bluuebunny/crossref_metadata_2025_split huggingface dataset:
Darinaparsin induces a unique cellular response and is active in an arsenic trioxide-resistant myeloma cell line
Authors: Matulis Shannon M. , Morales Alejo A. , Yehiayan Lucy , Croutch Claire , Gutman Delia , Cai Yong , Lee Kelvin P. , Boise Lawrence H. 
Published: May 2009

Abstract
Here, we report on the organic arsenical darinaparsin (ZIO-101, S-dimethylarsino-glutathione) and its anti-myeloma activity compared with inorganic arsenic trioxide. Darinaparsin induced apoptosis in multiple myeloma cell lines in a dose-dependent manner, and the addition of N-acetylcysteine, which increases intracellular glutathione (GSH), blocked cytotoxicity of both darinaparsin and arsenic trioxide. In contrast to arsenic trioxide, intracellular GSH does not appear to be important for darinaparsin metabolism, as an inhibitor of GSH synthesis, buthionine sulfoximine, had little effect on drug activity. This discrepancy was resolved when we determined the effects of thiols on drug uptake. The addition of exogenous GSH, l-cysteine, or d-cysteine prevented darinaparsin cellular uptake and cell death but had no effect on the uptake or activity of arsenic trioxide, suggesting a difference in the transport mechanism of these two drugs. In addition, gene expression profiling revealed differences in the signaling of protective responses between darinaparsin and arsenic trioxide. Although both arsenicals induced a transient heat shock response, only arsenic trioxide treatment induced transcription of metal response genes and anti-oxidant genes related to the Nrf2-Keap1 pathway. In contrast to the protective responses, both arsenicals induced up-regulation of BH3-only proteins. Moreover, silencing of BH3-only proteins Noxa, Bim, and Bmf protected myeloma cells from darinaparsin-induced cell death. Finally, treatment of an arsenic trioxide-resistant myeloma cell line with darinaparsin resulted in dose-dependent apoptosis, indicating that cross-resistance does not necessarily develop between these two forms of arsenic in multiple myeloma cell lines. These results suggest darinaparsin may be useful as an alternative treatment in arsenic trioxide-resistant hematologic cancers.[Mol Cancer Ther 2009;8(5):OF1–10]
Cell surface profiling with peptide libraries yields ligand arrays that classify breast tumor subtypes
Authors: Dane Karen Y. , Gottstein Claudia , Daugherty Patrick S. 
Published: May 2009

Abstract
Cancer heterogeneity renders risk stratification and therapy decisions challenging. Thus, genomic and proteomic methodologies have been used in an effort to identify biomarkers that can differentiate tumor subtypes to improve therapeutic outcome. Here, we report a generally applicable strategy to generate tumor type–specific peptide ligand arrays. Peptides that specifically recognize breast tumor-derived cell lines (MDA-MB-231, MCF-7, and T47-D) were identified using cell-displayed peptide libraries carrying an intrinsic fluorescent marker allowing for sorting and characterization with quantitative flow cytometry. Tumor cell specificity was achieved by depleting libraries of ligands binding to normal mammary epithelial cells (HMEC and MCF-10A). Although integrin binding RGD motifs were favored by some cell lines, screening with RGD competitors yielded several novel consensus motifs exhibiting improved tumor specificity. The resultant peptide array contained multiple consensus motifs exhibiting strong similarity to breast tumor–associated proteins. Profiling a panel of breast cancer cell lines with the peptide array revealed receptor expression patterns distinctive for luminal or basal tumor subtypes. In addition, peptide displaying bacteria and peptide functionalized microparticles enabled fluorescent labeling of tumor cells and frozen tumor tissue sections. Our results indicate that cell surface profiling using highly specific breast tumor cell binding ligands may provide an efficient route for tumor subtype classification, biomarker identification, and for the development of targeted diagnostics and therapeutics. [Mol Cancer Ther 2009;8(5):1312–8]
Comment On: Probiotic Prophylaxis in Predicted Severe Acute Pancreatitis: A Randomized, Double‐Blind, Placebo‐Controlled Trial
Authors: McClave Stephen A. , Heyland Daren K. , Wischmeyer Paul E. 
Published: May 2009

