bluuebunny/crossref_metadata_2025 huggingface dataset:
Association between plasma omega-3 fatty acids and cardiovascular disease risk factors
Authors: Garneau Véronique , Rudkowska Iwona , Paradis Ann-Marie , Godin Gaston , Julien Pierre , Pérusse Louis , Vohl Marie-Claude
Published: November 2012

The consumption of omega-3 (n-3) fatty acids (FA), namely eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), have been linked to reduced cardiovascular disease (CVD) risk. The objective of this study was to examine the relation between n-3 FA in plasma phospholipid (PL) levels and CVD risk factors. n-3 FA levels in plasma PL were determined using gas chromatography in 100 obese (body mass index (BMI), ≥30 kg·m−2) and 100 nonobese selected individuals from the Quebec City metropolitan area. The CVD risk factors analysed were BMI, blood pressure, plasma lipids levels, and fasting plasma glucose. Significantly higher levels of alpha-linolenic acid (ALA) and docosapentaenoic acid (DPA) were observed in obese subjects, whereas significantly higher levels of DHA were observed in nonobese subjects. For CVD risk factors, ALA levels were positively correlated with plasma triglyceride concentrations and negatively associated with diastolic blood pressure. None of the CVD risk factors studied was linked to EPA levels. In addition, DPA was negatively related to high-density lipoprotein cholesterol (HDL-C) and positively correlated with the total cholesterol/HDL-C ratio. DHA levels were negatively correlated with BMI, waist circumference, and plasma triglyceride levels, whereas a positive association was observed with HDL-C levels. Total n-3 FA percentages were negatively correlated with BMI. In conclusion, higher DHA percentages in plasma PL are associated with a more favourable CVD risk profile, whereas higher DPA percentages in plasma PL are associated with a more deteriorated CVD risk profile.
Assessment of energy expenditure in elite jockeys during simulated race riding and a working day: implications for making weight
Authors: Wilson George , Sparks S. Andy , Drust Barry , Morton James P. , Close Graeme L.
Published: November 2012

Professional jockeys are unique amongst weight-making athletes in that they are required to make weight on a daily basis by often using potentially hazardous methods, such as food deprivation, dehydration, and forced vomiting. To allow the prescription of accurate energy intake (EI), it is essential to understand the energy requirements of jockeys; however, these data are currently not known. Therefore, we measured the energy expenditure (EE) of professional jockeys during a simulated race ride and for a working day (nonracing) that involved typical stable duties. The accuracy of 2 portable lightweight devices, the Polar RS400 commercial heart rate monitor (CHRM) and the Actiheart monitor (AH) were initially assessed during 30 min of exercise compared with respiratory gas analysis (GA) (n = 9). No significant difference was observed (p > 0.05) and 95% limits of agreement analysis (LoA) showed that CHRM was more closely related to GA (bias: –0.015; LoA: –0.049, +0.019 MJ) than AH (bias: –0.007; LoA: –0.073, +0.059 MJ). A laboratory-based 2-mile (3.2-km) racing protocol was created and EE was assessed using CHRM, GA, and AH. We report that a typical race expends 0.18 (SD ±0.03) MJ. Finally, in a separate group of jockeys (n = 8), 24-h EE was assessed using CHRM. The mean (±SD) EE for a typical day was 11.26 (±1.49) MJ. Additionally, we measured EI using 7-day self-reporting food record diaries. Mean EI was 7.24 (±0.92) MJ, largely consumed as 2 main meals. These data provide a platform to implement dietary strategies that create appropriate weight-loss targets and therefore improve the physical and mental well-being of professional jockeys.
Raman microspectroscopy as a diagnostic tool to study single living nasopharyngeal carcinoma cell lines
Authors: Li Zuanfang , Chen Yang , Li Yongzeng , Chen Weiwei , Pan Jianji , Su Ying , Zou Changyan
Published: November 2012

Raman spectroscopy can provide molecular-level fingerprint information about the biochemical composition and structure of cells and tissues with excellent spatial resolution. In this study, Raman spectroscopy of 3 different nasopharyngeal carcinoma cell lines C666-1, CNE1, and CNE2 and 1 nasopharyngeal normal cell line NP69 acquired on a piece of silica glass slide are presented to investigate the differences among them. The results show the ratio of I1657/I1449 (= 0.7) could provide good distinction between tumor and normal cell lines very easily, which coincides with existing reports about the study of different cell lines and bronchial tissue. In addition, several statistical analytical methods were used to classify these 4 different cell lines and then achieved an exciting result with great sensitivity and specificity of >90%, respectively. The findings of this work further support former work where cells' Raman spectra were acquired on a different substrate. All of these results indicate Raman spectroscopy has the potential to discriminate between normal and tumor cells and have potential use in early diagnosis of nasopharyngeal carcinoma.
XRCC4 and XLF form long helical protein filaments suitable for DNA end protection and alignment to facilitate DNA double strand break repair
Authors: Mahaney Brandi L. , Hammel Michal , Meek Katheryn , Tainer John A. , Lees-Miller Susan P.
Published: November 2012

