bluuebunny/crossref_metadata_2025 huggingface dataset:
Bi20 (fBTA05), a novel trifunctional bispecific antibody (anti‐CD20 × anti‐CD3), mediates efficient killing of B‐cell lymphoma cells even with very low CD20 expression levels
Authors: Stanglmaier Michael , Faltin Margot , Ruf Peter , Bodenhausen Annette , Schröder Petra , Lindhofer Horst
Published: June 2008

Trifunctional bispecific antibodies can efficiently mediate tumor cell killing by redirecting T cells and immune accessory cells to the tumor cell. Here, we describe the new trifunctional antibody, Bi20 (FBTA05, anti‐CD20 × anti‐CD3), that connects B cells and T cells via its variable regions and recruits FcγRI+ accessory immune cells via its Fc region. Bi20 mediated efficient and specific lysis of B‐cell lines and of B cells with low CD20 expression levels that were derived from CLL patients. Remarkably, T‐cell activation and tumor cell killing occurred in an entirely autologous setting without additional effector cells in 5 of 8 samples. In comparison, rituximab, a chimeric monoclonal CD20 antibody, demonstrated a significantly lower B‐cell eradication rate. Additionally, Bi20, but not rituximab, upregulated the activation markers CD25 and CD69 on both CD4+ and CD8+ T cells in the presence of accessory immune cells. CD14+ accessory cells and the monocyte cell line THP‐1 were activated via binding of the Fc region of Bi20, given that T cells were simultaneously engaged by the antibody. Bi20 induced a strong Th1 cytokine pattern characterized by high IFN‐γ and very low IL‐4 secretion. In conclusion, Bi20 may offer new immunotherapeutic options for the treatment of B‐cell lymphomas. © 2008 Wiley‐Liss, Inc.
Global analysis of metastasis‐associated gene expression in primary cultures from clinical specimens of clear‐cell renal‐cell carcinoma
Authors: Tan Xiaojie , Zhai Yujia , Chang Wenjun , Hou Jianguo , He Songqin , Lin Liping , Yu Yongwei , Xu Danfeng , Xiao Jianru , Ma Liye , Wang Guoping , Cao Tinghu , Cao Guangwen
Published: June 2008

Metastatic clear‐cell renal‐cell carcinoma (ccRCC) has a poor prognosis and unpredictable course, and there are no molecular markers that reliably predict ccRCC metastasis. In this study, ccRCC specimens from 84 patients were directly cultured in vitro. Primary cultures from 38 of 94 specimens contained more than 90% tumor cells at the fourth passage. After identification by immunostaining, the primary cultures of metastatic and nonmetastatic ccRCC specimens from the age‐ and gender‐matched patients were subjected to cDNA microarray assays. A total of 842 differentially expressed genes with a FDR (false discovery rate) of 4.79% were identified. Pathway analysis and co‐occurrence with “cancer”, “metastasis” and “invasion” in the literature annotations functionally enriched the 842 genes and provided an indication of the reliability of our microarray assays. Novel genes associated with metastasis were selected based on protein‐protein interactions between 205 differentially expressed genes that co‐occurred with “metastasis” and those that did not co‐occur with “metastasis” on Medline, and the results of co‐expression analysis between the co‐occurred genes and unpublished genes. FSTL1, AV722783, SLC15A1, DDX17, ORC2L and PKMYT1 were found to be potential ccRCC metastasis‐associated novel genes, according to expression patterns in cultures and tumor tissues. Interestingly, the upregulated genes (CAV1, PKMYT1 and ORC2L) were also upregulated and the downregulated genes (FSTL1, GSTM3, CYR61, SLC15A1 and AV722783) were also downregulated in the primary ccRCC specimens compared with expression in adjacent renal tissues in 37 patients. This study has identified new candidate biomarkers and targets for the early diagnosis and treatment of ccRCC metastasis. © 2008 Wiley‐Liss, Inc.
The high affinity peroxisome proliferator‐activated receptor‐gamma agonist RS5444 inhibits both initiation and progression of colon tumors in azoxymethane‐treated mice
Authors: Su Weidong , Necela Brian M. , Fujiwara Kosaku , Kurakata Shinichi , Murray Nicole R. , Fields Alan P. , Thompson E. Aubrey
Published: June 2008

We evaluated RS5444, a thiazolidinedione high affinity PPARγ agonist, for the ability to inhibit colon carcinogenesis in azoxymethane (AOM)‐treated mice. In our initial experiment, mice were treated with RS5444 during AOM treatment, and the drug was withdrawn 12 weeks after the last injection of AOM. RS5444 significantly inhibited aberrant crypt focus formation under these circumstances. Furthermore, exposure to RS5444 during the course of AOM treatment effectively blocked colon tumor formation after withdrawal of the agonist. PPARγ expression and nuclear localization were reduced in adenomas. RS5444 did not inhibit DNA synthesis in tumor cells, suggesting that PPARγ activity was impaired in adenomas. To test this hypothesis, pre‐existing adenomas were treated with RS5444 for 16 weeks. We observed a slight, albeit not statistically significant, reduction in tumor incidence in RS5444‐treated mice. However, histological examination revealed that tumors from RS5444‐treated mice were of significantly lower grade, as evaluated by the extent of dysplasia. Furthermore, carcinoma in situ was observed in about one‐third of control tumors, but was never observed in RS5444‐treated tumors. We conclude that RS5444 inhibits both initiation and progression of colon tumors in the AOM model of sporadic colon carcinogenesis. © 2008 Wiley‐Liss, Inc.
Dietary α‐, β‐, γ‐ and δ‐tocopherols in lung cancer risk
Authors: Mahabir Somdat , Schendel Kalli , Dong Yong Quan , Barrera Stephanie L. , Spitz Margaret R. , Forman Michele R.
Published: June 2008

