bluuebunny/crossref_metadata_2025 huggingface dataset:
Novel Piston Motion Opto-Mechanical Sensor for Nanoscale Motion Detection
Authors: Lim Si-Hyung “Shawn” , Horowitz Roberto , Majumdar Arun
Published: October 2008

To increase the sensitivity of a micromechanical structure to temperature (in thermal sensing) and surface stress (in biochemical sensing) change, a novel Flip-Over-Bimorph (FOB) structure has been proposed. For detecting physically induced nanoscale motion, the operation of a piston motion optomechanical sensor using the FOB design has been demonstrated. The piston motion opto-mechanical sensor has a symmetric structure such that the structural deflection is converted into a linear displacement of a reflecting surface, which is used for optical interferometry. Through the optical measurement setup using the He-Ne laser and CCD, light intensity changes for chip temperature changes are measured, and the thermo-mechanical sensitivity of the designed sensor is 180 nm/K.
Phosphorylation Networks Regulating JNK Activity in Diverse Genetic Backgrounds
Authors: Bakal Chris , Linding Rune , Llense Flora , Heffern Elleard , Martin-Blanco Enrique , Pawson Tony , Perrimon Norbert
Published: October 2008

Cellular signaling networks have evolved to enable swift and accurate responses, even in the face of genetic or environmental perturbation. Thus, genetic screens may not identify all the genes that regulate different biological processes. Moreover, although classical screening approaches have succeeded in providing parts lists of the essential components of signaling networks, they typically do not provide much insight into the hierarchical and functional relations that exist among these components. We describe a high-throughput screen in which we used RNA interference to systematically inhibit two genes simultaneously in 17,724 combinations to identify regulators of
Drosophila
JUN NH
2
-terminal kinase (JNK). Using both genetic and phosphoproteomics data, we then implemented an integrative network algorithm to construct a JNK phosphorylation network, which provides structural and mechanistic insights into the systems architecture of JNK signaling.
Remeasuring the Double Helix
Authors: Mathew-Fenn Rebecca S. , Das Rhiju , Harbury Pehr A. B.
Published: October 2008

DNA is thought to behave as a stiff elastic rod with respect to the ubiquitous mechanical deformations inherent to its biology. To test this model at short DNA lengths, we measured the mean and variance of end-to-end length for a series of DNA double helices in solution, using small-angle x-ray scattering interference between gold nanocrystal labels. In the absence of applied tension, DNA is at least one order of magnitude softer than measured by single-molecule stretching experiments. Further, the data rule out the conventional elastic rod model. The variance in end-to-end length follows a quadratic dependence on the number of base pairs rather than the expected linear dependence, indicating that DNA stretching is cooperative over more than two turns of the DNA double helix. Our observations support the idea of long-range allosteric communication through DNA structure.
From Tacoma to Thermal Diffusion
Authors: Prewitt Charles T.
Published: October 2008

Uncle Phil and the Atomic Bomb
.
By John Abelson and Philip H. Abelson
. Roberts, Greenwood Village, CO, 2007. 151 pp. $25. ISBN 9780974707778.

Pieced together by John Abelson from an unpublished autobiographical sketch by his uncle and various conversations, the book offers a first-person account of Phil Abelson's life and research
The Extreme Kuiper Belt Binary 2001 QW
322
Authors: Petit J.-M. , Kavelaars J. J. , Gladman B. J. , Margot J. L. , Nicholson P. D. , Jones R. L. , Parker J. Wm. , Ashby M. L. N. , Bagatin A. Campo , Benavidez P. , Coffey J. , Rousselot P. , Mousis O. , Taylor P. A.
Published: October 2008

The study of binary Kuiper Belt objects helps to probe the dynamic conditions present during planet formation in the solar system. We report on the mutual-orbit determination of 2001 QW
322
, a Kuiper Belt binary with a very large separation whose properties challenge binary-formation and -evolution theories. Six years of tracking indicate that the binary's mutual-orbit period is ≈25 to 30 years, that the orbit pole is retrograde and inclined 50° to 62° from the ecliptic plane, and, most surprisingly, that the mutual orbital eccentricity is <0.4. The semimajor axis of 105,000 to 135,000 kilometers is 10 times that of other near-equal-mass binaries. Because this weakly bound binary is prone to orbital disruption by interlopers, its lifetime in its present state is probably less than 1 billion years.
The Value of Women
Authors: Ash Caroline
Published: October 2008

La forêt danse
. [The Dancing Forest].
By Brice Lainé
. United Kingdom, 2008. 76 minutes. In French and Nawdem with English subtitles.

Lainé's debut film, about a grassroots agricultural project in a Togo village, offers a hopeful vision of development in Africa.
Real-Time PCR with an Internal Control for Detection of All Known Human Adenovirus Serotypes
Authors: Damen Marjolein , Minnaar René , Glasius Patricia , van der Ham Alwin , Koen Gerrit , Wertheim Pauline , Beld Marcel
Published: October 2008

