To Kill, Stay or Flee: The Effects of Lions and Landscape Factors on Habitat and Kill Site Selection of Cheetahs in South Africa

Science.gov (United States)

Rostro-García, Susana; Kamler, Jan F.; Hunter, Luke T. B.

2015-01-01

Understanding how animals utilize available space is important for their conservation, as it provides insight into the ecological needs of the species, including those related to habitat, prey and inter and intraspecific interactions. We used 28 months of radio telemetry data and information from 200 kill locations to assess habitat selection at the 3rd order (selection of habitats within home ranges) and 4th order (selection of kill sites within the habitats used) of a reintroduced population of cheetahs Acinonyx jubatus in Phinda Private Game Reserve, South Africa. Along with landscape characteristics, we investigated if lion Panthera leo presence affected habitat selection of cheetahs. Our results indicated that cheetah habitat selection was driven by a trade-off between resource acquisition and lion avoidance, and the balance of this trade-off varied with scale: more open habitats with high prey densities were positively selected within home ranges, whereas more closed habitats with low prey densities were positively selected for kill sites. We also showed that habitat selection, feeding ecology, and avoidance of lions differed depending on the sex and reproductive status of cheetahs. The results highlight the importance of scale when investigating a species’ habitat selection. We conclude that the adaptability of cheetahs, together with the habitat heterogeneity found within Phinda, explained their success in this small fenced reserve. The results provide information for the conservation and management of this threatened species, especially with regards to reintroduction efforts in South Africa. PMID:25693067

To kill, stay or flee: the effects of lions and landscape factors on habitat and kill site selection of cheetahs in South Africa.

Science.gov (United States)

Rostro-García, Susana; Kamler, Jan F; Hunter, Luke T B

2015-01-01

Understanding how animals utilize available space is important for their conservation, as it provides insight into the ecological needs of the species, including those related to habitat, prey and inter and intraspecific interactions. We used 28 months of radio telemetry data and information from 200 kill locations to assess habitat selection at the 3rd order (selection of habitats within home ranges) and 4th order (selection of kill sites within the habitats used) of a reintroduced population of cheetahs Acinonyx jubatus in Phinda Private Game Reserve, South Africa. Along with landscape characteristics, we investigated if lion Panthera leo presence affected habitat selection of cheetahs. Our results indicated that cheetah habitat selection was driven by a trade-off between resource acquisition and lion avoidance, and the balance of this trade-off varied with scale: more open habitats with high prey densities were positively selected within home ranges, whereas more closed habitats with low prey densities were positively selected for kill sites. We also showed that habitat selection, feeding ecology, and avoidance of lions differed depending on the sex and reproductive status of cheetahs. The results highlight the importance of scale when investigating a species' habitat selection. We conclude that the adaptability of cheetahs, together with the habitat heterogeneity found within Phinda, explained their success in this small fenced reserve. The results provide information for the conservation and management of this threatened species, especially with regards to reintroduction efforts in South Africa.

Electroporation driven delivery of both an IL-12 expressing plasmid and cisplatin synergizes to inhibit B16 melanoma tumor growth through an NK cell mediated tumor killing mechanism.

Science.gov (United States)

Kim, Ha; Sin, Jeong-Im

2012-11-01

Combined therapy using chemotherapeutic drugs and immunotherapeutics offers some promise for treating patients with cancer. In this study, we evaluated whether cisplatin delivered by intratumoral (IT)-electroporation (EP) might enhance antitumor activity against established B16 melanoma and whether further addition of intramuscular (IM)-EP of IL-12 cDNA to IT-EP of cisplatin might augment antitumor therapeutic activity, with a focus on the underlining antitumor mechanism(s). When tumor (7 mm)-bearing animals were treated locally with cisplatin by IT-EP, they showed tumor growth inhibition significantly more than those without IT-EP. Moreover, IL-12 cDNA delivered by IM-EP was also able to inhibit tumor growth significantly more than control vector delivery. This tumor growth inhibition was mediated by NK cells, but not CD4+ T or CD8+ T cells, as determined by immune cell subset depletion and IFN-γ induction. Moreover, concurrent therapy using IT-EP of cisplatin plus IM-EP of IL-12 cDNA displayed antitumor therapeutic synergy. This therapeutic synergy appeared to be mediated by increased sensitivity of cisplatin-treated tumors to NK cell-mediated tumor killing. Taken together, these data support that cisplatin delivery by IT-EP plus IL-12 gene delivery by IM-EP are more effective at inducing antitumor therapeutic responses through increased sensitivity of cisplatin-treated tumors to NK cell-mediated tumor killing. This combined approach might have some implication for treating melanoma in patients.

Killing effect of carboranyl uridine on boron neutron capture reaction

International Nuclear Information System (INIS)

Takagaki, M.; Oda, Y.; Zhang, Z.

1994-01-01

This paper deals with the killing effect of carboranyl uridine (CU) on thermal neutron capture reaction in cultured glioma cell line (C6). The tumoricidal effect of CU for boron neutron capture therapy in the cultured cell system is presented. To assess the uptake of CU, the number of germ cells was determined by comparing protein concentrations of C6 cells in vitro with that of intracranially transplanted C6 tumor cells in vivo. To assess tumoricidal effects of CU, human glioma cells (T98G), containing 25 ppm natural boron of CU, were irradiated with various doses of thermal neutrons at a constant fluence rate. The uptake and killing effects of mercaptoboron and boric acid were also investigated as controls. Subcellular boron concentrations confirmed the selective affinity to the nucleic acid synthesis. CU was found to have an affinity to nucleic acid synthesis and to be accumulated into nucleus of tumor cells. The irradiation dose which yielded 37% survival rate in the case of CU and control were 3.78+12E nvt and 5.80+12E nvt, respectively. The killing effect of CU was slightly higher than that of B-SH or BA. The effective way of CU injection should be further studied to obtain the uniform CU uptake in tumor cells. (N.K.)

Killing of Brain Tumor Cells by Hypoxia-Responsive Element Mediated Expression of BAX

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Hangjun Ruan

1999-11-01

Full Text Available The presence of radioresistant hypoxic cells in human brain tumors limits the overall effectiveness of conventional fractionated radiation therapy. Tumor-specific therapies that target hypoxic cells are clearly needed. We have investigated the expression of suicide genes under hypoxia by a hypoxia-responsive element (HRE, which can be activated through hypoxia-inducible factor-1 (HIF-1. We transfected plasmids containing multiple copies of HIRE into U-87 MG and U-251 MG-NCI human brain tumor cells and tested their ability to induce LacZ gene expression under anoxia. Gene expression under anoxia versus oxia was increased about 12-fold for U-87 MG cells and about fourfold for U-251 MG-NCI cells. At intermediate hypoxic conditions, increased LacZ gene expression in U-87 MG cells was induced by the plasmid that contained three HREs, but not by the plasmid with two HREs. Lastly, when we placed a suicide gene BAX under the control of HREs, cells transfected with the BAX plasmids were preferentially killed through apoptosis under anoxia. Our studies demonstrate that HRE-regulated gene expression is active in brain tumor cells, and that the amount of increased gene expression obtained is dependent on the cell line, the HIRE copy number, and the degree of hypoxia.

Chlorin e6 Conjugated Interleukin-6 Receptor Aptamers Selectively Kill Target Cells Upon Irradiation

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Sven Kruspe

2014-01-01

Full Text Available Photodynamic therapy (PDT uses the therapeutic properties of light in combination with certain chemicals, called photosensitizers, to successfully treat brain, breast, prostate, and skin cancers. To improve PDT, current research focuses on the development of photosensitizers to specifically target cancer cells. In the past few years, aptamers have been developed to directly deliver cargo molecules into target cells. We conjugated the photosensitizer chlorin e6 (ce6 with a human interleukin-6 receptor (IL-6R binding RNA aptamer, AIR-3A yielding AIR-3A-ce6 for application in high efficient PDT. AIR-3A-ce6 was rapidly and specifically internalized by IL-6R presenting (IL-6R+ cells. Upon light irradiation, targeted cells were selectively killed, while free ce6 did not show any toxic effect. Cells lacking the IL-6R were also not affected by AIR-3A-ce6. With this approach, we improved the target specificity of ce6-mediated PDT. In the future, other tumor-specific aptamers might be used to selectively localize photosensitizers into cells of interest and improve the efficacy and specificity of PDT in cancer and other diseases.

In vivo tyrosinase mini-gene transfer enhances killing effect of BNCT on amelanotic melanoma

International Nuclear Information System (INIS)

Kondoh, H.; Mishima, Y.; Hiratsuka, J.; Iwakura, M.

2000-01-01

Using accentuated melanogenesis principally occurring within melanoma cells, we have successfully treated human malignant melanoma (Mm) with 10 B-BPA BNCT. Despite this success, there are still remaining issues for poorly melanogenic Mm and further non-pigment cell tumors. We found the selective accumulation of 10 B-BPA to Mm is primarily due to the complex formation of BPA and melanin-monomers activity synthesized within Mm cells. Then, we succeeded in transferring the tyrosinase gene into amelanotic to substantially produce melanin monomers. These cells has demonstrated increased boron accumulation and enhanced killing effect of BNCT. Further, transfection of TRP-2 (DOPAchrome tautomerase) gene into poorly eumelanotic and slightly phenomelanotic Mm cells in culture cell systems also led to increased BPA accumulation. Thereafter, we studied in vivo gene transfer. We transferred the tyrosinase mini-gene by intra-tumor injection into poorly melanotic Mm proliferating subcutaneously in hamster skin, and performed BNCT. Compared to control tumors, gene-transferred tumors showed increased BPA accumulation leading to enhanced killing effect. (author)

Surface-Selective Preferential Production of Reactive Oxygen Species on Piezoelectric Ceramics for Bacterial Killing.

Science.gov (United States)

Tan, Guoxin; Wang, Shuangying; Zhu, Ye; Zhou, Lei; Yu, Peng; Wang, Xiaolan; He, Tianrui; Chen, Junqi; Mao, Chuanbin; Ning, Chengyun

2016-09-21

Reactive oxygen species (ROS) can be used to kill bacterial cells, and thus the selective generation of ROS from material surfaces is an emerging direction in antibacterial material discovery. We found the polarization of piezoelectric ceramic causes the two sides of the disk to become positively and negatively charged, which translate into cathode and anode surfaces in an aqueous solution. Because of the microelectrolysis of water, ROS are preferentially formed on the cathode surface. Consequently, the bacteria are selectively killed on the cathode surface. However, the cell experiment suggested that the level of ROS is safe for normal mammalian cells.

Double suicide genes selectively kill human umbilical vein endothelial cells

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Liu Lunxu

2011-02-01

Full Text Available Abstract Background To construct a recombinant adenovirus containing CDglyTK double suicide genes and evaluate the killing effect of the double suicide genes driven by kinase domain insert containing receptor (KDR promoter on human umbilical vein endothelial cells. Methods Human KDR promoter, Escherichia coli (E. coli cytosine deaminase (CD gene and the herpes simplex virus-thymidine kinase (TK gene were cloned using polymerase chain reaction (PCR. Plasmid pKDR-CDglyTK was constructed with the KDR promoter and CDglyTK genes. A recombinant adenoviral plasmid AdKDR-CDglyTK was then constructed and transfected into 293 packaging cells to grow and harvest adenoviruses. KDR-expressing human umbilical vein endothelial cells (ECV304 and KDR-negative liver cancer cell line (HepG2 were infected with the recombinant adenoviruses at different multiplicity of infection (MOI. The infection rate was measured by green fluorescent protein (GFP expression. The infected cells were cultured in culture media containing different concentrations of prodrugs ganciclovir (GCV and/or 5-fluorocytosine (5-FC. The killing effects were measured using two different methods, i.e. annexin V-FITC staining and terminal transferase-mediated dUTP nick end-labeling (TUNEL staining. Results Recombinant adenoviruses AdKDR-CDglyTK were successfully constructed and they infected ECV304 and HepG2 cells efficiently. The infection rate was dependent on MOI of recombinant adenoviruses. ECV304 cells infected with AdKDR-CDglyTK were highly sensitive to GCV and 5-FC. The cell survival rate was dependent on both the concentration of the prodrugs and the MOI of recombinant adenoviruses. In contrast, there were no killing effects in the HepG2 cells. The combination of two prodrugs was much more effective in killing ECV304 cells than GCV or 5-FC alone. The growth of transgenic ECV304 cells was suppressed in the presence of prodrugs. Conclusion AdKDR-CDglyTK/double prodrog system may be a useful

4β-Hydroxywithanolide E selectively induces oxidative DNA damage for selective killing of oral cancer cells.

Science.gov (United States)

Tang, Jen-Yang; Huang, Hurng-Wern; Wang, Hui-Ru; Chan, Ya-Ching; Haung, Jo-Wen; Shu, Chih-Wen; Wu, Yang-Chang; Chang, Hsueh-Wei

2018-03-01

Reactive oxygen species (ROS) induction had been previously reported in 4β-hydroxywithanolide (4βHWE)-induced selective killing of oral cancer cells, but the mechanism involving ROS and the DNA damage effect remain unclear. This study explores the role of ROS and oxidative DNA damage of 4βHWE in the selective killing of oral cancer cells. Changes in cell viability, morphology, ROS, DNA double strand break (DSB) signaling (γH2AX foci in immunofluorescence and DSB signaling in western blotting), and oxidative DNA damage (8-oxo-2'deoxyguanosine [8-oxodG]) were detected in 4βHWE-treated oral cancer (Ca9-22) and/or normal (HGF-1) cells. 4βHWE decreased cell viability, changed cell morphology and induced ROS generation in oral cancer cells rather than oral normal cells, which were recovered by a free radical scavenger N-acetylcysteine (NAC). For immunofluorescence, 4βHWE also accumulated more of the DSB marker, γH2AX foci, in oral cancer cells than in oral normal cells. For western blotting, DSB signaling proteins such as γH2AX and MRN complex (MRE11, RAD50, and NBS1) were overexpressed in 4βHWE-treated oral cancer cells in different concentrations and treatment time. In the formamidopyrimidine-DNA glycolyase (Fpg)-based comet assay and 8-oxodG-based flow cytometry, the 8-oxodG expressions were higher in 4βHWE-treated oral cancer cells than in oral normal cells. All the 4βHWE-induced DSB and oxidative DNA damage to oral cancer cells were recovered by NAC pretreatment. Taken together, the 4βHWE selectively induced DSB and oxidative DNA damage for the ROS-mediated selective killing of oral cancer cells. © 2017 Wiley Periodicals, Inc.

LuIII parvovirus selectively and efficiently targets, replicates in, and kills human glioma cells.

Science.gov (United States)

Paglino, Justin C; Ozduman, Koray; van den Pol, Anthony N

2012-07-01

Because productive infection by parvoviruses requires cell division and is enhanced by oncogenic transformation, some parvoviruses may have potential utility in killing cancer cells. To identify the parvovirus(es) with the optimal oncolytic effect against human glioblastomas, we screened 12 parvoviruses at a high multiplicity of infection (MOI). MVMi, MVMc, MVM-G17, tumor virus X (TVX), canine parvovirus (CPV), porcine parvovirus (PPV), rat parvovirus 1A (RPV1A), and H-3 were relatively ineffective. The four viruses with the greatest oncolytic activity, LuIII, H-1, MVMp, and MVM-G52, were tested for the ability, at a low MOI, to progressively infect the culture over time, causing cell death at a rate higher than that of cell proliferation. LuIII alone was effective in all five human glioblastomas tested. H-1 progressively infected only two of five; MVMp and MVM-G52 were ineffective in all five. To investigate the underlying mechanism of LuIII's phenotype, we used recombinant parvoviruses with the LuIII capsid replacing the MVMp capsid or with molecular alteration of the P4 promoter. The LuIII capsid enhanced efficient replication and oncolysis in MO59J gliomas cells; other gliomas tested required the entire LuIII genome to exhibit enhanced infection. LuIII selectively infected glioma cells over normal glial cells in vitro. In mouse models, human glioblastoma xenografts were selectively infected by LuIII when administered intratumorally; LuIII reduced tumor growth by 75%. LuIII also had the capacity to selectively infect subcutaneous or intracranial gliomas after intravenous inoculation. Intravenous or intracranial LuIII caused no adverse effects. Intracranial LuIII caused no infection of mature mouse neurons or glia in vivo but showed a modest infection of developing neurons.

IMPROVED TUMOR CELL KILLING BY TRAIL REQUIRES SELECTIVE AND HIGH AFFINITY RECEPTOR ACTIVATION

NARCIS (Netherlands)

Szegezdi, Eva; van der Sloot, Almer M.; Alessandro, Natoni; Mahalingam, Devalingam; Cool, Robbert H.; Munoz, Ines G.; Montoya, Guillermo; Quax, Wim J.; Luis Serrano, Steven de Jong; Samali, Afshin; Wallach, D; Kovalenko, A; Feldman, M

2011-01-01

Apoptosis can be activated by tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) in a wide range of tumor cells, but not in non-transformed cells. TRAIL interaction with receptors DR4 or DR5 induces apoptosis, whereas DcR1, DcR2 and osteoprotegerin are decoy receptors for TRAIL. TRAIL

The yield of DNA double strand breaks determined after exclusion of those forming from heat-labile lesions predicts tumor cell radiosensitivity to killing.

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Cheng, Yanlei; Li, Fanghua; Mladenov, Emil; Iliakis, George

2015-09-01

The radiosensitivity to killing of tumor cells and in-field normal tissue are key determinants of radiotherapy response. In vitro radiosensitivity of tumor- and normal-tissue-derived cells often predicts radiation response, but high determination cost in time and resources compromise utility as routine response-predictor. Efforts to use induction or repair of DNA double-strand-breaks (DSBs) as surrogate-predictors of cell radiosensitivity to killing have met with limited success. Here, we re-visit this issue encouraged by our recent observations that ionizing radiation (IR) induces not only promptly-forming DSBs (prDSBs), but also DSBs developing after irradiation from the conversion to breaks of thermally-labile sugar-lesions (tlDSBs). We employ pulsed-field gel-electrophoresis and flow-cytometry protocols to measure total DSBs (tDSB=prDSB+tlDSBs) and prDSBs, as well as γH2AX and parameters of chromatin structure. We report a fully unexpected and in many ways unprecedented correlation between yield of prDSBs and radiosensitivity to killing in a battery of ten tumor cell lines that is not matched by yields of tDSBs or γH2AX, and cannot be explained by simple parameters of chromatin structure. We propose the introduction of prDSBs-yield as a novel and powerful surrogate-predictor of cell radiosensitivity to killing with potential for clinical application. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

Targeting hunter distribution based on host resource selection and kill sites to manage disease risk

DEFF Research Database (Denmark)

Dugal, Cherie; van Beest, Floris; Vander Wal, Eric

2013-01-01

Endemic and emerging diseases are rarely uniform in their spatial distribution or prevalence among cohorts of wildlife. Spatial models that quantify risk-driven differences in resource selection and hunter mortality of animals at fine spatial scales can assist disease management by identifying high-risk...... areas and individuals. We used resource selection functions (RSFs) and selection ratios (SRs) to quantify sex- and age-specific resource selection patterns of collared (n = 67) and hunter-killed (n = 796) nonmigratory elk (Cervus canadensis manitobensis) during the hunting season between 2002 and 2012...... juvenile males and hunter-killed adult females. In instances where disease infects a metapopulation and eradication is infeasible, a principle goal of management is to limit the spread of disease among infected animals. We map high-risk areas that are regularly used by potentially infectious hosts...

In vivo tyrosinase mini-gene transfer enhances killing effect of BNCT on amelanotic melanoma

Energy Technology Data Exchange (ETDEWEB)

Kondoh, H.; Mishima, Y. [Mishima Institute for Dermatological Research, Kobe, Hyogo (Japan); Hiratsuka, J. [Kawasaki Medical School, Dept. of Radiation Oncology, Kurashiki, Okayama (Japan); Iwakura, M. [Kobe Univ. (Japan). School of Medicine

2000-10-01

Using accentuated melanogenesis principally occurring within melanoma cells, we have successfully treated human malignant melanoma (Mm) with {sup 10}B-BPA BNCT. Despite this success, there are still remaining issues for poorly melanogenic Mm and further non-pigment cell tumors. We found the selective accumulation of {sup 10}B-BPA to Mm is primarily due to the complex formation of BPA and melanin-monomers activity synthesized within Mm cells. Then, we succeeded in transferring the tyrosinase gene into amelanotic to substantially produce melanin monomers. These cells has demonstrated increased boron accumulation and enhanced killing effect of BNCT. Further, transfection of TRP-2 (DOPAchrome tautomerase) gene into poorly eumelanotic and slightly phenomelanotic Mm cells in culture cell systems also led to increased BPA accumulation. Thereafter, we studied in vivo gene transfer. We transferred the tyrosinase mini-gene by intra-tumor injection into poorly melanotic Mm proliferating subcutaneously in hamster skin, and performed BNCT. Compared to control tumors, gene-transferred tumors showed increased BPA accumulation leading to enhanced killing effect. (author)

HUMAN NK CELLS: FROM SURFACE RECEPTORS TO THE THERAPY OF LEUKEMIAS AND SOLID TUMORS

Directory of Open Access Journals (Sweden)

LORENZO eMORETTA

2014-03-01

Full Text Available Natural Killer (NK cells are major effector cells of the innate immunity. The discovery, over two decades ago, of MHC-class I specific NK receptors and subsequently of activating receptors, recognizing ligands expressed by tumor or virus-infected cells, paved the way to our understanding of the mechanisms of selective recognition and killing of tumor cells. Although NK cells can efficiently kill tumor cells of different histotypes in vitro, their activity may be limited in vivo by their inefficient trafficking to tumor lesions and by the inhibition of their function induced by tumor cells themselves and by the tumor microenvironment. On the other hand, the important role of NK cells has been clearly demonstrated in the therapy of high risk leukemias in the haploidentical hematopoietic cell (HSC transplantation setting. NK cells derived from donor HSC kill leukemic cells residual after the conditioning regimen, thus preventing leukemia relapses. In addition, they also kill residual dendritic cells and T lymphocytes, thus preventing both GvHD and graft rejection.

Vitamin C selectively kills KRAS and BRAF mutant colorectal cancer cells by targeting GAPDH.

Science.gov (United States)

Yun, Jihye; Mullarky, Edouard; Lu, Changyuan; Bosch, Kaitlyn N; Kavalier, Adam; Rivera, Keith; Roper, Jatin; Chio, Iok In Christine; Giannopoulou, Eugenia G; Rago, Carlo; Muley, Ashlesha; Asara, John M; Paik, Jihye; Elemento, Olivier; Chen, Zhengming; Pappin, Darryl J; Dow, Lukas E; Papadopoulos, Nickolas; Gross, Steven S; Cantley, Lewis C

2015-12-11

More than half of human colorectal cancers (CRCs) carry either KRAS or BRAF mutations and are often refractory to approved targeted therapies. We found that cultured human CRC cells harboring KRAS or BRAF mutations are selectively killed when exposed to high levels of vitamin C. This effect is due to increased uptake of the oxidized form of vitamin C, dehydroascorbate (DHA), via the GLUT1 glucose transporter. Increased DHA uptake causes oxidative stress as intracellular DHA is reduced to vitamin C, depleting glutathione. Thus, reactive oxygen species accumulate and inactivate glyceraldehyde 3-phosphate dehydrogenase (GAPDH). Inhibition of GAPDH in highly glycolytic KRAS or BRAF mutant cells leads to an energetic crisis and cell death not seen in KRAS and BRAF wild-type cells. High-dose vitamin C impairs tumor growth in Apc/Kras(G12D) mutant mice. These results provide a mechanistic rationale for exploring the therapeutic use of vitamin C for CRCs with KRAS or BRAF mutations. Copyright © 2015, American Association for the Advancement of Science.

Killing malignant melanoma cells with protoporphyrin IX-loaded polymersome-mediated photodynamic therapy and cold atmospheric plasma

Directory of Open Access Journals (Sweden)

Wang M

2017-05-01

Full Text Available Mian Wang,1 Benjamin M Geilich,2 Michael Keidar,3 Thomas J Webster1,4 1Department of Chemical Engineering, 2Department of Bioengineering, Northeastern University, Boston, MA, 3Department of Mechanical and Aerospace Engineering, George Washington University, Washington, DC, USA; 4Wenzhou Institute of Biomaterials and Engineering, Wenzhou Medical University, Wenzhou, People’s Republic of China Abstract: Traditional cancer treatments contain several limitations such as incomplete ablation and multidrug resistance. It is known that photodynamic therapy (PDT is an effective treatment for several tumor types especially melanoma cells. During the PDT process, protoporphyrin IX (PpIX, an effective photosensitizer, can selectively kill cancer cells by activating a special light source. When tumor cells encapsulate a photosensitizer, they can be easily excited into an excited state by a light source. In this study, cold atmospheric plasma (CAP was used as a novel light source. Results of some studies have showed that cancer cells can be effectively killed by using either a light source or an individual treatment due to the generation of reactive oxygen species and electrons from a wide range of wavelengths, which suggest that CAP can act as a potential light source for anticancer applications compared with UV light sources. Results of the present in vitro study indicated for the first time that PpIX can be successfully loaded into polymersomes. Most importantly, cell viability studies revealed that PpIX-loaded polymersomes had a low toxicity to healthy fibroblasts (20% were killed at a concentration of 400 µg/mL, but they showed a great potential to selectively kill melanoma cells (almost 50% were killed. With the application of CAP posttreatment, melanoma cell viability significantly decreased (80% were killed compared to not using a light source (45% were killed or using a UV light source (65% were killed. In summary, these results indicated for the

A hypoxia- and {alpha}-fetoprotein-dependent oncolytic adenovirus exhibits specific killing of hepatocellular carcinomas.

Science.gov (United States)

Kwon, Oh-Joon; Kim, Pyung-Hwan; Huyn, Steven; Wu, Lily; Kim, Minjung; Yun, Chae-Ok

2010-12-15

Oncolytic adenoviruses (Ad) constitute a new promising modality of cancer gene therapy that displays improved efficacy over nonreplicating Ads. We have previously shown that an E1B 19-kDa-deleted oncolytic Ad exhibits a strong cell-killing effect but lacks tumor selectivity. To achieve hepatoma-restricted cytotoxicity and enhance replication of Ad within the context of tumor microenvironment, we used a modified human α-fetoprotein (hAFP) promoter to control the replication of Ad with a hypoxia response element (HRE). We constructed Ad-HRE(6)/hAFPΔ19 and Ad-HRE(12)/hAFPΔ19 that incorporated either 6 or 12 copies of HRE upstream of promoter. The promoter activity and specificity to hepatoma were examined by luciferase assay and fluorescence-activated cell sorting analysis. In addition, the AFP expression- and hypoxia-dependent in vitro cytotoxicity of Ad-HRE(6)/hAFPΔ19 and Ad-HRE(12)/hAFPΔ19 was determined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay and cytopathic effect assay. In vivo tumoricidal activity on subcutaneous and liver orthotopic model was monitored by noninvasive molecular imaging. Ad-HRE(12)/hAFPΔ19 exhibited enhanced tumor selectivity and cell-killing activity when compared with Ad-hAFPΔ19. The tumoricidal activity of Ad-HRE(12)/hAFPΔ19 resulted in significant inhibition of tumor growth in both subcutaneous and orthotopic models. Histologic examination of the primary tumor after treatment confirmed accumulation of viral particles near hypoxic areas. Furthermore, Ad-HRE(12)/hAFPΔ19 did not cause severe inflammatory immune response and toxicity after systemic injection. The results presented here show the advantages of incorporating HREs into a hAFP promoter-driven oncolytic virus. This system is unique in that it acts in both a tissue-specific and tumor environment-selective manner. The greatly enhanced selectivity and tumoricidal activity of Ad-HRE(12)/hAFPΔ19 make it a promising therapeutic agent in the treatment

Radiogenetic therapy: strategies to overcome tumor resistance.

Science.gov (United States)

Marples, B; Greco, O; Joiner, M C; Scott, S D

2003-01-01

The aim of cancer gene therapy is to selectively kill malignant cells at the tumor site, by exploiting traits specific to cancer cells and/or solid tumors. Strategies that take advantage of biological features common to different tumor types are particularly promising, since they have wide clinical applicability. Much attention has focused on genetic methods that complement radiotherapy, the principal treatment modality, or that exploit hypoxia, the most ubiquitous characteristic of most solid cancers. The goal of this review is to highlight two promising gene therapy methods developed specifically to target the tumor volume that can be readily used in combination with radiotherapy. The first approach uses radiation-responsive gene promoters to control the selective expression of a suicide gene (e.g., herpes simplex virus thymidine kinase) to irradiated tissue only, leading to targeted cell killing in the presence of a prodrug (e.g., ganciclovir). The second method utilizes oxygen-dependent promoters to produce selective therapeutic gene expression and prodrug activation in hypoxic cells, which are refractive to conventional radiotherapy. Further refining of tumor targeting can be achieved by combining radiation and hypoxia responsive elements in chimeric promoters activated by either and dual stimuli. The in vitro and in vivo studies described in this review suggest that the combination of gene therapy and radiotherapy protocols has potential for use in cancer care, particularly in cases currently refractory to treatment as a result of inherent or hypoxia-mediated radioresistance.

Hematoporphyrin monomethyl ether-mediated photodynamic therapy selectively kills sarcomas by inducing apoptosis.

Directory of Open Access Journals (Sweden)

Hui Zeng

Full Text Available We investigated the antitumor effect and mechanism of hematoporphyrin monomethyl ether-mediated photodynamic therapy (HMME-PDT in sarcomas. Intracellular uptake of HMME by osteosarcoma cells (LM8 and K7 was time- and dose-dependent, while this was not observed for myoblast cells (C2C12 and fibroblast cells (NIH/3T3. HMME-PDT markedly inhibited the proliferation of sarcoma cell lines (LM8, MG63, Saos-2, SW1353, TC71, and RD (P<0.05, and the killing effect was improved with increased HMME concentration and energy intensity. Flow cytometry analysis revealed that LM8, MG63, and Saos-2 cells underwent apoptosis after treatment with HMME-PDT. Additionally, apoptosis was induced after HMME-PDT in a three-dimensional culture of osteosarcoma cells. Hoechst 33342 staining confirmed apoptosis. Cell death caused by PDT was rescued by an irreversible inhibitor (Z-VAD-FMK of caspase. However, cell viability was not markedly decreased compared with the HMME-PDT group. Expression levels of caspase-1, caspase-3, caspase-6, caspase-9, and poly (ADP-ribose polymerase (PARP proteins were markedly up-regulated in the treatment groups and increased with HMME concentration as determined by western blot analysis. In vivo, tumor volume markedly decreased at 7-16 days post-PDT. Hematoxylin and eosin staining revealed widespread necrotic and infiltrative inflammatory cells in the HMME-PDT group. Immunohistochemistry analysis also showed that caspase-1, caspase-3, caspase-6, caspase-9, and PARP proteins were significantly increased in the HMME-PDT group. These results indicate that HMME-PDT has a potent killing effect on osteosarcoma cells in vitro and significantly inhibits tumor growth in vivo, which is associated with the caspase-dependent pathway.

Oligo-branched peptides for tumor targeting: from magic bullets to magic forks.

Science.gov (United States)

Falciani, Chiara; Pini, Alessandro; Bracci, Luisa

2009-02-01

Selective targeting of tumor cells is the final goal of research and drug discovery for cancer diagnosis, imaging and therapy. After the invention of hybridoma technology, the concept of magic bullet was introduced into the field of oncology, referring to selective killing of tumor cells, by specific antibodies. More recently, small molecules and peptides have also been proposed as selective targeting agents. We analyze the state of the art of tumor-selective agents that are presently available and tested in clinical settings. A novel approach based on 'armed' oligo-branched peptides as tumor targeting agents, is discussed and compared with existing tumor-selective therapies mediated by antibodies, small molecules or monomeric peptides. Oligo-branched peptides could be novel drugs that combine the advantages of antibodies and small molecules.

Plasma-activated medium (PAM) kills human cancer-initiating cells.

Science.gov (United States)

Ikeda, Jun-Ichiro; Tanaka, Hiromasa; Ishikawa, Kenji; Sakakita, Hajime; Ikehara, Yuzuru; Hori, Masaru

2018-01-01

Medical non-thermal plasma (NTP) treatments for various types of cancers have been reported. Cells with tumorigenic potential (cancer-initiating cells; CICs) are few in number in many types of tumors. CICs efficiently eliminate anti-cancer chemicals and exhibit high-level aldehyde dehydrogenase (ALDH) activity. We previously examined the effects of direct irradiation via NTP on cancer cells; even though we targeted CICs expressing high levels of ALDH, such treatment affected both non-CICs and CICs. Recent studies have shown that plasma-activated medium (PAM) (culture medium irradiated by NTP) selectively induces apoptotic death of cancer but not normal cells. Therefore, we explored the anti-cancer effects of PAM on CICs among endometrioid carcinoma and gastric cancer cells. PAM reduced the viability of cells expressing both low and high levels of ALDH. Combined PAM/cisplatin appeared to kill cancer cells more efficiently than did PAM or cisplatin alone. In a mouse tumor xenograft model, PAM exerted an anti-cancer effect on CICs. Thus, our results suggest that PAM effectively kills both non-CICs and CICs, as does NTP. Therefore, PAM may be a useful new anti-cancer therapy, targeting various cancer cells including CICs. © 2017 Japanese Society of Pathology and John Wiley & Sons Australia, Ltd.

Selective cytotoxicity of transformed cells but not normal cells by a sialoglycopeptide growth regulator in the presence of tumor necrosis factor

Science.gov (United States)

Woods, K. M.; Fattaey, H.; Johnson, T. C.; Chapes, S. K.; Spooner, B. S. (Principal Investigator)

1994-01-01

The tumor necrosis factor-alpha (TNF)-resistant, SV40-transformed, murine fibroblast cell lines, F5b and F5m, became sensitive to TNF-mediated cytolysis after treatment with a biologically active 18 kDa peptide fragment (SGP) derived from a 66-kDa parental cell surface sialoglycoprotein. Neither TNF nor the SGP alone exhibited cytotoxicity to the two SV40-transformed cell lines. However, Balb/c 3T3 cells, incubated with SGP alone or with SGP and TNF, were not killed. Therefore, SGP can selectively sensitize cells for TNF alpha-mediated cytotoxicity. This selective sensitization may be due to the previously documented ability of the SGP to selectively mediate cell cycle arrest.

Enhancement of tumor cell killing in vitro by pre- and post-irradiation exposure to aclacinomycin A

International Nuclear Information System (INIS)

Bill, C.A.; Mendoza, A.; Vrdoljak, E.; Tofilon, P.J.

1993-01-01

Aclacinomycin A (ACM), a potent inducer of leukemic cell differentiation, significantly enhances the radiosensitivity of a human colon tumor cell line (Clone A) when cultures are exposed to 15-nM concentrations for 3 days before irradiation. We now demonstrate that incubation with ACM after irradiation can also enhance Clone A cell killing. The maximum increase in cell killing, based on colony-forming ability, occurred when Clone A cells were exposed for 1 h to 5 μM ACM model added 1 or 2 h after irradiation. The post-irradiation ACM protocol reduced the terminal slope (as reflected by D o ) of the radiation cell survival curve with no change in the low-dose, shoulder region of the curve (D q value). In contrast, for pre-irradiation treatment with ACM (15 nM, 3 days), the shoulder region of the curve was reduced with no change in the terminal slope. For pre- and post-irradiation ACM treatment the dose enhancement factors at 0.10 survival were 1.22 and 1.28, respectively. When ACM was given both before and after irradiation both the shoulder and terminal slope values decreased to produce a dose enhancement factor at a surviving fraction of 0.10 of 1.50. These data suggest that the enhanced cell killing produced by pre- and post-irradiation treatment with ACM is achieved through different mechanisms. (author) 26 refs., 3 tabs., 2 figs

Sinularin Selectively Kills Breast Cancer Cells Showing G2/M Arrest, Apoptosis, and Oxidative DNA Damage

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Hurng-Wern Huang

2018-04-01

Full Text Available The natural compound sinularin, isolated from marine soft corals, is antiproliferative against several cancers, but its possible selective killing effect has rarely been investigated. This study investigates the selective killing potential and mechanisms of sinularin-treated breast cancer cells. In 3-(4,5-dimethylthiazol-2-yl-5-(3-carboxymethoxyphenyl-2-(4-sulfophenyl-2H- tetrazolium, inner salt (MTS assay, sinularin dose-responsively decreased the cell viability of two breast cancer (SKBR3 and MDA-MB-231 cells, but showed less effect on breast normal (M10 cells after a 24 h treatment. According to 7-aminoactinomycin D (7AAD flow cytometry, sinularin dose-responsively induced the G2/M cycle arrest of SKBR3 cells. Sinularin dose-responsively induced apoptosis on SKBR3 cells in terms of a flow cytometry-based annexin V/7AAD assay and pancaspase activity, as well as Western blotting for cleaved forms of poly(ADP-ribose polymerase (PARP, caspases 3, 8, and 9. These caspases and PARP activations were suppressed by N-acetylcysteine (NAC pretreatment. Moreover, sinularin dose-responsively induced oxidative stress and DNA damage according to flow cytometry analyses of reactive oxygen species (ROS, mitochondrial membrane potential (MitoMP, mitochondrial superoxide, and 8-oxo-2′-deoxyguanosine (8-oxodG. In conclusion, sinularin induces selective killing, G2/M arrest, apoptosis, and oxidative DNA damage of breast cancer cells.

Killing tensors and conformal Killing tensors from conformal Killing vectors

International Nuclear Information System (INIS)

Rani, Raffaele; Edgar, S Brian; Barnes, Alan

2003-01-01

Koutras has proposed some methods to construct reducible proper conformal Killing tensors and Killing tensors (which are, in general, irreducible) when a pair of orthogonal conformal Killing vectors exist in a given space. We give the completely general result demonstrating that this severe restriction of orthogonality is unnecessary. In addition, we correct and extend some results concerning Killing tensors constructed from a single conformal Killing vector. A number of examples demonstrate that it is possible to construct a much larger class of reducible proper conformal Killing tensors and Killing tensors than permitted by the Koutras algorithms. In particular, by showing that all conformal Killing tensors are reducible in conformally flat spaces, we have a method of constructing all conformal Killing tensors, and hence all the Killing tensors (which will in general be irreducible) of conformally flat spaces using their conformal Killing vectors

Stimulation of cytolytic T lymphocytes by azaguanine-resistant mouse tumor cells in selective hat medium

International Nuclear Information System (INIS)

Snick, J. van; Uyttenhove, C.; Pel, A. van; Boon, T.

1981-01-01

Primed syngeneic or umprimed allogeneic mouse spleen cells were stimulated with azaguanine-resistant P815 tumor cells that were killed by the addition of aminopterin to the stimulation medium. The recovery of lymphocytes and their cytolytic activity and specificity were similar to those obtained after stimulation with irradiated cells. This method conveniently replaces the inactivation of stimulatory cells by irradiation or mitomycin treatment. Moreover, it has the advantage of inactivating not only the stimulatory cells but also the tumor cells that often contaminate the spleens of tumor-bearing animals, provided these animals have been inoculated with azaguanine-resistant tumor cell mutants. (Auth.)

Updates in the Development of ImmunoRNases for the Selective Killing of Tumor Cells

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Sandra Jordaan

2018-03-01

Full Text Available Targeted cancer therapy includes, amongst others, antibody-based delivery of toxic payloads to selectively eliminate tumor cells. This payload can be either a synthetic small molecule drug composing an antibody-drug conjugate (ADC or a cytotoxic protein composing an immunotoxin (IT. Non-human cytotoxic proteins, while potent, have limited clinical efficacy due to their immunogenicity and potential off-target toxicity. Humanization of the cytotoxic payload is essential and requires harnessing of potent apoptosis-inducing human proteins with conditional activity, which rely on targeted delivery to contact their substrate. Ribonucleases are attractive candidates, due to their ability to induce apoptosis by abrogating protein biosynthesis via tRNA degradation. In fact, several RNases of the pancreatic RNase A superfamily have shown potential as anti-cancer agents. Coupling of a human RNase to a humanized antibody or antibody derivative putatively eliminates the immunogenicity of an IT (now known as a human cytolytic fusion protein, hCFP. However, RNases are tightly regulated in vivo by endogenous inhibitors, controlling the ribonucleolytic balance subject to the cell’s metabolic requirements. Endogenous inhibition limits the efficacy with which RNase-based hCFPs induce apoptosis. However, abrogating the natural interaction with the natural inhibitors by mutation has been shown to significantly enhance RNase activity, paving the way toward achieving cytolytic potency comparable to that of bacterial immunotoxins. Here, we review the immunoRNases that have undergone preclinical studies as anti-cancer therapeutic agents.

Updates in the Development of ImmunoRNases for the Selective Killing of Tumor Cells.

Science.gov (United States)

Jordaan, Sandra; Akinrinmade, Olusiji A; Nachreiner, Thomas; Cremer, Christian; Naran, Krupa; Chetty, Shivan; Barth, Stefan

2018-03-05

Targeted cancer therapy includes, amongst others, antibody-based delivery of toxic payloads to selectively eliminate tumor cells. This payload can be either a synthetic small molecule drug composing an antibody-drug conjugate (ADC) or a cytotoxic protein composing an immunotoxin (IT). Non-human cytotoxic proteins, while potent, have limited clinical efficacy due to their immunogenicity and potential off-target toxicity. Humanization of the cytotoxic payload is essential and requires harnessing of potent apoptosis-inducing human proteins with conditional activity, which rely on targeted delivery to contact their substrate. Ribonucleases are attractive candidates, due to their ability to induce apoptosis by abrogating protein biosynthesis via tRNA degradation. In fact, several RNases of the pancreatic RNase A superfamily have shown potential as anti-cancer agents. Coupling of a human RNase to a humanized antibody or antibody derivative putatively eliminates the immunogenicity of an IT (now known as a human cytolytic fusion protein, hCFP). However, RNases are tightly regulated in vivo by endogenous inhibitors, controlling the ribonucleolytic balance subject to the cell's metabolic requirements. Endogenous inhibition limits the efficacy with which RNase-based hCFPs induce apoptosis. However, abrogating the natural interaction with the natural inhibitors by mutation has been shown to significantly enhance RNase activity, paving the way toward achieving cytolytic potency comparable to that of bacterial immunotoxins. Here, we review the immunoRNases that have undergone preclinical studies as anti-cancer therapeutic agents.

Stem-like tumor-initiating cells isolated from IL13Rα2 expressing gliomas are targeted and killed by IL13-zetakine-redirected T Cells.

Science.gov (United States)

Brown, Christine E; Starr, Renate; Aguilar, Brenda; Shami, Andrew F; Martinez, Catalina; D'Apuzzo, Massimo; Barish, Michael E; Forman, Stephen J; Jensen, Michael C

2012-04-15

To evaluate IL13Rα2 as an immunotherapeutic target for eliminating glioma stem-like cancer initiating cells (GSC) of high-grade gliomas, with particular focus on the potential of genetically engineered IL13Rα2-specific primary human CD8(+) CTLs (IL13-zetakine(+) CTL) to target this therapeutically resistant glioma subpopulation. A panel of low-passage GSC tumor sphere (TS) and serum-differentiated glioma lines were expanded from patient glioblastoma specimens. These glioblastoma lines were evaluated for expression of IL13Rα2 and for susceptibility to IL13-zetakine(+) CTL-mediated killing in vitro and in vivo. We observed that although glioma IL13Rα2 expression varies between patients, for IL13Rα2(pos) cases this antigen was detected on both GSCs and more differentiated tumor cell populations. IL13-zetakine(+) CTL were capable of efficient recognition and killing of both IL13Rα2(pos) GSCs and IL13Rα2(pos) differentiated cells in vitro, as well as eliminating glioma-initiating activity in an orthotopic mouse tumor model. Furthermore, intracranial administration of IL13-zetakine(+) CTL displayed robust antitumor activity against established IL13Rα2(pos) GSC TS-initiated orthotopic tumors in mice. Within IL13Rα2 expressing high-grade gliomas, this receptor is expressed by GSCs and differentiated tumor populations, rendering both targetable by IL13-zetakine(+) CTLs. Thus, our results support the potential usefullness of IL13Rα2-directed immunotherapeutic approaches for eradicating therapeutically resistant GSC populations. ©2012 AACR.

Is it beneficial to selectively boost high-risk tumor subvolumes? A comparison of selectively boosting high-risk tumor subvolumes versus homogeneous dose escalation of the entire tumor based on equivalent EUD plans

International Nuclear Information System (INIS)

Kim, Yusung; To me, Wolfgang A.

2008-01-01

Purpose. To quantify and compare expected local tumor control and expected normal tissue toxicities between selective boosting IMRT and homogeneous dose escalation IMRT for the case of prostate cancer. Methods. Four different selective boosting scenarios and three different high-risk tumor subvolume geometries were designed to compare selective boosting and homogeneous dose escalation IMRT plans delivering the same equivalent uniform dose (EUD) to the entire PTV. For each scenario, differences in tumor control probability between both boosting strategies were calculated for the high-risk tumor subvolume and remaining low-risk PTV, and were visualized using voxel based iso-TCP maps. Differences in expected rectal and bladder complications were quantified using radiobiological indices (generalized EUD (gEUD) and normal tissue complication probability (NTCP)) as well as %-volumes. Results. For all investigated scenarios and high-risk tumor subvolume geometries, selective boosting IMRT improves expected TCP compared to homogeneous dose escalation IMRT, especially when lack of control of the high-risk tumor subvolume could be the cause for tumor recurrence. Employing, selective boosting IMRT significant increases in expected TCP can be achieved for the high-risk tumor subvolumes. The three conventional selective boosting IMRT strategies, employing physical dose objectives, did not show significant improvement in rectal and bladder sparing as compared to their counterpart homogeneous dose escalation plans. However, risk-adaptive optimization, utilizing radiobiological objective functions, resulted in reduction in NTCP for the rectum when compared to its corresponding homogeneous dose escalation plan. Conclusions. Selective boosting is a more effective method than homogeneous dose escalation for achieving optimal treatment outcomes. Furthermore, risk-adaptive optimization increases the therapeutic ratio as compared to conventional selective boosting IMRT

Immunoediting: evidence of the multifaceted role of the immune system in self-metastatic tumor growth.

Science.gov (United States)

Enderling, Heiko; Hlatky, Lynn; Hahnfeldt, Philip

2012-07-28

The role of the immune system in tumor progression has been a subject for discussion for many decades. Numerous studies suggest that a low immune response might be beneficial, if not necessary, for tumor growth, and only a strong immune response can counter tumor growth and thus inhibit progression. We implement a cellular automaton model previously described that captures the dynamical interactions between the cancer stem and non-stem cell populations of a tumor through a process of self-metastasis. By overlaying on this model the diffusion of immune reactants into the tumor from a peripheral source to target cells, we simulate the process of immune-system-induced cell kill on tumor progression. A low cytotoxic immune reaction continuously kills cancer cells and, although at a low rate, thereby causes the liberation of space-constrained cancer stem cells to drive self-metastatic progression and continued tumor growth. With increasing immune system strength, however, tumor growth peaks, and then eventually falls below the intrinsic tumor sizes observed without an immune response. With this increasing immune response the number and proportion of cancer stem cells monotonically increases, implicating an additional unexpected consequence, that of cancer stem cell selection, to the immune response. Cancer stem cells and immune cytotoxicity alone are sufficient to explain the three-step "immunoediting" concept - the modulation of tumor growth through inhibition, selection and promotion.

Killing effect of peripheral blood mononuclear cells irradiated by γ ray on human gastric cancer MKN-28 cell

International Nuclear Information System (INIS)

Wu Daocheng; Zhang Xianqing; Mu Shijie; Liu Zhongxiang; Xia Aijun; Huang Xiaofeng; An Qunxing

2007-01-01

Objective: To observe the killing effect of peripheral blood mononuclear cells (PBMCs) irradiated by γ ray on cultured human gastric cancer cell line MKN-28. Methods: The experiment were divided into MKN-28 tumor cell control group, PBMCs groups and MKN-28 cells with irradiated or non-irradiated PBMCs co-culture groups. Radidation dosage were from 0.5 to 3 Gy, acridine orange/ethidium bromide (AO/EB) staining were used to observe the kill effect of PBMCs on tumor cells in different period. Results: After culture for 144h, the dead cells of several dosage irradiated PBMCs are much more than those of non-irradiated PBMCs group. At 240 hours of culture, the alive PBMCs deareses in number in both irradiated and non-irradiared groups, but decreases in radiated groups are more obvious. After culture for 72 h in the co-cultured groups, the difference is not evident among all radiation dosage groups. After 96-240 h of co-culture, the killing effect of 0.5-2Gy irradiated PBMCs on tumor cells is very strong, especially in 1Gy group, but the killing effect of PBMCs irradiated by 2.5-3Gy on tumor cells were weaker than that of 0.5-2Gy irradiated groups. At 240 hours co-cultured groups irradiated by 2.5-3Gy, tumor cells still survive and proliferate. Conclusion: Gamma ray irradiation have killing effect to some PBMCs. The cytocidal effect of PBMCs irradiated by 0.5-2Gy on tumor cells were increased. Chemotaxis and cytocidal effect of tumor cells to postirradiated PBMCs were also found. The killing effect of PBMCs irradiated by 2.5 and 3 Gy on tumor cells were restrained. (authors)

Determinates of tumor response to radiation: Tumor cells, tumor stroma and permanent local control

International Nuclear Information System (INIS)

Li, Wende; Huang, Peigen; Chen, David J.; Gerweck, Leo E.

2014-01-01

Background and purpose: The causes of tumor response variation to radiation remain obscure, thus hampering the development of predictive assays and strategies to decrease resistance. The present study evaluates the impact of host tumor stromal elements and the in vivo environment on tumor cell kill, and relationship between tumor cell radiosensitivity and the tumor control dose. Material and methods: Five endpoints were evaluated and compared in a radiosensitive DNA double-strand break repair-defective (DNA-PKcs −/− ) tumor line, and its DNA-PKcs repair competent transfected counterpart. In vitro colony formation assays were performed on in vitro cultured cells, on cells obtained directly from tumors, and on cells irradiated in situ. Permanent local control was assessed by the TCD 50 assay. Vascular effects were evaluated by functional vascular density assays. Results: The fraction of repair competent and repair deficient tumor cells surviving radiation did not substantially differ whether irradiated in vitro, i.e., in the absence of host stromal elements and factors, from the fraction of cells killed following in vivo irradiation. Additionally, the altered tumor cell sensitivity resulted in a proportional change in the dose required to achieve permanent local control. The estimated number of tumor cells per tumor, their cloning efficiency and radiosensitivity, all assessed by in vitro assays, were used to predict successfully, the measured tumor control doses. Conclusion: The number of clonogens per tumor and their radiosensitivity govern the permanent local control dose

Selective killing of hepatocellular carcinoma HepG2 cells by three-dimensional nanographene nanoparticles based on triptycene

Science.gov (United States)

Xiong, Xiaoqin; Gan, Lu; Liu, Ying; Zhang, Chun; Yong, Tuying; Wang, Ziyi; Xu, Huibi; Yang, Xiangliang

2015-03-01

Carbon-based materials have been widely used in the biomedical fields including drug delivery and cancer therapies. In this paper, a recently synthesized three-dimensional nanographene (NG) based on triptycene self-assembles into nanoparticles which selectively kill human hepatocellular carcinoma HepG2 cells as compared to human normal liver HL7702 cells. Obvious differences in cellular accumulation, the endocytic pathway and intracellular trafficking of NG nanoparticles are observed in HepG2 cells and HL7702 cells. Further studies reveal that NG nanoparticles significantly increase the levels of reactive oxygen species (ROS) in HepG2 cells, but not in HL7702 cells. NG nanoparticle-induced ROS result in apoptosis induction and the decrease in mitochondrial membrane potential in HepG2 cells. Moreover, IKK/nuclear factor-κB (NF-κB) signaling is found to be activated by NG nanoparticle-induced ROS and serves to antagonize NG nanoparticle-induced apoptosis in HepG2 cells. Our studies show that the distinct behaviors of cellular uptake and ROS-mediated cytotoxicity are responsible for the selective killing of HepG2 cells. This study provides a foundation for understanding the mechanism of selective induction of apoptosis in cancer cells by NG nanoparticles and designing more effective chemotherapeutical agents.Carbon-based materials have been widely used in the biomedical fields including drug delivery and cancer therapies. In this paper, a recently synthesized three-dimensional nanographene (NG) based on triptycene self-assembles into nanoparticles which selectively kill human hepatocellular carcinoma HepG2 cells as compared to human normal liver HL7702 cells. Obvious differences in cellular accumulation, the endocytic pathway and intracellular trafficking of NG nanoparticles are observed in HepG2 cells and HL7702 cells. Further studies reveal that NG nanoparticles significantly increase the levels of reactive oxygen species (ROS) in HepG2 cells, but not in HL7702

Prolonged early G1 arrest by selective CDK4/CDK6 inhibition sensitizes myeloma cells to cytotoxic killing through cell cycle–coupled loss of IRF4

Science.gov (United States)

Huang, Xiangao; Di Liberto, Maurizio; Jayabalan, David; Liang, Jun; Ely, Scott; Bretz, Jamieson; Shaffer, Arthur L.; Louie, Tracey; Chen, Isan; Randolph, Sophia; Hahn, William C.; Staudt, Louis M.; Niesvizky, Ruben; Moore, Malcolm A. S.

2012-01-01

Dysregulation of cyclin-dependent kinase 4 (CDK4) and CDK6 by gain of function or loss of inhibition is common in human cancer, including multiple myeloma, but success in targeting CDK with broad-spectrum inhibitors has been modest. By selective and reversible inhibition of CDK4/CDK6, we have developed a strategy to both inhibit proliferation and enhance cytotoxic killing of cancer cells. We show that induction of prolonged early-G1 arrest (pG1) by CDK4/CDK6 inhibition halts gene expression in early-G1 and prevents expression of genes programmed for other cell-cycle phases. Removal of the early-G1 block leads to S-phase synchronization (pG1-S) but fails to completely restore scheduled gene expression. Consequently, the IRF4 protein required to protect myeloma cells from apoptosis is markedly reduced in pG1 and further in pG1-S in response to cytotoxic agents, such as the proteasome inhibitor bortezomib. The coordinated loss of IRF4 and gain of Bim sensitize myeloma tumor cells to bortezomib-induced apoptosis in pG1 in the absence of Noxa and more profoundly in pG1-S in cooperation with Noxa in vitro. Induction of pG1 and pG1-S by reversible CDK4/CDK6 inhibition further augments tumor-specific bortezomib killing in myeloma xenografts. Reversible inhibition of CDK4/CDK6 in sequential combination therapy thus represents a novel mechanism-based cancer therapy. PMID:22718837

Prolonged early G(1) arrest by selective CDK4/CDK6 inhibition sensitizes myeloma cells to cytotoxic killing through cell cycle-coupled loss of IRF4.

Science.gov (United States)

Huang, Xiangao; Di Liberto, Maurizio; Jayabalan, David; Liang, Jun; Ely, Scott; Bretz, Jamieson; Shaffer, Arthur L; Louie, Tracey; Chen, Isan; Randolph, Sophia; Hahn, William C; Staudt, Louis M; Niesvizky, Ruben; Moore, Malcolm A S; Chen-Kiang, Selina

2012-08-02

Dysregulation of cyclin-dependent kinase 4 (CDK4) and CDK6 by gain of function or loss of inhibition is common in human cancer, including multiple myeloma, but success in targeting CDK with broad-spectrum inhibitors has been modest. By selective and reversible inhibition of CDK4/CDK6, we have developed a strategy to both inhibit proliferation and enhance cytotoxic killing of cancer cells. We show that induction of prolonged early-G(1) arrest (pG1) by CDK4/CDK6 inhibition halts gene expression in early-G(1) and prevents expression of genes programmed for other cell-cycle phases. Removal of the early-G(1) block leads to S-phase synchronization (pG1-S) but fails to completely restore scheduled gene expression. Consequently, the IRF4 protein required to protect myeloma cells from apoptosis is markedly reduced in pG1 and further in pG1-S in response to cytotoxic agents, such as the proteasome inhibitor bortezomib. The coordinated loss of IRF4 and gain of Bim sensitize myeloma tumor cells to bortezomib-induced apoptosis in pG1 in the absence of Noxa and more profoundly in pG1-S in cooperation with Noxa in vitro. Induction of pG1 and pG1-S by reversible CDK4/CDK6 inhibition further augments tumor-specific bortezomib killing in myeloma xenografts. Reversible inhibition of CDK4/CDK6 in sequential combination therapy thus represents a novel mechanism-based cancer therapy.

Surface-Selective Preferential Production of Reactive Oxygen Species on Piezoelectric Ceramics for Bacterial Killing

OpenAIRE

Tan, Guoxin; Wang, Shuangying; Zhu, Ye; Zhou, Lei; Yu, Peng; Wang, Xiaolan; He, Tianrui; Chen, Junqi; Mao, Chuanbin; Ning, Chengyun

2016-01-01

Reactive oxygen species (ROS) can be used to kill bacterial cells, and thus the selective generation of ROS from material surfaces is an emerging direction in antibacterial material discovery. We found the polarization of piezoelectric ceramic causes the two sides of the disk to become positively and negatively charged, which translate into cathode and anode surfaces in an aqueous solution. Because of the microelectrolysis of water, ROS are preferentially formed on the cathode surface. Conseq...

Influence of sequential 125I particle chain implantation and transcatheter arterial chemoembolization on tumor cell killing effect in patients with liver cancer

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Wei Dai

2017-07-01

Full Text Available Objective: To study the influence of sequential 125I particle chain implantation and transcatheter arterial chemoembolization (TACE on tumor cell killing effect in patients with liver cancer. Methods: A total of 82 cases of patients with advanced liver cancer who were treated in our hospital between September 2014 and December 2016 were collected, reviewed and then divided into the control group (n=45 who received TACE alone and the observation group (n=37 who received sequential 125I particle chain implantation and TACE. Serum levels of tumor markers, angiogenesis indexes and apoptosis molecules before and after treatments were compared between two groups of patients. Results: Before treatment, differences in serum levels of tumor markers, angiogenesis indexes and apoptosis molecules were not statistically significant between two groups of patients. After treatment, serum tumor markers AFP, CA199, CA153 and Ferritin levels in observation group were lower than those in control group; serum angiogenesis indexes VEGF, PEDF, ES and bFGF contents were lower than those in control group; serum apoptosis molecules p53 and Fas contents were higher than those in control group. Conclusion: Sequential 125I particle chain implantation and TACE treatment of advanced liver cancer can effectively reduce tumor malignancy and promote tumor apoptosis.

[Methylation of selected tumor-supressor genes in benign and malignant ovarian tumors].

