bluuebunny/crossref_metadata_2025 huggingface dataset:
Coordinated multitissue transcriptional and plasma metabonomic profiles following acute caloric restriction in mice
Authors: Selman Colin , Kerrison Nicola D. , Cooray Anisha , Piper Matthew D. W. , Lingard Steven J. , Barton Richard H. , Schuster Eugene F. , Blanc Eric , Gems David , Nicholson Jeremy K. , Thornton Janet M. , Partridge Linda , Withers Dominic J.
Published: August 2006

Caloric restriction (CR) increases healthy life span in a range of organisms. The underlying mechanisms are not understood but appear to include changes in gene expression, protein function, and metabolism. Recent studies demonstrate that acute CR alters mortality rates within days in flies. Multitissue transcriptional changes and concomitant metabolic responses to acute CR have not been described. We generated whole genome RNA transcript profiles in liver, skeletal muscle, colon, and hypothalamus and simultaneously measured plasma metabolites using proton nuclear magnetic resonance in mice subjected to acute CR. Liver and muscle showed increased gene expressions associated with fatty acid metabolism and a reduction in those involved in hepatic lipid biosynthesis. Glucogenic amino acids increased in plasma, and gene expression for hepatic gluconeogenesis was enhanced. Increased expression of genes for hormone-mediated signaling and decreased expression of genes involved in protein binding and development occurred in hypothalamus. Cell proliferation genes were decreased and cellular transport genes increased in colon. Acute CR captured many, but not all, hepatic transcriptional changes of long-term CR. Our findings demonstrate a clear transcriptional response across multiple tissues during acute CR, with congruent plasma metabolite changes. Liver and muscle switched gene expression away from energetically expensive biosynthetic processes toward energy conservation and utilization processes, including fatty acid metabolism and gluconeogenesis. Both muscle and colon switched gene expression away from cellular proliferation. Mice undergoing acute CR rapidly adopt many transcriptional and metabolic changes of long-term CR, suggesting that the beneficial effects of CR may require only a short-term reduction in caloric intake.
Strong law of large numbers for ρ*‐mixing sequences with different distributions
Authors: Cai Guang-Hui
Published: August 2006

Strong law of large numbers and complete convergence for ρ*‐mixing sequences with different distributions are investigated. The results obtained improve the relevant results by Utev and Peligrad (2003).
Minimum principle and controllability for multiparameter discrete inclusions via derived cones
Authors: Cernea Aurelian
Published: August 2006

We consider a multiparameter discrete inclusion and we prove that the reachable set of a certain variational multiparameter discrete inclusion is a derived cone in the sense of Hestenes to the reachable set of the discrete inclusion. This result allows to obtain sufficient conditions for local controllability along a reference trajectory and a new proof of the minimum principle for an optimization problem given by a multiparameter discrete inclusion with endpoint constraints.
Some new generalizations of Hardy′s integral inequality
Authors: Sunanda S. K. , Nahak C. , Nanda S.
Published: August 2006

We have studied some new generalizations of Hardy′s integral
inequality using the generalized Holder′s inequality.
Common random fixed points of compatible random operators
Authors: Beg Ismat , Abbas Mujahid
Published: August 2006

We construct a random iteration scheme and study necessary conditions for its convergence to a common random fixed point of two pairs of compatible random operators satisfying Meir‐Keeler type conditions in Polish spaces. Some random fixed point theorems for weakly compatible random operators under generalized contractive conditions in the framework of symmetric spaces are also proved.
On semilattices of groups whose arrows are epimorphisms
Authors: Abdallah M. El-Ghali M. , Gab-Alla L. N. , Elagan Sayed K. M.
Published: August 2006

A q partial group is defined to be a partial group, that is, a
strong semilattice of groups S = [E(S); Se, ϕe,f] such that S has an identity 1 and ϕ1,e is an epimorphism for all e ∈ E(S). Every partial group S with identity contains a unique maximal q partial group Q(S) such that (Q(S)) 1 = S1. This Q operation is proved to commute with Cartesian products and preserve normality. With Q extended to idempotent separating congruences on
S, it is proved that Q(ρK) = ρQ(K) for every normal K in S. Proper q partial groups are defined in such a way that associated to any group G, there is a proper
q partial group P(G) with (P(G)) 1 = G. It is proved that a q partial group S is proper if and only if S≅P(S1) and hence that if S is any partial group, there exists a group M such that S is embedded in P(M). P epimorphisms of proper q partial groups are
defined with which the category of proper q partial groups is
proved to be equivalent to the category of groups and epimorphisms
of groups.
The formal Laplace‐Borel transform of Fliess operatorsand the composition product
Authors: Li Yaqin , Gray W. Steven
Published: August 2006

The formal Laplace‐Borel transform of an analytic integral operator, known as a Fliess operator, is defined and developed. Then, in conjunction with the composition product over formal power series, the formal Laplace‐Borel transform is shown to provide an isomorphism between the semigroup of all Fliess operators under operator composition and the semigroup of all locally convergent formal power series under the composition product. Finally, the formal Laplace‐Borel transform is applied in a systems theory setting to explicitly derive the relationship between the formal Laplace transform of the input and output functions of a Fliess operator. This gives a compact interpretation of the operational calculus of Fliess for computing the output response of an analytic nonlinear system.
On the pointwise multiplication in Besov and Lizorkin‐Triebel spaces
Authors: Drihem Douadi , Moussai Madani
Published: August 2006

Under some sufficient conditions satisfied by F‐space of
Lizorkin and Triebel and B‐space of Besov, we prove some
embeddings of types F · B↪F, F · F↪F, and B · B↪B.
General variational inclusions in Lp spaces
Authors: Noor Muhammad Aslam
Published: August 2006

