bluuebunny/crossref_metadata_2025 huggingface dataset:
EXPERIMENTAL STUDIES OF ANTIKAON MEDIATED BOUND NUCLEAR SYSTEMS
Authors: KIENLE PAUL
Published: May 2007

Recent experimental studies of the synthesis and properties of deeply bound antikaon mediated nuclear systems are reviewed. Following a brief introduction in the basic properties of the antikaon–nucleon interaction which may lead to cold and dense antikaonic nuclear systems, we review the results of very first experiments which give indications of the existence of such exotic clusters of matter. Then ongoing efforts to substantiate the early findings are presented and future experimental approaches which will allow a very detailed study of the decay modes, the sizes and density distributions of these kaonic nuclear clusters are discussed including their relevance for possible phase transitions in cold dense matter.
CHARMONIUM AND EXOTIC HADRONS AT PANDA
Authors: PETERS K.
Published: May 2007

Recently GSI presented the plans for a major new international research facility, called FAIR. A key feature of this new facility will be the delivery of intense, high-quality secondary beams which embody the production of antiprotons. For the antiproton beams a High Energy Storage Ring (HESR) is comprised. The design luminosity is 2·1032 cm -2 s -1. Experiments will take place at an internal target. The rich spectroscopy program on exotic hadrons with antiproton beams is presented.
SPATIAL ORIENTATION BY QUANTUM TELEPATHY
Authors: BOVINO F. A. , GIARDINA M. , SVOZIL K. , VEDRAL V.
Published: May 2007

We implemented the protocol of entanglement assisted orientation in the space proposed by Brukner et al. (quant-ph/0509123). We used min-max principle to evaluate the optimal entangled state and the optimal direction of polarization measurements which violate the classical bound.
CHARACTERIZING AND MEASURING MULTIPARTITE ENTANGLEMENT
Authors: FACCHI P. , FLORIO G. , PASCAZIO S.
Published: May 2007

A method is proposed to characterize and quantify multipartite entanglement in terms of the probability density function of bipartite entanglement over all possible balanced bipartitions of an ensemble of qubits. The method is tested on a class of random pure states.
SENSITIVITY OF HILBERT AND BURES DISTANCES TO QUBIT PERTURBATIONS
Authors: SALVINI SIMONA , OLIVARES STEFANO , PARIS MATTEO G. A.
Published: May 2007

We compare the sensitivity of Hilbert and Bures distances between two qubits in revealing small perturbations occurring to one of the qubits. We also analyze sensitivity in revealing perturbations to noise parameter of a depolarizing channel.
ON THE PRACTICALITY OF ADIABATIC QUANTUM COMPUTING WITH OPTICAL SCHEMES
Authors: GOSWAMI DEBABRATA
Published: May 2007

A robust implementation of quantum logical gates for a multilevel system is possible through decoherence control under the quantum adiabatic method using simple phase modulated laser pulses. Selective population inversion and Hamiltonian evolution with time through ultrafast pulse shaping techniques essentially amount to adiabatic quantum computing (AQC) instead of the standard unitary transformation. An important aspect of the AQC model is in addressing the atomic or molecular ensemble and hence in robust implementation. We argue that experimental demonstrations of selective population transfer through adiabatic rapid passage form useful adiabatic quantum computing logic. Similarly, a simple Hadamard operation can be demonstrated with phase-modulated laser pulses. Finally, we present a framework to efficiently solve approximate Euclidean Traveling Salesman Problem (Approx-TSP) with bounded error in the AQC model. We present an efficient and intuitive encoding for Approx-TSP in a quantum computing paradigm. Optical approaches to quantum computing have the potential to be used in a distributive sense to defray the present caveat of limited resources and scalability. We present how we make use of such schemes towards practicality issues in AQC. As far as we know, our results are the first realistic demonstration of the possibility of using ensemble states for AQC in multilevel systems.
WELL-BEHAVED NONLINEAR EVOLUTION EQUATION FOR STEEPEST-ENTROPY-ASCENT DISSIPATIVE QUANTUM DYNAMICS
Authors: BERETTA GIAN PAOLO
Published: May 2007

In this paper, we outline the main features of the nonlinear quantum evolution equation proposed by the present author. Such an equation may be used as a model of reduced subsystem dynamics to complement various historical and contemporary efforts to extend linear Markovian theories of dissipative phenomena and relaxation based on master equations, Lindblad and Langevin equations, to the nonlinear and far nonequilibrium domain. It may also be used as the fundamental dynamical principle in theories that attempt to unite mechanics and thermodynamics, such as the Hatsopoulos–Gyftopoulos unified theory which motivated the original development of this well-behaved general nonlinear equation for the evolution of the density operator capable of generating irreversible deterministic relaxation to thermodynamic equilibrium from any far nonequilibrium state even for an isolated system.
RECENT EXPERIMENTS PERFORMED AT "CARLO NOVERO" LAB AT INRIM ON QUANTUM INFORMATION AND FOUNDATIONS OF QUANTUM MECHANICS
Authors: BRIDA G. , ANTONIETTI N. , GRAMEGNA M. , KRIVITSKY L. , PIACENTINI F. , RASTELLO M. L. , BERCHERA I. RUO , TRAINA P. , GENOVESE M. , PREDAZZI E.
Published: May 2007

In this paper we present some recent work performed at "Carlo Novero" lab on quantum information and foundations of quantum mechanics.
RESTRICTIONS ON INFORMATION TRANSFER IN QUANTUM MEASUREMENTS
Authors: MAYBUROV S.
Published: May 2007

