bluuebunny/crossref_metadata_2025 huggingface dataset:
A quasi-classical trajectory study of the reagent initial rotation quantum state effect on the reaction He + T2+→ HeT+ + T using an improved ab initio potential energy surface
Authors: Zhao Ningjiu , Liu Yufang
Published: January 2012

In this work, we employed the quasi-classical trajectory (QCT) method to study the vector correlations and the influence of the reagent initial rotational quantum number j for the reaction He + T2+(v = 0, j = 0–3) → HeT+ + T on a new potential energy surface (PES). The PES was improved by Aquilanti co-workers (Chem. Phys. Lett. 2009. 469: 26–30). The polarization-dependent differential cross sections (PDDCSs) and the distributions of P(θr), P([Formula: see text]r), and P(θr, [Formula: see text]r) are presented in this work. The plots of the PDDCSs provide us with abundant information about the distribution of the product angular momentum polarization. The P(θr) is used to describe the correlation between k (the relative velocity of the reagent) and j′ (the product rotational angular momentum). The distribution of dihedral angle P([Formula: see text]r) shows the k–k′–j′ (k′ refers to the relative velocity of the product) correlation. The PDDCS calculations illustrate that the product of this reaction is mainly backward scatter and it has the strongest polarization in the backward and sideways scattering directions. At the same time, the results of the P([Formula: see text]r) demonstrate that the product HeT+tends to be oriented along the positive direction of the y axis and it tends to rotate right-handedly in planes parallel to the scattering plane. Moreover, the distribution of the P(θr) manifests that the product angular momentum is aligned along different directions relative to k. The direction of the product alignment may be perpendicular, opposite, or parallel to k. Moreover, our calculations are independent of the initial rotational quantum number.
ENHANCING THE YIELD OF HIGH-DENSITY ELECTRODE ARRAYS THROUGH AUTOMATED ELECTRODE SELECTION
Authors: VAN DIJCK GERT , SEIDL KARSTEN , PAUL OLIVER , RUTHER PATRICK , VAN HULLE MARC M. , MAEX REINOUD
Published: January 2012

Recently developed CMOS-based microprobes contain hundreds of electrodes on a single shaft with inter-electrode distances as small as 30 μm. So far, neuroscientists needed to select electrodes manually from hundreds of electrodes. Here we present an electronic depth control algorithm that allows to select electrodes automatically, hereby allowing to reduce the amount of data and locating those electrodes that are close to neurons. The electrodes are selected according to a new penalized signal-to-noise ratio (PSNR) criterion that demotes electrodes from becoming selected if their signals are redundant with previously selected electrodes. It is shown that, using the PSNR, interneurons generating smaller spikes are also selected. We developed a model that aims to evaluate algorithms for electronic depth control, but also generates benchmark data for testing spike sorting and spike detection algorithms. The model comprises a realistic tufted pyramidal cell, non-tufted pyramidal cells and inhibitory interneurons. All neurons are synaptically activated by hundreds of fibers. This arrangement allows the algorithms to be tested in more realistic conditions, including backgrounds of synaptic potentials, varying spike rates with bursting and spike amplitude attenuation.
MULTIVERSE IN THE THIRD QUANTIZED HORAVA–LIFSHITZ THEORY OF GRAVITY
Authors: FAIZAL MIR
Published: January 2012

In this paper we analyze the third quantization of Horava–Lifshitz theory of gravity without detail balance. We show that the Wheeler–DeWitt equation for Horava–Lifshitz theory of gravity in minisuperspace approximation becomes the equation for time-dependent harmonic oscillator. After interpreting the scaling factor as the time, we are able to derive the third quantized wave function for multiverse. We also show in third quantized formalism it is possible that the universe can form from nothing. Then we go on to analyze the effect of introducing interactions in the Wheeler–DeWitt equation. We see how this model of interacting universes can be used to explain baryogenesis with violation of baryon number conservation in the multiverse. We also analyze how this model can possibly explain the present value of the cosmological constant. Finally we analyze the possibility of the multiverse being formed from perturbations around a false vacuum and its decay to a true vacuum.
DIRAC EQUATION ON A CURVED (2+1)-DIMENSIONAL HYPERSURFACE
Authors: OLPAK MEHMET ALI
Published: January 2012

Interest on (2+1)-dimensional electron systems has increased considerably after the realization of novel properties of graphene sheets, in which the behavior of electrons is effectively described by relativistic equations. Having this fact in mind, the following problem is studied in this work: when a spin-1/2 particle is constrained to move on a curved surface, is it possible to describe this particle without giving reference to the dimensions external to the surface? As a special case of this, a relativistic spin-1/2 particle which is constrained to move on a (2+1)-dimensional hypersurface of the (3+1)-dimensional Minkowskian spacetime is considered, and an effective Dirac equation for this particle is derived using the so-called thin layer method. Some of the results are compared with those obtained in a previous work by Burgess and Jensen.
THE ORBITAL ORDERING OF THE CUBIC KCrF3
Authors: ZHANG MINPING , WANG GUANGTAO
Published: January 2012

The electronic, magnetic and orbital structures of KCrF 3 in the cubic phase are studied by first principles method. In the cubic phase, the three Cr - F bonds distance are equal. If the Jahn–Teller distortion is the origin of the orbital polarization, the orbital ordering would disappear. However, our theoretical calculations show that the orbital ordering exists even without the Jahn–Teller distortion. By studying how the orbital polarization changes with the electron correlation and the Jahn–Teller distortion, we found that the origin of the orbital polarization should be the electron correlation and the Jahn–Teller distortion can reinforced such polarization.
SOME CHARACTERISTICS AND APPLICATIONS OF PARALLEL PLATE AVALANCHE DETECTORS (A REVIEW)
Authors: YASIN ZAFAR
Published: January 2012

