bluuebunny/crossref_metadata_2025 huggingface dataset:
Decreases in splanchnic vascular resistance contribute to hypotensive effects ofl-serine in hypertensive rats
Authors: Mishra Ramesh C. , Tripathy Saswati , Gandhi Jugal D. , Balsevich John , Akhtar Jawed , Desai Kaushik M. , Gopalakrishnan Venkat
Published: March 2010

l-Serine administration reduces mean arterial pressure (MAP) in spontaneously hypertensive rats (SHR) and Wistar-Kyoto (WKY) rats rendered hypertensive by chronic oral treatment with the nitric oxide synthase inhibitor Nω-nitro-l-arginine methyl ester (l-NAME). To determine if the fall in MAP was due to decreases in vascular resistance or cardiac output (CO), and to record regional hemodynamic effects, we measured the distribution of fluorescent microspheres to single bolus intravenous injections of l-serine (1 mmol/kg) in 14-wk-old male WKY, SHR, and l-NAME-treated WKY rats. MAP and total peripheral resistance (TPR) were significantly higher ( P < 0.01), whereas CO was lower in l-NAME-treated WKY ( P < 0.01) and SHR ( P < 0.05). l-Serine administration led to a rapid fall in MAP (WKY 22%, l-NAME-WKY 46%, SHR 34%,) and TPR (WKY 24%, l-NAME-WKY 68%, SHR 53%), whereas CO was elevated. In WKY rats, l-serine induced an increase in blood flow only in the small intestine (53%) while it was more profound in several vascular beds of hypertensive rats [l-NAME-WKY: small intestine (238%), spleen (184%), diaphragm (85%), and liver (65%); SHR: small intestine (217%), spleen (202%), diaphragm (116%), large intestine (105%), pancreas (96%), and liver (93%)]. Pretreatment with a combination of apamin (a small calcium-activated potassium channel inhibitor) and charybdotoxin (an intermediate calcium-activated potassium channel inhibitor) abolished the l-serine-induced changes in blood flow and TPR. l-Serine acts predominantly on apamin- and charybdotoxin-sensitive potassium channels in the splanchnic circulation to increase blood flow, thereby contributing to the fall in TPR and the pronounced blood pressure-lowering effect of l-serine in hypertensive rats.
Defective angiogenesis in hypoplastic human fetal lungs correlates with nitric oxide synthase deficiency that occurs despite enhanced angiopoietin-2 and VEGF
Authors: Boucherat Olivier , Franco-Montoya Marie-Laure , Delacourt Christophe , Martinovic Jelena , Masse Virginie , Elie Caroline , Thébaud Bernard , Benachi Alexandra , Bourbon Jacques R.
Published: March 2010

Lung hypoplasia (LH) is a life-threatening congenital abnormality with various causes. It involves vascular bed underdevelopment with abnormal arterial muscularization leading to pulmonary hypertension. Because underlying molecular changes are imperfectly known and sometimes controversial, we determined key factors of angiogenesis along intrauterine development, focusing at the angiopoietin (ANG)/Tie-2 system. Lung specimens from medical terminations of pregnancy (9–37 wk) were used, including LH due to congenital diaphragmatic hernia (CDH) or other causes, and nonpulmonary disease samples were used as controls. ELISA determination indicated little ANG-1 change during pregnancy and no effect of LH, whereas Tie-2 declined similarly between 9 and 37 wk in LH and controls. By contrast, ANG-2 markedly increased in LH from 24 wk, whereas it remained stable in controls. Because VEGF increased also, this was interpreted as an attempt to overcome vascular underdevelopment. Hypothesizing that its inefficiency might be due to impaired downstream mechanism, endothelial nitric oxide synthase (eNOS) was determined by semiquantitative Western blot and found to be reduced by ∼75%, mostly in the instance of CDH. In conclusion, angiogenesis remains defective in hypoplastic lungs despite reactive enhancement of VEGF and ANG-2 production, which could be due, at least in part, to insufficient eNOS expression.
Fibroblast-specific expression of AC6 enhances β-adrenergic and prostacyclin signaling and blunts bleomycin-induced pulmonary fibrosis
Authors: Liu Xiaoqiu , Li Fengying , Sun Shu Qiang , Thangavel Muthusamy , Kaminsky Joseph , Balazs Louisa , Ostrom Rennolds S.
Published: March 2010

Pulmonary fibroblasts regulate extracellular matrix production and degradation and are critical in maintenance of lung structure, function, and repair, but they also play a central role in lung fibrosis. cAMP-elevating agents inhibit cytokine- and growth factor-stimulated myofibroblast differentiation and collagen synthesis in pulmonary fibroblasts. In the present study, we overexpressed adenylyl cyclase 6 (AC6) in pulmonary fibroblasts and measured cAMP production and collagen synthesis. AC6 overexpression enhanced cAMP production and the inhibition of collagen synthesis mediated by isoproterenol and beraprost, but not the responses to butaprost or PGE2. To examine if increased AC6 expression would impact the development of fibrosis in an animal model, we generated transgenic mice that overexpress AC6 under a fibroblast-specific promoter, FTS1. Lung fibrosis was induced in FTS1-AC6+/−mice and littermate controls by intratracheal instillation of saline or bleomycin. Wild-type mice treated with bleomycin showed extensive peribronchial and interstitial fibrosis and collagen deposition. By contrast, FTS1-AC6+/−mice displayed decreased fibrotic development, lymphocyte infiltration (as determined by pathological scoring), and lung collagen content. Thus, AC6 overexpression inhibits fibrogenesis in the lung by reducing pulmonary fibroblast-mediated collagen synthesis and myofibroblast differentiation. Because AC6 overexpression does not lead to enhanced basal or PGE2-stimulated levels of cAMP, we conclude that endogenous catecholamines or prostacyclin is produced during bleomycin-induced lung fibrosis and that these signals have antifibrotic potential.
Cerebrovascular responses in mice deficient in the potassium channel, TREK-1
Authors: Namiranian Khodadad , Lloyd Eric E. , Crossland Randy F. , Marrelli Sean P. , Taffet George E. , Reddy Anilkumar K. , Hartley Craig J. , Bryan Robert M.
Published: March 2010

