bluuebunny/crossref_metadata_2025 huggingface dataset:
Effect of formoterol with or without budesonide in repeated low-dose allergen challenge
Authors: Dahlén B. , Lantz A-S. , Ihre E. , Skedinger M. , Henriksson E. , Jörgensen L. , Ekström T. , Dahlén S-E. , Larsson K.
Published: January 2009

The use of combination therapy in mild asthma is debated. The current authors evaluated the effects of formoterol alone and a formoterol/budesonide combination inhaler on asthma deterioration induced by repeated low-dose allergen exposure.

In total, 15 subjects with intermittent allergic asthma inhaled low doses of allergen on seven consecutive weekdays in a three-period, crossover, double-blind, double-dummy comparison between formoterol 4.5 μg TurbuhalerTM, budesonide 160 μg/formoterol 4.5 μg TurbuhalerTMand placebo, each taken as two puffs 30 min after allergen dosing. The outcome variables were: provocative dose of methacholine causing a 20% fall in forced expiratory volume in one second (PD20), exhaled nitric oxide fraction (FeNO), sputum eosinophils and prostaglandin D2, and diary card recordings of symptoms (on a scale of 0–10), short-acting β2-agonist use and evening forced expiratory volume in one second (FEV1).

With placebo treatment, allergen exposure caused significant increases in airway hyperresponsiveness (geometric mean (coefficient of variation) PD20: 397 (98) μg beforeversus168 (82) μg after),FeNO(mean±sd46±31 ppb beforeversus73±46 ppb after) and asthma symptom score (mean±sd0.39±0.55 beforeversus0.68±0.67 after). Budesonide/formoterol abolished these changes and significantly improved baseline FEV1. Formoterol alone, while providing symptom relief, was no better than placebo in protecting against the allergen-induced increase in airway inflammation.

Signs of deteriorating asthma, provoked by low-dose allergen, are prevented by short-term use of budesonide/formoterol but not by temporary use of formoterol alone.
Efficacy of confronting smokers with airflow limitation for smoking cessation
Authors: Kotz D. , Wesseling G. , Huibers M. J. H. , van Schayck O. C. P.
Published: January 2009

The objective of the present study was to test whether confronting smokers with previously undetected chronic obstructive pulmonary disease (COPD) increases the rate of smoking cessation.

In total, 296 smokers with no prior diagnosis of COPD were detected with mild-to-moderate airflow limitation by means of spirometry and randomly allocated to: confrontational counselling by a nurse with nortriptyline for smoking cessation (experimental group); regular counselling by a nurse with nortriptyline (control group 1); or “care as usual” for smoking cessation by the general practitioner (control group 2). Only the experimental group was confronted with their abnormal spirometry (mean forced expiratory volume in one second (FEV1) post-bronchodilator 80.5% predicted, mean FEV1/forced vital capacity post-bronchodilator 62.5%).

There was no difference in cotinine-validated prolonged abstinence rate between the experimental group (11.2%) and control group 1 (11.6%) from week 5–52 (odds ratio (OR) 0.96, 95% confidence interval (CI) 0.43–2.18). The abstinence rate was approximately twice as high in the experimental group compared with control group 2 (5.9%), but this difference was not statistically significant (OR 2.02, 95% CI 0.63–6.46).

The present study did not provide evidence that the confrontational approach increases the rate of long-term abstinence from smoking compared with an equally intensive treatment in which smokers were not confronted with spirometry. The high failure rates (≥88%) highlight the need for treating tobacco addiction as a chronic relapsing disorder.
Maternal smoking during pregnancy induces airway remodelling in mice offspring
Authors: Blacquière M. J. , Timens W. , Melgert B. N. , Geerlings M. , Postma D. S. , Hylkema M. N.
Published: January 2009

Children from smoking mothers have an increased risk of developing asthma for reasons largely unknown. The effects of maternal smoking during pregnancy on remodelling, allergic airway inflammation and hyperresponsiveness in offspring were investigated in an experimental asthma model.

Mice were exposed to fresh air or cigarette smoke from 3 weeks prior to conception until birth. Offspring were exposed to house dust mite (HDM) or PBS intranasally four times per week from week 5 to week 10 after birth onwards.

Maternal smoking increased airway smooth muscle layer, collagen III deposition and HDM-induced goblet cell numbers in offspring. It additionally increased methacholine responsiveness, which correlated significantly with increased airway smooth muscle layer and collagen deposition. Maternal smoking increased HDM-induced numbers of neutrophils and mast cells in lung tissue. No further effects were observed.

Smoking during pregnancy induces airway remodelling in mice offspring, which may contribute to increased methacholine responsiveness. This takes place irrespective of allergen exposure but may worsen the outcome of the allergic stimulus, resulting in higher methacholine responsiveness in house dust mite-exposed offspring from smoking mothers when compared to nonsmoking mothers. The results provide a possible mechanism behind the association between maternal smoking and asthma.
Large-scale prediction of long disordered regions in proteins using random forests
Authors: Han Pengfei , Zhang Xiuzhen , Norton Raymond S , Feng Zhi-Ping
Published: January 2009

Background

Many proteins contain disordered regions that lack fixed three-dimensional (3D) structure under physiological conditions but have important biological functions. Prediction of disordered regions in protein sequences is important for understanding protein function and in high-throughput determination of protein structures. Machine learning techniques, including neural networks and support vector machines have been widely used in such predictions. Predictors designed for long disordered regions are usually less successful in predicting short disordered regions. Combining prediction of short and long disordered regions will dramatically increase the complexity of the prediction algorithm and make the predictor unsuitable for large-scale applications. Efficient batch prediction of long disordered regions alone is of greater interest in large-scale proteome studies.

