bluuebunny/crossref_metadata_2025 huggingface dataset:
A novel human monoclonal antibody that binds with high affinity to mesothelin-expressing cells and kills them by antibody-dependent cell-mediated cytotoxicity
Authors: Feng Yang , Xiao Xiaodong , Zhu Zhongyu , Streaker Emily , Ho Mitchell , Pastan Ira , Dimitrov Dimiter S.
Published: May 2009

Mesothelin is a potential new target for cancer immunotherapy because it is present at relatively low levels only in mesothelial cells of pleura, peritoneum, and pericardium of healthy people, but is significantly elevated in a number of tumors, including mesothelioma, ovarian, pancreatic, and lung cancers. However, all currently available antibodies against mesothelin are either murine or chimeric, which could limit their use because of increased likelihood of immunogenicity compared with fully human antibodies. Here, we report the identification and characterization of a novel fully human monoclonal antibody, m912, which was isolated from a human Fab library by panning against recombinant mesothelin. This antibody in scFv, Fab, and IgG1 formats bound specifically and with high affinity (equilibrium dissociation constant in the nmol/L range) to cell surface-associated human mesothelin and to recombinant mesothelin. It specifically lysed cancer cells engineered to express mesothelin in the presence of peripheral blood mononuclear cells isolated from healthy donors most likely by antibody-dependent cellular cytotoxicity. M912 is the first reported fully human monoclonal antibody to mesothelin, which has potential for cancer treatment and diagnosis. [Mol Cancer Ther 2009;8(5):1113–8]
Ligation of cancer cell surface GRP78 with antibodies directed against its COOH-terminal domain up-regulates p53 activity and promotes apoptosis
Authors: Misra Uma Kant , Mowery Yvonne , Kaczowka Steven , Pizzo Salvatore Vincent
Published: May 2009

Binding of activated α2-macroglobulin to GRP78 on the surface of human prostate cancer cells promotes proliferation by activating signaling cascades. Autoantibodies directed against the activated α2-macroglobulin binding site in the NH2-terminal domain of GRP78 are receptor agonists, and their presence in the sera of cancer patients is a poor prognostic indicator. We now show that antibodies directed against the GRP78 COOH-terminal domain inhibit [3H]thymidine uptake and cellular proliferation while promoting apoptosis as measured by DNA fragmentation, Annexin V assay, and clonogenic assay. These antibodies are receptor antagonists blocking autophosphorylation and activation of GRP78. Using 1-LN and DU145 prostate cancer cell lines and A375 melanoma cells, which express GRP78 on their cell surface, we show that antibodies directed against the COOH-terminal domain of GRP78 up-regulate the tumor suppressor protein p53. By contrast, antibody directed against the NH2-terminal domain of GRP78 shows negligible effects on p53 expression. PC-3 prostate cancer cells, which do not express GRP78 on their cell surface, are refractory to the effects of anti-GRP78 antibodies directed against either the COOH- or NH2-terminal domains. However, overexpression of GRP78 in PC-3 cells causes translocation of GRP78 to the cell surface and promotes apoptosis when these cells are treated with antibody directed against its COOH-terminal domain. Silencing GRP78 or p53 expression by RNA interference significantly blocked the increase in p53 induced by antibodies. Antibodies directed against the COOH-terminal domain may play a therapeutic role in cancer patients whose tumors trigger the production of autoantibodies directed against the NH2-terminal domain of GRP78. [Mol Cancer Ther 2009;8(5):1350–62]
Dual targeting of AKT and mammalian target of rapamycin: A potential therapeutic approach for malignant peripheral nerve sheath tumor
Authors: Zou Changye Y. , Smith Kerrington D. , Zhu Quan-Sheng , Liu Jun , McCutcheon Ian E. , Slopis John M. , Meric-Bernstam Funda , Peng Zhenghong , Bornmann William G. , Mills Gordon B. , Lazar Alexander J. , Pollock Raphael E. , Lev Dina
Published: May 2009

