bluuebunny/crossref_metadata_2025 huggingface dataset:
How generalisable to community samples are clinical trial results for treatment of nicotine dependence: a comparison of common eligibility criteria with respondents of a large representative general population survey
Authors: Le Strat Yann , Rehm Jürgen , Le Foll Bernard
Published: January 2011

Objective

To examine the generalisability of findings from clinical trials of individuals with nicotine dependence to a large general population sample.

Methods

Eligibility criteria were drawn from typical criteria of clinical trials for nicotine dependence. The National Epidemiological Survey on Alcohol and Related Conditions (NESARC), a large national sample of the US population, was used to assess how many potentially eligible people would fulfil the eligibility criteria. NESARC interviewed more than 43 000 adults aged 18 years and older. We applied a standard set of eligibility criteria representative of smoking cessation clinical trials to all the 4962 adults with nicotine dependence in the past 12 months, and then to a subgroup of participants motivated to quit (n=4121).

Results

We found that approximately six out of 10 participants (65.89%) with nicotine dependence were excluded by at least one criterion. In the subgroup of nicotine-dependent participants motivated to quit, more than half (58.60%) were excluded by at least one criterion. For the overall sample, smoking 10 cigarettes per day or less and lack of motivation to quit were the two criteria leading to exclusion for the greatest percentage of individuals (32.02% and 17.60%, respectively). For the sample motivated to quit, smoking 10 cigarettes or fewer per day and current depression led most frequently to exclusion (33.79% and 15.71%, respectively).

Conclusions

Further studies and interventions should explore the efficacy of tobacco treatment interventions in a larger segment of the population, notably in the subpopulations of people with nicotine dependence who smoke fewer than 10 cigarettes per day or who have comorbid depression.
rDNA internal transcribed spacer sequence analysis of Craterellus tubaeformis from North America and Europe
Authors: Guo-ying Zhou , Liang Guo , Lin Li , He Li
Published: January 2011

The basidiomycete Craterellus tubaeformis (Fries) Quélet is an important widespread ectomycorrhizal basidiomycete found in the Northern Hemisphere. In this study, 12 samples of C. tubaeformis from North America and Europe were analyzed using internal transcribed spacer (ITS) sequences to reveal the correlation between ITS genotypes and geographic locations and to provide molecular evidence for the identification of C. tubaeformis from different habitats in North America and Europe. The analyses identified abundant sequence variations within C. tubaeformis. The length of the ITS region varied from 571 to 640 bp. The proportion of variable sites was 17.6%, and the proportion of parsimony information sites was 16.7%. Phylogenetic analysis showed some correlations between the ITS genotypes and geographic locations of C. tubaeformis; however, some discrepancies between geographical location and affinity were also found. The results indicated that C. tubaeformis from different habitats in North America and Europe underwent genetic drifting and evolved into 2 different species. nrDNA ITS could be a good markers for distinguishing among C. tubaeformis from different habitats, but rational affinity should be determined by associating the available ITS data with other information sources.
THE ONE-PARAMETER MODEL AT LHC
Authors: MAXIN JAMES , MAYES VAN E. , NANOPOULOS D. V.
Published: January 2011

No-scale supergravity is a framework where it is possible to naturally explain radiative electroweak symmetry breaking and correlate it with the effective SUSY breaking scale. Many string compactifications have a classical no-scale structure, resulting in a one-parameter model (OPM) for the supersymmetry breaking soft terms, which results in a highly constrained subset of mSUGRA. We investigate the allowed supersymmetry parameter space for a generic one-parameter model taking into account the most recent experimental constraints. We also survey the possible signatures which may be observable at the Large Hadron Collider (LHC). Finally, we compare collider signatures of OPM to those from a model with non-universal soft terms, in particular those of an intersecting D6-brane model.
SCALAR–TENSOR THEORY IN TEN DIMENSIONS WITH ANISOTROPIC MATTER
Authors: LEE SUNGGEUN
Published: January 2011

The cosmological behavior is investigated for ten-dimensional scalar–tensor theory with matter. The matter is taken as an anisotropic fluid. As a simple ansatz, the anisotropic fluid for each four and six dimensions satisfies the same type of the equation of state with different coefficients, px,y = γx,yρ. Following the ansatz of the anisotropic matter, the spacetime then has a product structure which means that the spacetime is decomposed as four-dimensional spacetime (Mx) and six-dimensional transverse space (My). We focus on the solution such that the scale factors in each four and six dimensions behave differently. The corresponding cosmological solutions are obtained for general γx,y. By giving specific numeric values for the coefficients of the equation of state γx,y, we find the solution which behaves in such a way that the spatial three dimensions are expanding while the extra six dimensions are contracting.
FORMAL DECOMPOSITION METHOD AND PARAMETRIC NORMAL FORMS
Authors: GAZOR MAJID , YU PEI
Published: January 2011

We introduce a formal decomposition method for efficiently computing the parametric normal form of nonlinear dynamical systems with multiple parameters. Recently introduced notions of formal basis style and costyle are applied through formal decomposition method to obtain the simplest parametric normal form for degenerate nonlinear parametric center. The necessary formulas are derived and implemented using Maple to compute the simplest parametric normal form of degenerate and nondegenerate nonlinear centers. Our program computes the order of any planar parametric systems associated with this singularity.
THE GEOMETRY OF QUADRATIC POLYNOMIAL DIFFERENTIAL SYSTEMS WITH A WEAK FOCUS AND AN INVARIANT STRAIGHT LINE
Authors: ARTÉS JOAN C. , LLIBRE JAUME , SCHLOMIUK DANA
Published: January 2011

