bluuebunny/crossref_metadata_2025 huggingface dataset:
Molecular Footprints of Neurotoxic Amphetamine Action
Authors: KUHN DONALD M. , GEDDES TIMOTHY J.
Published: July 2010

Methamphetamine (METH) and 3,4‐methylenedioxymethamphetamine (MDMA or Ecstasy) are amphetamine analogs with high abuse potential. These drugs also cause damage to dopamine and serotonin nerve terminalsin vivo.The mechanisms by which these drugs cause neurotoxicity are not known, but a great deal of attention has been focused on reactive oxygen species (ROS) and reactive nitrogen species (RNS) as mediators of this toxicity. ROS and RNS have very short biological half‐livesin vivo, and it is virtually impossible to measure them in brain directly. However, ROS and RNS are also characterized by their extreme reactivity with proteins and nucleotides. Tryptophan hydroxylase (TPH) and tyrosine hydroxylase (TH), the initial and rate limiting enzymes in the synthesis of serotonin and dopamine, respectively, are identified targets for the actions of METH and MDMA. Using recombinant forms of these proteins, we have found that nitric oxide, catechol‐quinones, and peroxynitrite, all of which are potentially produced by the neurotoxic amphetamines, covalently modify both TPH and TH. The ROS and RNS cause reductions in catalytic function of these enzymes in a manner that is consistent with the effects of METH and MDMAin vivo.Protein‐bound ROS or RNS may serve as molecular footprints of neurotoxic amphetamine action.
Expression and Function of Na+HCO3− Cotransporters in the Gastrointestinal Tract
Authors: SEIDLER URSULA , ROSSMANN HEIDI , JACOB PETRA , BACHMANN OLIVER , CHRISTIANI STEPHANIE , LAMPRECHT GEORG , GREGOR MICHAEL
Published: July 2010

Abstract: The stomach, duodenum, colon, and pancreas secrete HCO3− ions into the lumen. Although the importance of HCO3− secretion for the maintenance of mucosal integrity, a normal digestion, and the reabsorption of Cl− has been well established, the molecular nature of the apical and basolateral HCO3− transporting proteins has remained largely unknown. Functional studies have suggested that a Na+HCO3− cotransport system, similar but not identical to the well‐characterized Na+HCO3− cotransporter in the basolateral membrane of the kidney proximal tubule, is present in duodenal and colonic enterocytes, pancreatic ducts cells, and gastric cells and involved in HCO3− uptake from the interstitium. This report describes our work towards understanding the molecular nature, cellular origin, and functional relevance of the Na+HCO3− cotransporter(s) in the stomach and intestine and reviews work by others on the function and localization of Na+HCO3− cotransport processes in the gastrointestinal tract.
Screwworm Eradication in the Americas
Authors: WYSS JOHN H.
Published: July 2010

Abstract: The screwworm fly, Cochliomyia hominivorax (Coquerel), is a parasite that attacks all warm‐blooded animals including humans. This parasite has caused significant losses to the livestock industries of the Americas. Since the screwworm eradication program was initiated in the Southeastern United States in 1957, the eradication program has successfully progressed to its current location in Panama. A variety of technologies and tools have been used in the eradication programs. The cooperative agreement has been a significant tool in the success of the program. In the United States, the State‐Federal Cooperative programs provided the mechanism for carrying out screwworm eradication. Once screwworms were eradicated from the United States, the need to expand the program internationally, in order to protect the United States, became evident. A cooperative agreement created the Mexico‐United States Commission for the Eradication of Screwworms (Commission). Commission‐Guatemala and Commission‐Belize Cooperative Agreements were used to eradicate screwworms from these countries. Followup programs in El Salvador, Honduras, Nicaragua, Costa Rica, and Panama were implemented by cooperative agreements between the United States Department of Agriculture and the individual countries. The positive and negative aspects, as well as the necessary elements of successful cooperative agreements, are discussed.
The Role of Bim, a Proapoptotic BH3‐Only Member of the Bcl‐2 Family, in Cell‐Death Control
Authors: STRASSER ANDREAS , PUTHALAKATH HAMSA , BOUILLET PHILIPPE , HUANG DAVID C.S. , O'CONNOR LIAM , O'REILLY LORRAINE A. , CULLEN LEONIE , CORY SUZANNE , ADAMS JERRY M.
Published: July 2010

Abstract: Apoptosis is an evolutionarily conserved process for killing unwanted cells. Genetic and biochemical experiments have indicated that three groups of proteins are necessary for activation of the cell‐death effector machinery: cysteine proteases, their adaptors, and proapoptotic Bcl‐2 family members. Antiapoptotic Bcl‐2 family members are needed for cell survival. We have cloned Bim, a proapoptotic Bcl‐2 family member that shares with the family only a 9‐16 aa region of homology [Bcl‐3 homology region (BH3)], but is otherwise unique. Bim requires its BH3 region for binding to Bcl‐2 and activation of apoptosis. Analysis of Bim‐deficient mice has shown that Bim is essential for the execution of some but not all apoptotic stimuli that can be antagonized by Bcl‐2. Bim‐deficient mice have increased numbers of lymphocytes, plasma cells, and myeloid cells, and most develop fatal autoimmune glomerulonephritis. In healthy cells, Bim is bound to the microtubule‐associated dynein motor complex, and is thereby sequestered from Bcl‐2. Certain apoptotic signals unleash Bim and allow it to translocate to intracellular membranes, where it interacts with Bcl‐2 or its homologues. These results indicate that BH3‐only proteins are essential inducers of apoptosis that can be unleashed by certain death signals. Unleashed BH3‐only proteins neutralize the prosurvival function of Bcl‐2‐like molecules, and this is thought to liberate Apaf‐l‐like adapters to activate caspase zymogens, which then initiate cell degradation.
Social Disruption, Immunity, and Susceptibility to Viral Infection: Role of Glucocorticoid Insensitivity and NGF
Authors: SHERIDAN J. F. , STARK J. L. , AVITSUR R. , PADGETT D. A.
Published: July 2010

