bluuebunny/crossref_metadata_2025_split huggingface dataset:
ebTrack: an environmental bioinformatics system built upon ArrayTrack™
Authors: Chen Minjun , Martin Jackson , Fang Hong , Isukapalli Sastry , Georgopoulos Panos G , Welsh William J , Tong Weida 
Published: June 2009

Abstract
ebTrack is being developed as an integrated bioinformatics system for environmental research and analysis by addressing the issues of integration, curation, management, first level analysis and interpretation of environmental and toxicological data from diverse sources. It is based on enhancements to the US FDA developed ArrayTrack™ system through additional analysis modules for gene expression data as well as through incorporation and linkages to modules for analysis of proteomic and metabonomic datasets that include tandem mass spectra. ebTrack uses a client-server architecture with the free and open source PostgreSQL as its database engine, and java tools for user interface, analysis, visualization, and web-based deployment. Several predictive tools that are critical for environmental health research are currently supported in ebTrack, including Significance Analysis of Microarray (SAM). Furthermore, new tools are under continuous integration, and interfaces to environmental health risk analysis tools are being developed in order to make ebTrack widely usable. These health risk analysis tools include the Modeling ENvironment for TOtal Risk studies (MENTOR) for source-to-dose exposure modeling and the DOse Response Information ANalysis system (DORIAN) for health outcome modeling. The design of ebTrack is presented in detail and steps involved in its application are summarized through an illustrative application.
Oncolytic adenovirus mediated Survivin knockdown by RNA interference suppresses human colorectal carcinoma growth in vitro and in vivo
Authors: Shen Wei , Wang Chun-Yi , Wang Xue-Hu , Fu Zhong-Xue 
Published: June 2009

Abstract

Background
Colorectal cancer is a one of the most common alimentary malignancies. Survivin has been proved by many studies to be an ideal target for cancer gene therapy because of its strong anti-apoptotic effect. The reduction of Survivin expression by means of chemically synthesized small interfering RNA or small hairpin RNA expressed from plasmid and resulted growth inhibition of cancer cells had been proved by many studies including ours, but the transfection efficiency was not encouraging. So for the first time we constructed the Survivin shRNA into an oncolytic adenovirus, tested its effects on colorectal cancer cell lines and nude mice xenograft model.

Methods
In this study, we constructed an oncolytic adenovirus with a Survivin targeted small hairpin RNA and a reporter gene (ZD55-Sur-EGFP). The expression of Survivin mRNA and protein were analyzed by RT-PCR and western blot. The cell growth and apoptosis were tested by in vitro cytopathic assay, MTT assay and flow cytometry respectively. The effect of the constructed virus on xenograft model was evaluated by tumor volume and western blot analysis.

Results
ZD55-Sur-EGFP replicated in cancer cells specifically, reduced the expression of Survivin mRNA and protein expression effectively (P < 0.0001), induced cancer cell apoptosis and inhibited SW480 cell growth both in vitro and in vivo significantly.

Conclusion
We conclude Survivin RNA interference combining with oncolytic adenovirus virotherapy to be a promising treatment for colorectal cancer.
Polymorphisms of TGFB1 and VEGF genes and survival of patients with gastric cancer
Authors: Guan Xiaoxiang , Zhao Hui , Niu Jiangong , Tan Dongfeng , Ajani Jaffer A , Wei Qingyi 
Published: June 2009

AbstractBackgroundSomeTGFB1andVEGFpolymorphisms are believed to be functional. Given that these genes are involved in tumor growth and progression including angiogenesis, dissemination, and invasiveness, we hypothesized that these polymorphisms would be associated with survival in patients with gastric cancer.MethodsWe genotypedTGFB1-509 C>T, +1869 T>C, and +915 G>C andVEGF-1498T>C, -634G>C, and +936C>T in 167 patients with gastric cancer. Using the Kaplan and Meier method, log-rank tests, and Cox proportional hazard models, we evaluated associations amongTGFB1andVEGFvariants with overall, 1-year, and 2-year survival rates.ResultsAlthough there were no significant differences in overall survival rates among all polymorphisms tested, patients withTGFB1+915CG and CC genotypes had a poorer 2-year survival (adjusted hazard ratio (HR), 3.06; 95% confidence interval (CI), 1.09–8.62;P= 0.034) than patients with the GG genotype had. In addition, patients heterozygous forVEGF-634CG also had a poorer 1-year survival (adjusted HR, 2.08; 95% CI, 1.03–4.22;P= 0.042) than patients with the -634GG genotype.ConclusionOur study suggested thatTGFB1+915CG/CC andVEGF-634CG genotypes may be associated with short-term survival in gastric cancer patients. However, larger studies are needed to verify these findings.
Early and long-standing rheumatoid arthritis: distinct molecular signatures identified by gene-expression profiling in synovia
Authors: Lequerré Thierry , Bansard Carine , Vittecoq Olivier , Derambure Céline , Hiron Martine , Daveau Maryvonne , Tron François , Ayral Xavier , Biga Norman , Auquit-Auckbur Isabelle , Chiocchia Gilles , Le Loët Xavier , Salier Jean-Philippe 
Published: June 2009

