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At least 37 records · Page 2

Chaetospirolactone reverses the apoptotic resistance towards TRAIL in pancreatic cancer

Highlights: • CSL reverses TRAIL-mediated apoptotic resistance. • DR4 is induced by CSL. • H3 lysine 27 trimethylation by EZH2 is inhibited by CSL. The pancreatic cancer is one of the most aggressive tumors. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) can trigger apoptosis by interaction with death receptors. However, in TRAIL-resistant pancreatic cancer, responsiveness to TRAIL treatment is terribly poor. In current work, we have demonstrated that a natural product chaetospirolactone (CSL) isolated from an endophytic fungus Chaetomium sp. NF00754 can enhance the susceptibility of TRAIL-resistant pancreatic cancer cells to apoptosis. CSL can induce apoptosis in TRAIL-treated pancreatic cancer cells. Furthermore, combined CSL and TRAIL treatment significantly inhibits viability and migration of pancreatic cancer cells. Combinatorial TRAIL and CSL treatment repressed xenograft tumor growth without substantially toxic side effects. CSL can specifically upregulate expression of death receptor 4 (DR4). Further study revealed that CSL represses the activities of an epigenetic regulator enhancer of zeste homolog 2 (EZH2) and consistently reduces histone H3 lysine 27 trimethylation (H3K27me3) to allow DR4 transcription. Taken together, CSL treatment may reverse TRAIL resistance in pancreatic cancer cells via epigenetic regulation of DR4 implying that administration of CSL might represent a putative strategy for pancreatic cancer therapy.

60 APPLIED LIFE SCIENCES↗

Certification trails for data structures

Certification trails are a recently introduced and promising approach to fault detection and fault tolerance. The applicability of the certification trail technique is significantly generalized. Previously, certification trails had to be customized to each algorithm application; trails appropriate to wide classes of algorithms were developed. These certification trails are based on common data-structure operations such as those carried out using these sets of operations such as those carried out using balanced binary trees and heaps. Any algorithms using these sets of operations can therefore employ the certification trail method to achieve software fault tolerance. To exemplify the scope of the generalization of the certification trail technique provided, constructions of trails for abstract data types such as priority queues and union-find structures are given. These trails are applicable to any data-structure implementation of the abstract data type. It is also shown that these ideals lead naturally to monitors for data-structure operations.

Sullivan, Gregory F.↗

Gingerol sensitizes TRAIL-induced apoptotic cell death of glioblastoma cells

Glioblastoma multiforme (GBM) is the most lethal and aggressive astrocytoma of primary brain tumors in adults. Although there are many clinical trials to induce the cell death of glioblastoma cells, most glioblastoma cells have been reported to be resistant to TRAIL-induced apoptosis. Here, we showed that gingerol as a major component of ginger can induce TRAIL-mediated apoptosis of glioblastoma. Gingerol increased death receptor (DR) 5 levels in a p53-dependent manner. Furthermore, gingerol decreased the expression level of anti-apoptotic proteins (survivin, c-FLIP, Bcl-2, and XIAP) and increased pro-apoptotic protein, Bax and truncate Bid, by generating reactive oxygen species (ROS). We also found that the sensitizing effects of gingerol in TRAIL-induced cell death were blocked by scavenging ROS or overexpressing anti-apoptotic protein (Bcl-2). Therefore, we showed the functions of gingerol as a sensitizing agent to induce cell death of TRAIL-resistant glioblastoma cells. This study gives rise to the possibility of applying gingerol as an anti-tumor agent that can be used for the purpose of combination treatment with TRAIL in TRAIL-resistant glioblastoma tumor therapy. - Highlights: • Most GBM cells have been reported to be resistant to TRAIL-induced apoptosis. • Gingerol enhances the expression level of anti-apoptotic proteins by ROS. • Gingerol enhances TRAIL-induced apoptosis through actions on the ROS–Bcl2 pathway.