Abstract: Glucocorticoid (cort) responses have been shown to suppress inflammatory reactions by inhibiting the trafficking of immune cells. Recently, it was demonstrated that restraint stress (RST) and psychosocial stress (social reorganization; SRO) differentially affected the pathophysiology and survival in the mouse influenza viral infection model. While both stressors activated the HPA axis, only SRO affected survival. in RST, elevated cort diminished recruitment of inflammatory cells following intranasal challenge of C57BL/6 mice with A/PR8 virus. However, infected SRO mice developed hypercellularity in the lungs and were more likely to die from lung consolidation than controls. Since elevated cort failed to be anti‐inflammatory in SRO mice, the hypothesis that psychosocial stress induced steroid insensitivity was tested. An in vitro cort suppression test was performed by stimulating splenocytes from SRO and control mice with mitogen in the presence or absence of cort. Proliferation of ConA‐stimulated cells was inhibited by cort in a dose‐dependent fashion in controls, but splenocytes from SRO mice stimulated with ConA were resistant to cort‐induced suppression. Thus, psychosocial stress induced a state of steroid insensitivity. SRO also induced the release of nerve growth factor (NGF) from the salivary glands into circulation; plasma NGF correlated with development of steroid insensitivity. NGF has been reported to negatively regulate the expression of type II glucocorticoid receptors, and thus may be a key factor in the induction of steroid insensitivity.
Molecular Anthropology and Race
Authors: DISOTELL TODD R.
Published: July 2010

Abstract: Molecular analyses have led to many recent advances in the study of human variation. The addition of DNA analyses of fossils now allows the testing of hypotheses derived from sampling living people. Further sampling of all of the regions of the human genome has led to a remarkably consistent evolutionary scenario that helps to explain the patterns of variation found today.
Bioelectrical Impedance Analysis What Does It Measure?
Authors: SCHOELLER DALE A.
Published: July 2010

Abstract: Bioelectrical impedance analysis (BIA) has been proposed for measuring fat‐free mass, total body water, percent fat, body cell mass, intracellular water, and extracellular water: a veritable laboratory in a box. Although it is unlikely that BIA is quite this versatile, correlations have been demonstrated between BIA and all of these body compartments. At the same time, it is known that all of the compartments are correlated among themselves. Because of this, it is difficult to determine whether BIA is specific for any or all of these compartments. To investigate this question, we induced acute changes in total body water and its compartments over a 3‐h period. Using this approach, we demonstrated that multifrequency BIA, using the Cole‐Cole model to calculate the zero frequency and infinite frequency resistance, measures extracellular and intracellular water.
The p53 Tumor Suppressor Gene: From Molecular Biology to Clinical Investigation
Authors: SOUSSI THIERRY
Published: July 2010

Abstract: The tumor suppressor p53 is a phosphoprotein barely detectable in the nucleus of normal cells. Upon cellular stress, particularly that induced by DNA damage, p53 can arrest cell cycle progression, thus allowing the DNA to be repaired; or it can lead to apoptosis. These functions are achieved, in part, by the transactivational properties of p53, which activate a series of genes involved in cell cycle regulation. In cancer cells bearing a mutant p53, this protein is no longer able to control cell proliferation, resulting in inefficient DNA repair and the emergence of genetically unstable cells. The most common changes of p53 in human cancers are point missense mutations within the coding sequences of the gene. Such mutations are found in all major histogenetic groups, including cancers of the colon (60%), stomach (60%), breast (20%), lung (70%), brain (40%), and esophagus (60%). It is estimated that p53 mutations are the most frequent genetic event in human cancers, accounting for more than 50% of cases. One of the most striking features of the inactive mutant p53 protein is its increased stability (half‐life of several hours, compared to 20 min for wild‐type p53) and its accumulation in the nucleus of neoplastic cells. Therefore, positive immunostaining is indicative of abnormalities of the p53 gene and its product. Several studies have shown that p53 mutations are associated with short survival in colorectal cancer, but the use of p53 as a tumoral marker is still a matter of debate.
The Parahippocampal Gyrus in Alzheimer's Disease: Clinical and Preclinical Neuroanatomical Correlates
Authors: VAN HOESEN GARY W. , AUGUSTINACK JEAN C. , DIERKING JASON , REDMAN SARAH J. , THANGAVEL RAMASAMY
Published: July 2010

