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1
Goodey, Dave. "Daisy Trail Cycle." Bereavement Care 35, no. 1 (January 2, 2016): 4–6. http://dx.doi.org/10.1080/02682621.2016.1160611.
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Ehrhardt, Harald, Catarina Castro Alves, Franziska Wachter, and Irmela Jeremias. "TRAIL Preferentially Affects Cell Cycle-Arrested Tumor Cells Including Stem- and Progenitor Cells From Patients with Acute Lymphoblastic Leukemia." Blood 120, no. 21 (November 16, 2012): 1879. http://dx.doi.org/10.1182/blood.v120.21.1879.1879.
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Abstract Abstract 1879 Leukemic stem- and progenitor cells exhibit low cycling activity which might represent a major cause for their increased treatment resistance. TRAIL (TNF-related apoptosis inducing ligand) is a novel putative anticancer drug currently in phase I and II clinical testing. We recently showed that TRAIL is able to address stem- and progenitor cells from patients with acute lymphoblastic leukemia (ALL) in xenotransplantation assays (Alves et al., Blood 2012,119,4224). As stem- and progenitor cells are often non-cycling, we asked here, whether TRAIL is able to address resting leukemia cells. We used cell lines and primary tumor cells from children with ALL which were amplified in severely immuno-compromised mice (NSG mice). Cell cycle arrest was induced (i) by addition of conventional cytotoxic drugs which are known to act as cytostatic drugs such as doxorubicine; (ii) by biochemical inhibitors known to induce cell cycle arrest at different defined points of the cell cycle such as mimosine; (iii) by molecular approaches and knockdown of cyclinB arresting cell cycle in G2 or knockdown of cyclinE arresting cell cycle in G1. Unexpectedly, TRAIL-induced apoptosis was enhanced, whenever cell cycle was arrested. Cell cycle arrest sensitized towards TRAIL-induced apoptosis independently from the point or phase of cell cycle which was arrested (G0, G1 or G2) and independently from the agent used to arrest the cell cycle. Similarly, knockdown of cyclinB or cyclinE both clearly sensitized cell line cells towards TRAIL-induced apoptosis. Cytotoxic drugs and cell cycle inhibitors might arrest the cell cycle by activation of p53. Accordingly, when caffeine was added which inhibited p53 activity and drug-induced cell cycle arrest, sensitization towards TRAIL-induced apoptosis was blocked. We have recently established a novel method which enables performing knockdown experiments in tumor cells derived from ALL patients (Höfig et al., Cell Comm. Signal. 2012,10,8). Using this method and most important for clinical translation, we could show that knockdown of either cyclinB or cyclinE clearly sensitized patient-derived ALL cells towards TRAIL-induced apoptosis. Taken together and in contrast to most conventional cytotoxic drugs, TRAIL exerts anti-tumor activity preferentially against tumor cells in cell cycle arrest and less against actively cycling tumor cells. This special feature of TRAIL might explain its anti-tumor activity against stem- and progenitor cells in patients with ALL. Thus, TRAIL might represent an interesting drug to treat disease stages with accumulation of stem- and progenitor cells and static tumor disease, e.g., during minimal residual disease. Disclosures: No relevant conflicts of interest to declare.
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Song, Kaimei, Yiguang Chen, Rüdiger Göke, Andreas Wilmen, Cheryl Seidel, Alexandra Göke, Brendan Hilliard, and Youhai Chen. "Tumor Necrosis Factor–Related Apoptosis-Inducing Ligand (Trail) Is an Inhibitor of Autoimmune Inflammation and Cell Cycle Progression." Journal of Experimental Medicine 191, no. 7 (March 27, 2000): 1095–104. http://dx.doi.org/10.1084/jem.191.7.1095.
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The tumor necrosis factor–related apoptosis-inducing ligand (TRAIL) induces apoptosis of tumor cells but not normal cells; its role in normal nontransformed tissues is unknown. We report here that chronic blockade of TRAIL in mice exacerbated autoimmune arthritis, and that intraarticular TRAIL gene transfer ameliorated the disease. In vivo, TRAIL blockade led to profound hyperproliferation of synovial cells and arthritogenic lymphocytes and heightened the production of cytokines and autoantibodies. In vitro, TRAIL inhibited DNA synthesis and prevented cell cycle progression of lymphocytes. Interestingly, TRAIL had no effect on apoptosis of inflammatory cells either in vivo or in vitro. Thus, unlike other members of the tumor necrosis factor superfamily, TRAIL is a prototype inhibitor protein that inhibits autoimmune inflammation by blocking cell cycle progression.
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Ritter, Scott M., James E. Barrick, and M. Randall Skinner. "Conodont sequence biostratigraphy of the Hermosa Group (Pennsylvanian) at Honaker Trail, Paradox Basin, Utah." Journal of Paleontology 76, no. 3 (May 2002): 495–517. http://dx.doi.org/10.1017/s0022336000037331.
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In cyclical Pennsylvanian strata, conodonts find their greatest stratigraphic utility as biotic signatures of physically defined stratigraphic entities (cycles, parasequences, high frequency sequences, etc.) rather then the primary means of stratigraphic subdivision (e.g., biostratigraphic interval zones). The practice of identifying depositional entities for purposes of regional correlation on the basis of their constituent conodont faunas is herein called conodont sequence biostratigraphy. In this paper, the concept is utilized to successfully correlate Pennsylvanian cycles of the Paradox basin with their Midcontinent counterparts.The Honaker Trail section is the most accessible and well-studied succession of carbonate shelf strata in the Paradox basin. Approximately 350 m of cyclically bedded limestone, sandstone, and shale comprising 53 fifth-order cycles are exposed along the cliffs of the deeply entrenched San Juan River. Maximum transgressive facies of 19 cycles yielded Idiognathodus-Neognathodus- and/or Streptognathodus-dominated conodont faunas. Those from the Chimney Rock, Gothic, LHT-5, UHT-3, UHT-5, UHT-8, unnamed limestone, and Shafer correspond to faunas from the Verdigris, Lower Fort Scott, Altamont (Lake Neosho), Lost Branch, Hertha (Mound City), Swope (Hushpuckney), Dennis (Stark), and South Bend cycles of the Midcontinent, respectively. By extrapolation, all minor cycles of the Marmaton, Pleasanton, and Bronson Groups (except for the Critzer) also appear to have counterparts at Honaker Trail.The position of the Desmoinesian–Missourian boundary in the Honaker Trail section can be approximated using conodonts in conjunction with fusulinids. The highest Desmoinesian conodont fauna, the Idiognathodus nodocarinatus fauna, occurs in cycle UHT-3 in the lower part of the Upper Honaker Trail sequence. The highest occurrence of Beedeina occurs in the same cycle. The lowest conodont fauna with the Missourian species I. eccentricus appears two cycles higher, in cycle UHT-5. Because in the Midcontinent region a small interval of strata separates the first appearance of I. eccentricus from the base of the Missourian, we place the base of the Missourian at the base of cycle UHT-4 (bed 105) at Honaker Trail. The appearance of Streptognathodus firmus and S. pawhuskaensis in the Shafer limestone indicates that the Missourian–Virgilian boundary lies slightly above or below this stratigraphic horizon.
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Secchiero, Paola, Arianna Gonelli, Claudio Celeghini, Prisco Mirandola, Lia Guidotti, Giuseppe Visani, Silvano Capitani, and Giorgio Zauli. "Activation of the nitric oxide synthase pathway represents a key component of tumor necrosis factor–related apoptosis-inducing ligand–mediated cytotoxicity on hematologic malignancies." Blood 98, no. 7 (October 1, 2001): 2220–28. http://dx.doi.org/10.1182/blood.v98.7.2220.
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Tumor necrosis factor (TNF)–related apoptosis-inducing ligand (TRAIL) induced both cytotoxic (apoptosis) and cytostatic (cell cycle perturbation) effects on the human myeloid K562 cell line. TRAIL stimulated caspase 3 and nitric oxide synthase (NOS) activities, and both pathways cooperate in mediating inhibition of K562 survival/growth. This was demonstrated by the ability of z-VAD-fmk, a broad inhibitor of effector caspases, and N-nitro-l-arginine methyl ester (L-NAME), an NOS pharmacologic inhibitor, to completely (z-VAD-fmk) or partially (L-NAME) suppress the TRAIL-mediated inhibitory activity. Moreover, z-VAD-fmk was able to block TRAIL-mediated apoptosis and cell cycle abnormalities and increase of NOS activity. The addition of the NO donor sodium nitroprusside (SNP) to K562 cells reproduced the cytostatic effect of TRAIL without inducing apoptosis. When TRAIL was associated to SNP, a synergistic increase of apoptosis and inhibition of clonogenic activity was observed in K562 cells as well as in other myeloblastic (HEL, HL-60), lymphoblastic (Jurkat, SupT1), and multiple myeloma (RPMI 8226) cell lines. Although SNP greatly augmented TRAIL-mediated antileukemic activity also on primary leukemic blasts, normal erythroid and granulocytic cells were less sensitive to the cytotoxicity mediated by TRAIL with or without SNP. These data indicate that TRAIL promotes cytotoxicity in leukemic cells by activating effector caspases, which directly lead to apoptosis and stimulate NO production, which mediates cell cycle abnormalities. Both mechanisms seem to be essential for TRAIL-mediated cytotoxicity.
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Palmer, Kristi L. "Introduction to Indy: Walk, cycle, ride the Cultural Trail." College & Research Libraries News 73, no. 9 (October 1, 2012): 518–22. http://dx.doi.org/10.5860/crln.73.9.8827.
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Devlin, David, Eva Szegezdi, Paavilainen Tanja, Orsolya Orosz, Michael O'Dwyer, Michael Carty, Afshin Samali, and Séverine Cruet Hennequart. "G2/M Arrest Sensitizes Chronic Myelogenous Leukemia Cells to TRAIL-Induced Apoptosis." Blood 116, no. 21 (November 19, 2010): 4465. http://dx.doi.org/10.1182/blood.v116.21.4465.4465.
