bluuebunny/crossref_metadata_2025 huggingface dataset:
Spatial and temporal relationships between Eocene sand horizons and iron contamination in stream water in the Thames Basin west of London, UK
Authors: Barrott J.J. , Dudeney A.W.L. , Mason P.J.
Published: August 2013

Analyses of stream water samples associated with Tertiary (Eocene) sands of the Bracklesham Formation 30–60 km west of London showed numerous occurrences of groundwater containing elevated iron(II) concentrations (1–15 mg/l Fe), which oxidise to red-brown ferrihydrite in localised wetlands and streams and join onward flows towards the River Thames. GIS mapping of iron concentrations in relation to topographical and geological data within a 20×30 km project area indicated some 168 km of iron-contaminated water.

The results are consistent with downward permeation of groundwater through contained Camberley, Windlesham and Bagshot sand horizons and predominant W-E groundwater flow of up to 35 km in the Bagshot horizon, which rests on impermeable London Clay. Glauconite, comprising up to 70% of the sand near the base of the Windlesham horizon, apparently provides the main source of soluble iron in the near-anoxic, near-neutral, conditions normally prevailing. Pyrite is also a possible source, especially where quarrying or other excavation releases water from previously isolated volumes, simultaneously causing elevated sulphate and acidity levels via relatively rapid sulphide oxidation. Mechanisms proposed are underpinned through comparison with reports on analogous systems in the UK and abroad.

Streams and lakes in the vicinity of seepages are highly visible and of decreased biodiversity. However, because of their natural origin, they are not subject to the same public concern and environmental control as compositionally similar near-neutral water from many former coal mines elsewhere - where iron derives primarily from pyrite. Also, while comparatively persistent, they appear destined for rapid depletion in geological terms: the unusual isolation of the sands until the Quaternary indicates a short leaching period and suggests a reason why iron-rich water from natural ferruginous sands is seldom of sufficient significance to be reported.
Application of staged factor analysis and logistic function to create a fuzzy stream sediment geochemical evidence layer for mineral prospectivity mapping
Authors: Yousefi Mahyar , Kamkar-Rouhani Abolghasem , Carranza Emmanuel John M.
Published: August 2013

Stream sediment geochemical data are usually subjected to methods of multivariate analysis (e.g. factor analysis) in order to extract an anomalous geochemical signature (factor) of the mineral deposit-type sought. A map of anomalous geochemical signature can be used as evidence, in combination with other layers of evidence, for mineral prospectivity mapping (MPM). Because factor analysis may yield more than one factor in a stream sediment dataset, it raises the challenge of how to recognize the factor that best indicates presence of the mineral deposit-type sought. In addition, MPM is faced with the challenge of how to assign weights to classes in a geochemical evidence map. Accordingly, a new approach is discussed in this paper for the extraction of significant anomalous geochemical signature of the mineral deposit-type sought and for assigning weights to anomaly classes in a geochemical evidence map. In this approach, we used a staged factor analysis and then applied a logistic function to transform factor scores representing an anomalous geochemical signature in order to derive a map of geochemical mineralisation prospectivity indices (GMPI) as a spatial evidence layer for MPM based on the theory of fuzzy sets and fuzzy logic. The GMPI is a fuzzy weight in the [0,1] range. We demonstrate the application of the GMPI for mapping prospectivity for Mississippi valley-type fluorite deposits in the Mazandaran province, north of Iran, which is a greenfield area.
Biogeochemical mapping of stream plants to trace acid sulphate soils: a comparison between water geochemistry and metal content in macrophytes
Authors: Öhlander Björn , Nordblad Fredrik , Lax Kaj , Ecke Frauke , Ingri Johan
Published: August 2013

The efficiency of biogeochemical mapping for identifying acid sulphate soils (AS soils) was studied by sampling and analysing water, transplanted aquatic moss (
Fontinalis antipyretica
) and leaves of the vascular plant
Calamagrostis purpurea
at two sites in a stream in northern Sweden with AS soils in its drainage area. One upstream sampling station (Mårtsmarken) was situated in an area dominated by till, and a downstream station (Persraningen) was situated in an area where AS soils are common. Metal contents in
F. antipyretica
and
C. purpurea
at these sites were compared to those in water (both unfiltered samples, and samples subjected to 0.22 µm membrane filtration and 1 kDa ultrafiltration to obtain data on metal speciation and its effects on uptake). Oxidation of sulphides with associated increases in acidity and release of metals were clearly reflected by differences in the water samples. At Persraningen the pH was lower than at Mårtsmarken, and the unfiltered concentrations of Al, Ca, Cd, Co, Cu, K, Mg, Mn, Ni, P, S, Sr, Y and Zn were higher. At the upstream station, Mårtsmarken, the suspended fraction was an important carrier of Fe and P, and the colloidal concentrations were higher than or similar to the dissolved concentrations for all determined elements except Na and K. At Persraningen the low pH resulted in changes of speciation, so that the dissolved concentrations were higher than the colloidal concentrations for most elements. For Al, As, Cr, Cu, Pb and Y, the dissolved and colloidal concentrations were similar. For Fe, the colloidal concentration was usually higher than the dissolved concentration, and suspended Fe was detected. Aluminium, Cr, Cu, Fe and Y concentrations were significantly higher in
Fontinalis antipyretica
at Persraningen than at Mårtsmarken. In addition, concentrations of Al and Fe in
C. purpurea
were significantly higher at Persraningen. Our results highlight the potential of biogeochemical mapping for predicting the occurrence of AS soils. A limitation is the strong pH dependence of the uptake of metals in the aquatic mosses resulting in that only a few of the elements typically occurring at high concentrations in waters draining AS soils are enriched in the macrophytes. A combination of maps showing both absolute concentrations and elemental ratios would be useful for this, including not only ratios of previously suggested utility (e.g. Y:Pb and Ni:Pb), but also others, such as Y:Ca, Al:Ca, Cu:Ca, Y:Mg, Al:Mg and Cu:Mg.
Introduction to special issue on alternatives to lecture in the computer science classroom
Authors: Grissom Scott
Published: August 2013

