bluuebunny/crossref_metadata_2025 huggingface dataset:
Analysis of the interplay among charge, hydration and shape of proteins through the modeling of their CZE mobility data
Authors: Piaggio Maria V. , Peirotti Marta B. , Deiber Julio A.
Published: June 2009

Electrophorectic mobility data of four proteins are analyzed and interpreted through a physicochemical CZE model, which provides estimates of quantities like equivalent hydrodynamic radius (size), effective charge number, shape orientation factor, hydration, actual pK values of ionizing groups, and pH near molecule, among others. Protein friction coefficients are simulated through the creeping flow theory of prolate spheroidal particles. The modeling of the effective electrophoretic mobility of proteins requires consideration of hydrodynamic size and shape coupled to hydration and effective charge. The model proposed predicts native protein hydrations within the range of values obtained experimentally from other techniques. Therefore, this model provides consistently other physicochemical properties such as average friction and diffusion coefficients and packing fractal dimension. As the pH varies from native conditions to those that are denaturing the protein, hydration and packing fractal dimension change substantially. Needs for further research are also discussed and proposed.
Chip‐based immunoaffinity CE: Application to the measurement of brain‐derived neurotrophic factor in skin biopsies
Authors: Phillips Terry M. , Wellner Edward F.
Published: June 2009

A chip‐based immunoaffinity CE system has been employed to measure the concentrations of brain‐derived neurotrophic factor in human skin biopsies, taken during atopic inflammatory events. The device employs a replaceable immunoaffinity disk to which capture antibodies have been chemically immobilized. Homogenates obtained from micro‐dissected human skin samples were injected into the system, where the analyte of interest was captured in the immunoextraction port, thus allowing non‐reactive materials to be removed prior to analysis. The captured analyte was labeled in situ with a red‐emitting laser dye before being released from the capture antibody, separated by electrophoresis, and the resolved peaks detected by online LIF. Comparison of this chip‐based system with conventional immunoassay demonstrated good correlation when analyzing both standards and patient samples. The system was semi‐automated resulting in a CE analysis within 1.5 min and a total of circa 5 min. Intra‐ and inter‐assay CV's of 3.85 and 4.19 were achieved with circa 98.8% recovery of brain‐derived neurotrophic factor at a concentration of 100 pg/mL. The assay demonstrated clear differences between clinical stages of atopic dermatitis in human patients and could run 10–15 samples per hour. This system holds the potential for being modified to be a portable unit that could be used in clinics and other biomedical screening studies.
A radar transparent layer in a temperate valley glacier: Bench Glacier, Alaska
Authors: Brown Joel , Harper Joel , Bradford John
Published: June 2009

Radar surveys of Bench Glacier, Alaska, collected over five field seasons between 2002 and 2006 reveal a surface layer of radar transparent ice in this temperate valley glacier. The transparent layer covers the up‐glacier half of the ablation zone and is defined by a distinct lack of the radar scattering events considered typical of temperate ice. Radar scattering ice underlies the transparent zone, and extends to the surface elsewhere on the glacier. We observed the layering in constant offset radar surveys conducted with characteristic frequencies ranging from 5 MHz to 100 MHz. The radar transparent layer extends from the surface to 20 m depth on average, but up to 50 m in some places. Bench Glacier's transparent layer appears similar to the cold surface layer of polythermal glaciers, however, observations in over 50 boreholes on Bench Glacier suggest there is no cold ice corresponding to the radar transparent layer. We conclude that spatially extensive radar‐transparent layers normally used to identify cold ice in polythermal glaciers are present in some temperate glaciers. Copyright © 2009 John Wiley & Sons, Ltd.
Experimentation at the interface of fluvial geomorphology, stream ecology and hydraulic engineering and the development of an effective, interdisciplinary river science
Authors: Rice Stephen P. , Lancaster Jill , Kemp Paul
Published: June 2009

One ‘2020 vision’ for fluvial geomorphology is that it sits alongside stream ecology and hydraulic engineering as a key element of an integrated, interdisciplinary river science. A challenge to this vision is that scientists from these three communities may approach problems from different perspectives with different questions and have different methodological outlooks. Refining interdisciplinary methodology is important in this context, but raises a number of issues for geomorphologists, ecologists and engineers alike. In particular, we believe that it is important that there is greater dialogue about the nature of mutually‐valued questions and the adoption of mutually‐acceptable methods. As a contribution to this dialogue we examine the benefits and challenges of using physical experimentation in flume laboratories to ask interdisciplinary questions. Working in this arena presents the same challenges that experimental geomorphologists and engineers are familiar with (scaling up results, technical difficulties, realism) and some new ones including recognizing the importance of biological processes, identifying hydraulically meaningful biological groups, accommodating the singular behaviour of individuals and species, understanding biological as well as physical stimuli, and the husbandry and welfare of live organisms. These issues are illustrated using two examples from flume experiments designed (1) to understand how the movement behaviours of aquatic insects through the near‐bed flow field of gravelly river beds may allow them to survive flood events, and (2) how an understanding of the way in which fish behaviours and swimming capability are affected by flow conditions around artificial structures can lead to the design of effective fish passages. In each case, an interdisciplinary approach has been of substantial mutual benefit and led to greater insights than discipline‐specific work would have produced. Looking forward to 2020, several key challenges for experimentalists working on the interface of fluvial geomorphology, stream ecology and hydraulic engineering are identified. Copyright © 2009 John Wiley & Sons, Ltd.
A beetle's eye view of London from the Mesolithic to Late Bronze Age
Authors: Elias Scott A. , Webster Lucy , Amer Marc
Published: June 2009