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Abstract Abstract 4465 The death ligand, tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) receives great interest as it targets and kills cancerous cells, but not non-transformed cells. While it is in phase I/II clinical trials for a range of solid tumours, the generally low sensitivity of leukemia cells to TRAIL makes it a less attractive therapeutic for these cancers. We found that doxorubicin and cytarabine, agents that induce DNA damage and impair cell cycle progression, can sensitize CML cells to TRAIL with CI<1 at Fa of ED25 and ED50 (based on median-effect method using the isobologram equation). Inhibition of the cell cycle checkpoint kinases Chk1/2 with UCN-01 did not influence TRAIL-induced apoptosis nor could it abolish the sensitizing effect of doxorubicin. Interestingly, inhibition of Ataxia Telangiectasia Mutated (ATM), a key DNA damage response kinase, with KU-55933 induced a G2/M arrest and enhanced TRAIL-induced apoptosis. Inhibition of ATM alone induced 22±3.1% apoptosis and increased TRAIL-induced apoptosis from 27.2±4.7% to 68±7.2%. Cell cycle analysis revealed that while the proportion of cells in the G0/G1 and S phases slightly increased, the proportion of the cells in the G2/M phase dropped by 31.6±3.2% (p<0.05) indicating that G2/M arrested cells were more sensitive to TRAIL than cells in G0/G1 and S phases. TRAIL-induced CML cell death was also synergistically enhanced by arresting the cells in G2/M using the microtubule disrupting drugs, nocodazole or colcemide. Cells were treated with a concentration of nocodazole or colcemide that induced above 90% G2/M arrest for 16 h (0.3 mM and 0.1 mg/ml, respectively) followed by treatment with 250 ng/ml of TRAIL for 24 h. Nocodazole, colcemide and TRAIL individually induced 19±3.7% 26.3±4.4% and 27.2±4.7% cell death, while combination of nocodazole or colcemide with TRAIL resulted 89±6.8% and 93±5.9% cell death, respectively. In summary, we found that induction of DNA damage sensitizes CML cells to TRAIL and that TRAIL-sensitivity of CML cells is cell cycle-dependent. Disclosures: O'Dwyer: Novartis: Honoraria.
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Rezácová, Martina, Jirina Vávrová, Doris Vokurková, Ales Tichý, Jirí Knízek, and Jan Psutka. "The importance of abrogation of G2-phase arrest in combined effect of TRAIL and ionizing radiation." Acta Biochimica Polonica 52, no. 4 (July 11, 2005): 889–96. http://dx.doi.org/10.18388/abp.2005_3403.
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In this work we studied the relationship between the enhanced expression of DR5 receptor and the effect of combination of TRAIL and ionizing radiation on cell cycle arrest and apoptosis induction in human leukemia cell line HL-60. DR5, APO2.7 and cell cycle were analyzed by flow cytometry. Proteins Bid and Mcl-1 were analyzed by Western-blotting. For clonogenic survival, colony assay on methylcellulose was used. Ionizing radiation caused significantly enhanced positivity of DR5 receptors 24 h after irradiation with high doses (6 and 8 Gy). An increase of DR5 receptor positivity after a dose of 2 Gy was not statistically significant and application of TRAIL 48 h after irradiation did not increase the apoptosis induction. However, a decrease of radiation-induced G(2) phase arrest and an increase of apoptosis were observed when TRAIL was applied 16 h before irradiation with the dose of 2 Gy. Incubation with 6 microg/l TRAIL for 16 h reduced D(0) value from 2.9 Gy to 1.5 Gy. The induction of apoptosis by TRAIL was accompanied by Bid cleavage and a decrease of antiapoptotic Mcl-1 16 h after incubation with TRAIL. TRAIL in concentration of 6 microg/l applied 16 h before irradiation by the dose of 1.5 Gy caused the death of 63% of clonogenic tumor cells, similarly as the dose of 2.9 Gy alone, which is in good correlation with the enhanced apoptosis induction.
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Quiroz-Reyes, Adriana G., Paulina Delgado-Gonzalez, Jose Francisco Islas, Juan Luis Delgado Gallegos, Javier Humberto Martínez Martínez Garza, and Elsa N. Garza-Treviño. "Behind the Adaptive and Resistance Mechanisms of Cancer Stem Cells to TRAIL." Pharmaceutics 13, no. 7 (July 10, 2021): 1062. http://dx.doi.org/10.3390/pharmaceutics13071062.
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Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL), also known as Apo-2 ligand (Apo2L), is a member of the TNF cytokine superfamily. TRAIL has been widely studied as a novel strategy for tumor elimination, as cancer cells overexpress TRAIL death receptors, inducing apoptosis and inhibiting blood vessel formation. However, cancer stem cells (CSCs), which are the main culprits responsible for therapy resistance and cancer remission, can easily develop evasion mechanisms for TRAIL apoptosis. By further modifying their properties, they take advantage of this molecule to improve survival and angiogenesis. The molecular mechanisms that CSCs use for TRAIL resistance and angiogenesis development are not well elucidated. Recent research has shown that proteins and transcription factors from the cell cycle, survival, and invasion pathways are involved. This review summarizes the main mechanism of cell adaption by TRAIL to promote response angiogenic or pro-angiogenic intermediates that facilitate TRAIL resistance regulation and cancer progression by CSCs and novel strategies to induce apoptosis.
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Ling, J., R. S. Herbst, D. S. Mendelson, S. G. Eckhardt, P. O’Dwyer, S. Ebbinghaus, R. Osborne, M. Cheu, G. Lieberman, and B. L. Lum. "Apo2L/TRAIL pharmacokinetics in a phase 1a trial in advanced cancer and lymphoma." Journal of Clinical Oncology 24, no. 18_suppl (June 20, 2006): 3047. http://dx.doi.org/10.1200/jco.2006.24.18_suppl.3047.
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3047 Background: Apo2L/TRAIL (Apo2L ligand/tumor necrosis factor-related apoptosis-inducing ligand) is the first recombinant human protein that selectively induces apoptosis or programmed cell death in cancer cells while sparing normal cells. The molecule used in this joint clinical development between Genentech, Inc. and Amgen, Inc., is an optimized recombinant human Apo2L/TRAIL protein produced in E. coli. It displays broad activity in preclinical models of a variety of solid and hematologic cancers. This is the first report of the pharmacokinetics of Apo2L/TRAIL in humans. Methods: Thirty-nine patients enrolled in a phase 1a study had PK assessments at dose levels ranging from 0.5–15 mg/kg in two cohorts, those with and those without liver metastases. Recombinant human Apo2L/TRAIL was administered as a 1-hr IV infusion for 5 consecutive days over a 21-day cycle. Serum concentrations were determined using a sensitive ELISA assay. PK calculations were performed using Non-compartmental analyses. Results: Currently Apo2L/TRAIL PK data are available for 27 patients, 15 in cohort 1 (no liver metastases) and 12 in cohort 2 (liver metastases). Mean (± SD) PK data for patients in cohort 1 and cohort 2 did not differ. PK data for cohort 1 are outlined in the table below. Apo2L/TRAIL clearance appeared proportional to dose and consistent with that predicted from nonclinical models. Cmax achieved at doses ≥ 4 mg/kg are equivalent to or greater than those displaying activity in preclinical models. There was no evidence of drug accumulation between day 1 and day 5 of treatment. Conclusions: Apo2L/TRAIL at doses which can be safely administered in humans produces serum concentrations consistent with those demonstrating efficacy in tumor xenograft models. Hepatic metastases with or without mild liver dysfunction do not appear to influence the PK of Apo2L/TRAIL. [Table: see text] [Table: see text]
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Ehrhardt, H., F. Wachter, M. Grunert, and I. Jeremias. "Cell cycle-arrested tumor cells exhibit increased sensitivity towards TRAIL-induced apoptosis." Cell Death & Disease 4, no. 6 (June 2013): e661-e661. http://dx.doi.org/10.1038/cddis.2013.179.
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Wang, Yun, Can Zhang, and Jin Chuan Zhang. "Research on Zero Release Closed Cycle Diesel Engine System." Advanced Materials Research 354-355 (October 2011): 429–32. http://dx.doi.org/10.4028/www.scientific.net/amr.354-355.429.
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To reduce exposure and increase concealment, AIP (Air Independent Propulsion) power plant came into being. In a variety of AIP power devices, closed cycle diesel CCD (Closed Cycle Diesel Engine System) AIP system is the most commonly used at present. Drawing on the principle of existing CCDAIP closed cycle diesel, This paper presents a design about Zero Release Closed Cycle Diesel Engine System, which uses oxygen generation device to produce O2 for the fuel combustion by absorbing CO2，in order to realize the truely zero emissions of conventional submarines without exhaust trail. The paper also takes a preliminary exploration of the design.
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Park, Shin Young, Ki Yun Kim, Do Youn Jun, Su-Kyeong Hwang, and Young Ho Kim. "G1 Cell Cycle Arrest and Extrinsic Apoptotic Mechanisms Underlying the Anti-Leukemic Activity of CDK7 Inhibitor BS-181." Cancers 12, no. 12 (December 19, 2020): 3845. http://dx.doi.org/10.3390/cancers12123845.
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In vitro antitumor activity of the CDK7 inhibitor BS-181 against human T-ALL Jurkat cells was determined. Treatment of Jurkat clones (JT/Neo) with BS-181 caused cytotoxicity and several apoptotic events, including TRAIL/DR4/DR5 upregulation, c-FLIP down-regulation, BID cleavage, BAK activation, ΔΨm loss, caspase-8/9/3 activation, and PARP cleavage. However, the BCL-2-overexpressing Jurkat clone (JT/BCL-2) abrogated these apoptotic responses. CDK7 catalyzed the activating phosphorylation of CDK1 (Thr161) and CDK2 (Thr160), and CDK-directed retinoblastoma phosphorylation was attenuated in both BS-181-treated Jurkat clones, whereas only JT/BCL-2 cells exhibited G1 cell cycle arrest. The G1-blocker hydroxyurea augmented BS-181-induced apoptosis by enhancing TRAIL/DR4/DR5 upregulation and c-FLIP down-regulation. BS-181-induced FITC–annexin V-positive apoptotic cells were mostly in the sub-G1 and G1 phases. BS-181-induced cytotoxicity and mitochondrial apoptotic events (BAK activation/ΔΨm loss/caspase-9 activation) in Jurkat clones I2.1 (FADD-deficient) and I9.2 (caspase-8-deficient) were significantly lower than in A3 (wild-type). Exogenously added recombinant TRAIL (rTRAIL) markedly synergized BS-181-induced apoptosis in A3 cells but not in normal peripheral T cells. The cotreatment cytotoxicity was significantly reduced by the DR5-blocking antibody but not by the DR4-blocking antibody. These results demonstrated that the BS-181 anti-leukemic activity is attributed to extrinsic TRAIL/DR5-dependent apoptosis preferentially induced in G1-arrested cells, and that BS-181 and rTRAIL in combination may hold promise for T-ALL treatment.
