bluuebunny/crossref_metadata_2025_split huggingface dataset:
Multiplexed genetic profiling of human blood platelets using fluorescent microspheres
Authors: Zhu Wei , Bahou Wadie F. , Gnatenko Dmitri V. 
Published: October 2008

SummaryHuman platelets have unique and reproducible mRNA profiles, with evidence for distinct profiles in haematopoietic stem cell disorders associated with thrombocytosis. Platelet transcript profiling is traditionally studied by microarray analysis, quantitative reverse transcription-PCR or serial analysis of gene ex-pression,techniques that are labor- and technically-intensive.We have now applied a novel multiplex-based platform for quantitative transcript profiling of human platelets.Simultaneous quantification of 17 platelet transcripts was assayed using intact platelet-rich plasma or gel-filtered platelets lysed in vitro.Accurate and reproducible profiles could be obtained from as few as 5 X 107 platelets (a platelet mass corresponding to ∼100 µl of whole blood), even for the low-abundant platelet transcripts. Correlation coefficients of this 17-member gene set to platelet Affymetrix microarrays were excellent (r2 = 0.949, p < 1 X 10–10), with no correlation to in kind-derived leukocyte profiles, highlighting the cell-specificity of the platform.These data demonstrate that transcript multiplexing using fluorescent micro-spheres can be adapted for rapid molecular profiling using intact platelets (bypassing the need for RNA isolation methods), with potential applicability irrespective of baseline platelet counts.
Treatment of acute pulmonary embolism as outpatients or following early discharge
Authors: Janjua Muhammad , Badshah Aaref , Matta Fadi , Danescu Liviu G. , Yaekoub Abdo Y. , Stein Paul D. 
Published: October 2008

SummaryThe purpose of this systematic review is to test the hypothesis that carefully selected low-risk patients with acute pulmonary embolism (PE) can safely be treated entirely as outpatients or after early hospital discharge.Included articles were required to describe inclusion or exclusion criteria and outcome of patients treated for PE.Early hospital discharge was defined as an average hospital stay ≤3 days.Six investigations included patients with PE who were treated entirely as outpatients; two investigations included patients with PE who were treated after early discharge. All investigations included only low-risk patients or patients with small or medium sized PE. Outcome after 3-46 months in patients treated entirely as outpatients showed recurrent PE in 0% to 6.2% of patients, major bleeding in 0% to 2.8% with one death from an intracerebral bleed. Definite death from PE did not occur, but there was one possible death from PE. Outcome in three months in patients treated after early discharge showed no instances of recurrent PE. Major bleeding occurred in 0% to 3.7% of patients.There were no deaths from PE, but there was one death from bleeding. In conclusion, outpatient therapy of acute PE is probably safe in low-risk,carefully selected compliant patients who have access to outpatient care if necessary. Such outpatient treatment would be cost-effective.
Characterization of calcium- and integrin-binding protein 1 (CIB1) knockout platelets: Potential compensation by CIB family members
Authors: Temple Brenda R. , Gentry Holly R. , DeNofrio Jan C. , Yuan Weiping , Parise Leslie V. 
Published: October 2008

SummaryPlatelet aggregation requires activation of the αIIbβ3 integrin,an event regulated by the integrin cytoplasmic tails. CIB1 binds to the cytoplasmic tail of the integrin αIIb subunit. Previous overexpression and knockdown studies in murine megakaryocytes demonstrated that CIB1 inhibits integrin αIIbβ3 activation.Here we analyzed Cib1-/-
mice to determine the function of CIB1 in platelets in vitro and in vivo. We found that although these mice had no overt platelet phenotype, mRNA level of CIB1 homolog CIB3 was increased in Cib1-/-
megakaryocytes. In vitro binding experiments showed that recombinant CIB1, -2 and -3 bound specifically to an αIIb cytoplasmic tail peptide. Subsequent protein modeling experiments indicated that CIBs 1–3 each have a highly conserved hydrophobic binding pocket. Therefore, the potential exists for compensation for the loss of CIB1 by these CIB family members, thereby preventing pathologic thrombus formation in Cib1-/-
mice.
Clinical outcome of patients with major bleeding after venous thromboembolism
Authors: Nieto José , Camara Timoteo , Gonzalez-Higueras Elena , Ruiz-Gimenez Nuria , Guijarro Ricardo , Marchena Pablo , Monreal Manuel ,   for the RIETE Investigators
Published: October 2008

