bluuebunny/crossref_metadata_2025 huggingface dataset:
Enhanced insulin sensitivity of gene-targeted mice lacking functional KCNQ1
Authors: Boini Krishna M. , Graf Dirk , Hennige Anita M. , Koka Saisudha , Kempe Daniela S. , Wang Kan , Ackermann Teresa F. , Föller Michael , Vallon Volker , Pfeifer Karl , Schleicher Erwin , Ullrich Susanne , Häring Hans-Ulrich , Häussinger Dieter , Lang Florian
Published: April 2009

The pore-forming K+-channel α-subunit KCNQ1 is expressed in a wide variety of tissues including heart, skeletal muscle, liver, and epithelia. Most recent evidence revealed an association of the KCNQ1 gene with the susceptibility to type 2 diabetes. KCNQ1 participates in the regulation of cell volume, which is, in turn, critically important for the regulation of metabolism by insulin. The present study explored the influence of KCNQ1 on insulin-induced cellular K+uptake and glucose metabolism. Insulin (100 nM)-induced K+uptake was determined in isolated perfused livers from KCNQ1-deficient mice ( kcnq1−/−) and their wild-type littermates ( kcnq1+/+). Moreover, plasma glucose and insulin levels, intraperitoneal glucose (3 g/kg) tolerance, insulin (0.15 U/kg)-induced hypoglycemia, and peripheral uptake of radiolabeled3H-deoxy-glucose were determined in both genotypes. Insulin-stimulated hepatocellular K+uptake was significantly more sustained in isolated perfused livers from kcnq1−/−mice than from kcnq1+/+mice. The decline of plasma glucose concentration following an intraperitoneal injection of insulin was again significantly more sustained in kcnq1−/−than in kcnq1+/+mice. Both fasted and nonfasted plasma glucose and insulin concentrations were significantly lower in kcnq1−/−than in kcnq1+/+mice. Following an intraperitoneal glucose injection, the peak plasma glucose concentration was significantly lower in kcnq1−/−than in kcnq1+/+mice. Uptake of3H-deoxy-glucose into skeletal muscle, liver, kidney and lung tissue was significantly higher in kcnq1−/−than in kcnq1+/+mice. In conclusion, KCNQ1 counteracts the stimulation of cellular K+uptake by insulin and thereby influences K+-dependent insulin signaling on glucose metabolism. The observations indicate that KCNQ1 is a novel molecule affecting insulin sensitivity of glucose metabolism.
Caveolin-1 directly interacts with UT-A1 urea transporter: the role of caveolae/lipid rafts in UT-A1 regulation at the cell membrane
Authors: Feng Xiuyan , Huang Haidong , Yang Yuan , Fröhlich Otto , Klein Janet D. , Sands Jeff M. , Chen Guangping
Published: April 2009

The cell plasma membrane contains specialized microdomains called lipid rafts which contain high amounts of sphingolipids and cholesterol. Lipid rafts are involved in a number of membrane protein functions. The urea transporter UT-A1, located in the kidney inner medullary collecting duct (IMCD), is important for urine concentrating ability. In this study, we investigated the possible role of lipid rafts in UT-A1 membrane regulation. Using sucrose gradient cell fractionation, we demonstrated that UT-A1 is concentrated in the caveolae-rich fraction both in stably expressing UT-A1 HEK293 cells and in freshly isolated kidney IMCD suspensions. In these gradients, UT-A1 at the cell plasma membrane is codistributed with caveolin-1, a major component of caveolae. The colocalization of UT-A1 in lipid rafts/caveolae was further confirmed in isolated caveolae from UT-A1-HEK293 cells. The direct association of UT-A1 and caveolin-1 was identified by immunoprecipitation and GST pull-down assay. Examination of internalized UT-A1 in pEGFP-UT-A1 transfected HEK293 cells fluorescent overlap with labeled cholera toxin subunit B, a marker of the caveolae-mediated endocytosis pathway. Disruption of lipid rafts by methyl-β-cyclodextrin or knocking down caveolin-1 by small-interference RNA resulted in UT-A1 cell membrane accumulation. Functionally, overexpression of caveolin-1 in oocytes decreased UT-A1 urea transport activity and UT-A1 cell surface expression. Our results indicate that lipid rafts/caveolae participate in UT-A1 membrane regulation and this effect is mediated via a direct interaction of caveolin-1 with UT-A1.
Ability of sat-1 to transport sulfate, bicarbonate, or oxalate under physiological conditions
Authors: Krick Wolfgang , Schnedler Nina , Burckhardt Gerhard , Burckhardt Birgitta C.
Published: April 2009

Tubular reabsorption of sulfate is achieved by the sodium-dependent sulfate transporter, NaSi-1, located at the apical membrane, and the sulfate-anion exchanger, sat-1, located at the basolateral membrane. To delineate the physiological role of rat sat-1, [35S]sulfate and [14C]oxalate uptake into sat-1-expressing oocytes was determined under various experimental conditions. Influx of [35S]sulfate was inhibited by bicarbonate, thiosulfate, sulfite, and oxalate, but not by sulfamate and sulfide, in a competitive manner with Kivalues of 2.7 ± 1.3 mM, 101.7 ± 9.7 μM, 53.8 ± 10.9 μM, and 63.5 ± 38.7 μM, respectively. Vice versa, [14C]oxalate uptake was inhibited by sulfate with a Kiof 85.9 ± 9.5 μM. The competitive type of inhibition indicates that these compounds are most likely substrates of sat-1. Physiological plasma bicarbonate concentrations (25 mM) reduced sulfate and oxalate uptake by more than 75%. Simultaneous application of sulfate, bicarbonate, and oxalate abolished sulfate as well as oxalate uptake. These data and electrophysiological studies using a two-electrode voltage-clamp device provide evidence that sat-1 preferentially works as an electroneutral sulfate-bicarbonate or oxalate-bicarbonate exchanger. In kidney proximal tubule cells, sat-1 likely completes sulfate reabsorption from the ultrafiltrate across the basolateral membrane in exchange for bicarbonate. In hepatocytes, oxalate extrusion is most probably mediated either by an exchange for sulfate or bicarbonate.
Ventilation-perfusion imbalance and chronic obstructive pulmonary disease staging severity
Authors: Rodríguez-Roisin Roberto , Drakulovic Mitra , Rodríguez Diego A. , Roca Josep , Barberà Joan Albert , Wagner Peter D.
Published: April 2009

