bluuebunny/crossref_metadata_2025 huggingface dataset:
In Astrocytes the Accumulation of the Immunity‐Related GTPases Irga6 and Irgb6 at the Vacuole of Toxoplasma gondii Is Dependent on the Parasite Virulence
Authors: Lubitz Felix P. , Degrandi Daniel , Pfeffer Klaus , Mausberg Anne K.
Published: November 2013

Toxoplasma gondii is an obligate intracellular
protozoan parasite responsible for a common infection of the central nervous system.
Interferon (IFN)γ is the key cytokine of host defence against
T. gondii. However, T. gondii strains differ in
virulence and T. gondii factors determining virulence are still poorly
understood. In astrocytes IFNγ primarily induces immunity‐related GTPases
(IRGs), providing a cell‐autonomous resistance system.
Here, we demonstrate that astrocytes prestimulated with IFNγ inhibit the proliferation of
various avirulent, but not virulent, T. gondii strains. The two analyzed immunity‐related
GTPases Irga6 and Irgb6 accumulate at the PV only of avirulent T. gondii strains,
whereas in virulent strains this accumulation is only detectable at very low levels. Both IRG proteins
could temporarily be found at the same PV, but did only partially colocalize. Coinfection of avirulent
and virulent parasites confirmed that the accumulation of the two analyzed IRGs was a characteristic
of the individual PV and not determined by the presence of other strains
of T. gondii in the same host cell. Thus, in
astrocytes the accumulation of Irga6 and Irgb6 significantly differs between avirulent and
virulent T. gondii strains correlating with the toxoplasmacidal properties
suggesting a role for this process in parasite virulence.
Neurolymphomatosis of Brachial Plexus in Patients with Non-Hodgkin's Lymphoma
Authors: Choi Yong Jun , Shin Jung A. , Kim Yong Hoon , Cha Soon Joo , Cho Joong-Yang , Kang Seung Hee , Yi Seong Yoon , Lee Hye Ran
Published: November 2013

Neurolymphomatosis (NL) is a rare clinical disease where neoplastic cells invade the cranial nerves and peripheral nerve roots, plexus, or other nerves in patients with hematologic malignancy. Most NL cases are caused by B-cell non-Hodgkin’s lymphoma (NHL). Diagnosis can be made by imaging with positron emission tomography (PET) and magnetic resonance imaging (MRI). We experienced two cases of NL involving the brachial plexus in patients with NHL. One patient, who had NHL with central nervous system (CNS) involvement, experienced complete remission after 8 cycles of R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) chemotherapy but relapsed into NL of the brachial plexus 5 months later. The other patient, who suffered from primary central nervous system lymphoma (PCNSL), had been undergoing chemoradiotherapy but progressed to NL of the brachial plexus.
Estrogens and Spermiogenesis: New Insights from Type 1 Cannabinoid Receptor Knockout Mice
Authors: Cacciola Giovanna , Chioccarelli Teresa , Fasano Silvia , Pierantoni Riccardo , Cobellis Gilda
Published: November 2013

Spermatogenesis is a complex mechanism which allows the production of male gametes; it consists of mitotic, meiotic, and differentiation phases. Spermiogenesis is the terminal differentiation process during which haploid round spermatids undergo several biochemical and morphological changes, including extensive remodelling of chromatin and nuclear shape. Spermiogenesis is under control of endocrine, paracrine, and autocrine factors, like gonadotropins and testosterone. More recently, emerging pieces of evidence are suggesting that, among these factors, estrogens may have a role. To date, this is a matter of debate and concern because of the agonistic and antagonistic estrogenic effects that environmental chemicals may have on animal and human with damaging outcome on fertility. In this review, we summarize data which fuel this debate, with a particular attention to our recent results, obtained using type 1 cannabinoid receptor knockout male mice as animal model.
Stability Analysis of a Class of Second Order Sliding Mode Control Including Delay in Input
Authors: Acosta Pedro R.
Published: November 2013

This paper deals with a class of second order sliding mode systems. Based on the derivative of the sliding surface, sufficient conditions are given for stability. However, the discontinuous control signal depend neither on the derivative of sliding surface nor on its estimate. Time delay in control input is also an important issue in sliding mode control for engineering applications. Therefore, also sufficient conditions are given for the time delay size on the discontinuous input signal, so that this class of second order sliding mode systems might have amplitude bounded oscillations. Moreover, amplitude of such oscillations may be estimated. Some numerical examples are given to validate the results. At the end, some conclusions are given on the possibilities of the results as well as their limitations.
Long-Term Effects of Nilvadipine against Progression of the Central Visual Field Defect in Retinitis Pigmentosa: An Extended Study
Authors: Nakazawa Mitsuru , Suzuki Yukihiko , Ito Tadashi , Metoki Tomomi , Kudo Takashi , Ohguro Hiroshi
Published: November 2013

Purpose. To assess the long-term effects of nilvadipine on the progression of central visual field defect in retinitis pigmentosa (RP).Methods. Patients with RP were randomly divided into a treated group receiving oral nilvadipine and a control group. Progression of RP was evaluated with MD slope and the average sensitivity of the central 2° (ΔCENT4).Results. The mean MD slopes were −0.55/−0.39 (right/left eyes,n=19) dB/year in the treated group and −1.37/−1.15 (right/left eyes,n=22) dB/year in the control group (P=0.016/0.050, resp.). In both eyes, however, no statistical difference was observed between the two groups for the ΔCENT4 values.Conclusion. Although we confirmed that nilvadipine significantly retarded the progression of the average of MD value defects in the central 10°, it was not specific for the central 2° of the visual field in RP.
Hypothermia Improves Oral and Gastric Mucosal Microvascular Oxygenation during Hemorrhagic Shock in Dogs
Authors: Vollmer Christian , Schwartges Ingo , Swertz Meike , Beck Christopher , Bauer Inge , Picker Olaf
Published: November 2013