Information-theoretical restrictions on the information transfer in quantum measurements are studied for practical systems. For the measurement of quantum system S by information system O such restrictions are described by a formalism of inference maps in Hilbert space, the resulting O restricted states ξO calculated from the agreement with Schrödinger S, O dynamics. It is shown that the principal S information losses stipulate the stochasticity of measurement outcomes; consequently ξO describes the random "pointer" outcomes qj observed by O in the individual events.
NONTRIVIAL PHOTON STATISTICS WITH LOW RESOLUTION-THRESHOLD PHOTON COUNTERS
Authors: ZAMBRA GUIDO , ALLEVI ALESSIA , ANDREONI ALESSANDRA , BONDANI MARIA , PARIS MATTEO G. A.
Published: May 2007

We address the reconstruction of photon statistics using realistic photodetectors having low quantum efficiency and finite resolution as photon counters. Using a maximum-likelihood method, based on measurements taken at different quantum efficiencies, we experimentally reconstruct the nontrivial photon statistics of the state obtained by mixing at a beam-splitter two phase-averaged coherent states. The effect of using different resolution thresholds is also discussed.
LOCAL ANALYSIS BY WAVELETS VERSUS NONLOCAL FOURIER ANALYSIS
Authors: CROCA J. R.
Published: May 2007

Orthodox quantum mechanics has another implicit postulate stating that temporal and spatial frequencies of the Planck–Einstein and de Broglie formulas can only be linked with the infinite, in time and space, harmonic plane waves of Fourier analysis. From this assumption, nonlocality either in space and time follows directly. This is what is called Fourier Ontology. In order to build nonlinear causal and local quantum physics, it is necessary to reject Fourier ontology and accept that in certain cases a finite wave may have a well defined frequency. Now the mathematical tool to describe this new approach is wavelet local analysis. This more general nonlinear local and causal quantum physics, in the limit of the linear approximation, contains formally orthodox quantum mechanics as a particular case.
Undernutrition enhances alcohol-induced hepatocyte proliferation in the liver of rats fed via total enteral nutrition
Authors: Baumgardner January N. , Shankar Kartik , Korourian Sohelia , Badger Thomas M. , Ronis Martin J. J.
Published: May 2007

To assess the relative contributions of undernutrition and ethanol (EtOH) exposure to alcohol-induced hepatotoxicity, female Sprague-Dawley rats were intragastrically infused liquid diets containing 187 or 154 kcal·kg−3/4·day−1 with or without 11 g·kg−1·day−1 EtOH. EtOH clearance was impaired in the 154 kcal·kg−3/4·day−1 EtOH group ( P ≤ 0.05). A combination of undernutrition and EtOH also increased the induction of hepatic cytochrome P-450 (CYP)2E1 and CYP4A1 mRNA, apoprotein, and activities ( P ≤ 0.05). This was accompanied by increased oxidative stress ( P ≤ 0.05). The severity of liver steatosis, macrophage infiltration, and focal necrosis was comparable in both EtOH groups. Alanine aminotransferase levels were elevated ( P ≤ 0.05) but did not significantly differ between the two EtOH groups. TUNEL analysis also demonstrated a comparable increase in apoptosis in the two EtOH groups ( P ≤ 0.05). The development of alcohol-induced liver pathology was accompanied by little change in fatty acid (FA) synthesis or degradation at 187 kcal·kg−3/4·day−1 but at 154 kcal·kg−3/4·day−1 was accompanied by decreased expression of FA synthesis genes and increased expression of peroxisome proliferator-activated receptor-α (PPAR-α)-regulated FA degradation pathways ( P ≤ 0.05). In addition, 154 kcal·kg−3/4·day−1 EtOH group livers exhibited greater hepatocyte proliferation ( P ≤ 0.05). We conclude that undernutrition does not exacerbate alcoholic steatohepatitis despite additional oxidative stress produced by an increased induction of CYP2E1 and CYP4A1. However, enhanced ethanol-induced cellular proliferation, perhaps as a result of enhanced PPAR-α signaling, may contribute to an increased risk of hepatocellular carcinoma in undernourished alcoholics.
Neonatal maternal separation of rat pups results in abnormal cholinergic regulation of epithelial permeability
Authors: Gareau Mélanie G. , Jury Jennifer , Perdue Mary H.
Published: May 2007

Neonatal maternal separation (MS) predisposes adult rats to develop stress-induced mucosal barrier dysfunction/visceral hypersensitivity and rat pups to develop colonic epithelial dysfunction. Our aim was to examine if enhanced epithelial permeability in such pups resulted from abnormal regulation by enteric nerves. Pups were separated from the dam for 3 h/day ( days 4– 20); nonseparated (NS) pups served as controls. On day 20, colonic tissues were removed and mounted in Ussing chambers. Horseradish peroxidase (HRP) flux was used to measure macromolecular permeability. HRP flux was increased in MS versus NS pups. The enhanced flux was inhibited by the cholinergic muscarinic antagonist atropine and the nicotinic antagonist hexamethonium. The cholinergic component was greater in tissues from MS versus NS pups, suggesting that increased cholinergic activity was responsible for the MS elevated permeability. Western blots and immunohistochemistry of colonic tissues demonstrated increased expression of choline acetyltransferase (ChAT) in MS pups, indicating greater synthesis of acetylcholine. Since a previous study indicated that corticotrophin-releasing factor (CRF) mediates barrier dysfunction in MS pups, we examined if the two pathways were linked. In MS tissues, nonselective CRF receptor antagonism inhibited the enhanced flux, and the addition of atropine did not produce further inhibition. Using selective receptor antagonists, we identified that CRF receptor 2 was involved in mediating this effect. These findings suggest that CRF, via CRF receptor 2, acts on cholinergic nerves to induce epithelial barrier dysfunction. Our study provides evidence that MS stimulates synthesis of acetylcholine, which, together with released CRF, creates a condition conducive to the development of epithelial barrier defects.
Raising end-expiratory volume relieves air hunger in mechanically ventilated healthy adults
Authors: Vovk A. , Binks A. P.
Published: May 2007

