210,650 research outputs found
Microsatellite instability, KRAS mutations and cellular distribution of TRAIL-receptors in early stage colorectal cancer.
No full textThus, we evaluated the immunofluorescence pattern of TRAIL-receptors and E-cadherin to assess the fraction of membrane-bound TRAIL-receptors in 231 selected patients with early-stage CRC undergoing surgical treatment only. Moreover, we investigated whether membrane staining for TRAIL-receptors as well as the presence of KRAS mutations or of microsatellite instability (MSI) had an effect on survival and thus a prognostic effect.
The fact that the receptors for the TNF-related apoptosis inducing ligand (TRAIL) are almost invariably expressed in colorectal cancer (CRC) represents the rationale for the employment of TRAIL-receptors targeting compounds for the therapy of patients affected by this tumor. Yet, first reports on the use of these bioactive agents provided disappointing results. We therefore hypothesized that loss of membrane-bound TRAIL-R might be a feature of some CRC and that the evaluation of membrane staining rather than that of the overall expression of TRAIL-R might predict the response to TRAIL-R targeting compounds in this tumor. As expected, almost all CRC samples stained positive for TRAIL-R1 and 2. Instead, membrane staining for these receptors was positive in only 71% and 16% of samples respectively. No correlation between KRAS mutation status or MSI-phenotype and prognosis could be detected. TRAIL-R1 staining intensity correlated with survival in univariate analysis, but only membranous staining of TRAIL-R1 and TRAIL-R2 on cell membranes was an independent predictor of survival (cox multivariate analysis: TRAIL-R1: p = 0.019, RR 2.06[1.12-3.77]; TRAIL-R2: p = 0.033, RR 3.63[1.11-11.84]). In contrast to the current assumptions, loss of membrane staining for TRAIL-receptors is a common feature of early stage CRC which supersedes the prognostic significance of their staining intensity. Failure to achieve therapeutic effects in recent clinical trials using TRAIL-receptors targeting compounds might be due to insufficient selection of patients bearing tumors with membrane-bound TRAIL-receptors
Design and engineering of human TRAIL variants
No full textTRAIL is een humaan eiwit dat bepaalde typen kankercellen aanzet tot geprogrammeerde celdood (apoptose) terwijl het normale cellen met rust laat. Hierdoor is TRAIL een veelbelovend potentieel anti kanker geneesmiddel. Promovendus Almer van der Sloot optimaliseerde TRAIL voor gebruik als geneesmiddel door het enerzijds stabieler te maken en anderzijds selectiever en actiever voor bepaalde typen kankercellen. Ook in combinatie met radiotherapie en bepaalde vormen van chemotherapie lijken de selectieve TRAIL varianten een meer potente anti kanker werking te hebben dan de oorspronkelijke. Hiervoor waren slechts een klein aantal veranderingen nodig in het TRAIL molecuul.
Pioglitazone inhibits growth of carcinoid cells and promotes TRAIL-induced apoptosis by induction of p21(waf1/cip1)
No full textBackground/Aims: We investigated the effect of the peroxisome proliferator-activated receptor-gamma (PPAR-gamma) agonist pioglitazone on growth and TRAIL-induced apoptosis in carcinoid cells. Methods: Carcinoid cells were incubated without and with pioglitazone. Effects on growth were examined by cell count and cell cycle analysis. p21(waf1/cip1) expression was determined by Western blotting. Cytotoxicity assay was performed by FACS analysis. Results: Pioglitazone suppressed the growth and induced apoptosis of carcinoid cells. Additionally, pioglitazone significantly enhanced carcinoid cell death induced by tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL). The enhancement of TRAIL-induced apoptosis was associated with an upregulation of cyclin-dependent kinase inhibitor p21(waf1/cip1) in pioglitazone-treated carcinoid cells. Importantly, overexpression of p21(waf1/cip1) in carcinoid cells by adenoviral gene transfer of p21 sensitized them to TRAIL-induced apoptosis. Conclusions: These results suggest that pioglitazone inhibits cell growth and sensitizes cells to TRAIL-induced apoptosis by induction of p21(waf1/cip1). Therefore, pioglitazone can be an effective therapeutic adjuvant for the treatment of carcinoid tumors. Copyright (C) 2001 S. Karger AG, Basel
Anti-Tumor Effects of TRAIL-Expressing Mesenchymal Stromal Cells in a Mouse Xenograft Model of Human Mesothelioma