Active learning in the college classroom has long been promoted as more effective than traditional lecture. Increased adoption of these instructional practices is recommended in several prominent national reports as well as a new National Science Foundation program. The goal of this special issue is to share evidence-based instructional practices that have been applied to computer science education. Withcollaborative learning, students interact with each other to achieve a common learning goal.Peer Instructionis an active pedagogy pioneered in Physics education in which most lecture time is replaced with students answering carefully designed multiple-choice questions. Chemistry faculty developed and refined aninquiry-based pedagogycalled Process-Oriented Guided-Inquiry Learning (POGIL). The fields of Architecture and Fine Arts promote student collaboration instudio-based learning.
Exploiting content relevance and social relevance for personalized ad recommendation on internet TV
Authors: Wang Bo , Wang Jinqiao , Lu Hanqing
Published: August 2013

There have been not many interactions between the two dominant forms of mass communication: television and the Internet, while nowadays the appearance of Internet television makes them more closely. Different with traditional TV in a passive mode of transmission, Internet TV makes it more possible to make personalized service recommendation because of the interactivity between users and the Internet. In this article, we introduce a scheme to provide targeted ad recommendation to Internet TV users by exploiting the content relevance and social relevance. First, we annotate TV videos in terms of visual content analysis and textual analysis by aligning visual and textual information. Second, with user-user, video-video and user-video relationships, we employ Multi-Relationship based Probabilistic Matrix Factorization (MRPMF) to learn representative tags for modeling user preference. And then semantic content relevance (between product/ad and TV video) and social relevance (between product/ad and user interest) are calculated by projecting the corresponding tags into our advertising concept space. Finally, with relevancy scores we make ranking for relevant product/ads to effectively provide users personalized recommendation. The experimental results demonstrate attractiveness and effectiveness of our proposed approach.
Nox2 as a potential target of mitochondrial superoxide and its role in endothelial oxidative stress
Authors: Nazarewicz Rafal R. , Dikalova Anna E. , Bikineyeva Alfiya , Dikalov Sergey I.
Published: August 2013

Superoxide (O2·−) production by the NADPH oxidases is implicated in the pathogenesis of many cardiovascular diseases, including hypertension. We have previously shown that activation of NADPH oxidases increases mitochondrial O2·−which is inhibited by the ATP-sensitive K+channel (mitoKATP) inhibitor 5-hydroxydecanoic acid and that scavenging of mitochondrial or cytoplasmic O2·−inhibits hypertension. We hypothesized that mitoKATP-mediated mitochondrial O2·−potentiates cytoplasmic O2·−by stimulation of NADPH oxidases. In this work we studied Nox isoforms as a potential target of mitochondrial O2·−. We tested contribution of reverse electron transfer (RET) from complex II to complex I in mitochondrial O2·−production and NADPH oxidase activation in human aortic endothelial cells. Activation of mitoKATPwith low dose of diazoxide (100 nM) decreased mitochondrial membrane potential (tetramethylrhodamine methyl ester probe) and increased production of mitochondrial and cytoplasmic O2·−measured by site-specific probes and mitoSOX. Inhibition of RET with complex II inhibitor (malonate) or complex I inhibitor (rotenone) attenuated the production of mitochondrial and cytoplasmic O2·−. Supplementation with a mitochondria-targeted SOD mimetic (mitoTEMPO) or a mitochondria-targeted glutathione peroxidase mimetic (mitoEbselen) inhibited production of mitochondrial and cytoplasmic O2·−. Inhibition of Nox2 (gp91ds) or Nox2 depletion with small interfering RNA but not Nox1, Nox4, or Nox5 abolished diazoxide-induced O2·−production in the cytoplasm. Treatment of angiotensin II-infused mice with RET inhibitor dihydroethidium (malate) significantly reduced blood pressure. Our study suggests that mitoKATP-mediated mitochondrial O2·−stimulates cytoplasmic Nox2, contributing to the development of endothelial oxidative stress and hypertension.
Endothelial cell transfusion ameliorates endothelial dysfunction in 5/6 nephrectomized rats
Authors: Pacurari Maricica , Xing Dongqi , Hilgers Rob H. P. , Guo Yuan Yuan , Yang Zhengqin , Hage Fadi G.
Published: August 2013

Endothelial dysfunction is prevalent in chronic kidney disease. This study tested the hypothesis that transfusion of rat aortic endothelial cells (ECs) ameliorates endothelial dysfunction in a rat model of chronic kidney disease. Male Sprague-Dawley rats underwent sham surgery or 5/6 nephrectomy (Nx). Five weeks after Nx, EC (1.5 × 106cells/rat) or vehicle were transfused intravenously. One week later, vascular reactivity of mesenteric artery was assessed on a wire myograph. Sensitivity of endothelium-dependent relaxation to acetylcholine and maximum vasodilation were impaired by Nx and improved by EC transfusion. Using selective pharmacological nitric oxide synthase isoform inhibitors, we demonstrated that the negative effect of Nx on endothelial function and rescue by EC transfusion are, at least in part, endothelial nitric oxide synthase mediated. Plasma asymmetric dimethylarginine was increased by Nx and decreased by EC transfusion, whereas mRNA expression of dimethylarginine dimethylaminohydrolases 1 (DDAH1) was decreased by Nx and restored by EC transfusion. Immunohistochemical staining confirmed that local expression of DDAH1 is decreased by Nx and increased by EC transfusion. In conclusion, EC transfusion attenuates Nx-induced endothelium-dependent vascular dysfunction by regulating DDAH1 expression and enhancing endothelial nitric oxide synthase activity. These results suggest that EC-based therapy could provide a novel therapeutic strategy to improve vascular function in chronic kidney disease.
Synergistic effects of hypertension and aging on cognitive function and hippocampal expression of genes involved in β-amyloid generation and Alzheimer's disease
Authors: Csiszar Anna , Tucsek Zsuzsanna , Toth Peter , Sosnowska Danuta , Gautam Tripti , Koller Akos , Deak Ferenc , Sonntag William E. , Ungvari Zoltan
Published: August 2013