Planar quadratic differential systems occur in many areas of applied mathematics. Although more than a thousand papers were written on these systems, a complete understanding of this family is still missing. Classical problems, and in particular, Hilbert's 16th problem [Hilbert, 1900, 1902], are still open for this family. In this article, we conduct a global study of the class QWI of all real quadratic differential systems which have a weak focus and invariant straight lines of total multiplicity of at least two. This family modulo the action of the affine group and time homotheties is three-dimensional and we give its bifurcation diagram with respect to a normal form, in the three-dimensional real projective space of the parameters of this form. The bifurcation diagram yields 73 phase portraits for systems in QWI plus 26 additional phase portraits with the center at its border points. Algebraic invariants are used to construct the bifurcation set. We show that all systems in QWI necessarily have their weak focus of order one and invariant straight lines of total multiplicity exactly two. The phase portraits are represented on the Poincaré disk. The bifurcation set is algebraic and all points in this set are points of bifurcation of singularities. We prove that there is no phase portrait with limit cycles in this class but that there is a total of five phase portraits with graphics, four having the invariant line as a regular orbit and one phase portrait with an infinity of graphics which are all homoclinic loops inside a heteroclinic graphic with two singularities, both at infinity.
CLASSIFICATION OF CHAOTIC REGIMES IN THE T SYSTEM BY USE OF COMPETITIVE MODES
Authors: VAN GORDER ROBERT A. , CHOUDHURY S. ROY
Published: January 2011

We study chaotic behavior of the T system, a three-dimensional autonomous nonlinear system introduced by G. Tigan [Analysis of a dynamical system derived from the Lorenz system, Sci. Bull. Politehnica Univ Timisoara50 (2005) 61–72] which has potential application in secure communications. The recently-developed technique of competitive modes analysis is applied to determine parameter regimes for which the system may exhibit chaotic behavior. We verify that the T system exhibits interesting behaviors in the many parameter regimes thus obtained, thereby demonstrating the great utility of the competitive modes approach in delineating chaotic regimes in multiparemeter systems, where their identification can otherwise involve tedious numerical searches. An additional, novel finding is that one may use competitive modes "at infinity" in order to identify parameter regimes admitting stable equilibria in dynamical models such as the T system.
MULTIDIMENSIONAL ONLINE MOTION PLANNING FOR A SPHERICAL ROBOT
Authors: KRAMER JOSH BROWN , SABALKA LUCAS
Published: January 2011

We consider three related problems of robot movement in arbitrary dimensions: coverage, search, and navigation. For each problem, a spherical robot is asked to accomplish a motion-related task in an unknown environment whose geometry is learned by the robot during navigation. The robot is assumed to have tactile and global positioning sensors. We view these problems from the perspective of (non-linear) competitiveness as defined by Gabriely and Rimon. We first show that in 3 dimensions and higher, there is no upper bound on competitiveness: every online algorithm can do arbitrarily badly compared to the optimal. We then modify the problems by assuming a fixed clearance parameter. We are able to give optimally competitive algorithms under this assumption. We show that these modified problems have polynomial competitiveness in the optimal path length, of degree equal to the dimension.
RELATIVISTIC EFFECTS IN NUCLEAR MATTER AND NUCLEI
Authors: VAN DALEN ERIC , MÜTHER HERBERT
Published: January 2011

The status of relativistic nuclear many-body calculations of nuclear systems to be built up in terms of protons and neutrons is reviewed. In detail, relativistic effects on several aspects of nuclear matter such as the effective mass, saturation mechanism, and the symmetry energy are considered. This review will especially focus on isospin asymmetric issues, since these aspects are of high interest in astrophysical and nuclear structure studies. Furthermore, from the experimental side these aspects are experiencing an additional boost from a new generation of radioactive beam facilities, e.g., the future GSI facility FAIR in Germany or SPIRAL2 at GANIL/France. Finally, the prospects of studying finite nuclei in microscopic calculations which are based on realistic NN interactions by including relativistic effects in calculations of low momentum interactions are discussed.
EXACT SOLUTIONS OF DIRAC EQUATION WITH HARTMANN POTENTIAL BY NIKIFOROV–UVAROV METHOD
Authors: HAMZAVI M. , HASSANABADI H. , RAJABI A. A.
Published: January 2011

We investigate the exact solution of the Dirac equation for the Hartmann potential. The radial and polar parts of the Dirac equation are solved by Nikiforov–Uvarov method. The bound state energy eigenvalues and the corresponding two-component spinor wave functions of the Dirac particles are obtained.
THE MASS OF THE NEUTRINOS
Authors: SIDHARTH B. G.
Published: January 2011

In the theory of the Dirac equation and in the standard model, the neutrino is massless. Both these theories use Lorentz invariance. In modern approaches however, spacetime is no longer smooth, and this modifies special relativity. We show how such a modification throws up the mass of the neutrino.
EXPERIMENTAL INVESTIGATION ON THE OPTIMAL DESIGN OF WATER TANK FOR DOMESTIC HOT WATER SUPPLY USING PEMFC CO-GENERATION SYSTEM
Authors: HWANG YUJIN , AHN YOUNGCHULL , CHEONG SEONGIR , JIN KEUNHO , LEE JAEKUEN
Published: January 2011

