Academic literature on the topic 'Mice trail following'
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Journal articles on the topic "Mice trail following"
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James, Britnie, Tamara Kucaba, and Thomas Griffith. "Plasmacytoid and CD8α DC are both necessary to generate antitumor immunity following Ad5-TRAIL/CpG immunotherapy (P2078)." Journal of Immunology 190, no. 1_Supplement (May 1, 2013): 132.29. http://dx.doi.org/10.4049/jimmunol.190.supp.132.29.
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Abstract It is now appreciated that there are distinct subsets of dendritic cells (DC) with specialized functions. Plasmacytoid DC (pDC) and CD8α DC can contribute to the priming, activation, and function of antitumor CD8 T cells; however, their specific roles and necessity in stimulating antitumor immunity is not clearly understood. Thus, we examined the distinct role pDC and CD8α DC play in an orthotopic model of metastatic renal cell carcinoma (RCC) treated with a recombinant adenovirus encoding TRAIL (Ad-TRAIL) combined with CpG ODN. Wild-type (WT) mice bearing RCC tumors and treated with Ad-TRAIL/CpG ODN cleared primary and metastatic tumors, and these mice survived long-term. In contrast, mice specifically depleted of either pDC (using an α-PDCA1 mAb) or CD8α DC (Batf -/- mice) had uncontrolled tumor growth and high mortality regardless of treatment. Both pDC-depleted and Batf3-/- mice exhibited significantly decreased infiltration of effector CD8 T cells in the primary tumor site, as compared to WT mice after therapy, possibly related to the reduced expression of pro-inflammatory cytokines in pDC-depleted mice and reduced uptake of apoptotic tumor cells in Batf3-/- mice. These data collectively suggest that both pDC and CD8αDC carry out independent, but complementary roles that are necessary to initiate an efficacious antitumor immune after Ad5-TRAIL/CpG ODN therapy.
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Giovarelli, Mirella, Piero Musiani, Gianni Garotta, Reinhard Ebner, Emma Di Carlo, Yunsoo Kim, Paola Cappello, et al. "A “Stealth Effect”: Adenocarcinoma Cells Engineered to Express TRAIL Elude Tumor-Specific and Allogeneic T Cell Reactions." Journal of Immunology 163, no. 9 (November 1, 1999): 4886–93. http://dx.doi.org/10.4049/jimmunol.163.9.4886.
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Abstract BALB/c mammary adenocarcinoma cells engineered to express TNF-related apoptosis-inducing ligand (TRAIL)/APO-2 ligand (APO-2L) on their membrane (TSA-TRAIL) grow with kinetics similar to that of parental cells (TSA-pc) in vitro and in nu/nu mice. In contrast, TSA-TRAIL cells grow faster than TSA-pc in normal BALB/c mice. In DBA/2 mice, which differ from BALB/c mice at minor histocompatibility Ags, they also grow faster and display a higher percentage of tumor takes than TSA-pc. In fully histoincompatible C57BL/6 (B6) mice, TSA-TRAIL cells form evident tumors that are slowly rejected by most mice, but outgrow in a few. In contrast, TSA-pc cells are rejected at once by B6 mice. Since TRAIL/APO-2L induces apoptosis by interacting with a variety of specific receptors, this rapid growth in both syngeneic and allogeneic mice may be the result of an immunosuppressive mechanism. The following evidence supports this hypothesis: 1) TSA-TRAIL cells overcome the strong immunity against TSA-pc cells elicited in BALB/c mice by preimmunization with TSA cells engineered to release IL-4; 2) their rejection by B6 mice does not prime a CTL-mediated memory; 3) thymidine uptake by T lymphocytes unstimulated or stimulated by allogeneic cells is inhibited when TSA-TRAIL cells are added as third party cells; 4) CTL kill TSA-pc but not TSA-TRAIL cells in 48-h assays; and 5) activated lymphocytes interacting with TSA-TRAIL cells in vivo and in vitro undergo apoptosis.
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Carlo-Stella, Carmelo, Cristiana Lavazza, Arianna Giacomini, Daniela Sia, Loredana Cleris, Massimo Di Nicola, Paolo Longoni, et al. "Human CD34+ Cells Expressing Membrane-Bound Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand (TRAIL) Exert a Potent Anti-Lymphoma Effects by Targeting Tumor Vasculature." Blood 110, no. 11 (November 16, 2007): 527. http://dx.doi.org/10.1182/blood.v110.11.527.527.
