bluuebunny/crossref_metadata_2025 huggingface dataset:
The effect of nickel(II) ions on the growth and bioaccumulation properties of Escherichia coli
Authors: Wu Laiyan , Yu Junxia , Sun Xiaomei , Li Buhai
Published: November 2008

The influence of nickel(II) ions concentration on the growth and nickel(II) bioaccumulation properties of Escherichia coli (cultivated in the LB medium) was studied. When the investigated initial concentration of nickel(II) was in the range of 20–300 mg L−1, it was found that the growth of E. coli was delayed obviously with the increasing nickel(II) ion concentration, while the accumulation capacity increased until the maximum was obtained. FTIR spectrum showed that the peak near 3300 cm−1 shifted remarkably, and simultaneously, the peaks at 1660 cm−1 strengthened according to the nickel(II) concentration. As shown by the X‐ray photoelectron spectroscopy analysis, the nitrogen, sulphur, and phosphorus contents of the cultivated cell were reduced, while the content of oxygen was increased. The biologic characteristics of the microorganism did not change as shown in the transmission electron microscope images. © 2008 American Institute of Chemical Engineers Environ Prog, 2009
Tick sizes and relative rates of price discovery in stock, futures, and options markets: Evidence from the Taiwan stock exchange
Authors: Chen Yu‐Lun , Gau Yin‐Feng
Published: November 2008

This study examines the competition in price discovery among stock index, index futures, and index options in Taiwan. The price‐discovery ability of the Taiwan Top 50 Tracker Fund, an exchange‐traded fund based on the Taiwan 50 index is examined. The authors find that, after the minimum tick size in the stock market decreases, the bid–ask spreads of the component stocks of the stock index and the Taiwan Top 50 Tracker Fund get lower, and the contribution of the spot market to price discovery increases. © 2008 Wiley Periodicals, Inc. Jrl Fut Mark 29:74–93, 2009
Modifications to the Patient Rule‐Induction Method that utilize non‐additive combinations of genetic and environmental effects to define partitions that predict ischemic heart disease
Authors: Dyson Greg , Frikke‐Schmidt Ruth , Nordestgaard Børge G. , Tybjærg‐Hansen Anne , Sing Charles F.
Published: November 2008

This article extends the Patient Rule‐Induction Method (PRIM) for modeling cumulative incidence of disease developed by Dyson et al. (Genet Epidemiol 31:515–527) to include the simultaneous consideration of non‐additive combinations of predictor variables, a significance test of each combination, an adjustment for multiple testing and a confidence interval for the estimate of the cumulative incidence of disease in each partition. We employ the partitioning algorithm component of the Combinatorial Partitioning Method to construct combinations of predictors, permutation testing to assess the significance of each combination, theoretical arguments for incorporating a multiple testing adjustment and bootstrap resampling to produce the confidence intervals. An illustration of this revised PRIM utilizing a sample of 2,258 European male participants from the Copenhagen City Heart Study is presented that assesses the utility of genetic variants in predicting the presence of ischemic heart disease beyond the established risk factors. Genet. Epidemiol. 2009. © 2008 Wiley‐Liss, Inc.
The prevention of dementia
Authors: Peters Ruth
Published: November 2008

Objective

Dementia is prevalent in older adults and the population is ageing. Many factors have been associated with dementia and anything that may aid the prevention of dementia is of importance.

Method

The literature in this area was evaluated and information relating to the various factors that may impact upon the prevention of dementia is presented below.

Results

Factors that have been associated with a possible increased risk of developing dementia include high blood pressure, (at least in midlife), high body mass index, smoking and possibly diabetes although the evidence is mixed. There is currently no clear evidence with regard to cholesterol and metabolic syndrome although both may be implicated. Having education and maintaining a Mediterranean diet, including vegetable, fruit and fish intake, have been linked to a lower incidence of dementia as has low to moderate alcohol intake. Although care must be taken with the latter given the different characteristics of the studies reporting on alcohol and dementia.

Conclusion

It may be that risk and protective factors vary with age, however, in the absence of prophylactic treatment it seems likely that the maintenance of a healthy lifestyle may represent the best option with regard to the prevention of dementia. Copyright © 2008 John Wiley & Sons, Ltd.
Selective neck dissection following adjuvant therapy for advanced head and neck cancer
Authors: Mukhija Vijay , Gupta Sachin , Jacobson Adam S. , Anderson Eloy Jean , Genden Eric M.
Published: November 2008

Background.

In the past, surgeons believed that in order to eradicate regional disease, a radical or modified radical neck dissection was necessary. An evolution in surgical principles and the popularization of primary chemoradiation has raised the questions regarding the role of neck dissection and the extent of neck dissection following therapy. The aim of this study was to determine the efficacy of selective neck dissection (SND) for patients with N2 or N3 disease following treatment with primary radiation therapy or chemoradiation.

Methods.

A retrospective review of 58 patients with stage III or IV head and neck squamous cell carcinoma was conducted. The primary sites included base of tongue (n = 15), hypopharynx (n = 12), tonsil (n = 16), larynx (n = 11), and unknown primary (n = 4). Definitive treatment consisted of either concomitant chemoradiation (67.2%) or external beam radiation therapy (32.8%). In the monotherapy group, all patients received a total curative dose of 66 to 72 Gy in once‐daily fractions of 180 to 200 cGy. The combined chemoradiation group received a similar radiation schedule and a 4‐day continuous infusion of cisplatin (20 mg/m2/day) and 5‐fluorouracil (1000 mg/m2/day). A planned SND of levels II to IV was performed on all the patients 3 to 6 weeks after completion of definitive medical therapy.

Results.

