bluuebunny/crossref_metadata_2025 huggingface dataset:
Active Airflow Generation to Assist Robotic Gas Source Localization: Initial Experiments in Outdoor Environment
Authors: Murai Ayano , Matsukura Haruka , Takemura Ryuichi , Ishida Hiroshi
Published: September 2016

A new gas source localization method that uses actively generated airflow is proposed. A gas source localization robot searches for the location of a gas source by tracking a gas plume in the upwind direction. However, the robot often fails in tracking the plume in an actual environment owing to the large fluctuations of the airflow field and the plume structure. To overcome this problem, we propose to deploy in the environment a swarm of mobile robots equipped with fans to generate a stable airflow field so that a stable gas plume will be formed and the robot can easily track it. Experimental results are presented to show that the variations of the airflow field can be suppressed by the actively generated airflow even in an outdoor environment. It is also shown that errors in the gas source direction estimated by the robot can be reduced by the proposed method.
(Invited) Design of Highly Sensitive and Selective Diode-Type H2 Sensors
Authors: Hyodo Takeo , Sakata Wataru , Kamada Kai , Ueda Taro , Shimizu Yasuhiro
Published: September 2016

Diode-type gas sensors employing an anodized TiO2 film and Pt electrodes modified with and without a small amount of Au (Au/Pt/TiO2 and Pt/TiO2, respectively) have been fabricated, and their H2-sensing properties have been investigated in detail. The Pt/TiO2 sensor showed much larger H2 response in N2 than that in air, but the surface modification of the Pt electrode with Au was quite effective in reducing the oxygen concentration dependence of the H2 response and enhancing the H2 selectivity against hydrocarbons such as C3H8 and C3H6 in both wet air and wet N2, at a forward bias of +100 mV at 250°C. In addition, the Au/Pt/TiO2 sensor showed relatively good H2-sensing properties at a low forward bias (+ 1 mV) at 250°C as well as at a forward bias of +100 mV at a low temperature (50°C) in both wet air and wet N2.
(Invited) Electrochemical Sensing Using Molecule-like Gold Nanoclusters
Authors: Kumar S. Senthil , Kwak Kyuju , Lee Dongil
Published: September 2016

Quantum-sized gold nanoclusters of size <2 nm possess unique and size-dependent redox behavior. Au25 nanoclusters (Au25NCs), in particular exhibit redox potentials closer to conventionally used mediators such as ferrocyanide and ferrocene and hence our objective was to utilize these clusters as mediators in the development of electrochemical sensors and biosensors. We have prepared modified electrodes containing Au25NCs and tested their electrocatalytic activity and amperometric sensing behavior. Au25NCs have behaved as an electronic conductor and redox mediator as well. Further, we have tuned the electrostatic charge on these clusters by using glutathione ligand and improved the selectivity of the modified electrode towards charged analytes. Finally, in order to examine the utility of the Au25NCs in electrochemical biosensing, an ionic liquid containing Au25NC has been prepared (Au25IL). The composite of Au25IL and glucose oxidase enzyme has exhibited to be an excellent biosensor towards the determination of glucose.
Thermal Stability of Phage Peptide Probes Vs. Aptamer for Salmonella Detection on Magnetoelastic Biosensors Platform
Authors: Chen I-Hsuan , Horikawa Shin , Du Songtao , Liu Yuzhe , Wikle Howard Clyde , Barbaree James M , Chin Bryan A
Published: September 2016

Rapid and reliable detections for foodborne pathogens are essential to monitor food and improve food safety procedures. Food monitoring, such as monitoring contaminated foods in poultry processing plants and/or field farms with high heat environments, requires thermostable bio-probes on the sensor surfaces for accurate detections. Phage based magnetoelastic (ME) biosensors have been recently developed as a real-time and wireless platform for Salmonella
enterica serotype Typhimurum detection in various food systems. The thermostability of phage and aptamer probes were studied here and their binding to Salmonella Typhimurium cells were evaluated using enzyme-linked immunosorbent assay (ELISA) format at various temperatures. The ELISA format can be used to mimic the probe immobilization conditions on ME sensor surfaces and can test bio-probes’ performance without the variability that arises from different ME sensor lots. The results of this study can be further applied in the development of the ME biosensor platform.
Sensor Design and New Material for an Intelligent System for People with Musculoskeletal Tension Problems
Authors: Plaza Mauricio , Aperador Willian , Cifuentes Mauricio
Published: September 2016

The purpose of the current research is the use of new materials and sensors for the Design supports system, reducing efforts for people with problems on musculoskeletal system. The specific objective of this research is to use physiological measurements and modern design techniques for the construction and validation of a novel ergonomic system for people with musculoskeletal problems, to avoid injury in back and spine, without degrading performance in work or proper military exercise by increased comfort and strength of musculoskeletal system of the soldiers and workers; using methods that promote improvements in critical aspects of the exercise of mobilization of heavy loads, with better load distribution in different parts of the body and an external support. The use of special adapted sensor systems allow measuring physiological conditions, allowing focus in the design process, reducing injury rates and the distribution load in accordance with the nature of it. The design process will be addressed by searching of optimization of the cost and improvement of the physical and functional characteristics of the prototype, by making harmless and noninvasive tests on potential end users and taking account of expert opinions, to ensure that the prototype provides protection and support expected.
Highly Sensitive Measurement of Bioelectric Potentials by Boron-Doped Diamond Electrodes for Plant Monitoring
Authors: Ochiai Tsuyoshi , Tago Shoko , Hayashi Mio , Fujishima Akira
Published: September 2016

