bluuebunny/crossref_metadata_2025_split huggingface dataset:
Analysing probabilistically constrained optimism
Authors: Lees Michael , Logan Brian , Theodoropoulos Georgios 
Published: March 2009

AbstractIn previous work we presented the DTRD algorithm, an optimistic synchronization algorithm for parallel discrete event simulation of multi‐agent systems, and showed that it outperforms Time Warp and time windows on a range of test cases. DTRD uses a decision‐theoretic model of rollback to derive an optimal time to delay read event so as to maximize the rate of LVT progression. The algorithm assumes that the inter‐arrival times (both virtual and real) of events are normally distributed. In this paper we present a more detailed evaluation of the DTRD algorithm, and specifically how the performance of the algorithm is affected when the inter‐arrival times do not follow the assumed distributions. Our analysis suggests that the performance of the algorithm is relatively insensitive to events whose inter‐arrival times are not normally distributed. However, as the variance of event inter‐arrival times increases, its performance degrades to that of Time Warp. The evaluation approach we present is generally applicable, and we sketch how a similar analysis may be performed for two other decision‐theoretic optimistic synchronization algorithms. Copyright © 2009 John Wiley & Sons, Ltd.
Organotypic glioma spheroids for screening of experimental therapies: How many spheroids and sections are required?
Authors: De Witt Hamer Philip C. , Leenstra Sieger , Van Noorden Cornelis J.F. , Zwinderman Aeilko H. 
Published: March 2009

AbstractCancer spheroids are a valuable model for screening anticancer strategies. However, studies are published using various numbers of spheroids and sections per spheroid. Here, we establish the sample size requirements for valid screening strategies to treat glioma: how many spheroids per experimental group and how many sections per spheroid are required to detect one‐third reduction in an endpoint measurement after treatment? From two glioblastoma patients, 32 untreated organotypic spheroids were cultured and sectioned entirely (14–100 sections per spheroid). The viable fraction was determined as endpoint by automated image analysis in sections and used to establish the minimally‐detectable difference between a treatment and reference group. Variance was considerable with a coefficient of variance of 21%. The biological variation in viability in sections of spheroids produced 97% of variance when sample size was large. Variance increased when numbers of spheroids but not numbers of sections per spheroid were reduced. A minimum of 12 spheroids per group and one section per spheroid was required for a valid comparison of a treatment group and a control group. When 10 treatment groups and one control group were compared, 16 spheroids per group were required. Thus, the statistical power depended almost entirely on the number of organotypic glioma spheroids and hardly on the number of sections per spheroid. The organotypic glioma spheroid model does not appear to be suitable for high‐throughput screening of anticancer strategies, because of the relatively large number of spheroids required. It is the model of choice for low‐throughput screening, because this model is far more representative for the parental tumor than any other more efficient glioma model. © 2009 International Society for Advancement of Cytometry
Effects of (−)‐carveol and HPMC on the in vitro ocular transport and the in vivo intraocular pressure lowering effects of dorzolamide formulations in normotensive New Zealand rabbits
Authors: Afouna Mohsen I. , Khedr Ala'a , Al‐Marzoqi Adnan 
Published: March 2009

AbstractThe objective of the current study was to maximize the ocular bioavailability of the carbonic anhydrase inhibitor, dorzolamide hydrochloride (DZD) via (a) enhancement of DZD corneal transport using terpene enhancers, (b) reducing pre‐corneal loss of the installed dose via increased formulation viscosity, and (c) assessment of the in vivo intraocular pressure (IOP) lowering effects of test formulations using rabbit. DZD was formulated as a 2% ophthalmic solution containing different concentrations of HPMC as a viscosity improving agent (VIA), and (−)‐carveol as a corneal penetration enhancer. The transport of DZD from test formulations was quantitatively determined using in vitro diffusion experiments, the permeability parameters were mathematically calculated, and the in vivo IOP lowering effects were assessed using a Tono‐Pen XL®tonometer. The results revealed a good correlation between the in vitro permeability parameters and the in vivo ΔIOP. The magnitude of the DZD‐IOP lowering effects and durations of actions for DZD formulations were dependent on (a) the concentration of (−)‐carveol, and (b) the contact period with ocular tissue which was found to be a single‐valued function of the HPMC as VIA. Drug Dev Res 70, 2009. © 2009 Wiley‐Liss, Inc.
Double bromodomain‐containing gene Brd2 is essential for embryonic development in mouse
Authors: Shang Enyuan , Wang Xiangyuan , Wen Duancheng , Greenberg David A. , Wolgemuth Debra J. 
Published: March 2009