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Tian, Shuang, Da-Hua Liu, Dan Wang, Fu Ren, and Pu Xia. "Aldehyde Dehydrogenase 1 (ALDH1) Promotes the Toxicity of TRAIL in Non-Small Cell Lung Cancer Cells via Post-Transcriptional Regulation of MEK-1 Expression." Cellular Physiology and Biochemistry 51, no. 1 (2018): 217–27. http://dx.doi.org/10.1159/000495202.
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Background/Aim: Tumor Necrosis Factor-Related Apoptosis Inducing Ligand (TRAIL)-based therapies have been used in many human cancers. However, some tumors are resistant to TRAIL-induced cell death. Aldehyde dehydrogenase 1 (ALDH1) is a functional marker for identification of CSCs. Methods: In this study, we used the colony formation assay, AnnexinV/ PI double staining and PI staining to detect proliferation, apoptosis and cell cycle in ALDH1+ non-small cell lung cancer (NSCLC) cells with TRAIL treatment. In addition, we established xenograft mouse models to confirm the anti-tumor roles of TRAIL in vivo. Finally, gene array and western blot were used to detect the deeper mechanism of the susceptibility of ALDH1+ NSCLC cells to TRAIL. Results: We confirmed that TRAIL could inhibit proliferation, and induce apoptosis and G1 arrest in ALDH1+ NSCLC cells. Correspondingly, TRAIL was associated with decreased tumor size and the favorable survival rate of ALDH1+ cells established xenograft mouse models. ALDH1 could increase the death receptors (DR) 4 and DR5 expression in ALDH1+ NSCLC cells via activating MEK/ERK signaling pathway. Conclusion: ALDH1 protein induced MEK-1 mRNA stability and promoted its translation via its 3’UTR.
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Yang, Yang, Shang-Ping Xie, and Jan Hafner. "The Thermal Wake of Kauai Island: Satellite Observations and Numerical Simulations*." Journal of Climate 21, no. 18 (September 15, 2008): 4568–86. http://dx.doi.org/10.1175/2008jcli1895.1.
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Abstract Island thermal effects on the trail cloud band over the central North Pacific are investigated for the lee of Hawaii using satellite observations and a regional atmospheric model. The trail cloud band develops around noon and peaks in cloudiness in the early afternoon. The analysis of numerical simulations of the Kauai wake suggests that a dynamically induced convergence zone forms in the lee of Kauai and Oahu (maximum elevation at 1.5 and 1.2 km, respectively) under the trade wind flow. The island thermal effect significantly modulates the island wake and creates a diurnal cycle of development and decay in the lee cloud band. As solar radiation heats up the island from morning to afternoon, warm air moves downstream (warm advection) from the island in the wake zone, increasing the air temperature, decreasing the air pressure, and enhancing low-level wind convergence in favor of the formation of the trail clouds. Conversely the cold advection during night suppresses cloud formation in the wake. The warm advection and the convergence in the wake increase with the upstream trade wind strength, consistent with satellite observations that the cloudiness increases in the wake under strong wind conditions in the afternoon. The similarity in the trail cloud and its diurnal cycle between Kauai and Oahu suggests that the thermal wake effect is quite common. The conditions for such a thermal wake are discussed.
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Eberle, Jürgen. "Countering TRAIL Resistance in Melanoma." Cancers 11, no. 5 (May 11, 2019): 656. http://dx.doi.org/10.3390/cancers11050656.
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Melanoma of the skin has become a prime example for demonstrating the success of targeted cancer therapy. Nevertheless, high mortality has remained, mainly related to tumor heterogeneity and inducible therapy resistance. But the development of new therapeutic strategies and combinations has raised hope of finally defeating this deadly disease. TNF-related apoptosis-inducing ligand (TRAIL) represents a promising antitumor strategy. The principal sensitivity of melanoma cells for TRAIL was demonstrated in previous studies; however, inducible resistance appeared as a major problem. To address this issue, combination strategies were tested, and survival pathway inhibitors were shown to sensitize melanoma cells for TRAIL-induced apoptosis. Finally, cell cycle inhibition was identified as a common principle of TRAIL sensitization in melanoma cells. Mitochondrial apoptosis pathways, pro- and antiapoptotic Bcl-2 proteins as well as the rheostat consisted of Smac (Second mitochondria-derived activator of caspase) and XIAP (X-linked inhibitor of apoptosis protein) appeared to be of particular importance. Furthermore, the role of reactive oxygen species (ROS) was recognized in this setting. Inducible TRAIL resistance in melanoma can be explained by (i) high levels of antiapoptotic Bcl-2 proteins, (ii) high levels of XIAP, and (iii) suppressed Bax activity. These hurdles have to be overcome to enable the use of TRAIL in melanoma therapy. Several strategies appear as particularly promising, including new TRAIL receptor agonists, Smac and BH3 mimetics, as well as selective kinase inhibitors.
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Davies, Alice, Beth Sage, Krishna Kolluri, Doraid Alrifai, Rebecca Graham, Ben Weil, Rita Rego, et al. "TACTICAL: A phase I/II trial to assess the safety and efficacy of MSCTRAIL in the treatment of metastatic lung adenocarcinoma." Journal of Clinical Oncology 37, no. 15_suppl (May 20, 2019): TPS9116. http://dx.doi.org/10.1200/jco.2019.37.15_suppl.tps9116.
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TPS9116 Background: Mesenchymal stromal cells (MSCs) migrate to and incorporate into tumour stroma allowing them to act as vehicles for delivering anti-cancer therapies. TNF-related apoptosis inducing ligand (TRAIL) selectively induces apoptosis in malignant cells however short biological half-life has its limited therapeutic efficacy. We have transduced umbilical cord MSCs with a lentiviral vector to express TRAIL (MSCTRAIL). These cells trigger apoptosis selectively in cancer cells with evidence of synergistic activity with other systemic anti-cancer therapies. Given their immune-privileged nature we are delivering ex vivo pooled MSCTRAIL from third party donors without tissue matching or immunosuppression. Efficacy has been demonstrated using in vitro co-culture assays and in vivo in orthotopic lung metastasis murine model, showing regression of metastases following treatment with intravenous MSCTRAIL [1]. Methods: TACTICAL is a phase I/II trial assessing safety and efficacy of MSCTRAIL in combination with first line standard of care (SOC); pemetrexed (500mg/m2) and cisplatin (75mg/m2) and/or pembrolizumab (200mg), in treatment naïve patients with stage IIIB/IV metastatic lung adenocarcinoma. Patients have no actionable driver mutations and ECOG performance status 0-1. Phase I is a dose de-escalation study, patients receive SOC on day 1 and 4x108 MSCTRAIL cells on day 2 of a 21 day cycle for 3 cycles. A Bayesian adaptive design will recommend dose reductions if excessive toxicities occur. Primary outcomes are to determine recommended phase II dose along with safety and tolerability of MSCTRAIL. 46 patients will then be randomised into a multi-centre phase II double blind, placebo-controlled trial to receive SOC and either MSCTRAIL or placebo (1:1). Primary outcome is tumour response rate by RECIST (v 1.1) criteria at 12 weeks. Secondary outcomes include, best overall response, duration of response, progression free survival and overall survival. TACTICAL is the first clinical trial of this novel cell and gene therapy and if successful will pave the way for future allogeneic MSC therapy in cancer. 1. Loebinger, M.R., et al., Mesenchymal stem cell delivery of TRAIL can eliminate metastatic cancer. Cancer Res, 2009. 69(10): p. 4134-42. Clinical trial information: NCT03298763.
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Ryan, Chris, Thu Thi Trinh, Minghui Sun, and Ping Li. "Assessing Usage of Rural Cycle Ways—Problems and Issues: A Case Study of the Hauraki Cycle Trail, North Island New Zealand." Tourism Review International 18, no. 1 (July 18, 2014): 105–13. http://dx.doi.org/10.3727/154427214x13990420684680.
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Wicker, Christina A., Ravi P. Sahu, Kashmira Kulkarni-Datar, Sanjay K. Srivastava, and Thomas L. Brown. "BITC Sensitizes Pancreatic Adenocarcinomas to TRAIL-induced Apoptosis." Cancer Growth and Metastasis 2 (January 2009): CGM.S3982. http://dx.doi.org/10.4137/cgm.s3982.
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Pancreatic adenocarcinoma is an aggressive cancer with a greater than 95% mortality rate and short survival after diagnosis. Chemotherapeutic resistance hinders successful treatment. This resistance is often associated with mutations in codon 12 of the K-Ras gene (K-Ras 12), which is present in over 90% of all pancreatic adenocarcinomas. Codon 12 mutations maintain Ras in a constitutively active state leading to continuous cellular proliferation. Our study determined if TRAIL resistance in pancreatic adenocarcinomas with K-Ras 12 mutations could be overcome by first sensitizing the cells with Benzyl isothiocyanate (BITC). BITC is a component of cruciferous vegetables and a cell cycle inhibitor. BxPC3, MiaPaCa2 and Panc-1 human pancreatic adenocarcinoma cell lines were examined for TRAIL resistance. Our studies show BITC induced TRAIL sensitization by dual activation of both the extrinsic and intrinsic apoptotic pathways.
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Richardson, Paul, P. Sonneveld, M. Schuster, D. Irwin, E. Stadtmauer, T. Facon, J. Harousseau, et al. "Bortezomib Continues Demonstrates Superior Efficacy Compared with High-Dose Dexamethasone in Relapsed Multiple Myeloma: Updated Results of the APEX Trail." Blood 106, no. 11 (November 16, 2005): 2547. http://dx.doi.org/10.1182/blood.v106.11.2547.2547.