Studies of vitamin E and cancer have focused on the α‐tocopherol form of the vitamin. However, other forms of vitamin E, in particular γ‐tocopherol may have unique mechanistic characteristics relevant to lung cancer prevention. In an ongoing study of 1,088 incident lung cancer cases and 1,414 healthy matched controls, we studied the associations between 4 tocopherols (α‐, β‐, γ‐, and δ‐tocopherol) in the diet and lung cancer risk. Using multiple logistic regression analysis, the adjusted odds ratios (OR) and 95% confidence intervals (CI) of lung cancer for increasing quartiles of dietary α‐tocopherol intake were 1.0, 0.63 (0.50–0.79), 0.58 (0.44–0.76) and 0.39 (0.28–0.53), respectively (p‐trend < 0.0001). For dietary intake of β‐tocopherol, the OR and 95% CI for all subjects were: 1.0, 0.79 (0.63–0.98), 0.59 (0.45–0.78) and 0.56 (0.42–0.74), respectively (p‐trend < 0.0001). Similar results for dietary γ‐tocopherol intake were observed: 1.0, 0.84 (0.67–1.06), 0.76 (0.59–0.97) and 0.56 (0.42–0.75), respectively (p‐ trend = 0.0002). No significant association between δ‐tocopherol intake and lung cancer risk was detected. When the 4 tocopherols were summed as total tocopherol intake, a monotonic risk reduction was also observed. When we entered the other tocopherols in our model, only the association with dietary α‐tocopherol intake remained significant; i.e., increasing intake of dietary α‐tocopherol accounted for 34–53% reductions in lung cancer risk. To the best of our knowledge, this is the first report of the independent associations of the 4 forms of dietary tocopherol (α‐, β‐, γ‐ and δ‐tocohperol) on lung cancer risk. Given the limitations with case‐control studies, these findings need to be confirmed in further investigations. © 2008 Wiley‐Liss, Inc.
CpG island methylator phenotype association with upregulated telomerase activity in hepatocellular carcinoma
Authors: Zhang Changsong , Guo Xianling , Jiang Guocheng , Zhang Li , Yang Yang , Shen Feng , Wu Mengchao , Wei Lixin
Published: June 2008

CpG island methylator phenotype (CIMP) involves the targeting of multiple genes by promoter hypermethylation. Telomerase plays an important role in the development of cellular immortality and oncogenesis. To gain insight into the role of epigenetic aberration of telomerase‐related genes in hepatocarcinogenesis, we determined a hypermethylation profile in HCC. We examined the promoter methylation status of 9 genes associated with telomerase activity in 120 HCC, 120 cirrhosis tissues and 10 normal liver tissues by methylation‐specific PCR. Assay of telomerase activity was by TRAP‐ELISA. The frequency of promoter methylation of each gene wasP2163.3%,P1542.5%,P1662.5%,P5314.2%,RB32.5%,P2748.3%,WTI54.2%,E2F‐170.8% andP30065.8% of 120 HCC. Methylation status ofP21,P15,P16, WTIandE2F‐1was significantly associated with HCC and nontumor tissues (p< 0.05). CIMP+ was detected in 61.7% (74/120) HCC and 15% (18/120) cirrhosis tissues, no CIMP+ was present in normal liver tissues (p< 0.001). A significant difference between CIMP status and metastasis was been found in HCC (p< 0.001). Results showed that 94.6% (70/74) HCC and 55.6% (10/18) cirrhosis patients with CIMP+ show expression of high telomerase activity than 45.5% (10/22) HCC and 6.25% (1/16) cirrhosis patients with CIMP− (p< 0.001). CIMP lead to high levels of expression of telomerase activity through the simultaneous inactivation of multiple genes associated with telomerase activity by concordant methylation. © 2008 Wiley‐Liss, Inc.
The Stream Inlet to a Shallow Bay of a Drinking Water Reservoir, a ‘Hot‐Spot’ forMicrocystisBlooms Initiation
Authors: Izydorczyk Katarzyna , Skowron Aleksandra , Wojtal Adrianna , Jurczak Tomasz
Published: June 2008

Stream inlets into shallow bays of reservoirs and lakes may be ‘hot‐spots’ for toxic cyanobacterial bloom initiation. These ‘hot‐spots’ may be connected with the permanent inflow of high nutrient concentrations from the catchment, optimal physical conditions (wind protected areas) that occur in shallow areas and/or ineffective top‐down control. Four sampling sites along a transect from stream to reservoir in a shallow bay of Sulejow Reservoir (Poland) were studied to test the above hypothesis, comprising a transition zone between lotic and pelagic habitats. Investigations showed that stream inlet into shallow bay acted as incubator forMicrocystisblooms. The nutrient level, especially phosphorus, was identified as the major cause of cyanobacterial bloom growth. The increase ofMicrocystisbiomass strongly correlated with increasing microcystin concentrations, however, a relationship with microcystin content was not observed. Toxicity of bloom demonstrated seasonal variability, reaching its maximum at the initial phase of bloom. (© 2008 WILEY‐VCH Verlag GmbH & Co. KGaA, Weinheim)
Effects of Leaf Litter Species on Macroinvertebrate Colonization during Decomposition in a Portuguese Stream
Authors: Abelho Manuela
Published: June 2008

