bluuebunny/crossref_metadata_2025 huggingface dataset:
LTP‐ and LTD‐inducing stimulations cause opposite changes in arc/arg3.1 mRNA level in hippocampal area CA1 in vivo
Authors: Yilmaz‐Rastoder Eser , Miyamae Takeaki , Braun Amy E. , Thiels Edda
Published: September 2010

Immediate early genes (IEGs) typically are the first genetic responders to a variety of cellular activations. The IEG that encodes activity‐regulated cytoskeleton‐associated protein (arc/arg3.1) has attracted much interest because its mRNA is transported to and translated near activated synapses. Moreover, arc has been implicated in both long‐term potentiation (LTP) and long‐term depression (LTD). However, little is known about the time course of altered arc expression during LTP and LTD. Here we characterized arc mRNA levels in area CA1 of the adult rat hippocampus in vivo after LTP‐ and LTD‐inducing stimulations that were identical, except for the temporal patterning of the stimulation pulses. We observed a persistent increase in arc mRNA level during LTP. In contrast, during LTD, arc mRNA level first was decreased and then transiently increased relative to control level. These findings demonstrate that arc mRNA is regulated differently during LTP and LTD, and they provide evidence for stimulation‐induced downregulation of mRNA availability during LTD. Findings of abbreviated LTD when transcription was inhibited indicate that the prolonged maintenance of the type of N‐methyl‐D‐aspartate receptor‐dependent LTD studied here requires de novo transcription. Furthermore, lack of evidence for a LTD‐associated change in the mRNA level of the IEG zif268 demonstrates that the decrease in arc mRNA during LTD is not a general genetic response. Thus, the regulation of arc expression not only differs between LTP and LTD, but also diverges from that of other IEGs implicated in activity‐dependent synaptic plasticity. © 2010 Wiley Periodicals, Inc.
High affinity group III mGluRs regulate mossy fiber input to CA3 interneurons
Authors: Cosgrove Kathleen E. , Meriney Stephen D. , Barrionuevo Germán
Published: September 2010

Stratum lacunosum‐moleculare interneurons (L‐Mi) in hippocampal area CA3 target the apical dendrite of pyramidal cells providing feedforward inhibition. Here we report that selective activation of group III metabotropic glutamate receptors (mGluRs) 4/8 with L(+)‐2‐amino‐4‐phosphnobytyric acid (L‐AP4; 10 μM) decreased the probability of glutamate release from the mossy fiber (MF) terminals synapsing onto L‐Mi. Consistent with this interpretation, application of L‐AP4 in the presence of 3 mM strontium decreased the frequency of asynchronous MF EPSCs in L‐Mi. Furthermore, the dose response curve showed that L‐AP4 at 400 μM produced no further decrease in MF EPSC amplitude compared with 20 μM L‐AP4, indicating the lack of mGluRs 7 at these MF terminals. We also found that one mechanism of mGluRs 4/8‐mediated inhibition of release is linked to N‐type voltage gated calcium channels at MF terminals. Application of the group III mGluR antagonist MSOP (100 μM) demonstrated that mGluRs 4/8 are neither tonically active nor activated by low and moderate frequencies of activity. However, trains of stimuli to the MF at 20 and 40 Hz delivered during the application of MSOP revealed a relief of inhibition of transmitter release and an increase in the overall probability of action potential firing in the postsynaptic L‐Mi. Interestingly, the time to first action potential was significantly shorter in the presence of MSOP, indicating that mGluR 4/8 activation delays L‐Mi firing in response to MF activity. Taken together, our data demonstrate that the timing and probability of action potentials in L‐Mi evoked by MF synaptic input is regulated by the activation of presynaptic high affinity group III mGluRs. © 2010 Wiley Periodicals, Inc.
Functional convergence of developmentally and adult‐generated granule cells in dentate gyrus circuits supporting hippocampus‐dependent memory
Authors: Stone Scellig S.D. , Teixeira Cátia M. , Zaslavsky Kirill , Wheeler Anne L. , Martinez‐Canabal Alonso , Wang Afra H. , Sakaguchi Masanori , Lozano Andres M. , Frankland Paul W.
Published: September 2010

In the hippocampus, the production of dentate granule cells (DGCs) persists into adulthood. As adult‐generated neurons are thought to contribute to hippocampal memory processing, promoting adult neurogenesis therefore offers the potential for restoring mnemonic function in the aged or diseased brain. Within this regenerative context, one key issue is whether developmentally generated and adult‐generated DGCs represent functionally equivalent or distinct neuronal populations. To address this, we labeled separate cohorts of developmentally generated and adult‐generated DGCs and used immunohistochemical approaches to compare their integration into circuits supporting hippocampus‐dependent memory in intact mice. First, in the water maze task, rates of integration of adult‐generated DGCs were regulated by maturation, with maximal integration not occurring until DGCs were five or more weeks in age. Second, these rates of integration were equivalent for embryonically, postnatally, and adult‐generated DGCs. Third, these findings generalized to another hippocampus‐dependent task, contextual fear conditioning. Together, these experiments indicate that developmentally generated and adult‐generated DGCs are integrated into hippocampal memory networks at similar rates, and suggest a functional equivalence between DGCs generated at different developmental stages. © 2010 Wiley Periodicals, Inc.
Delineation of hydrologically similar units in a watershed based on fuzzy classification of soil hydraulic properties
Authors: Santra Priyabrata , Das Bhabani Sankar , Chakravarty Debashish
Published: September 2010

