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1
Liu, Chang S. B. Massachusetts Institute of Technology. "Radiation-induced bystander fibroblasts both reduce and amplify micronuclei induction through the reciprocal bystander effect and the secondary bystander effect." Thesis, Massachusetts Institute of Technology, 2016. http://hdl.handle.net/1721.1/106695.
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Thesis: S.B., Massachusetts Institute of Technology, Department of Nuclear Science and Engineering, 2016.This electronic version was submitted by the student author. The certified thesis is available in the Institute Archives and Special Collections.
Cataloged from student-submitted PDF version of thesis.
Includes bibliographical references (pages 25-27).
Aside from directly causing DNA damage, the traversal of radiation through cells also induces the bystander effect, which is the biological response of unirradiated cells that are neighboring or sharing medium with the irradiated cells. Although the mechanisms through which irradiated cells send signals to the bystander cells are not well understood, the bystander effect could potentially have clinical relevance or play a significant role in low dose radiation environments. The research in this thesis focuses on the ability of the bystander cells to influence the behavior of cells that share medium with them, which can be separated into three categories: unirradiated cells, irradiated cells, and the original irradiated cells that caused the bystander effect. These can be considered the "secondary bystanders." Human AG01522 fibroblasts were irradiated with 250 kVp X-rays and co-cultured with unirradiated fibroblasts to generate bystander cells, which were then cocultured with one of the three types of secondary bystander cells. The micronucleus assay was used to analyze the amount of chromosome aberrations present. In the unirradiated secondary bystander population, an increase in percentage of binucleated cells with micronuclei from the background level to approximately the level of the primary bystander cells was observed, indicating that bystander cells can send damaging signals. The data also showed that there was a lower frequency of micronuclei formation in the irradiated population with bystander inserts in comparison to irradiated populations without bystanders. However, there were no conclusive data on the effect of the bystander cells on other irradiated cells. Overall, the results suggest that bystander fibroblasts are capable of sending both detrimental and beneficial signals and can induce a range of behaviors in other cells.
by Chang Liu.
S.B.
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Zemp, Franz Joseph, and University of Lethbridge Faculty of Arts and Science. "The bystander effect : animal and plant models." Thesis, Lethbridge, Alta. : University of Lethbridge, Faculty of Arts and Science, 2008, 2008. http://hdl.handle.net/10133/685.
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Bystander effects are traditionally known as a phenomenon whereby unexposed cells exhibit the molecular symptoms of stress exposure when adjacent or nearby cells are traversed by ionizing radiation. However, the realm of bystander effects can be expanded to include any systemic changes to cellular homeostasis in response to a number of biotic or abiotic stresses, in any molecular system. This thesis encompasses three independent experiments looking at bystander and bystander-like responses in both plant and animal models. In plants, an investigation into the regulation of small RNAs has given us some insights into the regulation of the plant hormone auxin in both stress-treated and systemic (bystander) leaves. Another plant model shows that a bystander-like plant-plant signal can be induced upon ionizing radiation to increase the genome instability of neighbouring unexposed (bystander) plants. In animals, it is shown that the microRNAome is largely affected in the bystander cells in a three-dimensional human tissue model. In silico and bioinfomatic analysis of this data provide us with clues as to the nature of bystander signalling in this human ‘in vivo’ model.xiv, 141 p. : ill. ; 29 cm.
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Nasse, Nicholas B. "Effect of Gender on Bystander Intervention." Scholarship @ Claremont, 2015. http://scholarship.claremont.edu/cmc_theses/1016.
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Since the murder of Kitty Genovese in 1964 research on the effect of group size on bystander intervention has risen quite rapidly. While this research on the “bystander effect” has proven quite useful there are many other factors that affect bystander intervention. One such factor is the gender of the bystander. This paper reviews current & groundbreaking literature pertaining to the effect of gender on bystander intervention in individual, group, low-severity, and high-severity situations. A review of the literature suggests that gender has a significant effect on bystander intervention. Research results were mixed with some research showing that individually males were more helpful in high-severity situations, while women tended to be more helpful in low-severity situations. Other research showed male or females more helpful in situations of all severities. The effect of gender in group variables showed to be inconclusive. These mixed results demonstrate a need for further empirical research to clarify the strength of the effect when accounting for situational covariates.