60 APPLIED LIFE SCIENCES↗

Atmospheric motion investigation for vapor trails and radio meteors

The dynamics are investigated of the lower thermosphere through comparison of optical observations of motions of ejected vapor trails with radar observations of motions of ionized meteor trails. In particular, the winds obtained from a series of vapor trail observations which occurred at Wallops Island, Virginia during the night of 14-15 December 1970 are to be compared with wind data deduced from radar observations of meteor trails during the same period. The comparison of these data is considered important for two reasons. First, the most widely used methods of measuring winds in the lower thermosphere are the vapor trails and the radar meteors. However, the two techniques differ markedly and the resultant sets of data have been analyzed and presented in different formats. Secondly, and possibly of greater immediate concern is the fact that the radar meteor method appears to be an appropriate approach to the synoptic measurement of winds. During the night of 14-15 December 1970, five vapor trails were ejected from Nike Apache rockets over Wallops Island, Virginia from 2208 EST through 0627 EST. The wind data which were obtained from these trails are presented, and features of the wind profiles which relate to the radar meteor trails results are discussed.

Bedinger, J.↗

Modeling and Evaluation of Miles-in-Trail Restrictions in the National Air Space

Miles-in-trail restrictions impact flights in the national air space on a daily basis and these restrictions routinely propagate between adjacent Air Route Traffic Control Centers. Since overly restrictive or ineffective miles-in-trail restrictions can reduce the overall efficiency of the national air space, decision support capabilities that model miles-in-trail restrictions should prove to be very beneficial. This paper presents both an analytical formulation and a linear programming approach for modeling the effects of miles-in-trail restrictions. A methodology for monitoring the conformance of an existing miles-in-trail restriction is also presented. These capabilities have been implemented in the Future ATM Concepts Evaluation Tool for testing purposes. To allow alternative restrictions to be evaluated in post-operations, a new mode of operation, which is referred to as the hybrid-playback mode, has been implemented in the simulation environment. To demonstrate the capabilities of these new algorithms, the miles-in-trail restrictions, which were in effect on June 27, 2002 in the New York Terminal Radar Approach Control, are examined. Results from the miles-in-trail conformance monitoring functionality are presented for the ELIOT, PARKE and WHITE departure fixes. In addition, the miles-in-trail algorithms are used to assess the impact of alternative restrictions at the PARKE departure fix.

Grabbe, Shon↗

Autophagy-mediated degradation of IAPs and c-FLIP L potentiates apoptosis induced by combination of TRAIL and Chal-24

Combination chemotherapy is an effective strategy for increasing anticancer efficacy, reducing side effects and alleviating drug resistance. In this paper, we report that combination of the recently identified novel chalcone derivative, chalcone-24 (Chal-24), and TNF-related apoptosis-inducing ligand (TRAIL) significantly increases cytotoxicity in lung cancer cells. Chal-24 treatment significantly enhanced TRAIL-induced activation of caspase-8 and caspase-3, and the cytotoxicity induced by combination of these agents was effectively suppressed by the pan-caspase inhibitor z-VAD-fmk. Chal-24 and TRAIL combination suppressed expression of cellular FLICE (FADD-like IL-1β-converting enzyme)-inhibitory protein large (c-FLIPL) and cellular inhibitor of apoptosis proteins (c-IAPs), and ectopic expression of c-FLIPL and c-IAPs inhibited the potentiated cytotoxicity. In addition, TRAIL and Chal-24 cooperatively activated autophagy. Suppression of autophagy effectively attenuated cytotoxicity induced by Chal-24 and TRAIL combination, which was associated with attenuation of c-FLIPL and c-IAPs degradation. In conclusion, these results suggest that Chal-24 potentiates the anticancer activity of TRAIL through autophagy-mediated degradation of c-FLIPL and c-IAPs, and that combination of Chal-24 and TRAIL could be an effective approach in improving chemotherapy efficacy.

59 BASIC BIOLOGICAL SCIENCES↗

Fiscal Year 2013 Trails Management Program Mitigation Action Plan Annual Report, October 2013

This Trails Management Program Mitigation Action Plan Annual Report (Trails MAPAR) has been prepared for the Department of Energy (DOE)/National Nuclear Security Administration (NNSA) as part of implementing the 2003 Final Environmental Assessment for the Proposed Los Alamos National Laboratory Trails Management Program (DOE 2003). The Trails Mitigation Action Plan (MAP) is now a part of the Site-Wide Environmental Impact Statement for the Continued Operation of Los Alamos National Laboratory (DOE/EIS 0380) Mitigation Action Plan (2008 SWEIS MAP) (DOE 2008). The MAP provides guidance for the continued implementation of the Trails Management Program at Los Alamos National Laboratory (LANL) and integration of future mitigation actions into the 2008 SWEIS MAP to decrease impacts associated with recreational trails use at LANL. This eighth MAPAR includes a summary of Trails Management Program activities and actions during Fiscal Year (FY) 2013, from October 2012 through September 2013.

