bluuebunny/crossref_metadata_2025 huggingface dataset:
Universal Superconducting Ground State in Nd1.85Ce0.15CuO4 and Nd2CuO4
Authors: Krockenberger Yoshiharu , Yamamoto Hideki , Mitsuhashi Masaya , Naito Michio
Published: December 2011

Superconducting Nd1.85Ce0.15CuO4 (T
c
zero = 24 K) and Nd2CuO4 (T
c
zero = 25 K) thin films have been grown by molecular beam epitaxy and their magneto-transport and structural properties have been investigated. The as-grown films are insulators irrespective of the substitution level, and superconductivity is induced after the samples are treated by an annealing process under reducing atmospheres. Though the metallic conductivity is higher in the Ce4+ substituted sample, the superconducting properties are quite similar between Ce4+ substituted and substitution-free samples. A similar upper critical magnetic field as well as a similar superconducting transition temperature of Nd1.85Ce0.15CuO4 and Nd2CuO4 shows that the addition of electrons merely influences the superconducting state. Consequently, the appearance of an antiferromagnetic Mott insulating state solely depends on the annealing process, not on the electron doping or cerium substitution level.
Characterization of Hf1-xZrxO2 Gate Dielectrics with 0≤x≤1 Prepared by Atomic Layer Deposition for Metal Oxide Semiconductor Field Effect Transistor Applications
Authors: Chiang Chen-Kuo , Wu Chien-Hung , Liu Chin-Chien , Lin Jin-Fu , Yang Chien-Lun , Wu Jiun-Yuan , Wang Shui-Jinn
Published: December 2011

In this work, we investigated the influence of incorporating zirconia (ZrO2) in HfO2 gate dielectric on the electrical properties and reliability of n-channel metal oxide semiconductor field effect transistors (nMOSFETs). Detailed film physical, chemical and optical properties of Hf1-x
Zr
x
O2 as a function of Zr content were studied using high resolution transmission electron microscopy (HR-TEM), angle resolved X-ray photoelectron spectroscopy (AR-XPS), and spectroscopic ellipsometer (SE). Compared to HfO2, Hf1-x
Zr
x
O2 provides not only higher k values for further equivalent oxide thickness (EOT) scaling but also lower capacitance–voltage (C–V) hysteresis, lower threshold voltage (V
t) shift (ΔV
t), and higher time-to-failure (TTF) lifetimes. Improved TTF lifetime of as high as three orders of magnitude and 35% lower V
t shift were achieved from the Hf1-x
Zr
x
O2 gate stack with x=0.8. The improved reliability of the Hf1-x
Zr
x
O2 gate dielectric is attributed to the reduced charge trapping in the Hf1-x
Zr
x
O2 gate dielectric caused by the ZrO2 incorporation.
Picosecond Soft-X-ray Laser Interferometer for Probing Nanometer Surface Structure
Authors: Ochi Yoshihiro , Terakawa Kota , Hasegawa Noboru , Yamamoto Minoru , Tomita Takuro , Kawachi Tetsuya , Minami Yasuo , Nishikino Masaharu , Imazono Takashi , Ishino Masahiko , Suemoto Tohru
Published: December 2011

We have developed a soft-X-ray laser interferometer based on a double Lloyd's mirror and obtained a single-shot interferogram using a 7-ps-duration pulse at a wavelength of 13.9 nm. Micrometer grooves with a depth of 5 nm were successfully reconstructed from the interferogram. The lateral and depth resolutions were estimated to be 1.5 µm and better than 1 nm, respectively. This interferometer will be an attractive diagnostic device for observing transiently changing nanometer-scale deviations on solid surfaces.
Aerobic exercise training conserves insulin sensitivity for 1 yr following weight loss in overweight women
Authors: Fisher Gordon , Hunter Gary R. , Gower Barbara A.
Published: December 2011

The objectives of this study were to 1) identify the independent effects of exercise (aerobic or resistance training) and weight loss on whole body insulin sensitivity and 2) determine if aerobic or resistance training would be more successful for maintaining improved whole body insulin sensitivity 1 yr following weight loss. Subjects were 97 healthy, premenopausal women, body mass index (BMI) 27–30 kg/m2. Following randomized assignment to one of three groups, diet only, diet + aerobic, or diet + resistance training until a BMI <25 kg/m2 was achieved, body composition, fat distribution, and whole body insulin sensitivity were determined at baseline, in the weight reduced state, and at 1-yr follow up. The whole body insulin sensitivity index (SI) was determined using a frequently sampled intravenous glucose tolerance test. Results of repeated-measures ANOVA indicated a significant improvement in SI following weight loss. However, there were no group or group×time interactions. At 1-yr follow up, there were no significant time or group interactions for SI; however, there was a significant group×time interaction for SI. Post hoc analysis revealed that women in the aerobic training group showed a significant increased SI from weight reduced to 1-yr follow up ( P < 0.05), which was independent of intra-abdominal adipose tissue and %fat. No significant differences in SI from weight reduced to 1-yr follow up were observed for diet only or diet + resistance groups. Additionally, multiple linear regression analysis revealed that change in whole body insulin sensitivity from baseline to 1-yr follow up was independently associated with the change in V̇o2max from baseline to 1-yr follow up ( P < 0.05). These results suggest that long-term aerobic exercise training may conserve improvements in SI following weight loss and that maintaining cardiovascular fitness following weight loss may be important for maintaining improvements in SI.
Nitric oxide modulates hypoxia-inducible factor-1 and poly(ADP-ribose) polymerase-1 cross talk in response to hypobaric hypoxia
Authors: Martínez-Romero Rubén , Cañuelo Ana , Siles Eva , Oliver F. Javier , Martínez-Lara Esther
Published: December 2011