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Abstract Introduction: In the international, multicenter phase 3 APEX trial, 669 patients (pts) with multiple myeloma (MM) who had relapsed after 1–3 prior therapies were randomized to receive bortezomib (VELCADE®) 1.3 mg/m2 IV d 1, 4, 8, 11 q3wk for 8 cycles followed by 3 cycles on d 1, 8, 15, 22 q5wk, or dexamethasone (Dex) 40 mg PO d 1–4, 9–12, 17–20 q5wk for 4 cycles followed by 5 cycles on d 1–4 q4wk. Pts refractory to Dex were excluded, and those with progressive disease on Dex were eligible to cross over to bortezomib. Pts receiving bortezomib achieved significant improvement in time to progression (TTP, primary end point), response rate (CR + PR using EBMT criteria), and survival (Richardson. NEJM.2005;352:2487), which resulted in early closure of the trial. The duration of response (DOR) was longer with bortezomib, and infections ≥ grade 3, time to skeletal events, grade 4 adverse events (AE), serious AE, and discontinuations due to AE were similar in the 2 treatment arms. Methods: In this analysis, updated response rates, time to response (TTR), DOR, survival, and TTP are presented after extended follow-up. A matched-pairs analysis comparing survival and TTP of pts on bortezomib in APEX with those in another trial of MM pts who received bortezomib after Dex will also be presented. Results: 669 pts received a median of 7 cycles of therapy. Based on a median follow-up of 15.8 months, the median TTP, 1-year and overall survival (OS), response rates, median TTR, and median DOR for pts receiving bortezomib are shown in the table. Median duration of therapy for responders (CR + PR) was 7.2 months. Improved response with longer therapy (after cycle 6) was observed in 76 pts (56% of responders) in the bortezomib arm (20 pts improved from MR or PR to CR, and 56 pts improved from MR to PR). Furthermore, 28 of 135 responders (21%) achieved first response (CR/PR) after cycle 4, including 18 pts (13%) on or after cycle 6, and 10 pts (7%) on or after cycle 8. OS increased substantially with more follow-up. Median TTR was more rapid, and median DOR was longer in pts achieving CR and near CR than in those with PR. Conclusion: Updated TTP, response rates, survival, TTR, and DOR for the bortezomib group continue to support the findings of the original analysis. Thus, the clinical benefits of single-agent bortezomib in pts with relapsed MM remain robust after extended follow-up, supporting its early use in relapsed MM and its further study in the treatment of newly diagnosed disease. Efficacy Bortezomib (n = 333) Median TTP, mo 6.2 1-year survival, % 80 Median OS, mo 25.4 Response rate, % (n/N) 43 (135/315) CR 9 (27/315) PR 34 (108/315) -near CR 7 (21/315) Median TTR, mo (range) 1.4 (0.5–6.0) CR 0.8 (0.5–4.0) PR 1.4 (0.5–6.0) -near CR 0.8 (0.6–2.4) Median DOR, mo 7.8 CR 9.9 PR 7.6 -near CR 11.5
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Leòn-Carriòn, José. "A Chronobiological Test for Cognitive Styles: Chrono-Trail Making." Perceptual and Motor Skills 69, no. 3_suppl (December 1989): 1115–22. http://dx.doi.org/10.2466/pms.1989.69.3f.1115.
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This paper presents a description of the test, Chrono-Trail Making, an adaptation of the format of the Trail Making Test of the Halstead-Reitan Neuropsychological Test Battery. Generated were 28 parallel forms adapted from Part A; another 28 forms were adapted from Part B. These forms are assumed to be of similar difficulty and to have the same physical characteristics as the two parts of the original test. Each of the series of 28 was given consecutively at 15-min. intervals. Examination of scores confirms the identification in 24 young men of a Basic Rest-Activity Cycle (BRAC) of 90- to 100-min. periods. These, it was proposed, may refer to two different cognitive styles.
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Leòn-Carriòn, José. "A Chronobiological Test for Cognitive Styles: Chrono-Trail Making." Perceptual and Motor Skills 69, no. 3-2 (December 1989): 1115–22. http://dx.doi.org/10.1177/00315125890693-210.
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This paper presents a description of the test, Chrono-Trail Making, an adaptation of the format of the Trail Making Test of the Halstead-Reitan Neuropsychological Test Battery. Generated were 28 parallel forms adapted from Part A; another 28 forms were adapted from Part B. These forms are assumed to be of similar difficulty and to have the same physical characteristics as the two parts of the original test. Each of the series of 28 was given consecutively at 15-min. intervals. Examination of scores confirms the identification in 24 young men of a Basic Rest-Activity Cycle (BRAC) of 90- to 100-min. periods. These, it was proposed, may refer to two different cognitive styles.
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Connell, J. "Bali Revisited: Death, Rejuvenation, and the Tourist Cycle." Environment and Planning D: Society and Space 11, no. 6 (December 1993): 641–61. http://dx.doi.org/10.1068/d110641.
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Since package tourism began on a small scale at the start of the 20th century, tourism and travel to Bali have gone through a series of overlapping and interlocking phases. By the 1930s the destruction of ‘authenticity’ and the process of transformation were already apparent to some. Tourism expanded and diversified. In the 1970s world travellers, and later ‘surfies’, contributed to the distinctiveness of Kuta, a way station on the Asian overland trail. Kuta grew, drew vibrant commerce, package tours, and a new youth scene, displacing world travellers to the periphery—the ‘interior’ or ‘up country’—in search of elusive authenticity. Tourism became introspective, as the gaze of mass tourists and chic tourists focused on hotels, resorts, and each other; international, as world consumer goods displaced local products; and youthful, with the emergence of specialised package holidays, centred on action and consumption. Resort cycles were grafted onto each other in an unwieldy social and geographical synthesis, as Bali, increasingly diverse yet inconspicuous, became ‘whatever you want it to be’.
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Roué, Gaël, Patricia Pérez-Galán, Mónica López-Guerra, Neus Villamor, Elias Campo, and Dolors Colomer. "Selective Inhibition of I kappaB Kinase Sensitizes Mantle Cell Lymphoma B Cells to TRAIL by Decreasing c-FLIP Level." Blood 108, no. 11 (November 16, 2006): 258. http://dx.doi.org/10.1182/blood.v108.11.258.258.
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Abstract Mantle cell lymphoma (MCL) is an aggressive B lymphoid neoplasm with a mature B-cell phenotype and genetically characterized by the t(11;14)(q13;q32) leading to cyclin D1 overexpression with the consequent deregulation of cell cycle at the G1-S checkpoint. MCL cells also present a constitutive activation of the NF-kappaB pathway which leads to the overexpression of several anti-apoptotic regulators. We have analyzed sensitivity to the extrinsic apoptotic signal triggered by tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) on six human MCL cell lines and primary cells from 10 MCL patients, which differ in their p53-dependent pathway status, growth characteristics and sensitivity to cytotoxic drugs. TRAIL has been shown to exert in vivo a selective anti-tumor activity with minimal toxicity on normal cells. We observed that TRAIL was able to trigger apoptosis in a majority of MCL cell lines and primary MCL tumor cells, while sparing normal peripheral B cells. TRAIL-induced cell death was characterized by a time- and dose-dependent loss of membrane potential, Bax and Bak activation, caspase activation and phophatidylserine exposure. MCL sensitivity to TRAIL was irrespective of TRAIL-R1 and TRAIL-R2 receptor levels, Bcl-2 family members or caspase regulators expression, but was closely linked to the activity of the NF-kappaB p50 factor and to the expression of c-FLIP, a NF-kappaB-regulated factor. C-FLIP accumulated into the TRAIL-dependent complex in resistant cells and its transient knockdown overcame MCL resistance to TRAIL. In parallel, NF-kappaB inhibitors differentially modulated TRAIL cytotoxicity. Indeed, sub-toxic doses of bortezomib increased TRAIL cytotoxic effects by up-regulating TRAIL-R2 receptor expression, but also led to the intracellular accumulation of c-FLIP, impeding full synergistic interaction in cells with highest c-FLIP basal level. In contrast, the IkappaB kinase (IKK) inhibitor BMS-354451 allowed to consistent reduction of NF-kappaB activity, decreased total and DISC-associated c-FLIP levels, and sensitized all MCL cells to TRAIL cytotoxic effects. These results indicate that pharmacological enhancement of MCL cells sensitivity to TRAIL does not depend on TRAIL receptors level but is rather regulated by NF-kappaB-regulated c-FLIP expression. Considering that both TRAIL and BMS-345541 have already demonstrated selective cytotoxicity against malignant cells, combining TRAIL, with pharmacological inhibitors of IkappaB kinase signaling may represent an attractive model for the design of a new and rational combination therapy for MCL.
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Johnston, Michael C., Christopher E. Holloway, and Robert S. Plant. "Cloud Trails past Bermuda: A Five-Year Climatology from 2012 to 2016." Monthly Weather Review 146, no. 12 (November 14, 2018): 4039–55. http://dx.doi.org/10.1175/mwr-d-18-0141.1.
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Abstract Cloud trails are primarily thermally forced bands of cloud that extend downwind of small islands. A novel algorithm to classify conventional geostationary visible-channel satellite images as cloud trail (CT), nontrail (NT), or obscured (OB) is defined. The algorithm is then applied to the warm season months of five years at Bermuda comprising 16 400 images. Bermuda’s low elevation and location make this island ideal for isolating the role of the island thermal contrast on CT formation. CTs are found to occur at Bermuda with an annual cycle, peaking in July, and a diurnal cycle that peaks in midafternoon. Composites of radiosonde observations and ERA-Interim data suggest that a warm and humid low-level environment is conducive for CT development. From a Lagrangian perspective, wind direction modulates CT formation by maximizing low-level heating on local scales when winds are parallel to the long axis of the island. On larger scales, low-level wind direction also controls low-level humidity through advection.
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Wang, Chunmei, Runzi Qi, Nan Li, Zhengxin Wang, Huazhang An, Qinghua Zhang, Yizhi Yu, and Xuetao Cao. "Notch1 Signaling Sensitizes Tumor Necrosis Factor-related Apoptosis-inducing Ligand-induced Apoptosis in Human Hepatocellular Carcinoma Cells by Inhibiting Akt/Hdm2-mediated p53 Degradation and Up-regulating p53-dependent DR5 Expression." Journal of Biological Chemistry 284, no. 24 (April 17, 2009): 16183–90. http://dx.doi.org/10.1074/jbc.m109.002105.