Abstract
Introduction
Rheumatoid arthritis (RA) is a heterogeneous disease and its underlying molecular mechanisms are still poorly understood. Because previous microarray studies have only focused on long-standing (LS) RA compared to osteoarthritis, we aimed to compare the molecular profiles of early and LS RA versus control synovia.

Methods
Synovial biopsies were obtained by arthroscopy from 15 patients (4 early untreated RA, 4 treated LS RA and 7 controls, who had traumatic or mechanical lesions). Extracted mRNAs were used for large-scale gene-expression profiling. The different gene-expression combinations identified by comparison of profiles of early, LS RA and healthy synovia were linked to the biological processes involved in each situation.

Results
Three combinations of 719, 116 and 52 transcripts discriminated, respectively, early from LS RA, and early or LS RA from healthy synovia. We identified several gene clusters and distinct molecular signatures specifically expressed during early or LS RA, thereby suggesting the involvement of different pathophysiological mechanisms during the course of RA.

Conclusions
Early and LS RA have distinct molecular signatures with different biological processes participating at different times during the course of the disease. These results suggest that better knowledge of the main biological processes involved at a given RA stage might help to choose the most appropriate treatment.
Myeloid dendritic cells correlate with clinical response whereas plasmacytoid dendritic cells impact autoantibody development in rheumatoid arthritis patients treated with infliximab
Authors: Richez Christophe , Schaeverbeke Thierry , Dumoulin Chantal , Dehais Joël , Moreau Jean-François , Blanco Patrick 
Published: June 2009

Abstract
Introduction
The objective of our study was to identify the significance of the subtypes of dendritic cell (DC), specifically myeloid DCs (mDCs) and plasmacytoid DCs (pDCs), in rheumatoid arthritis (RA) pathogenesis through their longitudinal follow-up in patients receiving infliximab.

Methods
Circulating mDC and pDC levels were evaluated by flow cytometry in RA patients (n = 61) and healthy volunteers (n = 30). In RA patients, these levels were measured before and during infliximab therapy. Their counts were correlated to RA disease activity markers and anti-nuclear antibody occurrence. IFNα production was measured by ELISA in serum of RA patients and, in vitro, in supernatant of peripheral blood mononuclear cells stimulated by influenza virus in the presence or absence of infliximab. Statistical evaluations were based on Mann–Whitney tests or Wilcoxon's signed-rank tests.

Results
RA patients with active disease were characterized by a baseline decrease in both circulating pDCs and mDCs. Disease activity markers inversely correlated only with mDC level. This level increased in RA patients responsive to infliximab therapy, to reach the level observed in controls. Conversely, anti-nuclear antibody appearance during infliximab therapy correlated inversely with pDC level and was associated with increased serum IFNα level and circulating plasma cells number. In vitro studies revealed that infliximab kept pDCs in an IFNα secreting state upon viral stimulation allowing differentiation of B cells into anti-nuclear antibody-secreting plasma cells.

Conclusions
This study reveals two distinct roles for pDC and mDC in RA. Circulating mDCs mainly contribute to RA activity, whereas pDCs seem to be involved in appearance of anti-nuclear antibodies under infliximab therapy through the ability of this drug to keep pDCs in an IFNα secreting state.
Targeting inhibitor of apoptosis proteins in combination with ErbB antagonists in breast cancer
Authors: Foster Fiona M , Owens Thomas W , Tanianis-Hughes Jolanta , Clarke Robert B , Brennan Keith , Bundred Nigel J , Streuli Charles H 
Published: June 2009

Abstract
Introduction
Inhibitor of apoptosis (IAPs) proteins are a family of proteins that can block apoptosis in normal cells and have been suggested to cause resistance to apoptosis in cancer. Overexpression of oncogenic receptor tyrosine kinases is common in breast cancer; in particular 20% of all cases show elevated Her2. Despite clinical success with the use of targeted therapies, such as Trastuzumab, only up to 35% of Her2-positive patients initially respond. We reasoned that IAP-mediated apoptosis resistance might contribute to this insensitivity to receptor tyrosine kinase therapy, in particular ErbB antagonists. Here we examine the levels of IAPs in breast cancer and evaluate whether targeting IAPs can enhance apoptosis in response to growth factor receptor antagonists and TRAIL.