The mammalian target of rapamycin (mTOR) pathway may constitute a potential target for the treatment of malignant peripheral nerve sheath tumors (MPNST). However, investigations of other cancers suggest that mTOR blockade can paradoxically induce activation of prosurvival, protumorigenic signaling molecules, especially upstream AKT. Consequently, we hypothesized that dual phosphatidylinositol 3-kinase (PI3K)/AKT-mTOR blockade might be applicable for MPNST treatment. Expression of activated mTOR downstream targets (p4EBP1 and pS6RP) and pAKT was evaluated immunohistochemically in a tissue microarray of human MPNSTs (n = 96) and benign neurofibromas (n = 31). Results were analyzed by Wilcoxon rank-sum tests. mTOR and AKT pathways in human MPNST cell lines, and the effects of rapamycin (mTOR inhibitor), LY294002 (dual PI3K/mTOR inhibitor), and PI-103 (potent dual PI3K/AKT-mTOR inhibitor) on pathway activation were evaluated by Western blot. Effects on cell growth were evaluated via MTS and colony formation assays. Cell cycle progression and apoptosis were assessed by propidium iodide/fluorescence-activated cell sorting staining and Annexin V assays. Acridine orange staining/fluorescence-activated cell sorting analysis, electron microscopy, and Western blot evaluated autophagy induction. p4EBP1, pS6Rp, and pAKT levels were found to be significantly higher in MPNST versus neurofibroma (P < 0.05 for all markers). mTOR and AKT pathways were found to be highly activated in MPNST cell lines. MPNST cells were sensitive to rapamycin; however, rapamycin enhanced pAKT and peIF4E expression. PI-103 abrogated MPNST cell growth and induced G1 cell cycle arrest potentially through repression of cyclin D1. PI-103 did not elicit apoptosis but significantly induced autophagy in MPNST cells. These results suggest further study of combined PI3K/AKT and mTOR inhibition as a novel therapy for patients harboring MPNST. [Mol Cancer Ther 2009;8(5):OF1–12]
Potentin vitroandin vivoanticancer activities of des-methyl, des-amino pateamine A, a synthetic analogue of marine natural product pateamine A
Authors: Kuznetsov Galina , Xu Qunli , Rudolph-Owen Lori , TenDyke Karen , Liu Junke , Towle Murray , Zhao Nanding , Marsh Joanne , Agoulnik Sergei , Twine Natalie , Parent Lana , Chen Zhihong , Shie Jue-Lon , Jiang Yimin , Zhang Huiming , Du Hong , Boivin Roch , Wang Yuan , Romo Daniel , Littlefield Bruce A.
Published: May 2009

We report here that des-methyl, des-amino pateamine A (DMDA-PatA), a structurally simplified analogue of the marine natural product pateamine A, has potent antiproliferative activity against a wide variety of human cancer cell lines while showing relatively low cytotoxicity against nonproliferating, quiescent human fibroblasts. DMDA-PatA retains almost full in vitro potency in P-glycoprotein-overexpressing MES-SA/Dx5-Rx1 human uterine sarcoma cells that are significantly resistant to paclitaxel, suggesting that DMDA-PatA is not a substrate for P-glycoprotein-mediated drug efflux. Treatment of proliferating cells with DMDA-PatA leads to rapid shutdown of DNA synthesis in the S phase of the cell cycle. Cell-free studies show that DMDA-PatA directly inhibits DNA polymerases α and γ in vitro albeit at concentrations considerably higher than those that inhibit cell proliferation. DMDA-PatA shows potent anticancer activity in several human cancer xenograft models in nude mice, including significant regressions observed in the LOX and MDA-MB-435 melanoma models. DMDA-PatA thus represents a promising natural product-based anticancer agent that warrants further investigation.[Mol Cancer Ther 2009;8(5):1250–60]
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

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

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]
Detection and Elimination of Microemboli Related to Cardiopulmonary Bypass
Authors: Groom Robert C. , Quinn Reed D. , Lennon Paul , Donegan Desmond J. , Braxton John H. , Kramer Robert S. , Weldner Paul W. , Russo Louis , Blank Seth D. , Christie Angus A. , Taenzer Andreas H. , Forest Richard J. , Clark Cantwell , Welch Janine , Ross Cathy S. , O'Connor Gerald T. , Likosky Donald S.
Published: May 2009

Background—

Neurobehavioral impairment is a common complication of coronary bypass surgery. Cerebral microemboli during cardiopulmonary bypass (CPB) are a principal mechanism of cognitive injury. The aim of this work was to study the occurrence of cerebral embolism during CPB and to evaluate the effectiveness of evidence-based CPB circuit component and process changes on the exposure of the patient to emboli.