The “gold standard” for the diagnosis of adenovirus (AV) infection is virus culture, which is rather time-consuming. Especially for immunocompromised patients, in whom severe infections with AV have been described, rapid diagnosis is important. Therefore, an internally controlled AV real-time PCR assay detecting all known human AV serotypes was developed. Primers were chosen from the hexon region, which is the most conserved region, and in order to cover all known serotypes, degenerate primers were used. The internal control (IC) DNA contained the same primer binding sites as the AV DNA control but had a shuffled probe region compared to the conserved 24-nucleotide consensus AV hexon probe region (the target). The IC DNA was added to the clinical sample in order to monitor extraction and PCR efficiency. The sensitivity and the linearity of the AV PCR were determined. For testing the specificity of this PCR assay for human AVs, a selection of 51 AV prototype strains and 66 patient samples positive for other DNA viruses were tested. Moreover, a comparison of the AV PCR method described herein with culture and antigen (Ag) detection was performed with a selection of 151 clinical samples. All 51 AV serotypes were detected in the selection of AV prototype strains. Concordant results from culture or Ag detection and PCR were found for 139 (92.1%) of 151 samples. In 12 cases (7.9%), PCR was positive while the culture was negative. In conclusion, a sensitive, internally controlled nonnested AV real-time PCR assay which is able to detect all known AV serotypes with higher sensitivity than a culture or Ag detection method was developed.
Performance of a Novel Human Immunodeficiency Virus (HIV) Type 1 Total Nucleic Acid-Based Real-Time PCR Assay Using Whole Blood and Dried Blood Spots for Diagnosis of HIV in Infants
Authors: Stevens Wendy , Erasmus Linda , Moloi Matsidisho , Taleng Thabo , Sarang Somaya
Published: October 2008

The new Cobas AmpliPrep/Cobas TaqMan HIV-1 Qual test offers advanced automation for the detection of human immunodeficiency virus type 1 (HIV-1) RNA and DNA in dried blood spots (DBS) and whole blood. An analytical evaluation using an HIV-1 secondary standard yielded limits of detection of 514, 710, and 1,090 HIV RNA copies/ml for EDTA plasma, whole blood, and DBS, respectively. The precision and reproducibility of HIV-1 detection was equivalent for DBS and whole blood. Inclusivity was demonstrated for a reference panel of HIV-1 subtypes A to N. A clinical evaluation of the Cobas AmpliPrep/Cobas TaqMan HIV-1 Qual test was performed at a center for routine diagnostics in Johannesburg, South Africa, using 1,013 clinical specimens from HIV-1 exposed children. The Amplicor HIV-1 DNA test v1.5 with the MagNApure DNA isolation procedure was used as the reference method. A total of 995 valid results for whole blood with both methods yielded 691 and 303 concordant negative and positive results for the Cobas AmpliPrep/Cobas TaqMan HIV-1 Qual test, respectively. For the 800 valid DBS specimen results, 495 and 300 concordant negative and positive results were obtained, respectively. The resulting clinical specificities and sensitivities of the new test were 100% and 99.7% for whole blood and DBS, respectively. The new test was characterized by its robustness, enhanced automation, and improved sample throughput. The Cobas AmpliPrep/Cobas TaqMan HIV-1 Qual test will support early, reliable diagnosis of HIV in children in routine laboratory settings.
Two Cases of Necrotizing Fasciitis Due toAcinetobacter baumannii
Authors: Charnot-Katsikas Angella , Dorafshar Amir H. , Aycock Joyce K. , David Michael Z. , Weber Stephen G. , Frank Karen M.
Published: October 2008

Necrotizing fasciitis has conventionally been associated with the streptococci, and when it is caused by other organisms, it is most often the result of a polymicrobial infection. We report on two cases of fatal monomicrobial necrotizing fasciitis due toAcinetobacter baumannii, an unusual finding that may be an indication of enhanced virulence of the organism.
Survival of
Acanthamoeba
Cysts after Desiccation for More than 20 Years
Authors: Sriram Rama , Shoff Megan , Booton Gregory , Fuerst Paul , Visvesvara Govinda S.
Published: October 2008

Acanthamoeba
is a free-living ameba that is found throughout the world and that causes encephalitis, keratitis, and cutaneous infections in humans. It has two stages in its life cycle: a trophic stage and a resistant cyst stage. We describe here the ability of
Acanthamoeba
cysts to survive desiccation for more than 20 years.
Ross River Virus Envelope Glycans Contribute to Type I Interferon Production in Myeloid Dendritic Cells
Authors: Shabman Reed S. , Rogers Kristin M. , Heise Mark T.
Published: October 2008

Alphaviruses are mosquito-transmitted viruses that cause significant human disease, and understanding how these pathogens successfully transition from the mosquito vector to the vertebrate host is an important area of research. Previous studies demonstrated that mosquito and mammalian-cell-derived alphaviruses differentially induce type I interferons (alpha/beta interferon [IFN-α/β]) in myeloid dendritic cells (mDCs), where the mosquito cell-derived virus is a poor inducer of IFN-α/β compared to the mammalian-cell-derived virus. Furthermore, the reduced IFN-α/β induction by the mosquito cell-derived virus is attributed to differential N-linked glycosylation (29). To further evaluate the role of viral envelope glycans in regulating the IFN-α/β response, studies were performed to assess whether the mosquito cell-derived virus actively inhibits IFN-α/β induction or is simply a poor inducer of IFN-α/β. Coinfection studies using mammalian- and mosquito cell-derived Ross River virus (mam-RRV and mos-RRV, respectively) indicated that mos-RRV was unable to suppress IFN-α/β induction by mam-RRV in mDC cultures. Additionally, a panel of mutant viruses lacking either individual or multiple N-linked glycosylation sites was used to demonstrate that N-linked glycans were essential for high-level IFN-α/β induction by the mammalian-cell-derived virus. These results suggest that the failure of the mosquito cell-derived virus to induce IFN-α/β is due to a lack of complex carbohydrates on the virion rather than the active suppression of the DC antiviral response.
BALB/
Mtv
-Null Mice Responding to Strong Mouse Mammary Tumor Virus Superantigens Restrict Mammary Tumorigenesis
Authors: Bhadra Sanchita , Lozano Mary M. , Dudley Jaquelin P.
Published: October 2008