SummaryThe natural history of patients with venous thromboembolism (VTE) who develop a major bleeding complication while on anticoagulant therapy is not well known. RIETE is a prospective registry of consecutive patients with symptomatic, objectively confirmed, acute VTE. The clinical characteristics, treatment decisions and outcome of all VTE patients who had major bleeding during the first three months of anticoagulant therapy were retrospectively studied. As of January 2007, 17,368 patients were included in RIETE. Of these, 407 (2.3%) had major bleeding during the study period: 144 gastrointestinal, 119 haematoma, 51 intracranial, 43 genitourinary, 50 other. In 286 (69%) patients anticoagulant therapy was discontinued, in 74 (18%) not modified, in 38 (9.1%) a vena cava filter was inserted. During the first 30 days after bleeding, 24 (5.9%) patients re-bled, 20 (4.9%) had recurrent VTE, 133 (33%) died. Of these, 75 died of bleeding, 12 of recurrent pulmonary embolism. Most deaths occurred shortly after the bleeding episode (median:1 day).On multivariate analysis, insertion of a vena cava filter was the only variable independently associated with a lower incidence of fatal bleeding (odds ratio [OR]: 0.10; 95% confidence interval [CI]: 0.01–0.79) and all-cause mortality (OR: 0.21; 95%CI: 0.07–0.63). In conclusion, the occurrence of major bleeding in patients with VTE is outstanding in terms of overall mortality (33% within 30 days), fatal bleeding (18%) or re-bleeding (5.9%). However, these patients also have an increased incidence of recurrent VTE (4.9%) and fatal pulmonary embolism (1.2%).
Lipid-specific immunoglobulin M in CSF predicts adverse long-term outcome in multiple sclerosis
Authors: Thangarajh M , Gomez-Rial J , Hedström AK , Hillert J , Alvarez-Cermeño JC , Masterman T , Villar LM 
Published: October 2008

Background and Objective The presence of lipid-specific immunoglobulin M bands in the cerebrospinal fluid (CSF) predicts an aggressive course in patients with relapsing–remitting multiple sclerosis (MS) during early stages of the disease. This study examined whether it is also a predictor of long-term prognosis in MS. Methods Eighty-one patients with MS and 22 headache controls were analyzed for anti-lipid IgM reactivity in CSF samples. The correlation between the presence of lipid-specific immunoglobulin M bands in CSF and disease progression was assessed in patients with MS who had been followed longitudinally for, on average, more than 11 years. Results Lipid-specific immunoglobulin M bands were detected in the CSF of 24 of 81 patients with MS and were absent in the CSF of all headache controls. Median time to conversion to a secondary progressive course was 11 years in patients with bands and 22 years in patients without bands. Median time to an Expanded Disability Status Scale score of 4 was 14 years in patients with bands and 24 years in patients without bands. Conclusion The presence of lipid-specific immunoglobulin M bands in CSF predicts a more adverse long-term outcome in patients with MS; it may thus define a subset of patients who might benefit from aggressive treatment during the early phase of the disease.
Artificial neural networks for surface modification of cobalt based tungsten cemented carbide deposits
Authors: Jean M.-D. , Lin B.-T. , Wu C.-S. 
Published: October 2008

This paper presents the application of artificial neural networks (ANNs) with statistical experiments to model and characterise WC/Co deposits of the plasma sprayings. In this study, the eight control factors were designed in a L18 factorial orthogonal array, and the effects of process conditions on the surface morphology were critically reviewed in the experiments. The surface topography properties and microstructure were studied. A gradient steepest descent algorithm in the trained ANN was used to explore the relationships between variables and responses. Artificial neural network modelling for WC/Co coatings estimation is compared by response surface methodology. The best values obtained were 2·164 and 2·871% of error percentage for the surface roughness by the best ANN and the response surface methodology model respectively. The experimental results indicate that using a statistical experiment coupled to an ANN strategy offers an effective, efficient and adaptive approach for developing a robust and highly efficient plasma sprayed process of high quality.
A critical role for direct TLR2-MyD88 signaling in CD8 T-cell clonal expansion and memory formation following vaccinia viral infection
Authors: Quigley Michael , Martinez Jennifer , Huang Xiaopei , Yang Yiping 
Published: October 2008