It is well known that the variational inclusions are equivalent to
the fixed point problems. We use this equivalent alternative
formulation to suggest and analyze some iterative methods for
solving variational inclusions in Lp spaces. We also consider the convergence analysis of these new iterative methods under some suitable conditions.
Existence of blowup solutions for nonlinear problems with a gradient term
Authors: Toumi Faten
Published: August 2006

We prove the existence of positive explosive solutions for the
equation Δu + λ(|x|)|∇u(x)| = ϕ(x, u(x)) in the whole space ℝN(N ≥ 3), where λ : [0, ∞) → [0, ∞) is a continuous function and ϕ : ℝN × [0, ∞) → [0, ∞) is
required to satisfy some hypotheses detailed below. More
precisely, we will give a necessary and sufficient condition for
the existence of a positive solution that blows up at infinity.
The solution of the third problem for the Laplace equation onplanar domains with smooth boundary and inside cracks and modifiedjump conditions on cracks
Authors: Medková Dagmar
Published: August 2006

This paper studies the third problem for the Laplace equation on a
bounded planar domain with inside cracks. The third condition
∂u/∂n + hu = f
is given on the boundary of the
domain. The skip of the function u+ − u− = g
and the modified
skip of the normal derivatives (∂u/∂n) + − (∂u/∂n) − + hu+ = f
are given on cracks. The
solution is looked for in the form of the sum of a modified
single‐layer potential and a double‐layer potential. The solution
of the corresponding integral equation is constructed.
Riesz‐Martin representation for positivesuper‐polyharmonic functions in A Riemannian manifold
Authors: Anandam V. , Othman S. I.
Published: August 2006

Let u be a super‐biharmonic function, that is, Δ2u ≥ 0, on the unit disc D
in the complex plane, satisfying certain
conditions. Then it has been shown that u has a representation
analogous to the Poisson‐Jensen representation for subharmonic
functions on D. In the same vein, it is shown here that a
function u on any Green domain Ω
in a Riemannian
manifold satisfying the conditions (−Δ) iu ≥ 0
for
0 ≤ i ≤ m
has a representation analogous to the Riesz‐Martin
representation for positive superharmonic functions on Ω.
Linear operators that preserve some test functions
Authors: Agratini Octavian
Published: August 2006

The paper centers around a pair of sequences of linear positive
operators. The former has the degree of exactness one and the
latter has its degree of exactness null, but, as a novelty, it
reproduces the third test function of Korovkin theorem.
Quantitative estimates of the rate of convergence are given in
different function spaces traveling from classical approximation
to approximation in abstract spaces. Particular classes are also
studied.
Optical PIV and LDV Comparisons of Internal Flow Investigations in SHF Impeller
Authors: Wuibaut G. , Bois G. , El Hajem M. , Akhras A. , Champagne J. Y.
Published: August 2006

The paper presents a comparison between two sets of experimental results in a centrifugal flow pump. The tested impeller is the so‐called SHF impeller for which many experimental data have been continuously produced to built databases for CFD code validations with various levels of approximation. Measurements have been performed using optical techniques: 2D particle image velocimetry (PIV) technique on an air test model and 2D laser doppler velocimetry (LDV) technique on a water model, both for different flow rates. For the present study, results obtained by these optical techniques are compared together in terms of phase averaged velocity and velocity fluctuations inside the impeller flow passage for design flow rate.
A review of Costas arrays
Authors: Drakakis Konstantinos
Published: August 2006

Costas arrays are not only useful in radar engineering, but they also present many interesting, and still open, mathematical problems. This work collects in it all important knowledge about them available today: some history of the subjects, density results, construction methods, construction algorithms with full proofs, and open questions. At the same time all the necessary mathematical background is offered in the simplest possible format and terms, so that this work can play the role of a reference for mathematicians and mathematically inclined engineers interested in the field.
A Homemade Autosampler/Injector Commutator for Flow Injection Analysis
Authors: de Figueiredo Eduardo Costa , de Souza Leandro Ruela , de Magalhães Cristiana Schmidt , Wisniewski Célio , Luccas Pedro Orival
Published: August 2006

An autosampler/injector commutator for flow injection analysis (FIA) was constructed with electronic components of used equipments. The apparatus is controlled by commercially available multifunctional interface (PCL711B) connected to a personal computer, and the software was written in Visual Basic language. The system was applied to water analysis and it presented satisfactory results. The low cost and simplicity are the principal characteristics of the autosampler/injector commutator.
Locally periodic homogenization of reflected diffusion
Authors: Diakhaby Aboubakary , Ouknine Youssef
Published: August 2006

We study the homogenization of reflected SDEs with locally periodic coefficients and highly oscillating drift. Our method is entirely probabilistic, and builds upon earlier works of Tanaka, Benchérif‐Madani and Pardoux, and Bensoussan et al We extend, to Tanaka′s theorem locally periodic case.
Optimal contracts in continuous‐time models
Authors: Cvitanić Jakša , Wan Xuhu , Zhang Jianfeng
Published: August 2006

We present a unified approach to solving contracting problems with
full information in models driven by Brownian motion. We apply the
stochastic maximum principle to give necessary and sufficient
conditions for contracts that implement the so‐called first‐best
solution. The optimal contract is proportional to the difference
between the underlying process controlled by the agent and a
stochastic, state‐contingent benchmark. Our methodology covers a
number of frameworks considered in the existing literature. The
main finance applications of this theory are optimal compensation
of company executives and of portfolio managers.
Heme Deficiency in Alzheimer’s Disease: A Possible Connection toPorphyria
Authors: Dwyer Barney E. , Stone Meghan L. , Zhu Xiongwei , Perry George , Smith Mark A.
Published: August 2006