The physiological response to hypobaric hypoxia represents a complex network of biochemical pathways in which the nitrergic system plays an important role. Previous studies have provided evidence for an interplay between the hypoxia-inducible factor-1 (HIF-1) and poly(ADP-ribose) polymerase-1 (PARP-1) under hypoxia. Here, we evaluate the potential involvement of nitric oxide (NO) in the cross talk between these two proteins. With this aim, we studied comparatively the effect of pharmacological inhibitors of NO production or PARP activity in the response of the mouse cerebral cortex to 4 h of exposure to a simulated altitude of 31,000 ft. Particularly, we analyzed the NO and reactive oxygen species production, the expression of NO synthase (NOS) isoforms, PARP-1 activity, HIF-1α expression and HIF-1 transcriptional activity, the protein level of the factor inhibiting HIF, and, finally, beclin-1 and fractin expression, as markers of cellular damage. Our results demonstrate that the reduction of NO level did not affect reactive oxygen species production but significantly 1) dampened the posthypoxic increase in neuronal NOS and inducible NOS expression without altering endothelial NOS protein level; 2) prevented PARP activation; 3) decreased HIF-1α response to hypoxia; 4) achieved a higher long-term HIF-1 transcriptional activity by reducing factor inhibiting HIF expression; and 5) reduced hypoxic damage. The pharmacological inhibition of PARP reproduced the NOS expression pattern and the HIF-1α response observed in NOS-inhibited mice, supporting its involvement in the NO-dependent regulation of hypoxia. As a whole, these results provide new data about the molecular mechanism underlying the beneficial effects of controlling NO production under hypobaric hypoxic conditions.
Measurement of plasma volume using fluorescent silica-based nanoparticles
Authors: Eisner Christoph , Ow Hooisweng , Yang Tianxin , Jia Zhanjun , Dimitriadis Emilios , Li Lingli , Wang Kenneth , Briggs Josephine , Levine Mark , Schnermann Jurgen , Espey Michael Graham
Published: December 2011

Plasma volume (PV) is an important determinant of cardiovascular function and organ perfusion, and it is the target of infusion and diuretic therapies in daily clinical practice. Despite its fundamental importance PV is not commonly measured because available methods of tracer dilution are reliant on dye substances that suffer from numerous drawbacks including binding plasma proteins, spectral changes, and clearance kinetics that complicate analysis and interpretation. To address these issues, we have tested the utility of fluorescent nanoparticles comprised of a dye-rich silica core and polyethylene glycol-coated shell. Photophysical and visual analysis showed discrete size-gradated nanoparticle populations could be synthesized within a distribution tolerance of ±4 nm, which were optically unaffected in the presence of plasma/albumin. In normal mice, the cutoff for renal filtration of nanoparticles from blood into urine was ≤11 nm. A linear relationship between body weight and PV was readily determined in mice administered far red fluorescent nanoparticles sized either 20 or 30 nm. PV measurements using nanoparticles were correlated to values obtained with Evans blue dye. Induced expansion or contraction of PV was demonstrated with albumin or furosemide administration, respectively, in mice. Longitudinal experiments >30 min required matched untreated control mice to correct for nanoparticle loss (≈30%) putatively to the reticuloendothelial/phagocyte system. Collectively, the findings support a nanotechnology-based solution to methodological problems in measure of PV, notably in clinical settings where information on hemodynamic changes may improve treatment of injury and disease.
Nucleotide Excision Repair Factor XPC Enhances DNA Damage–Induced Apoptosis by Downregulating the Antiapoptotic Short Isoform of Caspase-2
Authors: Wang Qi-En , Han Chunhua , Zhang Bo , Sabapathy Kanaga , Wani Altaf A.
Published: December 2011

XPC protein is a critical DNA damage recognition factor in nucleotide excision repair for which genetic deficiency confers a predisposition to cancer. In this study, we show that XPC has a function that is independent of its canonical function in DNA repair, potentially altering the interpretation of how XPC deficiency leads to heightened cancer susceptibility. XPC enhances apoptosis induced by DNA damage in a p53 nullizygous background, acting downstream of mitochondrial permeabilization and upstream of caspase-9 activation in the DNA damage–induced apoptosis cascade. We found that deficiency in XPC upregulated production of the short isoform of caspase-2 (casp-2S). This upregulation occurred at both protein and mRNA levels through repression of the caspase-2 promoter by XPC protein. Targeted RNAi-mediated downregulation of casp-2S–enhanced UV-induced apoptosis as well as activation of caspase-9 and caspase-6 in XPC-deficient cells, but not in XPC-proficient cells. In addition, XPC overexpression in various p53-deficient cancer cells resistant to cisplatin improved their sensitivity to cisplatin-induced apoptosis. Given that casp-2S functions as an antiapoptotic protein, our findings suggest that XPC enhances DNA damage–induced apoptosis through inhibition of casp-2S transcription. Together, these findings offer a mechanistic foundation to overcome the resistance of highly prevalent p53-deficient tumors to cell death induced by DNA-damaging therapeutic agents, by targeting strategies that inhibit the expression or function of casp-2S. Cancer Res; 72(3); 666–75. ©2011 AACR.
Didymin Induces Apoptosis by Inhibiting N-Myc and Upregulating RKIP in Neuroblastoma
Authors: Singhal Jyotsana , Nagaprashantha Lokesh Dalasanur , Vatsyayan Rit , Ashutosh  , Awasthi Sanjay , Singhal Sharad S.
Published: December 2011

