bluuebunny/crossref_metadata_2025 huggingface dataset:
The Association between Primary Endometrioid Carcinoma of the Ovary and Synchronous Malignancy of the Endometrium
Authors: van Niekerk Catharina C. , Bulten Johan , Vooijs G. Peter , Verbeek André L. M.
Published: December 2009

Objective. Ovarian and endometrial cancers coincide rather frequently in the same patient. Few data are available on the involvement of the specific morphological subtypes. To identify histological pathways in the synchronous occurrence, a population‐based study was performed in The Netherlands. Methods. Using the national pathology database (PALGA) information of ovarian cancers and of earlier or later cancer in the endometrium was obtained. 5366 Patients were identified with primary malignant epithelial or borderline malignancy. Results. In 157 cases (2.9%) a new primary malignancy in the endometrium was diagnosed (146 within 1 year). The ratio of observed versus expected number of synchronous malignancy in the endometrium was estimated at 3.6 (95% CI: 2.7–4.7). Among 460 ovarian endometrioid carcinoma patients 53 cases showed a second primary endometrial cancer; 40 out of these 53 cases (75.5%) showed at both organ sites an endometrioid adenocarcinoma. Conclusion. These findings suggest an important role for the endometrioid subtype and prompt to mechanism‐based studies incorporating molecular techniques.
Prediction of Survival following First-Line Chemotherapy in Men with Castration-Resistant Metastatic Prostate Cancer
Authors: Armstrong Andrew J. , Garrett-Mayer Elizabeth , de Wit Ronald , Tannock Ian , Eisenberger Mario
Published: December 2009

Purpose: We sought to evaluate predictors of overall survival following progression after systemic chemotherapy in men with metastatic castration-resistant prostate cancer.

Experimental Design: For our study population, we used the TAX327 multicenter randomized phase III trial comparing administration of docetaxel and prednisone every 3 weeks, weekly administration of docetaxel and prednisone, and administration of mitoxantrone and prednisone every 3 weeks. Progression was defined as the earliest of prostate-specific antigen (PSA), tumor, or pain progression. We analyzed predictors of postprogression survival according to both prechemotherapy and postchemotherapy variables with adjustment for potential confounders.

Results: Among 1,006 men, 640 had evaluable information on protocol-defined progression leading to further therapy. Median postprogression survival was 14.5 months. In the multivariable analysis, several pretreatment factors were associated with postprogression survival: pain, performance status, alkaline phosphatase, number of sites of metastatic disease, liver metastases, hemoglobin, PSA, and time since diagnosis. In addition, we found that the number of progression factors (PSA, pain, and tumor size), the duration of first-line chemotherapy, and whether progression occurred during chemotherapy independently predicted postprogression survival. We found evidence for the benefit of continuation of chemotherapy beyond progression only for men who had isolated worsening of pain. A nomogram was constructed and internally validated with a concordance index of 0.70.

Conclusions: An internally validated model to predict postchemotherapy survival was developed. Evaluation of men in the postdocetaxel setting should consider the type of progression, duration of therapy, and known pretreatment prognostic factors. Definitions of progression in castration-resistant prostate cancer that include pain should also consider composite measures of tumor or PSA progression. External validation is planned. Clin Cancer Res; 16(1); 203–11
Topical ‘Sydney’ Propolis Protects against UV-Radiation-Induced Inflammation, Lipid Peroxidation and Immune Suppression in Mouse Skin
Authors: Cole Nerida , Sou Paul W. , Ngo Alanna , Tsang Karen H. , Severino Joseph A.J. , Arun Sondur J. , Duke Colin C. , Reeve Vivienne E.
Published: December 2009

Background: Propolis is a honeybee product that has been used in traditional medicine for antioxidant, immune-stimulating, anti-inflammatory and anti-cancer effects. Here, the potential of the topical application of a crude ethanolic extract of Sydney propolis to protect against UV-radiation-induced impairments associated with an increased risk of photocarcinogenesis has been tested in the hairless mouse. Methods: Solutions providing between 10 and 200 mg/kg propolis were applied to the skin following UV irradiation. The inflammation from exposure to UV (290–400 nm) was quantitated by measurement of increased skinfold thickness; lipid peroxidation was assayed by the induction of thiobarbituric acid reactive species in the skin; immune function was measured by the contact hypersensitivity (CHS) reaction and supported by the changes in epidermal cytokine expression. Results: Propolis protected significantly and dose-dependently against both sunburn oedema and the suppression of CHS, and (at 100 mg/kg) against lipid peroxidation. The overexpression of IL-10 and the depletion of IL-12 characteristic of photoimmune suppression were markedly reduced by propolis. Further, the upregulation of IL-6 was decreased, and the associated induction of haem oxygenase was shown to play a role in propolis skin protection. Conclusions: Sydney propolis was able to effectively reduce cutaneous inflammation, immunosuppression and lipid peroxidation induced by UV exposure. It is concluded that Sydney propolis might have strong beneficial protective effects against photodamage and skin cancer development in humans.
A Toll-Like Receptor 2/6 Agonist Reduces Allergic Airway Inflammation in Chronic Respiratory Sensitisation to Timothy Grass Pollen Antigens
Authors: Fuchs Barbara , Knothe Saskia , Rochlitzer Sabine , Nassimi Matthias , Greweling Marina , Lauenstein Hans-Dieter , Nassenstein Christina , Müller Meike , Ebensen Thomas , Dittrich Anna-Maria , Krug Norbert , Guzman Carlos A. , Braun Armin
Published: December 2009

