bluuebunny/crossref_metadata_2025 huggingface dataset:
Lung heparan sulfates modulate Kfc during increased vascular pressure: evidence for glycocalyx-mediated mechanotransduction
Authors: Dull Randal O. , Cluff Mark , Kingston Joseph , Hill Denzil , Chen Haiyan , Hoehne Soeren , Malleske Daniel T. , Kaur Rajwinederjit
Published: December 2011

Lung endothelial cells respond to changes in vascular pressure through mechanotransduction pathways that alter barrier function via non-Starling mechanism(s). Components of the endothelial glycocalyx have been shown to participate in mechanotransduction in vitro and in systemic vessels, but the glycocalyx's role in mechanosensing and pulmonary barrier function has not been characterized. Mechanotransduction pathways may represent novel targets for therapeutic intervention during states of elevated pulmonary pressure such as acute heart failure, fluid overload, and mechanical ventilation. Our objective was to assess the effects of increasing vascular pressure on whole lung filtration coefficient ( Kfc) and characterize the role of endothelial heparan sulfates in mediating mechanotransduction and associated increases in Kfc. Isolated perfused rat lung preparation was used to measure Kfc in response to changes in vascular pressure in combination with superimposed changes in airway pressure. The roles of heparan sulfates, nitric oxide, and reactive oxygen species were investigated. Increases in capillary pressure altered Kfc in a nonlinear relationship, suggesting non-Starling mechanism(s). nitro-l-arginine methyl ester and heparanase III attenuated the effects of increased capillary pressure on Kfc, demonstrating active mechanotransduction leading to barrier dysfunction. The nitric oxide (NO) donor S-nitrosoglutathione exacerbated pressure-mediated increase in Kfc. Ventilation strategies altered lung NO concentration and the Kfc response to increases in vascular pressure. This is the first study to demonstrate a role for the glycocalyx in whole lung mechanotransduction and has important implications in understanding the regulation of vascular permeability in the context of vascular pressure, fluid status, and ventilation strategies.
Nadph oxidase regulates alveolar epithelial sodium channel activity and lung fluid balance in vivo via O2− signaling
Authors: Goodson Preston , Kumar Amrita , Jain Lucky , Kundu Kousik , Murthy Niren , Koval Michael , Helms My N.
Published: December 2011

To define roles for reactive oxygen species (ROS) and epithelial sodium channel (ENaC) in maintaining lung fluid balance in vivo, we used two novel whole animal imaging approaches. Live X-ray fluoroscopy enabled quantification of air space fluid content of C57BL/6J mouse lungs challenged by intratracheal (IT) instillation of saline; results were confirmed by using conventional lung wet-to-dry weight ratios and Evans blue as measures of pulmonary edema. Visualization and quantification of ROS produced in lungs was performed in mice that had been administered a redox-sensitive dye, hydro-Cy7, by IT instillation. We found that inhibition of NADPH oxidase with a Rac-1 inhibitor, NSC23766, resulted in alveolar flooding, which correlated with a decrease in lung ROS production in vivo. Consistent with a role for Nox2 in alveolar fluid balance, Nox2−/− mice showed increased retention of air space fluid compared with wild-type controls. Interestingly, fluoroscopic analysis of C57BL/6J lungs IT instilled with LPS showed an acute stimulation of lung fluid clearance and ROS production in vivo that was abrogated by the ROS scavenger tetramethylpiperidine- N-oxyl (TEMPO). Acute application of LPS increased the activity of 20 pS nonselective ENaC channels in rat type 1 cells; the average number of channel and single-channel open probability ( NPo) increased from 0.14 ± 0.04 to 0.62 ± 0.23. Application of TEMPO to the same cell-attached recording caused an immediate significant decrease in ENaC NPo to 0.04 ± 0.03. These data demonstrate that, in vivo, ROS has the capacity to stimulate lung fluid clearance by increasing ENaC activity.
Pulmonary T cell activation in response to chronic particulate air pollution
Authors: Deiuliis Jeffrey A. , Kampfrath Thomas , Zhong Jixin , Oghumu Steve , Maiseyeu Andrei , Chen Lung Chi , Sun Qinghua , Satoskar Abhay R. , Rajagopalan Sanjay
Published: December 2011

The purpose of this study was to investigate the effects of chronically inhaled particulate matter <2.5 μm (PM2.5) on inflammatory cell populations in the lung and systemic circulation. A prominent component of air pollution exposure is a systemic inflammatory response that may exaggerate chronic diseases such as atherosclerosis and insulin resistance. T cell response was measured in wild-type C57B/L6, Foxp3-green fluorescent protein (GFP) “knockin,” and chemokine receptor 3 knockout (CXCR3−/−) mice following 24–28 wk of PM2.5or filtered air. Chronic PM2.5exposure resulted in increased CXCR3-expressing CD4+and CD8+T cells in the lungs, spleen, and blood with elevation in CD11c+macrophages in the lung and oxidized derivatives of 1-palmitoyl-2-arachidonyl-sn-glycero-3-phosphorylcholine in wild-type mice. CXCR3 deficiency decreased T cells in the lung. GFP+regulatory T cells increased with PM2.5exposure in the spleen and blood of Foxp3-GFP mice but were present at very low levels in the lung irrespective of PM2.5exposure. Mixed lymphocyte cultures using primary, PM2.5-treated macrophages demonstrated enhanced T cell proliferation. Our experiments indicate that PM2.5potentiates a proinflammatory Th1 response involving increased homing of CXCR3+T effector cells to the lung and modulation of systemic T cell populations.
Geranylgeranyl transferase 1 modulates autophagy and apoptosis in human airway smooth muscle
Authors: Ghavami Saeid , Mutawe Mark M. , Schaafsma Dedmer , Yeganeh Behzad , Unruh Helmut , Klonisch Thomas , Halayko Andrew J.
Published: December 2011