We tested the hypothesis that TREK-1, a two-pore domain K channel, is involved with dilations in arteries. Because there are no selective activators or inhibitors of TREK-1, we generated a mouse line deficient in TREK-1. Endothelium-mediated dilations were not different in arteries from wild-type (WT) and TREK-1 knockout (KO) mice. This includes dilations of the middle cerebral artery to ATP, dilations of the basilar artery to ACh, and relaxations of the aorta to carbachol, a cholinergic agonist. The nitric oxide (NO) and endothelium-dependent hyperpolarizing factor components of ATP dilations were identical in the middle cerebral arteries of WT and TREK-1 KO mice. Furthermore, the NO and cyclooxygenase-dependent components were identical in the basilar arteries of the different genotypes. Dilations of the basilar artery to α-linolenic acid, an activator of TREK-1, were not affected by the absence of TREK-1. Whole cell currents recorded using patch-clamp techniques were similar in cerebrovascular smooth muscle cells (CVSMCs) from WT and TREK-1 KO mice. α-linolenic acid or arachidonic acid increased whole cell currents in CVSMCs from both WT and TREK-1 KO mice. The selective blockers of large-conductance Ca-activated K channels, penitrem A and iberiotoxin, blocked the increased currents elicited by either α-linolenic or arachidonic acid. In summary, dilations were similar in arteries from WT and TREK-1 KO mice. There was no sign of TREK-1-like currents in CVSMCs from WT mice, and there were no major differences in currents between the genotypes. We conclude that regulation of arterial diameter is not altered in mice lacking TREK-1.
Variation in levels of luteinizing hormone and reproductive photoresponsiveness in a population of white-footed mice (Peromyscus leucopus)
Authors: Heideman Paul D. , Pittman Julian T. , Schubert Kristin A. , Dubois Christen M. R. , Bowles Jennifer , Lowe Sean M. , Price Matthew R.
Published: March 2010

Natural genetic variation in reproduction and life history strategies is a manifestation of variation in underlying regulatory neuronal and endocrine systems. A test of the hypothesis that genetic variation in luteinizing hormone (LH) level could be related to a life history trait, seasonal reproduction, was conducted on artificial selection lines from a wild-source population of white-footed mice ( Peromyscus leucopus ). Variation exists in the degree of suppression of reproduction by winter short-day photoperiods (SD) in wild-source individuals and in the laboratory population. In this population, most individuals from a photoperiod-responsive (R) artificial selection line are strongly suppressed reproductively in SD, while most individuals from a photoperiod-nonresponsive (NR) artificial selection line are only weakly reproductively suppressed in SD. We assayed levels of LH to test for genetic variation between lines that could contribute to variation in reproductive status in SD. Females from both lines were raised in long-day photoperiods (LD) or SD, ovariectomized under isoflurane anesthesia, and given estradiol implants. Levels of LH were significantly higher in the NR line than in the R line, indicating genetic variation for levels of LH. Levels of LH were higher in LD than in SD, indicating that levels of LH were sensitive to photoperiod treatment even with a controlled level of estradiol negative feedback. The results indicate that there is genetic variation in levels of LH that could be functionally important both in the laboratory in SD and in the wild population in winter. Thus genetic variation in levels of LH is a plausible causal factor determining winter reproductive phenotype in the wild population.
Dendritic Kv3.3 Potassium Channels in Cerebellar Purkinje Cells Regulate Generation and Spatial Dynamics of Dendritic Ca2+Spikes
Authors: Zagha Edward , Manita Satoshi , Ross William N. , Rudy Bernardo
Published: March 2010

Purkinje cell dendrites are excitable structures with intrinsic and synaptic conductances contributing to the generation and propagation of electrical activity. Voltage-gated potassium channel subunit Kv3.3 is expressed in the distal dendrites of Purkinje cells. However, the functional relevance of this dendritic distribution is not understood. Moreover, mutations in Kv3.3 cause movement disorders in mice and cerebellar atrophy and ataxia in humans, emphasizing the importance of understanding the role of these channels. In this study, we explore functional implications of this dendritic channel expression and compare Purkinje cell dendritic excitability in wild-type and Kv3.3 knockout mice. We demonstrate enhanced excitability of Purkinje cell dendrites in Kv3.3 knockout mice, despite normal resting membrane properties. Combined data from local application pharmacology, voltage clamp analysis of ionic currents, and assessment of dendritic Ca2+spike threshold in Purkinje cells suggest a role for Kv3.3 channels in opposing Ca2+spike initiation. To study the physiological relevance of altered dendritic excitability, we measured [Ca2+]ichanges throughout the dendritic tree in response to climbing fiber activation. Ca2+signals were specifically enhanced in distal dendrites of Kv3.3 knockout Purkinje cells, suggesting a role for dendritic Kv3.3 channels in regulating propagation of electrical activity and Ca2+influx in distal dendrites. These findings characterize unique roles of Kv3.3 channels in dendrites, with implications for synaptic integration, plasticity, and human disease.
Identifying physiological origins of baroreflex dysfunction in salt-sensitive hypertension in the Dahl SS rat
Authors: Bugenhagen Scott M. , Cowley Allen W. , Beard Daniel A.
Published: March 2010