Background: The hygiene hypothesis negatively correlates the microbial burden of the environment with the prevalence of T helper type 2 (Th2)-related disorders, e.g. allergy and asthma. This is explained by Th1 triggering through pathogen-associated molecular patterns via Toll-like receptors (TLRs). In this study, the biological effects of a TLR2/6 agonist as a potential treatment of allergic inflammation are explored. Methods: In a model of chronic allergic airway inflammation induced by intranasal administration of Timothy grass pollen allergen extract, early TLR agonism and/or interferon (IFN)-γ administration was compared to the therapeutic and immune-modulating effects of dexamethasone with regard to the cellular inflammation and cytokine profiles. Results: Eosinophilic inflammation was clearly reduced by TLR2/6 agonism. This effect was also seen without simultaneous administration of IFN-γ. However, lymphocyte counts were not affected among the different treatment groups. More precise determination of the lymphocyte-mediated immune reaction showed that TLR2/6 agonism induced neither CD4+foxp3+ regulatory T cells in draining lymph nodes nor a pronounced Th1 immune response. In contrast, dexamethasone reduced both sensitisation as well as allergic inflammation and, in addition, CD11c+ antigen-presenting cells in lymph nodes. Our data clearly point to the potential to rebalance Th2-skewed allergic immune responses by therapeutic TLR2/6 agonist administration. Conclusion: The use of the TLR2/6 agonist is a promising therapeutic approach in diseases with an imbalance in T cell responses, such as allergy and asthma.
Regulation of CXCR/IL-8 in Human Airway Epithelial Cells
Authors: Gras Delphine , Tiers Laurent , Vachier Isabelle , de Senneville Laure Denis , Bourdin Arnaud , Godard Philippe , Lehman Sylvain , Chanez Pascal
Published: December 2009

Background: Severe asthma is characterized by neutrophilic inflammation and high levels of interleukin (IL)-8. Airway epithelial cells play a pivotal role in the pathogenesis and chronicity of asthma. The objective of this work was to determine whether CXC receptors were involved in human small airway epithelial cell (SAEC) activity by incubating them with IL-8; the investigation also included a proteomic approach. Methods: IL-6 and intercellular adhesion molecule-1 (ICAM-1) were assessed by ELISA and flow cytometry, respectively. CXCR-1 and CXCR-2 receptor mRNA and protein expressions were analyzed by RT-PCR, immunocytochemistry and flow cytometry. Cells were incubated with different concentrations (0–100 ng/ml) of IL-8. The involvement of both receptors was assessed using specific antibodies. Results: Only the CXCR-1 receptor was expressed in SAECs. IL-8 (50 ng/ml, 12 h) induced the release of IL-6 and had no effect on ICAM-1. Supernatants analyzed by surface enhanced laser desorption ionization time of flight mass spectrometry (SELDI-TOF MS) showed very weak differences in peptide profiles. Interestingly, 4,820-m/z peptide release was detected in the presence of IL-8 and abolished by CXCR-1 antibody. Discussion: The present study illustrated the fact that IL-8 mediated by CXCR-1 increased IL-6. We also highlight the usefulness of SELDI ProteinChip technology to confirm the potential variation of peptide profile. Moreover, we were able to detect the 4,820-m/z peptide secreted in vitro by human airway epithelial cells induced by IL-8 via CXCR-1 receptor. Determination of the protein secretion profile in response to inflammatory stimuli could be an important therapeutic strategy in severe asthma.
Occupational Endotoxin Exposure Reduces the Risk of Atopic Sensitization but Increases the Risk of Bronchial Hyperresponsiveness
Authors: Smit Lidwien A.M. , Heederik Dick , Doekes Gert , Lammers Jan-Willem J. , Wouters Inge M.
Published: December 2009

Background: Microbial exposures in both childhood and adult life are protective against atopy, allergic rhinitis and atopic asthma. In adults, this protective effect is paralleled by an increased prevalence of non-atopic asthma. This study was undertaken to investigate associations between occupational endotoxin exposure and atopic sensitization and bronchial hyperresponsiveness to methacholine (BHR) in agricultural workers. In addition, the role of atopy in endotoxin-related respiratory effects was studied. Methods: Data were available for 427 farmers and agricultural industry workers, for whom airborne endotoxin exposure levels were estimated by 249 personal exposure measurements. Atopy was assessed as specific serum IgE to common inhalant allergens, and respiratory symptoms and personal characteristics by standardized questionnaires. BHR was determined in a subset of 113 subjects. Associations were adjusted for age, sex, smoking and living on a farm during childhood. Results: Endotoxin exposure was positively associated with BHR and wheeze (p < 0.05). In contrast, endotoxin exposure was inversely associated with atopy and IgE to grass pollen (p < 0.001). The proportions of wheeze and BHR that were attributable to atopy were only 16.6 and 32.8%, respectively. Conclusions: High endotoxin exposure is a risk factor for BHR and wheeze, which were characterized by a predominantly non-atopic phenotype. At the same time, endotoxin exposure is related to a reduced risk of atopy and IgE to grass pollen in adults. It is unlikely that this is entirely a result of healthy worker selection, as significant inverse associations between endotoxin and IgE to grass pollen were found regardless of reported allergic symptoms.
Site-Specific Connexin Phosphorylation Is Associated with Reduced Heterocellular Communication between Smooth Muscle and Endothelium
Authors: Straub Adam C. , Johnstone Scott R. , Heberlein Katherine R. , Rizzo Michael J. , Best Angela K. , Boitano Scott , Isakson Brant E.
Published: December 2009

