bluuebunny/crossref_metadata_2025 huggingface dataset:
The Ouachita system
Authors: Arbenz J. Kaspar
Published: October 2013

During the Paleozoic, the southern margin of the North American craton underwent one major ocean margin cycle (“Wilson cycle”) lasting from the Late Proterozoic into the Permian. Breakup of a preexisting continent may have begun in the Late Proterozoic and lasted to the Middle Cambrian along a series of divergent rifts and transforms, which gave the margin between southern Alabama and northern Mexico an angular appearance. The breakup was accompanied by a system of rift arms and fault systems that reached far into the cratonic interior. The cycle ended with the formation of a collisional orogenic belt known as the Ouachita system.

The Ouachita Mountains of Oklahoma and Arkansas, the Marathon uplift of west Texas, and the Solitario (a small outcrop of Paleozoic rocks west of the Marathon region) are the only outcrop areas of the Ouachita system in the United States (Fig. 1). In northern Mexico, a number of small outcrops of Ouachita-facies rocks appear as inliers of the eastern Cordilleran orogen. The remainder of the frontal elements of the Ouachita system and the entire hinterland are covered by postorogenic Permian, Mesozoic, and Tertiary rocks of the Gulf Coastal Plain. Thus, some 90 percent of this orogenic belt cannot be inspected at the surface and must be mapped from subsurface borehole and geophysical data. Regional tectonic interpretations remain therefore rather tentative, especially in the deep hinterland, where boreholes are sparse.
Fresh water of the North American continent; A profile
Authors: Meyer Gerald
Published: October 2013

The eminent global hydrologist R. L. Nace (1969, p. 11)noted that “the story of the growth of civilization and science could be written largely in terms of human concern with water.” That quotation applies fittingly to the North American continent, whose economic and social development are intimately tied to its natural water supply. Demographic, agricultural, and industrial expansion have evolved largely around opportunities proffered by the continent’s surface, ground, and soil water.

Cultural and economic gains attributable to water development have been aided by coincident advances in knowledge of the hydrology and geology of the continent, accompanied by parallel progress in understanding of basic principles of the science of geohydrology. North American scientists have exercised leadership in both applied and basic geohydrological investigation. The significant roles of water in the continent’s geophysical and geochemical processes are only now being more fully recognized and integrated into the earth sciences, with both scientific and pragmatic benefits. It is now understood that water, whether in its liquid, vapor, or solid (ice) form, fulfills many fundamentally important physical and chemical functions in virtually all Earth environments.

This overview chapter is concerned primarily with the geohydrology of North America, and most particularly with the natural occurrence of fresh surface and ground water of the continent, with less attention to practical water-supply and water-use aspects. This is true also for Wolman and Riggs (1989) and Back and others (1988) of this series of volumes. Those two volumes provide, respectively, comprehensive descriptions of the surface and ground-water hydrology of the continent.
The Atlantic passive margin
Authors: Sheridan Robert E.
Published: October 2013

The eastern North American passive margin includes the Atlantic continental margin from the Bahamas to Baffin Bay. Formed by the rifting, breakup, and drift of North America away from Africa and Europe, the margin′s thick sedimentary cover of Mesozoic to Cenozoic age lying over the Coastal Plain, continental shelf, slope, and rise straddles three distinct basement types: continental, transitional, and oceanic. The emerged Coastal Plain, which is a seaward-thickening wedge of sediments 1 to 2 km thick, extends from Florida to Long Island (Fig. 1). It exists as a submerged wedge off Canada (Fig. 2). The continental crust under the inner continental shelf, Coastal Plain, and landward is marked by exposed and buried rift basins formed by asymmetric half grabens (Fig. 1). The continental crust consists of three grossly different ages and terranes: the Precambrian shield from Labrador northward (Fig. 2); the Paleozoic orogenic belt from Newfoundland to Georgia (Figs. 1 and 2); and the African Precambrian and Paleozoic Terranes of Florida (Fig. 1). The transitional crust under the outer continental shelves and marginal plateaus is deeply subsided and underlies major sedimentary basins. These deep sedimentary basins are: (1) South Florida Bahamas Basin, (2) Blake Plateau Basin, (3) Carolina Trough, (4) Baltimore Canyon Trough, (5) Georges Bank Basin (Fig. 1), (6) Scotian Shelf Basin, (7) Grand Bank Basins, and (8) Labrador Shelf Basins (Fig. 2). The boundary between the transitional crust and the true oceanic crust is marked by the linear East Coast magnetic anomaly north of Florida, and farther east by the Blake Spur magnetic anomaly in the Blake-Bahamas region (Fig. 1).
Vancomycin-induced thrombocytopaenia in a patient with severe pancreatitis
Authors: Rowland Simon P , Rankin Iain , Sheth Hemant
Published: October 2013

Vancomycin-induced thrombocytopenia is a rare side effect of a commonly used drug that may cause life-threatening disease. A 51-year-old man was treated for an episode of acute severe alcohol-induced pancreatitis complicated by development of a peripancreatic fluid collection. He developed fever of unknown origin and was treated with intravenous vancomycin and piperacillin with tazobactam. On day 6 of vancomycin therapy his platelet count dropped to 46×109/L (237×109/L on day 1 of treatment) and by day 8 of therapy platelets had fallen to a nadir of 9×109/L. The patient at this stage displayed a florid purpuric rash and haematoma formation on attempted intravenous cannulation. A clinical diagnosis of vancomycin-induced thrombocytopaenia was made and the drug withdrawn. After 3 days a significant improvement in the platelet count was noted, rising to 56 × 109/L. Immunofluorescence testing (PIFT) ruled out teicoplanin and heparin as causes of drug-induced thrombocytopenia.
Carbon monoxide poisoning in patients presenting to the emergency department with a headache in winter months
Authors: Zorbalar Nilay , Yesilaras Murat , Aksay Ersin
Published: October 2013

