bluuebunny/crossref_metadata_2025 huggingface dataset:
Identity Gene Expression in Proteus mirabilis
Authors: Gibbs Karine A. , Wenren Larissa M. , Greenberg E. Peter
Published: May 2011

Swarming colonies of independent
Proteus mirabilis
isolates recognize each other as foreign and do not merge together, whereas apposing swarms of clonal isolates merge with each other. Swarms of mutants with deletions in the
ids
gene cluster do not merge with their parent. Thus,
ids
genes are involved in the ability of
P. mirabilis
to distinguish self from nonself. Here we have characterized expression of the
ids
genes. We show that
idsABCDEF
genes are transcribed as an operon, and we define the promoter region upstream of
idsA
by deletion analysis. Expression of the
ids
operon increased in late logarithmic and early stationary phases and appeared to be bistable. Approaching swarms of nonself populations led to increased
ids
expression and increased the abundance of
ids
-expressing cells in the bimodal population. This information on
ids
gene expression provides a foundation for further understanding the molecular details of self-nonself discrimination in
P. mirabilis
.
Genetic Transformation of the Relapsing Fever Spirochete Borrelia hermsii: Stable Integration and Expression of Green Fluorescent Protein from Linear Plasmid 200
Authors: Fine Lindy M. , Earnhart Christopher G. , Marconi Richard T.
Published: May 2011

Tick-borne relapsing fever (TBRF) is a spirochetal disease caused by at least 15 different
Borrelia
species. It is a serious human health concern in regions of endemicity throughout the world. Transmission to humans occurs through the bites of infected
Ornithodoros
ticks. In North America, the primary
Borrelia
species associated with human disease are
B. hermsii
and
B. turicatae
. Direct demonstration of the role of putative TBRF spirochete virulence factors in the disease process has been hindered by the lack of a genetic manipulation system and complete genome sequences. Expanding on recent developments in these areas, here we demonstrate the successful generation of a clone of
B. hermsii
YOR that constitutively produces green fluorescent protein (GFP) (
B. hermsii
YOR::
kan gfp
). This strain was generated through introduction of a
kan-gfp
cassette into a noncoding region of the 200-kb
B. hermsii
linear plasmid lp200. Genetic manipulation did not affect the growth rate or trigger the loss of native plasmids.
B. hermsii
YOR::
kan gfp
retained infectivity and elicited host seroconversion. Stable production of GFP was demonstrated both
in vitro
and
in vivo
. This study represents a significant step forward in the development of tools that can be employed to study the virulence mechanisms of TBRF spirochetes.
Complete Genome Sequence of Metallosphaera cuprina, a Metal Sulfide-Oxidizing Archaeon from a Hot Spring
Authors: Liu Li-Jun , You Xiao-Yan , Zheng Huajun , Wang Shengyue , Jiang Cheng-Ying , Liu Shuang-Jiang
Published: May 2011

The genome of the metal sulfide-oxidizing, thermoacidophilic strain
Metallosphaera cuprina
Ar-4 has been completely sequenced and annotated. Originally isolated from a sulfuric hot spring, strain Ar-4 grows optimally at 65°C and a pH of 3.5. The
M. cuprina
genome has a 1,840,348-bp circular chromosome (2,029 open reading frames [ORFs]) and is 16% smaller than the previously sequenced
Metallosphaera sedula
genome. Compared to the
M. sedula
genome, there are no counterpart genes in the
M. cuprina
genome for about 480 ORFs in the
M. sedula
genome, of which 243 ORFs are annotated as hypothetical protein genes. Still, there are 233 ORFs uniquely occurring in
M. cuprina
. Genome annotation supports that
M. cuprina
lives a facultative life on CO
2
and organics and obtains energy from oxidation of sulfidic ores and reduced inorganic sulfuric compounds.
Genome Sequence of the Clinical O4:K12 Serotype Vibrio parahaemolyticus Strain 10329
Authors: Gonzalez-Escalona N. , Strain E. A. , De Jesús A. J. , Jones J. L. , DePaola A.
Published: May 2011

Vibrio parahaemolyticus
is the leading cause of food-borne illnesses worldwide. Here, we report a draft genome of
V. parahaemolyticus
strain 10329 of the O4:K12 serotype. It belongs to the main U.S. West Coast clonal complex of
V. parahaemolyticus
(sequence type 36 [ST36]) causing oyster-associated human illness. It contains the virulence determinants
tdh
and
trh
but appears to infect at much lower doses than
V. parahaemolyticus
strains with these same determinants from other areas, such as the U.S. Gulf and Atlantic coasts.
Genome Sequences of Listeria monocytogenes Strains J1816 and J1-220, Associated with Human Outbreaks
Authors: Chen Y. , Strain E. A. , Allard M. , Brown E. W.
Published: May 2011

Listeria monocytogenes
has caused numerous human outbreaks. Here we report draft genomes of
L. monocytogenes
J1816 and J1-220, which belong to epidemic clones II and IV, respectively. Whole-genome sequence analysis of these strains provides a tool for studying the short-term evolution of these epidemic clones.
Draft Genome Sequence of the Marine Bacterium Streptomyces griseoaurantiacus M045, Which Produces Novel Manumycin-Type Antibiotics with a pABA Core Component
Authors: Li Fuchao , Jiang Peng , Zheng Huajun , Wang Shengyue , Zhao Guoping , Qin Song , Liu Zhaopu
Published: May 2011

Streptomyces griseoaurantiacus
M045, isolated from marine sediment, produces manumycin and chinikomycin antibiotics. Here we present a high-quality draft genome sequence of
S. griseoaurantiacus
M045, the first marine
Streptomyces
species to be sequenced and annotated. The genome encodes several gene clusters for biosynthesis of secondary metabolites and has provided insight into genomic islands linking secondary metabolism to functional adaptation in marine
S. griseoaurantiacus
M045.
Complete Genome Sequence of the Plant Growth-Promoting Endophyte Burkholderia phytofirmans Strain PsJN
Authors: Weilharter Alexandra , Mitter Birgit , Shin Maria V. , Chain Patrick S. G. , Nowak Jerzy , Sessitsch Angela
Published: May 2011