There are many attempts to use a fuel cell system as a residential power generation system. The purpose of this study is to investigate the optimal design of a water tank for a hot water system when the fuel cell co-generation system is combined with a domestic hot water supply system. The demands of hot water supply per month per home for 76–168 m2 of acreage are investigated in Busan for a year. It showed somewhat large differences between the actual demand and the designed demand of hot water, but the actual capacity of hourly averaged hot water demands is analyzed as 60 ℓ/h in this study based on the actual demand. The experiments are performed in the various inlet and outlet locations of nozzles in the hot water tank, and the hot water consumption rates. The experimental results showed that the optimal capacity of the water tank is 200 ℓ when the thermal efficiency, the storing capacity of hot water and the space for installation are considered.
REALIZATION OF HIGH IPF ICE SLURRY FOR DISTRICT COOLING
Authors: LEE YOON PYO , LEE SANG HOON , YOO HOSEON
Published: January 2011

The Production of high IPF (ice packing factor) ice slurry was realized. The ice slurry maker which can efficiently produce ice slurry under ice particles in-flowing condition was revised. We removed the stagnant region at the top of the ice slurry maker, thereby high IPF ice slurry was realized. The IPF controller with 6 mm diameter holes could not control IPF in a pipe. This is because ice particles in ice slurry flow exist homogeneously not only at the upper part but also at the bottom part. We changed the hole size at the surface of the IPF controller by means of fine meshes, which, then, increased the IPF in the pipe by 70% when the mesh size was 80 μm or less.
Adaptive induction of NF-E2-related factor-2-driven antioxidant genes in endothelial cells in response to hyperglycemia
Authors: Ungvari Zoltan , Bailey-Downs Lora , Gautam Tripti , Jimenez Rosario , Losonczy Gyorgy , Zhang Cuihua , Ballabh Praveen , Recchia Fabio A. , Wilkerson Donald C. , Sonntag William E. , Pearson Kevin , de Cabo Rafael , Csiszar Anna
Published: January 2011

Hyperglycemia in diabetes mellitus promotes oxidative stress in endothelial cells, which contributes to development of cardiovascular diseases. Nuclear factor erythroid 2-related factor-2 (Nrf2) is a transcription factor activated by oxidative stress that regulates expression of numerous reactive oxygen species (ROS) detoxifying and antioxidant genes. This study was designed to elucidate the homeostatic role of adaptive induction of Nrf2-driven free radical detoxification mechanisms in endothelial protection under diabetic conditions. Using a Nrf2/antioxidant response element (ARE)-driven luciferase reporter gene assay we found that in a cultured coronary arterial endothelial cell model hyperglycemia (10–30 mmol/l glucose) significantly increases transcriptional activity of Nrf2 and upregulates the expression of the Nrf2 target genes NQO1, GCLC, and HMOX1. These effects of high glucose were significantly attenuated by small interfering RNA (siRNA) downregulation of Nrf2 or overexpression of Keap-1, which inactivates Nrf2. High-glucose-induced upregulation of NQO1, GCLC, and HMOX1 was also prevented by pretreatment with polyethylene glycol (PEG)-catalase or N-acetylcysteine, whereas administration of H2O2 mimicked the effect of high glucose. To test the effects of metabolic stress in vivo, Nrf2+/+ and Nrf2−/− mice were fed a high-fat diet (HFD). HFD elicited significant increases in mRNA expression of Gclc and Hmox1 in aortas of Nrf2+/+ mice, but not Nrf2−/− mice, compared with respective standard diet-fed control mice. Additionally, HFD-induced increases in vascular ROS levels were significantly greater in Nrf2−/− than Nrf2+/+ mice. HFD-induced endothelial dysfunction was more severe in Nrf2−/− mice, as shown by the significantly diminished acetylcholine-induced relaxation of aorta of these animals compared with HFD-fed Nrf2+/+ mice. Our results suggest that adaptive activation of the Nrf2/ARE pathway confers endothelial protection under diabetic conditions.
Some New Iterative Methods for Nonlinear Equations
Authors: Noor Muhammad Aslam , Noor Khalida Inayat , Al-Said Eisa , Waseem Muhammad
Published: January 2011

We suggest and analyze some new iterative methods for solving the nonlinear equations f(x) = 0 using the decomposition technique coupled with the system of equations. We prove that new methods have convergence of fourth order. Several numerical examples are given to illustrate the efficiency and performance of the new methods. Comparison with other similar methods is given.
Template‐Based Electrochemically Controlled Growth of Segmented Multimetal Nanorods
Authors: Kim Mee Rahn , Lee Dong Ki , Jang Du-Jeon
Published: January 2011

Multisegmented one‐dimensional nanostructures composed of gold, copper, and nickel have been fabricated by depositing metals electrochemically in the pores of anodic aluminum oxide (AAO) templates. The electrodeposition process has been carried out using a direct current in a two‐electrode electrochemical cell, where a silver‐evaporated AAO membrane and a platinum plate have served as a working electrode and a counter electrode, respectively. The striped multimetal rods with an average diameter of about 300 nm have tunable lengths ranging from a few hundred nanometers to a few micrometers. The lengths and the sequence of metal segments in a striped rod can be tailored readily by controlling the durations of electrodeposition and the order of electroplating solutions, respectively.
Positive Solutions for Multipoint Boundary Value Problem of Fractional Differential Equations
Authors: Zhong Wenyong
Published: January 2011