This study evaluated if there are differences in leaf breakdown and invertebrate colonization among tree species differing in quality (toughness), and which factors could influence these differences. Common alder leaves decomposed significantly faster then either sweet chestnut or Spanish oak (k values of –0.0332, –0.0108, and –0.0112, respectively) during the first 2 months. Shredder abundance was highest when leaf mass remaining was 50%, and the samples clustered in mixed groups of sampling dates and leaf species, suggesting that stage of decomposition was an important factor influencing shredder colonization. During the first two months of decomposition, the physicochemical characteristics of leaf litter and the interaction between leaf toughness and the occurrence of frequent spates seemed to be the main factors affecting leaf breakdown rates in the stream. (© 2008 WILEY‐VCH Verlag GmbH & Co. KGaA, Weinheim)
The spliced variant of hepatitis B virus protein, HBSP, interacts with Bcl‐2/Bcl‐xl in vitro and induces apoptosis in HepG2 cells
Authors: Lu Yi Wei , Ren Yu Dan , Bai Jing , Chen Wei Ning
Published: June 2008

We have recently reported that the naturally occurring spliced variant of Hepatitis B virus protein, HBSP, displayed proapoptotic activity through its BH3 domain. To investigate whether the BH3 domain in HBSP interacted with Bcl‐2 family of proteins, HBSP and Bcl‐2 family of proteins were cloned and expressed in our mammalian two‐hybrid system. Interaction assays were carried out in HepG2 cells and measured by the activity of the reporter gene product luciferase. Our results indicated that HBSP interacted with Bcl‐2/Bcl‐xl in vitro and induced apoptosis in HepG2 cells. © 2008 IUBMB IUBMB Life, 60(10): 700–702, 2008
Hydrophilic electrospun polyurethane nanofiber matrices for hMSC culture in a microfluidic cell chip
Authors: Lee Kwang Ho , Kwon Gu Han , Shin Su Jung , Baek Ju‐Yeoul , Han Dong Keun , Park Yongdoo , Lee Sang Hoon
Published: June 2008

Mimicking cellular microenvironments by MEMS technology is one of the emerging research areas. Integrated biomimetic systems with nanofiber polymer networks and microfluidic chips were fabricated and cellular behaviors were observed by changing surface characteristics of nanofibers and flow rates of microchannels. Modification of polyurethane nanofiber surfaces were achieved by grafting acrylic acid with plasma treatment and these nanofiber matrices were employed in a poly(dimethylsiloxane) based microfluidic chip. The surface characteristics of both electrospun nanofiber matrices was evaluated by measuring contact angle, porosity, and chemical structure using attenuated total reflection‐Fourier transform infrared spectrometry. After modification, a terminal carboxyl group formed on the nanofiber surface and the wettability increased significantly. Human MSCs were seeded on the nanofiber matrices and a morphological investigation with actin filament staining and scanning electron microscopy was performed. A proliferation test by WST‐1 and Live/Dead assay were performed to investigate the cell culture environment. It was observed that the cells on the AA‐grafted nanofibers spread and proliferate compared to untreated nanofibers. It has also shown that flow rates in the microchannels played an important role for cell proliferation (Sim et al., Lab Chip 2007;7:1775‐1782). Integration of nanofiber matrices into the microchannels provides the useful tools for mimicking cellular microenvironments and elucidating basic questions of cell and ECM assembly and interactions. © 2008 Wiley Periodicals, Inc. J Biomed Mater Res, 2009
Elastomeric high‐mineral content hydrogel‐hydroxyapatite composites for orthopedic applications
Authors: Song Jie , Xu Jianwen , Filion Tera , Saiz Eduardo , Tomsia Antoni P. , Lian Jane B. , Stein Gary S. , Ayers David C. , Bertozzi Carolyn R.
Published: June 2008

The design of synthetic bone grafts that mimic the structure and composition of bone and possess good surgical handling characteristics remains a major challenge. We report the development of poly(2‐hydroxyethyl methacrylate) (pHEMA)‐hydroxyapatite (HA) composites termed “FlexBone” that possess osteoconductive mineral content approximating that of human bone yet exhibit elastomeric properties enabling the press‐fitting into a defect site. The approach involves crosslinking pHEMA hydrogel in the presence of HA using viscous ethylene glycol as a solvent. The composites exhibit excellent structural integration between the apatite mineral component and the hydroxylated hydrogel matrix. The stiffness of the composite and the ability to withstand compressive stress correlate with the microstructure and content of the mineral component. The incorporation of porous aggregates of HA nanocrystals rather than compact micrometer‐sized calcined HA effectively improved the resistance of the composite to crack propagation under compression. Freeze‐dried FlexBone containing 50 wt % porous HA nanocrystals could withstand hundreds‐of‐megapascals compressive stress and >80% compressive strain without exhibiting brittle fractures. Upon equilibration with water, FlexBone retained good structural integration and withstood repetitive moderate (megapascals) compressive stress at body temperature. When subcutaneously implanted in rats, FlexBone supported osteoblastic differentiation of the bone marrow stromal cells pre‐seeded on FlexBone. Taken together, the combination of high osteoconductive mineral content, excellent organic‐inorganic structural integration, elasticity, and the ability to support osteoblastic differentiation in vivo makes FlexBone a promising candidate for orthopedic applications. © 2008 Wiley Periodicals, Inc. J Biomed Mater Res, 2009
Injection of a novel synthetic hydrogel preserves left ventricle function after myocardial infarction
Authors: Jiang Xue‐Jun , Wang Tao , Li Xiao‐Yan , Wu De‐Qun , Zheng Zhao‐Bin , Zhang Jin‐Feng , Chen Jin‐Ling , Peng Bin , Jiang Hong , Huang Congxin , Zhang Xian‐Zheng
Published: June 2008

