bluuebunny/crossref_metadata_2025 huggingface dataset:
Lipoxin A
4
Inhibits
Porphyromonas gingivalis
-Induced Aggregation and Reactive Oxygen Species Production by Modulating Neutrophil-Platelet Interaction and CD11b Expression
Authors: Börgeson Emma , Lönn Johanna , Bergström Ida , Brodin Veronika Patcha , Ramström Sofia , Nayeri Fariba , Särndahl Eva , Bengtsson Torbjörn
Published: January 2011

Porphyromonas gingivalis
is an etiological agent that is strongly associated with periodontal disease, and it correlates with numerous inflammatory disorders, such as cardiovascular disease. Circulating bacteria may contribute to atherogenesis by promoting CD11b/CD18-mediated interactions between neutrophils and platelets, causing reactive oxygen species (ROS) production and aggregation. Lipoxin A
4
(LXA
4
) is an endogenous anti-inflammatory and proresolving mediator that is protective of inflammatory disorders. The aim of this study was to investigate the effect of LXA
4
on the
P. gingivalis
-induced activation of neutrophils and platelets and the possible involvement of Rho GTPases and CD11b/CD18 integrins. Platelet/leukocyte aggregation and ROS production was examined by lumiaggregometry and fluorescence microscopy. Integrin activity was studied by flow cytometry, detecting the surface expression of CD11b/CD18 as well as the exposure of the high-affinity integrin epitope, whereas the activation of Rac2/Cdc42 was examined using a glutathione
S
-transferase pulldown assay. The study shows that
P. gingivalis
activates Rac2 and Cdc42 and upregulates CD11b/CD18 and its high-affinity epitope on neutrophils, and that these effects are diminished by LXA
4
. Furthermore, we found that LXA
4
significantly inhibits
P. gingivalis
-induced aggregation and ROS generation in whole blood. However, in platelet-depleted blood and in isolated neutrophils and platelets, LXA
4
was unable to inhibit either aggregation or ROS production, respectively. In conclusion, this study suggests that LXA
4
antagonizes
P. gingivalis
-induced cell activation in a manner that is dependent on leukocyte-platelet interaction, likely via the inhibition of Rho GTPase signaling and the downregulation of CD11b/CD18. These findings may contribute to new strategies in the prevention and treatment of periodontitis-induced inflammatory disorders, such as atherosclerosis.
Actin Polymerization Drives Septation of
Listeria monocytogenes namA
Hydrolase Mutants, Demonstrating Host Correction of a Bacterial Defect
Authors: Alonzo Francis , McMullen P. David , Freitag Nancy E.
Published: January 2011

The Gram-positive bacterial cell wall presents a structural barrier that requires modification for protein secretion and large-molecule transport as well as for bacterial growth and cell division. The Gram-positive bacterium
Listeria monocytogenes
adjusts cell wall architecture to promote its survival in diverse environments that include soil and the cytosol of mammalian cells. Here we provide evidence for the enzymatic flexibility of the murein hydrolase NamA and demonstrate that bacterial septation defects associated with a loss of NamA are functionally complemented by physical forces associated with actin polymerization within the host cell cytosol.
L. monocytogenes
Δ
namA
mutants formed long bacterial chains during exponential growth in broth culture; however, normal septation could be restored if mutant cells were cocultured with wild-type
L. monocytogenes
bacteria or by the addition of exogenous NamA. Surprisingly, Δ
namA
mutants were not significantly attenuated for virulence in mice despite the pronounced exponential growth septation defect. The physical force of
L. monocytogenes
-mediated actin polymerization within the cytosol was sufficient to sever Δ
namA
mutant intracellular chains and thereby enable the process of bacterial cell-to-cell spread so critical for
L. monocytogenes
virulence. The inhibition of actin polymerization by cytochalasin D resulted in extended intracellular bacterial chains for which septation was restored following drug removal. Thus, despite the requirement for NamA for the normal septation of exponentially growing
L. monocytogenes
cells, the hydrolase is essentially dispensable once
L. monocytogenes
gains access to the host cell cytosol. This phenomenon represents a notable example of eukaryotic host cell complementation of a bacterial defect.
Role of
Salmonella
Pathogenicity Island 1 Protein IacP in
Salmonella enterica
Serovar Typhimurium Pathogenesis
Authors: Kim Jin Seok , Eom Jeong Seon , Jang Jung Im , Kim Hyeon Guk , Seo Doo Won , Bang Iel-Soo , Bang Seong Ho , Lee In Soo , Park Yong Keun
Published: January 2011

Gram-negative bacteria, including
Salmonella enterica
serovar Typhimurium, exploit type III secretion systems (T3SSs) through which virulence proteins are delivered into the host cytosol to reinforce invasive and replicative niches in their host. Although many secreted effector proteins and membrane-bound structural proteins in the T3SS have been characterized, the functions of many cytoplasmic proteins still remain unknown. In this study, we found that IacP, encoded by
Salmonella
pathogenicity island 1, was important for nonphagocytic cell invasion and bacterial virulence. When the
iacP
gene was deleted from several
Salmonella
serovar Typhimurium strains, the invasion into INT-407 epithelial cells was significantly decreased compared to that of their parental strains, and retarded rearrangements of actin fibers were observed for the
iacP
mutant-infected cells. Although IacP had no effect on the secretion of type III translocon proteins, the levels of secretion of the effector proteins SopB, SopA, and SopD into the culture medium were decreased in the
iacP
mutant. In a mouse infection model, mice infected with the
iacP
mutant exhibited alleviated pathological signs in the intestine and survived longer than did wild-type-infected mice. Taken together, IacP plays a key role in
Salmonella
virulence by regulating the translocation of T3SS effector proteins.
An experimental and theoretical study on siderol isolated from Sideritis species
Authors: Azizoglu Akin , Özer Zuleyha , Kiliç Turgut
Published: January 2011