Evaluation of flow and transport processes in a watershed‐scale requires that the watershed be divided into homogenous spatial units referred to as hydrologically similar units (HSUs). Although a few discretization schemes are already in use, a universally acceptable method of obtaining HSUs is yet to emerge. In this study, we developed a fuzzy inference system (FIS) to classify the saturated hydraulic conductivity (Ks) and two water‐retention parameters α and n into fuzzy logic‐based soil hydrologic classes (FSHCs). Analysis of these classes showed that soil properties within an FSHC have less variability and those between two FSHCs have large variability. This result suggested that soils belonging to a specific FSHC may be more similar than those across different FSHCs and may be grouped together to represent an HSU. Soils within a specific hydrologic class were aggregated to delineate HSUs within the watershed. For the Dengei Pahad micro‐watershed (DPW), this approach showed five distinct regions representing a discretized zone having similar soil hydraulic properties. Application of this approach on a larger international database of soil hydraulic properties revealed that the developed hydrologic classes are quite comparable across different databases. The delineated HSUs based on these FSHCs were also better than the soil series map of the watershed in maintaining the soil heterogeneity of the watershed. Moreover, this new discretization scheme using the SWAT modelling environment showed better performance than the soil series‐based discretization approach. Copyright © 2010 John Wiley & Sons, Ltd.
Hydrological response of a Brazilian semi‐arid catchment to different land use and climate change scenarios: a modelling study
Authors: Montenegro A. , Ragab R.
Published: September 2010

Brazilian semi‐arid regions are characterized by water scarcity, vulnerability to desertification, and climate variability. The investigation of hydrological processes in this region is of major interest not only for water planning strategies but also to address the possible impact of future climate and land‐use changes on water resources. A hydrological distributed catchment‐scale model (DiCaSM) has been applied to simulate hydrological processes in a small representative catchment of the Brazilian northeast semi‐arid region, and also to investigate the impact of climate and land‐use changes, as well as changes associated with biofuel/energy crops production. The catchment is part of the Brazilian network for semi‐arid hydrology, established by the Brazilian Federal Government. Estimating and modelling streamflow (STF) and recharge in semi‐arid areas is a challenging task, mainly because of limitation in in situ measurements, and also due to the local nature of some processes. Direct recharge measurements are very difficult in semi‐arid catchments and contain a high level of uncertainty. The latter is usually addressed by short‐ and long‐time‐scale calibration and validation at catchment scale, as well as by examining the model sensitivity to the physical parameters responsible for the recharge. The DiCaSM model was run from 2000 to 2008, and streamflow was successfully simulated, with a Nash–Sutcliffe (NS) efficiency coefficient of 0·73, and R2 of 0·79. On the basis of a range of climate change scenarios for the region, the DiCaSM model forecasted a reduction by 35%, 68%, and 77%, in groundwater recharge (GWR), and by 34%, 65%, and 72%, in streamflow, for the time spans 2010–2039, 2040–2069, and 2070–2099, respectively, could take place for a dry future climate scenario. These reductions would produce severe impact on water availability in the region. Introducing castor beans to the catchment would increase the GWR and streamflow, mainly if the caatinga areas would be converted into castor beans production. Changing an area of 1000 ha from caatinga to castor beans would increase the GWR by 46% and streamflow by 3%. If the same area of pasture is converted into castor beans, there would be an increase in GWR and streamflow by 24% and 5%, respectively. Such results are expected to contribute towards environmental policies for north‐east Brazil (NEB), and to biofuel production perspectives in the region. Copyright © 2010 John Wiley & Sons, Ltd.
Suspended solid yield from forest harvesting on upland blanket peat
Authors: Rodgers Michael , O'Connor Mark , Robinson Mark , Muller Markus , Poole Russell , Xiao Liwen
Published: September 2010

Forest harvesting activities, if not carefully carried out, can disturb the forest soils and can cause significant suspended solid concentration increases in receiving water. This study examined how harvesting, following forestry guidelines, influenced suspended solid concentrations and loads in the receiving water of a blanket peat salmonid catchment. The study site comprised of two forest coupes of 34‐year‐old conifers drained by a first‐order stream. The upper coupe was not felled and acted as a baseline ‘control’ catchment; the downstream coupe was completely harvested in summer 2005 and served as the ‘experimental’ catchment. Good management practices such as the proper use of brash mats and harvesting only in dry weather were implemented to minimize soil surface disturbance and streambank erosion. Stream flow and suspended solid measurements at an upstream station (US) and a downstream station (DS) in the study stream commenced over a year before felling took place. The suspended solid concentrations, yields and release patterns at US and DS were compared before and after harvesting. These showed that post‐guideline harvesting of upland blanket peat forest did not significantly increase the suspended solid concentrations in the receiving water and the aquatic zone need not be adversely affected by soil releases from sites without a buffer strip. Copyright © 2010 John Wiley & Sons, Ltd.
Understanding and modelling spatial drain–aquifer interactions in a low‐lying coastal aquifer—the Thurne catchment, Norfolk, UK
Authors: Simpson Trevor B. , Holman Ian P. , Rushton Ken R.
Published: September 2010