Methods
IAP levels were examined in a breast cancer cell line panel and in patient samples. IAPs were inhibited using siRNA or cell permeable mimetics of endogenous inhibitors. Cells were then exposed to TRAIL, Trastuzumab, Lapatinib, or Gefitinib for 48 hours. Examining nuclear morphology and staining for cleaved caspase 3 was used to score apoptosis. Proliferation was examined by Ki67 staining.

Results
Four members of the IAP family, Survivin, XIAP, cIAP1 and cIAP2, were all expressed to varying extents in breast cancer cell lines or tumours. MDAMB468, BT474 and BT20 cells all expressed XIAP to varying extents. Depleting the cells of XIAP overcame the intrinsic resistance of BT20 and MDAMB468 cells to TRAIL. Moreover, siRNA-based depletion of XIAP or use of a Smac mimetic to target multiple IAPs increased apoptosis in response to the ErbB antagonists, Trastuzumab, Lapatinib or Gefitinib in Her2-overexpressing BT474 cells, or Gefitinib in EGFR-overexpressing MDAMB468 cells.

Conclusions
The novel findings of this study are that multiple IAPs are concomitantly expressed in breast cancers, and that, in combination with clinically relevant Her2 treatments, IAP antagonists promote apoptosis and reduce the cell turnover index of breast cancers. We also show that combination therapy of IAP antagonists with some pro-apoptotic agents (for example, TRAIL) enhances apoptosis of breast cancer cells. In some cases (for example, MDAMB468 cells), the enhanced apoptosis is profound.
The role of YY1 in reduced HP1α gene expression in invasive human breast cancer cells
Authors: Lieberthal Jason G , Kaminsky Marissa , Parkhurst Christopher N , Tanese Naoko 
Published: June 2009

Abstract
Introduction
Heterochromatin protein 1 (HP1) associates with chromatin by binding to histone H3 and contributes to gene silencing. There are three isoforms of HP1 in mammals: HP1α, β, and γ. Studies have shown that the level of HP1α is reduced in invasive human breast cancer cell lines such as MDA-MB-231 and HS578T compared with non-invasive cell lines such as MCF7 and T47D. It is hypothesized that reduced HP1α expression may lead to impaired epigenetic silencing of genes that are important in the acquisition of an invasive phenotype. We set out to determine whether reduced expression of HP1α in invasive breast cancer cell lines occurs at the level of transcription.

Methods
We used transient transfection assays to investigate the mechanism of differential transcriptional activity of the human HP1α gene promoter in different cell lines. Mutational analysis of putative transcription factor binding sites in an HP1α gene reporter construct was performed to identify transcription factors responsible for the differential activity. SiRNA-mediated knockdown and chromatin immunoprecipitation experiments were performed to determine the role of a specific transcription factor in regulating the HP1α gene.

Results
The transcription factor yin yang 1 (YY1) was found to play a role in differential transcriptional activity of the HP1α gene. Examination of the YY1 protein and mRNA levels revealed that both were reduced in the invasive cell line HS578T compared with MCF7 cells. YY1 knockdown in MCF7 cells resulted in a decreased level of HP1α mRNA, indicating that YY1 positively regulates HP1α expression. Chromatin immunoprecipitation experiments verified YY1 occupancy at the HP1α gene promoter in MCF7 cells but not HS578T cells. Overexpression of YY1 in HS578T cells decreased cell migration in a manner independent of HP1α overexpression.

Conclusions
Our data suggests that a reduction of YY1 expression in breast cancer cells could contribute to the acquisition of an invasive phenotype through increased cell migration as well as by reduced expression of HP1α.
Prevalence of endotoxemia after surgery and its association with ICU length of stay
Authors: Valenza Franco , Fagnani Lorella , Coppola Silvia , Froio Sara , Sacconi Francesca , Tedesco Cecilia , Maffioletti Micol , Pizzocri Marta , Salice Valentina , Ranzi Maria Luisa , Marenghi Cristina , Gattinoni Luciano 
Published: June 2009

Abstract
Introduction
The aim of this observational study was to investigate the prevalence of endotoxemia after surgery and its association with ICU length of stay.

