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Sample records for radiation targeted tnf

  1. Biological agents targeting beyond TNF-alpha

    Directory of Open Access Journals (Sweden)

    Sharma Rashmi

    2008-01-01

    Full Text Available Biological agents represent an important addition to the therapies for immuno-inflammatory conditions and have a great impact on the disease course and quality of life of these patients. However, recent reports of serious infections like tuberculosis, demyelinating and neurodegenerative diseases, pancytopenia, cardiovascular diseases, etc. after anti-TNF therapy raised questions on their safety. Hence, focus is shifted towards drugs targeting cytokine checkpoints in the inflammatory cascades beyond TNF-a. Existing therapeutic targets include the biological agents acting as antagonists of various inflammatory cytokines (Anakinra, Tocilizumab, Atlizumab and modulators of CD80 or CD86-CD28 co-stimulatory signal (Abatacept, CD2 receptors on T-cells (Alefacept, CD11a, subunit of leukocyte function-associated antigen 1 (Efalizumab, vitronectin receptor and CD20 antigen on pre-B, immature and mature B cells (Rituximab. With the introduction of these novel molecules the future for immunomodulatory intervention in rheumatology, asthma, crohn′s disease, septic shock etc. looks very promising. These novel therapeutic agents could truly give a new hope to the clinician to modify the disease and achieve tangible improvements in the lives of the patients.

  2. Biological agents targeting beyond TNF-alpha

    Science.gov (United States)

    Sharma, Rashmi; Sharma, Chaman Lal; Mahajan, Annil

    2008-01-01

    Biological agents represent an important addition to the therapies for immuno-inflammatory conditions and have a great impact on the disease course and quality of life of these patients. However, recent reports of serious infections like tuberculosis, demyelinating and neurodegenerative diseases, pancytopenia, cardiovascular diseases, etc. after anti-TNF therapy raised questions on their safety. Hence, focus is shifted towards drugs targeting cytokine checkpoints in the inflammatory cascades beyond TNF-α. Existing therapeutic targets include the biological agents acting as antagonists of various inflammatory cytokines (Anakinra, Tocilizumab, Atlizumab) and modulators of CD80 or CD86-CD28 co-stimulatory signal (Abatacept), CD2 receptors on T-cells (Alefacept), CD11a, subunit of leukocyte function-associated antigen 1 (Efalizumab), vitronectin receptor and CD20 antigen on pre-B, immature and mature B cells (Rituximab). With the introduction of these novel molecules the future for immunomodulatory intervention in rheumatology, asthma, crohn's disease, septic shock etc. looks very promising. These novel therapeutic agents could truly give a new hope to the clinician to modify the disease and achieve tangible improvements in the lives of the patients. PMID:19742267

  3. Tristetraprolin mediates radiation-induced TNF-α production in lung macrophages.

    Science.gov (United States)

    Ray, Dipankar; Shukla, Shirish; Allam, Uday Sankar; Helman, Abigail; Ramanand, Susmita Gurjar; Tran, Linda; Bassetti, Michael; Krishnamurthy, Pranathi Meda; Rumschlag, Matthew; Paulsen, Michelle; Sun, Lei; Shanley, Thomas P; Ljungman, Mats; Nyati, Mukesh K; Zhang, Ming; Lawrence, Theodore S

    2013-01-01

    The efficacy of radiation therapy for lung cancer is limited by radiation-induced lung toxicity (RILT). Although tumor necrosis factor-alpha (TNF-α) signaling plays a critical role in RILT, the molecular regulators of radiation-induced TNF-α production remain unknown. We investigated the role of a major TNF-α regulator, Tristetraprolin (TTP), in radiation-induced TNF-α production by macrophages. For in vitro studies we irradiated (4 Gy) either a mouse lung macrophage cell line, MH-S or macrophages isolated from TTP knockout mice, and studied the effects of radiation on TTP and TNF-α levels. To study the in vivo relevance, mouse lungs were irradiated with a single dose (15 Gy) and assessed at varying times for TTP alterations. Irradiation of MH-S cells caused TTP to undergo an inhibitory phosphorylation at Ser-178 and proteasome-mediated degradation, which resulted in increased TNF-α mRNA stabilization and secretion. Similarly, MH-S cells treated with TTP siRNA or macrophages isolated from ttp (-/-) mice had higher basal levels of TNF-α, which was increased minimally after irradiation. Conversely, cells overexpressing TTP mutants defective in undergoing phosphorylation released significantly lower levels of TNF-α. Inhibition of p38, a known kinase for TTP, by either siRNA or a small molecule inhibitor abrogated radiation-induced TNF-α release by MH-S cells. Lung irradiation induced TTP(Ser178) phosphorylation and protein degradation and a simultaneous increase in TNF-α production in C57BL/6 mice starting 24 h post-radiation. In conclusion, irradiation of lung macrophages causes TTP inactivation via p38-mediated phosphorylation and proteasome-mediated degradation, leading to TNF-α production. These findings suggest that agents capable of blocking TTP phosphorylation or stabilizing TTP after irradiation could decrease RILT.

  4. Tristetraprolin mediates radiation-induced TNF-α production in lung macrophages.

    Directory of Open Access Journals (Sweden)

    Dipankar Ray

    Full Text Available The efficacy of radiation therapy for lung cancer is limited by radiation-induced lung toxicity (RILT. Although tumor necrosis factor-alpha (TNF-α signaling plays a critical role in RILT, the molecular regulators of radiation-induced TNF-α production remain unknown. We investigated the role of a major TNF-α regulator, Tristetraprolin (TTP, in radiation-induced TNF-α production by macrophages. For in vitro studies we irradiated (4 Gy either a mouse lung macrophage cell line, MH-S or macrophages isolated from TTP knockout mice, and studied the effects of radiation on TTP and TNF-α levels. To study the in vivo relevance, mouse lungs were irradiated with a single dose (15 Gy and assessed at varying times for TTP alterations. Irradiation of MH-S cells caused TTP to undergo an inhibitory phosphorylation at Ser-178 and proteasome-mediated degradation, which resulted in increased TNF-α mRNA stabilization and secretion. Similarly, MH-S cells treated with TTP siRNA or macrophages isolated from ttp (-/- mice had higher basal levels of TNF-α, which was increased minimally after irradiation. Conversely, cells overexpressing TTP mutants defective in undergoing phosphorylation released significantly lower levels of TNF-α. Inhibition of p38, a known kinase for TTP, by either siRNA or a small molecule inhibitor abrogated radiation-induced TNF-α release by MH-S cells. Lung irradiation induced TTP(Ser178 phosphorylation and protein degradation and a simultaneous increase in TNF-α production in C57BL/6 mice starting 24 h post-radiation. In conclusion, irradiation of lung macrophages causes TTP inactivation via p38-mediated phosphorylation and proteasome-mediated degradation, leading to TNF-α production. These findings suggest that agents capable of blocking TTP phosphorylation or stabilizing TTP after irradiation could decrease RILT.

  5. Transmembrane TNF-alpha reverse signaling leading to TGF-beta production is selectively activated by TNF targeting molecules: Therapeutic implications.

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    Szondy, Zsuzsa; Pallai, Anna

    2017-01-01

    Tumor necrosis factor (TNF)-α is a potent pro-inflammatory cytokine exerting pleiotropic effects on various cell types. It is synthesized in a precursor form called transmembrane TNF-α (mTNF-α) which, after being processed by metalloproteinases, is released in a soluble form to mediate its biological activities through Type 1 and 2 TNF receptors in TNF receptor expressing cells. In addition to acting in soluble form, TNF-α also acts in the transmembrane form both as a ligand by activating TNF receptors, as well as a receptor that transmits outside-to-inside (reverse) signals back into mTNF-α bearing cells. Since the discovery that TNF-α plays a determining role in the pathogenesis of several chronic inflammatory diseases, anti-TNF agents are increasingly being used in the treatment of a rapidly expanding number of rheumatic and systemic autoimmune diseases, such as rheumatoid arthritis, Crohn's disease, psoriasis, psoriatic arthritis, ankyloting spondylitis, Wegener granulomatosis and sarcoidosis. There are 5 TNF antagonists currently available: etanercept, a soluble TNF receptor construct; infliximab, a chimeric monoclonal antibody; adalimumab and golimumab, fully human antibodies; and certolizumab pegol, an Fab' fragment of a humanized anti-TNF-α antibody. Though each compound can efficiently neutralize TNF-α, increasing evidence suggests that they show different efficacy in the treatment of these diseases. These observations indicate that in addition to neutralizing TNF-α, other biological effects induced by TNFtargeting molecules dictate the success of the therapy. Recently, we found that mTNF-α reverse signaling leads to transforming growth factor (TGF)-β production in macrophages and anti-TNF agents selectively trigger this pathway. In this review we will focus on the potential contribution of the activation of the mTNF-α signaling pathway to the success of the anti-TNF therapy.

  6. Chinese Medicine Angelica Sinensis Suppresses Radiation-induced TNF-αand TGF-β_1 Expression in Mice

    Institute of Scientific and Technical Information of China (English)

    2005-01-01

    1 IntroductionLung is a major organ targeted by radiation in radiotherapy of the thoracic tumors and often suffers from radiation-induced injury such as pneumonitis and excessive fibrosis. Now, the pathogenesis of radiation-induced lung injury is found mainly due to the release of cytokines which can activate many signal transduction pathways~([1]). Among these cytokines, TNF-α and TGF-β_1 are regarded as the key factors responsible for tissue damage. Angelica Sinensis, a Chinese medicine, is currently in u...

  7. Evaluation of pGL1-TNF-alpha therapy in combination with radiation

    Science.gov (United States)

    Li, J.; Andres, M. L.; Fodor, I.; Nelson, G. A.; Gridley, D. S.

    1998-01-01

    Long-term control of high-grade brain tumors is rarely achieved with current therapeutic regimens. In this study a new plasmid-based human tumor necrosis factor-alpha (TNF-alpha) expression vector was synthesized (pGL1-TNF-alpha) and evaluated together with radiation in the aggressive, rapidly growing C6 rat glioma model. pGL1-TNF-alpha was successfully transfected into C6 cells in vitro using a cationic polyamine method. Expression was detected up to 7 days and averaged 0.4 ng of TNF-alpha in the culture medium from 1x10(5) cells. The expressed protein was biologically functional, as evidenced by growth inhibition of L929, a TNF-alpha-susceptible cell line. Using fluorescence-labeled monoclonal antibodies and laser scanning cytometry, we confirmed that both the P55 and P75 receptors for TNF-alpha were present on the C6 cell membrane. However, the receptors were present at low density and P55 was expressed more than the P75 receptor. These findings were in contrast to results obtained with TNF-alpha-susceptible L929 cells. Tests in athymic mice showed that pGL1-TNF-alpha administered intratumorally 16-18 h before radiation (each modality given three times) significantly inhibited C6 tumor progression (Ptumor growth and radiation alone had little effect on tumor growth. These results indicate that pGL1-TNF-alpha has potential to augment the antitumor effects of radiation against a tumor type that is virtually incurable.

  8. Evaluation of pGL1-TNF-alpha therapy in combination with radiation

    Science.gov (United States)

    Li, J.; Andres, M. L.; Fodor, I.; Nelson, G. A.; Gridley, D. S.

    1998-01-01

    Long-term control of high-grade brain tumors is rarely achieved with current therapeutic regimens. In this study a new plasmid-based human tumor necrosis factor-alpha (TNF-alpha) expression vector was synthesized (pGL1-TNF-alpha) and evaluated together with radiation in the aggressive, rapidly growing C6 rat glioma model. pGL1-TNF-alpha was successfully transfected into C6 cells in vitro using a cationic polyamine method. Expression was detected up to 7 days and averaged 0.4 ng of TNF-alpha in the culture medium from 1x10(5) cells. The expressed protein was biologically functional, as evidenced by growth inhibition of L929, a TNF-alpha-susceptible cell line. Using fluorescence-labeled monoclonal antibodies and laser scanning cytometry, we confirmed that both the P55 and P75 receptors for TNF-alpha were present on the C6 cell membrane. However, the receptors were present at low density and P55 was expressed more than the P75 receptor. These findings were in contrast to results obtained with TNF-alpha-susceptible L929 cells. Tests in athymic mice showed that pGL1-TNF-alpha administered intratumorally 16-18 h before radiation (each modality given three times) significantly inhibited C6 tumor progression (Pradiation alone had little effect on tumor growth. These results indicate that pGL1-TNF-alpha has potential to augment the antitumor effects of radiation against a tumor type that is virtually incurable.

  9. Autoimmune diseases induced by TNF-targeted therapies: analysis of 233 cases.

    Science.gov (United States)

    Ramos-Casals, Manuel; Brito-Zerón, Pilar; Muñoz, Sandra; Soria, Natalia; Galiana, Diana; Bertolaccini, Laura; Cuadrado, Maria-Jose; Khamashta, Munther A

    2007-07-01

    Tumor necrosis factor (TNF)-targeted therapies are increasingly used for a rapidly expanding number of rheumatic and autoimmune diseases. With this use and longer follow-up periods of treatment, there are a growing number of reports of the development of autoimmune processes related to anti-TNF agents. We have analyzed the clinical characteristics, outcomes, and patterns of association with the different anti-TNF agents used in all reports of autoimmune diseases developing after TNF-targeted therapy found through a MEDLINE search of articles published between January 1990 and December 2006. We identified 233 cases of autoimmune diseases (vasculitis in 113, lupus in 92, interstitial lung diseases in 24, and other diseases in 4) secondary to TNF-targeted therapies in 226 patients. The anti-TNF agents were administered for rheumatoid arthritis (RA) in 187 (83%) patients, Crohn disease in 17, ankylosing spondylitis in 7, psoriatic arthritis in 6, juvenile RA in 5, and other diseases in 3. The anti-TNF agents administered were infliximab in 105 patients, etanercept in 96, adalimumab in 21, and other anti-TNF agents in 3. We found 92 reported cases of lupus following anti-TNF therapy (infliximab in 40 cases, etanercept in 37, and adalimumab in 15). Nearly half the cases fulfilled 4 or more classification criteria for systemic lupus erythematosus (SLE), which fell to one-third after discarding preexisting lupus-like features. One hundred thirteen patients developed vasculitis after receiving anti-TNF agents (etanercept in 59 cases, infliximab in 47, adalimumab in 5, and other agents in 2). Leukocytoclastic vasculitis was the most frequent type of vasculitis, and purpura was the most frequent cutaneous lesion. A significant finding was that one-quarter of patients with vasculitis related to anti-TNF agents had extracutaneous involvement. Twenty-four cases of interstitial lung disease associated with the use of anti-TNF agents were reported. In these patients, 2 specific

  10. Radiation target analysis of RNA.

    Science.gov (United States)

    Benstein, S L; Kempner, E

    1996-06-25

    Ribozymes are polynucleotide molecules with intrinsic catalytic activity, capable of cleaving nucleic acid substrates. Large RNA molecules were synthesized containing a hammerhead ribozyme moiety of 52 nucleotides linked to an inactive leader sequence, for total lengths of either 262 or 1226 nucleotides. Frozen RNAs were irradiated with high energy electrons. Surviving ribozyme activity was determined using the ability of the irradiated ribozymes to cleave a labeled substrate. The amount of intact RNA remaining was determined from the same irradiated samples by scanning the RNA band following denaturing gel electrophoresis. Radiation target analyses of these data revealed a structural target size of 80 kDa and a ribozyme activity target size of 15 kDa for the smaller ribozyme, and 319 kDa and 16 kDa, respectively, for the larger ribozyme. The disparity in target size for activity versus structure indicates that, in contrast to proteins, there is no spread of radiation damage far from the primary site of ionization in RNA molecules. The smaller target size for activity indicates that only primary ionizations occurring in the specific active region are effective. This is similar to the case for oligosaccharides. We concluded that the presence of the ribose sugar in the polymer chain restricts radiation damage to a small region and prevents major energy transfer throughout the molecule. Radiation target analysis should be a useful technique for evaluating local RNA:RNA and RNA:protein interactions in vitro.

  11. Is TNF-a-targeted short hairpin RNA (shRNA) a novel potential therapeutic tool in psoriasis treatment?

    DEFF Research Database (Denmark)

    Stenderup, Karin; Jakobsen, Maria; Rosada, Cecilia

    2008-01-01

      TNF-α is a well known target in psoriasis treatment and biological treatments targeting TNF-a are already clinically used against psoriasis and psoriasis arthritis. Attention is however given to a novel therapeutic tool: RNA interference that controls gene silencing. This study investigates...... the efficiency of targeting TNF-a with specific short hairpin RNA (shRNA) and explores its potential in treating psoriasis. ShRNAs targeting human TNF-α mRNA were generated. Their efficiency in down-regulating TNF-a protein expression was evaluated using a Renilla luciferase screening-assay and a transient co......-transfection assay. The expression cassette encoding the most efficient TNF-a shRNA was inserted into a lentiviral vector, allowing proficient gene delivery. The lentiviral vector is integrated into the host genome and establishes life-long infection and persistent shRNA expression. The lentiviral vector expressing...

  12. Molecular probing of TNF: From identification of therapeutic target to guidance of therapy in inflammatory diseases.

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    Chu, Cong-Qiu

    2016-09-12

    Therapy by blocking tumor necrosis factor (TNF) activity is highly efficacious and profoundly changed the paradigm of several inflammatory diseases. However, a significant proportion of patients with inflammatory diseases do not respond to TNF inhibitors (TNFi). Prediction of therapeutic response is required for TNFi therapy. Isotope labeled anti-TNF antibodies or TNF receptor have been investigated to localize TNF production at inflammatory tissue in animal models and in patients with inflammatory diseases. The in vivo detection of TNF has been associated with treatment response. Recently, fluorophore labeled anti-TNF antibody in combination with confocal laser endomicroscopy in patients with Crohn's disease yielded more accurate and quantitative in vivo detection of TNF in the diseased mucosa. More importantly, this method demonstrated high therapeutic predication value. Fluorophore labeled TNF binding aptamers in combination with modern imaging technology offers additional tools for in vivo TNF probing.

  13. The expected radiation damage of CSNS target

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    Yin, W.; Yu, Q. Z.; Lu, Y. L.; Wang, S. L.; Tong, J. F.; Liang, T. J.

    2012-12-01

    The radiation damage to the tungsten target and its SS316 vessel for Chinese Spallation Neutron Source (CSNS) has been estimated with a Monte-Carlo simulation code MCNPX2.5.0. We compare the effects on the radiation damage due to two different proton beam profiles: a uniform distribution and a Gaussian distribution. We also discuss the dependence of the radiation damage estimation on different physics models. The results show the peak displacement productions in vessel and the fourth target plate are 2.5 and 5.5 dpa/y, respectively, under a Gaussian proton beam. The peak helium productions in the vessel and the fourth target are 305 and 353 appm/y, respectively, under the same proton beam. Based on these results and the allowable dpa values we have estimated the lifetime of the tungsten target and its vessel.

  14. [Construction and functional analysis of a bispecific antibody that targets TNF-α and ED-B].

    Science.gov (United States)

    Li, Lu-Jun; Yang, Yan-Qun; Hu, Xue-Ping; Xie, Mian; Liu, Meng-Yuan

    2014-12-01

    In order to enhance the specificity of TNF-α monoclonal antibody to inflamed site, a bispecific antibody BsDb that targets TNF-α and the extra-domain B (ED-B) of fibronectin (FN) was constructed by covalently linking the anti-TNF-α single chain Fv antibody (TNF-scFv) and the anti-ED-B scFv L19 via a flexible peptide linker deriving from human serum albumin (HSA). ED-B is an antigen specifically expressed at the inflamed site. BsDb is expressed in E. coli, identified by immunoblot, and purified with affinity chromatography. This was followed by further examination of its bioactivities and pharmacokinetics. We demonstrated that BsDb retained the immunoreactivity of its original antibodies as it could simultaneously bind to TNF-α and ED-B and neutralize the biological action of TNF-α. In the collagen-induced arthritis mice model, BsDb selectively accumulate in the inflamed joint with a maximal uptake of (12.2 ± 1.50)% ID/g in a single inflamed paw and retain in the inflamed paw for at least 72 h. In contrast, BsDb showed a short serum half-life of (0.50 ± 0.05) h and a rapid clearance from normal tissues. The findings reported herein indicate that BsDb has good specificity to the inflamed site and low toxicity to normal tissues. BsDb is therefore likely to have greater clinical applications in the treatment of rheumatoid arthritis and other autoimmune diseases. This laid a stable basis for its preclinical study.

  15. Human cytomegalovirus infection inhibits tumor necrosis factor alpha (TNF-alpha) signaling by targeting the 55-kilodalton TNF-alpha receptor.

    Science.gov (United States)

    Baillie, J; Sahlender, D A; Sinclair, J H

    2003-06-01

    Infection with human cytomegalovirus (HCMV) results in complex interactions between viral and cellular factors which perturb many cellular functions. HCMV is known to target the cell cycle, cellular transcription, and immunoregulation, and it is believed that this optimizes the cellular environment for viral DNA replication during productive infection or during carriage in the latently infected host. Here, we show that HCMV infection also prevents external signaling to the cell by disrupting the function of TNFRI, the 55-kDa receptor for tumor necrosis factor alpha (TNF-alpha), one of the receptors for a potent cytokine involved in eliciting a wide spectrum of cellular responses, including antiviral responses. HCMV infection of fully permissive differentiated monocytic cell lines and U373 cells resulted in a reduction in cell surface expression of TNFRI. The reduction appeared to be due to relocalization of TNFRI from the cell surface and was reflected in the elimination of TNF-alpha-induced Jun kinase activity. Analysis of specific phases of infection suggested that viral early gene products were responsible for this relocalization. However, a mutant HCMV in which all viral gene products known to be involved in down-regulation of major histocompatibility complex (MHC) class I were deleted still resulted in relocalization of TNFRI. Consequently, TNFRI relocalization by HCMV appears to be mediated by a novel viral early function not involved in down-regulation of cell surface MHC class I expression. We suggest that upon infection, HCMV isolates the cell from host-mediated signals, forcing the cell to respond only to virus-specific signals which optimize the cell for virus production and effect proviral responses from bystander cells.

  16. Radioimmunotherapy Using Vascular Targeted 213Bi: The Role of TNF-Alpha in the Development of Pulmonary Fibrosis

    Energy Technology Data Exchange (ETDEWEB)

    Davis, I.A.; Kennel, S.J.

    1998-10-14

    A monoclonal antibody (201B) specific to murine thrombomodulin, covalently linked to CHX-b-DTPA, successfully delivers chelated 213Bi, an {alpha}-particle emitter, (213Bi-201B) rapidly to lungvascular endothelium. When injected at doses of l MBq/mouse, 213Bi-201B destroyed most of the 100 colonies of EMT-6 mammary carcinomas growing as lung tumors of up to 2000 cells/colony. Some mice were cured of lung tumors and others had extended life-spans compared to untreated control animals but eventually succumbed to tumor recurrence. At injected doses of 4-6 MBq/mouse, 100% of lung tumor colonies were eliminated; however, 3-4 months later these mice developed pulmonary fibrosis and died. The mechanisms leading to the fibrotic response in other pulmonary irradiation models strongly implicate tumor necrosis factor-alpha (TNF-{alpha}), released from damaged tissues, as the pivotal inflammatory cytokine in a cascade of events which culminate in fibrosis. Attempts to prevent the development of pulmonary fibrosis, by using antibodies or soluble receptor (Enbrel{trademark}) as inhibitors of TNF-{alpha}, were unsuccessful. Additionally, mice genetically deficient for TNF-{alpha} production developed pulmonary fibrosis following 213Bi-201B treatment. Interestingly, non-tumor bearing BALB/c mice receiving Enbrel{trademark} or mice genetically deficient in TNF-{alpha} production and treated with 213Bi-201B, had significantly reduced life spans compared to mice receiving no treatment or 213Bi-201B alone. We speculate that, in normal mice, while TNF-{alpha} may induce an inflammatory response following {alpha}-particle radiation mediated tumor clearance and pulmonary damage, its effects in the post-tumor clearance time period may actually retard the development of fibrosis.

  17. Target volume definition in radiation oncology

    CERN Document Server

    Grosu, Anca-Ligia

    2015-01-01

    The main objective of this book is to provide radiation oncologists with a clear, up-to-date guide to tumor delineation and contouring of organs at risk. With this in mind, a detailed overview of recent advances in imaging for radiation treatment planning is presented. Novel concepts for target volume delineation are explained, taking into account the innovations in imaging technology. Special attention is paid to the role of the newer imaging modalities, such as positron emission tomography and diffusion and perfusion magnetic resonance imaging. All of the most important tumor entities treate

  18. Target volume definition in radiation oncology

    Energy Technology Data Exchange (ETDEWEB)

    Grosu, Anca-Ligia [Univ. Medical Center Freiburg (Germany). Dept. of Radiation Oncology; Nieder, Carsten (ed.) [Nordland Hospital, Bodo (Norway). Dept. of Oncology

    2015-05-01

    The main objective of this book is to provide radiation oncologists with a clear, up-to-date guide to tumor delineation and contouring of organs at risk. With this in mind, a detailed overview of recent advances in imaging for radiation treatment planning is presented. Novel concepts for target volume delineation are explained, taking into account the innovations in imaging technology. Special attention is paid to the role of the newer imaging modalities, such as positron emission tomography and diffusion and perfusion magnetic resonance imaging. All of the most important tumor entities treated with radiation therapy are covered in the book. Each chapter is devoted to a particular tumor type and has been written by a recognized expert in that topic.

  19. Novel anti-apoptotic mechanism of A20 through targeting ASK1 to suppress TNF-induced JNK activation.

    Science.gov (United States)

    Won, M; Park, K A; Byun, H S; Sohn, K-C; Kim, Y-R; Jeon, J; Hong, J H; Park, J; Seok, J H; Kim, J M; Yoon, W-H; Jang, I-S; Shen, H M; Liu, Z G; Hur, G M

    2010-12-01

    The zinc-finger protein A20 has crucial physiological functions as a dual inhibitor of nuclear factor-κB (NF-κB) activation and apoptosis in tumor necrosis factor (TNF) receptor 1 signaling pathway. Although the molecular basis for the anti-NF-κB function of A20 has been well elucidated, the anti-apoptotic function of A20 is largely unknown. Here, we report a novel mechanism underlying the anti-apoptotic function of A20: A20 blocks TNF-induced apoptosis through suppression of c-jun N-terminal kinase (JNK) by targeting apoptosis signal-regulating kinase1 (ASK1). First, the ectopic expression of A20 drastically inhibits TNF-induced JNK activation and apoptosis in multiple cell types including those deficient of NF-κB activation. Unexpectedly, the blunting effect of A20 on TNF-induced JNK activation is not mediated by affecting the TNFR1 signaling complex formation. Instead, A20 interacts with ASK1, an important MAPKK kinase in the JNK signaling cascade. More importantly, overexpression of wild-type A20, but not of mutant A20 (ZnF4; C624A, C627A), promotes degradation of the ASK1 through the ubiquitin-proteasome system. Taken together, the results from this study reveal a novel anti-apoptotic mechanism of A20 in TNF signaling pathway: A20 binds to ASK1 and mediates ASK1 degradation, leading to suppression of JNK activation and eventually blockage of apoptosis.

  20. Interleukin-1beta and TNF-alpha: reliable targets for protective therapies in Parkinson´s Disease?

    Directory of Open Access Journals (Sweden)

    María Celeste Leal

    2013-04-01

    Full Text Available Neuroinflammation has received increased attention as a target for putative neuroprotective therapies in Parkinson´s Disease (PD. Two prototypic pro-inflammatory cytokines Interleukin-1beta (IL-1 and Tumor necrosis factor-alpha (TNF have been implicated as main effectors of the functional consequences of neuroinflammation on neurodegeneration in PD models. In this review, we describe that the functional interaction between these cytokines in the brain differs from the periphery (e.g. their expression is not induced by each other and present data showing predominantly a toxic effect of these cytokines when expressed at high doses and for a sustained period of time in the substantia nigra pars compacta (SN. In addition, we highlight opposite evidence showing protective effects of these two main cytokines when conditions of duration, amount of expression or state of activation of the target or neighboring cells are changed. Furthermore, we discuss these results in the frame of previous disappointing results from anti-TNF clinical trials against Multiple Sclerosis, another neurodegenerative disease with a clear neuroinflammatory component. In conclusion, we hypothesize that the available evidence suggests that the duration and dose of IL-1 or TNF expression is crucial to predict their functional effect on the SN. Since these parameters are not amenable for measurement in the SN of PD patients, we call for an in-depth analysis to identify downstream mediators that could be common to the toxic (and not the protective effects of these cytokines in the SN. This strategy could spare the possible neuroprotective effect of these cytokines operative in the patient at the time of treatment, increasing the probability of efficacy in a clinical setting. Alternatively, receptor-specific agonists or antagonists could also provide a way to circumvent undesired effects of general anti-inflammatory or specific anti IL-1 or TNF therapies against PD.

  1. Radiation studies for the MOMENT target station

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    Xu, Qing-Nian; Tong, Jian-Fei; Vassilopoulos, Nikolaos; Cao, Jun; He, Miao; Hou, Zhi-Long; Jing, Han-Tao; Liu, Huai-Min; Lü, Xiao-Rui; Tang, Jing-Yu; Yuan, Ye; Zhao, Guang; Zheng, Yang-Heng

    2016-12-01

    The discovery of the neutrino mixing angle θ13 opens new opportunities for the discovery of leptonic CP violation at high intensity neutrino beams. MOMENT, a future neutrino facility with a high-power proton beam of 15 MW from a continuous-wave linac, is focused on that discovery. The high power of the proton beam causes extreme radiation conditions for the facility and especially for the target station, where the pion capture system of five superconducting solenoids is located. In this paper initial studies are performed for the effects of the radiation on the solenoid structure and the area surrounding it. A concept cooling system is also proposed. Supported by National Natural Science Foundation of China (11425524, 11527811, 11575226) and Strategic Priority Research Program of the Chinese Academy of Sciences (XDA10010100)

  2. TNF-α in a molecularly targeted therapy of psoriasis and psoriatic arthritis.

    Science.gov (United States)

    Wcisło-Dziadecka, Dominika; Zbiciak-Nylec, Martyna; Brzezińska-Wcisło, Ligia; Mazurek, Urszula

    2016-03-01

    Psoriasis is a chronic immunological skin disease and patients with this disorder typically experience a significant decrease in their quality of life. The disease is traditionally managed with topical and systemic agents (retinoids, ciclosporin A, methotrexate), but these treatment options are often long-term and their effects can be inconsistent and not ideal. The use of biological drugs in dermatological treatment is relatively new and began in the early 2000s. It should be noted that, in most countries, in order for biological treatment to be administered, specific criteria must be met. The current treatment options for psoriasis and psoriatic arthritis include tumour necrosis factor alpha (TNF-α) blockers, interleukin (IL)-12 and IL-23 inhibitors, T cell inhibitors and B cell inhibitors. These classes of biological drugs are characterised by protein structure as well as high molecular weight and their effectiveness is evaluated based on the Psoriasis Area and Severity Index (PASI), Body Surface Area (BSA) and the Dermatology Life Quality Index (DLQI). TNF-α antagonists are one such class of biological drugs which includes infliximad, etanercept and adalimumab. Infliximab is a chimeric protein that is administered via intravenous infusions as a monotherapy in psoriasis vulgaris. Etanercept is indicated for use in both psoriasis vulgaris and psoriatic arthritis and it is the only drug that can be used as a treatment for children under the age of 8 with psoriasis. The drug is administered subcutaneously. Finally, adalimumab is a fully human monoclonal antibody that neutralises both free and membrane-bound TNF-α and is used in the treatment of psoriasis vulgaris and psoriatic arthritis. This article reviews the latest research in the use of TNF-α for the treatment of moderate to severe psoriasis and psoriatic arthritis. The results of research in this field are promising and confirm the effectiveness and safety of biological drugs as dermatological treatments

  3. Localized External Beam Radiation Therapy (EBRT) to the Pelvis Induces Systemic IL-1Beta and TNF-Alpha Production: Role of the TNF-Alpha Signaling in EBRT-Induced Fatigue.

    Science.gov (United States)

    McDonald, Tasha L; Hung, Arthur Y; Thomas, Charles R; Wood, Lisa J

    2016-01-01

    Prostate cancer patients undergoing localized external beam radiation therapy (EBRT) can experience a progressive increase in fatigue, which can affect physical functioning and quality of life. The purpose of this study was to develop a mouse EBRT prostate cancer treatment model with which to determine the role of pro-inflammatory cytokines in the genesis of EBRT-related fatigue. We assessed voluntary wheel-running activity (VWRA) as a proxy for fatigue, food intake and body weight in male C57BL/6 mice undergoing EBRT to the pelvis. In the first experiment, anesthetized male C57BL/6 mice underwent fractionated EBRT to the pelvis for a total dose of 68.2 Gy, thereby mimicking a clinically relevant therapeutic dose and frequency. The day after the last treatment, levels of IL-1β and TNF-α in plasma along with mRNA levels in liver, colon and whole brain were measured. EBRT-induced fatigue resulted in reduced body weight, diminished food intake, and increased plasma and tissue levels of IL-1β and TNF-α. In a follow-up experiment, we used TNF-α-deficient mice to further delineate the role of TNF-α signaling in EBRT-induced sickness behavior. EBRT-induced changes in fatigue, food intake and body weight were no different between TNF-α deficient mice and their wild-type counterparts. Taken together our data demonstrate that a clinically relevant localized irradiation of the pelvis induces a systemic IL-1β and TNF-α response and sickness behavior in mice, but the TNF-α signaling pathway alone does not independently mediate these effects.

  4. Calculation of Radiation Damage in SLAC Targets

    Energy Technology Data Exchange (ETDEWEB)

    Wirth, B D; Monasterio, P; Stein, W

    2008-04-03

    Ti-6Al-4V alloys are being considered as a positron producing target in the Next Linear Collider, with an incident photon beam and operating temperatures between room temperature and 300 C. Calculations of displacement damage in Ti-6Al-4V alloys have been performed by combining high-energy particle FLUKA simulations with SPECTER calculations of the displacement cross section from the resulting energy-dependent neutron flux plus the displacements calculated from the Lindhard model from the resulting energy-dependent ion flux. The radiation damage calculations have investigated two cases, namely the damage produced in a Ti-6Al-4V SLAC positron target where the irradiation source is a photon beam with energies between 5 and 11 MeV. As well, the radiation damage dose in displacements per atom, dpa, has been calculated for a mono-energetic 196 MeV proton irradiation experiment performed at Brookhaven National Laboratory (BLIP experiment). The calculated damage rate is 0.8 dpa/year for the Ti-6Al-4V SLAC photon irradiation target, and a total damage exposure of 0.06 dpa in the BLIP irradiation experiment. In both cases, the displacements are predominantly ({approx}80%) produced by recoiling ions (atomic nuclei) from photo-nuclear collisions or proton-nuclear collisions, respectively. Approximately 25% of the displacement damage results from the neutrons in both cases. Irradiation effects studies in titanium alloys have shown substantial increases in the yield and ultimate strength of up to 500 MPa and a corresponding decrease in uniform ductility for neutron and high energy proton irradiation at temperatures between 40 and 300 C. Although the data is limited, there is an indication that the strength increases will saturate by doses on the order of a few dpa. Microstructural investigations indicate that the dominant features responsible for the strength increases were dense precipitation of a {beta} (body-centered cubic) phase precipitate along with a high number density

  5. TNF autovaccination induces self anti-TNF antibodies and inhibits metastasis in a murine melanoma model

    OpenAIRE

    Waterston, AM; Salway, F; Andreakos, E; Butler, DM; FELDMANN M.; Coombes, RC

    2004-01-01

    TNF is a proinflammatory cytokine involved in the pathogenesis of chronic inflammatory diseases, but also in metastasis in certain types of cancer. In terms of therapy, TNF is targeted by anti-TNF neutralising monoclonal antibodies or soluble TNF receptors. Recently, a novel strategy based on the generation of self anti-TNF antibodies (TNF autovaccination) has been developed. We have previously shown that TNF autovaccination successfully generates high anti-TNF antibody titres, blocks TNF and...

  6. Orally delivered thioketal nanoparticles loaded with TNF-α-siRNA target inflammation and inhibit gene expression in the intestines

    Science.gov (United States)

    Wilson, D. Scott; Dalmasso, Guillaume; Wang, Lixin; Sitaraman, Shanthi V.; Merlin, Didier; Murthy, Niren

    2010-11-01

    Small interfering RNAs (siRNAs) directed against proinflammatory cytokines have the potential to treat numerous diseases associated with intestinal inflammation; however, the side-effects caused by the systemic depletion of cytokines demands that the delivery of cytokine-targeted siRNAs be localized to diseased intestinal tissues. Although various delivery vehicles have been developed to orally deliver therapeutics to intestinal tissue, none of these strategies has demonstrated the ability to protect siRNA from the harsh environment of the gastrointestinal tract and target its delivery to inflamed intestinal tissue. Here, we present a delivery vehicle for siRNA, termed thioketal nanoparticles (TKNs), that can localize orally delivered siRNA to sites of intestinal inflammation, and thus inhibit gene expression in inflamed intestinal tissue. TKNs are formulated from a polymer, poly-(1,4-phenyleneacetone dimethylene thioketal), that degrades selectively in response to reactive oxygen species (ROS). Therefore, when delivered orally, TKNs release siRNA in response to the abnormally high levels of ROS specific to sites of intestinal inflammation. Using a murine model of ulcerative colitis, we demonstrate that orally administered TKNs loaded with siRNA against the proinflammatory cytokine tumour necrosis factor-alpha (TNF-α) diminish TNF-α messenger RNA levels in the colon and protect mice from ulcerative colitis.

  7. The tumor vessel targeting agent NGR-TNF controls the different stages of the tumorigenic process in transgenic mice by distinct mechanisms

    Science.gov (United States)

    Porcellini, Simona; Asperti, Claudia; Valentinis, Barbara; Tiziano, Elena; Mangia, Patrizia; Bordignon, Claudio; Rizzardi, Gian-Paolo; Traversari, Catia

    2015-01-01

    NGR-TNF is a vascular targeting agent in advanced clinical development, coupling tumor necrosis factor-α (TNF) with the CNGRCG peptide, which targets a CD13 isoform specifically expressed by angiogenic vessels. Antitumor efficacy of NGR-TNF has been described in different transplantation tumor models. Nevertheless, the mechanism underlying its activity is not fully understood. In the wild type and in the immunodeficient (RAG−/−) RIP1-Tag2 models of multistage pancreatic carcinogenesis, we demonstrate that CD13 is highly expressed on endothelial cells of hyperplastic and angiogenic islets, whereas its expression is down regulated in tumors where it partially colocalize with pericytes. In vivo CNGRCG peptides coupled to fluorescent nanoparticles (quantum dots) bind to CD13 and colocalize with anti-CD31, in pancreatic islets. At early stage, low doses of NGR-murine (m)TNF have a direct cytotoxic effect inducing endothelial cell apoptosis, reducing vessel density and eventually inhibiting the development of angiogenic islets. At a later stage, NGR-mTNF is able to reduce tumor growth inducing vascular normalization, exclusively when treatment is carried out in the immunocompetent mice. Interestingly, NGR-mTNF-treated tumors from these mice are characterized by CD8+ T cell infiltration. At molecular level, overexpression of genes involved in vessels normalization was detected only in NGR-mTNF-treated tumors from immunocompetent mice. These findings identified a new mechanism of action of NGR-mTNF, providing support for the development of new therapeutic strategies combining chemotherapy or active/adoptive immunotherapies to low dose NGR-TNF treatment. PMID:26451306

  8. Modeling and analysis of ground target radiation cross section

    Institute of Scientific and Technical Information of China (English)

    SHI Xiang; LOU GuoWei; LI XingGuo

    2008-01-01

    Based on the analysis of the passive millimeter wave (MMW) radiometer detection, the ground target radiation cross section is modeled as the new token for the target MMW radiant characteristics. Its ap-plication and actual testing are discussed and analyzed. The essence of passive MMW stealth is target radiation cross section reduction.

  9. Targeting Notch to overcome radiation resistance.

    Science.gov (United States)

    Yahyanejad, Sanaz; Theys, Jan; Vooijs, Marc

    2016-02-16

    Radiotherapy represents an important therapeutic strategy in the treatment of cancer cells. However, it often fails to eliminate all tumor cells because of the intrinsic or acquired treatment resistance, which is the most common cause of tumor recurrence. Emerging evidences suggest that the Notch signaling pathway is an important pathway mediating radiation resistance in tumor cells. Successful targeting of Notch signaling requires a thorough understanding of Notch regulation and the context-dependent interactions between Notch and other therapeutically relevant pathways. Understanding these interactions will increase our ability to design rational combination regimens that are more likely to be safe and effective. Here we summarize the role of Notch in mediating resistance to radiotherapy, the different strategies to block Notch in cancer cells and how treatment scheduling can improve tumor response. Finally, we discuss a need for reliable Notch related biomarkers in specific tumors to measure pathway activity and to allow identification of a subset of patients who are likely to benefit from Notch targeted therapies.

  10. Effects of the tumor vasculature targeting agent NGR-TNF on the tumor microenvironment in murine lymphomas.

    NARCIS (Netherlands)

    Laarhoven, H.W.M. van; Gambarota, G.; Heerschap, A.; Lok, J.; Verhagen, I.; Corti, A.; Toma, S.; Gallo Stampino, C.; Kogel, A.J. van der; Punt, C.J.A.

    2006-01-01

    TNF-alpha may improve drug delivery to tumors by alteration of vascular permeability. However, toxicity precludes its systemic administration in patients. NGR-TNF comprises TNF coupled to the peptide CNGRC, which is a ligand for CD13. CD13 is expressed on tumor vasculature. Therefore, to assess the

  11. Radiation Target Area Sample Environmental Chamber (RTASEC) Project

    Data.gov (United States)

    National Aeronautics and Space Administration — Payload Systems Inc. proposes the Radiation Target Area Sample Environmental Chamber (RTASEC) as an innovative approach enabling radiobiologists to investigate the...

  12. Selective protection of human liver tissue in TNF-targeting of cancers of the liver by transient depletion of adenosine triphosphate.

    Directory of Open Access Journals (Sweden)

    Timo Weiland

    Full Text Available BACKGROUND: Tumor necrosis factor alpha (TNF is able to kill cancer cells via receptor-mediated cell death requiring adenosine triphosphate (ATP. Clinical usage of TNF so far is largely limited by its profound hepatotoxicity. Recently, it was found in the murine system that specific protection of hepatocytes against TNF's detrimental effects can be achieved by fructose-mediated ATP depletion therein. Before employing this quite attractive selection principle in a first clinical trial, we here comprehensively investigated the interdependence between ATP depletion and TNF hepatotoxicity in both in vitro and ex vivo experiments based on usage of primary patient tissue materials. METHODS: Primary human hepatocytes, and both non-tumorous and tumorous patient-derived primary liver tissue slices were used to elucidate fructose-induced ATP depletion and TNF-induced cytotoxicity. RESULTS: PHH as well as tissue slices prepared from non-malignant human liver specimen undergoing a fructose-mediated ATP depletion were both demonstrated to be protected against TNF-induced cell death. In contrast, due to tumor-specific overexpression of hexokinase II, which imposes a profound bypass on hepatocytic-specific fructose catabolism, this was not the case for human tumorous liver tissues. CONCLUSION: Normal human liver tissues can be protected transiently against TNF-induced cell death by systemic pretreatment with fructose used in non-toxic/physiologic concentrations. Selective TNF-targeting of primary and secondary tumors of the liver by transient and specific depletion of hepatocytic ATP opens up a new clinical avenue for the TNF-based treatment of liver cancers.

  13. Targeted therapy of renal cell carcinoma: synergistic activity of cG250-TNF and IFNg.

    NARCIS (Netherlands)

    Bauer, S.; Oosterwijk-Wakka, J.C.; Adrian, N.; Oosterwijk, E.; Fischer, E.; Wuest, T.; Stenner, F.; Perani, A.; Cohen, L.; Knuth, A.; Divgi, C.; Jager, D.; Scott, A.M.; Ritter, G.; Old, L.J.; Renner, C.

    2009-01-01

    Immunotherapeutic targeting of G250/Carbonic anhydrase IX (CA-IX) represents a promising strategy for treatment of renal cell carcinoma (RCC). The well characterized human-mouse chimeric G250 (cG250) antibody has been shown in human studies to specifically enrich in CA-IX positive tumors and was cho

  14. The Anti-TNF-α Antibody Infliximab Inhibits the Expression of Fat-Transporter-Protein FAT/CD36 in a Selective Hepatic-Radiation Mouse Model

    Directory of Open Access Journals (Sweden)

    Gesa Martius

    2015-03-01

    Full Text Available Previously, we reported a radiation-induced inflammation triggering fat-accumulation through fatty-acid-translocase/cluster of differentiation protein 36 (FAT/CD36 in rat liver. Furthermore, inhibition of radiation-induced FAT/CD36-expression by anti-tumor necrosis factor-α (anti-TNF-α (infliximab was shown in vitro. The current study investigates fat-accumulation in a mouse-model of single-dose liver-irradiation (25-Gray and the effect of anti-TNF-α-therapy on FAT/CD36 gene-expression. Mice livers were selectively irradiated in vivo in presence or absence of infliximab. Serum- and hepatic-triglycerides, mRNA, and protein were analyzed by colorimetric assays, RT-PCR, Immunofluorescence and Western-Blot, respectively. Sudan-staining was used demonstrating fat-accumulation in tissue. In mice livers, early (1–3 h induction of TNF-α-expression, a pro-inflammatory cytokine, was observed. It was followed by elevated hepatic-triglyceride level (6–12 h, compared to sham-irradiated controls. In contrast, serum-triglyceride level was decreased at these time points. Similar to triglyceride level in mice livers, Sudan staining of liver cryosections showed a quick (6–12 h increase of fat-droplets after irradiation. Furthermore, expression of fat-transporter-protein FAT/CD36 was increased at protein level caused by radiation or TNF-α. TNF-α-blockage by anti-TNF-α showed an early inhibition of radiation-induced FAT/CD36 expression in mice livers. Immunohistochemistry showed basolateral and cytoplasmic expression of FAT/CD36 in hepatocytes. Moreover, co-localization of FAT/CD36 was detected with α-smooth muscle actin (α-SMA+ cells and F4/80+ macrophages. In summary, hepatic-radiation triggers fat-accumulation in mice livers, involving acute-phase-processes. Accordingly, anti-TNF-α-therapy prevented early radiation-induced expression of FAT/CD36 in vivo.

  15. The anti-TNF-α antibody infliximab inhibits the expression of fat-transporter-protein FAT/CD36 in a selective hepatic-radiation mouse model.

    Science.gov (United States)

    Martius, Gesa; Cameron, Silke; Rave-Fränk, Margret; Hess, Clemens F; Wolff, Hendrik A; Malik, Ihtzaz A

    2015-03-02

    Previously, we reported a radiation-induced inflammation triggering fat-accumulation through fatty-acid-translocase/cluster of differentiation protein 36 (FAT/CD36) in rat liver. Furthermore, inhibition of radiation-induced FAT/CD36-expression by anti-tumor necrosis factor-α (anti-TNF-α) (infliximab) was shown in vitro. The current study investigates fat-accumulation in a mouse-model of single-dose liver-irradiation (25-Gray) and the effect of anti-TNF-α-therapy on FAT/CD36 gene-expression. Mice livers were selectively irradiated in vivo in presence or absence of infliximab. Serum- and hepatic-triglycerides, mRNA, and protein were analyzed by colorimetric assays, RT-PCR, Immunofluorescence and Western-Blot, respectively. Sudan-staining was used demonstrating fat-accumulation in tissue. In mice livers, early (1-3 h) induction of TNF-α-expression, a pro-inflammatory cytokine, was observed. It was followed by elevated hepatic-triglyceride level (6-12 h), compared to sham-irradiated controls. In contrast, serum-triglyceride level was decreased at these time points. Similar to triglyceride level in mice livers, Sudan staining of liver cryosections showed a quick (6-12 h) increase of fat-droplets after irradiation. Furthermore, expression of fat-transporter-protein FAT/CD36 was increased at protein level caused by radiation or TNF-α. TNF-α-blockage by anti-TNF-α showed an early inhibition of radiation-induced FAT/CD36 expression in mice livers. Immunohistochemistry showed basolateral and cytoplasmic expression of FAT/CD36 in hepatocytes. Moreover, co-localization of FAT/CD36 was detected with α-smooth muscle actin (α-SMA+) cells and F4/80+ macrophages. In summary, hepatic-radiation triggers fat-accumulation in mice livers, involving acute-phase-processes. Accordingly, anti-TNF-α-therapy prevented early radiation-induced expression of FAT/CD36 in vivo.

  16. Targeted Radiation Therapy for Cancer Initiative

    Science.gov (United States)

    2015-09-01

    and whether this difference changed the outcome for palliative patients, 6) use of the Calypso system, and other advanced radiation therapy equipment...use of advanced technology radiation therapy techniques, such as IMRT and VMAT, in treating palliative patients. The main obstacle to overcome in...treating low-to-intermediate risk prostate cancer with intensity modulated radiation therapy (IMRT) using an electromagnetic localization system. IMRT

  17. Is TNF-a-targeted short hairpin RNA (shRNA) a novel potential therapeutic tool in psoriasis treatment?

    DEFF Research Database (Denmark)

    Stenderup, Karin; Jakobsen, Maria; Rosada, Cecilia

    2008-01-01

    TNF-a shRNA was used to transduce HEK293 cells and verify vector-derived TNF-a knockdown in vitro. In vivo, psoriasis skin was exposed to lentiviral TNF-a shRNAs by a single intra-dermal injection. Psoriasis skin for the in vivo study was obtained from psoriatic plaque skin biopsies that were...... transplanted onto SCID mice employing the psoriasis xenograft model. Three weeks after exposure, biopsies were taken and the epidermal thickness as an endpoint for evaluating psoriasis and the levels of TNF-a mRNA were measured. The lentiviral TNF-a shRNAs down-regulated the TNF-a expression in vitro...

  18. miR-146a-5p inhibits TNF-α-induced adipogenesis via targeting insulin receptor in primary porcine adipocytes.

    Science.gov (United States)

    Wu, Di; Xi, Qian-Yun; Cheng, Xiao; Dong, Tao; Zhu, Xiao-Tong; Shu, Gang; Wang, Li-Na; Jiang, Qing-Yan; Zhang, Yong-Liang

    2016-08-01

    TNF-α is a multifunctional cytokine participating in immune disorders, inflammation, and tumor development with regulatory effects on energy metabolism. Our work focused on the function of TNF-α in adipogenesis of primary porcine adipocytes. TNF-α could suppress the insulin receptor (IR) at the mRNA and protein levels. Microarray analysis of TNF-α-treated porcine adipocytes was used to screen out 29 differentially expressed microRNAs (miRNAs), 13 of which were remarkably upregulated and 16 were intensely downregulated. These 29 differentially expressed miRNAs were predicted to mainly participate in the insulin signaling pathway, adipocytokine signaling pathway, and type 2 diabetes mellitus pathway by Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analyses. miR-146a-5p, reportedly involved in immunity and cancer relevant processes, was one of the most highly differentially expressed miRNAs after TNF-α treatment. Red Oil O staining and TG assay revealed that miR-146a-5p suppressed adipogenesis. A dual-luciferase reporter and siRNA assay verified that miR-146a-5p targeted IR and could inhibit its protein expression. miR-146a-5p was also validated to be involved in the insulin signaling pathway by reducing tyrosine phosphorylation of insulin receptor substrate-1. Our study provides the first evidence of miR-146a-5p targeting IR, which facilitates future studies related to obesity and diabetes using pig models.

  19. Targeted and non-targeted effects of ionizing radiation

    Directory of Open Access Journals (Sweden)

    Omar Desouky

    2015-04-01

    Full Text Available For a long time it was generally accepted that effects of ionizing radiation such as cell death, chromosomal aberrations, DNA damage, mutagenesis, and carcinogenesis result from direct ionization of cell structures, particularly DNA, or from indirect damage through reactive oxygen species produced by radiolysis of water, and these biological effects were attributed to irreparable or misrepaired DNA damage in cells directly hit by radiation. Using linear non-threshold model (LNT, possible risks from exposure to low dose ionizing radiation (below 100 mSv are estimated by extrapolating from data obtained after exposure to higher doses of radiation. This model has been challenged by numerous observations, in which cells that were not directly traversed by the ionizing radiation exhibited responses similar to those of the directly irradiated cells. Therefore, it is nowadays accepted that the detrimental effects of ionizing radiation are not restricted only in the irradiated cells, but also to non-irradiated bystander or even distant cells manifesting various biological effects.

  20. Amorfrutin A inhibits TNF-α-induced NF-κB activation and NF-κB-regulated target gene products.

    Science.gov (United States)

    Shi, Hui; Ma, Juan; Mi, Chunliu; Li, Jing; Wang, Fei; Lee, Jung Joon; Jin, Xuejun

    2014-07-01

    The nuclear factor-κB (NF-κB) transcription factors control many physiological processes including inflammation, immunity, apoptosis, and angiogenesis. In our search for NF-κB inhibitors from natural resources, we identified amorfrutin A as an inhibitor of NF-κB activation from the fruits of Amorpha fruticosa L. In present study, this compound significantly inhibited the TNF-α-induced expression of NF-κB reporter gene. Further analysis revealed that amorfrutin A was a potent inhibitor of NF-κB activation by the suppression of TNF-α-induced inhibitor of κBα (IκBα) degradation, p65 nuclear translocation, and DNA-binding activity of NF-κB. We also demonstrated that pretreatment of cells with this compound prevented the TNF-α-induced expression of NF-κB target genes, such as antiapoptosis (cIAP-1 and FLIP), proliferation (COX-2 and cyclinD1), invasion (MMP-9), angiogenesis (VEGF), and major inflammatory cytokines (TNF-α, IL-8, and MCP1). Furthermore, our results suggest that amorfrutin A potentiates TNF-α-induced apoptosis. Taken together, amorfrutin A could be a valuable candidate for the intervention of NF-κB-dependent pathological conditions such as inflammation.

  1. SOD2-mediated adaptive responses induced by low-dose ionizing radiation via TNF signaling and amifostine.

    Science.gov (United States)

    Murley, J S; Baker, K L; Miller, R C; Darga, T E; Weichselbaum, R R; Grdina, D J

    2011-11-15

    Manganese superoxide dismutase (SOD2)-mediated adaptive processes that protect against radiation-induced micronucleus formation can be induced in cells after a 2-Gy exposure by previously exposing them to either low-dose ionizing radiation (10cGy) or WR1065 (40μM), the active thiol form of amifostine. Although both adaptive processes culminate in elevated levels of SOD2 enzymatic activity, the underlying pathways differ in complexity, with the tumor necrosis factor α (TNFα) signaling pathway implicated in the low-dose radiation-induced response, but not in the thiol-induced pathway. The goal of this study was the characterization of the effects of TNFα receptors 1 and 2 (TNFR1, TNFR2) on the adaptive responses induced by low-dose irradiation or thiol exposure using micronucleus formation as an endpoint. BFS-1 wild-type cells with functional TNFR1 and 2 were exposed 24h before a 2-Gy dose of ionizing radiation to either 10cGy or a 40μM dose of WR1065. BFS2C-SH02 cells, defective in TNFR1, and BFS2C-SH22 cells, defective in both TNFR1 and TNFR2 and generated from BFS2C-SH02 cells by transfection with a murine TNFR2-targeting vector and confirmed to be TNFR2 defective by quantitative PCR, were also exposed under similar conditions for comparison. A 10-cGy dose of radiation induced a significant elevation in SOD2 activity in BFS-1 (Pradiation-induced micronuclei was observed in each cell line when exposure to a 2-Gy challenge dose of radiation occurred during the period of maximal elevation in SOD2 activity. However, this adaptive effect was completely inhibited if the cells were transfected 24h before low-dose radiation or thiol exposure with SOD2 siRNA. Under the conditions tested, TNFR1 and 2 inhibition negatively affected the low-dose radiation-induced but not the thiol-induced adaptive responses observed to be mediated by elevations in SOD2 activity. Copyright © 2011 Elsevier Inc. All rights reserved.

  2. Radiation-Force Assisted Targeting Facilitates Ultrasonic Molecular Imaging

    Directory of Open Access Journals (Sweden)

    Shukui Zhao

    2004-07-01

    Full Text Available Ultrasonic molecular imaging employs contrast agents, such as microbubbles, nanoparticles, or liposomes, coated with ligands specific for receptors expressed on cells at sites of angiogenesis, inflammation, or thrombus. Concentration of these highly echogenic contrast agents at a target site enhances the ultrasound signal received from that site, promoting ultrasonic detection and analysis of disease states. In this article, we show that acoustic radiation force can be used to displace targeted contrast agents to a vessel wall, greatly increasing the number of agents binding to available surface receptors. We provide a theoretical evaluation of the magnitude of acoustic radiation force and show that it is possible to displace micron-sized agents physiologically relevant distances. Following this, we show in a series of experiments that acoustic radiation force can enhance the binding of targeted agents: The number of biotinylated microbubbles adherent to a synthetic vessel coated with avidin increases as much as 20-fold when acoustic radiation force is applied; the adhesion of contrast agents targeted to αvβ3 expressed on human umbilical vein endothelial cells increases 27-fold within a mimetic vessel when radiation force is applied; and finally, the image signal-to-noise ratio in a phantom vessel increases up to 25 dB using a combination of radiation force and a targeted contrast agent, over use of a targeted contrast agent alone.

  3. Targeted Radiation Therapy for Cancer Initiative

    Science.gov (United States)

    2016-09-01

    Localization System will help to spare toxicity to the heart, 5) a military medical center department, with essentially fixed costs and without financial ...research was presented at the ACRO ( American College of Radiation Oncology) Annual Meeting in Orlando, FL March 17-19, 2016. We continue to analyze...data endpoints as the remaining subjects complete the follow-up phase. Databases have been created for the raw data gained from the Expanded Prostate

  4. Studies of Non-Targeted Effects of Ionising Radiation

    Energy Technology Data Exchange (ETDEWEB)

    Oleg V Belyakov; Heli Mononen; Marjo Peraelae [STUK - Radiation and Nuclear Safety Authority, Helsinki (Finland)

    2006-07-01

    The discovery of ionising radiation induced non-targeted effects is important for understanding the dose-response mechanisms relevant to low dose irradiation in vivo. One important question is whether the non-targeted effects relates to a protective mechanism or whether, conversely, it amplifies the number of cells damaged by the isolated radiation tracks of low dose exposures leading to an increased risk of carcinogenesis. One theory supported by the experimental data obtained during this project is that the main functions of the non-targeted effects are to decrease the risk of transformation in a multicellular organism exposed to radiation. Differences in the gene expression profiles, temporal and spatial patterns of key proteins expressed in directly irradiated and bystander cells may determine how the cells ultimately respond to low doses of radiation. Such a mechanism of co-operative response would make the tissue system much more robust. (N.C.)

  5. Mir-338-3p Mediates Tnf-A-Induced Hepatic Insulin Resistance by Targeting PP4r1 to Regulate PP4 Expression.

    Science.gov (United States)

    Dou, Lin; Wang, Shuyue; Sun, Libo; Huang, Xiuqing; Zhang, Yang; Shen, Tao; Guo, Jun; Man, Yong; Tang, Weiqing; Li, Jian

    2017-01-01

    Insulin resistance is a critical factor contributing to the pathogenesis of type 2 diabetes and other metabolic diseases. Recent studies have indicated that miR-338-3p plays an important role in cancer. Here, we investigated whether miR-338-3p mediates tumour necrosis factor-α (TNF-α)-induced hepatic insulin resistance. The activation of the insulin signalling pathway and the level of glycogenesis were examined in the livers of the db/db and high fat diet (HFD)-fed mice and in HEP1-6 cells transfected with miR-338-3p mimic or inhibitor. Computational prediction of microRNA target, luciferase assay and Western blot were used to assess the miR-338-3p target. Chromatin immunoprecipitation (ChIP) assay was used to determine the transcriptional regulator of miR-338-3p. miR-338-3p was down-regulated in the livers of the db/db, HFD-fed and TNF-α-treated C57BL/6J mice, as well as in mouse HEP1-6 hepatocytes treated with TNF-α. Importantly the down-regulation of miR-338-3p induced insulin resistance, as indicated by impaired glucose tolerance and insulin tolerance. Further research showed that the down-regulated miR-338-3p resulted in the impaired AKT/ glycogen synthase kinase 3 beta (GSl·Gβ) signalling pathway and glycogen synthesis. In contrast, hepatic over-expression of miR-338-3p rescued the TNF-α-induced insulin resistance. Moreover, protein phosphatase 4 regulator subunit 1 (PP4R1) was identified as a direct target of miR-338-3p that mediated hepatic insulin signalling by regulating protein phosphatase 4 (PP4). Finally we identified hepatic nuclear factor 4 alpha (HNF-4α) as the transcriptional regulator of miRNA-338-3p. Our studies provide novel insight into the critical role and molecular mechanism by which miR-338-3p is involved in TNF-α-induced hepatic insulin resistance. miR-338-3p might mediate TNF-α-induced hepatic insulin resistance by targeting PP4R1 to regulate PP4 expression. © 2017 The Author(s). Published by S. Karger AG, Basel.

  6. Targeted Radiation Therapy for Cancer Initiative

    Science.gov (United States)

    2012-09-01

    technique for treating left-sided breast cancer, which allows sparing of the heart. The Calypso system provides a previously unavailable level of...from both centers. Task 6. Post-prostatectomy Daily Target Guided Radiotherapy Using Real-Time, State-of-the-Art Motion Tracking with the Calypso...the skin surface to track breathing motion during a breath-hold technique for left-sided breast cancer treatment. Analysis would reveal the

  7. Rheumatoid Arthritis-Associated MicroRNA-155 Targets SOCS1 and Upregulates TNF-α and IL-1β in PBMCs

    Directory of Open Access Journals (Sweden)

    Xiaochuan Li

    2013-12-01

    Full Text Available miR-155 plays a crucial role in proinflammatory activation. This study was carried out to assess the association of abnormal expression of miR-155 in peripheral blood of patients with Rheumatoid arthritis with the expression of TNF-α and IL-1β. Release of TNF-α and IL-1β, and expression of miR-155 were determined in RA peripheral blood or peripheral blood macrophages, followed by correlation analysis of the cytokines release and miR-155 expression. Furthermore, in vitro studies indicate that miR-155 inhibited the expression of SOCS1. Our results suggest that there is a correlation between the high-level expression of miR-155 and the enhanced expression of TNF-α and IL-1β. miR-155 targets and suppresses the expression of SOCS1, and the decrease of SOCS1 may lead to the upregulation of TNF-α and IL-1β.

  8. Baicalein inhibits TNF-α-induced NF-κB activation and expression of NF-κB-regulated target gene products.

    Science.gov (United States)

    Li, Junbo; Ma, Juan; Wang, Ke Si; Mi, Chunliu; Wang, Zhe; Piao, Lian Xun; Xu, Guang Hua; Li, Xuezheng; Lee, Jung Joon; Jin, Xuejun

    2016-11-01

    The nuclear factor-κB (NF-κB) transcription factors control many physiological processes including inflammation, immunity, apoptosis and angiogenesis. In our search for NF-κB inhibitors from natural resources, we identified baicalein from Scutellaria baicalensis as an inhibitor of NF-κB activation. As examined by the NF-κB luciferase reporter assay, we found that baicalein suppressed TNF-α-induced NF-κB activation in a dose-dependent manner. It also inhibited TNF-α-induced nuclear translocation of p65 through inhibition of phosphorylation and degradation of IκBα. Furthermore, baicalein blocked the TNF-α-induced expression of NF-κB target genes involved in anti-apoptosis (cIAP-1, cIAP-2, FLIP and BCL-2), proliferation (COX-2, cyclin D1 and c-Myc), invasion (MMP‑9), angiogenesis (VEGF) and major inflammatory cytokines (IL-8 and MCP1). The flow cytometric analysis indicated that baicalein potentiated TNF-α-induced apoptosis and induced G1 phase arrest in HeLa cells. Moreover, baicalein significantly blocked activation of p38, extracellular signal-regulated kinase 1/2 (ERK1/2). Our results imply that baicalein could be a lead compound for the modulation of inflammatory diseases as well as certain cancers in which inhibition of NF-κB activity may be desirable.

  9. Targeting cytokines: production and characterization of anti-TNF-α scFvs by phage display technology.

    Science.gov (United States)

    Abdolalizadeh, Jalal; Nouri, Mohammad; Zolbanin, Jafar Majidi; Barzegari, Abolfazl; Baradaran, Behzad; Barar, Jaleh; Coukos, George; Omidi, Yadollah

    2013-01-01

    The antibody display technology (ADT) such as phage display (PD) has substantially improved the production of monoclonal antibodies (mAbs) and Ab fragments through bypassing several limitations associated with the traditional approach of hybridoma technology. In the current study, we capitalized on the PD technology to produce high affinity single chain variable fragment (scFv) against tumor necrosis factor-alpha (TNF- α), which is a potent pro-inflammatory cytokine and plays important role in various inflammatory diseases and malignancies. To pursue production of scFv antibody fragments against human TNF- α, we performed five rounds of biopanning using stepwise decreased amount of TNF-α (1 to 0.1 μ g), a semi-synthetic phage antibody library (Tomlinson I + J) and TG1 cells. Antibody clones were isolated and selected through enzyme-linked immunosorbent assay (ELISA) screening. The selected scFv antibody fragments were further characterized by means of ELISA, PCR, restriction fragment length polymorphism (RFLP) and Western blot analyses as well as fluorescence microscopy and flow cytometry. Based upon binding affinity to TNF-α , 15 clones were selected out of 50 positive clones enriched from PD in vitro selection. The selected scFvs displayed high specificity and binding affinity with Kd values at nm range to human TNF-α . The immunofluorescence analysis revealed significant binding of the selected scFv antibody fragments to the Raji B lymphoblasts. The effectiveness of the selected scFv fragments was further validated by flow cytometry analysis in the lipopolysaccharide (LPS) treated mouse fibroblast L929 cells. Based upon these findings, we propose the selected fully human anti-TNF-α scFv antibody fragments as potential immunotherapy agents that may be translated into preclinical/clinical applications.

  10. Non-targeted effects of ionising radiation - Implications for radiation protection

    Energy Technology Data Exchange (ETDEWEB)

    Sisko Salomaa [STUK - Radiation and Nuclear Safety Authority, Helsinki (Finland)

    2006-07-01

    The universality of the target theory of radiation-induced effects is challenged by observations on non-targeted effects such as bystander effects, genomic instability and adaptive response. Essential features of non-targeted effects are that they do not require direct nuclear exposure by radiation and they are particularly significant at low doses. This new evidence suggests a need for a new paradigm in radiation biology. The new paradigm should cover both the classical (targeted) and the non-targeted effects. New aspects include the role of cellular communication and tissue-level responses. A better understanding of non-targeted effects may have important consequences for health risk assessment and, consequently, on radiation protection. Non-targeted effects may contribute to the estimation of cancer risk from occupational, medical and environmental exposures. In particular, they may have implications for the applicability of the Linear-No-Threshold (LNT) model in extrapolating radiation risk data into the low-dose region. This also means that the adequacy of the concept of dose to estimate risk is challenged by these findings. Moreover, these effects may provide new mechanistic explanations for the development of non-cancer diseases. Further research is required to determine if these effects, typically measured in cell cultures, are applicable in tissue level, whole animals, and ultimately in humans. (author)

  11. Sequential Targeting of CD52 and TNF Allows Early Minimization Therapy in Kidney Transplantation: From a Biomarker to Targeting in a Proof-Of-Concept Trial

    Science.gov (United States)

    Viklicky, Ondrej; Hruba, Petra; Tomiuk, Stefan; Schmitz, Sabrina; Gerstmayer, Bernhard; Sawitzki, Birgit; Miqueu, Patrick; Mrazova, Petra; Tycova, Irena; Svobodova, Eva; Honsova, Eva; Janssen, Uwe

    2017-01-01

    Background There is high medical need for safe long-term immunosuppression monotherapy in kidney transplantation. Selective targeting of post-transplant alloantigen-(re)activated effector-T cells by anti-TNF antibodies after global T cell depletion may allow safe drug minimization, however, it is unsolved what might be the best maintenance monotherapy. Methods In this open, prospective observational single-centre trial, 20 primary deceased donor kidney transplant recipients received 2x20 mg Alemtuzumab (d0/d1) followed by 5 mg/kg Infliximab (d2). For 14 days all patients received only tacrolimus, then they were allocated to either receive tacrolimus (TAC, n = 13) or sirolimus (SIR, n = 7) monotherapy, respectively. Protocol biopsies and extensive immune monitoring were performed and patients were followed-up for 60 months. Results TAC-monotherapy resulted in excellent graft survival (5yr 92%, 95%CI: 56.6–98.9) and function, normal histology, and no proteinuria. Immune monitoring revealed low intragraft inflammation (urinary IP-10) and hints for the development of operational tolerance signature in the TAC- but not SIR-group. Remarkably, the TAC-monotherapy was successful in all five presensitized (ELISPOT+) patients. However, recruitment into SIR-arm was stopped (after n = 7) because of high incidence of proteinuria and acute/chronic rejection in biopsies. No opportunistic infections occurred during follow-up. Conclusions In conclusion, our novel fast-track TAC-monotherapy protocol is likely to be safe and preliminary results indicated an excellent 5-year outcome, however, a full–scale study will be needed to confirm our findings. Trial Registration EudraCT Number: 2006-003110-18 PMID:28085915

  12. Plenary panel 1: The scientific bases of radiation protection. Non-targeted effects of ionising radiation - Implications for radiation protection

    Energy Technology Data Exchange (ETDEWEB)

    Salomaa, S. [STUK - Radiation and Nuclear Safety Authority, Helsinki (Finland)

    2006-07-01

    The universality of the target theory of radiation-induced effects is challenged by observations on non-targeted effects such as bystander effects, genomic instability and adaptive response. Essential features of non-targeted effects are that they do not require direct nuclear exposure by radiation and they are particularly significant at low doses. This new evidence suggests a need for a new paradigm in radiation biology. The new paradigm should cover both the classical (targeted) and the non-targeted effects. New aspects include the role of cellular communication and tissue-level responses. A better understanding of non-targeted effects may have important consequences for health risk assessment and, consequently, on radiation protection. Non-targeted effects may contribute to the estimation of cancer risk from occupational, medical and environmental exposures. In particular, they may have implications for the applicability of the Linear-No-Threshold (L.N.T.) model in extrapolating radiation risk data into the low-dose region. This also means that the adequacy of the concept of dose to estimate risk is challenged by these findings. Moreover, these effects may provide new mechanistic explanations for the development of non-cancer diseases. Further research is required to determine if these effects, typically measured in cell cultures, are applicable in tissue level, whole animals, and ultimately in humans. (authors)

  13. Effects of radiation on direct-drive laser target interaction

    Science.gov (United States)

    Colombant, D. G.

    1999-11-01

    Radiation may be useful for reducing laser imprint and Rayleigh-Taylor (RT) growth in direct-drive target pellets. We will discuss the important role of radiation in a proposed direct-drive X-ray preheated target concept(S.Bodner et al., Phys. Plasmas 5,1901(1998)). In this design, a high-Z coating surrounds a thin plastic coat, over a DT-wicked foam and on top of the DT fuel. Radiation effects will be examined and discussed in the context of this design. The soft X-ray radiation emitted during the foot of the laser pulse - at a few 10^12W/cm^2- preheats the foam ablator which contributes to the reduction of the RT instability. The ablator also stops the radiation, allowing the fuel to stay on a low adiabat. Radiation in the blow-off corona of the target establishes a long scalelength plasma. This separates the ablation region from the laser absorption region where the remaining defects in laser uniformity/pellet surface finish constitute the seed for hydrodynamic instabilities. However, when the pulse intensity rises, the pressure generated by the laser in combination with the changing opacity of the plasma causes the plasma to be pushed back toward the ablator. This is called a Radiative Plasma Structure (RPS)(J.Dahlburg et al., J.Q.S.R.T. 54,113(1995)). These RPS's are a potential problem because they may carry with them the imprint which was present in the low-density corona. We will show and discuss these various effects, as well as some of the experimental work(C.Pawley et al., this conference) under way in connection with this program. These experiments are essential in order to validate both the design concepts and the numerical models, which include on-line state-of-the-art atomic physics modeling(M.Klapisch et al.,Phys. Plasmas 5,1919(1998)).

  14. 4',6-Dihydroxy-4-methoxyisoaurone inhibits TNF-α-induced NF-κB activation and expressions of NF-κB-regulated target gene products.

    Science.gov (United States)

    Ma, Juan; Mi, Chunliu; Wang, Ke Si; Lee, Jung Joon; Jin, Xuejun

    2016-02-01

    The nuclear factor-κB (NF-κB) transcription factors control many physiological processes including inflammation, apoptosis, and angiogenesis. In our search for NF-κB inhibitors from natural resources, we identified 4',6-dihydroxy-4-methoxyisoaurone (ISOA) as an inhibitor of NF-κB activation from the seeds of Trichosanthes kirilowii. However, the mechanism by which ISOA inhibits NF-κB activation is not fully understood. In the present study, we demonstrated the effect of ISOA on NF-κB activation in TNF-α-stimulated HeLa cells. This compound suppressed NF-κB activation through the inhibition of IκB kinase (IKK) activation. ISOA also has an influence on upstream signaling of IKK through the inhibition of expression of adaptor proteins, TNF receptor-associated factor 2 (TRAF2) and receptor interacting protein 1 (RIP1). Consequently, ISOA blocked the phosphorylation and degradation of the inhibitor of NF-κB alpha (IκBα), and subsequent phosphorylation and nuclear translocation of p65. The suppression of NF-κB activation by ISOA led to the down-regulation of target genes involved in inflammation, proliferation, as well as potentiation of TNF-α-induced apoptosis. Taken together, this study extends our understanding on the mechanisms underlying the anti-inflammatory and anti-cancer activities of ISOA. Our findings provide new insight into the molecular mechanisms and a potential application of ISOA for inflammatory diseases as well as certain cancers.

  15. Radiation damage of the ILC positron source target

    Energy Technology Data Exchange (ETDEWEB)

    Ushakov, A.; Riemann, S.

    2007-11-15

    The radiation damage of the positron source target for the International Linear Collider (ILC) has been studied. The displacement damage in target material due to multi-MeV photons has been calculated by combining FLUKA simulations for secondary particle production, SPECTER data for neutron displacement cross-sections and the Lindhard model for estimations of displacement damage by ions. The radiation damage of a stationary Ti6Al4V target in units of displacements per atom (dpa) has been estimated for photons from an undulator with strength 0.92 and period 1.15 cm. The calculated damage is 7 dpa. Approximately 12.5% of displacement damage result from neutrons. (orig.)

  16. Radiation damage of the ILC positron source target

    Energy Technology Data Exchange (ETDEWEB)

    Ushakov, A.; Riemann, S.

    2007-11-15

    The radiation damage of the positron source target for the International Linear Collider (ILC) has been studied. The displacement damage in target material due to multi-MeV photons has been calculated by combining FLUKA simulations for secondary particle production, SPECTER data for neutron displacement cross-sections and the Lindhard model for estimations of displacement damage by ions. The radiation damage of a stationary Ti6Al4V target in units of displacements per atom (dpa) has been estimated for photons from an undulator with strength 0.92 and period 1.15 cm. The calculated damage is 7 dpa. Approximately 12.5% of displacement damage result from neutrons. (orig.)

  17. Radiation Studies for the Target Station of the MOMENT

    CERN Document Server

    Xu, Qing-Nian; Vassilopoulos, Nikolaos; Cao, Jun; He, Miao; Hou, Zhi-Long; Jing, Han-Tao; Liu, Huai-Min; Lyu, Xiao-Rui; Tang, Jing-Yu; Yuan, Ye; Zhao, Guang; Zheng, Yang-Heng

    2016-01-01

    The discovery of the neutrino mixing angle $\\theta_{13}$ opens new opportunities for the discovery of the leptonic CP violation for high intensity neutrino beams. MOMENT a future neutrino facility with a high-power proton beam of 15 MW from a continuous-wave linac is focused on that discovery. The high power of the proton beam causes extreme radiation conditions for the facility and especially for the target station where the pion capture system of five superconducting solenoids is located. In this paper initial studies are performed for the effects of the radiation on the solenoid structure and the area surrounding it. A concept cooling system is also proposed.

  18. Tnf-α inhibition by infliximab as a new target for the prevention of glycerol-contrast-induced nephropathy.

    Science.gov (United States)

    Saritemur, Murat; Un, Harun; Cadirci, Elif; Karakus, Emre; Akpinar, Erol; Halici, Zekai; Ugan, Rustem Anil; Karaman, Adem; Atmaca, Hasan Tarik

    2015-03-01

    Contrast medium-induced nephropathy (CIN) remains as a problem with high incidence and mortality rates. The aim of this study is to examine the roles of infliximab (INF) in the glycerol (GLY) and CIN model in rats. The rats were separated into five groups (n=8): Healthy, GLY, GLY+CM, GLY+CM+INF 5mg/kg intraperitoneally (i.p.), and GLY+CM+INF 7 mg/kg (i.p.). Antioxidant levels in the therapy groups were observed to be quite similar to those in the healthy group. In this study, while the kidney TNF-α, IL-1β, TGF-1β and Caspase 3 gene expressions' levels increased in the nephrotoxic groups, these levels were found to have decreased in the treatment groups. Moreover, histopathologic examination showed that hyaline, haemorrhagic casts and necrosis were increased in nephrotoxicity group, whereas they decreased in the therapy group. Furthermore, TNF-α and NF-κB expression were decreased with infliximab administrated groups similar to control group. In conclusion, we suggest that infliximab have protective roles on CIN.

  19. Semapimod sensitizes glioblastoma tumors to ionizing radiation by targeting microglia.

    Directory of Open Access Journals (Sweden)

    Ian S Miller

    Full Text Available Glioblastoma is the most malignant and lethal form of astrocytoma, with patients having a median survival time of approximately 15 months with current therapeutic modalities. It is therefore important to identify novel therapeutics. There is mounting evidence that microglia (specialized brain-resident macrophages play a significant role in the development and progression of glioblastoma tumors. In this paper we show that microglia, in addition to stimulating glioblastoma cell invasion, also promote glioblastoma cell proliferation and resistance to ionizing radiation in vitro. We found that semapimod, a drug that selectively interferes with the function of macrophages and microglia, potently inhibits microglia-stimulated GL261 invasion, without affecting serum-stimulated glioblastoma cell invasion. Semapimod also inhibits microglia-stimulated resistance of glioblastoma cells to radiation, but has no significant effect on microglia-stimulated glioblastoma cell proliferation. We also found that intracranially administered semapimod strongly increases the survival of GL261 tumor-bearing animals in combination with radiation, but has no significant benefit in the absence of radiation. In conclusion, our observations indicate that semapimod sensitizes glioblastoma tumors to ionizing radiation by targeting microglia and/or infiltrating macrophages.

  20. Semapimod sensitizes glioblastoma tumors to ionizing radiation by targeting microglia.

    Science.gov (United States)

    Miller, Ian S; Didier, Sebastien; Murray, David W; Turner, Tia H; Issaivanan, Magimairajan; Ruggieri, Rosamaria; Al-Abed, Yousef; Symons, Marc

    2014-01-01

    Glioblastoma is the most malignant and lethal form of astrocytoma, with patients having a median survival time of approximately 15 months with current therapeutic modalities. It is therefore important to identify novel therapeutics. There is mounting evidence that microglia (specialized brain-resident macrophages) play a significant role in the development and progression of glioblastoma tumors. In this paper we show that microglia, in addition to stimulating glioblastoma cell invasion, also promote glioblastoma cell proliferation and resistance to ionizing radiation in vitro. We found that semapimod, a drug that selectively interferes with the function of macrophages and microglia, potently inhibits microglia-stimulated GL261 invasion, without affecting serum-stimulated glioblastoma cell invasion. Semapimod also inhibits microglia-stimulated resistance of glioblastoma cells to radiation, but has no significant effect on microglia-stimulated glioblastoma cell proliferation. We also found that intracranially administered semapimod strongly increases the survival of GL261 tumor-bearing animals in combination with radiation, but has no significant benefit in the absence of radiation. In conclusion, our observations indicate that semapimod sensitizes glioblastoma tumors to ionizing radiation by targeting microglia and/or infiltrating macrophages.