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Abstract Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is expected to play a key role in cancer therapy due to its high cancer cell-specificity and potent antitumor activity. We have previously demonstrated that CD34+ cells transduced with an adenovirus encoding the full-length human TRAIL gene (CD34-TRAIL+) exert a potent anti-lymphoma effect in NOD/SCID mice. To investigate the mechanism of action of CD34-TRAIL+ cells, in vivo experiments were perfomed to analyze the tumor homing capacity of CD34-TRAIL+ cells and the effects of transduced cells on tumor vasculature. Tumor homing of CD34-TRAIL+ cells was investigated in NOD/SCID mice bearing subcutaneous lymphoid tumors. Following a single intravenous injection of CD34-TRAIL+ cells (5 x 106), nodules were excised at different time-points and immunostained with an anti-human CD45 antibody. Sections were digitally recorded and the total number of CD45+ cells per tissue section was then counted using the imaging software ImageJ (http://rsb.info.nih.gov/ij/). Tumor homing of CD34-TRAIL+ cells peaked 24 hours after cell injection when a mean of 200 CD34-TRAIL+ cells was recorded per 1 x 105 tumor cells (0.2% CD45+ cells per 1 x 105 tumor cells). Mice pretreatment with the anti-VCAM-1 antibody or the CXCR4 antagonist AMD3100 significantly reduced tumor homing of CD34-TRAIL+ cells, with 0.09% and 0.05% CD45+ cells being recorded per 1 x 105 tumor cells, respectively. To analyze the effects of CD34-TRAIL+ cells on tumor vasculature, mice were injected with sulfo-biotin (0.1 mg, IV, 15 min) and tumor endotelial cells (TEC) were then revealed by staining frozen sections with horseradish peroxidase (HRP)-conjugated streptavidin. As compared with CD34-mock- or soluble (s)TRAIL-treated mice, treatment with CD34-TRAIL+ cells induced within 24 hours a significant (P ≤.001) increase of the thickness of the vessell wall (3.7 ± 1 μm vs 3.4 ± 1 μm vs 6 ± 1 μm, respectively) as well as the endothelial surface (10 ± 4% vs 7 ± 4% vs 21 ± 6% of total tissue section, respectively), suggesting that CD34-TRAIL+ cells induce an early vascular disruption. Confocal microscopic imaging of tumor sections double-stained with anti-CD31 and anti-TRAIL-R2 showed that this receptor was expressed by 8–12% of large tumor vessels. Interestingly, upon treatment with CD34-TRAIL+ cells, but not sTRAIL, TUNEL staining revealed an extensive apoptosis of CD31+/TRAIL-R2+ TEC. Forty-eight hours following injection of CD34-TRAIL+ cells, a 21-fold increase of apoptotic index was detected, which was associated with extensive necrotic areas (20% to 25% of tissue section). These data show that: tumor homing of CD34-TRAIL+ cells induces extensive vascular damage, hemorrhagic necrosis and tumor destruction; the antitumor effect of CD34-TRAIL+ cells is mediated by both indirect vascular-disrupting mechanisms and direct tumor cell killing.
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Loeuillard, Emilien, Jingchun Yang, Dong Haidong, Gregory Gores, and Sumera Ilyas. "Abstract PO032: Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand (TRAIL)-TRAIL-R Mediates Cholangiocarcinoma Tumor Immune Evasion by Enhancing Myeloid-Derived Suppressive Cell Population." Clinical Cancer Research 28, no. 17_Supplement (September 1, 2022): PO032. http://dx.doi.org/10.1158/1557-3265.liverca22-po032.
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Abstract Background and Aims: Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), a member of TNF superfamily, is predominantly expressed on immune cells. Engagement of TRAIL with its cognate receptor, TRAIL-R (TR), leads to cancer cells apoptosis. Although the anti-tumor role of TRAIL-TR has been extensively studied, TRAIL agonists have had very limited anti-cancer activity in human clinical trials. TRAIL signaling can facilitate the myeloid response. However, this potential immunosuppressive function of TRAIL has not been examined extensively in cancer biology. Cholangiocarcinoma (CCA), a highly lethal biliary tract cancer, has a dense immunosuppressive microenvironment. Accordingly, CCA provides a model to examine the potential immune regulatory function of TRAIL in cancer biology. Methods: Using syngeneic, orthotopic murine models of CCA, (PMID: 29464042), murine CCA cells (SB cells) that express both Trail and Trail receptor (Tr) were implanted into livers of WT Tr− / − and LyzcreTrf/f mice, the latter have a specific deletion of TRAIL-R on myeloid cells. Hence, in this model the host immune cells express Trail but not the receptor; therefore, they would be capable of inducing TRAIL-mediated apoptosis in CCA cells but would be resistant to TRAIL-mediated immunosuppression. After 4 weeks of tumor growth, mice were sacrificed, and tumors were characterized using flow cytometry. Results: We observed that Tr− / − mice had a significant reduction in tumor burden compared to WT mice. Myeloid-derived suppressor cells (MDSCs) were significantly decreased in Tr− / − tumors compared to WT tumors. Implantation of SB cells into LyzcreTrf/f mice resulted in a marked reduction in tumor burden and attenuation of MDSC infiltration compared to Lyzcre mice. In vitro functional studies employing MDSCs from mice deficient in Tr (MDSC-Tr −/−) were carried out. Compared to WT MDSCs, coculture of MDSC-Tr− /- with SB cells resulted in a significant reduction in the proliferation and immunosuppressive function of MDSCs. Moreover, following cocultured with SB cells, immunofluorescence analysis demonstrated that MDSC-Tr− / − had a reduction in the nuclear translocation of the NFkB subunit P65 compared to WT MDSCs. These data suggest that TRAIL-TR augments MDSC proliferation via NFkB. In conclusion, we have demonstrated that Tr− / − mice have a significant reduction in CCA tumor burden and MDSC infiltration. These results indicate that TRAIL-TR facilitates tumor immune escape and progression by fostering MDSC immunosuppressive function and infiltration, in an NFkB-dependent manner. Direct targeting of TRAIL on CCA cells is a potential anti-tumor strategy. Citation Format: Emilien Loeuillard, Jingchun Yang, Dong Haidong, Gregory Gores, Sumera Ilyas. Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand (TRAIL)-TRAIL-R Mediates Cholangiocarcinoma Tumor Immune Evasion by Enhancing Myeloid-Derived Suppressive Cell Population [abstract]. In: Proceedings of the AACR Special Conference: Advances in the Pathogenesis and Molecular Therapies of Liver Cancer; 2022 May 5-8; Boston, MA. Philadelphia (PA): AACR; Clin Cancer Res 2022;28(17_Suppl):Abstract nr PO032.