Background

Carbon monoxide (CO) poisoning is an important reason for emergency department (ED) visits during winter months, but because there are no specific symptoms it can be difficult to diagnose. We aimed to determine the frequency of CO poisoning in patients presenting to the ED with headaches during winter months and evaluate the ability of non-invasive carboxyhaemoglobin measurement (SpCO) to screen for CO poisoning in these patients.

Methods

SpCO measurement values of adult patients were measured non-invasively with a Rad-57 Pulse CO-Oximeter. Patients whose initial SpCO reading was over 10% underwent a venous blood draw for laboratory determination of invasive carboxyhaemoglobin (COHb) measurement. Patients with a invasive COHb level of over 10% were diagnosed with CO poisoning. Percentage of screened patients with suspected and occult CO poisoning, the distribution of patients with CO poisoning by time of day of the ED visit and the positive predictive value of SpCO to detect CO poisoning were calculated.

Results

483 patients presenting with headaches were screened with SpCO measurement. Thirty-eight had a mean SpCO value of over 10%, 31 (6.4% of the study population) of which had elevated COHb confirmed by laboratory determination. SpCO measurement, therefore, had a positive predictive value of 82% for CO poisoning. Twenty-four (77%) of the CO poisoning cases were suspected and seven (23%) were occult. CO poisoning was detected more frequently in patients visiting the ED after midnight and during morning hours.

Conclusions

CO poisoning should be kept in mind in patients presenting to the ED with a headache. SpCO is an effective screening tool to detect CO poisoning in these patients.
Investigation of excited-state intramolecular proton transfer coupled charge transfer reaction of paeonol
Authors: Hu Shanshan , Liu Kun , Li Yuanzuo , Ding Qianqian , Peng Wei , Chen Maodu
Published: October 2013

An excited-state intramolecular proton transfer (ESIPT) coupled charge transfer reaction of paeonol was investigated both experimentally and theoretically. The ESIPT reaction of paeonol was predicted based on the large Stokes shift, which is observed in steady-state absorption and fluorescence spectra in an ethanol solution. The steady-state spectra in some solutions, such as methanol, ethanol, propanol, dichloromethane, and n-hexane, illustrate that the ESIPT reaction of paeonol has no dependence on the solvent properties. Therefore, the excited-state intermolecular proton transfer cannot be generated in protic solvents. Using the density functional theory and time-dependent density functional theory methods, we make a subsequent theoretical calculation that indicates that the ESIPT reaction of paeonol occurs through the intramolecular hydrogen bond O−H···O=C. The excited-state potential energy curve of paeonol indicates that the ESIPT reaction is a barrierless process, and the fluorescence emission of paeonol at 493 nm in the ethanol solution was assigned to the keto isomer fluorescence. Additionally, we also found an intramolecular charge transfer in the excited state by analysing the frontier molecular orbitals of paeonol.
Towards attomolar detection using a surface-enhanced Raman spectroscopy platform fabricated by nanosphere lithography
Authors: Wallace Gregory Q. , Tabatabaei Mohammadali , Lagugné-Labarthet François
Published: October 2013

The limit of detection of 4-nitrothiophenol adsorbed onto the surface of a platform fabricated by nanosphere lithography is investigated by surface-enhanced Raman spectroscopy. Critical factors such as the functionalization time and the change of sharpness of the gold nanostructures upon annealing are studied. Platforms for surface-enhanced Raman spectroscopy provide detection ranging from monolayers down to isolated molecules. For a functionalization time of 24 h, a limit of detection of 10−16 mol/L (100 amol/L) is achieved. Furthermore, by shortening the functionalization time to 30 min, a significantly higher limit of detection is determined ranging from 10−6 to 10−9 mol/L. By altering the shape of the nanotriangles via annealing, a loss in signal intensity occurs. Optimizing the factors that enable a lower limit of detection is critical for many applications where surface-enhanced Raman spectroscopy can be considered as a promising analytical alternative.
Synthesis and characterization of extremely bulky amido-germanium(II) halide complexes
Authors: Hadlington Terrance J. , Li Jiaye , Jones Cameron
Published: October 2013

