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Sample records for augments tumor killing

  1. IL-2 augments the therapeutic efficacy of adoptively transferred B cells which directly kill tumor cells via the CXCR4/CXCL12 and perforin pathways

    PubMed Central

    Chen, Xin; Xia, Leiming; Zhou, Li; Wang, Yi; Bao, Yangyi; Huang, Shiang; Ren, Xiubao; Lundy, Steven K.; Dai, Fu; Li, Qiao; Chang, Alfred E.

    2016-01-01

    We previously reported that antitumor B cells directly kill tumor cells via the Fas/FasL pathway and are regulated by IL-10. In this study, we defined additional mechanisms involved in B cell antitumor immunity. Administration of IL-2 significantly augmented the therapeutic efficacy of adoptively transferred tumor-draining lymph node (TDLN) B cells which express IL- 2R. Culture supernatant of purified B splenocytes harvested from the mice that received adoptive transfer of 4T1 TDLN B cells plus IL-2 administration produced larger amounts of IgG which bound to 4T1, resulting in 4T1 lysis. Furthermore, we detected CXCR4 expression on 4T1 TDLN B cells, and 4T1 tumor cells produced its ligand CXCL12. Transwell experiments demonstrated the chemoattraction of CXCR4-expressing 4T1 TDLN B cells towards CXCL12- producing 4T1 cells. Blockade of CXCR4 using a CXCR4-specific inhibitor, AMD3100, significantly reduced the killing of 4T1 tumor cells by 4T1 TDLN B cells. Blockade of FasL and CXCR4 concurrently inhibited B cell-mediated direct killing of tumor cells in an additive manner, indicating that both Fas/FasL and CXCL12/CXCR4 pathways are involved in the direct killing of 4T1 cells by 4T1 TDLN B cells. TDLN B cells produced perforin. Additional transwell experiments showed that effector B cells could directly kill tumor cells in cell-cell contact via the Fas/FasL and CXCR4/CXCL12 pathways as well as perforin, while without cell contact, perforin secreted by B cells led to tumor cell cytotoxicity. These findings underscore the diversity of function by which B cells can play an important role in the host immune response to tumor. PMID:27528023

  2. Glucose Augments Killing Efficiency of Daptomycin Challenged Staphylococcus aureus Persisters.

    PubMed

    Prax, Marcel; Mechler, Lukas; Weidenmaier, Christopher; Bertram, Ralph

    2016-01-01

    Treatment of Staphylococcus aureus in stationary growth phase with high doses of the antibiotic daptomycin (DAP) eradicates the vast majority of the culture and leaves persister cells behind. Despite resting in a drug-tolerant and dormant state, persister cells exhibit metabolic activity which might be exploited for their elimination. We here report that the addition of glucose to S. aureus persisters treated with DAP increased killing by up to five-fold within one hour. This glucose-DAP effect also occurred with strains less sensitive to the drug. The underlying mechanism is independent of the proton motive force and was not observed with non-metabolizable 2-deoxy-glucose. Our results are consistent with two hypotheses on the glucose-DAP interplay. The first is based upon glucose-induced carbohydrate transport proteins that may influence DAP and the second suggests that glucose may trigger the release or activity of cell-lytic proteins to augment DAP's mode of action.

  3. Glucose Augments Killing Efficiency of Daptomycin Challenged Staphylococcus aureus Persisters

    PubMed Central

    Prax, Marcel; Mechler, Lukas; Weidenmaier, Christopher; Bertram, Ralph

    2016-01-01

    Treatment of Staphylococcus aureus in stationary growth phase with high doses of the antibiotic daptomycin (DAP) eradicates the vast majority of the culture and leaves persister cells behind. Despite resting in a drug-tolerant and dormant state, persister cells exhibit metabolic activity which might be exploited for their elimination. We here report that the addition of glucose to S. aureus persisters treated with DAP increased killing by up to five-fold within one hour. This glucose-DAP effect also occurred with strains less sensitive to the drug. The underlying mechanism is independent of the proton motive force and was not observed with non-metabolizable 2-deoxy-glucose. Our results are consistent with two hypotheses on the glucose-DAP interplay. The first is based upon glucose-induced carbohydrate transport proteins that may influence DAP and the second suggests that glucose may trigger the release or activity of cell-lytic proteins to augment DAP’s mode of action. PMID:26960193

  4. Augmented reality for breast tumors visualization.

    PubMed

    Ghaderi, Mohammad Ali; Heydarzadeh, Mehrdad; Nourani, Mehrdad; Gupta, Gopal; Tamil, Lakshman

    2016-08-01

    3D visualization of breast tumors are shown to be effective by previous studies. In this paper, we introduce a new augmented reality application that can help doctors and surgeons to have a more accurate visualization of breast tumors; this system uses a marker-based image-processing technique to render a 3D model of the tumors on the body. The model can be created using a combination of breast 3D mammography by experts. We have tested the system using an Android smartphone and a head-mounted device. This proof of concept can be useful for oncologists to have a more effective screening, and surgeons to plan the surgery.

  5. Newcastle disease virus selectively kills human tumor cells.

    PubMed

    Reichard, K W; Lorence, R M; Cascino, C J; Peeples, M E; Walter, R J; Fernando, M B; Reyes, H M; Greager, J A

    1992-05-01

    Newcastle disease virus (NDV), strain 73-T, has previously been shown to be cytolytic to mouse tumor cells. In this study, we have evaluated the ability of NDV to replicate in and kill human tumor cells in culture and in athymic mice. Plaque assays were used to determine the cytolytic activity of NDV on six human tumor cell lines, fibrosarcoma (HT1080), osteosarcoma (KHOS), cervical carcinoma (KB8-5-11), bladder carcinoma (HCV29T), neuroblastoma (IMR32), and Wilm's tumor (G104), and on nine different normal human fibroblast lines. NDV formed plaques on all tumor cells tested as well as on chick embryo cells (CEC), the native host for NDV. Plaques did not form on any of the normal fibroblast lines. To detect NDV replication, virus yield assays were performed which measured virus particles in infected cell culture supernatants. Virus yield increased 10,000-fold within 24 hr in tumor and CEC supernatants. Titers remained near zero in normal fibroblast supernatants. In vivo tumoricidal activity was evaluated in athymic nude Balb-c mice by subcutaneous injection of 9 x 10(6) tumor cells followed by intralesional injection of either live or heat-killed NDV (1.0 x 10(6) plaque forming units [PFU]), or medium. After live NDV treatment, tumor regression occurred in 10 out of 11 mice bearing KB8-5-11 tumors, 8 out of 8 with HT-1080 tumors, and 6 out of 7 with IMR-32 tumors. After treatment with heat-killed NDV no regression occurred (P less than 0.01, Fisher's exact test). Nontumor-bearing mice injected with 1.0 x 10(8) PFU of NDV remained healthy. These results indicate that NDV efficiently and selectively replicates in and kills tumor cells, but not normal cells, and that intralesional NDV causes complete tumor regression in athymic mice with a high therapeutic index.

  6. From growing plants to killing tumors.

    PubMed

    Flinn, E D

    2000-04-01

    A technique called photodynamic therapy, originally developed for commercial plant growth research on the Space Shuttle, has been used by surgeons in two successful operations for brain tumors. The device uses pin-head-size light emitting diodes (LEDs) that release long, cool, wavelengths of light which activate photosensitive antineoplastic drugs. The device is being adapted to non-space uses through a Small Business Innovation Research grant. The LEDs also are used to treat skin cancer, psoriasis, and rheumatoid arthritis. Research is being conducted regarding LED use in wound healing, tissue growth, and prevention of muscle and bone atrophy in astronauts.

  7. Biosystems Engineering of Prokaryotes with Tumor-Killing Capacities.

    PubMed

    Kalyoncu, Ebuzer; Olmez, Tolga T; Ozkan, Alper D; Sarioglu, Omer F

    2016-01-01

    Certain bacteria selectively attack tumor tissues and trigger tumor shrinkage by producing toxins and modulating the local immune system, but their clinical utility is limited because of the dangers posed by systemic infection. Genetic engineering can be used to minimize the risks associated with tumor-targeting pathogens, as well as to increase their efficiency in killing tumor cells. Advances in genetic circuit design have led to the development of bacterial strains with enhanced tumor-targeting capacities and the ability to secrete therapeutics, cytotoxic proteins and prodrug-cleaving enzymes, which allows their safe and effective use for cancer treatment. The present review details the recent advances in the design and application of these modified bacterial strains.

  8. Nexavar/Stivarga and Viagra Interact to Kill Tumor Cells

    PubMed Central

    Tavallai, Mehrad; Hamed, Hossein A.; Roberts, Jane L.; Cruickshanks, Nichola; Chuckalovcak, John; Poklepovic, Andrew; Booth, Laurence

    2015-01-01

    We determined whether the multi‐kinase inhibitor sorafenib or its derivative regorafenib interacted with phosphodiesterase 5 (PDE5) inhibitors such as Viagra (sildenafil) to kill tumor cells. PDE5 and PDGFRα/β were over‐expressed in liver tumors compared to normal liver tissue. In multiple cell types in vitro sorafenib/regorafenib and PDE5 inhibitors interacted in a greater than additive fashion to cause tumor cell death, regardless of whether cells were grown in 10 or 100% human serum. Knock down of PDE5 or of PDGFRα/β recapitulated the effects of the individual drugs. The drug combination increased ROS/RNS levels that were causal in cell killing. Inhibition of CD95/FADD/caspase 8 signaling suppressed drug combination toxicity. Knock down of ULK‐1, Beclin1, or ATG5 suppressed drug combination lethality. The drug combination inactivated ERK, AKT, p70 S6K, and mTOR and activated JNK. The drug combination also reduced mTOR protein expression. Activation of ERK or AKT was modestly protective whereas re‐expression of an activated mTOR protein or inhibition of JNK signaling almost abolished drug combination toxicity. Sildenafil and sorafenib/regorafenib interacted in vivo to suppress xenograft tumor growth using liver and colon cancer cells. From multiplex assays on tumor tissue and plasma, we discovered that increased FGF levels and ERBB1 and AKT phosphorylation were biomarkers that were directly associated with lower levels of cell killing by ‘rafenib + sildenafil. Our data are now being translated into the clinic for further determination as to whether this drug combination is a useful anti‐tumor therapy for solid tumor patients. J. Cell. Physiol. 230: 2281–2298, 2015. © 2015 The Authors. Journal of Cellular Physiology Published by Wiley Periodicals, Inc. PMID:25704960

  9. Biodegradable polymeric micelle-encapsulated doxorubicin suppresses tumor metastasis by killing circulating tumor cells

    NASA Astrophysics Data System (ADS)

    Deng, Senyi; Wu, Qinjie; Zhao, Yuwei; Zheng, Xin; Wu, Ni; Pang, Jing; Li, Xuejing; Bi, Cheng; Liu, Xinyu; Yang, Li; Liu, Lei; Su, Weijun; Wei, Yuquan; Gong, Changyang

    2015-03-01

    Circulating tumor cells (CTCs) play a crucial role in tumor metastasis, but it is rare for any chemotherapy regimen to focus on killing CTCs. Herein, we describe doxorubicin (Dox) micelles that showed anti-metastatic activity by killing CTCs. Dox micelles with a small particle size and high encapsulation efficiency were obtained using a pH-induced self-assembly method. Compared with free Dox, Dox micelles exhibited improved cytotoxicity, apoptosis induction, and cellular uptake. In addition, Dox micelles showed a sustained release behavior in vitro, and in a transgenic zebrafish model, Dox micelles exhibited a longer circulation time and lower extravasation from blood vessels into surrounding tissues. Anti-tumor and anti-metastatic activities of Dox micelles were investigated in transgenic zebrafish and mouse models. In transgenic zebrafish, Dox micelles inhibited tumor growth and prolonged the survival of tumor-bearing zebrafish. Furthermore, Dox micelles suppressed tumor metastasis by killing CTCs. In addition, improved anti-tumor and anti-metastatic activities were also confirmed in mouse tumor models, where immunofluorescent staining of tumors indicated that Dox micelles induced more apoptosis and showed fewer proliferation-positive cells. There were decreased side effects in transgenic zebrafish and mice after administration of Dox micelles. In conclusion, Dox micelles showed stronger anti-tumor and anti-metastatic activities and decreased side effects both in vitro and in vivo, which may have potential applications in cancer therapy.

  10. Morphological effect of oscillating magnetic nanoparticles in killing tumor cells

    NASA Astrophysics Data System (ADS)

    Cheng, Dengfeng; Li, Xiao; Zhang, Guoxin; Shi, Hongcheng

    2014-04-01

    Forced oscillation of spherical and rod-shaped iron oxide magnetic nanoparticles (MNPs) via low-power and low-frequency alternating magnetic field (AMF) was firstly used to kill cancer cells in vitro. After being loaded by human cervical cancer cells line (HeLa) and then exposed to a 35-kHz AMF, MNPs mechanically damaged cell membranes and cytoplasm, decreasing the cell viability. It was found that the concentration and morphology of the MNPs significantly influenced the cell-killing efficiency of oscillating MNPs. In this preliminary study, when HeLa cells were pre-incubated with 100 μg/mL rod-shaped MNPs (rMNP, length of 200 ± 50 nm and diameter of 50 to 120 nm) for 20 h, MTT assay proved that the cell viability decreased by 30.9% after being exposed to AMF for 2 h, while the cell viability decreased by 11.7% if spherical MNPs (sMNP, diameter of 200 ± 50 nm) were used for investigation. Furthermore, the morphological effect of MNPs on cell viability was confirmed by trypan blue assay: 39.5% rMNP-loaded cells and 15.1% sMNP-loaded cells were stained after being exposed to AMF for 2 h. It was also interesting to find that killing tumor cells at either higher (500 μg/mL) or lower (20 μg/mL) concentration of MNPs was less efficient than that achieved at 100 μg/mL concentration. In conclusion, the relatively asymmetric morphological rod-shaped MNPs can kill cancer cells more effectively than spherical MNPs when being exposed to AMF by virtue of their mechanical oscillations.

  11. Tumor necrosis factor: a potent effector molecule for tumor cell killing by activated macrophages.

    PubMed Central

    Urban, J L; Shepard, H M; Rothstein, J L; Sugarman, B J; Schreiber, H

    1986-01-01

    Activated macrophages (aM phi) destroy more effectively cancer cells than normal cells. The mechanism by which macrophages destroy cancer cells is not known. We report here that tumor cells susceptible to aM phi were killed by recombinant (r) tumor necrosis factor type alpha (TNF-alpha), whereas variant tumor cells resistant to aM phi after selection in vitro or in vivo were resistant to killing by rTNF-alpha. The converse selection for rTNF-alpha-resistant variants resulted in cells that were also resistant to killing by aM phi. The sensitivity of macrophage-resistant variants was not changed to other tumoricidal cells or soluble mediators, except that the macrophage-resistant variants were also resistant to the effects of another cytotoxic protein, B-cell lymphotoxin, which is structurally related to rTNF-alpha. Similar results were obtained regardless of whether short-term or long-term cytotoxic effects of aM phi were measured. Finally, it was shown that killing of tumor cells by murine aM phi was completely inhibited with a polyclonal antibody that neutralizes the effects of murine TNF-alpha. These results suggest a major role for TNF-alpha in tumor cell destruction by aM phi in vitro and in vivo. PMID:3487788

  12. Nanotechnology for the detection and kill of circulating tumor cells

    NASA Astrophysics Data System (ADS)

    Gao, Yang; Yuan, Zhou

    2014-09-01

    Circulating tumor cells (CTCs) represent a surrogate biomarker of hematogenous metastases and thus could be considered as a `liquid biopsy' which reveals metastasis in action. But it is absolutely a challenge to detect CTCs due to their extreme rarity. At present, the most common principle is to take advantage of the epithelial surface markers of CTCs which attach to a specific antibody. Antibody-magnetic nanobeads combine with the epithelial surface markers, and then the compound is processed by washing, separation, and detection. However, a proportion of CTC antigen expressions are down-regulated or lost in the process of epithelial-mesenchymal transition (EMT), and thus, this part of CTCs cannot be detected by classical detection methods such as CellSearch. To resolve this problem, some multiple-marker CTC detections have been developed rapidly. Additionally, nanotechnology is a promising approach to kill CTCs with high efficiency. Implantable nanotubes coated with apoptosis-promoting molecules improve the disease-free survival and overall survival. The review introduces some novel CTC detection techniques and therapeutic methods by virtue of nanotechnology to provide a better knowledge of the progress about CTC study.

  13. Nanotechnology for the detection and kill of circulating tumor cells

    PubMed Central

    2014-01-01

    Circulating tumor cells (CTCs) represent a surrogate biomarker of hematogenous metastases and thus could be considered as a ‘liquid biopsy’ which reveals metastasis in action. But it is absolutely a challenge to detect CTCs due to their extreme rarity. At present, the most common principle is to take advantage of the epithelial surface markers of CTCs which attach to a specific antibody. Antibody-magnetic nanobeads combine with the epithelial surface markers, and then the compound is processed by washing, separation, and detection. However, a proportion of CTC antigen expressions are down-regulated or lost in the process of epithelial-mesenchymal transition (EMT), and thus, this part of CTCs cannot be detected by classical detection methods such as CellSearch. To resolve this problem, some multiple-marker CTC detections have been developed rapidly. Additionally, nanotechnology is a promising approach to kill CTCs with high efficiency. Implantable nanotubes coated with apoptosis-promoting molecules improve the disease-free survival and overall survival. The review introduces some novel CTC detection techniques and therapeutic methods by virtue of nanotechnology to provide a better knowledge of the progress about CTC study. PMID:25258614

  14. Enhanced Performance of Brain Tumor Classification via Tumor Region Augmentation and Partition.

    PubMed

    Cheng, Jun; Huang, Wei; Cao, Shuangliang; Yang, Ru; Yang, Wei; Yun, Zhaoqiang; Wang, Zhijian; Feng, Qianjin

    2015-01-01

    Automatic classification of tissue types of region of interest (ROI) plays an important role in computer-aided diagnosis. In the current study, we focus on the classification of three types of brain tumors (i.e., meningioma, glioma, and pituitary tumor) in T1-weighted contrast-enhanced MRI (CE-MRI) images. Spatial pyramid matching (SPM), which splits the image into increasingly fine rectangular subregions and computes histograms of local features from each subregion, exhibits excellent results for natural scene classification. However, this approach is not applicable for brain tumors, because of the great variations in tumor shape and size. In this paper, we propose a method to enhance the classification performance. First, the augmented tumor region via image dilation is used as the ROI instead of the original tumor region because tumor surrounding tissues can also offer important clues for tumor types. Second, the augmented tumor region is split into increasingly fine ring-form subregions. We evaluate the efficacy of the proposed method on a large dataset with three feature extraction methods, namely, intensity histogram, gray level co-occurrence matrix (GLCM), and bag-of-words (BoW) model. Compared with using tumor region as ROI, using augmented tumor region as ROI improves the accuracies to 82.31% from 71.39%, 84.75% from 78.18%, and 88.19% from 83.54% for intensity histogram, GLCM, and BoW model, respectively. In addition to region augmentation, ring-form partition can further improve the accuracies up to 87.54%, 89.72%, and 91.28%. These experimental results demonstrate that the proposed method is feasible and effective for the classification of brain tumors in T1-weighted CE-MRI.

  15. Enhanced Performance of Brain Tumor Classification via Tumor Region Augmentation and Partition

    PubMed Central

    Cheng, Jun; Huang, Wei; Cao, Shuangliang; Yang, Ru; Yang, Wei; Yun, Zhaoqiang; Wang, Zhijian; Feng, Qianjin

    2015-01-01

    Automatic classification of tissue types of region of interest (ROI) plays an important role in computer-aided diagnosis. In the current study, we focus on the classification of three types of brain tumors (i.e., meningioma, glioma, and pituitary tumor) in T1-weighted contrast-enhanced MRI (CE-MRI) images. Spatial pyramid matching (SPM), which splits the image into increasingly fine rectangular subregions and computes histograms of local features from each subregion, exhibits excellent results for natural scene classification. However, this approach is not applicable for brain tumors, because of the great variations in tumor shape and size. In this paper, we propose a method to enhance the classification performance. First, the augmented tumor region via image dilation is used as the ROI instead of the original tumor region because tumor surrounding tissues can also offer important clues for tumor types. Second, the augmented tumor region is split into increasingly fine ring-form subregions. We evaluate the efficacy of the proposed method on a large dataset with three feature extraction methods, namely, intensity histogram, gray level co-occurrence matrix (GLCM), and bag-of-words (BoW) model. Compared with using tumor region as ROI, using augmented tumor region as ROI improves the accuracies to 82.31% from 71.39%, 84.75% from 78.18%, and 88.19% from 83.54% for intensity histogram, GLCM, and BoW model, respectively. In addition to region augmentation, ring-form partition can further improve the accuracies up to 87.54%, 89.72%, and 91.28%. These experimental results demonstrate that the proposed method is feasible and effective for the classification of brain tumors in T1-weighted CE-MRI. PMID:26447861

  16. HAMLET kills tumor cells by apoptosis: structure, cellular mechanisms, and therapy.

    PubMed

    Gustafsson, Lotta; Hallgren, Oskar; Mossberg, Ann-Kristin; Pettersson, Jenny; Fischer, Walter; Aronsson, Annika; Svanborg, Catharina

    2005-05-01

    New cancer treatments should aim to destroy tumor cells without disturbing normal tissue. HAMLET (human alpha-lactalbumin made lethal to tumor cells) offers a new molecular approach to solving this problem, because it induces apoptosis in tumor cells but leaves normal differentiated cells unaffected. After partial unfolding and binding to oleic acid, alpha-lactalbumin forms the HAMLET complex, which enters tumor cells and freezes their metabolic machinery. The cells proceed to fragment their DNA, and they disintegrate with apoptosis-like characteristics. HAMLET kills a wide range of malignant cells in vitro and maintains this activity in vivo in patients with skin papillomas. In addition, HAMLET has striking effects on human glioblastomas in a rat xenograft model. After convection-enhanced delivery, HAMLET diffuses throughout the brain, selectively killing tumor cells and controlling tumor progression without apparent tissue toxicity. HAMLET thus shows great promise as a new therapeutic with the advantage of selectivity for tumor cells and lack of toxicity.

  17. Hypofractionation Results in Reduced Tumor Cell Kill Compared to Conventional Fractionation for Tumors With Regions of Hypoxia

    SciTech Connect

    Carlson, David J.; Keall, Paul J.; Loo, Billy W.; Chen, Zhe J.; Brown, J. Martin

    2011-03-15

    Purpose: Tumor hypoxia has been observed in many human cancers and is associated with treatment failure in radiation therapy. The purpose of this study is to quantify the effect of different radiation fractionation schemes on tumor cell killing, assuming a realistic distribution of tumor oxygenation. Methods and Materials: A probability density function for the partial pressure of oxygen in a tumor cell population is quantified as a function of radial distance from the capillary wall. Corresponding hypoxia reduction factors for cell killing are determined. The surviving fraction of a tumor consisting of maximally resistant cells, cells at intermediate levels of hypoxia, and normoxic cells is calculated as a function of dose per fraction for an equivalent tumor biological effective dose under normoxic conditions. Results: Increasing hypoxia as a function of distance from blood vessels results in a decrease in tumor cell killing for a typical radiotherapy fractionation scheme by a factor of 10{sup 5} over a distance of 130 {mu}m. For head-and-neck cancer and prostate cancer, the fraction of tumor clonogens killed over a full treatment course decreases by up to a factor of {approx}10{sup 3} as the dose per fraction is increased from 2 to 24 Gy and from 2 to 18 Gy, respectively. Conclusions: Hypofractionation of a radiotherapy regimen can result in a significant decrease in tumor cell killing compared to standard fractionation as a result of tumor hypoxia. There is a potential for large errors when calculating alternate fractionations using formalisms that do not account for tumor hypoxia.

  18. Hyperoxygenation enhances the direct tumor cell killing of photofrin-mediated photodynamic therapy

    NASA Astrophysics Data System (ADS)

    Huang, Zheng; Chen, Qun; Shakil, Abdus; Chen, Hua; Beckers, Jill; Shapiro, Howard; Hetzel, Fred W.

    2003-06-01

    Tumor hypoxia, either pre-existing or as a result of oxygen bleaching during Photodynamic Therapy (PDT) light irradiation, can significantly reduce the effectiveness of PDT induced cell killing. To overcome the effect of tumor hypoxia and improve tumor cell killing, we propose using supplemental hyperoxygenation during Photofrin PDT. Our previous study has demonstrated that, in an in vivo model, tumor control can be improved by normobaric or hyperbaric 100% oxygen supply. The mechanism for the tumor cure enhancement of the hyperoxygenation-PDT combined therapy is investigated in this study by using an in vivo/in vitro technique. A hypoxic tumor model was established by implanting mammary adenocarcinoma (MCA) in hind legs of C3H mice. Light irradiation (200 J/cm2 at either 75 or 150 mW/cm2), under various oxygen supplemental conditions (room air or carbogen or 100% normobaric or hyperbaric 100% oxygen), was delivered through an optical fiber with a microlens to animals who received 12.5 mg/kg Photofrin 24 hours prior to light irradiation. Tumors treated with PDT were harvested and grown in vitro for colony formation analysis. Treated tumors were also analyzed histologically. The results show that, when combined with hyperoxygenation, the cell killing rate immediately after a PDT treatment is significantly improved over that treated without hyperoxygenation, suggesting an enhanced direct cell killing. This study further confirms our earlier observation that when a PDT treatment is combined with hyperoxygenation, it can be more effective in controlling hypoxic tumors. H&E stain revealed that PDT induced tumor necrosis and hemorrhage. In conclusion, by using an in vivo/in vitro assay, we have shown that PDT combined with hyper-oxygenation can enhance direct cell killing and improve tumor cure.

  19. Capacity of tumor necrosis factor to augment lymphocyte-mediated tumor cell lysis of malignant mesothelioma

    SciTech Connect

    Bowman, R.V.; Manning, L.S.; Davis, M.R.; Robinson, B.W. )

    1991-01-01

    Recombinant human tumor necrosis factor (rHuTNF) was evaluated both for direct anti-tumor action against human malignant mesothelioma and for its capacity to augment the generation and lytic phases of lymphocyte-mediated cytotoxicity against this tumor. rHuTNF was directly toxic by MTT assay to one of two mesothelioma cell lines evaluated, but had no effect on susceptibility to subsequent lymphocyte-mediated lysis of either line. TNF alone was incapable of generating anti-mesothelioma lymphokine-activated killer cell (LAK) activity. Furthermore, it did not augment the degree or LAK activity produced by submaximal interleukin-2 (IL-2) concentrations nor did it augment lysis of mesothelioma cells by natural killer (NK) or LAK effector cells during the 4-hr 51chromium release cytolytic reaction. The studies also suggest that mesothelioma targets are less responsive to TNF plus submaximal IL-2 concentrations than the standard LAK sensitive target Daudi, raising the possibility that intermediate LAK sensitive tumors such as mesothelioma may require separate and specific evaluation in immunomodulation studies. This in vitro study indicates that use of low-dose rHuTNF and IL-2 is unlikely to be an effective substitute for high-dose IL-2 in generation and maintenance of LAK activity in adoptive immunotherapy for mesothelioma.

  20. CAR-T Cells Inflict Sequential Killing of Multiple Tumor Target Cells.

    PubMed

    Davenport, Alexander J; Jenkins, Misty R; Cross, Ryan S; Yong, Carmen S; Prince, H Miles; Ritchie, David S; Trapani, Joseph A; Kershaw, Michael H; Darcy, Phillip K; Neeson, Paul J

    2015-05-01

    Adoptive therapy with chimeric antigen receptor (CAR) T cells shows great promise clinically. However, there are important aspects of CAR-T-cell biology that have not been explored, particularly with respect to the kinetics of activation, immune synapse formation, and tumor cell killing. Moreover, the effects of signaling via the endogenous T-cell receptor (TCR) or CAR on killing kinetics are unclear. To address these issues, we developed a novel transgenic mouse (designated CAR.OT-I), in which CD8(+) T cells coexpressed the clonogenic OT-I TCR, recognizing the H-2K(b)-presented ovalbumin peptide SIINFEKL, and an scFv specific for human HER2. Primed CAR.OT-I T cells were mixed with SIINFEKL-pulsed or HER2-expressing tumor cells and visualized in real-time using time-lapse microscopy. We found that engagement via CAR or TCR did not affect cell death kinetics, except that the time from degranulation to CAR-T-cell detachment was faster when CAR was engaged. We showed, for the first time, that individual CAR.OT-I cells can kill multiple tumor cells ("serial killing"), irrespective of the mode of recognition. At low effector:target ratios, the tumor cell killing rate was similar via TCR or CAR ligation over the first 20 hours of coincubation. However, from 20 to 50 hours, tumor cell death mediated through CAR became attenuated due to CAR downregulation throughout the time course. Our study provides important insights into CAR-T-tumor cell interactions, with implications for single- or dual receptor-focused T-cell therapy.

  1. Dynamic visualization the whole process of cytotoxic T lymphocytes killing the B16 tumor cells in vitro

    NASA Astrophysics Data System (ADS)

    Qi, Shuhong; Zhang, Zhihong

    2016-03-01

    Cytotoxic T lymphocytes (CTLs) played a key role in the immune system to destroy the tumor cells. Although some mechanisms of CTLs killing the tumor cells are revealed already, the dynamic information of CTLs interaction with tumor cells are still not known very clearly. Here we used confocal microscopy to visualize the whole process of CTLs killing the tumor cells in vitro. The imaging data showed that CTLs destroyed the target tumor cells rapidly and efficiently. Several CTLs surrounded one or some tumor cells and the average time for CTLs destroying one tumor cell is just a few minutes in vitro. The study displayed the temporal events of CTLs interacting with tumor cells at the beginning and finally killing them and directly presented the efficient tumor cell cytotoxicity of the CTLs. The results helped us to deeply understand the mechanism of the CTLs destroying the tumor cells and to develop the cancer immunotherapy.

  2. Depolarization Controls TRAIL-Sensitization and Tumor-Selective Killing of Cancer Cells: Crosstalk with ROS

    PubMed Central

    Suzuki-Karasaki, Yoshihiro; Suzuki-Karasaki, Miki; Uchida, Mayumi; Ochiai, Toyoko

    2014-01-01

    Conventional genotoxic anti-cancer drugs target the proliferative advantage of tumor cells over normal cells. This kind of approach lacks the selectivity of treatment to cancer cells, because most of the targeted pathways are essential for the survival of normal cells. As a result, traditional cancer treatments are often limited by undesirable damage to normal cells (side-effects). Ideal anti-cancer drugs are expected to be highly effective against malignant tumor cells with minimal cytotoxicity toward normal cells. Such selective killing can be achieved by targeting pathways essential for the survival of cancer cells, but not normal cells. As cancer cells are characterized by their resistance to apoptosis, selective apoptosis induction is a promising approach for selective killing of cancer cells. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a promising tumor-selective anti-cancer drug. However, the congenital and acquired resistance of some cancer cell types, including malignant melanoma cells, currently impedes effective TRAIL therapy, and an innovative approach that can override TRAIL resistance is urgently required. Apoptosis is characterized by cell shrinkage caused by disruption of the maintenance of the normal physiological concentrations of K+ and Na+ and intracellular ion homeostasis. The disrupted ion homeostasis leads to depolarization and apoptosis. Recent evidence suggests that depolarization is an early and prerequisite event during TRAIL-induced apoptosis. Moreover, diverse natural products and synthetic chemicals capable of depolarizing the cell membrane exhibit tumor-selective killing and TRAIL-sensitizing effects. Here, we discuss the role of depolarization in selective killing of cancer cells in connection with the emerging concept that oxidative stress is a critical mediator of mitochondrial and endoplasmic reticulum dysfunctions and serves as a tumor-selective target in cancer treatment. PMID:24910845

  3. Oncolytic herpes simplex virus kills stem-like tumor-initiating colon cancer cells

    PubMed Central

    Warner, Susanne G; Haddad, Dana; Au, Joyce; Carson, Joshua S; O’Leary, Michael P; Lewis, Christina; Monette, Sebastien; Fong, Yuman

    2016-01-01

    Stem-like tumor-initiating cells (TICs) are implicated in cancer progression and recurrence, and can be identified by sphere-formation and tumorigenicity assays. Oncolytic viruses infect, replicate in, and kill a variety of cancer cells. In this study, we seek proof of principle that TICs are susceptible to viral infection. HCT8 human colon cancer cells were subjected to serum-free culture to generate TIC tumorspheres. Parent cells and TICs were infected with HSV-1 subtype NV1066. Cytotoxicity, viral replication, and Akt1 expression were assessed. TIC tumorigenicity was confirmed and NV1066 efficacy was assessed in vivo. NV1066 infection was highly cytotoxic to both parent HCT8 cells and TICs. In both populations, cell-kill of >80% was achieved within 3 days of infection at a multiplicity of infection (MOI) of 1.0. However, the parent cells required 2-log greater viral replication to achieve the same cytotoxicity. TICs overexpressed Akt1 in vitro and formed flank tumors from as little as 100 cells, growing earlier, faster, larger, and with greater histologic atypia than tumors from parent cells. Treatment of TIC-induced tumors with NV1066 yielded tumor regression and slowed tumor growth. We conclude that colon TICs are selected for by serum-free culture, overexpress Akt1, and are susceptible to oncolytic viral infection. PMID:27347556

  4. Combinatorial BTK and MALT1 inhibition augments killing of CD79 mutant diffuse large B cell lymphoma.

    PubMed

    Nagel, Daniel; Bognar, Miriam; Eitelhuber, Andrea C; Kutzner, Kerstin; Vincendeau, Michelle; Krappmann, Daniel

    2015-12-08

    Survival of activated B cell-subtype (ABC) of diffuse large B cell lymphoma (DLBCL) is driven by chronic B cell receptor (BCR) signaling that activates the canonical NF-κB pathway. Inhibition of BTK by Ibrutinib has been shown to kill ABC DLBCL cells that carry activating mutations in the BCR adaptor CD79. However, mutations in BTK or in downstream components such as CARMA1/CARD11 can render lymphomas Ibrutinib resistant. Therefore, we assessed here the simultaneous inhibition of BTK and the protease MALT1 that acts downstream of CARMA1 and is essential for ABC DLBCL tumor growth. We show that in CD79 mutant cells BTK is a crucial upstream regulator of MALT1, but dispensable in CARMA1 mutant ABC DLBCL. Combined inhibition of BTK by Ibrutinib and MALT1 by S-Mepazine additively impaired MALT1 cleavage activity and expression of NF-κB pro-survival factors. Thereby, combinatorial Ibrutinib and S-Mepazine treatment enhanced killing of CD79 mutant ABC DLBCL cells. Moreover, while expression of oncogenic CARMA1 in CD79 mutant cells conferred Ibrutinib resistance, double mutant cells were still sensitive to MALT1 inhibition by S-Mepazine. Thus, based on the genetic background combinatorial BTK and MALT1 inhibition may improve effectiveness of therapeutic treatment and reduce the chances for the development of drug resistances.

  5. Systemic Delivery of Fusogenic Membrane Glycoprotein-expressing Neural Stem Cells to Selectively Kill Tumor Cells

    PubMed Central

    Zhu, Detu; Lam, Dang Hoang; Purwanti, Yovita Ida; Goh, Sal Lee; Wu, Chunxiao; Zeng, Jieming; Fan, Weimin; Wang, Shu

    2013-01-01

    Intravenously injected neural stem cells (NSCs) can infiltrate both primary and metastatic tumor sites; thus, they are attractive tumor-targeting vehicles for delivering anticancer agents. However, because the systemic distribution of the injected NSCs involves normal organs and might induce off-target actions leading to unintended side effects, clinical applications of this approach is impeded. Given that the vesicular stomatitis virus glycoprotein (VSV-G) can promote the formation of multinucleated syncytia to kill cells in a pH-dependent manner, we engineered a pH sensor of VSV-G and generated a novel VSV-G mutant that efficiently promotes syncytium formation at the tumor extracellular pH (pHe) but not at pH 7.4. Using transduced NSCs derived from induced pluripotent stem cells (iPSCs), the VSV-G mutant was delivered into mice with metastatic breast cancers in the lung through tail vein injection. Compared with the conventional stem cell-based gene therapy that uses the herpes simplex virus thymidine kinase (HSVtk) suicide gene, this treatment did not display toxicity to normal non-targeted organs while retaining therapeutic effects in tumor-bearing organs. Our findings demonstrate the effectiveness of a new approach for achieving tumor-selective killing effects following systemic stem cell administration. Its potential in stem cell-based gene therapy for metastatic cancer is worthy of further exploration. PMID:23752308

  6. Tadalafil augments tumor specific immunity in patients with head and neck squamous cell carcinoma

    PubMed Central

    Califano, Joseph A; Khan, Zubair; Noonan, Kimberly A.; Rudraraju, Lakshmi; Zhang, Zhe; Wang, Hao; Goodman, Steven; Gourin, Christine G.; Ha, Patrick K.; Fakhry, Carole; Saunders, John; Levine, Marshall; Tang, Mei; Neuner, Geoffrey; Richmon, Jeremy D.; Blanco, Ray; Agrawal, Nishant; Koch, Wayne M.; Marur, Shanthi; Weed, Donald T.; Serafini, Paolo; Borrello, Ivan

    2015-01-01

    Purpose To determine if phosphodiesterase 5 (PDE5) inhibitors can augment immune function in head and neck cancer patients through inhibition of myeloid derived suppressor cells (MDSCs). Experimental Design We performed a randomized, prospective, double blinded, placebo controlled, phase II clinical trial to determine the in vivo effects of systemic PDE5 inhibition on immune function in head and neck squamous cell carcinoma (HNSCC) patients. Results Tadalafil augmented immune response, increasing ex vivo T cell expansion to a mean 2.4 fold increase compared to 1.1 fold in control patients (P= 0.01), reducing peripheral MDSC numbers to mean 0.81 fold change compared to a 1.26 fold change in control patients (P=0.001), and increasing general immunity as measured by delayed type hypersensitivity response (P=0.002). Tumor specific immunity in response to HNSCC tumor lysate was augmented in tadalafil treated patients (P=0.04). Conclusions These findings demonstrate that tadalafil augments general and tumor-specific immunity in HNSCC patients and has therapeutic potential in HNSCC. Evasion of immune surveillance and suppression of systemic and tumor specific immunity is a significant feature of head and neck cancer development. This study demonstrates that a PDE5 inhibitor, tadalafil, can reverse tumor specific immune suppression in head and neck cancer patients, with potential for therapeutic application. PMID:25564570

  7. Peptide targeting of adenoviral vectors to augment tumor gene transfer.

    PubMed

    Ballard, E N; Trinh, V T; Hogg, R T; Gerard, R D

    2012-07-01

    Adenovirus serotype 5 remains one of the most promising vectors for delivering genetic material to cancer cells for imaging or therapy, but optimization of these agents to selectively promote tumor cell infection is needed to further their clinical development. Peptide sequences that bind to specific cell surface receptors have been inserted into adenoviral capsid proteins to improve tumor targeting, often in the background of mutations designed to ablate normal ligand:receptor interactions and thereby reduce off target effects and toxicities in non-target tissues. Different tumor types also express highly variable complements of cell surface receptors, so a customized targeting strategy using a particular peptide in the context of specific adenoviral mutations may be needed to achieve optimal efficacy. To further investigate peptide targeting strategies in adenoviral vectors, we used a set of peptide motifs originally isolated using phage display technology that evince tumor specificity in vivo. To demonstrate their abilities as targeting motifs, we genetically incorporated these peptides into a surface loop of the fiber capsid protein to construct targeted adenovirus vectors. We then systematically evaluated the ability of these peptide targeted vectors to infect several tumor cell types, both in vitro and in vivo, in a variety of mutational backgrounds designed to reduce CAR and/or HSG-mediated binding. Results from this study support previous observations that peptide insertions in the HI loop of the fiber knob domain are generally ineffective when used in combination with HSG detargeting mutations. The evidence also suggests that this strategy can attenuate other fiber knob interactions, such as CAR-mediated binding, and reduce overall viral infectivity. The insertion of peptides into fiber proved more effective for targeting tumor cell types expressing low levels of CAR receptor, as this strategy can partially compensate for the very low infectivity of wild

  8. Photoradiation therapy causing selective tumor kill in a rat glioma model

    SciTech Connect

    Kaye, A.H.; Morstyn, G.

    1987-03-01

    We evaluated the effect of photoradiation therapy using the photosensitizer, hematoporphyrin derivative (HpD), and the argon-pumped rhodamine dye laser tuned to 630 nm in the rat C6 glioma model. Animal models of cerebral glioma were established by implanting 10(6) C6 glioma cells in adult Wistar rats, and craniotomies were performed on normal and tumor-bearing animals. HpD in doses of up to 80 mg/kg followed by craniotomy resulted in no damage to the normal brain, and laser light at doses of up to 1200 joules/cm2 without the prior administration of HpD produced no significant damage if the craniotomy site was irrigated with normal saline to prevent a temperature rise. Photoradiation caused no brain necrosis in non-tumor bearing animals if less than 20 mg of HpD per kg and 200 joules of red light per cm2 were used. At higher doses of HpD and light, cerebral necrosis did occur. The depth of necrosis depended on the dose of both HpD and light. Treatment with 40 mg of HpD per kg and 400 joules of light per cm2 resulted in cerebral necrosis in 50% of the treated animals. The mean depth of brain necrosis was 1.3 mm. Selective kill of a cerebral glioma with sparing of the normal brain was achieved with photoradiation therapy at doses of HpD of less than 20 mg/kg and light doses of less than 200 joules/cm2. At these doses, the mean depth of tumor kill was 4.5 mm. In 2 of 10 animals, the depth of tumor destruction was more than 6 mm.

  9. Sorafenib/Regorafenib and Lapatinib interact to kill CNS tumor cells

    PubMed Central

    Hamed, Hossein A.; Tavallai, Seyedmehrad; Grant, Steven; Poklepovic, Andrew; Dent, Paul

    2014-01-01

    The present studies were to determine whether the multi-kinase inhibitor sorafenib or its derivative regorafenib interacted with the ERBB1/ERBB2 inhibitor lapatinib to kill CNS tumor cells. In multiple CNS tumor cell types sorafenib and lapatinib interacted in a greater than additive fashion to cause tumor cell death. Tumor cells lacking PTEN, and anoikis or lapatinib resistant cells were as sensitive to the drug combination as cells expressing PTEN or parental cells, respectively. Similar data were obtained using regorafenib. Treatment of brain cancer cells with [sorafenib + lapatinib] enhanced radiation toxicity. The drug combination increased the numbers of LC3-GFP vesicles; this correlated with a reduction in endogenous LC3II, and p62 and LAMP2 degradation. Knock down of Beclin1 or ATG5 significantly suppressed drug combination lethality. Expression of c-FLIP-s, BCL-XL or dominant negative caspase 9 reduced drug combination toxicity; knock down of FADD or CD95 was protective. Expression of both activated AKT and activated MEK1 or activated mTOR was required to strongly suppress drug combination lethality. As both lapatinib and sorafenib are FDA approved agents, our data argue for further determination as to whether lapatinib and sorafenib is a useful glioblastoma therapy. PMID:24911215

  10. Anti-platelet agents augment cisplatin nanoparticle cytotoxicity by enhancing tumor vasculature permeability and drug delivery

    NASA Astrophysics Data System (ADS)

    Pandey, Ambarish; Sarangi, Sasmit; Chien, Kelly; Sengupta, Poulomi; Papa, Anne-Laure; Basu, Sudipta; Sengupta, Shiladitya

    2014-11-01

    Tumor vasculature is critically dependent on platelet mediated hemostasis and disruption of the same can augment delivery of nano-formulation based chemotherapeutic agents which depend on enhanced permeability and retention for tumor penetration. Here, we evaluated the role of Clopidogrel, a well-known inhibitor of platelet aggregation, in potentiating the tumor cytotoxicity of cisplatin nano-formulation in a murine breast cancer model. In vivo studies in murine syngeneic 4T1 breast cancer model showed a significant greater penetration of macromolecular fluorescent nanoparticles after clopidogrel pretreatment. Compared to self-assembling cisplatin nanoparticles (SACNs), combination therapy with clopidogrel and SACN was associated with a 4 fold greater delivery of cisplatin to tumor tissue and a greater reduction in tumor growth as well as higher survival rate. Clopidogrel enhances therapeutic efficiency of novel cisplatin based nano-formulations agents by increasing tumor drug delivery and can be used as a potential targeting agent for novel nano-formulation based chemotherapeutics.

  11. High CD46 receptor density determines preferential killing of tumor cells by oncolytic measles virus.

    PubMed

    Anderson, Bambi D; Nakamura, Takafumi; Russell, Stephen J; Peng, Kah-Whye

    2004-07-15

    Live attenuated Edmonston B strain of measles virus (MV-Edm) is a potent and specific oncolytic agent, but the mechanism underlying its tumor selectivity is unknown. The virus causes cytopathic effects (CPEs) of extensive syncytial formation in tumor cells but minimal damage or cell killing in normal cells. The CPE is dependent on expression of viral proteins and the presence of CD46, the major cellular receptor of MV-Edm. Using a virally encoded soluble marker peptide to provide a quantitative readout of the level of viral gene expression, we determined that tumor cells and normal cells expressed comparable levels of viral proteins. CD46 mediates virus attachment, entry, and virus-induced cell-to-cell fusion. Using engineered cells expressing a range of CD46 densities, we determined that whereas virus entry increased progressively with CD46 density, cell fusion was minimal at low receptor densities but increased dramatically above a threshold density of CD46 receptors. It is well established that tumor cells express abundant CD46 receptors on their surfaces compared with their normal counterparts. Thus, at low CD46 densities typical of normal cells, infection occurs, but intercellular fusion is negligible. At higher densities typical of tumor cells, infection leads to extensive cell fusion. Intercellular fusion also results in enhancement of viral gene expression through recruitment of neighboring uninfected cells into the syncytium, further amplifying the CPE. Discrimination between high and low CD46 receptor density provides a compelling basis for the oncolytic specificity of MV-Edm and establishes MV-Edm as a promising CD46-targeted cancer therapeutic agent.

  12. A CSPG4-specific immunotoxin kills rhabdomyosarcoma cells and binds to primary tumor tissues.

    PubMed

    Brehm, Hannes; Niesen, Judith; Mladenov, Radoslav; Stein, Christoph; Pardo, Alessa; Fey, Georg; Helfrich, Wijnand; Fischer, Rainer; Gattenlöhner, Stefan; Barth, Stefan

    2014-10-01

    The treatment of rhabdomyosarcoma (RMS) remains challenging, with metastatic and alveolar RMS offering a particularly poor prognosis. Therefore, the identification and evaluation of novel antigens, which are suitable targets for immunotherapy, is one attractive possibility to improve the treatment of this disease. Here we show that chondroitin sulfate proteoglycan 4 (CSPG4) is expressed on RMS cell lines and RMS patient material. We evaluated the immunotoxin (IT) αMCSP-ETA', which specifically recognizes CSPG4 on the RMS cell lines RD, FL-OH1, TE-671 and Rh30. It is internalized rapidly, induces apoptosis and thus kills RMS cells selectively. We also demonstrate the specific binding of this IT to RMS primary tumor material from three different patients.

  13. Co-Expression of Tumor Antigen and Interleukin-2 From an Adenoviral Vector Augments the Efficiency of Therapeutic Tumor Vaccination

    PubMed Central

    Jensen, Benjamin Anderschou Holbech; Steffensen, Maria Abildgaard; Nielsen, Karen Nørgaard; Christensen, Jan Pravsgaard; Thomsen, Allan Randrup; Holst, Peter Johannes

    2014-01-01

    We have previously shown that for the majority of antigens, adenoviral vaccines expressing the target antigen fused to the MHC associated invariant chain (Ii) induce an accelerated, augmented, and prolonged transgene-specific CD8+ T-cell response. Here we describe a new adenoviral vaccine vector approach where the target antigen fused to Ii is expressed from the adenoviral E1 region and IL-2 is expressed from the E3 region. Immunization of mice with this new vector construct resulted in an augmented primary effector CD8+ T-cell response. Furthermore, in a melanoma model we observed significantly prolonged tumor control in vaccinated wild type (WT) mice. The improved tumor control required antigen-specific cells, since no tumor control was observed, unless the melanoma cells expressed the vaccine targeted antigen. We also tested our new vaccine in immunodeficient (CD80/86 deficient) mice. Following vaccination with the IL-2 expressing construct, these mice were able to raise a delayed but substantial CD8+ T-cell response, and to control melanoma growth nearly as efficaciously as similarly vaccinated WT mice. Taken together, these results demonstrate that current vaccine vectors can be improved and even tailored to meet specific demands: in the context of therapeutic vaccination, the capacity to promote an augmented effector T-cell response. PMID:25023330

  14. Augmented anti-tumor activity of NK-92 cells expressing chimeric receptors of TGF-βR II and NKG2D.

    PubMed

    Wang, Zhongjuan; Guo, Linghua; Song, Yuan; Zhang, Yinsheng; Lin, Dandan; Hu, Bo; Mei, Yu; Sandikin, Dedy; Liu, Haiyan

    2017-04-01

    The capacity of natural killer (NK) cells to kill tumor cells without specific antigen recognition provides an advantage over T cells and makes them potential effectors for tumor immunotherapy. However, the efficacy of NK cell adoptive therapy can be limited by the immunosuppressive tumor microenvironment. Transforming growth factor-β (TGF-β) is a potent immunosuppressive cytokine that can suppress NK cell function. To convert the suppressive signal induced by TGF-β to an activating signal, we genetically modified NK-92 cells to express a chimeric receptor with TGF-β type II receptor extracellular and transmembrane domains and the intracellular domain of NK cell-activating receptor NKG2D (TN chimeric receptor). NK-92 cells expressing TN receptors were resistant to TGF-β-induced suppressive signaling and did not down-regulate NKG2D. These modified NK-92 cells had higher killing capacity and interferon γ (IFN-γ) production against tumor cells compared with the control cells and their cytotoxicity could be further enhanced by TGF-β. More interestingly, the NK-92 cells expressing TN receptors were better chemo-attracted to the tumor cells expressing TGF-β. The presence of these modified NK-92 cells significantly inhibited the differentiation of human naïve CD4(+) T cells to regulatory T cells. NK-92-TN cells could also inhibit tumor growth in vivo in a hepatocellular carcinoma xenograft tumor model. Therefore, TN chimeric receptors can be a novel strategy to augment anti-tumor efficacy in NK cell adoptive therapy.

  15. Activity levels of cathepsins B and L in tumor cells are a biomarker for efficacy of reovirus-mediated tumor cell killing.

    PubMed

    Terasawa, Y; Hotani, T; Katayama, Y; Tachibana, M; Mizuguchi, H; Sakurai, F

    2015-03-01

    Reovirus has gained much attention as an anticancer agent; however, the mechanism of the tumor cell-specific replication of reovirus is not fully understood. Although Ras activation is known to be crucial for tumor cell-specific replication of reovirus, it remains controversial which cellular factors are required for the reovirus-mediated tumor cell killing. In this study, we systematically investigated which cellular factors determined the efficiencies of reovirus-mediated tumor cell killing in various human cultured cell lines. The efficiency of reovirus-mediated cell killing varied widely among the cell lines. Junction adhesion molecule-A, a reovirus receptor, was highly expressed in almost all cell lines examined. Ras activation levels were largely different between the cell lines; however, there were no apparent correlations among the reovirus-mediated cell killing efficiencies and Ras activation status. On the other hand, activity levels of the cysteine proteases cathepsins B and L, which are crucial for proteolytic disassembly of the outer capsid proteins of reovirus, showed a tendency to be correlated with the efficiency of reovirus-mediated cell killing. These results indicate that the activity of cathepsins B and L is the most suitable as a biomarker for the efficacy of reovirus-mediated oncolysis among the factors examined in this study.

  16. Efficient killing of CD22{sup +} tumor cells by a humanized diabody-RNase fusion protein

    SciTech Connect

    Krauss, Juergen . E-mail: juergen.krauss@uni-essen.de; Arndt, Michaela A.E.; Vu, Bang K.; Newton, Dianne L.; Seeber, Siegfried; Rybak, Susanna M.

    2005-06-03

    We report on the generation of a dimeric immunoenzyme capable of simultaneously delivering two ribonuclease (RNase) effector domains on one molecule to CD22{sup +} tumor cells. As targeting moiety a diabody derived from the previously humanized scFv SGIII with grafted specificity of the murine anti-CD22 mAb RFB4 was constructed. Further engineering the interface of this construct (V{sub L}36{sub Leu{yields}}{sub Tyr}) resulted in a highly robust bivalent molecule that retained the same high affinity as the murine mAb RFB4 (K{sub D} 0.2 nM). A dimeric immunoenzyme comprising this diabody and Rana pipiens liver ribonuclease I (rapLRI) was generated, expressed as soluble protein in bacteria, and purified to homogeneity. The dimeric fusion protein killed several CD22{sup +} tumor cell lines with high efficacy (IC{sub 50} = 3-20 nM) and exhibited 9- to 48-fold stronger cytotoxicity than a monovalent rapLRI-scFv counterpart. Our results demonstrate that engineering of dimeric antibody-ribonuclease fusion proteins can markedly enhance their biological efficacy.

  17. Cancer-induced defective cytotoxic T lymphocyte effector function: another mechanism how antigenic tumors escape immune-mediated killing.

    PubMed Central

    Radoja, S.; Frey, A. B.

    2000-01-01

    BACKGROUND: The notion that a deficit in immune cell functions permits tumor growth has received experimental support with the discovery of several different biochemical defects in T lymphocytes that infiltrate cancers. Decreased levels of enzymes involved with T-cell signal transduction have been reported by several laboratories, suggesting that tumors or host cells recruited to the tumor site actively down-regulate antitumor T-cell immune response. This permits tumor escape from immune-mediated killing. The possibility that defects in T-cell signal transduction can be reversed, which would potentially permit successful vaccination or adoptive immunotherapy, motivates renewed interest in the field. Summarizing the literature concerning tumor-induced T-cell dysfunction, we focus on the end stage of immune response to human cancer, that of defective cytotoxic T lymphocyte killing function. Based on the data from several laboratories, we hypothesize a biochemical mechanism that accounts for the unusual phenotype of antitumor T-cell accumulation in tumors, but with defective killing function. PMID:10972084

  18. Tumor cell-specific photothermal killing by SELEX-derived DNA aptamer-targeted gold nanorods

    NASA Astrophysics Data System (ADS)

    Chandrasekaran, Ramya; Lee, Alexander Sheng Wei; Yap, Lim Wei; Jans, David A.; Wagstaff, Kylie M.; Cheng, Wenlong

    2015-12-01

    Despite widespread availability of cytotoxic chemotherapeutic agents, the killing of tumour cells without affecting healthy surrounding tissue remains elusive, although recent developments in terms of plasmonic nanoparticles capable of photothermal killing have some promise. Here we describe novel DNA aptamer-tethered gold nanorods (GNRs) that act as efficient photothermal therapeutics against tumour cells, but not their isogenic normal cell counterparts. A modified Cell-SELEX process was developed to select a novel DNA aptamer (KW16-13) that specifically recognised and was internalised by cells of the MCF10CA1h human breast ductal carcinoma line but not by those of its isogenic normal counterpart (MCF10A). GNRs conjugated to KW16-13 were readily internalized by the MCF10CA1h tumour cells with minimal uptake by MCF10A normal cells. Upon near infrared (NIR) light irradiation, tumour cell death of >96%, could be effected, compared to <1% in the normal cells or cells incubated with GNRs alone, our KW16-13 aptamer-targeted GNRs thus showing >71-fold tumor cell death than GNRs-targeted with a previously described aptamer. This demonstrates the significant potential for aptamer functionalised-GNRs to be used effective and above all selective anti-cancer photothermal therapeutics.Despite widespread availability of cytotoxic chemotherapeutic agents, the killing of tumour cells without affecting healthy surrounding tissue remains elusive, although recent developments in terms of plasmonic nanoparticles capable of photothermal killing have some promise. Here we describe novel DNA aptamer-tethered gold nanorods (GNRs) that act as efficient photothermal therapeutics against tumour cells, but not their isogenic normal cell counterparts. A modified Cell-SELEX process was developed to select a novel DNA aptamer (KW16-13) that specifically recognised and was internalised by cells of the MCF10CA1h human breast ductal carcinoma line but not by those of its isogenic normal

  19. Failure of anti tumor-derived endothelial cell immunotherapy depends on augmentation of tumor hypoxia.

    PubMed

    Pezzolo, Annalisa; Marimpietri, Danilo; Raffaghello, Lizzia; Cocco, Claudia; Pistorio, Angela; Gambini, Claudio; Cilli, Michele; Horenstein, Alberto; Malavasi, Fabio; Pistoia, Vito

    2014-11-15

    We have previously demonstrated that Tenascin-C (TNC)(+) human neuroblastoma (NB) cells transdifferentiate into tumor-derived endothelial cells (TDEC), which have been detected both in primary tumors and in tumors formed by human NB cell lines in immunodeficient mice. TDEC are genetically unstable and may favor tumor progression, suggesting that their elimination could reduce tumor growth and dissemination. So far, TDEC have never been targeted by antibody-mediated immunotherapy in any of the tumor models investigated. To address this issue, immunodeficient mice carrying orthotopic NB formed by the HTLA-230 human cell line were treated with TDEC-targeting cytotoxic human (h)CD31, that spares host-derived endothelial cells, or isotype-matched mAbs. hCD31 mAb treatment did not affect survival of NB-bearing mice, but increased significantly hypoxia in tumor microenvironment, where apoptotic and proliferating TDEC coexisted, indicating the occurrence of vascular remodeling. Tumor cells from hCD31 mAb treated mice showed i) up-regulation of epithelial-mesenchymal transition (EMT)-related and vascular mimicry (VM)-related gene expression, ii) expression of endothelial (i.e. CD31 and VE-cadherin) and EMT-associated (i.e. Twist-1, N-cadherin and TNC) immunophenotypic markers, and iii) up-regulation of high mobility group box-1 (HMGB-1) expression. In vitro experiments with two NB cell lines showed that hypoxia was the common driver of all the above phenomena and that human recombinant HMGB-1 amplified EMT and TDEC trans-differentiation. In conclusion, TDEC targeting with hCD31 mAb increases tumor hypoxia, setting the stage for the occurrence of EMT and of new waves of TDEC trans-differentiation. These adaptive responses to the changes induced by immunotherapy in the tumor microenvironment allow tumor cells to escape from the effects of hCD31 mAb.

  20. Enhancement of macrophage-mediated tumor cell killing by bacterial outer membrane proteins (porins).

    PubMed Central

    Weinberg, J B; Ribi, E; Wheat, R W

    1983-01-01

    Various microbial products are known to influence the function of mouse peritoneal macrophages. Lipopolysaccharide (LPS) and certain lipid A-associated proteins are known to enhance the tumoricidal effects of macrophages. The purpose of this study was to determine whether porins (outer membrane proteins) of Salmonella typhimurium G30/C21 would influence the activity of macrophages from lipid A-responsive and -unresponsive mice. Porins, extracted by a combined sodium dodecyl sulfate-EDTA method from cell walls, were free of LPS as determined by Limulus amebocyte lysate assay and appeared as a band at approximately 36,000 molecular weight on sodium dodecyl sulfate-polyacrylamide gel electrophoresis. In tumor cell killing assays done under LPS-free conditions, the porins in doses of 1 to 10 ng/ml enhanced the tumoricidal effect of macrophages from bacillus Calmette-Guérin-infected C3H/HeN or C3H/HeJ mice. Protein-free LPS enhanced the tumoricidal activity of macrophages from bacillus Calmette-Guérin-infected C3H/HeN but not C3H/HeJ mice. The tumoricidal-enhancing activity of protein-free LPS was blocked by the lipid A-binding antibiotic polymyxin B sulfate, but the effects of porins were not altered by the polymyxin B sulfate. These results suggest that porins, proteins known to alter membrane function, may alter macrophage function by interaction with macrophage membranes. Images PMID:6311745

  1. Recombinant interleukin-2 significantly augments activity of rituximab in human tumor xenograft models of B-cell non-Hodgkin lymphoma.

    PubMed

    Lopes de Menezes, Daniel E; Denis-Mize, Kimberly; Tang, Yan; Ye, Helen; Kunich, John C; Garrett, Evelyn N; Peng, Jing; Cousens, Lawrence S; Gelb, Arnold B; Heise, Carla; Wilson, Susan E; Jallal, Bahija; Aukerman, Sharon L

    2007-01-01

    Recombinant interleukin-2 (rIL-2) is a pleiotropic cytokine that activates select immune effector cell responses associated with antitumor activity, including antibody-dependent cellular cytotoxicity (ADCC). Rituximab is an anti-CD20 monoclonal antibody that activates ADCC in non-Hodgkin lymphoma (NHL). The ability of rIL-2 to augment rituximab-dependent tumor responses was investigated. The efficacy of rIL-2 in combination with rituximab was evaluated in 2 NHL tumor xenograft models: the CD20hi, rituximab-sensitive, low-grade Daudi model and the CD20lo, aggressive, rituximab-resistant Namalwa model. Combination of rIL-2 plus rituximab was synergistic in a rituximab-sensitive Daudi tumor model, as evidenced by significant tumor regressions and increased time to tumor progression, compared with rIL-2 and rituximab single agents. In contrast, rituximab-resistant Namalwa tumors were responsive to single-agent rIL-2 and showed an increased response when combined with rituximab. Using in vitro killing assays, rIL-2 was shown to enhance activity of rituximab by activating ADCC and lymphokine-activated killer activity. Additionally, the activity of rIL-2 plus rituximab F(ab')2 was similar to that of rIL-2 alone, indicating a critical role for immunoglobulin G1 Fc-FcgammaR-effector responses in mediating ADCC. Antiproliferative and apoptotic tumor responses, along with an influx of immune effector cells, were observed by immunohistochemistry. Collectively, the data suggest that rIL-2 mediates potent tumoricidal activity against NHL tumors, in part, through activation and trafficking of monocytes and natural killer cells to tumors. These data support the mechanistic and therapeutic rationale for combination of rIL-2 with rituximab in NHL clinical trials and for single-agent rIL-2 in rituximab-resistant NHL patients.

  2. Two-stage model of radon-induced malignant lung tumors in rats: effects of cell killing

    NASA Technical Reports Server (NTRS)

    Luebeck, E. G.; Curtis, S. B.; Cross, F. T.; Moolgavkar, S. H.

    1996-01-01

    A two-stage stochastic model of carcinogenesis is used to analyze lung tumor incidence in 3750 rats exposed to varying regimens of radon carried on a constant-concentration uranium ore dust aerosol. New to this analysis is the parameterization of the model such that cell killing by the alpha particles could be included. The model contains parameters characterizing the rate of the first mutation, the net proliferation rate of initiated cells, the ratio of the rates of cell loss (cell killing plus differentiation) and cell division, and the lag time between the appearance of the first malignant cell and the tumor. Data analysis was by standard maximum likelihood estimation techniques. Results indicate that the rate of the first mutation is dependent on radon and consistent with in vitro rates measured experimentally, and that the rate of the second mutation is not dependent on radon. An initial sharp rise in the net proliferation rate of initiated cell was found with increasing exposure rate (denoted model I), which leads to an unrealistically high cell-killing coefficient. A second model (model II) was studied, in which the initial rise was attributed to promotion via a step function, implying that it is due not to radon but to the uranium ore dust. This model resulted in values for the cell-killing coefficient consistent with those found for in vitro cells. An "inverse dose-rate" effect is seen, i.e. an increase in the lifetime probability of tumor with a decrease in exposure rate. This is attributed in large part to promotion of intermediate lesions. Since model II is preferable on biological grounds (it yields a plausible cell-killing coefficient), such as uranium ore dust. This analysis presents evidence that a two-stage model describes the data adequately and generates hypotheses regarding the mechanism of radon-induced carcinogenesis.