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Griffith, Thomas, Jacqueline Unsinger, Hirotaka Kazama, Jacqueline McDonough, Richard Hotchkiss, and Thomas Ferguson. "Sepsis-induced immunosuppression is mediated by TRAIL-expressing CD8+ regulatory T cells (87.13)." Journal of Immunology 184, no. 1_Supplement (April 1, 2010): 87.13. http://dx.doi.org/10.4049/jimmunol.184.supp.87.13.
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Abstract Patients who survive severe sepsis often display severely compromised immune function. One hallmark of such immune suppression in septic patients is an impaired delayed-type hypersensitivity (DTH) response, manifested by a loss of skin testing to recall antigens. Since sepsis induces significant apoptosis in lymphoid and myeloid cells and apoptotic cells are themselves tolerogenic, we tested the hypothesis that suppression of DTH is mediated by tolerogenic properties of the apoptotic cells generated during sepsis. Mice subjected to cecal ligation and puncture (CLP) demonstrated a loss of DTH for the 7 days following CLP; however, the immune response returned to normal by day 10. Blocking sepsis-induced apoptosis via Bcl-2 overexpression or Bim deficiency prevented the loss of DTH. Importantly, injection of apoptotic cells into Bim-/- mice prevented an effective DTH response, thereby suggesting a causal link between apoptotic cells and immune suppression. Surprisingly, when Trail-/- mice were examined, we found that these animals had significant apoptosis but retained their DTH responses. Further studies revealed that apoptotic cells generated during sepsis induced a CD8+ regulatory T cell (Treg) that mediated suppressed DTH by TRAIL production. These results establish a link between apoptotic cells and immune suppression during sepsis, and suggest TRAIL may be a viable therapeutic target for boosting the adaptive immune response following sepsis.
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Mercer-Smith, Alison, Wulin Jiang, Alain Valdivia, Noah Bell, Alex Woodell, Scott Floyd, and Shawn Hingtgen. "MMAP-04 CYTOTOXIC, TUMOR-HOMING INDUCED NEURAL STEM CELLS AS AN ADJUVANT TO RADIATION IN THE TREATMENT OF NON-SMALL CELL LUNG CANCER LEPTOMENINGEAL METASTASES." Neuro-Oncology Advances 4, Supplement_1 (August 1, 2022): i15. http://dx.doi.org/10.1093/noajnl/vdac078.060.
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Abstract INTRODUCTION Non-small cell lung cancer (NSCLC) is the most common cancer to spread to the brain, and spread to the leptomeninges is particularly devastating, with a median survival of only months. While radiation may offer symptomatic relief, new adjuvant therapies are needed for more durable tumor kill. Spheroidal, human induced neural stem cells (hiNeuroS) transdifferentiated from fibroblasts are inherently tumoritropic. When engineered to secrete the cytotoxic protein TRAIL, they provide the potential for a personalized, targeted approach to NSCLC leptomeningeal metastases. METHODS hiNeuroS-TRAIL in vivo efficacy was determined by tracking the progression and survival of mice with NSCLC leptomeningeal tumors treated with intracerebroventricular hiNeuroS, radiation, or both. To determine the impact of radiation on the tumor tropism of hiNeuroS, we performed 2-dimensional motion assays on hiNeuroS with and without the presence of NSCLC pre- and post-radiation. Migrational capacity in vivo was determined by infusing hiNeuroS into the lateral ventricles of mice with established NSCLC tumors and monitoring hiNeuroS accumulation using post-mortem fluorescent analysis. RESULTS/CONCLUSION Mice treated with the combination of hiNeuroS-TRAIL and 2 Gy showed a significantly reduced mean tumor signal (2.7%) compared to controls (100%) or 2 Gy-only (54.9%). Mice treated with 2 Gy alone showed no significant survival difference compared to controls. Both combination and hiNeuroS-TRAIL-only-treated mice showed a significant improvement in median survival compared to controls (36.6% and 46.3% improvement, respectively). hiNeuroS showed enhanced directionality and displacement in the presence of NSCLC in 2-dimensional motion assays, indicating directional migration, and they maintained this ability following exposure to radiation. Co-localization of hiNeuroS with NSCLC was also observed in vivo. These results suggest the potential of hiNeuroS-TRAIL as a powerful adjuvant to radiation in the treatment of leptomeningeal NSCLC.
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Mercer-Smith, Alison, Wulin Jiang, Alain Valdivia, Juli Bago, Scott Floyd, Simon Khagi, and Shawn Hingtgen. "EXTH-07. TUMOR-HOMING INDUCED NEURAL STEM CELLS SECRETING A CYTOTOXIC PAYLOAD AS AN ADJUVANT TREATMENT FOR NON-SMALL CELL LUNG CANCER BRAIN METASTASES." Neuro-Oncology 22, Supplement_2 (November 2020): ii88. http://dx.doi.org/10.1093/neuonc/noaa215.361.