DNA double strand breaks (DSBs), induced by ionizing radiation (IR) and endogenous stress including replication failure, are the most cytotoxic form of DNA damage. In human cells, most IR-induced DSBs are repaired by the nonhomologous end joining (NHEJ) pathway. One of the most critical steps in NHEJ is ligation of DNA ends by DNA ligase IV (LIG4), which interacts with, and is stabilized by, the scaffolding protein X-ray cross-complementing gene 4 (XRCC4). XRCC4 also interacts with XRCC4-like factor (XLF, also called Cernunnos); yet, XLF has been one of the least mechanistically understood proteins and precisely how XLF functions in NHEJ has been enigmatic. Here, we examine current combined structural and mutational findings that uncover integrated functions of XRCC4 and XLF and reveal their interactions to form long, helical protein filaments suitable to protect and align DSB ends. XLF–XRCC4 provides a global structural scaffold for ligating DSBs without requiring long DNA ends, thus ensuring accurate and efficient ligation and repair. The assembly of these XRCC4–XLF filaments, providing both DNA end protection and alignment, may commit cells to NHEJ with general biological implications for NHEJ and DSB repair processes and their links to cancer predispositions and interventions.
Effect of grain size on service life of MSW landfill drainage systems
Authors: Yu Yan , Rowe R. Kerry
Published: November 2012

A numerical model “BioClog-2D” is used to examine the service life and clogging of leachate collection systems with granular drainage material of different grain sizes. The modelling shows that the leachate characteristics at the end of the drainage pipe are significantly different from those in the leachate entering the leachate collection system and this reduction in leachate strength corresponds to an accumulation of clog mass within the saturated drainage layer. The calculated clog mass within the saturated drainage layer is dominated by the inorganic material, which is in encouraging agreement with field-observed data. The service life of leachate collection systems is increased with an increase in the grain size of the drainage material and decreased with an increase in the length of the drainage path. The service life of the drainage layer is shown to vary from a few years to over 100 years depending on the design of the system. The results indicate that in addition to the particle size of the granular material, the infiltration rate and leachate strength history greatly affect the estimated service life of leachate collection systems.
Single-nucleotide polymorphisms reveal distribution and migration of Chinook salmon (Oncorhynchus tshawytscha) in the Bering Sea and North Pacific Ocean
Authors: Larson Wesley A. , Utter Fred M. , Myers Katherine W. , Templin William D. , Seeb James E. , Guthrie III Charles M. , Bugaev Alexander V. , Seeb Lisa W.
Published: November 2012

We genotyped Chinook salmon (Oncorhynchus tshawytscha) from the Bering Sea and North Pacific Ocean for 43 single-nucleotide polymorphisms (SNPs) to investigate seasonal distribution and migration patterns. We analyzed 3563 immature fish from 22 spatiotemporal strata; composition analyses were performed using genotype data from spawning stocks spanning the species range. Substantial variation in stock composition existed among spatial and seasonal strata. We inferred patterns of seasonal migration based upon these data along with data from previous tag, scale, and parasite studies. We found that stocks from western Alaska and Yukon River overwinter on the Alaska continental shelf then travel to the middle and western Bering Sea during spring–fall. Stocks from California to Southeast Alaska were distributed in Gulf of Alaska year-round, with a substantial portion of this group migrating northward to the eastern Bering Sea during spring–fall. Proportions of Russian stocks increase when moving east to west in both the Bering Sea and North Pacific Ocean. These data can be used to better understand the impacts of fisheries and climate change on this valuable resource.
Etiology of a recent white spruce decline: role of potassium deficiency, past disturbances, and climate change
Authors: Ouimet Rock , Moore Jean-David , Duchesne Louis , Camiré Claude
Published: November 2012

Along with climate, multiple global or large-scale change agents shape forest ecosystem health. We present a case study where we attempted to elucidate the driving factors causing decline symptoms in white spruce (Picea glauca (Moench) Voss) in young spruce–fir boreal stands. Tree defoliation rate in the studied areas was related to the foliage discoloration intensity of the 2-year old needles and the decreasing stem basal area increment from 1997 to 2008. The onset of this growth decline in 1997 coincided with the occurrence of extremes for four climatic indices. The foliage of affected trees was deficient in K. The relationship between tree decline and K deficiency was tested through a diagnostic fertilization trial using a two-level factorial combination of N, K, and Mg. The trial indicated that K was the single limiting nutrient among the three tested elements. A single K addition increased stem basal area by 43% on average after 11 years. It is hypothesized that the poor K status of trees can be attributed to a series of natural and anthropogenic disturbances along with past forest management activities. Climate change in the region since the last decades also may have contributed to exacerbate K deficiency in such forest ecosystems.
Lifshitz holographic renormalization from anti-de Sitter
Authors: Chemissany Wissam , Geissbühler David , Hartong Jelle , Rollier Blaise
Published: November 2012

Lifshitz space–times with critical exponent z = 2 can be obtained by dimensional reduction of Schrödinger space–times with critical exponent z = 0. The latter space–times are asymptotically anti-de Sitter (AdS) solutions of AdS gravity coupled to an axion–dilaton system (or even just a massless scalar field). This basic observation is used to perform holographic renormalization for four-dimensional asymptotically locally Lifshitz space–times by dimensional reduction of the corresponding problem of holographic renormalization for five-dimensional asymptotically AdS space–times coupled to an axion–dilaton system. In this setup the four-dimensional structure of the Lifshitz – Fefferman-Graham expansion and the structure of the counterterm action, including the scale anomaly, will be summarized.
Bioretention cell efficacy in cold climates: Part 1 — hydrologic performance
Authors: Khan U.T. , Valeo C. , Chu A. , van Duin B.
Published: November 2012

