bluuebunny/crossref_metadata_2025 huggingface dataset:
GENERATING HYPERCHAOTIC ATTRACTORS VIA APPROXIMATE TIME DELAYED STATE FEEDBACK
Authors: HU GUOSI , JIANG SHIQIN
Published: January 2009

This letter presents a new hyperchaotic system, which was constructed by adding an approximate time delayed state feedback to the second equation of Lorenz chaotic system. The constructed system is not only demonstrated by numerical simulations but also implemented via an electronic circuit, showing very good agreement with the simulation results.
GENERATING AN ASSORTATIVE NETWORK WITH A GIVEN DEGREE DISTRIBUTION
Authors: ZHOU JIN , XU XIAOKE , ZHANG JIE , SUN JUNFENG , SMALL MICHAEL , LU JUN-AN
Published: January 2009

Recently, the assortative mixing of complex networks has received much attention partly because of its significance in various social networks. In this paper, a new scheme to generate an assortative growth network with given degree distribution is presented using a Monte Carlo sampling method. Since the degrees of a great number of real-life networks obey either power-law or Poisson distribution, we employ these two distributions to grow our models. The models generated by this method exhibit interesting characteristics such as high average path length, high clustering coefficient and strong rich-club effects.
FRACTAL GEOMETRY OF WEIERSTRASS-TYPE FUNCTIONS
Authors: CARVALHO ABEL
Published: January 2009

The aim of this paper is twofold. First, with reference to Refs. 1 and 2 we show maximal and minimal box and Hausdorff dimensions over all continuous real functions compactly supported on ℝn, with integrability 0 < p ≤ ∞ and exact smoothness s > 0. We estimate also the box dimensions of trigonometrical Weierstrass-type functions. Secondly, we investigate some criteria in order to decide when the graph of a function is not a d-set. Moreover, for each d between n and n + 1 we construct a function on [0,1]nthe graph of which is a d-set.
ON THE DIMENSION OF SIERPIŃSKI PEDAL TRIANGLES
Authors: DING JIU , LI ZHAO
Published: January 2009

We provide a solution to the conjecture of Ref. 1 on the global minimal fractal dimension of Sierpiński petal triangles. We show that the dimension, ln 3/ln 2, of the Sierpiński triangle is the strict minimal value of the dimensions among all Sierpiński pedal triangles associated with acute triangles.
A PRIMER OF NEGATIVE TEST DIMENSIONS AND DEGREES OF EMPTINESS FOR LATENT SETS
Authors: MANDELBROT BENOIT B. , FRAME MICHAEL
Published: January 2009

Applied blindly, the formula for the dimension of the intersection can give negative results. Extending Minkowski's definition of the dimension by ∊-neighborhoods to ∊-pseudo-neighborhoods, that is, replacing (A ∩ B)∊ with A∊ ∩ B∊, we introduce the notion of negative dimensions through several examples of random fractal constructions.
SITE AND BOND PERCOLATION PROBLEM FOR CONSTRUCTION OF MACROSCOPIC SURFACE IN A CUBIC LATTICE
Authors: YAMAMOTO KEIZO , YOSHINAGA HIROYUKI , MIYAZIMA SASUKE
Published: January 2009

When we distribute particles and bonds onto a cubic lattice, we assume that a plaquette is formed, if four corner sites of a square are occupied or four bonds of a square are occupied. When these plaquettes are produced in a cubic lattice and occupy a certain number of square surfaces in the cubic lattice, then a macroscopic surface is formed following a chain construction. This is the second phase transition added to usual site and bond percolation problems where a spreading chain is formed.
ANALYTICAL TREATMENT OF NUCLEAR MAGNETIC SHIELDING TENSOR INTEGRALS OVER EXPONENTIAL-TYPE FUNCTIONS
Authors: BERLU LILIAN , SAFOUHI HASSAN
Published: January 2009

The present work concerns the analytical and numerical development of three-center molecular integrals over Slater-type functions (STFs) and B functions of the second order involving [Formula: see text] in the operator. These integrals appear in the analytic expression of the nuclear magnetic shielding tensor.

The basis set of STFs is used to represent atomic orbitals. These STFs are expressed in terms of B functions, which are better suited to apply the Fourier transform method thoroughly developed by Steinborn group.

Analytic expressions are obtained for the integrals of the second order involved in nuclear magnetic resonance shielding tensor over B functions. These expressions turned out to be similar to those obtained for the usual molecular multi-center integrals. Consequently, the numerical evaluation of the integrals under consideration will benefit from the work previously done on the molecular multi-center integrals.
DFT/TDDFT STUDY ON DNA-BINDING AND SPECTRAL PROPERTIES OF "LIGHT SWITCH" COMPLEX [Ru(phen)2 (taptp)]2+ IN AQUEOUS SOLUTION
Authors: LI JUN , XU LIAN-CAI , LIAO SI-YAN , ZHENG KANG-CHENG , JI LIANG-NIAN
Published: January 2009