Geranylgeranyl transferase 1 (GGT1) is involved in the posttranslational prenylation of signaling proteins, such as small GTPases. We have shown that blocking the formation of isoprenoids with statins regulates survival of human lung mesenchymal cells; thus, we tested the hypothesis that GGT1 may specifically modulate programmed cell death pathways in these cells. To this end, human airway smooth muscle (HASM) cells were treated with the selective GGT1 inhibitor GGTi-298. Apoptosis was seen using assays for cellular DNA content and caspase activation. Induction of autophagy was observed using transmission electron microscopy, immunoblotting for LC3 lipidation and Atg5-12 complex content, and confocal microscopy to detect formation of lysosome-localized LC3 punctae. Notably, GGT1 inhibition induced expression of p53-dependent proteins, p53 upregulated modulator of apoptosis (Noxa), and damage-regulated autophagy modulator (DRAM), this was inhibited by the p53 transcriptional activation inhibitor cyclic-pifithrin-α. Inhibition of autophagy with bafilomycin-A1 or short-hairpin RNA silencing of Atg7 substantially augmented GGTi-298-induced apoptosis. Overall, we demonstrate for the first time that pharmacological inhibition of GGT1 induces simultaneous p53-dependent apoptosis and autophagy in HASM. Moreover, autophagy regulates apoptosis induction. Thus, our findings identify GGT1 as a key regulator of HASM cell viability.
Intra-amniotic LPS and antenatal betamethasone: inflammation and maturation in preterm lamb lungs
Authors: Kuypers Elke , Collins Jennifer J. P. , Kramer Boris W. , Ofman Gaston , Nitsos Ilias , Pillow J. Jane , Polglase Graeme R. , Kemp Matthew W. , Newnham John P. , Gavilanes Antonio W. D. , Nowacki Relana , Ikegami Machiko , Jobe Alan H. , Kallapur Suhas G.
Published: December 2011

The proinflammatory stimulus of chorioamnionitis is commonly associated with preterm delivery. Women at risk of preterm delivery receive antenatal glucocorticoids to functionally mature the fetal lung. However, the effects of the combined exposures of chorioamnionitis and antenatal glucocorticoids on the fetus are poorly understood. Time-mated ewes with singleton fetuses received an intra-amniotic injection of lipopolysaccharide (LPS) either preceding or following maternal intramuscular betamethasone 7 or 14 days before delivery, and the fetuses were delivered at 120 days gestational age (GA) (term = 150 days GA). Gestation matched controls received intra-amniotic and maternal intramuscular saline. Compared with saline controls, intra-amniotic LPS increased inflammatory cells in the bronchoalveolar lavage and myeloperoxidase, Toll-like receptor 2 and 4 mRNA, PU.1, CD3, and Foxp3-positive cells in the fetal lung. LPS-induced lung maturation measured as increased airway surfactant and improved lung gas volumes. Intra-amniotic LPS-induced inflammation persisted until 14 days after exposure. Betamethasone treatment alone induced modest lung maturation but, when administered before intra-amniotic LPS, suppressed lung inflammation. Interestingly, betamethasone treatment after LPS did not counteract inflammation but enhanced lung maturation. We conclude that the order of exposures of intra-amniotic LPS or maternal betamethasone had large effects on fetal lung inflammation and maturation.
TLR4-dependent GM-CSF protects against lung injury in Gram-negative bacterial pneumonia
Authors: Standiford Louis R. , Standiford Theodore J. , Newstead Michael J. , Zeng Xianying , Ballinger Megan N. , Kovach Melissa A. , Reka Ajaya K. , Bhan Urvashi
Published: December 2011

Toll-like receptors (TLRs) are required for protective host defense against bacterial pathogens. However, the role of TLRs in regulating lung injury during Gram-negative bacterial pneumonia has not been thoroughly investigated. In this study, experiments were performed to evaluate the role of TLR4 in pulmonary responses against Klebsiella pneumoniae (Kp). Compared with wild-type (WT) (Balb/c) mice, mice with defective TLR4 signaling (TLR4lps-dmice) had substantially higher lung bacterial colony-forming units after intratracheal challenge with Kp, which was associated with considerably greater lung permeability and lung cell death. Reduced expression of granulocyte-macrophage colony-stimulating factor (GM-CSF) mRNA and protein was noted in lungs and bronchoalveolar lavage fluid of TLR4 mutant mice postintratracheal Kp compared with WT mice, and primary alveolar epithelial cells (AEC) harvested from TLR4lps-dmice produced significantly less GM-CSF in vitro in response to heat-killed Kp compared with WT AEC. TLR4lps-dAEC underwent significantly more apoptosis in response to heat-killed Kp in vitro, and treatment with GM-CSF protected these cells from apoptosis in response to Kp. Finally, intratracheal administration of GM-CSF in TLR4lps-dmice significantly decreased albumin leak, lung cell apoptosis, and bacteremia in Kp-infected mice. Based on these observations, we conclude that TLR4 plays a protective role on lung epithelium during Gram-negative bacterial pneumonia, an effect that is partially mediated by GM-CSF.
Complex Behavior in a Fish Algae Consumption Model with Impulsive Control Strategy
Authors: Yang Jin , Zhao Min
Published: December 2011

