bluuebunny/crossref_metadata_2025 huggingface dataset:
Fetal Responses to Maternal Strength Conditioning Exercises in Late Gestation
Authors: Avery Nicole D. , Stocking Kimberley D. , Tranmer Joan E. , Davies Gregory A.L. , Wolfe Larry A.
Published: June 2009

Cardiovascular responses to strength conditioning exercises were examined in 12 healthy pregnant women and their unborn fetuses during the third trimester. A group of 12 healthy nonpregnant women of similar ages, parity, body height, and pre-pregnant body mass was also studied. Maternal heart rate and blood pressure and fetal heart rate (FHR) responses were measured in both the supine (30° tilt) and seated postures during handgrip (HG), single-leg extension (SL), and double-leg extension (DL) exercise. Subjects performed 3 sets of 10 reps at 50, 70, and 90% of their 10-repetition maximum (10-RM) for each exercise in both postures. Pregnant subjects exhibited higher heart rates but similar blood pressure responses to control subjects under all experimental conditions. Significant increases were observed for the frequency of FHR accelerations (0.10 to 0.27/min) from rest to DL in the sitting posture at 90% RM. Moderate fetal bradycardia was observed occasionally in the tilted supine posture at rest and both during (SL, DL) and following (HG, SL, DL) exercise, suggesting that this posture should be avoided in late gestation. The results support the safety of moderate strength conditioning exercises in healthy pregnancy. Keywords: pregnancy, resistance exercise, fetal heart rate, maternal cardiovascular responses
Dietary Carbohydrate and its Effects on Metabolism and Substrate Stores in Sedentary and Active Individuals
Authors: Graham Terry E. , Adamo Kristi B.
Published: June 2009

This review of carbohydrate (CHO) ingestion and exercise addresses three major issues: (a) how CHO ingestion influences CHO and fat stores, (b) how exercise, by changing CHO stores, alters the responses to CHO or fat ingestion, and (c) the roles of CHO in exercise performance and metabolism. Dietary manipulation is not a simple issue; increasing the dietary content of any specific nutrient alters the entire diet composition. High CHO diets are often low fat diets, hence changing the metabolism and storage of both fat and CHO. Acute CHO ingestion increases CHO oxidation and the "spared" fats are deposited as fat. Chronic high CHO ingestion (without an active lifestyle) leads to muscle becoming insulin-insensitive, adipose tissue processing CHO to fatty acids, and the liver increasing production of VLDL triglycerides. CHO ingestion prior to and during prolonged exercise can increase endurance. It has been suggested that moderate or low glycemic index forms be used prior to and during the exercise, but there is no consensus as to whether it should be a recommendation. The physiological nature of the regulation of CHO stores is poorly understood, but the recent identification of a key enzyme, glycogenin, and two forms of glycogen (pro- and macroglycogen) show promise of a deeper understanding. Key words: insulin, glycogen, triglyceride, liver, adipose tissue, de novo lipogenesis
Nasal Dilator Strips Delay the Onset of Oral Route Breathing During Exercise
Authors: Seto-Poon Margaret , Amis Terence C. , P.Kirkness Jason , Wheatley John R.
Published: June 2009

The external nasal dilator strip (ENDS) device (Breathe Right®, CNS Inc., Chanhassen, MN, USA) has been adopted by athletes to promote nasal route breathing during exercise. We studied the influence of ENDS on the switching point from nasal-only to oro-nasal breathing during exercise in 4 healthy men (age 25 ± 2 yrs, mean ± SEM) and 5 women (age 30 ± 5 yrs). Resting inspiratory nasal airflow resistance decreased from 0.33 ± 0.02 kPa/L/s without ENDS to 0.22 ± 0.01 kPa/L/s with ENDS (p < 0.01). ENDS delayed the onset of oro-nasal breathing such that the time from commencement of exercise to switching increased by 15.2%, and maximum levels of inspiratory nasal airflow and ventilation achieved prior to switching increased by 14.9% and 14.3%, respectively (all p < 0.05). We conclude that, in normal healthy subjects, ENDS does promote nasal route breathing during exercise, but any delay in the onset of oral route breathing during a progressive exercise task appears relatively small. Key words: upper airway, nose, mouth breathing
ENCODINGS OF MULTISETS
Authors: CIOBANU GABRIEL , GONTINEAC MIHAI
Published: June 2009

The purpose of this paper is to present various algebraic views of multisets, and certain connections between the theory of multisets (with multiplicities in the semiring of positive integers) and natural computing, in particular membrane and DNA computing. We introduce a Gödel encoding of multisets, and find some results regarding this encoding together with new connections and interpretations. We also introduce the norm of a multiset and we find some relationships between multiset theory and number theory.
REGISTER MACHINE COMPUTATIONS ON BINARY NUMBERS BY OSCILLATING AND CATALYTIC CHEMICAL REACTIONS MODELLED USING MASS-ACTION KINETICS
Authors: HINZE THOMAS , FASSLER RAFFAEL , LENSER THORSTEN , DITTRICH PETER
Published: June 2009