Results

A new algorithm, IUPforest-L, for predicting long disordered regions using the random forest learning model is proposed in this paper. IUPforest-L is based on the Moreau-Broto auto-correlation function of amino acid indices (AAIs) and other physicochemical features of the primary sequences. In 10-fold cross validation tests, IUPforest-L can achieve an area of 89.5% under the receiver operating characteristic (ROC) curve. Compared with existing disorder predictors, IUPforest-L has high prediction accuracy and is efficient for predicting long disordered regions in large-scale proteomes.

Conclusion

The random forest model based on the auto-correlation functions of the AAIs within a protein fragment and other physicochemical features could effectively detect long disordered regions in proteins. A new predictor, IUPforest-L, was developed to batch predict long disordered regions in proteins, and the server can be accessed from http://dmg.cs.rmit.edu.au/IUPforest/IUPforest-L.php
Genes involved in arsenic transformation and resistance associated with different levels of arsenic-contaminated soils
Authors: Cai Lin , Liu Guanghui , Rensing Christopher , Wang Gejiao
Published: January 2009

Background

Arsenic is known as a toxic metalloid, which primarily exists in inorganic form [As(III) and As(V)] and can be transformed by microbial redox processes in the natural environment. As(III) is much more toxic and mobile than As(V), hence microbial arsenic redox transformation has a major impact on arsenic toxicity and mobility which can greatly influence the human health. Our main purpose was to investigate the distribution and diversity of microbial arsenite-resistant species in three different arsenic-contaminated soils, and further study the As(III) resistance levels and related functional genes of these species.

Results

A total of 58 arsenite-resistant bacteria were identified from soils with three different arsenic-contaminated levels. Highly arsenite-resistant bacteria (MIC > 20 mM) were only isolated from the highly arsenic-contaminated site and belonged to Acinetobacter, Agrobacterium, Arthrobacter, Comamonas, Rhodococcus, Stenotrophomonas and Pseudomonas. Five arsenite-oxidizing bacteria that belonged to Achromobacter, Agrobacterium and Pseudomonas were identified and displayed a higher average arsenite resistance level than the non-arsenite oxidizers. 5 aoxB genes encoding arsenite oxidase and 51 arsenite transporter genes [18 arsB, 12 ACR3(1) and 21 ACR3(2)] were successfully amplified from these strains using PCR with degenerate primers. The aoxB genes were specific for the arsenite-oxidizing bacteria. Strains containing both an arsenite oxidase gene (aoxB) and an arsenite transporter gene (ACR3 or arsB) displayed a higher average arsenite resistance level than those possessing an arsenite transporter gene only. Horizontal transfer of ACR3(2) and arsB appeared to have occurred in strains that were primarily isolated from the highly arsenic-contaminated soil.

Conclusion

Soils with long-term arsenic contamination may result in the evolution of highly diverse arsenite-resistant bacteria and such diversity was probably caused in part by horizontal gene transfer events. Bacteria capable of both arsenite oxidation and arsenite efflux mechanisms had an elevated arsenite resistance level.
A multiple-method approach reveals a declining amount of chloroplast DNA during development in Arabidopsis
Authors: Rowan Beth A , Oldenburg Delene J , Bendich Arnold J
Published: January 2009

Background

A decline in chloroplast DNA (cpDNA) during leaf maturity has been reported previously for eight plant species, including Arabidopsis thaliana. Recent studies, however, concluded that the amount of cpDNA during leaf development in Arabidopsis remained constant.

Results

To evaluate alternative hypotheses for these two contradictory observations, we examined cpDNA in Arabidopsis shoot tissues at different times during development using several methods: staining leaf sections as well as individual isolated chloroplasts with 4',6-diamidino-2-phenylindole (DAPI), real-time quantitative PCR with DNA prepared from total tissue as well as from isolated chloroplasts, fluorescence microscopy of ethidium-stained DNA molecules prepared in gel from isolated plastids, and blot-hybridization of restriction-digested total tissue DNA. We observed a developmental decline of about two- to three-fold in mean DNA per chloroplast and two- to five-fold in the fraction of cellular DNA represented by chloroplast DNA.

Conclusion

Since the two- to five-fold reduction in cpDNA content could not be attributed to an artifact of chloroplast isolation, we conclude that DNA within Arabidopsis chloroplasts is degraded in vivo as leaves mature.
A prospective, non-randomized phase II trial of Trastuzumab and Capecitabine in patients with HER2 expressing metastasized pancreatic cancer
Authors: Mihaljevic Andre , Büchler Peter , Harder Jan , Hofheinz Ralf , Gregor Michael , Kanzler Stephan , Schmiegel Wolff , Heinemann Volker , Endlicher Esther , Klöppel Günter , Seufferlein Thomas , Geissler Michael
Published: January 2009

Background

Pancreatic cancer is the fourth most common cause of cancer related death in Western countries. Advantages in surgical techniques, radiation and chemotherapy had almost no impact on the long term survival of affected patients. Therefore, the need for better treatment strategies is urgent. HER2, a receptor tyrosine kinase of the EGFR family, involved in signal transduction pathways leading to cell growth and differentiation is overexpressed in a number of cancers, including breast and pancreatic cancer. While in breast cancer HER2 has already been successfully used as a treatment target, there are only limited data evaluating the effects of inhibiting HER2 tyrosine kinases in patients with pancreatic cancer.