Neuroblastomas arise from the neural crest cells and represent the most common solid tumors outside the nervous system in children. The amplification of N-Myc plays a primary role in the pathogenesis of neuroblastomas, whereas acquired mutations of p53 lead to refractory and relapsed cases of neuroblastomas. In this regard, dietary compounds which can target N-Myc and exert anticancer effects independent of p53 status acquire significance in the management of neuroblastomas. Hence, we investigated the anticancer properties of the flavonoid didymin in neuroblastomas. Didymin effectively inhibited proliferation and induced apoptosis irrespective of p53 status in neuroblastomas. Didymin downregulated phosphoinositide 3-kinase, pAkt, Akt, vimentin, and upregulated RKIP levels. Didymin induced G2/M arrest along with decreasing the levels of cyclin D1, CDK4, and cyclin B1. Importantly, didymin inhibited N-Myc as confirmed at protein, mRNA, and transcriptional level by promoter–reporter assays. High-performance liquid chromatography analysis of didymin-treated (2 mg/kg b.w.) mice serum revealed effective oral absorption with free didymin concentration of 2.1 μmol/L. Further in vivo mice xenograft studies revealed that didymin-treated (2 mg/kg b.w.) animals had significant reductions in tumors size compared with controls. Didymin strongly inhibited the proliferation (Ki67) and angiogenesis (CD31) markers, as well as N-Myc expression, as revealed by the histopathologic examination of paraffin-embedded section of resected tumors. Collectively, our in vitro and in vivo studies elucidated the anticancer properties and mechanisms of action of a novel, orally active, and palatable flavonoid didymin, which makes it a potential new approach for neuroblastoma therapy (NANT) to target pediatric neuroblastomas. Cancer Prev Res; 5(3); 473–83. ©2011 AACR.
Recurrent Pericarditis after Chemotherapy for Acute Myeloid Leukemia: A Case Report and a Modern Approach to Chemotherapy-Induced Pericarditis
Authors: Lee Ga Yeon , Ahn Kye Taek , Jung Chul Won , Chang Sung-A
Published: December 2011

Chemotherapy-induced pericarditis has been reported in a limited number of case series. Furthermore, the management of acute pericarditis associated with chemotherapy is not standardized. In a few case reports, pericarditis associated with chemotherapy has been treated with pericardiocentesis or anti-inflammatory drugs such as steroid or nonsteroidal anti-inflammatory drugs. Recently, colchicine was introduced as an effective tool in order to manage idiopathic recurrent pericarditis. However, the effectiveness of colchicine in chemotherapy-induced pericarditis has never been reported. We report a case of recurrent pericarditis associated with chemotherapy, which was successfully treated with colchicine and ibuprofen. We maintained colchicine when the patient required repeated chemotherapy for relapsed leukemia. And the concomitant use of colchicine prevented the patient from the full development of acute pericarditis. Colchicine may be effective in the treatment and prevention not only of idiopathic recurrent pericarditis but also of acute pericarditis associated with chemotherapy as in this case.
The Longitudinal Relation between Smoking and Muscle Strength in Healthy Adults
Authors: Kok Maarten O. , Hoekstra Trynke , Twisk Jos W.R.
Published: December 2011

Aim: To assess longitudinally whether smoking tobacco is related to muscle strength in healthy adults and to assess the influence of lifestyle covariates on this relation. Methods: Data were obtained from the observational Amsterdam Growth and Health Longitudinal Study, with four repeated measurements at the ages of 21 (n = 181), 27 (n = 144), 32 (n = 426) and 36 (n = 373) years. Knee muscle strength (KMS) was measured at an angle of 300° per second. Smoking and the covariates physical activity and dietary intake were assessed with a questionnaire. Other covariates included physical fitness and body fat percentage. Cardiopulmonary fitness was assessed with a maximal running test and body fatness with skinfold measurements. Sex-specific longitudinal analyses were carried out using generalized estimating equations. Results: In men and women, an inverse relationship between smoking tobacco and KMS was found. Smoking 100 g of tobacco a week resulted in a reduction of 2.9% in KMS in men and a reduction of 5.0% in women. This relation existed largely independently of lifestyle covariates. Conclusion: This study indicates that smoking is inversely related to skeletal muscle strength in healthy adults.
The Increased Risk for Pneumocystis Pneumonia in Patients Receiving Rituximab-CHOP-14 Can Be Prevented by the Administration of Trimethoprim/Sulfamethoxazole: A Single-Center Experience
Authors: Hardak Emilia , Oren Ilana , Dann Eldad J. , Yigla Mordechai , Faibish Tal , Rowe Jacob M. , Avivi Irit
Published: December 2011

