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Expression and function of the TRAIL apoptotic pathway was investigated in normal and malignant breast epithelial cells. Glutathione-S-transferase (GST)-TRAIL extracellular domain fusion proteins were produced to analyze TRAIL-induced apoptosis. Only GST-TRAIL constructs containing regions homologous to the Fas self-association and ligand binding domains could induce apoptosis. GST-TRAIL induced significant (>90%) apoptosis in just one of eight normal and one of eight malignant breast cell lines. All other lines were relatively resistant to TRAIL-induced apoptosis. Activating TRAIL receptors DR4 and DR5 were expressed in all normal and malignant breast cell lines. The inhibitory receptor TRID was highly expressed in one of four normal and two of seven malignant breast cell lines. DR4, DR5, or TRID expression did not correlate with sensitivity to TRAIL-induced apoptosis. Incubation of cell lines with doxorubicin or 5-fluorouracil significantly augmented TRAIL-induced apoptosis in most breast cell lines. By fractional inhibition analysis, the toxicity of the combination of TRAIL and doxorubicin or 5-fluorouracil was synergistic compared with either agent alone. In contrast, melphalan and paclitaxel augmented TRAIL-induced apoptosis in few cell lines, and methotrexate did not augment it in any cell line. Augmentation of TRAIL-induced apoptosis by doxorubicin or 5-fluorouracil was mediated through caspase activation. This was evidenced by the fact that chemotherapy agents that synergized with TRAIL (e.g., doxorubicin) themselves caused cleavage of caspase-3 and poly(ADP-ribose) polymerase (PARP), and their toxicity was blocked by the caspase inhibitor Z-Val-Ala-Asp(OMe)-CH2 (ZVAD-fmk). The combination of TRAIL and doxorubicin caused significantly greater caspase-3 and PARP cleavage, and the combined toxicity also was inhibited by ZVAD-fmk. In contrast, chemotherapy agents that did not augment TRAIL-induced apoptosis (e.g., methotrexate) caused minimal caspase-3 and PARP cleavage by themselves, and their toxicity was not inhibited by ZVAD-fmk. These drugs also did not increase caspase-3 or PARP cleavage when combined with TRAIL. In summary, few breast cell lines are sensitive to TRAIL-induced apoptosis, and no difference in sensitivity is found between normal and malignant cell lines. Treatment with chemotherapy provides an approach to sensitize breast cancer cells to TRAIL-induced apoptosis.

The observation that TNF-related apoptosis-inducing ligand (TRAIL), a member of the TNF cytokine family, induces apoptosis in a number of different tumor cell types led us to compare the tumoricidal effects of TRAIL to those of other TNF family molecules on human melanoma cells. We found that a high proportion of the melanoma cell lines tested were killed by TRAIL, whereas all the melanoma lines were resistant to the other TNF family cytokines tested. TRAIL-induced death was characterized by caspase activation and cellular protein cleavage within minutes of TRAIL addition, and death could be completely inhibited by the caspase inhibitors Ile-Glu-Thr-Asp (IETD) and Val-Ala-Asp (VAD), indicating the presence of a TRAIL receptor signaling pathway similar to that identified for Fas and TNF receptors. Specific TRAIL receptor expression was determined by RT-PCR, and the presence of mRNA encoding the "protective" TRAIL receptors did not correspond to resistance or sensitivity to TRAIL-induced apoptosis. Addition of protein synthesis inhibitors to TRAIL-resistant melanomas rendered them sensitive to TRAIL, indicating that the presence or the absence of intracellular apoptosis inhibitors may mediate resistance or sensitivity to TRAIL-mediated apoptosis. Expression of one such inhibitor, FLICE-inhibitory protein (FLIP), was highest in the TRAIL-resistant melanomas, while being low or undetectable in the TRAIL-sensitive melanomas. Furthermore, addition of actinomycin D to TRAIL-resistant melanomas resulted in decreased intracellular concentrations of FLIP, which correlated with their acquisition of TRAIL sensitivity. Collectively, our results indicate that TRAIL-induced apoptosis occurs through a caspase signaling cascade and that resistance is controlled by intracellular regulators of apoptosis.