Salt-sensitive hypertension is known to be associated with dysfunction of the baroreflex control system in the Dahl salt-sensitive (SS) rat. However, neither the physiological mechanisms nor the genomic regions underlying the baroreflex dysfunction seen in this rat model are definitively known. Here, we have adopted a mathematical modeling approach to investigate the physiological and genetic origins of baroreflex dysfunction in the Dahl SS rat. We have developed a computational model of the overall baroreflex heart rate control system based on known physiological mechanisms to analyze telemetry-based blood pressure and heart rate data from two genetic strains of rat, the SS and consomic SS.13BN, on low- and high-salt diets. With this approach, physiological parameters are estimated, unmeasured physiological variables related to the baroreflex control system are predicted, and differences in these quantities between the two strains of rat on low- and high-salt diets are detected. Specific findings include: a significant selective impairment in sympathetic gain with high-salt diet in SS rats and a protection from this impairment in SS.13BNrats, elevated sympathetic and parasympathetic offsets with high-salt diet in both strains, and an elevated sympathetic tone with high-salt diet in SS but not SS.13BNrats. In conclusion, we have associated several important physiological parameters of the baroreflex control system with chromosome 13 and have begun to identify possible physiological mechanisms underlying baroreflex impairment and hypertension in the Dahl SS rat that may be further explored in future experimental and modeling-based investigation.
Automatic TV Broadcast Structuring
Authors: Manson Gaël , Berrani Sid-Ahmed
Published: March 2010

TV broadcast structuring is needed to precisely extract long useful programs. These can be either archived as part of our audio-visual heritage or used to build added-value novel TV services like TVoD or Catch-up-TV. First, the problem of digital TV content structuring is positioned. Related work and existing solutions are deeply and carefully analyzed. This paper presents then DealTV, our fully automatic system. It is based on studying repeated sequences in the TV stream in order to segment it. Segments are then classified using an inductive logic programming-based technique that makes use of the temporal relationships between segments. Metadata are finally used to label and extract programs using simple overlapping-based criteria. Each processing step of DealTV has been separately evaluated in order to carefully analyze its impact on the final results. The system has been proven on a real TV stream to be very effective.
Changes in Activity and Kinetic Properties of the Proteasome in Different Rat Organs during Development and Maturation
Authors: Petersen A. , Honarvar A. , Zetterberg M.
Published: March 2010

The proteasome is considered the most important proteolytic system for removal of damaged proteins with aging. Using fluorogenic peptide substrates, the chymotrypsin-like, the trypsin-like, and the peptidylglutamyl peptidase activities of the proteasome were measured in the soluble fractions of liver, brain, and lens rat homogenates. Specific activity was significantly decreased in liver and brain homogenates with maturation of the animal, that is, from newborn (7 days old) to fertile rats (2–4 months old). Rat lens homogenate exhibited an increase in activity with maturation and also with aging. Chymotrypsin-like activity was stimulated by calcium and this proteolytic activity was significantly decreased with maturation of the rat brain. The Michaelis-Menten constant (Km) increased with age in rat liver and lens, indicating a loss of affinity for its substrates by the proteasome in the animal with maturation and aging. The present data suggest that the loss of function of the proteasome with maturation may be due to structural changes of the proteasome or a decreased content of regulatory components.
Preoperative Assessment of Adult Patients for Intracranial Surgery
Authors: Sivanaser Vanitha , Manninen Pirjo
Published: March 2010

The preoperative assessment of the patient for neurosurgical and endovascular procedures involves the understanding of the neurological disease and its systemic presentation, and the requirements of the procedure. There is a wide spectrum of different neurosurgical disorders and procedures. This article provides an overview of the preoperative evaluation of these patients with respect to general principles of neuroanesthesia, and considerations for specific intracranial and vascular neurosurgical and interventional neuroradiological procedures.
Low‐Power Ultrasounds as a Tool to Culture Human Osteoblasts inside Cancellous Hydroxyapatite
Authors: Fassina Lorenzo , Saino Enrica , Cusella De Angelis Maria Gabriella , Magenes Giovanni , Benazzo Francesco , Visai Livia
Published: March 2010

Bone graft substitutes and cancellous biomaterials have been widely used to heal critical‐size long bone defects due to trauma, tumor resection, and tissue degeneration. In particular, porous hydroxyapatite is widely used in reconstructive bone surgery owing to its biocompatibility. In addition, the in vitro modification of cancellous hydroxyapatite with osteogenic signals enhances the tissue regeneration in vivo, suggesting that the biomaterial modification could play an important role in tissue engineering. In this study, we have followed a tissue‐engineering strategy where ultrasonically stimulated SAOS‐2 human osteoblasts proliferated and built their extracellular matrix inside a porous hydroxyapatite scaffold. The ultrasonic stimulus had the following parameters: average power equal to 149 mW and frequency of 1.5 MHz. In comparison with control conditions, the ultrasonic stimulus increased the cell proliferation and the surface coating with bone proteins (decorin, osteocalcin, osteopontin, type‐I collagen, and type‐III collagen). The mechanical stimulus aimed at obtaining a better modification of the biomaterial internal surface in terms of cell colonization and coating with bone matrix. The modified biomaterial could be used, in clinical applications, as an implant for bone repair.
Dwarf Galaxies in Voids: Dark Matter Halos and Gas Cooling
Authors: Hoeft Matthias , Gottlöber Stefan
Published: March 2010

