bluuebunny/crossref_metadata_2025 huggingface dataset:
Neutrophil gelatinase-associated lipocalin in gastric carcinoma cells and its induction by TPA are controlled by C/EBPβ
Authors: Du Ze-Peng , Yuan Hua-Min , Wu Bing-Li , Chang Jing-Xia , Lv Zhuo , Shen Jian , Wu Jian-Yi , Chen Hai-Bin , Li En-Min , Xu Li-Yan
Published: July 2011

Neutrophil gelatinase-associated lipocalin (NGAL) expression has been found to be upregulated in a variety of tumors, but the mechanism of NGAL elevation in gastric carcinoma remains unknown. Here, immunohistochemistry was applied to analyze NGAL expression in gastric carcinoma patients. Reverse transcription PCR, Western blot, and enzyme-linked immunosorbent assay (ELISA) were performed to evaluate NGAL mRNA and protein levels before and after 12-O-tetradecanoylphorbol-13-acetate (TPA) induction. Luciferase reporter assay was carried out to identify the core cis element in NGAL promoter. The binding ability and specificity of transcription factors were analyzed by electrophoretic mobility-shift assay (EMSA) and chromatin immunoprecipitation (ChIP), respectively. Results showed that NGAL was overexpressed in gastric tumor tissues. Gastric cancer cells treated with TPA resulted in the transactivation of NGAL promoter and the upregulation of its mRNA and protein levels. We identified the −110 to −79 sequence segment upstream from the transcription initiation site of NGAL as a TPA responsive element (TRE) and confirmed that C/EBPβ was able to bind to the −87 to −79 segment. Forced expression of C/EBPβ significantly increased the promoter activity of NGAL as well as its mRNA level. These results suggest that NGAL is overexpressed in gastric cancer, the binding of C/EBPβ to the TRE of its gene promoter mediates its TPA-induced overexpression in gastric carcinoma cells.
The lipopolysaccharide core ofActinobacillus suisand its relationship to those ofActinobacillus pleuropneumoniae
Authors: Ganeshapillai Jeyabarathy , Boncheff Alexander G. , Slavic Durda , MacInnes Janet , Monteiro Mario A.
Published: July 2011

The Gram-negative bacteria Actinobacillus suis colonizes the upper respiratory and genital tracts of swine. Along with capsular polysaccharides, lipopolysaccharides (O-chain→core→lipid A~cell) are a main cell-surface component of A. suis. In this study, we determined that A. suis lipopolysaccharide incorporates a conserved core that shares some structural features with several core types of A. pleuropneumoniae . These common core structural features likely account for the observed serological cross-reactivity between A. suis and A. pleuropneumoniae, and the data suggest that the structural epitopes responsible for immunogenicity are those in the outer core domain.
PEDESTRIAN DYNAMICS IN A TWO-DIMENSIONAL COMPLEX SCENARIO USING A LOCAL VIEW FLOOR FIELD MODEL
Authors: ZENG JIA-BEI , LENG BIAO , XIONG ZHANG , QIN ZHENG
Published: July 2011

In this paper, an extended FF model (floor field model) to simulate pedestrian dynamics in complex scenarios is proposed. Considering that pedestrians are unaware of the global view of traffic path, we introduce pedestrians' local views and propose a framework to change a pedestrian's static floor field each time they enter a new convex area. A pedestrian's view is limited to a convex polygon. When they travel from one convex area to another, they make decisions about the next goal according to the distances between them and the candidate goals, as well as densities of capacity and herding behaviors. Meanwhile, after making an initial decision about the next goal, a pedestrian can estimate the travel time to reach each visible goal and change their path adaptively within the convex area. Simulations in two scenarios are conducted and the results show that pedestrians under local views behave more practically than those under global views in complex scenarios. Parameter settings are also discussed along with suggestions that can be given to designers for improving traffic management.
NEUTRINO-LESS DOUBLE BETA DECAY AND PARTICLE PHYSICS
Authors: RODEJOHANN WERNER
Published: July 2011

We review the particle physics aspects of neutrino-less double beta decay. This process can be mediated by light massive Majorana neutrinos (standard interpretation) or by something else (non-standard interpretations). The physics potential of both interpretations is summarized and the consequences of future measurements or improved limits on the half-life of neutrino-less double beta decay are discussed. We try to cover all proposed alternative realizations of the decay, including light sterile neutrinos, supersymmetric or left-right symmetric theories, Majorons, and other exotic possibilities. Ways to distinguish the mechanisms from one another are discussed. Experimental and nuclear physics aspects are also briefly touched, alternative processes to double beta decay are discussed, and an extensive list of references is provided.
AN IMAGE FUSION FRAMEWORK BASED ON HUMAN VISUAL SYSTEM IN FRAMELET DOMAIN
Authors: BHATNAGAR GAURAV , WU Q. M. JONATHAN
Published: July 2011

In this paper, a novel image fusion algorithm based on framelet transform is presented. The core idea is to decompose all the images to be fused into low and high-frequency bands using framelet transform. For fusion, two different selection strategies are developed and used for low and high-frequency bands. The first strategy is adaptive weighted average based on local energy and is applied to fuse the low-frequency bands. In order to fuse high-frequency bands, a new strategy is developed based on texture while exploiting the human visual system characteristics, which can preserve more details in source images and further improve the quality of fused image. Experimental results demonstrate the efficiency and better performance than existing image fusion methods both in visual inspection and objective evaluation criteria.
Bed rest reduces metabolic protein content and abolishes exercise-induced mRNA responses in human skeletal muscle
Authors: Ringholm Stine , Biensø Rasmus S. , Kiilerich Kristian , Guadalupe-Grau Amelia , Aachmann-Andersen Niels Jacob , Saltin Bengt , Plomgaard Peter , Lundby Carsten , Wojtaszewski Jørgen F. P. , Calbet Jose A. , Pilegaard Henriette
Published: July 2011