Hypothermia is known to improve tissue function in different organs during physiological and pathological conditions. The aim of this study was to evaluate the effects of hypothermia on oral and gastric mucosal microvascular oxygenation (μHbO2) and perfusion (μflow) under physiological and hemorrhagic conditions. Five dogs were repeatedly anesthetized. All animals underwent each experimental protocol (randomized cross-over design): hypothermia (34°C), hypothermia during hemorrhage, normothermia, and normothermia during hemorrhage. Microcirculatory and hemodynamic variables were recorded. Systemic (DO2) and oral mucosal (μDO2) oxygen delivery were calculated. Hypothermia increased oralμHbO2with no effect on gastricμHbO2. Hemorrhage reduced oral and gastricμHbO2during normothermia (−36 ± 4% and −27 ± 7%); however, this effect was attenuated during additional hypothermia (−15 ± 5% and −11 ± 5%). The improvedμHbO2might be based on an attenuated reduction inμflow during hemorrhage and additional hypothermia (−51 ± 21 aU) compared to hemorrhage and normothermia (−106 ± 19 aU).μDO2was accordingly attenuated under hypothermia during hemorrhage whereas DO2did not change. Thus, in this study hypothermia alone improves oralμHbO2and attenuates the effects of hemorrhage on oral and gastricμHbO2. This effect seems to be mediated by an increasedμDO2on the basis of increasedμflow.
Relevance of Biofilms in the Pathogenesis of Shiga‐Toxin‐Producing Escherichia coli Infection
Authors: Angel Villegas Natalia , Baronetti José , Albesa Inés , Polifroni Rosana , Parma Alberto , Etcheverría Analía , Becerra Maria , Padola Nora , Paraje Maria
Published: November 2013

The present study was designed to determine the relationships among biofilm formation, cellular stress and release of Shiga toxin (Stx) by three different clinical Shiga toxin‐producing Escherichia coli (STEC) strains. The biofilm formation was determined using crystal violet stain in tryptic soy broth or thioglycollate medium with the addition of sugars (glucose or mannose) or hydrogen peroxide. The reactive oxygen species (ROSs) were detected by the reduction of nitro blue tetrazolium and reactive nitrogen intermediates (RNI) determined by the Griess assay. In addition, the activities of two antioxidant enzymes, superoxide dismutase (SOD) and catalase (CAT), were studied. For the cytotoxicity studies, Vero cells were cultured with Stx released of STEC biofilms. The addition of sugars in both culture mediums resulted in an increase in biofilm biomass, with a decrease in ROS and RNI production, low levels of SOD and CAT activity, and minimal cytotoxic effects. However, under stressful conditions, an important increase in the antioxidant enzyme activity and high level of Stx production were observed. The disturbance in the prooxidant‐antioxidant balance and its effect on the production and release of Stx evaluated under different conditions of biofilm formation may contribute to a better understanding of the relevance of biofilms in the pathogenesis of STEC infection.
A Critical Review of Computational Methods and Their Application in Industrial Fan Design
Authors: Corsini Alessandro , Delibra Giovanni , Sheard Anthony G.
Published: November 2013

Members of the aerospace fan community have systematically developed computational methods over the last five decades. The complexity of the developed methods and the difficulty associated with their practical application ensured that, although commercial computational codes date back to the 1980s, they were not fully exploited by industrial fan designers until the beginning of the 2000s. The application of commercial codes proved to be problematic as, unlike aerospace fans, industrial fans include electrical motors and other components from which the flow will invariably separate. Consequently, industrial fan designers found the application of commercial codes challenging. The decade from 2000 to 2010 was focused on developing techniques that would facilitate converged solutions that predicted the fans’ performance characteristics over the stable part of their operating range with reasonable accuracy, using a practical computational effort. In this paper, we focus on elucidating aspects of the flow physics that one cannot easily study in a laboratory environment, discussing the challenges involved and the relative merits of the available modelling techniques. The paper ends with a discussion of the practical problems associated with the use of commercial codes in a development environment and finally the legislation that is driving the need for aerospace style computation methods.
Diagnosis of Cryptococcosis and Prevention of Cryptococcal Meningitis Using a Novel Point-of-Care Lateral Flow Assay
Authors: Dhana Ashar
Published: November 2013

Despite access to antiretroviral therapy, mortality from cryptococcal meningitis (CM) is high among persons with advanced HIV infection in sub-Saharan Africa. Cryptococcal antigen (CrAg) is present several weeks to months before the onset of symptoms of meningitis and can be screened to prevent life threatening meningitis. Recently, the World Health Organisation recommended that a new rapid CrAg lateral flow ‘‘dipstick’’ assay (LFA) is to be used to screen HIV-infected persons with CD4 counts of less than 100 cells/µL. In this paper, we describe two cases of cryptococcosis with differing outcomes. In the first case, the new CrAg LFA was used as part of a screen and preemptive treatment strategy to prevent CM. In the second case, our patient had no access to the CrAg LFA and subsequently developed life threatening meningitis. To the best of our knowledge, this is the first case report of cryptococcosis diagnosed using this novel assay.
Acute Thoracic Aortic Dissection (Stanford Type B) Complicated with Acute Renal Failure
Authors: Li Li , Zhuang ShunJiu , Qi ShaoHong , Cui JiaSheng , Zhou JunWen , Zhu Huaqi , Zhang Wan , Li Ming , Fu Weiguo
Published: November 2013

