bluuebunny/crossref_metadata_2025 huggingface dataset:
Perturbation to the magnetic field strength
Authors: Boozer Allen H.
Published: April 2006

The variation in the magnetic field strength on a magnetic surface as a function of the magnetic angles is one of the most important properties of an equilibrium because it determines the trajectories of the charged particles. Even a small change in the field strength can produce a qualitative change in the trajectories. The perturbed magnetic field strength as a function of magnetic coordinates is derived for a given displacement ξ⃗ of the magnetic field lines. Ideal magnetohydrodynamics stability theory can be used to determine the field line displacement ξ⃗ of a perturbed plasma equilibria and, therefore, the perturbed field strength.
Kinetic theory of acoustic wave in pair-ion plasmas
Authors: Saleem H.
Published: April 2006

A theoretical analysis of the ion acoustic wave in pair-ion plasmas is presented using a kinetic model. It is shown that a small concentration of electrons in pair-ion plasmas can break down the quasineutrality in perturbed systems because the electron Debye length can become very large. In the limit 1⪡λDe2k2 (where λDe is the electron Debye length), the damping is reduced and hence the acoustic wave can be easily excited. The real frequency of acoustic wave can be larger than the ion plasma oscillation frequency in this case. But the decreasing number density of electrons can increase the Landau damping significantly in the limit λDe2k2⪡1. The results are discussed in comparison with the recent experimental and theoretical findings. It is pointed out that this investigation can be very useful for further research on pair-ion plasmas.
Effect of annealing on dielectric behavior and conduction transport of Bi doped SrTiO3
Authors: Ang Chen , Yu Zhi
Published: April 2006

The dielectric behavior and electrical conduction in Bi doped SrTiO3 annealed in both oxidizing (air and oxygen) and reducing atmospheres (nitrogen and “hydrogen+argon”) are studied in this letter. The dielectric constant and electrical conductivity are greatly enhanced in the sample annealed in a reducing atmosphere compared with that annealed in an oxidizing atmosphere. A Mott’s variable range hopping (VRH) conduction mechanism, σ=σ0exp[−(T0∕T)1∕4], is observed in a strongly reduced sample, where a significant dielectric relaxation process is present. No direct correlation is found between the VRH conduction and the dielectric relaxation. The underlying physics of these results are briefly discussed.
Excitation mechanism of visible, Tb3+ photoluminescence from Tb-doped silicon oxynitride
Authors: Jeong Hoon , Seo Se-Young , Shin Jung H.
Published: April 2006

The excitation mechanism of visible luminescence from Tb3+-doped silicon oxynitride is investigated. Tb-doped silicon oxynitride films were deposited by inductive-coupled plasma-enhanced chemical vapor deposition of SiH4, O2, and N2 with concurrent sputtering of Tb. Luminescences from both the host matrix and the Tb3+ intra-4f transition are observed, but no correlation is found between them as the composition and the annealing conditions were varied. Photoluminescence excitation spectroscopy shows a strong increase in the Tb3+ luminescence intensity as the pump energy is increased above 3.5eV while the host matrix luminescence decreases. Taken together, the results that there is little energy transfer between band-tail states of silicon oxynitride and Tb3+, and that efficient excitation of Tb3+ by carriers requires excitation of carriers into the extended states of oxynitride.
Characterization and luminescence properties of Sr2Si5N8:Eu2+ phosphor for white light-emitting-diode illumination
Authors: Piao Xianqing , Horikawa Takashi , Hanzawa Hiromasa , Machida Ken-ichi
Published: April 2006

Eu 2 + -doped ternary nitride phosphor, Sr2Si5N8:Eu2+, was prepared by the carbothermal reduction and nitridation method. The Rietveld refinement analysis showed that the single phase products were obtained. Two main absorption bands were observed on the diffuse reflection spectra peaking at about 330 and 420nm, so that the resultant phosphor can be effectively excited by InGaN light-emitting diodes. The emission peak position of (Sr1−xEux)2Si5N8:Eu2+ series varied from 618to690nm with increasing Eu2+ ion concentration. The redshift behavior of the emission band was discussed on the basis of the configuration coordination model.
Staphylococcus AureusColonization and the Risk of Infection in Critically Ill Patients
Authors: Keene Adam , Vavagiakis Peter , Lee Mei-Ho , Finnerty Kathryn , Nicolls Deborah , Cespedes Christian , Quagliarello Bianca , Chiasson Mary Ann , Chong David , Lowy Franklin D.
Published: April 2006

Objective:

To evaluate the relationship betweenStaphylococcus aureusnasal and tracheal colonization and infection in medical intensive care unit (MICU) patients. The primary outcome was the incidence ofS. aureusinfection in colonized versus non-colonized patients.

Design:

Prospective, observational cohort study. Patients admitted to the MICU during the study period were screened forS. aureusnasal and tracheal colonization by culture and a PCR assay twice weekly. Demographic, clinical, and microbiologic data were collected in the MICU and for 30 days after discharge. PFGE and antibiotic susceptibility testing were performed on allS. aureusnasal, tracheal, and clinical isolates.

Results:

Twenty-three percent of patients (47 of 208) were nasally colonized withS. aureus. Twenty-four percent of these patients developedS. aureusinfections versus 2% of noncolonized patients (P< .01). Nine of 11 patients with both nasal colonization and infection were infected by their colonizing strain. Two of 47 nasally colonized patients developed an infection with a different strain ofS. aureus. Fifty-three percent of intubated patients with nasal colonization (10 of 19) had tracheal colonization withS. aureusas opposed to 4.9% of intubated, non-colonized patients (3 of 61) (P< .01). Parenteral antibiotics were ineffective at clearing nasal colonization. PCR detectedS. aureuscolonization (nasal and tracheal) within 6.5 hours with a sensitivity of 83% and a specificity of 99%.