Seventy neck dissections were performed on 58 patients with advanced neck disease following radiation or chemoradiation. The median time of follow‐up was 34 months (range, 9–71 months) following the neck dissection. Pathologically, 22.4% (13/58) of the patients had viable tumor cells identified in the neck dissection specimen. Seventy‐two percent of the patients are currently alive, and 28% died as a result of distant disease, local or regional recurrence, or other causes. Of patients who died from distant disease, 11% had pathological evidence of residual tumor cells identified in the neck dissection specimen. Of patients who died from local or regional disease, 50% had pathological evidence of residual tumor cells identified in the neck dissection specimen.

Conclusion.

The rate of regional recurrence following SND is similar to reported rates following modified/radical neck dissection. This suggests that SND provides an appropriate surgical option for advanced neck disease in select patients following adjuvant therapy. © 2008 Wiley Periodicals, Inc. Head Neck, 2009.
CD133+ liver cancer stem cells from methionine adenosyl transferase 1A–deficient mice demonstrate resistance to transforming growth factor (TGF)-β–induced apoptosis #
Authors: Ding Wei , Mouzaki Marialena , You Hanning , Laird Joshua C. , Mato Jose , Lu Shelly C. , Rountree Bart C.
Published: November 2008

Methionine adenosyltransferase (MAT) is an essential enzyme required for S-adenosylmethionine biosynthesis. Hepatic MAT activity falls during chronic liver injury, and mice lacking Mat1a develop spontaneous hepatocellular carcinoma by 18 months. We have previously demonstrated that CD133+CD45− oval cells isolated from 16-month-old Mat1a
−/− mice represent a liver cancer stem cell population. The transforming growth factor β (TGF-β) pathway constitutes a central signaling network in proliferation, apoptosis, and tumorigenesis. In this study, we tested the response of tumorigenic liver stem cells to TGF-β. CD133+CD45− oval cells were isolated from premalignant 16-month-old Mat1a
−/− mice by flow cytometry and expanded as five clone lines derived from a single cell. All clone lines demonstrated expression of both hepatocyte and cholangiocyte markers and maintained a small population (0.5% to 2%) of CD133+ cells in vitro, and three of five clone lines produced tumors. Although TGF-β1 inhibited cell growth equally in CD133− and CD133+ cells from each clone line, the CD133+ population demonstrated significant resistance to TGF-β–induced apoptosis compared with CD133− cells. Furthermore, CD133+ cells demonstrated a substantial increase in mitogen-activated protein kinase (MAPK) pathway activation, as demonstrated by phosphorylated extracellular signal-regulated kinase levels before and after TGF-β stimulation. MAPK inhibition using mitogen-activated protein kinase kinase 1 (MEK1) inhibitor PD98059 led to a significant increase in TGF-β–induced apoptosis in CD133+ cells. Conversely, a constitutively active form of MEK1 blocked the apoptotic effects of TGF-β in CD133− cells. Conclusion: CD133+ liver cancer stem cells exhibit relative resistance to TGF-β–induced apoptosis. One mechanism of resistance to TGF-β–induced apoptosis in CD133+ cancer stem cells is an activated mitogen-activated protein kinase/extracellular signal-regulated kinase pathway. (Hepatology 2009.)
Factors of accuracy of transient elastography (fibroscan) for the diagnosis of liver fibrosis in chronic hepatitis C #
Authors: Lucidarme Damien , Foucher Juliette , Le Bail Brigitte , Vergniol Julien , Castera Laurent , Duburque Clotilde , Forzy Gérard , Filoche Bernard , Couzigou Patrice , de Lédinghen Victor
Published: November 2008

The purpose of this study was to assess the influence of success rate and interquartile range on the accuracy of transient elastography for the diagnostic of fibrosis in hepatitis C virus infection. Two-hundred fifty-four consecutive patients had liver stiffness measurements and liver biopsy of at least 15 mm. Discordances of at least two stages between transient elastography and histological assessment were observed in 28 cases (11%). Factors of discordance were assessed by comparing the 28 misclassified cases with the 226 others. In multivariate analysis, fibrosis stage (F0–F2 versus F3–F4) and the ratio interquartile range/median value of liver stiffness measurement (IQR/M) were associated with discordances (P ≤ 0.05). The most significantly discriminant cutoff value was 0.21. For IQR/M < 0.21 versus IQR/M ≥ 0.21, discordances of at least two stages of fibrosis were respectively observed in 10 of 135 cases (7.4%) versus 18 of 119 cases (15.1%) (P ≤ 0.05). In patients with IQR/M ≥ 0.21 versus IQR/M < 0.21, for the diagnosis of liver fibrosis F ≥ 2, F ≥ 3, F = 4, areas under the receiver operating characteristic curve (AUROCs) were 0.80 (95% confidence interval [CI], 0.73–0.89) versus 0.81 (95% CI, 0.70–0.90), (P = NS); 0.80 (95% CI, 0.72–0.88) versus 0.89 (95% CI, 0.83–0.95) (P = 0.04); and 0.86 (95% CI, 0.77–0.94) versus 0.95 (95% CI, 0.92–0.99) (P = NS). No association was found between success rate and discordance. Conclusion: IQR/M is a factor of overestimation of liver fibrosis, and the most discriminant cutoff value is 0.21. Success rate is not a factor of accuracy for the diagnosis of hepatic fibrosis. (Hepatology 2009.)
Hepatitis B virus suppresses toll-like receptor–mediated innate immune responses in murine parenchymal and nonparenchymal liver cells #
Authors: Wu Jun , Meng Zhongji , Jiang Min , Pei Rongjuan , Trippler Martin , Broering Ruth , Bucchi Agnes , Sowa Jan-Peter , Dittmer Ulf , Yang Dongliang , Roggendorf Michael , Gerken Guido , Lu Mengji , Schlaak Joerg F.
Published: November 2008

