bluuebunny/crossref_metadata_2025 huggingface dataset:
Mobile Metal Ion
®
analysis of European agricultural soils: bioavailability, weathering, geogenic patterns and anthropogenic anomalies
Authors: Mann A. , Reimann C. , de Caritat P. , Turner N. , Birke M. ,   GEMAS Project Team
Published: November 2014

Two thousand one hundred and eight agricultural soils (0–20 cm depth) collected at a density of one sample per 2500 km
2
under the auspices of the Geochemical Mapping of Agricultural Soils (GEMAS) project over most of the European continent have been analysed using the Mobile Metal Ion (MMI
®
) partial extraction technique with ICP-MS finish. For a number of elements, notably Ce, Ni, and Ca, coherent geogenic patterns have been observed which relate to underlying lithology. For Fe and Al, coherent patterns are also observed but the effects of weathering are evident, and provide a mechanism to explain the acidity of soils in high rainfall areas. Individual anomalies, many related to anthropogenic activity (mining, metallurgy, agriculture) have been observed for Ag, Au, Cu, Pb, Cd and Zn. Comparison of the results with aqua regia digestion and the equivalent National Geochemistry Survey of Australia (NGSA) provides insights into weathering processes and the concept of bioavailability.
A comprehensive approach to understanding ore deposits using portable X-ray fluorescence (pXRF) data at the Plutonic Gold Mine, Western Australia
Authors: Gazley Michael F. , Duclaux Guillaume , Fisher Louise A. , Tutt Chelsea M. , Latham Aaron R. , Hough Rob M. , De Beer Sam J. , Taylor Mike D.
Published: November 2014

Since 2009 all underground face samples and diamond-drill core samples at the Plutonic Gold Mine (Plutonic), Marymia Inlier, Western Australia have been analysed by portable X-ray fluorescence (pXRF) following a systematic approach. This method is rapid and cost-effective and provides analyses of a large suite of chemical elements which can be used to characterize lithology and alteration. The delivery of a comprehensive workflow for sample preparation, analysis, results correction, and rapid processing enabled a quantum leap in the way mine geologists use geochemistry in modelling the ore body. Interpretation of the mine-site dataset of over 200 000 multi-element analyses has resulted in significant improvements in the understanding of the Plutonic deposit. In this contribution, we review how our understanding of Plutonic has been significantly improved through the use of pXRF geochemical analyses. Incorporation of pXRF data into routine geological modelling at Plutonic has resulted in improved confidence in the models of the ore bodies themselves and late-stage dolerite intrusives. It has allowed better management of milling processes through the development of metallurgical proxies and for significant insights into the role of stratigraphy in controlling the location of gold mineralization. We highlight the potential that a systematic approach to collecting pXRF data can have in a mining environment. These same techniques could be adapted and used in other mine and/or exploration settings.
Application of a multi-fractal model for identification of Cu, Au and Zn anomalies in Western Yunnan, Southwestern China
Authors: Huang Jingning , Zhao Peangda
Published: November 2014

Western Yunnan Province covers an area of about 220 000 km
2
in Southwestern China, and is located at the boundary between the Indian Plate and the Yangtze Plate. It is an important part of the Eastern Tethyan ore-forming belt. The region contains numerous base and precious metal deposits, including a few super-large ore deposits, such as the Pulang porphyry Cu deposit, the Beiya and the Laowangzhai hydrothermal Au deposits, and the Jinding MVT Pb-Zn deposit. It is difficult to decompose anomalies related to mineralization from the geochemical data with multi-patterns using conventional statistical methods, such as multi-variate statistical analysis. In this study, the spectrum-area (S-A) fractal method based on a multi-fractal model is adopted to separate anomalies from Cu, Zn and Au stream sediment data. The model results are as follows. Using the S-A method, both Cu and Au local anomalies can be effectively decomposed from the high geochemical backgrounds that arise from the Permian basalt, while the local geochemical anomalies of Zn are identified along a North-Northeast trend. The distribution patterns of local Cu, Au and Zn geochemical anomalies are useful for indicating areas where new deposits may exist. Regional and local anomaly maps of Cu were depicted based on different thresholds obtained from the log–log plot. We showed that multi-fractal methods effectively and efficiently decompose geochemical data with complicated patterns into different, meaningful indictor components compared to conventional statistical methods.
From tree-tops to massive sulphide in the Mabel Lake area, British Columbia, Canada
Authors: Dunn Colin E. , Thompson Robert I. , Hetherington Renée , Cornelius Matthias , Ringrose Christopher R.
Published: November 2014

