bluuebunny/crossref_metadata_2025 huggingface dataset:
Dynamic Relations between Stock Returns and Exchange Rate Changes
Authors: Inci A. Can , Lee Bong Soo
Published: July 2011

We re‐examine the relation between stock returns and exchange rate changes in five major European countries (France, Germany, Italy, Switzerland, and the UK), the USA, Canada, and Japan by taking into account dynamic effects, including lagged changes of variables, and employing causal relations. We find that lagged exchange rates have a significant impact on stock returns. We find evidence of Granger causality from exchange rate changes to stock returns, and also for the reverse direction. Furthermore, the dynamic relation has been more significant and stronger in recent years and recession periods than in early periods and expansion periods.
Accessibility interrupted: the Shimshal road, Gilgit‐Baltistan, Pakistan
Authors: Butz David A. , Cook Nancy E.
Published: July 2011

Geographers working in mountainous northern Pakistan note that gains in accessibility following the Karakoram Highway's official opening in 1978 significantly reshaped social organization, economic activity, and land use across the region. These valuable regional‐scale analyses provide few insights regarding the contingent and variable ways new roads are conceived and experienced at the community and household level by the people whose mobility they drastically impact. This article addresses that limitation of regional research by focusing on an individual agricultural community called Shimshal that in 2003 completed a 40‐kilometre link‐road connecting it to the highway. Drawing from qualitative information gathered before and after the Shimshal road's completion, we briefly describe the community's motivation for constructing the road, villagers’ accessibility‐related hopes and concerns as it was being built, and some of the social, cultural, and economic changes that followed the road's completion. The article concludes by summarizing the community's response so far to landslide‐induced destruction of over 20 kilometres of the Karakoram Highway which, since January 2010, has left community members without vehicular access to the rest of Pakistan just seven years after their link‐road's completion.
On the importance of intraspecific variability for the quantification of functional diversity
Authors: Albert Cécile H. , de Bello Francesco , Boulangeat Isabelle , Pellet Gilles , Lavorel Sandra , Thuiller Wilfried
Published: July 2011

Functional diversity (FD) is a key facet of biodiversity used to address central questions in ecology. Despite recent methodological advances, FD remains a complex concept and no consensus has been reached either on how to quantify it, or on how it influences ecological processes. Here we define FD as the distribution of trait values within a community. When and how to account for intraspecific trait variability (ITV) when measuring FD remains one of the main current debates. It remains however unclear to what extent accounting for population‐level ITV would modify FD quantification and associated conclusions. In this paper, we address two critical questions: (1) How sensitive are different components of FD to the inclusion of population‐level ITV? (2) Does the omission of ITV obscure the understanding of ecological patterns? Using a mixture of empirical data and simulation experiments, we conducted a sensitivity analysis of four commonly used FD indices (community weighted mean traits, functional richness, Rao's quadratic entropy, Petchey and Gaston's FD index) and their relationships with environmental gradients and species richness, by varying both the extent (plasticity or not) and the structure (contingency to environmental gradient due to local adaptation) of population‐level ITV. Our results suggest that ITV may strongly alter the quantification of FD and the detection of ecological patterns. Our analysis highlights that 1) species trait values distributions within communities are crucial to the sensitivity to ITV, 2) ITV structure plays a major role in this sensitivity and 3) different indices are not evenly sensitive to ITV, the single‐trait FD from Petchey and Gaston being the most sensitive among the four metrics tested. We conclude that the effects of intraspecific variability in trait values should be more systematically tested before drawing central conclusions on FD, and suggest the use of simulation studies for such sensitivity analyses.
Analysis of the Flow
in the Combustor—Transition Piece Considering the Variation in the Fuel
Composition
Authors: Arturo
Alfaro-Ayala J. , Gallegos-Muñoz A. , Manuel
Riesco-Ávila J. , Flores-López M. , Campos-Amezcua A. , Germán Mani-González A.
Published: July 2011

An analysis of the flow that depends on the fuel composition (natural gas) in the combustor–transition piece system, applying computational fluid dynamics, is presented. The study defines the velocity and temperature profiles at the exit of the transition piece and the hot streak along the system. The variation of the composition in the fuel depends of the amount of N2 contained in the fuel, and the hot track influences on the temperature distribution at the input of the first stage of vanes and blades of the gas turbine. The study takes place in a three-dimensional model in steady state using FLUENT® 6.3.26, applying the k-ε turbulence model and chemical equilibrium to the combustion process. The results show the influence of the transition piece geometry over the velocity and temperature profiles, principally, in the radial direction. The velocity profiles on the radial direction can be represented by six order polynomial and the temperature profile by third order polynomial. The temperature and velocity profiles keep a symmetry profile and they can be represented by six order polynomial at the circumferential direction. Knowing these profiles, it is possible to compute a more exact study of the heat transfer at vanes and blades of the first stage of the turbine to evaluate the performance and life of them. On the other hand, considering from 2% to 10% of N2 in the fuel composition, the maximum temperature is reduced in the combustion process and consequently the NOx emissions too.
Rational Design of a Meningococcal Antigen Inducing Broad Protective Immunity
Authors: Scarselli Maria , Aricò Beatrice , Brunelli Brunella , Savino Silvana , Di Marcello Federica , Palumbo Emmanuelle , Veggi Daniele , Ciucchi Laura , Cartocci Elena , Bottomley Matthew James , Malito Enrico , Lo Surdo Paola , Comanducci Maurizio , Giuliani Marzia Monica , Cantini Francesca , Dragonetti Sara , Colaprico Annalisa , Doro Francesco , Giannetti Patrizia , Pallaoro Michele , Brogioni Barbara , Tontini Marta , Hilleringmann Markus , Nardi-Dei Vincenzo , Banci Lucia , Pizza Mariagrazia , Rappuoli Rino
Published: July 2011