Strong epidemiological and experimental evidence indicate that hypertension in the elderly predisposes to the development of Alzheimer's disease (AD), but the underlying mechanisms remain elusive. The present study was designed to characterize the additive/synergistic effects of hypertension and aging on the expression of genes involved in β-amyloid generation and AD in the hippocampus, an area of brain contributing to higher cognitive function, which is significantly affected by AD both in humans and in mouse models of the disease. To achieve that goal, we induced hypertension in young (3 mo) and aged (24 mo) C57BL/6 mice by chronic (4 wk) infusion of angiotensin II and assessed changes in hippocampal mRNA expression of genes involved in amyloid precursor protein (APP)-dependent signaling, APP cleavage, Aβ processing and Aβ-degradation, synaptic function, dysregulation of microtubule-associated τ protein, and apolipoprotein-E signaling. Aged hypertensive mice exhibited spatial memory impairments in the Y-maze and impaired performance in the novel object recognition assay. Surprisingly, hypertension in aging did not increase the expression of APP, β- and γ-secretases, or genes involved in tauopathy. These genes are all involved in the early onset form of AD. Yet, hypertension in aging was associated with changes in hippocampal expression of APP binding proteins, e.g., [Mint3/amyloid β A4 precursor protein-binding family A member 3 (APBA3), Fe65/amyloid β A4 precursor protein-binding family B member 1 (APBB1)], amyloid β (A4) precursor-like protein 1 (APLP1), muscarinic M1 receptor, and serum amyloid P component, all of which may have a role in the pathogenesis of late-onset AD. The hippocampal gene expression signature observed in aged hypertensive mice in the present study provides important clues for subsequent studies to elucidate the mechanisms by which hypertension may contribute to the pathogenesis and clinical manifestation of AD.
Quantitative optical imaging of vascular response in vivo in a model of peripheral arterial disease
Authors: Poole Kristin M. , Tucker-Schwartz Jason M. , Sit Wesley W. , Walsh Alex J. , Duvall Craig L. , Skala Melissa C.
Published: August 2013

The mouse hind limb ischemia (HLI) model is well established for studying collateral vessel formation and testing therapies for peripheral arterial disease, but there is a lack of quantitative techniques for intravitally analyzing blood vessel structure and function. To address this need, non-invasive, quantitative optical imaging techniques were developed to assess the time-course of recovery in the mouse HLI model. Hyperspectral imaging and optical coherence tomography (OCT) were used to non-invasively image hemoglobin oxygen saturation and microvessel morphology plus blood flow, respectively, in the anesthetized mouse after induction of HLI. Hyperspectral imaging detected significant increases in hemoglobin saturation in the ischemic paw as early as 3 days after femoral artery ligation ( P < 0.01), and significant increases in distal blood flow were first detected with OCT 14 days postsurgery ( P < 0.01). Intravital OCT images of the adductor muscle vasculature revealed corkscrew collateral vessels characteristic of the arteriogenic response to HLI. The hyperspectral imaging and OCT data significantly correlated with each other and with laser Doppler perfusion imaging (LDPI) and tissue oxygenation sensor data ( P < 0.01). However, OCT measurements acquired depth-resolved information and revealed more sustained flow deficits following surgery that may be masked by more superficial measurements (LDPI, hyperspectral imaging). Therefore, intravital OCT may provide a robust biomarker for the late stages of ischemic limb recovery. This work validates non-invasive acquisition of both functional and morphological data with hyperspectral imaging and OCT. Together, these techniques provide cardiovascular researchers an unprecedented and comprehensive view of the temporal dynamics of HLI recovery in living mice.
LPS Increases MUC5AC by TACE/TGF-α/EGFR Pathway in Human Intrahepatic Biliary Epithelial Cell
Authors: Liu Zipei , Tian Feng , Feng Xiaobin , He Yu , Jiang Peng , Li Jianwei , Guo Fei , Zhao Xin , Chang Hong , Wang Shuguang
Published: August 2013

Background. Mucin 5AC (MUC5AC) overproduction plays important roles in stone formation and recurrence of hepatolithiasis. We aim to investigate the involved mechanism and the potential target to block this process.Methods. 42 bile duct samples from hepatolithiasis and 15 normal bile duct samples from hemangioma patients were collected for detecting MUC5AC expression by immunohistochemistry. MUC5AC and phosphoepidermal growth factor receptor (pEGFR) expressions in human intrahepatic biliary epithelial cells (HIBECs) cultured with or without lipopolysaccharide (LPS) were detected by real-time PCR and western blot analysis. Transforming growth factor-α(TGF-α) secretion in HIBECs was detected by ELISA.Results. MUC5AC was overexpressed in bile ducts of hepatolithiasis samples compared with bile ducts from hemangioma samples. LPS upregulated MUC5AC expression in HIBECs. LPS promoted EGFR activation, and inhibiting EGFR activation by AG1478 significantly decreased LPS-induced MUC5AC overexpression in HIBECs. Moreover, LPS increased TGF-αsecretion, and inhibiting tumor necrosis factor-αconverting enzyme (TACE), which has been implicated in ectodomain cleavage of TGF-α, significantly inhibited LPS-induced EGFR activation and subsequent MUC5AC overexpression in HIBECs.Conclusion. Our results suggested that LPS increases MUC5AC expression through the TACE/TGF-α/EGFR pathway in HIBECs. This new finding might give light to the prevention of stone formation and recurrence of hepatolithiasis.
Comparison of Engine Simulation Software for Development of Control System
Authors: Chan KinYip , Ordys Andrzej , Volkov Konstantin , Duran Olga
Published: August 2013