Glacial deposits, dense vegetation and rugged terrain pose challenges to conventional mineral exploration in the Mabel Lake area of southern British Columbia, where metamorphosed schists, quartzites and calcareous rocks of the Monashee sequence are known to host significant Pb-Zn deposits such as Kingfisher and Ruddock Creek. In 2006, the Geological Survey of Canada conducted a reconnaissance tree-top sampling programme to provide a biogeochemical dataset for
c
. 700 km
2
of this region. Douglas-fir tree-top samples from 562 sample stations were collected from a helicopter, and analysis of the tissues indicated several Tl and Cd anomalies. Detailed follow-up sampling east of Mabel Lake using western hemlock bark confirmed a Tl anomaly extending
c
. 600 × 600 m. Data from these surveys were published but received little attention for several years until the area surrounding the main Tl anomaly was staked and detailed exploration commenced. Ah soil horizon sampling within the Tl anomaly identified multi-element anomalies including high concentrations of Mo and Zn. Indicator minerals from a few stream sediments included gahnite and goldmanite providing further evidence for the presence of base metal mineralization.

Follow-up work that involved 391 m of excavations along 3 parallel trenches revealed a gossan-rich zone, 10–35 m wide and >50 m long with best concentrations of 8.98% Zn (over 3 m); 580 ppb Re; 1339 ppm Mo, and anomalous concentrations of Cd, Cu, Bi, Ni, Pb, Sn, Tl, V and W. Subsequently, a HeliTEM® electromagnetic survey was flown over
c
. 12 km
2
of the contiguous claims and a small drilling programme has intersected Zn-rich massive sulphide. This grassroots study demonstrates the evolution of an exploration programme that started with a chronological order of: (a) reconnaissance biogeochemical survey; (b) detailed biogeochemistry; (c) Ah soil horizon geochemistry; (d) indicator mineral stream sediment survey; (e) trenching; (f) airborne geophysics; and (g) drilling that has identified significant base metal mineralization.
The zircon archive of continent formation through time
Authors: Roberts Nick M. W. , Spencer Christopher J.
Published: November 2014

The strong resilience of the mineral zircon and its ability to host a wealth of isotopic information make it the best deep-time archive of Earth's continental crust. Zircon is found in most felsic igneous rocks, can be precisely dated and can fingerprint magmatic sources; thus, it has been widely used to document the formation and evolution of continental crust, from pluton- to global-scale. Here, we present a review of major contributions that zircon studies have made in terms of understanding key questions involving the formation of the continents. These include the conditions of continent formation on early Earth, the onset of plate tectonics and subduction, the rate of crustal growth through time and the governing balance of continental addition v. continental loss, and the role of preservation bias in the zircon record.