Burkholderia phytofirmans
PsJN
T
is able to efficiently colonize the rhizosphere, root, and above-ground plant tissues of a wide variety of genetically unrelated plants, such as potatoes, canola, maize, and grapevines. Strain PsJN shows strong plant growth-promoting effects and was reported to enhance plant vigor and resistance to biotic and abiotic stresses. Here, we report the genome sequence of this strain, which indicates the presence of multiple traits relevant for endophytic colonization and plant growth promotion.
Complete Genome Sequence of Bacillus amyloliquefaciens LL3, Which Exhibits Glutamic Acid-Independent Production of Poly-γ-Glutamic Acid
Authors: Geng Weitao , Cao Mingfeng , Song Cunjiang , Xie Hui , Liu Li , Yang Chao , Feng Jun , Zhang Wei , Jin Yinghong , Du Yang , Wang Shufang
Published: May 2011

Bacillus amyloliquefaciens
is one of most prevalent Gram-positive aerobic spore-forming bacteria with the ability to synthesize polysaccharides and polypeptides. Here, we report the complete genome sequence of
B. amyloliquefaciens
LL3, which was isolated from fermented food and presents the glutamic acid-independent production of poly-γ-glutamic acid.
Genome Sequence of Strain TW15, a Novel Member of the Genus Ruegeria, Belonging to the Marine Roseobacter Clade
Authors: Lee Jina , Roh Seong Woon , Whon Tae Woong , Shin Na-Ri , Kim Young-Ok , Bae Jin-Woo
Published: May 2011

Ruegeria
sp. TW15, which belongs to the family
Rhodobacteraceae
, was isolated from an ark clam in the South Sea of Korea. Here is presented the draft genome sequence of
Ruegeria
sp. TW15 (4,490,771 bp with a G+C content of 55.7%), a member of the marine
Roseobacter
clade, which comprises up to 20% of the bacterioplankton in the coastal and oceanic mixed layer.
Complete Genome of Pseudomonas mendocina NK-01, Which Synthesizes Medium-Chain-Length Polyhydroxyalkanoates and Alginate Oligosaccharides
Authors: Guo Wenbin , Wang Yuanyuan , Song Cunjiang , Yang Chao , Li Qiang , Li Baobin , Su Wenping , Sun Xiumei , Song Dongfang , Yang Xiaojuan , Wang Shufang
Published: May 2011

Pseudomonas mendocina
NK-01 can synthesize medium-chain-length polyhydroxyalkanoate (PHA
MCL
) and alginate oligosaccharides (AO) simultaneously from glucose under conditions of limited nitrogen. Here, we report the complete sequence of the 5.4-Mbp genome of
Pseudomonas mendocina
NK-01, which was isolated from farmland soil in Tianjin, China.
Streptococcus pneumoniae Serotype 6C: an Intra- and Interclonal Complex Comparison
Authors: Thomas J. C. , Kong Y. , Sabharwal V. , Pelton S. I. , Pettigrew M. M.
Published: May 2011

We report the annotated draft genome sequences of four serotype 6C
Streptococcus pneumoniae
isolates of differing genetic backgrounds. Serotype 6C isolates are increasing in prevalence and becoming progressively more resistant to antibiotics. As a result, these strains are likely to become more important in the near future.
Genome Sequence of Vibrio rotiferianus Strain DAT722
Authors: Chowdhury Piklu Roy , Boucher Yan , Hassan Karl A. , Paulsen Ian T. , Stokes H. W. , Labbate Maurizio
Published: May 2011

Vibrio rotiferianus
is a marine pathogen capable of causing disease in various aquatic organisms. We announce the genome sequence of
V. rotiferianus
DAT722, which has a large chromosomal integron containing 116 gene cassettes and is a model organism for studying the role of this system in vibrio evolution.
Genome Sequence of the Ethene- and Vinyl Chloride-Oxidizing Actinomycete Nocardioides sp. Strain JS614
Authors: Coleman Nicholas V. , Wilson Neil L. , Barry Kerrie , Brettin Thomas S. , Bruce David C. , Copeland Alex , Dalin Eileen , Detter John C. , del Rio Tijana Glavina , Goodwin Lynne A. , Hammon Nancy M. , Han Shunsheng , Hauser Loren J. , Israni Sanjay , Kim Edwin , Kyrpides Nikolaos , Land Miriam L. , Lapidus Alla , Larimer Frank W. , Lucas Susan , Pitluck Sam , Richardson Paul , Schmutz Jeremy , Tapia Roxanne , Thompson Sue , Tice Hope N. , Spain Jim C. , Gossett James G. , Mattes Timothy E.
Published: May 2011

Nocardioides
sp. strain JS614 grows on ethene and vinyl chloride (VC) as sole carbon and energy sources and is of interest for bioremediation and biocatalysis. Sequencing of the complete genome of JS614 provides insight into the genetic basis of alkene oxidation, supports ongoing research into the physiology and biochemistry of growth on ethene and VC, and provides biomarkers to facilitate detection of VC/ethene oxidizers in the environment. This is the first genome sequence from the genus
Nocardioides
and the first genome of a VC/ethene-oxidizing bacterium.
Genome Sequence of Strain IMCC3088, a Proteorhodopsin-Containing Marine Bacterium Belonging to the OM60/NOR5 Clade
Authors: Jang Yoonra , Oh Hyun-Myung , Kang Ilnam , Lee Kiyoung , Yang Seung-Jo , Cho Jang-Cheon
Published: May 2011