The theoretical studies on the electronic structure, DNA-binding, and absorption-spectral properties of "light switch" complex [ Ru ( phen )2( taptp )]2+ (phen = 1,10-phenanthroline; taptp = 4,5,9,18-tetraazaphenanthreno-[9,10-b]triphenylene) in aqueous solution have been carried out using density functional theory (DFT) and time-dependent DFT (TDDFT) methods. The results show the following: (i) The solvent effect makes all the frontier molecular orbital energies of complex to increase to a certain extent; however, the energies (ε LUMO + x) of some frontier unoccupied molecular orbitals (MOs) in aqueous solution are still negative and rather lower than those of the energies (ε HOMO - x) of some frontier-occupied MOs of DNA-base pairs, and thus the complex in aqueous solution is still an excellent electron-acceptor in its DNA-binding. (ii) The solvent effect further shows that simply increasing the conjugative planar area of intercalative ligand may be ineffective on the improvement of DNA-binding of the resulting complex because of going along with the increase in the LUMO (and LUMO + x) energy. It is the reason why the DNA-binding affinity of "light switch" complex [ Ru ( phen )2( taptp )]2+ is not better than that of the well-known complex [ Ru ( phen )2( dppz )]2+ yet. (iii) The three main experimental bands (~450 nm, ~360 nm, and ~290 nm) of the studied complex in aqueous solution were further well calculated, simulated, and explained by the TDDFT computations.
School-Based Interventions for Health Promotion and Weight Control: Not Just Waiting on the World to Change
Authors: Katz D.L.
Published: January 2009

Controversy persists regarding the utility of school-based interventions for obesity prevention and control and for related health promotion. This article reviews the pertinent evidence, based partly on a recent systematic review and meta-analysis by the author and colleagues. Of 64 relevant papers, 21 papers representing 19 distinct studies met quality criteria; half of these were published since 2000. Despite marked variation in measures, methods, and populations that handicap interpretation of this literature, evidence clearly demonstrated that school-based interventions had significant effects on weight. Thus available research evidence does present a case for school-based interventions. Despite the fact that such evidence is limited to date, the urgency of the obesity and diabetes epidemics cries out for action. Intervention is warranted on the basis of both extant evidence and common sense, with methodologically robust evaluation concomitantly to test our assumptions and verify our intuition.
Differences in lung glutathione metabolism may account for rodent susceptibility in elastase-induced emphysema development
Authors: Borzone Gisella R. , Liberona Leonel F. , Bustamante Andrea P. , Saez Claudia G. , Olmos Pablo R. , Vecchiola Andrea , Villagrán Andrea , Serrano Carolina , Reyes Tatiana P.
Published: January 2009

Syrian Golden hamsters develop more severe emphysema than Sprague-Dawley rats after intratracheal instillation of the same dose of elastase/body weight. Although species variations in antielastase defenses may largely explain these results, other variables, such as differences in lung antioxidants, cannot be overlooked since oxidative stress modulates antiprotease activity. We propose that elastase instillation might affect lung glutathione (GSH) metabolism differently in these species. Our aim was to study in hamsters and rats, lung glutathione metabolism at different times, from the stage of diffuse alveolar damage to advanced emphysema. We measured total and oxidized glutathione content as well as activity and expression of enzymes related to GSH synthesis and redox cycling: γ-glutamylcysteine synthetase, glutathione peroxidase, and glutathione reductase. Whereas rats showed no significant changes in these measurements, hamsters showed significant derangement in GSH metabolism early after elastase instillation: 25% fall in total GSH ( P < 0.05) with no increase in oxidized glutathione associated with reduced enzyme activities 24 h after elastase [60% for γ-glutamylcysteine synthetase ( P < 0.01), 30% for glutathione peroxidase ( P < 0.01), and 75% for glutathione reductase ( P < 0.001)]. GSH homeostasis was restored at the end of the first week, involving transient increased expression of these enzymes. We conclude that elastase induces significant alterations in GSH metabolism of hamster lungs and no overall change in rat lungs. Although differences in disease severity may account for our findings, the hamster becomes vulnerable to functional inhibition of α1-antitrypsin by oxidants and thus, even more susceptible to injury than it would be, considering only its low α1-antitrypsin level.
A new strategy to analyze possible association structures between dynamic nocturnal hormone activities and sleep alterations in humans
Authors: Kalus Stefanie , Kneib Thomas , Steiger Axel , Holsboer Florian , Yassouridis Alexander
Published: January 2009

The human sleep process shows dynamic alterations during the night. Methods are needed to examine whether and to what extent such alterations are affected by internal, possibly time-dependent, factors, such as endocrine activity. In an observational study, we examined simultaneously sleep EEG and nocturnal levels of renin, growth hormone (GH), and cortisol (between 2300 and 0700) in 47 healthy volunteers comprising 24 women (41.67 ± 2.93 yr of age) and 23 men (37.26 ± 2.85 yr of age). Hormone concentrations were measured every 20 min. Conventional sleep stage scoring at 30-s intervals was applied. Semiparametric multinomial logit models are used to study and quantify possible time-dependent hormone effects on sleep stage transition courses. Results show that increased cortisol levels decrease the probability of transition from rapid-eye-movement (REM) sleep to wakefulness (WAKE) and increase the probability of transition from REM to non-REM (NREM) sleep, irrespective of the time in the night. Via the model selection criterion Akaike's information criterion, it was found that all considered hormone effects on transition probabilities with the initial state WAKE change with time. Similarly, transition from slow-wave sleep (SWS) to light sleep (LS) is affected by a “hormone-time” interaction for cortisol and renin, but not GH. For example, there is a considerable increase in the probability of SWS-LS transition toward the end of the night, when cortisol concentrations are very high. In summary, alterations in human sleep possess dynamic forms and are partially influenced by the endocrine activity of certain hormones. Statistical methods, such as semiparametric multinomial and time-dependent logit regression, can offer ambitious ways to investigate and estimate the association intensities between the nonstationary sleep changes and the time-dependent endocrine activities.
Functional characterization ofActinobacillus pleuropneumoniaeurea transport protein, ApUT
Authors: Godara Geeta , Smith Craig , Bosse Janine , Zeidel Mark , Mathai John
Published: January 2009