We study the existence and multiplicity of positive solutions for the fractional m‐point boundary value problem , 0 < t < 1, u(0) = u′(0) = 0, , where 2 < α < 3, is the standard Riemann‐Liouville fractional derivative, and f : [0,1]×[0, ∞)↦[0, ∞) is continuous. Here, ai⩾0 for i = 1, …, m − 2, 0 < ξ1 < ξ2 < ⋯<ξm−2 < 1, and with ρ < 1. In light of some fixed point theorems, some existence and multiplicity results of positive solutions are obtained.
Screening for EGFR Mutations in Patients with Head and Neck Cancer Treated with Gefitinib on a Compassionate-Use Program: A Hellenic Cooperative Oncology Group Study
Authors: Murray Samuel , Bobos Mattheos , Angouridakis Nikolaos , Nikolaou Angelos , Linardou Helena , Razis Evangelia , Fountzilas George
Published: January 2011

Background and Aim. EGFR is commonly expressed in cancers of the head and neck (H and N), and anti-EGFR agents have demonstrated improvements in outcomes (TTP and OS). The aim of this study was to determine EGFR gene status in H and N cancer patients treated with gefitinib and to correlate mutational status with clinico-pathological data and response.Patients and Methods. Patients with histologically confirmed H and N cancer having failed prior treatment for advanced disease entered this compassionate-use-program. Nineteen patients received gefitinib. EGFR expression was assessed by IHC, gene copy number by FISH, and mutation analysis was conducted forEGFR(18-21),KRAS,BRAF(V600E), andHER-2 exon 20. An additional TKI naive cohort of 73 patients was also screened.Results. Mutations were detected in 6/19 patients (3×EGFR, 1×KRAS, and 2×HER2-exon 20). There were no significant differences in TTP or OS for patients with somaticEGFRmutations. NoBRAFmutations were detected.Conclusions. The incidence ofEGFRmutations in H and N cancer in this study was 5.3%. No statistically relevant correlations between mutation or gene gain and response or survival were observed. Due to the limited number of patients and low incidence of genetic aberrations in the genes analyzed, additional studies are warranted.
Dyon Condensation and Dual Superconductivity in Abelian Higgs Model of QCD
Authors: Rajput B. S. , Kumar Sandeep
Published: January 2011

Constructing the effective action for dyonic field in Abelian projection of QCD, it has been demonstrated that any charge (electrical or magnetic) of dyon screens its own direct potential to which it minimally couples and antiscreens the dual potential leading to dual superconductivity in accordance with generalized Meissner effect. Taking the Abelian projection of QCD, an Abelian Higgs model, incorporating dual superconductivity and confinement, has been constructed and its representation has been obtained in terms of average of Wilson loop.
Short-and Long-Term Clinical Outcomes of Infliximab in Fulminant Ulcerative Colitis
Authors: Florholmen J. , Øverland G. , Olsen T. , Rismo R. , Cui G. , Christiansen I. , Paulssen E. J. , Goll R.
Published: January 2011

The aim was to characterize short- and long-term clinical outcomes of infliximab in fulminant ulcerative colitis. Patients with severe ulcerative colitis meeting the criteria of fulminant colitis after 3 days of glucocorticosteroid treatment were randomized to control or additional induction therapy of infliximab followed by an on demand/maintenance therapy of infliximab. Twenty six patients with fulminant colitis were equally randomized. At Day 7, ten patients in the control group and none in the infliximab group were in the need of colectomy (). Due to superior effect of infliximab, patients in the control group were of ethical reasons transformed to infliximab treatment instead of performing colectomy. The probability to avoid colectomy was 0.66 with a median observation time of 52 months and a maximal of 91 months. The addition of azathioprine reduced the risk of late colectomy. We conclude that infliximab is effective in preventing early and late colectomy in fulminant colitis.
Homotopy Analysis Method for Nonlinear Dynamical System of an Electrostatically Actuated Microcantilever
Authors: Chen Y. M. , Meng G. , Liu J. K. , Jing J. P.
Published: January 2011

The homotopy analysis method (HAM) is employed to propose an approach for solving the nonlinear dynamical system of an electrostatically actuated micro‐cantilever in MEMS. There are two relative merits of the presented HAM compared with some usual procedures of the HAM. First, a new auxiliary linear operator is constructed. This operator makes it unnecessary to eliminate any secular terms. Furthermore, all the deformation equations are purely linear. Numerical examples show the excellent agreement of the attained solutions with numerical ones. The respective effects of applied voltage, cubic nonlinear stiffness, gap distance, and squeeze film damping on vibration responses are analyzed detailedly.
A Construction of Mirror Q‐Algebras
Authors: So Keum Sook
Published: January 2011

We investigate how to construct mirror
Q‐algebras of a
Q‐algebra, and we obtain the necessary conditions for
M(X) to be a Q‐algebra.
Mouse Models of Escherichia coli O157:H7 Infection and Shiga Toxin Injection
Authors: Mohawk Krystle L. , O′Brien Alison D.
Published: January 2011

Escherichia coli O157:H7 has been responsible for multiple food‐ and waterborne outbreaks of diarrhea and/or hemorrhagic colitis (HC) worldwide. More importantly, a portion of E. coli O157:H7‐infected individuals, particularly young children, develop a life‐threatening sequela of infection called hemolytic uremic syndrome (HUS). Shiga toxin (Stx), a potent cytotoxin, is the major virulence factor linked to the presentation of both HC and HUS. Currently, treatment of E. coli O157:H7 and other Stx‐producing E. coli (STEC) infections is limited to supportive care. To facilitate development of therapeutic strategies and vaccines for humans against these agents, animal models that mimic one or more aspect of STEC infection and disease are needed. In this paper, we focus on the characteristics of various mouse models that have been developed and that can be used to monitor STEC colonization, disease, pathology, or combinations of these features as well as the impact of Stx alone.
Japan′s Evolving Nested Municipal Hierarchy: The Race for Local Power in the 2000s
Authors: Jacobs A. J.
Published: January 2011