Science.gov (United States)

Cul'bová, M; Lasabová, Z; Stanclová, A; Tilandyová, P; Zúbor, P; Fiolka, R; Danko, J; Visnovský, J

2011-09-01

To evaluate the usefullness of examination of methylation status of selected tumor-supressor genes in early diagnosis of ovarian cancer. Prospective clinical study. Department of Gynecology and Obstetrics, Department of Molecular Biology, Jessenius Medical Faculty, Commenius University, Martin, Slovak Republic. In this study we analyzed hypermethylation of 5 genes RASSF1A, GSTP, E-cadherin, p16 and APC in ovarian tumor samples from 34 patients - 13 patients with epithelial ovarian cancer, 2 patients with border-line ovarian tumors, 12 patients with benign lesions of ovaries and 7 patients with healthy ovarian tissue. The methylation status of promoter region of tumor-supressor genes was determined by Methylation Specific Polymerase Chain Reaction (MSP) using a nested two-step approach with bisulfite modified DNA template and specific primers. Gene methylation analysis revealed hypermethylation of gene RASSF1A (46%) and GSTP (8%) only in malignant ovarian tissue samples. Ecad, p16 and APC genes were methylated both in maignant and benign tissue samples. Methylation positivity in observed genes was present independently to all clinical stages of ovarian cancer and to tumor grades. However, there was observed a trend of increased number and selective involvement of methylated genes with increasing disease stages. Furthermore, there was no association between positive methylation status and histological subtypes of ovarian carcinomas. RASSF1A and GSTP promoter methylation positivity is associated with ovarian cancer. The revealed gene-selective methylation positivity and the increased number of methylated genes with advancing disease stages could be considered as a useful molecular marker for early detection of ovarian cancer. However, there is need to find diagnostic approach of specifically and frequently methylated genes to determining a methylation phenotype for early detection of ovarian malignancies.

Tumor response to ionizing radiation and combined 2-deoxy-D-glucose application in EATC tumor bearing mice: monitoring of tumor size and microscopic observations

International Nuclear Information System (INIS)

Latz, D.; Thonke, A.; Jueling-Pohlit, L.; Pohlit, W.

1993-01-01

The present study deals with the changes induced by two fractionation schedules (5x9 Gy and 10x4.5 Gy; 30 MeV-electrons) of ionizing radiations and 2-Deoxy-D-Glucose (2-DG) application on EATC tumor bearing swiss albino mice. The monitoring of tumor response was carried out by means of calliper measurement on the macroscopic level and by histopathological examination of tumor preparations stained with hematoxiline and eosine on the microscopic level. The tumor material was assessed at suitable intervals after treatment by killing the animals. The tumor response was analysed in the histological preparations and the thickness of the tumor band was determined quantitatively by an ocularmicrometric technique. Tumor damage was most extensive in the combined treated animals (5x9 Gy + 2-DG). Only in this group local tumor control was achievable. The histological analysis of tumor preparations revealed additional data about treatment-induced changes in the tumor compared to the measurement of the tumor volume with mechanical callipers. We also found that the treatment outcome could be predicted from the histopathological analysis. It is concluded that studies involving histopathological examinations may give some insight into the way cancer is controlled by radiotherapy and may be of value in prognosis and selection of treatment in patients. (orig.) [de

Selected anti-tumor vaccines merit a place in multimodal tumor therapies

Energy Technology Data Exchange (ETDEWEB)

Weiss, Eva-Maria; Wunderlich, Roland [Department of Radiation Oncology, University Hospital Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen (Germany); Ebel, Nina [Department of Process Technology and Machinery, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen (Germany); Rubner, Yvonne [Department of Radiation Oncology, University Hospital Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen (Germany); Schlücker, Eberhard [Department of Process Technology and Machinery, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen (Germany); Meyer-Pittroff, Roland [Competence Pool Weihenstephan, Technische Universität München, Freising (Germany); Ott, Oliver J.; Fietkau, Rainer; Gaipl, Udo S.; Frey, Benjamin, E-mail: benjamin.frey@uk-erlangen.de [Department of Radiation Oncology, University Hospital Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen (Germany)

2012-10-09

Multimodal approaches are nowadays successfully applied in cancer therapy. Primary locally acting therapies such as radiotherapy (RT) and surgery are combined with systemic administration of chemotherapeutics. Nevertheless, the therapy of cancer is still a big challenge in medicine. The treatments often fail to induce long-lasting anti-tumor responses. Tumor recurrences and metastases result. Immunotherapies are therefore ideal adjuncts to standard tumor therapies since they aim to activate the patient's immune system against malignant cells even outside the primary treatment areas (abscopal effects). Especially cancer vaccines may have the potential both to train the immune system against cancer cells and to generate an immunological memory, resulting in long-lasting anti-tumor effects. However, despite promising results in phase I and II studies, most of the concepts finally failed. There are some critical aspects in development and application of cancer vaccines that may decide on their efficiency. The time point and frequency of medication, usage of an adequate immune adjuvant, the vaccine's immunogenic potential, and the tumor burden of the patient are crucial. Whole tumor cell vaccines have advantages compared to peptide-based ones since a variety of tumor antigens (TAs) are present. The master requirements of cell-based, therapeutic tumor vaccines are the complete inactivation of the tumor cells and the increase of their immunogenicity. Since the latter is highly connected with the cell death modality, the inactivation procedure of the tumor cell material may significantly influence the vaccine's efficiency. We therefore also introduce high hydrostatic pressure (HHP) as an innovative inactivation technology for tumor cell-based vaccines and outline that HHP efficiently inactivates tumor cells by enhancing their immunogenicity. Finally studies are presented proving that anti-tumor immune responses can be triggered by combining RT with selected

Selective Killing Effects of Cold Atmospheric Pressure Plasma with NO Induced Dysfunction of Epidermal Growth Factor Receptor in Oral Squamous Cell Carcinoma.

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Jung-Hwan Lee

Full Text Available The aim of this study is to investigate the effects of cold atmospheric pressure plasma (CAP-induced radicals on the epidermal growth factor receptor (EGFR, which is overexpressed by oral squamous cell carcinoma, to determine the underlying mechanism of selective killing. CAP-induced highly reactive radicals were observed in both plasma plume and cell culture media. The selective killing effect was observed in oral squamous cell carcinoma compared with normal human gingival fibroblast. Degradation and dysfunction of EGFRs were observed only in the EGFR-overexpressing oral squamous cell carcinoma and not in the normal cell. Nitric oxide scavenger pretreatment in cell culture media before CAP treatment rescued above degradation and dysfunction of the EGFR as well as the killing effect in oral squamous cell carcinoma. CAP may be a promising cancer treatment method by inducing EGFR dysfunction in EGFR-overexpressing oral squamous cell carcinoma via nitric oxide radicals.

Selective Killing Effects of Cold Atmospheric Pressure Plasma with NO Induced Dysfunction of Epidermal Growth Factor Receptor in Oral Squamous Cell Carcinoma.

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Lee, Jung-Hwan; Om, Ji-Yeon; Kim, Yong-Hee; Kim, Kwang-Mahn; Choi, Eun-Ha; Kim, Kyoung-Nam

2016-01-01

The aim of this study is to investigate the effects of cold atmospheric pressure plasma (CAP)-induced radicals on the epidermal growth factor receptor (EGFR), which is overexpressed by oral squamous cell carcinoma, to determine the underlying mechanism of selective killing. CAP-induced highly reactive radicals were observed in both plasma plume and cell culture media. The selective killing effect was observed in oral squamous cell carcinoma compared with normal human gingival fibroblast. Degradation and dysfunction of EGFRs were observed only in the EGFR-overexpressing oral squamous cell carcinoma and not in the normal cell. Nitric oxide scavenger pretreatment in cell culture media before CAP treatment rescued above degradation and dysfunction of the EGFR as well as the killing effect in oral squamous cell carcinoma. CAP may be a promising cancer treatment method by inducing EGFR dysfunction in EGFR-overexpressing oral squamous cell carcinoma via nitric oxide radicals.

Release of tumor necrosis factor alpha and interleukin 6 during antibiotic killing of Escherichia coli in whole blood: influence of antibiotic class, antibiotic concentration, and presence of septic serum

NARCIS (Netherlands)

Prins, J. M.; Kuijper, E. J.; Mevissen, M. L.; Speelman, P.; van Deventer, S. J.

1995-01-01

The concentration and accessibility of endotoxin can increase following antibiotic killing of gram-negative bacteria. There are indications that antibiotics may differ in this respect. We measured endotoxin levels in RPMI 1640 and tumor necrosis factor alpha (TNF-alpha) and interleukin-6 production

Adenoviral delivery of pan-caspase inhibitor p35 enhances bystander killing by P450 gene-directed enzyme prodrug therapy using cyclophosphamide+

International Nuclear Information System (INIS)

Doloff, Joshua C; Su, Ting; Waxman, David J

2010-01-01

Cytochrome P450-based suicide gene therapy for cancer using prodrugs such as cyclophosphamide (CPA) increases anti-tumor activity, both directly and via a bystander killing mechanism. Bystander cell killing is essential for the clinical success of this treatment strategy, given the difficulty of achieving 100% efficient gene delivery in vivo using current technologies. Previous studies have shown that the pan-caspase inhibitor p35 significantly increases CPA-induced bystander killing by tumor cells that stably express P450 enzyme CYP2B6 (Schwartz et al, (2002) Cancer Res. 62: 6928-37). To further develop this approach, we constructed and characterized a replication-defective adenovirus, Adeno-2B6/p35, which expresses p35 in combination with CYP2B6 and its electron transfer partner, P450 reductase. The expression of p35 in Adeno-2B6/p35-infected tumor cells inhibited caspase activation, delaying the death of the CYP2B6 'factory' cells that produce active CPA metabolites, and increased bystander tumor cell killing compared to that achieved in the absence of p35. Tumor cells infected with Adeno-2B6/p35 were readily killed by cisplatin and doxorubicin, indicating that p35 expression is not associated with acquisition of general drug resistance. Finally, p35 did not inhibit viral release when the replication-competent adenovirus ONYX-017 was used as a helper virus to facilitate co-replication and spread of Adeno-2B6/p35 and further increase CPA-induced bystander cell killing. The introduction of p35 into gene therapeutic regimens constitutes an effective approach to increase bystander killing by cytochrome P450 gene therapy. This strategy may also be used to enhance other bystander cytotoxic therapies, including those involving the production of tumor cell toxic protein products

Tumor immune evasion arises through loss of TNF sensitivity.

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Kearney, Conor J; Vervoort, Stephin J; Hogg, Simon J; Ramsbottom, Kelly M; Freeman, Andrew J; Lalaoui, Najoua; Pijpers, Lizzy; Michie, Jessica; Brown, Kristin K; Knight, Deborah A; Sutton, Vivien; Beavis, Paul A; Voskoboinik, Ilia; Darcy, Phil K; Silke, John; Trapani, Joseph A; Johnstone, Ricky W; Oliaro, Jane

2018-05-18

Immunotherapy has revolutionized outcomes for cancer patients, but the mechanisms of resistance remain poorly defined. We used a series of whole-genome clustered regularly interspaced short palindromic repeat (CRISPR)-based screens performed in vitro and in vivo to identify mechanisms of tumor immune evasion from cytotoxic lymphocytes [CD8 + T cells and natural killer (NK) cells]. Deletion of key genes within the tumor necrosis factor (TNF) signaling, interferon-γ (IFN-γ) signaling, and antigen presentation pathways provided protection of tumor cells from CD8 + T cell-mediated killing and blunted antitumor immune responses in vivo. Deletion of a number of genes in the TNF pathway also emerged as the key mechanism of immune evasion from primary NK cells. Our screens also identified that the metabolic protein 2-aminoethanethiol dioxygenase (Ado) modulates sensitivity to TNF-mediated killing by cytotoxic lymphocytes and is required for optimal control of tumors in vivo. Remarkably, we found that tumors delete the same genes when exposed to perforin-deficient CD8 + T cells, demonstrating that the dominant immune evasion strategy used by tumor cells is acquired resistance to T cell-derived cytokine-mediated antitumor effects. We demonstrate that TNF-mediated bystander killing is a potent T cell effector mechanism capable of killing antigen-negative tumor cells. In addition to highlighting the importance of TNF in CD8 + T cell- and NK cell-mediated killing of tumor cells, our study also provides a comprehensive picture of the roles of the TNF, IFN, and antigen presentation pathways in immune-mediated tumor surveillance. Copyright © 2018 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.

ANALYZE THE IMPACT OF HABITAT PATCHES ON WILDLIFE ROAD-KILL

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S. Seok

2015-10-01

Full Text Available The ecosystem fragmentation due to transportation infrastructure causes a road-kill phenomenon. When making policies for mitigating road-kill it is important to select target-species in order to enhance its efficiency. However, many wildlife crossing structures have been questioned regarding their effectiveness due to lack of considerations such as target-species selection, site selection, management, etc. The purpose of this study is to analyse the impact of habitat patches on wildlife road-kill and to suggest that spatial location of habitat patches should be considered as one of the important factors when making policies for mitigating road-kill. Habitat patches were presumed from habitat variables and a suitability index on target-species that was chosen by literature review. The road-kill hotspot was calculated using Getis-Ord Gi*. After that, we performed a correlation analysis between Gi Z-score and the distance from habitat patches to the roads. As a result, there is a low negative correlation between two variables and it increases the Gi Z-score if the habitat patches and the roads become closer.

Analyze the Impact of Habitat Patches on Wildlife Road-Kill

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Seok, S.; Lee, J.

2015-10-01

The ecosystem fragmentation due to transportation infrastructure causes a road-kill phenomenon. When making policies for mitigating road-kill it is important to select target-species in order to enhance its efficiency. However, many wildlife crossing structures have been questioned regarding their effectiveness due to lack of considerations such as target-species selection, site selection, management, etc. The purpose of this study is to analyse the impact of habitat patches on wildlife road-kill and to suggest that spatial location of habitat patches should be considered as one of the important factors when making policies for mitigating road-kill. Habitat patches were presumed from habitat variables and a suitability index on target-species that was chosen by literature review. The road-kill hotspot was calculated using Getis-Ord Gi*. After that, we performed a correlation analysis between Gi Z-score and the distance from habitat patches to the roads. As a result, there is a low negative correlation between two variables and it increases the Gi Z-score if the habitat patches and the roads become closer.

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

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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.

Indocyanine green loaded graphene oxide for high-efficient photoacoustic tumor therapy

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Baoyun Yan

2016-07-01

Full Text Available Photoacoustic therapy, using the photoacoustic effect of agents for selectively killing tumor cells, has shown promising for treating tumor. Utilization of high optical absorption probes can help to effectively improve the photoacoustic therapy efficiency. Herein, we report a novel high-absorption photoacoustic probe that is composed of indocyanine green (ICG and graphene oxide (GO, entitled GO-ICG, for photoacoustic therapy. The attached ICG with narrow absorption spectral profile has strong optical absorption in the infrared region. The absorption spectrum of the GO-ICG solution reveals that the GO-ICG particles exhibited a 10-fold higher absorbance at 780nm (its peak absorbance as compared with GO. Importantly, ICG’s fluorescence is quenched by GO via fluorescence resonance energy transfer. As a result, GO-ICG can high-efficiently convert the absorbed light energy to acoustic wave under pulsed laser irradiation. We further demonstrate that GO-ICG can produce stronger photoacoustic wave than the GO and ICG alone. Moreover, we conjugate this contrast agent with integrin αvβ3 mono-clonal antibody to molecularly target the U87-MG human glioblastoma cells for selective tumor cell killing. Finally, our results testify that the photoacoustic therapy efficiency of GO-ICG is higher than the existing photoacoustic therapy agent. Our work demonstrates that GO-ICG is a high-efficiency photoacoustic therapy agent. This novel photoacoustic probe is likely to be an available candidate for tumor therapy.

Selective Killing of Breast Cancer Cells by Doxorubicin-Loaded Fluorescent Gold Nanoclusters: Confocal Microscopy and FRET.

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Chattoraj, Shyamtanu; Amin, Asif; Jana, Batakrishna; Mohapatra, Saswat; Ghosh, Surajit; Bhattacharyya, Kankan

2016-01-18

Fluorescent gold nanoclusters (AuNCs) capped with lysozymes are used to deliver the anticancer drug doxorubicin to cancer and noncancer cells. Doxorubicin-loaded AuNCs cause the highly selective and efficient killing (90 %) of breast cancer cells (MCF7) (IC50 =155 nm). In contrast, the killing of the noncancer breast cells (MCF10A) by doxorubicin-loaded AuNCs is only 40 % (IC50 =4500 nm). By using a confocal microscope, the fluorescence spectrum and decay of the AuNCs were recorded inside the cell. The fluorescence maxima (at ≈490-515 nm) and lifetime (≈2 ns), of the AuNCs inside the cells correspond to Au10-13 . The intracellular release of doxorubicin from AuNCs is monitored by Förster resonance energy transfer (FRET) imaging. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

ANALYZE THE IMPACT OF HABITAT PATCHES ON WILDLIFE ROAD-KILL

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Seok, S.; Lee, J.

2015-01-01

The ecosystem fragmentation due to transportation infrastructure causes a road-kill phenomenon. When making policies for mitigating road-kill it is important to select target-species in order to enhance its efficiency. However, many wildlife crossing structures have been questioned regarding their effectiveness due to lack of considerations such as target-species selection, site selection, management, etc. The purpose of this study is to analyse the impact of habitat patches on wildlife road-...

Metformin kills and radiosensitizes cancer cells and preferentially kills cancer stem cells

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Song, Chang W.; Lee, Hyemi; Dings, Ruud P. M.; Williams, Brent; Powers, John; Santos, Troy Dos; Choi, Bo-Hwa; Park, Heon Joo

2012-01-01

The anti-cancer effects of metformin, the most widely used drug for type 2 diabetes, alone or in combination with ionizing radiation were studied with MCF-7 human breast cancer cells and FSaII mouse fibrosarcoma cells. Clinically achievable concentrations of metformin caused significant clonogenic death in cancer cells. Importantly, metformin was preferentially cytotoxic to cancer stem cells relative to non-cancer stem cells. Metformin increased the radiosensitivity of cancer cells in vitro, and significantly enhanced the radiation-induced growth delay of FSaII tumors (s.c.) in the legs of C3H mice. Both metformin and ionizing radiation activated AMPK leading to inactivation of mTOR and suppression of its downstream effectors such as S6K1 and 4EBP1, a crucial signaling pathway for proliferation and survival of cancer cells, in vitro as well as in the in vivo tumors. Conclusion: Metformin kills and radiosensitizes cancer cells and eradicates radioresistant cancer stem cells by activating AMPK and suppressing mTOR. PMID:22500211

Antimicrobial Activities and Time-Kill Kinetics of Extracts of Selected Ghanaian Mushrooms

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Theresa Appiah

2017-01-01

Full Text Available The rapid rise of antimicrobial resistance is a worldwide problem. This has necessitated the need to search for new antimicrobial agents. Mushrooms are rich sources of potential antimicrobial agents. This study investigated the antimicrobial properties of methanol extracts of Trametes gibbosa, Trametes elegans, Schizophyllum commune, and Volvariella volvacea. Agar well diffusion, broth microdilution, and time-kill kinetic assays were used to determine the antimicrobial activity of the extracts against selected test organisms. Preliminary mycochemical screening revealed the presence of tannins, flavonoids, triterpenoids, anthraquinones, and alkaloids in the extracts. Methanol extracts of T. gibbosa, T. elegans, S. commune, and V. volvacea showed mean zone of growth inhibition of 10.00±0.0 to 21.50±0.84, 10.00±0.0 to 22.00±1.10, 9.00±0.63 to 21.83±1.17, and 12.00±0.0 to 21.17±1.00 mm, respectively. The minimum inhibitory concentration of methanol extracts of T. gibbosa, T. elegans, S. commune, and V. volvacea ranged from 4.0 to 20, 6.0 to 30.0, 8.0 to 10.0, and 6.0 to 20.0 mg/mL, respectively. Time-kill kinetics studies showed that the extracts possess bacteriostatic action. Methanol extracts of T. gibbosa, T. elegans, S. commune, and V. volvacea exhibited antimicrobial activity and may contain bioactive compounds which may serve as potential antibacterial and antifungal agents.

Cuprous oxide nanoparticles selectively induce apoptosis of tumor cells

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Wang, Ye; Zi, Xiao-Yuan; Su, Juan; Zhang, Hong-Xia; Zhang, Xin-Rong; Zhu, Hai-Ying; Li, Jian-Xiu; Yin, Meng; Yang, Feng; Hu, Yi-Ping

2012-01-01

In the rapid development of nanoscience and nanotechnology, many researchers have discovered that metal oxide nanoparticles have very useful pharmacological effects. Cuprous oxide nanoparticles (CONPs) can selectively induce apoptosis and suppress the proliferation of tumor cells, showing great potential as a clinical cancer therapy. Treatment with CONPs caused a G1/G0 cell cycle arrest in tumor cells. Furthermore, CONPs enclosed in vesicles entered, or were taken up by mitochondria, which damaged their membranes, thereby inducing apoptosis. CONPs can also produce reactive oxygen species (ROS) and initiate lipid peroxidation of the liposomal membrane, thereby regulating many signaling pathways and influencing the vital movements of cells. Our results demonstrate that CONPs have selective cytotoxicity towards tumor cells, and indicate that CONPs might be a potential nanomedicine for cancer therapy. PMID:22679374

Recent Trends in Multifunctional Liposomal Nanocarriers for Enhanced Tumor Targeting

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Federico Perche

2013-01-01

Full Text Available Liposomes are delivery systems that have been used to formulate a vast variety of therapeutic and imaging agents for the past several decades. They have significant advantages over their free forms in terms of pharmacokinetics, sensitivity for cancer diagnosis and therapeutic efficacy. The multifactorial nature of cancer and the complex physiology of the tumor microenvironment require the development of multifunctional nanocarriers. Multifunctional liposomal nanocarriers should combine long blood circulation to improve pharmacokinetics of the loaded agent and selective distribution to the tumor lesion relative to healthy tissues, remote-controlled or tumor stimuli-sensitive extravasation from blood at the tumor’s vicinity, internalization motifs to move from tumor bounds and/or tumor intercellular space to the cytoplasm of cancer cells for effective tumor cell killing. This review will focus on current strategies used for cancer detection and therapy using liposomes with special attention to combination therapies.

Emergent Stratification in Solid Tumors Selects for Reduced Cohesion of Tumor Cells: A Multi-Cell, Virtual-Tissue Model of Tumor Evolution Using CompuCell3D.

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Maciej H Swat

Full Text Available Tumor cells and structure both evolve due to heritable variation of cell behaviors and selection over periods of weeks to years (somatic evolution. Micro-environmental factors exert selection pressures on tumor-cell behaviors, which influence both the rate and direction of evolution of specific behaviors, especially the development of tumor-cell aggression and resistance to chemotherapies. In this paper, we present, step-by-step, the development of a multi-cell, virtual-tissue model of tumor somatic evolution, simulated using the open-source CompuCell3D modeling environment. Our model includes essential cell behaviors, microenvironmental components and their interactions. Our model provides a platform for exploring selection pressures leading to the evolution of tumor-cell aggression, showing that emergent stratification into regions with different cell survival rates drives the evolution of less cohesive cells with lower levels of cadherins and higher levels of integrins. Such reduced cohesivity is a key hallmark in the progression of many types of solid tumors.

Tumor Cells Surviving Exposure to Proton or Photon Radiation Share a Common Immunogenic Modulation Signature, Rendering Them More Sensitive to T Cell–Mediated Killing

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Gameiro, Sofia R.; Malamas, Anthony S. [Laboratory of Tumor Immunology and Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland (United States); Bernstein, Michael B. [Division of Radiation Oncology, M. D. Anderson Cancer Center, Houston, Texas (United States); Tsang, Kwong Y. [Laboratory of Tumor Immunology and Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland (United States); Vassantachart, April; Sahoo, Narayan; Tailor, Ramesh; Pidikiti, Rajesh [Division of Radiation Oncology, M. D. Anderson Cancer Center, Houston, Texas (United States); Guha, Chandan P. [Department of Radiation Oncology, Montefiore Medical Center, Bronx, New York (United States); Hahn, Stephen M.; Krishnan, Sunil [Division of Radiation Oncology, M. D. Anderson Cancer Center, Houston, Texas (United States); Hodge, James W., E-mail: jh241d@nih.gov [Laboratory of Tumor Immunology and Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland (United States)

2016-05-01

Purpose: To provide the foundation for combining immunotherapy to induce tumor antigen–specific T cells with proton radiation therapy to exploit the activity of those T cells. Methods and Materials: Using cell lines of tumors frequently treated with proton radiation, such as prostate, breast, lung, and chordoma, we examined the effect of proton radiation on the viability and induction of immunogenic modulation in tumor cells by flow cytometric and immunofluorescent analysis of surface phenotype and the functional immune consequences. Results: These studies show for the first time that (1) proton and photon radiation induced comparable up-regulation of surface molecules involved in immune recognition (histocompatibility leukocyte antigen, intercellular adhesion molecule 1, and the tumor-associated antigens carcinoembryonic antigen and mucin 1); (2) proton radiation mediated calreticulin cell-surface expression, increasing sensitivity to cytotoxic T-lymphocyte killing of tumor cells; and (3) cancer stem cells, which are resistant to the direct cytolytic activity of proton radiation, nonetheless up-regulated calreticulin after radiation in a manner similar to non-cancer stem cells. Conclusions: These findings offer a rationale for the use of proton radiation in combination with immunotherapy, including for patients who have failed radiation therapy alone or have limited treatment options.

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

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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.

An evolved ribosome-inactivating protein targets and kills human melanoma cells in vitro and in vivo

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Green David E

2010-02-01

Full Text Available Abstract Background Few treatment options exist for patients with metastatic melanoma, resulting in poor prognosis. One standard treatment, dacarbazine (DTIC, shows low response rates ranging from 15 to 25 percent with an 8-month median survival time. The development of targeted therapeutics with novel mechanisms of action may improve patient outcome. Ribosome-inactivating proteins (RIPs such as Shiga-like Toxin 1 (SLT-1 represent powerful scaffolds for developing selective anticancer agents. Here we report the discovery and properties of a single chain ribosome-inactivating protein (scRIP derived from the cytotoxic A subunit of SLT-1 (SLT-1A, harboring the 7-amino acid peptide insertion IYSNKLM (termed SLT-1AIYSNKLM allowing the toxin variant to selectively target and kill human melanoma cells. Results SLT-1AIYSNKLM was able to kill 7 of 8 human melanoma cell lines. This scRIP binds to 518-A2 human melanoma cells with a dissociation constant of 18 nM, resulting in the blockage of protein synthesis and apoptosis in such cells. Biodistribution and imaging studies of radiolabeled SLT-1AIYSNKLM administered intravenously into SCID mice bearing a human melanoma xenograft indicate that SLT-1AIYSNKLM readily accumulates at the tumor site as opposed to non-target tissues. Furthermore, the co-administration of SLT-1AIYSNKLM with DTIC resulted in tumor regression and greatly increased survival in this mouse xenograft model in comparison to DTIC or SLT-1AIYSNKLM treatment alone (115 day median survival versus 46 and 47 days respectively; P values IYSNKLM is stable in serum and its intravenous administration resulted in modest immune responses following repeated injections in CD1 mice. Conclusions These results demonstrate that the evolution of a scRIP template can lead to the discovery of novel cancer cell-targeted compounds and in the case of SLT-1AIYSNKLM can specifically kill human melanoma cells in vitro and in vivo.

Anti-tumor effect of total body irradiation of low doses on WHT/Ht mice

International Nuclear Information System (INIS)

Miyamoto, Miyako; Sakamoto, Kiyohiko

1987-01-01

The effect of low dose (0.05 - 1.0 Gy) of total body irradiation (TBI) on non-tumor bearing and tumor bearing mice were investigated. Mice received TBI of 0.1 Gy during 6 - 12 hours before tumor cell inoculation demonstrated to need larger number of tumor cells (approximately 2.5 times) for 50 per cent tumor incidence, compared to recipient mice not to receive TBI. On the other hand, in tumor bearing mice given 0.1 Gy of TBI only tumor cell killing effect was not detected, however enhancement of tumor cell killing effect and prolonged growth delay were observed when tumor bearing mice were treated with 0.1 Gy of TBI in combined with local irradiation on tumors, especially cell killing effect was remarkable in dose range over 6 Gy of local exposure. The mechanism of the effect of 0.1 Gy TBI is considered to be host mediated reactions from the other our experimental results. (author)

Agentes antineoplásicos biorredutíveis: uma nova alternativa para o tratamento de tumores sólidos

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Oliveira Renata Barbosa de

2002-01-01

Full Text Available A problem often encountered in cancer therapy is the presence of tumor cell subpopulation that are resistant to treatment. Solid tumors frequently contain hypoxic cells that are resistant to killing by ionizing radiation and also by many chemotherapeutic agents. However, these hypoxic cells can be exploited for therapy by non-toxic hypoxic-activated prodrugs. Bioreductive drugs require metabolic reduction to generate cytotoxic metabolites. This process is facilitated by appropriate reductases and the lower oxygen conditions present in solid tumors. The unique presence of hypoxic cells in human tumors provides an important target for selective cancer therapy.

Patient-Derived Antibody Targets Tumor Cells

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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.

Tumor immunology

International Nuclear Information System (INIS)

Otter, W. den

1987-01-01

Tumor immunology, the use of immunological techniques for tumor diagnosis and approaches to immunotherapy of cancer are topics covered in this multi-author volume. Part A, 'Tumor Immunology', deals with present views on tumor-associated antigens, the initiation of immune reactions of tumor cells, effector cell killing, tumor cells and suppression of antitumor immunity, and one chapter dealing with the application of mathematical models in tumor immunology. Part B, 'Tumor Diagnosis and Imaging', concerns the use of markers to locate the tumor in vivo, for the histological diagnosis, and for the monitoring of tumor growth. In Part C, 'Immunotherapy', various experimental approaches to immunotherapy are described, such as the use of monoclonal antibodies to target drugs, the use of interleukin-2 and the use of drugs inhibiting suppression. In the final section, the evaluation, a pathologist and a clinician evaluate the possibilities and limitations of tumor immunology and the extent to which it is useful for diagnosis and therapy. refs.; figs.; tabs

Improving the selective cancer killing ability of ZnO nanoparticles using Fe doping.

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Thurber, Aaron; Wingett, Denise G; Rasmussen, John W; Layne, Janet; Johnson, Lydia; Tenne, Dmitri A; Zhang, Jianhui; Hanna, Charles B; Punnoose, Alex

2012-06-01

This work reports a new method to improve our recent demonstration of zinc oxide (ZnO) nanoparticles (NPs) selectively killing certain human cancer cells, achieved by incorporating Fe ions into the NPs. Thoroughly characterized cationic ZnO NPs (∼6 nm) doped with Fe ions (Zn(1-x )Fe (x) O, x = 0-0.15) were used in this work, applied at a concentration of 24 μg/ml. Cytotoxicity studies using flow cytometry on Jurkat leukemic cancer cells show cell viability drops from about 43% for undoped ZnO NPs to 15% for ZnO NPs doped with 7.5% Fe. However, the trend reverses and cell viability increases with higher Fe concentrations. The non-immortalized human T cells are markedly more resistant to Fe-doped ZnO NPs than cancerous T cells, confirming that Fe-doped samples still maintain selective toxicity to cancer cells. Pure iron oxide samples displayed no appreciable toxicity. Reactive oxygen species generated with NP introduction to cells increased with increasing Fe up to 7.5% and decreased for >7.5% doping.

Drug selection principles in intra-arterial infusion chemotherapy

International Nuclear Information System (INIS)

Wang Gefang; Cheng Yongde

2009-01-01

The intra-arterial infusion chemotherapy is an effective treatment for malignant tumors. The following ten principles should be taken into account when the choice of infusion medication is to be made. (1) The tumor-sensitive drugs should be selected. (2) Pay attention to the compatibility of medicines. (3) Select the type of drug compatibility and drug interactions. (4) Concentration-dependent drugs are the drugs of first choice. (5) Pay attention to side effects when anti-cancer drug compatibility is considered.(6) The perfusion anti-cancer drugs exert their killing effect on the tumor cells in their prototype. (7) Pay attention to the administration order of the drugs and the intervals of treatment. (8) The medication should be individualized as the physical condition and tumor's heterogeneity are different from patient to patient. It is one of the fundamental principles to formulate a specific scheme for every given patient. (9) Make full use of the pharmacokinetics features of the anti-cancer drugs in clinical practice. (10) To be familiar with commonly used drugs and common tumor chemotherapeutic formulae is a matter of cardinal significance. (authors)

Selection, calibration, and validation of models of tumor growth.

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Lima, E A B F; Oden, J T; Hormuth, D A; Yankeelov, T E; Almeida, R C

2016-11-01

This paper presents general approaches for addressing some of the most important issues in predictive computational oncology concerned with developing classes of predictive models of tumor growth. First, the process of developing mathematical models of vascular tumors evolving in the complex, heterogeneous, macroenvironment of living tissue; second, the selection of the most plausible models among these classes, given relevant observational data; third, the statistical calibration and validation of models in these classes, and finally, the prediction of key Quantities of Interest (QOIs) relevant to patient survival and the effect of various therapies. The most challenging aspects of this endeavor is that all of these issues often involve confounding uncertainties: in observational data, in model parameters, in model selection, and in the features targeted in the prediction. Our approach can be referred to as "model agnostic" in that no single model is advocated; rather, a general approach that explores powerful mixture-theory representations of tissue behavior while accounting for a range of relevant biological factors is presented, which leads to many potentially predictive models. Then representative classes are identified which provide a starting point for the implementation of OPAL, the Occam Plausibility Algorithm (OPAL) which enables the modeler to select the most plausible models (for given data) and to determine if the model is a valid tool for predicting tumor growth and morphology ( in vivo ). All of these approaches account for uncertainties in the model, the observational data, the model parameters, and the target QOI. We demonstrate these processes by comparing a list of models for tumor growth, including reaction-diffusion models, phase-fields models, and models with and without mechanical deformation effects, for glioma growth measured in murine experiments. Examples are provided that exhibit quite acceptable predictions of tumor growth in laboratory

Melanoma stem cells in experimental melanoma are killed by radioimmunotherapy

International Nuclear Information System (INIS)

Jandl, Thomas; Revskaya, Ekaterina; Jiang, Zewei; Harris, Matthew; Dorokhova, Olena; Tsukrov, Dina; Casadevall, Arturo; Dadachova, Ekaterina

2013-01-01

Introduction: In spite of recently approved B-RAF inhibitors and immunomodulating antibodies, metastatic melanoma has poor prognosis and novel treatments are needed. Melanoma stem cells (MSC) have been implicated in the resistance of this tumor to chemotherapy. Recently we demonstrated in a Phase I clinical trial in patients with metastatic melanoma that radioimmunotherapy (RIT) with 188-Rhenium( 188 Re)-6D2 antibody to melanin was a safe and effective modality. Here we investigated the interaction of MSC with RIT as a possible mechanism for RIT efficacy. Methods: Mice bearing A2058 melanoma xenografts were treated with either 1.5 mCi 188 Re-6D2 antibody, saline, unlabeled 6D2 antibody or 188 Re-labeled non-specific IgM. Results: On Day 28 post-treatment the tumor size in the RIT group was 4-times less than in controls (P < 0.001). The tumors were analyzed by immunohistochemistry and FACS for two MSC markers — chemoresistance mediator ABCB5 and H3K4 demethylase JARID1B. There were no significant differences between RIT and control groups in percentage of ABCB5 or JARID1B-positive cells in the tumor population. Our results demonstrate that unlike chemotherapy, which kills tumor cells but leaves behind MSC leading to recurrence, RIT kills MSC at the same rate as the rest of tumor cells. Conclusions: These results have two main implications for melanoma treatment and possibly other cancers. First, the susceptibility of ABCB5 + and JARID1B + cells to RIT in melanoma might be indicative of their susceptibility to antibody-targeted radiation in other cancers where they are present as well. Second, specifically targeting cancer stem cells with radiolabeled antibodies to ABCB5 or JARID1B might help to completely eradicate cancer stem cells in various cancers

Cuprous oxide nanoparticles selectively induce apoptosis of tumor cells

Directory of Open Access Journals (Sweden)

Wang Y

2012-05-01

Full Text Available Ye Wang,1,2,* Xiao-Yuan Zi,1,* Juan Su,1 Hong-Xia Zhang,1 Xin-Rong Zhang,3 Hai-Ying Zhu,1 Jian-Xiu Li,1 Meng Yin,3 Feng Yang,3 Yi-Ping Hu,11Department of Cell Biology, 2School of Clinical Medicine, 3Department of Pharmaceuticals, Second Military Medical University, Shanghai, People's Republic of China*Authors contributed equally.Abstract: In the rapid development of nanoscience and nanotechnology, many researchers have discovered that metal oxide nanoparticles have very useful pharmacological effects. Cuprous oxide nanoparticles (CONPs can selectively induce apoptosis and suppress the proliferation of tumor cells, showing great potential as a clinical cancer therapy. Treatment with CONPs caused a G1/G0 cell cycle arrest in tumor cells. Furthermore, CONPs enclosed in vesicles entered, or were taken up by mitochondria, which damaged their membranes, thereby inducing apoptosis. CONPs can also produce reactive oxygen species (ROS and initiate lipid peroxidation of the liposomal membrane, thereby regulating many signaling pathways and influencing the vital movements of cells. Our results demonstrate that CONPs have selective cytotoxicity towards tumor cells, and indicate that CONPs might be a potential nanomedicine for cancer therapy.Keywords: nanomedicine, selective cytotoxicity, apoptosis, cell cycle arrest, mitochondrion-targeted nanomaterials

Prairie dogs increase fitness by killing interspecific competitors.

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Hoogland, John L; Brown, Charles R

2016-03-30

Interspecific competition commonly selects for divergence in ecology, morphology or physiology, but direct observation of interspecific competition under natural conditions is difficult. Herbivorous white-tailed prairie dogs (Cynomys leucurus) employ an unusual strategy to reduce interspecific competition: they kill, but do not consume, herbivorous Wyoming ground squirrels (Urocitellus elegans) encountered in the prairie dog territories. Results from a 6-year study in Colorado, USA, revealed that interspecific killing of ground squirrels by prairie dogs was common, involving 47 different killers; 19 prairie dogs were serial killers in the same or consecutive years, and 30% of female prairie dogs killed at least one ground squirrel over their lifetimes. Females that killed ground squirrels had significantly higher annual and lifetime fitness than non-killers, probably because of decreased interspecific competition for vegetation. Our results document the first case of interspecific killing of competing individuals unrelated to predation (IK) among herbivorous mammals in the wild, and show that IK enhances fitness for animals living under natural conditions. © 2016 The Author(s).

The folate receptor as a molecular target for tumor-selective radionuclide delivery

International Nuclear Information System (INIS)

Ke, C.-Y.; Mathias, Carla J.; Green, Mark A.

2003-01-01

The cell-membrane folate receptor is a potential molecular target for tumor-selective drug delivery, including radiolabeled folate-chelate conjugates for diagnostic imaging. We review here some background on the folate receptor as tumor-associated molecular target for drug delivery, and briefly survey the literature on tumor-targeting with radiolabeled folate-chelate conjugates

Oroxin B selectively induces tumor-suppressive ER stress and concurrently inhibits tumor-adaptive ER stress in B-lymphoma cells for effective anti-lymphoma therapy

International Nuclear Information System (INIS)

Yang, Ping; Fu, Shilong; Cao, Zhifei; Liao, Huaidong; Huo, Zihe; Pan, Yanyan; Zhang, Gaochuan; Gao, Aidi; Zhou, Quansheng

2015-01-01

Cancer cells have both tumor-adaptive and -suppressive endoplasmic reticulum (ER) stress machineries that determine cell fate. In malignant tumors including lymphoma, constant activation of tumor-adaptive ER stress and concurrent reduction of tumor-suppressive ER stress favors cancer cell proliferation and tumor growth. Current ER stress-based anti-tumor drugs typically activate both tumor-adaptive and -suppressive ER stresses, resulting in low anti-cancer efficacy; hence, selective induction of tumor-suppressive ER stress and inhibition of tumor-adaptive ER stress are new strategies for novel anti-cancer drug discovery. Thus far, specific tumor-suppressive ER stress therapeutics have remained absent in clinical settings. In this study, we explored unique tumor-suppressive ER stress agents from the traditional Chinese medicinal herb Oroxylum indicum, and found that a small molecule oroxin B selectively induced tumor-suppressive ER stress in malignant lymphoma cells, but not in normal cells, effectively inhibited lymphoma growth in vivo, and significantly prolonged overall survival of lymphoma-xenografted mice without obvious toxicity. Mechanistic studies have revealed that the expression of key tumor-adaptive ER-stress gene GRP78 was notably suppressed by oroxin B via down-regulation of up-stream key signaling protein ATF6, while tumor-suppressive ER stress master gene DDIT3 was strikingly activated through activating the MKK3-p38 signaling pathway, correcting the imbalance between tumor-suppressive DDIT3 and tumor-adaptive GRP78 in lymphoma. Together, selective induction of unique tumor-suppressive ER stress and concurrent inhibition of tumor-adaptive ER stress in malignant lymphoma are new and feasible approaches for novel anti-lymphoma drug discovery and anti-lymphoma therapy. - Highlights: • Oroxin B selectively induces tumor-suppressive ER stress in B-lymphoma cells. • Oroxin B significantly prolonged overall survival of lymphoma-xenografted mice. �

Oroxin B selectively induces tumor-suppressive ER stress and concurrently inhibits tumor-adaptive ER stress in B-lymphoma cells for effective anti-lymphoma therapy

Energy Technology Data Exchange (ETDEWEB)

Yang, Ping; Fu, Shilong; Cao, Zhifei; Liao, Huaidong; Huo, Zihe; Pan, Yanyan; Zhang, Gaochuan; Gao, Aidi; Zhou, Quansheng, E-mail: zhouqs@suda.edu.cn

2015-10-15

Cancer cells have both tumor-adaptive and -suppressive endoplasmic reticulum (ER) stress machineries that determine cell fate. In malignant tumors including lymphoma, constant activation of tumor-adaptive ER stress and concurrent reduction of tumor-suppressive ER stress favors cancer cell proliferation and tumor growth. Current ER stress-based anti-tumor drugs typically activate both tumor-adaptive and -suppressive ER stresses, resulting in low anti-cancer efficacy; hence, selective induction of tumor-suppressive ER stress and inhibition of tumor-adaptive ER stress are new strategies for novel anti-cancer drug discovery. Thus far, specific tumor-suppressive ER stress therapeutics have remained absent in clinical settings. In this study, we explored unique tumor-suppressive ER stress agents from the traditional Chinese medicinal herb Oroxylum indicum, and found that a small molecule oroxin B selectively induced tumor-suppressive ER stress in malignant lymphoma cells, but not in normal cells, effectively inhibited lymphoma growth in vivo, and significantly prolonged overall survival of lymphoma-xenografted mice without obvious toxicity. Mechanistic studies have revealed that the expression of key tumor-adaptive ER-stress gene GRP78 was notably suppressed by oroxin B via down-regulation of up-stream key signaling protein ATF6, while tumor-suppressive ER stress master gene DDIT3 was strikingly activated through activating the MKK3-p38 signaling pathway, correcting the imbalance between tumor-suppressive DDIT3 and tumor-adaptive GRP78 in lymphoma. Together, selective induction of unique tumor-suppressive ER stress and concurrent inhibition of tumor-adaptive ER stress in malignant lymphoma are new and feasible approaches for novel anti-lymphoma drug discovery and anti-lymphoma therapy. - Highlights: • Oroxin B selectively induces tumor-suppressive ER stress in B-lymphoma cells. • Oroxin B significantly prolonged overall survival of lymphoma-xenografted mice. �

Selective tumor cell targeting by the disaccharide moiety of bleomycin.

Science.gov (United States)

Yu, Zhiqiang; Schmaltz, Ryan M; Bozeman, Trevor C; Paul, Rakesh; Rishel, Michael J; Tsosie, Krystal S; Hecht, Sidney M

2013-02-27

In a recent study, the well-documented tumor targeting properties of the antitumor agent bleomycin (BLM) were studied in cell culture using microbubbles that had been derivatized with multiple copies of BLM. It was shown that BLM selectively targeted MCF-7 human breast carcinoma cells but not the "normal" breast cell line MCF-10A. Furthermore, it was found that the BLM analogue deglycobleomycin, which lacks the disaccharide moiety of BLM, did not target either cell line, indicating that the BLM disaccharide moiety is necessary for tumor selectivity. Not resolved in the earlier study were the issues of whether the BLM disaccharide moiety alone is sufficient for tumor cell targeting and the possible cellular uptake of the disaccharide. In the present study, we conjugated BLM, deglycoBLM, and BLM disaccharide to the cyanine dye Cy5**. It was found that the BLM and BLM disaccharide conjugates, but not the deglycoBLM conjugate, bound selectively to MCF-7 cells and were internalized. The same was also true for the prostate cancer cell line DU-145 (but not for normal PZ-HPV-7 prostate cells) and for the pancreatic cancer cell line BxPC-3 (but not for normal SVR A221a pancreas cells). The targeting efficiency of the disaccharide was only slightly less than that of BLM in MCF-7 and DU-145 cells and comparable to that of BLM in BxPC-3 cells. These results establish that the BLM disaccharide is both necessary and sufficient for tumor cell targeting, a finding with obvious implications for the design of novel tumor imaging and therapeutic agents.

Essentials in clinical application of p53 for tumors intervention-example of liver cancer

International Nuclear Information System (INIS)

Guan Yongsong; He Qing

2008-01-01

Recombinant human adenovirus p53 (Ad-p53)injection has been used for treating tumors in combination with several local therapeutic methods. Taking liver cancer as an example, this article introduces the combination of Ad-p53 in procedures of interventional therapy. Mechanisms of their effects are emphasized to pursue an optimal synergism in killing tumors. Intratumoral injection is suggested as the first choice of Ad- p53 administration with the least recommended dosage for a single tumor. The optimal time for intervention of liver cancer is supposed to be 2 to 5 days after the administration of Ad-p53. There are several theories on the therapeutic method taking p53 as a target, some of them are contradictional; therefore one has to select either activating or inhibiting the p53 pathway beforehand. For advanced malignancies, the selection should be cautious for appropriater cases from the proper candidates. (authors)

Epirubicin-adsorbed nanodiamonds kill chemoresistant hepatic cancer stem cells.

Science.gov (United States)

Wang, Xin; Low, Xinyi Casuarine; Hou, Weixin; Abdullah, Lissa Nurrul; Toh, Tan Boon; Mohd Abdul Rashid, Masturah; Ho, Dean; Chow, Edward Kai-Hua

2014-12-23

Chemoresistance is a primary cause of treatment failure in cancer and a common property of tumor-initiating cancer stem cells. Overcoming mechanisms of chemoresistance, particularly in cancer stem cells, can markedly enhance cancer therapy and prevent recurrence and metastasis. This study demonstrates that the delivery of Epirubicin by nanodiamonds is a highly effective nanomedicine-based approach to overcoming chemoresistance in hepatic cancer stem cells. The potent physical adsorption of Epirubicin to nanodiamonds creates a rapidly synthesized and stable nanodiamond-drug complex that promotes endocytic uptake and enhanced tumor cell retention. These attributes mediate the effective killing of both cancer stem cells and noncancer stem cells in vitro and in vivo. Enhanced treatment of both tumor cell populations results in an improved impairment of secondary tumor formation in vivo compared with treatment by unmodified chemotherapeutics. On the basis of these results, nanodiamond-mediated drug delivery may serve as a powerful method for overcoming chemoresistance in cancer stem cells and markedly improving overall treatment against hepatic cancers.

Selective Inhibition of Tumor Growth by Clonal NK Cells Expressing an ErbB2/HER2-Specific Chimeric Antigen Receptor

Science.gov (United States)

Schönfeld, Kurt; Sahm, Christiane; Zhang, Congcong; Naundorf, Sonja; Brendel, Christian; Odendahl, Marcus; Nowakowska, Paulina; Bönig, Halvard; Köhl, Ulrike; Kloess, Stephan; Köhler, Sylvia; Holtgreve-Grez, Heidi; Jauch, Anna; Schmidt, Manfred; Schubert, Ralf; Kühlcke, Klaus; Seifried, Erhard; Klingemann, Hans G; Rieger, Michael A; Tonn, Torsten; Grez, Manuel; Wels, Winfried S

2015-01-01

Natural killer (NK) cells are an important effector cell type for adoptive cancer immunotherapy. Similar to T cells, NK cells can be modified to express chimeric antigen receptors (CARs) to enhance antitumor activity, but experience with CAR-engineered NK cells and their clinical development is still limited. Here, we redirected continuously expanding and clinically usable established human NK-92 cells to the tumor-associated ErbB2 (HER2) antigen. Following GMP-compliant procedures, we generated a stable clonal cell line expressing a humanized CAR based on ErbB2-specific antibody FRP5 harboring CD28 and CD3ζ signaling domains (CAR 5.28.z). These NK-92/5.28.z cells efficiently lysed ErbB2-expressing tumor cells in vitro and exhibited serial target cell killing. Specific recognition of tumor cells and antitumor activity were retained in vivo, resulting in selective enrichment of NK-92/5.28.z cells in orthotopic breast carcinoma xenografts, and reduction of pulmonary metastasis in a renal cell carcinoma model, respectively. γ-irradiation as a potential safety measure for clinical application prevented NK cell replication, while antitumor activity was preserved. Our data demonstrate that it is feasible to engineer CAR-expressing NK cells as a clonal, molecularly and functionally well-defined and continuously expandable cell therapeutic agent, and suggest NK-92/5.28.z cells as a promising candidate for use in adoptive cancer immunotherapy. PMID:25373520

Expression of Herpes Simplex Virus Thymidine Kinase/Ganciclovir by RNA Trans-Splicing Induces Selective Killing of HIV-Producing Cells

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Carin K. Ingemarsdotter

2017-06-01

Full Text Available Antiviral strategies targeting hijacked cellular processes are less easily evaded by the virus than viral targets. If selective for viral functions, they can have a high therapeutic index. We used RNA trans-splicing to deliver the herpes simplex virus thymidine kinase-ganciclovir (HSV-tk/GCV cell suicide system into HIV-producing cells. Using an extensive in silico bioinformatics and RNA structural analysis approach, ten HIV RNA trans-splicing constructs were designed targeting eight different HIV splice donor or acceptor sites and were tested in cells expressing HIV. Trans-spliced mRNAs were identified in HIV-expressing cells using qRT-PCR with successful detection of fusion RNA transcripts between HIV RNA and the HSV-tk RNA transcripts from six of ten candidate RNA trans-splicing constructs. Conventional PCR and Sanger sequencing confirmed RNA trans-splicing junctions. Measuring cell viability in the presence or absence of GCV expression of HSV-tk by RNA trans-splicing led to selective killing of HIV-producing cells using either 3′ exon replacement or 5′ exon replacement in the presence of GCV. Five constructs targeting four HIV splice donor and acceptor sites, D4, A5, A7, and A8, involved in regulating the generation of multiple HIV RNA transcripts proved to be effective for trans-splicing mediated selective killing of HIV-infected cells, within which individual constructs targeting D4 and A8 were the most efficient.

A novel gene therapy-based approach that selectively targets hypoxic regions within solid tumors

International Nuclear Information System (INIS)

Dougherty, S.T.; Dougherty, G.J.; Davis, P.D.

2003-01-01

There is compelling evidence that malignant cells present within the hypoxic regions that are commonly found within solid tumors contribute significantly to local recurrence following radiation therapy. We describe now a novel strategy designed to target such cells that exploits the differential production within hypoxic regions of the pro-angiogenic cytokine vascular endothelial cell growth factor (VEGF). Specifically, we have generated cDNA constructs that encode two distinct chimeric cell surface proteins that incorporate, respectively, the extracellular domains of the VEGF receptors Flk-1 or Flt-1, fused in frame to the membrane spanning and cytoplasmic domains of the pro-apoptotic protein Fas. Both chimeric proteins (Flk/Fas and Flt/Fas) appear stable and can be readily detected on the surface of transfected cells by Western blot and/or FACS analysis. Importantly, tumor cells expressing the chimeric proteins were rapidly killed in a dose-dependent fashion upon the addition of exogenous recombinant VEGF. Adenoviral vectors encoding Flk/Fas have been generated and shown to induce tumor cells to undergo apoptosis upon transfer to hypoxic conditions in vitro. This activity is dependent upon the endogenous production of VEGF. Studies are currently underway to test the ability of adenoviral Flk/Fas (Ad.Flk/Fas) to reduce tumor recurrence in vivo when used as an adjuvant therapy in conjunction with clinically relevant doses of ionizing radiation

Ruxolitinib synergizes with DMF to kill via BIM+BAD-induced mitochondrial dysfunction and via reduced SOD2/TRX expression and ROS.

Science.gov (United States)

Tavallai, Mehrad; Booth, Laurence; Roberts, Jane L; McGuire, William P; Poklepovic, Andrew; Dent, Paul

2016-04-05

We determined whether the myelofibrosis drug ruxolitinib, an inhibitor of Janus kinases 1/2 (JAK1 and JAK2), could interact with the multiple sclerosis drug dimethyl-fumarate (DMF) to kill tumor cells; studies used the in vivo active form of the drug, mono-methyl fumarate (MMF). Ruxolitinib interacted with MMF to kill brain, breast, lung and ovarian cancer cells, and enhanced the lethality of standard of care therapies such as paclitaxel and temozolomide. MMF also interacted with other FDA approved drugs to kill tumor cells including Celebrex® and Gilenya®. The combination of [ruxolitinib + MMF] inactivated ERK1/2, AKT, STAT3 and STAT5; reduced expression of MCL-1, BCL-XL, SOD2 and TRX; increased BIM expression; decreased BAD S112 S136 phosphorylation; and enhanced pro-caspase 3 cleavage. Expression of activated forms of STAT3, MEK1 or AKT each significantly reduced drug combination lethality; prevented BAD S112 S136 dephosphorylation and decreased BIM expression; and preserved TRX, SOD2, MCL-1 and BCL-XL expression. The drug combination increased the levels of reactive oxygen species in cells, and over-expression of TRX or SOD2 prevented drug combination tumor cell killing. Over-expression of BCL-XL or knock down of BAX, BIM, BAD or apoptosis inducing factor (AIF) protected tumor cells. The drug combination increased AIF : HSP70 co-localization in the cytosol but this event did not prevent AIF : eIF3A association in the nucleus.

Glycan elongation beyond the mucin associated Tn antigen protects tumor cells from immune-mediated killing.

Directory of Open Access Journals (Sweden)

Caroline B Madsen

Full Text Available Membrane bound mucins are up-regulated and aberrantly glycosylated during malignant transformation in many cancer cells. This results in a negatively charged glycoprotein coat which may protect cancer cells from immune surveillance. However, only limited data have so far demonstrated the critical steps in glycan elongation that make aberrantly glycosylated mucins affect the interaction between cancer cells and cytotoxic effector cells of the immune system. Tn (GalNAc-Ser/Thr, STn (NeuAcα2-6GalNAc-Ser/Thr, T (Galβ1-3GalNAc-Ser/Thr, and ST (NeuAcα2-6Galβ1-3GalNAc-Ser/Thr antigens are recognized as cancer associated truncated glycans, and are expressed in many adenocarcinomas, e.g. breast- and pancreatic cancer cells. To investigate the role of the cancer associated glycan truncations in immune-mediated killing we created glyco-engineered breast- and pancreatic cancer cells expressing only the shortest possible mucin-like glycans (Tn and STn. Glyco-engineering was performed by zinc finger nuclease (ZFN knockout (KO of the Core 1 enzyme chaperone COSMC, thereby preventing glycan elongation beyond the initial GalNAc residue in O-linked glycans. We find that COSMC KO in the breast and pancreatic cancer cell lines T47D and Capan-1 increases sensitivity to both NK cell mediated antibody-dependent cellular-cytotoxicity (ADCC and cytotoxic T lymphocyte (CTL-mediated killing. In addition, we investigated the association between total cell surface expression of MUC1/MUC16 and NK or CTL mediated killing, and observed an inverse correlation between MUC16/MUC1 expression and the sensitivity to ADCC and CTL-mediated killing. Together, these data suggest that up-regulation of membrane bound mucins protects cells from immune mediated killing, and that particular glycosylation steps, as demonstrated for glycan elongation beyond Tn and STn, can be important for fine tuning of the immune escape mechanisms in cancer cells.

The Killing

DEFF Research Database (Denmark)

Agger, Gunhild

2013-01-01

This article tracks the uncanny locations of The Killing (2007–2012), relating them to place, space and atmosphere, putting bits and pieces from the topographic puzzle together with cues from the symbolic space in order to see how they fit into the overall pattern of Nordic Noir. In The Killing......, the abstract level of space and atmosphere meets the concrete level of place, both influencing the notion of location. This meeting, I suggest, has contributed towards the simultaneous domestic and international appeal of The Killing....

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

Science.gov (United States)

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 (DC(8,9)PC). 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

Adoptively transferred human lung tumor specific cytotoxic T cells can control autologous tumor growth and shape tumor phenotype in a SCID mouse xenograft model

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Ferrone Soldano

2007-06-01

Full Text Available Abstract Background The anti-tumor efficacy of human immune effector cells, such as cytolytic T lymphocytes (CTLs, has been difficult to study in lung cancer patients in the clinical setting. Improved experimental models for the study of lung tumor-immune cell interaction as well as for evaluating the efficacy of adoptive transfer of immune effector cells are needed. Methods To address questions related to the in vivo interaction of human lung tumor cells and immune effector cells, we obtained an HLA class I + lung tumor cell line from a fresh surgical specimen, and using the infiltrating immune cells, isolated and characterized tumor antigen-specific, CD8+ CTLs. We then established a SCID mouse-human tumor xenograft model with the tumor cell line and used it to study the function of the autologous CTLs provided via adoptive transfer. Results The tumor antigen specific CTLs isolated from the tumor were found to have an activated memory phenotype and able to kill tumor cells in an antigen specific manner in vitro. Additionally, the tumor antigen-specific CTLs were fully capable of homing to and killing autologous tumors in vivo, and expressing IFN-γ, each in an antigen-dependent manner. A single injection of these CTLs was able to provide significant but temporary control of the growth of autologous tumors in vivo without the need for IL-2. The timing of injection of CTLs played an essential role in the outcome of tumor growth control. Moreover, immunohistochemical analysis of surviving tumor cells following CTL treatment indicated that the surviving tumor cells expressed reduced MHC class I antigens on their surface. Conclusion These studies confirm and extend previous studies and provide additional information regarding the characteristics of CTLs which can be found within a patient's tumor. Moreover, the in vivo model described here provides a unique window for observing events that may also occur in patients undergoing adoptive cellular

Treatment with 5-Aza-2'-Deoxycytidine Induces Expression of NY-ESO-1 and Facilitates Cytotoxic T Lymphocyte-Mediated Tumor Cell Killing.

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Agnes S Klar

Full Text Available NY-ESO-1 belongs to the cancer/testis antigen (CTA family and represents an attractive target for cancer immunotherapy. Its expression is induced in a variety of solid tumors via DNA demethylation of the promoter of CpG islands. However, NY-ESO-1 expression is usually very low or absent in some tumors such as breast cancer or multiple myeloma. Therefore, we established an optimized in vitro treatment protocol for up-regulation of NY-ESO-1 expression by tumor cells using the hypomethylating agent 5-aza-2'-deoxycytidine (DAC.We demonstrated de novo induction of NY-ESO-1 in MCF7 breast cancer cells and significantly increased expression in U266 multiple myeloma cells. This effect was time- and dose-dependent with the highest expression of NY-ESO-1 mRNA achieved by the incubation of 10 μM DAC for 72 hours. NY-ESO-1 activation was also confirmed at the protein level as shown by Western blot, flow cytometry, and immunofluorescence staining. The detection and quantification of single NY-ESO-1 peptides presented at the tumor cell surface in the context of HLA-A*0201 molecules revealed an increase of 100% and 50% for MCF7 and U266 cells, respectively. Moreover, the enhanced expression of NY-ESO-1 derived peptides at the cell surface was accompanied by an increased specific lysis of MCF7 and U266 cells by HLA-A*0201/NY-ESO-1(157-165 peptide specific chimeric antigen receptor (CAR CD8+ T cells. In addition, the killing activity of CAR T cells correlated with the secretion of higher IFN-gamma levels.These results indicate that NY-ESO-1 directed immunotherapy with specific CAR T cells might benefit from concomitant DAC treatment.