No full textMalignant mesothelioma (MM) remains a highly deadly malignancy with poor treatment option. The MM cells further promote a highly inflammatory microenvironment which contributes to tumor initiation, development, severity, and propagation. We reasoned that the anti-inflammatory actions of mesenchymal stromal cells (MSCs) and further anti-tumor effects of MSCs engineered to over-express TNF-related apoptosis inducing ligand (TRAIL) protein (MSC-TRAIL) would effectively inhibit mesothelioma growth. Using a mouse xenograft model of intraperitoneal human mesothelioma, native mouse (mMSC) or human (hMSC) MSCs were administered either systemically (IV) or intraperitoneally (IP) at various times following tumor inoculation. Both mMSCs and hMSCs localized at sites of MM tumor growth in vivo and decreased local inflammation. Further, a trend towards decrease in tumor burden was observed. Parallel studies of in vitro exposure of nine primary human mesothelioma cell lines to mMSCs or hMSCs demonstrated reduced tumor cell migration. In contrast MSC-TRAIL exposure induced apoptosis of TRAIL sensitive MM cells in vitro and both mouse and human MSC-TRAIL significantly reduced the inflammatory tumor environment in vivo. Moreover human MSC-TRAIL administration significantly reduced peritoneal tumor burden in vivo and increased tumor cell apoptosis. These proof-of-concept studies suggest that TRAIL-expressing MSCs may be useful against malignant mesothelioma
Differential activation of JNK1 isoforms by TRAIL receptors modulate apoptosis of colon cancer cell lines
No full textTumour necrosis factor-related apoptosis-inducing ligand (TRAIL) induces apoptosis on binding to its receptors, death receptor 4 and 5 (DR4, DR5). TRAIL can also activate c-Jun N-terminal kinase (JNK) through the adaptor molecules, TNF receptor-associated factor 2 (TRAF2) and receptor-interacting protein (RIP). The role of JNK in TRAIL-induced tumour cell apoptosis is unclear. In this study, we demonstrate that JNK is activated by TRAIL in colon cancer cells. Inhibition of JNK with L-JNKI reduced rhTRAIL-induced cell death but enhanced cell death induced by selective activation of DR4 or DR5. This difference was unrelated to receptor internalisation or differential activation of c-Jun, but activation of different JNK isoforms. Our data demonstrate that JNK1, but not JNK2 is activated by rhTRAIL in the examined colon cancer cell lines. Although rhTRAIL activated both the long and short isoforms of JNK1, selective activation of DR4 or DR5 led to predominant activation of the short JNK1 isoforms (JNK1 alpha 1 and/or JNK1 beta 1). Knockdown of JNK1 alpha 1 by shRNA enhanced apoptosis induced by TRAIL, agonistic DR4 or DR5 antibodies. On the other hand, knockdown of the long JNK1 isoforms (JNK1 alpha 2 and JNK1 beta 2) had the opposite effect; it reduced TRAIL-induced cell death. These data indicate that the short JNK1 isoforms transmit an antiapoptotic signal, whereas the long isoforms (JNK1 alpha 2 or JNK1 beta 2) act in a proapoptotic manner.peer-reviewe
Recreational Demand for Equestrian Trail-Riding
No full textUsing data collected from a combination of on-site and on-line surveys, this study examines recreational demand for equestrian trail-riding in Kentucky. A truncated, negative binomial regression is applied to analyze individuals’ visitation behavior consistent with a travel cost model. Results suggest that distance is the most significant determinant of average annual visits to a particular site. Various trail site characteristics, such as trail length, scenic overlooks, and trail markers, affect the number of visits an individual takes. Geographic information system (GIS) analysis permits the identification of equestrian population centers. Information obtained from this study offers a decision base for policymakers to use to manage existing equestrian trails and locate new ones.equestrian trail-riding, GIS analysis, truncated negative binomial, travel cost method, Resource /Energy Economics and Policy,
The Kicking Horse Trail
No full textAmong the long-closed regions of wonder and romance into which a way has at last been found are the Canadian Rockies. Each year the door has been opened a little farther, until now a good part of the most beautiful sections of these glorious ranges is within the motorist’s reach. The completion of the new highway, “The Kicking Horse Trail,” marks the fulfilment of one more daring engineering conception, the building of a transmontane highway through the heart of the Central Rockies, across the difficult regions traversed by the Canadian Pacific railway.