Biocomputing emerged as a promising paradigm capable of coping efficiently with challenges of programming decentralized but concerted reaction systems. The chemical programming metaphor subsumes different encoding techniques into molecular or spatial structures in conjunction with artificial reaction networks. Here, a variety of supplementary assumptions like predefined polymeric sequences or availability of inhibiting reactions is frequently used. Inspired by the idea to build chemical computers based on minimal requirements in chemistry from a theoretical perspective, we introduce a pure chemical register machine model operating on binary numbers. The register machine architecture is composed of reaction network motifs acting as fast switching logic gates, oscillators, and self-reproducible bit storage units. The dynamical machine behavior consistently employs mass-action kinetics. Two case studies, calculating the maximum of three natural numbers as well as numerical addition, illustrate the practicability of the design along with dynamical simulations.
MODULAR ASSEMBLY OF CELL SYSTEMS BIOLOGY MODELS USINGPSYSTEMS
Authors: ROMERO-CAMPERO FRANCISCO J. , TWYCROSS JAMIE , CÁMARA MIGUEL , BENNETT MALCOLM , GHEORGHE MARIAN , KRASNOGOR NATALIO
Published: June 2009

In this paper we propose an extension of a systems/synthetic biology modelling framework based on P systems that explicitly includes modularity. Modularisation in cellular systems can be produced by chemical specificity, spatial localisation and/or temporal modulation within cellular compartments. The first two of these modularisation features, the focus of this paper, can be easily specified and analysed in P systems using sets of rewriting rules to describe chemical specificity and membranes to represent spatial localisation. Our methodology enables the assembly of cell systems biology models by combining modules which represent functional subsystems. A case study consisting of a bacterial colony system is presented to illustrate our approach.
A CONSTANT TIME ALGORITHM FOR DNA ADD
Authors: AHRABIAN H. , NOWZARI-DALINI A. , ZARE-MIRAKABAD F.
Published: June 2009

We present a new molecular algorithm for adding two binary numbers with n bits. Without considering the generation of input, this algorithm can be performed in O(1) in a test tube using O(n) different types of DNA strands, and the output can be detected in O ( n ). The output strands, prior to read out operation, can serve as the input strands for another round of addition. The algorithm can be easily extended to any other logical operation, and even for adding two decimal numbers.
Chiral Dynamics in Photopion Physics: Theory, Experiment, and Future Studies at the HIγS Facility
Authors: Bernstein Aron M. , Ahmed Mohammad W. , Stave Sean , Wu Ying K. , Weller Henry R.
Published: June 2009

We review photopion experiments on the nucleon in the near-threshold region. We compare the results with the predictions of the low-energy theorems of quantum chromodynamics calculated using chiral perturbation theory (ChPT), which is based on the spontaneous breaking of chiral symmetry as well as explicit breaking due to the finite quark masses. As a result of the vanishing of the threshold amplitudes in the chiral limit, the experiments are difficult to perform because the cross sections are small. Nevertheless, the field is now mature in terms of accuracy and sensitivity. We also discuss the accomplishments and limitations of past measurements, as well as future planned experiments at Mainz and HIγS. The technical developments required for the HIγS facility are emphasized. Finally, we show that future experiments will provide even more accurate tests of ChPT and will be sensitive to isospin-breaking dynamics due to the mass difference between the up and down quarks.
Advances in Inflation in String Theory
Authors: Baumann Daniel , McAllister Liam
Published: June 2009

We provide a pedagogical overview of inflation in string theory. We focus upon the sensitivity of inflation to Planck-scale physics, which we argue provides both the primary motivation and the central theoretical challenge for the subject. We illustrate these issues through two case studies of inflationary scenarios in string theory: warped d-brane inflation and axion monodromy inflation. Finally, we indicate how future observations can test scenarios of inflation in string theory.
Lorentz Violation: Motivation and New Constraints
Authors: Liberati Stefano , Maccione Luca
Published: June 2009

We review the main theoretical motivations and observational constraints on Planck scale–suppressed violations of Lorentz invariance. After introducing the problems related to the phenomenological study of quantum gravitational effects, we discuss the main theoretical frameworks within which possible departures from Lorentz invariance can be described. In particular, we focus on the framework of effective field theory, describing several possible ways of including Lorentz violation therein and discussing their theoretical viability. We review the main low-energy effects that are expected in this framework. We discuss the current observational constraints on such a framework, focusing on those achievable through high-energy astrophysics observations. In this context, we present a summary of the most recent and strongest constraints on quantum electrodynamics with Lorentz-violating nonrenormalizable operators. Finally, we discuss the status of the field and its future perspectives.
Titanium particles stimulate COX-2 expression in synovial fibroblasts through an oxidative stress-induced, calpain-dependent, NF-κB pathway
Authors: Wei Xiaochao , Zhang Xinping , Flick Lisa M. , Drissi Hicham , Schwarz Edward M. , O'Keefe Regis J.
Published: June 2009

In prosthetic loosening, bone resorption is induced by wear debris particles generated from the artificial joint articulation. Our prior work showed that synovial-like fibroblasts respond to titanium particles by producing receptor activator of NF-κB ligand (RANKL), a critical activator of osteoclastogenesis. While this effect occurs through a cyclooxygenase-2 (COX-2)-dependent pathway, the mechanism of COX-2 stimulation by titanium particles is not clear. Here we show that titanium particles induce COX-2 gene expression by activating NF-κB signaling. Inhibitor of NF-κB (IκBα) is degraded following particle treatment, permitting active NF-κB to translocate to the nucleus where it interacts with the COX-2 promoter and drives transcription. NF-κB activation is dependent on reactive oxygen species since antioxidants block the NF-κB signaling induced by particles. Surprisingly, IκBα degradation is independent of IKK (IκB kinase) and the 26S proteasome. Instead, calpain inhibitor can block the IκBα degradation induced by particles. Furthermore, the calpain-targeted COOH-terminal PEST sequence of IκBα is necessary for phosphorylation and degradation, consistent with a proteasome-independent mechanism of catabolism. Altogether, the data demonstrate a signaling pathway by which titanium particles induce oxidative stress, stimulate calpain-mediated NF-κB activation, and activate target gene expression, including COX-2. These findings define important targets for osteolysis but may also have importance in other diseases where fibroblasts respond to environmental particles, including pulmonary diseases.
A novel mechanism of natural vitamin E tocotrienol activity: involvement of ERβ signal transduction
Authors: Comitato Raffaella , Nesaretnam Kalanithi , Leoni Guido , Ambra Roberto , Canali Raffaella , Bolli Alessandro , Marino Maria , Virgili Fabio
Published: June 2009