Background/Aims: Myoendothelial junctions (MEJs) represent a specialized signaling domain between vascular smooth muscle cells (VSMC) and endothelial cells (EC). The functional consequences of phosphorylation state of the connexins (Cx) at the MEJ have not been explored. Methods/Results: Application of adenosine 3′,5′-cyclic monophosphate sodium (pCPT) to mouse cremasteric arterioles reduces the detection of connexin 43 (Cx43) phosphorylated at its carboxyl terminal serine 368 site (S368) at the MEJ in vivo. After single-cell microinjection of a VSMC in mouse cremaster arterioles, only in the presence of pCPT was dye transfer to EC observed. We used a vascular cell co-culture (VCCC) and applied the phorbol ester 12-O-tetradecanoylphorbol 13-acetate (PMA) or fibroblast growth factor-2 (FGF-2) to induce phosphorylation of Cx43 S368. This phosphorylation event was associated with a significant reduction in dye transfer and calcium communication. Using a novel method to monitor increases in intracellular calcium across the in vitro MEJ, we noted that PMA and FGF-2 both inhibited movement of inositol 1,4,5-triphosphate (IP3), but to a lesser extent Ca2+. Conclusion: These data indicate that site-specific connexin phosphorylation at the MEJ can potentially regulate the movement of solutes between EC and VSMC in the vessel wall.
Explaining East-West Differences in the Likelihood of Making Favorable Self-Evaluations: The Role of Evaluation Apprehension and Directness of Expression
Authors: Kim Young-Hoon , Chiu Chi-Yue , Peng Siqing , Cai Huajian , Tov William
Published: December 2009

The authors contend that although people in both Eastern and Western cultures are motivated to make favorable self-evaluations, the actual likelihood of expressing favorable self-evaluations in a concrete situation depends on (a) the dominant self-presentation norms in the culture, (b) how salient the norm is in the immediate situation, and (c) the availability of normatively permissible means to make favorable self-evaluations. The authors tested this proposal in three studies. Study 1 showed that given the strong influence of the modesty norm in Eastern cultures, Chinese are more comfortable making favorable self-evaluations when evaluation apprehension pressure in the immediate situation is reduced. Furthermore, Studies 2 and 3 showed that Asian Americans and Chinese are more comfortable making favorable self-evaluations when they can do it indirectly by denying possession of negative traits than when they have to do it directly by claiming possession of positive traits. In contrast, among European Americans, given the relative weak influence of the modesty norm in their culture, they are equally comfortable with making favorable self-evaluations in public and private situations through affirmation of positive self-aspects and repudiation of negative self-aspects.
Dialecticism and the Co-occurrence of Positive and Negative Emotions Across Cultures
Authors: Spencer-Rodgers Julie , Peng Kaiping , Wang Lei
Published: December 2009

Emotional complexity (the co-occurrence of positive and negative affect) is more prevalent in East Asian than North American cultures. Although researchers have attributed this robust finding to dialectical thinking (tolerance of contradiction), this hypothesis has not been experimentally tested. In this study, dialectical thinking about salient life events was manipulated among mainland Chinese and Euro-American participants, and increased dialectical thinking led to greater emotional complexity. Moreover, Chinese exhibited greater dialectical thinking and emotional complexity than did Euro-Americans, and cultural differences in emotional complexity were mediated by a direct measure of dialecticism (Dialectical Self Scale).
Review Essay: Perspectival Realism, Representational Models, and the Social Sciences
Authors: Brante Thomas
Published: December 2009

In this book, Ronald Giere seeks to resolve the opposition between objectivism and constructivism by suggesting a third way, perspectival realism, according to which both sides are partly right. To prove his case, Giere reconstructs some of the acknowledged puzzle pieces in the philosophy of science (theory, observation, etc.). To my mind, of most interest is the piece Giere calls “representional model.” Constituting the basis of every science, it functions as a template that governs data collection as well as theory development. Throughout the book, Giere illustrates his various propositions with examples taken from the natural sciences. I contend that the propositions are just as relevant for the social sciences and present some examples in order to indicate this. Especially, the concept of model is useful both for a better understanding of social science and for increasing its cumulativity.
The Limits of Mindreading
Authors: Erneling Christina E.
Published: December 2009

Contemporary cognitive psychology is dominated by an individualistic and mentalistic approach to the mind.This Cartesian heritage is evident in studies of social understanding, that is, how we understand others. It is argued that this approach and metaphors like reading minds have failed, and should be replaced with a discursive approach, where public and shared socio-linguistic intenand normative activities order and shape individual mental activities.
The Thin Red Line
Authors: Taylor Brian D. , Kim Eugene J. , Gahbauer John E.
Published: December 2009