Parallel plate avalanche detectors (PPADs) are new gas detectors and are being extensively used to detect heavy ions, fission fragments and minimum ionizing particles. Due to their excellent timing characteristics and low cost, they are being widely used in different areas of science and technology, particularly as start and stop detectors in different experiments. These detectors are ideal for coincidence measurements and for photofission studies. Different characteristics; construction operation, performance, time resolution, energy resolution and experimental techniques based on PPADs are reviewed in this paper.
Yet another technology cusp
Authors: Norman Donald A.
Published: January 2012

Considering the unexpected risks associated with seemingly minor technological changes.
What have we learned about software engineering?
Authors: Zelkowitz Marvin V.
Published: January 2012

Upon closer examination, everything old appears to be new again in the realm of software engineering.
Advances and challenges in log analysis
Authors: Oliner Adam , Ganapathi Archana , Xu Wei
Published: January 2012

Logs contain a wealth of information to help manage systems.
Text-mining the voice of the people
Authors: Evangelopoulos Nicholas , Visinescu Lucian
Published: January 2012

Statistical techniques help public leaders turn text in unstructured citizen feedback into responsive e-democracy.
Programming by optimization
Authors: Hoos Holger H.
Published: January 2012

Avoid premature commitment, seek design alternatives, and automatically generate performance-optimized software.
Increased expression of miR-325-3p by urocortin 2 and its involvement in stress-induced suppression of LH secretion in rat pituitary
Authors: Nemoto Takahiro , Mano Asuka , Shibasaki Tamotsu
Published: January 2012

Urocortin 2 (Ucn2) is a member of the corticotropin releasing factor (CRF) peptide family, which binds to CRF type 2 receptor. We previously reported on expression of Ucn2 in proopiomelanocortin cells of rat pituitary and its inhibitory action on LH secretion. We also demonstrated that Ucn2 is involved in the mechanism underlying immobilization-induced suppression of LH secretion; the details remain unclear. Here, we found that Ucn2 increased the expression of miR-325-3p, one of three microRNAs with predicted sequence for binding to LH β-subunit 3′-untranslated region (3′-UTR) in monolayer cultured rat anterior pituitary cells, and that miR-325-3p was expressed in LH cells of the anterior pituitary. Immobilization also increased miR-325-3p expression in the anterior pituitary, and its increase was blocked by pretreatment with anti-Ucn2 IgG. Overexpression of miR-325-3p in cultured pituitary cells significantly suppressed intracellular contents and secretion of LH, while miR-325-3p knockdown blocked Ucn2-induced suppression of intracellular contents and secretion of LH. Coexpression of miR-325-3p with LH β-subunit 3′-UTR-fused luciferase vector significantly suppressed luciferase activity compared with that of mock transfectants. These results suggest that miR-325-3p is involved in immobilization-induced suppression of LH translation and secretion and that Ucn2 plays a role in the increase in miR-325-3p expression.
Remote-Sensing-Based Estimation of Surface Nitrate and Its Variability in the Southern Peninsular Indian Waters
Authors: Sarangi R. K.
Published: January 2012

A relationship between sea surface temperature (SST) and surface nitrate concentrations has been obtained for the first time based on in situ datasets retrieved from U.S. JGOFS (1991–96) and Indian cruises (2000–2006) in the Arabian Sea, Bay of Bengal and Indian Ocean region around the southern Indian tip. The dataset includes 1537 points. A sigmoid relationship obtained with value 0.912. NOAA-AVHRR pathfinder satellite monthly averaged SST data retrieved from the PODAAC/JPL/NASA archive during July 1999–June 2004. The datasets imported in the ERDAS-Imagine software and SST images generated on monthly and seasonal scales, for latitudes 5–12°N and longitudes 75–85°E. The ocean surface nitrate images retrieved based on the established sigmoid relationship with SST. The nitrate concentrations ranged between 0.01–3.0 μM and categorized into five ranges. The significant seasonal upwelling zone around the southwest coast of India (Kerala coast, Latitude 80.10–9.30°N and Longitude 75.60–76.20°E) was identified during July–September 1999–2004 with very high nitrate concentration (~1.00 μM). Low nitrate and nitrate-depleted zones observed during summer (March–May). In the Arabian Sea and northern Indian Ocean, high nitrate concentration (~0.50 μM) observed during the southwest monsoon (SWM), whereas the Bay of Bengal was marked with high nitrate (~0.50 μM) during the northeast monsoon (NEM). SST was high (~29°C) in the Bay of Bengal and low (~26°C) in the Arabian Sea and northern Indian Ocean during SWM and vice versa during the NEM. There is a clear inverse relationship between nitrate and SST in the study area during July 1999–June 2004.
Policy for Prevention of a Retained Sponge after Vaginal Delivery
Authors: Garry David J. , Asanjarani Sandra , Geiss Donna M.
Published: January 2012

Background. Policies for sponge count are not routine practice in most labor and delivery rooms. Ignored or hidden retained vaginal foreign bodies has potentially significant health care morbidity.Case. This was a case of a retained vaginal sponge following an uncomplicated spontaneous vaginal delivery. Delivery room policy resulted in the discovery of the sponge on X-ray when an incorrect sponge count occurred and physical exam did not find the sponge.Conclusion. This emphasizes the use of protocols to enhance patient safety and prevent medical error.
Definitive Radiotherapy versus Postoperative Radiotherapy of Patients with Oro- and Hypopharyngeal Cancer: Impact of Prognostic Factors
Authors: Rudat Volker , Ahmet-Osman Salia , Schramm Oliver , Dietz Andreas
Published: January 2012