The extremely bulky aryl/silyl secondary amines, HN(Ar)(SiMe3), Ar = C6H2-i-Pr2(CPh3)-2,6,4 (LDipH), C6H2{C(H)Ph2}2-i-Pr-2,6,4 (L†H), or C6H2{C(H)Ph2}2-t-Bu-2,6,4 (Lt-BuH), have been synthesized via salt metathesis reactions between the appropriate lithium anilide complex and ClSiMe3. The related diaryl secondary amines, HN(Ar*)(R), Ar* = C6H2{C(H)Ph2}2Me-2,6,4 and R = C6H3Me2-3,5 (LMeH), C6H3(CF3)2-3,5 (LCF3H), or C6H2-i-Pr3-2,4,6 (LTripH), were prepared via palladium catalyzed cross-coupling reactions. Three of the amines were crystallographically characterized. Treatment of GeCl2·dioxane with 1 equiv. of each of the deprotonated amines led to the isolation of the amido-germanium(II) chloride complexes, [LGeCl] (L = L†, Lt-Bu, LCF3, or LTrip). Similarly, reaction of the known amido-digermyne, [L*Ge–GeL*] (L* = –N(Ar*)(SiMe3)), with I2 resulted in the oxidative cleavage of the Ge–Ge bond of the digermyne, and the formation of the first two-coordinate amido-germanium(II) iodide complex, [L*GeI]. Crystallographic characterization of [Lt-BuGeCl] and [L*GeI] revealed both to have similar monomeric structures. The compounds described in this study should prove useful as synthons for synthetic chemists working in the field of low oxidation state main group chemistry.
Silver nanoparticle modified MoO3 with enhanced electrochemical properties for a lithium-ion battery
Authors: Xu Yuandong , Cao Xiaoyu , Zhang Yujun
Published: October 2013

MoO3 nanorods prepared by using a hydrothermal process were firstly coated with silver nanoparticles as the electrode materials for lithium-ion batteries by the traditional silver mirror reaction. The physical properties of the samples were investigated by field emission scanning electron microscopy and X-ray diffraction spectroscopy. The charge–discharge properties, differential capacity curves, and cycle performance for the as-prepared samples were examined in detail. The results showed that silver additive significantly improved the reversible capacity and the cycling stability of the MoO3 nanorods under the experimental conditions.
23Na magic-angle spinning and double-rotation NMR study of solid forms of sodium valproate
Authors: Dicaire Nuiok M. , Perras Frédéric A. , Bryce David L.
Published: October 2013

Sodium valproate is a pharmaceutical with applications in the treatment of epilepsy, bipolar disorder, and other ailments. Sodium valproate can exist in many hydrated and acid-stabilized forms in the solid state, and it can be difficult to obtain precise structural information about many of these. Here, we present a 13C and 23Na solid-state NMR study of several forms of sodium valproate, only one of which has been previously structurally characterized by single-crystal X-ray diffraction. 23Na magic-angle spinning (MAS), double-rotation (DOR), and multiple-quantum magic-angle spinning (MQMAS) NMR spectra are shown to provide useful information on the number of molecules in the asymmetric unit, the local coordination geometry of the sodium cations, and the presence of amorphous phases. Two previously identified forms are shown to be highly similar, or identical, according to the 23Na NMR data. The utility of carrying out both DOR and MQMAS NMR experiments to identify all crystallographically unique sites is demonstrated. 13C cross-polarization MAS NMR spectra also provide complementary information on the number of molecules in the asymmetric unit and the crystallinity of the sample.
Firm performance, business environment, and outlook for social and environmental responsibility during the economic downturn: findings and implications from the forest sector
Authors: Hansen Eric , Nybakk Erlend , Panwar Rajat
Published: October 2013

The recent economic downturn severely affected the US forest sector from a macroeconomic perspective but little is known about changes in firm-level performance. In this study we investigate the changes in financial, social and environmental performance of forest sector firms during a period that approximately corresponds to the downturn. We also assess industry dynamism and industry’s view about social and environmental responsibility as a competitive tool. We conducted a national survey of wood, furniture, and paper companies. Approximately 60% of our respondents reported a decline in financial performance during the downturn. With respect to social and environmental performance, customer-oriented actions show mixed trends, employee matters remained somewhat unaltered, community engagement significantly decreased, and engagement in environmental activities significantly increased. Respondents view their operating business environment as highly dynamic and difficult and they do not view engagement in social and environmental responsibility activities leading to either financial or nonfinancial benefits.
Greater risk of physical damage caused by debris fall to understory plants and tree seedlings in old-growth forests than in young forests
Authors: Larson Andrew J.
Published: October 2013

Falling canopy debris causes injury and mortality of tree seedlings and understory plants in a wide variety of forests. Canopy structure and dynamics differ between young and old-growth forests: old forests are taller and have more aboveground biomass and greater annual mortality of bole biomass. I predicted that risk of damage caused by debris fall in the understory is greater in old-growth forests than in young forests. I tested this prediction by tracking for 1 year the fates of artificial seedlings placed in young (stand age 31 to 61 years) and old-growth (stand age circa 500 years) Pseudotsuga–Tsuga forests. The risk of physical damage caused by debris fall in old-growth forests was significantly greater than in young forests (P = 0.001). Seedling models were damaged by falling debris at a rate of 4.4%·year−1 and 0.8%·year−1 in old-growth and young forests, respectively. More seedling models were damaged by fallen coarse woody debris in old-growth forests than in young forests, although this trend was not significant (P = 0.134). Approximately 25% of seedling models in both young and old-growth forests were damaged by something other than fallen canopy debris, most likely snow accumulation.
Rhizobia survival in seeds coated with polyvinyl alcohol (PVA) electrospun nanofibres
Authors: Damasceno Raquel , Roggia Isabel , Pereira Claudio , de Sá Enilson
Published: October 2013