The absence of endogenous mouse mammary tumor viruses (MMTVs) in the congenic mouse strain, BALB/
Mtv
-null, restricts the early steps of exogenous C3H MMTV infection, preventing the superantigen (Sag) response and mammary tumorigenesis. Here we demonstrate that BALB/
Mtv
-null mice also resist tumor induction by FM MMTV, which encodes a stronger Sag compared to C3H MMTV. In contrast to infections with C3H MMTV,
Mtv
-null mice show FM-MMTV Sag-specific responses comparable to those observed in susceptible BALB/c mice. Neither virus shows significant replication in the spleen or mammary gland. Thus,
Mtv
-null mice restrict MMTV replication and mammary tumorigenesis even after a robust Sag response.
A NEW FEATURE ON THE SUDDEN DEATH OF ENTANGLEMENT
Authors: YAN XUE-QUN
Published: October 2008

Based on the exactly analytic solution obtained of the intensity-dependent Jaynes–Cummings model for a certain class of initial entangled mixed states, we explore the time evolution of the entanglement between two atoms, initially non-locally correlated and separately interacting with two distinct cavities. The results show that entanglement sudden death is dependent on the different initial states of atoms, and the length of the time interval for the zero entanglement is invariant for a certain class of initial mixed states.
THE TEMPERATURE DEPENDENT ENTHALPY OF VAPORIZATION OF PURE SUBSTANCES
Authors: TIAN JIANXIANG
Published: October 2008

Recently the universal behavior of the temperature dependent enthalpy of vaporization along with the whole liquid–vapor coexistence curve at equilibrium is described and explained by Roman et al.5 The work (called RWVM relation) succeeds in the combination of the linear relation near the triple point and the renormalization group theory result near the critical point. For the convenience of chemical designs and engineering applications, we report its b values yielding the minimum average absolute deviation (AAD) for 74 pure substances from the NIST web-book and compare the results with other correlations. We find that with an adapted b value, the RWVM relation predicts the data of 47 pure substances with an AAD less than 0.0093, with six more than 0.02 and all less than 0.03 except quantum fluid hydrogen, that is clearly better than other correlations. For most pure substances, b covers the range from 0 to 1. Only one negative value stands for the quantum fluid helium because of its enthalpy of vaporization being experimentally not a monotonic function of the temperature in the range near the triple point.
124Te AND THE E(5) CRITICAL POINT SYMMETRY
Authors: GHIŢĂ D. G. , CĂTA-DANIL G. , BUCURESCU D. , CĂTA-DANIL I. , IVASCU M. , MIHAI C. , SULIMAN G. , STROE L. , SAVA T. , ZAMFIR N. V.
Published: October 2008

We present a new study of the low-lying states in 124 Te nucleus by γ-ray spectroscopy following 124 I β+/ε decay. The β radioactive sources were produced in the 124 Te ( p, n )124 I reaction induced by 11 MeV protons, delivered by the Bucharest FN Tandem Accelerator. The γ-rays were measured in a low background area with three large volume HPGe detectors. A total number of 276 milion double coincidence events were recorded in a six-day run. Most of the gamma line intensities previously measured were confirmed with improved accuracy and several gamma lines were obtained for the first time. Our results, combined with those from a recent ( n , γ) study are compared with the predictions of the E(5) critical point symmetry model and numerical IBA-1 model calculations at the critical point of the U(5)–O(6) phase transition.
Advanced Passenger Transport Technologies
Authors: Sperling Daniel , Gordon Deborah
Published: October 2008

Passenger transportation has evolved toward greater reliance on light-duty vehicles. The result, especially in the United States but increasingly elsewhere, is a car-centric transportation monoculture. Conventional cars provide a high level of personal freedom and convenience but are expensive, inefficient, and damaging to the global environment. This article reviews the literature and critically examines the debate about two fundamental challenges: (a) transforming vehicles to dramatically reduce oil use and greenhouse gas (GHG) emissions and (b) transforming the larger transportation system to expand personal mobility options and reduce their environmental and spatial footprints. The technologies and tools are at hand to achieve both. It will take a concerted effort from industry, government, and consumers to facilitate these transportation transformations.
Global Environmental Governance: Taking Stock, Moving Forward
Authors: Biermann Frank , Pattberg Philipp
Published: October 2008

This article provides a focused review of the current literature on global environmental governance. In the first part, we differentiate between three usages of the term “global environmental governance,” which we describe as analytical, programmatic, and critical. In the second part, we highlight three key characteristics of global environmental governance that make it different, in our view, from traditional international environmental politics: first, the emergence of new types of agency and of actors in addition to national governments, the traditional core actors in international environmental politics; second, the emergence of new mechanisms and institutions of global environmental governance that go beyond traditional forms of state-led, treaty-based regimes; and third, increasing segmentation and fragmentation of the overall governance system across levels and functional spheres. In the last section, we present an outlook on future study needs in this field.
Regulation of angiotensin II receptors and extracellular matrix turnover in human retinal pigment epithelium: role of angiotensin II
Authors: Striker Gary E. , Praddaude Francoiçe , Alcazar Oscar , Cousins Scott W. , Marin-Castaño Maria E.
Published: October 2008