A single chimeric protein induces protective immunity against all meningococcal B strains with implications for producing broadly protective vaccines.
Randomised trial comparing hand expression with breast pumping for mothers of term newborns feeding poorly
Authors: Flaherman Valerie J , Gay Barbara , Scott Cheryl , Avins Andrew , Lee Kathryn A , Newman Thomas B
Published: July 2011

Objective

Breast pumping or hand expression may be recommended when newborns latch or suck poorly. A recent trial found worse outcomes among mothers who used a breast pump in the early postpartum period. The objective of this study was to compare bilateral electric breast pumping to hand expression among mothers of healthy term infants feeding poorly at 12–36 h after birth.

Design

Randomised controlled trial.

Setting

Well-baby nursery and postpartum unit.

Patients

68 mothers of newborns 12–36 h old who were latching or sucking poorly were randomly assigned to either 15 min of bilateral electric pumping or 15 min of hand expression.

Mainoutcome measures

Milk transfer, maternal pain, breastfeeding confidence and breast milk expression experience (BMEE) immediately after the intervention, and breastfeeding rates at 2 months after birth.

Results

The median volume of expressed milk (range) was 0.5 (0–5) ml for hand expressing mothers and 1 (0–40) ml for pumping mothers (p=0.07). Maternal pain, breastfeeding confidence and BMEE did not differ by intervention. At 2 months, mothers assigned to hand expression were more likely to be breastfeeding (96.1%) than mothers assigned to breast pumping (72.7%) (p=0.02).

Conclusions

Hand expression in the early postpartum period appears to improve eventual breastfeeding rates at 2 months after birth compared with breast pumping, but further research is needed to confirm this. However, in circumstances where either pumping or hand expression would be appropriate for healthy term infants 12–36 h old feeding poorly, providers should consider recommending hand expression.
INTRODUCTION TO SUPERGEOMETRY
Authors: CATTANEO ALBERTO S. , SCHÄTZ FLORIAN
Published: July 2011

These notes are based on a series of lectures given by the first author at the school of "Poisson 2010", held at IMPA, Rio de Janeiro. They contain an exposition of the theory of super- and graded manifolds, cohomological vector fields, graded symplectic structures, reduction and the AKSZ-formalism.
COMPUTATIONAL FLUID DYNAMICS FOR TISSUE ENGINEERING APPLICATIONS
Authors: HE JIANKANG , LI DICHEN , LIU YAXIONG , LI XIAO , XU SHANGLONG , LU BINGHENG
Published: July 2011

Hydrodynamic cellular environment plays an important role in translating engineered tissue constructs into clinically useful grafts. However, the cellular fluid dynamic environment inside bioreactor systems is highly complex and it is normally impractical to experimentally characterize the local flow patterns at the cellular scale. Computational fluid dynamics (CFD) has been recognized as an invaluable and reliable alternative to investigate the complex relationship between hydrodynamic environments and the regeneration of engineered tissues at both the macroscopic and microscopic scales. This review describes the applications of CFD simulations to probe the hydrodynamic environment parameters (e.g., flow rate, shear stress, etc.) and the corresponding experimental validations. We highlight the use of CFD to optimize bioreactor design and scaffold architectures for improved ex-vivo hydrodynamic environments. It is envisioned that CFD could be used to customize specific hydrodynamic cellular environments to meet the unique requirements of different cell types in combination with advanced manufacturing techniques and finally facilitate the maturation of tissue-engineered constructs.
A FRAMEWORK FOR REPRESENTING AND PRODUCING MOVIES ON QUANTUM COMPUTERS
Authors: ILIYASU ABDULLAH M. , LE PHUC Q. , DONG FANGYAN , HIROTA KAORU
Published: July 2011

Adopting a generalization of the DiVincenzo criteria for the physical realization of quantum devices, a standalone component each, is proposed to prepare, manipulate, and measure the various content required to represent and produce movies on quantum computers. The quantum CD encodes, prepares, and initializes the broad content or key frames conveying the movie script. The quantum player uses the simple motion operations to manipulate the contents of the key frames in order to interpolate the missing viewing frames required to effectively depict the shots and scenes of the movie. The movie reader combines the projective measurement technique and the ancilla-driven quantum computation to retrieve the classical movie sequence comprising of both the key and viewing frames for each shot. At appropriate frame transition rates, this sequence creates the impression of continuity in order to depict the various movements and actions in the movie. Two well-thought-out examples demonstrate the feasibility of the proposed framework. Concatenated, these components together facilitate the proposed framework for quantum movie representation and production, thus, opening the door towards manipulating quantum circuits aimed at applications for information representation and processing.
VERY WELL-COVERED GRAPHS OF GIRTH AT LEAST FOUR AND LOCAL MAXIMUM STABLE SET GREEDOIDS
Authors: LEVIT VADIM E. , MANDRESCU EUGEN
Published: July 2011