Most commonly used commercial engine simulation packages generate detailed estimation of the combustion and gas flow parameters. These parameters are required for advanced research on fluid flow and heat transfer and development of geometries of engine components. However, engine control involves different operating parameters. Various sensors are installed into the engine, the combustion performance is recorded, and data is sent to engine control unit (ECU). ECU computes the new set of parameters to make fine adjustments to actuators providing better engine performance. Such techniques include variable valve timing, variable ignition timing, variable air to fuel ratio, and variable compression ratio. In the present study, two of the commercial packages, Ricardo Wave and Lotus Engine Simulation, have been tested on the capabilities for engine control purposes. These packages are compared with an in-house developed package and with reference results available from the literature. Different numerical experiments have been carried out from which it can be concluded that all packages predict similar profiles of pressure and temperature in the engine cylinder. Moreover, those are in reasonable agreement with the reference results while in-house developed package is possible to run simulations with changing speed for engine control purpose.
Mechanisms of Nanoparticle-Induced Oxidative Stress and Toxicity
Authors: Manke Amruta , Wang Liying , Rojanasakul Yon
Published: August 2013

The rapidly emerging field of nanotechnology has offered innovative discoveries in the medical, industrial, and consumer sectors. The unique physicochemical and electrical properties of engineered nanoparticles (NP) make them highly desirable in a variety of applications. However, these novel properties of NP are fraught with concerns for environmental and occupational exposure. Changes in structural and physicochemical properties of NP can lead to changes in biological activities including ROS generation, one of the most frequently reported NP-associated toxicities. Oxidative stress induced by engineered NP is due to acellular factors such as particle surface, size, composition, and presence of metals, while cellular responses such as mitochondrial respiration, NP-cell interaction, and immune cell activation are responsible for ROS-mediated damage. NP-induced oxidative stress responses are torch bearers for further pathophysiological effects including genotoxicity, inflammation, and fibrosis as demonstrated by activation of associated cell signaling pathways. Since oxidative stress is a key determinant of NP-induced injury, it is necessary to characterize the ROS response resulting from NP. Through physicochemical characterization and understanding of the multiple signaling cascades activated by NP-induced ROS, a systemic toxicity screen with oxidative stress as a predictive model for NP-induced injury can be developed.
Hbo1 Is a Cyclin E/CDK2 Substrate That Enriches Breast Cancer Stem-like Cells
Authors: Duong MyLinh T. , Akli Said , Macalou Sira , Biernacka Anna , Debeb Bisrat G. , Yi Min , Hunt Kelly K. , Keyomarsi Khandan
Published: August 2013

Expression of cyclin E proteolytic cleavage products, low-molecular weight cyclin E (LMW-E), is associated with poor clinical outcome in patients with breast cancer and it enhances tumorigenecity in mouse models. Here we report that LMW-E expression in human mammary epithelial cells induces an epithelial-to-mesenchymal transition phenotype, increases the CD44hi/CD24lo population, enhances mammosphere formation, and upregulates aldehyde dehydrogenase expression and activity. We also report that breast tumors expressing LMW-E have a higher proportion of CD44hi/CD24lo tumor cells as compared with tumors expressing only full-length cyclin E. In order to explore how LMW-E enriches cancer stem cells in breast tumors, we conducted a protein microarray analysis that identified the histone acetyltransferase (HAT) Hbo1 as a novel cyclin E/CDK2 substrate. The LMW-E/CDK2 complex phosphorylated Hbo1 at T88 without affecting its HAT activity. When coexpressed with LMW-E/CDK2, wild-type Hbo1 promoted enrichment of cancer stem-like cells (CSC), whereas the T88 Hbo1 mutant reversed the CSC phenotype. Finally, doxorubicin and salinomycin (a CSC-selective cytotoxic agent) synergized to kill cells expressing LMW-E, but not full-length cyclin E. Collectively, our results suggest that the heightened oncogenecity of LMW-E relates to its ability to promote CSC properties, supporting the design of therapeutic strategies to target this unique function. Cancer Res; 73(17); 5556–68. ©2013 AACR.
Formalizing an Integrative, Multidisciplinary Cancer Therapy Discovery Workflow
Authors: McGuire Mary F. , Enderling Heiko , Wallace Dorothy I. , Batra Jaspreet , Jordan Marie , Kumar Sushil , Panetta John C. , Pasquier Eddy
Published: August 2013