We have previously shown that Toll-like receptor (TLR)-activated murine nonparenchymal liver cells [(NPC); Kupffer cells (KC), liver sinusoidal endothelial cells (LSEC)] can suppress hepatitis B virus (HBV) replication. Therefore, the aim of this study was to investigate whether HBV has the ability to counteract the TLR-mediated control of its replication. Freshly purified murine hepatocytes and NPCs obtained from C57BL6 mice were stimulated by TLR 1-9 ligands in the presence or absence of hepatitis B surface antigen (HBsAg), hepatitis B e antigen (HBeAg), HBV virions, or supernatants from HBV-producing HBV-Met cells, and HBV replication was suppressed by anti- hepatitis B virus X protein (HBx) small interfering RNA (siRNA) in HBV-Met cells. Supernatants were collected and tested for antiviral cytokines by viral protection assay. HBV gene expression and replication was analyzed by southern blot. RNA and proteins were analyzed by quantitative reverse transcription polymerase chain reaction (RT-PCR) or western blot and enzyme-linked immunosorbent assay, respectively. Pretreatment of hepatocytes and NPCs with HBV-Met cells supernatants, HBsAg, HBeAg, or HBV virions almost completely abrogated TLR-induced antiviral activity, which correlated with suppression of interferon beta (IFN-β) production and subsequent interferon-stimulated gene induction as well as suppressed activation of interferon regulatory factor 3 (IRF-3), nuclear factor kappa B (NF-κB), and extracellular signal-regulated kinase (ERK) 1/2. In HBV-infected HBV-Met cells, TLR stimulation did not induce antiviral cytokines in contrast to primary hepatocytes. TLR-stimulated expression of proinflammatory cytokines [tumor necrosis factor alpha (TNF-α), interleukin-6 (IL-6)], and activation of IRF-3 was suppressed after up-regulation of HBV replication in HBV-Met cells. Accordingly, suppression of HBV replication by siRNA led to activation or expression of proinflammatory transcription factors and cytokines. Conclusion: Our data indicate that HBV can suppress the TLR-induced antiviral activity of liver cells. This has major implications for the interaction between HBV and the immune system. (Hepatology 2009.)
Towards a functional organization of the medial temporal lobe memory system: Role of the parahippocampal and medial entorhinal cortical areas
Authors: Eichenbaum Howard , Lipton Paul A.
Published: November 2008

Whereas substantial recent evidence has suggested to some that the medial entorhinal cortexá (MEC) plays a specialized role in spatial navigation, here we present evidence consistent with a broader role of the MEC in memory. A consideration of evidence on the anatomy and functional roles of medial temporal cortical areas and the hippocampus, and evidence from recordings from MEC neurons in rats performing a spatial memory task, suggest that the MEC may process information about both spatial and temporal context in support of episodic memory. © 2008 Wiley‐Liss, Inc.
Computation by oscillations: Implications of experimental data for theoretical models of grid cells
Authors: Giocomo Lisa M. , Hasselmo Michael E.
Published: November 2008

Recordings in awake, behaving animals demonstrate that cells in medial entorhinal cortex (mEC) show “grid cell” firing activity when a rat explores an open environment. Intracellular recording in slices from different positions along the dorsal to ventral axis show differences in intrinsic properties such as subthreshold membrane potential oscillations (MPO), resonant frequency, and the presence of the hyperpolarization‐activated cation current (h‐current). The differences in intrinsic properties correlate with differences in grid cell spatial scale along the dorsal–ventral axis of mEC. Two sets of computational models have been proposed to explain the grid cell firing phenomena: oscillatory interference models and attractor‐dynamic models. Both types of computational models are briefly reviewed, and cellular experimental evidence is interpreted and presented in the context of both models. The oscillatory interference model has variations that include an additive model and a multiplicative model. Experimental data on the voltage‐dependence of oscillations presented here support the additive model. The additive model also simulates data from ventral neurons showing large spacing between grid firing fields within the limits of observed MPO frequencies. The interactions of h‐current with synaptic modification suggest that the difference in intrinsic properties could also contribute to differences in grid cell properties due to attractor dynamics along the dorsal to ventral axis of mEC. Mechanisms of oscillatory interference and attractor dynamics may make complementary contributions to the properties of grid cell firing in entorhinal cortex. © 2008 Wiley‐Liss, Inc.
Progressive increase in grid scale from dorsal to ventral medial entorhinal cortex
Authors: Brun Vegard Heimly , Solstad Trygve , Kjelstrup Kirsten Brun , Fyhn Marianne , Witter Menno P. , Moser Edvard I. , Moser May‐Britt
Published: November 2008

Grid cells are topographically organized in the sense that, within the dorsal part of the medial entorhinal cortex, the scale of the grid increases systematically with anatomical distance from the dorsal border of this brain area. The ventral limit of the spatial map is currently not known. To determine if the grid map extends into the intermediate and ventral parts of the medial entorhinal cortex, we recorded activity from entorhinal principal cells at multiple dorsoventral levels while rats shuttled back and forth on an 18 m long linear track. The recordings spanned a range of more than 3 mm, covering approximately three quarters of the dorsoventral extent of the medial entorhinal cortex. Distinct periodic firing fields were observed at all recording levels. The average interpeak distance between the fields increased from ∼50 cm in the most dorsal part to ∼3 m at the most ventral recording positions. The increase in grid scale was accompanied by a decrease in the frequency of theta modulation and the rate of phase precession. The increase in average spacing and field size was approximately linear but this relationship coincided with a substantial increase in the variability of each measure. Taken together, the observations suggest that the spatial scale of the grid representation increases progressively along most of the dorsoventral axis of the medial entorhinal cortex, mirroring the topographical scale expansion observed in place cells in the hippocampus. © 2008 Wiley‐Liss, Inc.
Conversion of a phase‐ to a rate‐coded position signal by a three‐stage model of theta cells, grid cells, and place cells
Authors: Blair Hugh T. , Gupta Kishan , Zhang Kechen
Published: November 2008