Purpose. To compare the impact of prognostic factors of patients treated with definitive radio(chemo)therapy versus patients treated with surgery and postoperative radiotherapy for squamous cell carcinoma of the oro- and hypopharynx.Patients and Methods. 162 patients treated with definitive radiotherapy and 126 patients treated with postoperative radiotherapy were retrospectively analysed. The impact of the prognostic factors gender, age, total tumor volume (TTV), pre-radiotherapy hemoglobin level (Hb-level), tumor site, T- and N-classification, radiotherapy interruptions >5 days, radiotherapy versus simultaneous radiochemotherapy, R-status and time interval between surgery and radiotherapy were investigated.Results. The median follow-up time for the censored patients treated with definitive radio(chemo)therapy was 28.5 months and for postoperative radiotherapy 36.5 months. On univariate analysis, the TTV, Hb-level, and simultaneous radiochemotherapy had a significant impact on the survival of patients treated with definitive radio(chemo)therapy. For patients treated with postoperative radiotherapy, only the TTV showed a statistical trend for the survival (P=0.13). On multivariate analysis, the TTV and simultaneous radiochemotherapy maintained their statistical significance for patients treated with definitive raditherapy, and the TTV, the statistical trend for patients treated with postoperative radiotherapy (P=0.19).Conclusions. The TTV was the predominant prognostic factor for both, patients treated with definitive or postoperative radiotherapy.
Toothbrush Contamination: A Review of the Literature
Authors: Frazelle Michelle R. , Munro Cindy L.
Published: January 2012

Toothbrushes are commonly used in hospital settings and may harbor potentially harmful microorganisms. A peer-reviewed literature review was conducted to evaluate the cumulative state of knowledge related to toothbrush contamination and its possible role in disease transmission. A systematic review was conducted on adult human subjects through three distinct searches. The review resulted in seven experimental and three descriptive studies which identified multiple concepts related to toothbrush contamination to include contamination, methods for decontamination, storage, design, and environmental factors. The selected studies found that toothbrushes of healthy and oral diseased adults become contaminated with pathogenic bacteria from the dental plaque, design, environment, or a combination of factors. There are no studies that specifically examine toothbrush contamination and the role of environmental factors, toothbrush contamination, and vulnerable populations in the hospital setting (e.g., critically ill adults) and toothbrush use in nursing clinical practice.
Correlations between Different Heavy Metals in Diverse Body Fluids: Studies of Human Semen Quality
Authors: Mínguez-Alarcón Lidia , Mendiola Jaime , Roca Manuela , López-Espín José J. , Guillén José J. , Moreno José M. , Moreno-Grau Stella , Martínez-García María J. , Vergara-Juárez Nuria , Elvira-Rendueles Belén , García-Sánchez Antonio , Ten Jorge , Bernabeu Rafael , Torres-Cantero Alberto M.
Published: January 2012

It has been hypothesized that exposure to heavy metals may impair male reproduction. To measure the effect produced by low doses of heavy metals on semen parameters, it is necessary to clarify in which body fluids those measurements must be performed. Sixty-one men attending infertility clinics participated in our study. Concentrations of lead, cadmium, and mercury were measured in whole blood, blood plasma, and seminal plasma using spectroanalytical and electrochemical methods. Semen analyses were performed according to World Health Organization criteria. For statistical analysis, Spearman's rank correlations, mean comparison tests, and discriminant analysis were calculated. Significant correlations between the measured concentrations of the three heavy metals in the same biological fluids were observed. However, no similar relationship was seen when comparing the concentrations in different body fluids of the same metal. According to our results and previous publications, seminal plasma might be the best body fluid for assessing impairment of human semen parameters.
Peripheral Galanin Receptor 2 as a Target for the Modulation of Pain
Authors: Hulse Richard P. , Donaldson Lucy F. , Wynick David
Published: January 2012

The neuropeptide galanin is widely expressed in the nervous system and has an important role in nociception. It has been shown that galanin can facilitate and inhibit nociception in a dose-dependent manner, principally through the central nervous system, with enhanced antinociceptive actions after nerve injury. However, following nerve injury, expression of galanin within the peripheral nervous system is dramatically increased up to 120-fold. Despite this striking increase in the peripheral nervous system, few studies have investigated the role that galanin plays in modulating nociception at the primary afferent nociceptor. Here, we summarise the recent work supporting the role of peripherally expressed galanin with particular reference to the dual actions of the galanin receptor 2 in neuropathic pain highlighting this as a potential target analgesic.
Stabilities of Cubic Mappings in Various Normed Spaces: Direct and Fixed Point Methods
Authors: Azadi Kenary H. , Rezaei H. , Talebzadeh S. , Lee S. Jin
Published: January 2012

In 1940 and 1964, Ulam proposed the general problem: “When is it true that by changing a little the hypotheses of a theorem one can still assert that the thesis of the theorem remains true or approximately true?”. In 1941, Hyers solved this stability problem for linear mappings. According to Gruber (1978) this kind of stability problems are of the particular interest in probability theory and in the case of functional equations of different types. In 1981, Skof was the first author to solve the Ulam problem for quadratic mappings. In 1982–2011, J. M. Rassias solved the above Ulam problem for linear and nonlinear mappings and established analogous stability problems even on restricted domains. The purpose of this paper is the generalized Hyers‐Ulam stability for the following cubic functional equation: f(mx + y) + f(mx − y) = mf(x + y) + mf(x − y) + 2(m 3 − m)f(x),  m ≥ 2 in various normed spaces.
Polarity Switchable Photovoltages in Miscut La0.67Ca0.33MnO3Films
Authors: Wang J. , Ni H. , Zhao K. , Kong Y.-C. , Wong H. K. , Zhong S. X.
Published: January 2012