The aim of this paper is to reconstruct the environmental history of the London region, based on changes in beetle faunal assemblages from the Mesolithic to Late Bronze Age. Eight sites were studied, all but one of which are within 2 km of the modern course of the Thames. The sites produced 128 faunal assemblages that yielded 218 identified species in 41 families of Coleoptera (beetles). Beetle faunas of Mesolithic age indicate extensive wetlands near the Thames, bordered by rich deciduous woodlands. The proportion of woodland species declined in the Neolithic, apparently because of the expansion of wetlands, rather than because of human activities. The Early Bronze Age faunas contained a greater proportion of coniferous woodland and aquatic (standing water) species. An increase in the dung beetle fauna indicates the presence of sheep, cattle and horses, and various beetles associated with crop lands demonstrate the local rise of agriculture, albeit several centuries after the beginnings of farming in other regions of Britain. Late Bronze Age faunas show the continued development of agriculture and animal husbandry along the lower Thames. About 33% of the total identified beetle fauna from the London area sites have limited modern distributions or are extinct in the U.K. Some of these species are associated with the dead wood found in primeval forests; others are wetland species whose habitat has been severely reduced in recent centuries. The third group is stream‐dwelling beetles that require clean, clear waters and river bottoms. Copyright © 2009 John Wiley & Sons, Ltd.
Anandamide enhances IL‐10 production in activated microglia by targeting CB2receptors: Roles of ERK1/2, JNK, and NF‐κB
Authors: Correa Fernando , Hernangómez Miriam , Mestre Leyre , Loría Frida , Spagnolo Alessandra , Docagne Fabian , Di Marzo Vicenzo , Guaza Carmen
Published: June 2009

The endocannabinoid system exhibits anti‐inflammatory properties by regulating cytokine production. Anandamide (AEA) down‐regulates proinflammatory cytokines in a viral model of multiple sclerosis (MS). However, little is known about the mechanisms by which AEA exerts these effects. Microglial cells are the main source of cytokines within the brain and the first barrier of defense against pathogens by acting as antigen presenting cells. IL‐10 is a key physiological negative regulator of microglial activation. In this study we show that AEA enhances LPS/IFNγ‐induced IL‐10 production in microglia by targeting CB2receptors through the activation of ERK1/2 and JNK MAPKs. AEA also inhibits NF‐κB activation by interfering with the phosphorylation of IκBα, which may result in an increase of IL‐10 production. Moreover, endogenously produced IL‐10 negatively regulates IL‐12 and IL‐23 cytokines, which in its turn modify the pattern of expression of transcription factorsinvolved in Th commitment of splenocytes. This suggeststhat by altering the cytokine network, AEA could indirectly modify the type of immune responses within the central nervous system (CNS). Accordingly, pharmacological modulation of AEA uptake and degradation might be a useful tool for treating neuroinflammatory diseases. © 2009 Wiley‐Liss, Inc.
Sciatic nerve injury induces apoptosis of dorsal root ganglion satellite glial cells and selectively modifies neurosteroidogenesis in sensory neurons
Authors: Schaeffer Véronique , Meyer Laurence , Patte‐mensah Christine , Eckert Anne , Mensah‐nyagan Ayikoe G.
Published: June 2009

Neurosteroids are synthesized either by glial cells, by neurons, or within the context of neuron‐glia cross‐talk. Various studies suggested neurosteroid involvement in the control of neurodegeneration but there is no evidence showing that the natural protection of nerve cells against apoptosis directly depends on their own capacity to produce neuroprotective neurosteroids. Here, we investigated the interactions between neurosteroidogenesis and apoptosis occurring in sensory structures of rats subjected to neuropathic pain generated by sciatic nerve chronic constriction injury (CCI). Using the terminal deoxynucleotidyl transferase‐mediated dUTP nick end labeling (TUNEL), we observed no apoptotic cells in the spinal cord up to 30 days after CCI although pain symptoms such as mechano‐allodynia, thermal and mechanical hyperalgesia were evidenced with the Hargreaves's behavioral and von Frey filament tests. In contrast, double‐labeling experiments combining TUNEL and immunostaining with antibodies against glutamine synthetase or neuronal nuclei protein revealed apoptosis occurrence in satellite glial cells (SGC) (not in neurons) of CCI rat ipsilateral dorsal root ganglia (DRG) at day 30 after injury. Pulse‐chase experiments coupled with high performance liquid chromatography and flow scintillation detection showed that, among numerous biosynthetic pathways converting [3H]pregnenolone into various [3H]neurosteroids, only [3H]estradiol formation was selectively modified and upregulated in DRG of CCI rats. Consistently, immunohistochemical investigations localized aromatase (estradiol‐synthesizing enzyme) in DRG neurons but not in SGC. Pharmacological inhibition of aromatase caused apoptosis of CCI rat DRG neurons. Altogether, our results suggest that endogenously produced neurosteroids such as estradiol may be pivotal for the protection of DRG sensory neurons against sciatic nerve CCI‐induced apoptosis. © 2009 Wiley‐Liss, Inc.
Setting of care modifies risk of nursing home placement for older adults with dementia
Authors: Temple April , Andel Ross , Dobbs Debra
Published: June 2009

Objective

The purpose of this study was to examine risk of nursing home (NH) placement among older adults receiving publicly funded home and community‐based services (HCBS) or assisted living (AL) and to explore whether these settings of care modify the relationship between dementia and risk of NH placement.

