bluuebunny/crossref_metadata_2025_split huggingface dataset:
Identification of Griseofulvin as an Inhibitor of Centrosomal Clustering in a Phenotype-Based Screen
Authors: Rebacz Blanka , Larsen Thomas O. , Clausen Mads H. , Rønnest Mads H. , Löffler Harald , Ho Anthony D. , Krämer Alwin 
Published: July 2007

Abstract
A major drawback of cancer chemotherapy is the lack of tumor-specific targets which would allow for the selective eradication of malignant cells without affecting healthy tissues. In contrast with normal cells, most tumor cells contain multiple centrosomes, associated with the formation of multipolar mitotic spindles and chromosome segregation defects. Many tumor cells regain mitotic stability after clonal selection by the coalescence of multiple centrosomes into two functional spindle poles. To overcome the limitations of current cancer treatments, we have developed a cell-based screening strategy to identify small molecules that inhibit centrosomal clustering and thus force tumor cells with supernumerary centrosomes to undergo multipolar mitoses, and subsequently, apoptosis. Using a chemotaxonomic selection of fungi from a large culture collection, a relatively small but diverse natural product extract library was generated. Screening of this compound library led to the identification of griseofulvin, which induced multipolar spindles by inhibition of centrosome coalescence, mitotic arrest, and subsequent cell death in tumor cell lines but not in diploid fibroblasts and keratinocytes with a normal centrosome content. The inhibition of centrosome clustering by griseofulvin was not restricted to mitotic cells but did occur during interphase as well. Whereas the formation of multipolar spindles was dynein-independent, depolymerization of interphase microtubules seemed to be mechanistically involved in centrosomal declustering. In summary, by taking advantage of the tumor-specific phenotype of centrosomal clustering, we have developed a screening strategy that might lead to the identification of drugs which selectively target tumor cells and spare healthy tissues. [Cancer Res 2007;67(13):6342–50]
Synergistic activity of troxacitabine (Troxatyl™) and gemcitabine in pancreatic cancer
Authors: Damaraju Vijaya L , Bouffard David Y , Wong Clarence KW , Clarke Marilyn L , Mackey John R , Leblond Lorraine , Cass Carol E , Grey Mike , Gourdeau Henriette 
Published: July 2007

Abstract

Background
Gemcitabine, a deoxycytidine nucleoside analog, is the current standard chemotherapy used as first-line treatment for patients with locally advanced or metastatic cancer of the pancreas, and extends life survival by 5.7 months. Advanced pancreatic cancer thus remains a highly unmet medical need and new therapeutic agents are required for this patient population. Troxacitabine (Troxatyl™) is the first unnatural L-nucleoside analog to show potent preclinical antitumor activity and is currently under clinical investigation. Troxacitabine was recently evaluated as a first-line therapy in 54 patients with advanced adenocarcinoma of the pancreas and gave comparable overall results to those reported with gemcitabine in recently published randomized trials.

Methods
The human pancreatic adenocarcinoma cell lines, AsPC-1, Capan-2, MIA PaCa-2 and Panc-1, were exposed to troxacitabine or gemcitabine alone or in combination, for 72 h, and the effects on cell growth were determined by electronic particle counting. Synergistic efficacy was determined by the isobologram and combination-index methods of Chou and Talalay. Mechanistic studies addressed incorporation of troxacitabine into DNA and intracellular levels of troxacitabine and gemcitabine metabolites. For in vivo studies, we evaluated the effect of both drugs, alone and in combination, on the growth of established human pancreatic (AsPC-1) tumors implanted subcutaneously in nude mice. Statistical analysis was calculated by a one-way ANOVA with Dunnett as a post-test and the two-tailed unpaired t test using GraphPad prism software.

Results
Synergy, evaluated using the CalcuSyn Software, was observed in all four cell-lines at multiple drug concentrations resulting in combination indices under 0.7 at Fa of 0.5 (50% reduction of cell growth). The effects of drug exposures on troxacitabine and gemcitabine nucleotide pools were analyzed, and although gemcitabine reduced phosphorylation of troxacitabine when cells were exposed at equal drug concentrations, there was no effect on phosphorylated pools at drug combinations that were synergistic. The amount of troxacitabine incorporated into DNA was also not affected by the presence of gemcitabine. In vivo testing against a human pancreatic (AsPC-1) xenograft mouse tumor model indicated that both drugs were more than additive at well-tolerated doses and schedule. The biological basis for this synergy is unclear as we did not observe changes in apoptosis, DNA repair, troxacitabine incorporation into DNA or troxacitabine metabolism in the presence of gemcitabine.