The Fourier transform infrared (FTIR) spectrum of siderol, extracted from the aerial parts of Sideritis Gülendamii, has been measured in the range 4000–400 cm–1. Vibrational assignments and analyses of the fundamental modes of siderol were performed using the observed FTIR data recorded in the solid phase. The vibrational frequencies determined experimentally are compared with those obtained theoretically from density functional theory (DFT) and Hartee–Fock (HF) calculations. Optimized geometrical parameters of the title compound are in agreement with similar reported structures. The 1H and 13C NMR spectra of siderol have also been calculated by means of DFT and HF methods. The comparison between the experimental and the theoretical results indicates that density functional methods, B3LYP and MPW1PW91 with 6-31G(d) basis set, are able to provide satisfactory results for predicting NMR properties. On the basis of vibrational analyses, the thermodynamic properties of the title molecule have also been computed.
The impact of coil shape design on angiographic occlusion, packing density and coil mass uniformity in aneurysm embolization: an in vitro study
Authors: Mehra Manik , Hurley Michael C , Gounis Matthew J , King Robert M , Shaibani Ali , Dabus Guilherme , Labdag Fatimaezzahra E , Levy Elad I , Bendok Bernard R
Published: January 2011

Objective

To investigate the impact of coil design on the distribution of the coil mass in a controlled in vitro experiment. A secondary objective was to study the relationship between angiographic occlusion, packing density and coil mass uniformity.

Methods

Sevensiliconside wall aneurysm models were embolized in each arm with a different coil design under fluoroscopic guidance. Packing density calculations and scoring of the angiographic occlusion were made. The models were embedded in epoxy and sectioned through the aneurysm neck and the dome. The sections were imaged and processed to derive the fractional surface area of coil material over the coil free area, a quantitative endpoint representing the percentage of the given region of interest consumed by coils. The SD of the surface area fractions is inversely proportional to the uniformity of coil distribution.

Results

The novel triangular primary wind design of the Deltapaq achieved a more homogenous distribution of coils within the aneurysm dome compared with the helical and complex microcoil systems (p=0.018). The packing density achieved by the Deltapaq (39.1±1.6%) was significantly higher than the complex (35.2±2.8%) and the helical (32.2±3.3%) coils. Angiographically, aneurysms coiled by the Deltapaq were more likely to obtain a Raymond score of class I.

Conclusion

Evaluation of emerging coil technologies with respect to treatment durability may be well served by an assessment of their uniformity of distribution within an aneurysm in addition of the traditional packing density and angiographic occlusion scoring methods.
Peripheral arterial disease: the evolving role of non-invasive imaging
Authors: Owen A R , Roditi G H
Published: January 2011

Peripheral arterial disease is usually secondary to stenotic or occlusive atherosclerosis and is both common and increasing in western society. The majority of symptomatic patients have intermittent claudication and only a minority (<2% and typically those with diabetes mellitus or renal failure) progress to critical limb ischaemia, heralded by the onset of rest pain and/or tissue loss. Imaging is largely reserved for patients with disabling symptoms in whom revascularisation is planned. In these patients, accurate depiction of the vascular anatomy is critical for clinical decision making as the distribution and severity of disease are key factors determining whether revascularisation should be by endovascular techniques or open surgery. Driven by advances in technology, non-invasive vascular imaging has recently undergone significant refinement and has replaced conventional digital subtraction angiography for many clinical indications. In this review, the relative merits and limitations of duplex ultrasound, CT angiography, and magnetic resonance angiography are discussed, emerging imaging techniques are described, and complications relating to the use of intravascular contrast agents are highlighted.
Efficiency of anthropometric indicators of obesity for identifying cardiovascular risk factors in a Chinese population
Authors: Dong Xiaolin , Liu Yang , Yang Jie , Sun Yu , Chen Li
Published: January 2011

Objective

To evaluate the predictive value of the body mass index (BMI), waist circumference (WC), and waist-to-height ratio (WHtR) for the presence of several cardiovascular risk conditions—hypertension, dyslipidaemia, metabolic syndrome (MS), and type 2 diabetes—in a Chinese population in Jinan, China.

Methods

Data for a representative, cross-sectional sample of 3006 adults (mean age; range 20–74 years) in Jinan from 2007 to 2008 were studied. The association of BMI, WC, and WHtR with cardiovascular risk conditions was assessed by use of receiver operating characteristic curve (ROC) analysis and by calculating the area under the ROC (AUC) and age adjusted odds ratios (ORs) for metabolic syndrome, dyslipidaemia, type 2 diabetes, and hypertension.

Results

AUC cut-off values showed that the association of WHtR and WC was higher than that for BMI for all risk conditions for both sexes, except for hypertension in men. The AUC values for WC showed a higher association with hypertension and metabolic syndrome for women than men (p<0.01 for hypertension, p<0.05 for metabolic syndrome). The ORs were highest for WHtR for metabolic syndrome, diabetes, and hypertension in women. The ORs were highest for BMI for hypertension in men.