Mechanisms that cause Alzheimer’s disease (AD), an invariably
fatal neurodegenerative disease, are unknown. Important recent
data indicate that neuronal heme deficiency may
contribute to AD pathogenesis. If true, factors that contribute to
the intracellular heme deficiency could potentially alter the
course of AD. The porphyrias are metabolic disorders characterized
by enzyme deficiencies in the heme biosynthetic pathway. We
hypothesize that AD may differ significantly in individuals
possessing the genetic trait for an acute hepatic porphyria. We
elaborate on this hypothesis and briefly review the
characteristics of the acute hepatic porphyrias that may be
relevant to AD. We note the proximity of genes encoding enzymes of
the heme biosynthesis pathway to genetic loci linked to sporadic,
late‐onset AD. In addition, we suggest that identification of
individuals carrying the genetic trait for acute porphyria may
provide a unique resource for investigating AD pathogenesis and
inform treatment and management decisions.
MicroRNAs in Gene Regulation: When the Smallest Governs It All
Authors: Ouellet Dominique L. , Perron Marjorie P. , Gobeil Lise-Andrée , Plante Pierre , Provost Patrick
Published: August 2006

Encoded by the genome of most eukaryotes examined so far,
microRNAs (miRNAs) are small ~21‐nucleotide (nt) noncoding
RNAs (ncRNAs) derived from a biosynthetic cascade involving
sequential processing steps executed by the ribonucleases
(RNases) III Drosha and Dicer. Following their recent
identification, miRNAs have rapidly taken the center stage as key
regulators of gene expression. In this review, we will summarize
our current knowledge of the miRNA biosynthetic pathway and its
protein components, as well as the processes it regulates via
miRNAs, which are known to exert a variety of biological functions
in eukaryotes. Although the relative importance of miRNAs remains
to be fully appreciated, deregulated protein expression resulting
from either dysfunctional miRNA biogenesis or abnormal miRNA‐based
gene regulation may represent a key etiologic factor in several,
as yet unidentified, diseases. Hence is our need to better understand
the complexity of the basic mechanisms underlying miRNA biogenesis
and function.
Atomic Layer Deposition for the Conformal Coating of Nanoporous Materials
Authors: Elam Jeffrey W. , Xiong Guang , Han Catherine Y. , Wang H. Hau , Birrell James P. , Welp Ulrich , Hryn John N. , Pellin Michael J. , Baumann Theodore F. , Poco John F. , Satcher Joe H.
Published: August 2006

Atomic layer deposition (ALD) is ideal for applying precise and
conformal coatings over nanoporous materials. We have recently
used ALD to coat two nanoporous solids: anodic aluminum oxide
(AAO) and silica aerogels. AAO possesses hexagonally ordered
pores with diameters d ~ 40 nm and pore length L ~ 70
microns. The AAO membranes were coated by ALD to fabricate catalytic membranes that demonstrate remarkable selectivity in the
oxidative dehydrogenation of cyclohexane. Additional AAO
membranes coated with ALD Pd films show promise as hydrogen
sensors. Silica aerogels have the lowest density and highest
surface area of any solid material. Consequently, these materials
serve as an excellent substrate to fabricate novel catalytic
materials and gas sensors by ALD.
Flunisolide Decreases Exhaled Nitric Oxide and Nitrotyrosine Levels in Asthmatic Children
Authors: Bodini A. , Peroni D. G. , Zardini F. , Corradi M. , Alinovi R. , Boner A. L. , Piacentini G. L.
Published: August 2006

Background.Exhaled nitric oxide (FeNO) has been reported to be elevated in the oxidative stress involved in asthmatic patients, and the reaction of nitric oxide (NO) with superoxide anions results in the formation of nitrotyrosine. The purpose of this study was to investigate the effect of inhaled steroid treatment on nitrotyrosine levels collected by exhaled breath condensate (EBC) and on FeNO.Methods.This was a single‐blind placebo‐controlled study. The lung function, FeNO, and nitrotyrosine levels were evaluated in 10 asthmatic children.Results.The nitrotyrosine levels were stable during the placebo period (T0 = 1.16 ng/ml versus T1 = 1.05 ng/ml; NS.), whereas they decreased after the treatment with flunisolide (T2 = 1.14 ng/ml versus T3 = 0.88 ng/ml;P< .001). No significant reduction in FeNO levels was observed after placebo treatment (T0 = 38.4 ppb versus T1 = 34.7 ppb, NS.). In contrast, FeNO values decreased significantly being at T3 = 14.9 ppb (T1 versus T3;P= .024).Conclusions.This study shows that corticosteroid treatment reduces nitrotyrosine levels in EBC of asthmatic subjects.
Effect of Target Dynamics on Pharmacokinetics of a Novel Therapeutic Antibody against the Epidermal Growth Factor Receptor: Implications for the Mechanisms of Action
Authors: Lammerts van Bueren Jeroen J. , Bleeker Wim K. , Bøgh Henrik O. , Houtkamp Mischa , Schuurman Janine , van de Winkel Jan G.J. , Parren Paul W.H.I.
Published: August 2006