Many critics of the federal transit finance program in the United States have argued that grantsmanship excessively influences the planning process, as local officials pressure transportation planners to produce cost and ridership forecasts that favor locally preferred projects. This article extends this critique from cost and patronage forecasting to other aspects of transit planning, particularly routing and tunneling safety evaluations, through a case study of the planning for the Wilshire “Red Line” subway in Los Angeles—a long-debated and still active project. Specifically, we examine the decision-making process behind the decades of planning of the Wilshire Red Line subway, which has seen conventional routing and alignment studies alternately manipulated, ignored, and blocked in response to the shifting views of key public officials. While political influence over planning processes is both inevitable and probably desirable, the extent to which modal, cost, ridership, and route analyses of the proposed Wilshire subway have been crafted, manipulated, and ignored to serve prevailing, if ever shifting, local political preferences calls into question the role and legitimacy of such analyses.
The Impact of Subregional Variations in Urban Sprawl on the Prevalence of Obesity and Related Morbidity
Authors: Lathey Vasudha , Guhathakurta Subhrajit , Aggarwal Rimjhim M.
Published: December 2009

This article examines the relationship between urban sprawl and health using a new methodological approach that accounts for the subregional variation in the different attributes of sprawl in metropolitan regions. We have developed several indicators of sprawl at the neighborhood level, including compactness, land use mix, automobile dependency, transportation connectivity, and walkability. We then use multinomial logistic models to estimate the contribution of these characteristics to the formation of high- and low-disease-prevalence clusters. Results indicate the significant role of walkability, percentage open space, and commute burden in explaining the prevalence of obesity and related diseases.
Effects of Individual Development Accounts (IDAs) on Household Wealth and Saving Taste
Authors: Jin Huang
Published: December 2009

This study examines effects of individual development accounts (IDAs) on household wealth of low-income participants. Methods: This study uses longitudinal survey data from the American Dream Demonstration (ADD) involving experimental design (treatment group = 537, control group = 566). Results: Results from quantile regression analysis indicate that IDA participants had more household financial assets, controlling for household saving taste and other demographic variables. Program participants did not reshuffle existing assets into IDAs and IDA savings was new household wealth. Low-wealth participants benefited more from the program than those with relatively more wealth. In addition, program participation changed participants’ saving behaviors and improved household saving taste. Conclusions: IDAs facilitate asset accumulation among low-income households. Implications for social work practice are discussed.
Intermittent Cancer Pain: Clinical Importance and an Updated Cancer Pain Classification
Authors: Lasheen Wael , Walsh Declan , Sarhill Nabeel , Davis Mellar
Published: December 2009

Aim: We report the characteristics of intermittent cancer pain. In addition, we propose a new clinically based classification. Methods: Consecutive patients with cancer referred to our palliative medicine service were consented and underwent a comprehensive pain evaluation including available laboratory and radiological studies, at the time of initial contact. Results and discussion: In total, 100 consecutive patients reported 158 different pain sites. Pain temporal pattern observed was 60% of patients had continuous (CP) plus intermittent pain (IP); 29% IP alone; and 11% CP alone. The etiology of IP was somatic (58%), visceral (24%), neuropathic (7%), and mixed (11%). Median duration of IP was 4 months with a median daily frequency of 4 episodes. Consequently, we propose that IP be classified into IP alone or nonbreakthrough pain (NBP; because there is no underlying CP or around-the-clock [ATC] opioids used) and breakthrough pain (BP; because there is underlying CP or/and ATC opioids used). We propose that both BP and NBP be each subclassified into 3 categories: (1) incident, (2) non-incident, and (3) mixed. In addition, a 4th category exclusive to BP: end-of-dose failure. Incident pains made up (N = 42, 47%) nearly half of all IP. According to our classification, incident pain was part of BP in 41% (N = 25) or NBP in 58% (N = 17). Incident NBP received less treatment than incident BP, and it was less controlled. Conclusion: (1) Intermittent pain is a major problem in patients with cancer, (2) NBP is a common but under-recognized form of cancer pain, (3) NBP is less defined and controlled than BP, (4) incident NBP accounts for 40% of all incident cancer pain, and (5) variable IP definitions and classifications make comparisons between studies difficult.
Assessing Changes in the Effect of Divorce Rates on Homicide Rates Across Large U.S. Cities, 1960-2000: Revisiting the Chicago School
Authors: Beaulieu Mark , Messner Steven F.
Published: December 2009

Researchers commonly include a measure of the level of divorce among the standard covariates in macro-level studies of homicide, justifying this practice with reference to social disorganization theory. We review the underlying logic for a divorce/homicide relationship, distinguishing between a “cultural/normative conflict” variant advanced by the classical Chicago School theorists and a “structural/control” variant associated with the neosocial disorganization perspective. We suggest that the cultural/normative conflict variant implies that the effects of divorce will become attenuated over time, whereas the structural/control variant implies stability in effects. We then assess the degree to which the effects of levels of divorce on homicide rates have changed with panel data for a sample of large U.S. cities during the period 1960-2000.The results of seemingly unrelated regression (SUR) analyses reveal considerable stability in the effects of a measure of divorce on homicide rates, especially if the divorce measure is combined with a “sibling” measure of family disorganization—the percentage of children not living with two parents. Our analyses suggest that the commonly observed positive effect of measures of divorce on homicide rates over recent decades is most plausibly interpreted with reference to the “structural/control” arguments associated with the neosocial disorganization perspective.
Cooperative Party Factions in American Politics
Authors: Koger Gregory , Masket Seth , Noel Hans
Published: December 2009

What are the primary factions within the Democratic and Republican parties, and to what extent do rival factions cooperate? We address these questions using a unique data set of information sharing between party organizations, media outlets, 527s, and interest groups. Using social network methods, we identify two major information-sharing clusters, or expanded party networks; these networks correspond to a liberal/Democratic grouping and a conservative/Republican grouping. We further identify factions within each party network, but we find a high degree of cooperation between party factions. That is, our data suggest that beneath the intraparty disagreements we observe in primary elections and policy debates there is a subterranean pattern of organizational cooperation.
Welfare Epics? The Rhetoric of Rewards in World of Warcraft
Authors: Paul Christopher A.
Published: December 2009