Methods and Results—

M-Mode Doppler was used to detect emboli in the inflow and outflow of cardiopulmonary circuit and in the right and left middle cerebral arteries. Doppler signals were merged into a single display to allow real-time associations between discrete clinical techniques and emboli detection. One hundred sixty-nine isolated coronary artery bypass grafting (CABG) patients were studied between 2002 and 2008. There was no statistical difference in median microemboli detected in the inflow of the CPB circuit, (Phase I, 931; Phase II, 1214; Phase III, 1253; Phase IV, 1125; F [3,158]=0.8,
P
=0.96). Significant changes occurred in median microemboli detected in the outflow of the CPB circuit across phases, (Phase I, 702; Phase II, 572; Phase III, 596; Phase IV, 85; F [3,157]=13.1,
P
<0.001). Significant changes also occurred in median microemboli detected in the brain across phases, (Phase I, 604; Phase II, 429; Phase III, 407; Phase IV, 138; F [3,153]=14.4,
P
<0.001). Changes in the cardiopulmonary bypass circuit were associated with an 87.9% (702 versus 85) reduction in median microemboli in the outflow of the CPB circuit (
P
<0.001), and a 77.2% (604 versus 146) reduction in microemboli in the brain (
P
<0.001).

Conclusions—

Changes in CPB techniques and circuit components, including filter size and type of pump, resulted in a reduction in more than 75% of cerebral microemboli.
Cardiovascular Risks of Nonsteroidal Antiinflammatory Drugs in Patients After Hospitalization for Serious Coronary Heart Disease
Authors: Ray Wayne A. , Varas-Lorenzo Cristina , Chung Cecilia P. , Castellsague Jordi , Murray Katherine T. , Stein C. Michael , Daugherty James R. , Arbogast Patrick G. , García-Rodríguez Luis A.
Published: May 2009

Background—

The cardiovascular safety of individual nonsteroidal antiinflammatory drugs (NSAIDs) is highly controversial, particularly in persons with serious coronary heart disease.

Methods and Results—

We conducted a multisite retrospective cohort study of commonly used individual NSAIDs in Tennessee Medicaid, Saskatchewan Health, and United Kingdom General Practice Research databases. The cohort included 48566 patients recently hospitalized for myocardial infarction, revascularization, or unstable angina pectoris with more than 111000 person-years of follow-up. Naproxen users had the lowest adjusted rates of serious coronary heart disease (myocardial infarction, coronary heart disease death) and serious cardiovascular disease (myocardial infarction, stroke)/death from any cause, with respective incidence rate ratios (relative to NSAID nonusers) of 0.88 (95% CI, 0.66 to 1.17) and 0.91 (0.78 to 1.06). Risk did not increase with doses ≥1000 mg. Relative to NSAID nonusers, serious coronary heart disease risk increased with short term (<90 days) use for ibuprofen (1.67 [1.09 to 2.57]), diclofenac (1.86 [1.18 to 2.92]), celecoxib (1.37 [0.96 to 1.94]), and rofecoxib (1.46 [1.03 to 2.07]), but not for naproxen (0.88 [0.50 to 1.55]). Relative to naproxen, current users of diclofenac had increased risk of serious coronary heart disease (1.44 [0.96 to 2.15],
P
=0.076) and serious cardiovascular disease/death (1.52 [1.22 to 1.89],
P
=0.0002), and those of ibuprofen had increased risk of the latter end point (1.25 [1.02 to 1.53],
P
=0.032). Compared to naproxen in doses ≥1000 mg, serious coronary heart disease incidence rate ratios were increased for rofecoxib >25 mg (2.29 [1.24 to 4.22],
P
=0.008) and celecoxib >200 mg (1.61 [1.01 to 2.57],
P
=0.046).