Air hunger is an unpleasant urge to breathe and a distressing respiratory symptom of cardiopulmonary patients. An increase in tidal volume relieves air hunger, possibly by increasing pulmonary stretch receptor cycle amplitude. The purpose of this study was to determine whether increasing end-expiratory volume (EEV) also relieves air hunger. Six healthy volunteers (3 women, 31 ± 4 yr old) were mechanically ventilated via a mouthpiece (12 breaths/min, constant end-tidal Pco2) at high minute ventilation (V̇e; 12 ± 2 l/min, control) and low V̇e (6 ± 1 l/min, air hunger). EEV was raised to ∼150, 400, 725, and 1,000 ml by increasing positive end-expiratory pressure (PEEP) to 2, 4, 6, and 8 cmH2O, respectively, for 1 min during high and low V̇e. The protocol was repeated with the subjects in the seated and supine positions to test for the effect of shifting baseline EEV. Air hunger intensity was rated at the end of each breath on a visual analog scale. The increase in EEV was the same in the seated and supine positions; however, air hunger was reduced to a greater extent in the seated position (13, 30, 31, and 44% seated vs. 3, 9, 23, and 27% supine at 2, 4, 6, and 8 cmH2O PEEP, respectively, P < 0.05). Removing PEEP produced a slight increase in air hunger that was greater than pre-PEEP levels ( P < 0.05). Air hunger is relieved by increases in EEV and tidal volume (presumably via an increase in mean pulmonary stretch receptor activity and cycle amplitude, respectively).
Systemic hypoxia causes cutaneous vasodilation in healthy humans
Authors: Simmons Grant H. , Minson Christopher T. , Cracowski Jean-Luc , Halliwill John R.
Published: May 2007

Hypoxia and hypercapnia represent special challenges to homeostasis because of their effects on sympathetic outflow and vascular smooth muscle. In the cutaneous vasculature, even small changes in perfusion can shift considerable blood volume to the periphery and thereby impact both blood pressure regulation and thermoregulation. However, little is known about the influence of hypoxia and hypercapnia on this circulation. In the present study, 35 healthy subjects were instrumented with two microdialysis fibers in the ventral forearm. Each site was continuously perfused with saline (control) or bretylium tosylate (10 mM) to prevent sympathetically mediated vasoconstriction. Skin blood flow was assessed at each site (laser-Doppler flowmetry), and cutaneous vascular conductance (CVC) was calculated as red blood cell flux/mean arterial pressure and normalized to baseline. In 13 subjects, isocapnic hypoxia (85 and 80% O2 saturation) increased CVC to 120 ± 10 and 126 ± 7% baseline in the control site (both P < 0.05) and 113 ± 3 ( P = 0.087) and 121 ± 4% baseline ( P < 0.05) in the bretylium site. Adrenergic blockade did not affect the magnitude of this response ( P > 0.05). In nine subjects, hyperpnea (matching hypoxic increases in tidal volume) caused no change in CVC in either site (both P > 0.05). In 13 subjects, hypercapnia (+5 and +9 Torr) increased CVC to 111 ± 4 and 111 ± 4% baseline, respectively, in the control site (both P < 0.05), whereas the bretylium site remained unchanged (both P > 0.05). Thus both hypoxia and hypercapnia cause modest vasodilation in nonacral skin. Adrenergic vasoconstriction of neural origin does not restrain hypoxic vasodilation, but may be important in hypercapnic vasodilation.
Motor unit composition has little effect on the short-range stiffness of feline medial gastrocnemius muscle
Authors: Cui Lei , Perreault Eric J. , Sandercock Thomas G.
Published: May 2007

Studies on skinned fibers and single motor units have indicated that slow-twitch fibers are stiffer than fast-twitch fibers. This suggests that skeletal muscles with different motor unit compositions may have different short-range stiffness (SRS) properties. Furthermore, the natural recruitment of slow before fast motor units may result in an SRS-force profile that is different from electrical stimulation. However, muscle architecture and the mechanical properties of surrounding tissues also contribute to the net SRS of a muscle, and it remains unclear how these structural features each contribute to the SRS of a muscle. In this study, the SRS-force characteristics of cat medial gastrocnemius muscle were measured during natural activation using the crossed-extension reflex, which activates slow before fast motor units, and during electrical activation, in which all motor units are activated synchronously. Short, rapid, isovelocity stretches were applied using a linear puller to measure SRS across the range of muscle forces. Data were collected from eight animals. Although there was a trend toward greater stiffness during natural activation, this trend was small and not statistically significant across the population of animals tested. A simple model, in which the slow-twitch fibers were assumed to be 30% stiffer than the fast-twitch fibers, was used to simulate the experimental results. Experimental and simulated results show that motor unit composition or firing rate has little effect on the SRS property of the cat MG muscle, suggesting that architectural features may be the primary determinant of SRS.
Attenuated Expression of Xeroderma Pigmentosum Group C Is Associated with Critical Events in Human Bladder Cancer Carcinogenesis and Progression
Authors: Chen Zhiwen , Yang Jin , Wang Gan , Song Bo , Li Jin , Xu Zhigang
Published: May 2007