After the Lead Content Designer of World of Warcraft (WoW), Tigole, deemed a new set of rewards ‘‘welfare’’ epics, the WoW player community responded in a multitude of fascinating ways. Using rhetorical analysis, gaming studies literature, and a critical analysis of welfare discourse, four rhetorical strategies can be seen in the discourse produced by the playing community. From directly confronting Tigole’s statements to lamenting a loss of avatar capital and analyzing the role the changes have on the multiplayer aspects of the game, the rhetoric of ‘‘welfare’’ epics offers unique insights into the importance of balance and scarcity in the normative structures of WoW, how players accept and perpetuate the belief that rewards in online games should be ‘‘earned,’’ and how WoW’s system of rewards has been fundamentally altered since the game’s launch.
The 2008 Physical Activity Guidelines for Americans: Implications for Clinical and Public Health Practice
Authors: Pate Russell R. , Yancey Antronette K. , Kraus William E.
Published: December 2009

The US government released its first formal recommendations on physical activity, the Physical Activity Guidelines for Americans, in 2008. By issuing the guidelines, the government has established increased physical activity as a major societal health target for the 21st century. The guidelines include recommendations of the types and amounts of physical activity that people should perform to gain important health benefits. Physicians and other health care providers can help people attain and maintain regular physical activity by providing advice on how to be active, appropriate types of activities, and ways to reduce the risk of injuries. Although training for providers on how to counsel patients about physical activity is limited, training of future providers offers an opportunity to improve this area of medical education. Public health practitioners have shifted their efforts to promote physical activity toward an environmental focus, usually incorporating organizational and community-level interventions. As federal health policy moves toward a greater emphasis on prevention of chronic diseases, it is expected that new resources will become available to support physical activity promotion in health care and public health settings. Familiarity with the guidelines should aid professionals in medicine and public health in responding effectively to these new expectations and opportunities.
Maintaining Weight Loss Momentum After Bariatric Surgery
Authors: Terre Lisa
Published: December 2009

Bariatric surgery holds considerable promise for initiating weight loss in extreme obesity. Yet, potential long-term benefits may not be fully realized without sustained lifestyle amelioration. This review discusses some key contributing dynamics as well as future research considerations for optimizing outcomes following weight loss surgery.
LOX-1 as a natural IFN-α–mediated signal for apoptotic cell uptake and antigen presentation in dendritic cells
Authors: Parlato Stefania , Romagnoli Giulia , Spadaro Francesca , Canini Irene , Sirabella Paolo , Borghi Paola , Ramoni Carlo , Filesi Ilaria , Biocca Silvia , Gabriele Lucia , Belardelli Filippo
Published: December 2009

The identification of molecules responsible for apoptotic cell (AC) uptake by dendritic cells (DCs) and induction of T-cell immunity against AC-associated antigens is a challenge in immunology. DCs differentiated in the presence of interferon-α (IFN-α–conditioned DCs) exhibit a marked phagocytic activity and a special attitude in inducing CD8+ T-cell response. In this study, we found marked overexpression of the scavenger receptor oxidized low-density lipoprotein receptor 1 (LOX-1) in IFN-α–conditioned DCs, which was associated with increased levels of genes belonging to immune response families and high competence in inducing T-cell immunity against antigens derived from allogeneic apoptotic lymphocytes. In particular, the capture of ACs by IFN-α DCs led to a substantial subcellular rearrangement of major histocompatibility complex class I and class II molecules, along with enhanced cross-priming of autologous CD8+ T cells and CD4+ T-cell activation. Remarkably, AC uptake, CD8+ T-cell cross-priming, and, to a lesser extent, priming of CD4+ T lymphocytes were inhibited by a neutralizing antibody to the scavenger receptor LOX-1 protein. These results unravel a novel LOX-1–dependent pathway by which IFN-α can, under both physiologic and pathologic conditions, render DCs fully competent for presenting AC-associated antigens for cross-priming CD8+ effector T cells, concomitantly with CD4+ T helper cell activation.
Prediction of protein-protein interaction sites using an ensemble method
Authors: Deng Lei , Guan Jihong , Dong Qiwen , Zhou Shuigeng
Published: December 2009

Background

Prediction of protein-protein interaction sites is one of the most challenging and intriguing problems in the field of computational biology. Although much progress has been achieved by using various machine learning methods and a variety of available features, the problem is still far from being solved.

Results

In this paper, an ensemble method is proposed, which combines bootstrap resampling technique, SVM-based fusion classifiers and weighted voting strategy, to overcome the imbalanced problem and effectively utilize a wide variety of features. We evaluate the ensemble classifier using a dataset extracted from 99 polypeptide chains with 10-fold cross validation, and get a AUC score of 0.86, with a sensitivity of 0.76 and a specificity of 0.78, which are better than that of the existing methods. To improve the usefulness of the proposed method, two special ensemble classifiers are designed to handle the cases of missing homologues and structural information respectively, and the performance is still encouraging. The robustness of the ensemble method is also evaluated by effectively classifying interaction sites from surface residues as well as from all residues in proteins. Moreover, we demonstrate the applicability of the proposed method to identify interaction sites from the non-structural proteins (NS) of the influenza A virus, which may be utilized as potential drug target sites.