Urea transporters (UTs) effect rapid flux of urea across biological membranes. In the mammalian kidney, UT activity is essential for effective urine concentration. In bacteria, UT-mediated urea uptake permits intracellular urease to degrade urea to ammonia and CO2, a process that either buffers acid loads or provides nutrient nitrogen. We have characterized the urea transport channel protein ApUT from Actinobacillus pleuropneumoniae. Kinetic analysis of bacterial inside-out membranes enriched in ApUT showed ∼28-fold increase in urea permeability (3.3 ± 0.4 × 10−4cm/s) compared with control vesicles (0.11 ± 0.02 × 10−4cm/s). In addition to urea, ApUT also conducts water. Urea and water transport across the channel was phloretin and mercury inhibitable, and the site of inhibition may be located on the cytoplasmic side of the protein. Glycerol and urea analogs, such as methylamine, dimethylurea, formamide, acetamide, methylurea, propanamide, and ethylamine did not permeate across ApUT.
Characterization of the chemosensitive response of individual solitary complex neurons from adult rats
Authors: Nichols Nicole L. , Mulkey Daniel K. , Wilkinson Katherine A. , Powell Frank L. , Dean Jay B. , Putnam Robert W.
Published: January 2009

We studied the CO2/H+-chemosensitive responses of individual solitary complex (SC) neurons from adult rats by simultaneously measuring the intracellular pH (pHi) and electrical responses to hypercapnic acidosis (HA). SC neurons were recorded using the blind whole cell patch-clamp technique and loading the soma with the pH-sensitive dye pyranine through the patch pipette. We found that SC neurons from adult rats have a lower steady-state pHithan SC neurons from neonatal rats. In the presence of chemical and electrical synaptic blockade, adult SC neurons have firing rate responses to HA (percentage of neurons activated or inhibited and the magnitude of response as determined by the chemosensitivity index) that are similar to SC neurons from neonatal rats. They also have a typical response to isohydric hypercapnia, including decreased ΔpHi, followed by pHirecovery, and increased firing rate. Thus, the chemosensitive response of SC neurons from adults is similar to the chemosensitive response of SC neurons from neonatal rats. Because our findings for adults are similar to previously reported values for neurons from neonatal rats, we conclude that intrinsic chemosensitivity is established early in development for SC neurons and is maintained throughout adulthood.
Participation of Kv1 Channels in Control of Membrane Excitability and Burst Generation in Mesencephalic V Neurons
Authors: Hsiao Chie-Fang , Kaur Gurvinder , Vong Angela , Bawa Harpreet , Chandler Scott H.
Published: January 2009

The function and biophysical properties of low threshold Kv1 current in control of membrane resonance, subthreshold oscillations, and bursting in mesencephalic V neurons (Mes V) were examined in rat brain stem slices (P8–P12) using whole cell current and voltage patch-clamp methods. α-dendrotoxin application, a toxin with high specificity for Kv1.1, 1.2, and 1.6 channels, showed the presence of a low-threshold K+current that activated rapidly around −50 mV and was relatively noninactivating over a 1-s period and had a V1/2max of −36.2 mV. Other toxins, specific for individual channels containing either Kv 1.1, 1.2, or 1.3 α-subunits, were applied individually, or in combination, and showed that Kv1 channels are heteromeric, composed of combinations of subunits. In current-clamp mode, toxin application transformed the high-frequency resonant properties of the membrane into a low-pass filter and concomitantly reduced the frequency of the subthreshold membrane oscillations. During this period, rhythmical bursting was transformed into low-frequency tonic discharge. Interestingly, in a subset of neurons that did not show bursting, low doses of α-dendrotoxin (α-DTX) sufficient to block 50% of the low threshold Kv1 channels induced bursting and increased the resonant peak impedance and subthreshold oscillations, which was replicated with computer simulation. This suggests that a critical balance between inward and outward currents is necessary for bursting. This was replicated with computer simulation. Single cell RT-PCR and immunohistochemical methods confirmed the presence of Kv1.1, 1.2, and 1.6 α-subunits in Mes V neurons. These data indicate that low threshold Kv1 channels are responsible for membrane resonance, contribute to subthreshold oscillations, and are critical for burst generation.
γ-Secretase Inhibitors Abrogate Oxaliplatin-Induced Activation of the Notch-1 Signaling Pathway in Colon Cancer Cells Resulting in Enhanced Chemosensitivity
Authors: Meng Raymond D. , Shelton Christopher C. , Li Yue-Ming , Qin Li-Xuan , Notterman Daniel , Paty Philip B. , Schwartz Gary K.
Published: January 2009