A maximum stable set in a graph G is a stable set of maximum cardinality. S is a local maximum stable set of G, and we write S ∈ Ψ(G), if S is a maximum stable set of the subgraph induced by S ∪ N(S), where N(S) is the neighborhood of S. Nemhauser and Trotter Jr. [Vertex packings: structural properties and algorithms, Math. Program.8 (1975) 232–248], proved that any S ∈ Ψ(G) is a subset of a maximum stable set of G. In [Levit and Mandrescu, A new greedoid: the family of local maximum stable sets of a forest, Discrete Appl. Math.124 (2002) 91–101] we have shown that the family Ψ(T) of a forest T forms a greedoid on its vertex set. The cases where G is bipartite, triangle-free, well-covered, while Ψ(G) is a greedoid, were analyzed in [Levit and Mandrescu, Local maximum stable sets in bipartite graphs with uniquely restricted maximum matchings, Discrete Appl. Math.132 (2004) 163–174], [Levit and Mandrescu, Triangle-free graphs with uniquely restricted maximum matchings and their corresponding greedoids, Discrete Appl. Math.155 (2007) 2414–2425], [Levit and Mandrescu, Well-covered graphs and greedoids, Proc. 14th Computing: The Australasian Theory Symp. (CATS2008), Wollongong, NSW, Conferences in Research and Practice in Information Technology, Vol. 77 (2008) 89–94], respectively. In this paper we demonstrate that if G is a very well-covered graph of girth ≥4, then the family Ψ(G) is a greedoid if and only if G has a unique perfect matching.
cAMP-secretion coupling is impaired in diabetic GK/Par rat β-cells: a defect counteracted by GLP-1
Authors: Dolz Manuel , Movassat Jamileh , Bailbé Danielle , Le Stunff Hervé , Giroix Marie-Hélène , Fradet Magali , Kergoat Micheline , Portha Bernard
Published: July 2011

cAMP-raising agents with glucagon-like peptide-1 (GLP-1) as the first in class, exhibit multiple actions that are beneficial for the treatment of type 2 diabetic (T2D) patients, including improvement of glucose-induced insulin secretion (GIIS). To gain additional insight into the role of cAMP in the disturbed stimulus-secretion coupling within the diabetic β-cell, we examined more thoroughly the relationship between changes in islet cAMP concentration and insulin release in the GK/Par rat model of T2D. Basal cAMP content in GK/Par islets was significantly higher, whereas their basal insulin release was not significantly different from that of Wistar (W) islets. Even in the presence of IBMX or GLP-1, their insulin release did not significantly change despite further enhanced cAMP accumulation in both cases. The high basal cAMP level most likely reflects an increased cAMP generation in GK/Par compared with W islets since 1) forskolin dose-dependently induced an exaggerated cAMP accumulation; 2) adenylyl cyclase (AC)2, AC3, and Gsα proteins were overexpressed; 3) IBMX-activated cAMP accumulation was less efficient and PDE-3B and PDE-1C mRNA were decreased. Moreover, the GK/Par insulin release apparatus appears less sensitive to cAMP, since GK/Par islets released less insulin at submaximal cAMP levels and required five times more cAMP to reach a maximal secretion rate no longer different from W. GLP-1 was able to reactivate GK/Par insulin secretion so that GIIS became indistinguishable from that of W. The exaggerated cAMP production is instrumental, since GLP-1-induced GIIS reactivation was lost in the presence the AC blocker 2′,5′-dideoxyadenosine. This GLP-1 effect takes place in the absence of any improvement of the [Ca2+]iresponse and correlates with activation of the cAMP-dependent PKA-dependent pathway.
Cholecystokinin facilitates neuronal excitability in the entorhinal cortex via activation of TRPC-like channels
Authors: Wang Shouping , Zhang An-Ping , Kurada Lalitha , Matsui Toshimitsu , Lei Saobo
Published: July 2011

Cholecystokinin (CCK) is one of the most abundant neuropeptides in the brain, where it interacts with two G protein-coupled receptors (CCK-1 and CCK-2). Activation of both CCK receptors increases the activity of PLC, resulting in increases in intracellular calcium ion (Ca2+) release and activation of PKC. Whereas high density of CCK receptors has been detected in the superficial layers of the entorhinal cortex (EC), the functions of CCK in this brain region have not been determined. Here, we studied the effects of CCK on neuronal excitability of layer III pyramidal neurons in the EC. Our results showed that CCK remarkably increased the firing frequency of action potentials (APs). The effects of CCK on neuronal excitability were mediated via activation of CCK-2 receptors and required the functions of G proteins and PLC. However, CCK-mediated facilitation of neuronal excitability was independent of inositol trisphosphate receptors and PKC. CCK facilitated neuronal excitability by activating a cationic channel to generate membrane depolarization. The effects of CCK were suppressed by the generic, nonselective cationic channel blockers, 2-aminoethyldiphenyl borate and flufenamic acid, but potentiated by gadolinium ion and lanthanum ion at 100 μM. Depletion of extracellular Ca2+ also counteracted CCK-induced increases in AC firing frequency. Moreover, CCK-induced enhancement of neuronal excitability was inhibited significantly by intracellular application of the antibody to transient receptor potential channel 5 (TRPC5), suggesting the involvement of TRPC5 channels. Our results provide a cellular and molecular mechanism to help explain the functions of CCK in vivo.
Postnatal maturation of the hyperpolarization-activated cation current, Ih, in trigeminal sensory neurons
Authors: Cho Hyun-jung , Furness John B. , Jennings Ernest A.
Published: July 2011

