bluuebunny/crossref_metadata_2025 huggingface dataset:
Pathological Plasticity in Fragile X Syndrome
Authors: Martin Brandon S. , Huntsman Molly M.
Published: July 2012

Deficits in neuronal plasticity are common hallmarks of many neurodevelopmental disorders. In the case of fragile-X syndrome (FXS), disruption in the function of a single gene,FMR1, results in a variety of neurological consequences directly related to problems with the development, maintenance, and capacity of plastic neuronal networks. In this paper, we discuss current research illustrating the mechanisms underlying plasticity deficits in FXS. These processes include synaptic, cell intrinsic, and homeostatic mechanisms both dependent on and independent of abnormal metabotropic glutamate receptor transmission. We place particular emphasis on how identified deficits may play a role in developmental critical periods to produce neuronal networks with permanently decreased capacity to dynamically respond to changes in activity central to learning, memory, and cognition in patients with FXS. Characterizing early developmental deficits in plasticity is fundamental to develop therapies that not only treat symptoms but also minimize the developmental pathology of the disease.
Ocular Manifestations of Systemic Lupus Erythematosus: A Review of the Literature
Authors: Palejwala Neal V. , Walia Harpreet S. , Yeh Steven
Published: July 2012

About one-third of patients suffering from systemic lupus erythematosus have ocular manifestations. The most common manifestation is keratoconjunctivitis sicca. The most vision threatening are retinal vasculitis and optic neuritis/neuropathy. Prompt diagnosis and treatment of eye disease is paramount as they are often associated with high levels of systemic inflammation and end-organ damage. Initial management with high-dose oral or IV corticosteroids is often necessary. Multiple “steroid-sparing” treatment options exist with the most recently studied being biologic agents.
Characterization of Holomorphic Bisectional Curvature ofGCR-Lightlike Submanifolds
Authors: Kumar Sangeet , Kumar Rakesh , Nagaich R. K.
Published: July 2012

We obtain the expressions for sectional curvature, holomorphic sectional curvature, and holomorphic bisectional curvature of aGCR-lightlike submanifold of an indefinite Kaehler manifold. We discuss the boundedness of holomorphic sectional curvature ofGCR-lightlike submanifolds of an indefinite complex space form. We establish a condition for aGCR-lightlike submanifold of an indefinite complex space form to be null holomorphically flat. We also obtain some characterization theorems for holomorphic sectional and holomorphic bisectional curvature.
Existence of Solutions for Fractional‐Order Neutral Differential Inclusions with Impulsive and Nonlocal Conditions
Authors: Song Chao , Zhu Tao , Cao Jinde
Published: July 2012

This paper investigates the existence of solutions for fractional‐order neutral impulsive differential
inclusions with nonlocal conditions. Utilizing the fractional calculus and fixed point theorem
for multivalued maps, new sufficient conditions are derived for ensuring the existence of solutions. The obtained results improve and generalize some existed results. Finally, an illustrative example is given to show the effectiveness of theoretical results.
Epstein-Barr Virus and Systemic Lupus Erythematosus
Authors: Draborg Anette Holck , Duus Karen , Houen Gunnar
Published: July 2012

The etiology of SLE is not fully established. SLE is a disease with periods of waning disease activity and intermittent flares. This fits well in theory to a latent virus infection, which occasionally switches to lytic cycle, and EBV infection has for long been suspected to be involved. This paper reviews EBV immunobiology and how this is related to SLE pathogenesis by illustrating uncontrolled reactivation of EBV as a disease mechanism for SLE. Studies on EBV in SLE patients show enlarged viral load, abnormal expression of viral lytic genes, impaired EBV-specific T-cell response, and increased levels of EBV-directed antibodies. These results suggest a role for reactivation of EBV infection in SLE. The increased level of EBV antibodies especially comprises an elevated titre of IgA antibodies, and the total number of EBV-reacting antibody isotypes is also enlarged. As EBV is known to be controlled by cell-mediated immunity, the reduced EBV-specific T-cell response in SLE patients may result in defective control of EBV causing frequent reactivation and expression of lytic cycle antigens. This gives rise to enhanced apoptosis and amplified cellular waste load resulting in activation of an immune response and development of EBV-directed antibodies and autoantibodies to cellular antigens.
Boundary Layer Flow and Heat Transfer with Variable Fluid Properties on a Moving Flat Plate in a Parallel Free Stream
Authors: Bachok Norfifah , Ishak Anuar , Pop Ioan
Published: July 2012

The steady boundary layer flow and heat transfer of a viscous fluid on a moving flat plate in a parallel free stream with variable fluid properties are studied. Two special cases, namely, constant fluid properties and variable fluid viscosity, are considered. The transformed boundary layer equations are solved numerically by a finite‐difference scheme known as Keller‐box method. Numerical results for the flow and the thermal fields for both cases are obtained for various values of the free stream parameter and the Prandtl number. It is found that dual solutions exist for both cases when the fluid and the plate move in the opposite directions. Moreover, fluid with constant properties shows drag reduction characteristics compared to fluid with variable viscosity.
Cloud Computing for Rigorous Coupled-Wave Analysis
Authors: Kazanskiy N. L. , Serafimovich P. G.
Published: July 2012

Design and analysis of complex nanophotonic and nanoelectronic structures require significant computing resources. Cloud computing infrastructure allows distributed parallel applications to achieve greater scalability and fault tolerance. The problems of effective use of high-performance computing systems for modeling and simulation of subwavelength diffraction gratings are considered. Rigorous coupled-wave analysis (RCWA) is adapted to cloud computing environment. In order to accomplish this, data flow of the RCWA is analyzed and CPU-intensive operations are converted to data-intensive operations. The generated data sets are structured in accordance with the requirements of MapReduce technology.
Restriction of Retroviral Replication by Tetherin/BST-2
Authors: Hammonds Jason , Wang Jaang-Jiun , Spearman Paul
Published: July 2012