Abstract: The human parahippocampal gyrus forms a large part of the limbic lobe along the ventromedial part of the temporal cortical mantle. It is a variable and complicated cortex in terms of structure, and the latter is aggravated further by interfaces with the anterior insula anteriorly and the cingulate gyrus and occipital lobe posteriorly. Additional complications relate to its lateral border with the temporal cortex and especially the sulcal configurations that define this junction. The rhinal sulcus, which separates parahippocampal and temporal cortices in other species, including the anthropoid apes, is either lacking or rudimentary in the human brain. Thus, defining this junction requires cytoarchitectural examination and precludes the use of mere inspection of sulcal existing patterns. The cortical areas that form the parahippocampal gyrus are vulnerable to pathological changes in Alzheimer's disease (AD), and its entorhinal and perirhinal subdivisions are both the most heavily damaged cortical areas and the focus for disease onset. The neurons that acquire neurofibrillary tangles (NFTs) occupy the junction of the isocortical mantle with the limbic cortical mantle, but share, or partially share, a vulnerability phenotype with large neurons in both domains. The differential expression of this phenotype across time creates the false impression of NFT spread in cross‐sectional comparisons of AD brains. The questions of what this phenotype is and why it is expressed first in the perirhinal and entorhinal cortices of the parahippocampal gyrus are the central molecular biological/neuroanatomical questions in understanding the etiology of AD.
Flow Loop Experiments Determine Hydrate Plugging Tendencies in the Field
Authors: MATTHEWS PATRICK N. , NOTZ PHIL K. , WIDENER MARK W. , PRUKOP GABRIEL
Published: July 2010

Abstract: Flow loop studies were conducted on live reservoir fluids from the Werner Bolley gas condensate well in Southern Wyoming to determine hydrate formation and plugging tendencies of the hydrocarbon fluids under field conditions. Field tests conducted by DeepStar in 1997 at Werner Bolley were summarized and the results were compared to data from flow loop studies. Subcooling measured in the flow loop was found to be comparable to that measured in the field near hydrate plug formations. Flow loop results indicated both the plugging tendency and the nature of plugging mechanism observed in the field. Used in conjunction with transient flow simulation, flow loop results indicated the most probable locations for plug formation.
VIP‐ and PACAP‐Induced Salivary Chromogranin A Secretion in the Isolated Perfused Submandibular Gland of Rats
Authors: YANAIHARA NOBORU , KANNO TOMIO , ASADA NAOTO , IWANAGA TOSHIHIKO , JUN LI , NAGASAWA SHINGO , YANAIHARA CHIZUKO
Published: July 2010

Abstract: In the study reported in this paper, sensitive ELISA for rat CgA was developed using synthetic rat CgA(359–389) as antigen, Nα‐biotinylated glycylglycyl rat CgA(359–389), and antirat CgA(359–389) serum for the measurement of CgA‐LI in rat saliva. CgA‐LI in rat submandibular tissues and saliva was characterized by both immunohistochemical and immunochemical methods. Using isolated perfused rat submandibular gland. VIP at 0.1–1.0 nM in the presence of 0.1 μM ACh was found to cause CgA‐LI secretion, whereas neither PACAP‐27 nor PACAP‐38 showed any effect on CgA secretion.
Integrative Mitogenic Role of Protein Kinase B/Akt in β‐Cells
Authors: TRÜMPER KATJA , TRÜMPER ANDREA , TRUSHEIM HEIDI , ARNOLD RUDOLF , GÖKE BURKHARD , HÖRSCH DIETER
Published: July 2010

Abstract: Protein kinase B/Akt (PKB/Akt) is activated by phosphatidylinositol 3‐kinase (PI 3‐K) and is a central mediator of cellular proliferation and protection against apoptosis. Insulin, insulin‐like growth factor (IGF‐1), and glucagon‐like peptide‐1 (GLP‐1) act as glucose‐dependent growth factors for pancreatic β‐cells. We assessed signaling pathways and stimulation patterns of PKB/Akt activation by these ligands in the β‐cell line INS‐1. Insulin, IGF‐1, and GLP‐1 induced distinctive time dependent, dose dependent, and glucose dependent phosphorylation of PKB/Akt. Insulin and IGF‐1 stimulated PI 3‐K activity was mainly associated with insulin receptor substrate (IRS) isoforms IRS‐1 and IRS‐2 and less so with the IRS‐isoform Grb‐2 associated binder‐1 (Gab‐1). In contrast, GLP‐1 induced PI 3‐K activity mainly in Gab‐1 and also in IRS‐2 immunoprecipitates, although in an attenuated kinetic. Thus, activation pathways of PKB/Akt by insulin, IGF‐1, and GLP‐1 converge at the level of IRS‐isoforms and PI 3‐K inducing differential activation of PKB/Akt. These data indicate an essential role of PKB/Akt in regulation of β‐cell proliferation.
Mechanism of Action of Camptothecin
Authors: LIU LEROY F. , DESAI SHYAMAL D. , LI TSAI‐KUN , MAO YONG , SUN MEI , SIM SAI‐PENG
Published: July 2010

Abstract:Camptothecin (CPT) class of compounds has been demonstrated to be effective against a broad spectrum of tumors. Their molecular target has been firmly established to be human DNA topoisomerase I (topo I). CPT inhibits topo I by blocking the rejoining step of the cleavage/religation reaction of topo‐I, resulting in accumulation of a covalent reaction intermediate, the cleavable complex. The primary mechanism of cell killing by CPT is S‐phase‐specific killing through potentially lethal collisions between advancing replication forks and topo‐I cleavable complexes. Collisions with the transcription machinery have also been shown to trigger the formation of long‐lived covalent topo‐I DNA complexes, which contribute to CPT cytotoxicity. Two novel repair responses to topo‐I‐mediated DNA damage involving covalent modifications of topo‐I have been discovered. The first involves activation of the ubiquitin/26S proteasome pathway, leading to degradation of topo‐I (CPT‐induced topo‐I downregulation). The second involves SUMO conjugation to topo‐I. The potential roles of these new mechanisms for repair of topo‐I‐mediated DNA damage in determining CPT sensitivity/resistance in tumor cells are discussed.
The Clinical Development of 9‐Aminocamptothecin
Authors: TAKIMOTO CHRIS H. , THOMAS REBECCA
Published: July 2010