In agreement with Nested City theory, this paper illustrates how Japan′s municipal hierarchy has evolved and remained embedded within that nation′s particular historical‐political‐economic context. It chronicles how municipalities have attained status based upon the role they have played in the country′s political, economic, and military history, and, more recently, their population size. It then shows how during the post‐war period, the tiers within this urban stratification system were expanded and institutionalized by national laws governing municipalities. Drawing upon more than 100 interviews with local government officials in nine prefectures, it then reveals how a shift in national policy toward decentralization in the late‐1990s sparked a race for higher municipal status in Japan′s national hierarchy, during the 2000s, and thereby, local power.
Multiphoton Microscopy for Ophthalmic Imaging
Authors: Gibson Emily A. , Masihzadeh Omid , Lei Tim C. , Ammar David A. , Kahook Malik Y.
Published: January 2011

We review multiphoton microscopy (MPM) including two-photon autofluorescence (2PAF), second harmonic generation (SHG), third harmonic generation (THG), fluorescence lifetime (FLIM), and coherent anti-Stokes Raman Scattering (CARS) with relevance to clinical applications in ophthalmology. The different imaging modalities are discussed highlighting the particular strength that each has for functional tissue imaging. MPM is compared with current clinical ophthalmological imaging techniques such as reflectance confocal microscopy, optical coherence tomography, and fluorescence imaging. In addition, we discuss the future prospects for MPM in disease detection and clinical monitoring of disease progression, understanding fundamental disease mechanisms, and real-time monitoring of drug delivery.
A Randomized Trial of Dietary Intervention for Breast Cancer Prevention
Authors: Martin Lisa J. , Li Qing , Melnichouk Olga , Greenberg Cary , Minkin Salomon , Hislop Greg , Boyd Norman F.
Published: January 2011

Epidemiologic data and animal experiments suggest that dietary fat may influence risk of breast cancer. To determine whether intervention with a low-fat, high-carbohydrate diet would reduce breast cancer incidence in women at increased risk of the disease, we carried out a randomized controlled trial in Canada. We recruited 4,690 women with extensive mammographic density and randomized them to an intervention group or a comparison group. The intervention group received intensive dietary counseling to reduce fat intake to a target of 15% of calories and increase carbohydrate to 65% of calories. Dietary intakes were assessed throughout using food records. Subjects were followed for at least 7 years and for an average of 10 years. The main outcome was invasive breast cancer. Percentage of calories from fat in the intervention group decreased from 30% at baseline to 20% after randomization and remained 9% to 10% lower than the comparison group throughout. There were 118 invasive breast cancers in the intervention group and 102 in the comparison group [adjusted hazard ratio = 1.19 (95% CI: 0.91–1.55)]. Analysis of food records showed that fat intake at baseline and after randomization was not associated with total breast cancer incidence. Greater weight and lower carbohydrate intake at baseline and after randomization were associated with an increased risk of estrogen receptor (ER)-positive breast cancer. Our findings suggest that a sustained reduction in dietary fat intake did not reduce risk of breast cancer in women with extensive mammographic density. Weight and carbohydrate intakes were associated with risk of ER-positive breast cancer. Cancer Res; 71(1); 123–33. ©2011 AACR.
Lactate Dehydrogenase B Is Critical for Hyperactive mTOR-Mediated Tumorigenesis
Authors: Zha Xiaojun , Wang Fang , Wang Ying , He Shaozong , Jing Yanling , Wu Xueyan , Zhang Hongbing
Published: January 2011

Mammalian target of rapamycin (mTOR) is a major downstream effector of the receptor tyrosine kinase (RTK)–phosphoinositide 3-kinase (PI3K)–v-akt murine thymoma viral oncogene homologue 1 (AKT) signaling pathway. Although this signaling network is frequently altered in cancer, the underlying mechanisms that cause tumorigenesis as a result of activated mTOR remain largely unknown. We report here that expression of lactate dehydrogenase B (LDHB), a critical enzymatic activator of glycolysis, was upregulated in an mTOR-dependent manner in TSC1−/−, TSC2−/−, PTEN−/−, or activated AKT1-expressing mouse embryonic fibroblasts (MEF). LDHB gene expression was transactivated by signal transducer and activator of transcription 3 (STAT3), a key tumorigenic driver in many cancers, acting as a downstream mTOR effector in both mouse MEFs and human cancer cells. LDHB attenuation blunted the tumorigenic potential of oncogenic TSC2-null cells in nude mice. We concluded that LDHB is a downstream target of mTOR that is critical for oncogenic mTOR-mediated tumorigenesis. Our findings offer proof of concept for targeting LDHB as a therapeutic strategy in cancers driven by aberrant activation of the RTK-PI3K-AKT-mTOR signaling cascade. Cancer Res; 71(1); 13–8. ©2011 AACR.
Plasminogen Activator uPA Is a Direct Transcriptional Target of the JAG1-Notch Receptor Signaling Pathway in Breast Cancer
Authors: Shimizu Mamiko , Cohen Brenda , Goldvasser Pavel , Berman Hal , Virtanen Carl , Reedijk Michael
Published: January 2011