Conclusions

Compared with BMI, measures of central obesity, particularly WHtR, show a better association with obesity related cardiovascular risk conditions for both sexes, except for hypertension in men, in Jinan, China.
DYNAMICS WITH CO-EVOLUTION OF INDIVIDUAL INCLINATION AND OPINION
Authors: XIONG FEI , LIU YUN , ZHANG ZHENJIANG
Published: January 2011

Based on the voter model, we present a new opinion formation model which takes into account the evolution of both opinions and individual inclinations. A memory-based inclination is developed gradually during the process of social interaction; however, if the individual inclination gets strong enough, it will react to opinion dynamics. We assume that an individual inclination increases with the number of times the individual has held its most frequent opinion in the past interactions. As a result of inclination choices the transition rate following neighbors decreases, thus slowing down the microscopic dynamics. Analytical and simulation results indicate the system under the action of opinion inclinations evolves to a more polarized state for average opinion. The appearance of extremists holding the minority opinion is observed in the final state, where one opinion predominates. It is also found that the stable opinion and relaxation time depend on network topology and memory length. Moreover, this model is not only valid to the voter model, but can also be applied to other spin systems.
SELF-ORGANIZATION IN THE BATTLE OF THE SEXES
Authors: ALONSO-SANZ RAMÓN
Published: January 2011

This paper presents a spatial version of the iterated battle of the sexes game in which every one individual plays with his nearest partners and imitates the optimal strategy of his nearest mate neighbors. It is concluded that the spatial structure enables the emergence of clusters of coincident choices, leading to the mean payoff per encounter to values that are accessible only in the cooperative two-person game scenario, which constitutes a notable case of self-organization.
ON THE CHAOTIC FLUX DYNAMICS IN A LONG JOSEPHSON JUNCTION
Authors: FENG Z. C. , LI Y. CHARLES
Published: January 2011

Flux dynamics in an annular long Josephson junction is studied. Three main topics are covered. The first is chaotic flux dynamics and its prediction via Melnikov integrals. It turns out that DC current bias cannot induce chaotic flux dynamics, while AC current bias can. The existence of a common root to the Melnikov integrals is a necessary condition for the existence of chaotic flux dynamics. The second topic is on the components of the global attractor and the bifurcation in the perturbation parameter measuring the strength of loss, bias and irregularity of the junction. The global attractor can contain coexisting local attractors, e.g. a local chaotic attractor and a local regular attractor. In the infinite dimensional phase space setting, the bifurcation is very complicated. Chaotic attractors can appear and disappear in a random fashion. Three types of attractors (chaos, breather, spatially uniform and temporally periodic attractor) are identified. The third topic is ratchet effect. Ratchet effect can be achieved by a current bias field which corresponds to an asymmetric potential, in which case the flux dynamics is ever lasting chaotic. When the current bias field corresponds to a symmetric potentially, the flux dynamics is often transiently chaotic, in which case the ratchet effect disappears after sufficiently long time.
RESIDUAL APERIODIC STOCHASTIC RESONANCE IN LÉVY NOISE
Authors: ZENG LINGZAO , LI JIANLONG
Published: January 2011

We investigate the effect of Lévy noise on the noise-induced residual aperiodic stochastic resonance (ASR). It is shown that, the residual ASR still exists when the noise is Lévy distributed. However, it is reduced by Lévy noise compared to that in the Gaussian noise with the same intensity. It is also shown that, the minimum bit error rate (BER) of the Lévy-noise-induced ASR is slightly higher than that of the Gaussian-noise-induced ASR, which indicates that tuning system parameters is a better approach to get the optimal performance.
EFFECT OF INLET CONFIGURATION ON DISTRIBUTION OF AIR–WATER UPWARD FLOW IN A HEADER OF A PARALLEL FLOW HEAT EXCHANGER
Authors: KIM NAE-HYUN , KIM SOO-HWAN , PARK JI-HOON
Published: January 2011

The effect of inlet configuration (parallel, normal, vertical) on flow distribution in a parallel flow heat exchanger consisting of round headers and ten flat tubes is experimentally studied using air and water. The effects of tube protrusion depth as well as header mass flux, and quality are investigated for upward flow configuration. It is shown that best flow distribution is obtained for vertical inlet configuration, followed by normal inlet and parallel inlet configuration. For upward flow, significant portion of the water flows through the rear part of the header. As protrusion depth increases, more water is forced to the rear part of the header. The effect is most significant for parallel inlet, followed by normal and vertical inlet. The effect of mass flux or quality is opposite to that of the protrusion depth. Possible explanation is provided from flow visualization results.
A REVIEW OF ENHANCEMENT OF BOILING HEAT TRANSFER THROUGH NANOFLUIDS AND NANOPARTICLE COATINGS
Authors: YOU SEUNG M. , AMAYA MIGUEL , KWARK SANG M.
Published: January 2011

This review traces the development of nanofluid pool boiling from its beginning (1984) to the present through a sampling of studies that have interested the authors and which have led to the latest findings at the University of Texas at Arlington (UTA). The studies of thermophysical properties of nanofluids are briefly covered. Several works in the last 7 years are highlighted to illustrate the modes of nanofluid pool boiling testing, the variability of nanofluid boiling heat transfer (BHT), and the postulations of causes of this behavior. Starting in 2006, the wettability increase in the nanoparticle coating, generated during the nanofluid pool boiling, is recognized as the source of critical heat flux (CHF) enhancement through its effect on the dynamics of hot spots and departing bubbles. The reasons for the observed contradictory BHT behavior are not yet fully clear, but recently at UTA, nanofluid boiling heat transfer has shown to be transient due to the dynamic nature of the formation of the nanoparticle coating. Also at UTA, the mechanism of nanoparticle deposition on the heated surface has been further confirmed. Thus, nanofluid boiling has led back to heat transfer enhancement through surface modification in nanoscale. These developments from 2006 are covered in more detail.
Perceptual effects of scene context and viewpoint for virtual pedestrian crowds
Authors: Ennis Cathy , Peters Christopher , O'Sullivan Carol
Published: January 2011

