bluuebunny/crossref_metadata_2025 huggingface dataset:
Analytical Modeling of Cutting Point Trajectories in Milling
Authors: Spiewak S. A.
Published: April 2008

A modeling methodology applicable to milling is proposed. This methodology represents a unified approach, in which the essential features of previously developed analytic and numerical models are integrated. It employs homogeneous transformation technique and matrix formulation of the tool geometry. A systematic approach underlying the methodology facilitates separation of various features and phenomena characteristic of milling in the process of model building. It also assures the coherence and compatibility of various derived models. Thus, these models can be developed incrementally, by increasing their sophistication until the desired level of agreement with the actual process is achieved. As an example, equations of cutting point trajectories in face milling are derived. These equations are used to estimate the actual tool geometry and texture of the generated surface on the basis of measured cutting forces.
Clonal Spread of Highly β-Lactam-Resistant
Streptococcus pneumoniae
Isolates in Taiwan
Authors: Hsieh Yu-Chia , Chang Kuang-Yi , Huang Yi-Chuan , Lin Hsiao-Chuan , Ho Yu-Huai , Huang Li-Min , Hsueh Po-Ren
Published: April 2008

This study aimed to evaluate the antimicrobial susceptibility profiles of 364
Streptococcus pneumoniae
isolates and studied the genotypes of
S. pneumoniae
with high level β-lactam resistance in Taiwan. Clonal complexes related to Spain
23F
-1, Taiwan
19F
-14, and Taiwan
23F
-15 were responsible for the spread of isolates with high β-lactam resistance.
Selection of Replicon Variants Resistant to ACH-806, a Novel Hepatitis C Virus Inhibitor with No Cross-Resistance to NS3 Protease and NS5B Polymerase Inhibitors
Authors: Yang Wengang , Zhao Yongsen , Fabrycki Joanne , Hou Xiaohong , Nie Xingtie , Sanchez Amy , Phadke Avinash , Deshpande Milind , Agarwal Atul , Huang Mingjun
Published: April 2008

We have discovered a novel class of compounds active against hepatitis C virus (HCV), using a surrogate cellular system, HCV replicon cells. The leading compound in the series, ACH-806 (GS-9132), is a potent and specific inhibitor of HCV. The selection of resistance replicon variants against ACH-806 was performed to map the mutations conferring resistance to ACH-806 and to determine cross-resistance profiles with other classes of HCV inhibitors. Several clones emerged after the addition of ACH-806 to HCV replicon cells at frequencies and durations similar to that observed with NS3 protease inhibitors and NS5B polymerase inhibitors. Phenotypic analyses of these clones revealed that they are resistant to ACH-806 but remain sensitive to other classes of HCV inhibitors. Moreover, no significant change in the susceptibility to ACH-806 was found when the replicon cellular clones resistant to NS3 protease inhibitors and NS5B polymerase inhibitors were examined. Sequencing of the entire coding region of ACH-806-resistant replicon variants yielded several consensus mutations. Reverse genetics identified two single mutations in NS3, a cysteine-to-serine mutation at amino acid 16 and an alanine-to-valine mutation at amino acid 39, that are responsible for the resistance of the replicon variants to ACH-806. Both mutations are located at the N terminus of NS3 where extensive interactions with the central hydrophobic region of NS4A exist. These data provide evidence that ACH-806 inhibits HCV replication by a novel mechanism.
Decrease of Atazanavir and Lopinavir Plasma Concentrations in a Boosted Double Human Immunodeficiency Virus Protease Inhibitor Salvage Regimen
Authors: von Hentig Nils , Kaykhin Pavel , Stephan Christoph , Babacan Errol , Stürmer Martin , Staszewski Schlomo , Lötsch Jörn
Published: April 2008

The human immunodeficiency virus protease inhibitor combination of atazanavir (ATV)-lopinavir-ritonavir was reported to exhibit a mutual pharmacoenhancement of plasma lopinavir and ATV concentrations which may be beneficial for salvage patients. We identified 17 patients in our pharmacokinetic database taking this combination and found conflicting results. Plasma concentrations of both ATV and lopinavir were modestly, although not significantly, decreased when the drugs were coadministered. Therefore, patients should be selected carefully for this regimen and frequent clinical and therapeutic drug monitoring is strongly advised.
Inhibition of
Neisseria gonorrhoeae
Epithelial Cell Interactions by Vaginal
Lactobacillus
Species
Authors: Spurbeck Rachel R. , Arvidson Cindy Grove
Published: April 2008

High levels of
Lactobacillus
, the dominant genus of the healthy human vaginal microbiota, have been epidemiologically linked to a reduced risk of infection following exposure to the sexually transmitted pathogen
Neisseria gonorrhoeae
. In this work, a cell culture model of gonococcal infection was adapted to examine the effects of lactobacilli on gonococcal interactions with endometrial epithelial cells in vitro. Precolonization of epithelial cells with
Lactobacillus jensenii
,
Lactobacillus gasseri
ATCC 33323, or
L. gasseri
ATCC 9857 reduced gonococcal adherence by nearly 50%. Lactobacilli also inhibited gonococcal invasion of epithelial cells by more than 60%, which was independent of the effect on adherence. Furthermore, lactobacilli were able to displace adherent gonococci from epithelial cells, suggesting that these organisms have potential as a postexposure prophylactic. Thus, vaginal lactobacilli have the ability to inhibit gonococci at two key steps of an infection, which might have a significant effect in determining whether the gonococcus will be able to successfully establish an infection following exposure in vivo.
Root cortex death and subsequent initiation and growth of lateral roots from bare steles of chickpeas
Authors: Spaeth Stephen C. , Cortes Peter M.
Published: April 2008