Now, as has been said, with the completion of The Kicking Horse trail, a new door opens. The whole beautiful region from Lake Louise west to the Columbia valley—pre-historic trench between the Rockies and the older ranges to the West—is at last accessible. Following the same route as the first transcontinental railway, the motorist may now cross the famous Kicking Horse pass to Yoho Park, visit the magnificent Yoho valley, see lovely Emerald lake, and then go on by the great Kicking Horse valley, to the western confines of Yoho Park and there cap his spectacular journey with the eleven-mile traverse of the thrilling Kicking Horse gorge. (Text from Chapter 1)
This is the 1930 edition of a guidebook first published in 1927 and written by M. B. Williams. The scenic trail between Lake Louise, Alberta and Golden, British Columbia is the jumping-off point for a fawning tribute to the automobile
Assessment, evaluation and a comparison of planned and unplanned walk trails in coastal south-western Australia
No full textThree walk trails, the ‘Bibbulmun Track’ in West Cape Howe National Park and The Bald Head and Peak Head trails, in Torndirrup National Park were compared and evaluated using a problem assessment method. Indicators used to categorise trail degradation in the problem-assessment-trail-census included trail depth, excessive width, root exposure and trail proliferation. Other environmental variables measured in the trail assessment were slope, soil type and trail-side vegetation. Maintenance features such as boardwalks, steps, water bars and signs were assigned a condition and effectiveness rating. The most prevalent degradation problems on the assessed trails were soil erosion, exposed roots and excessive width. Trail proliferation was problematic in sections of indistinct trail or where a view could be accessed. The Bald Head and Peak Head trails were highly degraded compared to the assessed section of the Bibbulmun Track, which has been subject to a higher level of planning and management intervention. An evaluation of past management actions in relation to present trail conditions for all three trails indicates that trail alignment following natural contours and the installation of maintenance features such as board-walks, water-bars and steps on sloped sections are crucial to sustainable trail management. The utility of a trail problem assessment method developed in mountainous areas of the US has worked well in the assessment of sandy coastal walking trails, with the monitoring of trail conditions recommended as part of a sustainable trail management program and made possible due to the data that has been generated during this trail assessment
The Hunter Skills Trail
No full text12 pp., 17 photosHunter education is most successful when it includes hands-on teaching about hunting and firearms safety. The Hunter Skills Trail is a proven technique for training both adults and young people, and this guide explains how to set up and conduct such a program
Cyclophosphamide chemotherapy sensitizes tumor cells to TRAIL-dependent CD8 T cell-mediated immune attack resulting in suppression of tumor growth
No full textBackground: Anti-cancer chemotherapy can be simultaneously lymphodepleting and immunostimulatory. Pre-clinical models clearly demonstrate that chemotherapy can synergize with immunotherapy, raising the question how the immune system can be mobilized to generate anti-tumor immune responses in the context of chemotherapy. Methods and Findings: We used a mouse model of malignant mesothelioma, AB1-HA, to investigate T cell-dependent tumor resolution after chemotherapy. Established AB1-HA tumors were cured by a single dose of cyclophosphamide in a CD8 T cell- and NK cell-dependent manner. This treatment was associated with an IFN-α/β response and a profound negative impact on the anti-tumor and total CD8 T cell responses. Despite this negative effect, CD8 T cells were essential for curative responses. The important effector molecules used by the anti-tumor immune response included IFN-γ and TRAIL. The importance of TRAIL was supported by experiments in nude mice where the lack of functional T cells could be compensated by agonistic anti-TRAIL-receptor (DR5) antibodies. Conclusion: The data support a model in which chemotherapy sensitizes tumor cells for T cell-, and possibly NK cell-, mediated apoptosis. A key role of tumor cell sensitization to immune attack is supported by the role of TRAIL in tumor resolution and explains the paradox of successful CD8 T cell-dependent anti-tumor responses in the absence of CD8 T cell expansion
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