Recent studies suggest an increased risk for Pneumocystis jirovecii pneumonia (PJP) in adults receiving short-interval rituximab-CHOP (cyclophosphamide, doxorubicin, vincristine and prednisone) therapy for diffuse large cell B cell lymphoma (DLBCL). This retrospective study evaluates precise PJP incidence and the efficacy of anti-PJP prophylaxis in DLBCL. Patients with DLBCL, aged ≧18 years and treated between December 2004 and December 2010, were included. Details of treatment-related respiratory infections, focusing on PJP incidence, risk factors and prophylaxis, were assessed. A total of 132 patients were analyzed; 47 were treated with rituximab-CHOP therapy every 21 days (R-CHOP-21) and 85 were treated every 14 days (R-CHOP-14). The incidence of treatment-related respiratory infections was higher in patients receiving R-CHOP-14. PJP was diagnosed in 5 patients: 4 in the R-CHOP-14 (6.6%) and 1 in the R-CHOP-21 cohort (2.6%), using triplex polymerase chain reaction (PCR) for PJ in bronchoalveolar fluid. None of the patients receiving P.jirovecii prophylaxis (n = 33) developed PJP, compared with 6.6% of those treated with R-CHOP-14 without such prophylaxis. An older age and R-CHOP administered every 14 rather than every 21 days increased the PJP risk. Trimethoprim/sulfamethoxazole prophylaxis is found to be highly efficient in preventing this life-threatening complication and, therefore, should be recommended for patients receiving the R-CHOP-14 regimen.
Coronary Artery Calcification in Hemophilia A
Authors: Tuinenburg Attie , Rutten Annemarieke , Kavousi Maryam , Leebeek Frank W.G. , Ypma Paula F. , Laros-van Gorkom Britta A.P. , Nijziel Marten R. , Kamphuisen Pieter W. , Mauser-Bunschoten Eveline P. , Roosendaal Goris , Biesma Douwe H. , van der Lugt Aad , Hofman Albert , Witteman Jacqueline C.M. , Bots Michiel L. , Schutgens Roger E.G.
Published: December 2011

Objective—

Ischemic heart disease mortality is lower in hemophilia patients than in the general male population. As coagulation plays a role in the inflammatory pathways involved in atherogenesis, we investigated whether the clotting factor deficiency protects hemophilia patients from developing atherosclerosis.

Methods and Results—

Coronary artery calcification, measured with multidetector-row computed tomography, was compared between 42 men, ≥59 years, with severe or moderate hemophilia A, and 613 nonhemophilic men from the Rotterdam Study, a prospective population-based study. None of the study subjects were HIV infected or had a history of cardiovascular disease. Coronary artery calcification was quantified by calculating the Agatston score and calcification mass. Data were analyzed using linear regression. Mean difference (β) of the natural log–transformed Agatston score between men with and without hemophilia was 0.141 (95% CI −0.602 to 0.885,
P
=0.709). Results did not change after adjustment for age, body mass index, hypercholesterolemia, hypertension, and use of antidiabetic medication (β=0.525, 95% CI −0.202 to 1.252,
P
=0.157). Comparable results were found for calcification mass.

Conclusion—

The extent of coronary artery atherosclerosis is comparable between elderly men with and without hemophilia. Results from this study underline the importance of screening and treating atherosclerosis risk factors in hemophilia patients.
Role of the Indian Ocean in the ENSO–Indian Summer Monsoon Teleconnection in the NCEP Climate Forecast System
Authors: Achuthavarier Deepthi , Krishnamurthy V. , Kirtman Ben P. , Huang Bohua
Published: December 2011

The observed negative correlation between El Niño–Southern Oscillation (ENSO) and the Indian summer monsoon is not simulated by the National Centers for Environmental Prediction (NCEP) Climate Forecast System (CFS) coupled model. The correlation is partially restored in the simulations where the Indian Ocean (IO) sea surface temperature (SST) is prescribed with the daily mean or climatology. Comparison among the simulations suggests that ENSO-induced SST anomalies form a strong dipole pattern oriented along the zonal direction in the IO in the coupled model, preventing the ENSO signals from reaching the Indian monsoon region. In the model, the dipole develops early in the monsoon season and extends to the central equatorial IO while it is formed at the end of the season in observations. The dipole modifies low-level winds and surface pressure, and grows in a positive feedback loop involving winds, surface pressure, and SST. Examination of the mean state in the model reveals that the thermocline is relatively shallow in the eastern IO. This preconditions the ocean such that the atmospheric fluxes can easily impart fluctuations in the subsurface temperature and thereby in the SST. These results suggest that biases in the IO can adversely affect the ENSO–monsoon teleconnection in a coupled model.
Modeling Air–Land–Sea Interactions Using the Integrated Regional Model System in Monterey Bay, California
Authors: Tseng Yu-Heng , Chien Shou-Hung , Jin Jiming , Miller Norman L.
Published: December 2011

The air–land–sea interaction in the vicinity of Monterey Bay, California, is simulated and investigated using a new Integrated Regional Model System (I-RMS). This new model realistically resolves coastal processes and submesoscale features that are poorly represented in atmosphere–ocean general circulation models where systematic biases are seen in the long-term model integration. The current I-RMS integrates version 3.1 of the Weather Research and Forecasting Model and version 3.0 of the Community Land Model with an advanced coastal ocean model, based on the nonhydrostatic Monterey Bay Area Regional Ocean Model. The daily land–sea-breeze circulations and the Santa Cruz eddy are fully resolved using high-resolution grids in the coastal margin. In the ocean, coastal upwelling and submesoscale gyres are also well simulated with this version of the coupled I-RMS. Comparison with observations indicates that the high-resolution, improved representation of ocean dynamics in the I-RMS increases the surface moisture flux and the resulting lower-atmospheric water vapor, a primary controlling mechanism for the enhancement of regional coastal fog formation, particularly along the West Coast of the conterminous United States. The I-RMS results show the importance of detailed ocean feedbacks due to coastal upwelling in the marine atmospheric boundary layer.
Four-Dimensional Variational Data Assimilation for the Canadian Regional Deterministic Prediction System
Authors: Tanguay Monique , Fillion Luc , Lapalme Ervig , Lajoie Manon
Published: December 2011