The anatomical responses of chickpea (Cicer arietinum L.) roots to aging and severe water deficits and their capacity for subsequent initiation and growth of new lateral roots after rewatering are only partially known. This study was conducted to characterize the degeneration of epidermal and cortical cells of chickpea roots and the subsequent initiation and growth of new roots from bare steles, i.e., steles surrounded by an endodermis but lacking other parts of the cortex. Chickpea plants were grown in pots in a greenhouse under standard culture conditions (potting mix and daily watering) or drought treatments. For drought treatments, plants were grown in sand and exposed to repeated 10-d treatments of water deficits and rewatering. In standard culture conditions, older cortices collapsed and deteriorated but not simply as a function of chronological age. After one 10-d drought treatment, the epidermis and outer cortex of primary and some secondary and tertiary roots collapsed and after a subsequent rewatering treatment, the epidermis and cortex deteriorated and sloughed from steles. In both standard and drought conditions, bare steles were able to sustain growing root tips, indicating that the endodermis was effective in preserving stelar functions. In droughted plants, bare steles were able to initiate new lateral roots from the pericycle after rewatering, indicating that cortical tissue other than the endodermis was not necessary for secondary and tertiary chickpea roots to initiate new lateral roots. In a given root system exposed to the drought treatments, although the cortex collapsed on some roots, the cortices of other secondary roots did not collapse or deteriorate under similar severe conditions. The reason for cortical survival is unclear, but the response of these roots was similar to roots that have a suberized hypodermal layer which protects underlying cortical tissues from excessive drying. Key words: chickpea, Cicer arietinum L., drought, lateral roots, rewatering.
Allometry in the histogenesis of Prunus fruits (Rosaceae)
Authors: Barabé Denis , Daigle Stéphane , Labrecque Michel , St-Arnaud Marc
Published: April 2008

The authors have analyzed the relative growth of the various tissues of the fruits of two species of Prunus during their development: Prunus serotina Ehrh. and Prunus virginiana L. The results show that tissue development is allometric before the complete formation of the embryo. Once the embryo is formed, a statistical correlation no longer prevails between the metric increase in diameter of the various tissues. These results indicate that the development of the fruit wall of Prunus proceeds in two periods. The first period, before the development of the embryo is completed, constitutes a morphogenetic period during which the various tissues differentiate. The relationship between the inner endocarp and the outer endocarp is linear contrary to that of the mesocarp and the total endocarp, which is non linear. The allometric analysis shows that the endocarp grows more rapidly with respect to the mesocarp in P. virginiana than in P. serotina. Key words: fruit, development, allometry, growth, heterochrony.
Northern Squawfish,Ptychocheilus oregonensis, O2Consumption Rate and Respiration Model: Effects of Temperature and Body Size
Authors: Cech Jr. Joseph J. , Castleberry Daniel T. , Hopkins Todd E. , Petersen James H.
Published: April 2008

Northern squawfish, Ptychocheilus oregonensis (live weight range 0.361–1.973 kg), O2consumption was measured with temperature-controlled, flow-through respirometers for >24 h. Mean standard O2consumption rate of northern squawfish increased with acclimation temperature: 24.3, 49.1, 75.0, and 89.4 mg∙kg−0.67∙h−1at 9, 15, 18, and 21 °C, respectively. Q10analysis showed that O2consumption rate temperature sensitivity was greatest at the intermediate acclimation temperatures (15–18 °C, Q10 = 4.10), moderate at the lower acclimation temperatures (9–15 °C, Q10 = 3.23), and lowest at the higher acclimation temperatures (18–21 °C, Q10 = 1.80). Overall Q10was 2.96 (9–21 °C). Body size (W, grams) and temperature (T, degrees Celcius) were related to O2consumption ([Formula: see text], grams per gram per day) by [Formula: see text]W−0.285∙e0.105T. Northern squawfish red to white muscle ratios significantly exceeded those of rainbow trout, Oncorhynchus mykiss, in cross sections at 50 and 75% of standard length. High metabolic rates and red to white muscle ratios argue for comparability of northern squawfish with active predators such as sympatric rainbow trout.
Temperature and CO2Effects on Blood O2Equilibria in Northern Squawfish,Ptychocheilus oregonensis
Authors: Cech Jr. Joseph J. , Castleberry Daniel T. , Hopkins Todd E.
Published: April 2008

In vitro blood O2equilibrium curves were constructed at 9, 15, 18, and 21 °C from temperature-acclimated northern squawfish, Ptychocheilus oregonensis. At low [Formula: see text] (<1 mm Hg, 1 mm Hg = 133.32 Pa), P50s generally showed variable increases with temperature from 3.6 mm Hg at 9 °C to 8.7 mm Hg at 21 °C, leading to whole-blood temperature effects (ΔH, kilocalories per mole O2) ranging from a low +4.4 at 15–18 °C to a peak −21.2 at 18–21 °C. High-[Formula: see text] (7.6 mm Hg) conditions decreased blood pH and increased P50s at each temperature (Bohr factor). Bohr factors (Φ) ranged from −0.46 at 21 °C to −0.70 at 18 °C. Considered together, ΔH and Φ values suggest an optimal temperature range of 15–18 °C for hemoglobin O2loading and unloading in northern squawfish. Nonbicarbonate buffer values ranged from −10.04 at 21 °C to −14.13 at 9 °C. Overall, the high O2affinities and hyperbolic blood O2equilibrium curves of northern squawfish resemble those of other large cyprinids (e.g., common carp, Cyprinus carpio, tench, Tinca tinca, Sacramento blackfish, Orthodon microlepidotus) indicating a better ability to tolerate hypoxic environments than sympatric rainbow trout, Oncorhynchus mykiss. High northern squawfish blood O2capacities and Φs suggest high aerobic capacity, especially at temperatures <21 °C.
Use of Otolith Morphology in Stock Discriminations of Atlantic Salmon (Salmo salar)
Authors: Friedland K. D. , Reddin D. G.
Published: April 2008