The aim was to test the hypothesis that 7 days of bed rest reduces mitochondrial number and expression and activity of oxidative proteins in human skeletal muscle but that exercise-induced intracellular signaling as well as mRNA and microRNA (miR) responses are maintained after bed rest. Twelve young, healthy male subjects completed 7 days of bed rest with vastus lateralis muscle biopsies taken before and after bed rest. In addition, muscle biopsies were obtained from six of the subjects prior to, immediately after, and 3 h after 45 min of one-legged knee extensor exercise performed before and after bed rest. Maximal oxygen uptake decreased by 4%, and exercise endurance decreased nonsignificantly, by 11%, by bed rest. Bed rest reduced skeletal muscle mitochondrial DNA/nuclear DNA content 15%, hexokinase II and sirtuin 1 protein content ∼45%, 3-hydroxyacyl-CoA dehydrogenase and citrate synthase activity ∼8%, and miR-1 and miR-133a content ∼10%. However, cytochrome c and vascular endothelial growth factor (VEGF) protein content as well as capillarization did not change significantly with bed rest. Acute exercise increased AMP-activated protein kinase phosphorylation, peroxisome proliferator activated receptor-γ coactivator-1α, and VEGF mRNA content in skeletal muscle before bed rest, but the responses were abolished after bed rest. The present findings indicate that only 7 days of physical inactivity reduces skeletal muscle metabolic capacity as well as abolishes exercise-induced adaptive gene responses, likely reflecting an interference with the ability of skeletal muscle to adapt to exercise.
Neural correlates of spatial orienting in the human superior colliculus
Authors: Anderson Elaine J. , Rees Geraint
Published: July 2011

A natural visual scene contains more information than the visual system has the capacity to simultaneously process, requiring specific items to be selected for detailed analysis at the expense of others. Such selection and inhibition are fundamental in guiding search behavior, but the neural basis of these mechanisms remains unclear. Abruptly appearing visual items can automatically capture attention, but once attention has been directed away from the salient event, return to that same location is slowed. In non-human primates, signals associated with attentional capture (AC) and subsequent inhibition of return (IOR) have been recorded from the superior colliculus (SC)—a structure known to play a pivotal role in reflexive spatial orienting. Here, we sought to establish whether similar signals could be recorded from the human SC, as well as early retinotopic cortical visual areas, where signals associated with AC and IOR have yet to be investigated with respect to oculomotor responses. Using an optimized oculomotor paradigm together with high-field, high-spatial resolution functional magnetic resonance imaging and high-speed eye tracking, we demonstrate that BOLD signal changes recorded from the human SC correlate strongly with our saccadic measures of AC and IOR. A qualitatively similar pattern of responses was found for V1, but only the inhibitory response associated with IOR persisted through V2 and V3. Although the SC plays a role in mediating these automatic attentional biasing signals, the source of these signals is likely to lie in higher cortical areas.
Labor Dystocia as First Presentation of Pelvic Malignancy
Authors: van Hamont Dennis , Zusterzeel Petra L. M.
Published: July 2011

The underlying causes of labor dystocia can be various. Lack of expulsive forces or fetal malpresentation are amongst the most common ones. However, pelvic masses are described as well. Here we describe two cases of labor dystocia as first presentation of pelvic malignancy.
Arens Regularity of Certain Class of Banach Algebras
Authors: Sahleh Abbas , Zivari-Kazempour Abbas
Published: July 2011

We study Arens regularity of the left and right module actions of A on A(n), where A(n) is the nth dual space of a Banach algebra A, and then
investigate (quotient) Arens regularity of U = A ⊕ A(n) as a module extension
of Banach algebras.
Surgical Treatment of Endometrial Cancer and Atypical Hyperplasia: A Trend Shift from Laparotomy to Laparoscopy
Authors: Qvigstad Erik , Lieng Marit
Published: July 2011

Background. Laparoscopic hysterectomy has proved to be a safe alternative to open surgery in women with benign indications. Few studies compare laparotomy and laparoscopy in gynecologic oncology, and the objective of this study was to analyze the feasibility and development of laparoscopic surgery in endometrial cancer patients.Material and Methods. Records from all women having a hysterectomy due to premalignant or malignant endometrial changes during the years 2002–2009 were examined retrospectively.Results. A total of 521 hysterectomies were performed during the study period. Laparoscopy was performed in about 20% of the cases in the first two years, increasing to 83% in the last year of the period. Moreover, the laparoscopic technique was increasingly applied in older women, more obese women and in women with high-risk preoperative diagnosis, without increasing the complication rate.Conclusions. As for benign indications, laparoscopic hysterectomy in endometrial cancer patients should be preferred whenever possible.
Testicular Arteriovenous Malformation: Gray-Scale and Color Doppler Ultrasonography Features
Authors: Gulsen Fatih , Mihmanli Ismail , Kantarci Fatih , Eren Abdulkadir , Ataus Suleyman Onder
Published: July 2011

Intratesticular arteriovenous malformations (AVMs) are extremely rare benign incidental lesions of the testis. Ultrasonography (US) generally reveals a hypoechoic solid mass within the testicular parenchyma. We describe a patient with intratesticular AVM which was found incidentally during workup for infertility. The gray-scale and Doppler US appearance of an intratesticular AVM and the differential diagnosis have been presented. Based on the gray-scale, US appearance differentiation from malignant testicular tumors is difficult. Doppler US examination aids in the diagnosis by demonstrating the vascular nature of the tumor.
Caroli's Disease: Current Knowledge of Its Biliary Pathogenesis Obtained from an Orthologous Rat Model
Authors: Sato Yasunori , Ren Xiang Shan , Nakanuma Yasuni
Published: July 2011