Methods

Here we report the design of a prospective, non-randomized multi-centered Phase II clinical study evaluating the effects of the Fluoropyrimidine-carbamate Capecitabine (Xeloda ®) and the monoclonal anti-HER2 antibody Trastuzumab (Herceptin®) in patients with non-resectable, HER2 overexpressing pancreatic cancer. Patients eligible for the study will receive Trastuzumab infusions on day 1, 8 and 15 concomitant to the oral intake of Capecitabine from day 1 to day 14 of each three week cylce. Cycles will be repeated until tumor progression. A total of 37 patients will be enrolled with an interim analysis after 23 patients.

Discussion

Primary end point of the study is to determine the progression free survival after 12 weeks of bimodal treatment with the chemotherapeutic agent Capecitabine and the anti-HER2 antibody Trastuzumab. Secondary end points include patient's survival, toxicity analysis, quality of life, the correlation of HER2 overexpression and clinical response to Trastuzumab treatment and, finally, the correlation of CA19-9 plasma levels and progression free intervals.
Albumin fibrillization induces apoptosis via integrin/FAK/Akt pathway
Authors: Huang Chun-Yung , Liang Chi-Ming , Chu Chiao-Li , Liang Shu-Mei
Published: January 2009

Background

Numerous proteins can be converted to amyloid-like fibrils to increase cytotoxicity and induce apoptosis, but the methods generally require a high concentration of protein, vigorous shaking, or fibril seed. As well, the detailed mechanism of the cytotoxic effects is not well characterized. In this study, we have developed a novel process to convert native proteins into the fibrillar form. We used globular bovine serum albumin (BSA) as a model protein to verify the properties of the fibrillar protein, investigated its cellular effects and studied the signaling cascade induced by the fibrillar protein.

Results

We induced BSA, a non-cytotoxic globular protein, to become fibril by a novel process involving Superdex-200 column chromatography in the presence of anionic or zwittergenic detergent(s). The column pore size was more important than column matrix composite in fibril formation. The fibrillar BSA induced apoptosis in BHK-21 cell as well as breast cancer cell line T47D. Pre-treating cells with anti-integrin antibodies blocked the apoptotic effect. Fibrillar BSA, but not globular BSA, bound to integrin, dephosphorylated focal adhesion kinase (FAK), Akt and glycogen synthase kinase-3β (GSK-3β).

Conclusion

We report on a novel process for converting globular proteins into fibrillar form to cause apoptosis by modulating the integrin/FAK/Akt/GSK-3β/caspase-3 signaling pathway. Our findings may be useful for understanding the pathogenesis of amyloid-like fibrils and applicable for the development of better therapeutic agents that target the underlying mechanism(s) of the etiologic agents.
Learning about protein solubility from bacterial inclusion bodies
Authors: Martínez-Alonso Mónica , González-Montalbán Nuria , García-Fruitós Elena , Villaverde Antonio
Published: January 2009

The progressive solving of the conformation of aggregated proteins and the conceptual understanding of the biology of inclusion bodies in recombinant bacteria is providing exciting insights on protein folding and quality. Interestingly, newest data also show an unexpected functional and structural complexity of soluble recombinant protein species and picture the whole bacterial cell factory scenario as more intricate than formerly believed.
Distribution of antibody titer against Salmonella enterica among healthy individuals in nepal
Authors: Pokhrel Bharat M , Karmacharya Rajendra , Mishra Shyam K , Koirala Janak
Published: January 2009

Background

Enteric fever is an endemic problem in Nepal and Widal agglutination test is widely used for its diagnosis but a normal baseline titer in healthy population and cutoff values have not been established.

Methods

We measured average baseline antibody titers against "O" and "H" antigens ofSalmonella entericaserotypeTyphiand "H" antigens of serotypesParatyphi AandParatyphi Bamong apparently healthy blood donors in Nepal. The antibody titers were measured using Standard Widal Confirmatory Quantitative Tube test.

Results

Among the 100 blood samples collected from healthy volunteers, 62 individuals had significant antibody titers (≥ 1:20) against one of the four antigens againstS. enterica. Among 54 samples with an anti-O titer against serotypeTyphi, 15 and 36 samples had titers of ≥ 1:60 and ≥ 1:40, respectively. A significant proportion (12% of all) had anti-O titer of ≥ 1:80. Similarly, among the 59 samples demonstrating anti-H titers of ≥ 1:20 toS. entericaserotypeTyphi, 29 had a titer of ≥ 1:80 and 12 had 1:160. ForS. entericaserotypesParatyphi AandB, anti-H titers of ≥ 1:20 were found only in 12% and 3%, respectively, of all samples tested.

Conclusion

When a single Widal agglutination titer is used for the diagnosis of enteric fever, it will be more appropriate to change the currently used cutoff levels againstS. entericaserotype Typhito > 1:80 for anti-O and > 1:160 for anti-H titers for Nepal.
Polyphenol-rich pomegranate fruit extract (POMx) suppresses PMACI-induced expression of pro-inflammatory cytokines by inhibiting the activation of MAP Kinases and NF-κB in human KU812 cells
Authors: Rasheed Zafar , Akhtar Nahid , Anbazhagan Arivarasu N , Ramamurthy Sangeetha , Shukla Meenakshi , Haqqi Tariq M
Published: January 2009

Background

Mast cells and basophils are multifunctional effector cells and contain plentiful secretary granules in their cytoplasm. These cell types are involved in several inflammatory and immune events and are known to produce an array of mediators including a broad spectrum of cytokines. Pomegranate fruit is rich in anthocyanins and hydrolysable tannins; a group of polyphenolic compounds shown to be potent antioxidant with anti-inflammatory activity. However, no studies have been undertaken to investigate whether a polyphenol-rich pomegranate fruit extract (POMx) inhibits the inflammatory activity of activated human mast cells and basophils. The aim of this study was to examine whether POMx modulates inflammatory reactions using human basophilic cell line KU812.