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Wordsworth, James William. "The senescent cell induced bystander effect." Thesis, University of Newcastle upon Tyne, 2014. http://hdl.handle.net/10443/2536.
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The induction of senescence in response to persistent stress induces major phenotypic changes in senescent cells, including the secretion of a host of inflammatory factors and reactive oxygen species. Recent evidence has implicated senescent cells in the diseases of ageing and cancer; however, the mechanism by which this occurs is still unknown. This thesis uses a reporter cell line with cells expressing a fluorescent conjugate that allows real time live cell imaging of a sub set of cells within a co-culture, to provide the first evidence that senescent cells can induce a DNA damage response in healthy cells, and thus implicates a potential mechanism by which senescent cells could non-autonomously contribute to the ageing process. The use of specific inhibitors, stimulation, and targeted repression indicate that gap junctions, reactive oxygen species, p38, mTOR and NF-κB all play a key role in this observed bystander effect of senescent cells, and offer potential targets for therapies designed to reduce the damaging effects of senescent cells.
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Serve, Kinta Marguerite-Culton. "Evaluating the effect of prodrug metabolism on the bystander effect in cancer gene therapy." Pullman, Wash. : Washington State University, 2010. http://www.dissertations.wsu.edu/Thesis/Spring2010/k_serve_0223120.pdf.
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Thesis (M.S. in molecular biosciences)--Washington State University, May 2010.Title from PDF title page (viewed on July 9, 2010). "School of Molecular Biosciences." Includes bibliographical references.
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Barnes, Charity Deanne. "The Effect of a Class-wide Training on Prosocial Bystander Behaviors." DigitalCommons@USU, 2015. https://digitalcommons.usu.edu/etd/4237.
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The purpose of this study was to decrease school bullying by implementing a class-wide intervention that targets bystanders. Hypotheses include that an intervention will increase prosocial bystander behaviors that will result in reduced rates of bullying and improved positive peer responses. Ross and Horner’s Positive Behavior Supports bullying prevention program was modified to increase incentives for students who defend others from bullying. A multiple baseline design across three general education classrooms was used to examine the effectiveness of the intervention in an elementary school in northwestern Utah. Pre- and posttests were administered to assess participant roles and student intervention acceptability. The findings of the study suggested that bullying behavior decreased and defending increased. Further, acceptability of the intervention and the skills taught to children were rated as moderately high across all classrooms. Even though bullying incidences decreased substantially, bullying behaviors were not eradicated completely in the three classrooms. To decrease rates of bullying further, secondary and tertiary interventions along with continued functional assessment on why bullying occurs are needed. Further, to help increase the practicality of teaching peers the critical skills of defending victims, research on how to increase students’ ability and motivation to intervene is essential.
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Nishiura, Hideki. "The bystander effect is a novel mechanism of UVA-induced melanogenesis." Kyoto University, 2012. http://hdl.handle.net/2433/157451.
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Christianson, Monica May. "Bystander Effect of Workplace Bullying, Perceived Organizational Support, and Work Engagement." ScholarWorks, 2015. https://scholarworks.waldenu.edu/dissertations/1685.