Vitamin E is a generic term used to indicate all tocopherol (TOC) and tocotrienol (TT) derivates. In the last few years, several papers have shown that a TT-rich fraction (TTRF) extracted from palm oil inhibits proliferation and induces apoptosis in a large number of cancer cells. However, the molecular mechanism(s) involved in TT action is still unclear. In the present study, we proposed for the first time a novel mechanism for TT activity that involves estrogen receptor (ER) signaling. In silico simulations and in vitro binding analyses indicated a high affinity of TTs for ERβ but not for ERα. In addition, in ERβ-containing MDA-MB-231 breast cancer cells, we demonstrated that TTs increase the ERβ translocation into the nucleus, which in turn activates estrogen-responsive genes ( MIC-1, EGR-1 and cathepsin D), as demonstrated by cell preincubation with the ER inhibitor ICI-182,780. Finally, we observed that TT treatment is associated with alteration of cell morphology, DNA fragmentation, and caspase-3 activation. Altogether, these experiments elucidated the molecular mechanism underling γ- and δ-TT effects.
Vascular actions of insulin with implications for endothelial dysfunction
Authors: Potenza Maria Assunta , Addabbo Francesco , Montagnani Monica
Published: June 2009

Hemodynamic actions of insulin depend largely on the hormone's ability to stimulate synthesis and release of endothelial mediators, whose balanced activity ensures dynamic control of vascular function. Nitric oxide (NO), endothelin-1 (ET-1), and reactive oxygen species (ROS) are important examples of endothelial mediators with opposing properties on vascular tone, hemostatic processes, and vascular permeability. Reduced NO bioavailability, resulting from either insufficient production or increased degradation of NO, characterizes endothelial dysfunction. In turn, endothelial dysfunction predicts vascular complications of metabolic and hemodynamic disorders. In the cardiovascular system, insulin stimulates the production and release of NO, ET-1, and ROS via activation of distinct intracellular signaling pathways. Under insulin-resistant conditions, increased insulin concentrations and/or impaired insulin-signaling pathways in the vasculature may contribute to imbalance in secretion of endothelial mediators that promote pathogenesis of vascular abnormalities. This short review describes signaling pathways involved in insulin-stimulated release of NO, ROS, and ET-1 and suggests possible molecular mechanisms by which abnormal insulin signaling may contribute to endothelial dysfunction.
A device for simultaneous live cell imaging during uni-axial mechanical strain or compression
Authors: Gerstmair Axel , Fois Giorgio , Innerbichler Siegfried , Dietl Paul , Felder Edward
Published: June 2009

Mechanical stimuli control multiple cellular processes such as secretion, growth, and differentiation. A widely used method to investigate cell strain ex vivo is stretching an elastic membrane to which cells adhere. However, simultaneous imaging of dynamic signals from single living cells grown on elastic substrates during uni-axial changes of cell length is usually hampered by the movement of the sample along the strain axis out of the narrow optical field of view. We used a thin, prestrained, elastic chamber as growth substrate for the cells and deformed the chamber with a computer-controlled stretch device. An algorithm that compensates the lateral displacement during stretch kept any selected point of the whole chamber at a constant position on the microscope during strain or relaxation (compression). Adherent cells or other materials that adhere to the bottom of the chamber at any given position could be imaged during controlled positive (stretch) or negative (compression) changes of cell length. The system was tested on living alveolar type II cells, in which mechanical effects on secretion have been intensively investigated in the past.
Persistence of Motor Memories Reflects Statistics of the Learning Event
Authors: Huang Vincent S. , Shadmehr Reza
Published: June 2009

Learning to control a new tool (i.e., a novel environment) produces an internal model, i.e., a motor memory that allows the brain to implicitly predict the behavior of the tool. Data from a wide array of experiments suggest that formation of motor memory is not a single process, but one that is due to multiple adaptive processes with different time constants. Here we asked whether these time constants are invariant or are they influenced by the statistics of the learning event. To measure the time constants, we controlled the statistics of the learning event in a reaching task and then assayed the decay rates of motor output in a set of trials in which errors were effectively removed. We found that prior experience with a rapid change in the environment increased the decay rate of memories acquired later in response to a gradual change in the same environment. Prior experience in an environment that changed gradually reduced the decay rates of memories acquired later in response to a rapid change in that same environment. Indeed we found that by manipulating the prior statistics of the learning experience, we could readily alter the decay rates of a given motor memory. This suggests that time scales of processes that support motor memory are not constant. Rather decay of motor memory is the brain's implicit estimate of how likely it is that the environment will change with time. During motor learning, prior statistics that suggest changes are likely to be permanent result in slowly decaying memories, whereas prior statistics that suggest changes are transient result in rapidly decaying memories.
Cannabinoid CB1Receptor-Dependent Long-Term Depression in Autaptic Excitatory Neurons
Authors: Kellogg Ryan , Mackie Ken , Straiker Alex
Published: June 2009