Bioretention cells are an emerging low impact development technology that address urban stormwater runoff concerns. Field and column experiments were conducted to assess the efficacy of bioretention cells in cold conditions. Field experiments in a prairie environment demonstrated a significant decrease (91.5%) in effluent volumes compared to influent volumes. The majority (∼60%) of the runoff percolated to the surrounding soils or evapotranspirated. Cold condition performance significantly impacted high volume events and was characterized by significantly higher effluent volumes, significantly lower runoff storage, higher effluent peak flow rates, and longer peak delays. A partially frozen surface layer caused the changes in performance. Long-term simulation experiments on the columns indicated a significant decrease in saturated hydraulic conductivity over the first 4 equivalent years of operation, before levelling to a constant value.
ON SEMICLASSICAL GROUND STATES OF A NONLINEAR DIRAC EQUATION
Authors: DING YANHENG , LIU XIAOYING
Published: November 2012

This paper is concerned with existence and concentration phenomena of semiclassical solutions of the following nonlinear Dirac equation [Formula: see text] for x ∈ ℝ3 where pj ∈ (2, 3) are subcritical. Under some conditions, we show that there are two families of semiclassical solutions, for ℏ > 0 small, with the least energy, one concentrating on the set of minimal points of V and another on the set of maximal points of Wj. Both are exponentially decay as |x| → ∞.
Systems Pharmacology to Predict Drug Toxicity: Integration Across Levels of Biological Organization
Authors: Bai Jane P.F. , Abernethy Darrell R.
Published: November 2012

To achieve sensitive and specific mechanism-based prediction of drug toxicity, the tools of systems pharmacology will be integrated using structured ontological approaches, analytics, mathematics, and statistics. Success of this effort is based on the assumption that a systems network that consists of drug-induced perturbations of physiological functions can be characterized. This network spans the hierarchy of biological organization, from gene to mRNA to protein to intracellular organelle to cell to organ to organism. It is populated with data from each of these levels of biological organization. These data, from disparate sources, include the published literature, drug development archives of all approved drugs and drug candidates that did not complete development, and various toxicity databases and adverse event reporting systems. The network contains interrelated genomics, transcriptomics, and metabolomics data, as well as organ and physiological functional data that are derived from the universe of information that describes and analyzes drug toxicity. Here we describe advances in bioinformatics, computer sciences, next-generation sequencing, and systems biology that create the opportunity for integrated systems pharmacology–based prediction of drug safety.
Direct-Acting Antiviral Agents for Hepatitis C Virus Infection
Authors: Kiser Jennifer J. , Flexner Charles
Published: November 2012

Two selective inhibitors of the hepatitis C virus (HCV) protease nearly double the cure rates for this infection when combined with peginterferon alfa and ribavirin. These drugs, boceprevir and telaprevir, received regulatory approval in 2011 and are the first direct-acting antiviral agents (DAAs) that selectively target HCV. During 2012, at least 30 additional DAAs were in various stages of clinical development. HCV protease inhibitors, polymerase inhibitors, and NS5A inhibitors (among others) can achieve high cure rates when combined with peginterferon alfa and ribavirin and demonstrate promise when used in combination with one another. Current research is attempting to improve the pharmacokinetics and tolerability of these agents, define the best regimens, and determine treatment strategies that produce the best outcomes. Several DAAs will reach the market simultaneously, and resources will be needed to guide the use of these drugs. We review the clinical pharmacology, trial results, and remaining challenges of DAAs for the treatment of HCV.
Hepatic and Intestinal Drug Transporters: Prediction of Pharmacokinetic Effects Caused by Drug-Drug Interactions and Genetic Polymorphisms
Authors: Yoshida Kenta , Maeda Kazuya , Sugiyama Yuichi
Published: November 2012

Recent studies of membrane transporters have revealed their importance in determining the pharmacokinetics of transporter substrates. When drug-drug interactions (DDIs) or genetic polymorphisms (i.e., pharmacogenetics) affect the activities of transporters, the pharmacokinetics of transporter substrate drugs is altered; this alteration influences the substrate drugs' subsequent pharmacological or toxicological effects. In predicting these effects quantitatively from in vitro experimental results, we must first determine the contribution of each transporter to the overall elimination process. Furthermore, the accurate estimation of effective inhibitor concentrations at the site of interaction (e.g., intestinal lumen, extracellular and intracellular space of hepatocytes) is challenging. In predicting pharmacogenetic effects, the extrapolation from in vitro observations to in vivo outcomes (e.g., changes in intrinsic activities and/or expression levels) is still evolving. In this review, we describe the current status of, and difficulties inherent in, the accurate prediction of the altered pharmacokinetics caused by transporter-mediated DDIs and pharmacogenetics.
Aging, Cellular Senescence, and Cancer
Authors: Campisi Judith
Published: November 2012

