bluuebunny/crossref_metadata_2025 huggingface dataset:
SCALED BOUNDARY FINITE ELEMENT METHOD FOR ACOUSTICS
Authors: LEHMANN L. , LANGER S. , CLASEN D.
Published: February 2007

When studying unbounded wave propagation phenomena, the Sommerfeld radiation condition has to be fulfilled. The artificial boundary of a domain discretized using standard finite elements produces errors. It reflects spurious energy back into the domain. The scaled boundary finite element method (SBFEM) overcomes this problem. It unites the concept of geometric similarity with the standard approach of finite elements assembly. Here, the SBFEM for acoustical problems and its coupling with the finite element method for an elastic structure is presented. The achieved numerical algorithm is best suited to study the sound propagation in an unbounded domain or interaction phenomena of a vibrating structure and an unbounded acoustical domain.

The SBFEM is applied to study the sound transmission through a separating component, and for the determination of the sound field around a sound insulating wall. The results are compared with a hybrid algorithm of Finite and Boundary Elements or with the Boundary Element Method, respectively.
BROADBAND MULTILEVEL FAST MULTIPOLE ALGORITHM FOR ACOUSTIC SCATTERING PROBLEMS
Authors: WALLÉN HENRIK , JÄRVENPÄÄ SEPPO , YLÄ-OIJALA PASI
Published: February 2007

A broadband multilevel fast multipole algorithm (MLFMA) for the acoustic scattering from a sound-hard obstacle is presented. The formulation is based on the Burton–Miller boundary integral equation and Galerkin's method, avoiding any hypersingular integral operators. The resulting matrix equation has good iterative properties for all frequencies and avoids the interior resonance problem. The main novel feature is the use of a broadband MLFMA to accelerate the iterative generalized minimal residual (GMRES) solver. The algorithm is based on a combination of Rokhlin's translation formula for large division cubes and the spectral representation of the Green's function for cubes smaller than one half wavelength, thereby avoiding the sub-wavelength breakdown of the high-frequency MLFMA.
Mechanism of regulation of rabbit intestinal villus cell brush border membrane Na/H exchange by nitric oxide
Authors: Coon Steven , Shao Guohong , Wisel Sheik , Vulaupalli Raju , Sundaram Uma
Published: February 2007

In the mammalian small intestine, coupled NaCl absorption occurs via the dual operation of Na/H and Cl/HCO3exchange on the villus cell brush border membrane (BBM). Although constitutive nitric oxide (cNO) has been demonstrated to alter gastrointestinal tract functions, how cNO may specifically alter these two transporters to regulate coupled NaCl absorption is unknown. In villus cells, inhibition of cNO synthase (cNOS) with l- NG-nitroarginine methylester (l-NAME) stimulated Na/H exchange whereas Cl/HCO3exchange was unaffected. In villus cell BBM vesicles (BBMV) prepared from rabbits treated with l-NAME, Na/H exchange was also stimulated. d-NAME, an inactive analog of l-NAME, and N6-(1-imonoethyl)-l-lysine dihydrochloride, a more selective inhibitor of inducible NO synthase, did not affect Na/H exchange. Kinetic studies demonstrated that the mechanism of stimulation is secondary to an increase in the maximal rate of uptake of Na, without an alteration in the affinity of the transporter for Na. Northern blot studies demonstrated an increase in the message for the BBM Na/H exchanger NHE3, and Western blot studies showed that the immunoreactive protein levels of NHE3 was increased when cNOS was inhibited. Thus these results indicate that cNO under nominal physiological states most likely maintains an inhibitory tone on small intestinal coupled NaCl absorption by specifically inhibiting BBM Na/H expression.
Nitrergic contribution to gastric relaxation induced by glucagon-like peptide-1 (GLP-1) in healthy adults
Authors: Andrews Christopher N. , Bharucha Adil E. , Camilleri Michael , Low Phillip A. , Seide Barbara , Burton Duane , Baxter Kari , Zinsmeister Alan R.
Published: February 2007

The incretin glucagon-like peptide-1 (GLP-1), which is used to treat diabetes mellitus, delays gastric emptying by inhibiting vagal activity. GLP-1 also increases fasting and postprandial gastric volume in humans. On the basis of animal studies, we hypothesized that nitric oxide mediates the effects of GLP-1 on gastric volumes. To assess the effects of nitrergic blockade on GLP-1-induced gastric accommodation in humans, in this double-blind study, 31 healthy volunteers were randomized to placebo (i.e., saline), GLP-1, or the nitric oxide synthase inhibitor NG-monomethyl-l-arginine acetate (l-NMMA; 4 mg·kg−1·h−1) alone or with GLP-1. Thereafter, 16 additional subjects were randomized to GLP-1 alone or together with a higher dose of l-NMMA (10 mg/kg bolus plus 8 mg·kg−1·h−1 infusion). Gastric volumes (fasting pre- and postdrug, postprandial postdrug) were measured by 99mTc-single-photon-emission computed tomography imaging. GLP-1 increased ( P = 0.04) fasting gastric volume by 83 ± 16 ml (vs. 17 ± 11 ml for placebo) and augmented ( P ≤ 0.01) postprandial accommodation by 688 ± 165 ml (vs. 542 ± 29 ml for placebo). l-NMMA (low dose) alone did not affect fasting or postprandial gastric volume. l-NMMA (low dose) did not attenuate the effect of GLP-1 on gastric volumes. In contrast, l-NMMA (high dose) did not affect fasting volume but blunted GLP-1-mediated postprandial accommodation (postprandial change = 494 ± 37 ml, P ≤ 0.01 vs. GLP-1 alone). These data are consistent with the hypothesis that nitric oxide partly mediates the effects of GLP-1 on postprandial but not fasting gastric volumes in humans.
A murine transgenic model for transcriptional regulation of the Na/Pi-IIa major renal phosphate cotransporter
Authors: Rosenberg Tzur , Shachaf Catherine , Tzukerman Maty , Skorecki Karl
Published: February 2007