A sensitive plant monitoring system for the detection of plant bioelectric potentials using boron-doped diamond (BDD) electrodes is presented. For sensor electrodes, commercially available BDD, Ag, Ag/AgCl, and Pt plate electrodes were used. This approach was tested on a hybrid species in the genus Opuntia (potted) and three different trees (ground-planted) in different locations in Japan. For the Opuntia, bioelectric potential changes were artificially induced by the surface potential using fingers. Substantial changes in bioelectric potentials were detected through all electrodes during finger touching on the potted Opuntia hybrid plant surfaces. However, the BDD electrodes were several times more sensitive to bioelectric potential changes compared to the other electrodes. For ground-planted trees, it was similarly found that both BDD and Pt electrodes detected bioelectric potential changes induced by altering environmental factors for multiple months. BDD electrodes were five to ten times more sensitive in this detection than Pt electrodes.
Ethanol Response of Semiconductor Gas Sensors Based on SnO2 Layer Prepared from Acidic Solution
Authors: Mori Masami , Sadaoka Yoshihiko , Ueda Tsuyoshi , Mitsuhashi Hirokazu , Nakatani Mikiya
Published: September 2016

We examined the response behavior of SnO2 based semiconductor gas sensors to ethanol. In this study, the sensing layer was fabricated from mixed solutions of tin acidic standard solution with zinc or titanium acidic standard solution. The sensitivity of SnO2 sensors prepared from acidic standard solutions to ethanol was higher than that of metal-doped SnO2 sensors prepared from SnO2 powders. The sensitivity of Zn-doped SnO2 sensors was depressed in the humidified environment, while the sensitivity of Ti-doped SnO2 sensors was not affected by humidity even if the relative humidity was high. SnO2 films prepared from SnO2 powders composed of particles with 100 nm mean particle diameter. By using tin standard solution as a material of film, semiconductor films formed of fine particles having 10 nm mean particle diameter was obtained. This film formation method using acidic standard solutions can control the thickness of film easy, and the thin SnO2 film with around 100 nm thickness could be obtained.
Fabrication of Nanopore on Electron Beam Induced Membrane for Single Molecule Analysis
Authors: Choi Seong Soo , Park Myoung Jin , Yamaguchi Tokutaro , Han Chul Hee , Oh Sae-Joong , Park Kyoung Jin , Yoo Jung Ho , Kim Yong-Sang , Park Nam kyou
Published: September 2016

We report fabrication of Au nanopore formation on pyramid by using focused ion beam technique and electron beam irradiation techniques. Under electron beam irradiations on the specimen, carbon incorporation with electron beam is reported. We initially observed the no Au nanoparticles on the diffused membrane by using transmission electron microscopy (TEM). After the samples were kept under the room environments for several months, Au particles were formed on the diffused membrane via Ostwald ripening. We also observed the bi-stable phase of Au crystalline structure on the diffused membrane during TEM imaging process via Spinodal decomposition. Fabricated nanopore integrated with Au particles can be utilized as optical nanopore for ultrafast genome sequencing.
Applications of Electrochemical Impedance Spectroscopy in pH Sensor Characterization and Failure Analysis
Authors: Huo Jinshan
Published: September 2016

This work presented some examples of electrochemical impedance spectra (EIS) of normally functional and failed pH sensors. EIS is found very useful as a non-destructive technique to identify some of the failure modes and root causes of pH sensors. It is also found valuable in study of the effects of steam sterilization process on pH glass membrane and the correlation between glass impedance components and pH sensor performances.
Three-Electrode on-Chip Sensors for Voltammetric Detection of Trace Metals in Natural Waters
Authors: Fighera Marianna , Van der wal Peter D. , Tercier-Waeber Mary-Lou , Shea Herbert
Published: September 2016

Newly designed three-electrode on-chip sensors for voltammetric detection of trace metals in the nanomolar range are presented. The iridium electrodes are used without further modification as the counter electrode (CE) and as a seed layer for post-processing in case of the working and reference electrode (WE, RE). The microdisc array WE is plated with Hg and the RE is realized by plating the electrode with Ag followed by a chloridation step and deposition of PVC/IL. The characterization of the on-chip three electrodes was performed using cyclic voltammetry and chronoamperometry and their performance for trace metal detection evaluated using square wave stripping voltammetry in synthetic and seawater samples. The results demonstrated the applicability of the newly designed interconnected arrays and the on-chip CE to highly sensitive detection of trace metals. They also revealed that the analytical approach proposed for the on-chip RE is promising, but further improvements are still required.
Exosomes Detection by a Label-free Localized Surface Plasmonic Resonance Method
Authors: Duraichelvan R. , Srinivas B. , Badilescu S. , Ouellette R. , Ghosh A. , Packirisamy Muthukumaran
Published: September 2016

Exosomes contain disease biomarkers for cancer and other pathological conditions. They are groups of nano-scale extracellular communication organelles which dynamically transport cargoes of molecules and genetic materials between cells. Exosomes circulating in our body-fluids provide a snap-shot in real-time for virtually all aspects of our physiology. Isolation detection and quantification methods of exosomes from various bio-fluids are challenging for clinical applications, like liquid biopsy. This paper presents a simple label-free technique to capture and detect exosomes integrating an exosome-capturing synthetic polypeptide (called Vn96). This exosome-capture can efficiently quantitate exosomes present in a fluid and will be used for subsequent molecular analysis (protein and nucleic acid) to facilitate liquid biopsy.
(Invited) Effect of Microfabrication Induced Stresses on the Sensing Characteristics of Dynamic MEMS Devices
Authors: Pratap Rudra , Dangi Ajay , Behera Amruta Ranjan
Published: September 2016