As a rat navigates through a familiar environment, its position in space is encoded by firing rates of place cells and grid cells. Oscillatory interference models propose that this positional firing rate code is derived from a phase code, which stores the rat's position as a pattern of phase angles between velocity‐modulated theta oscillations. Here we describe a three‐stage network model, which formalizes the computational steps that are necessary for converting phase‐coded position signals (represented by theta oscillations) into rate‐coded position signals (represented by grid cells and place cells). The first stage of the model proposes that the phase‐coded position signal is stored and updated by a bank of ring attractors, like those that have previously been hypothesized to perform angular path integration in the head‐direction cell system. We show analytically how ring attractors can serve as central pattern generators for producing velocity‐modulated theta oscillations, and we propose that such ring attractors may reside in subcortical areas where hippocampal theta rhythm is known to originate. In the second stage of the model, grid fields are formed by oscillatory interference between theta cells residing in different (but not the same) ring attractors. The model's third stage assumes that hippocampal neurons generate Gaussian place fields by computing weighted sums of inputs from a basis set of many grid fields. Here we show that under this assumption, the spatial frequency spectrum of the Gaussian place field defines the vertex spacings of grid cells that must provide input to the place cell. This analysis generates a testable prediction that grid cells with large vertex spacings should send projections to the entire hippocampus, whereas grid cells with smaller vertex spacings may project more selectively to the dorsal hippocampus, where place fields are smallest. © 2008 Wiley‐Liss, Inc.
Influence of boundary removal on the spatial representations of the medial entorhinal cortex
Authors: Savelli Francesco , Yoganarasimha D. , Knierim James J.
Published: November 2008

The medial entorhinal cortex (MEC) is thought to create and update a dynamical representation of the animal's spatial location. Most suggestive of this process are grid cells, whose firing locations occur periodically in space. Prior studies in small environments were ambiguous as to whether all spatially modulated cells in MEC were variants of grid cells or whether a subset resembled classic place cells of the hippocampus. Recordings from the dorsal and ventral MEC were performed as four rats foraged in a small square box centered inside a larger one. After 6 min, without removing the rat from the enclosure, the walls of the small box were quickly removed, leaving the rat free to continue foraging in the whole area enclosed by the larger box. The rate‐responses of most recorded cells (70 out of 93 cells, including 15 of 16 putative interneurons) were considered spatially modulated based on information‐theoretic analysis. A number of cells that resembled classic hippocampal place cells in the small box were revealed to be grid cells in the larger box. In contrast, other cells that fired along the boundaries or corners of the small box did not show grid‐cell firing in the large box, but instead fired along the corresponding locations of the large box. Remapping of the spatial response in the area corresponding to the small box after the removal of its walls was prominent in most spatially modulated cells. These results show that manipulation of local boundaries can exert a powerful influence on the spatial firing patterns of MEC cells even when the manipulations leave global cues unchanged and allow uninterrupted, self‐motion‐based localization. Further, they suggest the presence of landmark‐related information in MEC, which might prevent cumulative drift of the spatial representation or might reset it to a previously learned configuration in a familiar environment. © 2008 Wiley‐Liss, Inc.
Grid cells and theta as oscillatory interference: Theory and predictions
Authors: Burgess Neil
Published: November 2008

The oscillatory interference model [Burgess et al. (2007) Hippocampus 17:801–802] of grid cell firing is reviewed as an algorithmic level description of path integration and as an implementation level description of grid cells and their inputs. New analyses concern the relationships between the variables in the model and the theta rhythm, running speed, and the intrinsic firing frequencies of grid cells. New simulations concern the implementation of velocity‐controlled oscillators (VCOs) with different preferred directions in different neurons. To summarize the model, the distance traveled along a specific direction is encoded by the phase of a VCO relative to a baseline frequency. Each VCO is an intrinsic membrane potential oscillation whose frequency increases from baseline as a result of depolarization by synaptic input from speed modulated head‐direction cells. Grid cell firing is driven by the VCOs whose preferred directions match the current direction of motion. VCOs are phase‐reset by location‐specific input from place cells to prevent accumulation of error. The baseline frequency is identified with the local average of VCO frequencies, while EEG theta frequency is identified with the global average VCO frequency and comprises two components: the frequency at zero speed and a linear response to running speed. Quantitative predictions are given for the inter‐relationships between a grid cell's intrinsic firing frequency and grid scale, the two components of theta frequency, and the running speed of the animal. Qualitative predictions are given for the properties of the VCOs, and the relationship between environmental novelty, the two components of theta, grid scale and place cell remapping. © 2008 Wiley‐Liss, Inc.
Grid cells: The position code, neural network models of activity, and the problem of learning
Authors: Welinder Peter E. , Burak Yoram , Fiete Ila R.
Published: November 2008

We review progress on the modeling and theoretical fronts in the quest to unravel the computational properties of the grid cell code and to explain the mechanisms underlying grid cell dynamics. The goals of the review are to outline a coherent framework for understanding the dynamics of grid cells and their representation of space; to critically present and draw contrasts between recurrent network models of grid cells based on continuous attractor dynamics and independent‐neuron models based on temporal interference; and to suggest open questions for experiment and theory. © 2008 Wiley‐Liss, Inc.
The emergence of grid cells: Intelligent design or just adaptation?
Authors: Kropff Emilio , Treves Alessandro
Published: November 2008