Seawater intrusion into fresh groundwater formations generally results inadvertently from human activities, such as over‐abstraction from coastal aquifers. This article describes the data analysis to quantify drain–aquifer interactions in a low‐lying pump‐drained coastal aquifer, which is subject to saline intrusion due to widespread land drainage, and the resulting development and application of a numerical groundwater model to understand the spatial groundwater system behaviour (including groundwater salinity fluxes). Without measured flow data in this pump‐drained catchment, a novel groundwater head‐dependent approach to hydrograph separation is described. Time‐variant and time‐invariant MODFLOW analyses are utilised to examine the flow processes. A new approach to calculate drain coefficients, which represent the extensive network of drainage ditches in the regional model, using field information, is described; the sum of the drainage coefficients are close to the values independently estimated from the head‐dependent hydrograph separation. Results show that (1) the groundwater flows into the drainage systems are well reproduced using the new drain coefficients, (2) particle tracking of fresh and saline water can explain observed spatial salinity distribution within drainage networks and (3) the modelled flow of seawater across the coast is approximately 25% greater than that discharged by the pumps, demonstrating the need for drainage management to be aware of the slow response of groundwater systems to past drainage system changes. The article demonstrates that numerical groundwater modelling can produce the improved understanding needed to inform management decisions in such complex environments. Copyright © 2010 John Wiley & Sons, Ltd.
Environmental controls of wood entrapment in upper Midwestern streams
Authors: Merten Eric Christopher , Finlay Jacques , Johnson Lucinda , Newman Raymond , Stefan Heinz , Vondracek Bruce
Published: September 2010

Wood deposited in streams provides a wide variety of ecosystem functions, including enhancing habitat for key species in stream food webs, increasing geomorphic and hydraulic heterogeneity and retaining organic matter. Given the strong role that wood plays in streams, factors that influence wood inputs, retention and transport are critical to stream ecology. Wood entrapment, the process of wood coming to rest after being swept downstream at least 10 m, is poorly understood, yet important for predicting stream function and success of restoration efforts. Data on entrapment were collected for a wide range of natural wood pieces (n= 344), stream geomorphology and hydraulic conditions in nine streams along the north shore of Lake Superior in Minnesota. Locations of pieces were determined in summer 2007 and again following an overbank stormflow event in fall 2007. The ratio of piece length to effective stream width (length ratio) and the weight of the piece were important in a multiple logistic regression model that explained 25% of the variance in wood entrapment. Entrapment remains difficult to predict in natural streams, and often may simply occur wherever wood pieces are located when high water recedes. However, this study can inform stream modifications to discourage entrapment at road crossings or other infrastructure by applying the model formula to estimate the effective width required to pass particular wood pieces. Conversely, these results could also be used to determine conditions (e.g. pre‐existing large, stable pieces) that encourage entrapment where wood is valued for ecological functions. Copyright © 2010 John Wiley & Sons, Ltd.
EGFR and HER3 mRNA expression levels predict distant metastases in locally advanced rectal cancer
Authors: Ho‐Pun‐Cheung Alexandre , Assenat Eric , Bascoul‐Mollevi Caroline , Bibeau Frédéric , Boissière‐Michot Florence , Cellier Dominic , Azria David , Rouanet Philippe , Senesse Pierre , Ychou Marc , Lopez‐Crapez Evelyne
Published: September 2010

Aberrant activation of the HER signaling pathways plays a critical role in the invasive and metastatic potential of tumors. The aim of this study was to address whether, in rectal cancer, alterations of these pathways could have a value as prognostic factors to be used to identify patients who are at risk of distant metastases. Therefore, the mRNA expression of the four members of the HER family as well as the frequency of PTEN allelic loss and KRAS/BRAF mutations were determined in pretreatment biopsies from a series of 100 locally advanced rectal cancers and then their ability to predict distant metastases was evaluated. Over‐expression of EGFR (p = 0.021), HER2 (p = 0.011) and HER3 (p = 0.020) was significantly associated with worse metastasis‐free survival in univariate analysis. In multivariate analysis, both over‐expression of EGFR (p = 0.028) and HER3 (p = 0.011) remained independent prognostic factors for distant metastasis. In conclusion, quantification of EGFR and HER3 mRNA expression in pretreatment biopsies may be useful to identify patients who are at risk of developing metastases.
Tumor‐reactive CD4+CD8αβ+ CD103+ αβT cells: A prevalent tumor‐reactive T‐cell subset in metastatic colorectal cancers
Authors: Sarrabayrouse Guillaume , Corvaisier Murielle , Ouisse Laure‐Hélène , Bossard Céline , Mével Bernard Le , Potiron Lucien , Meurette Guillaume , Gervois Nadine , Jotereau Francine
Published: September 2010

High level of T‐cell infiltration in colorectal carcinomas (CRCs) is a good prognostic indicator, but the tumor reactivity of this infiltrate (tumor infiltrating lymphocytes [TIL]) is poorly documented. This study examined the presence, phenotype and functional features of tumor‐reactive lymphocytes in human CRC. Freshly dissociated TIL and T cell lines were isolated from CRC samples and from some paired normal colonic mucosa. Four tumor cell lines were obtained. Autologous tumor reactivity of CRC TIL and tumor‐reactive cell features were analyzed. We demonstrate the presence among CRC TIL of variable fractions (up to 18%) of double positive CD4+CD8αβ+ (DP) αβ T cells. Interestingly, a high proportion (16–20%) of this TIL subset displayed tumor reactivity, whilst this was the case for no or few single positive TIL. Low levels of DP TIL were found in most CRC samples and in normal colonic mucosa, but these cells were higher in metastatic CRC. Furthermore, we showed that DP TIL were polyclonal, restricted by HLA class‐I, proliferated poorly and secreted higher amounts of IL‐4 and IL‐13 than single positive T cells, on cognate or CD3 stimulation. DP CRC TIL also expressed CD103, confirming their mucosal origin. Increased frequencies of tumor‐reactive DP TIL in metastatic CRC suggest that these cells play a role in the metastatic process of this cancer. Based on their high secretion of IL‐4 and IL‐13 and on previously described roles of these cytokines in cancers, we postulate that DP TIL could favor CRC growth or metastasis and/or downmodulate immune responses to these tumors.
Identification of frequently mutated genes with relevance to nonsense mediated mRNA decay in the high microsatellite instability cancers
Authors: Shin Nara , You Kwon Tae , Lee Hanna , Kim Won Kyu , Song Meiying , Choi Hee‐Jung , Rhee Hwanseok , Nam Suk Woo , Kim Hoguen
Published: September 2010

