bluuebunny/crossref_metadata_2025 huggingface dataset:
β-Adrenergic signaling stimulates osteoclastogenesis via reactive oxygen species
Authors: Kondo Hisataka , Takeuchi Shoko , Togari Akifumi
Published: November 2012

Sympathetic signaling regulates bone resorption through receptor activator of nuclear factor-κB ligand (RANKL) expression via the β-adrenergic receptor (β-AR) on osteoblasts. Reactive oxygen species (ROS) are known as one type of osteoclast regulatory molecule. Here we show that an antioxidant, α-lipoic acid (α-LA), treatment prevent the β-adrenergic signaling-induced bone loss by suppressing osteoclastogenesis, and sympathetic signaling directly regulates osteoclastogenesis through β2-AR expressed on osteoclasts via intracellular ROS generation. In an in vitro study, the β-AR agonist isoprenaline increased intracellular ROS generation in osteoclasts prepared from bone marrow macrophages (BBMs) and RAW 264.7 cells. Isoprenaline enhanced osteoclastogenesis through β2-AR expressed on BMMs and RAW 264.7 cells. The antioxidant α-LA inhibited isoprenaline-enhanced osteoclastogenesis. Isoprenaline increased the expression of osteoclast-related genes such as nuclear factor of activated T cells, cytoplasmic, calcineurin-dependent 1, tartrate-resistant acid phosphatase, and cathepsin K on osteoclasts. α-LA also inhibited isoprenaline-induced increases of these gene expressions. These in vitro results led to the hypothesis that β-adrenergic signaling directly stimulates osteoclastogenesis via ROS generation. In an in vivo study, isoprenaline treatment alone caused oxidative damage in local bone and reduced bone mass because of an increase in bone resorption, and, in α-LA-treated mice, isoprenaline did not increase tibial osteoclast number even though the RANKL-to-osteoprotegerin ratio increased. These in vitro and in vivo results indicate that β-adrenergic signaling, at least in part, directly stimulates osteoclastogenesis through β2-AR on osteoclasts via ROS generation.
Long-term, intermittent, insulin-induced hypoglycemia produces marked obesity without hyperphagia or insulin resistance: A model for weight gain with intensive insulin therapy
Authors: McNay Ewan C. , Teske Jennifer A. , Kotz Catherine M. , Dunn-Meynell Ambrose , Levin Barry E. , McCrimmon Rory J. , Sherwin Robert S.
Published: November 2012

A major side effect of insulin treatment of diabetes is weight gain, which limits patient compliance and may pose additional health risks. Although the mechanisms responsible for this weight gain are poorly understood, it has been suggested that there may be a link to the incidence of recurrent episodes of hypoglycemia. Here we present a rodent model of marked weight gain associated with weekly insulin-induced hypoglycemic episodes in the absence of diabetes. Insulin treatment caused a significant increase in both body weight and fat mass, accompanied by reduced motor activity, lowered thermogenesis in response to a cold challenge, and reduced brown fat uncoupling protein mRNA. However, there was no effect of insulin treatment on total food intake nor on hypothalamic neuropeptide Y or proopiomelanocortin mRNA expression, and insulin-treated animals did not become insulin-resistant. Our results suggest that repeated iatrogenic hypoglycemia leads to weight gain, and that such weight gain is associated with a multifaceted deficit in metabolic regulation rather than to a chronic increase in caloric intake.
Constitutive expression of pregnancy-associated plasma protein-A in arterial smooth muscle reduces the vascular response to injury in vivo
Authors: Bale Laurie K. , Resch Zachary T. , Harstad Sara L. , Overgaard Michael T. , Conover Cheryl A.
Published: November 2012

Pregnancy-associated plasma protein-A (PAPP-A) functions to increase local IGF-I bioactivity. In this study, we used transgenic mice that constitutively express human PAPP-A in arterial smooth muscle to test the hypothesis that overexpression of PAPP-A enhances vascular smooth muscle cell (SMC) response to IGF-I in vivo. PAPP-A transgenic (Tg) and wild-type (WT) mice underwent unilateral carotid ligation, a model of injury-induced SMC hyperplasia and neointimal formation. In both WT and PAPP-A Tg mice, endogenous PAPP-A mRNA expression showed peak elevation 5 days after carotid ligation. However, PAPP-A Tg mice had 70–75% less neointima than WT at 5 and 10 days postligation, with a significant reduction in occlusion of the ligated artery. WT and PAPP-A Tg mice had equivalent increases in medial area and vessel remodeling postligation. There was little change in medial area and no evidence of neointima in the contralateral carotid of WT or PAPP-A Tg mice. Both WT and PAPP-A Tg carotids exhibited signs of dedifferentiation of SMC, which precedes the increase in proliferation and migration that results in neointimal formation. However, the number of proliferating cells in the media and neointima of the ligated PAPP-A Tg artery was reduced by 90% on day 5 postsurgery compared with WT. This decrease was associated with a significant decrease in an in vivo marker of IGF-I bioactivity and reduced IGF-I-stimulated receptor phosphorylation ex vivo. These data suggest differential effects of chronic (transgenic) and transient (endogenous) PAPP-A expression on neointimal formation following vascular injury that may be due in part to the differential impact on IGF-I signaling.
Enhancing Scalability in On-Demand Video Streaming Services for P2P Systems
Authors: Arockia Xavier Annie R. , Yogesh P. , Kannan A.
Published: November 2012