We report the transient laser-induced anomalous photovoltaic effect in the La0.67Ca0.33MnO3film grown on miscut LaSrAlO4(001) substrate under 248 nm pulsed laser irradiation at ambient temperature without any applied bias. A photovoltaic pulse signal was observed when the La0.67Ca0.33MnO3film was irradiated directly, and the signal polarity was reversed when the sample was irradiated through the LaSrAlO4substrate, while the signal recorded between the two electrodes on the surface of LaSrAlO4was not reversed when the sample was irradiated through La0.67Ca0.33MnO3film rather than at the surface of LaSrAlO4. The switchable signal polarity provides a potential application of miscut manganite films as optical components. A possible mechanism is introduced to explain the experiment results.
3D Nonparametric Neural Identification
Authors: Fuentes Rita Q. , Chairez Isaac , Poznyak Alexander , Poznyak Tatyana
Published: January 2012

This paper presents the state identification study of 3D partial differential equations (PDEs) using the differential neural networks (DNNs) approximation. There are so many physical situations in applied mathematics and engineering that can be described by PDEs; these models possess the disadvantage of having many sources of uncertainties around their mathematical representation. Moreover, to find the exact solutions of those uncertain PDEs is not a trivial task especially if the PDE is described in two or more dimensions. Given the continuous nature and the temporal evolution of these systems, differential neural networks are an attractive option as nonparametric identifiers capable of estimating a 3D distributed model. The adaptive laws for weights ensure the “practical stability” of the DNN trajectories to the parabolic three-dimensional (3D) PDE states. To verify the qualitative behavior of the suggested methodology, here a nonparametric modeling problem for a distributed parameter plant is analyzed.
Parameterization Method on B‐Spline Curve
Authors: Haron H. , Rehman A. , Adi D. I. S. , Lim S. P. , Saba T.
Published: January 2012

The use of computer graphics in many areas allows a real object to be transformed into a three‐dimensional computer model (3D) by developing tools to improve the visualization of two‐dimensional (2D) and 3D data from series of data point. The tools involved the representation of 2D and 3D primitive entities and parameterization method using B‐spline interpolation. However, there is no parameterization method which can handle all types of data points such as collinear data points and large distance of two consecutive data points. Therefore, this paper presents a new parameterization method that is able to solve those drawbacks by visualizing the 2D primitive entity of scanned data point of a real object and construct 3D computer model. The new method has improved a hybrid method by introducing exponential parameterization method in the beginning of the reconstruction process, followed by computing B‐spline basis function to find maximum value of the function. The improvement includes solving a linear system of the B‐spline basis function using numerical method. Improper selection of the parameterization method may lead to the singularity matrix of the system linear equations. The experimental result on different datasets show that the proposed method performs better in constructing the collinear and two consecutive data points compared to few parameterization methods.
Improved Acuity and Dexterity but Unchanged Touch and Pain Thresholds following Repetitive Sensory Stimulation of the Fingers
Authors: Kowalewski Rebecca , Kattenstroth Jan-Christoph , Kalisch Tobias , Dinse Hubert R.
Published: January 2012

Neuroplasticity underlies the brain’s ability to alter perception and behavior through training, practice, or simply exposure to sensory stimulation. Improvement of tactile discrimination has been repeatedly demonstrated after repetitive sensory stimulation (rSS) of the fingers; however, it remains unknown if such protocols also affect hand dexterity or pain thresholds. We therefore stimulated the thumb and index finger of young adults to investigate, besides testing tactile discrimination, the impact of rSS on dexterity, pain, and touch thresholds. We observed an improvement in the pegboard task where subjects used the thumb and index finger only. Accordingly, stimulating 2 fingers simultaneously potentiates the efficacy of rSS. In fact, we observed a higher gain of discrimination performance as compared to a single-finger rSS. In contrast, pain and touch thresholds remained unaffected. Our data suggest that selecting particular fingers modulates the efficacy of rSS, thereby affecting processes controlling sensorimotor integration.
STAT3 Regulates Proliferation and Immunogenicity of the Ewing Family of TumorsIn Vitro
Authors: Behjati Sam , Basu B. Piku , Wallace Rebecca , Bier Nelly , Sebire Neil , Hasan Fyeza , Anderson John
Published: January 2012

The Ewing sarcoma family of tumors (ESFT) represents an aggressive spectrum of malignant tumour types with common defining histological and cytogenetic features. To evaluate the functional activation of signal transducer and activator of transcription 3 (STAT3) in ESFT, we evaluated its activation in primary tissue sections and observed the functional consequences of its inhibition in ESFT cell lines. STAT3 was activated (tyrosine 705-phosphorylated) in 18 out of 31 primary tumours (58%), either diffusely (35%) or focally (23%). STAT3 was constitutively activated in 3 out of 3 ESFT cell lines tested, and its specific chemical inhibition resulted in complete loss of cell viability. STAT3 inhibition in ESFT cell lines was associated with several consistent changes in chemokine profile suggesting a role of STAT3 in ESFT in both cell survival and modification of the cellular immune environment. Together these data support the investigation of STAT3 inhibitors for the Ewing family of tumors.
Enhanced Apoptosis and Tumor Growth Suppression Elicited by Combination of MEK (Selumetinib) and mTOR Kinase Inhibitors (AZD8055)
Authors: Holt Sarah V. , Logie Armelle , Davies Barry R. , Alferez Denis , Runswick Sarah , Fenton Sarah , Chresta Christine M. , Gu Yi , Zhang Jingchuan , Wu Yi-Long , Wilkinson Robert W. , Guichard Sylvie M. , Smith Paul D.
Published: January 2012