Levels of the type IIa Na/Pi(Na/Pi-IIa) cotransporter, which serves as the principal mediator of phosphate reabsorption in the kidney, can be modulated through posttranscriptional or posttranslational mechanisms by dietary, hormonal, and pharmacological influences. Previous studies have not demonstrated clear-cut evidence for modulation of Na/Pi-IIa cotransporter levels through transcriptional mechanisms. We have previously demonstrated that a 4.7-kb rat genomic fragment upstream of the rodent Npt2 gene encoding the Na/Pi-IIa cotransporter, is sufficient to mediate its transcriptional activity in vitro (Shachaf C, Skorecki KL, Tzukerman M. Am J Physiol Renal Physiol 278: F406–F416, 2000). Accordingly, we have established an in vivo experimental model in which this Npt2 genomic fragment fused upstream of a Lac Z reporter gene was expressed as a transgene in mice. The nine independent transgenic founder lines generated exhibited Lac Z reporter gene expression specifically in the renal cortex. This renal cortical-specific expression driven by the Npt2 promoter was confirmed at the mRNA and protein levels using RT-PCR, histochemistry, and Lac Z enzymatic activity. Furthermore, the expression of the transgene correlated with expression of the endogenous Npt2 gene during embryonic and early postnatal development. Thus we have generated a transgenic mouse model which will enable in vivo investigation of the contribution of transcriptional mechanisms to the overall regulation of Na/Pi-IIa expression under physiological and pathophysiological conditions.
Roles of Ionic Currents in Lamprey CPG Neurons: A Modeling Study
Authors: Huss Mikael , Lansner Anders , Wallén Peter , El Manira Abdeljabbar , Grillner Sten , Kotaleski Jeanette H.
Published: February 2007

The spinal network underlying locomotion in the lamprey consists of a core network of glutamatergic and glycinergic interneurons, previously studied experimentally and through mathematical modeling. We present a new and more detailed computational model of lamprey locomotor network neurons, based primarily on detailed electrophysiological measurements and incorporating new experimental findings. The model uses a Hodgkin–Huxley-like formalism and consists of 86 membrane compartments containing 12 types of ion currents. One of the goals was to introduce a fast, transient potassium current (Kt) and two sodium-dependent potassium currents, one faster (KNaF) and one slower (KNaS), in the model. Not only has the model lent support to the interpretation of experimental results but it has also provided predictions for further experimental analysis of single-network neurons. For example, Kt was shown to be one critical factor for controlling action potential duration. In addition, the model has proved helpful in investigating the possible influence of the slow afterhyperpolarization on repetitive firing during ongoing activation. In particular, the balance between the simulated slow sodium-dependent and calcium-dependent potassium currents has been explored, as well as the possible involvement of dendritic conductances.
Ion Channels Generating Complex Spikes in Cartwheel Cells of the Dorsal Cochlear Nucleus
Authors: Kim Yuil , Trussell Laurence O.
Published: February 2007

Cartwheel cells are glycinergic interneurons that modify somatosensory input to the dorsal cochlear nucleus. They are characterized by firing of mixtures of both simple and complex action potentials. To understand what ion channels determine the generation of these two types of spike waveforms, we recorded from cartwheel cells using the gramicidin perforated-patch technique in brain slices of mouse dorsal cochlear nucleus and applied channel-selective blockers. Complex spikes were distinguished by whether they arose directly from a negative membrane potential or later during a long depolarization. Ca2+ channels and Ca2+-dependent K+ channels were major determinants of complex spikes. Onset complex spikes required T-type and possibly R-type Ca2+ channels and were shaped by BK and SK K+ channels. Complex spikes arising later in a depolarization were dependent on P/Q- and L-type Ca2+ channels as well as BK and SK channels. BK channels also contributed to fast repolarization of simple spikes. Simple spikes featured an afterdepolarization that is probably the trigger for complex spiking and is shaped by T/R-type Ca2+ and SK channels. Fast spikes were dependent on Na+ channels; a large persistent Na+ current may provide a depolarizing drive for spontaneous activity in cartwheel cells. Thus the diverse electrical behavior of cartwheel cells is determined by the interaction of a wide variety of ion channels with a prominent role played by Ca2+.
Heat Sensitization in Skin and Muscle Nociceptors Expressing Distinct Combinations of TRPV1 and TRPV2 Protein
Authors: Rau K. K. , Jiang N. , Johnson R. D. , Cooper B. Y.
Published: February 2007