Myocardial infarction (MI) and the subsequent heart failure remain one of the leading causes of morbidity and mortality world wide. A number of studies have demonstrated that bioderived materials improve cardiac function after implantation because of their angiogenic potential. In this study, we hypothesized that injection of biomaterials into infarcted myocardium can preserve left ventricular (LV) function through its prevention of paradoxical systolic bulging. To test this hypothesis, infarction was induced in rabbit myocardium by coronary artery ligation. After 1 week, 200‐μL α‐cyclodextrin (α‐CD)/MPEG‐PCL‐MPEG hydrogel was injected into the infarcted myocardium. Injection of phosphate buffered saline (PBS) served as controls. Twenty‐eight days after the treatment, histological analysis indicated that the injection of hydrogel prevented scar expansion and wall thinning compared with the control (p < 0.05) without more microvessel density in infarcted myocardium (p = 0.70). LV ejection fraction, determined by echocardiography, was significantly greater in the hydrogel‐treated group (56.09% ± 8.42%) than the control group (37.26% ± 6.36%, p = 0.001). The LV end‐diastolic and end‐systolic diameters were 2.07 ± 0.33 cm and 1.74 ± 0.30 cm, respectively, in the control group. Smaller LV end‐diastolic diameter (1.61 ± 0.26 cm, p = 0.005) and smaller end‐systolic diameter (1.17 ± 0.23 cm, p = 0.001) were found in the hydrogel‐treated group. These results suggest that α‐CD/MPEG‐PCL‐MPEG hydrogel could serve as an injectable biomaterial that prevents LV remodeling and dilation for the treatment of MI. © 2008 Wiley Periodicals, Inc. J Biomed Mater Res, 2009
Computer simulated screening of dentin bonding primer monomers through analysis of their chemical functions and their spatial 3D alignment
Authors: Vaidyanathan J. , Vaidyanathan T. K. , Ravichandran S.
Published: June 2008

Binding interactions between dentin bonding primer monomers and dentinal collagen were studied by an analysis of their chemical functions and their spatial 3D alignment. A trial set of 12 monomers used as primers in dentin adhesives was characterized to assess them for binding to a complementary target. HipHop utility in the Catalyst software from Accelrys was used for the study. Ten hypotheses were generated by HipHop procedures involving (a) conformational generation using a poling technique to promote conformational variation, (b) extraction of functions to remodel ligands as function‐based structures, and (c) identification of common patterns of functional alignment displayed by low energy conformations. The hypotheses, designated as pharmacaphores, were also scored and ranked. Analysis of pharmacaphore models through mapping of ligands revealed important differences between ligands. Top‐ranked poses from direct docking simulations using type 1 collagen target were mapped in a rigid manner to the highest ranked pharmacophore model. The visual match observed in mapping and associated fit values suggest a strong correspondence between direct and indirect docking simulations. The results elegantly demonstrate that an indirect approach used to identify pharmacaphore models from adhesive ligands without a target may be a simple and viable approach to assess their intermolecular interactions with an intended target. Inexpensive indirect/direct virtual screening of hydrophilic monomer candidates may be a practical way to assess their initial promise for dentin primer use well before additional experimental evaluation of their priming/bonding efficacy. This is also of value in the search/design of new compounds for priming dentin. © 2008 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 2009
Suitability of differently designed matrix‐based implant surface coatings: An animal study on bone formation
Authors: Stadlinger Bernd , Pilling Eckart , Huhle Matthias , Khavkin Evgenij , Bierbaum Susanne , Scharnweber Dieter , Kuhlisch Eberhard , Eckelt Uwe , Mai Ronald
Published: June 2008

Introduction: The aim of the present study was to assay how bone formation around dental implants is influenced by differently composed collagen matrices and RGD peptide as implant surface coatings compared to a sandblasted titanium surface. Material and Methods: Five different implant surface coatings were designed: titanium (sandblasted), collagen type I, collagen type I&III, RGD‐peptide, and mineralized collagen. Sixty experimental implants of a square‐shaped design were inserted into the mandibles of 12 minipigs, 3 months following extraction of the premolar teeth. During the 6‐month study period, sequential polyfluorochrome labeling was performed. After sacrifice, bone implant contact (BIC) was evaluated using histologic and histomorphometric methods. Results: New bone formation was observed against all implant surfaces. Polyfluorochrome labeling showed that bone growth started from the host bone in the majority of samples. The highest BIC was measured for collagen I and collagen I/III coated implants; however, significant differences between the coatings could not be found. Conclusion: Osseointegration was achieved for all implant surfaces. Although a statistically significant increase in BIC could not be demonstrated for the experimental coatings after the 6 months study period, there was also no discernible detrimental effect of the coatings in comparison to the uncoated titanium surfaces. © 2008 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 2008
Investigation of the antiadhesive properties of human mesothelial cells cultured in vitro on implantable surgical materials
Authors: Wilshaw Stacy‐Paul , Burke Dermot , Fisher John , Ingham Eileen
Published: June 2008

The aim of the study was to evaluate the interactions of Permacol, Prolene mesh, Surgisis Gold, and Alloderm with human mesothelial cells in vitro. The capacity of primary human mesothelial cells to adhere to the surface of Alloderm, Surgisis Gold, Prolene mesh, and Permacol as well as support the proliferation and viability of the seeded cells was determined. Production of antifibrinolytic, fibrinolytic, and inflammatory mediators (IL‐8, TPA, MMP‐1, PAI‐1, and TGF‐β) was assessed over an 8‐day period. The adhesive nature of the implantable materials was determined by assessment of the strength of any fibrin clots formed between two surfaces of each implant material. Surgisis Gold and Permacol were capable of supporting the attachment and proliferation of primary human mesothelial cells and maintaining viability over an 8‐day culture period. Mesothelial cells were shown to have covered the surface of Permacol and Surgisis Gold in a monolayer. The viability of cells cultured on Permacol was significantly greater than the other implant materials tested. Mesothelial cells cultured on Permacol or Surgisis were shown to be producing high levels of fibrinolytic compounds and low levels of antifibrinolytic and inflammatory mediators. Alloderm was shown to produce high levels of IL‐8 and antifibrinolytic mediators when compared with the other implantable materials. Permacol was shown to be an unreliable surface for clot formation in vitro and any clots formed were shown to be significantly weaker than the clots produced between two surfaces of tissue culture plastic, Prolene mesh, Alloderm, and Surgisis Gold. This in vitro study indicated that Permacol and Surgisis Gold supported the growth and fibrinolytic activity of human mesothelial cells; however, Permacol was shown to be superior in this respect. © 2008 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 2009
Evaluation of substrates for 90° peel adhesion—A collaborative study. II. Transdermal drug delivery systems
Authors: Wokovich Anna M. , Brown Stanley A. , Shen Meiyu , Doub William H. , Cai Bing , Sadrieh Nakissa , Chen Mei Ling , Machado Stella , Buhse Lucinda F.
Published: June 2008