This paper investigates a dynamic mathematical model of fish algae consumption with an impulsive control strategy analytically. It is proved that the system has a globally asymptotically stable algae‐eradication periodic solution and is permanent by using the theory of impulsive equations and small‐amplitude perturbation techniques. Numerical results for impulsive perturbations demonstrate the rich dynamic behavior of the system. Further, we have also compared biological control with chemical control. All these results may be useful in controlling eutrophication.
Relative Quantification of Several Plasma Proteins during Liver Transplantation Surgery
Authors: Parviainen Ville , Joenväärä Sakari , Tukiainen Eija , Ilmakunnas Minna , Isoniemi Helena , Renkonen Risto
Published: December 2011

Plasma proteome is widely used in studying changes occurring in human body during disease or other disturbances. Immunological methods are commonly used in such studies. In recent years, mass spectrometry has gained popularity in high‐throughput analysis of plasma proteins. In this study, we tested whether mass spectrometry and iTRAQ‐based protein quantification might be used in proteomic analysis of human plasma during liver transplantation surgery to characterize changes in protein abundances occurring during early graft reperfusion. We sampled blood from systemic circulation as well as blood entering and exiting the liver. After immunodepletion of six high‐abundant plasma proteins, trypsin digestion, iTRAQ labeling, and cation‐exchange fractionation, the peptides were analyzed by reverse phase nano‐LC‐MS/MS. In total, 72 proteins were identified of which 31 could be quantified in all patient specimens collected. Of these 31 proteins, ten, mostly medium‐to‐high abundance plasma proteins with a concentration range of 50–2000 mg/L, displayed relative abundance change of more than 10%. The changes in protein abundance observed in this study allow further research on the role of several proteins in ischemia‐reperfusion injury during liver transplantation and possibly in other surgery.
An Optically Controlled 3D Cell Culturing System
Authors: Ishii Kelly S. , Hu Wenqi , Namekar Swapnil A. , Ohta Aaron T.
Published: December 2011

A novel 3D cell
culture system was developed and tested. The
cell culture device consists of a microfluidic
chamber on an optically absorbing substrate.
Cells are suspended in a thermoresponsive
hydrogel solution, and optical patterns are
utilized to heat the solution, producing
localized hydrogel formation around cells of
interest. The hydrogel traps only the desired
cells in place while also serving as a
biocompatible scaffold for supporting the
cultivation of cells in 3D. This is demonstrated
with the trapping of MDCK II and HeLa cells. The
light intensity from the optically induced
hydrogel formation does not significantly affect
cell viability.
GenSensor Suite: A Web-Based Tool for the Analysis of Gene and Protein Interactions, Pathways, and Regulation
Authors: Gosink Mark , Khuri Sawsan , Valdes Camilo , Jiang Zhijie , Tsinoremas Nicholas F.
Published: December 2011

The GenSensor Suite consists of four web tools for elucidating relationships among genes and proteins. GenPath results show which biochemical, regulatory, or other gene set categories are over- or under-represented in an input list compared to a background list. All common gene sets are available for searching in GenPath, plus some specialized sets. Users can add custom background lists. GenInteract builds an interaction gene list from a single gene input and then analyzes this in GenPath. GenPubMed uses a PubMed query to identify a list of PubMed IDs, from which a gene list is extracted and queried in GenPath. GenViewer allows the user to query one gene set against another in GenPath. GenPath results are presented with relevant P- and q-values in an uncluttered, fully linked, and integrated table. Users can easily copy this table and paste it directly into a spreadsheet or document.
Race/Ethnicity, Gender, Weight Status, and Colorectal Cancer Screening
Authors: Fagan Heather Bittner , Myers Ronald E. , Daskalakis Constantine , Sifri Randa , Mainous Arch G. , Wender Richard
Published: December 2011

Background. The literature on colorectal cancer (CRC) screening is contradictory regarding the impact of weight status on CRC screening. This study was intended to determine if CRC screening rates among 2005 National Health Interview Survey (NHIS) respondent racial/ethnic and gender subgroups were influenced by weight status.Methods. Univariable and multivariable logistic regression analyses were performed to determine if CRC screening use differed significantly among obese, overweight, and normal-weight individuals in race/ethnic and gender subgroups.Results. Multivariable analyses showed that CRC screening rates did not differ significantly for individuals within these subgroups who were obese or overweight as compared to their normal-weight peers.Conclusion. Weight status does not contribute to disparities in CRC screening in race/ethnicity and gender subgroups.
FDG-PET Quantification of Lung Inflammation with Image-Derived Blood Input Function in Mice
Authors: Locke Landon W. , Williams Mark B. , Fairchild Karen D. , Zhong Min , Kundu Bijoy K. , Berr Stuart S.
Published: December 2011

Dynamic FDG-PET imaging was used to study inflammation in lungs of mice following administration of a virulent strain ofKlebsiella (K.) pneumoniae. Net whole-lung FDG influx constant (Ki) was determined in a compartment model using an image-derived blood input function.Methods.K. pneumoniae(~3 x 105CFU) was intratracheally administered to six mice with 6 other mice serving as controls. Dynamic FDG-PET and X-Ray CT scans were acquired 24 hr afterK. pneumoniaeadministration. The experimental lung time activity curves were fitted to a 3-compartment FDG model to obtainKi. Following imaging, lungs were excised and immunohistochemistry analysis was done to assess the relative presence of neutrophils and macrophages.Results. MeanKifor control andK. pneumoniaeinfected mice were (5.1±1.2)×10-3versus (11.4±2.0)×10-3 min−1, respectively, revealing a 2.24 fold significant increase (P=0.0003) in the rate of FDG uptake in the infected lung. Immunohistochemistry revealed that cellular lung infiltrate was almost exclusively neutrophils. ParametricKimaps by Patlak analysis revealed heterogeneous inflammatory foci within infected lungs.Conclusion. The kinetics of FDG uptake in the lungs of mice can be noninvasively quantified by PET with a 3-compartment model approach based on an image-derived input function.
Parallel Tracking and Mapping for Controlling VTOL Airframe
Authors: Jama Michal , Schinstock Dale
Published: December 2011