54 ENVIRONMENTAL SCIENCES↗

Development of TRAIL Resistance by Radiation-Induced Hypermethylation of DR4 CpG Island in Recurrent Laryngeal Squamous Cell Carcinoma

Purpose: There are limited therapeutic options for patients with recurrent head and neck cancer after radiation therapy failure. To assess the use of tumor necrosis factor–related apoptosis-inducing ligand (TRAIL) as a salvage chemotherapeutic agent for recurrent cancer after radiation failure, we investigated the effect of clinically relevant cumulative irradiation on TRAIL-induced apoptosis. Methods and Materials: Using a previously established HN3 cell line from a laryngeal carcinoma patient, we generated a chronically irradiated HN3R isogenic cell line. Viability and apoptosis in HN3 and HN3R cells treated with TRAIL were analyzed with MTS and PI/annexin V-FITC assays. Western blotting and flow cytometry were used to determine the underlying mechanism of TRAIL resistance. DR4 expression was semiquantitatively scored in a tissue microarray with 107 laryngeal cancer specimens. Methylation-specific polymerase chain reaction and bisulfite sequencing for DR4 were performed for genomic DNA isolated from each cell line. Results: HN3R cells were more resistant than HN3 cells to TRAIL-induced apoptosis because of significantly reduced levels of the DR4 receptor. The DR4 staining score in 37 salvage surgical specimens after radiation failure was lower in 70 surgical specimens without radiation treatment (3.03 ± 2.75 vs 5.46 ± 3.30, respectively; P<.001). HN3R cells had a methylated DR4 CpG island that was partially demethylated by the DNA demethylating agent 5-aza-2′-deoxycytidine. Conclusion: Epigenetic silencing of the TRAIL receptor by hypermethylation of a DR4 CpG island might be an underlying mechanism for TRAIL resistance in recurrent laryngeal carcinoma treated with radiation.

62 RADIOLOGY AND NUCLEAR MEDICINE↗

α-Hispanolol sensitizes hepatocellular carcinoma cells to TRAIL-induced apoptosis via death receptor up-regulation

Hispanolone derivatives have been previously described as anti-inflammatory and antitumoral agents. However, their effects on overcoming Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) resistance remain to be elucidated. In this study, we analyzed the cytotoxic effects of the synthetic hispanolone derivative α-hispanolol (α-H) in several tumor cell lines, and we evaluated the induction of apoptosis, as well as the TRAIL-sensitizing potential of α-H in the hepatocellular carcinoma cell line HepG2. Our data show that α-H decreased cell viability in a dose-dependent manner in HeLa, MDA-MB231, U87 and HepG2 cell lines, with a more prominent effect in HepG2 cells. Interestingly, α-H had no effect on non-tumoral cells. α-H induced activation of caspase-8 and caspase-9 and also increased levels of the proapoptotic protein Bax, decreasing antiapoptotic proteins (Bcl-2, X-IAP and IAP-1) in HepG2 cells. Specific inhibition of caspase-8 abrogated the cascade of caspase activation, suggesting that the extrinsic pathway has a critical role in the apoptotic events induced by α-H. Furthermore, combined treatment of α-H with TRAIL enhanced apoptosis in HepG2 cells, activating caspase-8 and caspase-9. This correlated with up-regulation of both the TRAIL death receptor DR4 and DR5. DR4 or DR5 neutralizing antibodies abolished the effect of α-H on TRAIL-induced apoptosis, suggesting that sensitization was mediated through the death receptor pathway. Our results demonstrate that α-H induced apoptosis in the human hepatocellular carcinoma cell line HepG2 through activation of caspases and induction of the death receptor pathway. In addition, we describe a novel function of α-H as a sensitizer on TRAIL-induced apoptotic cell death in HepG2 cells. - Highlights: • α-Hispanolol induced apoptosis in the human hepatocellular carcinoma cell line HepG2. • α-Hispanolol induced activation of caspases and the death receptor pathway. • α-Hispanolol enhanced TRAIL-induced apoptosis through upregulation of death receptors.