Hyperpolarization-activated inward currents ( Ih) contribute to neuronal excitability in sensory neurons. Four subtypes of hyperpolarization-activated cyclic nucleotide-gated (HCN) channels generate Ih, with different activation kinetics and cAMP sensitivities. The aim of the present study was to examine the postnatal development of Ih and HCN channel subunits in trigeminal ganglion (TG) neurons. Ih was investigated in acutely dissociated TG neurons from rats aged between postnatal day (P)1 and P35 with whole cell patch-clamp electrophysiology. In voltage-clamp studies, Ih was activated by a series of hyperpolarizing voltage steps from −40 mV to −120 mV in −10-mV increments. Tail currents from a common voltage step (−100 mV) were used to determine Ih voltage dependence. Ih activation was faster in older rats and occurred at more depolarized potentials; the half-maximal activation voltage ( V1/2) changed from −89.4 mV (P1) to −81.6 mV (P35). In current-clamp studies, blocking Ih with ZD7288 caused membrane hyperpolarization and increases in action potential half-duration at all postnatal ages examined. ZD7288 also reduced the action potential firing frequency in multiple-firing neurons. Western blot analysis of the TG detected immunoreactive bands corresponding to all HCN subtypes. HCN1 and HCN2 band density increased with postnatal age, whereas the low-intensity HCN3 and moderate-intensity HCN4 bands were not changed. This study suggests that functional Ih are activated in rat trigeminal sensory neurons from P1 during postnatal development, have an increasing role with age, and modify neuronal excitability.
Ribosomal genes and heat shock proteins as putative markers for chronic, sublethal heat stress in Arctic charr: applications for aquaculture and wild fish
Authors: Quinn Nicole L. , McGowan Colin R. , Cooper Glenn A. , Koop Ben F. , Davidson William S.
Published: July 2011

Arctic charr thrive at high densities and can live in freshwater year round, making this species especially suitable for inland, closed containment aquaculture. However, it is a cold-water salmonid, which both limits where the species can be farmed and places wild populations at particular risk to climate change. Previously, we identified genes associated with tolerance and intolerance to acute, lethal temperature stress in Arctic charr. However, there remained a need to examine the genes involved in the stress response to more realistic temperatures that could be experienced during a summer heat wave in grow-out tanks that are not artificially cooled, or under natural conditions. Here, we exposed Arctic charr to sublethal heat stress of 15–18°C for 72 h, and gill tissues extracted before, during (i.e., at 72 h), immediately after cooling and after 72 h of recovery at ambient temperature (6°C) were used for gene expression profiling by microarray and qPCR analyses. The results revealed an expected pattern for heat shock protein expression, which was highest during heat exposure, with significantly reduced expression (approaching control levels) quickly thereafter. We also found that the expression of numerous ribosomal proteins was significantly elevated immediately and 72 h after cooling, suggesting that the gill tissues were undergoing ribosome biogenesis while recovering from damage caused by heat stress. We suggest that these are candidate gene targets for the future development of genetic markers for broodstock development or for monitoring temperature stress and recovery in wild or cultured conditions.
T-Cell Immune Function in Tumor, Skin, and Peripheral Blood of Advanced Stage Melanoma Patients: Implications for Immunotherapy
Authors: Tjin Esther P.M. , Konijnenberg Debby , Krebbers Gabrielle , Mallo Henk , Drijfhout Jan W. , Franken Kees L.M.C. , van der Horst Chantal M.A.M. , Bos Jan D. , Nieweg Omgo E. , Kroon Bin B.R. , Haanen John B.A.G. , Melief Cornelis J.M. , Vyth-Dreese Florry A. , Luiten Rosalie M.
Published: July 2011

Purpose: To predict the potential antitumor effect of antigen-specific T cells in melanoma patients, we investigated T-cell effector function in relation to tumor-escape mechanisms.

Experimental Design: CD8+ T cells isolated from tumor, adjacent normal skin, and peripheral blood of 17 HLA-A2+ patients with advanced-stage melanoma were analyzed for their antigen specificity and effector function against melanocyte differentiation antigens MART-1, gp100, and tyrosinase by using HLA-A2/peptide tetramers and functional assays. In addition, the presence of tumor-escape mechanisms PD-L1/PD-1 pathway, FoxP3 and loss of HLA or melanocyte differentiation antigens, both required for tumor cell recognition and killing, were studied.

Results: Higher percentages of melanocyte antigen-specific CD8+ T cells were found in the melanoma tissues as compared with adjacent normal skin and peripheral blood. Functional analysis revealed 2 important findings: (i) in 5 of 17 patients, we found cytokine production after specific peptide stimulation by tumor-infiltrating lymphocytes (TIL), not by autologous peripheral blood lymphocytes (PBL); (ii) CD8+ T cells from 7 of 17 patients did not produce cytokines after specific stimulation, which corresponded with significant loss of tumor HLA-A2 expression. The presence of other tumor-escape mechanisms did not correlate to T-cell function.

Conclusions: Our data show that functional T-cell responses could be missed when only PBL and not TIL are evaluated, emphasizing the importance of TIL analysis for immunomonitoring. Furthermore, loss of tumor HLA-A2 may explain the lack of T-cell functionality. These findings have important implications for selecting melanoma patients who may benefit from immunotherapy. Clin Cancer Res; 17(17); 5736–47. ©2011 AACR.
Molecular Characteristics of ERCC1-Negative versus ERCC1-Positive Tumors in Resected NSCLC
Authors: Friboulet Luc , Barrios-Gonzales Daniel , Commo Frédéric , Olaussen Ken André , Vagner Stephan , Adam Julien , Goubar Aïcha , Dorvault Nicolas , Lazar Vladimir , Job Bastien , Besse Benjamin , Validire Pierre , Girard Philippe , Lacroix Ludovic , Hasmats Johanna , Dufour Fabienne , André Fabrice , Soria Jean-Charles
Published: July 2011

Purpose: Excision repair cross-complementation group 1 (ERCC1) is a protein involved in repair of DNA platinum adducts and stalled DNA replication forks. We and others have previously shown the influence of ERCC1 expression upon survival rates and benefit of cisplatin-based chemotherapy in patients with resected non–small-cell lung cancer (NSCLC). However, little is known about the molecular characteristics of ERCC1-positive and ERCC1-negative tumors.