The early stage of age-related macular degeneration (AMD) is characterized by the formation of subretinal pigment epithelium (RPE) deposits as a result of the dysregulation in the turnover of extracellular matrix (ECM) molecules. However, the mechanism involved remains unclear. Hypertension (HTN) is an important risk factor for AMD, and angiotensin II (ANG II) is the most important hormone associated with HTN. However, the relevance of ANG II receptors and ANG II effects on RPE have not been investigated yet. Therefore, the expression and regulation of ANG II receptors as well as the ECM turnover were studied in human RPE. ANG II receptors were expressed and upregulated by ANG II in human RPE. This regulation resulted in functional receptor expression, since an increase in intracellular concentration of calcium was observed upon ANG II stimulation. ANG II also increased matrix metalloproteinase (MMP)-2 activity and MMP-14 at the mRNA and protein levels as well as type IV collagen degradation. These ANG II effects were abolished in the presence of the ANG II receptor subtype 1 (AT1) receptor antagonist candesartan. In contrast, ANG II decreased type IV collagen via both AT1 and AT2 receptors, suggesting a synergistic effect of the two receptor subtypes. In conclusion, we have confirmed the presence of ANG II receptors in human RPE and their regulation by ANG II as well as the regulation of ECM molecules via ANG II receptors. Our data support the hypothesis that ANG II may exert biological function in RPE through ANG II receptors and that ANG II may cause dysregulation of molecules that play a major role in the turnover of ECM in RPE basement membrane and Bruch's membrane, suggesting a pathogenic mechanism to explain the link between HTN and AMD.
Contribution of actin filaments and microtubules to quasi-in situ tensile properties and internal force balance of cultured smooth muscle cells on a substrate
Authors: Nagayama Kazuaki , Matsumoto Takeo
Published: October 2008

The effects of actin filaments (AFs) and microtubules (MTs) on quasi-in situ tensile properties and intracellular force balance were studied in cultured rat aortic smooth muscle cells (SMCs). A SMC cultured on substrates was held using a pair of micropipettes, gradually detached from the substrate while maintaining in situ cell shape and cytoskeletal integrity, and then stretched up to ∼15% and unloaded three times at the rate of 1 μm every 5 s. Cell stiffness was ∼20 nN per percent strain in the untreated case and decreased by ∼65% and ∼30% following AF and MT disruption, respectively. MT augmentation did not affect cell stiffness significantly. The roles of AFs and MTs in resisting cell stretching and shortening were assessed using the area retraction of the cell upon noninvasive detachment from thermoresponsive gelatin-coated dishes. The retraction was ∼40% in untreated cells, while in AF-disrupted cells it was <20%. The retraction increased by ∼50% and decreased by ∼30% following MT disruption and augmentation, respectively, suggesting that MTs resist intercellular tension generated by AFs. Three-dimensional measurements of cell morphology using confocal microscopy revealed that the cell volume remained unchanged following drug treatment. A concomitant increase in cell height and decrease in cell area was observed following AF disruption and MT augmentation. In contrast, MT disruption significantly reduced the cell height. These results indicate that both AFs and MTs play crucial roles in maintaining whole cell mechanical properties of SMCs, and that while AFs act as an internal tension generator, MTs act as a tension reducer, and these contribute to intracellular force balance three dimensionally.
Rac1 promotes intestinal epithelial restitution by increasing Ca2+ influx through interaction with phospholipase C-γ1 after wounding
Authors: Rao Jaladanki N. , Liu Stephen V. , Zou Tongtong , Liu Lan , Xiao Lan , Zhang Xian , Bellavance Emily , Yuan Jason X.-J. , Wang Jian-Ying
Published: October 2008

Intestinal mucosal restitution occurs as a consequence of epithelial cell migration and reseals superficial wounds after injury. This rapid reepithelialization is mediated in part by a phospholipase C-γ1 (PLC-γ1)-induced Ca2+ signaling, but the exact mechanism underlying such signaling and its regulation remains elusive. The small GTP-binding protein Rac1 functions as a pivotal regulator of several signaling networks and plays an important role in regulating cell motility. The current study tests the hypothesis that Rac1 modulates intestinal epithelial cell migration after wounding by altering PLC-γ1-induced Ca2+ signaling. Inhibition of Rac1 activity by treatment with its inhibitor NSC-23766 or Rac1 silencing with small interfering RNA decreased store depletion-induced Ca2+ influx and suppressed cell migration during restitution, whereas ectopic overexpression of Rac1 increased Ca2+ influx and promoted cell migration. Rac1 physically interacted with PLC-γ1 and formed Rac1/PLC-γ1 complex in intestinal epithelial cells. PLC-γ1 silencing in cells overexpressing Rac1 prevented stimulation of store depletion-induced Ca2+ influx and cell migration after wounding. Polyamine depletion inhibited expression of both Rac1 and PLC-γ1, decreased Rac1/PLC-γ1 complex levels, reduced Ca2+ influx, and repressed cell migration. Overexpression of Rac1 alone failed to rescue Ca2+ influx after store depletion and cell migration in polyamine-deficient cells, because it did not alter PLC-γ1 levels. These results indicate that Rac1 promotes intestinal epithelial cell migration after wounding by increasing Ca2+ influx as a result of its interaction with PLC-γ1.
Purinergic activation of anion conductance and osmolyte efflux in cultured rat hippocampal neurons
Authors: Li Guangze , Olson James E.
Published: October 2008

The majority of mammalian cells demonstrate regulatory volume decrease (RVD) following swelling caused by hyposmotic exposure. A critical signal initiating RVD is activation of nucleotide receptors by ATP. Elevated extracellular ATP in response to cytotoxic cell swelling during pathological conditions also may initiate loss of taurine and other intracellular osmolytes via anion channels. This study characterizes neuronal ATP-activated anion current and explores its role in net loss of amino acid osmolytes. To isolate anion currents, we used CsCl as the major electrolyte in patch electrode and bath solutions and blocked residual cation currents with NiCl2and tetraethylammonium. Anion currents were activated by extracellular ATP with a Kmof 70 μM and increased over fourfold during several minutes of ATP exposure, reaching a maximum after 9.0 min (SD 4.2). The currents were blocked by inhibitors of nucleotide receptors and volume-regulated anion channels (VRAC). Currents showed outward rectification and inactivation at highly depolarizing membrane potentials, characteristics of swelling-activated anion currents. P2X agonists failed to activate the anion current, and an inhibitor of P2X receptors did not block the effect of ATP. Furthermore, current activation was observed with extracellular ADP and 2-(methylthio)adenosine 5′-diphosphate, a P2Y1receptor-specific agonist. Much less current activation was observed with extracellular UTP, suggesting the response is mediated predominantly by P2Y1receptors. ATP caused a dose-dependent loss of taurine and alanine that could be blocked by inhibitors of VRAC. ATP did not inhibit the taurine uptake transporter. Thus extracellular ATP triggers a loss of intracellular organic osmolytes via activation of anion channels. This mechanism may facilitate neuronal volume homeostasis during cytotoxic edema.
Breathing cardiovascular variability and baroreflex in mechanically ventilated patients
Authors: Van de Louw Andry , Médigue Claire , Papelier Yves , Cottin François
Published: October 2008