  1. Mitochondria as Sub-cellular Targets of Space Radiation

    Science.gov (United States)

    Hei, Tom; Zhang, Bo; Davidson, Mercy

    High linear energy transfer (LET) radiation including alpha particles and heavy ions is the major type of radiation find in space and is considered a potential health risk for astronauts. Even though the chance that these high LET particles traversing through the cytoplasm of cells is higher than that through the nuclei, the contribution of targeted cytoplasmic irradiation, to the induction of genomic instability and other chromosomal damages induced by high LET radiation is not known. Mitochondria are the sole energy center of a cell and normal mitochondria are highly dynamic organelles that move along microtubules or microfilaments and continuously fuse and divide in healthy cells. A balance between mitochondrial fusion and fission is essential to maintain normal mitochondrial function. Targeted cytoplasmic irradiation by high LET alpha particles induced DNA oxidative damage and double strand breaks in wild type rho+ human small airway epithelial (SAE) cells. Furthermore, there was a significant increase in autophagy and micronuclei, which is an indication of genomic instability, together with the activation of nuclear factor kappa-B (NF-kappaB) and mitochondrial inducible nitric oxide synthase (iNOS) signaling pathways in rho+ SAE cells. In contrast, SAE cells with depleted mitochondrial DNA (rho0) and, therefore, no oxidative metabolic functions, exhibited a significantly lower response to these same endpoints examined after cytoplasmic irradiation with high LET alpha particles. The results indicate that normal mitochondrial function is essential in mediating radiation induced genotoxic damages in mammalian cells. Furthermore, the findings may shed some light in the design of countermeasures for space radiation protection.

  2. Neutrophils, a candidate biomarker and target for radiation therapy?

    Science.gov (United States)

    Schernberg, Antoine; Blanchard, Pierre; Chargari, Cyrus; Deutsch, Eric

    2017-08-23

    Neutrophils are the most abundant blood-circulating white blood cells, continuously generated in the bone marrow. Growing evidence suggests they regulate the innate and adaptive immune system during tumor evolution. This review will first summarize the recent findings on neutrophils as a key player in cancer evolution, then as a potential biomarker, and finally as therapeutic targets, with respective focuses on the interplay with radiation therapy. A complex interplay: Neutrophils have been associated with tumor progression through multiple pathways. Ionizing radiation has cytotoxic effects on cancer cells, but the sensitivity to radiation therapy in vivo differ from isolated cancer cells in vitro, partially due to the tumor microenvironment. Different microenvironmental states, whether baseline or induced, can modulate or even attenuate the effects of radiation, with consequences for therapeutic efficacy. Inflammatory biomarkers: Inflammation-based scores have been widely studied as prognostic biomarkers in cancer patients. We have performed a large retrospective cohort of patients undergoing radiation therapy (1233 patients), with robust relationship between baseline blood neutrophil count and 3-year's patient's overall survival in patients with different cancer histologies. (Pearson's correlation test: p = .001, r = -.93). Therapeutic approaches: Neutrophil-targeting agents are being developed for the treatment of inflammatory and autoimmune diseases. Neutrophils either can exert antitumoral (N1 phenotype) or protumoral (N2 phenotype) activity, depending on the Tumor Micro Environment. Tumor associated N2 neutrophils are characterized by high expression of CXCR4, VEGF, and gelatinase B/MMP9. TGF-β within the tumor microenvironment induces a population of TAN with a protumor N2 phenotype. TGF-β blockade slows tumor growth through activation of CD8 + T cells, macrophages, and tumor associated neutrophils with an antitumor N1 phenotype. This supports

  3. Radiation damage/activity calculation for CSNS target station

    Science.gov (United States)

    Yin, W.; Liang, T. J.; Yu, Q. Z.; Jia, X. J.

    2010-03-01

    The radiation damages have been performed for Chinese spallation neutron source (CSNS) target center components that relies on Monte Carlo simulation code MCNPX. During the calculation, Bertini intranuclear cascade model, three level-density formulation GCCI, and multistage pre-equilibrium model MPM on which are provided within MCNPX are employed. We calculate the displacement per atom (DPA) and afterheat of the tungsten target, the stainless steel target vessel window and the aluminum alloy moderator vessel. As a hundred kW-level source, these spallation center components have the lifetime more than 5 year. We also give the activity for the T0 chopper of the beam line HIPD to get the primary data for making out a maintenance scenario.

  4. VISRAD, 3-D Target Design and Radiation Simulation Code

    Science.gov (United States)

    Golovkin, Igor; Macfarlane, Joseph; Golovkina, Viktoriya

    2016-10-01

    The 3-D view factor code VISRAD is widely used in designing HEDP experiments at major laser and pulsed-power facilities, including NIF, OMEGA, OMEGA-EP, ORION, LMJ, Z, and PLX. It simulates target designs by generating a 3-D grid of surface elements, utilizing a variety of 3-D primitives and surface removal algorithms, and can be used to compute the radiation flux throughout the surface element grid by computing element-to-element view factors and solving power balance equations. Target set-up and beam pointing are facilitated by allowing users to specify positions and angular orientations using a variety of coordinates systems (e.g., that of any laser beam, target component, or diagnostic port). Analytic modeling for laser beam spatial profiles for OMEGA DPPs and NIF CPPs is used to compute laser intensity profiles throughout the grid of surface elements. We will discuss recent improvements to the software package and plans for future developments.

  5. The combination of novel targeted molecular agents and radiation in the treatment of pediatric gliomas.

    Science.gov (United States)

    Dasgupta, Tina; Haas-Kogan, Daphne A

    2013-01-01

    microenvironment, including IL-2, IFN-γ, TNF-α, and IL-10, and is currently being evaluated in clinical trials for the treatment of recurrent or refractory pediatric central nervous system tumors. In summary, several targeted inhibitors with radiation are currently under investigation in both translational bench research and early clinical trials. This review article summarizes the molecular rationale for, and the pre-clinical data supporting the combinations of these targeted agents with other anti-cancer agents and XRT in pediatric gliomas. In many cases, parallels are drawn to molecular mechanisms and targeted inhibitors of adult gliomas. We additionally discuss the potential mechanisms underlying the efficacy of these agents.

  6. Targeting Nucleophosmin 1 Represents a Rational Strategy for Radiation Sensitization

    Energy Technology Data Exchange (ETDEWEB)

    Sekhar, Konjeti R. [Department of Radiation Oncology, Vanderbilt University School of Medicine, Nashville, Tennessee (United States); Benamar, Mouadh [Department of Radiation Oncology, University of Virginia School of Medicine, Charlottesville, Virginia (United States); Venkateswaran, Amudhan; Sasi, Soumya [Department of Radiation Oncology, Vanderbilt University School of Medicine, Nashville, Tennessee (United States); Penthala, Narsimha R.; Crooks, Peter A. [Department of Pharmaceutical Sciences, College of Pharmacy, University of Arkansas for Medical Sciences, Little Rock, Arkansas (United States); Hann, Stephen R. [Department of Cell and Developmental Biology, Vanderbilt University School of Medicine, Nashville, Tennessee (United States); Geng, Ling [Department of Radiation Oncology, Vanderbilt University School of Medicine, Nashville, Tennessee (United States); Balusu, Ramesh [Department of Internal Medicine, University of Kansas Medical Center, Kansas City, Kansas (United States); Abbas, Tarek [Department of Radiation Oncology, University of Virginia School of Medicine, Charlottesville, Virginia (United States); Freeman, Michael L., E-mail: michael.freeman@vanderbilt.edu [Department of Radiation Oncology, Vanderbilt University School of Medicine, Nashville, Tennessee (United States)

    2014-08-01

    Purpose: To test the hypothesis that small molecule targeting of nucleophosmin 1 (NPM1) represents a rational approach for radiosensitization. Methods and Materials: Wilde-type and NPM1-deficient mouse embryo fibroblasts (MEFs) were used to determine whether radiosensitization produced by the small molecule YTR107 was NPM1 dependent. The stress response to ionizing radiation was assessed by quantifying pNPM1, γH2AX, and Rad51 foci, neutral comet tail moment, and colony formation. NPM1 levels in a human-derived non-small-cell lung cancer (NSCLC) tissue microarray (TMA) were determined by immunohistochemistry. YTR107-mediated radiosensitization was assessed in NSCLC cell lines and xenografts. Results: Use of NPM1-null MEFs demonstrated that NPM1 is critical for DNA double- strand break (DSB) repair, that loss of NPM1 increases radiation sensitivity, and that YTR107-mediated radiosensitization is NPM1 dependent. YTR107 was shown to inhibit NPM1 oligomerization and impair formation of pNPM1 irradiation-induced foci that colocalized with γH2AX foci. Analysis of the TMA demonstrated that NPM1 is overexpressed in subsets of NSCLC. YTR107 inhibited DNA DSB repair and radiosensitized NSCLC lines and xenografts. Conclusions: These data demonstrate that YTR107-mediated targeting of NPM1 impairs DNA DSB repair, an event that increases radiation sensitivity.

  7. Simulation of transition radiation based beam imaging from tilted targets

    Science.gov (United States)

    Sukhikh, L. G.; Kube, G.; Potylitsyn, A. P.

    2017-03-01

    Transverse beam profile diagnostics in linear electron accelerators is usually based on direct imaging of a beam spot via visible transition radiation. In this case the fundamental resolution limit is determined by radiation diffraction in the optical system. A method to measure beam sizes beyond the diffraction limit is to perform imaging dominated by a single-particle function (SPF), i.e. when the recorded image is dominated not by the transverse beam profile but by the image function of a point source (single electron). Knowledge of the SPF for an experimental setup allows one to extract the transverse beam size from an SPF dominated image. This paper presents an approach that allows one to calculate two-dimensional SPF dominated beam images, taking into account the target inclination angle and the depth-of-field effect. In conclusion, a simple fit function for beam size determination in the case under consideration is proposed and its applicability is tested under various conditions.

  8. Baicalin Protects against TNF-α-Induced Injury by Down-Regulating miR-191a That Targets the Tight Junction Protein ZO-1 in IEC-6 Cells.

    Science.gov (United States)

    Wang, Li; Zhang, Ren; Chen, Jian; Wu, Qihui; Kuang, Zaoyuan

    2017-04-01

    Tumor necrosis factor-alpha (TNF-α) plays an important role in the developing process of inflammatory bowel disease. Tight junction protein zonula occludens-1 (ZO-1), one of epithelial junctional proteins, maintains the permeability of intestinal barrier. The objective of this study was to investigate the mechanism of the protective effect of baicalin on TNF-α-induced injury and ZO-1 expression in intestinal epithelial cells (IECs). We found that baicalin pretreatment significantly improved cell viability and cell migration following TNF-α stimulation. miR-191a inhibitor increased the protective effect of baicalin on cell motility injured by TNF-α. In addition, miR-191a down-regulated the mRNA and protein level of its target gene ZO-1. TNF-α stimulation increased miR-191a expression, leading to the decline of ZO-1 mRNA and protein. Moreover, pretreatment with baicalin reversed TNF-α induced decrease of ZO-1 and increase of miR-191a, miR-191a inhibitor significantly enhanced ZO-1 protein expression restored by baicalin. These results indicate that baicalin exerts a protective effect on IEC-6 (rat small intestinal epithelial cells) cells against TNF-α-induced injury, which is at least partly via inhibiting the expression of miR-191a, thus increasing ZO-1 mRNA and protein levels.

  9. Radiation Damage of Polypropylene Fiber Targets in Storage Rings

    CERN Document Server

    Rohdjess, H; Bisplinghoff, J; Bollmann, R; Büsser, K; Diehl, O; Dohrmann, F; Engelhardt, H P; Eversheim, P D; Greiff, J; Gross, A; Gross-Hardt, R; Hinterberger, F; Igelbrink, M; Langkau, R; Maier, R; Mosel, F; Müller, M; Muenstermann, M; Prasuhn, D; Von Rossen, P; Scheid, H; Schirm, N; Schwandt, F; Scobel, W; Trelle, H J; Wellinghausen, A; Wiedmann, W; Woller, K; Ziegler, R

    2004-01-01

    Thin polypropylene (CH$_2$) fibers have been used for internal experiments in storage rings as an option for hydrogen targets. The change of the hydrogen content due to the radiation dose applied by the circulating proton beam has been investigated in the range $1\\cdot10^6$ to $2\\cdot10^8$~Gy at beam momenta of 1.5 to 3 GeV/c by comparing the elastic pp-scattering yield to that from inelastic p-carbon reactions. It is found that the loss of hydrogen as a function of applied dose receives contributions from a fast and a slow component.

  10. Selective TNFtargeting with infliximab attenuates impaired oxygen metabolism and contractile function induced by an acute exposure to air particulate matter.

    Science.gov (United States)

    Marchini, Timoteo; D'Annunzio, Verónica; Paz, Mariela L; Cáceres, Lourdes; Garcés, Mariana; Perez, Virginia; Tasat, Deborah; Vanasco, Virginia; Magnani, Natalia; Gonzalez Maglio, Daniel; Gelpi, Ricardo J; Alvarez, Silvia; Evelson, Pablo

    2015-11-15

    Inflammation plays a central role in the onset and progression of cardiovascular diseases associated with the exposure to air pollution particulate matter (PM). The aim of this work was to analyze the cardioprotective effect of selective TNFtargeting with a blocking anti-TNF-α antibody (infliximab) in an in vivo mice model of acute exposure to residual oil fly ash (ROFA). Female Swiss mice received an intraperitoneal injection of infliximab (10 mg/kg body wt) or saline solution, and were intranasally instilled with a ROFA suspension (1 mg/kg body wt). Control animals were instilled with saline solution and handled in parallel. After 3 h, heart O2 consumption was assessed by high-resolution respirometry in left ventricle tissue cubes and isolated mitochondria, and ventricular contractile reserve and lusitropic reserve were evaluated according to the Langendorff technique. ROFA instillation induced a significant decrease in tissue O2 consumption and active mitochondrial respiration by 32 and 31%, respectively, compared with the control group. While ventricular contractile state and isovolumic relaxation were not altered in ROFA-exposed mice, impaired contractile reserve and lusitropic reserve were observed in this group. Infliximab pretreatment significantly attenuated the decrease in heart O2 consumption and prevented the decrease in ventricular contractile and lusitropic reserve in ROFA-exposed mice. Moreover, infliximab-pretreated ROFA-exposed mice showed conserved left ventricular developed pressure and cardiac O2 consumption in response to a β-adrenergic stimulus with isoproterenol. These results provides direct evidence linking systemic inflammation and altered cardiac function following an acute exposure to PM and contribute to the understanding of PM-associated cardiovascular morbidity and mortality.

  11. Wavelength scaling of terahertz radiation in plasma gas targets

    Science.gov (United States)

    Zhao, Hang; Huang, Suxia; Zhang, Cunlin; Zhang, Liangliang

    2016-11-01

    In our experiments, terahertz radiation via two-color generated laser plasma gas targets is studied using nitrogen and the noble gases (helium, neon, argon, krypton, and xenon) as the generation media. Carried out at the infrared beam of the advanced laser light source, we studied the effects of different pump wavelengths (between 1200 nm and 1600 nm) on THz generation. Terahertz pulse energy is measured as functions of input pulse energy, gas species, gas pressure. The experimental results show that the terahertz pulse energy approach a maximum value of 0.0578 μJ per pulse in xenon gas when the input 1600 nm pulse energy is 0.4 mJ per pulse.

  12. Simulation of transition radiation based beam imaging from tilted targets

    Directory of Open Access Journals (Sweden)

    L. G. Sukhikh

    2017-03-01

    Full Text Available Transverse beam profile diagnostics in linear electron accelerators is usually based on direct imaging of a beam spot via visible transition radiation. In this case the fundamental resolution limit is determined by radiation diffraction in the optical system. A method to measure beam sizes beyond the diffraction limit is to perform imaging dominated by a single-particle function (SPF, i.e. when the recorded image is dominated not by the transverse beam profile but by the image function of a point source (single electron. Knowledge of the SPF for an experimental setup allows one to extract the transverse beam size from an SPF dominated image. This paper presents an approach that allows one to calculate two-dimensional SPF dominated beam images, taking into account the target inclination angle and the depth-of-field effect. In conclusion, a simple fit function for beam size determination in the case under consideration is proposed and its applicability is tested under various conditions.

  13. Gene therapy for neuropathic pain by silencing of TNF-α expression with lentiviral vectors targeting the dorsal root ganglion in mice.

    Directory of Open Access Journals (Sweden)

    Nobuhiro Ogawa

    Full Text Available Neuropathic pain can be a debilitating condition. Many types of drugs that have been used to treat neuropathic pain have only limited efficacy. Recent studies indicate that pro-inflammatory mediators including tumor necrosis factor α (TNF-α are involved in the pathogenesis of neuropathic pain. In the present study, we engineered a gene therapy strategy to relieve neuropathic pain by silencing TNF-α expression in the dorsal root ganglion (DRG using lentiviral vectors expressing TNF short hairpin RNA1-4 (LV-TNF-shRNA1-4 in mice. First, based on its efficacy in silencing TNF-α in vitro, we selected shRNA3 to construct LV-TNF-shRNA3 for in vivo study. We used L5 spinal nerve transection (SNT mice as a neuropathic pain model. These animals were found to display up-regulated mRNA expression of activating transcription factor 3 (ATF3 and neuropeptide Y (NPY, injury markers, and interleukin (IL-6, an inflammatory cytokine in the ipsilateral L5 DRG. Injection of LV-TNF-shRNA3 onto the proximal transected site suppressed significantly the mRNA levels of ATF3, NPY and IL-6, reduced mechanical allodynia and neuronal cell death of DRG neurons. These results suggest that lentiviral-mediated silencing of TNF-α in DRG relieves neuropathic pain and reduces neuronal cell death, and may constitute a novel therapeutic option for neuropathic pain.

  14. Coherent forward and backward diffraction radiation of relativistic electrons in a dielectric targets

    Science.gov (United States)

    Naumenko, G. A.; Shevelev, M. V.; Popov, Yu A.

    2016-08-01

    During the interaction of the relativistic electrons field with a dielectric target various types of electromagnetic radiation, such as Cerenkov radiation, diffraction radiation, transition radiation can be generated. In this report we present the results of experimental studies of the diffraction radiation generated by relativistic electrons in a dielectric target at the interface vacuum-insulator and insulator-conductor in the millimeter wavelength range. The experimental results show that the component of the diffraction radiation of relativistic electrons at the interface insulator-conductor, for any significant refractive index of insulator, is suppressed. The analysis of the results from different points of view was done.

  15. All-Trans Retinoic Acid Modulates TLR4/NF-κB Signaling Pathway Targeting TNF-α and Nitric Oxide Synthase 2 Expression in Colonic Mucosa during Ulcerative Colitis and Colitis Associated Cancer

    Science.gov (United States)

    Rafa, Hayet; Benkhelifa, Sarra; AitYounes, Sonia; Saoula, Houria; Belhadef, Said; Belkhelfa, Mourad; Boukercha, Aziza; Toumi, Ryma; Soufli, Imene; de Launoit, Yvan; Mahfouf, Hassen; Nakmouche, M'hamed

    2017-01-01

    Colitis associated cancer (CAC) is the colorectal cancer (CRC) subtype that is associated with bowel disease such as ulcerative colitis (UC). The data on role of NF-κB signaling in development and progression of CAC were derived from preclinical studies, whereas data from human are rare. The aim of this work was to study the contribution of NF-κB pathway during UC and CAC, as well as the immunomodulatory effect of all-trans retinoic acid (AtRA). We analyzed the expression of NOS2, TNF-α, TLR4, and NF-κB, in colonic mucosa. We also studied NO/TNF-α modulation by LPS in colonic mucosa pretreated with AtRA. A marked increase in TLR4, NF-κB, TNF-α, and NOS2 expression was reported in colonic mucosa. The relationship between LPS/TLR4 and TNF-α/NO production, as well as the role of NF-κB signaling, was confirmed by ex vivo experiments and the role of LPS/TLR4 in NOS2/TNF-α induction through NF-κB pathway was suggested. AtRA downregulates NOS2 and TNF-α expression. Collectively, our study indicates that AtRA modulates in situ LPS/TLR4/NF-κB signaling pathway targeting NOS2 and TNF-α expression. Therefore, we suggest that AtRA has a potential value in new strategies to improve the current therapy, as well as in the clinical prevention of CAC development and progression.

  16. Modulation of Anti-Tumor Necrosis Factor Alpha (TNF-α) Antibody Secretion in Mice Immunized with TNF-α Kinoid

    OpenAIRE

    Assier, Eric; Semerano, Luca; Duvallet, Emilie; Delavallée, Laure; Bernier, Emilie; Laborie, Marion; Grouard-Vogel, Géraldine; Larcier, Patrick; Bessis, Natacha; Boissier, Marie-Christophe

    2012-01-01

    Tumor necrosis factor alpha (TNF-α) blockade is an effective treatment for patients with TNF-α-dependent chronic inflammatory diseases, such as rheumatoid arthritis, Crohn's disease, and psoriasis. TNF-α kinoid, a heterocomplex of human TNF-α and keyhole limpet hemocyanin (KLH) (TNF-K), is an active immunotherapy targeting TNF-α. Since the TNF-K approach is an active immunization, and patients receiving this therapy also receive immunosuppressant treatment, we evaluated the effect of some imm...

  17. Biologics beyond TNF-α inhibitors and the effect of targeting the homologues TL1A-DR3 pathway in chronic inflammatory disorders

    DEFF Research Database (Denmark)

    Tougaard, Peter; Zervides, Kristoffer Alexander; Skov, Søren

    2016-01-01

    not respond to anti-TNF-α treatment and one possible explanation may be the heterogeneity of chronic inflammatory diseases and a dominance of other significant TNF family members. Indeed, polymorphisms in the TNF family member, TL1A gene, is associated with the development of IBD and increased serum...... concentrations of TL1A has been demonstrated in patients with various chronic inflammatory disorders. Here, we describe the current knowledge of TL1As immunobiology and present results from human disease, animal models, and pre-clinical intervention studies that point toward development of anti-TL1A therapy...

  18. Molecular targeted treatment and radiation therapy for rectal cancer

    Energy Technology Data Exchange (ETDEWEB)

    Marquardt, Friederike; Roedel, Franz; Capalbo, Gianni; Weiss, Christian; Roedel, Claus [Dept. of Radiation Therapy, Univ. of Frankfurt/Main (Germany)

    2009-06-15

    Background: EGFR (epidermal growth factor receptor) and VEGF (vascular endothelial growth factor) inhibitors confer clinical benefit in metastatic colorectal cancer when combined with chemotherapy. An emerging strategy to improve outcomes in rectal cancer is to integrate biologically active, targeted agents as triple therapy into chemoradiation protocols. Material and methods: cetuximab and bevacizumab have now been incorporated into phase I-II studies of preoperative chemoradiation therapy (CRT) for rectal cancer. The rationale of these combinations, early efficacy and toxicity data, and possible molecular predictors for tumor response are reviewed. Computerized bibliographic searches of Pubmed were supplemented with hand searches of reference lists and abstracts of ASCO and ASTRO meetings. Results: the combination of cetuximab and CRT can be safely applied without dose compromises of the respective treatment components. Disappointingly low rates of pathologic complete remission have been noted in several phase II studies. The K-ras mutation status and the gene copy number of EGFR may predict tumor response. The toxicity pattern (radiation-induced enteritis, perforations) and surgical complications (wound healing, fistula, bleeding) observed in at least some of the clinical studies with bevacizumab and CRT warrant further investigations. Conclusion: longer follow-up (and, finally, randomized trials) is needed to draw any firm conclusions with respect to local and distant failure rates, and toxicity associated with these novel treatment approaches. (orig.)

  19. Radiation force on absorbing targets and power measurements of a high intensity focused ultrasound (HIFU) source

    Institute of Scientific and Technical Information of China (English)

    2010-01-01

    Based on the analytic expressions for the radiated field of a circular concave piston given by Hasegawa et al.,an integral for calculation of the radiation force on a plane absorbing target in a spherically focused field is derived.A general relation between acoustic power P and normal radiation force Fn is obtained under the condition of kr 1.Numerical computation is carried out by using the symbolic computation program for practically focused sources and absorbing circular targets.The results show that,for a given source,there is a range of target positions where the radiation force is independent of the target’s position under the assumption that the contribution of the acoustic field behind the target to the radiation force can be neglected.The experiments are carried out and confirm that there is a range of target positions where the measured radiation force is basically independent of the target’s position even at high acoustic power (up to 700 W).It is believed that when the radiation force method is used to measure the acoustic power radiated from a focused source,the size of the target must be selected in such a way that no observable sound can be found in the region behind the target.

  20. Nuclear Targets for a Precision Measurement of the Neutral Pion Radiative Width

    Energy Technology Data Exchange (ETDEWEB)

    Martel, Philippe; Clinton, Eric; McWilliams, R.; Lawrence, Dave; Miskimen, Rory; Ahmidouch, Abdellah; Ambrozewicz, Pawel; Asaturyan, Arshak; Baker, O.; Benton, LaRay; Bernstein, Aron; Cole, Philip; Collins, Patrick; Dale, Daniel; Danagoulian, Samuel; Davidenko, G.; Demirchyan, Raphael; Deur, Alexandre; DOLGOLENKO, A.; Dzyubenko, Georgiy; Evdokimov, Anatoly; Feng, JIng; Gabrielyan, Marianna; Gan, Liping; Gasparian, Ashot; Glamazdin, Oleksandr; Goryachev, Vladimir; Gyurjyan, Vardan; Hardy, K.; Ito, Mark; Khandaker, Mahbubul; Kingsberry, Paul; Kolarkar, Ameya; Konchatnyi, Mykhailo; Korchin, O.; Korsch, Wolfgang; Kowalski, Stanley; Kubantsev, Mikhail; Kubarovsky, Valery; LARIN, Ilya; MATVEEV, V.; McNulty, Dustin; Milbrath, Brian; Minehart, Ralph; Mochalov, Vasiliy; Mtingwa, Sekazi; Nakagawa, Itaru; Overby, Steven; Pasyuk, Evgueni; Payen, Marvin; Pedroni, Ronald; Prok, Yelena; Ritchie, Barry; Salgado, Carlos; Sitnikov, Anatoly; Sober, Daniel; Stephens, W.; Teymurazyan, Aram; Underwood, Jarreas; VASILIEV, A.; VEREBRYUSOV, V.; Vishnyakov, Vladimir; Wood, Michael

    2009-12-01

    A technique is presented for precision measurements of the area densities, density * T, of approximately 5% radiation length carbon and 208Pb targets used in an experiment at Jefferson Laboratory to measure the neutral pion radiative width. The precision obtained in the area density for the carbon target is +/- 0.050%, and that obtained for the lead target through an x-ray attenuation technique is +/- 0.43%.

  1. TNF-α-induced NF-κB activation upregulates microRNA-150-3p and inhibits osteogenesis of mesenchymal stem cells by targeting β-catenin.

    Science.gov (United States)

    Wang, Nan; Zhou, Zubin; Wu, Tianyi; Liu, Wei; Yin, Peipei; Pan, Chenhao; Yu, Xiaowei

    2016-03-01

    Although systemic or local inflammation, commonly featured by cytokine activation, is implicated in patients with bone loss, the underlying mechanisms are still elusive. As microRNAs (miR), a class of small non-coding RNAs involved in essential physiological processes, have been found in bone cells, we aimed to investigate the role of miR for modulating osteogenesis in inflammatory milieu using human bone marrow mesenchymal stem cells (hBM-MSCs). Induced by proinflammatory cytokine TNF-α, miR-150-3p was identified as a key player in suppressing osteogenic differentiation through downregulating β-catenin, a transcriptional co-activator promoting bone formation. TNF-α treatment increased the levels of miR-150-3p, which directly targeted the 3'-UTR of β-catenin mRNA and in turn repressed its expression. In addition, we observed that miR-150-3p expression was increased by TNF-α via IKK-dependent NF-κB signalling. There are three putative NF-κB binding sites in the promoter region of miR-150, and we identified -686 region as the major NF-κB binding site for stimulation of miR-150 expression by TNF-α. Finally, the osteogenic differentiation of hBM-MSCs was inhibited by either miR-150-3p overexpression or TNF-α treatment, which was prevented by anti-miR-150-3p oligonucleotides. Taken together, our data suggested that miR-150-3p integrated inflammation signalling and osteogenic differentiation and may contribute to the inhibition effects of inflammation on bone formation, thus expanding the pathophysiological functions of microRNAs in bone diseases.

  2. Estimations of neutron yield from beryllium target irradiated by SPring-8 hard synchrotron radiation

    CERN Document Server

    Gryaznykh, D A; Plokhoi, V V

    2000-01-01

    The possibility of creating a neutron source based on ''SPring-8'' synchrotron radiation interaction with beryllium targets is discussed. The possible neutron yield is estimated to be of order 10 sup 1 sup 2 s sup - sup 1 .

  3. Non-targeted and delayed effects of exposure to ionizing radiation: I. Radiation-induced genomic instability and bystander effects in vitro

    Science.gov (United States)

    Morgan, William F.

    2003-01-01

    A long-standing dogma in the radiation sciences is that energy from radiation must be deposited in the cell nucleus to elicit a biological effect. A number of non-targeted, delayed effects of ionizing radiation have been described that challenge this dogma and pose new challenges to evaluating potential hazards associated with radiation exposure. These effects include induced genomic instability and non-targeted bystander effects. The in vitro evidence for non-targeted effects in radiation biology will be reviewed, but the question as to how one extrapolates from these in vitro observations to the risk of radiation-induced adverse health effects such as cancer remains open.

  4. Accurate Targeting of Liver Tumors in Stereotactic Radiation Therapy

    NARCIS (Netherlands)

    W. Wunderink (Wouter)

    2011-01-01

    textabstractThis doctoral thesis concerns the treatment of liver cancer patients using external beam radiotherapy. The quality of this treatment greatly depends on delivering a high radiation dose to the tumor while keeping the dose as low as possible to surrounding healthy tissues. One of the major

  5. CHANGES AND SIGNIFICANES OF TGF-β1, TNF-α AND HYDROXYPROLINE IN RADIATION-INDUCED PULMONARY INJURY%TGF-β1、TNF-α及羟脯胺酸在大鼠放射性肺损伤中的变化及意义

    Institute of Scientific and Technical Information of China (English)

    何天楚; 李坚; 邱俊

    2011-01-01

    Objective: To investigate the possible mechanisms of radiation-induced lung fibrosis. Methods: The right hemithorax of SD rats were irradiated with a single dose of 7. 0 Gy and 14. 4 Gy. All animals were sacrificed and the lungs were removed at 1, 7, 30 and 90 days after radiation. The histopathological changes, hydroxyproline content and expression of transforming growth factor-β1 (TGF-β1 ) , tumor necrosis fac-tor-α (TNF-α) between the radiation and control groups were analyzed by HE staining. Masson staining and immunohistochemistry. Results:In control group and 7. 0 Gy groups, there were no notable histopathological changes, just including little tissue exudates, congestion, edema and infiltration of inflammatory cells, red blood cell leakage. However, the formation of collagen and fibrosis could be observed in 14. 4 Gy group. The expression of TGF-β1 , TNF-a was negative or weak positive in the control group and radiation groups. But, both them were increased in 14. 4 Gy group. The content of hydroxyproline was little changes in the control and 7. 0 Gy groups at every time point, it increased at 30 days significantly, and up to maximum at 90 days in 14. 4 Gy group after radiation. Conclusion: Radiation-induced lung injury in the inflammatory response stimulated radiation lung injury and fibrosis process.%目的:探讨大鼠放射性肺损伤与炎症反应、纤维化改变的相关机制.方法:SD大鼠分为3组:对照组、7.0 Gy放射损伤组、14.4 Gy放射损伤组.其中放射损伤组大鼠麻醉后用60Co治疗机单次照射右全肺;在照射后的1,7,30,90d,取大鼠右肺组织进行HE、Masson染色检查;免疫组化检测肺组织转化生长因子β1(TGF-β1)、肿瘤坏死因子(TNF-α)的表达,并检测羟脯胺酸的含量变化.结果:14.4 Gy组观察到明显的纤维化改变;免疫组化染色显示在各观察时点TGF-β1、TNF-α均为阳性表达;羟脯胺酸含量30 d后明显增加,至90 d时达最大值,与对照

  6. Adenovirus-mediated siRNA targeting TNF-α and overexpression of bone morphogenetic protein-2 promotes early osteoblast differentiation on a cell model of Ti particle-induced inflammatory response in vitro

    Energy Technology Data Exchange (ETDEWEB)

    Guo, H.H.; Yu, C.C.; Sun, S.X. [Affiliated Hospital of Ningxia Medical University, Department of Orthopedic Surgery, Yinchuan (China); Ma, X.J. [Ningxia Medical Autonomous Region of the First People' s Hospital, Department of Orthopedic Surgery, Yinchuan (China); Yang, X.C.; Sun, K.N.; Jin, Q.H. [Affiliated Hospital of Ningxia Medical University, Department of Orthopedic Surgery, Yinchuan (China)

    2013-10-02

    Wear particles are phagocytosed by macrophages and other inflammatory cells, resulting in cellular activation and release of proinflammatory factors, which cause periprosthetic osteolysis and subsequent aseptic loosening, the most common causes of total joint arthroplasty failure. During this pathological process, tumor necrosis factor-alpha (TNF-α) plays an important role in wear-particle-induced osteolysis. In this study, recombination adenovirus (Ad) vectors carrying both target genes [TNF-α small interfering RNA (TNF-α-siRNA) and bone morphogenetic protein 2 (BMP-2)] were synthesized and transfected into RAW264.7 macrophages and pro-osteoblastic MC3T3-E1 cells, respectively. The target gene BMP-2, expressed on pro-osteoblastic MC3T3-E1 cells and silenced by the TNF-α gene on cells, was treated with titanium (Ti) particles that were assessed by real-time PCR and Western blot. We showed that recombinant adenovirus (Ad-siTNFα-BMP-2) can induce osteoblast differentiation when treated with conditioned medium (CM) containing RAW264.7 macrophages challenged with a combination of Ti particles and Ad-siTNFα-BMP-2 (Ti-ad CM) assessed by alkaline phosphatase activity. The receptor activator of nuclear factor-κB ligand was downregulated in pro-osteoblastic MC3T3-E1 cells treated with Ti-ad CM in comparison with conditioned medium of RAW264.7 macrophages challenged with Ti particles (Ti CM). We suggest that Ad-siTNFα-BMP-2 induced osteoblast differentiation and inhibited osteoclastogenesis on a cell model of a Ti particle-induced inflammatory response, which may provide a novel approach for the treatment of periprosthetic osteolysis.

  7. Adenovirus-mediated siRNA targeting TNF-α and overexpression of bone morphogenetic protein-2 promotes early osteoblast differentiation on a cell model of Ti particle-induced inflammatory response in vitro.

    Science.gov (United States)

    Guo, H H; Yu, C C; Sun, S X; Ma, X J; Yang, X C; Sun, K N; Jin, Q H

    2013-10-01

    Wear particles are phagocytosed by macrophages and other inflammatory cells, resulting in cellular activation and release of proinflammatory factors, which cause periprosthetic osteolysis and subsequent aseptic loosening, the most common causes of total joint arthroplasty failure. During this pathological process, tumor necrosis factor-alpha (TNF-α) plays an important role in wear-particle-induced osteolysis. In this study, recombination adenovirus (Ad) vectors carrying both target genes [TNF-α small interfering RNA (TNF-α-siRNA) and bone morphogenetic protein 2 (BMP-2)] were synthesized and transfected into RAW264.7 macrophages and pro-osteoblastic MC3T3-E1 cells, respectively. The target gene BMP-2, expressed on pro-osteoblastic MC3T3-E1 cells and silenced by the TNF-α gene on cells, was treated with titanium (Ti) particles that were assessed by real-time PCR and Western blot. We showed that recombinant adenovirus (Ad-siTNFα-BMP-2) can induce osteoblast differentiation when treated with conditioned medium (CM) containing RAW264.7 macrophages challenged with a combination of Ti particles and Ad-siTNFα-BMP-2 (Ti-ad CM) assessed by alkaline phosphatase activity. The receptor activator of nuclear factor-κB ligand was downregulated in pro-osteoblastic MC3T3-E1 cells treated with Ti-ad CM in comparison with conditioned medium of RAW264.7 macrophages challenged with Ti particles (Ti CM). We suggest that Ad-siTNFα-BMP-2 induced osteoblast differentiation and inhibited osteoclastogenesis on a cell model of a Ti particle-induced inflammatory response, which may provide a novel approach for the treatment of periprosthetic osteolysis.

  8. Online virtual isocenter based radiation field targeting for high performance small animal microirradiation

    Science.gov (United States)

    Stewart, James M. P.; Ansell, Steve; Lindsay, Patricia E.; Jaffray, David A.

    2015-12-01

    Advances in precision microirradiators for small animal radiation oncology studies have provided the framework for novel translational radiobiological studies. Such systems target radiation fields at the scale required for small animal investigations, typically through a combination of on-board computed tomography image guidance and fixed, interchangeable collimators. Robust targeting accuracy of these radiation fields remains challenging, particularly at the millimetre scale field sizes achievable by the majority of microirradiators. Consistent and reproducible targeting accuracy is further hindered as collimators are removed and inserted during a typical experimental workflow. This investigation quantified this targeting uncertainty and developed an online method based on a virtual treatment isocenter to actively ensure high performance targeting accuracy for all radiation field sizes. The results indicated that the two-dimensional field placement uncertainty was as high as 1.16 mm at isocenter, with simulations suggesting this error could be reduced to 0.20 mm using the online correction method. End-to-end targeting analysis of a ball bearing target on radiochromic film sections showed an improved targeting accuracy with the three-dimensional vector targeting error across six different collimators reduced from 0.56+/- 0.05 mm (mean  ±  SD) to 0.05+/- 0.05 mm for an isotropic imaging voxel size of 0.1 mm.

  9. Delineation of Supraclavicular Target Volumes in Breast Cancer Radiation Therapy

    Energy Technology Data Exchange (ETDEWEB)

    Brown, Lindsay C. [Department of Radiation Oncology, Mayo Clinic, Rochester, Minnesota (United States); Diehn, Felix E. [Department of Radiology, Mayo Clinic, Rochester, Minnesota (United States); Boughey, Judy C. [Department of Surgery, Mayo Clinic, Rochester, Minnesota (United States); Childs, Stephanie K.; Park, Sean S.; Yan, Elizabeth S.; Petersen, Ivy A. [Department of Radiation Oncology, Mayo Clinic, Rochester, Minnesota (United States); Mutter, Robert W., E-mail: mutter.robert@mayo.edu [Department of Radiation Oncology, Mayo Clinic, Rochester, Minnesota (United States)

    2015-07-01

    Purpose: To map the location of gross supraclavicular metastases in patients with breast cancer, in order to determine areas at highest risk of harboring subclinical disease. Methods and Materials: Patients with axial imaging of gross supraclavicular disease were identified from an institutional breast cancer registry. Locations of the metastatic lymph nodes were transferred onto representative axial computed tomography images of the supraclavicular region and compared with the Radiation Therapy Oncology Group (RTOG) breast cancer atlas for radiation therapy planning. Results: Sixty-two patients with 161 supraclavicular nodal metastases were eligible for study inclusion. At the time of diagnosis, 117 nodal metastases were present in 44 patients. Forty-four nodal metastases in 18 patients were detected at disease recurrence, 4 of whom had received prior radiation to the supraclavicular fossa. Of the 161 nodal metastases, 95 (59%) were within the RTOG consensus volume, 4 nodal metastases (2%) in 3 patients were marginally within the volume, and 62 nodal metastases (39%) in 30 patients were outside the volume. Supraclavicular disease outside the RTOG consensus volume was located in 3 regions: at the level of the cricoid and thyroid cartilage (superior to the RTOG volume), in the posterolateral supraclavicular fossa (posterolateral to the RTOG volume), and in the lateral low supraclavicular fossa (lateral to the RTOG volume). Only women with multiple supraclavicular metastases had nodal disease that extended superiorly to the level of the thyroid cartilage. Conclusions: For women with risk of harboring subclinical supraclavicular disease warranting the addition of supraclavicular radiation, coverage of the posterior triangle and the lateral low supraclavicular region should be considered. For women with known supraclavicular disease, extension of neck coverage superior to the cricoid cartilage may be warranted.

  10. Delineation of Supraclavicular Target Volumes in Breast Cancer Radiation Therapy.

    Science.gov (United States)

    Brown, Lindsay C; Diehn, Felix E; Boughey, Judy C; Childs, Stephanie K; Park, Sean S; Yan, Elizabeth S; Petersen, Ivy A; Mutter, Robert W

    2015-07-01

    To map the location of gross supraclavicular metastases in patients with breast cancer, in order to determine areas at highest risk of harboring subclinical disease. Patients with axial imaging of gross supraclavicular disease were identified from an institutional breast cancer registry. Locations of the metastatic lymph nodes were transferred onto representative axial computed tomography images of the supraclavicular region and compared with the Radiation Therapy Oncology Group (RTOG) breast cancer atlas for radiation therapy planning. Sixty-two patients with 161 supraclavicular nodal metastases were eligible for study inclusion. At the time of diagnosis, 117 nodal metastases were present in 44 patients. Forty-four nodal metastases in 18 patients were detected at disease recurrence, 4 of whom had received prior radiation to the supraclavicular fossa. Of the 161 nodal metastases, 95 (59%) were within the RTOG consensus volume, 4 nodal metastases (2%) in 3 patients were marginally within the volume, and 62 nodal metastases (39%) in 30 patients were outside the volume. Supraclavicular disease outside the RTOG consensus volume was located in 3 regions: at the level of the cricoid and thyroid cartilage (superior to the RTOG volume), in the posterolateral supraclavicular fossa (posterolateral to the RTOG volume), and in the lateral low supraclavicular fossa (lateral to the RTOG volume). Only women with multiple supraclavicular metastases had nodal disease that extended superiorly to the level of the thyroid cartilage. For women with risk of harboring subclinical supraclavicular disease warranting the addition of supraclavicular radiation, coverage of the posterior triangle and the lateral low supraclavicular region should be considered. For women with known supraclavicular disease, extension of neck coverage superior to the cricoid cartilage may be warranted. Copyright © 2015 Elsevier Inc. All rights reserved.

  11. Experimental Research of the Diffraction and Vavilov-Cherenkov Radiation Generation in a Teflon Target

    CERN Document Server

    Shevelev, M; Potylitsyn, A; Popov, Yu

    2011-01-01

    Geometry of Vavilov-Cherekov (VChR) radiation when an electron moves close to a dielectric target is in analogy to diffraction radiation (DR) geometry. In this case we may expect DR generation from the upstream face of the target besides that VChR. The joint observation of these booth types of radiation is very interesting from the pseudo-photon viewpoint, which is applicable for relativistic electrons. Unexpected results obtained in our experiment insist on reflection about nature both DR and VChR. The experiment was performed on the relativistic electron beam of the microtron of Tomsk Polytechnic University.

  12. AA, radiation shielding curtain along the target area

    CERN Multimedia

    1980-01-01

    At the far left is the beam tube for the high-intensity proton beam from the 26 GeV PS. The tube ends in a thin window and the proton beam continues in air through a hole in the shielding blocks (see also 8010308), behind which the target (see 7905091, 7905094)was located. After the target followed the magnetic horn, focusing the antiprotons, and the first part of the injection line with a proton dump. The antiprotons, deflected by a magnet, left the target area through another shielding wall, to make their way to the AA ring. Laterally, this sequence of components was shielded with movable, suspended, concrete blocks: the "curtain". Balasz Szeless, who had constructed it, is standing at its side.

  13. Cherenkov radiation from the target with predetermined dielectric properties, produced by a 3D-printer

    Science.gov (United States)

    Naumenko, G.; Potylitsyn, A.; Bleko, V.; Soboleva, V.; Stuchebrov, S.

    2017-07-01

    Most targets made of industrial materials, used for the generation of Cherenkov radiation (ChR) have a refractive index n > 1.4 in millimeter wavelength region. It is often a problem to get out the radiation from such cylindrical or flat targets because the angle of incidence of ChR on the outer surface of target is greater than the angle of total internal reflection. In this work we present the solution of this problem by the usage of the targets with predetermined dielectric properties, manufactured using 3-D printer. We demonstrate the emission of ChR in millimeter wavelength region from the such flat target with the refractive index n = 1.37 . Suggested technique allows us to fabricate targets with turned refractive index.

  14. Chemoradiation for Ductal Pancreatic Carcinoma: Principles of Combining Chemotherapy with Radiation, Definition of Target Volume and Radiation Dose

    Directory of Open Access Journals (Sweden)

    Heinemann V

    2005-05-01

    Full Text Available Review of the role of chemoradiotherapy in the treatment of locally advanced pancreatic cancer with a specific focus on the technical feasibility and the integration of chemoradiotherapy into multimodal treatment concepts. Combined chemoradiotherapy of pancreatic cancer is a safe treatment with an acceptable profile of side effects when applied with modern planning and radiation techniques as well as considering tissue tolerance. Conventionally fractionated radiation regimens with total doses of 45-50 Gy and small-volume boost radiation with 5.4 Gy have found the greatest acceptance. Locoregional lymphatic drainage should be included in the planning of target volumes because the risk of tumor involvement and local or loco-regional recurrence is high. Up to now, 5-fluorouracil has been considered the "standard" agent for concurrent chemoradiotherapy. The role of gemcitabine given concurrently with radiation has not yet been defined, since high local efficacy may also be accompanied by enhanced toxicities. In addition, no dose or administration form has been determined to be "standard" up to now. The focus of presently ongoing research is to define an effective and feasible regimen of concurrent chemoradiotherapy. While preliminary results indicate promising results using gemcitabine-based chemoradiotherapy, reliable data derived from mature phase III trials are greatly needed. Intensity-modulated radiotherapy has been developed to improve target-specific radiation and to reduce organ toxicity. Its clinical relevance still needs to be defined.

  15. Molecular targets in cellular response to ionizing radiation and implications in space radiation protection

    Energy Technology Data Exchange (ETDEWEB)

    Belli, M.; Tabocchini, M.A. [Istituto Superiore di Sanita, Rome (Italy). Physics Lab.; Sapora, O. [Istituto Superiore di Sanita, Rome (Italy). Comparative Toxicology Lab.

    2002-12-01

    DNA repair systems and cell cycle checkpoints closely co-operate in the attempt of maintaining the genomic integrity of cells damaged by ionizing radiation. DNA double-strand breaks (DSB) are considered as the most biologically important radiation-induced damage. Their spatial distribution and association with other types of damage depend on radiation quality. It is believed these features affect damage reparability, thus explaining the higher efficiency for cellular effects of densely ionizing radiation with respect to {gamma}-rays. DSB repair systems identified in mammalian cells are homologous recombination (HR), single-strand annealing (SSA) and non-homologous end-joining (NHEJ). Some enzymes may participate in more than one of these repair systems. DNA damage also triggers biochemical signals activating checkpoints responsible for delay in cell cycle progression that allows more time for repair. Those at G1/S and S phases prevent replication of damaged DNA and those at G2/M phase prevent segregation of changed chromosomes. Individuals with lack or alterations of genes involved in DNA DSB repair and cell cycle checkpoints exhibit syndromes characterized by genome instability and predisposition to cancer. Information reviewed in this paper on the basic mechanisms of cellular response to ionizing radiation indicates their importance for a number of issues relevant to protection of astronauts from space radiation. (author)

  16. Effects of target fragmentation on evaluation of LET spectra from space radiations: implications for space radiation protection studies

    Science.gov (United States)

    Cucinotta, F. A.; Wilson, J. W.; Shinn, J. L.; Badavi, F. F.; Badhwar, G. D.

    1996-01-01

    We present calculations of linear energy transfer (LET) spectra in low earth orbit from galactic cosmic rays and trapped protons using the HZETRN/BRYNTRN computer code. The emphasis of our calculations is on the analysis of the effects of secondary nuclei produced through target fragmentation in the spacecraft shield or detectors. Recent improvements in the HZETRN/BRYNTRN radiation transport computer code are described. Calculations show that at large values of LET (> 100 keV/micrometer) the LET spectra seen in free space and low earth orbit (LEO) are dominated by target fragments and not the primary nuclei. Although the evaluation of microdosimetric spectra is not considered here, calculations of LET spectra support that the large lineal energy (y) events are dominated by the target fragments. Finally, we discuss the situation for interplanetary exposures to galactic cosmic rays and show that current radiation transport codes predict that in the region of high LET values the LET spectra at significant shield depths (> 10 g/cm2 of Al) is greatly modified by target fragments. These results suggest that studies of track structure and biological response of space radiation should place emphasis on short tracks of medium charge fragments produced in the human body by high energy protons and neutrons.

  17. The influence of the earth radiation on space target detection system

    Science.gov (United States)

    Su, Xiaofeng; Chen, FanSheng; Cuikun, .; Liuyan, .

    2017-05-01

    In the view of space remote sensing such as satellite detection space debris detection etc. visible band is usually used in order to have the all-weather detection capability, long wavelength infrared (LWIR) detection is also an important supplement. However, in the tow wave band, the earth can be a very strong interference source, especially in the dim target detecting. When the target is close to the earth, especially the LEO target, the background radiation of the earth will also enter into the baffle, and became the stray light through reflection, the stray light can reduce the signal to clutter ratio (SCR) of the target and make it difficult to be detected. In the visible band, the solar albedo by the earth is the main clutter source while in the LWIR band the radiation of the earth is the main clutter source. So, in this paper, we establish the energy transformation from the earth background radiation to the detection system to assess the effects of the stray light. Firstly, we discretize the surface of the earth to different unit, and using MODTRAN to calculate the radiation of the discrete point in different light and climate conditions, then, we integral all the radiation which can reach the baffle in the same observation angles to get the energy distribution, finally, according the target energy and the non-uniformity of the detector, we can calculate the design requirement of the system stray light suppression, which provides the design basis for the optical system.

  18. High-Temperature Target Recognition Based on Spectral Radiation Information

    Institute of Scientific and Technical Information of China (English)

    Fan Xueliang; Cheng Xiaofang; Xu Jun

    2006-01-01

    Based on the principles of optics and radiometry, the imaging mathematical model is established and the factors of the contrast (signal-noise-ratio) of high-temperature target and the scenery are given. By analyzing not only the differences in spectral properties between objects in the scene, but also the CCD spectral response theoretically, a new method of enhancement of contrast is given. By optimizing the initial image capture stage, using liquid crystal light valve to make a simple modification of the imaging system, the goal of high-temperature object recognition is achieved. The experimental results agree with the theoretical predict.

  19. Adaptive Radiation Therapy for Postprostatectomy Patients Using Real-Time Electromagnetic Target Motion Tracking During External Beam Radiation Therapy

    Energy Technology Data Exchange (ETDEWEB)

    Zhu, Mingyao [Department of Radiation Oncology, Washington University School of Medicine, Saint Louis, Missouri (United States); Bharat, Shyam [Philips Research North America, Briarcliff Manor, New York (United States); Michalski, Jeff M.; Gay, Hiram A. [Department of Radiation Oncology, Washington University School of Medicine, Saint Louis, Missouri (United States); Hou, Wei-Hsien [St Louis University School of Medicine, St Louis, Missouri (United States); Parikh, Parag J., E-mail: pparikh@radonc.wustl.edu [Department of Radiation Oncology, Washington University School of Medicine, Saint Louis, Missouri (United States)

    2013-03-15

    Purpose: Using real-time electromagnetic (EM) transponder tracking data recorded by the Calypso 4D Localization System, we report inter- and intrafractional target motion of the prostate bed, describe a strategy to evaluate treatment adequacy in postprostatectomy patients receiving intensity modulated radiation therapy (IMRT), and propose an adaptive workflow. Methods and Materials: Tracking data recorded by Calypso EM transponders was analyzed for postprostatectomy patients that underwent step-and-shoot IMRT. Rigid target motion parameters during beam delivery were calculated from recorded transponder positions in 16 patients with rigid transponder geometry. The delivered doses to the clinical target volume (CTV) were estimated from the planned dose matrix and the target motion for the first 3, 5, 10, and all fractions. Treatment adequacy was determined by comparing the delivered minimum dose (D{sub min}) with the planned D{sub min} to the CTV. Treatments were considered adequate if the delivered CTV D{sub min} is at least 95% of the planned CTV D{sub min}. Results: Translational target motion was minimal for all 16 patients (mean: 0.02 cm; range: −0.12 cm to 0.07 cm). Rotational motion was patient-specific, and maximum pitch, yaw, and roll were 12.2, 4.1, and 10.5°, respectively. We observed inadequate treatments in 5 patients. In these treatments, we observed greater target rotations along with large distances between the CTV centroid and transponder centroid. The treatment adequacy from the initial 10 fractions successfully predicted the overall adequacy in 4 of 5 inadequate treatments and 10 of 11 adequate treatments. Conclusion: Target rotational motion could cause underdosage to partial volume of the postprostatectomy targets. Our adaptive treatment strategy is applicable to post-prostatectomy patients receiving IMRT to evaluate and improve radiation therapy delivery.

  20. Adaptive radiation therapy for postprostatectomy patients using real-time electromagnetic target motion tracking during external beam radiation therapy.

    Science.gov (United States)

    Zhu, Mingyao; Bharat, Shyam; Michalski, Jeff M; Gay, Hiram A; Hou, Wei-Hsien; Parikh, Parag J

    2013-03-15

    Using real-time electromagnetic (EM) transponder tracking data recorded by the Calypso 4D Localization System, we report inter- and intrafractional target motion of the prostate bed, describe a strategy to evaluate treatment adequacy in postprostatectomy patients receiving intensity modulated radiation therapy (IMRT), and propose an adaptive workflow. Tracking data recorded by Calypso EM transponders was analyzed for postprostatectomy patients that underwent step-and-shoot IMRT. Rigid target motion parameters during beam delivery were calculated from recorded transponder positions in 16 patients with rigid transponder geometry. The delivered doses to the clinical target volume (CTV) were estimated from the planned dose matrix and the target motion for the first 3, 5, 10, and all fractions. Treatment adequacy was determined by comparing the delivered minimum dose (Dmin) with the planned Dmin to the CTV. Treatments were considered adequate if the delivered CTV Dmin is at least 95% of the planned CTV Dmin. Translational target motion was minimal for all 16 patients (mean: 0.02 cm; range: -0.12 cm to 0.07 cm). Rotational motion was patient-specific, and maximum pitch, yaw, and roll were 12.2, 4.1, and 10.5°, respectively. We observed inadequate treatments in 5 patients. In these treatments, we observed greater target rotations along with large distances between the CTV centroid and transponder centroid. The treatment adequacy from the initial 10 fractions successfully predicted the overall adequacy in 4 of 5 inadequate treatments and 10 of 11 adequate treatments. Target rotational motion could cause underdosage to partial volume of the postprostatectomy targets. Our adaptive treatment strategy is applicable to post-prostatectomy patients receiving IMRT to evaluate and improve radiation therapy delivery. Copyright © 2013 Elsevier Inc. All rights reserved.

  1. Local-linear-prediction analysis for underwater acoustic target radiated noise

    Institute of Scientific and Technical Information of China (English)

    LIANG Juan; LU Jiren

    2002-01-01

    Local-linear-prediction in phase space is performed for the underwater acoustic target radiated noise. Relation curve of average prediction error versus neighboring points' number is calculated. The result is used in judging the nonlinearity of radiated noise time series, and obtaining the appropriate form and coefficients of predicting model. The line and continuous spectral component are predicted respectively. Choice of some model parameters minimizing the prediction error is also discussed.

  2. Design of the EURISOL multi-MW target assembly radiation and safety issues

    CERN Document Server

    Felcini, Marta; Kadi, Yacine; Otto, Thomas; Tecchio, L

    2006-01-01

    The multi-MW target proposed for the EURISOL facility will be based on fission of uranium (or thorium) compounds to produce rare isotopes far from stability. A two-step process is used for the isotope production. First, neutrons are generated in a liquid mercury target, irradiated by the 1 GeV proton or deuteron beam, provided by the EURISOL linac driver. Then, the neutrons induce fission in a surrounding assembly of uranium carbide. R&D projects on several aspects of the target assembly are ongoing. Key criteria for the target design are a maximum beam power capability of 4 MW, a remote handling system with minimum downtime and maximum reliability, as well as radiation safety, minimization of hazards and the classification of the facility. In the framework of the ongoing radiation characterization and safety studies, radiation transport simulations have been performed to calculate the prompt radiation dose in the target and surrounding materials, as well as to determine shielding material and angle-depen...

  3. Design of the EURISOL multi-MW target assembly: radiation and safety issues

    CERN Document Server

    Felcini, M; Kadi, Y; Otto, T; Tecchio, L; Otto, Th.

    2006-01-01

    The multi-MW target proposed for the EURISOL facility will be based on fission of uranium (or thorium) compounds to produce rare isotopes far from stability. A two-step process is used for the isotope production. First, neutrons are generated in a liquid mercury target, irradiated by the 1 GeV proton or deuteron beam, provided by the EURISOL linac driver. Then, the neutrons induce fission in a surrounding assembly of uranium carbide. R&D projects on several aspects of the target assembly are ongoing. Key criteria for the target design are a maximum beam power capability of 4 MW, a remote handling system with minimum downtime and maximum reliability, as well as radiation safety, minimization of hazards and the classification of the facility. In the framework of the ongoing radiation characterization and safety studies, radiation transport simulations have been performed to calculate the prompt radiation dose in the target and surrounding materials, as well as to determine shielding material and angle-depen...

  4. EURISOL-DS Multi‐MW Target: Radiological Protection, Radiation Safety and Shielding Aspects

    CERN Document Server

    Y. Romanets and R. Luís (ITN)

    The objective of this work was to carry out a detailed study and analysis of all aspects related toradioprotection and radiation safety of the spallation target area and the whole spaces reservedfor the fission targets and spallation target maintenance. Operational and no‐operationalconditions were considered for an evaluation of the radiation safety conditions.An analysis of the proposed shielding dimensions and configuration was performed for thesystem during operation time. Parameters as activation, dose rate, energy deposition, etc. aremore important for the no‐operation period, in order to evaluate the hazard level anddetermine the staff access type to the maintenance areas (direct or remote control).Such elements as the fission targets and the whole structure involved on it were studied in moredetail because of the disposal issues, after operation. Activation, dose rate and residual nuclideswere studied for each element of the assembly. All parameters were analyzed according to their...

  5. A synthetic peptide derived from A1 module in CRD4 of human TNF receptor-1 inhibits binding and proinflammatory effect of human TNF-alpha.

    Science.gov (United States)

    Cao, Yingnan; Wang, Zhaohe; Bu, Xianzhang; Tang, Shu; Mei, Zhengrong; Liu, Peiqing

    2009-06-01

    Tumour necrosis factor alpha (TNF-alpha) is a proinflammatory cytokine, which has been shown to be a causative factor in rheumatoid arthritis, inflammatory bowel disease and septic shock. Proinflammatory effect of TNF-alpha is activated mainly through human TNF receptor-1 (TNF-R1). However, the role of the fourth cystein-rich domain (CRD4) of TNF-R1 extracellular portion in the interaction of TNF-alpha with TNF-R1 is still unclear. In the present study, binding activity of TNF-alpha to TNF-R1 and protein levels of IkappaB-alpha and nuclear transcription factor kappa B (NF-kappaB) p65 subunit in HeLa cells were measured using enzyme-linked immunosorbent assay (ELISA) and western-blot analysis. Pep 3 (LRENECVS) which was derived from the hydrophilic region of A1 module in CRD4 remarkably inhibited the binding of TNF-alpha to TNF-R1, and also reversed TNF-alpha-induced degradation of IkappaB-alpha and nuclear translocation of NF-kappaB p65 subunit in HeLa cells. Our results confirmed that the hydrophilic region of A1 module in CRD4 participated in the interaction of TNF-alpha with TNF-R1, and demonstrated the potential of small-molecule TNF-alpha extracellular inhibitors targeting at A1 module in CRD4 of TNF-R1 in suppressing proinflammatory effect of TNF-alpha.

  6. Cellular Pathways in Response to Ionizing Radiation and Their Targetability for Tumor Radiosensitization.

    Science.gov (United States)

    Maier, Patrick; Hartmann, Linda; Wenz, Frederik; Herskind, Carsten

    2016-01-14

    During the last few decades, improvements in the planning and application of radiotherapy in combination with surgery and chemotherapy resulted in increased survival rates of tumor patients. However, the success of radiotherapy is impaired by two reasons: firstly, the radioresistance of tumor cells and, secondly, the radiation-induced damage of normal tissue cells located in the field of ionizing radiation. These limitations demand the development of drugs for either radiosensitization of tumor cells or radioprotection of normal tissue cells. In order to identify potential targets, a detailed understanding of the cellular pathways involved in radiation response is an absolute requirement. This review describes the most important pathways of radioresponse and several key target proteins for radiosensitization.

  7. Cellular Pathways in Response to Ionizing Radiation and Their Targetability for Tumor Radiosensitization

    Directory of Open Access Journals (Sweden)

    Patrick Maier

    2016-01-01

    Full Text Available During the last few decades, improvements in the planning and application of radiotherapy in combination with surgery and chemotherapy resulted in increased survival rates of tumor patients. However, the success of radiotherapy is impaired by two reasons: firstly, the radioresistance of tumor cells and, secondly, the radiation-induced damage of normal tissue cells located in the field of ionizing radiation. These limitations demand the development of drugs for either radiosensitization of tumor cells or radioprotection of normal tissue cells. In order to identify potential targets, a detailed understanding of the cellular pathways involved in radiation response is an absolute requirement. This review describes the most important pathways of radioresponse and several key target proteins for radiosensitization.

  8. A prediction model of radiation-induced necrosis for intracranial radiosurgery based on target volume.

    Science.gov (United States)

    Zhao, Bo; Wen, Ning; Chetty, Indrin J; Huang, Yimei; Brown, Stephen L; Snyder, Karen C; Siddiqui, Farzan; Movsas, Benjamin; Siddiqui, M Salim

    2017-08-01

    This study aims to extend the observation that the 12 Gy-radiosurgical-volume (V12Gy) correlates with the incidence of radiation necrosis in patients with intracranial tumors treated with radiosurgery by using target volume to predict V12Gy. V12Gy based on the target volume was used to predict the radiation necrosis probability (P) directly. Also investigated was the reduction in radiation necrosis rates (ΔP) as a result of optimizing the prescription isodose lines for linac-based SRS. Twenty concentric spherical targets and 22 patients with brain tumors were retrospectively studied. For each case, a standard clinical plan and an optimized plan with prescription isodose lines based on gradient index were created. V12Gy were extracted from both plans to analyze the correlation between V12Gy and target volume. The necrosis probability P as a function of V12Gy was evaluated. To account for variation in prescription, the relation between V12Gy and prescription was also investigated. A prediction model for radiation-induced necrosis was presented based on the retrospective study. The model directly relates the typical prescribed dose and the target volume to the radionecrosis probability; V12Gy increased linearly with the target volume (R(2)  > 0.99). The linear correlation was then integrated into a logistic model to predict P directly from the target volume. The change in V12Gy as a function of prescription was modeled using a single parameter, s (=-1.15). Relatively large ΔP was observed for target volumes between 7 and 28 cm(3) with the maximum reduction (8-9%) occurring at approximately 18 cm(3) . Based on the model results, optimizing the prescription isodose line for target volumes between 7 and 28 cm(3) results in a significant reduction in necrosis probability. V12Gy based on the target volume could provide clinicians a predictor of radiation necrosis at the contouring stage thus facilitating treatment decisions. © 2017 American Association of

  9. Whole brain radiation-induced cognitive impairment: pathophysiological mechanisms and therapeutic targets.

    Science.gov (United States)

    Lee, Yong Woo; Cho, Hyung Joon; Lee, Won Hee; Sonntag, William E

    2012-07-01

    Radiation therapy, the most commonly used for the treatment of brain tumors, has been shown to be of major significance in tu-mor control and survival rate of brain tumor patients. About 200,000 patients with brain tumor are treated with either partial large field or whole brain radiation every year in the United States. The use of radiation therapy for treatment of brain tumors, however, may lead to devastating functional deficits in brain several months to years after treatment. In particular, whole brain radiation therapy results in a significant reduction in learning and memory in brain tumor patients as long-term consequences of treatment. Although a number of in vitro and in vivo studies have demonstrated the pathogenesis of radiation-mediated brain injury, the cel-lular and molecular mechanisms by which radiation induces damage to normal tissue in brain remain largely unknown. Therefore, this review focuses on the pathophysiological mechanisms of whole brain radiation-induced cognitive impairment and the iden-tification of novel therapeutic targets. Specifically, we review the current knowledge about the effects of whole brain radiation on pro-oxidative and pro-inflammatory pathways, matrix metalloproteinases (MMPs)/tissue inhibitors of metalloproteinases (TIMPs) system and extracellular matrix (ECM), and physiological angiogenesis in brain. These studies may provide a foundation for defin-ing a new cellular and molecular basis related to the etiology of cognitive impairment that occurs among patients in response to whole brain radiation therapy. It may also lead to new opportunities for therapeutic interventions for brain tumor patients who are undergoing whole brain radiation therapy.

  10. Activity and radiation protection studies for the W-Ta target of CSNS.

    Science.gov (United States)

    Yu, Q Z; Liang, T J; Yin, W

    2009-09-01

    The Chinese government initiated a conceptual design for the project of China Spallation Neutron Source (CSNS), which consists of an H-linear accelerator, a rapid cycling synchrotron accelerating the beam to 1.6 GeV, a target station converting proton beam into lower energy (radiation protection of the CSNS target station. The shielding design of the service cell for the decay gamma ray induced from the W-Ta target and its vessel shows that the ambient dose rate decreases exponentially with increasing heavy concrete thickness. And 80 cm thickness of heavy concrete for each side of the service cell can satisfy the safety requirement.

  11. Modes of targets in water excited and identified using radiation pressure of modulated focused ultrasound

    Science.gov (United States)

    Daniel, Timothy; Fortuner, Auberry; Abawi, Ahmad; Kirsteins, Ivars; Marston, Philip

    2016-11-01

    The modulated radiation pressure (MRP) of ultrasound has been widely used to selectively excite low frequency modes of fluid objects. We previously used MRP to excite less compliant metallic object in water including the low frequency modes of a circular metal plate in water. A larger focused ultrasonic transducer allows us to drive modes of larger more-realistic targets. In our experiments solid targets are suspended by strings or supported on sand and the modulated ultrasound is focused on the target's surface. Target sound emissions were recorded and a laser vibrometer was used to measure the surface velocity of the target to give the magnitude of the target response. The source transducer was driven with a doublesideband suppressed carrier voltage as in. By varying the modulation frequency and monitoring target response, resonant frequencies can be measured and compared to finite element models. We also demonstrate the radiation torque of a focused first-order acoustic vortex beam associated with power absorption in the Stokes layer adjacent to a sphere. Funded by ONR.

  12. Non-targeted and delayed effects of exposure to ionizing radiation: II. Radiation-induced genomic instability and bystander effects in vivo, clastogenic factors and transgenerational effects

    Science.gov (United States)

    Morgan, William F.

    2003-01-01

    The goal of this review is to summarize the evidence for non-targeted and delayed effects of exposure to ionizing radiation in vivo. Currently, human health risks associated with radiation exposures are based primarily on the assumption that the detrimental effects of radiation occur in irradiated cells. Over the years a number of non-targeted effects of radiation exposure in vivo have been described that challenge this concept. These include radiation-induced genomic instability, bystander effects, clastogenic factors produced in plasma from irradiated individuals that can cause chromosomal damage when cultured with nonirradiated cells, and transgenerational effects of parental irradiation that can manifest in the progeny. These effects pose new challenges to evaluating the risk(s) associated with radiation exposure and understanding radiation-induced carcinogenesis.

  13. Proton Acceleration with Double-Layer Targets in the Radiation Pressure Dominant Regime

    Institute of Scientific and Technical Information of China (English)

    LU Hai-Yang; WANG Cheng; LIU Jian-Sheng

    2011-01-01

    @@ Acceleration of protons by a circularly polarized laser pulse irradiating on a double-layer target is investigated by a theoretical model and particle-in-cell simulations.The target is made up of a heavy ion layer coated with a proton layer on the rear surface.The results show that when the first layer is transparent induced by the hole-boring effect, the whole proton layer is accelerated by the transmitted laser pulse to high energy with low energy spread.The quality of the proton beam generated from a double-layer target is better than that from a single-layer target.The improvement is attributed to the flat top structure of the electrostatic field caused by the electrons injected into the second layer.It is easier to control the spectrum quality by using a double-layer target rather than using a single-layer one when the radiation pressure acceleration is dominant.

  14. Targeted therapies and radiation for the treatment of head and neck cancer

    Energy Technology Data Exchange (ETDEWEB)

    Kim, Gwi Eon [Yonsei University College of Medicine, Seoul (Korea, Republic of)

    2004-06-15

    The purpose of this review is to provide an update on novel radiation treatments for head and neck cancer. Despite the remarkable advances in chemotherapy and radiotherapy techniques, the management of advanced head and neck cancer remains challenging. Epidermal growth factor receptor (EGFR) is an appealing target for novel therapies in head and neck cancer because not only EGFR activation stimulates many important signaling pathways associated with cancer development and progression, and importantly, resistance to radiation. Furthermore, EGFR overexpression is known to be portended for a worse outcome in patients with advanced head and neck cancer. Two categories of compounds designed to abrogate EGFR signaling, such as monoclonal antibodies (Cetuximab) and tyrosine kinase inhibitors (ZD1839 and OSI-774) have been assessed and have been most extensively studied in preclinical models and clinical trials. Additional TKIs in clinical trials include a reversible agent, Cl-1033, which blocks activation of all erbB receptors. Encouraging preclinical data for head and neck cancers resulted in rapid translation into the clinic. Results from initial clinical trials show rather surprisingly that only minority of patients benefited from EGFR inhibition as monotherapy or in combination with chemotherapy. In this review, we begin with a brief summary of erbB-mediated signal transduction. Subsequently, we present data on prognostic-predictive value of erbB receptor expression in HNC followed by preclinical and clinical data on the role of EGFR antagonists alone or in combination with radiation in the treatment of HNC. Finally, we discuss the emerging thoughts on resistance to EGFR blockade and efforts in the development of multiple-targeted therapy for combination with chemotherapy or radiation. Current challenges for investigators are to determine (1) who will benefit from targeted agents and which agents are most appropriate to combine with radiation and/or chemotherapy, (2

  15. Anti-TNF drives regulatory T cell expansion by paradoxically promoting membrane TNF-TNF-RII binding in rheumatoid arthritis.

    Science.gov (United States)

    Nguyen, Dao Xuan; Ehrenstein, Michael R

    2016-06-27

    The interplay between inflammatory and regulatory pathways orchestrates an effective immune response that provides protection from pathogens while limiting injury to host tissue. Tumor necrosis factor (TNF) is a pivotal inflammatory cytokine, but there is conflicting evidence as to whether it boosts or inhibits regulatory T cells (T reg cells). In this study, we show that the therapeutic anti-TNF antibody adalimumab, but not the soluble TNF receptor etanercept, paradoxically promoted the interaction between monocytes and T reg cells isolated from patients with rheumatoid arthritis (RA). Adalimumab bound to monocyte membrane TNF from RA patients and unexpectedly enhanced its expression and its binding to TNF-RII expressed on T reg cells. As a consequence, adalimumab expanded functional Foxp3(+) T reg cells equipped to suppress Th17 cells through an IL-2/STAT5-dependent mechanism. Our data not only highlight the beneficial effect of membrane TNF on T reg cell numbers during chronic inflammation, but in addition reveal how a therapeutic antibody that is thought to act by simply blocking its target can enhance the regulatory properties of this proinflammatory cytokine.

  16. The Clinical Development of Molecularly Targeted Agents in Combination With Radiation Therapy: A Pharmaceutical Perspective

    Energy Technology Data Exchange (ETDEWEB)

    Ataman, Ozlem U., E-mail: ouataman@hotmail.com [Global Medicines Development, AstraZeneca, Alderley Park, Macclesfield, Cheshire (United Kingdom); Sambrook, Sally J. [Global Medicines Development, AstraZeneca, Alderley Park, Macclesfield, Cheshire (United Kingdom); Wilks, Chris [Innovative Medicines, AstraZeneca, Alderley Park, Macclesfield, Cheshire (United Kingdom); Lloyd, Andrew [Global Medicines Development, AstraZeneca, Alderley Park, Macclesfield, Cheshire (United Kingdom); Taylor, Amanda E. [Yellow Delaney Communications Ltd, Wilmslow, Cheshire (United Kingdom); Wedge, Stephen R. [Innovative Medicines, AstraZeneca, Alderley Park, Macclesfield, Cheshire (United Kingdom)

    2012-11-15

    Summary: This paper explores historical and current roles of pharmaceutical industry sponsorship of clinical trials testing radiation therapy combinations with molecularly targeted agents and attempts to identify potential solutions to expediting further combination studies. An analysis of clinical trials involving a combination of radiation therapy and novel cancer therapies was performed. Ongoing and completed trials were identified by searching the (clinicaltrials.gov) Web site, in the first instance, with published trials of drugs of interest identified through American Society of Clinical Oncology, European CanCer Organisation/European Society for Medical Oncology, American Society for Radiation Oncology/European Society for Therapeutic Radiology and Oncology, and PubMed databases and then cross-correlated with (clinicaltrials.gov) protocols. We examined combination trials involving radiation therapy with novel agents and determined their distribution by tumor type, predominant molecular mechanisms examined in combination to date, timing of initiation of trials relative to a novel agent's primary development, and source of sponsorship of such trials. A total of 564 studies of targeted agents in combination with radiation therapy were identified with or without concomitant chemotherapy. Most studies were in phase I/II development, with only 36 trials in phase III. The tumor site most frequently studied was head and neck (26%), followed by non-small cell lung cancer. Pharmaceutical companies were the sponsors of 33% of studies overall and provided support for only 16% of phase III studies. In terms of pharmaceutical sponsorship, Genentech was the most active sponsor of radiation therapy combinations (22%), followed by AstraZeneca (14%). Most radiation therapy combination trials do not appear to be initiated until after drug approval. In phase III studies, the most common (58%) primary endpoint was overall survival. Collectively, this analysis suggests that

  17. Radiation binary targeted therapy for HER-2 positive breast cancers: assumptions, theoretical assessment and future directions

    Energy Technology Data Exchange (ETDEWEB)

    Mundy, Daniel W [School of Nuclear Engineering, Purdue University, 400 Central Drive, West Lafayette, IN 47909 (United States); Harb, Wael [Horizon Oncology, The Care Group, Unity Medical Center, Lafayette, IN 47901 (United States); Jevremovic, Tatjana [School of Nuclear Engineering, Purdue University, 400 Central Drive, West Lafayette, IN 47909 (United States)

    2006-03-21

    A novel radiation targeted therapy is investigated for HER-2 positive breast cancers. The proposed concept combines two known approaches, but never used together for the treatment of advanced, relapsed or metastasized HER-2 positive breast cancers. The proposed radiation binary targeted concept is based on the anti HER-2 monoclonal antibodies (MABs) that would be used as vehicles to transport the nontoxic agent to cancer cells. The anti HER-2 MABs have been successful in targeting HER-2 positive breast cancers with high affinity. The proposed concept would utilize a neutral nontoxic boron-10 predicting that anti HER-2 MABs would assure its selective delivery to cancer cells. MABs against HER-2 have been a widely researched strategy in the clinical setting. The most promising antibody is Trastuzumab (Herceptin (registered) ). Targeting HER-2 with the MAB Trastuzumab has been proven to be a successful strategy in inducing tumour regression and improving patient survival. Unfortunately, these tumours become resistant and afflicted women succumb to breast cancer. In the proposed concept, when the tumour region is loaded with boron-10 it is irradiated with neutrons (treatment used for head and neck cancers, melanoma and glioblastoma for over 40 years in Japan and Europe). The irradiation process takes less than an hour producing minimal side effects. This paper summarizes our recent theoretical assessments of radiation binary targeted therapy for HER-2 positive breast cancers on: the effective drug delivery mechanism, the numerical model to evaluate the targeted radiation delivery and the survey study to find the neutron facility in the world that might be capable of producing the radiation effect as needed. A novel method of drug delivery utilizing Trastuzumab is described, followed by the description of a computational Monte Carlo based breast model used to determine radiation dose distributions. The total flux and neutron energy spectra of five currently available

  18. Targeted knockout of TNF-α by injection of lentivirus-mediated siRNA into the subacromial bursa for the treatment of subacromial bursitis in rats.

    Science.gov (United States)

    Wang, Yi; Li, Quan; Wei, Xianzhao; Xu, Jie; Chen, Qi; Song, Shuang; Lu, Zhe; Wang, Zimin

    2015-09-01

    Subacromial bursitis (SAB) is the major source of pain in rotator cuff disease. Although multiple investigations have provided support for the role of inflammatory cytokines in SAB, few have focussed on the use these cytokines in the treatment of SAB. The aim of the present study was to observe the therapeutic efficacy of lentivirus‑mediated RNA interference (RNAi) on carrageenan‑induced SAB by injecting lentivirus‑tumor necrosis factor (TNF)‑α‑RNAi expressing TNF‑α small interfering (si)RNA. Using screened siRNA segments, an siRNA was designed. A lentivirus vector expressing siRNA was established and packed as lentivirus particles. A lentivirus that expressed the negative sequence was used as a lentivirus‑negative control (NC). The carrageenan‑induced SAB model was established in 32 male Sprague‑Dawley rats. The modeled rats were randomly assigned to four groups: Lentivirus‑RNAi treatment group, lentivirus‑NC group, SAB group and phosphate‑buffered saline (PBS) blank control group. The lentivirus was injected (1x10(7) transducing units) into the subacromial bursa of the rats in the lentivirus‑RNAi group and lentivirus‑NC group, whereas 100 µl PBS was injected at the same site in the SAB group and the PBS blank control group. At 5 weeks following injection, the animals were sacrificed and venous blood was obtained. The effect of TNF‑α interference and the expression of inflammatory cytokines were determined by reverse transcription‑quantitative polymerase chain reaction, western blotting, hematoxylin and eosin staining, Van Gieson's staining and immunofluorescence. The expression of TNF‑α was decreased in the lentivirus‑TNF‑α‑RNAi group compared with that in the SAB group. Morphological observations revealed that the number of inflammatory cells were reduced and damage to tendon fibers was attenuated in this group, suggesting that the downregulation of the protein expression levels of TNF‑α‑associated nuclear

  19. RADIATION DOSE MEASUREMENTS FOR HIGH-INTENSITY LASER INTERACTIONS WITH SOLID TARGETS AT SLAC.

    Science.gov (United States)

    Liang, T; Bauer, J; Cimeno, M; Ferrari, A; Galtier, E; Granados, E; Lee, H J; Liu, J; Nagler, B; Prinz, A; Rokni, S; Tran, H; Woods, M

    2016-12-01

    A systematic study of photon and neutron radiation doses generated in high-intensity laser-solid interactions is underway at SLAC National Accelerator Laboratory. These laser-solid experiments are being performed using a 25 TW (up to 1 J in 40 fs) femtosecond pulsed Ti:sapphire laser at the Linac Coherent Light Source's (LCLS) Matter in Extreme Conditions (MEC) facility. Radiation measurements were performed with passive and active detectors deployed at various locations inside and outside the target chamber. Results from radiation dose measurements for laser-solid experiments at SLAC MEC in 2014 with peak intensity between 10(18) and 7.1 × 10(19) W cm(-2) are presented.

  20. Radiation Dose Measurement for High-Intensity Laser Interactions with Solid Targets at SLAC

    Energy Technology Data Exchange (ETDEWEB)

    Liang, Taiee [SLAC National Accelerator Lab., Menlo Park, CA (United States)

    2015-09-25

    A systematic study of photon and neutron radiation doses generated in high-intensity laser-solid interactions is underway at SLAC National Accelerator Laboratory. We found that these laser-solid experiments are being performed using a 25 TW (up to 1 J in 40 fs) femtosecond pulsed Ti:sapphire laser at the Linac Coherent Light Source’s (LCLS) Matter in Extreme Conditions (MEC) facility. Additionally, radiation measurements were performed with passive and active detectors deployed at various locations inside and outside the target chamber. Results from radiation dose measurements for laser-solid experiments at SLAC MEC in 2014 with peak intensity between 1018 to 7.1x1019 W/cm2 are presented.

  1. Enhanced radiation response in radioresistant MCF-7 cells by targeting peroxiredoxin II

    Directory of Open Access Journals (Sweden)

    Diaz AJG

    2013-10-01

    Full Text Available Anthony Joseph Gomez Diaz,1 Daniel Tamae,2 Yun Yen,3 JianJian Li,4 Tieli Wang1 1Department of Chemistry and Biochemistry, California State University at Dominguez Hills, Carson, CA, 2Center of Excellence in Environmental Toxicology, Department of Pharmacology, University of Pennsylvania, Philadelphia, PA, 3Department of Clinical and Molecular Pharmacology, Beckman Research Institute of City of Hope National Medical Center, Duarte, CA, 4Department of Radiation Oncology, University of California Davis, Sacramento, CA, USA Abstract: In our previous study, we identified that a protein target, peroxiredoxin II (PrxII, is overexpressed in radioresistant MCF+FIR3 breast-cancer cells and found that its expression and function is associated with breast-cancer radiation sensitivity or resistance. Small interference RNA (siRNA targeting PrxII gene expression was able to sensitize MCF+FIR3 radioresistant breast-cancer cells to ionizing radiation. The major focus of this work was to investigate how the radiation response of MCF+FIR3 radioresistant cells was affected by the siRNA that inhibits PrxII gene expression. Our results, presented here, show that silencing PrxII gene expression increased cellular toxicity by altering cellular thiol status, inhibiting Ca2+ efflux from the cells, and perturbing the intracellular Ca2+ homeostasis. By combining radiotherapy and siRNA technology, we hope to develop new therapeutic strategies that may have potential to enhance the efficacy of chemotherapeutic agents due to this technology's property of targeting to specific cancer-related genes. Keywords: siRNA, PrxII, radiation resistance, Ca2+, MCF+FIR3

  2. Shock-Timing Experiment Using a Two-Step Radiation Pulse with a Polystyrene Target

    Institute of Scientific and Technical Information of China (English)

    WANG Feng; PENG Xiao-Shi; JIAO Chun-Ye; LIU Shen-Ye; JIANG Xiao-Hua; DING Yong-Kun

    2011-01-01

    @@ A shock-timing experiment plays an important role in inertial confinement fusion studies, and the timing of multiple shock waves is crucial to the performance of inertial confinement fusion ignition targets.We present an experimental observation of a shock wave driven by a two-step radiation pulse in a polystyrene target.The experiment is carried out at Shen Guang 11 Yuan Xing (SGNYX) laser facility in China, and the generation and coalescence of the two shock waves, originating from each of the two radiation steps, is clearly seen with two velocity interferometers.This two-shock-wave coalescence is also simulated by the radioactive hydrodynamic code of a multi-1D program.The experimental measurements are compared with the simulations and quite good agreements are found, with relatively small discrepancies in shock timing.