The mitogen-activated protein kinase (MAPK) and phosphoinositide 3-kinase/AKT signaling pathways interact at multiple nodes in cancer, including at mTOR complexes, suggesting an increased likelihood of redundancy and innate resistance to any therapeutic effects of single pathway inhibition. In this study, we investigated the therapeutic effects of combining the MAPK extracellular signal–regulated kinase (MEK)1/2 inhibitor selumetinib (AZD6244) with the dual mTORC1 and mTORC2 inhibitor (AZD8055). Concurrent dosing in nude mouse xenograft models of human lung adenocarcinoma (non–small cell lung cancers) and colorectal carcinoma was well tolerated and produced increased antitumor efficacy relative to the respective monotherapies. Pharmacodynamic analysis documented reciprocal pathway inhibition associated with increased apoptosis and Bim expression in tumor tissue from the combination group, where key genes such as DUSP6 that are under MEK functional control were also modulated. Our work offers a strong rationale to combine selumetinib and AZD8055 in clinical trials as an attractive therapeutic strategy. Cancer Res; 72(7); 1804–13. ©2012 AACR.
Epithelial–Mesenchymal Transition Induced by TNF-α Requires NF-κB–Mediated Transcriptional Upregulation of Twist1
Authors: Li Chia-Wei , Xia Weiya , Huo Longfei , Lim Seung-Oe , Wu Yun , Hsu Jennifer L. , Chao Chi-Hong , Yamaguchi Hirohito , Yang Neng-Kai , Ding Qingqing , Wang Yan , Lai Yun-Ju , LaBaff Adam M. , Wu Ting-Jung , Lin Been-Ren , Yang Muh-Hwa , Hortobagyi Gabriel N. , Hung Mien-Chie
Published: January 2012

Proinflammatory cytokines produced in the tumor microenvironment facilitate tumor development and metastatic progression. In particular, TNF-α promotes cancer invasion and angiogenesis associated with epithelial–mesenchymal transition (EMT); however, the mechanisms underlying its induction of EMT in cancer cells remain unclear. Here we show that EMT and cancer stemness properties induced by chronic treatment with TNF-α are mediated by the upregulation of the transcriptional repressor Twist1. Exposure to TNF-α rapidly induced Twist1 mRNA and protein expression in normal breast epithelial and breast cancer cells. Both IKK-β and NF-κB p65 were required for TNF-α–induced expression of Twist1, suggesting the involvement of canonical NF-κB signaling. In support of this likelihood, we defined a functional NF-κB–binding site in the Twist1 promoter, and overexpression of p65 was sufficient to induce transcriptional upregulation of Twist1 along with EMT in mammary epithelial cells. Conversely, suppressing Twist1 expression abrogated p65-induced cell migration, invasion, EMT, and stemness properties, establishing that Twist1 is required for NF-κB to induce these aggressive phenotypes in breast cancer cells. Taken together, our results establish a signaling axis through which the tumor microenvironment elicits Twist1 expression to promote cancer metastasis. We suggest that targeting NF-κB–mediated Twist1 upregulation may offer an effective a therapeutic strategy for breast cancer treatment. Cancer Res; 72(5); 1290–300. ©2012 AACR.
Prospective Trial of Synchronous Bevacizumab, Erlotinib, and Concurrent Chemoradiation in Locally Advanced Head and Neck Cancer
Authors: Yoo David S. , Kirkpatrick John P. , Craciunescu Oana , Broadwater Gloria , Peterson Bercedis L. , Carroll Madeline D. , Clough Robert , MacFall James R. , Hoang Jenny , Scher Richard L. , Esclamado Ramon M. , Dunphy Frank R. , Ready Neal E. , Brizel David M.
Published: January 2012

Purpose: We assessed the safety and efficacy of synchronous VEGF and epidermal growth factor receptor (EGFR) blockade with concurrent chemoradiation (CRT) in locally advanced head and neck cancer (HNC).

Experimental Design: Newly diagnosed patients with stage III/IV HNC received a 2-week lead-in of bevacizumab and/or erlotinib, followed by both agents with concurrent cisplatin and twice daily radiotherapy. Safety was assessed using Common Toxicity Criteria version 3.0. The primary efficacy endpoint was clinical complete response (CR) rate after CRT.

Results: Twenty-nine patients enrolled on study, with 27 completing therapy. Common grade III toxicities were mucositis (n = 14), dysphagia (n = 8), dehydration (n = 7), osteoradionecrosis (n = 3), and soft tissue necrosis (n = 2). Feeding tube placement was required in 79% but no patient remained dependent at 12-month posttreatment. Clinical CR after CRT was 96% [95% confidence interval (CI), 82%–100%]. Median follow-up was 46 months in survivors, with 3-year locoregional control and distant metastasis-free survival rates of 85% and 93%. Three-year estimated progression-free survival, disease-specific survival, and overall survival rates were 82%, 89%, and 86%, respectively. Dynamic contrast enhanced MRI (DCE-MRI) analysis showed that patients who had failed had lower baseline pretreatment median Ktrans values, with subsequent increases after lead-in therapy and 1 week of CRT. Patients who did not fail had higher median Ktrans values that decreased during therapy.