In a previous study on peel adhesion for medical tapes, it was shown that a stainless steel (SS) substrate better discriminated among medical tapes than a high‐density polyethylene (HDPE) substrate. The objective of this study was to determine if a SS substrate would also better distinguish among transdermal drug delivery systems (TDDSs). Five TDDSs (Vivelle Dot®, Climara®, Catapres‐TTS®, Duragesic®, and Mylan Fentanyl) were evaluated on three different substrates (SS, HDPE, and human cadaver skin). All measurements were made using a dwell time of ∼3 min, a peel angle of 90°, and a peel speed of 300 mm/min. Differences among TDDSs were greater for SS than for HDPE, using the F statistic for testing for differences among TDDSs means as a measure of heterogeneity, thereby indicating greater discrimination by SS. © 2008 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 2009
The mismatch repair‐mediated cell cycle checkpoint response to fluorodeoxyuridine
Authors: Liu Angen , Yoshioka Ken‐ichi , Salerno Vincenzo , Hsieh Peggy
Published: June 2008

The loss of DNA mismatch repair (MMR) is responsible for hereditary nonpolyposis colorectal cancer and a subset of sporadic tumors. Acquired resistance or tolerance to some anti‐cancer drugs occurs when MMR function is impaired. 5‐Fluorouracil (FU), an anti‐cancer drug used in the treatment of advanced colorectal and other cancers, and its metabolites are incorporated into RNA and DNA and inhibit thymidylate synthase resulting in depletion of dTTP and incorporation in DNA of uracil. Although the MMR deficiency has been implicated in tolerance to FU, the mechanism of cell killing remains unclear. Here, we examine the cellular response to fluorodeoxyuridine (FdU) and the role of the MMR system. After brief exposure of cells to low doses of FdU, MMR mediates DNA damage signaling during S‐phase and triggers arrest in G2/M in the first cell cycle in a manner requiring MutSα, MutLα, and DNA replication. Cell cycle arrest is mediated by ATR kinase and results in phosphorylation of Chk1 and SMC1. MutSα binds FdU:G mispairs in vitro consistent with its being a DNA damage sensor. Prolonged treatment with FdU results in an irreversible arrest in G2 that is independent of MMR status and leads to the accumulation of DNA lesions that are targeted by the base excision repair (BER) pathway. Thus, MMR can act as a direct sensor of FdU‐mediated DNA lesions eliciting cell cycle arrest via the ATR/Chk1 pathway. However, at higher levels of damage, other damage surveillance pathways such as BER also play important roles. J. Cell. Biochem. 105: 245–254, 2008. © 2008 Wiley‐Liss, Inc.
Increased hepatic UCP2 expression in rats with nonalcoholic steatohepatitis is associated with upregulation of Sp1 binding to its motif within the proximal promoter region
Authors: Jiang Ying , Zhang Hua , Dong Ling‐yue , Wang Dan , An Wei
Published: June 2008

Uncoupling protein‐2 (UCP2) is a mitochondrial inner‐membrane carrier protein that is involved in the control of fatty acid metabolism. To understand the mechanism of the transcriptional regulation ofucp2in the pathogenesis of nonalcoholic steatohepatitis (NASH), we cloned 500 bp upstream of theucp2exon 1 from a rat liver cDNA library and identifiedcis‐acting regulatory elements. The transcriptional start site was identified as “C,” −359 bp from the ATG codon. A reporter gene assay showed that deletion of the nucleotide sequence between −264 and −60 bp resulted in a significant decrease in promoter activity in HepG2 and H4IIE cells. Electrophoretic mobility shift assay (EMSA) and chromatin immunoprecipitation (ChIP) revealed that the increase in promoter activity is related to an enhanced ability of Sp1 to bind to its motifs at −84 to −61 bp within theucp2proximal promoter. Overexpression of exogenous Sp1 in H4IIE cells also increased the promoter activity. We demonstrated that the expression of UCP2 mRNA and protein is markedly increased in rats with nonalcoholic steatohepatitis (NASH). Coincidently, levels of Sp1 binding to −84/−61 bp were also increased. Overall, our data indicate that the Sp1‐binding site located at the proximal promoter is involved in the regulation of rat UCP2 expression. J. Cell. Biochem. 105: 277–289, 2008. © 2008 Wiley‐Liss, Inc.
Association of Sp3 and estrogen receptor α with the transcriptionally active trefoil factor 1 promoter in MCF‐7 breast cancer cells
Authors: Li Lin , Davie James R.
Published: June 2008