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Abstract INTRODUCTION Non-small cell lung cancer (NSCLC) is the most common cancer to form brain metastases. Radiation treatment is standard-of-care, but recurrence is still observed in 40% of patients. An adjuvant treatment is desperately needed to track down and kill tumor remnants after radiation. Tumoritropic neural stem cells (NSCs) that can home to and deliver a cytotoxic payload offer potential as such an adjuvant treatment. Here we show the transdifferentiation of human fibroblasts into tumor-homing induced neural stem cells (hiNSCs) that secrete the cytotoxic protein TRAIL (hiNSC-TRAIL) and explore the use of hiNSC-TRAIL to treat NSCLC brain metastases. METHODS To determine the migratory capacity of hiNSCs, hiNSCs were infused intracerebroventricularly (ICV) into mice bearing established bilateral NSCLC H460 brain tumors. hiNSC accumulation at tumor foci was monitored using bioluminescent imaging and post-mortem fluorescent analysis. To determine synergistic effects of radiation with TRAIL on NSCLC, we performed in vitro co-culture assays and isobologram analysis. In vivo, efficacy was determined by tracking the progression and survival of mice bearing intracranial H460 treated with hiNSC-TRAIL alone or in combination with 2 Gy radiation. RESULTS/CONCLUSION Following ICV infusion, hiNSCs persisted in the brain for > 1 week and migrated from the ventricles to colocalize with bilateral tumor foci. In vitro, viability assays and isobologram analysis revealed the combination treatment of hiNSC-TRAIL and 2 Gy radiation induced synergistic killing (combination index=0.64). In vivo, hiNSC-TRAIL/radiation combination therapy reduced tumor volumes > 90% compared to control-treated animals while radiation-only and hiNSC-TRAIL-only treated mice showed 21% and 52% reduced volumes, respectively. Dual-treatment extended survival 40%, increasing survival from a median of 20 days in controls to 28 days in the treatment group. These results suggest hiNSC-TRAIL can improve radiation therapy for NSCLC brain metastases and could potentially improve outcomes for patients suffering from this aggressive form of cancer.
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Carlo-Stella, Carmelo, Cristiana Lavazza, Massimo Di Nicola, Loredana Cleris, Paolo Longoni, Marco Milanesi, Michele Magni, et al. "Antitumor Activity of Human CD34+ Cells Expressing Membrane-Bound Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand (mTRAIL)." Blood 108, no. 11 (November 16, 2006): 233. http://dx.doi.org/10.1182/blood.v108.11.233.233.
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Abstract Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is expected to play a key role in anti-cancer therapy due to its high cancer cell-specificity and potent antitumor activity. The clinical development of soluble (s)TRAIL is however hampered by several limitations, includingshort plasma half-life;liver toxicity;tumor cell resistance. To overcome these limitations, we used CD34+ cells transduced with an adenovirus encoding the full-length human TRAIL gene (CD34−TRAIL+) as vehicles for intra-tumor delivery of membrane-bound (m)TRAIL. The mean (±SD) transduction efficiency of CD34+ cells exposed to a multiplicity of infection (MOI) of 500 was 83 ± 8% (range 70 – 95%) with a cell viability ≥85%. In vitro, exposure of the sTRAIL-sensitive KMS-11 cell line to CD34−TRAIL+, but not mock-transduced CD34+ cells consistently resulted in caspase-3, -8, and -9 activation and in PARP cleavage, as well as in potent induction of apoptosis (up to 80% after a 48-hour co-culture). Exposure of the sTRAIL-resistant JVM-2 cell line to CD34−TRAIL+ cells resulted in significant levels of tumor cell death (up to 50% after a 48-hour co-culture). Studies in nonobese diabetic/severe combined immunodeficient (NOD/SCID) mice xenografted with KMS-11 cell line showed that CD34−TRAIL+ cells significantly increased the median survival of mice bearing early-stage (92 vs 55 days, P ≤ 0.0001) and advanced-stage (83 vs 55 days, P ≤ 0.0001) disease, as compared with controls. Additionally, CD34−TRAIL+ cells significantly prolonged the median survival of mice xenografted with the sTRAIL-resistant JVM-2 (40 vs 31 days, P ≤ 0.0001) and SU-DHL-4V (38 vs 30 days, P ≤ 0.0001) cell lines. No obvious toxicity was observed upon administration of CD34−TRAIL+ cells. Histological analysis of subcutaneous lymphoma revealed an efficient tumor homing of transduced cells and high level expression of the agonistic TRAIL-R2 receptor by tumor endothelial cells. Following injection of CD34−TRAIL+ cells, but not mock-transduced CD34+ cells, TUNEL staining revealed increasing amounts of apoptotic cells with a 21-fold increase of the apoptotic index at 120 hour post-injection. Additionally, CD34−TRAIL+ cells induced signs of vascular damage leading to a progressive disintegration of the vascular bed, suggesting that tumor endothelial cells represent an early target of CD34−TRAIL+ cells. Our experiments show that:in vitro, the co-culture of tumor cells and CD34−TRAIL+ cells resulted in a marked apoptosis of both sTRAIL-sensitive and sTRAIL-resistant tumor cells;in vivo, injection of CD34−TRAIL+ cells in mice bearing advanced-stage tumors as well as sTRAIL-resistant tumors was associated with a significant prolongation of survival. These results show that CD34−TRAIL+ cells might be an efficient vehicle for mTRAIL delivery to tumors, where they exert a potent antitumor effect possibly mediated by both direct tumor cell killing and indirect vascular-disrupting mechanisms.