Conclusions: Dual VEGF/EGFR inhibition can be integrated with CRT in locally advanced HNC, with efficacy that compares favorably with historical controls albeit with an increased risk of osteoradionecrosis. Pretreatment and early DCE-MRI may prospectively identify patients at high risk of failure. Clin Cancer Res; 18(5); 1404–14. ©2012 AACR.
SKI-606, an Src Inhibitor, Reduces Tumor Growth, Invasion, and Distant Metastasis in a Mouse Model of Thyroid Cancer
Authors: Kim Won Gu , Guigon Celine J. , Fozzatti Laura , Park Jeong Won , Lu Changxue , Willingham Mark C. , Cheng Sheue-yann
Published: January 2012

Purpose: Src is overexpressed or hyperactivated in a variety of human cancers, including thyroid carcinoma. Src is a central mediator in multiple signaling pathways that are important in oncogenesis and cancer progression. In this study, we evaluated the effects of an Src inhibitor, SKI-606 (bosutinib), in a spontaneous metastatic thyroid cancer model with constitutively activated Src (ThrbPV/PVPten+/− mice).

Experimental Design: ThrbPV/PVPten+/− mice were treated with SKI-606 or vehicle controls, beginning at 6 weeks of age until the mice succumbed to thyroid cancer. We assessed the effects of SKI-606 on thyroid cancer progression and analyzed the impact of SKI-606 on aberrant Src-mediated signaling.

Results: SKI-606 effectively inhibited aberrant activation of Src and its downstream targets to markedly inhibit the growth of thyroid tumor, thereby prolonging the survival of treated mice. While Src inhibition did not induce cell apoptosis, it decreased cell proliferation by affecting the expression of key regulators of cell-cycle progression. Importantly, SKI-606 dramatically prevented dedifferentiation, vascular invasion, and lung metastasis of thyroid cancer cells. These responses were meditated by downregulation of mitogen-activated protein kinase pathways and inhibition of the epithelial–mesenchymal transition.

Conclusions: Our findings suggest that Src is critical in the progression of thyroid cancer, making oral SKI-606 a promising treatment strategy for refractory thyroid cancer. Clin Cancer Res; 18(5); 1281–90. ©2012 AACR.
Next Generation Sequencing of Prostate Cancer from a Patient Identifies a Deficiency of Methylthioadenosine Phosphorylase, an Exploitable Tumor Target
Authors: Collins Colin C. , Volik Stanislav V. , Lapuk Anna V. , Wang Yuwei , Gout Peter W. , Wu Chunxiao , Xue Hui , Cheng Hongwei , Haegert Anne , Bell Robert H. , Brahmbhatt Sonal , Anderson Shawn , Fazli Ladan , Hurtado-Coll Antonio , Rubin Mark A. , Demichelis Francesca , Beltran Himisha , Hirst Martin , Marra Marco , Maher Christopher A. , Chinnaiyan Arul M. , Gleave Martin , Bertino Joseph R. , Lubin Martin , Wang Yuzhuo
Published: January 2012

Castrate-resistant prostate cancer (CRPC) and neuroendocrine carcinoma of the prostate are invariably fatal diseases for which only palliative therapies exist. As part of a prostate tumor sequencing program, a patient tumor was analyzed using Illumina genome sequencing and a matched renal capsule tumor xenograft was generated. Both tumor and xenograft had a homozygous 9p21 deletion spanning the MTAP, CDKN2, and ARF genes. It is rare for this deletion to occur in primary prostate tumors, yet approximately 10% express decreased levels of methylthioadenosine phosphorylase (MTAP) mRNA. Decreased MTAP expression is a prognosticator for poor outcome. Moreover, it seems that this deletion is more common in CRPC than in primary prostate cancer. We show for the first time that treatment with methylthioadenosine and high dose 6-thioguanine causes marked inhibition of a patient-derived neuroendocrine xenograft growth while protecting the host from 6-thioguanine toxicity. This therapeutic approach can be applied to other MTAP-deficient human cancers as deletion or hypermethylation of the MTAP gene occurs in a broad spectrum of tumors at high frequency. The combination of genome sequencing and patient-derived xenografts can identify candidate therapeutic agents and evaluate them for personalized oncology. Mol Cancer Ther; 11(3); 775–83. ©2012 AACR.
The Oncogenic RNA-Binding Protein Musashi1 Is Regulated by HuR via mRNA Translation and Stability in Glioblastoma Cells
Authors: Vo Dat T. , Abdelmohsen Kotb , Martindale Jennifer L. , Qiao Mei , Tominaga Kumiko , Burton Tarea L. , Gelfond Jonathan A.L. , Brenner Andrew J. , Patel Vyomesh , Trageser Daniel , Scheffler Björn , Gorospe Myriam , Penalva Luiz O.F.
Published: January 2012

Musashi1 (Msi1) is an evolutionarily conserved RNA-binding protein (RBP) that has profound implications in cellular processes such as stem cell maintenance, nervous system development, and tumorigenesis. Msi1 is highly expressed in many cancers, including glioblastoma, whereas in normal tissues, its expression is restricted to stem cells. Unfortunately, the factors that modulate Msi1 expression and trigger high levels in tumors are largely unknown. The Msi1 mRNA has a long 3′ untranslated region (UTR) containing several AU- and U-rich sequences. This type of sequence motif is often targeted by HuR, another important RBP known to be highly expressed in tumor tissue such as glioblastoma and to regulate a variety of cancer-related genes. In this report, we show an interaction between HuR and the Msi1 3′-UTR, resulting in a positive regulation of Msi1 expression. We show that HuR increased MSI1 mRNA stability and promoted its translation. We also present evidence that expression of HuR and Msi1 correlate positively in clinical glioblastoma samples. Finally, we show that inhibition of cell proliferation, increased apoptosis, and changes in cell-cycle profile as a result of silencing HuR are partially rescued when Msi1 is ectopically expressed. In summary, our results suggest that HuR is an important regulator of Msi1 in glioblastoma and that this regulation has important biological consequences during gliomagenesis. Mol Cancer Res; 10(1); 143–55. ©2012 AACR.
Immune Dysregulation in Chronic Stress: A Quantitative and Functional Assessment of Regulatory T Cells
Authors: Kim Hyung-Ran , Moon Sohyeon , Lee Hyeon Kook , Kang Jihee Lee , Oh Seikwan , Seoh Ju-Young
Published: January 2012