Methods
102 patients admitted to a university ICU after surgery were recruited. Within four hours of admission, functional data were collected and APACHE II severity score calculated. Arterial blood samples were taken and endotoxemia was measured by chemiluminescence (Endotoxin Activity (EA)). Patients were stratified according to their endotoxin levels (low, intermediate and high) and according to their surgical procedures. Differences between endotoxin levels were assessed by ANOVA, accepting P < 0.05 as significant. Data are expressed as mean ± SD.

Results
EA levels were low in 68 (66%) patients, intermediate in 17 (17%) and high in 17 (17%). Age (61 ± 17 years) and APACHE II score 8.3 ± 3.7 (P = 0.542) were not significantly different in the three EA groups. Functional parameters on admission were similar between EA groups: white blood cells 11093 ± 4605 cells/mm3 (P = 0.385), heart rate 76 ± 16 bpm (P = 0.898), mean arterial pressure 88.8 ± 13.6 mmHg (P = 0.576), lactate 1.18 ± 0.77 mmol/L (P = 0.370), PaO2/FiO2 383 ± 109 mmHg (P = 0.474). Patients with high levels of EA were characterized by longer length of stay in the ICU: 1.9 ± 3.0 days in the low EA group, 1.8 ± 1.4 days in intermediate and 5.2 ± 7.8 days in high group (P = 0.038).

Conclusions
17% of our patients were characterized by high levels of endotoxemia as assessed by EA assay, despite their low level of complexity on admission. High levels of endotoxin were associated with a longer ICU length of stay.
Protein disulfide isomerase (PDI) associates with NADPH oxidase and is required for phagocytosis of Leishmania chagasi promastigotes by macrophages
Authors: Santos Célio X C , Stolf Beatriz S , Takemoto Paulo V A , Amanso Angélica M , Lopes Lucia R , Souza Edna B , Goto Hiro , Laurindo Francisco R M 
Published: June 2009

Abstract
Macrophage infection by Leishmania parasite is prone to oxidative stress in a redox-regulated way by protein disulfide isomerase which is closely associated to NADPH oxidase activity.
PDI, a redox chaperone, is involved in host cell uptake of bacteria/viruses, phagosome formation, and vascular NADPH oxidase regulation. PDI involvement in phagocyte infection by parasites has been poorly explored. Here, we investigated the role of PDI in in vitro infection of J774 macrophages by amastigote and promastigote forms of the protozoan Leishmania chagasi and assessed whether PDI associates with the macrophage NADPH oxidase complex. Promastigote but not amastigote phagocytosis was inhibited significantly by macrophage incubation with thiol/PDI inhibitors DTNB, bacitracin, phenylarsine oxide, and neutralizing PDI antibody in a parasite redox-dependent way. Binding assays indicate that PDI preferentially mediates parasite internalization. Bref-A, an ER-Golgi-disrupting agent, prevented PDI concentration in an enriched macrophage membrane fraction and promoted a significant decrease in infection. Promastigote phagocytosis was increased further by macrophage overexpression of wild-type PDI and decreased upon transfection with an antisense PDI plasmid or PDI siRNA. At later stages of infection, PDI physically interacted with L. chagasi, as revealed by immunoprecipitation data. Promastigote uptake was inhibited consistently by macrophage preincubation with catalase. Additionally, loss- or gain-of-function experiments indicated that PMA-driven NADPH oxidase activation correlated directly with PDI expression levels. Close association between PDI and the p22phox NADPH oxidase subunit was shown by confocal colocalization and coimmunoprecipitation. These results provide evidence that PDI not only associates with phagocyte NADPH oxidase but also that PDI is crucial for efficient macrophage infection by L. chagasi.
TLR4-mediated Cox-2 expression increases intestinal ischemia/reperfusion-induced damage
Authors: Moses Tiffany , Wagner Lynn , Fleming Sherry D 
Published: June 2009