The epidermal growth factor receptor (EGFR) is overexpressed on many solid tumors and represents an attractive target for antibody therapy. Here, we describe the effect of receptor-mediated antibody internalization on the pharmacokinetics and dose-effect relationship of a therapeutic monoclonal antibody (mAb) against EGFR (2F8). This mAb was previously found therapeutically active in mouse tumor models by two dose-dependent mechanisms of action: blockade of ligand binding and induction of antibody-dependent cell-mediated cytotoxicity. In vitro studies showed 2F8 to be rapidly internalized by EGFR-overexpressing cells. In vivo, accelerated 2F8 clearance was observed in cynomolgus monkeys at low doses but not at high doses. This enhanced clearance seemed to be receptor dependent and was included in a pharmacokinetic model designed to explain its nonlinearity. Receptor-mediated clearance was also found to affect in situ antibody concentrations in tumor tissue. Ex vivo analyses of xenograft tumors of 2F8-treated nude mice revealed that relatively high antibody plasma concentrations were required for maximum EGFR saturation in high-EGFR-expressing human A431 tumors, in contrast to lower-EGFR-expressing human xenograft tumors. In summary, receptor-mediated antibody internalization and degradation provides a saturable route of clearance that significantly affects pharmacokinetics, particularly at low antibody doses. EGFR saturation in normal tissues does not predict saturation in tumor tissue as local antibody concentrations in EGFR-overexpressing tumors may be more rapidly reduced by antibody internalization. Consequently, antibody saturation of the receptor may be affected, thereby affecting the local mechanism of action. (Cancer Res 2006; 66(15): 7630-8)
Androgens Induce Prostate Cancer Cell Proliferation through Mammalian Target of Rapamycin Activation and Post-transcriptional Increases in Cyclin D Proteins
Authors: Xu Youyuan , Chen Shao-Yong , Ross Kenneth N. , Balk Steven P.
Published: August 2006

Androgen receptor (AR) plays a central role in prostate cancer, with most tumors responding to androgen deprivation therapies, but the molecular basis for this androgen dependence has not been determined. Androgen [5α-dihydrotestosterone (DHT)] stimulation of LNCaP prostate cancer cells, which have constitutive phosphatidylinositol 3-kinase (PI3K)/Akt pathway activation due to PTEN loss, caused increased expression of cyclin D1, D2, and D3 proteins, retinoblastoma protein hyperphosphorylation, and cell cycle progression. However, cyclin D1 and D2 message levels were unchanged, indicating that the increases in cyclin D proteins were mediated by a post-transcriptional mechanism. This mechanism was identified as mammalian target of rapamycin (mTOR) activation. DHT treatment increased mTOR activity as assessed by phosphorylation of the downstream targets p70 S6 kinase and 4E-BP1, and mTOR inhibition with rapamycin blocked the DHT-stimulated increase in cyclin D proteins. Significantly, DHT stimulation of mTOR was not mediated through activation of the PI3K/Akt or mitogen-activated protein kinase/p90 ribosomal S6 kinase pathways and subsequent tuberous sclerosis complex 2/tuberin inactivation or by suppression of AMP-activated protein kinase. In contrast, mTOR activation by DHT was dependent on AR-stimulated mRNA synthesis. Oligonucleotide microarrays showed that DHT-stimulated rapid increases in multiple genes that regulate nutrient availability, including transporters for amino acids and other organic ions. These results indicate that a critical function of AR in PTEN-deficient prostate cancer cells is to support the pathologic activation of mTOR, possibly by increasing the expression of proteins that enhance nutrient availability and thereby prevent feedback inhibition of mTOR. (Cancer Res 2006; 66(15): 7783-92)
The DNAN-Glycosylase MED1 Exhibits Preference for Halogenated Pyrimidines and Is Involved in the Cytotoxicity of 5-Iododeoxyuridine
Authors: Turner David P. , Cortellino Salvatore , Schupp Jane E. , Caretti Elena , Loh Tamalette , Kinsella Timothy J. , Bellacosa Alfonso
Published: August 2006

The base excision repair protein MED1 (also known as MBD4), an interactor with the mismatch repair protein MLH1, has a central role in the maintenance of genomic stability with dual functions in DNA damage response and repair. MED1 acts as a thymine and uracil DNA N-glycosylase on T:G and U:G mismatches that occur at cytosine-phosphate-guanine (CpG) methylation sites due to spontaneous deamination of 5-methylcytosine and cytosine, respectively. To elucidate the mechanisms that underlie sequence discrimination by MED1, we did single-turnover kinetics with the isolated, recombinant glycosylase domain of MED1. Quantification of MED1 substrate hierarchy confirmed MED1 preference for mismatches within a CpG context and showed preference for hemimethylated base mismatches. Furthermore, the kst values obtained with the uracil analogues 5-fluorouracil and 5-iodouracil were over 20- to 30-fold higher than those obtained with uracil, indicating substantially higher affinity for halogenated bases. A 5-iodouracil precursor is the halogenated nucleotide 5-iododeoxyuridine (5IdU), a cytotoxic and radiosensitizing agent. Cultures of mouse embryo fibroblasts (MEF) with different Med1 genotype derived from mice with targeted inactivation of the gene were evaluated for sensitivity to 5IdU. The results revealed that Med1-null MEFs are more sensitive to 5IdU than wild-type MEFs in both 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide and colony formation assays. Furthermore, high-performance liquid chromatography analyses revealed that Med1-null cells exhibit increased levels of 5IdU in their DNA due to increased incorporation or reduced removal. These findings establish MED1 as a bona fide repair activity for the removal of halogenated bases and indicate that MED1 may play a significant role in 5IdU cytotoxicity. (Cancer Res 2006; 66(15): 7686-93)
Adenosine-Mediated Inhibition of the Cytotoxic Activity and Cytokine Production by Activated Natural Killer Cells
Authors: Lokshin Anna , Raskovalova Tatiana , Huang Xiaojun , Zacharia Lefteris C. , Jackson Edwin K. , Gorelik Elieser
Published: August 2006