Because Notch signaling is implicated in colon cancer tumorigenesis and protects cells from apoptosis by inducing prosurvival targets, it was hypothesized that inhibition of Notch signaling with γ-secretase inhibitors (GSI) may enhance the chemosensitivity of colon cancer cells. We first show that the Notch-1 receptor, as well as its downstream target Hes-1, is up-regulated with colon cancer progression, similar to other genes involved in chemoresistance. We then report that chemotherapy induces Notch-1, as oxaliplatin, 5-fluorouracil (5-FU), or SN-38 (the active metabolite of irinotecan) induced Notch-1 intracellular domain (NICD) protein and activated Hes-1. Induction of NICD by oxaliplatin was caused by an increase in the activity and expression of γ-secretase complex, as suppression of the protein subunit nicastrin with small interfering RNA (siRNA) prevented NICD induction after oxaliplatin. Subsequent inhibition of Notch-1 signaling with a sulfonamide GSI (GSI34) prevented the induction of NICD by chemotherapy and blunted Hes-1 activation. Blocking the activation of Notch signaling with GSI34 sensitized cells to chemotherapy and was synergistic with oxaliplatin, 5-FU, and SN-38. This chemosensitization was mediated by Notch-1, as inhibition of Notch-1 with siRNA enhanced chemosensitivity whereas overexpression of NICD increased chemoresistance. Down-regulation of Notch signaling also prevented the induction of prosurvival pathways, most notably phosphoinositide kinase-3/Akt, after oxaliplatin. In summary, colon cancer cells may up-regulate Notch-1 as a protective mechanism in response to chemotherapy. Therefore, combining GSIs with chemotherapy may represent a novel approach for treating metastatic colon cancers by mitigating the development of chemoresistance. [Cancer Res 2009;69(2):573–82]
Molecular Classification and Prognostication of Adrenocortical Tumors by Transcriptome Profiling
Authors: Giordano Thomas J. , Kuick Rork , Else Tobias , Gauger Paul G. , Vinco Michelle , Bauersfeld Juliane , Sanders Donita , Thomas Dafydd G. , Doherty Gerard , Hammer Gary
Published: January 2009

Purpose: Our understanding of adrenocortical carcinoma (ACC) has improved considerably, yet many unanswered questions remain. For instance, can molecular subtypes of ACC be identified? If so, what is their underlying pathogenetic basis and do they possess clinical significance?

Experimental Design: We did a whole genome gene expression study of a large cohort of adrenocortical tissues annotated with clinicopathologic data. Using Affymetrix Human Genome U133 Plus 2.0 oligonucleotide arrays, transcriptional profiles were generated for 10 normal adrenal cortices (NC), 22 adrenocortical adenomas (ACA), and 33 ACCs.

Results: The overall classification of adrenocortical tumors was recapitulated using principal component analysis of the entire data set. The NC and ACA cohorts showed little intragroup variation, whereas the ACC cohort revealed much greater variation in gene expression. A robust list of 2,875 differentially expressed genes in ACC compared with both NC and ACA was generated and used in functional enrichment analysis to find pathways and attributes of biological significance. Cluster analysis of the ACCs revealed two subtypes that reflected tumor proliferation, as measured by mitotic counts and cell cycle genes. Kaplan-Meier analysis of these ACC clusters showed a significant difference in survival (P < 0.020). Multivariate Cox modeling using stage, mitotic rate, and gene expression data as measured by the first principal component for ACC samples showed that gene expression data contains significant independent prognostic information (P < 0.017).

Conclusions: This study lays the foundation for the molecular classification and prognostication of adrenocortical tumors and also provides a rich source of potential diagnostic and prognostic markers.
Invariant Natural Killer T Cells Regulate Breast Cancer Response to Radiation and CTLA-4 Blockade
Authors: Pilones Karsten A. , Kawashima Noriko , Yang Anne Marie , Babb James S. , Formenti Silvia C. , Demaria Sandra
Published: January 2009

Purpose: Immunoregulatory and suppressive mechanisms represent major obstacles to the success of immunotherapy in cancer patients. We have shown that the combination of radiotherapy to the primary tumor and CTL-associated protein 4 (CTLA-4) blockade induces antitumor immunity, inhibiting metastases and extending the survival of mice bearing the poorly immunogenic and highly metastatic 4T1 mammary carcinoma. Similarly to patients with metastatic cancer, however, mice were seldom cured. Here we tested the hypothesis that invariant natural killer T (iNKT) cells, a subset with unique regulatory functions, can regulate the response to radiotherapy and CTLA-4 blockade.

Experimental Design: The growth of 4T1 primary tumors and lung metastases was compared in wild-type and iNKT cell–deficient (iNKT-/-) mice. Treatment was started on day 13 when the primary tumors were palpable. Mice received radiotherapy to the primary tumor in two doses of 12 Gy in combination or not with 9H10 monoclonal antibody against CTLA-4. Response to treatment was assessed by measuring primary tumor growth delay/regression, survival, and number of lung metastases.

Results: The response to radiotherapy plus 9H10 was markedly enhanced in the absence of iNKT cells, with 50% of iNKT-/- versus 0% of wild-type mice showing complete tumor regression, long-term survival, and resistance to a challenge with 4T1 cells. Administration of the iNKT cell activator α-galactosylceramide did not enhance the response of wild-type mice to radiotherapy plus 9H10. Tumor-infiltrating iNKT cells were markedly reduced in wild-type mice treated with radiotherapy plus 9H10.

Conclusions: iNKT cells play a major role in regulating the response to treatment with local radiotherapy and CTLA-4 blockade.
A Novel Cancer Therapy by Skin Delivery of Indoleamine 2,3-Dioxygenase siRNA
Authors: Yen Meng-Chi , Lin Chi-Chen , Chen Yi-Ling , Huang Shih-Shien , Yang Huei-Jiun , Chang Chih-Peng , Lei Huan-Yao , Lai Ming-Derg
Published: January 2009

Purpose: Indoleamine 2,3-dioxygenase (IDO), an enzyme that degrades tryptophan, is a negative immune regulatory molecule of dendritic cells. IDO-expressing dendritic cells suppress T cell responses and may be immunosuppressive in vivo. We hypothesized that silencing the IDO expression in skin dendritic cells in vivo could elicit antitumor activity in tumor-draining lymph nodes.