Methods

The sample consisted of dually eligible Medicare and Medicaid beneficiaries age 65 and older who received HCBS (n = 1630) or resided in AL (n = 836) in Florida between July 1999 and June 2000. Cox proportional hazards regression was used to estimate risk of NH placement over a 5‐year study period and to test the interaction of setting of care by dementia status.

Results

In all, 15% of HCBS participants were placed in a NH compared to 26% of AL participants. As indicated by a significant interaction term in the regression model, setting of care modified the relationship between dementia and NH placement (HR = 0.45, CI = 0.31–0.66). In post hoc analyses stratified by setting of care, dementia was associated with a 50% increased risk of NH placement from HCBS (HR = 1.50, CI = 1.12–2.02) but was not associated with placement from AL (HR = 0.86, CI = 0.63–1.16).

Conclusion

The findings suggest that differences in care provided in HCBS and AL may influence subsequent NH placement for older adults with dementia. Copyright © 2009 John Wiley & Sons, Ltd.
Diagnosis and staging of mild cognitive impairment, using a modification of the clinical dementia rating scale: the mCDR
Authors: Duara Ranjan , Loewenstein David A. , Greig‐Custo Maria T. , Raj Ashok , Barker Warren , Potter Elizabeth , Schofield Elizabeth , Small Brent , Schinka John , Wu Yougui , Potter Huntington
Published: June 2009

Objective

To examine the reliability and validity of the mCDR, a modified version of the clinical dementia rating (CDR) scale.

Methods

The mCDR is an informant‐based, technician‐administered, structured interview with multiple choice responses, which does not include objective cognitive testing. Subjects (n = 556) with no cognitive impairment (NCI), amnestic mild cognitive impairment (aMCI), and dementia were assessed with mCDR, CDR, and neuropsychological evaluation, while medial temporal atrophy (MTA) was measured on MRI scans. The mCDR and CDR were compared with respect to inter‐rater reliability, validity, and ability to predict progression in cognitive diagnosis at 12 month follow‐up.

Results

The mCDR can be administered in less than one third of the time required to administer the CDR (30 min). Inter‐rater reliability (Cohen's weighted κ) was 0.86 for the mCDR and 0.56 for the CDR. Ability to distinguish between NCI, aMCI, and Dementia subjects, and correlations to memory and non‐memory measures were marginally better for the CDR, in comparison to the mCDR. Correlations of mCDR and CDR scores to MTA scores did not differ. Baseline mCDR scores predicted transition from NCI to aMCI, whereas baseline CDR scores predicted transition from aMCI to Dementia.

Conclusions

The mCDR, as compared to the CDR, is briefer and more reliable, and is a valid measure of functional ability among subjects with normal cognition, mild cognitive impairment, and mild dementia. The mCDR should be particularly useful as a reliable and economical instrument for assessing change in functional abilities, especially in multi‐center clinical trials and population studies of MCI and mild dementia. Copyright © 2009 John Wiley & Sons, Ltd.
Somatosensory working memory performance in humans depends on both engagement and disengagement of regions in a distributed network
Authors: Haegens Saskia , Osipova Daria , Oostenveld Robert , Jensen Ole
Published: June 2009

Successful working memory (WM) requires the engagement of relevant brain areas but possibly also the disengagement of irrelevant areas. We used magnetoencephalography (MEG) to elucidate the temporal dynamics of areas involved in a somatosensory WM task. We found an increase in gamma band activity in the primary and secondary somatosensory areas during encoding and retention, respectively. This was accompanied by an increase of alpha band activity over task‐irrelevant regions including posterior and ipsilateral somatosensory cortex. Importantly, the alpha band increase was strongest during successful WM performance. Furthermore, we found frontal gamma band activity that correlated both with behavioral performance and the alpha band increase. We suggest that somatosensory gamma band activity reflects maintenance and attention‐related components of WM operations, whereas alpha band activity reflects frontally controlled disengagement of task‐irrelevant regions. Our results demonstrate that resource allocation involving the engagement of task‐relevant and disengagement of task‐irrelevant regions is needed for optimal task execution. Hum Brain Mapp, 2010. © 2009 Wiley‐Liss, Inc.
Triptolide functions as a potent angiogenesis inhibitor
Authors: He Ming‐Fang , Huang Yi‐Hsien , Wu Li‐Wha , Ge Wei , Shaw Pang‐Chui , But Paul Pui‐Hay
Published: June 2009

Triptolide is a key anti‐inflammatory compound of the Chinese herbal medicine Tripterygium wilfordii Hook. f. (Celastraceae). It also possesses potent antitumor activity. In this study, we show that triptolide is an angiogenesis inhibitor based on various angiogenesis assays. The IC50 in in vitro assays was 45 nM, which was much lower than the plasma concentrations of triptolide in the rat or human administered with T. wilfordii extracts for treating inflammation. When dosed in vivo, triptolide potently inhibited angiogenesis at 100 nM in Matrigel plug assay. Triptolide at 0.75 mg/kg/day significantly blocked tumor angiogenesis and tumor progression in murine tumorigenesis assay. The underlying mechanism of triptolide correlated with downregulation of proangiogenic Tie2 and VEGFR‐2 expression in human umbilical vein endothelial cell by semiquantitative RT‐PCR and western blot analysis. Although Tie2 inhibition appeared to be a later event as compared with VEGFR‐2, Tie2 overexpression significantly attenuated the inhibitory effect of triptolide on endothelial proliferation and network formation. By contrast, Tie2 knockdown mimicked the inhibitory effect of triptolide on endothelial network formation. Our findings suggest that antitumor action of triptolide is partly via inhibition of tumor angiogenesis by blocking 2 endothelial receptor‐mediated signaling pathways, and triptolide can be a promising antiangiogenic agent.
European disparities in malignant digestive endocrine tumours survival
Authors: Lepage C. , Ciccolallo L. , De Angelis R. , Bouvier A.M. , Faivre J. , Gatta G. ,   The EUROCARE working group
Published: June 2009