Recently, many video applications like video telephony, video conferencing, Video-on-Demand (VoD), and so forth have produced heterogeneous consumers in the Internet. In such a scenario, media servers play vital role when a large number of concurrent requests are sent by heterogeneous users. Moreover, the server and distributed client systems participating in the Internet communication have to provide suitable resources to heterogeneous users to meet their requirements satisfactorily. The challenges in providing suitable resources are to analyze the user service pattern, bandwidth and buffer availability, nature of applications used, and Quality of Service (QoS) requirements for the heterogeneous users. Therefore, it is necessary to provide suitable techniques to handle these challenges. In this paper, we propose a framework for peer-to-peer- (P2P-) based VoD service in order to provide effective video streaming. It consists of four functional modules, namely, Quality Preserving Multivariate Video Model (QPMVM) for efficient server management, tracker for efficient peer management, heuristic-based content distribution, and light weight incentivized sharing mechanism. The first two of these modules are confined to a single entity of the framework while the other two are distributed across entities. Experimental results show that the proposed framework avoids overloading the server, increases the number of clients served, and does not compromise on QoS, irrespective of the fact that the expected framework is slightly reduced.
Effects of Subsetting by Carbon Content, Soil Order, and Spectral Classification on Prediction of Soil Total Carbon with Diffuse Reflectance Spectroscopy
Authors: McDowell Meryl L. , Bruland Gregory L. , Deenik Jonathan L. , Grunwald Sabine
Published: November 2012

Subsetting of samples is a promising avenue of research for the continued improvement of prediction models for soil properties with diffuse reflectance spectroscopy. This study examined the effects of subsetting by soil total carbon (Ct) content, soil order, and spectral classification withk-means cluster analysis on visible/near-infrared and mid-infrared partial least squares models forCtprediction. Our sample set was composed of various Hawaiian soils from primarily agricultural lands withCtcontents from <1% to 56%. Slight improvements in the coefficient of determination (R2) and other standard model quality parameters were observed in the models for the subset of the high activity clay soil orders compared to the models of the full sample set. The other subset models explored did not exhibit improvement across all parameters. Models created from subsets consisting of only lowCtsamples (e.g.,Ct< 10%) showed improvement in the root mean squared error (RMSE) and percent error of prediction for lowCtsoil samples. These results provide a basis for future study of practical subsetting strategies for soilCtprediction.
Analysis of an Ecoepidemiological Model with Prey Refuges
Authors: Wang Shufan , Ma Zhihui
Published: November 2012

An ecoepidemiological system with prey refuges and disease in prey is proposed. Bilinear incidence and Holling III functional response are used to model the contact process and the predation process, respectively. We will study the stability behavior of the basic system from a local to a global perspective. Permanence of the considered system is also investigated.
Discovery of Biomarkers for Osteosarcoma by Proteomics Approaches
Authors: Suehara Yoshiyuki , Kubota Daisuke , Kikuta Kazutaka , Kaneko Kazuo , Kawai Akira , Kondo Tadashi
Published: November 2012

Osteosarcomas are the most common malignant bone tumors, and the identification of useful tumor biomarkers and target proteins is required to predict the clinical outcome of patients and therapeutic response as well as to develop novel therapeutic strategies. Global protein expression studies, namely, proteomic studies, can offer important clues to understanding the tumor biology that cannot be obtained by other approaches. These studies, such as two-dimensional gel electrophoresis and mass spectrometry, have provided protein expression profiles of osteosarcoma that can be used to develop novel diagnostic and therapeutic biomarkers, as well as to understand biology of tumor progression and malignancy. In this paper, a brief description of the methodology will be provided followed by a few examples of the recent proteomic studies that have generated new information regarding osteosarcomas.
A Reference Finding Rarely Seen in Primary Hyperparathyroidism: Brown Tumor
Authors: Mantar F. , Gunduz S. , Gunduz U. R.
Published: November 2012

Primary hyperparathyroidism is an endocrinopathy which is characterized with the hypersecretion of parathormone. During the progress of the disease bone loss takes place due to resorption on the subperiosteal and endosteal surfaces. Brown tumor is a localized form of osteitis fibrosa cystica, being part of the hyperparathyroid bone disease. It is rarely the first symptom of hyperparathyroidism. Nowadays, the diagnosis is made at an asymptomatic or minimally symptomatic stage. We present a male patient presented with a massive painless swelling in the left maxilla as the first manifestation of primary hyperparathyroidism due to a parathyroid adenoma. Parathyroidectomy was performed, and there was a regression of the bone lesion, without the need of performing other local surgical procedures.
On a Stability of Logarithmic‐Type Functional Equation in Schwartz Distributions
Authors: Chung Jae-Young
Published: November 2012

We prove the Hyers‐Ulam stability of the logarithmic functional equation of Heuvers and Kannappan f(x + y) − g(xy) − h(1/x + 1/y) = 0,   x, y > 0, in both classical and distributional senses. As a classical sense, the Hyers‐Ulam stability of the inequality |f(x + y) − g(xy) − h(1/x + 1/y)| ≤ ϵ,   x, y > 0 will be proved, where f, g, h : ℝ+ → ℂ. As a distributional analogue of the above inequality, the stability of inequality ∥u∘(x + y) − v∘(xy) − w∘(1/x + 1/y)∥ ≤ ϵ will be proved, where u, v, w ∈ 𝒟′(ℝ+) and ∘ denotes the pullback of distributions.
Highly Efficient and Facile Method for Synthesis of 2-Substituted Benzimidazoles via Reductive Cyclization of O-Nitroaniline and Aryl Aldehydes
Authors: Naeimi Hossein , Alishahi Nasrin
Published: November 2012