Tetherin/BST-2 is an important host restriction factor that limits the replication of HIV and other enveloped viruses. Tetherin is a type II membrane glycoprotein with a very unusual domain structure that allows it to engage budding virions and retain them on the plasma membrane of infected cells. Following the initial report identifying tetherin as the host cell factor targeted by the HIV-1 Vpu gene, knowledge of the molecular, structural, and cellular biology of tetherin has rapidly advanced. This paper summarizes the discovery and impact of tetherin biology on the HIV field, with a focus on recent advances in understanding its structure and function. The relevance of tetherin to replication and spread of other retroviruses is also reviewed. Tetherin is a unique host restriction factor that is likely to continue to provide new insights into host-virus interactions and illustrates well the varied ways by which host organisms defend against viral pathogens.
Acute Liver Failure Caused byAmanita phalloidesPoisoning
Authors: Santi Luca , Maggioli Caterina , Mastroroberto Marianna , Tufoni Manuel , Napoli Lucia , Caraceni Paolo
Published: July 2012

Mushroom poisoning is a relatively rare cause of acute liver failure (ALF). The present paper analyzes the pathogenesis, clinical features, prognostic indicators, and therapeutic strategies of ALF secondary to ingestion ofAmanita phalloides, which represents the most common and deadly cause of mushroom poisoning. Liver damage fromAmanita phalloidesis related to the amanitins, powerful toxins that inhibit RNA polymerase II resulting in a deficient protein synthesis and cell necrosis. After an asymptomatic lag phase, the clinical picture is characterized by gastrointestinal symptoms, followed by the liver and kidney involvement. Amatoxin poisoning may progress into ALF and eventually death if liver transplantation is not performed. The mortality rate afterAmanita phalloidespoisoning ranges from 10 to 20%. The management of amatoxin poisoning consists of preliminary medical care, supportive measures, detoxification therapies, and orthotopic liver transplantation. The clinical efficacy of any modality of treatment is difficult to demonstrate since randomized, controlled clinical trials have not been reported. The use of extracorporeal liver assist devices as well as auxiliary liver transplantation may represent additional therapeutic options.
Fibroblast Growth Factor and Mineral Metabolism Parameters among Prevalent Kidney Transplant Patients
Authors: Rao Madhumathi , Jain Priyanka , Ojo Temitope , Surya Gautam , Balakrishnan Vaidyanathapuram
Published: July 2012

Background. Chronic kidney disease (CKD) related mineral bone disorders persist after kidney transplantation, but little is known about the relationship between fibroblast growth factor-23 (FGF-23) and mineral metabolism in prevalent post-transplant patients.Objectives. To examine mineral metabolism parameters and their relationship to FGF-23 and parathyroid hormone (PTH) in prevalent kidney transplant patients.Methods. Cross-sectional study of 106 kidney transplant patients enrolled November 2005–October 2009 at Tufts Medical Center (TMC), Boston.Results. The prevalence of hypophosphatemia was 34%, hypercalcemia 3%, and elevated PTH levels 66%, at a median (25th–75th percentile) duration of 12.8 (7.5–30.9) months post-transplant. Males had significantly higher levels of PTH (P=0.04) and lower levels of serum phosphate (P=0.002). Serum PTH levels did not relate to eGFR, corrected calcium levels or serum phosphate. FGF-23 levels were above the reference limits in 7% of patients; higher levels were associated with higher serum phosphate and PTH levels after adjustment for transplant kidney function.Conclusion. FGF-23 is an important driver of mineral metabolism in prevalent transplant patients. Its modulatory role in mineral metabolism homeostasis may be heightened as feedback suppression of PTH is disturbed. Its role in long term cardiovascular and graft outcomes needs further study.
Detailed Analysis of Apoptosis and Delayed Luminescence of Human Leukemia Jurkat T Cells after Proton Irradiation and Treatments with Oxidant Agents and Flavonoids
Authors: Baran Irina , Ganea Constanta , Privitera Simona , Scordino Agata , Barresi Vincenza , Musumeci Francesco , Mocanu Maria Magdalena , Condorelli Daniele F. , Ursu Ioan , Grasso Rosaria , Gulino Marisa , Garaiman Alexandru , Musso Nicolò , Cirrone Giuseppe A. Pablo , Cuttone Giacomo
Published: July 2012

Following previous work, we investigated in more detail the relationship between apoptosis and delayed luminescence (DL) in human leukemia Jurkat T cells under a wide variety of treatments. We used menadione and hydrogen peroxide to induce oxidative stress and two flavonoids, quercetin, and epigallocatechin gallate, applied alone or in combination with menadione or H2O2. 62 MeV proton beams were used to irradiate cells under a uniform dose of 2 or 10 Gy, respectively. We assessed apoptosis, cell cycle distributions, and DL. Menadione, H2O2and quercetin were potent inducers of apoptosis and DL inhibitors. Quercetin decreased clonogenic survival and the NAD(P)H level in a dose-dependent manner. Proton irradiation with 2 Gy but not 10 Gy increased the apoptotic rate. However, both doses induced a substantial G2/M arrest. Quercetin reduced apoptosis and prolonged the G2/M arrest induced by radiation. DL spectroscopy indicated that proton irradiation disrupted the electron flow within Complex I of the mitochondrial respiratory chain, thus explaining the massive necrosis induced by 10 Gy of protons and also suggested an equivalent action of menadione and quercetin at the level of the Fe/S center N2, which may be mediated by their binding to a common site within Complex I, probably the rotenone-binding site.
Pheromone of the Banana-Spotting Bug,Amblypelta lutescens lutescensDistant (Heteroptera: Coreidae): Identification, Synthesis, and Field Bioassay
Authors: Khrimian Ashot , Fay Harry A. C. , Guzman Filadelfo , Chauhan Kamlesh , Moore Chris , Aldrich Jeffrey R.
Published: July 2012