This work presents a vision based system for navigation on a vertical takeoff and landing unmanned aerial vehicle (UAV). This is a monocular vision based, simultaneous localization and mapping (SLAM) system, which measures the position and orientation of the camera and builds a map of the environment using a video stream from a single camera. This is different from past SLAM solutions on UAV which use sensors that measure depth, like LIDAR, stereoscopic cameras or depth cameras. Solution presented in this paper extends and significantly modifies a recent open‐source algorithm that solves SLAM problem using approach fundamentally different from a traditional approach. Proposed modifications provide the position measurements necessary for the navigation solution on a UAV. The main contributions of this work include: (1) extension of the map building algorithm to enable it to be used realistically while controlling a UAV and simultaneously building the map; (2) improved performance of the SLAM algorithm for lower camera frame rates; and (3) the first known demonstration of a monocular SLAM algorithm successfully controlling a UAV while simultaneously building the map. This work demonstrates that a fully autonomous UAV that uses monocular vision for navigation is feasible.
Clinical Application of Mesenchymal Stem Cells in the Treatment and Prevention of Graft-versus-Host Disease
Authors: Lin Yi , Hogan William J.
Published: December 2011

Mesenchymal stem cells (MSCs) represent a heterogeneous population of stromal cells with pluripotent mesenchymal differentiation potential. They have been found to have immunosuppressive properties and the ability to modulate angiogenesis and endogenous tissue repair byin vitroand animal studies. Clinical trials have examined the utility of these cells in autoimmune and inflammatory conditions. In particular, in allogeneic hematopoietic stem cell transplant (HSCT), multiple studies have been conducted to explore the use of MSC to treat acute and chronic graft-versus-host disease (GVHD) and for cotransplantation with HSCT to promote HSC engraftment and prevent GVHD. We review here the results of these studies and discuss some challenges of this treatment modality in this disease setting.
A Rare Case Report of Extensive Polyostotic Gorham's Disappearing Bone Disease Involving the Upper Extremity
Authors: Ahlmann Elke R. , Ma Yanling , Tunru-Dinh Vonny
Published: December 2011

Gorham's disease is a rare disorder involving the proliferation of endothelial channels resulting in resorption and disappearance of bone. An unusual case of polyostotic Gorham's disease affecting the scapula, humerus, radius, and ulna in a 39-year-old woman is described. The patient had extensive disease spreading across both the glenohumeral and humeroulnar joints. This is the first report of Gorham's disease spreading across multiple joints in the upper extremity.
The Use of Pluripotent Stem Cell for Personalized Cell Therapies against Neurological Disorders
Authors: Ha Hye-Yeong , Jang Si-Hyong , Jung Ji-Won
Published: December 2011

Although there are a number of weaknesses for clinical use, pluripotent stem cells are valuable sources for patient‐specific cell therapies against various diseases. Backed‐up by a huge number of basic researches, neuronal differentiation mechanism is well established and pluripotent stem cell therapies against neurological disorders are getting closer to clinical application. However, there are increasing needs for standardization of the sourcing pluripotent stem cells by establishing stem cell registries and banking. Global harmonization will accelerate practical use of personalized therapies using pluripotent stem cells.
Effect of a Targeted Women's Health Intervention in an Inner-City Emergency Department
Authors: Houry Debra , Hankin Abigail , Daugherty Jill , Smith L. Shakiyla , Kaslow Nadine
Published: December 2011

Objective.To evaluate the effect of an Emergency Department (ED) based, educational intervention for at-risk health behaviors.Methods.A randomized trial over a one-year period. African American women, aged 21–55, presenting to the ED waiting room were eligible. Each participant took a computer-based survey on health risk behaviors. Participants who screened positive on any of four validated scales (for IPV, nicotine, alcohol, or drug dependence) were randomized to standard information about community resources (control) or to targeted educational handouts based upon their screening results (intervention). Participants were surveyed at 3 months regarding contacts with community resources and harm-reduction actions.Results.610 women were initially surveyed; 326 screened positive (13.7% for IPV, 40.1% for nicotine addiction, 26.6% for alcohol abuse, and 14.4% for drug abuse). 157 women were randomized to intervention and 169 to control. Among women who completed follow-up (), women in the Intervention Group were significantly more likely to have contacted local resources (37% versus 9%, ) and were more likely to have taken risk-reducing action (97% versus 79%, ).Conclusion.Targeted, brief educational interventions may be an effective method for targeting risk behaviors among vulnerable ED populations.
Fixed‐Effects Modeling of Cohen′s Weighted Kappa for Bivariate Multinomial Data: A Perspectiveof Generalized Inverse
Authors: Yang Jingyun , Chinchilli Vernon M.
Published: December 2011

Cohen′s kappa and weighted kappa statistics are the conventional methods used frequently in measuring agreement for categorical responses. In this paper, through the perspective of a generalized inverse, we propose an alternative general framework of the fixed‐effects modeling of Cohen′s weighted kappa, proposed by Yang and Chinchilli (2011). Properties of the proposed method are provided. Small sample performance is investigated through bootstrap simulation studies, which demonstrate good performance of the proposed method. When there are only two categories, the proposed method reduces to Cohen′s kappa.
Evidence of Acute Mycoplasma Infection in a Patient with Incomplete and Atypical Kawasaki Disease: A Case Report
Authors: Ebrahim M. , Gabay M. , Rivas-Chacon R. F.
Published: December 2011