  3. Extraction and application of the low dimensional dynamical component from underwater acoustic target radiating noise

    Institute of Scientific and Technical Information of China (English)

    LIANG Juan; LU Jiren

    2001-01-01

    Signal processing in phase space based on nonlinear dynamics theory is a new method for underwater acoustic signal processing. One key problem when analyzing actual acoustic signal in phase space is how to reduce the noise and lower the embedding dimension. In this paper, local-geometric-projection method is applied to obtain low dimensional element from various target radiating noise and the derived phase portraits show obviously low dimensional attractors. Furthermore, attractor dimension and cross prediction error are used for classification. It concludes that combining these features representing the geometric and dynamical properties respectively shows effects in target classification.

  4. Retroperitoneal Sarcoma Target Volume and Organ at Risk Contour Delineation Agreement Among NRG Sarcoma Radiation Oncologists

    Energy Technology Data Exchange (ETDEWEB)

    Baldini, Elizabeth H., E-mail: ebaldini@partners.org [Department of Radiation Oncology, Dana-Farber Cancer Institute, Brigham and Women' s Hospital, Boston, Massachusetts (United States); Abrams, Ross A. [Department of Radiation Oncology, Rush University Medical Center, Chicago, Illinois (United States); Bosch, Walter [Department of Radiation Oncology, Washington University, St. Louis, Missouri (United States); Roberge, David [Department of Radiation Oncology, Centre Hospitalier de l' Universite de Montreal, Montreal, Quebec (Canada); Haas, Rick L.M. [Department of Radiotherapy, Netherlands Cancer Institute, Amsterdam (Netherlands); Catton, Charles N. [Department of Radiation Oncology, Princess Margaret Cancer Centre, Toronto, Ontario (Canada); Indelicato, Daniel J. [Department of Radiation Oncology, University of Florida Medical Center, Jacksonville, Florida (United States); Olsen, Jeffrey R. [Department of Radiation Oncology, Washington University, St. Louis, Missouri (United States); Deville, Curtiland [Department of Radiation Oncology, University of Pennsylvania, Philadelphia, Pennsylvania (United States); Chen, Yen-Lin [Department of Radiation Oncology, Massachusetts General Hospital, Boston, Massachusetts (United States); Finkelstein, Steven E. [Translational Research Consortium, 21st Century Oncology, Scottsdale, Arizona (United States); DeLaney, Thomas F. [Department of Radiation Oncology, Massachusetts General Hospital, Boston, Massachusetts (United States); Wang, Dian [Department of Radiation Oncology, Rush University Medical Center, Chicago, Illinois (United States)

    2015-08-01

    Purpose: The purpose of this study was to evaluate the variability in target volume and organ at risk (OAR) contour delineation for retroperitoneal sarcoma (RPS) among 12 sarcoma radiation oncologists. Methods and Materials: Radiation planning computed tomography (CT) scans for 2 cases of RPS were distributed among 12 sarcoma radiation oncologists with instructions for contouring gross tumor volume (GTV), clinical target volume (CTV), high-risk CTV (HR CTV: area judged to be at high risk of resulting in positive margins after resection), and OARs: bowel bag, small bowel, colon, stomach, and duodenum. Analysis of contour agreement was performed using the simultaneous truth and performance level estimation (STAPLE) algorithm and kappa statistics. Results: Ten radiation oncologists contoured both RPS cases, 1 contoured only RPS1, and 1 contoured only RPS2 such that each case was contoured by 11 radiation oncologists. The first case (RPS 1) was a patient with a de-differentiated (DD) liposarcoma (LPS) with a predominant well-differentiated (WD) component, and the second case (RPS 2) was a patient with DD LPS made up almost entirely of a DD component. Contouring agreement for GTV and CTV contours was high. However, the agreement for HR CTVs was only moderate. For OARs, agreement for stomach, bowel bag, small bowel, and colon was high, but agreement for duodenum (distorted by tumor in one of these cases) was fair to moderate. Conclusions: For preoperative treatment of RPS, sarcoma radiation oncologists contoured GTV, CTV, and most OARs with a high level of agreement. HR CTV contours were more variable. Further clarification of this volume with the help of sarcoma surgical oncologists is necessary to reach consensus. More attention to delineation of the duodenum is also needed.

  5. Protein disulphide isomerase as a target for nanoparticle-mediated sensitisation of cancer cells to radiation

    Science.gov (United States)

    Taggart, L. E.; McMahon, S. J.; Butterworth, K. T.; Currell, F. J.; Schettino, G.; Prise, K. M.

    2016-05-01

    Radiation resistance and toxicity in normal tissues are limiting factors in the efficacy of radiotherapy. Gold nanoparticles (GNPs) have been shown to be effective at enhancing radiation-induced cell death, and were initially proposed to physically enhance the radiation dose deposited. However, biological responses of GNP radiosensitization based on physical assumptions alone are not predictive of radiosensitisation and therefore there is a fundamental research need to determine biological mechanisms of response to GNPs alone and in combination with ionising radiation. This study aimed to identify novel mechanisms of cancer cell radiosensitisation through the use of GNPs, focusing on their ability to induce cellular oxidative stress and disrupt mitochondrial function. Using N-acetyl-cysteine, we found mitochondrial oxidation to be a key event prior to radiation for the radiosensitisation of cancer cells and suggests the overall cellular effects of GNP radiosensitisation are a result of their interaction with protein disulphide isomerase (PDI). This investigation identifies PDI and mitochondrial oxidation as novel targets for radiosensitisation.

  6. Extracorporeal adsorption therapy: A Method to improve targeted radiation delivered by radiometal-labeled monoclonal antibodies.

    Energy Technology Data Exchange (ETDEWEB)

    Nemecek, Eneida R.; Green, Damian J.; Fisher, Darrell R.; Pagal, John M.; Lin, Yukang; Gopal, A. K.; Durack, Lawrence D.; Rajendran, Joseph G.; Wilbur, D. S.; Nilsson, Rune; Sandberg, Bengt; Press, Oliver W.

    2008-04-01

    Many investigators have demonstrated the ability to treat hematologic malignancies with radiolabeled monoclonal antibodies targeting hematopoietic antigens such as anti-CD20 and anti-CD45. [1-5] Although the remission rates achieved with radioimmunotherapy (RIT) are relatively high, many patients subsequently relapse presumably due to suboptimal delivery of enough radiation to eradicate the malignancy. The dose-response of leukemia and lymphoma to radiation has been proven. Substantial amounts of radiation can be delivered by RIT if followed by hematopoietic cell transplantation to rescue the bone marrow from myeloablation.[ref] However, the maximum dose of RIT that can be used is still limited by toxicity to normal tissues affected by nonspecific delivery of radiation. Efforts to improve RIT focus on improving the therapeutic ratios of radiation in target versus non-target tissues by removing the fraction of radioisotope that fails to bind to target tissues and circulates freely in the bloodstream perfusing non-target tissues. Our group and others have explored several alternatives for removal of unbound circulating antibody. [refs] One such method, extracorporeal adsorption therapy (ECAT) consists of removing unbound antibody by a method similar to plasmapheresis after critical circulation time and distribution of antibody into target tissues have been achieved. Preclinical studies of ECAT in murine xenograft models demonstrated significant improvement in therapeutic ratios of radioactivity. Chen and colleagues demonstrated that a 2-hour ECAT procedure could remove 40 to 70% of the radioactivity from liver, lung and spleen. [ref] Although isotope concentration in the tumor was initially unaffected, a 50% decrease was noted approximately 36 hours after the procedure. This approach was also evaluated in a limited phase I pilot study of patients with refractory B-cell lymphoma. [ref] After radiographic confirmation of tumor localization of a test dose of anti-CD20

  7. Comparative study of radiation emission without and with target in a 2.2 kJ plasma focus device

    Energy Technology Data Exchange (ETDEWEB)

    Khan, Muhammad Zubair, E-mail: mzubairkhan-um76@yahoo.com [Plasma Technology Research Center, Department of Physics, Faculty of Science, University Malaya, 50603 Kuala Lumpur Malaysia and Department of Physics, Federal Urdu University of Arts, Science and Technology, 45320 Islamabad (Pakistan); Ling, Yap Seong; San, Wong Chiow [Plasma Technology Research Center, Department of Physics, Faculty of Science, University Malaya, 50603 Kuala Lumpur (Malaysia)

    2014-03-24

    The radiation emission in a 2.2 kJ Mather-type dense plasma focus device is investigated using a five channel BPX65 PIN diode spectrometer. Estimated X-ray associated with the hollow anode without and with target in Argon gas medium is compared. At optimum conditions, the radiation emission from the system is found to be strongly influenced with target in hollow anode and the filling gas pressure. The maximum X-ray yield in 4π sr was obtained in case of hollow anode in argon gas medium with target 'Lead' due to interaction of electron beam. Results indicated that an appropriate design of hollow anode with target could enhance the radiation emission by more intense interaction of expected electron beam with target. The outcomes are helpful in designing a plasma focus with enhanced X-ray radiation with improved shot to shot reproducibility in plasma focus device.

  8. Interactome of Radiation-Induced microRNA-Predicted Target Genes

    Directory of Open Access Journals (Sweden)

    Tenzin W. Lhakhang

    2012-01-01

    Full Text Available The microRNAs (miRNAs function as global negative regulators of gene expression and have been associated with a multitude of biological processes. The dysfunction of the microRNAome has been linked to various diseases including cancer. Our laboratory recently reported modulation in the expression of miRNA in a variety of cell types exposed to ionizing radiation (IR. To further understand miRNA role in IR-induced stress pathways, we catalogued a set of common miRNAs modulated in various irradiated cell lines and generated a list of predicted target genes. Using advanced bioinformatics tools we identified cellular pathways where miRNA predicted target genes function. The miRNA-targeted genes were found to play key roles in previously identified IR stress pathways such as cell cycle, p53 pathway, TGF-beta pathway, ubiquitin-mediated proteolysis, focal adhesion pathway, MAPK signaling, thyroid cancer pathway, adherens junction, insulin signaling pathway, oocyte meiosis, regulation of actin cytoskeleton, and renal cell carcinoma pathway. Interestingly, we were able to identify novel targeted pathways that have not been identified in cellular radiation response, such as aldosterone-regulated sodium reabsorption, long-term potentiation, and neutrotrophin signaling pathways. Our analysis indicates that the miRNA interactome in irradiated cells provides a platform for comprehensive modeling of the cellular stress response to IR exposure.

  9. Effects of target pre-heating and expansion on terahertz radiation production from intense laser-solid interactions

    Institute of Scientific and Technical Information of China (English)

    X.H.Yuan; Y.Fang; D.C.Carroll; D.A.MacLellan; F.Du; N.Booth; M.Burza; M.Chen; R.J.Gray; Y.F.Jin; Y.T.Li; Y.Liu; D.Neely; H.Powell; G.Scott; C.-G.Wahlstrm; J.Zhang; P.McKenna; Z.M.Sheng

    2014-01-01

    The first experimental measurements of intense(~7 × 1019 W cm-2) laser-driven terahertz(THz) radiation from a solid target which is preheated by an intense pulse of laser-accelerated protons is reported. The total energy of the THz radiation is found to decrease by approximately a factor of 2 compared to a cold target reference. This is attributed to an increase in the scale length of the preformed plasma, driven by proton heating, at the front surface of the target,where the THz radiation is generated. The results show the importance of controlling the preplasma scale length for THz production.

  10. Endothelial Adhesion of Targeted Microbubbles in Both Small and Great Vessels Using Ultrasound Radiation Force

    Directory of Open Access Journals (Sweden)

    Jia Liu

    2012-01-01

    Full Text Available The effectiveness of microbubble-mediated ultrasound molecular imaging and drug delivery has been significantly affected by the axial laminar flow of vessels which prevents ultrasound contrast agents (UCAs from targeting vascular endothelium. Studies show that acoustic manipulation could increase targeted UCA adhesion in microcirculation and some small vessels. In this study we demonstrate that ultrasound radiation force (USRF can also significantly enhance the targeted adhesion of microbubbles in both small and great vessels. Our results indicate that the UCA adhesion targeted to ICAM-1 expressed on mouse cremaster microvascular endothelial cells increase about 9-fold when USRF is applied at 1 MHz and 73.9 kPa. The adhesion of anti-CD34 microbubbles to the endothelia of rat abdominal aorta was visually analyzed using scanning electron microscopy for the first time and thousands of microbubbles were found attached to the aortic endothelia after USRF application at the same acoustic parameters. Our data illustrate that targeted adhesion of anti-CD34 microbubbles is possible in normal abdominal aorta and we demonstrate the potential of using USRF in molecular imaging of a vascular target.

  11. Toxicity risk of non-target organs at risk receiving low-dose radiation: case report

    Directory of Open Access Journals (Sweden)

    Chen Yu-Jen

    2009-12-01

    Full Text Available Abstract The spine is the most common site for bone metastases. Radiation therapy is a common treatment for palliation of pain and for prevention or treatment of spinal cord compression. Helical tomotherapy (HT, a new image-guided intensity modulated radiotherapy (IMRT, delivers highly conformal dose distributions and provides an impressive ability to spare adjacent organs at risk, thus increasing the local control of spinal column metastases and decreasing the potential risk of critical organs under treatment. However, there are a lot of non-target organs at risk (OARs occupied by low dose with underestimate in this modern rotational IMRT treatment. Herein, we report a case of a pathologic compression fracture of the T9 vertebra in a 55-year-old patient with cholangiocarcinoma. The patient underwent HT at a dose of 30 Gy/10 fractions delivered to T8-T10 for symptom relief. Two weeks after the radiotherapy had been completed, the first course of chemotherapy comprising gemcitabine, fluorouracil, and leucovorin was administered. After two weeks of chemotherapy, however, the patient developed progressive dyspnea. A computed tomography scan of the chest revealed an interstitial pattern with traction bronchiectasis, diffuse ground-glass opacities, and cystic change with fibrosis. Acute radiation pneumonitis was diagnosed. Oncologists should be alert to the potential risk of radiation toxicities caused by low dose off-targets and abscopal effects even with highly conformal radiotherapy.

  12. The combination of novel targeted molecular agents and radiation in the treatment of pediatric gliomas

    Directory of Open Access Journals (Sweden)

    Tina eDasgupta

    2013-05-01

    Full Text Available Brain tumors are the most common solid pediatric malignancy. For high-grade, recurrent or refractory pediatric brain tumors, radiation therapy (XRT is an integral treatment modality. In the era of personalized cancer therapy, molecularly targeted agents have been designed to inhibit pathways critical to tumorigenesis. Our evolving knowledge of genetic aberrations in low-grade gliomas is being exploited with targeted inhibitors. These agents are also being combined with XRT to increase their efficacy. In this review, we discuss novel agents targeting three different pathways in low-grade gliomas, and their potential combination with XRT. B-Raf is a kinase in the Ras/Raf/MAPK kinase pathway, which is integral to cellular division, survival and metabolism. In low-grade pediatric gliomas, point mutations in BRAF (BRAF V600E or a BRAF fusion mutation (KIAA1549:BRAF causes overactivation of the MEK/MAPK pathway. Pre-clinical data shows cooperation between XRT and tagrgeted inhibitors of BRAF V600E, and MEK and mTOR inhibitors in the gliomas with the BRAF fusion. A second important signaling cascade in pediatric glioma pathogenesis is the PI3 kinase (PI3K/mTOR pathway. Dual PI3K/mTOR inhibitors are poised to enter studies of pediatric tumors. Finally, many brain tumors express potent stimulators of angiogenesis. Several inhibitors of immunomodulators are currently being evaluated in in clinical trials for the treatment of recurrent or refractory pediatric central nervous system (CNS tumors. In summary, combinations of these targeted inhibitors with radiation are currently under investigation in both translational bench research and early clinical trials. We summarize the molecular rationale for, and the pre-clinical data supporting the combinations of these targeted agents with other anti-cancer agents and XRT in pediatric gliomas. Parallels are drawn to adult gliomas, and the molecular mechanisms underlying the efficacy of these agents is discussed

  13. Acoustic-wave generation in the process of CO2-TEA-laser-radiation interaction with metal targets in air

    Science.gov (United States)

    Apostol, Ileana; Teodorescu, G.; Serbanescu-Oasa, Anca; Dragulinescu, Dumitru; Chis, Ioan; Stoian, Razvan

    1995-03-01

    Laser radiation interaction with materials is a complex process in which creation of acoustic waves or stress waves is a part of it. As a function of the laser radiation energy and intensity incident on steel target surface ultrasound signals were registered and studied. Thermoelastic, ablation and breakdown mechanisms of generation of acoustic waves were analyzed.

  14. Targeted overexpression of mitochondrial catalase prevents radiation-induced cognitive dysfunction.

    Science.gov (United States)

    Parihar, Vipan K; Allen, Barrett D; Tran, Katherine K; Chmielewski, Nicole N; Craver, Brianna M; Martirosian, Vahan; Morganti, Josh M; Rosi, Susanna; Vlkolinsky, Roman; Acharya, Munjal M; Nelson, Gregory A; Allen, Antiño R; Limoli, Charles L

    2015-01-01

    Radiation-induced disruption of mitochondrial function can elevate oxidative stress and contribute to the metabolic perturbations believed to compromise the functionality of the central nervous system. To clarify the role of mitochondrial oxidative stress in mediating the adverse effects of radiation in the brain, we analyzed transgenic (mitochondrial catalase [MCAT]) mice that overexpress human catalase localized to the mitochondria. Compared with wild-type (WT) controls, overexpression of the MCAT transgene significantly decreased cognitive dysfunction after proton irradiation. Significant improvements in behavioral performance found on novel object recognition and object recognition in place tasks were associated with a preservation of neuronal morphology. While the architecture of hippocampal CA1 neurons was significantly compromised in irradiated WT mice, the same neurons in MCAT mice did not exhibit extensive and significant radiation-induced reductions in dendritic complexity. Irradiated neurons from MCAT mice maintained dendritic branching and length compared with WT mice. Protected neuronal morphology in irradiated MCAT mice was also associated with a stabilization of radiation-induced variations in long-term potentiation. Stabilized synaptic activity in MCAT mice coincided with an altered composition of the synaptic AMPA receptor subunits GluR1/2. Our findings provide the first evidence that neurocognitive sequelae associated with radiation exposure can be reduced by overexpression of MCAT, operating through a mechanism involving the preservation of neuronal morphology. Our article documents the neuroprotective properties of reducing mitochondrial reactive oxygen species through the targeted overexpression of catalase and how this ameliorates the adverse effects of proton irradiation in the brain.

  15. TNF-alpha inhibitors: Current indications

    Directory of Open Access Journals (Sweden)

    Sharma Rashmi

    2007-01-01

    Full Text Available Advances in the DNA hybrid technology led to the development of various biologicals that specifically target TNF-α. There are currently three anti- TNF- α drugs available- etanercept, infliximab and adalimumab. Etanercept is approved by FDA for rheumatoid arthritis (RA in 2000 followed by its approval for ankylosing spondylitis, psoriasis and psoriatic arthritis. Infliximab and adalimumab are approved by FDA in 2002 for RA. Infliximab is also approved for ankylosing spondylitis, psoriasis, psoriatic arthritis, crohn′s disease and ulcerative colitis and adalimumab for psoriatic arthritis and ankylosing spondylitis. Other conditions like bronchial asthma, diabetes mellitus, malignancies, septic shock, behcet′s disease, bullous dermatitis, neutrophilic dermatitis, toxic epidermal necrolysis, systemic vasculitis, pyoderma gangrenosum, pustular dermatitis, alcoholic hepatitis, cerebral malaria, hemolytic uremic syndrome, pre-eclampsia, allograft rejection, uveitis, otitis media, snakebite, erythema nodosum, myelodysplastic syndromes, graft versus host disease, dermatomyositis and polymyositis are the potential targets for anti-TNF- α therapy. There are resent reports of serious infections like tuberculosis with the use of anti-TNF therapy. In developing country like India these agents should be used with strict pharmaco-vigilance and chemo-prophylaxis for tuberculosis.

  16. A transition radiation detector interleaved with low-density targets for the NOE experiment

    CERN Document Server

    Alexandrov, K V; Bernardini, P; Brigida, M; Campana, D; Candela, A M; Caruso, R; Cassese, F; Ceres, A; D'Aquino, B; De Cataldo, G; De Mitri, I; Di Credico, A; Favuzzi, C; Fusco, P; Gargano, F; Giglietto, N; Giordano, F; Grillo, A; Guarino, F; Gustavino, C; Lamanna, E; Lauro, A; Leone, A; Loparco, F; Mancarella, G; Martello, D; Mazziotta, M N; Mikheyev, S P; Mongelli, M; Osteria, G; Palladino, Vittorio; Passeggio, G; Perchiazzi, M; Pontoniere, G; Rainó, A; Rocco, R; Romanucci, E; Rubizzo, U; Sacchetti, A; Scapparone, E; Spinelli, P; Tikhomirov, V; Vaccina, A; Vanzanella, E; Weber, M

    2001-01-01

    The NOE Collaboration has proposed a transition radiation detector (TRD) interleaved with marble targets to tag the electron decay channel of tau leptons produced by nu /sub tau /, eventually originated by nu /sub mu / oscillations in a long base line experiment. A reduced scale TRD detector prototype has been built and exposed to an electron/pion beam at the CERN PS. Discrimination capabilities between electrons and both charged and neutral pions, representing the main source of background for our measurement, have been determined obtaining rejection factors of the order of the tenth of percent for charged pions, and of a few percent for the neutral pion, matching the experiment requirements. The capabilities of this detector to measure the energy released by particles that start showering inside the targets are shown. A momentum resolution sigma /sub p//P

  17. Recent Developments in the VISRAD 3-D Target Design and Radiation Simulation Code

    Science.gov (United States)

    Macfarlane, Joseph; Woodruff, P.; Golovkin, I.

    2011-10-01

    The 3-D view factor code VISRAD is widely used in designing HEDP experiments at major laser and pulsed-power facilities, including NIF, OMEGA, OMEGA-EP, ORION, Z, and PLX. It simulates target designs by generating a 3-D grid of surface elements, utilizing a variety of 3-D primitives and surface removal algorithms, and can be used to compute the radiation flux throughout the surface element grid by computing element-to-element view factors and solving power balance equations. Target set-up and beam pointing are facilitated by allowing users to specify positions and angular orientations using a variety of coordinates systems (e . g . , that of any laser beam, target component, or diagnostic port). Analytic modeling for laser beam spatial profiles for OMEGA DPPs and NIF CPPs is used to compute laser intensity profiles throughout the grid of surface elements. VISRAD includes a variety of user-friendly graphics for setting up targets and displaying results, can readily display views from any point in space, and can be used to generate image sequences for animations. We will discuss recent improvements to the software package and plans for future developments.

  18. Targeted computerised tomography scanning of the ankle syndesmosis with low dose radiation exposure

    Energy Technology Data Exchange (ETDEWEB)

    Kotwal, Rahul [Princess of Wales Hospital, Bridgend (United Kingdom); Rath, Narendra [Royal Gwent Hospital, Newport (United Kingdom); Paringe, Vishal; Hemmadi, Sandeep; Thomas, Rhys; Lyons, Kath [University Hospital of Wales, Cardiff (United Kingdom)

    2016-03-15

    To devise a new protocol for targeted CT scanning of the distal tibiofibular syndesmosis with minimal radiation exposure to patients. We also aimed to correlate the reduction of the syndesmosis as seen on CT scans with the functional outcome of patients. Prospective study. Forty adults undergoing surgical stabilisation of an acute distal tibiofibular syndesmosis injury were recruited. A targeted five-cut computerised tomography scan protocol was developed. The radiation exposure to the patient with this protocol was only 0.002 mSv. Scans were performed 12 weeks after surgery. The contralateral ankle of every patient was used as a control to determine the accuracy of the reduction of the syndesmosis for that individual patient. American Orthopaedic Foot and Ankle Society (AOFAS) scores were obtained at a minimum of 1 year after surgery. After considering the exclusions, 36 patients formed the study group. A wide variation was observed in the anatomy of the normal syndesmosis. If we considered a difference of more than 2 mm between the normal and injured syndesmosis relationship as significant, 15 (41.6 %) of our patients had a significant difference between the injured and normal sides. AOFAS scores were available for 13 of these patients and were good to excellent in 11(84.6 %). Our study describes a reliable new CT scanning technique for the distal tibiofibular syndesmosis using only five cuts and a low-radiation-dose protocol. Clinical correlation of the findings on the scan with functional outcomes suggests that routine post-operative CT of the syndesmosis is probably not justified. (orig.)

  19. Use of I-131- CRTX for targeting malignant adenocarcinoma in mice: biodistribution and radiation dosimetry

    Energy Technology Data Exchange (ETDEWEB)

    Santos, Raquel Gouvea dos; Soares, Marcella Araugio; Andrade, Henrique Martins de, E-mail: santosr@cdtn.br [Centro de Desenvolvimento da Tecnologia Nuclear (CDTN/CNEN-MG), Belo Horizonte, MG (Brazil); Santos, Marcos Antonio da Cunha [Universidade Federal de Minas Gerais (UFMG), Belo Horizonte, MG (Brazil). Departamento de Estatistica

    2008-07-01

    uptake. In conclusion, {sup 131}I-Crtx had a high concentration in tumor and low concentration in normal organs in mice bearing Erlich tumor. Tumor-to-normal tissue radiation dose ratio, for intratumor injected {sup 131}I-Crtx, were more than 60-fold higher depending on the organ. Our results indicate that Cdt components may provide interesting templates for development of a tool for targeted radiotherapy against adenocarcinoma. (author)

  20. Reducing ion energy spread in hole-boring radiation pressure acceleration by using two-ion-species targets

    CERN Document Server

    Weng, S M; Sheng, Z M

    2014-01-01

    The generation of fast ion beams in the hole-boring radiation pressure acceleration by intense laser pulses has been studied for targets with different ion components. We find that the oscillation of the longitudinal electric field for accelerating ions can be effectively suppressed by using a two-ion-species target, because fast ions from a two-ion-species target are distributed into more bunches and each bunch bears less charge. Consequently, the energy spread of ion beams generated in the hole-boring radiation pressure acceleration can be greatly reduced down to 3.7% according to our numerical simulation.

  1. TNF — EDRN Public Portal

    Science.gov (United States)

    TNF (tumor necrosis factor) is a cytokine involved in many biological processes including cell proliferation, differentiation, apoptosis, lipid metabolism, and coagulation. TNF belongs to the TNF superfamily. It is mainly secreted by macrophages and can induce cell death of certain tumor cell lines. TNF binds to its receptors TNFRSF1A/TNFR1 and TNFRSF1B/TNFBR, through which it functions. It is involved in cellular responses to stimuli such as cytokines and stress and plays a key role in regulating the immune response to infection. This cytokine is a pyrogen, causing fever by direct action or by stimulation of interleukin-1 secretion and is implicated in the induction of cachexia. TNF has been implicated in a variety of diseases, including autoimmune diseases, insulin resistance, and cancer. Knockout studies in mice also suggest this cytokine has a neuroprotective function. TNF is cleaved into two chains, tumor necrosis factor, membrane form and tumor necrosis factor, soluble form.

  2. Anti-TNF-α biotherapies

    DEFF Research Database (Denmark)

    Bendtzen, Klaus

    2012-01-01

    This article discusses the rationale behind recommending immunopharmacological guidance of long-term therapies with genetically engineered anti-TNF-α immunoglobulin constructs. Arguments why therapeutic decision-making should not rely on clinical outcome alone are presented. Central to this is th......This article discusses the rationale behind recommending immunopharmacological guidance of long-term therapies with genetically engineered anti-TNF-α immunoglobulin constructs. Arguments why therapeutic decision-making should not rely on clinical outcome alone are presented. Central....... Large-scale immunopharmacological knowledge of how patients 'handle' TNF-α biopharmaceuticals would also help industry develop more effective and safer TNF-α inhibitors....

  3. TNF signaling inhibition in the CNS: implications for normal brain function and neurodegenerative disease

    Directory of Open Access Journals (Sweden)

    Tansey Malú G

    2008-10-01

    Full Text Available Abstract The role of tumor necrosis factor (TNF as an immune mediator has long been appreciated but its function in the brain is still unclear. TNF receptor 1 (TNFR1 is expressed in most cell types, and can be activated by binding of either soluble TNF (solTNF or transmembrane TNF (tmTNF, with a preference for solTNF; whereas TNFR2 is expressed primarily by microglia and endothelial cells and is preferentially activated by tmTNF. Elevation of solTNF is a hallmark of acute and chronic neuroinflammation as well as a number of neurodegenerative conditions including ischemic stroke, Alzheimer's (AD, Parkinson's (PD, amyotrophic lateral sclerosis (ALS, and multiple sclerosis (MS. The presence of this potent inflammatory factor at sites of injury implicates it as a mediator of neuronal damage and disease pathogenesis, making TNF an attractive target for therapeutic development to treat acute and chronic neurodegenerative conditions. However, new and old observations from animal models and clinical trials reviewed here suggest solTNF and tmTNF exert different functions under normal and pathological conditions in the CNS. A potential role for TNF in synaptic scaling and hippocampal neurogenesis demonstrated by recent studies suggest additional in-depth mechanistic studies are warranted to delineate the distinct functions of the two TNF ligands in different parts of the brain prior to large-scale development of anti-TNF therapies in the CNS. If inactivation of TNF-dependent inflammation in the brain is warranted by additional pre-clinical studies, selective targeting of TNFR1-mediated signaling while sparing TNFR2 activation may lessen adverse effects of anti-TNF therapies in the CNS.

  4. Targeting head and neck cancer stem cells to overcome resistance to photon and carbon ion radiation.

    Science.gov (United States)

    Bertrand, Gérald; Maalouf, Mira; Boivin, Antony; Battiston-Montagne, Priscillia; Beuve, Michael; Levy, Antonin; Jalade, Patrice; Fournier, Claudia; Ardail, Dominique; Magné, Nicolas; Alphonse, Gersende; Rodriguez-Lafrasse, Claire

    2014-02-01

    Although promising new radiation therapy techniques such as hadrontherapy are currently being evaluated in the treatment of head and neck malignancies, local control of head and neck squamous cell carcinoma (HNSCC) remains low. Here, we investigated the involvement of cancer stem-like cells (CSCs) in a radioresistant HNSCC cell line (SQ20B). Stem-like cells SQ20B/SidePopulation(SP)/CD44(+)/ALDH(high) were more resistant to both photon and carbon ion irradiation compared with non-CSCs. This was confirmed by a BrdU labeling experiment, which suggests that CSCs were able to proliferate and to induce tumorigenicity after irradiation. SQ20B/SP/CD44(+)/ALDH(high) were capable of an extended G2/M arrest phase in response to photon or carbon ion irradiation compared with non-CSCs. Moreover, our data strongly suggest that resistance of CSCs may result from an imbalance between exacerbated self-renewal and proliferative capacities and the decrease in apoptotic cell death triggering. In order to modulate these processes, two targeted pharmacological strategies were tested. Firstly, UCN-01, a checkpoint kinase (Chk1) inhibitor, induced the relapse of G2/M arrest and radiosensitization of SQ20B-CSCs. Secondly, all-trans retinoic acid (ATRA) resulted in an inhibition of ALDH activity, and induction of the differentiation and radiosensitization of SQ20B/SP/CD44(+)/ALDH(high) cells. The combination of ATRA and UCN-01 treatments with irradiation drastically decreased the surviving fraction at 2Gy of SQ20B-CSCs from 0.85 to 0.38 after photon irradiation, and from 0.45 to 0.21 in response to carbon ions. Taken together, our results suggest that the combination of UCN-01 and ATRA represent a promising pharmacological-targeted strategy that significantly sensitizes CSCs to photon or carbon ion radiation.

  5. RESULTS OF IMPLEMENTATION OF TARGET PROGRAMS ON RADIATION ACCIDENT REMEDIATION FOR THE PERIOD TO 2010 AND PROSPECTS OF FURTHER ACTIVITIES

    Directory of Open Access Journals (Sweden)

    T. A. Marchenko

    2008-01-01

    Full Text Available The report contains information about measures undertaken by the Ministry of Civil Defense and Emergencies of the Russian Federation in the framework of implementation of the state policy in the field of radiation accidents remediation. Results of works realized in the framework of target programs on remediation of radiation accidents at Chernobyl NPP and Production Association MAYAK, and on problems caused by nuclear weapon tests at Seminalatinsk test site are presented.

  6. Systematic study of target localization for bioluminescence tomography guided radiation therapy

    Energy Technology Data Exchange (ETDEWEB)

    Yu, Jingjing [Department of Radiation Oncology and Molecular Radiation Sciences, Johns Hopkins University, Baltimore, Maryland 21231 and School of Physics and Information Technology, Shaanxi Normal University, Shaanxi 710119 (China); Zhang, Bin; Reyes, Juvenal; Wong, John W.; Wang, Ken Kang-Hsin, E-mail: kwang27@jhmi.edu [Department of Radiation Oncology and Molecular Radiation Sciences, Johns Hopkins University, Baltimore, Maryland 21231 (United States); Iordachita, Iulian I. [Laboratory for Computational Sensing and Robotics, Johns Hopkins University, Baltimore, Maryland 21218 (United States); Lu, Zhihao [Department of Oncology and Department of Surgery, Johns Hopkins University, Baltimore, Maryland 21231 and Key laboratory of Carcinogenesis and Translational Research, Department of GI Oncology, Peking University, Beijing Cancer Hospital and Institute, Beijing 100142 (China); Brock, Malcolm V. [Department of Oncology and Department of Surgery, Johns Hopkins University, Baltimore, Maryland 21231 (United States); Patterson, Michael S. [Department of Medical Physics and Applied Radiation Sciences, McMaster University, Hamilton, Ontario L8S 4L8 (Canada)

    2016-05-15

    Purpose: To overcome the limitation of CT/cone-beam CT (CBCT) in guiding radiation for soft tissue targets, the authors developed a spectrally resolved bioluminescence tomography (BLT) system for the small animal radiation research platform. The authors systematically assessed the performance of the BLT system in terms of target localization and the ability to resolve two neighboring sources in simulations, tissue-mimicking phantom, and in vivo environments. Methods: Multispectral measurements acquired in a single projection were used for the BLT reconstruction. The incomplete variables truncated conjugate gradient algorithm with an iterative permissible region shrinking strategy was employed as the optimization scheme to reconstruct source distributions. Simulation studies were conducted for single spherical sources with sizes from 0.5 to 3 mm radius at depth of 3–12 mm. The same configuration was also applied for the double source simulation with source separations varying from 3 to 9 mm. Experiments were performed in a standalone BLT/CBCT system. Two self-illuminated sources with 3 and 4.7 mm separations placed inside a tissue-mimicking phantom were chosen as the test cases. Live mice implanted with single-source at 6 and 9 mm depth, two sources at 3 and 5 mm separation at depth of 5 mm, or three sources in the abdomen were also used to illustrate the localization capability of the BLT system for multiple targets in vivo. Results: For simulation study, approximate 1 mm accuracy can be achieved at localizing center of mass (CoM) for single-source and grouped CoM for double source cases. For the case of 1.5 mm radius source, a common tumor size used in preclinical study, their simulation shows that for all the source separations considered, except for the 3 mm separation at 9 and 12 mm depth, the two neighboring sources can be resolved at depths from 3 to 12 mm. Phantom experiments illustrated that 2D bioluminescence imaging failed to distinguish two sources

  7. Effect of sheath potential on electromagnetic radiation emitted from the rear surface of a metallic foil target

    Institute of Scientific and Technical Information of China (English)

    2007-01-01

    In ultra-intense laser-matter interactions, intense electric fields formed at the rear surface of a foil target may have strong influences on the motion of energetic electrons, and thereby affect the electromagnetic emissions from the rear surface, usually ascribed to transition radiation. Due to the electric fields, transition radiation occurs twice and bremsstrahlung radiation also happens because the electrons will cross the rear surface twice and have large accelerations.In the optic region, transition radiation is dominant. The radiation spectrum depends on the electric field only when the electrons are monochromatic, and becomes independent of the electric field when the electrons have a broadband momentum distribution. Therefore, in an actual experiment, the electric field at the rear surface of a foil could not be studied just with the measurement of optic emissions. In the terahertz region, both bremsstrahlung and transition radiations should be taken into account, and the radiation power could be enhanced in comparison with that without the inclusion of bremsstrahlung radiation. The frequency at which the maximum terahertz radiation appears depends on the electric field.

  8. The scattering of a bremsstrahlung radiation of electrons with energy 13 and 22 MeV from plane targets

    CERN Document Server

    Asatov, U T

    2002-01-01

    In the present work the characteristics of backward (90 sup d egradiation originating at interaction of a beam of a bremsstrahlung radiation of electrons with energy 13 and 22 MeV with plane targets of different thickness from glass textolite, aluminium, iron, lead and their combination are investigated. The dependence of thickness of saturation of 'forward' scattered gamma radiation, a on angles of detection (theta sub s) and orientation (phi) of plane targets depending on a direction of probing beam was observed for the first time. For the first time, the numerical performances of beams of forward scattered gamma radiation from different targets were investigated and determined depending on their orientation and thickness. The new and corrected data on numerical performances of beams of the inverse scattered gamma radiation is obtained. The distinction in characteristics of beams of the scattered gamma radiation is s...

  9. Improving superficial target delineation in radiation therapy with endoscopic tracking and registration

    Energy Technology Data Exchange (ETDEWEB)

    Weersink, R. A.; Qiu, J.; Hope, A. J.; Daly, M. J.; Cho, B. C. J.; DaCosta, R. S.; Sharpe, M. B.; Breen, S. L.; Chan, H.; Jaffray, D. A. [Radiation Medicine Program, Princess Margaret Hospital, Toronto, Ontario M5G 2M9 (Canada) and Ontario Cancer Institute, University Health Network, Toronto, Ontario M5G 2M9 (Canada); Radiation Medicine Program, Princess Margaret Hospital, Toronto, Ontario M5G 2M9 (Canada); Radiation Medicine Program, Princess Margaret Hospital, Toronto, Ontario M5G 2M9, Canada and Department of Radiation Oncology, University of Toronto, Toronto, Ontario M5G 2M9 (Canada); Radiation Medicine Program, Princess Margaret Hospital, Toronto, Ontario M5G 2M9 (Canada); Radiation Medicine Program, Princess Margaret Hospital, Toronto, Ontario M5G 2M9 (Canada) and Department of Radiation Oncology, University of Toronto, Toronto, Ontario M5G 2M9 (Canada); Radiation Medicine Program, Princess Margaret Hospital, Toronto, Ontario M5G 2M9, Canada and Ontario Cancer Institute, University Health Network, Toronto, Ontario M5G 2M9 (Canada); Radiation Medicine Program, Princess Margaret Hospital, Toronto, Ontario M5G 2M9 (Canada) and Department of Radiation Oncology, University of Toronto, Toronto, Ontario M5G 2M9 (Canada); Radiation Medicine Program, Princess Margaret Hospital, Toronto, Ontario M5G 2M9 (Canada); Radiation Medicine Program, Princess Margaret Hospital, Toronto, Ontario M5G 2M9 (Canada); Department of Radiation Oncology, University of Toronto, Toronto, Ontario M5G 2M9 (Canada) and Ontario Cancer Institute, University Health Network, Toronto, Ontario M5G 2M9 (Canada)

    2011-12-15

    Purpose: Target delineation within volumetric imaging is a critical step in the planning process of intensity modulated radiation therapy. In endoluminal cancers, endoscopy often reveals superficial areas of visible disease beyond what is seen on volumetric imaging. Quantitatively relating these findings to the volumetric imaging is prone to human error during the recall and contouring of the target. We have developed a method to improve target delineation in the radiation therapy planning process by quantitatively registering endoscopic findings contours traced on endoscopic images to volumetric imaging. Methods: Using electromagnetic sensors embedded in an endoscope, 2D endoscopic images were registered to computed tomography (CT) volumetric images by tracking the position and orientation of the endoscope relative to a CT image set. Regions-of-interest (ROI) in the 2D endoscopic view were delineated. A mesh created within the boundary of the ROI was projected onto the 3D image data, registering the ROI with the volumetric image. This 3D ROI was exported to clinical radiation treatment planning software. The precision and accuracy of the procedure was tested on two solid phantoms with superficial markings visible on both endoscopy and CT images. The first phantom was T-shaped tube with X-marks etched on the interior. The second phantom was an anatomically correct skull phantom with a phantom superficial lesion placed on the pharyngeal surface. Markings were contoured on the endoscope images and compared with contours delineated in the treatment planning system based on the CT images. Clinical feasibility was tested on three patients with early stage glottic cancer. Image-based rendering using manually identified landmarks was used to improve the registration. Results: Using the T-shaped phantom with X-markings, the 2D to 3D registration accuracy was 1.5-3.5 mm, depending on the endoscope position relative to the markings. Intraobserver standard variation was 0

  10. Robust broadband beam-forming based on the feature of underwater target radiated noise

    Science.gov (United States)

    Chen, Xin-hua; Liu, Chao; Yu, Hua-bing; Zheng, En-ming; Sun, Chang-yu

    2016-12-01

    To the problem of the unknown underwater target detection, according to the feature that the underwater target radiated noise contains the stable line spectrum, a weighted method based on the main-to-side lobe ratio (MSLR) is proposed for broadband beam-forming. This weighted method can be implemented by using the following steps. Firstly, optimize the spatial spectrum of each frequency unit by the second-order cone programming (SOCP), and obtain the optimized spatial spectrum with lower side lobe. Secondly, construct weighting factors based on the MSLR of the optimized spatial spectrums to from weight factors. Lastly, cumulate the spatial spectrum of each frequency unit via the weight statistical method of this paper. This method can restrain the disturbance of background noise, enhance the output signal-to-noise ratio (SNR), and overcome the difficulty of traditional four-dimensional display. The theoretical analysis and simulation results both verify that this method can well enhance the spatial spectrum of line spectrum units, restrain the spatial spectrum of background noise units, and improve the performance of the broadband beam-forming.

  11. Solar radiation management - on feasibility, side effects, and reaching the 2 degree target

    Science.gov (United States)

    Korhonen, Hannele; Laakso, Anton; Ekholm, Tommi; Maalick, Zubair; Partanen, Antti-Ilari; Kokkola, Harri; Romakkaniemi, Sami

    2015-04-01

    Solar radiation management (SRM), i.e. artificially increasing the reflectivity of the Earth, has been suggested as a fast-response, low-cost method to mitigate the impacts of potential rapid future climate change. We have used 1) large eddy simulations as well as an aerosol-climate model and an earth system model to investigate the feasibility and side effects of two types of SRM (marine cloud brightening and stratospheric sulfur injections) and 2) a sequential decision-making approach to determine strategies that combine emission reductions and an uncertain SRM option to limit global mean temperature increase to 2 degree. Regarding stratospheric injections, we find that a large explosive volcanic eruption taking place while SRM is in full force would result in overcooling of the planet, as expected; however, the radiative and climate effects would be clearly smaller than could be expected from the sum of the effects from volcanic eruption alone or SRM alone. In addition, the stratospheric sulphur load would recover from the eruption faster under SRM and natural conditions. If the eruption took place in the high latitudes, the resulting global forcing would be highly dependent on the season of the eruption. Furthermore, regarding marine cloud brightening we find that the spraying of sea water drops leads to cooling due to evaporation and leads to delay in particle dispersion. This delay enhances particle scavenging, and can influence the efficacy of cloud seeding. In terms of combining emission reductions and SRM to reach the 2° C warming target, we find that before the termination risk for SRM can be completely excluded, the acceptable greenhouse gas emission pathways remain only slightly higher than in scenarios without SRM. More generally, the uncertainties in SRM start time, acceptable magnitude and sustainability mean that it can be only a limited substitute to greenhouse gas (GHG) emission reductions. If an additional constraint for CO2 concentration to

  12. Dosimetric Advantages of Midventilation Compared With Internal Target Volume for Radiation Therapy of Pancreatic Cancer

    Energy Technology Data Exchange (ETDEWEB)

    Lens, Eelco, E-mail: e.lens@amc.uva.nl; Horst, Astrid van der; Versteijne, Eva; Tienhoven, Geertjan van; Bel, Arjan

    2015-07-01

    Purpose: The midventilation (midV) approach can be used to take respiratory-induced pancreatic tumor motion into account during radiation therapy. In this study, the dosimetric consequences for organs at risk and tumor coverage of using a midV approach compared with using an internal target volume (ITV) were investigated. Methods and Materials: For each of the 18 patients, 2 treatment plans (25 × 2.0 Gy) were created, 1 using an ITV and 1 using a midV approach. The midV dose distribution was blurred using the respiratory-induced motion from 4-dimensional computed tomography. The resulting planning target volume (PTV) coverage for this blurred dose distribution was analyzed; PTV coverage was required to be at least V{sub 95%} >98%. In addition, the change in PTV size and the changes in V{sub 10Gy}, V{sub 20Gy}, V{sub 30Gy}, V{sub 40Gy}, D{sub mean} and D{sub 2cc} for the stomach and for the duodenum were analyzed; differences were tested for significance using the Wilcoxon signed-rank test. Results: Using a midV approach resulted in sufficient target coverage. A highly significant PTV size reduction of 13.9% (P<.001) was observed. Also, all dose parameters for the stomach and duodenum, except the D{sub 2cc} of the duodenum, improved significantly (P≤.002). Conclusions: By using the midV approach to account for respiratory-induced tumor motion, a significant PTV reduction and significant dose reductions to the stomach and to the duodenum can be achieved when irradiating pancreatic tumors.

  13. TNF Superfamily: A Growing Saga of Kidney Injury Modulators

    Directory of Open Access Journals (Sweden)

    Maria D. Sanchez-Niño

    2010-01-01

    Full Text Available Members of the TNF superfamily participate in kidney disease. Tumor necrosis factor (TNF and Fas ligand regulate renal cell survival and inflammation, and therapeutic targeting improves the outcome of experimental renal injury. TNF-related apoptosis-inducing ligand (TRAIL and its potential decoy receptor osteoprotegerin are the two most upregulated death-related genes in human diabetic nephropathy. TRAIL activates NF-kappaB in tubular cells and promotes apoptosis in tubular cells and podocytes, especially in a high-glucose environment. By contrast, osteoprotegerin plays a protective role against TRAIL-induced apoptosis. Another family member, TNF-like weak inducer of apoptosis (TWEAK induces inflammation and tubular cell death or proliferation, depending on the microenvironment. While TNF only activates canonical NF-kappaB signaling, TWEAK promotes both canonical and noncanonical NF-kappaB activation in tubular cells, regulating different inflammatory responses. TWEAK promotes the secretion of MCP-1 and RANTES through NF-kappaB RelA-containing complexes and upregulates CCl21 and CCL19 expression through NF-kappaB inducing kinase (NIK- dependent RelB/NF-kappaB2 complexes. In vivo TWEAK promotes postnephrectomy compensatory renal cell proliferation in a noninflammatory milieu. However, in the inflammatory milieu of acute kidney injury, TWEAK promotes tubular cell death and inflammation. Therapeutic targeting of TNF superfamily cytokines, including multipronged approaches targeting several cytokines should be further explored.

  14. Margin selection to compensate for loss of target dose coverage due to target motion during external-beam radiation therapy of the lung.

    Science.gov (United States)

    Foster, W Kyle; Osei, Ernest; Barnett, Rob

    2015-01-08

    The aim of this study is to provide guidelines for the selection of external-beam radiation therapy target margins to compensate for target motion in the lung during treatment planning. A convolution model was employed to predict the effect of target motion on the delivered dose distribution. The accuracy of the model was confirmed with radiochromic film measurements in both static and dynamic phantom modes. 502 unique patient breathing traces were recorded and used to simulate the effect of target motion on a dose distribution. A 1D probability density function (PDF) representing the position of the target throughout the breathing cycle was generated from each breathing trace obtained during 4D CT. Changes in the target D95 (the minimum dose received by 95% of the treatment target) due to target motion were analyzed and shown to correlate with the standard deviation of the PDF. Furthermore, the amount of target D95 recovered per millimeter of increased field width was also shown to correlate with the standard deviation of the PDF. The sensitivity of changes in dose coverage with respect to target size was also determined. Margin selection recommendations that can be used to compensate for loss of target D95 were generated based on the simulation results. These results are discussed in the context of clinical plans. We conclude that, for PDF standard deviations less than 0.4 cm with target sizes greater than 5 cm, little or no additional margins are required. Targets which are smaller than 5 cm with PDF standard deviations larger than 0.4 cm are most susceptible to loss of coverage. The largest additional required margin in this study was determined to be 8 mm.

  15. Treatment of spondyloarthritis beyond TNF-alpha blockade.

    Science.gov (United States)

    Van den Bosch, Filip; Deodhar, Atul

    2014-10-01

    The advent of biologics targeting tumor necrosis factor-alpha (TNF-alpha) has revolutionized the field of rheumatology in general and the treatment of spondyloarthritis (SpA) in particular, since - apart from non-steroidal anti-inflammatory agents - no disease modifying treatments are available for this frequent, inflammatory rheumatic condition. The significant improvements in signs and symptoms observed with TNF-blockers in this group of diseases, have raised the bar with regard to treatment goals, including clinical remission. Even if treatment failure with TNF-blocking agents may be a relatively rare phenomenon, cases of primary non-responders, secondary loss-of-efficacy and intolerance, have been described. Results with abatacept, rituximab and tocilizumab - all effective in the treatment of rheumatoid arthritis - were disappointing, especially in patients that had previously failed anti-TNF therapy. On the other hand, there is increasing evidence that targeting the cytokines of the Th-17 axis is associated with major improvements of skin psoriasis and its associated arthritis. In axial spondyloarthritis, preliminary proof-of-concept studies with ustekinumab and interleukin-17 targeting therapies suggest that these agents could become the first new treatment options, not targeting TNF. Finally, the advent of small molecules targeting inflammatory, intracellular signalling pathways, may further change our future therapeutic approach. Copyright © 2014 Elsevier Ltd. All rights reserved.

  16. The non-targeted effects of radiation are perpetuated by exosomes.

    Science.gov (United States)

    Al-Mayah, Ammar; Bright, Scott; Chapman, Kim; Irons, Sarah; Luo, Ping; Carter, David; Goodwin, Edwin; Kadhim, Munira

    2015-02-01

    Exosomes contain cargo material from endosomes, cytosol, plasma membrane and microRNA molecules, they are released by a number of non-cancer and cancer cells into both the extracellular microenvironment and body fluids such as blood plasma. Recently we demonstrated radiation-induced non-targeted effects [NTE: genomic instability (GI) and bystander effects (BE)] are partially mediated by exosomes, particularly the RNA content. However the mechanistic role of exosomes in NTE is yet to be fully understood. The present study used MCF7 cells to characterise the longevity of exosome-induced activity in the progeny of irradiated and unirradiated bystander cells. Exosomes extracted from conditioned media of irradiated and bystander progeny were added to unirradiated cells. Analysis was carried out at 1 and 20/24 population doublings following medium/exosome transfer for DNA/chromosomal damage. Results confirmed exosomes play a significant role in mediating NTE of ionising radiation (IR). This effect was remarkably persistent, observed >20 doublings post-irradiation in the progeny of bystander cells. Additionally, cell progeny undergoing a BE were themselves capable of inducing BE in other cells via exosomes they released. Furthermore we investigated the role of exosome cargo. Culture media from cells exposed to 2 Gy X-rays was subjected to ultracentrifugation and four inoculants prepared, (a) supernatants with exosomes removed, and pellets with (b) exosome proteins denatured, (c) RNA degraded, and (d) a combination of protein-RNA inactivation. These were added to separate populations of unirradiated cells. The BE was partially inhibited when either exosome protein or exosome RNA were inactivated separately, whilst combined RNA-protein inhibition significantly reduced or eliminated the BE. These results demonstrate that exosomes are associated with long-lived signalling of the NTE of IR. Both RNA and protein molecules of exosomes work in a synergistic manner to initiate NTE

  17. [Mitochondria-targeted antioxidant SkQR1 selectively protects MDR-negative cells against ionizing radiation].

    Science.gov (United States)

    Fetisova, E K; Antoshina, M M; Cherepanynets, V D; Izumov, D S; Kireev, I I; Kireev, R I; Lyamzaev, K G; Riabchenko, N I; Chernyak, B V; Skulachev, V P

    2014-01-01

    Radioprotection appeared to be an important problem of today due to atom energetic development and utilization of radiation material in the industry, science and medicine. It has been shown that mitochondrial targeted antioxidant SkQR1 could attenuate radiation injury of human erythroleukemia K562 cells. Pretreatment with SkQR1 before irradiation decreased DNA double strand breaks formation, diminished the number of chromosomal aberrations and suppressed delayed ROS production. Prevention of oxidative stress and normalization of mitochondrial function by mitochondria-targeted antioxidants may be a potential therapeutic strategy not only against immediate consequences of radiation, but, either against its late consequences such as genomic instability. SkQR1 did not protect against radiation-induced damage the K562 subline with high level of multidrug resistance (MDR) due to SkQR1 extrusion with Pgp 170 MDR pump. We suggest that mitochondria-targeted antioxidants might be used for selective protection of normal cells against radiation-induced damage without interference with radiotherapy of MDR-positive tumors.

  18. p53 activated by AND gate genetic circuit under radiation and hypoxia for targeted cancer gene therapy.

    Science.gov (United States)

    Ding, Miao; Li, Rong; He, Rong; Wang, Xingyong; Yi, Qijian; Wang, Weidong

    2015-09-01

    Radio-activated gene therapy has been developed as a novel therapeutic strategy against cancer; however, expression of therapeutic gene in peritumoral tissues will result in unacceptable toxicity to normal cells. To restrict gene expression in targeted tumor mass, we used hypoxia and radiation tolerance features of tumor cells to develop a synthetic AND gate genetic circuit through connecting radiation sensitivity promoter cArG6 , heat shock response elements SNF1, HSF1 and HSE4 with retroviral vector plxsn. Their construction and dynamic activity process were identified through downstream enhanced green fluorescent protein and wtp53 expression in non-small cell lung cancer A549 cells and in a nude mice model. The result showed that AND gate genetic circuit could be activated by lower required radiation dose (6 Gy) and after activated, AND gate could induce significant apoptosis effects and growth inhibition of cancer cells in vitro and in vivo. The radiation- and hypoxia-activated AND gate genetic circuit, which could lead to more powerful target tumoricidal activity represented a promising strategy for both targeted and effective gene therapy of human lung adenocarcinoma and low dose activation character of the AND gate genetic circuit implied that this model could be further exploited to decrease side-effects of clinical radiation therapy.

  19. Target volume delineation and field setup. A practical guide for conformal and intensity-modulated radiation therapy

    Energy Technology Data Exchange (ETDEWEB)

    Lee, Nancy Y. [Memorial Sloan-Kettering Cancer Center, New York, NY (United States). Radiation Oncology; Lu, Jiade J. (eds.) [National Univ. Health System, Singapore (Singapore). Dept. of Radiation Oncology; National Univ. of Singapore (Singapore). Dept. of Medicine

    2013-03-01

    Practical handbook on selection and delineation of tumor volumes and fields for conformal radiation therapy, including IMRT. Helpful format facilitating use on a step-by-step basis in daily practice. Designed to ensure accurate coverage of commonly encountered tumors along their routes of spread. This handbook is designed to enable radiation oncologists to appropriately and confidently delineate tumor volumes/fields for conformal radiation therapy, including intensity-modulated radiation therapy (IMRT), in patients with commonly encountered cancers. The orientation of this handbook is entirely practical, in that the focus is on the illustration of clinical target volume (CTV) delineation for each major malignancy. Each chapter provides guidelines and concise knowledge on CTV selection for a particular disease, explains how the anatomy of lymphatic drainage shapes the selection of the target volume, and presents detailed illustrations of volumes, slice by slice, on planning CT images. While the emphasis is on target volume delineation for three-dimensional conformal therapy and IMRT, information is also provided on conventional radiation therapy field setup and planning for certain malignancies for which IMRT is not currently suitable.

  20. The non-targeted effects of radiation are perpetuated by exosomes

    Energy Technology Data Exchange (ETDEWEB)

    Al-Mayah, Ammar; Bright, Scott; Chapman, Kim [Genomic Instability Group, Oxford Brookes University, Gipsy Lane Campus, Headington, Oxford OX3 0BP (United Kingdom); Irons, Sarah [Insect Virus Research Group, Oxford Brookes University, Gipsy Lane Campus, Headington, Oxford OX3 0BP (United Kingdom); Luo, Ping [Izon Science Ltd., The Oxford Science Park, Magdalen Centre, Robert Robinson Avenue, Oxford OX4 4GA (United Kingdom); Carter, David [Chromatin and non-coding RNA, Oxford Brookes University, Gipsy Lane Campus, Headington, Oxford OX3 0BP (United Kingdom); Goodwin, Edwin [The New Mexico Consortium, Los Alamos, NM 87544 (United States); Kadhim, Munira, E-mail: mkadhim@brookes.ac.uk [Genomic Instability Group, Oxford Brookes University, Gipsy Lane Campus, Headington, Oxford OX3 0BP (United Kingdom)

    2015-02-15

    Highlights: • Radiation induces a DNA damaging process in bystander cells through cell–cell signalling. • Exosome RNA and protein molecules play crucial roles in bystander effects. • Cell progeny inherit the ability to secret bystander effect-inducing exosomes. • This mechanism is most likely accountable for the propagation of GI. - Abstract: Exosomes contain cargo material from endosomes, cytosol, plasma membrane and microRNA molecules, they are released by a number of non-cancer and cancer cells into both the extracellular microenvironment and body fluids such as blood plasma. Recently we demonstrated radiation-induced non-targeted effects [NTE: genomic instability (GI) and bystander effects (BE)] are partially mediated by exosomes, particularly the RNA content. However the mechanistic role of exosomes in NTE is yet to be fully understood. The present study used MCF7 cells to characterise the longevity of exosome-induced activity in the progeny of irradiated and unirradiated bystander cells. Exosomes extracted from conditioned media of irradiated and bystander progeny were added to unirradiated cells. Analysis was carried out at 1 and 20/24 population doublings following medium/exosome transfer for DNA/chromosomal damage. Results confirmed exosomes play a significant role in mediating NTE of ionising radiation (IR). This effect was remarkably persistent, observed >20 doublings post-irradiation in the progeny of bystander cells. Additionally, cell progeny undergoing a BE were themselves capable of inducing BE in other cells via exosomes they released. Furthermore we investigated the role of exosome cargo. Culture media from cells exposed to 2 Gy X-rays was subjected to ultracentrifugation and four inoculants prepared, (a) supernatants with exosomes removed, and pellets with (b) exosome proteins denatured, (c) RNA degraded, and (d) a combination of protein–RNA inactivation. These were added to separate populations of unirradiated cells. The BE was

  1. NF kappa B activity and target gene expression in the rat brain after one and two exposures to ionizing radiation.

    Science.gov (United States)

    Raju, U; Gumin, G J; Tofilon, P J

    1999-01-01

    The central nervous system injury that can result after radiotherapy has been suggested to involve induced gene expression and cytokine production. We have previously shown that irradiation of primary cultures of rat astrocytes results in the activation of NF kappa B. To determine whether such an effect also occurs in vivo, NF kappa B activity was analyzed in the cerebral cortex of the rat brain after whole body irradiation. After a single dose of 15 Gy, NF kappa B activity was increased by 2 h postirradiation, returning to unirradiated levels by 8 hours. The increase was dose-dependent beginning at 2 Gy and continuing to at least 22.5 Gy. NF kappa B activity in the irradiated cortex was not accompanied by I kappa B alpha degradation. When 7.5 Gy was delivered 24 h before the 15 Gy, the increase in NF kappa B activity after 15 Gy was significantly reduced. These results suggest that an initial exposure to radiation induced a refractory period in the brain during which the susceptibility of NF kappa B to activation by subsequent irradiation was significantly reduced. This period of reduced sensitivity to radiation was also apparent for the induction of the NF kappa B-regulated cytokines IL-1 beta, IL-6, and TNF alpha.

  2. Alternative for anti-TNF antibodies for arthritis treatment.

    Science.gov (United States)

    Paquet, Joseph; Henrionnet, Christel; Pinzano, Astrid; Vincourt, Jean-Baptiste; Gillet, Pierre; Netter, Patrick; Chary-Valckenaere, Isabelle; Loeuille, Damien; Pourel, Jacques; Grossin, Laurent

    2011-10-01

    Tumor necrosis factor-α (TNF-α), a proinflammatory cytokine, plays a key role in the pathogenesis of many inflammatory diseases, including arthritis. Neutralization of this cytokine by anti-TNF-α antibodies has shown its efficacy in rheumatoid arthritis (RA) and is now widely used. Nevertheless, some patients currently treated with anti-TNF-α remain refractory or become nonresponder to these treatments. In this context, there is a need for new or complementary therapeutic strategies. In this study, we investigated in vitro and in vivo anti-inflammatory potentialities of an anti-TNF-α triplex-forming oligonucleotide (TFO), as judged from effects on two rat arthritis models. The inhibitory activity of this TFO on articular cells (synoviocytes and chondrocytes) was verified and compared to that of small interfering RNA (siRNA) in vitro. The use of the anti-TNF-α TFO as a preventive and local treatment in both acute and chronic arthritis models significantly reduced disease development. Furthermore, the TFO efficiently blocked synovitis and cartilage and bone destruction in the joints. The results presented here provide the first evidence that gene targeting by anti-TNF-α TFO modulates arthritis in vivo, thus providing proof-of-concept that it could be used as therapeutic tool for TNF-α-dependent inflammatory disorders.

  3. Honokiol in combination with radiation targets notch signaling to inhibit colon cancer stem cells.

    Science.gov (United States)

    Ponnurangam, Sivapriya; Mammen, Joshua M V; Ramalingam, Satish; He, Zhiyun; Zhang, Youcheng; Umar, Shahid; Subramaniam, Dharmalingam; Anant, Shrikant

    2012-04-01

    Cancer stem cells are implicated in resistance to ionizing radiation (IR) and chemotherapy. Honokiol, a biphenolic compound has been used in traditional Chinese medicine for treating various ailments. In this study, we determined the ability of honokiol to enhance the sensitivity of colon cancer stem cells to IR. The combination of honokiol and IR suppressed proliferation and colony formation while inducing apoptosis of colon cancer cells in culture. There were also reduced numbers and size of spheroids, which was coupled with reduced expression of cancer stem cell marker protein DCLK1. Flow cytometry studies confirmed that the honokiol-IR combination reduced the number of DCLK1+ cells. In addition, there were reduced levels of activated Notch-1, its ligand Jagged-1, and the downstream target gene Hes-1. Furthermore, expression of components of the Notch-1 activating γ-secretase complex, presenilin 1, nicastrin, Pen2, and APH-1 was also suppressed. On the other hand, the honokiol effects were mitigated when the Notch intracellular domain was expressed. To determine the effect of honokiol-IR combination on tumor growth in vivo, nude mice tumor xenografts were administered honokiol intraperitoneally and exposed to IR. The honokiol-IR combination significantly inhibited tumor xenograft growth. In addition, there were reduced levels of DCLK1 and the Notch signaling-related proteins in the xenograft tissues. Together, these data suggest that honokiol is a potent inhibitor of colon cancer growth that targets the stem cells by inhibiting the γ-secretase complex and the Notch signaling pathway. These studies warrant further clinical evaluation for the combination of honokiol and IR for treating colon cancers.

  4. Regulation of tumour necrosis factor (TNF) induced apoptosis by soluble TNF receptors in Helicobacter pylori infection

    OpenAIRE

    Shibata, J; Goto, H.; Arisawa, T.; Niwa, Y.; Hayakawa, T.; Nakayama, A.; Mori, N.

    1999-01-01

    BACKGROUND—Tumour necrosis factor (TNF) is a predominant cytokine produced in the gastric mucosa of patients with Helicobacter pylori infection. TNF induces apoptosis in a variety of cells. The soluble TNF receptors (sTNF-Rs) can be divided into sTNF-RI and sTNF-RII, both of which inhibit TNF activity. However, their precise mechanisms remain unclear.
AIM—To investigate the role of sTNF-Rs in H pylori infection.
METHODS—In 40 patients, production of TNF and sTNF-Rs in gastric mucosa was measu...

  5. Anti-TNF treatment in rheumatoid arthritis.

    Science.gov (United States)

    Geiler, Janina; Buch, Maya; McDermott, Michael F

    2011-01-01

    Rheumatoid arthritis (RA), the most common autoimmune disease, is characterized by persistent synovitis and systemic inflammation. Genetic predisposition as well as autoantibodies and environmental factors, such as smoking, are associated with an increased risk of RA. Traditionally RA has been treated with disease modifying anti-rheumatic drugs (DMARDs) but in the last 15 years or so the introduction of biological response modifiers has revolutionized the treatment of RA. Among these anti-tumor necrosis factor (TNF) agents were the first to be successfully used in treating RA. The goal in treating RA is to induce remission or very low disease activity; remission is now accepted as the ultimate therapeutic goal by adoption of a "treat to target" strategy to achieve tight disease control. Therefore early diagnosis, as well as immediate intervention, are of the utmost importance. This review of the role of TNF in RA pathogenesis describes the mechanisms of action of currently used anti-TNF agents and the adverse events and safety of these drugs. Guidance on the use of anti-TNFs during pregnancy and prior to surgical procedures is also discussed. The intense efforts currently being made to identify biomarkers of response to anti-TNF therapy and recent progress in defining genetic predictors of response using genome- wide association studies (GWAS) are covered. However, so far, none of these studies have been translated into clinical application. The development of biosimilars or follow-on biologicals is also discussed and the first reported study of a biosimilar, involving a multicenter study of an etanercept biosimilar, Etanar, is described.

  6. Locally Targeted Delivery of a Micron-Size Radiation Therapy Source Using Temperature-Sensitive Hydrogel

    Energy Technology Data Exchange (ETDEWEB)

    Kim, Yusung, E-mail: yusung-kim@uiowa.edu [Department of Radiation Oncology, The University of Iowa, Iowa City, Iowa (United States); Seol, Dong Rim [Department of Orthopaedic Surgery, The University of Iowa, Iowa City, Iowa (United States); Mohapatra, Sucheta [Department of Biomedical Engineering, The University of Iowa, Iowa City, Iowa (United States); Sunderland, John J. [Department of Radiology, The University of Iowa, Iowa City, Iowa (United States); Schultz, Michael K. [Department of Radiation Oncology, The University of Iowa, Iowa City, Iowa (United States); Department of Radiology, The University of Iowa, Iowa City, Iowa (United States); Domann, Frederick E. [Department of Radiation Oncology, The University of Iowa, Iowa City, Iowa (United States); Department of Surgery, The University of Iowa, Iowa City, Iowa (United States); Lim, Tae-Hong [Department of Biomedical Engineering, The University of Iowa, Iowa City, Iowa (United States)

    2014-04-01

    Purpose: To propose a novel radiation therapy (RT) delivery modality: locally targeted delivery of micron-size RT sources by using temperature-sensitive hydrogel (RT-GEL) as an injectable vehicle. Methods and Materials: Hydrogel is a water-like liquid at room temperature but gels at body temperature. Two US Food and Drug Administration-approved polymers were synthesized. Indium-111 (In-111) was used as the radioactive RT-GEL source. The release characteristics of In-111 from polymerized RT-GEL were evaluated. The injectability and efficacy of RT-GEL delivery to human breast tumor were tested using animal models with control datasets of RT-saline injection. As proof-of-concept studies, a total of 6 nude mice were tested by injecting 4 million tumor cells into their upper backs after a week of acclimatization. Three mice were injected with RT-GEL and 3 with RT-saline. Single-photon emission computed tomography (SPECT) and CT scans were performed on each mouse at 0, 24, and 48 h after injection. The efficacy of RT-GEL was determined by comparison with that of the control datasets by measuring kidney In-111 accumulation (mean nCi/cc), representing the distant diffusion of In-111. Results: RT-GEL was successfully injected into the tumor by using a 30-gauge needle. No difficulties due to polymerization of hydrogel during injection and intratumoral pressure were observed during RT-GEL injection. No back flow occurred for either RT-GEL or RT-saline. The residual tumor activities of In-111 were 49% at 24 h (44% at 48 h, respectively) for RT-GEL and 29% (22%, respectively) for RT-saline. Fused SPECT-CT images of RT-saline showed considerable kidney accumulation of In-111 (2886%, 261%, and 262% of RT-GEL at 0, 24, and 48 h, respectively). Conclusions: RT-GEL was successfully injected and showed much higher residual tumor activity: 170% (200%, respectively), than that of RT-saline at 24 h (48 h, respectively) after injection with a minimal accumulation of In-111 to the

  7. The role of TNF-α and TNF-β gene polymorphism in the pathogenesis of Rheumatoid Arthritis

    Directory of Open Access Journals (Sweden)

    Hannan Al- Rayes

    2013-01-01

    Full Text Available Rheumatoid arthritis (RA is a chronic systemic inflammatory disorder of unknown etiology that affects the synovial membrane of multiple joints. The clinical presentation of RA may vary from mild to severe with excessive erosions of periarticular bone leading to the loss of functional capacity. Both genetic and environmental factors are important in the development of this disorder. The genetic contribution to susceptibility for RA is underlined by a three-to four-fold higher concordance percentage for clinically expressed disease in monozygotic twins compared to dizygotic twins. The severity and long term outcome of RA have also been related to various genetic factors. Tumor necrosis factor (TNF, a pro-inflammatory cytokine, is involved in the pathogenesis of a variety of autoimmune disorders, including RA. A large number of studies have been undertaken to determine the role of TNF-α promoter polymorphisms in the pathogenesis of RA. On the other hand few attempts have been made to identify the association between TNF-α (lymphotoxin-alfa polymorphism and RA. In this narrative review of published literature, an attempt has been made to determine the association between TNF-α promoter polymorphisms at positions –308, –238, –489, –857, –863 and TNF-β at +252 with respect to susceptibility to and severity of RA, as well as response to drug therapy. In spite of intra-and inter-ethnic variations, analysis of data suggests a significant role of TNF-α/TNF-β polymorphisms in determining the susceptibility/severity of RA and responsiveness to anti-TNF drug therapy. The TNF gene polymorphisms may be an interesting target for novel strategies to prevent RA and/or in its early treatment. Further studies using larger samples are needed to pinpoint the regulatory polymorphisms or haplotypes and their effects on the development of certain manifestations in RA.

  8. Immune and inflammatory responses in TNF alpha-deficient mice: a critical requirement for TNF alpha in the formation of primary B cell follicles, follicular dendritic cell networks and germinal centers, and in the maturation of the humoral immune response

    OpenAIRE

    1996-01-01

    To investigate the role of TNF alpha in the development of in vivo immune response we have generated TNF alpha-deficient mice by gene targeting. Homozygous mutant mice are viable and fertile, develop lymph nodes and Peyer's patches and show no apparent phenotypic abnormalities, indicating that TNF alpha is not required for normal mouse development. In the absence of TNF alpha mice readily succumb to L. monocytogenes infections and show reduced contact hypersensitivity responses. Furthermore, ...

  9. Low Z target switching to increase tumor endothelial cell dose enhancement during gold nanoparticle-aided radiation therapy

    Energy Technology Data Exchange (ETDEWEB)

    Berbeco, Ross I., E-mail: rberbeco@partners.org; Detappe, Alexandre [Department of Radiation Oncology, Brigham and Women’s Hospital, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts 02115 (United States); Tsiamas, Panogiotis [Department of Radiation Oncology, St. Jude Children’s Hospital, Memphis, Tennessee 38105 (United States); Parsons, David; Yewondwossen, Mammo; Robar, James [Department of Radiation Oncology and Department of Physics and Atmospheric Science, Dalhousie University, Halifax, Nova Scotia B3H 1V7 (Canada)

    2016-01-15

    Purpose: Previous studies have introduced gold nanoparticles as vascular-disrupting agents during radiation therapy. Crucial to this concept is the low energy photon content of the therapy radiation beam. The authors introduce a new mode of delivery including a linear accelerator target that can toggle between low Z and high Z targets during beam delivery. In this study, the authors examine the potential increase in tumor blood vessel endothelial cell radiation dose enhancement with the low Z target. Methods: The authors use Monte Carlo methods to simulate delivery of three different clinical photon beams: (1) a 6 MV standard (Cu/W) beam, (2) a 6 MV flattening filter free (Cu/W), and (3) a 6 MV (carbon) beam. The photon energy spectra for each scenario are generated for depths in tissue-equivalent material: 2, 10, and 20 cm. The endothelial dose enhancement for each target and depth is calculated using a previously published analytic method. Results: It is found that the carbon target increases the proportion of low energy (<150 keV) photons at 10 cm depth to 28% from 8% for the 6 MV standard (Cu/W) beam. This nearly quadrupling of the low energy photon content incident on a gold nanoparticle results in 7.7 times the endothelial dose enhancement as a 6 MV standard (Cu/W) beam at this depth. Increased surface dose from the low Z target can be mitigated by well-spaced beam arrangements. Conclusions: By using the fast-switching target, one can modulate the photon beam during delivery, producing a customized photon energy spectrum for each specific situation.

  10. Human biodistribution and radiation dosimetry of novel PET probes targeting the deoxyribonucleoside salvage pathway

    Energy Technology Data Exchange (ETDEWEB)

    Schwarzenberg, Johannes [David Geffen School of Medicine, University of California, Department of Molecular and Medical Pharmacology, Ahmanson Biological Imaging Division, Los Angeles, CA (United States); Medical University of Vienna, Department of Pediatrics, Vienna (Austria); Radu, Caius G.; Tran, Andrew Q.; Phelps, Michael E.; Satyamurthy, Nagichettiar [David Geffen School of Medicine, University of California, Department of Molecular and Medical Pharmacology, Crump Institute for Molecular Imaging, Los Angeles, CA (United States); Benz, Matthias; Fueger, Barbara; Czernin, Johannes; Schiepers, Christiaan [David Geffen School of Medicine, University of California, Department of Molecular and Medical Pharmacology, Ahmanson Biological Imaging Division, Los Angeles, CA (United States); Witte, Owen N. [David Geffen School of Medicine, University of California, Howard Hughes Medical Institute and Department of Microbiology, Immunology, and Molecular Genetics, Los Angeles, CA (United States)

    2011-04-15

    Deoxycytidine kinase (dCK) is a rate-limiting enzyme in deoxyribonucleoside salvage, a metabolic pathway involved in the production and maintenance of a balanced pool of deoxyribonucleoside triphosphates (dNTPs) for DNA synthesis. dCK phosphorylates and therefore activates nucleoside analogs such as cytarabine, gemcitabine, decitabine, cladribine, and clofarabine that are used routinely in cancer therapy. Imaging probes that target dCK might allow stratifying patients into likely responders and nonresponders with dCK-dependent prodrugs. Here we present the biodistribution and radiation dosimetry of three fluorinated dCK substrates, {sup 18}F-FAC, L-{sup 18}F-FAC, and L-{sup 18}F-FMAC, developed for positron emission tomography (PET) imaging of dCK activity in vivo. PET studies were performed in nine healthy human volunteers, three for each probe. After a transmission scan, the radiopharmaceutical was injected intravenously and three sequential emission scans acquired from the base of the skull to mid-thigh. Regions of interest encompassing visible organs were drawn on the first PET scan and copied to the subsequent scans. Activity in target organs was determined and absorbed dose estimated with OLINDA/EXM. The standardized uptake value was calculated for various organs at different times. Renal excretion was common to all three probes. Bone marrow had higher uptake for L-{sup 18}F-FAC and L-{sup 18}F-FMAC than {sup 18}F-FAC. Prominent liver uptake was seen in L-{sup 18}F-FMAC and L-{sup 18}F-FAC, whereas splenic activity was highest for {sup 18}F-FAC. Muscle uptake was also highest for {sup 18}F-FAC. The critical organ was the bladder wall for all three probes. The effective dose was 0.00524, 0.00755, and 0.00910 mSv/MBq for {sup 18}F-FAC, L-{sup 18}F-FAC, and L-{sup 18}F-FMAC, respectively. The biodistribution of {sup 18}F-FAC, L-{sup 18}F-FAC, and L-{sup 18}F-FMAC in humans reveals similarities and differences. Differences may be explained by different probe

  11. TU-F-CAMPUS-T-04: Using Gold Nanoparticles to Target Mitochondria in Radiation Therapy

    Energy Technology Data Exchange (ETDEWEB)

    McNamara, A [Massachusetts General Hospital & Harvard Med. Sch., Boston, MA (United States); McMahon, S [Massachusetts General Hospital, Boston, Ma (United States); Lin, Y [Massachusetts General Hospital and Harvard Medical School, Boston, MA (United States); Paganetti, H; Schuemann, J [Massachusetts General Hospital, Boston, MA (United States); Kuncic, Z [University of Sydney, Sydney, NSW (Australia)

    2015-06-15

    Purpose: The mitochondrion, like the cell nucleus, contains genetic material and plays several critical roles that determine the cell viability, including neutralization of free radicals within the cell. Studies have shown that irradiated cells with impaired mitochondria will incur more damage to the cell nucleus. This study investigates the potential use of GNPs to enhance radiation-induced damage to the organelle. Methods: The compositions of the organelles of a JURKAT cell were determined experimentally. Using Monte Carlo simulations, we investigate the significance of dose enhancement in a monoenergetic (10–50 keV and 6 MeV) x-ray irradiated cell cytoplasm, consisting of the experimentally determined composition. We also investigate the track structure of secondary electrons in the mitochondria using Geant4-DNA in the presence and absence of GNPs for incident protons and photons. The biological effect was determined using an approach based on the local effect model, assuming the mitochondrial DNA (mtDNA) was the primary target. Results: Adding 0.01% of gold to the cell cytoplasm material can cause substantial dose enhancement, dependent on the incident x-ray energy. Track structure Monte Carlo (MC) simulations show an increased number of ionization events within the mitochondrion structure. The close proximity of GNPs to the mtDNA storing nucleoid may cause the mtDNA to receive doses above ∼100 Gy for keV x-rays, leading to mitochondrial dysfunction. Conclusion: A substantial increase in ionization events can occur in the mitochondria in the presence of GNPs. If GNPs can be delivered to tumors and attached to a sufficient number of mitochondria inside the tumor cells, mitochondrial induced cell death could be a prevalent cause of cell death. The biological structures developed here will be included in the biological MC toolkit, TOPAS-nBio.

  12. Are we ready for positron emission tomography/computed tomography-based target volume definition in lymphoma radiation therapy?

    Science.gov (United States)

    Yeoh, Kheng-Wei; Mikhaeel, N George

    2013-01-01

    Fluorine-18 fluorodeoxyglucose (FDG)-positron emission tomography (PET)/computed tomography (CT) has become indispensable for the clinical management of lymphomas. With consistent evidence that it is more accurate than anatomic imaging in the staging and response assessment of many lymphoma subtypes, its utility continues to increase. There have therefore been efforts to incorporate PET/CT data into radiation therapy decision making and in the planning process. Further, there have also been studies investigating target volume definition for radiation therapy using PET/CT data. This article will critically review the literature and ongoing studies on the above topics, examining the value and methods of adding PET/CT data to the radiation therapy treatment algorithm. We will also discuss the various challenges and the areas where more evidence is required.

  13. Transmembrane TNF-α: structure, function and interaction with anti-TNF agents

    OpenAIRE

    Horiuchi, Takahiko; Mitoma, Hiroki; Harashima, Shin-ichi; Tsukamoto, Hiroshi; Shimoda, Terufumi

    2010-01-01

    Transmembrane TNF-α, a precursor of the soluble form of TNF-α, is expressed on activated macrophages and lymphocytes as well as other cell types. After processing by TNF-α-converting enzyme (TACE), the soluble form of TNF-α is cleaved from transmembrane TNF-α and mediates its biological activities through binding to Types 1 and 2 TNF receptors (TNF-R1 and -R2) of remote tissues. Accumulating evidence suggests that not only soluble TNF-α, but also transmembrane TNF-α is involved in the inflamm...

  14. Adaptive Radiation Therapy for Post-Prostatectomy Patients Using Real-Time Electromagnetic Target Motion Tracking During External Beam Radiotherapy

    Science.gov (United States)

    Zhu, Mingyao; Bharat, Shyam; Michalski, Jeff M.; Gay, H; Hou, Wei-Hsien; Parikh, Parag J.