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

Science.gov (United States)

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 requirements...

Targeted killing with drones? Old arguments, new technologies

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Meisels Tamar

2018-01-01

Full Text Available The question of how to contend with terrorism in keeping with our preexisting moral and legal commitments now challenges Europe as well as Israel and the United States: how do we apply Just War Theory and International Law to asymmetrical warfare, specifically to our counter terrorism measures? What can the classic moral argument in Just and Unjust Wars teach us about contemporary targeted killings with drones? I begin with a defense of targeted killing, arguing for the advantages of pin pointed attacks over any alternative measure available for combatting terrorism. Assuming the legitimacy of killing combatants in wartime, I argue, there is nothing wrong, and in fact much that is right, with targeting particular terrorists selected by name, as long as their assassinations can be reasonably expected to reduce terrorist hostilities rather than increase it. Subsequently, I offer some further thoughts and comments on the use of remotely piloted aircrafts to carry out targeted killings, and address the various sources for discomfort with this practice identified by Michael Walzer and others.

Dietary branched-chain amino acid (BCAA) and tumor growth

Energy Technology Data Exchange (ETDEWEB)

Chan, W.; Baron, L.; Baron, P.; White, F.; Banks, W.L. Jr.

1986-03-05

The effects of high dietary BCAA on tumor growth was examined in adult male Fischer 344 rats inoculated with 10/sup 6/ viable MCA fibrosarcoma cells. Ten days after tumor inoculation, when tumors were of palpable size, rats were divided into two groups at random. The experimental(E) group was fed the AIN-76 diet supplemented with 4X the BCAA content of diet casein and the control(C) group was fed the AIN-76 made isonitrogenous with the E diet by glutamic acid supplementation. Five rats from each group were killed at days 0,3,6, and 9. Rats were injected with /sup 14/C-Tyrosine and /sup 3/H-Thymidine i.p. (2 and 4 uCi/100g BW, respectively) an hour before they were killed. The incorporation of /sup 14/C and /sup 3/H into the acid insoluble fraction of the tumor tissues samples were measured. Single cell suspension of tumor were prepared for cell cycle kinetics analysis using a Coulter EPICS IV flow microflorometer. The percentage of normal and hyperdiploid cells were analyzed. Results showed that both tumor size and weight were doubled at each time point the rats were killed. At day 0, the /sup 3/H and /sup 14/C incorporation were 32 +/- 10dpm and 27 +/- 4dpm/mg tumor, respectively. The /sup 3/H incorporation dropped in both diet groups at days 6 and 9 but the /sup 14/C incorporation showed a decrease only at day 9. These changes were statistically significant, P>0.05. No difference in the tumor growth parameters used in this study can be attributed to the high dietary BCAA.

Dietary branched-chain amino acid (BCAA) and tumor growth

International Nuclear Information System (INIS)

Chan, W.; Baron, L.; Baron, P.; White, F.; Banks, W.L. Jr.

1986-01-01

The effects of high dietary BCAA on tumor growth was examined in adult male Fischer 344 rats inoculated with 10 6 viable MCA fibrosarcoma cells. Ten days after tumor inoculation, when tumors were of palpable size, rats were divided into two groups at random. The experimental(E) group was fed the AIN-76 diet supplemented with 4X the BCAA content of diet casein and the control(C) group was fed the AIN-76 made isonitrogenous with the E diet by glutamic acid supplementation. Five rats from each group were killed at days 0,3,6, and 9. Rats were injected with 14 C-Tyrosine and 3 H-Thymidine i.p. (2 and 4 uCi/100g BW, respectively) an hour before they were killed. The incorporation of 14 C and 3 H into the acid insoluble fraction of the tumor tissues samples were measured. Single cell suspension of tumor were prepared for cell cycle kinetics analysis using a Coulter EPICS IV flow microflorometer. The percentage of normal and hyperdiploid cells were analyzed. Results showed that both tumor size and weight were doubled at each time point the rats were killed. At day 0, the 3 H and 14 C incorporation were 32 +/- 10dpm and 27 +/- 4dpm/mg tumor, respectively. The 3 H incorporation dropped in both diet groups at days 6 and 9 but the 14 C incorporation showed a decrease only at day 9. These changes were statistically significant, P>0.05. No difference in the tumor growth parameters used in this study can be attributed to the high dietary BCAA

Selective tumor irradiation by infusional brachytherapy in nonresectable pancreatic cancer: a phase I study

International Nuclear Information System (INIS)

Order, Stanley E.; Siegel, Jeffry A.; Principato, Robert; Zeiger, Louis E.; Johnson, Elizabeth; Lang, Patricia; Lustig, Robert; Wallner, Paul E.

1996-01-01

Purpose: Selective high-dose radiation of solid tumors has been a goal of radiation oncology. The physiological barriers of solid tumors (high interstitial tumor pressure, reduced tumor vascularity, and poor perfusion) have been major barriers in achieving significant tumor dose of systemically infused radioconjugates. Direct tumor infusional brachytherapy overcomes these barriers and leads to selective high tumor doses. Methods and Materials: The development of interstitial tumor infusion of macroaggregated albumin (MAA) followed by colloidal chromic phosphate 32 P has overcome solid tumor obstacles in 47 patients with nonresectable pancreatic cancer in a Phase I dose escalation study. The colloidal 32 P infusion was followed by external radiation and five fluorouracil. Results: Of the 28 patients with cancer limited to the pancreas, 15 of 16 patients retained 86-100% (mean 96%) of the infused colloidal 32 P isotope. While the other 12 patients had partial shunting to the liver, shunting to the liver was due to high interstitial resistance with tumor dose deposition of 17-88% (mean 52%). Of the 19 patients with metastatic pancreas cancer, colloidal 32 P tumor deposition ranged from 22 to 100% of the infused dose (mean 79%). The less than optimal tumor deposition led to our increasing the MAA from 600,000 to 1.5-2.5 million particles. Interstitial dexamethasone 2 mg and later 4 mg was infused first and prevented liver shunting by somehow reducing tumor resistance. The median survival in 28 Phase I patients with nonresectable pancreas cancer without metastasis, was 12 months. No significant toxicity occurred when treatment was limited to two infusions with as much as 30 mCi each. The maximum tumor dose was 17,000 Gy (1.700,000 cGy). In 19 non-resectable pancreatic cancer patients with metastasis, a 6.9 months median survival was observed. Conclusions: Infusional brachytherapy is an outpatient procedure that delivers high-dose radiation selectively to pancreatic

Systematic Analysis of Time-Series Gene Expression Data on Tumor Cell-Selective Apoptotic Responses to HDAC Inhibitors

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Yun-feng Qi

2014-01-01

Full Text Available SAHA (suberoylanilide hydroxamic acid or vorinostat is the first nonselective histone deacetylase (HDAC inhibitor approved by the US Food and Drug Administration (FDA. SAHA affects histone acetylation in chromatin and a variety of nonhistone substrates, thus influencing many cellular processes. In particularly, SAHA induces selective apoptosis of tumor cells, although the mechanism is not well understood. A series of microarray experiments was recently conducted to investigate tumor cell-selective proapoptotic transcriptional responses induced by SAHA. Based on that gene expression time series, we propose a novel framework for detailed analysis of the mechanism of tumor cell apoptosis selectively induced by SAHA. Our analyses indicated that SAHA selectively disrupted the DNA damage response, cell cycle, p53 expression, and mitochondrial integrity of tumor samples to induce selective tumor cell apoptosis. Our results suggest a possible regulation network. Our research extends the existing research.

Can dendritic cells improve whole cancer cell vaccines based on immunogenically killed cancer cells?

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Cicchelero, Laetitia; Denies, Sofie; Devriendt, Bert; de Rooster, Hilde; Sanders, Niek N

2015-01-01

Immunogenic cell death (ICD) offers interesting opportunities in cancer cell (CC) vaccine manufacture, as it increases the immunogenicity of the dead CC. Furthermore, fusion of CCs with dendritic cells (DCs) is considered a superior method for generating whole CC vaccines. Therefore, in this work, we determined in naive mice whether immunogenically killed CCs per se (CC vaccine) elicit an antitumoral immune response different from the response observed when immunogenically killed CCs are associated with DCs through fusion (fusion vaccine) or through co-incubation (co-incubation vaccine). After tumor inoculation, the type of immune response in the prophylactically vaccinated mice differed between the groups. In more detail, fusion vaccines elicited a humoral anticancer response, whereas the co-incubation and CC vaccine mainly induced a cellular response. Despite these differences, all three approaches offered a prophylactic protection against tumor development in the murine mammary carcinoma model. In summary, it can be concluded that whole CC vaccines based on immunogenically killed CCs may not necessarily require association with DCs to elicit a protective anticancer immune response. If this finding can be endorsed in other cancer models, the manufacture of CC vaccines would greatly benefit from this new insight, as production of DC-based vaccines is laborious, time-consuming and expensive. PMID:26587315

Determination of the Mutant Selection Window and Evaluation of the Killing of Mycoplasma gallisepticum by Danofloxacin, Doxycycline, Tilmicosin, Tylvalosin and Valnemulin

OpenAIRE

Zhang, Nan; Ye, Xiaomei; Wu, Yuzhi; Huang, Zilong; Gu, Xiaoyan; Cai, Qinren; Shen, Xiangguang; Jiang, Hongxia; Ding, Huanzhong

2017-01-01

Mycoplasma gallisepticum is a common etiological cause of a chronic respiratory disease in chickens; its increasing antimicrobial resistance compromises the use of tetracyclines, macrolides and quinolones in the farm environment. Mutant selection window (MSW) determination was used to investigate the propensity for future resistance induction by danofloxacin, doxycycline, tilmicosin, tylvalosin and valnemulin. Killing of M. gallisepticum strain S6 by these antimicrobials was also studied by i...

Constructing TC-1-GLUC-LMP2 Model Tumor Cells to Evaluate the Anti-Tumor Effects of LMP2-Related Vaccines

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Sun, Liying; Hao, Yanzhe; Wang, Zhan; Zeng, Yi

2018-01-01

Epstein-Barr virus (EBV) is related to a variety of malignant tumors, and its encoded protein, latent membrane protein 2 (LMP2), is an effective target antigen that is widely used to construct vector vaccines. However, the model cells carrying LMP2 have still not been established to assess the oncolytic effect of LMP2-related vaccines at present. In this study, TC-1-GLUC-LMP2 tumor cells were constructed as target cells to evaluate the anti-tumor effects of LMP2-assosiated vaccines. The results showed that both LMP2 and Gaussia luciferase (GLuc) genes could be detected by polymerase chain reaction (PCR) and reverse transcription-polymerase chain reaction (RT-PCR) in TC-1-GLUC-LMP2 cells. Western blot results showed that the LMP2 and Gaussia luciferase proteins were stably expressed in tumor cells for at least 30 generations. We mixed 5 × 104 LMP2-specific mouse splenic lymphocytes with 5 × 103 TC-1-GLUC-LMP2 target cells and found that the target cells were killed as the specific killing effect was obviously enhanced by the increased quantities of LMP2-peptide stimulated spleens. Furthermore, the tumor cells could not be observed in the mice inoculated TC-1-GLUC-LMP2 cells after being immunized with vaccine-LMP2, while the vaccine-NULL immunized mice showed that tumor volume gradually grew with increased inoculation time. These results indicated that the TC-1-GLUC-LMP2 cells stably expressing LMP2 and GLuc produced tumors in mice, and that the LMP2-specific cytotoxic T lymphocyte (CTL) effectively killed the cells in vitro and in vivo, suggesting that TC-1-GLUC-LMP2 cells can be used as model cells to assess the immune and antitumor effects of LMP2-related vaccines. PMID:29570629

A novel bispecific antibody, S-Fab, induces potent cancer cell killing.

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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.

Psychological traits underlying different killing methods among Malaysian male murderers.

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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

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

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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

Cancer vaccines: the challenge of developing an ideal tumor killing system.

Science.gov (United States)

Mocellin, Simone

2005-09-01

Despite the evidence that the immune system plays a significant role in controlling tumor growth in natural conditions and in response to therapeutic vaccination, cancer cells can survive their attack as the disease progresses and no vaccination regimen should be currently proposed to patients outside experimental clinical trials. Clinical results show that the immune system can be actively polarized against malignant cells by means of a variety of vaccination strategies, and that in some cases this is associated with tumor regression. This implies that under some unique circumstances, the naturally "dormant" immune effectors can actually be put at work and used as endogenous weapons against malignant cells. Consequently, the main challenge of tumor immunologists appears to lie on the ability of reproducing those conditions in a larger set of patients. The complexity of the immune network and the still enigmatic host-tumor interactions make these tasks at the same time challenging and fascinating. Recent tumor immunology findings are giving new impetus to the development of more effective vaccination strategies and might revolutionize the way of designing the next generation of cancer vaccines. In the near future, the implementation of these insights in the clinical setting and the completion/conduction of comparative randomized phase III trials will allow oncologists to define the actual role of cancer vaccines in the fight against malignancy.

Immune selection of tumor cells in TCR β-chain transgenic mice.

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Silaeva, Yulia Yu; Grinenko, Tatyana S; Vagida, Murad S; Kalinina, Anastasia A; Khromykh, Ludmila M; Kazansky, Dmitry B

2014-10-01

The concept of immunological surveillance implies that immunogenic variants of tumor cells arising in the organism can be recognized by the immune system. Tumor progression is provided by somatic evolution of tumor cells under the pressure of the immune system. The loss of MHC Class I molecules on the surface of tumor cells is one of the most known outcomes of immune selection. This study developed a model of immune selection based on the immune response of TCR 1d1 single β-chain transgenic B10.D2(R101) (K(d)I(d)D(b)) mice to allogeneic EL4 (H-2(b)) thymoma cells. In wild-type B10.D2(R101) mice, immunization with EL4 cells induced a vigorous CTL response targeted to the H-2K(b) molecule and results in full rejection of the tumor cells. In contrast, transgenic mice developed a compromised proliferative response in mixed-lymphocyte response assays and were unable to reject transplanted allogeneic EL4 cells. During the immune response to EL4 cells, CD8(+) T-lymphocytes with endogenous β-chains accumulated predominantly in the spleen of transgenic mice and only a small part of the T-lymphocytes expressing transgenic β-chains became CD8(+)CD44(+)CD62L(-) effectors. Then, instead of a full elimination of tumor cells as in wild-type mice, a reproducible prolonged equilibrium phase and subsequent escape was observed in transgenic mice that resulted in death of 90% of the mice in 40-60 days after grafting. Prolonged exposure of tumor cells to the pressure of the immune system in transgenic mice in vivo resulted in a stable loss of H-2K(b) molecules on the EL4 cell surface. Genetic manipulation of the T-lymphocyte repertoire was sufficient to reproduce the classic pattern of interactions between tumor cells and the immune system, usually observed in reliable syngeneic models of anti-tumor immunity. This newly-developed model could be used in further studies of immunoregulatory circuits common for transplantational and anti-tumor immune responses.

Determination of cytotoxicity in vivo using 111Indium-labelled human tumor cells

International Nuclear Information System (INIS)

Lockshin, Arnold; Giovanella, B.C.; Kolielski, Tony; Stehlin, J.S. Jr.

1984-01-01

Loss of radioactivity from nude mice was determined after inoculation of human tumor cells prelabelled with ( 111 In)indium oxine ( 111 InOx). Elimination of 111 In was increased somewhat by treating the mice with diphtheria toxin (DT), which is toxic selectively for human cells compared to mice. Calcium disodium edetate (CaNa 2 EDTA), a metal chelating agent, facilitated elimination of 111 In and increased the difference in the rates of loss of radioactivity from mice bearing viable compared to DT-killed cells. (author)

Killing Range

Science.gov (United States)

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

Hybrid Calcium Phosphate-Polymeric Micelles Incorporating Gadolinium Chelates for Imaging-Guided Gadolinium Neutron Capture Tumor Therapy.

Science.gov (United States)

Mi, Peng; Dewi, Novriana; Yanagie, Hironobu; Kokuryo, Daisuke; Suzuki, Minoru; Sakurai, Yoshinori; Li, Yanmin; Aoki, Ichio; Ono, Koji; Takahashi, Hiroyuki; Cabral, Horacio; Nishiyama, Nobuhiro; Kataoka, Kazunori

2015-06-23

Gadolinium (Gd) chelates-loaded nanocarriers have high potential for achieving magnetic resonance imaging (MRI)-guided Gd neutron capture therapy (GdNCT) of tumors. Herein, we developed calcium phosphate micelles hybridized with PEG-polyanion block copolymers, and incorporated with the clinical MRI contrast agent Gd-diethylenetriaminepentaacetic acid (Gd-DTPA/CaP). The Gd-DTPA/CaP were nontoxic to cancer cells at the concentration of 100 μM based on Gd-DTPA, while over 50% of the cancer cells were killed by thermal neutron irradiation at this concentration. Moreover, the Gd-DTPA/CaP showed a dramatically increased accumulation of Gd-DTPA in tumors, leading to the selective contrast enhancement of tumor tissues for precise tumor location by MRI. The enhanced tumor-to-blood distribution ratio of Gd-DTPA/CaP resulted in the effective suppression of tumor growth without loss of body weight, indicating the potential of Gd-DTPA/CaP for safe cancer treatment.

Killing-Yano tensors, rank-2 Killing tensors, and conserved quantities in higher dimensions

Energy Technology Data Exchange (ETDEWEB)

Krtous, Pavel [Institute of Theoretical Physics, Charles University, V Holesovickach 2, Prague (Czech Republic); Kubiznak, David [Institute of Theoretical Physics, Charles University, V Holesovickach 2, Prague (Czech Republic); Page, Don N. [Theoretical Physics Institute, University of Alberta, Edmonton T6G 2G7, Alberta (Canada); Frolov, Valeri P. [Theoretical Physics Institute, University of Alberta, Edmonton T6G 2G7, Alberta (Canada)

2007-02-15

From the metric and one Killing-Yano tensor of rank D-2 in any D-dimensional spacetime with such a principal Killing-Yano tensor, we show how to generate k = [(D+1)/2] Killing-Yano tensors, of rank D-2j for all 0 {<=} j {<=} k-1, and k rank-2 Killing tensors, giving k constants of geodesic motion that are in involution. For the example of the Kerr-NUT-AdS spacetime (hep-th/0604125) with its principal Killing-Yano tensor (gr-qc/0610144), these constants and the constants from the k Killing vectors give D independent constants in involution, making the geodesic motion completely integrable (hep-th/0611083). The constants of motion are also related to the constants recently obtained in the separation of the Hamilton-Jacobi and Klein-Gordon equations (hep-th/0611245)

Killing-Yano tensors, rank-2 Killing tensors, and conserved quantities in higher dimensions

International Nuclear Information System (INIS)

Krtous, Pavel; Kubiznak, David; Page, Don N.; Frolov, Valeri P.

2007-01-01

From the metric and one Killing-Yano tensor of rank D-2 in any D-dimensional spacetime with such a principal Killing-Yano tensor, we show how to generate k = [(D+1)/2] Killing-Yano tensors, of rank D-2j for all 0 ≤ j ≤ k-1, and k rank-2 Killing tensors, giving k constants of geodesic motion that are in involution. For the example of the Kerr-NUT-AdS spacetime (hep-th/0604125) with its principal Killing-Yano tensor (gr-qc/0610144), these constants and the constants from the k Killing vectors give D independent constants in involution, making the geodesic motion completely integrable (hep-th/0611083). The constants of motion are also related to the constants recently obtained in the separation of the Hamilton-Jacobi and Klein-Gordon equations (hep-th/0611245)

Sensitive and selective tumor imaging with novel and highly activatable fluorescence probes

International Nuclear Information System (INIS)

Urano, Yasuteru

2008-01-01

Selective and sensitive tumor imaging in vivo is one of the most requested methodologies in medical sciences. Although several imaging modalities have been developed including positron emission tomography (PET) and magnetic resonance (MR) imaging for the detection of tumors, none of these modalities can activate the signals upon being accumulated or uptaken to tumor sites. Among these modalities, only optical fluorescence imaging has a marked advantage, that is, their signals can be dramatically increased upon detecting some biological features. In this short review, I will introduce some recent strategies for activatable optical fluorescence imaging of tumors, and discuss their advantages over other modalities. (author)

Selective killing of cancer cells by leaf extract of Ashwagandha: components, activity and pathway analyses.

Science.gov (United States)

Widodo, Nashi; Takagi, Yasuomi; Shrestha, Bhupal G; Ishii, Tetsuro; Kaul, Sunil C; Wadhwa, Renu

2008-04-08

Ashwagandha, also called as "Queen of Ayurveda" and "Indian ginseng", is a commonly used plant in Indian traditional medicine, Ayurveda. Its roots have been used as herb remedy to treat a variety of ailments and to promote general wellness. However, scientific evidence to its effects is limited to only a small number of studies. We had previously identified anti-cancer activity in the leaf extract (i-Extract) of Ashwagandha and demonstrated withanone as a cancer inhibitory factor (i-Factor). In the present study, we fractionated the i-Extract to its components by silica gel column chromatography and subjected them to cell based activity analyses. We found that the cancer inhibitory leaf extract (i-Extract) has, at least, seven components that could cause cancer cell killing; i-Factor showed the highest selectivity for cancer cells and i-Factor rich Ashwagandha leaf powder was non-toxic and anti-tumorigenic in mice assays. We undertook a gene silencing and pathway analysis approach and found that i-Extract and its components kill cancer cells by at least five different pathways, viz. p53 signaling, GM-CFS signaling, death receptor signaling, apoptosis signaling and G2-M DNA damage regulation pathway. p53 signaling was most common. Visual analysis of p53 and mortalin staining pattern further revealed that i-Extract, fraction F1, fraction F4 and i-Factor caused an abrogation of mortalin-p53 interactions and reactivation of p53 function while the fractions F2, F3, F5 work through other mechanisms.

Tumor vascular-targeted co-delivery of anti-angiogenesis and chemotherapeutic agents by mesoporous silica nanoparticle-based drug delivery system for synergetic therapy of tumor

Directory of Open Access Journals (Sweden)

Li X

2015-12-01

Full Text Available Xiaoyu Li, Meiying Wu, Limin Pan, Jianlin Shi State Key Laboratory of High Performance Ceramics and Superfine Microstructure, Shanghai Institute of Ceramics, Chinese Academy of Sciences, Shanghai, People’s Republic of China Abstract: To overcome the drawback of drug non-selectivity in traditional chemotherapy, the construction of multifunctional targeting drug delivery systems is one of the most effective and prevailing approaches. The intratumoral anti-angiogenesis and the tumor cell-killing are two basic approaches in fighting tumors. Herein we report a novel tumor vascular-targeting multidrug delivery system using mesoporous silica nanoparticles as carrier to co-load an antiangiogenic agent (combretastatin A4 and a chemotherapeutic drug (doxorubicin and conjugate with targeting molecules (iRGD peptide for combined anti-angiogenesis and chemotherapy. Such a dual-loaded drug delivery system is capable of delivering the two agents at tumor vasculature and then within tumors through a differentiated drug release strategy, which consequently results in greatly improved antitumor efficacy at a very low doxorubicin dose of 1.5 mg/kg. The fast release of the antiangiogenic agent at tumor vasculatures led to the disruption of vascular structure and had a synergetic effect with the chemotherapeutic drug slowly released in the following delivery of chemotherapeutic drug into tumors. Keywords: mesoporous silica nanoparticles, drug delivery, tumor vasculatures targeting, antiangiogenic agent

A conceptual design of neutron tumor therapy reactor facility with a YAYOI based fast neutron source reactor

International Nuclear Information System (INIS)

Wakabayashi, Hiroaki; An, Shigehiro.

1983-01-01

Fast neutron is known as one of useful radiations for radiation therapy of tumors. Boron neutron capture therapy (BNCT) of tumors which makes use of 10 B(n, α) 7 Li reaction of 10 B compounds selectively attached to tumor cells with thermal and intermediate neutrons is another way of neutron based radiation therapy which is, above all, attractive enough to kill tumor cells selectively sparing normal tissue. In Japan, BNCT has already been applied and leaned to be effective. After more than a decade operational experiences and the specific experiments designed for therapeutical purposes, in this paper, a conceptual design of a special neutron therapy reactor facility based on YAYOI - fast neutron source reactor of Nuclear Engineering Research Laboratory, Faculty of Engineering, the University of Tokyo - modified to provide an upward beam of fast and intermediate neutrons is presented. Emphasis is placed on the in-house nature of facility and on the coordinating capability of biological and physical researches as well as maintenances of the facility. (author)

Evaluation of texaphyrins as tumor selective radiation sensitizers

International Nuclear Information System (INIS)

Qing Fan; Woodburn, Kathryn W.; Young, Stuart W.

1997-01-01

Texaphyrins are expanded porphyrin macrocycles that selectively localize and are retained in cancerous lesions. The function of the texaphyrin can be manipulated by the incorporation of different metal ions into the macrocycle's central cavity. Gadolinium texaphyrin (Gd-Tex) and lutetium texaphyrin (Lu-Tex) were evaluated as radiation sensitizers. Radiation sensitization studies were performed using SMT-F and EMT6 mammary tumor-bearing mice. Single and multifraction dose regimens were performed. SMT-F bearing DBA/2N mice and EMT6 bearing Balb/c mice were intravenously administered with Gd-Tex of Lu-Tex (5-40 μmol/kg) 30 minutes to 5 hours prior to radiation (10-50 Gray) for the single fraction studies. The more radioresistant EMT-6 sarcoma model was used for the multifraction studies. The tumor bearing animals were injected with Gd-Tex (5, 20, or 40 μmol/kg) to 2 hours prior radiation (1, 2, or 4 Gray), this regimen was performed for five consecutive days. Gd-Tex is paramagnetic and has a strong fluorescence signal. Tumor selectivity was determined by MRI and fluorescence spectral imaging before and up to 24 hours following the administration of Gd-Tex. Gd-Tex but not Lu-Tex, proved to be an effective radiation sensitizer. Administration of Gd-Tex (40 μmol/kg) prior to a single dose of 30 Gray radiation provided a significant improvement in survival in SMT-F-bearing DBA/2N mice as compared to animals receiving radiation alone (p = 0.0034). A significant radiation sensitization effect was also found in multiple fraction studies (five consecutive days) with Balb/C mice bearing EMT-6 neoplasma-- following 1 Gray of radiation for 5 days there was a significant difference between the 20 and 40 μmol/kg group and controls (p = 0.003, p = 0.005 respectively). MRI and fluorescence spectral imaging studies of tumor bearing animals revealed excellent contrast enhancement of the tumor which persisted up to 24 hours. Texaphyrins localize in neoplasms as visualized using MRI

Continued biological investigations of boron-rich oligomeric phosphate diesters (OPDs). Tumor-selective boron agents for BNCT

International Nuclear Information System (INIS)

Lee, Mark W.; Shelly, Kenneth; Kane, Robert R.; Hawthorne, M. Frederick

2006-01-01

Clinical success of Boron Neutron Capture Therapy will rely on the selective intracellular delivery of high concentrations of boron-10 to tumor tissue. In order for a boron agent to facilitate clinical success, the simultaneous needs of obtaining a high tumor dose, high tumor selectivity, and low systemic toxicity must be realized. Boron-rich oligomeric phosphate diesters (OPDs) are a class of highly water-soluble compounds containing up to 40% boron by weight. Previous work in our groups demonstrated that once placed in the cytoplasm of tumor cells, OPDs quickly accumulate within the cell nucleus. The objective of the current study was to determine the biodistribution of seven different free OPDs in BALB/c mice bearing EMT6 tumors. Fructose solutions containing between 1.4 and 6.4 micrograms of boron per gram of tissue were interveinously injected in mice seven to ten days after tumor implantation. At intervals during the study, animals were euthanized and samples of tumor, blood, liver, kidney, brain and skin were collected and analyzed for boron content using ICP-AES. Tumor boron concentrations of between 5 and 29 ppm were achieved and maintained over the 72-hour time course of each experiment. Several OPDs demonstrated high tumor selectivity with one oligomer exhibiting a tumor to blood ratio of 35:1. The apparent toxicity of each oligomer was assessed through animal behavior during the experiment and necropsy of each animal upon sacrifice. (author)

Mathematical models of tumor growth: translating absorbed dose to tumor control probability

International Nuclear Information System (INIS)

Sgouros, G.

1996-01-01

Full text: The dose-rate in internal emitter therapy is low and time-dependent as compared to external beam radiotherapy. Once the total absorbed dose delivered to a target tissue is calculated, however, most dosimetric analyses of radiopharmaceuticals are considered complete. To translate absorbed dose estimates obtained for internal emitter therapy to biologic effect, the growth characteristics, repair capacity, and radiosensitivity of the tumor must be considered. Tumor growth may be represented by the Gompertz equation in which tumor cells increase at an exponential growth rate that is itself decreasing at an exponential rate; as the tumor increases in size, the growth rate diminishes. The empirical Gompertz expression for tumor growth may be derived from a mechanistic model in which growth is represented by a balance between tumor-cell birth and loss. The birth rate is assumed to be fixed, while the cell loss rate is time-dependent and increases with tumor size. The birth rate of the tumors may be related to their potential doubling time. Multiple biopsies of individual tumors have demonstrated a heterogeneity in the potential doubling time of tumors. By extending the mechanistic model described above to allow for sub-populations of tumor cells with different birth rates, the effect of kinetic heterogeneity within a tumor may be examined. Model simulations demonstrate that the cell kinetic parameters of a tumor are predicted to change over time and measurements obtained using a biopsy are unlikely to reflect the kinetics of the tumor throughout its growth history. A decrease in overall tumor mass, in which each sub-population is reduced in proportion to its cell number, i.e., the log-kill assumption, leads to re-growth of a tumor that has a greater proliferation rate. Therapy that is linked to the potential doubling time or to the effective proliferation rate of the tumor may lead to re-growth of a tumor that is kinetically unchanged. The simplest model of

Photoexcited quantum dots for killing multidrug-resistant bacteria

Science.gov (United States)

Courtney, Colleen M.; Goodman, Samuel M.; McDaniel, Jessica A.; Madinger, Nancy E.; Chatterjee, Anushree; Nagpal, Prashant

2016-05-01

Multidrug-resistant bacterial infections are an ever-growing threat because of the shrinking arsenal of efficacious antibiotics. Metal nanoparticles can induce cell death, yet the toxicity effect is typically nonspecific. Here, we show that photoexcited quantum dots (QDs) can kill a wide range of multidrug-resistant bacterial clinical isolates, including methicillin-resistant Staphylococcus aureus, carbapenem-resistant Escherichia coli, and extended-spectrum β-lactamase-producing Klebsiella pneumoniae and Salmonella typhimurium. The killing effect is independent of material and controlled by the redox potentials of the photogenerated charge carriers, which selectively alter the cellular redox state. We also show that the QDs can be tailored to kill 92% of bacterial cells in a monoculture, and in a co-culture of E. coli and HEK 293T cells, while leaving the mammalian cells intact, or to increase bacterial proliferation. Photoexcited QDs could be used in the study of the effect of redox states on living systems, and lead to clinical phototherapy for the treatment of infections.

Tumor-Selective Cytotoxicity of Nitidine Results from Its Rapid Accumulation into Mitochondria

Directory of Open Access Journals (Sweden)

Hironori Iwasaki

2017-01-01

Full Text Available We identified a nitidine- (NTD- accumulating organelle and evaluated the net cytotoxicity of accumulated NTD. To evaluate tumor cell selectivity of the drug, we evaluated its selective cytotoxicity against 39 human cancer cell lines (JFCR39 panel, and the profile was compared with those of known anticancer drugs. Organelle specificity of NTD was visualized using organelle-targeted fluorescent proteins. Real-time analysis of cell growth, proliferation, and cytotoxicity was performed using the xCELLigence system. Selectivity of NTD in the JFCR39 panel was evaluated. Mitochondria-specific accumulation of NTD was observed. Real-time cytotoxicity analysis suggested that the mechanism of NTD-induced cell death is independent of the cell cycle. Short-term treatment indicated that this cytotoxicity only resulted from the accumulation of NTD into the mitochondria. The results from the JFCR39 panel indicated that NTD-mediated cytotoxicity resulted from unique mechanisms compared with those of other known anticancer drugs. These results suggested that the cytotoxicity of NTD is only induced by its accumulation in mitochondria. The drug triggered mitochondrial dysfunction in less than 2 h. Similarity analysis of the selectivity of NTD in 39 tumor cell lines strongly supported the unique tumor cell specificity of NTD. Thus, these features indicate that NTD may be a promising antitumor drug for new combination chemotherapies.

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

Science.gov (United States)

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.

In vivo imaging of cytotoxic T cell infiltration and elimination of a solid tumor.

Science.gov (United States)

Boissonnas, Alexandre; Fetler, Luc; Zeelenberg, Ingrid S; Hugues, Stéphanie; Amigorena, Sebastian

2007-02-19

Although the immune system evolved to fight infections, it may also attack and destroy solid tumors. In most cases, tumor rejection is initiated by CD8(+) cytotoxic T lymphocytes (CTLs), which infiltrate solid tumors, recognize tumor antigens, and kill tumor cells. We use a combination of two-photon intravital microscopy and immunofluorescence on ordered sequential sections to analyze the infiltration and destruction of solid tumors by CTLs. We show that in the periphery of a thymoma growing subcutaneously, activated CTLs migrate with high instantaneous velocities. The CTLs arrest in close contact to tumor cells expressing their cognate antigen. In regions where most tumor cells are dead, CTLs resume migration, sometimes following collagen fibers or blood vessels. CTLs migrating along blood vessels preferentially adopt an elongated morphology. CTLs also infiltrate tumors in depth, but only when the tumor cells express the cognate CTL antigen. In tumors that do not express the cognate antigen, CTL infiltration is restricted to peripheral regions, and lymphocytes neither stop moving nor kill tumor cells. Antigen expression by tumor cells therefore determines both CTL motility within the tumor and profound tumor infiltration.

How Do CD4+ T Cells Detect and Eliminate Tumor Cells That Either Lack or Express MHC Class II Molecules?

Science.gov (United States)

Haabeth, Ole Audun Werner; Tveita, Anders Aune; Fauskanger, Marte; Schjesvold, Fredrik; Lorvik, Kristina Berg; Hofgaard, Peter O.; Omholt, Hilde; Munthe, Ludvig A.; Dembic, Zlatko; Corthay, Alexandre; Bogen, Bjarne

2014-01-01

CD4+ T cells contribute to tumor eradication, even in the absence of CD8+ T cells. Cytotoxic CD4+ T cells can directly kill MHC class II positive tumor cells. More surprisingly, CD4+ T cells can indirectly eliminate tumor cells that lack MHC class II expression. Here, we review the mechanisms of direct and indirect CD4+ T cell-mediated elimination of tumor cells. An emphasis is put on T cell receptor (TCR) transgenic models, where anti-tumor responses of naïve CD4+ T cells of defined specificity can be tracked. Some generalizations can tentatively be made. For both MHCIIPOS and MHCIINEG tumors, presentation of tumor-specific antigen by host antigen-presenting cells (APCs) appears to be required for CD4+ T cell priming. This has been extensively studied in a myeloma model (MOPC315), where host APCs in tumor-draining lymph nodes are primed with secreted tumor antigen. Upon antigen recognition, naïve CD4+ T cells differentiate into Th1 cells and migrate to the tumor. At the tumor site, the mechanisms for elimination of MHCIIPOS and MHCIINEG tumor cells differ. In a TCR-transgenic B16 melanoma model, MHCIIPOS melanoma cells are directly killed by cytotoxic CD4+ T cells in a perforin/granzyme B-dependent manner. By contrast, MHCIINEG myeloma cells are killed by IFN-γ stimulated M1-like macrophages. In summary, while the priming phase of CD4+ T cells appears similar for MHCIIPOS and MHCIINEG tumors, the killing mechanisms are different. Unresolved issues and directions for future research are addressed. PMID:24782871

How do CD4+ T cells detect and eliminate tumor cells that either lack or express MHC class II molecules?

Directory of Open Access Journals (Sweden)

Ole Audun Werner Haabeth

2014-04-01

Full Text Available CD4+ T cells contribute to tumor eradication, even in the absence of CD8+ T cells. Cytotoxic CD4+ T cells can directly kill MHC class II positive tumor cells. More surprisingly, CD4+ T cells can indirectly eliminate tumor cells that lack MHC class II expression. Here, we review the mechanisms of direct and indirect CD4+ T cell-mediated elimination of tumor cells. An emphasis is put on T cell receptor (TCR transgenic models, where anti-tumor responses of naïve CD4+ T cells of defined specificity can be tracked. Some generalizations can tentatively be made. For both MHCIIPOS and MHCIINEG tumors, presentation of tumor specific antigen by host antigen presenting cells (APCs appears to be required for CD4+ T cell priming. This has been extensively studied in a myeloma model (MOPC315, where host APCs in tumor-draining lymph nodes are primed with secreted tumor antigen. Upon antigen recognition, naïve CD4+ T cells differentiate into Th1 cells and migrate to the tumor. At the tumor site, the mechanisms for elimination of MHCIIPOS and MHCIINEG tumor cells differ. In a TCR transgenic B16 melanoma model, MHCIIPOS melanoma cells are directly killed by cytotoxic CD4+ T cells in a perforin/granzyme B-dependent manner. By contrast, MHCIINEG myeloma cells are killed by IFN-g stimulated M1-like macrophages. In summary, while the priming phase of CD4+ T cells appears similar for MHCIIPOS and MHCIINEG tumors, the killing mechanisms are different. Unresolved issues and directions for future research are addressed.

Cannibalism: a way to feed on metastatic tumors.

Science.gov (United States)

Fais, Stefano

2007-12-18

Cannibalism of tumors is an old story for pathologists, but it remained a mystery for at least one century. Recent data highlighted tumor cannibalism as a key advantage in tumor malignancy, possibly involved in resistance of tumors to the specific immune reaction. However, new data suggests also that metastatic tumor cells may use this peculiar function to feed in conditions of low nutrient supply. This makes malignant cancer cells more similar to microorganisms, rather than to normal cells undergoing malignant transformation. In cytological or histological samples of human tumors it is common to detect cells with one or many vacuoles, possibly containing cells under degradation, that push the nucleus to the periphery giving it the shape of a crescent moon. The cannibal cells may feed on sibling tumor cells, but also of the lymphocytes that should kill them. Cannibal cells eat everything without distinguishing between the feeding materials, with a mechanism that mostly differ from typical phagocytosis. Despite such phenomenon is considered mainly non-selective, a molecular framework of factors that contribute to cannibalism has been described. This machinery includes the presence of an acidic environment that allows a continuous activation of specific lytic enzymes, such as cathepsin B. Cannibalism occurs in apparently well defined structures whose main actors are big caveolar-like vacuoles and a connection between caveolin-1 and the actin cytoskeleton through the actin-linker molecule ezrin. Each of the components of the cannibal framework may represent specific tumor targets for future new strategies against cancer.

Can selective pharmaco-angiography of renal tumor replace the examination under surgery?

International Nuclear Information System (INIS)

Will, C.H.; Bach, D.; Koop, H.; Impekoven, P.

1996-01-01

Can primary nephrectomy be performed without preliminary sample excision of the tumor if pharmaco-angiography of the kidney has demonstrated the typical tumor vascularization? To clarify this question in 32 patients with 'displacing mass' of the kidney, verified in sonography and computer-tomography, or hematuria of unknown origin, we prospectively performed an additional pharmaco-angiography of the respective kidney. In 18 patients with tumor vascularization in the pharmaco-angiography, intraoperatively we found 15 malignant renal cell carcinomas, 1 patient with transitional cell carcinoma of the renal pelvis, 1 leiomyosarcoma, and 1 high-differentiated tumor of only 2 cm in diameter with unclear dignity, which was treated by enucleation. In cases of an intrarenal lesion of more than 3 cm in diameter and additional tumor vascularization seen in selective pharmaco-angiography, the kidney undoubtedly can be removed by primary nephrectomy without a preliminary sample excision to confirm the diagnosis. For tumors with a diameter of less than 3 cm and additional tumor-vascularization, the option should be enucleation. If there is a 'tumor' without typical malignant vascularization, the exploration by sample excision should be performed. Depending on the histological result the tumor should be removed by enucleation or nephrectomy. (orig.) [de

Analysing the Wrongness of Killing

DEFF Research Database (Denmark)

Di Nucci, Ezio

2014-01-01

This article provides an in-depth analysis of the wrongness of killing by comparing different versions of three influential views: the traditional view that killing is always wrong; the liberal view that killing is wrong if and only if the victim does not want to be killed; and Don Marquis‟ future...... of value account of the wrongness of killing. In particular, I illustrate the advantages that a basic version of the liberal view and a basic version of the future of value account have over competing alternatives. Still, ultimately none of the views analysed here are satisfactory; but the different...

Cloning, killing, and identity.

Science.gov (United States)

McMahan, J

1999-01-01

One potentially valuable use of cloning is to provide a source of tissues or organs for transplantation. The most important objection to this use of cloning is that a human clone would be the sort of entity that it would be seriously wrong to kill. I argue that entities of the sort that you and I essentially are do not begin to exist until around the seventh month of fetal gestation. Therefore to kill a clone prior to that would not be to kill someone like you or me but would be only to prevent one of us from existing. And even after one of us begins to exist, the objections to killing it remain comparatively weak until its psychological capacities reach a certain level of maturation. These claims support the permissibility of killing a clone during the early stages of its development in order to use its organs for transplantation. PMID:10226909

Microwave pumped high-efficient thermoacoustic tumor therapy with single wall carbon nanotubes.

Science.gov (United States)

Wen, Liewei; Ding, Wenzheng; Yang, Sihua; Xing, Da

2016-01-01

The ultra-short pulse microwave could excite to the strong thermoacoustic (TA) shock wave and deeply penetrate in the biological tissues. Based on this, we developed a novel deep-seated tumor therapy modality with mitochondria-targeting single wall carbon nanotubes (SWNTs) as microwave absorbing agents, which act efficiently to convert ultra-short microwave energy into TA shock wave and selectively destroy the targeted mitochondria, thereby inducing apoptosis in cancer cells. After the treatment of SWNTs (40 μg/mL) and ultra-short microwave (40 Hz, 1 min), 77.5% of cancer cells were killed and the vast majority were caused by apoptosis that initiates from mitochondrial damage. The orthotopic liver cancer mice were established as deep-seated tumor model to investigate the anti-tumor effect of mitochondria-targeting TA therapy. The results suggested that TA therapy could effectively inhibit the tumor growth without any observable side effects, while it was difficult to achieve with photothermal or photoacoustic therapy. These discoveries implied the potential application of TA therapy in deep-seated tumor models and should be further tested for development into a promising therapeutic modality for cancer treatment. Copyright © 2015 Elsevier Ltd. All rights reserved.

The Endosymbiotic Bacterium Wolbachia Selectively Kills Male Hosts by Targeting the Masculinizing Gene.

Directory of Open Access Journals (Sweden)

Takahiro Fukui

2015-07-01

Full Text Available Pathogens are known to manipulate the reproduction and development of their hosts for their own benefit. Wolbachia is an endosymbiotic bacterium that infects a wide range of insect species. Wolbachia is known as an example of a parasite that manipulates the sex of its host's progeny. Infection of Ostrinia moths by Wolbachia causes the production of all-female progeny, however, the mechanism of how Wolbachia accomplishes this male-specific killing is unknown. Here we show for the first time that Wolbachia targets the host masculinizing gene of Ostrinia to accomplish male-killing. We found that Wolbachia-infected O. furnacalis embryos do not express the male-specific splice variant of doublesex, a gene which acts at the downstream end of the sex differentiation cascade, throughout embryonic development. Transcriptome analysis revealed that Wolbachia infection markedly reduces the mRNA level of Masc, a gene that encodes a protein required for both masculinization and dosage compensation in the silkworm Bombyx mori. Detailed bioinformatic analysis also elucidated that dosage compensation of Z-linked genes fails in Wolbachia-infected O. furnacalis embryos, a phenomenon that is extremely similar to that observed in Masc mRNA-depleted male embryos of B. mori. Finally, injection of in vitro transcribed Masc cRNA into Wolbachia-infected embryos rescued male progeny. Our results show that Wolbachia-induced male-killing is caused by a failure of dosage compensation via repression of the host masculinizing gene. Our study also shows a novel strategy by which a pathogen hijacks the host sex determination cascade.

"Guns do not kill, people do!"

DEFF Research Database (Denmark)

Lemche, Niels Peter

2011-01-01

The Bible does not kill, but many people who have read the Bible (in their way) have killed, virtually or in real.......The Bible does not kill, but many people who have read the Bible (in their way) have killed, virtually or in real....

The in vivo mechanism of action of CD20 monoclonal antibodies depends on local tumor burden

Science.gov (United States)

Boross, Peter; Jansen, J.H. Marco; de Haij, Simone; Beurskens, Frank J.; van der Poel, Cees E.; Bevaart, Lisette; Nederend, Maaike; Golay, Josée; van de Winkel, Jan G.J.; Parren, Paul W.H.I.; Leusen, Jeanette H.W.

2011-01-01

Background CD20 monoclonal antibodies are widely used in clinical practice. Antibody-dependent cellular cytotoxicity, complement-dependent cytotoxicity and direct cell death have been suggested to be important effector functions for CD20 antibodies. However, their specific contributions to the in vivo mechanism of action of CD20 immunotherapy have not been well defined. Design and Methods Here we studied the in vivo mechanism of action of type I (rituximab and ofatumumab) and type II (HuMab-11B8) CD20 antibodies in a peritoneal, syngeneic, mouse model with EL4-CD20 cells using low and high tumor burden. Results Interestingly, we observed striking differences in the in vivo mechanism of action of CD20 antibodies dependent on tumor load. In conditions of low tumor burden, complement was sufficient for tumor killing both for type I and type II CD20 antibodies. In contrast, in conditions of high tumor burden, activating FcγR (specifically FcγRIII), active complement and complement receptor 3 were all essential for tumor killing. Our data suggest that complement-enhanced antibody-dependent cellular cytotoxicity may critically affect tumor killing by CD20 antibodies in vivo. The type II CD20 antibody 11B8, which is a poor inducer of complement activation, was ineffective against high tumor burden. Conclusions Tumor burden affects the in vivo mechanism of action of CD20 antibodies. Low tumor load can be eliminated by complement alone, whereas elimination of high tumor load requires multiple effector mechanisms. PMID:21880632

O-naphthoquinone isolated from Capraria biflora L. induces selective cytotoxicity in tumor cell lines.

Science.gov (United States)

de S Wisintainer, G G N; Scola, G; Moura, S; Lemos, T L G; Pessoa, C; de Moraes, M O; Souza, L G S; Roesch-Ely, M; Henriques, J A P

2015-12-21

Biflorin is an o-naphthoquinone isolated from the roots of the plant Capraria biflora L. (Scrophulariaceae). In this study, the cytotoxic effects of biflorin were verified, and late apoptosis was detected in various cancer cell lines by in situ analysis. The cytotoxicity was further evaluated exclusively for 48 h of treatment in different tumor and non-tumor cell lines (Hep-2, HeLa, HT-29, A-375, and A-549, and HEK-293, respectively). The results indicated that biflorin induced selective cytotoxicity in tumor cells. HeLa cells were more susceptible to biflorin, followed by HT-29, A-549, A-375, and Hep-2 at all concentrations (range 5-50 μg/mL), and the highest half-maximal inhibitory concentration IC50 (56.01 ± 1.17 μg/mL) was observed in HEK-293 cells. Late apoptotic/necrotic events, observed by in situ immunostaining with Annexin V, varied with each cell line; an increase in late apoptotic events was observed corresponding to the increase in biflorin dosage. Hep-2 cells showed a greater percentage of late apoptotic events among the tumor cell lines when treated with higher concentrations of biflorin (69.63 ± 2.28%). The non-tumor HEK-293 line showed greater resistance to late apoptotic events, as well as a lower level of cytotoxicity (77.69 ± 6.68%) than the tested tumor lines. The data presented indicate that biflorin showed an important, possibly selective, cytotoxicity against tumor cell lines, thereby revealing a promising novel substance with potential anticancer activity for tumor therapy.

Nanoparticle Delivery of Artesunate Enhances the Anti-tumor Efficiency by Activating Mitochondria-Mediated Cell Apoptosis

Science.gov (United States)

Liu, Rui; Yu, Xiwei; Su, Chang; Shi, Yijie; Zhao, Liang

2017-06-01

Artemisinin and its derivatives were considered to exert a broad spectrum of anti-cancer activities, and they induced significant anti-cancer effects in tumor cells. Artemisinin and its derivatives could be absorbed quickly, and they were widely distributed, selectively killing tumor cells. Since low concentrations of artesunate primarily depended on oncosis to induce cell death in tumor cells, its anti-tumor effects were undesirable and limited. To obtain better anti-tumor effects, in this study, we took advantage of a new nanotechnology to design novel artesunate-loaded bovine serum albumin nanoparticles to achieve the mitochondrial accumulation of artesunate and induce mitochondrial-mediated apoptosis. The results showed that when compared with free artesunate's reliance on oncotic death, artesunate-loaded bovine serum albumin nanoparticles showed higher cytotoxicity and their significant apoptotic effects were induced through the distribution of artesunate in the mitochondria. This finding indicated that artesunate-loaded bovine serum albumin nanoparticles damaged the mitochondrial integrity and activated mitochondrial-mediated cell apoptosis by upregulating apoptosis-related proteins and facilitating the rapid release of cytochrome C.

Cavitation-enhanced delivery of a replicating oncolytic adenovirus to tumors using focused ultrasound.

Science.gov (United States)

Bazan-Peregrino, Miriam; Rifai, Bassel; Carlisle, Robert C; Choi, James; Arvanitis, Costas D; Seymour, Leonard W; Coussios, Constantin C

2013-07-10

Oncolytic viruses (OV) and ultrasound-enhanced drug delivery are powerful novel technologies. OV selectively self-amplify and kill cancer cells but their clinical use has been restricted by limited delivery from the bloodstream into the tumor. Ultrasound has been previously exploited for targeted release of OV in vivo, but its use to induce cavitation, microbubble oscillations, for enhanced OV tumor extravasation and delivery has not been previously reported. By identifying and optimizing the underlying physical mechanism, this work demonstrates that focused ultrasound significantly enhances the delivery and biodistribution of systemically administered OV co-injected with microbubbles. Up to a fiftyfold increase in tumor transgene expression was achieved, without any observable tissue damage. Ultrasound exposure parameters were optimized as a function of tumor reperfusion time to sustain inertial cavitation, a type of microbubble activity, throughout the exposure. Passive detection of acoustic emissions during treatment confirmed inertial cavitation as the mechanism responsible for enhanced delivery and enabled real-time monitoring of successful viral delivery. Copyright © 2013 Elsevier B.V. All rights reserved.

Time-kill profiles and cell-surface morphological effects of crude ...

African Journals Online (AJOL)

Methods: Time-kill assays were conducted by incubating test bacteria with the extract and sampling at selected time points within ... activity against both bacteria and fungi [14]. Also, a protein ..... be developed as novel drugs for the treatment of.

A comparison study on of tumor cell-killing effects between low-dose-rate β-irradiation of 32P and γ-irradiation of 60Co

International Nuclear Information System (INIS)

Feng Huiru; Tian Jiahe; Ding Weimin; Zhang Jinming; Chen Yingmao

2004-01-01

The paper is to elucidate radiobiological characteristics and radiobiological mechanism in killing tumor cells with low dose rate β-rays and high dose rate γ-rays. HeLa cells were exposed to low-rate β-irradiation of 32 P or high-dose-rate γ-irradiation of 60 Co. Cell response-patterns were compared between two the types of radiations in terms of their inhibition of cell proliferation and cell cycle blockage, evaluated by trypanblue excluded method and flow cytometry, respectively. Results show that there is a different way in growth inhibition effect on HeLa cells between low-dose-rate irradiation of 32 P and high-dose-rate irradiation of 60 Co γ. In exposure to 32 P, the inhibition of cell proliferation in HeLa cell was a prolong course, whereas and the effect was in a more serious and quick way in 60 Co irradiation. Cell cycle arrest in G 2 phase induced by 32 P was lower and more prolong than that induced by 60 Co. The inhibition effect on tumor cells between the two types of radiations is different. Impaired DNA repair system by continuous low-dose-rate radiation might contribute to the final radiation effect of 32 P

Co-stimulatory signaling determines tumor antigen sensitivity and persistence of CAR T cells targeting PSCA+ metastatic prostate cancer.

Science.gov (United States)

Priceman, Saul J; Gerdts, Ethan A; Tilakawardane, Dileshni; Kennewick, Kelly T; Murad, John P; Park, Anthony K; Jeang, Brook; Yamaguchi, Yukiko; Yang, Xin; Urak, Ryan; Weng, Lihong; Chang, Wen-Chung; Wright, Sarah; Pal, Sumanta; Reiter, Robert E; Wu, Anna M; Brown, Christine E; Forman, Stephen J

2018-01-01

Advancing chimeric antigen receptor (CAR)-engineered adoptive T cells for the treatment of solid cancers is a major focus in the field of immunotherapy, given impressive recent clinical responses in hematological malignancies. Prostate cancer may be amenable to T cell-based immunotherapy since several tumor antigens, including prostate stem-cell antigen (PSCA), are widely over-expressed in metastatic disease. While antigen selectivity of CARs for solid cancers is crucial, it is problematic due to the absence of truly restricted tumor antigen expression and potential safety concerns with "on-target off-tumor" activity. Here, we show that the intracellular co-stimulatory signaling domain can determine a CAR's sensitivity for tumor antigen expression. A 4-1BB intracellular co-stimulatory signaling domain in PSCA-CARs confers improved selectivity for higher tumor antigen density, reduced T cell exhaustion phenotype, and equivalent tumor killing ability compared to PSCA-CARs containing the CD28 co-stimulatory signaling domain. PSCA-CARs exhibit robust in vivo anti-tumor activity in patient-derived bone-metastatic prostate cancer xenograft models, and 4-1BB-containing CARs show superior T cell persistence and control of disease compared with CD28-containing CARs. Our study demonstrates the importance of co-stimulation in defining an optimal CAR T cell, and also highlights the significance of clinically relevant models in developing solid cancer CAR T cell therapies.

Two avirulent, lentogenic strains of Newcastle disease virus are cytotoxic for some human pancreatic tumor lines in vitro.

Science.gov (United States)

Walter, Robert J; Attar, Bashar M; Rafiq, Asad; Delimata, Megan; Tejaswi, Sooraj

2012-09-10

Pancreatic cancer is the fourth leading cause of cancer death in the U.S. Highly infectious Newcastle disease virus (NDV) strains are known to be very cytotoxic for an array of human tumor cell types in vitro and in vivo but the effects of these and avirulent NDV strains on pancreatic neoplasms are little known. Here, the direct cytolytic effects of the avirulent Hitchner-B1 (B1) and Ulster (U) NDV strains on 7 human pancreatic tumor cell lines and 4 normal human cell lines were studied. Cytotoxicity assays used serially diluted NDV to determine minimum cytotoxic plaque forming unit (PFU) doses. For NDV-B1, normal human cells were killed only by relatively high doses (range: 471-3,724 PFU) whereas NDV-U killed these cells at low PFU (range: 0.32-1.60 PFU). Most pancreatic cancer cell types were killed by much lower NDV-B1 doses (range: 0.40-2.60 PFU) while NDV-U killed Capan-1 and SU.86.86 cultures at very low doses (0.00041 PFU and 0.0034 PFU, respectively). On average, 1,555 times more NDV-B1 was needed to kill normal cells than most pancreatic tumor cells and 558 times more NDV-U to kill the two most sensitive pancreatic cancer lines. These innately-targeted lentogenic viruses may have meaningful potential in treating pancreatic cancer.

Exploiting tumor shrinkage through temporal optimization of radiotherapy

International Nuclear Information System (INIS)

Unkelbach, Jan; Craft, David; Hong, Theodore; Papp, Dávid; Wolfgang, John; Bortfeld, Thomas; Ramakrishnan, Jagdish; Salari, Ehsan

2014-01-01

In multi-stage radiotherapy, a patient is treated in several stages separated by weeks or months. This regimen has been motivated mostly by radiobiological considerations, but also provides an approach to reduce normal tissue dose by exploiting tumor shrinkage. The paper considers the optimal design of multi-stage treatments, motivated by the clinical management of large liver tumors for which normal liver dose constraints prohibit the administration of an ablative radiation dose in a single treatment. We introduce a dynamic tumor model that incorporates three factors: radiation induced cell kill, tumor shrinkage, and tumor cell repopulation. The design of multi-stage radiotherapy is formulated as a mathematical optimization problem in which the total dose to the normal tissue is minimized, subject to delivering the prescribed dose to the tumor. Based on the model, we gain insight into the optimal administration of radiation over time, i.e. the optimal treatment gaps and dose levels. We analyze treatments consisting of two stages in detail. The analysis confirms the intuition that the second stage should be delivered just before the tumor size reaches a minimum and repopulation overcompensates shrinking. Furthermore, it was found that, for a large range of model parameters, approximately one-third of the dose should be delivered in the first stage. The projected benefit of multi-stage treatments in terms of normal tissue sparing depends on model assumptions. However, the model predicts large dose reductions by more than a factor of 2 for plausible model parameters. The analysis of the tumor model suggests that substantial reduction in normal tissue dose can be achieved by exploiting tumor shrinkage via an optimal design of multi-stage treatments. This suggests taking a fresh look at multi-stage radiotherapy for selected disease sites where substantial tumor regression translates into reduced target volumes. (paper)

Assessment of prey vulnerability through analysis of wolf movements and kill sites.

Science.gov (United States)

Bergman, Eric J; Garrott, Robert A; Creel, Scott; Borkowski, John J; Jaffe, Rosemary; Watson, E G R

2006-02-01

Within predator-prey systems behavior can heavily influence spatial dynamics, and accordingly, the theoretical study of how spatial dynamics relate to stability within these systems has a rich history. However, our understanding of these behaviors in large mammalian systems is poorly developed. To address the relationship between predator selection patterns, prey density, and prey vulnerability, we quantified selection patterns for two fine-scale behaviors of a recovering wolf (Canis lupus) population in Yellowstone National Park, Wyoming, USA. Wolf spatial data were collected between November and May from 1998-1999 until 2001-2002. Over four winters, 244 aerial locations, 522 ground-based telemetry locations, 1287 km of movement data from snow tracking, and the locations of 279 wolf kill sites were recorded. There was evidence that elk (Cervus elaphus) and bison (Bison bison) densities had a weak effect on the sites where wolves traveled and made kills. Wolf movements showed a strong selection for geothermal areas, meadows, and areas near various types of habitat edges. Proximity to edge and habitat class also had a strong influence on the locations where elk were most vulnerable to predation. There was little evidence that wolf kill sites differed from the places where wolves traveled, indicating that elk vulnerability influenced where wolves selected to travel. Our results indicate that elk are more vulnerable to wolves under certain conditions and that wolves are capable of selecting for these conditions. As such, vulnerability plays a central role in predator-prey behavioral games and can potentially impact the systems to which they relate.

Tumor-selective replication herpes simplex virus-based technology significantly improves clinical detection and prognostication of viable circulating tumor cells

DEFF Research Database (Denmark)

Zhang, Wen; Bao, Li; Yang, Shaoxing

2016-01-01

Detection of circulating tumor cells remains a significant challenge due to their vast physical and biological heterogeneity. We developed a cell-surface-marker-independent technology based on telomerase-specific, replication-selective oncolytic herpes-simplex-virus-1 that targets telomerase......-reverse-transcriptase-positive cancer cells and expresses green-fluorescent-protein that identifies viable CTCs from a broad spectrum of malignancies. Our method recovered 75.5-87.2% of tumor cells spiked into healthy donor blood, as validated by different methods, including single cell sequencing. CTCs were detected in 59-100% of 326...