The electrospinning technique of rhizobia immobilization in nanofibres is an innovative and promising alternative for reducing the harmful effects of environmental stress on bacteria strains in a possible inoculant nanotechnology product for use in agriculture. The use of polyvinyl alcohol (PVA) shows up as an effective polymer in cell encapsulation because of its physical characteristics, such as viscosity and power of scattering. The aim of these studies has been to evaluate the survival of rhizobia incorporated in PVA nanofibres, which were applied to soybean seed and then subjected to different storage times and exposure to fungicide. The maintenance of the symbiotic characteristics of the incorporated bacterial strains was also evaluated, noting the formation of nodules in the soybean seedlings. No significant differences in the cell survival at 0 h and after 24 h of storage were observed. After 48 h, a significant difference in the bacterial cell concentration of the seeds affixed with PVA nanofibres was observed. Exposure to the fungicide decreased the viability of the bacteria strains even when coated with the nanofibres. A larger number of nodules formed in soybean seedlings from seeds inoculated with rhizobia incorporated in PVA nanofibres than from seeds inoculated with rhizobia without PVA. Thus, the electrospinning technique is a great alternative to the usual protector inoculants because of its unprecedented capacity to control the release of bacteria.
Multiconfigurational Dirac–Fock atomic structure calculations for Cl-like tungsten
Authors: Mohan Man , Aggarwal Sunny , Singh Narendra
Published: October 2013

Energy levels, lifetimes, and wavefunction compositions have been calculated for all levels of odd parity 3s23p5 ground configuration as well as 3s3p6 and 3s23p43d even parity excited configurations in highly charged Cl-like tungsten ion. Transition probabilities, oscillator strengths, and line strengths for E1, E2, M1, and M2 transitions have been obtained using the fully relativistic multiconfiguration Dirac–Fock (MCDF) approach including the correlations within the n = 3 complex, some n = 3 → n = 4 single and double excitations and Breit and quantum electrodynamics effects. For comparison from our calculated energy levels, we have also calculated the energy levels by using the fully relativistic flexible atomic code (FAC). The validity of the method is assessed by comparison with previously published experimental and theoretical data. The excellent agreement observed between our calculated results and those obtained using different approaches confirm the accuracy of our results. Additionally, we have predicted some new atomic data for W57+ that are not available so far and may be important for plasma diagnostic analysis in fusion plasma.
Photoionization of Al X from ground state using the relativistic R-matrix close-coupling method
Authors: Liang Liang , Liu Xu-yang , Zhou Chao
Published: October 2013

The relativistic R-matrix method is used to calculate the total photoionization cross sections from the ground state 1s22s2 1S0 of Al X for photon energies ranges from the first ionization threshold to just above the eighth threshold of the residual ion Al XI. In this work, the relativistic distorted-wave method is employed to calculate the fine-structure energy levels and radial functions. The lowest eight level target states of Al XI are used in the photoionization calculations of Al X and should provide a reasonably complete database for practical application for photoionization cross section for Al X. The resonance energy levels and widths of 18 Rydberg series have been investigated.
The effects of two fish predators on Wood Frog (Lithobates sylvaticus) tadpoles in a subarctic wetland: Hudson Bay Lowlands, Canada
Authors: Davenport J.M. , Seiwert P.A. , Fishback L.A. , Cash W.B.
Published: October 2013

Fish can have strong predatory impacts on aquatic food webs. Indeed, fish are known to have strong effects on amphibians, with some species being excluded from communities where fish are present. Most research with amphibians and fish has focused on lower latitudes and very little is known of amphibian–fish interactions at higher latitudes. Therefore, we conducted an enclosure experiment in a subarctic natural wetland to examine the predatory effects of two species of fish, brook sticklebacks (Culaea inconstans (Cuvier, 1829)) and ninespine sticklebacks (Pungitius pungitius (L., 1758)), on the survival and growth of Wood Frogs (Lithobates sylvaticus (LeConte, 1825)). We found no significant difference in survival and size at metamorphosis among the two fish species treatments and fish-free treatments. We found that individuals from fish-free treatments metamorphosed earlier than those from either fish species present treatment. Our work suggests that stickleback fish predation may not have a major impact on Wood Frog tadpole survival and growth in a subarctic wetland. Sticklebacks may still have an impact on earlier developmental stages of Wood Frogs. This work begins to fill an important gap in potential factors that may impact larval amphibian survival and growth at higher latitudes.
COEXISTENCE OF DIFFERENT TYPES OF TRANSVERSE CONDUCTIVITY IN Y1-xPrxBa2Cu3 O7-δ SINGLE CRYSTALS WITH DIFFERENT PRASEODYMIUM CONCENTRATIONS
Authors: VOVK R. V. , VOVK N. R. , GOULATIS I. L. , CHRONEOS A.
Published: October 2013

In this paper, the influence of praseodymium doping on the conductivity across (transverse) the basal plane of high-temperature superconducting Y 1-x Pr x Ba 2 Cu 3 O 7-δ single crystals is investigated. It is determined that an increase of praseodymium doping leads to increased localization effects and the implementation of a metal–insulator transition Y 1-x Pr x Ba 2 Cu 3 O 7-δ, which always precedes the superconducting transition. The increase of the praseodymium concentration also leads to a significant displacement of the point of the metal–insulator transition to the low temperature region.
MECHANICAL CHARACTERIZATION OF MATERIALS AND DIAGNOSIS OF STRUCTURES BY INVERSE ANALYSES: SOME INNOVATIVE PROCEDURES AND APPLICATIONS
Authors: MAIER GIULIO , BULJAK VLADIMIR , GARBOWSKI TOMASZ , COCCHETTI GIUSEPPE , NOVATI GIORGIO
Published: October 2013