Supplementary material:

A compilation used in this study of previously published detrital zircon U-Pb-Hf isotope data are available at
http://www.geolsoc.org.uk/SUP18791
Scalable and interactive visual computing in geosciences and reservoir engineering
Authors: Costa Sousa Mario , Vital Brazil Emilio , Sharlin Ehud
Published: November 2014

Visual computing technologies enable more intuitive data modelling, visualization and analysis, facilitating these processes by real-time interactive visual interfaces. These technologies are essential for software in the oil and gas industry, allowing users to gain insights and actionable information when dealing with increasingly complex, multidisciplinary datasets and processes. In the context of the oil and gas industry, interactive visual computing should also scale well with the growing data size and other components of a data analytics pipeline. We present key problems and challenges motivating the research and development of scalable and interactive visual computing systems, followed by a classification of the most important research themes and related topics. Eleven case studies developed with the industry are also presented, highlighting the main cutting edge findings, limitations and achievements.
Downregulation of adenine nucleotide translocator 1 exacerbates tumor necrosis factor-α-mediated cardiac inflammatory responses
Authors: Pan Shi , Wang Nadan , Bisetto Sara , Yi Bing , Sheu Shey-Shing
Published: November 2014

Inflammation contributes significantly to cardiac dysfunction. Although the initial phase of inflammation is essential for repair and healing, excessive proinflammatory cytokines are detrimental to the heart. We found that adenine nucleotide translocator isoform-1 (ANT1) protein levels were significantly decreased in the inflamed heart of C57BL/6 mice following cecal ligation and puncture. To understand the molecular mechanisms involved, we performed small-interfering RNA-mediated knockdown of ANT1 and studied tumor necrosis factor-α (TNFα)-induced inflammatory responses in myocardium-derived H9c2 cells and cardiomyocytes. ANT1 knockdown significantly increased swollen mitochondria and mitochondrial reactive oxygen species, concomitant with increased TNFα-induced NF-κB reporter gene activity and interleukin-6 and TNFα expression. A mitochondrial-targeted antioxidant mito-TEMPO attenuated TNFα-induced mitochondrial reactive oxygen species, NF-κB reporter gene activity, and cytokine expression in ANT1 knockdown cells. Interestingly, TNFα or lipopolysaccharide (LPS) treatment significantly decreased ANT1 protein levels, suggesting a feed-forward regulation of proinflammatory cytokine expression activated by ANT1 downregulation. These data suggest that ANT1 downregulation contributes to cardiac inflammation post-cecal ligation and puncture. Preventing ANT1 downregulation could provide a novel molecular target to temper cardiac inflammation.
SnoN as a novel negative regulator of TGF-β/Smad signaling: a target for tailoring organ fibrosis
Authors: Zeglinski Matthew R. , Hnatowich Mark , Jassal Davinder S. , Dixon Ian M. C.
Published: November 2014

Remodeling of the extracellular matrix is beneficial during the acute wound healing stage following tissue injury. In the short term, resident fibroblasts and myofibroblasts regulate the matrix remodeling process through production of matricellular protein components that provide structural support to the damaged tissue. This process is largely governed by the transforming growth factor-β1(TGF-β1) pathway, a critical mediator of the remodeling process. In the long term, chronic activation of the TGF-β1pathway promotes excessive synthesis and deposition of matrix proteins, including fibrillar collagens, which ultimately leads to organ failure. SnoN (and its alternatively-spliced isoforms SnoN2, SnoA, and SnoI) is one of four members of a family of negative regulators of TGF-β1signaling that includes Ski and functional Smad-suppressing elements on chromosomes 15 and 18. SnoN has been shown to be structurally and functionally similar to Ski and has been demonstrated to directly interact with Ski to abrogate gene expression. Despite this, little progress has been made in delineating a specific role for SnoN in the regulation of myofibroblast phenotype and function. This review outlines the current body of knowledge of what we refer to as the “Ski-Sno superfamily,” with a focus on the structural and functional importance of SnoN in mediating the fibrotic response by myofibroblasts following tissue injury.
Akt/eNOS signaling pathway mediates inhibition of endothelial progenitor cells by palmitate-induced ceramide
Authors: Fu Minghuan , Li Zhihong , Tan Tao , Guo Weixin , Xie Nanzi , Liu Qing , Zhu Hua , Xie Xiaoyun , Lei Han
Published: November 2014