The etiology of Kawasaki disease remains unknown despite extensive studies. Some researchers suggest that it is caused by an infectious agent. This is a case report where a patient with incomplete Kawasaki disease was found to have evidence compatible with acuteMycoplasma pneumoniaeinfection. This is one of the several case reports linkingMycoplasma pneumoniaeto Kawasaki disease as a possible trigger. This is perhaps due to a superantigen or is mediated by some other mechanism. Accurate and timely testing forMycoplasma infectionsis difficult and has its limitations. Despite this,Mycoplasma pneumoniaeshould be considered in the differential and workup for Kawasaki disease.
Work, Stress, and Diurnal Bruxism: A Pilot Study among Information Technology Professionals in Bangalore City, India
Authors: Rao S. K. , Bhat M. , David J.
Published: December 2011

The study assessed the prevalence of diurnal bruxism among information technology (IT) professionals and explored plausible predictors associated with the parafunctional habit. A cross-sectional study was designed and IT professionals were invited to participate. The inclusion criteria composed of participants in service for at least one year, having natural dentition, no history of cervical or facial injury and not undergoing orthodontic therapy. The participants () were interviewed by a trained interviewer to record information. A pre-tested questionnaire that included questions related to work, stress symptoms and diurnal bruxism was completed by each participant. The prevalence of self-reported diurnal bruxism was 59%. Bivariate analyses revealed that work () and work experience () were significantly associated with self-reported diurnal bruxism. In the binary logistic regression analysis stress (Odds Ratio [OR] , 95% Confidence Interval [CI] 2.6–13.3) was identified to be a strong predictor of diurnal bruxism. Professionals with 11 or more years of experience were less likely to report diurnal bruxism (, 95% CI 0.00–0.43) than those with 1 to 5 years of work experience. The study revealed that stress and less work experience were associated with diurnal bruxism among IT professionals in Bangalore city.
A Nonlinear Solute Transport Model and Data Reconstruction with Parameter Determination in an Undisturbed Soil‐Column Experiment
Authors: Li Gongsheng , Yao De , Wang Yongzai , Jia Xianzheng
Published: December 2011

A real undisturbed soil‐column infiltrating experiment in Zibo, Shandong, China, is investigated, and a nonlinear transport model for a solute ion penetrating through the column is put forward by using nonlinear Freundlich′s adsorption isotherm. Since Freundlich′s exponent and adsorption coefficient and source/sink terms in the model cannot be measured directly, an inverse problem of determining these parameters is encountered based on additional breakthrough data. Furthermore, an optimal perturbation regularization algorithm is introduced to determine the unknown parameters simultaneously. Numerical simulations are carried out and then the inversion algorithm is applied to solve the real inverse problem and reconstruct the measured data successfully. The computational results show that the nonlinear advection‐dispersion equation discussed in this paper can be utilized by hydrogeologists to research solute transport behaviors with nonlinear adsorption in porous medium.
Challenges in Immunotherapy Presented by the Glioblastoma Multiforme Microenvironment
Authors: Jackson Christopher , Ruzevick Jacob , Phallen Jillian , Belcaid Zineb , Lim Michael
Published: December 2011

Glioblastoma multiforme (GBM) is the most common and aggressive primary brain tumor in adults. Despite intensive treatment, the prognosis for patients with GBM remains grim with a median survival of only 14.6 months. Immunotherapy has emerged as a promising approach for treating many cancers and affords the advantages of cellular-level specificity and the potential to generate durable immune surveillance. The complexity of the tumor microenvironment poses a significant challenge to the development of immunotherapy for GBM, as multiple signaling pathways, cytokines, and cell types are intricately coordinated to generate an immunosuppressive milieu. The development of new immunotherapy approaches frequently uncovers new mechanisms of tumor-mediated immunosuppression. In this review, we discuss many of the current approaches to immunotherapy and focus on the challenges presented by the tumor microenvironment.
DrosophilaSOCS Proteins
Authors: Stec Wojciech J. , Zeidler Martin P.
Published: December 2011

The importance of signal transduction cascades such as the EGFR and JAK/STAT pathways for development and homeostasis is highlighted by the high levels of molecular conservation maintained between organisms as evolutionary diverged as fruit flies and humans. This conservation is also mirrored in many of the regulatory mechanisms that control the extent and duration of signallingin vivo. One group of proteins that represent important physiological regulators of both EGFR and JAK/STAT signalling is the members of the SOCS family. Only 3 SOCS-like proteins are encoded by theDrosophilagenome, and despite this low complexity,DrosophilaSOCS proteins share many similarities to their human homologues. SOCS36E is both a target gene and negative regulator of JAK/STAT signalling while SOCS44A and SOCS36E represent positive and negative regulators of EGFR signalling. Here we review our current understanding ofDrosophilaSOCS proteins, their rolesin vivo,and future approaches to elucidating their functions.
Androgen Receptor Regulates Transcription of the ZEB1 Transcription Factor
Authors: Anose Bynthia M. , Sanders Michel M.
Published: December 2011