Frameshift mutations at coding mononucleotide repeats (cMNR) are frequent in high‐microsatellite instability (MSI‐H) cancers. Frameshift mutations in cMNR result in the formation of a premature termination codon (PTC) in the transcribed mRNA, and these abnormal mRNAs are generally degraded by nonsense mediated mRNA decay (NMD). We have identified novel genes that are frequently mutated at their cMNR by blocking NMD in two MSI‐H cancer cell lines. After blocking NMD, we screened for differentially expressed genes using DNA microarrays, and then used database analysis to select 28 candidate genes containing cMNR with more than 9 nucleotide repeats. cMNR mutations have not been previously reported in MSI‐H cancers for 15 of the 28 genes. We analyzed the cMNR mutation of each of the 15 genes in 10 MSI‐H cell lines and 21 MSI‐H cancers, and found frequent mutations of 12 genes in MSI‐H cell lines and cancers, but not in microsatellite stable (MSS) cancers. Among these genes, the most frequently mutated in MSI‐H cell lines were MLL3 (70%), PHACTR4 (70%), RUFY2 (50%) and TBC1D23 (50%). MLL3, which has already been implicated in cancer, had the highest mutation frequency in MSI‐H cancers (48%). Our combined approach of NMD block, database search, and mutation analysis has identified a large number of genes mutated in their cMNR in MSI‐H cancers. The identified mutations are expected to contribute to MSI‐H tumorigenesis by causing an absence of gene expression or low gene dosage effects.
Enhancement of a multianalyte serum biomarker panel to identify lymph node metastases in non‐small cell lung cancer with circulating autoantibody biomarkers
Authors: Patel Kalpa , Farlow Erin C. , Kim Anthony W. , Lee Bao‐Shiang , Basu Sanjib , Coon John S. , DeCresce David , Thimothy Lida , Walters Kelly A. , Fhied Cristina , Chang Christopher , Chen Ssu‐Hsien , Faber L. Penfield , Bonomi Philip , Liptay Michael J. , Borgia Jeffrey A.
Published: September 2010

We recently reported the development of a multianalyte serum algorithm to identify nodal status in non‐small cell lung cancer (NSCLC) patients facing an anatomic resection with curative intent. This study aims to enhance the overall performance characteristics of this test by adding autoantibody biomarkers identified through immunoproteomic discovery. More specifically, we used sera from 20 NSCLC patients to probe 2‐D immunoblots of HCC827 lysates for tumor‐associated autoantigens. Relevant differences in immunoreactivity associated with pathological nodal status were then identified via tandem mass spectrometry. Identified autoantigens were then developed into Luminex immunobead assays alongside a series of autoantigen targets relevant to early‐disease detection. These assays were then used to measure circulating autoantibody levels in the identical cohort of NSCLC patients used in our original study. This strategy identified 11 autoantigens found primarily in patients with disease progression to the locoregional lymph nodes. Custom Luminex‐based “direct‐capture” assays (25 total; including autoantibody targets relevant to early‐disease detection) were assembled to measure autoantibody levels in sera from 107 NSCLC patients. Multivariate classification algorithms were then used to identify the optimal combination of biomarkers when considered collectively with our original 6‐analyte serum panel. The new algorithm resulting from this analysis consists of TNF‐α, TNF‐RI, MIP‐1α and autoantibodies against Ubiquilin‐1, hydroxysteroid‐(17‐β)‐dehydrogenase, and triosephosphate isomerase. The inclusion of autoantibody biomarkers provided a dramatic improvement in the overall test performance characteristics, relative to the original test panel, including an 11% improvement in the classification efficiency.
Affinity‐matured anti‐glycoprotein NMB recombinant immunotoxins targeting malignant gliomas and melanomas
Authors: Kuan Chien‐Tsun , Wakiya Kenji , Keir Stephen T. , Li Jianjun , Herndon James E. , Pastan Ira , Bigner Darell D.
Published: September 2010

Glycoprotein NMB (GPNMB), a transmembrane glycoprotein highly expressed in high‐grade gliomas (HGGs), is an attractive target in cancer immunotherapy. We isolated a GPNMB‐specific scFv clone, G49, from a human synthetic phage‐display library. To obtain mutant single‐chain variable‐fragment antibodies (scFvs) with improved affinity and immunotoxins with increased activity, we subjected G49 to in vitro affinity maturation by a complementarity‐determining‐region (CDR) random‐mutagenesis technique. Using light‐chain CDR3 mutagenesis, cell‐based panning by phage display, subsequent heavy‐chain CDR1 mutagenesis, and flow‐cytometric selection by yeast‐surface display, we generated the mutant scFv clone 902V, with an overall 11‐fold increase in affinity for GPNMB. Clone 902V was further randomized throughout the whole scFv by error‐prone PCR, and one mutant, F6V, was selected by yeast‐surface display. F6V scFv, differing from 902V by one amino‐acid change in the light‐chain CDR2, exhibited an affinity for GPNMB of 0.30 nM. The F6V mutant scFv clone was fused with a truncated form of Pseudomonas exotoxin A to form the immunotoxin F6V‐PE38. F6V‐PE38 demonstrated significant protein‐synthesis‐inhibition activity on GPNMB‐expressing glioma and malignant melanoma cells (IC50 = 0.5 ng/ml [8 pM]), a 60‐fold improvement over G49 activity, but no cytotoxicity on GPNMB‐negative cells. Furthermore, F6V‐PE38 exhibited significant antitumor activity against subcutaneous malignant glioma xenografts in two nude‐mouse models and a melanoma neoplastic meningitis model in athymic rats. These GPNMB‐specific scFv antibodies and immunotoxins hold promise as reagents in targeted therapy for HGGs and other GPNMB‐expressing malignancies.
Recent trends in colorectal cancer mortality in Europe
Authors: Bosetti Cristina , Levi Fabio , Rosato Valentina , Bertuccio Paola , Lucchini Franca , Negri Eva , La Vecchia Carlo
Published: September 2010