Caroli's disease belongs to a group of hepatic fibropolycystic diseases and is a hepatic manifestation of autosomal recessive polycystic kidney disease (ARPKD). It is a congenital disorder characterized by segmental saccular dilatations of the large intrahepatic bile duct and is frequently associated with congenital hepatic fibrosis (CHF). The most viable theory explaining its pathogenesis suggests that it is related to ductal plate malformation. The development of the polycystic kidney (PCK) rat, an orthologous rodent model of Caroli's disease with CHF as well as ARPKD, has allowed the molecular pathogenesis of the disease and the therapeutic options for its treatment to be examined. The relevance of the findings of studies using PCK rats and/or the cholangiocyte cell line derived from them to the pathogenesis of human Caroli's disease is currently being analyzed. Fibrocystin/polyductin, the gene product responsible for ARPKD, is normally localized to primary cilia, and defects in the fibrocystin from primary cilia are observed in PCK cholangiocytes. Ciliopathies involving PCK cholangiocytes (cholangiociliopathies) appear to be associated with decreased intracellular calcium levels and increased cAMP concentrations, causing cholangiocyte hyperproliferation, abnormal cell matrix interactions, and altered fluid secretion, which ultimately result in bile duct dilatation. This article reviews the current knowledge about the pathogenesis of Caroli's disease with CHF, particularly focusing on studies of the mechanism responsible for the biliary dysgenesis observed in PCK rats.
Engagement of I-Branching β-1, 6-N-Acetylglucosaminyltransferase 2 in Breast Cancer Metastasis and TGF-β Signaling
Authors: Zhang Haijun , Meng Fanyan , Wu Sherwin , Kreike Bas , Sethi Seema , Chen Wei , Miller Fred R. , Wu Guojun
Published: July 2011

In this study, we have showed that GCNT2, a gene-encoding glucosaminyl (N-acetyl) transferase 2, I-branching enzyme, is overexpressed in highly metastatic breast cancer cell lines of human and mouse origin and basal-like breast tumor samples. GCNT2 expression is also significantly correlated to the metastatic phenotype in breast tumor samples. Functional studies showed that ectopic expression of GCNT2 enhances cell detachment, adhesion to endothelial cells, cell migration and invasion in vitro, and lung metastasis of breast cancer cells in vivo. Knockdown of GCNT2 expression decreases cell migration and invasion in vitro and lung metastasis in vivo. We have further shown the involvement of GCNT2 in the epithelial-to-mesenchymal transition (EMT). Specifically, the expression of E-cadherin is significantly changed upon GCNT2 expression at the protein level but not at the RNA level. Moreover, we have shown that GCNT2 is a direct target of the TGF-β–smad pathway and that change in GCNT2 expression modulates EMT induced by TGF-β1 treatment. Finally, we have shown that diminution of the glycosyltransferase activity of I-branching β-1, 6-N-acetylglucosaminyl transferase 2 (GCNT2) abrogates its cell migration and invasion-promoting function and synergistic effect with TGF-β to induce EMT. Our study for the first time showed that GCNT2 is a novel gene contributing to breast cancer metastasis with preferential expression in basal-like breast cancer. Moreover, we discovered that involvement of GCNT2 in EMT and TGF-β signaling, and further glycosylation modification of E-cadherin by GCNT2, are the underlying integrative mechanisms for breast cancer metastasis, implying that blocking TGF-β/GCNT2 signaling is a promising approach for targeting metastatic breast cancer. Cancer Res; 71(14); 4846–56. ©2011 AACR.
Early Tumor Progression Associated with Enhanced EGFR Signaling with Bortezomib, Cetuximab, and Radiotherapy for Head and Neck Cancer
Authors: Argiris Athanassios , Duffy Austin G. , Kummar Shivaani , Simone Nicole L. , Arai Yoshio , Kim Seungwon W. , Rudy Susan F. , Kannabiran Vishnu R. , Yang Xinping , Jang Minyoung , Chen Zhong , Suksta Nanette , Cooley-Zgela Theresa , Ramanand Susmita G. , Ahsan Aarif , Nyati Mukesh K. , Wright John J. , Van Waes Carter
Published: July 2011

Purpose: A phase I clinical trial and molecular correlative studies were conducted to evaluate preclinical evidence for combinatorial activity of the proteasome inhibitor bortezomib, the epidermal growth factor receptor (EGFR) inhibitor cetuximab, and radiation therapy.

Experimental Design: Patients with radiotherapy-naive stage IV or recurrent squamous cell carcinoma of the head and neck (SCCHN) were studied. Escalating doses of bortezomib (0.7, 1.0, and 1.3 mg/m2) were given intravenously twice weekly on days 1, 4, 8, and 11, every 21 days, with weekly cetuximab beginning 1 week prior and concurrently with intensity-modulated radiotherapy, delivered in 2 Gy fractions to 70 to 74 Gy. Molecular effects were examined in serial serum and SCCHN tumor specimens and the cell line UMSCC-1.