Palmitate (PA) impairs endothelial progenitor cells (EPCs). However, the molecular mechanism underlying the suppressive function of PA remains largely unknown. Ceramide, a free fatty acid metabolite, mediates multiple cellular signals. We hypothesized that ceramide acts as an intermediate molecule to mediate inhibition of EPCs by PA. We first demonstrated that PA could inhibit the attachment, migration, and tube formation of EPCs through suppression of the Akt/endothelial nitric oxide (NO) synthase (eNOS) signaling pathway. In addition, we observed that PA could induce ceramide accumulation in EPCs. To test whether the accumulation of ceramide causes EPC dysfunction, the ceramide synthesis inhibitors myriocin and fumonisin B1 were used. We that found both inhibitors could effectively abolish PA-mediated EPC inhibition. Furthermore, the ceramide deacylation inhibitor N-oleoylethanolamine could augment the inhibitory effect of PA on EPCs, indicating that it is ceramide, not its metabolites, that mediates the suppression of EPCs by PA. We have previously shown that Akt/eNOS phosphorylation was reduced after PA treatment, which, in turn, hampered the normal bioavailability of NO, leading to impaired functions of EPCs. To test the role for ceramide in this process, a clinically used NO donor, sodium nitroprusside, was used. We found that sodium nitroprusside could rescue the suppressive effects of ceramide on EPCs, suggesting that ceramide-mediated EPC inhibition might be through reduction of NO production. Taken together, our findings indicated that ceramide-induced reduction of NO might be the molecular mechanism for PA-mediated EPC inhibition; thus, targeting either ceramide or NO production might be an effective means for improvement of EPC functions in diseases.
Distribution volumes of macromolecules in human ovarian and endometrial cancers—effects of extracellular matrix structure
Authors: Haslene-Hox Hanne , Oveland Eystein , Woie Kathrine , Salvesen Helga B. , Tenstad Olav , Wiig Helge
Published: November 2014

Elements of the extracellular matrix (ECM), notably collagen and glucosaminoglycans, will restrict part of the space available for soluble macromolecules simply because the molecules cannot occupy the same space. This phenomenon may influence macromolecular drug uptake. To study the influence of steric and charge effects of the ECM on the distribution volumes of macromolecules in human healthy and malignant gynecologic tissues we used as probes 15 abundant plasma proteins quantified by high-resolution mass spectrometry. The available distribution volume (VA) of albumin was increased in ovarian carcinoma compared with healthy ovarian tissue. Furthermore, VAof plasma proteins between 40 and 190 kDa decreased with size for endometrial carcinoma and healthy ovarian tissue, but was independent of molecular weight for the ovarian carcinomas. An effect of charge on distribution volume was only found in healthy ovaries, which had lower hydration and high collagen content, indicating that a condensed interstitium increases the influence of negative charges. A number of earlier suggested biomarker candidates were detected in increased amounts in malignant tissue, e.g., stathmin and spindlin-1, showing that interstitial fluid, even when unfractionated, can be a valuable source for tissue-specific proteins. We demonstrate that the distribution of abundant plasma proteins in the interstitium can be elucidated by mass spectrometry methods and depends markedly on hydration and ECM structure. Our data can be used in modeling of drug uptake, and give indications on ECM components to be targeted to increase the uptake of macromolecular substances.
Restoration of thyroid hormone balance: a game changer in the treatment of heart failure?
Authors: Gerdes A. Martin
Published: November 2014