Objective: Chronic stress is closely related to immune dysfunction. Immune parameters have been analyzed in many ways in humans and animals under chronic stress. Recently, it has been proved that FoxP3+ regulatory T cells (Tregs) play a key role in immune regulation in vivo. However, it has not yet been elucidated how Tregs respond to chronic stress in vivo. Therefore, in the present study, we investigated the frequency of and functional changes in Tregs from mice under chronic stress. Methods: Spleen cells were separated from C57/BL6 mice that had been exposed to immobilization stress for 3 weeks. The frequencies of FoxP3+ and CD4+ CD25+ cells were analyzed by flow cytometry. CD4+CD25– cells (effector T cells, Teffs), CD4+CD25+ cells (Tregs) and CD4– cells (antigen-presenting cells, APCs) were separated for the functional assessment of the proliferative activity of Teffs, the suppressive activity of Tregs and the feeder activity of APCs. Results: The results showed that chronic immobilization stress significantly increased the frequencies of CD4+CD25+ and CD4+FoxP3+ cells. Chronic immobilization stress also enhanced the suppressive function of CD4+ CD25+ Tregs. On the other hand, the proliferative activity of Teffs and the feeder activity of APCs were decreased in the mice under chronic immobilization stress. Conclusion: Taken together, it is suggested that increased number and function of Tregs may actively contribute to the immune dysfunction in chronic immobilization stress, synergizing with the decreased function of Teffs and APCs.
Persistence, Adherence and Outcomes with Antiplatelet Regimens following Cerebral Infarction in the Tayside Stroke Cohort
Authors: Flynn Robert W.V. , MacDonald Thomas M. , Murray Gordon D. , MacWalter Ronald S. , Doney Alexander S.F.
Published: January 2012

Background: Co-prescribed aspirin and dipyridamole are more effective than aspirin alone following cerebral infarction; however, patients may struggle with this more complex regimen. The objectives of this study were: (1) to describe postdischarge prescribing of antiplatelet regimens, (2) to measure patient persistence with different antiplatelet regimens, and (3) to measure whether persistence impacts on outcomes. Methods: We used record linkage of the Tayside Stroke Cohort with community dispensed prescribing data from 1994 to 2005. All patients had suffered a radiologically confirmed cerebral infarction and were excluded if they had previously used or had other indications for antiplatelet agents. We measured persistence to initial and any antiplatelet regimen using survival analysis. To assess the impact of therapy we used survival analysis to follow up until the APTC endpoint of serious vascular event (myocardial infarction, stroke or vascular death) or censored. Antiplatelet regimen was entered as a time-dependent covariate in a Cox model that also adjusted for age, sex, history of diabetes and baseline use of nitrates and statins. Results: The study cohort contained 1,407 stroke patients (mean age 70.3 years, 46.8% male), with a total follow-up of 4,243 patient-years. Patients initiated on aspirin with dipyridamole had a worse persistence to their initial regimen compared with those initiated on aspirin alone (hazard ratio for non-persistence 1.62; 95% CI 1.37–1.92), but better persistence with any antiplatelet medication long term (hazard ratio 0.86; 95% CI 0.73–1.02). Compared to aspirin monotherapy, receiving no antiplatelet therapy was associated with significantly worse patient outcomes (hazard ratio 1.50; 95% CI 1.21–1.87), whilst receiving prescribed aspirin with dipyridamole was associated with better outcomes (hazard ratio 0.75; 95% CI 0.56–0.99). Only a few patients received clopidogrel or other antiplatelet regimens. Conclusions: Patients discharged on dual therapy have worse adherence to their initial regimen but better persistence to any antiplatelet agents in the long term. Continued exposure to antiplatelet regimens predicts good outcomes in patients with cerebral infarction.
CD24 Gene Allele Variation Is Not Associated with Oligoclonal IgG Bands and IgG Index of Multiple Sclerosis Patients
Authors: Saadatnia Mohammad , Najafi Mohammad Reza , Najafi Faride , Davoudi Vahid , Keyhanian Kiandokht , Maghzi Amir Hadi
Published: January 2012

Objective: Multiple sclerosis (MS) shows evidence of many distinctive aspects of an autoimmune disorder, including a polygenic inheritance. A recent candidate gene for susceptibility to MS is CD24, which has also been shown to be associated with disease progression. This study was designed to examine whether there is a relationship between the CD24 genotype, oligoclonal band (OCB) status and IgG index in the cerebrospinal fluid (CSF) of MS patients. Methods: A total of 27 definite MS patients were enrolled in this cross-sectional study. Blood samples were collected from a peripheral vein, and CSF was obtained by lumbar puncture. The CD24 gene was sequenced in the blood specimen, and albumin and IgG concentrations were measured in both CSF and serum. We compared both IgG index and OCB status in patients with and without CD24V/V. The correlation between MS severity score (MSSS), OCB status, CD24 genotype and IgG index was studied. Results: Only 15 patients were OCB positive. Among patients with negative OCBs, only 2 patients had the V/V genotype. Furthermore, in those with the V/V genotype, IgG index was not significantly elevated (p = 0.322). Patients with the V/V genotype had a significantly higher MSSS (p = 0. 04), but neither the presence of OCBs nor the IgG index showed significant correlation with MSSS (p = 0.379 and 0.20, respectively). Conclusion: We could not show any relationship between the CD24V/V genotype, OCB status and IgG index. This could be interpreted as indicating that the CD24V/V allele exerts its effects on the disease course independently of CSF IgG synthesis.
Pancreatic Ductal Cells Acquire Mesenchymal Characteristics through Cell Fusion with Bone Marrow-Derived Mesenchymal Stem Cells and SIRT1 Attenuates the Apoptosis of Hybrid Cells
Authors: Gou Shanmiao , Liu Tao , Li Xiangsheng , Cui Jing , Wan Chidan , Wang Chunyou
Published: January 2012