A versatile and convenient synthesis of 2-substituted benzimidazoles, using o-nitroaniline as starting material with several aryl aldehydes, has been accomplished by using a small amount of a reluctant agent. The reaction was carried out under very mild conditions at room temperature. The yields obtained are very good in reasonably short reaction times.
Esthetic Composition of Smile in Individuals with Cleft Lip, Alveolus, and Palate: Visibility of the Periodontium and the Esthetics of Smile
Authors: Esper Luis Augusto , Sbrana Michyele Cristhiane , Cunha Mércia Jussara da Silva , Moreira Guilherme Santos , de Almeida Ana Lúcia Pompéia Fraga
Published: November 2012

Objective. To evaluate characteristics of smile related to visibility in individuals with cleft lip, alveolus, and palate. Design. Cross-sectional. Setting. HRAC/USP, Brazil. Patients. Individuals with repaired complete unilateral cleft lip and palate , aged 15–30 years. Interventions. Frontal facial photographs were obtained in natural and forced smiles . Six specialists in periodontics evaluated the photographs as to the smile line, thickness, and curve of the upper lip. Main Outcome Measures. The cleft area was compared with the contralateral region. Results were expressed as percentages and means. The findings were compared between groups of periodontists. Results. Statistically significant relationship was observed in the smile line between examiners and between natural and forced smiles, regardless of the association with the cleft side. The lip was thicker at rest and thinner in the forced smile, as also evaluated by the group not experienced with cleft care. The curve of the upper lip in natural and forced smiles was considered as close to straight by both groups, regardless of the cleft. Conclusion. The smile in individuals with clefts was regarded as average for both cleft and noncleft sides. The thickness was characterized as average to thin, being thinner in forced smile and when analyzed by the group not experienced with cleft care. In the average, the curve of the upper lip was considered as straight. The present study elucidates some characteristics related to the smile in individuals with repaired unilateral cleft lip, alveolus, and palate.
Preparation and Hydrogen Storage Properties of Mg‐Rich Mg‐Ni Ultrafine Particles
Authors: Zou Jianxin , Sun Haiquan , Zeng Xiaoqin , Ji Gang , Ding Wenjiang
Published: November 2012

In the present work, Mg‐rich Mg‐Ni ultrafine powders were prepared through an arc plasma method. The phase components, microstructure, and hydrogen storage properties of the powders were carefully investigated. It is found that Mg2Ni and MgNi2 could be obtained directly from the vapor state reactions between Mg and Ni, depending on the local vapor content in the reaction chamber. A nanostructured MgH2 + Mg2NiH4 hydrogen storage composite could be generated after hydrogenation of the Mg‐Ni ultrafine powders. After dehydrogenation, MgH2 and Mg2NiH4 decomposed into nanograined Mg and Mg2Ni, respectively. Thermogravimetry/differential scanning calorimetry (TG/DSC) analyses showed that Mg2NiH4 phase may play a catalytic role in the dehydriding process of the hydrogenated Mg ultrafine particles.
Pathologic Etiologies of Late and Very Late Stent Thrombosis following First-Generation Drug-Eluting Stent Placement
Authors: Otsuka Fumiyuki , Nakano Masataka , Ladich Elena , Kolodgie Frank D. , Virmani Renu
Published: November 2012

Several randomized and observational studies have reported steady increase in cumulative incidence of late and very late ST (LST/VLST) following first-generation drug-eluting stents (DES: sirolimus-(SES) and paclitaxel-(PES)) up to 5 years. Pathologic studies have identified uncovered struts as the primary substrate responsible for LST/VLST following DES, where delayed arterial healing is associated with stent struts penetrating into the necrotic core, long/overlapping stents, and bifurcation stenting especially in flow divider region. Grade V stent fracture also induces LST/VLST and restenosis. Hypersensitivity reaction is exclusive to SES as an etiology of LST/VLST, whereas malapposition secondary to excessive fibrin deposition is associated with PES. Uncovered struts can be identified in SES and PES with duration of implant beyond 12 months, particularly in stents placed for “off-label” indications. Neoatherosclerosis is another important contributing factor for VLST in DES and bare metal stents (BMS); however, DES shows rapid and more frequent development of neoatherosclerosis than BMS. Future pathologic studies should address the long-term safety of newer generation DES including zotarolimus- and everolimus-eluting stents in terms of the improvement in reendothelialization, decreased inflammation and fibrin deposition as well as a lower incidence of stent fracture-related adverse events, and reduced neoatherosclerosis, which likely contribute to the decreased risk of LST/VLST and better patient outcomes.
Theorem to Generate Independently and Uniformly Distributed Chaotic Key Stream via Topologically Conjugated Maps of Tent Map
Authors: Xu Zheng guang , Tian Qing , Tian Li
Published: November 2012

This paper proposes a theorem to generate chaotic key stream from topologically conjugated maps of Tent Map. In this theorem, the condition for topological conjugation between Tent Map and a class of chaotic maps is first determined. Then, the chaotic attractor of the maps is divided into 2n unequal subintervals, the chaotic orbit is sampled once in n time iteration, and, finally, the independently and uniformly distributed 2n phase key stream is obtained. The theoretical and numerical analyses show that the chaotic key stream generated by the proposed theorem successfully is independent and uniform, has a certain complex degree close to the maximum approximate entropy for 2n phase key stream, and satisfies the randomness requirement defined in NIST SP800‐22. This theorem can be used in fields such as cryptography and numerical simulation.
Iatrogenic Aortocoronary Arteriovenous Fistula following Coronary Artery Bypass Surgery: A Case Report and Complete Review of the Literature
Authors: Gardner Jonathan D. , Maddox William R. , Calkins Joe B.
Published: November 2012