Chronic obstructive pulmonary disease (COPD) is characterized by a decline in forced expiratory volume in 1 s (FEV1) and, in many advanced patients, by arterial hypoxemia with or without hypercapnia. Spirometric and gas exchange abnormalities have not been found to relate closely, but this may reflect a narrow range of severity in patients studied. Therefore, we assessed the relationship between pulmonary gas exchange and airflow limitation in patients with COPD across the severity spectrum. Ventilation-perfusion (V̇A/Q̇) mismatch was measured using the multiple inert gas elimination technique in 150 patients from previous studies. The distribution of patients according to the GOLD stage of COPD was: 15 with stage 1; 40 with stage 2; 32 with stage 3; and 63 with stage 4. In GOLD stage 1, AaPo2 and V̇A/Q̇ mismatch were clearly abnormal; thereafter, hypoxemia, AaPo2, and V̇A/Q̇ imbalance increased, but the changes from GOLD stages 1–4 were modest. Postbronchodilator FEV1 was related to PaO2 ( r = 0.62) and PaCO2 ( r = −0.59) and to overall V̇A/Q̇ heterogeneity ( r = −0.48) ( P < 0.001 each). Pulmonary gas exchange abnormalities in COPD are related to FEV1 across the spectrum of severity. V̇A/Q̇ imbalance, predominantly perfusion heterogeneity, is disproportionately greater than airflow limitation in GOLD stage 1, suggesting that COPD initially involves the smallest airways, parenchyma, and pulmonary vessels with minimal spirometric disturbances. That progression of V̇A/Q̇ inequality with spirometric severity is modest may reflect pathogenic processes that reduce both local ventilation and blood flow in the same regions through airway and alveolar disease and capillary involvement.
Organization of Color-Selective Neurons in Macaque Visual Area V4
Authors: Kotake Yasuyo , Morimoto Hiroshi , Okazaki Yasutaka , Fujita Ichiro , Tamura Hiroshi
Published: April 2009

Cortical area V4 in monkeys contains neurons that respond selectively to particular colors. It has been controversial how these color-selective neurons are spatially organized in V4. One view asserts that color-selective neurons are organized in columns with different colors orderly mapped across the cortex, whereas other studies have found no evidence for columnar organization or any other clustered structure. In the present study, we reexamined the functional organization of color-selective neurons in area V4 by quantitatively evaluating and comparing the color selectivity of nearby neurons as well as those encountered along electrode penetrations. Using a multiple single-unit recording technique, we recorded extracellular activities simultaneously from groups of nearby V4 neurons. Color discrimination and color preferences exhibited a moderate correlation between nearby neurons, consistent with neurons in a local region of V4 sharing similar responses to stimulus color. However, the degree of clustering was variable across recording sites. Some regions contained neurons with similar color preferences, whereas others contained neurons with diverse color preferences. Neurons in penetrations normal to the cortical surface responded to an overlapping range of colors and maintained a moderate correlation. Neurons in penetrations tangential to the cortical surface differed dramatically in their preferred color and exhibited a negative correlation. We conclude that neurons in area V4 are moderately clustered according to their color selectivity and that this weak clustering is columnar in structure.
Conceptual Binding: Integrated Visual Cues Reduce Processing Costs in Bimanual Movements
Authors: Wenderoth N. , Van Dooren M. , Vandebroek A. , De Vos J. , Vangheluwe S. , Stinear C. M. , Byblow W. D. , Swinnen S. P.
Published: April 2009

In discrete reaction time (RT) tasks, it has been shown that nonsymmetric bimanual movements are initiated slower than symmetric movements in response to symbolic cues. By contrast, no such RT differences are found in response to direct cues (“direct cue effect”). Here, we report three experiments showing that the direct cue effect generalizes to rhythmical bimanual movements and that RT cost depends on different cue features: 1) symbolic versus direct or 2) integrated (i.e., action of both hands is indicated as one entity) versus dissociated (i.e., action of each hand is indicated separately). Our main finding was that dissociated symbolic cues were most likely processed serially, resulting in the longest RTs, which were substantially reduced with integrated symbolic cues. However, extra RT costs for switching to nonsymmetrical bimanual movements were overcome only when the integrated cues were direct. We conclude that computational resources might have been exceeded when the response needs to be determined for each hand separately, but not when a common response for both hands is selected. This supports the idea that bimanual control benefits from conceptual binding.
Fire and Gas Barrier Properties of Poly(styrene-co-acrylonitrile) Nanocomposites Using Polycaprolactone/Clay Nanohybrid Based-Masterbatch
Authors: Benali S. , Olivier A. , Brocorens P. , Bonnaud L. , Alexandre M. , Bourbigot S. , Espuche E. , Gouanve F. , Lazzaroni R. , Dubois Ph.
Published: April 2009