The banana-spotting bug,Amblypelta lutescens lutescensDistant (Heteroptera: Coreidae), is one of the principal pests of tree fruits and nuts across northern and eastern Australia. Apart from visual damage assessment, there are currently no reliable methods for monitoring bug activity to aid management decisions. An attractant pheromone for this species that could be used as a trap lure could potentially fill this void. Earlier, two male-specific compounds were identified in airborne extracts fromA. lutescens lutescens, (E,E)-α-farnesene and (R,E)-nerolidol; an unknown compound with a molecular weight 220 was also detected. We now report the identification of this hitherto unknown compound as (R,E,E)-α-farnesene-10,11-oxide. Synthesis of this epoxide was conducted using a regioselective asymmetric dihydroxylation of a sulfolene. A blend mimicking the natural proportions of (E,E)-α-farnesene, (R,E)-nerolidol, and (R,E,E)-α-farnesene-10,11-oxide attracted male and femaleA. lutescens lutescensas well as nymphs in the field, verifying that the aggregation pheromone comprises or is contained within this group of compounds.
Regulation of Signal Transduction and Role of Platelets in Liver Regeneration
Authors: Nowatari Takeshi , Fukunaga Kiyoshi , Ohkohchi Nobuhiro
Published: July 2012

Among all organs, the liver has a unique regeneration capability after sustaining injury or the loss of tissue that occurs mainly due to mitosis in the hepatocytes that are quiescent under normal conditions. Liver regeneration is induced through a cascade of various cytokines and growth factors, such as, tumor necrosis factor alpha, interleukin-6, hepatocyte growth factor, and insulin-like growth factor, which activate nuclear factorκB, signal transducer and activator of transcription 3, and phosphatidyl inositol 3-kinase signaling pathways. We previously reported that platelets can play important roles in liver regeneration through a direct effect on hepatocytes and collaborative effects with the nonparenchymal cells of the liver, including Kupffer cells and liver sinusoidal endothelial cells, which participate in liver regeneration through the production of various growth factors and cytokines. In this paper, the roles of platelets and nonparenchymal cells in liver regeneration, including the associated cytokines, growth factors, and signaling pathways, are described.
Effect of Hetero Atom on the Hammett’s Reaction Constant (ρ) from the Physical Basis of Dissociation Equilibriums of (Dithio) Benzoic Acids and (Thio) Phenols and Its Application to Solvolysis Reactions and Some Free Radical Reactions
Authors: Vandanapu Jagannadham , Rachuru Sanjeev
Published: July 2012

The emergence of putative Hammett equation in mid 1930s was a boon to physical-organic chemists to elucidate the reaction mechanisms of several organic reactions. Based on the concept of this equation several hundreds of papers have emerged in chemical literature in the last century on the effect of structure, on reactivity, and very few on thermodynamic stability and kinetic reactivity of intermediates. In this article an attempt is made to explain the effect of hetero atom on Hammett’s reaction constant (ρ) taking the dissociation equilibriums of benzoic acids, dithiobenzoic acids, phenols, and thiophenols.
A Clinical Approach to Neuraxial Morphine for the Treatment of Postoperative Pain
Authors: Mugabure Bujedo Borja
Published: July 2012

Opioids are considered a “gold standard” in clinical practice for the treatment of postoperative pain. The spinal administration of an opioid drug does not guarantee selective action and segmental analgesia in the spine. Evidence from experimental studies in animals indicates that bioavailability in the spinal cord biophase is negatively correlated with liposolubility, and is higher for hydrophilic opioids, such as morphine, than lipophilic opioids, such as fentanyl, sufentanil and alfentanil. Epidural morphine sulphate has proven analgesic efficacy and superiority over systemically administered morphine for improving postoperative pain. However, pain relief after a single epidural injection of morphine could last less than 24 hours. Techniques used to administered and prolong opioid epidural analgesia, can be costly and inconvenient. Moreover, complications can arise from indwelling epidural catheterization, particularly in patients receiving anticoagulants. Clinical trials have shown that epidural morphine in the form of extended-release liposome injections (EREM) gives good analgesia for a period of 48 hours, with no need for epidural catheterisation. Intrathecal morphine produces intense analgesia for up to 24 hours with a single shot, and clinical recommendation is to choose the minimum effective dose and do not exceed 300 μg to prevent the delay respiratory depression.
Localization and Perturbations of Roots to Systems of Polynomial Equations
Authors: Gil' Michael
Published: July 2012

We establish estimates for the sums of absolute values of solutions of a zero-dimensional polynomial system. By these estimates, inequalities for the counting function of the roots are derived. In addition, bounds for the roots of perturbed systems are suggested.
On Fuzzy Corsini′s Hyperoperations
Authors: Feng Yuming , Corsini P.
Published: July 2012