Xeroderma pigmentosum group C (XPC) is an important DNA damage recognition protein that binds to damaged DNA at a very early stage during DNA repair. The XPC protein is also involved in DNA damage–induced cell cycle checkpoint regulation and apoptosis. XPC defects are associated with many types of solid tumors. The mechanism of the XPC protein in cancer progression, however, remains unclear. In this report, we showed the strong correlation between bladder cancer progression and attenuated XPC protein expression using tissues derived from patients with bladder cancer. The results obtained from our immunohistochemical studies further revealed a strong correlation of XPC deficiency, p53 mutation, and the degree of malignancy of bladder tumors. In addition, the results obtained from our studies have also shown that HT1197 bladder cancer cells, which carry a low-level XPC protein, exhibited a decreased DNA repair capability and were resistant to cisplatin treatment. When an XPC gene cDNA-expression vector was stably transfected into the HT1197 cells, however, the cisplatin treatment–induced apoptotic cell death was increased. Increased p53 and p73 responses following cisplatin treatment were also observed in HT1197 cells stably transfected with XPC cDNA. Taken together, these results suggest that XPC deficiency is an important contributing factor in bladder tumor progression and bladder cancer cell drug resistance. [Cancer Res 2007;67(10):4578–85]
Angiostatin-Like Activity of a Monoclonal Antibody to the Catalytic Subunit of F1F0 ATP Synthase
Authors: Chi Sulene L. , Wahl Miriam L. , Mowery Yvonne M. , Shan Siqing , Mukhopadhyay Somnath , Hilderbrand Susana C. , Kenan Daniel J. , Lipes Barbara D. , Johnson Carrie E. , Marusich Michael F. , Capaldi Roderick A. , Dewhirst Mark W. , Pizzo Salvatore V.
Published: May 2007

The antiangiogenic protein angiostatin inhibits ATP synthase on the endothelial cell surface, blocking cellular proliferation. To examine the specificity of this interaction, we generated monoclonal antibodies (mAb) directed against ATP synthase. mAb directed against the β-catalytic subunit of ATP synthase (MAb3D5AB1) inhibits the activity of the F1 domain of ATP synthase and recognizes the catalytic β-subunit of ATP synthase. We located the antibody recognition site of MAb3D5AB1 in domains containing the active site of the β-subunit. MAb3D5AB1 also binds to purified Escherichia coli F1 with an affinity 25-fold higher than the affinity of angiostatin for this protein. MAb3D5AB1 inhibits the hydrolytic activity of F1 ATP synthase at lower concentrations than angiostatin. Like angiostatin, MAb3D5AB1 inhibits ATP generation by ATP synthase on the endothelial cell surface in acidic conditions, the typical tumor microenvironment where cell surface ATP synthase exhibits greater activity. MAb3D5AB1 disrupts tube formation and decreases intracellular pH in endothelial cells exposed to low extracellular pH. Neither angiostatin nor MAb3D5AB1 showed an antiangiogenic effect in the corneal neovascularization assay; however, both were effective in the low-pH environment of the chicken chorioallantoic membrane assay. Thus, MAb3D5AB1 shows angiostatin-like properties superior to angiostatin and may be exploited in cancer chemotherapy. [Cancer Res 2007;67(10):4716–24]
Modulation of Intracellular Ceramide Using Polymeric Nanoparticles to Overcome Multidrug Resistance in Cancer
Authors: van Vlerken Lilian E. , Duan Zhenfeng , Seiden Michael V. , Amiji Mansoor M.
Published: May 2007

Although multidrug resistance (MDR) is known to develop through a variety of molecular mechanisms within the tumor cell, many tend to converge toward the alteration of apoptotic signaling. The enzyme glucosylceramide synthase (GCS), responsible for bioactivation of the proapoptotic mediator ceramide to a nonfunctional moiety glucosylceramide, is overexpressed in many MDR tumor types and has been implicated in cell survival in the presence of chemotherapy. The purpose of this study was to investigate the therapeutic strategy of coadministering ceramide with paclitaxel, a commonly used chemotherapeutic agent, in an attempt to restore apoptotic signaling and overcome MDR in the human ovarian cancer cell line SKOV3. Poly(ethylene oxide)-modified poly(epsilon-caprolactone) (PEO-PCL) nanoparticles were used to encapsulate and deliver the therapeutic agents for enhanced efficacy. Results show that indeed the cotherapy eradicates the complete population of MDR cancer cells when they are treated at their IC50 dose of paclitaxel. More interestingly, when the cotherapy was combined with the properties of nanoparticle drug delivery, the MDR cells can be resensitized to a dose of paclitaxel near the IC50 of non-MDR (drug sensitive) cells, indicating a 100-fold increase in chemosensitization via this approach. Molecular analysis of activity verified the hypothesis that the efficacy of this therapeutic approach is indeed due to a restoration in apoptotic signaling, although the beneficial properties of PEO-PCL nanoparticle delivery seemed to enhance the therapeutic success even further, showing the promising potential for the clinical use of this therapeutic strategy to overcome MDR. [Cancer Res 2007;67(10):4843–50]
Repression of Sestrin Family Genes Contributes to Oncogenic Ras-Induced Reactive Oxygen Species Up-regulation and Genetic Instability
Authors: Kopnin Pavel B. , Agapova Larissa S. , Kopnin Boris P. , Chumakov Peter M.
Published: May 2007

Oncogenic mutations within RAS genes and inactivation of p53 are the most common events in cancer. Earlier, we reported that activated Ras contributes to chromosome instability, especially in p53-deficient cells. Here we show that an increase in intracellular reactive oxygen species (ROS) and oxidative DNA damage represents a major mechanism of Ras-induced mutagenesis. Introduction of oncogenic H- or N-Ras caused elevated intracellular ROS, accumulation of 8-oxo-2′-deoxyguanosine, and increased number of chromosome breaks in mitotic cells, which were prevented by antioxidant N-acetyl-l-cysteine. By using Ras mutants that selectively activate either of the three major targets of Ras (Raf, RalGDS, and phosphatidylinositol-3-kinase) as well as dominant-negative Rac1 and RalA mutants and inhibitors of mitogen-activated protein kinase (MAPK)/extracellular signal–regulated kinases kinase-1 and p38 MAPKs, we have shown that several Ras effectors independently mediate ROS up-regulation. Introduction of oncogenic RAS resulted in repression of transcription from sestrin family genes SESN1 and SESN3, which encode antioxidant modulators of peroxiredoxins. Inhibition of mRNAs from these genes in control cells by RNA interference substantially increased ROS levels and mutagenesis. Ectopic expression of SESN1 and SESN3 from lentiviral constructs interfered with Ras-induced ROS increase, suggesting their important contribution to the effect. The stability of Ras-induced increase in ROS was dependent on a p53 function: in the p53-positive cells displaying activation of p53 in response to Ras, only transient (4–7 days) elevation of ROS was observed, whereas in the p53-deficient cells the up-regulation was permanent. The reversion to normal ROS levels in the Ras-expressing p53-positive cells correlated with up-regulation of p53-responsive genes, including reactivation of SESN1 gene. Thus, changes in expression of sestrins can represent an important determinant of genetic instability in neoplastic cells showing simultaneous dysfunctions of Ras and p53. [Cancer Res 2007;67(10):4671–8]
SOCS1 Silencing Enhances Antitumor Activity of Type I IFNs by Regulating Apoptosis in Neuroendocrine Tumor Cells
Authors: Zitzmann Kathrin , Brand Stephan , De Toni Enrico N. , Baehs Sebastian , Göke Burkhard , Meinecke Jennifer , Spöttl Gerald , Meyer Heinrich H.H.D. , Auernhammer Christoph J.
Published: May 2007