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Notch signaling plays a critical role in regulating cell proliferation, differentiation, and apoptosis. Our previous study showed that overexpression of Notch1 could inhibit human hepatocellular carcinoma (HCC) cell growth by arresting the cell cycle and inducing apoptosis. HCC cells are resistant to apoptotic induction by tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), so new therapeutic approaches have been explored to sensitize HCC cells to TRAIL-induced apoptosis. We are wondering whether and how Notch1 signaling can enhance the sensitivity of HCC cells to TRAIL-induced apoptosis. In this study, we found that overexpression of ICN, the constitutive activated form of Notch1, up-regulated p53 protein expression in HCC cells by inhibiting proteasome degradation. p53 up-regulation was further observed in human primary hepatocellular carcinoma cells after activation of Notch signaling. Inhibition of the Akt/Hdm2 pathway by Notch1 signaling was responsible for the suppression of p53 proteasomal degradation, thus contributing to the Notch1 signaling-mediated up-regulation of p53 expression. Accordingly, Notch1 signaling could make HCC cells more sensitive to TRAIL-induced apoptosis, whereas Notch1 signaling lost the synergistic promotion of TRAIL-induced apoptosis in p53-silenced HepG2 HCC cells and p53-defective Hep3B HCC cells. The data suggest that enhancement of TRAIL-induced apoptosis by Notch1 signaling is dependent upon p53 up-regulation. Furthermore, Notch1 signaling could enhance DR5 expression in a p53-dependent manner. Taken together, Notch1 signaling sensitizes TRAIL-induced apoptosis in HCC cells by inhibiting Akt/Hdm2-mediated p53 degradation and up-regulating p53-dependent DR5 expression. Thus, our results suggest that activation of Notch1 signaling may be a promising approach to improve the therapeutic efficacy of TRAIL-resistant HCC.
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Peterson, Lillian K., and John E. Davis. "Effects of Hiking the Appalachian Trail on Energy Availability, Body Composition, and Menstrual Cycle Function." Medicine & Science in Sports & Exercise 40, Supplement (May 2008): S413. http://dx.doi.org/10.1249/01.mss.0000322762.07794.93.
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Wu, Bin, Kwan L. Yeung, and Pin-Han Ho. "ILP formulations for non-simple p-cycle and p-trail design in WDM mesh networks." Computer Networks 54, no. 5 (April 2010): 716–25. http://dx.doi.org/10.1016/j.comnet.2009.09.019.
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Chen, Wenming, Lugui Qiu, Jian Hou, Xuejun Zhang, Xiaoyan Ke, Zhao Wang, Fang Zhou, et al. "Phase Ib Study of Recombinant Circularly Permuted TRAIL (CPT) in Relapsed or Refractory multiple Myeloma Patients." Blood 120, no. 21 (November 16, 2012): 1857. http://dx.doi.org/10.1182/blood.v120.21.1857.1857.
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Abstract Abstract 1857 Background: Circularly permuted TRAIL (CPT) is a recombinant mutant of human Apo2L/TRAIL developed by Beijing Sunbio Biotech Co. Ltd. as a targeted therapy for multiple myeloma and other hematologic malignancies. CPT is a dual pro-apoptotic receptor agonist that directly activates both pro-apoptotic receptors TRAIL-R1 (DR4) and TRAIL-R2 (DR5). CPT selectively induces apoptosis in a variety of cancer cells, while sparing most normal cells in the preclinical models. Objective: The safety, pharmacokinetics and preliminary efficacy of CPT in relapsed or refractory multiple myeloma patients (Ral/Ref MM) has been evaluated. Methods: This is a phase Ib, multiple-center, open-label, single/multiple dose-escalation study,18 patients were enrolled in the single dose-escalation study, and 29 patients were recruited in multiple dose-escalation study (including some patients from single dose-escalation study of CPT). Five escalation dosage levels include 5.0, 6.5, 8.0, 10.0 and 15.0 mg/kg/day. Patients received single dose of CPT, or once daily for 5 consecutive days (multiple dose) of each 21-days cycle. Patients receiving multiple doses were treated up to 4 cycles. The clinical response was evaluated at the end of each cycle by an independent review committee according to the criteria of the European Group for Blood and Marrow Transplantation (EBMT). Results: In single dose-escalation study, no dose limiting toxicity (DLT) and maximum tolerated dose (MTD) was observed. The most common treatment-related adverse events (≥10%) were elevated AST, fever, elevated LDH, leucopenia and shivers. In multiple dose-escalation study, the most common treatment-related adverse events(≥10%) were fever, leucopenia, elevated AST, fatigue and vomit. No significant difference of related adverse event was observed among the different dose groups. Two patients (33.3%) experienced laboratorial or clinical tumor lysis syndrome in 15.0 mg/kg multiple dose. The efficacy was evaluated in 27 patients, 1 patient achieved complete response (CR), 4 partial response (PR), 4 minor response (MR) and 12 no change (NC). No response better than MR was observed in 5.0mg/kg and 6.5mg/kg group. In 8.0mg/kg, 10.0mg/kg and 15.0mg/kg groups, the overall response rate (CR+PR %) was 33.33%, 16.67% and 33.33%, respectively. The disease control rate for five dose groups was 50.00%, 66.67%, 83.33%, 83.33% and 100% respectively, indicating that the optimal dose for CPT may be between 8.0 and 15.0mg/kg. PK results are linear at dose range from 5 mg/kg to 15 mg/kg with CL of 32.47±9.33 ml/h/kg, Vd of 51.89±9.20 ml/kg and t1/2 of 1.16±0.22h. No drug accumulation was observed in repeated administration. No anti-drug antibodies were detected after 1 to 4 cycle's treatment. Conclusion: CPT was well tolerated up to 15mg/kg with promising efficacy in patients with Ral/Ref MM. The MTD has not been reached. A randomized phase 2 trial in patients with Ral/Ref MM is ongoing. Disclosures: Yang: Beijing Sunbio Biotech Co., Ltd.: Employment. Zhu:Beijing Sunbio Biotech Co., Ltd.: Employment.
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David, Ebenezer, Rajni Sinha, Jonathan L. Kaufman, and Sagar Lonial. "Perifosine Induces DR4/DR5 Expression Leading to Apoptosis That Can Be Enhanced with Exogenous TRAIL, and Blocked with Strategies Directed at DR4/DR5 Inhibition." Blood 108, no. 11 (November 16, 2006): 3446. http://dx.doi.org/10.1182/blood.v108.11.3446.3446.
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Abstract Background: Perifosine is an oral AKT inhibitor which exerts a marked cytotoxic effect on human tumor cell lines. It is currently being tested in several phase II trials for the treatment of major cancers including multiple myeloma. While the proposed mechanism of action relates to downregulation of AKT expression, overepxression of constitutively active AKT does not abrogate perifosine induced cell death suggesting alternative mechanisms. Hypothesis: Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL, Apo2 ligand) effectively kills multiple myeloma cells in vitro after binding to their membrane specific receptors TRAIL-R1 (DR4) and TRAIL-R2 (DR5). It is our hypothesis that DR4/DR5 upregulation occurs in response to perifosine treatment, and thus may be additive with exogenous TRAIL. Materials and Methods: TRAIL-sensitive myeloma cell lines (MM.1S, RPMI8226, MM.1R) and TRAIL- resistant myeloma cell lines (U266) were used in this study. Apoptosis was assessed by annexin-V binding assay using flow-cytometry and cell death was assessed by MTT assay. Recombinant human TRAIL, chimeras of DR4 and DR5 were obtained from R&D systems. Results: Perifosine alone(5μM and 10μM) induced apoptosis of MM.1S in 40% and 50% of the treated cells as measured by flow cytometry, that increased to 81% and 91% when 50ng/ml of TRAIL was added to 5μM and 10 μM of perifosine. TRAIL alone induced only nominal apoptosis. Use of the TRAIL resistant U266 cell line showed only minimal apoptosis in response to perifosine, TRAIL, or the combination of both agents. Perifosine also induced DR4 and DR5 expression in less than 2hrs upon the Perifosine exposure in MM.1S as shown by RT-PCR. The combination of perifosine and TRAIL was not sequence specific. Furthermore, we observed that the enhanced apoptosis induced by perifosine and TRAIL in combination was almost or partially blocked by the administration of the DR4 and DR5 blocking antibodies only in the case of MM.1S, MM.1R, RPMI8226 TRAIL sensitive cells lines. Apoptosis was completely blocked in the case of U266 TRAIL resistant cell line when the chimera antibodies were used with perifosine alone or in combination with TRAIL. Conclusion and future directions: Perifosine, an agent proposed to function via inhibition of p-AKT and PDK-1, may have other effects on cell cycle regulation and it pro-apoptotic effects may be partially related to the TRAIL pathway. Our data suggests that an additional mechanism of action relates to the effect perifosine has on DR4 and DR5 expression thus directly effecting apoptosis via the TRAIL mediated effects. The limited response the trail resistant cell line U266 cells suggest that the TRAIL resistant myeloma cells have less DR4 or DR5 surface receptors as compared to the TRAIL sensitive cell lines, MM.1S, MM.1R, and RPMI8226 further validating this alternative mechanism. Further experiments such as inhibition of DR4, DR5, and FADD by small interfering RNAs, RT-PCR, the response in primary myeloma cells and also using more TRAIL resistant cell lines to support our preliminary observations are currently in progress.
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Meng, Xin, Jinrui Zhang, Hao Wu, Dahai Yu, and Xuexun Fang. "Akkermansia muciniphila Aspartic Protease Amuc_1434* Inhibits Human Colorectal Cancer LS174T Cell Viability via TRAIL-Mediated Apoptosis Pathway." International Journal of Molecular Sciences 21, no. 9 (May 11, 2020): 3385. http://dx.doi.org/10.3390/ijms21093385.
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Mucin2 (Muc2) is the main component of the intestinal mucosal layer and is highly expressed in mucous colorectal cancer. Previous studies conducted by our lab found that the recombinant protein Amuc_1434 (expressed in Escherichia coli prokaryote cell system, hereinafter termed Amuc_1434*), derived from Akkermansia muciniphila, can degrade Muc2. Thus, the main objective of this study was to explore the effects of Amuc_1434* on LS174T in colorectal cancer cells expressing Muc2. Results from this study demonstrated that Amuc_1434* inhibited the proliferation of LS174T cells, which was related to its ability to degrade Muc2. Amuc_1434* also blocked the G0/G1 phase of the cell cycle of LS174T cells and upregulated the expression of tumor protein 53 (p53), which is a cell cycle-related protein. In addition, Amuc_1434* promoted apoptosis of LS174T cells and increased mitochondrial ROS levels in LS174T cells. The mitochondrial membrane potential of LS174T cells was also downregulated by Amuc_1434*. Amuc_1434* can activate the death receptor pathway and mitochondrial pathway of apoptosis by upregulating tumor-necrosis-factor-related apoptosis-inducing ligand (TRAIL). In conclusion, our study was the first to demonstrate that the protein Amuc_1434* derived from Akkermansia muciniphila suppresses LS174T cell viability via TRAIL-mediated apoptosis pathway.