Heart rate and blood pressure variations during spontaneous ventilation are related to the negative airway pressure during inspiration. Inspiratory airway pressure is positive during mechanical ventilation, suggesting that reversal of the normal baroreflex-mediated pattern of variability may occur. We investigated heart rate and blood pressure variability and baroreflex sensitivity in 17 mechanically ventilated patients. ECG (RR intervals), invasive systolic blood pressure (SBP), and respiratory flow signals were recorded. High-frequency (HF) amplitude of RR and SBP time series and HF phase differences between RR, SBP, and ventilatory signals were continuously computed by Complex DeModulation (CDM). Cross-spectral analysis was used to assess the coherence and the gain functions between RR and SBP, yielding baroreflex sensitivity indices. The HF phase difference between SBP and ventilatory signals was nearly constant in all patients with inversion of SBP variability during the ventilator cycle compared with cycling with negative inspiratory pressure to replicate spontaneous breathing. In 12 patients ( group 1), the phase difference between RR and ventilatory signals changed over time and the HF-RR amplitude varied. In the remaining five patients ( group 2), RR-ventilatory signal phase and HF-RR amplitude showed little change; however, only one of these patients exhibited a RR-ventilatory signal phase difference mimicking the normal pattern of respiratory sinus arrhythmia. Spectral coherence between RR and SBP was lower in the group with phase difference changes. Positive pressure ventilation exerts mainly a mechanical effect on SBP, whereas its influence on HR variability seems more complex, suggesting a role for neural influences.
Potent osmoregulatory actions of homologous adrenomedullins administered peripherally and centrally in eels
Authors: Ogoshi Maho , Nobata Shigenori , Takei Yoshio
Published: October 2008

The teleost adrenomedullin (AM) family consists of three groups, AM1/AM4, AM2/AM3, and AM5. In the present study, we examined the effects of homologous AM1, AM2, and AM5 on drinking and renal function after peripheral or central administration in conscious freshwater eels. AM2 and AM5, but not AM1, exhibited dose-dependent (0.01–1 nmol/kg) dipsogenic and antidiuretic effects after intra-arterial bolus injection. The antidiuretic effect was significantly correlated with the degree of associated hypotension. To avoid the potential indirect osmoregulatory effects of AM-induced hypotension, infusion of AMs was also performed at nondepressor doses. Drinking was enhanced dose-dependently at 0.1–3 pmol·kg−1·min−1 of AM2 and AM5, matching the potency and efficacy of angiotensin II (ANG II), the most potent dipsogenic hormone known thus far. AM2 and AM5 infusion also induced mild antidiuresis, while AM1 caused antinatriuresis. Additionally, AMs were injected into the third and fourth ventricles of conscious eels to assess their site of dipsogenic action. However, none of the AMs at 0.05–0.5 nmol induced drinking, while ANG II was highly dipsogenic. AM2 and ANG II injected into the third ventricle increased arterial pressure while AM5 decreased it in a dose-dependent manner, and both AM2 and AM5 decreased blood pressure when injected into the fourth ventricle. These data suggest that circulating AM2 and AM5 act on a target site in the brain that lacks the blood-brain barrier. Collectively, the present study showed that AM2 and AM5 are potent osmoregulatory hormones in the eel, and their actions imply involvement in seawater adaptation of this euryhaline species.
Novel Photocatalytic Reactor Development for Removal of Hydrocarbons from Water
Authors: Adams Morgan , Campbell Ian , Robertson Peter K. J.
Published: October 2008

Hydrocarbons contamination of the marine environment generated by the offshore oil and gas industry is generated from a number of sources including oil contaminated drill cuttings and produced waters. The removal of hydrocarbons from both these sources is one of the most significant challenges facing this sector as it moves towards zero emissions. The application of a number of techniques which have been used to successfully destroy hydrocarbons in produced water and waste water effluents has previously been reported. This paper reports the application of semiconductor photocatalysis as a final polishing step for the removal of hydrocarbons from two waste effluent sources. Two reactor concepts were considered: a simple flat plate immobilised film unit, and a new rotating drum photocatalytic reactor. Both units proved to be effective in removing residual hydrocarbons from the effluent with the drum reactor reducing the hydrocarbon content by 90% under 10 minutes.
New Two-Photon Activated Photodynamic Therapy Sensitizers Induce Xenograft Tumor Regressions after Near-IR Laser Treatment through the Body of the Host Mouse
Authors: Starkey Jean R. , Rebane Aleksander K. , Drobizhev Mikhail A. , Meng Fanqing , Gong Aijun , Elliott Aleisha , McInnerney Kate , Spangler Charles W.
Published: October 2008

Purpose: The aim of this study was to show that novel photodynamic therapy (PDT) sensitizers can be activated by two-photon absorption in the near-IR region of the spectrum and to show, for the first time, that such activation can lead to tumor regressions at significant tissue depth. These experiments also evaluated effects of high-energy femtosecond pulsed laser irradiation on normal tissues and characterized the response of xenograft tumors to our PDT protocols.