Conclusion

Our experimental results show that the ensemble classifiers are quite effective in predicting protein interaction sites. The Sub-EnClassifiers with resampling technique can alleviate the imbalanced problem and the combination of Sub-EnClassifiers with a wide variety of feature groups can significantly improve prediction performance.
In silico method for systematic analysis of feature importance in microRNA-mRNA interactions
Authors: Xiao Jiamin , Li Yizhou , Wang Kelong , Wen Zhining , Li Menglong , Zhang Lifang , Guang Xuanmin
Published: December 2009

Background

MicroRNA (miRNA), which is short non-coding RNA, plays a pivotal role in the regulation of many biological processes and affects the stability and/or translation of mRNA. Recently, machine learning algorithms were developed to predict potential miRNA targets. Most of these methods are robust but are not sensitive to redundant or irrelevant features. Despite their good performance, the relative importance of each feature is still unclear. With increasing experimental data becoming available, research interest has shifted from higher prediction performance to uncovering the mechanism of microRNA-mRNA interactions.

Results

Systematic analysis of sequence, structural and positional features was carried out for two different data sets. The dominant functional features were distinguished from uninformative features in single and hybrid feature sets. Models were developed using only statistically significant sequence, structural and positional features, resulting in area under the receiver operating curves (AUC) values of 0.919, 0.927 and 0.969 for one data set and of 0.926, 0.874 and 0.954 for another data set, respectively. Hybrid models were developed by combining various features and achieved AUC of 0.978 and 0.970 for two different data sets. Functional miRNA information is well reflected in these features, which are expected to be valuable in understanding the mechanism of microRNA-mRNA interactions and in designing experiments.

Conclusions

Differing from previous approaches, this study focused on systematic analysis of all types of features. Statistically significant features were identified and used to construct models that yield similar accuracy to previous studies in a shorter computation time.
Performance of the tuberculin skin test and interferon-γ release assay for detection of tuberculosis infection in immunocompromised patients in a BCG-vaccinated population
Authors: Kim Eun Young , Lim Ju Eun , Jung Ji Ye , Son Ji Young , Lee Kyung Jong , Yoon Yoe Wun , Park Byung Hoon , Moon Jin Wook , Park Moo Suk , Kim Young Sam , Kim Se Kyu , Chang Joon , Kang Young Ae
Published: December 2009

Background

Interferon-γ release assay (IGRA) may improve diagnostic accuracy for latent tuberculosis infection (LTBI). This study compared the performance of the tuberculin skin test (TST) with that of IGRA for the diagnosis of LTBI in immunocompromised patients in an intermediate TB burden country where BCG vaccination is mandatory.

Methods

We conducted a retrospective observational study of patients given the TST and an IGRA, the QuantiFERON-TB Gold In-Tube (QFT-IT), at Severance Hospital, a tertiary hospital in South Korea, from December 2006 to May 2009.

Results

Of 211 patients who underwent TST and QFT-IT testing, 117 (55%) were classified as immunocompromised. Significantly fewer immunocompromised than immunocompetent patients had positive TST results (10.3% vs. 27.7%, p 0.001), whereas the percentage of positive QFT-IT results was comparable for both groups (21.4% vs. 25.5%). However, indeterminate QFT-IT results were more frequent in immunocompromised than immunocompetent patients (21.4% vs. 9.6%, p 0.021). Agreement between the TST and QFT-IT was fair for the immunocompromised group (κ = 0.38), but moderate agreement was observed for the immunocompetent group (κ = 0.57). Indeterminate QFT-IT results were associated with anaemia, lymphocytopenia, hypoproteinemia, and hypoalbuminemia.

Conclusion

In immunocompromised patients, the QFT-IT may be more sensitive than the TST for detection of LTBI, but it resulted in a considerable proportion of indeterminate results. Therefore, both tests may maximise the efficacy of screening for LTBI in immunocompromised patients.
Concerns about anti-angiogenic treatment in patients with glioblastoma multiforme
Authors: Verhoeff Joost JC , van Tellingen Olaf , Claes An , Stalpers Lukas JA , van Linde Myra E , Richel Dirk J , Leenders William PJ , van Furth Wouter R
Published: December 2009

Background

The relevance of angiogenesis inhibition in the treatment of glioblastoma multiforme (GBM) should be considered in the unique context of malignant brain tumours. Although patients benefit greatly from reduced cerebral oedema and intracranial pressure, this important clinical improvement on its own may not be considered as an anti-tumour effect.

Discussion

GBM can be roughly separated into an angiogenic component, and an invasive or migratory component. Although this latter component seems inert to anti-angiogenic therapy, it is of major importance for disease progression and survival. We reviewed all relevant literature. Published data support that clinical symptoms are tempered by anti-angiogenic treatment, but that tumour invasion continues. Unfortunately, current imaging modalities are affected by anti-angiogenic treatment too, making it even harder to define tumour margins. To illustrate this we present MRI, biopsy and autopsy specimens from bevacizumab-treated patients.

Moreover, while treatment of other tumour types may be improved by combining chemotherapy with anti-angiogenic drugs, inhibiting angiogenesis in GBM may antagonise the efficacy of chemotherapeutic drugs by normalising the blood-brain barrier function.