In this article, we evaluate the effects of position, orientation, and camera viewpoint on the plausibility of pedestrian formations. In a set of three perceptual studies, we investigated how humans perceive characteristics of virtual crowds in static scenes reconstructed from annotated still images, where the orientations and positions of the individuals have been modified. We found that by applying rules based on the contextual information of the scene, we improved the perceived realism of the crowd formations when compared to random formations. We also examined the effect of camera viewpoint on the plausibility of virtual pedestrian scenes, and we found that an eye-level viewpoint is more effective for disguising random behaviors, while a canonical viewpoint results in these behaviors being perceived as less realistic than an isometric or top-down viewpoint. Results from these studies can help in the creation of virtual crowds, such as computer graphics pedestrian models or architectural scenes, and identify situations when users' perception is less accurate.
An other-race effect for face recognition algorithms
Authors: Phillips P. Jonathon , Jiang Fang , Narvekar Abhijit , Ayyad Julianne , O'Toole Alice J.
Published: January 2011

Psychological research indicates that humans recognize faces of their own race more accurately than faces of other races. This “other-race effect” occurs for algorithms tested in a recent international competition for state-of-the-art face recognition algorithms. We report results for a Western algorithm made by fusing eight algorithms from Western countries and an East Asian algorithm made by fusing five algorithms from East Asian countries. At the low false accept rates required for most security applications, the Western algorithm recognized Caucasian faces more accurately than East Asian faces and the East Asian algorithm recognized East Asian faces more accurately than Caucasian faces. Next, using a test that spanned all false alarm rates, we compared the algorithms with humans of Caucasian and East Asian descent matching face identity in an identical stimulus set. In this case, both algorithms performed better on the Caucasian faces—the “majority” race in the database. The Caucasian face advantage, however, was far larger for the Western algorithm than for the East Asian algorithm. Humans showed the standard other-race effect for these faces, but showed more stable performance than the algorithms over changes in the race of the test faces. State-of-the-art face recognition algorithms, like humans, struggle with “other-race face” recognition.
Human-inspired search for redundancy in automatic sign language recognition
Authors: Holt Gineke A. Ten , Doorn Andrea J. Van , Reinders Marcel J. T. , Hendriks Emile A. , Ridder Huib De
Published: January 2011

Human perception of sign language can serve as inspiration for the improvement of automatic recognition systems. Experiments with human signers show that sign language signs contain redundancy over time. In this article, experiments are conducted to investigate whether comparable redundancies also exist for an automatic sign language recognition system. Such redundancies could be exploited, for example, by reserving more processing resources for the more informative phases of a sign, or by discarding uninformative phases. In the experiments, an automatic system is trained and tested on isolated fragments of sign language signs. The stimuli used were similar to those of the human signer experiments, allowing us to compare the results. The experiments show that redundancy over time exists for the automatic recognizer. The central phase of a sign is the most informative phase, and the first half of a sign is sufficient to achieve a recognition performance similar to that of the entire sign. These findings concur with the results of the human signer studies. However, there are differences as well, most notably the fact that human signers score better on the early phases of a sign than the automatic system. The results can be used to improve the automatic recognizer, by using only the most informative phases of a sign as input.
Annotated probabilistic temporal logic
Authors: Shakarian Paulo , Parker Austin , Simari Gerardo , Subrahmanian Venkatramana V. S.
Published: January 2011

The semantics of most logics of time and probability is given via a probability distribution over
threads
, where a thread is a structure specifying what will be true at different points in time (in the future). When assessing the probabilities of statements such as “Event
a
will occur within 5 units of time of event
b
,” there are many different semantics possible, even when assessing the truth of this statement within a single thread. We introduce the syntax of annotated probabilistic temporal (APT) logic programs and axiomatically introduce the key notion of a frequency function (for the first time) to capture different types of intrathread reasoning, and then provide a semantics for intrathread and interthread reasoning in APT logic programs parameterized by such frequency functions. We develop a comprehensive set of complexity results for consistency checking and entailment in APT logic programs, together with sound and complete algorithms to check consistency and entailment. The basic algorithms use linear programming, but we then show how to substantially and correctly reduce the sizes of these linear programs to yield better computational properties. We describe a real world application we are developing using APT logic programs.
Mechanizing the metatheory of LF
Authors: Urban Christian , Cheney James , Berghofer Stefan
Published: January 2011

LF is a dependent type theory in which many other formal systems can be conveniently embedded. However, correct use of LF relies on nontrivial metatheoretic developments such as proofs of correctness of decision procedures for LF's judgments. Although detailed informal proofs of these properties have been published, they have not been formally verified in a theorem prover. We have formalized these properties within Isabelle/HOL using the Nominal Datatype Package, closely following a recent article by Harper and Pfenning. In the process, we identified and resolved a gap in one of the proofs and a small number of minor lacunae in others. We also formally derive a version of the type checking algorithm from which Isabelle/HOL can generate executable code. Besides its intrinsic interest, our formalization provides a foundation for studying the adequacy of LF encodings, the correctness of Twelf-style metatheoretic reasoning, and the metatheory of extensions to LF.
Persistent queries in the behavioral theory of algorithms
Authors: Blass Andreas , Gurevich Yuri
Published: January 2011