We report a recent case and review some literatures of acute aortic dissection (AAD) Stanford type B complicated with late onset of acute renal failure. The patient underwent preoperational peritoneal dialysis followed by thoracic endovascular aortic repair (TEVAR) and was fully recovered and discharged soon after surgery. We conclude that an AAD case is difficult to achieve a timely diagnosis, but with attention to systemic symptoms and dedication thorough treatment plan, a full recovery and positive prognosis are expected.
Review on Conventional Air Conditioning, Alternative Refrigerants, and CO2 Heat Pumps for Vehicles
Authors: Lee Moo-Yeon , Lee Dong-Yeon
Published: November 2013

With the reinforced ODP and GWP regulations, clean refrigerants including CO2, energy saving technology for fuel economy, especially focused on development and control strategy for the effective air conditioning system, and heat pump for vehicles have been widely investigated. Recently, the automotive CO2 heat pump for the next generation vehicles as an alternative to that of internal combustion engines has been evaluated and studied as a good option. In this paper, first part is reviewed on the performance characteristics and improvement articles for the conventional automotive air conditioning systems and individual components as well as various alternative refrigerant articles for conventional automotive air conditioning systems. Second part deals with the feasibility of the automotive CO2 heat pump for next generation vehicles without internal combustion engines.
Therapeutic Potential of Tolerogenic Dendritic Cells in IBD: From Animal Models to Clinical Application
Authors: Cabezón Raquel , Benítez-Ribas Daniel
Published: November 2013

The gut mucosa undergoes continuous antigenic exposure from food antigens, commensal flora derived ligands, and pathogens. This constant stimulation results in controlled inflammatory responses that are effectively suppressed by multiple factors. This tight regulation, necessary to maintain intestinal homeostasis, is affected during inflammatory bowel diseases (IBD) resulting in altered immune responses to harmless microorganisms. Dendritic cells (DCs) are sentinels of immunity, located in peripheral and lymphoid tissues, which are essential for homeostasis of T cell-dependent immune responses. The expression of a particular set of pathogen recognition receptors allows DCs to initiate immune responses. However, in the absence of danger signals, different DC subsets can induce active tolerance by inducing regulatory T cells (Treg), inhibiting inflammatory T helper cell responses, or both. Interestingly, several protocols to generate clinical grade tolerogenic DC (tol-DCs)in vitrohave been described, opening the possibility to restore the intestinal homeostasis to bacterial flora by cellular therapy. In this review, we discuss different DC subsets and their role in IBD. Additionally, we will review preclinical studies performed in animal models while describing recent characterization of tol-DCs from Crohn’s disease patients for clinical application.
The Efficacy and Safety of Rituximab in a Patient with Rheumatoid Spondylitis
Authors: Kobak Şenol , Karaarslan Ahmet , Oksel Fahrettin
Published: November 2013

Rheumatoid arthritis (RA) is considered as a connective tissue disease while ankylosing spondylitis (AS) is a prototype of spondyloarthritis. These diseases are seen concomitantly only very rarely. Also, rituximab has proven efficacy in the treatment of RA while its role in the treatment of AS is unclear. In this presentation, the concomitant presence of RA and AS in a 43-year-old male patient as well as the efficacy and safety of rituximab is discussed. Rituximab was given due to lack of response to treatment with anti-TNF-alpha. Evaluations made at the 6th and 12th months of treatment showed complete response for RA and partial response for AS.
Pareto Optimal Solutions for Stochastic Dynamic Programming Problems via Monte Carlo Simulation
Authors: Cardoso R. T. N. , Takahashi R. H. C. , Cruz F. R. B.
Published: November 2013

A heuristic algorithm is proposed for a class of stochastic discrete-time continuous-variable dynamic programming problems submitted to non-Gaussian disturbances. Instead of using the expected values of the objective function, the randomness nature of the decision variables is kept along the process, while Pareto fronts weighted by all quantiles of the objective function are determined. Thus, decision makers are able to choose any quantile they wish. This new idea is carried out by using Monte Carlo simulations embedded in an approximate algorithm proposed to deterministic dynamic programming problems. The new method is tested in instances of the classical inventory control problem. The results obtained attest for the efficiency and efficacy of the algorithm in solving these important stochastic optimization problems.
Concurrent Complementary and Alternative Medicine CAM and Conventional Rehabilitation Therapy in the Management of Children with Developmental Disorders
Authors: Kim Soo Yeon , Shin Yong-Il , Nam Sang-Ook , Lee Chang-Hyung , Shin Yong Beom , Ko Hyun-Yoon , Yun Young-Ju
Published: November 2013

Background. We investigated the concurrent use of conventional rehabilitations and complementary and alternative medicine (CAM) therapies for the long-term management of children with developmental disorders (DDs).Methods. The parents or caregivers of 533 children with DDs (age range, 1–19 years) who visited the rehabilitation centers were surveyed using in depth face-to-face interviews.Results. Of the 533 patients enrolled, 520 completed the questionnaire (97% response rate). A total of 292 (56%) children were receiving multiple therapies, more than two conventional rehabilitations and CAM, at the time of the interview. A total of 249 (48%) children reported lifetime CAM use, 23% used CAM at the time of the interview, and 62% of the patients planned to use CAM therapy in the future. Conventional rehabilitation therapies used at the time of the interview included physical therapy (30%), speech therapy (28%), and occupational therapy (19%), and the CAM therapies included herbal medicine (5%) and acupuncture or moxibustion (3%). The respondents indicated that in the future they planned to use acupuncture or moxibustion (57%), occupational therapy (18%), cognitive behavioral therapy (16%), speech therapy (10%), and physical therapy (8%).Conclusion. Concurrent management as conventional rehabilitations and CAM therapies is widely used by children with DDs.
The Roles of Genetic Polymorphisms and Human Immunodeficiency Virus Infection in Lipid Metabolism
Authors: de Almeida Elaine Regina Delicato , Reiche Edna Maria Vissoci , Kallaur Ana Paula , Flauzino Tamires , Watanabe Maria Angelica Ehara
Published: November 2013