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Cheng, Chieh-Fang, I.-Huang Lu, Hsiang-Wen Tseng, Chung-Yuan Sun, Li-Tsen Lin, Zong-Keng Kuo, I.-Horng Pan, and Ching-Huai Ko. "Antitumor Effect of Periplocin in TRAIL-Resistant Human Hepatocellular Carcinoma Cells through Downregulation of IAPs." Evidence-Based Complementary and Alternative Medicine 2013 (2013): 1–11. http://dx.doi.org/10.1155/2013/958025.
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Cortex periplocae is the dried root bark ofPeriploca sepiumBge., a traditional Chinese herb medicine. It contains high amounts of cardiac glycosides. Several cardiac glycosides have been reported to inhibit tumor growth or induce tumor cell apoptosis. We extracted and purified cortex periplocae and identified periplocin as the active ingredient that inhibited the growth of TNF-related apoptosis-inducing ligand-(TRAIL-) resistant hepatocellular carcinoma cells. The antitumor activity of periplocin was further increased by TRAIL cotreatment. Periplocin sensitized TRAIL-resistant HCC through the following two mechanisms. First, periplocin induced the expression of DR4 and FADD. Second, the cotreatment of TRAIL and periplocin suppressed several inhibitors of apoptosis (IAPs). Both mechanisms resulted in the activation of caspase 3, 8, and 9 and led to cell apoptosis. In addition, intraperitoneal injection (IP) of periplocin repressed the growth of hepatocellular carcinoma (HCC) in xenograft tumor model in mice. In summary, periplocin sensitized TRAIL-resistant HCC cells to TRAIL treatment and resulted in tumor cell apoptosis and the repression of tumor growthin vivo.
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Stuart, Patrick, and Megan Rogge. "Soluble FasL therapy reduces Herpetic Stromal Keratitis (154.23)." Journal of Immunology 186, no. 1_Supplement (April 1, 2011): 154.23. http://dx.doi.org/10.4049/jimmunol.186.supp.154.23.
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Abstract Fas ligand (FasL) signals apoptosis in Fas+ cells, and plays a vital role in controlling the entrance of inflammatory cells and neovascularization of ocular tissue. We tested the therapeutic value of soluble FasL in both an acute and recurrent model of HSK using BALB/c and BALB-lpr mice. sFasL was administered in a topical ointment and by subconjunctival injection following infection or reactivation. The controls were treatment with ointment alone or with soluble TRAIL (sTRAIL). These mice were evaluated for corneal disease by a masked observer who scored the corneas for opacity and neovascularization. Following acute infection, wild-type BALB/c mice treated with sFasL displayed reduced incidence of opacity and neovascularization when compared to the sTRAIL and ointment groups post infection. When the Fas deficient BALB-lpr mice were used, results showed no difference in HSK between sFasL and sTRAIL treated groups, as expected. When BALB/c mice undergoing recurrent HSK were treated with sFasL, we saw a decrease in both opacity and neovascularization as compared to the sTRAIL treated mice. These data we believe are due to the apoptotic signaling by sFasL of the Fas molecule found on inflammatory cells and vascular endothelium of newly growing vessels which are attempting to invade the cornea following infection or reactivation.
Books on the topic "Mice trail following"
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Following The Trail Of Marco Polo. Papercutz, 2010.
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Thomson, Peter. Sacred Sea. Oxford University Press, 2007. http://dx.doi.org/10.1093/oso/9780195170511.001.0001.
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Absoliutno blagopoluchnoe ozero Baikal! the Russian scientist looking out over the great lake says. "Lake Baikal is Perfect!" And humans can never harm it. For a man cut loose from his life in the U.S., Lake Baikal-Siberia's sacred inland sea-becomes a place of pilgrimage, the focal point of a 25,000-mile journey by land and sea in search of connection, permanence, restoration and hope. Following a difficult divorce, veteran environmental journalist Peter Thomson sets off from Boston with his younger brother for one of nature's most remarkable creations, in one of the farthest corners of the planet. Lake Baikal, a gargantuan crack in the Siberian plateau, is the world's largest body of fresh water, its deepest and oldest lake, and a cauldron of evolution, home to hundreds of unique creatures, including the world's only freshwater seal. It's also among the most pristine lakes on earth, with a mythical ability to protect itself from the growing human impact-a "perfect," self-cleansing ecosystem. A trip halfway around the world by train, cargo ship and rubber raft brings the brothers to a place of sublime beauty, deep history and immense natural power. But at Baikal they also find ominous signs that this perfect piece of nature could yet succumb to the even more powerful forces of human hubris, carelessness and ignorance. They find that despite its isolation, Baikal is connected to everything else on Earth, and that it will need the love and devotion of people around the world to protect it. On their trek to and from Siberia the author and his brother also encounter a stream of people who are also lonely, displaced and yearning for something beyond the limits of their own lives, but many of whom are also big-hearted and deeply connected to their own communities and the world around them. What begins as a search for restoration in nature becomes as well a discovery of the restorative power of trust, faith and human connection.