We generalize the concept of C‐hyperoperation and introduce the concept of F‐C‐hyperoperation. We list some basic properties of F‐C‐hyperoperation and the relationship between the concept of C‐hyperoperation and the concept of F‐C‐hyperoperation. We also research F‐C‐hyperoperations associated with special fuzzy relations.
On Concircular -Recurrent -Contact Manifold Admitting Semisymmetric Metric Connection
Authors: Venkatesha  , Pradeep Kumar K. T. , Bagewadi C. S. , Ingalahalli Gurupadavva
Published: July 2012

In the present paper, we have studied -recurrent and concircular -recurrent -contact manifold with respect to semisymmetric metric connection and obtained some interesting results.
Atypical Presentation of Skull Metastasis from Rectal Adenocarcinoma as an Initial Symptom of Recurrence
Authors: Fırat Cemal , Aytekin Ahmet Hamdi , Erbatur Serkan , Aydın Nasuhi Engin , Selcuk Engin Burak
Published: July 2012

Most malignant rectal tumors are histopathologically characterized as adenocarcinoma and generally metastasize to distant organs such as the lungs or the liver. Metastasis of rectal carcinomas to the skull is extremely rare. This study reports the initial diagnosis of rectal adenocarcinoma recurrence in a 65-year-old female with scalp metastasis. The patient’s history indicated a colorectal adenocarcinoma that was resected five years earlier. A skull metastasis from a rectal adenocarcinoma has not yet been reported in the literature as an initial symptom for recurrence. This paper suggests that skull metastasis from any part of the body must be considered in the differential diagnosis of soft tissue tumors in the skull even in the absence of intestinal symptoms.
Evaluating Projects Based on Intuitionistic Fuzzy Group Decision Making
Authors: Rouyendegh Babak Daneshvar
Published: July 2012

There are various methods regarding project selection in different fields. This paper deals with an actual application of construction project selection, using two aggregation operators. First, the opinion of experts is used in a model of group decision making called intuitionistic fuzzy TOPSIS (IFT). Secondly, project evaluation is formulated by dynamic intuitionistic fuzzy weighted averaging (DIFWA). Intuitionistic fuzzy weighted averaging (IFWA) operator is utilized to aggregate individual opinions of decision makers (DMs) for rating the importance of criteria and alternatives. A numerical example for project selection is given to clarify the main developed result in this paper.
Design and Fabrication of a Novel T-Shaped Piezoelectric ZnO Cantilever Sensor
Authors: Yang Kai , Li Zhigang , Chen Dapeng
Published: July 2012

A novel T-shaped piezoelectric ZnO cantilever sensor for chem/bio-detection is designed and fabricated with MEMS technology. By using Rayleigh-Ritz method, the fundamental resonant frequency formula of T-shaped cantilevers is deduced for the first time and is validated by simulation results and experimental results. From this formula, we can easily find the superiority of adopting T-shape for the cantilevers. The complete process of the cantilever sensor is then successfully developed. The cantilever sensor is actuated by a layer of high-quality ZnO film with preferred (002) orientation, which is evaluated by SEM and XRD. The key step of the process is protecting the ZnO film from KOH etching by a novel and effective method, which has rarely appeared in the literature. Finally, this cantilever sensor is measured by a network analyzer, and it has a fundamental resonant frequency of 24.60 kHz. The cantilever sensor developed in this study illustrates the feasibility and potential for many miniaturized sensor applications.
Electrochemical Characterization of Li4Ti5O12/C Anode Material Prepared by Starch‐Sol‐Assisted Rheological Phase Method for Li‐Ion Battery
Authors: Wang Zhenpo , Xie Guowei , Gao Lijun
Published: July 2012

Li4Ti5O12/C composite was synthesized by starch‐sol‐assisted rheological phase method using inexpensive raw material starch as carbon coating precursor. The Li4Ti5O12/C powder was characterized using XRD, SEM, and TG techniques. The synthesized Li4Ti5O12 crystallites are cohesively covered by conductive carbon from starch sol which leads to increased conductivity, and the particle size of Li4Ti5O12/C is about 500 nm. The electrochemical performance of Li4Ti5O12/C was characterized by galvanostatic charge/discharge and EIS methods, and the results show that the Li4Ti5O12/C presents a high discharge capacity, high rate capability, and long cycle life. The capacity retention was at 87% (500 cycles at 1C) and 73.0% (2000 cycles at 20C) indicating promising high rate performance of Li4Ti5O12/C as anode material for lithium ion battery.
Antipodal Vivaldi Antenna for Water Pipe Sensor and Telemetry
Authors: Ruvio Giuseppe , Gaetano Domenico , Ammann Max J. , McEvoy Patrick
Published: July 2012

An antipodal Vivaldi antenna operates simultaneously for telemetry and sensing when placed conformally onto PVC pipes. Good radiation efficiency is realised and the antenna impedance matching remains stable when a pipe is empty or contains water. The fidelity factor performance based on an input Ultra-Wideband Gaussian pulse is a suitable figure of merit to detect water presence. Different water levels and pipe conditions correspond to fidelity factors between 90% and 96%, which are a suitable dynamic range for sensing and the appropriate quality for pulse communications for remote monitoring.
Mithramycin Represses Basal and Cigarette Smoke–Induced Expression ofABCG2and Inhibits Stem Cell Signaling in Lung and Esophageal Cancer Cells
Authors: Zhang Mary , Mathur Aarti , Zhang Yuwei , Xi Sichuan , Atay Scott , Hong Julie A. , Datrice Nicole , Upham Trevor , Kemp Clinton D. , Ripley R. Taylor , Wiegand Gordon , Avital Itzak , Fetsch Patricia , Mani Haresh , Zlott Daniel , Robey Robert , Bates Susan E. , Li Xinmin , Rao Mahadev , Schrump David S.
Published: July 2012