Dyslipidemia has been frequently observed among individuals infected with human immunodeficiency virus type 1 (HIV-1), and factors related to HIV-1, the host, and antiretroviral therapy (ART) are involved in this phenomenon. This study reviews the roles of genetic polymorphisms, HIV-1 infection, and highly active antiretroviral therapy (HAART) in lipid metabolism. Lipid abnormalities can vary according to the HAART regimen, such as those with protease inhibitors (PIs). However, genetic factors may also be involved in dyslipidemia because not all patients receiving the same HAART regimen and with comparable demographic, virological, and immunological characteristics develop variations in the lipid profile. Polymorphisms in a large number of genes are involved in the synthesis of structural proteins, and enzymes related to lipid metabolism account for variations in the lipid profile of each individual. As some genetic polymorphisms may cause dyslipidemia, these allele variants should be investigated in HIV-1-infected patients to identify individuals with an increased risk of developing dyslipidemia during treatment with HAART, particularly during therapy with PIs. This knowledge may guide individualized treatment decisions and lead to the development of new therapeutic targets for the treatment of dyslipidemia in these patients.
Development of Dengue Infection Severity Score
Authors: Pongpan Surangrat , Wisitwong Apichart , Tawichasri Chamaiporn , Patumanond Jayanton , Namwongprom Sirianong
Published: November 2013

Objectives. To develop a simple scoring system to predict dengue infection severity based on patient characteristics and routine clinical profiles.
Methods. Retrospective data of children with dengue infection from 3 general hospitals in Thailand were reviewed. Dengue infection was categorized into 3 severity levels: dengue infection (DF), dengue hemorrhagic fever (DHF), and dengue shock syndrome (DSS). Coefficients of significant predictors of disease severity under ordinal regression analysis were transformed into item scores. Total scores were used to classify patients into 3 severity levels. Results. Significant clinical predictors of dengue infection severity were age >6 years, hepatomegaly, hematocrit ≥40%, systolic pressure <90 mmHg, white cell count >5000 /μL, and platelet ≤50000 /μL. The derived total scores, which ranged from 0 to 18, classified patients into 3 severity levels: DF (scores <2.5, n=451, 58.1%), DHF (scores 2.5–11.5, n=276, 35.5%), and DSS (scores >11.5, n=50, 6.4%). The derived score correctly classified patients into their original severity levels in 60.7%. An under-estimation of 25.7% and an over-estimation of 13.5% were clinically acceptable. Conclusions. The derived dengue infection severity score classified patients into DF, DHF, or DSS, correctly into their original severity levels. Validation of the score should be reconfirmed before application of routine practice.
A Giant Coronary Artery Aneurysm with Coronary Arteriovenous Fistula in Asymptomatic Elderly Patient
Authors: Milici Caterina , Bovelli Daniella , Borghetti Valentino , Khoury Georgette , Bazzucchi Marco , Principi Massimo , Dominici Marcello , Boschetti Enrico
Published: November 2013

Coronary Arteriovenous Fistula (CAF) is a rare defect that occurs in 0.1-0.2% of patients undergoing coronary angiography; Coronary Artery Aneurism (CAA) also occurs in approximately 15–19% of patients with CAF. It is usually congenital, but in rare occasions it occurs after chest trauma, cardiac surgery, or coronary interventions. The case described is that of a 72-year-old woman, without previous history of cardiovascular disease, who presented a huge cardiac mass. A multimodal approach was necessary to diagnose a giant CAA with CAF responsible for compression and displacement of cardiac structures. Due to likely congenitally origin of the lesion and the absence of symptoms correlated to the CAA and to the CAF we decided to avoid invasive interventions and to treat the patient with medical therapy.
Dynamic Mechanical Behaviors of 6082-T6 Aluminum Alloy
Authors: Yibo Peng , Gang Wang , Tianxing Zhu , Shangfeng Pan , Yiming Rong
Published: November 2013

The structural components of high speed trains are usually made of aluminum alloys, for example, 6082. The dynamic mechanical behavior of the material is one of key factors considered in structural design and safety assessment. In this paper, dynamic mechanical experiments were conducted with strain rate ranging from 0.001 s−1 to 100 s−1 using Instron tensile testing machine. The true stress-strain curves were fitted based on experimental data. Johnson-Cook model of 6082-T6 aluminum alloy was built to investigate the effect of strain and strain rate on flow stress. It has shown that the flow stress was sensitive to the strain rate. Yield strength and tensile strength increased with a high strain rate, which showed strain rate effect to some extent. Fracture analysis was carried out by using Backscattered Electron imaging (BSE). As strain rate increased, more precipitates were generated in fracture.
On the Accurate Identification of Network Paths Having a Common Bottleneck
Authors: Yousaf Muhammad Murtaza , Welzl Michael
Published: November 2013

We present a new mechanism for detecting shared bottlenecks between end‐to‐end paths in a network. Our mechanism, which only needs one‐way delays from endpoints as an input, is based on the well‐known linear algebraic approach: singular value decomposition (SVD). Clusters of flows which share a bottleneck are extracted from SVD results by applying an outlier detection method. Simulations with varying topologies and different network conditions show the high accuracy of our technique.
Turing Patterns in a Predator-Prey System with Self-Diffusion
Authors: Yin Hongwei , Xiao Xiaoyong , Wen Xiaoqing
Published: November 2013