AbstractThe BET subfamily of bromodomain‐containing genes is characterized by the presence of two bromodomains and a unique ET domain at their carboxyl termini. Here, we show that the founding member of this subfamily, Brd2, is an essential gene by generating a mutant mouse line lacking Brd2 function. Homozygous Brd2 mutants are embryonic lethal, with most Brd2−/− embryos dying by embryonic day 11.5. Before death, the homozygous embryos were notably smaller and exhibited abnormalities in the neural tube where the gene is highly expressed. Brd2‐deficient embryonic fibroblast cells were observed to proliferate more slowly than controls. Experiments to explore whether placental insufficiency could be a cause of the embryonic lethality showed that injecting diploid mutant embryonic stem cells into tetraploid wild‐type blastocysts did not rescue the lethality; that is Brd2‐deficient embryos could not be rescued by wild‐type extraembryonic tissues. Furthermore, there were enhanced levels of cell death in Brd2‐deficient embryos. Developmental Dynamics 238:908–917, 2009. © 2009 Wiley‐Liss, Inc.
1,7‐Electrocyclization Reactions of 2‐Aza‐4,5‐benzoheptatrienyl‐ and 4‐Aza‐6,7‐benzononatetraenyllithium Compounds: Synthesis of Novel 2‐Benzazepines and (Benzocyclooctenyl)amines
Authors: Sajitz Melanie , Fröhlich Roland , Würthwein Ernst‐Ulrich 
Published: March 2009

AbstractDeprotonation reactions of N‐benzyl‐ and N‐allylimines 1 and 4 led to benzo‐annulated 2‐azaheptatrienyl‐ and 4‐azanonatetraenyllithium compounds, which underwent 1,7‐electrocyclization reactions to yield the novel 2,3‐dihydro‐1H‐benzo[c]azepines 3, 5, 11 and 13 or the (5,6‐dihydrobenzocycloocten‐5‐yl)amines 6 after subsequent addition of acyl chlorides, carbamoyl chlorides, imidoyl chlorides or pivaldehyde, respectively. Acyl and carbamoyl chlorides reacted as electrophiles at the nitrogen atom, whereas imidoyl halides and pivaldehyde attacked position C‐5 in the seven‐membered ring. In the case of pivaldehyde, the final tricyclic product 13 is the result of a subsequent nucleophilic attack at the imine moiety after a proton shift. The temperature dependence of the reaction cascades was studied, allowing preferred formation either of the seven‐membered heterocyclic systems 3 and 5 or of the eight‐membered carbocycles 6. All compounds were fully characterized, including by X‐ray diffraction studies of 6c, 6f, 11a and 13a. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2009)
N‐Heterocyclic Carbene Derived Nickel–Pincer Complexes: Efficient and Applicable Catalysts for Suzuki–Miyaura Coupling Reactions of Aryl/Alkenyl Tosylates and Mesylates
Authors: Kuroda Jun‐ichi , Inamoto Kiyofumi , Hiroya Kou , Doi Takayuki 
Published: March 2009

AbstractCatalytic activities of NHC‐derived nickel–pincer complexes for the Suzuki–Miyaura coupling reactions of aryl/alkenyl tosylates and mesylates are described. In the presence of a catalytic amount of nickelacycle 1a, a wide array of tosylates and mesylates reacted with several aryl‐ and alkenylboronic acids to afford the coupling products, generally in high yields. Fine tuning of the reaction conditions for each class of electrophiles was achieved only by choosing the appropriate reaction medium (DME for tosylates, dioxane for mesylates).(© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2009)
Concentration and drug prices in the retail market for malaria treatment in rural Tanzania
Authors: Goodman Catherine , Kachur S. Patrick , Abdulla Salim , Bloland Peter , Mills Anne 
Published: March 2009