Long-term depression (LTD) of synaptic signaling—lasting from tens of minutes to hours or longer—is a widespread form of synaptic plasticity in the brain. Neurons express diverse forms of LTD, including autaptic LTD (autLTD) observed in cultured hippocampal neurons, the mechanism of which remains unknown. We have recently reported that autaptic neurons express both endocannabinoid-mediated depolarization-induced suppression of excitation (DSE) and metabotropic suppression of excitation (MSE). We now report that activating cannabinoid CB1receptors is necessary for the induction of autLTD. Most surprisingly, CB1does not induce autLTD via the Gi/oproteins typically activated by this receptor nor with Gs. Rather, the requirements of presynaptic phospholipase C and filled calcium stores suggest Gq. In autLTD, a 3- to 4-min activation of the receptor by the endocannabinoid 2-arachidonoyl glycerol leads to prolonged inhibition while leaving short-term inhibition (e.g., DSE) intact. autLTD requires activation of both metabo- and ionotropic glutamate receptors. autLTD also requires MEK/ERK activation. Under certain conditions, one or more DSE stimuli will elicit autLTD. It is becoming evident that cannabinoids mediate multiple forms of plasticity at a single synapse, stretching temporally from tens of seconds (DSE/MSE) to tens of minutes (autLTD) to hours (CB1desensitization). Our findings imply a remarkable flexibility for the cannabinoid signaling system whereby discrete mechanisms of CB1activation within a single neuron yield temporally and mechanistically distinct forms of plasticity.
Substance P Enhances Excitatory Synaptic Transmission on Spinally Projecting Neurons in the Rostral Ventromedial Medulla After Inflammatory Injury
Authors: Zhang Liang , Hammond Donna L.
Published: June 2009

It has been proposed, but not directly tested, that persistent inflammatory nociception enhances excitatory glutamatergic inputs to neurons in the rostral ventromedial medulla (RVM), altering the activity and function of these neurons. This study used whole cell patch-clamp methods to record evoked excitatory postsynaptic currents (eEPSCs) in spinally projecting RVM neurons from rats injected with saline or complete Freund's adjuvant (CFA) 3–4 days earlier and to examine the role of substance P (SP) in modulating excitatory synaptic transmission. Input-output relationships demonstrated that CFA treatment facilitated fast excitatory glutamatergic inputs to type 1 and type 2 nonserotonergic spinally projecting RVM neurons, but not to type 3 neurons. The facilitation in type 1 and 2 neurons was dependent on neurokinin-1 (NK1) and N-methyl-d-aspartate (NMDA) receptors and prevented by the PKC inhibitor GF109203X. In a subset of neurons from naïve rats, SP mimicked the effects of CFA and increased the potency and efficacy of glutamatergic synaptic transmission. The facilitation was prevented by 10 μM GF109203X, but not by 10 μM KN93, a CaMKII inhibitor. SP (0.3–3 μM) by itself produced concentration-dependent inward currents in most nonserotonergic, but not serotonergic neurons. The present study is the first demonstration, at the cellular level, that persistent inflammatory nociception leads to a sustained facilitation of fast excitatory glutamatergic inputs to RVM neurons by an NK1 and NMDA receptor-dependent mechanism that involves PKC. Further, it demonstrates that the facilitation is restricted to specific populations of RVM neurons that by inference may be pain facilitatory neurons.
Unconstrained Finite Element for Geometrical Nonlinear Dynamics of Shells
Authors: Coda Humberto Breves , Paccola Rodrigo Ribeiro
Published: June 2009

This paper presents a positional FEM formulation to deal with geometrical nonlinear dynamics of shells. The main objective is to develop a new FEM methodology based on the minimum potential energy theorem written regarding nodal positions and generalized unconstrained vectors not displacements and rotations. These characteristics are the novelty of the present work and avoid the use of large rotation approximations. A nondimensional auxiliary coordinate system is created, and the change of configuration function is written following two independent mappings from which the strain energy function is derived. This methodology is called positional and, as far as the authors′ knowledge goes, is a new procedure to approximated geometrical nonlinear structures. In this paper a proof for the linear and angular momentum conservation property of the Newmark β algorithm is provided for total Lagrangian description. The proposed shell element is locking free for elastic stress‐strain relations due to the presence of linear strain variation along the shell thickness. The curved, high‐order element together with an implicit procedure to solve nonlinear equations guarantees precision in calculations. The momentum conserving, the locking free behavior, and the frame invariance of the adopted mapping are numerically confirmed by examples.
A Bayesian Approach to Multistage Fitting of the Variation of the Skeletal Age Features
Authors: Hua Dong , Chen Dechang , Liu Fang , Youssef Abdou
Published: June 2009

Accurate assessment of skeletal maturity is important clinically. Skeletal age assessment is usually based on features encoded in ossification centers. Therefore, it is critical to design a mechanism to capture as much as possible characteristics of features. We have observed that given a feature, there exist stages of the skeletal age such that the variation pattern of the feature differs in these stages. Based on this observation, we propose a Bayesian cut fitting to describe features in response to the skeletal age. With our approach, appropriate positions for stage separation are determined automatically by a Bayesian approach, and a model is used to fit the variation of a feature within each stage. Our experimental results show that the proposed method surpasses the traditional fitting using only one line or one curve not only in the efficiency and accuracy of fitting but also in global and local feature characterization.
ProbioticLactobacillus rhamnosusGR-1 andLactobacillus reuteriRC-14 May Help Downregulate TNF-Alpha, IL-6, IL-8, IL-10 and IL-12 (p70) in the Neurogenic Bladder of Spinal Cord Injured Patient with Urinary Tract Infections: A Two-Case Study
Authors: Anukam Kingsley C. , Hayes Keith , Summers Kelly , Reid Gregor
Published: June 2009