Strain IMCC3088, cultivated from the Yellow Sea, is a novel isolate belonging to the OM60/NOR5 clade and is closely related to clone OM241,
Congregibacter litoralis
, and strain HTCC2080. Here, the genome sequence of strain IMCC3088 is presented, showing the absence of photosynthetic gene clusters and the presence of proteorhodopsin.
Complete Genome Sequence of Carnobacterium sp. 17-4
Authors: Voget Sonja , Klippel Barbara , Daniel Rolf , Antranikian Garabed
Published: May 2011

Members of the carnobacteria have been extensively studied as probiotic cultures in aquacultures and protective cultures in seafood, diary, and meat. We report on the finished genome sequence of
Carnobacterium
sp. 17-4, which has been isolated from permanently cold seawater. The genetic information reveals a new circular bacteriocin biosynthesis cluster.
Complete Genome Sequence of Staphylococcus aureus T0131, an ST239-MRSA-SCC
mec
Type III Clone Isolated in China
Authors: Li Yang , Cao Boyang , Zhang Yongfu , Zhou Jiali , Yang Bin , Wang Lei
Published: May 2011

We report here the complete genome sequence of
Staphylococcus aureus
T0131, which is a multiresistant clinical isolate recovered in China and the first sequenced epidemic ST239-MRSA-SCC
mec
type III strain obtained in Asia. Comparison with two published genomes of ST239 reveals the polymorphism among strains of this type from different continents.
Draft Genome of Phaeobacter gallaeciensis ANG1, a Dominant Member of the Accessory Nidamental Gland of Euprymna scolopes
Authors: Collins Andrew J. , Nyholm Spencer V.
Published: May 2011

Phaeobacter gallaeciensis
strain ANG1 represents the dominant member of the bacterial consortium within the reproductive accessory nidamental gland (ANG) of the squid
Euprymna scolopes
. We present a 4.59-Mb assembly of its genome, which may provide clues as to how it benefits its host.
Genome Sequence of Gluconacetobacter sp. Strain SXCC-1, Isolated from Chinese Vinegar Fermentation Starter
Authors: Du Xin-jun , Jia Shi-ru , Yang Yue , Wang Shuo
Published: May 2011

Gluconacetobacter
strains are prominent bacteria during traditional vinegar fermentation. Here, we report a draft genome sequence of
Gluconacetobacter
sp. strain SXCC-1. This strain was isolated from a fermentation starter (Daqu) used for commercial production of Shanxi vinegar, the best-known vinegar of China.
New method to measure coronary velocity and coronary flow reserve
Authors: Zhang Z.-D. , Svendsen M. , Choy J. S. , Sinha A. K. , Huo Y. , Yoshida K. , Molloi S. , Kassab G. S.
Published: May 2011

Coronary flow reserve (CFR) is an important index of coronary microcirculatory function. The objective of this study was to validate the reproducibility and accuracy of intravascular conductance catheter-based method for measurements of baseline and hyperemic coronary flow velocity (and hence CFR). The absolute coronary blood velocity was determined by measuring the time of transit of a saline injection between two pairs of electrodes (known distance) on a conductance catheter during a routine saline injection without the need for reference flow. In vitro validation was made in the velocity range of 5 to 70 cm/s in reference to the volume collection method. In 10 swine, velocity measurements were compared with those from a flow probe in coronary arteries at different CFR attained by microsphere embolization. In vitro, the mean difference between the proposed method and volume collection was 0.7 ± 1.34 cm/s for steady flow and −0.77 ± 2.22 cm/s for pulsatile flow. The mean difference between duplicate measurements was 0 ± 1.4 cm/s. In in vivo experiments, the flow (product of velocity and lumen cross-sectional area that is also measured by the conductance catheter) was determined in both normal and stenotic vessels and the mean difference between the proposed method and flow probe was −1 ± 12 ml/min (flow ranged from 10 to 130 ml/min). For CFR, the mean difference between the two methods was 0.06 ± 0.28 (range of 1 to 3). Our results demonstrate the reproducibility and accuracy of velocity and CFR measurements with a conductance catheter by use of a standard saline injection. The ability of the combined measurement of coronary lumen area (as previously validated) and current velocity and CFR measurements provides an integrative diagnostic tool for interventional cardiology.
Uridine adenosine tetraphosphate-induced contraction is increased in renal but not pulmonary arteries from DOCA-salt hypertensive rats
Authors: Matsumoto Takayuki , Tostes Rita C. , Webb R. Clinton
Published: May 2011

Uridine adenosine tetraphosphate (Up4A) was reported as a novel endothelium-derived contracting factor. Up4A contains both purine and pyrimidine moieties, which activate purinergic (P2)X and P2Y receptors. However, alterations in the vasoconstrictor responses to Up4A in hypertensive states remain unclear. The present study examined the effects of Up4A on contraction of isolated renal arteries (RA) and pulmonary arteries (PA) from DOCA-salt rats using isometric tension recording. RA from DOCA-salt rats exhibited increased contraction to Up4A versus arteries from control uninephrectomized rats in the absence and presence of NG-nitro-l-arginine (nitric oxide synthase inhibitor). On the other hand, the Up4A-induced contraction in PA was similar between the two groups. Up4A-induced contraction was inhibited by suramin (nonselective P2 antagonist) but not by diinosine pentaphosphate pentasodium salt hydrate (Ip5I; P2X1 antagonist) in RA from both groups. Furthermore, 2-thiouridine 5′-triphosphate tetrasodium salt (2-ThioUTP; P2Y2 agonist)-, uridine-5′-(γ-thio)-triphosphate trisodium salt (UTPγS; P2Y2/P2Y4 agonist)-, and 5-iodouridine-5′- O-diphosphate trisodium salt (MRS 2693; P2Y6 agonist)-induced contractions were all increased in RA from DOCA-salt rats. Protein expression of P2Y2-, P2Y4-, and P2Y6 receptors in RA was similar between the two groups. In DOCA-salt RA, the enhanced Up4A-induced contraction was reduced by PD98059, an ERK pathway inhibitor, and Up4A-stimulated ERK activation was increased. These data are the first to indicate that Up4A-induced contraction is enhanced in RA from DOCA-salt rats. Enhanced P2Y receptor signaling and activation of the ERK pathway together represent a likely mechanism mediating the enhanced Up4A-induced contraction. Up4A might be of relevance in the pathophysiology of vascular tone regulation and renal dysfunction in arterial hypertension.
Thirty years of the heart as an endocrine organ: physiological role and clinical utility of cardiac natriuretic hormones
Authors: Clerico Aldo , Giannoni Alberto , Vittorini Simona , Passino Claudio
Published: May 2011