Aberrant activation of the Notch receptor signaling pathway and overexpression of the Notch ligand JAG1 are associated with poor outcome in breast cancer. The plasminogen activator system, which includes urokinase-type plasminogen activator (uPA), has been validated as a marker of recurrence, high metastasis risk and death in breast malignancy. By using microarray profiling of breast cancer cell lines that had undergone siRNA-mediated abrogation of Notch signaling we uncovered a link between activated Notch signaling and uPA expression. An association between elevated expression of the Notch ligand JAG1, uPA, and the basal-like breast cancer subtype was confirmed in breast cancer cell lines. The association between JAG1 and uPA expression persisted in a survey of primary carcinomas of the breast. We found that Notch knockdown reduced transcription of uPA and phenocopied uPA knockdown in breast cancer cells. Through mutational analysis we identified a CBF-1 binding site in the uPA promoter that is required for direct transcriptional regulation by Notch. These data suggest that JAG1-induced Notch activation results in breast cancer progression through upregulation of the plasminogen activator system, directly linking these 2 important pathways of poor prognosis. Cancer Res; 71(1); 277–86. ©2010 AACR.
High Basal Nuclear Levels of Nrf2 in Acute Myeloid Leukemia Reduces Sensitivity to Proteasome Inhibitors
Authors: Rushworth Stuart A. , Bowles Kristian M. , MacEwan David J.
Published: January 2011

Proteasome inhibitors such as bortezomib exhibit clinical efficacy in multiple myeloma, but studies in acute myeloid leukemia (AML) have been disappointing to date. The apparent failure in AML likely reflects a lack of biological understanding that might clarify applications of proteosome inhibitors in this disease. Here we show that AML cells are considerably less sensitive than control noncancerous cells to bortezomib-induced cytotoxicity, permitting most bortezomib-treated AML cells to survive treatment. We traced reduced bortezomib sensitivity to increased basal levels of nuclear Nrf2, a transcription factor that stimulates protective antioxidant enzymes. Bortezomib stimulates cytotoxicity through accumulation of reactive oxygen species (ROS) but elevated basal levels of nuclear Nrf2 present in AML cells reduced ROS levels, permitting AML cells to survive drug treatment. We further found that the Nrf2 transcriptional repressor Bach1 is rapidly inactivated by bortezomib, allowing rapid induction of Nrf2-regulated cytoprotective and detoxification genes that protect AML cells from bortezomib-induced apoptosis. By contrast, nonmalignant control cells lacked constitutive activation of Nrf2, such that bortezomib-mediated inactivation of Bach1 led to a delay in induction of Nrf2-regulated genes, effectively preventing the manifestation of apoptotic protection that is seen in AML cells. Together, our findings argue that AML might be rendered sensitive to proteasome inhibitors by cotreatment with either an Nrf2-inhibitory or Bach1-inhibitory treatment, rationalizing a targeted therapy against AML. Cancer Res; 71(5); 1999–2009. ©2011 AACR.
Detection of Circulating Tumor Cells in Human Peripheral Blood Using Surface-Enhanced Raman Scattering Nanoparticles
Authors: Wang Xu , Qian Ximei , Beitler Jonathan J. , Chen Zhuo Georgia , Khuri Fadlo R. , Lewis Melinda M. , Shin Hyung Ju C. , Nie Shuming , Shin Dong M.
Published: January 2011

The detection and characterization of circulating tumor cells (CTC) holds great promise for personalizing medicine and optimizing systemic therapy. However, low specificity, low sensitivity, and the time consuming nature of current approaches have impeded clinical adoption. Here we report a new method using surface-enhanced Raman spectroscopy (SERS) to directly measure targeted CTCs in the presence of white blood cells. SERS nanoparticles with epidermal growth factor peptide as a targeting ligand have successfully identified CTCs in the peripheral blood of 19 patients with squamous cell carcinoma of the head and neck (SCCHN), with a range of 1 to 720 CTCs per milliliter of whole blood. Our technique may provide an important new clinical tool for management of patients with SCCHN and other cancers. Cancer Res; 71(5); 1526–32. ©2011 AACR.
Negative Regulation of the Hippo Pathway by E3 Ubiquitin Ligase ITCH Is Sufficient to Promote Tumorigenicity
Authors: Salah Zaidoun , Melino Gerry , Aqeilan Rami I.
Published: January 2011

The Hippo tumor suppressor pathway, originally defined in fruit flies, regulates cellular proliferation and survival and exerts profound effects on normal mammalian cell fate and tumorigenesis. The present understanding of Hippo pathway components and mechanisms remains incomplete in cancer. WW domain-containing proteins regulate diverse biological processes through interaction with proline-tyrosine (PPxY)-containing targets. In this study, we report that the E3 ubiquitin ligase ITCH regulates stability of LATS1, a serine/threonine kinase in the Hippo pathway, through protein–protein interaction of the PPxY motifs of LATS1 with the WW domains of ITCH. Ubiquitination of LATS1 catalyzed by ITCH stimulated the proteasomal degradation of LATS1. Furthermore, ITCH-mediated degradation of LATS1 was associated with enhanced cell growth, induction of epithelial-mesenchymal transition, and increased tumorigenicity. Conversely, ITCH depletion increased LATS1 levels, enhancing FAS-induced apoptosis and reducing proliferation, survival, and migration. These phenotypes were rescued when both ITCH and LATS1 were depleted. Together, our results reveal a novel functional link between ITCH and the Hippo pathway, deepening their critical roles in tumorigenesis. Cancer Res; 71(5); 2010–20. ©2011 AACR.
Nonmotor Disturbances in Parkinson’s Disease
Authors: Bassetti Claudio L.
Published: January 2011