    2012-01-01

    Purpose Using real-time electromagnetic (EM) transponder tracking data recorded by the Calypso® 4D Localization System, we report inter- and intrafractional target motion of the prostate bed, describe a strategy to evaluate treatment adequacy in post-prostatectomy patients receiving intensity modulated radiation therapy (IMRT), and propose an adaptive workflow. Methods and Materials Tracking data recorded by Calypso EM transponders was analyzed for post-prostatectomy patients that underwent step-and-shoot IMRT. Rigid target motion parameters during beam delivery were calculated from recorded transponder positions in 16 patients with rigid transponder geometry. The delivered doses to the clinical target volume (CTV) were estimated from the planned dose matrix and the target motion for the first 3, 5, 10, and all fractions. Treatment adequacy was determined by comparing the delivered minimum dose (Dmin) with the planned Dmin to the CTV. Treatments were considered adequate if the delivered CTV Dmin is at least 95% of the planned CTV Dmin. Results Translational target motion was minimal for all 16 patients (mean: 0.02 cm; range: − 0.12 cm to 0.07 cm). Rotational motion was patient-specific, and maximum pitch, yaw, and roll were 12.2, 4.1, and 10.5 degrees, respectively. We observed inadequate treatments in 5 patients. In these treatments, we observed greater target rotations along with large distances between the CTV centroid and transponder centroid. The treatment adequacy from the initial 10 fractions successfully predicted the overall adequacy in 4 of 5 inadequate treatments and 10 of 11 adequate treatments. Conclusion Target rotational motion could cause under-dosage to partial volume of the post-prostatectomy targets. Our adaptive treatment strategy is applicable to post-prostatectomy patients receiving IMRT to evaluate and improve radiation therapy delivery. PMID:23021439

  15. Dose painting to treat single-lobe prostate cancer with hypofractionated high-dose radiation using targeted external beam radiation: Is it feasible?

    Energy Technology Data Exchange (ETDEWEB)

    Amini, Arya; Westerly, David C.; Waxweiler, Timothy V.; Ryan, Nicole; Raben, David, E-mail: david.raben@ucdenver.edu

    2015-10-01

    Targeted focal therapy strategies for treating single-lobe prostate cancer are under investigation. In this planning study, we investigate the feasibility of treating a portion of the prostate to full-dose external beam radiation with reduced dose to the opposite lobe, compared with full-dose radiation delivered to the entire gland using hypofractionated radiation. For 10 consecutive patients with low- to intermediate-risk prostate cancer, 2 hypofractionated, single-arc volumetric-modulated arc therapy (VMAT) plans were designed. The first plan (standard hypofractionation regimen [STD]) included the entire prostate gland, treated to 70 Gy delivered in 28 fractions. The second dose painting plan (DP) encompassed the involved lobe treated to 70 Gy delivered in 28 fractions, whereas the opposing, uninvolved lobe received 50.4 Gy in 28 fractions. Mean dose to the opposing neurovascular bundle (NVB) was considerably lower for DP vs STD, with a mean dose of 53.9 vs 72.3 Gy (p < 0.001). Mean penile bulb dose was 18.6 Gy for DP vs 19.2 Gy for STD (p = 0.880). Mean rectal dose was 21.0 Gy for DP vs 22.8 Gy for STD (p = 0.356). Rectum V{sub 70} (the volume receiving ≥70 Gy) was 2.01% for DP vs 2.74% for STD (p = 0.328). Bladder V{sub 70} was 1.69% for DP vs 2.78% for STD (p = 0.232). Planning target volume (PTV) maximum dose points were 76.5 and 76.3 Gy for DP and STD, respectively (p = 0.760). This study demonstrates the feasibility of using VMAT for partial-lobe prostate radiation in patients with prostate cancer involving 1 lobe. Partial-lobe prostate plans appeared to spare adjacent critical structures including the opposite NVB.

  16. Effects of tumor necrosis factor-alpha (TNF alpha) in epidermal keratinocytes revealed using global transcriptional profiling.

    Science.gov (United States)

    Banno, Tomohiro; Gazel, Alix; Blumenberg, Miroslav

    2004-07-30

    Identification of tumor necrosis factor-alpha (TNF alpha) as the key agent in inflammatory disorders, e.g. rheumatoid arthritis, Crohn's disease, and psoriasis, led to TNF alpha-targeting therapies, which, although avoiding many of the side-effects of previous drugs, nonetheless causes other side-effects, including secondary infections and cancer. By controlling gene expression, TNF alpha orchestrates the cutaneous responses to environmental damage and inflammation. To define TNF alpha action in epidermis, we compared the transcriptional profiles of normal human keratinocytes untreated and treated with TNF alpha for 1, 4, 24, and 48 h by using oligonucleotide microarrays. We found that TNF alpha regulates not only immune and inflammatory responses but also tissue remodeling, cell motility, cell cycle, and apoptosis. Specifically, TNF alpha regulates innate immunity and inflammation by inducing a characteristic large set of chemokines, including newly identified TNF alpha targets, that attract neutrophils, macrophages, and skin-specific memory T-cells. This implicates TNF alpha in the pathogenesis of psoriasis, fixed drug eruption, atopic and allergic contact dermatitis. TNF alpha promotes tissue repair by inducing basement membrane components and collagen-degrading proteases. Unexpectedly, TNF alpha induces actin cytoskeleton regulators and integrins, enhancing keratinocyte motility and attachment, effects not previously associated with TNF alpha. Also unanticipated was the influence of TNF alpha upon keratinocyte cell fate by regulating cell-cycle and apoptosis-associated genes. Therefore, TNF alpha initiates not only the initiation of inflammation and responses to injury, but also the subsequent epidermal repair. The results provide new insights into the harmful and beneficial TNF alpha effects and define the mechanisms and genes that achieve these outcomes, both of which are important for TNF alpha-targeted therapies.

  17. Quantitative Phosphoproteomics Identifies Filaggrin and other Targets of Ionizing Radiation in a Human Skin Model

    Energy Technology Data Exchange (ETDEWEB)

    Yang, Feng; Waters, Katrina M.; Webb-Robertson, Bobbie-Jo M.; Sowa, Marianne B.; Freiin von Neubeck, Claere H.; Aldrich, Joshua T.; Markillie, Lye Meng; Wirgau, Rachel M.; Gristenko, Marina A.; Zhao, Rui; Camp, David G.; Smith, Richard D.; Stenoien, David L.

    2012-04-17

    Our objective here was to perform a quantitative phosphoproteomic study on a reconstituted human skin tissue to identify low and high dose ionizing radiation dependent signaling in a complex 3-dimensional setting. Application of an isobaric labeling strategy using sham and 3 radiation doses (3, 10, 200 cGy) resulted in the identification of 1113 unique phosphopeptides. Statistical analyses identified 151 phosphopeptides showing significant changes in response to radiation and radiation dose. Proteins responsible for maintaining skin structural integrity including keratins and desmosomal proteins (desmoglein, desmoplakin, plakophilin 1 and 2,) had altered phosphorylation levels following exposure to both low and high doses of radiation. A phosphorylation site present in multiple copies in the linker regions of human profilaggrin underwent the largest fold change. Increased phosphorylation of these sites coincided with altered profilaggrin processing suggesting a role for linker phosphorylation in human profilaggrin regulation. These studies demonstrate that the reconstituted human skin system undergoes a coordinated response to ionizing radiation involving multiple layers of the stratified epithelium that serve to maintain skin barrier functions and minimize the damaging consequences of radiation exposure.

  18. Quantitative phosphoproteomics identifies filaggrin and other targets of ionizing radiation in a human skin model.

    Science.gov (United States)

    Yang, Feng; Waters, Katrina M; Webb-Robertson, Bobbie-Jo; Sowa, Marianne B; von Neubeck, Claere; Aldrich, Josh T; Markillie, Lye Meng; Wirgau, Rachel M; Gritsenko, Marina A; Zhao, Rui; Camp, David G; Smith, Richard D; Stenoien, David L

    2012-05-01

    Our objective here was to perform a quantitative phosphoproteomic study on a reconstituted human skin tissue to identify low- and high-dose ionizing radiation-dependent signalling in a complex three-dimensional setting. Application of an isobaric labelling strategy using sham and three radiation doses (3, 10, 200 cGy) resulted in the identification of 1052 unique phosphopeptides. Statistical analyses identified 176 phosphopeptides showing significant changes in response to radiation and radiation dose. Proteins responsible for maintaining skin structural integrity including keratins and desmosomal proteins (desmoglein, desmoplakin, plakophilin 1, 2 and 3) had altered phosphorylation levels following exposure to both low and high doses of radiation. Altered phosphorylation of multiple sites in profilaggrin linker domains coincided with altered profilaggrin processing suggesting a role for linker phosphorylation in human profilaggrin regulation. These studies demonstrate that the reconstituted human skin system undergoes a coordinated response to both low and high doses of ionizing radiation involving multiple layers of the stratified epithelium that serve to maintain tissue integrity and mitigate effects of radiation exposure.

  19. Target size analysis by radiation inactivation: a large capacity tube rack for irradiation in a Gammacell 220.

    Science.gov (United States)

    Beauregard, G; Giroux, S; Potier, M

    1983-07-15

    Target size analysis by radiation inactivation is now a well-established method to study structure-function relationships in biologically active macromolecules without prior purification or even solubilization. Recently, it was reported that a relatively low-dose-rate but commonly available gamma source such as the Gammacell 220 (Atomic Energy of Canada, Ltd.) can be used to carry out radiation inactivation experiments providing it is appropriately calibrated with enzymes of known radiation sensitivities (G. Beauregard and M. Potier (1982) Anal. Biochem. 122, 379-384). In this report, a tube rack designed to fit into the irradiation chamber of the Gammacell 220 which allows five experiments (at 30 tubes per experiment) to be carried out simultaneously with both standard and unknown samples is described. The dose rates delivered at different positions in the rack were determined by irradiating rat liver cytosolic neuraminidase, an enzyme of known radiation sensitivity. A better than 2.7% agreement was obtained between experimental dose rate and computed values from isodose curves previously published by other authors (O. A. Curzio and H. O. Quaranta (1982) Int. J. Appl. Radiat. Isot. 33, 1-3).

  20. Relationship between chromatin structure and sensitivity to molecularly targeted auger electron radiation therapy.

    NARCIS (Netherlands)

    Terry, S.Y.A.; Vallis, K.A.

    2012-01-01

    PURPOSE: The open structure of euchromatin renders it susceptible to DNA damage by ionizing radiation (IR) compared with compact heterochromatin. The effect of chromatin configuration on the efficacy of Auger electron radiotherapy was investigated. METHODS AND MATERIALS: Chromatin structure was

  1. Amelioration of psoriasis by anti-TNF-alpha RNAi in the xenograft transplantation model

    DEFF Research Database (Denmark)

    Jakobsen, Maria; Stenderup, Karin; Rosada, Cecilia;

    2009-01-01

    RNA as detected in skin biopsies 3 weeks after a single vector injection of lentiviral vectors encoding TNF-alpha shRNA. Our data show efficient lentiviral gene delivery to psoriatic skin and therapeutic applicability of anti-TNF-alpha shRNAs in human skin. These findings validate TNF-alpha mRNA as a target...... molecule for a potential persistent RNA-based treatment of psoriasis and establish the use of small RNA effectors as a novel platform for target validation in psoriasis and other skin disorders.......Tumor necrosis factor-alpha (TNF-alpha) is upregulated in psoriatic skin and represents a prominent target in psoriasis treatment. The level of TNF-alpha-encoding mRNA, however, is not increased in psoriatic skin, and it remains unclear whether intervention strategies based on RNA interference...

  2. Modern Radiation Therapy for Nodal Non-Hodgkin Lymphoma—Target Definition and Dose Guidelines From the International Lymphoma Radiation Oncology Group

    Energy Technology Data Exchange (ETDEWEB)

    Illidge, Tim, E-mail: Tim.Illidge@ics.manchester.ac.uk [Institute of Cancer Sciences, University of Manchester, Manchester Academic Health Sciences Centre, The Christie National Health Service Foundation Trust, Manchester (United Kingdom); Specht, Lena [Department of Oncology and Hematology, Rigshospitalet, University of Copenhagen, Copenhagen (Denmark); Yahalom, Joachim [Department of Radiation Oncology, Memorial Sloan-Kettering Cancer Center, New York, New York (United States); Aleman, Berthe [Department of Radiotherapy, The Netherlands Cancer Institute, Amsterdam (Netherlands); Berthelsen, Anne Kiil [Department of Radiation Oncology and PET Centre, Rigshospitalet, University of Copenhagen, Copenhagen (Denmark); Constine, Louis [Departments of Radiation Oncology and Pediatrics, James P. Wilmot Cancer Center, University of Rochester Medical Center, Rochester, New York (United States); Dabaja, Bouthaina [Division of Radiation Oncology, Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas (United States); Dharmarajan, Kavita [Department of Radiation Oncology, Memorial Sloan-Kettering Cancer Center, New York, New York (United States); Ng, Andrea [Department of Radiation Oncology, Brigham and Women' s Hospital and Dana-Farber Cancer Institute, Harvard University, Boston, Massachusetts (United States); Ricardi, Umberto [Radiation Oncology Unit, Department of Oncology, University of Torino, Torino (Italy); Wirth, Andrew [Division of Radiation Oncology, Peter MacCallum Cancer Institute, St. Andrews Place, East Melbourne (Australia)

    2014-05-01

    Radiation therapy (RT) is the most effective single modality for local control of non-Hodgkin lymphoma (NHL) and is an important component of therapy for many patients. Many of the historic concepts of dose and volume have recently been challenged by the advent of modern imaging and RT planning tools. The International Lymphoma Radiation Oncology Group (ILROG) has developed these guidelines after multinational meetings and analysis of available evidence. The guidelines represent an agreed consensus view of the ILROG steering committee on the use of RT in NHL in the modern era. The roles of reduced volume and reduced doses are addressed, integrating modern imaging with 3-dimensional planning and advanced techniques of RT delivery. In the modern era, in which combined-modality treatment with systemic therapy is appropriate, the previously applied extended-field and involved-field RT techniques that targeted nodal regions have now been replaced by limiting the RT to smaller volumes based solely on detectable nodal involvement at presentation. A new concept, involved-site RT, defines the clinical target volume. For indolent NHL, often treated with RT alone, larger fields should be considered. Newer treatment techniques, including intensity modulated RT, breath holding, image guided RT, and 4-dimensional imaging, should be implemented, and their use is expected to decrease significantly the risk for normal tissue damage while still achieving the primary goal of local tumor control.

  3. Assessment of tumor response to radiation and vascular targeting therapy in mice using quantitative ultrasound spectroscopy

    Energy Technology Data Exchange (ETDEWEB)

    El Kaffas, Ahmed; Sadeghi-Naini, Ali; Falou, Omar; Tran, William Tyler; Czarnota, Gregory J., E-mail: gregory.czarnota@sunnybrook.ca [Department of Radiation Oncology, Sunnybrook Health Sciences Centre, Toronto, Ontario M4N 3M5 (Canada); Imaging Research and Physical Sciences, Sunnybrook Health Sciences Centre, Toronto, Ontario M4N 3M5 (Canada); Departments of Medical Biophysics and Radiation Oncology, Faculty of Medicine, University of Toronto, Toronto, Ontario M5G 1L7 (Canada); Zhou, Stephanie; Fernandes, Jason; Giles, Anoja [Imaging Research and Physical Sciences, Sunnybrook Health Sciences Centre, Toronto, Ontario M4N 3M5 (Canada); Hashim, Amr [Department of Radiation Oncology, Sunnybrook Health Sciences Centre, Toronto, Ontario M4N 3M5, Canada and Imaging Research and Physical Sciences, Sunnybrook Health Sciences Centre, Toronto, Ontario M4N 3M5 (Canada)

    2015-08-15

    Purpose: It is now recognized that the tumor vasculature is in part responsible for regulating tumor responses to radiation therapy. However, the extent to which radiation-based vascular damage contributes to tumor cell death remains unknown. In this work, quantitative ultrasound spectroscopy (QUS) methods were used to investigate the acute responses of tumors to radiation-based vascular treatments. Methods: Tumor xenografts (MDA-MB-231) were treated with single radiation doses of 2 or 8 Gy alone, or in combination with pharmacological agents that modulate vascular radiosensitivity. The midband fit, the slope, and the 0-MHz intercept QUS parameters were obtained from a linear-regression fit to the averaged power spectrum of frequency-dependent ultrasound backscatter and were used to quantify acute tumor responses following treatment administration. Power spectrums were extracted from raw volumetric radio-frequency ultrasound data obtained before and 24 h following treatment administration. These parameters have previously been correlated to tumor cell death. Staining using in situ end labeling, carbonic anhydrase 9 and cluster of differentiation 31 of tumor sections were used to assess cell death, oxygenation, and vasculature distributions, respectively. Results: Results indicate a significant midband fit QUS parameter increases of 3.2 ± 0.3 dBr and 5.4 ± 0.5 dBr for tumors treated with 2 and 8 Gy radiation combined with the antiangiogenic agent Sunitinib, respectively. In contrast, tumors treated with radiation alone demonstrated a significant midband fit increase of 4.4 ± 0.3 dBr at 8 Gy only. Preadministration of basic fibroblast growth factor, an endothelial radioprotector, acted to minimize tumor response following single large doses of radiation. Immunohistochemical analysis was in general agreement with QUS findings; an R{sup 2} of 0.9 was observed when quantified cell death was correlated with changes in midband fit. Conclusions: Results from QUS

  4. Reverse-Contrast Imaging and Targeted Radiation Therapy of Advanced Pancreatic Cancer Models

    Energy Technology Data Exchange (ETDEWEB)

    Thorek, Daniel L.J., E-mail: dthorek1@jhmi.edu [Division of Nuclear Medicine, The Russell H. Morgan Department of Radiology and Radiological Sciences, The Johns Hopkins School of Medicine, Baltimore, MD (United States); Kramer, Robin M. [Tri-Institutional Training Program in Laboratory Animal Medicine and Science, Memorial Sloan-Kettering Cancer Center (MSKCC), Weill Cornell Medical College, The Rockefeller University, New York, NY (United States); Chen, Qing; Jeong, Jeho; Lupu, Mihaela E. [Department of Medical Physics, MSKCC, New York, NY (United States); Lee, Alycia M.; Moynahan, Mary E.; Lowery, Maeve [Department of Medicine, MSKCC, New York, NY (United States); Ulmert, David [Molecular Pharmacology and Chemistry Program, MSKCC, New York, NY (United States); Department of Surgery (Urology), Skåne University Hospital, Malmö (Sweden); Zanzonico, Pat; Deasy, Joseph O.; Humm, John L. [Department of Medical Physics, MSKCC, New York, NY (United States); Russell, James, E-mail: russellj@mskcc.org [Department of Medical Physics, MSKCC, New York, NY (United States)

    2015-10-01

    Purpose: To evaluate the feasibility of delivering experimental radiation therapy to tumors in the mouse pancreas. Imaging and treatment were performed using combined CT (computed tomography)/orthovoltage treatment with a rotating gantry. Methods and Materials: After intraperitoneal administration of radiopaque iodinated contrast, abdominal organ delineation was performed by x-ray CT. With this technique we delineated the pancreas and both orthotopic xenografts and genetically engineered disease. Computed tomographic imaging was validated by comparison with magnetic resonance imaging. Therapeutic radiation was delivered via a 1-cm diameter field. Selective x-ray radiation therapy of the noninvasively defined orthotopic mass was confirmed using γH2AX staining. Mice could tolerate a dose of 15 Gy when the field was centered on the pancreas tail, and treatment was delivered as a continuous 360° arc. This strategy was then used for radiation therapy planning for selective delivery of therapeutic x-ray radiation therapy to orthotopic tumors. Results: Tumor growth delay after 15 Gy was monitored, using CT and ultrasound to determine the tumor volume at various times after treatment. Our strategy enables the use of clinical radiation oncology approaches to treat experimental tumors in the pancreas of small animals for the first time. We demonstrate that delivery of 15 Gy from a rotating gantry minimizes background healthy tissue damage and significantly retards tumor growth. Conclusions: This advance permits evaluation of radiation planning and dosing parameters. Accurate noninvasive longitudinal imaging and monitoring of tumor progression and therapeutic response in preclinical models is now possible and can be expected to more effectively evaluate pancreatic cancer disease and therapeutic response.

  5. Dynamics of wound healing signaling as a potential therapeutic target for radiation-induced tissue damage.

    Science.gov (United States)

    Chung, Yih-Lin; Pui, Newman N M

    2015-01-01

    We hypothesized the histone deacetylase inhibitor phenylbutyrate (PB) has beneficial effects on radiation-induced injury by modulating the expression of DNA repair and wound healing genes. Hamsters received a radiosurgical dose of radiation (40 Gy) to the cheek and were treated with varying PB dosing regimens. Gross alteration of the irradiated cheeks, eating function, histological changes, and gene expression during the course of wound healing were compared between treatment groups. Pathological analysis showed decreased radiation-induced mucositis, facilitated epithelial cell growth, and preventing ulcerative wound formation, after short-term PB treatment, but not after vehicle or sustained PB. The radiation-induced wound healing gene expression profile exhibited a sequential transition from the inflammatory and DNA repair phases to the tissue remodeling phase in the vehicle group. Sustained PB treatment resulted in a prolonged wound healing gene expression profile and delayed the wound healing process. Short-term PB shortened the duration of inflammatory cytokine expression, triggered repeated pulsed expression of cell cycle and DNA repair-regulating genes, and promoted earlier oscillatory expression of tissue remodeling genes. Distinct gene expression patterns between sustained and short-term treatment suggest dynamic profiling of wound healing gene expression can be an important part of a biological therapeutic strategy to mitigate radiation-related tissue injury.

  6. Myeloid and T Cell-Derived TNF Protects against Central Nervous System Tuberculosis

    Science.gov (United States)

    Hsu, Nai-Jen; Francisco, Ngiambudulu M.; Keeton, Roanne; Allie, Nasiema; Quesniaux, Valérie F. J.; Ryffel, Bernhard; Jacobs, Muazzam

    2017-01-01

    Tuberculosis of the central nervous system (CNS-TB) is a devastating complication of tuberculosis, and tumor necrosis factor (TNF) is crucial for innate immunity and controlling the infection. TNF is produced by many cell types upon activation, in particularly the myeloid and T cells during neuroinflammation. Here we used mice with TNF ablation targeted to myeloid and T cell (MT-TNF−/−) to assess the contribution of myeloid and T cell-derived TNF in immune responses during CNS-TB. These mice exhibited impaired innate immunity and high susceptibility to cerebral Mycobacterium tuberculosis infection, a similar phenotype to complete TNF-deficient mice. Further, MT-TNF−/− mice were not able to control T cell responses and cytokine/chemokine production. Thus, our data suggested that collective TNF production by both myeloid and T cells are required to provide overall protective immunity against CNS-TB infection. PMID:28280495

  7. Automatic online adaptive radiation therapy techniques for targets with significant shape change: a feasibility study.

    Science.gov (United States)

    Court, Laurence E; Tishler, Roy B; Petit, Joshua; Cormack, Robert; Chin, Lee

    2006-05-21

    This work looks at the feasibility of an online adaptive radiation therapy concept that would detect the daily position and shape of the patient, and would then correct the daily treatment to account for any changes compared with planning position. In particular, it looks at the possibility of developing algorithms to correct for large complicated shape change. For co-planar beams, the dose in an axial plane is approximately associated with the positions of a single multi-leaf collimator (MLC) pair. We start with a primary plan, and automatically generate several secondary plans with gantry angles offset by regular increments. MLC sequences for each plan are calculated keeping monitor units (MUs) and number of segments constant for a given beam (fluences are different). Bulk registration (3D) of planning and daily CT images gives global shifts. Slice-by-slice (2D) registration gives local shifts and rotations about the longitudinal axis for each axial slice. The daily MLC sequence is then created for each axial slice/MLC leaf pair combination, by taking the MLC positions from the pre-calculated plan with the nearest rotation, and shifting using a beam's-eye-view calculation to account for local linear shifts. A planning study was carried out using two head and neck region MR images of a healthy volunteer which were contoured to simulate a base-of-tongue treatment: one with the head straight (used to simulate the planning image) and the other with the head tilted to the left (the daily image). Head and neck treatment was chosen to evaluate this technique because of its challenging nature, with varying internal and external contours, and multiple degrees of freedom. Shape change was significant: on a slice-by-slice basis, local rotations in the daily image varied from 2 to 31 degrees, and local shifts ranged from -0.2 to 0.5 cm and -0.4 to 0.0 cm in right-left and posterior-anterior directions, respectively. The adapted treatment gave reasonable target coverage (100

  8. Variability of Target and Normal Structure Delineation Using Multimodality Imaging for Radiation Therapy of Pancreatic Cancer

    Energy Technology Data Exchange (ETDEWEB)

    Dalah, Entesar; Moraru, Ion [Department of Radiation Oncology, Medical College of Wisconsin, Milwaukee, Wisconsin (United States); Paulson, Eric [Department of Radiation Oncology, Medical College of Wisconsin, Milwaukee, Wisconsin (United States); Department of Radiology, Medical College of Wisconsin, Milwaukee, Wisconsin (United States); Erickson, Beth [Department of Radiation Oncology, Medical College of Wisconsin, Milwaukee, Wisconsin (United States); Li, X. Allen, E-mail: ali@mcw.edu [Department of Radiation Oncology, Medical College of Wisconsin, Milwaukee, Wisconsin (United States)

    2014-07-01

    Purpose: To explore the potential of multimodality imaging (dynamic contrast–enhanced magnetic resonance imaging [DCE-MRI], apparent diffusion-coefficient diffusion-weighted imaging [ADC-DWI], fluorodeoxyglucose positron emission tomography [FDG-PET], and computed tomography) to define the gross tumor volume (GTV) and organs at risk in radiation therapy planning for pancreatic cancer. Delineated volumetric changes of DCE-MRI, ADC-DWI, and FDG-PET were assessed in comparison with the finding on 3-dimensional/4-dimensional CT with and without intravenous contrast, and with pathology specimens for resectable and borderline resectable cases of pancreatic cancer. Methods and Materials: We studied a total of 19 representative patients, whose DCE-MRI, ADC-DWI, and FDG-PET data were reviewed. Gross tumor volume and tumor burden/active region inside pancreatic head/neck or body were delineated on MRI (denoted GTV{sub DCE}, and GTV{sub ADC}), a standardized uptake value (SUV) of 2.5, 40%SUVmax, and 50%SUVmax on FDG-PET (GTV2.5, GTV{sub 40%}, and GTV{sub 50%}). Volumes of the pancreas, duodenum, stomach, liver, and kidneys were contoured according to CT (V{sub CT}), T1-weighted MRI (V{sub T1}), and T2-weighted MRI (V{sub T2}) for 7 patients. Results: Significant statistical differences were found between the GTVs from DCE-MRI, ADC-DW, and FDG-PET, with a mean and range of 4.73 (1.00-9.79), 14.52 (3.21-25.49), 22.04 (1.00-45.69), 19.10 (4.84-45.59), and 9.80 (0.32-35.21) cm{sup 3} for GTV{sub DCE}, GTV{sub ADC}, GTV2.5, GTV{sub 40%}, and GTV{sub 50%}, respectively. The mean difference and range in the measurements of maximum dimension of tumor on DCE-MRI, ADC-DW, SUV2.5, 40%SUVmax, and 50%SUVmax compared with pathologic specimens were −0.84 (−2.24 to 0.9), 0.41 (−0.15 to 2.3), 0.58 (−1.41 to 3.69), 0.66 (−0.67 to 1.32), and 0.15 (−1.53 to 2.38) cm, respectively. The T1- and T2-based volumes for pancreas, duodenum, stomach, and liver were generally smaller

  9. Radiation inactivation (target size analysis) of the gonadotropin-releasing hormone receptor: evidence for a high molecular weight complex

    Energy Technology Data Exchange (ETDEWEB)

    Conn, P.M.; Venter, J.C.

    1985-04-01

    In the present study we used radiation inactivation (target size analysis) to measure the functional mol wt of the GnRH receptor while it is still a component of the plasma membrane. This technique is based on the observation that an inverse relationship exists between the dose-dependent inactivation of a macromolecule by ionizing radiation and the size of that macromolecule. This method demonstrates a mol wt of 136,346 +/- 8120 for the GnRH receptor. This estimate is approximately twice that obtained (60,000) by photoaffinity labeling with a radioactive GnRH analog followed by electrophoresis under denaturing conditions and, accordingly, presents the possibility that the functional receptor consists of a high mol wt complex in its native state. The present studies indicate that the GnRH receptor is either a single weight class of protein or several closely related weight classes, such as might occur due to protein glycosylation.

  10. Experimental Study on Fast Electrons Transport in Ultra-intense Laser Irradiated Solid Targets by Transition Radiation

    Science.gov (United States)

    Zhijian, Zheng; Guangcan, Wang; Yuqiu, Gu

    2008-11-01

    The experiment was performed with SILEX laser facility(Ti-saphhire) at LFRC in China. The SILEX parameter: wavelength 0.8μm, duration 35fs, output power 280TW, contrast 5*105, The focal spot φ10μm(F/1.7), intensity on target surface 1*10^19W/cm^2(F/3). The main diagnostic equipments are the electron spectrometer, OMA spectrometer, optical streak camera. Some experimental results are given: The spectrum of optical emission from rear surface is rather narrow around some particular frequencies(1φ, 2φ, 3φ), We ascribe and confirm that the spike-like spectral line that is coherent transition radiation; The coherent light is also seen on time-integrated image with ring-patter due to Weibel instability of the fast electron transport; Obtained experimental cure of target thickness vs OTR image intensity is relative to mean free path of fast electron; The measuring optical transition radiation(OTR) duration of 171ps much longer than 1ps duration of fast electron transport target, the possible explanation is that the OTR duration to be determined magnetic diffusion time.

  11. The controversial role of TNF in melanoma

    DEFF Research Database (Denmark)

    Donia, Marco; Kjeldsen, Julie Westerlin; Svane, Inge Marie

    2016-01-01

    TNF has been associated with both inhibition and promotion of tumor growth. We recently described a mechanism by which tumor cells attract TNF producing cells via expression of MHC class II molecules....

  12. Molecular mechanism of TNF signaling and beyond

    Institute of Scientific and Technical Information of China (English)

    Zheng-gang LIU

    2005-01-01

    Tumor necrosis factor (TNF) is a proinflammatory cytokine that plays a critical role in diverse cellular events,including cell proliferation, differentiation and apoptosis. TNF is also involved in many types of diseases. In recent years, the molecular mechanisms of TNF functions have been intensively investigated. Studies from many laboratories have demonstrated that the TNF-mediated diverse biological responses are achieved through activating multiple signaling pathways. Especially the activation of transcription factors NF-κB and AP-1 plays a critical role in mediating these cellular responses. Several proteins, including FADD, the death domain kinase RIP and the TNF receptor associated factor TRAF2 have been identified as the key effectors of TNF signaling. Recently, we found that the effector molecules of TNF signaling, such as RIP and TRAF2, are also involved in other cellular responses. These finding suggests that RIP and TRAF2 serve a broader role than as just an effector of TNF signaling.

  13. Burning up TNF toxicity for cancer therapy

    OpenAIRE

    Leist, Marcel; Jäättelä, Marja

    2002-01-01

    The tumor-killing capacity and the systemic toxicity of the cytokine tumor necrosis factor (TNF) have appeared inseparable. Now a study shows that TNF loses its toxicity but still kills tumors in heat-treated mice.

  14. Threshold segmentation for PET target volume delineation in radiation treatment planning: the role of target-to-background ratio and target size.

    Science.gov (United States)

    Brambilla, M; Matheoud, R; Secco, C; Loi, G; Krengli, M; Inglese, E

    2008-04-01

    A multivariable approach was adopted to study the dependence of the percentage threshold [TH(%)] used to define the boundaries of 18F-FDG positive tissue on emission scan duration (ESD) and activity at the start of acquisition (Aacq) for different target sizes and target-to-background (T/B) ratios. An anthropomorphic model, at least for counting rate characteristics, was used to study this dependence in conditions resembling the ones that can be encountered in the clinical studies. An annular ring of water bags of 3 cm thickness was fitted over an International Electro-technical Commission (IEC) phantom in order to obtain counting rates similar to those found in average patients. The scatter fraction of the modified IEC phantom was similar to the mean scatter fraction measured on patients, with a similar scanner. A supplemental set of microhollow spheres was positioned inside the phantom. The NEMA NU 2-2001 scatter phantom was positioned at the end of the IEC phantom to approximate the clinical situation of having activity that extends beyond the scanner field of view. The phantoms were filled with a solution of water and 18F (12 kBq/mL) and the spheres with various T/B ratios of 22.5, 10.3, and 3.6. Sequential imaging was performed to acquire PET images with varying background activity concentrations of about 12, 9, 6.4, 5.3, and 3.1 kBq/mL. The ESD was set to 60, 120, 180, and 240 s/bed. Data were fitted using two distinct multiple linear regression models for sphere ID 10 mm. The fittings of both models were good with an R2 of 0.86 in both cases. Neither ESD nor Aacq resulted as significant predictors of the TH(%). For sphere ID 10 mm the explanatory power of the target size and T/B ratio were reversed, the T/B ratio being now the most important predictor of the TH(%). Both the target size and T/B ratio play a major role in explaining the variance of the TH(%), throughout the whole range of target sizes and T/B ratios examined. Thus, algorithms aimed at

  15. Augmentation of radiation response by motesanib, a multikinase inhibitor that targets vascular endothelial growth factor receptors.

    NARCIS (Netherlands)

    Kruser, T.J.; Wheeler, D.L.; Armstrong, E.A.; Iida, M.; Kozak, K.R.; Kogel, A.J. van der; Bussink, J.; Coxon, A.; Polverino, A.; Harari, P.M.

    2010-01-01

    BACKGROUND: Motesanib is a potent inhibitor of vascular endothelial growth factor receptors (VEGFR) 1, 2, and 3, platelet-derived growth factor receptor, and Kit receptors. In this report we examine the interaction between motesanib and radiation in vitro and in head and neck squamous cell carcinoma

  16. Treatment outcome of radiation therapy and concurrent targeted molecular therapy in spinal metastasis from renal cell carcinoma

    Energy Technology Data Exchange (ETDEWEB)

    Park, Sang Joon; Kim, Kyung Hwan; Rhee, Woo Joong; Lee, Jeong Shin; Cho, Yeo Na; Koom, Woong Sub [Dept. of Radiation Oncology, Yonsei University College of Medicine, Seoul (Korea, Republic of)

    2016-06-15

    To evaluate the clinical outcomes of patients who underwent radiation therapy with or without targeted molecular therapy for the treatment of spinal metastasis from renal cell carcinoma (RCC). A total of 28 spinal metastatic lesions from RCC patients treated with radiotherapy between June 2009 and June 2015 were retrospectively reviewed. Thirteen lesions were treated concurrently with targeted molecular therapy (concurrent group) and 15 lesions were not (nonconcurrent group). Local control was defined as lack of radiographically evident local progression and neurological deterioration. At a median follow-up of 11 months (range, 2 to 58 months), the 1-year local progression-free rate (LPFR) was 67.0%. The patients with concurrent targeted molecular therapy showed significantly higher LPFR than those without (p = 0.019). After multivariate analysis, use of concurrent targeted molecular therapy showed a tendency towards improved LPFR (hazard ratio, 0.13; 95% confidence interval, 0.01 to 1.16). There was no difference in the incidence of systemic progression between concurrent and nonconcurrent groups. No grade ≥2 toxicities were observed during or after radiotherapy. Our study suggests the possibility that concurrent use of targeted molecular therapy during radiotherapy may improve LPFR. Further study with a large population is required to confirm these results.

  17. Impaired on/off regulation of TNF biosynthesis in mice lacking TNF AU-rich elements: implications for joint and gut-associated immunopathologies.

    Science.gov (United States)

    Kontoyiannis, D; Pasparakis, M; Pizarro, T T; Cominelli, F; Kollias, G

    1999-03-01

    We addressed the impact of deleting TNF AU-rich elements (ARE) from the mouse genome on the regulation of TNF biosynthesis and the physiology of the host. Absence of the ARE affected mechanisms responsible for TNF mRNA destabilization and translational repression in hemopoietic and stromal cells. In stimulated conditions, TNF ARE were required both for the alleviation and reinforcement of message destabilization and translational silencing. Moreover, the mutant mRNA was no longer responsive to translational modulation by the p38 and JNK kinases, demonstrating that TNF ARE are targets for these signals. Development of two specific pathologies in mutant mice, i.e., chronic inflammatory arthritis and Crohn's-like inflammatory bowel disease, suggests that defective function of ARE may be etiopathogenic for the development of analogous human pathologies.

  18. TARGET:?

    National Research Council Canada - National Science Library

    James M Acton

    2014-01-01

      By 2003. as military planners had become worried that the country's long-range conventional weapons, such as cruise missiles, might be too slow to reach hypothetical distant targets that needed to be struck urgently...

  19. Interaction of the radiation of the high-power ytterbium-fiber laser with inhomogeneous dielectric targets

    OpenAIRE

    Lisenkov, V. V.; Osipov, V. V.; Platonov, V. V.

    2013-01-01

    The action of the radiation of the ytterbium-fiber laser (λ = 1.07 μm) on the Nd3+Y2O3 target with nonuniform transparency in the course of the nanopowder production is studied. It is demonstrated that the laser irradiation leads to an extremely rough surface with the stalagmite roughness due to a relatively large melting depth. The resulting powder consists of two fractions. The first fraction (99% of the total mass of the powder) consists of nanoparticles with a mean size of 29 nm (BET data...

  20. Impact of [{sup 11}C]Methionine Positron Emission Tomography for Target Definition of Glioblastoma Multiforme in Radiation Therapy Planning

    Energy Technology Data Exchange (ETDEWEB)

    Matsuo, Masayuki, E-mail: matsuo@kizawa-memorial-hospital.jp [Department of Radiation Oncology, Kizawa Memorial Hospital, Minokamo (Japan); Miwa, Kazuhiro [Chubu Medical Center for Prolonged Traumatic Brain Dysfunction and Department of Clinical Brain Sciences, Gifu University Graduate School of Medicine, Minokamo (Japan); Tanaka, Osamu [Department of Radiation Oncology, Kizawa Memorial Hospital, Minokamo (Japan); Shinoda, Jun [Chubu Medical Center for Prolonged Traumatic Brain Dysfunction and Department of Clinical Brain Sciences, Gifu University Graduate School of Medicine, Minokamo (Japan); Nishibori, Hironori; Tsuge, Yusuke [Department of Radiology, Kizawa Memorial Hospital, Minokamo (Japan); Yano, Hirohito; Iwama, Toru [Department of Neurosurgery, Gifu University School of Medicine, Gifu (Japan); Hayashi, Shinya; Hoshi, Hiroaki [Department of Radiology, Gifu University School of Medicine, Gifu (Japan); Yamada, Jitsuhiro [Chubu Medical Center for Prolonged Traumatic Brain Dysfunction and Department of Clinical Brain Sciences, Gifu University Graduate School of Medicine, Minokamo (Japan); Kanematsu, Masayuki [Department of Radiology, Gifu University School of Medicine, Gifu (Japan); Aoyama, Hidefumi [Department of Radiology, Niigata University School of Medicine, Niigata (Japan)

    2012-01-01

    Purpose: The purpose of this work was to define the optimal margins for gadolinium-enhanced T{sub 1}-weighted magnetic resonance imaging (Gd-MRI) and T{sub 2}-weighted MRI (T{sub 2}-MRI) for delineating target volumes in planning radiation therapy for postoperative patients with newly diagnosed glioblastoma multiforme (GBM) by comparison to carbon-11-labeled methionine positron emission tomography ([{sup 11}C]MET-PET) findings. Methods and Materials: Computed tomography (CT), MRI, and [{sup 11}C]MET-PET were separately performed for radiation therapy planning for 32 patients newly diagnosed with GBM within 2 weeks after undergoing surgery. The extent of Gd-MRI (Gd-enhanced clinical target volume [CTV-Gd]) uptake and that of T{sub 2}-MRI of the CTV (CTV-T{sub 2}) were compared with the extent of [{sup 11}C]MET-PET (CTV--[{sup 11}C]MET-PET) uptake by using CT--MRI or CT--[{sup 11}C]MET-PET fusion imaging. We defined CTV-Gd (x mm) and CTV-T{sub 2} (x mm) as the x-mm margins (where x = 0, 2, 5, 10, and 20 mm) outside the CTV-Gd and the CTV-T{sub 2}, respectively. We evaluated the relationship between CTV-Gd (x mm) and CTV-- [{sup 11}C]MET-PET and the relationship between CTV-T{sub 2} (x mm) and CTV-- [{sup 11}C]MET-PET. Results: The sensitivity of CTV-Gd (20 mm) (86.4%) was significantly higher than that of the other CTV-Gd. The sensitivity of CTV-T{sub 2} (20 mm) (96.4%) was significantly higher than that of the other CTV-T{sub 2} (x = 0, 2, 5, 10 mm). The highest sensitivity and lowest specificity was found with CTV-T{sub 2} (x = 20 mm). Conclusions: It is necessary to use a margin of at least 2 cm for CTV-T{sub 2} for the initial target planning of radiation therapy. However, there is a limit to this setting in defining the optimal margin for Gd-MRI and T{sub 2}-MRI for the precise delineation of target volumes in radiation therapy planning for postoperative patients with GBM.

  1. Infection of epithelial cells with Chlamydia trachomatis inhibits TNF-induced apoptosis at the level of receptor internalization while leaving non-apoptotic TNF-signalling intact.

    Science.gov (United States)

    Waguia Kontchou, Collins; Tzivelekidis, Tina; Gentle, Ian E; Häcker, Georg

    2016-11-01

    Chlamydia trachomatis is an obligate intracellular bacterial pathogen of medical importance. C. trachomatis develops inside a membranous vacuole in the cytosol of epithelial cells but manipulates the host cell in numerous ways. One prominent effect of chlamydial infection is the inhibition of apoptosis in the host cell, but molecular aspects of this inhibition are unclear. Tumour necrosis factor (TNF) is a cytokine with important roles in immunity, which is produced by immune cells in chlamydial infection and which can have pro-apoptotic and non-apoptotic signalling activity. We here analysed the signalling through TNF in cells infected with C. trachomatis. The pro-apoptotic signal of TNF involves the activation of caspase-8 and is controlled by inhibitor of apoptosis proteins. We found that in C. trachomatis-infected cells, TNF-induced apoptosis was blocked upstream of caspase-8 activation even when inhibitor of apoptosis proteins were inhibited or the inhibitor of caspase-8 activation, cFLIP, was targeted by RNAi. However, when caspase-8 was directly activated by experimental over-expression of its upstream adapter Fas-associated protein with death domain, C. trachomatis was unable to inhibit apoptosis. Non-apoptotic TNF-signalling, particularly the activation of NF-κB, initiates at the plasma membrane, while the activation of caspase-8 and pro-apoptotic signalling occur subsequently to internalization of TNF receptor and the formation of a cytosolic signalling complex. In C. trachomatis-infected cells, NF-κB activation through TNF was unaffected, while the internalization of the TNF-TNF-receptor complex was blocked, explaining the lack of caspase-8 activation. These results identify a dichotomy of TNF signalling in C. trachomatis-infected cells: Apoptosis is blocked at the internalization of the TNF receptor, but non-apoptotic signalling through this receptor remains intact, permitting a response to this cytokine at sites of infection.

  2. Low-Z linac targets for low-MV gold nanoparticle radiation therapy

    Energy Technology Data Exchange (ETDEWEB)

    Tsiamas, P.; Mishra, P.; Berbeco, R. I.; Marcus, K.; Zygmanski, P., E-mail: pzygmanski@lroc.harvard.edu, E-mail: Erno-Sajo@uml.edu [Department of Radiation Oncology, Brigham and Women' s Hospital, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts 02215 (United States); Cifter, F.; Sajo, E., E-mail: pzygmanski@lroc.harvard.edu, E-mail: Erno-Sajo@uml.edu [Medical Physics Program, Department of Physics and Applied Physics, University of Massachusetts Lowell, Lowell, Massachusetts 01854 (United States)

    2014-02-15

    Purpose: To investigate the potential of low-Z/low-MV (low-Z) linac targets for gold nanoparticle radiotherapy (GNPT) and to determine the microscopic dose enhancement ratio (DER) due to GNP for the alternative beamlines. In addition, to evaluate the degradation of dose enhancement arising from the increased attenuation of x rays and larger skin dose in water for the low-MV beams compared to the standard linac. Methods: Monte Carlo simulations were used to compute dose and DER for various flattening-filter-free beams (2.5, 4, 6.5 MV). Target materials were beryllium, diamond, and tungsten-copper high-Z target. Target thicknesses were selected based on 20%, 60%, 70%, and 80% of the continuous slowing down approximation electron ranges for a given target material and energy. Evaluation of the microscopic DER was carried out for 100 nm GNP including the degradation factors due to beam attenuation. Results: The greatest increase in DER compared to the standard 6.5 MV linac was for a 2.5 MV Be-target (factor of ∼2). Skin dose ranged from ∼10% (Be, 6.5 MV-80%) to ∼85% (Be, 2.5 MV-20%) depending on the target case. Attenuation of 2.5 MV beams at 22 cm was higher by ∼75% compared with the standard beam. Taking into account the attenuation at 22 cm depth, the effective dose enhancement was up to ∼60% above the DER of the high-Z target. For these cases the effective DER ranged between ∼1.6 and 6 compared with the standard linac. Conclusions: Low-Z (2.5 MV) GNPT is possible even after accounting for greater beam attenuation for deep-seated tumors (22 cm) and the increased skin dose. Further, it can lead to significant sparing of normal tissue while simultaneously escalating the dose in the tumor cells.

  3. Bright betatronlike x rays from radiation pressure acceleration of a mass-limited foil target.

    Science.gov (United States)

    Yu, Tong-Pu; Pukhov, Alexander; Sheng, Zheng-Ming; Liu, Feng; Shvets, Gennady

    2013-01-25

    By using multidimensional particle-in-cell simulations, we study the electromagnetic emission from radiation pressure acceleration of ultrathin mass-limited foils. When a circularly polarized laser pulse irradiates the foil, the laser radiation pressure pushes the foil forward as a whole. The outer wings of the pulse continue to propagate and act as a natural undulator. Electrons move together with ions longitudinally but oscillate around the latter transversely, forming a self-organized helical electron bunch. When the electron oscillation frequency coincides with the laser frequency as witnessed by the electron, betatronlike resonance occurs. The emitted x rays by the resonant electrons have high brightness, short durations, and broad band ranges which may have diverse applications.

  4. Inactivation of TNF Signaling by Rationally Designed Dominant-Negative TNF Variants

    Science.gov (United States)

    Steed, Paul M.; Tansey, Malú G.; Zalevsky, Jonathan; Zhukovsky, Eugene A.; Desjarlais, John R.; Szymkowski, David E.; Abbott, Christina; Carmichael, David; Chan, Cheryl; Cherry, Lisa; Cheung, Peter; Chirino, Arthur J.; Chung, Hyo H.; Doberstein, Stephen K.; Eivazi, Araz; Filikov, Anton V.; Gao, Sarah X.; Hubert, René S.; Hwang, Marian; Hyun, Linus; Kashi, Sandhya; Kim, Alice; Kim, Esther; Kung, James; Martinez, Sabrina P.; Muchhal, Umesh S.; Nguyen, Duc-Hanh T.; O'Brien, Christopher; O'Keefe, Donald; Singer, Karen; Vafa, Omid; Vielmetter, Jost; Yoder, Sean C.; Dahiyat, Bassil I.

    2003-09-01

    Tumor necrosis factor (TNF) is a key regulator of inflammatory responses and has been implicated in many pathological conditions. We used structure-based design to engineer variant TNF proteins that rapidly form heterotrimers with native TNF to give complexes that neither bind to nor stimulate signaling through TNF receptors. Thus, TNF is inactivated by sequestration. Dominant-negative TNFs represent a possible approach to anti-inflammatory biotherapeutics, and experiments in animal models show that the strategy can attenuate TNF-mediated pathology. Similar rational design could be used to engineer inhibitors of additional TNF superfamily cytokines as well as other multimeric ligands.

  5. Poxvirus-encoded TNF decoy receptors inhibit the biological activity of transmembrane TNF

    OpenAIRE

    Pontejo, Sergio M; Alejo, Alí; Alcamí, Antonio

    2015-01-01

    © 2015 The Authors. Poxviruses encode up to four different soluble TNF receptors, named cytokine response modifier B (CrmB), CrmC, CrmD and CrmE. These proteins mimic the extracellular domain of the cellular TNF receptors to bind and inhibit the activity of TNF and, in some cases, other TNF superfamily ligands. Most of these ligands are released after the enzymic cleavage of a membrane precursor. However, transmembrane TNF (tmTNF) is not only a precursor of soluble TNF but also exerts specifi...

  6. [Non-targeted effects (bystander, abscopal) of external beam radiation therapy: an overview for the clinician].

    Science.gov (United States)

    Sun, R; Sbai, A; Ganem, G; Boudabous, M; Collin, F; Marcy, P-Y; Doglio, A; Thariat, J

    2014-12-01

    Radiotherapy is advocated in the treatment of cancer of over 50 % of patients. It has long been considered as a focal treatment only. However, the observation of effects, such as fatigue and lymphopenia, suggests that systemic effects may also occur. The description of bystander and abscopal effects suggests that irradiated cells may exert an action on nearby or distant unirradiated cells, respectively. A third type of effect that involves feedback interactions between irradiated cells was more recently described (cohort effect). This new field of radiation therapy is yet poorly understood and the definitions suffer from a lack of reproducibility in part due to the variety of experimental models. The bystander effect might induce genomic instability in non-irradiated cells and is thus extensively studied for a potential risk of radiation-induced cancer. From a therapeutic perspective, reproducing an abscopal effect by using a synergy between ionizing radiation and immunomodulatory agents to elicit or boost anticancer immune responses is an interesting area of research. Many applications are being developed in particular in the field of hypofractionated stereotactic irradiation of metastatic disease. Copyright © 2014 Société française de radiothérapie oncologique (SFRO). Published by Elsevier SAS. All rights reserved.

  7. Imprinted genes and transpositions: epigenomic targets for low dose radiation effects. Final report

    Energy Technology Data Exchange (ETDEWEB)

    Jirtle, Randy L.

    2012-10-11

    The overall hypothesis of this grant application is that low dose ionizing radiation (LDIR) elicits adaptive responses in part by causing heritable DNA methylation changes in the epigenome. This novel postulate was tested by determining if the level of DNA methylation at the Agouti viable yellow (A{sup vy}) metastable locus is altered, in a dose-dependent manner, by low dose radiation exposure (<10 cGy) during early gestation. This information is particularly important to ascertain given the increased use of CT scans in disease diagnosis, increased number of people predicted to live and work in space, and the present concern about radiological terrorism. We showed for the first time that LDIR significantly increased DNA methylation at the A{sup vy} locus in a sex-specific manner (p=0.004). Average DNA methylation was significantly increased in male offspring exposed to doses between 0.7 cGy and 7.6 cGy with maximum effects at 1.4 cGy and 3.0 cGy (p<0.01). Offspring coat color was concomitantly shifted towards pseudoagouti (p<0.01). Maternal dietary antioxidant supplementation mitigated both the DNA methylation changes and coat color shift in the irradiated offspring (p<0.05). Thus, LDIR exposure during gestation elicits epigenetic alterations that lead to positive adaptive phenotypic changes that are negated with antioxidants, indicating they are mediated in part by oxidative stress. These findings provide evidence that in the isogenic Avy mouse model epigenetic alterations resulting from LDIR play a role in radiation hormesis, bringing into question the assumption that every dose of radiation is harmful. Our findings not only have significant implications concerning the mechanism of hormesis, but they also emphasize the potential importance of this phenomenon in determining human risk at low radiation doses. Since the epigenetic regulation of genes varies markedly between species, the effect of LDIR on other epigenetically labile genes (e.g. imprinted genes) in

  8. Long Baseline Neutrino Experiment Target Material Radiation Damage Studies Using Energetic Protons of the Brookhaven Linear Isotope Production (BLIP) Facility

    CERN Document Server

    Simos, N; Hurh, P; Mokhov, N; Kotsina, Z

    2014-01-01

    One of the future multi-MW accelerators is the LBNE Experiment where Fermilab aims to produce a beam of neutrinos with a 2.3 MW proton beam as part of a suite of experiments associated with Project X. Specifically, the LBNE Neutrino Beam Facility aims for a 2+ MW, 60 -120 GeV pulsed, high intensity proton beam produced in the Project X accelerator intercepted by a low Z solid target to facilitate the production of low energy neutrinos. The multi-MW level LBNE proton beam will be characterized by intensities of the order of 1.6 e+14 p/pulse, {\\sigma} radius of 1.5 -3.5 mm and a 9.8 microsecond pulse length. These parameters are expected to push many target materials to their limit thus making the target design very challenging. To address a host of critical design issues revealed by recent high intensity beam on target experience a series of experimental studies on radiation damage and thermal shock response conducted at BNL focusing on low-Z materials have been undertaken with the latest one focusing on LBNE.

  9. Radiation protection aspects of the EURISOL Multi-MW target shielding

    CERN Document Server

    Ene, D; Doré, D; Rapp, B; Ridikas, D

    This paper which will be submitted to Annals in Nuclear Energy is focused on the approach used to assess the radiological characterisation and to support waste analysis for the multi-MW power target shielding being the most challenging both in terms of technological and safety issues.

  10. The Role of MRSI in Target Volume Definition for Radiation Therapy of Prostate Cancer

    Directory of Open Access Journals (Sweden)

    Mostafa Robatjazi

    2011-09-01

    Full Text Available Introduction: Recently, magnetic resonance spectroscopic imaging (MRSI, as a functional imaging method, has been used for clinical target volume definition. In this study, we used this method to define the target volume in prostate radiotherapy. Material and Method: In this study, we used images of 20 prostate cancer cases. MRSI and MRI images were fused with CT images. Then, treatment planning was preformed for each patient using three methods: CT, CT+MRI and CT+MRSI planning. Results: The volumes of MRICTV and MRIPTV were on average 12.83% and 8.97% lower than the corresponding CTCTV and CTPTV volumes, respectively. For MRSI, the CTV and PTV volumes were 21% and 27.41% greater than the corresponding CT-based volumes. Maximum dose to rectum showed a 0.58% increase in MRSI relative to CT, and 1.09% reduction in MRI relative to CT. Maximum dose variation in femoral heads showed a 5.4% increase in MRSI relative to CT and 0.67% reduction in MRI relative to CT. Discussion and Conclusion: Application of MRSI for target volume definition of prostate cancer leads to an increase in this volume in comparison to CT planning alone. In this imaging technique, protocol and resolution should be considered to determine the target volume exactly.

  11. Measurements and simulations of the BLM response to a radiation field inside the CERF target area

    CERN Document Server

    Lebbos, E; Dehning, B; Effinger, E; Ferrari, A; Kramer, D; Nordt, A; Roeed, K; Roesler, S; Sapinski, M; Vlachoudis, V; CERN. Geneva. EN Department

    2010-01-01

    The CERN-EU high-energy reference field (CERF) facility is installed in one of the secondary beam lines (H6) of the Super Proton Synchrotron (SPS), in the North Experimental Area at CERN. This facility is used as a reference for testing, inter-comparing and calibrating passive and active instruments. In May 2009, the SPS provided a mixed hadron beam (protons, pions and kaons) during a few days, in order to perform several measurements with different devices such as the Radiation Protection Monitor used for residual dose rates due to Induced Radioactivity in the LHC (PMI), the Secondary Emission Monitor used for high beam losses (SEM), the Radiation Monitor for electronics (RadMon), and the Beam Loss Monitor for the LHC (BLM). This report focuses on the measurements of the BLM response during this year’s operation at CERF. The measurements evaluate the sensitivity of the BLM signal to the particle energy spectrum, with special attention to the contribution coming from thermal neutrons. For this purpose, meas...

  12. Measurements and simulations of the BLM response to a radiation field inside the CERF target area

    CERN Document Server

    Lebbos, E; Dehning, B; Effinger, E; Ferrari, A; Kramer, D; Nordt, A; Roeed, K; Roesler, S; Sapinski, M; Vlachoudis, V

    2010-01-01

    The CERN-EU high-energy reference field (CERF) facility is installed in one of the secondary beam lines (H6) of the Super Proton Synchrotron (SPS), in the North Experimental Area at CERN. This facility is used as a reference for testing, inter-comparing and calibrating passive and active instruments. In May 2009, the SPS provided a mixed hadron beam (protons, pions and kaons) during a few days, in order to perform several measurements with different devices such as the Radiation Protection Monitor used for residual dose rates due to Induced Radioactivity in the LHC (PMI), the Secondary Emission Monitor used for high beam losses (SEM), the Radiation Monitor for electronics (RadMon), and the Beam Loss Monitor for the LHC (BLM). This report focuses on the measurements of the BLM response during this year’s operation at CERF. The measurements evaluate the sensitivity of the BLM signal to the particle energy spectrum, with special attention to the contribution coming from thermal neutrons. For this purpose, meas...

  13. Hot electron refluxing in the short intense laser pulse interactions with solid targets and its influence on K-α radiation

    Directory of Open Access Journals (Sweden)

    Horný Vojtěch

    2015-06-01

    Full Text Available Fast electrons created as a result of the laser beam interaction with a solid target penetrate into the target material and initialize processes leading to the generation of the characteristic X-ray K-α radiation. Due to the strong electric field induced at the rear side of a thin target the transmitted electrons are redirected back into the target. These refluxing electrons increase the K-α radiation yield, as well as the duration of the X-ray pulse and the size of the radiation emitting area. A model describing the electron refluxing was verified via particle-in-cell simulations for non-relativistic electron energies. Using this model it was confirmed that the effect of the electron refluxing on the generated X-ray radiation depends on the target thickness and the target material. A considarable increase of the number of the emitted K-α photons is observed especially for thin targets made of low-Z materials, and for higher hot electron temperatures.

  14. A Powerful Mitochondria-Targeted Iron Chelator Affords High Photoprotection against Solar Ultraviolet A Radiation.

    Science.gov (United States)

    Reelfs, Olivier; Abbate, Vincenzo; Hider, Robert C; Pourzand, Charareh

    2016-08-01

    Mitochondria are the principal destination for labile iron, making these organelles particularly susceptible to oxidative damage on exposure to ultraviolet A (UVA, 320-400 nm), the oxidizing component of sunlight. The labile iron-mediated oxidative damage caused by UVA to mitochondria leads to necrotic cell death via adenosine triphosphate depletion. Therefore, targeted removal of mitochondrial labile iron via highly specific tools from these organelles may be an effective approach to protect the skin cells against the harmful effects of UVA. In this work, we designed a mitochondria-targeted hexadentate (tricatechol-based) iron chelator linked to mitochondria-homing SS-like peptides. The photoprotective potential of this compound against UVA-induced oxidative damage and cell death was evaluated in cultured primary skin fibroblasts. Our results show that this compound provides unprecedented protection against UVA-induced mitochondrial damage, adenosine triphosphate depletion, and the ensuing necrotic cell death in skin fibroblasts, and this effect is fully related to its potent iron-chelating property in the organelle. This mitochondria-targeted iron chelator has therefore promising potential for skin photoprotection against the deleterious effects of the UVA component of sunlight. Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

  15. Linear energy transfer and track pattern recognition of secondary radiation generated in hadron therapy beam in a PMMA target

    Science.gov (United States)

    Opalka, L.; Granja, C.; Hartmann, B.; Jakubek, J.; Jaekel, O.; Martisikova, M.; Pospisil, S.; Solc, J.

    2013-02-01

    Hadron therapy uses ion beams for irradiation of cancerous tissue taking advantage of the highly localized dose deposition in the target tumor. For a correct estimation of dose deposited in tissue surrounding the target it is necessary to consider also the contribution of energetic secondary radiation generated by primary ions. It was already experimentally demonstrated that this contribution can be measured using the semiconductor pixel detector Timepix (256 × 256 pixels with 55 μm pitch) visualizing traces of secondary particles. The resolving power of the detector enables the differentiation of traces of different types of particles. In this work we studied the possibilities of determination of different types of secondary particles in correlation with their flight direction. Such identification allows correct assignment of dose for each type of particle. The distribution of secondary particles was compared to Monte Carlo simulations. Measurements were performed with a PMMA target irradiated with a therapeutic carbon beam at the Heidelberg Ion-Beam Therapy Center (HIT).

  16. Anti-TNF drives regulatory T cell expansion by paradoxically promoting membrane TNF-TNF-RII binding in rheumatoid arthritis

    OpenAIRE

    Nguyen, D. X.; Ehrenstein, M R

    2016-01-01

    The interplay between inflammatory and regulatory pathways orchestrates an effective immune response that provides protection from pathogens while limiting injury to host tissue. Tumor necrosis factor (TNF) is a pivotal inflammatory cytokine, but there is conflicting evidence as to whether it boosts or inhibits regulatory T cells (T reg cells). In this study, we show that the therapeutic anti-TNF antibody adalimumab, but not the soluble TNF receptor etanercept, paradoxically promoted the inte...

  17. Targeted radiotherapy dosimetry of 153Sm hydroxide macroaggregates for radiation synovectomy

    Science.gov (United States)

    Villarreal, José E.; Ferro, Guillermina; Hernández, Omar; Carmona, Juan

    2001-10-01

    The dosimetry of the recently developed 153Sm hydroxide macroaggregates (153Sm-MH) for radiation synovectomy has been studied as an agent for the treatment of arthritic synovial joint diseases. This pharmaceutical formulation presents optimal properties in terms of particle size (average 4 μm) sedimentation (0.008 cm min-1) and biological behavior. Direct measurements of depth dose distributions for this beta-gamma emitter present a difficult task; therefore, calculations of depth dose profiles are an invaluable tool for investigating the effectiveness of this therapeutic technique. In spite of the importance of these calculations there are only a few studies dealing with the experimental validation of these calculated depth dose distributions. On the present work the Monte Carlo (MCNP4B) calculated beta-gamma depth dose profiles for a liquid 153Sm beta-gamma source used in radiation synovectomy are compared with experimental depth dose distribution obtained using radiochromic dye film dosimetry (GafChromic™). The calculated and experimental depth dose distribution showed a very good agreement (within 5%) on the region where the dose deposition is dominated by the bëta-particle component (first 800 microns depth on tissue equivalent material). The agreement worsens reaching a maximum deviation of 15% at depths close to the maximum range of the beta-particles. Finally the agreement improves for the region where the gamma component accounts for one third of the total absorbed dose (depths>1 mm). The possible contributions to these differences are discussed as well as their relevance for the application of 153Sm for the treatment of rheumatoid arthritis.

  18. Kaempferol targets RSK2 and MSK1 to suppress UV radiation-induced skin cancer.

    Science.gov (United States)

    Yao, Ke; Chen, Hanyong; Liu, Kangdong; Langfald, Alyssa; Yang, Ge; Zhang, Yi; Yu, Dong Hoon; Kim, Myoung Ok; Lee, Mee-Hyun; Li, Haitao; Bae, Ki Beom; Kim, Hong-Gyum; Ma, Wei-Ya; Bode, Ann M; Dong, Ziming; Dong, Zigang

    2014-09-01

    Solar UV (SUV) irradiation is a major factor in skin carcinogenesis, the most common form of cancer in the United States. The MAPK cascades are activated by SUV irradiation. The 90 kDa ribosomal S6 kinase (RSK) and mitogen and stress-activated protein kinase (MSK) proteins constitute a family of protein kinases that mediate signal transduction downstream of the MAPK cascades. In this study, phosphorylation of RSK and MSK1 was upregulated in human squamous cell carcinoma (SCC) and SUV-treated mouse skin. Kaempferol, a natural flavonol, found in tea, broccoli, grapes, apples, and other plant sources, is known to have anticancer activity, but its mechanisms and direct target(s) in cancer chemoprevention are unclear. Kinase array results revealed that kaempferol inhibited RSK2 and MSK1. Pull-down assay results, ATP competition, and in vitro kinase assay data revealed that kaempferol interacts with RSK2 and MSK1 at the ATP-binding pocket and inhibits their respective kinase activities. Mechanistic investigations showed that kaempferol suppresses RSK2 and MSK1 kinase activities to attenuate SUV-induced phosphorylation of cAMP-responsive element binding protein (CREB) and histone H3 in mouse skin cells. Kaempferol was a potent inhibitor of SUV-induced mouse skin carcinogenesis. Further analysis showed that skin from the kaempferol-treated group exhibited a substantial reduction in SUV-induced phosphorylation of CREB, c-Fos, and histone H3. Overall, our results identify kaempferol as a safe and novel chemopreventive agent against SUV-induced skin carcinogenesis that acts by targeting RSK2 and MSK1.

  19. Generation of soft x-ray radiation by laser irradiation of a gas puff xenon target

    Energy Technology Data Exchange (ETDEWEB)

    Fiedorowicz, H.; Bartnik, A.; Szczurek, M. [Military Univ. of Technology, Warsaw (Poland). Inst. of Optoelectronics] [and others

    1995-12-31

    Plasmas produced from laser-irradiated gas puff xenon targets, created by pulsed injection of xenon with high-pressure solenoid valve, offer the possibility of realizing a debrisless x-ray point source for the x-ray lithography applications. In this paper the authors present results of the experimental investigations on the x-ray generation from a gas puff xenon target irradiated with nanosecond high-power laser pulses produced using two different laser facilities: a Nd:glass laser operating at 1.06 {micro}m, which generated 10--15 J pulses in 1 ns FWHM, and Nd:glass slab laser, producing pulses of 10 ns duration with energy reaching 12 J for a 0.53 {micro}m wavelength or 20 J for 1.05 {micro}m. To study the x-ray emission different x-ray diagnostic methods have been used. X-ray spectra were registered using a flat CsAP crystal spectrograph with an x-ray film or a curved KAP crystal spectrograph with a convex curvature to an x-ray CCD readout detector. X-ray images have been taken using pinhole cameras with an x-ray film or a CCD array. X-ray yield was measured with the use of semiconductor detectors (silicon photodiodes or diamond photoconductors).

  20. Vascular-targeted photodynamic of prostate cancer phase with Tookad for recurrent prostate cancer following radiation therapy: initial clinical studies

    Science.gov (United States)

    Weersink, Robert A.; Wilson, Brian C.; Bogaards, Arjen; Gertner, Mark R.; Davidson, Sean R. H.; Haider, Masoom A.; Elhilali, Mostafa; Trachtenberg, John

    2007-02-01

    We report on the first clinical application of vascular-targeted photodynamic therapy using a bacteriopheophorbide derivative, Tookad, in patients with localized prostate cancer following external beam radiation therapy. Patients received either escalating intravenous drug doses at a fixed light dose or escalated light doses at the highest photosensitizer dose. Two cylindrically diffusing fibers were placed transperineally in the prostate, along with light monitoring fibers in the prostate, urethra and rectum. Treatment response was assessed with 7-day gadolinium-enhanced T1-weighted MRI and 6-month biopsy. Lesion formation was strongly drug and light dose-dependent, with an apparent threshold response. Early biochemical and MRI responses support the clinical potential of TOOKAD-PDT to treat locally-recurrent prostate cancer.

  1. Antithrombotic activity of TNF

    OpenAIRE

    Cambien, Beatrice; Bergmeier, Wolfgang; Saffaripour, Simin; Mitchell, Heather A.; Wagner, Denisa D.

    2003-01-01

    Basic and clinical observations suggest that thrombosis and inflammation are closely related. Here we addressed the role played by TNF-α in thrombus formation and growth in an in vivo mouse model. Using intravital microscopy, we show that systemic administration of TNF-α at doses found in sepsis transiently inhibits thrombus formation and delays arterial occlusion upon vascular injury. These results were reflected in a prolonged bleeding time. Platelets isolated from the TNF-α–treated mice sh...

  2. miR-21 modulates resistance of HR-HPV positive cervical cancer cells to radiation through targeting LATS1

    Energy Technology Data Exchange (ETDEWEB)

    Liu, Shikai; Song, Lili, E-mail: commasll@163.com; Zhang, Liang; Zeng, Saitian; Gao, Fangyuan

    2015-04-17

    Although multiple miRNAs are found involved in radioresistance development in HR-HPV positive (+) cervical cancer, only limited studies explored the regulative mechanism of the miRNAs. miR-21 is one of the miRNAs significantly upregulated in HR-HPV (+) cervical cancer is also significantly associated with radioresistance. However, the detailed regulative network of miR-21 in radioresistance is still not clear. In this study, we confirmed that miR-21 overexpression was associated with higher level of radioresistance in HR-HPV (+) cervical cancer patients and thus decided to further explore its role. Findings of this study found miR-21 can negatively affect radiosensitivity of HR-HPV (+) cervical cancer cells and decrease radiation induced G2/M block and increase S phase accumulation. By using dual luciferase assay, we verified a binding site between miR-21 and 3′-UTR of large tumor suppressor kinase 1 (LATS1). Through direct binding, miR-21 can regulate LATS1 expression in cervical cancer cells. LATS1 overexpression can reverse miR-21 induced higher colony formation rate and also reduced miR-21 induced S phase accumulation and G2/M phase block reduction under radiation treatment. These results suggested that miR-21-LATS1 axis plays an important role in regulating radiosensitivity. - Highlights: • miR-21 is highly expressed in HR-HPV (+) radioresistant cervical cancer patients. • miR-21 can negatively affect radiosensitivity of HR-HPV (+) cervical cancer cells. • miR-21 can decrease radiation induced G2/M block and increase S phase accumulation. • miR-21 modulates radiosensitivity cervical cancer cell by directly targeting LATS1.

  3. A Phylogenomic Perspective on the Radiation of Ray-Finned Fishes Based upon Targeted Sequencing of Ultraconserved Elements (UCEs.

    Directory of Open Access Journals (Sweden)

    Brant C Faircloth

    Full Text Available Ray-finned fishes constitute the dominant radiation of vertebrates with over 32,000 species. Although molecular phylogenetics has begun to disentangle major evolutionary relationships within this vast section of the Tree of Life, there is no widely available approach for efficiently collecting phylogenomic data within fishes, leaving much of the enormous potential of massively parallel sequencing technologies for resolving major radiations in ray-finned fishes unrealized. Here, we provide a genomic perspective on longstanding questions regarding the diversification of major groups of ray-finned fishes through targeted enrichment of ultraconserved nuclear DNA elements (UCEs and their flanking sequence. Our workflow efficiently and economically generates data sets that are orders of magnitude larger than those produced by traditional approaches and is well-suited to working with museum specimens. Analysis of the UCE data set recovers a well-supported phylogeny at both shallow and deep time-scales that supports a monophyletic relationship between Amia and Lepisosteus (Holostei and reveals elopomorphs and then osteoglossomorphs to be the earliest diverging teleost lineages. Our approach additionally reveals that sequence capture of UCE regions and their flanking sequence offers enormous potential for resolving phylogenetic relationships within ray-finned fishes.

  4. BNip3 is a mediator of TNF-induced necrotic cell death.

    Science.gov (United States)

    Kim, Jee-Youn; Kim, Yong-Jun; Lee, Sun; Park, Jae-Hoon

    2011-02-01

    Tumor necrosis factor (TNF) is a pleiotropic cytokine involved in immune modulation, inflammatory reactions, and target cell death in many pathologic conditions. The cell death pathways triggered by TNF include the caspase-8/Bid-dependent apoptotic pathway and the caspase-independent necrosis pathway (necroptosis). While the signaling pathways activated after binding of TNF to the TNF receptor (TNFR) and subsequent insertion of Bid/Bax/Bik into the outer mitochondrial membrane are relatively well known, other cell death pathways and the participating signaling molecules remain to be clarified. BNip3 is a pro-death protein and a member of the BH3-only Bcl-2 family. When ectopically overexpressed or induced by hypoxia, BNip3 induces various types of cell death via mitochondrial or non-mitochondrial death cascades. In this study using A549 alveolar epithelial cells of the lung, we show that BNip3 is transcriptionally and translationally upregulated by TNF, and its expression level determines the sensitivity to necroptosis induced by TNF. However, BNip3 does not appear to be involved in caspase-8/Bid-dependent apoptotic cell death in these alveolar lung cells. Finally, we show that the generation of reactive oxygen species (ROS) is essential for mitochondrial insertion of BNip3, which is an important step in BNip3-induced mitochondrial catastrophe. Our results indicate that BNip3 is a candidate therapeutic target in pathologic conditions in which TNF causes tissue damage.

  5. Laser acceleration of protons from near critical density targets for application to radiation therapy

    CERN Document Server

    Bulanov, S S; Pirozhkov, A S; Thomas, A G R; Willingale, L; Krushelnick, K; Maksimchuk, A

    2010-01-01

    Laser accelerated protons can be a complimentary source for treatment of oncological diseases to the existing hadron therapy facilities. We demonstrate how the protons, accelerated from near-critical density plasmas by laser pulses having relatively small power, reach energies which may be of interest for medical applications. When an intense laser pulse interacts with near-critical density plasma it makes a channel both in the electron and then in the ion density. The propagation of a laser pulse through such a self-generated channel is connected with the acceleration of electrons in the wake of a laser pulse and generation of strong moving electric and magnetic fields in the propagation channel. Upon exiting the plasma the magnetic field generates a quasi-static electric field that accelerates and collimates ions from a thin filament formed in the propagation channel. Two-dimensional Particle-in-Cell simulations show that a 100 TW laser pulse tightly focused on a near-critical density target is able to acce...

  6. Design and characterization of HER-2-targeted gold nanoparticles for enhanced X-radiation treatment of locally advanced breast cancer.

    Science.gov (United States)

    Chattopadhyay, Niladri; Cai, Zhongli; Pignol, Jean-Philippe; Keller, Brian; Lechtman, Eli; Bendayan, Reina; Reilly, Raymond M

    2010-12-06

    Our purpose was to develop a human epidermal growth factor receptor-2 (HER-2) targeted nanotechnology-based radiosensitizer. HER-2 is overexpressed in 20-30% of all breast cancers and up to 2-fold higher in locally advanced disease (LABC). Trastuzumab was derivatized with a polyethylene glycol (OPSS-PEG-SVA) cross-linker to produce trastuzumab-PEG-OPSS. These immunoconjugates were analyzed by SDS-PAGE, and their immunoreactivity was assessed by flow cytometry using HER-2 overexpressing SK-BR-3 breast cancer cells. Reacting trastuzumab with increasing ratios of PEG resulted in an increase in molecular weight from approximately 148 kDa to 243 kDa, associated with increasing PEG substitution (0.6 to 18.9 PEG chains per trastuzumab). Attachment of approximately 7 PEG chains per trastuzumab resulted in 56% retention in immunoreactivity assessed by flow cytometry. The conjugates were then linked to 30 nm AuNPs. Using a novel (123)iodine-radiotracer based assay that overcomes the current limitations of spectrophotometric quantification of biological molecules on AuNPs we estimate 14.3 ± 2.7 antibodies were attached to each AuNP when 2 × 10(11) AuNPs were reacted with 20 μg of trastuzumab-PEG-OPSS. Specificity of trastuzumab-PEG-AuNPs for HER-2 and internalization in SK-BR-3 cells was demonstrated by comparing the uptake of trastuzumab-PEG-AuNPs or PEG-AuNPs by darkfield microscopy. The ability of trastuzumab-PEG-AuNPs in combination with 300 kVp X-rays to enhance DNA double strand breaks (DSBs) in SK-BR-3 cells was assessed by immunofluorescence using the γ-H2AX assay. γ-H2AX assay results revealed 5.1-fold higher DNA-DSBs with trastuzumab-PEG-AuNPs and X-radiation as compared to treatment with X-radiation alone. The trastuzumab-PEG-AuNPs are a promising targeted nanotechnology-based radiosensitizer for improving LABC therapy. The design and systematic approaches taken to surface modify and characterize trastuzumab-PEG-AuNPs described in this study would have

  7. Partial Correction of Psoriasis upon Genetic Knock-Down of Human TNF-α by Lentivirus-Encoded shRNAs in a Xenograft Mouse Model

    DEFF Research Database (Denmark)

    Jakobsen, Maria; Stenderup, Karin; Rosada, Cecilia

    with lentiviral vectors encoding an irrelevant shRNA. In conclusion, our results demonstrate that lentiviral vector-encoded TNF- shRNAs have the potential to down-regulate TNF- production both in vitro and in vivo. Phenotypic changes in shRNA-treated psoriatic skin suggest that TNF- -encoding RNA is a valid......The proinflammatory cytokine Tumor Necrosis Factor alpha (TNF- ) is upregulated in inflammatory psoriatic skin. The increased level of TNF- protein is thought to cause keratinocyte hyperproliferation, leukocyte infiltration as well as growth and dilation of superficial blood vessels, which are all...... characteristics of human psoriasis skin. Blockade of TNF- function with specific inhibitors at the protein level has resulted in a rapid clinical improvement in psoriasis patients, demonstrating that TNF- inhibition offers a promising therapy of psoriasis. Whether TNF- -encoding RNA is a valid therapeutic target...

  8. Targeted nanoparticles for enhanced X-ray radiation killing of multidrug-resistant bacteria

    Science.gov (United States)

    Luo, Yang; Hossain, Mainul; Wang, Chaoming; Qiao, Yong; An, Jincui; Ma, Liyuan; Su, Ming

    2012-12-01

    This paper describes a nanoparticle enhanced X-ray irradiation based strategy that can be used to kill multidrug resistant (MDR) bacteria. In the proof-of-concept experiment using MDR Pseudomonas aeruginosa (P. aeruginosa) as an example, polyclonal antibody modified bismuth nanoparticles are introduced into bacterial culture to specifically target P. aeruginosa. After washing off uncombined bismuth nanoparticles, the bacteria are irradiated with X-rays, using a setup that mimics a deeply buried wound in humans. Results show that up to 90% of MDR P. aeruginosa are killed in the presence of 200 μg ml-1 bismuth nanoparticles, whereas only ~6% are killed in the absence of bismuth nanoparticles when exposed to 40 kVp X-rays for 10 min. The 200 μg ml-1 bismuth nanoparticles enhance localized X-ray dose by 35 times higher than the control with no nanoparticles. In addition, no significant harmful effects on human cells (HeLa and MG-63 cells) have been observed with 200 μg ml-1 bismuth nanoparticles and 10 min 40 kVp X-ray irradiation exposures, rendering the potential for future clinical use. Since X-rays can easily penetrate human tissues, this bactericidal strategy has the potential to be used in effectively killing deeply buried MDR bacteria in vivo.This paper describes a nanoparticle enhanced X-ray irradiation based strategy that can be used to kill multidrug resistant (MDR) bacteria. In the proof-of-concept experiment using MDR Pseudomonas aeruginosa (P. aeruginosa) as an example, polyclonal antibody modified bismuth nanoparticles are introduced into bacterial culture to specifically target P. aeruginosa. After washing off uncombined bismuth nanoparticles, the bacteria are irradiated with X-rays, using a setup that mimics a deeply buried wound in humans. Results show that up to 90% of MDR P. aeruginosa are killed in the presence of 200 μg ml-1 bismuth nanoparticles, whereas only ~6% are killed in the absence of bismuth nanoparticles when exposed to 40 kVp X

  9. TNF and ROS Crosstalk in Inflammation

    DEFF Research Database (Denmark)

    Blaser, Heiko; Dostert, Catherine; Mak, Tak W

    2016-01-01

    Tumor necrosis factor (TNF) is tremendously important for mammalian immunity and cellular homeostasis. The role of TNF as a master regulator in balancing cell survival, apoptosis and necroptosis has been extensively studied in various cell types and tissues. Although these findings have revealed ...

  10. 目标反射环境红外辐射的模拟研究%Simulation of environment infrared radiation reflected by target

    Institute of Scientific and Technical Information of China (English)

    王雨飞; 李强; 廖胜

    2011-01-01

    When detecting extraatmospheric target based on IR radiation, the infrared radiation received by detector contains not only the target radiation, but also the reflection of environment source radiation, mainly the sun radiation, earth radiation and earth-reflection radiation. The simulation of target signature based on physical principle was performed. By calculating the position vector of sun, target, earth, observation station and the corresponding angles in the same reference frame at the given observation time, the sun radiation reflected by cylindrical target with solar battery plane was simulated. And the radiance of observation place of earth infrared radiation and earth -reflection reflected by target was calculated, using the improved random simulation method. At the end, spectral irradiance received by the detector at the given time was discussed by analyzing the simulation result, and the rule of total irradiance changing with orbit position change was given.%基于红外辐射探测大气层外目标时,探测器接收到的目标红外波段辐射不仅包含目标自身辐射,也包含对环境光源辐射的反射,主要为对太阳辐射、地球辐射、地球反照太阳辐射的反射.在按照基本物理原理进行建模的过程中,通过计算给定探测时间太阳、目标、地球以及观测站点在统一坐标系中位置矢量及其相应夹角,模拟了带太阳能帆板的圆柱主体目标反射的太阳辐射,并使用改进的随机模拟方法计算了地球红外辐射和地球反照经目标反射在探测位置的辐照度.最后,通过分析仿真结果,讨论了选定时间探测到的各辐射光谱辐照度,并给出其总辐照度随轨道位置的变化规律.