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Workplace environments and the dynamics that exist within them affect everyone involved, especially coworkers. Although research has investigated how workplace bullying impacts its victims and the organization, little research has examined the effects of workplace bullying from the role of the bystander. Fewer have investigated how Perceived of Organizational Support (POS) may affect the employee's work engagement of those witnesses. The goal of this quantitative study was to determine the effect of POS on work engagement in the employees who witness workplace bullying. An online survey was used with the Negative Acts Questionnaire-Revised, (NAQ-R), Utrecht Work Engagement Scale (UWES) and POS instruments. It was launched on LinkedIn and 152 respondents participated and were asked to snowball the link. The study employed the affective events theory that presupposes that the occupational atmosphere influences those in proximity to negative behaviors. Regression results showed that only POS (t (150) = 5.14, p < 0.001) predicted employees' work engagement. On the other hand, witnessing workplace bullying (t (150) = -0.69, p = 0.49) did not affect employees' work engagement. This study provides a useful framework to illustrate how the environment of workplace bullying affects an organization's human and fiscal resources, contributing to the body of knowledge that can benefit organizations by helping to affect social change.
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Anzenberg, Vered. "Do heavy ions induce the bystander effect? : study to determine the induction of the bystander effect from Fe ion beam compared to X-rays in human keratinocytes." Thesis, Massachusetts Institute of Technology, 2005. http://hdl.handle.net/1721.1/34458.
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Thesis (S.M.)--Massachusetts Institute of Technology, Dept. of Nuclear Engineering, 2005.Includes bibliographical references (leaves 62-65).
The bystander effect is the observation that non-irradiated cells near a cell traversed by radiation express biological responses such as micronuclei formation and genomic instability. Most published studies of the bystander effect have been conducted using alpha particles, a high LET radiation. A few studies have been done with low LET radiation. This project studies the bystander effect from both low LET x-rays and high LET Fe particle beam irradiation. Using a transwell insert system, the bystander effect was studied in hTERT immortalized human keratinocytes. Cells are plated in a 6-well plate and in a companion permeable membrane insert. Cells in the 6-well plate are irradiated using conventional 250 kVp X-rays or 1000 MeV/nucleon Fe ion beam, LET of 151 keV/pm, from the NASA Space Radiation Laboratory at Brookhaven National Lab. After irradiation, inserts are immediately placed into the 6 well plate so that the irradiated and unirradiated cells are sharing medium but are not in contact. For both beams, frequency of micronuclei, chromatin bridges, and p21 wafl induction as well as cell cycle phase analysis were determined in both directly irradiated and bystander cells from 0.1 Gy to 5 Gy. From x-rays, a two-fold bystander effect at 24 h after irradiation with elevated p21' wafl induction and micronuclei was seen but in Fe ion irradiation, the p21 wafl bystander effect was delayed to 40-50 h after irradiation and no MN bystander effect was observed.
(cont.) Cell cycle analysis showed a slight G2 arrest in keratinocytes 5 h after x-rays but a strong G2 arrest until 40-50 h was seen after Fe ion irradiation. Bystander keratinocytes co-cultured with directly irradiated human fibroblasts AGO 1522 cells showed a two-fold p21 wafl and MN bystander effect 24 h after x-rays, and a potential 2-fold MN bystander effect 50 h after Fe ions. Bystander AGO1522 cells co-cultured with directly irradiated keratinocytes showed a two-fold MN bystander effect 24 h after x-rays, but no MN bystander response was seen at any time points studied from Fe ions. Striking differences in the bystander response were shown from the two radiation types, but the reason remains to be clarified.
by Vered Anzenberg.
S.M.
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Schillinger, Thomas. "Bystander Effect and Religious Group Affiliation: Terrorism and the Diffusion of Responsibility." ScholarWorks, 2014. https://scholarworks.waldenu.edu/dissertations/126.
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The collective nature of group affiliation may inhibit an individual from exhibiting prosocial behavior regarding acts of religiously-motivated terror. This study's purpose was to investigate the nature of bystander intervention as it relates to religious group affiliation. Darley and Latane's bystander effect theory provided the theoretical framework for this study. The research questions examined the impact of religious group affiliation and group size on the dependent variables of civic moral disengagement (CMD) and commitment to the war on terror (CWT). Three validated survey instruments were administered to a random participant pool of 206 respondents. An ANCOVA and Spearman's rho correlation were employed to address the research questions. Findings revealed that neither religious group affiliation nor group size significantly predicts either CWT or CMD after controlling for the degree of religious commitment. Further research should test alternative theories associated with leadership and group dynamics. Positive social change is advanced by acknowledging that bystanders to acts of terrorism may not be influenced by factors such as group affiliation or size of religious group affiliations. These findings underscore the complexity of the relationship between behavior and religious affiliation. Policy makers and future researchers may benefit by redirecting their focus for prevention and intervention toward influences such as the motivational dynamic between religious leaders and their followers.