60 APPLIED LIFE SCIENCES↗

Interferon-α and cyclooxygenase-2 inhibitor cooperatively mediates TRAIL-induced apoptosis in hepatocellular carcinoma

Hepatocellular carcinoma (HCC) is a leading cause of cancer-related mortality worldwide. Interferon-alpha (IFN-α) has recently been recognized to harbor therapeutic potential in the prevention and treatment of HCC, but it remains controversial as to whether IFN-α exerts direct cytotoxicity against HCC. Cyclooxygenase-2 (COX-2) is overexpressed in HCC and is considered to play a role in hepatocarcinogenesis. Therefore, we aimed to elucidate the combined effect of a COX-2 inhibitor, celecoxib, and IFN-α on in vitro growth suppression of HCC using the hepatoma cell line HLCZ01 and the in vivo nude mouse xenotransplantation model using HLCZ01 cells. Treatment with celecoxib and IFN-α synergistically inhibited cell proliferation in a dose- and time-dependent manner. Apoptosis was identified by 4',6-diamidino-2-phenylindole dihydrochloride and fluorescent staining. IFN-α upregulated the expression of TRAIL, while celecoxib increased the expression of TRAIL receptors. The combined regimen with celecoxib and IFN-α reduced the growth of xenotransplanted HCCs in nude mice. The regulation of IFN-α- and COX-2 inhibitor-induced cell death is impaired in a subset of TRAIL-resistant cells. The molecular mechanisms of HCC cells resistant to TRAIL-induced apoptosis were explored using molecular biological and immunological methods. Interferon-α and the COX-2 inhibitor celecoxib synergistically increased TRAIL-induced apoptosis in hepatocellular carcinoma. These data suggest that IFN-α and celecoxib may offer a novel role with important implications in designing new therapeutics for TRAIL-resistant tumors. - Highlights: ●The cytotoxic effect of TRAIL on a developed HCC HLCZ01 cells infected with HBV. ●IFN-α and celecoxib induced apoptosis in HLCZ01 cells infected with HBV. ●The combined regime reduced the growth of xenotransplanted HCCs in nude mice model.

60 APPLIED LIFE SCIENCES↗

DRBE comet trails

Re-examination of the Cosmic Background Explorer Diffuse Infrared Background Experiment (DIRBE) data reveals the thermal emission of several comet dust trails. The dust trails of 1P/Halley, 169P/NEAT, and 3200 Phaethon have not been previously reported. The known trails of 2P/Encke and 73P/Schwassmann–Wachmann 3 are also seen. The dust trails have 12 and 25 μm surface brightnesses of <0.1 and <0.15 MJy sr{sup −1}, respectively, which is <1% of the zodiacal light intensity. The trails are very difficult to see in any single daily image of the sky, but are evident as rapidly moving linear features in movies of the DIRBE data. Some trails are clearest when crossing through the orbital plane of the parent comet, but others are best seen at high ecliptic latitudes as the Earth passes over or under the dust trail. All these comets have known associations with meteor showers. This re-examination also reveals 1 additional comet and 13 additional asteroids that had not previously been recognized in the DIRBE data.

79 ASTRONOMY AND ASTROPHYSICS↗

Aggregation-fragmentation-diffusion model for trail dynamics

We investigate statistical properties of trails formed by a random process incorporating aggregation, fragmentation, and diffusion. In this stochastic process, which takes place in one spatial dimension, two neighboring trails may combine to form a larger one, and also one trail may split into two. In addition, trails move diffusively. The model is defined by two parameters which quantify the fragmentation rate and the fragment size. In the long-time limit, the system reaches a steady state, and our focus is the limiting distribution of trail weights. We find that the density of trail weight has power-law tail P(w)~w –γ for small weight w. We obtain the exponent γ analytically and find that it varies continuously with the two model parameters. In conclusion, the exponent γ can be positive or negative, so that in one range of parameters small-weight trails are abundant and in the complementary range they are rare.