IFN-α is commonly used for biotherapy of neuroendocrine carcinomas. However, its antitumor efficacy is often limited due to IFN resistance. In this study, we evaluate the role of suppressor of cytokine signaling protein 1 (SOCS1) in modulating the effects of type I IFNs (IFN-α and IFN-β) in human neuroendocrine BON1 and CM tumor cells. In both cell lines, type I IFNs activated signal transducers and activators of transcription (STAT) and significantly decreased cell viability. However, the effects of IFN-β were significantly more pronounced than those of IFN-α and involved the induction of the intrinsic apoptotic pathway as shown by cleavage of caspase-8, Bid, and caspase-9. Stable overexpression of SOCS1 completely abolished the apoptotic effects of both type I IFNs. In contrast, small interfering RNA (siRNA)–mediated silencing of SOCS1 resulted in strongly enhanced type I IFN signaling as shown by increased and prolonged STAT phosphorylation and stronger induction of apoptosis. Silencing of SOCS1 was associated with down-regulation of basal Bcl-2 and Bcl-xL and up-regulation of basal Bak and Bax, suggesting that reduced SOCS1 expression might lower the threshold of susceptibility to type I IFN–mediated apoptosis by decreasing the ratio of antiapoptotic to proapoptotic molecules. In summary, our results indicate an important role of SOCS1 in IFN resistance of neuroendocrine tumor cells, mediated through negative regulation of type I IFN–induced Jak/STAT signaling. Knocking down SOCS1 by siRNA is a promising new approach to enhance the therapeutic potency of type I IFNs in neuroendocrine tumors. [Cancer Res 2007;67(10):5025–32]
Towards Clinical Application of Methylated DNA Sequences as Cancer Biomarkers: A Joint NCI's EDRN and NIST Workshop on Standards, Methods, Assays, Reagents and Tools
Authors: Kagan Jacob , Srivastava Sudhir , Barker Peter E. , Belinsky Steven A. , Cairns Paul
Published: May 2007

The workshop report, entitled Towards Clinical Application of Methylated DNA Sequences as Cancer Biomarkers: A Joint National Cancer Institute's Early Detection Research Network and National Institute of Standards and Technology Workshop, presents a summary of the main issues, current challenges, outcomes, and recommendations toward application of methylated DNA sequences as cancer biomarkers. [Cancer Res 2007;67(10):4545–9]
Scavenger Receptor-A Negatively Regulates Antitumor Immunity
Authors: Wang Xiang-Yang , Facciponte John , Chen Xing , Subjeck John R. , Repasky Elizabeth A.
Published: May 2007

The scavenger receptor-A (SR-A), originally recognized by its ability to internalize modified lipoproteins, has largely been studied in relation to atherosclerosis as well as innate immunity against pathogen infection. SR-A was recently shown to be a receptor on antigen-presenting cell for heat shock protein (HSP) and was implicated in the cross-presentation of HSP-chaperoned antigens. Here, we show that SR-A is not required for antitumor immunity generated by HSP-based (e.g., grp170) vaccine approaches in vivo. The lack of SR-A significantly enhances HSP- or lipopolysaccharide-mediated vaccine activities against poorly immunogenic tumors, indicating that SR-A is able to attenuate immunostimulatory effects of adjuvants or “danger” molecules. The improved antitumor response in SR-A knockout mice is correlated with an increased antigen-specific T-cell response. Moreover, SR-A–deficient dendritic cells are more responsive to inflammatory stimuli and display a more effective antigen-presenting capability compared with wild-type cells. This is the first report illustrating that SR-A negatively regulates antigen-specific antitumor immunity, which has important clinical implications in vaccine design for cancer immunotherapy. [Cancer Res 2007;67(10):4996–5002]
High-Level Expression of Chemokine CXCL16 by Tumor Cells Correlates with a Good Prognosis and Increased Tumor-Infiltrating Lymphocytes in Colorectal Cancer
Authors: Hojo Shozo , Koizumi Keiichi , Tsuneyama Koichi , Arita Yoshihisa , Cui Zhengguo , Shinohara Kanna , Minami Takayuki , Hashimoto Isaya , Nakayama Takashi , Sakurai Hiroaki , Takano Yasuo , Yoshie Osamu , Tsukada Kazuhiro , Saiki Ikuo
Published: May 2007