Experimental Design: Human small cell lung cancer (NCI-H69), non-small cell lung cancer (A549), and breast cancer (MDA-MB-231) xenografts were induced in SCID mice. Irradiation of sensitized tumors was undertaken through the bodies of tumor-bearing mice to give a treatment depth of 2 cm. Posttreatment tumor regressions and histopathology were carried out to determine the nature of the response to these new PDT agents. Microarray expression profiles were conducted to assess the similarity of responses to single and two-photon activated PDT.

Results: Regressions of all tumor types tested were seen. Histopathology was consistent with known PDT effects, and no, or minimal, changes were noted in irradiated normal tissues. Cluster analysis of microarray expression profiling showed reproducible changes in transcripts associated with apoptosis, stress, oxygen transport, and gene regulation.

Conclusions: These new PDT sensitizers can be used at a depth of 2 cm to produce excellent xenograft regressions. The tumor response was consistent with known responses to single-photon activated PDT. Experiments in larger animals are warranted to determine the maximal achievable depth of treatment.
Antiapoptotic Activity of Autocrine Interleukin-22 and Therapeutic Effects of Interleukin-22-Small Interfering RNA on Human Lung Cancer Xenografts
Authors: Zhang Weici , Chen Yongyan , Wei Haiming , Zheng Chaogu , Sun Rui , Zhang Jian , Tian Zhigang
Published: October 2008

Purpose: Non–small cell lung carcinoma (NSCLC) is one of most common malignant diseases and usually is resistant against apoptosis-inducing chemotherapy. This study is to explore the antiapoptotic mechanisms of interleukin (IL)-22 in human lung cancer.

Experimental Design: Nineteen cases with stage I to III NSCLC were collected to determine the expression of IL-22. Stable transfection of human IL-22 cDNA into A549 and PG cells and transfection of IL-22-RNA interference (RNAi) into these cancer cell lines were done to reveal the molecular mechanisms of IL-22.

Results: It was found that IL-22 was highly expressed in primary tumor tissue, malignant pleural effusion, and serum of patients with NSCLC. IL-22R1 mRNA was also detected in lung cancer tissues as well as lung cancer cell lines. Overexpression of IL-22 protected lung cancer cell lines from serum starvation-induced and chemotherapeutic drug-induced apoptosis via activation of STAT3 and its downstream antiapoptotic proteins such as Bcl-2 and Bcl-xL and inactivation of extracellular signal-regulated kinase 1/2. Exposure to blocking antibodies against IL-22R1 or transfection with the IL-22-RNAi plasmid in vitro resulted in apoptosis of these lung cancer cells via STAT3 and extracellular signal-regulated kinase 1/2 pathways. Furthermore, an in vivo xenograft study showed that administration of IL-22-RNAi plasmids significantly inhibited the human tumor cell growth in BALB/c nude mice.

Conclusions: Our study indicates that autocrine production of IL-22 contributes to human lung cancer cell survival and resistance to chemotherapy through the up-regulation of antiapoptotic proteins.
Overexpression of 5-Lipoxygenase in Colon Polyps and Cancer and the Effect of 5-LOX Inhibitors In vitro and in a Murine Model
Authors: Melstrom Laleh G. , Bentrem David J. , Salabat Mohammad R. , Kennedy Timothy J. , Ding Xian-Zhong , Strouch Matthew , Rao Sambasiva M. , Witt Richard C. , Ternent Charles A. , Talamonti Mark S. , Bell Richard H. , Adrian Thomas A.
Published: October 2008

Purpose: Arachidonic acid metabolism via the cyclooxygenase (COX) and 5-lipoxygenase (5-LOX) pathways modulates cell growth and apoptosis. Many studies have examined the effects of COX inhibitors on human colorectal cancer, but the role of 5-LOX in colonic cancer development has not been well studied. The purpose of this study was to evaluate the expression of 5-LOX in colonic polyps and cancer and the effect of 5-LOX inhibition on colon cancer cell proliferation.

Experimental Design: Colonic polyps, cancer, and normal mucosa were evaluated for 5-LOX expression by immunohistochemistry. Reverse transcription-PCR was used to establish 5-LOX expression in colon cancer cells. Thymidine incorporation and cell counts were used to determine the effect of the nonspecific LOX inhibitor Nordihydroguaiaretic Acid and the 5-LOX inhibitor Rev5901 on DNA synthesis. A heterotopic xenograft model in athymic mice using HT29 and LoVo human colon cancer cells was used to evaluate the effect of the 5-LOX inhibitor zileuton on tumor growth.

Results: 5-LOX is overexpressed in adenomatous polyps and cancer compared with that of normal colonic mucosa. LOX inhibition and 5-LOX inhibition decreased DNA synthesis in a concentration- and time-dependent manner in the Lovo cell line (P < 0.05). Inhibition of 5-LOX in an in vivo colon cancer xenograft model inhibited tumor growth compared with that of controls (P < 0.05).