Conclusions—

In patients recently hospitalized for serious coronary heart disease, naproxen had better cardiovascular safety than did diclofenac, ibuprofen, and higher doses of celecoxib and rofecoxib.
The Impact of a Multidisciplinary Information Technology–Supported Program on Blood Pressure Control in Primary Care
Authors: Rinfret Stéphane , Lussier Marie-Thérèse , Peirce Anthony , Duhamel Fabie , Cossette Sylvie , Lalonde Lyne , Tremblay Chantal , Guertin Marie-Claude , LeLorier Jacques , Turgeon Jacques , Hamet Pavel
Published: May 2009

Background—

Hypertension is a leading mortality risk factor yet inadequately controlled in most affected subjects. Effective programs to address this problem are lacking. We hypothesized that an information technology–supported management program could help improve blood pressure (BP) control.

Methods and Results—

This randomized controlled trial included 223 primary care hypertensive subjects with mean 24-hour BP >130/80 and daytime BP >135/85 mm Hg measured with ambulatory monitoring (ABPM). Intervention subjects received a BP monitor and access to an information technology–supported adherence and BP monitoring system providing nurses, pharmacists, and physicians with monthly reports. Control subjects received usual care. The mean (�SD) follow-up was 348 (�78) and 349 (�84) days in the intervention and control group, respectively. The primary end point of the change in the mean 24-hour ambulatory BP was consistently greater in intervention subjects for both systolic (−11.9 versus −7.1 mm Hg;
P
<0.001) and diastolic BP (−6.6 versus −4.5 mm Hg;
P
=0.007). The proportion of subjects that achieved Canadian Guideline target BP (46.0% versus 28.6%) was also greater in the intervention group (
P
=0.006). We observed similar BP declines for ABPM and self-recorded home BP suggesting the latter could be an alternative for confirming BP control. The intervention was associated with more physician-driven antihypertensive dose adjustments or changes in agents (
P
=0.03), more antihypertensive classes at study end (
P
=0.007), and a trend toward improved adherence measured by prescription refills (
P
=0.07).

Conclusions—

This multidisciplinary information technology–supported program that provided feedback to patients and healthcare providers significantly improved blood pressure levels in a primary care setting.
Positive Transcription Elongation Factor b Activity in Compensatory Myocardial Hypertrophy is Regulated by Cardiac Lineage Protein-1
Authors: Espinoza-Derout Jorge , Wagner Michael , Salciccioli Louis , Lazar Jason M. , Bhaduri Sikha , Mascareno Eduardo , Chaqour Brahim , Siddiqui M.A.Q.
Published: May 2009

Emerging evidence illustrates the importance of the positive transcription elongation factor (P-TEF)b in control of global RNA synthesis, which constitutes a major feature of the compensatory response to diverse hypertrophic stimuli in cardiomyocytes. P-TEFb complex, composed of cyclin T and cdk9, is critical for elongation of nascent RNA chains via phosphorylation of the carboxyl-terminal domain of RNA polymerase (Pol) II. We and others have shown that the activity of P-TEFb is inhibited by its association with cardiac lineage protein (CLP)-1, the mouse homolog of human HEXIM1, in various physiological and pathological conditions. To investigate the mechanism of control of P-TEFb activity by CLP-1 in cardiac hypertrophy, we used a transgenic mouse model of hypertrophy caused by overexpression of calcineurin in the heart. We observed that the level of CLP-1 associated with P-TEFb was reduced markedly in hypertrophic hearts. We also generated bigenic mice (MHC–cyclin T1/CLP-1
+/−
) by crossing MHC–cyclin T1 transgenic mice with CLP-1 heterozygote. The bigenic mice exhibit enhanced susceptibility to hypertrophy that is accompanied with an increase in cdk9 activity via an increase in serine 2 phosphorylation of carboxyl-terminal domain and an increase in GLUT1/GLUT4 ratio. These mice have compensated systolic function without evidence of fibrosis and reduced lifespan. These data suggest that the reduced level of CLP-1 introduced in the background of elevated levels of cyclin T1 elevates derepression of P-TEFb activity and emphasizes the importance of the role of CLP-1 in the mechanism governing compensatory hypertrophy in cardiomyocytes.
Linking Social Deprivation and Digital Exclusion in England
Authors: Longley Paul A. , Singleton Alexander D.
Published: May 2009