Recordings were made from small and medium diameter dorsal root ganglia (DRG) neurons that expressed transient receptor potential (TRP) proteins. Physiologically characterized skin nociceptors expressed either TRPV1 (type 2) or TRPV2 (type 4) in isolation. Other nociceptors co-expressed both TRP proteins and innervated deep tissue sites (gastrocnemius muscle, distal colon; type 5, type 8) and skin (type 8). Subpopulations of myelinated (type 8) and unmyelinated (type 5) nociceptors co-expressed both TRPs. Cells that expressed TRPV1 were excellent transducers of intense heat. Proportional inward currents were obtained from a threshold of ∼46.5 to ∼56°C. In contrast, cells expressing TRPV2 alone (52°C threshold) did not reliably transduce the intensity of thermal events. Studies were undertaken to assess the capacity of skin and deep nociceptors to exhibit sensitization to repeated intense thermal stimuli [heat-heat sensitization (HHS)]. Only nociceptors that expressed TRPV2, alone or in combination with TRPV1, exhibited HHS. HHS was shown to be Ca2+dependent in either case. Intracellular Ca2+dependent pathways to HHS varied with the pattern of TRP protein expression. Cells co-expressing both TRPs modulated heat reactivity through serine/threonine phosphorylation or PLA2-dependent pathways. Cells expressing only TRPV2 may have relied on tyrosine kinases for HHS. We conclude that heat sensitization in deep and superficial capsaicin and capsaicin-insensitive C and Aδ nociceptors varies with the distribution of TRPV1 and TRPV2 proteins. The expression pattern of these proteins are specific to subclasses of physiologically identified C and A fiber nociceptors with highly restricted tissue targets.
Differential Effects of Opioids on Sacrocaudal Afferent Pathways and Central Pattern Generators in the Neonatal Rat Spinal Cord
Authors: Blivis D. , Mentis G. Z. , O'Donovan M. J. , Lev-Tov A.
Published: February 2007

The effects of opioids on sacrocaudal afferent (SCA) pathways and the pattern-generating circuitry of the thoracolumbar and sacrocaudal segments of the spinal cord were studied in isolated spinal cord and brain stem-spinal cord preparations of the neonatal rat. The locomotor and tail moving rhythm produced by activation of nociceptive and nonnociceptive sacrocaudal afferents was completely blocked by specific application of the μ-opioid receptor agonist [d-Ala2, N-Me-Phe4, Gly5-ol]-enkephalin acetate salt (DAMGO) to the sacrocaudal but not the thoracolumbar segments of the spinal cord. The rhythmic activity could be restored after addition of the opioid receptor antagonist naloxone to the experimental chamber. The opioid block of the SCA-induced rhythm is not due to impaired rhythmogenic capacity of the spinal cord because a robust rhythmic activity could be initiated in the thoracolumbar and sacrocaudal segments in the presence of DAMGO, either by stimulation of the ventromedial medulla or by bath application of N-methyl-d-aspartate/serotonin. We suggest that the opioid block of the SCA-induced rhythm involves suppression of synaptic transmission through sacrocaudal interneurons interposed between SCA and the pattern-generating circuitry. The expression of μ opioid receptors in several groups of dorsal, intermediate and ventral horn interneurons in the sacrocaudal segments of the cord, documented in this study, provides an anatomical basis for this suggestion.
Increased Expression of SIM2-s Protein Is a Novel Marker of Aggressive Prostate Cancer
Authors: Halvorsen Ole Johan , Rostad Kari , Øyan Anne Margrete , Puntervoll Hanne , Bø Trond Hellem , Stordrange Laila , Olsen Sue , Haukaas Svein Andreas , Hood Leroy , Jonassen Inge , Kalland Karl-Henning , Akslen Lars Andreas
Published: February 2007

Purpose: The human SIM2 gene is located within the Down's syndrome critical region of chromosome 21 and encodes transcription factors involved in brain development and neuronal differentiation. SIM2 has been assigned a possible role in the pathogenesis of solid tumors, and the SIM2-short isoform (SIM2-s) was recently proposed as a molecular target for cancer therapy. We previously reported SIM2 among the highly up-regulated genes in 29 prostate cancers, and the purpose of our present study was to examine the expression status of SIM2 at the transcriptional and protein level as related to outcome in prostate cancer.

Experimental Design: By quantitative PCR, mRNA in situ hybridization, and immunohistochemistry, we evaluated the expression and significance of SIM2 isoforms in 39 patients with clinically localized prostate cancer and validated the expression of SIM2-s protein in an independent cohort of 103 radical prostatectomies from patients with long and complete follow-up.

Results: The SIM2 isoforms (SIM2-s and SIM2-l) were significantly coexpressed and increased in prostate cancer. Tumor cell expression of SIM2-s protein was associated with adverse clinicopathologic factors like increased preoperative serum prostate-specific antigen, high histologic grade, invasive tumor growth with extra-prostatic extension, and increased tumor cell proliferation by Ki-67 expression. SIM2-s protein expression was significantly associated with reduced cancer-specific survival in multivariate analyses.

Conclusions: These novel findings indicate for the first time that SIM2 expression might be important for clinical progress of human cancer and support the recent proposal of SIM2-s as a candidate for targeted therapy in prostate cancer.
Decreased Expression of Gene Cluster at Chromosome 1q21 Defines Molecular Subgroups of Chemoradiotherapy Response in Esophageal Cancers
Authors: Luthra Madan G. , Ajani Jaffer A. , Izzo Julie , Ensor Joe , Wu Tsung-Teh , Rashid Asif , Zhang Li , Phan Alexandria , Fukami Norio , Luthra Rajyalakshmi
Published: February 2007

Purpose: Resistance to preoperative chemoradiotherapy (CTXRT) in 75% of patients with esophageal adenocarcinoma (EAC) underscores the need for identification of biomarkers of CTXRT response. We previously noted an association between decreased expression of epidermal differentiation complex (EDC) genes S100A2 and SPRR3 at chromosome 1q21 and CTXRT resistance. In the current study, we did an in-depth investigation of the expression of 1q21-1q25 region genes to uncover the role of the EDC and its flanking genes in CTXRT response.