A survey is presented herein of some recent research contributions to the methodology of inverse structural analysis based on statical tests for diagnosis of possibly damaged structures and for mechanical characterization of materials in diverse industrial environments. The following issues are briefly considered: identifications of parameters in material models and of residual stresses on the basis of indentation experiments; mechanical characterization of free-foils and laminates by cruciform and compression tests and digital image correlation measurements; diagnosis, both superficially and in depth, of concrete dams, possibly affected by alkali-silica-reaction or otherwise damaged.
S-FEM FOR FRACTURE PROBLEMS, THEORY, FORMULATION AND APPLICATION
Authors: LIU GUI RONG , CHEN LEI , LI MING
Published: October 2013

This paper briefs some of recent works on applications of the smoothed finite element method (SFEM) to fracture problems. In the SFEM formulation for simulating the singular filed near the crack-tip, it is known that one can directly enrich the filed by adding in proper terms needed to simulate the singularity, which can be done in a number of ways (see the SFEM book). In this work a generalized technique called the "enriched linear PIM" for constructing shape functions is used to formulate a special "five-node (T5) singular crack-tip element" that can produce a proper order of stress singularity near the crack-tip. One layer of T5 crack-tip singular elements are used in a basic mesh of linear elements leading to a very simple model that can be crated automatically for complicated geometry. Because the SFEM uses weakened weak formulations, such a simple model does not require transition elements and the compatibility is ensured. In addition, the singular terms of functions as well as mapping procedures are no longer necessary to compute the stiffness matrix. Thus, the singular SFEM method is straightforward and can be easily implemented in the existing codes. The stress intensity factors of mix-modes can also be easily evaluated by an appropriate treatment during the domain form of the interaction integral, due to the use of simple triangular mesh. The effectiveness of the present singular T5 element is demonstrated via benchmark examples.
Sestrin 3 regulation in type 2 diabetic patients and its influence on metabolism and differentiation in skeletal muscle
Authors: Nascimento Emmani BM , Osler Megan E. , Zierath Juleen R.
Published: October 2013

In mammals, the sestrin family is composed of three stress-responsive genes. Ablation of sestrin in Drosophila attenuates longevity, which is accompanied by increased S6K phosphorylation and decreased AMPK phosphorylation. Nevertheless, the metabolic role of sestrins in mammals is not comprehensively understood. We characterized the expression of individual sestrin family members and determined their role in vastus lateralis muscle biopsies from participants with normal glucose tolerance (NGT) or type 2 diabetes (T2D). Expression of sestrin 1 or sestrin 2 mRNA was unaltered between the NGT and T2D participants. Conversely, sestrin 3 mRNA was increased in T2D patients and correlated with fasting plasma glucose, 2-h postprandial plasma glucose and HbA1c. A trend for increased sestrin 3 protein was observed in T2D patients. In human primary myotubes, sestrin 3 mRNA increased during differentiation, and this response was unaltered in T2D-derived myotubes. Long-term treatment of myotubes with insulin or AICAR decreased sestrin 3 mRNA. Exposure of myotubes to the reactive oxygen species H2O2increased mRNA expression of sestrin 1 and 2, whereas sestrin 3 was unaltered. siRNA-mediated silencing of sestrin 3 in myotubes was without effect on insulin-stimulated glucose incorporation into glycogen or AICAR-stimulated palmitate oxidation. These results provide evidence against sestrin 3 in the direct control of glucose or lipid metabolism in human skeletal muscle. However, siRNA-mediated sestrin 3 gene silencing in myotubes increased myostatin expression. Collectively, our results indicate sestrin 3 is upregulated in T2D and could influence skeletal muscle differentiation without altering glucose and lipid metabolism.
Eplerenone ameliorates the phenotypes of metabolic syndrome with NASH in liver-specific SREBP-1c Tg mice fed high-fat and high-fructose diet
Authors: Wada Tsutomu , Miyashita Yusuke , Sasaki Motohiro , Aruga Yusuke , Nakamura Yuto , Ishii Yoko , Sasahara Masakiyo , Kanasaki Keizo , Kitada Munehiro , Koya Daisuke , Shimano Hitoshi , Tsuneki Hiroshi , Sasaoka Toshiyasu
Published: October 2013

Because the renin-angiotensin-aldosterone system has been implicated in the development of insulin resistance and promotion of fibrosis in some tissues, such as the vasculature, we examined the effect of eplerenone, a selective mineralocorticoid receptor (MR) antagonist, on nonalcoholic steatohepatitis (NASH) and metabolic phenotypes in a mouse model reflecting metabolic syndrome in humans. We adopted liver-specific transgenic (Tg) mice overexpressing the active form of sterol response element binding protein-1c (SREBP-1c) fed a high-fat and fructose diet (HFFD) as the animal model in the present study. When wild-type (WT) C57BL/6 and liver-specific SREBP-1c Tg mice grew while being fed HFFD for 12 wk, body weight and epididymal fat weight increased in both groups with an elevation in blood pressure and dyslipidemia. Glucose intolerance and insulin resistance were also observed. Adipose tissue hypertrophy and macrophage infiltration with crown-like structure formation were also noted in mice fed HFFD. Interestingly, the changes noted in both genotypes fed HFFD were significantly ameliorated with eplerenone. HFFD-fed Tg mice exhibited the histological features of NASH in the liver, including macrovesicular steatosis and fibrosis, whereas HFFD-fed WT mice had hepatic steatosis without apparent fibrotic changes. Eplerenone effectively ameliorated these histological abnormalities. Moreover, the direct suppressive effects of eplerenone on lipopolysaccharide-induced TNFα production in the presence and absence of aldosterone were observed in primary-cultured Kupffer cells and bone marrow-derived macrophages. These results indicated that eplerenone prevented the development of NASH and metabolic abnormalities in mice by inhibiting inflammatory responses in both Kupffer cells and macrophages.
Characterizing the Temporal Dynamics of Human Papillomavirus DNA Detectability Using Short-Interval Sampling
Authors: Liu Su-Hsun , Cummings Derek A.T. , Zenilman Jonathan M. , Gravitt Patti E. , Brotman Rebecca M.
Published: October 2013

Background: Variable detection of human papillomavirus (HPV) DNA can result in misclassification of infection status, but the extent of misclassification has not been quantitatively evaluated.