Results: Seven patients were accrued before the study was terminated when five of six previously untreated patients with favorable prognosis oropharyngeal SCCHN progressed within 1 year (progression-free survival = 4.8 months; 95% CI, 2.6–6.9). Three patients each received bortezomib 0.7 or 1.0 mg/m2, without dose-limiting toxicities; one patient treated at 1.3 mg/m2 was taken off study due to recurring cetuximab infusion reaction and progressive disease (PD). Expected grade 3 toxicities included radiation mucositis (n = 4), dermatitis (n = 4), and rash (n = 1). SCCHN-related cytokines increased in serial serum specimens of patients developing PD (P = 0.029). Bortezomib antagonized cetuximab- and radiation-induced cytotoxicity, degradation of EGFR, and enhanced prosurvival signal pathway activation in SCCHN tumor biopsies and UMSCC-1.

Conclusions: Combining bortezomib with cetuximab and radiation therapy showed unexpected early progression, evidence for EGFR stabilization, increased prosurvival signaling, and SCCHN cytokine expression, warranting avoidance of this combination. Clin Cancer Res; 17(17); 5755–64. ©2011 AACR.
PF-04691502, a Potent and Selective Oral Inhibitor of PI3K and mTOR Kinases with Antitumor Activity
Authors: Yuan Jing , Mehta Pramod P. , Yin Min-Jean , Sun Shaoxian , Zou Aihua , Chen Jeffrey , Rafidi Kristina , Feng Zheng , Nickel Jeffrey , Engebretsen Jon , Hallin Jill , Blasina Alessandra , Zhang Eric , Nguyen Leslie , Sun Minghao , Vogt Peter K. , McHarg Aileen , Cheng Hengmiao , Christensen James G. , Kan Julie L.C. , Bagrodia Shubha
Published: July 2011

Deregulation of the phosphoinositide 3-kinase (PI3K) signaling pathway such as by PTEN loss or PIK3CA mutation occurs frequently in human cancer and contributes to resistance to antitumor therapies. Inhibition of key signaling proteins in the pathway therefore represents a valuable targeting strategy for diverse cancers. PF-04691502 is an ATP-competitive PI3K/mTOR dual inhibitor, which potently inhibited recombinant class I PI3K and mTOR in biochemical assays and suppressed transformation of avian fibroblasts mediated by wild-type PI3K γ, δ, or mutant PI3Kα. In PIK3CA-mutant and PTEN-deleted cancer cell lines, PF-04691502 reduced phosphorylation of AKT T308 and AKT S473 (IC50 of 7.5–47 nmol/L and 3.8–20 nmol/L, respectively) and inhibited cell proliferation (IC50 of 179–313 nmol/L). PF-04691502 inhibited mTORC1 activity in cells as measured by PI3K-independent nutrient stimulated assay, with an IC50 of 32 nmol/L and inhibited the activation of PI3K and mTOR downstream effectors including AKT, FKHRL1, PRAS40, p70S6K, 4EBP1, and S6RP. Short-term exposure to PF-04691502 predominantly inhibited PI3K, whereas mTOR inhibition persisted for 24 to 48 hours. PF-04691502 induced cell cycle G1 arrest, concomitant with upregulation of p27 Kip1 and reduction of Rb. Antitumor activity was observed in U87 (PTEN null), SKOV3 (PIK3CA mutation), and gefitinib- and erlotinib-resistant non–small cell lung carcinoma xenografts. In summary, PF-04691502 is a potent dual PI3K/mTOR inhibitor with broad antitumor activity. PF-04691502 has entered phase I clinical trials. Mol Cancer Ther; 10(11); 2189–99. ©2011 AACR.
In VitroandIn VivoResponses of Advanced Prostate Tumors to PSMA ADC, an Auristatin-Conjugated Antibody to Prostate-Specific Membrane Antigen
Authors: Wang Xinning , Ma Dangshe , Olson William C. , Heston Warren D.W.
Published: July 2011

Prostate-specific membrane antigen (PSMA) is a membrane protein that is overexpressed manifold in prostate cancer and provides an attractive target for therapy. PSMA ADC is an antibody-drug conjugate (ADC) that consists of a fully human anti-PSMA monoclonal antibody conjugated to monomethylauristatin E through a valine-citrulline linker. In this study, the antitumor activity of PSMA ADC was evaluated against a panel of prostate cancer cell lines in vitro and in a novel in vivo model of taxane-refractory human prostate cancer. In vitro cell killing was efficient for cells with abundant PSMA expression (>105 molecules/cell; IC50 ≤ 0.022 nmol/L) and 1,000-fold less efficient for cells with undetectable PSMA (IC50 > 30 nmol/L). Intermediate potency (IC50 = 0.80 nmol/L) was observed for cells with approximately 104 molecules of PSMA per cell, indicating a threshold PSMA level for selective cell killing. Similar in vitro activity was observed against androgen-dependent and -independent cells that had abundant PSMA expression. In vitro activity of PSMA ADC was also dependent on internalization and proper N-glycosylation/folding of PSMA. In contrast, less potent and nonselective cytotoxic activity was observed for a control ADC, free monomethylauristatin E, and other microtubule inhibitors. PSMA ADC showed high in vivo activity in treating xenograft tumors that had progressed following an initial course of docetaxel therapy, including tumors that were large (>700 mm3) before treatment with PSMA ADC. This study defines determinants of antitumor activity of a novel ADC. The findings here support the clinical evaluation of this agent in advanced prostate cancer. Mol Cancer Ther; 10(9); 1728–39. ©2011 AACR.
Paraoxonase Gene Polymorphism and the Risk for Alzheimer’s Disease in the Polish Population
Authors: Klimkowicz-Mrowiec A. , Marona M. , Wolkow P. , Witkowski A. , Maruszak A. , Styczynska M. , Barcikowska M. , Szczudlik A. , Slowik A.
Published: July 2011