Experimental Design: We took advantage of a cohort of 91 patients with resected NSCLC, for which we had matched frozen and paraffin-embedded samples to explore the comparative molecular portraits of ERCC1-positive and ERCC1-negative tumors of NSCLC. We carried out a global molecular analysis including assessment of ERCC1 expression levels by using both immunohistochemistry (IHC) and quantitative reverse transcriptase PCR (qRT-PCR), genomic instability, global gene and miRNA expression, and sequencing of selected key genes involved in lung carcinogenesis.

Results: ERCC1 protein and mRNA expression were significantly correlated. However, we observed several cases with clear discrepancies. We noted that ERCC1-negative tumors had a higher rate of genomic abnormalities versus ERCC1-positive tumors. ERCC1-positive tumors seemed to share a common DNA damage response (DDR) phenotype with the overexpression of seven genes linked to DDR. The miRNA expression analysis identified miR-375 as significantly underexpressed in ERCC1-positive tumors.

Conclusions: Our data show inconsistencies in ERCC1 expression between IHC and qRT-PCR readouts. Furthermore, ERCC1 status is not linked to specific mutational patterns or frequencies. Finally, ERCC1-negative tumors have a high rate of genomic aberrations that could consequently influence prognosis in patients with resected NSCLC. Clin Cancer Res; 17(17); 5562–72. ©2011 AACR.
Genomic Profiling in CEPH Cell Lines Distinguishes between the Camptothecins and Indenoisoquinolines
Authors: Watson Venita Gresham , Hardison Nicholas E. , Harris Tyndall , Motsinger-Reif Alison , McLeod Howard L.
Published: July 2011

We have attempted to use a familial genetics strategy to study mechanisms of topoisomerase 1 (Top1) inhibition. Investigations have steadily been chipping away at the pathways involved in cellular response following Top1 inhibition for more than 20 years. Our system-wide approach, which phenotypes a collection of genotyped human cell lines for sensitivity to compounds and interrogates all genes and molecular pathways simultaneously. Previously, we characterized the in vitro sensitivity of 15 families of Centre d'Etude Polymorphisme Humain (CEPH) cell lines (n = 142) to 9 camptothecin analogues. Linkage analysis revealed a pattern of 7 quantitative trait loci (QTL) shared by all of the camptothecins. To identify which, if any, QTLs are related to the general mechanism of Top1 inhibition or should be considered camptothecin specific, we characterized the in vitro sensitivity of the same panel of CEPH cell lines to the indenisoquinolones, a structurally distinct class of Top1 inhibitors. Four QTLs on chromosomes 1, 5, 11, and 16 were shared by both the camptothecins and the indenoisoquinolines and are considered associated with the general mechanism of Top1 inhibition. The remaining 3 QTLs (chromosomes 6 and 20) are considered specific to camptothecin-induced cytotoxicity. Finally, 8 QTLs were identified, which were unique to the indenoisoquinolines. Mol Cancer Ther; 10(10); 1839–45. ©2011 AACR.
Carfilzomib Interacts Synergistically with Histone Deacetylase Inhibitors in Mantle Cell Lymphoma Cells In Vitro and In Vivo
Authors: Dasmahapatra Girija , Lembersky Dmitry , Son Minkyeong P. , Attkisson Elisa , Dent Paul , Fisher Richard I. , Friedberg Jonathan W. , Grant Steven
Published: July 2011

Interactions between the proteasome inhibitor carfilzomib and the histone deacetylase (HDAC) inhibitors vorinostat and SNDX-275 were examined in mantle cell lymphoma (MCL) cells in vitro and in vivo. Coadministration of very low, marginally toxic carfilzomib concentrations (e.g., 3–4 nmol/L) with minimally lethal vorinostat or SNDX-275 concentrations induced sharp increases in mitochondrial injury and apoptosis in multiple MCL cell lines and primary MCL cells. Enhanced lethality was associated with c-jun-NH,-kinase (JNK) 1/2 activation, increased DNA damage (induction of λH2A.X), and ERK1/2 and AKT1/2 inactivation. Coadministration of carfilzomib and histone deacetylase inhibitors (HDACI) induced a marked increase in reactive oxygen species (ROS) generation and G2–M arrest. Significantly, the free radical scavenger tetrakis(4-benzoic acid) porphyrin (TBAP) blocked carfilzomib/HDACI-mediated ROS generation, λH2A.X formation, JNK1/2 activation, and lethality. Genetic (short hairpin RNA) knockdown of JNK1/2 significantly attenuated carfilzomib/HDACI-induced apoptosis, but did not prevent ROS generation or DNA damage. Carfilzomib/HDACI regimens were also active against bortezomib-resistant MCL cells. Finally, carfilzomib/vorinostat coadministration resulted in a pronounced reduction in tumor growth compared with single agent treatment in an MCL xenograft model associated with enhanced apoptosis, λH2A.X formation, and JNK activation. Collectively, these findings suggest that carfilzomib/HDACI regimens warrant attention in MCL. Mol Cancer Ther; 10(9); 1686–97. ©2011 AACR.
Inhibition of Dynamin by Dynole 34-2 Induces Cell Death following Cytokinesis Failure in Cancer Cells
Authors: Chircop Megan , Perera Swetha , Mariana Anna , Lau Hui , Ma Maggie P.C. , Gilbert Jayne , Jones Nigel C. , Gordon Christopher P. , Young Kelly A. , Morokoff Andrew , Sakoff Jennette , O'Brien Terence J. , McCluskey Adam , Robinson Phillip J.
Published: July 2011