Shape of sagittal otoliths was used to develop discriminant function models to classify Atlantic salmon (Salmo salar) by continent and country of origin. The outline shape was digitized with an image processor and used to calculate a complex Fourier transform of the closed contour and two shape indices, rectangularly and circularity. The shape indices and the magnitudes of the first 20 nonzero or nonidentity harmonics were used as input variables. Samples were obtained from known-origin one-sea-winter salmon captured in either Canada or West Greenland during 1986–88. Classification by continent of origin was designed to discriminate between North American and European salmon. Jackknifed classification efficiency was 88% for the continent model. Classification by country of origin was designed to discriminate between salmon of United States and Canada origin and between salmon of Ireland and United Kingdom origin; these models performed with classification efficiencies of 64 and 69%, respectively. These results suggest that otolith morphology may be an effective tool to identify continent of origin for salmon fisheries management. However, before the model is implemented, the discriminant function training set should be broadened to include a wider cross section of stocks likely to occur in mixed-stock fisheries.
Observations of Adult Atlantic Cod (Gadus morhua) Overwintering in Nearshore Waters of Trinity Bay, Newfoundland
Authors: Wroblewski J. S. , Bailey Wade L. , Howse Kristine A.
Published: April 2008

In the Random Island region of Trinity Bay, Newfoundland, individual adult Atlantic cod (Gadus morhua) with surgically implanted sonic transmitters were repeatedly relocated during the winter of 1990–91. Cod remained near shore, where seawater temperatures were as low as −1.5 °C. These fish did not move in the fall to offshore continental shelf waters as do most northern cod, nor did they move into the deeper waters of Trinity Bay that were slightly warmer than those in the nearshore zone. Of 12 cod released with transmitters in the fall and early winter, two were caught by local inshore fishermen the following spring, providing evidence that adult cod that overwinter nearshore become available to the spring inshore fishery. Another three were caught within a year of release. One fish was hooked in Fortune Bay on the southern coast of Newfoundland, having traveled a minimum distance of 305 nautical miles. These results demonstrate that northern cod can survive the surgical implantation of transmitters for at least a year and that this method is a valid technique for studying the behavior of northern cod. The main limitation to our sonic tracking was the relatively short range of signal reception (<1 nautical mile).
Zooplankton Communities and Water Chemistry of Sudbury Area Lakes: Changes Related to pH Recovery
Authors: Locke Andrea , Sprules W. Gary , Keller W. , Pitblado J. Roger
Published: April 2008

Temporal trends in pH, alkalinity, and crustacean zooplankton species richness and community composition were studied in 80 Sudbury area lakes sampled in 1971–76, 1981, and 1988–90. Alkalinity and pH have increased in recent years, but many of the study lakes remain quite acidic (modal pH 4.5–4.9). Species richness has also increased, on average, by 1.9 species/lake but is still low in many acid lakes relative to that in circumneutral lakes. Community composition differed among lakes of pH <5.0, 5.0–5.9, and ≥6.0, with some overlap between these groups because zooplankton recovery has lagged behind chemical recovery. Trajectories of community change in recovering acid lakes varied substantially in the early stages of recovery from highly acidic (pH <5.0) to moderately acidic pH (5.0–5.9). In contrast, trajectories in lakes recovered to pH ≥6.0 converged toward the community structure more typical of circumneutral lakes in the 1970's. This suggests that given sufficient time, zooplankton community structure of recovering lakes may approach that of circumneutral lakes.
Introduction
Authors: Bowyer Kevin , Martin Dianne
Published: April 2008

The Schubmehl-Prein Competition is open each year to high school juniors. The firstplace prize is $1,000, the second-place prize is $500, and the third-place prize is $250. Winning entries have also traditionally been published in the Association for Computing Machinery's Computers and Society online magazine.
What needs to be done: protecting critical infrastructure
Authors: Soyinka Tunlewa
Published: April 2008

It begins as a regular day in March of 1997, but by 9:00 a.m. all communications are down at the Worcester Airport in Massachusetts (Rindskopf). Telephone service at the airport and its fire department are cut off without warning. Six hours later all telephone service has been disabled in the entire surrounding area. Emergency services are jeopardized as the city's residents have lost the means to make calls for help, putting the health and safety of the public at risk. The airplanes have lost the means to coordinate landings and takeoffs at the airport, creating delays across the nation. In the span of a few hours, a juvenile computer hacker has single-handedly disrupted several sectors of the nation's critical infrastructure using only his personal computer as an aid (Rindskopf). This is just one of the thousands of instances in the past decade in which a cyber security breach has jeopardized the critical infrastructure of this nation.
A critical look at the TAB benchmark for physical design tools
Authors: Bruno Nicolas
Published: April 2008