Adenosine is an important signaling molecule that regulates multiple physiologic processes and exerts major anti-inflammatory actions. Tumors have high concentrations of adenosine, which could inhibit the function of tumor-infiltrating lymphoid cells. We investigated the ability of adenosine and its stable analogue 2-chloroadenosine (CADO) to inhibit cytokine production and cytotoxic activity of lymphokine-activated killer (LAK) cells and determined whether both these effects are initiated via a common pathway. CADO strongly inhibited cytotoxic activity of LAK cells and attenuated the production of IFN-γ, granulocyte macrophage colony-stimulating factor, tumor necrosis factor α, and macrophage inflammatory protein-1α by LAK cells stimulated by cross-linking of the Ly49D receptor. These inhibitory effects were associated with the ability of CADO to stimulate cyclic AMP (cAMP) production and activate protein kinase A (PKA). Using cAMP analogues with different affinities for the A and B sites of the regulatory subunits of PKA types I and II, we found that activation of PKA I, but not PKA II, mimicked the inhibitory effects of CADO on LAK cell cytotoxic activity and cytokine production. Inhibitors of the PKA catalytic subunits (H89 and PKI14-22 peptide) failed to abrogate the inhibitory effects of CADO whereas Rp-8-Br-cAMPS, an antagonist of the RI subunit, blocked the inhibitory effects of CADO. We conclude that the inhibitory effects of adenosine are probably mediated via cAMP-dependent activation of the RI subunits of PKA I but are independent of the catalytic activity of PKA. Tumor-produced adenosine could be a potent tumor microenvironmental factor inhibiting the functional activity of tumor-infiltrating immune cells. (Cancer Res 2006; 66(15): 7758-65)
High-Grade Glioma Formation Results from Postnatal Pten Loss or Mutant Epidermal Growth Factor Receptor Expression in a Transgenic Mouse Glioma Model
Authors: Wei Qingxia , Clarke Laura , Scheidenhelm Danielle K. , Qian Baoping , Tong Amanda , Sabha Nesrin , Karim Zia , Bock Nicholas A. , Reti Robert , Swoboda Rolf , Purev Enkhtsetseg , Lavoie Jean-Francois , Bajenaru M. Livia , Shannon Patrick , Herlyn Dorothee , Kaplan David , Henkelman R. Mark , Gutmann David H. , Guha Abhijit
Published: August 2006

High-grade gliomas are devastating brain tumors associated with a mean survival of <50 weeks. Two of the most common genetic changes observed in these tumors are overexpression/mutation of the epidermal growth factor receptor (EGFR) vIII and loss of PTEN/MMAC1 expression. To determine whether somatically acquired EGFRvIII expression or Pten loss accelerates high-grade glioma development, we used a previously characterized RasB8 glioma-prone mouse strain, in which these specific genetic changes were focally introduced at 4 weeks of age. We show that both postnatal EGFRvIII expression and Pten inactivation in RasB8 mice potentiate high-grade glioma development. Moreover, we observe a concordant loss of Pten and EGFR overexpression in nearly all high-grade gliomas induced by either EGFRvIII introduction or Pten inactivation. This novel preclinical model of high-grade glioma will be useful in evaluating brain tumor therapies targeted to the pathways specifically dysregulated by EGFR expression or Pten loss. (Cancer Res 2006; 66(15): 7429-37)
MicroRNA-Cancer Connection: The Beginning of a New Tale
Authors: Calin George Adrian , Croce Carlo Maria
Published: August 2006

Cancer initiation and progression can involve microRNAs (miRNA), which are small noncoding RNAs that can regulate gene expression. Their expression profiles can be used for the classification, diagnosis, and prognosis of human malignancies. Loss or amplification of miRNA genes has been reported in a variety of cancers, and altered patterns of miRNA expression may affect cell cycle and survival programs. Germ-line and somatic mutations in miRNAs or polymorphisms in the mRNAs targeted by miRNAs may also contribute to cancer predisposition and progression. We propose that alterations in miRNA genes play a critical role in the pathophysiology of many, perhaps all, human cancers. (Cancer Res 2006; 66(15): 7390-4)
Notch Pathway Inhibition Depletes Stem-like Cells and Blocks Engraftment in Embryonal Brain Tumors
Authors: Fan Xing , Matsui William , Khaki Leila , Stearns Duncan , Chun Jiong , Li Yue-Ming , Eberhart Charles G.
Published: August 2006

The Notch signaling pathway is required in both nonneoplastic neural stem cells and embryonal brain tumors, such as medulloblastoma, which are derived from such cells. We investigated the effects of Notch pathway inhibition on medulloblastoma growth using pharmacologic inhibitors of γ-secretase. Notch blockade suppressed expression of the pathway target Hes1 and caused cell cycle exit, apoptosis, and differentiation in medulloblastoma cell lines. Interestingly, viable populations of better-differentiated cells continued to grow when Notch activation was inhibited but were unable to efficiently form soft-agar colonies or tumor xenografts, suggesting that a cell fraction required for tumor propagation had been depleted. It has recently been hypothesized that a small population of stem-like cells within brain tumors is required for the long-term propagation of neoplastic growth and that CD133 expression and Hoechst dye exclusion (side population) can be used to prospectively identify such tumor-forming cells. We found that Notch blockade reduced the CD133-positive cell fraction almost 5-fold and totally abolished the side population, suggesting that the loss of tumor-forming capacity could be due to the depletion of stem-like cells. Notch signaling levels were higher in the stem-like cell fraction, providing a potential mechanism for their increased sensitivity to inhibition of this pathway. We also observed that apoptotic rates following Notch blockade were almost 10-fold higher in primitive nestin-positive cells as compared with nestin-negative ones. Stem-like cells in brain tumors thus seem to be selectively vulnerable to agents inhibiting the Notch pathway. (Cancer Res 2006; 66(15): 7445-52)
Responses of Human Colorectal Tumor Cells to Treatment with the Anti–Epidermal Growth Factor Receptor Monoclonal Antibody ICR62 Used Alone and in Combination with the EGFR Tyrosine Kinase Inhibitor Gefitinib
Authors: Cunningham Matthew P. , Thomas Hilary , Fan Zhen , Modjtahedi Helmout
Published: August 2006