71 CLASSICAL AND QUANTUM MECHANICS, GENERAL PHYSIC↗

Critical review of the trailing edge condition in steady and unsteady flow. Blade flutter in compressors and fans: Numerical simulation of the aerodynamic loading

Existing interpretations of the trailing edge condition, addressing both theoretical and experimental works in steady, as well as unsteady flows are critically reviewed. The work of Kutta and Joukowski on the trailing edge condition in steady flow is reviewed. It is shown that for most practical airfoils and blades (as in the case of most turbomachine blades), this condition is violated due to rounded trailing edges and high frequency effects, the flow dynamics in the trailing edge region being dominated by viscous forces; therefore, any meaningful modelling must include viscous effects. The question of to what extent the trailing edge condition affects acoustic radiation from the edge is raised; it is found that violation of the trailing edge condition leads to significant sound diffraction at the tailing edge, which is related to the problem of noise generation. Finally, various trailing edge conditions in unsteady flow are discussed, with emphasis on high reduced frequencies.

Radwan, S. F.↗

Preliminary analysis of cometary dust trails

Dust trails are observed in the orbits of some short-period comets. Large particles, having diameters in the submillimeter range and larger, are ejected by these comets into orbits close to that of the parent comet. By considering the effects of ejection and radiation forces, the spread of particles of different diameters along a parent comet's orbit, both ahead and behind the comet in mean anomaly were modeled. Using this model, the ages of the dust trail material associated with P/Tempel 2, P/Gunn, P/Encke, and P/Schwassmann-Wachmann 1 were estimated; they are found to consist of emissions occurring over a minimum of one to a few orbital periods. It also becomes possible to constrain the particle diameters in a trail segment forward of a comet's orbital position. Such a forward extension is observed in the Tempel 2 and Gunn dust trails, but not the Encke and S-W 1 dust trails. Relative particle sizes among these trails are discussed. The Tempel 2 dust trail is found to have an excess of particles with diameters greater than 1 mm.

Sykes, M. V.↗

Numerical study of the trailing vortex of a wing with wing-tip blowing

Trailing vortices generated by lifting surfaces such as helicopter rotor blades, ship propellers, fixed wings, and canard control surfaces are known to be the source of noise, vibration, cavitation, degradation of performance, and other hazardous problems. Controlling these vortices is, therefore, of practical interest. The formation and behavior of the trailing vortices are studied in the present research. In addition, wing-tip blowing concepts employing axial blowing and spanwise blowing are studied to determine their effectiveness in controlling these vortices and their effects on the performance of the wing. The 3D, unsteady, thin-layer compressible Navier-Stokes equations are solved using a time-accurate, implicit, finite difference scheme that employs LU-ADI factorization. The wing-tip blowing is simulated using the actuator plane concept, thereby, not requiring resolution of the jet slot geometry. Furthermore, the solution blanking feature of the chimera scheme is used to simplify the parametric study procedure for the wing-tip blowing. Computed results are shown to compare favorably with experimental measurements. It is found that axial wing-tip blowing, although delaying the rolling-up of the trailing vortices and the near-field behavior of the flowfield, does not dissipate the circulation strength of the trailing vortex farther downstream. Spanwise wing-tip blowing has the effect of displacing the trailing vortices outboard and upward. The increased 'wing-span' due to the spanwise wing-tip blowing has the effect of lift augmentation on the wing and the strengthening of the trailing vortices. Secondary trailing vortices are created at high spanwise wing-tip blowing intensities.