Individual medial entorhinal cortex (mEC) ‘grid’ cells provide a representation of space that appears to be essentially invariant across environments, modulo simple transformations, in contrast to multiple, rapidly acquired hippocampal maps; it may therefore be established gradually during rodent development. We explore with a simplified mathematical model the possibility that the self‐organization of multiple grid fields into a triangular grid pattern may be a single‐cell process, driven by firing rate adaptation and slowly varying spatial inputs. A simple analytical derivation indicates that triangular grids are favored asymptotic states of the self‐organizing system, and computer simulations confirm that such states are indeed reached during a model learning process, provided it is sufficiently slow to effectively average out fluctuations. The interactions among local ensembles of grid units serve solely to stabilize a common grid orientation. Spatial information, in the real mEC network, may be provided by any combination of feedforward cortical afferents and feedback hippocampal projections from place cells, since either input alone is likely sufficient to yield grid fields. © 2008 Wiley‐Liss, Inc.
The effect of cantharidins on leukemic stem cells
Authors: Dorn David C. , Kou Cynthia A. , Png Kim J. , Moore Malcolm A.S.
Published: November 2008

To identify an agent with specific activity against leukemic stem cells (LSCs), we evaluated compounds that targeted hepatic leukemia factor (HLF), a gene implicated in hematopoietic stem cell (HSCs) regulation, that we found overexpressed in LSCs. Cantharidin, a natural toxin from blister beetles, used as medicinal agent since antiquity, has been described to modulate theHLFcompetitorNFIL3and is under clinical evaluation as an antitumor and antimetastatic agent. The molecule is not a substrate for multidrug resistant pumps and does not cause myelosuppression, and therefore it represents a promising compound for selective ablation of LSCs. Cantharidin and norcantharidin, a derivative with reduced toxicity, decreased HLF protein levels and induced apoptosis in the AML cell line MV4‐11 by modulating the expression of several molecules that govern survival pathway, including HLF, SLUG, NFIL3 and c‐myc, thereby inducing p53 and the mitochondrial caspase cascade.In vitro, cantharidin readily targeted primary AML stem and progenitor cells in contrast to conventional chemotherapeutic agents, such as Ara‐C and daunorubicin, that mainly targeted more differentiated leukemic cells.In vitrothe compound did not exhibit a therapeutic window, being equally toxic to normal HSCs and LSCs.In vivocantharidin did not produce myelosuppression. Because of dose‐limiting toxicityin vivo, neither cantharidin nor norcantharidin proved therapeutical benefit in AML xenograft models as a single agent. However, its potentin vitroLSC activity and pathway targeting may still be exploited clinically with a new generation of cantharidin derivatives or formulations and with appropriate drug combinations. © 2008 Wiley‐Liss, Inc.
Salvianolic acid B inhibits growth of head and neck squamous cell carcinoma in vitro and in vivovia cyclooxygenase‐2 and apoptotic pathways
Authors: Hao Yubin , Xie Tianpei , Korotcov Alexandru , Zhou Yanfei , Pang Xiaowu , Shan Liang , Ji Hongguang , Sridhar Rajagopalan , Wang Paul , Califano Joseph , Gu Xinbin
Published: November 2008

Overexpression of cyclooxygenase‐2 (COX‐2) in oral mucosa has been associated with increased risk of head and neck squamous cell carcinoma (HNSCC). Celecoxib is a nonsteroidal anti‐inflammatory drug, which inhibits COX‐2 but not COX‐1. This selective COX‐2 inhibitor holds promise as a cancer preventive agent. Concerns about cardiotoxicity of celecoxib, limits its use in long‐term chemoprevention and therapy. Salvianolic acid B (Sal‐B) is a leading bioactive component of Salvia miltiorrhiza Bge, which is used for treating neoplastic and chronic inflammatory diseases in China. The purpose of this study was to investigate the mechanisms by which Sal‐B inhibits HNSCC growth. Sal‐B was isolated from S. miltiorrhiza Bge by solvent extraction followed by 2 chromatographic steps. Pharmacological activity of Sal‐B was assessed in HNSCC and other cell lines by estimating COX‐2 expression, cell viability and caspase‐dependent apoptosis. Sal‐B inhibited growth of HNSCC JHU‐022 and JHU‐013 cells with IC50 of 18 and 50 μM, respectively. Nude mice with HNSCC solid tumor xenografts were treated with Sal‐B (80 mg/kg/day) or celecoxib (5 mg/kg/day) for 25 days to investigate in vivo effects of the COX‐2 inhibitors. Tumor volumes in Sal‐B treated group were significantly lower than those in celecoxib treated or untreated control groups (p < 0.05). Sal‐B inhibited COX‐2 expression in cultured HNSCC cells and in HNSCC cells isolated from tumor xenografts. Sal‐B also caused dose‐dependent inhibition of prostaglandin E2 synthesis, either with or without lipopolysaccharide stimulation. Taken together, Sal‐B shows promise as a COX‐2 targeted anticancer agent for HNSCC prevention and treatment. © 2008 Wiley‐Liss, Inc.
Inhibition of prostaglandin synthesis and actions by genistein in human prostate cancer cells and by soy isoflavones in prostate cancer patients
Authors: Swami Srilatha , Krishnan Aruna V. , Moreno Jacqueline , Bhattacharyya Rumi S. , Gardner Christopher , Brooks James D. , Peehl Donna M. , Feldman David
Published: November 2008