The anti–epidermal growth factor receptor (EGFR) monoclonal antibody cetuximab has been approved for the treatment of patients with metastatic colorectal cancer. However, there is currently no reliable marker for response to therapy with the EGFR inhibitors. In this study, we investigated the sensitivity of 10 human colorectal tumor cell lines (DiFi, CCL218, CCL221, CCL225, CCL227, CCL228, CCL231, CCL235, CCL244, and HCT-116) to treatment with our anti-EGFR monoclonal antibody, ICR62, and/or the EGFR tyrosine kinase inhibitor, gefitinib. Of the cells examined, only DiFi contained high levels of constitutively active EGFR and were highly sensitive to treatment with both ICR62 (IC50 = 0.52 nmol/L) and gefitinib (IC50 = 27.5 nmol/L). In contrast, the growth of other tumor cell lines, which contained low levels of the EGFR, HER-2, and pAkt but comparable or even higher basal levels of phosphorylated mitogen-activated protein kinase (pMAPK), were relatively resistant to treatment with both inhibitors. Both ICR62 and gefitinib induced EGFR down-regulation, reduced the basal levels of pEGFR at five known tyrosine residues, pMAPK, and pAkt, and increased the sub-G1 population in DiFi cells. However, treatment with a combination of ICR62 and gefitinib neither sensitized colorectal tumor cells that were insensitive to treatment with the single agent nor enhanced the growth-inhibitory effect of the single agent in DiFi cells. These results indicate that basal levels of pMAPK and pAkt are not good indicators of response to the EGFR inhibitors in colorectal cancer cells and dual targeting of the EGFR by a combination of ICR62 and gefitinib is not superior to treatment with a single agent. (Cancer Res 2006; 66(15): 7708-15)
Gene Expression Signatures for Predicting Prognosis of Squamous Cell and Adenocarcinomas of the Lung
Authors: Raponi Mitch , Zhang Yi , Yu Jack , Chen Guoan , Lee Grace , Taylor Jeremy M.G. , MacDonald James , Thomas Dafydd , Moskaluk Christopher , Wang Yixin , Beer David G.
Published: August 2006

Non–small-cell lung cancers (NSCLC) compose 80% of all lung carcinomas with squamous cell carcinomas (SCC) and adenocarcinoma representing the majority of these tumors. Although patients with early-stage NSCLC typically have a better outcome, 35% to 50% will relapse within 5 years after surgical treatment. We have profiled primary squamous cell lung carcinomas from 129 patients using Affymetrix U133A gene chips. Unsupervised analysis revealed two clusters of SCC that had no correlation with tumor stage but had significantly different overall patient survival (P = 0.036). The high-risk cluster was most significantly associated with down-regulation of epidermal development genes. Cox proportional hazard models identified an optimal set of 50 prognostic mRNA transcripts using a 5-fold cross-validation procedure. Quantitative reverse transcription-PCR and immunohistochemistry using tissue microarrays were used to validate individual gene candidates. This signature was tested in an independent set of 36 SCC samples and achieved 84% specificity and 41% sensitivity with an overall predictive accuracy of 68%. Kaplan-Meier analysis showed clear stratification of high-risk and low-risk patients [log-rank P = 0.04; hazard ratio (HR), 2.66; 95% confidence interval (95% CI), 1.01-7.05]. Finally, we combined the SCC classifier with our previously identified adenocarcinoma prognostic signature and showed that the combined classifier had a predictive accuracy of 71% in 72 NSCLC samples also showing significant differences in overall survival (log-rank P = 0.0002; HR, 3.54; 95% CI, 1.74-7.19). This prognostic signature could be used to identify patients with early-stage high-risk NSCLC who might benefit from adjuvant therapy following surgery. (Cancer Res 2006; 66(15): 7466-72)
Loss of p63 Leads to Increased Cell Migration and Up-regulation of Genes Involved in Invasion and Metastasis
Authors: Barbieri Christopher E. , Tang Luo Jia , Brown Kimberly A. , Pietenpol Jennifer A.
Published: August 2006

p63, a homologue of the tumor suppressor p53, is critical for the development and maintenance of squamous epithelia. p63 is specifically expressed in the basal layers of stratified epithelial tissues and is considered a specific marker for cells of this type. The role of p63 in tumorigenesis remains poorly defined. Numerous studies have highlighted the oncogenic potential of the predominant p63 isoform ΔNp63α; however, data suggest that other p63 proteins can act as tumor suppressors or alter the metastatic potential of tumors. ΔNp63α can act as a transcriptional repressor, but the link between the transcriptional functions of p63 and its biological role is still unclear. In this study, we used a loss-of-function approach to investigate the transcriptional programs controlled by p63. Disruption of p63 in squamous cell lines resulted in down-regulation of transcripts specifically expressed in squamous tissues and a significant alteration of keratinocyte differentiation. Interestingly, we found that disruption of p63 led to up-regulation of markers of nonepithelial tissues (mesenchyme and neural tissue) in both primary and immortalized squamous cells. Many of these up-regulated genes are associated with increased capacity for invasion and metastasis in tumors. Furthermore, loss of p63 expression was accompanied by a shift toward mesenchymal morphology and an increase in motility in primary keratinocytes and squamous cell lines. We conclude that loss of endogenous p63 expression results in up-regulation of genes associated with invasion and metastasis, and predisposes to a loss of epithelial and acquisition of mesenchymal characteristics. These findings have implications for the role of p63 in both development and tumorigenesis. (Cancer Res 2006; 66(15): 7589-97)
Modified Low-Density Lipoproteins and High-Density Lipoproteins
Authors: Koller Elisabeth , Volf Ivo , Gurvitz Aner , Koller Franz
Published: August 2006