Bone marrow-derived mesenchymal stem cells (bMSCs) contribute to tissue repair and regeneration. Cell fusion between somatic cells and bMSCs to form hybrid cells may have an important role in tissue repair through the subsequent reprogramming of the somatic cell nucleus. Few studies have assessed the mesenchymal characteristics of fusion-induced hybrid cells and their survival mechanisms. In this study, we investigated the effect of cell fusion on the biological characteristics of pancreatic ductal cells (PDCs) and on the survival mechanism of hybrid cells. To this end, we generated mouse-mouse hybrid cells in vitro by polyethylene glycol-mediated fusion of primary mouse bMSCs with primary mouse PDCs. Hybrid cells showed an enhanced capacity for proliferation and self-renewal compared with PDCs. No PDC had the capacity for anchorage-independent growth or invasion into Matrigel, but some hybrid cells were able to form colonies in soft agar and invade Matrigel. Expression of the tumor suppressor protein p53, which initiates apoptosis, was detected in hybrid cells but not in PDCs or bMSCs. However, the p53 deacetylase, sirtuin 1 (SIRT1), was also detected in hybrid cells, and the level of acetylated p53, the active form, was low. The addition of nicotinamide (Nam) inhibited the deacetylation activity of SIRT1 on p53 and induced cell apoptosis in hybrid cells. This study demonstrated that PDCs could obtain high proliferation rates, self-renewal capabilities, and mesenchymal characteristics by fusion with bMSCs. SIRT1 expression in the hybrid cells attenuated their apoptosis.
Role of Water Fleas (Daphniamagna) in the Accumulation of Avian Influenza Viruses from the Surrounding Water
Authors: Abbas Maha Diekan , Nazir Jawad , Stumpf Petra , Marschang Rachel E.
Published: January 2012

Objective: To determine the role of water fleas in accumulating avian influenza viruses (AIV) from the surrounding water and to estimate their role as a vector of AIV. Methods: Water fleas were exposed to H4N6 and H5N1 AIV-contaminated water in a closed system. The potential of water fleas to take up and retain the viruses was estimated by quantitative real-time RT-PCR (qRRT-PCR) and titration on cell culture. Results: Contamination trials showed that significantly higher amounts of viral RNA were detectable per gram of water fleas as compared to per milliliter of the surrounding water at 1, 4, and 6 days of incubation. Viral infectivity was only detectable in the water samples collected immediately after mixing the virus in water containing the water fleas, while no virus was detectable in any of the water fleas or water samples collected afterwards. Conclusions: Water fleas are able to accumulate AIV from surrounding water based upon the qRRT-PCR detection of viral RNA. Additional studies are necessary to investigate the inactivation potential of water fleas on viral infectivity.
Validity of Cochlear Microphonics at High Sound Pressure Levels as an Important Clinical Aspect
Authors: Teschner M. , Lenarz T. , Battmer R.-D.
Published: January 2012

Introduction: Cochlear microphonics are electrical stimulus responses of the inner ear, generated by mechanical displacement of the hair cells caused by acoustic stimulation. As cochlear microphonics are often used in the diagnosis of hearing impairment and deafness, in preliminary investigations it was seen that obliteration or ossification have no effect on the extent to which cochlear microphonics can be recorded at high sound pressure levels. As artifacts at high sound pressure levels suggested, measurements were subsequently conducted using temporal bone specimens. Methods: In a test setup equivalent to that for electrocochleography, a needle electrode was placed on the cochlear promontory and used to record potentials following application of an acoustic stimulus. Results: Curves comparable to cochlear microphonics were registrable down to a threshold of 80 dB HL. Additional measurements conducted on damp cloths yielded comparable findings. Conclusions: Registration of cochlear microphonics at high sound pressure levels does not serve as an indicator of hair cell function, but should instead be regarded as artifacts. The possible sources are discussed.
Meta-Analysis on the Effects of the Smoke-Free Class Competition on Smoking Prevention in Adolescents
Authors: Isensee Barbara , Hanewinkel Reiner
Published: January 2012

Background: The ‘Smoke-Free Class competition’ (SFC) is a school-based smoking prevention programme including commitment not to smoke, contract management and prizes as rewards broadly implemented in Europe. Objectives: To meta-analyse (randomised) controlled trials on the effects of SFC on current smoking at latest follow-up in adolescents. Methods: A systematic review of articles using MEDLINE and the Cochrane Library was conducted. The study selection included randomised controlled trials and controlled trials with follow-up assessment that investigated the efficacy of SFC on current smoking in students participating in SFC compared to non-participating students. Independent extraction of articles was performed by both authors. Results: Of 24 records identified, five fulfilled the inclusion criteria. These studies were conducted in three European countries (Finland, The Netherlands and Germany) and recruited 16,302 students altogether. A random effects meta-analysis of these five studies revealed a pooled risk ratio of 0.86 (95% CI 0.79–0.94; z = 3.44, p = 0.001) on current smoking at follow-up by participation in the competition. Conclusion: SFC appears to be an effective tool in school-based smoking prevention.