Exfoliated nanocomposites are prepared by dispersion of poly(ε-caprolactone) (PCL) grafted montmorillonite nanohybrids used as masterbatches in poly(styrene-co-acrylonitrile) (SAN). The PCL-grafted clay nanohybrids with high inorganic content are synthesized by in situ intercalative ring-opening polymerization ofε-caprolactone between silicate layers organomodified by alkylammonium cations bearing two hydroxyl functions. The polymerization is initiated by tin alcoholate species derived from the exchange reaction of tin(II) bis(2-ethylhexanoate) with the hydroxyl groups borne by the ammonium cations that organomodified the clay. These highly filled PCL nanocomposites (25 wt% in inorganics) are dispersed as masterbatches in commercial poly(styrene-co-acrylonitrile) by melt blending. SAN-based nanocomposites containing 3 wt% of inorganics are accordingly prepared. The direct blend of SAN/organomodified clay is also prepared for sake of comparison. The clay dispersion is characterized by wide-angle X-ray diffraction (WAXD), atomic force microscopy (AFM), and solid state NMR spectroscopy measurements. The thermal properties are studied by thermogravimetric analysis. The flame retardancy and gas barrier resistance properties of nanocomposites are discussed both as a function of the clay dispersion and of the matrix/clay interaction.
Zinc Sulfide Tubes Reinforced with Carbon Nanofibers
Authors: Kolesnikov N. N. , Borisenko D. N. , Borisenko E. B. , Timonina A. V. , Kveder V. V.
Published: April 2009

Zinc sulfide submicron and nanotubes with outer diameters in the range from 100 to 1000 nm were produced through chemical deposition from vapor under argon pressure. The novel process provides formation of ZnS tubes reinforced with carbon nanofibers. This is the first time that the ZnS tubes are grown with fibers during deposition.
The Kinetics of Ampicillin Release from Hydroxyapatite for Bones Regeneration
Authors: da Silva Giovanilton Ferreira , Albuquerque José Sílvio Veras , de Oliveira Caroliny Gomes , Nogueira Ricardo Emilio Ferreira Quevedo , Ferreira Andrea Lopes de Oliveira
Published: April 2009

Semisynthetic beta-lactam antibiotics are among the most used pharmaceuticals. Their use in veterinary and human medicine is in continuous expansion. There is a growing need for developing bioactive implants. Advantages of implantable drug delivery tools can include high release efficiency, precise dose control, low toxicity, and allow to overcome disadvantages connected with conventional methods. In this respect, hydroxyapatite (HA) is an elective material. It enables to produce architectures similar to those of real bones. Here we studied a kinetic model to describe ampicillin release from HA. In the course of adsorption experiment, ampicillin was dissolved, maintained at and shaken at 60 strokes/minute. Samples were withdrawn periodically for analysis and then returned to the mixture. Adsorbed amounts were measured by the difference of the concentration of the antibiotics before and after adsorption using UV adsorption at 225 nm. The aim of this work was to evaluate its application as ampicillin delivery carrier.
Sensing of Ethanol with Nanosize Fe‐ZnO Thin Films
Authors: Kuo G.-H. , Wang H. Paul , Hsu H. H. , Wang James , Chiu Y. M. , Jou C.-J. G. , Hsu T. F. , Chen F.-L.
Published: April 2009

Sensing of ethanol with iron doped ZnO (Fe‐ZnO) thin films has been studied in this work. By X‐ray diffraction spectroscopy, it is found that ZnO is the main compound in the low‐iron
(<10%) doped ZnO thin films. ZnFe2O4 is also found as 20–50% of iron are doped on the thin films. The 5% Fe‐ZnO thin film has a very high sensitivity
(Rair/Rethanol > 70) to 1000 ppm of ethanol at 300 K. It seems that iron can promote the sensivity of the ZnO thin film. The thin film doped with a greater amount (20–50%) of iron has, however, a much less sensitivity (<15) to ethanol. The chemical interactions between oxygen of ethanol and zinc on the Fe‐ZnO thin film cause changes of the bond distances of Zn–O and Fe–O in the thin films to 1.90 and 1.98 Å which can be restored to 1.91 and 1.97 Å, respectively, in the absence of ethanol.
Screening for Residual Disease in Pediatric Burkitt Lymphoma Using Consensus Primer Pools
Authors: Agsalda Melissa , Kusao Ian , Troelstrup David , Shiramizu Bruce
Published: April 2009

Assessing molecular persistent or minimal residual disease (PD/MRD) in childhood Burkitt lymphoma (BL) is challenging because access to original tumor is usually needed to design patient-specific primers (PSPs). Because BL is characterized by rearranged immunoglobulin heavy chain (IgVH) genes,IgVHprimer pools fromIgVH1–IgVH7regions were tested to detect PD/MRD, thus eliminating the need for original tumor. The focus of the current study was to assess the feasibility of usingIgVHprimer pools to detect disease in clinical specimens. Fourteen children diagnosed with B-NHL had follow-up repository specimens available to assess PD/MRD. Of the 14 patients, 12 were PD/MRD negative after 2 months of therapy and remained in remission at the end of therapy; 2/14 patients were PD/MRD positive at 2-3 months and later relapsed. PSP-based assays from these 14 patients showed 100% concordance with the current assay. This feasibility study warrants further investigation to assess PD/MRD usingIgVHprimer pools, which could have clinical significance as a real-time assessment tool to monitor pediatric BL and possibly other B-cell non-Hodgkin lymphoma therapy.
Warranty Optimization in a Dynamic Environment
Authors: Dimitrov Nedialko B. , Chukova Stefanka
Published: April 2009

A product warranty is an agreement offered by a producer to a consumer
to replace or repair a faulty item, or to partially or fully reimburse
the consumer in the event of a failure. Warranties are very
widespread and serve many purposes, including protection for producer,
seller, and consumer. They are used as signals of quality and
as elements of marketing strategies. In this study we review the notion
of an online convex optimization algorithm and its variations,
and apply it in warranty context. We introduce a class of profit functions,
which are functions of warranty, and use it to formulate the
problem of maximizing the company's profit over time as an online
convex optimization problem. We use this formulation to present an
approach to setting the warranty based on an online algorithm with
low regret. Under a dynamic environment, this algorithm provides
a warranty strategy for the company that maximises its profit over
time.
Heart and Brain Tissue Banks for Research on Co-Occurring Cardiovascular and Neurological/Psychiatric Disorders
Authors: Ikonomovic Milos D.
Published: April 2009