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Koturbash, Igor, and University of Lethbridge Faculty of Arts and Science. "Molecular mechanisms of radiation-induced bystander effects in vivo." Thesis, Lethbridge, Alta. : University of Lethbridge, Faculty of Arts and Science, 2008, 2008. http://hdl.handle.net/10133/664.
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Ionizing radiation (IR), along with being an important diagnostic and treatment
modality, is a potent tumor-causing agent, and the risk of secondary radiation
treatment-related cancers is a growing clinical problem. Now some studies propose to
link secondary radiation-induced cancers to an enigmatic phenomenon of bystander
effects, whereby the exposed cells send signal damage and distress to their naïve
neighbors and result in genome destabilization and carcinogenesis. Yet, no data
existed on the bystander effects in an organ other than an exposed one. With this in
mind, we focused on the analysis of existence and mechanisms of radiation-induced
bystander effects in vivo. We have found that bystander effects occur in vivo in
distant skin and spleen following half-body or cranial irradiation. These bystander
effects resulted in elevated DNA damage, profound dysregulation of epigenetic
machinery, and pronounced alterations in apoptosis, proliferation and gene
expression. Bystander effects also exhibited persistency and sex specificity. The
results obtained while using the animal model systems can potentially be extrapolated
to different animals and humans.xiii, 208 leaves : ill. ; 29 cm.
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Karlberg, Emma. "Högstadieelevers upplevelser av två reklamfilmer mot mobbing." Thesis, Stockholm University, Department of Psychology, 2006. http://urn.kb.se/resolve?urn=urn:nbn:se:su:diva-1084.
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Denna studie har genom halvstrukturerade kvalitativa intervjuer med 13 högstadieelever undersökt hur eleverna upplever två reklamfilmer mot mobbing. Filmerna har lanserats av stiftelsen Friends och utgör en del i deras arbete mot mobbing. Resultatet sammanställdes genom induktiv tematisk analys och åtta teman framkom. Temana var: Känsloprocess, Indirekt mobbing berör mer än direkt mobbing, Kan hända vem som helst, Förståelse för mobboffret, Hjälparen väcker beundran, Medlöparens brist på ingripande, Lärarens passivitet irriterar samt Alla kan hjälpa till. Det resultat som framkom jämfördes med det som Friends önskade att åskådaren skulle uppleva. Resultatet kopplades även ihop med teorierna bystander-effect och empati. Det visade sig att intervjupersonerna i stort upplevde filmerna som Friends önskade.
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Sheppard, Sarah (Sarah Elizabeth). "The effect of temperature on the bystander effect as examined in human prostate carcinoma cells with alpha particle irradiation." Thesis, Massachusetts Institute of Technology, 2006. http://hdl.handle.net/1721.1/41596.
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Thesis (S.B.)--Massachusetts Institute of Technology, Dept. of Nuclear Science and Engineering, 2006."June 2006."
Includes bibliographical references (p. 30-32).
The bystander effect is seen when irradiated cells release a factor that can produce damage or death in neighboring "bystander" cells that are not actually hit by any radiation. One proposed mechanism involves the irradiated cells releasing a soluble factor into the medium that can cause damage to the non-irradiated cells. Previous studies in the Coderre lab showed that the soluble factor released by DU-145 human prostate carcinoma cells was a short-lived, free radical species (Wang and Coderre, Rad. Res., 164, 711-722, 2005). This thesis examined the effect of temperature on the bystander effect. A co-culture system was used to create irradiated and bystander DU-145 cells in the same medium. This thesis showed that a decrease in temperature lessens or prevents the bystander effect. Researching the bystander effect will allow a better understanding of a process that may already be occurring during alpha-particle based therapies such as boron neutron capture therapy (BNCT) and tumor radioimmunotherapy and could provide a means to improve these therapies.
by Sarah Sheppard.