AbstractThe impact of market concentration has been little studied in markets for ambulatory care in the developing world, where the retail sector often accounts for a high proportion of treatments. This study begins to address this gap through an analysis of the consumer market for malaria treatment in rural areas of three districts in Tanzania. We developed methods for investigating market definition, sales volumes and concentration, and used these to explore the relationship between antimalarial retail prices and competition.The market was strongly geographically segmented and highly concentrated in terms of antimalarial sales. Antimalarial prices were positively associated with market concentration. High antimalarial prices were likely to be an important factor in the low proportion of care‐seekers obtaining appropriate treatment.Retail sector distribution of subsidised antimalarials has been proposed to increase the coverage of effective treatment, but this analysis indicates that local market power may prevent such subsidies from being passed on to rural customers. Policymakers should consider the potential to maintain lower retail prices by decreasing concentration among antimalarial providers and recommending retail price levels. Copyright © 2009 John Wiley & Sons, Ltd.
Inhibiting glycosphingolipid synthesis ameliorates hepatic steatosis in obese mice #
Authors: Zhao Hongmei , Przybylska Malgorzata , Wu I-Huan , Zhang Jinhua , Maniatis Panagiotis , Pacheco Joshua , Piepenhagen Peter , Copeland Diane , Arbeeny Cynthia , Shayman James A. , Aerts Johannes M. , Jiang Canwen , Cheng Seng H. , Yew Nelson S. 
Published: March 2009

Abstract
Steatosis in the liver is a common feature of obesity and type 2 diabetes and the precursor to the development of nonalcoholic steatohepatitis (NASH), cirrhosis, and liver failure. It has been shown previously that inhibiting glycosphingolipid (GSL) synthesis increases insulin sensitivity and lowers glucose levels in diabetic rodent models. Here we demonstrate that inhibiting GSL synthesis in ob/ob mice not only improved glucose homeostasis but also markedly reduced the development of hepatic steatosis. The ob/ob mice were treated for 7 weeks with a specific inhibitor of glucosylceramide synthase, the initial enzyme involved in the synthesis of GSLs. Besides lowering glucose and hemoglobin A1c (HbA1c) levels, drug treatment also significantly reduced the liver/body weight ratio, decreased the accumulation of triglycerides, and improved several markers of liver pathology. Drug treatment reduced liver glucosylceramide (GL1) levels in the ob/ob mouse. Treatment also reduced the expression of several genes associated with hepatic steatosis, including those involved in lipogenesis, gluconeogenesis, and inflammation. In addition, inhibiting GSL synthesis in diet-induced obese mice both prevented the development of steatosis and partially reversed preexisting steatosis. Conclusion: These data indicate that inhibiting GSL synthesis ameliorates the liver pathology associated with obesity and diabetes, and may represent a novel strategy for treating fatty liver disease and NASH. (Hepatology 2009.)
HFE C282Y/H63D compound heterozygotes are at low risk of hemochromatosis-related morbidity # †
Authors: Gurrin Lyle C. , Bertalli Nadine A. , Dalton Gregory W. , Osborne Nicholas J. , Constantine Clare C. , McLaren Christine E. , English Dallas R. , Gertig Dorota M. , Delatycki Martin B. , Nicoll Amanda J. , Southey Melissa C. , Hopper John L. , Giles Graham G. , Anderson Gregory J. , Olynyk John K. , Powell Lawrie W. , Allen Katrina J. 
Published: March 2009

Abstract
The risk of hemochromatosis-related morbidity is unknown among HFE compound heterozygotes (C282Y/H63D). We used a prospective population-based cohort study to estimate the prevalence of elevated iron indices and hemochromatosis-related morbidity for compound heterozygotes. In all, 31,192 subjects of northern European descent were genotyped for HFE C282Y and H63D. An HFE-genotype stratified random sample of 1,438 subjects, followed for an average of 12 years to a mean age of 65 years, completed questionnaires and gave blood. Clinical examinations were blinded to HFE genotype. A total of 180 (84 males) clinically examined C282Y/H63D participants were compared with 330 (149 males) controls with neither HFE mutation; 132 (65 males) and 270 (122 males), respectively, had serum iron measures at both timepoints. Mean serum ferritin (SF) and transferrin saturation (TS) were significantly greater for male and female compound heterozygotes than for wild-types at baseline and follow-up (all P < 0.02) except for females who were premenopausal at baseline, where SF was similar in both genotype groups. For subjects with serum measures from both baseline and follow-up, mean SF and TS levels did not change significantly for men or for postmenopausal women, but for premenopausal women SF levels increased from 43 to 109 μg/L for compound heterozygotes and from 35 to 64 μg/L for wild-types (both P < 0.001). Male and female compound heterozygotes had a similar prevalence of hemochromatosis-related morbidity to wild-types. One of 82 males and zero of 95 females had documented iron overload-related disease. Conclusion: For male compound heterozygotes, mean iron indices do not change during middle age but for female compound heterozygotes menopause results in increased mean SF. Although compound heterozygotes might maintain elevated iron indices during middle age, documented iron overload-related disease is rare. (Hepatology 2009;50:94–101.)
Joint interpretation of hydrological and geophysical data: electrical resistivity tomography results from a process hydrological research site in the Black Forest Mountains, Germany
Authors: Koch Kristof , Wenninger Jochen , Uhlenbrook Stefan , Bonell Mike 
Published: March 2009