For a predator-prey system, cross-diffusion has been confirmed to emerge Turing patterns. However, in the real world, the tendency for prey and predators moving along the direction of lower density of their own species, called self-diffusion, should be considered. For this, we investigate Turing instability for a predator-prey system with nonlinear diffusion terms including the normal diffusion, cross-diffusion, and self-diffusion. A sufficient condition of Turing instability for this system is obtained by analyzing the linear stability of spatial homogeneous equilibrium state of this model. A series of numerical simulations reveal Turing parameter regions of the interaction of diffusion parameters. According to these regions, we further demonstrate dispersion relations and spatial patterns. Our results indicate that self-diffusion plays an important role in the spatial patterns.
Continuous Auricular Electroacupuncture Can Significantly Improve Heart Rate Variability and Clinical Scores in Patients with Depression: First Results from a Transcontinental Study
Authors: Shi Xian , Litscher Gerhard , Wang Huan , Wang Lu , Zhao Zengkai , Litscher Daniela , Tao Jingqiao , Gaischek Ingrid , Sheng Zemin
Published: November 2013

The goal of this study was to investigate the impact and acceptability of providing continuous auricular electroacupuncture as an adjunct to conventional medications for patients with depression. Ten patients with a mean age ± SD of 43.3 ± 10.4 years were able to provide informed consent. The quantitative and qualitative outcome measures were heart rate, heart rate variability (HRV), and different clinical scores. The study documented that a special kind of auricular electro acupuncture, applied over a period of three days, can improve various aspects of quality of life significantly but also highlighted the significant increase of HRV whilst having acupuncture treatment. In conclusion, our study shows stimulation-related and quantifiable clinical and physiological alterations in parameters after continuous auricular acupoint stimulation in patients with depression. Improved access to electro acupuncture treatment would be of major benefit for these patients. Further studies are necessary in order to verify the gained results.
Haptic-Based Neurorehabilitation in Poststroke Patients: A Feasibility Prospective Multicentre Trial for Robotics Hand Rehabilitation
Authors: Turolla Andrea , Daud Albasini Omar A. , Oboe Roberto , Agostini Michela , Tonin Paolo , Paolucci Stefano , Sandrini Giorgio , Venneri Annalena , Piron Lamberto
Published: November 2013

Background. Haptic robots allow the exploitation of known motorlearning mechanisms, representing a valuable option for motor treatment after stroke. The aim of this feasibility multicentre study was to test the clinical efficacy of a haptic prototype, for the recovery of hand function after stroke.Methods. A prospective pilot clinical trial was planned on 15 consecutive patients enrolled in 3 rehabilitation centre in Italy. All the framework features of the haptic robot (e.g., control loop, external communication, and graphic rendering for virtual reality) were implemented into a real-time MATLAB/Simulink environment, controlling a five-bar linkage able to provide forces up to 20 [N] at the end effector, used for finger and hand rehabilitation therapies. Clinical (i.e., Fugl-Meyer upper extremity scale; nine hold pegboard test) and kinematics (i.e., time; velocity; jerk metric; normalized jerk of standard movements) outcomes were assessed before and after treatment to detect changes in patients' motor performance. Reorganization of cortical activation was detected in one patient by fMRI.Results and Conclusions. All patients showed significant improvements in both clinical and kinematic outcomes. Additionally, fMRI results suggest that the proposed approach may promote a better cortical activation in the brain.
A Chattering Free Discrete-Time Global Sliding Mode Controller for Optoelectronic Tracking System
Authors: Ren Yan , Liu Zhenghua , Liu Xiaodong , Zhang Yu
Published: November 2013

Aiming at the uncertainties including parameter variations and external disturbances in optoelectronic tracking system, a discrete-time global sliding mode controller (DGSMC) is proposed. By the design of nonlinear switching function, the initial state of control system is set on the switching surface. An adaptive discrete-time reaching law is introduced to suppress the high-frequency chattering at control input, and a linear extrapolation method is employed to estimate the unknown uncertainties and commands. The global reachability for sliding mode and the chattering-free property are proven by means of mathematical derivation. Numerical simulation presents that the proposed DGSMC scheme not only ensures strong robustness against system uncertainties and small tracking error, but also suppresses the high-frequency chattering at control input effectively, compared with the SMC scheme using conventional discrete-time reaching law.
D538G Mutation in Estrogen Receptor-α: A Novel Mechanism for Acquired Endocrine Resistance in Breast Cancer
Authors: Merenbakh-Lamin Keren , Ben-Baruch Noa , Yeheskel Adva , Dvir Addie , Soussan-Gutman Lior , Jeselsohn Rinath , Yelensky Roman , Brown Myles , Miller Vincent A. , Sarid David , Rizel Shulamith , Klein Baruch , Rubinek Tami , Wolf Ido
Published: November 2013

Resistance to endocrine therapy occurs in virtually all patients with estrogen receptor α (ERα)-positive metastatic breast cancer, and is attributed to various mechanisms including loss of ERα expression, altered activity of coregulators, and cross-talk between the ERα and growth factor signaling pathways. To our knowledge, acquired mutations of the ERα have not been described as mediating endocrine resistance. Samples of 13 patients with metastatic breast cancer were analyzed for mutations in cancer-related genes. In five patients who developed resistance to hormonal therapy, a mutation of A to G at position 1,613 of ERα, resulting in a substitution of aspartic acid at position 538 to glycine (D538G), was identified in liver metastases. Importantly, the mutation was not detected in the primary tumors obtained prior to endocrine treatment. Structural modeling indicated that D538G substitution leads to a conformational change in the ligand-binding domain, which mimics the conformation of activated ligand-bound receptor and alters binding of tamoxifen. Indeed, experiments in breast cancer cells indicated constitutive, ligand-independent transcriptional activity of the D538G receptor, and overexpression of it enhanced proliferation and conferred resistance to tamoxifen. These data indicate a novel mechanism of acquired endocrine resistance in breast cancer. Further studies are needed to assess the frequency of D538G-ERα among patients with breast cancer and explore ways to inhibit its activity and restore endocrine sensitivity. Cancer Res; 73(23); 6856–64. ©2013 AACR.
Targeted Imaging of Ewing Sarcoma in Preclinical Models Using a 64Cu-Labeled Anti-CD99 Antibody
Authors: O'Neill Allison F. , Dearling Jason L.J. , Wang Yuchuan , Tupper Tanya , Sun Yanping , Aster Jon C. , Calicchio Monica L. , Perez-Atayde Antonio R. , Packard Alan B. , Kung Andrew L.
Published: November 2013