Effect of hGC-MSCs from human gastric cancer tissue on cell proliferation, invasion and epithelial-mesenchymal transition in tumor tissue of gastric cancer tumor-bearing mice.

Science.gov (United States)

Song, Lin; Zhou, Xin; Jia, Hong-Jun; Du, Mei; Zhang, Jin-Ling; Li, Liang

2016-08-01

To study the effect of hGC-MSCs from human gastric cancer tissue on cell proliferation, invasion and epithelial-mesenchymal transition in tumor tissue of gastric cancer tumor-bearing mice. BABL/c nude mice were selected as experimental animals and gastric cancer tumor-bearing mice model were established by subcutaneous injection of gastric cancer cells, randomly divided into different intervention groups. hGC-MSCs group were given different amounts of gastric cancer cells for subcutaneous injection, PBS group was given equal volume of PBS for subcutaneous injection. Then tumor tissue volume were determined, tumor-bearing mice were killed and tumor tissues were collected, mRNA expression of proliferation, invasion, EMT-related molecules were determined. 4, 8, 12, 16, 20 d after intervention, tumor tissue volume of hGC-MSCs group were significantly higher than those of PBS group and the more the number of hGC-MSCs, the higher the tumor tissue volume; mRNA contents of Ki-67, PCNA, Bcl-2, MMP-2, MMP-7, MMP-9, MMP-14, N-cadherin, vimentin, Snail and Twist in tumor tissue of hGC-MSCs group were higher than those of PBS group, and mRNA contents of Bax, TIMP1, TIMP2 and E-cadherin were lower than those of PBS group. hGC-MSCs from human gastric cancer tissue can promote the tumor growth in gastric cancer tumor-bearing mice, and the molecular mechanism includes promoting cell proliferation, invasion and epithelial-mesenchymal transition. Copyright © 2016 Hainan Medical College. Production and hosting by Elsevier B.V. All rights reserved.

Selective anti-tumor activity of the novel fluoropyrimidine polymer F10 towards G48a orthotopic GBM tumors.

Science.gov (United States)

Gmeiner, William H; Lema-Tome, Carla; Gibo, Denise; Jennings-Gee, Jamie; Milligan, Carol; Debinski, Waldemar

2014-02-01

F10 is a novel anti-tumor agent with minimal systemic toxicity in vivo and which displays strong cytotoxicity towards glioblastoma (GBM) cells in vitro. Here we investigate the cytotoxicity of F10 towards GBM cells and evaluate the anti-tumor activity of locally-administered F10 towards an orthotopic xenograft model of GBM. The effects of F10 on thymidylate synthase (TS) inhibition and Topoisomerase 1 (Top1) cleavage complex formation were evaluated using TS activity assays and in vivo complex of enzyme bioassays. Cytotoxicity of F10 towards normal brain was evaluated using cortices from embryonic (day 18) mice. F10 displays minimal penetrance of the blood-brain barrier and was delivered by intra-cerebral (i.c.) administration and prospective anti-tumor response towards luciferase-expressing G48a human GBM tumors in nude mice was evaluated using IVIS imaging. Histological examination of tumor and normal brain tissue was used to assess the selectivity of anti-tumor activity. F10 is cytotoxic towards G48a, SNB-19, and U-251 MG GBM cells through dual targeting of TS and Top1. F10 is not toxic to murine primary neuronal cultures. F10 is well-tolerated upon i.c. administration and induces significant regression of G48a tumors that is dose-dependent. Histological analysis from F10-treated mice revealed tumors were essentially completely eradicated in F10-treated mice while vehicle-treated mice displayed substantial infiltration into normal tissue. F10 displays strong efficacy for GBM treatment with minimal toxicity upon i.c. administration establishing F10 as a promising drug-candidate for treating GBM in human patients.

Killing-Yano tensors and Nambu mechanics

International Nuclear Information System (INIS)

Baleanu, D.

1998-01-01

Killing-Yano tensors were introduced in 1952 by Kentaro-Yano from mathematical point of view. The physical interpretation of Killing-Yano tensors of rank higher than two was unclear. We found that all Killing-Yano tensors η i 1 i 2 . .. i n with covariant derivative zero are Nambu tensors. We found that in the case of flat space case all Killing-Yano tensors are Nambu tensors. In the case of Taub-NUT and Kerr-Newmann metric Killing-Yano tensors of order two generate Nambu tensors of rank 3

Selection of monoclonal anti-CEA antibody fragments for tumor detection by immunoscintigraphy

International Nuclear Information System (INIS)

Mach, J.P.; Buchegger, F.

1986-01-01

It is described how individual MAb directed against carcinoembryotic antigen (CEA) is selected which does not crossreact with granulocytes and gives the best tumor localization in the model of nude mice grafted with human colon carcinoma. Using this model, the superiority of F(ab')/sub 2/ and particularly Fab fragments from high affinity MAb for the localization of relatively small tumor nodules is demonstrated. These MAb fragments are also successfully used in an ongoing clinical trial for the detection of primary and metastatic colorectal carcinomas

"The Killing Fields" of Innovation

DEFF Research Database (Denmark)

Ingerslev, Karen

2014-01-01

to clustering of ideas, a design strategy which seemed to kill unique ideas. The reframing of innovation as a radical endeavor killed learning from others for being not innovative. The findings of this paper supplement theories of deliberate killing of ideas by suggesting framing, design and facilitation......This paper points to seemingly contradicted processes of framing innovation, idea generation and killing ideas. It reports from a yearlong innovation project, where health care professionals explored problems and tested ideas for solutions, regarding a future downsizing of the case hospital....... Theories in various ways describe the opening and closing phases of innovation. Exploration and idea generation opens a field of interest, which is then closed by making choices of ideas to further explore in the next opening phase. These choices deliberately kill a lot of ideas. In the innovation project...

Habitat or matrix: which is more relevant to predict road-kill of vertebrates?

Science.gov (United States)

Bueno, C; Sousa, C O M; Freitas, S R

2015-11-01

We believe that in tropics we need a community approach to evaluate road impacts on wildlife, and thus, suggest mitigation measures for groups of species instead a focal-species approach. Understanding which landscape characteristics indicate road-kill events may also provide models that can be applied in other regions. We intend to evaluate if habitat or matrix is more relevant to predict road-kill events for a group of species. Our hypothesis is: more permeable matrix is the most relevant factor to explain road-kill events. To test this hypothesis, we chose vertebrates as the studied assemblage and a highway crossing in an Atlantic Forest region in southeastern Brazil as the study site. Logistic regression models were designed using presence/absence of road-kill events as dependent variables and landscape characteristics as independent variables, which were selected by Akaike's Information Criterion. We considered a set of candidate models containing four types of simple regression models: Habitat effect model; Matrix types effect models; Highway effect model; and, Reference models (intercept and buffer distance). Almost three hundred road-kills and 70 species were recorded. River proximity and herbaceous vegetation cover, both matrix effect models, were associated to most road-killed vertebrate groups. Matrix was more relevant than habitat to predict road-kill of vertebrates. The association between river proximity and road-kill indicates that rivers may be a preferential route for most species. We discuss multi-species mitigation measures and implications to movement ecology and conservation strategies.

Cyanine 5.5 conjugated nanobubbles as a tumor selective contrast agent for dual ultrasound-fluorescence imaging in a mouse model.

Directory of Open Access Journals (Sweden)

Liyi Mai

Full Text Available Nanobubbles and microbubbles are non-invasive ultrasound imaging contrast agents that may potentially enhance diagnosis of tumors. However, to date, both nanobubbles and microbubbles display poor in vivo tumor-selectivity over non-targeted organs such as liver. We report here cyanine 5.5 conjugated nanobubbles (cy5.5-nanobubbles of a biocompatible chitosan-vitamin C lipid system as a dual ultrasound-fluorescence contrast agent that achieved tumor-selective imaging in a mouse tumor model. Cy5.5-nanobubble suspension contained single bubble spheres and clusters of bubble spheres with the size ranging between 400-800 nm. In the in vivo mouse study, enhancement of ultrasound signals at tumor site was found to persist over 2 h while tumor-selective fluorescence emission was persistently observed over 24 h with intravenous injection of cy5.5-nanobubbles. In vitro cell study indicated that cy5.5-flurescence dye was able to accumulate in cancer cells due to the unique conjugated nanobubble structure. Further in vivo fluorescence study suggested that cy5.5-nanobubbles were mainly located at tumor site and in the bladder of mice. Subsequent analysis confirmed that accumulation of high fluorescence was present at the intact subcutaneous tumor site and in isolated tumor tissue but not in liver tissue post intravenous injection of cy5.5-nanobubbles. All these results led to the conclusion that cy5.5-nanobubbles with unique crosslinked chitosan-vitamin C lipid system have achieved tumor-selective imaging in vivo.

Natural killer cells and interleukin-1: a possible role in natural killer-tumor cell interaction

Energy Technology Data Exchange (ETDEWEB)

Traub, L M

1986-01-01

Effector cells with broad cytolytic reactivity against various tumor cell lines have been detected in the peripheral blood of normal individuals. This phenomenon, known as natural killing, appeared to be significantly depressed in a small group of patients with extensive primary hepatocellular carcinoma. These data, together with that of others showing depressed interleukin-1 (IL-1) production in these patients, were taken to indicate that IL-1 played a functional role in natural killer (NK) cell biology. The hypothesis was confirmed by the demonstration that preincubation of tumor target cells with IL-1 enhanced their susceptibility to NK cell killing. In this study tumor target cells were labelled with /sup 51/Cr.

Optimum location of external markers using feature selection algorithms for real-time tumor tracking in external-beam radiotherapy: a virtual phantom study.

Science.gov (United States)

Nankali, Saber; Torshabi, Ahmad Esmaili; Miandoab, Payam Samadi; Baghizadeh, Amin

2016-01-08

In external-beam radiotherapy, using external markers is one of the most reliable tools to predict tumor position, in clinical applications. The main challenge in this approach is tumor motion tracking with highest accuracy that depends heavily on external markers location, and this issue is the objective of this study. Four commercially available feature selection algorithms entitled 1) Correlation-based Feature Selection, 2) Classifier, 3) Principal Components, and 4) Relief were proposed to find optimum location of external markers in combination with two "Genetic" and "Ranker" searching procedures. The performance of these algorithms has been evaluated using four-dimensional extended cardiac-torso anthropomorphic phantom. Six tumors in lung, three tumors in liver, and 49 points on the thorax surface were taken into account to simulate internal and external motions, respectively. The root mean square error of an adaptive neuro-fuzzy inference system (ANFIS) as prediction model was considered as metric for quantitatively evaluating the performance of proposed feature selection algorithms. To do this, the thorax surface region was divided into nine smaller segments and predefined tumors motion was predicted by ANFIS using external motion data of given markers at each small segment, separately. Our comparative results showed that all feature selection algorithms can reasonably select specific external markers from those segments where the root mean square error of the ANFIS model is minimum. Moreover, the performance accuracy of proposed feature selection algorithms was compared, separately. For this, each tumor motion was predicted using motion data of those external markers selected by each feature selection algorithm. Duncan statistical test, followed by F-test, on final results reflected that all proposed feature selection algorithms have the same performance accuracy for lung tumors. But for liver tumors, a correlation-based feature selection algorithm, in

c-Myc oncogene expression in selected odontogenic cysts and tumors: An immunohistochemical study

Science.gov (United States)

Moosvi, Zama; Rekha, K

2013-01-01

Aim: To investigate the role of c-Myc oncogene in selected odontogenic cysts and tumors. Materials and Methods: Ten cases each of ameloblastoma, adenomatoid odontogenic tumor (AOT), odontogenic keratocyst (OKC), dentigerous cyst, and radicular cyst were selected and primary monoclonal mouse anti-human c-Myc antibody was used in a dilution of 1: 50. Statistical Analysis was performed using Mann Whitney U test. Results: 80% positivity was observed in ameloblastoma, AOT and OKC; 50% positivity in radicular cyst and 20% positivity in dentigerous cyst. Comparison of c-Myc expression between ameloblastoma and AOT did not reveal significant results. Similarly, no statistical significance was observed when results of OKC were compared with ameloblastoma and AOT. In contrast, significant differences were seen on comparison of dentigerous cyst with ameloblastoma and AOT and radicular cyst with AOT. Conclusion: From the above data we conclude that (1) Ameloblastoma and AOT have similar proliferative potential and their biologic behavior cannot possibly be attributed to it. (2) OKC has an intrinsic growth potential which is absent in other cysts and reinforces its classification as keratocystic odontogenic tumor. PMID:23798830

Co-stimulatory signaling determines tumor antigen sensitivity and persistence of CAR T cells targeting PSCA+ metastatic prostate cancer

Science.gov (United States)

Priceman, Saul J.; Gerdts, Ethan A.; Tilakawardane, Dileshni; Kennewick, Kelly T.; Murad, John P.; Park, Anthony K.; Jeang, Brook; Yamaguchi, Yukiko; Urak, Ryan; Weng, Lihong; Chang, Wen-Chung; Wright, Sarah; Pal, Sumanta; Reiter, Robert E.; Brown, Christine E.; Forman, Stephen J.

2018-01-01

ABSTRACT Advancing chimeric antigen receptor (CAR)-engineered adoptive T cells for the treatment of solid cancers is a major focus in the field of immunotherapy, given impressive recent clinical responses in hematological malignancies. Prostate cancer may be amenable to T cell-based immunotherapy since several tumor antigens, including prostate stem-cell antigen (PSCA), are widely over-expressed in metastatic disease. While antigen selectivity of CARs for solid cancers is crucial, it is problematic due to the absence of truly restricted tumor antigen expression and potential safety concerns with “on-target off-tumor” activity. Here, we show that the intracellular co-stimulatory signaling domain can determine a CAR's sensitivity for tumor antigen expression. A 4-1BB intracellular co-stimulatory signaling domain in PSCA-CARs confers improved selectivity for higher tumor antigen density, reduced T cell exhaustion phenotype, and equivalent tumor killing ability compared to PSCA-CARs containing the CD28 co-stimulatory signaling domain. PSCA-CARs exhibit robust in vivo anti-tumor activity in patient-derived bone-metastatic prostate cancer xenograft models, and 4-1BB-containing CARs show superior T cell persistence and control of disease compared with CD28-containing CARs. Our study demonstrates the importance of co-stimulation in defining an optimal CAR T cell, and also highlights the significance of clinically relevant models in developing solid cancer CAR T cell therapies. PMID:29308300

Tumor recognition in wireless capsule endoscopy images using textural features and SVM-based feature selection.

Science.gov (United States)

Li, Baopu; Meng, Max Q-H

2012-05-01

Tumor in digestive tract is a common disease and wireless capsule endoscopy (WCE) is a relatively new technology to examine diseases for digestive tract especially for small intestine. This paper addresses the problem of automatic recognition of tumor for WCE images. Candidate color texture feature that integrates uniform local binary pattern and wavelet is proposed to characterize WCE images. The proposed features are invariant to illumination change and describe multiresolution characteristics of WCE images. Two feature selection approaches based on support vector machine, sequential forward floating selection and recursive feature elimination, are further employed to refine the proposed features for improving the detection accuracy. Extensive experiments validate that the proposed computer-aided diagnosis system achieves a promising tumor recognition accuracy of 92.4% in WCE images on our collected data.

Determination of the Mutant Selection Window and Evaluation of the Killing of Mycoplasma gallisepticum by Danofloxacin, Doxycycline, Tilmicosin, Tylvalosin and Valnemulin.

Science.gov (United States)

Zhang, Nan; Ye, Xiaomei; Wu, Yuzhi; Huang, Zilong; Gu, Xiaoyan; Cai, Qinren; Shen, Xiangguang; Jiang, Hongxia; Ding, Huanzhong

2017-01-01

Mycoplasma gallisepticum is a common etiological cause of a chronic respiratory disease in chickens; its increasing antimicrobial resistance compromises the use of tetracyclines, macrolides and quinolones in the farm environment. Mutant selection window (MSW) determination was used to investigate the propensity for future resistance induction by danofloxacin, doxycycline, tilmicosin, tylvalosin and valnemulin. Killing of M. gallisepticum strain S6 by these antimicrobials was also studied by incubating M. gallisepticum into medium containing the compounds at the minimal concentration that inhibits colony formation by 99% (MIC99) and the mutant prevention concentration (MPC). Based on the morphology and colony numbers of M. gallisepticum on agar plates, the four kinds of sera in the order of the applicability for culturing M. gallisepticum were swine serum > horse serum > bovine serum > mixed serum. The MPC/MIC99 values for each agent were as follows: danofloxacin > tilmicosin > tylvalosin > doxycycline > valnemulin. MPC generated more rapid and greater magnitude killing than MIC99 against M. gallisepticum. Under exposure of 105-109 CFU/mL at MPC drug levels, valnemulin had the slowest rate of reduction in viable organisms and danofloxacin had the highest rate of reduction.

Determination of the Mutant Selection Window and Evaluation of the Killing of Mycoplasma gallisepticum by Danofloxacin, Doxycycline, Tilmicosin, Tylvalosin and Valnemulin.

Directory of Open Access Journals (Sweden)

Nan Zhang

Full Text Available Mycoplasma gallisepticum is a common etiological cause of a chronic respiratory disease in chickens; its increasing antimicrobial resistance compromises the use of tetracyclines, macrolides and quinolones in the farm environment. Mutant selection window (MSW determination was used to investigate the propensity for future resistance induction by danofloxacin, doxycycline, tilmicosin, tylvalosin and valnemulin. Killing of M. gallisepticum strain S6 by these antimicrobials was also studied by incubating M. gallisepticum into medium containing the compounds at the minimal concentration that inhibits colony formation by 99% (MIC99 and the mutant prevention concentration (MPC. Based on the morphology and colony numbers of M. gallisepticum on agar plates, the four kinds of sera in the order of the applicability for culturing M. gallisepticum were swine serum > horse serum > bovine serum > mixed serum. The MPC/MIC99 values for each agent were as follows: danofloxacin > tilmicosin > tylvalosin > doxycycline > valnemulin. MPC generated more rapid and greater magnitude killing than MIC99 against M. gallisepticum. Under exposure of 105-109 CFU/mL at MPC drug levels, valnemulin had the slowest rate of reduction in viable organisms and danofloxacin had the highest rate of reduction.

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

Science.gov (United States)

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.

Habitat or matrix: which is more relevant to predict road-kill of vertebrates?

Directory of Open Access Journals (Sweden)

C. Bueno

Full Text Available Abstract We believe that in tropics we need a community approach to evaluate road impacts on wildlife, and thus, suggest mitigation measures for groups of species instead a focal-species approach. Understanding which landscape characteristics indicate road-kill events may also provide models that can be applied in other regions. We intend to evaluate if habitat or matrix is more relevant to predict road-kill events for a group of species. Our hypothesis is: more permeable matrix is the most relevant factor to explain road-kill events. To test this hypothesis, we chose vertebrates as the studied assemblage and a highway crossing in an Atlantic Forest region in southeastern Brazil as the study site. Logistic regression models were designed using presence/absence of road-kill events as dependent variables and landscape characteristics as independent variables, which were selected by Akaike’s Information Criterion. We considered a set of candidate models containing four types of simple regression models: Habitat effect model; Matrix types effect models; Highway effect model; and, Reference models (intercept and buffer distance. Almost three hundred road-kills and 70 species were recorded. River proximity and herbaceous vegetation cover, both matrix effect models, were associated to most road-killed vertebrate groups. Matrix was more relevant than habitat to predict road-kill of vertebrates. The association between river proximity and road-kill indicates that rivers may be a preferential route for most species. We discuss multi-species mitigation measures and implications to movement ecology and conservation strategies.

Whole tumor antigen vaccination using dendritic cells: Comparison of RNA electroporation and pulsing with UV-irradiated tumor cells

Directory of Open Access Journals (Sweden)

Benencia Fabian

2008-04-01

Full Text Available Abstract 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.

Influence of WR-2721 on metastatic tumor spread after irradiation

International Nuclear Information System (INIS)

Ullrich, R.L.; Jernigan, M.C.; Yuhas, J.M.

1975-01-01

The Line 1 alveolar cell carcinoma is a transplantable murine tumor which, unlike most others, kills the host by means of metastatic spread. Attempts to cure this tumor with localized radiation therapy often fail, in spite of local tumor control, because the metastases evade the treatment. These facts suggest that host-tumor interactions may play a particularly important role in determining the ultimate survival of the tumor bearing animal. In order to initially evaluate the possible importance of normal regional tissues in host-tumor interactions the influence of WR-2721, a radioprotective drug, was examined for local tumor control and subsequent survival of the tumor bearing animal after localized radiation. Results indicated that WR-2721 can decrease metastasis. (U.S.)

Evaluation of Honour Killings in Turkey

OpenAIRE

Celbis, Osman; Ozdemir, Bora; Oruc, Mucahit; Dogan, Mustafa; Egri, Mucahit

2013-01-01

Honour killings are still pervasive in many societies.  The aim of this study is to reveal the characteristics of the victims of honour killings and honour killers in Malatya province between 2000 and 2004, and to review the concept of honour killings in Turkey.  Data are collected from the records of Malatya Higher Criminal Court.  The results are discussed in the light of the data obtained from Turkish Republic Ministry of Justice.  There were 36 honour killings in Malatya between 2000 and ...

Optimum location of external markers using feature selection algorithms for real‐time tumor tracking in external‐beam radiotherapy: a virtual phantom study

Science.gov (United States)

Nankali, Saber; Miandoab, Payam Samadi; Baghizadeh, Amin

2016-01-01

In external‐beam radiotherapy, using external markers is one of the most reliable tools to predict tumor position, in clinical applications. The main challenge in this approach is tumor motion tracking with highest accuracy that depends heavily on external markers location, and this issue is the objective of this study. Four commercially available feature selection algorithms entitled 1) Correlation‐based Feature Selection, 2) Classifier, 3) Principal Components, and 4) Relief were proposed to find optimum location of external markers in combination with two “Genetic” and “Ranker” searching procedures. The performance of these algorithms has been evaluated using four‐dimensional extended cardiac‐torso anthropomorphic phantom. Six tumors in lung, three tumors in liver, and 49 points on the thorax surface were taken into account to simulate internal and external motions, respectively. The root mean square error of an adaptive neuro‐fuzzy inference system (ANFIS) as prediction model was considered as metric for quantitatively evaluating the performance of proposed feature selection algorithms. To do this, the thorax surface region was divided into nine smaller segments and predefined tumors motion was predicted by ANFIS using external motion data of given markers at each small segment, separately. Our comparative results showed that all feature selection algorithms can reasonably select specific external markers from those segments where the root mean square error of the ANFIS model is minimum. Moreover, the performance accuracy of proposed feature selection algorithms was compared, separately. For this, each tumor motion was predicted using motion data of those external markers selected by each feature selection algorithm. Duncan statistical test, followed by F‐test, on final results reflected that all proposed feature selection algorithms have the same performance accuracy for lung tumors. But for liver tumors, a correlation‐based feature

Enhanced killing of chordoma cells by antibody-dependent cell-mediated cytotoxicity employing the novel anti-PD-L1 antibody avelumab.

Science.gov (United States)

Fujii, Rika; Friedman, Eitan R; Richards, Jacob; Tsang, Kwong Y; Heery, Christopher R; Schlom, Jeffrey; Hodge, James W

2016-06-07

Chordoma, a rare bone tumor derived from the notochord, has been shown to be resistant to conventional therapies. Checkpoint inhibition has shown great promise in immune-mediated therapy of diverse cancers. The anti-PD-L1 mAb avelumab is unique among checkpoint inhibitors in that it is a fully human IgG1 capable of mediating antibody-dependent cell-mediated cytotoxicity (ADCC) of PD-L1-expressing tumor cells. Here, we investigated avelumab as a potential therapy for chordoma. We examined 4 chordoma cell lines, first for expression of PD-L1, and in vitro for ADCC killing using NK cells and avelumab. PD-L1 expression was markedly upregulated by IFN-γ in all 4 chordoma cell lines, which significantly increased sensitivity to ADCC. Brachyury is a transcription factor that is uniformly expressed in chordoma. Clinical trials are ongoing in which chordoma patients are treated with brachyury-specific vaccines. Co-incubating chordoma cells with brachyury-specific CD8+ T cells resulted in significant upregulation of PD-L1 on the tumor cells, mediated by the CD8+ T cells' IFN-γ production, and increased sensitivity of chordoma cells to avelumab-mediated ADCC. Residential cancer stem cell subpopulations of chordoma cells were also killed by avelumab-mediated ADCC to the same degree as non-cancer stem cell populations. These findings suggest that as a monotherapy for chordoma, avelumab may enable endogenous NK cells, while in combination with T-cell immunotherapy, such as a vaccine, avelumab may enhance NK-cell killing of chordoma cells via ADCC.

Killing, letting die and euthanasia.

Science.gov (United States)

Husak, D N

1979-12-01

Medical ethicists debate whether or not the moral assessment of cases of euthanasia should depend on whether the patient is 'killed' or 'allowed to die'. The usual presupposition is that a clear distinction between killing and letting die can be drawn so that this substantive question is not begged. I contend that the categorisation of cases of instances of killing rather than as instances of letting die depends in part on a prior moral assessment of the case. Hence is it trivially rather than substantively true that the distinction has moral significance. But even if a morally neutral (ie non-question begging) distinction could be drawn, its application to the euthanasia controversy is problematic. I illustrate the difficulties of employing this distinction to reach moral conclusions by critically discussing Philippa Foot's recent treatment of euthanasia. I conclude that even if an act of euthanasia is an instance of killing, and there exists a prima facie moral duty not to kill, and no more stringent duty overrides this duty, one still cannot determine such an act to be morally impermissible.

Killing, letting die and euthanasia.

Science.gov (United States)

Husak, D N

1979-01-01

Medical ethicists debate whether or not the moral assessment of cases of euthanasia should depend on whether the patient is 'killed' or 'allowed to die'. The usual presupposition is that a clear distinction between killing and letting die can be drawn so that this substantive question is not begged. I contend that the categorisation of cases of instances of killing rather than as instances of letting die depends in part on a prior moral assessment of the case. Hence is it trivially rather than substantively true that the distinction has moral significance. But even if a morally neutral (ie non-question begging) distinction could be drawn, its application to the euthanasia controversy is problematic. I illustrate the difficulties of employing this distinction to reach moral conclusions by critically discussing Philippa Foot's recent treatment of euthanasia. I conclude that even if an act of euthanasia is an instance of killing, and there exists a prima facie moral duty not to kill, and no more stringent duty overrides this duty, one still cannot determine such an act to be morally impermissible. PMID:541821

Complement Receptor 3 Has Negative Impact on Tumor Surveillance through Suppression of Natural Killer Cell Function

Directory of Open Access Journals (Sweden)

Cheng-Fei Liu

2017-11-01

Full Text Available Complement receptor 3 (CR3 is expressed abundantly on natural killer (NK cells; however, whether it plays roles in NK cell-dependent tumor surveillance is largely unknown. Here, we show that CR3 is an important negative regulator of NK cell function, which has negative impact on tumor surveillance. Mice deficient in CR3 (CD11b−/− mice exhibited a more activated NK phenotype and had enhanced NK-dependent tumor killing. In a B16-luc melanoma-induced lung tumor growth and metastasis model, mice deficient in CR3 had reduced tumor growth and metastases, compared with WT mice. In addition, adaptive transfer of NK cells lacking CR3 (into NK-deficient mice mediated more efficient suppression of tumor growth and metastases, compared with the transfer of CR3 sufficient NK cells, suggesting that CR3 can impair tumor surveillance through suppression of NK cell function. In vitro analyses showed that engagement of CR3 with iC3b (classical CR3 ligand on NK cells negatively regulated NK cell activity and effector functions (i.e. direct tumor cell killing, antibody-dependent NK-mediated tumor killing. Cell signaling analyses showed that iC3b stimulation caused activation of Src homology 2 domain-containing inositol-5-phosphatase-1 (SHIP-1 and JNK, and suppression of ERK in NK cells, supporting that iC3b mediates negative regulation of NK cell function through its effects on SHIP-1, JNK, and ERK signal transduction pathways. Thus, our findings demonstrate a previously unknown role for CR3 in dysregulation of NK-dependent tumor surveillance and suggest that the iC3b/CR3 signaling is a critical negative regulator of NK cell function and may represent a new target for preserving NK cell function in cancer patients and improving NK cell-based therapy.

New frontiers in oncolytic viruses: optimizing and selecting for virus strains with improved efficacy

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Lundstrom K

2018-02-01

Full Text Available Kenneth Lundstrom PanTherapeutics, Lutry, Switzerland Abstract: Oncolytic viruses have demonstrated selective replication and killing of tumor cells. Different types of oncolytic viruses – adenoviruses, alphaviruses, herpes simplex viruses, Newcastle disease viruses, rhabdoviruses, Coxsackie viruses, and vaccinia viruses – have been applied as either naturally occurring or engineered vectors. Numerous studies in animal-tumor models have demonstrated substantial tumor regression and prolonged survival rates. Moreover, clinical trials have confirmed good safety profiles and therapeutic efficacy for oncolytic viruses. Most encouragingly, the first cancer gene-therapy drug – Gendicine, based on oncolytic adenovirus type 5 – was approved in China. Likewise, a second-generation oncolytic herpes simplex virus-based drug for the treatment of melanoma has been registered in the US and Europe as talimogene laherparepvec. Keywords: immunotherapy, viral vectors, clinical trials, drug approval

Heat shock protein 90-mediated peptide-selective presentation of cytosolic tumor antigen for direct recognition of tumors by CD4(+) T cells.

Science.gov (United States)

Tsuji, Takemasa; Matsuzaki, Junko; Caballero, Otavia L; Jungbluth, Achim A; Ritter, Gerd; Odunsi, Kunle; Old, Lloyd J; Gnjatic, Sacha

2012-04-15

Tumor Ag-specific CD4(+) T cells play important functions in tumor immunosurveillance, and in certain cases they can directly recognize HLA class II-expressing tumor cells. However, the underlying mechanism of intracellular Ag presentation to CD4(+) T cells by tumor cells has not yet been well characterized. We analyzed two naturally occurring human CD4(+) T cell lines specific for different peptides from cytosolic tumor Ag NY-ESO-1. Whereas both lines had the same HLA restriction and a similar ability to recognize exogenous NY-ESO-1 protein, only one CD4(+) T cell line recognized NY-ESO-1(+) HLA class II-expressing melanoma cells. Modulation of Ag processing in melanoma cells using specific molecular inhibitors and small interfering RNA revealed a previously undescribed peptide-selective Ag-presentation pathway by HLA class II(+) melanoma cells. The presentation required both proteasome and endosomal protease-dependent processing mechanisms, as well as cytosolic heat shock protein 90-mediated chaperoning. Such tumor-specific pathway of endogenous HLA class II Ag presentation is expected to play an important role in immunosurveillance or immunosuppression mediated by various subsets of CD4(+) T cells at the tumor local site. Furthermore, targeted activation of tumor-recognizing CD4(+) T cells by vaccination or adoptive transfer could be a suitable strategy for enhancing the efficacy of tumor immunotherapy.

Targeted Therapy of Cancer Using Photodynamic Therapy in Combination with Multi-faceted Anti-Tumor Modalities

Directory of Open Access Journals (Sweden)

Malini Olivo

2010-05-01

Full Text Available Photodynamic therapy (PDT has emerged as one of the important therapeutic options in the management of cancer and other diseases. PDT involves a tumor-localized photosensitizer (PS, which when appropriately illuminated by visible light converts oxygen into cytotoxic reactive oxygen species (ROS, that attack key structural entities within the targeted cells, ultimately resulting in necrosis or apoptosis. Though PDT is a selective modality, it can be further enhanced by combining other targeted therapeutic strategies that include the use of synthetic peptides and nanoparticles for selective delivery of photosensitizers. Another potentially promising strategy is the application of targeted therapeutics that exploit a myriad of critical pathways involved in tumorigenesis and metastasis. Vascular disrupting agents that eradicate tumor vasculature during PDT and anti-angiogenic agents that targets specific molecular pathways and prevent the formation of new blood vessels are novel therapeutic approaches that have been shown to improve treatment outcome. In addition to the well-documented mechanisms of direct cell killing and damage to the tumor vasculature, PDT can also activate the body’s immune response against tumors. Numerous pre-clinical studies and clinical observations have demonstrated the immuno-stimulatory capability of PDT. Herein, we aim to integrate the most important findings with regard to the combination of PDT and other novel targeted therapy approaches, detailing its potential in cancer photomedicine.

Breast cancer tumor classification using LASSO method selection approach

International Nuclear Information System (INIS)

Celaya P, J. M.; Ortiz M, J. A.; Martinez B, M. R.; Solis S, L. O.; Castaneda M, R.; Garza V, I.; Martinez F, M.; Ortiz R, J. M.

2016-10-01

Breast cancer is one of the leading causes of deaths worldwide among women. Early tumor detection is key in reducing breast cancer deaths and screening mammography is the widest available method for early detection. Mammography is the most common and effective breast cancer screening test. However, the rate of positive findings is very low, making the radiologic interpretation monotonous and biased toward errors. In an attempt to alleviate radiological workload, this work presents a computer-aided diagnosis (CAD x) method aimed to automatically classify tumor lesions into malign or benign as a means to a second opinion. The CAD x methos, extracts image features, and classifies the screening mammogram abnormality into one of two categories: subject at risk of having malignant tumor (malign), and healthy subject (benign). In this study, 143 abnormal segmentation s (57 malign and 86 benign) from the Breast Cancer Digital Repository (BCD R) public database were used to train and evaluate the CAD x system. Percentile-rank (p-rank) was used to standardize the data. Using the LASSO feature selection methodology, the model achieved a Leave-one-out-cross-validation area under the receiver operating characteristic curve (Auc) of 0.950. The proposed method has the potential to rank abnormal lesions with high probability of malignant findings aiding in the detection of potential malign cases as a second opinion to the radiologist. (Author)

Breast cancer tumor classification using LASSO method selection approach

Energy Technology Data Exchange (ETDEWEB)

Celaya P, J. M.; Ortiz M, J. A.; Martinez B, M. R.; Solis S, L. O.; Castaneda M, R.; Garza V, I.; Martinez F, M.; Ortiz R, J. M., E-mail: morvymm@yahoo.com.mx [Universidad Autonoma de Zacatecas, Av. Ramon Lopez Velarde 801, Col. Centro, 98000 Zacatecas, Zac. (Mexico)

2016-10-15

Breast cancer is one of the leading causes of deaths worldwide among women. Early tumor detection is key in reducing breast cancer deaths and screening mammography is the widest available method for early detection. Mammography is the most common and effective breast cancer screening test. However, the rate of positive findings is very low, making the radiologic interpretation monotonous and biased toward errors. In an attempt to alleviate radiological workload, this work presents a computer-aided diagnosis (CAD x) method aimed to automatically classify tumor lesions into malign or benign as a means to a second opinion. The CAD x methos, extracts image features, and classifies the screening mammogram abnormality into one of two categories: subject at risk of having malignant tumor (malign), and healthy subject (benign). In this study, 143 abnormal segmentation s (57 malign and 86 benign) from the Breast Cancer Digital Repository (BCD R) public database were used to train and evaluate the CAD x system. Percentile-rank (p-rank) was used to standardize the data. Using the LASSO feature selection methodology, the model achieved a Leave-one-out-cross-validation area under the receiver operating characteristic curve (Auc) of 0.950. The proposed method has the potential to rank abnormal lesions with high probability of malignant findings aiding in the detection of potential malign cases as a second opinion to the radiologist. (Author)

Natural killer cell lines preferentially kill clonogenic multiple myeloma cells and decrease myeloma engraftment in a bioluminescent xenograft mouse model.

Science.gov (United States)

Swift, Brenna E; Williams, Brent A; Kosaka, Yoko; Wang, Xing-Hua; Medin, Jeffrey A; Viswanathan, Sowmya; Martinez-Lopez, Joaquin; Keating, Armand

2012-07-01

Novel therapies capable of targeting drug resistant clonogenic MM cells are required for more effective treatment of multiple myeloma. This study investigates the cytotoxicity of natural killer cell lines against bulk and clonogenic multiple myeloma and evaluates the tumor burden after NK cell therapy in a bioluminescent xenograft mouse model. The cytotoxicity of natural killer cell lines was evaluated against bulk multiple myeloma cell lines using chromium release and flow cytometry cytotoxicity assays. Selected activating receptors on natural killer cells were blocked to determine their role in multiple myeloma recognition. Growth inhibition of clonogenic multiple myeloma cells was assessed in a methylcellulose clonogenic assay in combination with secondary replating to evaluate the self-renewal of residual progenitors after natural killer cell treatment. A bioluminescent mouse model was developed using the human U266 cell line transduced to express green fluorescent protein and luciferase (U266eGFPluc) to monitor disease progression in vivo and assess bone marrow engraftment after intravenous NK-92 cell therapy. Three multiple myeloma cell lines were sensitive to NK-92 and KHYG-1 cytotoxicity mediated by NKp30, NKp46, NKG2D and DNAM-1 activating receptors. NK-92 and KHYG-1 demonstrated 2- to 3-fold greater inhibition of clonogenic multiple myeloma growth, compared with killing of the bulk tumor population. In addition, the residual colonies after treatment formed significantly fewer colonies compared to the control in a secondary replating for a cumulative clonogenic inhibition of 89-99% at the 20:1 effector to target ratio. Multiple myeloma tumor burden was reduced by NK-92 in a xenograft mouse model as measured by bioluminescence imaging and reduction in bone marrow engraftment of U266eGFPluc cells by flow cytometry. This study demonstrates that NK-92 and KHYG-1 are capable of killing clonogenic and bulk multiple myeloma cells. In addition, multiple myeloma

Selective changes in expression of HLA class I polymorphic determinants in human solid tumors

International Nuclear Information System (INIS)

Natali, P.G.; Nicotra, M.R.; Bigotti, A.; Venturo, I.; Giacomini, P.; Marcenaro, L.; Russo, C.

1989-01-01

Analysis of surgical biopsies with monoclonal antibodies (mAbs) to framework determinants of major histocompatibility complex class I antigens has shown that malignant transformation is frequently associated with a marked loss of these cell surface molecules. The present study sought to determine whether more selective losses of major histocompatibility complex class I expression occur. Multiple specimens from 13 different types of primary and metastatic tumors were tested utilizing mAb BB7.2, which recognizes a polymorphic HLA-A2 epitope. In each case, expression of HLA-A,B,C molecules was determined by testing with mAb W6/32 directed to a framework HLA class I determinant. The authors have found that in HLA-A2-positive patients, HLA-A2 products are not detectable or are reduced in their expression in 70-80% of endometrial, colorectal, mammary, and renal tumors; in 40-60% of soft-tissue, skin, ovary, urinary bladder, prostate, and stomach tumors; and in 25-30% of melanomas and lung carcinomas tested. All tumors expressed the framework HLA-A,B.C determinant. The HLA-A2 epitope recognized by mAb BB7.2 is located in a portion of the HLA-A2 molecule postulated to react with the T-cell receptor. The selective loss of an HLA class I polymorphic epitope shown in this study may explain the mechanism by which tumor cells escape both T-cell recognition and natural killer cell surveillance

Notes on super Killing tensors

Energy Technology Data Exchange (ETDEWEB)

Howe, P.S. [Department of Mathematics, King’s College London,The Strand, London WC2R 2LS (United Kingdom); Lindström, University [Department of Physics and Astronomy, Theoretical Physics, Uppsala University,SE-751 20 Uppsala (Sweden); Theoretical Physics, Imperial College London,Prince Consort Road, London SW7 2AZ (United Kingdom)

2016-03-14

The notion of a Killing tensor is generalised to a superspace setting. Conserved quantities associated with these are defined for superparticles and Poisson brackets are used to define a supersymmetric version of the even Schouten-Nijenhuis bracket. Superconformal Killing tensors in flat superspaces are studied for spacetime dimensions 3,4,5,6 and 10. These tensors are also presented in analytic superspaces and super-twistor spaces for 3,4 and 6 dimensions. Algebraic structures associated with superconformal Killing tensors are also briefly discussed.

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

Science.gov (United States)

2010-10-12

... DEPARTMENT OF HOMELAND SECURITY Coast Guard 33 CFR Part 117 [Docket No. USCG-2010-0907] Drawbridge Operation Regulations; Newtown Creek, Dutch Kills, English Kills, and Their Tributaries, NY, Maintenance AGENCY: Coast Guard, DHS. ACTION: Notice of temporary deviation from regulations. SUMMARY: The Commander...

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

Science.gov (United States)

2010-06-01

... DEPARTMENT OF HOMELAND SECURITY Coast Guard 33 CFR Part 117 [Docket No. USCG-2010-0355] Drawbridge Operation Regulations; Newtown Creek, Dutch Kills, English Kills, and Their Tributaries, NY, Maintenance AGENCY: Coast Guard, DHS. ACTION: Notice of temporary deviation from regulations. SUMMARY: The Commander...

On integrability of the Killing equation

Science.gov (United States)

Houri, Tsuyoshi; Tomoda, Kentaro; Yasui, Yukinori

2018-04-01

Killing tensor fields have been thought of as describing the hidden symmetry of space(-time) since they are in one-to-one correspondence with polynomial first integrals of geodesic equations. Since many problems in classical mechanics can be formulated as geodesic problems in curved space and spacetime, solving the defining equation for Killing tensor fields (the Killing equation) is a powerful way to integrate equations of motion. Thus it has been desirable to formulate the integrability conditions of the Killing equation, which serve to determine the number of linearly independent solutions and also to restrict the possible forms of solutions tightly. In this paper, we show the prolongation for the Killing equation in a manner that uses Young symmetrizers. Using the prolonged equations, we provide the integrability conditions explicitly.

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

Directory of Open Access Journals (Sweden)

Sine J

2014-12-01

Full Text Available Jessica Sine,1,* Cordula Urban,2,* Derek Thayer,1 Heather Charron,2 Niksa Valim,2 Darrell B Tata,3 Rachel Schiff,4 Robert Blumenthal,1 Amit Joshi,2 Anu Puri1 1Membrane Structure and Function Section, Basic Research Laboratory, Center for Cancer Research, National Cancer Institute – Frederick, Frederick, MD, USA; 2Department of Radiology, Baylor College of Medicine, Houston, TX, USA; 3US Food and Drug Administration, CDRH/OSEL/Division of Physics, White Oak Campus, MD, USA; 4Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, TX, USA *These authors contributed equally to this work Abstract: 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

Spacetimes foliated by Killing horizons

International Nuclear Information System (INIS)

Pawlowski, Tomasz; Lewandowski, Jerzy; Jezierski, Jacek

2004-01-01

It seems to be expected that a horizon of a quasi-local type, such as a Killing or an isolated horizon, by analogy with a globally defined event horizon, should be unique in some open neighbourhood in the spacetime, provided the vacuum Einstein or the Einstein-Maxwell equations are satisfied. The aim of our paper is to verify whether that intuition is correct. If one can extend a so-called Kundt metric, in such a way that its null, shear-free surfaces have spherical spacetime sections, the resulting spacetime is foliated by so-called non-expanding horizons. The obstacle is Kundt's constraint induced at the surfaces by the Einstein or the Einstein-Maxwell equations, and the requirement that a solution be globally defined on the sphere. We derived a transformation (reflection) that creates a solution to Kundt's constraint out of data defining an extremal isolated horizon. Using that transformation, we derived a class of exact solutions to the Einstein or Einstein-Maxwell equations of very special properties. Each spacetime we construct is foliated by a family of the Killing horizons. Moreover, it admits another, transversal Killing horizon. The intrinsic and extrinsic geometries of the transversal Killing horizon coincide with the one defined on the event horizon of the extremal Kerr-Newman solution. However, the Killing horizon in our example admits yet another Killing vector tangent to and null at it. The geometries of the leaves are given by the reflection

PESAN MORAL DALAM FILM TO KILL A MOCKINGBIRD (ANALISIS SEMIOTIKA PADA FILM TO KILL A MOCKINGBIRD

OpenAIRE

RENYOET, JAQUILINE MELISSA

2014-01-01

2014 JAQUILINE MELISSA RENYOET. Pesan Moral Dalam Film To Kill A Mockingbird (Analisis Semiotika Pada Film To Kill A Mockingbird). (Dibimbing oleh Muh. Nadjib dan Alem Febri Sonni). Tujuan Penelitian ini adalah mengidentifikasi bentuk pesan moral dan memahami makna pesan moral dalam film To Kill A Mockingbird. Penelitian ini dilakukan selama kurang lebih 2 bulan yaitu Maret ??? Mei 2014. Metode yang digunakan untuk penelitian ini adalah metode penelitian kualitatif den...

Antibody Fc engineering improves frequency and promotes kinetic boosting of serial killing mediated by NK cells

Science.gov (United States)

Romain, Gabrielle; Senyukov, Vladimir; Rey-Villamizar, Nicolas; Merouane, Amine; Kelton, William; Liadi, Ivan; Mahendra, Ankit; Charab, Wissam; Georgiou, George; Roysam, Badrinath; Lee, Dean A.

2014-01-01

The efficacy of most therapeutic monoclonal antibodies (mAbs) targeting tumor antigens results primarily from their ability to elicit potent cytotoxicity through effector-mediated functions. We have engineered the fragment crystallizable (Fc) region of the immunoglobulin G (IgG) mAb, HuM195, targeting the leukemic antigen CD33, by introducing the triple mutation Ser293Asp/Ala330Leu/Ile332Glu (DLE), and developed Time-lapse Imaging Microscopy in Nanowell Grids to analyze antibody-dependent cell-mediated cytotoxicity kinetics of thousands of individual natural killer (NK) cells and mAb-coated target cells. We demonstrate that the DLE-HuM195 antibody increases both the quality and the quantity of NK cell-mediated antibody-dependent cytotoxicity by endowing more NK cells to participate in cytotoxicity via accrued CD16-mediated signaling and by increasing serial killing of target cells. NK cells encountering targets coated with DLE-HuM195 induce rapid target cell apoptosis by promoting simultaneous conjugates to multiple target cells and induce apoptosis in twice the number of target cells within the same period as the wild-type mAb. Enhanced target killing was also associated with increased frequency of NK cells undergoing apoptosis, but this effect was donor-dependent. Antibody-based therapies targeting tumor antigens will benefit from a better understanding of cell-mediated tumor elimination, and our work opens further opportunities for the therapeutic targeting of CD33 in the treatment of acute myeloid leukemia. PMID:25232058

Timelike Killing spinors in seven dimensions

International Nuclear Information System (INIS)

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

2004-01-01

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

Archivists Killed for Political Reasons

NARCIS (Netherlands)

de Baets, Antoon

2015-01-01

This essay, Archivists Killed for Political Reasons, offers an overview of archivists who were killed for political reasons through the ages. After determining the criteria for inclusion, sixteen such political murders of archivists are briefly discussed. These cases were distributed over six

Splenomegaly and tumor marker response following selective internal radiation therapy for non-resectable liver metastases from neuroendocrine tumor

International Nuclear Information System (INIS)

Shehata, M.; Yan, K.; Itoh, Seiji; King, J.; Glenn, D.; Quinn, R.; Morris, D.L.

2009-01-01

The aim of this study was to investigate changes in spleen size, the level of chromogranin A as a tumor marker, and the relationship between these two parameters before and 3 months after selective internal radiation therapy (SIRT) for non-resectable liver metastases from neuroendocrine tumor (NET). Our first serious adverse event with this relatively new treatment is also discussed. A retrospective review of a prospective database identified patients with non-resectable liver metastases from NET who underwent SIRT between 2003 and 2007. Patients who underwent CT scans before and 3 months after treatment were included. The patients were divided into two groups: those with and without a 20% or more increase in splenic volume on the CT scans. The percentages of patients showing a tumor marker response in the two groups were then compared. Fourteen patients were included in the present analysis. A tumor marker response was seen in 6 of 7 patients (85.7%) who showed an increase in splenic volume of >20%, and in 3 of 7 patients (42.9%) without an increase in splenic volume (p=0.266). There was one death as a result of oesophageal variceal bleeding due to portal hypertension at 9 months after treatment. Splenic enlargement after SIRT may be associated with tumor marker response, although this could not be confirmed statistically in this study due to the small number of patients. Long-term splenomegaly and portal hypertension may be important complications of SIRT. This issue needs to be investigated further using a larger number of patients and longer follow-up. (author)

9 CFR 113.213 - Pseudorabies Vaccine, Killed Virus.

Science.gov (United States)

2010-01-01

... 9 Animals and Animal Products 1 2010-01-01 2010-01-01 false Pseudorabies Vaccine, Killed Virus..., DEPARTMENT OF AGRICULTURE VIRUSES, SERUMS, TOXINS, AND ANALOGOUS PRODUCTS; ORGANISMS AND VECTORS STANDARD REQUIREMENTS Killed Virus Vaccines § 113.213 Pseudorabies Vaccine, Killed Virus. Pseudorabies Vaccine, Killed...

Killing superalgebras for Lorentzian four-manifolds

International Nuclear Information System (INIS)

Medeiros, Paul de; Figueroa-O’Farrill, José; Santi, Andrea

2016-01-01

We determine the Killing superalgebras underpinning field theories with rigid unextended supersymmetry on Lorentzian four-manifolds by re-interpreting them as filtered deformations of ℤ-graded subalgebras with maximum odd dimension of the N=1 Poincaré superalgebra in four dimensions. Part of this calculation involves computing a Spencer cohomology group which, by analogy with a similar result in eleven dimensions, prescribes a notion of Killing spinor, which we identify with the defining condition for bosonic supersymmetric backgrounds of minimal off-shell supergravity in four dimensions. We prove that such Killing spinors always generate a Lie superalgebra, and that this Lie superalgebra is a filtered deformation of a subalgebra of the N=1 Poincaré superalgebra in four dimensions. Demanding the flatness of the connection defining the Killing spinors, we obtain equations satisfied by the maximally supersymmetric backgrounds. We solve these equations, arriving at the classification of maximally supersymmetric backgrounds whose associated Killing superalgebras are precisely the filtered deformations we classify in this paper.

Killing superalgebras for Lorentzian four-manifolds

Energy Technology Data Exchange (ETDEWEB)

Medeiros, Paul de [Department of Mathematics and Natural Sciences, University of Stavanger,4036 Stavanger (Norway); Figueroa-O’Farrill, José; Santi, Andrea [Maxwell Institute and School of Mathematics, The University of Edinburgh,James Clerk Maxwell Building, Peter Guthrie Tait Road, Edinburgh EH9 3FD, Scotland (United Kingdom)

2016-06-20

We determine the Killing superalgebras underpinning field theories with rigid unextended supersymmetry on Lorentzian four-manifolds by re-interpreting them as filtered deformations of ℤ-graded subalgebras with maximum odd dimension of the N=1 Poincaré superalgebra in four dimensions. Part of this calculation involves computing a Spencer cohomology group which, by analogy with a similar result in eleven dimensions, prescribes a notion of Killing spinor, which we identify with the defining condition for bosonic supersymmetric backgrounds of minimal off-shell supergravity in four dimensions. We prove that such Killing spinors always generate a Lie superalgebra, and that this Lie superalgebra is a filtered deformation of a subalgebra of the N=1 Poincaré superalgebra in four dimensions. Demanding the flatness of the connection defining the Killing spinors, we obtain equations satisfied by the maximally supersymmetric backgrounds. We solve these equations, arriving at the classification of maximally supersymmetric backgrounds whose associated Killing superalgebras are precisely the filtered deformations we classify in this paper.

Isolated Horizon, Killing Horizon and Event Horizon

OpenAIRE

Date, G.

2001-01-01

We consider space-times which in addition to admitting an isolated horizon also admit Killing horizons with or without an event horizon. We show that an isolated horizon is a Killing horizon provided either (1) it admits a stationary neighbourhood or (2) it admits a neighbourhood with two independent, commuting Killing vectors. A Killing horizon is always an isolated horizon. For the case when an event horizon is definable, all conceivable relative locations of isolated horizon and event hori...

Conformal Killing vectors in Robertson-Walker spacetimes

International Nuclear Information System (INIS)

Maartens, R.; Maharaj, S.d.

1986-01-01

It is well known that Robertson-Walker spacetimes admit a conformal Killingl vector normal to the spacelike homogeneous hypersurfaces. Because these spacetimes are conformally flat, there are a further eight conformal Killing vectors, which are neither normal nor tangent to the homogeneous hypersurfaces. The authors find these further conformal Killing vectors and the Lie algebra of the full G 15 of conformal motions. Conditions on the metric scale factor are determined which reduce some of the conformal Killing vectors to homothetic Killing vectors or Killing vectors, allowing one to regain in a unified way the known special geometries. The non-normal conformal Killing vectors provide a counter-example to show that conformal motions do not, in general, map a fluid flow conformally. These non-normal vectors are also used to find the general solution of the null geodesic equation and photon Liouville equation. (author)

TH-E-BRF-01: Exploiting Tumor Shrinkage in Split-Course Radiotherapy

International Nuclear Information System (INIS)

Unkelbach, J; Craft, D; Hong, T; Papp, D; Wolfgang, J; Bortfeld, T; Ramakrishnan, J; Salari, E

2014-01-01

Purpose: In split-course radiotherapy, a patient is treated in several stages separated by weeks or months. This regimen has been motivated by radiobiological considerations. However, using modern image-guidance, it also provides an approach to reduce normal tissue dose by exploiting tumor shrinkage. In this work, we consider the optimal design of split-course treatments, motivated by the clinical management of large liver tumors for which normal liver dose constraints prohibit the administration of an ablative radiation dose in a single treatment. Methods: We introduce a dynamic tumor model that incorporates three factors: radiation induced cell kill, tumor shrinkage, and tumor cell repopulation. The design of splitcourse radiotherapy is formulated as a mathematical optimization problem in which the total dose to the liver is minimized, subject to delivering the prescribed dose to the tumor. Based on the model, we gain insight into the optimal administration of radiation over time, i.e. the optimal treatment gaps and dose levels. Results: We analyze treatments consisting of two stages in detail. The analysis confirms the intuition that the second stage should be delivered just before the tumor size reaches a minimum and repopulation overcompensates shrinking. Furthermore, it was found that, for a large range of model parameters, approximately one third of the dose should be delivered in the first stage. The projected benefit of split-course treatments in terms of liver sparing depends on model assumptions. However, the model predicts large liver dose reductions by more than a factor of two for plausible model parameters. Conclusion: The analysis of the tumor model suggests that substantial reduction in normal tissue dose can be achieved by exploiting tumor shrinkage via an optimal design of multi-stage treatments. This suggests taking a fresh look at split-course radiotherapy for selected disease sites where substantial tumor regression translates into reduced

TH-E-BRF-01: Exploiting Tumor Shrinkage in Split-Course Radiotherapy

Energy Technology Data Exchange (ETDEWEB)

Unkelbach, J; Craft, D; Hong, T; Papp, D; Wolfgang, J; Bortfeld, T [Massachusetts General Hospital, Boston, MA (United States); Ramakrishnan, J [University of Wisconsin, Madison, Wisconsin (United States); Salari, E [Wichita State University, Wichita, KS (United States)

2014-06-15

Purpose: In split-course radiotherapy, a patient is treated in several stages separated by weeks or months. This regimen has been motivated by radiobiological considerations. However, using modern image-guidance, it also provides an approach to reduce normal tissue dose by exploiting tumor shrinkage. In this work, we consider the optimal design of split-course treatments, motivated by the clinical management of large liver tumors for which normal liver dose constraints prohibit the administration of an ablative radiation dose in a single treatment. Methods: We introduce a dynamic tumor model that incorporates three factors: radiation induced cell kill, tumor shrinkage, and tumor cell repopulation. The design of splitcourse radiotherapy is formulated as a mathematical optimization problem in which the total dose to the liver is minimized, subject to delivering the prescribed dose to the tumor. Based on the model, we gain insight into the optimal administration of radiation over time, i.e. the optimal treatment gaps and dose levels. Results: We analyze treatments consisting of two stages in detail. The analysis confirms the intuition that the second stage should be delivered just before the tumor size reaches a minimum and repopulation overcompensates shrinking. Furthermore, it was found that, for a large range of model parameters, approximately one third of the dose should be delivered in the first stage. The projected benefit of split-course treatments in terms of liver sparing depends on model assumptions. However, the model predicts large liver dose reductions by more than a factor of two for plausible model parameters. Conclusion: The analysis of the tumor model suggests that substantial reduction in normal tissue dose can be achieved by exploiting tumor shrinkage via an optimal design of multi-stage treatments. This suggests taking a fresh look at split-course radiotherapy for selected disease sites where substantial tumor regression translates into reduced

9 CFR 113.206 - Wart Vaccine, Killed Virus.

Science.gov (United States)

2010-01-01

... 9 Animals and Animal Products 1 2010-01-01 2010-01-01 false Wart Vaccine, Killed Virus. 113.206... AGRICULTURE VIRUSES, SERUMS, TOXINS, AND ANALOGOUS PRODUCTS; ORGANISMS AND VECTORS STANDARD REQUIREMENTS Killed Virus Vaccines § 113.206 Wart Vaccine, Killed Virus. Wart Vaccine, Killed Virus, shall be prepared...

Targeting of nucleotide-binding proteins by HAMLET--a conserved tumor cell death mechanism.

Science.gov (United States)

Ho, J C S; Nadeem, A; Rydström, A; Puthia, M; Svanborg, C

2016-02-18

HAMLET (Human Alpha-lactalbumin Made LEthal to Tumor cells) kills tumor cells broadly suggesting that conserved survival pathways are perturbed. We now identify nucleotide-binding proteins as HAMLET binding partners, accounting for about 35% of all HAMLET targets in a protein microarray comprising 8000 human proteins. Target kinases were present in all branches of the Kinome tree, including 26 tyrosine kinases, 10 tyrosine kinase-like kinases, 13 homologs of yeast sterile kinases, 4 casein kinase 1 kinases, 15 containing PKA, PKG, PKC family kinases, 15 calcium/calmodulin-dependent protein kinase kinases and 13 kinases from CDK, MAPK, GSK3, CLK families. HAMLET acted as a broad kinase inhibitor in vitro, as defined in a screen of 347 wild-type, 93 mutant, 19 atypical and 17 lipid kinases. Inhibition of phosphorylation was also detected in extracts from HAMLET-treated lung carcinoma cells. In addition, HAMLET recognized 24 Ras family proteins and bound to Ras, RasL11B and Rap1B on the cytoplasmic face of the plasma membrane. Direct cellular interactions between HAMLET and activated Ras family members including Braf were confirmed by co-immunoprecipitation. As a consequence, oncogenic Ras and Braf activity was inhibited and HAMLET and Braf inhibitors synergistically increased tumor cell death in response to HAMLET. Unlike most small molecule kinase inhibitors, HAMLET showed selectivity for tumor cells in vitro and in vivo. The results identify nucleotide-binding proteins as HAMLET targets and suggest that dysregulation of the ATPase/kinase/GTPase machinery contributes to cell death, following the initial, selective recognition of HAMLET by tumor cells. The findings thus provide a molecular basis for the conserved tumoricidal effect of HAMLET, through dysregulation of kinases and oncogenic GTPases, to which tumor cells are addicted.

9 CFR 113.209 - Rabies Vaccine, Killed Virus.

Science.gov (United States)

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 prepared from virus-bearing cell cultures or nerve tissues obtained from animals that have developed rabies...