Background: The relationship between different paraoxonase (PON) gene polymorphisms and the risk of Alzheimer’s disease (AD) was studied several times and the results were controversial. Methods: We investigated the association of 4 single-nucleotide polymorphisms (SNPs) of the PON1 (M55L; Q192R; –161C/T) and the PON2 (C311S) genes that were shown to affect the risk of sporadic AD. We studied 360 Caucasian cases with late-onset AD and 354 nondemented controls. Results: No significant differences were observed between the studied PON SNPs and AD risk. The results did not change after stratification of the apolipoprotein E status. Meta-analyses of studies in Caucasians assessing the associations between the PON1 M55L, –161C/T and Q192R SNPs and the risk of AD were performed, and no associations were found. Conclusion: Our results suggest that the studied PON1 and PON2 polymorphisms are not associated with late-onset AD.
Convection-Driven Melting near the Grounding Lines of Ice Shelves and Tidewater Glaciers
Authors: Jenkins Adrian
Published: July 2011

Subglacial meltwater draining along the bed of fast-flowing, marine-terminating glaciers emerges at the grounding line, where the ice either goes afloat to form an ice shelf or terminates in a calving face. The input of freshwater to the ocean provides a source of buoyancy and drives convective motion alongside the ice–ocean interface. This process is modeled using the theory of buoyant plumes that has previously been applied to the study of the larger-scale circulation beneath ice shelves. The plume grows through entrainment of ocean waters, and the heat brought into the plume as a result drives melting at the ice–ocean interface. The equations are nondimensionalized by using scales appropriate for the region where the subglacial drainage, rather than the subsequent addition of meltwater, supplies the majority of the buoyancy forcing. It is found that the melt rate within this region can be approximated reasonably well by a function that is linear in ocean temperature, has a cube root dependence on the flux of subglacial meltwater, and has a complex dependency on the slope of the ice–ocean interface. The model is used to investigate variability in melting induced by changes in both ocean temperature and subglacial discharge for a number of realistic examples of ice shelves and tidewater glaciers. The results show how warming ocean waters and increasing subglacial drainage both generate increases in melting near the grounding line.
Comments on “The Depth-Dependent Current and Wave Interaction Equations: A Revision”
Authors: Bennis Anne-Claire , Ardhuin Fabrice
Published: July 2011

Equations for the wave-averaged three-dimensional momentum equations have been published in this journal. It appears that these equations are not consistent with the known depth-integrated momentum balance, especially over a sloping bottom. These equations should thus be considered with caution, because they can produce erroneous flows, particularly outside of the surf zone. It is suggested that the inconsistency in the equations may arise from the different averaging operators applied to the different terms of the momentum equation. It is concluded that other forms of the momentum equations, expressed in terms of the quasi-Eulerian velocity, are better suited for three-dimensional modeling of wave–current interactions.
JAK2V617F mutation and hydroxyurea treatment as determinants of immature platelet parameters in essential thrombocythemia and polycythemia vera patients
Authors: Panova-Noeva Marina , Marchetti Marina , Buoro Sabrina , Russo Laura , Leuzzi Annamaria , Finazzi Guido , Rambaldi Alessandro , Ottomano Cosimo , ten Cate Hugo , Falanga Anna
Published: July 2011

Immature platelets (IPFs), which are hemostatically more active than mature platelets, have been found elevated in essential thrombocythemia and polycythemia vera, 2 myeloproliferative neoplasms (MPN) characterized by an increased risk of thrombosis. It is not known whether the IPF levels are influenced by pathogenetic factors, including JAK2V617F mutational status, or by treatment regimen. To address this point, in 46 essential thrombocythemia and 38 polycythemia vera consecutive patients, we measured IPF and correlated the results to JAK2V617F mutation and myelosuppressive treatment with hydroxyurea. This analysis provides 2 new elements regarding IPF and MPN. The first finding is that the JAK2V617F mutation is linked to the quantity of IPF in patients with MPN, which might contribute to the prothrombotic phenotype in these patients. The second finding is that IPF is susceptible to myelosuppressive treatment, which may additionally explain the favorable effect of hydroxyurea therapy on MPN outcome as well as the associated thrombotic risk.
Reduction in plasma cell proliferation after initial therapy in newly diagnosed multiple myeloma measures treatment response and predicts improved survival
Authors: Larsen Jeremy T. , Chee Cheng E. , Lust John A. , Greipp Philip R. , Rajkumar S. Vincent
Published: July 2011

Standard myeloma treatment response criteria are determined principally by changes in the monoclonal protein. Reduction in the size of the proliferative component of malignant plasma cells may be an additional metric of assessing response to therapy. We retrospectively analyzed 176 patients with newly diagnosed myeloma with a measurable plasma cell labeling index (PCLI) at diagnosis and repeat measurement 4 months after initiation of therapy. PCLI response was defined as a ≥ 60% reduction. Baseline PCLI is an independent prognostic factor; therefore, we categorized patients into 3 groups: PCLI ≥ 3% (high), ≥ 1% (intermediate), and < 1% (low). Patients achieving a greater PCLI response had improved median overall survival of 54 months compared with 29 months in nonresponders (P = .02). Improved median overall survival with PCLI response occurred in the high initial PCLI group (28 vs 7 months; P = .003) and intermediate group (64 vs 24 months; P = .002). The application of PCLI response and serum M-spike response together provided further prognostic information. On multivariate analysis, the prognostic value of PCLI response was independent of β2-microglobulin, elevated creatinine, serum M-spike response, and baseline PCLI. We conclude that a significant reduction in plasma cell proliferation in patients with newly diagnosed myeloma is an important predictor of survival.
Health-related quality of life in chronic myeloid leukemia patients receiving long-term therapy with imatinib compared with the general population
Authors: Efficace Fabio , Baccarani Michele , Breccia Massimo , Alimena Giuliana , Rosti Gianantonio , Cottone Francesco , Deliliers Giorgio Lambertenghi , Baratè Claudia , Rossi Antonella Russo , Fioritoni Giuseppe , Luciano Luigia , Turri Diamante , Martino Bruno , Di Raimondo Francesco , Dabusti Melissa , Bergamaschi Micaela , Leoni Pietro , Simula Maria Pina , Levato Luciano , Ulisciani Stefano , Veneri Dino , Sica Simona , Rambaldi Alessandro , Vignetti Marco , Mandelli Franco ,   for GIMEMA
Published: July 2011