S.B.
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Gonon, Géraldine. "Space radiation-induced bystander effect : kinetics of biologic responses, mechanisms, and significance of secondary radiations." Phd thesis, Université de Franche-Comté, 2011. http://tel.archives-ouvertes.fr/tel-00987717.
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Widespread evidence indicates that exposure of cell cultures to α particles results in significant biological changes in both the irradiated and non-irradiated bystander cells in the population. The induction of non-targeted biological responses in cell cultures exposed to low fluences of high charge (Z) and high energy (E) particles is relevant to estimates of the health risks of space radiation and to radiotherapy. Here, we investigated the mechanisms underlying the induction of stressful effects in confluent normal human fibroblast cultures exposed to low fluences of 1000 MeV/u iron ions (linear energy transfer (LET) ~151 keV/µm), 600 MeV/u silicon ions (LET ~50 keV/µm) or 290 MeV/u carbon ions (LET ~13 keV/µm). We compared the results with those obtained in cell cultures exposed, in parallel, to low fluences of 0.92 MeV/u α particles (LET ~109 keV/µm).Induction of DNA damage, changes in gene expression, protein carbonylation and lipid peroxidation during 24 h after exposure of confluent cultures to mean doses as low as 0.2 cGy of iron or silicon ions strongly supported the propagation of stressful effects from irradiated to bystander cells. At a mean dose of 0.2 cGy, only ~1 and 3 % of the cells would be targeted through the nucleus by an iron or silicon ion, respectively. Within 24 h post-irradiation, immunoblot analyses revealed significant increases in the levels of phospho-TP53 (serine 15), p21Waf1 (also known as CDKN1A), HDM2, phospho-ERK1/2, protein carbonylation and lipid peroxidation. The magnitude of the responses suggested participation of non-targeted cells in the response. Furthermore, when the irradiated cell populations were subcultured in fresh medium shortly after irradiation, greater than expected increases in the levels of these markers were also observed during 24 h. Together, the results imply a rapidly propagated and persistent bystander effect. In situ analyses in confluent cultures showed 53BP1 foci formation, a marker of DNA damage, in more cells than expected based on the fraction of cells traversed through the nucleus by an iron or silicon ion. The effect was expressed as early as 15 min after exposure, peaked at 1 h and decreased by 24 h. A similar tendency occurred after exposure to a mean absorbed dose of 0.2 cGy of 3.7 MeV α particles, but not after 0.2 cGy of 290 MeV/u carbon ions.Analyses in dishes that incorporate a CR-39 solid state nuclear track detector bottom identified the cells irradiated with iron or silicon ions and further supported the participation of bystander cells in the stress response. Mechanistic studies indicated that gap junction intercellular communication, DNA repair, and oxidative metabolism participate in the propagation of the induced effects.We also considered the possible contribution of secondary particles produced along the primary particle tracks to the biological responses. Simulations with the FLUKA multi-particle transport code revealed that fragmentation products, other than electrons, in cells cultures exposed to HZE particles comprise <1 % of the absorbed dose. Further, the radial spread of dose due to secondary heavy ion fragments is confined to approximately 10-20 µm Thus, the latter are unlikely to significantly contribute to the stressful effects in cells not targeted by primary HZE particles.
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Winberg, Hanna, and Viktor Cortes. "I åskådarens sfär - Mellanstadielärares perspektiv på mobbning i skolmiljö." Thesis, Malmö universitet, Fakulteten för hälsa och samhälle (HS), 2018. http://urn.kb.se/resolve?urn=urn:nbn:se:mau:diva-25045.