Soy and its constituent isoflavone genistein inhibit the development and progression of prostate cancer (PCa). Our study in both cultured cells and PCa patients reveals a novel pathway for the actions of genistein, namely the inhibition of the synthesis and biological actions of prostaglandins (PGs), known stimulators of PCa growth. In the cell culture experiments, genistein decreased cyclooxygenase‐2 (COX‐2) mRNA and protein expression in both human PCa cell lines (LNCaP and PC‐3) and primary prostate epithelial cells and increased 15‐hydroxyprostaglandin dehydrogenase (15‐PGDH) mRNA levels in primary prostate cells. As a result genistein significantly reduced the secretion of PGE2 by these cells. EP4 and FP PG receptor mRNA were also reduced by genistein, providing an additional mechanism for the suppression of PG biological effects. Further, the growth stimulatory effects of both exogenous PGs and endogenous PGs derived from precursor arachidonic acid were attenuated by genistein. We also performed a pilot randomised double blind clinical study in which placebo or soy isoflavone supplements were given to PCa patients in the neo‐adjuvant setting for 2 weeks before prostatectomy. Gene expression changes were measured in the prostatectomy specimens. In PCa patients ingesting isoflavones, we observed significant decreases in prostate COX‐2 mRNA and increases in p21 mRNA. There were significant correlations between COX‐2 mRNA suppression, p21 mRNA stimulation and serum isoflavone levels. We propose that the inhibition of the PG pathway contributes to the beneficial effect of soy isoflavones in PCa chemoprevention and/or treatment. © 2008 Wiley‐Liss, Inc.
DNA adduct formation and induction of micronuclei and mutations in B6C3F1/Tk mice treated neonatally with acrylamide or glycidamide
Authors: Von Tungeln Linda S. , Churchwell Mona I. , Doerge Daniel R. , Shaddock Joseph G. , McGarrity Lynda J. , Heflich Robert H. , Gamboa da Costa Gonçalo , Marques M. Matilde , Beland Frederick A.
Published: November 2008

Acrylamide, a food contaminant, is carcinogenic in experimental animals, with both genotoxic and nongenotoxic pathways being proposed. To obtain information regarding mechanisms of acrylamide tumorigenesis, we compared the extent of DNA adduct formation and induction of micronuclei and mutations in mice treated neonatally with acrylamide and its electrophilic metabolite glycidamide. Male and female B6C3F1/Tk mice were treated intraperitoneally on postnatal days (PNDs) 1, 8 and 15 or PNDs 1–8 with 0.14 or 0.70 mmol acrylamide or glycidamide per kg body weight per day. One day after the final dose, B6C3F1/Tk+/+ mice were killed to measure DNA adduct levels and peripheral blood micronuclei. Three weeks after the last treatment, B6C3F1/Tk+/− mice were killed to assess the Hprt and Tk mutant frequencies in spleen lymphocytes. The levels of N7‐(2‐carbamoyl‐2‐hydroxyethyl)guanine, the major glycidamide‐DNA adduct, decreased in the order 0.70 mmol glycidamide > 0.70 mmol acrylamide > 0.14 mmol glycidamide ∼ 0.14 mmol acrylamide. Only glycidamide increased the frequency of micronucleated reticulocytes and normochromatic erythrocytes. In mice treated on PNDs 1, 8 and 15, the Hprt mutant frequency was increased by 0.70 mmol glycidamide. In mice dosed on PNDs 1–8, 0.70 mmol glycidamide caused extensive mortality; each of the other treatments increased the Tk mutant frequency, whereas acrylamide increased the Hprt mutant frequency. These data suggest that the mutagenic response in neonatal mice treated on PNDs 1, 8 and 15 is due to glycidamide, whereas mutations resulting from dosing on PNDs 1–8 are due to another mechanism. © 2008 Wiley‐Liss, Inc.
Two distinct expression patterns of urokinase, urokinase receptor and plasminogen activator inhibitor‐1 in colon cancer liver metastases
Authors: Illemann Martin , Bird Nigel , Majeed Ali , Lærum Ole D. , Lund Leif R. , Danø Keld , Nielsen Boye Schnack
Published: November 2008

Metastatic growth and invasion by colon cancer cells in the liver requires the ability of the cancer cells to interact with the new tissue environment. Plasmin(ogen) is activated on cell surfaces by urokinase‐type PA (uPA), and is regulated by uPAR and plasminogen activator inhibitor‐1 (PAI‐1). To compare the expression patterns of uPA, uPAR and PAI‐1 in colon cancer with that in their liver metastases, we analysed matched samples from 14 patients. In all 14 primary colon cancers, we found upregulation of uPAR, uPA mRNA and PAI‐1 in primarily stromal cells at the invasive front. In 5 of the 14 liver metastases, we found intense expression of uPAR, uPA‐mRNA and PAI‐1 in primarily stromal cells at the metastases periphery, and in an expression pattern similar to that found in the primary tumours. In the remaining 9 liver metastases, uPAR and uPA‐mRNA were only seen associated with the presence of necrosis within the liver metastases. In addition, PAI‐1‐immunoreactivity was in all liver metastases seen in hepatocytes at the metastases periphery. Interestingly, the former 5 liver metastases positive for uPAR, uPA mRNA and PAI‐1 at the metastasis periphery all had a predominantly desmoplastic reaction, whereas 8 of the remaining 9 showed direct contact between the cancer cells and the liver parenchyma. We conclude that there are 2 distinct patterns of expression of uPAR, uPA and PAI‐1 in colon cancer liver metastases and that these correlate closely with 2 morphological growth patterns. These findings may have implication for the treatment of patients with metastatic disease. © 2008 Wiley‐Liss, Inc.
Hepatocarcinogenesis in mice with a conditional knockout of the hepatocyte growth factor receptor c‐Met
Authors: Marx‐Stoelting Philip , Borowiak Malgorzata , Knorpp Thomas , Birchmeier Carmen , Buchmann Albrecht , Schwarz Michael
Published: November 2008