Bimodal CD40/Fas-Dependent Crosstalk between iNKT Cells and Tumor-Associated Macrophages Impairs Prostate Cancer Progression.

Science.gov (United States)

Cortesi, Filippo; Delfanti, Gloria; Grilli, Andrea; Calcinotto, Arianna; Gorini, Francesca; Pucci, Ferdinando; Lucianò, Roberta; Grioni, Matteo; Recchia, Alessandra; Benigni, Fabio; Briganti, Alberto; Salonia, Andrea; De Palma, Michele; Bicciato, Silvio; Doglioni, Claudio; Bellone, Matteo; Casorati, Giulia; Dellabona, Paolo

2018-03-13

Heterotypic cellular and molecular interactions in the tumor microenvironment (TME) control cancer progression. Here, we show that CD1d-restricted invariant natural killer (iNKT) cells control prostate cancer (PCa) progression by sculpting the TME. In a mouse PCa model, iNKT cells restrained the pro-angiogenic and immunosuppressive capabilities of tumor-infiltrating immune cells by reducing pro-angiogenic TIE2 + , M2-like macrophages (TEMs), and sustaining pro-inflammatory M1-like macrophages. iNKT cells directly contacted macrophages in the PCa stroma, and iNKT cell transfer into tumor-bearing mice abated TEMs, delaying tumor progression. iNKT cells modulated macrophages through the cooperative engagement of CD1d, Fas, and CD40, which promoted selective killing of M2-like and survival of M1-like macrophages. Human PCa aggressiveness associate with reduced intra-tumoral iNKT cells, increased TEMs, and expression of pro-angiogenic genes, underscoring the clinical significance of this crosstalk. Therefore, iNKT cells may control PCa through mechanisms involving differential macrophage modulation, which may be harnessed for therapeutically reprogramming the TME. Copyright © 2018 The Author(s). Published by Elsevier Inc. All rights reserved.

Intercellular Communication of Tumor Cells and Immune Cells after Exposure to Different Ionizing Radiation Qualities

OpenAIRE

Diegeler, Sebastian; Hellweg, Christine E.

2017-01-01

Ionizing radiation can affect the immune system in many ways. Depending on the situation, the whole body or parts of the body can be acutely or chronically exposed to different radiation qualities. In tumor radiotherapy, a fractionated exposure of the tumor (and surrounding tissues) is applied to kill the tumor cells. Currently, mostly photons, and also electrons, neutrons, protons, and heavier particles such as carbon ions, are used in radiotherapy. Tumor elimination can be supported by an e...

NK-cell-dependent killing of colon carcinoma cells is mediated by natural cytotoxicity receptors (NCRs) and stimulated by parvovirus infection of target cells

International Nuclear Information System (INIS)

Bhat, Rauf; Rommelaere, Jean

2013-01-01

Investigating how the immune system functions during malignancies is crucial to developing novel therapeutic strategies. Natural killer (NK) cells, an important component of the innate immune system, play a vital role in immune defense against tumors and virus-infected cells. The poor survival rate in colon cancer makes it particularly important to develop novel therapeutic strategies. Oncolytic viruses, in addition to lysing tumor cells, may have the potential to augment antitumor immune responses. In the present study, we investigate the role of NK cells and how parvovirus H-1PV can modulate NK-cell mediated immune responses against colon carcinoma. Human NK cells were isolated from the blood of healthy donors. The cytotoxicity and antibody-mediated inhibition of NK cells were measured in chromium release assays. Phenotypic assessment of colon cancer and dendritic cells was done by FACS. The statistical significance of the results was calculated with Student’s t test (*p <0.05; **, p < 0.01; ***, p < 0.001). We show that IL-2-activated human NK cells can effectively kill colon carcinoma cells. Killing of colon carcinoma cells by NK cells was further enhanced upon infection of the former cells with parvovirus H-1PV. H-1PV has potent oncolytic activity against various tumors, yet its direct killing effect on colon carcinoma cells is limited. The cytotoxicity of NK cells towards colon carcinoma cells, both mock- and H-1PV-infected, was found to be mostly mediated by a combination of natural cytotoxicity receptors (NCRs), namely NKp30, 44, and 46. Colon carcinoma cells displayed low to moderate expression of NK cell ligands, and this expression was modulated upon H-1PV infection. Lysates of H-1PV-infected colon carcinoma cells were found to increase MHC class II expression on dendritic cells. Altogether, these data suggest that IL-2-activated NK cells actively kill colon carcinoma cells and that this killing is mediated by several natural cytotoxicity receptors

Reduction of radiation-induced cell cycle blocks by caffeine does not necessarily lead to increased cell killing

Energy Technology Data Exchange (ETDEWEB)

Musk, S.R. (Institute of Cancer Research, Sutton, Surrey (England))

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.

HAMLET (human alpha-lactalbumin made lethal to tumor cells) triggers autophagic tumor cell death.

Science.gov (United States)

Aits, Sonja; Gustafsson, Lotta; Hallgren, Oskar; Brest, Patrick; Gustafsson, Mattias; Trulsson, Maria; Mossberg, Ann-Kristin; Simon, Hans-Uwe; Mograbi, Baharia; Svanborg, Catharina

2009-03-01

HAMLET, a complex of partially unfolded alpha-lactalbumin and oleic acid, kills a wide range of tumor cells. Here we propose that HAMLET causes macroautophagy in tumor cells and that this contributes to their death. Cell death was accompanied by mitochondrial damage and a reduction in the level of active mTOR and HAMLET triggered extensive cytoplasmic vacuolization and the formation of double-membrane-enclosed vesicles typical of macroautophagy. In addition, HAMLET caused a change from uniform (LC3-I) to granular (LC3-II) staining in LC3-GFP-transfected cells reflecting LC3 translocation during macroautophagy, and this was blocked by the macroautophagy inhibitor 3-methyladenine. HAMLET also caused accumulation of LC3-II detected by Western blot when lysosomal degradation was inhibited suggesting that HAMLET caused an increase in autophagic flux. To determine if macroautophagy contributed to cell death, we used RNA interference against Beclin-1 and Atg5. Suppression of Beclin-1 and Atg5 improved the survival of HAMLET-treated tumor cells and inhibited the increase in granular LC3-GFP staining. The results show that HAMLET triggers macroautophagy in tumor cells and suggest that macroautophagy contributes to HAMLET-induced tumor cell death.

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

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Jacqueline T Davis

Full Text Available 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.

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

Science.gov (United States)

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.

Mountain lions prey selectively on prion-infected mule deer

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Krumm, Caroline E.; Conner, Mary M.; Hobbs, N. Thompson; Hunter, Don O.; Miller, Michael W.

2010-01-01

The possibility that predators choose prey selectively based on age or condition has been suggested but rarely tested. We examined whether mountain lions (Puma concolor) selectively prey upon mule deer (Odocoileus hemionus) infected with chronic wasting disease, a prion disease. We located kill sites of mountain lions in the northern Front Range of Colorado, USA, and compared disease prevalence among lion-killed adult (≥2 years old) deer with prevalence among sympatric deer taken by hunters in the vicinity of kill sites. Hunter-killed female deer were less likely to be infected than males (odds ratios (OR) = 0.2, 95% confidence intervals (CI) = 0.1–0.6; p = 0.015). However, both female (OR = 8.5, 95% CI = 2.3–30.9) and male deer (OR = 3.2, 95% CI = 1–10) killed by a mountain lion were more likely to be infected than same-sex deer killed in the vicinity by a hunter (p < 0.001), suggesting that mountain lions in this area actively selected prion-infected individuals when targeting adult mule deer as prey items. PMID:19864271

The irreversible ERBB1/2/4 inhibitor neratinib interacts with the BCL-2 inhibitor venetoclax to kill mammary cancer cells.

Science.gov (United States)

Booth, Laurence; Roberts, Jane L; Avogadri-Connors, Francesca; Cutler, Richard E; Lalani, Alshad S; Poklepovic, Andrew; Dent, Paul

2018-03-04

The irreversible ERBB1/2/4 inhibitor, neratinib, down-regulates the expression of ERBB1/2/4 as well as the levels of MCL-1 and BCL-XL. Venetoclax (ABT199) is a BCL-2 inhibitor. At physiologic concentrations neratinib interacted in a synergistic fashion with venetoclax to kill HER2 + and TNBC mammary carcinoma cells. This was associated with the drug-combination: reducing the expression and phosphorylation of ERBB1/2/3; in an eIF2α-dependent fashion reducing the expression of MCL-1 and BCL-XL and increasing the expression of Beclin1 and ATG5; and increasing the activity of the ATM-AMPKα-ULK1 S317 pathway which was causal in the formation of toxic autophagosomes. Although knock down of BAX or BAK reduced drug combination lethality, knock down of BAX and BAK did not prevent the drug combination from increasing autophagosome and autolysosome formation. Knock down of ATM, AMPKα, Beclin1 or over-expression of activated mTOR prevented the induction of autophagy and in parallel suppressed tumor cell killing. Knock down of ATM, AMPKα, Beclin1 or cathepsin B prevented the drug-induced activation of BAX and BAK whereas knock down of BID was only partially inhibitory. A 3-day transient exposure of established estrogen-independent HER2 + BT474 mammary tumors to neratinib or venetoclax did not significantly alter tumor growth whereas exposure to [neratinib + venetoclax] caused a significant 7-day suppression of growth by day 19. The drug combination neither altered animal body mass nor behavior. We conclude that venetoclax enhances neratinib lethality by facilitating toxic BH3 domain protein activation via autophagy which enhances the efficacy of neratinib to promote greater levels of cell killing.

Tumor cell phenotype is sustained by selective MAPK oxidation in mitochondria.

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Soledad Galli

2008-06-01

Full Text Available Mitochondria are major cellular sources of hydrogen peroxide (H(2O(2, the production of which is modulated by oxygen availability and the mitochondrial energy state. An increase of steady-state cell H(2O(2 concentration is able to control the transition from proliferating to quiescent phenotypes and to signal the end of proliferation; in tumor cells thereby, low H(2O(2 due to defective mitochondrial metabolism can contribute to sustain proliferation. Mitogen-activated protein kinases (MAPKs orchestrate signal transduction and recent data indicate that are present in mitochondria and regulated by the redox state. On these bases, we investigated the mechanistic connection of tumor mitochondrial dysfunction, H(2O(2 yield, and activation of MAPKs in LP07 murine tumor cells with confocal microscopy, in vivo imaging and directed mutagenesis. Two redox conditions were examined: low 1 microM H(2O(2 increased cell proliferation in ERK1/2-dependent manner whereas high 50 microM H(2O(2 arrested cell cycle by p38 and JNK1/2 activation. Regarding the experimental conditions as a three-compartment model (mitochondria, cytosol, and nuclei, the different responses depended on MAPKs preferential traffic to mitochondria, where a selective activation of either ERK1/2 or p38-JNK1/2 by co-localized upstream kinases (MAPKKs facilitated their further passage to nuclei. As assessed by mass spectra, MAPKs activation and efficient binding to cognate MAPKKs resulted from oxidation of conserved ERK1/2 or p38-JNK1/2 cysteine domains to sulfinic and sulfonic acids at a definite H(2O(2 level. Like this, high H(2O(2 or directed mutation of redox-sensitive ERK2 Cys(214 impeded binding to MEK1/2, caused ERK2 retention in mitochondria and restricted shuttle to nuclei. It is surmised that selective cysteine oxidations adjust the electrostatic forces that participate in a particular MAPK-MAPKK interaction. Considering that tumor mitochondria are dysfunctional, their inability to

Chemically enhanced sunlight for killing bacteria

International Nuclear Information System (INIS)

Block, S.S.; Goswami, D.Y.

1995-01-01

Solar ultraviolet (UV) photocatalyzed oxidation of chemicals with titanium dioxide (TiO 2 ) has received considerable attention. Much less recognized, however, is the ability of the same system to destroy bacteria. This study examined this phenomenon and the conditions that affect it. Bacteria in aqueous solution were given solar exposure with titanium dioxide and their survival with time was determined. Lamps with a predominantly solar ultraviolet spectrum were also used in the experiments. Without exposure to UV light, TiO 2 had no deleterious effect on the bacteria. However, several common bacteria on solar exposure in the presence of TiO 2 were killed in just a few minutes, whereas without TiO 2 it took over an hour to destroy them. A concentration of 0.01% TiO 2 was most effective in killing bacteria and 10-fold concentrations lower or higher were successively less effective. Inorganic and organic compounds in solution, even in small amounts, interfered with the efficiency of killing. Alkaline solution also reduced the bactericidal activity. Circulation and agitation provided by stirring to keep the TiO 2 particles suspended reduced the time necessary to kill the bacteria. Time-intensity curves for killing bacteria were the same general shape with or without TiO 2 , indicating that TiO 2 served merely as a catalyst to increase the rate of the reaction but that the mechanism of action was not changed. The shape of the curves show that the organisms are sensitized with a minimum intensity of radiation and that an increase doesn't greatly increase the rate of kill. Below this critical intensity, however, the time required for killing markedly increases as the intensity is decreased

Tumor therapy with 125I-octreotide and 125I-UdR

International Nuclear Information System (INIS)

Fan, W.; Zhu, R.; Yang, C.; Sun, J.J.; Xu, Y.J.; Zhang, Y.J.; Wu, M.J.; Wang, D.J.

2005-01-01

is observed before reaching peak value. As a control, very low radioactivities in cells and in neucleus are measured in Na 125 I case. Incubating for 36 h, the amount of 125 I-UdR entering into the cells and nucleus are 1000 times more than that with Na 125 I. The 125 I-UdR killing effect of 100 kBq to Bax-Pc cells is 60 times more than Na 125 I after 36 h incubation. The Sca-BER bladder carcinoma cells growth cycle in the treatment group with 125 I-UdR is suppressed and clonogenic formation is lower in experimental group than in control group. Proliferation fraction and S phase cell fraction decrease and apoptosis fraction increase with 125 I-UdR treatment time. The results of confocal microscope shows the Sca-BER cells of treatment group at 48h after administration are entirely broken. Conclusion: 125 I-TOC has a better specificity to the somatostatin positive tumors. 125 I-UdR is a cell cycle dependent agent. It can be incorporated into DNA of Bax-Pc cells and can selectively kill tumor cells in S phase. Both 125 I-TOC and 125 I-UdR are more effective for killing tumor cells than Na 125 I.

Cytotoxic T lymphocyte-dependent tumor growth inhibition by a vascular endothelial growth factor-superantigen conjugate

Energy Technology Data Exchange (ETDEWEB)

Sun, Qingwen [Shanghai Chest Hospital, Shanghai 200433 (China); State Key Laboratory of Genetic Engineering, Fudan University, Shanghai 200433 (China); Jiang, Songmin [State Key Laboratory of Genetic Engineering, Fudan University, Shanghai 200433 (China); Han, Baohui [Shanghai Chest Hospital, Shanghai 200433 (China); Sun, Tongwen [Wuhan Junyu Innovation Pharmaceuticals, Inc., Wuhan 430079 (China); Li, Zhengnan; Zhao, Lina; Gao, Qiang [College of Biotechnology, Tianjin University of Science and Technology, Tianjin 300457 (China); Sun, Jialin, E-mail: jialin_sun@126.com [Wuhan Junyu Innovation Pharmaceuticals, Inc., Wuhan 430079 (China)

2012-11-02

Highlights: Black-Right-Pointing-Pointer We construct and purify a fusion protein VEGF-SEA. Black-Right-Pointing-Pointer VEGF-SEA strongly repressed the growth of murine solid sarcoma 180 (S180) tumors. Black-Right-Pointing-Pointer T cells driven by VEGF-SEA were accumulated around tumor cells bearing VEGFR by mice image model. Black-Right-Pointing-Pointer VEGF-SEA can serve as a tumor targeting agent and sequester CTLs into the tumor site. Black-Right-Pointing-Pointer The induced CTLs could release the cytokines, perforins and granzyme B to kill the tumor cells. -- Abstract: T cells are major lymphocytes in the blood and passengers across the tumor vasculature. If these T cells are retained in the tumor site, a therapeutic potential will be gained by turning them into tumor-reactive cytotoxic T lymphocytes (CTLs). A fusion protein composed of human vascular endothelial growth factor (VEGF) and staphylococcal enterotoxin A (SEA) with a D227A mutation strongly repressed the growth of murine solid sarcoma 180 (S180) tumors (control versus VEGF-SEA treated with 15 {mu}g, mean tumor weight: 1.128 g versus 0.252 g, difference = 0.876 g). CD4{sup +} and CD8{sup +} T cells driven by VEGF-SEA were accumulated around VEGFR expressing tumor cells and the induced CTLs could release the tumoricidal cytokines, such as interferon-gamma (IFN-gamma) and tumor necrosis factor-alpha (TNF-alpha). Meanwhile, intratumoral CTLs secreted cytolytic pore-forming perforin and granzyme B proteins around tumor cells, leading to the death of tumor cells. The labeled fusion proteins were gradually targeted to the tumor site in an imaging mice model. These results show that VEGF-SEA can serve as a tumor targeting agent and sequester active infiltrating CTLs into the tumor site to kill tumor cells, and could therefore be a potential therapeutical drug for a variety of cancers.

Cytotoxic T lymphocyte-dependent tumor growth inhibition by a vascular endothelial growth factor–superantigen conjugate

International Nuclear Information System (INIS)

Sun, Qingwen; Jiang, Songmin; Han, Baohui; Sun, Tongwen; Li, Zhengnan; Zhao, Lina; Gao, Qiang; Sun, Jialin

2012-01-01

Highlights: ► We construct and purify a fusion protein VEGF–SEA. ► VEGF–SEA strongly repressed the growth of murine solid sarcoma 180 (S180) tumors. ► T cells driven by VEGF–SEA were accumulated around tumor cells bearing VEGFR by mice image model. ► VEGF–SEA can serve as a tumor targeting agent and sequester CTLs into the tumor site. ► The induced CTLs could release the cytokines, perforins and granzyme B to kill the tumor cells. -- Abstract: T cells are major lymphocytes in the blood and passengers across the tumor vasculature. If these T cells are retained in the tumor site, a therapeutic potential will be gained by turning them into tumor-reactive cytotoxic T lymphocytes (CTLs). A fusion protein composed of human vascular endothelial growth factor (VEGF) and staphylococcal enterotoxin A (SEA) with a D227A mutation strongly repressed the growth of murine solid sarcoma 180 (S180) tumors (control versus VEGF–SEA treated with 15 μg, mean tumor weight: 1.128 g versus 0.252 g, difference = 0.876 g). CD4 + and CD8 + T cells driven by VEGF–SEA were accumulated around VEGFR expressing tumor cells and the induced CTLs could release the tumoricidal cytokines, such as interferon-gamma (IFN-gamma) and tumor necrosis factor-alpha (TNF-alpha). Meanwhile, intratumoral CTLs secreted cytolytic pore-forming perforin and granzyme B proteins around tumor cells, leading to the death of tumor cells. The labeled fusion proteins were gradually targeted to the tumor site in an imaging mice model. These results show that VEGF–SEA can serve as a tumor targeting agent and sequester active infiltrating CTLs into the tumor site to kill tumor cells, and could therefore be a potential therapeutical drug for a variety of cancers.

Tumor Restrictive Suicide Gene Therapy for Glioma Controlled by the FOS Promoter.

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Jianqing Pan

Full Text Available Effective suicide gene delivery and expression are crucial to achieving successful effects in gene therapy. An ideal tumor-specific promoter expresses therapeutic genes in tumor cells with minimal normal tissue expression. We compared the activity of the FOS (FBJ murine osteosarcoma viral oncogene homolog promoter with five alternative tumor-specific promoters in glioma cells and non-malignant astrocytes. The FOS promoter caused significantly higher transcriptional activity in glioma cell lines than all alternative promoters with the exception of CMV. The FOS promoter showed 13.9%, 32.4%, and 70.8% of the transcriptional activity of CMV in three glioma cell lines (U87, U251, and U373. Importantly, however, the FOS promoter showed only 1.6% of the transcriptional activity of CMV in normal astrocytes. We also tested the biologic activity of recombinant adenovirus containing the suicide gene herpes simplex virus thymidine kinase (HSV-tk driven by the FOS promoter, including selective killing efficacy in vitro and tumor inhibition rate in vivo. Adenoviral-mediated delivery of the HSV-tk gene controlled by the FOS promoter conferred a cytotoxic effect on human glioma cells in vitro and in vivo. This study suggests that use of the FOS-tk adenovirus system is a promising strategy for glioma-specific gene therapy but still much left for improvement.

Glycan elongation beyond the mucin associated Tn antigen protects tumor cells from immune-mediated killing

DEFF Research Database (Denmark)

Madsen, Caroline B; Lavrsen, Kirstine; Steentoft, Catharina

2013-01-01

are recognized as cancer associated truncated glycans, and are expressed in many adenocarcinomas, e.g. breast- and pancreatic cancer cells. To investigate the role of the cancer associated glycan truncations in immune-mediated killing we created glyco-engineered breast- and pancreatic cancer cells expressing...... only the shortest possible mucin-like glycans (Tn and STn). Glyco-engineering was performed by zinc finger nuclease (ZFN) knockout (KO) of the Core 1 enzyme chaperone COSMC, thereby preventing glycan elongation beyond the initial GalNAc residue in O-linked glycans. We find that COSMC KO in the breast...

Selected Alkylating Agents Can Overcome Drug Tolerance of G0-like Tumor Cells and Eradicate BRCA1-Deficient Mammary Tumors in Mice.

Science.gov (United States)

Pajic, Marina; Blatter, Sohvi; Guyader, Charlotte; Gonggrijp, Maaike; Kersbergen, Ariena; Küçükosmanoğlu, Aslι; Sol, Wendy; Drost, Rinske; Jonkers, Jos; Borst, Piet; Rottenberg, Sven

2017-11-15

Purpose: We aimed to characterize and target drug-tolerant BRCA1-deficient tumor cells that cause residual disease and subsequent tumor relapse. Experimental Design: We studied responses to various mono- and bifunctional alkylating agents in a genetically engineered mouse model for BRCA1/p53 -mutant breast cancer. Because of the large intragenic deletion of the Brca1 gene, no restoration of BRCA1 function is possible, and therefore, no BRCA1-dependent acquired resistance occurs. To characterize the cell-cycle stage from which Brca1 -/- ;p53 -/- mammary tumors arise after cisplatin treatment, we introduced the fluorescent ubiquitination-based cell-cycle indicator (FUCCI) construct into the tumor cells. Results: Despite repeated sensitivity to the MTD of platinum drugs, the Brca1 -mutated mammary tumors are not eradicated, not even by a frequent dosing schedule. We show that relapse comes from single-nucleated cells delaying entry into the S-phase. Such slowly cycling cells, which are present within the drug-naïve tumors, are enriched in tumor remnants. Using the FUCCI construct, we identified nonfluorescent G 0 -like cells as the population most tolerant to platinum drugs. Intriguingly, these cells are more sensitive to the DNA-crosslinking agent nimustine, resulting in an increased number of multinucleated cells that lack clonogenicity. This is consistent with our in vivo finding that the nimustine MTD, among several alkylating agents, is the most effective in eradicating Brca1 -mutated mouse mammary tumors. Conclusions: Our data show that targeting G 0 -like cells is crucial for the eradication of BRCA1/p53-deficient tumor cells. This can be achieved with selected alkylating agents such as nimustine. Clin Cancer Res; 23(22); 7020-33. ©2017 AACR . ©2017 American Association for Cancer Research.

Trastuzumab triggers phagocytic killing of high HER2 cancer cells in vitro and in vivo by interaction with Fcγ receptors on macrophages.

Science.gov (United States)

Shi, Yun; Fan, Xuejun; Deng, Hui; Brezski, Randall J; Rycyzyn, Michael; Jordan, Robert E; Strohl, William R; Zou, Quanming; Zhang, Ningyan; An, Zhiqiang

2015-05-01

Trastuzumab has been used for the treatment of HER2-overexpressing breast cancer for more than a decade, but the mechanisms of action for the therapy are still being actively investigated. Ab-dependent cell-mediated cytotoxicity mediated by NK cells is well recognized as one of the key mechanisms of action for trastuzumab, but trastuzumab-mediated Ab-dependent cellular phagocytosis (ADCP) has not been established. In this study, we demonstrate that macrophages, by way of phagocytic engulfment, can mediate ADCP and cancer cell killing in the presence of trastuzumab. Increased infiltration of macrophages in the tumor tissue was associated with enhanced efficacy of trastuzumab whereas depletion of macrophages resulted in reduced antitumor efficacy in mouse xenograft tumor models. Among the four mouse FcγRs, FcγRIV exhibits the strongest binding affinity to trastuzumab. Knockdown of FcγRIV in mouse macrophages reduced cancer cell killing and ADCP activity triggered by trastuzumab. Consistently, an upregulation of FcγRIV expression by IFN-γ triggered an increased ADCP activity by trastuzumab. In an analogous fashion, IFN-γ priming of human macrophages increased the expression of FcγRIII, the ortholog of murine FcγRIV, and increased trastuzumab-mediated cancer cell killing. Thus, in two independent systems, the results indicated that activation of macrophages in combination with trastuzumab can serve as a therapeutic strategy for treating high HER2 breast cancer by boosting ADCP killing of cancer cells. Copyright © 2015 by The American Association of Immunologists, Inc.

Cryptococcus neoformans modulates extracellular killing by neutrophils

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Asfia eQureshi

2011-09-01

Full Text Available We recently established a key role for host sphingomyelin synthase (SMS in the regulation of the killing activity of neutrophils against Cryptococcus neoformans. In this work, we studied the effect of C. neoformans on the killing activity of neutrophils and whether SMS would still be a player against C. neoformans in immunocompromised mice lacking T and NK cells (Tgε26 mice. To this end, we analyzed whether C. neoformans would have any effect on neutrophil survival and killing in vitro and in vivo. We show that unlike C. albicans, neither the presence nor the capsule size of C. neoformans cells have any effect on neutrophil viability. Interestingly, melanized C. neoformans cells totally abrogated the killing activity of neutrophils. Next, we monitored how exposure of neutrophils to C. neoformans cells would interfere with any further killing activity of the medium and found that pre-incubation with live but not heat-killed fungal cells significantly inhibits further killing activity of the medium. We next studied whether activation of SMS at the site of C. neoformans infection is dependent on T and NK cells. Using matrix-assisted laser desorption-ionization (MALDI tissue imaging in infected lung we found that similarly to previous observations in the isogenic wild type CBA/J mice, SM 16:0 levels are significantly elevated at the site of infection in mice lacking T and NK cells but only at early time points. This study highlights that C. neoformans may negatively regulate the killing activity of neutrophils and that SMS activation in neutrophils appears to be partially independent of T and/or NK cells.

MUC1-specific CTLs are non-functional within a pancreatic tumor microenvironment.

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Mukherjee, P; Ginardi, A R; Madsen, C S; Tinder, T L; Jacobs, F; Parker, J; Agrawal, B; Longenecker, B M; Gendler, S J

2001-01-01

Pancreatic cancer is a highly aggressive, treatment refractory disease and is the fourth leading cause of death in the United States. In humans, 90% of pancreatic adenocarcinomas over-express altered forms of a tumor-associated antigen, MUC1 (an epithelial mucin glycoprotein), which is a target for immunotherapy. Using a clinically relevant mouse model of pancreas cancer that demonstrates peripheral and central tolerance to human MUC1 and develops spontaneous tumors of the pancreas, we have previously reported the presence of functionally active, low affinity, MUC1-specific precursor cytotoxic T cells (pCTLs). Hypothesis for this study is that MUC1-based immunization may enhance the low level MUC1-specific immunity that may lead to an effective anti-tumor response. Data demonstrate that MUC1 peptide-based immunization elicits mature MUC1-specific CTLs in the peripheral lymphoid organs. The mature CTLs secrete IFN-gamma and are cytolytic against MUC1-expressing tumor cells in vitro. However, active CTLs that infiltrate the pancreas tumor microenvironment become cytolytically anergic and are tolerized to MUC1 antigen, allowing the tumor to grow. We demonstrate that the CTL tolerance could be reversed at least in vitro with the use of anti-CD40 co-stimulation. The pancreas tumor cells secrete immunosuppressive cytokines, including IL-10 and TGF-beta that are partly responsible for the down-regulation of CTL activity. In addition, they down-regulate their MHC class I molecules to avoid immune recognition. CD4+ CD25+ T regulatory cells, which secrete IL-10, were also found in the tumor environment. Together these data indicate the use of several immune evasion mechanisms by tumor cells to evade CTL killing. Thus altering the tumor microenvironment to make it more conducive to CTL killing may be key in developing a successful anti-cancer immunotherapy.

Interleukin-15 stimulates natural killer cell-mediated killing of both human pancreatic cancer and stellate cells

Science.gov (United States)

Van Audenaerde, Jonas R.M.; De Waele, Jorrit; Marcq, Elly; Van Loenhout, Jinthe; Lion, Eva; Van den Bergh, Johan M.J.; Jesenofsky, Ralf; Masamune, Atsushi; Roeyen, Geert; Pauwels, Patrick; Lardon, Filip; Peeters, Marc; Smits, Evelien L.J.

2017-01-01

Pancreatic ductal adenocarcinoma (PDAC) is the 4th leading cause of cancer-related death in Western countries with a 5-year survival rate below 5%. One of the hallmarks of this cancer is the strong desmoplastic reaction within the tumor microenvironment (TME), orchestrated by activated pancreatic stellate cells (PSC). This results in a functional and mechanical shield which causes resistance to conventional therapies. Aiming to overcome this resistance by tackling the stromal shield, we assessed for the first time the capacity of IL-15 stimulated natural killer (NK) cells to kill PSC and pancreatic cancer cells (PCC). The potency of IL-15 to promote NK cell-mediated killing was evaluated phenotypically and functionally. In addition, NK cell and immune checkpoint ligands on PSC were charted. We demonstrate that IL-15 activated NK cells kill both PCC and PSC lines (range 9-35% and 20-50%, respectively) in a contact-dependent manner and significantly higher as compared to resting NK cells. Improved killing of these pancreatic cell lines is, at least partly, dependent on IL-15 induced upregulation of TIM-3 and NKG2D. Furthermore, we confirm significant killing of primary PSC by IL-15 activated NK cells in an ex vivo autologous system. Screening for potential targets for immunotherapeutic strategies, we demonstrate surface expression of both inhibitory (PD-L1, PD-L2) and activating (MICA/B, ULBPs and Galectin-9) ligands on primary PSC. These data underscore the therapeutic potential of IL-15 to promote NK cell-mediated cytotoxicity as a treatment of pancreatic cancer and provide promising future targets to tackle remaining PSC. PMID:28915646

Fiber mediated receptor masking in non-infected bystander cells restricts adenovirus cell killing effect but promotes adenovirus host co-existence.

Directory of Open Access Journals (Sweden)

Johan Rebetz

Full Text Available The basic concept of conditionally replicating adenoviruses (CRAD as oncolytic agents is that progenies generated from each round of infection will disperse, infect and kill new cancer cells. However, CRAD has only inhibited, but not eradicated tumor growth in xenograft tumor therapy, and CRAD therapy has had only marginal clinical benefit to cancer patients. Here, we found that CRAD propagation and cancer cell survival co-existed for long periods of time when infection was initiated at low multiplicity of infection (MOI, and cancer cell killing was inefficient and slow compared to the assumed cell killing effect upon infection at high MOI. Excessive production of fiber molecules from initial CRAD infection of only 1 to 2% cancer cells and their release prior to the viral particle itself caused a tropism-specific receptor masking in both infected and non-infected bystander cells. Consequently, the non-infected bystander cells were inefficiently bound and infected by CRAD progenies. Further, fiber overproduction with concomitant restriction of adenovirus spread was observed in xenograft cancer therapy models. Besides the CAR-binding Ad4, Ad5, and Ad37, infection with CD46-binding Ad35 and Ad11 also caused receptor masking. Fiber overproduction and its resulting receptor masking thus play a key role in limiting CRAD functionality, but potentially promote adenovirus and host cell co-existence. These findings also give important clues for understanding mechanisms underlying the natural infection course of various adenoviruses.

A multiplexed microfluidic system for evaluation of dynamics of immune-tumor interactions.

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Moore, N; Doty, D; Zielstorff, M; Kariv, I; Moy, L Y; Gimbel, A; Chevillet, J R; Lowry, N; Santos, J; Mott, V; Kratchman, L; Lau, T; Addona, G; Chen, H; Borenstein, J T

2018-05-25

Recapitulation of the tumor microenvironment is critical for probing mechanisms involved in cancer, and for evaluating the tumor-killing potential of chemotherapeutic agents, targeted therapies and immunotherapies. Microfluidic devices have emerged as valuable tools for both mechanistic studies and for preclinical evaluation of therapeutic agents, due to their ability to precisely control drug concentrations and gradients of oxygen and other species in a scalable and potentially high throughput manner. Most existing in vitro microfluidic cancer models are comprised of cultured cancer cells embedded in a physiologically relevant matrix, collocated with vascular-like structures. However, the recent emergence of immune checkpoint inhibitors (ICI) as a powerful therapeutic modality against many cancers has created a need for preclinical in vitro models that accommodate interactions between tumors and immune cells, particularly for assessment of unprocessed tumor fragments harvested directly from patient biopsies. Here we report on a microfluidic model, termed EVIDENT (ex vivo immuno-oncology dynamic environment for tumor biopsies), that accommodates up to 12 separate tumor biopsy fragments interacting with flowing tumor-infiltrating lymphocytes (TILs) in a dynamic microenvironment. Flow control is achieved with a single pump in a simple and scalable configuration, and the entire system is constructed using low-sorption materials, addressing two principal concerns with existing microfluidic cancer models. The system sustains tumor fragments for multiple days, and permits real-time, high-resolution imaging of the interaction between autologous TILs and tumor fragments, enabling mapping of TIL-mediated tumor killing and testing of various ICI treatments versus tumor response. Custom image analytic algorithms based on machine learning reported here provide automated and quantitative assessment of experimental results. Initial studies indicate that the system is capable of

Gadolinium neutron capture therapy for brain tumors. Biological aspects

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Takagaki, Masao; Oda, Yoshifumi; Matsumoto, Masato; Kikuchi, Haruhiko; Kobayashi, Tooru; Kanda, Keiji; Ujeno, Yowri.

1994-01-01

This study investigated the tumoricidal effect of gadolinium neutron capture therapy (Gd-NCT) in in vitro and in vivo systems using Gd-DTPA. In in vitro study, a certain amount of Gd-DTPA, yielding 5000 ppm Gd-n, was added to human glioma cells, T98G, upon which thermal neutrons were exposed. After irradiation, the cells were incubated and the colonies were counted 10 days later. In in vivo study, Fisher-344 rats with experimentally induced gliosarcoma cells (9L) were exposed to thermal neutrons at a fluence rate of 3E+9/s for 1 h immediately after iv injection of Gd-DTPA. Two weeks after irradiation, brain samples were histologically examined. Tumor clearance of Gd-DTPA was also determined. In vitro analysis showed that a 1% survival level was obtained at 3.75E+12 (n/cm 2 ) for the Gd (+) medium and 2.50E+13 (n/cm 2 ) for the Gd (-) medium. In in vivo analysis, the concentration of Gd in 9L-rat brain tumor after iv injection of 0.2 mg/kg Gd-DTPA was found to be less than 100 ppm, but Gd-NCT on 9L-rat brain tumor administered with a ten-fold dose showed a substantial killing effect on tumor without serious injury to the normal brain structure. The killing effect of Gd-NCT was confirmed in in vitro and in vivo systems. (N.K.)

Brain tumor radiosurgery. Current status and strategies to enhance the effect of radiosurgery

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Niranjan, A.; Lunsford, L.D.; Gobbel, G.T.; Kondziolka, D.; Maitz, A.; Flickinger, J.C.

2000-01-01

First, the current status of brain tumor radiosurgery is reviewed, and radiosurgery for brain tumors, including benign tumors, malignant tumors, primary glial tumors, and metastatic tumors, is described. Rapid developments in neuroimaging, stereotactic techniques, and robotic technology in the last decade have contributed to improved results and wider applications of radiosurgery. Radiosurgery has become the preferred management modality for many intracranial tumors, including schwannomas, meningiomas, and metastatic tumors. Although radiosurgery provides survival benefits in patients with diffuse malignant brain tumors, cure is still not possible. Microscopic tumor infiltration into surrounding normal tissue is the main cause of recurrence. Additional strategies are needed to specifically target tumor cells. Next, strategies to enhance the effect of radiosurgery are reviewed. Whereas the long-term clinical results of radiosurgery have established its role in the treatment of benign tumors, additional strategies are needed to improve cell killing in malignant brain tumors and to protect normal surrounding brain. The first strategy included the use of various agents to protect normal brain while delivering a high dose to the tumor cells, but finding an effective radioprotective agent has been problematic. Pentobarbital and 21-aminosteroid (21-AS) are presented as examples. The second strategy for radiation protection aimed at the repair of radiation-induced damage to the normal brain. The cause of radiation-induced breakdown of normal tissue is unclear. The white matter and the cerebral vasculature appear to be particularly susceptible to radiation. Oligodendrocytes and endothelial cells may be critical targets of radiation. The authors hypothesize that radiation-induced damage to these cell types can be repaired by neural stem cells. They also describe the use of tumor necrosis factor alpha (TNF-alpha) and neural stem cells as a means of enhancing the effect of

Dirac operators and Killing spinors with torsion; Dirac-Operatoren und Killing-Spinoren mit Torsion

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Becker-Bender, Julia

2012-12-17

On a Riemannian spin manifold with parallel skew torsion, we use the twistor operator to obtain an eigenvalue estimate for the Dirac operator with torsion. We consider the equality case in dimensions four and six. In odd dimensions we describe Sasaki manifolds on which equality in the estimate is realized by Killing spinors with torsion. In dimension five we characterize all Killing spinors with torsion and obtain certain naturally reductive spaces as exceptional cases.

Anuran road-kills neighboring a peri-urban reserve in the Atlantic Forest, Brazil.

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Coelho, Igor Pfeifer; Teixeira, Fernanda Zimmermann; Colombo, Patrick; Coelho, Artur Vicente Pfeifer; Kindel, Andreas

2012-12-15

Mortality from road-kills may figure among the important causes of decline in amphibian populations and species extinctions worldwide. Evaluation of the magnitude, composition, and temporal and spatial distributions of amphibian road-kills is a key step for mitigation planning, especially in peri-urban reserves. Once a month for 16 months, we surveyed, on foot, a 4.4 km section of state road ERS-389 bordering the Itapeva reserve in the southern Atlantic Forest. We recorded 1433 anuran road-kills and estimated a mortality rate of 9002 road-kills/km/year. The species most often recorded were the largest ones: Leptodactylus latrans, Rhinella icterica, Leptodactylus gracilis and Hypsiboas faber; 54.5% of the carcasses could not be identified. Anuran mortality was concentrated in summer, and was associated with temperature, rainfall and photoperiod. Leptodactylus road-kills were strongly influenced by vehicle traffic, probably because of its high abundance during the entire study period. Road-kill hotspots differed for anurans as a group and for single species, and we found an association among spatial patterns of mortality and types of land cover, distance from the nearest waterbody, roadside ditches, and artificial light. Traffic should be banned temporarily during periods of high mortality, which can be forecasted based on meteorological data. A comprehensive mitigation approach should take into account hotspots of all anuran records, and also of target species for selecting locations for amphibian passages and fencing. Roadside ditches, artificial waterbodies, and conventional street lights should be reduced as much as possible, since they may represent ecological traps for anuran populations. Copyright © 2012 Elsevier Ltd. All rights reserved.

Low concentrations of Rhodamine-6G selectively destroy tumor cells and improve survival of melanoma transplanted mice.

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Kutushov, M; Gorelik, O

2013-01-01

Rhodamine-6G is a fluorescent dye binding to mitochondria, thus reducing the intact mitochondria number and inhibiting mitochondrial metabolic activity. Resultantly, the respiratory chain functioning becomes blocked, the cell "suffocated" and eventually destroyed. Unlike normal cells, malignant cells demonstrate a priori reduced mitochondrial numbers and aberrant metabolism. Therefore, a turning point might exist, when Rhodamine-induced loss of active mitochondria would selectively destroy malignant, but spare normal cells. Various malignant vs. non-malignant cell lines were cultured with Rhodamine-6G at different concentrations. In addition, C57Bl mice were implanted with B16-F10 melanoma and treated with Rhodamine-6G at different dosage/time regimens. Viability and proliferation of cultured tumor cells were time and dose-dependently inhibited, up to 90%, by Rhodamine-6G, with profound histological signs of cell death. By contrast, inhibition of normal control cell proliferation hardly exceeded 15-17%. Melanoma-transplanted mice receiving Rhodamine-6G demonstrated prolonged survival, improved clinical parameters, inhibited tumor growth and metastases count, compared to their untreated counterparts. Twice-a-week 10-6M Rhodamine-6G regimen yielded the most prominent results. We conclude that malignant, but not normal, cells are selectively destroyed by low doses of Rhodamine-6G. In vivo, such treatment selectively suppresses tumor progression and dissemination, thus improving prognosis. We suggest that selective anti-tumor properties of Rhodamine-6G are based on unique physiologic differences in energy metabolism between malignant and normal cells. If found clinically relevant, low concentrations of Rhodamine-6G might be useful for replacing, or backing up, more aggressive nonselective chemotherapeutic compounds.

Nurses Writing about Psychiatric Nurses' Involvement in Killings during the Nazi Era: A Preliminary Discourse Analysis.

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Holmes, Colin A; McAllister, Margaret; Crowther, Andrew

2016-01-01

Nurses actively killed people in Nazi Europe between 1939 and 1945. The so-called ‘science of eugenics’ underpinned Nazi ideology, used to further the Nazi racist agenda. Edicts sanctioned selection and medically supervised killing of people, and nurses, principally in mental hospitals, participated in the killing of between 100–300 thousand patients. Erroneously termed ‘euthanasia', there were three phases: the initial programme involving children, the T4 adult programme, and ‘wild euthanasia'. Unofficial killings also took place before 1939. This paper uses discourse analysis to map and analyse published texts which explore the role of nurses in Nazi Germany. The aim is to identify its characteristics as a body of literature, to note strengths and weaknesses, emphases and silences, and to note aspects that need further exploration. It acknowledges that how these events are to be understood and represented in contemporary discourse constitutes a significant problem for historians of nursing.

High hydrostatic pressure affects antigenic pool in tumor cells: Implication for dendritic cell-based cancer immunotherapy.

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Urbanova, Linda; Hradilova, Nada; Moserova, Irena; Vosahlikova, Sarka; Sadilkova, Lenka; Hensler, Michal; Spisek, Radek; Adkins, Irena

2017-07-01

High hydrostatic pressure (HHP) can be used to generate dendritic cell (DC)-based active immunotherapy for prostate, lung and ovarian cancer. We showed here that HHP treatment of selected human cancer cell lines leads to a degradation of tumor antigens which depends on the magnitude of HHP applied and on the cancer cell line origin. Whereas prostate or ovarian cell lines displayed little protein antigen degradation with HHP treatment up to 300MPa after 2h, tumor antigens are hardly detected in lung cancer cell line after treatment with HHP 250MPa at the same time. On the other hand, quick reduction of tumor antigen-coding mRNA was observed at HHP 200MPa immediately after treatment in all cell lines tested. To optimize the DC-based active cellular therapy protocol for HHP-sensitive cell lines the immunogenicity of HHP-treated lung cancer cells at 150, 200 and 250MPa was compared. Lung cancer cells treated with HHP 150MPa display characteristics of immunogenic cell death, however cells are not efficiently phagocytosed by DC. Despite induction of the highest number of antigen-specific CD8 + T cells, 150 MPa-treated lung cancer cells survive in high numbers. This excludes their use in DC vaccine manufacturing. HHP of 200MPa treatment of lung cancer cells ensures the optimal ratio of efficient immunogenic killing and delivery of protein antigens in DC. These results represent an important pre-clinical data for generation of immunogenic killed lung cancer cells in ongoing NSCLC Phase I/II clinical trial using DC-based active cellular immunotherapy (DCVAC/LuCa). Copyright © 2017 European Federation of Immunological Societies. Published by Elsevier B.V. All rights reserved.

Enhanced killing of mammalian cells by radiation combined with m-AMSA

International Nuclear Information System (INIS)

Roberts, P.B.; Millar, B.C.

1980-01-01

m-AMSA is an intercalating agent at present on Phase II trial as a chemotherapeutic drug. A 30min exposure of Chinese hamster (Line V79-753B) cells to submicromolar concentrations of m-AMSA killed 50% of the cells. The survivors had an enhanced sensitivity to radiation-induced cell killing. Depending upon the conditions, m-AMSA enhanced the radiation effect by either a decrease in the survival-curve shoulder or by an increase in slope. m-AMSA may act partly by suppressing the accumulation of sublethal damage but, if so, recovery from damage as measured in split-dose experiments with cells pretreated with the drug is not affected. m-AMSA increased radiation lethality throughout the cell cycle, but a contribution to its radiation effect from selective toxicity to cells in a radioresistant phase of the cell cycle cannot be excluded. Radiation and the drug interacted to give increased cell killing, even when the exposures to each agent were separated in time. It is concluded that m-ASMA may behave like actinomycin D and adriamycin, and enhance clinical radiation responses. In vivo testing to determine the effect of m-AMSA on the therapeutic index is recommended. (author)

Enhanced killing of mammalian cells by radiation combined with m-AMSA

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Roberts, P B; Millar, B C [Institute of Cancer Research, Sutton (UK). Surrey Branch

1980-11-01

m-AMSA is an intercalating agent at present on Phase II trial as a chemotherapeutic drug. A 30 min exposure of Chinese hamster (Line V79-753B) cells to submicromolar concentrations of m-AMSA killed 50% of the cells. The survivors had an enhanced sensitivity to radiation-induced cell killing. Depending upon the conditions, m-AMSA enhanced the radiation effect by either a decrease in the survival-curve shoulder or by an increase in slope. m-AMSA may act partly by suppressing the accumulation of sublethal damage but, if so, recovery from damage as measured in split-dose experiments with cells pretreated with the drug is not affected. m-AMSA increased radiation lethality throughout the cell cycle, but a contribution to its radiation effect from selective toxicity to cells in a radioresistant phase of the cell cycle cannot be excluded. Radiation and the drug interacted to give increased cell killing, even when the exposures to each agent were separated in time. It is concluded that m-ASMA may behave like actinomycin D and adriamycin, and enhance clinical radiation responses. In vivo testing to determine the effect of m-AMSA on the therapeutic index is recommended.

Interstitial administration of perfluorochemical emulsions for reoxygenation of hypoxic tumor cells

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Woo, D.V.; Seegenschmiedt, H.; Schweighardt, F.K.; Emrich, J.; McGarvey, K.; Caridi, M.; Brady, L.W.

1987-01-01

Microparticulate perfluorochemical (PFC) emulsions have the capacity to solubilize significant quantities of oxygen compared to water. Although systemic administration of such emulsions may enhance oxygen delivery to some tissues, hypoxic tumor cells have marginal vascular supplies. The authors report studies which directly attempt to oxygenate hypoxic tumor cells by interstitial administration of oxygenated PFC emulsions followed by radiation therapy. Fortner MMI malignant melanomas (21 day old) grown in Syrian Golden hamsters were injected directly with either oxygenated PFC emulsions or Ringers solution. The volume of test substance administered was equal to 50% of the tumor volume. The tumors were immediately irradiated with 25 Gy of 10 MeV photons (Clinac 18). The tumor dimensions were measured daily post irradiation and the tumor doubling time determined. The results suggest that interstitial administration of oxygenated PFC emulsions directly into tumors followed by radiation therapy may increase the likelihood of killing hypoxic tumor cells

Identification and structural analysis of an L-asparaginase enzyme from guinea pig with putative tumor cell killing properties.

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

2014-11-28

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. © 2014 by The American Society for Biochemistry and Molecular Biology, Inc.

Honor Killing: Where Pride Defeats Reason.

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Kanchan, Tanuj; Tandon, Abhishek; Krishan, Kewal

2016-12-01

Honor killings are graceless and ferocious murders by chauvinists with an antediluvian mind. These are categorized separately because these killings are committed for the prime reason of satisfying the ego of the people whom the victim trusts and always looks up to for support and protection. It is for this sole reason that honor killings demand strict and stern punishment, not only for the person who committed the murder but also for any person who contributed or was party to the act. A positive change can occur with stricter legislation and changes in the ethos of the society we live in today.

T-peptide Enhances the Killing Effects of Cisplatinum on Lung Cancer

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Hongyi ZHANG

2017-02-01

Full Text Available Background and objective T peptide is extensively used in anti-tumor treatment. The aims of this study were to investigate whether T peptide enhances cisplatinum efficiency while reducing its side effects and to identify its effective mechanisms. Methods (1 Human macrophage U937 cells were treated with T peptide and/or cisplatinum. The levels of tumor necrosis factor-α (TNF-α and interferon-γ (IFN-γ of each group were detected by enzyme-linked immunosorbent assay (ELISA; (2 Xenograft mouse models of human lung cancer were treated with T peptide and/or cisplatinum once every five days for three times. Tumor volumes were measured during treatment; (3 The percentages of macrophages in the peripheral blood of the xenograft mouse models were measured by FACS. Results (1 Compared with other groups, the level of TNF-α was significantly higher in the human macrophage U937 cells that were treated with T peptide combined with cisplatinum. The levels of IFN-γ were significantly higher in human macrophage U937 cells that were treated with T peptide alone or T peptide combined with cisplatinum; (2 In the xenograft mouse models, T peptide combined with cisplatinum treatment significantly inhibited tumor growth without weight loss compared with the other groups; (3 The percentages of macrophages in the peripheral blood were significantly higher in the xenograft mouse models that were treated with T peptide combined with cisplatinum compared with in the other groups. Conclusion T peptide promotes macrophage proliferation and increases tumor cell killing factors (TNF-α, IFN-γ in vitro. Moreover, T peptide enhances the efficacy of cisplatin and reduces its toxicity in vivo.

Lines of Descent Under Selection

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Baake, Ellen; Wakolbinger, Anton

2017-11-01

We review recent progress on ancestral processes related to mutation-selection models, both in the deterministic and the stochastic setting. We mainly rely on two concepts, namely, the killed ancestral selection graph and the pruned lookdown ancestral selection graph. The killed ancestral selection graph gives a representation of the type of a random individual from a stationary population, based upon the individual's potential ancestry back until the mutations that define the individual's type. The pruned lookdown ancestral selection graph allows one to trace the ancestry of individuals from a stationary distribution back into the distant past, thus leading to the stationary distribution of ancestral types. We illustrate the results by applying them to a prototype model for the error threshold phenomenon.

It’s Not Just Conflict That Motivates Killing of Orangutans

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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. PMID:24130707

Road-Killed Animals as Resources for Ecological Studies.

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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…

Enhanced tumor control of human Glioblastoma Multiforme xenografts with the concomitant use of radiotherapy and an attenuated herpes simplex-1 virus (ASTRO research fellowship)

International Nuclear Information System (INIS)

Song, Paul Y.; Sibley, Gregory S.; Advani, Sunil; Hallahan, Dennis; Hyland, John; Kufe, Donald W.; Chou, Joany; Roizman, Bernard; Weichselbaum, Ralph R.

1996-01-01

Purpose: Glioblastoma Multiforme remains one of the most incurable of human tumors. The current treatment outcomes are dismal. There are several recent reports which suggest that some human glioblastoma xenografts implanted in the brains of athymic mice may be potentially cured with the use of an attenuated herpes simplex-1 virus alone. We have chosen a replication competent, non-neurovirulent HSV-1 mutant, designated R3616 to determine whether there is an interactive cell killing and enhanced tumor control with radiotherapy in the treatment of a human glioblastoma xenograft. Materials and Methods: In vivo, 1 mm 3 pieces of U-87 human glioblastoma cell line xenografts were implanted into the right hind limb of athymic mice and grown to > 200 mm 3 . A total of 112 mice were then equally distributed within four treatment arms (see chart below) based upon tumor volume. Xenografts selected to receive virus as part of the therapy were inoculated with three injections of 2 x 10 7 plaque forming units (PFU) of R3616 virus given on day 1, 2, and 3 for a total dose of 6 x 10 7 PFU. R3616 is a non-neurovirulent HSV-1 mutant created by the deletion of the γ 34.5 gene. Local field irradiation was delivered on day 2 (20 Gy) and day 3 (25 Gy). The mice were then followed for 60 days during which time the xenografts were measured twice weekly. A clinically non-palpable tumor (< 10% original volume) was scored as a cure. In addition percent-fractional tumor volume (FTV) and mean tumor volume (MTV) were calculated for each group. Results: Conclusion: While our tumor control with R3616 alone is similar to that reported in the literature, we have seen significantly enhanced tumor control and cell killing with the addition of RT suggesting a synergistic interaction between an oncolytic virus and radiation in the treatment of human glioblastoma multiforme xenografts

Novel Selective Detection Method of Tumor Angiogenesis Factors Using Living Nano-Robots.

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Al-Fandi, Mohamed; Alshraiedeh, Nida; Owies, Rami; Alshdaifat, Hala; Al-Mahaseneh, Omamah; Al-Tall, Khadijah; Alawneh, Rawan

2017-07-14

This paper reports a novel self-detection method for tumor cells using living nano-robots. These living robots are a nonpathogenic strain of E. coli bacteria equipped with naturally synthesized bio-nano-sensory systems that have an affinity to VEGF, an angiogenic factor overly-expressed by cancer cells. The VEGF-affinity/chemotaxis was assessed using several assays including the capillary chemotaxis assay, chemotaxis assay on soft agar, and chemotaxis assay on solid agar. In addition, a microfluidic device was developed to possibly discover tumor cells through the overexpressed vascular endothelial growth factor (VEGF). Various experiments to study the sensing characteristic of the nano-robots presented a strong response toward the VEGF. Thus, a new paradigm of selective targeting therapies for cancer can be advanced using swimming E. coli as self-navigator miniaturized robots as well as drug-delivery vehicles.

Some basic properties of Killing spinors

International Nuclear Information System (INIS)

Hacyan, S.; Plebanski, J.

1976-01-01

The concept of Killing spinor is analyzed in a general way by using the spinorial formalism. It is shown, among other things, that higher derivatives of Killing spinors can be expressed in terms of lower order derivatives. Conformal Killing vectors are studied in some detail in the light of spinorial analysis: Classical results are formulated in terms of spinors. A theorem on Lie derivatives of Debever--Penrose vectors is proved, and it is shown that conformal motion in vacuum with zero cosmological constant must be homothetic, unless the conformal tensor vanishes or is of type N. Our results are valid for either real or complex space--time manifolds

Killing vectors in algebraically special space-times

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Torres del Castillo, G.F.

1984-01-01

The form of the isometric, homothetic, and conformal Killing vectors for algebraically special metrics which admit a shear-free congruence of null geodesics is obtained by considering their complexification, using the existence of a congruence of null strings. The Killing equations are partially integrated and the reasons which permit this reduction are exhibited. In the case where the congruence of null strings has a vanishing expansion, the Killing equations are reduced to a single master equation

Phantom metrics with Killing spinors

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W.A. Sabra

2015-11-01

Full Text Available We study metric solutions of Einstein–anti-Maxwell theory admitting Killing spinors. The analogue of the IWP metric which admits a space-like Killing vector is found and is expressed in terms of a complex function satisfying the wave equation in flat (2+1-dimensional space–time. As examples, electric and magnetic Kasner spaces are constructed by allowing the solution to depend only on the time coordinate. Euclidean solutions are also presented.

Metformin decreases the dose of chemotherapy for prolonging tumor remission in mouse xenografts involving multiple cancer cell types.

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Iliopoulos, Dimitrios; Hirsch, Heather A; Struhl, Kevin

2011-05-01

Metformin, the first-line drug for treating diabetes, selectively kills the chemotherapy resistant subpopulation of cancer stem cells (CSC) in genetically distinct types of breast cancer cell lines. In mouse xenografts, injection of metformin and the chemotherapeutic drug doxorubicin near the tumor is more effective than either drug alone in blocking tumor growth and preventing relapse. Here, we show that metformin is equally effective when given orally together with paclitaxel, carboplatin, and doxorubicin, indicating that metformin works together with a variety of standard chemotherapeutic agents. In addition, metformin has comparable effects on tumor regression and preventing relapse when combined with a four-fold reduced dose of doxorubicin that is not effective as a monotherapy. Finally, the combination of metformin and doxorubicin prevents relapse in xenografts generated with prostate and lung cancer cell lines. These observations provide further evidence for the CSC hypothesis for cancer relapse, an experimental rationale for using metformin as part of combinatorial therapy in a variety of clinical settings, and for reducing the chemotherapy dose in cancer patients.

Generalized Killing-Yano equations in D=5 gauged supergravity

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Kubiznak, David; Kunduri, Hari K.; Yasui, Yukinori

2009-01-01

We propose a generalization of the (conformal) Killing-Yano equations relevant to D=5 minimal gauged supergravity. The generalization stems from the fact that the dual of the Maxwell flux, the 3-form *F, couples naturally to particles in the background as a 'torsion'. Killing-Yano tensors in the presence of torsion preserve most of the properties of the standard Killing-Yano tensors - exploited recently for the higher-dimensional rotating black holes of vacuum gravity with cosmological constant. In particular, the generalized closed conformal Killing-Yano 2-form gives rise to the tower of generalized closed conformal Killing-Yano tensors of increasing rank which in turn generate the tower of Killing tensors. An example of a generalized Killing-Yano tensor is found for the Chong-Cvetic-Lue-Pope black hole spacetime [Z.W. Chong, M. Cvetic, H. Lu, C.N. Pope, (hep-th/0506029)]. Such a tensor stands behind the separability of the Hamilton-Jacobi, Klein-Gordon, and Dirac equations in this background.

Spatially selective depleting tumor-associated negative regulatory T-(Treg) cells with near infrared photoimmunotherapy (NIR-PIT): A new cancer immunotherapy (Conference Presentation)

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Kobayashi, Hisataka

2017-02-01

Near infrared photoimmunotherapy (NIR-PIT) is a new type of molecularly-targeted photo-therapy based on conjugating a near infrared silica-phthalocyanine dye, IR700, to a monoclonal antibody (MAb) targeting target-specific cell-surface molecules. When exposed to NIR light, the conjugate rapidly induces a highly-selective cell death only in receptor-positive, MAb-IR700-bound cells. Current immunotherapies for cancer seek to modulate the balance among different immune cell populations, thereby promoting anti-tumor immune responses. However, because these are systemic therapies, they often cause treatment-limiting autoimmune adverse effects. It would be ideal to manipulate the balance between suppressor and effector cells within the tumor without disturbing homeostasis elsewhere in the body. CD4+CD25+Foxp3+ regulatory T cells (Tregs) are well-known immune-suppressor cells that play a key role in tumor immuno-evasion and have been the target of systemic immunotherapies. We used CD25-targeted NIR-PIT to selectively deplete Tregs, thus activating CD8+ T and NK cells and restoring local anti-tumor immunity. This not only resulted in regression of the treated tumor but also induced responses in separate untreated tumors of the same cell-line derivation. We conclude that CD25-targeted NIR-PIT causes spatially selective depletion of Tregs, thereby providing an alternative approach to cancer immunotherapy that can treat not only local tumors but also distant metastatic tumors.

Advances in Attract-and-Kill for Agricultural Pests: Beyond Pheromones.