Inhibitors of mitotic proteins such as Aurora kinase and polo-like kinase have shown promise in preclinical or early clinical development for cancer treatment. We have reported that the MiTMAB class of dynamin small molecule inhibitors are new antimitotic agents with a novel mechanism of action, blocking cytokinesis. Here, we examined 5 of the most potent of a new series of dynamin GTPase inhibitors called dynoles. They all induced cytokinesis failure at the point of abscission, consistent with inhibition of dynamin while not affecting other cell cycle stages. All 5 dynoles inhibited cell proliferation (MTT and colony formation assays) in 11 cancer cell lines. The most potent GTPase inhibitor, dynole 34-2, also induced apoptosis, as revealed by cell blebbing, DNA fragmentation, and PARP cleavage. Cell death was induced specifically following cytokinesis failure, suggesting that dynole 34-2 selectively targets dividing cells. Dividing HeLa cells were more sensitive to the antiproliferative properties of all 5 dynoles compared with nondividing cells, and nontumorigenic fibroblasts were less sensitive to cell death induced by dynole 34-2. Thus, the dynoles are a second class of dynamin GTPase inhibitors, with dynole 34-2 as the lead compound, that are novel antimitotic compounds acting specifically at the abscission stage. Mol Cancer Ther; 10(9); 1553–62. ©2011 AACR.
Epigallocatechin-gallate Suppresses Tumorigenesis by Directly Targeting Pin1
Authors: Urusova Darya V. , Shim Jung-Hyun , Kim Dong Joon , Jung Sung Keun , Zykova Tatyana A. , Carper Andria , Bode Ann M. , Dong Zigang
Published: July 2011

The most active anticancer component in green tea is epigallocatechin-3-gallate (EGCG). The human peptidyl prolyl cis/trans isomerase (Pin1) plays a critical role in oncogenic signaling. Herein, we report the X-ray crystal structure of the Pin1/EGCG complex resolved at 1.9 Å resolution. Notably, the structure revealed the presence of EGCG in both the WW and PPIase domains of Pin1. The direct binding of EGCG with Pin1 was confirmed and the interaction inhibited Pin1 PPIase activity. In addition, proliferation of cells expressing Pin1 was inhibited and tumor growth in a xenograft mouse model was suppressed. The binding of EGCG with Arg17 in the WW domain prevented the binding of c-Jun, a well-known Pin1 substrate. EGCG treatment corresponded with a decreased abundance of cyclin D1 and diminution of 12-O-tetradecanoylphorbol-l3-acetate–induced AP-1 or NF-κB promoter activity in cells expressing Pin1. Overall, these results showed that EGCG directly suppresses the tumor-promoting effect of Pin1. Cancer Prev Res; 4(9); 1366–77. ©2011 AACR.
Population-Based Distribution and Psychometric Properties of a Short Cognitive Performance Measure in the Population-Based Heinz Nixdorf Recall Study
Authors: Wege Natalia , Dlugaj Martha , Siegrist Johannes , Dragano Nico , Erbel Raimund , Jöckel Karl-Heinz , Moebus Susanne , Weimar Christian ,   on behalf of the Heinz Nixdorf Recall Study Investigative Group
Published: July 2011

Background: Providing a valid and sensitive measure of different domains of cognitive performance in epidemiologic studies of early old-age populations presents a methodological challenge, given the broad range of variability in cognitive functioning in this age group. Objectives: (1) To provide data on the distribution of cognitive performance scores in a representative sample of an early old-age population, and (2) to assess psychometric properties of a short cognitive performance measure developed within the framework of a cohort study. Design: Population-based cohort study. Setting and Participants: As part of the second examination of the Heinz Nixdorf Recall Study, 4,145 participants aged 50–80 years underwent a short cognitive performance assessment composed of 5 subtests with a mean duration of 7.31 min. Additionally, a subsample of 656 participants had a detailed neuropsychological and neurological examination. Methods: Age- and education-specific cognitive performance scores in the total sample were calculated. Based on data from the subsample, concurrent validity was examined by comparing findings with a clinically validated neuropsychological assessment. Results: In the total sample, younger and more highly educated participants had higher scores of cognitive performance. In the subsample, a good accuracy [area under the curve (AUC) = 0.81 (0.74–0.87)] of the short cognitive performance assessment compared with results from a clinically established Alzheimer disease assessment scale and diagnosis of mild cognitive impairment [AUC = 0.82 (0.78–0.82)] was observed. Conclusion: This brief, cognitive performance measure, documenting good psychometric properties, can be useful in future epidemiological investigations exploring different domains and overall cognitive functioning in early old-age populations.
Does Cervical Radiculopathy Have an Effect on Peripheral Nerve Conduction Studies? An Electrophysiological Evaluation
Authors: Balci Kemal , Asil Talip , Tekinaslan Ilkay , Ir Nasif
Published: July 2011

Background: Peripheral nerve neuropathies are more common in patients with cervical radiculopathy (CR) and a proximal lesion along an axon might predispose that nerve to injury at distal sites. To evaluate this hypothesis, the frequency of median nerve neuropathy at the wrist and the frequency of ulnar nerve neuropathy at the elbow were investigated in 80 patients with one-sided CR. Methods: The symptomatic and asymptomatic extremities were compared for the electrophysiological parameters of ulnar and median nerve conduction studies. The patients were divided into three diagnostic subgroups (C5/C6 radiculopathy, C7 radiculopathy and C8/Th1 radiculopathy), and ulnar nerve conduction studies were compared between symptomatic and asymptomatic extremities in each subgroup. Results: Although, the median and ulnar nerves are mainly derived from C8/Th1 roots, we did not observe an increased frequency of ulnar nerve involvement at the elbow (3.7% in symptomatic, 2.5% in asymptomatic extremities) while increased median nerve involvement was present at the wrist (27.5% in symptomatic, 12.5% in asymptomatic extremities). Conclusion: The electrophysiological data and the frequency of ulnar and median nerve neuropathy did not support an etiological association between CR and distal neuropathy. Significance: the association between CR and peripheral neuropathy is associational rather than causative.
Implication de la régulation homéostatique du fer dans le statut ferrique du nourrisson et de l’enfant
Authors: Lönnerdal Bo , Hernell Olle
Published: July 2011