CXCL16 is a new member of the chemokine superfamily, which exists in a transmembrane as well as a soluble form. Its receptor CXCR6 is detected on CD4+ T cells, CD8+ T cells, and natural killer T cells. Here, we report a significant correlation of CXCL16 expression by tumor cells with the infiltration of T cells and prognosis in colorectal cancer (CRC). We first found that CXCL16 expression was consistently up-regulated more in tumor tissues than in normal mucosa derived from the same CRC patients. Four human CRC cell lines also expressed CXCL16 mRNA and secreted soluble CXCL16. We next examined the expression of CXCL16 and infiltration of lymphocytes in CRC specimens (n = 58) by immunohistochemistry. CRC patients with high levels of CXCL16 expression (n = 43) had higher levels of CD4+ and CD8+ tumor-infiltrating lymphocytes (TIL; P < 0.01) than those with low levels of CXCL16 expression (n = 15). Furthermore, the high CXCL16 expression group showed significantly better prognosis than the low CXCL16 expression group (P < 0.05). Collectively, our data suggest that the expression of CXCL16 by tumor cells enhances the recruitment of TILs, thereby bringing about a better prognosis in CRC. Thus, CXCL16 is a new prognostic biomarker and may be useful for the development of a more effective therapeutic strategy for CRC. [Cancer Res 2007;67(10):4725–31]
Extensive Methylation Is Associated with β-Catenin Mutations in Hepatocellular Carcinoma: Evidence for Two Distinct Pathways of Human Hepatocarcinogenesis
Authors: Nishida Naoshi , Nishimura Takafumi , Nagasaka Takeshi , Ikai Iwao , Ajay Goel , Boland C. Richard
Published: May 2007

Hepatocellular carcinoma (HCC) with p53 mutations is usually characterized by extensive chromosomal instability (CIN), whereas those with β-catenin mutations have relatively less CIN and the molecular pathogenesis of these tumors is unknown. Methylation of CpG dinucleotides in the promoters of cancer-related genes is another characteristic feature of HCCs. The aim of this study was to determine the contribution of the methylator phenotype to HCC and its relationship to genomic instability. Fractional allelic loss (FAL) was determined using 400 microsatellite markers in 81 HCCs and 77 corresponding noncancerous livers as a measure of CIN. Methylation of 21 genetic loci was quantitated using combined bisulfite restriction analysis. Using hierarchical clustering analysis based upon the quantification of methylation levels, all HCCs were segregated into two groups characterized by either limited or extensive methylation. Mutations in the β-catenin and p53 genes were determined by DNA sequencing. We found that the methylation levels were significantly higher in the HCCs than in noncancerous livers in 18 of the 21 loci (P values ranged from 0.035 to <0.0001). Among 18 loci, elevated levels of methylation at nine loci were significantly associated with β-catenin mutations (P values ranged from 0.02 to <0.0001). In addition, the presence of β-catenin mutations was associated with HCCs in the extensive methylation group (P < 0.0001), whereas p53 mutations correlated with high FAL scores (P = 0.0036). These data suggest that HCCs can be classified into two distinct categories based upon promoter methylation, CIN, and mutations of cancer-related genes. HCCs with extensive methylation harbor frequent β-catenin mutations, whereas HCCs with high levels of CIN are associated with p53 mutations, suggesting the presence of two independent pathways for the pathogenesis of HCC. [Cancer Res 2007;67(10):4586–94]
Functional Analysis of Human MLH1 Variants Using Yeast and In vitro Mismatch Repair Assays
Authors: Takahashi Masanobu , Shimodaira Hideki , Andreutti-Zaugg Corinne , Iggo Richard , Kolodner Richard D. , Ishioka Chikashi
Published: May 2007

The functional characterization of nonsynonymous single nucleotide polymorphisms in human mismatch repair (MMR) genes has been critical to evaluate their pathogenicity for hereditary nonpolyposis colorectal cancer. We previously established an assay for detecting loss-of-function mutations in the MLH1 gene using a dominant mutator effect of human MLH1 expressed in Saccharomyces cerevisiae. The purpose of this study is to extend the functional analyses of nonsynonymous single nucleotide polymorphisms in the MLH1 gene both in quality and in quantity, and integrate the results to evaluate the variants for pathogenic significance. The 101 MLH1 variants, which covered most of the reported MLH1 nonsynonymous single nucleotide polymorphisms and consisted of one 3-bp deletion, 1 nonsense and 99 missense variants, were examined for the dominant mutator effect by three yeast assays and for the ability of the variant to repair a heteroduplex DNA with mismatch bases by in vitro MMR assay. There was diversity in the dominant mutator effects and the in vitro MMR activities among the variants. The majority of functionally inactive variants were located around the putative ATP-binding pocket of the NH2-terminal domain or the whole region of the COOH-terminal domain. Integrated functional evaluations contribute to a better prediction of the cancer risk in individuals or families carrying MLH1 variants and provide insights into the function-structure relationships in MLH1. [Cancer Res 2007;67(10):4595–604]
Mitochondrial Genetic Background Modifies Breast Cancer Risk
Authors: Bai Ren-Kui , Leal Suzanne M. , Covarrubias Daniel , Liu Aiyi , Wong Lee-Jun C.
Published: May 2007