For most species, aging promotes a host of degenerative pathologies that are characterized by debilitating losses of tissue or cellular function. However, especially among vertebrates, aging also promotes hyperplastic pathologies, the most deadly of which is cancer. In contrast to the loss of function that characterizes degenerating cells and tissues, malignant (cancerous) cells must acquire new (albeit aberrant) functions that allow them to develop into a lethal tumor. This review discusses the idea that, despite seemingly opposite characteristics, the degenerative and hyperplastic pathologies of aging are at least partly linked by a common biological phenomenon: a cellular stress response known as cellular senescence. The senescence response is widely recognized as a potent tumor suppressive mechanism. However, recent evidence strengthens the idea that it also drives both degenerative and hyperplastic pathologies, most likely by promoting chronic inflammation. Thus, the senescence response may be the result of antagonistically pleiotropic gene action.
Mammalian Phospholipase C
Authors: Kadamur Ganesh , Ross Elliott M.
Published: November 2012

Phospholipase C (PLC) converts phosphatidylinositol 4,5-bisphosphate (PIP2) to inositol 1,4,5-trisphosphate (IP3) and diacylglycerol (DAG). DAG and IP3 each control diverse cellular processes and are also substrates for synthesis of other important signaling molecules. PLC is thus central to many important interlocking regulatory networks. Mammals express six families of PLCs, each with both unique and overlapping controls over expression and subcellular distribution. Each PLC also responds acutely to its own spectrum of activators that includes heterotrimeric G protein subunits, protein tyrosine kinases, small G proteins, Ca2+, and phospholipids. Mammalian PLCs are autoinhibited by a region in the catalytic TIM barrel domain that is the target of much of their acute regulation. In combination, the PLCs act as a signaling nexus that integrates numerous signaling inputs, critically governs PIP2 levels, and regulates production of important second messengers to determine cell behavior over the millisecond to hour timescale.
Years in Cologne
Authors: Rajewsky Klaus
Published: November 2012

This review describes the building and scientific activity of the Immunology Department at the Institute for Genetics in Cologne, cofounded by Max Delbrück in post–World War II Germany. The protagonist, a child of Russian emigrants, became interested in antibodies as a postdoc at the Pasteur Institute in Paris and a proponent of the antigen-bridge model of T-B cell collaboration during his early time in Cologne. He was challenged by the gap between cellular immunology and molecular genetics and profited from the advances of the latter as well as postwar economic growth in Germany. The Immunology Department became a place, and little universe in itself, where young scientists from all over the world came together to study cellular and molecular mechanisms of antibody formation. This included work on normal and malignant B cells in the human, particularly the origin of Hodgkin lymphoma, but the main focus was on B cell development and homeostasis, the germinal center reaction, and immunological memory, developing recombinase-assisted and conditional gene targeting in mice as a main technical tool.
Activation of cannabinoid receptor 2 reduces inflammation in acute experimental pancreatitis via intra-acinar activation of p38 and MK2-dependent mechanisms
Authors: Michler Thomas , Storr Martin , Kramer Johannes , Ochs Stefanie , Malo Antje , Reu Simone , Göke Burkhard , Schäfer Claus
Published: November 2012

The endocannabinoid system has been shown to mediate beneficial effects on gastrointestinal inflammation via cannabinoid receptors 1 (CB1) and 2 (CB2). These receptors have also been reported to activate the MAP kinases p38 and c-Jun NH2-terminal kinase (JNK), which are involved in early acinar events leading to acute pancreatitis and induction of proinflammatory cytokines. Our aim was to examine the role of cannabinoid receptor activation in an experimental model of acute pancreatitis and the potential involvement of MAP kinases. Cerulein pancreatitis was induced in wild-type, CB1−/−, and MK2−/− mice pretreated with selective cannabinoid receptor agonists or antagonists. Severity of pancreatitis was determined by serum amylase and IL-6 levels, intracellular activation of pancreatic trypsinogen, lung myeloperoxidase activity, pancreatic edema, and histological examinations. Pancreatic lysates were investigated by Western blotting using phospho-specific antibodies against p38 and JNK. Quantitative PCR data, Western blotting experiments, and immunohistochemistry clearly show that CB1 and CB2 are expressed in mouse pancreatic acini. During acute pancreatitis, an upregulation especially of CB2 on apoptotic cells occurred. The unselective CB1/CB2 agonist HU210 ameliorated pancreatitis in wild-type and CB1−/− mice, indicating that this effect is mediated by CB2. Furthermore, blockade of CB2, not CB1, with selective antagonists engraved pathology. Stimulation with a selective CB2 agonist attenuated acute pancreatitis and an increased activation of p38 was observed in the acini. With use of MK2−/− mice, it could be demonstrated that this attenuation is dependent on MK2. Hence, using the MK2−/− mouse model we reveal a novel CB2-activated and MAP kinase-dependent pathway that modulates cytokine expression and reduces pancreatic injury and affiliated complications.
Modulation of the gut microbiota with antibiotic treatment suppresses whole body urea production in neonatal pigs
Authors: Puiman Patrycja , Stoll Barbara , Mølbak Lars , de Bruijn Adrianus , Schierbeek Henk , Boye Mette , Boehm Günther , Renes Ingrid , van Goudoever Johannes , Burrin Douglas
Published: November 2012