Le fer étant important dans le développement neurologique et la fonction cognitive, il est fondamental de prévenir la carence en fer et l’anémie ferriprive. Les bébés nés à terme et allaités ou nourris avec des préparations infantiles enrichies en fer présentent généralement un statut ferrique normal pendant les six premiers mois de leur vie. Cependant, l’évaluation du statut martial des nourrissons et les solutions pour répondre à leurs besoins ferriques sont sujets à controverse, surtout chez les bébés prématurés, nés avec de faibles réserves en fer, et pour lesquels les recommandations concernant les apports ferriques varient considérablement. Ceci est probablement dû en partie à l’immaturité de la régulation de l’homéostasie du fer chez les nourrissons. En effet, les nourrissons de 9 mois semblent être en mesure de diminuer leur absorption en fer lorsque leurs réserves ferriques sont maximales, alors que les nourrissons de 6 mois n’en sont pas capables. Le fer peut être administré aux nourrissons sous forme de gouttes ou de produits enrichis en fer, mais ces formes peuvent être métabolisées différemment, et l’excès de fer apporté par les gouttes peut provoquer des effets indésirables, probablement en raison d’une capacité limitée des nourrissons à réguler l’absorption du fer. Les effets indésirables se manifestent par une diminution de la croissance: en terme de taille chez les nourrissons bien nourris et en terme de poids chez les bébés malnutris. Le mécanisme expliquant cette diminution de la croissance reste à élucider, mais l’action du fer sur les radicaux libres ou une interaction avec l’absorption ou l’homéostasie du zinc pourraient être impliquées. Les enfants n’ayant pas besoin d’une complémentation en fer ne devraient donc pas se voir administrés de fer sous forme de gouttes.
La carence en fer durant l’enfance: causes et conséquences pour le développement de l’enfant
Authors: Grantham-McGregor Sally , Baker-Henningham Helen
Published: July 2011

Les principales causes de la carence en fer (CF) sont brièvement discutées, puis un examen des études s’intéressant à la CF et classées en fonction de leur méthodologie et design, a été réalisé, à la recherche de liens de causalité entre la CF et le comportement et le développement cognitif et moteur de l’enfant. L’anémie ferriprive (AF) est associée à de nombreux problèmes psychosociaux et économiques qui peuvent affecter le développement de l’enfant et pourraient expliquer la relation, souvent observée, entre AF et troubles du développement et du comportement. De nombreuses données indiquent des modifications du fonctionnement cérébral chez les nourrissons présentant une AF. Cependant, de nombreux essais visant à traiter la CF manquent de puissance statistique en raison d’un faible effectif, de l’inclusion d’enfants non carencés, ou d’un traitement induisant peu ou pas de différence sur le statut ferrique entre le groupe placebo et le(s) groupe(s) traité(s). Chez les enfants de moins de 3 ans présentant une AF, les essais randomisés indiquent qu’une complémentation en fer est généralement bénéfique pour le développement moteur, mais pas nécessairement pour le développement mental. Une complémentation en fer a également des effets bénéfiques sur la fonction cognitive chez les enfants en âge scolaire présentant une AF. Il ne semble pas exister de seuil au-delà duquel une CF affecterait le développement de l’enfant, mais ceux dont la CF est suffisemment importante pour provoquer une AF devraient bénéficier en priorité d’une complémentation en fer. Cependant, les effets délétères d’une complémentation martiale sur la croissance et la morbidité chez des enfants non carencés doivent être pris en considération lors de l’élaboration de tels programmes interventionnels ou de politiques de santé publique.
Risk Factors of In-Hospital Mortality of Intracerebral Hemorrhage and Comparison of ICH Scores in a Taiwanese Population
Authors: Chen Huan-Sheng , Hsieh Chuan-Fa , Chau Tang-Tat , Yang Chih-Dong , Chen Yu-Wei
Published: July 2011

Background and Purpose: Intracerebral hemorrhage (ICH) is associated with substantial morbidity and mortality. This study aimed to explore the risk factors associated with mortality and unfavorable outcome of ICH in Taiwan and to compare the predictive power with the existing ICH scores. Methods: Medical records of the ICH patients consecutively admitted to a regional hospital between January 2003 and December 2006 were reviewed retrospectively. The demographics, outcome, clinical and radiological characteristics were also analyzed. Results: A total of 61 among 285 (21.4%) ICH patients died during hospitalization. Diabetes mellitus, lower scores of initial Glasgow Coma Scale, initial ICH volume >30 ml, and intraventricular hematoma were identified as major independent risk factors associated with in-hospital mortality in the logistic regression model. In comparison to the predictive power for mortality and unfavorable outcome, Barthel Index <40 at discharge, the results showed no significant difference among the scores derived from our study, the ICH score by Hemphill and the modified ICH score developed in Taiwan. Conclusions: Although these ICH scores developed with various measurements, no significant difference in predicting mortality and unfavorable functional outcomes was found. The results supporting the ICH score by Hemphill may provide a good prediction in acute outcome across ethnic groups.
Prévention de la carence en fer chez le nourrisson, l’enfant et l’adolescent
Authors: Andersson Maria , Hurrell Richard F.
Published: July 2011