Methods

KU812 cells were stimulated with phorbol-12-myristate 13-acetate plus calcium inophore A23187 (PMACI). The inhibitory effect of POMx on pro-inflammatory cytokine gene expression and production by stimulated KU812 cells was measured by quantitative RT-PCR, and cytokine-specific ELISA assays, respectively. Western blotting was used to analyze the effect of POMx on the activation of mitogen-activated protein kinases (MAPKs), and the nuclear factor (NF)-κB in PMACI stimulated KU812 cells. Effect on the activity of NF-κB was determined using Luciferase reporter assay. Significance of differences from control values were analyzed by means of standard statistical methods.

Results

POMx significantly decreased PMACI stimulated inflammatory gene expression and production of interleukin (IL)-6 and IL-8 in KU812 cells. The inhibitory effect of POMx on the pro-inflammatory cytokines was MAPK subgroups c-jun N-terminal kinase (JNK)- and extracellular-regulated kinase (ERK) dependent. In addition, POMx suppressed the NF-κB activation induced by PMACI by inhibiting IκB-degradation in human basophil cells. POMx also suppressed the powerful induction of NF-κB promoter-mediated luciferase activity in transiently transfected KU812 cells.

Conclusion

These novel pharmacological actions of POMx provide new suggestion that POMx or POMx-derived compounds may be of therapeutic use for the treatment of inflammatory diseases by suppressing mast cells/basophils activation.
Modulation of human uterine smooth muscle cell collagen contractility by thrombin, Y-27632, TNF alpha and indomethacin
Authors: Fitzgibbon Joan , Morrison John J , Smith Terry J , O'Brien Margaret
Published: January 2009

Background

Preterm labour occurs in approximately 10% of pregnancies and is a major cause of infant morbidity and mortality. However, the pathways involved in regulating contractility in normal and preterm labour are not fully elucidated. Our aim was to utilise a human myometrial contractility model to investigate the effect of a number of uterine specific contractility agents in this system. Therefore, we investigated the contractile response of human primary uterine smooth muscle cells or immortalised myometrial smooth muscle cells cultured within collagen lattices, to known mediators of uterine contractility, which included thrombin, the ROCK-1 inhibitor Y-27632, tumour necrosis factor alpha (TNF alpha) and the non-steroidal anti-inflammatory indomethacin.

Methods

Cell contractility was calculated over time, with the collagen gel contraction assay, utilising human primary uterine smooth muscle cells (hUtSMCs) and immortalised myometrial smooth muscle cells (hTERT-HM): a decrease in collagen gel area equated to an increase in contractility. RNA was isolated from collagen embedded cells and gene expression changes were analysed by real time fluorescence reverse transcription polymerase chain reaction. Scanning electron and fluorescence microscopy were employed to observe cell morphology and cell collagen gel interactions. Statistical analysis was performed using ANOVA followed by Tukey's post hoc tests.

Results

TNF alpha increased collagen contractility in comparison to the un-stimulated collagen embedded hUtSMC cells, which was inhibited by indomethacin, while indomethacin alone significantly inhibited contraction. Thrombin augmented the contractility of uterine smooth muscle cell and hTERT-HM collagen gels, this effect was inhibited by the thrombin specific inhibitor, hirudin. Y-27632 decreased both basal and thrombin-induced collagen contractility in the hTERT-HM embedded gels. mRNA expression of the thrombin receptor, F2R was up-regulated in hUtSMCs isolated from collagen gel lattices, following thrombin-stimulated contractility.

Conclusion

TNF alpha and thrombin increased uterine smooth muscle cell collagen contractility while indomethacin had the opposite effect. Thrombin-induced collagen contractility resulted in F2R activation which may in part be mediated by the ROCK-1 pathway. This study established the in vitro human myometrial model as a viable method to assess the effects of a range of uterotonic or uterorelaxant agents on contractility, and also permits investigation of the complex regulatory pathways involved in mediating myometrial contractility at labour.
MDM2 is a novel E3 ligase for HIV-1 Vif
Authors: Izumi Taisuke , Takaori-Kondo Akifumi , Shirakawa Kotaro , Higashitsuji Hiroaki , Itoh Katsuhiko , Io Katsuhiro , Matsui Masashi , Iwai Kazuhiro , Kondoh Hiroshi , Sato Toshihiro , Tomonaga Mitsunori , Ikeda Satoru , Akari Hirofumi , Koyanagi Yoshio , Fujita Jun , Uchiyama Takashi
Published: January 2009