Purpose: Ewing sarcoma is a tumor of the bone and soft tissue characterized by diffuse cell membrane expression of CD99 (MIC2). Single-site, surgically resectable disease is associated with an excellent 5-year event-free survival; conversely, patients with distant metastases have a poor prognosis. Noninvasive imaging is the standard approach to identifying sites of metastatic disease. We sought to develop a CD99-targeted imaging agent for staging Ewing sarcoma and other CD99-expressing tumors.

Experimental Design: We identified a CD99 antibody with highly specific binding in vitro and labeled this antibody with 64Cu. Mice with either subcutaneous Ewing sarcoma xenograft tumors or micrometastases were imaged with the 64Cu-labeled anti-CD99 antibody and these results were compared with conventional MRI and 2[18F]fluoro-2-deoxy-d-glucose–positron emission tomography (FDG–PET) imaging.

Results: 64Cu-labeled anti-CD99 antibody demonstrated high avidity for the CD99-positive subcutaneous tumors, with a high tumor-to-background ratio, greater than that demonstrated with FDG–PET. Micrometastases, measuring 1 to 2 mm on MRI, were not detected with FDG–PET but were readily visualized with the 64Cu-labeled anti-CD99 antibody. Probe biodistribution studies demonstrated high specificity of the probe for CD99-positive tumors.

Conclusions: 64Cu-labeled anti-CD99 antibody can detect subcutaneous Ewing sarcoma tumors and metastatic sites with high sensitivity, outperforming FDG–PET in preclinical studies. This targeted radiotracer may have important implications for the diagnosis, surveillance, and treatment of Ewing sarcoma. Similarly, it may impact the management of other CD99 positive tumors. Clin Cancer Res; 20(3); 678–87. ©2013 AACR.
Tumor-Reactive CD8+ T Cells in Metastatic Gastrointestinal Cancer Refractory to Chemotherapy
Authors: Turcotte Simon , Gros Alena , Tran Eric , Lee Chyi-Chia R. , Wunderlich John R. , Robbins Paul F. , Rosenberg Steven A.
Published: November 2013

Purpose: To evaluate whether patients with metastatic gastrointestinal adenocarcinomas refractory to chemotherapy harbor tumor-reactive cytotoxic T cells.

Experimental Design: Expansion of CD8+ tumor-infiltrating lymphocytes (TIL) and cancer cell lines was attempted from gastrointestinal cancer metastases in 16 consecutive patients for the study of antitumor immune recognition. Retroviral transduction of genes encoding T-cell receptors (TCR) was used to define HLA-restriction elements and specific reactivity.

Results: TIL were expanded from metastases in all patients, and new tumor cell lines were generated in 5 patients. Autologous tumor recognition without cross-reactivity against allogeneic HLA-matched gastrointestinal tumors was found in CD8+ TIL from 3 of these 5 patients. In a patient with gastric cancer liver metastases, the repertoire of CD8+ TIL was dominated by cytolytic sister clones reactive to 2 out of 4 autologous cancer cell lines restricted by HLA-C*0701. From the same patient, a rare CD8+ TIL clone with a distinct TCR recognized all four cancer cell lines restricted by HLA-B*4901. In a patient with bile duct cancer, two distinct antitumor cytolytic clones were isolated from a highly polyclonal CD8+ TIL repertoire. TCRs isolated from these clones recognized epitopes restricted by HLA-A*0201. In a third patient, CD8+ TIL reactivity was progressively lost against an autologous colon cancer cell line that displayed loss of HLA haplotype.

Conclusions: This study provides a basis for the development of immunotherapy for patients with advanced gastrointestinal malignancies by first establishing the presence of naturally occurring tumor-reactive CD8+ TIL at the molecular level. Clin Cancer Res; 20(2); 331–43. ©2013 AACR.
Busulfan in Infant to Adult Hematopoietic Cell Transplant Recipients: A Population Pharmacokinetic Model for Initial and Bayesian Dose Personalization
Authors: McCune Jeannine S. , Bemer Meagan J. , Barrett Jeffrey S. , Scott Baker K. , Gamis Alan S. , Holford Nicholas H.G.
Published: November 2013

Purpose: Personalizing intravenous busulfan doses to a target plasma concentration at steady state (Css) is an essential component of hematopoietic cell transplantation (HCT). We sought to develop a population pharmacokinetic model to predict i.v. busulfan doses over a wide age spectrum (0.1–66 years) that accounts for differences in age and body size.

Experimental Design: A population pharmacokinetic model based on normal fat mass and maturation based on postmenstrual age was built from 12,380 busulfan concentration time points obtained after i.v. busulfan administration in 1,610 HCT recipients. Subsequently, simulation results of the initial dose necessary to achieve a target Css with this model were compared with pediatric-only models.