Experimental Design: We compared 19 pretreatment EAC specimens with normal squamous mucosa for the expression of 517 genes at chromosome 1q21-1q25 and selected target genes based on their differential expression. Using the pathologic complete-response (pathCR) status of the resected specimens as a representation of CTXRT sensitivity, we assessed the association between the expression of target genes and CTXRT response and clinical outcomes.

Results: On the basis of the expression levels of IVL, CRNN, NICE-1, S100A2, and SPPR3, genes within and in close proximity to the EDC, cancers were segregated into high (subgroup I) or low (subgroup II) expressers. Four of the five pathCRs were high expressers. Thus, low expressers, with one exception, were all nonresponders. Patients in subgroup I also had longer survival than those in subgroup II, although this result was not statistically significant owing to the small study number.

Conclusions: The expression levels of genes mapping within and close to the EDC define CTXRT response subgroups in EACs.
Cyclophosphamide-Using Nonmyeloablative Allogeneic Cell Therapy against Renal Cancer with a Reduced Risk of Graft-versus-Host Disease
Authors: Eto Masatoshi , Harano Masahiko , Tatsugami Katsunori , Harada Mamoru , Kamiryo Yoriyuki , Kiyoshima Keijiro , Hamaguchi Masumitsu , Tsuneyoshi Masazumi , Yoshikai Yasunobu , Naito Seiji
Published: February 2007

Purpose: Much attention has been paid to nonmyeloablative allogeneic stem cell transplantation for the treatment of renal cancer. We recently proposed a cyclophosphamide-using nonmyeloablative cell therapy in which donor lymphocyte infusion (DLI) was carried out after the tolerance induction to donor cells. In considering the clinical application of the cyclophosphamide-using cell therapy, attempts to reduce graft-versus-host disease (GVHD) are crucial. The aim of the present study was to modify the cyclophosphamide-using cell therapy to reduce the risk of GVHD while preserving the antitumor activity against renal cancer.

Experimental Design: We assessed whether a delay in performing DLI from day 1 to day 5 after the cyclophosphamide treatment could reduce the risk of GVHD while preserving antitumor activity against RENCA, a murine carcinogen-induced renal cell carcinoma, in the cyclophosphamide-using cell therapy.

Results: Regarding the in vivo antitumor effect, there was no difference between DLI on day 1 and day 5 after the cyclophosphamide treatment, whereas the histologic findings of the small intestine showed that the cyclophosphamide-using cell therapy with DLI on day 5 decreased the risk of GVHD. In addition, the acquired immunity against RENCA was also observed in the RENCA-rejected mice that had been treated with DLI on day 5.

Conclusions: Our results show that a delay in DLI during cyclophosphamide-using nonmyeloablative cell therapy can dissociate graft-versus-tumor effects from GVHD by reducing the risk of GVHD.
The ABCA5 Protein: A Urine Diagnostic Marker for Prostatic Intraepithelial Neoplasia
Authors: Hu Youji , Wang Min , Veverka Karen , Garcia Fernando U. , Stearns Mark E.
Published: February 2007

Purpose: To develop a urine diagnostic test for preneoplastic intraepithelial neoplasia of the prostate.

Experimental Design: We have used a DNA-binding assay and electrophoretic mobility shift assays (EMSA) to screen for novel duplexed DNA-binding sequences, which bind protein(s) overexpressed in crude protein extracts from high-grade prostatic intraepithelial neoplasia (HGPIN). EMSAs, immunohistochemistry, and ELISAs were used to measure expression of the ABCA5 protein identified as a specific marker in prostate tissue and patient urine.

Results: Following screening of 4,096 sequences, an 8-bp dsDNA sequence (i.e., TCCAGCGA) was identified, which binds the ABCA5 protein, a member of the ATP-binding cassette multidrug resistant family. EMSAs showed that ABCA5 was overexpressed in HGPIN tissue (n = 11/11) and in the urine of patients with HGPIN (n = 18/18) but was not expressed in prostate cancer, benign prostatic hyperplasia, or stroma. Immunohistochemistry indicated that ABCA5 was overexpressed in foci of intermediate basal cells in normal glands and in HGPIN. ABCA5 was faintly expressed in prostate cancer glands. ELISAs showed in ‘blinded studies’ that ABCA5 was a highly sensitive (>98% sensitivity) urine diagnostic marker for HGPIN in biopsy-positive patients (n = 107) at a ‘cutoff’ of 25 ng/mL. ABCA5 was present at very low levels (i.e., <25 ng/mL) in the urine of patients diagnosed with benign prostatic hyperplasia (n = 79) or prostatitis or kidney and bladder cancer (>86% specificity).

Conclusions: The data indicate that ABCA5 might be a specific urine marker for diagnosis of patients with HGPIN.
An Optimized Clinical Regimen for the Oncolytic Virus PV701
Authors: Hotte Sébastien J. , Lorence Robert M. , Hirte Hal W. , Polawski Susan R. , Bamat Michael K. , O'Neil James D. , Roberts M. Scot , Groene William S. , Major Pierre P.
Published: February 2007

Purpose: Previous phase 1 trials of i.v.-administered PV701 have shown this virus to be well-tolerated with toxicity primarily associated with the first dose. Our hypothesis, based on preclinical evidence, was that patient tolerability could be improved by slowing the i.v. infusion rate, and that this approach would allow for the safe administration of higher doses. Additionally, this phase 1 trial was the first to measure PV701 clearance.

