BAY 87-2243, a novel small-molecule inhibitor of mitochondrial complex I as a function of hypoxia-inducible factor-1α (HIF1α) activity.
Experimental Design: Four PET tracers [18F-FDG, 18F-Fpp(RGD)2, 18F-FLT, and 18F-FAZA] were assessed for uptake into tumor xenografts of drug-responsive (H460, PC3) or drug-resistant (786-0) carcinoma cells. Mice were treated with BAY 87-2243 or vehicle. At each point, RNA from treated and vehicle H460 tumor xenografts (n = 3 each) was isolated and analyzed for target genes.
Results: Significant changes in uptake of 18F-FAZA, 18F-FLT, and 18F-Fpp(RGD)2 (P &lt; 0.01) occurred with BAY 87-2243 treatment with 18F-FAZA being the most prominent. 18F-FDG uptake was unaffected. 18F-FAZA tumor uptake declined by 55% to 70% (1.21% ± 0.10%ID/g to 0.35 ± 0.1%ID/g; n = 6, vehicle vs. treatment) in both H460 (P &lt; 0.001) and PC3 (P &lt; 0.05) xenografts 1 to 3 days after drug administration. 18F-FAZA uptake in 786-0 xenografts was unaffected. Decline occurred before significant differences in tumor volume, thus suggesting 18F-FAZA decrease reflected early changes in tumor metabolism. BAY 87-2243 reduced expression of hypoxia-regulated genes CA IX, ANGPTL4, and EGLN-3 by 99%, 93%, and 83%, respectively (P &lt; 0.001 for all), which corresponds with reduced 18F-FAZA uptake upon drug treatment. Heterogeneous expression of genes associated with glucose metabolism, vessel density, and proliferation was observed.
Conclusions: Our studies suggest suitability of 18F-FAZA-PET as an early pharmacodynamic monitor on the efficacy of anticancer agents that target the mitochondrial complex I and intratumor oxygen levels (e.g., BAY 87-2243). Clin Cancer Res; 21(2); 335–46. ©2014 AACR.
Development of Circulating Tumor Cell-Endocrine Therapy Index in Patients with Hormone Receptor–Positive Breast Cancer
Authors: Paoletti Costanza , Muñiz Maria C. , Thomas Dafydd G. , Griffith Kent A. , Kidwell Kelley M. , Tokudome Nahomi , Brown Martha E. , Aung Kimberly , Miller M. Craig , Blossom Dorothy L. , Schott Anne F. , Henry N. Lynn , Rae James M. , Connelly Mark C. , Chianese David A. , Hayes Daniel F. 
Published: November 2014

AbstractBackground: Endocrine therapy (ET) fails to induce a response in one half of patients with hormone receptor (HR)–positive metastatic breast cancer (MBC), and almost all will eventually become refractory to ET. Circulating tumor cells (CTC) are associated with worse prognosis in patients with MBC, but enumeration alone is insufficient to predict the absolute odds of benefit from any therapy, including ET. We developed a multiparameter CTC-Endocrine Therapy Index (CTC-ETI), which we hypothesize may predict resistance to ET in patients with HR-positive MBC.Methods: The CTC-ETI combines enumeration and CTC expression of four markers: estrogen receptor (ER), B-cell lymphoma 2 (BCL-2), Human Epidermal Growth Factor Receptor 2 (HER2), and Ki67. The CellSearch System and reagents were used to capture CTC and measure protein expression by immunofluorescent staining on CTC.Results: The feasibility of determining CTC-ETI was initially established in vitro and then in a prospective single-institution pilot study in patients with MBC. CTC-ETI was successfully determined in 44 of 50 (88%) patients. Eighteen (41%), 9 (20%), and 17 (39%) patients had low, intermediate, and high CTC-ETI scores, respectively. Interobserver concordance of CTC-ETI determination was from 94% to 95% (Kappa statistic, 0.90–0.91). Inter- and cell-to-cell intrapatient heterogeneity of expression of each of the CTC markers was observed. CTC biomarker expression was discordant from both primary and metastatic tissues.Conclusions: CTC expression of ER, BCL-2, HER2, and Ki67 can be reproducibly measured with high analytical validity using the CellSearch System. The clinical implications of CTC-ETI, and of the heterogeneity of CTC biomarker expression, are being evaluated in an ongoing prospective trial. Clin Cancer Res; 21(11); 2487–98. ©2014 AACR.See related commentary by Mathew et al., p. 2421
Combination Strategy Targeting VEGF and HGF/c-met in Human Renal Cell Carcinoma Models
Authors: Ciamporcero Eric , Miles Kiersten Marie , Adelaiye Remi , Ramakrishnan Swathi , Shen Li , Ku ShengYu , Pizzimenti Stefania , Sennino Barbara , Barrera Giuseppina , Pili Roberto 
Published: November 2014