Nonmotor disturbances (NMDs) affect most patients with Parkinson’s disease (PD) and often have a profound impact on their quality of life. NMDs such as depression, anxiety, fatigue, REM sleep behavior disorder, constipation, delayed gastric emptying, altered olfaction and pain can precede the onset of motor symptoms. Other NMDs, including hallucinations, dementia, excessive daytime sleepiness, insomnia, orthostatic hypotension and bladder disturbances, typically appear later in the course of PD. For most NMDs of PD, nondopaminergic and non-nigrostriatal mechanisms (e.g. neurodegeneration of other transmitter systems in the cortex and brainstem, side effects of medications, genetic and psychosocial factors) are considered more relevant than the ‘classical’ dopaminergic-nigrostriatal dysfunction. The recognition of NMDs requires a high degree of clinical suspicion, the use of specific questionnaires and ancillary tests. Pharmacological and nonpharmacological approaches can be effective, but for most forms of treatment of NMDs, the scientific evidence is limited.
Do Depressed Patients Lose Their Sense of Humor
Authors: Falkenberg Irina , Jarmuzek Jana , Bartels Mathias , Wild Barbara
Published: January 2011

Background: Humor is an important coping mechanism and can improve mood. However, it is unclear whether depressed patients are able to enjoy funny material, e.g. jokes, and make use of their sense of humor for coping with adverse situations. This study aims at investigating the influence of depression on various aspects of humor abilities such as sense of humor, appraisal of funny material and exhilaration. Sampling and Methods: Nineteen patients with major depression and 18 healthy controls were examined with standardized self-assessment questionnaires to study potential group differences in humor type preferences, state and trait cheerfulness, seriousness and bad mood as well as humor coping. Results: Patients and controls did not differ in their humor type preferences and the degree to which humorous stimuli were rated as being funny. The readiness to react to funny stimuli with exhilaration was significantly less pronounced in the patient group. The patients’ tendency to use humor as a coping strategy was significantly lower than in the control group. Conclusion: The susceptibility to humorous material seems to be unaffected by the disorder. Introducing means to promote humor behavior might therefore be beneficial to depressed patients. Study limitations were that only self-rating instruments were used and that the medication was inhomogeneous.
Neural Substrates of Affective Face Recognition in Alexithymia: A Functional Magnetic Resonance Imaging Study
Authors: Lee Byeong-Taek , Lee Hwa-Young , Park Sae-Ah , Lim Jin-Young , Tae Woo Suk , Lee Min-Soo , Joe Sook-Haeng , Jung In-Kwa , Ham Byung-Joo
Published: January 2011

Background: Alexithymia is a condition characterized by deficits in cognitive processing and the regulation of emotions. Several theories have been proposed for the underlying neurobiology, but the etiology of alexithymia remains unclear. Methods: Using functional magnetic resonance imaging, we investigated brain activation measured on the scale of alexithymia in 38 individuals who were presented with neutral, sad, or angry affective facial stimuli. Results: We found significant inverse correlations between the degree of alexithymia represented by the Korean version of the Toronto Alexithymia Scale (TAS-20K) and the intensity of the neural response to angry facial stimuli over neutral facial stimuli in the right caudate. This result was mainly due to the activations in factor 2 (difficulty describing feelings) in TAS-20K scale. Conclusions: The results suggest that functional impairments in the caudate of the fronto-striatal circuitry may play important roles in the pathophysiology of alexithymia.
The Prevalence of Delusion-Like Beliefs Relative to Sociocultural Beliefs in the General Population
Authors: Pechey Rachel , Halligan Peter
Published: January 2011

Background: Delusions are defined as false beliefs different from those that almost everyone else believes. The aim was to develop a new measure (the Cardiff Beliefs Questionnaire, CBQ) to establish the range and prevalence of delusion-like beliefs (DLB) and compare these to other types of beliefs in the general population. Sampling and Methods: A total of 1,000 participants completed the CBQ, which uniquely assesses a broader range of currently held beliefs [delusion-like (bizarre and non-bizarre), paranormal and religious and general political/social beliefs) using this large stratified sample. Results: Strong belief in 1 or more DLB was reported by 39% of the participants (91% reporting ‘weak’, ‘moderate’ or ‘strong’ belief in at least 1 DLB). Moreover, 25% endorsed at least 1 bizarre DLB (76% one or more at any strength). Endorsements of DLB were strongly correlated with paranormal and religious beliefs but not general political/social beliefs. Conclusions: Both bizarre and non-bizarre DLB are frequently found in the general population, lending support to the psychosis continuum account and need to revise key clinical criteria used to diagnose delusions. The good psychometric properties demonstrated by the CBQ indicate that this measure is a useful tool to investigate the wider continuum of beliefs held in the general population.
Birch Pollen Honey for Birch Pollen Allergy – A Randomized Controlled Pilot Study
Authors: Saarinen K. , Jantunen J. , Haahtela T.
Published: January 2011