There has recently been considerable research on physical design tuning algorithms. At the same time, there is only one published methodology to evaluate the quality of different, competing approaches: the TAB benchmark. In this paper we describe our experiences with TAB. We first report an experimental evaluation of TAB on our latest prototype for physical design tuning. We then identify certain weakness in the benchmark and briefly comment on alternatives to improve its usefulness.
Nulls, three-valued logic, and ambiguity in SQL
Authors: Rubinson Claude
Published: April 2008

Date's popular critique of SQL's three-valued logic [4, 3] purports to demonstrate that SQL queries can produce erroneous results when nulls are present in the database. I argue that this critique is flawed in that Date misinterprets the meaning of his example query. In fact, SQL returns the correct answer to the query posed; Date, however, believes that he is asking a different question. Although his critique is flawed, I agree with Date's general conclusion: SQL's use of nulls and three-valued logic introduces a startling amount of complexity into seemingly straightforward queries.
Report on the First International Workshop on Ranking in Databases (DBRank'07)
Authors: Ilyas Ihab F. , Das Gautam
Published: April 2008

This report summarizes the presentations, keynotes and discussions that took place during the first international workshop on ranking in databases (DBRank'07). The workshop was held on April 16, 2007, in conjunction with ICDE in Istanbul, Turkey.
Cyclin D1 and CDK4 Activity Contribute to the Undifferentiated Phenotype in Neuroblastoma
Authors: Molenaar Jan J. , Ebus Marli E. , Koster Jan , Sluis Peter van , van Noesel Carel J.M. , Versteeg Rogier , Caron Huib N.
Published: April 2008

Genomic aberrations of Cyclin D1 (CCND1), CDK4, and CDK6 in neuroblastoma indicate that dysregulation of the G1 entry checkpoint is an important cell cycle aberration in this pediatric tumor. Here, we report that analysis of Affymetrix expression data of primary neuroblastic tumors shows an extensive overexpression of Cyclin D1, which correlates with histologic subgroups. Immunohistochemical analysis showed overexpression of Cyclin D1 in neuroblasts and low Cyclin D1 expression in all cell types in ganglioneuroma. This suggests an involvement of G1-regulating genes in neuronal differentiation processes which we further evaluated using RNA interference against Cyclin D1 and its kinase partners CDK4 and CDK6 in several neuroblastoma cell lines. The Cyclin D1 and CDK4 knockdown resulted in pRb pathway inhibition as shown by an almost complete disappearance of CDK4/CDK6-specific pRb phosphorylation, reduction of E2F transcriptional activity, and a decrease of Cyclin A protein levels. Phenotype analysis showed a significant reduction in cell proliferation, a G1-specific cell cycle arrest, and, moreover, an extensive neuronal differentiation. Affymetrix microarray profiling of small interfering RNA–treated cells revealed a shift in expression profile toward a neuronal phenotype. Several new potential downstream players are identified. We conclude that neuroblastoma functionally depend on overexpression of G1-regulating genes to maintain their undifferentiated phenotype. [Cancer Res 2008;68(8):2599–609]
Matrix Metalloproteinase-8 Functions as a Metastasis Suppressor through Modulation of Tumor Cell Adhesion and Invasion
Authors: Gutiérrez-Fernández Ana , Fueyo Antonio , Folgueras Alicia R. , Garabaya Cecilia , Pennington Caroline J. , Pilgrim Simon , Edwards Dylan R. , Holliday Deborah L. , Jones J. Louise , Span Paul N. , Sweep Fred C.G.J. , Puente Xose S. , López-Otín Carlos
Published: April 2008

Collagenase-2 (matrix metalloproteinase-8, MMP-8) is an MMP mainly produced by neutrophils and associated with many inflammatory conditions. We have previously described that MMP-8 plays a protective role in cancer through its ability to regulate the inflammatory response induced by carcinogens. Moreover, it has been reported that experimental manipulation of the expression levels of this enzyme alters the metastatic behavior of human breast cancer cells. In this work, we have used mutant mice deficient in MMP-8 and syngenic melanoma and lung carcinoma tumor cells lines overexpressing this enzyme to further explore the putative antimetastatic potential of MMP-8. We report herein that MMP-8 prevents metastasis formation through the modulation of tumor cell adhesion and invasion. Thus, tumor cells overexpressing MMP-8 have an increased adhesion to extracellular matrix proteins, whereas their invasive ability through Matrigel is substantially reduced when compared with control cells. Analysis of MMP-8 in breast cancer patients revealed that the expression of this metalloproteinase by breast tumors correlates with a lower incidence of lymph node metastasis and confers good prognosis to these patients. On this basis, we propose that MMP-8 is a tumor protective factor, which also has the ability to reduce the metastatic potential of malignant cells in both mice and human. [Cancer Res 2008;68(8):2755–63]
Genome-Wide Promoter Analysis Uncovers Portions of the Cancer Methylome
Authors: Hoque Mohammad Obaidul , Kim Myoung Sook , Ostrow Kimberly Laskie , Liu Junwei , Wisman G. Bea A. , Park Hannah Lui , Poeta Maria Luana , Jeronimo Carmen , Henrique Rui , Lendvai Ágnes , Schuuring Ed , Begum Shahnaz , Rosenbaum Eli , Ongenaert Maté , Yamashita Keishi , Califano Joseph , Westra William , van der Zee Ate G.J. , Criekinge Wim Van , Sidransky David
Published: April 2008