Although many clinicians and researchers work to understand cancer, there has been limited success to effectively combine forces and collaborate over time, distance, data, and budget constraints. Here we present a workflow template for multidisciplinary cancer therapy that was developed during the 2nd Annual Workshop on Cancer Systems Biology sponsored by Tufts University, Boston, Massachusetts, in July 2012. The template was applied to the development of a metronomic therapy backbone for neuroblastoma. Three primary groups were identified: clinicians, biologists, and quantitative scientists (mathematicians, computer scientists, and engineers). The workflow described their integrative interactions; parallel or sequential processes; data sources and computational tools at different stages as well as the iterative nature of therapeutic development from clinical observations to in vitro, in vivo, and clinical trials. We found that theoreticians in dialog with experimentalists could develop calibrated and parameterized predictive models that inform and formalize sets of testable hypotheses, thus speeding up discovery and validation while reducing laboratory resources and costs. The developed template outlines an interdisciplinary collaboration workflow designed to systematically investigate the mechanistic underpinnings of a new therapy and validate that therapy to advance development and clinical acceptance. Cancer Res; 73(20); 6111–7. ©2013 AACR.
Adenomatous Polyps Are Driven by Microbe-Instigated Focal Inflammation and Are Controlled by IL-10–Producing T Cells
Authors: Dennis Kristen L. , Wang Yunwei , Blatner Nichole R. , Wang Shuya , Saadalla Abdulrahman , Trudeau Erin , Roers Axel , Weaver Casey T. , Lee James J. , Gilbert Jack A. , Chang Eugene B. , Khazaie Khashayarsha
Published: August 2013

Interleukin (IL)-10 is elevated in cancer and is thought to contribute to immune tolerance and tumor growth. Defying these expectations, the adoptive transfer of IL-10–expressing T cells to mice with polyposis attenuates microbial-induced inflammation and suppresses polyposis. To gain better insights into how IL-10 impacts polyposis, we genetically ablated IL-10 in T cells in APCΔ468 mice and compared the effects of treatment with broad-spectrum antibiotics. We found that T cells and regulatory T cells (Treg) were a major cellular source of IL-10 in both the healthy and polyp-bearing colon. Notably, T cell–specific ablation of IL-10 produced pathologies that were identical to mice with a systemic deficiency in IL-10, in both cases increasing the numbers and growth of colon polyps. Eosinophils were found to densely infiltrate colon polyps, which were enriched similarly for microbiota associated previously with colon cancer. In mice receiving broad-spectrum antibiotics, we observed reductions in microbiota, inflammation, and polyposis. Together, our findings establish that colon polyposis is driven by high densities of microbes that accumulate within polyps and trigger local inflammatory responses. Inflammation, local microbe densities, and polyp growth are suppressed by IL-10 derived specifically from T cells and Tregs. Cancer Res; 73(19); 5905–13. ©2013 AACR.
Predicting Cancer Prognosis Using Interactive Online Tools: A Systematic Review and Implications for Cancer Care Providers
Authors: Rabin Borsika A. , Gaglio Bridget , Sanders Tristan , Nekhlyudov Larissa , Dearing James W. , Bull Sheana , Glasgow Russell E. , Marcus Alfred
Published: August 2013

Cancer prognosis is of keen interest for patients with cancer, their caregivers, and providers. Prognostic tools have been developed to guide patient–physician communication and decision-making. Given the proliferation of prognostic tools, it is timely to review existing online cancer prognostic tools and discuss implications for their use in clinical settings. Using a systematic approach, we searched the Internet, Medline, and consulted with experts to identify existing online prognostic tools. Each was reviewed for content and format. Twenty-two prognostic tools addressing 89 different cancers were identified. Tools primarily focused on prostate (n = 11), colorectal (n = 10), breast (n = 8), and melanoma (n = 6), although at least one tool was identified for most malignancies. The input variables for the tools included cancer characteristics (n = 22), patient characteristics (n = 18), and comorbidities (n = 9). Effect of therapy on prognosis was included in 15 tools. The most common predicted outcome was cancer-specific survival/mortality (n = 17). Only a few tools (n = 4) suggested patients as potential target users. A comprehensive repository of online prognostic tools was created to understand the state-of-the-art in prognostic tool availability and characteristics. Use of these tools may support communication and understanding about cancer prognosis. Dissemination, testing, refinement of existing, and development of new tools under different conditions are needed. Cancer Epidemiol Biomarkers Prev; 22(10); 1645–56. ©2013 AACR.
Breast Implants and Anaplastic Large-Cell Lymphoma: A Danish Population-Based Cohort Study
Authors: Vase Maja Ølholm , Friis Søren , Bautz Andrea , Bendix Knud , Sørensen Henrik Toft , d'Amore Francesco
Published: August 2013

Background: A potential link between breast implants and anaplastic large-cell lymphoma (ALCL) has been suggested.

Methods: We examined lymphoma occurrence in a nationwide cohort of 19,885 Danish women who underwent breast implant surgery during 1973–2010. Standardized incidence ratios (SIR), with 95% confidence intervals (CI), for ALCL and lymphoma overall associated with breast implantation were calculated.

Results: During 179,246 person-years of follow-up, we observed 31 cases of lymphoma among cohort members. No cases of ALCL were identified. SIRs for ALCL and lymphoma overall were zero (95% CI, 0–10.3) and 1.20 (95% CI, 0.82–1.70), respectively.

Conclusions: In our nationwide cohort study, we did not find an increased risk of lymphoma in general, or ALCL in particular, among Danish women who underwent breast implantation. However, our evaluation of ALCL risk was limited by the rarity of the disease.

Impact: Our results do not support an association between breast implants and ALCL and are consistent with other studies on cancer risk and breast implants. Cancer Epidemiol Biomarkers Prev; 22(11); 2126–9. ©2013 AACR.
Cumulative Genetic Risk Predicts Platinum/Taxane-Induced Neurotoxicity
Authors: McWhinney-Glass Sarah , Winham Stacey J. , Hertz Daniel L. , Yen Revollo Jane , Paul Jim , He Yijing , Brown Robert , Motsinger-Reif Alison A. , McLeod Howard L. ,   For the Scottish Gynaecological Clinical Trials Group
Published: August 2013

Purpose: The combination of a platinum and taxane are standard of care for many cancers, but the utility is often limited due to debilitating neurotoxicity. We examined whether single-nucleotide polymorphisms (SNP) from annotated candidate genes will identify genetic risk for chemotherapy-induced neurotoxicity.