  11. Energy release, beam attenuation radiation damage, gas production and accumulation of long-lived activity in Pb, Pb-Bi and Hg targets

    Energy Technology Data Exchange (ETDEWEB)

    Shubin, Yu.N. [IPPE, Obninsk (Russian Federation)

    1996-06-01

    The calculation and analysis of the nuclei concentrations and long-lived residual radioactivity accumulated in Pb, Pb-Bi and Hg targets irradiated by 800 MeV, 30 mA proton beam have been performed. The dominating components to the total radioactivity of radionuclides resulting from fission and spallation reactions and radiative capture by both target nuclei and accumulated radioactive nuclei for various irradiation and cooling times were analyzed. The estimations of spectral component contributions of neutron and proton fluxes to the accumulated activity were carried out. The contributions of fission products to the targets activity and partial activities of main long-lived fission products to the targets activity and partial activities of main long-lived fission products were evaluated. The accumulation of Po isotopes due to reactions induced by secondary alpha-particles were found to be important for the Pb target as compared with two-step radiative capture. The production of Tritium in the targets and its contribution to the total targets activity was considered in detail. It is found that total activities of both targets are close to one another.

  12. INTERACTION OF LASER RADIATION WITH MATTER: Influence of a target on operation of a pulsed CO2 laser emitting microsecond pulses

    Science.gov (United States)

    Baranov, V. Yu; Dolgov, V. A.; Malyuta, D. D.; Mezhevov, V. S.; Semak, V. V.

    1987-12-01

    The profile of pulses emitted by a TEA CO2 laser with an unstable resonator changed as a result of interaction of laser radiation with the surface of a metal in the presence of a breakdown plasma. This influence of a target on laser operation and its possible applications in laser processing of materials are analyzed.

  13. Impact of [F-18]-fluoro-ethyl-tyrosine PET imaging on target definition for radiation therapy of high-grade glioma

    DEFF Research Database (Denmark)

    af Rosenschold, Per Munck; Costa, Junia; Engelholm, Svend Aage

    2015-01-01

    BACKGROUND: We sought to assess the impact of amino-acid (18)F-fluoro-ethyl-tyrosine (FET) positron emission tomography (PET) on the volumetric target definition for radiation therapy of high-grade glioma versus the current standard using MRI alone. Specifically, we investigated the influence...

  14. INTERACTION OF LASER RADIATION WITH MATTER. LASER PLASMA: Structure of flows due to interaction of CO2 laser pulse pairs with a target in air

    Science.gov (United States)

    Bakeev, A. A.; Nikolashina, L. I.; Potashkin, M. N.; Prokopenko, N. V.

    1991-06-01

    An analysis is made of two pulses from an electric-discharge CO2 laser, of 6-12 μs duration and separated in time, incident on a target surrounded by air of normal density. The main attention is concentrated on breakdown of air by the second pulse at a boundary separating the "cold gas" and the plasma generated by the first pulse ("hot gas"). A gasdynamic system of waves is then generated. It consists of an absorption wave traveling along the cold gas opposite to the laser radiation and a wave propagating along the hot gas toward the target. The best agreement between the theory and experiment is obtained employing a model in which an absorption wave travels along the hot gas in an overcompressed detonation regime. The density of the radiation flux needed to maintain such a wave is 20-30% of the average density of the laser radiation flux carried by the second pulse.

  15. Transactivation of EGF receptor and ErbB2 protects intestinal epithelial cells from TNF-induced apoptosis.

    Science.gov (United States)

    Yamaoka, Toshimitsu; Yan, Fang; Cao, Hanwei; Hobbs, Stuart S; Dise, Rebecca S; Tong, Wei; Polk, D Brent

    2008-08-19

    TNF is a pleiotropic cytokine that activates both anti- and proapoptotic signaling pathways, with cell fate determined by the balance between these two pathways. Activation of ErbB family members, including EGF receptor (EGFR/ErbB1), promotes cell survival and regulates several signals that overlap with those stimulated by TNF. This study was undertaken to determine the effects of TNF on EGFR and ErbB2 activation and intestinal epithelial cell survival. Mice, young adult mouse colon epithelial cells, and EGFR knockout mouse colon epithelial cells were treated with TNF. Activation of EGFR, ErbB2, Akt, Src, and apoptosis were determined in vivo and in vitro. TNF stimulated EGFR phosphorylation in young adult mouse colon epithelial cells, and loss of EGFR expression or inhibition of kinase activity increased TNF-induced apoptosis, which was prevented in WT but not by kinase-inactive EGFR expression. Similarly, TNF injection stimulated apoptosis in EGFR-kinase-defective mice (EGFR(wa2)) compared with WT mice. TNF also activated ErbB2, and loss of ErbB2 expression increased TNF-induced apoptosis. Furthermore, Src-kinase activity and the expression of both EGFR and ErbB2 were required for TNF-induced cell survival. Akt was shown to be a downstream target of TNF-activated EGFR and ErbB2. These findings demonstrate that EGFR and ErbB2 are critical mediators of TNF-regulated antiapoptotic signals in intestinal epithelial cells. Given evidence for TNF signaling in the development of colitis-associated carcinoma, this observation has significant implications for understanding the role of EGFR in maintaining intestinal epithelial cell homeostasis during cytokine-mediated inflammatory responses.

  16. Meeting the Radiative Forcing Targets of the Representative Concentration Pathways in a World with Agricultural Climate Impacts

    Energy Technology Data Exchange (ETDEWEB)

    Kyle, G. Page; Mueller, C.; Calvin, Katherine V.; Thomson, Allison M.

    2014-02-28

    This study assesses how climate impacts on agriculture may change the evolution of the agricultural and energy systems in meeting the end-of-century radiative forcing targets of the Representative Concentration Pathways (RCPs). We build on the recently completed ISI-MIP exercise that has produced global gridded estimates of future crop yields for major agricultural crops using climate model projections of the RCPs from the Coupled Model Intercomparison Project Phase 5 (CMIP5). For this study we use the bias-corrected outputs of the HadGEM2-ES climate model as inputs to the LPJmL crop growth model, and the outputs of LPJmL to modify inputs to the GCAM integrated assessment model. Our results indicate that agricultural climate impacts generally lead to an increase in global cropland, as compared with corresponding emissions scenarios that do not consider climate impacts on agricultural productivity. This is driven mostly by negative impacts on wheat, rice, other grains, and oil crops. Still, including agricultural climate impacts does not significantly increase the costs or change the technological strategies of global, whole-system emissions mitigation. In fact, to meet the most aggressive climate change mitigation target (2.6 W/m2 in 2100), the net mitigation costs are slightly lower when agricultural climate impacts are considered. Key contributing factors to these results are (a) low levels of climate change in the low-forcing scenarios, (b) adaptation to climate impacts, simulated in GCAM through inter-regional shifting in the production of agricultural goods, and (c) positive average climate impacts on bioenergy crop yields.

  17. Targeting of CD25 and glucocorticoid-induced TNF receptor family-related gene-expressing T cells differentially modulates asthma risk in offspring of asthmatic and normal mother mice.

    Science.gov (United States)

    Hubeau, Cedric; Apostolou, Irina; Kobzik, Lester

    2007-02-01

    Immunological mechanisms leading to increased asthma susceptibility in early life remain obscure. In this study, we examined the effects of neonatal Ab treatments targeting T cell populations on the development of an asthma syndrome. We used a model of increased asthma susceptibility where offspring of asthmatic BALB/c mother mice are more prone (than normal pups) to develop the disease. Neonatal pretreatment of naive pups with mAb directed against the IL-2Ralpha chain (CD25), the costimulatory molecule glucocorticoid-induced TNFR family related gene, and the inhibitory molecule CTLA-4 elicited contrasting effects in offspring depending on the mother's asthma status. Specifically, neonatal CD25(high) T cell depletion stimulated asthma susceptibility in normal offspring whereas it ameliorated the condition of pups born of asthmatic mothers. Conversely, glucocorticoid-induced TNFR family related gene ligation as a primary signal reduced the spleen cellularity and largely abrogated asthma susceptibility in asthma-prone offspring, without inducing disease in normal pups. Striking changes in Th1/Th2 cytokine levels, especially IL-4, followed mAb pretreatment and were consistent with the impact on asthma susceptibility. These results point to major differences in neonatal T cell population and responsiveness related to maternal asthma history. Interventions that temporarily remove and/or inactivate specific T cell subsets may therefore prove useful to attenuate early life asthma susceptibility and prevent the development of Th2-driven allergic airway disease.

  18. Nanolabel for TNF-α determination

    Science.gov (United States)

    Say, Rıdvan; Diltemiz, Sibel Emir; Çelik, Suzan; Ersöz, Arzu

    2013-06-01

    Tumor necrosis factor-α (TNF-α), also known as cachectin, is one of the most important regulatory cytokines and mediates a variety of cell functions, including the stimulation of nitric oxide (NO) production which has been related to oxidative stress and diseases such as arthritis, diabetes, stroke, and chronic inflammation. Determination of TNF-α concentration in human serum might be helpful in the staging and prognosis of diseases. And it is also very important for the understanding of tumor biological processes, inherent mechanisms, and discovering drugs as well as having a therapeutic potential for the treatment of diseases. So, in this study, sensor systems based on Reflectometric Interference Spectroscopy (RIfS) have been prepared for selectively recognition and binding of TNF-α biomolecules. For this purpose, photosensitive nano structured TNF-α has been synthesized applying AmiNoAcid (monomer) Decorated and Light Underpining Conjugation Approach (ANADOLUCA) method using bis (2-2'-bipyridyl) MATyr-MATyr-ruthenium(II) (MATyr-Ru-MATyr) as a photosensitive monomer. Then, these photosensitive nano structured TNF-α have been used for TNF-α recognition as an alternative and unique sensor method. Also, the affinity constant of RIfS sensor has been calculated. The method has been showed high sensitivity, good precision and accuracy, and suited for the detection of TNF-α from aqueous solution.

  19. Nanolabel for TNF-α determination

    Energy Technology Data Exchange (ETDEWEB)

    Say, Rıdvan, E-mail: rsay@anadolu.edu.tr [Anadolu University, Faculty of Sciences, Department of Chemistry 26470 Eskişehir (Turkey); Diltemiz, Sibel Emir, E-mail: semir@anadolu.edu.tr [Anadolu University, Faculty of Sciences, Department of Chemistry 26470 Eskişehir (Turkey); Çelik, Suzan, E-mail: syazar@gmail.com [Sanovel İlaç San. ve Tic. A.Ş. 34460 İstinye, Sarıyer/Istanbul (Turkey); Ersöz, Arzu, E-mail: arzuersoz@anadolu.edu.tr [Anadolu University, Faculty of Sciences, Department of Chemistry 26470 Eskişehir (Turkey)

    2013-06-15

    Tumor necrosis factor-α (TNF-α), also known as cachectin, is one of the most important regulatory cytokines and mediates a variety of cell functions, including the stimulation of nitric oxide (NO) production which has been related to oxidative stress and diseases such as arthritis, diabetes, stroke, and chronic inflammation. Determination of TNF-α concentration in human serum might be helpful in the staging and prognosis of diseases. And it is also very important for the understanding of tumor biological processes, inherent mechanisms, and discovering drugs as well as having a therapeutic potential for the treatment of diseases. So, in this study, sensor systems based on Reflectometric Interference Spectroscopy (RIfS) have been prepared for selectively recognition and binding of TNF-α biomolecules. For this purpose, photosensitive nano structured TNF-α has been synthesized applying AmiNoAcid (monomer) Decorated and Light Underpining Conjugation Approach (ANADOLUCA) method using bis (2-2′-bipyridyl) MATyr-MATyr-ruthenium(II) (MATyr-Ru-MATyr) as a photosensitive monomer. Then, these photosensitive nano structured TNF-α have been used for TNF-α recognition as an alternative and unique sensor method. Also, the affinity constant of RIfS sensor has been calculated. The method has been showed high sensitivity, good precision and accuracy, and suited for the detection of TNF-α from aqueous solution.

  20. Prepulse-induced shock waves in the gas jet target of a laser plasma EUV radiation source

    Science.gov (United States)

    Garbaruk, A. V.; Gritskevich, M. S.; Kalmykov, S. G.; Mozharov, A. M.; Sasin, M. E.

    2017-01-01

    In experiments with a laser-plasma EUV-radiation source, the main IR Nd:YAG laser pulse was preceded by that of a UV KrF excimer laser. Dramatic modulations of EUV plasma emissivity have been observed at long interpulse times, from hundreds of nanoseconds up to microseconds. To discover the nature of these prepulse-produced long-living perturbations of the target, a fluid dynamics numerical simulation of the Xe gas jet has been carried out. The prepulse has been found to generate a quasi-spherical shock wave with a thin dense front layer and a vast rarefied inside area. In the course of time, the front expands and simultaneously drifts downstream along with the gas. Depending on the interpulse time, the IR laser beam either intersects the dense layer or propagates within the rarefied gas cavity whereby the above-mentioned variations in the plasma emission can be explained. The possibilities of making use of the discovered phenomena to enhance the observed EUV plasma brightness are discussed.

  1. Transmembrane TNF-α Reverse Signaling Inhibits Lipopolysaccharide-Induced Proinflammatory Cytokine Formation in Macrophages by Inducing TGF-β: Therapeutic Implications.

    Science.gov (United States)

    Pallai, Anna; Kiss, Beáta; Vereb, György; Armaka, Marietta; Kollias, George; Szekanecz, Zoltán; Szondy, Zsuzsa

    2016-02-01

    TNF-α, a potent proinflammatory cytokine, is generated in a precursor form called transmembrane (m)TNF-α that is expressed as a type II polypeptide on the surface of certain cells. mTNF-α was shown to act both as a ligand by binding to TNF-α receptors, as well as a receptor that transmits outside-to-inside (reverse) signals back into the mTNF-α-bearing cells. In this study, we show that nonactivated macrophages express basal levels of mTNF-α and respond to anti-TNF-α Abs by triggering the MAPK kinase 4 signaling pathway. The pathway induces TGF-β. Based on inhibitory experiments, the production of TGF-β1 is regulated via Jun kinases, whereas that of other TGF-βs is regulated via p38 MAPKs. Exposure to LPS further induced the expression of mTNF-α, and triggering of mTNF-α strongly suppressed the LPS-induced proinflammatory response. Neutralizing TGF-β by Abs prevented the mTNF-α-mediated suppression of LPS-induced proinflammatory cytokine formation, indicating that the immune-suppressive effect of mTNF-α is mediated via TGF-β. Although apoptotic cells are also known to suppress LPS-induced proinflammatory cytokine formation in macrophages by upregulating TGF-β, we show that they do not use the mTNF-α signaling pathway. Because TGF-β possesses a wide range of immune-suppressive effects, our data indicate that upregulation of TGF-β synthesis by those TNF-α-targeting molecules, which are able to trigger mTNF-α, might contribute to their therapeutic effect in the treatment of certain inflammatory diseases such as Crohn's disease, Wegener's granulomatosis, or sarcoidosis. Additionally, none of the TNF-α-targeting molecules is expected to interfere with the immune-silencing effects of apoptotic cells.

  2. Drugs for Autoimmune Inflammatory Diseases: From Small Molecule Compounds to Anti-TNF Biologics

    Directory of Open Access Journals (Sweden)

    Ping Li

    2017-07-01

    more effective treatment, as proposed by some recent studies. In this review article, the historical development of anti-inflammatory drugs after World War II as briefly described above will be reviewed and analyzed. The future trend in the development of novel TNF receptor-targeting therapeutics will be discussed in the context of latest progress in the research of TNF biology.

  3. TNF-α Gene Knockout in Triple Negative Breast Cancer Cell Line Induces Apoptosis

    Directory of Open Access Journals (Sweden)

    Valentina Pileczki

    2012-12-01

    Full Text Available Tumor necrosis factor alpha (TNF-α is a pro-inflammatory cytokine involved in the promotion and progression of cancer, including triple negative breast cancer cells. Thus, there is significant interest in understanding the molecular signaling pathways that connect TNF-α with the survival of tumor cells. In our experiments, we used as an in vitro model for triple negative breast cancer the cell line Hs578T. The purpose of this study is to determine the gene expression profiling of apoptotic signaling networks after blocking TNF-α formation by using specially designed siRNA molecules to target TNF-α messenger RNA. Knockdown of TNF-α gene was associated with cell proliferation inhibition and apoptosis, as observed by monitoring the cell index using the xCELLigence RTCA System and flow cytometry. PCR array technology was used to examine the transcript levels of 84 genes involved in apoptosis. 15 genes were found to be relevant after comparing the treated group with the untreated one of which 3 were down-regulated and 12 up-regulated. The down-regulated genes are all involved in cell survival, whereas the up-regulated ones are involved in and interact with pro-apoptotic pathways. The results described here indicate that the direct target of TNF-α in the Hs578T breast cancer cell line increases the level of certain pro-apoptotic factors that modulate different cellular networks that direct the cells towards death.

  4. Mathematical models of tissue stem and transit target cell divisions and the risk of radiation- or smoking-associated cancer.

    Science.gov (United States)

    Little, Mark P; Hendry, Jolyon H

    2017-02-01

    There is compelling biological data to suggest that cancer arises from a series of mutations in single target cells, resulting in defects in cell renewal and differentiation processes which lead to malignancy. Because much mutagenic damage is expressed following cell division, more-rapidly renewing tissues could be at higher risk because of the larger number of cell replications. Cairns suggested that renewing tissues may reduce cancer risk by partitioning the dividing cell populations into lineages comprising infrequently-dividing long-lived stem cells and frequently-dividing short-lived daughter transit cells. We develop generalizations of three recent cancer-induction models that account for the joint maintenance and renewal of stem and transit cells, also competing processes of partially transformed cell proliferation and differentiation/apoptosis. We are particularly interested in using these models to separately assess the probabilities of mutation and development of cancer associated with "spontaneous" processes and with those linked to a specific environmental mutagen, specifically ionizing radiation or cigarette smoking. All three models demonstrate substantial variation in cancer risks, by at least 20 orders of magnitude, depending on the assumed number of critical mutations required for cancer, and the stem-cell and transition-cell mutation rates. However, in most cases the conditional probabilities of cancer being mutagen-induced range between 7-96%. The relative risks associated with mutagen exposure compared to background rates are also stable, ranging from 1.0-16.0. Very few cancers, generally Little difference is made to relative risks if competing processes of proliferation and differentiation in the partially transformed stem and transit cell population are allowed for, nor is any difference made if one assumes that transit cells require an extra mutation to confer malignancy from the number required by stem cells. The probability of a cancer

  5. Developmental effects of exposure to ultraviolet B radiation on the freshwater prawn Macrobrachium olfersi: Mitochondria as a target of environmental UVB radiation.

    Science.gov (United States)

    de Quadros, Thaline; Schramm, Heloísa; Zeni, Eliane C; Simioni, Carmen; Allodi, Silvana; Müller, Yara M R; Ammar, Dib; Nazari, Evelise M

    2016-10-01

    In South America, increased UVB radiation has become an important environmental issue that is potentially threatening aquatic ecosystems. Considering that species exhibit different degrees of sensitivity to UVB radiation and that embryos are more sensitive than organisms at later life stages, the aim of this study was to characterize the effects of UVB radiation on subcellular compartments of embryos of the freshwater prawn Macrobrachium olfersi. This species lives and reproduces in clear and shallow waters, where UV radiation can fully penetrates. Embryos were irradiated with a UVB 6W lamp for 30min and examined after 1h, 12h, 24h and 48h of exposure. The irradiance of the UVB used simulates the UV radiation that embryos receive in the natural environment. The subcellular compartment most affected by the UVB radiation was the mitochondria, which exhibited a circular shape, a decrease in mitochondrial cristae, rupture of membranes and a morphology compatible with fission. These impairments were observed simultaneously with increased ROS production, just after 1h of UVB exposure. Thus, we investigated proteins related to mitochondrial fission (Drp-1) and fusion (Mfn-1), which are essential to cell maintenance. We found a significant increase in Drp-1 expression at all analyzed time-points and a significant decrease in Mfn-1 expression only after 24h of UVB exposure. Additionally, a decrease in embryonic cell viability was verified via the mitochondrial integrity assay. To conclude, we observed important mitochondrial dysfunctions against the environmental stress caused by UVB radiation. Moreover, the cellular responses found are critical and should not be disregarded, because they impact embryos that can potentially compromise the aquatic ecosystems.

  6. BRCA1, FANCD2 and Chk1 are potential molecular targets for the modulation of a radiation-induced DNA damage response in bystander cells.

    Science.gov (United States)

    Burdak-Rothkamm, Susanne; Rothkamm, Kai; McClelland, Keeva; Al Rashid, Shahnaz T; Prise, Kevin M

    2015-01-28

    Radiotherapy is an important treatment option for many human cancers. Current research is investigating the use of molecular targeted drugs in order to improve responses to radiotherapy in various cancers. The cellular response to irradiation is driven by both direct DNA damage in the targeted cell and intercellular signalling leading to a broad range of bystander effects. This study aims to elucidate radiation-induced DNA damage response signalling in bystander cells and to identify potential molecular targets to modulate the radiation induced bystander response in a therapeutic setting. Stalled replication forks in T98G bystander cells were visualised via bromodeoxyuridine (BrdU) nuclear foci detection at sites of single stranded DNA. γH2AX co-localised with these BrdU foci. BRCA1 and FANCD2 foci formed in T98G bystander cells. Using ATR mutant F02-98 hTERT and ATM deficient GM05849 fibroblasts it could be shown that ATR but not ATM was required for the recruitment of FANCD2 to sites of replication associated DNA damage in bystander cells whereas BRCA1 bystander foci were ATM-dependent. Phospho-Chk1 foci formation was observed in T98G bystander cells. Clonogenic survival assays showed moderate radiosensitisation of directly irradiated cells by the Chk1 inhibitor UCN-01 but increased radioresistance of bystander cells. This study identifies BRCA1, FANCD2 and Chk1 as potential targets for the modulation of radiation response in bystander cells. It adds to our understanding of the key molecular events propagating out-of-field effects of radiation and provides a rationale for the development of novel molecular targeted drugs for radiotherapy optimisation. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

  7. MiR-663 inhibits radiation-induced bystander effects by targeting TGFB1 in a feedback mode

    Science.gov (United States)

    Hu, Wentao; Xu, Shuai; Yao, Bin; Hong, Mei; Wu, Xin; Pei, Hailong; Chang, Lei; Ding, Nan; Gao, Xiaofei; Ye, Caiyong; Wang, Jufang; Hei, Tom K; Zhou, Guangming

    2014-01-01

    The mechanisms of radiation-induced bystander effects (RIBE) have been investigated intensively over the past two decades. Although quite a few reports demonstrated that cytokines such as TGF-β1 are induced within the directly irradiated cells and play critical roles in mediating the bystander effects, little is known about the signaling pathways that occur in bystander cells. The crucial question as to why RIBE signals cannot be infinitely transmitted, therefore, remains unclear. In the present study, we showed that miR-663, a radiosensitive microRNA, participates in the regulation of biological effects in both directly irradiated and bystander cells via its targeting of TGF-β1. MiR-663 was downregulated, while TGFB1 was upregulated in directly irradiated cells. The regulation profile of miR-663 and TGFB1, on the other hand, was reversed in bystander cells, in which an elevated miR-663 expression was exhibited and led to downregulation of TGF-β1. Further studies revealed that miR-663 interacts with TGFB1 directly and that through its binding to the core regulation sequence, miR-663 suppresses the expression of TGFB1. Based on the results, we propose that miR-663 inhibits the propagation of RIBE in a feedback mode, in which the induction of TGF-β1 by reduced miR-663 in directly irradiated cells leads to increased level of miR-663 in bystander cells. The upregulation of miR-663 in turn suppresses the expression of TGF-β1 and limits further transmission of the bystander signals. PMID:25483041

  8. Generation of heavy ion beams using femtosecond laser pulses in the target normal sheath acceleration and radiation pressure acceleration regimes

    Science.gov (United States)

    Petrov, G. M.; McGuffey, C.; Thomas, A. G. R.; Krushelnick, K.; Beg, F. N.

    2016-06-01

    Theoretical study of heavy ion acceleration from sub-micron gold foils irradiated by a short pulse laser is presented. Using two dimensional particle-in-cell simulations, the time history of the laser pulse is examined in order to get insight into the laser energy deposition and ion acceleration process. For laser pulses with intensity 3 × 10 21 W / cm 2 , duration 32 fs, focal spot size 5 μm, and energy 27 J, the calculated reflection, transmission, and coupling coefficients from a 20 nm foil are 80%, 5%, and 15%, respectively. The conversion efficiency into gold ions is 8%. Two highly collimated counter-propagating ion beams have been identified. The forward accelerated gold ions have average and maximum charge-to-mass ratio of 0.25 and 0.3, respectively, maximum normalized energy 25 MeV/nucleon, and flux 2 × 10 11 ions / sr . An analytical model was used to determine a range of foil thicknesses suitable for acceleration of gold ions in the radiation pressure acceleration regime and the onset of the target normal sheath acceleration regime. The numerical simulations and analytical model point to at least four technical challenges hindering the heavy ion acceleration: low charge-to-mass ratio, limited number of ions amenable to acceleration, delayed acceleration, and high reflectivity of the plasma. Finally, a regime suitable for heavy ion acceleration has been identified in an alternative approach by analyzing the energy absorption and distribution among participating species and scaling of conversion efficiency, maximum energy, and flux with laser intensity.

  9. Determination of Internal Target Volume for Radiation Treatment Planning of Esophageal Cancer by Using 4-Dimensional Computed Tomography (4DCT)

    Energy Technology Data Exchange (ETDEWEB)

    Chen, Xiaojian [Department of Radiation Oncology, Medical College of Wisconsin, Milwaukee, Wisconsin (United States); Lu, Haijun [Department of Radiation Oncology, Medical College of Wisconsin, Milwaukee, Wisconsin (United States); Radiation Oncology Center, Affiliated Hospital of Medical College, Qingdao University, Qingdao (China); Tai, An; Johnstone, Candice; Gore, Elizabeth [Department of Radiation Oncology, Medical College of Wisconsin, Milwaukee, Wisconsin (United States); Li, X. Allen, E-mail: ali@mcw.edu [Department of Radiation Oncology, Medical College of Wisconsin, Milwaukee, Wisconsin (United States)

    2014-09-01

    Purpose: To determine an efficient strategy for the generation of the internal target volume (ITV) for radiation treatment planning for esophageal cancer using 4-dimensional computed tomography (4DCT). Methods and Materials: 4DCT sets acquired for 20 patients with esophageal carcinoma were analyzed. Each of the 4DCT sets was binned into 10 respiratory phases. For each patient, the gross tumor volume (GTV) was delineated on the 4DCT set at each phase. Various strategies to derive ITV were explored, including the volume from the maximum intensity projection (MIP; ITV{sub M}IP), unions of the GTVs from selected multiple phases ITV2 (0% and 50% phases), ITV3 (ITV2 plus 80%), and ITV4 (ITV3 plus 60%), as well as the volumes expanded from ITV2 and ITV3 with a uniform margin. These ITVs were compared to ITV10 (the union of the GTVs for all 10 phases) and the differences were measured with the overlap ratio (OR) and relative volume ratio (RVR) relative to ITV10 (ITVx/ITV10). Results: For all patients studied, the average GTV from a single phase was 84.9% of ITV10. The average ORs were 91.2%, 91.3%, 94.5%, and 96.4% for ITV{sub M}IP, ITV2, ITV3, and ITV4, respectively. Low ORs were associated with irregular breathing patterns. ITV3s plus 1 mm uniform margins (ITV3+1) led to an average OR of 98.1% and an average RVR of 106.4%. Conclusions: The ITV generated directly from MIP underestimates the range of the respiration motion for esophageal cancer. The ITV generated from 3 phases (ITV3) may be used for regular breathers, whereas the ITV generated from 4 phases (ITV4) or ITV3 plus a 1-mm uniform margin may be applied for irregular breathers.

  10. Gene-targeted radiation therapy mediated by radiation-sensitive promoter in lung adenocarcinoma and the feasibility of micro-PET / CT in evaluation of therapeutic effectiveness in small animals

    Institute of Scientific and Technical Information of China (English)

    徐昊平

    2014-01-01

    Objective To explore the combined anti-tumor effect of radiation therapy and gene-targeted suppression of tumor neovasculature in lung adenocarcinoma in vivo,and to explore the feasibility of micro-PET/CT in dynamic evaluation of treatment effectiveness.Methods Thirty5-6 week old male BALB/c nude mice were used in this study.The mouse models of xenotransplanted human

  11. Therapeutic TNF Inhibitors can Differentially Stabilize Trimeric TNF by Inhibiting Monomer Exchange

    Science.gov (United States)

    van Schie, Karin A.; Ooijevaar-de Heer, Pleuni; Dijk, Lisanne; Kruithof, Simone; Wolbink, Gertjan; Rispens, Theo

    2016-01-01

    Tumor necrosis factor (TNF) is a homotrimeric cytokine that is a key mediator of inflammation. It is unstable at physiological concentrations and slowly converts into an inactive form. Here, we investigated the mechanism of this process by using a Förster resonance energy transfer (FRET) assay that allowed monitoring of monomeric subunit exchange in time. We observed continuous exchange of monomeric subunits even at concentrations of TNF high enough to maintain its bioactivity. The kinetics of this process closely corresponds with the appearance of monomeric subunits and disappearance of trimeric TNF in time at ng/ml concentrations as monitored by high-performance size-exclusion chromatography (HP-SEC). Furthermore, of the five therapeutic TNF inhibitors that are currently used in the clinic, three (adalimumab, infliximab, etanercept) were found to completely inhibit the monomer exchange reaction and stabilize TNF trimers, whereas golimumab and certolizumab could not prevent monomer exchange, but did slow down the exchange process. These differences were not correlated with the affinities of the TNF inhibitors, measured with both surface plasmon resonance (SPR) and in fluid phase using fluorescence-assisted HP-SEC. The stabilizing effect of these TNF inhibitors might result in prolonged residual TNF bioactivity under conditions of incomplete blocking, as observed in vitro for adalimumab. PMID:27605058

  12. Mesenchymal stem cells respond to TNF but do not produce TNF.

    NARCIS (Netherlands)

    Berk, L.C.J. van den; Jansen, B.J.H.; Siebers-Vermeulen, K.G.C.; Roelofs, H.; Figdor, C.G.; Adema, G.J.; Torensma, R.

    2010-01-01

    Previously, we demonstrated that several TLRs are expressed on cord blood-derived USSC. Stimulation of USSC with TLR agonists resulted in a marked increase of IL-6 and IL-8 production. Interestingly, TNF was undetectable after TLR stimulation, which appeared to be a result of an inactivated TNF prom

  13. Estimate of the radiation source term for 18F production via thick H218O targets bombarded with 18 MeV protons

    Science.gov (United States)

    Cruzate, Juan Ángel

    2015-12-01

    The positron-emitting radionuclide most important from the point of view of radiation protection is 18F. This isotope is usually produced by bombarding 18O-enriched water with protons. Currently there are few experimental data on the radiation source term generated during these reactions. In addition, presently there is no theoretical estimates of this source term, for use in radiation protection, validated by experimental data. Up till now this term is calculated by using nuclear interactions' simulation codes, such as ALICE91. An estimate of the energy spectra for neutrons and photons, induced by 18 MeV protons on H218O target, have been calculated by using MCNPX code with cross sections from release 0 of ENDF/B VII library for all materials except 18O, for which TENDL-2012 library was used. This estimate was validated against a recent experiment carried out at the Japan Atomic Energy Agency (JAEA). The calculated spectra have generally well reproduced experiments. The results show that the calculated radiation source term may be used to estimate the neutron activation of the accelerator components and the cyclotron building, to calculate the cyclotron shielding, and to carry out radiation protection evaluations in general, for the case of cyclotrons producing 18F by means of the 18O(p,n)18F nuclear reactions, for proton energies up to 18 MeV.

  14. TNF gene expression in macrophage activation and endotoxin tolerance

    OpenAIRE

    Chow, Nancy Ann-Marie

    2013-01-01

    TNF is an inflammatory cytokine that plays a critical role in the acute phase response to infection, and its dysregulation has been implicated in the pathology of several inflammatory and autoimmune disorders. TNF gene expression is regulated in a cell type- and inducer-specific manner that involves chromatin alterations at both the TNF promoter and distal DNase I hypersensitive (DH) sites within the TNF/LT locus. While the mechanisms underlying TNF gene activation in monocytes/macrophages an...

  15. miR-15a/16 Enhances Radiation Sensitivity of Non-Small Cell Lung Cancer Cells by Targeting the TLR1/NF-κB Signaling Pathway

    Energy Technology Data Exchange (ETDEWEB)

    Lan, Fengming [Radiation Oncology Department, PLA Airforce General Hospital, Beijing (China); Radiation Oncology Department, Tianjin Hospital, Tianjin (China); Yue, Xiao [Tianjin Huanhu Hospital, Tianjin Neurosurgery Institute, Tianjin (China); Ren, Gang; Li, Hongqi; Ping, Li; Wang, Yingjie [Radiation Oncology Department, PLA Airforce General Hospital, Beijing (China); Xia, Tingyi, E-mail: xiatingyi1959@163.com [Radiation Oncology Department, PLA Airforce General Hospital, Beijing (China)

    2015-01-01

    Purpose: Many miRNAs have been identified as essential issues and core determining factors in tumor radiation. Recent reports have demonstrated that miRNAs and Toll-like receptors could exert reciprocal effects to control cancer development in various ways. However, a novel role of miR-15a/16 in enhancing radiation sensitivity by directly targeting TLR1 has not been reported, to our knowledge. Methods and Materials: Bioinformatic analyses, luciferase reporter assay, biochemical assays, and subcutaneous tumor establishment were used to characterize the signaling pathways of miRNA-15a/16 in response to radiation treatment. Results: First, an inverse correlation between the expression of miR-15a/16 and TLR1 protein was revealed in non-small cell lung cancer (NSCLC) and normal lung tissues. Next, we corroborated that miR-15a/16 specifically bound to TLR1 3′UTR and inhibited the expression of TLR1 in H358 and A549 cells. Furthermore, miR-15a/16 downregulated the activity of the NF-κB signaling pathway through TLR1. In addition, overexpression of miR-15a/16 inhibited survival capability and increased radiation-induced apoptosis, resulting in enhancement of radiosensitivity in H358 and A549 cells. Finally, subcutaneous tumor bearing NSCLC cells in a nude mice model was established, and the results showed that combined groups (miR-15a/16 + radiation) inhibited tumor growth more significantly than did radiation alone. Conclusions: We mainly elucidate that miRNA-15a/16 can enhance radiation sensitivity by regulating the TLR1/NF-κB signaling pathway and act as a potential therapeutic approach to overcome radioresistance for lung cancer treatment.

  16. RNAi-mediated silencing of TNF-α converting enzyme to down-regulate soluble TNF-α production for treatment of acute and chronic colitis.

    Science.gov (United States)

    Song, Yoonsung; Kim, Ye-Ram; Kim, So Mi; Ul Ain, Qurrat; Jang, Kiseok; Yang, Chul-Su; Kim, Yong-Hee

    2016-10-10

    Elevated level of tumor necrosis factor-α (TNF-α), one of the inflammatory cytokines, is considered to be a potential target for the inflammatory bowel disease (IBD) therapy. Recently, TNF-α converting enzyme (TACE), a sheddase playing an important role in cleaving and releasing bioactive soluble TNF-α, has been challenged with inhibitors to treat inflammatory diseases. Here, we report a novel anti-TNF-α strategy using a short hairpin RNA silencing TACE (shTACE) to prevent and treat colitis. The shTACE formed stable complexes with nona-arginine-based bio-cleavable disulfide bond-linked poly (arginine) (PAs-s) for enhanced gene delivery. Systemically administered shTACE/PAs-s peptoplexes efficiently decreased TNF-α levels, increased survival and alleviated pathophysiological parameters representing colitis severity. Our results demonstrate effectiveness and safety of shTACE/PAs-s peptoplexes with the capacity of overcoming acute and chronic ulcerative colitis through modulation of excessive inflammatory responses in the colon, providing a strong potential as a therapeutic agent for a broad variety of inflammatory diseases.

  17. Modern Radiation Therapy for Nodal Non-Hodgkin Lymphoma—Target Definition and Dose Guidelines From the International Lymphoma Radiation Oncology Group

    DEFF Research Database (Denmark)

    Illidge, Tim; Specht, Lena; Yahalom, Joachim

    2014-01-01

    Radiation therapy (RT) is the most effective single modality for local control of non-Hodgkin lymphoma (NHL) and is an important component of therapy for many patients. Many of the historic concepts of dose and volume have recently been challenged by the advent of modern imaging and RT planning...... tools. The International Lymphoma Radiation Oncology Group (ILROG) has developed these guidelines after multinational meetings and analysis of available evidence. The guidelines represent an agreed consensus view of the ILROG steering committee on the use of RT in NHL in the modern era. The roles...... of reduced volume and reduced doses are addressed, integrating modern imaging with 3-dimensional planning and advanced techniques of RT delivery. In the modern era, in which combined-modality treatment with systemic therapy is appropriate, the previously applied extended-field and involved-field RT...

  18. Evaluation of F8-TNF-α in Models of Early and Progressive Metastatic Osteosarcoma

    Directory of Open Access Journals (Sweden)

    Bernhard Robl

    2017-06-01

    Full Text Available The targeted delivery of tumor necrosis factor-α (TNF-α with antibodies specific to splice isoforms of fibronectin [e.g., F8-TNF, specific to the extra-domain A (EDA domain of fibronectin] has already shown efficacy against experimental sarcomas but has not yet been investigated in orthotopic sarcomas. Here, we investigated F8-TNF in a syngeneic K7 M2–derived orthotopic model of osteosarcoma as a treatment against pulmonary metastases, the most frequent cause of osteosarcoma-related death. Immunofluorescence on human osteosarcoma tissue confirmed the presence of EDA in primary tumors (PTs as well as metastases. In mice, the efficacy of F8-TNF against PTs and early pulmonary metastases was evaluated. Intratibial PT growth was not affected by F8-TNF, yet early micrometastases were reduced possibly due to an F8-TNF–dependent attraction of pulmonary CD4+, CD8+, and natural killer cells. Furthermore, immunofluorescence revealed stronger expression of EDA in early pulmonary metastases compared with PT tissue. To study progressing pulmonary metastases, a hind limb amputation model was established, and the efficacy of F8-TNF, alone or combined with doxorubicin, was investigated. Despite the presence of EDA in metastases, no inhibition of progressive metastatic growth was detected. No significant differences in numbers of CD4+ or CD8+ cells or F4/80+ and Ly6G+ myeloid-derived cells were observed, although a strong association between metastatic growth and presence of pulmonary Ly6G+ myeloid-derived cells was detected. In summary, these findings demonstrate the potential of F8-TNF in activating the immune system and reducing early metastatic growth yet suggest a lack of efficacy of F8-TNF alone or combined with doxorubicin against progressing osteosarcoma metastases.

  19. Histamine derived from probiotic Lactobacillus reuteri suppresses TNF via modulation of PKA and ERK signaling.

    Directory of Open Access Journals (Sweden)

    Carissa M Thomas

    Full Text Available Beneficial microbes and probiotic species, such as Lactobacillus reuteri, produce biologically active compounds that can modulate host mucosal immunity. Previously, immunomodulatory factors secreted by L. reuteri ATCC PTA 6475 were unknown. A combined metabolomics and bacterial genetics strategy was utilized to identify small compound(s produced by L. reuteri that were TNF-inhibitory. Hydrophilic interaction liquid chromatography-high performance liquid chromatography (HILIC-HPLC separation isolated TNF-inhibitory compounds, and HILIC-HPLC fraction composition was determined by NMR and mass spectrometry analyses. Histamine was identified and quantified in TNF-inhibitory HILIC-HPLC fractions. Histamine is produced from L-histidine via histidine decarboxylase by some fermentative bacteria including lactobacilli. Targeted mutagenesis of each gene present in the histidine decarboxylase gene cluster in L. reuteri 6475 demonstrated the involvement of histidine decarboxylase pyruvoyl type A (hdcA, histidine/histamine antiporter (hdcP, and hdcB in production of the TNF-inhibitory factor. The mechanism of TNF inhibition by L. reuteri-derived histamine was investigated using Toll-like receptor 2 (TLR2-activated human monocytoid cells. Bacterial histamine suppressed TNF production via activation of the H(2 receptor. Histamine from L. reuteri 6475 stimulated increased levels of cAMP, which inhibited downstream MEK/ERK MAPK signaling via protein kinase A (PKA and resulted in suppression of TNF production by transcriptional regulation. In summary, a component of the gut microbiome, L. reuteri, is able to convert a dietary component, L-histidine, into an immunoregulatory signal, histamine, which suppresses pro-inflammatory TNF production. The identification of bacterial bioactive metabolites and their corresponding mechanisms of action with respect to immunomodulation may lead to improved anti-inflammatory strategies for chronic immune-mediated diseases.

  20. Immunogenicity of Anti-TNF-α Biotherapies

    DEFF Research Database (Denmark)

    Bendtzen, Klaus

    2015-01-01

    Specific inhibition of the cytokine, tumor necrosis factor-α (TNF), has revolutionized the treatment of patients with several autoimmune diseases, and genetically engineered anti-TNF antibody constructs now constitute a heavy medicinal expenditure in many countries. Unfortunately, up to 30......% of patients do not respond and about 50% of those who do loose response with time. Furthermore, safety may be compromised by immunogenicity with the induction of anti-drug-antibodies (ADA). Assessment of drug pharmacokinetics and ADA is increasingly recognized as a requirement for safe and rational use...... of protein drugs. The use of therapeutic strategies based on anti-TNF drug levels and ADA rather than dose-escalation has also proven to be cost-effective, as this allows individualized patient-tailored strategies rather than the current universal approach to loss of response. The objective of the present...

  1. Soluble tumor necrosis factor (TNF) receptors are effective therapeutic agents in lethal endotoxemia and function simultaneously as both TNF carriers and TNF antagonists.

    Science.gov (United States)

    Mohler, K M; Torrance, D S; Smith, C A; Goodwin, R G; Stremler, K E; Fung, V P; Madani, H; Widmer, M B

    1993-08-01

    Two forms (monomeric or dimeric) of the extracellular, ligand-binding portion of the human p80 cell-surface receptor for TNF were used to antagonize TNF activity in vitro and in vivo. The dimeric sTNFR:Fc molecule was a more potent inhibitor of TNF than the monomeric sTNFR (50 to 1000x), as assessed in vitro by inhibition of TNF binding or bioactivity and in vivo by protection of mice from an otherwise lethal injection of LPS. Surprisingly, the dimeric sTNFR:Fc construct demonstrated a beneficial effect even when administered 3 h after a lethal LPS injection (i.e., after serum TNF levels had peaked and receded). To study the mechanism by which the soluble TNFR functions in vivo, serum TNF levels were examined in mice given LPS in the presence or absence of soluble receptor. Administration of a mortality-reducing dose of sTNFR:Fc ablated the rise in serum TNF bioactivity that normally occurs in response to LPS. However, TNF bioactivity was revealed in these "TNF-negative" serum samples when the L929 bioassay was modified by inclusion of a mAb that blocks the binding of murine TNF to the human soluble TNFReceptor. These results indicate that the absence of direct cytolytic activity in the L929 assay was caused by neutralization of TNF, rather than to an absence of TNF in the serum. Moreover, administration of either monomeric sTNFR or low doses of dimeric sTNFR:Fc actually resulted in increased serum TNF levels compared to mice given LPS but no soluble receptor. However, these "agonistic" doses of soluble receptor did not lead to increased mortality when an LD60 dose of LPS was given. Thus, dimeric sTNFR are effective inhibitors of TNF and under some circumstances function simultaneously as both TNF "carriers" and antagonists of TNF biologic activity.

  2. TNF-alpha polymorphisms and breast cancer.

    Science.gov (United States)

    Yang, Yu; Feng, Rennan; Bi, Sheng; Xu, Yuqing

    2011-09-01

    Tumor necrosis factor-α (TNF-α) is an important pro-inflammatory cytokine in the development and progress in human cancer. TNF-α polymorphisms have been confirmed to influence the risk for several types of cancer, however, the associations between TNF-α polymorphisms and breast cancer (BC) remain controversial and ambiguous. The aim of this meta-analysis is to explore more precise estimations regarding this point. Electronic searches of several databases were conducted for all online publications on the associations between TNF-α-238, -308, -857, -863, -1031, -1210 polymorphisms and BC through March 2011. Odds ratios (OR) with 95% confidence intervals (95% CI) were calculated to assess the strength of these associations in fixed- and random-effect models with Review manager 5.0. A total of 17 studies with 44,442 BC patients and 49,926 controls involved were identified. This meta-analysis showed no significant association between TNF-α-308 polymorphism and BC (AA + GA vs. GG: OR = 0.95, 95% CI = 0.82-1.09) in overall and (OR = 1.44, 95% CI = 0.61-3.40) Asian populations, however, a negative association was shown in Caucasian subgroup (OR = 0.91, 95% CI = 0.85-0.97). As regards the TNF-α-238 polymorphism, the OR values (95% CI) were 0.99 (0.94-1.05), 0.94 (0.78-1.14), and 1.00 (0.95-1.05) for the overall, Asian, and Caucasian studies, respectively. No significant associations were found for other polymorphisms. Furthermore, there was a coincidence in the sensitivity analysis of these associations. No publication bias was detected in this study. To sum up, no significant associations were found between the TNF-α-308, -238, -857, -863, -1031, -1210 polymorphisms and the risk for BC in overall populations, whereas a negative association was found between TNF-α-308 polymorphism and BC in Caucasian populations.

  3. RBP-J-Regulated miR-182 Promotes TNF-α-Induced Osteoclastogenesis.

    Science.gov (United States)

    Miller, Christine H; Smith, Sinead M; Elguindy, Mahmoud; Zhang, Tuo; Xiang, Jenny Z; Hu, Xiaoyu; Ivashkiv, Lionel B; Zhao, Baohong

    2016-06-15

    Increased osteoclastogenesis is responsible for osteolysis, which is a severe consequence of inflammatory diseases associated with bone destruction, such as rheumatoid arthritis and periodontitis. The mechanisms that limit osteoclastogenesis under inflammatory conditions are largely unknown. We previously identified transcription factor RBP-J as a key negative regulator that restrains TNF-α-induced osteoclastogenesis and inflammatory bone resorption. In this study, we tested whether RBP-J suppresses inflammatory osteoclastogenesis by regulating the expression of microRNAs (miRNAs) important for this process. Using high-throughput sequencing of miRNAs, we obtained the first, to our knowledge, genome-wide profile of miRNA expression induced by TNF-α in mouse bone marrow-derived macrophages/osteoclast precursors during inflammatory osteoclastogenesis. Furthermore, we identified miR-182 as a novel miRNA that promotes inflammatory osteoclastogenesis driven by TNF-α and whose expression is suppressed by RBP-J. Downregulation of miR-182 dramatically suppressed the enhanced osteoclastogenesis program induced by TNF-α in RBP-J-deficient cells. Complementary loss- and gain-of-function approaches showed that miR-182 is a positive regulator of osteoclastogenic transcription factors NFATc1 and B lymphocyte-induced maturation protein-1. Moreover, we identified that direct miR-182 targets, Foxo3 and Maml1, play important inhibitory roles in TNF-α-mediated osteoclastogenesis. Thus, RBP-J-regulated miR-182 promotes TNF-α-induced osteoclastogenesis via inhibition of Foxo3 and Maml1. Suppression of miR-182 by RBP-J serves as an important mechanism that restrains TNF-α-induced osteoclastogenesis. Our results provide a novel miRNA-mediated mechanism by which RBP-J inhibits osteoclastogenesis and suggest that targeting of the newly described RBP-J-miR-182-Foxo3/Maml1 axis may represent an effective therapeutic approach to suppress inflammatory osteoclastogenesis and bone

  4. The role of TNF-α in mice with type 1- and 2- diabetes.

    Directory of Open Access Journals (Sweden)

    Maria Koulmanda

    Full Text Available BACKGROUND: Previously, we have demonstrated that short-term treatment of new onset diabetic Non-obese diabetic (NOD mice, mice that are afflicted with both type 1 (T1D and type 2 (T2D diabetes with either Power Mix (PM regimen or alpha1 antitrypsin (AAT permanently restores euglycemia, immune tolerance to self-islets and normal insulin signaling. METHODOLOGY AND PRINCIPAL FINDINGS: To search for relevant therapeutic targets, we have applied genome wide transcriptional profiling and systems biology oriented bioinformatics analysis to examine the impact of the PM and AAT regimens upon pancreatic lymph node (PLN and fat, a crucial tissue for insulin dependent glucose disposal, in new onset diabetic non-obese diabetic (NOD mice. Systems biology analysis identified tumor necrosis factor alpha (TNF-α as the top focus gene hub, as determined by the highest degree of connectivity, in both tissues. In PLNs and fat, TNF-α interacted with 53% and 32% of genes, respectively, associated with reversal of diabetes by previous treatments and was thereby selected as a therapeutic target. Short-term anti-TNF-α treatment ablated a T cell-rich islet-invasive and beta cell-destructive process, thereby enhancing beta cell viability. Indeed anti-TNF-α treatment induces immune tolerance selective to syngeneic beta cells. In addition to these curative effects on T1D anti-TNF-α treatment restored in vivo insulin signaling resulting in restoration of insulin sensitivity. CONCLUSIONS: In short, our molecular analysis suggested that PM and AAT both may act in part by quenching a detrimental TNF-α dependent effect in both fat and PLNs. Indeed, short-term anti-TNF-α mAb treatment restored enduring euglycemia, self-tolerance, and normal insulin signaling.

  5. Target and peripheral dose from radiation sector motions accompanying couch repositioning of patient coordinates with the Gamma Knife® Perfexion™

    Science.gov (United States)

    Tran, Tuan-Anh; Wu, Vincent; Malhotra, Harish; Steinman, James P.; Prasad, Dheerendra; Podgorsak, Matthew B.

    2011-01-01

    Background The GammaPlan™ treatment planning system (TPS) does not fully account for shutter dose when multiple shots are required to deliver a patient’s treatment. The unaccounted exposures to the target site and its periphery are measured in this study. The collected data are compared to a similar effect from the Gamma Knife® model 4C. Materials and methods. A stereotactic head frame was attached to a Leksell® 16 cm diameter spherical phantom; using a fiducial-box, CT images of the phantom were acquired and registered in the TPS. Measurements give the relationship of measured dose to the number of repositions with the patient positioning system (PPS) and to the collimator size. An absorbed dose of 10 Gy to the 50% isodose line was prescribed to the target site and all measurements were acquired with an ionization chamber. Results Measured dose increases with frequency of repositioning and with collimator size. As the radiation sectors transition between the beam on and beam off states, the target receives more shutter dose than the periphery. Shutter doses of 3.53±0.04 and 1.59±0.04 cGy/reposition to the target site are observed for the 16 and 8 mm collimators, respectively. The target periphery receives additional dose that varies depending on its position relative to the target. Conclusions The radiation sector motions for the Gamma Knife® Perfexion™ result in an additional dose due to the shutter effect. The magnitude of this exposure is comparable to that measured for the model 4C. PMID:22933947

  6. Construction of eukaryotic expression vectors of siRNA against TNF-α gene and their silencing effects on TNF-α and TGF-β1 in A549 cells%TNF-α基因siRNA真核表达载体的构建及其对A549细胞TNF-α和TGF-β1表达的影响

    Institute of Scientific and Technical Information of China (English)

    张立英; 刘绍霞; 赵国强; 张国俊

    2012-01-01

    目的:构建靶向肿瘤坏死因子α(TNF-α)基因的小干扰RNA(siRNA)真核表达载体,观察其对人肺腺癌A549细胞中TNF-α和转化生长因子-β1(TGF-β1)表达的影响.方法:依据GenBank中人TNF-α(NM_000594)序列和siRNA靶序列设计原则,设计并合成一对针对TNF-α的特异性序列(siTNF-α)和一对无关序列(siCon).退火合成DNA双链,再分别重组入pRNAT-U6.1载体,经过PCR和DNA测序鉴定.将构建好的重组载体pRNAT-U6.1-siTNF-α、pRNAT-U6.1-siCon及空载体pRNAT-U6.1用脂质体介导转染A549细胞株,分别采用Real time PCR和Western blot方法检测细胞中TNF-α和TGF-β1 mRNA和蛋白的表达水平.结果:PCR和DNA测序鉴定证实载体构建成功;转染pRNAT-U6.1-siTNF-α的A549细胞中TNF-α和TGF-β1 mRNA和蛋白表达水平均低于其他3组(FmRNA=478.663,4.081;F蛋白=123.420,6.312,P均<0.05).结论:成功构建了靶向TNF-α基因的siRNA真核表达载体,该载体能够有效沉默A549细胞中TNF-α的表达,TGF-β1基因表达亦受到抑制.%Aim: To clone the eukaryotic expression vectors of small interfering RNA ( siRNA ) against TNF-a gene and to evaluate their silencing effects on TNF-a and TGF-β1 in A549 cells. Methods: According to TNF-a gene ( NM_ 000594 ) sequence of GenBank, using RNAi Designer software to design the siRNA specific target sequence ( siTNF-α ) and the unrelated control sequence ( siCon ) for TNF-α. The annealing products were recombined into pRNAT-U6. 1, PCR and DNA sequencing confirmed the insertion sequence. The recombinant plasmids ( pRNAT-U6. l-siTNF-a,pRNAT-U6. 1-siCon ) were transfected to the A549 cells with lipofectamine,and the expressions of TNF-α, TGF-β1 mRNA and protein in cells detected by Real time PCR and Western blot methods. Results: PCR and DNA sequencing confirmed the vectors were consistent;the expressions of TNF-α, TGF-β1 mRNA and protein in the cells transfected pRNAT-U6. 1-siTNF-a were markedly lower than the other three

  7. Localization accuracy from automatic and semi-automatic rigid registration of locally-advanced lung cancer targets during image-guided radiation therapy

    Science.gov (United States)

    Robertson, Scott P.; Weiss, Elisabeth; Hugo, Geoffrey D.

    2012-01-01

    Purpose: To evaluate localization accuracy resulting from rigid registration of locally-advanced lung cancer targets using fully automatic and semi-automatic protocols for image-guided radiation therapy. Methods: Seventeen lung cancer patients, fourteen also presenting with involved lymph nodes, received computed tomography (CT) scans once per week throughout treatment under active breathing control. A physician contoured both lung and lymph node targets for all weekly scans. Various automatic and semi-automatic rigid registration techniques were then performed for both individual and simultaneous alignments of the primary gross tumor volume (GTVP) and involved lymph nodes (GTVLN) to simulate the localization process in image-guided radiation therapy. Techniques included “standard” (direct registration of weekly images to a planning CT), “seeded” (manual prealignment of targets to guide standard registration), “transitive-based” (alignment of pretreatment and planning CTs through one or more intermediate images), and “rereferenced” (designation of a new reference image for registration). Localization error (LE) was assessed as the residual centroid and border distances between targets from planning and weekly CTs after registration. Results: Initial bony alignment resulted in centroid LE of 7.3 ± 5.4 mm and 5.4 ± 3.4 mm for the GTVP and GTVLN, respectively. Compared to bony alignment, transitive-based and seeded registrations significantly reduced GTVP centroid LE to 4.7 ± 3.7 mm (p = 0.011) and 4.3 ± 2.5 mm (p < 1 × 10−3), respectively, but the smallest GTVP LE of 2.4 ± 2.1 mm was provided by rereferenced registration (p < 1 × 10−6). Standard registration significantly reduced GTVLN centroid LE to 3.2 ± 2.5 mm (p < 1 × 10−3) compared to bony alignment, with little additional gain offered by the other registration techniques. For simultaneous target alignment, centroid LE as low as 3

  8. Tumour necrosis factor-alpha (TNF), lymphotoxin and TNF receptor levels in serum from patients with Wegener's granulomatosis

    DEFF Research Database (Denmark)

    Jónasdóttir, O; Petersen, J; Bendtzen, K

    2001-01-01

    -R), and these receptors are often found in soluble forms (sTNF-R), which can modulate TNFalpha actions. To evaluate the clinical importance of the TNF family of cytokines, the serum levels of TNFalpha, TNFbeta, now termed lymphotoxin (LTalpha), and sTNF-R1 and sTNF-R2 were measured by ELISA in 8 patients with WG during......Wegener's granulomatosis (WG) is a systemic inflammatory disease with vasculitis as the key feature. Abnormal expression of tumour necrosis factor alpha (TNFalpha) is considered of prime pathogenic importance in several inflammatory diseases. The effects of TNFa are mediated by TNF receptors (TNF...... of the relative amounts of TNFalpha and sTNF-R indicated that TNFalpha was mostly bound to its soluble receptors. In WG, the serum levels of sTNF-R1 and sTNF-R2 were dramatically increased (p...

  9. Radiation damage effects on the silicon microstrip detector in E789 - a fixed target experiment at Fermilab

    Energy Technology Data Exchange (ETDEWEB)

    Kapustinsky, J.S.; Apolinski, M.; Boissevain, J.; Brown, C.N.; Brown, G.; Carey, T.A.; Chen, Y.C.; Childers, R.; Cooper, W.E.; Darden, C.W.; Gidal, G.; Glass, H.D.; Gounder, K.N.; Ho, P.M.; Isenhower, D.; Jansen, D.M.; Jeppesen, R.; Kaplan, D.M.; Kiang, G.C.; Kowitt, M.S.; Lane, D.W.; Lederman, L.; Leitch, M.J.; Lillberg, J.W.; Luebke, W.; Luk, K.B.; Martin, V.M.; McGaughey, P.L.; Mishra, C.S.; Moss, J.M.; Peng, J.C.; Preston, R.S.; Pripstein, D.; Sa, J.; Sadler, M.; Schnathorst, R.; Schub, M.H.; Schwint, R.; Snodgrass, D.; Tanikella, V.N.; Teng, P.K.; Wilson, J.W. (Los Alamos National Lab., Los Alamos, NM (United States) Northern Illinois Univ., Dekalb, IL (United States) Fermi National Accelerator Lab., Batavia, IL (United States) Abilene Christian Univ., Abilene, TX (United States) Academia Sinica (Taiwan, Province of China) National Cheng Kung Univ., Tainan (Taiwan, Province of China) Univ. of South Carolina, Columbia, SC (United States) Lawrence Berkeley Lab., CA (United States)

    1993-05-01

    A Silicon Microstrip Spectrometer has been installed and successfully operated in experiment E789 at Fermilab. The main physics goal of the experiment is to search for charged particle decays of B and D Mesons. Damage effects due to ionizing radiation exposure to the silicon during the experiment are reported. (orig.)

  10. BCL-XL regulates TNF-α-mediated cell death independently of NF-кB,FLIP and IAPs

    Institute of Scientific and Technical Information of China (English)

    Raffaella Gozzelino; Nahuai Badiola; Daniel Sanchis; Jose Rodriguez-Alvarez; Ramon Trullas; Victor J Yuste; Joan X Comella; Carme Sole; Nuria Llecha; Miguel F Segura; Rana S Moubarak; Victoria Iglesias-Guima-rais; M Jose Perez-Garcia; Stephanie Reix; Jisheng Zhang

    2008-01-01

    Upon activation,tumor necrosis factor alpha (TNF-α) receptor can engage apoptotic or survival pathways.Inhibition of macromolecular synthesis is known to sensitize cells to TNF-α-induced cell death.It is believed that this sensitization is due to the transcriptional blockade of genes regulated by NF-κB.Nevertheless,such evidence has remained elusive in the nervous system.Here,we show that TNF-α cannot normally induce apoptosis in PC12 cells or cortical neurons.However,cells treated with Actinomycin D (ActD) become susceptible to TNF-α-induced cell death through the activation of caspase-8,generation of tBid and activation of caspase-9 and -3.Analysis of several proteins involved in TNF-α receptor signaling showed no significant downregulation of NF-κB target genes,such as IAPs or FLIP,under such conditions.However,Bcl-xL protein levels,but not those of Bcl-2,Bax and Bak,are reduced by ActD or TNF-α/ActD treatments.Moreover,Bcl-xL overexpression fully protects cells against TNF-α/ActD-induced cell death.When endogenous levels of Bcl-XL are specifically downregulated by ientiviral-based RNAi,cells no longer require ActD to be sensitive to TNF-α-triggered apoptosis.Furthermore,Bcl-xL downregulation does not affect TNF-α-mediated NF-κB activation.Altogether,our results demonstrate that Bcl-xL,and not Bcl-2,FLIP or IAPs,acts as the endogenous regulator of neuronal resistance/sensitivity to TNF-α-induced apoptosis in an NF-KB-independent manner.

  11. Colocalization of endogenous TNF with a functional intracellular splice form of human TNF receptor type 2

    Directory of Open Access Journals (Sweden)

    Schütze Stephan

    2005-07-01

    Full Text Available Abstract Background Tumor necrosis factor (TNF is a pleiotropic cytokine involved in a broad spectrum of inflammatory and immune responses including proliferation, differentiation, and cell death. The biological effects of TNF are mediated via two cell surface TNF receptors: p55TNFR (TNFR1; CD120a and p75TNFR (TNFR2; CD120b. Soluble forms of these two receptors consisting of the extracellular domains are proteolytically cleaved from the membrane and act as inhibitors. A novel p75TNFR isoform generated by the use of an additional transcriptional start site has been described and was termed hicp75TNFR. We focused on the characterization of this new isoform as this protein may be involved in chronic inflammatory processes. Methods Cell lines were retroviraly transduced with hp75TNFR isoforms. Subcellular localization and colocalization studies with TNF were performed using fluorescence microscopy including exhaustive photon reassignment software, flow cytometry, and receptosome isolation by magnetic means. Biochemical properties of the hicp75TNFR were determined by affinity chromatography, ELISA, and western blot techniques. Results We describe the localization and activation of a differentially spliced and mainly intracellularly expressed isoform of human p75TNFR, termed hicp75TNFR. Expression studies with hicp75TNFR cDNA in different cell types showed the resulting protein mostly retained in the trans-Golgi network and in endosomes and colocalizes with endogenous TNF. Surface expressed hicp75TNFR behaves like hp75TNFR demonstrating susceptibility for TACE-induced shedding and NFκB activation after TNF binding. Conclusion Our data demonstrate that intracellular hicp75TNFR is not accessible for exogenously provided TNF but colocalizes with endogenously produced TNF. These findings suggest a possible intracellular activation mechanism of hicp75TNFR by endogenous TNF. Subsequent NFκB activation might induce anti-apoptotic mechanisms to protect TNF

  12. Analysis of the common deletions in the mitochondrial DNA is a sensitive biomarker detecting direct and non-targeted cellular effects of low dose ionizing radiation

    Energy Technology Data Exchange (ETDEWEB)

    Schilling-Toth, Boglarka; Sandor, Nikolett; Kis, Eniko [Department of Molecular and Tumor Radiobiology, Frederic Joliot-Curie National Research Institute for Radiobiology and Radiohygiene, Anna u 5, H-1221 Budapest (Hungary); Kadhim, Munira [Genomic Instability Research Group, School of Life Sciences, Oxford Brookes University, Oxford OX3 0BP (United Kingdom); Safrany, Geza, E-mail: safrany.geza@osski.hu [Department of Molecular and Tumor Radiobiology, Frederic Joliot-Curie National Research Institute for Radiobiology and Radiohygiene, Anna u 5, H-1221 Budapest (Hungary); Hegyesi, Hargita [Department of Molecular and Tumor Radiobiology, Frederic Joliot-Curie National Research Institute for Radiobiology and Radiohygiene, Anna u 5, H-1221 Budapest (Hungary)

    2011-11-01

    One of the key issues of current radiation research is the biological effect of low doses. Unfortunately, low dose science is hampered by the unavailability of easily performable, reliable and sensitive quantitative biomarkers suitable detecting low frequency alterations in irradiated cells. We applied a quantitative real time polymerase chain reaction (qRT-PCR) based protocol detecting common deletions (CD) in the mitochondrial genome to assess direct and non-targeted effects of radiation in human fibroblasts. In directly irradiated (IR) cells CD increased with dose and was higher in radiosensitive cells. Investigating conditioned medium-mediated bystander effects we demonstrated that low and high (0.1 and 2 Gy) doses induced similar levels of bystander responses and found individual differences in human fibroblasts. The bystander response was not related to the radiosensitivity of the cells. The importance of signal sending donor and signal receiving target cells was investigated by placing conditioned medium from a bystander response positive cell line (F11-hTERT) to bystander negative cells (S1-hTERT) and vice versa. The data indicated that signal sending cells are more important in the medium-mediated bystander effect than recipients. Finally, we followed long term effects in immortalized radiation sensitive (S1-hTERT) and normal (F11-hTERT) fibroblasts up to 63 days after IR. In F11-hTERT cells CD level was increased until 35 days after IR then reduced back to control level by day 49. In S1-hTERT cells the increased CD level was also normalized by day 42, however a second wave of increased CD incidence appeared by day 49 which was maintained up to day 63 after IR. This second CD wave might be the indication of radiation-induced instability in the mitochondrial genome of S1-hTERT cells. The data demonstrated that measuring CD in mtDNA by qRT-PCR is a reliable and sensitive biomarker to estimate radiation-induced direct and non-targeted effects.

  13. Analysis of the common deletions in the mitochondrial DNA is a sensitive biomarker detecting direct and non-targeted cellular effects of low dose ionizing radiation.

    Science.gov (United States)

    Schilling-Tóth, Boglárka; Sándor, Nikolett; Kis, Eniko; Kadhim, Munira; Sáfrány, Géza; Hegyesi, Hargita

    2011-11-01

    One of the key issues of current radiation research is the biological effect of low doses. Unfortunately, low dose science is hampered by the unavailability of easily performable, reliable and sensitive quantitative biomarkers suitable detecting low frequency alterations in irradiated cells. We applied a quantitative real time polymerase chain reaction (qRT-PCR) based protocol detecting common deletions (CD) in the mitochondrial genome to assess direct and non-targeted effects of radiation in human fibroblasts. In directly irradiated (IR) cells CD increased with dose and was higher in radiosensitive cells. Investigating conditioned medium-mediated bystander effects we demonstrated that low and high (0.1 and 2Gy) doses induced similar levels of bystander responses and found individual differences in human fibroblasts. The bystander response was not related to the radiosensitivity of the cells. The importance of signal sending donor and signal receiving target cells was investigated by placing conditioned medium from a bystander response positive cell line (F11-hTERT) to bystander negative cells (S1-hTERT) and vice versa. The data indicated that signal sending cells are more important in the medium-mediated bystander effect than recipients. Finally, we followed long term effects in immortalized radiation sensitive (S1-hTERT) and normal (F11-hTERT) fibroblasts up to 63 days after IR. In F11-hTERT cells CD level was increased until 35 days after IR then reduced back to control level by day 49. In S1-hTERT cells the increased CD level was also normalized by day 42, however a second wave of increased CD incidence appeared by day 49 which was maintained up to day 63 after IR. This second CD wave might be the indication of radiation-induced instability in the mitochondrial genome of S1-hTERT cells. The data demonstrated that measuring CD in mtDNA by qRT-PCR is a reliable and sensitive biomarker to estimate radiation-induced direct and non-targeted effects.

  14. SU-D-207A-04: Use of Gradient Echo Plural Contrast Imaging (GEPCI) in MR-Guided Radiation Therapy: A Feasibility Study Targeting Brain Treatment

    Energy Technology Data Exchange (ETDEWEB)

    Cai, B; Rao, Y; Tsien, C; Huang, J; Green, O; Mutic, S; Gach, H [Department of Radiation Oncology, Washington University School of Medicine, St. Louis, MO (United States); Wen, J; Yablonskiy, D [Department of Radiology, Washington University School of Medicine, St Louis, MO (United States)

    2016-06-15

    Purpose: To implement the Gradient Echo Plural Contrast Imaging(GEPCI) technique in MRI-simulation for radiation therapy and assess the feasibility of using GEPCI images with advanced inhomogeneity correction in MRI-guided radiotherapy for brain treatment. Methods: An optimized multigradient-echo GRE sequence (TR=50ms;TE1=4ms;delta-TE=4ms;flip angle=300,11 Echoes) was developed to generate both structural (T1w and T2*w) and functional MRIs (field and susceptibility maps) from a single acquisition. One healthy subject (Subject1) and one post-surgical brain cancer patient (Subject2) were scanned on a Philips Ingenia 1.5T MRI used for radiation therapy simulation. Another healthy subject (Subject3) was scanned on a 0.35T MRI-guided radiotherapy (MR-IGRT) system (ViewRay). A voxel spread function (VSF) was used to correct the B0 inhomogeneities caused by surgical cavities and edema for Subject2. GEPCI images and standard radiotherapy planning MRIs for this patient were compared focusing the delineation of radiotherapy target region. Results: GEPCI brain images were successfully derived from all three subjects with scan times of <7 minutes. The images derived for Subjects1&2 demonstrated that GEPCI can be applied and combined into radiotherapy MRI simulation. Despite low field, T1-weighted and R2* images were successfully reconstructed for Subject3 and were satisfactory for contour and target delineation. The R2* distribution of grey matter (center=12,FWHM=4.5) and white matter (center=14.6, FWHM=2) demonstrated the feasibility for tissue segmentation and quantification. The voxel spread function(VSF) corrected surgical site related inhomogeneities for Subject2. R2* and quantitative susceptibility map(QSM) images for Subject2 can be used to quantitatively assess the brain structure response to radiation over the treatment course. Conclusion: We implemented the GEPCI technique in MRI-simulation and in MR-IGRT system for radiation therapy. The images demonstrated that it

  15. The Role of Target and Bystander Cells in Dose-Response Relationship of Radiation-Induced Bystander Effects in Two Cell Lines

    Science.gov (United States)

    Soleymanifard, Shokouhozaman; Bahreyni Toossi, Mohammad Taghi; Sazgarnia, Ameneh; Mohebbi, Shokoufe

    2013-01-01

    Objective(s): Radiation effect induced in nonirradiated cells which are adjacent or far from irradiated cells is termed radiation-induced bystander effect (RIBE). Published data on dose-response relationship of RIBE is controversial. In the present study the role of targeted and bystander cells in RIBE dose-response relationship of two cell lines have been investigated. Materials and Methods: Two cell lines (QU-DB and MRC5) which had previously exhibited different dose-response relationship were selected. In the previous study the two cell lines received medium from autologous irradiated cells and the results showed that the magnitude of damages induced in QU-DB cells was dependent on dose unlike MRC5 cells. In the present study, the same cells irradiated with 0.5, 2 and 4 Gy gamma rays and their conditioned media were transferred to nonautologous bystander cells; such that the bystander effects due to cross-interaction between them were studied. Micronucleus assay was performed to measure the magnitude of damages induced in bystander cells (RIBE level). Results: QU-DB cells exhibited a dose-dependent response. RIBE level in MRC5 cells which received medium from 0.5 and 2 Gy QU-DB irradiated cells was not statistically different, but surprisingly when they received medium from 4Gy irradiated QU-DB cells, RIBE was abrogated. Conclusion: Results pertaining to QU-DB and MRC5 cells indicated that both target and bystander cells determined the outcome. Triggering the bystander effect depended on the radiation dose and the target cell-type, but when RIBE was triggered, dose-response relationship was predominantly determined by the bystander cell type. PMID:24298387

  16. Scattering and emission from inhomogeneous vegetation canopy and alien target beneath by using three-dimensional vector radiative transfer (3D-VRT) equation

    Energy Technology Data Exchange (ETDEWEB)

    Jin Yaqiu [Center for Wave Scattering and Remote Sensing, Fudan University, Shanghai 200433 (China)]. E-mail: yqjin@fundan.ac.cn; Liang Zichang [Center for Wave Scattering and Remote Sensing, Fudan University, Shanghai 200433 (China)

    2005-05-15

    To solve the 3D-VRT equation for the model of spatially inhomogeneous scatter media, the finite enclosure of the scatter media is geometrically divided, in both vertical z and transversal (x,y) directions, to form very thin multi-boxes. The zeroth order emission, first-order Mueller matrix of each thin box and an iterative approach of high-order radiative transfer are applied to derive high-order scattering and emission of whole inhomogeneous scatter media. Numerical results of polarized brightness temperature at microwave frequency and under different radiometer resolutions from inhomogeneous scatter model such as vegetation canopy and alien target beneath canopy are simulated and discussed.

  17. TIME- AND DOSE-DEPENDENT UP-REGULATION OF TNF-α mRNA AFTER IRRADIATION OF HUMAN NSCLC CELL LINES IN VITRO

    Institute of Scientific and Technical Information of China (English)

    2006-01-01

    Objective: Even though radiotherapy plays a major role in the local treatment of non-small cell lung cancer (NSCLC), little is known about the molecular effects of irradiation in this tumor. In the present study, we examined two NSCLC cell lines for their endogenous production of TNF-α after irradiation. To investigate the radiation-induced TNF-α production in NSCLC cell lines. Methods: Two human NSCLC cell lines (A549: squamous; NCI-H596: adenosquamous) were investigated for their TNF-α mRNA (real-time RT-PCR) after exposure to different irradiation doses (2, 5, 10, 20, 30, 40 Gy) and time intervals (1, 3, 6, 12, 24, 48 or 72 h). The TNF-α mRNA expression was quantified by real-time RT-PCR. The clonogenic survival was evaluated after irradiation with 2, 4, 6 and 8 Gy. Results: Non-irradiated NSCLC cells exhibited no or very low TNF-α expression. For the NCI-H596 cell line, TNF-α expression was significantly elevated 1~12 h (maximum 6h: 568fold increase relative to unirradiated cells) in a time-dependent manner. The radiation-induced increase could be observed after irradiation with 2 Gy reaching maximal at 40 Gy, with 83 times higher than normal controls. The clonogenic survival of these cell lines was nearly identical. Conclusion: NCI-H596 cells produce significant quantities of TNF-α following irradiation in a time- and dose-dependent manner. The pro-inflammatory cytokine TNF-α is a key mediator for the pathogenesis of radiation pneumonitis. Radiation-induced endogenous TNF-α expression in NSCLC cells may affect the normal lung adjacent to the tumor and may be associated with an adverse clinical outcome of the patient.

  18. Complications of TNF-α antagonists and iron homeostasis

    Science.gov (United States)

    TNF-α is a central regulator of inflammation and its blockade downregulates other proinflammatory cytokines, chemokines, and growth factors. Subsequently, TNF-α antagonists are currently used in treatment regimens directed toward several inflammatory diseases. Despite a beneficia...

  19. A Phylogenomic Perspective on the Radiation of Ray-Finned Fishes Based upon Targeted Sequencing of Ultraconserved Elements (UCEs)

    National Research Council Canada - National Science Library

    Faircloth, Brant C; Sorenson, Laurie; Santini, Francesco; Alfaro, Michael E

    2013-01-01

    .... Here, we provide a genomic perspective on longstanding questions regarding the diversification of major groups of ray-finned fishes through targeted enrichment of ultraconserved nuclear DNA elements (UCEs...

  20. Production, purification, and characterization of scFv TNF ligand fusion proteins.

    Science.gov (United States)

    Fick, Andrea; Wyzgol, Agnes; Wajant, Harald

    2012-01-01

    Single-chain variable fragments (scFvs) specific for tumor-associated cell surface antigens are the most broadly used reagents to direct therapeutic or diagnostic effector molecules, such as toxins, radioisotopes, and CD3-stimulating scFvs, to tumors. One novel class of effector molecules that can be targeted to tumors by scFvs are ligands of the tumor necrosis factor (TNF) family. Typically, these molecules have apoptosis inducing and/or immune stimulating properties and are therefore highly attractive for cancer treatment. N-terminal fusion of scFvs does not interfere with the receptor binding capabilities of TNF ligands and thus allows the straightforward generation of scFv TNF ligand fusion proteins. We report here a protocol for the purification of eukaryotically produced scFv TNF ligand fusion proteins based on affinity chromatography on anti-Flag agarose and further describe assays for the determination of the targeting index of this type of scFv-targeted proteins.

  1. Tools and techniques to study ligand-receptor interactions and receptor activation by TNF superfamily members.

    Science.gov (United States)

    Schneider, Pascal; Willen, Laure; Smulski, Cristian R

    2014-01-01

    Ligands and receptors of the TNF superfamily are therapeutically relevant targets in a wide range of human diseases. This chapter describes assays based on ELISA, immunoprecipitation, FACS, and reporter cell lines to monitor interactions of tagged receptors and ligands in both soluble and membrane-bound forms using unified detection techniques. A reporter cell assay that is sensitive to ligand oligomerization can identify ligands with high probability of being active on endogenous receptors. Several assays are also suitable to measure the activity of agonist or antagonist antibodies, or to detect interactions with proteoglycans. Finally, self-interaction of membrane-bound receptors can be evidenced using a FRET-based assay. This panel of methods provides a large degree of flexibility to address questions related to the specificity, activation, or inhibition of TNF-TNF receptor interactions in independent assay systems, but does not substitute for further tests in physiologically relevant conditions.

  2. Secondary radiation measurements for particle therapy applications: Charged secondaries produced by 4He and 12C ion beams in a PMMA target at large angle

    CERN Document Server

    Rucinski, A; Battistoni, G; Collamati, F; Faccini, R; Frallicciardi, P M; Mancini-Terracciano, C; Marafini, M; Mattei, I; Muraro, S; Paramatti, R; Piersanti, L; Pinci, D; Russomando, A; Sarti, A; Sciubba, A; Camillocci, E Solfaroli; Toppi, M; Traini, G; Voena, C; Patera, V

    2016-01-01

    Measurements performed with the purpose of characterizing the charged secondary radiation for dose release monitoring in particle therapy are reported. Charged secondary yields, energy spectra and emission profiles produced in poly-methyl methacrylate (PMMA) target by 4He and 12C beams of different therapeutic energies were measured at 60 and 90 degree with respect to the primary beam direction. The secondary yields of protons produced along the primary beam path in PMMA target were obtained. The energy spectra of charged secondaries were obtained from time-of-flight information, whereas the emission profiles were reconstructed exploiting tracking detector information. The measured charged secondary yields and emission profiles are in agreement with the results reported in literature and confirm the feasibility of ion beam therapy range monitoring using 12C ion beam. The feasibility of range monitoring using charged secondary particles is also suggested for 4He ion beam.

  3. Generation of quasi-monoenergetic protons from a double-species target driven by the radiation pressure of an ultraintense laser pulse

    Science.gov (United States)

    Pae, Ki Hong; Kim, Chul Min; Nam, Chang Hee

    2016-03-01

    In laser-driven proton acceleration, generation of quasi-monoenergetic proton beams has been considered a crucial feature of the radiation pressure acceleration (RPA) scheme, but the required difficult physical conditions have hampered its experimental realization. As a method to generate quasi-monoenergetic protons under experimentally viable conditions, we investigated using double-species targets of controlled composition ratio in order to make protons bunched in the phase space in the RPA scheme. From a modified optimum condition and three-dimensional particle-in-cell simulations, we showed by varying the ion composition ratio of proton and carbon that quasi-monoenergetic protons could be generated from ultrathin plane targets irradiated with a circularly polarized Gaussian laser pulse. The proposed scheme should facilitate the experimental realization of ultrashort quasi-monoenergetic proton beams for unique applications in high field science.

  4. Necroptosis Mediates TNF-Induced Toxicity of Hippocampal Neurons

    OpenAIRE

    2014-01-01

    Tumor necrosis factor-α (TNF-α) is a critical proinflammatory cytokine regulating neuroinflammation. Elevated levels of TNF-α have been associated with various neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease. However, the signaling events that lead to TNF-α-initiated neurotoxicity are still unclear. Here, we report that RIP3-mediated necroptosis, a form of regulated necrosis, is activated in the mouse hippocampus after intracerebroventricular injection of TNF-α....

  5. Lab-scale EUV nano-imaging employing a gas-puff-target source: image quality versus plasma radiation characteristics

    Science.gov (United States)

    Wachulak, Przemyslaw; Bartnik, Andrzej; Fiedorowicz, Henryk

    2012-01-01

    In this chapter we report a desk-top microscopy reaching 50nm spatial resolution in very compact setup using a gas-puff laser plasma EUV source. We present the study of source bandwidth influence on the extreme ultraviolet (EUV) microscope spatial resolution. EUV images of object obtained by illumination with variable bandwidth EUV radiation were compared in terms of knife-edge spatial resolution to study the wide bandwidth parasitic influence on spatial resolution in the EUV microscopy.

  6. Biological response to ionizing radiation in mouse embryo fibroblasts with a targeted disruption of the DNA polymerase beta gene.