Conclusions:

The incidence ofS. aureusinfection was significantly elevated in nasally colonized MICU patients. Techniques to rapidly detect colonization in this population may make targeted topical prevention strategies feasible. (Infect Control Hosp Epidemiol 2005;26:622-628)
The Effects of Prolonged Ethanol Exposure on the Mechanical Properties of Polyurethane and Silicone Catheters Used for Intravascular Access
Authors: Crnich Christopher J. , Halfmann Jeremy A. , Crone Wendy C. , Maki Dennis G.
Published: April 2006

Background:

Products containing alcohol are commonly used with intravascular devices at insertion, to remove lipids from occluded intravascular devices used during parenteral nutrition, and increasingly for the prevention and treatment of intravascular device-related bloodstream infection. The effects of alcohol on the integrity of intravascular devices remain unknown.

Methods:

Two types of widely used commercial peripherally inserted central catheters, one made of polyether-urethane and one made of silicone, were exposed to a 70% etha-nol lock solution for up to 10 weeks. Mechanical testing was performed to identify force-at-break, stress, strain, modulus of elasticity, modulus of toughness, and wall area of ethanol-exposed and control catheters.

Results:

No significant differences between exposed and unexposed catheters were identified for any of the mechanical parameters tested except for a marginal reduction in the modulus of elasticity for both polyetherurethane and silicone catheters and minor increases in the wall area of polyetherurethane catheters.

Conclusions:

These data indicate that exposure to a 70% ethanol lock solution does not appreciably alter the integrity of selected commercial polyetherurethane and silicone catheters. Given the greatly expanded use of alcoholic solutions with intravascular devices of all types, we believe that manufacturers would be well advised to subject their catheters and other intravascular devices to formal testing of the type employed in this study.
A Large Nosocomial Outbreak of Hepatitis C Virus Infections at a Hemodialysis Center
Authors: Savey Anne , Simon Fernando , Izopet Jacques , Lepoutre Agnès , Fabry Jacques , Desenclos Jean-Claude
Published: April 2006

Objective:

To identify modes of HCV transmission during an outbreak of HCV infection in a hemodialysis unit.

Design:

An epidemiologic study, virologie analysis, assessment of infection control practices and procedures, and technical examination of products and dialysis machines.

Setting:

A private hemodialysis unit treating approximately 70 patients.

Patients:

Detection of HCV RNA by PCR was performed among patients receiving dialysis in 2001. Case-patients were patients who had a first positive result for HCV RNA between January 2001 and January 2002 and either acute hepatitis, a seroconversion for HCV antibodies, or a previous negative result. Three control-patients were randomly selected per case-patient.

Results:

Of the 61 patients treated in the unit in 2001 and not infected with HCV, 22 (36.1%) became case-patients with onset from May 2001 to January 2002 for an incidence density rate of 70 per 100 patient-years. Phylogenic analysis identified four distinct HCV groups and an index case-patient for each with a similar virus among patients already known to be infected. No multidose medication vials or material was shared between patients. Connection to a dialysis machine by a nurse who had connected an HCV-infected patient “just before” or “one patient before” increased the risk of HCV infection, whereas using the same dialysis machine after a patient infected with HCV did not. Understating, lack of training, and breaches in infection control were documented. Direct observation of practices revealed frequent flooding of blood into the double filter on the arterial pressure tubing set.

Conclusions:

During this outbreak, HCV transmission was mainly patient to patient via healthcare workers' hands. However, transmission via dialysis machines because of possible contamination of internal components could not be excluded.
Usefulness of a Rapid Human Immunodeficiency Virus-1 Antibody Test for the Management of Occupational Exposure to Blood and Body Fluid
Authors: Landrum Michael L. , Wilson Clarissa H. , Perii Luci P. , Hannibal Sandra L. , O'Connell Robert J.
Published: April 2006

Objective:

To describe the usefulness of the OraQuick Rapid HIV-1 Antibody Test (OraSure Technologies, Bethlehem, PA) in cases of occupational exposure regarding its use with source-patient sera, effects on post-exposure prophylaxis (PEP) use, potential cost savings, and effects on healthcare worker (HCW) stress reaction symptoms.

Design:

Before-and-after analysis.

Setting:

A 269-bed, tertiary-care medical center with adjacent clinics.

Participants:

All source-patients and HCWs experiencing an occupational exposure during the study period.

Methods:

Use of the OraQuick test with patient sera was validated prior to its use for occupational exposures. Exposures from January 1 through July 10, 2003 (enzyme immunoassay [EIA] group) and July 11 through December 31, 2003 (OraQuick group) were retrospectively reviewed and the use and cost of PEP was compared for each group. Randomly selected HCWs from both groups completed a survey to assess their stress reaction symptoms.

Results:

After exclusion, there were 71 exposures in the EIA group and 79 in the OraQuick group. OraQuick results were 100% concordant with the reference standard of EIA and Western blot using patient sera. The mean number of doses ingested per course of PEP was significantly higher for HCWs in the EIA group (3.8; range, 0 to 6) compared with the OraQuick group (1.2; range, 0 to 3; P = .016). Cost analysis revealed a mean savings of $6.62 with the OraQuick test per occupational exposure. Although the survey failed to detect an overall reduction in HCW stress reaction symptoms using OraQuick for source-patient testing, 11 HCWs in the EIA group had repetitive thoughts of the exposure compared with 5 in the OraQuick group (P= .049).