We examined whether changes in the gut microbiota induced by clinically relevant interventions would impact the bioavailability of dietary amino acids in neonates. We tested the hypothesis that modulation of the gut microbiota in neonatal pigs receiving no treatment (control), intravenously administered antibiotics, or probiotics affects whole body nitrogen and amino acid turnover. We quantified whole body urea kinetics, threonine fluxes, and threonine disposal into protein, oxidation, and tissue protein synthesis with stable isotope techniques. Compared with controls, antibiotics reduced the number and diversity of bacterial species in the distal small intestine (SI) and colon. Antibiotics decreased plasma urea concentrations via decreased urea synthesis. Antibiotics elevated threonine plasma concentrations and turnover, as well as whole body protein synthesis and proteolysis. Antibiotics decreased protein synthesis rate in the proximal SI and liver but did not affect the distal SI, colon, or muscle. Probiotics induced a bifidogenic microbiota and decreased plasma urea concentrations but did not affect whole body threonine or protein metabolism. Probiotics decreased protein synthesis in the proximal SI but not in other tissues. In conclusion, modulation of the gut microbiota by antibiotics and probiotics reduced hepatic ureagenesis and intestinal protein synthesis, but neither altered whole body net threonine balance. These findings suggest that changes in amino acid and nitrogen metabolism resulting from antibiotic- or probiotic-induced shifts in the microbiota are localized to the gut and liver and have limited impact on whole body growth and anabolism in neonatal piglets.
d-Glucose modulates intestinal Niemann-Pick C1-like 1 (NPC1L1) gene expression via transcriptional regulation
Authors: Malhotra Pooja , Boddy Craig S. , Soni Vinay , Saksena Seema , Dudeja Pradeep K. , Gill Ravinder K. , Alrefai Waddah A.
Published: November 2012

The expression of intestinal Niemann-Pick C1-like 1 (NPC1L1) cholesterol transporter has been shown to be elevated in patients with diseases associated with hypercholesterolemia such as diabetes mellitus. High levels of glucose were shown to directly increase the expression of NPC1L1 in intestinal epithelial cells, but the underlying mechanisms are not fully defined. The present studies were, therefore, undertaken to examine the transcriptional regulation of NPC1L1 expression in human intestinal Caco2 cells in response to glucose. Removal of glucose from the culture medium of Caco2 cells for 24 h significantly decreased the NPC1L1 mRNA, protein expression, as well as the promoter activity. Glucose replenishment significantly increased the promoter activity of NPC1L1 in a dose-dependent manner compared with control cells. Exposure of Caco2 cells to nonmetabolizable form of glucose, 3- O-methyl-d-glucopyranose (OMG) had no effect on NPC1L1 promoter activity, indicating that the observed effects are dependent on glucose metabolism. Furthermore, glucose-mediated increase in promoter activity was abrogated in the presence of okadaic acid, suggesting the involvement of protein phosphatases. Glucose effects on several deletion constructs of NPC1L1 promoter demonstrated that cis elements mediating the effects of glucose are located in the region between −291 and +56 of NPC1L1 promoter. Consistent with the effects of glucose removal on NPC1L1 expression in Caco2 cells, 24-h fasting resulted in a significant decrease in the relative expression of NPC1L1 in mouse jejunum. In conclusion, glucose appears to directly modulate NPC1L1 expression via transcriptional mechanisms and the involvement of phosphatase-dependent pathways.
Capsaicin induces NKCC1 internalization and inhibits chloride secretion in colonic epithelial cells independently of TRPV1
Authors: Bouyer Patrice G. , Tang Xu , Weber Christopher R. , Shen Le , Turner Jerrold R. , Matthews Jeffrey B.
Published: November 2012

Colonic chloride secretion is regulated via the neurohormonal and immune systems. Exogenous chemicals (e.g., butyrate, propionate) can affect chloride secretion. Capsaicin, the pungent ingredient of the chili peppers, exerts various effects on gastrointestinal function. Capsaicin is known to activate the transient receptor potential vanilloid type 1 (TRPV1), expressed in the mesenteric nervous system. Recent studies have also demonstrated its presence in epithelial cells but its role remains uncertain. Because capsaicin has been reported to inhibit colonic chloride secretion, we tested whether this effect of capsaicin could occur by direct action on epithelial cells. In mouse colon and model T84 human colonic epithelial cells, we found that capsaicin inhibited forskolin-dependent short-circuit current (FSK- Isc). Using PCR and Western blot, we demonstrated the presence of TRPV1 in colonic epithelial cells. In T84 cells, TRPV1 localized at the basolateral membrane and in vesicular compartments. In permeabilized monolayers, capsaicin activated apical chloride conductance, had no effect on basolateral potassium conductance, but induced NKCC1 internalization demonstrated by immunocytochemistry and basolateral surface biotinylation. AMG-9810, a potent inhibitor of TRPV1, did not prevent the inhibition of the FSK- Iscby capsaicin. Neither resiniferatoxin nor N-oleoyldopamine, two selective agonists of TRPV1, blocked the FSK- Isc. Conversely capsaicin, resiniferatoxin, and N-oleoyldopamine raised intracellular calcium ([Ca2+]i) in T84 cells and AMG-9810 blocked the rise in [Ca2+]iinduced by capsaicin and resiniferatoxin suggesting the presence of a functional TRPV1 channel. We conclude that capsaicin inhibits chloride secretion in part by causing NKCC1 internalization, but by a mechanism that appears to be independent of TRPV1.
The magnitude of heat stress-induced reductions in cerebral perfusion does not predict heat stress-induced reductions in tolerance to a simulated hemorrhage
Authors: Lee Joshua F. , Harrison Michelle L. , Brown Skyler R. , Brothers R. Matthew
Published: November 2012