  3. Killing tumor cells: the effect of photodynamic therapy using mono-l-aspartyl chlorine and NS-398

    PubMed Central

    Harvey, Elizabeth H.; Webber, John; Kessel, David; Fromm, David

    2015-01-01

    Background Photodynamic therapy (PDT) is a useful treatment for malignant tumors. PDT involves the administration of a photosensitive drug that is selected by neoplastic tissues and their vasculature. One such photosensitizer is mono-l-aspartyl chlorine e6 (NPe6). Recent evidence suggests that the presence of the cyclooxygenase-2 (COX-2) inhibitor NS-398 may potentiate the effect of photosensitizing agents. This study was designed to determine if the addition of NS-398 to NPe6-induced PDT in single or fractionated dosing would result in greater tumor kill. Methods Colon-38 tumor was subcutaneously implanted into both flanks of mice and allowed to grow to 0.5 to 1.0 cm. Mice were randomly allocated to 5 groups: (1) single dose of NPe6; (2) fractionated dose of NPe6; (3) NS-398 only; (4) single dose of NPe6 + NS-398; and (5) fractionated dose of NPe6 + NS-398. The left flank was shielded from exposure to irradiation. Tumor size was measured before initiation of PDT and at the time of sacrifice. Results The initial tumor weights of both flanks were not significantly different between all groups. Tumor weights at the time of death after PDT using NPe6 were significantly less than their paired tumors in the untreated flanks (P <0.0001). Tumor weights in the treated flanks were significantly less in the group receiving the fractionated dosing of NPe6 as compared to the single dose of NPe6 (P = 0.0037). NS-398 plus the single dose of NPe6 significantly decreased tumor weight in the PDT-treated flank (P = 0.035) at a level equivalent to that observed with fractionated dosing of the photosensitizer in the absence of NS-398. NS-398 did not significantly further decrease tumor weight in the group that received the fractionated dose of NPe6. Conclusions Fractionated dosing of NPe6 demonstrated the best tumor kill. However, NS-398 did not potentiate the effect of PDT using fractionated dosing of NPe6. While PDT using the single NPe6 dose significantly decreased tumor weight

  4. Real-time dynamic optical imaging of ACC-M tumor cells killed by HSV-tk/ACV system.

    PubMed

    Xiong, Tao; Li, Yongjin; Li, Zhiyang; Xie, Xiangmo; Lu, Lisha

    2013-01-01

    HSV-tk/ACV induced and killed human adenoid cystic carcinoma cell (ACC-M) in vivo and in vitro, which were observed through optical imaging and green fluorescence protein (GFP) tagging technique. ACC-M was transfected with TK-GFP, and the single clone cell ACC-M-TK-GFP was selected by G418. With fluorescent stereomicroscope, whole-body fluorescent imaging system and fluorescent microscope, we could observe ACV treated ACC-M-TK-GFP cells in cell level and nude mice. The therapies of tumor were visualized clearly with optical imaging. This study proves that optical imaging is a very good approach for studying the effect of HSV-tk/ACV on the ACC-M tumor cells and decreasing the amount of vessel about tumors cell. Optical imaging will become a visual groundwork for monitoring tumor growth and evaluating in vivo curative effect of antitumor drugs.

  5. Genetic control of natural killing and in vivo tumor elimination by the Chok locus.

    PubMed

    Idris, A H; Iizuka, K; Smith, H R; Scalzo, A A; Yokoyama, W M

    1998-12-21

    The molecular mechanisms underlying target recognition during natural killing are not well understood. One approach to dissect the complexities of natural killer (NK) cell recognition is through exploitation of genetic differences among inbred mouse strains. In this study, we determined that interleukin 2-activated BALB/c-derived NK cells could not lyse Chinese hamster ovary (CHO) cells as efficiently as C57BL/6-derived NK cells, despite equivalent capacity to kill other targets. This strain-determined difference was also exhibited by freshly isolated NK cells, and was determined to be independent of host major histocompatibility haplotype. Furthermore, CHO killing did not correlate with expression of NK1.1 or 2B4 activation molecules. Genetic mapping studies revealed linkage between the locus influencing CHO killing, termed Chok, and loci encoded within the NK gene complex (NKC), suggesting that Chok encodes an NK cell receptor specific for CHO cells. In vivo assays recapitulated the in vitro data, and both studies determined that Chok regulates an NK perforin-dependent cytotoxic process. These results may have implications for the role of NK cells in xenograft rejection. Our genetic analysis suggests Chok is a single locus that affects NK cell-mediated cytotoxicity similar to other NKC loci that also regulate the complex activity of NK cells.

  6. Anti-tumor activity of heat-killed Lactobacillus plantarum BF-LP284 on Meth-A tumor cells in BALB/c mice.

    PubMed

    Shin, Ryoichi; Itoh, Yukie; Kataoka, Motoyuki; Iino-Miura, Shiori; Miura, Ryosuke; Mizutani, Takeo; Fujisawa, Tomohiko

    2016-09-01

    Probiotics exert numerous effects on human well-being. Here, heat-killed Lactobacillus plantarum BF-LP284 (H-Lp) was isolated as a potent immuno-modulator among 15 strains of lactobacilli in terms of TNF-α induction ability in peritoneal macrophages. In vitro TNF-α and IFN-γ induction in Peyer's patch (PP) cells was higher when incubated with H-Lp than with live L. plantarum BF-LP284 (L-Lp). Suppression of syngeneic Meth-A tumors in a murine model by oral administration of H-Lp was also greater than that of L-Lp and of controls. H-Lp stimulated IFN-γ production in spleen cells, which displayed inhibited tumor growth in Winn assays when treated with H-Lp. Moreover, H-Lp increased the ratio of CD3(+ )cells among peripheral blood mononuclear cells in Meth-A tumor-bearing mice, suggesting an H-Lp-mediated anti-tumor mechanism whereby immune cells that are activated by H-Lp in PP and acquire anti-tumor activity in the spleen migrate to tumor sites through lymphocyte homing to inhibit tumor growth.

  7. Augmented macrophage differentiation and polarization of tumor-associated macrophages towards M1 subtype in listeria-administered tumor-bearing host.

    PubMed

    Rai, Rakesh K; Vishvakarma, Naveen K; Mohapatra, Tribhuban M; Singh, Sukh Mahendra

    2012-09-01

    This study investigates the effect of Listeria administration on differentiation of macrophages from precursor bone marrow cells and functional status of tumor-associated macrophages (TAM). Listeria administration not only resulted in an augmented infiltration of tumor by F4/80 macrophages but also repolarized the functional status of TAM displaying features of some M1 macrophage subtype with upregulated phagocytosis and tumoricidal activity accompanied by altered expression of monocarboxylate transporter-1, toll-like receptor-2, surface markers: CD11c, interleukin-2 receptor, CD62L, and secreted molecules: nitric oxide, interleukin (IL)-1, IL-6, tumor necrosis factor-α, and vascular endothelial growth factor. Declined tumor cell survival and modulated repertoire of cytokines: interferon-γ, IL-6, IL-10, and transforming growth factor-β in tumor microenvironment indicated their role in polarization of TAM towards proinflammatory state. Bone marrow cell of Listeria-administered tumor-bearing mice showed augmented survival, declined expression of p53 upregulated modulator of apoptosis with an upregulated differentiation into activation responsive bone marrow-derived macrophages along with altered expression of macrophage-colony stimulating factor, macrophage-colony stimulating factor receptor, and granulocyte macrophage-colony stimulating factor receptor. These findings indicate that Listeria infection is associated with an augmented differentiation of macrophages accompanied by tumoricidal activation of TAM.

  8. Tcr-like antibody drug conjugates mediate killing of tumor cells with low peptide/hla targets.

    PubMed

    Lowe, Devin B; Bivens, Camille K; Mobley, Alexis S; Herrera, Christian E; McCormick, Amanda L; Wichner, Timea; Sabnani, Manoj K; Wood, Laurence M; Weidanz, Jon A

    2017-03-08

    The currently marketed antibody-drug conjugates (ADC) destabilize microtubule assembly in cancer cells and initiate apoptosis in patients. However, few tumor antigens (TA) are expressed at high densities on cancer lesions, potentially minimizing the therapeutic index of current ADC regimens. The peptide/human leukocyte antigen (HLA) complex can be specifically targeted by therapeutic antibodies (designated T cell receptor [TCR]-like antibodies) and adequately distinguish malignant cells, but has not been the focus of ADC development. We analyzed the killing potential of TCR-like ADCs when cross-linked to the DNA alkylating compound duocarmycin. Our data comprise proof-of-principle results that TCR-like ADCs mediate potent tumor cytotoxicity, particularly under common scenarios of low TA/HLA density, and support their continued development alongside agents that disrupt DNA replication. Additionally, TCR-like antibody ligand binding appears to play an important role in ADC functionality and should be addressed during therapy development to avoid binding patterns that negate ADC killing efficacy.

  9. HAMLET kills tumor cells by an apoptosis-like mechanism--cellular, molecular, and therapeutic aspects.

    PubMed

    Svanborg, Catharina; Agerstam, Helena; Aronson, Annika; Bjerkvig, Rolf; Düringer, Caroline; Fischer, Walter; Gustafsson, Lotta; Hallgren, Oskar; Leijonhuvud, Irene; Linse, Sara; Mossberg, Ann-Kristin; Nilsson, Hanna; Pettersson, Jenny; Svensson, Malin

    2003-01-01

    HAMLET (human alpha-lactalbumin made lethal to tumor cells) is a protein-lipid complex that induces apoptosis-like death in tumor cells, but leaves fully differentiated cells unaffected. This review summarizes the information on the in vivo effects of HAMLET in patients and tumor models on the tumor cell biology, and on the molecular characteristics of the complex. HAMLET limits the progression of human glioblastomas in a xenograft model and removes skin papillomas in patients. This broad anti-tumor activity includes >40 different lymphomas and carcinomas and apoptosis is independent of p53 or bcl-2. In tumor cells HAMLET enters the cytoplasm, translocates to the perinuclear area, and enters the nuclei where it accumulates. HAMLET binds strongly to histones and disrupts the chromatin organization. In the cytoplasm, HAMLET targets ribosomes and activates caspases. The formation of HAMLET relies on the propensity of alpha-lactalbumin to alter its conformation when the strongly bound Ca2+ ion is released and the protein adopts the apo-conformation that exposes a new fatty acid binding site. Oleic acid (C18:1,9 cis) fits this site with high specificity, and stabilizes the altered protein conformation. The results illustrate how protein folding variants may be beneficial, and how their formation in peripheral tissues may depend on the folding change and the availability of the lipid cofactor. One example is the acid pH in the stomach of the breast-fed child that promotes the formation of HAMLET. This mechanism may contribute to the protective effect of breastfeeding against childhood tumors. We propose that HAMLET should be explored as a novel approach to tumor therapy.

  10. Augmented IFN-γ and TNF-α Induced by Probiotic Bacteria in NK Cells Mediate Differentiation of Stem-Like Tumors Leading to Inhibition of Tumor Growth and Reduction in Inflammatory Cytokine Release; Regulation by IL-10

    PubMed Central

    Bui, Vickie T.; Tseng, Han-Ching; Kozlowska, Anna; Maung, Phyu Ou; Kaur, Kawaljit; Topchyan, Paytsar; Jewett, Anahid

    2015-01-01

    Our previous reports demonstrated that the magnitude of natural killer (NK) cell-mediated cytotoxicity correlate directly with the stage and level of differentiation of tumor cells. In addition, we have shown previously that activated NK cells inhibit growth of cancer cells through induction of differentiation, resulting in the resistance of tumor cells to NK cell-mediated cytotoxicity through secreted cytokines, as well as direct NK-tumor cell contact. In this report, we show that in comparison to IL-2 + anti-CD16mAb-treated NK cells, activation of NK cells by probiotic bacteria (sAJ2) in combination with IL-2 and anti-CD16mAb substantially decreases tumor growth and induces maturation, differentiation, and resistance of oral squamous cancer stem cells, MIA PaCa-2 stem-like/poorly differentiated pancreatic tumors, and healthy stem cells of apical papillae through increased secretion of IFN-γ and TNF-α, as well as direct NK-tumor cell contact. Tumor resistance to NK cell-mediated killing induced by IL-2 + anti-CD16mAb + sAJ2-treated NK cells is induced by combination of IFN-γ and TNF-α since antibodies to both, and not each cytokine alone, were able to restore tumor sensitivity to NK cells. Increased surface expression of CD54, B7H1, and MHC-I on NK-differentiated tumors was mediated by IFN-γ since the addition of anti-IFN-γ abolished their increase and restored the ability of NK cells to trigger cytokine and chemokine release; whereas differentiated tumors inhibited cytokine release by the NK cells. Monocytes synergize with NK cells in the presence of probiotic bacteria to induce regulated differentiation of stem cells through secretion of IL-10 resulting in resistance to NK cell-mediated cytotoxicity and inhibition of cytokine release. Therefore, probiotic bacteria condition activated NK cells to provide augmented differentiation of cancer stem cells resulting in inhibition of tumor growth, and decreased inflammatory cytokine release. PMID

  11. Theory and Experimental Validation of a Spatio-temporal Model of Chemotherapy Transport to Enhance Tumor Cell Kill

    PubMed Central

    Wang, Zhihui; Chuang, Yao-Li; Dogra, Prashant; Butner, Joseph D.; Day, Armin; Xu, Rong; Shen, Haifa; Simbawa, Eman; AL-Fhaid, A. S.; Mahmoud, S. R.; Curley, Steven A.; Ferrari, Mauro; Cristini, Vittorio

    2016-01-01

    It has been hypothesized that continuously releasing drug molecules into the tumor over an extended period of time may significantly improve the chemotherapeutic efficacy by overcoming physical transport limitations of conventional bolus drug treatment. In this paper, we present a generalized space- and time-dependent mathematical model of drug transport and drug-cell interactions to quantitatively formulate this hypothesis. Model parameters describe: perfusion and tissue architecture (blood volume fraction and blood vessel radius); diffusion penetration distance of drug (i.e., a function of tissue compactness and drug uptake rates by tumor cells); and cell death rates (as function of history of drug uptake). We performed preliminary testing and validation of the mathematical model using in vivo experiments with different drug delivery methods on a breast cancer mouse model. Experimental data demonstrated a 3-fold increase in response using nano-vectored drug vs. free drug delivery, in excellent quantitative agreement with the model predictions. Our model results implicate that therapeutically targeting blood volume fraction, e.g., through vascular normalization, would achieve a better outcome due to enhanced drug delivery. Author Summary Cancer treatment efficacy can be significantly enhanced through the elution of drug from nano-carriers that can temporarily stay in the tumor vasculature. Here we present a relatively simple yet powerful mathematical model that accounts for both spatial and temporal heterogeneities of drug dosing to help explain, examine, and prove this concept. We find that the delivery of systemic chemotherapy through a certain form of nano-carriers would have enhanced tumor kill by a factor of 2 to 4 over the standard therapy that the patients actually received. We also find that targeting blood volume fraction (a parameter of the model) through vascular normalization can achieve more effective drug delivery and tumor kill. More importantly

  12. A Nanoparticle-Based Combination Chemotherapy Delivery System for Enhanced Tumor Killing by Dynamic Rewiring of Signaling Pathways

    PubMed Central

    Morton, Stephen W.; Lee, Michael J.; Deng, Zhou J.; Dreaden, Erik C.; Siouve, Elise; Shopsowitz, Kevin E.; Shah, Nisarg J.; Yaffe, Michael B.; Hammond, Paula T.

    2014-01-01

    Exposure to the EGFR (epidermal growth factor receptor) inhibitor erlotinib promotes the dynamic rewiring of apoptotic pathways, which sensitizes cells within a specific period to subsequent exposure to the DNA-damaging agent doxorubicin. A critical challenge for translating this therapeutic network rewiring into clinical practice is the design of optimal drug delivery systems. We report the generation of a nanoparticle delivery vehicle that contained more than one therapeutic agent and produced a controlled sequence of drug release. Liposomes, representing the first clinically approved nanomedicine systems, are well-characterized, simple, and versatile platforms for the manufacture of functional and tunable drug carriers. Using the hydrophobic and hydrophilic compartments of liposomes, we effectively incorporated both hydrophobic (erlotinib) and hydrophilic (doxorubicin) small molecules, through which we achieved the desired time sequence of drug release. We also coated the liposomes with folate to facilitate targeting to cancer cells. When compared to the time-staggered application of individual drugs, staggered release from tumor-targeted single liposomal particles enhanced dynamic rewiring of apoptotic signaling pathways, resulting in improved tumor cell killing in culture and tumor shrinkage in animal models. PMID:24825919

  13. Evaluation of a Novel Thermal Accelerant for Augmentation of Microwave Energy during Image-guided Tumor Ablation

    PubMed Central

    Park, William Keun Chan; Maxwell, Aaron Wilhelm Palmer; Frank, Victoria Elizabeth; Primmer, Michael Patrick; Collins, Scott Andrew; Baird, Grayson Luderman; Dupuy, Damian Edward

    2017-01-01

    The primary challenge in thermal ablation of liver tumors (e.g. hepatocellular carcinoma and hepatic colorectal cancer) is the relatively high recurrence rate (~30%) for which incomplete ablation at the periphery of the tumor is the most common reason. In an attempt to overcome this, we have developed a novel thermal accelerant (TA) agent capable of augmenting microwave energy from a distance normally unattainable by a single microwave ablation antenna. This cesium-based block co-polymer compound transforms from a liquid to a gel at body temperature and is intrinsically visible by computed tomography. Using an agarose phantom model, herein we demonstrate that both the rate and magnitude of temperature increase during microwave ablation were significantly greater in the presence of TA when compared with controls. These results suggest robust augmentation of microwave energy, and may translate into larger ablation zone volumes within biologic tissues. Further work using in vivo techniques is necessary to confirm these findings. PMID:28382173

  14. Augmenting tumor uptake of Tc-99m monoclonal antibodies (MAbs) with biological response modifiers: Influence of interferon

    SciTech Connect

    Li, J.; Thakur, M.L.; Wilder, S.

    1994-05-01

    Following the evaluation of radiolabeled MAbs for scintigraphic imaging or therapy, low tumor uptake emerged as one of the most prominent problems. The aim of this investigation was to examine the influence of interferon (IFN)-{alpha}2b in augmenting uptake of Tc-99m labeled antimelanoma MAb 31.3 in nude mice bearing experimental human melanoma. MAb was labeled with Tc-99m by our ascorbic acid mediated reduction technique, analyzed and 20 {mu}g containing 40-120 {mu}Ci Tc-99m were administered i.v., 1 hr following i.m. or i.v. administration of 10K, 20K, or 100K i.u. IFN-{alpha}2b. Animals receiving 0.9% saline similarly served as controls. 4 and 24 hrs later, animals were sacrificed, imaged, and dissected for tissue distribution studies. Tumor blood flow was measured before and after administration of IFN by color Doppler imaging technique, intratumoral temperature was recorded using thermocouples, and tumor histology was performed to visualize tumor lymphocytic infiltration. Although no excessive lymphocytic infiltration was seen within 72 hr post-injection of IFN, and only a modest increase in tumor temperature was noted, a significant increase in blood flow was observed within 45 min. as differentiated by amplitudes at peak systolic and end diastolic cardiac cycles. The best tumor uptake enhancement was noted at 24 hr following i.m. administration of 20K i.u. IFN and measured greater than 300% of the control value (7.2{plus_minus}1.2%/g vs. 2.2{plus_minus}1.4%/g). IFN-{alpha}2b enhances tumor blood flow in experimental tumors and significantly augments the uptake of radiolabeled MAbs.

  15. Nitric oxide prodrug JS-K inhibits ubiquitin E1 and kills tumor cells retaining wild-type p53.

    PubMed

    Kitagaki, J; Yang, Y; Saavedra, J E; Colburn, N H; Keefer, L K; Perantoni, A O

    2009-01-29

    Nitric oxide (NO) is a major effector molecule in cancer prevention. A number of studies have shown that NO prodrug JS-K (O(2)-(2,4-dinitrophenyl) 1-[(4-ethoxycarbonyl)piperazin-1-yl]diazen-1-ium-1,2-diolate) induces apoptotic cell death in vitro and in vivo, indicating that it is a promising new therapeutic for cancer. However, the mechanism of its tumor-killing activity remains unclear. Ubiquitin plays an important role in the regulation of tumorigenesis and cell apoptosis. Our earlier report has shown that inactivation of the ubiquitin system through blocking E1 (ubiquitin-activating enzyme) activity preferentially induces apoptosis in p53-expressing transformed cells. As E1 has an active cysteine residue that could potentially interact with NO, we hypothesized that JS-K could inactivate E1 activity. E1 activity was evaluated by detecting ubiquitin-E1 conjugates through immunoblotting. JS-K strikingly inhibits the ubiquitin-E1 thioester formation in cells in a dose-dependent manner with an IC(50) of approximately 2 microM, whereas a JS-K analog that cannot release NO did not affect these levels in cells. Moreover, JS-K decreases total ubiquitylated proteins and increases p53 levels, which is mainly regulated by ubiquitin and proteasomal degradation. Furthermore, JS-K preferentially induces cell apoptosis in p53-expressing transformed cells. These findings indicate that JS-K inhibits E1 activity and kills transformed cells harboring wild-type p53.

  16. Clinical-scale laser-based scanning and processing of live cells: selective photothermal killing of fluorescent tumor targets for autologous stem cell transplantation

    NASA Astrophysics Data System (ADS)

    Koller, Manfred R.; Hanania, Elie G.; Eisfeld, Timothy; O'Neal, Robert A.; Khovananth, Kevin M.; Palsson, Bernhard O.

    2001-04-01

    High-dose chemotherapy, followed by autologous hematopoietic stem cell (HSC) transplantation, is widely used for the treatment of cancer. However, contaminating tumor cells within HSC harvests continue to be of major concern since re-infused tumor cells have proven to contribute to disease relapse. Many tumor purging methods have been evaluated, but all leave detectable tumor cells in the transplant and result in significant loss of HSCs. These shortcomings cause engraftment delays and compromise the therapeutic value of purging. A novel approach integrating automated scanning cytometry, image analysis, and selective laser-induced killing of labeled cells within a cell mixture is described here. Non-Hodgkin's lymphoma (NHL) cells were spiked into cell mixtures, and fluorochrome-conjugated antibodies were used to label tumor cells within the mixture. Cells were then allowed to settle on a surface, and as the surface was scanned with a fluorescence excitation source, a laser pulse was fired at every detected tumor cell using high-speed beam steering mirrors. Tumor cells were selectively killed with little effect on adjacent non-target cells, demonstrating the feasibility of this automated cell processing approach. This technology has many potential research and clinical applications, one example of which is tumor cell purging for autologous HSC transplantation.

  17. Whole recombinant Pichia pastoris expressing HPV16 L1 antigen is superior in inducing protection against tumor growth as compared to killed transgenic Leishmania

    PubMed Central

    Bolhassani, Azam; Muller, Martin; Roohvand, Farzin; Motevalli, Fatemeh; Agi, Elnaz; Shokri, Mehdi; Rad, Mahdieh Motamedi; Hosseinzadeh, Sahar

    2015-01-01

    The development of an efficient vaccine against high-risk HPV types can reduce the incidence rates of cervical cancer by generating anti-tumor protective responses. Traditionally, the majority of prophylactic viral vaccines are composed of live, attenuated or inactivated viruses. Among them, the design of an effective and low-cost vaccine is critical. Inactivated vaccines especially heat-killed yeast cells have emerged as a promising approach for generating antigen-specific immunotherapy. Recent studies have indicated that yeast cell wall components possess adjuvant activities. Moreover, a non-pathogenic protozoan, Leishmania tarentolae (L.tar) has attracted a great attention as a live candidate vaccine. In current study, immunological and protective efficacy of whole recombinant killed Pichia pastoris and Leishmania tarentolae expressing HPV16 L1 capsid protein was evaluated in tumor mice model. We found that Pichia-L1, L.tar-L1 and Gardasil groups increase the IgG2a/IgG1 ratio, indicating a relative preference for the induction of Th1 immune responses. Furthermore, subcutaneous injection of killed Pichia-L1 generated the significant L1-specific IFN-γ immune response as well as the best protective effects in vaccinated mice as compared to killed L.tar-L1, killed Pichia pastoris, killed L.tar and PBS groups. Indeed, whole recombinant Leishmania tarentolae could not protect mice against C3 tumor mice model. These data suggest that Pichia-L1 may be a candidate for the control of HPV infections. PMID:25668661

  18. Augmenting antitumor T-cell responses to mimotope vaccination by boosting with native tumor antigens.

    PubMed

    Buhrman, Jonathan D; Jordan, Kimberly R; U'ren, Lance; Sprague, Jonathan; Kemmler, Charles B; Slansky, Jill E

    2013-01-01

    Vaccination with antigens expressed by tumors is one strategy for stimulating enhanced T-cell responses against tumors. However, these peptide vaccines rarely result in efficient expansion of tumor-specific T cells or responses that protect against tumor growth. Mimotopes, or peptide mimics of tumor antigens, elicit increased numbers of T cells that crossreact with the native tumor antigen, resulting in potent antitumor responses. Unfortunately, mimotopes may also elicit cells that do not crossreact or have low affinity for tumor antigen. We previously showed that one such mimotope of the dominant MHC class I tumor antigen of a mouse colon carcinoma cell line stimulates a tumor-specific T-cell clone and elicits antigen-specific cells in vivo, yet protects poorly against tumor growth. We hypothesized that boosting the mimotope vaccine with the native tumor antigen would focus the T-cell response elicited by the mimotope toward high affinity, tumor-specific T cells. We show that priming T cells with the mimotope, followed by a native tumor-antigen boost, improves tumor immunity compared with T cells elicited by the same prime with a mimotope boost. Our data suggest that the improved tumor immunity results from the expansion of mimotope-elicited tumor-specific T cells that have increased avidity for the tumor antigen. The enhanced T cells are phenotypically distinct and enriched for T-cell receptors previously correlated with improved antitumor immunity. These results suggest that incorporation of native antigen into clinical mimotope vaccine regimens may improve the efficacy of antitumor T-cell responses.

  19. The augmented anti-tumor effects of Antrodia camphorata co-fermented with Chinese medicinal herb in human hepatoma cells.

    PubMed

    Li, Shun-Lai; Huang, Zih-Ning; Hsieh, Hsiao-Hui; Yu, Wen-Chun; Tzeng, Win-Yu; Lee, Guo-Yang; Chen, Yi-Peng; Chang, Chia-Yu; Chuu, Jiunn-Jye

    2009-01-01

    Antrodia camphorata, unique fungal specie, has been used as a folk medicine in Taiwan for many years. The purpose of this study was to compare the extracts from the solid-state culture of A. camphorata co-fermented with Chinese medicinal herb (AC-CF) with two other extracts from fruiting bodies (AC-FB) or solid-state culture (AC-SS), for their anti-tumor effects in human hepatoma HepG2 cells. We measured in vitro cell proliferation, percentage of apoptosis, population distribution of cell cycles, Western blot analysis of multiple drugs resistance-1 (MDR-1), and apoptosis-related proteins in HepG2 cells treated with three different preparations of A. camphorate extracts. Our results showed that AC-CF had better anti-proliferation effect on human hepatoma HepG2 cells than AC-FB or AC-SS dose-dependently. In addition, AC-CF in combination with anti-tumor agents (mitomycin C or methotrexate) showed better adjuvant anti-tumor effects than AC-FB or AC-SS. We further demonstrated the augmented adjuvant anti-tumor effects of AC-CF not only through down regulation of MDR-1 expression but also through a COX-2 dependent apoptosis pathway, involving down-regulation of COX-2 and p-AKT and up-regulation of PARP-1. In conclusion, in this study, we have demonstrated a novel strategy of fermenting A. camphorata with Chinese medicinal herb (AC-CF), which augmented their anti-tumor effects in human hepatoma HepG2 cells as compared to the traditional ones (AC-FB or AC-SS).

  20. Cytolethal distending toxin B as a cell-killing component of tumor-targeted anthrax toxin fusion proteins.

    PubMed

    Bachran, C; Hasikova, R; Leysath, C E; Sastalla, I; Zhang, Y; Fattah, R J; Liu, S; Leppla, S H

    2014-01-16

    Cytolethal distending toxin (Cdt) is produced by Gram-negative bacteria of several species. It is composed of three subunits, CdtA, CdtB, and CdtC, with CdtB being the catalytic subunit. We fused CdtB from Haemophilus ducreyi to the N-terminal 255 amino acids of Bacillus anthracis toxin lethal factor (LFn) to design a novel, potentially potent antitumor drug. As a result of this fusion, CdtB was transported into the cytosol of targeted cells via the efficient delivery mechanism of anthrax toxin. The fusion protein efficiently killed various human tumor cell lines by first inducing a complete cell cycle arrest in the G2/M phase, followed by induction of apoptosis. The fusion protein showed very low toxicity in mouse experiments and impressive antitumor effects in a Lewis Lung carcinoma model, with a 90% cure rate. This study demonstrates that efficient drug delivery by a modified anthrax toxin system combined with the enzymatic activity of CdtB has great potential as anticancer treatment and should be considered for the development of novel anticancer drugs.

  1. The Smac Mimetic BV6 Improves NK Cell-Mediated Killing of Rhabdomyosarcoma Cells by Simultaneously Targeting Tumor and Effector Cells.

    PubMed

    Fischer, Kyra; Tognarelli, Sara; Roesler, Stefanie; Boedicker, Cathinka; Schubert, Ralf; Steinle, Alexander; Klingebiel, Thomas; Bader, Peter; Fulda, Simone; Ullrich, Evelyn

    2017-01-01

    Rhabdomyosarcoma (RMS), the most common cancer of connective tissues in pediatrics, is often resistant to conventional therapies. One underlying mechanism of this resistance is the overexpression of Inhibitor of Apoptosis (IAP) proteins, leading to a dysfunctional cell death program within tumor cells. Smac mimetics (SM) are small molecules that can reactivate the cell death program by antagonizing IAP proteins and thereby compensating their overexpression. Here, we report that SM sensitize two RMS cell lines (RD and RH30) toward natural killer (NK) cell-mediated killing on the one hand, and increase the cytotoxic potential of NK cells on the other. The SM-induced sensitization of RH30 cells toward NK cell-mediated killing is significantly reduced through blocking tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) on NK cells prior to coculture. In addition, the presence of zVAD.fmk, a pancaspase inhibitor, rescues tumor cells from the increase in killing, indicating an apoptosis-dependent cell death. On the NK cell side, the presence of SM in addition to IL-2 during the ex vivo expansion leads to an increase in their cytotoxic activity against RH30 cells. This effect is mainly TNFα-dependent and partially mediated by NK cell activation, which is associated with transcriptional upregulation of NF-κB target genes such as IκBα and RelB. Taken together, our findings implicate that SM represent a novel double-hit strategy, sensitizing tumor and activating NK cells with one single drug.

  2. Tumor-Unrelated CD4 T Cell Help Augments CD134 plus CD137 Dual Costimulation Tumor Therapy

    PubMed Central

    Mittal, Payal; St Rose, Marie-Clare; Wang, Xi; Ryan, Joseph M.; Wasser, Jeffrey S.; Vella, Anthony T.; Adler, Adam J.

    2015-01-01

    The ability of immune-based cancer therapies to elicit beneficial CD8+ CTL is limited by tolerance pathways that inactivate tumor-specific CD4 helper T cells. A strategy to bypass this problem is to engage tumor-unrelated CD4 helper T cells. Thus, CD4 T cells, regardless of their specificity per se, can boost CD8+ CTL priming so long as the cognate epitopes are linked via presentation on the same dendritic cell. Here, we assessed the therapeutic impact of engaging tumor-unrelated CD4 T cells during dual costimulation with CD134 plus CD137 that not only provide help via the above-mentioned classical linked pathway, but also provide non-linked help that facilitates CTL function in T cells not directly responding to cognate antigen. We found that engagement of tumor-unrelated CD4 helper T cells dramatically boosted the ability of dual costimulation to control the growth of established B16 melanomas. Surprisingly, this effect depended upon a CD134-dependent component that was extrinsic to the tumor-unrelated CD4 T cells, suggesting that the dual-costimulated helper cells are themselves helped by a CD134+ cell(s). Nevertheless, the delivery of therapeutic help tracked with an increased frequency of tumor-infiltrating granzyme B+ effector CD8 T cells and a reciprocal decrease in Foxp3+CD4+ cell frequency. Notably, the tumor-unrelated CD4 helper T cells also infiltrated the tumors, and their deletion several days following initial T cell priming negated their therapeutic impact. Taken together, dual costimulation programs tumor-unrelated CD4 T cells to deliver therapeutic help during both the priming and effector stages of the anti-tumor response. PMID:26561553

  3. Defects in the Acquisition of Tumor-Killing Capability of CD8+ Cytotoxic T Cells in Streptozotocin-Induced Diabetic Mice

    PubMed Central

    Chen, Shu-Ching; Su, Yu-Chia; Lu, Ya-Ting; Ko, Patrick Chow-In; Chang, Pei-Yu; Lin, Hung-Ju; Ho, Hong-Nerng; Lai, Yo-Ping

    2014-01-01

    Emerging evidences have shown that diabetes mellitus not only raises risk but also heightens mortality rate of cancer. It is not clear, however, whether antitumor CD8+ cytotoxic T lymphocyte (CTL) response is down-modulated in diabetic hosts. We investigated the impact of hyperglycemia on CTLs' acquisition of tumor-killing capability by utilizing streptozotocin-induced diabetic (STZ-diabetic) mice. Murine diabetes was induced by intraperitoneal injection of STZ (200 mg/kg) in C57BL/6 mice, 2C-T cell receptor (TCR) transgenic and P14-TCR transgenic mice. The study found that, despite harboring intact proliferative capacity measured with CFSE labeling and MTT assay, STZ-diabetic CD8+ CTLs displayed impaired effector functions. After stimulation, STZ-diabetic CD8+ CTLs produced less perforin and TNFα assessed by intracellular staining, as well as expressed less CD103 protein. Furthermore, adoptive transfer of STZ-diabetic P14 CD8+ effector cells showed an insufficient recruitment to the B16.gp33 melanoma and inadequate production of perforin, granzyme B and TNFα determined by immunohistochemistry in the tumor milieu. As a result, STZ-diabetic CD8+ effector cells were neither able to eliminate tumor nor to improve survival of tumor-bearing mice. Taken together, our data suggest that CD8+ CTLs are crippled to infiltrate into tumors and thus fail to acquire tumor-killing capability in STZ-diabetic hosts. PMID:25390652

  4. Combining Heavy Ion Radiation and Artificial MicroRNAs to Target the Homologous Recombination Repair Gene Efficiently Kills Human Tumor Cells

    SciTech Connect

    Zheng Zhiming; Wang Ping; Wang Hongyan; Zhang Xiangming; Wang Minli; Cucinotta, Francis A.; Wang Ya

    2013-02-01

    Purpose: Previously, we demonstrated that heavy ions kill more cells at the same dose than X-rays because DNA-clustered lesions produced by heavy ions affect nonhomologous end-joining (NHEJ) repair but not homologous recombination repair (HRR). We have also shown that our designed artificial microRNAs (amiRs) could efficiently target XRCC4 (an essential factor for NHEJ) or XRCC2 (an essential factor for HRR) and sensitize human tumor cells to X-rays. Based on these data, we were interested in testing the hypothesis that combining heavy ions and amiRs to target HRR but not NHEJ should more efficiently kill human tumor cells. Methods and Materials: Human tumor cell lines (U87MG, a brain tumor cell line, and A549, a lung cancer cell line) and their counterparts, overexpressed with amiR to target XRCC2, XRCC4 or both, were used in this study. Survival sensitivities were examined using a clonogenic assay after these cells were exposed to X-rays or heavy ions. In addition, these cell lines were subcutaneously injected into nude mice to form xenografts and the tumor size was compared after the tumor areas were exposed to X-rays or heavy ions. Results: Although targeting either XRCC4 (NHEJ factor) or XRCC2 (HRR factor) sensitized the human tumor cells to X-rays, in vitro and the xenograft animal model, targeting only XRCC2 but not XRCC4 sensitized the human tumor cells to heavy ions in vitro and in the xenograft animal model. Conclusions: Combining heavy ions with targeting the HRR pathway, but not the NHEJ pathway, could significantly improve the efficiency of tumor cell death.

  5. Local tumor irradiation augments the response to IL-2 therapy in a murine renal adenocarcinoma.

    PubMed

    Younes, E; Haas, G P; Dezso, B; Ali, E; Maughan, R L; Kukuruga, M A; Montecillo, E; Pontes, J E; Hillman, G G

    1995-10-15

    We have previously demonstrated that local tumor irradiation effectively enhanced the therapeutic effect of IL-2 therapy on pulmonary metastases from a murine renal adenocarcinoma, Renca. Irradiation with 300 rad to the left lung only, followed by systemic IL-2 therapy, results in increased tumor reduction in both lungs, suggesting that radiation enhances the systemic effect of immunotherapy. In this study, we show that irradiation of the tumor-bearing organ is essential for the combined effect of both modalities. This effect is radiation dose-dependent as increases in the radiation dosage result in greater tumor reduction in the irradiated field as well as systemically in nonirradiated fields when combined with immunotherapy. We find that irradiation has a direct inhibitory effect on Renca cell growth in vitro. Irradiation of Renca cells also causes an upregulation in H-2Kd class I MHC antigen detectable at 300 rad and more pronounced with 800 rad. By in vivo selective depletion of lymphocyte subsets, we demonstrate the involvement of Lyt-2+ and L3T4+ T cell subsets and AsGM1+ cells, including NK cells, in the antitumor effect mediated by tumor irradiation and IL-2 therapy. Immunohistochemistry studies, performed on lung sections, showed a significant infiltration of CD3+ T cells and macrophages in the tumor nodules following treatment with tumor irradiation and IL-2 therapy. Our studies indicate that the mechanism of interaction between tumor irradiation and immunotherapy may include radiation-induced alterations in the tumor growth and antigenicity which may enhance or trigger an anti-tumor response elicited by IL-2 and mediated by T cells, AsGM1+ cells, and macrophages.

  6. Evidence for induction of humoral and cytotoxic immune responses against devil facial tumor disease cells in Tasmanian devils (Sarcophilus harrisii) immunized with killed cell preparations.

    PubMed

    Kreiss, A; Brown, G K; Tovar, C; Lyons, A B; Woods, G M

    2015-06-12

    Tasmanian devils (Sarcophilus harrisii) risk extinction from a contagious cancer, devil facial tumour disease (DFTD) in which the infectious agent is the tumor cell itself. Because devils are unable to produce an immune response against the tumor cells no devil has survived 'infection'. To promote an immune response we immunized healthy devils with killed DFTD tumor cells in the presence of adjuvants. Immune responses, including cytotoxicity and antibody production, were detected in five of the six devils. The incorporation of adjuvants that act via toll like receptors may provide additional signals to break 'immunological ignorance'. One of these devils was protected against a challenge with viable DFTD cells. This was a short-term protection as re-challenge one year later resulted in tumor growth. These results suggest that Tasmanian devils can generate immune responses against DFTD cells. With further optimization of immune stimulation it should be possible to protect Tasmanian devils against DFTD with an injectable vaccine.

  7. The Smac Mimetic BV6 Improves NK Cell-Mediated Killing of Rhabdomyosarcoma Cells by Simultaneously Targeting Tumor and Effector Cells

    PubMed Central

    Fischer, Kyra; Tognarelli, Sara; Roesler, Stefanie; Boedicker, Cathinka; Schubert, Ralf; Steinle, Alexander; Klingebiel, Thomas; Bader, Peter; Fulda, Simone; Ullrich, Evelyn

    2017-01-01

    Rhabdomyosarcoma (RMS), the most common cancer of connective tissues in pediatrics, is often resistant to conventional therapies. One underlying mechanism of this resistance is the overexpression of Inhibitor of Apoptosis (IAP) proteins, leading to a dysfunctional cell death program within tumor cells. Smac mimetics (SM) are small molecules that can reactivate the cell death program by antagonizing IAP proteins and thereby compensating their overexpression. Here, we report that SM sensitize two RMS cell lines (RD and RH30) toward natural killer (NK) cell-mediated killing on the one hand, and increase the cytotoxic potential of NK cells on the other. The SM-induced sensitization of RH30 cells toward NK cell-mediated killing is significantly reduced through blocking tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) on NK cells prior to coculture. In addition, the presence of zVAD.fmk, a pancaspase inhibitor, rescues tumor cells from the increase in killing, indicating an apoptosis-dependent cell death. On the NK cell side, the presence of SM in addition to IL-2 during the ex vivo expansion leads to an increase in their cytotoxic activity against RH30 cells. This effect is mainly TNFα-dependent and partially mediated by NK cell activation, which is associated with transcriptional upregulation of NF-κB target genes such as IκBα and RelB. Taken together, our findings implicate that SM represent a novel double-hit strategy, sensitizing tumor and activating NK cells with one single drug. PMID:28326081

  8. Phenothiazine Inhibitors of TLKs Affect Double-Strand Break Repair and DNA Damage Response Recovery and Potentiate Tumor Killing with Radiomimetic Therapy.

    PubMed

    Ronald, Sharon; Awate, Sanket; Rath, Abhijit; Carroll, Jennifer; Galiano, Floyd; Dwyer, Donard; Kleiner-Hancock, Heather; Mathis, J Michael; Vigod, Simone; De Benedetti, Arrigo

    2013-01-01

    The Tousled-like kinases (TLKs) are involved in chromatin assembly, DNA repair, and transcription. Two TLK genes exist in humans, and their expression is often dysregulated in cancer. TLKs phosphorylate Asf1 and Rad9, regulating double-strand break (DSB) repair and the DNA damage response (DDR). TLKs maintain genomic stability and are important therapeutic intervention targets. We identified specific inhibitors of TLKs from several compound libraries, some of which belong to the family of phenothiazine antipsychotics. The inhibitors prevented the TLK-mediated phosphorylation of Rad9(S328) and impaired checkpoint recovery and DSB repair. The inhibitor thioridazine (THD) potentiated tumor killing with chemotherapy and also had activity alone. Staining for γ-H2AX revealed few positive cells in untreated tumors, but large numbers in mice treated with low doxorubicin or THD alone, possibly the result of the accumulation of DSBs that are not promptly repaired as they may occur in the harsh tumor growth environment.

  9. Augmented lymphocyte expansion from solid tumors with engineered cells for costimulatory enhancement

    PubMed Central

    Friedman, Kevin M; DeVillier, Laura E; Feldman, Steven A; Rosenberg, Steven A; Dudley, Mark E

    2011-01-01

    Treatment of patients with adoptive T cell therapy requires expansion of unique tumor-infiltrating lymphocyte (TIL) cultures from single cell suspensions processed from melanoma biopsies. Strategies which increase the expansion and reliability of TIL generation from tumor digests are necessary to improve access to TIL therapy. Prior work evaluated artificial antigen presenting cells (aAPCs) for their antigen-specific and costimulatory properties. We investigated engineered cells for co-stimulatory enhancement (ECCE) consisting of K562 cells which express 4-1BBL in the absence of artificial antigen stimulation. ECCE accelerated TIL expansion and significantly improved TIL numbers (p=0.001) from single cell melanoma suspensions. TIL generated with ECCE contain significantly more CD8+CD62L+ and CD8+CD27+ T cells then comparable IL-2-expanded TIL and maintained anti-tumor reactivity. Moreover, ECCE improved TIL expansion from non-melanoma cell suspensions similar to that seen with melanoma tumors. These data demonstrate that ECCE addition to TIL production will enable treatment of patients ineligible using current methods. PMID:21989413

  10. Lapatinib and Obatoclax Kill Tumor Cells through Blockade of ERBB1/3/4 and through Inhibition of BCL-xL and MCL-1

    PubMed Central

    Cruickshanks, Nichola; Hamed, Hossein A.; Bareford, M. Danielle; Poklepovic, Andrew; Fisher, Paul B.; Grant, Steven

    2012-01-01

    Prior studies in breast cancer cells have shown that lapatinib and obatoclax interact in a greater than additive fashion to cause cell death and do so through a toxic form of autophagy. The present studies sought to extend our analyses to the central nervous system (CNS) tumor cells and to further define mechanisms of drug action. Lapatinib and obatoclax killed multiple CNS tumor isolates. Cells lacking PTEN (phosphatase and tensin homolog on chromosome 10) function were relatively resistant to drug combination lethality; expression of PTEN in PTEN-null cells restored drug sensitivity, and knockdown of PTEN promoted drug resistance. On the basis of knockdown of ERBB1-4 (erythroblastic leukemia viral oncogene homolog 1–4), we discovered that the inhibition of ERBB1/3/4 receptors were most important for enhancing obatoclax lethality rather than ERBB2. In parallel, we noted in CNS tumor cells that knockdown of BCL-xL (B-cell lymphoma-extra large)and MCL-1 (myeloid cell leukemia-1) interacted in an additive fashion to facilitate lapatinib lethality. Pretreatment of tumor cells with obatoclax enhanced the lethality of lapatinib to a greater extent than concomitant treatment. Treatment of animals carrying orthotopic CNS tumor isolates with lapatinib- and obatoclax-prolonged survival. Altogether, our data show that lapatinib and obatoclax therapy could be of use in the treatment of tumors located in the CNS. PMID:22357666

  11. Augmented lymphocyte expansion from solid tumors with engineered cells for costimulatory enhancement.

    PubMed

    Friedman, Kevin M; Devillier, Laura E; Feldman, Steven A; Rosenberg, Steven A; Dudley, Mark E

    2011-01-01

    Treatment of patients with adoptive T-cell therapy requires expansion of unique tumor-infiltrating lymphocyte (TIL) cultures from single-cell suspensions processed from melanoma biopsies. Strategies which increase the expansion and reliability of TIL generation from tumor digests are necessary to improve access to TIL therapy. Previous studies have evaluated artificial antigen presenting cells for their antigen-specific and costimulatory properties. We investigated engineered cells for costimulatory enhancement (ECCE) consisting of K562 cells that express 4-1BBL in the absence of artificial antigen stimulation. ECCE accelerated TIL expansion and significantly improved TIL numbers (P=0.001) from single-cell melanoma suspensions. TIL generated with ECCE contain significantly more CD8CD62L and CD8CD27 T cells then comparable interleukin-2-expanded TIL and maintained antitumor reactivity. Moreover, ECCE improved TIL expansion from nonmelanoma-cell suspensions similar to that seen with melanoma tumors. These data demonstrate that the addition of ECCE to TIL production will enable the treatment of patients that are ineligible using current methods.

  12. Proline biosynthesis augments tumor cell growth and aerobic glycolysis: involvement of pyridine nucleotides.

    PubMed

    Liu, Wei; Hancock, Chad N; Fischer, Joseph W; Harman, Meredith; Phang, James M

    2015-11-24

    The metabolism of the nonessential amino acid proline contributes to tumor metabolic reprogramming. Previously we showed that MYC increases proline biosynthesis (PB) from glutamine. Here we show MYC increases the expression of the enzymes in PB at both protein and mRNA levels. Blockade of PB decreases tumor cell growth and energy production. Addition of Δ(1)-pyrroline-5-carboxylate (P5C) or proline reverses the effects of P5C synthase knockdown but not P5C reductases knockdown. Importantly, the reversal effect of proline was blocked by concomitant proline dehydrogenase/oxidase (PRODH/POX) knockdown. These findings suggest that the important regulatory contribution of PB to tumor growth derives from metabolic cycling between proline and P5C rather than product proline or intermediate P5C. We further document the critical role of PB in maintaining pyridine nucleotide levels by connecting the proline cycle to glycolysis and to the oxidative arm of the pentose phosphate pathway. These findings establish a novel function of PB in tumorigenesis, linking the reprogramming of glucose, glutamine and pyridine nucleotides, and may provide a novel target for antitumor therapy.

  13. Inhibition of lung tumor growth and augmentation of radiosensitivity by decreasing peroxiredoxin I expression

    SciTech Connect

    Chen, M.-F.; Keng, Peter C.; Shau Hungyi; Wu, C.-T.; Hu, Y.-C.; Liao, S.-K.; Chen, W.-C. . E-mail: miaofen@adm.cgmh.org.tw

    2006-02-01

    Purpose: In this study, we examined the role of peroxiredoxin I (Prx I) in lung cancer cell growth in vitro and in vivo and its influence on these tumor cells' sensitivity to radiotherapy. Methods and materials: We established stable transfectants of A549 (p53+) and H1299 (p53-) lung carcinoma cell lines with Prx I antisense to downregulate their Prx I protein. We then examined their in vitro biologic changes and used nude mice xenografts of these cell lines to compare tumor invasion, spontaneous metastatic capacity, and sensitivity to radiotherapy. Results: The Prx I antisense transfectants of both cell lines showed a significant reduction in Prx I protein production. Prx I antisense transfectants grew more slowly than did the wild type. As xenografts in mice, A549 Prx I antisense transfectants showed a threefold delay in the generation of palpable tumors. The incidence of spontaneous metastasis of Prx I antisense transfectants was significantly less than that of the wild-type cells. Furthermore, irradiation of Prx I antisense transfectants caused more than twice the growth delay compared with the wild type. Conclusion: The results of these studies suggest that inactivation of Prx I may be a promising approach to improve the treatment outcome of patients with lung cancer.

  14. Myeloid-specific deletion of tumor suppressor PTEN augments neutrophil transendothelial migration during inflammation.

    PubMed

    Sarraj, Bara; Massberg, Steffen; Li, Yitang; Kasorn, Anongnard; Subramanian, Kulandayan; Loison, Fabien; Silberstein, Leslie E; von Andrian, Ulrich; Luo, Hongbo R

    2009-06-01

    Phosphatidylinositol 3,4,5-trisphosphate (PIP(3)) is a second messenger that is involved in a number of cell activities including cell growth, proliferation, and motility. PIP(3) is produced by PI3K and regulated by PTEN (phosphatase and tensin homolog deleted on chromosome 10) and SHIP lipid phosphatases. Evidence from our experiments shows that enhanced PIP(3) production results in elevated neutrophil recruitment under inflammatory conditions. However, the mechanism of this elevation is not well understood. We used intravital video microscopy to investigate neutrophil recruitment in the cremaster venules of wild-type and PTEN knockout (KO) mice. Neutrophil transmigration was augmented in PTEN KO mice 4 h after TNF-alpha intrascrotal injection. PTEN KO neutrophils also showed significantly enhanced transmigration 2 h after MIP-2 intrascrotal injection, an effect that dramatically decreased when PI3K or Src kinase inhibitor treatments preceded MIP-2 stimulation. Similarly, fMLP superfusion of the cremaster muscle lead to enhanced emigration in PTEN KO mice. The observed elevation in neutrophil emigration was likely caused by increased speed of crawling, crossing the venular wall, and migrating through the muscular tissue in PTEN KO mice because the effect of PTEN depletion on neutrophil rolling or adhesion was minimal. Interestingly, chemoattractant-induced release of gelatinase and elastase was also elevated in PTEN null neutrophils, providing a potential mechanism for the enhanced neutrophil migration in the PTEN KO mice. Collectively, these results demonstrate that PTEN deletion in neutrophils enhances their invasivity and recruitment to inflamed sites more likely by raising the cell physical capability to cross the vascular and tissue barriers.

  15. Resveratrol synergistically augments anti-tumor effect of 5-FU in vitro and in vivo by increasing S-phase arrest and tumor apoptosis

    PubMed Central

    Dun, Jiening; Chen, Xueyan; Gao, Haixia; Zhang, Yan; Zhang, Huajun

    2015-01-01

    Many studies have shown that natural dietary agents, in combination with chemical agents, can improve the therapeutic response of cancers to chemotherapy and reduce the associated side-effects. In the present study, we investigated the therapeutic potential and mechanisms of anticancer effects for the combination of 5-fluorouracil (5-FU) and resveratrol (Res). In these studies, we employed the cancer cell lines TE-1 and A431 and an animal model of skin cancer. The presented results provide the first evidence that Res can enhance the anti-tumor potency of 5-FU by inducing S-phase arrest. The combination of Res and 5-FU demonstrates synergistic efficacy, causing tumor regression in a two-stage model of mouse skin carcinogenesis induced by DMBA and TPA. There was clear evidence of Res augmenting the growth inhibitory effect of 5-FU on the TE-1 and A431 cancer cells in vitro. In the in vivo studies, the tumor regression rate in the combination group increased significantly after four weeks of treatment (P < 0.01). The combination of 5-FU and Res significantly increased the percentage of apoptotic cells and the level of activated caspase-3, cleaved PARP and p53 proteins as well as increased the Bax/Bcl-2 ratio. In conclusion, the 5-FU/Res combination enabled a more effective inhibition of cell growth and the induction of apoptosis in cancer cells than 5-FU alone. The results of this study suggest that chemotherapy using natural dietary agents with chemical agents represents a superior cancer treatment option. PMID:25736303

  16. Resveratrol synergistically augments anti-tumor effect of 5-FU in vitro and in vivo by increasing S-phase arrest and tumor apoptosis.

    PubMed

    Dun, Jiening; Chen, Xueyan; Gao, Haixia; Zhang, Yan; Zhang, Huajun; Zhang, Yongjian

    2015-12-01

    Many studies have shown that natural dietary agents, in combination with chemical agents, can improve the therapeutic response of cancers to chemotherapy and reduce the associated side-effects. In the present study, we investigated the therapeutic potential and mechanisms of anticancer effects for the combination of 5-fluorouracil (5-FU) and resveratrol (Res). In these studies, we employed the cancer cell lines TE-1 and A431 and an animal model of skin cancer. The presented results provide the first evidence that Res can enhance the anti-tumor potency of 5-FU by inducing S-phase arrest. The combination of Res and 5-FU demonstrates synergistic efficacy, causing tumor regression in a two-stage model of mouse skin carcinogenesis induced by DMBA and TPA. There was clear evidence of Res augmenting the growth inhibitory effect of 5-FU on the TE-1 and A431 cancer cells in vitro. In the in vivo studies, the tumor regression rate in the combination group increased significantly after four weeks of treatment (P < 0.01). The combination of 5-FU and Res significantly increased the percentage of apoptotic cells and the level of activated caspase-3, cleaved PARP and p53 proteins as well as increased the Bax/Bcl-2 ratio. In conclusion, the 5-FU/Res combination enabled a more effective inhibition of cell growth and the induction of apoptosis in cancer cells than 5-FU alone. The results of this study suggest that chemotherapy using natural dietary agents with chemical agents represents a superior cancer treatment option.

  17. A novel, native-format bispecific antibody triggering T-cell killing of B-cells is robustly active in mouse tumor models and cynomolgus monkeys

    PubMed Central

    Smith, Eric J.; Olson, Kara; Haber, Lauric J.; Varghese, Bindu; Duramad, Paurene; Tustian, Andrew D.; Oyejide, Adelekan; Kirshner, Jessica R.; Canova, Lauren; Menon, Jayanthi; Principio, Jennifer; MacDonald, Douglas; Kantrowitz, Joel; Papadopoulos, Nicholas; Stahl, Neil; Yancopoulos, George D.; Thurston, Gavin; Davis, Samuel

    2015-01-01

    Bispecific antibodies, while showing great therapeutic potential, pose formidable challenges with respect to their assembly, stability, immunogenicity, and pharmacodynamics. Here we describe a novel class of bispecific antibodies with native human immunoglobulin format. The design exploits differences in the affinities of the immunoglobulin isotypes for Protein A, allowing efficient large-scale purification. Using this format, we generated a bispecific antibody, REGN1979, targeting the B cell marker, CD20, and the CD3 component of the T cell receptor, which triggers redirected killing of B cells. In mice, this antibody prevented growth of B cell tumors and also caused regression of large established tumors. In cynomolgus monkeys, low doses of REGN1979 caused prolonged depletion of B cells in peripheral blood with a serum half-life of approximately 14 days. Further, the antibody induced a deeper depletion of B cells in lymphoid organs than rituximab. This format has broad applicability for development of clinical bispecific antibodies. PMID:26659273

  18. Recombinant human tumor necrosis factor alpha does not potentiate cell killing after photodynamic therapy with a silicon phthalocyanine in A431 human epidermoid carcinoma cells.

    PubMed

    Azizuddin, K; Kalka, K; Chiu, S M; Ahmad, N; Mukhtar, H; Separovic, D

    2001-02-01

    Photodynamic therapy (PDT) is a novel cancer treatment utilizing a photosensitizer, visible light and oxygen. PDT with the silicon phthalocyanine Pc 4, a new photosensitizer, is highly effective in cancer cell destruction and tumor ablation. The mechanisms underlying cancer cell killing by PDT are not fully understood. Tumor necrosis factor alpha (TNF) is a multifunctional cytokine that has been implicated in photocytotoxicity. We asked whether recombinant human TNF (rhTNF) affects Pc 4-PDT cytotoxicity in A431 human epidermoid carcinoma cells. Co-treatment of A431 cells with various doses of Pc 4-PDT and a sub-lethal rhTNF dose led to a sub-additive reduction in cell survival. In addition, in the presence of Pc 4-PDT or rhTNF, caspase-3 activity and apoptosis were induced. The combined treatment, however, did not potentiate either caspase-3 activity or apoptosis. Similar to previous findings we observed that Pc 4-PDT initiated a time-dependent extracellular TNF accumulation. The data suggest that: a) PDT and rhTNF induce cancer cell killing through different mechanisms; and b) Pc 4-PDT-induced TNF production is a stress response that may not directly affect photocytotoxicity.

  19. Multi-drug analyses in patients distinguish efficacious cancer agents based on both tumor cell killing and immunomodulation.

    PubMed

    Frazier, Jason; Bertout, Jessica A; Kerwin, William S; Moreno-Gonzalez, Alicia; Casalini, Joey R; Grenley, Marc O; Beirne, Emily; Watts, Kori L; Keener, Andy; Thirstrup, Derek J; Tretyak, Ilona; Ditzler, Sally; Tripp, Chelsea D; Choy, Kevin; Gillings, Sarah; Breit, Megan N; Meleo, Karri A; Rizzo, Vanessa; Herrera, Chamisa L; Perry, James A; Amaravadi, Ravi K; Olson, James M; Klinghoffer, Richard

    2017-03-31

    The vision of a precision medicine-guided approach to novel cancer drug development is challenged by high intra-tumor heterogeneity and interpatient diversity. This complexity is rarely modeled accurately during preclinical drug development, hampering predictions of clinical drug efficacy. To address this issue, we developed CIVO (Comparative In Vivo Oncology) arrayed microinjection technology to test tumor responsiveness to simultaneous microdoses of multiple drugs directly in a patient's tumor. Here, in a study of 18 canine patients with soft tissue sarcoma (STS), CIVO captured complex, patient-specific tumor responses encompassing both cancer cells and multiple immune infiltrates following localized exposure to different chemotherapy agents. CIVO also classified patient-specific tumor resistance to the most effective agent, doxorubicin, and further enabled assessment of a preclinical autophagy inhibitor, PS-1001, to reverse doxorubicin resistance. In a CIVO-identified subset of doxorubicin-resistant tumors, PS-1001 resulted in enhanced anti-tumor activity, increased infiltration of macrophages, and skewed this infiltrate toward M1 polarization. The ability to evaluate and cross-compare multiple drugs and drug combinations simultaneously in living tumors and across a diverse immune-competent patient population may provide a foundation from which to make informed drug development decisions. This method also represents a viable functional approach to complement current precision oncology strategies.

  20. EGFR‐targeted Chimeras of Pseudomonas ToxA released into the extracellular milieu by attenuated Salmonella selectively kill tumor cells

    PubMed Central

    Quintero, David; Carrafa, Jamie; Vincent, Lena

    2016-01-01

    ABSTRACT Tumor‐targeted Salmonella VNP20009 preferentially replicate within tumor tissue and partially suppress tumor growth in murine tumor models. These Salmonella have the ability to locally induce apoptosis when they are in direct contact with cancer cells but they lack significant bystander killing, which may correlate with their overall lack of antitumor activity in human clinical studies. In order to compensate for this deficiency without enhancing overall toxicity, we engineered the bacteria to express epidermal growth factor receptor (EGFR)‐targeted cytotoxic proteins that are released into the extracellular milieu. In this study, we demonstrate the ability of the Salmonella strain VNP20009 to produce three different forms of the Pseudomonas exotoxin A (ToxA) chimeric with a tumor growth factor alpha (TGFα) which results in its producing culture supernatants that are cytotoxic and induce apoptosis in EGFR positive cancer cells as measured by the tetrazolium dye reduction, and Rhodamine 123 and JC‐10 mitochondrial depolarization assays. In addition, exchange of the ToxA REDLK endoplasmic reticulum retention signal for KDEL and co‐expression of the ColE3 lysis protein resulted in an overall increased cytotoxicity compared to the wild type toxin. This approach has the potential to significantly enhance the antitumor activity of VNP20009 while maintaining its previously established safety profile. Biotechnol. Bioeng. 2016;113: 2698–2711. © 2016 The Authors. Biotechnology and Bioengineering published by Wiley Periodicals, Inc. PMID:27260220

  1. Identification and Structural Analysis of an l-Asparaginase Enzyme from Guinea Pig with Putative Tumor Cell Killing Properties*

    PubMed Central

    Schalk, Amanda M.; Nguyen, Hien-Anh; Rigouin, Coraline; Lavie, Arnon

    2014-01-01

    The initial observation that guinea pig serum kills lymphoma cells marks the serendipitous discovery of a new class of anti-cancer agents. The serum cell killing factor was shown to be an enzyme with l-asparaginase (ASNase) activity. As a direct result of this observation, several bacterial l-asparaginases were developed and are currently approved by the Food and Drug Administration for the treatment of the subset of hematological malignancies that are dependent on the extracellular pool of the amino acid asparagine. As drugs, these enzymes act to hydrolyze asparagine to aspartate, thereby starving the cancer cells of this amino acid. Prior to the work presented here, the precise identity of this guinea pig enzyme has not been reported in the peer-reviewed literature. We discovered that the guinea pig enzyme annotated as H0W0T5_CAVPO, which we refer to as gpASNase1, has the required low Km property consistent with that possessed by the cell-killing guinea pig serum enzyme. Elucidation of the ligand-free and aspartate complex gpASNase1 crystal structures allows a direct comparison with the bacterial enzymes and serves to explain the lack of l-glutaminase activity in the guinea pig enzyme. The structures were also used to generate a homology model for the human homolog hASNase1 and to help explain its vastly different kinetic properties compared with gpASNase1, despite a 70% sequence identity. Given that the bacterial enzymes frequently present immunogenic and other toxic side effects, this work suggests that gpASNase1 could be a promising alternative to these bacterial enzymes. PMID:25320094

  2. A Chimeric Switch-Receptor Targeting PD1 Augments the Efficacy of Second-Generation CAR T Cells in Advanced Solid Tumors.

    PubMed

    Liu, Xiaojun; Ranganathan, Raghuveer; Jiang, Shuguang; Fang, Chongyun; Sun, Jing; Kim, Soyeon; Newick, Kheng; Lo, Albert; June, Carl H; Zhao, Yangbing; Moon, Edmund K

    2016-03-15

    Chimeric antigen receptor (CAR)-modified adoptive T-cell therapy has been successfully applied to the treatment of hematologic malignancies, but faces many challenges in solid tumors. One major obstacle is the immune-suppressive effects induced in both naturally occurring and genetically modified tumor-infiltrating lymphocytes (TIL) by inhibitory receptors (IR), namely PD1. We hypothesized that interfering with PD1 signaling would augment CAR T-cell activity against solid tumors. To address this possibility, we introduced a genetically engineered switch receptor construct, comprising the truncated extracellular domain of PD1 and the transmembrane and cytoplasmic signaling domains of CD28, into CAR T cells. We tested the effect of this supplement, "PD1CD28," on human CAR T cells targeting aggressive models of human solid tumors expressing relevant tumor antigens. Treatment of mice bearing large, established solid tumors with PD1CD28 CAR T cells led to significant regression in tumor volume due to enhanced CAR TIL infiltrate, decreased susceptibility to tumor-induced hypofunction, and attenuation of IR expression compared with treatments with CAR T cells alone or PD1 antibodies. Taken together, our findings suggest that the application of PD1CD28 to boost CAR T-cell activity is efficacious against solid tumors via a variety of mechanisms, prompting clinical investigation of this potentially promising treatment modality.

  3. Immune evasion of mantle cell lymphoma: expression of B7-H1 leads to inhibited T-cell response to and killing of tumor cells.