Thirty years ago, De Bold et al. ( 20 ) reported that atrial extracts contain some biologically active peptides, which promote a rapid and massive diuresis and natriuresis when injected in rats. It is now clear that the heart also exerts an endocrine function and in this way plays a key role in the regulation of cardiovascular and renal systems. The aim of this review is to discuss some recent insights and still-debated findings regarding the cardiac natriuretic hormones (CNHs) produced and secreted by cardiomyocytes (i.e., atrial natriuretic peptide and B-type natriuretic peptide). The functional status of the CNH system depends not only on the production/secretion of CNHs by cardiomyocytes but also on both the peripheral activation of circulating inactive precursor of natriuretic hormones and the transduction of the hormone signal by specific receptors. In this review, we will discuss the data supporting the hypothesis that the production and secretion of CNHs is the result of a complex integration among mechanical, chemical, hemodynamic, humoral, ischemic, and inflammatory inputs. The cross talk among endocrine function, adipose tissue, and sex steroid hormones will be discussed more in detail, considering the clinically relevant relationships linking together cardiovascular risk, sex, and body fat development and distribution. Finally, we will review the pathophysiological role and the clinical relevance of both peripheral maturation of the precursor of B-type natriuretic peptides and hormone signal transduction .
Development of a preclinical model of ischemic cardiomyopathy in swine
Authors: Ishikawa Kiyotake , Ladage Dennis , Takewa Yoshiaki , Yaniz Elisa , Chen Jiqiu , Tilemann Lisa , Sakata Susumu , Badimon Juan J. , Hajjar Roger J. , Kawase Yoshiaki
Published: May 2011

A number of promising therapies for ischemic cardiomyopathy are emerging, and the role of translational research in testing the efficacy and safety of these agents in relevant clinical models has become important. The goal of this study was to develop a chronic model of ischemic cardiomyopathy in a large animal model. In this study, 40 consecutive pigs were initially enrolled. To induce progressive stenosis, a plastic occluder with a fixed diameter of 1.0 mm fitted with an 18-gauge copper wire was placed around the proximal left anterior descending (LAD) coronary artery. Coronary angiography, hemodynamic measurements, and echocardiography were performed at 2 wk and 1, 2, and 3 mo. Overall mortality was 26% at 3 mo, and up to 80% of the pigs showed total occlusion of LAD at 1 mo. A significant depression of peak LV pressure rate of rise (+dP/d tmax) was observed in the animals showing total artery occlusion throughout the study. Left ventricular ejection fraction was also impaired, and the left ventricular volumes tended to be larger in the pigs with occlusion. Approximately 10% of scar tissue was found in the LAD occluded pigs, whereas the coronary flow pattern in the rest of the area took the pattern of hibernating myocardium. At the same time, histological and protein analysis established the presence of fibrosis and ongoing apoptosis in the ischemic area. In this model, the timing and incidence of total occlusion and low mortality offer significant advantages over other ischemic cardiomyopathy models in conducting preclinical studies.
Doxycycline, a matrix metalloprotease inhibitor, reduces vascular remodeling and damage after cerebral ischemia in stroke-prone spontaneously hypertensive rats
Authors: Pires Paulo W. , Rogers Curt T. , McClain Jonathon L. , Garver Hannah S. , Fink Gregory D. , Dorrance Anne M.
Published: May 2011

Matrix metalloproteases (MMPs) are a family of zinc peptidases involved in extracellular matrix turnover. There is evidence that increased MMP activity is involved in remodeling of resistance vessels in chronic hypertension. Thus we hypothesized that inhibition of MMP activity with doxycycline (DOX) would attenuate vascular remodeling. Six-week-old male stroke-prone spontaneously hypertensive rats (SHRSP) were treated with DOX (50 mg·kg−1·day−1 in the drinking water) for 6 wk. Untreated SHRSP were controls. Blood pressure was measured by telemetry during the last week. Middle cerebral artery (MCA) and mesenteric resistance artery (MRA) passive structures were assessed by pressure myography. MMP-2 expression in aortas was measured by Western blot. All results are means ± SE. DOX caused a small increase in mean arterial pressure (SHRSP, 154 ± 1; SHRSP + DOX, 159 ± 3 mmHg; P < 0.001). Active MMP-2 expression was reduced in aorta from SHRSP + DOX (0.21 ± 0.06 vs. 0.49 ± 0.13 arbitrary units; P < 0.05). In the MCA, at 80 mmHg, DOX treatment increased the lumen (273.2 ± 4.7 vs. 238.3 ± 6.3 μm; P < 0.05) and the outer diameter (321 ± 5.3 vs. 290 ± 7.6 μm; P < 0.05) and reduced the wall-to-lumen ratio (0.09 ± 0.002 vs. 0.11 ± 0.003; P < 0.05). Damage after transient cerebral ischemia (transient MCA occlusion) was reduced in SHRSP + DOX (20.7 ± 4 vs. 45.5 ± 5% of hemisphere infarcted; P < 0.05). In the MRA, at 90 mmHg DOX, reduced wall thickness (29 ± 1 vs. 22 ± 1 μm; P < 0.001) and wall-to-lumen ratio (0.08 ± 0.004 vs. 0.11 ± 0.008; P < 0.05) without changing lumen diameter. These results suggest that MMPs are involved in hypertensive vascular remodeling in both the peripheral and cerebral vasculature and that DOX reduced brain damage after cerebral ischemia.
Effect of age on high-fat diet-induced hypertension
Authors: Erdos Benedek , Kirichenko Nataliya , Whidden Melissa , Basgut Bilgen , Woods Mary , Cudykier Idan , Tawil Rabih , Scarpace Philip J. , Tumer Nihal
Published: May 2011