DNA methylation has a role in mediating epigenetic silencing of CpG island genes in cancer and other diseases. Identification of all gene promoters methylated in cancer cells “the cancer methylome” would greatly advance our understanding of gene regulatory networks in tumorigenesis. We previously described a new method of identifying methylated tumor suppressor genes based on pharmacologic unmasking of the promoter region and detection of re-expression on microarray analysis. In this study, we modified and greatly improved the selection of candidates based on new promoter structure algorithm and microarray data generated from 20 cancer cell lines of 5 major cancer types. We identified a set of 200 candidate genes that cluster throughout the genome of which 25 were previously reported as harboring cancer-specific promoter methylation. The remaining 175 genes were tested for promoter methylation by bisulfite sequencing or methylation-specific PCR (MSP). Eighty-two of 175 (47%) genes were found to be methylated in cell lines, and 53 of these 82 genes (65%) were methylated in primary tumor tissues. From these 53 genes, cancer-specific methylation was identified in 28 genes (28 of 53; 53%). Furthermore, we tested 8 of the 28 newly identified cancer-specific methylated genes with quantitative MSP in a panel of 300 primary tumors representing 13 types of cancer. We found cancer-specific methylation of at least one gene with high frequency in all cancer types. Identification of a large number of genes with cancer-specific methylation provides new targets for diagnostic and therapeutic intervention, and opens fertile avenues for basic research in tumor biology. [Cancer Res 2008;68(8):2661–70]
NOV-002, a Glutathione Disulfide Mimetic, as a Modulator of Cellular Redox Balance
Authors: Townsend Danyelle M. , He Lin , Hutchens Steven , Garrett Tracy E. , Pazoles Christopher J. , Tew Kenneth D.
Published: April 2008

NOV-002 is a novel glutathione disulfide mimetic that when administered in combination with standard chemotherapeutic regimens has resulted in increased efficacy (survival, tumor response) and improved tolerance to chemotherapy (e.g., hematologic recovery) in advanced non–small cell lung cancer patients. We show that NOV-002, which is not cytotoxic as a single agent, generated time- and concentration-dependent oxidative signals at the cell surface (reduction in protein thiols) and intracellularly [altered oxidized glutathione (GSSG) and reduced glutathione levels and ratio; increased reactive oxygen species] in the premyeloid HL-60 cell line and that this was associated with an increase in S-glutathionylation of cell proteins, particularly actin. Commensurate with these effects, NOV-002 activated p38, c-Jun-NH2-kinase, and extracellular signal-regulated kinase and caused a dose-dependent increase in phosphorylation of three proteins that have previously been linked with hematopoiesis, AKT, JAK2, and STAT5. The effect of NOV-002 on enzymes involved in glutathione metabolism was evaluated. Relative to oxidized glutathione, NOV-002 was an equivalent substrate for glutathione reductase and was an inhibitor of protein disulfide isomerase, one of the components of the redox-sensitive unfolded protein response pathway. These redox-stimulated cell signaling actions occurred in the context of increased HL-60 cell proliferation after treatment with NOV-002. Overall, the pleiotropic pharmacologic effects of NOV-002 can be attributed to the GSSG component of the drug, and modulation of cellular redox balance is a feature central to the mechanism of action of NOV-002. Such modulation may underlie its clinical actions, including hematologic recovery and immunostimulation in the face of chemosuppression. [Cancer Res 2008;68(8):2870–7]
A New Pharmacologic Action of CCI-779 Involves FKBP12-Independent Inhibition of mTOR Kinase Activity and Profound Repression of Global Protein Synthesis
Authors: Shor Boris , Zhang Wei-Guo , Toral-Barza Lourdes , Lucas Jessica , Abraham Robert T. , Gibbons James J. , Yu Ker
Published: April 2008

The mammalian target of rapamycin (mTOR) inhibitor CCI-779 (temsirolimus) is a recently Food and Drug Administration–approved anticancer drug with efficacy in certain solid tumors and hematologic malignancies. In cell culture studies, CCI-779 at the commonly used nanomolar concentrations generally confers a modest and selective antiproliferative activity. Here, we report that, at clinically relevant low micromolar concentrations, CCI-779 completely suppressed proliferation of a broad panel of tumor cells. This “high-dose” drug effect did not require FKBP12 and correlated with an FKBP12-independent suppression of mTOR signaling. An FKBP12-rapamycin binding domain (FRB) binding–deficient rapamycin analogue failed to elicit both the nanomolar and micromolar inhibitions of growth and mTOR signaling, implicating FRB binding in both actions. Biochemical assays indicated that CCI-779 and rapamycin directly inhibited mTOR kinase activity with IC50 values of 1.76 ± 0.15 and 1.74 ± 0.34 μmol/L, respectively. Interestingly, a CCI-779–resistant mTOR mutant (mTOR-SI) displayed an 11-fold resistance to the micromolar CCI-779 in vitro (IC50, 20 ± 3.4 μmol/L) and conferred a partial protection in cells exposed to micromolar CCI-779. Treatment of cancer cells with micromolar but not nanomolar concentrations of CCI-779 caused a marked decline in global protein synthesis and disassembly of polyribosomes. The profound inhibition of protein synthesis was accompanied by rapid increase in the phosphorylation of translation elongation factor eEF2 and the translation initiation factor eIF2α. These findings suggest that high-dose CCI-779 inhibits mTOR signaling through an FKBP12-independent mechanism that leads to profound translational repression. This distinctive high-dose drug effect could be directly related to the antitumor activities of CCI-779 and other rapalogues in human cancer patients. [Cancer Res 2008;68(8):2934–43]
DNA Methyltransferase 1 and 3B Activate BAG-1 Expression via Recruitment of CTCFL/BORIS and Modulation of Promoter Histone Methylation
Authors: Sun Lunching , Huang Lei , Nguyen Phuongmai , Bisht Kheem S. , Bar-Sela Gil , Ho Allen S. , Bradbury C. Matthew , Yu Wenqiang , Cui Hengmi , Lee Sunmin , Trepel Jane B. , Feinberg Andrew P. , Gius David
Published: April 2008