Galaxy surveys have shown that luminous galaxies are mainly distributed in large filaments and galaxy clusters. The remaining large volumes are virtually devoid of luminous galaxies. This is in concordance with the formation of the large‐scale structure in the universe as derived from cosmological simulations. However, the numerical results indicate that cosmological voids are abundantly populated with dark matter haloes which may in principle host dwarf galaxies. Observational efforts have in contrast revealed that voids are apparently devoid of dwarf galaxies. We investigate the formation of dwarf galaxies in voids by hydrodynamical cosmological simulations. Due to the cosmic ultraviolet background radiation low‐mass haloes show generally a reduced baryon fraction. We determine the characteristic mass below which dwarf galaxies are baryon deficient. We show that the circular velocity below which the accretion of baryons is suppressed is approximately 40 kms−1. The suppressed baryon accretion is caused by the photo‐heating due to the UV background. We set up a spherical halo model and show that the effective equation of the state of the gas in the periphery of dwarf galaxies determines the characteristic mass. This implies that any process which heats the gas around dwarf galaxies increases the characteristic mass and thus reduces the number of observable dwarf galaxies.
Effect of Soil Physical State on the Earthworms in Hungary
Authors: Birkas Marta , Bottlik Laszlo , Stingli Attila , Gyuricza Csaba , Jolánkai Márton
Published: March 2010

Hungarian authors have long been discussing the role of earthworms in improving soil productivity. Earthworm counts in our higher quality soils are similar to those found in soils where more attention is paid to earthworm activity. Negative impacts that are independent of farming—such as sustained dry spells in the summer—also affect earthworm counts. Negative impacts that definitely depend on farming include land use causing soil moisture loss, deep stubble treatment leaving the soil without cover, and ploughing in the summer without subsequent pressing. The climate change is having both positive and negative impacts. Weather patterns are causing losses but adopting climate mitigating tillage are generating benefits. In the trials results so far show that tillage focusing on preserving soil moisture, structure, and organic materials, covering the surface in the critical months as well as adequate soil loosening are fundamental pre-requisites for making the soil a favourable habitat for earthworms.
Mycoplasma genitaliumamong Young, Urban Pregnant Women
Authors: Short Vanessa L. , Jensen Jørgen S. , Nelson Deborah B. , Murray Pamela J. , Ness Roberta B. , Haggerty Catherine L.
Published: March 2010

Objective. As the consequences ofMycoplasma genitaliumin pregnant women are unknown, we examined the relationship between prenatalM. genitaliuminfection and SAB.Methods. The presence ofM. genitaliumwas determined by PCR in urine from 82 women who subsequently experienced a SAB and 134 women who maintained their pregnancies past 22 weeks gestation. The relationships betweenM. genitaliumand subsequent SAB, demographic, current pregnancy, and reproductive health history characteristics were evaluated.Results. Compared to women withoutM. genitalium, women withM. genitaliumwere more likely to report nulliparity (41.7% versus 17.4%,P=.04), history of pelvic inflammatory disease (27.3% versus 8.8%,P=.08), priorC. trachomatisinfection (63.6% versus 36.9%,P=.11,) and problems getting pregnant (18.2% versus 4.4%,P=.10).M. genitaliumwas not associated with SAB (AOR 0.9, 95% CI 0.2–3.8).Conclusions. Pregnant women who test positive forM. genitaliumdo not have an increased risk of SAB but report a history of reproductive morbidities.
Variation in Anastrozole Metabolism and Pharmacodynamics in Women with Early Breast Cancer
Authors: Ingle James N. , Buzdar Aman U. , Schaid Daniel J. , Goetz Matthew P. , Batzler Anthony , Robson Mark E. , Northfelt Donald W. , Olson Janet E. , Perez Edith A. , Desta Zeruesenay , Weintraub Randy A. , Williard Clark V. , Flockhart David A. , Weinshilboum Richard M.
Published: March 2010

Aromatase inhibitors play a prominent role in the management of postmenopausal women with endocrine-sensitive breast cancer, but there is large variability in both efficacy and tolerability. The purpose of our study was to define interindividual variation in anastrozole metabolism and pharmacodynamics among patients treated with the approved daily dose of 1 mg in a standard practice setting as adjuvant therapy for resected early breast cancer. This study was performed in 191 women in whom pretreatment and during anastrozole plasma concentrations of estrone (E1), estradiol (E2), estrone conjugates, androstenedione, and testosterone were determined and correlated with plasma concentrations of anastrozole and anastrozole metabolites. There were large interindividual variations in plasma anastrozole and anastrozole metabolite concentrations, as well as pretreatment and postdrug plasma E1, E2, and E1 conjugate and estrogen precursor (androstenedione and testosterone) concentrations. E1 and E2 concentrations were below the lower limit of quantitation (LLQ) in most patients after anastrozole therapy (83% for both), but those with detectable concentrations had a broad range (1.58–45.2 and 0.635–97.0 pg/mL, respectively). E1 conjugates after anastrozole therapy were above the LLQ in most patients (93%), with wide interpatient variability (3.50–2,990 pg/mL). Two patients seemed to extensively metabolize anastrozole and failed to display substantial decreases in estrogens. Acknowledging the potential factor of variable compliance, our results showed large interindividual variation in anastrozole metabolism and its effect on circulating estrogens in postmenopausal patients. These findings may have implications with regard to efficacy and adverse events and may indicate the need to “individualize” therapy with this drug. Cancer Res; 70(8); 3278–86. ©2010 AACR.
The Antidepressant Sertraline Inhibits Translation Initiation by Curtailing Mammalian Target of Rapamycin Signaling
Authors: Lin Chen-Ju , Robert Francis , Sukarieh Rami , Michnick Stephen , Pelletier Jerry
Published: March 2010