    PubMed

    Wang, Lijuan; Qian, Jianfei; Lu, Yong; Li, Haiyan; Bao, Hanying; He, Donghua; Liu, Zhiqiang; Zheng, Yuhuan; He, Jin; Li, Yi; Neelapu, Sattva; Yang, Jing; Kwak, Larry W; Yi, Qing; Cai, Zhen

    2013-09-01

    Clinical trials of immunotherapy in mantle cell lymphoma have not yet delivered desirable results, partly because of the inhibitory machinery of the tumor and its microenvironment. Here we investigated the role of B7-H1, a member of the B7 family of co-stimulatory/co-inhibitory ligands, in mantle cell lymphoma-mediated immunosuppression. Allogeneic CD3(+), CD4(+) and CD8(+) T cells were purified and co-cultured with irradiated mantle cell lymphoma cells. Mantle cell lymphoma-reactive T-cell lines from HLA-A*0201(+) healthy blood donors were generated after in vitro restimulation, and were subjected to functional tests. We found that B7-H1 expressed on mantle cell lymphoma cells was able to inhibit T-cell proliferation induced by the tumor cells, impair the generation of antigen-specific T-cell responses, and render mantle cell lymphoma cells resistant to T-cell-mediated cytolysis. Blocking or knocking down B7-H1 on mantle cell lymphoma cells enhanced T-cell responses and restored tumor-cell sensitivity to T-cell-mediated killing in vitro and in vivo. Knocking down B7-H1 on mantle cell lymphoma cells primed more CD4(+) or CD8(+) memory effector T cells. Our study demonstrates for the first time that lymphoma cell-expressed B7-H1 may lead to the suppression of host anti-tumor immune responses in mantle cell lymphoma and targeting tumor cell B7-H1 may represent a novel approach to improve the efficacy of immunotherapy in patients with mantle cell lymphoma.

  4. Photo activation of HPPH encapsulated in “Pocket” liposomes triggers multiple drug release and tumor cell killing in mouse breast cancer xenografts

    PubMed Central

    Sine, Jessica; Urban, Cordula; Thayer, Derek; Charron, Heather; Valim, Niksa; Tata, Darrell B; Schiff, Rachel; Blumenthal, Robert; Joshi, Amit; Puri, Anu

    2015-01-01

    We recently reported laser-triggered release of photosensitive compounds from liposomes containing dipalmitoylphosphatidylcholine (DPPC) and 1,2 bis(tricosa-10,12-diynoyl)-sn-glycero-3-phosphocholine (DC8,9PC). We hypothesized that the permeation of photoactivated compounds occurs through domains of enhanced fluidity in the liposome membrane and have thus called them “Pocket” liposomes. In this study we have encapsulated the red light activatable anticancer photodynamic therapy drug 2-(1-Hexyloxyethyl)-2-devinyl pyropheophorbide-a (HPPH) (Ex/Em410/670 nm) together with calcein (Ex/Em490/517 nm) as a marker for drug release in Pocket liposomes. A mole ratio of 7.6:1 lipid:HPPH was found to be optimal, with >80% of HPPH being included in the liposomes. Exposure of liposomes with a cw-diode 660 nm laser (90 mW, 0–5 minutes) resulted in calcein release only when HPPH was included in the liposomes. Further analysis of the quenching ratios of liposome-entrapped calcein in the laser treated samples indicated that the laser-triggered release occurred via the graded mechanism. In vitro studies with MDA-MB-231-LM2 breast cancer cell line showed significant cell killing upon treatment of cell-liposome suspensions with the laser. To assess in vivo efficacy, we implanted MDA-MB-231-LM2 cells containing the luciferase gene along the mammary fat pads on the ribcage of mice. For biodistribution experiments, trace amounts of a near infrared lipid probe DiR (Ex/Em745/840 nm) were included in the liposomes. Liposomes were injected intravenously and laser treatments (90 mW, 0.9 cm diameter, for an exposure duration ranging from 5–8 minutes) were done 4 hours postinjection (only one tumor per mouse was treated, keeping the second flank tumor as control). Calcein release occurred as indicated by an increase in calcein fluorescence from laser treated tumors only. The animals were observed for up to 15 days postinjection and tumor volume and luciferase expression was measured. A

  5. Binocular Goggle Augmented Imaging and Navigation System provides real-time fluorescence image guidance for tumor resection and sentinel lymph node mapping

    PubMed Central

    B. Mondal, Suman; Gao, Shengkui; Zhu, Nan; Sudlow, Gail P.; Liang, Kexian; Som, Avik; Akers, Walter J.; Fields, Ryan C.; Margenthaler, Julie; Liang, Rongguang; Gruev, Viktor; Achilefu, Samuel

    2015-01-01

    The inability to identify microscopic tumors and assess surgical margins in real-time during oncologic surgery leads to incomplete tumor removal, increases the chances of tumor recurrence, and necessitates costly repeat surgery. To overcome these challenges, we have developed a wearable goggle augmented imaging and navigation system (GAINS) that can provide accurate intraoperative visualization of tumors and sentinel lymph nodes in real-time without disrupting normal surgical workflow. GAINS projects both near-infrared fluorescence from tumors and the natural color images of tissue onto a head-mounted display without latency. Aided by tumor-targeted contrast agents, the system detected tumors in subcutaneous and metastatic mouse models with high accuracy (sensitivity = 100%, specificity = 98% ± 5% standard deviation). Human pilot studies in breast cancer and melanoma patients using a near-infrared dye show that the GAINS detected sentinel lymph nodes with 100% sensitivity. Clinical use of the GAINS to guide tumor resection and sentinel lymph node mapping promises to improve surgical outcomes, reduce rates of repeat surgery, and improve the accuracy of cancer staging. PMID:26179014

  6. Binocular Goggle Augmented Imaging and Navigation System provides real-time fluorescence image guidance for tumor resection and sentinel lymph node mapping

    NASA Astrophysics Data System (ADS)

    B. Mondal, Suman; Gao, Shengkui; Zhu, Nan; Sudlow, Gail P.; Liang, Kexian; Som, Avik; Akers, Walter J.; Fields, Ryan C.; Margenthaler, Julie; Liang, Rongguang; Gruev, Viktor; Achilefu, Samuel

    2015-07-01

    The inability to identify microscopic tumors and assess surgical margins in real-time during oncologic surgery leads to incomplete tumor removal, increases the chances of tumor recurrence, and necessitates costly repeat surgery. To overcome these challenges, we have developed a wearable goggle augmented imaging and navigation system (GAINS) that can provide accurate intraoperative visualization of tumors and sentinel lymph nodes in real-time without disrupting normal surgical workflow. GAINS projects both near-infrared fluorescence from tumors and the natural color images of tissue onto a head-mounted display without latency. Aided by tumor-targeted contrast agents, the system detected tumors in subcutaneous and metastatic mouse models with high accuracy (sensitivity = 100%, specificity = 98% ± 5% standard deviation). Human pilot studies in breast cancer and melanoma patients using a near-infrared dye show that the GAINS detected sentinel lymph nodes with 100% sensitivity. Clinical use of the GAINS to guide tumor resection and sentinel lymph node mapping promises to improve surgical outcomes, reduce rates of repeat surgery, and improve the accuracy of cancer staging.

  7. Cbx3/HP1γ deficiency confers enhanced tumor-killing capacity on CD8+ T cells

    PubMed Central

    Sun, Michael; Ha, Ngoc; Pham, Duc-Hung; Frederick, Megan; Sharma, Bandana; Naruse, Chie; Asano, Masahide; Pipkin, Matthew E.; George, Rani E.; Thai, To-Ha

    2017-01-01

    Cbx3/HP1γ is a histone reader whose function in the immune system is not completely understood. Here, we demonstrate that in CD8+ T cells, Cbx3/HP1γ insufficiency leads to chromatin remodeling accompanied by enhanced Prf1, Gzmb and Ifng expression. In tumors obtained from Cbx3/HP1γ-insufficient mice or wild type mice treated with Cbx3/HP1γ-insufficient CD8+ T cells, there is an increase of CD8+ effector T cells expressing the stimulatory receptor Klrk1/NKG2D, a decrease in CD4+ CD25+ FOXP3+ regulatory T cells (Treg cells) as well as CD25+ CD4+ T cells expressing the inhibitory receptor CTLA4. Together these changes in the tumor immune environment may have mitigated tumor burden in Cbx3/HP1γ-insufficient mice or wild type mice treated with Cbx3/HP1γ-insufficient CD8+ T cells. These findings suggest that targeting Cbx3/HP1γ can represent a rational therapeutic approach to control growth of solid tumors. PMID:28220815

  8. Targeted Killings

    DTIC Science & Technology

    2013-03-01

    American territory in history. Two aircraft torpedoed into the Twin Towers in New York City at speeds of over 490mph killing 2,595 people . Shortly...bomb exploded in the World Trade Center in New York City, killing a half-dozen people and wounding over a thousand. Over the next three years Al...executed his most incredible attack killing close to 3,000 people . President Bush announced to the world that, “U.S. troops will hunt down terrorists and

  9. Polo-like kinase 1 inhibition kills glioblastoma multiforme brain tumor cells in part through loss of SOX2 and delays tumor progression in mice.

    PubMed

    Lee, Cathy; Fotovati, Abbas; Triscott, Joanna; Chen, James; Venugopal, Chitra; Singhal, Ash; Dunham, Christopher; Kerr, John M; Verreault, Maite; Yip, Stephen; Wakimoto, Hiroaki; Jones, Chris; Jayanthan, Aarthi; Narendran, Aru; Singh, Sheila K; Dunn, Sandra E

    2012-06-01

    Glioblastoma multiforme (GBM) ranks among the deadliest types of cancer and given these new therapies are urgently needed. To identify molecular targets, we queried a microarray profiling 467 human GBMs and discovered that polo-like kinase 1 (PLK1) was highly expressed in these tumors and that it clustered with the proliferative subtype. Patients with PLK1-high tumors were more likely to die from their disease suggesting that current therapies are inactive against such tumors. This prompted us to examine its expression in brain tumor initiating cells (BTICs) given their association with treatment failure. BTICs isolated from patients expressed 110-470 times more PLK1 than normal human astrocytes. Moreover, BTICs rely on PLK1 for survival because the PLK1 inhibitor BI2536 inhibited their growth in tumorsphere cultures. PLK1 inhibition suppressed growth, caused G(2) /M arrest, induced apoptosis, and reduced the expression of SOX2, a marker of neural stem cells, in SF188 cells. Consistent with SOX2 inhibition, the loss of PLK1 activity caused the cells to differentiate based on elevated levels of glial fibrillary acidic protein and changes in cellular morphology. We then knocked glial fibrillary acidic protein (GFAP) down SOX2 with siRNA and showed that it too inhibited cell growth and induced cell death. Likewise, in U251 cells, PLK1 inhibition suppressed cell growth, downregulated SOX2, and induced cell death. Furthermore, BI2536 delayed tumor growth of U251 cells in an orthotopic brain tumor model, demonstrating that the drug is active against GBM. In conclusion, PLK1 level is elevated in GBM and its inhibition restricts the growth of brain cancer cells.

  10. Lipophilic triphenylphosphonium derivatives enhance radiation-induced cell killing via inhibition of mitochondrial energy metabolism in tumor cells.

    PubMed

    Yasui, Hironobu; Yamamoto, Kumiko; Suzuki, Motofumi; Sakai, Yuri; Bo, Tomoki; Nagane, Masaki; Nishimura, Eri; Yamamori, Tohru; Yamasaki, Toshihide; Yamada, Ken-Ichi; Inanami, Osamu

    2017-04-01

    It has recently been reported that radiation enhances mitochondrial energy metabolism in various tumor cell lines. To examine how this radiation-induced alteration in mitochondrial function influences tumor cell viability, various lipophilic triphenylphosphonium (TPP(+)) cation derivatives and related compounds such as 4-hydroxy-2,2,6,6-tetramethyl-1-oxy-piperidin (Tempol) with TPP(+) (named "Mito-") were designed to inhibit the mitochondrial electron transport chain. Mito-(CH2)10-Tempol (M10T) and its derivatives, Mito-(CH2)5-Tempol (M5T), Mito-(CH2)10-Tempol-Methyl (M10T-Me), Mito-C10H21 (M10), and C10H21-Tempol (10T), were prepared. In HeLa human cervical adenocarcinoma cells and A549 human lung carcinoma cells, the fractional uptake of the compound into mitochondria was highest among the TTP(+) analogs conjugated with Tempol (M10T, M5T, and 10T). M10T, M10T-Me, and M10 exhibited strong cytotoxicity and enhanced X-irradiation-induced reproductive cell death, while 10T and M5T did not. Furthermore, M10T, M10T-Me, and M10 decreased basal mitochondrial membrane potential and intracellular ATP. M10T treatment inhibited X-ray-induced increases in ATP production. These results indicate that the TPP cation and a long hydrocarbon linker are essential for radiosensitization of tumor cells. The reduction in intracellular ATP by lipophilic TPP(+) is partly responsible for the observed radiosensitization.

  11. Preparation of Conjugated Polymer Grafted with H2O2-Sensitive Prodrug for Cell Imaging and Tumor Cell Killing.

    PubMed

    Li, Meng; Li, Shengliang; Chen, Hui; Hu, Rong; Liu, Libing; Lv, Fengting; Wang, Shu

    2016-01-13

    In this work, a new conjugated polymer poly(fluorene-co-phenylene) derivative containing pendent quaternized chlormethine (PFP-Chl) was synthesized by covalent linking small molecular prodrug groups onto conjugated polymer side chains. H2O2-sensitive prodrug with an eight-member-cyclic boronate ester structure could suffer from H2O2-triggered nitrogen mustard release and further DNA cross-linking and alkylation. PFP-Chl combines therapeutic characteristic with excellent optical property of conjugated polymers. It is found that PFP-Chl could enter into cells by endocytosis to simultaneously exhibit abilities of fluorescent imaging and tumor cell inhibition.

  12. Augmented Oxygen-Dependent Killing of Leishmania.

    DTIC Science & Technology

    1992-06-30

    amphotericin B. Evidence for radical formation in the process of autooxidation. J Antibiot 1985; 38:753-757. 5. New RRC, Chance ML, Heath S. Antileishmanial...activity of amphotericin and other antifungal agents entrapped in liposomes . J Antimicrobial Chemother 1981; 8:371-381. 6. lkxmaih j, Wy±t: -. - r...rress, New iork, 19ab. 15 13. Urbina JA, Cohen BE, Perozo E, Cornivelli E. Spin-labeled amphotericin B: synthesis, characterization, biological and

  13. Selective photothermal laser-tissue interaction with augmentation of immunoadjuvants in treatment of DMBA-4 metastatic mammary tumors in rats

    NASA Astrophysics Data System (ADS)

    Chen, Wei R.; Liu, Hong; Wolf, Roman F.; Lucroy, Michael D.; Nordquist, Robert E.

    2002-09-01

    Induced anti-tumor immunity can be the most effective and long-term cure for cancers, particularly for metastatic tumors. Laser immunotherapy has been developed to induce such immunological responses in rats bearing DMBA-4 metastatic mammary tumors. It involves an intratumoral administration of a laser-absorbing dye (indocyanine green) and a specially formulated immunoadjuvant (glycated chitosan), followed by an irradiation of a near-infrared laser (805-nm diode laser). To understand the immunity induced in this tumor model, immunization using freeze-thaw cell lysates against the DMBA-4 tumors was performed, followed by the tumor challenge twenty-one days later. Also performed is the surgical removal of the primary tumors of the rats before the observation of metastatic tumors. The immunization only delayed the emergence of the primary and metastases in the rats but did not provide immunity against the tumor challenge. After surgical removal of the primary tumors, the tumors re-emerged at the primary sites and the metastases developed at multiple remote sites. In contrast, laser immunotherapy cured rats experienced tumor regression and eradication. Our research has provided strong support for the working mechanism of laser immunotherapy. The experimental results showed that selective photothermal laser-tissue interaction with a complementary use of immunoadjuvant could be a potential therapy for treatment of metastatic tumors by inducing a tumor-specific, long-lasting immunity.

  14. Killing Range

    PubMed Central

    Asal, Victor; Rethemeyer, R. Karl; Horgan, John

    2015-01-01

    This paper presents an analysis of the Provisional Irish Republican Army's (PIRA) brigade level behavior during the Northern Ireland Conflict (1970-1998) and identifies the organizational factors that impact a brigade's lethality as measured via terrorist attacks. Key independent variables include levels of technical expertise, cadre age, counter-terrorism policies experienced, brigade size, and IED components and delivery methods. We find that technical expertise within a brigade allows for careful IED usage, which significantly minimizes civilian casualties (a specific strategic goal of PIRA) while increasing the ability to kill more high value targets with IEDs. Lethal counter-terrorism events also significantly affect a brigade's likelihood of killing both civilians and high-value targets but in different ways. Killing PIRA members significantly decreases IED fatalities but also significantly decreases the possibility of zero civilian IED-related deaths in a given year. Killing innocent Catholics in a Brigade's county significantly increases total and civilian IED fatalities. Together the results suggest the necessity to analyze dynamic situational variables that impact terrorist group behavior at the sub-unit level. PMID:25838603

  15. Synergistic Tumor-Killing Effect of Radiation and Berberine Combined Treatment in Lung Cancer: The Contribution of Autophagic Cell Death

    SciTech Connect

    Peng Peiling; Kuo, W.-H.; Tseng, H.-C.; Chou, F.-P.

    2008-02-01

    Purpose: Radiotherapy is the most efficacious strategies for lung cancer. The radiation-enhancing effects and the underlying mechanisms of berberine were investigated both in vitro and in vivo. Methods and Materials: Clonogenic survival assays were used to evaluate the radio-sensitivity of berberine on non-small-cell lung cancer. Electron microscopic observation of the features of cell death, flow cytometry of acidic vascular organelles formation, mitochondria membrane potential and cell-cycle progression, and Western blotting of caspase 3, PARP, and LC3 were performed to identify the mechanisms underlying the enhancing effects. Lewis lung carcinoma model in mice was conducted to evaluate the possible application of berberine in synergistic treatment with irradiation. Results: Compared with radiation alone (SF2 = 0.423; D{sub 0} = 5.29 Gy), berberine at 5 and 10 {mu}M concentrations in combination with radiation showed significant enhancement on radiation-induced clonogenic inhibition (SF2 = 0.215: D{sub 0} = 2.70 Gy and SF2 = 0.099: D{sub 0} = 1.24 Gy) on A549 cells. The cellular ultrastructure showed the presence of autophagosome and an increased proportion of acridine orange stain-positive cells, demonstrating that berberine enhanced radiosensitivity via autophagy. The process involved LC3 modification and mitochondrial disruption. The animal model verified the synergistic cytotoxic effect of berberine and irradiation resulting in a substantial shrinkage of tumor volume. Conclusion: Supplement of berberine enhanced the cytotoxicity of radiation in both in vivo and in vitro models of lung cancer. The mechanisms underlying this synergistic effect involved the induction of autophagy. It suggests that berberine could be used as adjuvant therapy to treat lung cancer.

  16. MIF-driven activation of macrophages induces killing of intracellular Trypanosoma cruzi dependent on endogenous production of tumor necrosis factor, nitric oxide and reactive oxygen species.

    PubMed

    Cutrullis, Romina A; Petray, Patricia B; Corral, Ricardo S

    2017-02-01

    The proinflammatory cytokine macrophage migration inhibitory factor (MIF) is a key player in innate immunity. MIF has been considered critical for controlling acute infection by the protozoan Trypanosoma cruzi, but the underlying mechanisms are poorly understood. Our study aimed to analyze whether MIF could favor microbicidal activity of the macrophage, a site where T. cruzi grows and the initial effector cell against this parasite. Using murine macrophages infected in vitro, we examined the effect of MIF on their parasiticidal ability and attempted to identify inflammatory agents involved in MIF-induced protection. Our findings show that MIF is readily secreted from peritoneal macrophages upon T. cruzi infection. MIF activates both primary and J774 phagocytes boosting the endogenous production of tumor necrosis factor-alpha via mitogen-activated protein kinase p38 signaling, as well as the release of nitric oxide and reactive oxygen species, leading to enhanced pathogen elimination. MIF can also potentiate the effect of interferon-gamma on T. cruzi killing by J774 and mouse peritoneal macrophages, rendering these cells more competent in reducing intracellular parasite burden. The present results unveil a novel innate immune pathway that contributes to host defense and broaden our understanding of the regulation of inflammatory mediators implicated in early parasite containment that is decisive for resistance to T. cruzi infection.

  17. Augmentation of Chemotherapeutic Infusion Effect by TSU-68, an Oral Targeted Antiangiogenic Agent, in a Rabbit VX2 Liver Tumor Model

    SciTech Connect

    Kim, Hyo-Cheol; Chung, Jin Wook Choi, Seung Hong; Im, Seock-Ah; Yamasaki, Yasundo; Jun, Suryoung; Jae, Hwan Jun; Park, Jae Hyung

    2012-02-15

    Purpose: This study was designed to investigate the in vivo effects of combination therapy with TSU-68 and chemotherapeutic infusion in a rabbit VX2 liver tumor model. Methods: This study was approved by the animal care committee at our institute. Three weeks before chemotherapeutic infusion, VX2 carcinoma was implanted into the livers of 32 rabbits. One week after chemotherapeutic infusion, vehicle was administered orally for 3 weeks in the control group (n = 16), and TSU-68 was administered orally at a daily dose of 200 mg/kg for 3 weeks in the treated group (n = 16). Computed tomography (CT) was performed before and 1, 2, 3, and 4 weeks after chemotherapeutic infusion. Tumor response was assessed according to the Response Evaluation Criteria in Solid Tumors (RECIST) on CT scan. The maximum thickness of viable tumor was measured on microscopic sections. Results: According to the RECIST, stable disease was observed in 9 (56%) rabbits and progressive disease in 7 (44%) in the control group, whereas partial response was observed in 1 (6%) rabbit and stable disease in 15 (94%) in the treated group. On pathologic examination, a viable lesion was present in 12 (75%) rabbits in the control group and in 6 (38%) rabbits in the treated group (P = 0.073). The mean maximum thickness of viable tumor in the treated group was significantly smaller than that in the control group (0.74 mm vs. 3.39 mm; P = 0.02). Conclusions: Oral administration of TSU-68 augmented the effect of chemotherapeutic infusion in a rabbit VX2 liver tumor model.

  18. Alkylating agent melphalan augments the efficacy of adoptive immunotherapy using tumor-specific CD4+ T cells

    PubMed Central

    Lu, Xiaoyun; Ding, Zhi-Chun; Cao, Yang; Liu, Chufeng; Habtetsion, Tsadik; Yu, Miao; Lemos, Henrique; Salman, Huda; Xu, Hongyan; Mellor, Andrew L.; Zhou, Gang

    2014-01-01

    In recent years the immune-potentiating effects of some widely used chemotherapeutic agents have been increasingly appreciated. This provides a rationale for combining conventional chemotherapy with immunotherapy strategies to achieve durable therapeutic benefits. Previous studies have implicated the immunomodulatory effects of melphalan, an alkylating agent commonly used to treat multiple myeloma, but the underlying mechanisms remain obscure. In the current study, we investigated the impact of melphalan on endogenous immune cells as well as adoptively transferred tumor-specific CD4+ T cells in tumor-bearing mice. We showed that melphalan treatment resulted in a rapid burst of inflammatory cytokines and chemokines during the cellular recovery phase after melphalan-induced myelo-leukodepletion. After melphalan treatment, tumor cells exhibited characteristics of immunogenic cell death, including membrane translocation of the endoplasmic reticulum resident calreticulin (CRT), and extracellular release of high-mobility group box 1 (HMGB1). In addition, there was enhanced tumor antigen uptake by dendritic cells in the tumor-draining lymph node. Consistent with these immunomodulatory effects, melphalan treatment of tumor-bearing mice led to the activation of the endogenous CD8+ T cells, and more importantly, effectively drove the clonal expansion and effector differentiation of adoptively transferred tumor-specific CD4+ T cells. Notably, the combination of melphalan and CD4+ T-cell adoptive cell therapy (ACT) was more efficacious than either treatment alone in prolonging the survival of mice with advanced B-cell lymphomas or colorectal tumors. These findings provide mechanistic insights into melphalan’s immunostimulatory effects, and demonstrate the therapeutic potential of combining melphalan with adoptive cell therapy utilizing antitumor CD4+ T cells. PMID:25560408

  19. The augmented anticancer potential of AP9-cd loaded solid lipid nanoparticles in human leukemia Molt-4 cells and experimental tumor.

    PubMed

    Bhushan, Shashi; Kakkar, Vandita; Pal, Harish Chandra; Mondhe, D M; Kaur, Indu Pal

    2016-01-25

    AP9-cd, a novel lignan composition from Cedrus deodara has significant anticancer potential, and to further enhance its activity, it was lucratively encumbered into solid lipid nanoparticles (SLNs). These nanoparticles were formulated by micro-emulsion technique with 70% drug trap competence. AP9-cd-SLNs were regular, solid, globular particles in the range of 100-200 nm, which were confirmed by electron microscopic studies. Moreover, AP9-cd-SLNs were found to be stable for up to six months in terms of color, particle size, zeta potential, drug content and entrapment. AP9-cd-SLNs have 30-50% higher cytotoxic and apoptotic potential than the AP9-cd alone. The augmented anticancer potential of AP9-cd-SLNs was observed in cytotoxic IC50 value, apoptosis signaling cascade and in Ehrlich ascites tumor (EAT) model. AP9-cd-SLNs induce apoptosis in Molt-4 cells via both intrinsic and extrinsic pathway. Moreover, the dummy nanoparticles (SLNs without AP9-cd) did not have any cytotoxic effect in cancer as well as in normal cells. Consequently, SLNs of AP9-cd significantly augment the apoptotic and antitumor potential of AP9-cd. The present study provides a podium for ornamental the remedial latent via novel delivery systems like solid lipid nanoparticles.

  20. Beyond killing

    PubMed Central

    Vale, Pedro F.; McNally, Luke; Doeschl-Wilson, Andrea; King, Kayla C.; Popat, Roman; Domingo-Sananes, Maria R.; Allen, Judith E.; Soares, Miguel P.; Kümmerli, Rolf

    2016-01-01

    The antibiotic pipeline is running dry and infectious disease remains a major threat to public health. An efficient strategy to stay ahead of rapidly adapting pathogens should include approaches that replace, complement or enhance the effect of both current and novel antimicrobial compounds. In recent years, a number of innovative approaches to manage disease without the aid of traditional antibiotics and without eliminating the pathogens directly have emerged. These include disabling pathogen virulence-factors, increasing host tissue damage control or altering the microbiota to provide colonization resistance, immune resistance or disease tolerance against pathogens. We discuss the therapeutic potential of these approaches and examine their possible consequences for pathogen evolution. To guarantee a longer half-life of these alternatives to directly killing pathogens, and to gain a full understanding of their population-level consequences, we encourage future work to incorporate evolutionary perspectives into the development of these treatments. PMID:27016341

  1. Stereotactic Radiation Therapy Augments Antigen-Specific PD-1-Mediated Anti-Tumor Immune Responses via Cross-Presentation of Tumor Antigen

    PubMed Central

    Sharabi, Andrew B.; Nirschl, Christopher J.; Kochel, Christina M.; Nirschl, Thomas R.; Francisca, Brian J.; Velarde, Esteban; Deweese, Theodore L.; Drake, Charles G.

    2014-01-01

    The immune-modulating effects of radiation therapy have gained considerable interest recently and there have been multiple reports of synergy between radiation and immunotherapy. However, additional pre-clinical studies are needed to demonstrate the antigen-specific nature of radiation-induced immune responses and elucidate potential mechanisms of synergy with immunotherapy. Here we demonstrate the ability of stereotactic radiotherapy to induce endogenous antigen-specific immune responses when combined with anti-PD-1 checkpoint blockade immunotherapy. Using the small animal radiation research platform (SARRP), image-guided stereotactic radiotherapy delivered to B16-OVA melanoma or 4T1-HA breast carcinoma tumors resulted in the development of antigen-specific T and B cell-mediated immune responses. These immune-stimulating effects of radiotherapy were significantly increased when combined with either anti-PD-1 therapy or regulatory T cell (Treg) depletion, resulting in improved local tumor control. Phenotypic analyses of antigen-specific CD8 T cells revealed that radiotherapy increased the percentage of antigen-experienced T cells and effector memory T cells. Mechanistically we found that radiotherapy up-regulates tumor-associated antigen-MHC complexes, enhances antigen cross-presentation in the draining lymph node, and increased T-cell infiltration into tumors. These findings demonstrate the ability of radiotherapy to prime an endogenous antigen-specific immune response and provide additional mechanistic rationale for combining radiation with PD-1 blockade in the clinic. PMID:25527358

  2. Targeted disruption of TC-PTP in the proliferative compartment augments STAT3 and AKT signaling and skin tumor development

    PubMed Central

    Lee, Hyunseung; Kim, Mihwa; Baek, Minwoo; Morales, Liza D.; Jang, Ik-Soon; Slaga, Thomas J.; DiGiovanni, John; Kim, Dae Joon

    2017-01-01

    Tyrosine phosphorylation is a vital mechanism that contributes to skin carcinogenesis. It is regulated by the counter-activities of protein tyrosine kinases (PTKs) and protein tyrosine phosphatases (PTPs). Here, we report the critical role of T-cell protein tyrosine phosphatase (TC-PTP), encoded by Ptpn2, in chemically-induced skin carcinogenesis via the negative regulation of STAT3 and AKT signaling. Using epidermal specific TC-PTP knockout (K14Cre.Ptpn2fl/fl) mice, we demonstrate loss of TC-PTP led to a desensitization to tumor initiator 7,12-dimethylbenz[a]anthracene (DMBA)-induced apoptosis both in vivo epidermis and in vitro keratinocytes. TC-PTP deficiency also resulted in a significant increase in epidermal thickness and hyperproliferation following exposure to the tumor promoter, 12-O-tetradecanoylphorbol-13-acetate (TPA). Western blot analysis showed that both phosphorylated STAT3 and phosphorylated AKT expressions were significantly increased in epidermis of TC-PTP-deficient mice compared to control mice following TPA treatment. Inhibition of STAT3 or AKT reversed the effects of TC-PTP deficiency on apoptosis and proliferation. Finally, TC-PTP knockout mice showed a shortened latency of tumorigenesis and significantly increased numbers of tumors during two-stage skin carcinogenesis. Our findings reveal that TC-PTP has potential as a novel target for the prevention of skin cancer through its role in the regulation of STAT3 and AKT signaling. PMID:28322331

  3. Cytokine induced killer cells as adoptive immunotherapy strategy to augment graft versus tumor after hematopoietic cell transplantation.

    PubMed

    Sangiolo, D; Mesiano, G; Carnevale-Schianca, F; Piacibello, W; Aglietta, M; Cignetti, A

    2009-07-01

    Donor lymphocyte infusion (DLI) is used to increase the graft versus tumor (GVT) effect after allogeneic hematopoietic cell transplant (HCT). The limited spectrum of activity and high risk of graft versus host disease (GVHD) remain major limitations of this approach. The finding of new cell populations for adoptive immunotherapy, with the ability to separate GVT from GVHD, would be useful. Here we review the main basic, preclinical and clinical research on cytokine-induced killer (CIK) cells, highlighting the aspects of their antitumor and alloreactive potentials that might favourably affect the balance between GVT and GVHD. CIK cells are ex vivo-expanded T lymphocytes sharing NK markers and endowed with a potent MHC-unrestricted antitumor activity against haematological and solid malignancies. Studies in preclinical animal models have demonstrated their low GVHD potential when infused across MHC-barriers, and recent clinical studies seem to confirm these findings in patients with hematological malignancies relapsing after HCT. If consolidated with larger clinical trials, adoptive immunotherapy with CIK cells might represent an effective alternative to classic DLI, helping HCT to succesfully meet current challenges like the extension across major HLA-barriers and application to solid tumors.

  4. Tethered IL-15 augments antitumor activity and promotes a stem-cell memory subset in tumor-specific T cells

    PubMed Central

    Hurton, Lenka V.; Singh, Harjeet; Najjar, Amer M.; Switzer, Kirsten C.; Mi, Tiejuan; Maiti, Sourindra; Olivares, Simon; Rabinovich, Brian; Huls, Helen; Forget, Marie-Andrée; Datar, Vrushali; Kebriaei, Partow; Lee, Dean A.; Champlin, Richard E.; Cooper, Laurence J. N.

    2016-01-01

    Adoptive immunotherapy retargeting T cells to CD19 via a chimeric antigen receptor (CAR) is an investigational treatment capable of inducing complete tumor regression of B-cell malignancies when there is sustained survival of infused cells. T-memory stem cells (TSCM) retain superior potential for long-lived persistence, but challenges exist in manufacturing this T-cell subset because they are rare among circulating lymphocytes. We report a clinically relevant approach to generating CAR+ T cells with preserved TSCM potential using the Sleeping Beauty platform. Because IL-15 is fundamental to T-cell memory, we incorporated its costimulatory properties by coexpressing CAR with a membrane-bound chimeric IL-15 (mbIL15). The mbIL15-CAR T cells signaled through signal transducer and activator of transcription 5 to yield improved T-cell persistence independent of CAR signaling, without apparent autonomous growth or transformation, and achieved potent rejection of CD19+ leukemia. Long-lived T cells were CD45ROnegCCR7+CD95+, phenotypically most similar to TSCM, and possessed a memory-like transcriptional profile. Overall, these results demonstrate that CAR+ T cells can develop long-term persistence with a memory stem-cell phenotype sustained by signaling through mbIL15. This observation warrants evaluation in clinical trials. PMID:27849617

  5. Tethered IL-15 augments antitumor activity and promotes a stem-cell memory subset in tumor-specific T cells.

    PubMed

    Hurton, Lenka V; Singh, Harjeet; Najjar, Amer M; Switzer, Kirsten C; Mi, Tiejuan; Maiti, Sourindra; Olivares, Simon; Rabinovich, Brian; Huls, Helen; Forget, Marie-Andrée; Datar, Vrushali; Kebriaei, Partow; Lee, Dean A; Champlin, Richard E; Cooper, Laurence J N

    2016-11-29

    Adoptive immunotherapy retargeting T cells to CD19 via a chimeric antigen receptor (CAR) is an investigational treatment capable of inducing complete tumor regression of B-cell malignancies when there is sustained survival of infused cells. T-memory stem cells (TSCM) retain superior potential for long-lived persistence, but challenges exist in manufacturing this T-cell subset because they are rare among circulating lymphocytes. We report a clinically relevant approach to generating CAR(+) T cells with preserved TSCM potential using the Sleeping Beauty platform. Because IL-15 is fundamental to T-cell memory, we incorporated its costimulatory properties by coexpressing CAR with a membrane-bound chimeric IL-15 (mbIL15). The mbIL15-CAR T cells signaled through signal transducer and activator of transcription 5 to yield improved T-cell persistence independent of CAR signaling, without apparent autonomous growth or transformation, and achieved potent rejection of CD19(+) leukemia. Long-lived T cells were CD45RO(neg)CCR7(+)CD95(+), phenotypically most similar to TSCM, and possessed a memory-like transcriptional profile. Overall, these results demonstrate that CAR(+) T cells can develop long-term persistence with a memory stem-cell phenotype sustained by signaling through mbIL15. This observation warrants evaluation in clinical trials.

  6. RIG-I-like helicases induce immunogenic cell death of pancreatic cancer cells and sensitize tumors toward killing by CD8+ T cells

    PubMed Central

    Duewell, P; Steger, A; Lohr, H; Bourhis, H; Hoelz, H; Kirchleitner, S V; Stieg, M R; Grassmann, S; Kobold, S; Siveke, J T; Endres, S; Schnurr, M

    2014-01-01

    Pancreatic cancer is characterized by a microenvironment suppressing immune responses. RIG-I-like helicases (RLH) are immunoreceptors for viral RNA that induce an antiviral response program via the production of type I interferons (IFN) and apoptosis in susceptible cells. We recently identified RLH as therapeutic targets of pancreatic cancer for counteracting immunosuppressive mechanisms and apoptosis induction. Here, we investigated immunogenic consequences of RLH-induced tumor cell death. Treatment of murine pancreatic cancer cell lines with RLH ligands induced production of type I IFN and proinflammatory cytokines. In addition, tumor cells died via intrinsic apoptosis and displayed features of immunogenic cell death, such as release of HMGB1 and translocation of calreticulin to the outer cell membrane. RLH-activated tumor cells led to activation of dendritic cells (DCs), which was mediated by tumor-derived type I IFN, whereas TLR, RAGE or inflammasome signaling was dispensable. Importantly, CD8α+ DCs effectively engulfed apoptotic tumor material and cross-presented tumor-associated antigen to naive CD8+ T cells. In comparison, tumor cell death mediated by oxaliplatin, staurosporine or mechanical disruption failed to induce DC activation and antigen presentation. Tumor cells treated with sublethal doses of RLH ligands upregulated Fas and MHC-I expression and were effectively sensitized towards Fas-mediated apoptosis and cytotoxic T lymphocyte (CTL)-mediated lysis. Vaccination of mice with RLH-activated tumor cells induced protective antitumor immunity in vivo. In addition, MDA5-based immunotherapy led to effective tumor control of established pancreatic tumors. In summary, RLH ligands induce a highly immunogenic form of tumor cell death linking innate and adaptive immunity. PMID:25012502

  7. Development of near-infrared photoactivable phthalocyanine-loaded nanoparticles to kill tumor cells: An improved tool for photodynamic therapy of solid cancers.

    PubMed

    Duchi, Serena; Ramos-Romero, Sara; Dozza, Barbara; Guerra-Rebollo, Marta; Cattini, Luca; Ballestri, Marco; Dambruoso, Paolo; Guerrini, Andrea; Sotgiu, Giovanna; Varchi, Greta; Lucarelli, Enrico; Blanco, Jeronimo

    2016-10-01

    Conventional photodynamic therapy has shown to be beneficial in the treatment of a variety of tumors. However, one of its major limitations is the inadequate penetration depth of visible light. In order to overcome this constraint, we developed 80nm poly-methylmethacrylate core-shell fluorescent nanoparticles (FNP) loaded with the photosensitizer tetrasulfonated aluminum phthalocyanine (Ptl). To demonstrate the efficacy of our Ptl@FNP we performed in vitro and in vivo studies using a human prostate tumor model. Our data reveal that Ptl@FNP are internalized by tumor cells, favour Ptl intracellular accumulation, and efficiently trigger cell death through the generation of ROS upon irradiation with 680nm light. When directly injected into tumors intramuscularly induced in SCID mice, Ptl@FNP upon irradiation significantly reduce tumor growth with higher efficiency than the bare Ptl. Collectively, these results demonstrate that the newly developed nanoparticles may be utilized as a delivery system for antitumor phototherapy in solid cancers.

  8. Anti-tumor activities of luteolin and silibinin in glioblastoma cells: overexpression of miR-7-1-3p augmented luteolin and silibinin to inhibit autophagy and induce apoptosis in glioblastoma in vivo.

    PubMed

    Chakrabarti, Mrinmay; Ray, Swapan K

    2016-03-01

    Glioblastoma is the deadliest brain tumor in humans. High systemic toxicity of conventional chemotherapies prompted the search for natural compounds for controlling glioblastoma. The natural flavonoids luteolin (LUT) and silibinin (SIL) have anti-tumor activities. LUT inhibits autophagy, cell proliferation, metastasis, and angiogenesis and induces apoptosis; while SIL activates caspase-8 cascades to induce apoptosis. However, synergistic anti-tumor effects of LUT and SIL in glioblastoma remain unknown. Overexpression of tumor suppressor microRNA (miR) could enhance the anti-tumor effects of LUT and SIL. Here, we showed that 20 µM LUT and 50 µM SIL worked synergistically for inhibiting growth of two different human glioblastoma U87MG (wild-type p53) and T98G (mutant p53) cell lines and natural combination therapy was more effective than conventional chemotherapy (10 µM BCNU or 100 µM TMZ). Combination of LUT and SIL caused inhibition of growth of glioblastoma cells due to induction of significant amounts of apoptosis and complete inhibition of invasion and migration. Further, combination of LUT and SIL inhibited rapamycin (RAPA)-induced autophagy, a survival mechanism, with suppression of PKCα and promotion of apoptosis through down regulation of iNOS and significant increase in expression of the tumor suppressor miR-7-1-3p in glioblastoma cells. Our in vivo studies confirmed that overexpression of miR-7-1-3p augmented anti-tumor activities of LUT and SIL in RAPA pre-treated both U87MG and T98G tumors. In conclusion, our results clearly demonstrated that overexpression of miR-7-1-3p augmented the anti-tumor activities of LUT and SIL to inhibit autophagy and induce apoptosis for controlling growth of different human glioblastomas in vivo.

  9. Human alpha-lactalbumin made lethal to tumor cells (HAMLET) kills human glioblastoma cells in brain xenografts by an apoptosis-like mechanism and prolongs survival.

    PubMed

    Fischer, Walter; Gustafsson, Lotta; Mossberg, Ann-Kristin; Gronli, Janne; Mork, Sverre; Bjerkvig, Rolf; Svanborg, Catharina

    2004-03-15

    Malignant brain tumors present a major therapeutic challenge because no selective or efficient treatment is available. Here, we demonstrate that intratumoral administration of human alpha-lactalbumin made lethal to tumor cells (HAMLET) prolongs survival in a human glioblastoma (GBM) xenograft model, by selective induction of tumor cell apoptosis. HAMLET is a protein-lipid complex that is formed from alpha-lactalbumin when the protein changes its tertiary conformation and binds oleic acid as a cofactor. HAMLET induces apoptosis in a wide range of tumor cells in vitro, but the therapeutic effect in vivo has not been examined. In this study, invasively growing human GBM tumors were established in nude rats (Han:rnu/rnu Rowett, n = 20) by transplantation of human GBM biopsy spheroids. After 7 days, HAMLET was administered by intracerebral convection-enhanced delivery for 24 h into the tumor area; and alpha-lactalbumin, the native, folded variant of the same protein, was used as a control. HAMLET reduced the intracranial tumor volume and delayed the onset of pressure symptoms in the tumor-bearing rats. After 8 weeks, all alpha-lactalbumin-treated rats had developed pressure symptoms, but the HAMLET-treated rats remained asymptomatic. Magnetic resonance imaging scans revealed large differences in tumor volume (456 versus 63 mm(3)). HAMLET caused apoptosis in vivo in the tumor but not in adjacent intact brain tissue or in nontransformed human astrocytes, and no toxic side effects were observed. The results identify HAMLET as a new candidate in cancer therapy and suggest that HAMLET should be additionally explored as a novel approach to controlling GBM progression.

  10. Chin augmentation

    MedlinePlus

    ... chisel to make a second cut through the jaw bone. The jaw bone is moved and wired or screwed in ... see the final appearance of your chin and jaw for 3 to 4 months. Alternative Names Augmentation ...

  11. Bystander killing effect of DS-8201a, a novel anti-human epidermal growth factor receptor 2 antibody-drug conjugate, in tumors with human epidermal growth factor receptor 2 heterogeneity.

    PubMed

    Ogitani, Yusuke; Hagihara, Katsunobu; Oitate, Masataka; Naito, Hiroyuki; Agatsuma, Toshinori

    2016-07-01

    Antibody-drug conjugates deliver anticancer agents selectively and efficiently to tumor tissue and have significant antitumor efficacy with a wide therapeutic window. DS-8201a is a human epidermal growth factor receptor 2 (HER2)-targeting antibody-drug conjugate prepared using a novel linker-payload system with a potent topoisomerase I inhibitor, exatecan derivative (DX-8951 derivative, DXd). It was effective against trastuzumab emtansine (T-DM1)-insensitive patient-derived xenograft models with both high and low HER2 expression. In this study, the bystander killing effect of DS-8201a was evaluated and compared with that of T-DM1. We confirmed that the payload of DS-8201a, DXd (1), was highly membrane-permeable whereas that of T-DM1, Lys-SMCC-DM1, had a low level of permeability. Under a coculture condition of HER2-positive KPL-4 cells and negative MDA-MB-468 cells in vitro, DS-8201a killed both cells, whereas T-DM1 and an antibody-drug conjugate with a low permeable payload, anti-HER2-DXd (2), did not. In vivo evaluation was carried out using mice inoculated with a mixture of HER2-positive NCI-N87 cells and HER2-negative MDA-MB-468-Luc cells by using an in vivo imaging system. In vivo, DS-8201a reduced the luciferase signal of the mice, indicating suppression of the MDA-MB-468-Luc population; however, T-DM1 and anti-HER2-DXd (2) did not. Furthermore, it was confirmed that DS-8201a was not effective against MDA-MB-468-Luc tumors inoculated at the opposite side of the NCI-N87 tumor, suggesting that the bystander killing effect of DS-8201a is observed only in cells neighboring HER2-positive cells, indicating low concern in terms of systemic toxicity. These results indicated that DS-8201a has a potent bystander effect due to a highly membrane-permeable payload and is beneficial in treating tumors with HER2 heterogeneity that are unresponsive to T-DM1.

  12. Gemcitabine directly inhibits myeloid derived suppressor cells in BALB/c mice bearing 4T1 mammary carcinoma and augments expansion of T cells from tumor-bearing mice.

    PubMed

    Le, Hanh K; Graham, Laura; Cha, Esther; Morales, Johanna K; Manjili, Masoud H; Bear, Harry D

    2009-07-01

    Myeloid derived suppressor cells (MDSCs) accumulate in 4T1 mammary carcinoma bearing mice and present a barrier to the success of adoptive immunotherapy (AIT) by suppressing T cell immunity. In this study, we investigated the inhibition of MDSCs by gemcitabine (GEM), a chemotherapy agent that may have favorable immunologic effects. BALB/c mice were inoculated with 4T1 mammary carcinoma cells and treated with GEM either once a week starting 5 days after tumor inoculation (EARLY GEM) or as a single dose at days 20-25 (LATE GEM). Splenic mononuclear cells were isolated, activated in vitro, expanded, and stimulated with tumor antigen. T cells were then used for AIT to treat tumor-bearing mice. EARLY GEM treatment of 4T1 tumor-bearing mice significantly inhibited tumor growth, reduced splenomegaly, and significantly decreased MDSC proportion in the spleen. Support for a direct effect was demonstrated through suppression of MDSCs in spleens, bone marrow, and blood harvested 24 and 48 h after LATE GEM treatment, despite no significant decrease in tumor burden. Interestingly, treatment of tumor-bearing mice with GEM augmented in vitro expansion of splenic T cells and boosted IFN-gamma secretion in response to stimulation by tumor antigen. However, despite GEM-mediated inhibition of MDSC suppression, splenic T cells from mice with advanced tumors were ineffective in vivo against established tumors. This study provides support for direct inhibition of MDSCs and direct reduction of tumor burden by GEM in 4T1 tumor-bearing mice. GEM treatment of mice with advanced tumors improves T cell function and growth in vitro.

  13. Serial killing of tumor cells by cytotoxic T cells redirected with a CD19-/CD3-bispecific single-chain antibody construct.

    PubMed

    Hoffmann, Patrick; Hofmeister, Robert; Brischwein, Klaus; Brandl, Christian; Crommer, Sandrine; Bargou, Ralf; Itin, Christian; Prang, Nadja; Baeuerle, Patrick A

    2005-05-20

    Certain bispecific antibodies exhibit an extraordinary potency and efficacy for target cell lysis by eliciting a polyclonal T-cell response. One example is a CD19-/CD3-bispecific single-chain antibody construct (bscCD19xCD3), which at femtomolar concentrations can redirect cytotoxic T cells to eliminate human B lymphocytes, B lymphoma cell lines and patient-derived malignant B cells. Here we have further explored the basis for this high potency. Using video-assisted microscopy, bscCD19xCD3 was found to alter the motility and activity of T cells from a scanning to a killing mode. Individual T cells could eliminate multiple target cells within a 9 hr time period, resulting in nuclear fragmentation and membrane blebbing of target cells. Complete target cell elimination was observed within 24 hr at effector-to-target cell ratios as low as 1:5. Under optimal conditions, cell killing started within minutes after addition of bscCD19xCD3, suggesting that the rate of serial killing was mostly determined by T-cell movement and target cell scanning and lysis. At all times, T cells remained highly motile, and no clusters of T and target cells were induced by the bispecific antibody. Bystanding target-negative cells were not detectably affected. Repeated target cell lysis by bscCD19xCD3-activated T cells increased the proportion of CD19/CD3 double-positive T cells, which was most likely a consequence of transfer of CD19 from B to T cells during cytolytic synapse formation. To our knowledge, this is the first study showing that a bispecific antibody can sustain multiple rounds of target cell lysis by T cells.

  14. Human Augmentics: augmenting human evolution.

    PubMed

    Kenyon, Robert V; Leigh, Jason

    2011-01-01

    Human Augmentics (HA) refers to technologies for expanding the capabilities, and characteristics of humans. One can think of Human Augmentics as the driving force in the non-biological evolution of humans. HA devices will provide technology to compensate for human biological limitations either natural or acquired. The strengths of HA lie in its applicability to all humans. Its interoperability enables the formation of ecosystems whereby augmented humans can draw from other realms such as "the Cloud" and other augmented humans for strength. The exponential growth in new technologies portends such a system but must be designed for interaction through the use of open-standards and open-APIs for system development. We discuss the conditions needed for HA to flourish with an emphasis on devices that provide non-biological rehabilitation.

  15. Molecular Mechanism of MART-1+/A*0201+ Human Melanoma Resistance to Specific CTL-Killing Despite Functional Tumor-CTL Interaction

    PubMed Central

    Jazirehi, Ali R.; Baritaki, Stavroula; Koya, Richard C.; Bonavida, Benjamin; Economou, James S.

    2014-01-01

    Durable responses in metastatic melanoma patients remain generally difficult to achieve. Adoptive cell therapy with ex vivo engineered lymphocytes expressing high affinity T cell receptors TCRα/β for the melanoma antigen MART-127-35/HLA A*0201 (recognized by F5 cytotoxic T lymphocytes [F5 CTLs]) has been found to benefit certain patients. However, many other patients are inherently unresponsive and/or relapse for unknown reasons. To analyze the basis for the acquired-resistance and strategies to reverse it, we established F5 CTLresistant (R) human melanoma clones from relatively sensitive parental lines under selective F5 CTL pressure. Surface MART-127-35/HLA-A*0201 in these clones was unaltered and F5 CTLs recognized and interacted with them similarly to the parental lines. Nevertheless, the R clones were resistant to F5 CTL killing, exhibited hyperactivation of the NF-κB survival pathway, and overexpression of the anti-apoptotic genes Bcl-2, Bcl-xL and Mcl-1. Sensitivity to F5 CTL-killing could be increased by pharmacological inhibition of the NF-κB pathway, Bcl-2 family members, or the proteasome, the latter of which reduced NF-κB activity and diminished anti-apoptotic gene expression. Specific gene-silencing (by siRNA) confirmed the protective role of anti-apoptotic factors by reversing R clone resistance. Together, our findings suggest that long-term immunotherapy may impose a selection for the development of resistant cells that are unresponsive to highly avid and specific melanoma-reactive CTLs, despite maintaining expression of functional peptide:MHC complexes, due to activation of anti-apoptotic signaling pathways. Though unresponsive to CTL, our results argue that resistant cells can be re-sensitized to immunotherapy with co-administration of targeted inhibitors to anti-apoptotic survival pathways. PMID:21159666

  16. Planning a dynamic kill

    SciTech Connect

    Abel, L.W.

    1996-05-01

    This article discusses the methodology, design philosophy, and guidelines for planning a dynamic-kill operation for a wild well. The topics covered are two methods of computer analysis for designing dynamic-kill requirements, the design process, determining the pumping spread, and the pitfalls that a designer faces in planning a dynamic kill.

  17. A novel single tetracycline-regulative adenoviral vector for tumor-specific Bax gene expression and cell killing in vitro and in vivo.

    PubMed

    Gu, Jian; Zhang, Lidong; Huang, Xuefeng; Lin, Tongyu; Yin, Min; Xu, Kai; Ji, Lin; Roth, Jack A; Fang, Bingliang

    2002-07-18

    Using a binary adenoviral system, we recently showed that the human telomerase reverse transcriptase (hTERT) promoter induces tumor-specific Bax gene expression. However, the strong cytotoxicity of Bax and other pro-apoptotic genes to packaging 293 cells has so far hindered construction of the desired single adenoviral vectors expressing toxic genes. We report here the construction of a single bicistronic adenoviral vector for tumor-specific Bax expression. The vector (Ad/gBax) utilizes the Tet-Off system and expresses a GFP/Bax fusion protein for easy detection. The hTERT promoter drives the expression of tTA, a transactivator capable of binding to TRE (tetracycline-responsive element) in the absence of tetracycline, which in turn induces expression of the GFP-Bax gene. The addition of tetracycline in 293 cells blocks the binding of tTA to TRE and substantially inhibits GFP-Bax expression and toxicity, thus allowing the packaging and production of Ad/gBax. Our data show that Ad/gBax could drive the high expression of GFP-Bax in tumor cells but not in normal cells and mouse tissues. Furthermore, the expression of GFP-Bax fusion protein elicited tumor-specific apoptosis in a variety of human cancer cells in vitro and in vivo at a level comparable to that induced by the binary system. Thus, Ad/gBax may become a potent therapeutic agent for the treatment of cancers.

  18. PEG-PE/phosphatidylcholine mixed immunomicelles specifically deliver encapsulated taxol to tumor cells of different origin and promote their efficient killing.

    PubMed

    Gao, Z; Lukyanov, A N; Chakilam, A R; Torchilin, V P

    2003-02-01

    Mixed micelles were prepared from poly(ethyleneglycol)-distearyl phosphoethanolamine (PEG2000-PE) and egg phosphatidylcholine. The micelles were covalently modified with the nucleosome-specific monoclonal antibody 2C5 known to recognize and bind a variety of tumor cells via their surface-bound nucleosomes. Covalent attachment of 2C5 antibody was performed via a micelle-incorporated PEG-PE with the distal terminus of the PEG block activated with p-nitrophenylcarbonyl group (pNP-PEG-PE). Micelle surface-attached 2C5 antibody maintained its specific activity. 2C5-targeted immunomicelles were able to carry more than 3 wt% of taxol. Taxol-loaded immunomicelles specifically recognized tumor cell lines of several types. The cytotoxicity of 2C5-targeted taxol-loaded immunomicelles in a cell culture model was much higher when compared with free taxol or taxol in non-targeted micelles.

  19. Mechanisms of Cell Killing Response from Low Linear Energy Transfer (LET) Radiation Originating from 177Lu Radioimmunotherapy Targeting Disseminated Intraperitoneal Tumor Xenografts

    PubMed Central

    Yong, Kwon Joong; Milenic, Diane E.; Baidoo, Kwamena E.; Brechbiel, Martin W.

    2016-01-01

    Radiolabeled antibodies (mAbs) provide efficient tools for cancer therapy. The combination of low energy β−-emissions (500 keVmax; 130 keVave) along with a γ-emission for imaging makes 177Lu (T1/2 = 6.7 day) a suitable radionuclide for radioimmunotherapy (RIT) of tumor burdens possibly too large to treat with α-particle radiation. RIT with 177Lu-trastuzumab has proven to be effective for treatment of disseminated HER2 positive peritoneal disease in a pre-clinical model. To elucidate mechanisms originating from this RIT therapy at the molecular level, tumor bearing mice (LS-174T intraperitoneal xenografts) were treated with 177Lu-trastuzumab comparatively to animals treated with a non-specific control, 177Lu-HuIgG, and then to prior published results obtained using 212Pb-trastuzumab, an α-particle RIT agent. 177Lu-trastuzumab induced cell death via DNA double strand breaks (DSB), caspase-3 apoptosis, and interfered with DNA-PK expression, which is associated with the repair of DNA non-homologous end joining damage. This contrasts to prior results, wherein 212Pb-trastuzumab was found to down-regulate RAD51, which is involved with homologous recombination DNA damage repair. 177Lu-trastuzumab therapy was associated with significant chromosomal disruption and up-regulation of genes in the apoptotic process. These results suggest an inhibition of the repair mechanism specific to the type of radiation damage being inflicted by either high or low linear energy transfer radiation. Understanding the mechanisms of action of β−- and α-particle RIT comparatively through an in vivo tumor environment offers real information suitable to enhance combination therapy regimens involving α- and β−-particle RIT for the management of intraperitoneal disease. PMID:27196891

  20. Potentiation of cell killing by fractionated radiation and suppression of proliferative recovery in MCF-7 breast tumor cells by the Vitamin D3 analog EB 1089.

    PubMed

    DeMasters, Gerald A; Gupta, Mona S; Jones, Kara R; Cabot, Myles; Wang, Hongtao; Gennings, Chris; Park, Misook; Bratland, Ase; Ree, Anne H; Gewirtz, David A

    2004-12-01

    A senescence-like growth arrest succeeded by recovery of proliferative capacity was observed in MCF-7 breast tumor cells exposed to fractionated radiation, 5 x 2 Gy. Exposure to EB 1089, an analog of the steroid hormone 1alpha, 25 dihydroxycholecalciferol (1alpha, 25 dihydroxy Vitamin D(3); calcitriol), prior to irradiation promoted cell death and delayed both the development of a senescent phenotype and the recovery of proliferative capacity. EB 1089 also reduced clonogenic survival over and above that produced by fractionated radiation alone and further conferred susceptibility to apoptosis in MCF-7 cells exposed to radiation. In contrast, EB 1089 failed to enhance the response to radiation (or to promote apoptosis) in normal breast epithelial cells or BJ fibroblast cells. EB 1089 treatment and fractionated radiation additively promoted ceramide generation and suppressed expression of polo-like kinase 1. Taken together, these data indicate that EB 1089 (and 1alpha, 25 dihydroxycholecalciferol or its analogs) could selectively enhance breast tumor cell sensitivity to radiation through the promotion of cell death, in part through the generation of ceramide and the suppression of polo-like kinase.

  1. Designing a HER2/neu promoter to drive α1,3galactosyltransferase expression for targeted anti-αGal antibody-mediated tumor cell killing

    PubMed Central

    Lanteri, Marion; Ollier, Laurence; Giordanengo, Valérie; Lefebvre, Jean-Claude

    2005-01-01

    Introduction Our goal was to specifically render tumor cells susceptible to natural cytolytic anti-αGal antibodies by using a murine α1,3galactosyltransferase (mαGalT) transgene driven by a designed form of HER2/neu promoter (pNeu), the transcription of which is frequently observed to be above basal in breast tumors. Indeed, the αGalT activity that promotes Galα1,3Galβ1,4GlcNAc-R (αGal) epitope expression has been mutationally disrupted during the course of evolution, starting from Old World primates, and this has led to the counter-production of large amounts of cytotoxic anti-αGal antibodies in recent primates, including man. Method Expression of the endogenous c-erbB-2 gene was investigated in various cell lines by northern blotting. A mαGalT cDNA was constructed into pcDNA3 vector downstream of the original CMV promoter (pCMV/mαGalT) and various forms of pNeu were prepared by PCR amplification and inserted in the pCMV/mαGalT construct upstream of the mαGalT cDNA, in the place of the CMV promoter. These constructs were transferred into HEK-293 control and breast tumor cell lines. Stably transfected cells were analyzed by northern blotting for their expression of αGalT and c-erbB-2, and by flow cytometry for their binding with fluorescein isothiocyanate-conjugated Griffonia simplicifolia/isolectin B4. Results We show that expression of the mαGalT was up- or down-modulated according to the level of endogenous pNeu activity and the particular form of constructed pNeu. Among several constructs, two particular forms of the promoter, pNeu250 containing the CCAAT box and the PEA3 motif adjacent to the TATAA box, and pNeu664, which has three additional PEA3 motifs upstream of the CCAAT box, were found to promote differential αGalT expression. Conclusion Our results strengthen current concepts about the crucial role played by the proximal PEA3 motif of pNeu, and may represent a novel therapeutic approach for the development of targeted transgene expression

  2. Null Killing vectors

    NASA Astrophysics Data System (ADS)

    Lukács, B.; Perjés, Z.; Sebestyén, Á.

    1981-06-01

    Space-times admitting a null Killing vector are studied, using the Newman-Penrose spin coefficient formalism. The properties of the eigenrays (principal null curves of the Killing bivector) are shown to be related to the twist of the null Killing vector. Among the electrovacs, the ones containing a null Maxwell field turn out to belong to the twist-free class. An electrovac solution is obtained for which the null Killing vector is twisting and has geodesic and shear-free eigenrays. This solution is parameterless and appears to be the field of a zero-mass, spinning, and charged source.

  3. Multi-kinase inhibitors interact with sildenafil and ERBB1/2/4 inhibitors to kill tumor cells in vitro and in vivo.

    PubMed

    Booth, Laurence; Albers, Thomas; Roberts, Jane L; Tavallai, Mehrad; Poklepovic, Andrew; Lebedyeva, Iryna O; Dent, Paul

    2016-06-28

    We have recently demonstrated that multi-kinase inhibitors such as sorafenib and pazopanib can suppress the detection of chaperones by in situ immuno-fluorescence, which is further enhanced by phosphodiesterase 5 inhibitors. Sorafenib and pazopanib inhibited the HSP90 ATPase activity with IC50 values of ~1.0 μM and ~75 nM, respectively. Pazopanib docked in silico with two possible poses into the HSP90 ATP binding pocket. Pazopanib and sildenafil combined to reduce the total protein levels of HSP1H/p105 and c-MYC and to reduce their co-localization. Sorafenib/pazopanib combined with sildenafil in a [GRP78+HSP27] -dependent fashion to: (i) profoundly activate an eIF2α/Beclin1 pathway; (ii) profoundly inactivate mTOR and increase ATG13 phosphorylation, collectively resulting in the formation of toxic autophagosomes. In a fresh PDX isolate of NSCLC combined knock down of [ERBB1+ERBB3] or use of the ERBB1/2/4 inhibitor afatinib altered cell morphology, enhanced ATG13 phosphorylation, inactivated NFκB, and further enhanced [sorafenib/pazopanib + sildenafil] lethality. Identical data to that with afatinib were obtained knocking down PI3K p110α/β or using buparlisib, copanlisib or the specific p110α inhibitor BYL719. Afatinib adapted NSCLC clones were resistant to buparlisib or copanlisib but were more sensitive than control clones to [sorafenib + sildenafil] or [pazopanib + sildenafil]. Lapatinib significantly enhanced the anti-tumor effect of [regorafenib + sildenafil] in vivo; afatinib and BYL719 enhanced the anti-tumor effects of [sorafenib + sildenafil] and [pazopanib] in vivo, respectively.

  4. Multi-kinase inhibitors interact with sildenafil and ERBB1/2/4 inhibitors to kill tumor cells in vitro and in vivo

    PubMed Central

    Booth, Laurence; Albers, Thomas; Roberts, Jane L.; Tavallai, Mehrad; Poklepovic, Andrew; Lebedyeva, Iryna O.; Dent, Paul

    2016-01-01

    We have recently demonstrated that multi-kinase inhibitors such as sorafenib and pazopanib can suppress the detection of chaperones by in situ immuno-fluorescence, which is further enhanced by phosphodiesterase 5 inhibitors. Sorafenib and pazopanib inhibited the HSP90 ATPase activity with IC50 values of ~1.0 μM and ~75 nM, respectively. Pazopanib docked in silico with two possible poses into the HSP90 ATP binding pocket. Pazopanib and sildenafil combined to reduce the total protein levels of HSP1H/p105 and c-MYC and to reduce their co-localization. Sorafenib/pazopanib combined with sildenafil in a [GRP78+HSP27] –dependent fashion to: (i) profoundly activate an eIF2α/Beclin1 pathway; (ii) profoundly inactivate mTOR and increase ATG13 phosphorylation, collectively resulting in the formation of toxic autophagosomes. In a fresh PDX isolate of NSCLC combined knock down of [ERBB1+ERBB3] or use of the ERBB1/2/4 inhibitor afatinib altered cell morphology, enhanced ATG13 phosphorylation, inactivated NFκB, and further enhanced [sorafenib/pazopanib + sildenafil] lethality. Identical data to that with afatinib were obtained knocking down PI3K p110α/β or using buparlisib, copanlisib or the specific p110α inhibitor BYL719. Afatinib adapted NSCLC clones were resistant to buparlisib or copanlisib but were more sensitive than control clones to [sorafenib + sildenafil] or [pazopanib + sildenafil]. Lapatinib significantly enhanced the anti-tumor effect of [regorafenib + sildenafil] in vivo; afatinib and BYL719 enhanced the anti-tumor effects of [sorafenib + sildenafil] and [pazopanib] in vivo, respectively. PMID:27259258

  5. Granzyme B-based cytolytic fusion protein targeting EpCAM specifically kills triple negative breast cancer cells in vitro and inhibits tumor growth in a subcutaneous mouse tumor model.