Dans le monde entier, la carence en fer (CF) est assez répandue chez les nourrissons, les enfants et les adolescents en raison de leurs besoins ferriques importants pendant la croissance, d’un apport alimentaire en fer souvent insuffisant et d’une mauvaise biodisponibilité de l’alimentation. Un faible statut en fer a des conséquences néfastes sur la santé pendant l’enfance. Les mesures de prévention doivent donc être mises en place précocement, telles qu’une complémentation martiale des femmes enceintes, une section tardive du cordon ombilical après l’accouchement et un allaitement maternel exclusif pendant 6 mois. Les apports en fer doivent augmenter fortement après les 4 à 6 premiers mois de vie et le contenu en ce minéral des aliments apportés au nourrisson en complément du lait maternel devient alors essentiel. L’enrichissement en fer des préparations pour nourrissons et des céréales infantiles, l’ajout de micronutriments en poudre dans les aliments préparés à la maison, ou l’administration de gouttes de fer sont les stratégies de prévention les plus efficaces chez les nourrissons au moment du sevrage. De plus, l’introduction précoce de produits carnés et l’introduction tardive du lait de vache sont également des mesures importantes. Les stratégies de prévention de la CF chez les enfants plus âgés reposent sur l’augmentation de la teneur et de la biodisponibilité du fer de l’alimentation et sur la consommation d’aliments enrichis en fer. Dans les régions à forte prévalence de CF, une complémentation martiale peut s’avérer nécessaire. Si le paludisme est également largement répandu, les quantités importantes de fer, dans le cadre d’une complémentation, ne devront être administrées qu’aux enfants présentant réellement une CF. Toutes les interventions permettant de prévenir la CF pédiatrique devraient être intégrées dans les programmes sanitaires nationaux et mondiaux destinés aux femmes enceintes et aux enfants, et notamment l’éducation à la santé, la prévention du paludisme et le déparasitage. L’impact de ces stratégies sur la prévalence de la CF devrait être suivi par des études transversales en mesurant régulièrement le statut en fer des populations.
Inflammatory Markers and Neuropsychological Functioning: The Framingham Heart Study
Authors: Jefferson Angela L. , Massaro Joseph M. , Beiser Alexa S. , Seshadri Sudha , Larson Martin G. , Wolf Philip A. , Au Rhoda , Benjamin Emelia J.
Published: July 2011

Background/Aims: We hypothesized that inflammatory markers are cross-sectionally and longitudinally associated with neuropsychological indicators of early ischemia and Alzheimer’s disease. Methods: Framingham Offspring Study participants, free of clinical stroke or dementia (n = 1,878; 60 ± 9 years; 54% women), underwent neuropsychological assessment and ascertainment of 11 inflammatory markers. Follow-up neuropsychological assessments (6.3 ± 1.0 years) were conducted on 1,352 of the original 1,878 participants. Results: Multivariable linear regression related the inflammatory markers to cross-sectional performance and longitudinal change in neuropsychological performances. Secondary models included a twelfth factor, tumor necrosis factor-α (TNF-α), available on a subset of the sample (n = 1,393 cross-sectional; n = 1,213 longitudinal). Results suggest a few modest cross-sectional inflammatory and neuropsychological associations, particularly for tests assessing visual organization (C-reactive protein, p = 0.007), and a few modest relations between inflammatory markers and neuropsychological change, particularly for executive functioning (TNF-α, p = 0.004). Secondary analyses suggested that inflammatory markers were cross-sectionally (TNF-α, p = 0.004) related to reading performance. Conclusions: Our findings are largely negative, but suggest that specific inflammatory markers may have limited associations with poorer cognition and reading performance among community-dwelling adults. Because of multiple testing concerns, our limited positive findings are offered as hypothesis generating and require replication in other studies.
Heat-Shock Proteins in Clinical Neurology
Authors: Romi Fredrik , Helgeland Geir , Gilhus Nils Erik
Published: July 2011

Heat-shock proteins (HSPs) are antigen-presenting protein-aggregation-preventing chaperones, induced by cellular stress in eukaryotic cells. In this review, we focus on recent HSP advances in neurological disorders. In myasthenia gravis, patients responding to immunosuppressive therapy have reduced serum HSP-71 antibodies. Generalized and ocular myasthenia gravis patients have elevated serum HSP-70 antibodies, indicating common pathogenic mechanisms. In Guillain-Barré syndrome, HSP-70 antibodies are elevated in serum and cerebrospinal fluid, and serum levels are higher than in myasthenia gravis and multiple sclerosis. In multiple sclerosis, serum HSP-27 antibodies are elevated during relapses providing disease activation marker, while α,β-crystallin expression in brain lesions indicates remission phase initiation. In acute stroke, serum HSP-27 antibodies are elevated irrespective of stroke type and duration. In epilepsy, HSP-27 is induced in patients’ astrocytes and cerebral blood vessel walls, and α,β-crystallin is expressed in epileptic foci. In neurodegenerative disorders such as Alzheimer dementia and Parkinson’s disease, HSPs are upregulated in brain tissue, and α,β-crystallin modulates superoxide dismutase-1 (SOD-1) tissue accumulation in familial amyotrophic lateral sclerosis. HSPs play an important role in antigen-presentation and tolerance development. Antibody-mediated interference with their function alters immune responses causing neuropathology. The role of HSPs in clinical neurology should be the subject of future investigation.