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Gregg, Peter C; Del Socorro, Alice P; Landolt, Peter J

2018-01-07

Attract-and-kill has considerable potential as a tactic in integrated management of pests of agricultural crops, but the use of sex pheromones as attractants is limited by male multiple mating and immigration of mated females into treated areas. Attractants for both sexes, and particularly females, would minimize these difficulties. Volatile compounds derived from plants or fermentation of plant products can attract females and have been used in traps for monitoring and control, and in sprayable attract-and-kill formulations or bait stations. Recent advances in fundamental understanding of insect responses to plant volatiles should contribute to the development of products that can help manage a wide range of pests with few impacts on nontarget organisms, but theory must be tempered with pragmatism in the selection of volatiles and toxicants and in defining their roles in formulations. Market requirements and regulatory factors must be considered in parallel with scientific constraints if successful products are to be developed.

Killing of intracellular Mycobacterium tuberculosis by receptor-mediated drug delivery

International Nuclear Information System (INIS)

Majumdar, S.; Basu, S.K.

1991-01-01

p-Aminosalicylic acid (PAS) conjugated to maleylated bovine serum albumin (MBSA) was taken up efficiently through high-affinity MBSA-binding sites on macrophages. Binding of the radiolabeled conjugate to cultured mouse peritoneal macrophages at 4 degrees C was competed for by MBSA but not by PAS. At 37 degrees C, the radiolabeled conjugate was rapidly degraded by the macrophages, leading to release of acid-soluble degradation products in the medium. The drug conjugate was nearly 100 times as effective as free PAS in killing the intracellular mycobacteria in mouse peritoneal macrophages infected in culture with Mycobacterium tuberculosis. The killing of intracellular mycobacteria mediated by the drug conjugate was effectively prevented by simultaneous addition of excess MBSA (100 micrograms/ml) or chloroquine (3 microM) to the medium, whereas these agents did not affect the microbicidal action of free PAS. These results suggest that (i) uptake of the PAS-MBSA conjugate was mediated by cell surface receptors on macrophages which recognize MBSA and (ii) lysosomal hydrolysis of the internalized conjugate resulted in intracellular release of a pharmacologically active form of the drug, which led to selective killing of the M. tuberculosis harbored by mouse macrophages infected in culture. This receptor-mediated modality of delivering drugs to macrophages could contribute to greater therapeutic efficacy and minimization of toxic side effects in the management of tuberculosis and other intracellular mycobacterial infections

Varying congruence of hygienic responses to Varroa destructor and freeze-killed brood among different types of honey bees

Science.gov (United States)

Different types of honey bees, Apis mellifera L., have been selectively bred for enhanced hygiene (i.e., removal of affected brood from sealed cells) to improve resistance to diseases and parasites. Bees selected for removal of freeze-killed brood (FKB) have protection from several microbial disease...

NK cell-released exosomes: Natural nanobullets against tumors.

Science.gov (United States)

Fais, Stefano

2013-01-01

We have recently reported that human natural killer (NK) cells release exosomes that express both NK-cell markers and cytotoxic molecules. Similar results were obtained with circulating exosomes from human healthy donors. Both NK-cell derived and circulating exosomes exerted a full functional activity and killed both tumor and activated immune cells. These findings indicate that NK-cell derived exosomes might constitute a new promising therapeutic tool.

Gefitinib-induced killing of NSCLC cell lines expressing mutant EGFR requires BIM and can be enhanced by BH3 mimetics.

Directory of Open Access Journals (Sweden)

Mark S Cragg

2007-10-01

Full Text Available The epidermal growth factor receptor (EGFR plays a critical role in the control of cellular proliferation, differentiation, and survival. Abnormalities in EGF-EGFR signaling, such as mutations that render the EGFR hyperactive or cause overexpression of the wild-type receptor, have been found in a broad range of cancers, including carcinomas of the lung, breast, and colon. EGFR inhibitors such as gefitinib have proven successful in the treatment of certain cancers, particularly non-small cell lung cancers (NSCLCs harboring activating mutations within the EGFR gene, but the molecular mechanisms leading to tumor regression remain unknown. Therefore, we wished to delineate these mechanisms.We performed biochemical and genetic studies to investigate the mechanisms by which inhibitors of EGFR tyrosine kinase activity, such as gefitinib, inhibit the growth of human NSCLCs. We found that gefitinib triggered intrinsic (also called "mitochondrial" apoptosis signaling, involving the activation of BAX and mitochondrial release of cytochrome c, ultimately unleashing the caspase cascade. Gefitinib caused a rapid increase in the level of the proapoptotic BH3-only protein BIM (also called BCL2-like 11 through both transcriptional and post-translational mechanisms. Experiments with pharmacological inhibitors indicated that blockade of MEK-ERK1/2 (mitogen-activated protein kinase kinase-extracellular signal-regulated protein kinase 1/2 signaling, but not blockade of PI3K (phosphatidylinositol 3-kinase, JNK (c-Jun N-terminal kinase or mitogen-activated protein kinase 8, or AKT (protein kinase B, was critical for BIM activation. Using RNA interference, we demonstrated that BIM is essential for gefitinib-induced killing of NSCLC cells. Moreover, we found that gefitinib-induced apoptosis is enhanced by addition of the BH3 mimetic ABT-737.Inhibitors of the EGFR tyrosine kinase have proven useful in the therapy of certain cancers, in particular NSCLCs possessing

Relationship between laminin binding capacity and laminin expression on tumor cells sensitive or resistant to natural cell-mediated cytotoxicity

International Nuclear Information System (INIS)

Laybourn, K.A.; Varani, J.; Fligiel, S.E.G.; Hiserodt, J.C.

1986-01-01

Previous studies have identified the presence of laminin binding sites on murine NK and NC sensitive tumor cells by 125 I-laminin binding and laminin induced cell-cell aggregation. The finding that the addition of exogenous laminin inhibits NK/NC binding to sensitive tumor cells suggests laminin binding sites may serve as target antigens for NK cells. The present study extends earlier reports by analyzing a large panel of tumor cells for laminin binding capacity, laminin expression and sensitivity to NK/NC killing. The data indicate that all tumor cells which bind to NK/NC cells (8 lines tested) express laminin binding sites. All of these tumor cells were capable of competing for NK lysis of YAC-1 cells in cold target competition assays, and all bound enriched NK cells in direct single cell binding assays. In contrast, tumor cells expressing high levels of surface laminin (B16 melanomas, C57B1/6 fibrosarcomas, and RAS transfected 3T3 fibroblasts) but low levels of laminin binding capacity did not bind NK/NC cells and were resistant to lysis. These data support the hypothesis that expression of laminin/laminin binding sites may contribute to tumor cell sensitivity to NK/NC binding and/or killing

Anti-tumor effects of 125I radioactive particles implantation on transplantated tumor model of human breast cancer cells in nude mice

International Nuclear Information System (INIS)

Xiao Zhongdi; Liang Chunlin; Zhang Guoli; Jing Yue; Zhang Yucheng; Gai Baodong

2011-01-01

Objective: To study the anti-tumor effects of 125 I radioactive particles implantation on transplantated tumor model of human breast cancer cells in nude mice and clarify their anti-tumor mechanisms. Methods 120 nude mice transplantated with human breast cancer cells MCF-7 were randomly divided into 3 groups (n=40): 125 I radioactive particles implanted group, non-radioactive particles implanted group and non-particles implanted group. The articles were implanted into mice according to Pairs system principle. The expressions of Fas mRNA and protein and the activaties of caspase-3 and caspase-8 enzyme were detected by RT-PCR and Western blotting. The changes of cell cycle were detected by flow cytometry. Results: Compared with non-radioactive particles implanted group and non-particles implanted group, the size of cancer tissues in 125 I radioactive particles implanted group was reduced significantly (P 0 /G 1 phase was significantly increased (P 125 I radioactive particles into transplantated tumor model of human breast cancer cells can kill tumor cells, inhibit the growth cycle of tumor cells and induce the apoptosis of tumor cells in nude mice. (authors)

Offensive Counterterrorism Targeted killing in eliminating terrorist target: the case of the USA and Israel

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Hermínio Matos

2012-01-01

Full Text Available Due to the "global terrorism project", some States have adopted offensive counterterrorism measures which, though within national strategies on security and defense, contemplate the use of military power and the use of lethal force against non-state actors - individuals, groups or terrorist organizations - beyond their national borders. Reformulating the security paradigm has led, in these cases, to policies against terrorism. This is the case of targeted killing - the killing of selected targets - by the USA and Israel. Targeted killing actions - using essentially but not only drones - in Pakistan and Yemen by the American administration, a well as the Israeli response to Palestinian terrorism, are under heated debate in terms of their efficiency and legality. Thus, this paper aims to not only provide an analytical framework on this theme but also analyze the scope and impact of these counter terrorist strategies by the two countries.

It?s Not Just Conflict That Motivates Killing of Orangutans

OpenAIRE

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 ...

Monitoring the Bystander Killing Effect of Human Multipotent Stem Cells for Treatment of Malignant Brain Tumors

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Cindy Leten

2016-01-01

Full Text Available Tumor infiltrating stem cells have been suggested as a vehicle for the delivery of a suicide gene towards otherwise difficult to treat tumors like glioma. We have used herpes simplex virus thymidine kinase expressing human multipotent adult progenitor cells in two brain tumor models (hU87 and Hs683 in immune-compromised mice. In order to determine the best time point for the administration of the codrug ganciclovir, the stem cell distribution and viability were monitored in vivo using bioluminescence (BLI and magnetic resonance imaging (MRI. Treatment was assessed by in vivo BLI and MRI of the tumors. We were able to show that suicide gene therapy using HSV-tk expressing stem cells can be followed in vivo by MRI and BLI. This has the advantage that (1 outliers can be detected earlier, (2 GCV treatment can be initiated based on stem cell distribution rather than on empirical time points, and (3 a more thorough follow-up can be provided prior to and after treatment of these animals. In contrast to rodent stem cell and tumor models, treatment success was limited in our model using human cell lines. This was most likely due to the lack of immune components in the immune-compromised rodents.

9 CFR 113.208 - Avian Encephalomyelitis Vaccine, Killed Virus.

Science.gov (United States)

2010-01-01

..., Killed Virus. 113.208 Section 113.208 Animals and Animal Products ANIMAL AND PLANT HEALTH INSPECTION SERVICE, DEPARTMENT OF AGRICULTURE VIRUSES, SERUMS, TOXINS, AND ANALOGOUS PRODUCTS; ORGANISMS AND VECTORS STANDARD REQUIREMENTS Killed Virus Vaccines § 113.208 Avian Encephalomyelitis Vaccine, Killed Virus. Avian...

Where and How Wolves (Canis lupus Kill Beavers (Castor canadensis.

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Thomas D Gable

Full Text Available 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.

Conformal Killing horizons and their thermodynamics

Science.gov (United States)

Nielsen, Alex B.; Shoom, Andrey A.

2018-05-01

Certain dynamical black hole solutions can be mapped to static spacetimes by conformal metric transformations. This mapping provides a physical link between the conformal Killing horizon of the dynamical black hole and the Killing horizon of the static spacetime. Using the Vaidya spacetime as an example, we show how this conformal relation can be used to derive thermodynamic properties of such dynamical black holes. Although these horizons are defined quasi-locally and can be located by local experiments, they are distinct from other popular notions of quasi-local horizons such as apparent horizons. Thus in the dynamical Vaidya spacetime describing constant accretion of null dust, the conformal Killing horizon, which is null by construction, is the natural horizon to describe the black hole.

Criteria for the selection of radionuclides for tumor radioimmunotherapy

Energy Technology Data Exchange (ETDEWEB)

Srivastava, S.C.; Mausner, L.F.; Mease, R.C.

1991-01-01

The potential of utilizing monoclonal antibodies as carriers of radionuclides for the selective destruction of tumors (radioimmunotherapy, RIT) has stimulated much research activity. From dosimetric and other considerations, the choice of radiolabel is an important factor that needs to be optimized for maximum effectiveness of RIT. This paper reviews and assesses a number of present and future radionuclides that are particularly suitable for RIT based on the various physical, chemical, and biological considerations. Intermediate to high-energy beta emitters' (with and without gamma photons in their emission) are emphasized since they possess a number of advantages over alpha and Auger emitters. Factors relating to the production and availability of candidate radiometals as well as their stable chemical attachment to monoclonal antibodies are discussed. 34 refs., 4 tabs.

Difluoromethylornithine enhanced uptake of tritiated putrescine in 9L rat brain tumors

International Nuclear Information System (INIS)

Redgate, E.S.; Grudziak, A.G.; Deutsch, M.; Boggs, S.S.

1997-01-01

] putrescine by rapidly dividing cells which are within a 1.4 mm diameter area at the cannula tip. Although these studies used [ 3 H] putrescine at trace doses, it is estimated that infusion of higher doses of [ 3 H] putrescine plus DFMO will selectively kill tumor cells

Tumor radiosensitizers-current status of development of various approaches: Report of an International Atomic Energy Agency meeting

International Nuclear Information System (INIS)

Horsman, Michael R.; Bohm, Lothar; Margison, Geoffrey P.; Milas, Luka; Rosier, Jean-Francois; Safrany, Geza; Selzer, Edgar; Verheij, Marcel; Hendry, Jolyon H.

2006-01-01

Purpose: The International Atomic Energy Agency (IAEA) held a Technical Meeting of Consultants to (1) discuss a selection of relatively new agents, not those well-established in clinical practice, that operated through a variety of mechanisms to sensitize tumors to radiation and (2) to compare and contrast their tumor efficacy, normal tissue toxicity, and status of development regarding clinical application. The aim was to advise the IAEA as to which developing agent or class of agents would be worth promoting further, by supporting additional laboratory research or clinical trials, with the eventual goal of improving cancer control rates using radiotherapy, in developing countries in particular. Results: The agents under discussion included a wide, but not complete, range of different types of drugs, and antibodies that interfered with molecules in cell signaling pathways. These were contrasted with new molecular antisense and gene therapy strategies. All the drugs discussed have previously been shown to act as tumor cell radiosensitizers or to kill hypoxic cells present in tumors. Conclusion: Specific recommendations were made for more preclinical studies with certain of the agents and for clinical trials that would be suitable for industrialized countries, as well as trials that were considered more appropriate for developing countries

Patterns and Composition of Road-Killed Wildlife in Northwest Argentina

Science.gov (United States)

Cuyckens, Griet An Erica; Mochi, Lucía Sol; Vallejos, María; Perovic, Pablo Gastón; Biganzoli, Fernando

2016-11-01

Roads have important effects on wildlife, such as natural habitat fragmentation and degradation and direct killing of fauna, which leads to reductions in wildlife population size. We focused on a principal road in Northwest Argentina to test for the effect of seasonality and landscape features on the composition of road-killed wildlife. We conducted regularly scheduled road trips during the dry and wet seasons. We recorded the presence or absence of a vegetation curtain or hedge along the road. We measured land use by remote sensing in a 500 m buffer along the road. We compared the abundance of animals killed between seasons (dry and wet) for different taxonomic groups (mammals, birds and reptiles) and for different origins (domestic and native). We built linear mixed models to test the effect of landscape features on the abundance of killed animals. Two hundred and ninety-three individuals were killed, belonging to 35 species; 75.8 % were native and 24.2 % domestic species. The majority of animals killed were mid-sized mammals. More animals were killed during the dry season. The most important factors to explain the wildlife road-killing were the season and the proportion of agricultural landscape. The composition of the killed animals changed with the season. The proportion of agricultural landscape incremented the number of killed birds and mammals during both seasons, without affecting reptiles. The ratio of wild to domestic animals killed was dependent on the season. This study sets a precedent as the first in road ecology in Northwest Argentina and should be taken into account for road planning and regulation.

Intergenomic arms races: detection of a nuclear rescue gene of male-killing in a ladybird.

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Tamsin M O Majerus

Full Text Available Many species of arthropod are infected by deleterious inherited micro-organisms. Typically these micro-organisms are inherited maternally. Consequently, some, particularly bacteria of the genus Wolbachia, employ a variety of strategies that favour female over male hosts. These strategies include feminisation, induction of parthenogenesis and male-killing. These strategies result in female biased sex ratios in host populations, which lead to selection for host factors that promote male production. In addition, the intra-genomic conflict produced by the difference in transmission of these cytoplasmic endosymbionts and nuclear factors will impose a pressure favouring nuclear factors that suppress the effects of the symbiont. During investigations of the diversity of male-killing bacteria in ladybirds (Coccinellidae, unexpected patterns of vertical transmission of a newly discovered male-killing taxon were observed in the ladybird Cheilomenes sexmaculata. Initial analysis suggested that the expression of the bacterial male-killing trait varies according to the male(s a female has mated with. By swapping males between females, a male influence on the expression of the male-killing trait was confirmed. Experiments were then performed to determine the nature of the interaction. These studies showed that a single dominant allele, which rescues male progeny of infected females from the pathological effect of the male-killer, exists in this species. The gene shows typical Mendelian autosomal inheritance and is expressed irrespective of the parent from which it is inherited. Presence of the rescue gene in either parent does not significantly affect the inheritance of the symbiont. We conclude that C. sexmaculata is host to a male-killing gamma-proteobacterium. Further, this beetle is polymorphic for a nuclear gene, the dominant allele of which rescues infected males from the pathogenic effects of the male-killing agent. These findings represent the first

9 CFR 113.204 - Mink Enteritis Vaccine, Killed Virus.

Science.gov (United States)

2010-01-01

... 9 Animals and Animal Products 1 2010-01-01 2010-01-01 false Mink Enteritis Vaccine, Killed Virus..., DEPARTMENT OF AGRICULTURE VIRUSES, SERUMS, TOXINS, AND ANALOGOUS PRODUCTS; ORGANISMS AND VECTORS STANDARD REQUIREMENTS Killed Virus Vaccines § 113.204 Mink Enteritis Vaccine, Killed Virus. Mink Enteritis Vaccine...

9 CFR 113.212 - Bursal Disease Vaccine, Killed Virus.

Science.gov (United States)

2010-01-01

... 9 Animals and Animal Products 1 2010-01-01 2010-01-01 false Bursal Disease Vaccine, Killed Virus..., DEPARTMENT OF AGRICULTURE VIRUSES, SERUMS, TOXINS, AND ANALOGOUS PRODUCTS; ORGANISMS AND VECTORS STANDARD REQUIREMENTS Killed Virus Vaccines § 113.212 Bursal Disease Vaccine, Killed Virus. Bursal Disease Vaccine...

Mass killings and detection of impacts

Science.gov (United States)

McLaren, Digby J.

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.

The eyeball killer: serial killings with postmortem globe enucleation.

Science.gov (United States)

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. © 2015 American Academy of Forensic Sciences.

Managing Threat, Cost, and Incentive to Kill: The Short- and Long-Term Effects of Intervention in Mass Killings

Science.gov (United States)

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…

9 CFR 113.201 - Canine Distemper Vaccine, Killed Virus.

Science.gov (United States)

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... canine distemper susceptible dogs (20 vaccinates and 5 controls) shall be used as test animals. Blood...

Systemic side effects of isolated limb perfusion with tumor necrosis factor alpha

NARCIS (Netherlands)

Zwaveling, Jan Harm

1997-01-01

The main function of tumor necrosis factor alpha (TNF-a), a small polypeptide shared by all mammals, is probably protection against invading bacteria, parasites and viruses; killing of these microorganisms is facilitated in the presence of TNF-a. However, as its name suggest, TNF-a is also capable

Enhanced relative biological effectiveness of proton radiotherapy in tumor cells with internalized gold nanoparticles

International Nuclear Information System (INIS)

Polf, Jerimy C.; Gillin, Michael; Bronk, Lawrence F.; Driessen, Wouter H. P.; Arap, Wadih; Pasqualini, Renata

2011-01-01

The development and use of sensitizing agents to improve the effectiveness of radiotherapy have long been sought to improve our ability to treat cancer. In this letter, we have studied the relative biological effectiveness of proton beam radiotherapy on prostate tumor cells with and without internalized gold nanoparticles. The effectiveness of proton radiotherapy for the killing of prostate tumor cells was increased by approximately 15%-20% for those cells containing internalized gold nanoparticles.

Intercellular Communication of Tumor Cells and Immune Cells after Exposure to Different Ionizing Radiation Qualities

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Sebastian Diegeler

2017-06-01

Full Text Available Ionizing radiation can affect the immune system in many ways. Depending on the situation, the whole body or parts of the body can be acutely or chronically exposed to different radiation qualities. In tumor radiotherapy, a fractionated exposure of the tumor (and surrounding tissues is applied to kill the tumor cells. Currently, mostly photons, and also electrons, neutrons, protons, and heavier particles such as carbon ions, are used in radiotherapy. Tumor elimination can be supported by an effective immune response. In recent years, much progress has been achieved in the understanding of basic interactions between the irradiated tumor and the immune system. Here, direct and indirect effects of radiation on immune cells have to be considered. Lymphocytes for example are known to be highly radiosensitive. One important factor in indirect interactions is the radiation-induced bystander effect which can be initiated in unexposed cells by expression of cytokines of the irradiated cells and by direct exchange of molecules via gap junctions. In this review, we summarize the current knowledge about the indirect effects observed after exposure to different radiation qualities. The different immune cell populations important for the tumor immune response are natural killer cells, dendritic cells, and CD8+ cytotoxic T-cells. In vitro and in vivo studies have revealed the modulation of their functions due to ionizing radiation exposure of tumor cells. After radiation exposure, cytokines are produced by exposed tumor and immune cells and a modulated expression profile has also been observed in bystander immune cells. Release of damage-associated molecular patterns by irradiated tumor cells is another factor in immune activation. In conclusion, both immune-activating and -suppressing effects can occur. Enhancing or inhibiting these effects, respectively, could contribute to modified tumor cell killing after radiotherapy.

Intercellular Communication of Tumor Cells and Immune Cells after Exposure to Different Ionizing Radiation Qualities.

Science.gov (United States)

Diegeler, Sebastian; Hellweg, Christine E

2017-01-01

Ionizing radiation can affect the immune system in many ways. Depending on the situation, the whole body or parts of the body can be acutely or chronically exposed to different radiation qualities. In tumor radiotherapy, a fractionated exposure of the tumor (and surrounding tissues) is applied to kill the tumor cells. Currently, mostly photons, and also electrons, neutrons, protons, and heavier particles such as carbon ions, are used in radiotherapy. Tumor elimination can be supported by an effective immune response. In recent years, much progress has been achieved in the understanding of basic interactions between the irradiated tumor and the immune system. Here, direct and indirect effects of radiation on immune cells have to be considered. Lymphocytes for example are known to be highly radiosensitive. One important factor in indirect interactions is the radiation-induced bystander effect which can be initiated in unexposed cells by expression of cytokines of the irradiated cells and by direct exchange of molecules via gap junctions. In this review, we summarize the current knowledge about the indirect effects observed after exposure to different radiation qualities. The different immune cell populations important for the tumor immune response are natural killer cells, dendritic cells, and CD8+ cytotoxic T-cells. In vitro and in vivo studies have revealed the modulation of their functions due to ionizing radiation exposure of tumor cells. After radiation exposure, cytokines are produced by exposed tumor and immune cells and a modulated expression profile has also been observed in bystander immune cells. Release of damage-associated molecular patterns by irradiated tumor cells is another factor in immune activation. In conclusion, both immune-activating and -suppressing effects can occur. Enhancing or inhibiting these effects, respectively, could contribute to modified tumor cell killing after radiotherapy.

p53 and PCNA Expression in Keratocystic Odontogenic Tumors Compared with Selected Odontogenic Cysts

Science.gov (United States)

Seyedmajidi, Maryam; Nafarzadeh, Shima; Siadati, Sepideh; Shafaee, Shahryar; Bijani, Ali; Keshmiri, Nazanin

2013-01-01

p53 and PCNA expression in keratocystic odontogenic tumors compared with selected odontogenic cysts Summary: The aim of this study was to evaluate p53 and PCNA expression in different odontogenic lesions regarding their different clinical behaviors. Slices prepared from 94 paraffin-embedded tissue blocks (25 radicular cysts (RC), 23 dentigerous cysts (DC), 23 keratocystic odontogenic tumors (KCOT) and 23 calcifying cystic odontogenic tumors (CCOT)) were stained with p53 and PCNA antibodies using immunohistochemistry procedure. The highest level of p53 expression was in the basal layer of RC, and the highest level of PCNA expression was in the suprabasal layer of KCOT. The differences of p53 expression in basal and suprabasal layers as well as PCNA expression in the suprabasal layer were significant but there was no significant difference in PCNA expression in the basal layer of these lesions. The expression of p53 in the basal layer of RC was higher than in other cysts. This may be due to intensive inflammatory infiltration. Also, the high level of PCNA expression in the suprabasal layer of KCOT may justify its neoplastic nature and tendency to recurrence. KCOT and calcifying cystic odontogenic tumors did not show similar expression of studied biomarkers. PMID:24551811

Temperate and lytic bacteriophages programmed to sensitize and kill antibiotic-resistant bacteria.

Science.gov (United States)

Yosef, Ido; Manor, Miriam; Kiro, Ruth; Qimron, Udi

2015-06-09

The increasing threat of pathogen resistance to antibiotics requires the development of novel antimicrobial strategies. Here we present a proof of concept for a genetic strategy that aims to sensitize bacteria to antibiotics and selectively kill antibiotic-resistant bacteria. We use temperate phages to deliver a functional clustered regularly interspaced short palindromic repeats (CRISPR)-CRISPR-associated (Cas) system into the genome of antibiotic-resistant bacteria. The delivered CRISPR-Cas system destroys both antibiotic resistance-conferring plasmids and genetically modified lytic phages. This linkage between antibiotic sensitization and protection from lytic phages is a key feature of the strategy. It allows programming of lytic phages to kill only antibiotic-resistant bacteria while protecting antibiotic-sensitized bacteria. Phages designed according to this strategy may be used on hospital surfaces and hand sanitizers to facilitate replacement of antibiotic-resistant pathogens with sensitive ones.

EGF receptor-targeted synthetic double-stranded RNA eliminates glioblastoma, breast cancer, and adenocarcinoma tumors in mice.

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Alexei Shir

2006-01-01

Full Text Available BACKGROUND: Glioblastoma multiforme (GBM is the most lethal form of brain cancer. With the available treatments, survival does not exceed 12-14 mo from the time of diagnosis. We describe a novel strategy to selectively induce the death of glioblastoma cells and other cancer cells that over-express the EGF receptor. Using a non-viral delivery vector that homes to the EGF receptor, we target synthetic anti-proliferative dsRNA (polyinosine-cytosine [poly IC], a strong activator of apoptosis, selectively to cancer cells. METHODS AND FINDINGS: Poly IC was delivered by means of a non-viral vector: 25kDa polyethylenimine-polyethyleneglycol-EGF (PEI25-PEG-EGF. EGFR-targeted poly IC induced rapid apoptosis in the target cells in vitro and in vivo. Expression of several cytokines and "bystander killing" of untransfected tumor cells was detected in vitro and in vivo. Intra-tumoral delivery of the EGFR-targeted poly IC induced the complete regression of pre-established intracranial tumors in nude mice, with no obvious adverse toxic effects on normal brain tissue. A year after treatment completion the treated mice remain cancer-free and healthy. Similarly, non-viral delivery of poly IC completely eliminated pre-established breast cancer and adenocarcinoma xenografts derived from EGFR over-expressing cancer cell lines, suggesting that the strategy is applicable to other EGFR-over-expressing tumors. CONCLUSION: The strategy described has yielded an effective treatment of EGFR over-expressing GBM in an animal model. If this strategy is translated successfully to the clinical setting, it may actually offer help to GBM patients. Moreover the elimination of two additional EGFR over-expressing cancers in vivo suggests that in principle this strategy can be applied to treat other tumors that over-express EGFR.

Macrophage biology plays a central role during ionizing radiation-elicited tumor response

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Qiuji Wu

2017-08-01

Full Text Available Radiation therapy is one of the major therapeutic modalities for most solid tumors. The anti-tumor effect of radiation therapy consists of the direct tumor cell killing, as well as the modulation of tumor microenvironment and the activation of immune response against tumors. Radiation therapy has been shown to promote immunogenic cells death, activate dendritic cells and enhance tumor antigen presentation and anti-tumor T cell activation. Radiation therapy also programs innate immune cells such as macrophages that leads to either radiosensitization or radioresistance, according to different tumors and different radiation regimen studied. The mechanisms underlying radiation-induced macrophage activation remain largely elusive. Various molecular players such as NF-κB, MAPKs, p53, reactive oxygen species, inflammasomes have been involved in these processes. The skewing to a pro-inflammatory phenotype thus results in the activation of anti-tumor immune response and enhanced radiotherapy effect. Therefore, a comprehensive understanding of the mechanism of radiation-induced macrophage activation and its role in tumor response to radiation therapy is crucial for the development of new therapeutic strategies to enhance radiation therapy efficacy.

From Attitudes to Actions: Predictors of Lion Killing by Maasai Warriors.

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Hazzah, Leela; Bath, Alistair; Dolrenry, Stephanie; Dickman, Amy; Frank, Laurence

2017-01-01

Despite legal protection, deliberate killing by local people is one of the major threats to the conservation of lions and other large carnivores in Africa. Addressing this problem poses particular challenges, mainly because it is difficult to uncover illicit behavior. This article examined two groups of Maasai warriors: individuals who have killed African lions (Panthera leo) and those who have not. We conducted interviews to explore the relationship between attitudes, intentions and known lion killing behavior. Factor analysis and logistic regression revealed that lion killing was mainly determined by: (a) general attitudes toward lions, (b) engagement in traditional customs, (c) lion killing intentions to defend property, and (d) socio-cultural killing intentions. Our results indicated that general attitudes toward lions were the strongest predictor of lion killing behavior. Influencing attitudes to encourage pro-conservation behavior may help reduce killing.

TRAIL-induced programmed necrosis as a novel approach to eliminate tumor cells

International Nuclear Information System (INIS)

Voigt, Susann; Kalthoff, Holger; Adam, Dieter; Philipp, Stephan; Davarnia, Parvin; Winoto-Morbach, Supandi; Röder, Christian; Arenz, Christoph; Trauzold, Anna; Kabelitz, Dieter; Schütze, Stefan

2014-01-01

The cytokine TRAIL represents one of the most promising candidates for the apoptotic elimination of tumor cells, either alone or in combination therapies. However, its efficacy is often limited by intrinsic or acquired resistance of tumor cells to apoptosis. Programmed necrosis is an alternative, molecularly distinct mode of programmed cell death that is elicited by TRAIL under conditions when the classical apoptosis machinery fails or is actively inhibited. The potential of TRAIL-induced programmed necrosis in tumor therapy is, however, almost completely uncharacterized. We therefore investigated its impact on a panel of tumor cell lines of wide-ranging origin. Cell death/viability was measured by flow cytometry/determination of intracellular ATP levels/crystal violet staining. Cell surface expression of TRAIL receptors was detected by flow cytometry, expression of proteins by Western blot. Ceramide levels were quantified by high-performance thin layer chromatography and densitometric analysis, clonogenic survival of cells was determined by crystal violet staining or by soft agarose cloning. TRAIL-induced programmed necrosis killed eight out of 14 tumor cell lines. Clonogenic survival was reduced in all sensitive and even one resistant cell lines tested. TRAIL synergized with chemotherapeutics in killing tumor cell lines by programmed necrosis, enhancing their effect in eight out of 10 tested tumor cell lines and in 41 out of 80 chemotherapeutic/TRAIL combinations. Susceptibility/resistance of the investigated tumor cell lines to programmed necrosis seems to primarily depend on expression of the pro-necrotic kinase RIPK3 rather than the related kinase RIPK1 or cell surface expression of TRAIL receptors. Furthermore, interference with production of the lipid ceramide protected all tested tumor cell lines. Our study provides evidence that TRAIL-induced programmed necrosis represents a feasible approach for the elimination of tumor cells, and that this treatment may

Killing machines: three pore-forming proteins of the immune system

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McCormack, Ryan; de Armas, Lesley; Shiratsuchi, Motoaki

2014-01-01

The evolution of early multicellular eukaryotes 400–500 million years ago required a defensive strategy against microbial invasion. Pore-forming proteins containing the membrane-attack-complex-perforin (MACPF) domain were selected as the most efficient means to destroy bacteria or virally infected cells. The mechanism of pore formation by the MACPF domain is distinctive in that pore formation is purely physical and unspecific. The MACPF domain polymerizes, refolds, and inserts itself into bilayer membranes or bacterial outer cell walls. The displacement of surface lipid/carbohydrate molecules by the polymerizing MACPF domain creates clusters of large, water-filled holes that destabilize the barrier function and provide access for additional anti-bacterial or anti-viral effectors to sensitive sites that complete the destruction of the invader via enzymatic or chemical attack. The highly efficient mechanism of anti-microbial defense by a combined physical and chemical strategy using pore-forming MACPF-proteins has been retargeted during evolution of vertebrates and mammals for three purposes: (1) to kill extracellular bacteria C9/polyC9 evolved in conjunction with complement, (2) to kill virus infected and cancer cells perforin-1/polyperforin-1 CTL evolved targeted by NK and CTL, and (3) to kill intracellular bacteria transmembrane perforin-2/putative polyperforin-2 evolved targeted by phagocytic and nonphagocytic cells. Our laboratory has been involved in the discovery and description of each of the three pore-formers that will be reviewed here. PMID:24293008

Targeting and killing of glioblastoma with activated T cells armed with bispecific antibodies

International Nuclear Information System (INIS)

Zitron, Ian M; Thakur, Archana; Norkina, Oxana; Barger, Geoffrey R; Lum, Lawrence G; Mittal, Sandeep

2013-01-01

Since most glioblastomas express both wild-type EGFR and EGFRvIII as well as HER2/neu, they are excellent targets for activated T cells (ATC) armed with bispecific antibodies (BiAbs) that target EGFR and HER2. ATC were generated from PBMC activated for 14 days with anti-CD3 monoclonal antibody in the presence of interleukin-2 and armed with chemically heteroconjugated anti-CD3×anti-HER2/neu (HER2Bi) and/or anti-CD3×anti-EGFR (EGFRBi). HER2Bi- and/or EGFRBi-armed ATC were examined for in vitro cytotoxicity using MTT and 51 Cr-release assays against malignant glioma lines (U87MG, U118MG, and U251MG) and primary glioblastoma lines. EGFRBi-armed ATC killed up to 85% of U87, U118, and U251 targets at effector:target ratios (E:T) ranging from 1:1 to 25:1. Engagement of tumor by EGFRBi-armed ATC induced Th1 and Th2 cytokine secretion by armed ATC. HER2Bi-armed ATC exhibited comparable cytotoxicity against U118 and U251, but did not kill HER2-negative U87 cells. HER2Bi- or EGFRBi-armed ATC exhibited 50—80% cytotoxicity against four primary glioblastoma lines as well as a temozolomide (TMZ)-resistant variant of U251. Both CD133– and CD133+ subpopulations were killed by armed ATC. Targeting both HER2Bi and EGFRBi simultaneously showed enhanced efficacy than arming with a single BiAb. Armed ATC maintained effectiveness after irradiation and in the presence of TMZ at a therapeutic concentration and were capable of killing multiple targets. High-grade gliomas are suitable for specific targeting by armed ATC. These data, together with additional animal studies, may provide the preclinical support for the use of armed ATC as a valuable addition to current treatment regimens

Overview of Methods Able to Overcome Impediments to tumor Drug Delivery with Special Attention to Tumor Interstitial Fluid.

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Gianfranco eBaronzio

2015-07-01

Full Text Available Every drug used to treat cancer (chemotherapeutics, immunologic, 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, beginning with tumor interstitial fluid pressure (TIFP and a multifactorial increase in composition of the extracellular matrix (ECM. A primary modifier of tumor microenvironment is hypoxia, which increases the production of growth factors such as vascular endothelial growth factor (VEGF and platelet-derived growth factor (PDGF. These growth factors released by both tumor cells and bone marrow recruited myeloid cells (MDS, 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 (TIF], ultimately creating an increased pressure (TIFP. Fibroblasts are also up-regulated by the tumor microenvironment, and deposit fibers that further augment the density of the extracellular matrix (ECM, thus, further worsening the TIFP. Increased TIFP with the ECM are the major obstacles to adequate drug delivery. By decreasing TIFP and decreasing 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, physical methods of treatment able to lower TIFP and to modify ECM that can be used for increasing drug concentration within the tumor tissue.

Killing vectors in empty space algebraically special metrics. II

International Nuclear Information System (INIS)

Held, A.

1976-01-01

Empty space algebraically special metrics possessing an expanding degenerate principal null vector and Killing vectors are investigated. Attention is centered on that class of Killing vector (called nonpreferred) which is necessarily spacelike in the asymptotic region. A detailed analysis of the relationship between the Petrov--Penrose classification and these Killing vectors is carried out

The combined status of ATM and p53 link tumor development with therapeutic response

DEFF Research Database (Denmark)

Jiang, Hai; Reinhardt, H Christian; Bartkova, Jirina

2009-01-01

commonly used by tumors to bypass early neoplastic checkpoints ultimately determine chemotherapeutic response and generate tumor-specific vulnerabilities that can be exploited with targeted therapies. Specifically, evaluation of the combined status of ATM and p53, two commonly mutated tumor suppressor...... genes, can help to predict the clinical response to genotoxic chemotherapies. We show that in p53-deficient settings, suppression of ATM dramatically sensitizes tumors to DNA-damaging chemotherapy, whereas, conversely, in the presence of functional p53, suppression of ATM or its downstream target Chk2...... actually protects tumors from being killed by genotoxic agents. Furthermore, ATM-deficient cancer cells display strong nononcogene addiction to DNA-PKcs for survival after DNA damage, such that suppression of DNA-PKcs in vivo resensitizes inherently chemoresistant ATM-deficient tumors to genotoxic...

Neutrophils kill the parasite Trichomonas vaginalis using trogocytosis

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Mercer, Frances; Ng, Shek Hang; Brown, Taylor M.; Boatman, Grace; Johnson, Patricia J.

2018-01-01

T. vaginalis, a human-infective parasite, causes the most common nonviral sexually transmitted infection (STI) worldwide and contributes to adverse inflammatory disorders. The immune response to T. vaginalis is poorly understood. Neutrophils (polymorphonuclear cells [PMNs]) are the major immune cell present at the T. vaginalis–host interface and are thought to clear T. vaginalis. However, the mechanism of PMN clearance of T. vaginalis has not been characterized. We demonstrate that human PMNs rapidly kill T. vaginalis in a dose-dependent, contact-dependent, and neutrophil extracellular trap (NET)-independent manner. In contrast to phagocytosis, we observed that PMN killing of T. vaginalis involves taking “bites” of T. vaginalis prior to parasite death, using trogocytosis to achieve pathogen killing. Both trogocytosis and parasite killing are dependent on the presence of PMN serine proteases and human serum factors. Our analyses provide the first demonstration, to our knowledge, of a mammalian phagocyte using trogocytosis for pathogen clearance and reveal a novel mechanism used by PMNs to kill a large, highly motile target. PMID:29408891

Induction of selective blood-tumor barrier permeability and macromolecular transport by a biostable kinin B1 receptor agonist in a glioma rat model.

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Côté, Jérôme; Bovenzi, Veronica; Savard, Martin; Dubuc, Céléna; Fortier, Audrey; Neugebauer, Witold; Tremblay, Luc; Müller-Esterl, Werner; Tsanaclis, Ana-Maria; Lepage, Martin; Fortin, David; Gobeil, Fernand

2012-01-01

Treatment of malignant glioma with chemotherapy is limited mostly because of delivery impediment related to the blood-brain tumor barrier (BTB). B1 receptors (B1R), inducible prototypical G-protein coupled receptors (GPCR) can regulate permeability of vessels including possibly that of brain tumors. Here, we determine the extent of BTB permeability induced by the natural and synthetic peptide B1R agonists, LysdesArg(9)BK (LDBK) and SarLys[dPhe(8)]desArg(9)BK (NG29), in syngeneic F98 glioma-implanted Fischer rats. Ten days after tumor inoculation, we detected the presence of B1R on tumor cells and associated vasculature. NG29 infusion increased brain distribution volume and uptake profiles of paramagnetic probes (Magnevist and Gadomer) at tumoral sites (T(1)-weighted imaging). These effects were blocked by B1R antagonist and non-selective cyclooxygenase inhibitors, but not by B2R antagonist and non-selective nitric oxide synthase inhibitors. Consistent with MRI data, systemic co-administration of NG29 improved brain tumor delivery of Carboplatin chemotherapy (ICP-Mass spectrometry). We also detected elevated B1R expression in clinical samples of high-grade glioma. Our results documented a novel GPCR-signaling mechanism for promoting transient BTB disruption, involving activation of B1R and ensuing production of COX metabolites. They also underlined the potential value of synthetic biostable B1R agonists as selective BTB modulators for local delivery of different sized-therapeutics at (peri)tumoral sites.

Local Control of Lung Derived Tumors by Diffusing Alpha-Emitting Atoms Released From Intratumoral Wires Loaded With Radium-224

International Nuclear Information System (INIS)

Cooks, Tomer; Schmidt, Michael; Bittan, Hadas; Lazarov, Elinor; Arazi, Lior; Kelson, Itzhak; Keisari, Yona

2009-01-01

Purpose: Diffusing alpha-emitters radiation therapy (DART) is a new form of brachytherapy enabling the treatment of solid tumors with alpha radiation. The present study examines the antitumoral effects resulting from the release of alpha emitting radioisotopes into solid lung carcinoma (LL2, A427, and NCI-H520). Methods and Materials: An in vitro setup tested the dose-dependent killing of tumor cells exposed to alpha particles. In in vivo studies, radioactive wires (0.3 mm diameter, 5 mm long) with 224 Ra activities in the range of 21-38 kBq were inserted into LL/2 tumors in C57BL/6 mice and into human-derived A427 or NCI-H520 tumors in athymic mice. The efficacy of the short-lived daughters of 224 Ra to produce tumor growth retardation and prolong life was assessed, and the spread of radioisotopes inside tumors was measured using autoradiography. Results: The insertion of a single DART wire into the center of 6- to 7-mm tumors had a pronounced retardation effect on tumor growth, leading to a significant inhibition of 49% (LL2) and 93% (A427) in tumor development and prolongations of 48% (LL2) in life expectancy. In the human model, more than 80% of the treated tumors disappeared or shrunk. Autoradiographic analysis of the treated sectioned tissue revealed the intratumoral distribution of the radioisotopes, and histological analysis showed corresponding areas of necrosis. In vitro experiments demonstrated a dose-dependent killing of tumors cells exposed to alpha particles. Conclusions: Short-lived diffusing alpha-emitters produced tumor growth retardation and increased survival in mice bearing lung tumor implants. These results justify further investigations with improved dose distributions.

Female serial killing: review and case report.

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Frei, Andreas; Völlm, Birgit; Graf, Marc; Dittmann, Volker

2006-01-01

Single homicide committed by women is rare. Serial killing is very infrequent, and the perpetrators are usually white, intelligent males with sadistic tendencies. Serial killing by women has, however, also been described. To conduct a review of published literature on female serial killers and consider its usefulness in assessing a presenting case. A literature review was conducted, after searching EMBASE, MEDLINE and PsycINFO. The presenting clinical case is described in detail in the context of the literature findings. Results The literature search revealed few relevant publications. Attempts to categorize the phenomenon of female serial killing according to patterns of and motives for the homicides have been made by some authors. The most common motive identified was material gain or similar extrinsic gratification while the 'hedonistic' sadistic or sexual serial killer seems to be extremely rare in women. There is no consistent theory of serial killing by women, but psychopathic personality traits and abusive childhood experiences have consistently been observed. The authors' case did not fit the description of a 'typical' female serial killer. In such unusual circumstances as serial killing by a woman, detailed individual case formulation is required to make sense of the psychopathology in each case. Publication of cases in scientific journals should be encouraged to advance our understanding of this phenomenon. Copyright (c) 2006 John Wiley & Sons, Ltd.

Enhanced relative biological effectiveness of proton radiotherapy in tumor cells with internalized gold nanoparticles

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Polf, Jerimy C.; Bronk, Lawrence F.; Driessen, Wouter H. P.; Arap, Wadih; Pasqualini, Renata; Gillin, Michael

2011-01-01

The development and use of sensitizing agents to improve the effectiveness of radiotherapy have long been sought to improve our ability to treat cancer. In this letter, we have studied the relative biological effectiveness of proton beam radiotherapy on prostate tumor cells with and without internalized gold nanoparticles. The effectiveness of proton radiotherapy for the killing of prostate tumor cells was increased by approximately 15%–20% for those cells containing internalized gold nanoparticles. PMID:21915155

Evaluation of RGD-targeted albumin carriers for specific delivery of auristatin E to tumor blood vessels.

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Temming, Kai; Meyer, Damon L; Zabinski, Roger; Dijkers, Eli C F; Poelstra, Klaas; Molema, Grietje; Kok, Robbert J

2006-01-01

Induction of apoptosis in endothelial cells is considered an attractive strategy to therapeutically interfere with a solid tumor's blood supply. In the present paper, we constructed cytotoxic conjugates that specifically target angiogenic endothelial cells, thus preventing typical side effects of apoptosis-inducing drugs. For this purpose, we conjugated the potent antimitotic agent monomethyl-auristatin-E (MMAE) via a lysosomal cleavable linker to human serum albumin (HSA) and further equipped this drug-albumin conjugate with cyclic c(RGDfK) peptides for multivalent interaction with alphavbeta3-integrin. The RGD-peptides were conjugated via either an extended poly(ethylene glycol) linker or a short alkyl linker. The resulting drug-targeting conjugates RGDPEG-MMAE-HSA and RGD-MMAE-HSA demonstrated high binding affinity and specificity for alphavbeta3-integrin expressing human umbilical vein endothelial cells (HUVEC). Both types of conjugates were internalized by endothelial cells and killed the target cells at low nM concentrations. Furthermore, we observed RGD-dependent binding of the conjugates to C26 carcinoma. Upon i.v. administration to C26-tumor bearing mice, both drug-targeting conjugates displayed excellent tumor homing properties. Our results demonstrate that RGD-modified albumins are suitable carriers for cell selective intracellular delivery of cytotoxic compounds, and further studies will be conducted to assess the antivascular and tumor inhibitory potential of RGDPEG-MMAE-HSA and RGD-MMAE-HSA.

Towards PDT with Genetically Encoded Photosensitizer KillerRed: A Comparison of Continuous and Pulsed Laser Regimens in an Animal Tumor Model.

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Marina Shirmanova

Full Text Available The strong phototoxicity of the red fluorescent protein KillerRed allows it to be considered as a potential genetically encoded photosensitizer for the photodynamic therapy (PDT of cancer. The advantages of KillerRed over chemical photosensitizers are its expression in tumor cells transduced with the appropriate gene and direct killing of cells through precise damage to any desired cell compartment. The ability of KillerRed to affect cell division and to induce cell death has already been demonstrated in cancer cell lines in vitro and HeLa tumor xenografts in vivo. However, the further development of this approach for PDT requires optimization of the method of treatment. In this study we tested the continuous wave (593 nm and pulsed laser (584 nm, 10 Hz, 18 ns modes to achieve an antitumor effect. The research was implemented on CT26 subcutaneous mouse tumors expressing KillerRed in fusion with histone H2B. The results showed that the pulsed mode provided a higher rate of photobleaching of KillerRed without any temperature increase on the tumor surface. PDT with the continuous wave laser was ineffective against CT26 tumors in mice, whereas the pulsed laser induced pronounced histopathological changes and inhibition of tumor growth. Therefore, we selected an effective regimen for PDT when using the genetically encoded photosensitizer KillerRed and pulsed laser irradiation.

Improved Killing of Ovarian Cancer Stem Cells by Combining a Novel Chimeric Antigen Receptor-Based Immunotherapy and Chemotherapy.

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Klapdor, Rüdiger; Wang, Shuo; Hacker, Ulrich; Büning, Hildegard; Morgan, Michael; Dörk, Thilo; Hillemanns, Peter; Schambach, Axel

2017-10-01

Ovarian cancer represents the most lethal gynecological cancer. Although cytoreductive chemotherapy and surgery lead to complete macroscopic tumor removal, most of the patients in advanced stages suffer from recurrent disease and subsequently die. This may be explained by the activity of cancer stem cells (CSC), which are a subpopulation of cells with an elevated chemoresistance and an increased capacity for self-renewal and metastatic spread. Specifically targeting these cells by adoptive immunotherapy represents a promising strategy to reduce the risk for recurrent disease. This study selected the widely accepted CSC marker CD133 as a target for a chimeric antigen receptor (CAR)-based immunotherapeutic approach to treat ovarian cancer. A lentiviral vector was generated encoding a third-generation anti-CD133-CAR, and clinically used NK92 cells were transduced. These engineered natural killer (NK) cells showed specific killing against CD133-positive ovarian cancer cell lines and primary ovarian cancer cells cultured from sequential ascites harvests. Additionally, specific activation of these engineered NK cells was demonstrated via interferon-gamma secretion assays. To improve clinical efficacy of ovarian cancer treatment, the effect of the chemotherapeutic agent cisplatin was evaluated together with CAR-transduced NK cell treatment. It was demonstrated that NK cells remain cytotoxic and active under cisplatin treatment and, importantly, that sequential treatment with cisplatin followed by CAR-NK cells led to the strongest killing effect. The specific eradication of ovarian CSCs by anti-CD133-CAR expressing NK92 cells represents a promising strategy and, when confirmed in vivo, shall be the basis of future clinical studies with the aim to prevent recurrent disease.

Broadening the future of value account of the wrongness of killing

DEFF Research Database (Denmark)

Di Nucci, Ezio

2015-01-01

On Don Marquis's future of value account of the wrongness of killing, 'what makes it wrong to kill those individuals we all believe it is wrong to kill, is that killing them deprives them of their future of value'. Marquis has recently argued for a narrow interpretation of his future of value...... account of the wrongness of killing and against the broad interpretation that I had put forward in response to Carson Strong. In this article I argue that the narrow view is problematic because it violates some basic principles of equality and because it allows for some of the very killing that Marquis...

Fractional Killing-Yano Tensors and Killing Vectors Using the Caputo Derivative in Some One- and Two-Dimensional Curved Space

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Ehab Malkawi

2014-01-01

Full Text Available The classical free Lagrangian admitting a constant of motion, in one- and two-dimensional space, is generalized using the Caputo derivative of fractional calculus. The corresponding metric is obtained and the fractional Christoffel symbols, Killing vectors, and Killing-Yano tensors are derived. Some exact solutions of these quantities are reported.

Selective targeting of brain tumors with gold nanoparticle-induced radiosensitization.

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Daniel Y Joh

Full Text Available Successful treatment of brain tumors such as glioblastoma multiforme (GBM is limited in large part by the cumulative dose of Radiation Therapy (RT that can be safely given and the blood-brain barrier (BBB, which limits the delivery of systemic anticancer agents into tumor tissue. Consequently, the overall prognosis remains grim. Herein, we report our pilot studies in cell culture experiments and in an animal model of GBM in which RT is complemented by PEGylated-gold nanoparticles (GNPs. GNPs significantly increased cellular DNA damage inflicted by ionizing radiation in human GBM-derived cell lines and resulted in reduced clonogenic survival (with dose-enhancement ratio of ~1.3. Intriguingly, combined GNP and RT also resulted in markedly increased DNA damage to brain blood vessels. Follow-up in vitro experiments confirmed that the combination of GNP and RT resulted in considerably increased DNA damage in brain-derived endothelial cells. Finally, the combination of GNP and RT increased survival of mice with orthotopic GBM tumors. Prior treatment of mice with brain tumors resulted in increased extravasation and in-tumor deposition of GNP, suggesting that RT-induced BBB disruption can be leveraged to improve the tumor-tissue targeting of GNP and thus further optimize the radiosensitization of brain tumors by GNP. These exciting results together suggest that GNP may be usefully integrated into the RT treatment of brain tumors, with potential benefits resulting from increased tumor cell radiosensitization to preferential targeting of tumor-associated vasculature.

Selective tumor cell death induced by irradiated riboflavin through recognizing DNA G-T mismatch.

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Yuan, Yi; Zhao, Yongyun; Chen, Lianqi; Wu, Jiasi; Chen, Gangyi; Li, Sheng; Zou, Jiawei; Chen, Rong; Wang, Jian; Jiang, Fan; Tang, Zhuo

2017-09-06

Riboflavin (vitamin B2) has been thought to be a promising antitumoral agent in photodynamic therapy, though the further application of the method was limited by the unclear molecular mechanism. Our work reveals that riboflavin was able to recognize G-T mismatch specifically and induce single-strand breaks in duplex DNA targets efficiently under irradiation. In the presence of riboflavin, the photo-irradiation could induce the death of tumor cells that are defective in mismatch repair system selectively, highlighting the G-T mismatch as potential drug target for tumor cells. Moreover, riboflavin is a promising leading compound for further drug design due to its inherent specific recognition of the G-T mismatch. © The Author(s) 2017. Published by Oxford University Press on behalf of Nucleic Acids Research.

Antibacterial activity of silver-killed bacteria: the "zombies" effect

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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.

Some spacetimes with higher rank Killing-Staeckel tensors

International Nuclear Information System (INIS)

Gibbons, G.W.; Houri, T.; Kubiznak, D.; Warnick, C.M.

2011-01-01

By applying the lightlike Eisenhart lift to several known examples of low-dimensional integrable systems admitting integrals of motion of higher-order in momenta, we obtain four- and higher-dimensional Lorentzian spacetimes with irreducible higher-rank Killing tensors. Such metrics, we believe, are first examples of spacetimes admitting higher-rank Killing tensors. Included in our examples is a four-dimensional supersymmetric pp-wave spacetime, whose geodesic flow is superintegrable. The Killing tensors satisfy a non-trivial Poisson-Schouten-Nijenhuis algebra. We discuss the extension to the quantum regime.

Imatinib and gastrointestinal stromal tumor (GIST: a selective targeted therapy Imatinib y tumor del estroma gastrointestinal (GIST: un tratamiento selectivo frente a una diana molecular

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A. Fernández

2004-10-01

Full Text Available Gastrointestinal stromal tumors are the most frequent mesenchymal tumors in the gastrointestinal tract. They originate from the interstitial cells of Cajal and are characterized by an anomalous receptor for a growth factor with tyrosine-kinase activity (c-kit. This anomaly causes a permanent activation of the receptor and uncontrolled cell growth. These tumors show a poor response to traditional chemotherapy drugs, and are thus associated with low survival in cases of advanced disease. Imatinib, a tyrosine kinase inhibitor, is an example of selective targeted oncologic therapy that induces improved survival in these patients. We discuss two cases of metastatic gastrointestinal stromal tumors with a good response to imatinib, and also review the pathophysiology and treatment-related outcome of this type of tumors. We include results from clinical phase-III studies.Los tumores del estroma gastrointestinal son los tumores mesenquimales más frecuentes del tracto digestivo y se originan de las células intersticiales de Cajal. Se caracterizan por presentar un receptor para el factor de crecimiento con actividad tirosin kinasa (c-kit anómalo que condiciona su activación permanente y un crecimiento celular incontrolado. Tienen una baja supervivencia en casos de enfermedad avanzada, con escasa respuesta a los agentes quimioterápicos tradicionales. El imatinib es un fármaco inhibidor de la tirosín kinasa y un ejemplo de terapia oncológica selectiva que condiciona un importante aumento en la supervivencia de estos pacientes. Se presentan 2 casos de enfermedad metastásica con buena respuesta a imatinib, así como una revisión sobre la fisiopatología y evolución en el tratamiento de este tipo de tumores, incluyendo resultados de estudios en fase III.

[gammadelta T cells stimulated by zoledronate kill osteosarcoma cells].

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Jiang, Hui; Xu, Qiang; Yang, Chao; Cao, Zhen-Guo; Li, Zhao-Xu; Ye, Zhao-Ming

2010-12-01

To investigate the cytotoxicity of human γδT cells from PBMCs stimulated by zoledronate against osteosarcoma cell line HOS in vitro and in vivo and evaluate the relavent pathways. The peripheral blood mononuclear cells (PBMCs)of healthy donors were stimulated by single dose zoledronate and cultured in the present of IL-2 for two weeks, analysising the percentage of γδT cells on a FACSCalibur cytometer.Study the cytotoxicity of γδT cells against the osteosarcoma line HOS using LDH release assay kit. Pre-treatment of γδT cells with anti-human γδTCR antibody, anti-human NKG2D antibody and concanamycin A to bolck the relavent pathways for evaluating the mechenisms of its cytotoxicity. In vivo, BALB/c mice were inoculated subcutaneously osteosarcoma cell HOS for developing hypodermal tumors. And they were randomized into two groups: unteated group, γδT cell therapy group. Tumor volume and weight of the two groups were compared. After two weeks of culture, γδT cells from zoledronate-stimulated PBMCs could reach (95±3)%. When the E:T as 6:1, 12:1, 25:1, 50:1, the percentage of osteosarcoma cell HOS killed by γδT cells was 26.8%, 31.5%, 37.8%, 40.9%, respectively.When anti-huma γδTCR antibody, anti-human NKG2D antibody and concanamycin A blocked the relavent pathways, the percentage was 32.3%, 4.7%, 16.7% ( E:T as 25:1), respectively. In vivo, the tumor inhibition rate of the group of γδT cell therapy was 42.78%. γδT cells derived from PBMCs stimulated by zoledronate can acquired pure γδT cells. And they show strong cytoxicity against osteosarcoma cell line HOS in vitro and in vivo.

Can patriotism justify killing in defense of one’s country?

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Pavković Aleksandar

2007-01-01

Full Text Available Cosmopolitan liberals would be ready to fight - and to kill and be killed for the sake of restoring international justice or for the abolition of profoundly unjust political institutions. Patriots are ready to do the same for their own country. Sometimes the cosmopolitan liberals and patriots would fight on the same side and sometimes on the opposite sides of the conflict. Thus the former would join the latter in the defense of Serbia against Austria-Hungary (in 1914 but would oppose the white Southerner patriots in the American Civil War (in 1861. In this paper I argue that fighting and killing for one’s country is, in both of those cases, different from the defense of one’s own life and the lives of those who cannot defend themselves. Killing for one’s country is killing in order to fulfill a particular political preference. The same is the case with fighting for the abolition of a profoundly unjust political institution. It is not amoral or immoral to refuse to kill for any one of these two political preferences because there is no reason to believe that either political preference trumps our moral constraints against killing.

Identification of cytotoxic drugs that selectively target tumor cells with MYC overexpression.

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Anna Frenzel

Full Text Available Expression of MYC is deregulated in a wide range of human cancers, and is often associated with aggressive disease and poorly differentiated tumor cells. Identification of compounds with selectivity for cells overexpressing MYC would hence be beneficial for the treatment of these tumors. For this purpose we used cell lines with conditional MYCN or c-MYC expression, to screen a library of 80 conventional cytotoxic compounds for their ability to reduce tumor cell viability and/or growth in a MYC dependent way. We found that 25% of the studied compounds induced apoptosis and/or inhibited proliferation in a MYC-specific manner. The activities of the majority of these were enhanced both by c-MYC or MYCN over-expression. Interestingly, these compounds were acting on distinct cellular targets, including microtubules (paclitaxel, podophyllotoxin, vinblastine and topoisomerases (10-hydroxycamptothecin, camptothecin, daunorubicin, doxorubicin, etoposide as well as DNA, RNA and protein synthesis and turnover (anisomycin, aphidicholin, gliotoxin, MG132, methotrexate, mitomycin C. Our data indicate that MYC overexpression sensitizes cells to disruption of specific pathways and that in most cases c-MYC and MYCN overexpression have similar effects on the responses to cytotoxic compounds. Treatment of the cells with topoisomerase I inhibitors led to down-regulation of MYC protein levels, while doxorubicin and the small molecule MYRA-A was found to disrupt MYC-Max interaction. We conclude that the MYC pathway is only targeted by a subset of conventional cytotoxic drugs currently used in the clinic. Elucidating the mechanisms underlying their specificity towards MYC may be of importance for optimizing treatment of tumors with MYC deregulation. Our data also underscores that MYC is an attractive target for novel therapies and that cellular screenings of chemical libraries can be a powerful tool for identifying compounds with a desired biological activity.