    PubMed

    Amoury, Manal; Kolberg, Katharina; Pham, Anh-Tuan; Hristodorov, Dmitrij; Mladenov, Radoslav; Di Fiore, Stefano; Helfrich, Wijnand; Kiessling, Fabian; Fischer, Rainer; Pardo, Alessa; Thepen, Theophilus; Hussain, Ahmad F; Nachreiner, Thomas; Barth, Stefan

    2016-03-28

    Triple-negative breast cancer (TNBC) is associated with poor prognosis and high prevalence among young premenopausal women. Unlike in other breast cancer subtypes, no targeted therapy is currently available. Overexpression of epithelial cell adhesion molecule (EpCAM) in 60% of TNBC tumors correlates with poorer prognosis and is associated with cancer stem cell phenotype. Thus, selective elimination of EpCAM(+) TNBC tumor cells is of clinical importance. Therefore, we constructed a fully human targeted cytolytic fusion protein, designated GbR201K-αEpCAM(scFv), in which an EpCAM-selective single-chain antibody fragment (scFv) is genetically fused to a granzyme B (Gb) mutant with reduced sensitivity to its natural inhibitor serpin B9. In vitro studies confirmed its specific binding, internalization and cytotoxicity toward a panel of EpCAM-expressing TNBC cells. Biodistribution kinetics and tumor-targeting efficacy using MDA-MB-468 cells in a human TNBC xenograft model in mice revealed selective accumulation of GbR201K-αEpCAM(scFv) in the tumors after i.v. injection. Moreover, treatment of tumor-bearing mice demonstrated a prominent inhibition of tumor growth of up to 50 % in this proof-of-concept study. Taken together, our results indicate that GbR201K-αEpCAM(scFv) is a promising novel targeted therapeutic for the treatment of TNBC.

  6. Ion-kill dosimetry

    NASA Technical Reports Server (NTRS)

    Katz, R.; Cucinotta, F. A.; Fromm, M.; Chambaudet, A.

    2001-01-01

    Unanticipated late effects in neutron and heavy ion therapy, not attributable to overdose, imply a qualitative difference between low and high LET therapy. We identify that difference as 'ion kill', associated with the spectrum of z/beta in the radiation field, whose measurement we label 'ion-kill dosimetry'.

  7. Tumor

    MedlinePlus

    ... plants (aflatoxins) Excessive sunlight exposure Genetic problems Obesity Radiation exposure Viruses Types of tumors known to be caused by or linked with viruses are: Cervical cancer (human papillomavirus) Most anal cancers (human papillomavirus) Some throat ...

  8. Evolution of coalitionary killing.

    PubMed

    Wrangham, R W

    1999-01-01

    Warfare has traditionally been considered unique to humans. It has, therefore, often been explained as deriving from features that are unique to humans, such as the possession of weapons or the adoption of a patriarchal ideology. Mounting evidence suggests, however, that coalitional killing of adults in neighboring groups also occurs regularly in other species, including wolves and chimpanzees. This implies that selection can favor components of intergroup aggression important to human warfare, including lethal raiding. Here I present the principal adaptive hypothesis for explaining the species distribution of intergroup coalitional killing. This is the "imbalance-of-power hypothesis," which suggests that coalitional killing is the expression of a drive for dominance over neighbors. Two conditions are proposed to be both necessary and sufficient to account for coalitional killing of neighbors: (1) a state of intergroup hostility; (2) sufficient imbalances of power between parties that one party can attack the other with impunity. Under these conditions, it is suggested, selection favors the tendency to hunt and kill rivals when the costs are sufficiently low. The imbalance-of-power hypothesis has been criticized on a variety of empirical and theoretical grounds which are discussed. To be further tested, studies of the proximate determinants of aggression are needed. However, current evidence supports the hypothesis that selection has favored a hunt-and-kill propensity in chimpanzees and humans, and that coalitional killing has a long history in the evolution of both species.

  9. Report Bee Kills

    EPA Pesticide Factsheets

    EPA uses incident report data to help inform our pesticide regulatory decisions. Information from these reports helps us identify patterns of bee kills associated with the use of specific pesticides or active ingredients. Here's how to report incidents.

  10. Assessment of Augmented Immune Surveillance and Tumor Cell Death by Cytoplasmic Stabilization of p53 as a Chemopreventive Strategy of 3 Promising Medicinal Herbs in Murine 2-Stage Skin Carcinogenesis.

    PubMed

    Ali, Farrah; Khan, Rehan; Khan, Abdul Quaiyoom; Lateef, Md Abdul; Maqbool, Tahir; Sultana, Sarwat

    2014-07-01

    Cancer is the final outcome of a plethora of events. Targeting the proliferation or inducing programmed cell death in a proliferating population is a major standpoint in the cancer therapy. However, proliferation is regulated by several cellular and immunologic processes. This study reports the inhibition of proliferation by augmenting immune surveillance, silencing acute inflammation, and inducing p53-mediated apoptosis of skin cancer by 3 promising medicinal extracts. We used the well-characterized model for experimental skin carcinogenesis in mice for 32 weeks to study the chemopreventive effect of the methanolic extracts of Trigonella foenumgraecum, Eclipta alba, and Calendula officinalis. All 3 extracts reduced the number, incidence, and multiplicity of tumors, which was confirmed by the pathologic studies that showed regressed tumors. There was a significant reduction in the PCNA+ nuclei in all treatment groups 32 weeks after the initiation. Mechanistic studies revealed that proliferative population in tumors is diminished by the restoration of the endogenous antioxidant defense, inhibition of the stress-related signal-transducing element NFκB, reduction of inflammation, enhancement of immunosurveillance of the genetically mutated cells, along with silencing of the cell cycle progression signals. Finally, all 3 medicinal extracts induced stable expression of p53 within the tumors, confirmed by the CFDA-Cy3 apoptosis assay. Results of our study confirm that these extracts not only limit the rate of proliferation by inhibition of the processes integral to cancer development but also induce stable cytoplasmic expression of p53-mediated apoptosis, leading to fewer and regressed tumors in mice.

  11. Immune deficiency augments the prevalence of p53 loss of heterozygosity in spontaneous tumors but not bi-directional loss of heterozygosity in bone marrow progenitors.

    PubMed

    Shetzer, Yoav; Napchan, Yael; Kaufman, Tom; Molchadsky, Alina; Tal, Perry; Goldfinger, Naomi; Rotter, Varda

    2017-03-15

    p53 loss of heterozygosity (LOH) is a frequent event in tumors of somatic and Li-Fraumeni syndrome patients harboring p53 mutation. Here, we focused on resolving a possible crosstalk between the immune-system and p53 LOH. Previously, we reported that p53 heterozygous bone-marrow mesenchymal progenitor cells undergo p53 LOH in-vivo. Surprisingly, the loss of either the wild-type p53 allele or mutant p53 allele was detected with a three-to-one ratio in favor of losing the mutant allele. In this study, we examined whether the immune-system can affect the LOH directionality in bone marrow progenitors. We found that mesenchymal progenitor cells derived from immune-deficient mice exhibited the same preference of losing the mutant p53 allele as immune-competent matched cells, nevertheless, these animals showed a significantly shorter tumor-free survival, indicating the possible involvement of immune surveillance in this model. Surprisingly, spontaneous tumors of p53 heterozygous immune-deficient mice exhibited a significantly higher incidence of p53 LOH compared to that observed in tumors derived of p53 heterozygous immune-competent mice. These findings indicate that the immune-system may affect the p53 LOH prevalence in spontaneous tumors. Thus suggesting that the immune-system may recognize and clear cells that underwent p53 LOH, whereas in immune-compromised mice, those cells will form tumors with shorter latency. In individuals with a competent immune-system, p53 LOH independent pathways may induce malignant transformation which requires a longer tumor latency. Moreover, this data may imply that the current immunotherapy treatment aimed at abrogating the inhibition of cellular immune checkpoints may be beneficial for LFS patients.

  12. Isorhamnetin augments the anti-tumor effect of capeciatbine through the negative regulation of NF-κB signaling cascade in gastric cancer.

    PubMed

    Manu, Kanjoormana A; Shanmugam, Muthu K; Ramachandran, Lalitha; Li, Feng; Siveen, Kodappully Sivaraman; Chinnathambi, Arunachalam; Zayed, M E; Alharbi, Sulaiman Ali; Arfuso, Frank; Kumar, Alan Prem; Ahn, Kwang Seok; Sethi, Gautam

    2015-07-10

    Development of drug resistance to standard chemotherapy is a common phenomenon that leads to poor prognosis in patients. Thus, novel agents that can attenuate chemoresistance are urgently needed. Therefore, we analyzed whether isorhamnetin (IH), a 3'-O-methylated metabolite of quercetin, can enhance the potential efficacy of capecitabine in gastric cancer. The potential effect of IH on viability was analyzed by MTT assay, apoptosis by flow cytometric analysis, and NF-κB activation by DNA binding as well as Western blot assays. The in vivo effect of IH was also examined on the growth of subcutaneously implanted tumors in nude mice. IH inhibited the viability, potentiated the apoptotic effects of capecitabine, abrogated NF-κB activation, and suppressed the expression of various NF-κB regulated gene products in tumor cells. In a gastric cancer xenograft model, administration of IH alone (1 mg/kg body weight, i.p.) significantly suppressed the tumor growth alone as well as in combination with capecitabine. IH further reduced NF-κB activation and the expression of various proliferative and oncogenic biomarkers in tumor tissues. Overall, our results demonstrate that IH can significantly enhance the anti-tumor effects of capecitabine through the negative regulation of NF-κB regulated oncogenic genes.

  13. Morinda citrifolia (Noni) Juice Augments Mammary Gland Differentiation and Reduces Mammary Tumor Growth in Mice Expressing the Unactivated c-erbB2 Transgene

    PubMed Central

    Clafshenkel, William P.; King, Tracy L.; Kotlarczyk, Mary P.; Cline, J. Mark; Foster, Warren G.; Davis, Vicki L.; Witt-Enderby, Paula A.

    2012-01-01

    Morinda citrifolia (noni) is reported to have many beneficial properties, including on immune, inflammatory, quality of life, and cancer endpoints, but little is known about its ability to prevent or treat breast cancer. To test its anticancer potential, the effects of Tahitian Noni Juice (TNJ) on mammary carcinogenesis were examined in MMTV-neu transgenic mice. Mammary tumor latency, incidence, multiplicity, and metastatic incidence were unaffected by TNJ treatment, which suggests that it would not increase or decrease breast cancer risk in women taking TNJ for its other benefits. However, noni may be useful to enhance treatment responses in women with existing HER2/neu breast cancer since TNJ resulted in significant reductions in tumor weight and volume and in longer tumor doubling times in mice. Remarkably, its ability to inhibit the growth of this aggressive form of cancer occurred with the mouse equivalent of a recommended dose for humans (<3 oz/day). A 30-day treatment with TNJ also induced significant changes in mammary secondary ductule branching and lobuloalveolar development, serum progesterone levels, and estrous cycling. Additional studies investigating TNJ-induced tumor growth suppression and modified reproductive responses are needed to characterize its potential as a CAM therapy for women with and without HER2+ breast cancer. PMID:22619689

  14. Morinda citrifolia (Noni) Juice Augments Mammary Gland Differentiation and Reduces Mammary Tumor Growth in Mice Expressing the Unactivated c-erbB2 Transgene.

    PubMed

    Clafshenkel, William P; King, Tracy L; Kotlarczyk, Mary P; Cline, J Mark; Foster, Warren G; Davis, Vicki L; Witt-Enderby, Paula A

    2012-01-01

    Morinda citrifolia (noni) is reported to have many beneficial properties, including on immune, inflammatory, quality of life, and cancer endpoints, but little is known about its ability to prevent or treat breast cancer. To test its anticancer potential, the effects of Tahitian Noni Juice (TNJ) on mammary carcinogenesis were examined in MMTV-neu transgenic mice. Mammary tumor latency, incidence, multiplicity, and metastatic incidence were unaffected by TNJ treatment, which suggests that it would not increase or decrease breast cancer risk in women taking TNJ for its other benefits. However, noni may be useful to enhance treatment responses in women with existing HER2/neu breast cancer since TNJ resulted in significant reductions in tumor weight and volume and in longer tumor doubling times in mice. Remarkably, its ability to inhibit the growth of this aggressive form of cancer occurred with the mouse equivalent of a recommended dose for humans (<3 oz/day). A 30-day treatment with TNJ also induced significant changes in mammary secondary ductule branching and lobuloalveolar development, serum progesterone levels, and estrous cycling. Additional studies investigating TNJ-induced tumor growth suppression and modified reproductive responses are needed to characterize its potential as a CAM therapy for women with and without HER2(+) breast cancer.

  15. Tc-99m labeled anti CEA F(ab{prime}){sub 2}: Augmenting tumor uptake with anitbody:Interferon (MAb:IFN-{alpha}-2b) conjugate

    SciTech Connect

    Thakur, M.L.; Donegan, M.; Li, J.

    1996-05-01

    Previously we have shown that IFN-{alpha}-2b, a potent biological response modifier (BRM) significantly enhanced tumor uptake of radiolabeled MAbs. Results were attributed to increased blood flow and upregulation of cell surface receptor glycoproteins. Probably because of the blood flow increase in all organs, radioactivity levels in other tissues, although to a lesser extent, were also enhanced. In order to validate our hypothesis that selective tumor targeting of IFN-{alpha}-2b (Schering-Plough, N.J.) may enhance tumor uptake and diminish uptake in normal organs, IFN-{alpha}-2b was conjugated with anti CEA MAb F-6 (IgG2a), by reacting with 1-cyclohexyl-3-(2-morpholinoethyl)carbodiimide metho-p-toluenesulfonate (CMC) and N-hydroxysulfosuccinimide (NHS) in a 1:2:50:50 ratio by weight at pH 9.2 (22{degrees}C) for 24 hr. The conjugate (30{mu}g) was administered i.v. to nude mice bearing human colorectal carcinoma LS174T, 3hr prior to the i.v. administration of 300uCi / 20ug (1.5Ci / uM) F-6F(ab{prime}){sub 2}. Animals not receiving the conjugate served as controls. The conjugation efficiency as determined using I-125-IFN-{alpha}-2b was >70% and MAb:IFN-{alpha}-2b ratio was approximately 1:1. In animals receiving IFN conjugate tumor uptake enhanced by 180% and liver uptake decreased to 56%. Radioactivity also decreased in most other tissues. Furthermore with conjugate, the tumor/muscle ratio increased by 210% (10 {plus_minus} 1.2 Vs 4.7 {plus_minus} 0.5), tumor/blood ratio by 220% (5.4 {plus_minus} 0.6 Vs 2.5 {plus_minus} 0.3), and tumor/liver ratio by 317% (0.7 {plus_minus} 0.1 Vs 0.2 {plus_minus} 0.05).

  16. Killing vectors and anisotropy

    SciTech Connect

    Krisch, J. P.; Glass, E. N.

    2009-08-15

    We consider an action that can generate fluids with three unequal stresses for metrics with a spacelike Killing vector. The parameters in the action are directly related to the stress anisotropies. The field equations following from the action are applied to an anisotropic cosmological expansion and an extension of the Gott-Hiscock cosmic string.

  17. Children Who Kill.

    ERIC Educational Resources Information Center

    Natale, Jo Anna

    1999-01-01

    Two recent books, "When Good Kids Kill," by Michael D. Kelleher, and "Lost Boys," by James Garbarino, explore how children become killers and suggest ways to reduce our high-pressure society's epidemic levels of youth violence. Physically or psychologically distant parents and unaffirmative media messages are negative…

  18. Elevated TAK1 augments tumor growth and metastatic capacities of ovarian cancer cells through activation of NF-κB signaling

    PubMed Central

    Cai, Patty C.H.; Shi, Lei; Liu, Vincent W.S.; Tang, Hermit W.M.; Liu, Iris J.; Leung, Thomas H.Y.; Chan, Karen K.L.; Yam, Judy W.P.; Yao, Kwok-Ming; Ngan, Hextan Y.S.; Chan, David W.

    2014-01-01

    Transforming growth factor (TGF)-β-activating kinase 1 (TAK1) is a serine/threonine kinase which is frequently associated with human cancer progression. However, its functional role in tumorigenesis is still controversial. Here, we report that TAK1 enhances the oncogenic capacity of ovarian cancer cells through the activation of NF-κB signaling. We found that TAK1 is frequently upregulated and significantly associated with high-grade and metastatic ovarian cancers. Mechanistic studies showed that Ser412 phosphorylation is required for TAK1 in activating NF-κB signaling and promotes aggressiveness of ovarian cancer cells. Conversely, suppression of TAK1 activity by point mutation at Ser412, RNAi mediated gene knockdown or TAK1 specific inhibitor ((5Z) -7-Oxozeaenol) remarkably impairs tumor growth and metastasis in ovarian cancer in vitro and in vivo. Our study underscores the importance of targeting TAK1 as a promising therapeutic approach to counteract the ovarian cancer progression. PMID:25277189

  19. Histone deacetylase inhibitors interact with melanoma differentiation associated-7/interleukin-24 to kill primary human glioblastoma cells.

    PubMed

    Hamed, Hossein A; Yacoub, Adly; Park, Margaret A; Archer, Kellie; Das, Swadesh K; Sarkar, Devanand; Grant, Steven; Fisher, Paul B; Dent, Paul

    2013-08-01

    We presently demonstrate that histone deacetylase inhibitors (HDACIs) enhance toxicity of melanoma differentiation-associated gene-7/interleukin 24 (mda-7/IL-24) in invasive primary human glioblastoma multiforme (GBM) cells. Additionally, a method is described to augment the efficacy of adenoviral delivery of mda-7/IL-24 in these cells. HDACIs synergized with melanoma differentiation-associated (MDA)-7/IL-24 killing GBM cells. Enhanced lethality correlated with increased autophagy that was dependent on the expression of ceramide synthase 6. HDACIs interacted with MDA-7/IL-24 prolonging generation of reactive oxygen species and Ca(2+). Quenching of reactive oxygen species and Ca(2+) blocked HDACI and MDA-7/IL-24 killing. In vivo MDA-7/IL-24 prolonged the survival of animals carrying orthotopic tumors, and HDACIs enhanced survival further. A serotype 5/3 adenovirus more effectively delivers mda-7/IL-24 to GBM tumors than a serotype 5 virus. Hence, we constructed a serotype 5/3 adenovirus that conditionally replicates in tumor cells expressing MDA-7/IL-24, in which the adenoviral early region 1A (E1A) gene was driven by the cancer-specific promoter progression elevated gene-3 [Ad.5/3 (INGN 241)-PEG-E1A-mda-7; also called Ad.5/3-CTV (cancer terminator virus)]. Ad.5/3-CTV increased the survival of mice carrying GBM tumors to a significantly greater extent than did a nonreplicative virus Ad.5/3-mda-7. Ad.5/3-CTV exhibited no toxicity in the brains of Syrian hamsters. Collectively our data demonstrate that HDACIs enhance MDA-7/IL-24 lethality, and adenoviral delivery of mda-7/IL-24 combined with tumor-specific viral replication is an effective preclinical GBM therapeutic.

  20. Direct transfection of miR-137 mimics is more effective than DNA demethylation of miR-137 promoter to augment anti-tumor mechanisms of delphinidin in human glioblastoma U87MG and LN18 cells.

    PubMed

    Chakrabarti, Mrinmay; Ray, Swapan K

    2015-11-15

    Glioblastoma is the deadliest brain tumor in humans. Recent studies suggested that 5-aza-2-deoxycytidine (AzaC) could inhibit cell cycle progression in human glioblastoma stem cells by an indirect increase in expression of the tumor suppressor microRNA-137 (miR-137). Delphinidin (DPN), a new anthocyanidin, inhibits cell growth in different cancers. We investigated inhibition of glioblastoma growth after indirect or direct overexpression of miR-137 and then DPN treatment. The highest inhibition of cell growth occurred due to treatment with combination of 10 μM AzaC and 50 μM DPN in human glioblastoma U87MG and LN18 cells. The methylation sensitive-polymerase chain reaction (MS-PCR) results showed that AzaC inhibited methylation of miR-137 promoter region, which was hypermethylated in both glioblastoma cell lines, to cause indirect increase in miR-137 expression. Our results also indicated the highest miR-137 expression after direct transfection of miR-137 mimics and DPN treatment. Combination of miR-137 mimics transfection and DPN treatment caused the highest inhibition of cell invasion and prevented angiogenic network formation due to the least expression of angiogenic factor (VEGF) in human glioblastoma cells in co-culture with human microvascular endothelial cells. This combination strategy most effectively inhibited survival factors (p-Akt and NF-κB), angiogenic factors (VEGF and b-FGF), growth factor receptor (EGFR), and invasive factors (MMP-9 and MMP-2). Direct overexpression of miR-137 most effectively augmented efficacy of DPN to induce apoptosis with activation of extrinsic and intrinsic pathways. So, sequential miR-137 overexpression and DPN treatment could be a promising combination treatment to inhibit growth of human glioblastoma cells.

  1. Charged conformal Killing spinors

    SciTech Connect

    Lischewski, Andree

    2015-01-15

    We study the twistor equation on pseudo-Riemannian Spin{sup c}-manifolds whose solutions we call charged conformal Killing spinors (CCKSs). We derive several integrability conditions for the existence of CCKS and study their relations to spinor bilinears. A construction principle for Lorentzian manifolds admitting CCKS with nontrivial charge starting from CR-geometry is presented. We obtain a partial classification result in the Lorentzian case under the additional assumption that the associated Dirac current is normal conformal and complete the classification of manifolds admitting CCKS in all dimensions and signatures ≤5 which has recently been initiated in the study of supersymmetric field theories on curved space.

  2. Medicalized killing in Auschwitz.

    PubMed

    Lifton, R J

    1982-11-01

    Since late 1977 I have been conducting a psychological study of medical behavior in Auschwitz, and of Nazi doctors in general. I have been especially interested in the relationship of doctors, SS doctors in particular, to the killing process--in the transformation from healer to killer. I am concerned with the importance of the medicalized pattern for the overall Nazi project of mass murder and have therefore tried to examine the interaction of biomedical ideology, political ideology, and individual behavior. Finally, the work raises questions of more general significance: for doctors and medicine elsewhere; for scientists, other professionals, and institutions of all kinds; for approaches to "triage" and control over life and death; and for our understanding of human nature and human values. After describing how I did the study, I will discuss what I call the Nazi "biomedical vision" and its relationship to the killing of mental patients as well as to Auschwitz. Next I will suggest features of the Auschwitz atmosphere, particularly in regard to the psychological factors, or mechanisms, that enabled the Nazi doctors to do what they did. Finally, I will turn very briefly to the more general problems raised by the study.

  3. Therapeutic Potential and Challenges of Natural Killer Cells in Treatment of Solid Tumors

    PubMed Central

    Gras Navarro, Andrea; Björklund, Andreas T.; Chekenya, Martha

    2015-01-01

    Natural killer (NK) cells are innate lymphoid cells that hold tremendous potential for effective immunotherapy for a broad range of cancers. Due to the mode of NK cell killing, requiring one-to-one target engagement and site-directed release of cytolytic granules, the therapeutic potential of NK cells has been most extensively explored in hematological malignancies. However, their ability to precisely kill antibody coated cells, cancer stem cells, and genotoxically altered cells, while maintaining tolerance to healthy cells makes them appealing therapeutic effectors for all cancer forms, including metastases. Due to their release of pro-inflammatory cytokines, NK cells may potently reverse the anti-inflammatory tumor microenvironment (TME) and augment adaptive immune responses by promoting differentiation, activation, and/or recruitment of accessory immune cells to sites of malignancy. Nevertheless, integrated and coordinated mechanisms of subversion of NK cell activity against the tumor and its microenvironment exist. Although our understanding of the receptor ligand interactions that regulate NK cell functionality has evolved remarkably, the diversity of ligands and receptors is complex, as is their mechanistic foundations in regulating NK cell function. In this article, we review the literature and highlight how the TME manipulates the NK cell phenotypes, genotypes, and tropism to evade tumor recognition and elimination. We discuss counter strategies that may be adopted to augment the efficacy of NK cell anti-tumor surveillance, the clinical trials that have been undertaken so far in solid malignancies, critically weighing the challenges and opportunities with this approach. PMID:25972872

  4. Augmented Reality in astrophysics

    NASA Astrophysics Data System (ADS)

    Vogt, Frédéric P. A.; Shingles, Luke J.

    2013-09-01

    Augmented Reality consists of merging live images with virtual layers of information. The rapid growth in the popularity of smartphones and tablets over recent years has provided a large base of potential users of Augmented Reality technology, and virtual layers of information can now be attached to a wide variety of physical objects. In this article, we explore the potential of Augmented Reality for astrophysical research with two distinct experiments: (1) Augmented Posters and (2) Augmented Articles. We demonstrate that the emerging technology of Augmented Reality can already be used and implemented without expert knowledge using currently available apps. Our experiments highlight the potential of Augmented Reality to improve the communication of scientific results in the field of astrophysics. We also present feedback gathered from the Australian astrophysics community that reveals evidence of some interest in this technology by astronomers who experimented with Augmented Posters. In addition, we discuss possible future trends for Augmented Reality applications in astrophysics, and explore the current limitations associated with the technology. This Augmented Article, the first of its kind, is designed to allow the reader to directly experiment with this technology.

  5. Overview of Methods for Overcoming Hindrance to Drug Delivery to Tumors, with Special Attention to Tumor Interstitial Fluid

    PubMed Central

    Baronzio, Gianfranco; Parmar, Gurdev; Baronzio, Miriam

    2015-01-01

    Every drug used to treat cancer (chemotherapeutics, immunological, monoclonal antibodies, nanoparticles, radionuclides) must reach the targeted cells through the tumor environment at adequate concentrations, in order to exert their cell-killing effects. For any of these agents to reach the goal cells, they must overcome a number of impediments created by the tumor microenvironment (TME), beginning with tumor interstitial fluid pressure (TIFP), and a multifactorial increase in composition of the extracellular matrix (ECM). A primary modifier of TME is hypoxia, which increases the production of growth factors, such as vascular endothelial growth factor and platelet-derived growth factor. These growth factors released by both tumor cells and bone marrow recruited myeloid cells form abnormal vasculature characterized by vessels that are tortuous and more permeable. Increased leakiness combined with increased inflammatory byproducts accumulates fluid within the tumor mass (tumor interstitial fluid), ultimately creating an increased pressure (TIFP). Fibroblasts are also up-regulated by the TME, and deposit fibers that further augment the density of the ECM, thus, further worsening the TIFP. Increased TIFP with the ECM are the major obstacles to adequate drug delivery. By decreasing TIFP and ECM density, we can expect an associated rise in drug concentration within the tumor itself. In this overview, we will describe all the methods (drugs, nutraceuticals, and physical methods of treatment) able to lower TIFP and to modify ECM used for increasing drug concentration within the tumor tissue. PMID:26258072

  6. Loss of DNAM-1 ligand expression by acute myeloid leukemia cells renders them resistant to NK cell killing.

    PubMed

    Kearney, Conor J; Ramsbottom, Kelly M; Voskoboinik, Ilia; Darcy, Phillip K; Oliaro, Jane

    2016-08-01

    Acute myeloid leukemia (AML) is associated with poor natural killer (NK) cell function through aberrant expression of NK-cell-activating receptors and their ligands on tumor cells. These alterations are thought to promote formation of inhibitory NK-target cell synapses, in which killer cell degranulation is attenuated. Allogeneic stem cell transplantation can be effective in treating AML, through restoration of NK cell lytic activity. Similarly, agents that augment NK-cell-activating signals within the immunological synapse may provide some therapeutic benefit. However, the receptor-ligand interactions that critically dictate NK cell function in AML remain undefined. Here, we demonstrate that CD112/CD155 expression is required for DNAM-1-dependent killing of AML cells. Indeed, the low, or absent, expression of CD112/CD155 on multiple AML cell lines resulted in failure to stimulate optimal NK cell function. Importantly, isolated clones with low CD112/155 expression were resistant to NK cell killing while those expressing abundant levels of CD112/155 were highly susceptible. Attenuated NK cell killing in the absence of CD112/CD155 originated from decreased NK-target cell conjugation. Furthermore, we reveal by time-lapse microscopy, a significant increase in NK cell 'failed killing' in the absence of DNAM-1 ligands. Consequently, NK cells preferentially lysed ligand-expressing cells within heterogeneous populations, driving clonal selection of CD112/CD155-negative blasts upon NK cell attack. Taken together, we identify reduced CD155 expression as a major NK cell escape mechanism in AML and an opportunity for targeted immunotherapy.

  7. Does smoking really kill anybody?

    PubMed

    Eysenck, H J

    1995-12-01

    Statements that so many people are killed by smoking use the term "kill" in a very unusual manner which is easily misunderstood by people not expert in epidemiology. In addition, the usual calculations leave out of account the fact that smoking interacts synergistically with other risk factors, so that it is a combination of risk factors rather than any specific one that is likely to have a causal influence on mortality. Strictly speaking it is quite inappropriate to state that smoking kills anybody, if we use the term "kill" in a meaningful fashion.

  8. Kill operation requires thorough analysis

    SciTech Connect

    Abel, L.W.

    1995-05-15

    Full control of a blowout well requires a properly designed post-capping kill operation because failures in regaining well control usually occur during the kill operation, not during capping. Capping (the installation of pressure control or diverter equipment on the wellhead) is generally very reliable in gaining control of a blowout well. The following techniques are some of the viable means of killing blowout wells once the capping assemblies are in place: direct shut in of the flow; bullheading; momentum kill; volumetric control for migration of fluids or lubrication after migration ceases; and dynamic kills (friction-based dynamic kills or mass flow rate kills) The objective of most post-capping operations is to stop the flow and put the well under hydrostatic control. The means of killing a blowout once capping assemblies are in place should be chosen with care to avoid problems such as cratering, equipment failure, and underground blowouts. The particular circumstances and well integrity will dictate which kill method will be the most viable. Each of these five methods are explained.

  9. Augmentation of CAR T-cell Trafficking and Antitumor Efficacy by Blocking Protein Kinase A Localization.

    PubMed

    Newick, Kheng; O'Brien, Shaun; Sun, Jing; Kapoor, Veena; Maceyko, Steven; Lo, Albert; Puré, Ellen; Moon, Edmund; Albelda, Steven M

    2016-06-01

    Antitumor treatments based on the infusion of T cells expressing chimeric antigen receptors (CAR T cells) are still relatively ineffective for solid tumors, due to the presence of immunosuppressive mediators [such as prostaglandin E2 (PGE2) and adenosine] and poor T-cell trafficking. PGE2 and adenosine activate protein kinase A (PKA), which then inhibits T-cell receptor (TCR) activation. This inhibition process requires PKA to localize to the immune synapse via binding to the membrane protein ezrin. We generated CAR T cells that expressed a small peptide called the "regulatory subunit I anchoring disruptor" (RIAD) that inhibits the association of PKA with ezrin, thus blunting the negative effects of PKA on TCR activation. After exposure to PGE2 or adenosine in vitro, CAR-RIAD T cells showed increased TCR signaling, released more cytokines, and showed enhanced killing of tumor cells compared with CAR T cells. When injected into tumor-bearing mice, the antitumor efficacy of murine and human CAR-RIAD T cells was enhanced compared with that of CAR T cells, due to resistance to tumor-induced hypofunction and increased T-cell infiltration of established tumors. Subsequent in vitro assays showed that both mouse and human CAR-RIAD cells migrated more efficiently than CAR cells did in response to the chemokine CXCL10 and also had better adhesion to various matrices. Thus, the intracellular addition of the RIAD peptide to adoptively transferred CAR T cells augments their efficacy by increasing their effector function and by improving trafficking into tumor sites. This treatment strategy, therefore, shows potential clinical application for treating solid tumors. Cancer Immunol Res; 4(6); 541-51. ©2016 AACR.

  10. Ultraviolet radiation-induced non-melanoma skin cancer in the Crl:SKH1:hr-BR hairless mouse: augmentation of tumor multiplicity by chlorophyllin and protection by indole-3-carbinol.

    PubMed

    Cope, R B; Loehr, C; Dashwood, R; Kerkvliet, N I

    2006-05-01

    Over 1 million new cases of ultraviolet radiation-induced non-melanoma skin cancers (NMSC) per year now occur in the USA and the incidence of these diseases continues to increase. New preventative strategies are required. The hypothesis tested was that dietary administration of the putative cancer chemopreventatives sodium-copper-chlorophyllin (Chlor) or indole-3-carbinol (I3C) would inhibit UV-induced skin carcinogenesis in the Crl:SKH1:hr-BR hairless mouse. Groups of 20 mice were pre-fed isocaloric/isonutritive 20% corn-oil AIN-76a based diets that contained either Chlor (1.52 g%), I3C (5.08 g%) or no chemopreventative (control) for 2 weeks followed by exposure of their dorsal skin to a 10 week incremental, sub-erythemal, carcinogenic simulated solar UV exposure regime. Feeding was continued for the duration of the experiment. Matched non-UV exposed dietary groups were also included in the experimental design. The diets had no significant (p > 0.05) effect on body weight, feed consumption, cutaneous methanol-extractable UV photoprotective substances or on cutaneous UV-reflective characteristics. By day 180, UV-irradiated mice fed the Chlor had a significantly (p < 0.05) higher tumor multiplicity (33.6 +/- 4.72; mean +/- SEM) than UV-irradiated control animals (22.8 +/- 4.25). UV-irradiated mice fed I3C had a significantly (p < 0.001) lower tumor multiplicity (13.0 +/- 2.42) than that of both the UV-irradiated control and UV-irradiated Chlor-fed mice. The Chlor or I3C diets did not significantly (p > 0.05) affect UV-induced systemic suppression of contact hypersensitivity responses. These results demonstrate augmentation of the UV-induced cutaneous carcinogenic process by dietary chlorophyllin and protection from this carcinogenic process by indole-3-carbinol via mechanisms that do not involve changes in skin optical properties, modulation of photoimmunosuppression or caloric/nutrient effects.

  11. Asymptotic symmetries on Killing horizons

    NASA Astrophysics Data System (ADS)

    Koga, Jun-Ichirou

    2001-12-01

    We investigate asymptotic symmetries regularly defined on spherically symmetric Killing horizons in Einstein theory with or without the cosmological constant. These asymptotic symmetries are described by asymptotic Killing vectors, along which the Lie derivatives of perturbed metrics vanish on a Killing horizon. We derive the general form of the asymptotic Killing vectors and find that the group of asymptotic symmetries consists of rigid O(3) rotations of a horizon two-sphere and supertranslations along the null direction on the horizon, which depend arbitrarily on the null coordinate as well as the angular coordinates. By introducing the notion of asymptotic Killing horizons, we also show that local properties of Killing horizons are preserved not only under diffeomorphisms but also under nontrivial transformations generated by the asymptotic symmetry group. Although the asymptotic symmetry group contains the Diff(S1) subgroup, which results from supertranslations dependent only on the null coordinate, it is shown that the Poisson brackets algebra of the conserved charges conjugate to asymptotic Killing vectors does not acquire nontrivial central charges. Finally, by considering extended symmetries, we discuss the fact that unnatural reduction of the symmetry group is necessary in order to obtain the Virasoro algebra with nontrivial central charges, which is not justified when we respect the spherical symmetry of Killing horizons.

  12. Equating of Augmented Subscores

    ERIC Educational Resources Information Center

    Sinharay, Sandip; Haberman, Shelby J.

    2011-01-01

    Recently, there has been an increasing level of interest in subscores for their potential diagnostic value. Haberman (2008b) suggested reporting an augmented subscore that is a linear combination of a subscore and the total score. Sinharay and Haberman (2008) and Sinharay (2010) showed that augmented subscores often lead to more accurate…

  13. Confronting an Augmented Reality

    ERIC Educational Resources Information Center

    Munnerley, Danny; Bacon, Matt; Wilson, Anna; Steele, James; Hedberg, John; Fitzgerald, Robert

    2012-01-01

    How can educators make use of augmented reality technologies and practices to enhance learning and why would we want to embrace such technologies anyway? How can an augmented reality help a learner confront, interpret and ultimately comprehend reality itself ? In this article, we seek to initiate a discussion that focuses on these questions, and…

  14. How electroshock weapons kill!

    NASA Astrophysics Data System (ADS)

    Lundquist, Marjorie

    2010-03-01

    Growing numbers of law enforcement officers now carry an electroshock weapon (ESW). Over 500 U.S. deaths have followed ESW use in the past 26 years; over 450 of these deaths followed use of an electromuscular disruptor in the past 9 years. Most training courses teach that ESWs are safe; that they can kill only by the direct effect of electric current on the heart; and that a death following use of an ESW always has some other cause. All these teachings are false! The last was disproved by Lundquist.^1 Williams^2 ruled out direct electrical effects as a cause of almost all the 213 deaths he studied, leaving disruption of normal physiological processes as the only alternative explanation. Careful study of all such deaths identifies 4 different ways that death has or could have been brought about by the ESW: kidney failure following rhabdomyolysis [rare]; cardiac arrest from hyperkalemia following rhabdomyolysis [undocumented]; lactic acid-induced ventricular fibrillation [conclusive proof impossible]; and [most common] anoxia from so much lactic acid in the circulating blood that it acts as an oxygen scavenger, continuously depleting the blood of oxygen until most of the lactate has been metabolized. ^1M. Lundquist, BAPS 54(1) K1.270(2009). ^2Howard E. Williams, Taser Electronic Control Devices and Sudden In-Custody Death, 2008.

  15. How honey kills bacteria.

    PubMed

    Kwakman, Paulus H S; te Velde, Anje A; de Boer, Leonie; Speijer, Dave; Vandenbroucke-Grauls, Christina M J E; Zaat, Sebastian A J

    2010-07-01

    With the rise in prevalence of antibiotic-resistant bacteria, honey is increasingly valued for its antibacterial activity. To characterize all bactericidal factors in a medical-grade honey, we used a novel approach of successive neutralization of individual honey bactericidal factors. All bacteria tested, including Bacillus subtilis, methicillin-resistant Staphylococcus aureus, extended-spectrum beta-lactamase producing Escherichia coli, ciprofloxacin-resistant Pseudomonas aeruginosa, and vancomycin-resistant Enterococcus faecium, were killed by 10-20% (v/v) honey, whereas > or = 40% (v/v) of a honey-equivalent sugar solution was required for similar activity. Honey accumulated up to 5.62 +/- 0.54 mM H(2)O(2) and contained 0.25 +/- 0.01 mM methylglyoxal (MGO). After enzymatic neutralization of these two compounds, honey retained substantial activity. Using B. subtilis for activity-guided isolation of the additional antimicrobial factors, we discovered bee defensin-1 in honey. After combined neutralization of H(2)O(2), MGO, and bee defensin-1, 20% honey had only minimal activity left, and subsequent adjustment of the pH of this honey from 3.3 to 7.0 reduced the activity to that of sugar alone. Activity against all other bacteria tested depended on sugar, H(2)O(2), MGO, and bee defensin-1. Thus, we fully characterized the antibacterial activity of medical-grade honey.

  16. AKT and oxidative stress team up to kill cancer cells.

    PubMed

    Dolado, Ignacio; Nebreda, Angel R

    2008-12-09

    AKT, a protein kinase frequently hyperactivated in cancer, plays an important role in cell survival and contributes to tumor cell resistance to cytotoxic therapies. A new study in this issue of Cancer Cell shows that AKT also induces the accumulation of oxygen radicals, which can be exploited to selectively kill cancer cells containing high levels of AKT activity.

  17. Breast augmentation surgery

    MedlinePlus

    ... the shape of your breasts. Talk with a plastic surgeon if you are considering breast augmentation. Discuss ... mammograms or breast x-rays before surgery. The plastic surgeon will do a routine breast exam. Several ...

  18. Oxidative Stress Induced by Polymyxin E Is Involved in Rapid Killing of Paenibacillus polymyxa

    PubMed Central

    Zhu, Yuyi; Qin, Wangrong

    2017-01-01

    Historically, the colistin has been thought to kill bacteria through membrane lysis. Here, we present an alternative mechanism that colistin induces rapid Paenibacillus polymyxa death through reactive oxygen species production. This significantly augments our understanding of the mechanism of colistin action, which is critical knowledge toward the yield development of colistin in the future. PMID:28321410

  19. Monoclonal Antibodies against Epidermal Growth Factor Receptor Acquire an Ability To Kill Tumor Cells through Complement Activation by Mutations That Selectively Facilitate the Hexamerization of IgG on Opsonized Cells.

    PubMed

    Tammen, Annalina; Derer, Stefanie; Schwanbeck, Ralf; Rösner, Thies; Kretschmer, Anna; Beurskens, Frank J; Schuurman, Janine; Parren, Paul W H I; Valerius, Thomas

    2017-02-15

    Triggering of the complement cascade induces tumor cell lysis via complement-dependent cytotoxicity (CDC) and attracts and activates cytotoxic cells. It therefore represents an attractive mechanism for mAb in cancer immunotherapy development. The classical complement pathway is initiated by IgG molecules that have assembled into ordered hexamers after binding their Ag on the tumor cell surface. The requirements for CDC are further impacted by factors such as Ab epitope, valency, and affinity. Thus, mAb against well-validated solid tumor targets, such as the epidermal growth factor receptor (EGFR) that effectively induces complement activation and CDC, are highly sought after. The potency of complement activation by IgG Abs can be increased via several strategies. We identified single-point mutations in the Fc domain (e.g., E345K or E430G) enhancing Fc:Fc interactions, hexamer formation, and CDC after Ab binds cell-surface Ag. We show that EGFR Abs directed against clinically relevant epitopes can be converted into mAb with unprecedented CDC activity. Alternative strategies rely on increasing the affinity of monomeric IgG for C1q by introduction of a quadruple mutation at the C1q binding site or via generation of an IgG1/IgG3 chimera. In this study we show that selective enhancement of C1q binding via avidity modulation is superior to the unattended increase in C1q binding via affinity approaches, particularly for target cells with reduced EGFR expression levels. Improving Fc:Fc interactions of Ag-bound IgG therefore represents a highly promising and novel approach for potentiating the anti-tumor activity of therapeutic mAb against EGFR and potentially other tumor targets.

  20. Patient-Derived Antibody Targets Tumor Cells

    Cancer.gov

    An NCI Cancer Currents blog on an antibody derived from patients that killed tumor cells in cell lines of several cancer types and slowed tumor growth in mouse models of brain and lung cancer without evidence of side effects.

  1. Percutaneous Vertebral Body Augmentation: An Updated Review

    PubMed Central

    Omidi-Kashani, Farzad

    2014-01-01

    There are many medical conditions like osteoporosis, tumor, or osteonecrosis that weaken the structural strength of the vertebral body and prone it to fracture. Percutaneous vertebral augmentation that is usually applied by polymethylmethacrylate is a relatively safe, effective, and long lasting procedure commonly performed in these situations. In this paper, we updated a review of biomechanics, indications, contraindications, surgical techniques, complications, and overall prognosis of these minimally invasive spinal procedures. PMID:25379561

  2. Augmenting computer networks

    NASA Technical Reports Server (NTRS)

    Bokhari, S. H.; Raza, A. D.

    1984-01-01

    Three methods of augmenting computer networks by adding at most one link per processor are discussed: (1) A tree of N nodes may be augmented such that the resulting graph has diameter no greater than 4log sub 2((N+2)/3)-2. Thi O(N(3)) algorithm can be applied to any spanning tree of a connected graph to reduce the diameter of that graph to O(log N); (2) Given a binary tree T and a chain C of N nodes each, C may be augmented to produce C so that T is a subgraph of C. This algorithm is O(N) and may be used to produce augmented chains or rings that have diameter no greater than 2log sub 2((N+2)/3) and are planar; (3) Any rectangular two-dimensional 4 (8) nearest neighbor array of size N = 2(k) may be augmented so that it can emulate a single step shuffle-exchange network of size N/2 in 3(t) time steps.

  3. Selective killing of nonreplicating mycobacteria.

    PubMed

    Bryk, Ruslana; Gold, Benjamin; Venugopal, Aditya; Singh, Jasbir; Samy, Raghu; Pupek, Krzysztof; Cao, Hua; Popescu, Carmen; Gurney, Mark; Hotha, Srinivas; Cherian, Joseph; Rhee, Kyu; Ly, Lan; Converse, Paul J; Ehrt, Sabine; Vandal, Omar; Jiang, Xiuju; Schneider, Jean; Lin, Gang; Nathan, Carl

    2008-03-13

    Antibiotics are typically more effective against replicating rather than nonreplicating bacteria. However, a major need in global health is to eradicate persistent or nonreplicating subpopulations of bacteria such as Mycobacterium tuberculosis (Mtb). Hence, identifying chemical inhibitors that selectively kill bacteria that are not replicating is of practical importance. To address this, we screened for inhibitors of dihydrolipoamide acyltransferase (DlaT), an enzyme required by Mtb to cause tuberculosis in guinea pigs and used by the bacterium to resist nitric oxide-derived reactive nitrogen intermediates, a stress encountered in the host. Chemical screening for inhibitors of Mtb DlaT identified select rhodanines as compounds that almost exclusively kill nonreplicating mycobacteria in synergy with products of host immunity, such as nitric oxide and hypoxia, and are effective on bacteria within macrophages, a cellular reservoir for latent Mtb. Compounds that kill nonreplicating pathogens in cooperation with host immunity could complement the conventional chemotherapy of infectious disease.

  4. Augmented Cognition Transition

    DTIC Science & Technology

    2009-05-01

    exercises at ATC’s Mulberry Point MOUT grounds. The troops received two days of training prior to executing data collection runs with the EEG system in...team leader (TL) led 12 soldiers on a mission to “kill or capture an HVT” whose last known location was in one of the buildings in Mulberry Point. Up

  5. Towards Pervasive Augmented Reality: Context-Awareness in Augmented Reality.

    PubMed

    Grubert, Jens; Langlotz, Tobias; Zollmann, Stefanie; Regenbrecht, Holger

    2016-03-17

    Augmented Reality is a technique that enables users to interact with their physical environment through the overlay of digital information. While being researched for decades, more recently, Augmented Reality moved out of the research labs and into the field. While most of the applications are used sporadically and for one particular task only, current and future scenarios will provide a continuous and multi-purpose user experience. Therefore, in this paper, we present the concept of Pervasive Augmented Reality, aiming to provide such an experience by sensing the user's current context and adapting the AR system based on the changing requirements and constraints. We present a taxonomy for Pervasive Augmented Reality and context-aware Augmented Reality, which classifies context sources and context targets relevant for implementing such a context-aware, continuous Augmented Reality experience. We further summarize existing approaches that contribute towards Pervasive Augmented Reality. Based our taxonomy and survey, we identify challenges for future research directions in Pervasive Augmented Reality.

  6. Computer Augmented Video Education.

    ERIC Educational Resources Information Center

    Sousa, M. B.

    1979-01-01

    Describes project CAVE (Computer Augmented Video Education), an ongoing effort at the U.S. Naval Academy to present lecture material on videocassette tape, reinforced by drill and practice through an interactive computer system supported by a 12 channel closed circuit television distribution and production facility. (RAO)

  7. Chin augmentation - slideshow

    MedlinePlus

    ... anatomy URL of this page: //medlineplus.gov/ency/presentations/100009.htm Chin augmentation - series—Normal anatomy To use the sharing features on this page, please enable JavaScript. Go to slide 1 out of 5 Go to slide 2 ...

  8. Augmentative & Alternative Communication

    ERIC Educational Resources Information Center

    Murphy, Patti

    2007-01-01

    There is no definitive recipe for augmentative and alternative communication (AAC) success, but its universal ingredients can be found at home. The main ones are: (1) Understanding that all children need to express themselves, however outgoing or shy they may be; (2) Willingness to embrace the technology that may help your child regardless of your…

  9. Augmented Thermal Bus

    NASA Technical Reports Server (NTRS)

    Schrage, Dean S. (Inventor)

    1996-01-01

    The present invention is directed to an augmented thermal bus. In the present design a plurality of thermo-electric heat pumps are used to couple a source plate to a sink plate. Each heat pump is individually controlled by a model based controller. The controller coordinates the heat pumps to maintain isothermality in the source.

  10. Augmented thermal bus

    NASA Technical Reports Server (NTRS)

    Schrage, Dean S. (Inventor)

    1993-01-01

    The present invention is directed to an augmented thermal bus. In the present design a plurity of thermo-electric heat pumps are used to couple a source plate to a sink plate. Each heat pump is individually controlled by a model based controller. The controller coordinates the heat pump to maintain isothermality in the source.

  11. Augmented Reality Binoculars.

    PubMed

    Oskiper, Taragay; Sizintsev, Mikhail; Branzoi, Vlad; Samarasekera, Supun; Kumar, Rakesh

    2015-05-01

    In this paper we present an augmented reality binocular system to allow long range high precision augmentation of live telescopic imagery with aerial and terrain based synthetic objects, vehicles, people and effects. The inserted objects must appear stable in the display and must not jitter and drift as the user pans around and examines the scene with the binoculars. The design of the system is based on using two different cameras with wide field of view and narrow field of view lenses enclosed in a binocular shaped shell. Using the wide field of view gives us context and enables us to recover the 3D location and orientation of the binoculars much more robustly, whereas the narrow field of view is used for the actual augmentation as well as to increase precision in tracking. We present our navigation algorithm that uses the two cameras in combination with an inertial measurement unit and global positioning system in an extended Kalman filter and provides jitter free, robust and real-time pose estimation for precise augmentation. We have demonstrated successful use of our system as part of information sharing example as well as a live simulated training system for observer training, in which fixed and rotary wing aircrafts, ground vehicles, and weapon effects are combined with real world scenes.

  12. Farm Education at Stony Kill.

    ERIC Educational Resources Information Center

    Parisio, Richard

    1986-01-01

    Describes typical winter farm lessons for students visiting Stony Kill Farm Environmental Education Center located 70 miles north of New York City: butter and corncake making, soil erosion experiments, dissecting and growing seeds. Emphasizes major theme of conservation of farmland from destructive farming practices and careless development. (NEC)

  13. Does Assessment Kill Student Creativity?

    ERIC Educational Resources Information Center

    Beghetto, Ronald A.

    2005-01-01

    Does assessment kill creativity? In this article, creativity is defined and discussed and an overview of creativity and motivational research is provided to describe how assessment practices can influence students' creativity. Recommendations for protecting creativity when assessing students also are provided.

  14. Batten augmented triangular beam

    NASA Technical Reports Server (NTRS)

    Adams, Louis R.; Hedgepeth, John M.

    1986-01-01

    The BAT (Batten-Augmented Triangular) BEAM is characterized by battens which are buckled in the deployed state, thus preloading the truss. The preload distribution is determined, and the effects of various external loading conditions are investigated. The conceptual design of a deployer is described and loads are predicted. The influence of joint imperfections on effective member stiffness is investigated. The beam is assessed structurally.

  15. Beetle Kill Wall at NREL

    ScienceCinema

    None

    2016-07-12

    When it comes to designing an interior decorative feature for one of the most energy efficient office buildings in the world, very few would consider bringing in a beetle to do the job. But thats what happened at the U.S. Department of Energy's (DOE) Research Support Facility (RSF) located on the National Renewable Energy Laboratory (NREL) campus.In June, the RSF will become home to more than 800 workers from DOE and NREL and building visitors will be greeted with a soaring, two-story high wall entirely covered with wood harvested from the bark beetle infestation that has killed millions of pine trees in the Western U.S. But, the use of beetle kill wood is just one example of the resources being leveraged to make the RSF a model for sustainability and one more step toward NRELs goal to be a net zero energy campus.

  16. Beetle Kill Wall at NREL

    SciTech Connect

    2010-01-01

    When it comes to designing an interior decorative feature for one of the most energy efficient office buildings in the world, very few would consider bringing in a beetle to do the job. But thats what happened at the U.S. Department of Energy's (DOE) Research Support Facility (RSF) located on the National Renewable Energy Laboratory (NREL) campus.In June, the RSF will become home to more than 800 workers from DOE and NREL and building visitors will be greeted with a soaring, two-story high wall entirely covered with wood harvested from the bark beetle infestation that has killed millions of pine trees in the Western U.S. But, the use of beetle kill wood is just one example of the resources being leveraged to make the RSF a model for sustainability and one more step toward NRELs goal to be a net zero energy campus.

  17. Simple Implant Augmentation Rhinoplasty

    PubMed Central

    Nguyen, Anh H.; Bartlett, Erica L.; Kania, Katarzyna; Bae, Sang Mo

    2015-01-01

    Augmentation rhinoplasty among Asian patients is often performed to improve the height of the nasal dorsum. As the use of autogenous tissues poses certain limitations, alloplastic materials are a viable alternative with a long history of use in Asia. The superiority of one implant prosthesis over another for augmentation rhinoplasty is a matter of debate, with each material representing varying strengths and weaknesses, indications for use, and precautions to consider in nasal implant placement. An implant prosthesis should be used on a case-by-case basis. Augmentation rhinoplasty requires the consideration of specific anatomical preoperative factors, including the external nose, nasal length, nasofrontal angle, humps, and facial proportions. It is equally important to consider several operative guidelines to appropriately shape implants to minimize the occurrence of adverse effects and postoperative complications. The most common postoperative complications include infection, nasal height change, movement of implant prosthesis, and silicone implant protrusion. In addition, the surgeon should consider the current standards of Asian beauty aesthetics to better understand the patient's desired outcome. PMID:26648804

  18. Women who kill their mates.

    PubMed

    Bourget, Dominique; Gagné, Pierre

    2012-01-01

    Spousal homicide perpetrators are much more likely to be men than women. Accordingly, little research has focused on delineating characteristics of women who have committed spousal homicide. A retrospective clinical review of coroners' files containing all cases of spousal homicide occurring in Quebec over a 20-year period was carried out. A total of 276 spousal homicides occurred between 1991 and 2010, with 42 homicides by female spouses and 234 homicides by male spouses. Differences between homicides committed by female offenders and male offenders are discussed, and findings on spousal homicide committed by women are compared with those of previous studies. Findings regarding offenses perpetrated by females in the context of mental illness, domestic violence, and homicide-suicide are explored. The finding that only 28% of the female offenders in the Quebec sample had previously been subjected to violence by their victim is in contrast to the popular belief and reports that indicate that most female-perpetrated spousal homicide occurs in self-defense or in reaction to long-term abuse. In fact, women rarely gave a warning before killing their mates. Most did not suffer from a mental illness, although one-fifth were acutely intoxicated at the time of the killing. In the vast majority of cases of women who killed their mates, there were very few indicators that might have signaled the risk and helped predict the violent lethal behavior.

  19. 33 CFR 117.702 - Arthur Kill.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... 33 Navigation and Navigable Waters 1 2011-07-01 2011-07-01 false Arthur Kill. 117.702 Section 117... OPERATION REGULATIONS Specific Requirements New Jersey § 117.702 Arthur Kill. (a) The draw of the Arthur Kill (AK) Railroad Bridge shall be maintained in the full open position for navigation at all...

  20. 33 CFR 117.702 - Arthur Kill.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... 33 Navigation and Navigable Waters 1 2013-07-01 2013-07-01 false Arthur Kill. 117.702 Section 117... OPERATION REGULATIONS Specific Requirements New Jersey § 117.702 Arthur Kill. (a) The draw of the Arthur Kill (AK) Railroad Bridge shall be maintained in the full open position for navigation at all...

  1. 33 CFR 117.702 - Arthur Kill.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... 33 Navigation and Navigable Waters 1 2012-07-01 2012-07-01 false Arthur Kill. 117.702 Section 117... OPERATION REGULATIONS Specific Requirements New Jersey § 117.702 Arthur Kill. (a) The draw of the Arthur Kill (AK) Railroad Bridge shall be maintained in the full open position for navigation at all...

  2. 33 CFR 117.702 - Arthur Kill.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... 33 Navigation and Navigable Waters 1 2014-07-01 2014-07-01 false Arthur Kill. 117.702 Section 117... OPERATION REGULATIONS Specific Requirements New Jersey § 117.702 Arthur Kill. (a) The draw of the Arthur Kill (AK) Railroad Bridge shall be maintained in the full open position for navigation at all...

  3. 33 CFR 117.702 - Arthur Kill.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 33 Navigation and Navigable Waters 1 2010-07-01 2010-07-01 false Arthur Kill. 117.702 Section 117... OPERATION REGULATIONS Specific Requirements New Jersey § 117.702 Arthur Kill. (a) The draw of the Arthur Kill (AK) Railroad Bridge shall be maintained in the full open position for navigation at all...

  4. Augmented reality in surgical procedures

    NASA Astrophysics Data System (ADS)

    Samset, E.; Schmalstieg, D.; Vander Sloten, J.; Freudenthal, A.; Declerck, J.; Casciaro, S.; Rideng, Ø.; Gersak, B.

    2008-02-01

    Minimally invasive therapy (MIT) is one of the most important trends in modern medicine. It includes a wide range of therapies in videoscopic surgery and interventional radiology and is performed through small incisions. It reduces hospital stay-time by allowing faster recovery and offers substantially improved cost-effectiveness for the hospital and the society. However, the introduction of MIT has also led to new problems. The manipulation of structures within the body through small incisions reduces dexterity and tactile feedback. It requires a different approach than conventional surgical procedures, since eye-hand co-ordination is not based on direct vision, but more predominantly on image guidance via endoscopes or radiological imaging modalities. ARIS*ER is a multidisciplinary consortium developing a new generation of decision support tools for MIT by augmenting visual and sensorial feedback. We will present tools based on novel concepts in visualization, robotics and haptics providing tailored solutions for a range of clinical applications. Examples from radio-frequency ablation of liver-tumors, laparoscopic liver surgery and minimally invasive cardiac surgery will be presented. Demonstrators were developed with the aim to provide a seamless workflow for the clinical user conducting image-guided therapy.

  5. 33 CFR 117.801 - Newtown Creek, Dutch Kills, English Kills and their tributaries.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... 33 Navigation and Navigable Waters 1 2014-07-01 2014-07-01 false Newtown Creek, Dutch Kills, English Kills and their tributaries. 117.801 Section 117.801 Navigation and Navigable Waters COAST GUARD....801 Newtown Creek, Dutch Kills, English Kills and their tributaries. (a) The following...

  6. 33 CFR 117.801 - Newtown Creek, Dutch Kills, English Kills and their tributaries.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 33 Navigation and Navigable Waters 1 2010-07-01 2010-07-01 false Newtown Creek, Dutch Kills, English Kills and their tributaries. 117.801 Section 117.801 Navigation and Navigable Waters COAST GUARD....801 Newtown Creek, Dutch Kills, English Kills and their tributaries. (a) The following...

  7. 33 CFR 117.801 - Newtown Creek, Dutch Kills, English Kills and their tributaries.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... 33 Navigation and Navigable Waters 1 2012-07-01 2012-07-01 false Newtown Creek, Dutch Kills, English Kills and their tributaries. 117.801 Section 117.801 Navigation and Navigable Waters COAST GUARD....801 Newtown Creek, Dutch Kills, English Kills and their tributaries. (a) The following...

  8. 33 CFR 117.801 - Newtown Creek, Dutch Kills, English Kills and their tributaries.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... 33 Navigation and Navigable Waters 1 2013-07-01 2013-07-01 false Newtown Creek, Dutch Kills, English Kills and their tributaries. 117.801 Section 117.801 Navigation and Navigable Waters COAST GUARD....801 Newtown Creek, Dutch Kills, English Kills and their tributaries. (a) The following...

  9. 33 CFR 117.801 - Newtown Creek, Dutch Kills, English Kills and their tributaries.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... 33 Navigation and Navigable Waters 1 2011-07-01 2011-07-01 false Newtown Creek, Dutch Kills, English Kills and their tributaries. 117.801 Section 117.801 Navigation and Navigable Waters COAST GUARD....801 Newtown Creek, Dutch Kills, English Kills and their tributaries. (a) The following...

  10. Mutually Augmented Cognition

    NASA Astrophysics Data System (ADS)

    Friesdorf, Florian; Pangercic, Dejan; Bubb, Heiner; Beetz, Michael

    In mac, an ergonomic dialog-system and algorithms will be developed that enable human experts and companions to be integrated into knowledge gathering and decision making processes of highly complex cognitive systems (e.g. Assistive Household as manifested further in the paper). In this event we propose to join algorithms and methodologies coming from Ergonomics and Artificial Intelligence that: a) make cognitive systems more congenial for non-expert humans, b) facilitate their comprehension by utilizing a high-level expandable control code for human experts and c) augment representation of such cognitive system into “deep representation” obtained through an interaction with human companions.

  11. Killing(-Yano) tensors in string theory

    NASA Astrophysics Data System (ADS)

    Chervonyi, Yuri; Lunin, Oleg

    2015-09-01

    We construct the Killing(-Yano) tensors for a large class of charged black holes in higher dimensions and study general properties of such tensors, in particular, their behavior under string dualities. Killing(-Yano) tensors encode the symmetries beyond isometries, which lead to insights into dynamics of particles and fields on a given geometry by providing a set of conserved quantities. By analyzing the eigenvalues of the Killing tensor, we provide a prescription for constructing several conserved quantities starting from a single object, and we demonstrate that Killing tensors in higher dimensions are always associated with ellipsoidal coordinates. We also determine the transformations of the Killing(-Yano) tensors under string dualities, and find the unique modification of the Killing-Yano equation consistent with these symmetries. These results are used to construct the explicit form of the Killing(-Yano) tensors for the Myers-Perry black hole in arbitrary number of dimensions and for its charged version.

  12. Hearing Loss: Hearing Augmentation.

    PubMed

    Atcherson, Samuel R; Moreland, Christopher; Zazove, Philip; McKee, Michael M

    2015-07-01

    Etiologies of hearing loss vary. When hearing loss is diagnosed, referral to an otology subspecialist, audiology subspecialist, or hearing aid dispenser to discuss treatment options is appropriate. Conventional hearing aids provide increased sound pressure in the ear canal for detection of sounds that might otherwise be soft or inaudible. Hearing aids can be used for sensorineural, conductive, or mixed hearing loss by patients with a wide range of hearing loss severity. The most common type of hearing loss is high-frequency, which affects audibility and perception of speech consonants, but not vowels. As the severity of hearing loss increases, the benefit of hearing aids for speech perception decreases. Implantable devices such as cochlear implants, middle ear implants, and bone-anchored implants can benefit specific patient groups. Hearing assistive technology devices provide auditory, visual, or tactile information to augment hearing and increase environmental awareness of sounds. Hearing assistive devices include wireless assistive listening device systems, closed captioning, hearing aid-compatible telephones, and other devices. For some patients, financial barriers and health insurance issues limit acquisition of hearing aids, implantable devices, and hearing assistive devices. Physicians should be aware that for some patients and families, hearing augmentation may not be desired for cultural reasons.

  13. Fish kill from underwater explosions

    USGS Publications Warehouse

    Stuart, David J.

    1962-01-01

    The U.S. Geological Survey has used 23 different shotpoints during two seasons of field work in our seismic study of crustal structure in western United States. Without exception, it has been found that under-water shotpoints result in a more efficient conversion of explosive energy into seismic energy than do drilled-hole shotpoints. This experience, together with elimination of drilling costs, has led to the use of underwater shotpoints wherever possible. Three of the 23 shotpoints were in the Pacific Ocean, and for these we have no detailed information on the fish kill. Another six shotpoints were located in inland bodies of water. These are: * Soda Lake near Fallon, Nevada * Mono Lake near Lee Vining, California * Lake Mead near Boulder City, Nevada * Shasta Lake near Redding, California * C.J. Strike Reservoir near Bruneau, Idaho * Lucky Peak Reservoir near Boise, Idaho The 22 high-explosive charges, weighing a total of 95,100 pounds, that were fired in lakes containing fish life resulted in the known death of 2,413 game fish with a total weight of 759 pounds. The average mortality was 110 game fish or 34.5 pounds of game fish killed per average shot of 4,325 pounds of high-explosives.

  14. Pilot-optimal augmentation synthesis

    NASA Technical Reports Server (NTRS)

    Schmidt, D. K.

    1978-01-01

    An augmentation synthesis method usable in the absence of quantitative handling qualities specifications, and yet explicitly including design objectives based on pilot-rating concepts, is presented. The algorithm involves the unique approach of simultaneously solving for the stability augmentation system (SAS) gains, pilot equalization and pilot rating prediction via optimal control techniques. Simultaneous solution is required in this case since the pilot model (gains, etc.) depends upon the augmented plant dynamics, and the augmentation is obviously not a priori known. Another special feature is the use of the pilot's objective function (from which the pilot model evolves) to design the SAS.

  15. Disparate effects of interferon-gamma and tumor necrosis factor-alpha on early neutrophil respiratory burst and fungicidal responses to Candida albicans hyphae in vitro.