The human immunodeficiency virus type 1 (HIV-1) Vif plays a crucial role in the viral life cycle by antagonizing a host restriction factor APOBEC3G (A3G). Vif interacts with A3G and induces its polyubiquitination and subsequent degradation via the formation of active ubiquitin ligase (E3) complex with Cullin5-ElonginB/C. Although Vif itself is also ubiquitinated and degraded rapidly in infected cells, precise roles and mechanisms of Vif ubiquitination are largely unknown. Here we report that MDM2, known as an E3 ligase for p53, is a novel E3 ligase for Vif and induces polyubiquitination and degradation of Vif. We also show the mechanisms by which MDM2 only targets Vif, but not A3G that binds to Vif. MDM2 reduces cellular Vif levels and reversely increases A3G levels, because the interaction between MDM2 and Vif precludes A3G from binding to Vif. Furthermore, we demonstrate that MDM2 negatively regulates HIV-1 replication in non-permissive target cells through Vif degradation. These data suggest that MDM2 is a regulator of HIV-1 replication and might be a novel therapeutic target for anti-HIV-1 drug.
Effect of sirolimus on urinary bladder cancer T24 cell line
Authors: Pinto-Leite Rosario , Botelho Pedro , Ribeiro Eufemia , Oliveira Paula A , Santos Lucios
Published: January 2009

Background

Sirolimus is recently reported to have antitumour effects on a large variety of cancers. The present study was performed to investigate sirolimus's ability to inhibit growth in T24 bladder cancer cells.

Methods

T24 bladder cancer cells were treated with various concentrations of sirolimus. MTT assay was used to evaluate the proliferation inhibitory effect on T24 cell line. The viability of T24 cell line was determined by Trypan blue exclusion analysis.

Results

Sirolimus inhibits the growth of bladder carcinoma cells and decreases their viability. Significant correlations were found between cell proliferation and sirolimus concentration (r = 0.830; p < 0.01) as well as between cell viability and sirolimus concentration (r = -0.896; p < 0.01).

Conclusion

Sirolimus has an anti-proliferation effect on the T24 bladder carcinoma cell line. The information from our results is useful for a better understanding sirolimus's anti-proliferative activity in the T24 bladder cancer cell line.
The differential expressions of 78-kDa glucose-regulated protein of infiltrating plasma cells in peripheral joints with the histopathological variants of rheumatoid synovitis
Authors: Dong Weijia , Li Xiaoyan , Feng Yuan , Fan Chunmei , Chen Zhinan , Zhu Ping
Published: January 2009

Introduction

The local production of pathogenic autoantibodies by plasma cells in synovium is one of the hallmarks of rheumatoid arthritis (RA). There may be a potential link between ectopic lymphoid neogenesis and the local autoimmunity in rheumatoid synovium. The unfolded protein response (UPR) has key roles in the development and maintenance of plasma cells secreting immunoglobulin. This study was designed to explore the potential links between the activation of the UPR of infiltrating plasma cells in inflamed peripheral joints and the histopathological variants of rheumatoid synovitis as well as the local production of pathogenic autoantibodies.

Methods

The variants of rheumatoid synovium were histopathologically classified into follicular and diffuse synovitis. Immunohistochemical and double-immunofluorescent stainings were performed to detect the expression of 78-kDa glucose-regulated protein (GRP78), a marker of activation of the UPR, in infiltrating plasma cells of synovium, and flow cytometry and immunoblotting analyses were performed to quantify GRP78 in plasma cells of synovial fluid in inflamed peripheral joints of RA. The detections were also taken in osteoarthritis (OA) as controls. The synovial fluid levels of anti-cyclic citrullinated peptide antibodies (anti-CCP) (IgG) were quantified with the enzyme-linked immunosorbent assay and corrected to those of total IgG in RA.

Results

Expressions of GRP78 were more intensive in infiltrating plasma cells in RA synovium relative to those in OA synovium (P < 0.001) and in synovium with follicular synovitis relative to that with diffuse synovitis (P < 0.001). Analyses by flow cytometry and immunoblotting showed that there was a significant upregulation of GRP78 of plasma cells from synovial fluid of RA compared with that of OA (P < 0.05) and from synovial fluid of follicular synovitis relative to that of diffuse synovitis (P < 0.05). Moreover, a positive relationship between the expression of GRP78 of plasma cells from synovial fluid and the corrected synovial levels of anti-CCP (IgG) was seen in RA (P < 0.001).

Conclusions

There may be a link between enhanced activation of the UPR of plasma cells and ectopic lymphoid neogenesis as well as the local production of anti-CCP (IgG) in inflamed peripheral joints of RA.
Phosphoinositide 3-kinase targeting by the β galactoside binding protein cytokine negates akt gene expression and leads aggressive breast cancer cells to apoptotic death
Authors: Wells Valerie , Mallucci Livio
Published: January 2009

Introduction

Phosphoinositide 3-kinase (PI3K)-activated signalling has a critical role in the evolution of aggressive tumourigenesis and is therefore a prime target for anticancer therapy. Previously we have shown that the β galactoside binding protein (βGBP) cytokine, an antiproliferative molecule, induces functional inhibition of class 1A and class 1B PI3K. Here, we have investigated whether, by targeting PI3K, βGBP has therapeutic efficacy in aggressive breast cancer cells where strong mitogenic input is fuelled by overexpression of the ErbB2 (also known as HER/neu, for human epidermal growth factor receptor 2) oncoprotein receptor and have used immortalised ductal cells and non-aggressive mammary cancer cells, which express ErbB2 at low levels, as controls.