Conclusion
These data, together with phase I clinical data showing tolerability of both agents when combined, suggest combination therapy with troxacitabine and gemcitabine warrants further evaluation in advanced pancreatic cancer patients.
Impairment of alternative splice sites defining a novel gammaretroviral exon within gagmodifies the oncogenic properties of Akv murine leukemia virus
Authors: Sørensen Annette Balle , Lund Anders H , Kunder Sandra , Quintanilla-Martinez Leticia , Schmidt Jörg , Wang Bruce , Wabl Matthias , Pedersen Finn Skou 
Published: July 2007

Abstract

Background
Mutations of an alternative splice donor site located within the gag region has previously been shown to broaden the pathogenic potential of the T-lymphomagenic gammaretrovirus Moloney murine leukemia virus, while the equivalent mutations in the erythroleukemia inducing Friend murine leukemia virus seem to have no influence on the disease-inducing potential of this virus. In the present study we investigate the splice pattern as well as the possible effects of mutating the alternative splice sites on the oncogenic properties of the B-lymphomagenic Akv murine leukemia virus.

Results
By exon-trapping procedures we have identified a novel gammaretroviral exon, resulting from usage of alternative splice acceptor (SA') and splice donor (SD') sites located in the capsid region of gag of the B-cell lymphomagenic Akv murine leukemia virus. To analyze possible effects in vivo of this novel exon, three different alternative splice site mutant viruses, mutated in either the SA', in the SD', or in both sites, respectively, were constructed and injected into newborn inbred NMRI mice. Most of the infected mice (about 90%) developed hematopoietic neoplasms within 250 days, and histological examination of the tumors showed that the introduced synonymous gag mutations have a significant influence on the phenotype of the induced tumors, changing the distribution of the different types as well as generating tumors of additional specificities such as de novo diffuse large B cell lymphoma (DLBCL) and histiocytic sarcoma. Interestingly, a broader spectrum of diagnoses was made from the two single splice-site mutants than from as well the wild-type as the double splice-site mutant. Both single- and double-spliced transcripts are produced in vivo using the SA' and/or the SD' sites, but the mechanisms underlying the observed effects on oncogenesis remain to be clarified. Likewise, analyses of provirus integration sites in tumor tissues, which identified 111 novel RISs (retroviral integration sites) and 35 novel CISs (common integration sites), did not clearly point to specific target genes or pathways to be associated with specific tumor diagnoses or individual viral mutants.

Conclusion
We present here the first example of a doubly spliced transcript within the group of gammaretroviruses, and we show that mutation of the alternative splice sites that define this novel RNA product change the oncogenic potential of Akv murine leukemia virus.
Ex Vivo Gene Therapy for Hemophilia A That Enhances Safe Delivery and Sustained In Vivo Factor VIII Expression from Lentivirally Engineered Endothelial Progenitors
Authors: Matsui Hideto , Shibata Masaru , Brown Brian , Labelle Andrea , Hegadorn Carol , Andrews Chandler , Hebbel Robert P. , Galipeau Jacques , Hough Christine , Lillicrap David 
Published: July 2007