Residual stresses play an important role in deciding the performance and reliability of MEMS devices. In this work we present one study each of the compressive residual stress induced effects and the tensile residual stress induced effects on the dynamic behavior of MEMS structures. We find that compressive residual stresses can be introduced with reasonable control to obtain 1-D MEMS structures with desired degree of buckling. We also present a case of multilayered suspended plate structure where the presence of residual tensile stress causes the structure to transition from plate behavior to membrane behavior thus significantly changing the characteristics of the structure when used as a sensor. We also present the applicability of residual stress engineering and stress tuning to these MEMS structure.
Effect of Post Deposition Annealing on ALD-ZrO2/SiON Gate Stacks for Advanced CMOS Technology
Authors: Gupta Richa , Vaid Rakesh
Published: September 2016

To meet the existing challenges associated with gate leakage current and scaling beyond 22 nm node, we report the fabrication of 8.46 nm thin ALD-ZrO2 film on silicon substrate with ~ 5.28 nm SiON as interfacial layer (IL). Electrical characterizations such as Capacitance-Voltage and Current-Voltage measurements reveal that the post deposition annealing (PDA) of ZrO2 in NH3 ambient results in improving various performance parameters such as leakage current density (92% decrease), effective oxide thickness (~22% decrease) and dielectric constant (~32% increase) when compared to PDA in N2 ambient. The surface roughness for N2 and NH3 annealed ZrO2 samples studied using AFM were found to be 0.49 nm and 0.13 nm respectively; thereby showing 73% decrease in surface roughness for NH3 annealed samples. The thicknesses of the grown films were corroborated by Ellipsometry and FESEM while the structural analysis was carried out using XRD technique. The results demonstrate that post deposition annealing of ZrO2 film in NH3 ambient at 5000 C using rapid thermal processing (RTP) gives reduced EOT (~ 1.7 nm), increased K (~30) along with the suppressed off-state leakage current density (2.1 × 10-9 A/cm2).
Electrocatalytic Sensing of Carbon Dioxide, Oxygen and Inert Inorganic Analytes at Network Films of Transition Metal Complexes
Authors: Kulesza Pawel J , Wadas Anna , Ozimek Weronika , Frik Malgorzata , Rutkowska Iwona Agnieszka
Published: September 2016

Nanostructured metallic Pd centers have been generated by electroreduction of PdII within the coordination architecture of tridentate Schiff-base-ligands. The resulting Pd nanoparticles (diameters, 5-10 nm) are stabilized and activated by ligand nitrogens, and the electrocatalytic system exhibits appreciable activity toward reduction of CO2 in 0.1 M KHCO3 (pH=8.8). Comparison has also been made to the behavior of conventional Pd nanoparticles. In addition to low degree of agglomeration and high active surface area of the Schiff-base-ligand-supported Pd nanocenters, specific interactions between electron-donor N-coordination sites and metallic Pd are expected. Furthermore, such Pd catalysts are highly active during reduction of O2 in alkaline medium (0.1 M KOH). Finally, the potent catalytic properties of Pd have been explored to study reduction of highly inert arsenate(V), OAs(OH)3, analytes in acid medium (0.5 M H2SO4).
Association of CYP2C19 variants and epoxyeicosatrienoic acids on patients with microvascular angina
Authors: Akasaka Tomonori , Sueta Daisuke , Arima Yuichiro , Tabata Noriaki , Takashio Seiji , Izumiya Yasuhiro , Yamamoto Eiichiro , Yamamuro Megumi , Tsujita Kenichi , Kojima Sunao , Kaikita Koichi , Kajiwara Ayami , Morita Kazunori , Oniki Kentaro , Saruwatari Junji , Nakagawa Kazuko , Ogata Yasuhiro , Matsui Kunihiko , Hokimoto Seiji
Published: September 2016

Categorization as a cytochrome P450 (CYP) 2C19 poor metabolizer (PM) is reported to be an independent risk factor for cardiovascular disease. Epoxyeicosatrienoic acids (EETs) are metabolites of arachidonic acid by CYP2C19 epoxygenases and anti-inflammatory properties, especially in microvascular tissues. We examined the association of CYP2C19 polymorphisms and EETs on microvascular angina (MVA) caused by coronary microvascular dysfunction. We examined CYP2C19 genotypes in patients with MVA ( n = 71) and healthy subjects as control ( n = 71). MVA was defined as the absence of coronary artery stenosis and epicardial spasms and the presence of inversion of lactic acid levels between intracoronary and coronary sinuses in acetylcholine-provocation test or the adenosine-triphosphate-induced coronary flow reserve ratio was below 2.5. CYP2C19 PM have two loss-of-functon alleles (*2, *3). We measured serum dihydroxyeicosatrienoic acid (DHET) as representative EET metabolite. MVA group showed significantly higher CYP2C19 PM incidence (35% vs. 16%; P = 0.007) and high sense C-reactive protein (hs-CRP) levels (0.127 ± 0.142 vs. 0.086 ± 0.097 mg/dl; P = 0.043) than those of controls. Moreover, in MVA group, hs-CRP levels in CYP2C19 PM were significantly higher than that of non-PM (0.180 ± 0.107 vs. 0.106 ± 0.149 mg/dl, P = 0.045). Multivariate analysis indicated that smoking, hypertension, high hs-CRP, and CYP2C19 PM are predictive factors for MVA. In MVA group, DHET levels for CYP2C19 PM were significantly lower than that of non-PM [10.9 ± 1.64 vs. 14.2 ± 5.39 ng/ml, P = 0.019 (11,12-DHET); 15.2 ± 4.39 vs. 17.9 ± 4.73 ng/ml, P = 0.025 (14,15-DHET)]. CYP2C19 variants are associated with MVA. The decline of EET-based defensive mechanisms owing to CYP2C19 variants may affect coronary microvascular dysfunction.
Regulation of pulmonary endothelial barrier function by kinases
Authors: Barabutis Nektarios , Verin Alexander , Catravas John D.
Published: September 2016