Aging and obesity both have a significant impact on central blood pressure (BP) regulation, and previous studies indicated that changes in central redox signaling with age may affect high-fat (HF) diet-induced cardiovascular responses. Therefore, we investigated the effects of 60% HF feeding on BP regulation in young adult (5 mo) and old (26 mo) Fischer-344 × Brown-Norway rats. Radiotelemetric transmitters were implanted to measure BP, heart rate (HR), locomotor activity, and spontaneous baroreflex sensitivity. Expression and activity of NADPH oxidase and ANG II type 1 receptor were assessed in the hypothalamus and in the nucleus tractus solitarii. Old animals gained more weight on HF diet compared with young, whereas central NADPH oxidase expression and activity elevated similarly in the two age groups. After an initial hypotensive and tachycardic response during the first week of HF feeding, BP in young animals increased and became significantly elevated after 6 wk of HF feeding. In contrast, BP in old animals remained depressed. Nighttime HR and locomotor activity decreased in both young and old rats fed with HF diet, but these changes were more significant in young rats. As a result, amplitudes of circadian variation of BP, HR, and activity that were originally higher in young rats declined significantly and became similar in the two age groups. In conclusion, our experiments led to the surprising finding that HF diet has a more serious impact on cardiovascular regulation in young animals compared with old.
Perinatal or Adult Nf1 Inactivation Using Tamoxifen-Inducible PlpCre Each Cause Neurofibroma Formation
Authors: Mayes Debra A. , Rizvi Tilat A. , Cancelas Jose A. , Kolasinski Nathan T. , Ciraolo Georgianne M. , Stemmer-Rachamimov Anat O. , Ratner Nancy
Published: May 2011

Plexiform neurofibromas are peripheral nerve sheath tumors initiated by biallelic mutation of the NF1 tumor suppressor gene in the Schwann cell lineage. To understand whether neurofibroma formation is possible after birth, we induced Nf1 loss of function with an inducible proteolipid protein Cre allele. Perinatal loss of Nf1 resulted in the development of small plexiform neurofibromas late in life, whereas loss in adulthood caused large plexiform neurofibromas and morbidity beginning 4 months after onset of Nf1 loss. A conditional EGFP reporter allele identified cells showing recombination, including peripheral ganglia satellite cells, peripheral nerve S100β+ myelinating Schwann cells, and peripheral nerve p75+ cells. Neurofibromas contained cells with Remak bundle disruption but no recombination within GFAP+ nonmyelinating Schwann cells. Extramedullary lympho-hematopoietic expansion was also observed in PlpCre;Nf1fl/fl mice. These tumors contained EGFP+/Sca-1+ stromal cells among EGFP-negative lympho-hematopoietic cells indicating a noncell autonomous effect and unveiling a role of Nf1-deleted microenvironment on lympho-hematopoietic proliferation in vivo. Together these findings define a tumor suppressor role for Nf1 in the adult and narrow the range of potential neurofibroma-initiating cell populations. Cancer Res; 71(13); 4675–85. ©2011 AACR.
Susceptible Stages in Schwann Cells for NF1-Associated Plexiform Neurofibroma Development
Authors: Le Lu Q. , Liu Chiachi , Shipman Tracey , Chen Zhiguo , Suter Ueli , Parada Luis F.
Published: May 2011

Stem cells are under strict regulation by both intrinsic factors and the microenvironment. There is increasing evidence that many cancers initiate through acquisition of genetic mutations (loss of intrinsic control) in stem cells or their progenitors, followed by alterations of the surrounding microenvironment (loss of extrinsic control). In neurofibromatosis type 1 (NF1), deregulation of Ras signaling results in development of multiple neurofibromas, complex tumors of the peripheral nerves. Neurofibromas arise from the Schwann cell lineage following loss of function at the NF1 locus, which initiates a cascade of interactions with other cell types in the microenvironment and additional cell autonomous modifications. In this study, we sought to identify whether a temporal “window of opportunity” exists during which cells of the Schwann cell lineage can give rise to neurofibromas following loss of NF1. We showed that acute loss of NF1 in both embryonic and adult Schwann cells can lead to neurofibroma formation. However, the embryonic period when Schwann cell precursors and immature Schwann cells are most abundant coincides with enhanced susceptibility to plexiform neurofibroma tumorigenesis. This model has important implications for understanding early cellular events that dictate neurofibroma development, as well as for the development of novel therapies targeting these tumors. Cancer Res; 71(13); 4686–95. ©2011 AACR.
Association of CHFR Promoter Methylation with Disease Recurrence in Locally Advanced Colon Cancer
Authors: Tanaka Motofumi , Chang Ping , Li Yanan , Li Donghui , Overman Michael , Maru Dipen M. , Sethi Salil , Phillips Jonathan , Bland Gail L. , Abbruzzese James L. , Eng Cathy
Published: May 2011

Purpose: This study was designed to determine whether DNA methylation biomarkers are associated with recurrence and survival in colon cancer patients.

Experimental Design: A retrospective analysis of 82 patients who received curative surgical resection for American Joint Committee on Cancer (AJCC) high-risk stage II or III colon cancer (1999–2007) was conducted. DNA methylation status was quantitatively evaluated by the pyrosequencing method. We preselected three tumor suppressor genes and one locus of interest; CHFR, ID4, RECK, and MINT1. Mean methylation levels of multiple CpG sites in the promoter regions were used for analysis; 15% or more was defined as methylation positive. The association of recurrence-free survival (RFS) and overall survival (OS) with methylation status was analyzed by the log-rank test, Kaplan–Meier method, and Cox proportional hazards model.