AbstractRecent advances have suggested a crucial role of the innate immunity in shaping adaptive immune responses. How activation of innate immunity promotes adaptive T-cell responses to pathogens in vivo is not fully understood. It has been thought that Toll-like receptor (TLR)–mediated control of adaptive T-cell responses is mainly achieved by the engagement of TLRs on antigen-presenting cells to promote their maturation and function. In this study, we showed that direct TLR2–myeloid differentiating factor 88 (MyD88) signaling in CD8 T cells was also required for their efficient clonal expansion by promoting the survival of activated T cells on vaccinia viral infection in vivo. Effector CD8 T cells that lacked direct TLR2-MyD88 signaling did not survive the contraction phase to differentiate into long-lived memory cells. Furthermore, we observed that direct TLR2 ligation on CD8 T cells promoted CD8 T-cell proliferation and survival in vitro in a manner dependent on the phosphatidylinositol 3-kinase (PI3K)–Akt pathway activation and that activation of Akt controlled memory cell formation in vivo. These results identify a critical role for intrinsic TLR2-MyD88 signaling and PI3K-Akt pathway activation in CD8 T-cell clonal expansion and memory formation in vivo and could lead to the development of new vaccine approaches.
Effective treatment of a murine model of adult T-cell leukemia using depsipeptide and its combination with unmodified daclizumab directed toward CD25
Authors: Chen Jing , Zhang Meili , Ju Wei , Waldmann Thomas A. 
Published: October 2008

AbstractAdult T-cell leukemia (ATL) is caused by human T-cell lymphotropic virus I (HTLV-1) and is an aggressive malignancy of CD4, CD25-expressing leukemia, and lymphoma cells. There is no accepted curative therapy for ATL. Depsipeptide, a histone deacetylase inhibitor, has demonstrated major antitumor effects in leukemias and lymphomas. In this study, we investigated the therapeutic efficacy of depsipeptide alone and in combination with daclizumab (humanized anti-Tac) in a murine model of human ATL. The Met-1 ATL model was established by intraperitoneal injection of ex vivo leukemic cells into nonobese diabetic/severe combined immunodeficiency mice. Either depsipeptide, given at 0.5 mg/kg every other day for 2 weeks, or daclizumab, given at 100 μg weekly for 4 weeks, inhibited tumor growth as monitored by serum levels of soluble IL-2R-α (sIL-2R-α) and soluble β2-microglobulin (β2μ) (P < .001), and prolonged survival of the leukemia-bearing mice (P < .001) compared with the control group. Combination of depsipeptide with daclizumab enhanced the antitumor effect, as shown by both sIL-2R-α and β2μ levels and survival of the leukemia-bearing mice, compared with those in the depsipeptide or daclizumab alone groups (P < .001). The significantly improved therapeutic efficacy by combining depsipeptide with daclizumab supports a clinical trial of this combination in the treatment of ATL.
SNX-2112, a selective Hsp90 inhibitor, potently inhibits tumor cell growth, angiogenesis, and osteoclastogenesis in multiple myeloma and other hematologic tumors by abrogating signaling via Akt and ERK
Authors: Okawa Yutaka , Hideshima Teru , Steed Paul , Vallet Sonia , Hall Steven , Huang Ken , Rice John , Barabasz Amy , Foley Brianna , Ikeda Hiroshi , Raje Noopur , Kiziltepe Tanyel , Yasui Hiroshi , Enatsu Sotaro , Anderson Kenneth C. 
Published: October 2008