Epidemiological studies point to a strong and possibly causal association of psychiatric and neurological disorders with cardiovascular disease (CVD). Mechanistic links between these co-occurring illnesses are not well understood. Better insight into their relationship could help identify novel diagnostic markers and therapeutic targets. For successful translation of basic biomedical research into clinical practice, analyses
of postmortem human tissues are essential. However, current tissue banks dedicated to psychiatric and neurological research collect only brain tissue samples
deemed most important to the institution's participating investigators. While this practice is often dictated by budget constraints, restricted tissue storage space and other practical reasons, it limits the ability of the biological research community to access and study multiple organ systems relevant to cardiovascular and neuronal systems dysfunction. This problem is worsened when clinical records pertaining to coexistent systemic pathology are not available. To promote further understanding of co-occurring CVD and psychiatric/neurological disorders, efforts should be made to support tissue banks that harvest heart, coronary arteries, and aorta samples as well as brain tissue, from the same subjects.
Strong Convergence Theorems for Countable Lipschitzian Mappings and Its Applications in Equilibrium and Optimization Problems
Authors: Yang Liping , Su Yongfu
Published: April 2009

The purpose of this paper is to propose a modified hybrid method in mathematical programming and to obtain some strong convergence theorems for common fixed points of a countable family of Lipschitzian mappings. Further, we apply our results to solve the equilibrium and optimization problems. The results of this paper improved and extended the results of W. Nilsrakoo and S. Saejung (2008) and some others in some respects.
A Nest of LTR Retrotransposons Adjacent the Disease Resistance‐Priming Gene NPR1 in Beta vulgaris L. U.S. Hybrid H20
Authors: Kuykendall David , Shao Jonathan , Trimmer Kenneth
Published: April 2009

A nest of long terminal repeat (LTR) retrotransposons (RTRs), discovered by LTR_STRUC analysis, is near core genes encoding the NPR1 disease resistance‐activating factor and a
heat‐shock‐factor‐(HSF‐) like protein in sugarbeet hybrid US H20. SCHULTE, a 10 833 bp LTR retrotransposon, with 1372 bp LTRs that are 0.7% divergent, has two ORFs with unexpected introns but encoding a reverse transcriptase with rve and Rvt2 domains similar to Ty1/copia‐type retrotransposons and a hypothetical protein. SCHULTE produced significant nucleotide BLAST alignments with repeat DNA elements from all four families of plants represented in the TIGR plant repeat database (PRD); the best nucleotide sequence alignment was to ToRTL1 in Lycopersicon esculentum. A second sugarbeet LTR retrotransposon, SCHMIDT, 11 565 bp in length, has 2561 bp LTRs that share 100% identity with each other and share 98‐99% nucleotide sequence identity over 10% of their length with DRVs, a family of highly repetitive, relatively small DNA sequences that are widely dispersed over the sugarbeet genome. SCHMIDT encodes a complete gypsy‐like polyprotein in a single ORF. Analysis using LTR_STRUC of an in silico deletion of both of the above two LTR retrotransposons found that SCHULTE and SCHMIDT had inserted within an older LTR retrotransposon, resulting in a nest that is only about 10 Kb upstream of NPR1 in sugarbeet hybrid US H20.
Sunflower Array Antenna with Adjustable Density Taper
Authors: Viganó Maria Carolina , Toso Giovanni , Caille Gerard , Mangenot Cyril , Lager Ioan E.
Published: April 2009

A deterministic procedure to design a nonperiodic planar array radiating a rotationally symmetric pencil beam pattern with an adjustable sidelobe level is proposed. The elements positions are derived by modifying the peculiar locations of the sunflower seeds in such a way that the corresponding spatial density fits a Taylor amplitude tapering law which guarantees the pattern requirements in terms of beamwidth and sidelobe level. Different configurations, based on a Voronoi cell spatial tessellation of the radiative aperture, are presented, having as a benchmark the requirements for a typical multibeam satellite antenna.
Production of Antibodies against Multipass Membrane Proteins Expressed in Human Tumor Cells Using Dendritic Cell Immunization
Authors: Tamura Takahiko , Chiba Joe
Published: April 2009

Antibody mediated therapeutic strategies against human malignant tumors have been widely authorized and clinically applied to cancer patients. In order to develop methods to generate antibodies reactive to the extracellular domains of multipass plasma membrane proteins specifically expressed in malignant tumors, we examined the use of dendritic cells (DCs) for immunization. DCs were transduced with genes encoding the human six transmembrane epithelial antigen of prostate 1 (STEAP1), STEAP4, and seven transmembrane prostate specific G‐protein coupled receptor (PSGR). Mice were immunized with these DCs and followed by repeated booster immunization with plasmids expressing each protein. The immunized mice produced significant amounts of antibodies against these proteins. Our results suggest that DC immunization is an effective method to produce antibodies reactive to extracellular regions of plasma membrane proteins with multiple‐transmembrane domains, and may be useful to develop antibody mediated antitumor therapies.
The Metal Chelators, Trientine and Citrate, Inhibit the Development of Cardiac Pathology in the Zucker Diabetic Rat
Authors: Baynes John W. , Murray David B.
Published: April 2009

Purpose. The objective of this study was to determine the efficacy of dietary supplementation with the metal chelators, trientine or citric acid, in preventing the development of cardiomyopathy in the Zucker diabetic rat.Hypothesis. We hypothesized that dietary chelators would attenuate metal-catalyzed oxidative stress and damage in tissues and protect against pathological changes in ventricular structure and function in type II diabetes.Methods. Animals (10 weeks old) included lean control (LC,fa/+), untreated Zucker diabetic fatty (ZDF,fa/fa), and ZDF rats treated with either trientine (triethylenetetramine) or citrate at 20 mg/d in drinking water, starting when rats were frankly diabetic. Cardiac functional assessment was determined using a Millar pressure/volume catheter placed in the left ventricle at 32 weeks of age.Results. End diastolic volume for the ZDF animals increased by 36% indicating LV dilatation (P<.05) and was accompanied by a 30% increase in the end diastolic pressure (P≤.05). Both trientine and citric acid prevented the increases in EDV and EDP (P<.05). Ejection fraction and myocardial relaxation were also significantly improved with chelator treatment.Conclusion. Dietary supplementation with trientine and citric acid significantly prevented structural and functional changes in the diabetic heart, supporting the merits of mild chelators for prevention of cardiovascular disease in diabetes.
Weight History, Smoking, Physical Activity and Breast Cancer Risk among French-Canadian Women Non-Carriers of More FrequentBRCA1/2Mutations
Authors: Bissonauth Vishnee , Shatenstein Bryna , Fafard Eve , Maugard Christine , Robidoux André , Narod Steven , Ghadirian Parviz
Published: April 2009