Book chapters on the topic "Mice trail following"
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Orr, David W. "A Higher Order of Heroism." In The Nature of Design. Oxford University Press, 2002. http://dx.doi.org/10.1093/oso/9780195148558.003.0025.
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In the towns and cities across America, it is common to find a town square with a large monument to one military hero or another. Seldom, however, does one find the designers of those towns or town squares similarly memorialized. A smarter and more durable society would first acknowledge those with the foresight and dedication to design our places well, not just those who defended them in times of trouble.We need to recognize a higher order of heroism—those who helped avoid conflict, harmonized human communities with their surroundings, preserved soil and biological diversity, and created the basis for a more permanent peace than that possible to forge by violence. These are quiet heroes and heroines who work mostly out of the light of publicity. The few who do receive public acclaim are mostly reticent about the attention they get. Some like Frederick Law Olmsted, Aldo Leopold, and Rachel Carson develop a wide international following. Most, however, labor in obscurity, content to do their work for the satisfaction of doing things well. John Lyle, professor of landscape architecture at California Polytechnic Institute, was such a man. I met John in the mid-1980s during a visit to Cal Poly. During the two days we spent together, we talked about his concept of regenerative design and his plans for the Center for Regenerative Studies, now named the Lyle Center, and walked over the site—located between a large landfill and the university. In subsequent years, John and I met at conferences and sometimes collaborated on design projects, including one located in a remote, hilly, southern rural community. Our first site visit coincided with an ice storm the previous day that had covered the region with an inch of ice. We got within a mile of the site in a rental car, but had to make our way down a long, steep hill with a sheer drop of several hundred feet on one side. For the final mile on what passed for a dirt road in that part of the country, the rental car was useless, so we began to slip, slide, and tumble our way down the hill. Near the bottom, the road banked steeply to the right, but we had to reach a trail on the left side.
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Morales-Villegas, Enrique C., and Kausik K. Ray. "PCSK9 Inhibition with Evolocumab Reaching Physiologic LDL-C Levels for Reducing Atherosclerotic Burden and Cardiovascular Disease-The Full Landscape." In Frontiers in Cardiovascular Drug Discovery: Volume 4, 148–85. BENTHAM SCIENCE PUBLISHERS, 2019. http://dx.doi.org/10.2174/9781681083995118040007.
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Physiologically, in the presence of an intracellular deficit of cholesterol, the LDLR synthesis, expression and function increase, thus uptaking and providing cholesterol to the cell. This process is counter-regulated by PCSK9 expression, the protease inducing LDLR proteolysis, thereby limiting its function maintaining a constant cholesterol intracellular concentration. Accordingly, the balance between PCSK9 and LDLR regulates the intracellular concentration of cholesterol and in consequence has impact on circulating LDL-cholesterol. This chapter reviews the brief and amazing recent history with PCSK9 inhibition from basic science to current clinical recommendations for MAbs-PCSK9. In 2003 and 2005, respectively, the pcsk9 gene mutations, determinants of the “gain of function” of PCSK9 and severe hypercholesterolemia, and the pcsk9 gene mutations with “loss of function” of PCSK9, determinants of hypocholesterolemia were described; subsequently, in 2006, the association between the pcsk9 gene mutations and the “loss of function” of PCSK9 with hypocholesterolemia and reduction of up to 88% for the risk of a coronary event in the “mutant” population versus the control population was published. Since evolocumab clinical research program has completed and published their phases I, II and III results including its cardiovascular outcomes trial, this chapter is focused in reviewing the results of evolocumab clinical research program. In 2009, the effect of a “full human” monoclonal antibody vs PCSK9 in mice and non-human primates was first reported; MAb-PCSK9, AMG-145 (evolocumab) produced in cynomolgus monkeys a doubling in the number of LDLR and an average 75% reduction in circulating LDL-cholesterol. In 2012, the first phase I study with evolocumab versus placebo were reported; this program informed very significant reductions in LDLcholesterol in healthy subjects and patients with familial and non-familial hyper cholesterolemia treated without/with statins; tolerability and safety of evolocumab were similar to placebo. With this evidence, the phase II and III investigations with evolocumab initiated; four years later, the OSLER trial allowed us to envisage the following scenario: MAb-PCSK9 evolocumab have a favorable effect on LDLcholesterol, other apo-B100 lipoproteins and overall mortality and myocardial infarction; all the aforementioned with a very favorable safety and tolerability profile. In the same direction, in 2016 was published the GLAGOV trial, wich demonstrates for the first time that the addition of a non-statin therapy -evolocumab- to the optimal treatment with statins is associated with atheroregression; and finally, in 2017, the FOURIER and the EBBINGHAUS trials were presented, wich confirmed that the addition of evolocumab to the optimal treatment with statins is associated with an additional and significant 20% relative risk reduction -26 months of follow-up- for cardiovascular mortality, myocardial infarction and/or ischemic stroke, all without neurocognitive risk. Beyond the currently approved indications by regulatory agencies, considering the high cost of PCSK9 inhibitors and financial restraints within healthcare budgets, for now and before definitive and necessary cost-effectiveness analysis and price optimization are in place, evolocumab is recommended in specific clinical scenarios reviewed in this chapter.