In a previous genomic analysis, using somatic methyltransferase (DNMT) knockout cells, we showed that hypomethylation decreased the expression of as many genes as were observed to increase, suggesting a previously unknown mechanism for epigenetic regulation. To address this idea, the expression of the BAG family genes was used as a model. These genes were used because their expression was decreased in DNMT1−/−, DNMT3B−/−, and double knockout cells and increased in DNMT1-overexpressing and DNMT3B-overexpressing cells. Chromatin immunoprecipitation analysis of the BAG-1 promoter in DNMT1-overexpressing or DNMT3B-overexpressing cells showed a permissive dimethyl-H3-K4/dimethyl-H3-K9 chromatin status associated with DNA-binding of CTCFL/BORIS, as well as increased BAG-1 expression. In contrast, a nonpermissive dimethyl-H3-K4/dimethyl-H3-K9 chromatin status was associated with CTCF DNA-binding and decreased BAG-1 expression in the single and double DNMT knockout cells. BORIS short hairpin RNA knockdown decreased both promoter DNA-binding, as well as BAG-1 expression, and changed the dimethyl-H3-K4/dimethyl-H3-K9 ratio to that characteristic of a nonpermissive chromatin state. These results suggest that DNMT1 and DNMT3B regulate BAG-1 expression via insulator protein DNA-binding and chromatin dynamics by regulating histone dimethylation. [Cancer Res 2008;68(8):2726–35]
Profound Inhibition of Antigen-Specific T-Cell Effector Functions by Dasatinib
Authors: Weichsel Ralf , Dix Carolin , Wooldridge Linda , Clement Matthew , Fenton-May Angharad , Sewell Andrew K. , Zezula Josef , Greiner Elisabeth , Gostick Emma , Price David A. , Einsele Hermann , Seggewiss Ruth
Published: April 2008

Purpose: The dual BCR-ABL/SRC kinase inhibitor dasatinib entered the clinic for the treatment of chronic myeloid leukemia and Ph+ acute lymphoblastic leukemia. Because SRC kinases are known to play an important role in physiologic T-cell activation, we analyzed the immunobiological effects of dasatinib on T-cell function. The effect of dasatinib on multiple T-cell effector functions was examined at clinically relevant doses (1-100 nmol/L); the promiscuous tyrosine kinase inhibitor staurosporine was used as a comparator.

Experimental Design: Purified human CD3+ cells and virus-specific CD8+ T cells from healthy blood donors were studied directly ex vivo; antigen-specific effects were confirmed in defined T-cell clones. Functional outcomes included cytokine production (interleukin-2, IFNγ, and tumor necrosis factor α), degranulation (CD107a/b mobilization), activation (CD69 up-regulation), proliferation (carboxyfluorescein diacetate succinimidyl ester dilution), apoptosis/necrosis induction, and signal transduction.

Results: Both dasatinib and staurosporine inhibited T-cell activation, proliferation, cytokine production, and degranulation in a dose-dependent manner. Mechanistically, this was mediated by the blockade of early signal transduction events and was not due to loss of T-cell viability. Overall, CD4+ T cells seemed to be more sensitive to these effects than CD8+ T cells, and naïve T cells more sensitive than memory T-cell subsets. The inhibitory effects of dasatinib were so profound that all T-cell effector functions were shut down at therapeutically relevant concentrations.

Conclusion: These findings indicate that caution is warranted with use of this drug in the clinical setting and provide a rationale to explore the potential of dasatinib as an immunosuppressant in the fields of transplantation and T-cell–driven autoimmune diseases.
Up-Regulation of Peroxiredoxin 1 in Lung Cancer and Its Implication as a Prognostic and Therapeutic Target
Authors: Kim Joo-Heon , Bogner Paul N. , Baek Sun-Hee , Ramnath Nithya , Liang Ping , Kim Hak-Ryul , Andrews Chris , Park Young-Mee
Published: April 2008

Purpose: Peroxiredoxin 1 and 2 are highly homologous members of the Prx (or Prdx) protein family. Prx1 and Prx2 are elevated in several human cancers, and this seems to confer increased treatment resistance and aggressive phenotypes. This study was undertaken to examine the expression profiles of Prx1 and Prx2 in non–small cell lung cancer (NSCLC), and to test their prognostic value in predicting patient survival.

Experimental Design: To gain insight into the regulatory mechanisms of Prx1 and Prx2 expression in NSCLC, their respective transcript profiles were examined in NSCLC cell lines from the NCI-60 panel Affymetrix database sets, and the promoter compositions of the two genes were investigated using computer-based multiple sequence alignment analyses. Immunohistochemical analyses of Prx1 and Prx2 were done on a total of 235 NSCLC specimens with stage I through IV disease. The expression profiles of Prx1 and Prx2 in tumor specimens, and their associations with survival, were investigated.