We propose an extension of the behavioral theory of interactive sequential algorithms to deal with the following situation. A query is issued during a certain step, but the step ends before any reply is received. Later, a reply arrives, and later yet the algorithm makes use of this reply. By a persistent query, we mean a query for which a late reply might be used. Our proposal involves issuing, along with a persistent query, a location where a late reply is to be stored. After presenting our proposal in general terms, we discuss the modifications that it requires in the existing axiomatics of interactive sequential algorithms and in the existing syntax and semantics of abstract state machines. To make that discussion self-contained, we include a summary of this material before the modifications. Fortunately, only rather minor modifications are needed.
Contributing vertices-based Minkowski sum of a nonconvex--convex pair of polyhedra
Authors: Barki Hichem , Denis Florence , Dupont Florent
Published: January 2011

The exact Minkowski sum of polyhedra is of particular interest in many applications, ranging from image analysis and processing to computer-aided design and robotics. Its computation and implementation is a difficult and complicated task when nonconvex polyhedra are involved. We present the NCC-CVMS algorithm, an exact and efficient contributing vertices-based Minkowski sum algorithm for the computation of the Minkowski sum of a nonconvex--convex pair of polyhedra, which handles nonmanifold situations and extracts eventual polyhedral holes inside the Minkowski sum outer boundary. Our algorithm does not output boundaries that degenerate into a polyline or a single point. First, we generate a superset of the Minkowski sum facets through the use of the contributing vertices concept and by summing only the features (facets, edges, and vertices) of the input polyhedra which have coincident orientations. Secondly, we compute the 2D arrangements induced by the superset triangles intersections. Finally, we obtain the Minkowski sum through the use of two simple properties of the input polyhedra and the Minkowski sum polyhedron itself, that is, the closeness and the two-manifoldness properties. The NCC-CVMS algorithm is efficient because of the simplifications induced by the use of the contributing vertices concept, the use of 2D arrangements instead of 3D arrangements which are difficult to maintain, and the use of simple properties to recover the Minkowski sum mesh. We implemented our NCC-CVMS algorithm on the base of CGAL and used exact number types. More examples and results of the NCC-CVMS algorithm can be found at: http://liris.cnrs.fr/hichem.barki/mksum/NCC-CVMS
A comprehensive theory of volumetric radiance estimation using photon points and beams
Authors: Jarosz Wojciech , Nowrouzezahrai Derek , Sadeghi Iman , Jensen Henrik Wann
Published: January 2011

We present two contributions to the area of volumetric rendering. We develop a novel, comprehensive theory of volumetric radiance estimation that leads to several new insights and includes all previously published estimates as special cases. This theory allows for estimating in-scattered radiance at a point, or accumulated radiance along a camera ray, with the standard photon particle representation used in previous work. Furthermore, we generalize these operations to include a more compact, and more expressive intermediate representation of lighting in participating media, which we call “photon beams.” The combination of these representations and their respective query operations results in a collection of nine distinct volumetric radiance estimates.

Our second contribution is a more efficient rendering method for participating media based on photon beams. Even when shooting and storing less photons and using less computation time, our method significantly reduces both bias (blur) and variance in volumetric radiance estimation. This enables us to render sharp lighting details (e.g., volume caustics) using just tens of thousands of photon beams, instead of the millions to billions of photon points required with previous methods.
17β-Hydroxyestra-4,9,11-trien-3-one (trenbolone) exhibits tissue selective anabolic activity: effects on muscle, bone, adiposity, hemoglobin, and prostate
Authors: Yarrow Joshua F. , Conover Christine F. , McCoy Sean C. , Lipinska Judyta A. , Santillana Cesar A. , Hance John M. , Cannady Darryl F. , VanPelt Tisha D. , Sanchez Joshua , Conrad Bryan P. , Pingel Jennifer E. , Wronski Thomas J. , Borst Stephen E.
Published: January 2011

Selective androgen receptor modulators (SARMs) now under development can protect against muscle and bone loss without causing prostate growth or polycythemia. 17β-Hydroxyestra-4,9,11-trien-3-one (trenbolone), a potent testosterone analog, may have SARM-like actions because, unlike testosterone, trenbolone does not undergo tissue-specific 5α-reduction to form more potent androgens. We tested the hypothesis that trenbolone-enanthate (TREN) might prevent orchiectomy-induced losses in muscle and bone and visceral fat accumulation without increasing prostate mass or resulting in adverse hemoglobin elevations. Male F344 rats aged 3 mo underwent orchiectomy or remained intact and were administered graded doses of TREN, supraphysiological testosterone-enanthate, or vehicle for 29 days. In both intact and orchiectomized animals, all TREN doses and supraphysiological testosterone-enanthate augmented androgen-sensitive levator ani/bulbocavernosus muscle mass by 35–40% above shams ( P ≤ 0.001) and produced a dose-dependent partial protection against orchiectomy-induced total and trabecular bone mineral density losses ( P < 0.05) and visceral fat accumulation ( P < 0.05). The lowest doses of TREN successfully maintained prostate mass and hemoglobin concentrations at sham levels in both intact and orchiectomized animals, whereas supraphysiological testosterone-enanthate and high-dose TREN elevated prostate mass by 84 and 68%, respectively ( P < 0.01). In summary, low-dose administration of the non-5α-reducible androgen TREN maintains prostate mass and hemoglobin concentrations near the level of shams while producing potent myotrophic actions in skeletal muscle and partial protection against orchiectomy-induced bone loss and visceral fat accumulation. Our findings indicate that TREN has advantages over supraphysiological testosterone and supports the need for future preclinical studies examining the viability of TREN as an option for androgen replacement therapy.
Prognostic Significance of p14ARF, p15INK4b, and p16INK4a Inactivation in Malignant Peripheral Nerve Sheath Tumors
Authors: Endo Makoto , Kobayashi Chikashi , Setsu Nokitaka , Takahashi Yusuke , Kohashi Kenichi , Yamamoto Hidetaka , Tamiya Sadafumi , Matsuda Shuichi , Iwamoto Yukihide , Tsuneyoshi Masazumi , Oda Yoshinao
Published: January 2011