Conference papers on the topic "Mice trail following"
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Gernand, Jeremy M. "Machine Learning Classification Models for More Effective Mine Safety Inspections." In ASME 2014 International Mechanical Engineering Congress and Exposition. American Society of Mechanical Engineers, 2014. http://dx.doi.org/10.1115/imece2014-38709.
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The safety of mining in the United States has improved significantly over the past few decades, although it remains one of the more dangerous occupations. Following the Sago mine disaster in January 2006, federal legislation (The Mine Improvement and New Emergency Response {MINER} Act of 2006) tightened regulations and sought to strengthen the authority and safety inspection practices of the Mine Safety and Health Administration (MSHA). While penalties and inspection frequency have increased, understanding of what types of inspection findings are most indicative of serious future incidents is limited. The most effective safety management and oversight could be accomplished by a thorough understanding of what types of infractions or safety inspection findings are most indicative of serious future personnel injuries. However, given the large number of potentially different and unique inspection findings, varied mine characteristics, and types of specific safety incidents, this question is complex in terms of the large number of potentially relevant input parameters. New regulations rely on increasing the frequency and severity of infraction penalties to encourage mining operations to improve worker safety, but without the knowledge of which specific infractions may truly be signaling a dangerous work environment. This paper seeks to inform the question, what types of inspection findings are most indicative of serious future incidents for specific types of mining operations? This analysis utilizes publicly available MSHA databases of cited infractions and reportable incidents. These inspection results are used to train machine learning Classification and Regression Tree (CART) and Random Forest (RF) models that divide the groups of mines into peer groups based on their recent infractions and other defining characteristics with the aim of predicting whether or not a fatal or serious disabling injury is more likely to occur in the following 12-month period. With these characteristics available, additional scrutiny may be appropriately directed at those mining operations at greatest risk of experiencing a worker fatality or disabling injury in the near future. Increased oversight and attention on these mines where workers are at greatest risk may more effectively reduce the likelihood of worker deaths and injuries than increased penalties and inspection frequency alone.
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Ames, Eric C., and Raja V. Pulikollu. "Virtual Life and Performance Modeling of Aerospace Spiral Bevel Gears." In ASME 2013 International Design Engineering Technical Conferences and Computers and Information in Engineering Conference. American Society of Mechanical Engineers, 2013. http://dx.doi.org/10.1115/detc2013-12351.
Full textAbstract:
Spiral bevel gears are widely used in the tail rotor drive trains of most rotorcraft. The loads associated with the tail rotor drive train are generally much more variable than those in the main rotor drive train primarily resulting from maneuvers. Over the life of any particular military rotorcraft it is not uncommon for the aircraft’s operating gross weight to steadily increase, causing the aircraft to fly at higher mean power levels and thus increasing the operating load spectrum associated with the tail rotor drive train. Special missions and equipment such as pulling a mine sweeping sled or very high altitude high gross weight assaults can put severe load demands on the tail drive train. This paper details an effort conducted to evaluate the effects of short to moderate duration overloads on the spiral bevel gears of the UH-60 helicopter tail rotor drive train. The focus of the effort was on the Tail Take-off gear mesh (TTO). An initial analytical assessment of the effect of loads above the endurance limit was conducted using an American Gear Manufacturers Association (AGMA) based approach. To confirm the validity of this approach, overload testing of the TTO gear mesh was conducted by the U.S. Army’s Aviation Applied Technology Directorate at the Navy’s test facility in Paxtuent River MD. Following the testing, the gear tooth bending and surface fatigue lives were analyzed using a microstructure based probabilistic tool developed by Sentient Corporation. The tool, known as Digital Clone was able to run hundreds of virtual tests that closely simulated the actual testing thus providing a low cost method for increasing the confidence associated with the effects of short to moderate high transient loads.
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Cummings, Scott M. "Prediction of Rolling Contact Fatigue Using Instrumented Wheelsets." In ASME 2008 Rail Transportation Division Fall Technical Conference. ASMEDC, 2008. http://dx.doi.org/10.1115/rtdf2008-74013.