The pulmonary endothelium is the target of continuous physiological and pathological stimuli that affect its crucial barrier function. The regulation, defense, and repair of endothelial barrier function require complex biochemical processes. This review examines the role of endothelial phosphorylating enzymes, kinases, a class with profound, interdigitating influences on endothelial permeability and lung function.
Correction of lung inflammation in a F508del CFTR murine cystic fibrosis model by the sphingosine-1-phosphate lyase inhibitor LX2931
Authors: Veltman Mieke , Stolarczyk Marta , Radzioch Danuta , Wojewodka Gabriella , De Sanctis Juan B. , Dik Willem A. , Dzyubachyk Oleh , Oravecz Tamas , de Kleer Ismé , Scholte Bob J.
Published: September 2016

Progressive lung disease with early onset is the main cause of mortality and morbidity in cystic fibrosis patients. Here we report a reduction of sphingosine-1-phosphate (S1P) in the lung of unchallenged Cftr tm1EUR F508del CFTR mutant mice. This correlates with enhanced infiltration by inducible nitric oxide synthase (iNOS)-expressing granulocytes, B cells, and T cells. Furthermore, the ratio of macrophage-derived dendritic cells (MoDC) to conventional dendritic cells (cDC) is higher in mutant mouse lung, consistent with unprovoked inflammation. Oral application of a S1P lyase inhibitor (LX2931) increases S1P levels in mutant mouse tissues. This normalizes the lung MoDC/cDC ratio and reduces B and T cell counts. Lung granulocytes are enhanced, but iNOS expression is reduced in this population. Although lung LyC6+ monocytes are enhanced by LX2931, they apparently do not differentiate to MoDC and macrophages. After challenge with bacterial toxins (LPS-fMLP) we observe enhanced levels of proinflammatory cytokines TNF-α, KC, IFNγ, and IL-12 and the inducible mucin MUC5AC in mutant mouse lung, evidence of deficient resolution of inflammation. LX2931 does not prevent transient inflammation or goblet cell hyperplasia after challenge, but it reduces MUC5AC and proinflammatory cytokine levels toward normal values. We conclude that lung pathology in homozygous mice expressing murine F508del CFTR, which represents the most frequent mutation in CF patients, is characterized by abnormal behavior of infiltrating myeloid cells and delayed resolution of induced inflammation. This phenotype can be partially corrected by a S1P lyase inhibitor, providing a rationale for therapeutic targeting of the S1P signaling pathway in CF patients.
Genome-wide association study of plasma resistin levels identified rs1423096 and rs10401670 as possible functional variants in the Japanese population
Authors: Kawamura Ryoichi , Tabara Yasuharu , Tsukada Akiko , Igase Michiya , Ohashi Jun , Yamada Ryo , Takata Yasunori , Kawamoto Ryuichi , Saito Isao , Onuma Hiroshi , Tanigawa Takeshi , Yamada Kazuya , Kato Norihiro , Ohyagi Yasumasa , Miki Tetsuro , Kohara Katsuhiko , Osawa Haruhiko
Published: September 2016

Resistin is a cytokine inducing insulin resistance in mice. We previously identified single nucleotide polymorphisms (SNPs) at −420 (rs1862513) and −358 (rs3219175) located in the human resistin gene ( RETN) promoter as strong determinants for circulating resistin in the Japanese population. The objective was to identify additional functional variants for circulating resistin. We conducted a genome-wide association study in 448 Japanese subjects. A peak association signal was found on chromosome 19 where RETN is located. The top-hit SNP was SNP −358 G>A, followed by rs1423096 C>T, SNP −420 C>G, and rs10401670 C>T ( P = 5.39×10−47, 1.81×10−22, 2.09×10−16, and 9.25×10−15, respectively). Meta-analysis including another two independent general Japanese populations showed that circulating resistin was most strongly associated with SNP-358, followed by SNP-420, rs1423096, and rs10401670. Rs1423096 and rs10401670 were located in the 3′-region of RETN and were in strong linkage disequilibrium. Although these SNPs were also in linkage disequilibrium with the promoter SNPs, conditional and haplotype association analyses identified rs1423096 and rs10401670 as independent determinants for circulating resistin. Functionally, nuclear proteins specifically recognized T but not C at rs10401670 as evidenced by an electrophoretic mobility shift assay. The promoter activity of a luciferase reporter with T at either rs1423096 or rs10401670 was lower than that with C in THP-1 human monocytes. Therefore, rs1423096 and rs10401670, in addition to SNP-420 and SNP-358, were identified as possible functional variants affecting circulating resistin by the genome-wide search in the Japanese population.
Effects of dietary forage and calf starter on ruminal pH and transcriptomic adaptation of the rumen epithelium in Holstein calves during the weaning transition
Authors: Kim Yo-Han , Toji Noriyuki , Kizaki Keiichiro , Kushibiki Shiro , Ichijo Toshihiro , Sato Shigeru
Published: September 2016

We investigated the relationship between ruminal pH and transcriptomic adaptation of the rumen epithelium (RE) of calves fed calf starter with and without forage during the weaning transition. Holstein calves were assigned to groups fed calf starter either with forage (HAY group, n = 3) or without forage (CON group, n = 4). Ruminal pH was measured continuously, and rumen fluid and epithelium were collected 3 wk after weaning. mRNA expression profiles of the RE were examined by one-color microarray. Differentially expressed genes (DEGs) were investigated using the Ingenuity Pathway Analysis (IPA). Mean and maximum ruminal pH were significantly ( P < 0.05) higher, and the duration of pH < 5.8 during 1 day was significantly ( P < 0.05) shorter, in the HAY group. The proportion of ruminal acetate and the acetate-to-propionate ratio were significantly ( P < 0.05) lower in the CON group. DEGs encoding transcription regulators (SREBP1), insulin-like growth factor binding proteins (IGFBP7 and CTGF), ketogenic enzymes (HMGCL, BDH1, and BDH2), and a transporter (SLC16A3) were identified ( P < 0.05) between the two groups. A growth factor (TGFB1) and signaling pathway (EGF and EGFR) were activated as upstream regulators. These results suggest that dietary forage alleviates ruminal acidosis, and the decrease in ruminal pH may damage the RE, leading to changes in gene expression to repair the damage. Furthermore, rumen development may be regulated by growth factor (TGFB1) and signaling pathways (EGF and IGFBP) for adaptation to feeding on calf starter with and without forage during the weaning transition.
Microbial short chain fatty acid metabolites lower blood pressure via endothelial G protein-coupled receptor 41
Authors: Natarajan Niranjana , Hori Daijiro , Flavahan Sheila , Steppan Jochen , Flavahan Nicholas A. , Berkowitz Dan E. , Pluznick Jennifer L.
Published: September 2016