The aim of this study was to report on malignant digestive endocrine tumours (MDET) prognosis in several European countries. We analysed survival data from 19 cancer registries in 12 European countries on 3,715 MDET diagnosed between 1985 and 1994. The overall 5‐year survival rate was 47.5%. It was 58.1% for differentiated MDET and 8.1% for small‐cell MDET (p < 0.001), 55.9% for patients under 65 and 37.0% for older patients. Survival rates for small intestinal and colorectal were higher than for the other sites. The 5‐year relative survival rates were 60.3% in Northern Europe, 53.6% in Western Continental Europe, 42.5% in the UK, 37.6% in Eastern Europe (p < 0.001). Among well‐differentiated pancreatic tumours, 5‐year relative survival was 55.6% for insulinoma, 48.4% for gastrinoma, 33.4% for glucagonoma, 28.8% for carcinoïd tumours and 49.9% for non‐functioning tumours. The relative excess risk of death was significantly lower in Western Continental Europe and Northern Europe and significantly higher in Easter European compared to the UK. MDET differentiation, site, geographic area, age and sex, were independent prognostic factors. Overall, in Europe approximately half of the patients with MDET survive 5 years after the initial diagnosis. Prognosis varies with tumour differentiation, anatomic site and histological type. There are significant differences in survival from MDET among European countries, independently of other prognostic factors.
Identification of novel hub genes associated with liver metastasis of gastric cancer
Authors: Chang Wenjun , Ma Liye , Lin Liping , Gu Liqiang , Liu Xiaokang , Cai Hui , Yu Yongwei , Tan Xiaojie , Zhai Yujia , Xu Xingxing , Zhang Minfeng , Wu Lingling , Zhang Hongwei , Hou Jianguo , Wang Hongyang , Cao Guangwen
Published: June 2009

Understanding hub genes involved in gastric cancer (GC) metastasis could lead to effective approaches to diagnose and treat cancer metastasis. In this study, 272 differentially expressed genes between synchronous liver metastasis and the paired GC were selected from microarray assays. KEGG pathway analysis indicated that of 13 enriched pathways, 8 were involved in cancer metastasis. Literature‐based annotations showed that the differentially expressed genes significantly enriched known metastasis‐related genes. With the use of protein–protein interaction network, we found a subnetwork significantly enriching the metastasis‐related genes and hubs. Unannotated hubs in this subnetwork were predicted to be novel metastasis‐associated genes. Nine hubs in this subnetwork were validated by using quantitative RT‐PCR, and 4 hubs were further validated by immunohistochemistry. NR4A2 was significantly down‐regulated in synchronous liver metastasis compared with the paired GC at both transcriptional and translational levels. NR4A2 immunostaining was apparent in the mesenchymal cells of pathologically normal gastric mucosa and in the epithelial cells of primary GC. HSP90AA1 was not only up‐regulated in the metastatic GC compared with primary GC at both transcriptional and translational levels, but also up‐regulated in primary GC compared with the normal mucosa at the translational level. NR4A2, NR3C1, ARF3, XAB2, and alternatively spliced variants of NR4A2, SP8 and SP‐novel, were significantly down‐regulated, whereas CCNE1 significantly up‐regulated, in primary GC compared with the normal gastric mucosa. Conclusively, NR4A2 and HSP90AA1 stand out as promising diagnostic markers and therapeutic targets for liver metastasis of GC. CCNE1 and NR3C1 indicate primary GC, rather than distant metastasis. © 2009 UICC
Tumor metastasis and the lymphatic vasculature
Authors: Sleeman Jonathan P. , Thiele Wilko
Published: June 2009

Tumor‐associated lymphatic vessels act as a conduit by which disseminating tumor cells access regional lymph nodes and form metastases there. Lymph node metastasis is of major prognostic significance for many types of cancer, although lymph node metastases are themselves rarely life‐threatening. These observations focus our attention on understanding how tumor cells interact with the lymphatic vasculature, and why this interaction is so significant for prognosis. Tumors interact with the lymphatic vasculature in a number of ways, including vessel co‐option, chemotactic migration and invasion into lymphatic vessels and induction of lymphangiogenesis. Tumor‐induced lymphangiogenesis both locally and in regional lymph nodes has been correlatively and functionally associated with metastasis formation and poor prognosis. The investigation of the molecular regulation of lymphangiogenesis has identified ways of interfering with prolymphangiogenic signaling. Blockade of tumor‐induced lymphangiogenesis in preclinical models inhibits metastasis formation in lymph nodes and often also in other organs, suggesting that blocking the lymphatic route of dissemination might suppress metastasis formation not only in lymph nodes but also in other organs. However, randomized clinical trials that have investigated the efficacy of therapeutic removal of lymph nodes have concluded that lymph node metastases act only as indicators that primary tumors have developed metastatic potential, and do not govern the further spread of metastatic cells. To reconcile these apparently paradoxical observations we suggest a model in which tumor‐induced lymphangiogenesis and lymph node metastasis formation act as indicators that tumors are producing factors that can act systemically to promote metastasis formation in distant organs. © 2009 UICC
Endogenous expression of the sodium iodide symporter mediates uptake of iodide in murine models of colorectal carcinoma
Authors: Gaertner Florian C. , Rohde Franziska , Mueller Jan , Blechert Birgit , Janssen Klaus‐Peter , Essler Markus
Published: June 2009