Pseudomonas piscicida kills vibrios by two distinct mechanisms

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Pseudoalteromonas piscicida is a naturally-occurring marine bacterium which kills competing bacteria, including vibrios. In studies by Richards et al. (AEM00175-17), three strains of P. piscicida were isolated and characterized. Strains secreted proteolytic enzymes which likely killed competing or...

Resveratrol and arsenic trioxide act synergistically to kill tumor cells in vitro and in vivo.

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Xiao-Yan Zhao

Full Text Available BACKGROUND AND AIMS: Arsenic trioxide (As2O3, which used as an effective agent in the treatment of leukaemia and other solid tumors, is largely limited by its toxicity. QT prolongation, torsades de pointes and sudden heart death have been implicated in the cardiotoxicity of As2O3. The present study was designed to explore whether the combination of As2O3 and resveratrol could generate a more powerful anti-cancer effect both in vitro and in vivo. MATERIALS AND METHODS: MTT assay was performed to assess the proliferation of Hela, MCF-7 and NB4 cells. Isobolographic analysis was used to evaluate combination index values from cell viability data. The apoptosis and the cellular reactive oxygen species (ROS level were assessed by fluorescent microscopy and flow cytometry separately in vitro. The effect of As2O3, alone and in combination with resveratrol on Hela tumor growth in an orthotopic nude mouse model was also investigated. The tumor volume and the immunohistochemical analysis of CD31, CD34 and VEGF were determined. RESULTS: Resveratrol dramatically enhanced the anti-cancer effect induced by As2O3 in vitro. In addition, isobolographic analysis further demonstrated that As2O3 and resveratrol generated a synergistic action. More apoptosis and ROS generation were observed in the combination treatment group. Similar synergistic effects were found in nude mice in vivo. The combination of As2O3 and resveratrol dramatically suppressed both tumor growth and angiogenesis in nude mice. CONCLUSIONS: Combining As2O3 with resveratrol would be a novel strategy to treat cancer in clinical practice.

Fabrication and characterization of UV-emitting nanoparticles as novel radiation sensitizers targeting hypoxic tumor cells

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Squillante, Michael R.; Jüstel, Thomas; Anderson, R. Rox; Brecher, Charles; Chartier, Daniel; Christian, James F.; Cicchetti, Nicholas; Espinoza, Sara; McAdams, Daniel R.; Müller, Matthias; Tornifoglio, Brooke; Wang, Yimin; Purschke, Martin

2018-06-01

Radiation therapy is one of the primary therapeutic techniques for treating cancer, administered to nearly two-thirds of all cancer patients. Although largely effective in killing cancer cells, radiation therapy, like other forms of cancer treatment, has difficulty dealing with hypoxic regions within solid tumors. The incomplete killing of cancer cells can lead to recurrence and relapse. The research presented here is investigating the enhancement of the efficacy of radiation therapy by using scintillating nanoparticles that emit UV photons. UV photons, with wavelengths between 230 nm and 280 nm, are able to inactivate cells due to their direct interaction with DNA, causing a variety of forms of damage. UV-emitting nanoparticles will enhance the treatment in two ways: first by generating UV photons in the immediate vicinity of cancer cells, leading to direct and oxygen-independent DNA damage, and second by down-converting the applied higher energy X-rays into softer X-rays and particles that are more efficiently absorbed in the targeted tumor region. The end result will be nanoparticles with a higher efficacy in the treatment of hypoxic cells in the tumor, filling an important, unmet clinical need. Our preliminary experiments show an increase in cell death using scintillating LuPO4:Pr nanoparticles over that achieved by the primary radiation alone. This work describes the fabrication of the nanoparticles, their physical characterization, and the spectroscopic characterization of the UV emission. The work also presents in vitro results that demonstrate an enhanced efficacy of cell killing with x-rays and a low unspecific toxicity of the nanoparticles.

Technical Aspects of Cyber Kill Chain

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Yadav, Tarun; Mallari, Rao Arvind

2016-01-01

Recent trends in targeted cyber-attacks has increased the interest of research in the field of cyber security. Such attacks have massive disruptive effects on rganizations, enterprises and governments. Cyber kill chain is a model to describe cyber-attacks so as to develop incident response and analysis capabilities. Cyber kill chain in simple terms is an attack chain, the path that an intruder takes to penetrate information systems over time to execute an attack on the target. This paper broa...

Structural equations for Killing tensors of order two. II

International Nuclear Information System (INIS)

Hauser, I.; Malhiot, R.J.

1975-01-01

In a preceding paper, a new form of the structural equations for any Killing tensor of order two have been derived; these equations constitute a system analogous to the Killing vector equations Nabla/sub alpha/ K/sub beta/ = ω/sub alpha beta/ = -ω/sub beta alpha/ and Nabla/sub gamma/ ω/sub alpha beta = R/sub alpha beta gamma delta/ K/sup delta/. The first integrability condition for the Killing tensor structural equations is now derived. The structural equations and the integrability condition have forms which can readily be expressed in terms of a null tetrad to furnish a Killing tensor parallel of the Newman--Penrose equations; this is briefly described. The integrability condition implies the new result, for any given space--time, that the dimension of the set of second-order Killing tensors attains its maximum possible value of 50 only if the space--time is of constant curvature. Potential applications of the structural equations are discussed

Simultaneous targeting of prostate stem cell antigen and prostate-specific membrane antigen improves the killing of prostate cancer cells using a novel modular T cell-retargeting system.

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Arndt, Claudia; Feldmann, Anja; Koristka, Stefanie; Cartellieri, Marc; Dimmel, Maria; Ehninger, Armin; Ehninger, Gerhard; Bachmann, Michael

2014-09-01

Recently, we described a novel modular platform technology in which T cell-recruitment and tumor-targeting domains of conventional bispecific antibodies are split to independent components, a universal effector module (EM) and replaceable monospecific/monovalent target modules (TMs) that form highly efficient T cell-retargeting complexes. Theoretically, our unique strategy should allow us to simultaneously retarget T cells to different tumor antigens by combining the EM with two or more different monovalent/monospecific TMs or even with bivalent/bispecific TMs, thereby overcoming limitations of a monospecific treatment such as the selection of target-negative tumor escape variants. In order to advance our recently introduced prostate stem cell antigen (PSCA)-specific modular system for a dual-targeting of prostate cancer cells, two additional TMs were constructed: a monovalent/monospecific TM directed against the prostate-specific membrane antigen (PSMA) and a bivalent/bispecific TM (bsTM) with specificity for PSMA and PSCA. The functionality of the novel dual-targeting strategies was analyzed by performing T cell activation and chromium release assays. Similar to the PSCA-specific modular system, the novel PSMA-specific modular system mediates an efficient target-dependent and -specific tumor cell lysis at low E:T ratios and picomolar Ab concentrations. Moreover, by combination of the EM with either the bispecific TM directed to PSMA and PSCA or both monospecifc TMs directed to either PSCA or PSMA, dual-specific targeting complexes were formed which allowed us to kill potential escape variants expressing only one or the other target antigen. Overall, the novel modular system represents a promising tool for multiple tumor targeting. © 2014 Wiley Periodicals, Inc.

Synchronization of tumor cells with 5-fluorouracil plus uracil and with vinblastine and irradiation of synchronized cultures

International Nuclear Information System (INIS)

Severin, E.; Hagenhoff, B.

1988-01-01

In this article, some arguments are put forward which support the conception of a combined radio-chemotherapy acting by a reversible inhibition of tumor cells with cytostatic drugs in a not cytocidal dose and the following selective killing by irradiation of the cells blocked in a radiosensitive phase. The two cytostatic drugs 5-fluorouracil (FU) and vinblastine (VLB), as inhibitors of DNA synthesis and mitosis, respectively, are tested in vitro both separately and combined in two tumor cell lines of the mouse, i.e. the Ehrlich ascites tumor and the sarcoma S 180. A cell-proliferative and, as far as possible, not cytocidal dose is used because of the inevitable side effects exerted by these drugs on normal tissues. A reversible synchronization of the ascites tumor is achieved even in the young mouse by FU in a dose of 15 ng to 500 ng (applied seven times every two hours), if the synchronization is controlled by applying the antimetabolite together with uracil in an equimolar concentration and then stimulating the growth of the cells inhibited during DNA synthesis by the administration of thymidine. The statistical analysis of dose-effect curves after X-ray irradiation shows an increased radiosensitivity of the synchronized cell population, provided that the optimum moment had been chosen for the irradiation. (orig.) [de

Risk-adaptive optimization: Selective boosting of high-risk tumor subvolumes

International Nuclear Information System (INIS)

Kim, Yusung; Tome, Wolfgang A.

2006-01-01

Background and Purpose: A tumor subvolume-based, risk-adaptive optimization strategy is presented. Methods and Materials: Risk-adaptive optimization employs a biologic objective function instead of an objective function based on physical dose constraints. Using this biologic objective function, tumor control probability (TCP) is maximized for different tumor risk regions while at the same time minimizing normal tissue complication probability (NTCP) for organs at risk. The feasibility of risk-adaptive optimization was investigated for a variety of tumor subvolume geometries, risk-levels, and slopes of the TCP curve. Furthermore, the impact of a correlation parameter, δ, between TCP and NTCP on risk-adaptive optimization was investigated. Results: Employing risk-adaptive optimization, it is possible in a prostate cancer model to increase the equivalent uniform dose (EUD) by up to 35.4 Gy in tumor subvolumes having the highest risk classification without increasing predicted normal tissue complications in organs at risk. For all tumor subvolume geometries investigated, we found that the EUD to high-risk tumor subvolumes could be increased significantly without increasing normal tissue complications above those expected from a treatment plan aiming for uniform dose coverage of the planning target volume. We furthermore found that the tumor subvolume with the highest risk classification had the largest influence on the design of the risk-adaptive dose distribution. The parameter δ had little effect on risk-adaptive optimization. However, the clinical parameters D 5 and γ 5 that represent the risk classification of tumor subvolumes had the largest impact on risk-adaptive optimization. Conclusions: On the whole, risk-adaptive optimization yields heterogeneous dose distributions that match the risk level distribution of different subvolumes within the tumor volume

Experiment study with baculovirus-mediated transfer of the thyroid sodium/iodide symporter gene into thyroid cancer for a targeted radiotherapy

International Nuclear Information System (INIS)

Zhang Yifan; Li Biao; Zhao Long; You Bei; Yin Guizhi; Zhu Chengmo

2004-01-01

Objective: To explore the feasibility of thyroid cancers for radiotherapy by using baculoviral vector to deliver the NIS gene into the tumor cells. Method: Constructed a recombinant baculovirus encoding the human NIS gene under the control of the cytomegalovirus promoter. Using a mouse monoclonal antibody and a FITC-labeled antimouse antibody to confirm expression of the NIS protein of infected tumor cells by immunofluorescence. In vitro iodide uptake experiments were carded out on BacNIS-infected tumor cells to further characterize the BacNIS virus, and cell killing with 131I and clonogenic assay were performed on BacNIS-infected cell to observe the selective killing effect of 1311 on NIS-expressing cells. Results: Infection of thyroidcancer cells (FTC-133, W3) with BacNIS resulted in perchlorate-sensitive 125I uptake by these cells to a higher level than that in noninfected cells. But 1251 uptake of 8505C is very low. Demonstrating that the BacNIS vector can function in tumor cells. In addition, AdNIS-infected tumor cells were selectively killed by exposure to 1311, as revealed by clonogenicassays, higher than that in nontreated tumors. Conclusions: AdNIS is very efficient in triggering iodide uptake by infected tumor cell, outlining the potential of this novel cancer gene therapy approach for a targeted radiotherapy. (authors)

Quantitation of Murine Stroma and Selective Purification of the Human Tumor Component of Patient-Derived Xenografts for Genomic Analysis.

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Valentina E Schneeberger

Full Text Available Patient-derived xenograft (PDX mouse models are increasingly used for preclinical therapeutic testing of human cancer. A limitation in molecular and genetic characterization of PDX tumors is the presence of integral murine stroma. This is particularly problematic for genomic sequencing of PDX models. Rapid and dependable approaches for quantitating stromal content and purifying the malignant human component of these tumors are needed. We used a recently developed technique exploiting species-specific polymerase chain reaction (PCR amplicon length (ssPAL differences to define the fractional composition of murine and human DNA, which was proportional to the fractional composition of cells in a series of lung cancer PDX lines. We compared four methods of human cancer cell isolation: fluorescence-activated cell sorting (FACS, an immunomagnetic mouse cell depletion (MCD approach, and two distinct EpCAM-based immunomagnetic positive selection methods. We further analyzed DNA extracted from the resulting enriched human cancer cells by targeted sequencing using a clinically validated multi-gene panel. Stromal content varied widely among tumors of similar histology, but appeared stable over multiple serial tumor passages of an individual model. FACS and MCD were superior to either positive selection approach, especially in cases of high stromal content, and consistently allowed high quality human-specific genomic profiling. ssPAL is a dependable approach to quantitation of murine stromal content, and MCD is a simple, efficient, and high yield approach to human cancer cell isolation for genomic analysis of PDX tumors.

The effect of iron-deficiency anemia on cytolytic activity of mice spleen and peritoneal cells against allogenic tumor cells

International Nuclear Information System (INIS)

Kuvibidila, S.R.; Baliga, B.S.; Suskind, R.M.

1983-01-01

The capacity of spleen and peritoneal cells from iron deficient mice, ad libitum fed control mice, and pair-fed mice to kill allogenic tumor cells (mastocytoma tumor P815) has been investigated. In the first study, mice were sensitized in vivo with 10(7) viable tumor cells 51 and 56 days after weaning. The capacity of splenic cells and peritoneal cells from sensitized and nonsensitized mice to kill tumor cells was evaluated 5 days after the second dose of tumor cells. At ratios of 2.5:1 to 100:1 of attacker to target cells, the percentage 51 Cr release after 4 h of incubation was significantly less in iron-deficient mice than control and/or pair-fed mice (p less than 0.05). Protein-energy undernutrition in pair-fed mice had no significant effect. In the second study, spleen cells and enriched T cell fractions were incubated in vitro for 5 days with uv irradiated Balb/C spleen cells in a 2:1 ratio. The cytotoxic capacity against the same allogenic tumor cells was again evaluated. The percentage chromium release at different attacker to target cells was less than 30% in the iron-deficient group compared to either control or pair-fed supporting the results of in vivo sensitized cells. The possible mode of impairment of the cytotoxic capacity is discussed

Killing spinors as a characterisation of rotating black hole spacetimes

International Nuclear Information System (INIS)

Cole, Michael J; Kroon, Juan A Valiente

2016-01-01

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. (paper)

The selection of patients for accelerated radiotherapy on the basis of tumor growth kinetics and intrinsic radiosensitivity

International Nuclear Information System (INIS)

Tucker, S.L.; Kang-Sow Chan

1990-01-01

Mathematical modelling was used to reach qualitative conclusions concerning the relative rate of local tumor control that might be achieved by using accelerated fractionation to treat only the patients with the most rapidly growing rumors, compared with the control rated that could be expected from either conventional or accelerated radiotherapy alone. The results suggest that concomitant boost therapy is equally or more effective than conventional dose fractionation for all tumors, regardless of their growth kinetics. For tumors with very short clonogen doubling times, CHART (continuous hyperfractionated accelerated radiotherapy) may be even more effective than concomitant boost treatment, but CHART is less effective than conventional or concomitant boost therapy for tumors with longer clonogen doubling times. Thus, there is a rationale for using a predictive assay of tumor clonogen doubling times to identify the patients who should be treated with CHART. However, improvements in local tumor control resulting from concomitant boost treatment or the selective use of CHART are not likely to be apparent in the population as a whole, because the overall control rated are largely determined by refractory tumors having little chance of control with any of the treatments and by higher responsive tumors that are likely to be controlled regardless of the treatment choice. Differences in control rated with different treatment strategies are most apparent in the stochastic fraction of the population, which excludes those patients for whom there is either very little change (e.g. 99%) of achieving local control with both treatments. The stochastic fraction can be approximated by excluding those patients with the most radioresistant and the most radiosensitive tumors, since intrinsic tumor radiosensitivity appears to be the single most important factor determining treatment outcome. (author). 32 refs.; 4 figs.; 5 tabs

Macrophage migration inhibitory factor deficiency is associated with impaired killing of gram-negative bacteria by macrophages and increased susceptibility to Klebsiella pneumoniae sepsis.

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Roger, Thierry; Delaloye, Julie; Chanson, Anne-Laure; Giddey, Marlyse; Le Roy, Didier; Calandra, Thierry

2013-01-15

The cytokine macrophage migration inhibitory factor (MIF) is an important component of the early proinflammatory response of the innate immune system. However, the antimicrobial defense mechanisms mediated by MIF remain fairly mysterious. In the present study, we examined whether MIF controls bacterial uptake and clearance by professional phagocytes, using wild-type and MIF-deficient macrophages. MIF deficiency did not affect bacterial phagocytosis, but it strongly impaired the killing of gram-negative bacteria by macrophages and host defenses against gram-negative bacterial infection, as shown by increased mortality in a Klebsiella pneumonia model. Consistent with MIF's regulatory role of Toll-like 4 expression in macrophages, MIF-deficient cells stimulated with lipopolysaccharide or Escherichia coli exhibited reduced nuclear factor κB activity and tumor necrosis factor (TNF) production. Addition of recombinant MIF or TNF corrected the killing defect of MIF-deficient macrophages. Together, these data show that MIF is a key mediator of host responses against gram-negative bacteria, acting in part via a modulation of bacterial killing by macrophages.

Using Targeted Virotherapy to Treat a Resistant Ewing Sarcoma Model: From the Bedside to the Bench and Back

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Hesham Abdelbary

2014-01-01

Full Text Available Metastatic Ewing sarcoma (EWS is often resistant to current multimodal chemotherapeutic regimens. Oncolytic virus therapy (OV is a novel therapeutic platform whereby viruses can selectively infect as well as replicate in and kill tumor cells, while sparing normal tissues. The purpose of this study is to investigate the efficacy of the biotherapeutic oncolytic agent, vesicular stomatitis virus (VSVΔM51, to kill EWS cells that are resistant to conventional therapy. Our hypothesis is that systemic delivery of VSVΔM51 can demonstrate tumor-specific killing of resistant EWS cells, as well as a significant decrease of tumor burden in EWS bearing mice. Methods. A biopsy sample was obtained from a patient with metastatic EWS and was used to establish a novel EWS cell line. In vitro assays evaluated the oncolytic effect of vesicular stomatitis virus (VSVΔM51 on this cell line. EWS xenograft mice model bearing either lung or subcutaneous tumors was established to evaluate the antitumor specific oncolytic effect of VSVΔM51 after local and systemic delivery. Results. The established EWS cell line shared similar molecular and genetic traits to the patient’s original tumor specimen. VSVΔM51 effectively infected and killed EWS cells in vitro. In vivo, VSVΔM51 selectively infected and killed EWS and led to significant delay in tumor growth. Conclusion. This study has been designed to implement a translational link between the bedside and the bench, where a specific challenging clinical scenario guided this basic science research. This research demonstrated that a sarcoma, which is resistant to current conventional standard therapies, is still susceptible to an alternative therapeutic platform, such as OV. Adding OV to the armamentarium of sarcoma treatment can enhance the future therapeutic approach towards these cancer patients.

The vascular disrupting agent ZD6126 shows increased antitumor efficacy and enhanced radiation response in large, advanced tumors

International Nuclear Information System (INIS)

Siemann, Dietmar W.; Rojiani, Amyn M.

2005-01-01

Purpose: ZD6126 is a vascular-targeting agent that induces selective effects on the morphology of proliferating and immature endothelial cells by disrupting the tubulin cytoskeleton. The efficacy of ZD6126 was investigated in large vs. small tumors in a variety of animal models. Methods and Materials: Three rodent tumor models (KHT, SCCVII, RIF-1) and three human tumor xenografts (Caki-1, KSY-1, SKBR3) were used. Mice bearing leg tumors ranging in size from 0.1-2.0 g were injected intraperitoneally with a single 150 mg/kg dose of ZD6126. The response was assessed by morphologic and morphometric means as well as an in vivo to in vitro clonogenic cell survival assay. To examine the impact of tumor size on the extent of enhancement of radiation efficacy by ZD6126, KHT sarcomas of three different sizes were irradiated locally with a range of radiation doses, and cell survival was determined. Results: All rodent tumors and human tumor xenografts evaluated showed a strong correlation between increasing tumor size and treatment effect as determined by clonogenic cell survival. Detailed evaluation of KHT sarcomas treated with ZD6126 showed a reduction in patent tumor blood vessels that was ∼20% in small ( 90% in large (>1.0 g) tumors. Histologic assessment revealed that the extent of tumor necrosis after ZD6126 treatment, although minimal in small KHT sarcomas, became more extensive with increasing tumor size. Clonogenic cell survival after ZD6126 exposure showed a decrease in tumor surviving fraction from approximately 3 x 10 -1 to 1 x 10 -4 with increasing tumor size. When combined with radiotherapy, ZD6126 treatment resulted in little enhancement of the antitumor effect of radiation in small (<0.3 g) tumors but marked increases in cell kill in tumors larger than 1.0 g. Conclusions: Because bulky neoplastic disease is typically the most difficult to manage, the present findings provide further support for the continued development of vascular disrupting agents such as

[Establishment of EL4 tumor-bearing mouse models and investigation on immunological mechanisms of anti-tumor effect of melphalan].

Science.gov (United States)

Li, Mo-lin; Li, Chuan-gang; Shu, Xiao-hong; Jia, Yu-jie; Qin, Zhi-hai

2006-03-01

To establish mouse lymphoma EL4 tumor-bearing mouse models in wild type C57BL/6 mice and nude C57BL/6 mice respectively, and to further investigate the immunological mechanisms of anti-tumor effect of melphalan. Mouse lymphoma EL4 cells were inoculated subcutaneously into wild type C57BL/6 mice (immune-competent mice). Twelve days later, melphalan of different doses were administered intraperitoneally to treat these wild type C57BL/6 tuomr-bearing mice. Tumor sizes were observed and recorded subsequently to find out the minimal dose of melphalan that could cure the tuomr-bearing mice. Then the same amount of EL4 tumor cells were inoculated subcutaneously into wild type C57BL/6 mice and nude C57BL/6 mice (T cell-deficient mice) simultaneously, which had the same genetic background of C57BL/6. Twelve days later, melphalan of the minimal dose was given intraperitoneally to treat both the wild type and nude C57BL/6 tuomr-bearing mice. Tumor sizes were observed and recorded in these two different types of mice subsequently. A single dose of melphalan (7.5 mg/kg) could cure EL4 tumor-bearing wild type C57BL/6 mice, but could not induce tumor regression in EL4 tumor-bearing nude C57BL/6 mice. A single dose of melphalan has obvious anti-tumor effect on mouse lymphoma EL4 tumor-bearing wild type C57BL/6mice, which requires the involvement of T lymphocytes in the host probably related to their killing functions.

Early circulating tumor DNA dynamics and clonal selection with palbociclib and fulvestrant for breast cancer.

Science.gov (United States)

O'Leary, Ben; Hrebien, Sarah; Morden, James P; Beaney, Matthew; Fribbens, Charlotte; Huang, Xin; Liu, Yuan; Bartlett, Cynthia Huang; Koehler, Maria; Cristofanilli, Massimo; Garcia-Murillas, Isaac; Bliss, Judith M; Turner, Nicholas C

2018-03-01

CDK4/6 inhibition substantially improves progression-free survival (PFS) for women with advanced estrogen receptor-positive breast cancer, although there are no predictive biomarkers. Early changes in circulating tumor DNA (ctDNA) level may provide early response prediction, but the impact of tumor heterogeneity is unknown. Here we use plasma samples from patients in the randomized phase III PALOMA-3 study of CDK4/6 inhibitor palbociclib and fulvestrant for women with advanced breast cancer and show that relative change in PIK3CA ctDNA level after 15 days treatment strongly predicts PFS on palbociclib and fulvestrant (hazard ratio 3.94, log-rank p = 0.0013). ESR1 mutations selected by prior hormone therapy are shown to be frequently sub clonal, with ESR1 ctDNA dynamics offering limited prediction of clinical outcome. These results suggest that early ctDNA dynamics may provide a robust biomarker for CDK4/6 inhibitors, with early ctDNA dynamics demonstrating divergent response of tumor sub clones to treatment.

Photodetection of early cancer by laser-induced fluorescence of a tumor-selective dye: apparatus design and realization

Science.gov (United States)

Wagnieres, Georges A.; Depeursinge, Christian D.; Monnier, Philippe; Savary, Jean-Francois; Cornaz, Piet F.; Chatelain, Andre; van den Bergh, Hubert

1990-07-01

An apparatus is designed and realized to detect "early" cancer at the surface of the hollow organs in the human body by endoscopic means. The tumor is localized by the laser induced fluorescence of a dye (HPD) which concentrates selectively in the neoplastic tissue after intravenous injection. Fluorescence contrast between the tumor and its normal surroundings is enhanced by subtracting the background autofluorescence which occurs in both types of tissue. This is done by means of 2-color digital images manipulation in real-time. Preliminary clinical tests of the apparatus demonstrated the detection of carcinoma in situ in the esophagus.

Theriocide: Naming Animal Killing

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Piers Beirne

2014-08-01

Full Text Available In this essay I recommend ‘theriocide’ as the name for those diverse human actions that cause the deaths of animals. Like the killing of one human by another, theriocide may be socially acceptable or unacceptable, legal or illegal. It may be intentional or unintentional and may involve active maltreatment or passive neglect. Theriocide may occur one-on-one, in small groups or in large-scale social institutions. The numerous and sometimes intersecting sites of theriocide include intensive rearing regimes; hunting and fishing; trafficking; vivisection; militarism; pollution; and human-induced climate change. If the killing of animals by humans is as harmful to them as homicide is to humans, then the proper naming of such deaths offers a remedy, however small, to the extensive privileging of human lives over those of other animals. Inevitably, the essay leads to a shocking question: Is theriocide murder?

Five-chlorodeoxycytidine, a tumor-selective enzyme-driven radiosensitizer, effectively controls five advanced human tumors in nude mice

International Nuclear Information System (INIS)

Greer, Sheldon; Alvarez, Marcy; Mas, Marisol; Wozniak, Chandra; Arnold, David; Knapinska, Anna; Norris, Christina; Burk, Ronald; Aller, Alex; Dauphinee, Michael

2001-01-01

Purpose: The study's goals were as follows: (1) to extend our past findings with rodent tumors to human tumors in nude mice, (2) to determine if the drug protocol could be simplified so that only CldC and one modulator, tetrahydrouridine (H 4 U), would be sufficient to obtain efficacy, (3) to determine the levels of deoxycytidine kinase and dCMP deaminase in human tumors, compared to adjacent normal tissue, and (4) to determine the effect of CldC on normal tissue radiation damage to the cervical spinal cord of nude mice. Methods and Materials: The five human tumors used were as follows: prostate tumors, PC-3 and H-1579; glioblastoma, SF-295; breast tumor, GI-101; and lung tumor, H-165. The duration of treatment was 3-5 weeks, with drugs administered on Days 1-4 and radiation on Days 3-5 of each week. The biomodulators of CldC were N-(Phosphonacetyl)-L-aspartate (PALA), an inhibitor of aspartyl transcarbamoylase, 5-fluorodeoxycytidine (FdC), resulting in tumor-directed inhibition of thymidylate synthetase, and H 4 U, an inhibitor of cytidine deaminase. The total dose of focused irradiation of the tumors was usually 45 Gy in 12 fractions. Results: Marked radiosensitization was obtained with CldC and the three modulators. The average days in tumor regrowth delay for X-ray compared to drugs plus X-ray, respectively, were: PC-3 prostate, 42-97; H-1579 prostate, 29-115; glioblastoma, 5-51; breast, 50-80; lung, 32-123. Comparative studies with PC-3 and H-1579 using CldC coadministered with H 4 U, showed that both PALA and FdC are dispensable, and the protocol can be simplified with equal and possibly heightened efficacy. For example, PC-3 with X-ray and (1) no drugs, (2) CldC plus the three modulators, (3) a high dose of CldC, and (4) escalating doses of CldC resulted in 0/10, 3/9, 5/10, and 6/9 cures, respectively. The tumor regrowth delay data followed a similar pattern. After treating mice only 1((1)/(2)) weeks with CldC + H 4 U, 92% of the PC-3 tumor cells were found

Mountain lions prey selectively on prion-infected mule deer

OpenAIRE

Krumm, Caroline E.; Conner, Mary M.; Hobbs, N. Thompson; Hunter, Don O.; Miller, Michael W.

2009-01-01

The possibility that predators choose prey selectively based on age or condition has been suggested but rarely tested. We examined whether mountain lions (Puma concolor) selectively prey upon mule deer (Odocoileus hemionus) infected with chronic wasting disease, a prion disease. We located kill sites of mountain lions in the northern Front Range of Colorado, USA, and compared disease prevalence among lion-killed adult (?2 years old) deer with prevalence among sympatric deer taken by hunters i...

Antioxidants Impair Anti-Tumoral Effects of Vorinostat, but Not Anti-Neoplastic Effects of Vorinostat and Caspase-8 Downregulation

OpenAIRE

Bergadà, Laura; Yeramian, Andree; Sorolla, Annabel; Matias-Guiu, Xavier; Dolcet, Xavier

2014-01-01

We have recently demonstrated that histone deacetylase inhibitor, Vorinostat, applied as a single therapy or in combination with caspase-8 downregulation exhibits high anti-tumoral activity on endometrial carcinoma cell lines. In the present study, we have assessed the signalling processes underlying anti-tumoral effects of Vorinostat. Increasing evidence suggests that reactive oxygen species are responsible for histone deacetylase inhibitor-induced cell killing. We have found that Vorinostat...

Tumor Cells Express FcγRl Which Contributes to Tumor Cell Growth and a Metastatic Phenotype

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M. Bud Nelson

2001-01-01

Full Text Available High levels of circulating immune complexes containing tumor-associated antigens are associated with a poor prognosis for individuals with cancer. The ability of B cells, previously exposed to tumor-associated antigens, to promote both in vitro and in vivo tumor growth formed the rationale to evaluate the mechanism by which immune complexes may promote tumor growth. In elucidating this mechanism, FcγRl expression by tumor cells was characterized by flow cytometry, polymerase chain reaction, and sequence analysis. Immune complexes containing shed tumor antigen and anti-shed tumor antigen Ab cross-linked FcγRl-expressing tumor cells, which resulted in an induction of tumor cell proliferation and of shed tumor antigen production. Use of selective tyrosine kinase inhibitors demonstrated that tumor cell proliferation induced by immune complex cross-linking of FcγRl is dependent on the tyrosine kinase signal transduction pathway. A selective inhibitor of phosphatidylinositol-3 kinase also inhibited this induction of tumor cell proliferation. These findings support a role for immune complexes and FcγRl expression by tumor cells in augmentation of tumor growth and a metastatic phenotype.

Molecular Imaging of Gene Expression and Efficacy following Adenoviral-Mediated Brain Tumor Gene Therapy

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Alnawaz Rehemtulla

2002-01-01

Full Text Available Cancer gene therapy is an active area of research relying upon the transfer and subsequent expression of a therapeutic transgene into tumor cells in order to provide for therapeutic selectivity. Noninvasive assessment of therapeutic response and correlation of the location, magnitude, and duration of transgene expression in vivo would be particularly useful in the development of cancer gene therapy protocols by facilitating optimization of gene transfer protocols, vector development, and prodrug dosing schedules. In this study, we developed an adenoviral vector containing both the therapeutic transgene yeast cytosine deaminase (yCD along with an optical reporter gene (luciferase. Following intratumoral injection of the vector into orthotopic 9L gliomas, anatomical and diffusion-weighted MR images were obtained over time in order to provide for quantitative assessment of overall therapeutic efficacy and spatial heterogeneity of cell kill, respectively. In addition, bioluminescence images were acquired to assess the duration and magnitude of gene expression. MR images revealed significant reduction in tumor growth rates associated with yCD/5-fluorocytosine (5FC gene therapy. Significant increases in mean tumor diffusion values were also observed during treatment with 5FC. Moreover, spatial heterogeneity in tumor diffusion changes were also observed revealing that diffusion magnetic resonance imaging could detect regional therapeutic effects due to the nonuniform delivery and/or expression of the therapeutic yCD transgene within the tumor mass. In addition, in vivo bioluminescence imaging detected luciferase gene expression, which was found to decrease over time during administration of the prodrug providing a noninvasive surrogate marker for monitoring gene expression. These results demonstrate the efficacy of the yCD/5FC strategy for the treatment of brain tumors and reveal the feasibility of using multimodality molecular and functional imaging

The potential of achiral sponge-derived and synthetic bromoindoles as selective cytotoxins against PANC-1 tumor cells.

Science.gov (United States)

Lorig-Roach, Nicholas; Hamkins-Indik, Frances; Johnson, Tyler A; Tenney, Karen; Valeriote, Frederick A; Crews, Phillip

2018-01-11

Our quest to isolate and characterize natural products with in vitro solid tumor selectivity is driven by access to repositories of Indo-Pacific sponge extracts. In this project an extract of a species of Haplosclerida sponge obtained from the US NCI Natural Products Repository displayed, by in vitro disk diffusion assay (DDA) and IC 50 determinations, selective cytotoxicity with modest potency to a human pancreatic cancer cell line (PANC-1) relative to the human lymphoblast leukemia cell line (CCRF-CEM). Two brominated indoles, the known 6-bromo conicamin ( 1 ) and the new derivative, 6-Br-8-keto-conicamin A ( 2 ), were identified and 2 (IC 50 1.5 μM for the natural product vs 4.1 μM for the synthetic material) was determined to be responsible for the cytotoxic activity of the extract against the PANC-1 tumor cell line. The new natural product and ten additional analogs were prepared for further SAR testing.

Induction of selective blood-tumor barrier permeability and macromolecular transport by a biostable kinin B1 receptor agonist in a glioma rat model.

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Jérôme Côté

Full Text Available Treatment of malignant glioma with chemotherapy is limited mostly because of delivery impediment related to the blood-brain tumor barrier (BTB. B1 receptors (B1R, inducible prototypical G-protein coupled receptors (GPCR can regulate permeability of vessels including possibly that of brain tumors. Here, we determine the extent of BTB permeability induced by the natural and synthetic peptide B1R agonists, LysdesArg(9BK (LDBK and SarLys[dPhe(8]desArg(9BK (NG29, in syngeneic F98 glioma-implanted Fischer rats. Ten days after tumor inoculation, we detected the presence of B1R on tumor cells and associated vasculature. NG29 infusion increased brain distribution volume and uptake profiles of paramagnetic probes (Magnevist and Gadomer at tumoral sites (T(1-weighted imaging. These effects were blocked by B1R antagonist and non-selective cyclooxygenase inhibitors, but not by B2R antagonist and non-selective nitric oxide synthase inhibitors. Consistent with MRI data, systemic co-administration of NG29 improved brain tumor delivery of Carboplatin chemotherapy (ICP-Mass spectrometry. We also detected elevated B1R expression in clinical samples of high-grade glioma. Our results documented a novel GPCR-signaling mechanism for promoting transient BTB disruption, involving activation of B1R and ensuing production of COX metabolites. They also underlined the potential value of synthetic biostable B1R agonists as selective BTB modulators for local delivery of different sized-therapeutics at (peritumoral sites.

Synergistically killing activity of aspirin and histone deacetylase inhibitor valproic acid (VPA) on hepatocellular cancer cells

Energy Technology Data Exchange (ETDEWEB)

Li, Xiaofei; Zhu, Yanshuang [Department of Infectious Diseases, Yiwu Central Hospita, 519 Nan men Street, Yiwu, Jinhua, Zhejing 322000 (China); He, Huabin [Department of Orthopedics, Yiwu Central Hospita, 519 Nan men Street, Yiwu, Jinhua, Zhejing 322000 (China); Lou, Lianqing; Ye, Weiwei; Chen, Yongxin [Department of Infectious Diseases, Yiwu Central Hospita, 519 Nan men Street, Yiwu, Jinhua, Zhejing 322000 (China); Wang, Jinghe, E-mail: Xiaofeili2000@163.com [Department of Infectious Diseases, Yiwu Central Hospita, 519 Nan men Street, Yiwu, Jinhua, Zhejing 322000 (China)

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.

Synergistically killing activity of aspirin and histone deacetylase inhibitor valproic acid (VPA) on hepatocellular cancer cells

International Nuclear Information System (INIS)

Li, Xiaofei; Zhu, Yanshuang; He, Huabin; Lou, Lianqing; Ye, Weiwei; Chen, Yongxin; Wang, Jinghe

2013-01-01

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

Contagion in Mass Killings and School Shootings.

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Sherry Towers

Full Text Available 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.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.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.

Contagion in Mass Killings and School Shootings.

Science.gov (United States)

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

2015-01-01

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. 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. 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.

The dissociation of tumor-induced weight loss from hypoglycemia in a transplantable pluripotent rat islet tumor results in the segregation of stable alpha- and beta-cell tumor phenotypes

DEFF Research Database (Denmark)

Madsen, O D; Karlsen, C; Nielsen, E

1993-01-01

that of starved rats until death results from cachexia. After tumor resection, animals immediately resume normal feeding behavior. Comparative studies of hormone release and mRNA content in anorectic lines, MSL-G-AN and NHI-5B-AN, vs. those in the insulinoma line, MSL-G2-IN, revealed selective glucagon gene...... in animals carrying tumor necrosis factor-producing experimental tumors....... markers. By selective transplantation, it was possible to segregate stable anorectic normoglycemic tumor lines, MSL-G-AN and NHI-5B-AN, from both clones. These tumors cause an abrupt onset of anorexia when they reach a size of 400-500 mg (

Effects of low dose radiation on tumor growth and changes of erythrocyte immune function and activity of SOD in tumor-bearing mice

International Nuclear Information System (INIS)

Yu Hongsheng; Lu Yanda

2001-01-01

Objective: To study the effect of low dose radiation on tumor growth and changes of erythrocyte immune function and activity of SOD in the tumor-bearing mice. Methods: Kunming strain male mice were implanted with S 180 sarcoma cells in the right inguen subcutaneously as an experimental in situ animal model. Six hours before implantation the mice were given 75 mG whole-body X-ray irradiation and tumor-formation rate was counted 5 days late. From then, every two days the tumor volume was measured to draw a tumor growth curve. Fifteen days later, all mice were killed to measure the tumor weight, observe the necrosis area and the tumor-infiltration lymphoreticular cells (TIL) in the tumor pathologically. At the same time, erythrocyte immune function and activity of SOD were tested. Results: (1) The mice pre-exposed to low dose radiation had a lower tumor formation rate than those without a pre-exposed (P < 0.05). (2) The tumor growth slowed down significantly in mice receiving a low does irradiation; The average tumor weight in mice receiving a low dose irradiation was lighter too (P < 0.05). (3) The tumor necrosis areas were larger and TILs were more in the irradiation group than those of the control group. (4) The erythrocyte immune function and activity of SOD in the irradiation group were all higher significantly than those of the control group ( P < 0.05). Conclusion: Low dose radiation could markedly increase anti-tumor ability of the organism and improve the erythrocyte immune function and activity of SOD in red cells, suggesting it could be useful in clinical cancer treatment

Reptile road-kills in Southern Brazil: Composition, hot moments and hotspots.

Science.gov (United States)

Gonçalves, Larissa Oliveira; Alvares, Diego Janisch; Teixeira, Fernanda Zimmermann; Schuck, Gabriela; Coelho, Igor Pfeifer; Esperandio, Isadora Beraldi; Anza, Juan; Beduschi, Júlia; Bastazini, Vinicius Augusto Galvão; Kindel, Andreas

2018-02-15

Understanding road-kill patterns is the first step to assess the potential effects of road mortality on wildlife populations, as well as to define the need for mitigation and support its planning. Reptiles are one of the vertebrate groups most affected by roads through vehicle collisions, both because they are intentionally killed by drivers, and due to their biological needs, such as thermoregulation, which make them more prone to collisions. We conducted monthly road surveys (33months), searching for carcasses of freshwater turtles, lizards, and snakes on a 277-km stretch of BR-101 road in Southernmost Brazil to estimate road-kill composition and magnitude and to describe the main periods and locations of road-kills. We modeled the distribution of road-kills in space according to land cover classes and local traffic volume. Considering the detection capacity of our method and carcass persistence probability, we estimated that 15,377 reptiles are road-killed per year (55reptiles/km/year). Road-kills, especially lizards and snakes, were concentrated during summer, probably due to their higher activity in this period. Road-kill hotspots were coincident among freshwater turtles, lizards, and snakes. Road-kill distribution was negatively related to pine plantations, and positively related to rice plantations and traffic volume. A cost-benefit analysis highlighted that if mitigation measures were installed at road-kill hotspots, which correspond to 21% of the road, they could have avoided up to 45% of recorded reptile fatalities, assuming a 100% mitigation effectiveness. Given the congruent patterns found for all three taxa, the same mitigation measures could be used to minimize the impacts of collision on local herpetofauna. Copyright © 2017 Elsevier B.V. All rights reserved.

Minimally cultured or selected autologous tumor-infiltrating lymphocytes after a lympho-depleting chemotherapy regimen in metastatic melanoma patients.

Science.gov (United States)

Besser, Michal J; Shapira-Frommer, Ronnie; Treves, Avraham J; Zippel, Dov; Itzhaki, Orit; Schallmach, Ester; Kubi, Adva; Shalmon, Bruria; Hardan, Izhar; Catane, Raphael; Segal, Eran; Markel, Gal; Apter, Sara; Nun, Alon Ben; Kuchuk, Iryna; Shimoni, Avichai; Nagler, Arnon; Schachter, Jacob

2009-05-01

Adoptive cell therapy with autologous tumor-infiltrating lymphocytes (TIL) and high-dose interleukin-2 (IL-2), after nonmyeloablative chemotherapy, has been shown to result in tumor regression in half of refractory metastatic melanoma patients. In the present study, we describe 2 separate clinical protocols. Twelve patients were treated with "Selected"-TIL, as previously reported and 8 patients with the modified version of "Young"-TIL. Selected-TIL protocol required the establishment of multiple T-cell cultures from 1 patient and in vitro selection of cultures secreting interferon-gamma upon antigenic stimulation. In contrast, Young-TIL are minimally cultured T cells with superior in vitro features that do not require further selection. Two of 12 Selected-TIL patients experienced objective clinical responses (1 complete response, 1 partial response). Out of 8 treated Young-TIL patients, 1 experienced complete response, 2 partial response, and 4 patients had disease stabilization. Twenty-one of 33 enrolled Selected-TIL patients were excluded from the protocol, mainly as cultures failed the interferon-gamma selection criteria or due to clinical deterioration, compared with only 3 Young-TIL patients. Expected bone marrow suppression and high-dose IL-2 toxicity were transient. There was no treatment-related mortality. This study vindicates the feasibility and effectiveness of TIL technology and calls for further efforts to implement and enhance this modality. The use of minimally cultured, unselected Young-TIL enables the treatment of most enrolled patients. Although the cohort of Young-TIL patients treated so far is rather small and the follow-up short, the response rate is encouraging.

CT perfusion of the liver during selective hepatic arteriography. Pure arterial blood perfusion of liver tumor and parenchyma

International Nuclear Information System (INIS)

Komemushi, Atsushi; Tanigawa, Noboru; Kojima, Hiroyuki; Kariya, Shuji; Sawada, Satoshi

2003-01-01

The purpose of this study was to quantify pure arterial blood perfusion of liver tumor and parenchyma by using CT perfusion during selective hepatic arteriography. A total of 44 patients underwent liver CT perfusion study by injection of contrast medium via the hepatic artery. CT-perfusion parameters including arterial blood flow, arterial blood volume, and arterial mean transit time in the liver parenchyma and liver tumor were calculated using the deconvolution method. The CT-perfusion parameters and vascularity of the tumor were compared. A complete analysis could be performed in 36 of the 44 patients. For liver tumor and liver parenchyma, respectively, arterial blood flow was 184.6±132.7 and 41.0±27.0 ml/min/100 g, arterial blood volume was 19.4±14.6 and 4.8±4.2 ml/100 g, and arterial mean transit time was 8.9±4.2 and 10.2±5.3 sec. Arterial blood flow and arterial blood volume correlated significantly with the vascularity of the tumor; however no correlation was detected between arterial mean transit time and the vascularity of the tumor. This technique could be used to quantify pure hepatic arterial blood perfusion. (author)

Evolution equations for Killing fields

International Nuclear Information System (INIS)

Coll, B.

1977-01-01

The problem of finding necessary and sufficient conditions on the Cauchy data for Einstein equations which insure the existence of Killing fields in a neighborhood of an initial hypersurface has been considered recently by Berezdivin, Coll, and Moncrief. Nevertheless, it can be shown that the evolution equations obtained in all these cases are of nonstrictly hyperbolic type, and, thus, the Cauchy data must belong to a special class of functions. We prove here that, for the vacuum and Einstein--Maxwell space--times and in a coordinate independent way, one can always choose, as evolution equations for the Killing fields, a strictly hyperbolic system: The above theorems can be thus extended to all Cauchy data for which the Einstein evolution problem has been proved to be well set

Dirac operators and Killing spinors with torsion

International Nuclear Information System (INIS)

Becker-Bender, Julia

2012-01-01

On a Riemannian spin manifold with parallel skew torsion, we use the twistor operator to obtain an eigenvalue estimate for the Dirac operator with torsion. We consider the equality case in dimensions four and six. In odd dimensions we describe Sasaki manifolds on which equality in the estimate is realized by Killing spinors with torsion. In dimension five we characterize all Killing spinors with torsion and obtain certain naturally reductive spaces as exceptional cases.

Inhibition of homologous recombination repair in irradiated tumor cells pretreated with Hsp90 inhibitor 17-allylamino-17-demethoxygeldanamycin

International Nuclear Information System (INIS)

Noguchi, Miho; Yu, Dong; Hirayama, Ryoichi; Ninomiya, Yasuharu; Sekine, Emiko; Kubota, Nobuo; Ando, Koichi; Okayasu, Ryuichi

2006-01-01

In order to investigate the mechanism of radio-sensitization by an Hsp90 inhibitor 17-allylamino-17-demethoxygeldanamycin (17-AAG), we studied repair of DNA double strand breaks (DSBs) in irradiated human cells pre-treated with 17-AAG. DSBs are thought to be the critical target for radiation-induced cell death. Two human tumor cell lines DU145 and SQ-5 which showed clear radio-sensitization by 17-AAG revealed a significant inhibition of DSB repair, while normal human cells which did not show radio-sensitization by the drug indicated no change in the DSB repair kinetics with 17-AAG. We further demonstrated that BRCA2 was a novel client protein for Hsp90, and 17-AAG caused the degradation of BRCA2 and in turn altered the behavior of Rad51, a critical protein for homologous recombination (HR) pathway of DSB repair. Our data demonstrate for the first time that 17-AAG inhibits the HR repair process and could provide a new therapeutic strategy to selectively result in higher tumor cell killing

Is oxygen important in the radiocurability of human tumors

International Nuclear Information System (INIS)

Withers, H.R.; Suit, H.D.

1974-01-01

It is quite likely that untreated human tumors contain hypoxic cells. Frequently, perhaps usually, the presence of these hypoxic cells does not influence radiocurability. If hypoxia limits radiocurability, it is more likely to do so in the treatment of large tumors and maybe with greater likelihood in tumors in certain sites. Hypoxia would also be more likely to affect response to a small number of fractions, since reoxygenation would need to be more complete in order that cell killing by the larger dose fractions used would not be prejudiced by the hypoxia of a small proportion of cells. Hyperbaric oxygen is disappointing as an adjuvant to radiotherapy. Results obtained are not better than those obtained using the best conventional fractionation regimes in air. This does not prove, however, that hypoxia is not a cause of failure to control tumors locally, since physiological adaptive mechanisms against HPO such as vasoconstriction may prevent better oxygenation of the tumor. If other methods such as high LET beams are to be used to reduce any effect hypoxia may have on radiocurability, their greatest benefit would be expected in the local control of late-stage disease and this benefit may be greater in some tumor sites than others. (U.S.)

Tumor microenvironmental changes induced by the sulfamate carbonic anhydrase IX inhibitor S4 in a laryngeal tumor model.

Directory of Open Access Journals (Sweden)

Tineke W H Meijer

Full Text Available BACKGROUND AND PURPOSE: Carbonic anhydrase IX (CAIX plays a pivotal role in pH homeostasis, which is essential for tumor cell survival. We examined the effect of the CAIX inhibitor 4-(3'(3",5"-dimethylphenyl-ureidophenyl sulfamate (S4 on the tumor microenvironment in a laryngeal tumor model by analyzing proliferation, apoptosis, necrosis, hypoxia, metabolism and CAIX ectodomain shedding. METHODS: SCCNij202 tumor bearing-mice were treated with S4 for 1, 3 or 5 days. CAIX ectodomain shedding was measured in the serum after therapy. Effects on tumor cell proliferation, apoptosis, necrosis, hypoxia (pimonidazole and CAIX were investigated with quantitative immunohistochemistry. Metabolic transporters and enzymes were quantified with qPCR. RESULTS: CAIX ectodomain shedding decreased after treatment with S4 (p<0.01. S4 therapy did neither influence tumor cell proliferation nor the amount of apoptosis and necrosis. Hypoxia (pimonidazole and CAIX expression were also not affected by S4. CHOP and MMP9 mRNA as a reference of intracellular pH did not change upon treatment with S4. Compensatory mechanisms of pH homeostasis at the mRNA level were not observed. CONCLUSION: As the clinical and biological meaning of the decrease in CAIX ectodomain shedding after S4 therapy is not clear, studies are required to elucidate whether the CAIX ectodomain has a paracrine or autocrine signaling function in cancer biology. S4 did not influence the amount of proliferation, apoptosis, necrosis and hypoxia. Therefore, it is unlikely that S4 can be used as single agent to influence tumor cell kill and proliferation, and to target primary tumor growth.

A chimeric antigen receptor for TRAIL-receptor 1 induces apoptosis in various types of tumor cells.

Science.gov (United States)

Kobayashi, Eiji; Kishi, Hiroyuki; Ozawa, Tatsuhiko; Hamana, Hiroshi; Nakagawa, Hidetoshi; Jin, Aishun; Lin, Zhezhu; Muraguchi, Atsushi

2014-10-31

Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) and its associated receptors (TRAIL-R/TR) are attractive targets for cancer therapy because TRAIL induces apoptosis in tumor cells through TR while having little cytotoxicity on normal cells. Therefore, many agonistic monoclonal antibodies (mAbs) specific for TR have been produced, and these induce apoptosis in multiple tumor cell types. However, some TR-expressing tumor cells are resistant to TR-specific mAb-induced apoptosis. In this study, we constructed a chimeric antigen receptor (CAR) of a TRAIL-receptor 1 (TR1)-specific single chain variable fragment (scFv) antibody (TR1-scFv-CAR) and expressed it on a Jurkat T cell line, the KHYG-1 NK cell line, and human peripheral blood lymphocytes (PBLs). We found that the TR1-scFv-CAR-expressing Jurkat cells killed target cells via TR1-mediated apoptosis, whereas TR1-scFv-CAR-expressing KHYG-1 cells and PBLs killed target cells not only via TR1-mediated apoptosis but also via CAR signal-induced cytolysis, resulting in cytotoxicity on a broader range if target cells than with TR1-scFv-CAR-expressing Jurkat cells. The results suggest that TR1-scFv-CAR could be a new candidate for cancer gene therapy. Copyright © 2014 Elsevier Inc. All rights reserved.

pH-Sensitive nanoparticles as smart carriers for selective intracellular drug delivery to tumor.

Science.gov (United States)

Li, Xin-Xin; Chen, Jing; Shen, Jian-Min; Zhuang, Ran; Zhang, Shi-Qi; Zhu, Zi-Yun; Ma, Jing-Bo

2018-05-05

Herein, a smart pH-sensitive nanoparticle (DGL-PEG-Tat-KK-DMA-DOX) was prepared to achieve the selective intracellular drug delivery. In this nanoparticle, a PEG-grafted cell penetrating peptide (PEG-Tat-KK) was designed and acted as the cell penetrating segment. By introducing the pH-sensitive amide bonds between the peptide and blocking agent (2,3-dimethylmaleic anhydride, DMA), the controllable moiety (PEG-Tat-KK-DMA) endowed the nanoparticle with a charge-switchable shell and temporarily blocked penetrating function, thus improving the specific internalization. Besides, dendrigraft poly-L-lysine (DGL) used as the skeleton can greatly improve the drug loading because of the highly dendritic framework. Under the stimuli of acidic pH, this nanoparticle exhibited a remarkable charge-switchable property. The drug release showed an expected behavior with little release in the neutral pH media but relatively fast release in the acidic media. The in vitro experiments revealed that the cellular uptake and cytotoxicity were significantly enhanced after the pH was decreased. In vivo biodistribution and antitumor research indicated that the nanoparticle had noteworthy specificity and antitumor efficacy with a tumor inhibition rate of 79.7%. These results verified this nanoparticle could efficiently improve the selective intracellular delivery and possessed a great potential in tumor treatment. Copyright © 2018 Elsevier B.V. All rights reserved.

Imaging and Targeting of Hypoxic Tumor Cells with Use of HIF-1-2

International Nuclear Information System (INIS)

Kizaka-Kondoh, Shinae; Harada, Hiroshi; Tanaka, Shotaro; Hiraoka, Masahiro

2006-01-01

This paper describes imaging (visualization) of transplanted tumor cells under hypoxia in vivo and molecular targeting to kill those cells by inducing their apoptosis. HIF (hypoxia inducible factor) concerned with angiogenesis is induced specifically in hypoxic tumor cells and its activity can be visualized by transfection of reporter vector construct of fluorescent protein GFP or luciferase. Authors established the transfected tumor cells with the plasmid p5HRE-luciferase and when transplanted in the nude mouse, those cells emitted light dependently to their hypoxic conditions, which could be visualized by in vivo imaging system (IVIS) with CCD camera. Authors prepared the oxygen-dependent degradation-procaspase 3-fusion protein (TOP3) to target the hypoxic tumor cells for enhancing their apoptotic signaling, whose apoptosis was actually observed by the IVIS. Reportedly, radiation transiently activates HIF-1 and combination treatment of radiation and TOP3 resulted in the enhanced death of tumor cells. Interestingly, the suppression of tumor growth lasted longer than expected, probably due to inhibition of angiogenesis. Authors called this anti-tumor strategy as the micro-environmental targeting. (T.I.)

Apoptosis and tumor cell death in response to HAMLET (human alpha-lactalbumin made lethal to tumor cells).

Science.gov (United States)

Hallgren, Oskar; Aits, Sonja; Brest, Patrick; Gustafsson, Lotta; Mossberg, Ann-Kristin; Wullt, Björn; Svanborg, Catharina

2008-01-01

HAMLET (human alpha-lactalbumin made lethal to tumor cells) is a molecular complex derived from human milk that kills tumor cells by a process resembling programmed cell death. The complex consists of partially unfolded alpha-lactalbumin and oleic acid, and both the protein and the fatty acid are required for cell death. HAMLET has broad antitumor activity in vitro, and its therapeutic effect has been confirmed in vivo in a human glioblastoma rat xenograft model, in patients with skin papillomas and in patients with bladder cancer. The mechanisms of tumor cell death remain unclear, however. Immediately after the encounter with tumor cells, HAMLET invades the cells and causes mitochondrial membrane depolarization, cytochrome c release, phosphatidyl serine exposure, and a low caspase response. A fraction of the cells undergoes morphological changes characteristic of apoptosis, but caspase inhibition does not rescue the cells and Bcl-2 overexpression or altered p53 status does not influence the sensitivity of tumor cells to HAMLET. HAMLET also creates a state of unfolded protein overload and activates 20S proteasomes, which contributes to cell death. In parallel, HAMLET translocates to tumor cell nuclei, where high-affinity interactions with histones cause chromatin disruption, loss of transcription, and nuclear condensation. The dying cells also show morphological changes compatible with macroautophagy, and recent studies indicate that macroautophagy is involved in the cell death response to HAMLET. The results suggest that HAMLET, like a hydra with many heads, may interact with several crucial cellular organelles, thereby activating several forms of cell death, in parallel. This complexity might underlie the rapid death response of tumor cells and the broad antitumor activity of HAMLET.

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

Science.gov (United States)

2010-01-01

... REQUIREMENTS Killed Virus Vaccines § 113.214 Parvovirus Vaccine, Killed Virus (Canine). Parvovirus Vaccine... antibody against canine parvovirus to determine susceptibility. A constant virus-varying serum... vaccinates and the controls shall be challenged with virulent canine parvovirus furnished or approved by...

In vitro interactions of lymphocytes and cultured cells from beagles with plutonium-induced bone tumors

International Nuclear Information System (INIS)

Frazier, M.E.; Lund, J.E.; Busch, R.H.