Conclusions: This study showed that 5-LOX is up-regulated in adenomatous colon polyps and cancer compared with normal colonic mucosa. The blockade of 5-LOX inhibits colon cancer cell proliferation both in vitro and in vivo and may prove a beneficial chemopreventive therapy in colon cancer.
The Type 1 Insulin-Like Growth Factor Receptor Pathway
Authors: Chitnis Meenali M. , Yuen John S.P. , Protheroe Andrew S. , Pollak Michael , Macaulay Valentine M.
Published: October 2008

Research conducted over the past two decades has shown the importance of the type 1 insulin-like growth factor receptor (IGF1R) in tumorigenesis, metastasis, and resistance to existing forms of cancer therapy. The IGF1R itself has only recently been accepted as a credible treatment target, however, perhaps reflecting the potential problems for drug design posed by normal tissue IGF1R expression, and close homology with the insulin receptor. Currently ∼12 anti-IGF1R therapeutics are undergoing clinical evaluation, including blocking antibodies and tyrosine kinase inhibitors. This review will summarize the principal signaling pathways activated by IGF1R and the preclinical data that validated this receptor as a treatment target. We will review clinical progress in the testing of IGF1R inhibitory drug candidates, the relative benefits and potential toxicities of coinhibition of the insulin receptor, and the rationale for combining IGF1R blockade with other cancer treatments. An understanding of IGF1R signaling is important because it will guide the incorporation of appropriate molecular markers into clinical trial design. This will be key to the identification of patients most likely to benefit, and so will influence the ability of IGF1R inhibition to make the transition from experimental intervention to clinical therapy.
Sunitinib Reverses Type-1 Immune Suppression and Decreases T-Regulatory Cells in Renal Cell Carcinoma Patients
Authors: Finke James H. , Rini Brian , Ireland Joanna , Rayman Patricia , Richmond Amy , Golshayan Ali , Wood Laura , Elson Paul , Garcia Jorge , Dreicer Robert , Bukowski Ronald
Published: October 2008

Purpose: Immune dysfunction is well documented in renal cell carcinoma (RCC) patients and likely contributes to tumor evasion. This dysfunction includes a shift from a type-1 to a type-2 T-cell cytokine response and enhanced T-regulatory (Treg) cell expression. Given the antitumor activity of select tyrosine kinase inhibitors such as sunitinib in metastatic RCC (mRCC) patients, it is relevant to assess their effect on the immune system.

Experimental Design: Type-1 (IFNγ) and type-2 (interleukin-4) responses were assessed in T cells at baseline and day 28 of treatment with sunitinib (50 mg/d) by measuring intracellular cytokines after in vitro stimulation with anti-CD3/anti-CD28 antibodies.

Results: After one cycle of treatment, there was a significant increase in the percentage of IFNγ-producing T cells (CD3+, P < 0.001; CD3+CD4+, P = 0.001), a reduction in interleukin-4 production (CD3+ cells, P = 0.05), and a diminished type-2 bias (P = 0.005). The increase in type-1 response may be partly related to modulation of Treg cells. The increased percentage of Treg cells noted in mRCC patients over healthy donors (P = 0.001) was reduced after treatment, although not reaching statistical significance. There was, however, an inverse correlation between the increase in type-1 response after two cycles of treatment and a decrease in the percentage of Treg cells (r = −0.64, P = 0.01). In vitro studies suggest that the effects of sunitinib on Treg cells are indirect.

Conclusions: The demonstration that sunitinib improved type-1 T-cell cytokine response in mRCC patients while reducing Treg function provides a basis for the rational combination of sunitinib and immunotherapy in mRCC.
Bevacizumab Increases Viral Distribution in Human Anaplastic Thyroid Carcinoma Xenografts and Enhances the Effects of E1A-Defective Adenovirus dl922-947
Authors: Libertini Silvana , Iacuzzo Irma , Perruolo Giuseppe , Scala Stefania , Ieranò Caterina , Franco Renato , Hallden Gunnel , Portella Giuseppe
Published: October 2008

Purpose: Anaplastic thyroid carcinoma is a prime target for innovative therapy because it represents one of the most lethal human neoplasms and is refractory to conventional treatments such as chemotherapy and radiotherapy. We have evaluated a novel therapeutic approach based on the oncolytic replication-selective adenovirus dl922-947.

Experimental Design: The antitumor efficacies of the E1AΔCR2 (dl922-947) and ΔE1B55K (dl1520) mutants were compared in human thyroid anaplastic carcinoma cells in culture and in xenografts in vivo. To enhance the effects of dl922-947, anaplastic thyroid carcinoma tumor xenografts were treated with dl922-947 in combination with bevacizumab.

Results: We showed that the efficacy of dl922-947 exceeded that of dl1520 in all tested anaplastic thyroid carcinoma cells in vitro and in vivo. Furthermore, bevacizumab in combination with dl922-947 significantly reduced tumor growth compared with single treatments alone. Bevacizumab treatment significantly improved viral distribution in neoplastic tissues.

Conclusions: Our data showed that dl922-947 had a higher oncolytic activity compared with dl1520 in anaplastic thyroid carcinoma cell lines and might represent a better option for virotherapy of anaplastic thyroid carcinoma. Moreover, bevacizumab increased the oncolytic effects of dl922-947 by enhancing viral distribution in tumors. The results described herein encourage the use of the dl922-947 virus in combination with bevacizumab.
Expression Analysis of Barrett's Esophagus–Associated High-Grade Dysplasia in Laser Capture Microdissected Archival Tissue
Authors: Sabo Edmond , Meitner Patricia A. , Tavares Rosemarie , Corless Christopher L. , Lauwers Gregory Y. , Moss Steven F. , Resnick Murray B.
Published: October 2008

Purpose: Identifying genes differentially expressed in nondysplastic BE (NDBE) from those expressed in high-grade dysplasia (HGD) should be of value in improving our understanding of this transition and may yield new diagnostic and/or prognostic markers. The aim of this study was to determine the differential transcriptome of HGD compared with NDBE through gene microarray analysis of epithelial cells microdissected from archival tissue specimens.

Experimental Design: Laser capture microdissection was used to isolate epithelial cells from adjacent inflammatory and stromal cells. Epithelial mRNA was extracted from areas of NDBE and HGD in matched biopsies from 11 patients. mRNA was reverse transcribed and applied on Affymetrix cDNA microarray chips customized for formalin-exposed tissue. For a subset of these genes, differential gene expression was confirmed by real-time PCR and immunohistochemistry.