Experimental Design: The efficiency of IDO-specific small interfering RNA (siRNA) was evaluated in vitro and in vivo. The therapeutic effect was evaluated in MBT-2 murine bladder tumor model and CT-26 colon tumor models.

Results: IDO expression was down-regulated in CD11c-positive lymphocytes after IDO siRNA treatment. In vivo skin administration of IDO siRNA inhibited tumor growth and prolonged survival in both tumor models. The number of infiltrated T cells and neutrophils increased at tumor sites, which are correlated with therapeutic efficacy. The T cells may be mainly responsible for the immunologic rejection because the effect was abolished by depletion of CD8-positive T cells. Adoptive transfer of CD11c-positive dendritic cells from vaccinated mice delayed tumor progression. The cancer therapeutic effect was reproducibly observed with another IDO siRNA targeting at different site, suggesting the effect was not due to off-target effect. In a neu-overexpressing MBT-2 tumor model, IDO siRNA enhanced the therapeutic efficacy of Her2/Neu DNA vaccine. Down-regulation of IDO2, an IDO homologue, with siRNA also generated antitumor immunity in vivo.

Conclusions: Antitumor immunity can be effectively elicited by physical delivery of siRNAs targeting immunoregulatory genes in skin dendritic cells in vivo, as shown by IDO and IDO2 in this report.
ABCB8 Mediates Doxorubicin Resistance in Melanoma Cells by Protecting the Mitochondrial Genome
Authors: Elliott Aaron M. , Al-Hajj Muhammad A.
Published: January 2009

Despite their initial effectiveness in the treatment of melanoma, chemotherapeutic agents are ultimately futile against this most aggressive form of skin cancer, and patients inevitably succumb to the disease. One of the mechanisms by which residual melanoma cells become chemoresistant is via the decreased efficiency of chemotherapeutics through the action of ATP-binding cassette (ABC) proteins that are variably expressed by the tumor cells. The clinical relevance of the ABC transporters in the context of cancer is paramount. Inhibitors of these transporters have been shown to increase the efficacy of standard therapy in experimental systems. Their clinical application requires better understanding of the role individual transporters play in the mechanism and the development of more specific inhibitors with minimal off target effects. ABC transporters in tumor cells have been shown to confer multidrug resistance in many solid tumors. However, their role in melanomas is far from clear. Here, we prospectively identify ABCB8 as a specific and major player in the chemoresistance of several melanoma cell lines. ABCB8 knockdown with shRNA reduced doxorubicin resistance ∼3- to 4-fold in these cells. Furthermore, we show that this reversal is specific to doxorubicin and not to other commonly used chemotherapeutics. Our results also provide evidence that ABCB8 conferred resistance through the protection of mitochondrial DNA from doxorubicin-induced DNA damage. (Mol Cancer Res 2009;7(1):79–87)
Establishment of a Dog Model for the p53 Family Pathway and Identification of a Novel Isoform of p21 Cyclin-Dependent Kinase Inhibitor
Authors: Zhang Jin , Chen Xiangling , Kent Michael S. , Rodriguez Carlos O. , Chen Xinbin
Published: January 2009

Spontaneous tumors in the dog offer a unique opportunity as models to study human cancer etiology and therapy. p53, the most commonly mutated gene in human cancers, is found to be altered in dog cancers. However, little is known about the role of p53 in dog tumorigenesis. Here, we found that on exposure to DNA damage agents or MDM2 inhibitor nutlin-3, canine p53 is accumulated and capable of inducing its target genes, MDM2 and p21. We also found that on DNA damage, canine p53 is accumulated in the nucleus, followed by MDM2 nuclear translocation and increased 53BP1 foci formation. In addition, we found that canine p63 and p73 are up-regulated by DNA damage agents. Furthermore, colony formation assay showed that canine tumor cells are sensitive to DNA damage agents and nutlin-3 in a p53-dependent manner. Surprisingly, canine p21 is expressed as two isoforms. Thus, we generated multiple canine p21 mutants and found that amino acids 129 to 142 are required, whereas amino acid 139 is one of the key determinants, for the expression of two p21 isoforms. Finally, we showed that although the full-length human p21 cDNA expresses one polypeptide, amino acid 139 seems to play a similar role as that in canine p21 for various migration patterns. Taken together, our results indicate that canine p53 family proteins have biological activities similar to human counterparts. These similarities make the dog an excellent outbred spontaneous tumor model, and the dog can serve as a translation model from benchtop to cage side and then to bedside. (Mol Cancer Res 2009;7(1):67–78)
Fish Oil Inhibits Human Lung Carcinoma Cell Growth by Suppressing Integrin-Linked Kinase
Authors: Han ShouWei , Sun XiaoJuan , Ritzenthaler Jeffrey D. , Roman Jesse
Published: January 2009