Patients and Methods: A candidate–gene association study was conducted to validate the relevance of 1,261 SNPs within 60 candidate genes in 404 ovarian cancer patients receiving platinum/taxane chemotherapy on the SCOTROC1 trial. Statistically significant variants were then assessed for replication in a separate 404 patient replication cohort from SCOTROC1.

Results: Significant associations with chemotherapy-induced neurotoxicity were identified and replicated for four SNPs in SOX10, BCL2, OPRM1, and TRPV1. The population attributable risk for each of the four SNPs ranged from 5% to 35%, with a cumulative risk of 62%. According to the multiplicative model, the odds of developing neurotoxicity increase by a factor of 1.64 for every risk genotype. Patients possessing three risk variants have an estimated OR of 4.49 (2.36–8.54) compared to individuals with 0 risk variants. Neither the four SNPs nor the risk score were associated with progression-free survival or overall survival.

Conclusions: This study shows that SNPs in four genes have a significant cumulative association with increased risk for the development of chemotherapy-induced neurotoxicity, independent of patient survival. Clin Cancer Res; 19(20); 5769–76. ©2013 AACR.
Overexpression of Asparagine Synthetase and Matrix Metalloproteinase 19 Confers Cisplatin Sensitivity in Nasopharyngeal Carcinoma Cells
Authors: Liu Ran-Yi , Dong Zizheng , Liu Jianguo , Zhou Ling , Huang Wenlin , Khoo Sok Kean , Zhang Zhongfa , Petillo David , Teh Bin Tean , Qian Chao-Nan , Zhang Jian-Ting
Published: August 2013

Platinum-based concurrent chemoradiotherapy is considered a standard treatment approach for locoregionally advanced nasopharyngeal carcinoma. However, only a minority of patients benefit from this treatment regimen compared with radiotherapy alone. Identification of a set of molecular markers predicting sensitivity of platinum-based chemotherapy may contribute to personalized treatment of patients with nasopharyngeal carcinoma for better clinical outcome with less toxicity. Previously, we generated a cisplatin-sensitive nasopharyngeal carcinoma cell line, S16, by clonal selection from CNE-2 cells and found that eIF3a is upregulated and contributes to cisplatin sensitivity by downregulating the synthesis of nucleotide excision repair proteins. In this study, we conducted a gene expression profiling analysis and found three other genes, asparagine synthetase (ASNS), choriogonadotropin α subunit (CGA), and matrix metalloproteinase 19 (MMP19), that are upregulated in the cisplatin-sensitive S16 cells compared with the CNE-2 cells. However, only ASNS and MMP19, but not CGA, contributes to cisplatin sensitivity by potentiating cisplatin-induced DNA damage and apoptosis. Thus, ASNS and MMP19, along with eIF3a, are the sensitivity factors for cisplatin treatment and may serve as potential candidate molecular markers for predicting cisplatin sensitivity of advanced nasopharyngeal carcinoma. Mol Cancer Ther; 12(10); 2157–66. ©2013 AACR.
Contribution of ATM and ATR to the Resistance of Glioblastoma and Malignant Melanoma Cells to the Methylating Anticancer Drug Temozolomide
Authors: Eich Marcus , Roos Wynand Paul , Nikolova Teodora , Kaina Bernd
Published: August 2013

The major cytotoxic DNA adduct induced by temozolomide and other methylating agents used in malignant glioma and metastasized melanoma therapy is O6-methylguanine (O6-MeG). This primary DNA damage is converted by mismatch repair into secondary lesions, which block replication and in turn induce DNA double-strand breaks that trigger the DNA damage response (DDR). Key upstream players in the DDR are the phosphoinositide 3-kinases ataxia telangiectasia mutated (ATM) and ataxia telangiectasia and Rad3 related (ATR). Here, we addressed the question of the importance of ATM and ATR in the cell death response following temozolomide. We show that (i) ATM- and ATR-mutated cells are hypersensitive to temozolomide, (ii) O6-MeG triggers ATM and ATR activation, (iii) knockdown of ATM and ATR enhances cell kill in gliobalstoma and malignant melanoma cells with a stronger and significant effect in ATR knockdown cells, (iv) ATR, but not ATM, knockdown abolished phosphorylation of H2AX, CHK1, and CHK2 in glioma cells, and (v) temozolomide-induced cell death was more prominently enhanced by pharmacologic inhibition of CHK1 compared with CHK2. The data suggest that ATM and, even better, ATR inhibition is a useful strategy in sensitizing cancer cells to temozolomide and presumably also other anticancer drugs. Mol Cancer Ther; 12(11); 2529–40. ©2013 AACR.
Mechanism-Based Epigenetic Chemosensitization Therapy of Diffuse Large B-Cell Lymphoma
Authors: Clozel Thomas , Yang ShaoNing , Elstrom Rebecca L. , Tam Wayne , Martin Peter , Kormaksson Matthias , Banerjee Samprit , Vasanthakumar Aparna , Culjkovic Biljana , Scott David W. , Wyman Sarah , Leser Micheal , Shaknovich Rita , Chadburn Amy , Tabbo Fabrizio , Godley Lucy A. , Gascoyne Randy D. , Borden Katherine L. , Inghirami Giorgio , Leonard John P. , Melnick Ari , Cerchietti Leandro
Published: August 2013

Although aberrant DNA methylation patterning is a hallmark of cancer, the relevance of targeting DNA methyltransferases (DNMT) remains unclear for most tumors. In diffuse large B-cell lymphoma (DLBCL) we observed that chemoresistance is associated with aberrant DNA methylation programming. Prolonged exposure to low-dose DNMT inhibitors (DNMTI) reprogrammed chemoresistant cells to become doxorubicin sensitive without major toxicity in vivo. Nine genes were recurrently hypermethylated in chemoresistant DLBCL. Of these, SMAD1 was a critical contributor, and reactivation was required for chemosensitization. A phase I clinical study was conducted evaluating azacitidine priming followed by standard chemoimmunotherapy in high-risk patients newly diagnosed with DLBCL. The combination was well tolerated and yielded a high rate of complete remission. Pre- and post-azacitidine treatment biopsies confirmed SMAD1 demethylation and chemosensitization, delineating a personalized strategy for the clinical use of DNMTIs.