The case of a patient who presented with angina following a coronary artery bypass (CABG) operation during which the left internal mammary artery was inadvertently anastomosed to a cardiac vein is presented. The literature concerning previously reported cases of aortocoronary arteriovenous fistulas (ACAVF) due to inadvertent grafting of a coronary vein is reviewed and the significance of this complication is discussed. ACAVF due to inadvertent grafting of a coronary vein is a rare complication of CABG and may be a more common cause of graft failure than has previously been recognized. Distortion of cardiac anatomy, the presence of epicardial fat, and an intramyocardial course of the artery intended for grafting are predisposing factors. Some patients present with angina pectoris and heart failure whereas others have no symptoms. The diagnostic test of choice is coronary angiography. Cardiac MRI and CT have a limited role due to the smaller size and the more clearly defined course of these fistulas. Asymptomatic patients are simply observed since spontaneous closure of these fistulas is reported. Symptomatic patients can be treated with combined medical management and percutaneous methods.
Arithmetic Identities Involving Bernoulli and Euler Numbers
Authors: Kim H.-M. , Kim D. S.
Published: November 2012

The purpose of this paper is to give some arithmatic identities for the Bernoulli and Euler numbers. These identities are derived from the severalp-adic integral equations onℤp.
A Rare Case of Prototheca Algaemia in a Patient with Systemic Lupus Erythematosus and Recent Belimumab Infusion
Authors: Mejia-Otero Carolina , Singh Shelley , Arias Urdaneta Luis , Sesin Carlos , Chakrabarti Anindita , Miller Nanci Mae , Tuda Claudio
Published: November 2012

Novel agents for the treatment of immune-mediated diseases such as systemic lupus erythematosus (SLE) have been increasingly used as an alternative to or in combination with conventional therapies. Belimumab, a human monoclonal antibody that inhibits B-cell activating factor (BAFF), has demonstrated efficacy in moderate-to-severe SLE with similar adverse effects when compared to other biologic agents and conventional SLE therapies. Here, we describe a woman with SLE and diabetes mellitus (DM) on immunosuppressive therapy for five years who was admitted to the hospital for pneumonia but had a complicated hospital course with multiple infections and, most notably, a nosocomial algaemia due toPrototheca wickerhamii, which was treated successfully with amphotericin B. She had recently received three belimumab infusions as an outpatient prior to admission to the hospital. To the best of our knowledge no cases of human protothecosis in patients receiving belimumab have been described in the English literature; however, unusual infections have to be considered in all patients undergoing immunosuppressive therapies who persist with fever despite conventional antimicrobials.
A Case of Human Oral Myiasis byLucilia sericatain a Hospitalized Patient in Extremadura, Spain
Authors: Pérez-Giraldo C. , Márquez-Laffón I. , Blanco M. T. , Muñoz del Rey J. R. , Chavero M. J. , Habela M. A. , Gómez-García A. C.
Published: November 2012

Myiasis is the term used to describe infestations, both obligatory and accidental, in vertebrate animals and humans by dipteral larvae. The oral cavity is rarely affected by this infestation and the circumstances which can lead to oral myiasis include persistent mouth opening together with poor hygiene, or facial traumatism. We present a case of oral myiasis by larvae ofLucilia sericata, a species present in the Iberian Peninsula, in a hospitalized patient with surgical problems.
Effect of Deep Brain Stimulation on Speech Performance in Parkinson's Disease
Authors: Skodda Sabine
Published: November 2012

Deep brain stimulation (DBS) has been reported to be successful in relieving the core motor symptoms of Parkinson's disease (PD) and motor fluctuations in the more advanced stages of the disease. However, data on the effects of DBS on speech performance are inconsistent. While there are some series of patients documenting that speech function was relatively unaffected by DBS of the nucleus subthalamicus (STN), other investigators reported on improvements of distinct parameters of oral control and voice. Though, these ameliorations of single speech modalities were not always accompanied by an improvement of overall speech intelligibility. On the other hand, there are also indications for an induction of dysarthria as an adverse effect of STN-DBS occurring at least in some patients with PD. Since a deterioration of speech function has more often been observed under high stimulation amplitudes, this phenomenon has been ascribed to a spread of current-to-adjacent pathways which might also be the reason for the sporadic observation of an onset of dysarthria under DBS of other basal ganglia targets (e.g., globus pallidus internus/GPi or thalamus/Vim). The aim of this paper is to review and evaluate reports in the literature on the effects of DBS on speech function in PD.
Characteristics of Plasmacytoid Dendritic Cell and CD4+ T Cell in HIV Elite Controllers
Authors: Herbeuval Jean-Philippe , Smith Nikaïa , Thèze Jacques
Published: November 2012

Despite variability, the majority of HIV-1-infected individuals progress to AIDS characterized by high viral load and massive CD4+ T-cell depletion. However, there is a subset of HIV-1-positive individuals that does not progress and spontaneously maintains an undetectable viral load. This infrequent patient population is defined as HIV-1 controllers (HIV controllers), and represents less than 1% of HIV-1-infected patients. HIV-1-specific CD4+ T cells and the pool of central memory CD4+ T cells are also preserved despite immune activation due to HIV-1 infection. The majority of HIV controllers are also defined by the absence of massive CD4+ T-cell depletion, even after 10 years of infection. However, the mechanisms involved in protection against HIV-1 disease progression have not been elucidated yet. Controllers represent a heterogeneous population; we describe in this paper some common characteristics concerning innate immune response and CD4+ T cells of HIV controllers.
Use of E-Beam for Shelf-Life Extension and Sanitizing of Marinated Pork Loin
Authors: García-Márquez I. , Ordóñez J. A. , Cambero M. I. , Cabeza M. C.
Published: November 2012