The main objective of this study was to investigate whether patients with chronic myeloid leukemia (CML) in treatment with long-term therapy imatinib have a different health-related quality-of-life (HRQOL) profile compared with the general population. In total, 448 CML patients were enrolled, and the SF-36 Health Survey was used to compare generic HRQOL profiles. Symptoms were also assessed. HRQOL comparisons were adjusted for key possible confounders. The median age of patients was 57 years and the median time of imatinib treatment was 5 years (range 3-9 years). The largest HRQOL differences were found in younger patients. In particular, patients aged between 18 and 39 years had marked impairments in role limitations because of physical and emotional problems, respectively: −22.6 (P < .001), −22.3 (P < .001). Patients with CML age 60 or older had a HRQOL profile very similar to that reported by the general population. Women had a worse profile than men when each were compared with their peers in the general population. Fatigue was the most frequently reported symptom. The HRQOL of CML patients is comparable with that of population norms in many areas, however, younger and female patients seem to report the major limitations.
Similarities and differences in inflammatory mechanisms of asthma and COPD
Authors: Barnes P.J.
Published: July 2011

Educational aims

To discuss the similarities and differences in inflammation between COPD and asthma

To consider the clinical relevance of these differences

To speculate about the therapeutic implications of this basic research
Differential modulation of cytokine, chemokine and Toll like receptor expression in chickens infected with classical and variant infectious bursal disease virus
Authors: Rauf Abdul , Khatri Mahesh , Murgia Maria V , Jung Kwonil , Saif Yehia M
Published: July 2011

Infectious bursal disease (IBD) is an important immunosuppressive disease of chickens. The causative agent, infectious bursal disease virus (IBDV), consists of two serotypes, 1 and 2. Serotype 1 consists of classic IBDV (cIBDV) and variant IBDV (vIBDV). Both of these strains vary in antigenicity and pathogenesis. The goal of this study was to compare the immunopathogenesis of cIBDV and vIBDV. Three-week-old specific pathogen free chickens were inoculated intraocularly with standard challenge strain (STC) (cIBDV) and a variant strain Indiana (IN) (vIBDV). The cIBDV produced more pronounced bursal damage, inflammatory response and infiltration of T cells as compared to vIBDV. There were significant differences in the expression of innate (IFN-α and IFN-β), proinflammatory cytokine and mediator (IL-6 and iNOS) in cIBDV- and vIBDV-infected bursas. The expression of chemokines genes, IL-8 and MIP-α was also higher in cIBDV-infected chickens during the early phase of infection. The expression of Toll like receptor 3 (TLR3) was downregulated at post inoculation days (PIDs) 3, 5, and 7 in the bursas of vIBDV-infected chickens whereas TLR3 was upregulated at PIDs 3 and 5 in cIBDV-infected bursas. In vIBDV-infected bursa, TLR7 expression was downregulated at PIDs 3 and 5 and upregulated at PID 7. However, TLR7 was upregulated at PIDs 3 and 7 in cIBDV-infected bursas. The expression of MyD88 was downregulated whereas TRIF gene expression was upregulated in cIBDV- and vIBDV-infected bursa. These findings demonstrate the critical differences in bursal lesions, infiltration of T cells, expression of cytokines, chemokines and TLRs in the bursa of cIBDV-and vIBDV-infected chickens.
Regulation of Caenorhabditis elegans vitellogenesis by DAF-2/IIS through separable transcriptional and posttranscriptional mechanisms
Authors: DePina Ana S , Iser Wendy B , Park Sung-Soo , Maudsley Stuart , Wilson Mark A , Wolkow Catherine A
Published: July 2011

Background

Evolutionary theories of aging propose that longevity evolves as a competition between reproduction and somatic maintenance for a finite pool of resources. Reproduction is thought to shorten lifespan by depleting resources from processes promoting somatic maintenance. Maternal yolk production, vitellogenesis, represents a significant maternal cost for reproduction and is suppressed under genetic and environmental conditions that extend lifespan. However, little is known about the pathways regulating vitellogenesis in response to prolongevity cues.

Results

In order to identify mechanisms that suppress vitellogenesis under prolongevity conditions, we studied factors regulating vitellogenesis in C. elegans nematodes. In C. elegans, vitellogenesis is depressed in the absence of insulin-like signaling (IIS). We found that the C. elegans daf-2/IIS pathway regulates vitellogenesis through two mechanisms. vit-2 transcript levels in daf-2 mutants were indirectly regulated through a germline-dependent signal, and could be rescued by introduction of daf-2(+) sperm. However, yolk protein (YP) levels in daf-2 mutants were also regulated by germline-independent posttranscriptional mechanisms.