TRAIL-R3, a new member of the TRAIL receptor family, has been cloned and characterized. TRAIL-R3 encodes a 299 amino acid protein with 58 and 54% overall identity to TRAIL-R1 and -R2, respectively. Transient expression and quantitative binding studies show TRAIL-R3 to be a plasma membrane-bound protein capable of high affinity interaction with the TRAIL ligand. The TRAIL-R3 gene maps to human chromosome 8p22-21, clustered with the genes encoding two other TRAIL receptors. In contrast to TRAIL-R1 and -R2, this receptor shows restricted expression, with transcripts detectable only in peripheral blood lymphocytes and spleen. The structure of TRAIL-R3 is unique when compared to the other TRAIL receptors in that it lacks a cytoplasmic domain and appears to be glycosyl-phosphatidylinositol-linked. Moreover, unlike TRAIL-R1 and -R2, in a transient overexpression system TRAIL-R3 does not induce apoptosis.

A human receptor for the cytotoxic ligand TRAIL (TRAIL receptor-1, designated DR4) was identified recently as a member of the tumor necrosis factor receptor family. In this report we describe the identification of two additional human TRAIL receptors, TRAIL receptor-2 and TRAIL receptor-3, that belong to the tumor necrosis factor receptor family. Interestingly, TRAIL receptor-2 but not TRAIL receptor-3 contains a cytoplasmic "death domain" necessary for induction of apoptosis and is hence designated death receptor-5 (DR5). Like DR4, DR5 engages the apoptotic pathway independent of the adaptor molecule FADD/MORT1. Because of its lack of a death domain, TRAIL receptor-3 is not capable of inducing apoptosis. However, by competing for TRAIL, it is capable of inhibiting TRAIL-induced apoptosis. Thus, TRAIL receptor-3 may function as an antagonistic decoy receptor to attenuate the cytotoxic effect of TRAIL in most tissues that are TRAIL+, DR4+, and DR5+.

Resistance to chemotherapeutic drugs is the major hindrance in the successful cancer therapy. The tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a member of the tumor necrosis factor (TNF) family of ligands, which initiates apoptosis in cancer cells through interaction with the death receptors DR4 and DR5. TRAIL is perceived as an attractive chemotherapeutic agent as it specifically targets cancer cells while sparing the normal cells. However, TRAIL therapy has a major limitation as a large number of the cancer develop resistance toward TRAIL and escape from the destruction by the immune system. Therefore, elucidation of the molecular targets and signaling pathways responsible for TRAIL resistance is imperative for devising effective therapeutic strategies for TRAIL resistant cancers. Although, various molecular targets leading to TRAIL resistance are well-studied, recent studies have implicated that the contribution of some key cellular processes toward TRAIL resistance need to be fully elucidated. These processes primarily include aberrant protein synthesis, protein misfolding, ubiquitin regulated death receptor expression, metabolic pathways, epigenetic deregulation, and metastasis. Novel synthetic/natural compounds that could inhibit these defective cellular processes may restore the TRAIL sensitivity and combination therapies with such compounds may resensitize TRAIL resistant cancer cells toward TRAIL-induced apoptosis. In this review, we have summarized the key cellular processes associated with TRAIL resistance and their status as therapeutic targets for novel TRAIL-sensitizing agents.

TRAIL is a tumor necrosis factor-related ligand that induces apoptosis upon binding to its death domain-containing receptors, DR4 and DR5. Two additional TRAIL receptors, TRID/DcR1 and DcR2, lack functional death domains and function as decoy receptors for TRAIL. We have identified a fifth TRAIL receptor, namely osteoprotegerin (OPG), a secreted tumor necrosis factor receptor homologue that inhibits osteoclastogenesis and increases bone density in vivo. OPG-Fc binds TRAIL with an affinity of 3.0 nM, which is slightly weaker than the interaction of TRID-Fc or DR5-Fc with TRAIL. OPG inhibits TRAIL-induced apoptosis of Jurkat cells. Conversely, TRAIL blocks the anti-osteoclastogenic activity of OPG. These data suggest potential cross-regulatory mechanisms by OPG and TRAIL.