    Science.gov (United States)

    Miura, M; Watanabe, H; Okochi, K; Sasaki, T; Shibuya, H

    2000-06-01

    Base excision repair (BER) is carried out by two distinct pathways in mammalian cells, one dependent on DNA polymerase beta (Polb) and the other on proliferating cell nuclear antigen (Pcna). We studied whether the Polb-dependent pathway plays an important role in BER in vivo after exposure to ionizing radiation. For this purpose, we used mouse embryo fibroblasts derived from wild-type and Polb gene knockout littermates. Both cell lines had essentially the same clonogenic cell survival and low levels of apoptosis as determined by a colony formation assay and by a change in mitochondrial membrane potential, respectively. No significant cleavage of protein kinase C delta (Pkcd) in vivo, which is a substrate for caspase 3, was detected, and intact Pkcd was retained in both cell lines for at least 72 h after irradiation. Similar significant increases in caspase 3-like activities as measured by Asp-Glu-Val-Asp (DEVD) cleaving activity in vitro were observed in both cell lines after irradiation. Radiation induced cell cycle arrest in the form of a G(2)-phase block, and G(2)/M-phase fractions reached a peak approximately 10 h after irradiation and decreased thereafter with a similar time course in both cell lines. Similar levels of chromatin-bound Pcna were observed immediately after irradiation in non-S-phase cells of both cell lines and disappeared by 4 h after irradiation. We conclude that the deficiency in Polb does not have a significant influence on the radiation responses of these cells. Together with evidence accumulated in vitro, these results strongly support the idea that the Pcna-dependent pathway predominantly acts in BER of radiation-induced DNA damage in vivo.

  7. Impact of 18-fluorodeoxyglucose positron emission tomography on computed tomography defined target volumes in radiation treatment planning of esophageal cancer: reduction in geographic misses with equal inter-observer variability: PET/CT improves esophageal target definition.

    Science.gov (United States)

    Schreurs, L M A; Busz, D M; Paardekooper, G M R M; Beukema, J C; Jager, P L; Van der Jagt, E J; van Dam, G M; Groen, H; Plukker, J Th M; Langendijk, J A

    2010-08-01

    Target volume definition in modern radiotherapy is based on planning computed tomography (CT). So far, 18-fluorodeoxyglucose positron emission tomography (FDG-PET) has not been included in planning modality in volume definition of esophageal cancer. This study evaluates fusion of FDG-PET and CT in patients with esophageal cancer in terms of geographic misses and inter-observer variability in volume definition. In 28 esophageal cancer patients, gross, clinical and planning tumor volumes (GTV; CTV; PTV) were defined on planning CT by three radiation oncologists. After software-based emission tomography and computed tomography (PET/CT) fusion, tumor delineations were redefined by the same radiation-oncologists. Concordance indexes (CCI's) for CT and PET/CT based GTV, CTV and PTV were calculated for each pair of observers. Incorporation of PET/CT modified tumor delineation in 17/28 subjects (61%) in cranial and/or caudal direction. Mean concordance indexes for CT-based CTV and PTV were 72 (55-86)% and 77 (61-88)%, respectively, vs. 72 (47-99)% and 76 (54-87)% for PET/CT-based CTV and PTV. Paired analyses showed no significant difference in CCI between CT and PET/CT. Combining FDG-PET and CT may improve target volume definition with less geographic misses, but without significant effects on inter-observer variability in esophageal cancer.

  8. WNT/β-catenin pathway modulates the TNF-α-induced inflammatory response in bronchial epithelial cells.

    Science.gov (United States)

    Jang, Jaewoong; Jung, Yoonju; Chae, Seyeon; Chung, Sang-In; Kim, Seok-Min; Yoon, Yoosik

    2017-03-04

    In this study, TNF-α was found to activate the WNT/β-catenin pathway in BEAS-2B human bronchial epithelial cells. Levels of phospho-LRP6, Dvl-2, and phospho-GSK-3β were elevated, while that of Axin was reduced by TNF-α treatment. Nuclear translocation of β-catenin and the reporter activity of a β-catenin-responsive promoter were increased by TNF-α treatment. Under the same experimental conditions, TNF-α activated the NF-κB signaling, which includes the phosphorylation and degradation of IκB and nuclear translocation and target DNA binding of NF-κB, and it was found that an inhibitor of NF-κB activation, JSH-23, inhibited TNF-α-induced Wnt signaling as well as NF-κB signaling. It was also found that recombinant Wnt proteins induced NF-κB nuclear translocations and its target DNA binding, suggesting that Wnt signaling and NF-κB signaling were inter-connected. TNF-α-induced modulations of IκB and NF-κB as well as pro-inflammatory cytokine expression were significantly suppressed by the transfection of β-catenin siRNA compared to that of control siRNA. Transfection of a β-catenin expression plasmid augmented the TNF-α-induced modulations of IκB and NF-κB as well as pro-inflammatory cytokine expression. These results clearly demonstrated that the WNT/β-catenin pathway modulates the inflammatory response induced by TNF-α, suggesting that this pathway may be a useful target for the effective treatment of bronchial inflammation.

  9. Taming TNF : strategies to restrain this proinflammatory cytokine

    NARCIS (Netherlands)

    Eigler, A; Sinha, B; Hartmann, G; Endres, S

    1997-01-01

    Recent studies have demonstrated the essential role of tumor necrosis factor alpha (TNF-alpha) in rheumatoid arthritis and Crohn's disease. This article discusses agents known to suppress the formation or activity of TNF-alpha, and summarizes clinical studies using anti-TNF-alpha antibodies.

  10. Effects of propyl gallate on interaction between TNF-α and sTNFR-I using an affinity biosensor

    Institute of Scientific and Technical Information of China (English)

    Jing LI; Jia-dong HUANG; Bao-yan WU; Qiang CHEN

    2005-01-01

    Aim: To study the effects of propyl gallate on the interaction of tumor necrosis factor-α (TNF-α) with its soluble receptor, sTNFR-I. Methods: Interactions between TNF-α and sTNFR-I were analyzed using an IAsys biosensor. sTNFR-I was immobilized on the carboxymethyl dextran (CMD) surface of the IAsys biosensor cuvettes, and TNF-α preincubated with different concentrations of propyl gallate was added to the cuvettes. The resonant angle shift caused by the binding between TNF-α and sTNFR-I was then recorded. Results: sTNFR-I was immobilized on the CMD surface at a density of 2.76 ng/mm2. TNF-α then bound the immobilized sTNFR-I specifically, and propyl gallate was able to enhance the binding between TNF-α and sTNFR-I in a dose-dependent manner. Conclusion:The binding between TNF-α and sTNFR-I is one of the targets that propyl gallate can act on in vivo. The IAsys biosensor offers a new clue as to the study on the mechanisms of action of propyl gallate.

  11. Anti-TNF drives regulatory T cell expansion by paradoxically promoting membrane TNF–TNF-RII binding in rheumatoid arthritis

    OpenAIRE

    Nguyen, Dao Xuan; Ehrenstein, Michael R.

    2016-01-01

    Nguyen and Ehrenstein reveal that anti-TNF antibodies paradoxically enhance membrane TNF–TNF-RII interactions to increase Foxp3 expression and confer upon T reg cells the ability to suppress Th17 cells in rheumatoid arthritis patients.

  12. TNF-α and adipocyte biology

    OpenAIRE

    Cawthorn, William P.; Sethi, Jaswinder K.

    2007-01-01

    Dyslipidemia and insulin resistance are commonly associated with catabolic or lipodystrophic conditions (such as cancer and sepsis) and with pathological states of nutritional overload (such as obesity-related type 2 diabetes). Two common features of these metabolic disorders are adipose tissue dysfunction and elevated levels of tumour necrosis factor-alpha (TNF-α). Herein, we review the multiple actions of this pro-inflammatory adipokine on adipose tissue biology. These include inhibition of...

  13. Effects of target fragmentation on evaluation of LET spectra from space radiation in low-earth orbit (LEO) environment: impact on SEU predictions

    Science.gov (United States)

    Shinn, J. L.; Cucinotta, F. A.; Wilson, J. W.; Badhwar, G. D.; O'Neill, P. M.; Badavi, F. F.

    1995-01-01

    Recent improvements in the radiation transport code HZETRN/BRYNTRN and galactic cosmic ray environmental model have provided an opportunity to investigate the effects of target fragmentation on estimates of single event upset (SEU) rates for spacecraft memory devices. Since target fragments are mostly of very low energy, an SEU prediction model has been derived in terms of particle energy rather than linear energy transfer (LET) to account for nonlinear relationship between range and energy. Predictions are made for SEU rates observed on two Shuttle flights, each at low and high inclination orbit. Corrections due to track structure effects are made for both high energy ions with track structure larger than device sensitive volume and for low energy ions with dense track where charge recombination is important. Results indicate contributions from target fragments are relatively important at large shield depths (or any thick structure material) and at low inclination orbit. Consequently, a more consistent set of predictions for upset rates observed in these two flights is reached when compared to an earlier analysis with CREME model. It is also observed that the errors produced by assuming linear relationship in range and energy in the earlier analysis have fortuitously canceled out the errors for not considering target fragmentation and track structure effects.

  14. A new analysis method using Bragg curve spectroscopy for a Multi-purpose Active-target Particle Telescope for radiation monitoring

    Science.gov (United States)

    Losekamm, M. J.; Milde, M.; Pöschl, T.; Greenwald, D.; Paul, S.

    2017-02-01

    Traditional radiation detectors can either measure the total radiation dose omnidirectionally (dosimeters), or determine the incoming particles characteristics within a narrow field of view (spectrometers). Instantaneous measurements of anisotropic fluxes thus require several detectors, resulting in bulky setups. The Multi-purpose Active-target Particle Telescope (MAPT), employing a new detection principle, is designed to measure particle fluxes omnidirectionally and be simultaneously a dosimeter and spectrometer. It consists of an active core of scintillating fibers whose light output is measured by silicon photomultipliers, and fits into a cube with an edge length of 10 cm. It identifies particles using extended Bragg curve spectroscopy, with sensitivity to charged particles with kinetic energies above 25 MeV. MAPT's unique layout results in a geometrical acceptance of approximately 800 cm2 sr and an angular resolution of less than 6°, which can be improved by track-fitting procedures. In a beam test of a simplified prototype, the energy resolution was found to be less than 1 MeV for protons with energies between 30 and 70 MeV. Possible applications of MAPT include the monitoring of radiation environments in spacecraft and beam monitoring in medical facilities.

  15. Changes in the planning target volume and liver volume dose based on the selected respiratory phase in respiratory-gated radiation therapy for a hepatocellular carcinoma

    Science.gov (United States)

    Lee, Jae-Seung; Im, In-Chul; Kang, Su-Man; Goo, Eun-Hoe; Baek, Seong-Min

    2013-11-01

    The aim of this study was to quantitatively analyze the changes in the planning target volume (PTV) and liver volume dose based on the respiratory phase to identify the optimal respiratory phase for respiratory-gated radiation therapy for a hepatocellular carcinoma (HCC). Based on the standardized procedure for respiratory-gated radiation therapy, we performed a 4-dimensional computed tomography simulation for 0 ˜ 90%, 30 ˜ 70%, and 40 ˜ 60% respiratory phases to assess the respiratory stability (S R ) and the defined PTV i for each respiratory phase i. A treatment plan was established, and the changes in the PTV i and dose volume of the liver were quantitatively analyzed. Most patients (91.5%) passed the respiratory stability test (S R = 0.111 ± 0.015). With standardized respiration training exercises, we were able to minimize the overall systematic error caused by irregular respiration. Furthermore, a quantitative analysis to identify the optimal respiratory phase revealed that when a short respiratory phase (40 ˜ 60%) was used, the changes in the PTV were concentrated inside the center line; thus, we were able to obtain both a PTV margin accounting for respiration and a uniform radiation dose within the PTV.

  16. Characterisation of TNF block haplotypes affecting the production of TNF and LTA.

    Science.gov (United States)

    Tan, J H; Temple, S E L; Kee, C; Waterer, G W; Tan, C R T; Gut, I; Price, P

    2011-02-01

    Polymorphisms in the central major histocompatibility complex (MHC) (particularly TNF and adjacent genes) associate with several immunopathological diseases and with susceptibility to pneumonia. The MHC is characterised by strong linkage disequilibrium (LD), so identification of loci affecting disease must be based on haplotypes. We have defined 31 tumour necrosis factor (TNF) block haplotypes (denoted FV1-31) in Caucasians, Asians and Australian Aboriginals. This study correlates the carriage of TNF block haplotypes with TNF and lymphotoxin alpha (LTA) protein production by peripheral blood mononuclear cells from 205 healthy Caucasian subjects, following in vitro stimulation with Streptococcus pneumoniae (S. pneumoniae; gram-positive bacteria), Escherichia coli (E. coli; gram-negative bacteria) or TNF over 4, 8 and 24 h. Fifteen haplotypes were present at >1%, accounting for 94.5% of the cohort. The haplotypes were grouped into five families based on common alleles. Following stimulation, cells from carriers of the FV10 haplotype (family 2) produced less LTA compared with non-FV10 carriers. Carriers of the FV18 haplotype (family 4) produced more LTA than other donors. Induction of TNF by S. pneumoniae following 24 h stimulation was also greater in donors with FV18. The FV18 haplotype associated with the 44.1 MHC ancestral haplotype (HLA-A2, -C5, -B44, -DRB1*0401 and -DQB1*0301) that has few disease associations. FV16 occurred in the 8.1 MHC haplotype (HLA-A2, B8, DR3) that is associated with multiple immunopathological diseases. FV16 did not affect TNF or LTA levels. The findings suggest that many genetic variations critical in vivo are not effectively modelled by short-term cultures.

  17. Interaction of human TNF and beta2-microglobulin with Tanapox virus-encoded TNF inhibitor, TPV-2L.

    Science.gov (United States)

    Rahman, Masmudur M; Jeng, David; Singh, Rajkumari; Coughlin, Jake; Essani, Karim; McFadden, Grant

    2009-04-10

    Tanapox virus (TPV) encodes and expresses a secreted TNF-binding protein, TPV-2L or gp38, that displays inhibitory properties against TNF from diverse mammalian species, including human, monkey, canine and rabbit. TPV-2L also has sequence similarity with the MHC-class I heavy chain and interacts differently with human TNF as compared to the known cellular TNF receptors or any of the known virus-encoded TNF receptor homologs derived from many poxviruses. In order to determine the TNF binding region in TPV-2L, various TPV-2L C-terminal truncations and internal deletions were created and the muteins were expressed using recombinant baculovirus vectors. C-terminal deletions from TPV-2L resulted in reduced binding affinity for human TNF and specific mutants of TNF that discriminate between TNF-R1 and TNF-R2. However, deletion of C-terminal 42 amino acid residues totally abolished the binding of human TNF and its mutants. Removal of any of the predicted internal domains resulted in a mutant TPV-2L protein incapable of binding to human TNF. Deletion of C-terminal residues also affected the ability of TPV-2L to block TNF-induced cellular cytotoxicity. In addition to TNF, TPV-2L can also form complexes with human beta2-microglobulin to form a novel macromolecular complex. In summary, the TPV-2L protein is a bona fide MHC-1 heavy chain family member that binds and inhibits human TNF in a fashion very distinct from other known poxvirus-encoded TNF inhibitors, and also can form a novel complex with the human MHC-1 light chain, beta2-microglobulin.

  18. Comparison of surface matching and target matching for image-guided pelvic radiation therapy for both supine and prone patient positions.

    Science.gov (United States)

    Zhao, Hui; Wang, Brian; Sarkar, Vikren; Rassiah-Szegedi, Prema; Huang, Y Jessica; Szegedi, Martin; Huang, Long; Gonzalez, Victor; Salter, Bill

    2016-05-01

    We investigate the difference between surface matching and target matching for pelvic radiation image guidance. The uniqueness of our study is that all patients have multiple CT-on-rails (CTOR) scans to compare to corresponding AlignRT images. Ten patients receiving pelvic radiation were enrolled in this study. Two simulation CT scans were performed in supine and prone positions for each patient. Body surface contours were generated in treatment planning system and exported to AlignRT to serve as reference images. During treatment day, the patient was aligned to treatment isocenter with room lasers, and then scanned with both CTOR and AlignRT. Image-guidance shifts were calculated for both modalities by comparison to the simulation CT and the differences between them were analyzed for both supine and prone positions, respectively. These procedures were performed for each patient once per week for five weeks. The difference of patient displacement between AlignRT and CTOR was analyzed. For supine position, five patients had an average difference of displacement between AlignRT and CTOR along any direction (vertical, longitudinal, and lateral) greater than 0.5 cm, and one patient greater than 1 cm. Four patients had a maximum difference greater than 1 cm. For prone position, seven patients had an average difference greater than 0.5 cm, and three patients greater than 1 cm. Nine patients had a maximum difference greater than 1 cm. The difference of displacement between AlignRT and CTOR was greater for the prone position than for the supine position. For the patients studied here, surface matching does not appear to be an advisable image-guidance approach for pelvic radiation therapy for patients with either supine or prone position. There appears to be a potential for large alignment discrepancies (up to 2.25 cm) between surface matching and target matching. PACS number(s): 87.55.-x.

  19. Radiation doses to operators performing transjugular intrahepatic portosystemic shunt using a flat-panel detector-based system and ultrasound guidance for portal vein targeting.

    Science.gov (United States)

    Miraglia, Roberto; Gerasia, Roberta; Maruzzelli, Luigi; D'Amico, Mario; Luca, Angelo

    2017-05-01

    The aim of this study was to prospectively evaluate effective dose (E) of operators performing transjugular intrahepatic portosystemic shunts (TIPS) in a single centre. Patients' radiation exposure was also collected. Between 8/2015 and 6/2016, 45 consecutive TIPS were performed in adult patients using a flat-panel detector-based system (FPDS) and real-time ultrasound guidance (USG) for portal vein targeting. Electronic personal dosimeters were used to measure radiation doses to the primary and assistant operators, anaesthesia nurse and radiographer. Patients' radiation exposure was measured with dose area product (DAP); fluoroscopy time (FT) was also collected. Mean E for the primary operator was 1.40 μSv (SD 2.68, median 0.42, range 0.12 - 12.18), for the assistant operator was 1.29 μSv (SD 1.79, median 0.40, range 0.10 - 4.89), for the anaesthesia nurse was 0.21 μSv (SD 0.67, median 0.10, range 0.03 - 3.99), for the radiographer was 0.42 μSv (SD 0.71, median 0.25, range 0.03 - 2.67). Mean patient DAP was 59.31 GyCm(2) (SD 56.91, median 31.58, range 7.66 - 281.40); mean FT was 10.20 min (SD 7.40, median 10.40, range 3.8 - 31.8). The use of FPDS and USG for portal vein targeting allows a reasonably low E to operators performing TIPS. • The operators' E vary according to the complexity of the procedure. • FPDS and USG allow a reasonably low E to TIPS operators. • FPDS and USG have an important role in reducing the occupational exposure.

  20. Comparison of surface matching and target matching for image-guided pelvic radiation therapy for both supine and prone patient positions.

    Science.gov (United States)

    Zhao, Hui; Wang, Brian; Sarkar, Vikren; Rassiah-Szegedi, Prema; Huang, Y Jessica; Szegedi, Martin; Huang, Long; Gonzalez, Victor; Salter, Bill

    2016-05-08

    We investigate the difference between surface matching and target matching for pelvic radiation image guidance. The uniqueness of our study is that all patients have multiple CT-on-rails (CTOR) scans to compare to corresponding AlignRT images. Ten patients receiving pelvic radiation were enrolled in this study. Two simulation CT scans were performed in supine and prone positions for each patient. Body surface contours were generated in treatment planning system and exported to AlignRT to serve as reference images. During treatment day, the patient was aligned to treatment isocenter with room lasers, and then scanned with both CTOR and AlignRT. Image-guidance shifts were calculated for both modalities by com-parison to the simulation CT and the differences between them were analyzed for both supine and prone positions, respectively. These procedures were performed for each patient once per week for five weeks. The difference of patient displace-ment between AlignRT and CTOR was analyzed. For supine position, five patients had an average difference of displacement between AlignRT and CTOR along any direction (vertical, longitudinal, and lateral) greater than 0.5 cm, and one patient greater than 1 cm. Four patients had a maximum difference greater than 1 cm. For prone position, seven patients had an average difference greater than 0.5 cm, and three patients greater than 1 cm. Nine patients had a maximum difference greater than 1 cm. The difference of displacement between AlignRT and CTOR was greater for the prone position than for the supine position. For the patients studied here, surface matching does not appear to be an advisable image-guidance approach for pelvic radiation therapy for patients with either supine or prone position. There appears to be a potential for large alignment discrepancies (up to 2.25 cm) between surface matching and target matching.

  1. TNF/TNFR1 signaling up-regulates CCR5 expression by CD8+ T lymphocytes and promotes heart tissue damage during Trypanosoma cruzi infection: beneficial effects of TNF-α blockade

    Directory of Open Access Journals (Sweden)

    Karina Kroll-Palhares

    2008-06-01

    Full Text Available In Chagas disease, understanding how the immune response controls parasite growth but also leads to heart damage may provide insight into the design of new therapeutic strategies. Tumor necrosis factor-alpha (TNF-α is important for resistance to acute Trypanosoma cruzi infection; however, in patients suffering from chronic T. cruzi infection, plasma TNF-α levels correlate with cardiomyopathy. Recent data suggest that CD8-enriched chagasic myocarditis formation involves CCR1/CCR5-mediated cell migration. Herein, the contribution of TNF-α, especially signaling through the receptor TNFR1/p55, to the pathophysiology of T. cruzi infection was evaluated with a focus on the development of myocarditis and heart dysfunction. Colombian strain-infected C57BL/6 mice had increased frequencies of TNFR1/p55+ and TNF-α+ splenocytes. Although TNFR1-/- mice exhibited reduced myocarditis in the absence of parasite burden, they succumbed to acute infection. Similar to C57BL/6 mice, Benznidazole-treated TNFR1-/- mice survived acute infection. In TNFR1-/- mice, reduced CD8-enriched myocarditis was associated with defective activation of CD44+CD62Llow/- and CCR5+ CD8+ lymphocytes. Also, anti-TNF-α treatment reduced the frequency of CD8+CCR5+ circulating cells and myocarditis, though parasite load was unaltered in infected C3H/HeJ mice. TNFR1-/- and anti-TNF-α-treated infected mice showed regular expression of connexin-43 and reduced fibronectin deposition, respectively. Furthermore, anti-TNF-α treatment resulted in lower levels of CK-MB, a cardiomyocyte lesion marker. Our results suggest that TNF/TNFR1 signaling promotes CD8-enriched myocarditis formation and heart tissue damage, implicating the TNF/TNFR1 signaling pathway as a potential therapeutic target for control of T. cruzi-elicited cardiomyopathy.

  2. TNF/TNFR1 signaling up-regulates CCR5 expression by CD8+ T lymphocytes and promotes heart tissue damage during Trypanosoma cruzi infection: beneficial effects of TNF-alpha blockade.

    Science.gov (United States)

    Kroll-Palhares, Karina; Silvério, Jaline Coutinho; Silva, Andrea Alice da; Michailowsky, Vladimir; Marino, Ana Paula; Silva, Neide Maria; Carvalho, Cristiano Marcelo Espinola; Pinto, Luzia Maria de Oliveira; Gazzinelli, Ricardo Tostes; Lannes-Vieira, Joseli

    2008-06-01

    In Chagas disease, understanding how the immune response controls parasite growth but also leads to heart damage may provide insight into the design of new therapeutic strategies. Tumor necrosis factor-alpha (TNF-alpha) is important for resistance to acute Trypanosoma cruzi infection; however, in patients suffering from chronic T. cruzi infection, plasma TNF-alpha levels correlate with cardiomyopathy. Recent data suggest that CD8-enriched chagasic myocarditis formation involves CCR1/CCR5-mediated cell migration. Herein, the contribution of TNF-alpha, especially signaling through the receptor TNFR1/p55, to the pathophysiology of T. cruzi infection was evaluated with a focus on the development of myocarditis and heart dysfunction. Colombian strain-infected C57BL/6 mice had increased frequencies of TNFR1/p55+ and TNF-alpha+ splenocytes. Although TNFR1-/- mice exhibited reduced myocarditis in the absence of parasite burden, they succumbed to acute infection. Similar to C57BL/6 mice, Benznidazole-treated TNFR1-/- mice survived acute infection. In TNFR1-/- mice, reduced CD8-enriched myocarditis was associated with defective activation of CD44+CD62Llow/- and CCR5+ CD8+ lymphocytes. Also, anti-TNF-alpha treatment reduced the frequency of CD8+CCR5+ circulating cells and myocarditis, though parasite load was unaltered in infected C3H/HeJ mice. TNFR1-/- and anti-TNF-alpha-treated infected mice showed regular expression of connexin-43 and reduced fibronectin deposition, respectively. Furthermore, anti-TNF-alpha treatment resulted in lower levels of CK-MB, a cardiomyocyte lesion marker. Our results suggest that TNF/TNFR1 signaling promotes CD8-enriched myocarditis formation and heart tissue damage, implicating the TNF/TNFR1 signaling pathway as a potential therapeutic target for control of T. cruzi-elicited cardiomyopathy.

  3. Targeting the Renin–Angiotensin System Combined With an Antioxidant Is Highly Effective in Mitigating Radiation-Induced Lung Damage

    Energy Technology Data Exchange (ETDEWEB)

    Mahmood, Javed [Ontario Cancer Institute and the Campbell Family Institute for Cancer Research, Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario (Canada); Radiation Medicine Program, STTARR Innovation Centre, Princess Margaret Cancer Centre, Toronto, Ontario (Canada); Jelveh, Salomeh [Radiation Medicine Program, STTARR Innovation Centre, Princess Margaret Cancer Centre, Toronto, Ontario (Canada); Zaidi, Asif [Ontario Cancer Institute and the Campbell Family Institute for Cancer Research, Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario (Canada); Doctrow, Susan R. [Pulmonary Center, Department of Medicine, Boston University, Boston, Massachusetts (United States); Medhora, Meetha [Department of Radiation Oncology, Medical College of Wisconsin, Milwaukee, Wisconsin (United States); Hill, Richard P., E-mail: hill@uhnres.utoronto.ca [Ontario Cancer Institute and the Campbell Family Institute for Cancer Research, Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario (Canada); Departments of Medical Biophysics and Radiation Oncology, University of Toronto, Toronto, Ontario (Canada)

    2014-07-15

    Purpose: To investigate the outcome of suppression of the renin angiotensin system using captopril combined with an antioxidant (Eukarion [EUK]-207) for mitigation of radiation-induced lung damage in rats. Methods and Materials: The thoracic cavity of female Sprague-Dawley rats was irradiated with a single dose of 11 Gy. Treatment with captopril at a dose of 40 mg/kg/d in drinking water and EUK-207 given by subcutaneous injection (8 mg/kg daily) was started 1 week after irradiation (PI) and continuing until 14 weeks PI. Breathing rate was monitored until the rats were killed at 32 weeks PI, when lung fibrosis was assessed by lung hydroxyproline content. Lung levels of the cytokine transforming growth factor-β1 and macrophage activation were analyzed by immunohistochemistry. Oxidative DNA damage was assessed by 8-hydroxy-2-deoxyguanosine levels, and lipid peroxidation was measured by a T-BARS assay. Results: The increase in breathing rate in the irradiated rats was significantly reduced by the drug treatments. The drug treatment also significantly decreased the hydroxyproline content, 8-hydroxy-2-deoxyguanosine and malondialdehyde levels, and levels of activated macrophages and the cytokine transforming growth factor-β1 at 32 weeks. Almost complete mitigation of these radiation effects was observed by combining captopril and EUK-207. Conclusion: Captopril and EUK-207 can provide mitigation of radiation-induced lung damage out to at least 32 weeks PI after treatment given 1-14 weeks PI. Overall the combination of captopril and EUK-207 was more effective than the individual drugs used alone.

  4. Development of a New Positron Emission Tomography Tracer for Targeting Tumor Angiogenesis: Synthesis, Small Animal Imaging, and Radiation Dosimetry

    Directory of Open Access Journals (Sweden)

    David S. Lalush

    2013-05-01

    Full Text Available Angiogenesis plays a key role in cancer progression and correlates with disease aggressiveness and poor clinical outcomes. Affinity ligands discovered by screening phage display random peptide libraries can be engineered to molecularly target tumor blood vessels for noninvasive imaging and early detection of tumor aggressiveness. In this study, we tested the ability of a phage-display-selected peptide sequence recognizing specifically bone marrow- derived pro-angiogenic tumor-homing cells, the QFP-peptide, radiolabeled with 64Cu radioisotope to selectively image tumor vasculature in vivo by positron emission tomography (PET. To prepare the targeted PET tracer we modified QFP-phage with the DOTA chelator and radiolabeled the purified QFP-phage-DOTA intermediate with 64Cu to obtain QFP-targeted radioconjugate with high radiopharmaceutical yield and specific activity. We evaluated the new PET tracer in vivo in a subcutaneous (s.c. Lewis lung carcinoma (LLC mouse model and conducted tissue distribution, small animal PET/CT imaging study, autoradiography, histology, fluorescence imaging, and dosimetry assessments. The results from this study show that, in the context of the s.c. LLC immunocompetent mouse model, the QFP-tracer can target tumor blood vessels selectively. However, further optimization of the biodistribution and dosimetry profile of the tracer is necessary to ensure efficient radiopharmaceutical applications enabled by the biological specificity of the QFP-peptide.

  5. Pathogenetic and Therapeutic Applications of Tumor Necrosis Factor-α (TNF-α in Major Depressive Disorder: A Systematic Review

    Directory of Open Access Journals (Sweden)

    Ke Ma

    2016-05-01

    Full Text Available Major depressive disorder (MDD is characterized by mood, vegetative, cognitive, and even psychotic symptoms and signs that can cause substantial impairments in quality of life and functioning. Up to now, the exact pathogenesis of MDD remains poorly understood. Recent research has begun to reveal that the pro-inflammatory cytokines, particularly, tumor necrosis factor-α (TNF-α, play an integral role in the pathophysiology of depressive disorders and the mechanism of antidepressant treatment. On the base of several observations: it is found that subsets of MDD patients have enhanced plasma levels TNF-α; antidepressant treatments had linked with the decline of TNF-α; central administration of TNF-α gives rise to sickness behavior which shares features with depression; and a blockade of it can ameliorate depressive symptomatology in animal models and clinical trials. In this review article, we focus on recent evidence linking TNF-α and MDD looking at data from animal and clinical studies, illustrating the pathophysiological role, susceptibility and its therapeutic application in depression. We conclude by discussing future directions for research, in particular the opportunities for the development of novel therapeutics that target TNF-α. This will be very important for designing preventative strategies and for the identification of new drug targets and preventative strategies.

  6. Pathogenetic and Therapeutic Applications of Tumor Necrosis Factor-α (TNF-α) in Major Depressive Disorder: A Systematic Review.

    Science.gov (United States)

    Ma, Ke; Zhang, Hongxiu; Baloch, Zulqarnain

    2016-05-14

    Major depressive disorder (MDD) is characterized by mood, vegetative, cognitive, and even psychotic symptoms and signs that can cause substantial impairments in quality of life and functioning. Up to now, the exact pathogenesis of MDD remains poorly understood. Recent research has begun to reveal that the pro-inflammatory cytokines, particularly, tumor necrosis factor-α (TNF-α), play an integral role in the pathophysiology of depressive disorders and the mechanism of antidepressant treatment. On the base of several observations: it is found that subsets of MDD patients have enhanced plasma levels TNF-α; antidepressant treatments had linked with the decline of TNF-α; central administration of TNF-α gives rise to sickness behavior which shares features with depression; and a blockade of it can ameliorate depressive symptomatology in animal models and clinical trials. In this review article, we focus on recent evidence linking TNF-α and MDD looking at data from animal and clinical studies, illustrating the pathophysiological role, susceptibility and its therapeutic application in depression. We conclude by discussing future directions for research, in particular the opportunities for the development of novel therapeutics that target TNF-α. This will be very important for designing preventative strategies and for the identification of new drug targets and preventative strategies.

  7. IGFBP-3 inhibits TNF-α production and TNFR-2 signaling to protect against retinal endothelial cell apoptosis.

    Science.gov (United States)

    Zhang, Qiuhua; Steinle, Jena J

    2014-09-01

    In models of diabetic retinopathy, insulin-like growth factor binding protein-3 (IGFBP-3) protects against tumor necrosis factors-alpha (TNF-α)-mediated apoptosis of retinal microvascular endothelial cells (REC), but the underlying mechanisms are unclear. Our current findings suggest that at least two discrete but complimentary pathways contribute to the protective effects of IGFBP-3; 1) IGFBP-3 directly activates the c-Jun kinase/tissue inhibitor of metalloproteinase-3/TNF-α converting enzyme (c-Jun/TIMP-3/TACE), pathway, which in turn inhibits TNF-α production; 2) IGFBP-3 acts through the IGFBP-3 receptor, low-density lipoprotein receptor-related protein 1 (LRP1), to inhibit signaling of TNF-α receptor 2 (TNFR2). Combined, these two IGFBP-3 pathways substantially reduce REC apoptosis and offer potential targets for the treatment of diabetic retinopathy.

  8. Superior serum half life of albumin tagged TNF ligands

    Energy Technology Data Exchange (ETDEWEB)

    Mueller, Nicole [Division of Molecular Internal Medicine, Department of Internal Medicine II, University Hospital Wuerzburg, Roentgenring 11, 97070 Wuerzburg (Germany); Schneider, Britta; Pfizenmaier, Klaus [Institute of Cell Biology and Immunology, University of Stuttgart, Allmandring 31, 70569 Stuttgart (Germany); Wajant, Harald, E-mail: harald.wajant@mail.uni-wuerzburg.de [Division of Molecular Internal Medicine, Department of Internal Medicine II, University Hospital Wuerzburg, Roentgenring 11, 97070 Wuerzburg (Germany)

    2010-06-11

    Due to their immune stimulating and apoptosis inducing properties, ligands of the TNF family attract increasing interest as therapeutic proteins. A general limitation of in vivo applications of recombinant soluble TNF ligands is their notoriously rapid clearance from circulation. To improve the serum half life of the TNF family members TNF, TWEAK and TRAIL, we genetically fused soluble variants of these molecules to human serum albumin (HSA). The serum albumin-TNF ligand fusion proteins were found to be of similar bioactivity as the corresponding HSA-less counterparts. Upon intravenous injection (i.v.), serum half life of HSA-TNF ligand fusion proteins, as determined by ELISA, was around 15 h as compared to approximately 1 h for all of the recombinant control TNF ligands without HSA domain. Moreover, serum samples collected 6 or 24 h after i.v. injection still contained high TNF ligand bioactivity, demonstrating that there is only limited degradation/inactivation of circulating HSA-TNF ligand fusion proteins in vivo. In a xenotransplantation model, significantly less of the HSA-TRAIL fusion protein compared to the respective control TRAIL protein was required to achieve inhibition of tumor growth indicating that the increased half life of HSA-TNF ligand fusion proteins translates into better therapeutic action in vivo. In conclusion, our data suggest that genetic fusion to serum albumin is a powerful and generally applicable mean to improve bioavailability and in vivo activity of TNF ligands.

  9. The cybernetics of TNF: Old views and newer ones.

    Science.gov (United States)

    Wallach, David

    2016-02-01

    The proinflammatory cytokine tumor necrosis factor (TNF) orchestrates complex multicellular processes through a wide variety of changes that it induces in cell functions. At various stages of the study of TNF, attention has been drawn to one of three different modes of its action. The work that led to the discovery of this cytokine addressed situations in which it inflicts massive damage to tissues through a mode of action that appeared to be unrestricted. In the years that followed, attention was drawn to the existence of negative feedback mechanisms that do restrict TNF formation and function, and of reciprocal mechanisms for negatively regulating TNF-induced gene activation and of cell death. Most recently, the discovery of the critical role of TNF in chronic inflammatory diseases directed attention to the ability of TNF also to act with no apparent time restriction. Major gaps still remain in our knowledge of the cellular and molecular basis for these three modes of TNF action.

  10. PI3Kδ inhibition reduces TNF secretion and neuroinflammation in a mouse cerebral stroke model.

    Science.gov (United States)

    Low, Pei Ching; Manzanero, Silvia; Mohannak, Nika; Narayana, Vinod K; Nguyen, Tam H; Kvaskoff, David; Brennan, Faith H; Ruitenberg, Marc J; Gelderblom, Mathias; Magnus, Tim; Kim, Hyun Ah; Broughton, Brad R S; Sobey, Christopher G; Vanhaesebroeck, Bart; Stow, Jennifer L; Arumugam, Thiruma V; Meunier, Frédéric A

    2014-03-14

    Stroke is a major cause of death worldwide and the leading cause of permanent disability. Although reperfusion is currently used as treatment, the restoration of blood flow following ischaemia elicits a profound inflammatory response mediated by proinflammatory cytokines such as tumour necrosis factor (TNF), exacerbating tissue damage and worsening the outcomes for stroke patients. Phosphoinositide 3-kinase delta (PI3Kδ) controls intracellular TNF trafficking in macrophages and therefore represents a prospective target to limit neuroinflammation. Here we show that PI3Kδ inhibition confers protection in ischaemia/reperfusion models of stroke. In vitro, restoration of glucose supply following an episode of glucose deprivation potentiates TNF secretion from primary microglia-an effect that is sensitive to PI3Kδ inhibition. In vivo, transient middle cerebral artery occlusion and reperfusion in kinase-dead PI3Kδ (p110δ(D910A/D910A)) or wild-type mice pre- or post-treated with the PI3Kδ inhibitor CAL-101, leads to reduced TNF levels, decreased leukocyte infiltration, reduced infarct size and improved functional outcome. These data identify PI3Kδ as a potential therapeutic target in ischaemic stroke.

  11. TNF-α induces vascular insulin resistance via positive modulation of PTEN and decreased Akt/eNOS/NO signaling in high fat diet-fed mice.

    Science.gov (United States)

    da Costa, Rafael Menezes; Neves, Karla Bianca; Mestriner, Fabíola Leslie; Louzada-Junior, Paulo; Bruder-Nascimento, Thiago; Tostes, Rita C

    2016-08-25

    High fat diet (HFD) induces insulin resistance in various tissues, including the vasculature. HFD also increases plasma levels of TNF-α, a cytokine that contributes to insulin resistance and vascular dysfunction. Considering that the enzyme phosphatase and tension homologue (PTEN), whose expression is increased by TNF-α, reduces Akt signaling and, consequently, nitric oxide (NO) production, we hypothesized that PTEN contributes to TNF-α-mediated vascular resistance to insulin induced by HFD. Mechanisms underlying PTEN effects were determined. Mesenteric vascular beds were isolated from C57Bl/6J and TNF-α KO mice submitted to control or HFD diet for 18 weeks to assess molecular mechanisms by which TNF-α and PTEN contribute to vascular dysfunction. Vasodilation in response to insulin was decreased in HFD-fed mice and in ex vivo control arteries incubated with TNF-α. TNF-α receptors deficiency and TNF-α blockade with infliximab abolished the effects of HFD and TNF-α on insulin-induced vasodilation. PTEN vascular expression (total and phosphorylated isoforms) was increased in HFD-fed mice. Treatment with a PTEN inhibitor improved insulin-induced vasodilation in HFD-fed mice. TNF-α receptor deletion restored PTEN expression/activity and Akt/eNOS/NO signaling in HFD-fed mice. TNF-α induces vascular insulin resistance by mechanisms that involve positive modulation of PTEN and inhibition of Akt/eNOS/NO signaling. Our findings highlight TNF-α and PTEN as potential targets to limit insulin resistance and vascular complications associated with obesity-related conditions.

  12. TNF receptor 1 genetic risk mirrors outcome of anti-TNF therapy in multiple sclerosis

    DEFF Research Database (Denmark)

    Gregory, Adam P; Dendrou, Calliope A; Attfield, Kathrine E;

    2012-01-01

    substantiate this through functional studies showing that the MS risk allele directs expression of a novel, soluble form of TNFR1 that can block TNF. Importantly, TNF-blocking drugs can promote onset or exacerbation of MS, but they have proven highly efficacious in the treatment of autoimmune diseases......), but not with other autoimmune conditions such as rheumatoid arthritis, psoriasis and Crohn’s disease. By analysing MS GWAS data in conjunction with the 1000 Genomes Project data we provide genetic evidence that strongly implicates this SNP, rs1800693, as the causal variant in the TNFRSF1A region. We further...... for which there is no association with rs1800693. This indicates that the clinical experience with these drugs parallels the disease association of rs1800693, and that the MS-associated TNFR1 variant mimics the effect of TNF-blocking drugs. Hence, our study demonstrates that clinical practice can...

  13. SU-E-T-338: Ultrastable PRNA 3WJ Nanoparticles as Potential I-125 and C-131 Carriers for Targeted Radiation Therapy

    Energy Technology Data Exchange (ETDEWEB)

    Luo, W; Li, H; Guo, P [University of Kentucky, Lexington, KY (United States)

    2014-06-01

    Purpose: To study the feasibility of using the pRNA 3WJ nanoparticles to carry I-125 or Cs-131 to target and treat cancer. As the first step, we investigated the stabilities of pRNA 3WJ nanoparticles that are essential for cancer targeting and treatment in this study. Methods: The thermodynamic stability of assembled RNA 3WJ nanoparticles was studied using the TGGE system. The nanoparticles were irradiated with I-125 or Cs-131 radioactive sources that were immersed in the RNA nanoparticle/DNA structure sample liquid contained in a small vial. The irradiation of the RNA samples was performed for different time periods and doses. The purpose was to distinguish the effects of radiation on DNA and RNA structures. Unradiated samples were used as control. Results: RNA nanoparticles were formed by mixing three pieces of oligos, 3WJa, 3WJb, and 3WJc at 1:1:1 molar ratio. Figure 4 demonstrates that 2′-F modified 3WJ nanoparticles remained stable at temperatures as high as 66.8 ± 2°C, and exhibited melting temperatures of 71 ± 2°C. The radiation stability test was performed with I- 125 and Cs-131 irradiation. Several DNA structures including plasmids were included as control. The first test introduced I-125 and a low dose of 1 Gy to both RNA and DNA samples, but no change was observed. When the dose was increased to 30 Gy, DNA was damaged while RNA remained unchanged. Three tests were also conducted with Cs-131 with 7 Gy, 21 Gy, 30 Gy, and 89 Gy, and the results were similar to those with I-125. Conclusion: pRNA 3WJ nanoparticles are able to form efficiently by onepot self-assembly. They remained stable at high temperatures and high therapeutic doses over a long time. These unique features suggest that RNA 3WJ nanoparticles have the potential to be used for targeted radiation therapy for cancer treatment.

  14. Immunogenicity of Anti-TNF-α Biotherapies

    DEFF Research Database (Denmark)

    Bendtzen, Klaus

    2015-01-01

    based on immunopharmacological evidence from individual patients (personalized medicine) is the use of assays for anti-drug antibodies (ADA) that are accurate and relevant in the clinical setting. This paper discusses immunogenicity of genetically engineered immunoglobulins directed against tumor......-necrosis factor-α (TNF). Emphasis will be on commonly used methods for detection of ADA in human serum including issues that question the clinical applicability of these methodologies. The use of dubious assays for ADA in a clinical context may not only contribute to confusion as to the importance of drug...

  15. Long range heliostat target using array of normal incidence pyranometers to evaluate a beam of solar radiation

    Science.gov (United States)

    Ghanbari, Cheryl M; Ho, Clifford K; Kolb, Gregory J

    2014-03-04

    Various technologies described herein pertain to evaluating a beam reflected by a heliostat. A portable target that has an array of sensors mounted thereupon is configured to capture the beam reflected by the heliostat. The sensors in the array output measured values indicative of a characteristic of the beam reflected by the heliostat. Moreover, a computing device can generate and output data corresponding to the beam reflected by the heliostat based on the measured values indicative of the characteristic of the beam received from the sensors in the array.

  16. Necroptosis Mediates TNF-Induced Toxicity of Hippocampal Neurons

    Directory of Open Access Journals (Sweden)

    Shan Liu

    2014-01-01

    Full Text Available Tumor necrosis factor-α (TNF-α is a critical proinflammatory cytokine regulating neuroinflammation. Elevated levels of TNF-α have been associated with various neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease. However, the signaling events that lead to TNF-α-initiated neurotoxicity are still unclear. Here, we report that RIP3-mediated necroptosis, a form of regulated necrosis, is activated in the mouse hippocampus after intracerebroventricular injection of TNF-α. RIP3 deficiency attenuates TNF-α-initiated loss of hippocampal neurons. Furthermore, we characterized the molecular mechanism of TNF-α-induced neurotoxicity in HT-22 hippocampal neuronal cells. HT-22 cells are sensitive to TNF-α only upon caspase blockage and subsequently undergo necrosis. The cell death is suppressed by knockdown of CYLD or RIP1 or RIP3 or MLKL, suggesting that this necrosis is necroptosis and mediated by CYLD-RIP1-RIP3-MLKL signaling pathway. TNF-α-induced necroptosis of HT-22 cells is largely independent of both ROS accumulation and calcium influx although these events have been shown to be critical for necroptosis in certain cell lines. Taken together, these data not only provide the first in vivo evidence for a role of RIP3 in TNF-α-induced toxicity of hippocampal neurons, but also demonstrate that TNF-α promotes CYLD-RIP1-RIP3-MLKL-mediated necroptosis of hippocampal neurons largely bypassing ROS accumulation and calcium influx.

  17. Evaluation of measurement of human TNF in plasma by ELISA.

    Science.gov (United States)

    Engelberts, I; Möller, A; Schoen, G J; van der Linden, C J; Buurman, W A

    1991-04-01

    The performance of a sandwich-ELISA for TNF measurement in plasma and serum was studied. The ELISA was first statistically analyzed. Interassay coefficient of variance and the intraassay coefficient of variance for the concentration range between 0.5 and 5 ng/ml was less than 10%. The sensitivity of the sandwich-ELISA for TNF in culture medium was 10 pg/ml. The ELISA was shown to be specific for biologically active TNF, since a good correlation between the ELISA and the WEHI bioassay was observed when partially inactive, denatured TNF was measured. The effect of various anticoagulation systems on the reliability of human TNF measurement has been evaluated. The oxalate/NaF and EDTA systems were both appropriate, as appeared from the observed blockade of the production of TNF in the tube, either in the cell-glycolysis-blocked or in the calcium-depleted situation, respectively. An eventual decrease in the recovery of rTNF after collection of blood was prevented in the oxalate/NaF tubes. Recovery of TNF in the ELISA was diminished in the presence of plasma or serum. Techniques to enhance the efficiency of the measurement of TNF in plasma by ELISA were compared. The data indicate that in the presence of 1.1 M NaCl, the TNF masking effect of normal plasma was largely abrogated. The presence and role of inhibiting plasma components in plasma of healthy and diseased individuals are discussed.

  18. Necroptosis mediates TNF-induced toxicity of hippocampal neurons.

    Science.gov (United States)

    Liu, Shan; Wang, Xing; Li, Yun; Xu, Lei; Yu, Xiaoliang; Ge, Lin; Li, Jun; Zhu, Yongjin; He, Sudan

    2014-01-01

    Tumor necrosis factor-α (TNF-α) is a critical proinflammatory cytokine regulating neuroinflammation. Elevated levels of TNF-α have been associated with various neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease. However, the signaling events that lead to TNF-α-initiated neurotoxicity are still unclear. Here, we report that RIP3-mediated necroptosis, a form of regulated necrosis, is activated in the mouse hippocampus after intracerebroventricular injection of TNF-α. RIP3 deficiency attenuates TNF-α-initiated loss of hippocampal neurons. Furthermore, we characterized the molecular mechanism of TNF-α-induced neurotoxicity in HT-22 hippocampal neuronal cells. HT-22 cells are sensitive to TNF-α only upon caspase blockage and subsequently undergo necrosis. The cell death is suppressed by knockdown of CYLD or RIP1 or RIP3 or MLKL, suggesting that this necrosis is necroptosis and mediated by CYLD-RIP1-RIP3-MLKL signaling pathway. TNF-α-induced necroptosis of HT-22 cells is largely independent of both ROS accumulation and calcium influx although these events have been shown to be critical for necroptosis in certain cell lines. Taken together, these data not only provide the first in vivo evidence for a role of RIP3 in TNF-α-induced toxicity of hippocampal neurons, but also demonstrate that TNF-α promotes CYLD-RIP1-RIP3-MLKL-mediated necroptosis of hippocampal neurons largely bypassing ROS accumulation and calcium influx.

  19. Role of TNF-alpha and its receptors in pericoronitis.

    Science.gov (United States)

    Beklen, A; Laine, M; Ventä, I; Hyrkäs, T; Konttinen, Y T

    2005-12-01

    The classic stimulus for cellular cytokine production is bacterial lipopolysaccharide (endotoxin). It was therefore hypothesized that tumor necrosis factor-alpha (TNF-alpha) may be responsible for pericoronitis. TNF-alpha and its receptors were detected by immunohistochemical staining in third molar pericoronitis in ten patients and ten healthy control samples. The percentage of TNF-alpha positive cells was high in pericoronitis (p = 0.0317). TNF receptors TNF-R1 and TNF-R2 were found in macrophage- and fibroblast-like cells, vascular endothelial cells in post-capillary venules, and basal epithelial cells in pericoronitis, but were only weakly expressed in controls. Increased expression of interleukin-1beta and vascular cell adhesion molecule-1 was found as a biological indicator of TNF-alpha ligand-receptor interaction. Explanted tissues acquired destructive potential upon TNF-alpha stimulation, whereas TNF-alpha blockers controlled it in inflamed tissues. These findings suggest that, in pericoronitis, inflammatory and resident cells produce and respond to potent pro-inflammatory cytokine TNF-alpha, with pathogenic and potential therapeutic relevance.

  20. Inflammatory cytokines IL-32 and IL-17 have common signaling intermediates despite differential dependence on TNF-receptor 1.

    Science.gov (United States)

    Turner-Brannen, Emily; Choi, Ka-Yee Grace; Arsenault, Ryan; El-Gabalawy, Hani; Napper, Scott; Mookherjee, Neeloffer

    2011-06-15

    Cytokines IL-32 and IL-17 are emerging as critical players in the pathophysiology of immune-mediated chronic inflammatory diseases. It has been speculated that the molecular mechanisms governing IL-32- and IL-17-mediated cellular responses are differentially dependent on the TNF pathway. In this study, kinome analysis demonstrated that following stimulation with cytokine IL-32, but not IL-17, there was increased phosphorylation of a peptide target corresponding to TNF-R1. Consistent with this observation, blocking TNF-R1 resulted in a suppression of IL-32-induced downstream responses, indicating that IL-32-mediated activity may be dependent on TNF-R1. In contrast, blocking TNF-R1 did not affect IL-17-induced downstream responses. Kinome analysis also implicated p300 (transcriptional coactivator) and death-associated protein kinase-1 (DAPK-1) as signaling intermediates for both IL-32 and IL-17. Phosphorylation of p300 and DAPK-1 upon stimulation with either IL-32 or IL-17 was confirmed by immunoblots. The presence of common targets was supported by results demonstrating similar downstream responses induced in the presence of IL-32 and IL-17, such as transcriptional responses and the direct activation of NF-κB. Furthermore, knockdown of p300 and DAPK-1 altered downstream responses induced by IL-32 and IL-17, and impacted certain cellular responses induced by TNF-α and IL-1β. We hypothesize that p300 and DAPK-1 represent nodes where the inflammatory networks of IL-32 and IL-17 overlap, and that these proteins would affect both TNF-R1-dependent and -independent pathways. Therefore, p300 and DAPK-1 are viable potential therapeutic targets for chronic inflammatory diseases.

  1. Secondary radiation measurements for particle therapy applications: prompt photons produced by $^{4}$He, $^{12}$C and $^{16}$O ion beams in a PMMA target

    CERN Document Server

    Mattei, Ilaria; De Lucia, Erika; Faccini, Riccardo; Frallicciardi, Paola Maria; Mancini-Terracciano, Carlo; Marafini, Michela; Muraro, Silvia; Paramatti, Riccardo; Patera, Vincenzo; Piersanti, Luca; Pinci, Davide; Rucinski, Antoni; Russomando, Andrea; Sarti, Alessio; Sciubba, Adalberto; Camillocci, Elena Solfaroli; Toppi, Marco; Traini, Giacomo; Voena, Cecilia; Battistoni, Giuseppe

    2016-01-01

    Charged particle beams are used in Particle Therapy (PT) to treat oncological patients due to their selective dose deposition in tissues and to their high biological effect in killing cancer cells with respect to photons and electrons used in conventional radiotherapy. Nowadays, protons and carbon ions are used in PT clinical routine but, recently, the interest on the potential application of helium and oxygen beams is growing due to their reduced multiple scattering inside the body and increased linear energy transfer, relative biological effectiveness and oxygen enhancement ratio. The precision of PT demands for online dose monitoring techniques, crucial to improve the quality assurance of treatments. The beam range confined in the irradiated target can be monitored thanks to the neutral or charged secondary radiation emitted by the interactions of hadron beams with matter. Prompt photons are produced by nuclear de-excitation processes and, at present, different dose monitoring and beam range verification t...

  2. Mathematical models of radiation action on living cells: From the target theory to the modern approaches. A historical and critical review.

    Science.gov (United States)

    Bodgi, Larry; Canet, Aurélien; Pujo-Menjouet, Laurent; Lesne, Annick; Victor, Jean-Marc; Foray, Nicolas

    2016-04-07

    Cell survival is conventionally defined as the capability of irradiated cells to produce colonies. It is quantified by the clonogenic assays that consist in determining the number of colonies resulting from a known number of irradiated cells. Several mathematical models were proposed to describe the survival curves, notably from the target theory. The Linear-Quadratic (LQ) model, which is to date the most frequently used model in radiobiology and radiotherapy, dominates all the other models by its robustness and simplicity. Its usefulness is particularly important because the ratio of the values of the adjustable parameters, α and β, on which it is based, predicts the occurrence of post-irradiation tissue reactions. However, the biological interpretation of these parameters is still unknown. Throughout this review, we revisit and discuss historically, mathematically and biologically, the different models of the radiation action by providing clues for resolving the enigma of the LQ model. Copyright © 2016 Elsevier Ltd. All rights reserved.

  3. The dosimetric impact of daily setup error on target volumes and surrounding normal tissue in the treatment of prostate cancer with intensity-modulated radiation therapy

    Energy Technology Data Exchange (ETDEWEB)

    Algan, Ozer, E-mail: oalgan@ouhsc.edu [Department of Radiation Oncology, Biostatistics and Epidemiology, University of Oklahoma Health Sciences Center, Oklahoma City, OK (United States); Jamgade, Ambarish; Ali, Imad; Christie, Alana; Thompson, J. Spencer; Thompson, David; Ahmad, Salahuddin; Herman, Terence [Department of Radiation Oncology, Biostatistics and Epidemiology, University of Oklahoma Health Sciences Center, Oklahoma City, OK (United States)

    2012-01-01

    The purpose of this study was to evaluate the impact of daily setup error and interfraction organ motion on the overall dosimetric radiation treatment plans. Twelve patients undergoing definitive intensity-modulated radiation therapy (IMRT) treatments for prostate cancer were evaluated in this institutional review board-approved study. Each patient had fiducial markers placed into the prostate gland before treatment planning computed tomography scan. IMRT plans were generated using the Eclipse treatment planning system. Each patient was treated to a dose of 8100 cGy given in 45 fractions. In this study, we retrospectively created a plan for each treatment day that had a shift available. To calculate the dose, the patient would have received under this plan, we mathematically 'negated' the shift by moving the isocenter in the exact opposite direction of the shift. The individualized daily plans were combined to generate an overall plan sum. The dose distributions from these plans were compared with the treatment plans that were used to treat the patients. Three-hundred ninety daily shifts were negated and their corresponding plans evaluated. The mean isocenter shift based on the location of the fiducial markers was 3.3 {+-} 6.5 mm to the right, 1.6 {+-} 5.1 mm posteriorly, and 1.0 {+-} 5.0 mm along the caudal direction. The mean D95 doses for the prostate gland when setup error was corrected and uncorrected were 8228 and 7844 cGy (p < 0.002), respectively, and for the planning target volume (PTV8100) was 8089 and 7303 cGy (p < 0.001), respectively. The mean V95 values when patient setup was corrected and uncorrected were 99.9% and 87.3%, respectively, for the PTV8100 volume (p < 0.0001). At an individual patient level, the difference in the D95 value for the prostate volume could be >1200 cGy and for the PTV8100 could approach almost 2000 cGy when comparing corrected against uncorrected plans. There was no statistically significant difference in the D35

  4. Stereotactic body radiation therapy for abdominal targets using volumetric intensity modulated arc therapy with RapidArc: Feasibility and clinical preliminary results

    Energy Technology Data Exchange (ETDEWEB)

    Scorsetti, Marta; Bignardi, Mario; Alongi, Filippo; Mancosu, Pietro; Navarria, Piera; Castiglioni, Simona; Pentimalli, Sara; Tozzi, Angelo (IRCCS Istituto Clinico Humanitas, Rozzano (Italy)), e-mail: pietro.mancosu@humanitas.it; Fogliata, Antonella; Cozzi, Luca (Oncology Inst. of Southern Switzerland, Bellinzona (Switzerland))

    2011-05-15

    Purpose. To report early clinical experience in stereotactic body radiation therapy (SBRT) delivered using volumetric intensity modulated arc therapy with RapidArc (RA) in patients with primary or metastatic tumours at abdominal sites. Material and methods. Thirty-seven consecutive patients were treated using RA. Of these, 16 had primary or metastatic liver tumours, nine had pancreatic cancer and 12 a nodal metastasis in the retro-peritoneum. Dose prescription varied from 45 to 75 Gy to the Clinical Target Volume in 3 to 6 fractions. The median follow-up was 12 months (6-22). Early local control and toxicity were investigated and reported. Results. Planning objectives on target volumes and organs at risk were met in most cases. Delivery time ranged from 2.8 +- 0.3 to 9.2 +- 2.4 minutes and pre-treatment plan verification resulted in a Gamma Agreement Index from 95.3 +- 3.8 to 98.3 +- 1.7%. At the time of analysis, local control (freedom from progression) at six months, was assessable in 24 of 37 patients and was achieved in 19 patients with a crude rate of 79.2%. Seven patients experienced treatment-related toxicity. Three patients experienced a mild and transient G1 enteritis and two showed a transient G1 liver damage. Two had late toxicity: one developed chronic enteritis causing G1 diarrhoea and G1 abdominal pain and one suffered at three months a G3 gastric bleeding. No patients experienced G4 acute toxicity. Conclusions. SBRT for abdominal targets delivered by means of RA resulted to be feasible with good early clinical results in terms of local control rate and acute toxicity profile. RA allowed to achieve required target coverage as well as to keep within normal tissue dose/volume constraints

  5. Radiation Therapy Oncology Group Consensus Panel Guidelines for the Delineation of the Clinical Target Volume in the Postoperative Treatment of Pancreatic Head Cancer

    Energy Technology Data Exchange (ETDEWEB)

    Goodman, Karyn A., E-mail: goodmank@mskcc.org [Memorial Sloan-Kettering Cancer Center, New York, New York (United States); Regine, William F. [University of Maryland School of Medicine, Baltimore, Maryland (United States); Dawson, Laura A. [Princess Margaret Hospital, University of Toronto, Toronto, Ontario (Canada); Ben-Josef, Edgar [University of Michigan Medical School, Ann Arbor, Michigan (United States); Haustermans, Karin [University Hospital Leuven, Leuven (Belgium); Bosch, Walter R. [Image-Guided Therapy QA Center, Washington University, St. Louis, Missouri (United States); Turian, Julius; Abrams, Ross A. [Rush University Medical College, Chicago, Illinois (United States)

    2012-07-01

    Purpose: To develop contouring guidelines to be used in the Radiation Therapy Oncology Group protocol 0848, a Phase III randomized trial evaluating the benefit of adjuvant chemoradiation in patients with resected head of pancreas cancer. Methods and Materials: A consensus committee of six radiation oncologists with expertise in gastrointestinal radiotherapy developed stepwise contouring guidelines and an atlas for the delineation of the clinical target volume (CTV) in the postoperative treatment of pancreas cancer, based on identifiable regions of interest and margin expansions. Areas at risk for subclinical disease to be included in the CTV were defined, including nodal regions, anastomoses, and the preoperative primary tumor location. Regions of interest that could be reproducibly contoured on postoperative imaging after a pancreaticoduodenectomy were identified. Standardized expansion margins to encompass areas at risk were developed after multiple iterations to determine the optimal margin expansions. Results: New contouring recommendations based on CT anatomy were established. Written guidelines for the delineation of the postoperative CTV and normal tissues, as well as a Web-based atlas, were developed. Conclusions: The postoperative abdomen has been a difficult area for effective radiotherapy. These new guidelines will help physicians create fields that better encompass areas at risk and minimize dose to normal tissues.

  6. Non-Target Effect for Chromosome Aberrations in Human Lymphocytes and Fibroblasts After Exposure to Very Low Doses of High LET Radiation

    Science.gov (United States)

    Hada, Megumi; George, Kerry A.; Cucinotta, F. A.

    2011-01-01

    The relationship between biological effects and low doses of absorbed radiation is still uncertain, especially for high LET radiation exposure. Estimates of risks from low-dose and low-dose-rates are often extrapolated using data from Japanese atomic bomb survivor with either linear or linear quadratic models of fit. In this study, chromosome aberrations were measured in human peripheral blood lymphocytes and normal skin fibroblasts cells after exposure to very low dose (.01 - 0.2 Gy) of 170 MeV/u Si-28-ions or 600 MeV/u Fe-56-ions. Chromosomes were analyzed using the whole chromosome fluorescence in situ hybridization (FISH) technique during the first cell division after irradiation, and chromosome aberrations were identified as either simple exchanges (translocations and dicentrics) or complex exchanges (involving >2 breaks in 2 or more chromosomes). The curves for doses above 0.1 Gy were more than one ion traverses a cell showed linear dose responses. However, for doses less than 0.1 Gy, Si-28-ions showed no dose response, suggesting a non-targeted effect when less than one ion traversal occurs. Additional findings for Fe-56 will be discussed.

  7. Tumor necrosis factor (TNF)-alpha, soluble TNF receptors and endometrial cancer risk : the EPIC study

    NARCIS (Netherlands)

    Dossus, Laure; Becker, Susen; Rinaldi, Sabina; Lukanova, Annekatrin; Tjonneland, Anne; Olsen, Anja; Overvad, Kim; Chabbert-Buffet, Nathalie; Boutron-Ruault, Marie-Christine; Clavel-Chapelon, Francoise; Teucher, Birgit; Chang-Claude, Jenny; Pischon, Tobias; Boeing, Heiner; Trichopoulou, Antonia; Benetou, Vasiliki; Valanou, Elisavet; Palli, Domenico; Sieri, Sabina; Tumino, Rosario; Sacerdote, Carlotta; Galasso, Rocco; Redondo, Maria-Luisa; Bonet Bonet, Catalina; Molina-Montes, Esther; Altzibar, Jone M.; Chirlaque, Maria-Dolores; Ardanaz, Eva; Bueno-de-Mesquita, H. Bas; van Duijnhoven, Franzel J. B.; Peeters, Petra H. M.; Onland-Moret, N. Charlotte; Lundin, Eva; Idahl, Annika; Khaw, Kay-Tee; Wareham, Nicholas; Allen, Naomi; Romieu, Isabelle; Fedirko, Veronika; Hainaut, Pierre; Romaguera, Dora; Norat, Teresa; Riboli, Elio; Kaaks, Rudolf

    2011-01-01

    Chronic inflammation has been hypothesized to play a role in endometrial cancer development. Tumor necrosis factor-alpha (TNF-alpha), one of the major pro-inflammatory cytokines, has also been implicated in endometrial physiology. We conducted a case-control study nested within the European prospect

  8. Dual role of the p75 tumor necrosis factor (TNF) receptor in TNF cytotoxicity

    DEFF Research Database (Denmark)

    Beletsky, I; Brakebusch, C; Varfolomeev, Y

    1994-01-01

    to the cytotoxicity of TNF using a wide panel of antibodies (Abs) against the receptor's extracellular domain. Two distinct Ab effects were observed. The Abs triggered signaling for cytotoxicity. This effect: (a) was correlated with the extent of p75-R expression by the cells; (b) was dependent on receptor cross...

  9. Fluid shear stress inhibits TNF-α-induced osteoblast apoptosis via ERK5 signaling pathway.

    Science.gov (United States)

    Bin, Geng; Cuifang, Wang; Bo, Zhang; Jing, Wang; Jin, Jiang; Xiaoyi, Tan; Cong, Chen; Yonggang, Chen; Liping, An; Jinglin, Ma; Yayi, Xia

    2015-10-09

    Fluid shear stress (FSS) is a potent mechanical stimulus and prevents cells from TNF-a-induced apoptosis. Recently, Extracellular-signal-regulated kinase 5 (ERK5) has been found to be involved in regulation of cell survival. However, little is known about the role of ERK5 signaling pathway in FSS-mediated anti-apoptotic effects in osteoblast. In this study, we show that FSS blocks TNF-a-induced apoptosis of MC3T3-E1 cells via ERK5 signaling pathway. We found that physiological FSS for 1 h significantly decreased TNF-α-induced MC3T3-E1 cells apoptosis. After inhibition of ERK5 activity by XMD8-92, a highly-selective inhibitor of ERK5 activity, the ability of FSS to inhibit TNF-α induced apoptosis was significantly decreased. Analysis of anti-apoptotic mechanisms indicated that exposure of MC3T3-E1 cells to FSS for 1 h increased phosphorylation of Bad and inhibited caspase-3 activity. After treatment with XMD8-92, phosphorylation of Bad by FSS was significantly blocked, but caspase-3 activity was increased. In summary, these findings indicated that FSS inhibits TNF-α-mediated signaling events in osteoblast by a mechanism dependent on activation of ERK5, and Bad is a crucial downstream target for ERK5. Those results implied that ERK5 signaling pathway play a crucial role in FSS-mediated anti-apoptotic effect in osteoblast. Thus, ERK5 signaling pathway may be a new drug treatment target of osteoporosis and related bone-wasting diseases.

  10. The status of targeted agents in the setting of neoadjuvant radiation therapy in locally advanced rectal cancers.

    Science.gov (United States)

    Glynne-Jones, Rob; Hadaki, Maher; Harrison, Mark

    2013-09-01

    Radiotherapy has a longstanding and well-defined role in the treatment of resectable rectal cancer to reduce the historically high risk of local recurrence. In more advanced borderline or unresectable cases, where the circumferential resection margin (CRM) is breached or threatened according to magnetic resonance imaging (MRI), despite optimized local multimodality treatment and the gains achieved by modern high quality total mesorectal excision (TME), at least half the patients fail to achieve sufficient downstaging with current schedules. Many do not achieve an R0 resection. In less locally advanced cases, even if local control is achieved, this confers only a small impact on distant metastases and a significant proportion of patients (30-40%) still subsequently develop metastatic disease. In fact, distant metastases have now become the predominant cause of failure in rectal cancer. Therefore, increasing the intensity and efficacy of chemotherapy and chemoradiotherapy by integrating additional cytotoxics and biologically targetted agents seems an appealing strategy to explore-with the aim of enhancing curative resection rates and improving distant control and survival. However, to date, we lack validated biomarkers for these biological agents apart from wild-type KRAS. For cetuximab, the appearance of an acneiform rash is associated with response, but low levels of magnesium appear more controversial. There are no molecular biomarkers for bevacizumab. Although some less invasive clinical markers have been proposed for bevacizumab, such as circulating endothelial cells (CECS), circulating levels of VEGF and the development of overt hypertension, these biomarkers have not been validated and are observed to emerge only after a trial of the agent. We also lack a simple method of ongoing monitoring of 'on target' effects of these biological agents, which could determine and pre-empt the development of resistance, prior to radiological and clinical assessessments or

  11. Bystander normal human fibroblasts reduce damage response in radiation targeted cancer cells through intercellular ROS level modulation

    Energy Technology Data Exchange (ETDEWEB)

    Widel, Maria, E-mail: maria.widel@polsl.pl [Biosystem Group, Department of Automatics, Electronics and Informatics, Silesian University of Technology, 16 Akademicka Street, 44-100 Gliwice (Poland); Przybyszewski, Waldemar M., E-mail: wmp@io.gliwice.pl [Center for Translational Research and Molecular Biology, Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology, Branch Gliwice, 15 Wybrzeze Armii Krajowej, 44-101 Gliwice (Poland); Cieslar-Pobuda, Artur [Biosystem Group, Department of Automatics, Electronics and Informatics, Silesian University of Technology, 16 Akademicka Street, 44-100 Gliwice (Poland); Saenko, Yuri V. [Department of Pharmacology and Biochemistry, Center of Nanotechnology and Materials, Ulyanovsk State University (Russian Federation); Rzeszowska-Wolny, Joanna [Biosystem Group, Department of Automatics, Electronics and Informatics, Silesian University of Technology, 16 Akademicka Street, 44-100 Gliwice (Poland)

    2012-03-01

    The radiation-induced bystander effect is a well-established phenomenon which results in damage in non-irradiated cells in response to signaling from irradiated cells. Since communication between irradiated and bystander cells could be reciprocal, we examined the mutual bystander response between irradiated cells and co-cultured with them non-irradiated recipients. Using a transwell culture system, irradiated human melanoma (Me45) cells were co-cultured with non-irradiated Me45 cells or normal human dermal fibroblasts (NHDF) and vice versa. The frequency of micronuclei and of apoptosis, ROS level, and mitochondrial membrane potential were used as the endpoints. Irradiated Me45 and NHDF cells induced conventional bystander effects detected as modest increases of the frequency of micronuclei and apoptosis in both recipient neighbors; the increase of apoptosis was especially high in NHDF cells co-cultured with irradiated Me45 cells. However, the frequencies of micronuclei and apoptosis in irradiated Me45 cells co-cultured with NHDF cells were significantly reduced in comparison with those cultured alone. This protective effect was not observed when irradiated melanomas were co-cultured with non-irradiated cells of the same line, or when irradiated NHDF fibroblasts were co-cultured with bystander melanomas. The increase of micronuclei and apoptosis in irradiated Me45 cells was paralleled by an increase in the level of intracellular reactive oxygen species (ROS), which was reduced significantly when they were co-cultured for 24 h with NHDF cells. A small but significant elevation of ROS level in NHDF cells shortly after irradiation was also reduced by co-culture with non-irradiated NHDF cells. We propose that in response to signals from irradiated cells, non-irradiated NHDF cells trigger rescue signals, whose nature remains to be elucidated, which modify the redox status in irradiated cells. This inverse bystander effect may potentially have implications in clinical

  12. MicroRNA-223 Enhances Radiation Sensitivity of U87MG Cells In Vitro and In Vivo by Targeting Ataxia Telangiectasia Mutated

    Energy Technology Data Exchange (ETDEWEB)

    Liang, Liping; Zhu, Ji [Departments of Radiation Oncology, Fudan University Shanghai Cancer Center, Department of Oncology, Shanghai Medical College, Fudan University, Shanghai (China); Zaorsky, Nicholas G. [Department of Radiation Oncology, Fox Chase Cancer Center, Philadelphia, Pennsylvania (United States); Deng, Yun [Departments of Radiation Oncology, Fudan University Shanghai Cancer Center, Department of Oncology, Shanghai Medical College, Fudan University, Shanghai (China); Wu, Xingzhong [Department of Biochemistry and Molecular Biology, Shanghai Medical College, Fudan University, Shanghai (China); Liu, Yong [Departments of Radiation Oncology, Fudan University Shanghai Cancer Center, Department of Oncology, Shanghai Medical College, Fudan University, Shanghai (China); Liu, Fangqi; Cai, Guoxiang; Gu, Weilie [Department of Colorectal Cancer, Fudan University, Shanghai Cancer Center, Shanghai (China); Shen, Lijun [Departments of Radiation Oncology, Fudan University Shanghai Cancer Center, Department of Oncology, Shanghai Medical College, Fudan University, Shanghai (China); Zhang, Zhen, E-mail: zhenzhang6@hotmail.com [Departments of Radiation Oncology, Fudan University Shanghai Cancer Center, Department of Oncology, Shanghai Medical College, Fudan University, Shanghai (China)

    2014-03-15

    Purpose: Ataxia telangiectasia mutated (ATM) protein is important in the DNA damage response because it repairs radiation-induced damage in cancers. We examined the effect of microRNA-223 (miR-223), a regulator of ATM expression, on radiation sensitivity of cancer cells. Methods and Materials: Human embryonic kidney 293 T (293T) cells were infected with pLL3.7-miR-223 plasmid to generate the pLL3.7-miR-223 and -empty virus (EV) lentivirus (miR-223 and EV). A dual luciferase assay in which the reporter contained wild-type 3′ untranslated region (UTR) of ATM was performed. U87MG cells were infected with miR-223 or EV to establish the overexpressed stable cell lines (U87-223 or U87-EV, respectively). Cells were irradiated in vitro, and dose enhancement ratios at 2 Gy (DER{sub 2}) were calculated. Hind legs of BALB/c athymic mice were injected with U87-223 or U87-EV cells; after 2 weeks, half of the tumors were irradiated. Tumor volumes were tracked for a total of 5 weeks. Results: The dual luciferase reporter assay showed a significant reduction in luciferase activity of 293T cells cotransfected with miR-223 and the ATM 3′UTR compared to that in EV control. Overexpression of miR-223 in U87MG cells showed that ATM expression was significantly downregulated in the U87-223 cells compared to that in U87-EV (ATM/β-actin mRNA 1.0 vs 1.5, P<.05). U87-223 cells were hypersensitive to radiation compared to U87-EV cells in vitro (DER{sub 2} = 1.32, P<.01). Mice injected with miR-223-expressing tumors had almost the same tumors after 3 weeks (1.5 cm{sup 3} vs 1.7 cm{sup 3}). However, irradiation significantly decreased tumor size in miR-223-expressing tumors compared to those in controls (0.033 cm{sup 3} vs 0.829 cm{sup 3}). Conclusions: miR-223 overexpression downregulates ATM expression and sensitizes U87 cells to radiation in vitro and in vivo. MicroRNA-223 may be a novel cancer-targeting therapy, although its cancer- and patient-specific roles are

  13. REGULATION OF PPARγ FUNCTION BY TNF

    OpenAIRE

    Ye, Jianping

    2008-01-01

    The nuclear receptor PPARγ is a lipid sensor that regulates lipid metabolism through gene transcription. Inhibition of PPARγ activity by TNF-α is involved in pathogenesis of insulin resistance, atherosclerosis, inflammation, and cancer cachexia. PPARγ activity is regulated by TNF-α at pre-translational and post-translational levels. Activation of serine kinases including IKK, ERK, JNK and p38 may be involved in the TNF-regulation of PPARγ. Of the four kinases, IKK is a dominant signaling mole...

  14. miR-346 controls release of TNF-α protein and stability of its mRNA in rheumatoid arthritis via tristetraprolin stabilization.

    Directory of Open Access Journals (Sweden)

    Noha Semaan

    Full Text Available TNF-α is a major cytokine implicated in rheumatoid arthritis. Its expression is regulated both at the transcriptional and posttranscriptional levels and recent data demonstrated that miRNAs are implicated in TNF-α response in macrophages. LPS-activated FLS isolated from RA patients express TNF-α mRNA but not the mature protein. This prompted us to look for miRNAs which could be implicated in this anti-inflammatory effect. Using a microarray, we found two miRNAs, miR-125b and miR-939 predicted to target the 3'-UTR of TNF-α mRNA, to be up-regulated in RA FLS in response to LPS, but their repression did not restore mature TNF-α expression in FLS. We showed previously that miR-346, which is upregulated in LPS-activated FLS, inhibited Btk expression that stabilized TNF-α mRNA. Blocking miR-346 reestablished TNF-α expression in activated FLS. Interestingly, transfection of miR-346 in LPS-activated THP-1 cells inhibited TNF-α secretion. We also demonstrated that TTP, a RNA binding protein which inhibited TNF-α synthesis, is overexpressed in activated FLS and that inhibition of miR-346 decreases its expression. Conversely, transfection of miR-346 in LPS-activated THP-1 cells increased TTP mRNA expression and inhibited TNF-α release. These results indicate that miR-346 controls TNF-α synthesis by regulating TTP expression.

  15. Concept of optimisation of the radiation protection system in the nuclear sector: management of individual cancer risks and providing targeted health care.

    Science.gov (United States)

    Ivanov, V K; Tsyb, A F; Agapov, A M; Panfilov, A P; Kaidalov, O V; Gorski, A I; Maksioutov, M A; Suspitsin, Y V; Vaizer, V I

    2006-12-01

    The paper discusses the provision of targeted health care to nuclear workers in Russia based on radiation-epidemiological estimates of cancer risks. Cancer incidence rates are analysed for the workers of the Institute of Physical Power Engineering (the first nuclear installation in the world) who were subjected to individual dosimetric monitoring from 1950 to 2002. The value of excess relative risk for solid cancers was found to be ERR Gy(-1) = 0.24 (95% CI: -4.22; 7.96). It has been shown that 81.8% of the persons covered by individual dosimetric monitoring have potential attributive risk up to 5%, and the risk is more than 10% for 3.7% of the workers. Among the detected cancer cases, 73.5% of the individuals show an attributive risk up to 5% and the risk is in excess of 10% for 3.9% of the workers. Principles for the provision of targeted health care, given voluntary health insurance, are outlined.

  16. The effect of uterine motion and uterine margins on target and normal tissue doses in intensity modulated radiation therapy of cervical cancer

    Energy Technology Data Exchange (ETDEWEB)

    Gordon, J J; Weiss, E; Abayomi, O K; Siebers, J V; Dogan, N, E-mail: jjgordon@vcu.edu [Department of Radiation Oncology, Virginia Commonwealth University, PO Box 980058, Richmond, VA 23298 (United States)

    2011-05-21

    In intensity modulated radiation therapy (IMRT) of cervical cancer, uterine motion can be larger than cervix motion, requiring a larger clinical target volume to planning target volume (CTV-to-PTV) margin around the uterine fundus. This work simulates different motion models and margins to estimate the dosimetric consequences. A virtual study used image sets from ten patients. Plans were created with uniform margins of 1 cm (PTV{sub A}) and 2.4 cm (PTV{sub C}), and a margin tapering from 2.4 cm at the fundus to 1 cm at the cervix (PTV{sub B}). Three inter-fraction motion models (MM) were simulated. In MM1, all structures moved with normally distributed rigid body translations. In MM2, CTV motion was progressively magnified as one moved superiorly from the cervix to the fundus. In MM3, both CTV and normal tissue motion were magnified as in MM2, modeling the scenario where normal tissues move into the void left by the mobile uterus. Plans were evaluated using static and percentile DVHs. For a conventional margin (PTV{sub A}), quasi-realistic uterine motion (MM3) reduces fundus dose by about 5 Gy and increases normal tissue volumes receiving 30-50 Gy by {approx}5%. A tapered CTV-to-PTV margin can restore fundus and CTV doses, but will increase normal tissue volumes receiving 30-50 Gy by a further {approx}5%.

  17. Tumor Necrosis Factor alpha (TNF{alpha}) regulates CD40 expression through SMAR1 phosphorylation

    Energy Technology Data Exchange (ETDEWEB)

    Singh, Kamini; Sinha, Surajit; Malonia, Sunil Kumar; Chattopadhyay, Samit, E-mail: samit@nccs.res.in

    2010-01-08

    CD40 plays an important role in mediating inflammatory response and is mainly induced by JAK/STAT phosphorylation cascade. TNF{alpha} is the key cytokine that activates CD40 during inflammation and tumorigenesis. We have earlier shown that SMAR1 can repress the transcription of Cyclin D1 promoter by forming a HDAC1 dependent repressor complex. In this study, we show that SMAR1 regulates the transcription of NF-{kappa}B target gene CD40. SMAR1 recruits HDAC1 and forms a repressor complex on CD40 promoter and keeps its basal transcription in check. Further, we show that TNF{alpha} stimulation induces SMAR1 phosphorylation at Ser-347 and promotes its cytoplasmic translocation, thus releasing its negative effect. Concomitantly, TNF{alpha} induced phosphorylation of STAT1 at Tyr-701 by JAK1 facilitates its nuclear translocation and activation of CD40 through p300 recruitment and core Histone-3 acetylation. Thus, TNF{alpha} mediated regulation of CD40 expression occurs by dual phosphorylation of SMAR1 and STAT1.

  18. Cell-Extrinsic TNF Collaborates with TRIF Signaling To Promote Yersinia-Induced Apoptosis.

    Science.gov (United States)

    Peterson, Lance W; Philip, Naomi H; Dillon, Christopher P; Bertin, John; Gough, Peter J; Green, Douglas R; Brodsky, Igor E

    2016-11-15

    Innate immune responses that are crucial for control of infection are often targeted by microbial pathogens. Blockade of NF-κB and MAPK signaling by the Yersinia virulence factor YopJ inhibits cytokine production by innate immune cells but also triggers cell death. This cell death requires RIPK1 kinase activity and caspase-8, which are engaged by TLR4 and the adaptor protein TRIF. Nevertheless, TLR4- and TRIF-deficient cells undergo significant apoptosis, implicating TLR4/TRIF-independent pathways in the death of Yersinia-infected cells. In this article, we report a key role for TNF/TNFR1 in Yersinia-induced cell death of murine macrophages, which occurs despite the blockade of NF-κB and MAPK signaling imposed by Yersinia on infected cells. Intriguingly, direct analysis of YopJ injection revealed a heterogeneous population of injection-high and injection-low cells, and demonstrated that TNF expression came from the injection-low population. Moreover, TNF production by this subpopulation was necessary for maximal apoptosis in the population of highly injected cells, and TNFR-deficient mice displayed enhanced susceptibility to Yersinia infection. These data demonstrate an important role for collaboration between TNF and pattern recognition receptor signals in promoting maximal apoptosis during bacterial infection, and demonstrate that heterogeneity in virulence factor injection and cellular responses play an important role in promoting anti-Yersinia immune defense. Copyright © 2016 by The American Association of Immunologists, Inc.