Conclusion:

Because of the reduction in ingested doses of unnecessary PEP and reduced cost of occupational exposure management with their use, rapid HJV-antibody tests should be the preferred method for source-patient testing following an occupational exposure.
Cherednik algebras and Hilbert schemes in characteristic 𝑝
Authors: Bezrukavnikov Roman , Finkelberg Michael , Ginzburg Victor
Published: April 2006

We prove a localization theorem for the type

A

n
−
1

\mathbf {A}_{n-1}

rational Cherednik algebra

H

c

=

H

1
,
c

(

A

n
−
1

)

\mathsf {H}_c=\mathsf {H}_{1,c}(\mathbf {A}_{n-1})

over

F

¯

p

\overline {\mathbb {F}}_p

, an algebraic closure of the finite field. In the most interesting special case where

c
∈

F

p

c\in \mathbb {F}_p

, we construct an Azumaya algebra

H
c

\scr H_c

on

Hilb
n

⁡

A

2

\operatorname {Hilb}^n{\mathbb {A}}^2

, the Hilbert scheme of

n
n

points in the plane, such that

Γ
(

Hilb
n

⁡

A

2

,

H
c

)
=

H

c

\Gamma (\operatorname {Hilb}^n{\mathbb {A}}^2, \,\scr H_c)=\mathsf {H}_c

. Our localization theorem provides an equivalence between the bounded derived categories of

H

c

\mathsf {H}_c

-modules and sheaves of coherent

H
c

\scr H_c

-modules on

Hilb
n

⁡

A

2

\operatorname {Hilb}^n{\mathbb {A}}^2

, respectively. Furthermore, we show that the Azumaya algebra splits on the formal neighborhood of each fiber of the Hilbert-Chow morphism. This provides a link between our results and those of Bridgeland, King and Reid, and Haiman.
Two-stage mechanism for activation of the DNA replication checkpoint kinase Cds1 in fission yeast
Authors: Xu Yong , Davenport Matthew , Kelly Thomas J.
Published: April 2006

The DNA replication checkpoint is a complex signal transduction pathway, present in all eukaryotic cells, that functions to maintain genomic integrity and cell viability when DNA replication is perturbed. In Schizosaccharomyces pombe the major effector of the replication checkpoint is the protein kinase Cds1. Activation of Cds1 is known to require the upstream kinase Rad3 and the mediator Mrc1, but the biochemical mechanism of activation is not well understood. We report that the replication checkpoint is activated in two stages. In the first stage, Mrc1 recruits Cds1 to stalled replication forks by interactions between the FHA domain of Cds1 and specific phosphorylated Rad3 consensus sites in Mrc1. Cds1 is then primed for activation by Rad3-dependent phosphorylation. In the second stage, primed Cds1 molecules dimerize via phospho-specific interactions mediated by the FHA domains and are activated by autophosphorylation. This two-stage activation mechanism for the replication checkpoint allows for rapid activation with a high signal-to-noise ratio.
Differential Functional Activation of Chemokine Receptor CXCR4 Is Mediated by G Proteins in Breast Cancer Cells
Authors: Holland Jane D. , Kochetkova Marina , Akekawatchai Chareeporn , Dottore Mara , Lopez Angel , McColl Shaun R.
Published: April 2006

CXCR4 is a G protein–coupled receptor of considerable biological significance, and among its numerous functions, it is suggested to play a critical role in cancer metastasis. We have investigated the expression and function of CXCR4 in a range of breast cancer cell lines covering a spectrum of invasive phenotypes and found that, while surface levels of CXCR4 were uniform across the entire panel, only highly invasive cells that are metastatic in immunocompromised mice expressed functional receptors. CXCL12/SDF-1 induced cellular responses such as calcium mobilization, actin polymerization, and chemotaxis in metastatic cells, whereas noninvasive cells were unresponsive. Moreover, CXCL12 activated multiple signaling pathways downstream of G proteins in highly invasive cells but failed to activate any of the examined kinase cascades in noninvasive cell lines. This blockade in nonmetastatic cell lines seems to be due to the inability of G protein α and β subunits to form a heterotrimeric complex with CXCR4. Gα and Gβ were able to bind to CXCR4 independently in all cell lines, but the association of G protein αβγ heterotrimers with the receptor, a prerequisite for signal transduction downstream from G protein–coupled receptors, was only observed in the highly invasive cell lines. Our findings show, for the first time, that CXCR4 function is subject to complex and potentially tightly controlled regulation in breast cancer cells via differential G protein–receptor complex formation, and this regulation may play a role in the transition from nonmetastatic to malignant tumors. (Cancer Res 2006; 66(8): 4117-24)
Growth-Regulated Oncogene Is Pivotal in Thrombin-Induced Angiogenesis
Authors: Caunt Maresa , Hu Liang , Tang Thomas , Brooks Peter C. , Ibrahim Sherif , Karpatkin Simon
Published: April 2006

The mechanism of thrombin-induced angiogenesis is poorly understood. Using a gene chip array to investigate the pro-malignant phenotype of thrombin-stimulated cells, we observed that thrombin markedly up-regulates growth-regulated oncogene-α (GRO-α) in several tumor cell lines as well as endothelial cells by mRNA and protein analysis. Thrombin enhanced the secretion of GRO-α from tumor cells 25- to 64-fold. GRO-α is a CXC chemokine with tumor-associated angiogenic as well as oncogenic activation following ligation of its CXCR2 receptor. GRO-α enhanced angiogenesis in the chick chorioallantoic membrane assay 2.2-fold, providing direct evidence for GRO-α as an angiogenic growth factor. Anti-GRO-α antibody completely inhibited the 2.7-fold thrombin-induced up-regulation of angiogenesis, as well as the 1.5-fold thrombin-induced up-regulation of both endothelial cell cord formation in Matrigel and growth in vitro. Thrombin as well as its PAR-1 receptor activation peptide [thrombin receptor activation peptide (TRAP)] as well as GRO-α all markedly increased vascular regulatory proteins and growth factors: matrix metalloproteinase (MMP)-1, MMP-2, vascular endothelial growth factor (VEGF), angiopoietin-2 (Ang-2), CD31, and receptors KDR and CXCR2 in human umbilical vein endothelial cells. All of the thrombin/TRAP gene up-regulations were completely inhibited by anti-GRO-α antibody and unaffected by irrelevant antibody. Similar inhibition of gene up-regulation as well as thrombin-induced chemotaxis was noted with small interfering RNA (shRNA) GRO-α KD 4T1 breast tumor and B16F10 melanoma cells. In vivo tumor growth studies in wild-type mice with shRNA GRO-α KD cells revealed 2- to 4-fold impaired tumor growth, metastasis, and angiogenesis, which was not affected by endogenous thrombin. Thus, thrombin-induced angiogenesis requires the up-regulation of GRO-α. Thrombin up-regulation of GRO-α in tumor cells as well as endothelial cells contributes to tumor angiogenesis. (Cancer Res 2006; 66(8): 4125-32)
Brain-Derived Neurotrophic Factor Activation of TrkB Induces Vascular Endothelial Growth Factor Expression via Hypoxia-Inducible Factor-1α in Neuroblastoma Cells
Authors: Nakamura Katsuya , Martin Kelly C. , Jackson Jennifer K. , Beppu Kiichiro , Woo Chan-Wook , Thiele Carol J.
Published: April 2006