Inefficient mitochondrial electron transport chain (ETC) function has been implicated in the vicious cycle of reactive oxygen species (ROS) production that may predispose an individual to late onset diseases, such as diabetes, hypertension, and cancer. Mitochondrial DNA (mtDNA) variations may affect the efficiency of ETC and ROS production, thus contributing to cancer risk. To test this hypothesis, we genotyped 69 mtDNA variations in 156 unrelated European-American females with familial breast cancer and 260 age-matched European-American female controls. Fisher's exact test was done for each single-nucleotide polymorphism (SNP)/haplogroup and the P values were adjusted for multiple testing using permutation. Odds ratio (OR) and its 95% confidence interval (95% CI) were calculated using the Sheehe correction. Among the 69 variations, 29 were detected in the study subjects. Three SNPs, G9055A (OR, 3.03; 95% CI, 1.63–5.63; P = 0.0004, adjusted P = 0.0057), A10398G (OR, 1.79; 95% CI, 1.14–2.81; P = 0.01, adjusted P = 0.19), and T16519C (OR, 1.98; 95% CI, 1.25–3.12; P = 0.0030, adjusted P = 0.0366), were found to increase breast cancer risk; whereas T3197C (OR, 0.31; 95% CI, 0.13–0.75; P = 0.0043, adjusted P = 0.0526) and G13708A (OR, 0.47; 95% CI, 0.24–0.92; P = 0.022, adjusted P = 0.267) were found to decrease breast cancer risk. Overall, individuals classified as haplogroup K show a significant increase in the risk of developing breast cancer (OR, 3.03; 95% CI, 1.63–5.63; P = 0.0004, adjusted P = 0.0057), whereas individuals bearing haplogroup U have a significant decrease in breast cancer risk (OR, 0.37; 95% CI, 0.19–0.73; P = 0.0023, adjusted P = 0.03). Our results suggest that mitochondrial genetic background plays a role in modifying an individual's risk to breast cancer. [Cancer Res 2007;67(10):4687–94]
The Ability of Versican to Simultaneously Cause Apoptotic Resistance and Sensitivity
Authors: LaPierre David P. , Lee Daniel Y. , Li Sen-Zhu , Xie Yi-Zhen , Zhong Ling , Sheng Wang , Deng Zhaoqun , Yang Burton B.
Published: May 2007

Expression of the extracellular matrix proteoglycan versican is associated with more than 10 types of cancers, often being secreted by stromal cells in response to tumor signals. Previous work in our lab has shown that overexpression of the V1 versican isoform in cultured fibroblasts (V1 cells) increases both proliferation and apoptotic resistance. We show here that V1 cells induced tumor formation in nude mice and that, in keeping with previously shown apoptotic resistance, V1 cells have down-regulated Fas mRNA and protein levels. Unexpectedly, however, V1 cells were found to be sensitized to a wide range of cytotoxic agents. This combination of selective apoptotic resistance and sensitivity is often seen in cancer cells. V1 cells were also shown to have high resting levels of p53 and murine double minute-2 proteins, correlating with apoptotic sensitivity. Treatment with UV radiation induced p21 expression in vector-transfected cells but not in V1 cells. As p21 induces cell cycle arrest and inhibits apoptosis, its loss in V1 cells, coupled with high resting levels of proapoptotic p53, may be at least partially involved in their premature death following cytotoxic treatment. This study further supports the importance of versican in cancer cell biology and the complexity of apoptosis regulation. [Cancer Res 2007;67(10):4742–50]
Fundamental Differences in Cell Cycle Deregulation in Human Papillomavirus–Positive and Human Papillomavirus–Negative Head/Neck and Cervical Cancers
Authors: Pyeon Dohun , Newton Michael A. , Lambert Paul F. , den Boon Johan A. , Sengupta Srikumar , Marsit Carmen J. , Woodworth Craig D. , Connor Joseph P. , Haugen Thomas H. , Smith Elaine M. , Kelsey Karl T. , Turek Lubomir P. , Ahlquist Paul
Published: May 2007

Human papillomaviruses (HPV) are associated with nearly all cervical cancers, 20% to 30% of head and neck cancers (HNC), and other cancers. Because HNCs also arise in HPV-negative patients, this type of cancer provides unique opportunities to define similarities and differences of HPV-positive versus HPV-negative cancers arising in the same tissue. Here, we describe genome-wide expression profiling of 84 HNCs, cervical cancers, and site-matched normal epithelial samples in which we used laser capture microdissection to enrich samples for tumor-derived versus normal epithelial cells. This analysis revealed that HPV+ HNCs and cervical cancers differed in their patterns of gene expression yet shared many changes compared with HPV− HNCs. Some of these shared changes were predicted, but many others were not. Notably, HPV+ HNCs and cervical cancers were found to be up-regulated in their expression of a distinct and larger subset of cell cycle genes than that observed in HPV− HNC. Moreover, HPV+ cancers overexpressed testis-specific genes that are normally expressed only in meiotic cells. Many, although not all, of the hallmark differences between HPV+ HNC and HPV− HNC were a direct consequence of HPV and in particular the viral E6 and E7 oncogenes. This included a novel association of HPV oncogenes with testis-specific gene expression. These findings in primary human tumors provide novel biomarkers for early detection of HPV+ and HPV− cancers, and emphasize the potential value of targeting E6 and E7 function, alone or combined with radiation and/or traditional chemotherapy, in the treatment of HPV+ cancers. [Cancer Res 2007;67(10):4605–19]
HIV Protease Inhibitors Enhance the Efficacy of Irradiation
Authors: Cuneo Kyle C. , Tu Tianxiang , Geng Ling , Fu Allie , Hallahan Dennis E. , Willey Christopher D.
Published: May 2007

Tumor vascular endothelium is rather resistant to the cytotoxic effects of radiation. The HIV protease inhibitors (HPI) amprenavir, nelfinavir, and saquinavir have previously been shown to sensitize tumor cells to the cytotoxic effects of radiation. Additionally, this class of drug has been shown to inhibit angiogenesis and tumor cell migration. Therefore, in the current study, we wanted to determine whether HPIs could enhance the effect of radiation on endothelial function. Our study shows that HPIs, particularly nelfinavir, significantly enhance radiations effect on human umbilical vein endothelial cells (HUVEC) and tumor vascular endothelium. We show that pretreatment of HUVEC with nelfinavir results in enhanced cytotoxicity, including increased apoptosis, when combined with radiation. Moreover, using several functional assays, we show that combination treatment effectively blocks endothelial cell migration and organization. These findings were accompanied by attenuation of Akt phosphorylation, a known pathway for radioresistance. Last, in vivo analysis of tumor microvasculature destruction showed a more than additive effect for nelfinavir and radiation. This study shows that HPIs can enhance the effect of ionizing radiation on vascular endothelium. Therefore, the Food and Drug Administration–approved drug, nelfinavir, may be an effective radiosensitizer in the clinic. [Cancer Res 2007;67(10):4886–93]
Novel Estrogen Receptor-α Binding Sites and Estradiol Target Genes Identified by Chromatin Immunoprecipitation Cloning in Breast Cancer
Authors: Lin Zhihong , Reierstad Scott , Huang Chiang-Ching , Bulun Serdar E.
Published: May 2007