The zinc finger E-box binding protein 1 (ZEB1) transcription factor belongs to a two-member family of zinc-finger homeodomain proteins involved in physiological and pathological events mostly relating to cell migration and epithelial to mesenchymal transitions (EMTs). ZEB1 (also known as δEF1, zfhx1a, TCF8, and Zfhep) plays a key role in regulating such diverse processes as T-cell development, skeletal patterning, reproduction, and cancer cell metastasis. However, the factors that regulate its expression and consequently the signaling pathways in which ZEB1 participates are poorly defined. Because it is induced by estrogen and progesterone and is high in prostate cancer, we investigated whethertcf8, which encodes ZEB1, is regulated by androgen. Data herein demonstrate thattcf8is induced by dihydrotestosterone (DHT) in the human PC-3/AR prostate cancer cell line and that this induction is mediated by two androgen response elements (AREs). These results demonstrate that ZEB1 is an intermediary in androgen signaling pathways.
ABO Incompatible Kidney Transplantation—Current Status and Uncertainties
Authors: Shin Milljae , Kim Sung-Joo
Published: December 2011

In the past, ABO blood group incompatibility was considered an absolute contraindication for kidney transplantation. Progress in defined desensitization practice and immunologic understanding has allowed increasingly successful ABO incompatible transplantation during recent years. This paper focused on the history, disserted outcomes, desensitization modalities and protocols, posttransplant immunologic surveillance, and antibody-mediated rejection in transplantation with an ABO incompatible kidney allograft. The mechanism underlying accommodation and antibody-mediated injury was also described.
Common Coupled Fixed-Point Theorems in Generalized Fuzzy Metric Spaces
Authors: Rao K. P. R. , Altun I. , Bindu S. Hima
Published: December 2011

We prove two unique common coupled fixed-point theorems for self maps in symmetricG-fuzzy metric spaces.
Dynamic Aerobic Exercise Induces Baroreflex Improvement in Diabetic Rats
Authors: Jorge Luciana , Pureza Demilto Y. da , Dias Danielle da Silva , Conti Filipe Fernandes , Irigoyen Maria-Cláudia , De Angelis Kátia
Published: December 2011

The objective of the present study was to investigate the effects of an acute aerobic exercise on arterial pressure (AP), heart rate (HR), and baroreflex sensitivity (BRS) in STZ-induced diabetic rats. Male Wistar rats were divided into control (n=8) and diabetic (n=8) groups. AP, HR, and BRS, which were measured by tachycardic and bradycardic (BR) responses to AP changes, were evaluated at rest (R) and postexercise session (PE) on a treadmill. At rest, STZ diabetes induced AP and HR reductions, associated with BR impairment. Attenuation in resting diabetes-induced AP (R:103±2versus PE:111±3 mmHg) and HR (R:290±7versus PE:328±10 bpm) reductions and BR dysfunction (R:-0.70±0.06versus PE:-1.21±0.09 bpm/mmHg) was observed in the postexercise period. In conclusion, the hemodynamic and arterial baro-mediated control of circulation improvement in the postexercise period reinforces the role of exercise in the management of cardiovascular risk in diabetes.
170 Years of “Lock-and-Key”: Genital Morphology and Reproductive Isolation
Authors: Masly John P.
Published: December 2011

The divergent genital morphology observed among closely related animal species has long been posited as a mechanism of reproductive isolation. Despite the intuitive appeal that rapidly evolving genitalia might cause speciation, evidence for its importance—or even its potential—in reproductive isolation is mixed. Most tests of genital structural isolation between species often fail to find convincing evidence that differences in morphology prevent copulation or insemination between species. However, recent work suggests that differences in genital morphology might contribute to reproductive isolation in less obvious ways through interactions with sensory mechanisms that result in lowered reproductive fitness in heterospecific matings. In this paper, I present a brief history of the “lock-and-key” hypothesis, summarize the evidence for the involvement of genital morphology in different mechanisms of reproductive isolation, discuss progress in identifying the molecular and genetic bases of species differences in genital morphology, and discuss prospects for future work on the role of genitalia in speciation.
Influence of Simulated Imazapic and Imazethapyr Herbicide Carryover on Cotton (Gossypium hirsutumL.)
Authors: Grichar W. James , Dotray Peter A. , Baughman Todd A.
Published: December 2011

Field studies were conducted during the 2001 and 2002 growing seasons in the Texas peanut growing regions to simulate residual concentrations of imazapic and imazethapyr in the soil and subsequent effects on cotton (Gossypium hirsutumL.). Simulated imazapic or imazethapyr rates included 0, 1/64X (1.09 g ai/ha), 1/32X (2.19 g ai/ha), 1/16X (4.38 g ai/ha), 1/8X (8.75 g ai/ha), 1/4X (17.5 g ai/ha), and 1/2X (35 g ai/ha) of the full labeled rate for peanut (Arachis hypogaeaL.) and incorporated prior to cotton planting. Cotton stunting with imazapic or imazethapyr was more severe at Denver City than other locations. All rates of imazapic and imazethapyr resulted in cotton stunting at Denver City while at Munday and Yoakum the 1/8X, 1/4X, and 1/2X rates of imazapic resulted in reduced cotton growth when compared with the untreated check. At all locations imazapic caused more stunted cotton than imazethapyr. Cotton lint yield was reduced by imazapic or imazethapyr at 1/4 X and 1/2 X rates at all locations when compared with the untreated check.
The Role of Oxidative Stress on the Pathogenesis of Graves' Disease
Authors: Žarković Miloš
Published: December 2011