We previously showed that synthetic peroxisome proliferator-activated receptor γ (PPARγ) ligands inhibit non–small cell lung carcinoma (NSCLC) cell growth through multiple signaling pathways. Here, we show that dietary compounds, such as fish oil (which contains certain kinds of fatty acids like ω3 and ω6 polyunsaturated fatty acids), also inhibit NSCLC cell growth by affecting PPARγ and by inhibiting the expression of integrin-linked kinase (ILK). Exogenous expression of ILK overcame, whereas silencing ILK enhanced the inhibitory effect of fish oil on cell growth. The inhibitor of p38 mitogen-activated protein kinase, SB239023, abrogated the inhibitory effect of fish oil on ILK expression, whereas the inhibitor of extracellular signal-regulated kinase, PD98059, had no effect. Transient transfection experiments showed that fish oil reduced ILK promoter activity, and this effect was abolished by AP-2α small interfering RNA and SB239023 and by deletion of a specific portion of the ILK gene promoter. Western blot analysis and gel mobility shift assay showed that fish oil significantly induced AP-2α protein expression and AP-2 DNA-binding activity in the ILK gene promoter and that this was dependent on PPARγ activation. Blockade of AP-2α abrogated the effect of fish oil on ILK expression and on cell growth, whereas exogenous expression of AP-2α enhanced cell growth in the setting of fish oil exposure. Taken together, these findings show that fish oil inhibits ILK expression through activation of PPARγ-mediated and p38 mitogen-activated protein kinase–mediated induction of AP-2α. In turn, this leads to inhibition of NSCLC cell proliferation. This study unveils a novel mechanism by which fish oil inhibits human lung cancer cell growth. (Mol Cancer Res 2009;7(1):108–17)
Targeting Mdm2 and Mdmx in Cancer Therapy: Better Living through Medicinal Chemistry?
Authors: Wade Mark , Wahl Geoffrey M.
Published: January 2009

Genomic and proteomic profiling of human tumor samples and tumor-derived cell lines are essential for the realization of personalized therapy in oncology. Identification of the changes required for tumor initiation or maintenance will likely provide new targets for small-molecule and biological therapeutics. For example, inactivation of the p53 tumor suppressor pathway occurs in most human cancers. Although this can be due to frank p53 gene mutation, almost half of all cancers retain the wild-type p53 allele, indicating that the pathway is disabled by other means. Alternate mechanisms include deletion or epigenetic inactivation of the p53-positive regulator arf, methylation of the p53 promoter, or elevated expression of the p53 regulators Mdm2 and Mdmx. This review discusses current models of p53 regulation by Mdm2 and Mdmx and presents the rationale for design of future Mdmx-specific therapeutics based on our knowledge of its structure and biological functions. (Mol Cancer Res 2009;7(1):1–11)
The Impact of Spatial Imbalance and Socioeconomic Characteristics on Average Distance Commuted in the Sydney Metropolitan Area
Authors: Watts Martin John
Published: January 2009

There is no consensus on the relationship between urban form and commuting behaviour in the international literature. However, there has been limited Australian research on commuting patterns. In this paper, an integrated spatial econometric model which utilises a number of proxies for urban form is employed to analyse the determinants of average commuting distance by occupation across Statistical Local Areas in the Sydney metropolitan area of New South Wales. It is found that, in contrast to a number of US studies, the jobs to residents ratio is an inadequate proxy for urban form and that both the minimum commute and measures of job proximity have superior explanatory power in concert with a range of socioeconomic variables, including occupational prestige, educational attainment and weekly hours of work.
Cities, Climate Change and Urban Heat Island Mitigation: Localising Global Environmental Science
Authors: Corburn Jason
Published: January 2009

This paper explores how city planners engaged with global climate scientists to devise contextually relevant strategies to address the urban heat island effect—a potentially dangerous heat event expected to increase along with global warming. Drawing original data from the New York City Regional Heat Island Initiative, a collaborative effort between scientists and urban planners, the paper highlights how global climate science is `localised' as researchers and policy-makers struggle to make technically legitimate and politically accountable decisions. The paper argues that the localisation of global science often involves a process of co-production, where technical issues are not divorced from their social setting and a diverse set of stakeholders engage in analytical reviews and the crafting of policy solutions. The paper argues that the co-production framework can contribute to more scientifically legitimate and publicly accountable decision-making related to urban climate change.
Age-Related Changes in Acute and Phase-Advancing Responses to Monochromatic Light
Authors: Sletten Tracey L. , Revell Victoria L. , Middleton Benita , Lederle Katharina A. , Skene Debra J.
Published: January 2009

Reduced sensitivity to short-wavelength (blue) light with age has been shown for light-induced melatonin suppression. The current research aimed to determine if a similar age-related reduction occurs in subjective alertness, mood, and circadian phase-advancing responses. Young ( n = 11, 23.0 ± 2.9 years) and older ( n = 15, 65.8 ± 5.0 years) healthy males participated in laboratory sessions that included a 2-h intermittent monochromatic light exposure, individually timed to begin 8.5 h after their dim light melatonin onset (DLMO) determined in a prior visit. In separate sessions, pupil-dilated subjects were exposed to short-wavelength blue (λ max 456 nm) and medium-wavelength green (λmax 548 nm) light matched for photon density (6 × 1013 photons/cm2/sec). Subjective alertness, sleepiness, and mood were verbally assessed every 15 to 30 min before, during, and up to 5 h after the light exposure. The magnitude of phase advance was assessed as the difference in plasma melatonin rhythm phase markers before and after light exposure. Following blue light exposure, responses in older men were significantly diminished compared with young men for subjective alertness ( p < 0.0001), sleepiness ( p < 0.0001), and mood ( p < 0.05) during and after light exposure. There was no significant effect of age on these parameters following green light exposure. The phase advances to both blue and green light were larger in the young than older subjects, but did not reach statistical significance. In general, phase advances to blue light were slightly larger than to green light in both young and old, but did not reach statistical significance. The current results add to previous findings demonstrating reduced responsiveness to the acute effects of blue light in older people (melatonin suppression, alertness). However, under the study paradigm, the phase-advancing response to light does not appear to be significantly impaired with age.
The Dynamics of Contracts and Generalized Trustworthiness
Authors: Simpson Brent , Eriksson Kimmo
Published: January 2009