  19. Interobserver Variability in Target Definition for Hepatocellular Carcinoma With and Without Portal Vein Thrombus: Radiation Therapy Oncology Group Consensus Guidelines

    Energy Technology Data Exchange (ETDEWEB)

    Hong, Theodore S., E-mail: tshong1@mgh.harvard.edu [Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts (United States); Bosch, Walter R. [Department of Radiation Oncology, Washington University in St. Louis School of Medicine, St. Louis, Missouri (United States); Krishnan, Sunil [Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas (United States); Kim, Tae K. [Department of Medical Imaging, University Health Network, Mount Sinai Hospital and Women' s College Hospital, University of Toronto, Toronto, Ontario (Canada); Mamon, Harvey J. [Department of Radiation Oncology, Dana-Farber Cancer Institute/Brigham and Women' s Hospital and Harvard Medical School, Boston, Massachusetts (United States); Shyn, Paul [Department of Radiology, Brigham and Women' s Hospital and Harvard Medical School, Boston, Massachusetts (United States); Ben-Josef, Edgar [Department of Radiation Oncology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania (United States); Seong, Jinsil [Department of Radiation Oncology, Yonsei University Medical College, Seoul (Korea, Republic of); Haddock, Michael G. [Department of Radiation Oncology, Mayo Clinic, Rochester, Minnesota (United States); Cheng, Jason C. [Department of Oncology, National Taiwan University Hospital, Taipei, Taiwan (China); Feng, Mary U. [Department of Radiation Oncology, University of Michigan Health System, Ann Arbor, Michigan (United States); Stephans, Kevin L. [Department of Radiation Oncology, Cleveland Clinic, Cleveland, Ohio (United States); Roberge, David [Department of Radiation Oncology, Montreal General Hospital/McGill University Health Centre, Montreal, Quebec (Canada); Crane, Christopher [Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas (United States); and others

    2014-07-15

    Purpose: Defining hepatocellular carcinoma (HCC) gross tumor volume (GTV) requires multimodal imaging, acquired in different perfusion phases. The purposes of this study were to evaluate the variability in contouring and to establish guidelines and educational recommendations for reproducible HCC contouring for treatment planning. Methods and Materials: Anonymous, multiphasic planning computed tomography scans obtained from 3 patients with HCC were identified and distributed to a panel of 11 gastrointestinal radiation oncologists. Panelists were asked the number of HCC cases they treated in the past year. Case 1 had no vascular involvement, case 2 had extensive portal vein involvement, and case 3 had minor branched portal vein involvement. The agreement between the contoured total GTVs (primary + vascular GTV) was assessed using the generalized kappa statistic. Agreement interpretation was evaluated using Landis and Koch's interpretation of strength of agreement. The S95 contour, defined using the simultaneous truth and performance level estimation (STAPLE) algorithm consensus at the 95% confidence level, was created for each case. Results: Of the 11 panelists, 3 had treated >25 cases in the past year, 2 had treated 10 to 25 cases, 2 had treated 5 to 10 cases, 2 had treated 1 to 5 cases, 1 had treated 0 cases, and 1 did not respond. Near perfect agreement was seen for case 1, and substantial agreement was seen for cases 2 and 3. For case 2, there was significant heterogeneity in the volume identified as tumor thrombus (range 0.58-40.45 cc). For case 3, 2 panelists did not include the branched portal vein thrombus, and 7 panelists contoured thrombus separately from the primary tumor, also showing significant heterogeneity in volume of tumor thrombus (range 4.52-34.27 cc). Conclusions: In a group of experts, excellent agreement was seen in contouring total GTV. Heterogeneity exists in the definition of portal vein thrombus that may impact treatment

  20. PENCEGAHAN KOMPLIKASI TUBERCULOSIS AKIBAT PEMBERIAN TNF-α ANTAGONIS

    Directory of Open Access Journals (Sweden)

    Huriatul Masdar

    2009-05-01

    Full Text Available AbstrakTNF-α antagonis telah digunakan secara luas dan menunjukan respon yang baik pada terapi penyakit-penyakit autoimun seperti Rheumatoid Artritis, psoriasis dan Inflammatory Bowel Diseases. Namun, beberapa penelitian melaporkan adanya komplikasi tuberculosis yang terjadi akibat penggunaan obat ini dalam jangka lama. Untuk meminimalisir komplikasi tersebut, skrining adanya TB dengan TST, IGRA dan pemeriksaan radiologi wajib dilakukan sebelum pemberian terapi dengan TNF-α antagonis. Pemeriksaan berkala adanya TB juga harus dilakukan selama pemberian terapi. Selain itu, pemilihan obat yang tepat dengan komplikasi minimal juga harus dilakukan untuk menekan aktivasi TB tersebut.Kata Kunci: TNF-α, TNF-α antagonis, penyakit autoimun, tuberculosis.AbstractTNF-α antagonist has been widely used and showed well responses in autoimmune diseases therapy such as Rheumatoid Arthritis, psoriasis and Inflammatory Bowel Diseases. However, many studies showed that the long time used of those biological agents activate tuberculosis infection. To minimize the complication, first, TB screening by TST, IGRA and radiology examination must be performed to exclude latent TB before starting the therapy using TNF-α antagonist. Second, regular TB check must also be done during TNF-α antagonist treatment. At last, choosing right agents for better treatment with less complication must be considered.Keywords: TNF-α, TNF-α antagonist, autoimmune diseases, tuberculosis.

  1. Identification of a 60-kD tumor necrosis factor (TNF) receptor as the major signal transducing component in TNF responses

    OpenAIRE

    1990-01-01

    We describe here a monoclonal antibody (H398) that immunoprecipitates a human 60-kD tumor necrosis factor (TNF) membrane receptor (p60) and competes with TNF binding to p60 but not to p85 TNF receptors. Despite partial inhibition of TNF binding capacity of cells coexpressing both TNF receptor molecules, H398 uniformly and completely inhibits very distinct TNF responses on a variety of cell lines. These data suggest a limited structural heterogeneity in those components actually contributing t...

  2. Secondary radiation measurements for particle therapy applications: nuclear fragmentation produced by $^4$He ion beams in a PMMA target

    CERN Document Server

    Marafini, M; Pinci, D; Battistoni, G; Collamati, F; De Lucia, E; Faccini, R; Frallicciardi, P M; Mancini-Terracciano, C; Mattei, I; Muraro, S; Piersanti, L; Rovituso, M; Rucinski, A; Russomando, A; Sarti, A; Sciubba, A; Camillocci, E Solfaroli; Toppi, M; Traini, G; Voena, C; Patera, V

    2016-01-01

    Nowadays there is a growing interest in Particle Therapy treatments exploiting light ion beams against tumors due to their enhanced Relative Biological Effectiveness and high space selectivity. In particular promising results are obtained by the use of $^4$He projectiles. Unlike the treatments performed using protons, the beam ions can undergo a fragmentation process when interacting with the atomic nuclei in the patient body. In this paper the results of measurements performed at the Heidelberg Ion-Beam Therapy center are reported. For the first time the absolute fluxes and the energy spectra of the fragments - protons, deuterons, and tritons - produced by $^4$He ion beams of 102, 125 and 145 MeV/u energies on a poly-methyl methacrylate target were evaluated at different angles. The obtained results are particularly relevant in view of the necessary optimization and review of the Treatment Planning Software being developed for clinical use of $^4$He beams in clinical routine and the relative benchmarking of ...

  3. Secondary radiation measurements for particle therapy applications: nuclear fragmentation produced by 4He ion beams in a PMMA target

    Science.gov (United States)

    Marafini, M.; Paramatti, R.; Pinci, D.; Battistoni, G.; Collamati, F.; De Lucia, E.; Faccini, R.; Frallicciardi, P. M.; Mancini-Terracciano, C.; Mattei, I.; Muraro, S.; Piersanti, L.; Rovituso, M.; Rucinski, A.; Russomando, A.; Sarti, A.; Sciubba, A.; Solfaroli Camillocci, E.; Toppi, M.; Traini, G.; Voena, C.; Patera, V.

    2017-02-01

    Nowadays there is a growing interest in particle therapy treatments exploiting light ion beams against tumors due to their enhanced relative biological effectiveness and high space selectivity. In particular promising results are obtained by the use of 4He projectiles. Unlike the treatments performed using protons, the beam ions can undergo a fragmentation process when interacting with the atomic nuclei in the patient body. In this paper the results of measurements performed at the Heidelberg Ion-Beam Therapy center are reported. For the first time the absolute fluxes and the energy spectra of the fragments—protons, deuterons, and tritons—produced by 4He ion beams of 102, 125 and 145 MeV u-1 energies on a poly-methyl methacrylate target were evaluated at different angles. The obtained results are particularly relevant in view of the necessary optimization and review of the treatment planning software being developed for clinical use of 4He beams in clinical routine and the relative bench-marking of Monte Carlo algorithm predictions.

  4. A Study of volumetric modulated arc therapy for stereotactic body radiation therapy in case of multi-target liver cancer using flattening filter free beam

    Energy Technology Data Exchange (ETDEWEB)

    Yeom, Mi Sook; Yoon, In Ha; Hong, Dong Gi; Back, Geum Mun [Dept. of Radiation Oncology, ASAN Medical Center, Seoul (Korea, Republic of)

    2015-06-15

    Stereotactic body radiation therapy (SBRT) has proved its efficacy in several patient populations with primary and metastatic limited tumors. Because SBRT prescription is high dose level than Conventional radiation therapy. SBRT plan is necessary for effective Organ at risk (OAR) protection and sufficient Planning target volume (PTV) dose coverage. In particular, multi-target cases may result excessive doses to OAR and hot spot due to dose overlap. This study evaluate usefulness of Volumetric modulated arc therapy (VMAT) in dosimetric and technical considerations using Flattening filter free (FFF) beam. The treatment plans for five patients, being treated on TrueBeam STx(Varian™, USA) with VMAT using 10MV FFF beam and Standard conformal radiotherapy (CRT) using 15MV Flattening filter (FF) beam. PTV, liver, duodenum, bowel, spinal cord, esophagus, stomach dose were evaluated using the dose volume histogram(DVH). Conformity index(CI), homogeneity index(HI), Paddick's index(PCI) for the PTV was assessed. Total Monitor unit (MU) and beam on time was assessed. Average value of CI, HI and PCI for PTV was 1.381±0.028, 1.096±0.016, 0.944±0.473 in VMAT and 1.381± 0.042, 1.136±0.042, 1.534±0.465 in CRT respectively. OAR dose in CRT plans evaluated 1.8 times higher than VMAT. Total MU in VMAT evaluated 1.3 times increase than CRT. Average beam on time was 6.8 minute in VMAT and 21.3 minute in CRT respectively. OAR dose in CRT plans evaluated 1.8 times higher than VMAT. Total MU in VMAT evaluated 1.3 times increase than CRT. Average beam on time was 6.8 minute in VMAT and 21.3 minute in CRT. VMAT for SBRT in multi-target liver cancer using FFF beam is effective treatment techniqe in dosimetric and technical considerations. VMAT decrease intra-fraction error due to treatment time shortening using high dose rate of FFF beam.

  5. The dosimetric impact of daily setup error on target volumes and surrounding normal tissue in the treatment of prostate cancer with intensity-modulated radiation therapy.

    Science.gov (United States)

    Algan, Ozer; Jamgade, Ambarish; Ali, Imad; Christie, Alana; Thompson, J Spencer; Thompson, David; Ahmad, Salahuddin; Herman, Terence

    2012-01-01

    The purpose of this study was to evaluate the impact of daily setup error and interfraction organ motion on the overall dosimetric radiation treatment plans. Twelve patients undergoing definitive intensity-modulated radiation therapy (IMRT) treatments for prostate cancer were evaluated in this institutional review board-approved study. Each patient had fiducial markers placed into the prostate gland before treatment planning computed tomography scan. IMRT plans were generated using the Eclipse treatment planning system. Each patient was treated to a dose of 8100 cGy given in 45 fractions. In this study, we retrospectively created a plan for each treatment day that had a shift available. To calculate the dose, the patient would have received under this plan, we mathematically "negated" the shift by moving the isocenter in the exact opposite direction of the shift. The individualized daily plans were combined to generate an overall plan sum. The dose distributions from these plans were compared with the treatment plans that were used to treat the patients. Three-hundred ninety daily shifts were negated and their corresponding plans evaluated. The mean isocenter shift based on the location of the fiducial markers was 3.3 ± 6.5 mm to the right, 1.6 ± 5.1 mm posteriorly, and 1.0 ± 5.0 mm along the caudal direction. The mean D95 doses for the prostate gland when setup error was corrected and uncorrected were 8228 and 7844 cGy (p 1200 cGy and for the PTV8100 could approach almost 2000 cGy when comparing corrected against uncorrected plans. There was no statistically significant difference in the D35 parameter for the surrounding normal tissue except for the dose received by the penile bulb and the right hip. Our dosimetric evaluation suggests significant underdosing with inaccurate target localization and emphasizes the importance of accurate patient setup and target localization. Further studies are needed to evaluate the impact of intrafraction organ motion, rotation

  6. MiR-467a is upregulated in radiation-induced mouse thymic lymphomas and regulates apoptosis by targeting Fas and Bax.

    Science.gov (United States)

    Gao, Fu; Chen, Song; Sun, Mingjuan; Mitchel, Ronald E J; Li, Bailong; Chu, Zhiyong; Cai, Jianming; Liu, Cong

    2015-01-01

    It has been reported dysregulation of certain microRNAs (miRNAs / miRs) is involved in tumorigenesis. However, the miRNAs associated with radiocarcinogenesis remain undefined. In this study, we validated the upregulation of miR-467a in radiation-induced mouse thymic lymphoma tissues. Then, we investigated whether miR-467a functions as an oncogenic miRNA in thymic lymphoma cells. For this purpose, we assessed the biological effect of miR-467a on thymic lymphoma cells. Using miRNA microarray, we found four miRNAs (miR-467a, miR-762, miR-455 and miR-714) were among the most upregulated (>4-fold) miRNAs in tumor tissues. Bioinformatics prediction suggests miR-467a may potentially regulate apoptosis pathway via targeting Fas and Bax. Consistently, in miR-467a-transfected cells, both proliferation and colony formation ability were significantly increased with decrease of apoptosis rate, while, in miR-467a-knockdown cells, proliferation was suppressed with increase of apoptosis rate, indicating that miR-467a may be involved in the regulation of apoptosis. Furthermore, miR-467a-knockdown resulted in smaller tumors and better prognosis in an in vivo tumor-transplanted model. To explain the mechanism of apoptosis suppression by miR-467a, we explore the expression of candidate target genes (Fas and Bax) in miR-467a-transfected relative to negative control transfected cells using flow cytometry and immunoblotting. Fas and Bax were commonly downregulated in miR-467a-transfected EL4 and NIH3T3 cells, and all of the genes harbored miR-467a target sequences in the 3'UTR of their mRNA. Fas and Bax were actually downregulated in radiation-induced thymic lymphoma tissues, and therefore both were identified as possible targets of miR-467a in thymic lymphoma. To ascertain whether downregulation of Fas and / or Bax is involved in apoptosis suppression by miR-467a, we transfected vectors expressing Fas and Bax into miR-467a-upregulated EL4 cells. Then we found that both Fas- and Bax

  7. TNF-α promotes osteoclastogenesis through JNK signaling-dependent induction of Semaphorin3D expression in estrogen-deficiency induced osteoporosis.

    Science.gov (United States)

    Sang, Chenglin; Zhang, Jiefeng; Zhang, Yongxian; Chen, Fangjing; Cao, Xuecheng; Guo, Lei

    2017-12-01

    Tumor necrosis factor α (TNF-α)-induced osteoclast formation have been demonstrated to play an important role in the pathogenesis of estrogen deficiency-mediated bone loss, but the exact mechanisms by which TNF-α enhanced osteoclast differentiation were not fully elucidated. The class III semaphorins members were critical to regulate bone homeostasis. Here, we identified a novel mechanism whereby TNF-α increasing Semaphorin3D expression contributes to estrogen deficiency-induced osteoporosis. In this study, we found that Semaphorin3D expression was upregulated by TNF-α during the process of RANKL-induced osteoclast differentiation. Inhibition of Semaphorin3D in pre-osteoclasts could attenuate the stimulatory effects of TNF-α on osteoclast proliferation and differentiation. Mechanistically, blocking of the Jun N-terminal kinase (JNK) signaling markedly rescued TNF-α-induced Semaphorin3D expression, suggesting that JNK signaling was involved in the regulation of Semaphorin3D expression by TNF-α. In addition, silencing of Semaphorin3D in vivo could alleviate estrogen deficiency-induced osteoporosis. Our results revealed a novel function for Semaphorin3D and suggested that increased Semaphorin3D may contribute to enhanced bone loss by increased TNF-α in estrogen deficiency-induced osteoporosis. Thus, Semaphorin3D may provide a potential therapeutic target for the treatment of estrogen-deficiency induced osteoporosis. © 2017 Wiley Periodicals, Inc.

  8. TIPE2 inhibits TNF-α-induced hepatocellular carcinoma cell metastasis via Erk1/2 downregulation and NF-κB activation.

    Science.gov (United States)

    Zhang, Yue Hua; Yan, Hong Qiong; Wang, Fang; Wang, Yan Yan; Jiang, Yi Na; Wang, Yi Nan; Gao, Feng Guang

    2015-01-01

    Tumor necrosis factor-α-induced protein 8-like 2 (TNFAIP8L2, TIPE2), which belongs to the TNF-α-induced protein 8 family, is a negative regulator of immune homeostasis. Although pro-inflammatory cytokines such as TNF-α have been reported to be involved in liver carcinoma metastasis, the effect of TIPE2 on hepatocellular carcinoma metastasis remains unknown. We demonstrate that TNF-α clearly augments MMP-13/MMP-3 expression and promotes cell migration in HepG2 cells through activation of the Erk1/2-NF-κB pathways. Interestingly, in addition to human PBLs, macrophages and fibroblasts, liver cancer cells specifically express TNF-α following LPS treatment. Most importantly, TIPE2 overexpression efficiently abrogates the effects of LPS on TNF-α secretion and abolishes the effects of TNF-α on MMP-13/MMP-3 upregulation, cell migration and Erk1/2-NF-κB activation. Taken together, these findings demonstrate that TIPE2 was able to suppress TNF-α-induced hepatocellular carcinoma metastasis by inhibiting Erk1/2 and NF-κB activation, indicating that both TNF-α and TIPE2 might be potential targets for the treatment of HCC metastasis.

  9. A long baseline RICH with a 27-kiloton water target and radiator for detection of neutrino oscillations

    Energy Technology Data Exchange (ETDEWEB)

    Ypsilantis, T.; Seguinot, J.; Zichichi, A.

    1997-01-01

    A 27 kt water volume is investigated as a target for a long baseline neutrino beam from CERN to Gran Sasso. Charged secondaries from the neutrino interactions produce Cherenkov photons in water which are imaged as rings by a spherical mirror. The photon detector elements are 14 400 photomultipliers (PM`s) of 127 mm diameter or 3600 HPD`s of 250 mm diameter with single photon sensitivity. A coincidence signal of about 300 pixel elements in time with the SPS beam starts readout in bins of 1 ns over a period of 128 ns. Momentum, direction, and velocity of hadrons and mucons are determined from the width, center, and radius of the rings, respectively. Momentum is measured if multiple scattering dominates the ring width, as is the case for most of the particles of interest. Momentum, direction, and velocity of hadrons and muons are determined from the width, center, and radius of the rings, respectively. Momentum is measured if multiple scattering dominates the ring width, as is the case for most of the particles of interest. Momentum resolutions of 1-10%, mass resolutions of 5-50 MeV, and direction resolutions of < 1 mrad are achievable. Thresholds in water for muons, pions, kaons, and protons are 0.12, 0.16, 0.55, and 1.05 GeV/c, respectively. Electrons and gammas can be measured with energy resolution {sigma}{sub E}/E{approx}8.5%/{radical}E(GeV) and with direction resolution {approx} 1 mrad. The detector can be sited either inside a Gran Sasso tunnel or above ground because it is directional and the SPS beam is pulsed; thus the rejection of cosmic ray background is excellent.

  10. Direct relationship between levels of TNF-α expression and endothelial dysfunction in reperfusion injury

    OpenAIRE

    Zhang, Cuihua; Wu, Junxi; Xu, Xiangbin; Potter, Barry J.; Gao, Xue

    2010-01-01

    We previously found that myocardial ischemia/reperfusion (I/R) initiates expression of tumor necrosis factor-α (TNF) leading to coronary endothelial dysfunction. However, it is not clear whether there is a direct relationship between levels of TNF expression and endothelial dysfunction in reperfusion injury. We studied levels of TNF expression by using different transgenic animals expressing varying amounts of TNF in I/R. We crossed TNF overexpression (TNF++/++) with TNF knockout (TNF−/−) mic...

  11. TNF-alpha blockade by a dimeric TNF type I receptor molecule selectively inhibits adaptive immune responses.

    Science.gov (United States)

    Colagiovanni, D B; Suniga, M A; Frazier, J L; Edwards, C K; Fleshner, M; McCay, J A; White, K L; Shopp, G M

    2000-11-01

    Tumor necrosis factor-alpha (TNF-alpha) is a mediator of severe inflammatory processes, including rheumatoid arthritis. Suppression of TNF with a soluble type I or type II receptor molecule (TNF-RI or TNF-RII) has the potential to decrease cytokine levels and modulate inflammatory diseases in humans. However, it has recently been reported that treatment of mice with a TNF-RI:Fc immunoadhesin protein augmented Gram positive infections and subsequent mortality. To determine if TNF-alpha blockade with soluble TNF-alpha receptors might alter immune system function, assays were assessed in rodents treated with a dimeric form of the p55 TNF-RI, Tumor Necrosis Factor-binding protein (TNFbp). Administration of TNFbp resulted in suppression of primary and secondary IgG antibody responses and cell-mediated immune function. No treatment-related differences were detected in immune-enhancing assays or non-specific immune function parameters. Bacterial host resistance assays with Listeria monocytogenes, Staphylococcus aureus or Escherichia coli showed an increase in tissue colony counts only with L. monocytogenes challenged animals following TNFbp administration. These results suggest that TNFbp has the capacity to inhibit adaptive immune function in experimental animal models. Studies suggest that while reducing TNF-alpha is important in controlling cytokine-dependent disease states, maintenance of a threshold level may be critical for normal immune function.

  12. Azadirachtin interacts with the tumor necrosis factor (TNF) binding domain of its receptors and inhibits TNF-induced biological responses.

    Science.gov (United States)

    Thoh, Maikho; Kumar, Pankaj; Nagarajaram, Hampathalu A; Manna, Sunil K

    2010-02-19

    The role of azadirachtin, an active component of a medicinal plant Neem (Azadirachta indica), on TNF-induced cell signaling in human cell lines was investigated. Azadirachtin blocks TNF-induced activation of nuclear factor kappaB (NF-kappaB) and also expression of NF-kappaB-dependent genes such as adhesion molecules and cyclooxygenase 2. Azadirachtin inhibits the inhibitory subunit of NF-kappaB (IkappaB alpha) phosphorylation and thereby its degradation and RelA (p65) nuclear translocation. It blocks IkappaB alpha kinase (IKK) activity ex vivo, but not in vitro. Surprisingly, azadirachtin blocks NF-kappaB DNA binding activity in transfected cells with TNF receptor-associated factor (TRAF)2, TNF receptor-associated death domain (TRADD), IKK, or p65, but not with TNFR, suggesting its effect is at the TNFR level. Azadirachtin blocks binding of TNF, but not IL-1, IL-4, IL-8, or TNF-related apoptosis-inducing ligand (TRAIL) with its respective receptors. Anti-TNFR antibody or TNF protects azadirachtin-mediated down-regulation of TNFRs. Further, in silico data suggest that azadirachtin strongly binds in the TNF binding site of TNFR. Overall, our data suggest that azadirachtin modulates cell surface TNFRs thereby decreasing TNF-induced biological responses. Thus, azadirachtin exerts an anti-inflammatory response by a novel pathway, which may be beneficial for anti-inflammatory therapy.

  13. TNF-alpha expression in embryos exposed to a teratogen.

    Science.gov (United States)

    Ivnitsky, I; Torchinsky, A; Gorivodsky, M; Zemliak, I; Orenstein, H; Savion, S; Shepshelovich, J; Carp, H; Fein, A; Toder, V

    1998-12-01

    The role of tumor necrosis factor (TNF)-alpha produced by embryonic cells in normal and abnormal development is poorly understood. To assess to what extent TNF-alpha may be involved in the process of induced dysmorphogenesis, the expression of TNF-alpha and TNF-alpha receptor (TNFRI) mRNA as well as TNF-alpha protein was evaluated in embryos responding to a cyclophosphamide (CP)-induced teratogenic insult. The effect of maternal immunostimulation increasing the embryo's tolerance to CP on TNF-alpha expression was also investigated. ICR female mice were treated intraperitoneally with 40 mg/kg CP on day 12 of pregnancy. The immunostimulator, xenogeneic rat splenocytes, was injected intrauterine 21 days before mating. Embryos were collected on days 13, 14, or 15 of pregnancy. TNF-alpha mRNA, TNFRI mRNA, and TNF-alpha protein expression were evaluated by in situ hybridization and immunostaining techniques in control, teratogen-treated, and immuno-stimulated teratogen-treated embryos. CP-treated embryos showed severe external brain and craniofacial anomalies already visible on day 14 of pregnancy. TNF-alpha mRNA transcripts were detected in cells of the brain and the head of 13-day embryos, which preceded the occurrence of CP-induced external craniofacial anomalies. On day 15 of pregnancy, when severe craniofacial anomalies increased, a significant increase in the intensity of TNF-alpha, TNFR1 mRNA transcripts, and TNF-alpha protein expression were observed in cells of the malformed regions of the head and the brain. In other nonmalformed organs of CP-treated embryos such as the liver (not macroscopically different from controls), neither TNF-alpha nor TNFR1 transcripts were detected. Immunostimulation substantially diminished the severity of CP-induced brain and craniofacial anomalies, decreased the resorption rate, and was associated with decreased intensity of TNF-alpha mRNA transcripts detected on day 15 of pregnancy in the head and the brain of CP-treated embryos

  14. TNFR1 mediates TNF-α-induced tumour lymphangiogenesis and metastasis by modulating VEGF-C-VEGFR3 signalling

    DEFF Research Database (Denmark)

    Ji, Hong; Cao, Renhai; Yang, Yunlong

    2014-01-01

    in Tnfr1(-/-) mice largely restores tumour lymphangiogenesis and lymphatic metastasis. These findings shed mechanistic light on the intimate interplay between inflammation and lymphangiogenesis in cancer metastasis, and propose therapeutic intervention of lymphatic metastasis by targeting the TNF-α-TNFR1...

  15. Intensity modulated radiation therapy (IMRT: differences in target volumes and improvement in clinically relevant doses to small bowel in rectal carcinoma

    Directory of Open Access Journals (Sweden)

    Delclos Marc E

    2011-06-01

    Full Text Available Abstract Background A strong dose-volume relationship exists between the amount of small bowel receiving low- to intermediate-doses of radiation and the rates of acute, severe gastrointestinal toxicity, principally diarrhea. There is considerable interest in the application of highly conformal treatment approaches, such as intensity-modulated radiation therapy (IMRT, to reduce dose to adjacent organs-at-risk in the treatment of carcinoma of the rectum. Therefore, we performed a comprehensive dosimetric evaluation of IMRT compared to 3-dimensional conformal radiation therapy (3DCRT in standard, preoperative treatment for rectal cancer. Methods Using RTOG consensus anorectal contouring guidelines, treatment volumes were generated for ten patients treated preoperatively at our institution for rectal carcinoma, with IMRT plans compared to plans derived from classic anatomic landmarks, as well as 3DCRT plans treating the RTOG consensus volume. The patients were all T3, were node-negative (N = 1 or node-positive (N = 9, and were planned to a total dose of 45-Gy. Pairwise comparisons were made between IMRT and 3DCRT plans with respect to dose-volume histogram parameters. Results IMRT plans had superior PTV coverage, dose homogeneity, and conformality in treatment of the gross disease and at-risk nodal volume, in comparison to 3DCRT. Additionally, in comparison to the 3DCRT plans, IMRT achieved a concomitant reduction in doses to the bowel (small bowel mean dose: 18.6-Gy IMRT versus 25.2-Gy 3DCRT; p = 0.005, bladder (V40Gy: 56.8% IMRT versus 75.4% 3DCRT; p = 0.005, pelvic bones (V40Gy: 47.0% IMRT versus 56.9% 3DCRT; p = 0.005, and femoral heads (V40Gy: 3.4% IMRT versus 9.1% 3DCRT; p = 0.005, with an improvement in absolute volumes of small bowel receiving dose levels known to induce clinically-relevant acute toxicity (small bowel V15Gy: 138-cc IMRT versus 157-cc 3DCRT; p = 0.005. We found that the IMRT treatment volumes were typically larger than that

  16. TNF phase III signalling in tolerant cells is tightly controlled by A20 and CYLD.

    Science.gov (United States)

    Bikker, Rolf; Christmann, Martin; Preuß, Katharina; Welz, Bastian; Friesenhagen, Judith; Dittrich-Breiholz, Oliver; Huber, René; Brand, Korbinian

    2017-09-01

    Following the acute phase of an inflammatory reaction, a strictly controlled resolution of inflammation is necessary. A dysregulation of this process leads to hyperinflammation, chronic inflammatory disease, or immune paralysis. Different mechanisms participate in the coordinated termination of the inflammatory process, e.g. the expression of antiinflammatory molecules and different forms of tolerance. To better understand the processes which mediate resolution of TNF-dependent inflammation and induce tolerance, it is necessary to characterize the signal transduction quality during TNF long-term (pre)incubation. Within a time frame from 12 to 48h, designated as phase III of the TNF response, we measured an ongoing, constitutive activation of TNFR1/NF-κB-dependent pathways in monocytic cells. Phase III signalling which was also named "constitutive signaling in TNF tolerant cells" induces the expression of low- and high-sensitive target genes including A20 which is differentially regulated by transcriptional and proteolytic events. A20 strictly controls TNF long-term constitutive signalling in an IκB kinase complex- and partially RIP-dependent manner supported by adjuvant ABIN1. In addition, CYLD proteins participate in the regulation of this late-phase signal transduction, whereas downstream molecules such as Bcl3 and p50 are not involved. A20 and CYLD are expressed with different mRNA kinetics resulting in a strong or only a modest increase in protein levels, respectively. The identification of mechanisms which contribute to the termination of inflammation will provide additional diagnostic and therapeutic aspects to specifically diagnose certain aspects of inflammation and specifically modulate them. Copyright © 2017 Elsevier Inc. All rights reserved.

  17. Metaxin deficiency alters mitochondrial membrane permeability and leads to resistance to TNF-induced cell killing.

    Science.gov (United States)

    Ono, Koh; Wang, Xiaofei; Kim, Sung Ouk; Armstrong, Lucas C; Bornstein, Paul; Han, Jiahuai

    2010-02-01

    Metaxin, a mitochondrial outer membrane protein, is critical for TNF-induced cell death in L929 cells. Its deficiency, caused by retroviral insertion-mediated mutagenesis, renders L929 cells resistance to TNF killing. In this study, we further characterized metaxin deficiency-caused TNF resistance in parallel with Bcl-X(L) overexpression-mediated death resistance. We did not find obvious change in mitochondria membrane potential in metaxin-deficient (Met(mut)) and Bcl-X(L)-overexpressing cells, but we did find an increase in the release rate of the mitochondrial membrane potential probe rhodamine 123 (Rh123) that was preloaded into mitochondria. In addition, overexpression of a function-interfering mutant of metaxin (MetaΔTM/C) or Bcl-X(L) in MCF-7.3.28 cells also resulted in an acquired resistance to TNF killing and a faster rate of Rh123 release, indicating a close correlation between TNF resistance and higher rates of the dye release from the mitochondria. The release of Rh123 can be controlled by the mitochondrial membrane permeability transition (PT) pore, as targeting an inner membrane component of the PT pore by cyclosporin A (CsA) inhibited Rh123 release. However, metaxin deficiency and Bcl-X(L) overexpression apparently affect Rh123 release from a site(s) different from that of CsA, as CsA can overcome their effect. Though both metaxin and Bcl-X(L) appear to function on the outer mitochondrial membrane, they do not interact with each other. They may use different mechanisms to increase the permeability of Rh123, since previous studies have suggested that metaxin may influence certain outer membrane porins while Bcl-X(L) may form pores on the outer membrane. The alteration of the mitochondrial outer membrane properties by metaxin deficiency and Bcl-X(L) overexpression, as indicated by a quicker Rh123 release, may be helpful in maintaining mitochondrial integrity.

  18. IL-17 induces hyperalgesia via TNF-dependent neutrophil infiltration.

    Science.gov (United States)

    McNamee, Kay E; Alzabin, Saba; Hughes, Jane P; Anand, Praveen; Feldmann, Marc; Williams, Richard O; Inglis, Julia J

    2011-08-01

    Interleukin-17 (IL-17) and tumour necrosis factor-α (TNF) are critical in the pathogenesis of arthritis but their relationship during inflammatory pain has received limited attention. We aimed to establish whether IL-17 can induce hyperalgesia in acute conditions, and investigated the role of TNF in mediating the pain response. Hyperalgesia was elicited in C57BL/6 mice by injection of recombinant IL-17, TNF or vehicle into the plantar tissue. Elevated pain was measured by the Hargreaves test for thermal hyperalgesia and Linton incapacitance tester for weight-bearing change. Cellular infiltration during hyperalgesia was determined by histological analysis and myeloperoxidase assay. IL-17 was found to induce hyperalgesia, but this was dependent on neutrophil migration and TNF binding to TNF receptor 1 (TNFR1). Because TNF-induced hyperalgesia was also dependent on neutrophil migration, the relationship between the resident fibroblasts, the cytokines and the migrating neutrophils was further investigated. By means of an air pouch model of cell migration, it was established that IL-17-induced neutrophil infiltration was dependent of TNF/TNFR1 as this interaction was required for the induction of the chemokine keratinocyte chemoattractant. These findings suggest that IL-17 causes acute hyperalgesia indirectly by inducing TNF from resident cells. The subsequent production of keratinocyte chemoattractant then triggers neutrophil chemotaxis to the plantar tissue, releasing algesic mediators locally to sensitise the nerve.

  19. Association of -308 TNF-alpha promoter polymorphism with viral ...

    African Journals Online (AJOL)

    2012-06-02

    Jun 2, 2012 ... as tumour necrosis factor alpha (TNF-α).10-12. TNF-α is the ... in HIV-1 patients may be associated with increased risk of HIV-1 ..... outcomes. To provide holistic management ... the relationship among insulin resistance, percent body fat, and ... alpha and interleukin 1 beta by monocytic cells infected with ...

  20. Kadar TNF-α dalam Zalir Peritoneal Penderita Endometriosis

    Directory of Open Access Journals (Sweden)

    TEDJA DANUDJA OEPOMO

    2005-11-01

    Full Text Available The aim of this research was to expose the role of tumor necrotic factor alpha (TNF-α in the pathogenetic endometriosis. This research had been done in dr. Muwardi Hospital Surakarta. Twenty patients undergoing laparoscopic operation because of endometriosis indication (Group I, 20 women (aged 23 to 40 who undergo interval sterilization by means of laparoscopic technique (Group II. During laparoscopic operation, peritoneal fluid is taken to examine TNF-α by ELISA technique. The results indicated that by independent t-test, a significant difference of concentration of TNF-α in the peritoneal fluid is found between endometriosis patients and normal women (who are sterilized (P=0.00. By chi-square test, the Ratio Odds value 171 shows that the high concentration of TNF-α will increase the possibility of endometriosis 171 times rather than the low TNF-α. It could be concluded the high concentration of TNF-α is the risk factor of endometriosis in comparison with the low TNF-α. It shows that quite possibly TNF-α has a role in the pathogenic endometriosis.

  1. Dichotomal role of TNF in experimental pulmonary edema reabsorption

    NARCIS (Netherlands)

    Braun, C; Hamacher, J; Morel, DR; Wendel, A; Lucas, R

    2005-01-01

    Distinct from its receptor binding sites, TNF carries a lectin-like domain, situated at the tip of the molecule, which specifically binds oligosaccharides, such as NN'-diacetylchitobiose. In view of the apparently conflicting data concerning TNF actions in pulmonary edema, we investigated the contri

  2. Regulation of NF-κB by TNF family cytokines.

    Science.gov (United States)

    Hayden, Matthew S; Ghosh, Sankar

    2014-06-01

    The NF-κB family of inducible transcription factors is activated in response to a variety of stimuli. Amongst the best-characterized inducers of NF-κB are members of the TNF family of cytokines. Research on NF-κB and TNF have been tightly intertwined for more than 25 years. Perhaps the most compelling examples of the interconnectedness of NF-κB and the TNF have come from analysis of knock-out mice that are unable to activate NF-κB. Such mice die embryonically, however, deletion of TNF or TNFR1 can rescue the lethality thereby illustrating the important role of NF-κB as the key regulator of transcriptional responses to TNF. The physiological connections between NF-κB and TNF cytokines are numerous and best explored in articles focusing on a single TNF family member. Instead, in this review, we explore general mechanisms of TNF cytokine signaling, with a focus on the upstream signaling events leading to activation of the so-called canonical and noncanonical NF-κB pathways by TNFR1 and CD40, respectively.

  3. Generation of nanosecond soft X-ray pulsed as a result of interaction of laser radiation with gas puff target; Wplyw nanosekundowych impulsow miekkiego promieniowania rentgenowskiego w wyniku oddzialywania promieniowania laserowego z impulsowa tarcza gazowa

    Energy Technology Data Exchange (ETDEWEB)

    Fiedorowicz, H.; Patron, Z.; Bartnik, A.; Parys, P. [Wojskowa Akademia Techniczna, Warsaw (Poland)

    1995-10-01

    A new method of generation of nanosecond soft x-ray pulsed with a photon energy around 1 keV is presented. X-rays are generated in a high-temperature plasma, which is created as a result of interaction of Nd:glass laser radiation with a gas puff target. The target was obtained by puffing a small amount of gas, through the nozzle, into the vacuum chamber, by means of a pressure electromagnetic valve. The pulses of laser radiation with the pulse duration of 1 ns and energy up to 15 J, generated in the system of a high-power Nd:glass laser, were for the target heating. Spatial, spectral and temporal measurements of X-ray emission have shown that the high-intensity soft X-ray are generated as a result of the interaction of nanosecond pulses of Nd:glass laser radiation with the gas puff target. High efficiency of X-ray generation is suggested to be related to the effect of condensation of the gas, outflowing from the valve nozzle and, in effect, to the interaction of laser radiation with matter in a form of aerosol. (author). 55 refs, 5 figs.

  4. A Prospective Pathologic Study to Define the Clinical Target Volume for Partial Breast Radiation Therapy in Women With Early Breast Cancer

    Energy Technology Data Exchange (ETDEWEB)

    Nguyen, Brandon T., E-mail: Brandon.Nguyen@act.gov.au [Department of Radiation Oncology, Peter MacCallum Cancer Centre, East Melbourne, Victoria (Australia); Canberra Hospital, Radiation Oncology Department, Garran, ACT (Australia); Deb, Siddhartha [Department of Anatomical Pathology, Peter MacCallum Cancer Centre, East Melbourne, Victoria (Australia); Victorian Cancer Biobank, Cancer Council of Victoria, Carlton, Victoria (Australia); Fox, Stephen [Department of Anatomical Pathology, Peter MacCallum Cancer Centre, East Melbourne, Victoria (Australia); Hill, Prudence [Department of Anatomical Pathology, St. Vincent' s Hospital Melbourne, Fitzroy, Victoria (Australia); Collins, Marnie [Centre for Biostatistics and Clinical Trials, Peter MacCallum Cancer Centre, East Melbourne, Victoria (Australia); Chua, Boon H. [Department of Radiation Oncology, Peter MacCallum Cancer Centre, East Melbourne, Victoria (Australia); University of Melbourne, Parkville, Victoria (Australia)

    2012-12-01

    Purpose: To determine an appropriate clinical target volume for partial breast radiation therapy (PBRT) based on the spatial distribution of residual invasive and in situ carcinoma after wide local excision (WLE) for early breast cancer or ductal carcinoma in situ (DCIS). Methods and Materials: We performed a prospective pathologic study of women potentially eligible for PBRT who had re-excision and/or completion mastectomy after WLE for early breast cancer or DCIS. A pathologic assessment protocol was used to determine the maximum radial extension (MRE) of residual carcinoma from the margin of the initial surgical cavity. Women were stratified by the closest initial radial margin width: negative (>1 mm), close (>0 mm and {<=}1 mm), or involved. Results: The study population was composed of 133 women with a median age of 59 years (range, 27-82 years) and the following stage groups: 0 (13.5%), I (40.6%), II (38.3%), and III (7.5%). The histologic subtypes of the primary tumor were invasive ductal carcinoma (74.4%), invasive lobular carcinoma (12.0%), and DCIS alone (13.5%). Residual carcinoma was present in the re-excision and completion mastectomy specimens in 55.4%, 14.3%, and 7.2% of women with an involved, close, and negative margin, respectively. In the 77 women with a noninvolved radial margin, the MRE of residual disease, if present, was {<=}10 mm in 97.4% (95% confidence interval 91.6-99.5) of cases. Larger MRE measurements were significantly associated with an involved margin (P<.001), tumor size >30 mm (P=.03), premenopausal status (P=.03), and negative progesterone receptor status (P=.05). Conclusions: A clinical target volume margin of 10 mm would encompass microscopic residual disease in >90% of women potentially eligible for PBRT after WLE with noninvolved resection margins.

  5. Salivary TNF-alpha: A potential marker of periodontal destruction

    Directory of Open Access Journals (Sweden)

    Pritma Singh

    2014-01-01

    Full Text Available Aims and Objectives: (1 To evaluate the effect of type 2 diabetes mellitus on salivary TNF-α level in chronic periodontitis. (2 To evaluate the effect of smoking on salivary TNF-α level in chronic periodontitis. (3 To compare and correlate TNF-α level with the healthy individuals. Materials and Methods: Subjects aged 30-35 years were included for the study and divided into four groups as a group of 20 systemically and periodontally healthy individuals (group I, a group of 20 subjects with pocket probing depth (PPD ≥5 mm and clinical attachment loss (CAL of ≥2 mm (group II, a group of 20 diabetic subjects (of more than 5 years with periodontal parameters as of group II as (group III and a group of 20 subjects smoking (≥10 cigarettes a day with periodontal parameters of group II as (group IV. Periodontal parameters of PPD, CAL, gingival index (GI, and plaque index (PI were measured using standard indices and criteria. Three milliliter of unstimulated saliva was taken and salivary TNF-α determined by using ELISA technique (Quantikine Human total TNF-A immunoassay kit. Results: Data revealed highest mean TNF-α in group III followed by group IV, group II, and group I. Mean TNF-α of both group III (76.1% and group IV (48.8% was significantly higher as compared to group I (P 0.05 and a significant negative correlation was observed between CAL and TNF-α in group IV. Conclusion: Our study clearly underlines a profound impact of diabetes and smoking on salivary TNF-α in chronic periodontitis subjects in comparison to healthy subjects. Moreover, diabetes status increased TNF-α significantly in comparison to smoking in chronic periodontitis patients.

  6. Activation of Sirt1 by resveratrol inhibits TNF-α induced inflammation in fibroblasts.

    Directory of Open Access Journals (Sweden)

    Xiaoxia Zhu

    Full Text Available Inflammation is one of main mechanisms of autoimmune disorders and a common feature of most diseases. Appropriate suppression of inflammation is a key resolution to treat the diseases. Sirtuin1 (Sirt1 has been shown to play a role in regulation of inflammation. Resveratrol, a potent Sirt1 activator, has anti-inflammation property. However, the detailed mechanism is not fully understood. In this study, we investigated the anti-inflammation role of Sirt1 in NIH/3T3 fibroblast cell line. Upregulation of matrix metalloproteinases 9 (MMP-9, interleukin-1beta (IL-1β, IL-6 and inducible nitric oxide synthase (iNOS were induced by tumor necrosis factor alpha (TNF-α in 3T3 cells and resveratrol suppressed overexpression of these pro-inflammatory molecules in a dose-dependent manner. Knockdown of Sirt1 by RNA interference caused 3T3 cells susceptible to TNF-α stimulation and diminished anti-inflammatory effect of resveratrol. We also explored potential anti-inflammatory mechanisms of resveratrol. Resveratrol reduced NF-κB subunit RelA/p65 acetylation, which is notably Sirt1 dependent. Resveratrol also attenuated phosphorylation of mammalian target of rapamycin (mTOR and S6 ribosomal protein (S6RP while ameliorating inflammation. Our data demonstrate that resveratrol inhibits TNF-α-induced inflammation via Sirt1. It suggests that Sirt1 is an efficient target for regulation of inflammation. This study provides insight on treatment of inflammation-related diseases.

  7. Anti-cytokine biologic treatment beyond anti-TNF in Behçet's disease.

    Science.gov (United States)

    Arida, Aikaterini; Sfikakis, Petros P

    2014-01-01

    Unmet therapeutic needs in Behçet's disease have drawn recent attention to biological agents targeting cytokines other than TNF. The anti-IL-17 antibody secukinumab and the anti-IL-2 receptor antibody daclizumab were not superior to placebo for ocular Behçet's in randomised controlled trials, comprising 118 and 17 patients, respectively. The anti-IL-1 agents anakinra and canakinumab and the anti-IL-6 agent tocilizumab were given to isolated refractory disease patients, who were either anti-TNF naïve (n=9) or experienced (n=18). No new safety signals were reported. Although a potential for bias to report positive effects and underreport negative cases may exist, Anakinra was partially effective, whereas disease remission was noted after canakinumab in some anti-TNF resistant patients. Tocilizumab appeared effective for neuro-Behçet's, but not for mucocutaneous manifestations. Finally, in a pilot study of 7 patients with relapsing posterior uveitis refractory to azathioprine and/or cyclosporine, the anti-IL-1β antibody Gevokizumab was beneficial. Collectively, it seems that IL-1 and IL-6 are promising targets in patients refractory or intolerant to other regimens including anti-TNFs. However, controlled studies are surely needed.

  8. Antibodies to a soluble form of a tumor necrosis factor (TNF) receptor have TNF-like activity

    DEFF Research Database (Denmark)

    Engelmann, H; Holtmann, H; Brakebusch, C

    1990-01-01

    . These antibodies are cytotoxic to cells which are sensitive to TNF toxicity, induce resistance to TNF toxicity, enhance the incorporation of thymidine into normal fibroblasts, inhibit the growth of chlamydiae, and induce the synthesis of prostaglandin E2. Monovalent F(ab) fragments of the polyclonal antibodies...

  9. {sup 213}Bi-DOTATOC receptor-targeted alpha-radionuclide therapy induces remission in neuroendocrine tumours refractory to beta radiation: a first-in-human experience

    Energy Technology Data Exchange (ETDEWEB)

    Kratochwil, C.; Giesel, F.L.; Mier, W.; Haberkorn, U. [University Hospital Heidelberg, Department of Nuclear Medicine, Heidelberg (Germany); Bruchertseifer, F.; Apostolidis, C.; Morgenstern, A. [European Commission, Institute for Transuranium Elements, Karlsruhe (Germany); Boll, R.; Murphy, K. [Oak Ridge National Laboratory, Oak Ridge, TN (United States)

    2014-11-15

    Radiopeptide therapy using a somatostatin analogue labelled with a beta emitter such as {sup 90}Y/{sup 177}Lu-DOTATOC is a new therapeutic option in neuroendocrine cancer. Alternative treatments for patients with refractory disease are rare. Here we report the first-in-human experience with {sup 213}Bi-DOTATOC targeted alpha therapy (TAT) in patients pretreated with beta emitters. Seven patients with progressive advanced neuroendocrine liver metastases refractory to treatment with {sup 90}Y/{sup 177}Lu-DOTATOC were treated with an intraarterial infusion of {sup 213}Bi-DOTATOC, and one patient with bone marrow carcinosis was treated with a systemic infusion of {sup 213}Bi-DOTATOC. Haematological, kidney and endocrine toxicities were assessed according to CTCAE criteria. Radiological response was assessed with contrast-enhanced MRI and {sup 68}Ga-DOTATOC-PET/CT. More than 2 years of follow-up were available in seven patients. The biodistribution of {sup 213}Bi-DOTATOC was evaluable with 440 keV gamma emission scans, and demonstrated specific tumour binding. Enduring responses were observed in all treated patients. Chronic kidney toxicity was moderate. Acute haematotoxicity was even less pronounced than with the preceding beta therapies. TAT can induce remission of tumours refractory to beta radiation with favourable acute and mid-term toxicity at therapeutic effective doses. (orig.)

  10. Thymoquinone inhibits TNF-α-induced inflammation and cell adhesion in rheumatoid arthritis synovial fibroblasts by ASK1 regulation

    Energy Technology Data Exchange (ETDEWEB)

    Umar, Sadiq; Hedaya, Omar; Singh, Anil K.; Ahmed, Salahuddin, E-mail: salah.ahmed@wsu.edu

    2015-09-15

    Tumor necrosis factor-α (TNF-α) is a pro-inflammatory cytokine produced by monocytes/macrophage that plays a pathological role in rheumatoid arthritis (RA). In this study, we investigate the effect of thymoquinone (TQ), a phytochemical found in Nigella sativa, in regulating TNF-α-induced RA synovial fibroblast (RA-FLS) activation. Treatment with TQ (1–5 μM) had no marked effect on the viability of human RA-FLS. Pre-treatment of TQ inhibited TNF-α-induced interleukin-6 (IL-6) and IL-8 production and ICAM-1, VCAM-1, and cadherin-11 (Cad-11) expression in RA-FLS (p < 0.01). Evaluation of the signaling events showed that TQ inhibited TNF-α-induced phospho-p38 and phospho-JNK expression, but had no inhibitory effect on NF-κB pathway, in RA-FLS (p < 0.05; n = 4). Interestingly, we observed that selective down-regulation of TNF-α-induced phospho-p38 and phospho-JNK activation by TQ is elicited through inhibition of apoptosis-regulated signaling kinase 1 (ASK1). Furthermore, TNF-α selectively induced phosphorylation of ASK1 at Thr845 residue in RA-FLS, which was inhibited by TQ pretreatment in a dose dependent manner (p < 0.01). Pre-treatment of RA-FLS with ASK1 inhibitor (TC ASK10), blocked TNF-α induced expression of ICAM-1, VCAM-1, and Cad-11. Our results suggest that TNF-α-induced ASK1-p38/JNK pathway is an important mediator of cytokine synthesis and enhanced expression of adhesion molecule in RA-FLS and TQ, by selectively inhibiting this pathway, may have a potential therapeutic value in regulating tissue destruction observed in RA. - Highlights: • Evolving evidence suggests that ASK1 plays a central role in rheumatic arthritis (RA). • TNF-α activates ASK1, which regulate downstream signaling through JNK/p38 activation in RA-FLS. • ASK1 may be used as a potential therapeutic target in RA. • Thymoquinone was able to selectively inhibit TNF-α-induced phosphorylation of ASK1 in RA-FLS. • Thymoquinone might serve as a potential small

  11. Anti-c-Met antibody bioconjugated with hollow gold nanospheres as a novel nanomaterial for targeted radiation ablation of human cervical cancer cell.

    Science.gov (United States)

    Liang, Ying; Liu, Jiao; Liu, Ting; Yang, Xingsheng

    2017-08-01

    Radiotherapy is preferred to chemotherapy as an adjuvant therapy for postoperative cervical cancer owing to its convenience and minimal effects on various non-targeted systems. The present study sought to investigate whether the utilization of anti-MET proto-oncogene, receptor tyrosine kinase (c-Met) antibodies conjugated to hollow gold nanospheres (anti-c-Met/HGNs) may enhance the efficiency of radiation therapy for cervical cancer. Anti-c-Met/HGNs were synthesized and confirmed to target c-Met, which was overexpressed on the cell membrane of multiple malignancies. The successful synthesis of HGNs was observed using transmission electron microscopy (TEM). Overrepresentation of c-Met in the human cervical cancer cell line CaSki was verified by immunofluorescence. The cellular uptake of HGNs was assessed using inductively coupled plasma atomic emission spectroscopy (ICP-AES). To assess the toxicity of functionalized gold nanospheres, a cell proliferation and toxicity assay was used and flow cytometry, with staining by propidium iodide (PI), was performed to study the cell cycle changes. Each experiment was conducted on three groups: Control, HGNs alone and anti-c-Met/HGNs, with each group also assessed with or without X-rays. The variation of apoptotic rate was observed by flow cytometry using a dual-staining Annexin V-fluorescein isothiocyanate/PI kit. Expression of apoptosis-associated proteins was examined by western blot analysis. TEM revealed a number of hollow spheres with cells with an average diameter of 56.25 nm and a mean wall thickness of 6.56 nm. CaSki cells were detected by inverted fluorescence microscopy via a layer of fluorescent green marker, and ICP-AES confirmed the distinct uptake of anti-c-Met/HGNs by each CaSki cell. Anti-c-Met/HGNs induced 38.7% of cells to stay in the G2/M phase, whereas the equivalent proportion in the control group was 19.8%. Compared with other groups, CaSki cells treated with anti-c-Met/HGNs and 5 Gy X-ray radiation

  12. TNF-alpha −308G/A and −238G/A polymorphisms and its protein network associated with type 2 diabetes mellitus

    Directory of Open Access Journals (Sweden)

    Kaiser Jamil

    2017-09-01

    Full Text Available Several reports document the role of tumor necrosis factor alpha (TNF-α and lipid metabolism in the context of acute inflammation as a causative factor in obesity-associated insulin resistance and as one of the causative parameter of type 2 diabetes mellitus (T2DM. Our aim was to investigate the association between −308G/A and −238G/A polymorphisms located in the promoter region of the TNF-α gene in T2DM in the Indian population with bioinformatics analysis of TNF-α protein networking with an aim to find new target sites for the treatment of T2DM. Demographics of 100 diabetes patients and 100 healthy volunteers were collected in a structured proforma and 3 ml blood samples were obtained from the study group, after approval of Institutional Ethics Committee of the hospital (IEC. The information on clinical parameters was obtained from medical records. Genomic DNA was extracted; PCR–RFLP was performed using TNF-α primers specific to detect the presence of SNPs. Various bioinformatics tools such as STRING software were used to determine its network with other associated genes. The PCR–RFLP studies showed that among the −238G/A types the GG genotype was 87%, GA genotype was 12% and AA genotype was 1%. Almost a similar pattern of results was obtained with TNF-α −308G/A polymorphism. The results obtained were evaluated statistically to determine the significance. By constructing TNF-α protein interaction network we could analyze ontology and hubness of the network to identify the networking of this gene which may influence the functioning of other genes in promoting T2DM. We could identify new targets in T2DM which may function in association with TNF-α. Through hub analysis of TNF-α protein network we have identified three novel proteins RIPK1, BIRC2 and BIRC3 which may contribute to TNF-mediated T2DM pathogenesis. In conclusion, our study indicated that some of the genotypes of TNF-α −308G/A, −238G/A were not significantly

  13. TNF-alpha -308G/A and -238G/A polymorphisms and its protein network associated with type 2 diabetes mellitus.

    Science.gov (United States)

    Jamil, Kaiser; Jayaraman, Archana; Ahmad, Javeed; Joshi, Sindhu; Yerra, Shiva Kumar

    2017-09-01

    Several reports document the role of tumor necrosis factor alpha (TNF-α) and lipid metabolism in the context of acute inflammation as a causative factor in obesity-associated insulin resistance and as one of the causative parameter of type 2 diabetes mellitus (T2DM). Our aim was to investigate the association between -308G/A and -238G/A polymorphisms located in the promoter region of the TNF-α gene in T2DM in the Indian population with bioinformatics analysis of TNF-α protein networking with an aim to find new target sites for the treatment of T2DM. Demographics of 100 diabetes patients and 100 healthy volunteers were collected in a structured proforma and 3 ml blood samples were obtained from the study group, after approval of Institutional Ethics Committee of the hospital (IEC). The information on clinical parameters was obtained from medical records. Genomic DNA was extracted; PCR-RFLP was performed using TNF-α primers specific to detect the presence of SNPs. Various bioinformatics tools such as STRING software were used to determine its network with other associated genes. The PCR-RFLP studies showed that among the -238G/A types the GG genotype was 87%, GA genotype was 12% and AA genotype was 1%. Almost a similar pattern of results was obtained with TNF-α -308G/A polymorphism. The results obtained were evaluated statistically to determine the significance. By constructing TNF-α protein interaction network we could analyze ontology and hubness of the network to identify the networking of this gene which may influence the functioning of other genes in promoting T2DM. We could identify new targets in T2DM which may function in association with TNF-α. Through hub analysis of TNF-α protein network we have identified three novel proteins RIPK1, BIRC2 and BIRC3 which may contribute to TNF-mediated T2DM pathogenesis. In conclusion, our study indicated that some of the genotypes of TNF-α -308G/A, -238G/A were not significantly associated to type 2 diabetes

  14. TRAF1 is a negative regulator of TNF signaling. enhanced TNF signaling in TRAF1-deficient mice.

    Science.gov (United States)

    Tsitsikov, E N; Laouini, D; Dunn, I F; Sannikova, T Y; Davidson, L; Alt, F W; Geha, R S

    2001-10-01

    TNF receptor-associated factor 1 (TRAF1) is a unique TRAF protein because it lacks a RING finger domain and is predominantly expressed in activated lymphocytes. To elucidate the function of TRAF1, we generated TRAF1-deficient mice. TRAF1(-/-) mice are viable and have normal lymphocyte development. TRAF1(-/-) T cells exhibit stronger than wild-type (WT) T cell proliferation to anti-CD3 mAb, which persisted in the presence of IL-2 or anti-CD28 antibodies. Activated TRAF1(-/-) T cells, but not TRAF1(+/+) T cells, responded to TNF by proliferation and activation of the NF-kappa B and AP-1 signaling pathways. This TNF effect was mediated by TNFR2 (p75) but not by TNFR1 (p55). Furthermore, skin from TRAF1(-/-) mice was hypersensitive to TNF-induced necrosis. These findings suggest that TRAF1 is a negative regulator of TNF signaling.

  15. TNF-alpha inhibitors for ankylosing spondylitis.

    Science.gov (United States)

    Maxwell, Lara J; Zochling, Jane; Boonen, Annelies; Singh, Jasvinder A; Veras, Mirella M S; Tanjong Ghogomu, Elizabeth; Benkhalti Jandu, Maria; Tugwell, Peter; Wells, George A

    2015-04-18

    TNF (tumor necrosis factor)-alpha inhibitors block a key protein in the inflammatory chain reaction responsible for joint inflammation, pain, and damage in ankylosing spondylitis. To assess the benefit and harms of adalimumab, etanercept, golimumab, and infliximab (TNF-alpha inhibitors) in people with ankylosing spondylitis. We searched the following databases to January 26, 2009: MEDLINE (from 1966); EMBASE (from 1980); the Cochrane Central Register of Controlled Trials (CENTRAL; 2008, Issue 4); ACP Journal Club; CINAHL (from 1982); and ISI Web of Knowledge (from 1900). We ran updated searches in May 2012, October 2013, and in June 2014 for McMaster PLUS. We searched major regulatory agencies for safety warnings and clinicaltrials.gov for registered trials. Randomized controlled trials (RCTs) comparing adalimumab, etanercept, golimumab and infliximab to placebo, other drugs or usual care in patients with ankylosing spondylitis, reported in abstract or full-text. Two authors independently assessed search results, risk of bias, and extracted data. We conducted Bayesian mixed treatment comparison (MTC) meta-analyses using WinBUGS software. To investigate a class-effect of harms across biologics, we pooled harms data using Review Manager 5. We included twenty-one, short-term (24 weeks or less) RCTs with a total of 3308 participants; 18 contributed data to the MTC analysis: adalimumab (4 studies), etanercept (8 studies), golimumab (2 studies), infliximab (3 studies), and one head-to-head study (etanercept versus infliximab) which was unblinded and considered at a higher risk of bias. The risk of selection and detection bias was low or unclear for most of the studies. The risk of selective outcome reporting was low for most studies as they reported on outcomes recommended by the Assessment of SpondyloArthritis international Society. We found little heterogeneity and no significant inconsistency in the MTC analyses. The majority of the studies were funded by

  16. Radiation target analysis of RNA.

    OpenAIRE

    Benstein, S L; Kempner, E

    1996-01-01

    Ribozymes are polynucleotide molecules with intrinsic catalytic activity, capable of cleaving nucleic acid substrates. Large RNA molecules were synthesized containing a hammerhead ribozyme moiety of 52 nucleotides linked to an inactive leader sequence, for total lengths of either 262 or 1226 nucleotides. Frozen RNAs were irradiated with high energy electrons. Surviving ribozyme activity was determined using the ability of the irradiated ribozymes to cleave a labeled substrate. The amount of i...

  17. Blocking TNF-α inhibits angiogenesis and growth of IFIT2-depleted metastatic oral squamous cell carcinoma cells.

    Science.gov (United States)

    Lai, Kuo-Chu; Liu, Chung-Ji; Lin, Tsung-Jen; Mar, Ai-Chung; Wang, Hsiu-Hua; Chen, Chi-Wei; Hong, Zi-Xuan; Lee, Te-Chang

    2016-01-28

    Our previous study demonstrated that the depletion of interferon-induced protein with tetratricopeptide repeats 2 (IFIT2) promoted metastasis and was associated with a poor prognosis in patients with oral squamous cell carcinoma (OSCC). Our current study explores the major downstream signaling involved in IFIT2 depletion-induced OSCC metastasis. To this end, we used two cell lines (designated sh-control-xeno and sh-IFIT2-xeno) derived from human OSCC xenografts expressing sh-control and sh-IFIT2, respectively, and one metastatic OSCC subline (sh-IFIT2-meta) from an IFIT2-depleted metastatic tumor. We found that the sh-IFIT2-meta cells proliferated more slowly than the sh-control-xeno cells but exhibited higher migration and chemoresistance. Using microarray technology and Ingenuity Pathway Analysis, we found that TNF-α was one of the major downstream targets in IFIT2-depleted OSCC cells. Quantitative real-time PCR, western blotting, and ELISA results confirmed that TNF-α was upregulated in the sh-IFIT2-meta cells. Blocking TNF-α abolished the angiogenic activity induced by the sh-IFIT2-meta cells. Furthermore, the human-specific TNF-α antibody golimumab significantly inhibited in vivo angiogenesis, tumor growth and metastasis of sh-IFIT2-meta cells. These results demonstrate that IFIT2 depletion results in TNF-α upregulation, leading to angiogenesis and metastasis of OSCC cells.

  18. BIOLOGICAL EFFECTS OF TNF-BINDING VARIOLAVIRUS RECOMBINANT PROTEIN

    Directory of Open Access Journals (Sweden)

    I. A. Orlovskaya

    2012-01-01

    Full Text Available Abstract. This review presents a summary of our data concerning in vivo and in vitro effects of recombinant TNF-binding protein from variola virus (VARVCrmB upon TNF-induced functional changes of human and murine cells. VARV-CrmB protein blocks TNF-induced production of IL-1β and IL-6 by human mononuclear cells, and their in vitro oxidation-related metabolic (OM activity. VARV-CrmB protein restores TNF-induced reduction of BFU-E+CFU-E colony-forming activity and normalizes TNF-induced effects upon CFU-GM formation in a colony-forming model of human and murine bone morrow cells (BMC. VARV-CrmB protein displays a pronounced in vivo alleviation of LPS-induced endotoxic shock symptoms in SPF BALB/C mice thus significantly increasing survival of experimental animals. Moreover, VARV-CrmBprotein decreases intensity of collagen-induced arthritis at early terms. Application of VARV-CrmB protein results in normalization of TNF-induced increase of migratory and OM activity of murine leukocytes, and exerts corrective effects upon colony-forming ability of murine hematopoietic precursors. Skin application of VARV-CrmB protein decreases leukocyte migration from a skin scrap in afferent phase of DNCB-induced contact reaction, as well as “ear oedema” index. Our results demonstrate TNF-blocking properties of VARVCrmB protein. In summary, our data allow to consider a recombinant variola virus VARV-CrmB as a new potential TNF-antagonist. Its effects can be explained by its ability of neutralizing TNF-induced activation of oxidation-related metabolic, cytokine-producing and migratory functions of effector cells in therapy of pathological inflammatory processes.

  19. NFAT regulates calcium-sensing receptor-mediated TNF production

    Energy Technology Data Exchange (ETDEWEB)

    abdullah, huda ismail; Pedraza, Paulina L.; Hao, Shoujin; Rodland, Karin D.; McGiff, John C.; Ferreri, Nicholas R.

    2006-05-01

    Because nuclear factor of activated T cells (NFAT) has been implicated in TNF production as well as osmoregulation and salt and water homeostasis, we addressed whether calcium-sensing receptor (CaR)-mediated TNF production in medullary thick ascending limb (mTAL) cells was NFAT dependent. TNF production in response to addition of extracellular Ca2+ (1.2 mM) was abolished in mTAL cells transiently transfected with a dominant-negative CaR construct (R796W) or pretreated with the phosphatidylinositol phospholipase C (PI-PLC) inhibitor U-73122. Cyclosporine A (CsA), an inhibitor of the serine/threonine phosphatase calcineurin, and a peptide ligand, VIVIT, that selectively inhibits calcineurin-NFAT signaling, also prevented CaR-mediated TNF production. Increases in calcineurin activity in cells challenged with Ca2+ were inhibited after pretreatment with U-73122 and CsA, suggesting that CaR activation increases calcineurin activity in a PI-PLC-dependent manner. Moreover, U-73122, CsA, and VIVIT inhibited CaR-dependent activity of an NFAT construct that drives expression of firefly luciferase in transiently transfected mTAL cells. Collectively, these data verify the role of calcineurin and NFAT in CaR-mediated TNF production by mTAL cells. Activation of the CaR also increased the binding of NFAT to a consensus oligonucleotide, an effect that was blocked by U-73122 and CsA, suggesting that a calcineurin- and NFAT-dependent pathway increases TNF production in mTAL cells. This mechanism likely regulates TNF gene transcription as U-73122, CsA, and VIVIT blocked CaR-dependent activity of a TNF promoter construct. Elucidating CaR-mediated signaling pathways that regulate TNF production in the mTAL will be crucial to understanding mechanisms that regulate extracellular fluid volume and salt balance.

  20. NFAT regulates calcium-sensing receptor-mediated TNF production.

    Science.gov (United States)

    Abdullah, Huda Ismail; Pedraza, Paulina L; Hao, Shoujin; Rodland, Karin D; McGiff, John C; Ferreri, Nicholas R

    2006-05-01

    Because nuclear factor of activated T cells (NFAT) has been implicated in TNF production as well as osmoregulation and salt and water homeostasis, we addressed whether calcium-sensing receptor (CaR)-mediated TNF production in medullary thick ascending limb (mTAL) cells was NFAT dependent. TNF production in response to addition of extracellular Ca(2+) (1.2 mM) was abolished in mTAL cells transiently transfected with a dominant-negative CaR construct (R796W) or pretreated with the phosphatidylinositol phospholipase C (PI-PLC) inhibitor U-73122. Cyclosporine A (CsA), an inhibitor of the serine/threonine phosphatase calcineurin, and a peptide ligand, VIVIT, that selectively inhibits calcineurin-NFAT signaling, also prevented CaR-mediated TNF production. Increases in calcineurin activity in cells challenged with Ca(2+) were inhibited after pretreatment with U-73122 and CsA, suggesting that CaR activation increases calcineurin activity in a PI-PLC-dependent manner. Moreover, U-73122, CsA, and VIVIT inhibited CaR-dependent activity of an NFAT construct that drives expression of firefly luciferase in transiently transfected mTAL cells. Collectively, these data verify the role of calcineurin and NFAT in CaR-mediated TNF production by mTAL cells. Activation of the CaR also increased the binding of NFAT to a consensus oligonucleotide, an effect that was blocked by U-73122 and CsA, suggesting that a calcineurin- and NFAT-dependent pathway increases TNF production in mTAL cells. This mechanism likely regulates TNF gene transcription as U-73122, CsA, and VIVIT blocked CaR-dependent activity of a TNF promoter construct. Elucidating CaR-mediated signaling pathways that regulate TNF production in the mTAL will be crucial to understanding mechanisms that regulate extracellular fluid volume and salt balance.

  1. MAJOR OUTCOMES OF THE WORK PERFORMED BY ST. PETERSBURG RESEARCH INSTITUTE OF RADIATION HYGIENE AFTER PROFESSOR P. V. RAMZAEV ON THE IMPLEMENTATION OF THE FEDERAL TARGETED PROGRAM “MITIGATION OF THE RADIATION ACCIDENTS’CONSEQUENCES UNTIL 2015” AND OF THE “JOINT ACTIVITIES PROGRAM ON MITIGATION OF THE CHERNOBYL DISASTER WITHIN THE UNION STATE FOR THE PERIOD UNTIL 2016“

    Directory of Open Access Journals (Sweden)

    A. N. Barkovskiy

    2016-01-01

    Full Text Available The article presents major results of the work performed by St. Petersburg Research Institute of Radiation Hygiene after Professor P. V. Ramzaev on public contracts signed within the implementation of the Federal targeted program “ Mitigation of the radiation accidents’ consequences for the period until 2015” ( Direction IV “ Streamlining of monitoring systems and their elements and situation forecasting on radioactively contaminated territories paragraph 14 “The analyses and comprehensive evaluation of radiation situation changes on radioactively contaminated territories “ aimed at compilation of radioactively contaminated zones’ settlements list and Direction VI “Awareness raising and social -psychological rehabilitation of radiation- affected residents”, paragraph 20 “Creation of unified informational system on ensuring population’s radiation safety and overcoming radiation accidents’ consequences via development of the federal and regional informational resources’ systems” and “ Joint activities program on mitigation of the Chernobyl disaster within the Union State for the period until 2016” ( Direction II “ Streamlining of unified radiation protection system in radioactively contaminated territories” paragraph 2.1 “ The harmonization of requirements, methods and technologies aimed at mitigation of Russian and Belorussian population’s internal and external exposure, the development of radiation control and monitoring unified system”, sub-paragraph 2.1.1 “The development of unified assessment and forecast system for population exposure doses and rationing of radionuclide – containing foodstuffs, agricultural products and forest preserves based on the international approaches” over the period from 2011 to 2015.

  2. TNF-alpha, leptin, and lymphocyte function in human aging

    DEFF Research Database (Denmark)

    Bruunsgaard, H.; Pedersen, Agnes Nadelmann; Schroll, M.

    2000-01-01

    associated with leptin, circulating interleukin-2 receptors (sIL-2R), and phytohaemagglutinin (PHA) induced IL-2 production in whole blood in elderly humans. Circulating levels of TNF-alpha and sIL-2R were higher in elderly humans (N=42) compared to a young control group (N=37) whereas...... regression analysis adjusting for the effect of gender and body mass index. Furthermore, TNF-alpha, but not leptin, was positively correlated to sIL-2R and negatively correlated to IL-2 production. In conclusion, increased plasma levels of TNF-alpha in aging is associated with poor IL-2 production ex vivo...

  3. Intractable pneumococcal meningoencephalitis associated with a TNF-α antagonist.

    Science.gov (United States)

    Kang, Seok-Jae; Kim, Hyun Young; Kim, Young Seo; Lee, Ha Neul; Kim, Hee Tae; Kim, Seung H

    2014-09-15

    A 34-year-old man was treated with a TNF-α antagonist for ankylosing spondylitis, and this subsequently developed a CNS infection. Magnetic resonance imaging showed diffuse subcortical white matter lesions. Streptococcus pneumoniae was cultured from the cerebrospinal fluid and blood. The patient died of multifocal widespread brain damage and subarachnoid hemorrhage, despite intensive antibacterial medication. Pneumococcal meningoencephalitis can occur in association with TNF-α antagonists. Clinicians should be aware of both the risk of fatal bacterial meningoencephalitis associated with TNF-α antagonists and the possibility of an unusual presentation of bacterial meningitis. Copyright © 2014. Published by Elsevier B.V.

  4. 潜伏活性的可溶性肿瘤坏死因子受体Ⅰ靶向治疗子宫内膜异位症的实验研究%Role of a latent soluble TNF receptor type Ⅰ (hsTNFR Ⅰ) fusion protein in targeted treatment of endometriosis

    Institute of Scientific and Technical Information of China (English)

    熊宙芳; 胡沙; 王泽华

    2010-01-01

    Objective To construct a latent human soluble tumor necrosis factor receptor Ⅰ(hsTNFR Ⅰ) using the latency associated protein (LAP) of transforming growth factor-β1 (TGF-β1) fused via a matrix metalloproteinase (MMP) cleavage site to hsTNFR Ⅰ so as to detect the latent biological activity of LAP-MMP-hsTNFR Ⅰ fusion protein. Methods A double-stranded deoxyoligonucleotide coding for MMP cleavage site was cloned into plasmid pcDNA3.1. LAP and hsTNFR Ⅰ cDNA were then inserted into both two sides of MMP cleavage site. After being transferred by LAP-MMP-hsTNFR Ⅰ fusion gene with liposome, the expression of fusion protein in COS-7 cells was detected by RT-PCR and Western blot. The inhibitory effect of fusion protein upon cytotoxicity of TNF-α was detected by methyl thiazolyl tetrazolium (MTT) assay before and after the fusion protein incubated in MMP or peritoneal fluid from endometriosis patients. Results The recombinant plasmid LAP-MMP-hsTNFR Ⅰ -pcDNA3. 1 was constructed successfully and was expressed effectively in COS-7 cells. The MTT assay showed that there was no difference in the mortality rote of L929 cells between LAP-MMP-hsTNFR Ⅰ -pcDNA3.1 and empty vector transfection groups (P>0.05). The mortality rates of L929 cells with 800 ng/L TNF-α in LAP-MMP-hsTNFR Ⅰ -pcDNA3.1 transfection group after incubation with MMP or peritoneal fluid from endometriosis patients were(44.5 ±2.4) % and(33.8±1.9) % respectively. And it was lower than the pre-incubation period (58.1± 2.4) %(P0.05).但在800 ng/L肿瘤坏死因子(TNF)-α作用下,重组质粒转染上清与MMP和子宫内膜异位症患者的腹腔液孵育后,L929细胞死亡率分别为(44.5±2.4)%和(33.8±1.9)%,显著低于孵育前(58.1±2.4)%,(P<0.05). 结论 LAP-MMP-hsTNFR Ⅰ重组融合蛋白的生物学活性可被LAP有效潜伏,并可被MMP和子宫内膜异位症患者的腹腔液激活,可应用于子宫内膜异位症的局部靶向治疗.

  5. A Hadron Radiation Installation and Verification Method

    NARCIS (Netherlands)

    Beekman, F.J.; Bom, V.R.

    2013-01-01

    A hadron radiation installation adapted to subject a target to irradiation by a hadron radiation beam, said installation comprising: - a target support configured to support, preferably immobilize, a target: - a hadron radiation apparatus adapted to emit a hadron radiation beam along a beam axis to

  6. Tumor necrosis factor (TNF) is induced in mice by Candida albicans: role of TNF in fibrinogen increase.

    Science.gov (United States)

    Riipi, L; Carlson, E

    1990-09-01

    One intraperitoneal dose of Candida albicans (10(8) CFU) caused a chronic (longer than 2 months), significant elevation of plasma fibrinogen levels (Clauss method) in mice of strain C3H/HeN. Even a small dose (10(6) CFU) resulted in a significant increase in fibrinogen level for 5 days following injection, whereas other blood parameters (leukocytes, erythrocytes, platelets, hematocrit, hemoglobin, blood urea nitrogen, aspartate aminotransferase, albumin, alkaline phosphatase, antithrombin III, glucose, calcium, and total protein) measured by standard methods were normal. Blood taken during this period was negative for C. albicans. The role of tumor necrosis factor (TNF) in C. albicans infections was investigated by measuring the fibrinogen response after the administration of C. albicans or recombinant mouse TNF-alpha. Both challenges resulted in an elevated fibrinogen level. When polyclonal antibodies to mouse TNF-alpha were given prior to challenge with C. albicans or mouse TNF-alpha, the fibrinogen increase was significantly inhibited. C. albicans injections were found to significantly elevate endogenous TNF levels in mice (enzyme-linked immunosorbent assay). It was concluded that C. albicans induces TNF in the mouse. Furthermore, these data give evidence which supports a relationship between TNF and the fibrinogen increase induced by C. albicans.

  7. Early-time radiation flux symmetry optimization and its effect on gas-filled hohlraum ignition targets on the National Ignition Facility

    Science.gov (United States)

    Milovich, J. L.; Dewald, E. L.; Pak, A.; Michel, P.; Town, R. P. J.; Bradley, D. K.; Landen, O.; Edwards, M. J.

    2016-03-01

    Achieving ignition on the National Ignition Facility (NIF) is tied to our ability to control and minimize deviations from sphericity of the capsule implosion. Low-mode asymmetries of the hot spot result from the combined effect of radiation drive asymmetries throughout the laser pulse and initial roughness on the capsule surface. In this paper, we report on simulations and experiments designed to assess, measure, and correct the drive asymmetries produced by the early-time (≈first 2 ns or "picket") period of the laser pulse. The drive asymmetry during the picket is commonly thought to introduce distortions in the hot-spot shape at ignition time. However, a more subtle effect not previously considered is that it also leads to an asymmetry in shock velocity and timing, thereby increasing the fuel adiabat and reducing the margin for ignition. It is shown via hydrodynamic simulations that minimizing this effect requires that the early-time asymmetry be kept below 7.5% in the second Legendre mode (P2), thus keeping the loss of performance margin below ≈10% for a layered implosion. Asymmetries during the picket of the laser pulse are measured using the instantaneous self-emission of a high-Z re-emission sphere in place of an ignition capsule in a hohlraum with large azimuthal diagnostic windows. Three dimensional simulations using the code HYDRA (to capture the effect of non-azimuthal hohlraum features) coupled to a cross-beam energy transfer model [Michel et al., Phys. Plasmas 17, 056305 (2010)] are used to establish the surrogacy of the re-emit target and to assess the early-time drive symmetry. Calculations using this model exhibit the same sensitivity to variations in the relative input powers between the different cones of NIF beams as measured for the "Rev5" CH target [Haan et al., Phys Plasmas 18, 051001 (2011)] and reported by Dewald et al. [Phys. Rev. Lett. 111, 235001 (2013)]. The same methodology applied to recently improved implosions using different

  8. Secondary radiation measurements for particle therapy applications: prompt photons produced by 4He, 12C and 16O ion beams in a PMMA target

    Science.gov (United States)

    Mattei, I.; Bini, F.; Collamati, F.; De Lucia, E.; Frallicciardi, P. M.; Iarocci, E.; Mancini-Terracciano, C.; Marafini, M.; Muraro, S.; Paramatti, R.; Patera, V.; Piersanti, L.; Pinci, D.; Rucinski, A.; Russomando, A.; Sarti, A.; Sciubba, A.; Solfaroli Camillocci, E.; Toppi, M.; Traini, G.; Voena, C.; Battistoni, G.

    2017-02-01

    Charged particle beams are used in particle therapy (PT) to treat oncological patients due to their selective dose deposition in tissues with respect to the photons and electrons used in conventional radiotherapy. Heavy (Z  >  1) PT beams can additionally be exploited for their high biological effectiveness in killing cancer cells. Nowadays, protons and carbon ions are used in PT clinical routines. Recently, interest in the potential application of helium and oxygen beams has been growing. With respect to protons, such beams are characterized by their reduced multiple scattering inside the body, increased linear energy transfer, relative biological effectiveness and oxygen enhancement ratio. The precision of PT demands online dose monitoring techniques, crucial to improving the quality assurance of any treatment: possible patient mis-positioning and biological tissue changes with respect to the planning CT scan could negatively affect the outcome of the therapy. The beam range confined in the irradiated target can be monitored thanks to the neutral or charged secondary radiation emitted by the interactions of hadron beams with matter. Among these secondary products, prompt photons are produced by nuclear de-excitation processes, and at present, different dose monitoring and beam range verification techniques based on prompt-γ detection are being proposed. It is hence of importance to perform γ yield measurement in therapeutic-like conditions. In this paper we report on the yields of prompt photons produced by the interaction of helium, carbon and oxygen ion beams with a poly-methyl methacrylate (PMMA) beam stopping target. The measurements were performed at the Heidelberg Ion-Beam Therapy Center (HIT) with beams of different energies. An LYSO scintillator, placed at {{60}\\circ} and {{90}\\circ} with respect to the beam direction, was used as the photon detector. The obtained γ yields for the carbon ion beams are compared with results from the literature

  9. Colitogenic role of tumour necrosis factor (TNF) receptors in trinitrobenzene sulphonic acid colitis: TNF-R1 ablation does not affect systemic inflammatory response.