Colorectal cancer mortality has been declining over the last two decades in Europe, particularly in women, the trends being, however, different across countries and age groups. We updated to 2007 colorectal cancer mortality trends in Europe using data from the World Health Organization (WHO). Rates were analyzed for the overall population and separately in young, middle‐age and elderly populations. In the European Union (EU), between 1997 and 2007 mortality from colorectal cancer declined by around 2% per year, from 19.7 to 17.4/100,000 men (world standardized rates) and from 12.5 to 10.5/100,000 women. Persisting favorable trends were observed in countries of western and northern Europe, while there were more recent declines in several countries of eastern Europe, including the Czech Republic, Hungary and Slovakia particularly in women (but not Romania and the Russian Federation). In 2007, a substantial excess in colorectal cancer mortality was still observed in Slovakia, Hungary, Croatia, the Czech Republic and Slovenia in men (rates over 25/100,000), and in Hungary, Norway, Denmark and Slovakia in women (rates over 14/100,000). Colorectal mortality trends were more favorable in the young (30–49 years) from most European countries, with a decline of ∼2% per year since the early 1990s in both men and women from the EU. The recent decreases in colorectal mortality rates in several European countries are likely due to improvements in (early) diagnosis and treatment, with a consequent higher survival from the disease. Interventions to further reduce colorectal cancer burden are, however, still warranted, particularly in eastern European countries.
Synergistic activation by p38MAPK and glucocorticoid signaling mediates induction of M2‐like tumor‐associated macrophages expressing the novel CD20 homolog MS4A8A
Authors: Schmieder Astrid , Schledzewski Kai , Michel Julia , Tuckermann Jan P. , Tome Lydia , Sticht Carsten , Gkaniatsou Cleopatra , Nicolay Jan P. , Demory Alexandra , Faulhaber Jörg , Kzhyshkowska Julia , Géraud Cyrill , Goerdt Sergij
Published: September 2010

Tumor‐associated macrophages (TAMs) represent alternatively activated (M2) macrophages that support tumor growth. Previously, we have described a special LYVE‐1+ M2 TAM subset in vitro and in vivo; gene profiling of this TAM subset identified MS4A8A as a novel TAM molecule expressed in vivo by TAM in mammary carcinoma and malignant melanoma. In vitro, Ms4a8a mRNA and MS4A8A protein expression was strongly induced in bone marrow‐derived macrophages (BMDMs) by combining M2 mediators (IL‐4, glucocorticoids) and tumor‐conditioned media (TCM). Admixture of MS4A8A+ TCM/IL‐4/GC‐treated BMDM significantly enhanced the tumor growth rate of subcutaneously transplanted TS/A mammary carcinomas. Upon forced overexpression of MS4A8A, Raw 264.7 macrophage‐like cells displayed a special gene signature. Admixture of these MS4A8A+ Raw 264.7 cells also significantly enhanced the tumor growth rate of subcutaneously transplanted mammary carcinomas. To identify the signaling pathways involved in synergistic induction of MS4A8A, the major signaling cascades with known functions in TAM were analyzed. Although inhibitors of NF‐κB activation and of the MAPK JNK and ERK did not show relevant effects, the p38α/β MAPK inhibitor SB203580 strongly and highly significantly (p > 0.001) inhibited MS4A8A expression on mRNA and protein level. In addition, MS4A8A expression was restricted in M2 BMDM from mice with defective GC receptor (GR) dimerization indicating that classical GR gene regulation is mandatory for MS4A8A induction. In conclusion, expression of MS4A8A within the complex signal integration during macrophage immune responses may act to fine tune gene regulation. Furthermore, MS4A8A+ TAM may serve as a novel cellular target for selective cancer therapy.
Anti‐breast cancer potential of SS5020, a novel benzopyran antiestrogen
Authors: Suzuki Naomi , Liu Xiaoping , Laxmi Y. R. Santosh , Okamoto Kanako , Kim Hyo Jeong , Zhang Guangxiang , Chen John J. , Okamoto Yoshinori , Shibutani Shinya
Published: September 2010