Conclusions

C. elegans vitellogenesis is regulated transcriptionally and posttranscriptionally in response to environmental and reproductive cues. The daf-2 pathway suppressed vitellogenesis through transcriptional mechanisms reflecting reproductive phenotypes, as well as distinct posttranscriptional mechanisms. This study reveals that pleiotropic effects of IIS pathway mutations can converge on a common downstream target, vitellogenesis, as a mechanism to modulate longevity.
Banf1 is required to maintain the self-renewal of both mouse and human embryonic stem cells
Authors: Cox Jesse L. , Mallanna Sunil K. , Ormsbee Briana D. , Desler Michelle , Wiebe Matthew S. , Rizzino Angie
Published: July 2011

Self-renewal is a complex biological process necessary for maintaining the pluripotency of embryonic stem cells (ESCs). Recent studies have used global proteomic techniques to identify proteins that associate with the master regulators Oct4, Nanog and Sox2 in ESCs or in ESCs during the early stages of differentiation. Through an unbiased proteomic screen, Banf1 was identified as a Sox2-associated protein. Banf1 has been shown to be essential for worm and fly development but, until now, its role in mammalian development and ESCs has not been explored. In this study, we examined the effect of knocking down Banf1 on ESCs. We demonstrate that the knockdown of Banf1 promotes the differentiation of mouse ESCs and decreases the survival of both mouse and human ESCs. For mouse ESCs, we demonstrate that knocking down Banf1 promotes their differentiation into cells that exhibit markers primarily associated with mesoderm and trophectoderm. Interestingly, knockdown of Banf1 disrupts the survival of human ESCs without significantly reducing the expression levels of the master regulators Sox2, Oct4 and Nanog or inducing the expression of markers of differentiation. Furthermore, we determined that the knockdown of Banf1 alters the cell cycle distribution of both human and mouse ESCs by causing an uncharacteristic increase in the proportion of cells in the G2–M phase of the cell cycle.
Protein 4.1R regulates cell migration and IQGAP1 recruitment to the leading edge
Authors: Ruiz-Sáenz Ana , Kremer Leonor , Alonso Miguel A. , Millán Jaime , Correas Isabel
Published: July 2011

In red blood cells, multifunctional protein 4.1R stabilizes the spectrin–actin network and anchors it to the plasma membrane. To contribute to the characterization of functional roles of 4.1R in nonerythroid cells, we have analyzed the participation of protein 4.1R in cell migration. The distribution of endogenous 4.1R is polarized towards the leading edge of migrating cells. Exogenous 4.1R isoforms containing a complete membrane-binding domain consistently localized to plasma membrane extensions enriched in F-actin. Silencing of 4.1R caused the loss of persistence of migration in subconfluent cells and of directional migration in cells moving into a wound. Coimmunoprecipitation and pull-down assays identified the scaffold protein IQGAP1 as a partner for protein 4.1R and showed that the 4.1R membrane-binding domain is involved in binding IQGAP1. Importantly, we show that protein 4.1R is necessary for the localization of IQGAP1 to the leading edge of cells migrating into a wound, whereas IQGAP1 is not required for protein 4.1R localization. Collectively, our results indicate a crucial role for protein 4.1R in cell migration and in the recruitment of the scaffold protein IQGAP1 to the cell front.
Dilatory is a Drosophila protein related to AZI1 (CEP131) that is located at the ciliary base and required for cilium formation
Authors: Ma Lina , Jarman Andrew P.
Published: July 2011

A significant number of ciliary disease genes have been found to encode proteins that localise to the basal body. By contrast, a large number of basal-body-associated proteins remain to be characterised. Here, we report the identification of a new basal body protein that is required for ciliogenesis in Drosophila. Dilatory (DILA) is a predicted coiled-coil protein homologous to vertebrate AZI1 (also known as CEP131). Mutations in dila specifically exhibit defects in ciliated cells (sensory neurons and sperm). Several features of the neuronal phenotype suggest a defect in intraflagellar transport. In sensory neuron cilia, DILA protein localises to the ciliary base, including the basal body and putative transition zone, and it interacts genetically with the ciliary coiled-coil protein, Uncoordinated. These data implicate DILA in regulating intraflagellar transport at the base of sensory cilia.
Elevated performance: the unique physiology of birds that fly at high altitudes
Authors: Scott Graham R.
Published: July 2011

Birds that fly at high altitudes must support vigorous exercise in oxygen-thin environments. Here I discuss the characteristics that help high fliers sustain the high rates of metabolism needed for flight at elevation. Many traits in the O2 transport pathway distinguish birds in general from other vertebrates. These include enhanced gas-exchange efficiency in the lungs, maintenance of O2 delivery and oxygenation in the brain during hypoxia, augmented O2 diffusion capacity in peripheral tissues and a high aerobic capacity. These traits are not high-altitude adaptations, because they are also characteristic of lowland birds, but are nonetheless important for hypoxia tolerance and exercise capacity. However, unique specializations also appear to have arisen, presumably by high-altitude adaptation, at every step in the O2 pathway of highland species. The distinctive features of high fliers include an enhanced hypoxic ventilatory response, an effective breathing pattern, larger lungs, haemoglobin with a higher O2 affinity, further augmentation of O2 diffusion capacity in the periphery and multiple alterations in the metabolic properties of cardiac and skeletal muscle. These unique specializations improve the uptake, circulation and efficient utilization of O2 during high-altitude hypoxia. High-altitude birds also have larger wings than their lowland relatives to reduce the metabolic costs of staying aloft in low-density air. High fliers are therefore unique in many ways, but the relative roles of adaptation and plasticity (acclimatization) in high-altitude flight are still unclear. Disentangling these roles will be instrumental if we are to understand the physiological basis of altitudinal range limits and how they might shift in response to climate change.
Light conditions affect sexual performance in a lekking tephritid fruit fly
Authors: Díaz-Fleischer Francisco , Arredondo José
Published: July 2011