Short chain fatty acid (SCFA) metabolites are byproducts of gut microbial metabolism that are known to affect host physiology via host G protein-coupled receptor (GPCRs). We previously showed that an acute SCFA bolus decreases blood pressure (BP) in anesthetized mice, an effect mediated primarily via Gpr41. In this study, our aims were to identify the cellular localization of Gpr41 and to determine its role in BP regulation. We localized Gpr41 to the vascular endothelium using RT-PCR: Gpr41 is detected in intact vessels (with endothelium) but is absent from denuded vessels (without endothelium). Furthermore, using pressure myography we confirmed that SCFAs dilate resistance vessels in an endothelium-dependent manner. Since we previously found that Gpr41 mediates a hypotensive response to acute SCFA administration, we hypothesized that Gpr41 knockout (KO) mice would be hypertensive. Here, we report that Gpr41 KO mice have isolated systolic hypertension compared with wild-type (WT) mice; diastolic BP was not different between WT and KO. Older Gpr41 KO mice also exhibited elevated pulse wave velocity, consistent with a phenotype of systolic hypertension; however, there was no increase in ex vivo aorta stiffness (measured by mechanical tensile testing). Plasma renin concentrations were also similar in KO and WT mice. The systolic hypertension in Gpr41 KO is not salt sensitive, as it is not significantly altered on either a high- or low-salt diet. In sum, these studies suggest that endothelial Gpr41 lowers baseline BP, likely by decreasing active vascular tone without altering passive characteristics of the blood vessels, and that Gpr41 KO mice have hypertension of a vascular origin.
Overexpression of Functional SLC6A3 in Clear Cell Renal Cell Carcinoma
Authors: Hansson Jennifer , Lindgren David , Nilsson Helén , Johansson Elinn , Johansson Martin , Gustavsson Lena , Axelson Håkan
Published: September 2016

Purpose: Renal cell carcinoma (RCC) is derived from a tissue with a remarkable capacity for vectorial transport. We therefore performed an unbiased exploration of transporter proteins in normal kidney and kidney cancer to discover novel clinical targets.

Experimental Design: Using The Cancer Genome Atlas (TCGA) database, we investigated differences in membrane transporter expression in clear cell RCC (ccRCC) and normal kidney. We identified the dopamine transporter SLC6A3 as a specific biomarker for ccRCC. To investigate the functionality of SLC6A3, we used a [3H]-dopamine uptake assay on ccRCC cells. We further explored the effect of hypoxia-inducible factor (HIF) proteins on SLC6A3 expression by introducing siRNA in ccRCC cells and by hypoxic treatment of nonmalignant cells.

Results: We show that ccRCC expresses very high transcript levels of SLC6A3 in contrast to normal kidney tissue and other tumor types, which do not express appreciable levels of this transporter. Importantly, we demonstrate that the elevated expression of SLC6A3 in ccRCC cells is associated with specific uptake of dopamine. By targeting the expression of HIF-1α and HIF-2α, we could show that SLC6A3 expression is primarily influenced by HIF-2α and that hypoxia can induce SLC6A3 expression in normal renal cells.

Conclusions: We conclude that the dopamine transporter SLC6A3 constitutes a novel biomarker that is highly specific for ccRCC. We further postulate that the protein can be exploited for diagnostic or therapeutic purposes for detection or treatment of ccRCC. Clin Cancer Res; 23(8); 2105–15. ©2016 AACR.
Selective Targeting of Cyclin E1-Amplified High-Grade Serous Ovarian Cancer by Cyclin-Dependent Kinase 2 and AKT Inhibition
Authors: Au-Yeung George , Lang Franziska , Azar Walid J. , Mitchell Chris , Jarman Kate E. , Lackovic Kurt , Aziz Diar , Cullinane Carleen , Pearson Richard B. , Mileshkin Linda , Rischin Danny , Karst Alison M. , Drapkin Ronny , Etemadmoghadam Dariush , Bowtell David D.L.
Published: September 2016

Purpose: Cyclin E1 (CCNE1) amplification is associated with primary treatment resistance and poor outcome in high-grade serous ovarian cancer (HGSC). Here, we explore approaches to target CCNE1-amplified cancers and potential strategies to overcome resistance to targeted agents.

Experimental Design: To examine dependency on CDK2 in CCNE1-amplified HGSC, we utilized siRNA and conditional shRNA gene suppression, and chemical inhibition using dinaciclib, a small-molecule CDK2 inhibitor. High-throughput compound screening was used to identify selective synergistic drug combinations, as well as combinations that may overcome drug resistance. An observed relationship between CCNE1 and the AKT pathway was further explored in genomic data from primary tumors, and functional studies in fallopian tube secretory cells.