Abstract
Novel therapeutic strategies for hemophilia must be at least as effective as current treatments and demonstrate long-term safety. To date, several small clinical trials of hemophilia gene transfer have failed to show the promise of preclinical evaluations. Therefore, we wanted to develop and evaluate the feasibility of a novel ex vivo gene transfer strategy whereby cells derived from progenitor cells are engineered to express factor VIII (FVIII) and then implanted subcutaneously to act as a depot for FVIII expression. Circulating blood outgrowth endothelial cells (BOECs) were isolated from canine and murine blood and transduced with a lentiviral vector encoding the canine FVIII transgene. To enhance safety, these cells were implanted subcutaneously in a Matrigel scaffold, and the efficacy of this strategy was compared with i.v. delivery of engineered BOECs in nonhemophilic nonobese diabetic/severe combined immunodeficiency mice. Therapeutic levels of FVIII persisted for 15 weeks, and these levels of stable expression were extended to 20 weeks when the cytomegalovirus promoter was replaced with the thrombomodulin regulatory element. Subsequent studies in immunocompetent hemophilic mice, pretreated with tolerizing doses of FVIII or with transient immunosuppression, showed therapeutic FVIII expression for 27 weeks before the eventual return to baseline levels. This loss of transgene expression appears to be due to the disappearance of the implanted cells. The animals treated with either of the two tolerizing regimens did not develop anti-FVIII antibodies. Biodistribution analysis demonstrated that BOECs were retained inside the subcutaneous implants. These results indicate, for the first time, that genetically modified endothelial progenitor cells implanted in a subcutaneous scaffold can provide sustained therapeutic levels of FVIII and are a promising and safe treatment modality for hemophilia A.
Disclosure of potential conflicts of interest is found at the end of this article.
Molecular and Secretory Profiles of Human Mesenchymal Stromal Cells and Their Abilities to Maintain Primitive Hematopoietic Progenitors
Authors: Wagner Wolfgang , Roderburg Christoph , Wein Frederik , Diehlmann Anke , Frankhauser Maria , Schubert Ralf , Eckstein Volker , Ho Anthony D. 
Published: July 2007

Abstract
Mesenchymal stromal cells (MSC) provide a supportive cellular microenvironment and are able to maintain the self-renewal capacity of hematopoietic progenitor cells (HPC). Isolation procedures for MSC vary extensively, and this may influence their biologic properties. In this study, we have compared human MSC isolated from bone marrow (BM) using two culture conditions, from cord blood (CB), and from adipose tissue (AT). The ability to maintain long-term culture-initiating cell frequency and a primitive CD34+CD38− immunophenotype was significantly higher for MSC derived from BM and CB compared with those from AT. These results were in line with a significantly higher adhesion of HPC to MSC from BM and CB versus MSC from AT. We have compared the cytokine production of MSC by cytokine antibody arrays, enzyme-linked immunosorbent assay, and a cytometric bead array. There were reproducible differences in the chemokine secretion profiles of various MSC preparations, but there was no clear concordance with differences in their potential to maintain primitive function of HPC. Global gene expression profiles of MSC preparations were analyzed and showed that adhesion proteins including cadherin-11, N-cadherin, vascular cell adhesion molecule 1, neural cell adhesion molecule 1, and integrins were highly expressed in MSC preparations derived from BM and CB. Thus, MSC from BM and CB are superior to MSC from AT for maintenance of primitive HPC. The latter property is associated with specific molecular profiles indicating the significance of cell-cell junctions but not with secretory profiles.
Disclosure of potential conflicts of interest is found at the end of this article.
Emigration and Brain Drain: Evidence from the Caribbean
Authors: Mishra Prachi 
Published: July 2007

Abstract
This paper quantifies the magnitude and nature of migration flows from the Caribbean and estimates their costs and benefits. The Caribbean countries have lost 1040 percent of their labor force due to emigration to OECD member countries. The migration rates are particularly striking for the high-skilled labor force. Many countries have lost more than 70 percent of their labor force with more than 12 years of completed schoolingamong the highest emigration rates in the world. The region is also the world's largest recipient of remittances as a percent of GDP. Remittances constituted about 13 percent of the regions GDP in 2002. Simple welfare calculations (under very conservative assumptions of elasticities) suggest that the losses due to high-skill migration (ceteris paribus) outweigh the official remittances to the Caribbean region.
Understanding the Internet's Relevance to Media Ownership Policy: A Model of Too Many Choices
Authors: Nagler Matthew G. 
Published: July 2007

Abstract
Does the Internet provide a failsafe against media consolidation in the wake of an easing of media ownership rules? This paper posits a model of news outlet selection on the Internet in which consumers experience cognitive costs that increase with the number of options faced. Consistent with psychological evidence, these costs may be reduced by constraining one's choice set to "safe bets" familiar from offline (e.g., CNN.com). It is shown that, as the number of outlets grows, dispersion of patronage across outlets inevitably declines. Consequently, independent Internet outlets may fail to mitigate lost outlet independence on other media.
Do Environmental Regulations Cost Jobs? An Industry-Level Analysis of the UK
Authors: Cole Matthew A , Elliott Rob J 
Published: July 2007