Abstract: 9‐Aminocamptothecin (9‐AC) is a topoisomerase I‐targeting agent first synthesized by Wani and Wall in 1986. Because of its potent in vitro effects and promising preclinical activity in colorectal cancer animal models, it was designated a high‐priority compound for further drug development by the NCI. In 1993, 9‐AC first entered clinical trials as a 72‐hour intravenous (i.v.) infusion. Predictable myelosuppression was the major dose‐limiting toxicity, and pharmacokinetic studies showed a relatively short plasma half‐life and unstable lactone ring. Unfortunately, phase II studies using this schedule showed minimal or no activity in tumors such as colorectal and lung cancer. Modest activity was observed in ovarian cancer and in refractory lymphomas. Efforts to improve systemic drug exposure by utilizing alternative schedules of administration of 9‐AC such as prolonged, continuous intravenous infusions have also been tested. However, phase II studies of 120‐hour weekly infusions of 9‐AC have not shown improved activity against solid tumors such as colorectal cancer. More recently, a daily times 5 days i.v. administration schedule has been tested. Currently, further development of intravenously administered 9‐AC for the treatment of colorectal cancer is not promising. Thus, topotecan and irinotecan remain the only two successfully developed topoisomerase I‐targeting drugs in the United States. This experience with 9‐AC raises important questions regarding how to best select new topoisomerase I‐targeting drugs for future clinical development.
Molecular Mechanisms of Hypo‐ and Afibrinogenemia
Authors: BRENNAN STEPHEN O. , FELLOWES ANDREW P. , GEORGE PETER M.
Published: July 2010

Abstract: Point mutations responsible for hypo‐ and afibrinogenemia are yielding new insights into amino acid side chains involved in the molecular processing, assembly, secretion, and domain stability of fibrinogen. Reverse phase chromatography, isoelectric focussing, electrospray mass spectrometry, and tryptic peptide mass mapping have shown that chains with heterozygous mutations of γ284 Gly→Arg, Bβ316 Asp→Tyr and γ371 Thr→Ile are absent from plasma fibrinogen. The nonexpression of these mutations appears to result from perturbation of the five‐stranded β sheet of the D domain. We propose that this is due to retention of the variant in the endoplasmic reticulum and that in turn this leads to hypofibrinogenemia. Other mutations effect intracellular proteolysis and chain assembly. For example the mutation, Aα20 Val→Asp, makes the protein a substrate for furin, which removes the first 19 residues of the Aα chain as the mature molecule transits the trans golgi complex. Transient expression of γ153 Cys→Arg chains together with Aα and Bβ chains suggests this mutation might perturb chain assembly, and the incorporation of mutations of Bβ353 Leu→Arg or Bβ400 Gly→Asp into intracellular fibrinogen precludes its subsequent export from host cells expressing fibrinogen genes. The graded severity of the hypo‐ and afibrinogenemias associated with homozygous Aα chain truncations suggest the absolute minimal requirement for molecular assembly is the formation of the C terminal disulfide ring of the coiled coil.
Characterization of Human Hematopoietic Cells with Short‐Lived in Vivo Repopulating Activity
Authors: Eaves C. , Glimm H. , Eisterer W. , Audet J. , Maguer‐Satta V. , Pireta J.
Published: July 2010

Abstract: Recent studies with purified hematopoietic stem cells in vitro support a model of stem cell self‐renewal control that involves distinct mechanisms regulating permissiveness to and execution of lineage restriction. Such a model predicts the existence of phenotypically separable populations of hematopoietic cells that are pluripotent and either capable or incapable of extensive self‐renewal. Such populations have been previously described in the mouse. We describe here the first evidence that such cells can now be identified in humans using different types of immunodeficient mice as hosts.
Effect of l‐Carnitine Pretreatment on 3‐Nitropropionic Acid‐Induced Inhibition of Rat Brain Succinate Dehydrogenase Activity
Authors: BINIENDA ZBIGNIEW K. , SADOVOVA NATALYA V. , ROUNTREE ROBERT L. , SCALLET ANDREW C. , ALI SYED F.
Published: July 2010

Abstract:l‐Carnitine (LC) plays an important regulatory role in the mitochondrial transport of long chain free fatty acids (FFA). 3‐Nitropropionic acid (3‐NPA) is known to induce cellular energy deficit and oxidative stress‐related neurotoxicity via an irreversible inhibition of mitochondrial succinate dehydrogenase (SDH). In the present study, activity of SDH was measured in order to evaluate neuroprotective effects of LC against the 3‐NPA‐induced neurotoxicity. Male, CD Sprague‐Dawley rats, three months old, were injected with either 50 or 100 mg/kg of LC, i.p., 30 min prior to 3‐NPA (30 mg/kg, s.c.) or with 3‐NPA alone. The activity of brain SDH was quantified spectrophotometrically in caudate nucleus (CN), frontal cortex (FC), and hippocampus (HIP) 60 min after the 3‐NPA injection. The SDH activity in the animals treated with 3‐NPA alone was 38% (CN), 50% (FC), and 36% (HIP) that of saline controls. Pretreatment with LC prior to 3‐NPA injection attenuated decreases of SDH activity by approximately 15 and 29% (LC low and high dose, respectively). Despite the attenuation of SDH inhibition, the activity of SDH in these regions remained significantly lower in treated than in control rats (p< 0.05). It appears that the protective effect of LC against 3‐NPA‐induced oxidative stress cannot be explained by the direct action of LC to interfere with the SDH inhibition but are rather achieved by LC actions downstream of the SDH inhibition.
New Tests of Vestibular Function
Authors: DEMER JOSEPH L. , CRANE BENJAMIN T. , TIAN JUN‐RU , WIEST GERALD
Published: July 2010