Generalized trust, or trust in strangers, has been traced to a wide range of societal benefits. But generalized trust is not sustainable in the absence of widespread generalized trustworthiness, that is, the tendency for strangers to honor trust extended to them. While there has been much work on the origins and consequences of generalized trust, surprisingly little research has addressed the antecedents of generalized trustworthiness. We argue that generalized trustworthiness is negatively affected by prior exposure to a ubiquitous extrinsic motivator of trustworthy behavior, contracts. Specifically, drawing on classic social psychological research on the overjustification effect, we argue that actors previously constrained by contracts will attribute their own `trustworthy' behavior in those interactions to the contract itself. According to overjustification arguments, this misattribution should lead to a decrease in intrinsic motivations to act trust-worthily in interactions where the actor is not constrained by the contract. Results of a new experiment support this argument.
Power Relations in Qualitative Research
Authors: Karnieli-Miller Orit , Strier Roni , Pessach Liat
Published: January 2009

This article focuses on the tensions between the commitment to power redistribution of the qualitative paradigm and the ethical and methodological complexity inherent in clinical research. Qualitative inquiry, in general, though there are significant variations between its different paradigms and traditions, proposes to reduce power differences and encourages disclosure and authenticity between researchers and participants. It clearly departs from the traditional conception of quantitative research, whereby the researcher is the ultimate source of authority and promotes the participants' equal participation in the research process. But it is precisely this admirable desire to democratize the research process, and the tendency to question traditional role boundaries, that raises multiple ethical dilemmas and serious methodological challenges. In this article, we offer a conceptual frame for addressing questions of power distribution in qualitative research through a developmental analysis of power relations across the different stages of the research process. We discuss ethical and methodological issues.
Natural Orifice Translumenal Thoracoscopic Surgery
Authors: Clark James , Sodergren Mikael , Correia-Pinto Jorge , Zacharakis Emmanouil , Teare Julian , Yang Guang-Zhong , Darzi Ara , Athanasiou Thanos
Published: January 2009

Context. Natural orifice translumenal endoscopic surgery (NOTES) is an emerging new technique but with much of the focus for the clinical applications of this technique centered on the abdomen. Concequently, its adaptation to the chest has been overlooked. The evidence for safe access, periprocedural complications and potential thoracic applications needs to be evaluated. Objective. This study systematically reviews the evidence for the feasibility and potential clinical applications of natural orifice translumenal thoracoscopic surgery. Data sources. MEDLINE and the Cochrane central database of controlled trials, from the earliest available date to July 2008. Study selection and data extraction. All studies evaluating the use of NOTES involving the thoracic cavity or structures therein were identified. The minimum inclusion criterion for each study was the extraction of discernible trial data. No restrictions were placed on language. Results. The literature search identified 197 citations. Review of abstracts led to 10 full-text articles for assessment; 7 articles were considered for this review, reporting on a total of 37 cases. All cases used the porcine model in both survival (7 to 42 days; mean 16; n = 5) and nonsurvival studies (n = 2). Mortality was 5% (n = 2) and morbidity 19% (n = 7); histopathological leak was detected on autopsy in 1 case. Conclusion. No human trials have currently been performed using NOTES within the thoracic cavity. There is a wide diversity of clinical applications from which cardiothoracic surgery could potentially benefit. There is a great deal of technical improvement that is still required before the technique is viable as an alternative surgical approach in humans.
Advances in the prevention of sudden cardiac death in the young
Authors: Shephard Rhian , Semsarian Christopher
Published: January 2009

Sudden cardiac death (SCD) is a tragic and devastating complication of a number of cardiovascular diseases. Although coronary artery disease accounts for a majority of these deaths across all ages, many other aetiologies contribute to this problem when it occurs in the young (age ≤ 35 years), where coronary artery disease is far less common. Specifically, genetic heart disorders are an important cause of SCD in the young. While pharmacological therapies have made some impact on prevention of SCD, the introduction of implantable cardioverter-defibrillator (ICD) therapy has been the single major advance in the prevention of SCD in the young. In addition, the awareness that most causes of SCD in the young are inherited, means family screening of relatives of young SCD victims allows identification of previously unrecognised at-risk individuals thereby enabling prevention of SCD in relatives. The role of genetic testing, both in living affected individuals and in the setting of a `molecular autopsy', is emerging as a key factor in early diagnosis of an underlying cardiovascular genetic disorder. Understanding the genetic basis of SCD, investigating the molecular mechanisms that lead from the gene defect to the clinical phenotype, and elucidating the specific environmental triggers for SCD, will most likely lead to further key improvements in the prevention of SCD in the young.
Evaluation of Lipid Profiles and the Use of Omega-3 Essential Fatty Acid in Professional Football Players
Authors: Yates Anthony , Norwig John , Maroon Joseph C. , Bost Jeffrey , Bradley James P. , Duca Mark , Wecht Daniel A. , Grove Ryan , Iso Ariko , Cobb Ingrid , Ross Nathan , Borden Meghan
Published: January 2009

Background:

Recent research showed 82% of 233 retired National Football League players under age 50 had abnormal narrowing and blockages in arteries compared to the general population of the same age. It has been suggested that early screening and intervention in this at-risk population be a priority.