Cigarette smoking at diagnosis or during therapy correlates with poor outcome in patients with lung and esophageal cancers, yet the underlying mechanisms remain unknown. In this study, we observed that exposure of esophageal cancer cells to cigarette smoke condensate (CSC) led to upregulation of the xenobiotic pump ABCG2, which is expressed in cancer stem cells and confers treatment resistance in lung and esophageal carcinomas. Furthermore, CSC increased the side population of lung cancer cells containing cancer stem cells. Upregulation of ABCG2 coincided with increased occupancy of aryl hydrocarbon receptor, Sp1, and Nrf2 within the ABCG2 promoter, and deletion of xenobiotic response elements and/or Sp1 sites markedly attenuated ABCG2 induction. Under conditions potentially achievable in clinical settings, mithramycin diminished basal as well as CSC-mediated increases in AhR, Sp1, and Nrf2 levels within the ABCG2 promoter, markedly downregulated ABCG2, and inhibited proliferation and tumorigenicity of lung and esophageal cancer cells. Microarray analyses revealed that mithramycin targeted multiple stem cell–related pathways in vitro and in vivo. Collectively, our findings provide a potential mechanistic link between smoking status and outcome of patients with lung and esophageal cancers, and support clinical use of mithramycin for repressing ABCG2 and inhibiting stem cell signaling in thoracic malignancies. Cancer Res; 72(16); 4178–92. ©2012 AACR.
Phase I Pharmacokinetic/Pharmacodynamic Study of MLN8237, an Investigational, Oral, Selective Aurora A Kinase Inhibitor, in Patients with Advanced Solid Tumors
Authors: Cervantes Andres , Elez Elena , Roda Desamparados , Ecsedy Jeffrey , Macarulla Teresa , Venkatakrishnan Karthik , Roselló Susana , Andreu Jordi , Jung JungAh , Sanchis-Garcia Juan Manuel , Piera Adelaida , Blasco Inma , Maños Laura , Pérez-Fidalgo José-Alejandro , Fingert Howard , Baselga Jose , Tabernero Josep
Published: July 2012

Purpose: Aurora A kinase (AAK) is a key regulator of mitosis and a target for anticancer drug development. This phase I study investigated the safety, pharmacokinetics, and pharmacodynamics of MLN8237 (alisertib), an investigational, oral, selective AAK inhibitor, in 59 adults with advanced solid tumors.

Experimental Design: Patients received MLN8237 once daily or twice daily for 7, 14, or 21 consecutive days, followed by 14 days recovery, in 21-, 28-, or 35-day cycles. Dose-limiting toxicities (DLT) and the maximum-tolerated dose (MTD) for the 7- and 21-day schedules were determined. Pharmacokinetic parameters were derived from plasma concentration–time profiles. AAK inhibition in skin and tumor biopsies was evaluated and antitumor activity assessed.

Results: Neutropenia and stomatitis were the most common DLTs. The MTD for the 7- and 21-day schedules was 50 mg twice daily and 50 mg once daily, respectively. MLN8237 absorption was fast (median time to maximum concentration, 2 hours). Mean terminal half-life was approximately 19 hours. At steady state, pharmacodynamic effects were shown by accumulation of mitotic and apoptotic cells in skin, and exposure-related increases in numbers of mitotic cells with characteristic spindle and chromosomal abnormalities in tumor specimens, supporting AAK inhibition by MLN8237. Stable disease was observed and was durable with repeat treatment cycles, administered over 6 months, in 6 patients, without notable cumulative toxicity.

Conclusions: The recommended phase II dose of MLN8237 is 50 mg twice daily on the 7-day schedule, which is being evaluated further in a variety of malignancies, including in a phase III trial in peripheral T-cell lymphoma. Clin Cancer Res; 18(17); 4764–74. ©2012 AACR.
Evidence for the Ubiquitin Protease UBP43 as an Antineoplastic Target
Authors: Guo Yongli , Chinyengetere Fadzai , Dolinko Andrey V. , Lopez-Aguiar Alexandra , Lu Yun , Galimberti Fabrizio , Ma Tian , Feng Qing , Sekula David , Freemantle Sarah J. , Andrew Angeline S. , Memoli Vincent , Dmitrovsky Ethan
Published: July 2012

New pharmacologic targets are needed for lung cancer. One candidate pathway to target is composed of the E1-like ubiquitin-activating enzyme (UBE1L) that associates with interferon-stimulated gene 15 (ISG15), which complexes with and destabilizes cyclin D1. Ubiquitin protease 43 (UBP43/USP18) removes ISG15 from conjugated proteins. This study reports that gain of UBP43 stabilized cyclin D1, but not other D-type cyclins or cyclin E. This depended on UBP43 enzymatic activity; an enzymatically inactive UBP43 did not affect cyclin D1 stability. As expected, small interfering RNAs that reduced UBP43 expression also decreased cyclin D1 levels and increased apoptosis in a panel of lung cancer cell lines. Forced cyclin D1 expression rescued UBP43 apoptotic effects, which highlighted the importance of cyclin D1 in conferring this. Short hairpin RNA-mediated reduction of UBP43 significantly increased apoptosis and reduced murine lung cancer growth in vitro and in vivo after transplantation of these cells into syngeneic mice. These cells also exhibited increased response to all-trans-retinoic acid, interferon, or cisplatin treatments. Notably, gain of UBP43 expression antagonized these effects. Normal-malignant human lung tissue arrays were examined independently for UBP43, cyclin D1, and cyclin E immunohistochemical expression. UBP43 was significantly (P < 0.01) increased in the malignant versus normal lung. A direct relationship was found between UBP43 and cyclin D1 (but not cyclin E) expression. Differential UBP43 expression was independently detected in a normal-malignant tissue array with diverse human cancers. Taken together, these findings uncovered UBP43 as a previously unrecognized antineoplastic target. Mol Cancer Ther; 11(9); 1968–77. ©2012 AACR.
Impact of Screening Test Performance and Cost on Mortality Reduction and Cost-effectiveness of Multimodal Ovarian Cancer Screening
Authors: Drescher Charles W. , Hawley Sarah , Thorpe Jason D. , Marticke Simone , McIntosh Martin , Gambhir Sanjiv S. , Urban Nicole
Published: July 2012