Significance: The problem of chemoresistant DLBCL remains the most urgent challenge in the clinical management of patients with this disease. We describe a mechanism-based approach toward the rational translation of DNMTIs for the treatment of high-risk DLBCL. Cancer Discov; 3(9); 1002–19. ©2013 AACR.

See related commentary by Steinhardt and Gartenhaus, p. 968

This article is highlighted in the In This Issue feature, p. 953
Macrophage MicroRNA-155 Promotes Cardiac Hypertrophy and Failure
Authors: Heymans Stephane , Corsten Maarten F. , Verhesen Wouter , Carai Paolo , van Leeuwen Rick E.W. , Custers Kevin , Peters Tim , Hazebroek Mark , Stöger Lauran , Wijnands Erwin , Janssen Ben J. , Creemers Esther E. , Pinto Yigal M. , Grimm Dirk , Schürmann Nina , Vigorito Elena , Thum Thomas , Stassen Frank , Yin Xiaoke , Mayr Manuel , de Windt Leon J. , Lutgens Esther , Wouters Kristiaan , de Winther Menno P.J. , Zacchigna Serena , Giacca Mauro , van Bilsen Marc , Papageorgiou Anna-Pia , Schroen Blanche
Published: August 2013

Background—

Cardiac hypertrophy and subsequent heart failure triggered by chronic hypertension represent major challenges for cardiovascular research. Beyond neurohormonal and myocyte signaling pathways, growing evidence suggests inflammatory signaling pathways as therapeutically targetable contributors to this process. We recently reported that
microRNA-155
is a key mediator of cardiac inflammation and injury in infectious myocarditis. Here, we investigated the impact of
microRNA-155
manipulation in hypertensive heart disease.

Methods and Results—

Genetic loss or pharmacological inhibition of the leukocyte-expressed
microRNA-155
in mice markedly reduced cardiac inflammation, hypertrophy, and dysfunction on pressure overload. These alterations were macrophage dependent because in vivo cardiomyocyte-specific
microRNA-155
manipulation did not affect cardiac hypertrophy or dysfunction, whereas bone marrow transplantation from wild-type mice into
microRNA-155
knockout animals rescued the hypertrophic response of the cardiomyocytes and vice versa. In vitro, media from
microRNA-155
knockout macrophages blocked the hypertrophic growth of stimulated cardiomyocytes, confirming that macrophages influence myocyte growth in a
microRNA-155
-dependent paracrine manner. These effects were at least partly mediated by the direct
microRNA-155
target suppressor of cytokine signaling 1 (Socs1) because Socs1 knockdown in
microRNA-155
knockout macrophages largely restored their hypertrophy-stimulating potency.

Conclusions—

Our findings reveal that
microRNA-155
expression in macrophages promotes cardiac inflammation, hypertrophy, and failure in response to pressure overload. These data support the causative significance of inflammatory signaling in hypertrophic heart disease and demonstrate the feasibility of therapeutic microRNA targeting of inflammation in heart failure.
Systemic Hypertension in Low-Gradient Severe Aortic Stenosis With Preserved Ejection Fraction
Authors: Eleid Mackram F. , Nishimura Rick A. , Sorajja Paul , Borlaug Barry A.
Published: August 2013

Background—

Low-gradient severe aortic stenosis with preserved ejection fraction is an increasingly recognized entity, and symptomatic patients may benefit from aortic valve replacement. However, systemic hypertension frequently coexists with low-gradient severe aortic stenosis, which itself may cause elevated left ventricular (LV) filling pressures with resultant symptoms of dyspnea.

Methods and Results—

Symptomatic patients with hypertension (aortic systolic pressure >140 mm Hg) and low-gradient (mean gradient <40 mm Hg) severe aortic stenosis (aortic valve area <1 cm
2
) with preserved ejection fraction (ejection fraction >50%) who underwent invasive hemodynamic catheterization of the left and right sides of the heart received infusion of intravenous sodium nitroprusside to reduce blood pressure and arterial afterload. At baseline, patients had severe hypertension (aortic systolic pressure, 176±26 mm Hg), pulmonary hypertension (mean pressure, 39±12 mm Hg), elevated LV end-diastolic pressure (19±5 mm Hg), and reduced stroke volume (33±8 mL/m
2
). All measures of afterload were reduced with nitroprusside (
P
<0.001 for all). Nitroprusside reduced mean pulmonary artery pressure (25±10 mm Hg) and LV end-diastolic pressure (11±5 mm Hg;
P
<0.001 for both compared with baseline). Aortic valve area (0.86±0.11 to 1.02±0.16 cm
2
;
P
=0.001) and mean gradient (27±5 to 29±6 mm Hg;
P
=0.02) increased with nitroprusside.