The receptor for the hepatocyte growth factor/scatter factor (HGF/SF), c‐Met, plays a role in tumour promotion, progression and metastasis. In this study, we analysed chemically induced hepatocarcinogenesis in mice lacking a functional HGF receptor in their liver. Control and c‐Met deficient mice were injected with a single dose of N‐nitrosodiethylamine (DEN, 90 μg/g b.wt.) at 6 weeks of age and mice were subsequently kept on a phenobarbital (PB) containing diet (0.05%) for 35 weeks or on control diet. At the end of the experiment, the carcinogenic response in liver of the animals was monitored. Conditional c‐met knockout (KO) mice showed a higher prevalence of macroscopically visible liver tumours and of glutamine synthetase positive and glucose‐6‐phosphatase deficient lesions in liver. Tumour promotion by PB led to significant increases in the number of preneoplastic and neoplastic lesions in liver of both wild‐type and c‐met knockout mice, with only minor differences in response. Our results indicate that a defect in c‐Met‐mediated signaling increases chemically induced tumour initiation in liver but does not significantly affect PB‐mediated tumour promotion. © 2008 Wiley‐Liss, Inc.
Pharmacogenomics and analogues of the antitumour agent N6‐isopentenyladenosine
Authors: Colombo Francesca , Falvella F. Stefania , De Cecco Loris , Tortoreto Monica , Pratesi Graziella , Ciuffreda Pierangela , Ottria Roberta , Santaniello Enzo , Cicatiello Luigi , Weisz Alessandro , Dragani Tommaso A.
Published: November 2008

N6‐isopentenyladenosine (i6A), a member of the cytokinin family of plant hormones, has potent in vitro antitumour activity in different types of human epithelial cancer cell lines. Gene expression profile analysis of i6A‐treated cells revealed induction of genes (e.g., PPP1R15A, DNAJB9, DDIT3, and HBP1) involved in the negative regulation of cell cycle progression and reportedly up‐regulated during cell cycle arrest in stress conditions. Of 6 i6A analogues synthesized, only the 1 with a saturated double bond of the isopentenyl side chain had in vitro antitumour activity, although weaker than that of i6A, suggesting that i6A biological activity is highly linked to its structure. In vivo analysis of i6A and the active analogue revealed no significant inhibition of cancer cell growth in mice by either reagent. Thus, although i6A may inhibit cell proliferation by regulating the cell cycle, further studies are needed to identify active analogues potentially useful in vivo. © 2008 Wiley‐Liss, Inc.
Murine osteosarcoma primary tumour growth and metastatic progression is maintained after marked suppression of serum insulin‐like growth factor I
Authors: Hong Sung‐Hyeok , Briggs Joseph , Newman Rachel , Hoffman Karen , Mendoza Arnulfo , LeRoith Derek , Helman Lee , Yakar Shoshana , Khanna Chand
Published: November 2008

The insulin‐like growth factor I (IGF‐I) signaling pathway has been shown to play an important role in several aspects of cancer biology, including metastasis. The aim of this study was to define the contribution of serum (endocrine) and local (tumour microenvironment) IGF‐I on osteosarcoma tumour growth and metastasis, a cancer that is known to be dependent on the IGF‐I axis. To test this hypothesis, we evaluated the primary tumour growth and metastatic progression of K7M2 murine osteosarcoma cells injected to a genetically engineered mouse [liver‐specific IGF‐I deficient (LID)] in which serum IGF‐I levels are reduced by 75%, while maintaining expression of IGF‐I in normal tissues. We first demonstrated that IGF‐I in the tumour and the tumour‐microenvironment were maintained in the LID mice. Within this designed model, there was no difference in primary tumour growth or in pulmonary metastasis in LID mice compared to control mice. Furthermore, there was no difference in the number or localization of single metastatic cells immediately after their arrival in the lungs of LID mice and control mice, as analysed by single cell video microscopy. Collectively, these data suggest that marked reduction in serum IGF‐I is not sufficient to slow the progression of either primary or metastatic models of osteosarcoma. © 2008 Wiley‐Liss, Inc.
Hydraulic calculation of mechanically arranged drainage lines with vertical bends
Authors: Gurklys Vidmantas , Rimkus Alfonsas , S̆aulys Valentinas
Published: November 2008

The mechanical opening of drainage trenches cannot ensure constant drain line slopes. Therefore vertical bends in the pipelines are being formed. Air accumulates in these bends. Consequently the conductivity of collector drains reduces. The air is carried out by the water flow. However significant air volumes are not removed until the beginning of the dry season. Particularly unfavourable conditions for drainage operation are created when the slope of the collector drains is undulating. For the hydraulic calculation of drain parameters, an estimation of air volumes accumulated in drainage systems at the control time has to be performed. The calculation of the air moving process is necessary during the entire snow melting period. The special hydraulic calculation method is needed for this purpose. The creation and applying of this method is described in the article. Copyright © 2008 John Wiley & Sons, Ltd.
Roscovitine up‐regulates p53 protein and induces apoptosis in human HeLaS3 cervix carcinoma cells
Authors: Węsierska‐Gądek Józefa , Wandl Stefanie , Kramer Matthias P. , Pickem Christian , Kryštof Vladimir , Hajek Susanne B.
Published: November 2008