Ongoing ovarian cancer screening trials are investigating the efficacy of a two-step screening strategy using currently available blood and imaging tests [CA125 and transvaginal sonography (TVS)]. Concurrently, efforts to develop new biomarkers and imaging tests seek to improve screening performance beyond its current limits. This study estimates the mortality reduction, years of life saved, and cost-effectiveness achievable by annual multimodal screening using increasing CA125 to select women for TVS, and predicts improvements achievable by replacing currently available screening tests with hypothetical counterparts with better performance characteristics. An existing stochastic microsimulation model is refined and used to screen a virtual cohort of 1 million women from ages 45 to 85 years. Each woman is assigned a detailed disease course and screening results timeline. The preclinical behavior of CA125 and TVS is simulated using empirical data derived from clinical trials. Simulations in which the disease incidence and performance characteristics of the screening tests are independently varied are conducted to evaluate the impact of these factors on overall screening performance and costs. Our results show that when applied to women at average risk, annual screening using increasing CA125 to select women for TVS achieves modest mortality reduction (∼13%) and meets currently accepted cost-effectiveness guidelines. Screening outcomes are relatively insensitive to second-line test performance and costs. Identification of a first-line test that does substantially better than CA125 and has similar costs is required for screening to reduce ovarian mortality by at least 25% and be reasonably cost-effective. Cancer Prev Res; 5(8); 1015–24. ©2012 AACR.
DDX5 Regulates DNA Replication and Is Required for Cell Proliferation in a Subset of Breast Cancer Cells
Authors: Mazurek Anthony , Luo Weijun , Krasnitz Alexander , Hicks James , Powers R. Scott , Stillman Bruce
Published: June 2012

Understanding factors required for DNA replication will enrich our knowledge of this important process and potentially identify vulnerabilities that can be exploited in cancer therapy. We applied an assay that measures the stability of maintenance of an episomal plasmid in human tissue culture cells to screen for new DNA replication factors. We identify an important role for DDX5 in G1–S-phase progression where it directly regulates DNA replication factor expression by promoting the recruitment of RNA polymerase II to E2F-regulated gene promoters. We find that the DDX5 locus is frequently amplified in breast cancer and that breast cancer–derived cells with amplification of DDX5 are much more sensitive to its depletion than breast cancer cells and a breast epithelial cell line that lacks DDX5 amplification. Our results show a novel role for DDX5 in cancer cell proliferation and suggest DDX5 as a therapeutic target in breast cancer treatment.

Significance: DDX5 is required for cell proliferation by controlling the transcription of genes expressing DNA replication proteins in cancer cells in which the DDX5 locus is amplified, and this has uncovered a dependence on DDX5 for cell proliferation. Given the high frequency of DDX5 amplification in breast cancer, our results highlight DDX5 as a promising candidate for targeted therapy of breast tumors with DDX5 amplification, and indeed we show that DDX5 inhibition sensitizes a subset of breast cancer cells to trastuzumab. Cancer Discov; 2(9); 812–25. ©2012 AACR.

This article is highlighted in the In This Issue feature, p. 753.
Headaches in Middle-Aged Women during Menopausal Transition: A Headache Clinic-Based Study
Authors: Oh Kyungmi , Jung Ki-Young , Choi Jeong-Yoon , Seo Woo-Keun , Park Kun-Woo
Published: July 2012

Middle-aged women are frequent visitors in headache clinics. We investigated the differences in headache characteristics of middle-aged women (aged 40–54 years) according to their menopausal status. In total, 229 women were divided into the following three groups: premenopausal (n = 78), perimenopausal (n = 69), and postmenopausal (n = 82). The prevalence of tension-type headaches was higher in the peri- and postmenopausal groups than in the premenopausal group (p < 0.05), whereas the prevalence of migraines was similar across the three groups. The proportion of patients with a short duration of headache history (<6 months) was significantly higher in the perimenopausal group (40.6%) than in the premenopausal (12.8%) or postmenopausal (17.1%) groups (p < 0.01). Analysis of headaches in perimenopausal patients who did not receive exogenous hormone treatment (n = 61) showed that current headaches were reported as new-onset headaches by 47.5% of subjects, as aggravations of prior headaches by 34.4% of subjects, or as unchanged from prior headaches in 18.0% of subjects. This study shows that the prevalence of tension-type headaches is different between menopausal periods, whereas the prevalence of migraines is not changed. Perimenopausal women tended to experience relatively more tension-type headaches and visited the hospital mainly due to new-onset headaches or aggravated headaches.
Coping Strategies in Multiple Sclerosis Patients with Frontal Cognitive Disorders
Authors: Montel S. , Spitz E. , Bungener C.
Published: July 2012