AbstractThe use of electrical resistivity tomography (ERT; non‐intrusive geophysical technique) was assessed to identify the hydrogeological conditions at a surface water/groundwater test site in the southern Black Forest, Germany. A total of 111 ERT transects were measured, which adopted electrode spacings from 0·5 to 5 m as well as using either Wenner or dipole‐dipole electrode arrays. The resulting two‐dimensional (2D) electrical resistivity distributions are related to the structure and water content of the subsurface. The images were interpreted with respect to previous classical hillslope hydrological investigations within the same research basin using both tracer methods and groundwater level observations. A raster‐grid survey provided a quasi 3D resistivity pattern of the floodplain. Strong structural heterogeneity of the subsurface could be demonstrated, and (non)connectivities between surface and subsurface bodies were mapped. Through the spatial identification of likely flow pathways and source areas of runoff, the deep groundwater within the steeper valley slope seems to be much more connected to runoff generation processes within the valley floodplain than commonly credited in such environmental circumstances. Further, there appears to be no direct link between subsurface water‐bodies adjacent to the stream channel. Deep groundwater sources are also able to contribute towards streamflow from exfiltration at the edge of the floodplain as well as through the saturated areas overlying the floodplain itself. Such exfiltrated water then moves towards the stream as channelized surface flow. These findings support previous tracer investigations which showed that groundwater largely dominates the storm hydrograph of the stream, but the source areas of this component were unclear without geophysical measurements. The work highlighted the importance of using information from previous, complementary hydrochemical and hydrometric research campaigns to better interpret the ERT measurements. On the other hand, the ERT can provide a better spatial understanding of existing hydrochemical and hydrometric data. Copyright © 2009 John Wiley & Sons, Ltd.
A frequent target of paraproteins in the sera of patients with multiple myeloma and MGUS
Authors: Preuss Klaus‐Dieter , Pfreundschuh Michael , Ahlgrimm Manfred , Fadle Natalie , Regitz Evi , Murawski Niels , Grass Sandra 
Published: March 2009

AbstractAntigenic targets of monoclonal gammopathy of undetermined significance (MGUS) and multiple myeloma (MM) paraproteins might play a role in the pathogenesis of these neoplasms. We screened a human fetal brain‐derived macroarray with the IgA or IgG containing sera of 192 consecutive MGUS and MM patients. Twenty‐nine of 192 (15.1%) paraproteins reacted with paratarg‐7, a protein of unknown function which is expressed in all human tissues. Paratarg‐7 reactivity was similarly frequent among IgA and IgG paraproteins, but all paratarg‐7 reactive IgG paraproteins belonged to the IgG3 subtype with 24/57 IgG3 (42.1%) paraproteins displaying this specificity. Sequence analysis of paratarg‐7 derived from patients having a paraprotein with specificity for paratarg‐7 revealed no differences to paratarg‐7 derived from patients with paraproteins of other specificities or healthy controls, excluding mutations or polymorphisms as a reason for its autoimmunogenicity. Similarly, Western‐blot analysis showed identical bands for paratarg‐7 derived from patients and controls. The above‐random frequency of paratarg‐7 as a paraprotein target suggests that paratarg‐7 might be involved in the development of the respective clonal proliferations. The identification of paratarg‐7 as an antigenic target enables the more detailed analysis of tumor–host interactions in these patients and their role in the pathogenesis of MM and MGUS. © 2009 UICC
Triterpenes augment the inhibitory effects of anticancer drugs on growth of human esophageal carcinoma cells in vitro and suppress experimental metastasis in vivo
Authors: Yamai Hiromichi , Sawada Naruhiko , Yoshida Takahiro , Seike Jyunichi , Takizawa Hiromitsu , Kenzaki Koichiro , Miyoshi Takanori , Kondo Kazuya , Bando Yoshimi , Ohnishi Yoshinari , Tangoku Akira 
Published: March 2009