Abstract
Alternative pathways to the VEGF, such as hepatocyte growth factor or HGF/c-met, are emerging as key players in tumor angiogenesis and resistance to anti-VEGF therapies. The aim of this study was to assess the effects of a combination strategy targeting the VEGF and c-met pathways in clear cell renal cell carcinoma (ccRCC) models. Male SCID mice (8/group) were implanted with 786-O tumor pieces and treated with either a selective VEGF receptor tyrosine kinase inhibitor, axitinib (36 mg/kg, 2×/day); a c-met inhibitor, crizotinib (25 mg/kg, 1×/day); or combination. We further tested this drug combination in a human ccRCC patient–derived xenograft, RP-R-01, in both VEGF-targeted therapy-sensitive and -resistant models. To evaluate the resistant phenotype, we established an RP-R-01 sunitinib-resistant model by continuous sunitinib treatment (60 mg/kg, 1×/day) of RP-R-01–bearing mice. Treatment with single-agent crizotinib reduced tumor vascularization but failed to inhibit tumor growth in either model, despite also a significant increase of c-met expression and phosphorylation in the sunitinib-resistant tumors. In contrast, axitinib treatment was effective in inhibiting angiogenesis and tumor growth in both models, with its antitumor effect significantly increased by the combined treatment with crizotinib, independently from c-met expression. Combination treatment also induced prolonged survival and significant tumor growth inhibition in the 786-O human RCC model. Overall, our results support the rationale for the clinical testing of combined VEGF and HGF/c-met pathway blockade in the treatment of ccRCC, both in first- and second-line setting. Mol Cancer Ther; 14(1); 101–10. ©2014 AACR.
Enhanced Colonic Tumorigenesis in Alkaline Sphingomyelinase (NPP7) Knockout Mice
Authors: Chen Ying , Zhang Ping , Xu Shu-Chang , Yang Liping , Voss Ulrikke , Ekblad Eva , Wu Yunjin , Min Yalan , Hertervig Erik , Nilsson Åke , Duan Rui-Dong 
Published: November 2014

Abstract
Intestinal alkaline sphingomyelinase (alk-SMase) generates ceramide and inactivates platelet-activating factor (PAF) and was previously suggested to have anticancer properties. The direct evidence is still lacking. We studied colonic tumorigenesis in alk-SMase knockout (KO) mice. Formation of aberrant crypt foci (ACF) was examined after azoxymethane (AOM) injection. Tumor was induced by AOM alone, a conventional AOM/dextran sulfate sodium (DSS) treatment, and an enhanced AOM/DSS method. β-Catenin was determined by immunohistochemistry, PAF levels by ELISA, and sphingomyelin metabolites by mass spectrometry. Without treatment, spontaneous tumorigenesis was not identified but the intestinal mucosa appeared thicker in KO than in wild-type (WT) littermates. AOM alone induced more ACF in KO mice but no tumors 28 weeks after injection. However, combination of AOM/DSS treatments induced colonic tumors and the incidence was significantly higher in KO than in WT mice. By the enhanced AOM/DSS method, tumor number per mouse increased 4.5 times and tumor size 1.8 times in KO compared with WT mice. Although all tumors were adenomas in WT mice, 32% were adenocarcinomas in KO mice. Compared with WT mice, cytosol expression of β-catenin was significantly increased and nuclear translocation in tumors was more pronounced in KO mice. Lipid analysis showed decreased ceramide in small intestine and increased sphingosine-1-phosphate (S1P) in both small intestine and colon in nontreated KO mice. PAF levels in feces were significantly higher in the KO mice after AOM/DSS treatment. In conclusion, lack of alk-SMase markedly increases AOM/DSS–induced colonic tumorigenesis associated with decreased ceramide and increased S1P and PAF levels. Mol Cancer Ther; 14(1); 259–67. ©2014 AACR.
Bicyclic Peptides Conjugated to an Albumin-Binding Tag Diffuse Efficiently into Solid Tumors
Authors: Pollaro Lisa , Raghunathan Sandeep , Morales-Sanfrutos Julia , Angelini Alessandro , Kontos Stephan , Heinis Christian 
Published: November 2014