Results: A two-compartment model with first-order elimination best fit the data. The population busulfan clearance was 12.4 L/h for an adult male with 62 kg normal fat mass (equivalent to 70 kg total body weight). Busulfan clearance, scaled to body size—specifically normal fat mass, is predicted to be 95% of the adult clearance at 2.5 years postnatal age. With a target Css of 770 ng/mL, a higher proportion of initial doses achieved the therapeutic window with this age- and size-dependent model (72%) compared with dosing recommended by the U.S. Food and Drug Administration (57%) or the European Medicines Agency (70%).

Conclusion: This is the first population pharmacokinetic model developed to predict initial i.v. busulfan doses and personalize to a target Css over a wide age spectrum, ranging from infants to adults. Clin Cancer Res; 20(3); 754–63. ©2013 AACR.
Erb-041, an Estrogen Receptor-β Agonist, Inhibits Skin Photocarcinogenesis in SKH-1 Hairless Mice by Downregulating the WNT Signaling Pathway
Authors: Chaudhary Sandeep C. , Singh Tripti , Talwelkar Sarang S. , Srivastava Ritesh K. , Arumugam Aadithya , Weng Zhiping , Elmets Craig A. , Afaq Farrukh , Kopelovich Levy , Athar Mohammad
Published: November 2013

Estrogen receptors (ER), including ER-α and ER-β, are known to regulate multiple biologic responses in various cell types. The expression of ER-β is lost in various cancers. ER-β agonists were shown to modulate inflammation, cancer cell proliferation, and differentiation. Here, we investigated the cancer chemopreventive properties of Erb-041, an ER-β agonist, using a model of UVB-induced photocarcinogenesis in SKH-1 mice. Erb-041 significantly reduced UVB-induced carcinogenesis. Tumor numbers and volume were reduced by 60% and 84%, respectively, in the Erb-041–treated group as compared with UVB (alone) control. This inhibition in tumorigenesis was accompanied by the decrease in proliferating cell nuclear antigen (PCNA), cyclin D1, VEGF, and CD31, and an increase in apoptosis. The lost ER-β expression in squamous cell carcinomas (SCC) was significantly recovered by Erb-041 treatment. In addition, the UVB-induced inflammatory responses were remarkably reduced. Myeloperoxidase activity, levels of cytokines (interleukin (IL)-1β, IL-6, and IL-10), and expression of p-ERK (extracellular signal–regulated kinase) 1/2, p-p38, p-IκB, iNOS, COX-2, and nuclear NF-κBp65 were diminished. The number of tumor-associated inflammatory cells (GR-1+/CD11b+ and F4/80+) was also decreased. Tumors excised from Erb-041–treated animal were less invasive and showed reduced epithelial–mesenchymal transition (EMT). The enhanced expression of E-cadherin with the concomitantly reduced expression of N-cadherin, Snail, Slug, and Twist characterized these lesions. The WNT/β-catenin signaling pathway, which underlies pathogenesis of skin cancer, was found to be downregulated by Erb-041 treatment. Similar but not identical changes in proliferation and EMT regulatory proteins were noticed following treatment of tumor cells with a WNT signaling inhibitor XAV939. Our results show that Erb-041 is a potent skin cancer chemopreventive agent that acts by dampening the WNT/β-catenin signaling pathway. Cancer Prev Res; 7(2); 186–98. ©2013 AACR.
Combined Targeting of Costimulatory (OX40) and Coinhibitory (CTLA-4) Pathways Elicits Potent Effector T Cells Capable of Driving Robust Antitumor Immunity
Authors: Redmond William L. , Linch Stefanie N. , Kasiewicz Melissa J.
Published: November 2013

Ligation of the TNF receptor family costimulatory molecule OX40 (CD134) with an agonist anti-OX40 monoclonal antibody (mAb) enhances antitumor immunity by augmenting T-cell differentiation as well as turning off the suppressive activity of the FoxP3+CD4+ regulatory T cells (Treg). In addition, antibody-mediated blockade of the checkpoint inhibitor CTLA-4 releases the “brakes” on T cells to augment tumor immunotherapy. However, monotherapy with these agents has limited therapeutic benefit particularly against poorly immunogenic murine tumors. Therefore, we examined whether the administration of agonist anti-OX40 therapy in the presence of CTLA-4 blockade would enhance tumor immunotherapy. Combined anti-OX40/anti-CTLA-4 immunotherapy significantly enhanced tumor regression and the survival of tumor-bearing hosts in a CD4 and CD8 T cell–dependent manner. Mechanistic studies revealed that the combination immunotherapy directed the expansion of effector T-bethigh/Eomeshigh granzyme B+ CD8 T cells. Dual immunotherapy also induced distinct populations of Th1 [interleukin (IL)-2, IFN-γ], and, surprisingly, Th2 (IL-4, IL-5, and IL-13) CD4 T cells exhibiting increased T-bet and Gata-3 expression. Furthermore, IL-4 blockade inhibited the Th2 response, while maintaining the Th1 CD4 and effector CD8 T cells that enhanced tumor-free survival. These data demonstrate that refining the global T-cell response during combination immunotherapy can further enhance the therapeutic efficacy of these agents. Cancer Immunol Res; 2(2); 142–53. ©2013 AACR.
Cancer–Testis Antigen Expression in Digestive Tract Carcinomas: Frequent Expression in Esophageal Squamous Cell Carcinoma and Its Precursor Lesions
Authors: Chen Yao-Tseng , Panarelli Nicole C. , Piotti Kathryn C. , Yantiss Rhonda K.
Published: November 2013