Abstract: The vestibulo‐ocular reflex (VOR) is the only drive for short‐latency eye movements stabilizing the retina during externally imposed, sudden, high‐head accelerations. New strategies can exploit this unique VOR feature to study it under conditions relevant to the daily lives of patients, and to exclude the contributions from confounding nonvestibular mechanisms. Testing of the yaw vestibulo‐ocular reflex (VOR) during random, whole‐body rotational transients at ≤2800°/s2 delivered about centered and eccentric axes enables measurement of gains and millisecond latencies of the canal and otolith VORs in humans. Repeated measurements in acute unilateral deafferentation show sequential recovery of canal and otolith VORs to contralesional rotation, but severe and permanent deficits to ipsilesional rotation. Patients with bilateral loss of caloric responses show severe bilateral loss of VORs to transient rotation, suggesting that the apparent preservation of their VORs during sinusoidal rotations at moderate frequencies may be due instead to somatosensory inputs.

Since visual acuity is degraded by retinal image motion, dynamic visual acuity (DVA) measured during imposed head‐on‐body or whole‐body transient motion can correlate closely with VOR performance only if optotypes are presented during directionally and temporally unpredictable, high‐acceleration head motion. Prediction and efference copy are relentlessly employed by vestibulopathic patients to enable good DVA during predictable or low‐acceleration head motion. The linear VOR to transient lateral acceleration is strongly dependent upon viewing distance. The latency of this otolith VOR is slightly longer and more variable than the canal VOR. Unlike the canal VOR, the otolith VOR does not develop a strong directional asymmetry in unilateral deafferentation. The otolith VOR is bilaterally attenuated in bilateral vestibulopathy, and loses target distance dependence in cerebellar degeneration.
Fertility and Maternal Age
Authors: KREY LEWIS , LIU HUI , ZHANG JOHN , GRIFO JAMIE
Published: July 2010

In humans, the live birth rate drops precipitously with increasing maternal age, and this decline is associated with increases in the incidence of oocyte and embryo aneuploidy. Preimplantation aneuploidy screening has improved pregnancy outcome by significantly lowering the miscarriage rate. Nevertheless, aneuploidy screening only identifies the affected embryos; it does not attempt to correct the underlying biologic problem. Anomalies in chromosome segregation can result from a dysfunctional first or second meiotic division in the egg or develop after fertilization during the first few mitoses of early embryonic development. In both instances, ooplasmic anomalies may account for the nuclear problem. Low cell levels of cytoplasmic proteins (e.g., cytoskeletal elements, enzymes, energy stores, cell cycle regulatory proteins) may lead to a dysfunctional division of chromosomes during egg maturation or following fertilization. Ooplasmic injection is a micromanipulation technique that has produced pregnancies in patients with a history of poor‐quality, fragmented embryos. Germinal vesicle transfer is a research procedure used to investigate the ooplasmic‐nuclear interplay regulating cell cycle, maturation, and fertilization. Both these techniques may prove to be effective in improving the quality of eggs from patients of advanced maternal age.
Potential Role of Recombinant Annexin II in Diabetic Vascular Injury
Authors: ISHII HIDETO , YOSHIDA MASAYUKI , HAJJAR KATHERINE A. , TANAKA AKIRA , YASUKOCHI YUKIO , SHIMOKADO KENTARO , NUMANO FUJIO
Published: July 2010

Abstract: Hyperinsulinemia and hyperglycemia have been associated with vascular injury such as atherosclerosis in diabetes mellitus. Recently, annexin II, a member of annexin family proteins, has been found to work as co‐receptor on endothelial cells for plasminogen and tissue plasminogen activator, facilitating plasmin generation on the surface of vascular endothelium. In this review, we overviewed the effect of glucose and insulin on plasmin generation in endothelial cells and its potential modulation by recombinant annexin II (rAN II) based on our data.
A Role for Rho in Smooth Muscle Phenotypic Regulation
Authors: WORTH NATHALIE F. , CAMPBELL GORDON R. , ROLFE BARBARA E.
Published: July 2010

Abstract: The role of the small GTP‐binding protein Rho in the process of smooth muscle cell (SMC) phenotypic modulation was investigated using cultured rabbit aortic SMCs. Both Rho transcription and Rho protein expression were high for the first 3 days of culture (“contractile” state cells), with expression decreasing after change to the “synthetic” state and peaking upon return to the contractile phenotype. Activation of Rho (indicated by translocation to the membrane) also peaked upon return to the contractile state and was low in synthetic state SMCs. Transient transfection of synthetic state rabbit SMCs with constitutively active Rho (val14rho) caused a dramatic decrease in cell size and reorganization of cytoskeletal proteins to resemble those of the contractile phenotype; α‐actin and myosin adopted a tightly packed, highly organized arrangement, whereas vimentin localized to the immediate perinuclear region and focal adhesions were enlarged. Conversely, specific inhibition of endogenous Rho, by expression of C3 transferase, resulted in the complete loss of actin and myosin filaments without affecting the distribution of vimentin. Focal adhesions were reduced in number. Thus, Rho plays a key role in regulating SMC phenotypic expression.
Eicosapentaenoic Acid Protects Endothelial Cell Function Injured by Hypoxia/Reoxygenation
Authors: MORITA IKUO , ZHANG YOU‐WEI , MUROTA SEI‐ITSU
Published: July 2010