    PubMed Central

    Diamond, R D; Lyman, C A; Wysong, D R

    1991-01-01

    We examined effects of priming with recombinant human interferon-gamma (IFN) or tumor necrosis factor-alpha (TNF) on neutrophil responses to Candida albicans hyphae. Both cytokines increased early superoxide generation after hyphal stimulation. The more pronounced effects of TNF were accompanied by an augmented surface membrane depolarization rate and were insensitive to both pertussis toxin and calcium ion chelation, but were negated by concomitant incubation with puromycin or cycloheximide during priming. IFN augmented hyphal killing despite its only minor enhancement of early respiratory burst responses, but TNF reduced neutrophil fungicidal activity to nearly 40% below those by unprimed control cells even though it enhanced early superoxide responses more dramatically. Though TNF-primed neutrophils killed hyphae at normal initial rates, IFN-primed or even unprimed cells manifested more fungicidal sustained activity. These disparate consequences of cytokine priming on hyphal destruction were paralleled by differences in late generation of potentially candidacidal oxidants, hydrogen peroxide, and hypochlorous acid. IFN added during priming failed to correct TNF-associated functional defects in neutrophil anti-Candida responses. Thus, augmentation of early respiratory burst responses to oxidant-sensitive organisms need not necessarily reflect concomitant salutary effects on microbicidal activity. Images PMID:1846880

  16. Dioscin augments HSV-tk-mediated suicide gene therapy for melanoma by promoting connexin-based intercellular communication

    PubMed Central

    Li, Bin; Wu, Yingya; Liu, Xijuan; Tan, Yuhui; Du, Biaoyan

    2017-01-01

    Suicide gene therapy is a promising strategy against melanoma. However, the low efficiency of the gene transfer technique can limit its application. Our preliminary data showed that dioscin, a glucoside saponin, could upregulate the expression of connexins Cx26 and Cx43, major components of gap junctions, in melanoma cells. We hypothesized that dioscin may increase the bystander effect of herpes simplex virus thymidine kinase/ganciclovir (HSV-tk/GCV) through increasing the formation of gap junctions. Further analysis showed that dioscin indeed could increase the gap junctional intercellular communication in B16 melanoma cells, resulting in more efficient GCV-induced bystander killing in B16tk cells. By contrast, overexpression of dominant negative Cx43 impaired the cell-cell communication of B16 cells and subsequently weakened the bystander effect of HSV-tk/GCV gene therapy. In vivo, combination treatment with dioscin and GCV of tumor-bearing mice with 30% positive B16tk cells and 70% wild-type B16 cells caused a significant reduction in tumor volume and weight compared to treatment with GCV or dioscin alone. Taken together, these results demonstrated that dioscin could augment the bystander effect of the HSV-tk/GCV system through increasing connexin-mediated gap junction coupling. PMID:27903977

  17. Decay Dynamics of Tumors

    PubMed Central

    2016-01-01

    The fractional cell kill is a mathematical expression describing the rate at which a certain population of cells is reduced to a fraction of itself. We investigate the mathematical function that governs the rate at which a solid tumor is lysed by a cell population of cytotoxic lymphocytes. We do it in the context of enzyme kinetics, using geometrical and analytical arguments. We derive the equations governing the decay of a tumor in the limit in which it is plainly surrounded by immune cells. A cellular automaton is used to test such decay, confirming its validity. Finally, we introduce a modification in the fractional cell kill so that the expected dynamics is attained in the mentioned limit. We also discuss the potential of this new function for non-solid and solid tumors which are infiltrated with lymphocytes. PMID:27310010

  18. NASA Communications Augmentation network

    NASA Technical Reports Server (NTRS)

    Omidyar, Guy C.; Butler, Thomas E.; Laios, Straton C.

    1990-01-01

    The NASA Communications (Nascom) Division of the Mission Operations and Data Systems Directorate (MO&DSD) is to undertake a major initiative to develop the Nascom Augmentation (NAUG) network to achieve its long-range service objectives for operational data transport to support the Space Station Freedom Program, the Earth Observing System (EOS), and other projects. The NAUG is the Nascom ground communications network being developed to accommodate the operational traffic of the mid-1990s and beyond. The NAUG network development will be based on the Open Systems Interconnection Reference Model (OSI-RM). This paper describes the NAUG network architecture, subsystems, topology, and services; addresses issues of internetworking the Nascom network with other elements of the Space Station Information System (SSIS); discusses the operations environment. This paper also notes the areas of related research and presents the current conception of how the network will provide broadband services in 1998.

  19. Augmented reality system

    NASA Astrophysics Data System (ADS)

    Lin, Chien-Liang; Su, Yu-Zheng; Hung, Min-Wei; Huang, Kuo-Cheng

    2010-08-01

    In recent years, Augmented Reality (AR)[1][2][3] is very popular in universities and research organizations. The AR technology has been widely used in Virtual Reality (VR) fields, such as sophisticated weapons, flight vehicle development, data model visualization, virtual training, entertainment and arts. AR has characteristics to enhance the display output as a real environment with specific user interactive functions or specific object recognitions. It can be use in medical treatment, anatomy training, precision instrument casting, warplane guidance, engineering and distance robot control. AR has a lot of vantages than VR. This system developed combines sensors, software and imaging algorithms to make users feel real, actual and existing. Imaging algorithms include gray level method, image binarization method, and white balance method in order to make accurate image recognition and overcome the effects of light.

  20. NAESA Augmentation Pilot Project

    NASA Technical Reports Server (NTRS)

    Hoover, John J.

    1998-01-01

    This project was one project within the Native American Earth and Space Academy (NAESA). NAESA is a national initiative comprised of several organizations that support programs which focus on 1) enhancing the technological, scientific and pedagogical skills of K-14 teachers who instruct Native Americans, 2) enhancing the understanding and applications of science, technology, and engineering of college-bound Native Americans and teaching them general college "survival skills" (e.g., test taking, time management, study habits), 3) enhancing the scientific and pedagogical skills of the faculty of tribally-controllcd colleges and community colleges with large Native American enrollments, and 4) strengthening the critical relationships between students, their parents, tribal elders, and their communities. This Augmentation Pilot Project focused on the areas of community-school alliances and intemet technology use in teaching and learning and daily living addressing five major objectives.

  1. Augmented nonlinear differentiator design

    NASA Astrophysics Data System (ADS)

    Shao, Xingling; Liu, Jun; Yang, Wei; Tang, Jun; Li, Jie

    2017-06-01

    This paper presents a sigmoid function based augmented nonlinear differentiator (AND) for calculating the noise-less time derivative from a noisy measurement. The prominent advantages of the present differentiation technique are: (i) compared to the existing tracking differentiators, better noise suppression ability can be achieved without appreciable delay; (ii) the enhanced noise-filtering mechanism not only can be applied to the designed differentiator, but also can be extended for improving noise-tolerance capability of the available differentiators. In addition, the convergence property and robustness performance against noises are investigated via singular perturbation theory and describing function method, respectively. Also, comparison with several classical differentiators is given to illustrate the superiority of AND in noise suppression. Finally, applications on autopilot design and displacement following for nonlinear mass spring mechanical system are given to demonstrate the effectiveness and applicability of the proposed AND technique.

  2. Magnetohydrodynamic Augmented Propulsion Experiment

    NASA Technical Reports Server (NTRS)

    Litchford, Ron J.

    2008-01-01

    Over the past several years, efforts have been under way to design and develop an operationally flexible research facility for investigating the use of cross-field MHD accelerators as a potential thrust augmentation device for thermal propulsion systems. The baseline configuration for this high-power experimental facility utilizes a 1.5-MWe multi-gas arc-heater as a thermal driver for a 2-MWe MHD accelerator, which resides in a large-bore 2-tesla electromagnet. A preliminary design study using NaK seeded nitrogen as the working fluid led to an externally diagonalized segmented MHD channel configuration based on an expendable heat-sink design concept. The current status report includes a review of engineering/design work and performance optimization analyses and summarizes component hardware fabrication and development efforts, preliminary testing results, and recent progress toward full-up assembly and testing

  3. Augmented Virtual Reality Laboratory

    NASA Technical Reports Server (NTRS)

    Tully-Hanson, Benjamin

    2015-01-01

    Real time motion tracking hardware has for the most part been cost prohibitive for research to regularly take place until recently. With the release of the Microsoft Kinect in November 2010, researchers now have access to a device that for a few hundred dollars is capable of providing redgreenblue (RGB), depth, and skeleton data. It is also capable of tracking multiple people in real time. For its original intended purposes, i.e. gaming, being used with the Xbox 360 and eventually Xbox One, it performs quite well. However, researchers soon found that although the sensor is versatile, it has limitations in real world applications. I was brought aboard this summer by William Little in the Augmented Virtual Reality (AVR) Lab at Kennedy Space Center to find solutions to these limitations.

  4. Targeted Inhibition of the miR-199a/214 Cluster by CRISPR Interference Augments the Tumor Tropism of Human Induced Pluripotent Stem Cell-Derived Neural Stem Cells under Hypoxic Condition

    PubMed Central

    Xu, Xuehu; An, Xiuli; Wang, Shu

    2016-01-01

    The human induced pluripotent stem cell (hiPSC) provides a breakthrough approach that helps overcoming ethical and allergenic challenges posed in application of neural stem cells (NSCs) in targeted cancer gene therapy. However, the tumor-tropic capacity of hiPSC-derived NSCs (hiPS-NSCs) still has much room to improve. Here we attempted to promote the tumor tropism of hiPS-NSCs by manipulating the activity of endogenous miR-199a/214 cluster that is involved in regulation of hypoxia-stimulated cell migration. We first developed a baculovirus-delivered CRISPR interference (CRISPRi) system that sterically blocked the E-box element in the promoter of the miR-199a/214 cluster with an RNA-guided catalytically dead Cas9 (dCas9). We then applied this CRISPRi system to hiPS-NSCs and successfully suppressed the expression of miR-199a-5p, miR-199a-3p, and miR-214 in the microRNA gene cluster. Meanwhile, the expression levels of their targets related to regulation of hypoxia-stimulated cell migration, such as HIF1A, MET, and MAPK1, were upregulated. Further migration assays demonstrated that the targeted inhibition of the miR-199a/214 cluster significantly enhanced the tumor tropism of hiPS-NSCs both in vitro and in vivo. These findings suggest a novel application of CRISPRi in NSC-based tumor-targeted gene therapy. PMID:27965712

  5. Augmented Reality Comes to Physics

    ERIC Educational Resources Information Center

    Buesing, Mark; Cook, Michael

    2013-01-01

    Augmented reality (AR) is a technology used on computing devices where processor-generated graphics are rendered over real objects to enhance the sensory experience in real time. In other words, what you are really seeing is augmented by the computer. Many AR games already exist for systems such as Kinect and Nintendo 3DS and mobile apps, such as…

  6. A kill curve for Phanerozoic marine species

    NASA Technical Reports Server (NTRS)

    Raup, D. M.

    1991-01-01

    A kill curve for Phanerozoic species is developed from an analysis of the stratigraphic ranges of 17,621 genera, as compiled by Sepkoski. The kill curve shows that a typical species' risk of extinction varies greatly, with most time intervals being characterized by very low risk. The mean extinction rate of 0.25/m.y. is thus a mixture of long periods of negligible extinction and occasional pulses of much higher rate. Because the kill curve is merely a description of the fossil record, it does not speak directly to the causes of extinction. The kill curve may be useful, however, to li inverted question markmit choices of extinction mechanisms.

  7. Timelike Killing spinors in seven dimensions

    SciTech Connect

    Cariglia, Marco; Conamhna, Oisin A.P. Mac

    2004-12-15

    We employ the G-structure formalism to study supersymmetric solutions of minimal and SU(2) gauged supergravities in seven dimensions admitting Killing spinors with an associated timelike Killing vector. The most general such Killing spinor defines a SU(3) structure. We deduce necessary and sufficient conditions for the existence of a timelike Killing spinor on the bosonic fields of the theories, and find that such configurations generically preserve one out of 16 supersymmetries. Using our general supersymmetric ansatz we obtain numerous new solutions, including squashed or deformed anti-de Sitter solutions of the gauged theory, and a large class of Goedel-like solutions with closed timelike curves.

  8. Antitumor Effects of Chimeric Receptor Engineered Human T Cells Directed to Tumor Stroma

    PubMed Central

    Kakarla, Sunitha; Chow, Kevin KH; Mata, Melinda; Shaffer, Donald R; Song, Xiao-Tong; Wu, Meng-Fen; Liu, Hao; Wang, Lisa L; Rowley, David R; Pfizenmaier, Klaus; Gottschalk, Stephen

    2013-01-01

    Cancer-associated fibroblasts (CAFs), the principle component of the tumor-associated stroma, form a highly protumorigenic and immunosuppressive microenvironment that mediates therapeutic resistance. Co-targeting CAFs in addition to cancer cells may therefore augment the antitumor response. Fibroblast activation protein-α (FAP), a type 2 dipeptidyl peptidase, is expressed on CAFs in a majority of solid tumors making it an attractive immunotherapeutic target. To target FAP-positive CAFs in the tumor-associated stroma, we genetically modified T cells to express a FAP-specific chimeric antigen receptor (CAR). The resulting FAP-specific T cells recognized and killed FAP-positive target cells as determined by proinflammatory cytokine release and target cell lysis. In an established A549 lung cancer model, adoptive transfer of FAP-specific T cells significantly reduced FAP-positive stromal cells, with a concomitant decrease in tumor growth. Combining these FAP-specific T cells with T cells that targeted the EphA2 antigen on the A549 cancer cells themselves significantly enhanced overall antitumor activity and conferred a survival advantage compared to either alone. Our study underscores the value of co-targeting both CAFs and cancer cells to increase the benefits of T-cell immunotherapy for solid tumors. PMID:23732988

  9. Glioma Stemlike Cells Enhance the Killing of Glioma Differentiated Cells by Cytotoxic Lymphocytes

    PubMed Central

    Bassoy, Esen Yonca; Chiusolo, Valentina; Jacquemin, Guillaume; Riccadonna, Cristina; Walker, Paul R.; Martinvalet, Denis

    2016-01-01

    Glioblastoma multiforme, the most aggressive primary brain tumor, is maintained by a subpopulation of glioma cells with self-renewal properties that are able to recapitulate the entire tumor even after surgical resection or chemo-radiotherapy. This typifies the vast heterogeneity of this tumor with the two extremes represented on one end by the glioma stemlike cells (GSC) and on the other by the glioma differentiated cells (GDC). Interestingly, GSC are more sensitive to immune effector cells than the GDC counterpart. However, how GSC impact on the killing on the GDC and vice versa is not clear. Using a newly developed cytotoxicity assay allowing to simultaneously monitor cytotoxic lymphocytes-mediated killing of GSC and GDC, we found that although GSC were always better killed and that their presence enhanced the killing of GDC. In contrast, an excess of GDC had a mild protective effect on the killing of GSC, depending on the CTL type. Overall, our results suggest that during combination therapy, immunotherapy would be the most effective after prior treatment with conventional therapies. PMID:27073883

  10. Magnetohydrodynamic Augmented Propulsion Experiment

    NASA Technical Reports Server (NTRS)

    Litchford, Ron J.; Cole, John; Lineberry, John; Chapman, Jim; Schmidt, Harold; Cook, Stephen (Technical Monitor)

    2002-01-01

    A fundamental obstacle to routine space access is the specific energy limitations associated with chemical fuels. In the case of vertical take-off, the high thrust needed for vertical liftoff and acceleration to orbit translates into power levels in the 10 GW range. Furthermore, useful payload mass fractions are possible only if the exhaust particle energy (i.e., exhaust velocity) is much greater than that available with traditional chemical propulsion. The electronic binding energy released by the best chemical reactions (e.g., LOX/LH2 for example, is less than 2 eV per product molecule (approx. 1.8 eV per H2O molecule), which translates into particle velocities less than 5 km/s. Useful payload fractions, however, will require exhaust velocities exceeding 15 km/s (i.e., particle energies greater than 20 eV). As an added challenge, the envisioned hypothetical RLV (reusable launch vehicle) should accomplish these amazing performance feats while providing relatively low acceleration levels to orbit (2-3g maximum). From such fundamental considerations, it is painfully obvious that planned and current RLV solutions based on chemical fuels alone represent only a temporary solution and can only result in minor gains, at best. What is truly needed is a revolutionary approach that will dramatically reduce the amount of fuel and size of the launch vehicle. This implies the need for new compact high-power energy sources as well as advanced accelerator technologies for increasing engine exhaust velocity. Electromagnetic acceleration techniques are of immense interest since they can be used to circumvent the thermal limits associated with conventional propulsion systems. This paper describes the Magnetohydrodynamic Augmented Propulsion Experiment (MAPX) being undertaken at NASA Marshall Space Flight Center (MSFC). In this experiment, a 1-MW arc heater is being used as a feeder for a 1-MW magnetohydrodynamic (MHD) accelerator. The purpose of the experiment is to demonstrate

  11. A General Functional Response of Cytotoxic T Lymphocyte-Mediated Killing of Target Cells

    PubMed Central

    Gadhamsetty, Saikrishna; Marée, Athanasius F.M.; Beltman, Joost B.; de Boer, Rob J.

    2014-01-01

    Cytotoxic T lymphocytes (CTLs) kill virus-infected cells and tumor cells, and play a critical role in immune protection. Our knowledge of how the CTL killing efficiency varies with CTL and target cell numbers is limited. Here, we simulate a region of lymphoid tissue using a cellular Potts model to characterize the functional response of CTL killing of target cells, and find that the total killing rate saturates both with the CTL and the target cell densities. The relative saturation in CTL and target cell densities is determined by whether a CTL can kill multiple target cells at the same time, and whether a target cell can be killed by many CTLs together. We find that all the studied regimes can be well described by a double-saturation (DS) function with two different saturation constants. We show that this DS model can be mechanistically derived for the cases where target cells are killed by a single CTL. For the other cases, a biological interpretation of the parameters is still possible. Our results imply that this DS function can be used as a tool to predict the cellular interactions in cytotoxicity data. PMID:24739177

  12. A general functional response of cytotoxic T lymphocyte-mediated killing of target cells.

    PubMed

    Gadhamsetty, Saikrishna; Marée, Athanasius F M; Beltman, Joost B; de Boer, Rob J

    2014-04-15

    Cytotoxic T lymphocytes (CTLs) kill virus-infected cells and tumor cells, and play a critical role in immune protection. Our knowledge of how the CTL killing efficiency varies with CTL and target cell numbers is limited. Here, we simulate a region of lymphoid tissue using a cellular Potts model to characterize the functional response of CTL killing of target cells, and find that the total killing rate saturates both with the CTL and the target cell densities. The relative saturation in CTL and target cell densities is determined by whether a CTL can kill multiple target cells at the same time, and whether a target cell can be killed by many CTLs together. We find that all the studied regimes can be well described by a double-saturation (DS) function with two different saturation constants. We show that this DS model can be mechanistically derived for the cases where target cells are killed by a single CTL. For the other cases, a biological interpretation of the parameters is still possible. Our results imply that this DS function can be used as a tool to predict the cellular interactions in cytotoxicity data.

  13. Control Augmented Structural Synthesis

    NASA Technical Reports Server (NTRS)

    Lust, Robert V.; Schmit, Lucien A.

    1988-01-01

    A methodology for control augmented structural synthesis is proposed for a class of structures which can be modeled as an assemblage of frame and/or truss elements. It is assumed that both the plant (structure) and the active control system dynamics can be adequately represented with a linear model. The structural sizing variables, active control system feedback gains and nonstructural lumped masses are treated simultaneously as independent design variables. Design constraints are imposed on static and dynamic displacements, static stresses, actuator forces and natural frequencies to ensure acceptable system behavior. Multiple static and dynamic loading conditions are considered. Side constraints imposed on the design variables protect against the generation of unrealizable designs. While the proposed approach is fundamentally more general, here the methodology is developed and demonstrated for the case where: (1) the dynamic loading is harmonic and thus the steady state response is of primary interest; (2) direct output feedback is used for the control system model; and (3) the actuators and sensors are collocated.

  14. Abstraction Augmented Markov Models.

    PubMed

    Caragea, Cornelia; Silvescu, Adrian; Caragea, Doina; Honavar, Vasant

    2010-12-13

    High accuracy sequence classification often requires the use of higher order Markov models (MMs). However, the number of MM parameters increases exponentially with the range of direct dependencies between sequence elements, thereby increasing the risk of overfitting when the data set is limited in size. We present abstraction augmented Markov models (AAMMs) that effectively reduce the number of numeric parameters of k(th) order MMs by successively grouping strings of length k (i.e., k-grams) into abstraction hierarchies. We evaluate AAMMs on three protein subcellular localization prediction tasks. The results of our experiments show that abstraction makes it possible to construct predictive models that use significantly smaller number of features (by one to three orders of magnitude) as compared to MMs. AAMMs are competitive with and, in some cases, significantly outperform MMs. Moreover, the results show that AAMMs often perform significantly better than variable order Markov models, such as decomposed context tree weighting, prediction by partial match, and probabilistic suffix trees.

  15. Augmented Likelihood Image Reconstruction.

    PubMed

    Stille, Maik; Kleine, Matthias; Hägele, Julian; Barkhausen, Jörg; Buzug, Thorsten M

    2016-01-01

    The presence of high-density objects remains an open problem in medical CT imaging. Data of projections passing through objects of high density, such as metal implants, are dominated by noise and are highly affected by beam hardening and scatter. Reconstructed images become less diagnostically conclusive because of pronounced artifacts that manifest as dark and bright streaks. A new reconstruction algorithm is proposed with the aim to reduce these artifacts by incorporating information about shape and known attenuation coefficients of a metal implant. Image reconstruction is considered as a variational optimization problem. The afore-mentioned prior knowledge is introduced in terms of equality constraints. An augmented Lagrangian approach is adapted in order to minimize the associated log-likelihood function for transmission CT. During iterations, temporally appearing artifacts are reduced with a bilateral filter and new projection values are calculated, which are used later on for the reconstruction. A detailed evaluation in cooperation with radiologists is performed on software and hardware phantoms, as well as on clinically relevant patient data of subjects with various metal implants. Results show that the proposed reconstruction algorithm is able to outperform contemporary metal artifact reduction methods such as normalized metal artifact reduction.

  16. Bull heading to kill live gas wells

    SciTech Connect

    Oudeman, P.; Avest, D. ter; Grodal, E.O.; Asheim, H.A.; Meissner, R.J.H.

    1994-12-31

    To kill a live closed-in gas well by bull heading down the tubing, the selected pump rate should be high enough to ensure efficient displacement of the gas into the formation (i.e., to avoid the kill fluid bypassing the gas). On the other hand, the pressures that develop during bull heading at high rate must not exceed wellhead pressure rating, tubing or casing burst pressures or the formation breakdown gradient, since this will lead, at best, to a very inefficient kill job. Given these constraints, the optimum kill rate, requited hydraulic horsepower, density and type of kill fluids have to be selected. For this purpose a numerical simulator has been developed, which predicts the sequence of events during bull heading. Pressures and flow rates in the well during the kill job are calculated, taking to account slip between the gas and kill fluid, hydrostatic and friction pressure drop, wellbore gas compression and leak-off to the formation. Comparison with the results of a dedicated field test demonstrates that these parameters can be estimated accurately. Example calculations will be presented to show how the simulator can be used to identify an optimum kill scenario.

  17. Augmented Reality Comes to Physics

    NASA Astrophysics Data System (ADS)

    Buesing, Mark; Cook, Michael

    2013-04-01

    Augmented reality (AR) is a technology used on computing devices where processor-generated graphics are rendered over real objects to enhance the sensory experience in real time. In other words, what you are really seeing is augmented by the computer. Many AR games already exist for systems such as Kinect and Nintendo 3DS and mobile apps, such as Tagwhat and Star Chart (a must for astronomy class). The yellow line marking first downs in a televised football game2 and the enhanced puck that makes televised hockey easier to follow3 both use augmented reality to do the job.

  18. Antibacterial surface design - Contact kill

    NASA Astrophysics Data System (ADS)

    Kaur, Rajbir; Liu, Song

    2016-08-01

    Designing antibacterial surfaces has become extremely important to minimize Healthcare Associated Infections which are a major cause of mortality worldwide. A previous biocide-releasing approach is based on leaching of encapsulated biocides such as silver and triclosan which exerts negative impacts on the environment and potentially contributes to the development of bacterial resistance. This drawback of leachable compounds led to the shift of interest towards a more sustainable and environmentally friendly approach: contact-killing surfaces. Biocides that can be bound onto surfaces to give the substrates contact-active antibacterial activity include quaternary ammonium compounds (QACs), quaternary phosphoniums (QPs), carbon nanotubes, antibacterial peptides, and N-chloramines. Among the above, QACs and N-chloramines are the most researched contact-active biocides. We review the engineering of contact-active surfaces using QACs or N-chloramines, the modes of actions as well as the test methods. The charge-density threshold of cationic surfaces for desired antibacterial efficacy and attempts to combine various biocides for the generation of new contact-active surfaces are discussed in detail. Surface positive charge density is identified as a key parameter to define antibacterial efficacy. We expect that this research field will continue to attract more research interest in view of the potential impact of self-disinfective surfaces on healthcare-associated infections, food safety and corrosion/fouling resistance required on industrial surfaces such as oil pipes and ship hulls.

  19. Momentum kill procedure can quickly control blowouts

    SciTech Connect

    Watson, W.D. ); Moore, P. )

    1993-08-30

    The momentum kill method can help in quickly regaining control of a blowing well, providing the blowing well rate and fluid properties can be estimated reasonably. The momentum of the kill fluid counteracts and overcomes the flowing momentum of formation fluids. In other words, sufficient mud density pumped at a sufficient rate is directed into the flow stream to force the escaping fluid column back into the well bore. Sufficient kill fluid hydrostatic pressure must be stacked'' in the hole so that the well remains dead after the operation. The momentum kill is not a panacea for all blowouts. An assessment must be made of the potential problems unique to this method, and certain requirements must be met if the technique is to be successful. The paper discusses some of the considerations for evaluating the use of the momentum kill method.

  20. Augmenter of liver regeneration.

    PubMed

    Gandhi, Chandrashekhar R

    2012-07-09

    'Augmenter of liver regeneration' (ALR) (also known as hepatic stimulatory substance or hepatopoietin) was originally found to promote growth of hepatocytes in the regenerating or injured liver. ALR is expressed ubiquitously in all organs, and exclusively in hepatocytes in the liver. ALR, a survival factor for hepatocytes, exhibits significant homology with ERV1 (essential for respiration and viability) protein that is essential for the survival of the yeast, Saccharomyces cerevisiae. ALR comprises 198 to 205 amino acids (approximately 22 kDa), but is post-translationally modified to three high molecular weight species (approximately 38 to 42 kDa) found in hepatocytes. ALR is present in mitochondria, cytosol, endoplasmic reticulum, and nucleus. Mitochondrial ALR may be involved in oxidative phosphorylation, but also functions as sulfhydryl oxidase and cytochrome c reductase, and causes Fe/S maturation of proteins. ALR, secreted by hepatocytes, stimulates synthesis of TNF-α, IL-6, and nitric oxide in Kupffer cells via a G-protein coupled receptor. While the 22 kDa rat recombinant ALR does not stimulate DNA synthesis in hepatocytes, the short form (15 kDa) of human recombinant ALR was reported to be equipotent as or even stronger than TGF-α or HGF as a mitogen for hepatocytes. Altered serum ALR levels in certain pathological conditions suggest that it may be a diagnostic marker for liver injury/disease. Although ALR appears to have multiple functions, the knowledge of its role in various organs, including the liver, is extremely inadequate, and it is not known whether different ALR species have distinct functions. Future research should provide better understanding of the expression and functions of this enigmatic molecule.

  1. Mersiline mesh in premaxillary augmentation.

    PubMed

    Foda, Hossam M T

    2005-01-01

    Premaxillary retrusion may distort the aesthetic appearance of the columella, lip, and nasal tip. This defect is characteristically seen in, but not limited to, patients with cleft lip nasal deformity. This study investigated 60 patients presenting with premaxillary deficiencies in which Mersiline mesh was used to augment the premaxilla. All the cases had surgery using the external rhinoplasty technique. Two methods of augmentation with Mersiline mesh were used: the Mersiline roll technique, for the cases with central symmetric deficiencies, and the Mersiline packing technique, for the cases with asymmetric deficiencies. Premaxillary augmentation with Mersiline mesh proved to be simple technically, easy to perform, and not associated with any complications. Periodic follow-up evaluation for a mean period of 32 months (range, 12-98 months) showed that an adequate degree of premaxillary augmentation was maintained with no clinically detectable resorption of the mesh implant.

  2. Spacetime encodings. III. Second order Killing tensors

    SciTech Connect

    Brink, Jeandrew

    2010-01-15

    This paper explores the Petrov type D, stationary axisymmetric vacuum (SAV) spacetimes that were found by Carter to have separable Hamilton-Jacobi equations, and thus admit a second-order Killing tensor. The derivation of the spacetimes presented in this paper borrows from ideas about dynamical systems, and illustrates concepts that can be generalized to higher-order Killing tensors. The relationship between the components of the Killing equations and metric functions are given explicitly. The origin of the four separable coordinate systems found by Carter is explained and classified in terms of the analytic structure associated with the Killing equations. A geometric picture of what the orbital invariants may represent is built. Requiring that a SAV spacetime admits a second-order Killing tensor is very restrictive, selecting very few candidates from the group of all possible SAV spacetimes. This restriction arises due to the fact that the consistency conditions associated with the Killing equations require that the field variables obey a second-order differential equation, as opposed to a fourth-order differential equation that imposes the weaker condition that the spacetime be SAV. This paper introduces ideas that could lead to the explicit computation of more general orbital invariants in the form of higher-order Killing tensors.

  3. [Special considerations in breast cancer treatment of an augmented breast].

    PubMed

    Mátrai, Zoltán; Gulyás, Gusztáv; Tóth, László; Sávolt, Akos; Kunos, Csaba; Pesthy, Pál; Bartal, Alexandra; Szabó, Eva; Kásler, Miklós

    2011-10-16

    Breast augmentation surgery involving the use of implants has been one of the most popular plastic surgical procedures for decades. As the multi-million female population who received breast implants ages, the risk of cancer is increasing rapidly, therefore the incidence of malignant disease in association with breast implants will increase as well. Although there is no relationship between tumor development and implants, these cases require special considerations in diagnostics, therapy and follow-up methods. Appropriate multidisciplinary treatment of tumors in augmented breasts corresponding with modern oncoplastic principles can only be accomplished based on adequate oncological, breast and plastic surgical knowledge. Supposing a possible increase of this condition in Hungary, too, authors provide a wide review of the literature on the special oncological and esthetic considerations, for the first time in Hungarian language.

  4. Preexisting antitumor immunity augments the antitumor effects of chemotherapy.

    PubMed

    Zhang, Lingbing; Feng, Dongdong; Yu, Lynda X; Tsung, Kangla; Norton, Jeffrey A

    2013-06-01

    Efficacy of cancer chemotherapy is generally believed to be the result of direct drug killing of tumor cells. However, increased tumor cell killing does not always lead to improved efficacy. Herein, we demonstrate that the status of antitumor immunity at the time of chemotherapy treatment is a critical factor affecting the therapeutic outcome in that tumor-bearing mice that possess preexisting antitumor immunity respond to chemotherapy much better than those that do not. Enhancing antitumor immunity before or at the time of chemotherapy-induced antigen release increases subsequent response to chemotherapy significantly. By in vitro and in vivo measurements of antitumor immunity, we found a close correlation between the intensity of antitumor immunity activated by chemotherapy and the efficacy of treatment. Immune intervention with interleukin-12 during the early phase of chemotherapy-induced immune activation greatly amplifies the antitumor response, often resulting in complete tumor eradication not only at the chemo-treated local site, but also systemically. These findings provide additional evidence for an immune-mediated antitumor response to chemotherapy. Further, our results show that timely immune modification of chemotherapy-activated antitumor immunity can result in enhanced antitumor-immune response and complete tumor eradication.

  5. Killing Initial Data on spacelike conformal boundaries

    NASA Astrophysics Data System (ADS)

    Paetz, Tim-Torben

    2016-08-01

    We analyze Killing Initial Data on Cauchy surfaces in conformally rescaled vacuum space-times satisfying Friedrich's conformal field equations. As an application, we derive the KID equations on a spacelike ℐ-.

  6. Killing vector fields and harmonic superfield theories

    SciTech Connect

    Groeger, Josua

    2014-09-15

    The harmonic action functional allows a natural generalisation to semi-Riemannian supergeometry, also referred to as harmonic, which resembles the supersymmetric sigma models studied in high energy physics. We show that Killing vector fields are infinitesimal supersymmetries of this harmonic action and prove three different Noether theorems in this context. En passant, we provide a homogeneous treatment of five characterisations of Killing vector fields on semi-Riemannian supermanifolds, thus filling a gap in the literature.

  7. Killing vector fields and harmonic superfield theories

    NASA Astrophysics Data System (ADS)

    Groeger, Josua

    2014-09-01

    The harmonic action functional allows a natural generalisation to semi-Riemannian supergeometry, also referred to as harmonic, which resembles the supersymmetric sigma models studied in high energy physics. We show that Killing vector fields are infinitesimal supersymmetries of this harmonic action and prove three different Noether theorems in this context. En passant, we provide a homogeneous treatment of five characterisations of Killing vector fields on semi-Riemannian supermanifolds, thus filling a gap in the literature.

  8. Bayesian Alternation during Tactile Augmentation

    PubMed Central

    Goeke, Caspar M.; Planera, Serena; Finger, Holger; König, Peter

    2016-01-01

    A large number of studies suggest that the integration of multisensory signals by humans is well-described by Bayesian principles. However, there are very few reports about cue combination between a native and an augmented sense. In particular, we asked the question whether adult participants are able to integrate an augmented sensory cue with existing native sensory information. Hence for the purpose of this study, we build a tactile augmentation device. Consequently, we compared different hypotheses of how untrained adult participants combine information from a native and an augmented sense. In a two-interval forced choice (2 IFC) task, while subjects were blindfolded and seated on a rotating platform, our sensory augmentation device translated information on whole body yaw rotation to tactile stimulation. Three conditions were realized: tactile stimulation only (augmented condition), rotation only (native condition), and both augmented and native information (bimodal condition). Participants had to choose one out of two consecutive rotations with higher angular rotation. For the analysis, we fitted the participants' responses with a probit model and calculated the just notable difference (JND). Then, we compared several models for predicting bimodal from unimodal responses. An objective Bayesian alternation model yielded a better prediction (χred2 = 1.67) than the Bayesian integration model (χred2 = 4.34). Slightly higher accuracy showed a non-Bayesian winner takes all (WTA) model (χred2 = 1.64), which either used only native or only augmented values per subject for prediction. However, the performance of the Bayesian alternation model could be substantially improved (χred2 = 1.09) utilizing subjective weights obtained by a questionnaire. As a result, the subjective Bayesian alternation model predicted bimodal performance most accurately among all tested models. These results suggest that information from augmented and existing sensory modalities in

  9. Secretome of tumor-associated leukocytes augment epithelial-mesenchymal transition in positive lymph node breast cancer patients via activation of EGFR/Tyr845 and NF-κB/p65 signaling pathway.

    PubMed

    Elghonaimy, Eslam A; Ibrahim, Sherif A; Youns, Amal; Hussein, Zeinab; Nouh, Mohamed Akram; El-Mamlouk, Tahani; El-Shinawi, Mohamed; Mostafa Mohamed, Mona

    2016-09-01

    Epithelial-mesenchymal transition (EMT) is an essential process in breast cancer metastasis. The aim of the present study was to determine the role of secretions of tumor-associated leukocytes (TALs) isolated from negative and positive lymph nodes (nLNs and pLNs, respectively) breast cancer patients in regulating EMT mechanism and the associated signaling pathways. We found an increased infiltration of TALs, which was associated with downregulation of E-cadherin and over-expression of vimentin in the breast carcinoma tissues of pLNs as compared to nLNs patients and normal breast tissues obtained from healthy volunteers during mammoplasty. Furthermore, TALs isolated from pLNs breast cancer patients secreted an elevated panel of cytokines by up to 2-5-fold when compared with those isolated from nLNs patients. Secretome of TALs of pLNs possessed higher TARC, IGF-1, IL-3, TNF-β, IL-5, G-CSF, IL-4, and IL-1α with more than a fivefold compared to those of nLNs. Using the human breast cancer cell lines MCF-7 and MDA-MB-231, we found that cytokines secreted by TALs isolated from nLNs and pLNs breast cancer patients promoted EMT via upregulation of TGF-β and vimentin and downregulation of E-cadherin at messenger RNA (mRNA) levels in both cell lines and at protein level in MCF-7. While TGF-β is over-expressed by MDA-MB-231 seeded in media conditioned by secretome of TALs isolated from nLNs and pLNs breast cancer patients. The downstream TGF-β signaling transcription factors, Snail, Slug, and Twist, known to be associated with EMT mechanism were over-expressed by MCF-7 and MDA-MB-231 seeded in media conditioned by secretome of TALs isolated from nLNs and pLNs breast cancer patients. Acquisition of EMT in MCF-7 cells is mechanistically attributed to the activation of EGFR((Tyr845)) and NF-κB/p65((Ser276)) signaling which are significantly highly expressed by MCF-7 cells seeded in media conditioned by secretome of TALs isolated from pLNs compared to nLNs patients. Overall

  10. Killing of Actinobacillus actinomycetemcomitans by human lactoferrin.

    PubMed Central

    Kalmar, J R; Arnold, R R

    1988-01-01

    Actinobacillus actinomycetemcomitans is a fastidious, facultative gram-negative rod associated with endocarditis, certain forms of periodontal disease, and other focal infections. Human neutrophils have demonstrated bactericidal activity against A. actinomycetemcomitans, and much of the oxygen-dependent killing has been attributed to the myeloperoxidase-H2O2-halide system. However, the contribution of other neutrophil components to killing activity is obscure. Lactoferrin, an iron-binding glycoprotein, is a major constituent of neutrophil-specific granules and is also found in mucosal secretions. In this report, we show that human lactoferrin is bactericidal for A. actinomycetemcomitans. Killing activity required an unsaturated (iron- and anion-free) molecule that produced a 2-log decrease in viability within 120 min at 37 degrees C at a concentration of 1.9 microM. Besides exhibiting concentration dependence, killing kinetics were affected by minor variations in temperature and pH. Magnesium, a divalent cation thought to stabilize lipopolysaccharide interactions on the surface of gram-negative organisms, enhanced lactoferrin killing of A. actinomycetemcomitans, while other cations, such as potassium and calcium, had no effect. Our data suggest that lactoferrin contributes to killing of A. actinomycetemcomitans by human neutrophils and that it may also play a significant role in innate secretory defense against this potential periodontopathogen. PMID:3417349

  11. Augmented Reality Tower Technology Assessment

    NASA Technical Reports Server (NTRS)

    Reisman, Ronald J.; Brown, David M.

    2009-01-01

    Augmented Reality technology may help improve Air Traffic Control Tower efficiency and safety during low-visibility conditions. This paper presents the assessments of five off-duty controllers who shadow-controlled' with an augmented reality prototype in their own facility. Initial studies indicated unanimous agreement that this technology is potentially beneficial, though the prototype used in the study was not adequate for operational use. Some controllers agreed that augmented reality technology improved situational awareness, had potential to benefit clearance, control, and coordination tasks and duties and could be very useful for acquiring aircraft and weather information, particularly aircraft location, heading, and identification. The strongest objections to the prototype used in this study were directed at aircraft registration errors, unacceptable optical transparency, insufficient display performance in sunlight, inadequate representation of the static environment and insufficient symbology.

  12. Augmentation cystoplasty in neurogenic bladder

    PubMed Central

    Kocjancic, Ervin; Demirdağ, Çetin

    2016-01-01

    The aim of this review is to update the indications, contraindications, technique, complications, and the tissue engineering approaches of augmentation cystoplasty (AC) in patients with neurogenic bladder. PubMed/MEDLINE was searched for the keywords "augmentation cystoplasty," "neurogenic bladder," and "bladder augmentation." Additional relevant literature was determined by examining the reference lists of articles identified through the search. The update review of of the indications, contraindications, technique, outcome, complications, and tissue engineering approaches of AC in patients with neurogenic bladder is presented. Although some important progress has been made in tissue engineering AC, conventional AC still has an important role in the surgical treatment of refractory neurogenic lower urinary tract dysfunction. PMID:27617312

  13. Therapeutic options for lip augmentation.

    PubMed

    Segall, Lorne; Ellis, David A F

    2007-11-01

    Aesthetic ideals vary with emerging fashion trends and within different cultures. However, over the past few decades, fuller lips have been considered a desirable trait. Many younger patients are presenting for lip augmentation to achieve the sought-after look commonly seen in many fashion magazines. In addition, as individuals age, they lose lip volume, with a thinning of the red lip, some effacement of the vermillion border, and elongation and flattening of the white portion of the lip. Rejuvenation of the lips plays a key role in restoring a more youthful appearance. As a result, lip augmentation appeals to a wide spectrum of patients who present with various different aesthetic goals and expectations. Numerous therapeutic options exist for aesthetic lip augmentation, ranging from temporary and permanent injectable fillers to implants and other surgical techniques.

  14. Augmentation-related brain plasticity

    PubMed Central

    Di Pino, Giovanni; Maravita, Angelo; Zollo, Loredana; Guglielmelli, Eugenio; Di Lazzaro, Vincenzo

    2014-01-01

    Today, the anthropomorphism of the tools and the development of neural interfaces require reconsidering the concept of human-tools interaction in the framework of human augmentation. This review analyses the plastic process that the brain undergoes when it comes into contact with augmenting artificial sensors and effectors and, on the other hand, the changes that the use of external augmenting devices produces in the brain. Hitherto, few studies investigated the neural correlates of augmentation, but clues on it can be borrowed from logically-related paradigms: sensorimotor training, cognitive enhancement, cross-modal plasticity, sensorimotor functional substitution, use and embodiment of tools. Augmentation modifies function and structure of a number of areas, i.e., primary sensory cortices shape their receptive fields to become sensitive to novel inputs. Motor areas adapt the neuroprosthesis representation firing-rate to refine kinematics. As for normal motor outputs, the learning process recruits motor and premotor cortices and the acquisition of proficiency decreases attentional recruitment, focuses the activity on sensorimotor areas and increases the basal ganglia drive on the cortex. Augmentation deeply relies on the frontoparietal network. In particular, premotor cortex is involved in learning the control of an external effector and owns the tool motor representation, while the intraparietal sulcus extracts its visual features. In these areas, multisensory integration neurons enlarge their receptive fields to embody supernumerary limbs. For operating an anthropomorphic neuroprosthesis, the mirror system is required to understand the meaning of the action, the cerebellum for the formation of its internal model and the insula for its interoception. In conclusion, anthropomorphic sensorized devices can provide the critical sensory afferences to evolve the exploitation of tools through their embodiment, reshaping the body representation and the sense of the self

  15. Combustion-augmented laser ramjets

    NASA Astrophysics Data System (ADS)

    Horisawa, Hideyuki; Tamada, Kazunobu; Kimura, Itsuro

    2006-05-01

    A preliminary study of combustion-augmented laser-ramjets was conducted, in which chemical propellant such as a gaseous hydrogen/air mixture was utilized and detonated with a focused laser beam in order to obtain a higher impulse compared to the case only using lasers. CFD analysis of internal conical-nozzle flows and experimental measurements including impulse measurement were conducted to evaluate effects of chemical reaction on thrust performance improvement. From the results, a significant improvement in the thrust performances was confirmed with addition of a small amount of hydrogen to propellant air, or in combustion-augmented operation.

  16. Rapid Killing of Acinetobacter baumannii by Polymyxins Is Mediated by a Hydroxyl Radical Death Pathway

    PubMed Central

    Sampson, Timothy R.; Liu, Xiang; Schroeder, Max R.; Kraft, Colleen S.; Burd, Eileen M.

    2012-01-01

    Acinetobacter baumannii is an opportunistic pathogen that is a cause of clinically significant nosocomial infections. Increasingly, clinical isolates of A. baumannii are extensively resistant to numerous antibiotics, and the use of polymyxin antibiotics against these infections is often the final treatment option. Historically, the polymyxins have been thought to kill bacteria through membrane lysis. Here, we present an alternative mechanism based on data demonstrating that polymyxins induce rapid cell death through hydroxyl radical production. Supporting this notion, we found that inhibition of radical production delays the ability of polymyxins to kill A. baumannii. Notably, we demonstrate that this mechanism of killing occurs in multidrug-resistant clinical isolates of A. baumannii and that this response is not induced in a polymyxin-resistant isolate. This study is the first to demonstrate that polymyxins induce rapid killing of A. baumannii and other Gram-negatives through hydroxyl radical production. This significantly augments our understanding of the mechanism of polymyxin action, which is critical knowledge toward the development of adjunctive therapies, particularly given the increasing necessity for treatment with these antibiotics in the clinical setting. PMID:22908157

  17. Rapid killing of Acinetobacter baumannii by polymyxins is mediated by a hydroxyl radical death pathway.

    PubMed

    Sampson, Timothy R; Liu, Xiang; Schroeder, Max R; Kraft, Colleen S; Burd, Eileen M; Weiss, David S

    2012-11-01

    Acinetobacter baumannii is an opportunistic pathogen that is a cause of clinically significant nosocomial infections. Increasingly, clinical isolates of A. baumannii are extensively resistant to numerous antibiotics, and the use of polymyxin antibiotics against these infections is often the final treatment option. Historically, the polymyxins have been thought to kill bacteria through membrane lysis. Here, we present an alternative mechanism based on data demonstrating that polymyxins induce rapid cell death through hydroxyl radical production. Supporting this notion, we found that inhibition of radical production delays the ability of polymyxins to kill A. baumannii. Notably, we demonstrate that this mechanism of killing occurs in multidrug-resistant clinical isolates of A. baumannii and that this response is not induced in a polymyxin-resistant isolate. This study is the first to demonstrate that polymyxins induce rapid killing of A. baumannii and other Gram-negatives through hydroxyl radical production. This significantly augments our understanding of the mechanism of polymyxin action, which is critical knowledge toward the development of adjunctive therapies, particularly given the increasing necessity for treatment with these antibiotics in the clinical setting.

  18. Top carnivores increase their kill rates on prey as a response to human-induced fear.

    PubMed

    Smith, Justine A; Wang, Yiwei; Wilmers, Christopher C

    2015-03-07

    The fear induced by predators on their prey is well known to cause behavioural adjustments by prey that can ripple through food webs. Little is known, however, about the analogous impacts of humans as perceived top predators on the foraging behaviour of carnivores. Here, we investigate the influence of human-induced fear on puma foraging behaviour using location and prey consumption data from 30 tagged individuals living along a gradient of human development. We observed strong behavioural responses by female pumas to human development, whereby their fidelity to kill sites and overall consumption time of prey declined with increasing housing density by 36 and 42%, respectively. Females responded to this decline in prey consumption time by increasing the number of deer they killed in high housing density areas by 36% over what they killed in areas with little residential development. The loss of food from declines in prey consumption time paired with increases in energetic costs associated with killing more prey may have consequences for puma populations, particularly with regard to reproductive success. In addition, greater carcass availability is likely to alter community dynamics by augmenting food resources for scavengers. In light of the extensive and growing impact of habitat modification, our study emphasizes that knowledge of the indirect effects of human activity on animal behaviour is a necessary component in understanding anthropogenic impacts on community dynamics and food web function.

  19. Augmented reality and cone beam CT guidance for transoral robotic surgery

    PubMed Central

    Richmon, Jeremy D.; Sorger, Jonathan M.; Azizian, Mahdi; Taylor, Russell H.

    2015-01-01

    In transoral robotic surgery preoperative image data do not reflect large deformations of the operative workspace from perioperative setup. To address this challenge, in this study we explore image guidance with cone beam computed tomographic angiography to guide the dissection of critical vascular landmarks and resection of base-of-tongue neoplasms with adequate margins for transoral robotic surgery. We identify critical vascular landmarks from perioperative c-arm imaging to augment the stereoscopic view of a da Vinci si robot in addition to incorporating visual feedback from relative tool positions. Experiments resecting base-of-tongue mock tumors were conducted on a series of ex vivo and in vivo animal models comparing the proposed workflow for video augmentation to standard non-augmented practice and alternative, fluoroscopy-based image guidance. Accurate identification of registered augmented critical anatomy during controlled arterial dissection and en bloc mock tumor resection was possible with the augmented reality system. The proposed image-guided robotic system also achieved improved resection ratios of mock tumor margins (1.00) when compared to control scenarios (0.0) and alternative methods of image guidance (0.58). The experimental results show the feasibility of the proposed workflow and advantages of cone beam computed tomography image guidance through video augmentation of the primary stereo endoscopy as compared to control and alternative navigation methods. PMID:26531203

  20. Augmented reality and cone beam CT guidance for transoral robotic surgery.

    PubMed

    Liu, Wen P; Richmon, Jeremy D; Sorger, Jonathan M; Azizian, Mahdi; Taylor, Russell H

    2015-09-01

    In transoral robotic surgery preoperative image data do not reflect large deformations of the operative workspace from perioperative setup. To address this challenge, in this study we explore image guidance with cone beam computed tomographic angiography to guide the dissection of critical vascular landmarks and resection of base-of-tongue neoplasms with adequate margins for transoral robotic surgery. We identify critical vascular landmarks from perioperative c-arm imaging to augment the stereoscopic view of a da Vinci si robot in addition to incorporating visual feedback from relative tool positions. Experiments resecting base-of-tongue mock tumors were conducted on a series of ex vivo and in vivo animal models comparing the proposed workflow for video augmentation to standard non-augmented practice and alternative, fluoroscopy-based image guidance. Accurate identification of registered augmented critical anatomy during controlled arterial dissection and en bloc mock tumor resection was possible with the augmented reality system. The proposed image-guided robotic system also achieved improved resection ratios of mock tumor margins (1.00) when compared to control scenarios (0.0) and alternative methods of image guidance (0.58). The experimental results show the feasibility of the proposed workflow and advantages of cone beam computed tomography image guidance through video augmentation of the primary stereo endoscopy as compared to control and alternative navigation methods.

  1. Bone tumor

    MedlinePlus

    Tumor - bone; Bone cancer; Primary bone tumor; Secondary bone tumor; Bone tumor - benign ... The cause of bone tumors is unknown. They often occur in areas of the bone that grow rapidly. Possible causes include: Genetic defects ...

  2. Comparison between three adjuvants for a vaccine against canine leishmaniasis: In vitro evaluation of macrophage killing ability.

    PubMed

    Trotta, T; Fasanella, A; Scaltrito, D; Gradoni, L; Mitolo, V; Brandonisio, O; Acquafredda, A; Panaro, M A

    2010-03-01

    The aim of this study was to evaluate, in terms of dog macrophage killing ability in vitro, a vaccine based on Leishmania infantum promastigote soluble antigen (LSA) formulated with three different adjuvants (BCG, AdjuPrime, MPL/TDM/CWS). A significant increase of the macrophage killing ability was observed in dogs vaccinated with LSA+MPL/TDM/CWS after 1 month from vaccination. A similar increase of macrophage parasitocidal ability was present only after 5 months in dogs vaccinated with LSA+BCG or LSA+AdjuPrime. In all dogs the augmented killing percentage was still present after 12 months from vaccination. Therefore, in particular LSA+MPL/TDM/CWS vaccine seems promising for further studies in dogs.

  3. 75 FR 62469 - Drawbridge Operation Regulations; Newtown Creek, Dutch Kills, English Kills, and Their...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-10-12

    ... From the Federal Register Online via the Government Publishing Office DEPARTMENT OF HOMELAND SECURITY Coast Guard 33 CFR Part 117 Drawbridge Operation Regulations; Newtown Creek, Dutch Kills, English Kills, and Their Tributaries, NY, Maintenance AGENCY: Coast Guard, DHS. ACTION: Notice of...

  4. 75 FR 30299 - Drawbridge Operation Regulations; Newtown Creek, Dutch Kills, English Kills, and Their...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-06-01

    ... From the Federal Register Online via the Government Publishing Office DEPARTMENT OF HOMELAND SECURITY Coast Guard 33 CFR Part 117 Drawbridge Operation Regulations; Newtown Creek, Dutch Kills, English Kills, and Their Tributaries, NY, Maintenance AGENCY: Coast Guard, DHS. ACTION: Notice of...

  5. 9 CFR 113.209 - Rabies Vaccine, Killed Virus.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... 9 Animals and Animal Products 1 2010-01-01 2010-01-01 false Rabies Vaccine, Killed Virus. 113.209... Killed Virus Vaccines § 113.209 Rabies Vaccine, Killed Virus. Rabies Vaccine (Killed Virus) shall be..., safe, and immunogenic shall be used for preparing the production seed virus for vaccine production....

  6. 9 CFR 113.216 - Bovine Rhinotracheitis Vaccine, Killed Virus.

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    ... 9 Animals and Animal Products 1 2011-01-01 2011-01-01 false Bovine Rhinotracheitis Vaccine, Killed... REQUIREMENTS Killed Virus Vaccines § 113.216 Bovine Rhinotracheitis Vaccine, Killed Virus. Infectious Bovine Rhinotracheitis Vaccine, Killed Virus, shall be prepared from virus-bearing cell culture fluids. Only Master...

  7. 9 CFR 113.211 - Feline Rhinotracheitis Vaccine, Killed Virus.

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    ... 9 Animals and Animal Products 1 2011-01-01 2011-01-01 false Feline Rhinotracheitis Vaccine, Killed... REQUIREMENTS Killed Virus Vaccines § 113.211 Feline Rhinotracheitis Vaccine, Killed Virus. Feline Rhinotracheitis Vaccine, Killed Virus, shall be prepared from virus-bearing cell culture fluids. Only Master...

  8. 9 CFR 113.206 - Wart Vaccine, Killed Virus.

    Code of Federal Regulations, 2013 CFR

    2013-01-01

    ... 9 Animals and Animal Products 1 2013-01-01 2013-01-01 false Wart Vaccine, Killed Virus. 113.206... Killed Virus Vaccines § 113.206 Wart Vaccine, Killed Virus. Wart Vaccine, Killed Virus, shall be prepared... content as prescribed in § 113.200(f). (d) Potency and efficacy. The efficacy of wart vaccine has...

  9. 9 CFR 113.211 - Feline Rhinotracheitis Vaccine, Killed Virus.

    Code of Federal Regulations, 2013 CFR

    2013-01-01

    ... 9 Animals and Animal Products 1 2013-01-01 2013-01-01 false Feline Rhinotracheitis Vaccine, Killed... REQUIREMENTS Killed Virus Vaccines § 113.211 Feline Rhinotracheitis Vaccine, Killed Virus. Feline Rhinotracheitis Vaccine, Killed Virus, shall be prepared from virus-bearing cell culture fluids. Only Master...

  10. 9 CFR 113.210 - Feline Calicivirus Vaccine, Killed Virus.

    Code of Federal Regulations, 2013 CFR

    2013-01-01

    ... 9 Animals and Animal Products 1 2013-01-01 2013-01-01 false Feline Calicivirus Vaccine, Killed... REQUIREMENTS Killed Virus Vaccines § 113.210 Feline Calicivirus Vaccine, Killed Virus. Feline Calicivirus Vaccine, Killed Virus, shall be prepared from virus-bearing cell culture fluids. Only Master Seed...

  11. 9 CFR 113.206 - Wart Vaccine, Killed Virus.

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    ... 9 Animals and Animal Products 1 2011-01-01 2011-01-01 false Wart Vaccine, Killed Virus. 113.206... Killed Virus Vaccines § 113.206 Wart Vaccine, Killed Virus. Wart Vaccine, Killed Virus, shall be prepared... content as prescribed in § 113.200(f). (d) Potency and efficacy. The efficacy of wart vaccine has...

  12. 9 CFR 113.213 - Pseudorabies Vaccine, Killed Virus.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... 9 Animals and Animal Products 1 2010-01-01 2010-01-01 false Pseudorabies Vaccine, Killed Virus... REQUIREMENTS Killed Virus Vaccines § 113.213 Pseudorabies Vaccine, Killed Virus. Pseudorabies Vaccine, Killed... established as pure, safe, and immunogenic shall be used for preparing seeds for vaccine production....

  13. 9 CFR 113.206 - Wart Vaccine, Killed Virus.

    Code of Federal Regulations, 2014 CFR

    2014-01-01

    ... 9 Animals and Animal Products 1 2014-01-01 2014-01-01 false Wart Vaccine, Killed Virus. 113.206... Killed Virus Vaccines § 113.206 Wart Vaccine, Killed Virus. Wart Vaccine, Killed Virus, shall be prepared... content as prescribed in § 113.200(f). (d) Potency and efficacy. The efficacy of wart vaccine has...

  14. 9 CFR 113.213 - Pseudorabies Vaccine, Killed Virus.

    Code of Federal Regulations, 2014 CFR

    2014-01-01

    ... 9 Animals and Animal Products 1 2014-01-01 2014-01-01 false Pseudorabies Vaccine, Killed Virus... REQUIREMENTS Killed Virus Vaccines § 113.213 Pseudorabies Vaccine, Killed Virus. Pseudorabies Vaccine, Killed... established as pure, safe, and immunogenic shall be used for preparing seeds for vaccine production....

  15. 9 CFR 113.210 - Feline Calicivirus Vaccine, Killed Virus.

    Code of Federal Regulations, 2012 CFR

    2012-01-01

    ... 9 Animals and Animal Products 1 2012-01-01 2012-01-01 false Feline Calicivirus Vaccine, Killed... REQUIREMENTS Killed Virus Vaccines § 113.210 Feline Calicivirus Vaccine, Killed Virus. Feline Calicivirus Vaccine, Killed Virus, shall be prepared from virus-bearing cell culture fluids. Only Master Seed...

  16. 9 CFR 113.209 - Rabies Vaccine, Killed Virus.

    Code of Federal Regulations, 2014 CFR

    2014-01-01

    ... 9 Animals and Animal Products 1 2014-01-01 2014-01-01 false Rabies Vaccine, Killed Virus. 113.209... Killed Virus Vaccines § 113.209 Rabies Vaccine, Killed Virus. Rabies Vaccine (Killed Virus) shall be..., safe, and immunogenic shall be used for preparing the production seed virus for vaccine production....

  17. 9 CFR 113.210 - Feline Calicivirus Vaccine, Killed Virus.

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    ... 9 Animals and Animal Products 1 2011-01-01 2011-01-01 false Feline Calicivirus Vaccine, Killed... REQUIREMENTS Killed Virus Vaccines § 113.210 Feline Calicivirus Vaccine, Killed Virus. Feline Calicivirus Vaccine, Killed Virus, shall be prepared from virus-bearing cell culture fluids. Only Master Seed...

  18. 9 CFR 113.213 - Pseudorabies Vaccine, Killed Virus.

    Code of Federal Regulations, 2012 CFR

    2012-01-01

    ... 9 Animals and Animal Products 1 2012-01-01 2012-01-01 false Pseudorabies Vaccine, Killed Virus... REQUIREMENTS Killed Virus Vaccines § 113.213 Pseudorabies Vaccine, Killed Virus. Pseudorabies Vaccine, Killed... established as pure, safe, and immunogenic shall be used for preparing seeds for vaccine production....

  19. 9 CFR 113.206 - Wart Vaccine, Killed Virus.

    Code of Federal Regulations, 2012 CFR

    2012-01-01

    ... 9 Animals and Animal Products 1 2012-01-01 2012-01-01 false Wart Vaccine, Killed Virus. 113.206... Killed Virus Vaccines § 113.206 Wart Vaccine, Killed Virus. Wart Vaccine, Killed Virus, shall be prepared... content as prescribed in § 113.200(f). (d) Potency and efficacy. The efficacy of wart vaccine has...

  20. 9 CFR 113.206 - Wart Vaccine, Killed Virus.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... 9 Animals and Animal Products 1 2010-01-01 2010-01-01 false Wart Vaccine, Killed Virus. 113.206... Killed Virus Vaccines § 113.206 Wart Vaccine, Killed Virus. Wart Vaccine, Killed Virus, shall be prepared... content as prescribed in § 113.200(f). (d) Potency and efficacy. The efficacy of wart vaccine has...

  1. 9 CFR 113.211 - Feline Rhinotracheitis Vaccine, Killed Virus.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... 9 Animals and Animal Products 1 2010-01-01 2010-01-01 false Feline Rhinotracheitis Vaccine, Killed... REQUIREMENTS Killed Virus Vaccines § 113.211 Feline Rhinotracheitis Vaccine, Killed Virus. Feline Rhinotracheitis Vaccine, Killed Virus, shall be prepared from virus-bearing cell culture fluids. Only Master...

  2. 9 CFR 113.203 - Feline Panleukopenia Vaccine, Killed Virus.

    Code of Federal Regulations, 2012 CFR

    2012-01-01

    ... 9 Animals and Animal Products 1 2012-01-01 2012-01-01 false Feline Panleukopenia Vaccine, Killed... REQUIREMENTS Killed Virus Vaccines § 113.203 Feline Panleukopenia Vaccine, Killed Virus. Feline Panleukopenia Vaccine, Killed Virus, shall be prepared from virus-bearing cell culture fluids. Only Master Seed...

  3. 9 CFR 113.210 - Feline Calicivirus Vaccine, Killed Virus.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... 9 Animals and Animal Products 1 2010-01-01 2010-01-01 false Feline Calicivirus Vaccine, Killed... REQUIREMENTS Killed Virus Vaccines § 113.210 Feline Calicivirus Vaccine, Killed Virus. Feline Calicivirus Vaccine, Killed Virus, shall be prepared from virus-bearing cell culture fluids. Only Master Seed...

  4. 9 CFR 113.203 - Feline Panleukopenia Vaccine, Killed Virus.

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    ... 9 Animals and Animal Products 1 2011-01-01 2011-01-01 false Feline Panleukopenia Vaccine, Killed... REQUIREMENTS Killed Virus Vaccines § 113.203 Feline Panleukopenia Vaccine, Killed Virus. Feline Panleukopenia Vaccine, Killed Virus, shall be prepared from virus-bearing cell culture fluids. Only Master Seed...

  5. 9 CFR 113.216 - Bovine Rhinotracheitis Vaccine, Killed Virus.

    Code of Federal Regulations, 2012 CFR

    2012-01-01

    ... 9 Animals and Animal Products 1 2012-01-01 2012-01-01 false Bovine Rhinotracheitis Vaccine, Killed... REQUIREMENTS Killed Virus Vaccines § 113.216 Bovine Rhinotracheitis Vaccine, Killed Virus. Infectious Bovine Rhinotracheitis Vaccine, Killed Virus, shall be prepared from virus-bearing cell culture fluids. Only Master...

  6. 9 CFR 113.216 - Bovine Rhinotracheitis Vaccine, Killed Virus.

    Code of Federal Regulations, 2014 CFR

    2014-01-01

    ... 9 Animals and Animal Products 1 2014-01-01 2014-01-01 false Bovine Rhinotracheitis Vaccine, Killed... REQUIREMENTS Killed Virus Vaccines § 113.216 Bovine Rhinotracheitis Vaccine, Killed Virus. Infectious Bovine Rhinotracheitis Vaccine, Killed Virus, shall be prepared from virus-bearing cell culture fluids. Only Master...

  7. 9 CFR 113.209 - Rabies Vaccine, Killed Virus.

    Code of Federal Regulations, 2013 CFR

    2013-01-01

    ... 9 Animals and Animal Products 1 2013-01-01 2013-01-01 false Rabies Vaccine, Killed Virus. 113.209... Killed Virus Vaccines § 113.209 Rabies Vaccine, Killed Virus. Rabies Vaccine (Killed Virus) shall be..., safe, and immunogenic shall be used for preparing the production seed virus for vaccine production....

  8. 9 CFR 113.209 - Rabies Vaccine, Killed Virus.

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    ... 9 Animals and Animal Products 1 2011-01-01 2011-01-01 false Rabies Vaccine, Killed Virus. 113.209... Killed Virus Vaccines § 113.209 Rabies Vaccine, Killed Virus. Rabies Vaccine (Killed Virus) shall be..., safe, and immunogenic shall be used for preparing the production seed virus for vaccine production....

  9. 9 CFR 113.203 - Feline Panleukopenia Vaccine, Killed Virus.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... 9 Animals and Animal Products 1 2010-01-01 2010-01-01 false Feline Panleukopenia Vaccine, Killed... REQUIREMENTS Killed Virus Vaccines § 113.203 Feline Panleukopenia Vaccine, Killed Virus. Feline Panleukopenia Vaccine, Killed Virus, shall be prepared from virus-bearing cell culture fluids. Only Master Seed...