Results: There were 131 genes overexpressed by at least 2.5-fold in HGD versus NDBE and 16 genes that were underexpressed by at least 2.5-fold. Among the overexpressed genes are several previously shown to be increased in the neoplastic progression of BE, as well as novel genes such as lipocalin-2, S100A9, matrix metallopeptidase 12, secernin 1, and topoisomerase IIα. Genes decreased in dysplastic epithelium include MUC5AC, trefoil factor 1 (TFF1), meprin A, and CD13. Real-time PCR validated the changes in expression in 24 of 28 selected genes. Immunohistochemistry confirmed increased protein expression for topoisomerase IIα, S100A9, and lipocalin-2 and decreased expression of TFF1 across the spectrum of BE-associated dysplasia from NDBE through adenocarcinoma.

Conclusions: This is the first study to identify epithelial genes differentially expressed in HGD versus NDBE in matched patient samples. The genes identified include several previously implicated in the pathogenesis of BE-associated dysplasia and new candidates for further investigation.
Mucosa-Associated Lymphoid Tissue Lymphoma: Novel Translocations Including Rearrangements of ODZ2, JMJD2C, and CNN3
Authors: Vinatzer Ursula , Gollinger Michaela , Müllauer Leonhard , Raderer Markus , Chott Andreas , Streubel Berthold
Published: October 2008

Purpose: The well-known translocations identified in MALT lymphomas include t(11;18)/API2-MALT1, t(1;14)/IGH-BCL10, and t(14;18)/IGH-MALT1. Molecular investigations have suggested that these three disparate translocations affect a common pathway, resulting in the constitutive activation of nuclear factor-κB. However, the vast majority of MALT lymphomas are negative for any of the above-mentioned translocations and the underlying pathogenesis is unclear.

Experimental Design: Fresh tissue of 29 gastric and extragastric MALT lymphomas was studied for genetic aberrations by conventional karyotyping, long-distance inverse PCR (LDI-PCR), fluorescence in situ hybridization (FISH), reverse transcription-PCR (RT-PCR), and real-time quantitative RT-PCR (QRT-PCR).

Results: Conventional cytogenetics, FISH, and RT-PCR identified aberrations in 26 of 29 MALT lymphoma. Balanced translocations were found in 21 cases. IGH was rearranged in the majority of cases with balanced translocations (n = 17/21); 3 cases had t(11;18)/API2-MALT1 and 1 case had novel t(6;7)(q25;q11), respectively. IGH partner genes involved MALT1, FOXP1, BCL6, and four new chromosomal regions on chromosome arms 1p, 1q, 5q, and 9p. LDI-PCR identified three novel partner genes on 1p (CNN3), 5q (ODZ2), and 9p (JMJD2C). FISH assays were established and confirmed LDI-PCR results. QRT-PCR showed deregulation of the novel genes in the translocation-positive cases.

Conclusions: Our study expands the knowledge on the genetic heterogeneity of MALT lymphomas.
The Wnt-5a–Derived Hexapeptide Foxy-5 Inhibits Breast Cancer MetastasisIn vivoby Targeting Cell Motility
Authors: Säfholm Annette , Tuomela Johanna , Rosenkvist Jeanette , Dejmek Janna , Härkönen Pirkko , Andersson Tommy
Published: October 2008

Purpose: An inherent problem in breast cancer treatment is that current therapeutic approaches fail to specifically target the dissemination of breast cancer cells from the primary tumor. Clinical findings show that the loss of Wnt-5a protein expression in the primary breast tumor predicts a faster tumor spread, and in vitro analyses reveal that it does so by inhibiting tumor cell migration. Therefore, we hypothesized that the reconstitution of Wnt-5a signaling could be a novel therapeutic strategy to inhibit breast cancer metastasis.

Experimental Design: We used in vitro techniques to show that 4T1 mouse breast cancer cells responded to the reconstitution of Wnt-5a signaling using our novel Wnt-5a mimicking hexapeptide, Foxy-5, in the same way as human breast cancer cells. Therefore, we could subsequently study its effect in vivo on the metastatic spread of cancer following the inoculation of 4T1 cells into mice.

Results: In vitro analyses revealed that both recombinant Wnt-5a and the Wnt-5a–derived Foxy-5 peptide impaired migration and invasion without affecting apoptosis or proliferation of 4T1 breast cancer cells. The in vivo experiments show that i.p. injections of Foxy-5 inhibited metastasis of inoculated 4T1 breast cancer cells from the mammary fat pad to the lungs and liver by 70% to 90%.

Conclusions: These data provide proof of principle that the reconstitution of Wnt-5a signaling in breast cancer cells is a novel approach to impair breast tumor metastasis by targeting cell motility. In combination with existing therapies, this approach represents a potential novel therapeutic strategy for the treatment of breast cancer patients.
Structural and Functional Basis for Therapeutic Modulation of p53 Signaling
Authors: Bassett Emily A. , Wang Wenge , Rastinejad Farzan , El-Deiry Wafik S.
Published: October 2008

Effective modulation of structural features and/or functional properties of the major tumor suppressor p53 as a wild-type or cancer-associated mutant protein represents a major challenge in drug development for cancer. p53 is an attractive target for therapeutic design because of its involvement as a mediator of growth arrest and apoptosis after exposure to chemoradiotherapy and/or radiotherapy. Although most clinically used cytotoxic agents target stabilization of wild-type p53, there are a number of approaches that hold promise for reactivation of mutant p53. On the other hand, brief blockade of p53 may reduce toxicity from systemic cytotoxic therapy. Screens for restoration of p53 transcriptional responses in p53-deficient cells may provide a functional means to develop anticancer therapeutics. Structure-based modulation continues to hold promise for development of peptides or small molecules capable of modulation of either wild-type or mutant p53 proteins.