The management of urinary tract infection (UTI) in individuals with spinal cord injury (SCI) continues to be of concern, due to complications that can occur. An emerging concept that is a common underlying pathophysiological process is involved, wherein pathogens causing UTI have a role in inflammatory progression. We hypothesized that members of the commensal flora, such as lactobacilli, may counter this reaction through anti-inflammatory mediation. This was assessed in a pilot two-patient study in which probioticLactobacillus rhamnosusGR-1 andLactobacillus reuteriwere administered to one patient and placebo to another, both along with antibiotics to treat acute UTI. Urinary TNF-alpha was significantly downregulated (P=.015) in the patient who received the probiotic and who used intermittent catheterization compared with patient on placebo and using an indwelling catheter. The extent to which this alteration resulted in improved well-being in spinal cord injured patients remains to be determined in a larger study.
Recovery of Otoacoustic Emission Function in Luetic Endolymphatic Hydrops: A Possible Measure of Improvement in Cochlear Function
Authors: Chun Robert H. , Pinto Jayant M. , Blankenhorn Rebecca , Dayal Vijay S.
Published: June 2009

Syphilis is a preventable and curable multi-organ disease caused byTreponema pallidumthat may also affect the inner ear. First reported in 1887 by Adam Politzer, luetic endolymphatic hydrops (LEH) is a treatable complication of syphilis which causes a potentially reversible sensorineural hearing loss. Symptoms of LEH include fluctuating hearing loss (often low frequency), tinnitus, and vertigo. Though audiometric parameters have been examined in patients with otosyphilis, few studies have examined the use of otoacoustic emissions (OAEs) as a tool to measure improvement in cochlear function. Here we report an improvement in hearing loss, speech discrimination, and OAEs following treatment of LEH.
White Adipose Tissue Cells Are Recruited by Experimental Tumors and Promote Cancer Progression in Mouse Models
Authors: Zhang Yan , Daquinag Alexes , Traktuev Dmitry O. , Amaya-Manzanares Felipe , Simmons Paul J. , March Keith L. , Pasqualini Renata , Arap Wadih , Kolonin Mikhail G.
Published: June 2009

The connection between obesity and accelerated cancer progression has been established, but the mediating mechanisms are not well understood. We have shown that stromal cells from white adipose tissue (WAT) cooperate with the endothelium to promote blood vessel formation through the secretion of soluble trophic factors. Here, we hypothesize that WAT directly mediates cancer progression by serving as a source of cells that migrate to tumors and promote neovascularization. To test this hypothesis, we have evaluated the recruitment of WAT-derived cells by tumors and the effect of their engraftment on tumor growth by integrating a transgenic mouse strain engineered for expansion of traceable cells with established allograft and xenograft cancer models. Our studies show that entry of adipose stromal and endothelial cells into systemic circulation leads to their homing to and engraftment into tumor stroma and vasculature, respectively. We show that recruitment of adipose stromal cells by tumors is sufficient to promote tumor growth. Finally, we show that migration of stromal and vascular progenitor cells from WAT grafts to tumors is also associated with acceleration of cancer progression. These results provide a biological insight for the clinical association between obesity and cancer, thus outlining potential avenues for preventive and therapeutic strategies. [Cancer Res 2009;69(12):5259–66]
Loss of Retinal Cadherin Facilitates Mammary Tumor Progression and Metastasis
Authors: Agiostratidou Georgia , Li Maomi , Suyama Kimita , Badano Ines , Keren Rinat , Chung Su , Anzovino Amy , Hulit James , Qian Binzhi , Bouzahzah Boumediene , Eugenin Eliseo , Loudig Olivier , Phillips Greg R. , Locker Joseph , Hazan Rachel B.
Published: June 2009

The mammary epithelium is thought to be stabilized by cell-cell adhesion mediated mainly by E-cadherin (E-cad). Here, we show that another cadherin, retinal cadherin (R-cad), is critical for maintenance of the epithelial phenotype. R-cad is expressed in nontransformed mammary epithelium but absent from tumorigenic cell lines. In vivo, R-cad was prominently expressed in the epithelium of both ducts and lobules. In human breast cancer, R-cad was down-regulated with tumor progression, with high expression in ductal carcinoma in situ and reduced expression in invasive duct carcinomas. By comparison, E-cad expression persisted in invasive breast tumors and cell lines where R-cad was lost. Consistent with these findings, R-cad knockdown in normal mammary epithelium stimulated invasiveness and disrupted formation of acini despite continued E-cad expression. Conversely, R-cad overexpression in aggressive cell lines induced glandular morphogenesis and inhibited invasiveness, tumor formation, and lung colonization. R-cad also suppressed the matrix metalloproteinase 1 (MMP1), MMP2, and cyclooxygenase 2 gene expression associated with pulmonary metastasis. The data suggest that R-cad is an adhesion molecule of the mammary epithelium, which acts as a critical regulator of the normal phenotype. As a result, R-cad loss contributes to epithelial suppression and metastatic progression. [Cancer Res 2009;69(12):5030–8]
Biological Significance of Prolactin in Gynecologic Cancers
Authors: Levina Vera V. , Nolen Brian , Su YunYun , Godwin Andrew K. , Fishman David , Liu Jinsong , Mor Gil , Maxwell Larry G. , Herberman Ronald B. , Szczepanski Miroslaw J. , Szajnik Marta E. , Gorelik Elieser , Lokshin Anna E.
Published: June 2009