  10. 9 CFR 113.216 - Bovine Rhinotracheitis Vaccine, Killed Virus.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... 9 Animals and Animal Products 1 2010-01-01 2010-01-01 false Bovine Rhinotracheitis Vaccine, Killed... REQUIREMENTS Killed Virus Vaccines § 113.216 Bovine Rhinotracheitis Vaccine, Killed Virus. Infectious Bovine Rhinotracheitis Vaccine, Killed Virus, shall be prepared from virus-bearing cell culture fluids. Only Master...

  11. 9 CFR 113.211 - Feline Rhinotracheitis Vaccine, Killed Virus.

    Code of Federal Regulations, 2012 CFR

    2012-01-01

    ... 9 Animals and Animal Products 1 2012-01-01 2012-01-01 false Feline Rhinotracheitis Vaccine, Killed... REQUIREMENTS Killed Virus Vaccines § 113.211 Feline Rhinotracheitis Vaccine, Killed Virus. Feline Rhinotracheitis Vaccine, Killed Virus, shall be prepared from virus-bearing cell culture fluids. Only Master...

  12. 9 CFR 113.213 - Pseudorabies Vaccine, Killed Virus.

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    ... 9 Animals and Animal Products 1 2011-01-01 2011-01-01 false Pseudorabies Vaccine, Killed Virus... REQUIREMENTS Killed Virus Vaccines § 113.213 Pseudorabies Vaccine, Killed Virus. Pseudorabies Vaccine, Killed... established as pure, safe, and immunogenic shall be used for preparing seeds for vaccine production....

  13. 9 CFR 113.209 - Rabies Vaccine, Killed Virus.

    Code of Federal Regulations, 2012 CFR

    2012-01-01

    ... 9 Animals and Animal Products 1 2012-01-01 2012-01-01 false Rabies Vaccine, Killed Virus. 113.209... Killed Virus Vaccines § 113.209 Rabies Vaccine, Killed Virus. Rabies Vaccine (Killed Virus) shall be..., safe, and immunogenic shall be used for preparing the production seed virus for vaccine production....

  14. 9 CFR 113.216 - Bovine Rhinotracheitis Vaccine, Killed Virus.

    Code of Federal Regulations, 2013 CFR

    2013-01-01

    ... 9 Animals and Animal Products 1 2013-01-01 2013-01-01 false Bovine Rhinotracheitis Vaccine, Killed... REQUIREMENTS Killed Virus Vaccines § 113.216 Bovine Rhinotracheitis Vaccine, Killed Virus. Infectious Bovine Rhinotracheitis Vaccine, Killed Virus, shall be prepared from virus-bearing cell culture fluids. Only Master...

  15. 9 CFR 113.213 - Pseudorabies Vaccine, Killed Virus.

    Code of Federal Regulations, 2013 CFR

    2013-01-01

    ... 9 Animals and Animal Products 1 2013-01-01 2013-01-01 false Pseudorabies Vaccine, Killed Virus... REQUIREMENTS Killed Virus Vaccines § 113.213 Pseudorabies Vaccine, Killed Virus. Pseudorabies Vaccine, Killed... established as pure, safe, and immunogenic shall be used for preparing seeds for vaccine production....

  16. 9 CFR 113.203 - Feline Panleukopenia Vaccine, Killed Virus.

    Code of Federal Regulations, 2014 CFR

    2014-01-01

    ... 9 Animals and Animal Products 1 2014-01-01 2014-01-01 false Feline Panleukopenia Vaccine, Killed... REQUIREMENTS Killed Virus Vaccines § 113.203 Feline Panleukopenia Vaccine, Killed Virus. Feline Panleukopenia Vaccine, Killed Virus, shall be prepared from virus-bearing cell culture fluids. Only Master Seed...

  17. 9 CFR 113.211 - Feline Rhinotracheitis Vaccine, Killed Virus.

    Code of Federal Regulations, 2014 CFR

    2014-01-01

    ... 9 Animals and Animal Products 1 2014-01-01 2014-01-01 false Feline Rhinotracheitis Vaccine, Killed... REQUIREMENTS Killed Virus Vaccines § 113.211 Feline Rhinotracheitis Vaccine, Killed Virus. Feline Rhinotracheitis Vaccine, Killed Virus, shall be prepared from virus-bearing cell culture fluids. Only Master...

  18. 9 CFR 113.210 - Feline Calicivirus Vaccine, Killed Virus.

    Code of Federal Regulations, 2014 CFR

    2014-01-01

    ... 9 Animals and Animal Products 1 2014-01-01 2014-01-01 false Feline Calicivirus Vaccine, Killed... REQUIREMENTS Killed Virus Vaccines § 113.210 Feline Calicivirus Vaccine, Killed Virus. Feline Calicivirus Vaccine, Killed Virus, shall be prepared from virus-bearing cell culture fluids. Only Master Seed...

  19. 'Total disability' and the wrongness of killing.

    PubMed

    Omelianchuk, Adam

    2015-08-01

    Walter Sinnott-Armstrong and Franklin G Miller recently argued that the wrongness of killing is best explained by the harm that comes to the victim, and that 'total disability' best explains the nature of this harm. Hence, killing patients who are already totally disabled is not wrong. I maintain that their notion of total disability is ambiguous and that they beg the question with respect to whether there are abilities left over that remain relevant for the goods of personhood and human worth. If these goods remain, then something more is lost in death than in 'total disability,' and their explanation of what makes killing wrong comes up short. But if total disability is equivalent with death, then their argument is an interesting one.

  20. Extracellular killing of inhaled pneumococci in rats

    SciTech Connect

    Coonrod, J.D.; Marple, S.; Holmes, G.P.; Rehm, S.R.

    1987-12-01

    Early clearance of inhaled Staphylococcus aureus is believed to be caused by phagocytosis by alveolar macrophages. In murine models inhaled pneumococci are cleared even more rapidly than S. aureus. Conventional opsonins appear to play no role in this clearance, and recently it has been shown that murine alveolar lining material contains free fatty acids and other soluble factors that are directly bactericidal for pneumococci. To determine whether non-phagocytic factors are involved in pneumococcal clearance, we compared the site of killing of inhaled pneumococci and S. aureus in rats using histologic methods and bronchoalveolar lavage. Spontaneous lysis of pneumococci was prevented by use of autolysin-defective pneumococci or by substitution of ethanolamine for choline in the cell wall. Histologic studies showed that the percent of inhaled staphylococci associated with alveolar macrophages always exceeded the percent of staphylococci cleared, whereas there was little association of pneumococci with macrophages during clearance. Analysis of the intracellular or extracellular location of iron 59 in bronchoalveolar lavage fluid of rats that had inhaled aerosols of /sup 59/Fe-labeled bacteria suggested that staphylococci were killed predominantly in macrophages and pneumococci in the extracellular space. When /sup 59/Fe-labeled pneumococci or staphylococci were ingested and killed by macrophages in vitro, the /sup 59/Fe remained with the macrophages, suggesting that the extracellular location of /sup 59/Fe during pneumococcal killing in vivo was not caused by rapid turnover of /sup 59/Fe in macrophages. Studies of the site of killing of inhaled type 25 pneumococci labeled exclusively in the cell wall with carbon 14-ethanolamine confirmed the results obtained with /sup 59/Fe-labeled pneumococci. Thus, early killing of inhaled pneumococci, unlike staphylococci, appears to take place outside of macrophages.

  1. MUC-1 Tumor Antigen Agonist Epitopes for Enhancing T-cell Responses to Human Tumors | NCI Technology Transfer Center | TTC

    Cancer.gov

    Scientists at NIH have identified 7 new agonist epitopes of the MUC-1 tumor associated antigen. Compared to their native epitope counterparts, peptides reflecting these agonist epitopes have been shown to enhance the generation of human tumor cells, which in turn have a greater ability to kill human tumor cells endogenously expressing the native MUC-1 epitope.

  2. Cytotoxic Killing and Immune Evasion by Repair

    NASA Astrophysics Data System (ADS)

    Chan, Cliburn; George, Andrew J. T.; Stark, Jaroslav

    2007-07-01

    The interaction between the immune system and pathogens is a complex one, with pathogens constantly developing new ways of evading destruction by the immune system. The immune system's task is made even harder when the pathogen in question is an intra-cellular one (such as a virus or certain bacteria) and it is necessary to kill the infected host cell in order to eliminate the pathogen. This causes damage to the host, and such killing therefore needs to be carefully controlled, particularly in tissues with poor regenerative potential, or those involved in the immune response itself. Host cells therefore possess repair mechanisms which can counteract killing by immune cells. These in turn can be subverted by pathogens which up-regulate the resistance of infected cells to killing. In this paper, we explore the hypothesis that this repair process plays an important role in determining the efficacy of evasion and escape from immune control. We model a situation where cytotoxic T lymphocytes (CTL) and natural killer (NK) cells kill pathogen-infected and tumour cells by directed secretion of preformed granules containing perforin and granzymes. Resistance to such killing can be conferred by the expression of serine protease inhibitors (serpins). These are utilized by several virally infected and tumour cells, as well as playing a role in the protection of host bystander, immune and immuneprivileged cells. We build a simple stochastic model of cytotoxic killing, where serpins can neutralize granzymes stoichiometrically by forming an irreversible complex, and the survival of the cell is determined by the balance between serpin depletion and replenishment, which in its simplest form is equivalent to the well known shot noise process. We use existing analytical results for this process, and additional simulations to analyse the effects of repair on cytotoxic killing. We then extend the model to the case of a replicating target cell population, which gives a branching process

  3. HIV transcription is induced with cell killing

    SciTech Connect

    Woloschak, G.E.; Schreck, S.; Chang-Liu, Chin-Mei; Panozzo, J.; Libertin, C.R.

    1993-11-01

    In this report, we demonstrate that this induction of HIV-LTR transcription occurs when stably transfected HeLa cells are exposed to agents which mediate cell killing, such as UV radiation, electroporation of sucrose buffer, prolonged heating, and low and high pH. Cells cultured following UV exposure demonstrated a peak in CAT expression that is evident in viable (but not necessarily cell division-competent) cells 24 h after exposure; this inductive response continued until at least 72 h after exposure. HIV-LTR induction was dose-dependent, and the amount of CAT transcription induced was correlated with the amount of cell killing that occurred in the culture.

  4. Microbial killing activity of peracetic acid.

    PubMed

    Thamlikitkul, V; Trakulsomboon, S; Louisirirotchanakul, S; Chaiprasert, A; Foongladda, S; Thipsuvan, K; Arjratanakool, W; Kunyok, R; Wasi, C; Santiprasitkul, S; Danchaivijitr, S

    2001-10-01

    In vitro killing activity of peracetic acid (Perasafe) at a concentration of 0.26 per cent w/v was tested against Escherichia coli, Enterobacter cloacae, Klebsiella pneumoniae, Pseudomonas aeruginosa, Salmonella typhi, Salmonella paratyphi A, Acinetobacter baumannii, Sternotrophomonas maltophilia, Enterococcus faecium, Enterococcus faecalis, methicillin-resistant Staphylococcus aureus (MRSA), Bacillus subtilis spore, Mycobacterium tuberculosis and human immuno-deficiency virus type I. Exposure to Peracetic acid (0.26% w/v) for 10 minutes resulted in massive killing of all the aforementioned organisms and spore.

  5. Augmented assessment as a means to augmented reality.

    PubMed

    Bergeron, Bryan

    2006-01-01

    Rigorous scientific assessment of educational technologies typically lags behind the availability of the technologies by years because of the lack of validated instruments and benchmarks. Even when the appropriate assessment instruments are available, they may not be applied because of time and monetary constraints. Work in augmented reality, instrumented mannequins, serious gaming, and similar promising educational technologies that haven't undergone timely, rigorous evaluation, highlights the need for assessment methodologies that address the limitations of traditional approaches. The most promising augmented assessment solutions incorporate elements of rapid prototyping used in the software industry, simulation-based assessment techniques modeled after methods used in bioinformatics, and object-oriented analysis methods borrowed from object oriented programming.

  6. Vertical Vergence Calibration for Augmented Reality Displays

    DTIC Science & Technology

    2006-03-01

    2006 2. REPORT TYPE 3. DATES COVERED 00-00-2006 to 00-00-2006 4. TITLE AND SUBTITLE Vertical Vergence Calibration for Augmented Reality Displays...8-98) Prescribed by ANSI Std Z39-18 Vertical Vergence Calibration for Augmented Reality Displays Mark A. Livingston∗ Adam Lederer Virtual Reality...dimensional Graphics and Realism—Virtual Reality Keywords: augmented reality , head-mounted display, vergence 1 INTRODUCTION Many augmented reality (AR

  7. Tissue Dimensionality Influences the Functional Response of Cytotoxic T Lymphocyte-Mediated Killing of Targets

    PubMed Central

    Gadhamsetty, Saikrishna; Marée, Athanasius F. M.; de Boer, Rob J.; Beltman, Joost B.

    2017-01-01

    Cytotoxic T lymphocyte (CTL)-mediated killing of virus infections and tumors occurs over a wide range of conditions. The spatial environments in which CTLs encounter target cells vary from narrow vessels, to two-dimensional epithelial tissues, to densely populated 3-dimensional (3D) T cell areas within lymphoid tissues. How such spatial environments alter the functional response of CTL-mediated killing, i.e., how the killing efficiency depends on cell densities, is unclear. In this study, we perform cellular Potts model simulations in different spatial configurations to investigate how the dimensionality of the space affects the functional response of CTL-mediated killing. Irrespective of the spatial configuration, the function with separate saturation constants for CTL and for target cell densities that we previously proposed can in all cases describe the response, demonstrating its generality. However, the tissue dimensionality determines at which cell densities the killing rate starts to saturate. We show that saturation in a fully 3D environment is stronger than in a “flat” 3D environment, which is largely due to accompanying differences in the CTL–target encounter rates. PMID:28123385

  8. Tissue Dimensionality Influences the Functional Response of Cytotoxic T Lymphocyte-Mediated Killing of Targets.

    PubMed

    Gadhamsetty, Saikrishna; Marée, Athanasius F M; de Boer, Rob J; Beltman, Joost B

    2016-01-01

    Cytotoxic T lymphocyte (CTL)-mediated killing of virus infections and tumors occurs over a wide range of conditions. The spatial environments in which CTLs encounter target cells vary from narrow vessels, to two-dimensional epithelial tissues, to densely populated 3-dimensional (3D) T cell areas within lymphoid tissues. How such spatial environments alter the functional response of CTL-mediated killing, i.e., how the killing efficiency depends on cell densities, is unclear. In this study, we perform cellular Potts model simulations in different spatial configurations to investigate how the dimensionality of the space affects the functional response of CTL-mediated killing. Irrespective of the spatial configuration, the function with separate saturation constants for CTL and for target cell densities that we previously proposed can in all cases describe the response, demonstrating its generality. However, the tissue dimensionality determines at which cell densities the killing rate starts to saturate. We show that saturation in a fully 3D environment is stronger than in a "flat" 3D environment, which is largely due to accompanying differences in the CTL-target encounter rates.

  9. EGFR-targeted magnetic nanoparticle heaters kill cancer cells without a perceptible temperature rise.

    PubMed

    Creixell, Mar; Bohórquez, Ana C; Torres-Lugo, Madeline; Rinaldi, Carlos

    2011-09-27

    It is currently believed that magnetic nanoparticle heaters (MNHs) can kill cancer cells only when the temperature is raised above 43 °C due to energy dissipation in an alternating magnetic field. On the other hand, simple heat conduction arguments indicate that in small tumors or single cells the relative rates of energy dissipation and heat conduction result in a negligible temperature rise, thus limiting the potential of MNHs in treating small tumors and metastatic cancer. Here we demonstrate that internalized MNHs conjugated to epidermal growth factor (EGF) and which target the epidermal growth factor receptor (EGFR) do result in a significant (up to 99.9%) reduction in cell viability and clonogenic survival in a thermal heat dose dependent manner, without the need for a perceptible temperature rise. The effect appears to be cell type specific and indicates that magnetic nanoparticles in alternating magnetic fields may effectively kill cancer cells under conditions previously considered as not possible.

  10. Effective Augmentation of Complex Networks

    PubMed Central

    Wang, Jinjian; Yu, Xinghuo; Stone, Lewi

    2016-01-01

    Networks science plays an enormous role in many aspects of modern society from distributing electrical power across nations to spreading information and social networking amongst global populations. While modern networks constantly change in size, few studies have sought methods for the difficult task of optimising this growth. Here we study theoretical requirements for augmenting networks by adding source or sink nodes, without requiring additional driver-nodes to accommodate the change i.e., conserving structural controllability. Our “effective augmentation” algorithm takes advantage of clusters intrinsic to the network topology, and permits rapidly and efficient augmentation of a large number of nodes in one time-step. “Effective augmentation” is shown to work successfully on a wide range of model and real networks. The method has numerous applications (e.g. study of biological, social, power and technological networks) and potentially of significant practical and economic value. PMID:27165120

  11. Effective Augmentation of Complex Networks

    NASA Astrophysics Data System (ADS)

    Wang, Jinjian; Yu, Xinghuo; Stone, Lewi

    2016-05-01

    Networks science plays an enormous role in many aspects of modern society from distributing electrical power across nations to spreading information and social networking amongst global populations. While modern networks constantly change in size, few studies have sought methods for the difficult task of optimising this growth. Here we study theoretical requirements for augmenting networks by adding source or sink nodes, without requiring additional driver-nodes to accommodate the change i.e., conserving structural controllability. Our “effective augmentation” algorithm takes advantage of clusters intrinsic to the network topology, and permits rapidly and efficient augmentation of a large number of nodes in one time-step. “Effective augmentation” is shown to work successfully on a wide range of model and real networks. The method has numerous applications (e.g. study of biological, social, power and technological networks) and potentially of significant practical and economic value.

  12. Augmented reality building operations tool

    SciTech Connect

    Brackney, Larry J.

    2014-09-09

    A method (700) for providing an augmented reality operations tool to a mobile client (642) positioned in a building (604). The method (700) includes, with a server (660), receiving (720) from the client (642) an augmented reality request for building system equipment (612) managed by an energy management system (EMS) (620). The method (700) includes transmitting (740) a data request for the equipment (612) to the EMS (620) and receiving (750) building management data (634) for the equipment (612). The method (700) includes generating (760) an overlay (656) with an object created based on the building management data (634), which may be sensor data, diagnostic procedures, or the like. The overlay (656) is configured for concurrent display on a display screen (652) of the client (642) with a real-time image of the building equipment (612). The method (700) includes transmitting (770) the overlay (656) to the client (642).

  13. The Unintended Consequences of Killing Civilians

    DTIC Science & Technology

    2012-05-17

    Approved for Public Release; Distribution is Unlimited The Unintended Consequences of Killing Civilians A Monograph by...13. ABSTRACT (Maximum 200 Words) Mistreatment of civilians not party to a large-scale, violent conflict is not new. The perceived lack of empathy...it is counterproductive to mission accomplishment and results in a decline in support for military intervention forces. Elaborated throughout this

  14. The evolution of reduced microbial killing.

    PubMed

    Vriezen, Jan A C; Valliere, Michael; Riley, Margaret A

    2009-10-20

    Bacteria engage in a never-ending arms race in which they compete for limited resources and niche space. The outcome of this intense interaction is the evolution of a powerful arsenal of biological weapons. Perhaps the most studied of these are colicins, plasmid-based toxins produced by and active against Escherichia coli. The present study was designed to explore the molecular responses of a colicin-producing strain during serial transfer evolution. What evolutionary changes occur when colicins are produced with no target present? Can killing ability be maintained in the absence of a target? To address these, and other, questions, colicinogenic strains and a noncolicinogenic ancestor were evolved for 253 generations. Samples were taken throughout the experiment and tested for killing ability. By the 38th transfer, a decreased killing ability and an increase in fitness were observed in the colicin-producing strains. Surprisingly, DNA sequence determination of the colicin plasmids revealed no changes in plasmid sequences. However, a set of chromosomally encoded loci experienced changes in gene expression that were positively associated with the reduction in killing. The most significant expression changes were observed in DNA repair genes (which were downregulated in the evolved strains), Mg ion uptake genes (which were upregulated), and late prophage genes (which were upregulated). These results indicate a fine-tuned response to the evolutionary pressures of colicin production, with far more genes involved than had been anticipated.

  15. Can Vet Schools Teach without Killing Animals?

    ERIC Educational Resources Information Center

    Mangan, Katherine S.

    2000-01-01

    Discusses a protest by students at the University of Illinois (Urbana) College of Veterinary Medicine over the killing of animals that led to temporary curtailing of lethal animal experiments. Examines the conflict between animal rights groups and some faculty who are openly skeptical about the effectiveness of alternatives to the hands-on…

  16. Mass killings and detection of impacts

    NASA Technical Reports Server (NTRS)

    Mclaren, Digby J.

    1988-01-01

    Highly energetic bolide impacts occur and their flux is known. For larger bodies the energy release is greater than for any other short-term global phenomenon. Such impacts produce or release a large variety of shock induced changes including major atmospheric, sedimentologic, seismic and volcanic events. These events must necessarily leave a variety of records in the stratigraphic column, including mass killings resulting in major changes in population density and reduction or extinction of many taxonomic groups, followed by characteristic patterns of faunal and flora replacement. Of these effects, mass killings, marked by large-scale loss of biomass, are the most easily detected evidence in the field but must be manifest on a near-global scale. Such mass killings that appear to be approximately synchronous and involve disappearance of biomass at a bedding plane in many sedimentologically independent sections globally suggest a common cause and probable synchroneity. Mass killings identify an horizon which may be examined for evidence of cause. Geochemical markers may be ephemeral and absence may not be significant. There appears to be no reason why ongoing phenomena such as climate and sea-level changes are primary causes of anomolous episodic events.

  17. School Shootings; Standards Kill Students and Society

    ERIC Educational Resources Information Center

    Angert, Betsy L.

    2008-01-01

    School shootings have been in the news of late. People ponder what occurs in classrooms today. Why would a young person wish to take a life? Within educational institutions, the killings are a concern. In our dire attempt to teach the children and ensure student success, it seems many of our offspring are lost. Some students feel separate from…

  18. Killing Hitler: A Writer's Journey and Angst.

    ERIC Educational Resources Information Center

    Thaler, Paul

    2002-01-01

    Describes the author's experiences in preparing a talk that "evokes the specter" of Adolf Hitler and in writing an historical account of a British plot to kill Hitler. Address the question of why the British allowed him to live that final year of the war. Muses on why scholars write, and the impact of violence and terrorism. (SG)

  19. Measuring patient outcomes in breast augmentation: introducing the BREAST-Q Augmentation module.

    PubMed

    Pusic, Andrea L; Reavey, Patrick L; Klassen, Anne F; Scott, Amie; McCarthy, Colleen; Cano, Stefan J

    2009-01-01

    The Breast-Q Augmentation module is a new and unique questionnaire for measuring patient-reported outcomes following breast augmentation. It has undergone a rigorous development and validation process and is currently the only questionnaire for breast augmentation that meets international and federal standards for questionnaire development. The Breast-Q Augmentation module covers a comprehensive set of concerns of breast augmentation patients, including satisfaction with breasts and impact on quality of life. With its excellent psychometric properties, the Breast-Q Augmentation module can provide clinicians and researchers with a wealth of essential data to improve the field of breast augmentation from the perspectives of both surgeons and patients.

  20. TDRSS Augmentation System for Satellites

    NASA Technical Reports Server (NTRS)

    Heckler, Gregory W.; Gramling, Cheryl; Valdez, Jennifer; Baldwin, Philip

    2016-01-01

    In 2015, NASA Goddard Space Flight Center (GSFC) reinvigorated the development of the TDRSS Augmentation Service for Satellites (TASS). TASS is a global, space-based, communications and navigation service for users of Global Navigation Satellite Systems(GNSS) and the Tracking and Data Relay Satellite System (TDRSS). TASS leverages the existing TDRSS to provide an S-band beacon radio navigation and messaging source to users at orbital altitudes 1400 km and below.

  1. Photon management for augmented photosynthesis

    NASA Astrophysics Data System (ADS)

    Ooms, Matthew D.; Dinh, Cao Thang; Sargent, Edward H.; Sinton, David

    2016-09-01

    Microalgae and cyanobacteria are some of nature's finest examples of solar energy conversion systems, effortlessly transforming inorganic carbon into complex molecules through photosynthesis. The efficiency of energy-dense hydrocarbon production by photosynthetic organisms is determined in part by the light collected by the microorganisms. Therefore, optical engineering has the potential to increase the productivity of algae cultivation systems used for industrial-scale biofuel synthesis. Herein, we explore and report emerging and promising material science and engineering innovations for augmenting microalgal photosynthesis.

  2. Hyperspectral-Augmented Target Tracking

    DTIC Science & Technology

    2008-03-01

    I am able to overcome my weaknesses and take advantage of my strengths. Second, I extend my love to my wife, son, and mother -in-law for their uncondi...technology to enhance its capability to “track, record, and analyze the movement of every vehicle in a foreign city” [41]. 1.1 Problems with...configurations and ambiguous scenarios, which are used for determining the feasibility of the hyperspectral-augmented tracker. This chapter also analyzes and

  3. Media-Augmented Exercise Machines

    NASA Astrophysics Data System (ADS)

    Krueger, T.

    2002-01-01

    Cardio-vascular exercise has been used to mitigate the muscle and cardiac atrophy associated with adaptation to micro-gravity environments. Several hours per day may be required. In confined spaces and long duration missions this kind of exercise is inevitably repetitive and rapidly becomes uninteresting. At the same time, there are pressures to accomplish as much as possible given the cost- per-hour for humans occupying orbiting or interplanetary. Media augmentation provides a the means to overlap activities in time by supplementing the exercise with social, recreational, training or collaborative activities and thereby reducing time pressures. In addition, the machine functions as an interface to a wide range of digital environments allowing for spatial variety in an otherwise confined environment. We hypothesize that the adoption of media augmented exercise machines will have a positive effect on psycho-social well-being on long duration missions. By organizing and supplementing exercise machines, data acquisition hardware, computers and displays into an interacting system this proposal increases functionality with limited additional mass. This paper reviews preliminary work on a project to augment exercise equipment in a manner that addresses these issues and at the same time opens possibilities for additional benefits. A testbed augmented exercise machine uses a specialty built cycle trainer as both input to a virtual environment and as an output device from it using spatialized sound, and visual displays, vibration transducers and variable resistance. The resulting interactivity increases a sense of engagement in the exercise, provides a rich experience of the digital environments. Activities in the virtual environment and accompanying physiological and psychological indicators may be correlated to track and evaluate the health of the crew.

  4. Augment railgun and sequential discharge

    NASA Astrophysics Data System (ADS)

    Kobayashi, K.

    1993-01-01

    Proprietary R&D efforts toward the creation of tactical weapon systems-applicable railguns are presented. Attention is given to measures taken for projectile velocity maximization and sequential-discharge operation, and to an augmenting railgun which has demonstrated a 66-percent efficiency improvement over the two-rail baseline railgun system. This device is characterized by strong interaction between capacitor bank submodules during sequential discharge.

  5. The Augmented REality Sandtable (ARES)

    DTIC Science & Technology

    2015-10-01

    end state is an augmented sand table platform that supports a variety of research, training, and operational needs. In recent years, several high-tech... ecommerce No Yes No No Petrasova (2014) GIS-Based Environmental Modeling with Tangible Interaction and Dynamic Visualization Follow-up to Tateosian... platform . Fig. 6 Tank combat game application • ARES Scalability Based on user requirements, a squad-sized version of ARES (7 × 4 ft) is

  6. Vortex Lift Augmentation by Suction

    NASA Technical Reports Server (NTRS)

    Taylor, A. H.; Jackson, L. R.; Huffman, J. K.

    1983-01-01

    Lift performance is improved on a 60 degrees swept Gothic wing. Vortex lift at moderate to high angles of attack on highly swept wings used to improve takeoff performance and maneuverability. New design proposed in which suction of propulsion system augments vortex. Turbofan placed at down stream end of leading-edge vortex system induces vortex to flow into inlet which delays onset of vortex breakdown.

  7. Contagion in Mass Killings and School Shootings

    PubMed Central

    Towers, Sherry; Gomez-Lievano, Andres; Khan, Maryam; Mubayi, Anuj; Castillo-Chavez, Carlos

    2015-01-01

    Background Several past studies have found that media reports of suicides and homicides appear to subsequently increase the incidence of similar events in the community, apparently due to the coverage planting the seeds of ideation in at-risk individuals to commit similar acts. Methods Here we explore whether or not contagion is evident in more high-profile incidents, such as school shootings and mass killings (incidents with four or more people killed). We fit a contagion model to recent data sets related to such incidents in the US, with terms that take into account the fact that a school shooting or mass murder may temporarily increase the probability of a similar event in the immediate future, by assuming an exponential decay in contagiousness after an event. Conclusions We find significant evidence that mass killings involving firearms are incented by similar events in the immediate past. On average, this temporary increase in probability lasts 13 days, and each incident incites at least 0.30 new incidents (p = 0.0015). We also find significant evidence of contagion in school shootings, for which an incident is contagious for an average of 13 days, and incites an average of at least 0.22 new incidents (p = 0.0001). All p-values are assessed based on a likelihood ratio test comparing the likelihood of a contagion model to that of a null model with no contagion. On average, mass killings involving firearms occur approximately every two weeks in the US, while school shootings occur on average monthly. We find that state prevalence of firearm ownership is significantly associated with the state incidence of mass killings with firearms, school shootings, and mass shootings. PMID:26135941

  8. Destruction of solid tumors by immune cells

    NASA Astrophysics Data System (ADS)

    López, Álvaro G.; Seoane, Jesús M.; Sanjuán, Miguel A. F.

    2017-03-01

    The fractional cell kill is a mathematical expression describing the rate at which a certain population of cells is reduced to a fraction of itself. In order to investigate the fractional cell kill that governs the rate at which a solid tumor is lysed by a cell population of cytotoxic CD8+ T cells (CTLs), we present several in silico simulations and mathematical analyses. When the CTLs eradicate efficiently the tumor cells, the models predict a correlation between the morphology of the tumors and the rate at which they are lysed. However, when the effectiveness of the immune cells is decreased, the mathematical function fails to reproduce the process of lysis. This limit is thoroughly discussed and a new fractional cell kill is proposed.

  9. Deprivations, futures and the wrongness of killing.

    PubMed

    Marquis, D

    2001-12-01

    In my essay, Why abortion is immoral, I criticised discussions of the morality of abortion in which the crucial issue is whether fetuses are human beings or whether fetuses are persons. Both argument strategies are inadequate because they rely on indefensible assumptions. Why should being a human being or being a person make a moral difference? I argued that the correct account of the morality of abortion should be based upon a defensible account of why killing children and adults is wrong. I claimed that what makes killing us wrong is that our premature deaths deprive us of our futures of value, that is, the goods of life we would have experienced had we survived. This account of the wrongness of killing explains why killing is one of the worst of crimes and how killing greatly harms the victim. It coheres with the attitudes of those with cancer or HIV facing premature death. It explains why we believe it is wrong to kill infants (as personhood theories do not). It does not entail that it wrongs a human being to end her life if she is in persistent vegetative state or if her future must consist only of unbearable physical suffering and she wants to die (as sanctity of human life theories do not). This account of the wrongness of killing implies (with some defensible additional assumptions) that abortion is immoral because we were fetuses once and we know those fetuses had futures of value. Mark Brown claims that this potential future of value account is unsound because it implies that we have welfare rights to what we need to stay alive that most people would reject. I argue that Brown is incorrect in two ways: a welfare right to what we need to stay alive is not directly implied by my account and, in addition, most of us do believe that dependent human beings have substantial welfare rights to what they need to stay alive. Brown argues that depriving us of a future of value of which we have mental representations both is a better explanation of the wrongness of

  10. Conformal killing tensors and covariant Hamiltonian dynamics

    SciTech Connect

    Cariglia, M.; Gibbons, G. W.; Holten, J.-W. van; Horvathy, P. A.; Zhang, P.-M.

    2014-12-15

    A covariant algorithm for deriving the conserved quantities for natural Hamiltonian systems is combined with the non-relativistic framework of Eisenhart, and of Duval, in which the classical trajectories arise as geodesics in a higher dimensional space-time, realized by Brinkmann manifolds. Conserved quantities which are polynomial in the momenta can be built using time-dependent conformal Killing tensors with flux. The latter are associated with terms proportional to the Hamiltonian in the lower dimensional theory and with spectrum generating algebras for higher dimensional quantities of order 1 and 2 in the momenta. Illustrations of the general theory include the Runge-Lenz vector for planetary motion with a time-dependent gravitational constant G(t), motion in a time-dependent electromagnetic field of a certain form, quantum dots, the Hénon-Heiles and Holt systems, respectively, providing us with Killing tensors of rank that ranges from one to six.

  11. Parricide: Children Who Kill Their Parents

    DTIC Science & Technology

    1988-01-01

    adolescents who kill their parents. The research centers on who is the offender, why he or she has used parricide as a solution to an unresolvable problem...parricide. Conclusions Reached Based on the results of the literature review three conclusions were reached. First, adolescents who commit parricide have been...at the hands of their abuser. Secondly, the treatment of these adolescents by the criminal justice system varies greatly depending on the willingness

  12. Webizing mobile augmented reality content

    NASA Astrophysics Data System (ADS)

    Ahn, Sangchul; Ko, Heedong; Yoo, Byounghyun

    2014-01-01

    This paper presents a content structure for building mobile augmented reality (AR) applications in HTML5 to achieve a clean separation of the mobile AR content and the application logic for scaling as on the Web. We propose that the content structure contains the physical world as well as virtual assets for mobile AR applications as document object model (DOM) elements and that their behaviour and user interactions are controlled through DOM events by representing objects and places with a uniform resource identifier. Our content structure enables mobile AR applications to be seamlessly developed as normal HTML documents under the current Web eco-system.

  13. Augmented-plane-wave forces

    NASA Astrophysics Data System (ADS)

    Soler, José M.; Williams, Arthur R.

    1990-11-01

    Results are presented that demonstrate the effectiveness of a calculational method of electronic-structure theory. The method combines the power (tractable basis-set size) and flexibility (transition and first-row elements) of the augmented-plane-wave method with the computational efficiency of the Car-Parrinello method of molecular dynamics and total-energy minimization. Equilibrium geometry and vibrational frequencies in agreement with experiment are presented for Si, to demonstrate agreement with existing methods and for Cu, N2, and H2O to demonstrate the broader applicability of the approach.

  14. GOETHALS BRIDGE FROM NORTH SIDE OVER ARTHUR KILL. RAILROAD BRIDGE ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    GOETHALS BRIDGE FROM NORTH SIDE OVER ARTHUR KILL. RAILROAD BRIDGE IN FOREGROUND - Goethals Bridge, Spanning Arthur Kill from New Jersey to Staten Island, Staten Island (subdivision), Richmond County, NY

  15. 11. GENERAL INTERIOR VIEW OF KILLING FLOOR ON LEVEL 4; ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    11. GENERAL INTERIOR VIEW OF KILLING FLOOR ON LEVEL 4; LOOKING SOUTHWEST TOWARD SPLITTERS' PLATFORMS - Rath Packing Company, Beef Killing Building, Sycamore Street between Elm & Eighteenth Streets, Waterloo, Black Hawk County, IA

  16. Bioengineered viral vectors for targeting and killing prostate cancer cells.

    PubMed

    Zhang, Kai-xin; Jia, William; Rennie, Paul S

    2010-01-01

    Enabling the transduction of therapeutic gene expression exclusively in diseased sites is the key to developing more effective treatments for advanced prostate cancer using viral-based therapy. While prostate cancers that express high levels of HER-2 are resistant to the killing effects of trastuzumab, they can be targeted for selective gene expression and destruction by lentiviruses with envelope proteins engineered to bind to this therapeutic antibody. More importantly, after intravenous injection, this trastuzumab-bound lentivirus is able to target castration-resistant prostate tumor xenografts, albeit with low efficiency. This proof of principle opens up multiple possibilities for the prevention and treatment of prostate cancer using a viral-based therapy. However, to be safe and more effective, the viral vectors must target prostate cancer cells more selectively and efficiently. A higher degree of specificity and efficiency of cancer cell targeting can be achieved by engineering viral vectors to bind to a specific cell surface marker and by controlling the expression of the therapeutic payload at transcriptional level, with a tissue-specific promoter, and at the translational level, with a regulatory sequences inserted into either the 5'UTR or 3'UTR regions of the therapeutic gene(s). The latter would be designed to ensure that translation of this mRNA occurs exclusively in malignant cells. Furthermore, in order to obtain a potent anti-tumor effect, viral vectors would be engineered to express pro-apoptotic genes, intra-cellar antibodies/nucleotide aptamers to block critical proteins, or siRNAs to knockdown essential cellular mRNAs. Alternatively, controlled expression of an essential viral gene would restore replication competence to the virus and enable selective oncolysis of tumor cells. Successful delivery of such bioengineered viruses may provide a more effective way to treat advanced prostate cancer.

  17. Designing surfaces that kill bacteria on contact

    NASA Astrophysics Data System (ADS)

    Tiller, Joerg C.; Liao, Chun-Jen; Lewis, Kim; Klibanov, Alexander M.

    2001-05-01

    Poly(4-vinyl-N-alkylpyridinium bromide) was covalently attached to glass slides to create a surface that kills airborne bacteria on contact. The antibacterial properties were assessed by spraying aqueous suspensions of bacterial cells on the surface, followed by air drying and counting the number of cells remaining viable (i.e., capable of growing colonies). Amino glass slides were acylated with acryloyl chloride, copolymerized with 4-vinylpyridine, and N-alkylated with different alkyl bromides (from propyl to hexadecyl). The resultant surfaces, depending on the alkyl group, were able to kill up to 94 ± 4% of Staphylococcus aureus cells sprayed on them. A surface alternatively created by attaching poly(4-vinylpyridine) to a glass slide and alkylating it with hexyl bromide killed 94 ± 3% of the deposited S. aureus cells. On surfaces modified with N-hexylated poly(4-vinylpyridine), the numbers of viable cells of another Gram-positive bacterium, Staphylococcus epidermidis, as well as of the Gram-negative bacteria Pseudomonas aeruginosa and Escherichia coli, dropped more than 100-fold compared with the original amino glass. In contrast, the number of viable bacterial cells did not decline significantly after spraying on such common materials as ceramics, plastics, metals, and wood.

  18. HIV transcription is induced with cell killing

    SciTech Connect

    Woloschak, G.E.; Schreck, S.; Chang-Liu, Chin Mei; Panozzo, J.; Libertin, C.R.

    1994-01-01

    Previous work has shown that HeLa cells stably transfected with an HIV-LTR-CAT construct are induced to express chloramphenicol acetyl transferase (CAT) following exposure to DNA-damaging agents such as ultraviolet radiation, {gamma} rays, neutrons, and others. In this report, the authors demonstrate that this induction of HIV-LTR transcription occurs when stably transfected HeLa cells are exposed to agents which mediate cell killing, such as UV radiation, electroporation of sucrose buffer, prolonged heating, and low and high pH. Cells cultured following UV exposure demonstrated a peak in CAT expression that is evidence in viable (but not necessarily cell division-competent) cells 24 h after exposure; this inductive response continued until at least 72 h after exposure. HIV-LTR induction was dose-dependent, and the amount of CAT transcription induced was correlated with the amount of cell killing that occurred in the culture. Other agents which caused no cell killing (such as heat-shock for up to 2 h, treatment with metronidazole, exposure to sunlight, vitamin C treatment, and others) had no effect on HIV-LTR induction. These results suggest that HIV transcription is induced as a consequence of the turn on of a cellular death or apoptotic pathway.

  19. 9 CFR 113.204 - Mink Enteritis Vaccine, Killed Virus.

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    ... 9 Animals and Animal Products 1 2011-01-01 2011-01-01 false Mink Enteritis Vaccine, Killed Virus... REQUIREMENTS Killed Virus Vaccines § 113.204 Mink Enteritis Vaccine, Killed Virus. Mink Enteritis Vaccine... prior to challenge. If unfavorable reactions attributable to the vaccine occur, the serial...

  20. 9 CFR 113.212 - Bursal Disease Vaccine, Killed Virus.

    Code of Federal Regulations, 2014 CFR

    2014-01-01

    ... 9 Animals and Animal Products 1 2014-01-01 2014-01-01 false Bursal Disease Vaccine, Killed Virus... REQUIREMENTS Killed Virus Vaccines § 113.212 Bursal Disease Vaccine, Killed Virus. Bursal Disease Vaccine... for vaccine production. All serials shall be prepared from the first through the fifth passage...

  1. 9 CFR 113.208 - Avian Encephalomyelitis Vaccine, Killed Virus.

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    ... 9 Animals and Animal Products 1 2011-01-01 2011-01-01 false Avian Encephalomyelitis Vaccine... STANDARD REQUIREMENTS Killed Virus Vaccines § 113.208 Avian Encephalomyelitis Vaccine, Killed Virus. Avian Encephalomyelitis Vaccine (Killed Virus) shall be prepared from virus-bearing tissues or fluids obtained...

  2. 9 CFR 113.201 - Canine Distemper Vaccine, Killed Virus.

    Code of Federal Regulations, 2014 CFR

    2014-01-01

    ... 9 Animals and Animal Products 1 2014-01-01 2014-01-01 false Canine Distemper Vaccine, Killed Virus... REQUIREMENTS Killed Virus Vaccines § 113.201 Canine Distemper Vaccine, Killed Virus. Canine Distemper Vaccine... been established as pure, safe, and immunogenic shall be used for vaccine production. All serials...

  3. 9 CFR 113.204 - Mink Enteritis Vaccine, Killed Virus.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... 9 Animals and Animal Products 1 2010-01-01 2010-01-01 false Mink Enteritis Vaccine, Killed Virus... REQUIREMENTS Killed Virus Vaccines § 113.204 Mink Enteritis Vaccine, Killed Virus. Mink Enteritis Vaccine... prior to challenge. If unfavorable reactions attributable to the vaccine occur, the serial...

  4. 9 CFR 113.214 - Parvovirus Vaccine, Killed Virus (Canine).

    Code of Federal Regulations, 2012 CFR

    2012-01-01

    ... 9 Animals and Animal Products 1 2012-01-01 2012-01-01 false Parvovirus Vaccine, Killed Virus... REQUIREMENTS Killed Virus Vaccines § 113.214 Parvovirus Vaccine, Killed Virus (Canine). Parvovirus Vaccine... Master Seed which has been established as pure, safe, and immunogenic shall be used for...

  5. 9 CFR 113.214 - Parvovirus Vaccine, Killed Virus (Canine).

    Code of Federal Regulations, 2014 CFR

    2014-01-01

    ... 9 Animals and Animal Products 1 2014-01-01 2014-01-01 false Parvovirus Vaccine, Killed Virus... REQUIREMENTS Killed Virus Vaccines § 113.214 Parvovirus Vaccine, Killed Virus (Canine). Parvovirus Vaccine... Master Seed which has been established as pure, safe, and immunogenic shall be used for...

  6. 9 CFR 113.212 - Bursal Disease Vaccine, Killed Virus.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... 9 Animals and Animal Products 1 2010-01-01 2010-01-01 false Bursal Disease Vaccine, Killed Virus... REQUIREMENTS Killed Virus Vaccines § 113.212 Bursal Disease Vaccine, Killed Virus. Bursal Disease Vaccine... for vaccine production. All serials shall be prepared from the first through the fifth passage...

  7. 9 CFR 113.205 - Newcastle Disease Vaccine, Killed Virus.

    Code of Federal Regulations, 2013 CFR

    2013-01-01

    ... 9 Animals and Animal Products 1 2013-01-01 2013-01-01 false Newcastle Disease Vaccine, Killed Virus. 113.205 Section 113.205 Animals and Animal Products ANIMAL AND PLANT HEALTH INSPECTION SERVICE... REQUIREMENTS Killed Virus Vaccines § 113.205 Newcastle Disease Vaccine, Killed Virus. Newcastle Disease...

  8. 9 CFR 113.212 - Bursal Disease Vaccine, Killed Virus.

    Code of Federal Regulations, 2013 CFR

    2013-01-01

    ... 9 Animals and Animal Products 1 2013-01-01 2013-01-01 false Bursal Disease Vaccine, Killed Virus... REQUIREMENTS Killed Virus Vaccines § 113.212 Bursal Disease Vaccine, Killed Virus. Bursal Disease Vaccine... for vaccine production. All serials shall be prepared from the first through the fifth passage...

  9. 9 CFR 113.201 - Canine Distemper Vaccine, Killed Virus.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... 9 Animals and Animal Products 1 2010-01-01 2010-01-01 false Canine Distemper Vaccine, Killed Virus... REQUIREMENTS Killed Virus Vaccines § 113.201 Canine Distemper Vaccine, Killed Virus. Canine Distemper Vaccine... been established as pure, safe, and immunogenic shall be used for vaccine production. All serials...

  10. 9 CFR 113.204 - Mink Enteritis Vaccine, Killed Virus.

    Code of Federal Regulations, 2012 CFR

    2012-01-01

    ... 9 Animals and Animal Products 1 2012-01-01 2012-01-01 false Mink Enteritis Vaccine, Killed Virus... REQUIREMENTS Killed Virus Vaccines § 113.204 Mink Enteritis Vaccine, Killed Virus. Mink Enteritis Vaccine... prior to challenge. If unfavorable reactions attributable to the vaccine occur, the serial...

  11. 9 CFR 113.205 - Newcastle Disease Vaccine, Killed Virus.

    Code of Federal Regulations, 2014 CFR

    2014-01-01

    ... 9 Animals and Animal Products 1 2014-01-01 2014-01-01 false Newcastle Disease Vaccine, Killed Virus. 113.205 Section 113.205 Animals and Animal Products ANIMAL AND PLANT HEALTH INSPECTION SERVICE... REQUIREMENTS Killed Virus Vaccines § 113.205 Newcastle Disease Vaccine, Killed Virus. Newcastle Disease...

  12. 9 CFR 113.204 - Mink Enteritis Vaccine, Killed Virus.

    Code of Federal Regulations, 2014 CFR

    2014-01-01

    ... 9 Animals and Animal Products 1 2014-01-01 2014-01-01 false Mink Enteritis Vaccine, Killed Virus... REQUIREMENTS Killed Virus Vaccines § 113.204 Mink Enteritis Vaccine, Killed Virus. Mink Enteritis Vaccine... prior to challenge. If unfavorable reactions attributable to the vaccine occur, the serial...

  13. 9 CFR 113.201 - Canine Distemper Vaccine, Killed Virus.

    Code of Federal Regulations, 2012 CFR

    2012-01-01

    ... 9 Animals and Animal Products 1 2012-01-01 2012-01-01 false Canine Distemper Vaccine, Killed Virus... REQUIREMENTS Killed Virus Vaccines § 113.201 Canine Distemper Vaccine, Killed Virus. Canine Distemper Vaccine... been established as pure, safe, and immunogenic shall be used for vaccine production. All serials...

  14. 9 CFR 113.204 - Mink Enteritis Vaccine, Killed Virus.

    Code of Federal Regulations, 2013 CFR

    2013-01-01

    ... 9 Animals and Animal Products 1 2013-01-01 2013-01-01 false Mink Enteritis Vaccine, Killed Virus... REQUIREMENTS Killed Virus Vaccines § 113.204 Mink Enteritis Vaccine, Killed Virus. Mink Enteritis Vaccine... prior to challenge. If unfavorable reactions attributable to the vaccine occur, the serial...

  15. 9 CFR 113.201 - Canine Distemper Vaccine, Killed Virus.

    Code of Federal Regulations, 2013 CFR

    2013-01-01

    ... 9 Animals and Animal Products 1 2013-01-01 2013-01-01 false Canine Distemper Vaccine, Killed Virus... REQUIREMENTS Killed Virus Vaccines § 113.201 Canine Distemper Vaccine, Killed Virus. Canine Distemper Vaccine... been established as pure, safe, and immunogenic shall be used for vaccine production. All serials...

  16. 9 CFR 113.201 - Canine Distemper Vaccine, Killed Virus.

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    ... 9 Animals and Animal Products 1 2011-01-01 2011-01-01 false Canine Distemper Vaccine, Killed Virus... REQUIREMENTS Killed Virus Vaccines § 113.201 Canine Distemper Vaccine, Killed Virus. Canine Distemper Vaccine... been established as pure, safe, and immunogenic shall be used for vaccine production. All serials...

  17. 9 CFR 113.208 - Avian Encephalomyelitis Vaccine, Killed Virus.

    Code of Federal Regulations, 2012 CFR

    2012-01-01

    ... 9 Animals and Animal Products 1 2012-01-01 2012-01-01 false Avian Encephalomyelitis Vaccine... STANDARD REQUIREMENTS Killed Virus Vaccines § 113.208 Avian Encephalomyelitis Vaccine, Killed Virus. Avian Encephalomyelitis Vaccine (Killed Virus) shall be prepared from virus-bearing tissues or fluids obtained...

  18. 9 CFR 113.212 - Bursal Disease Vaccine, Killed Virus.

    Code of Federal Regulations, 2012 CFR

    2012-01-01

    ... 9 Animals and Animal Products 1 2012-01-01 2012-01-01 false Bursal Disease Vaccine, Killed Virus... REQUIREMENTS Killed Virus Vaccines § 113.212 Bursal Disease Vaccine, Killed Virus. Bursal Disease Vaccine... for vaccine production. All serials shall be prepared from the first through the fifth passage...

  19. 9 CFR 113.205 - Newcastle Disease Vaccine, Killed Virus.

    Code of Federal Regulations, 2012 CFR

    2012-01-01

    ... 9 Animals and Animal Products 1 2012-01-01 2012-01-01 false Newcastle Disease Vaccine, Killed Virus. 113.205 Section 113.205 Animals and Animal Products ANIMAL AND PLANT HEALTH INSPECTION SERVICE... REQUIREMENTS Killed Virus Vaccines § 113.205 Newcastle Disease Vaccine, Killed Virus. Newcastle Disease...

  20. 9 CFR 113.208 - Avian Encephalomyelitis Vaccine, Killed Virus.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... 9 Animals and Animal Products 1 2010-01-01 2010-01-01 false Avian Encephalomyelitis Vaccine... STANDARD REQUIREMENTS Killed Virus Vaccines § 113.208 Avian Encephalomyelitis Vaccine, Killed Virus. Avian Encephalomyelitis Vaccine (Killed Virus) shall be prepared from virus-bearing tissues or fluids obtained...

  1. 9 CFR 113.214 - Parvovirus Vaccine, Killed Virus (Canine).

    Code of Federal Regulations, 2013 CFR

    2013-01-01

    ... 9 Animals and Animal Products 1 2013-01-01 2013-01-01 false Parvovirus Vaccine, Killed Virus... REQUIREMENTS Killed Virus Vaccines § 113.214 Parvovirus Vaccine, Killed Virus (Canine). Parvovirus Vaccine... Master Seed which has been established as pure, safe, and immunogenic shall be used for...

  2. 9 CFR 113.208 - Avian Encephalomyelitis Vaccine, Killed Virus.

    Code of Federal Regulations, 2013 CFR

    2013-01-01

    ... 9 Animals and Animal Products 1 2013-01-01 2013-01-01 false Avian Encephalomyelitis Vaccine... STANDARD REQUIREMENTS Killed Virus Vaccines § 113.208 Avian Encephalomyelitis Vaccine, Killed Virus. Avian Encephalomyelitis Vaccine (Killed Virus) shall be prepared from virus-bearing tissues or fluids obtained...

  3. 9 CFR 113.208 - Avian Encephalomyelitis Vaccine, Killed Virus.

    Code of Federal Regulations, 2014 CFR

    2014-01-01

    ... 9 Animals and Animal Products 1 2014-01-01 2014-01-01 false Avian Encephalomyelitis Vaccine... STANDARD REQUIREMENTS Killed Virus Vaccines § 113.208 Avian Encephalomyelitis Vaccine, Killed Virus. Avian Encephalomyelitis Vaccine (Killed Virus) shall be prepared from virus-bearing tissues or fluids obtained...

  4. 9 CFR 113.205 - Newcastle Disease Vaccine, Killed Virus.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... 9 Animals and Animal Products 1 2010-01-01 2010-01-01 false Newcastle Disease Vaccine, Killed Virus. 113.205 Section 113.205 Animals and Animal Products ANIMAL AND PLANT HEALTH INSPECTION SERVICE... REQUIREMENTS Killed Virus Vaccines § 113.205 Newcastle Disease Vaccine, Killed Virus. Newcastle Disease...

  5. 9 CFR 113.205 - Newcastle Disease Vaccine, Killed Virus.

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    ... 9 Animals and Animal Products 1 2011-01-01 2011-01-01 false Newcastle Disease Vaccine, Killed Virus. 113.205 Section 113.205 Animals and Animal Products ANIMAL AND PLANT HEALTH INSPECTION SERVICE... REQUIREMENTS Killed Virus Vaccines § 113.205 Newcastle Disease Vaccine, Killed Virus. Newcastle Disease...

  6. 9 CFR 113.214 - Parvovirus Vaccine, Killed Virus (Canine).

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    ... 9 Animals and Animal Products 1 2011-01-01 2011-01-01 false Parvovirus Vaccine, Killed Virus... REQUIREMENTS Killed Virus Vaccines § 113.214 Parvovirus Vaccine, Killed Virus (Canine). Parvovirus Vaccine... Master Seed which has been established as pure, safe, and immunogenic shall be used for...

  7. 9 CFR 113.212 - Bursal Disease Vaccine, Killed Virus.

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    ... 9 Animals and Animal Products 1 2011-01-01 2011-01-01 false Bursal Disease Vaccine, Killed Virus... REQUIREMENTS Killed Virus Vaccines § 113.212 Bursal Disease Vaccine, Killed Virus. Bursal Disease Vaccine... for vaccine production. All serials shall be prepared from the first through the fifth passage...

  8. 9 CFR 113.214 - Parvovirus Vaccine, Killed Virus (Canine).

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... 9 Animals and Animal Products 1 2010-01-01 2010-01-01 false Parvovirus Vaccine, Killed Virus... REQUIREMENTS Killed Virus Vaccines § 113.214 Parvovirus Vaccine, Killed Virus (Canine). Parvovirus Vaccine... Master Seed which has been established as pure, safe, and immunogenic shall be used for...

  9. 7 CFR 29.1018 - Fire-killed.

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    ... 7 Agriculture 2 2011-01-01 2011-01-01 false Fire-killed. 29.1018 Section 29.1018 Agriculture... Type 92) § 29.1018 Fire-killed. Any leaf of which 5 percent or more of its surface has a set green... tobacco may be described as fire-killed. (See Rule 23.)...

  10. 7 CFR 29.1018 - Fire-killed.

    Code of Federal Regulations, 2012 CFR

    2012-01-01

    ... 7 Agriculture 2 2012-01-01 2012-01-01 false Fire-killed. 29.1018 Section 29.1018 Agriculture... Type 92) § 29.1018 Fire-killed. Any leaf of which 5 percent or more of its surface has a set green... tobacco may be described as fire-killed. (See Rule 23.)...

  11. It's not just conflict that motivates killing of orangutans.

    PubMed

    Davis, Jacqueline T; Mengersen, Kerrie; Abram, Nicola K; Ancrenaz, Marc; Wells, Jessie A; Meijaard, Erik

    2013-01-01

    We investigated why orangutans are being killed in Kalimantan, Indonesia, and the role of conflict in these killings. Based on an analysis of interview data from over 5,000 respondents in over 450 villages, we also assessed the socio-ecological factors associated with conflict and non-conflict killings. Most respondents never kill orangutans. Those who reported having personally killed an orangutan primarily did so for non-conflict reasons; for example, 56% of these respondents said that the reason they had killed an orangutan was to eat it. Of the conflict-related reasons for killing, the most common reasons orangutans were killed was fear of orangutans or in self-defence. A similar pattern was evident among reports of orangutan killing by other people in the villages. Regression analyses indicated that religion and the percentage of intact forest around villages were the strongest socio-ecological predictors of whether orangutans were killed for conflict or non-conflict related reasons. Our data indicate that between 44,170 and 66,570 orangutans were killed in Kalimantan within the respondents' active hunting lifetimes: between 12,690 and 29,024 for conflict reasons (95%CI) and between 26,361 and 41,688 for non-conflict reasons (95% CI). These findings confirm that habitat protection alone will not ensure the survival of orangutans in Indonesian Borneo, and that effective reduction of orangutan killings is urgently needed.

  12. Road-Killed Animals as Resources for Ecological Studies.

    ERIC Educational Resources Information Center

    Adams, Clark E.

    1983-01-01

    Summarizes 19 literature sources identifying road-killed vertebrates and frequency of kill by numbers. Examples of how these animals can be incorporated into curricula (integrating biology, society, people, and values) are given, followed by an illustrated example of how a road-killed raccoon's skull demonstrated a human/wildlife interaction prior…

  13. 78 FR 43063 - Drawbridge Operation Regulations; Arthur Kill, NY

    Federal Register 2010, 2011, 2012, 2013, 2014

    2013-07-19

    ... SECURITY Coast Guard 33 CFR Part 117 Drawbridge Operation Regulations; Arthur Kill, NY AGENCY: Coast Guard... District, has issued a temporary deviation from the regulations governing the operation of the Arthur Kill AK Railroad Bridge across Arthur Kill, mile 11.6, between Staten Island, New York and Elizabeth,...

  14. Psychotherapy Augmentation through Preconscious Priming

    PubMed Central

    Borgeat, François; O’Connor, Kieron; Amado, Danielle; St-Pierre-Delorme, Marie-Ève

    2013-01-01

    Objective: To test the hypothesis that repeated preconscious (masked) priming of personalized positive cognitions could augment cognitive change and facilitate achievement of patients’ goals following a therapy. Methods: Twenty social phobic patients (13 women) completed a 36-weeks study beginning by 12 weeks of group behavioral therapy. After the therapy, they received 6 weeks of preconscious priming and 6 weeks of a control procedure in a randomized cross-over design. The Priming condition involved listening twice daily with a passive attitude to a recording of individualized formulations of appropriate cognitions and attitudes masked by music. The Control condition involved listening to an indistinguishable recording where the formulations had been replaced by random numbers. Changes in social cognitions were measured by the Social Interaction Self Statements Test (SISST). Results: Patients improved following therapy. The Priming procedure was associated with increased positive cognitions and decreased negative cognitions on the SISST while the Control procedure was not. The Priming procedure induced more cognitive change when applied immediately after the group therapy. Conclusion: An effect of priming was observed on social phobia related cognitions in the expected direction. This self administered addition to a therapy could be seen as an augmentation strategy. PMID:23508724

  15. EGFR-targeted diphtheria toxin stimulates TRAIL killing of glioblastoma cells by depleting anti-apoptotic proteins.

    PubMed

    Horita, Henrick; Thorburn, Jacqueline; Frankel, Arthur E; Thorburn, Andrew

    2009-11-01

    Current treatments for Glioblastoma multiforme (GBM) involve surgery, radiotherapy, and cytotoxic chemotherapy; however, these treatments are not effective and there is an urgent need for better treatments. We investigated GBM cell killing by a novel drug combination involving DT-EGF, an Epidermal Growth Factor Receptor-targeted bacterial toxin, and Tumor Necrosis Factor-Related Apoptosis Inducing Ligand (TRAIL) or antibodies that activate the TRAIL receptors DR4 and DR5. DT-EGF kills GBM cells by a non apoptotic mechanism whereas TRAIL kills by inducing apoptosis. GBM cells treated with DT-EGF and TRAIL were killed in a synergistic fashion in vitro and the combination was more effective than either treatment alone in vivo. Tumor cell death with the combination occurred by caspase activation and apoptosis due to DT-EGF positively regulating TRAIL killing by depleting FLIP, a selective inhibitor of TRAIL receptor-induced apoptosis. These data provide a mechanism-based rationale for combining targeted toxins and TRAIL receptor agonists to treat GBM.

  16. A Tracker Alignment Framework for Augmented Reality

    DTIC Science & Technology

    2003-01-01

    A Tracker Alignment Framework for Augmented Reality Yohan Baillot and Simon J. Julier ITT Advanced Engineering & Sciences 2560 Huntington Ave...with as few as three measurements. 1. Introduction Almost all Augmented Reality (AR) systems use a track- ing system to capture motion of objects in...DATES COVERED 00-00-2003 to 00-00-2003 4. TITLE AND SUBTITLE A Tracker Alignment Framework for Augmented Reality 5a. CONTRACT NUMBER 5b. GRANT

  17. Augmented Reality for Maintenance and Repair (ARMAR)

    DTIC Science & Technology

    2007-08-01

    The purpose of this research, Augmented Reality for Maintenance and Repair (ARMAR), was to research the design and development of experimental... augmented reality systems for maintenance job aiding. The goal was to explore and evaluate the feasibility of developing prototype adaptive augmented ... reality systems that can be used to investigate how real time computer graphics, overlaid on and registered with the actual equipment being maintained, can

  18. Developing a New Medical Augmented Reality System.

    DTIC Science & Technology

    1996-05-01

    Augmented reality is a technique for combining supplementary imagery such that it appears as part of the scene and can be used for guidance, training...and locational aids. In the medical domain, augmented reality can be used to combine medical imagery to the physician’s view of a patient to help...the physician establish a direct relation between the imagery and the patient. This project report will examine medical augmented reality systems for

  19. Eyekon: Distributed Augmented Reality for Soldier Teams

    DTIC Science & Technology

    2003-06-01

    Eyekon: Distributed Augmented Reality for Soldier Teams TOPIC: Information Superiority/Information Operations and Information Age... Augmented Reality for Soldier Teams 5a. CONTRACT NUMBER 5b. GRANT NUMBER 5c. PROGRAM ELEMENT NUMBER 6. AUTHOR(S) 5d. PROJECT NUMBER 5e. TASK NUMBER...by ANSI Std Z39-18 Eyekon: Distributed Augmented Reality for Soldier Teams Abstract The battlefield is a place of violence ruled by

  20. A Drosera-bioinspired hydrogel for catching and killing cancer cells

    PubMed Central

    Li, Shihui; Chen, Niancao; Gaddes, Erin R.; Zhang, Xiaolong; Dong, Cheng; Wang, Yong

    2015-01-01

    A variety of bioinspired materials have been successfully synthesized to mimic the sophisticated structures or functions of biological systems. However, it is still challenging to develop materials with multiple functions that can be performed synergistically or sequentially. The purpose of this work was to demonstrate a novel bioinspired hydrogel that can interact with cancer cells, functionally similar to Drosera in catching and killing prey. This hydrogel had two layers with the top one functionalized with oligonucleotide aptamers and the bottom one functionalized with double-stranded DNA. The results show that the top hydrogel layer was able to catch target cells with high efficiency and specificity, and that the bottom hydrogel layer could sequester doxorubicin (Dox) for sustained drug release. Importantly, the released Dox could kill 90% of the cells after 1-h residence of the cells on the hydrogel. After the cell release, this bifunctional hydrogel could be regenerated for continuous cell catching and killing. Therefore, the data presented in this study has successfully demonstrated the potential of developing a material system with the functions of attracting, catching and killing diseased cells (e.g., circulating tumor cells) or even invading microorganisms (e.g., bacteria). PMID:26396063

  1. Stepwise cytoskeletal polarization as a series of checkpoints in innate but not adaptive cytolytic killing

    NASA Astrophysics Data System (ADS)

    Wülfing, Christoph; Purtic, Bozidar; Klem, Jennifer; Schatzle, John D.

    2003-06-01

    Cytolytic killing is a major effector mechanism in the elimination of virally infected and tumor cells. The innate cytolytic effectors, natural killer (NK) cells, and the adaptive effectors, cytotoxic T cells (CTL), despite differential immune recognition, both use the same lytic mechanism, cytolytic granule release. Using live cell video fluorescence microscopy in various primary cell models of NK cell and CTL killing, we show here that on tight target cell contact, a majority of the NK cells established cytoskeletal polarity required for effective lytic function slowly or incompletely. In contrast, CTLs established cytoskeletal polarity rapidly. In addition, NK cell killing was uniquely sensitive to minor interference with cytoskeletal dynamics. We propose that the stepwise NK cell cytoskeletal polarization constitutes a series of checkpoints in NK cell killing. In addition, the use of more deliberate progression to effector function to compensate for inferior immune recognition specificity provides a mechanistic explanation for how the same effector function can be used in the different functional contexts of the innate and adaptive immune response.