Several lifestyle factors play a significant role in determining an individual's risk of breast cancer. Many of them could be modified to protect against the malignancy. A nested case-control study was conducted to examine the association between selected lifestyle factors and non-BRCA-related breast cancer risk among French-Canadian women. Some 280 women with breast cancer and who were nongene carriers of mutatedBRCAgene were recruited as cases. Another 280 women, without any cancer and nongene carriers of mutatedBRCAgene served as controls. A tested lifestyle questionnaire was interviewer administered to incident cases to obtain information on weight history, smoking, physical activity, and other lifestyle risk factors. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated in logistic regression models. Comparing cases to controls, breast cancer risk was higher among subjects who reached their maximum body mass index (BMI) at an older age (>50 years) (OR=2.83; 95% CI: 2.34–2.91). A positive association was noted between breast cancer risk and weight gain of>34 lbs compared to weight gain of≤15 lbs, since the age of 20 (OR=1.68; 95% CI: 1.10–2.58). Weight gain of>24 lbs compared to weight gain of≤9 lbs, since the age of 30 also resulted in the same relationship (OR=1.96; 95% CI: 1.46–3.06). Similarly, since the age of 40, weight gain of>12 lbs compared to weight gain of≤1 lb was associated with increased breast cancer risk (OR=1.91; 95% CI: 1.53–2.66). Women who smoked>9 pack-years of cigarettes had a 59% higher breast cancer risk (P=.05). Subjects who engaged in>24.8 metabolic-equivalent- (MET-) hours per week compared to≤10.7 MET-hours per week of moderate physical activity had a 52% (P=.01) decreased risk and total physical activity between 16.2 and 33.2 MET-hours per week compared to≤16.2 MET-hours per week, resulted in a 43% (P=.05) lower risk of breast cancer. In conclusion, weight history did affect breast cancer risk. Moreover, smoking appeared to raise the risk, whereas moderate physical activity had a protective effect.
Periodic Solutions for a System of Difference Equations
Authors: Kang Shugui , Shi Bao
Published: April 2009

This paper deals with the second‐order nonlinear systems of difference equations, we obtain the existence theorems of periodic solutions. The theorems are proved by using critical point theory.
Modulation of CXC Chemokine Receptor Expression and Function in Human Neutrophils during Aging In Vitro Suggests a Role in Their Clearance from Circulation
Authors: Weisel Katja C. , Bautz Frank , Seitz Gabriele , Yildirim Sedat , Kanz Lothar , Möhle Robert
Published: April 2009

In mice, differential regulation of CXC chemokine receptor expression in circulating polymorphonuclear neutrophils (PMNs) undergoing senescence results in homing to the bone marrow. However, the role of this compartment and of the chemokine receptor CXCR4 is still under discussion, and only scarce data exist about CXCR4 function in human PMN. In our study, we provide evidence that also in human neutrophils, expression (cell surface and mRNA), chemotactic and signaling functions of the homing-related chemokine receptor CXCR4 are upregulated during aging in vitro, independent of addition of stimulatory cytokines (TNF, IL-1, IL-8, G-CSF). In contrast, interleukin-8 receptors are downmodulated (CXCR2) or remain unchanged (CXCR1), suggesting that human PMNs undergoing senescence acquire a phenotype that impairs inflammatory extravasation and favors homing to the bone marrow or other tissues involved in sequestration. Partially retained responsiveness to interleukin-8 may be important for neutrophil function when senescence occurs after extravasation in inflamed tissues.
Labor Augmentation with Oxytocin Decreases Glutathione Level
Authors: Schneid-Kofman Naomi , Silberstein Tali , Saphier Oshra , Shai Iris , Tavor Dorith , Burg Ariela
Published: April 2009

Objective. To compare oxidative stress following spontaneous vaginal delivery with that induced by Oxytocin augmented delivery.Methods. 98 women recruited prior to labor. 57 delivered spontaneously, while 41 received Oxytocin for augmentation of labor. Complicated deliveries and high-risk pregnancies were excluded. Informed consent was documented. Arterial cord blood gases, levels of Hematocrit, Hemoglobin, and Bilirubin were studied. Glutathione (GSH) concentration was measured by a spectroscopic method. Plasma and red blood cell (RBC) levels of Malondialdehyde indicated lipid peroxidation. RBC uptake of phenol red denoted cell penetrability. SPSS data analysis was used.Results. Cord blood GSH was significantly lower in the Oxytocin group ( mM versus  mM, ). No differences were found in plasma or RBC levels of MDA or in uptake of Phenol red between the groups.Conclusion. Lower GSH levels following Oxytocin augmentation indicate an oxidative stress, though selected measures of oxidative stress demonstrate no cell damage.
Impact of Hepatitis B Exposure on Sustained Virological Response Rates of Highly Viremic Chronic Hepatitis C Patients
Authors: Elefsiniotis Ioannis S. , Pavlidis Christos , Vezali Elena , Mariolis-Sapsakos Theodoros , Koutsounas Sotirios , Saroglou George
Published: April 2009