As a second step in the development of the Canadian Regional Data Assimilation System following Fillion et al., this study extends the approach to the four-dimensional variational data assimilation (4D-Var) context. Emphasis is first put on illustrating the importance of controlling lateral boundary conditions (LBCs). The use in the minimization of a horizontal grid over a domain exceeding the horizontal grid of the high-resolution nonlinear model is then proposed. The authors examine the performance of this 4D-Var formulation as an upcoming upgrade to the currently operational regional three-dimensional variational data assimilation (3D-Var) system. Forecast verifications against radiosonde data for 118 winter cases and 118 summer cases were performed. Results indicate a slight positive impact up to 48 h against North American radiosondes, but with a significant positive impact (especially for winds) at mid- and high latitudes during the summer. Accumulated precipitation scores over 24 h, whether during the first or second day of the forecasts, are slightly improved. The regional 4D-Var analysis system described in this study can run within current real-time “regional run” allocation for operations at the Canadian Meteorological Center (CMC). Future improvements of this system are briefly mentioned especially regarding the upcoming computer upgrade at CMC.
Pharmacodynamic Effects of Steady‐State Fingolimod on Antibody Response in Healthy Volunteers: A 4‐Week, Randomized, Placebo‐Controlled, Parallel‐Group, Multiple‐Dose Study
Authors: Boulton Craig , Meiser Karin , David Olivier J. , Schmouder Robert
Published: December 2011

Fingolimod, a first‐in‐class oral sphingosine 1‐phosphate receptor (S1PR) modulator, is approved in many countries for relapsing‐remitting multiple sclerosis, at a once‐daily 0.5‐mg dose. A reduction in peripheral lymphocyte count is an expected consequence of the fingolimod mechanism of S1PR modulation. The authors investigated if this pharmacodynamic effect impacts humoral and cellular immunogenicity. In this double‐blind, parallel‐group, 4‐week study, 72 healthy volunteers were randomized to steady state, fingolimod 0.5 mg, 1.25 mg, or to placebo. The authors compared T‐cell dependent and independent responses to the neoantigens, keyhole limpet hemocyanin (KLH), and pneumococcal polysaccharides vaccine (PPV‐23), respectively, and additionally recall antigen response (tetanus toxoid [TT]) and delayed‐type hypersensitivity (DTH) to KLH, TT, and Candida albicans. Fingolimod caused mild to moderate decreases in anti‐KLH and anti‐PPV‐23 IgG and IgM levels versus placebo. Responder rates were identical between placebo and 0.5‐mg groups for anti‐KLH IgG (both > 90%) and comparable for anti‐PPV‐23 IgG (55% and 41%, respectively). Fingolimod did not affect anti‐TT immunogenicity, and DTH response did not differ between placebo and fingolimod 0.5‐mg groups. Expectedly, lymphocyte count reduced substantially in the fingolimod groups versus placebo but reversed by study end. Fingolimod was well tolerated, and the observed safety profile was consistent with previous reports.
Modulation of Lymphangiogenesis: A New Target for Aspirin and Other Nonsteroidal Anti‐inflammatory Agents? A Systematic Review
Authors: Yiannakopoulou Eugenia
Published: December 2011

Recent studies have implicated that lymphangiogenesis plays a role in the development of metastasis in experimental cancer models and in certain types of human tumors. Epidemiological and laboratory data suggest that non steroidal anti‐inflammatory agents (NSAIDs) have antitumor activities, although the mechanisms have not been elucidated. This systematic review aimed to synthesize data on the effect of aspirin and other NSAIDs on lymphangiogenesis. In particular, an answer was attempted to be found for the following primary questions: Is there an effect of aspirin and NSAIDs on lymphangiogenesis? If yes, is this effect mediated through COX‐II inhibition or through COX‐II‐independent mechanisms? Electronical databases were searched with the appropriate search terms for the period from 1966 up to and including February 2011. The few identified experimental trials indicated that aspirin and other NSAIDs inhibit lymphangiogenesis, with a potential decrease in metastatic spread, possibly through COX‐II‐dependent regulation of VEGF‐C expression. COX‐II‐independent mechanisms of inhibition of lymphangiogenesis by salicylates and the other NSAIDs have not been investigated. Although further research validation is needed, this proposed effect of NSAIDs might have therapeutic implications in chemoprevention, adjuvant chemotherapy, and treatment of metastatic disease.
Defense mechanisms against herbivory in Picea: sequence evolution and expression regulation of gene family members in the phenylpropanoid pathway
Authors: Porth Ilga , Hamberger Björn , White Richard , Ritland Kermit
Published: December 2011

Background

In trees, a substantial amount of carbon is directed towards production of phenolics for development and defense. This metabolic pathway is also a major factor in resistance to insect pathogens in spruce. In such gene families, environmental stimuli may have an important effect on the evolutionary fate of duplicated genes, and different expression patterns may indicate functional diversification.

Results

Gene families in spruce (Picea) have expanded to superfamilies, including O-methyltransferases, cytochrome-P450, and dirigents/classIII-peroxidases. Neo-functionalization of superfamily members from different clades is reflected in expression diversification. Genetical genomics can provide new insights into the genetic basis and evolution of insect resistance in plants. Adopting this approach, we merged genotype data (252 SNPs in a segregating pedigree), gene expression levels (for 428 phenylpropanoid-related genes) and measures of susceptibility to Pissodes stobi, using a partial-diallel crossing-design with white spruce (Picea glauca). Thirty-eight expressed phenylpropanoid-related genes co-segregated with weevil susceptibility, indicating either causative or reactive effects of these genes to weevil resistance. We identified eight regulatory genomic regions with extensive overlap of quantitative trait loci from susceptibility and growth phenotypes (pQTLs) and expression QTL (eQTL) hotspots. In particular, SNPs within two different CCoAOMT loci regulate phenotypic variation from a common set of 24 genes and three resistance traits.