Results: Methylation levels of ID4, MINT1, and RECK did not correlate with RFS or OS. CHFR was methylation positive in 63% patients. When methylation status was dichotomized (negative or low: <30%, high: ≥30%), patients with CHFR methylation-high (44%) had worse RFS (P = 0.006) and reduced OS (P = 0.069). When stratified by stage, CHFR methylation-high was associated with reduced RFS (P = 0.004) and OS (P = 0.010) in stage III patients. CHFR methylation-high was commonly associated with N2 disease (P = 0.04) and proximal tumors (P = 0.002). Multivariate analysis indicated AJCC T4 disease and CHFR methylation-high (P = 0.001 and P = 0.015, respectively) were independent predictors for recurrence.

Conclusions: The extent of CHFR promoter methylation correlates with RFS, indicating it is a promising epigenetic marker for recurrence. Clin Cancer Res; 17(13); 4531–40. ©2011 AACR.
Foretinib (GSK1363089), an Orally Available Multikinase Inhibitor of c-Met and VEGFR-2, Blocks Proliferation, Induces Anoikis, and Impairs Ovarian Cancer Metastasis
Authors: Zillhardt Marion , Park Sun-Mi , Romero Iris L. , Sawada Kenjiro , Montag Anthony , Krausz Thomas , Yamada S. Diane , Peter Marcus E. , Lengyel Ernst
Published: May 2011

Purpose: Currently, there are no approved targeted therapies for the treatment of ovarian cancer, despite the fact that it is the most lethal gynecological malignancy. One proposed target is c-Met, which has been shown to be an important prognostic indicator in a number of malignancies, including ovarian cancer. The objective of this study was to determine whether an orally available multikinase inhibitor of c-Met and vascular endothelial growth factor receptor-2 (foretinib, GSK1363089) blocks ovarian cancer growth.

Experimental Design: The effect of foretinib was tested in a genetic mouse model of endometrioid ovarian cancer, several ovarian cancer cell lines, and an organotypic 3D model of the human omentum.

Results: In the genetic mouse model, treatment with foretinib prevented the progression of primary tumors to invasive adenocarcinoma. Invasion through the basement membrane was completely blocked in treated mice, whereas in control mice, invasive tumors entirely replaced the normal ovary. In 2 xenograft mouse models using human ovarian cancer cell lines, the inhibitor reduced overall tumor burden (86% inhibition, P < 0.0001) and metastasis (67% inhibition, P < 0.0001). The mechanism of inhibition by foretinib involved (a) inhibition of c-Met activation and downstream signaling, (b) reduction of ovarian cancer cell adhesion, (c) a block in migration and invasion, (d) reduced proliferation mediated by a G2–M cell-cycle arrest, and (e) induction of anoikis.

Conclusions: This study shows that foretinib blocks tumorigenesis and reduces invasive tumor growth in different models of ovarian cancer by affecting several critical tumor functions. We believe that it provides a rationale for the further clinical development of foretinib for the treatment of ovarian cancer. Clin Cancer Res; 17(12); 4042–51. ©2011 AACR.
E7080 Suppresses Hematogenous Multiple Organ Metastases of Lung Cancer Cells with Nonmutated Epidermal Growth Factor Receptor
Authors: Ogino Hirokazu , Hanibuchi Masaki , Kakiuchi Soji , Trung Van The , Goto Hisatsugu , Ikuta Kenji , Yamada Tadaaki , Uehara Hisanori , Tsuruoka Akihiko , Uenaka Toshimitsu , Wang Wei , Li Qi , Takeuchi Shinji , Yano Seiji , Nishioka Yasuhiko , Sone Saburo
Published: May 2011

While epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors improve the prognosis of patients with EGFR mutant lung cancer, the prognosis of patients with nonmutant EGFR lung cancer, especially those with metastases, is still extremely poor. We have assessed the therapeutic efficacy of E7080, an orally available inhibitor of multiple tyrosine kinases including VEGF receptor 2 (VEGFR-2) and VEGFR-3, in experimental multiple organ metastasis of lung cancer cell lines without EGFR mutations. E7080 markedly inhibited the in vitro proliferation of VEGF-stimulated microvascular endothelial cells. Intravenous inoculation into natural killer cell–depleted severe combined immunodeficient mice of the small cell lung cancer cell lines H1048 (producing low amounts of VEGF) and SBC-5 (producing intermediate amounts of VEGF) resulted in hematogenous metastases into multiple organs, including the liver, lungs, kidneys, and bones, whereas intravenous inoculation of PC14PE6, a non–small cell lung cancer cell line producing high amounts of VEGF, resulted in lung metastases followed by massive pleural effusion. Daily treatment with E7080 started after the establishment of micrometastases significantly reduced the number of large (>2 mm) metastatic nodules and the amount of pleural effusion, and prolonged mouse survival. Histologically, E7080 treatment reduced the numbers of endothelial and lymph endothelial cells and proliferating tumor cells and increased the number of apoptotic cells in metastatic nodules. These results suggest that E7080 has antiangiogenic and antilymphangiogenic activity and may be of potential therapeutic value in patients with nonmutant EGFR lung cancer and multiple organ metastases. Mol Cancer Ther; 10(7); 1218–28. ©2011 AACR.
Sorafenib Enhances the Antitumor Effects of Chemoradiation Treatment by Downregulating ERCC-1 and XRCC-1 DNA Repair Proteins
Authors: Yadav Arti , Kumar Bhavna , Teknos Theodoros N. , Kumar Pawan
Published: May 2011