AbstractThe antineoplastic effects of combinations of anticancer drugs (5‐fluorouracil, irinotecan and cisplatin) and triterpenes (ursolic acid, betulinic acid, oleanolic acid and a Japanese apricot extract (JAE) containing triterpenes) on esophageal squamous carcinoma cells were examined by the WST‐8 (2‐(2‐methoxy‐ 4‐nitrophenyl)‐3‐(4‐nitrophenyl)‐5‐(2,4‐disulfophenyl)‐2H‐tetrazolium, monosodium salt) assay in vitro and by an animal model in vivo. Triterpenes and JAE showed additive and synergistic cytotoxic effects, respectively, on esophageal squamous carcinoma cells (YES‐2cells) by combinational use of 5‐fluorouracil. JAE and 5‐fluorouracil induced cell cycle arrest at G2/M phase and at S phase, respectively, and caused apoptosis in YES‐2 cells. A new animal model of esophageal cancer causing tumor colonization of the peritoneal cavity and producing bloody ascites was made by injecting YES‐2 cells into the peritoneal cavity of a severe combined immunodeficiency mouse. In this model, 5‐fluorouracil inhibited colonization of tumor cells in the peritoneum. The addition of JAE to 5‐fluorouracil augmented the suppression of experimental metastasis of the peritoneum. The numbers of peritoneal nodules of more than 2 mm in diameter in mice treated with 5‐fluorouracil and JAE were less than those in mice treated with 5‐fluorouracil alone or JAE alone. These results suggest that triterpenes, especially JAE, are effective supplements for enhancing the chemotherapeutic effect of 5‐fluorouracil on esophageal cancer. © 2009 UICC
HOX D13 expression across 79 tumor tissue types
Authors: Cantile Monica , Franco Renato , Tschan Adrienne , Baumhoer Daniel , Zlobec Inti , Schiavo Giulia , Forte Iris , Bihl Michel , Liguori Giuseppina , Botti Gerardo , Tornillo Luigi , Karamitopoulou‐Diamantis Eva , Terracciano Luigi , Cillo Clemente 
Published: March 2009

AbstractHOX genes control normal development, primary cellular processes and are characterized by a unique genomic network organization. Locus D HOX genes play an important role in limb generation and mesenchymal condensation. Dysregulated HOXD13 expression has been detected in breast cancer, melanoma, cervical cancer and astrocytomas. We have investigated the epidemiology of HOXD13 expression in human tissues and its potential deregulation in the carcinogenesis of specific tumors. HOXD13 homeoprotein expression has been detected using microarray technology comprising more than 4,000 normal and neoplastic tissue samples including 79 different tumor categories. Validation of HOXD13 expression has been performed, at mRNA level, for selected tumor types. Significant differences are detectable between specific normal tissues and corresponding tumor types with the majority of cancers showing an increase in HOXD13 expression (16.1% normal vs. 57.7% cancers). In contrast, pancreas and stomach tumor subtypes display the opposite trend. Interestingly, detection of the HOXD13 homeoprotein in pancreas‐tissue microarrays shows that its negative expression has a significant and adverse effect on the prognosis of patients with pancreatic cancer independent of the T or N stage at the time of diagnosis. Our study provides, for the first time, an overview of a HOX protein expression in a large series of normal and neoplastic tissue types, identifies pancreatic cancer as one of the most affected by the HOXD13 hoemoprotein and underlines the way homeoproteins can be associated to human cancerogenesis. © 2009 UICC
Design of a multiphase osteochondral scaffold III: Fabrication of layered scaffolds with continuous interfaces
Authors: Harley Brendan A. , Lynn Andrew K. , Wissner‐Gross Zachary , Bonfield William , Yannas Ioannis V. , Gibson Lorna J. 
Published: March 2009

AbstractThere is a need to improve current treatments for articular cartilage injuries. This article is the third in a series describing the design and development of an osteochondral scaffold based on collagen‐glycosaminoglycan and calcium phosphate technologies for regenerative repair of articular cartilage defects. The previous articles in this series described methods for producing porous, three‐dimensional mineralized collagen‐GAG (CGCaP) scaffolds whose composition can be reproducibly varied to mimic the composition of subchondral bone, and pore microstructure and mineral phase can be modified. This article describes a method, “liquid‐phase cosynthesis,” that enables the production of porous, layered scaffolds that mimic the composition and structure of articular cartilage on one side, subchondral bone on the other side, and the continuous, gradual or “soft” interface between these tissues: the tidemark of articular joints. This design enables the layered scaffolds to be inserted into the subchondral bone at an osteochondral defect site without the need for sutures, glue, or screws, with a highly interconnected porous network throughout the entire osteochondral defect. Moreover, the differential moduli of the osseous and cartilaginous compartments enable these layered scaffolds to exhibit compressive deformation behavior that mimics the behavior observed in natural articular joints. © 2009 Wiley Periodicals, Inc. J Biomed Mater Res, 2010