Purpose: p14ARF, p15INK4b, and p16INK4a are tumor suppressor genes that are located closely at 9p21 and are often coinactivated by genetic or epigenetic alterations. Malignant peripheral nerve sheath tumor (MPNST) is a rare sarcoma with poor prognosis. However, the prognostic implications of inactivation of p14ARF, p15INK4b, and p16INK4a in MPNSTs have not been adequately investigated. Here we carried out a genetic, epigenetic, and expression analysis of p14ARF, p15INK4b, and p16INK4a, and clarified the prognostic significance of their inactivation in MPNSTs.

Experimental Design: p14ARF, p15INK4b, and p16INK4a protein expressions were assessed by immunohistochemistry in 129 formalin-fixed samples of MPNST including 85 primary tumors. Thirty-nine samples, for which frozen material was available, were also investigated by Western blotting and quantitative reverse transcription PCR (RT-PCR) to detect p14ARF, p15INK4b, and p16INK4a protein and mRNA expression, and by multiplex real-time PCR, PCR single strand conformation polymorphism and methylation-specific PCR to detect p14ARF, p15INK4b, and p16INK4a gene alterations.

Results: Immunohistochemically decreased expressions of p14ARF, p15INK4b, and p16INK4a were observed in 48%, 54%, and 49% of primary MPNSTs, respectively, and were significantly correlated with their concordant mRNA levels. As for gene alterations, homozygous deletion of CDKN2A was detected in one third of the cases. Inactivation of p14ARF and p16INK4a was associated with poor prognosis by both univariate and multivariate analyses. Furthermore, cases with inactivation of all p14ARF, p15INK4b, and p16INK4a genes showed the worst prognosis in a combined prognostic assessment.

Conclusion: A comprehensive analysis of p14ARF, p15INK4b, and p16INK4a inactivation status provides useful prognostic information in MPNSTs. Clin Cancer Res; 17(11); 3771–82. ©2011 AACR.
Osteopontin-c Splicing Isoform Contributes to Ovarian Cancer Progression
Authors: Tilli Tatiana M. , Franco Vanessa Ferreira , Robbs Bruno Kaufmann , Wanderley João Luiz Mendes , de Azevedo da Silva Fabrício Ribeiro , de Mello Kivvi Duarte , Viola João P. B. , Weber Georg F. , Gimba Etel R.
Published: January 2011

Ovarian carcinoma is one of the most aggressive gynecological diseases and generally diagnosed at advanced stages. Osteopontin (OPN) is one of the proteins overexpressed in ovarian cancer and is involved in tumorigenesis and metastasis. Alternative splicing of OPN leads to 3 isoforms, OPNa, OPNb, and OPNc. However, the expression pattern and the roles of each of these isoforms have not been previously characterized in ovarian cancer. Herein, we have evaluated the expression profiling of OPN isoforms in ovarian tumor and nontumor samples and their putative roles in ovarian cancer biology using in vitro and in vivo functional assays. OPNa and OPNb were expressed both in tumor and nontumor ovarian samples, whereas OPNc was specifically expressed in ovarian tumor samples. The isoform OPNc significantly activated OvCar-3 cell proliferation, migration, invasion, anchorage-independent growth and tumor formation in vivo. Additionally, we have also shown that some of the OPNc-dependent protumorigenic roles are mediated by PI3K/Akt signaling pathway. OPNc stimulated immortalized ovarian epithelial IOSE cell proliferation, indicating a role for this isoform in ovarian cancer tumorigenesis. Functional assays using OPNc conditioned medium and an anti-OPNc antibody have shown that most cellular effects observed herein were promoted by the secreted OPNc. According to our data, OPNc-specific expression in ovarian tumor samples and its role on favoring different aspects of ovarian cancer progression suggest that secreted OPNc contributes to the physiopathology of ovarian cancer progression and tumorigenesis. Altogether, the data open possibilities of new therapeutic approaches for ovarian cancer that selectively down regulate OPNc, altering its properties favoring ovarian tumor progression. Mol Cancer Res; 9(3); 280–93. ©2011 AACR.
Assessment of Inflammatory and Fibrotic Stenoses in Patients with Crohn’s Disease Using Contrast-Enhanced Ultrasound and Computerized Algorithm: A Pilot Study
Authors: Schirin-Sokhan Ramin , Winograd Ron , Tischendorf Stefanie , Wasmuth Hermann E. , Streetz Konrad , Tacke Frank , Trautwein Christian , Tischendorf Jens J.W.
Published: January 2011