To further explore the role of Sp1 and Sp3 in the estrogen regulated TFF1 gene transcription, chromatin immunoprecipitation (ChIP) assay was used to determine the association of estrogen receptor α (ERα), Sp1 and Sp3 with the endogenous trefoil factor 1 (TFF1) gene promoter in MCF‐7 breast cancer cells. ERα and serine 5 phosphorylated RNA polymerase II, the form of RNA polymerase II associated with transcription initiation, were recruited to the TFF1 gene promoter following estrogen addition to MCF‐7 cells cultured under estrogen deplete conditions. Both Sp1 and Sp3 were bound to the TFF1 gene promoter before and after estrogen treatment. Using the re‐ChIP assay, we demonstrate that either Sp1 or Sp3 but not both bind to a TFF1 promoter. The co‐occupancy of ERα and Sp1 on TFF1 promoter remains at similar level with and without estrogen, while that of ERα and Sp3 increased in the presence of estrogen. Further, we observed increased co‐occupancy of Sp3 and serine 5 phosphorylated RNA polymerase II on the TFF1 promoter after estrogen treatment of cells. Taken together, these results provide evidence that Sp3 and ERα are involved in the estrogen induced transcription of the TFF1 gene. J. Cell. Biochem. 105: 365–369, 2008. © 2008 Wiley‐Liss, Inc.
The binding of heparin to the extracellular matrix of endothelial cells up‐regulates the synthesis of an antithrombotic heparan sulfate proteoglycan
Authors: Trindade Edvaldo S. , Oliver Constance , Jamur Maria C. , Rocha Hugo A.O. , Franco Célia R.C. , Bouças Rodrigo I. , Jarrouge Thais R. , Pinhal Maria A.S. , Tersariol Ivarne L.S. , Gouvêa Tiago C. , Dietrich Carl P. , Nader Helena B.
Published: June 2008

Exposure of endothelial cells to heparin and other antithrombotic drugs specifically stimulates the synthesis of an antithrombotic heparan sulfate (HS). In the present work, biotinylated heparin (BiotHep) was used to characterize the binding site(s) of heparin responsible for the stimulus in HS synthesis on endothelial cells. No differences were observed between biotinylated and non‐biotinylated heparin in their ability to increase the synthesis of HS. In kinetic studies the BiotHep showed fast, saturable and specific binding with an apparent KD of 83 nM to adherent cells and 44 nM to the extracellular matrix (ECM) in the absence of cells. By confocal and electron microscopy, BiotHep bound only to the ECM, co‐localizing with fibronectin. The same pattern of binding to the ECM was observed using heparin conjugated with FITC or Alexa Fluor 488 in the presence or absence of fetal calf serum. However, after degradation of HS, heparin binds to the cell surface, indicating that endogenous HS possibly occupied the heparin binding sites. Analyses by flow cytometry and confocal microscopy of cells with non‐associated ECM, showed labeling of the cell surface using syndecan‐4 monoclonal antibody as well as wheat germ agglutinin, but no binding of heparin. Furthermore, the stimulation in HS synthesis is not elicited by heparin in the absence of ECM. These results indicate that the stimulus for the synthesis of HS does not require binding of the heparin to the cell surface, and the signaling may be mediated through the ECM. J. Cell. Physiol. 217: 328–337, 2008. © 2008 Wiley‐Liss, Inc.
Distinct pattern of microglial response, cyclooxygenase‐2, and inducible nitric oxide synthase expression in the aged rat brain after excitotoxic damage
Authors: Campuzano O. , Castillo‐Ruiz M.M. , Acarin L. , Castellano B. , Gonzalez B.
Published: June 2008

Microglial and inflammatory responses to acute damage in aging are still poorly understood, although the aged brain responds differently to injury, showing poor lesion outcome. In this study, excitotoxicity was induced by intrastriatal injection of N‐methyl‐D‐aspartate in adult (3–4 months) and aged (22–24 months) rats. Cryostat brain sections were processed for the analysis of microglial response by lectin histochemistry and cyclooxygenase 2 (COX2) and inducible nitric oxide synthase (iNOS) expression by immunohistochemistry and confocal analysis. Aged injured animals showed more widespread area of microglial response at 12 hr postlesion (hpl) and greater microglia/macrophage density at 3 days postlesion (dpl). However, aged reactive microglia showed prevalence of ramified morphologies and fewer amoeboid/round forms. Aged injured animals presented a diminished area of COX2 expression, but a significantly larger density of COX2+cells, with higher numbers of COX2+neurons during the first 24 hpl and COX2+microglia/macrophages later. In contrast, the amount of COX2+neutrophils was diminished in the aged. iNOS was more rapidly induced in the aged injured striatum, with higher cell density at 12 hpl, when expression was mainly neuronal. From 1 dpl, both the iNOS+area and the density of iNOS+cells were reduced in the aged, with lower numbers of iNOS+neurons, microglia/macrophages, neutrophils, and astrocytes. In conclusion, excitotoxic damage in aging induces a distinct pattern of microglia/macrophage response and expression of inflammatory enzymes, which may account for the changes in lesion outcome in the aged, and highlight the importance of using aged animals for the study of acute age‐related insults. © 2008 Wiley‐Liss, Inc.
Thyroid hormone increases astrocytic glutamate uptake and protects astrocytes and neurons against glutamate toxicity
Authors: Mendes‐de‐Aguiar Cláudia Beatriz Nedel , Alchini Ricardo , Decker Helena , Alvarez‐Silva Marcio , Tasca Carla Inês , Trentin Andréa Gonçalves
Published: June 2008