Methods

Aggressive BT474 and SKBR3 cancer cells where ErbB2 is overexpressed, MCF10A immortalised ductal cells and non-invasive MCF-7 cancer cells which express low levels of ErbB2, both in their naive state and when forced to mimic aggressive behaviour, were used. Class IA PI3K was immunoprecipitated and the conversion of phosphatidylinositol (4,5)-biphosphate (PIP2) to phosphatidylinositol (3,4,5)-trisphosphate (PIP3) assessed by ELISA. The consequences of PI3K inhibition by βGBP were analysed at proliferation level, by extracellular signal-regulated kinase (ERK) activation, by akt gene expression and by apoptosis. Apoptosis was documented by changes in mitochondrial membrane potential, alteration of the plasma membrane, caspase 3 activation and DNA fragmentation. Phosphorylated and total ERK were measured by Western blot analysis and akt mRNA levels by Northern blot analysis. The results obtained with the BT474 and SKBR3 cells were validated in the MCF10A ductal cells and in non-invasive MCF-7 breast cancer cells forced into mimicking the in vitro behaviour of the BT474 and SKBR3 cells.

Results

In aggressive breast cancer cells, where mitogenic signalling is enforced by the ErbB2 oncoprotein receptor, functional inhibition of the catalytic activity of PI3K by the βGBP cytokine and loss of akt mRNA results in apoptotic death. A functional correlation between ERK and the kt gene was also found. The relationship between ERK, akt mRNA, PI3K and cell vulnerability to βGBP challenge was sustained both in mammary ductal cells forced to mimic an aggressive behaviour and in non-aggressive breast cancer cells undergoing an enforced shift into an aggressive phenotype.

Conclusions

βGBP, a newly discovered physiological inhibitor of PI3K, is a selective and potent inducer of apoptosis in aggressive breast cancer cells. Due to its physiological nature, which carries no chemotherapeutic disadvantages, βGBP has the potential to be safely tested in clinical trials.
Histone deacetylase inhibition improves differentiation of dendritic cells from leukemic blasts of patients with TEL/AML1-positive acute lymphoblastic leukemia
Authors: Schmidt Kerstin , Seeger Karl , Scheibenbogen Carmen , Bender Roderich , Abdulla Majd , Süssmilch Sina , Salama Abdulgabar , Moldenhauer Anja
Published: January 2009

Histone deacetylase inhibitors (HdI) could potentially improve the differentiation of leukemic dendritic cells (DC). Therefore, bone marrow samples from 100 children with acute lymphoblastic leukemia (ALL) were cultured in the cytokines TNF-α, GM-CSF, c-kit ligand, and fetal liver tyrosine kinase 3 ligand, with or without IL-3 and −4 and after administration of HdI valproic acid (VAL), suberoylanilide hydroxamic acid (SAHA), isobutyramid, or trichostatin A. Among the tested samples, 25 were positive for the chromosomal translocation t(12;21), encoding the fusion gene translocation ETS-like leukemia/acute myeloid leukemia 1 (TEL/AML1). SAHA increased CD83 expression of TEL/AML1-positive blasts in conditions without ILs, and SAHA and VAL increased the number of CD86(+)80(–) cells in the presence of ILs. VAL and isobutyramid supported the allostimulatory capacities of TEL/AML1-positive, leukemic DC; VAL and SAHA reduced those of TEL/AML1-negative DC. Cytotoxic T cells sensitized with leukemic DC produced more IFN-γ and TNF-α upon presentation of the TEL/AML1 peptide. They also induced the cytotoxic lysis of nondifferentiated blasts, which was enhanced when TEL/AML1-positive DC had developed after addition of VAL or SAHA. Therefore, the use of HdI in the differentiation of leukemic DC from patients with TEL/AML1-positive ALL is recommended.
Activation of nucleotide oligomerization domain 2 exacerbates a murine model of proteoglycan-induced arthritis
Authors: Rosenzweig H L , Jann M M , Glant T T , Martin T M , Planck S R , van Eden W , van Kooten P J S , Flavell R A , Kobayashi K S , Rosenbaum J T , Davey M P
Published: January 2009

In addition to its role in innate immunity, nucleotide oligomerization domain 2 (NOD2) has been shown to play a suppressive role in models of colitis. Notably, mutations in NOD2 cause the inherited granulomatous disease of the joints called Blau syndrome, thereby linking NOD2 with joint disease as well. However, the role of NOD2 in joint inflammation has not been clarified. We demonstrate here that NOD2 is functional within the mouse joint and promotes inflammation, as locally or systemically administered muramyl dipeptide (MDP; the NOD2 agonist) resulted in significant joint inflammation that was abolished in NOD2-deficient mice. We then sought to investigate the role of NOD2 in a mouse model of inflammatory arthritis dependent on adaptive immunity using TCR-transgenic mice whose T cells recognized the dominant epitope of proteoglycan (PG). Mice immunized with PG in the presence of MDP developed a more severe inflammatory arthritis and histopathology within the joints. Antigen-specific activation of splenocytes was enhanced by MDP with respect to IFN-γ production, which would be consistent with the Th1-mediated disease in vivo. Intriguingly, NOD2 deficiency did not alter the PG-induced arthritis, indicating that NOD2 does not play an essential role in this model of joint disease when it is not activated by MDP. In conclusion, we demonstrate that in a model of inflammatory arthritis dependent on T and B cell priming, NOD2 activation potentiates disease. However, the absence of NOD2 does not alter the course of inflammatory arthritis, in contrast to models of intestinal inflammation.
Role of atopic status in Toll-like receptor (TLR)7- and TLR9-mediated activation of human eosinophils
Authors: Månsson Anne , Cardell Lars-Olaf
Published: January 2009