There is increasing evidence that prolactin (PRL), a hormone/cytokine, plays a role in breast, prostate, and colorectal cancers via local production or accumulation. Elevated levels of serum PRL in ovarian and endometrial cancers have been reported, indicating a potential role for PRL in endometrial and ovarian carcinogenesis. In this study, we show that serum PRL levels are significantly elevated in women with a strong family history of ovarian cancer. We show dramatically increased expression of PRL receptor in ovarian and endometrial tumors as well as in endometrial hyperplasia, signifying the importance of PRL signaling in malignant and premalignant conditions. PRL mRNA was expressed in ovarian and endometrial tumors, indicating the presence of an autocrine loop. PRL potently induced proliferation in several ovarian and endometrial cancer cell lines. Binding of PRL to its receptor was followed by rapid phosphorylation of extracellular signal-regulated kinase (ERK) 1/2, mitogen-activated protein kinase/ERK kinase 1, signal transducer and activator of transcription 3, CREB, ATF-2, and p53 and activation of 37 transcription factors in ovarian and endometrial carcinoma cells. PRL also activated Ras oncogene in these cells. When human immortalized normal ovarian epithelial cells were chronically exposed to PRL, a malignant transformation occurred manifested by the acquired ability of transformed cells to form clones, grow in soft agar, and form tumors in severe combined immunodeficient-beige mice. Transformation efficiency was diminished by a Ras inhibitor, providing proof that PRL-induced transformation uses the Ras pathway. In summary, we present findings that indicate an important role for PRL in ovarian and endometrial tumorigenesis. PRL may represent a risk factor for ovarian and endometrial cancers. [Cancer Res 2009;69(12):5226–33]
N-myc Downstream Regulated Gene 1/Cap43 Suppresses Tumor Growth and Angiogenesis of Pancreatic Cancer through Attenuation of Inhibitor of κB Kinase β Expression
Authors: Hosoi Fumihito , Izumi Hiroto , Kawahara Akihiko , Murakami Yuichi , Kinoshita Hisafumi , Kage Masayoshi , Nishio Kazuto , Kohno Kimitoshi , Kuwano Michihiko , Ono Mayumi
Published: June 2009

N-myc downstream regulated gene 1 (NDRG1)/Cap43 expression is a predictive marker of good prognosis in patients with pancreatic cancer as we reported previously. In this study, NDRG1/Cap43 decreased the expression of various chemoattractants, including CXC chemokines for inflammatory cells, and the recruitment of macrophages and neutrophils with suppression of both angiogenesis and growth in mouse xenograft models. We further found that NDRG1/Cap43 induced nuclear factor-κB (NF-κB) signaling attenuation through marked decreases in inhibitor of κB kinase (IKK) β expression and IκBα phosphorylation. Decreased IKKβ expression in cells overexpressing NDRG1/Cap43 resulted in reduction of both nuclear translocation of p65 and p50 and their binding to the NF-κB motif. The introduction of an exogenous IKKβ gene restored NDRG1/Cap43-suppressed expression of melanoma growth-stimulating activity α/CXCL1, epithelial-derived neutrophil activating protein-78/CXCL5, interleukin-8/CXCL8 and vascular endothelial growth factor-A, accompanied by increased phosphorylation of IκBα in NDRG1/Cap43-expressing cells. In patients with pancreatic cancer, NDRG1/Cap43 expression levels were also inversely correlated with the number of infiltrating macrophages in the tumor stroma. This study suggests a novel mechanism by which NDRG1/Cap43 modulates tumor angiogenesis/growth and infiltration of macrophages/neutrophils through attenuation of NF-κB signaling. [Cancer Res 2009;69(12):4983–91]
Cancer Prevention: From 1727 to Milestones of the Past 100 Years
Authors: Lippman Scott M. , Hawk Ernest T.
Published: June 2009

The rich, multidisciplinary history of cancer prevention recounted here begins with surgical and workplace recommendations of the 1700s and ends with 2009 results of the enormous (35,535 men) Selenium and Vitamin E [prostate] Cancer Prevention Trial (SELECT). This history comprises a fascinating array of chemopreventive, vaccine, surgical, and behavioral science research, both preclinical and clinical. Preclinical milestones of cancer prevention include the 1913 and 1916 mouse studies by Lathrop and Loeb of cancer development associated with pregnancy or cancer prevention through castration (oophorectomy), preventing chemically induced mouse carcinogenesis as early as 1929, energy restriction studies in the 1940s, the 1950s discoveries and later molecular characterizations of field cancerization and multistep carcinogenesis, and the effects of angiogenesis inhibition in genetically engineered mice reported in 2009. The extraordinary panoply of clinical research includes numerous large and smaller chemoprevention studies of nutritional supplements, other dietary approaches, a Bacillus Calmette-Guérin trial in 1976, molecular-targeted agents, and agents to prevent infection-related cancers such as hepatitis B virus vaccine to prevent liver cancer in 1984. Clinical surgical prevention includes removal of intraepithelial neoplasia detected by screening (including Pap testing developed in 1929 and culposcopy for cervical premalignancy and colonoscopy and polypectomy to prevent colorectal cancer begun in the 1960s) and prophylactic surgeries, such as in Lynch syndrome patients begun in 1977. Behavioral studies include smoking cessation and control beginning in the 1950s, obesity control rooted in studies of 1841, and genetic-counseling and cancer-survivorship studies. This history of pioneering events may help in better understanding who we are and what we want to achieve as cancer prevention researchers and practitioners. [Cancer Res 2009;69(13):5269–84]
Targeting Tumor Endothelial Marker 8 in the Tumor Vasculature of Colorectal Carcinomas in Mice
Authors: Fernando Stephen , Fletcher Bradley S.
Published: June 2009