The extent of angiogenesis and/or vascular endothelial growth factor (VEGF) expression in neuroblastoma tumors correlates with metastases, N-myc amplification, and poor clinical outcome. Recently, we have shown that insulin-like growth factor-I and serum-derived growth factors stimulate VEGF expression in neuroblastoma cells via induction of hypoxia-inducible factor-1α (HIF-1α). Because another marker of poor prognosis in neuroblastoma tumors is high expression of brain-derived neurotrophic factor (BDNF) and its tyrosine kinase receptor, TrkB, we sought to evaluate the involvement of BDNF and TrkB in the regulation of VEGF expression. VEGF mRNA levels in neuroblastoma cells cultured in serum-free media increased after 8 to 16 hours in BDNF. BDNF induced increases in VEGF and HIF-1α protein, whereas HIF-1β levels were unaffected. BDNF induced a 2- to 4-fold increase in VEGF promoter activity, which could be abrogated if the hypoxia response element in the VEGF promoter was mutated. Transfection of HIF-1α small interfering RNA blocked BDNF-stimulated increases in VEGF promoter activity and VEGF protein expression. The BDNF-stimulated increases in HIF-1α and VEGF expression required TrkB tyrosine kinase activity and were completely blocked by inhibitors of phosphatidylinositol 3-kinase (PI3K) and mammalian target of rapamycin (mTOR) pathways. These data indicate that BDNF plays a role in regulating VEGF levels in neuroblastoma cells and that targeted therapies to BDNF/TrkB, PI3K, mTOR signal transduction pathways, and/or HIF-1α have the potential to inhibit VEGF expression and limit neuroblastoma tumor growth. (Cancer Res 2006; 66(8): 4249-55)
Nitric Oxide–Donating Aspirin Prevents Pancreatic Cancer in a Hamster Tumor Model
Authors: Ouyang Nengtai , Williams Jennie L. , Tsioulias George J. , Gao Jianjun , Iatropoulos Michael J. , Kopelovich Levy , Kashfi Khosrow , Rigas Basil
Published: April 2006

To evaluate the chemopreventive effect of nitric oxide–donating aspirin (NO-ASA), an ASA bearing a NO-releasing moiety, against pancreatic cancer, we studied six groups of female Syrian golden hamsters: groups 1 to 3 (n = 12 each) were given saline and groups 4 to 6 (n = 17) the carcinogen N-nitrosobis(2-oxopropyl)amine (BOP) s.c. in five weekly injections (the first, 70 mg/kg, and the remaining, 20 mg/kg each). Control and BOP-treated hamsters were fed a NO-ASA 3,000 ppm or conventional ASA 3,000 ppm or control diet for 19 weeks. Groups 1 to 3 had no tumors. Compared with the BOP/vehicle group, NO-ASA reduced the incidence (88.9%, P < 0.003) and multiplicity (94%, P < 0.05) of pancreatic cancer; ASA had no statistically significant effect. NO-ASA arrested the transition from PanIN2 to PanIN3 and carcinoma. The proliferation (proliferating cell nuclear antigen) / apoptosis (terminal deoxyribonucleotide transferase–mediated nick-end labeling) ratio of ductal cells increased with the histologic severity of the ductal lesion; NO-ASA suppressed it significantly during all stages except PanIN1A. p21WAF1/CIP1, undetectable in normal cells, was progressively induced in neoplastic cells and suppressed by NO-ASA up to PanIN3. Nuclear factor-κB activation, absent in normal tissue, increased progressively (17-fold in cancer); NO-ASA suppressed it throughout and significantly in PanIN1B and PanIN2. Cyclooxygenase-2 expression, absent during early stages, was induced 6-fold in carcinoma and suppressed by NO-ASA in PanIN3 and carcinoma. Conventional ASA had no effect on these molecular markers. Thus, NO-ASA profoundly prevented pancreatic cancer and modulated multiple molecular targets in this model system; conventional ASA had no such effects. NO-ASA merits further evaluation as a chemopreventive agent against pancreatic cancer. (Cancer Res 2006; 66(8): 4503-11)
Subtractive Transcriptomics: Establishing Polarity Drives In vitro Human Endothelial Morphogenesis
Authors: Glesne David A. , Zhang Wen , Mandava Suneeta , Ursos Lyann , Buell Margaret E. , Makowski Lee , Rodi Diane J.
Published: April 2006