Hypothesis:

Omega-3 essential fatty acid has been shown to improve cardiovascular lipid risk factors and should improve lipid profiles in professional football players to help reduce their recently shown accelerated risk of developing cardiovascular disease.

Methods:

A total of 36 active national football players were randomly assigned to 2 groups: the first group (n = 20) was provided fish oil capsules (2200 mg of mixed docosahexaenoic acid and eicosapentaenoic acid and 360 mg of other omega-3s), and the second group (n = 16) served as controls during a 60-day trial. Vertical Auto Profile cholesterol tests directly measuring serum low-density lipoprotein, high-density lipoprotein, and other subfractions were performed. Compliance, side effects, and seafood consumption data were also collected. Baseline, midpoint, and poststudy blood work measured plasma docosahexaenoic acid and eicosapentaenoic acid.

Results:

Treatment increased high-density lipoprotein (average percent change: +25.96, control +14.16), decreased triglycerides treatment (–8.06, control +43.98), very low-density lipoprotein treatment (–13.98, control +23.18), intermediate density lipoprotein (–27.58, control +12.07), remnant lipoproteins (–23.86, control +8.33), and very low-density lipoprotein-3 (–17.10, control +7.77). An average increase of 106.67% for docosahexaenoic acid and 365.82% for eicosapentaenoic acid compared to control was also shown.

Conclusion:

Omega-3 supplementation significantly improved the lipid profile of active players randomized to treatment. These results suggest that fish oil supplementation is an effective way to increase eicosapentaenoic acid and docosahexaenoic acid levels in plasma and should be considered as a method to improve modifiable cardiovascular risk lipid factors in professional football players.

Clinical Relevance:

A prospective study examining the effects of 60 days of a highly purified fish oil supplementation in professional football players.
Enhanced activation of STAT pathways and overexpression of survivin confer resistance to FLT3 inhibitors and could be therapeutic targets in AML
Authors: Zhou Jianbiao , Bi Chonglei , Janakakumara Jasinghe V. , Liu Shaw-Cheng , Chng Wee-Joo , Tay Kian-Ghee , Poon Lai-Fong , Xie Zhigang , Palaniyandi Senthilnathan , Yu Hanry , Glaser Keith B. , Albert Daniel H. , Davidsen Steven K. , Chen Chien-Shing
Published: January 2009

To further investigate potential mechanisms of resistance to FLT3 inhibitors, we developed a resistant cell line by long-term culture of MV4-11 cells with ABT-869, designated as MV4-11-R. Gene profiling reveals up-regulation of FLT3LG (FLT3 ligand) and BIRC5 (survivin), but down-regulation of SOCS1, SOCS2, and SOCS3 in MV4-11-R cells. Hypermethylation of these SOCS genes leads to their transcriptional silencing. Survivin is directly regulated by STAT3. Stimulation of the parental MV4-11 cells with FLT3 ligand increases the expression of survivin and phosphorylated protein STAT1, STAT3, STAT5. Targeting survivin by short-hairpin RNA (shRNA) in MV4-11-R cells induces apoptosis and augments ABT-869–mediated cytotoxicity. Overexpression of survivin protects MV4-11 from apoptosis. Subtoxic dose of indirubin derivative (IDR) E804 resensitizes MV4-11-R to ABT-869 treatment by inhibiting STAT signaling activity and abolishing survivin expression. Combining IDR E804 with ABT-869 shows potent in vivo efficacy in the MV4-11-R xenograft model. Taken together, these results demonstrate that enhanced activation of STAT pathways and overexpression of survivin are important mechanisms of resistance to ABT-869, suggesting that the STAT pathways and survivin could be potential targets for reducing resistance developed in patients receiving FLT3 inhibitors.
Plasmacytoid dendritic cells prime alloreactive T cells to mediate graft-versus-host disease as antigen-presenting cells
Authors: Koyama Motoko , Hashimoto Daigo , Aoyama Kazutoshi , Matsuoka Ken-ichi , Karube Kennosuke , Niiro Hiroaki , Harada Mine , Tanimoto Mitsune , Akashi Koichi , Teshima Takanori
Published: January 2009

Dendritic cells (DCs) can be classified into 2 distinct subsets: conventional DCs (cDCs) and plasmacytoid DCs (pDCs). cDCs can prime antigen-specific T-cell immunity, whereas in vivo function of pDCs as antigen-presenting cells remains controversial. We evaluated the contribution of pDCs to allogeneic T-cell responses in vivo in mouse models of graft-versus-host disease (GVHD) after allogeneic hematopoietic stem cell transplantation by an add-back study of MHC-expressing pDCs into major histocompatibility complex-deficient mice that were resistant to GVHD. Alloantigen expression on pDCs alone was sufficient to prime alloreactive T cells and cause GVHD. An inflammatory environment created by host irradiation has the decisive role in maturing pDCs for T-cell priming but this process does not require Toll-like receptor signaling. Thus, functional outcomes of pDC–T-cell interactions depend on the immunologic context of encounter. To our knowledge, these results are the first to directly demonstrate an in vivo pathogenic role of pDCs as antigen-presenting cells in an antigen-specific T cell–mediated disease in the absence of other DC subsets and to provide important insight into developing strategies for tolerance induction in transplantation.