Tumor endothelial marker 8 (TEM8) is a recently described protein that is preferentially expressed within tumor endothelium. We have developed a fusion protein that targets TEM8 and disrupts tumor vasculature by promoting localized thrombosis. Fusion protein specificity and function were evaluated using Western blot analysis, ELISA, and enzymatic assays. A xenograft model of colorectal carcinoma was used to test the efficacy of targeted and control fusion proteins. Mice treated with the gene encoding anti-TEM8/truncated tissue factor exhibited a 53% reduction in tumor volume when compared with the untreated animals (P < 0.0001; n = 10) and achieved a 49% increase in tumor growth delay by Kaplan-Meier analysis (P = 0.0367; n = 6). Immunohistochemistry confirmed tumor endothelial expression of TEM8, fusion protein homing to tumor vasculature, decrease in vessel density, and localized areas of thrombosis. These data support the hypothesis that targeting TEM8 can be an effective approach to influence tumor development by disrupting tumor vasculature. [Cancer Res 2009;69(12):5126–32]
Leucine Leucine-37 Uses Formyl Peptide Receptor–Like 1 to Activate Signal Transduction Pathways, Stimulate Oncogenic Gene Expression, and Enhance the Invasiveness of Ovarian Cancer Cells
Authors: Coffelt Seth B. , Tomchuck Suzanne L. , Zwezdaryk Kevin J. , Danka Elizabeth S. , Scandurro Aline B.
Published: June 2009

Emerging evidence suggests that the antimicrobial peptide, leucine leucine-37 (LL-37), could play a role in the progression of solid tumors. LL-37 is expressed as the COOH terminus of human cationic antimicrobial protein-18 (hCAP-18) in ovarian, breast, and lung cancers. Previous studies have shown that the addition of LL-37 to various cancer cell lines in vitro stimulates proliferation, migration, and invasion. Similarly, overexpression of hCAP-18/LL-37 in vivo accelerates tumor growth. However, the receptor or receptors through which these processes are mediated have not been thoroughly examined. In the present study, expression of formyl peptide receptor–like 1 (FPRL1) was confirmed on ovarian cancer cells. Proliferation assays indicated that LL-37 does not signal through a G protein–coupled receptor, such as FPRL1, to promote cancer cell growth. By contrast, FPRL1 was required for LL-37–induced invasion through Matrigel. The peptide stimulated mitogen-activated protein kinase and Janus-activated kinase/signal transducers and activators of transcription signaling cascades and led to the significant activation of several transcription factors, through both FPRL1-dependent and FPRL1-independent pathways. Likewise, expression of some LL-37–stimulated genes was attenuated by the inhibition of FPRL1. Increased expression of CXCL10, EGF, and PDGF-BB as well as other soluble factors was confirmed from conditioned medium of LL-37–treated cells. Taken together, these data suggest that LL-37 potentiates a more aggressive behavior from ovarian cancer cells through its interaction with FPRL1. (Mol Cancer Res 2009;7(6):907–15)
The MDM2-A Splice Variant of MDM2 Alters Transformation In vitro and the Tumor Spectrum in Both Arf- and p53-Null Models of Tumorigenesis
Authors: Volk Erin L. , Fan Liying , Schuster Katja , Rehg Jerold E. , Harris Linda C.
Published: June 2009

MDM2-A is a common splice variant of murine double minute 2 (MDM2) that is frequently detected in many tumor types. Our previous work has characterized MDM2-A as an activator of p53, and therefore, in a wild-type p53 background, this splice variant would be predicted to confer p53-dependent tumor protection. To test this hypothesis, we used Mdm2-a transgenic mice to assess transformation and tumorigenesis in tumor susceptible murine models. A MDM2-A–dependent decrease in transformation was observed in Arf-null mouse embryonic fibroblasts (MEF) or when wild-type MEFs were exposed to the carcinogen ethylnitrosourea. However, this reduced transformation did not confer tumor protection in vivo; Mdm2-a/Arf-null mice and ethylnitrosourea-treated MDM2-expressing mice developed similar tumor types with equivalent latency compared with their respective controls. Interestingly, when p53 was deleted, MDM2-A expression enhanced transformation of p53-null MEFs and altered tumor spectrum in vivo. In addition, p53-heterozygous mice that expressed MDM2-A developed aggressive mammary tumors that were not observed in p53-heterozygous controls. In conclusion, we found that although MDM2-A expression enhances p53 activity and decreases transformation in vitro, it cannot confer tumor protection. In contrast, MDM2-A seems to exhibit a novel transforming potential in cells where p53 function is compromised. These data show that MDM2 splice variants, such as MDM2-A, may provide protection against transformation of normal tissues having intact p53. However, when such splice variants are expressed in tumors that have defects in the p53 pathway, these isoforms may contribute to tumor progression, which could explain why their expression is often associated with aggressive tumor types. (Mol Cancer Res 2009;7(6):863–9)
The genetics of venous thromboembolism
Authors: Gohil Reya , Peck George , Sharma Pankaj
Published: June 2009

We conducted a systematic and comprehensive meta-analysis on all candidate genes to assess their genetic contribution to the aetiology of venous thromboembolism (VTE) (pulmonary embolism and deep venous thrombosis) in all ethnic groups. Electronic databases were searched until and including January 2008 for any candidate gene investigated in VTE. Odds ratios (OR) and 95% confidence intervals (CI) were determined for each gene disease association using fixed and random effect models. Our meta-analyses included ∼126,525 cases and 184,068 controls derived from 173 case-control studies, which included 21 genes (28 polymorphisms). Statistically significant associations with VTE were identified for factor V G1691A (OR 9.45; 95% CI 6.72–13.30, p<0.0001), factor V A4070G (OR 1.24; 95% CI
Treatment of Atrial Fibrillation With Antiarrhythmic Drugs or Radiofrequency Ablation
Authors: Calkins Hugh , Reynolds Matthew R. , Spector Peter , Sondhi Manu , Xu Yingxin , Martin Amber , Williams Catherine J. , Sledge Isabella
Published: June 2009

Background—

Although radiofrequency catheter ablation (RFA) has evolved from an experimental procedure to an important treatment option for atrial fibrillation, the relative safety and efficacy of catheter ablation relative to that of antiarrhythmic drug (AAD) therapy has not been established.