Results and Conclusion: The levels of prx1 transcript were higher than those of prx2 in NSCLC cell lines, and the upstream regulatory sequences of the two genes display striking differences. The relative risk of death increased as Prx1 expression levels increased (P = 0.036) in a multivariate Cox model, independent of other clinicopathologic variables associated with survival. No statistically significant correlation was observed between Prx2 and survival. These results suggest that Prx1 may possess unique functions and regulatory mechanisms in NSCLC which are not shared with Prx2, and that Prx1 may serve as a new prognostic biomarker and therapeutic target in NSCLC.
Effects of protein kinase C modulation by PEP005, a novel ingenol angelate, on mitogen-activated protein kinase and phosphatidylinositol 3-kinase signaling in cancer cells
Authors: Serova Maria , Ghoul Aïda , Benhadji Karim A. , Faivre Sandrine , Le Tourneau Christophe , Cvitkovic Esteban , Lokiec Francois , Lord Janet , Ogbourne Steven M. , Calvo Fabien , Raymond Eric
Published: April 2008

PEP005 (ingenol-3-angelate) is a novel anticancer agent extracted from Euphorbia peplus that was previously shown to modulate protein kinase C (PKC), resulting in antiproliferative and proapoptotic effects in several human cancer cell lines. In Colo205 colon cancer cells, exposure to PEP005 induced a time- and concentration-dependent decrease of cells in S phase of cell cycle and apoptosis. In Colo205 cells exposed to PEP005, a variety of signaling pathways were activated as shown by increased phosphorylation of PKCδ, Raf1, extracellular signal-regulated kinase 1/2 mitogen-activated protein kinase (MAPK), c-Jun NH2-terminal kinase, p38 MAPK, and PTEN. PEP005-induced activation of PKCδ was associated with its translocation from the cytosol to the nucleus and other cellular membranes. Interestingly, PEP005 treatment also resulted in reduced expression of PKCα and reduced levels of phosphorylated active form of AKT/protein kinase B. These data suggest that PEP005-induced activation of PKCδ and reduced expression of PKCα resulted in apoptosis by mechanisms mediated by activation of Ras/Raf/MAPK and inhibition of the phosphatidylinositol 3-kinase/AKT signaling pathways. This study supports ongoing efforts targeting PKC isoforms in cancer therapy with PEP005 alone and in combination with other cytotoxic agents. [Mol Cancer Ther 2008;7(4):915–22]
Pharmacological Inhibition of ε-Protein Kinase C Attenuates Cardiac Fibrosis and Dysfunction in Hypertension-Induced Heart Failure
Authors: Inagaki Koichi , Koyanagi Tomoyoshi , Berry Natalia C. , Sun Lihan , Mochly-Rosen Daria
Published: April 2008

Studies on genetically manipulated mice suggest a role for ε-protein kinase C (εPKC) in cardiac hypertrophy and in heart failure. The potential clinical relevance of these findings was tested here using a pharmacological inhibitor of εPKC activity during the progression to heart failure in hypertensive Dahl rats. Dahl rats, fed an 8% high-salt diet from the age of 6 weeks, exhibited compensatory cardiac hypertrophy by 11 weeks, followed by heart failure at ≈17 weeks and death by the age of ≈20 weeks (123±3 days). Sustained treatment between weeks 11 and 17 with the selective εPKC inhibitor εV1-2 or with an angiotensin II receptor blocker olmesartan prolonged animal survival by ≈5 weeks (εV1-2: 154±7 days; olmesartan: 149±5 days). These treatments resulted in improved fractional shortening (εV1-2: 58±2%; olmesartan: 53±2%; saline: 41±6%) and decreased cardiac parenchymal fibrosis when measured at 17 weeks without lowering blood pressure at any time during the treatment. Combined treatment with εV1-2, together with olmesartan, prolonged animal survival by 5 weeks (37 days) relative to olmesartan alone (from 160±5 to 197±14 days, respectively) and by ≈11 weeks (74 days) on average relative to saline-treated animals, suggesting that the pathway inhibited by εPKC inhibition is not identical to the olmesartan-induced effect. These data suggest that an εPKC-selective inhibitor such as εV1-2 may have a potential in augmenting current therapeutic strategies for the treatment of heart failure in humans.
Two-Sample Kalman Filter for Steady-State Data Assimilation
Authors: Sumihar Julius H. , Verlaan Martin , Heemink Arnold W.
Published: April 2008

In this paper, a new iterative algorithm for computing a steady-state Kalman gain is proposed. This algorithm utilizes two model forecasts with statistically independent random perturbations to determine the error covariance used to define a Kalman gain matrix for steady-state data assimilation. It is based on the assumption that the error process is weakly stationary and ergodic. The algorithm consists of an iterative procedure for improving the covariance estimate, which requires a fixed observation network. Two twin experiments using a simple wave model and an operational storm surge prediction model are performed to demonstrate the performance of the proposed algorithm. The experiments show that the results obtained by using the proposed algorithm converge to the ones produced by the classic Kalman filter algorithm. An additional experiment using the three-variable Lorenz model is also performed to demonstrate its potential applicability in unstable dynamical systems.
Dilemmas of Local Governance under the Development Zone Fever in China: A Case Study of the Suzhou Region
Authors: Yang Daniel You-Ren , Wang Hung-Kai
Published: April 2008