It has long been known that the oxidative state of the various plasma lipoproteins modulates platelet aggregability, thereby contributing to atherogenesis. Low-density lipoprotein (LDL), occurring in vivo both in the native and oxidised forms, interacts directly with platelets, by binding to specific receptors. While the identity of the receptors for native LDL and some subfractions of high-density lipoproteins (HDL) remains disputed, apoE-containing HDL2 binds to LRP8. The nature of these interactions as well as the distinction between candidate receptor proteins was elucidated using covalently modified apolipoproteins, which pointed to the participation of apolipoproteins in high affinity binding. However, the platelet effects initiated by binding of native lipoproteins remain controversial. Some of this ambiguity can be traced to the fact that native LDL inevitably undergoes substantial oxidisation upon modification, including by radiolabelling. The platelet-activating effects provoked by oxidised LDL are irrefutable, but many details remain unknown. The role of CD36 in platelet binding by oxidised LDL is well established, although additional receptors may exist. Much less is known about the interaction of oxidised HDL with platelets, since platelet activation was observed in some, but not all studies. Various frequently applied in vitro oxidation methods produce modified lipoprotein species that may not be relevant in vivo. Based on the reported modifications obtained by in vitro oxidation of LDL, early investigations focused mainly on the formation and the eventual effects of oxidised lipids. More recently, alterations to lipoproteins performed using hypochloric acid and myeloperoxidase redirected the attention to the role of modified apoproteins in triggering platelet responses.
Recent Trends in Minimally Invasive Cardiac Surgery
Authors: Kypson Alan P.
Published: August 2006

Evolving technologies have resulted in an increase in minimally invasive cardiac surgery. Currently, robotic systems allow surgeons to perform a variety of procedures through small incisions. This changing paradigm is reviewed.
Lack of Reciprocity between Opioid and 5-HT3 Receptors for Antinociception in Rat Spinal Cord
Authors: Yoon Myung Ha , Bae Hong Beom , Choi Jeong Il , Kim Seok Jai , Chung Sung Tae , Kim Chang Mo
Published: August 2006

We examined the properties of the drug interaction between morphine and 5-HT3 receptor antagonist at the spinal level. The nociceptive state was induced by subcutaneously injecting formalin solution (5%, 50 µl) into the hindpaw of the rats. Intrathecal morphine and m-CPBG (5-HT3 receptor agonist) dose-dependently decreased the flinching response during phase 1 and phase 2 in the formalin test. Intrathecal 5-HT3 receptor antagonists (LY-278,584 and ondansetron) did not reverse the antinociceptive effect of intrathecal morphine. Intrathecal naloxone had little effect on attenuation of the antinociception of intrathecal m-CPBG. Taken together, no reciprocal interaction was noted between 5-HT3 receptor and opioid receptors at the spinal level. Thus, the 5-HT3 receptor antagonist may be useful to manage opioid-induced emesis at the spinal level.
The APL Test: Extension to General Nuclear Families and Haplotypes and Examination of Its Robustness
Authors: Chung Ren-Hua , Hauser Elizabeth R. , Martin Eden R.
Published: August 2006

Objective: The Association in the Presence of Linkage test (APL) is a powerful statistical method that allows for missing parental genotypes in nuclear families. However, in its original form, the statistic does not easily extend to mixed nuclear family structures nor to multiple-marker haplotypes. Furthermore, the robustness of APL in practice has not been examined. Here we present a generalization of the APL model and examination of its robustness under a variety of non-standard scenarios. Methods: The generalization is made possible by incorporating a bootstrap variance estimator instead of the original robust variance estimator. This allows for use of more than two affected siblings. Haplotype analysis was accomplished by combining estimation of haplotype phase into the EM algorithm. Computer simulation was used to examine robustness of the APL to departures from test assumptions. Results: The extended APL tests both single-marker and multiple-marker haplotypes and shows more power than other association methods. Simulation results showed that the single-marker APL test is robust to the departure from HWE. For the haplotype test, violation of the HWE assumption can inflate type I error. We also evaluated general guidelines for the validity of APL with rare alleles and rare haplotypes. Software for the APL test is available from http://www.chg.duke.edu/research/apl.html.
An Alternative Foundation for the Planning and Evaluation of Linkage Analysis
Authors: Strug Lisa J. , Hodge Susan E.
Published: August 2006