Viral respiratory infections are increasingly implicated in allergic exacerbations. The mechanisms behind this are not known, but a virus-induced activation of eosinophils through TLRs could be involved. Herein, we investigated the expression and function of TLR7 and TLR9 in purified eosinophils from peripheral blood and assessed their role in allergic airway inflammation. Eosinophils expressed TLR7 and TLR9 proteins. Stimulation with the cognate ligands R-837 and CpG was found to prolong survival, up-regulate expression of CD11b and conversely down-regulate L-selectin expression, increase expression of the activation marker CD69, facilitate the chemotactic migration, and enhance IL-8 secretion by eosinophils. Also, CpG induced release of eosinophil-derived neurotoxin (EDN), and R-837 failed to do so. Analogously, eosinophils activated by CpG, but not R-837, promoted airway epithelial cell death and cytokine release. Priming with the allergic mediators histamine, IL-4, and most prominently IL-5, augmented the TLR-induced IL-8 and EDN secretion, revealing an ability to sensitize eosinophils for TLR7 and TLR9 activation. Moreover, the TLR responses of eosinophils were higher in allergic as compared with healthy subjects, manifested by an increase in IL-8 and EDN release. Correspondingly, allergic subjects displayed an elevated serum level of IL-5, suggesting increased IL-5-mediated priming. This study shows that activation via TLR7 and TLR9 affects several eosinophil functions and that the atopic status of the donor and the presence of a Th2-like cytokine milieu affect the outcome of the response. Thus, eosinophil activation via TLR7 and TLR9 might engender a link between viral infection and allergic exacerbations.
The Option Value of Returns: Theory and Empirical Evidence
Authors: Anderson Eric T. , Hansen Karsten , Simester Duncan
Published: January 2009

When a firm allows the return of previously purchased merchandise, it provides customers with an option that has measurable value. Whereas the option to return merchandise leads to an increase in gross revenue, it also creates additional costs. Selecting an optimal return policy requires balancing both demand and cost implications. In this paper, we develop a structural model of a consumer's decision to purchase and return an item that nests extant choice models as a special case. The model enables a firm to both measure the value to consumers of the return option and balance the costs and benefits of different return policies.

We apply the model to a sample of data provided by a mail-order catalog company. We find considerable variation in the value of returns across customers and categories. When the option value is large, there are large increases in demand. For example, the option to return women's footwear is worth an average of more than $15 per purchase to customers and increases average purchase rates by more than 50%. We illustrate how the model can be used by a retailer to optimize his return policies across categories and customers.
Identification of Amyloidogenic Light Chains Requires the Combination of Serum-Free Light Chain Assay with Immunofixation of Serum and Urine
Authors: Palladini Giovanni , Russo Paola , Bosoni Tiziana , Verga Laura , Sarais Gabriele , Lavatelli Francesca , Nuvolone Mario , Obici Laura , Casarini Simona , Donadei Simona , Albertini Riccardo , Righetti Gabriella , Marini Maddalena , Graziani Maria Stella , Melzi D'Eril Gian Vico , Moratti Remigio , Merlini Giampaolo
Published: January 2009

Background: The diagnosis of systemic immunoglobulin light-chain (AL) amyloidosis requires demonstration of amyloid deposits in a tissue biopsy and amyloidogenic monoclonal light chains. The optimal strategy to identify the amyloidogenic clone has not been established. We prospectively assessed the diagnostic sensitivity of the serum free light chain (FLC) κ/λ ratio, a commercial serum and urine agarose gel electrophoresis immunofixation (IFE), and the high-resolution agarose gel electrophoresis immunofixation (HR-IFE) developed at our referral center in patients with AL amyloidosis, in whom the amyloidogenic light chain was unequivocally identified in the amyloid deposits.

Methods: The amyloidogenic light chain was identified in 121 consecutive patients with AL amyloidosis by immunoelectron microscopy analysis of abdominal fat aspirates and/or organ biopsies. We characterized the monoclonal light chain by using IFE and HR-IFE in serum and urine and the FLC κ/λ ratio in serum. We then compared the diagnostic sensitivities of the 3 assays.

Results: The HR-IFE of serum and urine identified the amyloidogenic light chain in all 115 patients with a monoclonal gammopathy. Six patients with a biclonal gammopathy were omitted from the statistical analysis. The diagnostic sensitivity of commercial serum and urine IFE was greater than that of the FLC κ/λ ratio (96% vs 76%). The combination of serum IFE and the FLC assay detected the amyloidogenic light chain in 96% of patients. The combination of IFE of both serum and urine with the FLC κ/λ ratio had a 100% sensitivity.

Conclusions: The identification of amyloidogenic light chains cannot rely on a single test and requires the combination of a commercially available FLC assay with immunofixation of both serum and urine.
Involvement of actin and microtubules in regulation of bioluminescence and translocation of chloroplasts in the dinoflagellate Pyrocystis lunula
Authors: Heimann Kirsten , Klerks Paul L. , Hasenstein Karl H.
Published: January 2009

Bioluminescence in Pyrocystis lunula depends on circadian movement of scintillons and chloroplasts between active and inactive locations. The involvement of the cytoskeleton in these transport processes was investigated using cytoskeleton-specific drugs. Chloroplast movements were visualized by chlorophyll autofluorescence and confocal scanning laser microscopy. Latrunculin B and Oryzalin prevented translocation of chloroplasts. Four hours after transition to the night phase, mechanically inducible bioluminescence was inhibited by Latrunculin B, the myosin inhibitor 2,3 butanedione monoxime, and Oryzalin in dose-dependent fashions. The actin stabilizer Jasplakinolide slightly enhanced bioluminescence but eliminated Latrunculin B effects. The microtubule depolymerizer Colchicine had no effect on bioluminescence. These results suggest that F-actin and microtubules are involved in the movements of chloroplasts and scintillons. Although the drugs tested affected bioluminescence, further experiments are needed to determine whether effects on bioluminescence were mediated by drug-induced failed translocations of scintillons or chloroplasts.
Protection mechanisms of DMDHEU treated wood against white and brown rot fungi
Authors: Verma Pradeep , Junga Ulrich , Militz Holger , Mai Carsten
Published: January 2009