Conclusions

Pest resistance was associated with individual candidate genes as well as with trans-regulatory hotspots along the spruce genome. Our results showed that specific genes within the phenylpropanoid pathway have been duplicated and diversified in the conifer in a process fundamentally different from short-lived angiosperm species. These findings add to the information about the role of the phenylpropanoid pathway in the evolution of plant defense mechanisms against insect pests and provide substantial potential for the functional characterization of several not yet resolved alternative pathways in plant defenses.
YY1 overexpression is associated with poor prognosis and metastasis-free survival in patients suffering osteosarcoma
Authors: de Nigris Filomena , Zanella Licciana , Cacciatore Francesco , Chiara Anna De , Fazioli Flavio , Chiappetta Gennaro , Apice Gaetano , Infante Teresa , Monaco Mario , Rossiello Raffaele , Rosa Gaetano De , Alberghini Marco , Napoli Claudio
Published: December 2011

Background

The polycomb transcription factor Yin Yang 1 (YY1) overexpression can be causally implicated in experimental tumor growth and metastasization. To date, there is no clinical evidence of YY1 involvement in outcome of patients with osteosarcoma. Prognosis of osteosarcoma is still severe and only few patients survive beyond five years. We performed a prospective immunohistochemistry analysis to correlate YY1 immunostaining with metastatic development and survival in a selected homogeneous group of patients with osteosarcoma.

Methods

We studied 41 patients suffering from osteosarcoma (stage II-IVa). Multivariate analysis was performed using Cox proportional hazard regression to evaluate the correlation between YY1 expression and both metastasis development and mortality.

Results

YY1 protein is not usually present in normal bone; in contrast, a high number of patients (61%) showed a high score of YY1 positive cells (51-100%) and 39% had a low score (10-50% positive cells). No statistical difference was found in histology, anatomic sites, or response to chemotherapy between the two degrees of YY1 expression. Cox regression analysis demonstrated that the highest score of YY1 expression was predictive of both low metastasis-free survival (HR = 4.690, 95%CI = 1.079-20.396; p = 0.039) and poor overall survival (HR = 8.353, 95%CI = 1.863-37.451 p = 0.006) regardless of the effects of covariates such as age, gender, histology and chemonecrosis.

Conclusion

Overexpression of YY1 in primary site of osteosarcoma is associated with the occurrence of metastasis and poor clinical outcome.
Highly sensitive proximity mediated immunoassay reveals HER2 status conversion in the circulating tumor cells of metastatic breast cancer patients
Authors: Kim Phillip , Liu Xinjun , Lee Tani , Liu Limin , Barham Robert , Kirkland Richard , Leesman Glen , Kuller Anne , Ybarrondo Belen , Ng Shi-Chung , Singh Sharat
Published: December 2011

Background

The clinical benefits associated with targeted oncology agents are generally limited to subsets of patients. Even with favorable biomarker profiles, many patients do not respond or acquire resistance. Existing technologies are ineffective for treatment monitoring as they provide only static and limited information and require substantial amounts of tissue. Therefore, there is an urgent need to develop methods that can profile potential therapeutic targets with limited clinical specimens during the course of treatment.

Methods

We have developed a novel proteomics-based assay,CollaborativeEnzymeEnhancedReactive-immunoassay (CEER) that can be used for analyzing clinical samples. CEER utilizes the formation of unique immuno-complex between capture-antibodies and two additional detector-Abs on a microarray surface. One of the detector-Abs is conjugated to glucose oxidase (GO), and the other is conjugated to Horse Radish Peroxidase (HRP). Target detection requires the presence of both detector-Abs because the enzyme channeling event between GO and HRP will not occur unless both Abs are in close proximity.

Results

CEER was able to detect single-cell level expression and phosphorylation of human epidermal growth factor receptor 2 (HER2) and human epidermal growth factor receptor 1 (HER1) in breast cancer (BCa) systems. The shift in phosphorylation profiles of receptor tyrosine kinases (RTKs) and other signal transduction proteins upon differential ligand stimulation further demonstrated extreme assay specificity in a multiplexed array format. HER2 analysis by CEER in 227 BCa tissues showed superior accuracy when compared to the outcome from immunohistochemistry (IHC) (83% vs. 96%). A significant incidence of HER2 status alteration with recurrent disease was observed via circulating tumor cell (CTC) analysis, suggesting an evolving and dynamic disease progression. HER2-positive CTCs were found in 41% (7/17) while CTCs with significant HER2-activation without apparent over-expression were found in 18% (3/17) of relapsed BCa patients with HER2-negative primary tumors. The apparent 'HER2 status conversion' observed in recurrent BCa may have significant implications on understanding breast cancer metastasis and associated therapeutic development.

Conclusion

CEER can be multiplexed to analyze pathway proteins in a comprehensive manner with extreme specificity and sensitivity. This format is ideal for analyzing clinical samples with limited availability.
The splenic Littoral cell angioma in China: a case report and review
Authors: Hu Zong-Qiang , A Yong-Jun , Sun Qiang-Ming , Li Wen , Li Li
Published: December 2011