Background: Many studies have demonstrated the relationship between multiple sclerosis (MS) and cognition disorder. The objective of this study was to investigate the coping style of patients with mild frontal cognitive disorder. Methods: 135 patients with MS were divided into two groups as a function of their cognitive states (‘mild frontal cognitive impairments’ or ‘without frontal cognitive impairments’). All were seen for a semi-structured interview in order to collect socio-demographic and clinical information, after which there was an assessment of their cognitive and mental states and fatigue (FAB, MADRS). Then, all patients completed three self-report questionnaires concerning their coping strategies (WCC, CHIP) as well as their fatigue state. Results: No significant differences were observed between the two groups as to coping strategies and mood. However, patients with mild cognitive impairments tended to use more emotion-focused coping strategies, especially self-blame (F(133) = 2.2; p = 0.14) and diversion (F(133) = 1.35; p = 0.24) than patients without cognitive impairments. Patients with mild cognitive impairments were more fatigued than other patients. Discussion: Our study showed that patients with mild cognitive impairments did not differ significantly of other MS patients with regard to coping strategies.
M1 Susceptibility Vessel Sign and Hyperdense Middle Cerebral Artery Sign in Hyperacute Stroke Patients
Authors: Sakamoto Yuki , Kimura Kazumi , Sakai Kenichiro
Published: July 2012

Background and Purpose: Vessel signs, such as the susceptibility vessel sign (SVS) on T2*-gradient echo imaging (T2*) and the hyperdense middle cerebral artery sign (HMCAS) on CT, are well-known markers of arterial occlusion. However, the relationship between the signs is not fully known. Methods: Patients suspected of having hyperacute (<3 h from symptom onset) stroke were prospectively enrolled. MRI including T2* and MR angiography, and thin-section CT were performed on admission. The consistency between SVS and HMCAS were evaluated. Results: A total of 67 patients [38 males, median age: 76 (interquartile range: 67–82) years, median NIHSS score: 12 (4–21)] were enrolled. SVS was observed in 6 patients (9%), and HMCAS was present in 8 (12%). Sixteen patients (24%) had middle cerebral artery proximal (M1) occlusion on MR angiography. The presence or absence of SVS was highly consistent with that of HMCAS when all cases were evaluated (ĸ = 0.841), as well as when only patients with M1 occlusion were assessed (ĸ = 0.750). Conclusion: SVS and HMCAS were highly consistent with each other in suspected hyperacute stroke patients. SVS and HMCAS may represent the same thrombus.
Beta-Adrenergic Receptors, from Their Discovery and Characterization through Their Manipulation to Beneficial Clinical Application
Authors: Wachter S. Blake , Gilbert Edward M.
Published: July 2012

β-Adrenergic receptors (β-AR) are central to the overall regulation of cardiac function. From the first proposed receptor/transmitter concept to the latest clinical β-blocker trials β-AR have been shown to play an important role in cardiac disease and heart failure in particular. This study provides a historical perspective, reviews the latest discoveries and beliefs, and discusses the current clinical practices of β-AR and their modulation with their associated guanine-nucleotide regulatory protein/adenylylcyclasesignal transduction pathways.
Racial and Ethnic Differences in Incident Hospitalized Heart Failure in Postmenopausal Women
Authors: Eaton Charles B. , Abdulbaki Abdulrahman M. , Margolis Karen L. , Manson JoAnn E. , Limacher Marian , Klein Liviu , Allison Matthew A. , Robinson Jennifer G. , Curb J. David , Martin Lisa A. , Liu Simin , Howard Barbara V.
Published: July 2012

Background—

The differences in the incidence of heart failure by race/ethnicity and the potential mechanisms for these differences are largely unexplored in women.

Methods and Results—

A total of 156 143 postmenopausal women free of self-reported heart failure enrolled from 1993 to 1998 at 40 clinical centers throughout the United States as part of the Women's Health Initiative and were followed up until 2005, for an average of 7.8 years, for incident hospitalized heart failure. Incident rates, hazard ratios (HRs), and 95% confidence intervals were determined by use of the Cox proportional hazard model comparing racial/ethnic groups, and population-attributable risk percentages were calculated for each racial/ethnic group. Blacks had the highest age-adjusted incidence of heart failure (380 in 100 000 person-years), followed by whites (274), Hispanics (193), and Asian/Pacific Islanders (103). The excess risk in blacks compared with whites (age-adjusted HR=1.45) was significantly attenuated by adjustment for household income (HR=0.97) and diabetes mellitus (HR=0.89), but the lower risk in Hispanics (age-adjusted HR=0.72) and Asian/Pacific Islanders (age-adjusted HR=0.44) remained despite adjustment for traditional risk factors, socioeconomic status, lifestyle, and access-to-care variables. The effect of adjustment for interim coronary heart disease on nonwhite versus white HRs for heart failure differed by race/ethnic group.

Conclusions—

Asian/Pacific Islander and Hispanic women have a lower incidence of heart failure and black women have higher rates of heart failure compared with white women. The excess risk of incident heart failure in black women is explained largely by adjustment for lower household incomes and diabetes mellitus in black women, whereas the lower rates of heart failure in Asian/Pacific Islanders and Hispanics are largely unexplained by the risk factors measured in this study.

Clinical Trial Registration—

URL:
http://www.clinicaltrials.gov
. Unique identifier: NCT00000611.
Ca
2+
-Stimulated Adenylyl Cyclase AC1 Generates Efficient Biological Pacing as Single Gene Therapy and in Combination With HCN2
Authors: Boink Gerard J.J. , Nearing Bruce D. , Shlapakova Iryna N. , Duan Lian , Kryukova Yelena , Bobkov Yevgeniy , Tan Hanno L. , Cohen Ira S. , Danilo Peter , Robinson Richard B. , Verrier Richard L. , Rosen Michael R.
Published: June 2012

Background—

Biological pacing performed solely via HCN2 gene transfer in vivo results in relatively slow idioventricular rates and only moderate autonomic responsiveness. We induced biological pacing using the Ca
2+
-stimulated adenylyl cyclase AC1 gene expressed alone or in combination with HCN2 and compared outcomes with those with single-gene HCN2 transfer.