Abstract
Monoclonal antibodies have long in vivo half-lives and reach high concentrations in tumors but cannot access all regions in the tissue, whereas smaller ligands such as peptides distribute better but are limited by low concentrations due to fast renal clearance. A potential solution to this problem might be offered by peptide-based ligands that are conjugated to an albumin-binding tag, and thus have a long plasma half-life. Herein, we tested if a small ligand based on a bicyclic peptide (1.9 kDa) conjugated to an albumin-binding peptide (2.3 kDa) can diffuse into tissues. Although the peptide conjugate (4.6 kDa) was most of the time bound to the large protein serum albumin (66.5 kDa), it diffused deeply into tissues and reached high nanomolar concentrations in wide areas of solid tumors. Most of the peptide conjugate isolated from tumor tissue was found to be fully intact 24 hours after administration. Because of its noncovalent interaction with albumin, the bicyclic peptide might dissociate to diffuse to tumor regions that are not accessible to larger ligands. Bicyclic peptides having high binding affinity for targets of interest and being proteolytically stable can be evolved by phage display; in conjunction with albumin-binding tags, they offer a promising format to access targets in solid tumors. Mol Cancer Ther; 14(1); 151–61. ©2014 AACR.
Identifying Actionable Targets through Integrative Analyses of GEM Model and Human Prostate Cancer Genomic Profiling
Authors: Wanjala Jackie , Taylor Barry S. , Chapinski Caren , Hieronymus Haley , Wongvipat John , Chen Yu , Nanjangud Gouri J. , Schultz Nikolaus , Xie Yingqiu , Liu Shenji , Lu Wenfu , Yang Qing , Sander Chris , Chen Zhenbang , Sawyers Charles L. , Carver Brett S. 
Published: November 2014

Abstract
Copy-number alterations (CNA) are among the most common molecular events in human prostate cancer genomes and are associated with worse prognosis. Identification of the oncogenic drivers within these CNAs is challenging due to the broad nature of these genomic gains or losses which can include large numbers of genes within a given region. Here, we profiled the genomes of four genetically engineered mouse prostate cancer models that reflect oncogenic events common in human prostate tumors, with the goal of integrating these data with human prostate cancer datasets to identify shared molecular events. Met was amplified in 67% of prostate tumors from Pten p53 prostate conditional null mice and in approximately 30% of metastatic human prostate cancer specimens, often in association with loss of PTEN and TP53. In murine tumors with Met amplification, Met copy-number gain and expression was present in some cells but not others, revealing intratumoral heterogeneity. Forced MET overexpression in non–MET-amplified prostate tumor cells activated PI3K and MAPK signaling and promoted cell proliferation and tumor growth, whereas MET kinase inhibition selectively impaired the growth of tumors with Met amplification. However, the impact of MET inhibitor therapy was compromised by the persistent growth of non–Met-amplified cells within Met-amplified tumors. These findings establish the importance of MET in prostate cancer progression but reveal potential limitations in the clinical use of MET inhibitors in late-stage prostate cancer. Mol Cancer Ther; 14(1); 278–88. ©2014 AACR.
miR-629 Targets TRIM33 to Promote TGFβ/Smad Signaling and Metastatic Phenotypes in ccRCC
Authors: Jingushi Kentaro , Ueda Yuko , Kitae Kaori , Hase Hiroaki , Egawa Hiroshi , Ohshio Ikumi , Kawakami Ryoji , Kashiwagi Yuri , Tsukada Yohei , Kobayashi Takumi , Nakata Wataru , Fujita Kazutoshi , Uemura Motohide , Nonomura Norio , Tsujikawa Kazutake 
Published: November 2014