BACKGROUND: Infectious complications and associated mortality are a major concern in acute pancreatitis. Enteral administration of probiotics could prevent infectious complications, but convincing evidence is scarce. Our aim was to assess the effects of probiotic prophylaxis in patients with predicted severe acute pancreatitis. METHODS: In this multicentre randomised, double‐blind, placebo‐controlled trial, 298 patients with predicted severe acute pancreatitis (Acute Physiology and Chronic health Evaluation [APACHE II] score > or =8, Imrie score > or =3, or C‐reactive protein >150 mg/L) were randomly assigned within 72 h of onset of symptoms to receive a multispecies probiotic preparation (n = 153) or placebo (n = 145), administered enterally twice daily for 28 days. The primary endpoint was the composite of infectious complications—ie, infected pancreatic necrosis, bacteraemia, pneumonia, urosepsis, or infected ascites—during admission and 90‐day follow‐up. Analyses were by intention to treat. This study is registered, number ISRCTN38327949. FINDINGS: One person in each group was excluded from analyses because of incorrect diagnoses of pancreatitis; thus, 152 individuals in the probiotics group and 144 in the placebo group were analysed. Groups were much the same at baseline in terms of patients' characteristics and disease severity. Infectious complications occurred in 46 (30%) patients in the probiotics group and 41 (28%) of those in the placebo group (relative risk 1.06, 95% CI 0.75‐1.51). 24 (16%) patients in the probiotics group died, compared with nine (6%) in the placebo group (relative risk 2.53, 95% CI 1.22‐5.25). Nine patients in the probiotics group developed bowel ischaemia (eight with fatal outcome), compared with none in the placebo group (p = 0.004). INTERPRETATION: In patients with predicted severe acute pancreatitis, probiotic prophylaxis with this combination of probiotic strains did not reduce the risk of infectious complications and was associated with an increased risk of mortality. Probiotic prophylaxis should therefore not be administered in this category of patients. (Lancet. 2008;371:651‐659)Besselink MG, van Santvoort HC, Buskens E, et al; Dutch Acute Pancreatitis Study Group
Magnetic Resonance Study of Lumbar Disks in Female Dancers
Authors: Capel Antonio , Medina Fernando Santonja , Medina Daniel , Gómez Sebastian 
Published: May 2009

BackgroundPrevious imaging studies have shown that degenerative disk disease is more common in the competitive female gymnast than in asymptomatic nonathletic people of the same age training to any degree. However, results of exposure-discordant monozygotic and classic twin studies suggest that physical loading specific to occupation and sport has a relatively minor role in disk degeneration, beyond that of upright postures and routine activities of daily living.HypothesisIntensive, regular, and prolonged dancing causes strain on the lumbar spine and can trigger or accelerate the development of degenerative diskopathy.Study DesignCross-sectional study; Level of evidence, 3.MethodsForty volunteer female dancers (20 ballet and 20 flamenco) aged between 18 and 31 years (mean = 24.2) underwent magnetic resonance imaging of the lumbar spine. They were compared against a control group of 20 women of the same age. A descriptive analysis was done, and the 2 groups were compared by contingency table analysis using the Pearson chi-square test complemented by an analysis of residuals.ResultsNine of the 20 women (45%) in the control group had disk degeneration compared with 13 of the 40 (32.5%) women in the dancer group, with a chi-square of 0.897 (not significant). There were 12 degenerated disks of the 100 explored (12%) in the control group compared with 21 of the 200 explored (10.5%) in the dancer group (chi-square = 0.153; not significant).ConclusionDancing cannot be considered a risk factor for lumbar disk degeneration in women.Clinical RelevanceThe present study indicates that dancing has no negative effect on the development of degenerative diskopathy.
Anti-DKK1 mAb (BHQ880) as a potential therapeutic agent for multiple myeloma
Authors: Fulciniti Mariateresa , Tassone Pierfrancesco , Hideshima Teru , Vallet Sonia , Nanjappa Puru , Ettenberg Seth A. , Shen Zhenxin , Patel Nipun , Tai Yu-tzu , Chauhan Dharminder , Mitsiades Constantine , Prabhala Rao , Raje Noopur , Anderson Kenneth C. , Stover David R. , Munshi Nikhil C. 
Published: May 2009