The resistance of beech and pine wood blocks treated with 1,3-dimethylol-4,5-dihydroxyethylene urea (DMDHEU) against Trametes versicolor and Coniophora puteana increased with increasing weight percent gain (WPG) of DMDHEU. Full protection [mass loss (ML) below 3%] was reached at WPGs of approximately 15% (beech) and 10% (pine). Untreated and DMDHEU treated blocks were infiltrated with nutrients and thiamine prior to fungal incubation and it was observed whether the destruction or removal of nutrients and vitamins during the modification process has an influence on the ML caused by the fungi. This study revealed that no considerable differences were found. Then, the cell wall integrity was partly destroyed by milling and the decay of the fine wood powder filled into steel mesh bags was compared to that of wood mini-blocks. The purpose of this study was to examine whether the effects of surface area, cell wall bulking, and reduction in micro-void diameters play a role in decay resistance. The ML caused by the fungi, however, also decreased with increasing WPG and showed comparable patterns similar to the case of mini-blocks. ML of powder bearing the highest WPG appeared to be caused by losses in DMDHEU during fungal incubation. For brown rotted wood, the infrared absorption ratios at 1030 cm-1 and 1505 cm-1 revealed decreasing decay of polysaccharides with increasing WPG of treated wood.
Redesigning a Graphic Weather Display for Pilots
Authors: O'Hare David , Stenhouse Neil
Published: January 2009

Before embarking on a flight, pilots need to acquire information about the actual and forecast weather conditions. Concerns have been raised about the traditional coded format used to provide this information. Software developers have recently provided tools for generating both plain-English and graphical versions of these coded weather observations. We show how we successfully applied a number of ergonomic display principles to improve the graphic display of weather information for general aviation pilots.
Morpholine Amide Solvent: A New Inert
Authors: Stern Alan J. , Ferguson David C.
Published: January 2009

A new solvent for agricultural formulation use is described. The solvent, an amide derived from a short chain fatty acid and morpholine, has many desirable physical and chemical properties. In addition to the physical and chemical properties, this paper will present the theoretical Hansen solubility parameters, and present data on solubility of selected agricultural chemicals in the solvent. Briefly, TSCA and FIFRA regulatory requirements for the solvent are covered.
Quantification of Effect of Enforced Cyclic Movement and Regional Exposure Factors on Weatherability of Construction Sealants
Authors: Enomoto Noriyoshi , Ito Akihiko , Tanaka Kyoji
Published: January 2009

This paper presents information on the weatherability of construction sealants based on a newly developed test specimen design that allows simultaneous exposure of the sealant to forced compression and extension movement in a single specimen. In this study, exposure to cyclic movement and weathering is carried out simultaneously. Furthermore, an evaluation method for surface cracks induced by weathering is presented that allows an assessment of the overall “degree of degradation,” a single number characterizing the state of degradation of the sealant surface. In order to study the effects of the extent of extension and compression as well as the regional exposure factors on the degree of degradation, twelve sealants were exposed to outdoor weathering for four years at three exposure sites, located in the northern, central, and southern areas of Japan. The evaluation of surface cracks was carried out according to the rating provided in ISO 4628-4, with the modification that new rating criteria were introduced to evaluate minute cracks. A mathematical equation determining the “degree of degradation” was obtained for each sealant, which is based on a component reflecting aging under static condition and another component reflecting the dynamic conditions induced by mechanical movement and regional exposure factors. This equation provides a reasonable relationship between the experimental observation and calculated degradation over the exposure period.
Strategien zur Regelung von HCCI-BrennverfahrenControl Concepts for a Gasoline HCCI Combustion Engine
Authors: Karrelmeyer Roland , Graf Gerald , Scherrer Daniel , Fischer Wolfgang , Harthout Jean-Pierre
Published: January 2009

Es werden Konzepte zur Regelung eines HCCI-Brennverfahrens (Homogeneous Charge Compression Ignition) mit interner Abgasrückführung (Trapping) bei Otto-Motoren vorgestellt. Die Konzepte basieren auf Verbrennungsmerkmalen, die aus dem Brennraumdrucksignal gewonnen werden. Zur Beeinflussung der Verbrennung stehen die Stellgrößen des Luft- und Kraftstoffsystems zur Verfügung. Die Arbeiten erfolgen an Motoren mit variablem Ventiltrieb mit unterschiedlicher Ausprägung der Variabilität und einem System zur Kraftstoffdirekteinspritzung. Im ersten Schritt wird von einer vollvariablen Ventilsteuerung ausgegangen, die eine zylinderindividuelle Verstellung der Gaswechselventile ermöglicht. Getrieben vom Einsatz kostenoptimaler Ventilsysteme wird in einem zweiten Schritt eine Regelungsstrategie vorgestellt, die diese Vorrausetzung der Zylinderindividualität fallen lässt und auf eine Ventilstrategie setzt, die mit konventionellen Phasenstellern realisierbar ist.