Sertraline, a selective serotonin reuptake inhibitor, is a widely used antidepressant agent. Here, we show that sertraline also exhibits antiproliferative activity. Exposure to sertraline leads to a concentration-dependent decrease in protein synthesis. Moreover, polysome profile analysis of sertraline-treated cells shows a reduction in polysome content and a concomitant increase in 80S ribosomes. The inhibition in translation caused by sertraline is associated with decreased levels of the eukaryotic initiation factor (eIF) 4F complex, altered localization of eIF4E, and increased eIF2α phosphorylation. The latter event leads to increased REDD1 expression, which in turn impinges on the mammalian target of rapamycin (mTOR) pathway by affecting TSC1/2 signaling. Sertraline also independently targets the mTOR signaling pathway downstream of Rheb. In the Eμ-myc murine lymphoma model where carcinogenesis is driven by phosphatase and tensin homologue (PTEN) inactivation, sertraline is able to enhance chemosensitivity to doxorubicin. Our results indicate that sertraline exerts antiproliferative activity by targeting the mTOR signaling pathway in a REDD1-dependent manner. Cancer Res; 70(8); 3199–208. ©2010 AACR.
MicroRNA-155 Functions as an OncomiR in Breast Cancer by Targeting theSuppressor of Cytokine Signaling 1Gene
Authors: Jiang Shuai , Zhang Hong-Wei , Lu Ming-Hua , He Xiao-Hong , Li Yong , Gu Hua , Liu Mo-Fang , Wang En-Duo
Published: March 2010

MicroRNA-155 (miR-155) is overexpressed in many human cancers; however, the mechanisms by which miR-155 functions as a putative oncomiR are largely unknown. Here, we report that the tumor suppressor gene suppressor of cytokine signaling 1 (socs1) is an evolutionarily conserved target of miR-155 in breast cancer cells. We found that mir-155 expression is inversely correlated with socs1 expression in breast cancer cell lines as well as in a subset of primary breast tumors. We also identified a 24A→G mutation in the miR-155 binding site of the SOCS1 3′ untranslated region in a breast tumor that reduced miR-155 repression, implicating a mechanism for miRNA targets to avoid repression. Ectopic expression of miR-155 significantly promoted the proliferation of breast cancer cells, the formation of soft agar foci in vitro, and the development of tumors in nude mice. In breast cancer cells, RNA interference silencing of socs1 recapitulates the oncogenic effects of miR-155, whereas restoration of socs1 expression attenuates the protumorigenesis function of miR-155, suggesting that miR-155 exerts its oncogenic role by negatively regulating socs1. Overexpression of miR-155 in breast cancer cells leads to constitutive activation of signal transducer and activator of transcription 3 (STAT3) through the Janus-activated kinase (JAK) pathway, and stimulation of breast cancer cells by the inflammatory cytokines IFN-γ and interleukin-6 (IL-6), lipopolysaccharide (LPS), and polyriboinosinic:polyribocytidylic acid [poly(I:C)] significantly upregulates mir-155 expression, suggesting that miR-155 may serve as a bridge between inflammation and cancer. Taken together, our study reveals that miR-155 is an oncomiR in breast cancer and that miR-155 may be a potential target in breast cancer therapy. Cancer Res; 70(8); 3119–27. ©2010 AACR.
Signaling From the Golgi: Mechanisms and Models for Golgi Phosphoprotein 3–Mediated Oncogenesis
Authors: Scott Kenneth L. , Chin Lynda
Published: March 2010

Golgi phosphoprotein 3 (GOLPH3; also known as GPP34/GMx33/MIDAS) represents an exciting new class of oncoproteins involved in vesicular trafficking. Encoded by a gene residing on human chromosome 5p13, which is frequently amplified in multiple solid tumor types, GOLPH3 was initially discovered as a phosphorylated protein localized to the Golgi apparatus. Recent functional, cell biological, and biochemical analyses show that GOLPH3 can function as an oncoprotein to promote cell transformation and tumor growth by enhancing activity of the mammalian target of rapamycin, a serine/threonine protein kinase known to regulate cell growth, proliferation, and survival. Although its precise mode of action in cancer remains to be elucidated, the fact that GOLPH3 has been implicated in protein trafficking, receptor recycling, and glycosylation points to potential links of these cellular processes to tumorigenesis. Understanding how these processes may be deregulated and contribute to cancer pathogenesis and drug response will uncover new avenues for therapeutic intervention. Clin Cancer Res; 16(8); 2229–34. ©2010 AACR.
Upregulation of DNA Methyltransferase–Mediated Gene Silencing, Anchorage-Independent Growth, and Migration of Colon Cancer Cells by Interleukin-6
Authors: Foran Eilis , Garrity-Park Megan M. , Mureau Coralie , Newell John , Smyrk Thomas C. , Limburg Paul J. , Egan Laurence J.
Published: March 2010