AbstractDecreased activity of osteoblasts (OBs) contributes to osteolytic lesions in multiple myeloma (MM). The production of the soluble Wnt inhibitor Dickkopf-1 (DKK1) by MM cells inhibits OB activity, and its serum level correlates with focal bone lesions in MM. Therefore, we have evaluated bone anabolic effects of a DKK1 neutralizing antibody (BHQ880) in MM. In vitro BHQ880 increased OB differentiation, neutralized the negative effect of MM cells on osteoblastogenesis, and reduced IL-6 secretion. In a severe combined immunodeficiency (SCID)–hu murine model of human MM, BHQ880 treatment led to a significant increase in OB number, serum human osteocalcin level, and trabecular bone. Although BHQ880 had no direct effect on MM cell growth, it significantly inhibited growth of MM cells in the presence of bone marrow stromal cells (BMSCs) in vitro. This effect was associated with inhibition of BMSC/MM cell adhesion and production of IL-6. In addition, BHQ880 up-regulated β-catenin level while down-regulating nuclear factor-κB (NF-κB) activity in BMSC. Interestingly, we also observed in vivo inhibition of MM cell growth by BHQ880 treatment in the SCID-hu murine model. These results confirm DKK1 as an important therapeutic target in myeloma and provide the rationale for clinical evaluation of BHQ880 to improve bone disease and to inhibit MM growth.
A chromosome 16 quantitative trait locus regulates allogeneic bone marrow engraftment in nonmyeloablated mice
Authors: Cao Thai M. , Thomas Alun , Wang Yuanyuan , Tsai Schickwann , Logronio Kathryn , Shizuru Judith A. 
Published: May 2009

AbstractIdentifying genes that regulate bone marrow (BM) engraftment may reveal molecular targets for overcoming engraftment barriers. To achieve this aim, we applied a forward genetic approach in a mouse model of nonmyeloablative BM transplantation. We evaluated engraftment of allogeneic and syngeneic BM in BALB.K and B10.BR recipients. This allowed us to partition engraftment resistance into its intermediate phenotypes, which are firstly the immune-mediated resistance and secondly the nonimmune rejection of donor BM cells. We observed that BALB.K and B10.BR mice differed with regard to each of these resistance mechanisms, thereby providing evidence that both are under genetic control. We then generated a segregating backcross (n = 200) between the BALB.K and B10.BR strains to analyze for genetic linkage to the allogeneic BM engraftment phenotype using a 127-marker genome scan. This analysis identified a novel quantitative trait locus (QTL) on chromosome 16, termed Bmgr5 (logarithm of odds 6.4, at 11.1 cM). The QTL encodes susceptibility alleles, from the BALB.K strain, that are permissive for allogeneic BM engraftment. Further identification of Bmgr5 genes by positional cloning may reveal new and effective approaches for overcoming BM engraftment obstacles.
Open Biomedical Ontology-based Medline exploration
Authors: Xuan Weijian , Dai Manhong , Mirel Barbara , Song Jean , Athey Brian , Watson Stanley J , Meng Fan 
Published: May 2009

Abstract

Background
Effective Medline database exploration is critical for the understanding of high throughput experimental results and the development of novel hypotheses about the mechanisms underlying the targeted biological processes. While existing solutions enhance Medline exploration through different approaches such as document clustering, network presentations of underlying conceptual relationships and the mapping of search results to MeSH and Gene Ontology trees, we believe the use of multiple ontologies from the Open Biomedical Ontology can greatly help researchers to explore literature from different perspectives as well as to quickly locate the most relevant Medline records for further investigation.

Results
We developed an ontology-based interactive Medline exploration solution called PubOnto to enable the interactive exploration and filtering of search results through the use of multiple ontologies from the OBO foundry. The PubOnto program is a rich internet application based on the FLEX platform. It contains a number of interactive tools, visualization capabilities, an open service architecture, and a customizable user interface. It is freely accessible at: http://brainarray.mbni.med.umich.edu/brainarray/prototype/pubonto.
Mutations in genes involved in nonsense mediated decay ameliorate the phenotype of sel-12 mutants with amber stop mutations in Caenorhabditis elegans
Authors: Gontijo Alisson M , Aubert Sylvie , Roelens Ingele , Lakowski Bernard 
Published: May 2009

Abstract

Background
Presenilin proteins are part of a complex of proteins that can cleave many type I transmembrane proteins, including Notch Receptors and the Amyloid Precursor Protein, in the middle of the transmembrane domain. Dominant mutations in the human presenilin genes PS1 and PS2 lead to Familial Alzheimer's disease. Mutations in the Caenorhabditis elegans sel-12 presenilin gene cause a highly penetrant egg-laying defect due to reduction of signalling through the lin-12/Notch receptor. Mutations in six spr genes (for s uppressor of pr esenilin) are known to strongly suppress sel-12. Mutations in most strong spr genes suppress sel-12 by de-repressing the transcription of the largely functionally equivalent hop-1 presenilin gene. However, how mutations in the spr-2 gene suppress sel-12 is unknown.