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Detta examensarbete ämnar undersöka den roll och påverkan elever som är åskådare till mobbning i skolmiljö har, utifrån teorin The Bystander Effect. Utgångspunkten är mellanstadielärares berättelser om, erfarenheter och upplevelser av mobbning mellan elever med ett särskilt fokus på de som är åskådare. Med en kvalitativ ansats har semi-strukturerade intervjuer med sex lärare som undervisar i årskurs 4–6 genomförts.Studiens resultat tyder på att åskådare spelar en viktig roll vid mobbning mellan elever, både genom att förstärka och upprätthålla mobbningen, men också genom att avbryta denna när de väljer att ingripa och hjälpa offret. En rad olika faktorer sågs påverka den roll åskådare antog, som passiva eller ingripande, varav de viktigaste ansågs vara gruppen och omgivningens klimat och normer samt de olika konsekvenser som beskrevs åtfölja såväl mobbning som ingripande. Centralt var också de olika typer av kontroll lärare försökte utöva för att påverka mobbningen, genom att definiera den, lära och utbilda elever om mobbning samt att själva inneha det huvudsakliga ansvaret för att ingripa och stoppa mobbningen. Genomgående i informanternas berättelse återfanns de mekanismer som stärker eller hämmar The Bystander Effect och åskådares passivitet kontra aktiva ingripande.The purpose of this essay is to analyze the effect that bullying has on the observing party with reference to The Bystander Effect. We have chosen to use semi—structured interviews with six different elementary school teachers, grade 4 to 6, as basis for our analysis. In the interviews the teachers referred to experiences where they had personally witnessed bullying amongst students; focusing on details regarding the bystanders.The data collected from the interviews leads us to believe that bystanders play a role in both enforcing and interrupting bullying. Many factors were observed that affected the bystanders' reaction whether passive or intrusive. These included the social norms, social climate and perceived consequence of both bullying and various forms of interference. Another key factor was the teachers' methods to minimize bullying and their ability to do so. The different interviews highlighted certain mechanisms that strengthened or weakened The Bystander Effect.
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McConnell, Erin Christine. "Bystander Intervention to Prevent Campus Sexual Violence: the Role of Sense of Community, Peer Norms, and Administrative Responding." PDXScholar, 2018. https://pdxscholar.library.pdx.edu/open_access_etds/4554.
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In recent years, the use of bystander intervention training to address campus sexual violence has risen rapidly. More research is critically needed to guide the ongoing development and implementation of prevention efforts by campuses utilizing this relatively new approach. This investigation examined associations between college students' bystander intervention behavior and three key factors: (1) perceived peer norms supportive of sexual violence; (2) perceived campus administrative response to sexual violence; and (3) sense of campus community. Data from a sample of 2370 college students was analyzed using hierarchical linear regression to test both direct and moderated effects. Findings revealed that both peer norms supportive of sexual violence and perceptions of campus administrative response to sexual violence were significantly associated with bystander intervention. No significant direct or moderating effects related to sense of campus community were uncovered in this sample. Implications of this study include contributing to the current knowledge base about factors associated with bystander intervention behavior, and informing campus efforts to make bystander training programs more effective.
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Hanot, Maïté. "Irradiation par microfaisceau de particules alpha : Implication des espèces réactives de l'oxygène dans l'effet de voisinage." Phd thesis, Université Paris Sud - Paris XI, 2008. http://tel.archives-ouvertes.fr/tel-00429902.