Inflammatory bowel disease is characterized by chronic inflammation which predisposes to colorectal cancer. The mechanisms by which inflammation promotes tumorigenesis are not fully known. We aimed to investigate the links between colonic inflammation and tumorigenesis via epigenetic gene silencing. Colon cancer specimens were assessed for the expression of DNA methyltransferase-1 (DNMT-1) using immunohistochemistry. Colorectal carcinoma cell lines were assessed for DNMT1 expression, methylcytosine content, promoter methylation, gene expression, and tumorigenesis in response to interleukin (IL)-6. DNMT1 was expressed at higher levels in both the peritumoral stroma and tumor in inflammatory bowel disease–associated cancers compared with sporadic colon cancers. IL-6 treatment of colon cancer cells resulted in an increase in DNMT1 expression, independent of de novo gene expression. IL-6 increased the methylation of promoter regions of genes associated with tumor suppression, adhesion, and apoptosis resistance. Expression of a subset of these genes was downregulated by IL-6, an effect that was prevented by preincubation with 5-azadeoxycytidine, a DNMT1 inhibitor. Anchorage-independent growth and migration of colon cancer cells was also increased by IL-6 in a 5-azadeoxycytidine–sensitive manner. Our results indicate that DNMT-mediated gene silencing may play a role in inflammation-associated colon tumorigenesis. Mol Cancer Res; 8(4); 471–81. ©2010 AACR.
Giant Haemangioma of the Liver: Observation or Resection?
Authors: Duxbury Mark S. , Garden O. James
Published: March 2010

Background: Haemangiomata are the most frequent benign solid liver lesion. The management of giant (≧5 cm) haemangiomata of the liver remains controversial. Methods: A search of relevant peer-reviewed literature was conducted using PubMed and original articles were reviewed. Results and Conclusions: The vast majority of giant haemangiomata remain asymptomatic and have a benign and uncomplicated natural history. Decisions regarding the optimal management of giant haemangiomata depend on a high level of confidence in diagnostic imaging. Diagnostic biopsy to differentiate giant haemangiomata from malignant lesions should be discouraged. Despite limitations and alternative modalities, surgery remains the only consistently effective curative treatment for giant haemangiomata. Surgery is not generally justified to prevent complications in asymptomatic patients. Principal indications for the surgical management of giant haemangiomata include established complications, incapacitating symptoms and uncertainty of diagnosis. Patients should only be selected for surgery based on a careful assessment of risks and benefits of intervention.
Subtype Classification of Hepatocellular Adenoma
Authors: Bioulac-Sage Paulette , Balabaud Charles , Zucman-Rossi Jessica
Published: March 2010

Hepatocellular adenomas (HCA) are rare benign tumours occurring mainly in women under oral contraceptives. HCA bleed frequently and transform rarely into hepatocellular carcinoma. Identification of genes recurrently mutated in HCA and good genotype/phenotype correlations provided the basis of a pathomolecular classification of different HCA subgroups, characterized using immunohistochemical markers. HNF1A-mutated HCA: Biallelic-inactivating mutations of HNF1A gene are identified in 35–40% of HCA. HNF1α-inactivated HCA display characteristic pathological features, including marked steatosis. The expression of FABP1 (which is a HNF1A target gene) is downregulated and the absence of L-FABP expression diagnosed this subgroup. β-Catenin-mutated HCA: β-catenin mutations leading to activation of the Wnt/β-catenin pathway represented 10–15% of HCA. They are characterized by overexpression of glutamine synthetase and aberrant nuclear β-catenin staining. These β-catenin-activated HCA are at greater risk of malignant transformation; they are difficult to differentiate from well-differentiated HCC. Inflammatory HCA (50%): These are defined by the presence of inflammatory infiltrates, sinusoidal dilatation and thick-walled arteries. Small in-frame deletions that target the binding site of gp130 for IL-6 have been reported in 60% of inflammatory HCA. There is an overexpression of the inflammatory proteins serum amyloid A and C-reactive protein in tumour hepatocytes both at mRNA and protein levels. Inflammatory HCA occurred more frequently in patients with high body mass index; they can be also mutated for β-catenin and therefore are probably at risk of HCC. Unclassified HCA: Less than 10% of HCA do not express any of the above-mentioned phenotypic markers. Taking into account noticeable differences between the HCA subgroups, in terms of clinical and prognostic features, phenotyping may become an important tool for HCA management strategy.
Imaging Modalities for Focal Nodular Hyperplasia and Hepatocellular Adenoma
Authors: van den Esschert Jacomina W. , van Gulik Thomas M. , Phoa Saffire S.K.S.
Published: March 2010

Background/Aims: There are several imaging modalities available for the detection of focal liver lesions. Differentiation between focal nodular hyperplasia (FNH) and hepatocellular adenoma (HCA) is important because of the consequences for management. However, differentiation based on imaging alone still shows limitations. Methods: We reviewed the literature for typical features of FNH and HCA on radiologic and nuclear imaging with emphasis on differentiation of both lesions. Results: Seven articles describe the performance of an imaging modality for the differentiation between FNH and HCA. Limitations of these studies are the small sample size and/or the lack of comparison with the ‘gold standard’, i.e. histological diagnosis. No studies are available that compare the accuracy of several imaging modalities in the differentiation of FNH and HCA. Conventional ultrasound (US) is not useful in the differentiation because of the non-specific features. On contrast-enhanced US, the arterial filling direction of FNH is centrifugal and centripetal in case of HCA. The parenchymal enhancement of FNH is sustained in the portal venous and delayed phases, but shows rapid washout in case of HCA. Multiphase CT scan can differentiate FNH from HCA when there is a central scar. FNH may have a slightly higher relative enhancement in the arterial phase. On MRI with hepatocyte-specific contrast agents, HCA does not show contrast uptake in the hepatobiliary phase in contrast to FNH. Conclusion: We conclude that there is limited evidence of the diagnostic performance of currently used imaging modalities for the differentiation of FNH and HCA. We therefore propose a prospective study (DiFA trial) to determine the accuracy of several radiologic and nuclear imaging studies in differentiating FNH and HCA.
A Capuchin Monkey (Cebus apella) Uses Video to Find Food
Authors: Potì Patrizia , Saporiti Martina
Published: March 2010