The link between low thyroid hormone (TH) function and heart failure is reviewed in the present report. The idea that TH dysfunction may contribute to diseases leading to HF has been discussed for over 60 yr. A growing body of evidence from animal and human studies, particularly in recent years, suggests that TH treatment may improve clinical outcomes. Indeed, if a similar amount of positive information were available for a newly developed heart drug, there is little doubt that large-scale clinical trials would be underway with considerable excitement. THs offer the promise of improving ventricular contraction and relaxation, improving coronary blood flow, and inhibiting atherosclerosis, and new results suggest they may even reduce the incidence of arrhythmias in heart diseases. Are the potential clinical benefits worth the risk of possible overdosing? After so many years, why has this question not been answered? Clearly, the concept has not been disproven. This review explores the body of clinical evidence related to TH dysfunction and heart failure, discuss insights into pathophysiological, cellular, and molecular mechanisms provided by animal research, and discuss what is needed to resolve this long-standing issue in cardiology and move forward.
Muscarinic M3receptors on structural cells regulate cigarette smoke-induced neutrophilic airway inflammation in mice
Authors: Kistemaker Loes E. M. , van Os Ronald P. , Dethmers-Ausema Albertina , Bos I. Sophie T. , Hylkema Machteld N. , van den Berge Maarten , Hiemstra Pieter S. , Wess Jürgen , Meurs Herman , Kerstjens Huib A. M. , Gosens Reinoud
Published: November 2014

Anticholinergics, blocking the muscarinic M3receptor, are effective bronchodilators for patients with chronic obstructive pulmonary disease. Recent evidence from M3receptor-deficient mice (M3R−/−) indicates that M3receptors also regulate neutrophilic inflammation in response to cigarette smoke (CS). M3receptors are present on almost all cell types, and in this study we investigated the relative contribution of M3receptors on structural cells vs. inflammatory cells to CS-induced inflammation using bone marrow chimeric mice. Bone marrow chimeras (C56Bl/6 mice) were generated, and engraftment was confirmed after 10 wk. Thereafter, irradiated and nonirradiated control animals were exposed to CS or fresh air for four consecutive days. CS induced a significant increase in neutrophil numbers in nonirradiated and irradiated control animals (4- to 35-fold). Interestingly, wild-type animals receiving M3R−/−bone marrow showed a similar increase in neutrophil number (15-fold). In contrast, no increase in the number of neutrophils was observed in M3R−/−animals receiving wild-type bone marrow. The increase in keratinocyte-derived chemokine (KC) levels was similar in all smoke-exposed groups (2.5- to 5.0-fold). Microarray analysis revealed that fibrinogen-α and CD177, both involved in neutrophil migration, were downregulated in CS-exposed M3R−/−animals receiving wild-type bone marrow compared with CS-exposed wild-type animals, which was confirmed by RT-qPCR (1.6–2.5 fold). These findings indicate that the M3receptor on structural cells plays a proinflammatory role in CS-induced neutrophilic inflammation, whereas the M3receptor on inflammatory cells does not. This effect is probably not mediated via KC release, but may involve altered adhesion and transmigration of neutrophils via fibrinogen-α and CD177.
A critical review of the American Journal of Physiology-Lung Cellular and Molecular Physiology: 2012–2015
Authors: Matalon Sadis
Published: November 2014

I have had the privilege of serving as Editor-in-Chief of the American Journal of Physiology: Lung Cellular and Molecular Physiology from 1/1/2012 to 1/1/2015 and have been reappointed for another 3-year term. When I took over as editor, I published an editorial in AJP-Lung in which I highlighted my vision and outlined the tasks to be accomplished to transform AJP-Lung into “The best place to publish basic, translational, and hypothesis-driven clinical lung research.” Herein I review our accomplishments during the first term. As promised, we review each article submitted to this journal and our reviews always help the quality and impact of every paper. We recognized the contributions of junior authors by establishing a number of awards and increased the visibility of AJP-Lung by establishing Facebook and Blog electronic pages and sponsoring symposia in scientific meetings. Our impact factor increased from 3.523 in 2011 to 4.041 in 2012 and, thanks to our calls for papers, we are receiving large numbers of high-quality papers in all aspects of pulmonary cell biology and lung diseases. The best is yet to come.
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

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

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

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 < 0.0005 (χ2 test)]. HPV16 decreased from 14.9% to 8.7% (−41.6%; P < 0.0005) and HPV18 decreased from 7.9% to 4.3% (−45.6%; P < 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

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

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 < 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 < 0.001) and PC3 (P < 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 < 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

Background: 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

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

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

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

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

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

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.