Experimental Design: For the first dose, a 3-h infusion was used compared with the 10- and 30-min infusions administered in the two previous trials. Subsequent doses were infused over 1 h. Six doses were given per 3-week cycle. Escalation of the first dose was done separately from the escalation of doses 2 to 6. Viral clearance was determined using whole blood reverse transcription-PCR.

Results: Eighteen patients with advanced chemorefractory cancer were enrolled. The first dose was safely escalated to 24 × 109 plaque-forming units/m2 and doses 2 to 6 were safely escalated to 120 × 109 plaque-forming units/m2. Tolerability was improved compared with the rapid bolus dosing used previously with the elimination of severe flu-like symptoms. Furthermore, infusion reactions were markedly decreased in this trial compared with previous PV701 trials. The presence of neutralizing antibodies did not significantly affect PV701 clearance. Four major and two minor tumor responses were observed.

Conclusions: Using slow infusion, patient tolerability was improved, while the first dose was safely escalated relative to two previous PV701 trials. Based on improved tolerability and encouraging signs of activity, this slow infusion regimen was selected for further PV701 clinical development.
Germline Mutations in theBRCA2Gene and Susceptibility to Hereditary Prostate Cancer
Authors: Agalliu Ilir , Kwon Erika M. , Zadory Daniel , McIntosh Laura , Thompson Joseph , Stanford Janet L. , Ostrander Elaine A.
Published: February 2007

Purpose: Several epidemiologic studies have reported that carriers of germline mutations in the BRCA2 gene have an increased risk of prostate cancer, with the highest risk observed in men diagnosed at earlier ages. However, studies of the contribution of BRCA2 mutations to the etiology of hereditary prostate cancer (HPC) have been inconsistent.

Experimental Design: To further address this issue, 266 subjects from 194 HPC families participating in the Seattle-based Prostate Cancer Genetic Research Study were screened for BRCA2 mutations by sequencing the coding regions, intron-exon boundaries, and suspected regulatory elements of this gene. Of selected HPC families, 32 had multiple breast or ovarian cancer cases, 16 were Jewish, 8 had a pancreatic cancer case, and 138 had at least one affected man diagnosed with prostate cancer at an early age (<60 years).

Results: No disease-associated protein truncating BRCA2 mutations were found in 266 subjects from HPC families. There were 61 DNA sequence variants, of which 31 (50.8%) changed the predicted amino acids. No associations were found between these missense changes and family characteristics. Among affected men with prostate cancer, there were no statistically significant differences between the genotype frequencies of DNA variants with a minor allele frequency of 1% or higher and between the strata defined by median age at diagnosis or by clinical features.

Conclusion: No evidence was found in this study for an association between BRCA2 mutations and susceptibility to HPC in men selected from high-risk families.
Cell Type–Specific, Topoisomerase II–Dependent Inhibition of Hypoxia-Inducible Factor-1α Protein Accumulation by NSC 644221
Authors: Creighton-Gutteridge Mark , Cardellina John H. , Stephen Andrew G. , Rapisarda Annamaria , Uranchimeg Badarch , Hite Karen , Denny William A. , Shoemaker Robert H. , Melillo Giovanni
Published: February 2007

Purpose: The discovery and development of small-molecule inhibitors of hypoxia-inducible factor-1 (HIF-1) is an attractive, yet challenging, strategy for the development of new cancer therapeutic agents. Here, we report on a novel tricyclic carboxamide inhibitor of HIF-1α, NSC 644221.

Experimental Design: We investigated the mechanism by which the novel compound NSC 644221 inhibited HIF-1α.

Results: NSC 644221 inhibited HIF-1–dependent, but not constitutive, luciferase expression in U251-HRE and U251-pGL3 cells, respectively, as well as hypoxic induction of vascular endothelial growth factor mRNA expression in U251 cells. HIF-1α, but not HIF-1β, protein expression was inhibited by NSC 644221 in a time- and dose-dependent fashion. Interestingly, NSC 644221 was unable to inhibit HIF-1α protein accumulation in the presence of the proteasome inhibitors MG132 or PS341, yet it did not directly affect the degradation of HIF-1α as shown by experiments done in the presence of cyclohexamide or pulse-chase labeling using [35S]methionine. In contrast, NSC 644221 decreased the rate of HIF-1α translation relative to untreated controls. Silencing of topoisomerase (topo) IIα, but not topo I, by specific small interfering RNA completely blocked the ability of NSC 644221 to inhibit HIF-1α. The data presented show that topo II is required for the inhibition of HIF-1α by NSC 644221. Furthermore, although NSC 644221 induced p21 expression, γH2A.X, and G2-M arrest in the majority of cell lines tested, it only inhibited HIF-1α in a distinct subset of cells, raising the possibility of pathway-specific “resistance” to HIF-1 inhibition in cancer cells.

Conclusions: NSC 644221 is a novel HIF-1 inhibitor with potential for use as both an analytic tool and a therapeutic agent. Our data provide a strong rationale for pursuing the preclinical development of NSC 644221 as a HIF-1 inhibitor.
FOXP3+ Regulatory T Cells Affect the Development and Progression of Hepatocarcinogenesis
Authors: Kobayashi Noritoshi , Hiraoka Nobuyoshi , Yamagami Wataru , Ojima Hidenori , Kanai Yae , Kosuge Tomoo , Nakajima Atsushi , Hirohashi Setsuo
Published: February 2007

Purpose: Tumor-infiltrating lymphocytes represent the host immune response to cancer. CD4+CD25+FOXP3+ regulatory T cells (Tregs) suppress the immune reaction. The aim of the present study was to investigate the clinicopathologic significance and roles of Tregs and CD8+ T cells during hepatocarcinogenesis.