This article aims to explore the mechanisms of the development zone fever in the Suzhou region, located in the fast-growing Yangtze River Delta, and investigates, from an institutional perspective, the practice of relevant intragovernmental governance in the context of rapid industrialisation since the 1990s. A specific mode of governance—the evaluative economic indicators scheme inherited from the earlier socialist planning system, combined with the party/state's promotion/evaluation system—plays an essential role in this transformation of farmland property rights. However, this model of development is not necessarily helpful for local financial conditions and it results in the disclacement of peasants and the loss of land resources. Based on the resulting `dilemmas of governance', it is argued that, in addition to the `economic paradigm', which focuses on consequences of fiscal reforms and devolution, scholars should pay more attention to factors such as the party/state's promotion/evaluation system and the stress between the evaluative indicators system maintained by the central/local sectoral command and the territorial jurisdictions. This could be helpful in gaining a fuller understanding of the dynamics and tensions of local developments in China.
Women's Leisure as Reproduction and Resistance
Authors: Jane Du
Published: April 2008

This article examines the experiences of 31 participants in three women's folk dance groups in Taiwan through the reproduction/resistance perspectives, which regard leisure as a means either to enhance or to challenge traditional gender ideologies and inequities. The findings suggest that the difference between reproducing or resisting societally imposed constraints lies in the negotiation strategy that is used, rather than in constraining factors, and that the coping strategy of negotiation is critical for women's resistance. Implications for social work are discussed.
Eight-year experience with allogeneic stem cell transplantation for relapsed follicular lymphoma after nonmyeloablative conditioning with fludarabine, cyclophosphamide, and rituximab
Authors: Khouri Issa F. , McLaughlin Peter , Saliba Rima M. , Hosing Chitra , Korbling Martin , Lee Ming S. , Medeiros L. Jeffrey , Fayad Luis , Samaniego Felipe , Alousi Amin , Anderlini Paolo , Couriel Daniel , de Lima Marcos , Giralt Sergio , Neelapu Sattva S. , Ueno Naoto T. , Samuels Barry I. , Hagemeister Fredrick , Kwak Larry W. , Champlin Richard E.
Published: April 2008

Nonmyeloablative stem cell transplantation in patients with follicular lymphoma has been designed to exploit the graft-versus-lymphoma immunity. The long-term effectiveness and toxicity of this strategy, however, is unknown. In this prospective study, we analyzed our 8-year experience. Patients received a conditioning regimen of fludarabine (30 mg/m2 daily for 3 days), cyclophosphamide (750 mg/m2 daily for 3 days), and rituximab (375 mg/m2 for 1 day plus 1000 mg/m2 for 3 days). They were then given an infusion of human leukocyte antigen-matched hematopoietic cells from related (n = 45) or unrelated donors (n = 2). Tacrolimus and methotrexate were used for graft-versus-host disease (GVHD) prophylaxis. Forty-seven patients were included. All patients experienced complete remission, with only 2 relapses. With a median follow-up time of 60 months (range, 19-94), the estimated survival and progression-free survival rates were 85% and 83%, respectively. All 18 patients who were tested and had evidence of JH/bcl-2 fusion transcripts in the bone marrow at study entry experienced continuous molecular remission. The incidence of grade 2-IV acute GVHD was 11%. Only 5 patients were still undergoing immunosuppressive therapy at the time of last follow-up. We believe that the described results are a step forward toward developing a curative strategy for recurrent follicular lymphoma.
Analysis of bacterial DNA in synovial tissue of Tunisian patients with reactive and undifferentiated arthritis by broad-range PCR, cloning and sequencing
Authors: Siala Mariam , Jaulhac Benoit , Gdoura Radhouane , Sibilia Jean , Fourati Hela , Younes Mohamed , Baklouti Sofien , Bargaoui Naceur , Sellami Slaheddine , Znazen Abir , Barthel Cathy , Collin Elody , Hammami Adnane , Sghir Abdelghani
Published: April 2008

Introduction

Bacteria and/or their antigens have been implicated in the pathogenesis of reactive arthritis (ReA). Several studies have reported the presence of bacterial antigens and nucleic acids of bacteria other than those specified by diagnostic criteria for ReA in joint specimens from patients with ReA and various arthritides. The present study was conducted to detect any bacterial DNA and identify bacterial species that are present in the synovial tissue of Tunisian patients with reactive arthritis and undifferentiated arthritis (UA) using PCR, cloning and sequencing.

Methods

We examined synovial tissue samples from 28 patients: six patients with ReA and nine with UA, and a control group consisting of seven patients with rheumatoid arthritis and six with osteoarthritis (OA). Using broad-range bacterial PCR producing a 1,400-base-pair fragment from the 16S rRNA gene, at least 24 clones were sequenced for each synovial tissue sample. To identify the corresponding bacteria, DNA sequences were compared with sequences from the EMBL (European Molecular Biology Laboratory) database.

Results

Bacterial DNA was detected in 75% of the 28 synovial tissue samples. DNA from 68 various bacterial species were found in ReA and UA samples, whereas DNA from 12 bacteria were detected in control group samples. Most of the bacterial DNAs detected were from skin or intestinal bacteria. DNA from bacteria known to trigger ReA, such as Shigella flexneri and Shigella sonnei, were detected in ReA and UA samples of synovial tissue and not in control samples. DNA from various bacterial species detected in this study have not previously been found in synovial samples.

Conclusion

This study is the first to use broad-range PCR targeting the full 16S rRNA gene for detection of bacterial DNA in synovial tissue. We detected DNA from a wide spectrum of bacterial species, including those known to be involved in ReA and others not previously associated with ReA or related arthritis. The pathogenic significance of some of these intrasynovial bacterial DNAs remains unclear.