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Mol Cancer Res; 13(3); 538–47. ©2014 AACR.
Measuring Residual Estrogen Receptor Availability during Fulvestrant Therapy in Patients with Metastatic Breast Cancer
Authors: van Kruchten Michel , de Vries Elisabeth G. , Glaudemans Andor W. , van Lanschot Meta C. , van Faassen Martijn , Kema Ido P. , Brown Myles , Schröder Carolien P. , de Vries Erik F. , Hospers Geke A.
Published: November 2014

It is unknown whether the current dose of fulvestrant, an estrogen receptor (ER) antagonist, is sufficient for maximal ER downregulation in patients with metastatic breast cancer. We performed a feasibility study to assess ER availability before and during fulvestrant. Sixteen patients with ER-positive metastatic breast cancer underwent positron emission tomography/computed tomography (PET/CT) at baseline (scan 1), day 28 (scan 2), and day 84 (scan 3) to monitor tumor [18F]fluoroestradiol (FES) uptake. Incomplete reduction in ER availability was predefined as <75% decrease in median tumor FES uptake and a residual standardized uptake value (SUVmax) of ≥1.5. In total, 131 FES-positive lesions were identified (median SUVmax of 2.9; range, 1.7–6.5). The median change in patients during fulvestrant treatment was −85% at scan 2, but varied widely (−99% to +60%). Fulvestrant reduced tumor FES uptake incompletely at scan 2 in 6 (38%) of the 16 patients, which was associated with early progression.

Significance: Serial imaging of tumor estrogen uptake by FES-PET can give insight into the dose needed for ER antagonists to completely abolish ER. FES-PET showed significant residual ER availability in tumors during fulvestrant therapy in 38% of patients, which was associated with early progression. Cancer Discov; 5(1); 72–81. ©2014 AACR.

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Relationship Between Catheter Contact Force and Radiofrequency Lesion Size and Incidence of Steam Pop in the Beating Canine Heart
Authors: Ikeda Atsushi , Nakagawa Hiroshi , Lambert Hendrik , Shah Dipen C. , Fonck Edouard , Yulzari Aude , Sharma Tushar , Pitha Jan V. , Lazzara Ralph , Jackman Warren M.
Published: November 2014

Background—

Electrode-tissue contact force (CF) is believed to be a major factor in radiofrequency lesion size. The purpose of this study was to determine, in the beating canine heart, the relationship between CF and radiofrequency lesion size and the accuracy of predicting CF and lesion size by measuring electrogram amplitude, impedance, and electrode temperature.

Methods and Results—

Eight dogs were studied closed chest. Using a 7F catheter with a 3.5 mm irrigated electrode and CF sensor (TactiCath, St. Jude Medical), radiofrequency applications were delivered to 3 separate sites in the right ventricle (30 W, 60 seconds, 17 mL/min irrigation) and 3 sites in the left ventricle (40 W, 60 seconds, 30 mL/min irrigation) at (1) low CF (median 8 g); (2) moderate CF (median 21 g); and (3) high CF (median 60 g). Dogs were euthanized and lesion size was measured. At constant radiofrequency and time, lesion size increased significantly with increasing CF (
P
<0.01). The incidence of a steam pop increased with both increasing CF and higher power. Peak electrode temperature correlated poorly with lesion size. The decrease in impedance during the radiofrequency application correlated well with lesion size for lesions in the left ventricle but less well for lesions in the right ventricle. There was a poor relationship between CF and the amplitude of the bipolar or unipolar ventricular electrogram, unipolar injury current, and impedance.

Conclusions—

Radiofrequencylesion size and the incidence of steam pop increase strikingly with increasing CF. Electrogram parameters and initial impedance are poor predictors of CF for radiofrequency ablation.