Full textAbstract:
The measured wheel/rail forces from four wheels in the leading truck of a coal hopper car during one revenue service roundtrip were used to by the Wheel Defect Prevention Research Consortium (WDPRC) to predict rolling contact fatigue (RCF) damage. The data was recorded in March 2005 by TTCI for an unrelated Strategic Research Initiatives project funded by the Association of American Railroads (AAR). RCF damage was predicted in only a small portion of the approximately 4,000 km (2,500 miles) for which data was analyzed. The locations where RCF damage was predicted to occur were examined carefully by matching recorded GPS and train speed/distance data with track charts. RCF is one way in which wheels can develop tread defects. Thermal mechanical shelling (TMS) is a subset of wheel shelling in which the heat from tread braking reduces a wheel’s fatigue resistance. RCF and TMS together are estimated to account for approximately half of the total wheel tread damage problem [1]. Other types of tread damage can result from wheel slides. The work described in this paper is concerning pure RCF, without regard to temperature effects or wheel slide events. It is important that the limitations of the analysis in this paper are recognized. The use of pre-existing data that was recorded two years prior to the analysis ruled out the possibility of determining the conditions of the track when the data was recorded (rail profile, friction, precise track geometry). Accordingly, the wheel/rail contact stress was calculated with an assumed rail crown profile radius of 356-mm (14 inches). RCF was predicted using shakedown theory, which does not account for wear and is the subject of some continuing debate regarding the exact conditions required for fatigue damage. The data set analyzed represents the wheel/rail forces from two wheelsets in a single, reasonably well maintained car. Wheelsets in other cars may produce different results. With this understanding, the following conclusions are made. - RCF damage is predicted to accumulate only at a small percentage of the total distance traveled. - RCF damage is predicted to accumulate on almost every curve 4 degrees or greater. - RCF damage is primarily predicted to accumulate while the car is loaded. - RCF damage is predicted to accumulate more heavily on the wheelset in the leading position of the truck than the trailing wheelset. - No RCF damage was predicted while the test car was on mine property. - Four unique curves (8 degrees, 7 degrees, 6 degrees, and 4 degrees) accounted for nearly half of the predicted RCF damage of the loaded trip. In each case, the RCF damage was predicted to accumulate on the low-rail wheel of the leading wheelset. - Wayside flange lubricators are located near many of the locations where RCF damage was predicted to accumulate, indicating that simply adding wayside lubricators will not solve the RCF problem. - The train was typically being operated below the balance speed of the curve when RCF damage was predicted to occur. - The worst track locations for wheel RCF tend to be on curves of 4 degrees or higher. For the route analyzed in this work, the worst locations for wheel RCF tended to be bunched in urban areas, where tight curvature generally prevails.
Reports on the topic "Mice trail following"
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Raymond, Kara, Laura Palacios, Cheryl McIntyre, and Evan Gwilliam. Status of climate and water resources at Saguaro National Park: Water year 2019. Edited by Alice Wondrak Biel. National Park Service, December 2021. http://dx.doi.org/10.36967/nrr-2288717.
Full textAbstract:
Climate and hydrology are major drivers of ecosystems. They dramatically shape ecosystem structure and function, particularly in arid and semi-arid ecosystems. Understanding changes in climate, groundwater, and water quality and quantity is central to assessing the condition of park biota and key cultural resources. The Sonoran Desert Network collects data on climate, groundwater, and surface water at 11 National Park Service units in south-ern Arizona and New Mexico. This report provides an integrated look at climate, groundwater, and springs conditions at Saguaro National Park (NP) during water year 2019 (October 2018–September 2019). Annual rainfall in the Rincon Mountain District was 27.36" (69.49 cm) at the Mica Mountain RAWS station and 12.89" (32.74 cm) at the Desert Research Learning Center Davis station. February was the wettest month, accounting for nearly one-quarter of the annual rainfall at both stations. Each station recorded extreme precipitation events (>1") on three days. Mean monthly maximum and minimum air temperatures were 25.6°F (-3.6°C) and 78.1°F (25.6°C), respectively, at the Mica Mountain station, and 37.7°F (3.2°C) and 102.3°F (39.1°C), respectively, at the Desert Research Learning Center station. Overall temperatures in WY2019 were cooler than the mean for the entire record. The reconnaissance drought index for the Mica Mountain station indicated wetter conditions than average in WY2019. Both of the park’s NOAA COOP stations (one in each district) had large data gaps, partially due to the 35-day federal government shutdown in December and January. For this reason, climate conditions for the Tucson Mountain District are not reported. The mean groundwater level at well WSW-1 in WY2019 was higher than the mean for WY2018. The water level has generally been increasing since 2005, reflecting the continued aquifer recovery since the Central Avra Valley Storage and Recovery Project came online, recharging Central Arizona Project water. Water levels at the Red Hills well generally de-clined starting in fall WY2019, continuing through spring. Monsoon storms led to rapid water level increases. Peak water level occurred on September 18. The Madrona Pack Base well water level in WY2019 remained above 10 feet (3.05 m) below measuring point (bmp) in the fall and winter, followed by a steep decline starting in May and continuing until the end of September, when the water level rebounded following a three-day rain event. The high-est water level was recorded on February 15. Median water levels in the wells in the middle reach of Rincon Creek in WY2019 were higher than the medians for WY2018 (+0.18–0.68 ft/0.05–0.21 m), but still generally lower than 6.6 feet (2 m) bgs, the mean depth-to-water required to sustain juvenile cottonwood and willow trees. RC-7 was dry in June–September, and RC-4 was dry in only September. RC-5, RC-6 and Well 633106 did not go dry, and varied approximately 3–4 feet (1 m). Eleven springs were monitored in the Rincon Mountain District in WY2019. Most springs had relatively few indications of anthropogenic or natural disturbance. Anthropogenic disturbance included spring boxes or other modifications to flow. Examples of natural disturbance included game trails and scat. In addition, several sites exhibited slight disturbance from fires (e.g., burned woody debris and adjacent fire-scarred trees) and evidence of high-flow events. Crews observed 1–7 taxa of facultative/obligate wetland plants and 0–3 invasive non-native species at each spring. Across the springs, crews observed four non-native plant species: rose natal grass (Melinis repens), Kentucky bluegrass (Poa pratensis), crimson fountaingrass (Cenchrus setaceus), and red brome (Bromus rubens). Baseline data on water quality and chemistry were collected at all springs. It is likely that that all springs had surface water for at least some part of WY2019. However, temperature sensors to estimate surface water persistence failed...