Unlike other members of the TNF superfamily, the TNF-related apoptosis-inducing ligand (TRAIL, also known as Apo2L) possesses the unique capacity to induce apoptosis selectively in cancer cells in vitro and in vivo. This exciting discovery provided the basis for the development of TRAIL-receptor agonists (TRAs), which have demonstrated robust anticancer activity in a number of preclinical studies. Subsequently initiated clinical trials testing TRAs demonstrated, on the one hand, broad tolerability but revealed, on the other, that therapeutic benefit was rather limited. Several factors that are likely to account for TRAs' sobering clinical performance have since been identified. First, because of initial concerns over potential hepatotoxicity, TRAs with relatively weak agonistic activity were selected to enter clinical trials. Second, although TRAIL can induce apoptosis in several cancer cell lines, it has now emerged that many others, and importantly, most primary cancer cells are resistant to TRAIL monotherapy. Third, so far patients enrolled in TRA-employing clinical trials were not selected for likelihood of benefitting from a TRA-comprising therapy on the basis of a valid(ated) biomarker. This review summarizes and discusses the results achieved so far in TRA-employing clinical trials in the light of these three shortcomings. By integrating recent insight on apoptotic and non-apoptotic TRAIL signaling in cancer cells, we propose approaches to introduce novel, revised TRAIL-based therapeutic concepts into the cancer clinic. These include (i) the use of recently developed highly active TRAs, (ii) the addition of efficient, but cancer-cell-selective TRAIL-sensitizing agents to overcome TRAIL resistance and (iii) employing proteomic profiling to uncover resistance mechanisms. We envisage that this shall enable the design of effective TRA-comprising therapeutic concepts for individual cancer patients in the future.

Ethanolic extract of propolis (EEP) is one of the richest sources of phenolic acids and flavonoids. EEP and its phenolic compounds have been known for various biological activities including immunopotentiation, chemopreventive and antitumor effects. Tumor necrosis factor related apoptosis inducing ligand (TRAIL) is a naturally occurring anticancer agent that preferentially induces apoptosis in cancer cells and is not toxic toward normal cells. We examined the cytotoxic and apoptotic effect of EEP and phenolic compounds identified in propolis in combination with TRAIL on HeLa cancer cells. HeLa cells were resistant to TRAIL-induced apoptosis. Our study demonstrated that EEP and its components significantly sensitize to TRAIL induced death in cancer cells. The percentage of the apoptotic cell after exposure to 50 microg/mL EEP and 100 ng/mL TRAIL increased to 71.10 +/- 1.16%. The strongest cytotoxic effect in combination with TRAIL on HeLa cells exhibited apigenin and CAPE at the concentration of 50 microM (58.87 +/- 0.75% and 49.59 +/- 0.39%, respectively). In this report, we show for the first time that EEP markedly augmented TRAIL mediated apoptosis in cancer cells and confirmed the importance of propolis in chemoprevention of malignant tumors.

TRAIL/Apo-2L induces rapid apoptosis of a variety of tumor cell lines. A family of tumor necrosis factor receptor-related molecules have been identified as receptors for TRAIL. Herein, we report the identification of another member of the TRAIL receptor family, TRUNDD (TRAIL receptor with a truncated death domain). The TRUNDD transcript was detected in multiple human tissues. TRUNDD is highly homologous to all known TRAIL receptors and has an extracellular TRAIL-binding domain but lacks a functional intracellular death domain and does not induce apoptosis. Consistent with an inhibitory role, ectopic expression of TRUNDD attenuated TRAIL-induced apoptosis in mammalian cells.

TRAIL, also called Apo2L, is a cytotoxic protein that induces apoptosis of many transformed cell lines but not of normal tissues, even though its death domain-containing receptor, DR4, is expressed on both cell types. An antagonist decoy receptor (designated as TRID for TRAIL receptor without an intracellular domain) that may explain the resistant phenotype of normal tissues was identified. TRID is a distinct gene product with an extracellular TRAIL-binding domain and a transmembrane domain but no intracellular signaling domain. TRID transcripts were detected in many normal human tissues but not in most cancer cell lines examined. Ectopic expression of TRID protected mammalian cells from TRAIL-induced apoptosis, which is consistent with a protective role. Another death domain-containing receptor for TRAIL (designated as death receptor-5), which preferentially engaged a FLICE (caspase-8)-related death protease, was also identified.