Estrogen receptor-α (ERα) and its ligand estradiol play critical roles in breast cancer growth and are important therapeutic targets for this disease. Using chromatin immunoprecipitation (ChIP)-on-chip, ligand-bound ERα was recently found to function as a master transcriptional regulator via binding to many cis-acting sites genome-wide. Here, we used an alternative technology (ChIP cloning) and identified 94 ERα target loci in breast cancer cells. The ERα-binding sites contained both classic estrogen response elements and nonclassic binding sequences, showed specific transcriptional activity in reporter gene assay, and interacted with the key transcriptional regulators, including RNA polymerase II and nuclear receptor coactivator-3. The great majority of the binding sites were located in either introns or far distant to coding regions of genes. Forty-three percent of the genes that lie within 50 kb to an ERα-binding site were regulated by estradiol. Most of these genes are novel estradiol targets encoding receptors, signaling messengers, and ion binders/transporters. mRNA profiling in estradiol-treated breast cancer cell lines and tissues revealed that these genes are highly ERα responsive both in vitro and in vivo. Among estradiol-induced genes, Wnt11 was found to increase cell survival by significantly reducing apoptosis in breast cancer cells. Taken together, we showed novel genomic binding sites of ERα that regulate a novel set of genes in response to estradiol in breast cancer. Our findings suggest that at least a subset of these genes, including Wnt11, may play important in vivo and in vitro biological roles in breast cancer. [Cancer Res 2007;67(10):5017–8]
Honokiol Induces a Necrotic Cell Death through the Mitochondrial Permeability Transition Pore
Authors: Li Ling , Han Weidong , Gu Ying , Qiu Shuang , Lu Qinghua , Jin Jie , Luo Jianhong , Hu Xun
Published: May 2007

Previous reports have shown that honokiol induces apoptosis in numerous cancer cell lines and showed preclinical efficacies against apoptosis-resistant B-cell chronic lymphocytic leukemia and multiple myeloma cells from relapse-refractory patients. Here, we show that honokiol can induce a cell death distinct from apoptosis in HL60, MCF-7, and HEK293 cell lines. The death was characterized by a rapid loss of integrity of plasma membrane without externalization of phosphatidyl serine. The broad caspase inhibitor z-VAD-fmk failed to prevent this cell death. Consistently, caspase activation and DNA laddering were not observed. The death was paralleled by a rapid loss of mitochondrial membrane potential, which was mechanistically associated with the mitochondrial permeability transition pore regulated by cyclophilin D (CypD) based on the following evidence: (a) cyclosporin A, an inhibitor of CypD (an essential component of the mitochondrial permeability transition pore), effectively prevented honokiol-induced cell death and loss of mitochondrial membrane potential; (b) inhibition of CypD by RNA interference blocked honokiol-induced cell death; (c) CypD up-regulated by honokiol was correlated with the death rates in HL60, but not in K562 cells, which underwent apoptosis after being exposed to honokiol. We further showed that honokiol induced a CypD-regulated death in primary human acute myelogenous leukemia cells, overcame Bcl-2 and Bcl-XL–mediated apoptotic resistance, and was effective against HL60 cells in a pilot in vivo study. To the best of our knowledge, this is the first report to document an induction of mitochondrial permeability transition pore–associated cell death by honokiol. [Cancer Res 2007;67(10):4894–903]
ERRγ Suppresses Cell Proliferation and Tumor Growth of Androgen-Sensitive and Androgen-Insensitive Prostate Cancer Cells and Its Implication as a Therapeutic Target for Prostate Cancer
Authors: Yu Shan , Wang Xianghong , Ng Chi-Fai , Chen Shiuan , Chan Franky L.
Published: May 2007

Estrogen receptor-related receptors (ERR) are orphan nuclear receptors, which are constitutively activated without estrogen binding. Recent evidence indicates that the ligand-independent ERRs may be involved in similar ER-mediated regulatory pathways and modulate estrogen responsiveness in certain target cells. We recently showed that an ERR subtype, ERRγ, is coexpressed with ERβ in normal human prostatic epithelial cells and exhibits reduced expression in many prostate cancer cell lines and clinical neoplastic prostate tissues. Based on this, we hypothesize that ERRγ may have growth regulatory roles in prostate and prostate cancer. We showed in this study that ERRγ was expressed in epithelial cell nuclei in fetal and pubertal human prostates, whereas its nuclear expression became reduced in advanced prostate cancer lesions. Stable ERRγ expression by retroviral transduction suppressed significantly both in vitro cell growth and in vivo tumorigenicity of two prostate cancer cell lines, LNCaP and DU145, as evidenced by a cell-cycle arrest at G1-S transition and also induction of two cyclin-dependent kinase inhibitors p21WAF1/CIP1 and p27KIP1. We further showed by reporter assay that induction of p21 and p27 by ERRγ was mediated through direct transactivation of their gene promoters. Moreover, we also showed that a selective ERRγ-agonist, DY131, could potentiate the ERRγ-induced growth inhibition in LNCaP-ERRγ and DU145-ERRγ cells in a dose-dependent manner compared with respective parental cells. Taken together, our results show that ERRγ may perform an antiproliferative or tumor-suppressing function in prostate cancer cells. More importantly, our results suggest that ERRγ could be a novel therapeutic target for prostate cancer treatment. [Cancer Res 2007;67(10):4904–14]