The effectiveness of E-beam radiation to extend the shelf-life of marinated pork loin slices stored at 4 and 8°C (temperature abuse) has been studied. The shelf-life was extended from 7 to 16 and >20 days after the application of 1 and 2 kGy, respectively. In the event of a temperature abuse occuring during the product distribution (e.g., increase to 8°C), the shelf-life would be extended from 5 to 10 and 16 days, respectively, when applying the doses mentioned previously. From a public health point of view, the irradiation of marinated pork loin may be marketable for a longer period of time of up to two weeks, and guarantees a practicallySalmonellaandListeria-free product. Minor changes are produced by the E-beam treatment in the main sensory and rheological characteristics. The odor was the most affected feature, but the off-odors diminished with increased storage. In any case, testers judged the samples to be adequate for marketing.
Conductometric Studies of Thermodynamics of 1,10‐Didecyl‐1,10‐diaza‐18‐crown‐6 Complexes with Li+, Na+, K+, Cs+, NH4+, Mg2+, and Ca2+ Ions in Acetonitrile, Methanol, and Ethanol Solutions
Authors: Taghdiri Mehdi , Payehghadr Mahmood , Behjatmanesh-Ardakani Reza , Movahhedi Sirous , Nourifard Farzaneh
Published: November 2012

The complexation reactions between 1,10‐didecyl‐1,10‐diaza‐18‐crown‐6 (DD18C6) and
Li+,
Na+,
K+,
Cs+,
Mg2+, and
Ca2+ ions were studied conductometrically in acetonitrile, methanol, and ethanol at various temperatures. The formation constants of the resulting 1 : 1 complexes were calculated from the computer fitting of the molar conductance‐mole ratio data at different temperatures. In the solvents studied, the stability of the resulting complexes varied in the order acetonitrile ≫ methanol > ethanol. The enthalpy and entropy changes of the complexation reactions were evaluated from the temperature dependence of formation constants. The TΔS° versus ΔH° plot of thermodynamic data obtained shows a linear correlation indicating the existence of enthalpy‐entropy compensation in the complexation reactions. The ab initio studies calculated at B3LYP/6‐31G level of theory indicate that the binding energy of complexes decreases with increasing cation size in the gas phase. The experimental data obtained in the solvents show different trends so that the stability constant of Li+ and Mg2+ complexes is lower than other alkali and alkaline earth ions, respectively due to the solvation of these small ions in solution.
Engineering Approaches for Investigating Tumor Angiogenesis: Exploiting the Role of the Extracellular Matrix
Authors: Hielscher Abigail C. , Gerecht Sharon
Published: November 2012

A major paradigm shift in cancer research is the emergence of multidisciplinary approaches to investigate complex cell behaviors, to elucidate regulatory mechanisms and to identify therapeutic targets. Recently, efforts are focused on the engineering of complex in vitro models, which more accurately recapitulate the growth and progression of cancer. These strategies have proven vital for investigating and targeting the events that control tumor angiogenesis. In this review, we explore how the emerging engineering approaches are being used to unlock the complex mechanisms regulating tumor angiogenesis. Emphasis is placed on models using natural and synthetic biomaterials to generate scaffolds mimicking the extracellular matrix, which is known to play a critical role in angiogenesis. While the models presented in this review are revolutionary, improvements are still necessary and concepts for advancing and perfecting engineering approaches for modeling tumor angiogenesis are proposed. Overall, the marriage between disparate scientific fields is expected to yield significant improvements in our understanding and treatment of cancer. Cancer Res; 72(23); 6089–96. ©2012 AACR.
Predictive Impact of Circulating Vascular Endothelial Growth Factor in Four Phase III Trials Evaluating Bevacizumab
Authors: Hegde Priti S. , Jubb Adrian M. , Chen Dafeng , Li Nicole F. , Meng Y. Gloria , Bernaards Coen , Elliott Rebecca , Scherer Stefan J. , Chen Daniel S.
Published: November 2012

Purpose: We evaluated the prognostic and predictive use of circulating VEGF-A levels in phase III trials of bevacizumab in colorectal cancer, lung cancer, and renal cell carcinoma.

Methods: Baseline plasma samples from 1,816 patients were analyzed for VEGF-A using an ELISA, which recognizes the major isoforms with equivalent sensitivity. HR and 95% confidence intervals (CI) for study end points were estimated using Cox regression analysis. A subset of matched archival tumor samples was analyzed for VEGF-A expression using in situ hybridization.

Results: Higher VEGF-A levels showed trends toward adverse prognostic significance in the control arms of multiple trials, reaching statistical significance for overall survival (OS) in AVF2107 (highest vs. lowest 50%: HR = 1.76; 95% CI, 1.28–2.41), AVAiL (HR = 1.52; 95% CI, 1.16–2.00), and AVOREN (HR = 1.67; 95% CI, 1.18–2.36). In predictive analyses, the HRs for progression-free survival were similar across low and high VEGF-A subgroups and favored bevacizumab-containing treatment. In the low VEGF-A subgroups, HRs (95% CIs) were 0.61 (0.43–0.87) in AVF2107, 0.71 (0.43–1.16) in E4599, 0.74 (0.59–0.94) in AVAiL (low-dose), 0.89 (0.70–1.13) in AVAiL (high-dose), and 0.56 (0.40–0.78) in AVOREN. Analyses of OS data have shown similar results. No correlation between primary tumor VEGF-A expression and plasma VEGF-A levels was observed.