Methods and Results—

Two separate systematic reviews were conducted: one on RFA and the other on AAD to provide accurate and broadly representative estimates of the clinical efficacy and safety of both therapies in the treatment of atrial fibrillation. Electronic searches were conducted in EMBASE and MEDLINE from 1990 to 2007. For the RFA review, all study designs were accepted. For the AAD review, articles were limited to prospective studies on the following drugs of interest: amiodarone, dofetilide, sotalol, flecainide, and propafenone. Data were extracted by 1 reviewer, with a second reviewer performing independent confirmation of extracted data. Sixty-three RFA and 34 AAD studies were included in the reviews. Patients enrolled in RFA studies tended to be younger (mean age, 55 versus 62 years), had longer duration of atrial fibrillation (6.0 versus 3.1 years), and had failed a greater number of prior drug trials (2.6 versus 1.7). The single-procedure success rate of ablation off AAD therapy was 57% (95% CI, 50% to 64%), the multiple procedure success rate off AAD was 71% (95% CI, 65% to 77%), and the multiple procedure success rate on AAD or with unknown AAD usage was 77% (95% CI, 73% to 81%). In comparison, the success rate for AAD therapy was 52% (95% CI, 47% to 57%). A major complication of catheter ablation occurred in 4.9% of patients. Adverse events for AAD studies, although more common (30% versus 5%), were less severe.

Conclusions—

Studies of RFA for treatment of atrial fibrillation report higher efficacy rates than do studies of AAD therapy and a lower rate of complications.
Economic Impact of Angina After an Acute Coronary Syndrome
Authors: Arnold Suzanne V. , Morrow David A. , Lei Yang , Cohen David J. , Mahoney Elizabeth M. , Braunwald Eugene , Chan Paul S.
Published: June 2009

Background—

Angina in patients with coronary artery disease is associated with worse quality of life; however, the relationship between angina frequency and resource utilization is unknown.

Methods and Results—

Using data from the MERLIN-TIMI 36 trial, we assessed the association between the extent of angina after an acute coronary syndrome (ACS) and subsequent cardiovascular resource utilization among 5460 stable outpatients who completed the Seattle Angina Questionnaire at 4 months after an ACS and who were then followed for an additional 8 months. Angina frequency was categorized as none (score, 100; 2739 patients), monthly (score, 61 to 99; 1608 patients), weekly (score, 31 to 60; 854 patients), and daily (score, 0 to 30; 259 patients). Multivariable regression models evaluated the association between angina frequency and overall costs attributable to cardiovascular hospitalizations, outpatient visits and procedures, and medications. As compared with no angina, overall costs increased in a graded fashion with higher angina frequency—no angina, $2928 (reference); monthly angina, $3909 (adjusted relative cost ratio, 1.29; 95% CI, 1.21 to 1.39); weekly angina, $4558 (adjusted relative cost ratio, 1.52; 95% CI, 1.48 to 1.67); and daily angina, $6949 (adjusted relative cost ratio, 2.32; 95% CI, 2.01 to 2.69;
P
for trend <0.001). Differences in costs were attributable primarily to higher rates of ACS hospitalization and coronary revascularization among patients with more severe angina.

Conclusion—

Among stable outpatients after ACS, a direct graded relationship was found between higher angina frequency and healthcare costs. As compared with patients without angina, patients with daily angina had a >2-fold increase in resource utilization and incremental costs of $4000 after 8 months of follow-up.
Evaluation of WRF and HadRM Mesoscale Climate Simulations over the U.S. Pacific Northwest*
Authors: Zhang Yongxin , Dulière Valérie , Mote Philip W. , Salathé Eric P.
Published: June 2009

This work compares the Weather Research and Forecasting (WRF) and Hadley Centre Regional Model (HadRM) simulations with the observed daily maximum and minimum temperature (Tmax and Tmin) and precipitation at Historical Climatology Network (HCN) stations over the U.S. Pacific Northwest for 2003–07. The WRF and HadRM runs were driven by the NCEP/Department of Energy (DOE) Atmospheric Model Intercomparison Project (AMIP)-II Reanalysis (R-2) data. The simulated Tmax in WRF and HadRM as well as in R-2 compares well with the observations. Predominantly cold biases of Tmax are noted in WRF and HadRM in spring and summer, while in winter and fall more stations show warm biases, especially in HadRM. Large cold biases of Tmax are noted in R-2 at all times. The simulated Tmin compares reasonably well with the observations, although not as well as Tmax in both models and in the reanalysis R-2. Warm biases of Tmin prevail in both model simulations, while R-2 shows mainly cold biases. The R-2 data play a role in the model biases of Tmax, although there are also clear indications of resolution dependency. The model biases of Tmin originate mainly from the regional models. The temporal correlation between the simulated and observed daily precipitation is relatively low in both models and in the reanalysis; however, the correlation increases steadily for longer averaging times. The high-resolution models perform better than R-2, although the nested WRF domains do have the largest biases in precipitation during the winter and spring seasons.