Results: We validate CDK2 as a therapeutic target by demonstrating selective sensitivity to gene suppression. However, we found that dinaciclib did not trigger amplicon-dependent sensitivity in a panel of HGSC cell lines. A high-throughput compound screen identified synergistic combinations in CCNE1-amplified HGSC, including dinaciclib and AKT inhibitors. Analysis of genomic data from TCGA demonstrated coamplification of CCNE1 and AKT2. Overexpression of Cyclin E1 and AKT isoforms, in addition to mutant TP53, imparted malignant characteristics in untransformed fallopian tube secretory cells, the dominant site of origin of HGSC.

Conclusions: These findings suggest a specific dependency of CCNE1-amplified tumors for AKT activity, and point to a novel combination of dinaciclib and AKT inhibitors that may selectively target patients with CCNE1-amplified HGSC. Clin Cancer Res; 23(7); 1862–74. ©2016 AACR.
Sequence-Specific Pharmacokinetic and Pharmacodynamic Phase I/Ib Study of Olaparib Tablets and Carboplatin in Women's Cancer
Authors: Lee Jung-Min , Peer Cody J. , Yu Minshu , Amable Lauren , Gordon Nicolas , Annunziata Christina M. , Houston Nicole , Goey Andrew K.L. , Sissung Tristan M. , Parker Bernard , Minasian Lori , Chiou Victoria L. , Murphy Robert F. , Widemann Brigitte C. , Figg William D. , Kohn Elise C.
Published: September 2016

Purpose: Our preclinical studies showed that the PARP inhibitor, olaparib, prior to carboplatin attenuated carboplatin cytotoxicity. We evaluated sequence-specific pharmacokinetic and pharmacodynamic effects, safety, and activity of the combination.

Experimental Design: Eligible patients had metastatic or recurrent women's cancer. Olaparib tablets were introduced (100 or 200 mg twice daily, days 1–7) in a 3 + 3 dose escalation with carboplatin AUC4 or 5 every 21 days, up to eight cycles, followed by olaparib 300 mg twice daily maintenance. Patients were randomly assigned to starting schedule: cohort A (olaparib days 1–7, carboplatin on day 8) or B (carboplatin on day 1, olaparib days 2–8) during cycle 1. Patients received the reversed scheme in cycle 2. Blood was collected for olaparib pharmacokinetics, platinum–DNA adducts, comet assay, and PAR concentrations. The primary objectives were to examine schedule-dependent effects on olaparib pharmacokinetics and platinum–DNA adducts.

Results: A total of 77 (60 ovarian, 14 breast, and 3 uterine cancer) patients were treated. Dose-limiting toxicity was thrombocytopenia and neutropenia, defining olaparib 200 mg twice daily + carboplatin AUC4 as the MTD. Olaparib clearance was increased approximately 50% when carboplatin was given 24 hours before olaparib. In vitro experiments demonstrated carboplatin preexposure increased olaparib clearance due to intracellular olaparib uptake. Quantities of platinum–DNA adducts were not different as a function of the order of drug administration. Responses included 2 CRs and 31 PRs (46%) with a higher RR in BRCA mutation carriers compared with nonmutation carriers (68% vs. 19%).

Conclusions: Tablet olaparib with carboplatin is a safe and active combination. Carboplatin preexposure causes intracellular olaparib accumulation reducing bioavailable olaparib, suggesting carboplatin should be administered prior to olaparib. Clin Cancer Res; 23(6); 1397–406. ©2016 AACR.
Bringing Blood-Based Molecular Testing to the Clinic
Authors: Janku Filip , Kurzrock Razelle
Published: September 2016

In cancer, plasma-derived cell-free DNA can be used for detection of oncogenic aberrations relevant for treatment selection. A cell-free DNA-based test for EGFR mutations has been approved as an alternative to tumor tissue analysis in lung cancer. Testing for other aberrations, including copy number alterations, continues to be investigated. Clin Cancer Res; 22(22); 5400–2. ©2016 AACR.

See related article by Chicard et al., p. 5564
Pharmacokinetically Guided Dosing of Oral Drugs: True Precision Oncology?
Authors: Ornstein Moshe C. , Rini Brian I.
Published: September 2016

Higher plasma concentrations of tyrosine kinase inhibitors (TKI), such as pazopanib, are associated with improved clinical outcomes. However, TKI pharmacokinetics exhibit significant interpatient variability, resulting in inconsistent and unpredictable plasma drug levels. An individualized dosing approach based on patient pharmacokinetics data and toxicity can potentially optimize plasma concentrations of pazopanib. Clin Cancer Res; 22(23); 5626–8. ©2016 AACR.

See related article by Verheijen et al., p. 5738
Implantation of the Medtronic Harmony Transcatheter Pulmonary Valve Improves Right Ventricular Size and Function in an Ovine Model of Postoperative Chronic Pulmonary Insufficiency
Authors: Schoonbeek Rosanne C. , Takebayashi Satoshi , Aoki Chikashi , Shimaoka Toru , Harris Matthew A. , Fu Gregory L. , Kim Timothy S. , Dori Yoav , McGarvey Jeremy , Litt Harold , Bouma Wobbe , Zsido Gerald , Glatz Andrew C. , Rome Jonathan J. , Gorman Robert C. , Gorman Joseph H. , Gillespie Matthew J.
Published: September 2016

Background—

Pulmonary insufficiency is the nexus of late morbidity and mortality after transannular patch repair of tetralogy of Fallot. This study aimed to establish the feasibility of implantation of the novel Medtronic Harmony transcatheter pulmonary valve (hTPV) and to assess its effect on pulmonary insufficiency and ventricular function in an ovine model of chronic postoperative pulmonary insufficiency.