Purpose: The development of stenosis is a typical complication of Crohn’s disease and represents a serious diagnostic and therapeutic challenge. The aim of the present study was to define objective quantitative measures of stricture characteristics (fibrostenotic/cicartricial vs. inflammatory) using contrast-enhanced ultrasound (CEUS) in patients with stenotic Crohn’s disease. Materials and Methods: During a period of 18 months, 18 consecutive patients with Crohn’s disease and manifestation of a localized significant small bowel stenosis were prospectively recruited. Standardized ultrasound (US) examination, color-coded duplex sonography and CEUS using SonoVue® were performed. Quantitative measurements of bowel wall vascularity were determined using computerized algorithms (Bracco QONTRAST software). The quality of stenosis (fibrostenotic vs. inflammatory) was classified in a 4-point scale, and the diagnostic/prognostic power of the US and clinical tests upon initial presentation were compared. Results: We established a novel standardized CEUS procedure using computerized algorithms to quantitatively examine stenoses in Crohn’s disease. An inflammatory origin of stenosis correlated significantly with a high Crohn’s Disease Activity Index (CDAI) (p < 0.01), the length of stenosis (p < 0.01) as well as the Limberg score (p < 0.01). There was no correlation between the type of stenosis and quantitative results of CEUS. Conclusion: Although bowel wall vascularity can be quantitatively assessed in stenotic areas by CEUS, this analysis does not improve the diagnostic power for the objective determination of the quality of stenosis at a single measurement. Semiquantitative analysis of bowel wall vascularity, length of stenosis, and CDAI may help to discriminate the origin of small bowel stenosis in Crohn’s disease.
Caspase-9-Dependent Nuclear Translocation of Cytochrome c in Hypoxic Injury
Authors: Kim Jee-Youn , Kim Yong-Jun , Seok Kum-Ok , Lee Sun , Park Jae-Hoon
Published: January 2011

Objective: Hypoxia signals the release of cytochrome c from mitochondria as well as sequential activation of caspase-9 and caspase-3 in the pathway to apoptosis. In this report, we describe novel mechanisms governing the nuclear translocation of cytochrome c during hypoxia-induced apoptosis in neuroepithelioma, SK-N-MC cells. Methods: This work focuses on an investigation of the mechanism of cytochrome c translocation by means of immunocytochemistry, cell fractionation, Western blot and caspase assay. Results: Using immunocytochemistry and subcellular fractionation, we found that caspase-9 activation precedes cytochrome c release and translocation. Inhibition of caspase-9 activity blocked these responses to hypoxia. Previous studies suggest a key role for c-Jun N-terminal kinase (JNK) in apoptosis regulation and accordingly we found that JNK activation was essential for caspase-9 activation and nuclear translocation of cytochrome c. Conclusions: In this report, we describe novel mechanisms of caspase-9-dependent nuclear translocation of cytochrome c in hypoxic injury.
Identification of New Susceptibility Regions for X;Y Translocations in Patients with Testicular Disorder of Sex Development
Authors: Beaulieu Bergeron M. , Lemyre E. , Lemieux N.
Published: January 2011

Testicular disorder of sex development in the presence of a 46,XX karyotype is a rare condition. In most instances, it is caused by an X;Y translocation in the paternal gametes, causing SRY to be transferred on the X chromosome. An abnormal recombination event between homologous genes PRKX and PRKY is implicated in approximately one third of the cases. In this study, we report the characterization by fluorescence in situ hybridization of four patients with a 46,X,der(X)t(X;Y) constitution: two monozygotic adult twins, one adult male and a young boy. Molecular cytogenetic analyses using BAC clones specific to the X and Y chromosomes revealed that the translocation is not mediated by an abnormal PRKX-PRKY recombination event in any of our patients. On the other hand, the twins and the adult male have similar breakpoints, having almost the entire short arm of the Y chromosome translocated on their der(X). On their der(X) chromosome, breakpoints are located close to PRKX, in an interval of less than 200 kb. As for the young boy, his breakpoints are located approximately 300 kb proximal to SRY, in Yp11.31, and at the beginning of the pseudoautosomal region in Xp22.33. Our data suggest that some regions are prone to breakage on the sex chromosomes and that these regions represent possible hot spots for X;Y translocations that are not mediated by abnormal recombination.
Expression Profiles of Reproduction- and Thyroid Hormone-Related Transcripts in the Brains of Chemically-Induced Intersex Frogs
Authors: Langlois V.S. , Duarte-Guterman P. , Trudeau V.L.
Published: January 2011

Endocrine disrupting chemicals can induce intersex animals in amphibians and fish. Our previous study in frogs demonstrated that chemically-induced intersex animals can display different hepatic profiles of transcript levels than normal animals. In this study, we extend the observations to the developing frog brain. We investigated the effects of finasteride and fadrozole known to induce female- and male-biased sexual development on Silurana tropicalis brain mRNA levels. Real-time RT-PCR analysis of transcript levels of sex steroid- and thyroid hormone-related genes in the brain demonstrated that in finasteride-induced intersex animals, the mRNA levels of aromatase, estrogen receptor α, thyroid hormone receptor β and deiodinase type 3 were higher compared to both control males and females. Furthermore, finasteride-induced intersex animals expressed higher mRNA levels of both androgen receptor and estrogen receptor β compared to control females and to control males, respectively. Furthermore, fadrozole did not affect any of the genes analyzed in the brain but was effective at reducing aromatase activity. Intersex animals display different profiles of transcript levels in the brain whether the intersex condition was induced by an anti-androgen or anti-estrogen treatment. Finally, we conclude that a complex relationship exists between thyroid hormone-responsive genes and androgen status in frogs.
Factor VIII delivered by haematopoietic stem cell-derived B cells corrects the phenotype of haemophilia A mice
Authors: Ramezani Ali , Zweier-Renn Lynnsey , Hawley Robert
Published: January 2011