We study the problem of perceiving forest or mountain trails from a single monocular image acquired from the viewpoint of a robot traveling on the trail itself. Previous literature focused on trail segmentation, and used low-level features such as image saliency or appearance contrast; we propose a different approach based on a deep neural network used as a supervised image classifier. By operating on the whole image at once, our system outputs the main direction of the trail compared to the viewing direction. Qualitative and quantitative results computed on a large real-world dataset (which we provide for download) show that our approach outperforms alternatives, and yields an accuracy comparable to the accuracy of humans that are tested on the same image classification task. Preliminary results on using this information for quadrotor control in unseen trails are reported. To the best of our knowledge, this is the first letter that describes an approach to perceive forest trials, which is demonstrated on a quadrotor micro aerial vehicle.

Abstract A new two-moment cloud microphysics scheme predicting the mixing ratios and number concentrations of five species (i.e., cloud droplets, cloud ice, snow, rain, and graupel) has been implemented into the Weather Research and Forecasting model (WRF). This scheme is used to investigate the formation and evolution of trailing stratiform precipitation in an idealized two-dimensional squall line. Results are compared to those using a one-moment version of the scheme that predicts only the mixing ratios of the species, and diagnoses the number concentrations from the specified size distribution intercept parameter and predicted mixing ratio. The overall structure of the storm is similar using either the one- or two-moment schemes, although there are notable differences. The two-moment (2-M) scheme produces a widespread region of trailing stratiform precipitation within several hours of the storm formation. In contrast, there is negligible trailing stratiform precipitation using the one-moment (1-M) scheme. The primary reason for this difference are reduced rain evaporation rates in 2-M compared to 1-M in the trailing stratiform region, leading directly to greater rain mixing ratios and surface rainfall rates. Second, increased rain evaporation rates in 2-M compared to 1-M in the convective region at midlevels result in weaker convective updraft cells and increased midlevel detrainment and flux of positively buoyant air from the convective into the stratiform region. This flux is in turn associated with a stronger mesoscale updraft in the stratiform region and enhanced ice growth rates. The reduced (increased) rates of rain evaporation in the stratiform (convective) regions in 2-M are associated with differences in the predicted rain size distribution intercept parameter (which was specified as a constant in 1-M) between the two regions. This variability is consistent with surface disdrometer measurements in previous studies that show a rapid decrease of the rain intercept parameter during the transition from convective to stratiform rainfall.

A characteristic feature of a steady trailing line vortex from one side of a wing, and of other types of line vortex, is the existence of strong axial currents near the axis of symmetry. The purpose of this paper is to account in general terms for this axial flow in trailing line vortices. the link between the azimuthal and axial components of motion in a steady line vortex is provided by the pressure; the radial pressure gradient balances the centrifugal force, and any change in the azimuthal motion with distance x downstream produces an axial pressure gradient and consequently axial acceleration. It is suggested, in a discussion of the evolution of an axisymmetric line vortex out of the vortex sheet shed from one side of a wing, that the two processes of rolling-up of the sheet and of concentration of the vorticity into a smaller cross-section should be distinguished; the former always occurs, whereas the latter seems not to be inevitable. In § 4 there is given a similarity solution for the flow in a trailing vortex far downstream where the departure of the axial velocity from the free stream speed is small. The continual slowing-down of the azimuthal motion by viscosity leads to a positive axial pressure gradient and consequently to continual loss of axial momentum, the asymptotic variation of the axial velocity defect at the centre being as x −1 log x . The concept of the drag associated with the core of a trailing vortex is introduced, and the drag is expressed as an integral over a transverse plane which is independent of x. This drag is related to the arbitrary constant appearing in the above similarity solution.

TRAIL (also known as Apo-2L) is a member of the tumor necrosis factor (TNF) ligand family that rapidly induces apoptosis in a variety of transformed cell lines. The human receptor for TRAIL was found to be an undescribed member of the TNF-receptor family (designated death receptor-4, DR4) that contains a cytoplasmic "death domain" capable of engaging the cell suicide apparatus but not the nuclear factor kappa B pathway in the system studied. Unlike Fas, TNFR-1, and DR3, DR4 could not use FADD to transmit the death signal, suggesting the use of distinct proximal signaling machinery. Thus, the DR4-TRAIL axis defines another receptor-ligand pair involved in regulating cell suicide and tissue homeostasis.