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Braun, Frank K., Rohit Mathur, Lalit Sehgal, Zuzana Berkova, and Felipe Samaniego. "Histone 3 Methyltransferase (EZH2) Inhibition Enhances TRAIL-Induced Apoptosis In Mantle Cell Lymphoma Cells By Accelerated cFLIP Degradation." Blood 122, no. 21 (November 15, 2013): 4425. http://dx.doi.org/10.1182/blood.v122.21.4425.4425.
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Introduction Mantle cell lymphoma (MCL) is an aggressive form of non-Hodgkin lymphoma that is characterized by the t(11:14)(q13:p32) translocation. MCL cells have altered cyclinD1 levels, impaired cell cycle regulation, DNA damage response, and likely defects in apoptosis signaling. Furthermore, up-regulated anti-apoptotic mediators such as the target of NF-κB c-FLIP were correlated with decreased apoptosis signaling. Also many cancer cells and malignant tumors show a prevalent resistance to apoptosis induction by TRAIL. Thus, by understanding the underpinnings of apoptosis resistance, we will be in a better position to develop strategies that improve TRAIL-induced killing of lymphoma cells. Methods/Results MCL cell lines (Mino, JeKo-1, JVM-2 and Z-138) were treated with DZNep (3-Deazaneplanocin A; 0.2-5µM) for 24 h followed by incubation with TRAIL (10-20ng/ml, 6-16h). Cell death, DNA fragmentation, and mitochondrial membrane potential (Δψm) were determined by calcein staining, subG1 analysis, and TMRM staining, respectively. Neither DZnep alone nor in combination with TRAIL showed a significant induction of necrosis as determined by LDH-release levels, but DZNep alone showed strong antiproliferative properties at higher concentrations (Promega CellTiter 96 assay). Activation of the caspase signaling cascade (caspase-8, -9, -3, Bid, and PARP cleavage) was analyzed by Western blotting. TRAIL-induced signaling was significantly increased and caspase-8 processing enhanced in DZNep pretreated cells indicating a regulation at the TRAIL/DISC. Although a reduced expression of DR5 in total cell lysates of DZNep treated cell was observed, the surface receptor levels were not altered. Interestingly, downregulation of the well-known caspase inhibitor, cFLIP, correlated with the DZNep-induced increased TRAIL sensitivity in MCL cell lines. However, it appears that cFLIP levels are not reduced due to blocked NF-kB signaling but rather by an accelerated ubiquitin-mediated degradation. Conclusions This study reveals that inhibition of histone methyltransferase (EZH2) activity by DZNep has a profound positive impact on TRAIL signaling; it enhances TRAIL sensitivity by promoting processing of caspase-8 through enhanced cFLIP degradation. The capacity of DZNep to target stability of cFLIP, which represents a center piece in DISC regulation underscores its potential for enhancing efficacy of TRAIL-based cancer therapies. Disclosures: No relevant conflicts of interest to declare.
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Cabrera-Muffly, Cristina, C. W. David Chang, and Liana Puscas. "Current Interview Trail Metrics in the Otolaryngology Match." Otolaryngology–Head and Neck Surgery 156, no. 6 (February 7, 2017): 1097–103. http://dx.doi.org/10.1177/0194599817690723.
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Objectives To identify how applicants to otolaryngology residency determine how to apply to, interview with, and rank programs on the interview trail and to determine the extent of the financial burden of the otolaryngology interview trail. Study Design Web-based survey distributed in March and April 2016. Setting Otolaryngology residency applicants throughout the United States. Subjects and Methods Applicants to otolaryngology residency during the 2016 match cycle and current otolaryngology residents were surveyed. Results Median number of applications, interview offers, interviews attended, and programs ranked was not different during the 2016 match and the previous 5 match years. The most important factor affecting the number of applications was the need to apply widely to ensure sufficient interview offers. The most common reason for declining an interview offer was scheduling conflict. Applicants during the 2016 match spent a median of $5400 applying and interviewing for otolaryngology residency. Conclusions Median number of applications, interview offers, interviews attended, and programs ranked has not changed. The most cited reason for applying to many programs was to increase the chances of matching, but this is not statistically likely to increase match success. We advocate for continued attempts to make the otolaryngology match process more transparent for both applicants and resident selection committees, but recognize that applicants are likely to continue to overapply for otolaryngology residency positions.
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Pundt, Noreen, Marvin A. Peters, Christina Wunrau, Simon Strietholt, Carsten Fehrmann, Katja Neugebauer, Christine Seyfert, Frans van Valen, Thomas Pap, and Ingmar Meinecke. "Susceptibility of rheumatoid arthritis synovial fibroblasts to FasL- and TRAIL-induced apoptosis is cell cycle-dependent." Arthritis Research & Therapy 11, no. 1 (2009): R16. http://dx.doi.org/10.1186/ar2607.
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He, Song-Qing, Hasibur Rehman, Ming-guang Gong, Yong-Zhong Zhao, Zhi-Yong Huang, Chang-Hai Li, Wan-Guang Zhang, and Xiao-Ping Chen. "Inhibiting survivin expression enhances TRAIL-induced tumoricidal activity in human hepatocellular carcinoma via cell cycle arrest." Cancer Biology & Therapy 6, no. 8 (August 2007): 1258–68. http://dx.doi.org/10.4161/cbt.6.8.4444.
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SOHN, B. Hwa, Hyung-Bae MOON, Tae-Yoon KIM, Han-Sung KANG, Yoon Soo BAE, Kyung-Kwang LEE, and Sun Jung KIM. "Interleukin-10 up-regulates tumour-necrosis-factor-α-related apoptosis-inducing ligand (TRAIL) gene expression in mammary epithelial cells at the involution stage." Biochemical Journal 360, no. 1 (November 8, 2001): 31–38. http://dx.doi.org/10.1042/bj3600031.
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Although interleukin-10 (IL-10) is known to contribute to inflammation and pathogenesis in mammalian organs, little is known about its precise role in the mammary gland. We found that IL-10 levels fluctuated during the mouse mammary cycle, showing little expression at the lactation stage and the highest expression at the involution stage. To reveal the effects of IL-10 on involution, expression profiles of apoptosis-related genes were examined in mice transgenic for IL-10 as well as in IL-10−/− mice. Mild inflammatory lesions by lymphocytes were observed in the mammary glands from four of seven transgenic lines at the lactation stage. It was striking that the expression of tumour-necrosis-factor-α-related apoptosis-inducing ligand (TRAIL) among the apoptosis-related genes was elevated approx. 7-fold in the transgenic mice, whereas others were almost unchanged. Furthermore, TRAIL was down-regulated 4-fold in the IL-10−/− mice at the involution stage. Elevated expression of TRAIL and of death receptor 4 (DR4) protein was identified at the involution stage of normal mammary glands as well as at the lactation stage of the IL-10 transgenic mice. These results indicate that the elevated expression of IL-10 at the involution stage recruits lymphocytes and induces the expression of TRAIL and DR4. These phenomena might partly contribute to apoptosis in the mammary epithelial cells for entering involution.
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Park, Joo-In, Hoon Han, Ji-Seon Han, Hyuk-Chan Kwon, Jin-Yeong Han, Jin-Sook Jeong, Yoe-Sik Bae, and Jong-Young Kwak. "Cotreatment with Pioglitazone, a Synthetic Ligand for Peroxisome Proliferator-Activated Receptor γ (PPARγ), Enhances Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand (TRAIL)-Induced Apoptosis of Human Leukemia Cells." Blood 104, no. 11 (November 16, 2004): 4377. http://dx.doi.org/10.1182/blood.v104.11.4377.4377.
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Abstract Imatinib (STI571, Glivec) is the choice treatment for Bcr/Abl-positive malignancies. Emergence of resistance to Imatinib warrants the exploration of novel well-tolerated anticancer agents. Peroxisome proliferator-activated receptor γ (PPARγ) is a nuclear receptor family, which mainly associates with the adipocyte differentiation, but also appears to facilitate cell differentiation or apoptosis in certain malignant cells. Previous studies imply that the PPARγ activation pathway may be a possible intervention mode for treatment of leukemia, which is resistant to imatinib (STI571). In this study, we investigated the effects of pioglitazone, a synthetic ligand for PPARg, on the cell growth and TRAIL-induced apoptosis in a novel imatinib (STI571) resistant acute myeloid cell line (SR-1), which we have established from an STI571 resistant blast crisis patient, as well as HL-60 cells. HL-60 and SR-1 cells are relatively resistant to TRAIL-induced apoptosis. Pioglitazone alone inhibited the cell growth of SR-1 and HL-60 cells, but did not induce the apoptosis of these cell lines. However, simultaneous exposure of cells to 100 ng/ml TRAIL with either 25 μM pioglitazone or 50 μM piogliazone resulted in a striking increase in apoptosis. To clarify the mechanism of pioglitazone to sensitize the leukemia cells to TRAIL-induced apoptosis, we investigated the change of the proteins related to cell cycle and apoptosis by western blot. As results, we observed the significant decrease of X-linked inhibitor of apoptosis (XIAP) and the increased expression of p21 by cotreatment of pioglitazone with TRAIL. Taken together, these findings indicate that pioglitazone may have promising activity in augmenting TRAIL-induced apoptosis of human acute leukemia cells including the imatinib (STI571) resistant acute myeloid cell line.
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Zhang, Bo, Hong Shan, Dan Li, Zheng-ran Li, Kang-shun Zhu, Zai-bo Jiang, and Ming-sheng Huang. "Different methods of detaching adherent cells significantly affect the detection of TRAIL receptors." Tumori Journal 98, no. 6 (November 2012): 800–803. http://dx.doi.org/10.1177/030089161209800619.