Thyroid hormone (T3) regulates the growth and differentiation of rat cerebellar astrocytes. Previously, we have demonstrated that these effects are due, at least in part, to the increased expression of extracellular matrix molecules and growth factors, such as fibroblast growth factor‐2. T3 also modulates neuronal development in an astrocyte‐mediated manner. In the mammalian central nervous system, excitatory neurotransmission is mediated mainly by glutamate. However, excessive stimulation of glutamate receptors can lead to excitotoxicity and cell death. Astrocytic glutamate transporters, GLT‐1 and GLAST, play an essential role in the clearance of the neuronal‐released glutamate from the extracellular space and are essential for maintaining physiological extracellular glutamate levels in the brain. In the present study, we showed that T3 significantly increased glutamate uptake by cerebellar astrocytes compared with control cultures. Inhibitors of glutamate uptake, such as L‐PDC and DL‐TBOA, abolished glutamate uptake on control or T3‐treated astrocytes. T3 treatment of astrocytes increased both mRNA levels and protein expression of GLAST and GLT‐1, although no significant changes on the distribution of these transporters were observed. The gliotoxic effect of glutamate on cultured cerebellar astrocytes was abolished by T3 treatment of astrocytes. In addition, the neuronal viability against glutamate challenge was enhanced on T3‐treated astrocytes, showing a putative neuroprotective effect of T3. In conclusion, our results showed that T3 regulates extracellular glutamate levels by modulating the astrocytic glutamate transporters. This represents an important mechanism mediated by T3 on the improvement of astrocytic microenvironment in order to promote neuronal development and neuroprotection. © 2008 Wiley‐Liss, Inc.
Non‐N‐methyl‐D‐aspartate glutamate receptors in the paraventricular nucleus of hypothalamus mediate the pressor response evoked by noradrenaline microinjected into the lateral septal area in rats
Authors: Scopinho América Augusto , Tavares Rodrigo Fiacadori , Busnardo Cristiane , Corrêa Fernando Morgan Aguiar
Published: June 2008

The lateral septal area (LSA) is a part of the limbic system and is involved in cardiovascular modulation. We previously reported that microinjection of noradrenaline (NA) into the LSA of unanesthetized rats caused pressor responses that are mediated by acute vasopressin release. Magnocellular neurons of the paraventricular (PVN) and supraoptic (SON) of the hypothalamus synthesize vasopressin. In the present work, we studied which of these nuclei is involved in the pressor pathway activated by unilateral NA injection into the LSA as well as the local neurotransmitter involved. Chemical ablation of the SON by unilateral injection of the nonspecific synapses blocker cobalt chloride (1 mM/100 nl) did not affect the pressor response evoked by NA (21 nmol/200 nl) microinjection into the LSA. However, the response to NA was blocked when cobalt chloride (1 mM/100 nl) was microinjected into the PVN, indicating that this hypothalamic nucleus is responsible for the mediation of the pressor response. There is evidence in the literature pointing to glutamate as a putative neurotransmitter activating magnocellular neurons. Pretreatment of the PVN with the selective non‐N‐methyl‐D‐asparate (NMDA) antagonist NBQX (2 nmol/100 nl) blocked the pressor response to NA microinjected into the LSA, whereas pretreatment with the selective NMDA antagonist LY235959 (2 nmol/100 nl) did not affect the response to NA. Our results implicate the PVN as the final structure in the pressor pathway activated by the microinjection of NA into the LSA. They also indicate that local glutamatergic synapses and non‐NMDA glutamatergic receptors mediate the response in the PVN. © 2008 Wiley‐Liss, Inc.
Analysis of historical changes in rainfall in the Indian Himalayas
Authors: Basistha Ashoke , Arya D. S. , Goel N. K.
Published: June 2008

The present study attempts to explore changes in rainfall pattern in the Indian Himalayas during 20th century using 80‐year data from 30 rain gauge stations maintained by the India Meteorological Department (IMD). Modified Mann–Kendall test (MMK) was applied to detect trend, and Pettitt–Mann–Whitney (PMW) test was employed to detect possible shift. Implication of the change is discussed in terms of percentage change over mean. The results show that the most probable year of change in annual as well as monsoon rainfall in the region is 1964. There was an increasing trend upto 1964 (corroborating with all India and nearby plains), followed by a decreasing trend in 1965–1980 (exclusive to this region). In the entire region, changes are most conspicuous over the Shivaliks and the southern part of the Lesser Himalayas. Copyright © 2008 Royal Meteorological Society
Interannual variations in the opening date of the Prudhoe Bay shipping season: links to atmospheric and surface conditions
Authors: Drobot S. D. , Maslanik J. A. , Anderson M. R.
Published: June 2008

This paper examines interannual variability in the opening date for the Prudhoe Bay shipping season (1953–2005), considers how variations in antecedent sea‐ice and atmospheric conditions influence the opening date, and then develops a forecasting technique to predict whether the opening date will be early, normal, or late. Analysis of antecedent sea ice and atmospheric conditions indicates that there are significant differences in the Bering Sea ice cover as early as February in years preceding early versus late opening dates. In particular, prior to early opening years, the sea‐ice cover in the southern Bering Sea is reduced in February, and as the season progresses, sea‐ice concentrations in the central and northern Bering Sea remain lower in years preceding early opening dates. Analysis of accumulated freezing degree days (FDDs) also suggests that temperatures are warmer over a broad area, ranging from the Bering Sea through the Chukchi Sea and the Beaufort Sea, in winter and spring months preceding early opening dates. Although the warmer temperatures may be related to reductions in sea ice in the Bering Sea, our results suggest that 500 hPa flow patterns and sea level pressure (SLP) patterns play are a larger role in controlling accumulations of FDD in the Chukchi and Beaufort seas. Finally, an ordinal regression model is presented to forecast whether the opening date will be early, normal, or late. On the basis of April sea‐ice concentrations and accumulated FDD, the model correctly forecasts the opening date class in 32 of the 53 years. Copyright © 2008 Royal Meteorological Society
Synthesis of Processable Inorganic‐Organic Hybrid Polymers Based on Poly(silsesquioxanes): Grafting from Polymerization Using ATRP
Authors: Kessler Daniel , Teutsch Carmen , Theato Patrick
Published: June 2008

Inorganic‐organic hybrid polymers have been synthesized utilizing atom transfer radical polymerization (ATRP) from a functionalized poly(methylsilsesquioxane) (PMSSQ) macroinitiator. Different polymeric ATRP initiators were prepared by co‐condensation of functionalized trichlorosilanes with methyltrimethoxysilane. Various vinyl monomers have been successfully grafted from these macroinitiators, demonstrating a highly variable synthetic concept, which offers the chance to synthesize a wide spectrum of inorganic‐organic hybrid polymers. All synthesized polymers were soluble in various organic solvents. Spin‐coating these hybrid materials onto various substrates could produce stable and adherent surface coatings. Successful surface functionalization could be achieved on silicon, glass, metals or polymeric materials.