Abstract
TLR4 stimulates Cox-2-mediated PGE2 production which is necessary but not sufficient for intestinal ischemia/reperfusion-induced damage and inflammation.
Mesenteric IR induces significant inflammation and immune-mediated mucosal damage. TLR4 is a critical receptor in the induction of the inflammatory response and plays a role in intestinal homeostasis. To determine the role of TLR4 in IR-induced epithelial damage, we performed IR studies using TLR4lps-def and TLR4lps-n mice and analyzed mucosal damage and inflammation. We found that the absence of TLR4 or TLR4-induced signaling attenuated local mucosal damage with significantly decreased cytokine and eicosanoid secretion including PGE2 production. Similar results were seen in MyD88−/− mice. Wild-type mice treated with NS-398 (a Cox-2 inhibitor) not only decreased PGE2 production but also attenuated tissue damage. In contrast, PGE2 was not sufficient to induce damage in the TLR4lps-def mice. Together, these data indicate that TLR4 stimulation of Cox-2 activation of PGE2 production is necessary but not sufficient for intestinal IR-induced damage and inflammation.
The alarmin HMGB1 acts in synergy with endogenous and exogenous danger signals to promote inflammation
Authors: Hreggvidsdottir Hulda Sigridur , Östberg Therese , Wähämaa Heidi , Schierbeck Hanna , Aveberger Ann-Charlotte , Klevenvall Lena , Palmblad Karin , Ottosson Lars , Andersson Ulf , Harris Helena Erlandsson 
Published: June 2009

Abstract
A prototypic mechanism for enhancement of inflammation by an endogenous molecule is described.
The nuclear protein HMGB1 has previously been demonstrated to act as an alarmin and to promote inflammation upon extracellular release, yet its mode of action is still not well defined. Access to highly purified HMGB1 preparations from prokaryotic and eukaryotic sources enabled studies of activation of human PBMC or synovial fibroblast cultures in response to HMGB1 alone or after binding to cofactors. HMGB1 on its own could not induce detectable IL-6 production. However, strong enhancing effects on induction of proinflammatory cytokine production occurred when the protein associated with each of the separate proinflammatory molecules, rhIL-1β, the TLR4 ligand LPS, the TLR9 ligand CpG-ODN, or the TLR1-TLR2 ligand Pam3CSK4. The bioactivities were recorded in cocultures with preformed HMGB1 complexes but not after sequential or simultaneous addition of HMGB1 and the individual ligands. Individual A-box and B-box domains of HMGB1 had the ability to bind LPS and enhance IL-6 production. Heat denaturation of HMGB1 eliminated this enhancement. Cocultures with HMGB1 and other proinflammatory molecules such as TNF, RANKL, or IL-18 did not induce enhancement. HMGB1 thus acts broadly with many but not all immunostimulatory molecules to amplify their activity in a synergistic manner.
The antihypoxia–adenosinergic pathogenesis as a result of collateral damage by overactive immune cells
Authors: Hatfield Stephen , Belikoff Bryan , Lukashev Dmitriy , Sitkovsky Michail , Ohta Akio 
Published: June 2009

AbstractThe consumption of natural A2A adenosine receptor antagonists, such as caffeine, as well as the use of supplemental oxygen during acute inflammation episodes may have undesirable effects.Here, we attract attention to the possibility of iatrogenic exacerbation of immune–mediated tissue damage as a result of the unintended weakening of the tissue–protecting, hypoxia–adenosinergic pathway. These immunosuppressive, anti–inflammatory pathways play a critical and nonredundant role in the protection of normal tissues from collateral damage during an inflammatory response. We believe that it is the tissue hypoxia associated with inflammatory damage that leads to local inhibition of overactive immune cells by activating A2AR and A2BR and stabilizing HIF–1α. We show in an animal model of acute lung injury that oxygenation (i.e., inspiring supplemental oxygen) reverses tissue hypoxia and exacerbates ongoing inflammatory lung tissue damage. However, little has been done to carefully investigate and prevent this in a clinical setting. Similarly, the consumption of caffeine antagonizes A2ARs, resulting in exacerbation of ongoing acute inflammation. It is suggested that although the elimination of hypoxia–adenosinergic immunosuppression is desirable to improve vaccines, it is important to take into account the unintentional effects of supplemental oxygen and caffeine, which may increase collateral, inflammatory tissue damage.
Cognitive–behavioural therapy as an adjunctive treatment in chronic physical illness
Authors: Halford Judith , Brown Tom 
Published: June 2009

SummaryChronic physical illness is a significant risk factor for psychological symptoms, psychiatric disorder and suicide. Properly targeted cognitive–behavioural therapy (CBT) can improve outcomes for people with chronic physical illnesses. This article looks at practical aspects of the use of CBT as part of the overall medical and psychiatric management of chronic physical illness.