Treatment with tamoxifen (TAM) increases the risk of developing endometrial cancer in women. The carcinogenic effect is thought to involve initiation and/or promotion resulting from DNA damage induced by TAM as well as its estrogenic action. To minimize this serious side‐effect while increasing the anti‐breast cancer potential, a new benzopyran antiestrogen, 2E‐3‐{4‐[(7‐hydroxy‐2‐oxo‐3‐phenyl‐2H‐chromen‐4‐yl)‐methyl]‐phenyl}‐acrylic acid (SS5020), was synthesized. Unlike TAM, SS5020 exhibits no genotoxic activity to damage DNA. Furthermore, SS5020 does not present significant uterotrophic potential in rats; in contrast, the structurally related compounds, TAM, toremifene, raloxifene (RAL) and SP500263 all have uterotrophic activity. At the human equivalent molar dose of TAM (0.33 or 1.0 mg/kg), SS5020 had much stronger antitumor potential than those same antiestrogens against 7,12‐dimethylbenz(a)anthracene‐induced mammary carcinoma in rats. The growth of human MCF‐7 breast cancer xenograft implanted into athymic nude mice was also effectively suppressed by SS5020. SS5020, lacking genotoxic and estrogenic actions, could be a safer and stronger antiestrogen alternative to TAM and RAL for breast cancer therapy and prevention.
The novel histone deacetylase inhibitor, AR‐42, inhibits gp130/Stat3 pathway and induces apoptosis and cell cycle arrest in multiple myeloma cells
Authors: Zhang Shuhong , Suvannasankha Attaya , Crean Colin D. , White Valerie L. , Chen Ching‐Shih , Farag Sherif S.
Published: September 2010

Multiple myeloma (MM) remains incurable with current therapy, indicating the need for continued development of novel therapeutic agents. We evaluated the activity of a novel phenylbutyrate‐derived histone deacetylase inhibitor, AR‐42, in primary human myeloma cells and cell lines. AR‐42 was cytotoxic to MM cells at a mean LC50 of 0.18 ± 0.06 μmol/l at 48 hr and induced apoptosis with cleavage of caspases 8, 9 and 3, with cell death largely prevented by caspase inhibition. AR‐42 downregulated the expression of gp130 and inhibited activation of STAT3, with minimal effects on the PI3K/Akt and MAPK pathways, indicating a predominant effect on the gp130/STAT‐3 pathway. AR‐42 also inhibited interleukin (IL)‐6‐induced STAT3 activation, which could not be overcome by exogenous IL‐6. AR‐42 also downregulated the expression of STAT3‐regulated targets, including Bcl‐xL and cyclin D1. Overexpression of Bcl‐xL by a lentivirus construct partly protected against cell death induced by AR‐42. The cyclin dependent kinase inhibitors, p16 and p21, were also significantly induced by AR‐42, which together with a decrease in cyclin D1, resulted in G1 and G2 cell cycle arrest. In conclusion, AR‐42 has potent cytotoxicity against MM cells mainly through gp130/STAT‐3 pathway. The results provide rationale for clinical investigation of AR‐42 in MM.
Podocyte‐specific VEGF down‐regulation and pathophysiological development
Authors: Zhang Shuzhi , Ji Yan , Liu Xiao , Lu Xiaodan , Su Weiheng , Zhang Di , Hao Feng , Yi Fei , Guo Lei , Li Xiaomeng , Zheng Yaowu
Published: September 2010

It is well‐known that vascular endothelial growth factor (VEGF) plays a key role in development and pathology, but its function in normal adult tissues is rarely understood. Increased use of anti‐angiogenic therapies targeting VEGF in human pathologies have shown more and more adverse effects. In this report, a conditional expression model (Tet‐On system) was used to down‐regulate podocyte VEGF in adult mice, which resulted in many kidney problems, characterized by glomerular morphological changes, proteinuria, reduced water consumption and urination, increased urine electro‐conductivity, as well as high susceptibility to BSA stress. Our findings indicated that podocyte‐specific VEGF down‐regulation resulted in poor kidney performance and led mice to be more susceptible to further kidney damages. © 2010 IUBMB IUBMB Life, 62(9): 677–683, 2010
An in vitro study of plasticized poly(lactic‐co‐glycolic acid) films as possible guided tissue regeneration membranes: Material properties and drug release kinetics
Authors: Owen Gethin Rh. , Jackson John K. , Chehroudi Babak , Brunette Donald M. , Burt Helen M.
Published: September 2010

Guided tissue regeneration (GTR), in periodontal therapy, involves the placement of a barrier membrane, to ensure the detached root surface becomes repopulated with periodontal ligament cells capable of regenerating this attachment. GTR procedures exhibit large variability in surgical outcome as a consequence of poor membrane performance. The objective of this study was to evaluate the suitability of plasticized poly(lactic‐co‐glycolic acid) (PLGA) as a material for GTR membranes. The material was also investigated as a localized controlled release system for the antibiotic, anti‐inflammatory agent tetracycline. Films made from PLGA (85:15), plasticized with either 10% w/v methoxypoly(ethyleneglycol) (MePEG) or a diblock copolymer [poly(D,L‐lactic acid)‐block‐methoxypoly(ethyleneglycol)] were loaded with tetracycline base (or hydrochloride salt) and cast by solvent evaporation. Drug release was measured using high performance liquid chromatography (HPLC). The time‐course of elasticity changes and swelling were determined using a stress–strain apparatus or gravimetric/dimensional determinations, respectively. Cells extracted from periodontal ligament cell explants were used to evaluate the effect of material and drug loading on cell morphology. Tetracycline·HCl released more rapidly than tetracycline from PLGA films. The addition of either MePEG or diblock caused a concentration dependent increase in release rates for both drugs. Release profiles ranged from a small initial burst phase followed by slow sustained release to almost full drug release after 1 day. After incubation in PBS, the films stiffened and swelled within 30 min. Periodontal ligament cell morphology was not affected by the inclusion of tetracycline. Plasticized PLGA films displayed desired features for possible use as GTR membranes. © 2010 Wiley Periodicals, Inc. J Biomed Mater Res Part A, 2010.
Genipin‐crosslinked silk fibroin/hydroxybutyl chitosan nanofibrous scaffolds for tissue‐engineering application
Authors: Zhang Kuihua , Qian Yongfang , Wang Hongsheng , Fan Linpeng , Huang Chen , Yin Anlin , Mo Xiumei
Published: September 2010