Conclusions—

Systemic hypertension in low-gradient severe aortic stenosis with preserved ejection fraction is associated with elevated LV filling pressures and pulmonary hypertension. Treatment of hypertension with vasodilator therapy results in a lowering of the total LV afterload, with a decrease in LV filling pressures and pulmonary artery pressures. These findings have important implications for the management of patients with low-gradient severe aortic stenosis with preserved ejection fraction and hypertension.
Blood Pressure Rhythmicity and Visceral Fat in Children With Hypertension
Authors: Niemirska Anna , Litwin Mieczysław , Feber Janusz , Jurkiewicz Elżbieta
Published: August 2013

Primary hypertension is associated with disturbed activity of the sympathetic nervous system and altered blood pressure rhythmicity. We analyzed changes in cardiovascular rhythmicity and its relation with target organ damage during 12 months of antihypertensive treatment in 50 boys with hypertension (median, 15.0 years). The following parameters were obtained before and after 12 months of antihypertensive treatment: 24-hour ambulatory blood pressure, left ventricular mass, carotid intima–media thickness, and MRI for visceral and subcutaneous adipose tissue. Amplitudes and acrophases of mean arterial pressure and heart rate rhythms were obtained for 24-, 12-, and 8-hour periods. After 1 year of treatment, 68% of patients were normotensive, and left ventricular mass and carotid intima–media thickness decreased in 60% and 62% of patients, respectively. Blood pressure and heart rate rhythmicity patterns did not change. Changes in blood pressure amplitude correlated with the decrease of waist circumference (
P
=0.035). Moreover, the decrease of visceral fat correlated with the decrease of 24-hour mean arterial pressure and heart rate acrophases (both
P
<0.05). There were no differences in changes of blood pressure and heart rate rhythms between patients who achieved or did not achieve normotension and regression of left ventricular mass and carotid intima–media thickness. It was concluded that abnormal cardiovascular rhythmicity persists in children with primary hypertension despite effective antihypertensive treatment, which suggests that it may be the primary abnormality. The correlation between changes in cardiovascular rhythmicity and visceral obesity may indicate that the visceral fat plays an important role in the sympathetic activity of adolescents with hypertension.
Hepatic Extracellular Signal–Regulated Kinase 2 Suppresses Endoplasmic Reticulum Stress and Protects From Oxidative Stress and Endothelial Dysfunction
Authors: Kujiraoka Takehiko , Satoh Yasushi , Ayaori Makoto , Shiraishi Yasunaga , Arai‐Nakaya Yuko , Hakuno Daihiko , Yada Hirotaka , Kuwada Naruo , Endo Shogo , Isoda Kikuo , Adachi Takeshi
Published: August 2013

Background

Insulin signaling comprises 2 major cascades: the insulin receptor substrate/phosphatidylinositol 3′‐kinase/protein kinase B and Ras/Raf/mitogen‐activated protein kinase/kinase/ERK pathways. While many studies on the tissue‐specific effects of the insulin receptor substrate/phosphatidylinositol 3′ ‐kinase/protein kinase B pathway have been conducted, the role of the other cascade in tissue‐specific insulin resistance has not been investigated. High glucose/fatty acid toxicity, inflammation, and oxidative stress, all of which are associated with insulin resistance, can activate
ERK
. The liver plays a central role in metabolism, and hepatosteatosis is associated with vascular diseases. The aim of study was to elucidate the role of hepatic
ERK
2 in hepatosteatosis, metabolic remodeling, and endothelial dysfunction.

Methods and Results

We created liver‐specific ERK2 knockout mice and fed them with a high‐fat/high‐sucrose diet for 20 weeks. The high‐fat/high‐sucrose diet–fed liver‐specific ERK2 knockout mice exhibited a marked deterioration in hepatosteatosis and metabolic remodeling represented by impairment of glucose tolerance and decreased insulin sensitivity without changes in body weight, blood pressure, and serum cholesterol/triglyceride levels. In the mice, endoplasmic reticulum stress was induced together with decreased
mRNA
and protein expressions of hepatic sarco/endoplasmic reticulum Ca
2+
‐ATPase 2. In a hepatoma cell line, inhibition of ERK activation– induced endoplasmic reticulum stress only in the presence of palmitate. Vascular reactive oxygen species were elevated with upregulation of nicotinamide adenine dinucleotide phosphate oxidase1 (Nox1) and Nox4 and decreased phosphorylation of endothelial nitric oxide synthase, which resulted in the remarkable endothelial dysfunction in high‐fat/high‐sucrose diet–fed liver‐specific ERK2 knockout mice.

Conclusions

Hepatic
ERK
2 suppresses endoplasmic reticulum stress and hepatosteatosis in vivo, which results in protection from vascular oxidative stress and endothelial dysfunction. These findings demonstrate a novel role of hepatic
ERK
2 in obese‐induced insulin resistance in the protection from hepatovascular metabolic remodeling and vascular diseases.
Contemporary Research on Proportionality in Armed Conflicts: A Select Review
Authors: Clarke Ben
Published: August 2013

In an attempt to impose limits on the level of acceptable incidental civilian suffering during armed conflict, international humanitarian law (IHL) articulates a proportionality formula as the test to determine whether or not an attack is lawful. Efforts to comply with that formula during the conduct of hostilities can involve a host of legal and operational challenges. These challenges have inspired a growing body of doctrinal and empirical research. A recent international conference in Jerusalem, co-sponsored by the Delegation of the International Committee of the Red Cross in Israel and the Occupied Territories and the Minerva Center for Human Rights at the Hebrew University of Jerusalem, brought together human rights lawyers, military experts and scholars from a variety of disciplines to assess recent developments relating to the proportionality principle in international humanitarian law. This report examines ten conference presentations which offer important insights into: the nature, scope of application and operational requirements of the proportionality principle under IHL; the modalities of investigation and review of proportionality decisions; and the challenges involved in proportionality decision-making.