Results
We show that spr-2 mutations increase the levels of sel-12 transcripts with Premature translation Termination Codons (PTCs) in embryos and L1 larvae. mRNA transcripts from sel-12 alleles with PTCs undergo degradation by a process known as Nonsense Mediated Decay (NMD). However, spr-2 mutations do not appear to affect NMD. Mutations in the smg genes, which are required for NMD, can restore sel-12(PTC) transcript levels and ameliorate the phenotype of sel-12 mutants with amber PTCs. However, the phenotypic suppression of sel-12 by smg genes is nowhere near as strong as the effect of previously characterized spr mutations including spr-2. Consistent with this, we have identified only two mutations in smg genes among the more than 100 spr mutations recovered in genetic screens.

Conclusion

spr-2 mutations do not suppress sel-12 by affecting NMD of sel-12(PTC) transcripts and appear to have a novel mechanism of suppression. The fact that mutations in smg genes can ameliorate the phenotype of sel-12 alleles with amber PTCs suggests that some read-through of sel-12(amber) alleles occurs in smg backgrounds.
Brucella melitensis global gene expression study provides novel information on growth phase-specific gene regulation with potential insights for understanding Brucella:host initial interactions
Authors: Rossetti Carlos A , Galindo Cristi L , Lawhon Sara D , Garner Harold R , Adams L Garry 
Published: May 2009

AbstractBackgroundBrucellaspp. are the etiological agents of brucellosis, a zoonotic infectious disease that causes abortion in animals and chronic debilitating illness in humans. NaturalBrucellainfections occur primarily through an incompletely defined mechanism of adhesion to and penetration of mucosal epithelium. In this study, we characterized changes in genome-wide transcript abundance of the most and the least invasive growth phases ofB. melitensiscultures to HeLa cells, as a preliminary approach for identifying candidate pathogen genes involved in invasion of epithelial cells.ResultsB. melitensisat the late logarithmic phase of growth are more invasive to HeLa cells than mid-logarithmic or stationary growth phases. Microarray analysis ofB. melitensisgene expression identified 414 up- and 40 down-regulated genes in late-log growth phase (the most invasive culture) compared to the stationary growth phase (the least invasive culture). As expected, the majority of up-regulated genes in late-log phase cultures were those associated with growth, including DNA replication, transcription, translation, intermediate metabolism, energy production and conversion, membrane transport, and biogenesis of the cell envelope and outer membrane; while the down-regulated genes were distributed among several functional categories.ConclusionThisBrucellaglobal expression profile study provides novel information on growth phase-specific gene expression. Further characterization of some genes found differentially expressed in the most invasive culture will likely bring new insights into the initial molecular interactions betweenBrucellaand its host.
ICE COLD ERIC – International collaborative effort on chronic obstructive lung disease: exacerbation risk index cohorts – Study protocol for an international COPD cohort study
Authors: Siebeling Lara , ter Riet Gerben , van der Wal Willem M , Geskus Ronald B , Zoller Marco , Muggensturm Patrick , Joleska Irena , Puhan Milo A 
Published: May 2009