  2. A Drosera-bioinspired hydrogel for catching and killing cancer cells.

    PubMed

    Li, Shihui; Chen, Niancao; Gaddes, Erin R; Zhang, Xiaolong; Dong, Cheng; Wang, Yong

    2015-09-23

    A variety of bioinspired materials have been successfully synthesized to mimic the sophisticated structures or functions of biological systems. However, it is still challenging to develop materials with multiple functions that can be performed synergistically or sequentially. The purpose of this work was to demonstrate a novel bioinspired hydrogel that can interact with cancer cells, functionally similar to Drosera in catching and killing prey. This hydrogel had two layers with the top one functionalized with oligonucleotide aptamers and the bottom one functionalized with double-stranded DNA. The results show that the top hydrogel layer was able to catch target cells with high efficiency and specificity, and that the bottom hydrogel layer could sequester doxorubicin (Dox) for sustained drug release. Importantly, the released Dox could kill 90% of the cells after 1-h residence of the cells on the hydrogel. After the cell release, this bifunctional hydrogel could be regenerated for continuous cell catching and killing. Therefore, the data presented in this study has successfully demonstrated the potential of developing a material system with the functions of attracting, catching and killing diseased cells (e.g., circulating tumor cells) or even invading microorganisms (e.g., bacteria).

  3. An Fc engineering approach that modulates antibody-dependent cytokine release without altering cell-killing functions.

    PubMed

    Kinder, Michelle; Greenplate, Allison R; Strohl, William R; Jordan, Robert E; Brezski, Randall J

    2015-01-01

    Cytotoxic therapeutic monoclonal antibodies (mAbs) often mediate target cell-killing by eliciting immune effector functions via Fc region interactions with cellular and humoral components of the immune system. Key functions include antibody-dependent cell-mediated cytotoxicity (ADCC), antibody-dependent cellular phagocytosis (ADCP), and complement-dependent cytotoxicity (CDC). However, there has been increased appreciation that along with cell-killing functions, the induction of antibody-dependent cytokine release (ADCR) can also influence disease microenvironments and therapeutic outcomes. Historically, most Fc engineering approaches have been aimed toward modulating ADCC, ADCP, or CDC. In the present study, we describe an Fc engineering approach that, while not resulting in impaired ADCC or ADCP, profoundly affects ADCR. As such, when peripheral blood mononuclear cells are used as effector cells against mAb-opsonized tumor cells, the described mAb variants elicit a similar profile and quantity of cytokines as IgG1. In contrast, although the variants elicit similar levels of tumor cell-killing as IgG1 with macrophage effector cells, the variants do not elicit macrophage-mediated ADCR against mAb-opsonized tumor cells. This study demonstrates that Fc engineering approaches can be employed to uncouple macrophage-mediated phagocytic and subsequent cell-killing functions from cytokine release.

  4. Augmented HR Repair Mediates Acquired Temozolomide Resistance in Glioblastoma.

    PubMed

    Gil Del Alcazar, Carlos Rodrigo; Todorova, Pavlina Krasimirova; Habib, Amyn A; Mukherjee, Bipasha; Burma, Sandeep

    2016-10-01

    Glioblastoma (GBM) is the most common and aggressive primary brain tumor in adults and is universally fatal. The DNA alkylating agent temozolomide is part of the standard-of-care for GBM. However, these tumors eventually develop therapy-driven resistance and inevitably recur. While loss of mismatch repair (MMR) and re-expression of MGMT have been shown to underlie chemoresistance in a fraction of GBMs, resistance mechanisms operating in the remaining GBMs are not well understood. To better understand the molecular basis for therapy-driven temozolomide resistance, mice bearing orthotopic GBM xenografts were subjected to protracted temozolomide treatment, and cell lines were generated from the primary (untreated) and recurrent (temozolomide-treated) tumors. As expected, the cells derived from primary tumors were sensitive to temozolomide, whereas the cells from the recurrent tumors were significantly resistant to the drug. Importantly, the acquired resistance to temozolomide in the recurrent lines was not driven by re-expression of MGMT or loss of MMR but was due to accelerated repair of temozolomide-induced DNA double-strand breaks (DSB). Temozolomide induces DNA replication-associated DSBs that are primarily repaired by the homologous recombination (HR) pathway. Augmented HR appears to underpin temozolomide resistance in the recurrent lines, as these cells were cross-resistant to other agents that induced replication-associated DSBs, exhibited faster resolution of damage-induced Rad51 foci, and displayed higher levels of sister chromatid exchanges (SCE). Furthermore, in light of recent studies demonstrating that CDK1 and CDK2 promote HR, it was found that CDK1/2 inhibitors countered the heightened HR in recurrent tumors and sensitized these therapy-resistant tumor cells to temozolomide.

  5. Ear Tumors

    MedlinePlus

    ... Outer Ear Ear Blockages Ear Tumors External Otitis (Swimmer's Ear) Malignant External Otitis Perichondritis Tumors of the ... Outer Ear Ear Blockages Ear Tumors External Otitis (Swimmer's Ear) Malignant External Otitis Perichondritis NOTE: This is ...

  6. Dynamic kill: controlling wild wells a new way

    SciTech Connect

    Blount, E.M.; Soeiinah, E.

    1981-10-01

    Dynamic kill describes a technique for terminating a blowout utilizing flowing frictional pressure to supplement the hydrostatic pressure of the kill fluid being injected through the relief well and up the blowing well. Therefore, a lighter kill fluid such as water can be implemented. The objective is to allow a blowout to be killed without breaking down the formation so the maximum amount of fluid can be circulated through the relief well by not losing fluid to a fractured formation. This allows optimum control during the kill operation and stable communication between the two wells. By allowing more fluid to be applied to the kill through one relief well, dynamic kill also increases the probability that one relief well will be sufficient. When the well is dynamically dead, the initial kill fluid, which will usually be too light to hold the well dead in a static condition, is replaced with a heavier kill mud. In fact, three weights of mud may be required to allow control during the transition from low density initial dynamic kill mud to heavy final kill mud. 5 refs.

  7. Successful treatment of metastatic pheochromocytoma in the spine with cement augmentation.

    PubMed

    Cai, Siyi; Kong, Xiangyi; Yan, Chengrui; Liu, Yong; Zhou, Xi; Qiu, Guixing

    2017-01-01

    Metastatic pheochromocytoma in the spine is rare, and there is no standard curative management. Treatment via open surgery is often risky in the perioperative period, while osteoplasty by cement augmentation is a less invasive option.We describe 2 patients with recurrence of pheochromocytoma involving the spine and the pelvis who were successfully treated with osteoplasty by cement augmentation. A 31-year-old female underwent cement augmentation for a pelvic lesion 6 months after the resection and screw fixation of an L3 lesion. A 58-year-old male underwent cement augmentation to directly destroy the functional tumor, with a surgical decompression 6 months later. Both patients showed appropriate destruction of the tumor, adequate pain relief, and the decreased release of catecholamine from metastatic lesions.Osteoplasty by cement augmentation may be a treatment option for patients with metastatic pheochromocytoma who cannot undergo appropriate surgery or decline surgery. This represents a safe approach to sustainably relieve pain and stabilize vertebral bodies with metastatic malignant pheochromocytoma.

  8. Successful treatment of metastatic pheochromocytoma in the spine with cement augmentation

    PubMed Central

    Cai, Siyi; Kong, Xiangyi; Yan, Chengrui; Liu, Yong; Zhou, Xi; Qiu, Guixing

    2017-01-01

    Abstract Metastatic pheochromocytoma in the spine is rare, and there is no standard curative management. Treatment via open surgery is often risky in the perioperative period, while osteoplasty by cement augmentation is a less invasive option. We describe 2 patients with recurrence of pheochromocytoma involving the spine and the pelvis who were successfully treated with osteoplasty by cement augmentation. A 31-year-old female underwent cement augmentation for a pelvic lesion 6 months after the resection and screw fixation of an L3 lesion. A 58-year-old male underwent cement augmentation to directly destroy the functional tumor, with a surgical decompression 6 months later. Both patients showed appropriate destruction of the tumor, adequate pain relief, and the decreased release of catecholamine from metastatic lesions. Osteoplasty by cement augmentation may be a treatment option for patients with metastatic pheochromocytoma who cannot undergo appropriate surgery or decline surgery. This represents a safe approach to sustainably relieve pain and stabilize vertebral bodies with metastatic malignant pheochromocytoma. PMID:28121933

  9. LOFT Augmented Operator Capability Program

    SciTech Connect

    Hollenbeck, D.A.; Krantz, E.A.; Hunt, G.L.; Meyer, O.R.

    1980-01-01

    The outline of the LOFT Augmented Operator Capability Program is presented. This program utilizes the LOFT (Loss-of-Fluid Test) reactor facility which is located at the Idaho National Engineering Laboratory and the LOFT operational transient experiment series as a test bed for methods of enhancing the reactor operator's capability for safer operation. The design of an Operational Diagnotics and Display System is presented which was backfit to the existing data acquisition computers. Basic color-graphic displays of the process schematic and trend type are presented. In addition, displays were developed and are presented which represent safety state vector information. A task analysis method was applied to LOFT reactor operating procedures to test its usefulness in defining the operator's information needs and workload.

  10. Unilateral galactocele following augmentation mammoplasty.

    PubMed

    Deloach, E D; Lord, S A; Ruf, L E

    1994-07-01

    Development of unilateral galactoceles following breast augmentation is reported in 2 young females. Both galactoceles were drained and cultured. In 1 patient the implant was removed and a delayed reinsertion was undertaken. In the second patient the implant was replaced at the time of the drainage procedure. Culture and sensitivity in 1 patient showed no growth and in the second patient revealed Staphylococcus aureus. Although the cause is unknown, galactocele formation may be due to manipulation of breast tissue during surgery. The use of oral contraceptives may also play a role in this process. Hormonal suppression of lactation and removal of the implants may be indicated in these patients. Consideration should be also given to the use of systemic antibiotics directed toward skin pathogens.

  11. Bacterial Killing by Dry Metallic Copper Surfaces▿

    PubMed Central

    Santo, Christophe Espírito; Lam, Ee Wen; Elowsky, Christian G.; Quaranta, Davide; Domaille, Dylan W.; Chang, Christopher J.; Grass, Gregor

    2011-01-01

    Metallic copper surfaces rapidly and efficiently kill bacteria. Cells exposed to copper surfaces accumulated large amounts of copper ions, and this copper uptake was faster from dry copper than from moist copper. Cells suffered extensive membrane damage within minutes of exposure to dry copper. Further, cells removed from copper showed loss of cell integrity. Acute contact with metallic copper surfaces did not result in increased mutation rates or DNA lesions. These findings are important first steps for revealing the molecular sensitive targets in cells lethally challenged by exposure to copper surfaces and provide a scientific explanation for the use of copper surfaces as antimicrobial agents for supporting public hygiene. PMID:21148701

  12. The killing efficiency of soft iron shot

    USGS Publications Warehouse

    Andrews, R.; Longcore, J.R.

    1969-01-01

    A cooperative research effort between the ammunition industry and the Bureau of Sport Fisheries and Wildlife is aimed at finding a suitable non-toxic substitute for lead shot. A contract study by an independent research organization evaluated ways of coating or detoxifying lead shot or replacing it with another metal. As a result of that study, the only promising candidate is soft iron. Previous tests of hard iron shot had suggested that its killing effectiveness was poor at longer ranges due to the lower density. In addition, its hardness caused excessive damage to shotgun barrels. A unique, automated shooting facility was constructed at the Patuxent Wildlife Research Center to test the killing effectiveness of soft iron shot under controlled conditions. Tethered game-farm mallards were transported across a shooting point in a manner simulating free flight. A microswitch triggered a mounted shotgun so that each shot was 'perfect.' A soft iron shot, in Number 4 size, was produced by the ammunition industry and loaded in 12-gauge shells to give optimum ballistic performance. Commercial loads of lead shot in both Number 4 and Number 6 size were used for comparison. A total of 2,010 ducks were shot at ranges of 30 to 65 yards and at broadside and head-on angles in a statistically designed procedure. The following data were recorded for each duck: time until death, broken wing or leg bones, and number of embedded shot. Those ducks not killed outright were held for 10 days. From these data, ducks were categorized as 'probably bagged,' 'probably lost cripples,' or survivors. The test revealed that the killing effectiveness of this soft iron shot was superior to its anticipated performance and close to that obtained with commercial lead loads containing an equal number of pellets. Bagging a duck, in terms of rapid death or broken wing, was primarily dependent on the probability of a shot striking that vital area, and therefore a function of range. There was no indication

  13. Micro-sociology of mass rampage killings.

    PubMed

    Collins, Randall

    2014-01-01

    Spectacular but very rare violent events such as mass killings by habitual non-criminals cannot be explained by factors which are very widespread, such as possession of firearms, being a victim of bullying, an introvert, or a career failure. A stronger clue is clandestine preparation of attack by one or two individuals, against randomly chosen representatives of a hated collective identity. Mass killers develop a deep back-stage, obsessed with planning their attack, overcoming social inferiority and isolation by an emotion of clandestine excitement.

  14. Enhancing Education through Mobile Augmented Reality

    ERIC Educational Resources Information Center

    Joan, D. R. Robert

    2015-01-01

    In this article, the author has discussed about the Mobile Augmented Reality and enhancing education through it. The aim of the present study was to give some general information about mobile augmented reality which helps to boost education. Purpose of the current study reveals the mobile networks which are used in the institution campus as well…

  15. Information Filtering for Mobile Augmented Reality

    DTIC Science & Technology

    2000-10-01

    Augmented reality is a potentially powerful paradigm for annotating the environment with computer-generated material. These benefits will be even...greater when augmented reality systems become mobile and wearable. However, to minimize the problem of clutter and maximize the effectiveness of the

  16. Urban Terrain Modeling for Augmented Reality Applications

    DTIC Science & Technology

    2001-01-01

    Augmented reality (AR) systems have arguably some of the most stringent requirements of any kind of three-dimensional synthetic graphic systems. AR...environment for a mobile augmented reality system. We review, describe and compare the effectiveness of a number of different modeling paradigms

  17. Information Filtering for Mobile Augmented Reality

    DTIC Science & Technology

    2002-07-02

    Augmented Reality (AR) has the potential to revolutionise the way in which information is delivered to a user. By tracking the user s position and...on the problem of developing mobile augmented reality systems which can be worn by an individual user operating in a large, complicated environment

  18. Embedding Augmentative Communication within Early Childhood Classrooms.

    ERIC Educational Resources Information Center

    DiCarlo, Cynthia; Banajee, Meher; Stricklin, Sarintha Buras

    2000-01-01

    This article first describes various augmentative communication systems including sign language, picture symbols, and voice output communication devices. It then explains ways to embed augmentative communication within four types of early childhood classroom activities: (1) special or planned activities, (2) meal time, (3) circle time, and (4)…

  19. Vertebral Augmentation for Osteoporotic Compression Fractures.

    PubMed

    Richmond, Bradford J

    2016-01-01

    Vertebral augmentation procedures such as vertebroplasty and kyphoplasty were developed to reduce pain and improve quality of life for patients with osteoporotic vertebral compression fractures. However, the use of vertebral augmentation has been debated and questioned since its inception. This article addresses some of these issues.

  20. Augmented Reality for Close Quarters Combat

    SciTech Connect

    2013-09-20

    Sandia National Laboratories has developed a state-of-the-art augmented reality training system for close-quarters combat (CQB). This system uses a wearable augmented reality system to place the user in a real environment while engaging enemy combatants in virtual space (Boston Dynamics DI-Guy). Umbra modeling and simulation environment is used to integrate and control the AR system.

  1. Augmented Reality for Close Quarters Combat

    ScienceCinema

    None

    2016-07-12

    Sandia National Laboratories has developed a state-of-the-art augmented reality training system for close-quarters combat (CQB). This system uses a wearable augmented reality system to place the user in a real environment while engaging enemy combatants in virtual space (Boston Dynamics DI-Guy). Umbra modeling and simulation environment is used to integrate and control the AR system.

  2. From Augmentation Media to Meme Media.

    ERIC Educational Resources Information Center

    Tanaka, Yuzuru

    Computers as meta media are now evolving from augmentation media vehicles to meme media vehicles. While an augmentation media system provides a seamlessly integrated environment of various tools and documents, meme media system provides further functions to edit and distribute tools and documents. Documents and tools on meme media can easily…

  3. Hyperprolactinemia and galactocele formation after augmentation mammoplasty.

    PubMed

    Chun, Yoon S; Taghinia, Amir

    2009-02-01

    Galactorrhea and galactocele formation are rare complications of augmentation mammoplasty. A number of case reports have been published in the literature; however, the etiology remains unclear. A case is presented of a unilateral galactocele associated with transient hyperprolactinemia after augmentation mammoplasty.

  4. A small molecule deubiquitinase inhibitor increases localization of inducible nitric oxide synthase to the macrophage phagosome and enhances bacterial killing.

    PubMed

    Burkholder, Kristin M; Perry, Jeffrey W; Wobus, Christiane E; Donato, Nicholas J; Showalter, Hollis D; Kapuria, Vaibhav; O'Riordan, Mary X D

    2011-12-01

    Macrophages are key mediators of antimicrobial defense and innate immunity. Innate intracellular defense mechanisms can be rapidly regulated at the posttranslational level by the coordinated addition and removal of ubiquitin by ubiquitin ligases and deubiquitinases (DUBs). While ubiquitin ligases have been extensively studied, the contribution of DUBs to macrophage innate immune function is incompletely defined. We therefore employed a small molecule DUB inhibitor, WP1130, to probe the role of DUBs in the macrophage response to bacterial infection. Treatment of activated bone marrow-derived macrophages (BMM) with WP1130 significantly augmented killing of the intracellular bacterial pathogen Listeria monocytogenes. WP1130 also induced killing of phagosome-restricted bacteria, implicating a bactericidal mechanism associated with the phagosome, such as the inducible nitric oxide synthase (iNOS). WP1130 had a minimal antimicrobial effect in macrophages lacking iNOS, indicating that iNOS is an effector mechanism for WP1130-mediated bacterial killing. Although overall iNOS levels were not notably different, we found that WP1130 significantly increased colocalization of iNOS with the Listeria-containing phagosome during infection. Taken together, our data indicate that the deubiquitinase inhibitor WP1130 increases bacterial killing in macrophages by enhancing iNOS localization to the phagosome and suggest a potential role for ubiquitin regulation in iNOS trafficking.

  5. Tumor Types: Understanding Brain Tumors

    MedlinePlus

    ... Resources Tools & Publications Tumor Types: Understanding Brain Tumors World Health Organization (WHO) Updates Official Classification of Tumors ... Central Nervous System On May 9, 2016, the World Health Organization (WHO) published an official reclassification of ...

  6. Food Web Responses to Augmenting the Entomopathogenic Nematodes in Bare and Animal Manure-Mulched Soil

    PubMed Central

    Duncan, L. W.; Graham, J. H.; Zellers, J.; Bright, D.; Dunn, D. C.; El-Borai, F. E.; Porazinska, D. L.

    2007-01-01

    Factorial treatments of entomopathogenic nematodes (EPN) and composted, manure mulches were evaluated for two years in a central Florida citrus orchard to study the post-application biology of EPN used to manage the root weevil, Diaprepes abbreviatus. Mulch treatments were applied once each year to study the effects of altering the community of EPN competitors (free-living bactivorous nematodes) and antagonists (nematophagous fungi (NF), predaceous nematodes and some microarthro-pods). EPN were augmented once with Steinernema riobrave in 2004 and twice in 2005. Adding EPN to soil affected the prevalence of organisms at several trophic levels, but the effects were often ephemeral and sometimes inconsistent. EPN augmentation always increased the mortality of sentinel weevil larvae, the prevalence of free-living nematodes in sentinel cadavers and the prevalence of trapping NF. Subsequent to the insecticidal effects of EPN augmentation in 2004, but not 2005, EPN became temporarily less prevalent, and fewer sentinel weevil larvae died in EPN-augmented compared to non-augmented plots. Manure mulch had variable effects on endoparasitic NF, but consistently decreased the prevalence of trapping NF and increased the prevalence of EPN and the sentinel mortality. Both temporal and spatial abundance of NF were inversely related to the prevalence of Steinernema diaprepesi, whereas Heterorhabditis zealandica prevalence was positively correlated with NF over time. The number of weevil larvae killed by EPN was likely greatest in 2005, due in part to non-target effects of augmentation on the endemic EPN community in 2004 that occurred during a period of peak weevil recruitment into the soil. PMID:19259487

  7. Positive and negative functions of B lymphocytes in tumors

    PubMed Central

    Shen, Meng; Sun, Qian; Wang, Jian; Pan, Wei; Ren, Xiubao

    2016-01-01

    Accumulating evidence indicated that B lymphocytes exerted complex functions in tumor immunity. On the one hand, B lymphocytes can inhibit tumor development through antibody generation, antigen presentation, tumor tissue interaction, and direct killing. On the other hand, B lymphocytes have tumor-promoting functions. A typical type of B lymphocytes, termed regulatory B cells, is confirmed to attenuate immune response in a tumor environment. In this paper, we summarize the current understanding of B-cell functions in tumor immunology, which may shed light on potential therapeutic strategies against cancer. PMID:27331871

  8. The Calabi complex and Killing sheaf cohomology

    NASA Astrophysics Data System (ADS)

    Khavkine, Igor

    2017-03-01

    It has recently been noticed that the degeneracies of the Poisson bracket of linearized gravity on constant curvature Lorentzian manifold can be described in terms of the cohomologies of a certain complex of differential operators. This complex was first introduced by Calabi and its cohomology is known to be isomorphic to that of the (locally constant) sheaf of Killing vectors. We review the structure of the Calabi complex in a novel way, with explicit calculations based on representation theory of GL(n) , and also some tools for studying its cohomology in terms of locally constant sheaves. We also conjecture how these tools would adapt to linearized gravity on other backgrounds and to other gauge theories. The presentation includes explicit formulas for the differential operators in the Calabi complex, arguments for its local exactness, discussion of generalized Poincaré duality, methods of computing the cohomology of locally constant sheaves, and example calculations of Killing sheaf cohomologies of some black hole and cosmological Lorentzian manifolds.

  9. Lung Mucosa Lining Fluid Modification of Mycobacterium tuberculosis to Reprogram Human Neutrophil Killing Mechanisms.

    PubMed

    Arcos, Jesús; Diangelo, Lauren E; Scordo, Julia M; Sasindran, Smitha J; Moliva, Juan I; Turner, Joanne; Torrelles, Jordi B

    2015-09-15

    We have shown that human alveolar lining fluid (ALF) contains homeostatic hydrolases capable of altering the Mycobacterium tuberculosis cell wall and subsequently its interaction with human macrophages. Neutrophils are also an integral part of the host immune response to M. tuberculosis infection. Here we show that the human lung mucosa influences M. tuberculosis interaction with neutrophils, enhancing the intracellular killing of ALF-exposed M. tuberculosis and up-regulating the expression of tumor necrosis factor and interleukin 8. In contrast, ALF-exposed M. tuberculosis does not induce neutrophil apoptosis or necrosis, degranulation, or release of extracellular traps, and it decreases the oxidative response. These results suggest an important role for the human alveolar mucosa: increasing the innate capacity of the neutrophil to recognize and kill M. tuberculosis by favoring the use of intracellular mechanisms, while at the same time limiting neutrophil extracellular inflammatory responses to minimize their associated tissue damage.

  10. A Small-Molecule Inhibitor of BCL6 Kills DLBCL Cells In Vitro and In Vivo

    SciTech Connect

    Cerchietti, L.C.; Ghetu, A.F.; Zhu, X.; Da Silva, G.F.; Zhong, S.; Matthews, M.; Bunting, K.L.; Polo, J.M.; Fares, C.; Arrowsmith, C.H.; Yang, S.N.; Garcia, M.; Coop, A.; Mackerell, A.D.; Prive, G.G.; Melnick, A.

    2010-09-22

    The BCL6 transcriptional repressor is the most frequently involved oncogene in diffuse large B cell lymphoma (DLBCL). We combined computer-aided drug design with functional assays to identify low-molecular-weight compounds that bind to the corepressor binding groove of the BCL6 BTB domain. One such compound disrupted BCL6/corepressor complexes in vitro and in vivo, and was observed by X-ray crystallography and NMR to bind the critical site within the BTB groove. This compound could induce expression of BCL6 target genes and kill BCL6-positive DLBCL cell lines. In xenotransplantation experiments, the compound was nontoxic and potently suppressed DLBCL tumors in vivo. The compound also killed primary DLBCLs from human patients.

  11. A novel bispecific antibody, S-Fab, induces potent cancer cell killing.

    PubMed

    Li, Li; He, Ping; Zhou, Changhua; Jing, Li; Dong, Bin; Chen, Siqi; Zhang, Ning; Liu, Yawei; Miao, Ji; Wang, Zhong; Li, Qing

    2015-01-01

    Bispecific antibodies that engage immune cells to kill cancer cells have been actively studied in cancer immunotherapy. In this study, we present a novel bispecific format, S-Fab, fabricated by linking a single-domain anti-carcinoembryonic antigen VHH to a conventional anti-CD3 Fab. In contrast to most bispecific antibodies, the S-Fab bispecific antibody can be efficiently expressed and purified from bacteria. The purified S-Fab is stable in serum and is able to recruit T cells to drive potent cancer cell killing. In xenograft models, the S-Fab antibody suppresses tumor growth in the presence of human immune cells. Our study suggested that the bispecific S-Fab format can be applied to a wide range of immunotherapies.

  12. Lung Mucosa Lining Fluid Modification of Mycobacterium tuberculosis to Reprogram Human Neutrophil Killing Mechanisms

    PubMed Central

    Arcos, Jesús; Diangelo, Lauren E.; Scordo, Julia M.; Sasindran, Smitha J.; Moliva, Juan I.; Turner, Joanne; Torrelles, Jordi B.

    2015-01-01

    We have shown that human alveolar lining fluid (ALF) contains homeostatic hydrolases capable of altering the Mycobacterium tuberculosis cell wall and subsequently its interaction with human macrophages. Neutrophils are also an integral part of the host immune response to M. tuberculosis infection. Here we show that the human lung mucosa influences M. tuberculosis interaction with neutrophils, enhancing the intracellular killing of ALF-exposed M. tuberculosis and up-regulating the expression of tumor necrosis factor and interleukin 8. In contrast, ALF-exposed M. tuberculosis does not induce neutrophil apoptosis or necrosis, degranulation, or release of extracellular traps, and it decreases the oxidative response. These results suggest an important role for the human alveolar mucosa: increasing the innate capacity of the neutrophil to recognize and kill M. tuberculosis by favoring the use of intracellular mechanisms, while at the same time limiting neutrophil extracellular inflammatory responses to minimize their associated tissue damage. PMID:25748325

  13. Piper betle extracts exhibit antitumor activity by augmenting antioxidant potential.

    PubMed

    Alam, Badrul; Majumder, Rajib; Akter, Shahina; Lee, Sang-Han

    2015-02-01

    The present study was conducted to evaluate the methanolic extract of Piper betle leaves (MPBL) and its organic fractions with regard to antitumor activity against Ehrlich ascites carcinoma (EAC) in Swiss albino mice and to confirm their antioxidant activities. At 24 h post-intraperitoneal inoculation of tumor cells into mice, extracts were administered at 25, 50 and 100 mg/kg body weight for nine consecutive days. The antitumor effects of the extracts were then assessed according to tumor volume, packed cell count, viable and non-viable tumor cell count, median survival time and increase in life span of EAC-bearing mice. Next, hematological profiles and serum biochemical parameters were calculated, and antioxidant properties were assessed by estimating lipid peroxidation, reduced glutathione (GSH), superoxide dismutase (SOD) and catalase (CAT) levels. MPBL and the ethylacetate fraction (EPBL) at a dose of 100 mg/kg induced a significant decrease in tumor volume, packed cell volume and viable cell count and increased the life span of the EAC-bearing mice (P<0.05). Hematological and serum biochemical profiles were restored to normal levels in the extract-treated mice compared with the EAC control mice. MPBL and EPBL treatment significantly decreased lipid peroxidation (P<0.05) and restored GSH, SOD and CAT levels towards normal compared with the EAC control. Taken together, the results of the present study demonstrated that Piper betle extracts exhibit significant antitumor activity, which may be attributed to the augmentation of endogenous antioxidant potential.

  14. Irradiated homologous costal cartilage for augmentation rhinoplasty

    SciTech Connect

    Lefkovits, G. )

    1990-10-01

    Although the ideal reconstructive material for augmentation rhinoplasty continues to challenge plastic surgeons, there exists no report in the literature that confines the use of irradiated homologous costal cartilage, first reported by Dingman and Grabb in 1961, to dorsal nasal augmentation. The purpose of this paper is to present a retrospective analysis of the author's experience using irradiated homologous costal cartilage in augmentation rhinoplasty. Twenty-seven dorsal nasal augmentations were performed in 24 patients between 16 and 49 years of age with a follow-up ranging from 1 to 27 months. Good-to-excellent results were achieved in 83.3% (20 of 24). Poor results requiring revision were found in 16.7% (4 of 24). Complication rates included 7.4% infection (2 of 27) and 14.8% warping (4 of 27). The resorption rate was zero. These results compare favorably with other forms of nasal augmentation. Advantages and disadvantages of irradiated homologous costal cartilage are discussed.

  15. Performance of a self-augmented railgun

    NASA Astrophysics Data System (ADS)

    Burton, Rodney L.; Witherspoon, F. D.; Goldstein, Shyke A.

    1991-10-01

    The accelerating force of a railgun can be increased by augmenting the self-induced magnetic field created by the armature current. Augmentation fields can be produced by external current coils or, as is done here, by shorting the railgun muzzle, and using the gun rails as the augmentation coil. Experimental results are presented for a 3.6-m railgun operated in this self-augmented mode, and effective inductance gradients are achieved which are as much as 9.3 times that of the unaugmented gun. A circuit model is presented which explains features of the measured shunt current and voltage. It is concluded that self-augmentation is an effective way to reduce ohmic heating in the armature of a railgun.

  16. Mertk on tumor macrophages is a therapeutic target to prevent tumor recurrence following radiation therapy

    PubMed Central

    Crittenden, Marka R.; Baird, Jason; Friedman, David; Savage, Talicia; Uhde, Lauren; Alice, Alejandro; Cottam, Benjamin; Young, Kristina; Newell, Pippa; Nguyen, Cynthia; Bambina, Shelly; Kramer, Gwen; Akporiaye, Emmanuel; Malecka, Anna; Jackson, Andrew; Gough, Michael J.

    2016-01-01

    Radiation therapy provides a means to kill large numbers of cancer cells in a controlled location resulting in the release of tumor-specific antigens and endogenous adjuvants. However, by activating pathways involved in apoptotic cell recognition and phagocytosis, irradiated cancer cells engender suppressive phenotypes in macrophages. We demonstrate that the macrophage-specific phagocytic receptor, Mertk is upregulated in macrophages in the tumor following radiation therapy. Ligation of Mertk on macrophages results in anti-inflammatory cytokine responses via NF-kB p50 upregulation, which in turn limits tumor control following radiation therapy. We demonstrate that in immunogenic tumors, loss of Mertk is sufficient to permit tumor cure following radiation therapy. However, in poorly immunogenic tumors, TGFb inhibition is also required to result in tumor cure following radiation therapy. These data demonstrate that Mertk is a highly specific target whose absence permits tumor control in combination with radiation therapy. PMID:27602953

  17. Scheduling Chemotherapy: Catch 22 between Cell Kill and Resistance Evolution

    DOE PAGES

    Gardner, Shea N.

    2000-01-01

    Dose response curves show that prolonged drug exposure at a low concentration may kill more cells than short exposures at higher drug concentrations, particularly for cell cycle phase specific drugs. Applying drugs at low concentrations for prolonged periods, however, allows cells with partial resistance to evolve higher levels of resistance through stepwise processes such as gene amplification. Models are developed for cell cycle specific (CS) and cell cycle nonspecific (CNS) drugs to identify the schedule of drug application that balances this tradeoff. The models predict that a CS drug may be applied most effectively by splitting the cumulative dose intomore » many (>40) fractions applied by long-term chemotherapy, while CNS drugs may be better applied in fewer than 10 fractions applied over a shorter term. The model suggests that administering each fraction by continuous infusion may be more effective than giving the drug as a bolus, whether the drug is CS or CNS. In addition, tumors with a low growth fraction or slow rate of cell division are predicted to be controlled more easily with CNS drugs, while those with a high proliferative fraction or fast cell division rate may respond better to CS drugs.« less

  18. Where and How Wolves (Canis lupus) Kill Beavers (Castor canadensis)

    PubMed Central

    Gable, Thomas D.; Windels, Steve K.; Bruggink, John G.; Homkes, Austin T.

    2016-01-01

    Beavers (Castor canadensis) can be a significant prey item for wolves (Canis lupus) in boreal ecosystems due to their abundance and vulnerability on land. How wolves hunt beavers in these systems is largely unknown, however, because observing predation is challenging. We inferred how wolves hunt beavers by identifying kill sites using clusters of locations from GPS-collared wolves in Voyageurs National Park, Minnesota. We identified 22 sites where wolves from 4 different packs killed beavers. We classified these kill sites into 8 categories based on the beaver-habitat type near which each kill occurred. Seasonal variation existed in types of kill sites as 7 of 12 (58%) kills in the spring occurred at sites below dams and on shorelines, and 8 of 10 (80%) kills in the fall occurred near feeding trails and canals. From these kill sites we deduced that the typical hunting strategy has 3 components: 1) waiting near areas of high beaver use (e.g., feeding trails) until a beaver comes near shore or ashore, 2) using vegetation, the dam, or other habitat features for concealment, and 3) immediately attacking the beaver, or ambushing the beaver by cutting off access to water. By identifying kill sites and inferring hunting behavior we have provided the most complete description available of how and where wolves hunt and kill beavers. PMID:27992441

  19. Where and How Wolves (Canis lupus) Kill Beavers (Castor canadensis).

    PubMed

    Gable, Thomas D; Windels, Steve K; Bruggink, John G; Homkes, Austin T

    2016-01-01

    Beavers (Castor canadensis) can be a significant prey item for wolves (Canis lupus) in boreal ecosystems due to their abundance and vulnerability on land. How wolves hunt beavers in these systems is largely unknown, however, because observing predation is challenging. We inferred how wolves hunt beavers by identifying kill sites using clusters of locations from GPS-collared wolves in Voyageurs National Park, Minnesota. We identified 22 sites where wolves from 4 different packs killed beavers. We classified these kill sites into 8 categories based on the beaver-habitat type near which each kill occurred. Seasonal variation existed in types of kill sites as 7 of 12 (58%) kills in the spring occurred at sites below dams and on shorelines, and 8 of 10 (80%) kills in the fall occurred near feeding trails and canals. From these kill sites we deduced that the typical hunting strategy has 3 components: 1) waiting near areas of high beaver use (e.g., feeding trails) until a beaver comes near shore or ashore, 2) using vegetation, the dam, or other habitat features for concealment, and 3) immediately attacking the beaver, or ambushing the beaver by cutting off access to water. By identifying kill sites and inferring hunting behavior we have provided the most complete description available of how and where wolves hunt and kill beavers.

  20. Whole tumor antigen vaccination using dendritic cells: Comparison of RNA electroporation and pulsing with UV-irradiated tumor cells

    PubMed Central

    Benencia, Fabian; Courrèges, Maria C; Coukos, George

    2008-01-01

    Because of the lack of full characterization of tumor associated antigens for solid tumors, whole antigen use is a convenient approach to tumor vaccination. Tumor RNA and apoptotic tumor cells have been used as a source of whole tumor antigen to prepare dendritic cell (DC) based tumor vaccines, but their efficacy has not been directly compared. Here we compare directly RNA electroporation and pulsing of DCs with whole tumor cells killed by ultraviolet (UV) B radiation using a convenient tumor model expressing human papilloma virus (HPV) E6 and E7 oncogenes. Although both approaches led to DCs presenting tumor antigen, electroporation with tumor cell total RNA induced a significantly higher frequency of tumor-reactive IFN-gamma secreting T cells, and E7-specific CD8+ lymphocytes compared to pulsing with UV-irradiated tumor cells. DCs electroporated with tumor cell RNA induced a larger tumor infiltration by T cells and produced a significantly stronger delay in tumor growth compared to DCs pulsed with UV-irradiated tumor cells. We conclude that electroporation with whole tumor cell RNA and pulsing with UV-irradiated tumor cells are both effective in eliciting antitumor immune response, but RNA electroporation results in more potent tumor vaccination under the examined experimental conditions. PMID:18445282

  1. Heterosigma bloom and associated fish kill

    USGS Publications Warehouse

    Hershberger, P.K.; Rensel, J.E.; Postel, J.R.; Taub, F.B.

    1997-01-01

    A bloom of the harmful marine phytoplankton, Heterosigma carterae occurred in upper Case Inlet, south Puget Sound, Washington in late September, 1994, correlating with the presence of at least 35 dead salmon. This marks the first time that this alga has been closely correlated with a wild fish kill; in the past it was thought to be associated with kills of penned fish at fish farms only. We were informed of the presence of a possible harmful algal bloom and dead salinois Ilear the town of Allyn on 27 September and a team was formed to investigate. We arrived at the Allyn waterfront at 17:30 hours the same day. Prior to our arrival, state agency personnel walked approximatcly two miles of shoreline from the powerlines north of the dock, to the mouth of Sherwood Creek and conducted the only official count of dead fish present along the shore consisting of 12 coho salmon (Oncorhynchus kisutch), 11 chum salmon (Oncorhynchus keta), 12 chinook salmon (Oncorhynchus tschawytscha), one flat fish, and one sculpin on the morning of 9/27. Since previous harmful blooms of Heterosigma have resultedin the majority of net penreared salmon sinking to the bottom of pens, and only approximately two miles of shoreline were sampled, it is suspected that many more exposed fish may have succumbed than were counted. Witnesses who explored the east side of the bay reported seeing many dead salmon there as well, but no counts were made. State agency personnel who observed the fish kill reported seeing “dying fish coming to the beach, gulping at the surface, trying to get out of the water” Scavengers were seen consuming the salmon carcasses; these included two harbor seals, a house cat, and Hymenopteran insects. None suffered any noticeable acute ill effects. Although precise cause of death has not been ascertained, visual inspection of the reproductive organs from a deceased male chum salmon found on the shore at Allyn confirmed that the fish was not yet reproductively mature and

  2. Canine parvovirus NS1 protein exhibits anti-tumor activity in a mouse mammary tumor model.

    PubMed

    Gupta, Shishir Kumar; Yadav, Pavan Kumar; Gandham, Ravi Kumar; Sahoo, A P; Harish, D R; Singh, Arvind Kumar; Tiwari, A K

    2016-02-02

    Many viral proteins have the ability to kill tumor cells specifically without harming the normal cells. These proteins, on ectopic expression, cause lysis or induction of apoptosis in the target tumor cells. Parvovirus NS1 is one of such proteins, which is known to kill high proliferating tumor cells. In the present study, we assessed the apoptosis inducing ability of canine parvovirus type 2 NS1 protein (CPV2.NS1) in vitro in 4T1 cells, and found it to cause significant cell death due to induction of apoptosis through intrinsic or mitochondrial pathway. Further, we also evaluated the oncolytic activity of CPV2.NS1 protein in a mouse mammary tumor model. The results suggested that CPV2.NS1 was able to inhibit the growth of 4T1 induced mouse mammary tumor as indicated by significantly reduced tumor volume, mitotic, AgNOR and PCNA indices. Further, inhibition of tumor growth was found to be because of induction of apoptosis in the tumor cells, which was evident by a significant increase in the number of TUNEL positive cells. Further, CPV2.NS1 was also able to stimulate the immune cells against the tumor antigens as indicated by the increased CD4+ and CD8+ counts in the blood of CVP2.NS1 treated mice. Further optimization of the delivery of NS1 protein and use of an adjuvant may further enhance its anti-tumor activity.

  3. Alpha-1 antitrypsin augmentation therapy.

    PubMed

    Wewers, Mark D; Crystal, Ronald G

    2013-03-01

    The therapy of alpha-1 antitrypsin deficiency (AATD) is an example of a medical triumph over a common hereditary disease. Based on the understanding of the pathogens of the disease as a deficiency in liver production of alpha-1 antitrypsin (AAT) resulting from inherited genetic variation in both parental AAT genes, the knowledge that A1AT functions primarily to inhibit neutrophil elastase (NE), and the observation that NE instilled into the lung of experimental animals resulted in emphysema, the concept evolved that the pulmonary manifestations of the disease could be halted by intermittent intravenous infusions of AAT purified from pooled human plasma. Following preliminary clinical studies in the academic community, and then pharmaceutical company development of large scale purification of human AAT, the FDA approved the use of weekly AAT augmentation therapy for AATD following a clinical trial which demonstrated that weekly infusions would raise to normal plasma and lung epithelial fluid levels of AAT in AAT-deficient individuals. The therapy is now used worldwide to treat AATD, the only pulmonary genetic disease with effective therapy for all affected individuals.

  4. Wireless Augmented Reality Prototype (WARP)

    NASA Technical Reports Server (NTRS)

    Devereaux, A. S.

    1999-01-01

    Initiated in January, 1997, under NASA's Office of Life and Microgravity Sciences and Applications, the Wireless Augmented Reality Prototype (WARP) is a means to leverage recent advances in communications, displays, imaging sensors, biosensors, voice recognition and microelectronics to develop a hands-free, tetherless system capable of real-time personal display and control of computer system resources. Using WARP, an astronaut may efficiently operate and monitor any computer-controllable activity inside or outside the vehicle or station. The WARP concept is a lightweight, unobtrusive heads-up display with a wireless wearable control unit. Connectivity to the external system is achieved through a high-rate radio link from the WARP personal unit to a base station unit installed into any system PC. The radio link has been specially engineered to operate within the high- interference, high-multipath environment of a space shuttle or space station module. Through this virtual terminal, the astronaut will be able to view and manipulate imagery, text or video, using voice commands to control the terminal operations. WARP's hands-free access to computer-based instruction texts, diagrams and checklists replaces juggling manuals and clipboards, and tetherless computer system access allows free motion throughout a cabin while monitoring and operating equipment.

  5. Postauricular fascia in augmentation rhinoplasty.

    PubMed

    Guerra, Aldo Benjamin

    2014-06-01

    Ten rhinoplasty operations performed using postauricular fascia for the purpose of augmenting the radix and dorsum of the nose were analyzed retrospectively. All the operations were performed over a 1-year period, between 2005 and 2006. The fascia of the postauricular area has been used as a source of pliable soft-tissue grafts in primary and revision rhinoplasty. It may be easily accessed using a single sulcus incision that also enables harvesting of ear cartilage grafts. Deficiency in the radix is an overlooked abnormality seen in many patients undergoing primary as well as revision rhinoplasty after aggressive hump removal. Recent trends in rhinoplasty have been to avoid the overly reduced nasal skeleton and to create a more balanced nasal surgery result. This article presents the use of the postauricular fascia as a radix graft that has been found to be simple to carry out, reliable, and long lasting. In addition, the fascia graft is useful in the camouflage of various nasal deformities in the dorsum and sidewalls. The average patient follow-up for the study was 24 months.

  6. The eyeball killer: serial killings with postmortem globe enucleation.

    PubMed

    Coyle, Julie; Ross, Karen F; Barnard, Jeffrey J; Peacock, Elizabeth; Linch, Charles A; Prahlow, Joseph A

    2015-05-01

    Although serial killings are relatively rare, they can be the cause of a great deal of anxiety while the killer remains at-large. Despite the fact that the motivations for serial killings are typically quite complex, the psychological analysis of a serial killer can provide valuable insight into how and why certain individuals become serial killers. Such knowledge may be instrumental in preventing future serial killings or in solving ongoing cases. In certain serial killings, the various incidents have a variety of similar features. Identification of similarities between separate homicidal incidents is necessary to recognize that a serial killer may be actively killing. In this report, the authors present a group of serial killings involving three prostitutes who were shot to death over a 3-month period. Scene and autopsy findings, including the unusual finding of postmortem enucleation of the eyes, led investigators to recognize the serial nature of the homicides.

  7. f(R)-gravity from Killing tensors

    NASA Astrophysics Data System (ADS)

    Paliathanasis, Andronikos

    2016-04-01

    We consider f(R)-gravity in a Friedmann-Lemaître-Robertson-Walker spacetime with zero spatial curvature. We apply the Killing tensors of the minisuperspace in order to specify the functional form of f(R) and for the field equations to be invariant under Lie-Bäcklund transformations, which are linear in momentum (contact symmetries). Consequently, the field equations to admit quadratic conservation laws given by Noether’s theorem. We find three new integrable f(R)-models, for which, with the application of the conservation laws, we reduce the field equations to a system of two first-order ordinary differential equations. For each model we study the evolution of the cosmological fluid. We find that for each integrable model the cosmological fluid has an equation of state parameter, in which there is linear behavior in terms of the scale factor which describes the Chevallier, Polarski and Linder parametric dark energy model.

  8. Advanced gel propulsion controls for kill vehicles

    NASA Astrophysics Data System (ADS)

    Yasuhara, W. K.; Olson, A.; Finato, S.

    1993-06-01

    A gel propulsion control concept for tactical applications is reviewed, and the status of the individual component technologies currently under development at the Aerojet Propulsion Division is discussed. It is concluded that a gel propellant Divert and Attitude Control Subsystem (DACS) provides a safe, insensitive munitions compliant alternative to current liquid Theater Missile Defense (TMD) DACS approaches. The gel kill vehicle (KV) control system packages a total impulse typical of a tactical weapon interceptor for the ground- or sea-based TMD systems. High density packaging makes it possible to increase firepower and to eliminate long-term high pressure gas storage associated with bipropellant systems. The integrated control subsystem technologies encompass solid propellant gas generators, insulated composite overwrapped propellant tanks, lightweight endoatmospheric thrusters, and insensitive munition gel propellants, which meet the requirements of a deployable, operationally safe KV.

  9. Killing, letting die and moral perception.

    PubMed

    Gillett, Grant

    1994-10-01

    There are a number of arguments that purport to show, in general terms, that there is no difference between killing and letting die. These are used to justify active euthanasia on the basis of the reasons given for allowing patients to die. I argue that the general and abstract arguments fail to take account of the complex and particular situations which are found in the care of those with terminal illness. When in such situations, there are perceptions and intuitions available that do not easily find propositional form but lead most of those whose practice is in the care of the dying to resist active euthanasia. I make a plea for their intuitions to be heeded above the sterile voice of abstract premises and arguments by examining the completeness of the outline form of the pro-euthanasia argument. In doing so, I make use of Nussbaum's discussion of moral perception and general claims to be found in the literature of moral particularism.

  10. Killing Sections and Sigma Models with Lie Algebroid Targets

    NASA Astrophysics Data System (ADS)

    Bruce, Andrew James

    2016-08-01

    We define and examine the notion of a Killing section of a Riemannian Lie algebroid as a natural generalisation of a Killing vector field. We show that the various expression for a vector field to be Killing naturally generalise to the setting of Lie algebroids. As an application we examine the internal symmetries of a class of sigma models for which the target space is a Riemannian Lie algebroid. Critical points of these sigma models are interpreted as generalised harmonic maps.

  11. Transverse conformal Killing forms on Kähler foliations

    NASA Astrophysics Data System (ADS)

    Jung, Seoung Dal

    2015-04-01

    On a closed, connected Riemannian manifold with a Kähler foliation of codimension q = 2 m, any transverse Killing r(≥ 2) -form is parallel (Jung and Jung, 2012). In this paper, we study transverse conformal Killing forms on Kähler foliations. In fact, if the foliation is minimal, then for any transverse conformal Killing r-form ϕ(2 ≤ r ≤ q - 2), Jϕ is parallel. Here J is defined in Section 4.

  12. Augmented reality-assisted skull base surgery.

    PubMed

    Cabrilo, I; Sarrafzadeh, A; Bijlenga, P; Landis, B N; Schaller, K

    2014-12-01

    Neuronavigation is widely considered as a valuable tool during skull base surgery. Advances in neuronavigation technology, with the integration of augmented reality, present advantages over traditional point-based neuronavigation. However, this development has not yet made its way into routine surgical practice, possibly due to a lack of acquaintance with these systems. In this report, we illustrate the usefulness and easy application of augmented reality-based neuronavigation through a case example of a patient with a clivus chordoma. We also demonstrate how augmented reality can help throughout all phases of a skull base procedure, from the verification of neuronavigation accuracy to intraoperative image-guidance.

  13. Augmented Reality in Architecture: Rebuilding Archeological Heritage

    NASA Astrophysics Data System (ADS)

    de la Fuente Prieto, J.; Castaño Perea, E.; Labrador Arroyo, F.

    2017-02-01

    With the development in recent years of augmented reality and the appearance of new mobile terminals and storage bases on-line, we find the possibility of using a powerful tool for transmitting architecture. This paper analyzes the relationship between Augmented Reality and Architecture. Firstly, connects the theoretical framework of both disciplines through the Representation concept. Secondly, describes the milestones and possibilities of Augmented Reality in the particular field of archaeological reconstruction. And lastly, once recognized the technology developed, we face the same analysis from a critical point of view, assessing their suitability to the discipline that concerns us is the architecture and within archeology.

  14. Killing spinors as a characterisation of rotating black hole spacetimes

    NASA Astrophysics Data System (ADS)

    Cole, Michael J.; Valiente Kroon, Juan A.

    2016-06-01

    We investigate the implications of the existence of Killing spinors in a spacetime. In particular, we show that in vacuum and electrovacuum a Killing spinor, along with some assumptions on the associated Killing vector in an asymptotic region, guarantees that the spacetime is locally isometric to the Kerr or Kerr-Newman solutions. We show that the characterisation of these spacetimes in terms of Killing spinors is an alternative expression of characterisation results of Mars (Kerr) and Wong (Kerr-Newman) involving restrictions on the Weyl curvature and matter content.

  15. Antibacterial activity of silver-killed bacteria: the "zombies" effect

    NASA Astrophysics Data System (ADS)

    Wakshlak, Racheli Ben-Knaz; Pedahzur, Rami; Avnir, David

    2015-04-01

    We report a previously unrecognized mechanism for the prolonged action of biocidal agents, which we denote as the zombies effect: biocidally-killed bacteria are capable of killing living bacteria. The concept is demonstrated by first killing Pseudomonas aeruginosa PAO1 with silver nitrate and then challenging, with the dead bacteria, a viable culture of the same bacterium: Efficient antibacterial activity of the killed bacteria is observed. A mechanism is suggested in terms of the action of the dead bacteria as a reservoir of silver, which, due to Le-Chatelier's principle, is re-targeted to the living bacteria. Langmuirian behavior, as well as deviations from it, support the proposed mechanism.

  16. Antibacterial activity of silver-killed bacteria: the "zombies" effect.

    PubMed

    Wakshlak, Racheli Ben-Knaz; Pedahzur, Rami; Avnir, David

    2015-04-23

    We report a previously unrecognized mechanism for the prolonged action of biocidal agents, which we denote as the zombies effect: biocidally-killed bacteria are capable of killing living bacteria. The concept is demonstrated by first killing Pseudomonas aeruginosa PAO1 with silver nitrate and then challenging, with the dead bacteria, a viable culture of the same bacterium: Efficient antibacterial activity of the killed bacteria is observed. A mechanism is suggested in terms of the action of the dead bacteria as a reservoir of silver, which, due to Le-Chatelier's principle, is re-targeted to the living bacteria. Langmuirian behavior, as well as deviations from it, support the proposed mechanism.

  17. Advancements in dynamic kill calculations for blowout wells

    SciTech Connect

    Kouba, G.E. . Production Fluids Div.); MacDougall, G.R. ); Schumacher, B.W. . Information Technology Dept.)

    1993-09-01

    This paper addresses the development, interpretation, and use of dynamic kill equations. To this end, three simple calculation techniques are developed for determining the minimum dynamic kill rate. Two techniques contain only single-phase calculations and are independent of reservoir inflow performance. Despite these limitations, these two methods are useful for bracketing the minimum flow rates necessary to kill a blowing well. For the third technique, a simplified mechanistic multiphase-flow model is used to determine a most-probable minimum kill rate.

  18. Autoradiographic and histopathological studies of boric acid-mediated BNCT in hepatic VX2 tumor-bearing rabbits: Specific boron retention and damage in tumor and tumor vessels.

    PubMed

    Yang, C H; Lin, Y T; Hung, Y H; Liao, J W; Peir, J J; Liu, H M; Lin, Y L; Liu, Y M; Chen, Y W; Chuang, K S; Chou, F I

    2015-12-01

    Hepatoma is a malignant tumor that responds poorly to conventional therapies. Boron neutron capture therapy (BNCT) may provide a better way for hepatoma therapy. In this research, (10)B-enriched boric acid (BA, 99% (10)B) was used as the boron drug. A multifocal hepatic VX2 tumor-bearing rabbit model was used to study the mechanisms of BA-mediated BNCT. Autoradiography demonstrated that BA was selectively targeted to tumors and tumor vessels. Histopathological examination revealed the radiation damage to tumor-bearing liver was concentrated in the tumor regions during BNCT treatment. The selective killing of tumor cells and the destruction of the blood vessels in tumor masses may be responsible for the success of BA-mediated BNCT for liver tumors.

  19. Augmented-reality visualization in iMRI operating room: system description and preclinical testing

    NASA Astrophysics Data System (ADS)

    Sauer, Frank; Khamene, Ali; Bascle, Benedicte; Vogt, Sebastian; Rubino, Gregory

    2002-05-01

    We developed an augmented reality system targeting image guidance for surgical procedures. The surgeon wears a video- see-through head mounted display that provides him with a stereo video view of the patient. The live video images are augmented with graphical representations of anatomical structures that are segmented from medical image data. The surgeon can see, e.g., a tumor in its actual location inside the patient. This in-situ visualization, where the computer maps the image information onto the patient, promises the most direct, intuitive guidance for surgical procedures. In this paper, we describe technical details of the system and its installation in UCLA's iMRI operating room. We added instrument tracking to the capabilities of our system to prepare it for minimally invasive procedures. We discuss several pre-clinical phantom experiments that support the potential clinical usefulness of augmented reality guidance.

  20. Augmentation of myelopoiesis in a murine host bearing a T cell lymphoma following in vivo administration of proton pump inhibitor pantoprazole.

    PubMed

    Vishvakarma, Naveen Kumar; Singh, Sukh Mahendra

    2011-10-01

    Proton pump inhibitors (PPI) are being proposed as potent antitumor agents, owing to their ability to specifically induce tumor cell death by reversing H(+) ion homeostasis. As tumor growth induces myelosuppression in tumor-bearing hosts, it remains unclear if PPI can also modulate tumor-induced myelosuppression. Thus, we studied the effect of in vivo administration of pantoprazole (PPZ), a PPI, on myelopoiesis in a murine model of a transplantable T cell lymphoma, designated as Dalton's lymphoma (DL). Intraperitoneal administration of PPZ to tumor-bearing mice resulted in an enhanced bone marrow cellularity, inhibited induction of apoptosis and augmented bone marrow cell (BMC) survival. BMC of PPZ-administered tumor-bearing mice showed elevated number of F4/80 positive cells, augmented colony forming ability and differentiation in bone marrow-derived macrophages (BMDM) with higher expression of F4/80 and CD11c markers. This study also presents evidences to indicate that PPZ-dependent augmentation of myelopoiesis in the tumor-bearing host is dependent on an enhanced expression of M-CSF and receptors for M-CSF & GM-CSF in BMC, along with a modulation in the expression of cell survival regulatory molecules PUMA, Bcl2, p53 and caspase-activated DNase (CAD). BMDM obtained from PPZ-administered tumor-bearing mice also showed an augmented expression of TLR-2, tumoricidal activity, production of NO and monokines: IL-1, IL-6 & TNF-α. The study discusses the possible mechanisms underlying PPZ-dependent augmentation of myelopoiesis. Taken together, the present study proposes that a PPZ-dependent alleviation of tumor-induced myelosuppression could contribute to an augmented myelopoiesis.

  1. Killing of human myelomonocytic leukemia and lymphocytic cell lines by Actinobacillus actinomycetemcomitans leukotoxin.

    PubMed Central

    Simpson, D L; Berthold, P; Taichman, N S

    1988-01-01

    The purified leukotoxin of Actinobacillus actinomycetemcomitans kills human leukemic cell lines (e.g., HL-60, U937, and KG-1) and human T- and B-cell lines (e.g., JURKAT, MOLT-4, Daudi, and Raji) in a dose- and time-dependent manner. The 50% effective doses for these cell lines are similar to those established for human polymorphonuclear leukocytes and monocytes. In contrast, other human and nonhuman tumor cell lines are not susceptible to the leukotoxin. These human leukemia and lymphoid cell lines will serve as useful model systems with which to study the molecular specificity and mechanism(s) of action of the actinobacillus leukotoxin. Images PMID:3258584

  2. Redundant contribution of myeloperoxidase-dependent systems to neutrophil-mediated killing of Escherichia coli.

    PubMed Central

    Rosen, H; Michel, B R

    1997-01-01

    Neutrophil microbicidal activity is a consequence of overlapping antimicrobial systems that vary in prominence according to the conditions of the neutrophil-microbe interaction, the nature of the microbe, and its metabolic state. In this study, normal, myeloperoxidase-deficient, and respiratory burst-deficient (chronic granulomatous disease [CGD]) neutrophils killed Escherichia coli with equivalent, high efficiencies. Killing by CGD and myeloperoxidase-deficient neutrophils was not augmented by supplements, such as exogenous H2O2 and myeloperoxidase, directed at ameliorating their metabolic defects, suggesting that nonoxidative microbicidal systems were sufficient for a full microbicidal effect. Neutrophils with an intact myeloperoxidase antimicrobial system (normal or appropriately supplemented deficient cells) were capable of rapidly suppressing E. coli DNA synthesis, while unsupplemented CGD or myeloperoxidase-deficient cells were far less effective, indicating that the myeloperoxidase system was active in normal neutrophils. The degree of DNA synthesis inhibition by myeloperoxidase-sufficient neutrophils could account, in a cell-free system, for most of the observed microbicidal activity. While the myeloperoxidase system was active and probably bactericidal, it was not rate limiting for microbicidal activity and appears to have been redundant with other microbicidal systems in the cell. Rapid and extensive inhibition of bacterial DNA synthesis appears to be an indicator of myeloperoxidase activity in neutrophils. PMID:9317024

  3. Diffuser for augmenting a wind turbine

    DOEpatents

    Foreman, Kenneth M.; Gilbert, Barry L.

    1984-01-01

    A diffuser for augmenting a wind turbine having means for energizing the boundary layer at several locations along the diffuser walls is improved by the addition of a short collar extending radially outward from the outlet of the diffuser.

  4. Improved diffuser for augmenting a wind turbine

    DOEpatents

    Foreman, K.M.; Gilbert, B.L.

    A diffuser for augmenting a wind turbine having means for energizing the boundary layer at several locations along the diffuser walls is improved by the addition of a short collar extending radially outward from the outlet of the diffuser.

  5. Augmented Reality Simulations on Handheld Computers

    ERIC Educational Resources Information Center

    Squire, Kurt; Klopfer, Eric

    2007-01-01

    Advancements in handheld computing, particularly its portability, social interactivity, context sensitivity, connectivity, and individuality, open new opportunities for immersive learning environments. This article articulates the pedagogical potential of augmented reality simulations in environmental engineering education by immersing students in…

  6. Kinetics of killing Listeria monocytogenes by macrophages: rapid killing accompanying phagocytosis

    SciTech Connect

    Davies, W.A.

    1983-08-01

    The kinetics of bactericidal activity of activated macrophages can be precisely described by a mathematical model in which phagocytosis, killing, digestion, and release of degraded bacterial material are considered to occur continuously. To gain a better understanding of these events, I have determined the period of time between first contact of bacteria with macrophages and the onset of killing. Activated rat peritoneal macrophages were incubated for various times up to 15 min with Listeria monocytogenes previously labeled with /sup 3/H-thymidine and the unassociated bacteria removed by two centrifugations through a density interface. Both cell-associated radioactivity and cell-associated viable bacteria, determined as colony forming units after sonication of the cell pellet, increased with time of incubation. However, the specific viability of these bacteria, expressed as the ratio of number of viable bacteria per unit radioactivity declined with time, as an approximate inverse exponential, after a lag period of 2.9 +/- 0.8 min. Evidence is given that other possible causes for this decline in specific viability, other than death of the bacteria, such as preferential ingestion of dead Listeria, clumping of bacteria, variations in autolytic activity, or release of Listericidins are unlikely. I conclude therefore that activated macrophages kill Listeria approximately 3 min after the cell and the bacterium first make contact.

  7. STABILITY/CONTROL AUGMENTATION SYSTEM EVALUATION.

    DTIC Science & Technology

    A study was made to evaluate competency of pilots trained in aircraft having a stability augmentation system . This is to determine the necessity of... Augmentation System . When the students reached private pilot proficiency, they were given three flight checks. The first with the system on, the...was to train five students to required flight performance for a private pilot certificate in a Cherokee-140 equipped with the Mitchell AK-153 Stability

  8. The Development of Mobile Augmented Reality

    DTIC Science & Technology

    2012-01-01

    This chapter provides a high-level overview of fifteen years of augmented reality research that was sponsored by the U.S. Office of Naval Research...years by a number of university and industrial research laboratories. It laid the groundwork for the development of many commercial mobile augmented ... reality (AR) applications that are currently available for smartphones and tablets. Furthermore, it helped shape a number of ongoing research activities in mobile AR.

  9. Tumor Therapy with Targeted Atomic Nanogenerators

    NASA Astrophysics Data System (ADS)

    McDevitt, Michael R.; Ma, Dangshe; Lai, Lawrence T.; Simon, Jim; Borchardt, Paul; Frank, R. Keith; Wu, Karen; Pellegrini, Virginia; Curcio, Michael J.; Miederer, Matthias; Bander, Neil H.; Scheinberg, David A.

    2001-11-01

    A single, high linear energy transfer alpha particle can kill a target cell. We have developed methods to target molecular-sized generators of alpha-emitting isotope cascades to the inside of cancer cells using actinium-225 coupled to internalizing monoclonal antibodies. In vitro, these constructs specifically killed leukemia, lymphoma, breast, ovarian, neuroblastoma, and prostate cancer cells at becquerel (picocurie) levels. Injection of single doses of the constructs at kilobecquerel (nanocurie) levels into mice bearing solid prostate carcinoma or disseminated human lymphoma induced tumor regression and prolonged survival, without toxicity, in a substantial fraction of animals. Nanogenerators targeting a wide variety of cancers may be possible.

  10. Tumor therapy with targeted atomic nanogenerators.

    PubMed

    McDevitt, M R; Ma, D; Lai, L T; Simon, J; Borchardt, P; Frank, R K; Wu, K; Pellegrini, V; Curcio, M J; Miederer, M; Bander, N H; Scheinberg, D A

    2001-11-16

    A single, high linear energy transfer alpha particle can kill a target cell. We have developed methods to target molecular-sized generators of alpha-emitting isotope cascades to the inside of cancer cells using actinium-225 coupled to internalizing monoclonal antibodies. In vitro, these constructs specifically killed leukemia, lymphoma, breast, ovarian, neuroblastoma, and prostate cancer cells at becquerel (picocurie) levels. Injection of single doses of the constructs at kilobecquerel (nanocurie) levels into mice bearing solid prostate carcinoma or disseminated human lymphoma induced tumor regression and prolonged survival, without toxicity, in a substantial fraction of animals. Nanogenerators targeting a wide variety of cancers may be possible.

  11. Mammary tumors

    SciTech Connect

    Weller, R.E.

    1988-10-01

    Mammary neoplasia is one of the more common malignancies affecting domestic species. Despite their importance, they are often over- diagnosed, undertreated and subject to several misconceptions propagated by veterinarians and pet owners alike. Mammary neoplasia is the most frequent tumor type encountered in the female accounting for almost half of all malignancies reported. The canine has the highest incidence of mammary tumors of all domestic species. In the dog, about 65 percent of mammary tumors are benign mixed tumors, and 25 percent are carcinomas. The rest are adenomas, myoepitheliomas, and malignant mixed tumors. The age distribution of mammary tumors closely follows the age distribution of most tumors in the dog. Mammary tumors are rare in dogs 2 years old, but incidence begins to increase sharply at approximately 6 years of age. Median age at diagnosis is about 10 years. No breed predilection has been consistently reported.

  12. Residual chromatin breaks as biodosimetry for cell killing by carbon ions

    NASA Astrophysics Data System (ADS)

    Suzuki, M.; Kase, Y.; Nakano, T.; Kanai, T.; Ando, K.