To improve water‐resistant ability and mechanical properties of silk fibroin (SF)/hydroxybutyl chitosan (HBC) nanofibrous scaffolds for tissue‐engineering applications, genipin, glutaraldehyde (GTA), and ethanol were used to crosslink electrospun nanofibers, respectively. The mechanical properties of nanofibrous scaffolds were obviously improved after 24 h of crosslinking with genipin and were superior to those crosslinked with GTA and ethanol for 24 h. SEM indicated that crosslinked nanofibers with genipin and GTA vapor had good water‐resistant ability. Characterization of the microstructure (porosity and pore structure) demonstrated crosslinked nanofibrous scaffolds with genipin and GTA vapor had lager porosities and mean diameters than those with ethanol. Characterization of FTIR‐ATR and 13C NMR clarified both genipin and GTA acted as crosslinking agents for SF and HBC. Furthermore, genipin could induce SF conformation from random coil or α‐helix to β‐sheet. Although GTA could also successfully crosslink SF/HBC nanofibrous scaffolds, in long run, genipin maybe a better method due to lower cytotoxicity than GTA. Cell viability studies and wound‐healing test in rats clarified that the genipin‐crosslinked SF/HBC nanofibrous scaffolds had a good biocompatibility both in vitro and in vivo. These results suggested that genipin‐crosslinked SF/HBC nanofibrous scaffolds might be potential candidates for wound dressing and tissue‐engineering scaffolds. © 2010 Wiley Periodicals, Inc. J Biomed Mater Res Part A, 2010.
Evidence‐based selection criteria to protect blood donors
Authors: Eder Anne
Published: September 2010

A safe and adequate blood supply depends on healthy, volunteer blood donors. Blood centers have instituted various screening procedures in an effort to determine that donors are free of diseases that can be transmitted to patients by blood transfusion and are able to tolerate the collection procedure without experiencing significant complications. This review focuses on selection criteria intended to minimize the risk to the blood donor. Defining a rational, evidence‐based approach to donor selection is crucial not only to take reasonable precautions to protect the donors' health but also to eliminate practices that lead to the unnecessary deferral of large numbers of people without improving the safety of the donation process. Donor selection criteria, including predonation pulse and blood pressure, donor weight and total blood volume, minimum hemoglobin and donation interval, are considered against the available evidence that support or suggest the need to modify the current approach to protect blood donor health. J. Clin. Apheresis, 2010. © 2010 Wiley‐Liss, Inc.
Teaching and learning apheresis medicine: The Bermuda Triangle in Education
Authors: Crookston Kendall P. , Richter Deana M.
Published: September 2010

Apheresis Medicine has evolved markedly due to an explosion of knowledge and technology, whereas the time available for training has shrunk as curricula have become increasingly overloaded. Apheresis teaching has inherited a strong clinical context where real patient problems are used in a hands‐on environment. To optimize instruction, those involved in the education of apheresis professionals need to have (1) knowledge of how clinical laboratory medicine education has developed as a field, (2) an understanding of what is known from theory and research about how people learn, and (3) the skills to design teaching/learning activities in ways consistent with literature‐based principles of adult education. These developments in education provide a context for curriculum projects currently underway by the American Society for Apheresis. Teachers must determine which competencies are central to the essence of a trained professional. Specific, robust, learning objectives targeted toward the development of higher levels of thinking, professional attitudes, and requisite skills are formulated to guide the learner toward mastering those competencies. Curriculum is developed for each objective, consisting of content and the best teaching/learning methods to help learners attain the objective. Appropriate assessment strategies are identified to determine whether the objective is being achieved. The integration of objectives, curriculum, and assessment creates The Bermuda Triangle of Education (Richter, The Circle of Learning and Bermuda Triangle in Education, University of New Mexico School of Medicine, 2004). When educators do not effectively navigate The Bermuda Triangle of Education, learning may disappear into the murky depths of confusion and apathy. When successfully navigated, the result will be a significant learning experience that leads to transformation through education. J. Clin. Apheresis, 2010. © 2010 Wiley‐Liss, Inc.
Effects of protein A immunoadsorption in patients with chronic dilated cardiomyopathy
Authors: Doesch Andreas O. , Mueller Susanne , Konstandin Mathias , Celik Sultan , Kristen Arnt , Frankenstein Lutz , Goeser Stefan , Kaya Ziya , Zugck Christian , Dengler Thomas J. , Katus Hugo A.
Published: September 2010

Objectives:

The objective of this study was to investigate functional effects of immunoadsorption (IA) in patients with chronic nonfamilial dilated cardiomyopathy (DCM) regarding clinical and humoral markers of heart failure.

Background:

IA has been shown to induce early hemodynamic improvement in patients with nonfamilial dilated cardiomyopathy (DCM).

Methods:

We performed IA using protein A agarose columns on five consecutive days in 51 patients with chronic DCM, congestive heart failure of NYHA class ≥ II, left ventricular ejection fraction ≤50%, and mean time since initial diagnosis of 5.0 ± 5.8 years.