Sensory systems are very susceptible to early environment experience. Mating success depends on the transmission of information from the signaller to the receiver, which means that sensory biases caused by developmental environment are likely to affect sexual selection. We investigated the impact of the developmental visual environment (light spectrum) on male copulation behaviour and female preference in the lekking tephritid Anastrepha ludens. We reared flies in four different light spectrum conditions – red light, blue light, shaded light and darkness – during their first 16 days after emerging from pupae. We found that the light environment experienced during early adulthood affected mating frequency and, in some cases, the latency to copulate, but not copulation duration. Males exposed to any of the three light treatments (red, blue or shaded light) were more frequently chosen as mating partners than dark-reared males. Flies reared under dark conditions exhibited the lowest mating performance out of any of the rearing environments. Under field cage conditions, a slight assortative mating between blue- and red-light-reared flies was detected. Additionally, females reared in blue light and darkness mated less compared with females reared in red and shaded light. Our data demonstrate that male mating behaviour is flexible in response to light environment. The findings suggest that light spectrum only weakly affects the direction of sexual selection by female choice; however, dark rearing environments deeply affect mating success.
Selective Serotonin Reuptake Inhibitor Treatment and Depression are Associated with Poststroke Mortality
Authors: Ried L Douglas , Jia Huanguang , Feng Hua , Cameon Randi , Wang Xinping , Tueth Michael , Wu Samuel S
Published: July 2011

Background:

Studies generally do not examine patients' prestroke depression diagnoses and treatments.

Objective:

To examine the association of depression diagnosis and prestroke and/or poststroke selective serotonin reuptake inhibitor (SSRI) treatment with poststroke mortality.

Methods:

We conducted a retrospective study of the medical records of a cohort of veterans with a stroke diagnosis between July 31, 2000, and September 30, 2001. Data regarding demographics, comorbidities, depression diagnosis, and treatment were abstracted from automated databases and electronic medical records for 6 months before and 1 year after the stroke index date. The survival rates of veterans who received an SSRI before and/or after the stroke were estimated using Kaplan-Meier survival analysis. Time-dependent Cox proportional hazards regression model was used to assess the association between risk factors and mortality.

Results:

Among 870 veterans, 80 died less than 60 days after their stroke. Among the remaining 790, 12% died within 1 year, 26% died by the end of follow-up (May 1, 2007), and more than 62% were alive at the end of follow-up. Veterans were 3 times as likely to die if they had been treated for depression with an SSRI only before their stroke (hazard ratio [HR], 3.12; 95% CI 1.60 to 6.09). In the time-dependent model, SSRI treatment both before and after the stroke was protective compared with no SSRI treatment during the year following the stroke (HR 0.31; 95% CI 0.11 to 0.86). However, the survival curves crossed over and SSRI treatment before and after stroke conferred greater risk at the end of 7 years (HR 1.36; 95% CI 1.00 to 1.87). Depression diagnosis was associated with greater risk of mortality (HR 1.87; 95% CI 1.24 to 2.82).

Conclusions:

Poststroke SSRI treatment was associated with longer survival even though depression diagnosis was associated with earlier mortality in the unadjusted model. After a stroke, SSRI initiation or resumption of treatment should be considered as part of a medication therapy management service, especially if the patient has a history of depression or was taking an SSRI before the stroke.
Assessing irreversible fouling behavior of membrane foulants in the ultrafiltration of natural water using principal component analysis of fluorescence excitation-emission matrices
Authors: Peiris R. H. , Budman H. , Legge R. L. , Moresoli C.
Published: July 2011

Natural river water is comprised of different foulant components such as natural organic matter and colloidal/particulate matter. Both individual and combined contributions of these foulant components results in different fouling behaviour. The ability to characterize these contributions that lead to reversible and irreversible membrane fouling would be beneficial for the implementation of fouling monitoring and control strategies for membrane-based drinking water treatment operations. A fluorescence excitation-emission matrix and principal component analysis-based approach was able to qualitatively estimate the accumulation of humic substances (HS)-, protein- and colloidal/particulate matter-like foulant components in membranes during the ultrafiltration (UF) of natural river water. A bench-scale flat sheet UF cross-flow set-up and successive permeation and membrane backwashing cycles were used. Analysis of the accumulation of these foulant components revealed that the increased levels of colloidal/particulate matter accumulation in the membranes appeared to have increased the extent of irreversible fouling by HS-like matter whereas lower irreversible fouling by protein-like matter was observed with increased colloidal/particulate matter accumulation. The results also indicate that the combined contributions by these foulants are important in the fouling of membranes during the UF of river water.
Integrated water management and environmental justice – public acceptability and fairness in adopting water innovations
Authors: Feldman David L.
Published: July 2011

Innovations to manage freshwater resources and avert shortages – including conservation through use of reclaimed wastewater, desalination, and demand-side management measures such as increasing block rate structures offer practical, effective remedies for meeting future water demands. We examine the challenges confronting adoption of these innovations that revolve around perceptions of fairness and public acceptability. A major obstacle to these approaches' adoption is environmental justice – that the risk and burden of resource solutions, as well as their benefits – should be borne equitably, despite differences of income or race. We first consider how debates regarding water supply are often disputes over different notions of environmental justice. We then examine general equity debates over adopting various innovations in one US state at the nexus of water demand and supply innovation: California. We contend that fairly adopting these innovations requires embracing open, inclusive, and transparent decision-making processes in which no important constituency is excluded from decisions, and in which different notions of environmental justice are embraced.