Abstract
This paper revisits the 'jobs versus the environment' debate and provides the first analysis for a country other than the US. We firstly examine the impact of environmental regulations on employment assuming such regulations are exogenous. However, for the first time in a study of this nature, we then allow environmental regulation costs and employment to be endogenously determined. Environmental regulation costs are not found to have a statistically significant effect on employment whether such costs are treated as being exogenous or endogenous. We therefore find no evidence of a trade-off between jobs and the environment.
The first record of Dracunculus mulbus (Nematoda: Dracunculidae) in the Papuan olive python Apodora papuana (Ophidia: Boidae)
Authors: Moravec F. , Gibson D. 
Published: July 2007

Abstract
A male specimen of Dracunculus (Nematoda: Dracunculidae), collected in 1973 from the lung of the Papuan olive python Apodora papuana (Peters et Doria) and now deposited in the helminthological collection of the Natural History Museum in London, is identified as Dracunculus mulbus Jones et Mulder, 2007, a species recently described from the water python Liasis fuscus Peters in northern Australia. Apodora papuana is a new host record for D. mulbus and Papua New Guinea is apparently a new geographical record.
The existence of multiple positive solutions of p-Laplacian boundary value problems
Authors: Liu Yuji 
Published: July 2007

Abstract
In this paper, we establish sufficient conditions to guarantee the existence of at least three or 2n − 1 positive solutions of nonlocal boundary value problems consisting of the second-order differential equation with p-Laplacian (1)
$$[\phi _p (x'(t))]' + f(t,x(t)) = 0, t \in (0,1),$$
and one of following boundary conditions (2)
$$x(0) = \int\limits_0^1 {x(s) dh(s),} \phi _p (x'(1)) = \int\limits_0^1 {\phi _p (x'(s)) dg(s)} ,$$
and (3)
$$\phi _p (x'(0)) = \int\limits_0^1 {\phi _p (x'(s)) dh(s),} x(1) = \int\limits_0^1 {x(s) dg(s)} .$$
Examples are presented to illustrate the main results.
When Mothers Have Favourites: Conditions under Which Mothers Differentiate among Their Adult Children
Authors: Suitor J. Jill , Sechrist Jori , Pillemer Karl 
Published: July 2007

ABSTRACTResearch has shown that mothers often differentiate among their adult children in terms of closeness and support; however, studies have not addressed why some mothers report preferences among children and others do not. To distinguish between mothers who do and do not report favouring some of their adult children, we used data from a within-family study in which 553 older mothers were interviewed about each of their children. Almost all of the mothers reported differentiating among their children regarding emotional closeness, confiding, or preference among caregivers. Multivariate analyses revealed that mothers' values and mother-child value similarity predicted which mothers differentiated among their children regarding closeness and confiding, whereas mothers' and children's demographic characteristics predicted which mothers differentiated regarding preferred caregivers. Black mothers were less likely than white mothers to differentiate when seeking a confidant; however, race played no role in mothers' likelihood of differentiating regarding emotional closeness or help during illness. Taken together, these findings indicate that differentiating among adult children is common; further, family-level predictors of mothers' differentiating mirror the patterns shown in dyad-level analyses of mothers' favouritism.
Living Long and Keeping Well: Elderly Canadians Account for Success in Aging
Authors: Bassett Raewyn , Bourbonnais Valérie , McDowell Ian 
Published: July 2007

ABSTRACTSenescence is a time of decline; yet many seniors remain active and engaged into very old age. How and why do some seniors live long and keep well? We report the responses to this question from a representative sample of 2,783 Canadian seniors.Overall, seniors placed primary responsibility for their long lives on their own individual practices, citing keeping active and maintaining good nutrition as the major themes. Physical illness was less significant than the will to adapt to illness and avoid further physical decline as long as possible. Francophone and anglophone respondents differed in the frequency with which they mentioned many of the themes. Francophones focused on life quality and family, while anglophones focused on the self. Systematic gender differences were also identified. Many responses validate existing theories of successful aging, and indicate that Canadian seniors are well-informed, insightful participants in the process of growing old.
W5O14 Nanowires
Authors: Remškar M. , Kovac J. , Viršek M. , Mrak M. , Jesih A. , Seabaugh A. 
Published: July 2007