Although investigations of mature normal and tumor-derived capillaries have resulted in characterization of these structures at the phenotypic level, less is known regarding the initial molecular cues for cellular assembly of endothelial cells into human capillaries. Here, we employ a novel combination of microenvironmental manipulation and microarray data filtration over narrowly delineated temporal data series to identify the morphogenesis component apart from the proliferation component, as pooled human microvascular-derived endothelial cells are induced to form capillary-like structures in vitro in a murine tumor-derived matrix. The 217 morphogenesis-specific genes identified using this subtractive transcriptomics approach are mostly independent of the angiogenic proteins currently used as therapeutic targets for aberrant angiogenesis. Quantitative real-time PCR was used to validate 20% of these transcripts. Immunofluorescent analysis of proliferating and tube-forming cells validates at the protein level the morphogenesis-specific expression pattern of 16 of the 217 gene products identified. The transcripts that are selectively up-regulated in tube-forming endothelial cells reveal a temporal expression pattern of genes primarily associated with intracellular trafficking, guided migration, cytoskeletal reorganization, cellular adhesion, and proliferation inhibition. These data show that a sequential up-regulation of genes that establish and maintain polarity occurs during migration and morphogenesis of in vitro human endothelial cells undergoing tubulogenesis; some of which may well be effective as novel antiangiogenic drug targets. (Cancer Res 2006; 66(8): 4030-40)
Inhibition of Mammalian Thioredoxin Reductase by Some Flavonoids: Implications for Myricetin and Quercetin Anticancer Activity
Authors: Lu Jun , Papp Laura V. , Fang Jianguo , Rodriguez-Nieto Salvador , Zhivotovsky Boris , Holmgren Arne
Published: April 2006

The thioredoxin system, composed of thioredoxin reductase (TrxR), thioredoxin (Trx), and NADPH, exerts a wide range of activities in cellular redox control, antioxidant function, cell viability, and proliferation. Recently, the selenocysteine (Sec)-containing mammalian TrxR has emerged as a new target for anticancer drug development because TrxR and Trx are overexpressed in many aggressive tumors and the tumor cells seem to be more dependent on Trx system than normal cells. Here we have investigated the inhibition of mammalian TrxR by flavonoids which have been presumed to be cancer chemoprevention agents because of their antioxidant activities. Myricetin and quercetin were found to have strong inhibitory effects on mammalian TrxRs with IC50 values of 0.62 and 0.97 μmol/L, respectively. The inhibition was shown to be concentration, NADPH, and time dependent and involved an attack on the reduced COOH-terminal -Cys-Sec-Gly active site of TrxR. Oxygen-derived superoxide anions enhanced the inhibitory effect whereas anaerobic conditions attenuated inhibition. Spectral analysis suggested that the flavonols might perform their inhibitory effects via semiquinone radicals. Additionally, the flavonols had the potential to inhibit the growth of A549 cells with the same potency as inhibition of TrxR. TrxR activity in the cell lysates was reduced on treatment with myricetin >50 μmol/L, which coincided with the oxidization of Trx. The cell cycle was arrested in S phase by quercetin and an accumulation of cells in sub-G1 was observed in response to myricetin. Thus, the anticancer activity of quercetin and myricetin may be due to inhibition of TrxR, consequently inducing cell death. (Cancer Res 2006; 66(8): 4410-8)
Maspin Retards Cell Detachment via a Novel Interaction with the Urokinase-Type Plasminogen Activator/Urokinase-Type Plasminogen Activator Receptor System
Authors: Yin Shuping , Lockett Jaron , Meng Yonghong , Biliran Hector , Blouse Grant E. , Li Xiaohua , Reddy Neelima , Zhao Zimin , Lin Xinli , Anagli John , Cher Michael L. , Sheng Shijie
Published: April 2006

It is well documented that tumor suppressive maspin inhibits tumor cell invasion and extracellular matrix remodeling. Maspin is a cytosolic, cell surface–associated, and secreted protein in the serine protease inhibitor superfamily. Although several molecules have been identified as candidate intracellular maspin targets, the extracellular maspin target(s) remains elusive. Although maspin does not directly inhibit urokinase-type plasminogen activator (uPA) activity, we have shown evidence that maspin may block the pericellular proteolysis mediated by cell surface–associated uPA. In the current study, maspin significantly inhibited the Ca2+ reduction–induced detachment of DU145 cells. This maspin effect was associated with increased and sustained levels of mature focal adhesion contacts (FAC). We noted that maspin (a) colocalized with uPA and uPA receptor (uPAR), (b) enhanced the interaction between uPAR and low-density lipoprotein receptor related protein, and (c) induced rapid internalization of uPA and uPAR. The maspin effects on surface-associated uPA and uPAR required the interaction between uPA and uPAR. Further biochemical and biophysical analyses revealed that maspin specifically bound to pro-uPA with a deduced Kd of 270 nmol/L and inhibited the plasmin-mediated pro-uPA cleavage. Interestingly, substitution of maspin p1′ site Arg340 in the reactive site loop (RSL) with alanine not only abolished the binding to pro-uPA but also diminished the maspin effects on pro-uPA cleavage and cell detachment. These data show an important role of maspin RSL in regulating the uPA/uPAR–dependent cell detachment. Together, our data led to a new hypothesis that maspin may stabilize mature FACs by quenching localized uPA/uPAR complex before uPA activation. (Cancer Res 2006; 66(8): 4173-81)
Antitumor Activity of a Small-Molecule Inhibitor of Human Silent Information Regulator 2 Enzymes
Authors: Heltweg Birgit , Gatbonton Tonibelle , Schuler Aaron D. , Posakony Jeff , Li Hongzhe , Goehle Sondra , Kollipara Ramya , DePinho Ronald A. , Gu Yansong , Simon Julian A. , Bedalov Antonio
Published: April 2006