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Aims and background As a powerful technique allowing analysis of large numbers of cells, fluorescence-activated cell sorting (FACS) is used more and more widely. For FACS analysis, adherent cells are usually detached by trypsinization, followed by centrifugation and resuspension. However, trypsinization can cut off some receptors from the cell surface like fine scissors, which will affect the accuracy of FACS results. Though non-enzymatic methods such as citric saline buffer have been used to determine cell surface receptors, how much of the receptors is cut off by trypsinization has been rarely studied. This work aimed to investigate whether different methods of detaching adherent cells could affect the detection of cell surface receptors. Methods Human hepatocellular carcinoma cell lines (HepG2, Huh7 and Hep3B) were detached enzymatically with trypsin-EDTA solution or non-enzymatically with citric saline buffer, and then the receptors of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) were detected by FACS analysis. Cell viability, cell cycle and apoptosis (sub-G1 fraction detected by FACS) of the trypsin-EDTA group and citric saline buffer group were also studied. Results Different methods of detaching adherent cells could significantly affect the detection of TRAIL receptors. Compared to the conventional trypsin-EDTA group, the non-enzymatic group showed a 3.42-fold increase in the mean fluorescence intensity index of DcR HepG2 and a 1.25-fold increase in DR Huh 7 (P <0.05). However, the viability, cell cycle and apoptosis of these cells were not affected. Conclusions Citric saline buffer might be recommended as the first choice to detach adherent cells for FACS analysis of cell surface receptors.
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Sunimah, Nani. "CONTEXTUAL MODEL APPLICATION TO IMPROVE STUDENT LEARNING OUTCOMES IN LEARNING CONCEPT TWO-DIMENTIONAL FIGURE." EDUTECH 15, no. 1 (May 9, 2016): 39. http://dx.doi.org/10.17509/edutech.v15i1.2229.
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Abstract. Cilengkrang Elementary School second grade students in learning are still having trouble getting up flat. Based on early research on learning outcomes, students who completed study on indicators to use a formula to calculate the flat wake, only reached 25%. To overcome this implemented so that students understand the contextual model for teaching students associated with the real world. The method used in this research is a classroom action research methods to the design of the research procedure refers to the spiral model Kemmis and MC. Taggart. Research data collection techniques are observation, interviews, field notes, and tests using instruments guidelines for observation, interview, field notes, journals and tests. As for data validation, used techniques chek members, triangulation, audit trail and expert opinion. Based on the implementation of the actions carried out by two cycles, as a whole has shown an increase from the initial data, both process and outcomes of learning. From the data obtained, the process of learning to teacher performance, tahapperencanaan the first cycle to IImencapai 100%, during the implementation phase, the first cycle of 75% and the second cycle of 100%, at this stage of the evaluation cycle I to II reached 100% target achievement completeness 80 %. On the percentage of student activity average values, the first cycle and the second cycle 67% 82% with a target of achieving completeness ≥ 80.64%. As for the study results, the percentage ketuntasannya, the first cycle and the second cycle 42% 87% with a target of achieving completeness ≥ 80.64%. So that the application of contextual models can enhance students' understanding of the class II SDN Cilengkrang Northern District of Sumedang Sumedang Regency to the concept of a flat wake. Keywords: Build Flat, Contextual Model, Mathematics Education Abstrak. Siswa kelas II SDN Cilengkrang dalam pembelajaran bangun datar masih mengalami kesulitan. Berdasarkan penelitian awal pada hasil belajar, siswa yang tuntas belajar pada indikator menggunakan rumus untuk menghitung bangun datar, hanya mencapai 25%. Untuk mengatasi hal tersebut diterapkan model kontekstual agar siswa paham karena pembelajaran dikaitkan dengan dunia nyata siswa. Metode penelitian yang digunakan dalam penelitian ini adalah metode penelitian tindakan kelas dengan rancangan prosedur penelitiannya mengacu pada model spiral Kemmis dan MC. Taggart. Teknik pengumpulan data penelitian yang digunakan adalah observasi, wawancara, catatan lapangan, dan tes dengan menggunakan instrumen pedoman observasi, pedoman wawancara, catatan lapangan, jurnal dan tes. Sedangkan untuk validasi data, digunakan teknik member chek, triangulasi,audit trail dan expert opinion. Berdasarkan pelaksanaan tindakan yang dilakukan sebanyak dua siklus, secara keseluruhan telah menunjukan adanya peningkatan dari data awal, baik dalam proses maupun hasil belajar. Dari data yang diperoleh, pada proses pembelajaran, untuk kinerja guru, tahapperencanaan siklus I sampai IImencapai 100%, pada tahap pelaksanaan, siklus I 75% dan siklus II 100 %, pada tahap evaluasi siklus I sampai II mencapai 100 % dengan target pencapaian ketuntasan 80 %. Pada aktivitas siswa persentase nilai rata-rata, siklus I 67%dan siklus II 82% dengan target pencapaian ketuntasan ≥ 80,64 %. Sedangkan untuk hasil belajar, persentase ketuntasannya, siklus I 42 %dan siklus II 87% dengan target pencapaian ketuntasan ≥ 80,64 %. Sehingga penerapan model kontekstual dapat meningkatkan pemahaman siswa kelas II SDN Cilengkrang Kecamatan Sumedang Utara Kabupaten Sumedang terhadap konsep bangun datar. Kata Kunci: Bangun Datar, Model Kontekstual, Pendidikan Matematika
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Ralston, W. T., J. A. Weitzen, and J. C. Ostergaard. "Distribution of underdense meteor trail durations and duty cycle and applications to meteor scatter communication system design." Radio Science 28, no. 5 (September 1993): 747–57. http://dx.doi.org/10.1029/92rs02879.
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Jiao, Peng, Yun-Sheng Zhou, Juan-Xia Yang, Ya-Li Zhao, Qiang-Qiang Liu, Chuang Yuan, and Feng-Ze Wang. "MK-2206 induces cell cycle arrest and apoptosis in HepG2 cells and sensitizes TRAIL-mediated cell death." Molecular and Cellular Biochemistry 382, no. 1-2 (June 25, 2013): 217–24. http://dx.doi.org/10.1007/s11010-013-1737-0.
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Abdel Salam, Nagwa, Ahmed A. Abd-Rabou, Hayat M. Sharada, Gehan G. Abd EL Samea, and Mohga Abdalla. "Combination Therapy of TRAIL and Thymoquinone Induce Breast Cancer Cell Cytotoxicity-Mediated Apoptosis and Cell Cycle Arrest." Asian Pacific Journal of Cancer Prevention 22, no. 5 (May 1, 2021): 1513–21. http://dx.doi.org/10.31557/apjcp.2021.22.5.1513.
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Cheng, F. J., J. Y. Zhang, Dong Po Wang, and S. P. Wu. "The Effect of Square Wave AC Parameters on Weld Forming Performance." Materials Science Forum 697-698 (September 2011): 361–64. http://dx.doi.org/10.4028/www.scientific.net/msf.697-698.361.
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The effects of weld current, voltage, frequency and duty cycle on weld forming performance were investigated in SAW (Submerged Arc Welding) with square wave AC mode. The results showed that the penetration increased with the decrease of frequency and increase of duty cycle, but weld width showed the opposite change tendency. Furthermore, some experiments were implemented to analyze the effect of wire extension length and arc voltage on bead appearance. All of these experimental data could provide proper parameters for the lead arc and the trail arc in tandem SAW using square wave AC and also testified square wave AC was preferred over DC and traditional 50Hz AC. The square wave AC power source could be applied widely in tandem SAW.
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Zakharov, S. G., A. K. Golenkov, V. A. Misyurin, E. V. Kataeva, M. A. Baryshnikova, Yu Yu Chuksina, T. A. Mitina, et al. "Expression levels of the apoptosis genes FAS, TNFR2, TRAIL, DR3 and DR4/5 in patients with newly diagnosed chronic lymphatic leukemia before and after treatment with fludarabine, cyclophosphamide and rituximab (FCR)." Almanac of Clinical Medicine 46, no. 8 (December 31, 2018): 734–41. http://dx.doi.org/10.18786/2072-0505-2018-46-8-734-741.
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Background: We have previously shown that the FAS, TNFR2, TRAIL, DR3, DR4/5 gene expression in patients with newly diagnosed chronic lymphoblastic leukemia (CLL) correlates with clinical manifestations of the disease: they are minimal in patients with high activity of the proapoptotic genes and low activity of the apoptosisinhibiting genes, and advanced in patients with high expression of the anti-apoptotic and low expression of the pro-apoptotic genes.Aim: To compare the levels of expression of the external apoptosis pathway genes in patients with newly diagnosed CLL before and after chemotherapy with fludarabine, cyclophosphamide and rituximab (FCR), taking into account baseline clinical data and the response to treatment.Materials and methods: This prospective one-center cohort study included 23 patients with newly diagnosed CLL, who underwent clinical and diagnostic assessments and treatment from November 2014 to December 2017. Immunophenotyping of peripheral blood lymphocytes for CLL diagnosis was done by fourcolor flow cytometry. Expression of the external apoptosis pathway genes was assessed by realtime reverse transcriptase polymerase chain reaction. All patients were treated with a standard FCR regimen with subsequent maintenance treatment with rituximab.Results: There were more men (n = 16) than women among our 23 CLL patients. Median age was 64 years (range, from 47 to 77 years). Sixteen (16) patients had CLL Rai Grade I and II, and 7 patients had CLL Grades III and IV. For convenience of analysis, all patients were divided into two groups depending on the FAS gene expression. At baseline, the patients with high FAS expression had higher TNFR2 (p < 0.0015) and TRAIL (p < 0.0053) expression levels. Before FCR therapy, the patients with low FAS expression had higher lymphocyte counts (р = 0.0016) and lower erythrocyte counts (р = 0.0159). At baseline, there were more Grade I and II patients in the group with higher FAS expression (р = 0.0205). At day 3 after the end of a four day FCR cycle, there was an increase only of the FAS (p = 0.0025) and TRAIL (p = 0.0045) expression. After the completion of the first FCR cycle, lymphocyte counts in the patients with low FAS expression decreased earlier than those in the patients with high FAS expression (p = 0.0019). After six FCR cycles, complete or partial remission was obtained in 82% (19/23) of the patients. The patients with high FAS expression had higher complete remission rate (р = 0.026). No adverse events related to FCR were registered.Conclusion: The external apoptosis pathway genes are one of the key factors of the tumor progression in CLL. Our data on the effect of FCR therapy on the FAS and TRAIL gene expression make it possible to consider them as a target for this combination regimen and may become the rationale to develop new pharmaceutical molecules.
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Berendt, Ferréol, Mathieu Fortin, Christian Suchomel, and Janine Schweier. "Productivity, Costs, and Selected Environmental Impacts of Remote-Controlled Mini Forestry Crawlers." Forests 9, no. 10 (September 21, 2018): 591. http://dx.doi.org/10.3390/f9100591.