Graves' disease is a most common cause of hyperthyroidism. It is an autoimmune disease, and autoimmune process induces an inflammatory reaction, and reactive oxygen species (ROSs) are among its products. When balance between oxidants and antioxidants is disturbed, in favour of the oxidants it is termed “oxidative stress” (OS). Increased OS characterizes Graves' disease. It seems that the level of OS is increased in subjects with Graves' ophthalmopathy compared to the other subjects with Graves' disease. Among the other factors, OS is involved in proliferation of orbital fibroblasts. Polymorphism of the 8-oxoG DNA N-glycosylase 1 (hOGG1) involved in repair of the oxidative damaged DNA increases in the risk for developing Grave's disease. Treatment with glucocorticoids reduces levels of OS markers. A recent large clinical trial evaluated effect of selenium on mild Graves' ophthalmopathy. Selenium treatment was associated with an improved quality of life and less eye involvement and slowed the progression of Graves' orbitopathy, compared to placebo.
Endoplasmic Reticulum Stress-Related Factors Protect against Diabetic Retinopathy
Authors: Hu Wei-Kun , Liu Rong , Pei Han , Li Bin
Published: December 2011

The endoplasmic reticulum (ER) is a principal mediator of signal transduction in the cell, and disruption of its normal function (a mechanism known as ER stress) has been associated with the pathogenesis of several diseases. ER stress has been demonstrated to contribute to onset and progression of diabetic retinopathy (DR) by induction of multiple inflammatory signaling pathways. Recent studies have begun to describe the gene expression profile of ER stress-related genes in DR; moreover, genes that play a protective role against DR have been identified.P58IPKwas determined to be able to reduce retinal vascular leakage under high glucose conditions, thus protecting retinal cells. It has also been found by our lab that ER-associated protein degradation factors exhibit significantly different expression patterns in rat retinas under sustained high glucose conditions. Future research based upon these collective genomic findings will contribute to our overall understanding of DR pathogenesis as well as identify potential therapeutic targets.
Biological Strategies to Enhance Healing of the Avascular Area of the Meniscus
Authors: Longo Umile Giuseppe , Campi Stefano , Romeo Giovanni , Spiezia Filippo , Maffulli Nicola , Denaro Vincenzo
Published: December 2011

Meniscal injuries in the vascularized peripheral part of the meniscus have a better healing potential than tears in the central avascular zone because meniscal healing principally depends on its vascular supply. Several biological strategies have been proposed to enhance healing of the avascular area of the meniscus: abrasion therapy, fibrin clot, organ culture, cell therapy, and applications of growth factors. However, data are too heterogeneous to achieve definitive conclusions on the use of these techniques for routine management of meniscal lesions. Although most preclinical and clinical studies are very promising, they are still at an experimental stage. More prospective randomised controlled trials are needed to compare the different techniques for clinical results, applicability, and cost-effectiveness.
Ants as Indicators in Brazil: A Review with Suggestions to Improve the Use of Ants in Environmental Monitoring Programs
Authors: Ribas Carla R. , Campos Renata B. F. , Schmidt Fernando A. , Solar Ricardo R. C.
Published: December 2011

We describe the use of ants as indicators in Brazil, based on a critical review of published articles. The analysis of fifty-eight papers, encompassing a range of almost 25 years, indicates an increased number of studies using ants as indicators in the last decade. Among the parameters analyzed in the papers, species composition is the most suitable to evaluate the effect of the disturbance on ant communities. The use of other metrics that consider the specificity and fidelity (e.g., IndVal index) of ant species to a level or state of disturbance is also highly desirable. We discuss several alternative ways of overcoming many of the drawbacks related to the robustness of the results and to reduce the financial, logistic, and time costs involved with the use of ants as indicators in monitoring programs. By doing so, we expect to encourage new research on ants as bioindicators as well as to summarize current knowledge, facilitating further research.
Feasibility, Safety, and Compliance in a Randomized Controlled Trial of Physical Therapy for Parkinson's Disease
Authors: McGinley Jennifer L. , Martin Clarissa , Huxham Frances E. , Menz Hylton B. , Danoudis Mary , Murphy Anna T. , Watts Jennifer J. , Iansek Robert , Morris Meg E.
Published: December 2011

Both efficacy and clinical feasibility deserve consideration in translation of research outcomes. This study evaluated the feasibility of rehabilitation programs within the context of a large randomized controlled trial of physical therapy. Ambulant participants with Parkinson's disease (PD) (n=210) were randomized into three groups: (1) progressive strength training (PST); (2) movement strategy training (MST); or (3) control (“life skills”). PST and MST included fall prevention education. Feasibility was evaluated in terms of safety, retention, adherence, and compliance measures. Time to first fall during the intervention phase did not differ across groups, and adverse effects were minimal. Retention was high; only eight participants withdrew during or after the intervention phase. Strong adherence (attendance>80%) did not differ between groups(P=.435). Compliance in the therapy groups was high. All three programs proved feasible, suggesting they may be safely implemented for people with PD in community-based clinical practice.
Competition for Aphid Prey between Different Lady Beetle Species in a Laboratory Arena
Authors: Leppanen Christy , Alyokhin Andrei , Gross Serena
Published: December 2011