We examined the ability of capuchin monkeys to use video without immediate visual-kinaesthetic feedback as a source of information to guide their action in the 3-dimensional world. In experiment 1, 2 capuchins learned to retrieve food under 1 of 2 different objects in 1 cage after watching the experimenter hiding food under 1 of 2 replica objects while in another cage. Information space and retrieval space were thus separate. The performance criterion was 71% first correct choices in blocks of 24 trials. However, when the subjects watched prerecorded videos of the hiding events, they chose randomly. In experiment 2, we gave the capuchins further trials with video and we enhanced the object shapes by line drawings. One capuchin eventually learned to use the video clips to locate food and he generalized this learning to 2 new objects.
Low Molecular Weight Glutenins in Wheat-Dependant, Exercise-Induced Anaphylaxis: Allergenicity and Antigenic Relationships with Omega 5-Gliadins
Authors: Bouchez-Mahiout Isabelle , Snégaroff Jacques , Tylichova Martina , Pecquet Catherine , Branlard Gérard , Laurière Michel
Published: March 2010

Background: Adults suffering from wheat-dependant, exercise-induced anaphylaxis (WDEIA) develop IgE directed against wheat ω5-gliadins (major allergens for this allergy) and against wheat low-molecular weight glutenin subunits (LMW-GS). However, the ability of LMW-GS to trigger an inflammatory response is still unknown. It also remains to be determined if IgE from these patients bind the same epitopes on LMW-GS and ω5-gliadins or if the epitopes are independent. Methods: WDEIA patients were selected and skin prick tests (SPTs) were performed on them using commercial gluten, wheat flour extracts, prolamin fractions and a purified natural LMW-GS P42. The IgE-binding ability of natural and recombinant wheat prolamins was verified by immunoblot experiments. Cross-reactivity between LMW-GS and ω5-gliadins was studied by immunoblot inhibition experiments, using purified natural ω5-gliadin as an inhibitor. Results: Patients developed positive SPTs with natural LMW-GS fractions and/or with the purified LMW-GS P42. Natural and recombinant LMW-GS were highly reactive with patient IgE in immunoblot experiments, as was ω5-gliadin. However, differences in reactivity were evident within the LMW-GS group. Except for one recombinant LMW-GS (P73), IgE cross-reactivity between LMW-GS and natural ω5-gliadin was only partial. Conclusion: LMW-GS are able to promote local inflammation and they share common epitopes with ω5-gliadins. The nature of these epitopes is discussed. LMW-GS also carried specific epitopes, completely independent from the ω5-gliadin epitopes. Thus, LMW-GS behaved partly as independent allergens.
Immunoglobulin E Sensitization to Cross-Reactive Carbohydrate Determinants: Epidemiological Study of Clinical Relevance and Role of Alcohol Consumption
Authors: Linneberg Allan , Fenger Runa Vavia , Husemoen Lise-Lotte N. , Vidal Carmen , Vizcaino Luis , Gonzalez-Quintela Arturo
Published: March 2010

Background: The determinants and biologic significance of IgE-mediated sensitization to cross-reactive carbohydrate determinants (CCDs) are not entirely known. An association between alcohol consumption and CCD sensitization has been reported in studies from Spain and Portugal. Objective: To investigate the relationship of alcohol consumption with CCD sensitization, the role of alcohol dehydrogenase gene polymorphisms, and the clinical consequences of CCD sensitization. Methods: Serum-specific IgE sensitization (≧0.1 kU/l) to a CCD (the N-glycan from bromelain) was assessed in 1,197 adults participating in a population-based study in Copenhagen, Denmark. Alcohol consumption and atopic symptoms (rhinitis, asthma and oral allergy syndrome) were assessed by questionnaire. Examinations included skin prick tests (SPTs), qualitative multiallergen IgE test (Phadiatop®), methacholine bronchial hyperreactivity, eosinophil cationic protein and alcohol dehydrogenase (ADH) gene polymorphisms. Results: Alcohol consumption was significantly associated with CCD sensitization and this was particularly evident in SPT-negative individuals. The fast-metabolizing allele of the ADH1b polymorphism was significantly associated with CCD sensitization in alcohol drinkers. CCD sensitization was associated with atopic symptoms, but associations attenuated markedly when adjusting for SPT reactivity. Conclusions: Our results suggest that the positive association between alcohol consumption and CCD sensitization is universal and not specific to certain populations. The observed association between the ADH1b polymorphism and CCD sensitization may support that alcohol is causally related to the risk of CCD sensitization. The observed association between CCD sensitization and atopic phenotypes did not appear to be independent of SPT reactivity indicating limited significance of CCD sensitization per se.
Infections and Hardware Salvage after Deep Brain Stimulation Surgery: A Single-Center Study and Review of the Literature
Authors: Bhatia Sanjay , Zhang Kai , Oh Michael , Angle Cindy , Whiting Donald
Published: March 2010