Littoral cell angioma (LCA) is a rare splenic vascular neoplasm that arises from the cells lining the red pulp sinuses. It is deemed to be a benign and incidental lesion. The earliest literature report of littoral cell angioma has been described by Falk. The examination of samples after splenectomy reveals similar pathological change and its change rule is summarized. However, many recent reports have described it to be a malignant tumor with congenital and immunological associations. Generally speaking, the definitive diagnosis can only be made after histological and immunohistochemical profiles. In this case report, we presented the case of a 48-year-old woman with multiple splenic LCAs. Initially, the patient was characteristics of abdominal distension, weakness and fatigue. Multiple hemangiomas were observed in the spleen through abdominal ultrasonic diagnosis. Computed tomography (CT) scans revealed the splenomegaly with multiple round and hyperdense lesions. The patient subsequently underwent splenectomy. Postoperative histological and immunohistochemical studies confirmed the diagnosis of LCA. Based on the presentation of this case, clinical, radiographic and pathological results of LCA as well as recent advances in our understanding of this uncommon splenic lesion were reviewed. LCA is an uncommon splenic tumor diagnosed in patients with or without abdominal discomfort. Only a few case reports regarding this kind of tumor have been published as inconsistent results. In the present paper, we have reported a case of LCA and reviewed the literature.
Biomarker analysis of Morquio syndrome: identification of disease state and drug responsive markers
Authors: Martell Lisa , Lau Kelly , Mei Miranda , Burnett Vicki , Decker Celeste , Foehr Erik D
Published: December 2011

Background

This study was conducted to identify potential biomarkers that could be used to evaluate disease progression and monitor responses to enzyme replacement therapy (ERT) in patients with mucopolysaccharidosis (MPS) IVA.

Methods

Levels of 88 candidate biomarkers were compared in plasma samples from 50 healthy controls and 78 MPSIVA patients not receiving ERT to test for significant correlations to the presence of MPSIVA. MPSIVA samples were also tested for correlations between candidate biomarkers and age, endurance, or urinary keratin sulfate (KS) levels. Then, levels of the same 88 analytes were followed over 36 weeks in 20 MPSIVA patients receiving ERT to test for significant correlations related to ERT, age, or endurance.

Results

Nineteen candidate biomarkers were significantly different between MPSIVA and unaffected individuals. Of these, five also changed significantly in response to ERT: alpha-1-antitrypsin, eotaxin, lipoprotein(a), matrix metalloprotein (MMP)-2, and serum amyloid P. Three of these were significantly lower in MPSIVA individuals versus unaffected controls and were increased during ERT: alpha-1-antitrypsin, lipoprotein(a), and serum amyloid P.

Conclusions

Candidate biomarkers alpha-1-antitrypsin, lipoprotein(a), and serum amyloid P may be suitable markers, in addition to urinary KS, to follow the response to ERT in MPSIVA patients.
Batch effect correction for genome-wide methylation data with Illumina Infinium platform
Authors: Sun Zhifu , Chai High Seng , Wu Yanhong , White Wendy M , Donkena Krishna V , Klein Christopher J , Garovic Vesna D , Therneau Terry M , Kocher Jean-Pierre A
Published: December 2011

Background

Genome-wide methylation profiling has led to more comprehensive insights into gene regulation mechanisms and potential therapeutic targets. Illumina Human Methylation BeadChip is one of the most commonly used genome-wide methylation platforms. Similar to other microarray experiments, methylation data is susceptible to various technical artifacts, particularly batch effects. To date, little attention has been given to issues related to normalization and batch effect correction for this kind of data.

Methods

We evaluated three common normalization approaches and investigated their performance in batch effect removal using three datasets with different degrees of batch effects generated from HumanMethylation27 platform: quantile normalization at average β value (QNβ); two step quantile normalization at probe signals implemented in "lumi" package of R (lumi); and quantile normalization of A and B signal separately (ABnorm). Subsequent Empirical Bayes (EB) batch adjustment was also evaluated.

Results

Each normalization could remove a portion of batch effects and their effectiveness differed depending on the severity of batch effects in a dataset. For the dataset with minor batch effects (Dataset 1), normalization alone appeared adequate and "lumi" showed the best performance. However, all methods left substantial batch effects intact in the datasets with obvious batch effects and further correction was necessary. Without any correction, 50 and 66 percent of CpGs were associated with batch effects in Dataset 2 and 3, respectively. After QNβ, lumi or ABnorm, the number of CpGs associated with batch effects were reduced to 24, 32, and 26 percent for Dataset 2; and 37, 46, and 35 percent for Dataset 3, respectively. Additional EB correction effectively removed such remaining non-biological effects. More importantly, the two-step procedure almost tripled the numbers of CpGs associated with the outcome of interest for the two datasets.

Conclusion

Genome-wide methylation data from Infinium Methylation BeadChip can be susceptible to batch effects with profound impacts on downstream analyses and conclusions. Normalization can reduce part but not all batch effects. EB correction along with normalization is recommended for effective batch effect removal.
A SNP in Steroid Receptor Coactivator-1 Disrupts a GSK3β Phosphorylation Site and Is Associated with Altered Tamoxifen Response in Bone
Authors: Hartmaier R. J. , Richter A. S. , Gillihan R. M. , Sallit J. Z. , McGuire S. E. , Wang J. , Lee A. V. , Osborne C. K. , O'Malley B. W. , Brown P. H. , Xu J. , Skaar T. C. , Philips S. , Rae J. M. , Azzouz F. , Li L. , Hayden J. , Henry N. L. , Nguyen A. T. , Stearns V. , Hayes D. F. , Flockhart D. A. , Oesterreich S.
Published: December 2011