Exposure of human HeLaS3 cervix carcinoma cells to high doses of conventional cytostatic drugs, e.g. cisplatin (CP) strongly inhibits their proliferation. However, most cytostatic agents are genotoxic and may generate a secondary malignancy. Therefore, therapeutic strategy using alternative, not cytotoxic drugs would be beneficial. Inhibition of cyclin‐dependent kinases (CDKs) by pharmacological inhibitors became recently a promising therapeutic option. Roscovitine (ROSC), a selective CDK inhibitor, efficiently targets human malignant cells. ROSC induces cell cycle arrest and apoptosis in human MCF‐7 breast cancer cells. ROSC also activates p53 protein. Activation of p53 tumor suppressor protein is essential for induction of apoptosis in MCF‐7 cells. Considering the fact that in HeLaS3 cells wt p53 is inactivated by the action of HPV‐encoded E6 oncoprotein, we addressed the question whether ROSC would be able to reactivate p53 protein in them. Their exposure to ROSC for 24 h induced cell cycle arrest at G2/M and reduced the number of viable cells. Unlike CP, ROSC in the used doses did not induce DNA damage and was not directly cytotoxic. Despite lack of detectable DNA lesions, ROSC activated wt p53 protein. The increase of p53 levels was attributable to the ROSC‐mediated protein stabilization. Further analyses revealed that ROSC induced site‐specific phosphorylation of p53 protein at Ser46. After longer exposure, ROSC induced apoptosis in HeLaS3 cells. These results indicate that therapy of HeLaS3 cells by ROSC could offer an advantage over that by CP due to its increased selectivity and markedly reduced risk of generation of a secondary cancer. J. Cell. Biochem. 105: 1161–1171, 2008. © 2008 Wiley‐Liss, Inc.
Estrogenic control of mitochondrial function and biogenesis
Authors: Klinge Carolyn M.
Published: November 2008

Estrogens have cell‐specific effects on a variety of physiological endpoints including regulation of mitochondrial biogenesis and activity. Estrogens regulate gene transcription by the classical genomic mechanism of binding to estrogen receptors α and β (ERα and ERβ) as well as the more recently described nongenomic pathways involving plasma membrane‐associated ERs that activate intracellular protein kinase‐mediated phosphorylation signaling cascades. Here I will review the rapid and longer‐term effects of estrogen on mitochondrial function. The identification of ERα and ERβ within mitochondria of various cells and tissues is discussed with a model of estrogen regulation of the transcription of nuclear respiratory factor‐1 (NRF‐1, NRF1). NRF‐1 subsequently promotes transcription of mitochondrial transcription factor Tfam (mtDNA maintenance factor, also called mtTFA) and then Tfam targets mtDNA‐encoded genes. The nuclear effects of estrogens on gene expression directly controlling mitochondrial biogenesis, oxygen consumption, mtDNA transcription, and apoptosis are reviewed. Overall, we are just beginning to evaluate the many direct and indirect effects of estrogens on mitochondrial activities. J. Cell. Biochem. 105: 1342–1351, 2008. © 2008 Wiley‐Liss, Inc.
Significance of donor‐derived isoagglutinins in ABO‐Incompatible hematopoietic stem cell transplantation
Authors: Chung Hee‐Jung , Lee Je‐Hwan , Kwon Seog‐Woon
Published: November 2008

Changes in isoagglutinin titers may have implications in the occurrence of hematological complications such as pure red cell aplasia or immune‐mediated hemolysis. Furthermore, isoagglutinin titers could reflect immunohematological reconstitution after transplantation. The objective of this study was to examine the relationship between donor‐derived isoagglutinins (DDIs) and graft‐versus‐host disease (GVHD). In total, 114 patients who underwent ABO‐incompatible allogeneic hematopoietic stem cell transplantation (HSCT) were analyzed. Among these patients, 27.7% demonstrated increased donor‐derived isoagglutinins (IDDIs) against red blood cells (RBCs) of the recipient, and 32.8% of the patients showed DDIs that were not against RBCs of the recipient. Patients with acute GVHD and DDIs against RBCs of the recipient tended to have higher incidences of IDDIs that occurred before posttransplant day 60 compared with patients without acute GVHD (17.3 vs. 3.9%, P=0.058). In patients with acute GVHD, IDDIs occurred significantly earlier (mean, day 32 vs. 181, P=0.046), the period of elevation was shorter (mean, day 36 vs. 134, P=0.033), and the donors were younger (mean, 28 vs. 36 years, P=0.01) than those without GVHD. Moreover, significant correlations were found between IDDIs and acute GVHD. Taken together, these data underscore a possible role for humoral immunity in GVHD after HSCT. J. Clin. Lab. Anal. 22:383–390, 2008. © 2008 Wiley‐Liss, Inc.
Different collection tubes in cardiac biomarkers detection
Authors: Daves Massimo , Trevisan Diego , Cemin Roberto
Published: November 2008

The role played by different collection tubes is one of the more frequently forgotten parameters, which influences the quality of laboratory results.

We aimed to determine whether there is a significant difference in assay of myoglobin, cardiac troponin I, and CK‐MB depending on the presence of anticoagulant and gel separator in the collecting tubes.

Blood samples were collected in 40 consecutive patients admitted for acute coronary syndrome. The samples were taken at the same moment in three different tubes (tubes without anticoagulant and with gel separator, heparin tubes with gel separator and heparin tubes without gelseparator;Venosafe, Terumo Europe, Leuven Belgium). Myoglobin, CK‐MB and cardiac troponin I were measured with a double side (sandwich) chemiluminescent immuenzymatic assay (Access Myoglobin, Access CK‐MB, Access AccuTnI).

Cardiac troponin I was not influenced by the type of collection tube used. On the contrary, myoglobin and CK‐MB showed a statistical difference depending on the test tube. In particular, there was a significant difference between tubes without anticoagulant and with gel separator and tubes with heparin and without gel. J. Clin. Lab. Anal. 22:391–394, 2008. © 2008 Wiley‐Liss, Inc.