Aims: Infection of hardware is a serious complication after deep brain stimulation (DBS), as this may result in additional surgery, cost and loss of treatment benefit for the patient. We report the incidence and management of infections after DBS in a single institution over the past 11 years. Methods: A database of 270 patients with 484 implants was used in the study. Incidence, clinical characteristics and management of infections were analyzed. Results: The overall infection rate was 9.3% (25/270) by patients and 6.8% (33/484) by episode/implants. The median time of infection after implantation was 64 days. Only 7/33 episodes (21.2%) occurred within 30 days after surgery, 22/33 episodes (66.7%) within 6 months and 28/33 episodes (84.8%) within 12 months. There was no age difference between infected and noninfected patients, while comorbidities were more frequent in the former. Infection rates before and after January 2003 were 14.3 and 4.9%, respectively. The rate of complete and partial hardware salvage was 30.3 and 21.2% while that of complete hardware removal was 48.5%. Patients with deep purulent infections and patients with Staphylococcus aureus as the causative organism were more likely to have their hardware removed. Conclusions: The incidence of hardware infections declined significantly over time. Improvements in hardware and implantation techniques may be responsible. Hardware can often be completely or partly saved in infected patients.
Effect of Various Surgical Modalities in Recurrent or Persistent Trigeminal Neuralgia
Authors: Han Inbo , Shin Dongah , Chang Jonghee , Kim Keungnyn , Chang Jinwoo , Huh Ryoong , Chung Sangsup
Published: March 2010

Background/Aims: In recurrent or persistent idiopathic trigeminal neuralgia (TN) after initial operation, additional surgical procedures may be required. There are numerous articles reporting the outcomes of additional surgical treatment and it is unclear how best to treat patients with recurrent or persistent TN. We evaluated the subsequent therapeutic options for recurrent or persistent TN. Methods: The study was a retrospective study. The authors reviewed 29 patients (15 female/14 male) who underwent retreatments for recurrent or persistent symptoms after an initial operation. Results: The mean follow-up duration was 56.4 months (range 12–78.7) from final treatment. Patients underwent a mean of 2.3 retreatments with a mean period of 26 months (range 1–72) between treatments. Final treatments were as follows: microvascular decompression (MVD) in 12 patients, percutaneous rhizotomy in 10, and radiosurgery in 7. Of the 29 patients, after final treatments, 9 patients (31%) achieved excellent results and 15 (52%) good results. Failure results were seen in 17% of patients with recurrent TN. Conclusion: In this study the authors demonstrate that percutaneous rhizotomy is recommended for most patients with recurrent pain after MVD, and MVD can be effective in patients with a history of failed percutaneous procedures. Radiosurgery can be utilized to treat those that have not responded to other surgical modalities.
Use of Thymidine Kinase Gene-Modified Endothelial Progenitor Cells as a Vector Targeting Angiogenesis in Glioma Gene Therapy
Authors: Zhang Jun-xia , Kang Chun-sheng , Shi Lei , Zhao Peng , Liu Ning , You Yong-ping
Published: March 2010

Objective: The poor prognosis of patients with glioma is due to infiltrative growth of glioma cells, which correlates with their ability to induce angiogenesis. Tumor angiogenesis is supported by the mobilization and functional incorporation of endothelial progenitor cells (EPCs). The aim of this study was to propose the use of gene-modified EPCs as a vector system that allowed systemic gene delivery into multiple areas of tumor angiogenesis for glioma therapy. Methods: Thymidine kinase (TK) gene-modified EPCs were mixed with glioma cells or human umbilical vein endothelial cells (HUVECs) at varying ratios for ganciclovir in vitro. Cell proliferation was evaluated by MTT assay, and apoptosis was examined by annexin-V and phosphatidylserine (propidium iodide) staining. EPCs were injected via tail vein into nude mice bearing glioma, and EPC incorporation into the tumor was determined immunohistochemically. The antitumor effects of TK gene-modified EPCs in vivo were evaluated by apoptosis assay and microvessel density analysis. Results: TK gene-modified EPCs exerted a potent bystander effect on glioma cells and HUVECs by induction of apoptosis via caspase activation in vitro. EPCs incorporated preferentially into glioma vasculatures. Furthermore, TK gene-modified EPCs clearly augmented the antitumor effect by inhibition of angiogenesis following repeated intravenous injection in vivo. Conclusion: The results indicate the feasibility of EPC-based gene delivery into disseminated areas of tumor angiogenesis as a rational strategy for glioma gene therapy.
Formalin Fixation Could Interfere with the Clinical Assessment of the Tumor-Free Margin in Tumor Surgery: Magnetic Resonance Imaging-Based Study
Authors: Docquier Pierre-Louis , Paul Laurent , Cartiaux Olivier , Lecouvet Frédéric , Dufrane Denis , Delloye Christian , Galant Christine
Published: March 2010

Objectives: The tumor-free margin in bone and soft-tissue cancer is a key factor for subsequent treatment. While flattening and shrinkage of specimens after formalin fixation have been described in breast cancer, there are no data for bone and soft tissue sarcoma. Fixation could interfere with the accuracy of the assessment of the tumor-free margin. Methods: The influence of formalin fixation was assessed on forelimb specimens in a preclinical porcine model. The specimens were subjected to magnetic resonance imaging before and after formalin fixation. Weight, width and height of the specimen were measured and different consecutive volumes (total, muscles, bones and fatty tissue) were obtained by segmentation. Results: After formalin fixation, the weight increased, total volume and muscle volume slightly increased while bone did not change and fatty tissue decreased. The width of the specimens increased while their height decreased. Conclusions: Formalin fixation caused slight muscle expansion, fatty tissue shrinkage and flattening of the specimen. These changes could interfere with the assessment of the tumor-free margin in clinical practice.