Cancer–testis (CT) antigens are attractive tumor antigens for cancer immunotherapy. They comprise a group of proteins normally expressed in germ cells and aberrantly activated in a variety of human cancers. The protein expression of eight cancer–testis antigens [MAGEA, NY-ESO-1, GAGE, MAGEC1 (CT7), MAGEC2 (CT10), CT45, SAGE1, and NXF2] was evaluated by immunohistochemistry in 61 esophageal carcinomas (40 adenocarcinoma and 21 squamous cell carcinoma), 50 gastric carcinomas (34 diffuse and 16 intestinal type), and 141 colorectal carcinomas. The highest frequency of expression was found in esophageal squamous cell carcinomas: Positive staining for MAGEA, CT45, CT7, SAGE1, GAGE, NXF2, NY-ESO-1, and CT10 was observed in 57%, 38%, 33%, 33%, 29%, 29%, 19%, and 14% of squamous cell carcinomas, respectively. Similar staining patterns were observed in squamous dysplasias. Expression frequencies of cancer–testis antigens were seen in 2% to 24% of gastroesophageal adenocarcinomas and were not significantly different between adenocarcinomas of the stomach versus the esophagus, or between diffuse and intestinal types of gastric adenocarcinomas. Colorectal cancers did not express NY-ESO-1, CT7, CT10, or GAGE, and only infrequently expressed SAGE1 (0.7%) MAGEA (1.4%), CT45 (3.5%), and NXF2 (8.5%). We conclude that cancer–testis antigens are frequently expressed in esophageal squamous neoplasms. Although cancer–testis antigens are generally considered to be expressed later in tumor progression, they are found in squamous dysplasias, suggesting a potential diagnostic role for cancer–testis antigens in the evaluation of premalignant squamous lesions. Cancer Immunol Res; 2(5); 480–6. ©2013 AACR.
In vitro Dissolution of Calcium Oxalate Stones with Ethylenediaminetetraacetic Acid and Snake Venom Thrombin-Like Enzyme
Authors: Zhou Xiang-Jun , Zhang Jie , Zhang Ci , Xu Chang-Geng
Published: November 2013

Objective: The aim of this study was to determine the feasibility of using snake venom thrombin-like enzyme (SVTLE) and/or ethylenediaminetetraacetic acid (EDTA) to dissolve calcium oxalate stones in vitro. Methods: Seven calcium oxalate stones were incubated with various chemolytic agents [EDTA, Tris-HCl/EDTA (TE) buffer or SVTLE diluted in TE buffer]. The pH, calcium concentration, stone weight and stone surface integrity were recorded, as well as related pathological changes to bladder mucosae. Results: Compared to all other solutions, those containing SVTLE and buffered EDTA had higher concentrations of mobilized calcium and caused significantly more stone weight loss, stone fragility and gaps in the calcium crystals. Also, there were no adverse pathological effects on rabbit bladder mucosae from any of the solutions. Conclusions: The data indicate that buffered EDTA and SVTLE can be used to dissolve calcium oxalate stones and, at the concentrations used here, do not damage tissue.
Natural Course and Surgical Management of High Myopic Foveoschisis
Authors: Rey Amanda , Jürgens Ignasi , Maseras Xavier , Carbajal Miriam
Published: November 2013

Purpose: To describe the spectral-domain optical coherence tomographic characteristics, natural course and surgical management for eyes with myopic foveoschisis. Methods: The medical records of 39 consecutive patients (56 eyes) with myopic foveoschisis were retrospectively reviewed. Pars plana vitrectomy with internal limiting membrane peeling and Brilliant Blue G staining was performed on 16 symptomatic eyes (14 patients). Results: Optical coherence tomography at baseline showed an isolated foveoschisis in 62.5%, foveal detachment in 21.4%, and a lamellar hole in 16.1% of the eyes. After a mean follow-up period of 15.7 months, 1.8% of the eyes developed a full-thickness macular hole and 28.5% of the eyes required surgery. The mean preoperative visual acuity (VA) was 20/63 and the mean central retinal thickness (CRT) was 507.6 µm. The mean postoperative VA was 20/40 and the mean CRT 282.9 µm. Anatomical success was achieved in 75% of the eyes at a mean of 3.3 months after surgery, and 81.2% of the eyes had an improvement of 2 lines of VA. Conclusion: Myopic foveoschisis remained stable in most eyes; however, 28.5% of the eyes had decreases in VA secondary to progression of the foveoschisis and required surgery.
Environmental and Occupational Risk Factors for Amyotrophic Lateral Sclerosis: A Case-Control Study
Authors: Malek Angela M. , Barchowsky Aaron , Bowser Robert , Heiman-Patterson Terry , Lacomis David , Rana Sandeep , Youk Ada , Stickler David , Lackland Daniel T. , Talbott Evelyn O.
Published: November 2013

Background/Aims: Environmental and occupational exposures are implicated as risk factors for amyotrophic lateral sclerosis (ALS), the etiology of which is largely unknown, although no causal relationships have been established. Objective: The aim of the study was to evaluate the associations of personal risk factors and self-reported environmental and occupational exposures with risk of ALS. Methods: The cases involved ALS patients (n = 66) identified from major neurological centers in Pittsburgh and Philadelphia, Pa., USA, from 2008 to 2010. The age-, race- and sex-matched controls included outpatient hospital and population-based controls (n = 66). A detailed questionnaire obtaining data on occupation, vocational and avocational exposure as well as personal lifestyle factors was administered. Results: Occupational exposure to metals (odds ratio, OR = 3.65; 95% CI: 1.15, 11.60) and pesticides (OR = 6.50; 95% CI: 1.78, 23.77) was related to increased risk of ALS after controlling for smoking and education. No associations were found for occupational exposure to organic or aromatic solvents. Conclusion: Workers exposed to metals and pesticides may be at greater risk of ALS. Future research should involve more accurate exposure assessment through the use of job exposure matrices, confirmation of occupation and biomarkers.