Abstract
Renal cell carcinoma (RCC) is the most common neoplasm of the adult kidney, and clear cell RCC (ccRCC) represents its most common histological subtype. To identify a therapeutic target for ccRCC, miRNA expression signatures from ccRCC clinical specimens were analyzed. miRNA microarray and real-time PCR analyses revealed that miR-629 expression was significantly upregulated in human ccRCC compared with adjacent noncancerous renal tissue. Functional inhibition of miR-629 by a hairpin miRNA inhibitor suppressed ccRCC cell motility and invasion. Mechanistically, miR-629 directly targeted tripartite motif-containing 33 (TRIM33), which inhibits the TGFβ/Smad signaling pathway. In clinical ccRCC specimens, downregulation of TRIM33 was observed with the association of both pathologic stages and grades. The miR-629 inhibitor significantly suppressed TGFβ-induced Smad activation by upregulating TRIM33 expression and subsequently inhibited the association of Smad2/3 and Smad4. Moreover, a miR-629 mimic enhanced the effect of TGFβ on the expression of epithelial–mesenchymal transition–related factors as well as on the motility and invasion in ccRCC cells. These findings identify miR-629 as a potent regulator of the TGFβ/Smad signaling pathway via TRIM33 in ccRCC.
Implications: This study suggests that miR-629 has biomarker potential through its ability to regulate TGFβ/Smad signaling and accelerate ccRCC cell motility and invasion. Mol Cancer Res; 13(3); 565–74. ©2014 AACR.
Survival Outcome and EMT Suppression Mediated by a Lectin Domain Interaction of Endo180 and CD147
Authors: Rodriguez-Teja Mercedes , Gronau Julian H. , Minamidate Ai , Darby Steven , Gaughan Luke , Robson Craig , Mauri Francesco , Waxman Jonathan , Sturge Justin 
Published: November 2014

Abstract
Epithelial cell–cell contacts maintain normal glandular tissue homeostasis, and their breakage can trigger epithelial-to-mesenchymal transition (EMT), a fundamental step in the development of metastatic cancer. Despite the ability of C-type lectin domains (CTLD) to modulate cell–cell adhesion, it is not known if they modulate epithelial adhesion in EMT and tumor progression. Here, the multi-CTLD mannose receptor, Endo180 (MRC2/uPARAP), was shown using the Kaplan–Meier analysis to be predictive of survival outcome in men with early prostate cancer. A proteomic screen of novel interaction partners with the fourth CTLD (CTLD4) in Endo180 revealed that its complex with CD147 is indispensable for the stability of three-dimensional acini formed by nontransformed prostate epithelial cells (PEC). Mechanistic study using knockdown of Endo180 or CD147, and treatment with an Endo180 mAb targeting CTLD4 (clone 39.10), or a dominant-negative GST-CTLD4 chimeric protein, induced scattering of PECs associated with internalization of Endo180 into endosomes, loss of E-cadherin (CDH1/ECAD), and unzipping of cell–cell junctions. These findings are the first to demonstrate that a CTLD acts as a suppressor and regulatory switch for EMT; thus, positing that stabilization of Endo180–CD147 complex is a viable therapeutic strategy to improve rates of prostate cancer survival.
Implications: This study identifies the interaction between CTLD4 in Endo180 and CD147 as an EMT suppressor and indicates that stabilization of this molecular complex improves prostate cancer survival rates.
Visual Overview: http://mcr.aacrjournals.org/content/13/3/538/F1.large.jpg
Mol Cancer Res; 13(3); 538–47. ©2014 AACR.