Methods and Results—

We implanted adenoviral HCN2, AC1, or HCN2/AC1 constructs into the left bundle branches of atrioventricular-blocked dogs. During steady-state gene expression (days 5–7), differences between AC1, HCN2/AC1, and HCN2 alone were evident in basal beating rate, escape time, and dependence on electronic backup pacing. In HCN2, AC1, and HCN2/AC1, these parameters were as follows: basal beating rate: 50±1.5, 60±5.0, and 129±28.9 bpm (
P
<0.05 for HCN2/AC1 versus HCN2 or AC1 alone), respectively; escape time: 2.4±0.2, 1.3±0.2, and 1.1±.0.4 seconds (
P
<0.05 for AC1 and HCN2/AC1 versus HCN2); and percent electronic beats: 34±8%, 2±1%, and 6±2% (
P
<0.05 for AC1 and HCN2/AC1 versus HCN2). Instantaneous (SD1) and long-term (SD2) heart rate variability and circadian rhythm analyzed via 24-hour Holter recordings showed a shift toward greater sensitivity to parasympathetic modulation in animals injected with AC1 and a high degree of sympathetic modulation in animals injected with HCN2/AC1.

Conclusion—

AC1 or HCN2/AC1 overexpression in left bundle branches provides highly efficient biological pacing and greater sensitivity to autonomic modulation than HCN2 alone.
Western-Style Fast Food Intake and Cardiometabolic Risk in an Eastern Country
Authors: Odegaard Andrew O. , Koh Woon Puay , Yuan Jian-Min , Gross Myron D. , Pereira Mark A.
Published: July 2012

Background—

Western-style fast food contributes to a dietary pattern portending poor cardiometabolic health in the United States. With globalization, this way of eating is becoming more common in developing and recently developed populations.

Methods and Results—

We examined the association of Western-style fast food intake with risk of incident type 2 diabetes mellitus and coronary heart disease mortality in Chinese Singaporeans. This analysis included men and women 45 to 74 years of age who enrolled in the Singapore Chinese Health Study from 1993 to 1998. For CHD mortality, 52 584 participants were included and 1397 deaths were identified through December 31, 2009, via registry linkage. For type 2 diabetes mellitus, 43 176 participants were included and 2252 cases were identified during the follow-up interview (1999–2004) and validated. Hazard ratios for incident type 2 diabetes mellitus and coronary heart disease mortality were estimated with thorough adjustment for demographic, lifestyle, and dietary factors. Chinese Singaporeans with relatively frequent intake of Western-style fast food items (≥2 times per week) had an increased risk of developing type 2 diabetes mellitus (hazard ratio, 1.27; 95% confidence interval, 1.03–1.54) and dying of coronary heart disease (hazard ratio, 1.56; 95% confidence interval, 1.18–2.06) relative to their peers with little or no reported intake. These associations were not materially altered by adjustments for overall dietary pattern, energy intake, and body mass index.

Conclusions—

Western-style fast food intake is associated with increased risk of developing type 2 diabetes mellitus and of coronary heart disease mortality in an Eastern population. These findings suggest the need for further attention to global dietary acculturation in the context of ongoing epidemiological and nutrition transitions.
Elevated Vascular Endothelial Growth Factor Receptor-2 Abundance Contributes to Increased Angiogenesis in Vascular Endothelial Growth Factor Receptor-1–Deficient Mice
Authors: Ho Vivienne C. , Duan Li-Juan , Cronin Chunxia , Liang Bruce T. , Fong Guo-Hua
Published: June 2012

Background—

Vascular endothelial growth factor receptor-1 (VEGFR-1/Flt-1) is a potential therapeutic target for cardiovascular diseases, but its role in angiogenesis remains controversial. Whereas germline
Vegfr-1
−/−
embryos die of abnormal vascular development in association with excessive endothelial differentiation, mice lacking only the kinase domain appear healthy.

Methods and Results—

We performed Cre-
lox
P–mediated knockout to abrogate the expression of all known VEGFR-1 functional domains in neonatal and adult mice and analyzed developmental, pathophysiological, and molecular consequences. VEGFR-1 deficiency promoted tip cell formation and endothelial cell proliferation and facilitated angiogenesis of blood vessels that matured and perfused properly. Vascular permeability was normal at the basal level but elevated in response to high doses of exogenous VEGF-A. In the postinfarct ischemic cardiomyopathy model, VEGFR-1 deficiency supported robust angiogenesis and protected against myocardial infarction. VEGFR-1 knockout led to abundant accumulation of VEGFR-2 at the protein level, increased VEGFR-2 tyrosine phosphorylation transiently, and enhanced serine phosphorylation of Akt and ERK. Interestingly, increased angiogenesis, tip cell formation, vascular permeability, VEGFR-2 accumulation, and Akt phosphorylation could be partially rescued or suppressed by one or more of the following manipulations, including injection of the VEGFR-2 selective inhibitor SU1498, anti-VEGF-A, or introduction of
Vegfr-2
+/−
heterozygosity into
Vegfr-1
somatic knockout mice.

Conclusions—

Upregulation of VEGFR-2 abundance at the protein level contributes in part to increased angiogenesis in VEGFR-1–deficient mice.