Experimental Design: We examined the infiltration of FOXP3+ Tregs and CD8+ T cells in the tumor stroma and nontumorous liver parenchyma using 323 hepatic nodules including precursor lesions, early hepatocellular carcinoma (HCC), and advanced HCC, along with 39 intrahepatic cholangiocarcinomas and 59 metastatic liver adenocarcinomas. We did immunohistochemical comparative studies.

Results: The prevalence of Tregs was significantly higher in HCC than in the nontumorous liver (P < 0.001). The patient group with a high prevalence of Tregs infiltrating HCC showed a significantly lower survival rate (P = 0.007). Multivariate analysis revealed that the prevalence of Tregs infiltrating HCC was an independent prognostic factor. The prevalence of Tregs increased in a stepwise manner (P < 0.001) and that of CD8+ T cells decreased during the progression of hepatocarcinogenesis (P < 0.001). Regardless of the presence of hepatitis virus infection or histopathologic evidence of hepatitis, the prevalence of Tregs was significantly increased in nontumorous liver bearing primary hepatic tumors.

Conclusions: Tregs play a role in controlling the immune response to HCC during the progression of hepatocarcinogenesis. It has been suggested that primary hepatic cancers develop in liver that is immunosuppressed by a marked infiltration of Tregs. A high prevalence of Tregs infiltrating HCC is thought to be an unfavorable prognostic indicator.
The Time-Resolved Fluorescence-Based PCA3 Test on Urinary Sediments after Digital Rectal Examination; a Dutch Multicenter Validation of the Diagnostic Performance
Authors: van Gils Martijn P.M.Q. , Hessels Daphne , van Hooij Onno , Jannink Sander A. , Peelen W. Pim , Hanssen Suzanne L.J. , Witjes J. Alfred , Cornel Erik B. , Karthaus Herbert F.M. , Smits Geert A.H.J. , Dijkman Gerhard A. , Mulders Peter F.A. , Schalken Jack A.
Published: February 2007

Purpose: To improve the specificity in prostate cancer diagnosis and to prevent unnecessary prostate biopsies, especially in the serum prostate-specific antigen (PSA) “gray zone” between 3 and 15 ng/mL, the implementation of prostate cancer–specific markers is urgently needed. The recently discovered prostate cancer antigen 3 (PCA3) is such a promising prostate cancer marker. In a previous single institution study, the PCA3 urine test clearly proved to be of diagnostic value. Therefore, the diagnostic performance of the PCA3 urine test was validated in a multicenter study.

Experimental Design: The first voided urine after digital rectal examination was collected from a total of 583 men with serum PSA levels between 3 and 15 ng/mL who were to undergo prostate biopsies. We determined the PCA3 score in these samples and correlated the results with the results of the prostate biopsies.

Results: A total of 534 men (92%) had an informative sample. The area under the receiver-operating characteristic curve, a measure of the diagnostic accuracy of a test, was 0.66 for the PCA3 urine test and 0.57 for serum PSA. The sensitivity for the PCA3 urine test was 65%, the specificity was 66% (versus 47% for serum PSA), and the negative predictive value was 80%.

Conclusions: In this multicenter study, we validated the diagnostic performance of the PCA3 urine test in the largest group studied thus far using a PCA3 gene-based test. This study shows that the PCA3 urine test, when used as a reflex test, can improve the specificity in prostate cancer diagnosis and could prevent many unnecessary prostate biopsies.
Addendum to “Personal and Public Safety Issues Related to Arrhythmias That May Affect Consciousness: Implications for Regulation and Physician Recommendations: A Medical/ Scientific Statement From the American Heart Association and the North American Society of Pacing and Electrophysiology” Public Safety Issues in Patients With Implantable Defibrillators A Scientific Statement From the American Heart Association and the Heart Rhythm Society
Authors: Epstein Andrew E. , Baessler Christina A. , Curtis Anne B. , Estes N.A. Mark , Gersh Bernard J. , Grubb Blair , Mitchell L. Brent
Published: February 2007

Overview—

In 1996, the American Heart Association developed a scientific statement entitled “Personal and Public Safety Issues Related to Arrhythmias That May Affect Consciousness: Implications for Regulation and Physician Recommendations.” Since then, multiple trials have established the role of implantable cardioverter-defibrillators (ICDs) for the primary prevention of sudden cardiac death in patients at risk for life-threatening ventricular arrhythmias.

Objective—

The issue of driving for patients with ICDs implanted for primary prevention was briefly discussed in the original statement, with the recommendation that such patients not be restricted from driving beyond the initial phase of healing. This scientific statement has been developed to extend the original 1996 recommendations and to provide specific recommendations on driving for individuals with ICDs implanted for primary prevention.