Methods: In 2005–2007, 33 women of ages 22 to 53 years self-collected vaginal swabs twice per week for 16 consecutive weeks. Each of the 955 swabs collected was tested for 37 HPV types/subtypes. Assuming that a woman's underlying infection status did not change over the short study period, biases in prevalence estimates obtained from single versus multiple swabs were calculated. Using event history analysis methods, time to recurrent gain and loss of at least one HPV type was determined, separately. Baseline any-type and high risk–type HPV prevalence was 60.6% and 24.2%, respectively. Cumulative any-HPV and high-risk HPV prevalence over the 16-week period was 84.8% and 60.6%, separately.

Results: Overall, there were 319 events of detection and 313 events of loss of detection. Median times to a recurrent detection and loss of detection were 11 and seven days, respectively. Neither vaginal sex nor condom use during follow-up was associated with recurrent viral detection or loss of detection. Assuming the cumulative 16-week prevalence reflects the true prevalence of infection, the baseline any-HPV prevalence underestimated infection status by 24.2%, with a bootstrapped mean of 20.2% [95% confidence interval (CI), 8.9%–29.6%].

Conclusions: These findings suggest that a substantial proportion of HPV-infected women are misclassified as being uninfected when using a single-time DNA measurement.

Impact: Short-term variation in detectable HPV DNA needs to be considered while interpreting the natural history of infections using single samples collected at long intervals. Cancer Epidemiol Biomarkers Prev; 23(1); 200–8. ©2013 AACR.
Maté Drinking and Esophageal Squamous Cell Carcinoma in South America: Pooled Results from Two Large Multicenter Case–Control Studies
Authors: Lubin Jay H. , De Stefani Eduardo , Abnet Christian C. , Acosta Gisele , Boffetta Paolo , Victora Cesar , Graubard Barry I. , Muñoz Nubia , Deneo-Pellegrini Hugo , Franceschi Silvia , Castellsagué Xavier , Ronco Alvaro L. , Dawsey Sanford M.
Published: October 2013

Background: Maté tea is a nonalcoholic infusion widely consumed in southern South America, and may increase risk of esophageal squamous cell carcinoma (ESCC) and other cancers due to polycyclic aromatic hydrocarbons (PAH) and/or thermal injury.

Methods: We pooled two case–control studies: a 1988 to 2005 Uruguay study and a 1986 to 1992 multinational study in Argentina, Brazil, Paraguay, and Uruguay, including 1,400 cases and 3,229 controls. We computed ORs and fitted a linear excess OR (EOR) model for cumulative maté consumption in liters/day–year (LPDY).

Results: The adjusted OR for ESCC with 95% confidence interval (CI) by ever compared with never use of maté was 1.60 (1.2–2.2). ORs increased linearly with LPDY (test of nonlinearity; P = 0.69). The estimate of slope (EOR/LPDY) was 0.009 (0.005–0.014) and did not vary with daily intake, indicating maté intensity did not influence the strength of association. EOR/LPDY estimates for consumption at warm, hot, and very hot beverage temperatures were 0.004 (−0.002–0.013), 0.007 (0.003–0.013), and 0.016 (0.009–0.027), respectively, and differed significantly (P < 0.01). EOR/LPDY estimates were increased in younger (<65) individuals and never alcohol drinkers, but these evaluations were post hoc, and were homogeneous by sex.

Conclusions: ORs for ESCC increased linearly with cumulative maté consumption and were unrelated to intensity, so greater daily consumption for shorter duration or lesser daily consumption for longer duration resulted in comparable ORs. The strength of association increased with higher maté temperatures.

Impact: Increased understanding of cancer risks with maté consumption enhances the understanding of the public health consequences given its purported health benefits. Cancer Epidemiol Biomarkers Prev; 23(1); 107–16. ©2013 AACR.
The Effect of VEGF-Targeted Therapy on Biomarker Expression in Sequential Tissue from Patients with Metastatic Clear Cell Renal Cancer
Authors: Sharpe Kevin , Stewart Grant D. , Mackay Alan , Van Neste Christophe , Rofe Charlotte , Berney Dan , Kayani Irfan , Bex Axel , Wan Elaine , O'Mahony Fiach C. , O'Donnell Marie , Chowdhury Simon , Doshi Rukma , Ho-Yen Colan , Gerlinger Marco , Baker Dawn , Smith Neil , Davies Barry , Sahdev Anju , Boleti Ekaterini , De Meyer Tim , Van Criekinge Wim , Beltran Luis , Lu Yong-Jie , Harrison David J. , Reynolds Andrew R. , Powles Tom
Published: October 2013

Purpose: To investigate how biologically relevant markers change in response to antiangiogenic therapy in metastatic clear cell renal cancer (mRCC) and correlate these changes with outcome.