The mechanisms responsible for heat stress-induced reductions in tolerance to a simulated hemorrhage are unclear. Although a high degree of variability exists in the level of reduction in tolerance amongst individuals, syncope will always occur when cerebral perfusion is inadequate. This study tested the hypothesis that the magnitude of reduction in cerebral perfusion during heat stress is related to the reduction in tolerance to a lower body negative pressure (LBNP) challenge. On different days (one during normothermia and the other after a 1.5°C rise in internal temperature), 20 individuals were exposed to a LBNP challenge to presyncope. Tolerance was quantified as a cumulative stress index, and the difference in cumulative stress index between thermal conditions was used to categorize individuals most (large difference) and least (small difference) affected by the heat stress. Cerebral perfusion, as indexed by middle cerebral artery blood velocity, was reduced during heat stress compared with normothermia ( P < 0.001); however, the magnitude of reduction did not differ between groups ( P = 0.51). In the initial stage of LBNP during heat stress (LBNP 20 mmHg), middle cerebral artery blood velocity and end-tidal Pco2 were lower; whereas, heart rate was higher in the large difference group compared with small difference group ( P < 0.05 for all). These data indicate that variability in heat stress-induced reductions in tolerance to a simulated hemorrhage is not related to reductions in cerebral perfusion in this thermal condition. However, responses affecting cerebral perfusion during LBNP may explain the interindividual variability in tolerance to a simulated hemorrhage when heat stressed.
Water drinking-related muscle contraction induces the pressor response via mechanoreceptors in conscious rats
Authors: Abe Chikara , Iwata Chihiro , Morita Hironobu
Published: November 2012

Water drinking is known to induce the pressor response. The efferent pathway in this response involves sympathoexcitation, because the pressor response was completely abolished by ganglionic blockade or an α1-adrenergic antagonist. However, the afferent pathway in this response has not been identified. In the present study, we hypothesized that water itself stimulates the upper digestive tract to induce the pressor response, and/or drinking-related muscle contraction induces the pressor response via mechanoreceptors. To examine this hypothesis, we evaluated the pressor response induced by spontaneous or passive water drinking in conscious rats. Since the baroreflex modulates and obscures the pressor response, the experiments were conducted using rats with sinoaortic denervation. The pressor response was not suppressed by 1) transient oral surface anesthesia using lidocaine, 2) bilateral denervation of the glossopharyngeal nerve and sensory branch of the superior laryngeal nerve, or 3) denervation of the tunica adventitia in the esophagus. However, the pressor response was significantly suppressed (by −52%) by intravenous gadolinium chloride administration. Electrical stimulation of the hypoglossal nerve induced the pressor response, which was significantly suppressed (by −57%) by intravenous gadolinium chloride administration and completely abolished by severing the distal end of this nerve. These results indicate that afferent signals from mechanoreceptors in drinking-related muscles are involved in the water drinking-induced pressor response.
FoxM1 and Wnt/β-Catenin Signaling in Glioma Stem Cells
Authors: Gong Aihua , Huang Suyun
Published: November 2012

Cancer stem cells may be responsible for tumor initiation and maintenance. The molecular mechanisms that control cancer stem cells are related to alterations in various signaling pathways, including the Wnt/β-catenin signaling pathway. The canonical Wnt/β-catenin signaling pathway is one of the major signaling systems in stem and progenitor cells, and aberrant activation of the Wnt/β-catenin signaling pathway is common in human cancers. As with β-catenin, FoxM1 has been found to play important roles in a number of cancers. In this review, we discuss the evidence that FoxM1 affects the expression and function of a variety of genes that are critical to the survival, proliferation, invasion, angiogenesis, and self-renewal of cancer stem cells. We highlight the pivotal roles of the Wnt/β-catenin and FoxM1 signaling pathways in neural stem and progenitor cells and glioma stem cells. We also discuss the evidence for cross-talk between the β-catenin and FoxM1 signaling pathways in the regulation of the stemness and tumorigenicity of glioma stem cells. Cancer Res; 72(22); 5658–62. ©2012 AACR.
Realizing the Clinical Potential of Cancer Nanotechnology by Minimizing Toxicologic and Targeted Delivery Concerns
Authors: Singh Sanjay , Sharma Arati , Robertson Gavin P.
Published: November 2012

Nanotechnology has the potential to make smart drugs that would be capable of targeting cancer but not normal cells and to load combinations of cooperating agents into a single nanosized particle to more effectively treat this disease. However, to realize the full potential of this technology, the negative aspects associated with these nanoparticles need to be overcome. This review discusses concerns in the field limiting realization of the full clinical potential of this technology, which are toxicity and targeted delivery. Strategies to overcome these hurdles are also reviewed, which could lead to attainment of the full clinical potential of this exciting technology. Cancer Res; 72(22); 5663–8. ©2012 AACR.
Cell Surface Receptor FPR2 Promotes Antitumor Host Defense by Limiting M2 Polarization of Macrophages
Authors: Liu Ying , Chen Keqiang , Wang Chunyan , Gong Wanghua , Yoshimura Teizo , Liu Mingyong , Wang Ji Ming
Published: November 2012