Background: Only a few randomized controlled trials have been carried out to evaluate various complementary treatments for allergic disorders. This study assessed the effects of the preseasonal use of birch pollen honey (BPH; birch pollen added to honey) or regular honey (RH) on symptoms and medication during birch pollen season. Methods: Forty-four patients (59% female, mean age 33 years) with physician-diagnosed birch pollen allergy consumed either BPH or RH daily in incremental amounts from November 2008 to March 2009. Seventeen patients (53% female, mean age 36 years) on their usual allergy medication served as the control group. From April to May, patients recorded daily rhinoconjunctival and other symptoms and their use of medication. Fifty patients completed the study. Results: During birch pollen season in 2009, BPH patients reported a 60% lower total symptom score (p < 0.01), twice as many asymptomatic days (p < 0.01), and 70% fewer days with severe symptoms (p < 0.001), and they used 50% less antihistamines (p < 0.001) compared to the control group. The differences between the BPH and RH groups were not significant. However, the BPH patients used less antihistamines than did the RH patients (p < 0.05). Conclusions: Patients who preseasonally used BPH had significantly better control of their symptoms than did those on conventional medication only, and they had marginally better control compared to those on RH. The results should be regarded as preliminary, but they indicate that BPH could serve as a complementary therapy for birch pollen allergy.
Arginine Kinase from the Cellar Spider (Holocnemus pluchei): A New Asthma-Causing Allergen
Authors: Bobolea Irina , Barranco Pilar , Pastor-Vargas Carlos , Iraola Victor , Vivanco Fernando , Quirce Santiago
Published: January 2011

Background: We report a 31-year-old farmer whose work consists in handling cereal and vegetables, who consulted our clinic because of asthma symptoms after inhalation of dust during manipulation of the deposited material, usually inside the warehouse. Methods and Results: Skin prick tests and specific immunoglobulin E (IgE) determinations were negative with common aeroallergens. The patient noted the presence of many spiders in the warehouse, which were identified as the cellar spider Holocnemus pluchei and the common house spider, Tegenaria domestica. Extracts of spider bodies brought in by the patient were obtained and used to perform in vivo and in vitro studies. Molecular characterization of IgE-binding bands was performed by mass spectrometry. We obtained positive prick tests to the extracts of the bodies of both spiders. Immunoblotting displayed different bands in both spider extracts, in a range of 20–70 kDa. All were hemocyanins, except for a 17-kDa protein of Holocnemus identified as an arginine kinase (AK). Bronchial challenge was positive with the extract of the cellar spider and with the AK, but was negative with the domestic house spider. Conclusion: We present the first case of respiratory allergy due to sensitization to AK from a common spider, confirmed by bronchial provocation tests.
Iniencephaly: Clinical, Radiological and Surgical Findings
Authors: Shams Amiri Rouzbeh , Faghih Jouibari Morteza , Nejat Farideh , El Khashab Mostafa
Published: January 2011

The authors report a case of iniencephaly in a 6-year-old boy with a huge occipital bone defect and encephalocele, extensive spina bifida of the cervical vertebrae and fixed retroflexion of the head due to Sprengel’s deformity. He presented with some cerebellar and cranial nerve symptoms and new episodes of neck pain and drop attacks. Brain imaging confirmed progressive deformity of the brain stem, cerebellar herniation into the encephalocele sac and ventriculomegaly. Surgical repair of the encephalocele was performed with preservation of all herniated cerebellar tissue and the release of thick arachnoid adhesions to make more space to return the herniated neural tissue from the sac to the cranium. The patient was found to have progressive facial palsy and intracranial hypertension 3 days after surgery, which improved with ventriculoperitoneal shunting. Iniencephaly is generally a fatal anomaly, and only 7 such patients have been reported to have survived. Because of the fatality of this anomaly, prenatal diagnosis of iniencephly and pregnancy termination are important. The patient presented herein is only the second patient with iniencephaly and encephalocele to be operated on. The severity of associated systemic and cranial abnormalities is fundamental with regard to survival. Essential points for surgery are preparing enough space to save herniated functional neural tissues, management of associated hydrocephalus and brain stem rotation/compression due to decreased postoperative space. In the surviving child, early correction of Sprengel’s deformity would provide a better aesthetic position of the neck with preservation of brachial plexus integrity.
Patients with Cluster A Personality Disorders in Psychotherapy: An Effectiveness Study
Authors: Bartak Anna , Andrea Helene , Spreeuwenberg Marieke D. , Thunnissen Moniek , Ziegler Uli M. , Dekker Jack , Bouvy Fleur , Hamers Elisabeth F.M. , Meerman Anke M.M.A. , Busschbach Jan J.V. , Verheul Roel , Stijnen Theo , Emmelkamp Paul M.G.
Published: January 2011

Background: While psychopharmacological studies are common in patients with cluster A personality disorders, the effects of psychotherapy have received little attention. The aim of this study is to explore whether psychotherapeutic treatment yields health gains for these patients. Methods: The study was conducted between March 2003 and June 2008 in 6 mental health care centres in the Netherlands, with a sample of 57 patients with a DSM-IV-TR axis II cluster A diagnosis. Patients were assigned to 3 settings of psychotherapeutic treatment (outpatient, day hospital, inpatient), and effectiveness was assessed at 18 months after baseline. An intention-to-treat analysis was conducted for psychiatric symptoms (Brief Symptom Inventory), psychosocial functioning (Outcome Questionnaire-45) and quality of life (EQ-5D), using multilevel statistical modelling. As the study was non-randomised, the propensity score method was used to control for initial differences. Results: Patients in the day hospital and inpatient group improved substantially in terms of psychiatric symptoms, social and interpersonal functioning, and quality of life. Patients in the outpatient group showed less improvement. Direct comparison of the improvement of psychiatric symptoms showed significant results in favour of day hospital (p = 0.046) and inpatient (p = 0.01) treatment, as compared to outpatient treatment. However, due to substantial baseline differences, this direct comparison should be judged carefully. Conclusions: Cluster A psychopathology is not a contraindication to benefit from psychotherapy. This is especially true for more intensive forms like inpatient and day hospital treatment. Future research should focus more on psychotherapeutic treatment to gain further insight into effective treatment options for this patient group.