TRAIL (also called Apo2L) belongs to the tumor necrosis factor family, activates rapid apoptosis in tumor cells, and binds to the death-signaling receptor DR4. Two additional TRAIL receptors were identified. The receptor designated death receptor 5 (DR5) contained a cytoplasmic death domain and induced apoptosis much like DR4. The receptor designated decoy receptor 1 (DcR1) displayed properties of a glycophospholipid-anchored cell surface protein. DcR1 acted as a decoy receptor that inhibited TRAIL signaling. Thus, a cell surface mechanism exists for the regulation of cellular responsiveness to pro-apoptotic stimuli.

The aim of this paper is to show the way in which the decision trail of a qualitative research process can be maintained. It is argued that the trustworthiness (rigour) of a study may be established if the reader is able to audit the events, influences and actions of the researcher. The actual study containing the recording of this decision trail aimed to express the concerns of older patients who were admitted to the acute care sector. The study took place in two care of the elderly wards in a 1000-bed National Health Service hospital in the UK, in 1991. Eventually, 14 patients were interviewed, each on several occasions, and their concerns are expressed in themes, namely: routine geriatric style of care, depersonalization, care deprivation and geriatric segregation. I describe the preparations that were undertaken before patient interviews could commence. The literature recording the process of the interviewer's experience as data in qualitative research is scarce. I show the researcher's participation in making the data as part of an existential phenomenological research process. Existential phenomenology relies on recording influences while generating data such as significant literature, media reports, my value position and journal data.

x(/3) Trailing vortices do not decay by simple diffusion. Usually they undergo a symmetric and nearly sinusoidal instability, until eventually they join at intervals to form a train of vortex rings. The present theory accounts for the instability during the early stages of its growth. The vortices are idealized as interacting lines; their core diameters are taken into account by a cutoff in the line integral representing self-induction. The equation relating induced velocity to vortex displacement gives rise to an eigenvalue problem for the growth rate of sinusoidal perturbations. Stability is found to depend on the products of vortex separation 6 and cutoff distance d times the perturbation wavenumber. Depending on those products, both symmetric and antisymmetric eigenmodes can be unstable, but only the symmetric mode involves strongly interacting long waves. An argument is presented that d/b = 0.063 for the vortices trailing from an elliptically loaded wing. In that case, the maximally unstable long wave has a length 8.66 and grows by a factor e in a time 9.4(^4#/CL)(6/F0), where AR is the aspect ratio, CL is the lift coefficient, and V0 is the speed of the aircraft. The vortex displacements are symmetric and are confined to fixed planes inclined at 48° to the horizontal.

Recent controversy surrounds the use of the Trail Making Test as a measure of cognitive flexibility, given that the Trail Making Test, Part B (TMT-B) also differs from Part A (TMT-A) in factors of motor control and perceptual complexity. The present study compared performance in the TMT and a set-switching task in order to test the assumption that cognitive flexibility is captured in TMT-B performance. Set-switching tasks have low motor and perceptual selection demands, and therefore provide a clearer index of executive function. In this study, participants made category judgments for digits, letters, or symbols across a series of trials, and performance for consecutive same-task trials was compared with task-switch trials. Results of the set-switching task indicated significant switch cost, but only for the situation of task alternation (e.g., an ABA series), suggesting that task-set inhibition may play a role in this effect. Alternating-switch cost was significantly correlated with TMT-B performance, especially with the TMT-B to TMT-A ratio (B/A). Cost for alternating switches was especially large for participants with B/A ratio > 3. These results provide direct evidence that the B/A ratio of performance in the TMT provides an index of executive function.

We describe the synthesis and properties of a small molecule mimic of Smac, a pro-apoptotic protein that functions by relieving inhibitor-of-apoptosis protein (IAP)-mediated suppression of caspase activity. The compound binds to X chromosome- encoded IAP (XIAP), cellular IAP 1 (cIAP-1), and cellular IAP 2 (cIAP-2) and synergizes with both tumor necrosis factor alpha (TNFalpha) and TNF-related apoptosis-inducing ligand (TRAIL) to potently induce caspase activation and apoptosis in human cancer cells. The molecule has allowed a temporal, unbiased evaluation of the roles that IAP proteins play during signaling from TRAIL and TNF receptors. The compound is also a lead structure for the development of IAP antagonists potentially useful as therapy for cancer and inflammatory diseases.