FPR2 (Fpr2 in mouse) is a G-protein–coupled receptor interacting with bacterial and host-derived chemotactic agonists. Fpr2 supports innate and adaptive immune responses as illustrated by the reduction in severity of allergic airway inflammation in Fpr2-KO mice, due to impaired trafficking of antigen-presenting dendritic cells (DC). The aim of this study is to examine the role of Fpr2 in host antitumor responses. We found that Fpr2-KO mice bearing subcutaneously implanted Lewis lung carcinoma (LLC) cells exhibited significantly shortened survival than normal mice due to more rapidly growing tumors. In contrast, in Fpr2-transgenic mice overexpressing Fpr2, subcutaneously implanted LLC tumors grew more slowly than those in wild-type (WT) littermates. Investigation of tumor tissues revealed an increased number of macrophages associated with tumors grown in Fpr2-KO mice. Macrophages derived from Fpr2-KO mice showed a more potent chemotactic response to LLC-derived supernatant (LLC Sup), which could be neutralized by an anti-CCL2 antibody. The increased chemotaxis of Fpr2-KO mouse macrophages in response to LLC Sup was due to their higher level expression of CCR4, a chemokine receptor that also recognizes the ligand CCL2. Furthermore, macrophages from Fpr2-KO mice acquired an M2 phenotype after stimulation with LLC Sup. These results suggest that Fpr2 plays an important role in host defense against implanted LLC by sustaining macrophages in an M1 phenotype with more potent antitumor activities. Cancer Res; 73(2); 550–60. ©2012 AACR.
SMAD2,SMAD3andSMAD4Mutations in Colorectal Cancer
Authors: Fleming Nicholas I. , Jorissen Robert N. , Mouradov Dmitri , Christie Michael , Sakthianandeswaren Anuratha , Palmieri Michelle , Day Fiona , Li Shan , Tsui Cary , Lipton Lara , Desai Jayesh , Jones Ian T. , McLaughlin Stephen , Ward Robyn L. , Hawkins Nicholas J. , Ruszkiewicz Andrew R. , Moore James , Zhu Hong-Jian , Mariadason John M. , Burgess Antony W. , Busam Dana , Zhao Qi , Strausberg Robert L. , Gibbs Peter , Sieber Oliver M.
Published: November 2012

Activation of the canonical TGF-β signaling pathway provides growth inhibitory signals in the normal intestinal epithelium. Colorectal cancers (CRCs) frequently harbor somatic mutations in the pathway members TGFBR2 and SMAD4, but to what extent mutations in SMAD2 or SMAD3 contribute to tumorigenesis is unclear. A cohort of 744 primary CRCs and 36 CRC cell lines were sequenced for SMAD4, SMAD2, and SMAD3 and analyzed for allelic loss by single-nucleotide polymorphism (SNP) microarray analysis. Mutation spectra were compared between the genes, the pathogenicity of mutations was assessed, and relationships with clinicopathologic features were examined. The prevalence of SMAD4, SMAD2, and SMAD3 mutations in sporadic CRCs was 8.6% (64 of 744), 3.4% (25 of 744), and 4.3% (32 of 744), respectively. A significant overrepresentation of two genetic hits was detected for SMAD4 and SMAD3, consistent with these genes acting as tumor suppressors. SMAD4 mutations were associated with mucinous histology. The mutation spectra of SMAD2 and SMAD3 were highly similar to that of SMAD4, both in mutation type and location within the encoded proteins. In silico analyses suggested the majority of the mutations were pathogenic, with most missense changes predicted to reduce protein stability or hinder SMAD complex formation. The latter altered interface residues or disrupted the phosphorylation-regulated Ser-Ser-X-Ser motifs within SMAD2 and SMAD3. Functional analyses of selected mutations showed reductions in SMAD3 transcriptional activity and SMAD2–SMAD4 complex formation. Joint biallelic hits in SMAD2 and SMAD3 were overrepresented and mutually exclusive to SMAD4 mutation, underlining the critical roles of these three proteins within the TGF-β signaling pathway. Cancer Res; 73(2); 725–35. ©2012 AACR.
Unfavourable cardiovascular disease risk profiles in a cohort of Dutch and British haemophilia patients
Authors: Fischer Kathelijn , Makris Michael , Tait Campbell R. , Chowdary Pratima , Collins Peter W. , Meijer Karina , Roosendaal Goris , Schutgens Roger E. G. , Mauser-Bunschoten Eveline P. , Fransen van de Putte Dietje E.
Published: November 2012

Cardiovascular disease (CVD) mortality is reported to be decreased in haemophilia patients, but reports on the prevalence of CVD risk factors are conflicting. A cross-sectional assessment of CVD risk profiles was performed in a large cohort of haemophilia patients. Baseline data on CVD risk factors of 709 Dutch and UK haemophilia patients aged ≥ 30 years were analysed and compared with the general age-matched male population. CVD risk profiles were assessed using the QRISK®2–2011 and SCORE algorithms. Although QRISK®2 was only validated in the UK, comparison with SCORE indicated similar properties of QRISK®2 in both Dutch and UK patients (correlation 0.86). Mean age was 49.8 years. Hypertension was more common in haemophilia patients than in the general population (49% vs. 40%), while the prevalences of obesity and hypercholesterolaemia were lower (15 vs. 20% and 44 vs. 68%, respectively), and those of diabetes and smoking were similar. The predicted 10-year QRISK®2 risk was significantly higher in haemophilia patients than in the general population (8.9 vs. 6.7%), indicating more unfavourable cardiovascular disease risk profiles. This increased risk became apparent after the age of 40 years. Our results indicate an increased prevalence of hypertension and overall more unfavourable CVD risk profiles in haemophilia patients compared with the general age-matched male population.
Circulating and platelet-derived microparticles in human blood enhance thrombosis on atherosclerotic plaques
Authors: Suades Rosa , Padró Teresa , Vilahur Gemma , Badimon Lina
Published: November 2012