1976-01-01

Cell cultures have been prepared from lung and bone tumors arising in beagle dogs following exposure to inhaled plutonium. Evaluation of the cultured cells by commonly applied criteria (i.e., cell morphology, lack of contact inhibitory mechanisms, cloning efficiency, growth in soft agar, and tumor production in vivo) indicated that tumor cells were being grown in culture. Blood leukocytes and peripheral lymphocytes from beagle dogs were tested for cytotoxic effects against several cell cultures. Lymphocytes from normal dogs or dogs with unrelated tumors would not kill the bone tumor cells unless monocytes (macrophage) were present, in which case the leukocyte preparation was capable of mounting de novo cytotoxic immune reactions after 3 to 5 days in culture. In contrast, the dogs with plutonium-induced bone tumors had circulating lymphocytes that appeared to have undergone presensitization to bone-tumor-distinctive antigens in vivo. Consequently these lymphocytes interacted with cultured cells promptly after encounter in vitro

Culture of Dendritic Cells in vitro and Its Anti-tumor Immonotherapy

Directory of Open Access Journals (Sweden)

Yanwen ZHOU

2010-05-01

Full Text Available Background and objective Immunocompromised patients with malignant tumor always lack of strong anti-tumor immune response, because the antigenicity of tumor cells is weak, and antigen-presenting cell function is low, so that can not be effectively presenting tumor antigens to the lymphocytes. Therefore, how to effectively induce anti-tumor immune response is the key issue. Through the study on establishing a method to culture dendritic cells (DC in vitro and to observe the anti-lung cancer immunological effect induced by DC, we provided definite experiment basis for the clinic application of vaccine based on DC. Methods Through the experiment we get the soluble antigen polypeptide from lung cancer cells GLC-82 by 3 mol/L potassium chloride. DCs are cultured and obtained from peripheral blood mononuclear cell by GM-CSF, IL-4 and TNF-a. DCs are identified by flow cytometer (FCM and immunostaining. DCs modified by lung cancer tumor soluble antigen (TSA and staphylococcal enterotox in A (SEA, DCs modified by TSA or DCs modified by SEA or DCs modified by nothing were cultivated together with T lymphocyte, and the obtained cells are named TSA-SEA-DCL or TSA-DCL or SEA-DCL or DCL as effector cells. The anti-tumor activity of every effector cells against target cells was assayed with MTT method. Shape of DCs and effector cells, and the process of killing target cells were observed in microscope. Results Induced DCs expressed more CD1a, CD80 and HLA-DR, which had typical cell traits such as tree branch. The killing ratio of the TSA-SEA-DCL in vitro to GLC-82 is larger than TSA-DCL, SEA-DCL and DCL, also larger than to K562. When the effector cells cultivate with target cells, we can observe the CTL approach and gather to the cancer cell, induce it necrosis and apoptosis. Conclusion Ripe DCs that have typical characteristic and phenotype could be induced successfully. High potency and relatively specific antilung caner effect can be prepared in virtue of

Systemic combinatorial peptide selection yields a non-canonical iron-mimicry mechanism for targeting tumors in a mouse model of human glioblastoma

Science.gov (United States)

Staquicini, Fernanda I.; Ozawa, Michael G.; Moya, Catherine A.; Driessen, Wouter H.P.; Barbu, E. Magda; Nishimori, Hiroyuki; Soghomonyan, Suren; Flores, Leo G.; Liang, Xiaowen; Paolillo, Vincenzo; Alauddin, Mian M.; Basilion, James P.; Furnari, Frank B.; Bogler, Oliver; Lang, Frederick F.; Aldape, Kenneth D.; Fuller, Gregory N.; Höök, Magnus; Gelovani, Juri G.; Sidman, Richard L.; Cavenee, Webster K.; Pasqualini, Renata; Arap, Wadih

2010-01-01

The management of CNS tumors is limited by the blood-brain barrier (BBB), a vascular interface that restricts the passage of most molecules from the blood into the brain. Here we show that phage particles targeted with certain ligand motifs selected in vivo from a combinatorial peptide library can cross the BBB under normal and pathological conditions. Specifically, we demonstrated that phage clones displaying an iron-mimic peptide were able to target a protein complex of transferrin and transferrin receptor (TfR) through a non-canonical allosteric binding mechanism and that this functional protein complex mediated transport of the corresponding viral particles into the normal mouse brain. We also showed that, in an orthotopic mouse model of human glioblastoma, a combination of TfR overexpression plus extended vascular permeability and ligand retention resulted in remarkable brain tumor targeting of chimeric adeno-associated virus/phage particles displaying the iron-mimic peptide and carrying a gene of interest. As a proof of concept, we delivered the HSV thymidine kinase gene for molecular-genetic imaging and targeted therapy of intracranial xenografted tumors. Finally, we established that these experimental findings might be clinically relevant by determining through human tissue microarrays that many primary astrocytic tumors strongly express TfR. Together, our combinatorial selection system and results may provide a translational avenue for the targeted detection and treatment of brain tumors. PMID:21183793

Holocaust and strategic bombing: case studies in the psychology, organization, and technology of mass killing in the twentieth century

Energy Technology Data Exchange (ETDEWEB)

Markusen, E.R.

1986-01-01

After preliminary discussion of the unprecedented scale of mass killing in the twentieth century, the threat of nuclear war, and the widespread neglect of these issues, the literature on two major types of government sanctioned mass killing is reviewed; genocide, in which a government slaughters its own citizens or subjects, and total war, in which two or more governments slaughter each other's civilian citizens or subjects. This literature review reaches two basic conclusions: (1) there is considerable inconsistency and ambiguity among definitions of genocide and total war; and (2) there is a controversy regarding how distinct or similar the two forms of mass killing actually are. A comparative historical analysis was undertaken in which the Nazi Holocaust was selected as an example of genocide, and the Allied strategic bombing campaigns during World War II were selected to exemplify total war. The two cases are compared in terms of a conceptual framework of five hypothesized facilitating factors. On the basis of this comparative analysis, four or the five hypothesized facilitating factors are found to have played important roles in both cases. The findings of the study are discussed, and their implications for the threat of nuclear holocaust are explored.

Therapeutic potential and challenges of Natural killer cells in treatment of solid tumors

Directory of Open Access Journals (Sweden)

Andrea eGras Navarro

2015-04-01

Full Text Available 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 (CSCs 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.

Clinical characteristics of patient selection and imaging predictors of outcome in solid tumors treated with checkpoint-inhibitors

International Nuclear Information System (INIS)

Rossi, Sabrina; Toschi, Luca; Castello, Angelo; Grizzi, Fabio; Mansi, Luigi; Lopci, Egesta

2017-01-01

The rapidly evolving knowledge on tumor immunology and the continuous implementation of immunotherapy in cancer have recently led to the FDA and EMA approval of several checkpoint inhibitors as immunotherapic agents in clinical practice. Anti-CTLA-4, anti-PD-1, and anti-PDL-1 antibodies are becoming standard of care in advanced melanoma, as well as in relapsed or metastatic lung and kidney cancer, demonstrating higher and longer response compared to standard chemotherapy. These encouraging results have fostered the evaluation of these antibodies either alone or in combination with other therapies in several dozen clinical trials for the treatment of multiple tumor types. However, not all patients respond to immune checkpoint inhibitors, hence, specific biomarkers are necessary to guide and monitor therapy. The utility of PD-L1 expression as a biomarker has varied in different clinical trials, but, to date, no consensus has been reached on whether PD-L1 expression is an ideal marker for response and patient selection; approximately 20-25% of patients will respond to immunotherapy with checkpoint inhibitors despite a negative PD-L1 staining. On the other hand, major issues concern the evaluation of objective response in patients treated with immunotherapy. Pure morphological criteria as commonly used in solid tumors (i.e. RECIST) are not sufficient because change in size is not an early and reliable marker of tumor response to biological therapies. Thus, the scientific community has required a continuous adaptation of immune-related response criteria (irRC) to overcome the problem. In this context, metabolic information and antibody-based imaging with positron emission tomography (PET) have been investigated, providing a powerful approach for an optimal stratification of patients at staging and during the evaluation of the response to therapy. In the present review we provide an overview on the clinical characteristics of patient selection when using imaging

Clinical characteristics of patient selection and imaging predictors of outcome in solid tumors treated with checkpoint-inhibitors

Energy Technology Data Exchange (ETDEWEB)

Rossi, Sabrina; Toschi, Luca [Humanitas Clinical and Research Hospital, Medical Oncology, Rozzano (Italy); Castello, Angelo [Humanitas Clinical and Research Hospital, Nuclear Medicine, Rozzano (Italy); Grizzi, Fabio [Humanitas Clinical and Research Hospital, Immunology and Inflammation, Rozzano (Italy); Mansi, Luigi [Seconda Universita di Napoli, Nuclear Medicine, Naples (Italy); Lopci, Egesta [Humanitas Clinical and Research Hospital, Nuclear Medicine, Rozzano (Italy); Humanitas Cancer Center, Humanitas Clinical and Research Hospital, Nuclear Medicine, Rozzano, MI (Italy)

2017-12-15

The rapidly evolving knowledge on tumor immunology and the continuous implementation of immunotherapy in cancer have recently led to the FDA and EMA approval of several checkpoint inhibitors as immunotherapic agents in clinical practice. Anti-CTLA-4, anti-PD-1, and anti-PDL-1 antibodies are becoming standard of care in advanced melanoma, as well as in relapsed or metastatic lung and kidney cancer, demonstrating higher and longer response compared to standard chemotherapy. These encouraging results have fostered the evaluation of these antibodies either alone or in combination with other therapies in several dozen clinical trials for the treatment of multiple tumor types. However, not all patients respond to immune checkpoint inhibitors, hence, specific biomarkers are necessary to guide and monitor therapy. The utility of PD-L1 expression as a biomarker has varied in different clinical trials, but, to date, no consensus has been reached on whether PD-L1 expression is an ideal marker for response and patient selection; approximately 20-25% of patients will respond to immunotherapy with checkpoint inhibitors despite a negative PD-L1 staining. On the other hand, major issues concern the evaluation of objective response in patients treated with immunotherapy. Pure morphological criteria as commonly used in solid tumors (i.e. RECIST) are not sufficient because change in size is not an early and reliable marker of tumor response to biological therapies. Thus, the scientific community has required a continuous adaptation of immune-related response criteria (irRC) to overcome the problem. In this context, metabolic information and antibody-based imaging with positron emission tomography (PET) have been investigated, providing a powerful approach for an optimal stratification of patients at staging and during the evaluation of the response to therapy. In the present review we provide an overview on the clinical characteristics of patient selection when using imaging

Mercy killing in neurology: The beginnings of neurology on screen (II).

Science.gov (United States)

Wijdicks, Eelco F M; Karenberg, Axel

2016-09-20

The history of Neurocinema includes neuroethics, and this theme was first used in 2 films released in the 1940s in both Germany and the United States. Ich Klage An (I Accuse) is about "terminal" multiple sclerosis in a young woman and the decision to determine one's own fate. The protagonist anticipates becoming "deaf, blind, and idiotic" and asks her husband to administer a toxic drug dose, which he does. The film disturbingly suggests that the diagnosis of multiple sclerosis is tantamount to a death sentence. Ich Klage An (1941) played during the medical murders era ("Aktion T-4" program) but has few references to National Socialism, except for judges with Nazi emblems on their robes making a brief Nazi salute and a jury chamber with a bust of Hitler. Party leadership agreed that the film made a deep impression, but the intended effect on the viewing public is largely unknown. An Act of Murder (1948) involves another young woman with an inoperable brain tumor. When her condition worsens during a trip, her husband deliberately crashes the car, killing her but surviving himself. A subsequent trial finds that she died of an overdose rather than the crash. The trial judge dismisses the murder charge, but the film argues the morals of mercy killing. These films came out during the Nazi euthanasia program and founding of the Euthanasia Society of America in 1938. The choice of neurologic disease by these filmmakers and scriptwriters to defend euthanasia is remarkable. © 2016 American Academy of Neurology.

Tumor Acidity as Evolutionary Spite

International Nuclear Information System (INIS)

Alfarouk, Khalid O.; Muddathir, Abdel Khalig; Shayoub, Mohammed E. A.

2011-01-01

Most cancer cells shift their metabolic pathway from a metabolism reflecting the Pasteur-effect into one reflecting the Warburg-effect. This shift creates an acidic microenvironment around the tumor and becomes the driving force for a positive carcinogenesis feedback loop. As a consequence of tumor acidity, the tumor microenvironment encourages a selection of certain cell phenotypes that are able to survive in this caustic environment to the detriment of other cell types. This selection can be described by a process which can be modeled upon spite: the tumor cells reduce their own fitness by making an acidic environment, but this reduces the fitness of their competitors to an even greater extent. Moreover, the environment is an important dimension that further drives this spite process. Thus, diminishing the selective environment most probably interferes with the spite process. Such interference has been recently utilized in cancer treatment

Control of Influenza and Poliomyelitis with Killed Virus Vaccines

Science.gov (United States)

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)

9 CFR 113.210 - Feline Calicivirus Vaccine, Killed Virus.

Science.gov (United States)

2010-01-01

... Virus. 113.210 Section 113.210 Animals and Animal Products ANIMAL AND PLANT HEALTH INSPECTION SERVICE, DEPARTMENT OF AGRICULTURE VIRUSES, SERUMS, TOXINS, AND ANALOGOUS PRODUCTS; ORGANISMS AND VECTORS STANDARD REQUIREMENTS Killed Virus Vaccines § 113.210 Feline Calicivirus Vaccine, Killed Virus. Feline Calicivirus...

9 CFR 113.211 - Feline Rhinotracheitis Vaccine, Killed Virus.

Science.gov (United States)

2010-01-01

... Virus. 113.211 Section 113.211 Animals and Animal Products ANIMAL AND PLANT HEALTH INSPECTION SERVICE, DEPARTMENT OF AGRICULTURE VIRUSES, SERUMS, TOXINS, AND ANALOGOUS PRODUCTS; ORGANISMS AND VECTORS STANDARD REQUIREMENTS Killed Virus Vaccines § 113.211 Feline Rhinotracheitis Vaccine, Killed Virus. Feline...

9 CFR 113.216 - Bovine Rhinotracheitis Vaccine, Killed Virus.

Science.gov (United States)

2010-01-01

... Virus. 113.216 Section 113.216 Animals and Animal Products ANIMAL AND PLANT HEALTH INSPECTION SERVICE, DEPARTMENT OF AGRICULTURE VIRUSES, SERUMS, TOXINS, AND ANALOGOUS PRODUCTS; ORGANISMS AND VECTORS STANDARD REQUIREMENTS Killed Virus Vaccines § 113.216 Bovine Rhinotracheitis Vaccine, Killed Virus. Infectious Bovine...

9 CFR 113.203 - Feline Panleukopenia Vaccine, Killed Virus.

Science.gov (United States)

2010-01-01

... Virus. 113.203 Section 113.203 Animals and Animal Products ANIMAL AND PLANT HEALTH INSPECTION SERVICE, DEPARTMENT OF AGRICULTURE VIRUSES, SERUMS, TOXINS, AND ANALOGOUS PRODUCTS; ORGANISMS AND VECTORS STANDARD REQUIREMENTS Killed Virus Vaccines § 113.203 Feline Panleukopenia Vaccine, Killed Virus. Feline Panleukopenia...

Vertebrate road kill survey on a highway in southern Brazil

Directory of Open Access Journals (Sweden)

Luiz Liberato Costa Corrêa

2017-06-01

Full Text Available Highways are a major factor acting in the decline of several wildlife populations. Impact occurs due to the continuous flow of motor vehicles over tracks and collision with animals using the same area. This study aimed to list road killed wild vertebrates found in highways in the Pampa Biome, state of Rio Grande do Sul, over an entire year. The taxa found (amphibians, reptiles, birds and mammals were identified to species level and their frequency of occurrence was seasonally registered. Along 2,160 km, we found 318 road killed individuals, totaling 65 species. This number represents an average of 0.147 road killed specimens by kilometer (that is, 1 individual each 7 km. Of these, seven species are under threat of extinction in the state of Rio Grande do Sul. We also found a seasonal pattern among road kills, in which the highest number of road killed animals was registered in the summer and spring months. These results contribute to increase knowledge about which species are most impacted by road kill on highways of the Pampa Biome. Such data can be used as an indicator for the implementation of measures by competent bodies to mitigate impacts of highways in the state of Rio Grande do Sul.

Role of nitric oxide and superoxide in Giardia lamblia killing

Directory of Open Access Journals (Sweden)

P.D. Fernandes

1997-01-01

Full Text Available Giardia lamblia trophozoites were incubated for 2 h with activated murine macrophages, nitric oxide (NO donors or a superoxide anion generator (20 mU/ml xanthine oxidase plus 1 mM xanthine. Activated macrophages were cytotoxic to Giardia trophozoites (~60% dead trophozoites. This effect was inhibited (>90% by an NO synthase inhibitor (200 µM and unaffected by superoxide dismutase (SOD, 300 U/ml. Giardia trophozoites were killed by the NO donors, S-nitroso-acetyl-penicillamine (SNAP and sodium nitroprusside (SNP in a dose-dependent manner (LD50 300 and 50 µM, respectively. A dual NO-superoxide anion donor, 3-morpholino-sydnonimine hydrochloride (SIN-1, did not have a killing effect in concentrations up to 1 mM. However, when SOD (300 U/ml was added simultaneously with SIN-1 to Giardia, a significant trophozoite-killing effect was observed (~35% dead trophozoites at 1 mM. The mixture of SNAP or SNP with superoxide anion, which yields peroxynitrite, abolished the trophozoite killing induced by NO donors. Authentic peroxynitrite only killed trophozoites at very high concentrations (3 mM. These results indicate that NO accounts for Giardia trophozoite killing and this effect is not mediated by peroxynitrite

Sleep quality and methylation status of selected tumor suppressor genes among nurses and midwives.

Science.gov (United States)

Bukowska-Damska, Agnieszka; Reszka, Edyta; Kaluzny, Pawel; Wieczorek, Edyta; Przybek, Monika; Zienolddiny, Shanbeh; Peplonska, Beata

2018-01-01

Chronic sleep restriction may affect metabolism, hormone secretion patterns and inflammatory responses. Limited reports suggest also epigenetic effects, such as changes in DNA methylation profiles. The study aims to assess the potential association between poor sleep quality or sleep duration and the levels of 5-methylcytosine in the promoter regions of selected tumor suppressor genes. A cross-sectional study was conducted on 710 nurses and midwives aged 40-60 years. Data from interviews regarding sleep habits and potential confounders were used. The methylation status of tumor suppressor genes was determined via qMSP reactions using DNA samples derived from leucocytes. No significant findings were observed in the total study population or in the two subgroups of women stratified by the current system of work. A borderline significance association was observed between a shorter duration of sleep and an increased methylation level in CDKN2A among day working nurses and midwives. Further studies are warranted to explore this under-investigated topic.

Competition between apex predators? Brown bears decrease wolf kill rate on two continents.

Science.gov (United States)

Tallian, Aimee; Ordiz, Andrés; Metz, Matthew C; Milleret, Cyril; Wikenros, Camilla; Smith, Douglas W; Stahler, Daniel R; Kindberg, Jonas; MacNulty, Daniel R; Wabakken, Petter; Swenson, Jon E; Sand, Håkan

2017-02-08

Trophic interactions are a fundamental topic in ecology, but we know little about how competition between apex predators affects predation, the mechanism driving top-down forcing in ecosystems. We used long-term datasets from Scandinavia (Europe) and Yellowstone National Park (North America) to evaluate how grey wolf ( Canis lupus ) kill rate was affected by a sympatric apex predator, the brown bear ( Ursus arctos ). We used kill interval (i.e. the number of days between consecutive ungulate kills) as a proxy of kill rate. Although brown bears can monopolize wolf kills, we found no support in either study system for the common assumption that they cause wolves to kill more often. On the contrary, our results showed the opposite effect. In Scandinavia, wolf packs sympatric with brown bears killed less often than allopatric packs during both spring (after bear den emergence) and summer. Similarly, the presence of bears at wolf-killed ungulates was associated with wolves killing less often during summer in Yellowstone. The consistency in results between the two systems suggests that brown bear presence actually reduces wolf kill rate. Our results suggest that the influence of predation on lower trophic levels may depend on the composition of predator communities. © 2017 The Authors.

Effect of SPG (Sonifilan) immunotherapy and PDT on murine tumor

International Nuclear Information System (INIS)

Korbelik, M.; Krosl, G.; Dougherty, G.J.; Chaplin, D.J.

1992-01-01

PhotoDynamic Therapy of solid tumors is unique in eliciting a strong host immune response unparalleled in other cancer therapies. This immune response is manifested as an acute inflammatory reaction, and can be readily seen as redness and edema around the treated area. Destruction of typical solid tumor cannot be accomplished solely by direct phototoxic action. This was shown to be the case even with drugs more potent in this direct killing effect than Photofrin, the photosensitizer presently used in clinical PDT. Limiting factors seem to be regional insufficiencies in supply of molecular oxygen, needed for generation of phototoxic species. They can be ascribed to the existence of chronically and acute hypoxic tumor regions, oxygen consumption by the photodynamic process, and vascular shutdown induced during PDT. The remaining tumor mass is eradicated by an indirect effect, necrosis induced by destruction of tumor vasculature. Since most events in PDT treated tumor that lead to vascular collapse are, in fact, typical inflammatory manifestations, it was suggested that PDT-induced acute inflammatory reaction actually leads to vascular damage. In a related report characteristics are shown of cellular inflammatory infiltrate in PDT-treated murine tumor. This work examines the effect of combining PDT with immunotherapy, in an attempt to investigate a possibility of amplification of immune reaction to PDT and its direction towards more pervasive destruction of treated tumors. (authors). 6 refs

Targeted Killings in Bangladesh: Diversity at Stake

OpenAIRE

Syed, Jawad

2016-01-01

Since 2013, Bangladesh has repeatedly been in headline news across the world due to systematic and incessant targeted killings. In the mainstream media, both in South Asia and the West, the focus has been generally on high profile murders of secular and progressive bloggers. This includes the recent worldwide broad coverage on the tragic murder of Xulhaz Mannan, editor of Bangladesh's first LGBT rights magazine. However, not many know that these killings are only one part of the story. Secula...

Contagion in Mass Killings and School Shootings

OpenAIRE

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 dat...

9 CFR 113.205 - Newcastle Disease Vaccine, Killed Virus.

Science.gov (United States)

2010-01-01

... Virus. 113.205 Section 113.205 Animals and Animal Products ANIMAL AND PLANT HEALTH INSPECTION SERVICE, DEPARTMENT OF AGRICULTURE VIRUSES, SERUMS, TOXINS, AND ANALOGOUS PRODUCTS; ORGANISMS AND VECTORS STANDARD REQUIREMENTS Killed Virus Vaccines § 113.205 Newcastle Disease Vaccine, Killed Virus. Newcastle Disease Vaccine...

Mitigation options for fish kills in L Lake and Pond C

International Nuclear Information System (INIS)

Paller, M.H.

1989-11-01

This report concerns mitigation options for reducing or eliminating the fish kills that occur in L Lake and Pond C as a result of reactor operations. These kills occur when fish that have entered the discharge areas during outages are killed by the rapid rises in temperature that follow reactor re-starts. Factors that have been observed to influence the severity of the kills include the length of the outage, season during which the outage occurs, reactor power level, and size of the fish in the discharge area. Without mitigation, fish kills can be expected to occur in Pond C with approximately the same frequency and severity as in the past. Even in the absence of mitigation, however, it is unlikely that future fish kills in L Lake will be as severe as the large kill that occurred in December 1986. Fish abundance in Region 2 of L Lake (where severe kills occurred in the past) has declined over 90% since 1986, largely due to a reduction in the abundance of juvenile sunfish (which constituted approximately 99% of past kills). There are basically three categories of mitigation options: changes in reactor operations, methods to exclude fish from time discharge areas, and methods to promote the escapement of fish from the discharge area. These options vary in approach, scope, and anticipated expense. Most would need to be researched in greater depth before it would be possible to predict their effectiveness more definitively. While the options have the potential to greatly reduce mortalities, none can totally eliminate mortalities. The only way of ensuring the elimination of all mortalities is to reduce effluent temperatures to sublethal levels with properly designed and operated cooling technology. 18 refs., 2 figs., 1 tab

Optical fiber biocompatible sensors for monitoring selective treatment of tumors via thermal ablation

Science.gov (United States)

Tosi, Daniele; Poeggel, Sven; Dinesh, Duraibabu B.; Macchi, Edoardo G.; Gallati, Mario; Braschi, Giovanni; Leen, Gabriel; Lewis, Elfed

2015-09-01

Thermal ablation (TA) is an interventional procedure for selective treatment of tumors, that results in low-invasive outpatient care. The lack of real-time control of TA is one of its main weaknesses. Miniature and biocompatible optical fiber sensors are applied to achieve a dense, multi-parameter monitoring, that can substantially improve the control of TA. Ex vivo measurements are reported performed on porcine liver tissue, to reproduce radiofrequency ablation of hepatocellular carcinoma. Our measurement campaign has a two-fold focus: (1) dual pressure-temperature measurement with a single probe; (2) distributed thermal measurement to estimate point-by-point cells mortality.

In vitro radiobiological evaluation of selective killing effects of 10B1-paraboronophenylalanine.HCl in the thermal neutron capture therapy of malignant melanoma cells

International Nuclear Information System (INIS)

Ichihashi, M.; Ueda, M.; Hayashibe, K.; Hatta, S.; Tsuji, M.; Mishima, Y.; Fukuda, H.; Kobayashi, T.; Kanda, K.

1985-01-01

In order to clarify the specific affinity of 10 B 1 -p-boronophenylalanine.HCl ( 10 B 1 -BPA) to melanoma cells, the killing effects of 10 B 1 -BPA in the thermal neutron capture treatment on both cultured melanotic and amelanotic melanoma cells were compared with those on non-melanoma cells, such as Alexander cells, HeLa cells and normal human fibroblasts. Cells in the plateau phase cultured in the usual medium for 4-7 days were incubated with the medium containing 50 μg/ml 10 B 1 -BPA for 20 hours until 2 hours before thermal neutron irradiation. After thermal neutron irradiation, the number of colonies consisting of more than 50 cells was counted to obtain the dose-survival curves. The melanotic cells pre-incubated with 10 B 1 -BPA had more enhanced killing sensitivity to thermal neutron irradiation than amelanotic melanoma cells pre-incubated similarly with 10 B 1 -BPA. 10 B 1 -BPA pre-incubation had no enhanced killing effects on Alexander cells, but had slightly enhanced killing effects on HeLa cells. These results indicate that 10 B 1 -BPA could be incorporated by a specific uptake mechanism of melanoma cells and accumulated within melanotic melanoma cells and that 10 B 1 -BPA at present could be the best chemical for the thermal neutron capture therapy of human malignant melanoma. (Namekawa, K.)

"Drone Killings in Principle and in Practice"

DEFF Research Database (Denmark)

Dige, Morten

2017-01-01

to argue that what we see in the real world cases of drone killings is not merely an accidental or contingent use of drone technology. The real life use reflects to a large extent features that are inherent of the dominant drone systems that has been developed to date. What is being imagined "in principle......" is thus to a large extent drone killings in dreamland. I use an historic example as a point of reference and departure: the debate over the lawfulness of nuclear weapons....

Comparison of two mathematical models for describing heat-induced cell killing

International Nuclear Information System (INIS)

Roti Roti, J.L.; Henle, K.J.

1980-01-01

A computer-based minimization algorithm is utilized to obtain the optimum fits of two models to hyperthermic cell killing data. The models chosen are the multitarget, single-hit equation, which is in general use, and the linear-quadratic equation, which has been applied to cell killing by ionizing irradiation but not to heat-induced cell killing. The linear-quadratic equation fits hyperthermic cell killing data as well as the multitarget, single-hit equation. Both parameters of the linear-quadratic equation obey the Arrhenius law, whereas only one of the two parameters of the multitarget, single-hit equation obeys the Arrhenius law. Thus the linear-quadratic function can completely define cell killing as a function of both time and temperature. In addition, the linear-quadratic model will provide a simplified approach to the study of the synergism between heat and X irradiation

Wind power and bird kills

International Nuclear Information System (INIS)

Raynolds, M.

1998-01-01

The accidental killing of birds by wind generators, and design improvements in the towers that support the turbines that might cut down on the bird killings were discussed. The first problem for the industry began in the late 1980s when the California Energy Commission reported as many as 160 birds (the majority being raptors, including the protected golden eagle) killed in one year in the vicinity of wind power plants. The key factor identified was the design of the towers as birds of prey are attracted to lattice towers as a place to hunt from. Tubular towers do not provide a place for the birds to perch, therefore they reduce the potential for bird strikes. Bird strikes also have been reported in Spain and the siting of the towers have been considered as the principal cause of the bird strikes. In view of these incidents, the wind power industry is developing standards for studying the potential of bird strikes and is continuing to study bird behaviour leading to collisions, the impact of topography, cumulative impacts and new techniques to reduce bird strikes. Despite the reported incidents, the risk of bird strikes by wind turbines, compared to other threats to birds such as pollution, oil spills, and other threats from fossil and nuclear fuels, is considered to be negligible. With continuing efforts to minimize incidents by proper design and siting, wind power can continue to grow as an environmentally sound and efficient source of energy

Wind power and bird kills

Energy Technology Data Exchange (ETDEWEB)

Raynolds, M.

1998-12-01

The accidental killing of birds by wind generators, and design improvements in the towers that support the turbines that might cut down on the bird killings were discussed. The first problem for the industry began in the late 1980s when the California Energy Commission reported as many as 160 birds (the majority being raptors, including the protected golden eagle) killed in one year in the vicinity of wind power plants. The key factor identified was the design of the towers as birds of prey are attracted to lattice towers as a place to hunt from. Tubular towers do not provide a place for the birds to perch, therefore they reduce the potential for bird strikes. Bird strikes also have been reported in Spain and the siting of the towers have been considered as the principal cause of the bird strikes. In view of these incidents, the wind power industry is developing standards for studying the potential of bird strikes and is continuing to study bird behaviour leading to collisions, the impact of topography, cumulative impacts and new techniques to reduce bird strikes. Despite the reported incidents, the risk of bird strikes by wind turbines, compared to other threats to birds such as pollution, oil spills, and other threats from fossil and nuclear fuels, is considered to be negligible. With continuing efforts to minimize incidents by proper design and siting, wind power can continue to grow as an environmentally sound and efficient source of energy.

Comparing Road-Kill Datasets from Hunters and Citizen Scientists in a Landscape Context

OpenAIRE

Florian Heigl; Carina R. Stretz; Wolfgang Steiner; Franz Suppan; Thomas Bauer; Gregor Laaha; Johann G. Zaller

2016-01-01

Road traffic has severe effects on animals, especially when road-kills are involved. In many countries, official road-kill data are provided by hunters or police; there are also road-kill observations reported by citizen scientists. The aim of the current study was to test whether road-kill reports by hunters stem from similar landscapes than those reported by citizen scientists. We analysed the surrounding landscapes of 712 road-kill reportings of European hares in the province of Lower Aust...

Cell-mediated immune response to syngeneic uv induced tumors. I. The presence of tumor associated macrophages and their possible role in the in vitro generation of cytotoxic lymphocytes

International Nuclear Information System (INIS)

Woodward, J.G.; Daynes, R.A.

1978-01-01

A primary in vitro sensitization system employing a chromium release assay was utilized to investigate reactivity of murine spleen cells toward syngeneic ultraviolet (uv) light induced fibrosarcomas. These tumors are immunologically rejected in vivo when implanted into normal syngeneic mice but grow progressively when implanted into syngeneic mice that had previously been irradiated with subcarcinogenic levels of uv light. Following appropriate sensitization, spleen cells from both normal and uv irradiated mice are capable of developing cytotoxic lymphocytes in vitro against the uv induced tumors. It was subsequently discovered that in situ uv induced tumors all contained macrophages of host origin that became demonstrable only after enzymatic dissociation of the tumor tissue. These macrophages were immunologically active in vitro as their presence in the stimulator cell population was necessary to achieve an optimum anti-tumor cytotoxic response following in vitro sensitization. Anti-tumor reactivity generated by mixing spleen cells and tumor cells in the absence of tumor derived macrophages could be greatly enhanced by the addition of normal syngeneic peritoneal macrophages. When in vitro anti-tumor reactivity of spleen cells from normal and uv treated mice was compared under these conditions we again found no significant difference in the magnitude of the responses. In addition, the cytotoxic cells generated in response to uv induced tumors appeared to be highly cross reactive with respect to their killing potential

The role of multimodal signals in species recognition between tree-killing bark beetles in a narrow sympatric zone.

Science.gov (United States)

Deepa S. Pureswaran; Richard W. Hofstetter; Brian Sullivan; Kristen A. Potter

2016-01-01

When related species coexist, selection pressure should favor evolution of species recognition mechanisms to prevent interspecific pairing and wasteful reproductive encounters. We investigated the potential role of pheromone and acoustic signals in species recognition between two species of tree-killing bark beetles, the southern pine beetle, Dendroctonus frontalis...

The modernizing bias of human rights: stories of mass killings and genocide in Central America.

Science.gov (United States)

Ekern, Stener

2010-01-01

This article analyses selected cases of mass killings and genocide during the civil wars in El Salvador and Guatemala in the 1980s and the way in which the truth commissions in both countries reframed locally grounded narratives to fit the state-centred language of human rights. Redefining wrongdoings as human rights violations produces stories that communicate poorly with local worldviews because the 'truths' that human rights language proposes disregard local realities and transform local conflicts into a type of 'modern', nationwide struggles. Thus, while the concept of genocide might capture well the horrendous nature of a mass killing, it will also ethnify the conflict. Comparisons between local readings and human rights-based reinterpretations reveal a 'modernizing' or 'Westernizing' bias of international law; the article argues for more awareness about such effects in analysis as well as in policy-making.

γ-rays kill grasshopper primary spermatocytes in groups

International Nuclear Information System (INIS)

Al-Taweel, A.A.; Shawkit, M.A.; Fox, D.P.

1985-01-01

Primary spermatocyte killing by γ-rays was studied in the grasshopper Heteracris littoralis in which spermatogenic development occurs in cysts containing a maximum of 64 cells during the first meiotic division. Cell killing at this stage is not random and mainly involves the death of whole cysts. The dose-response curve for cell killing has complex kinetics with at least two components but lacks any shoulder at low doses, thus indicating no repair of the lethal damage. Cell loss is apparent from surviving cysts as early as 45 min post irradiation but loss of > 24 cells is incompatible with cyst survival. Loss of fewer than 24 cells also is not random since certain values for cell loss are frequently observed while other, interspersed values are not seen at all. (Auth.)

The effect of low-dose total body irradiation on tumor control

International Nuclear Information System (INIS)

Sakamoto, Kiyohiko; Miyamoto, Miyako; Watabe, Nobuyuki.

1987-01-01

Total body irradiation (TBI) is considered to bring about an immunosuppressive effect on an organism, on the basis of data obtained from sublethal doses of TBI. However, there are no data on how low-dose TBI affects an organism. Over the last five years, we have been studying the effects of low-dose TBI on normal or tumor-bearing mice and the immunological background of these effects. In experimental studies, an increase in the TD50 value (the number of cells required for a tumor incidence of 50 %) in mice exposed to 10 rad was recognized and showed a remarkable increase at 6 hours to 15 hours after irradiation. TBI of 10 rad also showed an enhancement effect on tumor cell killing when given 12 hours before local tumor irradiation. In order to clarify the mechanism of this kind of effect, some immunological studies were performed using several immunological procedures, and the results suggested that 10 rad of TBI caused increasing tumor immunity in irradiated mice. Clinical trials in some patients with advanced tumors are now being undertaken on the basis of these experimental data, and the effect of TBI on tumor control appears promising, although it is too early to draw conclusions. (author)

The Organisation of the Killings and the Interaction between State and Society in Central Java, 1965

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Mathias Hammer

2013-01-01

Full Text Available This article investigates how the Indonesian state organised the killing of approx. 100,000 communists and alleged communists in Central Java in 1965. It presents the argument that even though state institutions unleashed the killings and perpetrated much of the violence, the state’s control over this violence was limited. In particular, decisions by state institutions as to who would be targeted by the violence at the individual level were considerably influenced by civilian actors. Six theses develop this argument by reconstructing these events. They highlight the fact that the Indonesian army faced capacity constraints (thesis 1 and relied on improvisation (2. The army detained many of the victims in improvised facilities prior to their deaths (3. In these installations, the army’s capacity to identify and select those of the detainees it wished to execute was constrained by a lack of reliable men among their forces. Chaotic conditions in the detention facilities put further limits on the state’s capacity to select people for execution. To counter these effects, auditing and investigation teams were put into place to carry out these selections (4. In doing so, they had to rely on information from their victims’ social environments (5, which identified candidates for detention and supplied details that helped the selection teams decide what to do with detainees (6. This information was supplied voluntarily, often as a result of personal initiative.

The selective Cox-2 inhibitor Celecoxib suppresses angiogenesis and growth of secondary bone tumors: An intravital microscopy study in mice

International Nuclear Information System (INIS)

Klenke, Frank Michael; Gebhard, Martha-Maria; Ewerbeck, Volker; Abdollahi, Amir; Huber, Peter E; Sckell, Axel

2006-01-01

The inhibition of angiogenesis is a promising strategy for the treatment of malignant primary and secondary tumors in addition to established therapies such as surgery, chemotherapy, and radiation. There is strong experimental evidence in primary tumors that Cyclooxygenase-2 (Cox-2) inhibition is a potent mechanism to reduce angiogenesis. For bone metastases which occur in up to 85% of the most frequent malignant primary tumors, the effects of Cox-2 inhibition on angiogenesis and tumor growth remain still unclear. Therefore, the aim of this study was to investigate the effects of Celecoxib, a selective Cox-2 inhibitor, on angiogenesis, microcirculation and growth of secondary bone tumors. In 10 male severe combined immunodeficient (SCID) mice, pieces of A549 lung carcinomas were implanted into a newly developed cranial window preparation where the calvaria serves as the site for orthotopic implantation of the tumors. From day 8 after tumor implantation, five animals (Celecoxib) were treated daily with Celecoxib (30 mg/kg body weight, s.c.), and five animals (Control) with the equivalent amount of the CMC-based vehicle. Angiogenesis, microcirculation, and growth of A549 tumors were analyzed by means of intravital microscopy. Apoptosis was quantified using the TUNEL assay. Treatment with Celecoxib reduced both microvessel density and tumor growth. TUNEL reaction showed an increase in apoptotic cell death of tumor cells after treatment with Celecoxib as compared to Controls. Celecoxib is a potent inhibitor of tumor growth of secondary bone tumors in vivo which can be explained by its anti-angiogenic and pro-apoptotic effects. The results indicate that a combination of established therapy regimes with Cox-2 inhibition represents a possible application for the treatment of bone metastases

Preliminary study of killing the larva of plodia interpunella by irradiation

International Nuclear Information System (INIS)

Wang Jide; Ma Xiaoping

1994-01-01

The results of killing the larva of plodia interpunella in the fruit by 60 Co γ-irradiation are described. The lowest effective dose for killing larva by irradiation is ca. 2000 Gy; the effective dose for immediately killing larva is 3000 Gy. The method is simple and easy and also suitable for the study of commercial irradiation of dry-fruit

Killing Horizons as Equipotential Hypersurfaces

OpenAIRE

Smolić, Ivica

2012-01-01

In this note we present a new proof that Killing horizons are equipotential hypersurfaces for the electric and the magnetic scalar potential, that makes no use of gravitational field equations or the assumption about the existence of bifurcation surface.

Opinions of university students on honour killings: Perspective from Islamabad and Rawalpindi.

Science.gov (United States)

Shaikh, Masood Ali; Kamal, Anila; Naqvi, Irum

2015-04-01

Honour killing incidents have been reported from every province of Pakistan. In 2014 a pregnant woman was killed in front of Lahore High Court, by her family members, in the name of honour. This study was conducted to determine the perspective of university students on honour killing with specific reference to one such killing incident in Lahore. Cumulatively, 989 students participated in the survey. Compared with female students, male students were less likely to agree and were more unequivocal that a woman has a right to marry any man she wants despite her family's disapproval, in a statistically significant manner. Similarly, male students were statistically significantly more likely to report that killing in the name of honour is always justified and were less equivocal about it compared to female students. Nonetheless, cumulatively 824 (83.3%) students believed that killing in the name of honour is not always justified.

TNF-Induced Target Cell Killing by CTL Activated through Cross-Presentation

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Dirk Wohlleber

2012-09-01

Full Text Available Viruses can escape cytotoxic T cell (CTL immunity by avoiding presentation of viral components via endogenous MHC class I antigen presentation in infected cells. Cross-priming of viral antigens circumvents such immune escape by allowing noninfected dendritic cells to activate virus-specific CTLs, but they remain ineffective against infected cells in which immune escape is functional. Here, we show that cross-presentation of antigen released from adenovirus-infected hepatocytes by liver sinusoidal endothelial cells stimulated cross-primed effector CTLs to release tumor necrosis factor (TNF, which killed virus-infected hepatocytes through caspase activation. TNF receptor signaling specifically eliminated infected hepatocytes that showed impaired anti-apoptotic defense. Thus, CTL immune surveillance against infection relies on two similarly important but distinct effector functions that are both MHC restricted, requiring either direct antigen recognition on target cells and canonical CTL effector function or cross-presentation and a noncanonical effector function mediated by TNF.

TNF-induced target cell killing by CTL activated through cross-presentation.

Science.gov (United States)

Wohlleber, Dirk; Kashkar, Hamid; Gärtner, Katja; Frings, Marianne K; Odenthal, Margarete; Hegenbarth, Silke; Börner, Carolin; Arnold, Bernd; Hämmerling, Günter; Nieswandt, Bernd; van Rooijen, Nico; Limmer, Andreas; Cederbrant, Karin; Heikenwalder, Mathias; Pasparakis, Manolis; Protzer, Ulrike; Dienes, Hans-Peter; Kurts, Christian; Krönke, Martin; Knolle, Percy A

2012-09-27

Viruses can escape cytotoxic T cell (CTL) immunity by avoiding presentation of viral components via endogenous MHC class I antigen presentation in infected cells. Cross-priming of viral antigens circumvents such immune escape by allowing noninfected dendritic cells to activate virus-specific CTLs, but they remain ineffective against infected cells in which immune escape is functional. Here, we show that cross-presentation of antigen released from adenovirus-infected hepatocytes by liver sinusoidal endothelial cells stimulated cross-primed effector CTLs to release tumor necrosis factor (TNF), which killed virus-infected hepatocytes through caspase activation. TNF receptor signaling specifically eliminated infected hepatocytes that showed impaired anti-apoptotic defense. Thus, CTL immune surveillance against infection relies on two similarly important but distinct effector functions that are both MHC restricted, requiring either direct antigen recognition on target cells and canonical CTL effector function or cross-presentation and a noncanonical effector function mediated by TNF. Copyright © 2012 The Authors. Published by Elsevier Inc. All rights reserved.

Effects of boron neutron capture therapy using borocaptate sodium in combination with a tumor-selective vasoactive agent in mice

International Nuclear Information System (INIS)

Ono, Koji; Masunaga, Shin-ichiro; Kinashi, Yuko; Takagaki, Masao; Akaboshi, Mitsuhiko; Suzuki, Minoru; Baba, Hideo.

1998-01-01

Boron neutron capture therapy (BNCT) destroys tumor cells by means of α particles and recoil protons emitted by 10 B(n,α) 7 Li reaction. For BNCT to be effective, the tumor/normal tissue concentration ratio of 10 B must be larger than 1.0, because neutron distribution is not selective. We examined the combination of 10 B-enriched borocaptate sodium (BSH) with flavone acetic acid (FAA) as a model compound which causes vascular collapse in squamous cell carcinoma in mice (SCCVII tumors) and would increase the tumor/normal tissue concentration ratio of 10 B. FAA (200 mg/kg, i.p.) was injected, and 5 min later BSH (75 mg/kg, i.v.) was administered, followed 15 to 180 min later by irradiation with thermal neutrons. The 10 B concentrations were measured by prompt gamma ray spectrometry. Without FAA, tumor 10 B concentrations were less than or equal to normal tissue concentrations at all time intervals, except that the concentrations were 1.7- to 2.7-fold greater in tumor than muscle at 15 and 180 min after injection of BSH. With FAA, 10 B concentrations 2.1- to 6.9-fold greater in tumor than in muscle were achieved at all intervals tested. For blood and skin, significant differential accumulations were found in tumors at 120 and 180 min. Tumor/liver ratios were less than 1 at all times. Cell survival was determined by in vivo/in vitro colony assay, and increasing radiosensitization correlated with increasing tumor 10 B concentrations, whether or not they were achieved with FAA. Tumor control rates, determined at 180 days after BNCT, similarly appeared to depend only on 10 B levels at the time of irradiation. Because 10 B levels correlate with the radiation response of tissues, a therapeutic gain would be expected whenever the tumor levels exceed normal tissue levels, such as in tumors located in muscle irradiated at 15-180 min after FAA+BSH, or in those in skin irradiated at 120 and 180 min. (author)

Peptidoglycan recognition proteins kill bacteria by inducing oxidative, thiol, and metal stress.

Directory of Open Access Journals (Sweden)

Des Raj Kashyap

2014-07-01

Full Text Available Mammalian Peptidoglycan Recognition Proteins (PGRPs are a family of evolutionary conserved bactericidal innate immunity proteins, but the mechanism through which they kill bacteria is unclear. We previously proposed that PGRPs are bactericidal due to induction of reactive oxygen species (ROS, a mechanism of killing that was also postulated, and later refuted, for several bactericidal antibiotics. Here, using whole genome expression arrays, qRT-PCR, and biochemical tests we show that in both Escherichia coli and Bacillus subtilis PGRPs induce a transcriptomic signature characteristic of oxidative stress, as well as correlated biochemical changes. However, induction of ROS was required, but not sufficient for PGRP killing. PGRPs also induced depletion of intracellular thiols and increased cytosolic concentrations of zinc and copper, as evidenced by transcriptome changes and supported by direct measurements. Depletion of thiols and elevated concentrations of metals were also required, but by themselves not sufficient, for bacterial killing. Chemical treatment studies demonstrated that efficient bacterial killing can be recapitulated only by the simultaneous addition of agents leading to production of ROS, depletion of thiols, and elevation of intracellular metal concentrations. These results identify a novel mechanism of bacterial killing by innate immunity proteins, which depends on synergistic effect of oxidative, thiol, and metal stress and differs from bacterial killing by antibiotics. These results offer potential targets for developing new antibacterial agents that would kill antibiotic-resistant bacteria.

political killings in South Africa

African Journals Online (AJOL)

mainly occurred in KwaZulu-Natal, with a much smaller number occurring in Mpumalanga and ... Though the problem is concentrated in specific provinces it is likely to impact on political life ... killings that are the focus of the article, including.

Killing horizons as equipotential hypersurfaces

International Nuclear Information System (INIS)

Smolić, Ivica

2012-01-01

In this note we present a new proof that Killing horizons are equipotential hypersurfaces for the electric and the magnetic scalar potential, which makes no use of gravitational field equations or the assumption about the existence of a bifurcation surface. (note)

Selective effects of whey protein concentrate on glutathione levels and apoptosis in rats with mammary tumors.

Science.gov (United States)

Cheng, Shih-Hsuan; Tseng, Yang-Ming; Wu, Szu-Hsien; Tsai, Shih-Meng; Tsai, Li-Yu

2017-09-01

Glutathione (GSH) plays an important role in antioxidant defense and regulation of apoptosis. GSH deficiency is related to many diseases, including cancer, and increased GSH levels in cancer cells are associated with chemotherapy resistance because of resistance to apoptosis. In this study, we investigated the effects of whey protein concentrate (WPC), a precursor of GSH, in rats with mammary tumors induced by treatment with 7,12-dimethylbenz(a)anthracene (DMBA). DMBA treatment results in cellular changes that mimic the initiation and promotion of carcinogenesis of breast tissue. We aimed to examine the possible preventive effects of diets containing whey protein on DMBA-induced mammary tumors in rats. The results indicate that WPC (0.334 g/kg) supplementation significantly increased the liver GSH levels by 92%, and were accompanied by low Bax/Bcl-2 ratio (from 5 to 3) and cleaved caspase-3/procaspase-3 ratio (from 2.4 to 1.2) in DMBA-treated rats. Furthermore, tumor GSH levels were decreased by 47% in WPC-supplemented rats, which resulted in increased Bax/Bcl-2 ratio (from 0.9 to 2) and cleaved caspase-3/procaspase-3 ratio (from 1.1 to 2.7). In conclusion, supplementation with WPC could selectively deplete tumor GSH levels and, therefore, WPC supplementation might be a promising strategy to overcome treatment resistance in cancer therapy. Copyright © 2017 Elsevier Ltd. All rights reserved.

HER2-Targeted Polyinosine/Polycytosine Therapy Inhibits Tumor Growth and Modulates the Tumor Immune Microenvironment.

Science.gov (United States)

Zigler, Maya; Shir, Alexei; Joubran, Salim; Sagalov, Anna; Klein, Shoshana; Edinger, Nufar; Lau, Jeffrey; Yu, Shang-Fan; Mizraji, Gabriel; Globerson Levin, Anat; Sliwkowski, Mark X; Levitzki, Alexander

2016-08-01

The development of targeted therapies that affect multiple signaling pathways and stimulate antitumor immunity is greatly needed. About 20% of patients with breast cancer overexpress HER2. Small molecules and antibodies targeting HER2 convey some survival benefits; however, patients with advanced disease succumb to the disease under these treatment regimens, possibly because HER2 is not completely necessary for the survival of the targeted cancer cells. In the present study, we show that a polyinosine/polycytosine (pIC) HER2-homing chemical vector induced the demise of HER2-overexpressing breast cancer cells, including trastuzumab-resistant cells. Targeting pIC to the tumor evoked a number of cell-killing mechanisms, as well as strong bystander effects. These bystander mechanisms included type I IFN induction, immune cell recruitment, and activation. The HER2-targeted pIC strongly inhibited the growth of HER2-overexpressing tumors in immunocompetent mice. The data presented here could open additional avenues in the treatment of HER2-positive breast cancer. Cancer Immunol Res; 4(8); 688-97. ©2016 AACR. ©2016 American Association for Cancer Research.

Kill rate of mastitis pathogens by a combination of cefalexin and kanamycin.

Science.gov (United States)

Maneke, E; Pridmore, A; Goby, L; Lang, I

2011-01-01

To assess the bacterial killing rate produced by a combination of cefalexin and kanamycin at two different concentration ratios. Time-kill kinetics of cefalexin and kanamycin, individually and in combination, were determined against one strain each of Escherichia coli, Staphylococcus aureus, Streptococcus agalactiae, Streptococcus dysgalactiae and Streptococcus uberis. The combination was tested using two fixed ratios (cefalexin : kanamycin ratios of 1·25 : 1 and 1 : 2·3) and two concentrations of each ratio. Time-kill curves produced with either ratio were quite similar. Against most bacterial species, higher concentrations produced faster kill. In all cases, the combination of cefalexin and kanamycin showed faster and greater kill at lower antibiotic concentrations than those observed with either drug alone. The combination of cefalexin and kanamycin results in a fast initial killing of major mastitis pathogens at both concentration ratios. The combination of cefalexin and kanamycin achieved rapid bacterial kill at concentrations and ratios that can be achieved in vivo following intramammary infusion of a mastitis treatment. © 2010 Boehringer Ingelheim Vetmedica GmbH. Journal of Applied Microbiology © 2010 The Society for Applied Microbiology.

Factors Affecting Zebra Mussel Kill by the Bacterium Pseudomonas fluorescens

Energy Technology Data Exchange (ETDEWEB)

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.

Active insecticides for Diaphania hyalinata selective for the natural enemy Solenopsis saevissima.

Science.gov (United States)

Aguiar, Alex R; Alvarenga, Elson S; Lopes, Mayara C; Santos, Izailda B Dos; Galdino, Tarcisio V; Picanço, Marcelo C

2016-09-01

The objective of this study was to determine the toxicity of the nine synthetic dienamides against the insect pest Diaphania hyalinata (melonworm) and the selectivity of these substances for the predator Solenopsis saevissima (fire ant). Four bioassays were conducted. To begin with, the dienamides that caused high mortality of D. hyalinata have been selected. In the second bioassay the dose-mortality curves of the selected dienamides have been constructed. In the third bioassay, the survival curves for D. hyalinata and the elapsed time to kill 50% of their population have been determined. In the fourth biological test, the selectivity of the substances to the predator S. saevissima has been evaluated. The most active (2E,4E)-N-butylhexa-2,4-dienamide 3d has killed 95% of the melonworm, D. hyalinata, and less than 10% of the natural enemy S. saevissima. The results presented by this compound are superior to the outcome displayed by the commercial insecticide Malathion®. Three of the dienamides prepared in this manuscript have proven to be selective in killing the pest, but not the beneficial insect.

Fluorine-Containing Taxoid Anticancer Agents and Their Tumor-Targeted Drug Delivery

OpenAIRE

Seitz, Joshua; Vineberg, Jacob G.; Zuniga, Edison S.; Ojima, Iwao

2013-01-01

A long-standing problem of conventional chemotherapy is the lack of tumor-specific treatments. Traditional chemotherapy relies on the premise that rapidly proliferating cancer cells are more likely to be killed by a cytotoxic agent. In reality, however, cytotoxic agents have very little or no specificity, which leads to systemic toxicity, causing undesirable severe side effects. Consequently, various “molecularly targeted cancer therapies” have been developed for use in specific cancers, incl...

Soluble fibrin inhibits monocyte adherence and cytotoxicity against tumor cells: implications for cancer metastasis

Directory of Open Access Journals (Sweden)

Patel Shonak

2006-08-01

Full Text Available Abstract Background Soluble fibrin (sFn is a marker for disseminated intravascular coagulation and may have prognostic significance, especially in metastasis. However, a role for sFn in the etiology of metastatic cancer growth has not been extensively studied. We have reported that sFn cross-linked platelet binding to tumor cells via the major platelet fibrin receptor αIIbβ3, and tumor cell CD54 (ICAM-1, which is the receptor for two of the leukocyte β2 integrins (αLβ2 and aMβ2. We hypothesized that sFn may also affect leukocyte adherence, recognition, and killing of tumor cells. Furthermore, in a rat experimental metastasis model sFn pre-treatment of tumor cells enhanced metastasis by over 60% compared to untreated cells. Other studies have shown that fibrin(ogen binds to the monocyte integrin αMβ2. This study therefore sought to investigate the effect of sFn on β2 integrin mediated monocyte adherence and killing of tumor cells. Methods The role of sFn in monocyte adherence and cytotoxicity against tumor cells was initially studied using static microplate adherence and cytotoxicity assays, and under physiologically relevant flow conditions in a microscope perfusion incubator system. Blocking studies were performed using monoclonal antibodies specific for β2 integrins and CD54, and specific peptides which inhibit sFn binding to these receptors. Results Enhancement of monocyte/tumor cell adherence was observed when only one cell type was bound to sFn, but profound inhibition was observed when sFn was bound to both monocytes and tumor cells. This effect was also reflected in the pattern of monocyte cytotoxicity. Studies using monoclonal blocking antibodies and specific blocking peptides (which did not affect normal coagulation showed that the predominant mechanism of fibrin inhibition is via its binding to αMβ2 on monocytes, and to CD54 on both leukocytes and tumor cells. Conclusion sFn inhibits monocyte adherence and cytotoxicity of

How does ionizing irradiation contribute to the induction of anti-tumor immunity?

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Yvonne eRubner

2012-07-01

Full Text Available Radiotherapy (RT with ionizing irradiation is commonly used to locally attack tumors. It induces a stop of cancer cell proliferation and finally leads to tumor cell death. During the last years it has become more and more evident that besides a timely and locally restricted radiation-induced immune suppression, a specific immune activation against the tumor and its metastases is achievable by rendering the tumor cells visible for immune attack. The immune system is involved in tumor control and we here outline how RT induces anti-inflammation when applied in low doses and contributes in higher doses to the induction of anti-tumor immunity. We especially focus on how local irradiation induces abscopal effects. The latter are partly mediated by a systemic activation of the immune system against the individual tumor cells. Dendritic cells are the key players in the initiation and regulation of adaptive anti-tumor immune responses. They have to take up tumor antigens and consecutively present tumor peptides in the presence of appropriate co-stimulation. We review how combinations of RT with further immune stimulators such as AnnexinA5 and hyperthermia foster the dendritic cell-mediated induction of anti-tumor immune responses and present reasonable combination schemes of standard tumor therapies with immune therapies. It can be concluded that RT leads to targeted killing of the tumor cells and additionally induces non-targeted systemic immune effects. Multimodal tumor treatments should therefore tend to induce immunogenic tumor cell death forms within a tumor microenvironment that stimulates immune cells.

How Does Ionizing Irradiation Contribute to the Induction of Anti-Tumor Immunity?

International Nuclear Information System (INIS)

Rubner, Yvonne; Wunderlich, Roland; Rühle, Paul-Friedrich; Kulzer, Lorenz; Werthmöller, Nina; Frey, Benjamin; Weiss, Eva-Maria; Keilholz, Ludwig; Fietkau, Rainer; Gaipl, Udo S.

2012-01-01

Radiotherapy (RT) with ionizing irradiation is commonly used to locally attack tumors. It induces a stop of cancer cell proliferation and finally leads to tumor cell death. During the last years it has become more and more evident that besides a timely and locally restricted radiation-induced immune suppression, a specific immune activation against the tumor and its metastases is achievable by rendering the tumor cells visible for immune attack. The immune system is involved in tumor control and we here outline how RT induces anti-inflammation when applied in low doses and contributes in higher doses to the induction of anti-tumor immunity. We especially focus on how local irradiation induces abscopal effects. The latter are partly mediated by a systemic activation of the immune system against the individual tumor cells. Dendritic cells are the key players in the initiation and regulation of adaptive anti-tumor immune responses. They have to take up tumor antigens and consecutively present tumor peptides in the presence of appropriate co-stimulation. We review how combinations of RT with further immune stimulators such as AnnexinA5 and hyperthermia foster the dendritic cell-mediated induction of anti-tumor immune responses and present reasonable combination schemes of standard tumor therapies with immune therapies. It can be concluded that RT leads to targeted killing of the tumor cells and additionally induces non-targeted systemic immune effects. Multimodal tumor treatments should therefore tend to induce immunogenic tumor cell death forms within a tumor microenvironment that stimulates immune cells.

Selection of radioresistant tumor cells and presence of ALDH1 activity in vitro

International Nuclear Information System (INIS)

Mihatsch, Julia; Toulany, Mahmoud; Bareiss, Petra M.; Grimm, Sabrina; Lengerke, Claudia; Kehlbach, Rainer; Rodemann, H. Peter

2011-01-01

Background: Tumor resistance to radiotherapy has been hypothesized to be mediated by a tumor subpopulation, called cancer stem cells (CSCs). Based on the proposed function of CSCs in radioresistance, we explored the cancer stem cell properties of cells selected for radioresistance phenotype. Materials and methods: A549 and SK-BR-3 cells were radioselected with four single doses of 4 or 3 Gy in intervals of 10-12 days and used for colony formation assay and γ-H2AX foci formation assay. Expression of putative stem cell markers, i.e. Sox2, Oct4, ALDH1, and CD133 were analyzed using Western blotting. A549 and SK-BR-3 cells sorted based on their ALDH1 activity were analyzed in clonogenic survival assays. Results: Radioselected A549 and SK-BR-3 cells (A549-R, SK-BR-3-R) showed increased radioresistance and A549-R cells presented enhanced repair of DNA-double strand breaks. PI3K inhibition significantly reduced radioresistance of A549-R cells. Cell line specific differences in the expression of the putative CSC markers Sox2 and Oct4 were observed when parental and radioselected cells were compared but could not be directly correlated to the radioresistant phenotype. However, enzyme activity of the putative stem cell marker ALDH1 showed a correlation to radioresistance. Conclusions: Subpopulations of pooled radioresistant colonies, selected by various radiation exposures were analyzed for the presence of putative stem cell markers. Although the pattern of Sox2, Oct4, and CD133 expression was not generally associated with radioresistance, presence of ALDH1 seems to be indicative for subpopulations with increased radioresistance.

Subcutaneous administration of ketoprofen delays Ehrlich solid tumor growth in mice

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C.M. Souza

2014-10-01

Full Text Available Ketoprofen, a nonsteroidal anti-inflammatory drug (NSAID has proven to exert anti-inflammatory, anti-proliferative and anti-angiogenic activities in both neoplastic and non-neoplastic conditions. We investigated the effects of this compound on tumor development in Swiss mice previously inoculated with Ehrlich tumor cells. To carry out this study the solid tumor was obtained from cells of the ascites fluid of Ehrlich tumor re-suspended in physiological saline to give 2.5x106 cells in 0.05mL. After tumor inoculation, the animals were separated into two groups (n = 10. The animals treated with ketoprofen 0.1µg/100µL/animal were injected intraperitoneally at intervals of 24h for 10 consecutive days. Animals from the control group received saline. At the end of the experiment the mice were killed and the tumor removed. We analyzed tumor growth, histomorphological and immunohistochemical characteristics for CDC47 (cellular proliferation marker and for CD31 (blood vessel marker. Animals treated with the ketoprofen 0.1µg/100µL/animal showed lower tumor growth. The treatment did not significantly influence the size of the areas of cancer, inflammation, necrosis and hemorrhage. Moreover, lower rates of tumor cell proliferation were observed in animals treated with ketoprofen compared with the untreated control group. The participation of ketoprofen in controlling tumor malignant cell proliferation would open prospects for its use in clinical and antineoplasic therapy.