Summary of Recommendations—

(1) Patients receiving ICDs for primary prevention should be restricted from driving a private automobile for at least 1 week to allow for recovery from implantation of the defibrillator. Thereafter, these driving privileges should not be restricted in the absence of symptoms potentially related to an arrhythmia. (2) Patients who have received an ICD for primary prevention who subsequently receive an appropriate therapy for ventricular tachycardia or ventricular fibrillation, especially with symptoms of cerebral hypoperfusion, should then be considered to be subject to the driving guidelines previously published for patients who received an ICD for secondary prevention. (3) Patients with ICDs for primary prevention must be instructed that impairment of consciousness is a possible future event. (4) These recommendations do not apply to the licensing of commercial drivers.
Polyester Composites Filled Carbon Black and Activated Carbon from Bamboo (Gigantochloa scortechinii): Physical and Mechanical Properties
Authors: Khalil H. P. S. Abdul , Noriman N. Z. , Ahmad M. N. , Ratnam M. M. , Fuaad N. A. Nik
Published: February 2007

Carbon black and activated carbon were produced from bamboo (Gigantochloa scortechinii) using pyrolysis (at 900°C) and zinc chloride (ZnCl2) chemical activation (at 700°C) and used as a filler in polyester composites. The composites were prepared at 10, 20, 30, and 40% filler loading. The effects of water absorption, water content, and density of composites were determined. Results showed that water content and water absorption slightly increased as filler loading increased, while density value decreased as filler loading increased. Tensile, flexural and impact tests were performed at different filler loading. The results indicated that tensile and flexural strength, elongation at break, toughness and impact properties decreased as filler loading increased. However, the tensile and flexural modulus exhibited the reverse phenomenon. The filler-matrix bonding from impact fracture was analyzed by scanning electron microscopy (SEM).
Numerical Simulation of Flow and Compaction During the Cure of Laminated Composites
Authors: Li Yanxia , Zhang Zuoguang , Li Min , Gu Yizhuo
Published: February 2007

The finite element formulation is developed to solve the flow and compaction problems to simulate the resin flow and laminate compaction during the hot-pressing process of fiber-reinforced composite laminates. The numerical flow-compaction model is based on the effective stress formulation, the continuity equations, and Darcy’s flow theory. Two methods are used to calculate the variation of the laminate thickness, the simulated results validate the relationship of fiber motion and resin flow velocity. Together with the post-processor software, the visual laminate deforming process is realized through the node moving. The comparison between the predicted and experimental data shows that the program is reliable to predict the laminate thickness and the final fiber volume fraction distribution in the thickness direction.
Diamond-Epoxy Composites
Authors: d’Almeida J. R. M. , Monteiro S. N. , Menezes G. W. , Rodriguez R. J. S.
Published: February 2007

Diamond filled polymeric matrix composites are an attractive issue for wear resistant tools. The performance of these composites depends on the proper association of the hard diamond particles and the soft polymeric matrix. In the present work, the tensile strength of epoxy matrix composites filled with 10, 20, and 30 wt% diamond particles was investigated. The effect of matrix deformability, by changing the epoxy monomer to hardener ratio, on the mechanical performance of the composites was also evaluated. The results showed that the strength of the composite decreases with the amount of diamond. This behavior was attributed to the development of a weak diamond/epoxy interface, as quantitatively described by the interaction parameter of the Turcsanyi model, and qualitatively corroborated by the analysis of the fracture surfaces and by the variation of tan of the composites. The best tensile behavior was obtained when the amine rich, off-stoichiometric matrix was used.
Water Absorption Behavior of Composites from Sawdust and Recycled Plastics
Authors: Najafi Saeed Kazemi , Kiaefar Azadeh , Hamidina Elham , Tajvidi Mehdi
Published: February 2007

The water absorption of wood plastic composites (WPCs) prepared from sawdust and virgin and/or recycled plastics (HDPE and PP) was studied. Wood flour was prepared from sawdust and mixed with different virgin or recycled plastics at 50% by weight fiber loading. The mixed materials were compression molded into panels. Long term water absorptions of manufactured WPCs were evaluated by immersing them in water at room temperature for several weeks (up to 1750 h). Water diffusion coefficients were also calculated by evaluating the water absorption isotherms. Results indicated that the maximum water absorption and diffusion coefficients increased by increasing the proportion of recycled HDPE and/or PP. Time to reach saturation also decreased at higher recycled plastic contents. Water absorption of the studied composites was proved to follow the kinetics of a Fickian diffusion process.
The Geography of Gross Employment Flows in British Manufacturing
Authors: Essletzbichler Jürgen
Published: February 2007

This article offers a first attempt to examine subnational differences in the determinants of gross employment flows in the British manufacturing sector utilizing the Annual Respondents Dataset (ARD) of the Office of National Statistics. The article has four broad aims. First, it examines how the job creation and destruction process in British manufacturing compares with the processes in other countries. Second, it examines how much job creation and destruction is the result of employment shifts from declining industries and post-code areas to growing industries and areas relative to employment turnover that occurs among plants within industries and areas.The results indicate that high rates of job creation and destruction occur simultaneously in contracting as well as expanding industries and areas, suggesting that differences in net employment change can only be considered as a first step to understanding employment turnover. Third, the article investigates differences in the driving forces of job creation and destruction for British postcode areas and uncovers pronounced variation in the forces generating and destroying employment. Fourth, the article examines how much of these subnational differences can be attributed to industrial structure and reveals that industry-mix accounts for a large part of employment turnover in postcode areas.The large variation in the driving forces of job creation and destruction leads to important consequences for employment policy.Policies which focus too narrowly on new-firm start-ups and small firms are likely to be insufficient in generating employment in all areas.
Geographies of Growth, Decline and Restructuring
Authors: Dunford Michael , Greco Lidia
Published: February 2007