Plaque rupture followed by thrombosis is the underlying cause of the majority of acute coronary syndromes. Circulating microparticles (cMPs), membrane blebs released into blood by activated cells, have been associated to vascular diseases. Specifically, high levels of platelet-derived microparticles (pMPs) have been found in patients with coronary disease. However, it is unknown whether microparticles have a contributing role to the development of damaged vessel wall-induced arterial thrombi. The aim of this proof of concept study was to investigate whether an increased number of cMPs and pMPs could functionally contribute to blood thrombogenicity on areas of arterial damage. Microparticles were isolated from blood of healthy volunteers and were characterised by flow cytometry. Effects of microparticles on platelet deposition were assessed under controlled flow conditions exposing damaged arterial wall in the Badimon perfusion chamber and collagen type-I in the flat perfusion chamber to human blood. Platelet deposition on damaged arteries was significantly increased in cMP- and pMP-enriched bloods (p<0.05). pMPs also induced increase in platelet (p<0.05) and fibrin (p<0.05) deposition on human atherosclerotic arteries and in platelet adhesion to purified collagen surfaces. pMP-enriched blood induced a dose-dependent shortening of epinephrine/collagen closure time evaluated by PFA-100 (p<0.001), increased lowdose ADP-induced platelet aggregation by LTA (p<0.05), and decreased clotting time by thromboelastography (p<0.01). In conclusion, an increased content of cMPs and pMPs, even in normal blood conditions, enhance platelet deposition and thrombus formation. This study shows for the first time that, beyond biomarkers of cell activation, blood microparticles have functional effects on cardiovascular atherothrombotic disease.
The use of weighted and scored risk assessment models for venous thromboembolism
Authors: McGinn Thomas , Khorana Alok , Spyropoulos Alex
Published: November 2012

Formalised risk assessment models (RAMs) for venous thromboembolism (VTE) using weighted and scored variables have only recently been widely incorporated into international antithrombotic guidelines.Scored and weighted VTE RAMs have advantages over a simplified group-specific VTE risk approach, with the potential to allow more tailored strategies for thromboprophylaxis and an improved estimation of the risk/benefit profile for a particular patient. The derivation of VTE RAMs should be based on variables that are a priori defined or identified in a univariate analysis and the predictive capability of each variable should be rigorously assessed for both clinical and statistical significance and internal consistency and completeness. The assessment of the RAM should include the goodness of fit of the model and construction of a prognostic index score. Any VTE RAM which has been derived must undergo validation of that model before it can be used in clinical practice. Validation of the model should be performed in a “deliberate”prospective fashion across several diverse clinical sites using pre-defined criteria using basic standards for performing model validation. We discuss the basic concepts in the derivation of recent scored and weighted VTE RAMs in hospitalised surgical and medical patients and cancer outpatients, the mechanisms for accurate external validation of the models, and implications for their use in clinical practice.
Upregulating Reverse Cholesterol Transport With Cholesteryl Ester Transfer Protein Inhibition Requires Combination With the LDL-Lowering Drug Berberine in Dyslipidemic Hamsters
Authors: Briand François , Thieblemont Quentin , Muzotte Elodie , Sulpice Thierry
Published: November 2012

Objective—

This study aimed to investigate whether cholesteryl ester transfer protein inhibition promotes in vivo reverse cholesterol transport in dyslipidemic hamsters.

Methods and Results—

In vivo reverse cholesterol transport was measured after an intravenous injection of
3
H-cholesteryl-oleate–labeled/oxidized low density lipoprotein particles (
3
H-oxLDL), which are rapidly cleared from plasma by liver-resident macrophages for further
3
H-tracer egress in plasma, high density lipoprotein (HDL), liver, and feces. A first set of hamsters made dyslipidemic with a high-fat and high-fructose diet was treated with vehicle or torcetrapib 30 mg/kg (TOR) over 2 weeks. Compared with vehicle, TOR increased apolipoprotein E–rich HDL levels and significantly increased
3
H-tracer appearance in HDL by 30% over 72 hours after
3
H-oxLDL injection. However, TOR did not change
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H-tracer recovery in liver and feces, suggesting that uptake and excretion of cholesterol deriving from apolipoprotein E-rich HDL is not stimulated. As apoE is a potent ligand for the LDL receptor, we next evaluated the effects of TOR in combination with the LDL-lowering drug berberine, which upregulates LDL receptor expression in dyslipidemic hamsters. Compared with TOR alone, treatment with TOR+berberine 150 mg/kg resulted in lower apolipoprotein E–rich HDL levels. After
3
H-oxLDL injection, TOR+berberine significantly increased
3
H-tracer appearance in fecal cholesterol by 109%.

Conclusion—

Our data suggest that cholesteryl ester transfer protein inhibition alone does not stimulate reverse cholesterol transport in dyslipidemic hamsters and that additional effects mediated by the LDL-lowering drug berberine are required to upregulate this process.