AbstractBackgroundChronic Obstructive Pulmonary Disease (COPD) is a systemic disease; morbidity and mortality due to COPD are on the increase, and it has great impact on patients' lives. Most COPD patients are managed by general practitioners (GP). Too often, GPs base their initial assessment of patient's disease severity mainly on lung function. However, lung function correlates poorly with COPD-specific health-related quality of life and exacerbation frequency. A validated COPD disease risk index that better represents the clinical manifestations of COPD and is feasible in primary care seems to be useful. The objective of this study is to develop and validate a practical COPD disease risk index that predicts the clinical course of COPD in primary care patients with GOLD stages 2–4.Methods/DesignWe will conduct 2 linked prospective cohort studies with COPD patients from GPs in Switzerland and the Netherlands. We will perform a baseline assessment including detailed patient history, questionnaires, lung function, history of exacerbations, measurement of exercise capacity and blood sampling. During the follow-up of at least 2 years, we will update the patients' profile by registering exacerbations, health-related quality of life and any changes in the use of medication. The primary outcome will be health-related quality of life. Secondary outcomes will be exacerbation frequency and mortality. Using multivariable regression analysis, we will identify the best combination of variables predicting these outcomes over one and two years and, depending on funding, even more years.DiscussionDespite the diversity of clinical manifestations and available treatments, assessment and management today do not reflect the multifaceted character of the disease. This is in contrast to preventive cardiology where, nowadays, the treatment in primary care is based on patient-specific and fairly refined cardiovascular risk profile corresponding to differences in prognosis. After completion of this study, we will have a practical COPD-disease risk index that predicts the clinical course of COPD in primary care patients with GOLD stages 2–4. In a second step we will incorporate evidence-based treatment effects into this model, such that the instrument may guide physicians in selecting treatment based on the individual patients' prognosis.Trial registrationClinicalTrials.gov Archive NCT00706602
Predation and fragmentation portrayed in the statistical structure of prey time series
Authors: Hendrichsen Ditte K , Topping Chris J , Forchhammer Mads C 
Published: May 2009

Abstract

Background
Statistical autoregressive analyses of direct and delayed density dependence are widespread in ecological research. The models suggest that changes in ecological factors affecting density dependence, like predation and landscape heterogeneity are directly portrayed in the first and second order autoregressive parameters, and the models are therefore used to decipher complex biological patterns. However, independent tests of model predictions are complicated by the inherent variability of natural populations, where differences in landscape structure, climate or species composition prevent controlled repeated analyses. To circumvent this problem, we applied second-order autoregressive time series analyses to data generated by a realistic agent-based computer model. The model simulated life history decisions of individual field voles under controlled variations in predator pressure and landscape fragmentation. Analyses were made on three levels: comparisons between predated and non-predated populations, between populations exposed to different types of predators and between populations experiencing different degrees of habitat fragmentation.

Results
The results are unambiguous: Changes in landscape fragmentation and the numerical response of predators are clearly portrayed in the statistical time series structure as predicted by the autoregressive model. Populations without predators displayed significantly stronger negative direct density dependence than did those exposed to predators, where direct density dependence was only moderately negative. The effects of predation versus no predation had an even stronger effect on the delayed density dependence of the simulated prey populations. In non-predated prey populations, the coefficients of delayed density dependence were distinctly positive, whereas they were negative in predated populations. Similarly, increasing the degree of fragmentation of optimal habitat available to the prey was accompanied with a shift in the delayed density dependence, from strongly negative to gradually becoming less negative.

Conclusion
We conclude that statistical second-order autoregressive time series analyses are capable of deciphering interactions within and across trophic levels and their effect on direct and delayed density dependence.
TLR2 and TLR4 triggering exerts contrasting effects with regard to HIV-1 infection of human dendritic cells and subsequent virus transfer to CD4+T cells
Authors: Thibault Sandra , Fromentin Rémi , Tardif Mélanie R , Tremblay Michel J 
Published: May 2009

AbstractBackgroundRecognition of microbial products through Toll-like receptors (TLRs) initiates inflammatory responses orchestrated by innate immune cells such as dendritic cells (DCs). As these cells are patrolling mucosal surfaces, a portal of entry for various pathogens including human immunodeficiency virus type-1 (HIV-1), we investigated the impact of TLR stimulation on productive HIV-1 infection of DCs and viral spreading to CD4+T cells.ResultsWe report here that engagement of TLR2 on DCs increases HIV-1 transmission toward CD4+T cells by primarily affectingde novovirus production by DCs. No noticeable and consistent effect was observed following engagement of TLR5, 7 and 9. Additional studies indicated that both HIV-1 infection of DCs and DC-mediated virus transmission to CD4+T cells were reduced upon TLR4 triggering due to secretion of type-I interferons.ConclusionIt can thus be proposed that exposure of DCs to TLR2-binding bacterial constituents derived, for example, from pathogens causing sexually transmissible infections, might influence the process of DC-mediated viral dissemination, a phenomenon that might contribute to a more rapid disease progression.