The sodium iodide symporter (NIS) mediates iodide uptake into the thyroid. Because of this mechanism, differentiated thyroid cancer is susceptible for radioiodine therapy. Functional NIS expression in extrathyroidal tumors has been reported mainly in breast cancer. We screened colorectal tumors for NIS expression and investigated the mechanisms regulating NIS activity. Cell lines were screened for iodide uptake in vitro and NIS expression was evaluated by real‐time RT‐PCR, immunocytochemistry and immunoblotting. Iodide and pertechnetate uptake were evaluated in allograft tumors by biodistribution studies and scintigraphy. Tumors of transgenic mouse models for colorectal cancer harboring mutations in the oncogenes KRAS, β‐catenin or the tumor‐suppressor gene adenomatous‐polyposis coli (APC) were screened for NIS expression by RT‐PCR. In vitro, functional NIS activity was detected in murine CMT93 rectal carcinoma cells and NIS expression was verified on mRNA and protein level. Inhibition of tyrosine kinases increased iodide uptake. Inhibition of tyrosine phosphatases decreased iodide uptake. In vivo, functional NIS expression was preserved in CMT93 tumors and tumor uptake could be enhanced by treatment of mice with tyrosine kinase inhibitors. In transgenic murine models of colorectal cancer, 14% of endogenous tumors expressed elevated levels of NIS mRNA. We conclude that NIS is functionally expressed in a subset of murine colorectal tumors and its activity is regulated by tyrosine phosphorylation. Therefore, with specific tyrosine kinase inhibition, these tumors might be susceptible for radioiodine treatment. Further studies are justified to identify the specific pathways regulating NIS activity and to transfer these findings to human cell lines and tissues. © 2009 UICC
Genome‐wide DNA methylation profiles in liver tissue at the precancerous stage and in hepatocellular carcinoma
Authors: Arai Eri , Ushijima Saori , Gotoh Masahiro , Ojima Hidenori , Kosuge Tomoo , Hosoda Fumie , Shibata Tatsuhiro , Kondo Tadashi , Yokoi Sana , Imoto Issei , Inazawa Johji , Hirohashi Setsuo , Kanai Yae
Published: June 2009

To clarify genome‐wide DNA methylation profiles during hepatocarcinogenesis, bacterial artificial chromosome (BAC) array‐based methylated CpG island amplification was performed on 126 tissue samples. The average numbers of BAC clones showing DNA hypo‐ or hypermethylation increased from noncancerous liver tissue obtained from patients with hepatocellular carcinomas (HCCs) (N) to HCCs. N appeared to be at the precancerous stage, showing DNA methylation alterations that were correlated with the future development of HCC. Using Wilcoxon test, 25 BAC clones, whose DNA methylation status was inherited by HCCs from N and were able to discriminate 15 N samples from 10 samples of normal liver tissue obtained from patients without HCCs (C) with 100% sensitivity and specificity, were identified. The criteria using the 25 BAC clones were able to discriminate 24 additional N samples from 26 C samples in the validation set with 95.8% sensitivity and 96.2% specificity. Using Wilcoxon test, 41 BAC clones, whose DNA methylation status was able to discriminate patients who survived more than 4 years after hepatectomy from patients who suffered recurrence within 6 months and died within a year after hepatectomy, were identified. The DNA methylation status of the 41 BAC clones was correlated with the cancer‐free and overall survival rates of patients with HCC. Multivariate analysis revealed that satisfying the criteria using the 41 BAC clones was an independent predictor of overall outcome. Genome‐wide alterations of DNA methylation may participate in hepatocarcinogenesis from the precancerous stage, and DNA methylation profiling may provide optimal indicators for carcinogenetic risk estimation and prognostication. © 2009 UICC
Recent developments in Fourier Domain Mode Locked lasers for optical coherence tomography: Imaging at 1310 nm vs. 1550 nm wavelength
Authors: Biedermann Benjamin R. , Wieser Wolfgang , Eigenwillig Christoph M. , Huber Robert
Published: June 2009

We report on recent progress in Fourier domain mode‐locking (FDML) technology. The paper focuses on developments beyond pushing the speed of these laser sources. After an overview of improvements to FDML over the last three years, a brief analysis of OCT imaging using FDML lasers with different wavelengths is presented. For the first time, high speed, high quality FDML imaging at 1550 nm is presented and compared to a system at 1310 nm. The imaging results of human skin for both wavelengths are compared and analyzed. Sample arm optics, power on the sample, heterodyne gain, detection bandwidth, colour cut levels and sample location have been identical to identify the influence of difference in scattering and water absorption. The imaging performance at 1310 nm in human skin is only slightly better and the results suggest that water absorption only marginally affects the penetration depth in human skin at 1550 nm. For several applications this wavelength may be preferred. (© 2009 WILEY‐VCH Verlag GmbH & Co. KGaA, Weinheim)
In vitro and In vivo studies of local arterial gene delivery and transfection using lipopolyplexes‐embedded stents
Authors: Brito Luis A. , Chandrasekhar Saradha , Little Steven R. , Amiji Mansoor M.
Published: June 2009