SIRT1 and other NAD-dependent deacetylases have been implicated in control of cellular responses to stress and in tumorigenesis through deacetylation of important regulatory proteins, including p53 and the BCL6 oncoprotein. Hereby, we describe the identification of a compound we named cambinol that inhibits NAD-dependent deacetylase activity of human SIRT1 and SIRT2. Consistent with the role of SIRT1 in promoting cell survival during stress, inhibition of SIRT1 activity with cambinol during genotoxic stress leads to hyperacetylation of key stress response proteins and promotes cell cycle arrest. Treatment of BCL6-expressing Burkitt lymphoma cells with cambinol as a single agent induced apoptosis, which was accompanied by hyperacetylation of BCL6 and p53. Because acetylation inactivates BCL6 and has the opposite effect on the function of p53 and other checkpoint pathways, the antitumor activity of cambinol in Burkitt lymphoma cells may be accomplished through a combined effect of BCL6 inactivation and checkpoint activation. Cambinol was well tolerated in mice and inhibited growth of Burkitt lymphoma xenografts. Inhibitors of NAD-dependent deacetylases may constitute novel anticancer agents. (Cancer Res 2006; 66(8): 4368-77)
Heat Shock Protein 70 Neutralization Exerts Potent Antitumor Effects in Animal Models of Colon Cancer and Melanoma
Authors: Schmitt Elise , Maingret Loic , Puig Pierre-Emmanuel , Rerole Anne-Laure , Ghiringhelli François , Hammann Arlette , Solary Eric , Kroemer Guido , Garrido Carmen
Published: April 2006

When overexpressed, the stress protein heat shock protein 70 (HSP70) increases the oncogenic potential of cancer cells in rodent models. HSP70 also prevents apoptosis, thereby increasing the survival of cells exposed to a wide range of otherwise lethal stimuli. These protective functions of HSP70 involve its interaction with and neutralization of the adaptor molecule apoptotic protease activation factor-1, implicated in caspase activation, and the flavoprotein apoptosis-inducing factor (AIF), involved in caspase-independent cell death. We have shown previously that a peptide containing the AIF sequence involved in its interaction with HSP70 (ADD70, amino acids 150-228) binds to and neutralizes HSP70 in the cytosol, thereby sensitizing cancer cells to apoptosis induced by a variety of death stimuli. Here, we show that expression of ADD70 in tumor cells decreases their tumorigenicity in syngeneic animals without affecting their growth in immunodeficient animals. ADD70 antitumorigenic effects are associated with an increase in tumor-infiltrating cytotoxic CD8+ T cells. In addition, ADD70 sensitizes rat colon cancer cells (PROb) and mouse melanoma cells (B16F10) to the chemotherapeutic agent cisplatin. ADD70 also shows an additive effect with HSP90 inhibition by 17-allylamino-17-demethoxygeldanamycin in vitro. Altogether, these data indicate the potential interest of targeting the HSP70 interaction with AIF for cancer therapy. (Cancer Res 2006; 66(8): 4191-7)
Inhibition of p38 by Vitamin D Reduces Interleukin-6 Production in Normal Prostate Cells via Mitogen-Activated Protein Kinase Phosphatase 5: Implications for Prostate Cancer Prevention by Vitamin D
Authors: Nonn Larisa , Peng Lihong , Feldman David , Peehl Donna M.
Published: April 2006

Although numerous studies have implicated vitamin D in preventing prostate cancer, the underlying mechanism(s) remains unclear. Using normal human prostatic epithelial cells, we examined the role of mitogen-activated protein kinase phosphatase 5 (MKP5) in mediating cancer preventive activities of vitamin D. Up-regulation of MKP5 mRNA by 1,25-dihydroxyvitamin-D3 (1,25D) was dependent on the vitamin D receptor. We also identified a putative positive vitamin D response element within the MKP5 promoter that associated with the vitamin D receptor following 1,25D treatment. MKP5 dephosphorylates/inactivates the stress-activated protein kinase p38. Treatment of prostate cells with 1,25D inhibited p38 phosphorylation, and MKP5 small interfering RNA blocked this effect. Activation of p38 and downstream production of interleukin 6 (IL-6) are proinflammatory. Inflammation and IL-6 overexpression have been implicated in the initiation and progression of prostate cancer. 1,25D pretreatment inhibited both UV- and tumor necrosis factor α–stimulated IL-6 production in normal cells via p38 inhibition. Consistent with inhibition of p38, 1,25D decreased UV-stimulated IL-6 mRNA stabilization. The ability of 1,25D to up-regulate MKP5 was maintained in primary prostatic adenocarcinoma cells but was absent in metastases-derived prostate cancer cell lines. The inability of 1,25D to regulate MKP5 in the metastasis-derived cancer cells suggests there may be selective pressure to eliminate key tumor suppressor functions of vitamin D during cancer progression. These studies reveal MKP5 as a mediator of p38 inactivation and decreased IL-6 expression by 1,25D in primary prostatic cultures of normal and adenocarcinoma cells, implicating decreased prostatic inflammation as a potential mechanism for prostate cancer prevention by 1,25D. (Cancer Res 2006; 66(8): 4516-24)
Detection of Recurrent Copy Number Loss at Yp11.2 Involving TSPY Gene Cluster in Prostate Cancer Using Array-Based Comparative Genomic Hybridization
Authors: Vijayakumar Sapna , Hall Devon C. , Reveles Xavier T. , Troyer Dean A. , Thompson Ian M. , Garcia Dawn , Xiang RuiHua , Leach Robin J. , Johnson-Pais Teresa L. , Naylor Susan L.
Published: April 2006