AbstractWe report on the synthesis of quasi‐1D W5O14 crystals using NiI2 as a growth promoter. Photoelectron spectroscopy revealed the metallic conductivity of the W5O14 nanowires, which was also confirmed by direct‐transport measurements on a double‐stranded nanowire. Scanning electron microscopy and transmission electron‐diffraction data are correlated with details of crystal growth revealing the possible mechanism of the formation of this rarely synthesized phase, which was reported as a homogeneous phase only in 1978 by McColm et al., and in the meantime has been declared as a compound that is rare.
Preparation and catalytic properties of a bimetallic SnPt complex in the supercages of NaY zeolite by use of surface organometallic chemistry
Authors: Zheng Ying , Wang Xuxu , Fu Xianzhi , Wei Kemei 
Published: July 2007

AbstractThe grafting reaction of SnMe4 on the surface of Pt/NaY zeolite was investigated in a 1.6 × 104 Pa hydrogen atmosphere. The chemical compositions, structure and properties of the resulting solid were characterized by in situ FTIR, ICP, XRD, XPS, temperature programmed decomposition and nitrogen adsorption. The results show that Pt atoms of Pt/NaY zeolite react with tetramethyltin to form a bimetallic Me3SnPt surface species in the presence of hydrogen at 353 K. The reaction does not destroy the zeolite framework, while its surface properties are changed. The BET surface area and the pore volume of the zeolite decrease significantly. The CO chemisorption results and the XPS results show that the electronic properties of the modified Pt atoms on the surface of NaY zeolite are altered remarkably by the inductive effect of electron between Pt and methyl groups. The grafted product has excellent selective hydrogenation of furfural to furfuryl alcohol. Copyright © 2007 John Wiley & Sons, Ltd.
Age‐related Changes in Marmoset Trabecular and Cortical Bone and Response to Alendronate Therapy Resemble Human Bone Physiology and Architecture
Authors: Bagi Cedo M. , Volberg Marlo , Moalli Maria , Shen Victor , Olson Ellen , Hanson Nels , Berryman Edwin , Andresen Catharine J. 
Published: July 2007

AbstractIn older humans, bone elongation ceases, periosteal expansion continues, and bone remodeling remains a dominant metabolic process. An appropriate animal model of type I and type II osteoporosis would be a species with sealed growth plates and persistence of bone remodeling. The rat is commonly used as a primary model, but due to delayed epiphyseal closure with continuous modeling and lack of Haversian remodeling, Food and Drug Administration guidelines recommend assessment of bone quality in an additional, nonrodent, remodeling species. This study investigated the skeletal characteristics of senescent marmosets to evaluate their suitability as an osteoporosis model. Animals were randomized across three experimental groups; controls for both sexes and marmosets receiving alendronate for either 30 or 60 days (28 μg/kg, sc, twice per week). Outcome measures included serum chemistry and bone biomarkers, DEXA, histomorphometry, micro‐computed tomography, and histopathology. Results showed that the adult marmoset skeleton has similar anatomical characteristics to the adult human, including the absence of growth plates, presence of Haversian system, and true remodeling of cancellous and cortical bone. Structural analyses of senescent marmoset cancellous bone demonstrated loss of trabecular mass and architecture similar to skeletal changes described for elderly men and women. Treatment with alendronate improved trabecular volume and number by reducing bone resorption, although bone formation was also reduced through coupling of bone remodeling. The common marmoset may provide a valuable model for research paradigms targeting human bone pathology and osteoporosis due to skeletal features that are similar to age‐related changes and response to bisphosphonate therapy reported for humans. Anat Rec, 2007. © 2007 Wiley‐Liss, Inc.
Conformationally Restrained Aromatic Analogues of Fosmidomycin and FR900098
Authors: Kurz Thomas , Schlüter Katrin , Pein Miriam , Behrendt Christoph , Bergmann Bärbel , Walter Rolf D. 
Published: July 2007

AbstractThe synthesis and in‐vitro antimalarial activity of conformationally restrained bis(pivaloyloxymethyl) ester analogues of the natural product fosmidomycin is presented. In contrast to α‐aryl‐substituted analogues, conformationally restrained aromatic analogues exhibit only moderate in‐vitro antimalarial activity against the chloroquine‐sensitive strain 3D7 of Plasmodium falciparum. The most active derivative displays an IC50 value of 47 μM.