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The electronic service quality model: The moderating effect of customer self‐efficacy
Authors: Yi Youjae , Gong Taeshik
Published: June 2008

The research in the area has largely ignored the moderating effects of the customer trait, self‐efficacy, on the electronic service quality model. This study examines the degree to which electronic service quality dimensions influence overall service quality, which in turn affects customer satisfaction and loyalty. On the basis of self‐efficacy theory, this paper argues that outcome quality is the most important predictor of overall quality, whereas environment quality is the least important predictor of overall quality, particularly when self‐efficacy is high. Additionally, the paper demonstrates that self‐efficacy strengthens the link between customer satisfaction and both repurchase intention and word of mouth. Data collected from 162 participants provide support for most of these hypotheses. © 2008 Wiley Periodicals, Inc.
Building customer relationships in an electronic age: The role of interactivity of E‐commerce Web sites
Authors: Yoon Doyle , Choi Sejung Marina , Sohn Dongyoung
Published: June 2008

This study examines the role of perceived interactivity and other marketing tactics in relationship building with customers in the online retail environment by applying a relationship investment model adapted from De Wulf, Odekerken‐Schröder, and Iacobucci (2001). A proposed structure model was tested with data collected from an online survey of 571 respondents. In the model, three subdimensions of perceived interactivity and three marketing tactic variables were incorporated as the antecedents of perceived relationship investment that subsequently influenced perceived relationship quality and behavioral loyalty. Results suggest that two marketing tactics—direct mail (e‐mail) and tangible rewards—and two dimensions of perceived interactivity—synchronicity and two‐way communication—play as significant antecedents for the relationshipbuilding process of online retail brands. In addition, the findings confirm the relationships among perceived relationship investment, relationship quality, and behavioral loyalty, which indicates that the fundamental process of relationship building remains similar in the online environment. Reflecting the unique nature of the online retail environment, the model also clarifies the roles of interactivity as well as traditional relationship investment strategies in facilitating online retailers' relationship building with customers. © 2008 Wiley Periodicals, Inc.
Barely or fairly balancing drug risks? Content and format effects in direct‐to‐consumer online prescription drug promotions
Authors: Kees Jeremy , Bone Paula Fitzgerald , Kozup John , Ellen Pam Scholder
Published: June 2008

A critical requirement of direct‐to‐consumer (DTC) drug promotion on the Internet is the concept of fair balance. This means that prescription drug Web sites should provide an accurate, balanced portrayal of the risks relative to the benefits of using prescription medications. However, one of the most pervasive findings in consumer research is that risk perceptions are often not aligned with the actual risk a consumer faces. This study examines the impact of certain presentation formats and types of risk information provided on a pharmaceutical Web site and the effect on consumers' perceptions of risk and fair balance. We find evidence of a bias of omission; that is, the risks of treating a health condition using a hypothetical prescription drug were perceived to be greater than the risk of inaction. Interestingly, we found no evidence that the presentation of a “black‐box” warning or the warning strength affected the broader construct of fair balance. © 2008 Wiley Periodicals, Inc.
Photoactive Polythiophene:Titania Hybrids with Excellent Miscibility for Use in Polymer Photovoltaic Cells
Authors: Chang Yi‐Ming , Su Wei‐Fang , Wang Leeyih
Published: June 2008

A series of poly{(3‐hexylthiophene)‐co‐[3‐(6‐hydroxyhexyl)thiophene]}:titania (P3HT‐OH:TiO2) hybrids were synthesized via the in situ polycondensation of titanium (IV) n‐butoxide in the presence of P3HT‐OH. Introducing a hydroxyl moiety onto the side‐chain of poly(3‐hexylthiophene) (P3HT) significantly promotes the polymer‐titania interaction, resulting in the formation of homogeneous hybrid colloids. The UV‐vis spectra of P3HT‐OH:TiO2 films demonstrate that TiO2 markedly affects the stacking structure and the chain conformation of P3HT‐OH. The maximum absorption wavelength of these hybrid materials can be tailor‐made by merely varying the weight percentage of TiO2. Moreover, P3HT‐OH:TiO2 can be further utilized as an efficient compatibilizer in preparing photoactive P3HT:P3HT‐OH:TiO2 films with excellent miscibility. The photovoltaic cell based on such a hybrid exhibited a 2.4‐fold higher value of power‐conversion efficiency compared to the cell based on P3HT:TiO2.

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Macromolecular Engineering of Biodegradable Polyesters by Ring‐Opening Polymerization and ‘Click’ Chemistry
Authors: Lecomte Philippe , Riva Raphaël , Jérôme Christine , Jérôme Robert
Published: June 2008

Biodegradability makes aliphatic polyesters valuable candidates for biomaterials and environmentally friendly thermoplastics. Nevertheless, their chemical modification, which is mandatory for a series of potential applications, is usually a problem because it must be carried out under very mild conditions in order to prevent degradation by hydrolysis and/or transesterification from occurring. In this review, the copper(I)‐catalyzed azide–alkyne cycloaddition, which is a click reaction, is shown to be very efficient to bypass these problems and to tailor the macromolecular architecture and functionality of those polyesters without facing undesired degradation reactions.

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