Head and neck squamous cell carcinoma remains a challenging clinical problem because of the persisting high rate of local and distant failure due to the acquisition of chemo- and radioresistance. In this study, we examined if treatment with sorafenib, a potent inhibitor of Raf kinase and VEGF receptor, could reverse the resistant phenotype in tumor and tumor-associated endothelial cells, thereby enhancing the therapeutic efficacy of currently used chemoradiation treatment. We used both in vitro and in vivo models to test the efficacy of sorafenib either as a single agent or in combination with chemoradiation. Sorafenib, as a single agent, showed antitumor and angiogenesis properties, but the effects were more pronounced when used in combination with chemoradiation treatment. Sorafenib significantly enhanced the antiproliferative effects of chemoradiation treatment by downregulating DNA repair proteins (ERCC-1 and XRCC-1) in a dose-dependent manner. In addition, combination treatment significantly inhibited tumor cell colony formation, tumor cell migration, and tumor cell invasion. Combination treatment was also very effective in inhibiting VEGF-mediated angiogenesis in vitro. In a severe combined immunodeficient mouse xenograft model, combination treatment was very well tolerated and significantly inhibited tumor growth and tumor angiogenesis. Interestingly, following combination treatment, low-dose sorafenib treatment alone was highly effective as a maintenance regimen. Taken together, our results suggest a potentially novel strategy to use sorafenib to overcome chemo- and radioresistance in tumor and tumor-associated endothelial to enhance the effectiveness of the chemoradiation therapy. Mol Cancer Ther; 10(7); 1241–51. ©2011 AACR.
Chemotherapy Dosing Schedule Influences Drug Resistance Development in Ovarian Cancer
Authors: De Souza Raquel , Zahedi Payam , Badame Rose M. , Allen Christine , Piquette-Miller Micheline
Published: May 2011

Drug resistance leads to chemotherapy failure and is responsible for the death of a great majority of patients with metastatic, late-stage ovarian cancer. The present study addressed whether changes in the chemotherapy dosing schedule affect the development, further worsening, or circumvention of drug resistance in chemosensitive and chemoresistant ovarian cancer. Severe combined immunodeficient mice bearing HeyA8 and HeyA8-MDR xenografts were treated with docetaxel intermittently (1×/wk or 3×/wk) or continuously for 21 days. Tumor mRNA expression of genes implicated in docetaxel resistance was measured by quantitative real-time-PCR. Analyzed genes included those encoding for the drug efflux transporters mdr1 and mrp7 and for molecules that interfere with or overcome the effects of docetaxel, including β-tubulinIII, actinin4, stathmin1, bcl2, rpn2, thoredoxin, and akt2. In both models, continuous docetaxel resulted in greater antitumor efficacy than 1×/wk or 3×/wk dosing and did not induce upregulation of any analyzed genes. Once weekly dosing caused upregulation of various drug resistance–related genes, especially in chemoresistant xenografts. More frequent, 3×/wk dosing diminished this effect, although levels of various genes were higher than for continuous chemotherapy. Drug efflux transporter expression was further examined by Western blotting, confirming that intermittent, but not continuous, docetaxel induced significant upregulation. Overall, our results show that the presence and length of treatment-free intervals contribute to the development of drug resistance. Elimination of these intervals by continuous dosing resulted in superior antitumor efficacy and prevented drug resistance induction in chemosensitive and chemoresistant disease. These results encourage the clinical implementation of continuous chemotherapy to overcome and/or prevent drug resistance in newly diagnosed and recurrent, refractory ovarian cancer. Mol Cancer Ther; 10(7); 1289–99. ©2011 AACR.
Proteomic Analysis Yields an Unexpected
Trans
-Acting Point in Control of the Human Sympathochromaffin Phenotype
Authors: Chiron Stéphane , Wei Zhiyun , Chen Yuqing , Zhang Kuixing , Wen Gen , Fischer Wolfgang H. , Mahata Sushil K. , O’Connor Daniel T.
Published: May 2011

Background—

The secretory protein chromogranin A (CHGA) plays a necessary role in formation of catecholamine storage vesicles and gives rise to a catecholamine release–inhibitory fragment. Because genetic variation in the proximal human
CHGA
promoter predicts autonomic function and blood pressure, we explored how a common genetic variant alters transcription of the gene.

Methods and Results—

Bioinformatic analysis suggested that the common G−462A promoter variant (rs9658634) may disrupt as many as 3 transcriptional control motifs: LEF1, COUP-TF, and PPARγ-RXRα. During electrophoretic mobility shifts, chromaffin cell nuclear proteins bound specifically to the A (though not G) allele of
CHGA
promoter G−462A. On oligonucleotide affinity chromatography followed by electrospray ionization followed by 2-dimensional (tandem) mass spectrometry analysis of A allele eluates, the transcription factor LEF1 (lymphoid enhancer-binding factor-1) was identified. Interaction of LEF1 with the A allele at G−462A was confirmed by supershift. On cotransfection, LEF1 discriminated between the allelic variants, especially in chromaffin cells. Allele specificity of
trans
-activation by LEF1 was transferable to an isolated G−462A element fused to a heterologous (SV40) promoter. Because β-catenin (CTNNB1) can heterodimerize with LEF1, we tested the effect of cotransfection of this factor and again found A allele–specific perturbation of
CHGA
transcription.

Conclusions—

Common genetic variation within the human
CHGA
promoter alters the interaction of specific factors in
trans
with the promoter, with LEF1 identified by proteomic analysis and confirmed by supershift. Coexpression experiments show functional effects of LEF1 and CTNNB1 on
CHGA
promoter. The findings document a novel role for components of the immune and WNT pathways in control of human sympathochromaffin phenotypes.
Sarcomere Gene Mutations in Isolated Left Ventricular Noncompaction Cardiomyopathy Do Not Predict Clinical Phenotype
Authors: Probst Susanne , Oechslin Erwin , Schuler Pia , Greutmann Matthias , Boyé Philipp , Knirsch Walter , Berger Felix , Thierfelder Ludwig , Jenni Rolf , Klaassen Sabine
Published: May 2011

Background—

Left ventricular noncompaction of the myocardium (LVNC) has been recognized as a cardiomyopathy with a genetic etiology. Mutations in genes encoding sarcomere proteins were shown to be associated with LVNC. We evaluated the potential clinical impact of genetic analysis of sarcomere genes in patients with LVNC.