Gene‐eluting stents can have profound impact in the treatment of coronary restenosis, especially when the encoded protein can re‐endothelialize the arterial lumen. In this study, we have examined gene delivery in vitro and in vivo using poly(beta‐amino ester) (PbAE) precondensed plasmid DNA‐containing cationic liposomes or lipopolyplexes (LPP) immobilized on stainless steel meshes and stents using gelatin coatings. In vitro studies using LPP‐immobilized on 50 mm round meshes using type A and B gelatin coatings showed that LPP were efficiently internalized in human aortic smooth muscle cells (SMC) over time, leading to green fluorescent protein (GFP) expression. Type B gelatin coating was found to be more effective in intracellular delivery and transgene expression efficiency and, as such, was used for stent coating. In vivo studies, carried out in iliac artery restenosis model in New Zealand white rabbits, also showed GFP expression in arterial tissues after 24 h of implantation. Based on these encouraging preliminary results, LPP‐based formulations can serve as a safe and effective nonviral gene delivery system for effective treatment of coronary restenosis. © 2009 Wiley Periodicals, Inc. J Biomed Mater Res, 2010
Biodegradable nitric oxide‐releasing poly(diol citrate) elastomers
Authors: Zhao Haichao , Serrano M. Concepcion , Popowich Daniel A. , Kibbe Melina R. , Ameer Guillermo A.
Published: June 2009

We have developed novel poly(diol citrate) elastomers, which are capable of providing localized and sustained release of nitric oxide (NO). The elastomer prepolymer was obtained by condensation of citric acid, 1,8‐octanediol, andN,N′‐bis(2‐hydroxyethyl)ethylenediamine at 130°C for 40 min. Films were prepared by solvent casting followed by crosslinking at 80°C for 4 days. Mechanical properties were tested. NO‐releasing expanded poly(tetrafluoroethylene) (ePTFE) vascular grafts were fabricated by coating the graft's lumen with the prepolymer and crosslinking it at 80°C for 4 days prior to diazeniumdiolation. Samples were diazeniumdiolated via exposure to pressurized NO. Cell compatibility was assessed by monitoring the proliferation of porcine aortic smooth muscle cells (PASMC) on the elastomers. Degradation in phosphate buffer saline (PBS) (pH = 7) at 37°C was evaluated for up to 6 weeks. The secondary amine‐containing poly(diol citrate) films had a Young's modulus that ranged from 5.91 to 32.64 MPa, an ultimate tensile stress that ranged from 1.47 to 10.71 MPa, and an elongation at break from 200 to 260%, depending on the content of secondary amine in the feed monomer. These elastomers were degradable and compatible with PASMC. Furthermore, degradation rate was found to be independent of the content of secondary amines in the prepolymer. The NO release from diazeniumdiolated films and ePTFE grafts was sustained for two days. In conclusion, these novel diazeniumdiolated polyester elastomers may be useful in medical devices that require blood contact or control of cell proliferation. © 2009 Wiley Periodicals, Inc. J Biomed Mater Res 2010
Citric acid‐based elastomers provide a biocompatible interface for vascular grafts
Authors: Kibbe Melina R. , Martinez Janet , Popowich Daniel A. , Kapadia Muneera R. , Ahanchi Sadaf S. , Aalami Oliver O. , Jiang Qun , Webb Antonio R. , Yang Jian , Carroll Timothy , Ameer Guillermo A.
Published: June 2009

Prosthetic vascular bypass grafting is associated with poor long‐term patency rates. Herein, we report on the mid‐term performance of expanded polytetrafluoroethylene (ePTFE) vascular grafts modified with a citric acid‐based biodegradable elastomer. Through a spin‐shearing method, ePTFE grafts were modified by mechanically coating a layer of poly(1,8 octanediol citrate) (POC) onto the luminal nodes and fibrils of the ePTFE. Control and POC‐ePTFE grafts were implanted into the porcine carotid artery circulation as end‐to‐side bypass grafts. Grafts were assessed by duplex ultrasonography, magnetic resonance angiography, and digital subtraction contrast angiography and were all found to be patent with no hemodynamically significant stenoses. At 4 weeks, POC‐ePTFE grafts were found to be biocompatible and resulted in a similar extent of neointimal hyperplasia as well as leukocyte and monocyte/macrophage infiltration as control ePTFE grafts. Furthermore, POC supported endothelial cell growth. Lastly, scanning electron microscopy confirmed the presence of POC on the ePTFE grafts at 4 weeks. Thus, these data reveal that surface modification of blood‐contacting surfaces with POC results in a biocompatible surface that does not induce any untoward effects or inflammation in the vasculature. These findings are important as they will serve as the foundation for the development of a drug‐eluting vascular graft. © 2009 Wiley Periodicals, Inc. J Biomed Mater Res, 2010
Modulation of hyaluronan catabolism in chondrocytes by mechanical stimuli
Authors: Tanimoto Kotaro , Kitamura Reiko , Tanne Yuki , Kamiya Takashi , Kunimatsu Ryo , Yoshioka Motoko , Tanaka Nobuaki , Tanaka Eiji , Tanne Kazuo
Published: June 2009