Abstract: Eicosapentaenoic acid (EPA) may protect against atherosclerosis by improving lipid metabolism and modulating vascular cell function. Ischemia/reperfusion injury is one risk factor for atherosclerosis. We investigated if EPA could improve hypoxia/reoxygenation (H/R)‐induced endothelial cell dysfunction of gap junctional intercellular communication (GJIC). GJIC in human umbilical vascular endothelial cells (HUVECs) was measured using a photobleaching technique. Results demonstrated that H (24h)/R 2h) induced a GJIC reduction in HUVECs; however, it was inhibited by EPA pretreatment. H/R produced reactive oxygen species, but it was not affected by EPA, and it contributed little to GJIC dysfunction. By contrast, tyrosine kinase activated by H/R was inhibited by EPA pretreatment, and tyrosine kinase inhibitors also abolished H/R‐induced GJIC reduction. The protective effects of EPA on the H/R‐induced GJIC reduction was also observed in cells treated with tyrosine phosphatase inhibitor. These data indicate the EPA improves H/R‐induced endothelial dysfunction through inhibition of tyrosine kinase activation, and it could lead to prevention of progression and/or initiation of atherosclerosis.
Biochemistry and Reproductive Endocrinology of Estrogen Sulfotransferase
Authors: SONG WEN‐CHAO
Published: July 2010

Abstract:Estrogen sulfotransferase is a cytosolic enzyme that catalyzes the sulfoconjugation and inactivation of estrogens. Significant progress has been made in the last few years regarding the structure, substrate specificity, tissue expression, and regulation of mammalian estrogen sulfotransferases. The enzyme has high affinity for estrogens and is expressed in a number of estrogen target tissues, including the male and female reproductive systems. Expression of the enzyme in the testis has been particularly well characterized. In the testis, estrogen sulfotransferase is localized selectively to Leydig cells and its expression in these cells is dependent on LH and androgen. It was concluded, from bothin vitroandin vivostudies, that estrogen sulfotransferase can function as an effective modulator of local estrogen activity in target tissues. The finding that certain hydroxylated polychlorinated biphenyls are potent inhibitors of the human estrogen sulfotransferase enzyme raises the possibility that environmental chemicals can cause endocrine disruption by enhancing endogenous estrogen activity through inhibition of steroid transformation enzymes such as estrogen sulfotransferase. This provides a new paradigm in explaining the endocrine disrupting potential of environmental chemicals that have low or no binding affinities for steroid hormone receptors.
Occurrence of Pharmaceutical Contaminants and Screening of Treatment Alternatives for Southeastern Louisiana
Authors: BOYD GLEN R. , GRIMM DEBORAH A.
Published: July 2010

Abstract: Recent studies conducted in Germany, Switzerland, Denmark, Brazil, Canada, the United States, and elsewhere indicate that low‐level concentrations of pharmaceuticals and personal‐care products (PPCPs) and their metabolites may be widespread contaminants in our aquatic environment. The persistence of pharmaceutical contaminants has been attributed to (1) human consumption of drugs and subsequent discharges from sewage treatment plants, and (2) veterinary use of drugs and nonpoint discharges from agricultural runoff. Contamination of water resources by these compounds, particularly endocrine disrupting chemicals (EDCs), is emerging as an international environmental concern. The long‐term effects of continuous, low‐level exposure to PPCPs is not well understood. Preliminary data for raw water samples collected from the Mississippi River and Lake Pontchartrain, Louisiana, are summarized. Three PPCP compounds (clofibric acid, naproxen, and estrone) were analyzed using solid‐phase extraction, derivatization, and GC/MS. Batch experiments also were conducted to determine equilibrium capacity of activated carbon for clofibric acid. Preliminary results indicate the occurrence of the selected PPCP contaminants in raw water samples at or near method‐detection limits. For batch equilibrium experiments, preliminary results indicate that activated carbon potentially can be used to remove clofibric acid from water. More research is needed to develop rapid and reliable methods for PPCP analysis and to determine the effectiveness of treatment processes for removal of PPCP contaminants in water.
Androgen Receptor: Structural Domains and Functional Dynamics after Ligand‐Receptor Interaction
Authors: ROY ARUN K. , TYAGI RAKESH K. , SONG CHUNG S. , LAVROVSKY YAN , AHN SOON C. , OH TAE‐SUNG , CHATTERJEE BANDANA
Published: July 2010

Abstract: Androgens are C‐19 steroids secreted primarily from the testes and adrenals that play a critical role in reproduction. Reproductive functions of androgens are mediated through coordination of diverse physiological processes ranging from brain functions to specific cell proliferation and apoptosis. At the molecular level, most of these regulatory influences are exerted by altered expression of appropriate genes by the androgen receptor (AR), a member of the nuclear receptor (NR) superfamily. The unliganded AR is a cytoplasmic protein and, upon ligand binding, it translocates into the nucleus. Thereafter, in conjunction with other transcription factors and coactivators, the AR influences transcription of target genes through a multistep process that includes its clustering in a subnuclear compartment. Here, we describe the genomic organization of the AR, the role of individual structural domains in specific AR function, and the influence of agonistic/antagonistic ligands in the intracellular movement of the receptor. We also show that the AR is capable of undergoing multiple rounds of nucleocytoplasmic recycling after ligand binding and dissociation. Xenobiotic ligands, considered as selective androgen receptor modulators (SARMs), can modulate AR activity by inhibiting either its nuclear translocation or its subnuclear clustering and subsequent transactivation function.
The Italian Breast Cancer Prevention Trial with Tamoxifen
Authors: GUERRIERI‐GONZAGA ALIANA , GALLI ARIANNA , ROTMENSZ NICOLE , DECENSI ANDREA
Published: July 2010