Experimental Design: The study used sequential tumor tissue and functional imaging (taken at baseline and 12–16 weeks) obtained from three similar phase II studies. All three studies investigated the role of VEGF tyrosine kinase inhibitors (TKI) before planned nephrectomy in untreated mRCC (n = 85). The effect of targeted therapy on ten biomarkers was measured from sequential tissue. Comparative genomic hybridization (CGH) array and DNA methylation profiling (MethylCap-seq) was performed in matched frozen pairs. Biomarker expression was correlated with early progression (progression as best response) and delayed progression (between 12–16 weeks).

Results: VEGF TKI treatment caused a significant reduction in vessel density (CD31), phospho-S6K expression, PDL-1 expression, and FOXP3 expression (P < 0.05 for each). It also caused a significant increase in cytoplasmic FGF-2, MET receptor expression in vessels, Fuhrman tumor grade, and Ki-67 (P < 0.05 for each). Higher levels of Ki-67 and CD31 were associated with delayed progression (P < 0.05). Multiple samples (n = 5) from the same tumor showed marked heterogeneity of tumor grade, which increased significantly with treatment. Array CGH showed extensive intrapatient variability, which did not occur in DNA methylation analysis.

Conclusion: TKI treatment is associated with dynamic changes in relevant biomarkers, despite significant heterogeneity in chromosomal and protein, but not epigenetic expression. Changes to Ki-67 expression and tumor grade indicate that treatment is associated with an increase in the aggressive phenotype of the tumor. Clin Cancer Res; 19(24); 6924–34. ©2013 AACR.
IGFBP2/FAK Pathway Is Causally Associated with Dasatinib Resistance in Non–Small Cell Lung Cancer Cells
Authors: Lu Haibo , Wang Li , Gao Wen , Meng Jieru , Dai Bingbing , Wu Shuhong , Minna John , Roth Jack A. , Hofstetter Wayne L. , Swisher Stephen G. , Fang Bingliang
Published: October 2013

Insulin-like growth factor (IGF)-binding protein-2 (IGFBP2) expression is increased in various types of cancers, including in a subset of patients with lung cancer. Because IGFBP2 is involved in signal transduction of some critical cancer-related pathways, we analyzed the association between IGFBP2 and response to pathway-targeted agents in seven human non–small cell lung cancer (NSCLC) cell lines. Western blot analysis and ELISA showed that four of the seven NSCLC cell lines analyzed expressed high levels of IGFBP2, whereas the remaining three had barely detectable IGFBP2. Susceptibilities of those seven cell lines to nine anticancer agents targeting to IGF1R, Src, FAK, MEK, and AKT were determined by a dose-dependent cell viability assay. The results showed that high IGFBP2 levels were associated with resistance to dasatinib and, to a lesser degree, to sacaratinib, but not to other agents. Ectopic IGFBP2 overexpression or knockdown revealed that changing IGFBP2 expression levels reversed dasatinib susceptibility phenotype, suggesting a causal relationship between IGFBP2 expression and dasatinib resistance. Molecular characterization revealed that focal adhesion kinase (FAK) activation was associated with increased IGFBP2 expression and partially contributed to IGFBP2-mediated dasatinib resistance. Treatment with a combination of dasatinib and FAK inhibitor led to enhanced antitumor activity in IGFBP2-overexpressing and dasatinib-resistant NSCLC cells in vitro and in vivo. Our results showed that the IGFBP2/FAK pathway is causally associated with dasatinib resistance and may be used as biomarkers for identification of dasatinib responders among patients with lung cancer. Simultaneous targeting on Src and FAK will likely improve the therapeutic efficacy of dasatinib for treatment of lung cancer. Mol Cancer Ther; 12(12); 2864–73. ©2013 AACR.
Cytoreductive Chemotherapy Improves the Biodistribution of Antibodies Directed against Tumor Necrosis in Murine Solid Tumor Models
Authors: Jang Julie K. , Khawli Leslie A. , Park Ryan , Wu Brian W. , Li Zibo , Canter David , Conti Peter S. , Epstein Alan L.
Published: October 2013

Current strategies in cancer treatment employ combinations of different treatment modalities, which include chemotherapy, radiotherapy, immunotherapy, and surgery. Consistent with that approach, the present study demonstrates how chemotherapeutic agents can potentiate the delivery of radiolabeled, necrosis-targeting antibodies (chTNT-3, NHS76) to tumor. All chemotherapeutics in this study (5-fluorouracil, etoposide, vinblastine, paclitaxel, and doxorubicin) resulted in statistically significant increases in tumor uptake of radiolabeled antibodies and their F(ab')2 fragments compared to no pretreatment with chemotherapy. Labeled antibodies were administered at various time points following a single dose of chemotherapy in multiple tumor models, and the biodistribution of the antibodies was determined by measuring radioactivity in harvested tissues. MicroPET/CT was also done to demonstrate clinical relevancy of using chemotherapy pretreatment to increase antibody uptake. Results of biodistribution and imaging data reveal specific time frames following chemotherapy when necrosis-targeting antibodies are best delivered, either for imaging or radiotherapy. Thus, the present work offers the prospect of using cytoreductive chemotherapy to increase tumor accumulation of select therapeutic antibodies, especially when combined with other forms of immunotherapy, for the successful treatment of solid tumors. Mol Cancer Ther; 12(12); 2827–36. ©2013 AACR.
Differential and Common DNA Repair Pathways for Topoisomerase I- and II-Targeted Drugs in a Genetic DT40 Repair Cell Screen Panel
Authors: Maede Yuko , Shimizu Hiroyasu , Fukushima Toru , Kogame Toshiaki , Nakamura Terukazu , Miki Tsuneharu , Takeda Shunichi , Pommier Yves , Murai Junko
Published: October 2013