    Science.gov (United States)

    Yang, Y; Wang, H; Dou, Y; Wang, Y; Han, G; Wang, Renxi; Wang, L; Guo, R; Xiao, H; Li, X; Shen, B; Shi, Y; Chen, G; Li, Y

    2011-09-01

    Tumour necrosis factor (TNF)-α plays a critical role in the pathogenesis of T helper type 1-mediated colitis such as Crohn's disease. However, the roles of its two receptors in mediating pathology remain largely unknown. In this study, trinitrobenzene sulphonic acid (TNBS) was used to induce colitis in TNF-receptor single or double knock-out (DKO) BALB/c mice and in wild-type counterparts. TNF-R1(-/-) mice had significantly less weight loss, reduced mortality, colon shortening and oedema, colon histological damage and lower levels of colon myeloperoxidase compared with wild-type (WT) BALB/c mice. A similar manifestation was also observed in TNF-R2(-/-) and TNF-R1(-/-) TNF-R2(-/-) (TNF-R DKO) mice. Strikingly, systemic inflammatory response (including splenomegaly and monocyte expansion) was found in WT and TNF-R1(-/-) mice after TNBS, instead of TNF-R2(-/-) and TNF-R DKO mice. Attenuated pathology of colitis in TNF-R1(-/-) or TNF-R2(-/-) mice correlated with lower amounts of interleukin (IL)-6, IL-1β, monocyte chemotactic protein (MCP)-1, IL-12p70 and interferon (IFN)-γ production in the colons. Importantly, ablation of TNF-R1 or TNF-R2 reduced the number of terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick end-labelling (TUNEL)-positive apoptotic epithelial cells in the affected colons compared with WT TNBS-instilled controls, which might be due to the heightened ratio of Bcl-2/Bax and reduced activity of nuclear factor (NF)-κB. These findings suggest that either TNF-R1 or TNF-R2 plays a pathogenic role in the pathology of colitis and TNF signalling via TNF-R1 or TNF-R2 alone is not sufficient for inducing mucosal damage.

  10. A histology-based atlas of the C57BL/6J mouse brain deformably registered to in vivo MRI for localized radiation and surgical targeting

    Science.gov (United States)

    Purger, David; McNutt, Todd; Achanta, Pragathi; Quiñones-Hinojosa, Alfredo; Wong, John; Ford, Eric

    2009-12-01

    The C57BL/6J laboratory mouse is commonly used in neurobiological research. Digital atlases of the C57BL/6J brain have been used for visualization, genetic phenotyping and morphometry, but currently lack the ability to accurately calculate deviations between individual mice. We developed a fully three-dimensional digital atlas of the C57BL/6J brain based on the histology atlas of Paxinos and Franklin (2001 The Mouse Brain in Stereotaxic Coordinates 2nd edn (San Diego, CA: Academic)). The atlas uses triangular meshes to represent the various structures. The atlas structures can be overlaid and deformed to individual mouse MR images. For this study, we selected 18 structures from the histological atlas. Average atlases can be created for any group of mice of interest by calculating the mean three-dimensional positions of corresponding individual mesh vertices. As a validation of the atlas' accuracy, we performed deformable registration of the lateral ventricles to 13 MR brain scans of mice in three age groups: 5, 8 and 9 weeks old. Lateral ventricle structures from individual mice were compared to the corresponding average structures and the original histology structures. We found that the average structures created using our method more accurately represent individual anatomy than histology-based atlases alone, with mean vertex deviations of 0.044 mm versus 0.082 mm for the left lateral ventricle and 0.045 mm versus 0.068 mm for the right lateral ventricle. Our atlas representation gives direct spatial deviations for structures of interest. Our results indicate that MR-deformable histology-based atlases represent an accurate method to obtain accurate morphometric measurements of a population of mice, and that this method may be applied to phenotyping experiments in the future as well as precision targeting of surgical procedures or radiation treatment.

  11. A histology-based atlas of the C57BL/6J mouse brain deformably registered to in vivo MRI for localized radiation and surgical targeting

    Energy Technology Data Exchange (ETDEWEB)

    Purger, David; McNutt, Todd; Wong, John; Ford, Eric [Department of Radiation Oncology and Molecular Radiation Sciences, Johns Hopkins University, 401 North Broadway, Suite 1440, Baltimore, MD 21231 (United States); Achanta, Pragathi; Quinones-Hinojosa, Alfredo [Department of Neurosurgery, Johns Hopkins University, Cancer Research Building II, 1550 Orleans Street, Room 247, Baltimore, MD 21231 (United States)], E-mail: eric.ford@jhmi.edu

    2009-12-21

    The C57BL/6J laboratory mouse is commonly used in neurobiological research. Digital atlases of the C57BL/6J brain have been used for visualization, genetic phenotyping and morphometry, but currently lack the ability to accurately calculate deviations between individual mice. We developed a fully three-dimensional digital atlas of the C57BL/6J brain based on the histology atlas of Paxinos and Franklin (2001 The Mouse Brain in Stereotaxic Coordinates 2nd edn (San Diego, CA: Academic)). The atlas uses triangular meshes to represent the various structures. The atlas structures can be overlaid and deformed to individual mouse MR images. For this study, we selected 18 structures from the histological atlas. Average atlases can be created for any group of mice of interest by calculating the mean three-dimensional positions of corresponding individual mesh vertices. As a validation of the atlas' accuracy, we performed deformable registration of the lateral ventricles to 13 MR brain scans of mice in three age groups: 5, 8 and 9 weeks old. Lateral ventricle structures from individual mice were compared to the corresponding average structures and the original histology structures. We found that the average structures created using our method more accurately represent individual anatomy than histology-based atlases alone, with mean vertex deviations of 0.044 mm versus 0.082 mm for the left lateral ventricle and 0.045 mm versus 0.068 mm for the right lateral ventricle. Our atlas representation gives direct spatial deviations for structures of interest. Our results indicate that MR-deformable histology-based atlases represent an accurate method to obtain accurate morphometric measurements of a population of mice, and that this method may be applied to phenotyping experiments in the future as well as precision targeting of surgical procedures or radiation treatment.

  12. Cloning of human tumor necrosis factor (TNF) receptor cDNA and expression of recombinant soluble TNF-binding protein.

    OpenAIRE

    Gray, P W; Barrett, K; Chantry, D; Turner, M.; Feldmann, M

    1990-01-01

    The cDNA for one of the receptors for human tumor necrosis factor (TNF) has been isolated. This cDNA encodes a protein of 455 amino acids that is divided into an extracellular domain of 171 residues and a cytoplasmic domain of 221 residues. The extracellular domain has been engineered for expression in mammalian cells, and this recombinant derivative binds TNF alpha with high affinity and inhibits its cytotoxic activity in vitro. The TNF receptor exhibits similarity with a family of cell surf...

  13. Insights into deregulated TNF and IL-10 production in malaria

    DEFF Research Database (Denmark)

    Boeuf, Philippe S; Loizon, Séverine; Awandare, Gordon A

    2012-01-01

    ABSTRACT: BACKGROUND: Severe malarial anaemia (SMA) is a major life-threatening complication of paediatric malaria. Protracted production of pro-inflammatory cytokines promoting erythrophagocytosis and depressing erythropoiesis is thought to play an important role in SMA, which is characterized...... by a high TNF/IL-10 ratio. Whether this TNF/IL-10 imbalance results from an intrinsic incapacity of SMA patients to produce IL-10 or from an IL-10 unresponsiveness to infection is unknown. Monocytes and T cells are recognized as the main sources of TNF and IL-10 in vivo, but little is known about...... the activation status of those cells in SMA patients. METHODS: The IL-10 and TNF production capacity and the activation phenotype of monocytes and T cells were compared in samples collected from 332 Ghanaian children with non-overlapping SMA (n = 108), cerebral malaria (CM) (n = 144) or uncomplicated malaria (UM...

  14. TNF-alpha, leptin, and lymphocyte function in human aging

    DEFF Research Database (Denmark)

    Bruunsgaard, H.; Pedersen, Agnes Nadelmann; Schroll, M.

    2000-01-01

    Aging is associated with increased inflammatory activity and concomitant decreased T cell mediated immune responses. Leptin may provide a link between inflammation and T cell function in aging. The aim of the study was to investigate if plasma levels of tumor necrosis factor (TNF)-alpha were...... there was no difference with regard to IL-2 production. Furthermore, there were no age-related differences in serum levels of leptin, However, women had higher levels than men. In the elderly people, serum levels of leptin were correlated with TNF-alpha in univariate regression analysis and in a multiple linear...... regression analysis adjusting for the effect of gender and body mass index. Furthermore, TNF-alpha, but not leptin, was positively correlated to sIL-2R and negatively correlated to IL-2 production. In conclusion, increased plasma levels of TNF-alpha in aging is associated with poor IL-2 production ex vivo...

  15. TNF Counterbalances the Emergence of M2 Tumor Macrophages

    Directory of Open Access Journals (Sweden)

    Franz Kratochvill

    2015-09-01

    Full Text Available Cancer can involve non-resolving, persistent inflammation where varying numbers of tumor-associated macrophages (TAMs infiltrate and adopt different activation states between anti-tumor M1 and pro-tumor M2 phenotypes. Here, we resolve a cascade causing differential macrophage phenotypes in the tumor microenvironment. Reduction in TNF mRNA production or loss of type I TNF receptor signaling resulted in a striking pattern of enhanced M2 mRNA expression. M2 gene expression was driven in part by IL-13 from eosinophils co-recruited with inflammatory monocytes, a pathway that was suppressed by TNF. Our data define regulatory nodes within the tumor microenvironment that balance M1 and M2 populations. Our results show macrophage polarization in cancer is dynamic and dependent on the balance between TNF and IL-13, thus providing a strategy for manipulating TAMs.

  16. TNF counterbalances the emergence of M2 tumor macrophages

    Science.gov (United States)

    Kratochvill, Franz; Neale, Geoffrey; Haverkamp, Jessica M.; de Velde, Lee-Ann Van; Smith, Amber M.; Kawauchi, Daisuke; McEvoy, Justina; Roussel, Martine F.; Dyer, Michael A.; Qualls, Joseph E.; Murray, Peter J.

    2015-01-01

    Cancer is a form of non-resolving, persistent inflammation where varying numbers of tumor-associated macrophages (TAMs) infiltrate and adopt different activation states between anti-tumor M1 and pro-tumor M2 phenotypes. Here we resolve a cascade causing differential macrophage phenotypes in the tumor microenvironment. Reduction in TNF mRNA production or loss of Type I TNF receptor signaling resulted in a striking pattern of enhanced M2 mRNA expression. M2 gene expression was driven in part by IL-13 from eosinophils co-recruited with inflammatory monocytes, a pathway that was suppressed by TNF. Our data define regulatory nodes within the tumor microenvironment that balance M1 and M2 populations. Our results show macrophage polarization in cancer is dynamic and dependent on the balance between TNF and IL-13, thus providing a strategy for manipulating TAMs. PMID:26365184

  17. A hot water extract of Curcuma longa inhibits adhesion molecule protein expression and monocyte adhesion to TNF-α-stimulated human endothelial cells.

    Science.gov (United States)

    Kawasaki, Kengo; Muroyama, Koutarou; Yamamoto, Norio; Murosaki, Shinji

    2015-01-01

    The recruitment of arterial leukocytes to endothelial cells is an important step in the progression of various inflammatory diseases. Therefore, its modulation is thought to be a prospective target for the prevention or treatment of such diseases. Adhesion molecules on endothelial cells are induced by proinflammatory cytokines, including tumor necrosis factor-α (TNF-α), and contribute to the recruitment of leukocytes. In the present study, we investigated the effect of hot water extract of Curcuma longa (WEC) on the protein expression of adhesion molecules, monocyte adhesion induced by TNF-α in human umbilical vascular endothelial cells (HUVECs). Treatment of HUVECs with WEC significantly suppressed both TNF-α-induced protein expression of adhesion molecules and monocyte adhesion. WEC also suppressed phosphorylation and degradation of nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor, alpha (IκBα) induced by TNF-α in HUVECs, suggesting that WEC inhibits the NF-κB signaling pathway.

  18. TRAF6 upregulation in spinal astrocytes maintains neuropathic pain by integrating TNF-α and IL-1β signaling.

    Science.gov (United States)

    Lu, Ying; Jiang, Bao-Chun; Cao, De-Li; Zhang, Zhi-Jun; Zhang, Xin; Ji, Ru-Rong; Gao, Yong-Jing

    2014-12-01

    The proinflammatory cytokines tumor necrosis factor (TNF) α and interleukin (IL) 1β have been strongly implicated in the pathogenesis of neuropathic pain, but the intracellular signaling of these cytokines in glial cells is not fully understood. TNF receptor-associated factor 6 (TRAF6) plays a key role in signal transduction in the TNF receptor superfamily and the IL-1 receptor superfamily. In this study, we investigated the role of TRAF6 in neuropathic pain in mice after spinal nerve ligation (SNL). SNL induced persistent TRAF6 upregulation in the spinal cord. Interestingly, TRAF6 was mainly colocalized with the astrocytic marker glial fibrillary acidic protein on SNL day 10 and partially expressed in microglia on SNL day 3. In cultured astrocytes, TRAF6 was upregulated after exposure to TNF-α or IL-1β. TNF-α or IL-1β also increased CCL2 expression, which was suppressed by both siRNA and shRNA targeting TRAF6. TRAF6 siRNA treatment also inhibited the phosphorylation of c-Jun N-terminal kinase (JNK) in astrocytes induced by TNF-α or IL-1β. JNK inhibitor D-NKI-1 dose-dependently decreased IL-1β-induced CCL2 expression. Moreover, spinal injection of TRAF6 siRNA decreased intrathecal TNF-α- or IL-1β-induced allodynia and hyperalgesia. Spinal TRAF6 inhibition via TRAF6 siRNA, shRNA lentivirus, or antisense oligodeoxynucleotides partially reversed SNL-induced neuropathic pain and spinal CCL2 expression. Finally, intrathecal injection of TNF-α-activated astrocytes induced mechanical allodynia, which was attenuated by pretreatment of astrocytes with TRAF6 siRNA. Taken together, the results suggest that TRAF6, upregulated in spinal cord astrocytes in the late phase after nerve injury, maintains neuropathic pain by integrating TNF-α and IL-1β signaling and activating the JNK/CCL2 pathway in astrocytes. Copyright © 2014 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.

  19. Safety of TNF-α inhibitors during IBD pregnancy

    DEFF Research Database (Denmark)

    Nielsen, Ole Haagen; Loftus, Edward V; Jess, Tine

    2013-01-01

    Tumor necrosis factor (TNF)-alpha inhibitors are increasingly being used in inflammatory bowel disease (IBD). Because this chronic intestinal disorder often affects women of fertile age, it is essential to assess the effect of biologics on pregnancy outcome.......Tumor necrosis factor (TNF)-alpha inhibitors are increasingly being used in inflammatory bowel disease (IBD). Because this chronic intestinal disorder often affects women of fertile age, it is essential to assess the effect of biologics on pregnancy outcome....

  20. Effekter av endringer i finansieringsansvaret for TNF-hemmere

    OpenAIRE

    Hagen, Terje P.; Bjarkum, Irina; Hobbel, Silje; Orderdalen, Karianne

    2009-01-01

    Tumor necreosis factor alfa (TNF-a) - hemmere, og andre biologiske inflammatoriske modifiserende legemidler blir brukt innen reumatologi, gastroenterologi og dermatologi. I denne rapporten analyseres effekter av endringer i finansieringssystemet for seks legemidler som faller innenfor disse legemiddelgruppene og som langt på vei er substitutter: Humira, Enbrel og Remicade som er TNF-hemmere, Raptiva og Orencia som er registrert under kategorien selektive immunsuppressiver og MabThera som er r...

  1. Notch Signaling Mediates TNF-α-Induced IL-6 Production in Cultured Fibroblast-Like Synoviocytes from Rheumatoid Arthritis

    Directory of Open Access Journals (Sweden)

    Zhijun Jiao

    2012-01-01

    Full Text Available It has been reported that Notch family proteins are expressed in synovium tissue and involved in the proliferation of synoviocyte from rheumatoid arthritis (RA. The aim of this paper was to investigate whether Notch signaling mediated TNF-α-induced cytokine production of cultured fibroblast-like synoviocytes (FLSs from RA. Exposure of RA FLSs to TNF-α (10 ng/ml led to increase of Hes-1, a target gene of Notch signaling, and a marked upregulation of Notch 2, Delta-like 1, and Delta-like 3 mRNA levels. Blockage of Notch signaling by a γ-secretase inhibitor (DAPT inhibited IL-6 secretion of RA FLSs in response to TNF-α while treatment with recombinant fusion protein of Notch ligand Delta-like 1 promoted such response. TNF-α stimulation also induced IL-6 secretion in OA FLSs; however, the Hes-1 level remained unaffected. Our data confirm the functional involvement of Notch pathway in the pathophysiology of RA FLSs which may provide a new target for RA therapy.

  2. Human endothelial senescence can be induced by TNF

    Institute of Scientific and Technical Information of China (English)

    2002-01-01

    TNF-α is one of the most important proinfiammatory cytokines in mediating multiple physio-pathological functions during immunological responses. Vascular endothelial cells, when stimulated by TNF-α2 can increase the expression of multiple cytokines and cellular adhesion molecules and, in turn, actively promote the inflammatory responses by recruiting and activating of leukocytes to the inflammatory site. In addition to endothelial death induced by TNF-α2 we found for the first time that TNF-α can also induce the human endothelial cells senescence. The induced senescent endothelial cells will display SA-β-Gal staining and they were arrested in G0-G1 phase. We found that Aψm would always be up-regulated in response to TNF-α stimulation at early time but when the cells become senescent, A ψmshows a tendency to decrease. It may reflect the sthenic function of mitochondria at early time in response to TNF-αstimulation and decay when the endothelial cells were induced senescent. ROS fluctuates at early time and also decreases when the endothelial cells become senescent. Our results show that the change of mitochondrial function may be related to the senescent process.``

  3. Effects of TNF-alpha on Endothelial Cell Collective Migration

    Science.gov (United States)

    Chen, Desu; Wu, Di; Helim Aranda-Espinoza, Jose; Losert, Wolfgang

    2013-03-01

    Tumor necrosis factor (TNF-alpha) is a small cell-signaling protein usually released by monocytes and macrophages during an inflammatory response. Previous work had shown the effects of TNF-alpha on single cell morphology, migration, and biomechanical properties. However, the effect on collective migrations remains unexplored. In this work, we have created scratches on monolayers of human umbilical endothelial cells (HUVECs) treated with 25ng/mL TNF-alpha on glass substrates. The wound healing like processes were imaged with phase contrast microscopy. Quantitative analysis of the collective migration of cells treated with TNF-alpha indicates that these cells maintain their persistent motion and alignment better than untreated cells. In addition, the collective migration was characterized by measuring the amount of non-affine deformations of the wound healing monolayer. We found a lower mean non-affinity and narrower distribution of non-affinities upon TNF-alpha stimulation. These results suggest that TNF-alpha introduces a higher degree of organized cell collective migration.

  4. Inhibition of ceramide production reverses TNF-induced insulin resistance.

    Science.gov (United States)

    Grigsby, R J; Dobrowsky, R T

    2001-10-12

    Ceramide has been implicated as a mediator of insulin resistance induced by tumor necrosis factor-alpha (TNF) in adipocytes. Adipocytes contain numerous caveolae, sphingolipid and cholesterol-enriched lipid microdomains, that are also enriched in insulin receptor (IR). Since caveolae may be important sites for crosstalk between tyrosine kinase and sphingolipid signaling pathways, we examined the role of increased caveolar pools of ceramide in regulating tyrosine phosphorylation of the IR and its main substrate, insulin receptor substrate-1 (IRS-1). Neither exogenous short-chain ceramide analogs nor pharmacologic increases in endogenous caveolar pools of ceramide inhibited insulin-induced tyrosine phosphorylation of the IR and IRS-1. However, inhibition of TNF-induced caveolar ceramide production reversed the decrease in IR tyrosine phosphorylation in response to TNF. These results suggest that TNF-independent increases in caveolar pools of ceramide are not sufficient to inhibit insulin signaling but that in conjunction with other TNF-dependent signals, caveolar pools of ceramide are a critical component for insulin resistance by TNF.

  5. The role of TNF-alpha in amygdala kindled rats.

    Science.gov (United States)

    Shandra, A A; Godlevsky, L S; Vastyanov, R S; Oleinik, A A; Konovalenko, V L; Rapoport, E N; Korobka, N N

    2002-02-01

    In the present study, the interaction between epileptogenesis and the immune system were studied in a kindling model. First, the effects of a single administration of TNF-alpha (5.0 microg/kg, i.p.) on seizure and EEG activity were investigated in amygdala-kindled rats. TNF-alpha treated rats showed more prolonged epileptiformic discharges than control rats. TNF-alpha also induced a decrease in the power of delta band and an increase in theta and alpha activity. In addition, a marked increase in the power of beta and gamma band was observed. The EEG changes were most numerous in the frontal cortex and amygdala. All effects were registered 24 h after TNF-alpha administration. Finally, electrical stimulation enhanced the level of TNF-alpha in blood serum from 1.9 +/- 1.5 to 12.7 +/- 3.8 pg/ml and in brain tissue 56.8 +/- 6.0 to 109.2 +/- 6.0 pg/mg, as was determined via the ELISA method. It can be concluded that there is a mutual facilitative interaction of both epileptogenic and cytokine-derived mechanisms on this type of seizure. The changes in the power spectrum of the EEG after TNF-alpha might contribute to intensify thalamic-derived facilitation of epileptic discharge in cortical structures.

  6. Radiation dosimetry and first therapy results with a {sup 124}I/{sup 131}I-labeled small molecule (MIP-1095) targeting PSMA for prostate cancer therapy

    Energy Technology Data Exchange (ETDEWEB)

    Zechmann, Christian M.; Afshar-Oromieh, Ali; Mier, Walter [University Hospital Heidelberg, Department of Nuclear Medicine, Heidelberg (Germany); Armor, Tom; Joyal, John [Molecular Insight Pharmaceuticals, Boston, MA (United States); Stubbs, James B. [Radiation Dosimetry Systems RDS, Inc., Apharetta, GA (United States); Hadaschik, Boris [University Hospital Heidelberg, Department of Urology, Heidelberg (Germany); Kopka, Klaus [Division Radiopharmaceutical Chemistry, DKFZ, Heidelberg (Germany); Debus, Juergen [University Hospital Heidelberg, Department of Radiation Oncology, Heidelberg (Germany); Babich, John W. [Molecular Insight Pharmaceuticals, Boston, MA (United States); Cornell University, Division of Radiopharmacy, Department of Radiology, New York, NY (United States); Haberkorn, Uwe [University Hospital Heidelberg, Department of Nuclear Medicine, Heidelberg (Germany); Clinical Cooperation Unit Nuclear Medicine, DKFZ, Heidelberg (Germany)

    2014-07-15

    Since the prostate-specific membrane antigen (PSMA) is frequently over-expressed in prostate cancer (PCa) several PSMA-targeting molecules are under development to detect and treat metastatic castration resistant prostate cancer (mCRPC). We investigated the tissue kinetics of a small molecule inhibitor of PSMA ((S)-2-(3-((S)-1-carboxy-5-(3-(4-[{sup 124}I]iodophenyl)ureido)pentyl)ureido) pentan edioicacid; MIP-1095) using PET/CT to estimate radiation dosimetry for the potential therapeutic use of {sup 131}I-MIP-1095 in men with mCRPC. We also report preliminary safety and efficacy of the first 28 consecutive patients treated under a compassionate-use protocol with a single cycle of {sup 131}I-MIP-1095. Sixteen patients with known prostate cancer underwent PET/CT imaging after i.v. administration of {sup 124}I-MIP-1095 (mean activity: 67.4 MBq). Each patient was scanned using PET/CT up to five times at 1, 4, 24, 48 and 72 h post injection. Volumes of interest were defined for tumor lesions and normal organs at each time point followed by dose calculations using the OLINDA/EXM software. Twenty-eight men with mCRPC were treated with a single cycle of {sup 131}I-MIP-1095 (mean activity: 4.8 GBq, range 2 to 7.2 GBq) and followed for safety and efficacy. Baseline and follow up examinations included a complete blood count, liver and kidney function tests, and measurement of serum PSA. I-124-MIP-1095 PET/CT images showed excellent tumor uptake and moderate uptake in liver, proximal intestine and within a few hours post-injection also in the kidneys. High uptake values were observed only in salivary and lacrimal glands. Dosimetry estimates for I-131-MIP-1095 revealed that the highest absorbed doses were delivered to the salivary glands (3.8 mSv/MBq), liver (1.7 mSv/MBq) and kidneys (1.4 mSv/MBq). The absorbed dose calculated for the red marrow was 0.37 mSv/MBq. PSA values decreased by >50 % in 60.7 % of the men treated. Of men with bone pain, 84.6 % showed complete or

  7. 红外双波段点目标双色比分析与处理%Analysis and processing of infrared dual waveband radiation ratio based point target

    Institute of Scientific and Technical Information of China (English)

    王文博; 王英瑞

    2015-01-01

    Infrared dual waveband radiation ratio can denote the blackbody’s temperature information, and can be used for temperature measurement. When using infrared dual waveband radiation ratio to measure the temperature of point target, it is difficult to achieve high-accuracy because of various kinds of noises. The recurrence plot theory was used to analyze the non-station of infrared dual waveband radiation ratio. According to the non-station of infrared dual waveband radiation ratio, the target’s response signal in IR single waveband was processed by moving average filter. The IR dual waveband radiation ratio was processed by wavelet soft-threshold filter. Experimental result indicate that, when the SNR>12, 1 K temperature accuracy can be achieved with above processing method for static point target, and 2 K temperature accuracy can be achieved for slow moving point target.%红外双色比能够表征目标的温度信息,但点目标双色比受噪声、探测器盲闪元以及跨像元因素干扰,难以准确测量,影响测温精度。应用递归图法定性分析和判断了点目标双色比的非平稳性。针对这一特性,先对点目标信号应用移动平均滤波做预处理,再通过小波软阈值去噪对双色比进行降噪处理。试验结果表明,在信噪比大于12的条件下,该方法可以实现静态点目标1 K温度分辨率,慢速动态点目标2K温度分辨率。

  8. Aldehyde modification and alum coadjuvancy enhance anti-TNF-α autovaccination and mitigate arthritis in rat.

    Science.gov (United States)

    Bavoso, Alfonso; Ostuni, Angela; De Vendel, Jolanda; Bracalello, Angelo; Shcheglova, Tatiana; Makker, Sudesh; Tramontano, Alfonso

    2015-05-01

    Experimental vaccination to induce antibodies (Abs) capable of cytokine antagonism shows promise as a novel immunotherapy for chronic inflammatory disease. We prepared a hybrid antigen consisting of residues 141-235 of rat TNF-α fused to the C-terminus of glutathione-S-transferase (GST), chemically modified to incorporate aldehyde residues, for development of an auto-vaccine eliciting anti-rTNF-α Abs. In rat immunization the soluble aldehyde-modified fusion protein did not generate observable Ab responses. By contrast, vaccination with the aldehyde-modified fusion protein adsorbed on alum induced anti-TNF-α autoAbs with high titer and neutralizing activity. Induction of adjuvant arthritis in rats pre-immunized with unmodified fusion protein or a control protein in alum resulted in severe inflammation and joint damage, whereas the disease induced in rats immunized with the aldehyde-bearing fusion protein in alum was markedly attenuated. Similar results were obtained in a collagen-induced rat arthritis model. Anti-collagen II IgG Ab titers did not deviate significantly in groups pre-immunized with modified fusion protein and control protein, suggesting that anti-TNF vaccination did not skew the immune response related to disease induction. This study demonstrates synergy between particulate alum and protein bound carbonyl residues for enhancement of protein immunogenicity. The antigen-specific co-adjuvant system could prove advantageous for breaking tolerance in emerging auto-vaccination therapies targeting inflammatory cytokines as well as for enhancing a broader category of subunit vaccines. Aldehyde adduction introduces a minimal modification which, together with the established use of alum as a safe adjuvant for human use, could be favorable for further vaccine development.

  9. Gallic acid induces necroptosis via TNF-α signaling pathway in activated hepatic stellate cells.

    Directory of Open Access Journals (Sweden)

    Ya Ju Chang

    Full Text Available Gallic acid (3, 4, 5-trihydroxybenzoic acid, GA, a natural phenolic acid widely found in gallnuts, tea leaves and various fruits, possesses several bioactivities against inflammation, oxidation, and carcinogenicity. The beneficial effect of GA on the reduction of animal hepatofibrosis has been indicated due to its antioxidative property. However, the cytotoxicity of GA autoxidation causing cell death has also been reported. Herein, we postulated that GA might target activated hepatic stellate cells (aHSCs, the cell type responsible for hepatofibrosis, to mitigate the process of fibrosis. The molecular cytotoxic mechanisms that GA exerted on aHSCs were then analyzed. The results indicated that GA elicited aHSC programmed cell death through TNF-α-mediated necroptosis. GA induced significant oxidative stress through the suppression of catalase activity and the depletion of glutathione (GSH. Elevated oxidative stress triggered the production of TNF-α facilitating the undergoing of necroptosis through the up-regulation of key necroptotic regulatory proteins TRADD and receptor-interacting protein 3 (RIP3, and the inactivation of caspase-8. Calmodulin and calpain-1 activation were engaged, which promoted subsequent lysosomal membrane permeabilization (LMP. The TNF-α antagonist (SPD-304 and the RIP1 inhibitor (necrostatin-1, Nec-1 confirmed GA-induced TNFR1-mediated necroptosis. The inhibition of RIP1 by Nec-1 diverted the cell death from necroptosis to apoptosis, as the activation of caspase 3 and the increase of cytochrome c. Collectively, this is the first report indicating that GA induces TNF signaling-triggered necroptosis in aHSCs, which may offer an alternative strategy for the amelioration of liver fibrosis.

  10. Secreted APE1/Ref-1 inhibits TNF-α-stimulated endothelial inflammation via thiol-disulfide exchange in TNF receptor

    OpenAIRE

    Myoung Soo Park; Sunga Choi; Yu Ran Lee; Hee Kyoung Joo; Gun Kang; Cuk-Seong Kim; Soo Jin Kim; Sang Do Lee; Byeong Hwa Jeon

    2016-01-01

    Apurinic apyrimidinic endonuclease 1/Redox factor-1 (APE1/Ref-1) is a multifunctional protein with redox activity and is proved to be secreted from stimulated cells. The aim of this study was to evaluate the functions of extracellular APE1/Ref-1 with respect to leading anti-inflammatory signaling in TNF-α-stimulated endothelial cells in response to acetylation. Treatment of TNF-α-stimulated endothelial cells with an inhibitor of deacetylase that causes intracellular acetylation, considerably ...

  11. TREM-1 is a positive regulator of TNF-α and IL-8 production in U937 foam cells.

    Science.gov (United States)

    Wang, Yu-Shi; Li, Xiang-Jun; Zhao, Wai-Ou

    2012-05-01

    The purpose of our study was to investigate the expression levels of TREM-1 (triggering receptor expressed on myeloid cells-1) in U937 foam cells and determine whether TREM-1 regulates the production of tumor necrosis factor-alpha and interleukin-8 in these cells. Human U937 cells were incubated with phorbol 12-myristate 13-acetate and then oxidized human low-density lipoprotein to induce foam cell formation. Oil red O staining was used to identify the foam cells. The production of IL-8 and TNF-α by U937 foam cells was assayed by enzyme-linked immunosorbent assay. The expression of TREM-1 mRNA in U937 foam cells was detected by reverse transcription-polymerase chain reaction. Moreover, U937 foam cells were transfected by small interfering RNA using Lipofectamine 2000 to knockdown TREM-1. Western blot was performed to assay protein expression of TREM-1 and ELISA was used to examine the effect of TREM-1 knockdown on IL-8 and TNF-α production. PMA and ox-LDL induced U937 cells to form foam cells. The production of TNF-α and IL-8 was found to be significantly elevated in U937 foam cells, concomitant with a significant up-regulation of TREM-1 mRNA. TREM-1 siRNA was able to partially silence the expression of TREM-1 protein and remarkably inhibited TNF-α and IL-8 production in U937 foam cells, suggesting that TREM-1 is a positive regulator of TNF-α and IL-8 production in U937 foam cells. Our finding that TREM-1 controls the production of IL-8 and TNF-α in U937 foam cells defines a potentially critical role of TREM-1 in the pathogenesis of atherosclerosis and implicates TREM-1 as a potential therapeutic target for the disease.

  12. Targeting apoptosis: preclinical and early clinical experience with mapatumumab, an agonist monoclonal antibody targeting TRAIL-R1.

    Science.gov (United States)

    Moretto, Patricia; Hotte, Sébastien J

    2009-03-01

    In spite of the advances in survival with chemotherapy and radiotherapy, many cancer patients continue to experience failure with treatments. Advances in molecular oncology and the development of numerous targeted therapies, used by themselves or in combination with at present available treatments such as chemotherapy and radiation, will hopefully improve the fate of these patients. It has been well understood for many years now that deregulation of apoptosis is a major hallmark of cancer cells. Mapatumumab, a fully human agonistic monoclonal antibody to TNF-related apoptosis-inducing ligand receptor 1, has been developed to induce apoptosis in cancer cells although having minimal effects on normal cells. This paper reviews the preclinical and early clinical data of this exciting new agent and discusses options for future development of mapatumumab, mostly in combinations with other therapies.

  13. Antiproton Target

    CERN Multimedia

    1980-01-01

    Antiproton target used for the AA (antiproton accumulator). The first type of antiproton production target used from 1980 to 1982 comprised a rod of copper 3mm diameter and 120mm long embedded in a graphite cylinder that was itself pressed into a finned aluminium container. This assembly was air-cooled and it was used in conjunction with the Van der Meer magnetic horn. In 1983 Fermilab provided us with lithium lenses to replace the horn with a view to increasing the antiproton yield by about 30%. These lenses needed a much shorter target made of heavy metal - iridium was chosen for this purpose. The 50 mm iridium rod was housed in an extension to the original finned target container so that it could be brought very close to the entrance to the lithium lens. Picture 1 shows this target assembly and Picture 2 shows it mounted together with the lithium lens. These target containers had a short lifetime due to a combination of beam heating and radiation damage. This led to the design of the water-cooled target in...

  14. Enhancement of Radiation Sensitivity in Lung Cancer Cells by a Novel Small Molecule Inhibitor That Targets the β-Catenin/Tcf4 Interaction.

    Science.gov (United States)

    Zhang, Qinghao; Gao, Mei; Luo, Guifen; Han, Xiaofeng; Bao, Wenjing; Cheng, Yanyan; Tian, Wang; Yan, Maocai; Yang, Guanlin; An, Jing

    2016-01-01

    Radiation therapy is an important treatment choice for unresectable advanced human lung cancers, and a critical adjuvant treatment for surgery. However, radiation as a lung cancer treatment remains far from satisfactory due to problems associated with radiation resistance in cancer cells and severe cytotoxicity to non-cancer cells, which arise at doses typically administered to patients. We have recently identified a promising novel inhibitor of β-catenin/Tcf4 interaction, named BC-23 (C21H14ClN3O4S), which acts as a potent cell death enhancer when used in combination with radiation. Sequential exposure of human p53-null non-small cell lung cancer (NSCLC) H1299 cells to low doses of x-ray radiation, followed 1 hour later by administration of minimally cytotoxic concentrations of BC-23, resulted in a highly synergistic induction of clonogenic cell death (combination index radiation effectiveness mediated by BC-23. BC-23 therefore represents a promising new class of radiation enhancer.

  15. Radiation Sensitization in Cancer Therapy.

    Science.gov (United States)

    Greenstock, Clive L.

    1981-01-01

    Discusses various aspects of radiation damage to biological material, including free radical mechanisms, radiation sensitization and protection, tumor hypoxia, mechanism of hypoxic cell radiosensitization, redox model for radiation modification, sensitizer probes of cellular radiation targets, pulse radiolysis studies of free radical kinetics,…

  16. Genetic polymorphisms of tumour necrosis factor alpha (TNF-α) promoter gene and response to TNF-α inhibitors in Spanish patients with inflammatory bowel disease.

    Science.gov (United States)

    López-Hernández, R; Valdés, M; Campillo, J A; Martínez-Garcia, P; Salama, H; Salgado, G; Boix, F; Moya-Quiles, M R; Minguela, A; Sánchez-Torres, A; Miras, M; Garcia, A; Carballo, F; Álvarez-López, M R; Muro, M

    2014-02-01

    Tumour necrosis factor alpha (TNF-α) has an important role in inflammatory response. Alterations in the regulation of TNF-α have been implicated in a variety of inflammatory disorders, including Inflammatory bowel disease (IBD). Indeed, a common treatment for IBD is the use of TNF-α inhibitors. Polymorphisms in the TNF-α promoter region are known to affect the level of gene expression. Our aim was to investigate the influence of these single nucleotide polymorphisms (SNPs) in TNF-α promoter gene play in the risk of IBD in a Spanish population and their individual response to anti-TNF-α treatment. DNA samples from patients with IBD and controls were screened for TNF-α -238G/A (rs361525) and -308G/A (rs1800629) SNPs by PCR-SSOP using a microbeads luminex assay and compared with response to TNF-α inhibitors. There were not statistical differences in -238G/A and -308G/A allele and genotype frequencies between patients. However, we found an increased frequency of -308A allele and -308GA genotype in these nonresponders patients to TNF-α inhibitors with respect to responders patients (Pc TNF-α inhibitors. TNF-α promoter gene polymorphism does not seem to play a role in IBD susceptibility, but particular TNF-α genotypes may be involved in the different responses to TNF-α inhibitor treatment in Spanish patients with IBD.

  17. Effects of DNA-targeted ionizing radiation produced by 5-[125I]iodo-2'-deoxyuridine on global gene expression in primary human cells

    Directory of Open Access Journals (Sweden)

    Panyutin Igor G

    2007-06-01

    differentially expressed transcripts reveal strikingly non-random chromosomal distribution in all the cell lines we used. Conclusion Our data suggest that DNA-targeted ionizing radiation produced by 125I-IUdR results in changes in expression of only a limited subset of genes in primary human cells. The responsive genes are distributed non-randomly among the chromosomes; and a significant fraction of them is p53-dependent in the transcriptional regulation.

  18. Contribution of {sup 68}Ga-DOTATOC PET/CT to Target Volume Delineation of Skull Base Meningiomas Treated With Stereotactic Radiation Therapy

    Energy Technology Data Exchange (ETDEWEB)

    Graf, Reinhold, E-mail: reinhold.graf@charite.de [Department of Radiation Oncology, Charite Universitaetsmedizin Berlin, Berlin (Germany); Nyuyki, Fonyuy; Steffen, Ingo G.; Michel, Roger; Fahdt, Daniel [Department of Nuclear Medicine, Charite Universitaetsmedizin Berlin, Berlin (Germany); Wust, Peter; Brenner, Winfried; Budach, Volker [Department of Radiation Oncology, Charite Universitaetsmedizin Berlin, Berlin (Germany); Wurm, Reinhard [Department of Radiation Oncology, Klinikum Frankfurt (Oder) (Germany); Plotkin, Michail [Department of Nuclear Medicine, Charite Universitaetsmedizin Berlin, Berlin (Germany)

    2013-01-01

    Purpose: To investigate the potential impact of {sup 68}Ga-DOTATOC positron emission tomography ({sup 68}Ga-DOTATOC-PET) in addition to magnetic resonance imaging (MRI) and computed tomography (CT) for retrospectively assessing the gross tumor volume (GTV) delineation of meningiomas of the skull base in patients treated with fractionated stereotactic radiation therapy (FSRT). Methods and Materials: The study population consisted of 48 patients with 54 skull base meningiomas, previously treated with FSRT. After scans were coregistered, the GTVs were first delineated with MRI and CT data (GTV{sub MRI/CT}) and then by PET (GTV{sub PET}) data. The overlapping regions of both datasets resulted in the GTV{sub common}, which was enlarged to the GTV{sub final} by adding volumes defined by only one of the complementary modalities (GTV{sub MRI/CT-added} or GTV{sub PET-added}). We then evaluated the contribution of conventional imaging modalities (MRI, CT) and {sup 68}Ga-DOTATOC-PET to the GTV{sub final}, which was used for planning purposes. Results: Forty-eight of the 54 skull base lesions in 45 patients showed increased {sup 68}Ga-DOTATOC uptake and were further analyzed. The mean GTV{sub MRI/CT} and GTV{sub PET} were approximately 21 cm{sup 3} and 25 cm{sup 3}, with a common volume of approximately 15 cm{sup 3}. PET contributed a mean additional GTV of approximately 1.5 cm{sup 3} to the common volume (16% {+-} 34% of the GTV{sub common}). Approximately 4.5 cm{sup 3} of the GTV{sub MRI/CT} was excluded from the contribution to the common volume. The resulting mean GTV{sub final} was significantly smaller than both the GTV{sub MRI/CT} and the GTV{sub PET}. Compared with the initial GTV{sub MRI/CT}, the addition of {sup 68}Ga-DOTATOC-PET resulted in more than 10% modification of the size of the GTV{sub final} in 32 (67%) meningiomas Conclusions: {sup 68}Ga-DOTATOC-PET/CT seems to improve the target volume delineation in skull base meningiomas, often leading to a reduction of

  19. Ordered transcriptional factor recruitment and epigenetic regulation of tnf-alpha in necrotizing acute pancreatitis.

    NARCIS (Netherlands)

    Sandoval, J.; Pereda, J.; Rodriguez, J.L.; Escobar, J.; Hidalgo, J.; Joosten, L.A.B.; Franco, L.; Sastre, J.; Lopez-Rodas, G.

    2010-01-01

    Tauhe expression of the critical initiator cytokine TNF-alpha was strongly upregulated in vivo in acute necrotic pancreatitis (AP) in rodents and in vitro in TNF-alpha activated acinar AR42J cells. Upregulation of tnf-alpha, inos, icam-1 and il-6 occurred both in TNF-alpha receptor 1 and 2 knock-out

  20. NcoI TNF-beta gene polymorphism and TNF expression are associated with an increased risk of developing Barrett's esophagus and esophageal adenocarcinoma

    NARCIS (Netherlands)

    Menke, Vivianda; van Zoest, Katinka P. M.; Moons, Leon M. G.; Hansen, Bettina; Pot, Raymond G. J.; Siersema, Peter D.; Kusters, Johannes G.; Kuipers, Ernst J.

    2012-01-01

    Objective. Esophageal cancer development is a sequence that starts with reflux esophagitis (RE), followed by Barrett's esophagitis (BE), dysplasia, and finally esophageal adenocarcinoma (EAC). Tumor necrosis factor (TNF) is a potent antineoplastic agent, hence DNA polymorphisms that reduce TNF level

  1. TNF-alpha-dependent regulation of acute pancreatitis severity by Ly-6C(hi) monocytes in mice.

    Science.gov (United States)

    Perides, George; Weiss, Eric R; Michael, Emily S; Laukkarinen, Johanna M; Duffield, Jeremy S; Steer, Michael L

    2011-04-15

    The roles of monocytes/macrophages and their mechanisms of action in the regulation of pancreatitis are poorly understood. To address these issues, we have employed genetically altered mouse strains that either express the human diphtheria toxin receptor (DTR) coupled to the CD11b promoter or have global deletion of TNF-α. Targeted, conditional depletion of monocytes/macrophages was achieved by administration of diphtheria toxin (DT) to CD11b-DTR mice. We show that in the absence of DT administration, pancreatitis is associated with an increase in pancreatic content of Ly-6C(hi) monocytes/macrophages but that this response is prevented by prior administration of DT to CD11b-DTR mice. DT administration also reduces pancreatic edema and acinar cell injury/necrosis in two dissimilar experimental models of acute pancreatitis (a secretagogue-induced model and a model elicited by retrograde pancreatic duct infusion of sodium taurocholate). In the secretagogue-elicited model, the DT-induced decrease in pancreatitis severity is reversed by adoptive transfer of purified Ly-6C(hi) monocytes harvested from non-DT-treated CD11b-DTR mice or by the transfer of purified Ly-6C(hi) monocytes harvested from TNF-α(+/+) donor mice, but it is not reversed by the transfer of Ly-6C(hi) monocytes harvested from TNF-α(-/-) donors. Our studies indicate that the Ly-6C(hi) monocyte subset regulates the severity of pancreatitis by promoting pancreatic edema and acinar cell injury/necrosis and that this phenomenon is dependent upon the expression of TNF-α by those cells. They suggest that therapies targeting Ly-6C(hi) monocytes and/or TNF-α expression by Ly-6C(hi) monocytes might prove beneficial in the prevention or treatment of acute pancreatitis.

  2. PCTAIRE1-knockdown sensitizes cancer cells to TNF family cytokines.

    Directory of Open Access Journals (Sweden)

    Teruki Yanagi

    Full Text Available While PCTAIRE1/PCTK1/Cdk16 is overexpressed in malignant cells and is crucial in tumorigenesis, its function in apoptosis remains unclear. Here we investigated the role of PCTAIRE1 in apoptosis, especially in the extrinsic cell death pathway. Gene-knockdown of PCTAIRE1 sensitized prostate cancer PPC1 and Du145 cells, and breast cancer MDA-MB-468 cells to TNF-family cytokines, including TNF-related apoptosis-inducing ligand (TRAIL. Meanwhile, PCTAIRE1-knockdown did not sensitize non-malignant cells, including diploid fibroblasts IMR-90 and the immortalized prostate epithelial cell line 267B1. PCTAIRE1-knockdown did not up-regulate death receptor expression on the cell surface or affect caspase-8, FADD and FLIP expression levels. PCTAIRE1-knockdown did promote caspase-8 cleavage and RIPK1 degradation, while RIPK1 mRNA knockdown sensitized PPC1 cells to TNF-family cytokines. Furthermore, the kinase inhibitor SNS-032, which inhibits PCTAIRE1 kinase activity, sensitized PPC1 cells to TRAIL-induced apoptosis. Together these results suggest that PCTAIRE1 contributes to the resistance of cancer cell lines to apoptosis induced by TNF-family cytokines, which implies that PCTAIRE1 inhibitors could have synergistic effects with TNF-family cytokines for cytodestruction of cancer cells.

  3. PCTAIRE1-knockdown sensitizes cancer cells to TNF family cytokines.

    Science.gov (United States)

    Yanagi, Teruki; Shi, Ranxin; Aza-Blanc, Pedro; Reed, John C; Matsuzawa, Shu-ichi

    2015-01-01

    While PCTAIRE1/PCTK1/Cdk16 is overexpressed in malignant cells and is crucial in tumorigenesis, its function in apoptosis remains unclear. Here we investigated the role of PCTAIRE1 in apoptosis, especially in the extrinsic cell death pathway. Gene-knockdown of PCTAIRE1 sensitized prostate cancer PPC1 and Du145 cells, and breast cancer MDA-MB-468 cells to TNF-family cytokines, including TNF-related apoptosis-inducing ligand (TRAIL). Meanwhile, PCTAIRE1-knockdown did not sensitize non-malignant cells, including diploid fibroblasts IMR-90 and the immortalized prostate epithelial cell line 267B1. PCTAIRE1-knockdown did not up-regulate death receptor expression on the cell surface or affect caspase-8, FADD and FLIP expression levels. PCTAIRE1-knockdown did promote caspase-8 cleavage and RIPK1 degradation, while RIPK1 mRNA knockdown sensitized PPC1 cells to TNF-family cytokines. Furthermore, the kinase inhibitor SNS-032, which inhibits PCTAIRE1 kinase activity, sensitized PPC1 cells to TRAIL-induced apoptosis. Together these results suggest that PCTAIRE1 contributes to the resistance of cancer cell lines to apoptosis induced by TNF-family cytokines, which implies that PCTAIRE1 inhibitors could have synergistic effects with TNF-family cytokines for cytodestruction of cancer cells.

  4. Radiation Therapy: Additional Treatment Options

    Science.gov (United States)

    ... Cancer Upper GI Cancers Search x FIND A RADIATION ONCOLOGIST CLOSE SNIPEND TREATMENT TYPES SNIPSTART Home / Treatment ... novel targeted therapies can act as radiosensitizers. Systemic Radiation Therapy Certain cancers may be treated with radioactive ...

  5. IL-4 inhibits TNF-α-mediated osteoclast formation by inhibition of RANKL expression in TNF-α-activated stromal cells and direct inhibition of TNF-α-activated osteoclast precursors via a T-cell-independent mechanism in vivo.

    Science.gov (United States)

    Fujii, Toshiya; Kitaura, Hideki; Kimura, Keisuke; Hakami, Zaki Weli; Takano-Yamamoto, Teruko

    2012-10-01

    It has been reported that osteoclastogenesis is induced by tumor necrosis factor (TNF)-α. Interleukin (IL)-4 is the most important cytokine involved in humoral immunity. However, no studies have investigated the effect of IL-4 on TNF-α-mediated osteoclast formation in vivo. In this study, we investigated the effect of IL-4 on TNF-α-mediated osteoclast formation in vivo. TNF-α was administered with and without IL-4 into the supracalvariae of mice. The number of osteoclasts and the levels of mRNA for cathepsin K and tartrate-resistant acid phosphate, both osteoclast markers, in mice administered TNF-α and IL-4 were lower than those in mice administered TNF-α alone. The level of tartrate-resistant acid phosphatase form 5b (TRACP5b) as a marker of bone resorption in mice administered both TNF-α and IL-4 was also lower. We showed that IL-4 inhibited TNF-α-mediated osteoclast formation in osteoclast precursors in vitro. Expression of receptor activator of NF-κB ligand (RANKL) in TNF-α-activated stromal cells was also inhibited. Furthermore, we investigated whether IL-4 had effects on both stromal cells and osteoclast precursors in TNF-α-mediated osteoclast formation in vivo. Using mice whose stromal cells and osteoclast precursors were chimeric for the presence of TNF receptors, IL-4 inhibited TNF-α-mediated osteoclast formation in the presence of TNF-α-responsive stromal cells, and TNF-α-responsive osteoclast precursors in vivo. IL-4 also inhibited TNF-α-induced RANKL expression in the presence of TNF-α-responsive stromal cells in vivo. This event is dependent on p38 inhibition in vitro. Additionally, IL-4 inhibited TNF-α-mediated osteoclast formation in T cell-depleted mice. In summary, we conclude that IL-4 inhibited TNF-α-mediated osteoclast formation by inhibiting expression of RANKL in TNF-α-activated stromal cells, and directly inhibited TNF-α-activated osteoclast precursors in vivo via a T cell-independent mechanism.

  6. Lobaric Acid Inhibits VCAM-1 Expression in TNF-α-Stimulated Vascular Smooth Muscle Cells via Modulation of NF-κB and MAPK Signaling Pathways.

    Science.gov (United States)

    Kwon, Ii-Seul; Yim, Joung-Han; Lee, Hong-Kum; Pyo, Suhkneung

    2016-01-01

    Lichens have been known to possess multiple biological activities, including anti-proliferative and anti-inflammatory activities. Vascular cell adhesion molecule-1 (VCAM-1) may play a role in the development of atherosclerosis. Hence, VCAM-1 is a possible therapeutic target in the treatment of the inflammatory disease. However, the effect of lobaric acid on VCAM-1 has not yet been investigated and characterized. For this study, we examined the effect of lobaric acid on the inhibition of VCAM-1 in tumor necrosis factor-alpha (TNF-α)-stimulated mouse vascular smooth muscle cells. Western blot and ELISA showed that the increased expression of VCAM-1 by TNF-α was significantly suppressed by the pre-treatment of lobaric acid (0.1-10 μg/ml) for 2 h. Lobaric acid abrogated TNF-α-induced NF-κB activity through preventing the degradation of IκB and phosphorylation of extracellular signal-regulated kinases (ERK), c-Jun N-terminal kinases (JNK), and p38 mitogen activated protein (MAP) kinase. Lobaric acid also inhibited the expression of TNF-α receptor 1 (TNF-R1). Overall, our results suggest that lobaric acid inhibited VCAM-1 expression through the inhibition of p38, ERK, JNK and NF-κB signaling pathways, and downregulation of TNF-R1 expression. Therefore, it is implicated that lobaric acid may suppress inflammation by altering the physiology of the atherosclerotic lesion.

  7. Expression and Purification of Recombinant Human Tumor Necrosis Factor α in Escherichia Coli%重组人TNF-α在大肠杆菌中的表达、纯化及生物学活性研究

    Institute of Scientific and Technical Information of China (English)

    缪小牛; 陈卫; 张娟; 解伟; 王旻

    2013-01-01

    Tumor necrosis factor a (TNF-α) is a cytokine that plays a major role in several chronic inflammatory disorders. Anti-TNF-α therapy has been widely employed in clinic. However, the source of natural human TNF-α is so limited that it's difficult to meet the research needs. The purpose of this project is to construct an effective prokaryotic expression system for recombinant human TNF α (rhTNF-α). The sequence of hTNF-α is retrieved from Entrez Gene at NCBI. The whole gene of hTNF-α is optimized, synthezied by a company, inserted into the expression vector pET-28a ( + ) and expressed in E. coli BL21 (DE3). The N-terminus of hTNF-α contains a His-tag and a TEV protease site. The 10 × His-tag is used to purify the protein by Ni + -NTA,and the TEV protease site is used to remove the His-tag. The soluble expression conditions of hTNF-α were optimized by orthogonal array design. The large-scale fermentation was carried out under optimized conditions. The expressed rhTNF-α protein was purified by Ni+ affinity chromatography. Then, the 10 × His tag was removed by TEV protease treatment and followed though Ni+ column again. The purification effect was identified by SDS-PAGE and western blot. The biological activity of rhTNF-α was evaluated by MTT method with L929 cells as target cells. The recombinant cloning and expressing plasmid of rhTNF-α was successfully constructed. The outflow from the Ni column was the purified rhTNF-α,showing single polypeptide band by SDS-PAGE. The productivity of purified rhTNF-α is about 4. 17 mg/L. L929 cell cytotoxicity assay showed IC50 < 10 ng/mL. An effective prokaryotic expression system for rhTNF α was successfully constructed in our study. The application of two-step Ni+ affinity chromatography purification method could produce soluble rhTNF-α protein with high purity and relative bioactivity.%构建有利于人肿瘤坏死因子α(TNF-α)大量表达及有效纯化的原核表达载体,并在大肠杆菌中诱导表

  8. Anti-TNF-Alpha Therapy and Systemic Vasculitis

    Directory of Open Access Journals (Sweden)

    Pierre-André Jarrot

    2014-01-01

    Full Text Available TNF-α is a pleiotropic cytokine, which plays a major role in the pathogenesis of numerous autoimmune and/or inflammatory systemic diseases. Systemic vasculitis constitutes a group of rare diseases, characterized by inflammation of the arterial or venous vessel wall, causing stenosis and thrombosis. Treatment of the different type of vasculitis mainly relies on steroids and immunosuppressive drugs. In case of refractory or relapsing diseases, however, a second line of treatment may be required. Anti-TNF-α drugs have been used in this setting during the last 15 years with inconsistent results. We reviewed herein the use of anti-TNF-α therapy in different kind of vasculitis and concluded that, except for Behcet’s disease, this therapeutic option has not demonstrated significant improvement in the treatment of vasculitis.

  9. Autoimmune Hepatitis Triggered by Anti-TNF- Therapy

    Directory of Open Access Journals (Sweden)

    Satoshi Nakayama

    2013-01-01

    Full Text Available Autoimmune hepatitis (AIH is occasionally triggered by drug treatments. Recently, as biological agents are becoming widely used for autoimmune disorders, there have been a growing number of reports of the development of autoimmune processes related to these agents. A 52-year-old Japanese woman with psoriasis developed liver damage two months after initiation of anti-TNF-α therapy with adalimumab. Liver histological findings were compatible with AIH, and positive conversions of ANAs were detected. The patient was treated with prednisolone and had a good response. While some cases of AIH triggered by anti-TNF-α therapies have been reported, the pathogenesis remains unspecified. When elevation of liver enzymes is observed with high IgG levels and seropositivity of ANA during the course of anti-TNF-α therapy, liver biopsy findings may be essential and important to make definitive diagnosis of AIH.

  10. AAV-dominant negative tumor necrosis factor (DN-TNF) gene transfer to the striatum does not rescue medium spiny neurons in the YAC128 mouse model of Huntington's disease.

    Science.gov (United States)

    Alto, Laura Taylor; Chen, Xi; Ruhn, Kelly A; Treviño, Isaac; Tansey, Malú G

    2014-01-01

    CNS inflammation is a hallmark of neurodegenerative disease, and recent studies suggest that the inflammatory response may contribute to neuronal demise. In particular, increased tumor necrosis factor (TNF) signaling is implicated in the pathology of both Parkinson's disease (PD) and Alzheimer's disease (AD). We have previously shown that localized gene delivery of dominant negative TNF to the degenerating brain region can limit pathology in animal models of PD and AD. TNF is upregulated in Huntington's disease (HD), like in PD and AD, but it is unknown whether TNF signaling contributes to neuronal degeneration in HD. We used in vivo gene delivery to test whether selective reduction of soluble TNF signaling could attenuate medium spiny neuron (MSN) degeneration in the YAC128 transgenic (TG) mouse model of Huntington's disease (HD). AAV vectors encoding cDNA for dominant-negative tumor necrosis factor (DN-TNF) or GFP (control) were injected into the striatum of young adult wild type WT and YAC128 TG mice and achieved 30-50% target coverage. Expression of dominant negative TNF protein was confirmed immunohistologically and biochemically and was maintained as mice aged to one year, but declined significantly over time. However, the extent of striatal DN-TNF gene transfer achieved in our studies was not sufficient to achieve robust effects on neuroinflammation, rescue degenerating MSNs or improve motor function in treated mice. Our findings suggest that alternative drug delivery strategies should be explored to determine whether greater target coverage by DN-TNF protein might afford some level of neuroprotection against HD-like pathology and/or that soluble TNF signaling may not be the primary driver of striatal neuroinflammation and MSN loss in YAC128 TG mice.

  11. Overexpression of TNF-α converting enzyme promotes adipose tissue inflammation and fibrosis induced by high fat diet.

    Science.gov (United States)

    Matsui, Yuki; Tomaru, Utano; Miyoshi, Arina; Ito, Tomoki; Fukaya, Shinji; Miyoshi, Hideaki; Atsumi, Tatsuya; Ishizu, Akihiro

    2014-12-01

    Obesity is a state in which chronic low-grade inflammation persists in adipose tissues. Pro-inflammatory cytokines, including TNF-α, produced by adipose tissues have been implicated as active participants in the development of obesity-related diseases. Since TNF-α converting enzyme (TACE) is the major factor that induces soluble TNF-α, TACE has been noted as a pivotal regulator in this field. To reveal the role of TACE in adipose tissue inflammation, TACE-transgenic (TACE-Tg) and wild type (WT) mice were fed with high fat diet (HFD) or control diet for 16 weeks. At 13 weeks after the beginning of the diet, serum TNF-α and macrophage-related cytokine/chemokine levels were elevated in TACE-Tg mice fed with HFD (Tg-HFD mice), and the number of the so-called crown-like adipocyte was significantly increased in adipose tissues of Tg-HFD mice at the end of the experiment. Although macrophage infiltration was not detected in the adipose tissues at this time, fibrosis was observed around the crown-like adipocytes. These findings suggested that TACE overexpression induced macrophage infiltration and subsequent fibrosis in adipose tissues under HFD regimen. The collective evidence suggested that TACE could be a therapeutic target of HFD-induced obesity-related adipose tissue inflammation.

  12. NBBA, a synthetic small molecule, inhibits TNF-{alpha}-induced angiogenesis by suppressing the NF-{kappa}B signaling pathway

    Energy Technology Data Exchange (ETDEWEB)

    Kim, Nam Hee; Jung, Hye Jin [Chemical Genomics Laboratory, Department of Biotechnology, Translational Research Center for Protein Function Control, College of Life Science and Biotechnology, Yonsei University, Seoul 120-749 (Korea, Republic of); Shibasaki, Futoshi [Translation Research Project, Tokyo Metropolitan Institute of Medical Science, Tokyo 156-8506 (Japan); Kwon, Ho Jeong, E-mail: kwonhj@yonsei.ac.kr [Chemical Genomics Laboratory, Department of Biotechnology, Translational Research Center for Protein Function Control, College of Life Science and Biotechnology, Yonsei University, Seoul 120-749 (Korea, Republic of)

    2010-01-15

    Nuclear factor-{kappa}B (NF-{kappa}B) is a crucial transcription factor that contributes to cancer development by regulating a number of genes involved in angiogenesis and tumorigenesis. Here, we describe (Z)-N-(3-(7-nitro-3-oxobenzo[d][1,2]selenazol-2(3H)-yl)benzylidene) propan-2-amine oxide (NBBA) as a new anti-angiogenic small molecule that targets NF-{kappa}B activity. NBBA showed stronger growth inhibition on human umbilical vein endothelial cells (HUVECs) than on the cancer cell lines we tested. Moreover, NBBA inhibited tumor necrosis factor-alpha (TNF-{alpha})-induced tube formation and invasion of HUVECs. In addition, NBBA suppressed the neovascularization of chorioallantonic membrane from growing chick embryos in vivo. To address the mode of action of the compound, the effect of NBBA on TNF-{alpha}-induced NF-{kappa}B transcription activity was investigated. NBBA suppressed TNF-{alpha}-induced c-Jun N-terminal kinase phosphorylation, which resulted in suppression of transcription of NF-{kappa}B and its target genes, including interleukin-8, interleukin-1{alpha}, and epidermal growth factor. Collectively, these results demonstrated that NBBA is a new anti-angiogenic small molecule that targets the NF-{kappa}B signaling pathway.

  13. Formation of a fine-dispersed liquid-metal target under the action of femto- and picosecond laser pulses for a laser-plasma radiation source in the extreme ultraviolet range

    Energy Technology Data Exchange (ETDEWEB)

    Vinokhodov, A Yu; Krivokorytov, M S [EUV Labs, Ltd., Troitsk, Moscow (Russian Federation); Koshelev, K N; Krivtsun, V M; Sidelnikov, Yu V; Medvedev, V V; Kompanets, V O; Melnikov, A A; Chekalin, S V [Institute of Spectroscopy, Russian Academy of Sciences, Troitsk, Moscow (Russian Federation)

    2016-01-31

    We report the results of studying the dynamics of deformation and fragmentation of liquid-metal droplets under the action of ultrashort laser pulses. The experiments have been performed to optimise the shape of the droplet target used in extreme ultraviolet (EUV) radiation sources based on the laser-produced plasma using the pre-pulse technology. The pre-pulse is generated by a system incorporating a master Ti : sapphire oscillator and a regenerative amplifier, allowing one to vary the pulse duration from 50 fs to 50 ps. The power density of laser radiation at the droplet target, averaged over the pulse duration and spatial coordinates, has reached 3 × 10{sup 15} W cm{sup -2}. The production of liquid-metal droplets has been implemented by means of a droplet generator based on a nozzle with a ring piezoceramic actuator. The droplet material is the eutectic indium – tin alloy. The droplet generator could operate in the droplet and jet regime with a maximal rate of stable operation 5 and 150 kHz, respectively. The spatial stability of droplet position σ = 1% – 2% of its diameter is achieved. The size of the droplets varied within 30 – 70 μm, their velocity was 2 – 8 m s{sup -1} depending on the operation regime. (interaction of laser radiation with matter. laser plasma)

  14. Severe inflammatory arthritis and lymphadenopathy in the absence of TNF

    OpenAIRE

    Campbell, Ian K.; O’Donnell, Kristy; Lawlor, Kate E.; Wicks, Ian P

    2001-01-01

    It has been postulated that TNF has a pivotal role in a cytokine cascade that results in joint inflammation and destruction in rheumatoid arthritis (RA). To evaluate this, we examined the response of TNF-deficient (Tnf–/–) mice in two models of RA. Collagen-induced arthritis (CIA) was induced by injection of chick type II collagen (CII) in CFA. Tnf–/– mice had some reduction in the clinical parameters of CIA and, on histology, significantly more normal joints. However, severe disease was evid...

  15. Cathepsin-D And Tnf-α in Bladder Cancer

    Directory of Open Access Journals (Sweden)

    T. Salman

    1996-01-01

    Full Text Available In a study of 34 normal healthy controls, 35 patients with urinary tract bilharziasis and 93 bladder cancer patients (62 of them are operable cases and 31 are non-operable ones, serum tumor necrosis factor alpha (TNF-α and cytosolic Cathepsin-D were estimated. Though both potential markers were elevated in bladder cancer patients, neither Cathepsin-D nor TNF-α showed associations of prognostic value since there were no positive correlations with tumor stages, grades or association of tumors with bilharzia ova or lymph node involvement.

  16. Isoliquiritigenin inhibits TNF-α-induced release of high-mobility group box 1 through activation of HDAC in human intestinal epithelial HT-29 cells.

    Science.gov (United States)

    Chi, Jin-Hua; Seo, Geom Seog; Cheon, Jae Hee; Lee, Sung Hee

    2017-02-05

    The suppression of pro-inflammatory cytokine-induced inflammation responses is an attractive pharmacological target for the development of therapeutic strategies for inflammatory bowel disease (IBD). In the present study, we evaluated the anti-inflammatory properties of flavonoid isoliquiritigenin (ISL) in intestinal epithelial cells and determined its mechanism of action. ISL suppressed the expression of inflammatory molecules, including IL-8, IL-1β and COX-2, in TNF-α-stimulated HT-29 cells. Moreover, ISL induced activation of Nrf2 and expression of its target genes, such as HO-1 and NQO1. ISL also inhibited the TNF-α-induced NF-κB activation in HT-29 cells. High-mobility group box 1 (HMGB1), which is one of the critical mediators of inflammation, is actively secreted from inflammatory cytokine-stimulated immune or non-immune cells. ISL inhibited HMGB1 secretion by preventing TNF-α-stimulated HMGB1 relocation, whereas the RNA and protein expression levels of cellular HMGB1 did not change in response to TNF-α or ISL. Moreover, we found that HMGB1 acetylation was associated with HMGB1 translocation to the cytoplasm and the extracellular release in TNF-α-stimulated HT-29 cells; however, ISL significantly decreased the amount of acetylated HMGB1 in both the cytoplasm and extracellular space of HT-29 cells. Histone deacetylase (HDAC) inhibition by Scriptaid abrogated ISL-induced HDAC activity and reversed the ISL-mediated decrease in acetylated HMGB1 release in TNF-α-stimulated HT-29 cells, suggesting that, at least in TNF-α-stimulated HT-29 cells, ISL suppresses acetylated HMGB1 release via the induction of HDAC activity. Together, the current results suggest that inhibition of HMGB1 release via the induction of HDAC activity using ISL may be a promising therapeutic intervention for IBD.

  17. Ginsenoside Rg3 sensitizes human non-small cell lung cancer cells to γ-radiation by targeting the nuclear factor-κB pathway.

    Science.gov (United States)

    Wang, Lei; Li, Xiankui; Song, Yi-Min; Wang, Bin; Zhang, Fu-Rui; Yang, Rui; Wang, Hua-Qi; Zhang, Guo-Jun

    2015-07-01

    At present, it is elusive how non-small cell lung cancer (NSCLC) develops resistance to γ-radiation; however, the transcription factor nuclear factor-κB (NF-κB) and NF-κB-regulated gene products have been proposed as mediators. Ginsenoside Rg3 is a steroidal saponin, which was isolated from Panax ginseng. Ginsenoside Rg3 possesses high pharmacological activity and has previously been shown to suppress NF-κB activation in various types of tumor cell. Therefore, the present study aimed to determine whether Rg3 could suppress NF-κB activation in NSCLC cells and sensitize NSCLC to γ-radiation, using an NSCLC cell line and NSCLC xenograft. A clone formation assay and lung tumor xenograft experiment were used to assess the radiosensitizing effects of ginsenoside Rg3. NF-κB/inhibitor of NF-κB (IκB) modulation was ascertained using an electrophoretic mobility shift assay and western blot analysis. NF-κB-regulated gene products were monitored by western blot analysis. The present study demonstrated that ginsenoside Rg3 was able to sensitize A549 and H1299 lung carcinoma cells to γ-radiation and significantly enhance the efficacy of radiation therapy in C57BL/6 mice bearing a Lewis lung carcinoma cell xenograft tumor. Furthermore, ginsenoside Rg3 suppressed NF-κB activation, phosphorylation of IκB protein and expression of NF-κB-regulated gene products (cyclin D1, c-myc, B-cell lymphoma 2, cyclooxygenase-2, matrix metalloproteinase-9 and vascular endothelial growth factor), a number of which were induced by radiation therapy and mediate radioresistance. In conclusion, the results of the present study suggested that ginsenoside Rg3 may potentiate the antitumor effects of radiation therapy in NSCLC by suppressing NF-κB activity and NF-κB-regulated gene products, leading to the inhibition of tumor progression.

  18. Irradiation with UV-C inhibits TNF-α-dependent activation of the NF-κB pathway in a mechanism potentially mediated by reactive oxygen species.

    Science.gov (United States)

    Szoltysek, Katarzyna; Walaszczyk, Anna; Janus, Patryk; Kimmel, Marek; Widlak, Piotr

    2017-01-01

    Pathways depending on the NF-κB transcription factor are essential components of cellular response to stress. Plethora of stimuli modulating NF-κB includes inflammatory signals, ultraviolet radiation (UV) and reactive oxygen species (ROS), yet interference between different factors affecting NF-κB remains relatively understudied. Here, we aim to characterize the influence of UV radiation on TNF-α-induced activity of the NF-κB pathway. We document inhibition of TNF-α-induced activation of NF-κB and subsequent suppression of NF-κB-regulated genes in cells exposed to UV-C several hours before TNF-α stimulation. Accumulation of ROS and subsequent activation of NRF2, p53, AP-1 and NF-κB-dependent pathways, with downstream activation of antioxidant mechanisms (e.g., SOD2 and HMOX1 expression), is observed in the UV-treated cells. Moreover, NF-κB inhibition is not observed if generation of UV-induced ROS is suppressed by chemical antioxidants. It is noteworthy that stimulation with TNF-α also generates a wave of ROS, which is suppressed in cells pre-treated by UV. We postulate that irradiation with UV-C activates antioxidant mechanisms, which in turn affect ROS-mediated activation of NF-κB by TNF-α. Considering a potential cross talk between p53 and NF-κB, we additionally compare observed effects in p53-proficient and p53-deficient cells and find the UV-mediated suppression of TNF-α-activated NF-κB in both types of cells.

  19. Secreted APE1/Ref-1 inhibits TNF-α-stimulated endothelial inflammation via thiol-disulfide exchange in TNF receptor.

    Science.gov (United States)

    Park, Myoung Soo; Choi, Sunga; Lee, Yu Ran; Joo, Hee Kyoung; Kang, Gun; Kim, Cuk-Seong; Kim, Soo Jin; Lee, Sang Do; Jeon, Byeong Hwa

    2016-03-11

    Apurinic apyrimidinic endonuclease 1/Redox factor-1 (APE1/Ref-1) is a multifunctional protein with redox activity and is proved to be secreted from stimulated cells. The aim of this study was to evaluate the functions of extracellular APE1/Ref-1 with respect to leading anti-inflammatory signaling in TNF-α-stimulated endothelial cells in response to acetylation. Treatment of TNF-α-stimulated endothelial cells with an inhibitor of deacetylase that causes intracellular acetylation, considerably suppressed vascular cell adhesion molecule-1 (VCAM-1). During TSA-mediated acetylation in culture, a time-dependent increase in secreted APE1/Ref-1 was confirmed. The acetyl moiety of acetylated-APE1/Ref-1 was rapidly removed based on the removal kinetics. Additionally, recombinant human (rh) APE1/Ref-1 with reducing activity induced a conformational change in rh TNF-α receptor 1 (TNFR1) by thiol-disulfide exchange. Following treatment with the neutralizing anti-APE1/Ref-1 antibody, inflammatory signals via the binding of TNF-α to TNFR1 were remarkably recovered, leading to up-regulation of reactive oxygen species generation and VCAM-1, in accordance with the activation of p66(shc) and p38 MAPK. These results strongly indicate that anti-inflammatory effects in TNF-α-stimulated endothelial cells by acetylation are tightly linked to secreted APE1/Ref-1, which inhibits TNF-α binding to TNFR1 by reductive conformational change, with suggestion as an endogenous inhibitor of vascular inflammation.

  20. Cell-type-restricted anti-cytokine therapy: TNF inhibition from one pathogenic source.

    Science.gov (United States)

    Efimov, Grigory A; Kruglov, Andrei A; Khlopchatnikova, Zoya V; Rozov, Fedor N; Mokhonov, Vladislav V; Rose-John, Stefan; Scheller, Jürgen; Gordon, Siamon; Stacey, Martin; Drutskaya, Marina S; Tillib, Sergei V; Nedospasov, Sergei A

    2016-03-15

    Overexpression of TNF contributes to pathogenesis of multiple autoimmune diseases, accounting for a remarkable success of anti-TNF therapy. TNF is produced by a variety of cell types, and it can play either a beneficial or a deleterious role. In particular, in autoimmunity pathogenic TNF may be derived from restricted cellular sources. In this study we evaluated the feasibility of cell-type-restricted TNF inhibition in vivo. To this end, we engineered MYSTI (Myeloid-Specific TNF Inhibitor)--a recombinant bispecific antibody that binds to the F4/80 surface molecule on myeloid cells and to human TNF (hTNF). In macrophage cultures derived from TNF humanized mice MYSTI could capture the secreted hTNF, limiting its bioavailability. Additionally, as evaluated in TNF humanized mice, MYSTI was superior to an otherwise analogous systemic TNF inhibitor in protecting mice from lethal LPS/D-Galactosamine-induced hepatotoxicity. Our results suggest a novel and more specific approach to inhibiting TNF in pathologies primarily driven by macrophage-derived TNF.

  1. Azadirachtin interacts with the tumor necrosis factor (TNF) binding domain of its receptors and inhibits TNF-induced biological responses.

    OpenAIRE

    Thoh, Maikho; Kumar, Pankaj; Nagarajaram, Hampathalu A.; Manna, Sunil K.

    2013-01-01

    The role of azadirachtin, an active component of a medicinal plant Neem (Azadirachta indica), on TNF-induced cell signaling in human cell lines was investigated. Azadirachtin blocks TNF-induced activation of nuclear factor κB (NF-κB) and also expression of NF-κB-dependent genes such as adhesion molecules and cyclooxygenase 2. Azadirachtin inhibits the inhibitory subunit of NF-κB (IκBα) phosphorylation and thereby its degradation and RelA (p65) nuclear translocation. It blocks IκBα kinase (IKK...

  2. NASA Space Radiation Laboratory

    Data.gov (United States)

    Federal Laboratory Consortium — The NASA Space Radiation Laboratory (NSRL) at Brookhaven National Laboratory is a NASA funded facility, delivering heavy ion beams to a target area where scientists...

  3. A potent and selective p38 inhibitor protects against bone damage in murine collagen-induced arthritis : a comparison with neutralization of mouse TNF alpha

    NARCIS (Netherlands)

    Mihara, K.; Almansa, C.; Smeets, R. L.; Loomans, E. E. M. G.; Dulos, J.; Vink, P. M. F.; Rooseboom, M.; Kreutzer, H.; Cavalcanti, F.; Boots, A. M.; Nelissen, R. L.

    2008-01-01

    Background and purpose: The p38 kinase regulates the release of proinflammatory cytokines including tumour-necrosis factor-alpha (TNF alpha) and is regarded as a potential therapeutic target in rheumatoid arthritis (RA). Using the novel p38 inhibitor Org 48762-0, we investigated the therapeutic pote

  4. 中子及γ线照射小鼠肠组织中TNF-α的表达及其意义%Expression and significance of TNF-α in intestine tissue of mice irradiated by neutron and γ rays

    Institute of Scientific and Technical Information of China (English)

    徐新萍; 彭瑞云; 高亚兵; 陈浩宇; 付凯飞; 马俊杰; 王瑞娟; 王晓民; 邱萍

    2007-01-01

    目的 研究经中子及γ线照射后小鼠肠组织中TNF-α的表达情况及其意义.方法 350只二级雄性BALB/c小鼠,经不同剂量的中子和γ线照射,于照后6、12h及1、2、3、4、5、7、10、14、21、28天分批活杀,采用免疫组化染色等技术观察TNF-α在肠组织中的表达情况.结果 在正常肠黏膜中,TNF-α主要见于肠绒毛间质、黏膜下及淋巴组织中的巨噬细胞浆内; 2.5Gy中子照后2天内,上述阳性部位TNF-α的表达进行性减少;3~7天其在巨噬细胞及隐窝细胞胞质内的表达明显增加,5天达高峰,14天恢复至正常水平.4.0Gy、5.5Gy中子及12Gyγ线照射后4天内,TNF-α的表达进行性减少;5.5Gy γ线照后6~12h,TNF-α的表达增多,照后1天减少,2~5天增加,3天达高峰,10天恢复至正常水平.TNF-α的表达在肠黏膜损伤时减少,于损伤后恢复的早期增多.结论 中子和γ线照后肠内源性TNF-α表达具有不同的变化规律,并参与了肠放射损伤及修复的病理生理过程.%Objective To study the expression of tumor necrosis factor alpha (TNF-α) in the intestine of mice irradiated by neutron and γ rays.Methods 350 male BALB/c mice were irradiated with neutron and γ rays of different doses, and sacrificed at 6 and 12hours, 1, 2, 3, 4, 5, 7, 10, 14, 21 and 28 days after irradiation.The TNF-α in the mice intestinal tissue was detected by means of immunohistochemistry and image analysis.Results In normal control mice, TNF-α was expressed in the cytoplasm of macrophages in intestinal villus interstitium, submucosa and lymph tissue.After 2.5Gy neutron radiation, TNF-α was decreased progressively within 2 days, increased obviously in macrophages and crypt cells during 3rd~7th day, reached the peak at 5th day and recovered to normal level at 14th day and TNF-α was decreased progressively within 4 days after 4.0 and 5.5Gy neutron and 12Gy ray irradiation.TNF-α was increased obviously in 6~12 hours, decreased at 1st

  5. Optimizing anti-TNF therapy in inflammatory bowel disease

    NARCIS (Netherlands)

    Brandse, J.F.

    2015-01-01

    Anti-TNF, zoals infliximab en adalimumab, zijn effectief voor de behandeling van chronische ontstekingsziekten van de darm (IBD): de ziekte van Crohn en colitis ulcerosa. Deze middelen zijn echter kostbaar en niet alle patiënten hebben baat bij de therapie. Dit proefschrift beschrijft hoe de mate va

  6. Managing risks of TNF inhibitors: an update for the internist.

    Science.gov (United States)

    Hadam, Jennifer; Aoun, Elie; Clarke, Kofi; Wasko, Mary Chester

    2014-02-01

    Tumor necrosis factor (TNF) inhibitors have many beneficial effects, but they also pose infrequent but significant risks, including serious infection and malignancy. These risks can be minimized by judicious patient selection, appropriate screening, careful monitoring during treatment, and close communication between primary care physicians and subspecialists.

  7. Influence of TNF-α gene polymorphisms on TNF-α production and disease%TNF-α基因多态性对TNF-α产物的影响及其与疾病的关系

    Institute of Scientific and Technical Information of China (English)

    郭芮兵; 陈仕林; 景华

    2003-01-01

    肿瘤坏死因子α(TNF-α) 是一种致炎因子.人类TNF-α基因位于染色体6p21.3区,这是个具有高度多态性的主要组织相容性复合体(MHC)区域.TNF基因族含有许多多态性,如微卫星(microsatellite)及单核苷酸多态性(SNPs).许多多态性与HLAⅠ、Ⅱ等位基因连锁不平衡,其中一些影响了如-308SNP 这样的TNF-α在体外的表达.许多研究表明,SNP及TNF-α基因中的其他多态性与不同炎症状态相关.这种现象是否由SNP直接作用所抑制或是与TNF基因或HLA系统的其他多态性所致,研究者们对此尚有争议.

  8. Is there a future for TNF promoter polymorphisms?

    NARCIS (Netherlands)

    Bayley, J.P.; Ottenhoff, TH; Verweij, C.L.

    2004-01-01

    The in vitro study of TNF promoter polymorphism (SNP) function was stimulated by the numerous case-control (association) studies of the polymorphisms in relation to human disease and the appearance of several studies claiming to show a functional role for these SNPs provided a further impetus to res

  9. Association of TNF, MBL, and VDR Polymorphisms with Leprosy Phenotypes

    Science.gov (United States)

    Sapkota, Bishwa R.; Macdonald, Murdo; Berrington, William R.; Misch, E. Ann; Ranjit, Chaman; Siddiqui, M. Ruby; Kaplan, Gilla; Hawn, Thomas R.

    2010-01-01

    Background Although genetic variants in tumor necrosis factor (TNF), mannose binding lectin (MBL), and the vitamin D receptor (VDR) have been associated with leprosy clinical outcomes these findings have not been extensively validated. Methods We used a case