Aim. To evaluate the impact of hepatitis B core antibody (anti-HBc) seropositivity in sustained virological response (SVR) rates in treatment-naïve, chronic hepatitis C (CHC) patients with high pretreatment viral load (>800000 IU/mL).Methods. 185 consecutive CHC patients (14.4% cirrhotics, 70.2% prior intravenous drug users) treated with pegylated interferon-a2b plus ribavirin, for 24 or 48 weeks based on viral genotype, were retrospectively analyzed. SVR was confirmed by undetectable serum HCV-RNA six months after the end of treatment schedule.Results. Thirty percent of CHC/HBsAg-negative patients were anti-HBc-positive. Anti-HBc positivity was more prevalent in cirrhotic, compared to noncirrhotic patients (76.9% versus 19.5%,P<.05). Serum HBV-DNA was detected in the minority of anti-HBc-positive patients (1.97%). Overall, 62.1% of patients exhibited SVR, while 28.6% did not; 71.4% of non-SVRs were infected with genotype 1. In the univariate analysis, the anti-HBc positivity was negatively associated with treatment outcome (P=.065). In the multivariate model, only the advanced stage of liver disease (P=.015) and genotype-1 HCV infection (P=.003), but not anti-HBc-status (P=.726), proved to be independent predictors of non-SVR.Conclusion. Serum anti-HBc positivity does not affect the SVR rates in treatment-naïve CHC patients with high pretreatment viral load, receiving the currently approved combination treatment.
Brown Tumour in a Patient with Secondary Hyperparathyroidism Resistant to Medical Therapy: Case Report on Successful Treatment after Subtotal Parathyroidectomy
Authors: Di Daniele Nicola , Condò Stefano , Ferrannini Michele , Bertoli Marta , Rovella Valentina , Di Renzo Laura , De Lorenzo Antonino
Published: April 2009

Brown tumour represents a serious complication of hyperparathyroidism.
Differential diagnosis, based on histological examination, is only presumptive and clinical, radiological and laboratory data are necessary for definitive diagnosis. Here we describe a case of a brown tumour localised in the maxilla due to secondary hyperparathyroidism in a young women with chronic renal failure. Hemodialysis and pharmacological treatment were unsuccessful in controlling secondary hyperparathyroidism making it necessary to proceed with a subtotal parathyroidectomy. The proper timing of the parathyroidectomy and its favourable effect on regression of the brown tumor made it possible to avoid a potentially disfiguring surgical removal of the brown tumor.
PPAR and Liver Injury in HIV‐Infected Patients
Authors: Lemoine Maud , Capeau Jacqueline , Serfaty Lawrence
Published: April 2009

Due to the introduction of active HIV antiretroviral treatment, AIDS‐related morbidity
and mortality have markedly decreased and liver diseases are now a major cause of morbidity and mortality in HIV‐infected patients. Chronic liver injury encompasses a wide spectrum of diseases due to HCV and HBV coinfection, drug‐related toxicity, and NASH. HIV‐infected patients who are receiving treatment present with a high prevalence of metabolic complications and lipodystrophy. Those patients are at high risk of nonalcoholic fatty liver disease, the liver feature of the metabolic syndrome. This review will focus on (1) the liver injuries in HIV‐infected patients; (2) both the current experimental and human data regarding PPAR and liver diseases; (3) the interactions between HIV and PPAR; (4) the potential use of PPAR agonists for the management of HIV‐related liver diseases.
Chromatin-associated proteins HMGB1/2 and PDIA3 trigger cellular response to chemotherapy-induced DNA damage
Authors: Krynetskaia Natalia F. , Phadke Manali S. , Jadhav Sachin H. , Krynetskiy Evgeny Y.
Published: April 2009

The identification of new molecular components of the DNA damage signaling cascade opens novel avenues to enhance the efficacy of chemotherapeutic drugs. High-mobility group protein 1 (HMGB1) is a DNA damage sensor responsive to the incorporation of nonnatural nucleosides into DNA; several nuclear and cytosolic proteins are functionally integrated with HMGB1 in the context of DNA damage response. The functional role of HMGB1 and HMGB1-associated proteins (high-mobility group protein B2, HMGB2; glyceraldehyde-3-phosphate dehydrogenase, GAPDH; protein disulfide isomerase family A member 3, PDIA3; and heat shock 70 kDa protein 8, HSPA8) in DNA damage response was assessed in human carcinoma cells A549 and UO31 by transient knockdown with short interfering RNAs. Using the cell proliferation assay, we found that knockdown of HMGB1-associated proteins resulted in 8-fold to 50-fold decreased chemosensitivity of A549 cells to cytarabine. Western blot analysis and immunofluorescent microscopy were used to evaluate genotoxic stress markers in knocked-down cancer cells after 24 to 72 hours of incubation with 1 μmol/L of cytarabine. Our results dissect the roles of HMGB1-associated proteins in DNA damage response: HMGB1 and HMGB2 facilitate p53 phosphorylation after exposure to genotoxic stress, and PDIA3 has been found essential for H2AX phosphorylation (no γ-H2AX accumulated after 24–72 hours of incubation with 1 μmol/L of cytarabine in PDIA3 knockdown cells). We conclude that phosphorylation of p53 and phosphorylation of H2AX occur in two distinct branches of the DNA damage response. These findings identify new molecular components of the DNA damage signaling cascade and provide novel promising targets for chemotherapeutic intervention.[Mol Cancer Ther 2009;8(4):864–72]
Tautomycetin and tautomycin suppress the growth of medullary thyroid cancer cells via inhibition of glycogen synthase kinase-3β
Authors: Adler Joel T. , Cook Mackenzie , Luo Yinggang , Pitt Susan C. , Ju Jianhua , Li Wenli , Shen Ben , Kunnimalaiyaan Muthusamy , Chen Herbert
Published: April 2009