Conclusions: In this comprehensive evaluation, pretreatment total circulating VEGF-A was prognostic for outcome in metastatic colorectal, lung, and renal cell cancers, but it was not predictive for bevacizumab-based treatment benefit. Clin Cancer Res; 19(4); 929–37. ©2012 AACR.
Durable Cancer Regression Off-Treatment and Effective Reinduction Therapy with an Anti-PD-1 Antibody
Authors: Lipson Evan J. , Sharfman William H. , Drake Charles G. , Wollner Ira , Taube Janis M. , Anders Robert A. , Xu Haiying , Yao Sheng , Pons Alice , Chen Lieping , Pardoll Drew M. , Brahmer Julie R. , Topalian Suzanne L.
Published: November 2012

Purpose: Results from the first-in-human phase I trial of the anti–programmed death-1 (PD-1) antibody BMS-936558 in patients with treatment-refractory solid tumors, including safety, tolerability, pharmacodynamics, and immunologic correlates, have been previously reported. Here, we provide long-term follow-up on three patients from that trial who sustained objective tumor regressions off therapy, and test the hypothesis that reinduction therapy for late tumor recurrence can be effective.

Experimental Design: Three patients with colorectal cancer, renal cell cancer, and melanoma achieved objective responses on an intermittent dosing regimen of BMS-936558. Following cessation of therapy, patients were followed for more than 3 years. A patient with melanoma who experienced a prolonged partial regression followed by tumor recurrence received reinduction therapy.

Results: A patient with colorectal cancer experienced a complete response, which is ongoing after 3 years. A patient with renal cell cancer experienced a partial response lasting 3 years off therapy, which converted to a complete response, which is ongoing at 12 months. A patient with melanoma achieved a partial response that was stable for 16 months off therapy; recurrent disease was successfully treated with reinduction anti-PD-1 therapy.

Conclusion: These data represent the most prolonged observation to date of patients with solid tumors responding to anti-PD-1 immunotherapy and the first report of successful reinduction therapy following delayed tumor progression. They underscore the potential for immune checkpoint blockade with anti-PD-1 to reset the equilibrium between tumor and the host immune system. Clin Cancer Res; 19(2); 462–8. ©2012 AACR.
Development of a Multifunctional Detoxifying Unit for Liver Failure Patients
Authors: Lee Kyungsoo , Mun Cho Hae , Min Byoung Goo
Published: November 2012

Background/Aims: Extracorporeal blood detoxification strategies aimed at supporting impaired liver function have been explored because of the imbalance between donor organs and waiting patients. A limited number of artificial devices are now available clinically, and these are characterized by the use of multistage adsorption procedures in conjunction with hemodialysis, but these features simultaneously increase system complexity and treatment costs. Methods: The authors developed a simpler strategy for liver dialysis based on the use of a multifunctional filter, which enables plasma separation and perfusion in a single unit. Results: Liver dialysis treatments were successfully performed using the devised unit when bovine blood containing uremic and hepatic toxins was circulated. Removal of the solutes under investigation was significant, and reduction ratios of 78% for urea, 98% for creatinine and 91% for bilirubin were achieved. Plasma free hemoglobin levels were reasonably maintained despite prolonged blood recirculation for 5 h, and platelet, hematocrit and hemoglobin levels remained uniform throughout liver dialysis sessions. Conclusion: The devised liver support unit may offer a straightforward and efficient means of cleansing blood for patients with hepatic failure.
New High-Cutoff Dialyzer Allows Improved Middle Molecule Clearance without an Increase in Albumin Loss: A Clinical Crossover Comparison in Extended Dialysis
Authors: Schmidt Julius J. , Hafer Carsten , Clajus Christian , Hadem Johannes , Beutel Gernot , Schmidt Bernhard M.W. , Kielstein Jan T.
Published: November 2012

Background: Accumulation of middle molecules is thought to have adverse effects in patients with acute kidney injury (AKI). Elimination of middle molecules by non-convective means, i.e. hemodialysis, remains difficult. The aim of the study was to investigate the removal characteristics of a new high permeability membrane in AKI patients undergoing extended dialysis (ED). Patients and Methods: We performed a prospective, crossover study comparing the EMiC2 dialyzer (1.8 m2, FMC, Germany) and AV 1000S (1.8 m2, FMC) in 11 critically ill patients with AKI. β2-Microglobulin, cystatin c, creatinine, and urea were measured before and after 0.5, 5.0 and 10 h of ED. Serum reduction ratios, dialyzer clearances, and mass in the total collected dialysate were determined. Results: Dialyzer clearance of β2-microglobulin (EMiC2: 52 ± 1.7 ml/min, AV 1000S: 41.7 ± 1.5 ml/min, p = 0.0002) and cystatin c (EMiC2: 47.2 ± 1.2 ml/min, AV 1000S: 34.2 ± 2.3 ml/min, p < 0.0001) was markedly different, as was the reduction of serum levels of β2-microglobulin (EMiC2: 54.3 ± 3.6%, AV 1000S: 39.1 ± 4.5%, p = 0.025) and cystatin c (EMiC2: 38.9 ± 2.6%, AV 1000S: 28.0 ± 3.9%, p = 0.043). Additionally, we observed a higher total amount of these substances in the collected dialysate. There was no significant difference in the total amount of albumin eliminated per treatment. Conclusion: The new EMiC2 dialyzer enhances removal of middle molecules without an increase in albumin loss. The clinical relevance of this finding needs to be determined.
Severe Neutropenia in Patients with Chronic Hepatitis C: A Benign Condition
Authors: Sheehan Vivien , Weir Alva , Waters Bradford
Published: November 2012