The main impediments to clinical application of haematopoietic stem cell (HSC) gene therapy for treatment of haemophilia A are the bone marrow transplant-related risks and the potential for insertional muta-genesis caused by retroviral vectors. To circumvent these limitations, we have adapted a non-myeloablative conditioning regimen and directed factor VIII (FVIII) protein synthesis to B lineage cells using an insulated lentiviral vector containing an immunoglobulin heavy chain enhancer-promoter. Transplantation of lentiviral vector-modified HSCs resulted in therapeutic levels of FVIII in the circulation of all transplanted mice for the duration of the study (six months). Immunostaining of spleen cells showed that the majority of FVIII was synthesised by B220+ B cells and CD138+ plasma cells. Subsequent challenge with recombinant FVIII elicited at most a minor anti-FVIII antibody response, demonstrating in-duction of immune hyporesponsiveness. All transplant recipients exhibited clot formation and survived tail clipping, indicating correction of their haemophilic phenotype. Therapeutic levels of FVIII could be transferred to secondary recipients by bone marrow transplantation, confirming gene transfer into long-term repopulating HSCs. Moreover, short-term therapeutic FVIII levels could also be achieved in secondary recipients by adoptive transfer of HSC-derived splenic B cells. Our findings support pursuit of B cell-directed protein delivery as a potential clinical approach to treat haemophilia A and other disorders correctable by systemically distributed proteins.
The role of vitamin E (tocopherol) supplementation in the prevention of stroke
Authors: Bin Qiong , Hu Xueying , Cao Yunfei , Gao Feng
Published: January 2011

It was the objective of this work to systematically evaluate the role of vitamin E supplementation in the prevention of stroke. Eligible studies were identified from Medline, Embase and Cochrane Library. The efficacy data is the relative risk (RR) for the events of stroke. Thirteen randomised controlled trials (RCTs), with 166,282 participants in total, were analysed. The pooled results showed no significant benefit in the vitamin E group with respect to stroke of any type (RR 1.01; 95% confidence interval [CI]: 0.96, 1.07); ischaemic stroke (RR 1.01; 95% CI: 0.94, 1.09), haemorrhagic stroke (RR 1.12; 95% CI: 0.94, 1.33), fatal stroke (RR 0.94; 95% CI: 0.77, 1.14), and non-fatal stroke (RR 0.99; 95% CI: 0.91, 1.08). Administration of vitamin E 300 IU/day or more also gain no benefit (RR 0.99; 95% CI: 0.92, 1.06), as well as vitamin E less than 300 IU (RR 1.05; 95% CI: 0.96, 1.15). Vitamin E supplementation gained benefit of preventing stroke for neither healthy people (0.92; 0.83, 1.03) nor others at high risks in baseline (RR 1.05; 95% CI: 0.98, 1.12). Administration of synthetic vitamin E gain no benefit (RR 1.02; 95% CI: 0.96, 1.09), as well as the natural source vitamin E (RR 0.99; 95% CI: 0.89, 1.09). In conclusion, there is a lack of statistically significant or clinically important benefit of vitamin E supplementation in the prevention of stroke.
Features of Disrupted Plaques by Coronary Computed Tomographic Angiography
Authors: Madder Ryan D. , Chinnaiyan Kavitha M. , Marandici Anna M. , Goldstein James A.
Published: January 2011

Background—

This study was designed as a “proof-of-concept” to establish whether coronary computed tomographic angiography (CTA) has the capability to identify morphological features of plaque disruption.

Methods and Results—

In patients with unstable angina undergoing CTA and invasive coronary angiography within 30 days, quantitative CTA analysis was performed on all plaques for percent stenosis, volume, remodeling index, and volume of low-attenuation plaque (<50 Hounsfield units). Plaques with >25% stenosis were evaluated for CTA features of disruption, including ulceration and intraplaque dye penetration. Using invasive coronary angiography complex plaque as the reference standard for disruption, the sensitivity and specificity of ulceration and intraplaque dye penetration by CTA were determined. In 60 patients, 294 plaques were identified by CTA, of which 109 (37%) had features of disruption, including ulceration in 53 (18%) lesions and intraplaque dye penetration in 80 (27%). Compared with nondisrupted lesions, plaques with ulceration or intraplaque dye penetration by CTA were more voluminous (313±356 mm
3
versus 118±93 mm
3
P
<0.0001), more often positively remodeled (94.5% versus 44.3%,
P
<0.0001), contained more low-attenuation plaque (99±161 mm
3
versus 19±18 mm
3
,
P
<0.0001), and were more often complex by ICA (57.8% versus 8.1%,
P
<0.0001). CTA features of disruption demonstrated modest to good sensitivity (53% to 81%) and good specificity (82% to 95%) for complex plaque by invasive coronary angiography.

Conclusions—

In this highly selected group of patients with unstable angina, CTA can delineate features of plaque disruption, including ulceration and intraplaque dye penetration, which are specific markers of invasively identified complex plaque. Further studies are needed to confirm the generalizability of the results and to explore the clinical and prognostic implications of these findings.