Prostate cancer is the second leading cause of cancer deaths among American men. The loss of Y chromosome has been frequently observed in primary prostate cancer as well as other types of cancer. Earlier, we showed that introduction of the human Y chromosome suppresses the in vivo tumorigenicity of the prostate cancer cell line PC-3. To further characterize the Y chromosome, we have developed a high-density bacterial artificial chromosome (BAC) microarray containing 178 BAC clones from the human Y chromosome. BAC microarray was used for array comparative genomic hybridization on prostate cancer samples and cell lines. The most prominent observation on prostate cancer specimens was a deletion at Yp11.2 containing the TSPY tandem gene array. Out of 36 primary prostate tumors analyzed, 16 (44.4%) samples exhibited loss of TSPY gene copies. Notably, we observed association between the number of TSPY copies in the blood and the incidence of prostate cancer. Moreover, PC-3 hybrids with an intact Yp11.2 did not grow tumors in nude mice, whereas PC-3 hybrids with a deletion at Yp11.2 grew tumors in nude mice. (Cancer Res 2006; 66(8): 4055-64)
Genetic Polymorphisms of Interleukin-1B (IL-1B), IL-6, IL-8, and IL-10 and Risk of Prostate Cancer
Authors: Michaud Dominique S. , Daugherty Sarah E. , Berndt Sonja I. , Platz Elizabeth A. , Yeager Meredith , Crawford E. David , Hsing Ann , Huang Wen-Yi , Hayes Richard B.
Published: April 2006

Chronic intraprostatic inflammation is suspected to play a role in the pathogenesis of prostate cancer. Polymorphisms in cytokine genes can influence inflammation and immune response and may be related to the risk of prostate cancer. Four common single nucleotide polymorphisms (SNPs) in the genes encoding interleukin-1B (IL-1B), IL-6, and IL-8 were assessed in 503 prostate cancer cases and 652 controls, and three SNPs in IL-10 were assessed in an additional 817 prostate cancer cases and 1,190 controls (for a total of 1,320 prostate cancer cases and 1,255 controls). Cases and controls were selected from the on-going Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial and were frequency matched on age, ethnicity, time-period since initial screening, and date of blood draw. Single-locus analyses were conducted using conditional logistic regression. In addition, we did a haplotype analysis for the three IL-10 SNPs tested. Overall, no associations were detected between the seven polymorphisms in the four cytokine genes examined in this study and prostate cancer risk. Further stratifying by use of nonsteroidal anti-inflammatory drugs did not modify the associations. Findings were similar for early or advanced prostate cancers. Similarly, we observed no association between the major IL-10 haplotypes and the risk of prostate cancer. At least seven common polymorphisms in genes of inflammatory cytokines IL-1B, IL-6, IL-8, and IL-10 do not seem to play a role in the risk of prostate cancer. (Cancer Res 2006; 66(8): 4525-30)
Combined cDNA Array Comparative Genomic Hybridization and Serial Analysis of Gene Expression Analysis of Breast Tumor Progression
Authors: Yao Jun , Weremowicz Stanislawa , Feng Bin , Gentleman Robert C. , Marks Jeffrey R. , Gelman Rebecca , Brennan Cameron , Polyak Kornelia
Published: April 2006

To identify genetic changes involved in the progression of breast carcinoma, we did cDNA array comparative genomic hybridization (CGH) on a panel of breast tumors, including 10 ductal carcinoma in situ (DCIS), 18 invasive breast carcinomas, and two lymph node metastases. We identified 49 minimal commonly amplified regions (MCRs) that included known (1q, 8q24, 11q13, 17q21-q23, and 20q13) and several uncharacterized (12p13 and 16p13) regional copy number gains. With the exception of the 17q21 (ERBB2) amplicon, the overall frequency of copy number alterations was higher in invasive tumors than that in DCIS, with several of them present only in invasive cancer. Amplification of candidate loci was confirmed by quantitative PCR in breast carcinomas and cell lines. To identify putative targets of amplicons, we developed a method combining array CGH and serial analysis of gene expression (SAGE) data to correlate copy number and expression levels for each gene within MCRs. Using this approach, we were able to distinguish a few candidate targets from a set of coamplified genes. Analysis of the 12p13-p12 amplicon identified four putative targets: TEL/ETV6, H2AFJ, EPS8, and KRAS2. The amplification of all four candidates was confirmed by quantitative PCR and fluorescence in situ hybridization, but only H2AFJ and EPS8 were overexpressed in breast tumors with 12p13 amplification compared with a panel of normal mammary epithelial cells. These results show the power of combined array CGH and SAGE analysis for the identification of candidate amplicon targets and identify H2AFJ and EPS8 as novel putative oncogenes in breast cancer. (Cancer Res 2006; 66(8): 4065-78)
Caspase-8 Promotes Cell Motility and Calpain Activity under Nonapoptotic Conditions
Authors: Helfer Brooke , Boswell Bernard C. , Finlay Darren , Cipres Angel , Vuori Kristiina , Bong Kang Tae , Wallach David , Dorfleutner Andrea , Lahti Jill M. , Flynn Daniel C. , Frisch Steven M.
Published: April 2006

Significant caspase-8 activity has been found in normal and certain tumor cells, suggesting that caspase-8 possesses an alternative, nonapoptotic function that may contribute to tumor progression. In this article, we report that caspase-8 promotes cell motility. In particular, caspase-8 is required for the optimal activation of calpains, Rac, and lamellipodial assembly. This represents a novel nonapoptotic function of caspase-8 acting at the intersection of the caspase-8 and calpain proteolytic pathways to coordinate cell death versus cell motility signaling. (Cancer Res 2006; 66(8): 4273-8)
Targeting Oncogenes to Improve Breast Cancer Chemotherapy
Authors: Christensen Laura A. , Finch Rick A. , Booker Adam J. , Vasquez Karen M.
Published: April 2006