AbstractHeat-shock protein 90 (Hsp90) acts as a molecular chaperone required for maintaining the conformational stability of client proteins regulating cell proliferation, survival, and apoptosis. Here we investigate the biologic significance of Hsp90 inhibition in multiple myeloma (MM) and other hematologic tumors using an orally available novel small molecule inhibitor SNX-2112, which exhibits unique activities relative to 17-allyamino-17-demethoxy-geldanamycin (17-AAG). SNX-2112 triggers growth inhibition and is more potent than 17-AAG against MM and other malignancies. It induces apoptosis via caspase-8, -9, -3, and poly (ADP-ribose) polymerase cleavage. SNX-2112 inhibits cytokine-induced Akt and extracellular signal-related kinase (ERK) activation and also overcomes the growth advantages conferred by interleukin-6, insulin-like growth factor-1, and bone marrow stromal cells. Importantly, SNX-2112 inhibits tube formation by human umbilical vein endothelial cells via abrogation of eNOS/Akt pathway and markedly inhibits osteoclast formation via down-regulation of ERK/c-fos and PU.1. Finally, SNX-2112, delivered by its prodrug SNX-5422, inhibits MM cell growth and prolongs survival in a xenograft murine model. Our results indicate that blockade of Hsp90 by SNX-2112 not only inhibits MM cell growth but also acts in the bone marrow microenvironment to block angiogenesis and osteoclastogenesis. Taken together, our data provide the framework for clinical studies of SNX-2112 to improve patient outcome in MM and other hematologic malignancies.
Developing and validating predictive decision tree models from mining chemical structural fingerprints and high–throughput screening data in PubChem
Authors: Han Lianyi , Wang Yanli , Bryant Stephen H 
Published: October 2008

AbstractBackgroundRecent advances in high-throughput screening (HTS) techniques and readily available compound libraries generated using combinatorial chemistry or derived from natural products enable the testing of millions of compounds in a matter of days. Due to the amount of information produced by HTS assays, it is a very challenging task to mine the HTS data for potential interest in drug development research. Computational approaches for the analysis of HTS results face great challenges due to the large quantity of information and significant amounts of erroneous data produced.ResultsIn this study, Decision Trees (DT) based models were developed to discriminate compound bioactivities by using their chemical structure fingerprints provided in the PubChem systemhttp://pubchem.ncbi.nlm.nih.gov. The DT models were examined for filtering biological activity data contained in four assays deposited in the PubChem Bioassay Database including assays tested for 5HT1a agonists, antagonists, and HIV-1 RT-RNase H inhibitors. The 10-fold Cross Validation (CV) sensitivity, specificity and Matthews Correlation Coefficient (MCC) for the models are 57.2~80.5%, 97.3~99.0%, 0.4~0.5 respectively. A further evaluation was also performed for DT models built for two independent bioassays, where inhibitors for the same HIV RNase target were screened using different compound libraries, this experiment yields enrichment factor of 4.4 and 9.7.ConclusionOur results suggest that the designed DT models can be used as a virtual screening technique as well as a complement to traditional approaches for hits selection.
Phenotypic screening, transcriptional profiling, and comparative genomic analysis of an invasive and non-invasive strain of Candida albicans
Authors: Thewes Sascha , Moran Gary P , Magee Beatrice B , Schaller Martin , Sullivan Derek J , Hube Bernhard 
Published: October 2008

Abstract

Background
Invasion of host tissue by the human fungal pathogen Candida albicans is an important step during the development of candidosis. However, not all C. albicans strains possess the same invasive and virulence properties. For example, the two clinical isolates SC5314 and ATCC10231 differ in their ability to invade host tissue and cause experimental infections. Strain SC5314 is invasive whereas strain ATCC10231 is non-invasive and strongly attenuated in virulence compared to SC5314. In this study we compare the in vitro phenotypic, transcriptional and genomic profiles of these two widely used laboratory strains in order to determine the principal biological and genetic properties responsible for their differential virulence.

Results
In all media tested, the two strains showed the same metabolic flexibility, stress resistance, adhesion properties and hydrolytic enzyme secretion in vitro. However, differences were observed in response to cell-surface disturbing agents and alkaline pH. Furthermore, reduced hyphal formation in strain ATCC10231 under certain conditions correlated with reduced invasive properties in an in vitro invasion assay and a reduced ability to invade epithelial tissue. Despite these diverse phenotypic properties, no substantial genomic differences were detected by comparative genome hybridisation within the open reading frames. However, in vitro transcriptional profiling displayed major differences in the gene expression of these two strains, even under normal in vitro growth conditions.

Conclusion
Our data suggest that the reason for differential virulence of C. albicans strains is not due to the absence of specific genes, but rather due to differences in the expression, function or activity of common genes.
New insights into SRY regulation through identification of 5' conserved sequences
Authors: Ross Diana GF , Bowles Josephine , Koopman Peter , Lehnert Sigrid 
Published: October 2008

Abstract

Background

SRY is the pivotal gene initiating male sex determination in most mammals, but how its expression is regulated is still not understood. In this study we derived novel SRY 5' flanking genomic sequence data from bovine and caprine genomic BAC clones.