This article deals with the recent evolution of the Italian steel industry and of steel-making activities in two localities in the Mezzogiorno. After providing an account of the rise and fall of the public steel sector in Italy and its role in shifting the industry’s centre of gravity to the South, it concentrates on a conceptually informed discussion of the remarkable rise of northern mini-mill operations and the subsequent acquisition by a few of these companies of the privatized public enterprises in the 1990s. Most attention is paid to two of the leading new companies (Lucchini and Riva) and to the trajectories of some of their steel-making activities in two localities in Basilicata and Apulia. The trajectories of these companies and localized steelmaking activities are themselves explained in the light of the resources and strategies of corporate actors and the context in which these actors operate. Actors’ strategies are driven by a quest for profits and a struggle to accumulate in the face of competition from rival producers, and are examined in relation to the economics of steel production in the Italian South, the processes of workforce recomposition in Taranto and the tensions between profitability and environmental protection. The context includes cyclical and secular trends in the consumption and production of steel, some of the aid and restructuring actions of the ECSC, some of the specific characteristics of accumulation and competition in the steel sector and the legacies of earlier phases of local development that helped shape actors’ strategies.
The flatiron mutation in mouse ferroportin acts as a dominant negative to cause ferroportin disease
Authors: Zohn Irene E. , De Domenico Ivana , Pollock Andrew , Ward Diane McVey , Goodman Jessica F. , Liang Xiayun , Sanchez Amaru J. , Niswander Lee , Kaplan Jerry
Published: February 2007

Ferroportin disease is caused by mutation of one allele of the iron exporter ferroportin (Fpn/IREG1/Slc40a1/MTP1). All reported human mutations are missense mutations and heterozygous null mutations in mouse Fpn do not recapitulate the human disease. Here we describe the flatiron (ffe) mouse with a missense mutation (H32R) in Fpn that affects its localization and iron export activity. Similar to human patients with classic ferroportin disease, heterozygous ffe/+ mice present with iron loading of Kupffer cells, high serum ferritin, and low transferrin saturation. In macrophages isolated from ffe/+ heterozygous mice and through the use of Fpn plasmids with the ffe mutation, we show that Fpnffe acts as a dominant negative, preventing wild-type Fpn from localizing on the cell surface and transporting iron. These results demonstrate that mutations in Fpn resulting in protein mislocalization act in a dominant-negative fashion to cause disease, and the Fpnffe mouse represents the first mouse model of ferroportin disease.
Hon-yaku: a biology-driven Bayesian methodology for identifying translation initiation sites in prokaryotes
Authors: Makita Yuko , de Hoon Michiel JL , Danchin Antoine
Published: February 2007

Background

Computational prediction methods are currently used to identify genes in prokaryote genomes. However, identification of the correct translation initiation sites remains a difficult task. Accurate translation initiation sites (TISs) are important not only for the annotation of unknown proteins but also for the prediction of operons, promoters, and small non-coding RNA genes, as this typically makes use of the intergenic distance. A further problem is that most existing methods are optimized for Escherichia coli data sets; applying these methods to newly sequenced bacterial genomes may not result in an equivalent level of accuracy.

Results

Based on a biological representation of the translation process, we applied Bayesian statistics to create a score function for predicting translation initiation sites. In contrast to existing programs, our combination of methods uses supervised learning to optimally use the set of known translation initiation sites. We combined the Ribosome Binding Site (RBS) sequence, the distance between the translation initiation site and the RBS sequence, the base composition of the start codon, the nucleotide composition (A-rich sequences) following start codons, and the expected distribution of the protein length in a Bayesian scoring function. To further increase the prediction accuracy, we also took into account the operon orientation. The outcome of the procedure achieved a prediction accuracy of 93.2% in 858 E. coli genes from the EcoGene data set and 92.7% accuracy in a data set of 1243 Bacillus subtilis 'non-y' genes. We confirmed the performance in the GC-rich Gamma-Proteobacteria Herminiimonas arsenicoxydans, Pseudomonas aeruginosa, and Burkholderia pseudomallei K96243.

Conclusion

Hon-yaku, being based on a careful choice of elements important in translation, improved the prediction accuracy in B. subtilis data sets and other bacteria except for E. coli. We believe that most remaining mispredictions are due to atypical ribosomal binding sequences used in specific translation control processes, or likely errors in the training data sets.
FlowerPower: clustering proteins into domain architecture classes for phylogenomic inference of protein function
Authors: Krishnamurthy Nandini , Brown Duncan , Sjölander Kimmen
Published: February 2007

Background

Function prediction by transfer of annotation from the top database hit in a homology search has been shown to be prone to systematic error. Phylogenomic analysis reduces these errors by inferring protein function within the evolutionary context of the entire family. However, accuracy of function prediction for multi-domain proteins depends on all members having the same overall domain structure. By contrast, most common homolog detection methods are optimized for retrieving local homologs, and do not address this requirement.

Results

We present FlowerPower, a novel clustering algorithm designed for the identification of global homologs as a precursor to structural phylogenomic analysis. Similar to methods such as PSIBLAST, FlowerPower employs an iterative approach to clustering sequences. However, rather than using a single HMM or profile to expand the cluster, FlowerPower identifies subfamilies using the SCI-PHY algorithm and then selects and aligns new homologs using subfamily hidden Markov models. FlowerPower is shown to outperform BLAST, PSI-BLAST and the UCSC SAM-Target 2K methods at discrimination between proteins in the same domain architecture class and those having different overall domain structures.

Conclusion

Structural phylogenomic analysis enables biologists to avoid the systematic errors associated with annotation transfer; clustering sequences based on sharing the same domain architecture is a critical first step in this process. FlowerPower is shown to consistently identify homologous sequences having the same domain architecture as the query.

Availability

FlowerPower is available as a webserver at http://phylogenomics.berkeley.edu/flowerpower/.