Although angiogenesis inhibition is of considerable value for symptom reduction in GBM patients, lack of proof of a true anti-tumour effect raises concerns about the place of this type of therapy in the treatment of GBM.
Whole blood angiopoietin-1 and -2 levels discriminate cerebral and severe (non-cerebral) malaria from uncomplicated malaria
Authors: Conroy Andrea L , Lafferty Erin I , Lovegrove Fiona E , Krudsood Srivicha , Tangpukdee Noppadon , Liles W Conrad , Kain Kevin C
Published: December 2009

Background

Severe and cerebral malaria are associated with endothelial activation. Angiopoietin-1 (ANG-1) and angiopoietin-2 (ANG-2) are major regulators of endothelial activation and integrity. The aim of this study was to investigate the clinical utility of whole blood angiopoietin (ANG) levels as biomarkers of disease severity in Plasmodium falciparum malaria.

Methods

The utility of whole blood ANG levels was examined in Thai patients to distinguish cerebral (CM; n = 87) and severe (non-cerebral) malaria (SM; n = 36) from uncomplicated malaria (UM; n = 70). Comparative statistics are reported using a non-parametric univariate analysis (Kruskal-Wallis test or Chi-squared test, as appropriate). Multivariate binary logistic regression was used to examine differences in whole blood protein levels between groups (UM, SM, CM), adjusting for differences due to ethnicity, age, parasitaemia and sex. Receiver operating characteristic curve analysis was used to assess the diagnostic accuracy of the ANGs in their ability to distinguish between UM, SM and CM. Cumulative organ injury scores were obtained for patients with severe disease based on the presence of acute renal failure, jaundice, severe anaemia, circulatory collapse or coma.

Results

ANG-1 and ANG-2 were readily detectable in whole blood. Compared to UM there were significant decreases in ANG-1 (p < 0.001) and significant increases in ANG-2 (p < 0.001) levels and the ratio of ANG-2: ANG-1 (p < 0.001) observed in patients with SM and CM. This effect was independent of covariates (ethnicity, age, parasitaemia, sex). Further, there was a significant decrease in ANG-1 levels in patients with SM (non-cerebral) versus CM (p < 0.001). In participants with severe disease, ANG-2, but not ANG-1, levels correlated with cumulative organ injury scores; however, ANG-1 correlated with the presence of renal dysfunction and coma. Receiver operating characteristic curve analysis demonstrated that the level of ANG-1, the level of ANG-2 or the ratio of ANG-2: ANG-1 discriminated between individuals with UM and SM (area under the curve, p-value: ANG-2, 0.763, p < 0.001; ANG-1, 0.884, p < 0.001; Ratio, 0.857, p < 0.001) or UM and CM (area under the curve, p-value: ANG-2, 0.772, p < 0.001; ANG-1, 0.778, p < 0.001; Ratio, 0.820, p < 0.001).

Conclusions

These results suggest that whole blood ANG-1/2 levels are promising clinically informative biomarkers of disease severity in malarial syndromes.
Perceived body image in men and women with type 2 diabetes mellitus: correlation of body mass index with the figure rating scale
Authors: Bays Harold E , Bazata Debbra D , Fox Kathleen M , Grandy Susan , Gavin James R ,   SHIELD Study Group
Published: December 2009

Background

Body mass index (BMI) is often used as an objective surrogate estimate of body fat. Increased BMI is directly associated with an increase in metabolic disease, such as type 2 diabetes mellitus (T2DM). The Stunkard Figure Rating Scale (FRS) is a subjective measure of body fat, and self-perceptions of body image conceivably impact the development and treatment of T2DM. This study examined the self-perception of body image to various levels of BMI among those with T2DM.

Methods

Respondents (n = 13,887) to the US
S
tudy to
H
elp
I
mprove
E
arly evaluation and management of risk factors
L
eading to
D
iabetes (SHIELD) 2006 survey self-reported their weight and height for BMI calculation. On the gender-specific Stunkard FRS, respondents selected the figure most closely resembling their body image. Spearman correlation was computed between perceived body image and BMI for men and women separately. Student's t-test analysis compared the mean BMI differences between respondents with and without T2DM.

Results

Men with T2DM did not significantly differ from men without diabetes mellitus in mean BMI per body image figure except at the extremes in body figures. Women with T2DM had a significantly higher BMI for the same body figure compared with women without diabetes mellitus for most figures (p < 0.05).

Conclusions

Individuals, particularly women, with T2DM may differ in their perception of body image compared with those without diabetes mellitus. It is unclear if these perceived differences increase the risk of T2DM, or if the diagnosis of T2DM alters body image perceptions.
RNA interference as a gene silencing therapy for mutant MYOC protein in primary open angle glaucoma
Authors: Li Mao , Xu Jianjiang , Chen Xueli , Sun Xinghuai
Published: December 2009

Background

Primary open-angle glaucoma (POAG) is the most common form of glaucoma which is an irreversible blind leading disease and lacks effective remedies. In recent years, POAG has been linked to the gene MYOC encoding myocilin that has been identified to harbor causal mutations. A variety of studies show that the mutant myocilin acts by gain of function. The mutant MYOC protein induces endoplasmic reticulum (ER) stress and the resultant unfolded protein response (UPR) induces apoptosis in the trabecular meshwork cells, which then leads to an increase in resistance to aqueous humor outflow, elevated intraocular pressure (IOP), and, ultimately, glaucoma. Culturing human trabecular meshwork (HTM) cells at a condition facilitating protein folding promotes secretion of mutant myocilin, normalizes cell morphology and reverses cell lethality.