The coregulator steroid receptor coactivator (SRC)-1 increases transcriptional activity of the estrogen receptor (ER) in a number of tissues including bone. Mice deficient in SRC-1 are osteopenic and display skeletal resistance to estrogen treatment. SRC-1 is also known to modulate effects of selective ER modulators like tamoxifen. We hypothesized that single nucleotide polymorphisms (SNP) in SRC-1 may impact estrogen and/or tamoxifen action. Because the only nonsynonymous SNP in SRC-1 (rs1804645; P1272S) is located in an activation domain, it was examined for effects on estrogen and tamoxifen action. SRC-1 P1272S showed a decreased ability to coactivate ER compared with wild-type SRC-1 in multiple cell lines. Paradoxically, SRC-1 P1272S had an increased protein half-life. The Pro to Ser change disrupts a putative glycogen synthase 3 (GSK3)β phosphorylation site that was confirmed by in vitro kinase assays. Finally, knockdown of GSK3β increased SRC-1 protein levels, mimicking the loss of phosphorylation at P1272S. These findings are similar to the GSK3β-mediated phospho-ubiquitin clock previously described for the related coregulator SRC-3. To assess the potential clinical significance of this SNP, we examined whether there was an association between SRC-1 P1272S and selective ER modulators response in bone. SRC-1 P1272S was associated with a decrease in hip and lumbar bone mineral density in women receiving tamoxifen treatment, supporting our in vitro findings for decreased ER coactivation. In summary, we have identified a functional genetic variant of SRC-1 with decreased activity, resulting, at least in part, from the loss of a GSK3β phosphorylation site, which was also associated with decreased bone mineral density in tamoxifen-treated women.
Limit Theorems for Depths and Distances in Weighted Random B-Ary Recursive Trees
Authors: Munsonius Götz Olaf , Rüschendorf Ludger
Published: December 2011

Limit theorems are established for some functionals of the distances between two nodes in weighted random b-ary recursive trees. We consider the depth of the nth node and of a random node, the distance between two random nodes, the internal path length, and the Wiener index. As an application, these limit results imply, by an imbedding argument, corresponding limit theorems for further classes of random trees: plane-oriented recursive trees and random linear recursive trees.
Structural studies on the interaction of saccharides and glycomimetics with galectin-1: A 3D perspective using a combined molecular modeling and NMR approach
Authors: Martín-Santamaría Sonsoles , Gabius Hans-Joachim , Jiménez-Barbero Jesús
Published: December 2011

The interaction of a variety of saccharides and mimetics thereof with lectin receptors has been studied using a combination of molecular modeling protocols and NMR spectroscopy techniques. It is shown that both methods complement each other in a synergistic manner to provide a detailed perspective of the conformational and structural features of the recognition process.
Get It? Got It. Good! Enhancing New Product Acceptance by Facilitating Resolution of Extreme Incongruity
Authors: Jhang Ji Hoon , Grant Susan Jung , Campbell Margaret C.
Published: December 2011

Highly innovative products may offer consumers greater benefits than incrementally new products, yet they have a higher failure rate. The current research addresses the challenge faced by new products that are extremely different from existing offerings by drawing on theory regarding the evaluation of schema incongruity. The authors posit that consumers' acceptance of extremely incongruent products will increase when firms use strategies that facilitate cognitive flexibility and thus the likelihood that consumers will be able to make sense of incongruent new products. The authors examine the influence of three manipulations of cognitive flexibility—positive affect, a future (vs. past) launch description, and a cognitive flexibility prime—on evaluations of new products. The results from four experiments show that these factors facilitate participants' ability to make sense of extremely incongruent new products and that incongruity resolution leads to more positive evaluations. The results also indicate that understanding the benefits provided by extremely new products, rather than affect arising from resolution, leads to higher evaluations of these products.
Virtual Nature
Authors: Bainbridge William Sims
Published: December 2011

The newest genre of popular culture, computer supported online gameworlds like World of Warcraft (WoW) and Lord of the Rings Online (LOTRO), offers fictional environments where people may explore real-world ethical issues. WoW assumes that people are inevitably locked in competition over scarce resources, and therefore cannot come to a consensus to preserve nature. LOTRO, in contrast, suggests that a religious consensus is possible, but it may never be able to triumph completely over evils like pollution. Both of these gameworlds offer environments where people may enjoy social life and achieve social status at lower resource use than in the so-called ‘real world’.
Volume 4 Peer Reviewers
Authors: Witt Joseph D
Published: December 2011

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‘In the Mills, We Are Not So Far from God and Nature’
Authors: Weiss Jane
Published: December 2011

Beginning in the 1820s, industrialization wrought profound and violent disruptions in the culture of the northeastern United States. Lowell, Massachusetts, grew from a rural village of 1500 people in 1820 to a manufacturing city of 33,000 in 1850. Newcomers found crowds, buildings, and noise spiritually assaultive: one yearned ‘to find myself alone for a brief space, that I might hold communion with my own heart undisturbed’. In response to these yearnings, Lowell’s developers and laborers eschewed artful fabrications of pastoral countryside or wilderness. Instead, they incorporated greenery into canals, factories, and streets, weaving sacred space into industrial urbanism. Writings by Lowell’s ‘mill girls’ detail the spiritual rewards—some actively sought, some serendipitous—of their lives in the city. Although the hopes of the city’s founders and workers that balance could be achieved between mass production of material goods and harmony with nature were not fully realized, the gardens, green spaces, and human ecology of Lowell provide models for sustainable and spiritually fruitful industrialization and urbanism in the twenty-first century.
Sacred Nature
Authors: Shibley Mark A.
Published: December 2011

There is a range of earth-based spirituality in the Paci?c Northwest of the United States that collectively amounts to Nature Religion—a popular religiosity that makes nature sacred. The mythic, experiential, ritualistic, and communal dimensions of this folk religion—expressed in regional literature, rituals of leisure, and the environmental movement—has come to have wide currency in public life. An understanding of this nature religion has broad implications for the study of American politics and religious diversity.