Lim, Hock-Bin↗

Experimental evaluation of the certification-trail method

Certification trails are a recently introduced and promising approach to fault-detection and fault-tolerance. A comprehensive attempt to assess experimentally the performance and overall value of the method is reported. The method is applied to algorithms for the following problems: huffman tree, shortest path, minimum spanning tree, sorting, and convex hull. Our results reveal many cases in which an approach using certification-trails allows for significantly faster overall program execution time than a basic time redundancy-approach. Algorithms for the answer-validation problem for abstract data types were also examined. This kind of problem provides a basis for applying the certification-trail method to wide classes of algorithms. Answer-validation solutions for two types of priority queues were implemented and analyzed. In both cases, the algorithm which performs answer-validation is substantially faster than the original algorithm for computing the answer. Next, a probabilistic model and analysis which enables comparison between the certification-trail method and the time-redundancy approach were presented. The analysis reveals some substantial and sometimes surprising advantages for ther certification-trail method. Finally, the work our group performed on the design and implementation of fault injection testbeds for experimental analysis of the certification trail technique is discussed. This work employs two distinct methodologies, software fault injection (modification of instruction, data, and stack segments of programs on a Sun Sparcstation ELC and on an IBM 386 PC) and hardware fault injection (control, address, and data lines of a Motorola MC68000-based target system pulsed at logical zero/one values). Our results indicate the viability of the certification trail technique. It is also believed that the tools developed provide a solid base for additional exploration.

Sullivan, Gregory F.↗

Using certification trails to achieve software fault tolerance

A conceptually novel and powerful technique to achieve fault tolerance in hardware and software systems is introduced. When used for software fault tolerance, this new technique uses time and software redundancy and can be outlined as follows. In the initial phase, a program is run to solve a problem and store the result. In addition, this program leaves behind a trail of data called a certification trail. In the second phase, another program is run which solves the original problem again. This program, however, has access to the certification trail left by the first program. Because of the availability of the certification trail, the second phase can be performed by a less complex program and can execute more quickly. In the final phase, the two results are accepted as correct; otherwise an error is indicated. An essential aspect of this approach is that the second program must always generate either an error indication or a correct output even when the certification trail it receives from the first program is incorrect. The certification trail approach to fault tolerance was formalized and it was illustrated by applying it to the fundamental problem of finding a minimum spanning tree. Cases in which the second phase can be run concorrectly with the first and act as a monitor are discussed. The certification trail approach was compared to other approaches to fault tolerance. Because of space limitations we have omitted examples of our technique applied to the Huffman tree, and convex hull problems. These can be found in the full version of this paper.

Sullivan, Gregory F.↗

Dust Trails of SP/Tuttle and the Unusual Outbursts of the Ursid Shower

Halley-type comets tend to have a series of dust trails that remain spatially correlated for extended periods of time, each dating from a specific return of the comet. Encounters with 1 - 9 revolution old individual dust trails of 55P/Tempel-Tuttle have led to well recognized Leonid shower maxim, the peak time of which was well predicted by recent models. Now. we used the same model to calculate the position of dust trails of comet Shuttle, a Halley-type comet in an (approximately) 13.6 year orbit passing just outside of Earth's orbit. We discovered that the meteoroids tend to be trapped in the 14:12 mean motion resonance with Jupiter, while the comet librates in a slightly shorter period orbit around the 13:15 resonance. It takes six centuries to change the orbit enough to intersect Earth's orbit. During that time, the meteoroids and comet separate in mean anomaly by six years. thus explaining the unusual aphelion occurrences of Ursid outbursts. The resonances also prevent dispersion, so that the dust trail encounters (specifically, from dust trails of AD 1378 - 1405) occur only in one year in each orbit. We predicted enhanced activity on December 22, 2000, at around 7:29 and 8:35 UT (universal time) from dust trails dating to the 1405 and 1392 return, respectively. This event was observed from California using video and photographic techniques. At the same time, five Global-MS-Net stations in Finland, Japan and Belgium counted meteors using forward meteor scatter. The outburst peaked at 8:06:07 UT, December 22, at Zenith Hourly Rate (approx.) 90 per hour. The Ursid rates were above half peak intensity during 4.2 hours. This is only the second Halley type comet for which a meteor outburst can be dated to a specific return of the parent comet, and traces their presence back form 9 to at least 45 revolutions of the comet. New orbital elements of Ursid meteoroids are presented. We find that most orbits do scatter around the anticipated positions, confirming the link with comet Shuttle and the epoch of ejection. The 1405 and.1392 dust trails appear to have contributed similar amounts to the activity profile. Some orbits provide a hint of much older debris being present as well. Some of the dispersion in the radiant position may reflect a true variation in inclinations, with two groupings at low and high values, which is not understood at present.

Jenniskens, Peter↗