Methods and Results—

Thirteen sheep underwent baseline cardiac magnetic resonance imaging, surgical pulmonary valvectomy, and transannular patch repair. One month after transannular patch repair, the hTPV was implanted, followed by serial magnetic resonance imaging and computed tomography imaging at 1, 5, and 8 month(s). hTPV implantation was successful in 11 animals (85%). There were 2 procedural deaths related to ventricular fibrillation. Seven animals survived the entire follow-up protocol, 5 with functioning hTPV devices. Two animals had occlusion of hTPV with aneurysm of main pulmonary artery. A strong decline in pulmonary regurgitant fraction was observed after hTPV implantation (40.5% versus 8.3%;
P
=0.011). Right ventricular end diastolic volume increased by 49.4% after transannular patch repair (62.3–93.1 mL/m
2
;
P
=0.028) but was reversed to baseline values after hTPV implantation (to 65.1 mL/m
2
at 8 months,
P
=0.045). Both right ventricular ejection fraction and left ventricular ejection fraction were preserved after hTPV implantation.

Conclusions—

hTPV implantation is feasible, significantly reduces pulmonary regurgitant fraction, facilitates right ventricular volume improvements, and preserves biventricular function in an ovine model of chronic pulmonary insufficiency. This percutaneous strategy could potentially offer an alternative for standard surgical pulmonary valve replacement in dilated right ventricular outflow tracts, permitting lower risk, nonsurgical pulmonary valve replacement in previously prohibitive anatomies.
Factors Associated With Initial Prasugrel Versus Clopidogrel Selection for Patients With Acute Myocardial Infarction Undergoing Percutaneous Coronary Intervention: Insights From the Treatment With ADP Receptor Inhibitors: Longitudinal Assessment of Treatment Patterns and Events After Acute Coronary Syndrome (TRANSLATE‐ACS) Study
Authors: Vora Amit N. , Peterson Eric D. , McCoy Lisa A. , Effron Mark B. , Anstrom Kevin J. , Faries Douglas E. , Zettler Marjorie E. , Fonarow Gregg C. , Baker Brian A. , Stone Gregg W. , Wang Tracy Y.
Published: September 2016

Background

Few studies have examined how antiplatelet therapies are selected during the routine care of acute myocardial infarction patients, particularly relative to the patient's estimated mortality and bleeding risks.

Methods and Results

We examined patients presenting with acute myocardial infarction treated with percutaneous coronary intervention at 233
US
hospitals in the
TRANSLATE
‐
ACS
observational study from April 2010 to October 2012. We developed a multivariable logistic regression model to identify factors associated with prasugrel selection. Prasugrel use rates and associated 1‐year risk‐adjusted major adverse cardiovascular events and Global Utilization of Streptokinase and t‐PA for Occluded Coronary Arteries (
GUSTO
) moderate/severe bleeding outcomes were also examined in relation to predicted mortality and bleeding using the validated Acute Coronary Treatment and Intervention Outcomes (
ACTION
) risk prediction scores. Among 11 969 patients, 3123 (26%) received prasugrel at the time of percutaneous coronary intervention. The strongest factors associated with prasugrel use included cardiogenic shock (odds ratio [
OR
] 1.68, 95%
CI
1.25–2.26), drug‐eluting stent use (
OR
1.45, 95%
CI
1.31–1.62), and ST‐segment elevation myocardial infarction presentation (
OR
1.23, 95%
CI
1.12–1.35). Older age (
OR
0.57, 95%
CI
0.0.53–0.61), dialysis (
OR
0.56, 95%
CI
0.32–0.96), prior history of stroke/transient ischemic attack (
OR
0.52, 95%
CI
0.38–0.73), and interhospital transfer (
OR
0.50, 95%
CI
0.46–0.55) were associated with lowest prasugrel selection. Prasugrel was used less often than clopidogrel in patients at higher predicted bleeding risk (21.9% versus 29.7%,
P
<0.001). Yet paradoxically, prasugrel was also less likely than clopidogrel to be used in patients with higher predicted mortality risk (21.1% versus 30.2%,
P
<0.001). Adjusted bleeding and outcomes events were similar among those receiving prasugrel and clopidogrel in the 4 subgroups of patients based on bleeding risk and ischemic benefits.

Conclusions

In community practice, prasugrel use may be driven more by bleeding risk rather than ischemic benefit. This may result in underutilization of higher potency ADP receptor inhibitor among patients more likely to derive ischemic benefit.
Effectiveness of
N
‐Acetylcysteine for the Prevention of Contrast‐Induced Nephropathy: A Systematic Review and Meta‐Analysis of Randomized Controlled Trials
Authors: Xu Renfan , Tao Anyu , Bai Yang , Deng Youbin , Chen Guangzhi
Published: September 2016

Background

Conflicting results have been obtained in trials that have evaluated the prophylactic efficacy of
N
‐acetylcysteine (
NAC
) pretreatment in the prevention of contrast‐induced nephropathy (
CIN
). In this meta‐analysis of randomized controlled trials, we aimed to assess the effectiveness of
NAC
treatment for the prevention of
CIN
.

Methods and Results

PubMed,
EMBASE
, and the Cochrane Library were electronically searched from inception to January 2016 for all relevant studies. The weighted relative risk (
RR
) and corresponding 95%
CI
for incident
CIN
were estimated using random effects models. Standard methods for assessing statistical heterogeneity and publication bias were used. The study included 11 480 participants and 1653 cases of
CIN
. The incidence of
CIN
was 12.8% in the
NAC
group versus 16.0% in the control group (
RR
: 0.76, 95%
CI
: 0.66–0.88,
P
=0.0002). In the patients undergoing coronary angiography, the incidence of
CIN
in the
NAC
group versus the control group was 13.7% versus 17.2% (
RR
: 0.74, 95%
CI
: 0.63–0.87,
P
=0.0002); in those undergoing peripheral angiography, the incidence was 6.4% versus 5.8% (
RR
: 1.00, 95%
CI
: 0.42–2.40,
P
=1.00); in those undergoing computed tomography, the incidence was 7.7% versus 14.8% (
RR
: 0.51, 95%
CI
: 0.29–0.89,
P
=0.02).