Abstract:The Italian Tamoxifen Prevention Study includes 5408 healthy hysterectomized women aged 35‐70 years who have been randomized to 20 mg/day of tamoxifen or placebo for 5 years. After 46 months median follow‐up, an increased risk of venous vascular events (38 women on tamoxifen vs. 18 women on placebo,P= 0.0053), mainly consisting of superficial phlebitis, has been observed and 41 breast cancers have occurred (19 on tamoxifen vs. 22 on placebo,P= 0.64). However, subgroup analyses indicated a borderline significant reduction of breast cancer among women continuously on estrogen replacement therapy (ERT, mostly transdermal) and receiving tamoxifen, with 8 cases of breast cancer among 390 ERT users on placebo versus 1 case among 362 ERT users on tamoxifen (RR = 0.13, 95% CI = 0.02‐1.02). Withdrawal rate (mainly due to menopausal symptoms) differed according to ERT use, with compliance being 78% and 75% at 3 and 5 years, respectively, for women who never took ERT, and 92% and 88% at 3 and 5 years, respectively, for women not on ERT at baseline, but who took ERT at some time during the trial. Pharmacokinetic and pharmacodynamic (surrogate end point biomarkers) studies showed that a lower dose of tamoxifen (such as 5 mg/day) does not affect the drug's activity on several biomarkers of both cardiovascular and breast cancer risk. We are therefore planning a multicenter placebo‐controlled phase III trial in postmenopausal healthy women on hormone replacement therapy (HRT) to test whether the combination of HRT and low‐dose tamoxifen retains the benefits while reducing the risks of either agent maintaining a high compliance rate.
The MORE Trial: Multiple Outcomes for Raloxifene Evaluation
Authors: DICKLER MAURA N. , NORTON LARRY
Published: July 2010

Abstract: Breast cancer is a common disease in the United States and Europe and is therefore a major target for prevention strategies. Estrogen plays a central role in its pathogenesis, and treatment with estrogen deprivation has long been recognized to be an effective therapy. Tamoxifen is the first selective estrogen receptor modulator (SERM) to be widely used for the treatment of breast cancer and has been demonstrated to reduce the risk of breast cancer in high‐risk women. Raloxifene is a second‐generation SERM that has estrogenic effects on bone and lipid metabolism, and antiestrogenic effects on breast tissue. Unlike tamoxifen, raloxifene displays antiestrogenic effects on the endometrium and may serve as a safer alternative to tamoxifen in the prevention setting. The MORE trial is a multicenter randomized placebo‐controlled trial designed to determine whether 3 years of raloxifene reduces the risk of fracture in postmenopausal women with osteoporosis. As a secondary end point of the trial, raloxifene was shown to reduce the risk of both in situ and invasive breast cancer by 65% (RR = 0.35; 95% CI = 0.21‐0.58; P < 0.001). The benefits were most significant in women who developed estrogen receptor (ER)‐positive cancers, with a relative risk of 0.10 (95% CI = 0.04‐0.24). This reduced incidence of breast cancer may be due to an anticarcinogenic effect or to a slowing of growth of occult ER‐positive cancer, with a shift to the right in the time‐to‐cancer curve. A second large‐scale prevention trial in breast cancer comparing tamoxifen to raloxifene is presently enrolling cancer‐free, but high‐risk postmenopausal women (the STAR trial). Future directions include combined estrogen blockade of the breast by the addition of an aromatase inhibitor to a SERM. New trial designs, including those based on biochemical changes at the tissue level, will be required to allow future progress in this field with adequate rapidity.
Effects of Hormone Replacement Therapy on Cognitive and Brain Aging
Authors: RESNICK SUSAN M. , MAKI PAULINE M.
Published: July 2010

Abstract: Recent reports suggest that hormone therapy may be associated with a reduced risk for Alzheimer's disease and may offer some protection against age‐associated declines in specific cognitive functions. The majority of these reports are based on observational studies, which are confounded by the “healthy user” bias—the tendency for women receiving hormone therapy to be younger, better educated, and have fewer medical problems. In one attempt to address these limitations, we conducted a series of studies examining effects of hormone therapy on cognitive and brain functioning in nondemented postmenopausal women in the Baltimore Longitudinal Study of Aging (BLSA). In this sample, women receiving hormone therapy and women who never received hormone therapy were comparable with respect to educational attainment, general medical health, and performance on a test of verbal knowledge. Despite these similarities, women receiving hormone therapy performed better on tests of verbal and visual memory compared to never‐treated women. The two groups also differed in the patterns of regional brain activation evoked during performance of delayed verbal and figural memory tasks. Furthermore, longitudinal comparisons revealed greater relative blood flow increases over two years in women receiving hormone therapy for the hippocampus and other mesial temporal lobe structures that subserve memory. These observational findings from our studies in the BLSA have led to the development of a large‐scale randomized clinical trial of hormone therapy and cognitive aging, the ancillary Women's Health Initiative Study of Cognitive Aging (WHISCA), and have important implications for studies of the effects of SERM's on cognitive and brain functioning.
Developing a SERM: Stringent Preclinical Selection Criteria Leading to an Acceptable Candidate (WAY‐140424) for Clinical Evaluation
Authors: KOMM BARRY S. , LYTTLE C. RICHARD
Published: July 2010