Background/Aims: Patients with chronic hepatitis C virus (HCV) infection may develop neutropenia, which can delay or prevent treatment. Severe neutropenia, absolute neutrophil counts (ANC) ≤0.500 × 109/l, is a rare finding, with only two isolated reports published in the literature. The aim of this study was to evaluate the incidence and natural history of severe neutropenia in hepatitis C patients. Methods: The records of 685 patients with active HCV were reviewed to identify those with severe neutropenia. The laboratory parameters and clinical history data of patients with severe neutropenia were then compared to a cohort of patients with HCV patients who had the more common minor neutropenia (ANC = 1.000–1.500 109/l). Results: There was no significant difference in race, MELD (Model for End Stage Liver Disease) scores, portal hypertension, splenomegaly, viral load, viral type, or hemoglobin or platelet levels. Neither group suffered serious systemic infections. Conclusions: Severe neutropenia in HCV patients is underreported and not associated with serious HCV complications such as elevated MELD score or cirrhosis. Serious infection is rare and patients respond well to granulocyte colony-stimulating factor. Severely neutropenic patients with HCV appear to have a benign course and may be candidates for antiviral therapy.
Fluoroquinolone Photodegradation Influences Specific Basophil Activation
Authors: Mayorga Cristobalina , Andreu Inmaculada , Aranda Ana , Doña Inmaculada , Montañez M. Isabel , Blanca-Lopez Natalia , Ariza Adriana , Nuin Edurne , Blanca Miguel , Miranda Miguel A. , Torres M. Jose
Published: November 2012

Fluoroquinolones (FQs) are photoreactive drugs, but it is not known whether laboratory light exposure can influence the induction of photoproducts and modify in vitro test results. The basophil activation test (BAT) has proven to be useful for evaluating immunoglobulin E (IgE)-mediated hypersensitivity to FQs, with a higher percentage of positive responders with ciprofloxacin (CIP) than with moxifloxacin (MOX). We studied the effect of laboratory light on CIP and MOX degradation, and drug-protein conjugate formation, and its influence on the BAT for evaluating IgE-mediated hypersensitivity to FQs. The results showed an important decrease in fluorescence emission intensity under light compared to dark conditions for MOX, and that BAT positivity was lower in light (17.9%) than in dark (35.7%) conditions. No changes were found for CIP in either fluorescence emission intensity or BAT results (46.4% in both conditions). We can conclude that light exposure is a critical factor in BAT results when photolabile drugs like MOX are used. Therefore, light is important when interpreting in vitro results.
Effects of Bilirubin on Neutrophil Responses in Newborn Infants
Authors: Weinberger Barry , Archer Faith E. , Kathiravan Suganya , Hirsch Daniel S. , Kleinfeld Alan M. , Vetrano Anna M. , Hegyi Thomas
Published: November 2012

Background: Newborns are susceptible to inflammatory diseases due to defects in clearing activated immune cells from tissues. Therefore, mechanisms have likely evolved to protect neonates from leukocyte-mediated cytotoxicity. Bilirubin has antioxidant activity, and it is possible that it also exerts effects on cellular immune responses in jaundiced infants. Objectives: We hypothesize that bilirubin increases expression of antioxidant genes and decreases production of inflammatory proteins in neonatal neutrophils. Methods: Neutrophils were isolated from umbilical cord blood, and from adults for comparison, and treated with bilirubin (10–300 µmol/l, equivalent to unbound bilirubin 3–40 nmol/l), in the presence or absence of lipopolysaccharide (LPS). Expression of genes for antioxidant enzymes [superoxide dismutase (SOD), heme-oxygenase-1 (HO-1)] and heme-dependent enzymes involved in inflammation [NADPH oxidase-1 (NOX-1), cyclooxygenase-2 (COX-2)] was measured by PCR. Inflammatory cytokines were measured by bead array analysis using flow cytometry. Results: We found that LPS induced production of interleukin (IL)-8, IL-1β, and macrophage inhibitory protein-1β (MIP-1β). Bilirubin increased basal production of IL-8 and IL-1β, but downregulated LPS-induced generation of IL-8 and MIP-1β. It also upregulated SOD and HO-1 gene expression. We observed an unexpected bilirubin-induced increase in gene expression of NOX-1 in LPS-activated cells, and of COX-2 in both resting and activated cells. Conclusions: These findings suggest that bilirubin suppresses inflammation and increases antioxidant enzyme generation in activated neonatal neutrophils. The unexpected increases in NOX-1 and COX-2 expression may represent an early response, with physiologic effects mitigated by increased antioxidant activity. Further studies will be needed to define levels of bilirubin that optimize its protective effects, while minimizing potential inflammatory toxicity.
Toll-Like Receptor 4 in Experimental Kidney Transplantation: Early Mediator of Endogenous Danger Signals
Authors: Bergler Tobias , Hoffmann Ute , Bergler Elisabeth , Jung Bettina , Banas Miriam C. , Reinhold Stephan W. , Krämer Bernhard K. , Banas Bernhard
Published: November 2012

The role of toll-like receptors (TLRs) has been described in the pathogenesis of renal ischemia/reperfusion injury, but data on the expression and function of TLR4 during renal allograft damage are still scarce. We analyzed the expression of TLR4 in an experimental rat model 6 and 28 days after allogeneic kidney transplantation in comparison to control rats and rats after syngeneic transplantation. On day 6, a significant induction in TLR4 expression – restricted to the glomerular compartment – was found in acute rejecting allografts only. TLR4 expression strongly correlated with renal function, and TLR4 induction was accompanied by a significant increase in CC chemokine expression within the graft as well as in urinary CC chemokine excretion. TLR4 induction may be caused by an influx of macrophages as well as TLR4-expressing intrinsic renal cells. Fibrinogen deposition in renal allografts correlated with renal TLR4 expression and may act as a potent stimulator of chemokine release via TLR4 activation. This study provides, for the first time, data about the precise intrarenal localization and TLR4 induction after experimental kidney transplantation. It supports the hypothesis that local TLR4 activation by endogenous ligands may be one pathological link from unspecific primary allograft damage to subsequent chemokine release, infiltration and activation of immune cells leading to deterioration of renal function and induction of renal fibrosis.
Prevalence and Management of Panic Attacks during Infliximab Infusion in Psoriatic Patients
Authors: Saraceno R. , Faleri S. , Ruzzetti M. , Centonze D. , Chimenti S.
Published: November 2012