This paper develops a cross-classification of material deprivation and lack of digital engagement, at a far more spatially disaggregated level than has previously been attempted in the UK. This is achieved by matching the 2004 Index of Multiple Deprivation (IMD) with a unique nation-wide geodemographic classification of ICT usage, aggregated to unit postcodes. The results of the cross-classification suggest that lack of digital engagement and material deprivation are linked, with high levels of material deprivation generally associated with low levels of engagement with ICTs and vice versa. However, some neighbourhoods are `digitally unengaged' but not materially deprived and the paper investigates the extent to which this outcome may be linked to factors such as lack of confidence, skills or motivation. As with material deprivation, there are distinctive regional and local geographies of digital unengagement and these have important implications for digital policy implementation.
How Does Urban Public Transport Change Cities? Correlations between Past and Present Transport and Urban Planning Policies
Authors: Pflieger Geraldine , Kaufmann Vincent , Pattaroni Luca , Jemelin Christophe
Published: May 2009

Is it possible to discern correlations between past and present urban policies? Do path dependencies exist at the urban level? If so, how do they differ from other links between the past and present? A preview of the literature dealing with dependencies and urban change, a presentation of the research methodology and an examination of the historical archives of six European cities in France, Germany and Switzerland enable us to identify three features common to both past and present transport and urban planning policies—namely, contingency, reproduction and innovation.
Effect of Glucose—Insulin—Potassium Infusion on Mortality in Critical Care Settings: A Systematic Review and Meta‐Analysis
Authors: Puskarich Michael A. , Runyon Michael S. , Trzeciak Stephen , Kline Jeffrey A. , Jones Alan E.
Published: May 2009

This study seeks to measure the treatment effect of glucose—insulin—potassium (GIK) infusion on mortality in critically ill patients. A systematic review of randomized controlled trials is conducted, comparing GIK treatment with standard care or placebo in critically ill adult patients. The primary outcome variable is mortality. Two authors independently extract data and assess study quality. The primary analysis is based on the random effects model to produce pooled odds ratios (ORs) with 95% confidence intervals (CIs). The search yields 1720 potential publications; 23 studies are included in the final analysis, providing a sample of 22 525 patients. The combined results demonstrate no heterogeneity (P = .57, I2 = 0%) and no effect on mortality (OR = 1.02; 95% CI, 0.93–1.11) with GIK treatment. No experimental studies of shock or sepsis populations are identified. This meta‐analysis finds that there is no mortality benefit to GIK infusion in critically ill patients; however, study populations are limited to acute myocardial infarction and cardiovascular surgery patients. No studies are identified using GIK in patients with septic shock or other forms of circulatory shock, providing an absence of evidence regarding the effect of GIK as a therapy in patients with shock.
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

Background

Previous 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.

Hypothesis

Intensive, regular, and prolonged dancing causes strain on the lumbar spine and can trigger or accelerate the development of degenerative diskopathy.

Study Design

Cross-sectional study; Level of evidence, 3.

Methods

Forty 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.

Results

Nine 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).

Conclusion

Dancing cannot be considered a risk factor for lumbar disk degeneration in women.