    1998-11-01

    We have studied the relationship between cell killing and the induction of residual chromatin breaks on various human cell lines and primary cultured cells obtained by biopsy from patients irradiated with either X-rays or heavy-ion beams to identify potential bio-marker of radiosensitivity for radiation-induced cell killing. The carbon-ion beams were accelerated with the Heavy Ion Medical Accelerator in Chiba (HIMAC). Six primary cultures obtained by biopsy from 6 patients with carcinoma of the cervix were irradiated with two different mono-LET beams (LET = 13 keV/μm, 76 keV/μm) and 200kV X rays. Residual chromatin breaks were measured by counting the number of non-rejoining chromatin fragments detected by the premature chromosome condensation (PCC) technique after a 24 hour post-irradiation incubation period. The induction rate of residual chromatin breaks per cell per Gy was the highest for 76 keV/μm beams on all of the cells. Our results indicated that cell which was more sensitive to the cell killing was similarly more susceptible to induction of residual chromatin breaks. Furthermore there is a good correlation between these two end points in various cell lines and primary cultured cells. This suggests that the detection of residual chromatin breaks by the PCC technique may be useful as a predictive assay of tumor response to cancer radiotherapy.

  13. Residual chromatin breaks as biodosimetry for cell killing by carbon ions.

    PubMed

    Suzuki, M; Kase, Y; Nakano, T; Kanai, T; Ando, K

    1998-01-01

    We have studied the relationship between cell killing and the induction of residual chromatin breaks on various human cell lines and primary cultured cells obtained by biopsy from patients irradiated with either X-rays or heavy-ion beams to identify potential bio-marker of radiosensitivity for radiation-induced cell killing. The carbon-ion beams were accelerated with the Heavy Ion Medical Accelerator in Chiba (HIMAC). Six primary cultures obtained by biopsy from 6 patients with carcinoma of the cervix were irradiated with two different mono-LET beams (LET = 13 keV/micrometer, 76 keV/micrometer) and 200kV X rays. Residual chromatin breaks were measured by counting the number of non-rejoining chromatin fragments detected by the premature chromosome condensation (PCC) technique after a 24 hour post-irradiation incubation period. The induction rate of residual chromatin breaks per cell per Gy was the highest for 76 keV/micrometer beams on all of the cells. Our results indicated that cell which was more sensitive to the cell killing was similarly more susceptible to induction of residual chromatin breaks. Furthermore there is a good correlation between these two end points in various cell lines and primary cultured cells. This suggests that the detection of residual chromatin breaks by the PCC technique may be useful as a predictive assay of tumor response to cancer radiotherapy.

  14. Mechanistic insights into selective killing of OXPHOS-dependent cancer cells by arctigenin.

    PubMed

    Brecht, Karin; Riebel, Virginie; Couttet, Philippe; Paech, Franziska; Wolf, Armin; Chibout, Salah-Dine; Pognan, Francois; Krähenbühl, Stephan; Uteng, Marianne

    2017-04-01

    Arctigenin has previously been identified as a potential anti-tumor treatment for advanced pancreatic cancer. However, the mechanism of how arctigenin kills cancer cells is not fully understood. In the present work we studied the mechanism of toxicity by arctigenin in the human pancreatic cell line, Panc-1, with special emphasis on the mitochondria. A comparison of Panc-1 cells cultured in glucose versus galactose medium was applied, allowing assessments of effects in glycolytic versus oxidative phosphorylation (OXPHOS)-dependent Panc-1 cells. For control purposes, the mitochondrial toxic response to treatment with arctigenin was compared to the anti-cancer drug, sorafenib, which is a tyrosine kinase inhibitor known for mitochondrial toxic off-target effects (Will et al., 2008). In both Panc-1 OXPHOS-dependent and glycolytic cells, arctigenin dissipated the mitochondrial membrane potential, which was demonstrated to be due to inhibition of the mitochondrial complexes II and IV. However, arctigenin selectively killed only the OXPHOS-dependent Panc-1 cells. This selective killing of OXPHOS-dependent Panc-1 cells was accompanied by generation of ER stress, mitochondrial membrane permeabilization and caspase activation leading to apoptosis and aponecrosis.

  15. Killing of bacteria during solar eclipse and its biological implications.

    PubMed

    Banerjee, S K; Chatterjee, S N

    1983-01-01

    Enhanced killing of bacteria was obtained by radiation reaching the earth during total solar eclipse (February 16, 1980) than during the corresponding time of a normal day (February 26, 1980). The killing was not due to the formation of sunlight induced photoproducts of tryptophan. The damage to the bacteria exposed to sunlight could be repaired by photoreactivation.

  16. The Seal Killing Controversy: What Are the Facts?

    ERIC Educational Resources Information Center

    Scheffer, Victor B.

    1973-01-01

    Discusses the seal controversy using the harp and Alaska fur seals to illustrate the two distinct issues, i.e., conservation (the effect of killing upon the animal population); and two, morality (the effect of killing upon the human spirit). Factual information combines with personal philosophy. (LK)

  17. 7 CFR 29.1018 - Fire-killed.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... 7 Agriculture 2 2010-01-01 2010-01-01 false Fire-killed. 29.1018 Section 29.1018 Agriculture Regulations of the Department of Agriculture AGRICULTURAL MARKETING SERVICE (Standards, Inspections, Marketing... Type 92) § 29.1018 Fire-killed. Any leaf of which 5 percent or more of its surface has a set...

  18. 7 CFR 29.1018 - Fire-killed.

    Code of Federal Regulations, 2014 CFR

    2014-01-01

    ... 7 Agriculture 2 2014-01-01 2014-01-01 false Fire-killed. 29.1018 Section 29.1018 Agriculture Regulations of the Department of Agriculture AGRICULTURAL MARKETING SERVICE (Standards, Inspections, Marketing... Type 92) § 29.1018 Fire-killed. Any leaf of which 5 percent or more of its surface has a set...

  19. 7 CFR 29.1018 - Fire-killed.

    Code of Federal Regulations, 2013 CFR

    2013-01-01

    ... 7 Agriculture 2 2013-01-01 2013-01-01 false Fire-killed. 29.1018 Section 29.1018 Agriculture Regulations of the Department of Agriculture AGRICULTURAL MARKETING SERVICE (Standards, Inspections, Marketing... Type 92) § 29.1018 Fire-killed. Any leaf of which 5 percent or more of its surface has a set...

  20. Control of Influenza and Poliomyelitis with Killed Virus Vaccines

    ERIC Educational Resources Information Center

    Salk, Jonas; Salk, Darrell

    1977-01-01

    Discusses control of poliomyelitis and influenza by live and killed virus vaccines. Considered are the etiological agents, pathogenic mechanisms and epidemiology of each disease. Reviews recent scientific studies of the diseases. Recommends use of killed virus vaccines in controlling both diseases. (CS)

  1. Null conformal Killing-Yano tensors and Birkhoff theorem

    NASA Astrophysics Data System (ADS)

    Ferrando, Joan Josep; Sáez, Juan Antonio

    2016-04-01

    We study the space-times admitting a null conformal Killing-Yano tensor whose divergence defines a Killing vector. We analyze the similarities and differences with the recently studied non null case (Ferrando and Sáez in Gen Relativ Gravit 47:1911, 2015). The results by Barnes concerning the Birkhoff theorem for the case of null orbits are analyzed and generalized.

  2. 7. LOOKING WEST TOWARD SHEEP KILL AREA ON SOUTH END ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    7. LOOKING WEST TOWARD SHEEP KILL AREA ON SOUTH END OF BUILDING 149; INCLINED CONVEYOR AT LEFT CENTER CARRIED TROLLEYS TO THE AUTOMATIC WASHER/OILER ON THE GALLERY LEVEL - Rath Packing Company, Beef Killing Building, Sycamore Street between Elm & Eighteenth Streets, Waterloo, Black Hawk County, IA

  3. Male Brown-headed Cowbird Attacks and Kills a Nestling

    USGS Publications Warehouse

    Igl, L.D.

    2003-01-01

    I observed a male Brown-headed Cowbird (Molothrus ater) attack and kill a nestling of an unidentified passerine in a grassland field in Day County, South Dakota, in June 2000. The killing or removal of nestlings by female cowbirds has been reported by others, but this behavior has not been documented previously in male cowbirds.

  4. Killing of bacteria by copper surfaces involves dissolved copper.

    PubMed

    Molteni, Cristina; Abicht, Helge K; Solioz, Marc

    2010-06-01

    Bacteria are rapidly killed on copper surfaces. However, the mechanism of this process remains unclear. Using Enterococcus hirae, the effect of inactivation of copper homeostatic genes and of medium compositions on survival and copper dissolution was tested. The results support a role for dissolved copper ions in killing.

  5. 9. GENERAL INTERIOR VIEW OF BEEF KILLING FLOOR; LOOKING SOUTHEAST; ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    9. GENERAL INTERIOR VIEW OF BEEF KILLING FLOOR; LOOKING SOUTHEAST; PLATFORMS IN FOREGROUND WERE USED BY SPLITTERS, TRIMMERS AND GOVERNMENT INSPECTORS; SKINNING TABLE RAN ALONG THE WINDOWS NEAR THE CENTER OF THE PHOTO - Rath Packing Company, Beef Killing Building, Sycamore Street between Elm & Eighteenth Streets, Waterloo, Black Hawk County, IA

  6. Augmenting digital displays with computation

    NASA Astrophysics Data System (ADS)

    Liu, Jing

    As we inevitably step deeper and deeper into a world connected via the Internet, more and more information will be exchanged digitally. Displays are the interface between digital information and each individual. Naturally, one fundamental goal of displays is to reproduce information as realistically as possible since humans still care a lot about what happens in the real world. Human eyes are the receiving end of such information exchange; therefore it is impossible to study displays without studying the human visual system. In fact, the design of displays is rather closely coupled with what human eyes are capable of perceiving. For example, we are less interested in building displays that emit light in the invisible spectrum. This dissertation explores how we can augment displays with computation, which takes both display hardware and the human visual system into consideration. Four novel projects on display technologies are included in this dissertation: First, we propose a software-based approach to driving multiview autostereoscopic displays. Our display algorithm can dynamically assign views to hardware display zones based on multiple observers' current head positions, substantially reducing crosstalk and stereo inversion. Second, we present a dense projector array that creates a seamless 3D viewing experience for multiple viewers. We smoothly interpolate the set of viewer heights and distances on a per-vertex basis across the arrays field of view, reducing image distortion, crosstalk, and artifacts from tracking errors. Third, we propose a method for high dynamic range display calibration that takes into account the variation of the chrominance error over luminance. We propose a data structure for enabling efficient representation and querying of the calibration function, which also allows user-guided balancing between memory consumption and the amount of computation. Fourth, we present user studies that demonstrate that the ˜ 60 Hz critical flicker fusion

  7. Brain Tumors

    MedlinePlus

    A brain tumor is a growth of abnormal cells in the tissues of the brain. Brain tumors can be benign, with no cancer cells, ... cancer cells that grow quickly. Some are primary brain tumors, which start in the brain. Others are ...

  8. Urogenital tumors

    SciTech Connect

    Weller, R.E.

    1994-03-01

    An overview is provided for veterinary care of urogenital tumors in companion animals, especially the dog. Neoplasms discussed include tumors of the kidney, urinary bladder, prostate, testis, ovary, vagina, vulva and the canine transmissible venereal tumor. Topics addressed include description, diagnosis and treatment.

  9. Wilms Tumor

    MedlinePlus

    ... Old Feeding Your 1- to 2-Year-Old Wilms Tumor KidsHealth > For Parents > Wilms Tumor Print A A A What's in this article? ... their child has cancer. Fortunately, most kids with Wilms tumor, a rare kidney cancer, survive and go on ...

  10. Nanotechnology to augment immunotherapy for the treatment of glioblastoma multiforme.

    PubMed

    Ung, Nolan; Yang, Isaac

    2015-07-01

    Glioblastoma multiforme (GBM) is characterized as one of the most common and most deadly malignant primary brain tumors. Current treatment modalities include the use of surgical resection and adjuvant chemotherapy and radiation therapy, though survival is still limited. Because of this, new treatment strategies are needed to improve overall survival. Immunotherapy has emerged as a potential treatment, but still possesses certain limitations to have a substantial clinical effect. In addition, nanotechnology has emerged as potent treatment effectors that have been shown to augment the effects of therapies including chemotherapy, gene therapy, and more. Nanoparticles possess a novel approach due to the myriad of functional groups that can create targeted treatments, though further optimization is still required. In this review, the authors will present the current uses and abilities of nanotechnology and its implication for use with immunotherapy in the treatment of GBM.

  11. Imaging Lung Clearance of Radiolabeled Tumor Cells to Study Mice with Normal, Activated or Depleted Natural Killer (NK) Cells

    NASA Astrophysics Data System (ADS)

    Kulkarni, P. V.; Bennett, M.; Constantinescu, A.; Arora, V.; Viguet, M.; Antich, P.; Parkey, R. W.; Mathews, D.; Mason, R. P.; Oz, O. K.

    2003-08-01

    Lung clearance of 51CR and 125I iododeoxyuridine (IUDR) labeled cancer cells assess NK cell activity. It is desirable to develop noninvasive imaging technique to assess NK activity in mice. We labeled target YAC-1 tumor cells with 125I, 111In, 99mTc, or 67Ga and injected I.V. into three groups of BALB/c mice. Animals were treated with medium (group I), 300mg/kg cyclophosmamide (CY) to kill NK cell (group II), or anti-LY49C/1) (ab')2 mAb to augment NK function (group III). Lungs were removed 15 min or 2 h later for tissue counting. Control and treated mice were imaged every 5 min with a scintillating camera for 1 h after 15 min of infusion of the 111In labeled cells. Lung clearance increased after 15 min (lodging: 60-80%) and (2 h retention: 3-7%). Similar results were obtained with all the isotopes studied. Images distinguished the control and treated mice for lung activity. Cells labeled with 111In, 99mTc or 67Ga are cleared similar to those labeled with 51Cr or 125I. NK cell destruction of tumor cells may be assessed by noninvasive imaging method either by SPECT (99mTc, 111In, 67Ga) or by PET (68Ga).

  12. Imaging Lung Clearance of Radiolabeled Tumor Cells to Study Mice with Normal, Activated or Depleted Natural Killer (NK) Cells

    SciTech Connect

    Kulkarni, P.V.; Bennett, M.; Constantinescu, A.; Arora, V.; Viguet, M.; Antich, P.; Parkey, R.W.; Mathews, D.; Mason, R.P.; Oz, O.K.

    2003-08-26

    Lung clearance of 51CR and 125I iododeoxyuridine (IUDR) labeled cancer cells assess NK cell activity. It is desirable to develop noninvasive imaging technique to assess NK activity in mice. We labeled target YAC-1 tumor cells with 125I, 111In, 99mTc, or 67Ga and injected I.V. into three groups of BALB/c mice. Animals were treated with medium (group I), 300mg/kg cyclophosmamide (CY) to kill NK cell (group II), or anti-LY49C/1) (ab')2 mAb to augment NK function (group III). Lungs were removed 15 min or 2 h later for tissue counting. Control and treated mice were imaged every 5 min with a scintillating camera for 1 h after 15 min of infusion of the 111In labeled cells. Lung clearance increased after 15 min (lodging: 60-80%) and (2 h retention: 3-7%). Similar results were obtained with all the isotopes studied. Images distinguished the control and treated mice for lung activity. Cells labeled with 111In, 99mTc or 67Ga are cleared similar to those labeled with 51Cr or 125I. NK cell destruction of tumor cells may be assessed by noninvasive imaging method either by SPECT (99mTc, 111In, 67Ga) or by PET (68Ga)

  13. Reduction of radiation-induced cell cycle blocks by caffeine does not necessarily lead to increased cell killing

    SciTech Connect

    Musk, S.R. )

    1991-03-01

    The effect of caffeine upon the radiosensitivities of three human tumor lines was examined and correlated with its action upon the radiation-induced S-phase and G2-phase blocks. Caffeine was found to reduce at least partially the S-phase and G2-phase blocks in all the cell lines examined but potentiated cytotoxicity in only one of the three tumor lines. That reductions have been demonstrated to occur in the absence of increased cell killing provides supporting evidence for the hypothesis that reductions may not be causal in those cases when potentiation of radiation-induced cytotoxicity is observed in the presence of caffeine.

  14. Clomipramine kills Trypanosoma brucei by apoptosis.

    PubMed

    de Silva Rodrigues, Jean Henrique; Stein, Jasmin; Strauss, Mariana; Rivarola, Héctor Walter; Ueda-Nakamura, Tânia; Nakamura, Celso Vataru; Duszenko, Michael

    2016-06-01

    Drug repositioning, i.e. use of existing medicals to treat a different illness, is especially rewarding for neglected tropical diseases (NTD), since in this field the pharmaceutical industry is rather reluctant to spend vast investments for drug development. NTDs afflict primarily poor populations in under-developed countries, which minimizes financial profit. Here we investigated the trypanocidal effect of clomipramine, a commercial antipsychotic drug, on Trypanosoma brucei. The data showed that this drug killed the parasite with an IC50 of about 5μM. Analysis of the involved cell death mechanism revealed furthermore an initial autophagic stress response and finally the induction of apoptosis. The latter was substantiated by a set of respective markers such as phosphatidylserine exposition, DNA degradation, loss of the inner mitochondrial membrane potential and characteristic morphological changes. Clomipramine was described as a trypanothione inhibitor, but as judged from our results it also showed DNA binding capacities and induced substantial morphological changes. We thus consider it likely that the drug induces a multifold adverse interaction with the parasite's physiology and induces stress in a way that trypanosomes cannot cope with.

  15. The Cell Killing Mechanisms of Hydroxyurea

    PubMed Central

    Singh, Amanpreet; Xu, Yong-Jie

    2016-01-01

    Hydroxyurea is a well-established inhibitor of ribonucleotide reductase that has a long history of scientific interest and clinical use for the treatment of neoplastic and non-neoplastic diseases. It is currently the staple drug for the management of sickle cell anemia and chronic myeloproliferative disorders. Due to its reversible inhibitory effect on DNA replication in various organisms, hydroxyurea is also commonly used in laboratories for cell cycle synchronization or generating replication stress. However, incubation with high concentrations or prolonged treatment with low doses of hydroxyurea can result in cell death and the DNA damage generated at arrested replication forks is generally believed to be the direct cause. Recent studies in multiple model organisms have shown that oxidative stress and several other mechanisms may contribute to the majority of the cytotoxic effect of hydroxyurea. This review aims to summarize the progress in our understanding of the cell-killing mechanisms of hydroxyurea, which may provide new insights towards the improvement of chemotherapies that employ this agent. PMID:27869662

  16. Mechanisms of Dendritic Cell Lysosomal Killing of Cryptococcus

    NASA Astrophysics Data System (ADS)

    Hole, Camaron R.; Bui, Hoang; Wormley, Floyd L.; Wozniak, Karen L.

    2012-10-01

    Cryptococcus neoformans is an opportunistic pulmonary fungal pathogen that disseminates to the CNS causing fatal meningitis in immunocompromised patients. Dendritic cells (DCs) phagocytose C. neoformans following inhalation. Following uptake, cryptococci translocate to the DC lysosomal compartment and are killed by oxidative and non-oxidative mechanisms. DC lysosomal extracts kill cryptococci in vitro; however, the means of antifungal activity remain unknown. Our studies determined non-oxidative antifungal activity by DC lysosomal extract. We examined DC lysosomal killing of cryptococcal strains, anti-fungal activity of purified lysosomal enzymes, and mechanisms of killing against C. neoformans. Results confirmed DC lysosome fungicidal activity against all cryptococcal serotypes. Purified lysosomal enzymes, specifically cathepsin B, inhibited cryptococcal growth. Interestingly, cathepsin B combined with its enzymatic inhibitors led to enhanced cryptococcal killing. Electron microscopy revealed structural changes and ruptured cryptococcal cell walls following treatment. Finally, additional studies demonstrated that osmotic lysis was responsible for cryptococcal death.

  17. 20 CFR 725.210 - Duration of augmented benefits.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 20 Employees' Benefits 4 2014-04-01 2014-04-01 false Duration of augmented benefits. 725.210... Entitlement Conditions and Duration of Entitlement: Miner's Dependents (augmented Benefits) § 725.210 Duration of augmented benefits. Augmented benefits payable on behalf of a spouse or divorced spouse, or...

  18. 20 CFR 725.210 - Duration of augmented benefits.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 20 Employees' Benefits 4 2013-04-01 2013-04-01 false Duration of augmented benefits. 725.210... Entitlement Conditions and Duration of Entitlement: Miner's Dependents (augmented Benefits) § 725.210 Duration of augmented benefits. Augmented benefits payable on behalf of a spouse or divorced spouse, or...

  19. 20 CFR 725.210 - Duration of augmented benefits.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 20 Employees' Benefits 3 2010-04-01 2010-04-01 false Duration of augmented benefits. 725.210... Entitlement Conditions and Duration of Entitlement: Miner's Dependents (augmented Benefits) § 725.210 Duration of augmented benefits. Augmented benefits payable on behalf of a spouse or divorced spouse, or...

  20. 20 CFR 725.210 - Duration of augmented benefits.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 20 Employees' Benefits 4 2012-04-01 2012-04-01 false Duration of augmented benefits. 725.210... Entitlement Conditions and Duration of Entitlement: Miner's Dependents (augmented Benefits) § 725.210 Duration of augmented benefits. Augmented benefits payable on behalf of a spouse or divorced spouse, or...

  1. 20 CFR 725.210 - Duration of augmented benefits.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 20 Employees' Benefits 3 2011-04-01 2011-04-01 false Duration of augmented benefits. 725.210... Entitlement Conditions and Duration of Entitlement: Miner's Dependents (augmented Benefits) § 725.210 Duration of augmented benefits. Augmented benefits payable on behalf of a spouse or divorced spouse, or...

  2. On pseudo-Riemannian manifolds with many Killing spinors

    SciTech Connect

    Alekseevsky, D. V.; Cortes, V.

    2009-02-02

    Let M be a pseudo-Riemannian spin manifold of dimension n and signature s and denote by N the rank of the real spinor bundle. We prove that M is locally homogeneous if it admits more than (3/4)N independent Killing spinors with the same Killing number, unless n {identical_to} 1(mod 4) and s {identical_to} 3(mod 4). We also prove that M is locally homogeneous if it admits k{sub +} independent Killing spinors with Killing number {lambda} and k{sub -} independent Killing spinors with Killing number -{lambda} such that k{sub +}+k{sub -}>(3/2)N, unless n {identical_to} s {identical_to} 3(mod 4). Similarly, a pseudo-Riemannian manifold with more than (3/4)N independent conformal Killing spinors is conformally locally homogeneous. For (positive or negative) definite metrics, the bounds (3/4)N and (3/2)N in the above results can be relaxed to (1/2)N and N, respectively. Furthermore, we prove that a pseudo-Riemannnian spin manifold with more than (3/4)N parallel spinors is flat and that (1/4)N parallel spinors suffice if the metric is definite. Similarly, a Riemannnian spin manifold with more than (3/8)N Killing spinors with the Killing number {lambda}(set-membership sign)R has constant curvature 4{lambda}{sup 2}. For Lorentzian or negative definite metrics the same is true with the bound (1/2)N. Finally, we give a classification of (not necessarily complete) Riemannian manifolds admitting Killing spinors, which provides an inductive construction of such manifolds.

  3. Evaluation of Bystander Cell Killing Effects in Suicide Gene Therapy of Cancer: Engineered Thymidylate Kinase (TMPK)/AZT Enzyme-Prodrug Axis.

    PubMed

    Sato, Takeya; Neschadim, Anton; Nakagawa, Ryo; Yanagisawa, Teruyuki; Medin, Jeffrey A

    2015-01-01

    Suicide gene therapy of cancer (SGTC) entails the introduction of a cDNA sequence into tumor cells whose polypeptide product is capable of either directly activating apoptotic pathways itself or facilitating the activation of pharmacologic agents that do so. The latter class of SGTC approaches is of the greater utility in cancer therapy owing to the ability of some small, activated cytotoxic compounds to diffuse from their site of activation into neighboring malignant cells, where they can also mediate destruction. This phenomenon, termed "bystander killing", can be highly advantageous in driving significant tumor regression in vivo without the requirement of transduction of each and every tumor cell with the suicide gene. We have developed a robust suicide gene therapy enzyme/prodrug system based on an engineered variant of the human thymidylate kinase (TMPK), which has been endowed with the ability to drive azidothymidine (AZT) activation. Delivery of this suicide gene sequence into tumors by means of recombinant lentivirus-mediated transduction embodies an SGTC strategy that successfully employs bystander cell killing as a mechanism to achieve significant ablation of solid tumors in vivo. Thus, this engineered TMPK/AZT suicide gene therapy axis holds great promise for clinical application in the treatment of inoperable solid tumors in the neoadjuvant setting. Here we present detailed procedures for the preparation of recombinant TMPK-based lentivirus, transduction of target cells, and various approaches for the evaluation of bystander cell killing effects in SGCT in both in vitro and in vivo models.

  4. Managing Threat, Cost, and Incentive to Kill: The Short- and Long-Term Effects of Intervention in Mass Killings

    ERIC Educational Resources Information Center

    Kathman, Jacob D.; Wood, Reed M.

    2011-01-01

    How do third-party interventions affect the severity of mass killings? The authors theorize that episodes of mass killing are the consequence of two factors: (1) the threat perceptions of the perpetrators and (2) the cost of implementing genocidal policies relative to other alternatives. To reduce genocidal hostilities, interveners must address…

  5. Tracheobronchial tumors

    PubMed Central

    Milenkovic, Branislava

    2016-01-01

    Tumors of trachea and bronchi are uncommon and can occur in the form of benign or low- and high-grade malignant tumors. Although tracheobronchial tumors (TBTs) represent only 0.6% of all pulmonary tumors, they are clinically significant. Delays in diagnosis of these tumors commonly occur because the signs and symptoms caused by these tumors are nonspecific and chest radiographs are often considered unremarkable. Therefore, novel radiological techniques and better access to flexible bronchoscopy enable detection of larger number of TBT. The purpose of this article is to provide a review of tracheal and bronchial tumors and discuss significant aspects of the different TBT with focus on clinical manifestations and diagnostic procedures. PMID:28066620

  6. Psychological traits underlying different killing methods among Malaysian male murderers.

    PubMed

    Kamaluddin, Mohammad Rahim; Shariff, Nadiah Syariani; Nurfarliza, Siti; Othman, Azizah; Ismail, Khaidzir H; Mat Saat, Geshina Ayu

    2014-04-01

    Murder is the most notorious crime that violates religious, social and cultural norms. Examining the types and number of different killing methods that used are pivotal in a murder case. However, the psychological traits underlying specific and multiple killing methods are still understudied. The present study attempts to fill this gap in knowledge by identifying the underlying psychological traits of different killing methods among Malaysian murderers. The study adapted an observational cross-sectional methodology using a guided self-administered questionnaire for data collection. The sampling frame consisted of 71 Malaysian male murderers from 11 Malaysian prisons who were selected using purposive sampling method. The participants were also asked to provide the types and number of different killing methods used to kill their respective victims. An independent sample t-test was performed to establish the mean score difference of psychological traits between the murderers who used single and multiple types of killing methods. Kruskal-Wallis tests were carried out to ascertain the psychological trait differences between specific types of killing methods. The results suggest that specific psychological traits underlie the type and number of different killing methods used during murder. The majority (88.7%) of murderers used a single method of killing. Multiple methods of killing was evident in 'premeditated' murder compared to 'passion' murder, and revenge was a common motive. Examples of multiple methods are combinations of stabbing and strangulation or slashing and physical force. An exception was premeditated murder committed with shooting, when it was usually a single method, attributed to the high lethality of firearms. Shooting was also notable when the motive was financial gain or related to drug dealing. Murderers who used multiple killing methods were more aggressive and sadistic than those who used a single killing method. Those who used multiple methods or

  7. Adenanthin targets peroxiredoxin I/II to kill hepatocellular carcinoma cells.

    PubMed

    Hou, J-K; Huang, Y; He, W; Yan, Z-W; Fan, L; Liu, M-H; Xiao, W-L; Sun, H-D; Chen, G-Q

    2014-09-04

    Adenanthin, a natural diterpenoid isolated from the leaves of Isodon adenanthus, has recently been reported to induce leukemic cell differentiation by targeting peroxiredoxins (Prx) I and II. On the other hand, increasing lines of evidence propose that these Prx proteins would become potential targets to screen drugs for the prevention and treatment of solid tumors. Therefore, it is of significance to explore the potential activities of adenanthin on solid tumor cells. Here, we demonstrate that Prx I protein is essential for the survival of hepatocellular carcinoma (HCC) cells, and adenanthin can kill these malignant liver cells in vitro and xenografts. We also show that the cell death-inducing activity of adenanthin on HCC cells is mediated by the increased reactive oxygen species (ROS) levels. Furthermore, the silencing of Prx I or Prx II significantly enhances the cytotoxic activity of adenanthin on HCC, whereas the ectopic expression of Prx I and Prx II but not their mutants of adenanthin-bound cysteines can rescue adenanthin-induced cytotoxicity in Prxs-silenced HCC cells. Taken together, our results propose that adenanthin targets Prx I/II to kill HCC cells and its therapeutic significance warrants to be further explored in HCC patients.

  8. Adenanthin targets peroxiredoxin I/II to kill hepatocellular carcinoma cells

    PubMed Central

    Hou, J-K; Huang, Y; He, W; Yan, Z-W; Fan, L; Liu, M-H; Xiao, W-L; Sun, H-D; Chen, G-Q

    2014-01-01

    Adenanthin, a natural diterpenoid isolated from the leaves of Isodon adenanthus, has recently been reported to induce leukemic cell differentiation by targeting peroxiredoxins (Prx) I and II. On the other hand, increasing lines of evidence propose that these Prx proteins would become potential targets to screen drugs for the prevention and treatment of solid tumors. Therefore, it is of significance to explore the potential activities of adenanthin on solid tumor cells. Here, we demonstrate that Prx I protein is essential for the survival of hepatocellular carcinoma (HCC) cells, and adenanthin can kill these malignant liver cells in vitro and xenografts. We also show that the cell death-inducing activity of adenanthin on HCC cells is mediated by the increased reactive oxygen species (ROS) levels. Furthermore, the silencing of Prx I or Prx II significantly enhances the cytotoxic activity of adenanthin on HCC, whereas the ectopic expression of Prx I and Prx II but not their mutants of adenanthin-bound cysteines can rescue adenanthin-induced cytotoxicity in Prxs-silenced HCC cells. Taken together, our results propose that adenanthin targets Prx I/II to kill HCC cells and its therapeutic significance warrants to be further explored in HCC patients. PMID:25188510

  9. Augmented Reality for the Improvement of Remote Laboratories: An Augmented Remote Laboratory

    ERIC Educational Resources Information Center

    Andujar, J. M.; Mejias, A.; Marquez, M. A.

    2011-01-01

    Augmented reality (AR) provides huge opportunities for online teaching in science and engineering, as these disciplines place emphasis on practical training and unsuited to completely nonclassroom training. This paper proposes a new concept in virtual and remote laboratories: the augmented remote laboratory (ARL). ARL is being tested in the first…

  10. ARSC: Augmented Reality Student Card--An Augmented Reality Solution for the Education Field

    ERIC Educational Resources Information Center

    El Sayed, Neven A. M.; Zayed, Hala H.; Sharawy, Mohamed I.

    2011-01-01

    Augmented Reality (AR) is the technology of adding virtual objects to real scenes through enabling the addition of missing information in real life. As the lack of resources is a problem that can be solved through AR, this paper presents and explains the usage of AR technology we introduce Augmented Reality Student Card (ARSC) as an application of…

  11. 76 FR 16715 - Drawbridge Operation Regulation; Raritan River, Arthur Kill and Their Tributaries, Staten Island...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-03-25

    ... Kill and Their Tributaries, Staten Island, NY and Elizabeth, NJ AGENCY: Coast Guard, DHS. ACTION... regulations governing the operation of the Arthur Kill (AK) Railroad Bridge at mile 11.6, across Arthur Kill... Kill (AK) Railroad Bridge at mile 11.6, across Arthur Kill, has a vertical clearance of 31 feet at...

  12. Macrophage elastase kills bacteria within murine macrophages.

    PubMed

    Houghton, A McGarry; Hartzell, William O; Robbins, Clinton S; Gomis-Rüth, F Xavier; Shapiro, Steven D

    2009-07-30

    Macrophages are aptly positioned to function as the primary line of defence against invading pathogens in many organs, including the lung and peritoneum. Their ability to phagocytose and clear microorganisms has been well documented. Macrophages possess several substances with which they can kill bacteria, including reactive oxygen species, nitric oxide, and antimicrobial proteins. We proposed that macrophage-derived proteinases may contribute to the antimicrobial properties of macrophages. Macrophage elastase (also known as matrix metalloproteinase 12 or MMP12) is an enzyme predominantly expressed in mature tissue macrophages and is implicated in several disease processes, including emphysema. Physiological functions for MMP12 have not been described. Here we show that Mmp12(-/-) mice exhibit impaired bacterial clearance and increased mortality when challenged with both gram-negative and gram-positive bacteria at macrophage-rich portals of entry, such as the peritoneum and lung. Intracellular stores of MMP12 are mobilized to macrophage phagolysosomes after the ingestion of bacterial pathogens. Once inside phagolysosomes, MMP12 adheres to bacterial cell walls where it disrupts cellular membranes resulting in bacterial death. The antimicrobial properties of MMP12 do not reside within its catalytic domain, but rather within the carboxy-terminal domain. This domain contains a unique four amino acid sequence on an exposed beta loop of the protein that is required for the observed antimicrobial activity. The present study represents, to our knowledge, the first report of direct antimicrobial activity by a matrix metallopeptidase, and describes a new antimicrobial peptide that is sequentially and structurally unique in nature.

  13. Did Vertigo Kill America's Forgotten Astronaut?

    NASA Technical Reports Server (NTRS)

    Bendrick, Gregg A.; Merlin, Peter W.

    2007-01-01

    On November 15, 1967, U.S. Air Force test pilot Major Michael J. Adams was killed while flying the X-15 rocket-propelled research vehicle in a parabolic spaceflight profile. This flight was part of a joint effort with NASA. An electrical short in one of the experiments aboard the vehicle caused electrical transients, resulting in excessive workload by the pilot. At altitude Major Adams inappropriately initiated a flat spin that led to a series of unusual aircraft attitudes upon atmospheric re-entry, ultimately causing structural failure of the airframe. Major Adams was known to experience vertigo (i.e. spatial disorientation) while flying the X-15, but all X-15 pilots most likely experienced vertigo (i.e. somatogravic, or "Pitch-Up", illusion) as a normal physiologic response to the accelerative forces involved. Major Adams probably experienced vertigo to a greater degree than did others, since prior aeromedical testing for astronaut selection at Brooks AFB revealed that he had an unusually high degree of labyrinthine sensitivity. Subsequent analysis reveals that after engine burnout, and through the zenith of the flight profile, he likely experienced the oculoagravic ("Elevator") illusion. Nonetheless, painstaking investigation after the mishap revealed that spatial disorientation (Type II, Recognized) was NOT the cause, but rather, a contributing factor. The cause was in fact the misinterpretation of a dual-use flight instrument (i.e. Loss of Mode Awareness), resulting in confusion between yaw and roll indications, with subsequent flight control input that was inappropriate. Because of the altitude achieved on this flight, Major Adams was awarded Astronaut wings posthumously. Understanding the potential for spatial disorientation, particularly the oculoagravic illusion, associated with parabolic spaceflight profiles, and understanding the importance of maintaining mode awareness in the context of automated cockpit design, are two lessons that have direct

  14. Laser Microbial Killing and Biofilm Disruption

    NASA Astrophysics Data System (ADS)

    Krespi, Yosef P.; Kizhner, Victor

    2009-06-01

    Objectives: To analyze the ability of NIR lasers to reduce bacterial load and demonstrate the capability of fiber-based Q-switched Nd:YAG laser disrupting biofilm. Study Design: NIR diode laser was tested in vitro and in vivo using pathogenic microorganisms (S. aureus, S. pneumoniae, P. aeruginosa). In addition biofilms were grown from clinical Pseudomonas isolates and placed in culture plates, screws, tympanostomy tubes and PET sutures. Methods: In the animal experiments acute rhinosinusitis model was created by packing the rabbit nose with bacteria soaked solution. The nasal pack was removed in two days and nose was exposed to laser irradiation. A 940 nm diode laser with fiber diffuser was used. Nasal cultures were obtained before and after the laser treatments. Animals were sacrificed fifteen days following laser treatment and bacteriologic/histologic results analyzed. Q-switched Nd:YAG laser generated shockwave pulses were delivered on biofilm using special probes over culture plates, screws, tubes, and PET sutures for the biofilm experiments. Results: Average of two log bacteria reduction was achieved with NIR laser compared to controls. Histologic studies demonstrated preservation of tissue integrity without significant damage to mucosa. Biofilms were imaged before, during and after treatment using a confocal microscope. During laser-generated shockwave application, biofilm was initially seen to oscillate and eventually break off. Large and small pieces of biofilm were totally and instantly removed from the surface to which they were attached in seconds. Conclusions: Significant bacterial reduction was achieved with NIR laser therapy in this experimental in vitro and animal study. In addition we disrupted Pseudomonas aeruginosa biofilms using Q-switched Nd:YAG laser and special probes generating plasma and shockwave. This new and innovative method of bacteria killing and biofilm disruption without injuring host tissue may have clinical application in the

  15. Stability-Augmentation Devices for Miniature Aircraft

    NASA Technical Reports Server (NTRS)

    Wood, RIchard M.

    2005-01-01

    Non-aerodynamic mechanical devices are under consideration as means to augment the stability of miniature autonomous and remotely controlled aircraft. Such aircraft can be used for diverse purposes, including military reconnaissance, radio communications, and safety-related monitoring of wide areas. The need for stability-augmentation devices arises because adverse meteorological conditions generally affect smaller aircraft more strongly than they affect larger aircraft: Miniature aircraft often become uncontrollable under conditions that would not be considered severe enough to warrant grounding of larger aircraft. The need for the stability-augmentation devices to be non-aerodynamic arises because there is no known way to create controlled aerodynamic forces sufficient to counteract the uncontrollable meteorological forces on miniature aircraft. A stability-augmentation device of the type under consideration includes a mass pod (a counterweight) at the outer end of a telescoping shaft, plus associated equipment to support the operation of the aircraft. The telescoping shaft and mass pod are stowed in the rear of the aircraft. When deployed, they extend below the aircraft. Optionally, an antenna for radio communication can be integrated into the shaft. At the time of writing this article, the deployment of the telescoping shaft and mass pod was characterized as passive and automatic, but information about the deployment mechanism(s) was not available. The feasibility of this stability-augmentation concept was demonstrated in flights of hand-launched prototype aircraft.

  16. The engineered thymidylate kinase (TMPK)/AZT enzyme-prodrug axis offers efficient bystander cell killing for suicide gene therapy of cancer.

    PubMed

    Sato, Takeya; Neschadim, Anton; Lavie, Arnon; Yanagisawa, Teruyuki; Medin, Jeffrey A

    2013-01-01

    We previously described a novel suicide (or 'cell fate control') gene therapy enzyme/prodrug system based on an engineered variant of human thymidylate kinase (TMPK) that potentiates azidothymidine (AZT) activation. Delivery of a suicide gene sequence into tumors by lentiviral transduction embodies a cancer gene therapy that could employ bystander cell killing as a mechanism driving significant tumor regression in vivo. Here we present evidence of a significant bystander cell killing in vitro and in vivo mediated by the TMPK/AZT suicide gene axis that is reliant on the formation of functional gap-junctional intercellular communications (GJICs). Potentiation of AZT activation by the engineered TMPK expressed in the human prostate cancer cell line, PC-3, resulted in effective bystander killing of PC-3 cells lacking TMPK expression--an effect that could be blocked by the GJIC inhibitor, carbenoxolone. Although GJICs are mainly formed by connexins, a new family of GJIC molecules designated pannexins has been recently identified. PC-3 cells expressed both connexin43 (Cx43) and Pannexin1 (Panx1), but Panx1 expression predominated at the plasma membrane, whereas Cx43 expression was primarily localized to the cytosol. The contribution of bystander effects to the reduction of solid tumor xenografts established by the PC-3 cell line was evaluated in an animal model. We demonstrate the contribution of bystander cell killing to tumor regression in a xenograft model relying on the delivery of expression of the TMPK suicide gene into tumors via direct intratumoral injection of recombinant therapeutic lentivirus. Taken together, our data underscore that the TMPK/AZT enzyme-prodrug axis can be effectively utilized in suicide gene therapy of solid tumors, wherein significant tumor regression can be achieved via bystander effects mediated by GJICs.

  17. A Numerical Investigation of the Electric and Thermal Cell Kill Distributions in Electroporation-Based Therapies in Tissue

    PubMed Central

    Garcia, Paulo A.; Davalos, Rafael V.; Miklavcic, Damijan

    2014-01-01

    Electroporation-based therapies are powerful biotechnological tools for enhancing the delivery of exogeneous agents or killing tissue with pulsed electric fields (PEFs). Electrochemotherapy (ECT) and gene therapy based on gene electrotransfer (EGT) both use reversible electroporation to deliver chemotherapeutics or plasmid DNA into cells, respectively. In both ECT and EGT, the goal is to permeabilize the cell membrane while maintaining high cell viability in order to facilitate drug or gene transport into the cell cytoplasm and induce a therapeutic response. Irreversible electroporation (IRE) results in cell kill due to exposure to PEFs without drugs and is under clinical evaluation for treating otherwise unresectable tumors. These PEF therapies rely mainly on the electric field distributions and do not require changes in tissue temperature for their effectiveness. However, in immediate vicinity of the electrodes the treatment may results in cell kill due to thermal damage because of the inhomogeneous electric field distribution and high current density during the electroporation-based therapies. Therefore, the main objective of this numerical study is to evaluate the influence of pulse number and electrical conductivity in the predicted cell kill zone due to irreversible electroporation and thermal damage. Specifically, we simulated a typical IRE protocol that employs ninety 100-µs PEFs. Our results confirm that it is possible to achieve predominant cell kill due to electroporation if the PEF parameters are chosen carefully. However, if either the pulse number and/or the tissue conductivity are too high, there is also potential to achieve cell kill due to thermal damage in the immediate vicinity of the electrodes. Therefore, it is critical for physicians to be mindful of placement of electrodes with respect to critical tissue structures and treatment parameters in order to maintain the non-thermal benefits of electroporation and prevent unnecessary damage to

  18. Tumor Endothelium FasL Establishes a Selective Immune Barrier Promoting Tolerance in Tumors

    PubMed Central

    Motz, Gregory T.; Santoro, Stephen P.; Wang, Li-Ping; Garrabrant, Tom; Lastra, Ricardo R.; Hagemann, Ian S.; Lal, Priti; Feldman, Michael D.; Benencia, Fabian; Coukos, George

    2014-01-01

    We describe a novel mechanism regulating the tumor endothelial barrier and T cell homing to tumors. Selective expression of the death mediator Fas ligand (FasL/CD95L) was detected in the vasculature of many human and mouse solid tumors but not in normal vasculature, and in these tumors it was associated with scarce CD8+ infiltration and predominance of FoxP3+ T regulatory (Treg) cells. Tumor-derived vascular endothelial growth factor A (VEGF-A), interleukin 10 (IL-10) and prostaglandin E2 (PGE2) cooperatively induced FasL expression on endothelial cells, which acquired the ability to kill effector CD8+ T cells, but not Treg cells, due to higher levels of cFLIP expression in Tregs. In the mouse, genetic or pharmacologic suppression of FasL produced a significant increase in the influx of tumor-rejecting CD8+ over FoxP3+ T cells. Pharmacologic inhibition of VEGF and PGE2 attenuated tumor endothelial FasL expression, produced a significant increase in the influx of tumor-rejecting CD8+ over FoxP3+ T cells, which was FasL-dependent, and led to CD8-dependent tumor growth suppression. Thus, tumor paracrine mechanisms establish a tumor endothelial death barrier, which plays a critical role in establishing immune tolerance and determining the fate of tumors. PMID:24793239

  19. Formwork application optimization by using augmented reality

    NASA Astrophysics Data System (ADS)

    Diaconu, R.; Petruse, R.; Brindasu, P. D.

    2016-11-01

    By using the PLM (Product Lifecycle Management) principle on the formwork case study, after determining the functions and the technical solutions, the application must be made as optimum as possible in order to assure productivity and provide the necessary information as quick as possible. The concept is to create a complex management for the formwork based on augmented reality. By taking into account the development rate of the information, augmented reality is tending to be one of the widest (in term of domain) visualization instrument. Also used in the construction domain, augmented reality can be applied also for the case of formwork design and management. The application of the solution will be retrieved in the construction of the product, its transportation and deposit. The usage of this concept will help reduce, even eliminate human or technical errors and can offer a precise state of a specific required formwork from the stock.

  20. Liquid injectable silicone for soft tissue augmentation.

    PubMed

    Prather, Chad L; Jones, Derek H

    2006-01-01

    Liquid injectable silicone is a unique soft tissue augmenting agent that may be effectively utilized for the correction of specific cutaneous and subcutaneous atrophies. Although historical complications have occurred, resulting likely from the presence of adulterants and impurities, modern purified silicone products approved by the Food and Drug Administration for injection into the human body may be employed with minimal complications when strict protocol is followed. In this article the present authors review the history and controversy regarding silicone as well as describe the appropriate indications, patient selection, instrumentation, treatment protocol, and anticipated complications involved with the use of liquid injectable silicone for soft tissue augmentation. Although its use is controversial, the present authors maintain that liquid injectable silicone is an important and effective augmenting agent for the long-term correction of scars and facial contour defects such as HIV facial lipoatrophy. Furthermore, it is a treatment modality deserving of continued investigation.

  1. HIV transcription is induced with some forms of cell killing

    SciTech Connect

    Woloschak, G.E.; Schreck, S.; Panozzo, J.; Chang-Liu, C.-M.; Libertin, C.R.

    1996-11-01

    Using HeLa cells stably transfected with an HIV-LTR-CAT construct`, we demonstrated a peak in CAT induction that occurs in viable (but not necessarily cell-division-competent) cells 24 h following exposure to some cell-killing agents. {Gamma} rays were the only cell-killing agent which did not induce HIV transcription; this can be attributed to the fact that {gamma}-ray-induced apoptotic death requires function p53, which is missing in HeLa cells. For all other agents, HIV-LTR induction was dose-dependent and correlated with the amount of cell killing that occurred in the culture.

  2. Factors Affecting Zebra Mussel Kill by the Bacterium Pseudomonas fluorescens

    SciTech Connect

    Daniel P. Molloy

    2004-02-24

    The specific purpose of this research project was to identify factors that affect zebra mussel kill by the bacterium Pseudomonas fluorescens. Test results obtained during this three-year project identified the following key variables as affecting mussel kill: treatment concentration, treatment duration, mussel siphoning activity, dissolved oxygen concentration, water temperature, and naturally suspended particle load. Using this latter information, the project culminated in a series of pipe tests which achieved high mussel kill inside power plants under once-through conditions using service water in artificial pipes.

  3. Exoatmospheric Kill Vehicle Quality Assurance and Reliability Assessment - Part A

    DTIC Science & Technology

    2014-09-08

    No. DODIG-2014-111 S E P T E M B E R 8 , 2 0 1 4 Exoatmospheric Kill Vehicle Quality Assurance and Reliability Assessment – Part A Report...REPORT TYPE 3. DATES COVERED 00-00-2014 to 00-00-2014 4. TITLE AND SUBTITLE Exoatmospheric Kill Vehicle Quality Assurance and Reliability...Department of Defense F r a u d , W a s t e & A b u s e DODIG-2014-111 (Project No. D2013-DT0TAD-0005.000) │ i Results in Brief Exoatmospheric Kill Vehicle

  4. Role of Peroxide in Phagocytic Killing of Pneumococci

    PubMed Central

    Pitt, Jane; Bernheimer, Harriet P.

    1974-01-01

    Two mutants of a pneumococcus type I with diminished peroxide production were selected from a population of nitrosoguanidine-treated cells. White cells of normal patients killed the mutant pneumococci as well as the otherwise isogenic wild-type strain. In patients studied with chronic granulomatous disease, however, the peroxide-poor strain was killed far less well than the wild type. These studies indicate that the removal of a peroxide-generating system in the phagocytic vacuole specifically brings forth the killing defect in chronic granulomatous disease. PMID:4148725

  5. Reprogramming the tumor microenvironment: tumor-induced immunosuppressive factors paralyze T cells

    PubMed Central

    Wu, Annie A; Drake, Virginia; Huang, Huai-Shiuan; Chiu, ShihChi; Zheng, Lei

    2015-01-01

    It has become evident that tumor-induced immuno-suppressive factors in the tumor microenvironment play a major role in suppressing normal functions of effector T cells. These factors serve as hurdles that limit the therapeutic potential of cancer immunotherapies. This review focuses on illustrating the molecular mechanisms of immunosuppression in the tumor microenvironment, including evasion of T-cell recognition, interference with T-cell trafficking, metabolism, and functions, induction of resistance to T-cell killing, and apoptosis of T cells. A better understanding of these mechanisms may help in the development of strategies to enhance the effectiveness of cancer immunotherapies. PMID:26140242

  6. Reprogramming the tumor microenvironment: tumor-induced immunosuppressive factors paralyze T cells.

    PubMed

    Wu, Annie A; Drake, Virginia; Huang, Huai-Shiuan; Chiu, ShihChi; Zheng, Lei

    2015-07-01

    It has become evident that tumor-induced immuno-suppressive factors in the tumor microenvironment play a major role in suppressing normal functions of effector T cells. These factors serve as hurdles that limit the therapeutic potential of cancer immunotherapies. This review focuses on illustrating the molecular mechanisms of immunosuppression in the tumor microenvironment, including evasion of T-cell recognition, interference with T-cell trafficking, metabolism, and functions, induction of resistance to T-cell killing, and apoptosis of T cells. A better understanding of these mechanisms may help in the development of strategies to enhance the effectiveness of cancer immunotherapies.

  7. Murine cytomegalovirus stimulates natural killer cell function but kills genetically resistant mice treated with radioactive strontium

    SciTech Connect

    Masuda, A.; Bennett, M.

    1981-12-01

    Treatment of C3H/St mice with 100 microCi of 89Sr weakened their genetic resistance to murine cytomegalovirus (MCMV) infection. The criteria utilized to detect increased susceptibility were: (i) survival of mice; (ii) numbers of MCMV-infected cells in the spleens and liver; and (iii) serum glutamic pyruvic transaminase levels. The natural killer (NK) cell activity of spleen cells from mice treated with 89Sr is very low. However, the NK activities of spleen cells of both normal and 89Sr-treated mice were greatly augmented 3 days after infection with MCMV. These NK cells lysed a variety of tumor cells and shared several features with conventional NK cells, but were not lysed by anti-Nk-1.2 serum (specific for NK cells) plus complement. Splenic adherent cells did not lyse tumor cells themselves but were necessary for the stimulation of NK cells by MCMV. The paradox of high NK cell function and poor survival in 89Sr-treated mice infected with MCMV was a surprise. We conclude that these augmented NK cells, of themselves, cannot account for the genetic resistance of C3H/St mice to infection with MCMV.

  8. Modification of tumor response by manipulation of tumor oxygenation

    NASA Astrophysics Data System (ADS)

    Chen, Qun; Beckers, Jill; Hetzel, Fred W.

    1999-07-01

    Photodynamic therapy (PDT) requires tissue oxygenation during light irradiation. Tumor hypoxia, either pre-existing or induced by PDT during light irradiation, can severely hamper the effectiveness of a PDT treatment. Lowering the light irradiation does rate or fractionating a light dose may improve cell kill of PDT induced hypoxic cells, but will have no effects on pre-existing hypoxic cells. In the current study, we used hyper-oxygenation during PDT to overcome cell hypoxia in PDT. C3H mice with transplanted mammary carcinoma tumor were injected with 12.5 mg/kg Photofrin and irradiated with 630 nm laser light 24 hours later. Tumor oxygenation was manipulated by subjecting the animals to 3 a.t.p. hyperbaric oxygen or normobaric oxygen during PDT light irradiation. The results show a significant improvement in tumor response when PDT was delivered during hyper-oxygenation. With hyper-oxygenation, up to 80% of treated tumors showed no re-growth after 60 days. In comparison, only 20% of tumors treated while animals breathed normal room air, did not re-grow. To quantitatively evaluate the effects of manipulating tumor oxygenation, tumor p02 was measured with microelectrodes positioned in pre-existing hypoxic regions before and during the PDT light irradiation. The results show that hyper-oxygenation may oxygenate pre-existing hypoxic cells and compensate oxygen depletion induced by PDT light irradiation. In conclusion, hyper-oxygenation may provide effective ways to improve PDT treatment efficiency by oxygenating both pre-existing and treatment induced cell hypoxia.

  9. Evaluation of low power augmented hydrazine thrusters

    NASA Astrophysics Data System (ADS)

    Hadar, Ilan; Gany, Alon

    1992-02-01

    A brief review of the current concepts of power addition to the widespread, low-power hydrazine thruster and a general analysis of the augmentation processes are presented. Among the devices surveyed are the resistojets (RJ) and the arcjets (AJ), which transfer electric energy by physical contact with the hydrazine decomposition gases, and the microwave thrusters (MW), which apply electromagnetic fields generated by microwaves. A comparison between the variety of present and future augmented hydrazine thrusters (AHT) suggests that the AJ is the most promising means for the energy addition procedure, when both reliability and performance are taken into account.

  10. Augmentation in contingency learning under time pressure.

    PubMed

    Vadillo, Miguel A; Matute, Helena

    2010-08-01

    Recent research suggests that cue competition effects in human contingency learning, such as blocking, are due to higher-order cognitive processes. Moreover, some experimental reports suggest that the effect opposite to blocking, augmentation, could occur in experimental preparations that preclude the intervention of reasoning mechanisms. In the present research, we tested this hypothesis by investigating cue interaction effects in an experimental task in which participants had to enter their responses under time pressure. The results show that under these conditions, augmentation, instead of blocking, is observed.

  11. Shuffle-exchanges on augmented meshes

    NASA Technical Reports Server (NTRS)

    Bokhari, S. H.

    1984-01-01

    A mesh connected array of size N = two to the Kth power, K an integer, can be augmented by adding at most one edge per node such that it can perform a shuffle-exchange of size N/2 in constant time. A shuffle-exchange of size N is performed on this augmented array in constant time. This is done by combining the available perfect shuffle of size N/2 with the existing nearest neighbor connections of the mesh. By carefully scheduling the different permutations that are composed in order to achieve the shuffle, the time required is reduced to 5 steps, which is optimal for this network.

  12. The augmentation algorithm and molecular phylogenetic trees

    NASA Technical Reports Server (NTRS)

    Holmquist, R.

    1978-01-01

    Moore's (1977) augmentation procedure is discussed, and it is concluded that the procedure is valid for obtaining estimates of the total number of fixed nucleotide substitutions both theoretically and in practice, for both simulated and real data, and in agreement, for experimentally dense data sets, with stochastic estimates of the divergence, provided the restrictions on codon mutability resulting from natural selection are explicitly allowed for. Tateno and Nei's (1978) critique that the augmentation procedure has a systematic bias toward overestimation of the total number of nucleotide replacements is disputed, and a data analysis suggests that ancestral sequences inferred by the method of parsimony contain a large number of incorrectly assigned nucleotides.

  13. Heating Augmentation for Short Hypersonic Protuberances

    NASA Technical Reports Server (NTRS)

    Mazaheri, Alireza R.; Wood, William A.

    2008-01-01

    Computational aeroheating analyses of the Space Shuttle Orbiter plug repair models are validated against data collected in the Calspan University of Buffalo Research Center (CUBRC) 48 inch shock tunnel. The comparison shows that the average difference between computed heat transfer results and the data is about 9:5%. Using CFD and Wind Tunnel (WT) data, an empirical correlation for estimating heating augmentation on short hyper- sonic protuberances (k/delta < 0.33) is proposed. This proposed correlation is compared with several computed flight simulation cases and good agreement is achieved. Accordingly, this correlation is proposed for further investigation on other short hypersonic protuberances for estimating heating augmentation.

  14. Heating Augmentation for Short Hypersonic Protuberances

    NASA Technical Reports Server (NTRS)

    Mazaheri, Ali R.; Wood, William A.

    2008-01-01

    Computational aeroheating analyses of the Space Shuttle Orbiter plug repair models are validated against data collected in the Calspan University of Buffalo Research Center (CUBRC) 48 inch shock tunnel. The comparison shows that the average difference between computed heat transfer results and the data is about 9.5%. Using CFD and Wind Tunnel (WT) data, an empirical correlation for estimating heating augmentation on short hypersonic protuberances (k/delta less than 0.3) is proposed. This proposed correlation is compared with several computed flight simulation cases and good agreement is achieved. Accordingly, this correlation is proposed for further investigation on other short hypersonic protuberances for estimating heating augmentation.

  15. Nasal dorsal augmentation with silicone implants.

    PubMed

    Erlich, Mark A; Parhiscar, Afshin

    2003-11-01

    Silicone rubber has been used safely and effectively for facial augmentation for nearly 5 decades in eastern Asia. We have used silicone rubber nasal implants in primary ethnic rhinoplasty and have found consistent and long-lasting results with low complication rates. Silicone dorsal nasal augmentation in primary rhinoplasty avoids donor site morbidity and implant resorption as seen with autogenous implants. Silicone nasal implants have a low extrusion and infection rate. In the appropriate patient with proper placement, silicone nasal implant is nearly the ideal implant material.

  16. Synergistically killing activity of aspirin and histone deacetylase inhibitor valproic acid (VPA) on hepatocellular cancer cells

    SciTech Connect

    Li, Xiaofei; Zhu, Yanshuang; He, Huabin; Lou, Lianqing; Ye, Weiwei; Chen, Yongxin; Wang, Jinghe

    2013-06-28

    Highlights: •Novel combination therapy using aspirin and valproic acid (VPA). •Combination of aspirin and VPA elicits synergistic cytotoxic effects. •Combination of aspirin and VPA significantly reduces the drug dosage required alone. •Combination of aspirin and VPA significantly inhibit tumor growth. •Lower dose of aspirin in combination therapy will minimize side effects of aspirin. -- Abstract: Aspirin and valproic acid (VPA) have been extensively studied for inducing various malignancies growth inhibition respectively, despite their severe side effects. Here, we developed a novel combination by aspirin and VPA on hepatocellular cancer cells (HCCs). The viability of HCC lines were analyzed by MTT assay, apoptotic analysis of HepG2 and SMMC-7721 cell was performed. Real time-PCR and Western blotting were performed to determine the expression of apoptosis related genes and proteins such as Survivin, Bcl-2/Bax, Cyclin D1 and p15. Moreover, orthotopic xenograft tumors were challenged in nude mice to establish murine model, and then therapeutic effect was analyzed after drug combination therapy. The viability of HCC lines’ significantly decreased after drug combination treatment, and cancer cell apoptosis in combination group increasingly induced compared with single drug use. Therapeutic effect was significantly enhanced by combination therapy in tumor volume and tumor weight decrease. From the data shown here, aspirin and VPA combination have a synergistic killing effect on hepatocellular cancers cells proliferation and apoptosis.

  17. Tumor immunogenicity determines the effect of B7 costimulation on T cell-mediated tumor immunity

    PubMed Central

    1994-01-01

    A costimulatory signal through B7 to its counter-receptor CD28 on T cells enhances T cell activation. We have generated recombinant retroviruses containing cDNA for murine B7 and transduced a panel of murine tumor lines with varying immunogenicity to study the effect of B7 costimulation on antitumor immunity. In contrast to the progressive outgrowth of all wild-type (B7-) tumors in unimmunized syngeneic mice, four immunogenic tumors, lymphoma RMA, EL4, mastocytoma P815, and melanoma E6B2, regressed completely when transduced with the B7 gene. In contrast, four nonimmunogenic tumors, sarcomas MCA101, MCA102, and Ag104, and melanoma B16, remained tumorigenic after transduction of the B7 gene. Immunization with B7-transduced immunogenic tumors enhanced protective immunity and increased specific cytotoxic T lymphocyte (CTL) activity against the respective wild-type tumors as compared to immunization with nontransduced or mock-transduced tumors. Moreover, cocultivation of CTL with B7-transduced EL4 cells augmented the specificity of tumor-reactive CTL in long-term cultures. Treatment by injection of B7-transduced tumor cells cured 60% of mice with established wild-type EL4 lymphoma. In contrast, immunization with nonimmunogenic tumors transduced with B7 did not provide protective immunity and did not increase specific CTL activity. Our results show that tumor immunogenicity is critical to the outcome of costimulation of T cell-mediated tumor immunity by B7. PMID:7507508

  18. Metabolic Hallmarks of Tumor and Immune Cells in the Tumor Microenvironment

    PubMed Central

    Renner, Kathrin; Singer, Katrin; Koehl, Gudrun E.; Geissler, Edward K.; Peter, Katrin; Siska, Peter J.; Kreutz, Marina

    2017-01-01

    Cytotoxic T lymphocytes and NK cells play an important role in eliminating malignant tumor cells and the number and activity of tumor-infiltrating T cells represent a good marker for tumor prognosis. Based on these findings, immunotherapy, e.g., checkpoint blockade, has received considerable attention during the last couple of years. However, for the majority of patients, immune control of their tumors is gray theory as malignant cells use effective mechanisms to outsmart the immune system. Increasing evidence suggests that changes in tumor metabolism not only ensure an effective energy supply and generation of building blocks for tumor growth but also contribute to inhibition of the antitumor response. Immunosuppression in the tumor microenvironment is often based on the mutual metabolic requirements of immune cells and tumor cells. Cytotoxic T and NK cell activation leads to an increased demand for glucose and amino acids, a well-known feature shown by tumor cells. These close metabolic interdependencies result in metabolic competition, limiting the proliferation, and effector functions of tumor-specific immune cells. Moreover, not only nutrient restriction but also tumor-driven shifts in metabolite abundance and accumulation of metabolic waste products (e.g., lactate) lead to local immunosuppression, thereby facilitating tumor progression and metastasis. In this review, we describe the metabolic interplay between immune cells and tumor cells and discuss tumor cell metabolism as a target structure for cancer therapy. Metabolic (re)education of tumor cells is not only an approach to kill tumor cells directly but could overcome metabolic immunosuppression in the tumor microenvironment and thereby facilitate immunotherapy. PMID:28337200

  19. Metabolic Hallmarks of Tumor and Immune Cells in the Tumor Microenvironment.

    PubMed

    Renner, Kathrin; Singer, Katrin; Koehl, Gudrun E; Geissler, Edward K; Peter, Katrin; Siska, Peter J; Kreutz, Marina

    2017-01-01

    Cytotoxic T lymphocytes and NK cells play an important role in eliminating malignant tumor cells and the number and activity of tumor-infiltrating T cells represent a good marker for tumor prognosis. Based on these findings, immunotherapy, e.g., checkpoint blockade, has received considerable attention during the last couple of years. However, for the majority of patients, immune control of their tumors is gray theory as malignant cells use effective mechanisms to outsmart the immune system. Increasing evidence suggests that changes in tumor metabolism not only ensure an effective energy supply and generation of building blocks for tumor growth but also contribute to inhibition of the antitumor response. Immunosuppression in the tumor microenvironment is often based on the mutual metabolic requirements of immune cells and tumor cells. Cytotoxic T and NK cell activation leads to an increased demand for glucose and amino acids, a well-known feature shown by tumor cells. These close metabolic interdependencies result in metabolic competition, limiting the proliferation, and effector functions of tumor-specific immune cells. Moreover, not only nutrient restriction but also tumor-driven shifts in metabolite abundance and accumulation of metabolic waste products (e.g., lactate) lead to local immunosuppression, thereby facilitating tumor progression and metastasis. In this review, we describe the metabolic interplay between immune cells and tumor cells and discuss tumor cell metabolism as a target structure for cancer therapy. Metabolic (re)education of tumor cells is not only an approach to kill tumor cells directly but could overcome metabolic immunosuppression in the tumor microenvironment and thereby facilitate immunotherapy.

  20. PFIESTERIA SHUMWAYAE KILLS FISH BY MICROPREDATION NOT ECOTOXIN SECRETION

    EPA Science Inventory

    Massive fish kills in mid-Atlantic USA estuaries involving several million Atlantic menhaden, Brevoortia tyrannus,have been attributed to dinoflagellates of the toxic Pfiesteria complex (TPC). Potent ichthyotoxins secreted during Pfiesteria blooms are thought to be responsible fo...