Medullary thyroid cancer (MTC) is a relatively uncommon neuroendocrine tumor that arises from the calcitonin-secreting parafollicular cells of the thyroid gland. Unfortunately, MTC frequently metastasizes, precluding curative surgical resection and causing significant morbidity. Thus, there is an urgent need for new treatment modalities. Tautomycin and tautomycetin are antifungal antibiotics isolated from Streptomyces spiroverticillatus and Streptomyces griseochromogens, respectively. Glycogen synthase kinase-3β is a serine/threonine protein kinase that regulates multiple cellular processes and is important in various cancers, including MTC. Treatment with tautomycin and tautomycetin decreased neuroendocrine markers, suppressed hormonal secretion, and inhibited growth through apoptosis in MTC cells. Importantly, we describe a novel action of these compounds: inhibition of glycogen synthase kinase-3β.[Mol Cancer Ther 2009;8(4):914–20]
The Aurora kinase inhibitor SNS-314 shows broad therapeutic potential with chemotherapeutics and synergy with microtubule-targeted agents in a colon carcinoma model
Authors: VanderPorten Erica C. , Taverna Pietro , Hogan Jennifer N. , Ballinger Marcus D. , Flanagan W. Michael , Fucini Raymond V.
Published: April 2009

Aurora kinases play key roles in regulating centrosome maturation, mitotic spindle formation, and cytokinesis during cell division, and are considered promising drug targets due to their frequent overexpression in a variety of human cancers. SNS-314 is a selective and potent pan Aurora inhibitor currently in a dose escalation phase 1 clinical trial for the treatment of patients with advanced solid tumors. Here, we report the antiproliferative effects of SNS-314 in combination with common chemotherapeutics in cell culture and xenograft models. The HCT116 colorectal carcinoma cell line, with intact or depleted p53 protein levels, was treated with SNS-314 and a cytotoxic chemotherapeutic from a panel comprised of gemcitabine, 5-fluorouracil (5-FU), carboplatin, daunomycin, SN-38 (the active metabolite of irinotecan), docetaxel, and vincristine. Combinations were administered under either concurrent or sequential schedules. SNS-314 has predominantly additive effects when administered concurrently with commonly used anticancer agents. Sequential administration of SNS-314 with chemotherapeutic compounds showed additive antiproliferative effects with carboplatin, gemcitabine, 5-FU, daunomycin, and SN-38, and synergy was observed in combination with gemcitabine, docetaxel, or vincristine. The most profound antiproliferative effects were observed with sequential administration of SNS-314 followed by docetaxel or vincristine. In vivo, SNS-314 potentiated the antitumor activity of docetaxel in xenografts. Both the in vitro synergies observed between SNS-314 and agents that target the mitotic spindle and the potentiation seen with docetaxel in vivo are consistent with a mechanism of action in which Aurora inhibition bypasses the mitotic spindle assembly checkpoint and prevents cytokinesis, augmenting subsequent spindle toxin–mediated mitotic catastrophe and cell death. [Mol Cancer Ther 2009;8(4):930–9]
Local enzymatic hydrolysis of an endogenously generated metabolite can enhance CPT-11 anticancer efficacy
Authors: Prijovich Zeljko M. , Chen Kai-Chuan , Roffler Steve R.
Published: April 2009

Irinotecan (CPT-11) is a clinically important anticancer prodrug that requires enzymatic hydrolysis by carboxyesterase to generate the active metabolite SN-38. However, SN-38 is further metabolized to inactive SN-38 glucuronide (SN-38G), thus diminishing the levels of active SN-38. Although exogenously administered glucuronide drugs are being investigated for cancer therapy, it is unknown if endogenously generated camptothecin glucuronide metabolites can be used for tumor therapy. Here, we tested the hypothesis that tumor-located hydrolysis of endogenously generated SN-38G can enhance the antitumor efficacy of CPT-11 therapy. EJ human bladder carcinoma cells expressing membrane-tethered β-glucuronidase (EJ/mβG cells) were used to selectively hydrolyze SN-38G to SN-38. Parental EJ and EJ/mβG cells displayed similar in vitro and in vivo growth rates and sensitivities to CPT-11 and SN-38. By contrast, EJ/mβG cells were more than 30 times more sensitive than EJ cells to SN-38G, showing that SN-38 could be generated from SN-38G in vitro. Systemic administration of CPT-11 resulted in tumor-located hydrolysis of SN-38G and accumulation of SN-38 in EJ/mβG subcutaneous tumors. Importantly, systemic administration of CPT-11, which itself is not a substrate for β-glucuronidase, dramatically delayed the growth of EJ/mβG xenografts without increased systemic toxicity. Thus, the anticancer activity of CPT-11 can be significantly enhanced by converting the relatively high levels of endogenously generated SN-38G to SN-38 in tumors. The high concentrations of SN-38G found in the serum of patients treated with CPT-11 suggest that clinical response to CPT-11 may be improved by elevating β-glucuronidase activity in tumors. [Mol Cancer Ther 2009;8(4):940–6]
DNA fingerprinting of the NCI-60 cell line panel
Authors: Lorenzi Philip L. , Reinhold William C. , Varma Sudhir , Hutchinson Amy A. , Pommier Yves , Chanock Stephen J. , Weinstein John N.
Published: April 2009

The National Cancer Institute's NCI-60 cell line panel, the most extensively characterized set of cells in existence and a public resource, is frequently used as a screening tool for drug discovery. Because many laboratories around the world rely on data from the NCI-60 cells, confirmation of their genetic identities represents an essential step in validating results from them. Given the consequences of cell line contamination or misidentification, quality control measures should routinely include DNA fingerprinting. We have, therefore, used standard DNA microsatellite short tandem repeats to profile the NCI-60, and the resulting DNA fingerprints are provided here as a reference. Consistent with previous reports, the fingerprints suggest that several NCI-60 lines have common origins: the melanoma lines MDA-MB-435, MDA-N, and M14; the central nervous system lines U251 and SNB-19; the ovarian lines OVCAR-8 and OVCAR-8/ADR (also called NCI/ADR); and the prostate lines DU-145, DU-145 (ATCC), and RC0.1. Those lines also show that the ability to connect two fingerprints to the same origin is not affected by stable transfection or by the development of multidrug resistance. As expected, DNA fingerprints were not able to distinguish different tissues-of-origin. The fingerprints serve principally as a barcodes.[Mol Cancer Ther 2009;8(4):713–24]
Apogossypol derivatives as antagonists of antiapoptotic Bcl-2 family proteins
Authors: Wei Jun , Kitada Shinichi , Rega Michele F. , Emdadi Aras , Yuan Hongbin , Cellitti Jason , Stebbins John L. , Zhai Dayong , Sun Jiazhi , Yang Li , Dahl Russell , Zhang Ziming , Wu Bainan , Wang Si , Reed Tyler A. , Lawrence Nicholas , Sebti Said , Reed John C. , Pellecchia Maurizio
Published: April 2009