Hyaluronan (HA) is a component of the extracellular matrices of cartilage contributing to the structural and functional integrity. HA metabolism is regulated by both anabolic and catabolic processes; however, a great deal more of the detail has been unknown yet. The purpose of this study was to clarify the effect of excessive mechanical load on the expression and activity of hyaluronidase (HYAL) in chondrocytes with a special reference to the expressions of IL‐1β and tumor necrosis factor (TNF)‐α. A cyclic tensile load of 22.8% cell elongation, regarded as an excessive mechanical stimulus, was applied to cultured rabbit knee articular chondrocytes. HYAL1, HYAL2, IL‐1β, and TNF‐α mRNA levels were examined by quantitative real‐time PCR analysis. The HYAL activity in culture medium was examined by HA zymography. Both HYAL1 and HYAL2 mRNA levels were upregulated significantly by the loading in cultured chondrocytes. HYAL activity was also enhanced as compared with unloaded controls. The IL‐1β mRNA level was upregulated significantly by the loading, and TNF‐α mRNA level was slightly upregulated. HYAL1 and HYAL2 mRNA levels were upregulated significantly by IL‐1β treatment, resulting in a slight increase in HYAL activity. These results show that the expression of HYAL1 and HYAL2 in articular chondrocytes is enhanced by excessive mechanical stimuli and affected in part by induction of IL‐1β, leading to HA catabolism in articular cartilage. © 2009 Wiley Periodicals, Inc. J Biomed Mater Res 2010
Biocompatibility and modification of the protein‐based adhesive secreted by the Australian frog Notaden bennetti
Authors: Graham Lloyd D. , Danon Stephen J. , Johnson Graham , Braybrook Carl , Hart Noel K. , Varley Russell J. , Evans Margaret D. M. , McFarland Gail A. , Tyler Michael J. , Werkmeister Jerome A. , Ramshaw John A. M.
Published: June 2009

When provoked, Notaden bennetti frogs secrete a proteinaceous exudate, which rapidly forms a tacky and elastic glue. This material has potential in biomedical applications. Cultured cells attached and proliferated well on glue‐coated tissue culture polystyrene, but migrated somewhat slower than on uncoated surfaces. In organ culture, dissolved glue successfully adhered collagen‐coated perfluoropolyether lenses to debrided bovine corneas and supported epithelial regrowth. Small pellets of glue implanted subcutaneously into mice were resorbed by surrounding tissues, and all of the animals made a full recovery. An initial but transient skin necrosis at the implant site was probably caused by some of the potentially toxic metabolites present in the frog secretion; these include sterols and carotenoids, as well as fatty alcohols, aldehydes, ketones, acids, and aromatic compounds. Removal of the carotenoid pigments did not significantly alter the glue's material properties. In contrast, peroxidase treatment of dissolved glue introduced unnatural crosslinks between molecules of the major protein (Nb‐1R) and resulted in the formation of a soft hydrogel, which was very different to the original material. © 2009 Wiley Periodicals, Inc. J Biomed Mater Res, 2010
A novel small animal model for biocompatibility assessment of polymeric materials for use in prosthetic heart valves
Authors: Wang Qiang , McGoron Anthony J. , Pinchuk Leonard , Schoephoerster Richard T.
Published: June 2009

A composite polymeric material, poly(styrene‐block‐isobutylene‐block‐styrene) (SIBS) with an embedded reinforcement polyethylene terephthalate (PET) fabric, is undergoing investigation for potential use in a novel heart valve. The purpose of this study was to develop and implement a small animal model to assess the biocompatibility of composite samples in a cardiovascular tissue and blood‐contacting environment. Composite samples were manufactured using dip coating and solvent casting with two coating thicknesses (25 and 50 μm). A novel rat abdominal aorta model was developed to test the dip‐coated samples in a similar pulsatile flow condition to its intended use, and both dip‐coated and solvent‐cast samples were tested using a rat subcutaneous model. Tissue response, defined by degree of cellular infiltration and encapsulation, was minimized when a smooth coating of SIBS shielded the PET fabric from exposure to blood and tissue, and the degree of tissue response was directly correlated with the degree of surface roughness. Surface modification using phospholipid further reduces the tissue response. We have demonstrated the applicability of using a novel rat abdominal aorta model for biocompatibility assessment of polymeric materials that will be used in cardiovascular implants. For the purpose of this study, our results indicate that solvent casting with a 25‐μm SIBS coating thickness will provide optimal biocompatibility for the SIBS valve. © 2009 Wiley Periodicals, Inc. J Biomed Mater Res 2010
Deregulated NFATc1 activity transforms murine fibroblasts via an autocrine growth factor‐mediated Stat3‐dependent pathway
Authors: Lagunas Lucio , Clipstone Neil A.
Published: June 2009

The nuclear factor of activated T cells (NFAT) family of transcription factors has recently been implicated with a role in tumorigenesis. Forced expression of a constitutively active NFATc1 mutant (caNFATc1) has been shown to transform immortalized murine fibroblasts in vitro, while constitutive activation of the NFAT‐signaling pathway has been found in a number of human cancers, where it has been shown to contribute towards various aspects of the tumor phenotype. Here we have investigated the molecular mechanisms underlying the oncogenic potential of deregulated NFAT activity. We now show that ectopic expression of caNFATc1 in murine 3T3‐L1 fibroblasts induces the secretion of an autocrine factor(s) that is sufficient to promote the transformed phenotype. We further demonstrate that this NFATc1‐induced autocrine factor(s) specifically induces the tyrosine phosphorylation of the Stat3 transcription factor via a JAK kinase‐dependent pathway. Interestingly, this effect of sustained NFAT signaling on the autocrine growth factor‐mediated activation of Stat3 is not restricted to murine fibroblasts, but is also observed in the PANC‐1 and MCF10A human cell lines. Most importantly, we find that the shRNA‐mediated depletion of endogenous Stat3 significantly attenuates the ability of caNFATc1 to transform 3T3‐L1 fibroblasts. Taken together, our results afford significant new insights into the molecular mechanisms underlying the oncogenic potential of deregulated NFATc1 activity by demonstrating that constitutive NFATc1 activity transforms cells via an autocrine factor‐mediated pathway that is critically dependent upon the activity of the Stat3 transcription factor. J. Cell. Biochem. 108: 237–248, 2009. © 2009 Wiley‐Liss, Inc.
DNA methylation‐mediated epigenetic control
Authors: Rottach Andrea , Leonhardt Heinrich , Spada Fabio
Published: June 2009