Despite recent advances in treatment, breast cancer remains a serious health threat for women. Traditional chemotherapies are limited by a lack of specificity for tumor cells and the cell cycle dependence of many chemotherapeutic agents. Here we report a novel strategy to help overcome these limitations. Using triplex-forming oligonucleotides (TFOs) to direct DNA damage site-specifically to oncogenes overexpressed in human breast cancer cells, we show that the effectiveness of the anticancer nucleoside analogue gemcitabine can be improved significantly. TFOs targeted to the promoter region of c-myc directly inhibited gene expression by ∼40%. When used in combination, specific TFOs increased the incorporation of gemcitabine at the targeted site ∼4-fold, presumably due to induction of replication-independent DNA synthesis. Cells treated with TFOs and gemcitabine in combination showed a reduction in both cell survival and capacity for anchorage-independent growth (∼19% of untreated cells). This combination affected the tumorigenic potential of these cancer cells to a significantly greater extent than either treatment alone. This novel strategy may be used to increase the range of effectiveness of antitumor nucleosides in any tumor which overexpresses a targetable oncogene. Multifaceted chemotherapeutic approaches such as this, coupled with triplex-directed gene targeting, may lead to more than incremental improvements in nonsurgical treatment of breast tumors. (Cancer Res 2006; 66(8): 4089-94)
Prevention of Azoxymethane-Induced Colon Cancer by Combination of Low Doses of Atorvastatin, Aspirin, and Celecoxib in F 344 Rats
Authors: Reddy Bandaru S. , Wang Chung Xiou , Kong Ah-Ng , Khor Tin Oo , Zheng Xi , Steele Vernon E. , Kopelovich Levy , Rao Chinthalapally V.
Published: April 2006

Preclinical and clinical studies have provided evidence that aspirin, celecoxib, (cyclooxygenase-2 inhibitor), and statins (3-hydroxy-3-methylglutaryl CoA reductase inhibitors) inhibit colon carcinogenesis. Chronic use of high doses of these agents may induce side effects in ostensibly normal individuals. Combining low doses of agents may be an effective way to increase their efficacy and minimize toxicity. We assessed the efficacy of atorvastatin (lipitor), celecoxib, and aspirin, given individually at high dose levels and in combination at lower doses against azoxymethane-induced colon carcinogenesis, in male F 344 rats. One day after the last azoxymethane treatment (15 mg/kg body weight, s.c., once weekly for 2 weeks), groups of male F 344 rats were fed the AIN-76A diet or AIN-76A diet containing 150 ppm atorvastatin, 600 ppm celecoxib, and 400 ppm aspirin, 100 ppm atorvastatin + 300 ppm celecoxib, and 100 ppm atorvastatin + 200 ppm aspirin. Rats were killed 42 weeks later, and colon tumors were processed histopathologically and analyzed for cell proliferation and apoptosis immunohistochemically. Administration of these agents individually and in combination significantly suppressed the incidence and multiplicity of colon adenocarcinomas. Low doses of these agents in combination inhibited colon carcinogenesis more effectively than when they were given individually at higher doses. Inhibition of colon carcinogenesis by these agents is associated with the inhibition of cell proliferation and increase in apoptosis in colon tumors. These observations are of clinical significance because this can pave the way for the use of combinations of these agents in small doses against colon cancer. (Cancer Res 2006; 66(8): 4542-6)
Antibody-Maytansinoid Conjugates Are Activated in Targeted Cancer Cells by Lysosomal Degradation and Linker-Dependent Intracellular Processing
Authors: Erickson Hans K. , Park Peter U. , Widdison Wayne C. , Kovtun Yelena V. , Garrett Lisa M. , Hoffman Karen , Lutz Robert J. , Goldmacher Victor S. , Blättler Walter A.
Published: April 2006

Antibody-drug conjugates are targeted anticancer agents consisting of a cytotoxic drug covalently linked to a monoclonal antibody for tumor antigen–specific activity. Once bound to the target cell-surface antigen, the conjugate must be processed to release an active form of the drug, which can reach its intracellular target. Here, we used both biological and biochemical methods to better define this process for antibody-maytansinoid conjugates. In particular, we examined the metabolic fate in cells of huC242-maytansinoid conjugates containing either a disulfide linker (huC242-SPDB-DM4) or a thioether linker (huC242-SMCC-DM1). Using cell cycle analysis combined with lysosomal inhibitors, we showed that lysosomal processing is required for the activity of antibody-maytansinoid conjugates, irrespective of the linker. We also identified and characterized the released maytansinoid molecules from these conjugates, and measured their rate of release compared with the kinetics of cell cycle arrest. Both conjugates are efficiently degraded in lysosomes to yield metabolites consisting of the intact maytansinoid drug and linker attached to lysine. The lysine adduct is the sole metabolite from the thioether-linked conjugate. However, the lysine metabolite generated from the disulfide-linked conjugate is reduced and S-methylated to yield the lipophilic and potently cytotoxic metabolite, S-methyl-DM4. These findings provide insight into the mechanism of action of antibody-maytansinoid conjugates in general, and more specifically, identify a biochemical mechanism that may account for the significantly enhanced antitumor efficacy observed with disulfide-linked conjugates. (Cancer Res 2006; 66(8): 4426-33)
Comparison of Model-Produced and Observed Microwave Radiances and Estimation of Background Error Covariances for Hydrometeor Variables within Hurricanes
Authors: Amerault Clark , Zou Xiaolei
Published: April 2006

A radiative transfer model was updated to better simulate Special Sensor Microwave Imager (SSM/I)–observed brightness temperatures in areas of high ice concentration. The difference between the lowest observed and model-produced brightness temperatures at 85 GHz has been reduced from over 100 K to roughly 20 K. Probability distribution functions of model-produced and SSM/I-observed brightness temperatures show that the model overestimates the areas of precipitation, but overall matches the SSM/I observations quite well.

Estimates of vertical background error covariance matrices and their inverses were calculated for all hydrometeor variables (both liquid and frozen). For cloud and rainwater, the largest values in the matrices are located in the lower levels of the atmosphere, while the largest values in the cloud ice, snow, and graupel matrices are in the upper levels of the atmosphere. The inverse background matrices can be used as weightings for hydrometeor variables in assimilation experiments involving rain-affected observations.