Guided by a combination of nuclear magnetic resonance binding assays and computational docking studies, we synthesized a library of 5,5′ substituted Apogossypol derivatives as potent Bcl-XL antagonists. Each compound was subsequently tested for its ability to inhibit Bcl-XL in an in vitro fluorescence polarization competition assay and exert single-agent proapoptotic activity in human cancer cell lines. The most potent compound BI79D10 binds to Bcl-XL, Bcl-2, and Mcl-1 with IC50 values of 190, 360, and 520 nmol/L, respectively, and potently inhibits cell growth in the H460 human lung cancer cell line with an EC50 value of 680 nmol/L, expressing high levels of Bcl-2. BI79D10 also effectively induces apoptosis of the RS11846 human lymphoma cell line in a dose-dependent manner and shows little cytotoxicity against bax−/−bak−/− mouse embryonic fibroblast cells, in which antiapoptotic Bcl-2 family proteins lack a cytoprotective phenotype, implying that BI79D10 has little off-target effects. BI79D10 displays in vivo efficacy in transgenic mice, in which Bcl-2 is overexpressed in splenic B cells. Together with its improved plasma and microsomal stability relative to Apogossypol, BI79D10 represents a lead compound for the development of novel apoptosis-based therapies for cancer. [Mol Cancer Ther 2009;8(4):904–13]
Valproic acid causes dose- and time-dependent changes in nuclear structure in prostate cancer cellsin vitroandin vivo
Authors: Kortenhorst Madeleine S.Q. , Isharwal Sumit , van Diest Paul J. , Chowdhury Wasim H. , Marlow Cameron , Carducci Michael A. , Rodriguez Ronald , Veltri Robert W.
Published: April 2009

Histone deacetylase inhibitors such as valproic acid (VPA) are promising anticancer agents that change the acetylation status of histones and loosen the chromatin structure. We assessed nuclear structure changes induced by VPA in prostate cancer LNCaP, CWR22R, DU145, and PC3 cell lines and xenografts and their potential use as a biomarker of treatment. In vitro tissue microarrays consisted of prostate cancer cell lines treated for 3, 7, or 14 days with 0, 0.6, or 1.2 mmol/L VPA. In vivo tissue microarrays consisted of cores from prostate cancer xenografts from nude mice treated for 30 days with 0.2% or 0.4% VPA in drinking water. Digital images of at least 200 Feulgen DNA-stained nuclei were captured using the Nikon CoolScope and nuclear alterations were measured. With a set of seven most frequently significant nuclear alterations (determined by univariate logistic regression analysis), control and VPA treatment nuclei were compared in vitro and in vivo. Depending on the cell line, area under the curve-receiver operating characteristics ranged between 0.6 and 0.9 and were dose- and time-dependent both in vitro and in vivo. Also, VPA treatment caused significant nuclear alterations in normal drug-filtering organs (liver and kidney tissue). In vitro and in vivo VPA treatment of prostate cancer cell lines results in significant dose- and time-dependent changes in nuclear structure. Further, VPA induces nuclear structural changes in normal liver and kidney tissue, which likely reflects a natural physiologic response. Therefore, nuclear structural alterations may serve as a biomarker for histone deacetylase inhibitor treatment. [Mol Cancer Ther 2009;8(4):802–8]
TW-37, a small-molecule inhibitor of Bcl-2, mediates S-phase cell cycle arrest and suppresses head and neck tumor angiogenesis
Authors: Ashimori Naoki , Zeitlin Benjamin D. , Zhang Zhaocheng , Warner Kristy , Turkienicz Ilan M. , Spalding Aaron C. , Teknos Theodoros N. , Wang Shaomeng , Nör Jacques E.
Published: April 2009

Members of the Bcl-2 family play a major role in the pathobiology of head and neck cancer. We have shown that Bcl-2 orchestrates a cross talk between tumor cells and endothelial cells that have a direct effect on the progression of head and neck squamous cell carcinoma (HNSCC). Notably, Bcl-2 is significantly up-regulated in the tumor-associated endothelial cells compared with the endothelial cells of normal oral mucosa in patients with HNSCC. Here, we evaluated the effect of TW-37, a small-molecule inhibitor of Bcl-2, on the cell cycle and survival of endothelial cells and HNSCC and on the progression of xenografted tumors. TW-37 has an IC50 of 1.1 μmol/L for primary human endothelial cells and averaged 0.3 μmol/L for head and neck cancer cells (OSCC3, UM-SCC-1, and UM-SCC-74A). The combination of TW-37 and cisplatin showed enhanced cytotoxic effects for endothelial cells and HNSCC in vitro, compared with single drug treatment. Notably, whereas cisplatin led to an expected G2-M cell cycle arrest, TW-37 mediated an S-phase cell cycle arrest in endothelial cells and in HNSCC. In vivo, TW-37 inhibited tumor angiogenesis and induced tumor apoptosis without significant systemic toxicities. Combination of TW-37 and cisplatin enhanced the time to tumor failure (i.e., 4-fold increase in tumor volume), compared with either drug given separately. Collectively, these data reveal that therapeutic inhibition of Bcl-2 function with TW-37 is sufficient to arrest endothelial cells and HNSCC in the S phase of the cell cycle and to inhibit head and neck tumor angiogenesis.[Mol Cancer Ther 2009;8(4):893–903]