Methods and Results—

We identified 5 mutations in cardiac myosin-binding protein C (
MYBPC3
) and 2 mutations in α-tropomyosin (
TPM1
) in a cohort of unrelated adult probands with isolated LVNC. The mutations in
MYBPC3
and
TPM1
and in 6 other previously reported sarcomere genes in this cohort resulted in a total of 18 (29%) heterozygous mutations in 63 probands. β-myosin heavy chain (
MYH7
) was the most prevalent disease gene and accounts for 13% of cases, followed by
MYBPC3
(8%). Comparing sarcomere mutation-positive and mutation-negative LVNC probands showed no significant differences in terms of average age, myocardial function, and presence of heart failure or tachyarrhythmias at initial presentation or at follow-up. Familial disease was found in 16 probands of whom 8 were sarcomere mutation positive. Nonpenetrance was detected in 2 of 8 mutation-positive families with LVNC.

Conclusions—

Mutations in sarcomere genes account for a significant (29%) proportion of cases of isolated LVNC in this cohort. The distribution of disease genes confirms genetic heterogeneity and opens new perspectives in genetic testing in patients with LVNC and their relatives at high risk of inheriting the cardiomyopathy. The presence or absence of a sarcomere gene mutation in LVNC cannot be related to the clinical phenotype.
Noninvasive Vascular Function Measurement in the Community
Authors: Schnabel Renate B. , Schulz Andreas , Wild Philipp S. , Sinning Christoph R. , Wilde Sandra , Eleftheriadis Medea , Herkenhoff Stephanie , Zeller Tanja , Lubos Edith , Lackner Karl J. , Warnholtz Ascan , Gori Tommaso , Blankenberg Stefan , Münzel Thomas
Published: May 2011

Background—

Several methods of noninvasive vascular function testing have been suggested for cardiovascular risk screening in the community. A direct comparison of the different methods and their relation to classical cardiovascular risk factors in a large cohort is missing.

Methods and Results—

In 5000 individuals (mean age, 55.5±10.9 years; age range, 35 to 74 years; women, 49.2%) of the population-based Gutenberg Heart Study, we performed simultaneous measurement of flow-mediated dilation (FMD) and peripheral arterial volume pulse determined by infrared photo (reflection index) and pneumatic plethysmography (PAT) and explored their associations. All function measures were recorded at baseline and after reactive hyperemia induced by 5-minute brachial artery occlusion. Correlations between different measures of vascular function were statistically significant but moderate. The strongest association for hyperemic response variables was observed for PAT ratio and FMD (Spearman
r
=0.17; age- and sex-adjusted partial correlation, 0.068). Classical risk factors explained between 15.8% (baseline reflection index) and 58.4% (brachial artery diameter) of the baseline values but only accounted for 3.2% (reflection index), 15.4% (FMD), and 13.9% (PAT ratio) of the variability of reflective hyperemic response. Regression models varied in their relations to classical risk factors for the individual vascular function measures. Consistently associated with different vascular function methods were age, sex, body mass index, and indicators of hypertension. Peripheral tonometry also showed a relation to fasting glucose concentrations.

Conclusions—

Noninvasive measures of conduit artery and peripheral arterial function are modestly correlated, differ in their relation to classical cardiovascular risk factors, and may thus reflect different pathologies.
Vectorized Algorithms for Spiking Neural Network Simulation
Authors: Brette Romain , Goodman Dan F. M.
Published: May 2011

High-level languages (Matlab, Python) are popular in neuroscience because they are flexible and accelerate development. However, for simulating spiking neural networks, the cost of interpretation is a bottleneck. We describe a set of algorithms to simulate large spiking neural networks efficiently with high-level languages using vector-based operations. These algorithms constitute the core of Brian, a spiking neural network simulator written in the Python language. Vectorized simulation makes it possible to combine the flexibility of high-level languages with the computational efficiency usually associated with compiled languages.
Projective Clustering Using Neural Networks with Adaptive Delay and Signal Transmission Loss
Authors: Wu Jianhong , Zivari-Piran Hossein , Hunter John D. , Milton John G.
Published: May 2011

We develop a new neural network architecture for projective clustering of data sets that incorporates adaptive transmission delays and signal transmission information loss. The resultant selective output signaling mechanism does not require the addition of multiple hidden layers but instead is based on the assumption that the signal transmission velocity between input processing neurons and clustering neurons is proportional to the similarity between the input pattern and the feature vector (the top-down weights) of the clustering neuron. The mathematical model governing the evolution of the signal transmission delay, the short-term memory traces, and the long-term memory traces represents a new class of large-scale delay differential equations where the evolution of the delay is described by a nonlinear differential equation involving the similarity measure already noted. We give a complete description of the computational performance of the network for a wide range of parameter values.
Insights from a Simple Expression for Linear Fisher Information in a Recurrently Connected Population of Spiking Neurons
Authors: Beck Jeffrey , Bejjanki Vikranth R. , Pouget Alexandre
Published: May 2011

A simple expression for a lower bound of Fisher information is derived for a network of recurrently connected spiking neurons that have been driven to a noise-perturbed steady state. We call this lower bound linear Fisher information, as it corresponds to the Fisher information that can be recovered by a locally optimal linear estimator. Unlike recent similar calculations, the approach used here includes the effects of nonlinear gain functions and correlated input noise and yields a surprisingly simple and intuitive expression that offers substantial insight into the sources of information degradation across successive layers of a neural network. Here, this expression is used to (1) compute the optimal (i.e., information-maximizing) firing rate of a neuron, (2) demonstrate why sharpening tuning curves by either thresholding or the action of recurrent connectivity is generally a bad idea, (3) show how a single cortical expansion is sufficient to instantiate a redundant population code that can propagate across multiple cortical layers with minimal information loss, and (4) show that optimal recurrent connectivity strongly depends on the covariance structure of the inputs to the network.