Direct competition for aphid prey (Hemiptera: Aphididae) was evaluated between and among several lady beetle species (Coleoptera: Coccinellidae). The behavior of three native (Coccinella trifasciata, Coleomegilla maculata,andHippodamia convergens) and four nonnative (Coccinella septempunctata,Harmonia axyridis,Hippodamia variegata,andPropylea quatuordecimpunctata) lady beetles was observed in laboratory arenas. The beetles were kept alone, paired with conspecifics or paired with heterospecifics, and presented with potato aphids (Macrosiphum euphorbiae).Harmonia axyridiswas the most successful aphid predator in our study, being able to find aphids more quickly and consume more of them compared to most other lady beetle species. It was also by far the most aggressive of the tested species.Coccinella septempunctata, C. trifasciata,andC. maculatagenerally followedH. axyridisin aphid consumption. Prey discovery, consumption, and aggressive behaviors were dependent on which species were present in the arena. Except for the generally superiorH. axyridis, there was no obvious dominance hierarchy among the other tested species and no dichotomy between the native and non-native species. Asymmetric interactions between lady beetle species may affect their abilities to coexist in the same habitat.
Immunotherapy with PI3K Inhibitor and Toll-Like Receptor Agonist Induces IFN-γ+IL-17+ Polyfunctional T Cells That Mediate Rejection of Murine Tumors
Authors: Marshall Neil A. , Galvin Karen C. , Corcoran Anna-Maria B. , Boon Louis , Higgs Rowan , Mills Kingston H.G.
Published: December 2011

The immunosuppressive microenvironment in tumors hampers the induction of antitumor immunity by vaccines or immunotherapies. Toll-like receptor (TLR) ligands have the potential to treat tumors, but they can exert a mixture of positive and negative effects on inflammation in the tumor microenvironment. In this study, we show that specific small molecule inhibitors of phosphoinositide 3-kinase (PI3K) relieve immunosuppression to heighten the proinflammatory effects of TLR ligands that support antitumor immunity. Multiple strategies to inhibit PI3K in dendritic cells (DC) each led to suppression of interleukin (IL)-10 and TGF-β but did affect IL-12 or IL-1β induction by the TLR5 ligand flagellin. In three different mouse models of cancer, combining flagellin with a class I PI3K inhibitor, either with or without a DC vaccine, delayed tumor growth and increased survival, with some animals exhibiting complete rejection and resistance to secondary challenge. Tumor growth suppression was associated with increased accumulation of polyfunctional T cells that secreted multiple effector cytokines, including IFN-γ, IL-17, and IL-2. Therapeutic protection was abolished in mice deficient in IL-17 or deprived of IFN-γ. Together, our results indicate that PI3K inhibition heighten the antitumor properties of TLR ligands, eliciting tumor regression directly but also indirectly by relieving suppressive signals that restrict potent antitumor T-cell responses. These findings suggest important uses for PI3K inhibitors in heightening responses to cancer immunotherapy and immunochemotherapy. Cancer Res; 72(3); 581–91. ©2011 AACR.
Targeting Protein Synthesis in a Myc/mTOR-Driven Model of Anorexia-Cachexia Syndrome Delays Its Onset and Prolongs Survival
Authors: Robert Francis , Mills John R. , Agenor Aouod , Wang Dantong , DiMarco Sergio , Cencic Regina , Tremblay Michel L. , Gallouzi Imed Eddine , Hekimi Siegfried , Wing Simon S. , Pelletier Jerry
Published: December 2011

Anorexia-cachexia syndrome (ACS) is a major determinant of cancer-related death that causes progressive body weight loss due to depletion of skeletal muscle mass and body fat. Here, we report the development of a novel preclinical murine model of ACS in which lymphomas harbor elevated Myc and activated mTOR signaling. The ACS phenotype in this model correlated with deregulated expression of a number of cytokines, including elevated levels of interleukin-10 which was under the direct translational control of mTOR. Notably, pharmacologic intervention to impair protein synthesis restored cytokine production to near-normal levels, delayed ACS progression, and extended host survival. Together, our findings suggest a new paradigm to treat ACS by strategies which target protein synthesis to block the production of procachexic factors. Cancer Res; 72(3); 747–56. ©2011 AACR.
Epithelial–Mesenchymal Transition Predicts Sensitivity to the Dual IGF-1R/IR Inhibitor OSI-906 in Hepatocellular Carcinoma Cell Lines
Authors: Zhao Hui , Desai Vidhi , Wang Jian , Epstein David M. , Miglarese Mark , Buck Elizabeth
Published: December 2011

A growing body of data indicates that inhibiting the type 1 insulin-like growth factor receptor (IGF-1R) might be an effective treatment strategy for hepatocellular carcinoma (HCC). OSI-906 is a dual IGF-1R/IR kinase inhibitor currently in phase II clinical development for HCC. However, biomarkers are lacking to help identify patients with HCC who are more likely to benefit from OSI-906 treatment. We sought to determine the effect of OSI-906 on proliferation against a panel of 21 HCC cell lines and to investigate molecular determinants of responsiveness to OSI-906. We identified a subset of HCC cell lines that was sensitive to OSI-906, and sensitivity is associated with elevated phosphorylation levels of IGF-1R and IR and greater inhibition of AKT signaling. Dual targeting of both receptors seems to be important for maximal inhibition as treatment with a selective IGF-1R–neutralizing antibody was associated with increased IR signaling, whereas OSI-906 fully inhibited both phosphorylated IR and IGF-1R and resulted in greater inhibition of the IRS/AKT pathway. Epithelial–mesenchymal transition (EMT) seems to predict HCC cell sensitivity to OSI-906, as the epithelial phenotype is strongly associated with expression of IGF-2 and IR, activation of IGF-1R and IR, and sensitivity to OSI-906, alone or in combination with erlotinib. Induction of EMT upon treatment with TGFβ reduced sensitivity to OSI-906. Collectively, these data support the concept for dual IGF-1R/IR targeting in HCC, where EMT status and expressions of IGF-2 and IR may be used to identify those patients who are most likely to benefit from treatment with an IGF-1R/IR dual inhibitor. Mol Cancer Ther; 11(2); 503–13. ©2011 AACR.