The ‘multiple testing problem’ currently bedevils the field of genetic epidemiology. Briefly stated, this problem arises with the performance of more than one statistical test and results in an increased probability of committing at least one Type I error. The accepted/conventional way of dealing with this problem is based on the classical Neyman-Pearson statistical paradigm and involves adjusting one’s error probabilities. This adjustment is, however, problematic because in the process of doing that, one is also adjusting one’s measure of evidence. Investigators have actually become wary of looking at their data, for fear of having to adjust the strength of the evidence they observed at a given locus on the genome every time they conduct an additional test. In a companion paper in this issue (Strug & Hodge I), we presented an alternative statistical paradigm, the ‘evidential paradigm’, to be used when planning and evaluating linkage studies. The evidential paradigm uses the lod score as the measure of evidence (as opposed to a p value), and provides new, alternatively defined error probabilities (alternative to Type I and Type II error rates). We showed how this paradigm separates or decouples the two concepts of error probabilities and strength of the evidence. In the current paper we apply the evidential paradigm to the multiple testing problem – specifically, multiple testing in the context of linkage analysis. We advocate using the lod score as the sole measure of the strength of evidence; we then derive the corresponding probabilities of being misled by the data under different multiple testing scenarios. We distinguish two situations: performing multiple tests of a single hypothesis, vs. performing a single test of multiple hypotheses. For the first situation the probability of being misled remains small regardless of the number of times one tests the single hypothesis, as we show. For the second situation, we provide a rigorous argument outlining how replication samples themselves (analyzed in conjunction with the original sample) constitute appropriate adjustments for conducting multiple hypothesis tests on a data set.
Chronic Hepatitis C and Crohn’s Disease: Nosocomial Infection Treatment with PEG-Interferon plus Ribavirin
Authors: Salcedo-Mora Xamila , Maté José , Medina Jesus , Nam Cha Syong J. , Gisbert Javier P. , Moreno-Otero Ricardo
Published: August 2006

We describe the case of a patient with a diagnosis of Crohn’s disease and accidental infection during abdominal surgery by hepatitis C virus (HCV) who received combination therapy with pegylated interferon-α2b (1.5 µg/kg weekly) plus ribavirin (10.6 mg/kg daily) for histologically demonstrated chronic hepatitis C. After 48 weeks treatment, serum transaminase levels were normal and viremia (HCV RNA) was negative (end-of-treatment response); 24 weeks later (follow-up period), a sustained virological response was demonstrated. The tolerance to combination antiviral therapy was good, without intestinal symptoms of inflammatory bowel disease recurrence. We conclude that current antiviral therapies with immunomodulatory effects may be helpful and safe for patients with inflammatory bowel disease infected by hepatitis C virus.
Decreased Endothelium-Dependent Vasodilation in Diabetic Female Rats: Role of Prostanoids
Authors: Akamine Eliana H. , Urakawa Tiyeko Anna Eliza V.M. , de Oliveira Maria Aparecida , Nigro Dorothy , de Carvalho Maria Helena C. , Tostes Rita de Cássia A. , Fortes Zuleica B.
Published: August 2006

Overproduction of vasoconstrictor prostanoids and reduced prostacyclin levels have been related to the male diabetic-linked vascular dysfunction. However, it is not clear yet if these changes also occur in diabetic females. The aim of this study was to verify the role of prostanoids in the vascular dysfunction of diabetic female rats. The parameters studied were the mesenteric arteriolar reactivity (intravital microscopy and isolated perfused arteriolar bed), prostanoid measurement (enzyme immunoassay), superoxide generation (intravital fluorescence microscopy), and the presence of peroxynitrite (Western blot for nitrotyrosine-containing proteins). The response to acetylcholine was decreased in arterioles of diabetic female rats and diclofenac, but not ridogrel, corrected the altered response. The unstimulated (basal) release of thromboxane B2 (TXB2), but not prostaglandin F2α (PGF2α) or 6-keto-PGF1α, was increased in the mesenteric perfusate from diabetic female rats. Increased production of PGF2α and 6-keto-PGF1α, but not TXB2, was induced by acetylcholine in diabetic arterioles. The superoxide generation was increased in diabetic female rats and diclofenac corrected it. Diabetes increased nitrotyrosine-containing proteins in mesenteric microvessels. In conclusion, our data show that the increase of constrictor prostanoid release, most likely PGF2α, could be involved in the reduced endothelium-dependent vasodilation of diabetic female rats. In addition, the enhanced activation of cyclooxygenase may be a source of superoxide anion generation in this model.
Spatially Filtered Magnetoencephalographic Analysis of Cortical Oscillatory Changes in Basic Brain Rhythms during the Japanese ‘Shiritori’ Word Generation Task
Authors: Yamamoto Masakiyo , Ukai Satoshi , Shinosaki Kazuhiro , Ishii Ryouhei , Kawaguchi Shunsuke , Ogawa Asao , Mizuno-Matsumoto Yuko , Fujita Norihiko , Yoshimine Toshiki , Takeda Masatoshi
Published: August 2006

Background: ‘Shiritori’ (capping verses) is a traditional Japanese word generation game, and is very familiar to native Japanese speakers. The shiritori task is expected to more strongly activate temporal language-related regions than conventional word generation to letters because of its characteristic way to make cue letters. Objectives: The aim of this study was to examine the cortical oscillatory changes in basic brain rhythms during silently performing a shiritori task. Methods: Using synthetic aperture magnetometry (SAM) analysis of magnetoencephalography, we estimated the tomographic distributions of the statistically significant differences of the power in the alpha and beta frequency bands between the resting and the task periods. Results: Significant event-related desynchronization (ERD) in the 8- to 25-Hz band, thought to reflect neural activation, was localized within task-related cortical regions with left-side dominance. The significant ERDs were estimated in both the frontal and temporal language-related regions encompassing Broca’s and Wernicke’s areas, although previous neuroimaging studies using word generation to letters showed neural activation predominantly in frontal regions. Conclusions: Our results show the potential of SAM analysis for reliable brain mapping of language processing, and suggest that the shiritori task might be more suitable for examining the language-related network in the brain than conventional word generation to letters.