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L'effet de voisinage radio-induit s'observe dans les cellules voisines de cellules irradiées mais non directement touchées par l'irradiation. A ce jour, les espèces réactives de l'oxygène (EROs) sont considérées comme ayant un rôle actif dans la survenue de réponse au voisinage, mais leur implication n'est pas encore totalement définie. Afin de déterminer leur impact dans la réponse au voisinage, à la fois temporellement et spatialement, des irradiations par microfaisceau de particules sont mises au point afin de cibler une fraction définie de cellules au niveau du noyau dans une culture cellulaire. Les irradiations sont pratiquées sur des cellules normales ostéoblastiques, à sous-confluence, nommées MC3T3-E1. L'observation directe de la génération d'EROs cellulaires et mitochondriales révèle que la réponse bystander est caractérisée par un stress cellulaire d'origine double et temporellement distinct. A court terme, la signalisation issue de la membrane induit une importante production d'EROs impliquée dans l'apparition de cassures double brin de l'ADN retardées. Les mitochondries produisant des EROs jusque 6 heures après l'irradiation semblent être impliquées dans un processus à long terme différent. L'étude indépendante de la réponse des cellules ciblées et voisines met en évidence un phénomène nouveau. L'effet de voisinage induit une réponse des cellules voisines mais est aussi impliqué dans une amplification de la réponse des cellules ciblées par l'irradiation. Ainsi toute cellule, irradiée ou non, peut recevoir ces signaux bystander et répondre. L'ensemble de cette étude mène à considérer les cultures cellulaires comme des réseaux complexes de communication; leurs réponses à l'irradiation indiquent une relation mêlée entre signaux relatifs à l'irradiation elle-même et réponse au voisinage. Cette complexité du phénomène d'effet de voisinage peut justifier que son incidence sur l'établissement de règles de radioprotection et sur la courbe linéaire sans seuil n'est pas encore clairement déterminée.
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Wedge, Marie-Ève. "Tailoring Oncolytic Viruses for the Treatment of Pancreatic Cancer." Thesis, Université d'Ottawa / University of Ottawa, 2020. http://hdl.handle.net/10393/40384.
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Pancreatic cancer (PC) is a highly aggressive disease with unmet therapeutic needs. Recent advances in the use of oncolytic viruses (OVs) as cancer therapeutic agents bring new hope to fight the notorious disease that is PC. Although OVs have shown promising results in certain cancers, some tumors remain resistant to OV therapy due to their inherent residual antiviral mechanisms. We hypothesized that the use of OV-encoded artificial microRNAs (amiRNAs) could help target the cellular antiviral components associated with the observed OV resistance and could also sensitize neighboring tumor cells to OV therapy and small molecule inhibitors through the secretion of amiRNA-containing extracellular vesicles (EVs) from infected cells. To find such amiRNAs, a viral surrogate library encoding ~16,000 unique amiRNAs was passaged in pancreatic cancer cell lines to enrich for sequences that could enhance OV replication. An amiRNA that improves PC cell killing when expressed from an OV was identified. Target identification of this amiRNA (amiR-4) revealed ARID1A as a key player in resistance to OV therapy in pancreatic cancers. This target is of particular interest, since its downregulation acts in a synthetic lethal fashion with inhibition of the EZH2 methyltransferase. Combining VSV51-amiR-4 with a small molecule inhibitor of EZH2 enhances PC cell death. Moreover, amiR-4 is packaged in cancer cell-secreted EVs which can reach neighboring naïve cells to sensitize them to EZH2 inhibition-mediated cell death and to spread the OV-mediated tumor killing effect throughout the tumor. This data translates into tumor debulking and survival in animal models of highly aggressive PC. This work not only broadens our knowledge on the resistance of select tumors to oncolytic virotherapy and the EV-mediated bystander killing effect in OV-infected tumors, but it also establishes OVs as a novel tool to produce anti-cancer therapeutic EVs in situ to improve therapeutic gain. Ultimately, our work provides new hope for a cure to the grim disease that is PC.
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Yamamoto, Noriyuki, Yasushi Hayashi, Hideaki Kagami, Takafumi Fukui, Hirokazu Fukuhara, Iwai Tohnai, Minoru Ueda, Masaaki Mizuno, and Jun Yoshida. "Suicide gene therapy using adenovirus vector for human oral squamous carcinoma cell line In vitro." Nagoya University School of Medicine, 2005. http://hdl.handle.net/2237/5408.