During differentiation and development cells undergo dramatic morphological and functional changes without any change in the DNA sequence. The underlying changes of gene expression patterns are established and maintained by epigenetic processes. Early mechanistic insights came from the observation that gene activity and repression states correlate with the DNA methylation level of their promoter region. DNA methylation is a postreplicative modification that occurs exclusively at the C5 position of cytosine residues (5mC) and predominantly in the context of CpG dinucleotides in vertebrate cells. Here, three major DNA methyltransferases (Dnmt1, 3a, and 3b) establish specific DNA methylation patterns during differentiation and maintain them over many cell division cycles. CpG methylation is recognized by at least three protein families that in turn recruit histone modifying and chromatin remodeling enzymes and thus translate DNA methylation into repressive chromatin structures. By now a multitude of histone modifications have been linked in various ways with DNA methylation. We will discuss some of the basic connections and the emerging complexity of these regulatory networks. J. Cell. Biochem. 108: 43–51, 2009. © 2009 Wiley‐Liss, Inc.
The cell adhesion nectin‐like molecules (Necl) 1 and 4 suppress the growth and tumorigenic ability of colon cancer cells
Authors: Raveh Shani , Gavert Nancy , Spiegel Ivo , Ben‐Ze'ev Avri
Published: June 2009

A key step in human colon cancer development includes the hyperactivation of Wnt/β‐catenin signaling and the induction of β‐catenin‐TCF target genes that participate in colon cancer progression. Recent studies identified members of the immunoglobulin‐like cell adhesion molecules (IgCAM) of the L1CAM family (L1 and Nr‐CAM) as targets of β‐catenin‐TCF signaling in colon cancer cells. L1 was detected at the invasive front of colon cancer tissue and confers metastasis when overexpressed in cells. In contrast to L1, we did not detect in colon cancer cells significant levels of another IgCAM family of molecules, the nectin‐like (Necl) receptors Necl1 and Necl4, while Necl4 was previously found in the normal small intestine and colon tissues. We studied the properties of colon cancer cells in which Necl4 and Necl1 were expressed either alone, or in combination, and found that such cells display a wide range of properties associated with tumor suppression. Expression of both Necl1 and Necl4 was the most efficient in suppressing the tumorigenicity of colon cancer cells. This was associated with enhanced rates of apoptosis and change in several apoptosis‐related markers. In contrast to its capacity to suppress tumorigenesis, Necl4 was unable to affect the highly malignant and metastatic capacities of colon cancer cells in which L1 was overexpressed. Our results suggest that various IgCAM receptor families play different roles in affecting the tumorigenic function of the same cells, and that Necl1 and Necl4 can fulfill a tumor suppressive role. J. Cell. Biochem. 108: 326–336, 2009. © 2009 Wiley‐Liss, Inc.
Identification of small molecule aggregators from large compound libraries by support vector machines
Authors: Rao Hanbing , Li Zerong , Li Xiangyuan , Ma Xiaohua , Ung Choongyong , Li Hu , Liu Xianghui , Chen Yuzong
Published: June 2009

Small molecule aggregators non‐specifically inhibit multiple unrelated proteins, rendering them therapeutically useless. They frequently appear as false hits and thus need to be eliminated in high‐throughput screening campaigns. Computational methods have been explored for identifying aggregators, which have not been tested in screening large compound libraries. We used 1319 aggregators and 128,325 non‐aggregators to develop a support vector machines (SVM) aggregator identification model, which was tested by four methods. The first is five fold cross‐validation, which showed comparable aggregator and significantly improved non‐aggregator identification rates against earlier studies. The second is the independent test of 17 aggregators discovered independently from the training aggregators, 71% of which were correctly identified. The third is retrospective screening of 13M PUBCHEM and 168K MDDR compounds, which predicted 97.9% and 98.7% of the PUBCHEM and MDDR compounds as non‐aggregators. The fourth is retrospective screening of 5527 MDDR compounds similar to the known aggregators, 1.14% of which were predicted as aggregators. SVM showed slightly better overall performance against two other machine learning methods based on five fold cross‐validation studies of the same settings. Molecular features of aggregation, extracted by a feature selection method, are consistent with published profiles. SVM showed substantial capability in identifying aggregators from large libraries at low false‐hit rates. © 2009 Wiley Periodicals, Inc.J Comput Chem, 2010
Covalent hydration energies for purine analogs by quantum chemical methods
Authors: Wang Selina C. , Beal Peter A. , Tantillo Dean J.
Published: June 2009

In this work, covalent hydration energies for a variety of azanaphthalenes and purine analogs have been calculated using a variety of quantum chemical methods. On the basis of these results, we recommend the CPCM(UA0)‐B3LYP/6‐31+G(d,p) level for rapid prediction of covalent hydration energies. However, we caution the use of this methodology for computing covalent hydration energies for fluorine‐containing compounds. © 2009 Wiley Periodicals, Inc. J Comput Chem, 2010