Presentation of the Hypothesis

We speculate that a complete elimination of mutant myocilin expression in trabecular meshwork cells is safe and that gives the possibility of avoiding the POAG phenotype.

Testing the Hypothesis

We propose RNA interference (RNAi) as a gene silencing therapy to eliminate the mutant myocilin proteins in the trabecular meshwork cells, either in a mutation-dependent or mutation-independent way due to the different engineering of the small interfering (si) RNA.

Implications of the Hypothesis

The RNAi strategy can reverse the pathological process of trabecular meshwork cells and thus treat the POAG caused by myocilin gene mutation. This strategy can also be applicable to many protein-misfolding diseases caused by gain-of-function mutant proteins.
Sustained Activity of the EGF Receptor Is an Absolute Requisite for LH-Induced Oocyte Maturation and Cumulus Expansion
Authors: Reizel Yitzhak , Elbaz Judith , Dekel Nava
Published: December 2009

Mammalian reproduction depends on the release of a mature oocyte from the ovarian follicle. Maturation of the oocyte and rupture of the follicle wall constitute part of the responses to the preovulatory surge of LH, which also include cumulus expansion and granulosa cell luteinization. It was previously shown that the epidermal growth factor receptor (EGFR) mediates the ovulatory response to LH in the ovarian follicle. We hypothesized that it is a sustained activity of the EGFR that generates oocyte maturation and cumulus expansion. We demonstrated that, whereas a transient exposure of rat isolated, intact, preovulatory follicles to either LH or forskolin was sufficient to induce oocyte maturation and cumulus expansion, these LH-induced responses were only generated upon a prolonged activity of the EGFR. In addition, the continuous activity of the EGFR is essential for the chronic phosphorylation of the ERK1/2 downstream signaling molecules, which were shown to be essential for oocyte maturation and cumulus expansion. Interestingly, EGFR-sustained activity was also necessary to maintain the up-regulation of Ptgs2, a gene essential for cumulus expansion. The unusual prolonged duration of ERK1/2 activity may possibly be attributed to the late induction of the ERK-specific phosphatase 3, demonstrated herein. These new data shed light on the unique characteristics of EGFR-ERK1/2 activity in the ovarian follicle and emphasize the fact that the ovulatory process involves a nonclassical activation of this pathway.
N-WASP is a novel regulator of hair-follicle cycling that controls antiproliferative TGFβ pathways
Authors: Lefever Tine , Pedersen Esben , Basse Astrid , Paus Ralf , Quondamatteo Fabio , Stanley Alanna C. , Langbein Lutz , Wu Xunwei , Wehland Jürgen , Lommel Silvia , Brakebusch Cord
Published: December 2009

N-WASP is a cytoplasmic molecule mediating Arp2/3 nucleated actin polymerization. Mice with a keratinocyte-specific deletion of the gene encoding N-WASP showed normal interfollicular epidermis, but delayed hair-follicle morphogenesis and abnormal hair-follicle cycling, associated with cyclic alopecia and prolonged catagen and telogen phases. The delayed anagen onset correlated with an increased expression of the cell-cycle inhibitor p21CIP, and increased activity of the TGFβ pathway, a known inducer of p21CIP expression. Primary N-WASP-null keratinocytes showed reduced growth compared with control cells and enhanced expression of the gene encoding the cell-cycle inhibitor p15INK4B, a TGFβ target gene. Inhibition of TGFβ signaling blocked overexpression of p15INK4B and restored proliferation of N-WASP-deficient keratinocytes in vitro. However, induction of N-WASP gene deletion in vitro did not result in obvious changes in TGFβ signaling or growth of keratinocytes, indicating that the in vivo environment is required for the phenotype development. These data identify the actin nucleation regulator N-WASP as a novel element of hair-cycle control that modulates the antiproliferative and pro-apoptotic TGFβ pathway in keratinocytes in vivo and in vitro.
Integrin activation by Fam38A uses a novel mechanism of R-Ras targeting to the endoplasmic reticulum
Authors: McHugh Brian J. , Buttery Robert , Lad Yatish , Banks Stephen , Haslett Christopher , Sethi Tariq
Published: December 2009

The integrin family of heterodimeric cell-surface receptors are fundamental in cell-cell and cell-matrix adhesion. Changes to either integrin-ligand affinity or integrin gene expression are central to a variety of disease processes, including inflammation, cardiovascular disease and cancer. In screening for novel activators of integrin-ligand affinity we identified the previously uncharacterised multi-transmembrane domain protein Fam38A, located at the endoplasmic reticulum (ER). siRNA knockdown of Fam38A in epithelial cells inactivates endogenous β1 integrin, reducing cell adhesion. Fam38A mediates integrin activation by recruiting the small GTPase R-Ras to the ER, which activates the calcium-activated protease calpain by increasing Ca2+ release from cytoplasmic stores. Fam38A-induced integrin activation is blocked by inhibition of either R-Ras or calpain activity, or by siRNA knockdown of talin, a well-described calpain substrate. This highlights a novel mechanism for integrin activation by Fam38A, utilising calpain and R-Ras signalling from the ER. These data represent the first description of a novel spatial regulator of R-Ras, of an alternative integrin activation-suppression pathway based on direct relocalisation of R-Ras to the ER, and of a mechanism linking R-Ras and calpain signalling from the ER with modulation of integrin-ligand affinity.