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An effective way to reduce off-road traffic in forests is to implement greater distances between skid trails. However, this implies that trees beyond the boom reach of the harvester need to be felled motor manually before being winched to the skid trail, for example using a remote-controlled mini forestry crawler (MFC). They are only a few local studies which have evaluated the performance of such MFCs. The use of MFCs for wood extraction operations in mixed soft- and hardwood stands is presented in this study conducted in Southwestern Germany. The aim of this study was to analyze the productivity, costs, and selected environmental impacts of mini forestry crawlers during winching operations through a time study. Using statistical regression, time consumption was analyzed in order to determine significant explanatory variables. Environmental impacts were evaluated using the life cycle assessment (LCA) methodology with Umberto software. The mean net cycle time was 4.82 min and the net productivity rate was 7.77 m3 by productive machine hour (PMH0). Explanatory variables which significantly affected the net cycle time were the winched volume, the number of trees per load, and winching distance. Environmental analysis showed that inputs of fossil energy were mostly due to diesel and lubricant consumption. Raw materials for machine manufacture and maintenance showed the highest impact in human toxicity potential category. The MFCs showed good environmental performances, but the harvesting system should become more productive in order to be more cost effective.
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Braun, Frank K., Rohit Mathur, Lalit Sehgal, Rachel Wilkie-Grantham, Joya Chandra, Zuzana Berkova, and Felipe Samaniego. "Accelerated Degradation of cFLIP Mediated By Inhibition of Methyltransferases Sensitizes B-Cell Lymphoma Cells to TRAIL-Induced Apoptosis." Blood 124, no. 21 (December 6, 2014): 920. http://dx.doi.org/10.1182/blood.v124.21.920.920.
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Abstract Introduction Non-Hodgkin lymphomas (NHLs) are characterized by specific abnormalities that alter cell cycle regulation, DNA damage response, and apoptotic signaling. Cancer cells can be particularly sensitive to cell death induced by tumor necrosis factor a–related apoptosis-inducing ligand (TRAIL). However, many cancer cells show blocked TRAIL signaling because up-regulated expression of anti-apoptotic factors such as cFLIP. Thus, by further understanding the underpinnings of apoptosis resistance, we will be in a better position to develop strategies that improve TRAIL-induced killing of lymphoma cells. Methods/Results NHL cell lines, including mantle cell lymphoma (MCL; Mino, JeKo-1, JVM-2 and Z-138), Burkitt lymphoma (BL; Bjab, Ramos, Daudi) and diffuse large B-cell lymphoma (DLBCL; SU-DHL-4, SU-DHL -6, SU-DHL-9) were treated with 3-Deazaneplanocin A (DZNep); 0.2-5µM) for 24 hours followed by incubation with TRAIL (10-20ng/ml, 6-16hours). Cell death, DNA fragmentation, and mitochondrial membrane potential (Δψm) were determined by calcein staining, subG1 analysis, and TMRM staining, respectively. Neither DZNep alone nor in combination with TRAIL showed a significant induction of necrosis as determined by LDH-release levels, but DZNep alone showed strong anti-proliferative properties at higher concentrations. Activation of the caspase signaling cascade (caspase-8, -3, and PARP cleavage) was analyzed by Western blotting. TRAIL-induced signaling was significantly increased and caspase-8 processing enhanced in DZNep pretreated cells indicating a regulation at the TRAIL/DISC assembly. Although we observed a reduced expression of DR5 in total cell lysates of DZNep treated cells, the surface receptor levels were not altered. Interestingly, down regulation of the well-known caspase inhibitor, cFLIP, correlated with the DZNep-induced increased TRAIL cell killing in all sensitive NHL cells. The DZNep-treatment did not block NF-kB signaling related to cFLIP expression but profoundly affected cFLIP mRNA and protein stability. Elevated levels of cFLIP targeting miRNA’s were observed and were attributed to some extend with cFLIP regulation. Conclusions: In this study, we investigated the impact of a pan-methyltransferase inhibitor (3-deazaneplanocin A, or DZNep) on TRAIL-induced apoptosis in aggressive NHLs: mantle cell, Burkitt, and diffuse large B-cell. We characterized TRAIL apoptosis regulation and caspase activation in several NHL cell lines pre-treated with DZNep. We found that DZNep increased cancer cell sensitivity to TRAIL signaling by promoting caspase-8 processing through accelerated cFLIP degradation. Blockage of methyltransferase activity induced by DZNep profoundly affected cFLIP mRNA and protein stability, at least in part through increased levels of cFLIP-targeting microRNAs (miR-512-3p and miR-346). However, additional microRNAs and cFLIP-regulating mechanisms appear to be involved in DZNep-mediated enhanced response to extrinsic apoptotic stimuli. The capacity of DZNep to target cFLIP expression on multiple levels underscores its potential in TRAIL-based therapies for NHLs. Disclosures No relevant conflicts of interest to declare.
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Chen, Wenming, Lugui Qiu, Jian Hou, Yaozhong Zhao, Ling Pan, Shifang Yang, Yun Leng, et al. "Recombinant Circularly Permuted TRAIL (CPT) for the Treatment of Relapsed or Refractory Multiple Myeloma: An Open-Label, Multicenter Phase II Clinical Trial." Blood 120, no. 21 (November 16, 2012): 78. http://dx.doi.org/10.1182/blood.v120.21.78.78.
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Abstract Abstract 78 Background: Circularly permuted TRAIL (CPT) is a recombinant mutant of human Apo2L/TRAIL developed by Beijing Sunbio Biotech Co., Ltd. as a targeted therapy for multiple myeloma and other hematologic malignancies. CPT is a dual pro-apoptotic receptor agonist that directly activates both pro-apoptotic receptors TRAIL-R1 (DR4) and TRAIL-R2 (DR5). CPT selectively induces apoptosis in a variety of cancer cells, while sparing most normal cells in preclinical models. Objective: CPT has shown preliminary activities for patients with relapsed or refractory multiple myeloma (Rel/Ref MM) in phase I study. The aim of this phase II study is to investigate the effect and safety of CPT for Rel/Ref MM patients. Methods: In this multi-center, open-label, single arm phase II study, twenty-seven Rel/Ref MM patients were enrolled to receive CPT treatment alone at the dose of 2.5 mg/kg/day intravenously, once daily for 14 consecutive days of each 21-day cycle. Clinical responses to CPT after 2 cycle's treatment were assessed by an independent review committee according to the criteria of the European Group for Blood and Marrow Transplantation (EBMT). Results: Among the 27 patients, one patient (3.7%) achieved near complete response (nCR) and eight patients (29.63%) exhibited partial response (PR). The overall response rate (ORR) was 33.3%. The median PFS was not reached within 2 cycle's treatment. The drug related adverse events (≥10%) included fever, AST/ALT elevation, leucopenia, neutropenia, rash, thrombocytopenia, and LDH elevation. The severe adverse events were occurred in 3 patients (11%), one of them was CPT-related liver injury. Anti-drug antibodies were detected in 6 patients without reduced efficacy or increased toxicities. Conclusions: The CPT is a very effective and well-tolerated new agent for Rel/Ref MM, and it is worthy to be further studied. Disclosures: Yang: Beijing Sunbio Biotech Co. Ltd.: Employment. Cui:Beijing Sunbio Biotech Co. Ltd.: Employment.
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Lees, Andrea, Alexander J. McIntyre, Nyree T. Crawford, Fiammetta Falcone, Christopher McCann, Caitriona Holohan, Gerard P. Quinn, et al. "The pseudo-caspase FLIP(L) regulates cell fate following p53 activation." Proceedings of the National Academy of Sciences 117, no. 30 (July 13, 2020): 17808–19. http://dx.doi.org/10.1073/pnas.2001520117.
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p53 is the most frequently mutated, well-studied tumor-suppressor gene, yet the molecular basis of the switch from p53-induced cell-cycle arrest to apoptosis remains poorly understood. Using a combination of transcriptomics and functional genomics, we unexpectedly identified a nodal role for the caspase-8 paralog and only human pseudo-caspase, FLIP(L), in regulating this switch. Moreover, we identify FLIP(L) as a direct p53 transcriptional target gene that is rapidly up-regulated in response to Nutlin-3A, an MDM2 inhibitor that potently activates p53. Genetically or pharmacologically inhibiting expression of FLIP(L) using siRNA or entinostat (a clinically relevant class-I HDAC inhibitor) efficiently promoted apoptosis in colorectal cancer cells in response to Nutlin-3A, which otherwise predominantly induced cell-cycle arrest. Enhanced apoptosis was also observed when entinostat was combined with clinically relevant, p53-activating chemotherapy in vitro, and this translated into enhanced in vivo efficacy. Mechanistically, FLIP(L) inhibited p53-induced apoptosis by blocking activation of caspase-8 by the TRAIL-R2/DR5 death receptor; notably, this activation was not dependent on receptor engagement by its ligand, TRAIL. In the absence of caspase-8, another of its paralogs, caspase-10 (also transcriptionally up-regulated by p53), induced apoptosis in Nutlin-3A-treated, FLIP(L)-depleted cells, albeit to a lesser extent than in caspase-8-proficient cells. FLIP(L) depletion also modulated transcription of canonical p53 target genes, suppressing p53-induced expression of the cell-cycle regulator p21 and enhancing p53-induced up-regulation of proapoptotic PUMA. Thus, even in the absence of caspase-8/10, FLIP(L) silencing promoted p53-induced apoptosis by enhancing PUMA expression. Thus, we report unexpected, therapeutically relevant roles for FLIP(L) in determining cell fate following p53 activation.
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Bosque, Alberto, Juan I. Aguiló, Manuel del Rey, Estela Paz-Artal, Luis M. Allende, Javier Naval, and Alberto Anel. "Cell cycle regulation by FasL and Apo2L/TRAIL in human T-cell blasts. Implications for autoimmune lymphoproliferative syndromes." Journal of Leukocyte Biology 84, no. 2 (May 15, 2008): 488–98. http://dx.doi.org/10.1189/jlb.0108043.
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Pazzi, Richard Werner, Azzedine Boukerche, Robson Eduardo De Grande, and Lynda Mokdad. "A clustered trail-based data dissemination protocol for improving the lifetime of duty cycle enabled wireless sensor networks." Wireless Networks 23, no. 1 (December 12, 2015): 177–92. http://dx.doi.org/10.1007/s11276-015-1089-7.
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