Abstract: Estrogens are represented by a diverse group of compounds. Within this large family of molecules are tissue‐selective estrogens that have been classified as selective estrogen receptor modulators (SERMs). These compounds are characterized by the fact that they exhibit both estrogen agonist and antagonist activity dependent upon the gene promoter and target tissue being examined. SERMs have been intensively studied over the past decade, especially since one, raloxifene, has been approved for the prevention and treatment of postmenopausal osteoporosis. While not a replacement for hormone replacement therapy (HRT), raloxifene can be an alternative to it and other treatments for osteoporosis. The ideal SERM would provide the positive benefits associated with HRT without the uterine and breast stimulation. Raloxifene does achieve some of the benefits of HRT, specifically on the skeleton and lipid metabolism with no apparent uterine effects, and a potential decreased risk of developing breast cancer associated with raloxifene therapy. However, there are a number of parameters that can be improved. A number of SERMs have been evaluated only to fail in development due to, for the most part, uterine safety issues. In order to develop an improved SERM, a stringent screening process was designed to select compounds that did not stimulate the uterus or breast. At the same time, these new compounds would have a positive impact on the skeleton and lipid metabolism with the additional improvement (over raloxifene) of a neutral effect on hot flashes. Under these strict conditions, WAY‐140424 was developed and, to date, the preclinical pharmacology data have accurately predicted the clinical response demonstrated in phase I and II trials.
Conclusions
Authors: DUNN BARBARA K. , ANTHONY MARIETTA , SHERMAN SHERRY , COSTANTINO JOSEPH P.
Published: July 2010

Abstract: The “considerations” addressed in this section consist of a number of thought‐provoking issues and unresolved questions that emerge from the papers in this volume. The evidence for tamoxifen carcinogenicity in animal models and, to a more restricted extent, in humans has led some investigators to question whether SERMs are ready or appropriate for clinical testing—specifically, in a disease prevention setting involving healthy but high‐risk individuals. There is, however, inconsistency in both efficacy and toxicity—specifically, carcinogenicity—between animal models and humans, leading others to question the value of basing the decision to proceed with clinical studies on preclinical results in animals. Although the molecular basis for SERM action is rapidly being clarified, the cellular activity of these agents is still elusive. We discuss the view that the efficacy of tamoxifen in breast cancer is based on its treatment of “occult cancers,” or small collections of cancer cells that are not clinically apparent, not only in the context of prevention but also in the treatment setting. As part of our approach that assumes estrogen activity to be the foundation upon which SERM development is being modeled, we discuss the inconsistency between the epidemiologic data and prospective randomized data with respect to the relationship between estrogen use and cardiovascular disease. The need to validate surrogate markers of SERM action is discussed in relation to bone but is clearly relevant to all disease sites. The semantics used in describing SERM action as agonistic or antagonistic in relation to estrogen at various target sites has been inconsistent, especially in the clinical context. We attempt to dissect out some of the inconsistencies in semantics in the hope that this will contribute to improved communication of data resulting from SERM research. In the clinical arena, we begin with the premise that the large, simple randomized trial offers the optimal design for the testing of SERMs. In view of limited resources, however, we counter this position with alternative, if less desirable, approaches to the clinical format for SERM testing. Finally, we explore the process by which statistically meaningful results from clinical trials are extrapolated into the specific drug indications that apply to clinical practice.
A New Angle on Gravitational Clustering
Authors: Scoccimarro Román
Published: July 2010

Abstract: A new approach to gravitational instability in large‐scale structure is described, where the equations of motion are written and solved as in field theory in terms of Feynman diagrams. The basic objects of interest are the propagator (which propagates solutions forward in time), the vertex (which describes nonlinear interactions between waves) and a source with prescribed statistics which describes the effect of initial conditions. We show that loop corrections renormalize these quantities, and discuss applications of this formalism to a better understanding of gravitational instability and to improving nonlinear perturbation theory in the transition to the nonlinear regime. We also consider the role of vorticity creation due to shell‐crossing and show using N‐body simulations for which at small (virialized) scales the velocity field reaches equipartition, that is, the vorticity power spectrum is about twice the divergence power spectrum.
Cosmic Statistics of Statistics: N‐point Correlations
Authors: Zapudi István
Published: July 2010

Abstract: The fully general calculation of the cosmic error on N‐point correlation functions and related quantities is presented. More precisely, the variance caused by the finite volume, discreteness, and edge effects is determined for any estimator which is based on a general function of N‐tuples, such as multi‐point correlation functions and multi‐spectra. The results are printed explicitly for the two‐point correlation function (or power‐spectrum), and for the three‐point correlation (or bispectrum). These are the most popular statistics in the study of large‐scale structure, yet the general calculation of their variance has not been performed until now.
Proteome and Proteomics for the Research on Protein Alterations in Aging
Authors: Toda Tosifusa
Published: July 2010

Abstract: Functional decline of tissues in aged animals is a result of cellular aging. Though any process of somatic cell aging basically depends on genomic instructions, phenotypes of aged cells are expressed in a given internal environment of each cell type that was made with translated proteins and post‐translationally modified products. Therefore, research on age‐dependent protein alterations in each cell type is very important in clarifying mechanisms of aging. The novel term “proteome” is a compound of “protein” and “genome,” which means constitutive whole proteins including post‐translationally modified products in a cell type. Proteomics is a novel strategy for analyzing proteomes. In proteomics, high resolution two‐dimensional electrophoresis is exclusively performed for isolation of proteins followed by mass spectrometry for identification of proteins and determination of modifications. Thus, proteomics is becoming appreciated as a powerful tool to find out proteins responsible for cellular aging, symptoms of senility and geriatric diseases.