Results
We identified four intervals of high homology upstream of SRY by comparison of human, bovine, pig, goat and mouse genomic sequences. These conserved regions contain putative binding sites for a large number of known transcription factor families, including several that have been implicated previously in sex determination and early gonadal development.

Conclusion
Our results reveal potentially important SRY regulatory elements, mutations in which might underlie cases of idiopathic human XY sex reversal.
An experimental in-vivo canine model for adult shunt infection
Authors: Bayston Roger , Brant Christine , Dombrowski Stephen M , Hall Geraldine , Tuohy Marion , Procop Gary , Luciano Mark G 
Published: October 2008

Abstract

Background
Detailed human studies of the mechanisms and development of shunt infection in real time are not possible, and we have developed a canine hydrocephalus model to overcome this. The intention of this pilot study was to show that the canine hydrocephalus model could be shunted using conventional "human" shunts, and that a shunt infection could be established so that further studies could then be planned.

Methods
Hydrocephalus was induced in seven dogs (Canis familiaris) by fourth ventricle obstruction. Four weeks later they were shunted using a Hakim Precision valve. Four of the dogs received shunts whose ventricular catheter had been inoculated with Staphylococcus epidermidis, and three were uninoculated controls. Four weeks after shunting the dogs were sacrificed and necropsy was performed. Removed shunts and tissue samples were examined microbiologically and isolates were subjected to detailed identification and genomic comparison.

Results
All the dogs remained well after shunting. Examination of removed shunt components revealed S. epidermidis in the brain and throughout the shunt system in the four inoculated animals, but in two of these Staphylococcus intermedius was also found. S. intermedius was also isolated from all three "negative" controls. There were slight differences between S. intermedius strains suggesting endogenous infection rather than cross- infection from a point source.

Conclusion
Shunt infection was established in the canine model, and had the experiment been extended beyond four weeks the typical microbiological, pathological and clinical features might have appeared. The occurrence of unplanned shunt infections in control animals due to canine normal skin flora reflects human clinical experience and underlines the usual source of bacteria causing shunt infection.
Simulating in vitro transcriptional response of zinc homeostasis system in Escherichia coli
Authors: Cui Jiangjun , Kaandorp Jaap A , Lloyd Catherine M 
Published: October 2008

Abstract

Background
The zinc homeostasis system in Escherichia coli is one of the most intensively studied prokaryotic zinc homeostasis systems. Its underlying regulatory machine consists of repression on zinc influx through ZnuABC by Zur (Z n2+
u ptake r egulator) and activation on zinc efflux via ZntA by ZntR (a zinc-responsive regulator). Although these transcriptional regulations seem to be well characterized, and there is an abundance of detailed in vitro experimental data available, as yet there is no mathematical model to help interpret these data. To our knowledge, the work described here is the first attempt to use a mathematical model to simulate these regulatory relations and to help explain the in vitro experimental data.

Results
We develop a unified mathematical model consisting of 14 reactions to simulate the in vitro transcriptional response of the zinc homeostasis system in E. coli. Firstly, we simulate the in vitro Zur-DNA interaction by using two of these reactions, which are expressed as 4 ordinary differential equations (ODEs). By imposing the conservation restraints and solving the relevant steady state equations, we find that the simulated sigmoidal curve matches the corresponding experimental data. Secondly, by numerically solving the ODEs for simulating the Zur and ZntR run-off transcription experiments, and depicting the simulated concentrations of zntA and znuC transcripts as a function of free zinc concentration, we find that the simulated curves fit the corresponding in vitro experimental data. Moreover, we also perform simulations, after taking into consideration the competitive effects of ZntR with the zinc buffer, and depict the simulated concentration of zntA transcripts as a function of the total ZntR concentration, both in the presence and absence of Zn(II). The obtained simulation results are in general agreement with the corresponding experimental data.

Conclusion
Simulation results show that our model can quantitatively reproduce the results of several of the in vitro experiments conducted by Outten CE and her colleagues. Our model provides a detailed insight into the dynamics of the regulatory system and also provides a general framework for simulating in vitro metal-binding and transcription experiments and interpreting the relevant experimental data.