Conclusions

Our meta‐analysis showed an inverse and significant association between
NAC
supplementation and risk of
CIN
in patients undergoing coronary angiography and computed tomography, while a protective role for
NAC
in patients undergoing peripheral angiography was not obvious.
Gender Difference in the Risk of Contrast-Induced Nephropathy in Patients Undergoing Coronary Angiography or Percutaneous Coronary Intervention
Authors: Barbieri Lucia , Verdoia Monica , Nardin Matteo , Marino Paolo , Suryapranata Harry , De Luca Giuseppe
Published: September 2016

Contrast-induced nephropathy (CIN) is a common complication of coronary angiography/percutaneous coronary intervention (PCI). Identification of high-risk patients and optimal periprocedural management are key points to reduce the incidence of this iatrogenic complication. We evaluated the impact of gender on CIN after coronary angiography/PCI. We enrolled 2851 consecutive patients (730 females and 1851 males) undergoing coronary angiography/PCI. Baseline clinical and procedural characteristics were collected according to gender. CIN was defined as an absolute ≥0.5mg/dL or a relative ≥25% increase in creatinine level 24 to 48 hours after the procedure. The incidence of CIN was 12.6% and was significantly higher among females (15.6% vs 11.4%, odds ratio (OR) [95% confidence interval (CI)] = 1.42 [1.11-1.82]; P = .004), but this result was not confirmed at multivariate analysis after correction for all baseline confounders (adjusted OR [95% CI] = 1.14 [0.81-1.60]; P = 0.45). In conclusion, we showed that female gender is associated with an increased risk of CIN after coronary angiography/PCI. However, this finding was not confirmed after correction for baseline confounders. Therefore, the higher risk profile rather than female gender itself may contribute to the higher occurrence of CIN among women.
A 10-Year Review of Necrotizing Fasciitis in the Pediatric Population: Delays to Diagnosis and Management
Authors: VanderMeulen Heather , Pernica Jeffrey M. , Roy Madan , Kam April J.
Published: September 2016

Objective. To assess the promptness and appropriateness of management in pediatric cases of necrotizing fasciitis (NF). Methods. A retrospective chart review examined cases of pediatric NF treated at a pediatric tertiary care center over a 10-year period. Results. Twelve patients were identified over the 10-year period. The median (25th to 75th centile) times to appropriate antibiotic administration, infectious disease consults, surgical consults and debridement surgeries were 2.6 (2.1-3.2), 7.7 (3.4-24.4), 4.6 (1.7-21.0), and 22.1 (10.3-28.4) hours following assessment at triage. The initial antibiotic(s) administered covered the causative organism in 9 of 12 cases. The median (25th to 75th centile) length of hospital stay was 21 (14.0-35.5) days. Conclusions. The large variability in the care of these patients speaks to the range of their presenting symptomatology. The lack of a standardized approach to the pediatric patient with suspected NF results in delays in management and suboptimal antibiotic choice.
Increasing Universal Lipid Screening Among 9- to 11-Year-Old Children Through a Quality Improvement Initiative
Authors: Kern Leah , Crow Janet , Williams Christine B. , Boies Eyla , Gahagan Sheila , Rhee Kyung E.
Published: September 2016

In 2011, the National Heart Lung and Blood Institute recommended universal lipid screening (ULS) in 9- to 11-year-old children. This study aimed to determine whether a quality improvement (QI) initiative increased ULS. Data were abstracted from the electronic medical record to compare screening behaviors 1 year preimplementation and postimplementation. A focus group was conducted to examine physicians’ attitudes. In preimplementation and postimplementation years, the number of 9- to 11-year-olds seen for well-child checks were 356 and 357, respectively. The first and second phases of the intervention were associated with a 64.3% ( P < .001) and 2.3% ( P = .75) increase in ordering, respectively. The rate of abnormal results was similar (21.4% vs 20.1%, P = .91). Physicians reported “some benefits” to screening but expressed concerns about cost-effectiveness and impact. The QI initiative resulted in high rates of ULS. Nonetheless, physicians continue to question the impact of screening on long-term health. More research on the benefits, costs, and outcomes of ULS is needed.
Challenging state modernity: Governmental adaptation and informal water politics in Mexico City
Authors: de Alba Felipe
Published: September 2016

This article analyzes political practices shaping water usage in the Mexico City region. Based on four different case studies, it reflects on the role of intermediaries in the state restructuring process. The cases explore political negotiation over the use of water in contexts of shortage or abundance, clean potable water, or waste water. The article illustrates how the use of natural resources affects the state’s role and how it reconfigures citizen participation. It compares traditional political mechanisms such as clientelism or electoral promotion, with emergent informal practices such as the multiplication of intermediaries who distribute water privately, but are ambiguously subsidized and organized by public institutions. It concludes that unequal water provision and intermediaries are key elements for the renewal of state legitimacy.
Housing Quality and Health: An Evaluation of Slum Rehabilitation in India
Authors: Vaid Uchita , Evans Gary W.
Published: September 2016

Slum rehabilitation programs in economically developing countries are designed to improve housing and enhance residents’ health and well-being. Yet no empirical research has directly investigated these objectives. Housing quality was assessed by trained raters on a walk-through among women in public housing as well as those currently in slums on wait-lists to relocate to public housing. Standardized, self-report measures of mental and physical health, quality of life, along with social ties in the neighborhood were assessed. Women who moved from slum housing to public housing manifest better physical and mental health but diminished social ties in comparison with women remaining in slum areas. Furthermore, housing quality, assessed by trained raters, largely explained the differences in health between the two groups. These quasi-experimental findings suggest that housing quality can enhance health and well-being of women, but that care must be taken to promote the maintenance of social capital following resettlement.