Results:

Immediately after IA, immunoglobulin G (IgG) decreased by 89.4% and IgG3 by 66.7% (both P < 0.0001). Median NT‐pro BNP was reduced from 1230.0 ng L−1 at baseline to 829.0 ng L−1 after 6 months (P < 0.0001). Also mean left ventricular ejection fraction (LVEF) was significantly improved (26.3% ± 9.4% to 28.7% ± 11.4% after 6 months, P = 0.016) and LVEF improved ≥5% (absolute) in 21 of 51 (41.2%) patients. After 6 months, bicycle spiroergometry showed a significant increase in exercise capacity from 82.0 ± 30.8 Watts to 93.1 ± 34.3 Watts (P = 0.008) while VO2max rose from 15.0 ± 4.1 to 16.4 ± 4.8 mL min−1 kg−1 (P = 0.01).

Conclusions:

In this study, on heart failure patients with nonfamilial DCM, IA therapy significantly improved clinical and humoral markers of heart failure severity. These promising results may be due to the selected study population, with a shorter disease duration and the higher amount of IgG 3 reduction. Future blinded prospective multicenter studies are necessary to identify those patients that benefit most. J. Clin. Apheresis, 2010. © 2010 Wiley‐Liss, Inc.
Change in defense mechanisms and coping over the course of short‐term dynamic psychotherapy for adjustment disorder
Authors: Kramer Ueli , Despland Jean‐Nicolas , Michel Luc , Drapeau Martin , de Roten Yves
Published: September 2010

Short‐term dynamic psychotherapy (STDP) has rarely been investigated with regard to its underlying mechanisms of change, even if psychoanalytic theory informs us about several potential putative mechanisms of change in patients. Change in overall defensive functioning is one. In this study, we explored the role of overall defensive functioning, by comparing it on the process level with the neighbouring concept of overall coping functioning. A total ofN=32 patients, mainly presenting adjustment disorder, were included in the study. The patients underwent STDP up to 40 sessions; three sessions per psychotherapy were transcribed and analyzed by using two observer‐rating scales: Defense Mechanism Rating Scales (Perry,1990) and Coping Action Patterns (Perry, Drapeau, Dunkley, & Blake,2005). Hierarchical linear modeling was applied to model the change over the course of therapy and relate it to outcome. Results suggest that STDP has an effect on the target variable of overall defensive functioning, which was absent for overall coping functioning. Links with outcome confirm the importance of the effect. These results are discussed from methodological and clinical viewpoints. © 2010 Wiley Periodicals, Inc. J Clin Psychol 66:1–10, 2010.
Hunter‐gatherer response to late Holocene climatic variability in northern and central Australia
Authors: Williams Alan N. , Ulm Sean , Goodwin Ian D. , Smith Mike
Published: September 2010

Sum probability analysis of 1275 radiometric ages from 608 archaeological sites across northern and central Australia demonstrates a changing archaeological signature that can be closely correlated with climate variability over the last 2 ka. Results reveal a marked increase in archaeological records across northern and central Australia over the last 2 ka, with notable declines in western and northern Australia between ca. AD 700 and 1000 and post‐AD 1500 – two periods broadly coeval with the Medieval Climatic Anomaly and the Little Ice Age as they have been documented in the Asia–Pacific region. Latitudinal and longitudinal analysis of the dataset suggests the increase in archaeological footprint was continent wide, while the declines were greatest from 9 to 20° S, 110 to 135° E and 143 to 150° E. The change in the archaeological data suggests that, combined with an increase in population over the late Holocene, a disruption or reorganisation of pre‐European resource systems occurred across Australia between ca. AD 700 and 1000 and post‐AD 1500. These archaeological responses can be broadly correlated with transitions of the El Niño–Southern Oscillation (ENSO) mean state on a multi‐decadal to centennial timescale. The latter involve a shift towards the La Niña‐like mean state with wetter conditions in the Australian region between AD 700 and 1150. A transition period in ENSO mean state occurred across Australia during AD 1150–1300, with persistent El Niño‐like and drier conditions to ca. AD 1500, and increasing ENSO variability post‐AD 1500 to the present. Copyright © 2010 John Wiley & Sons, Ltd.
A 70 ka record of explosive eruptions from the TALDICE ice core (Talos Dome, East Antarctic plateau)
Authors: Narcisi Biancamaria , Petit Jean Robert , Chappellaz Jérôme
Published: September 2010

The new Antarctic TALDICE ice core (72° 49′ S, 159° 11′ E, 1620 m depth), containing abundant primary tephras, provides the opportunity to elucidate the late Quaternary volcanic history of the south polar region, as well as to broaden the East Antarctic tephrostratigraphic framework. Here grain size and glass compositional data for representative tephra layers from the last 70 ka core section are used for source identification. Results point to origin of layers from centres of the Melbourne Volcanic Province (McMurdo Volcanic Group), located ∼250 km from the coring site. Occurrence of tephra layers within the ice core record suggests that explosive activity in the identified source was not constant over the considered period, with a minimum of activity between 20 and 35 ka, and increased activity back to 65 ka. In addition to palaeovolcanic implications, the TALDICE tephra layers offer prospects for firm correlations between diverse widely separated palaeoarchives and for accurate dating of the Antarctic climatic record. Copyright © 2010 John Wiley & Sons, Ltd.
Increasing flexibility and value of management education during the present economic downturn
Authors: Jaradat Suhair , Qablan Ahmad
Published: September 2010

Management education, which traditionally has been delivered on site in business schools, is now offering increased flexibility by allowing learners to select the timing and location of their learning experiences while causing substantial cost‐reducing and financial benefits to the teaching environment.