Clinical topoisomerase I (Top1) and II (Top2) inhibitors trap topoisomerases on DNA, thereby inducing protein-linked DNA breaks. Cancer cells resist the drugs by removing topoisomerase-DNA complexes, and repairing the drug-induced DNA double-strand breaks (DSB) by homologous recombination and nonhomologous end joining (NHEJ). Because numerous enzymes and cofactors are involved in the removal of the topoisomerase-DNA complexes and DSB repair, it has been challenging to comprehensively analyze the relative contribution of multiple genetic pathways in vertebrate cells. Comprehending the relative contribution of individual repair factors would give insights into the lesions induced by the inhibitors and genetic determinants of response. Ultimately, this information would be useful to target specific pathways to augment the therapeutic activity of topoisomerase inhibitors. To this end, we put together 48 isogenic DT40 mutant cells deficient in DNA repair and generated one cell line deficient in autophagy (ATG5). Sensitivity profiles were established for three clinically relevant Top1 inhibitors (camptothecin and the indenoisoquinolines LMP400 and LMP776) and three Top2 inhibitors (etoposide, doxorubicin, and ICRF-193). Highly significant correlations were found among Top1 inhibitors as well as Top2 inhibitors, whereas the profiles of Top1 inhibitors were different from those of Top2 inhibitors. Most distinct repair pathways between Top1 and Top2 inhibitors include NHEJ, TDP1, TDP2, PARP1, and Fanconi Anemia genes, whereas homologous recombination seems relevant especially for Top1 and, to a lesser extent, for Top2 inhibitors. We also found and discuss differential pathways among Top1 inhibitors and Top2 inhibitors. Mol Cancer Ther; 13(1); 214–20. ©2013 AACR.
Black Raspberries Protectively Regulate Methylation of Wnt Pathway Genes in Precancerous Colon Tissue
Authors: Wang Li-Shu , Kuo Chieh-Ti , Huang Tim H.-M. , Yearsley Martha , Oshima Kiyoko , Stoner Gary D. , Yu Jianhua , Lechner John F. , Huang Yi-Wen
Published: October 2013

Ulcerative colitis is frequently an intermediate step to colon cancer. The interleukin-10 knockout mouse is a genetic model of this progression. We report that knockout mice fed 5% black raspberries (BRB) had significantly less colonic ulceration as compared with knockout mice that consumed the control diet. Dysfunction of the Wnt signaling pathway is a key event in ulcerative colitis–associated colon carcinogenesis. Therefore, we investigated the effects of BRBs on the Wnt pathway and found that the BRB-fed knockout mice exhibited a significantly lower level of β-catenin nuclear translocation. We followed-up this observation by evaluating the effect of BRBs on selected Wnt pathway antagonists. The mRNA expression levels of wif1, sox17, and qki were diminished in the knockout mice, whereas they were expressed at normal levels in knockout mice that were fed BRBs. The lower mRNA expression of these genes in the colon from the knockout mice correlated with hypermethylation of their promoter regions; BRBs decreased their promoter methylation and increased mRNA expression of these genes. This hypomethylation was associated with elevated protein expression of key proteins/enzymes that augment methylation, for example, dnmt3b, hdac1, hdac2, and mbd2 in the knockout mice; in addition, BRBs decreased the protein expression of these proteins/enzymes. The knockout mouse model recapitulates what occurs in human ulcerative colitis. Promoter methylation of CDH1 and SFRP1 was significantly higher in human ulcerative colitis tissues compared with their adjacent normal tissues. In conclusion, our results suggest that BRBs inhibit colonic ulceration and, ultimately, colon cancer partly through inhibiting aberrant epigenetic events that dysregulate Wnt signaling. Cancer Prev Res; 6(12); 1317–27. ©2013 AACR.
Prospective Randomized Comparison of Retroperitoneoscopic Pyelolithotomy versus Percutaneous Nephrolithotomy for Solitary Large Pelvic Kidney Stones
Authors: Singh Vishwajeet , Sinha Rahul Janak , Gupta Dheeraj Kumar , Pandey Mohit
Published: October 2013

Objectives: We performed a prospective randomized comparison of retroperitoneoscopic pyelolithotomy (RP) versus percutaneous nephrolithotomy (PNL) for solitary pelvic stones >3 cm and assessed the outcome results. Methods: From 2010 to 2012, 44 patients with a solitary pelvic stone >3 cm without any anatomical abnormality were randomized to either RP or PNL on a 1:1 ratio. Stone-free rate, number of procedures per patient and complications were recorded. Results: The stone-free rate on the first postoperative day was 95.5% in the RP group versus 72.7% in the PNL group (p = 0.04). The stone-free rates at 3 months were similar between the two groups. Blood loss, visual pain analog score and analgesic requirement on the first postoperative day were significantly higher in the PNL group whereas the mean operative time and overall complications were similar between the two groups. Conclusion: In patients with solitary large pelvic stones, RP is associated with lesser blood loss, postoperative pain and analgesia as well as with a higher stone-free rate in the immediate postoperative period in comparison to PNL. However, the stone clearance rate remains the same at 3 months in both groups.