Background: Psoriasis is a chronic, inflammatory skin disease associated with anxiety and depression. Infliximab (IFX) is a human/mouse chimeric anti-TNF-α antibody effective in the treatment of psoriasis. Objective: The aim of this study was to evaluate the prevalence of panic disorders in psoriatic patients during IFX infusions. Methods: A retrospective study was performed on patients affected with psoriasis who were treated with IFX from 2002 to 2011 at a single center. Panic disorders were defined using the clinical criteria of the Diagnostic and Statistical Manual of Mental Disorders, 4th edition. A population of dermatological patients under treatment with IVG, rituximab, apheresis, intravenous corticosteroids and antibiotics was considered as the control group. Results: A total of 141 patients were evaluated. Of these, 6 (4.25%) experienced panic attacks during the infusion; 16 (11.3%) had a medical history of panic attack and of those 5/16 (31%) experienced panic attacks during IFX infusion. In the control group panic attacks were not recorded. Conclusion: We describe 6 cases of patients in whom panic attacks were triggered by IFX infusion. Premedication with oral benzodiazepine and a slow rate of infusion is recommended.
Cryosurgery Treatment of Actinic Keratoses Monitored by Optical Coherence Tomography: A Pilot Study
Authors: Themstrup Lotte , Banzhaf Christina , Mogensen Mette , Jemec Gregor B.E.
Published: November 2012

Background: Optical coherence tomography (OCT) is a non-invasive optical imaging technique providing high-resolution images. OCT may be useful as a monitoring tool during treatment of actinic keratoses (AK) and skin cancer. Objective: To examine and describe how OCT skin morphology changes when the tissue is exposed to the effects of cryotherapy. Methods: Normal ex vivo skin and in vivo AK lesions were examined. Cryotherapy was applied and OCT images were acquired at defined time points. OCT morphology was described. Results: Cryotherapy treatment produced an opaque iceball, and freezing depth could not be monitored by OCT. Vesicle formation after cryotherapy could be identified in OCT images. In ex vivo skin no vesicle formation occurred. Conclusion: OCT cannot monitor the freezing depth, but OCT was able to visualise AK lesions and vesicle formation shortly after cryotherapy. Results add to the assumption that OCT could be used in monitoring non-invasive treatments.
Bevacizumab Alone or in Combination with Irinotecan in Recurrent WHO Grade II and Grade III Gliomas
Authors: Seystahl Katharina , Wiestler Benedikt , Hundsberger Thomas , Happold Caroline , Wick Wolfgang , Weller Michael , Wick Antje
Published: November 2012

Background: The repertoire of salvage regimens for patients with WHO grade II and III gliomas recurring or progressing after surgery, radiotherapy and temozolomide chemotherapy is limited. Based on promising response and progression-free survival (PFS) data in recurrent glioblastoma, the use of bevacizumab (BEV) has been extended to recurrent grade II/III gliomas. Methods: We retrospectively assessed the safety and efficacy of BEV alone or combined with irinotecan in 39 patients with recurrent grade II/III gliomas. Results: Both BEV monotherapy and its combination with irinotecan were well tolerated. Response rates were 26% as monotherapy and 33% in combination using Macdonald and RANO criteria. The median PFS was 4.2 months and the PFS rate at 6 months 29% for BEV alone, and 4.7 months and 42% for the combination. The median overall survival was 14.8 months for BEV monotherapy and 8.1 months for the combination. Outcome after failure of BEV was better when patients continued BEV beyond progression. Conclusion: BEV has limited activity in recurrent grade II/III gliomas. The additional value of irinotecan remains questionable. Prospective studies with BEV-free control groups are required to better define the role of BEV among the limited options in patients with recurrent grade II/III gliomas.
Expression and Functional Characterization of Retinoic Acid-Inducible Gene-I-Like Receptors of Mast Cells in Response to Viral Infection
Authors: Fukuda Minoru , Ushio Hiroko , Kawasaki Junko , Niyonsaba Francois , Takeuchi Mizuho , Baba Tadashi , Hiramatsu Keiichi , Okumura Ko , Ogawa Hideoki
Published: November 2012

To investigate the precise mechanisms of virus recognition by mast cells, the expression and functional characteristics of virus recognition receptors that lead to mast cell activation were investigated. Our results suggest that mast cells are partly responsible for the early in vivo production of antiviral cytokines and chemokines upon vesicular stomatitis virus (VSV) infection. Analysis of the expression of double-stranded RNA (dsRNA) recognition receptors in murine bone marrow-derived mast cells (BMMCs) revealed that BMMCs express melanoma differentiation-associated gene 5 (MDA5), protein kinase RNA-activated, retinoic acid-inducible gene-I (RIG-I) and Toll-like receptor 3. The expression levels of these receptors were found to increase upon stimulation of mast cells with VSV as well as synthetic dsRNA: polyinosinic-polycytidylic acid. Moreover, small interfering RNA analysis to identify the receptors responsible for mast cell activation by VSV revealed that both RIG-I and MDA5 were involved in cytokine production but not in the degranulation of mast cells. Our findings suggest that mast cells produce cytokines and chemokines in the early infection stage after recognizing viruses via RIG-I and MDA5, and may contribute to antiviral responses. These data provide additional novel information that improves our understanding of antiviral innate responses that involve mast cells.