Clinical Relevance

The present study indicates that dancing has no negative effect on the development of degenerative diskopathy.
Municipalities and the Search for the Local Past
Authors: Ochman Ewa
Published: May 2009

In administratively decentralized Poland it is the self-governing and revived municipality that is in charge of historical memory. While urban centers need to respond to a historical heritage that impacts their socioeconomic future, local authorities emerge as active constructors of commemorative practices. To connect with their electorate and define the relationship between the municipality and its citizens, not only in terms of citizens' rights, but also with reference to their responsibilities, they need to draw on a communal past to legitimize their activities and to forge a shared local identity that would promote communal solidarity. Moreover, municipal authorities, while operating in distinct urban landscapes and responding to specific challenges and needs, conduct divergent politics of memory. It is this fragmentation and diversification of commemorative practices at local level that has the most potential to challenge a nationalizing version of historical past propagated by the state.
Improving Medication Error Reporting in Hospice Care
Authors: Boyer Rachel , McPherson Mary Lynn , Deshpande Guarav , Weiss Smith Sheila
Published: May 2009

The aims of this study are to determine the incidence of medication errors, characterize the type/severity of errors, and estimate the impact of an educational intervention on medication error processes in a hospice population. Medication errors from 2 hospice organizations were collected and coded for type of error/ outcome severity. The educational intervention included a 2-hour in-service and twice weekly reminders. A survey to assess participants’ change in knowledge and attitudes regarding medication error reporting through the study period and was administered at 3 different time points. Data analysis revealed that medication error reporting increased in one hospice program, that participants’ ability to correctly identify medication errors increased (P < .001), and awareness of medication errors in hospice care increased (P < .01) after the intervention.
Construct Validation Using Computer-Aided Text Analysis (CATA)
Authors: Short Jeremy C. , Broberg J. Christian , Cogliser Claudia C. , Brigham Keith H.
Published: May 2009

Construct validity continues to pose challenges in the organizational sciences. To capture difficult-to-measure constructs of interest, researchers have often relied on content analysis. One content analysis technique, computer-aided text analysis (CATA), is particularly attractive because of the ability to process large samples with high speeds and reliabilities. Unfortunately, inconsistent guidance exists to guide researchers through the use of this tool in a manner compatible with accepted methods used to validate constructs in a rigorous manner. The authors review research using content analysis to examine the extent to which such studies integrate methods for assessing content, external, discriminant, and predictive validity. To provide direction for organizational researchers interested in using CATA to measure theoretically based constructs relevant to the management field, they suggest a number of possible procedures to enhance construct validity. They illustrate these procedures using the construct of entrepreneurial orientation.
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

Decreased 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

Identifying 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

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

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

Background

Brucellaspp. 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.

Results

B. 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.

Conclusion

ThisBrucellaglobal 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

Background

Chronic 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/Design

We 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.

Discussion

Despite 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 registration

ClinicalTrials.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

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

Background

Recognition 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.

Results

We 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.

Conclusion

It 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.
Proteasome-independent degradation of HIV-1 in naturally non-permissive human placental trophoblast cells
Authors: Ross Anna Laura , Cannou Claude , Barré-Sinoussi Françoise , Menu Elisabeth
Published: May 2009

Background

The human placenta-derived cell line BeWo has been demonstrated to be restrictive to cell-free HIV-1 infection. BeWo cells are however permissive to infection by VSV-G pseudotyped HIV-1, which enters cells by a receptor-independent mechanism, and to infection by HIV-1 via a cell-to-cell route.

Results

Here we analysed viral entry in wild type BeWo (CCR5+, CXCR4+) and BeWo-CD4+ (CD4+, CCR5+, CXCR4+) cells. We report that HIV-1 internalisation is not restricted in either cell line. Levels of internalised p24 antigen between VSV-G HIV-1 pseudotypes and R5 or X4 virions were comparable. We next analysed the fate of internalised virions; X4 and R5 HIV-1 virions were less stable over time in BeWo cells than VSV-G HIV-1 pseudotypes. We then investigated the role of the proteasome in restricting cell-free HIV-1 infection in BeWo cells using proteasome inhibitors. We observed an increase in the levels of VSV-G pseudotyped HIV-1 infection in proteasome-inhibitor treated cells, but the infection by R5-Env or X4-Env pseudotyped virions remains restricted.

Conclusion

Collectively these results suggest that cell-free HIV-1 infection encounters a surface block leading to a non-productive entry route, which either actively targets incoming virions for non-proteasomal degradation, and impedes their release into the cytoplasm, or causes the inactivation of mechanisms essential for viral replication.