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Touraine, Renaud Laurian. "L'effet de proximité ("bystander effect") dans le système suicide Thymidine kinase/Ganciclovir de thérapie génique : implication de la communication jonctionnelle intercellulaire." Lyon 1, 1999. http://www.theses.fr/1999LYO1T011.
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Marshall, Heather D. "Sensitization of CD8 T Cells During Acute Viral Infections Impacts Bystander and Latecomer CD8 T Cell Responses : A Dissertation." eScholarship@UMMS, 2009. https://escholarship.umassmed.edu/gsbs_diss/440.
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Many virus infections induce a transient state of immune suppression in the infected host. Virus-induced T cell suppression can be caused by T cell activation-induced cell death (AICD), dendritic cell (DC) apoptosis, DC dysfunction, and/or the enhanced expression of immune-suppressive cytokines. It has been previously demonstrated that naïve bystander CD8 T cells derived from hosts experiencing an acute virus-specific T cell response underwent AICD when polyclonally activated by anti-CD3 in vitro (Zarozinski et al., 2000). Susceptibility of naïve bystander T cells to AICD could prevent the development of a new T cell response during an ongoing immune response, and thus render infected hosts immune suppressed. Although immune suppression could result in an enhanced susceptibility to superinfections, virus-infected individuals are more commonly resistant to superinfecting pathogens. Because of these seemingly contradictory conditions, we sought to investigate how acute viral infections impact naïve bystander CD8 T cells in vivo. More specifically, we asked whether bystander CD8 T cells are susceptible to immune suppression or whether they can contribute to the resistance to superinfections. In order to address this, we examined the responses of bystander CD8 T cells activated with cognate antigen during acute viral infections in vivo. We generated several in vivomodels using P14 (LCMV glycoprotein-specific), HY (male antigen-specific), and OT-I (ovalbumin-specific) transgenic CD8 T cells, which we defined as bystander during acute infections with lymphocytic choriomeningitis virus (LCMV), Pichinde virus (PV), vaccinia virus (VV), and murine cytomegalovirus (MCMV).
Consistent with the enhanced susceptibility to cell death noted in vitro, we found that bystander CD8 T cells activated with cognate antigen in vivo during acute viral infections underwent markedly reduced proliferation. Virus-induced transient T cell suppression in vivo was not exclusively mediated by Fas-FasL- or TNF-induced AICD or due to an enhanced susceptibility to apoptosis. Instead, immune suppression in vivowas associated with a delayed onset of division, which we found not to be due to a defect in antigen presentation, but rather due to a T cell intrinsic defect.
Despite the suppressed proliferation of TCR-stimulated bystander CD8 T cells in vivo, we found an enhancement of the effector functions exerted by bystander CD8 T cells activated during acute viral infections. During acute viral infections or after stimulation with type 1 IFN (IFN-αβ) inducers, some bystander CD8 T cells were sensitized to immediately exert effector functions such as IFN-γ production and degranulation upon stimulation with high affinity cognate antigen. Sensitization of naïve CD8 T cells required self-MHC I and indirect effects of IFN-αβ, while IL-12, IL-18, and IFN-γ were not individually required. IL-15 was not required for the rapid expression of IFN-γ, but was required for up-regulation of granzyme B (GrzB). P14 and OT-I CD8 T cells, which are capable of homeostatic proliferation, could be sensitized by poly(I:C), but HY CD8 T cells, which are poor at homeostatic proliferation, could not, suggesting that the requirement for MHC I may be to present low affinity cryptically cross-reactive self antigens. Sensitized naive CD8 T cells up-regulated the t-box transcription factor Eomesodermin (Eomes), which can regulate these rapid effector functions.
In conclusion, we demonstrate in this thesis that acute viral infections impact naïve bystander CD8 T cells such that their response to cognate antigen is altered. Prior to cognate antigen engagement, bystander CD8 T cells up-regulated Eomes, CD122, and GrzB. Following cognate antigen engagement, bystander CD8 T cells rapidly degranulated and expressed the effector cytokine IFN-γ. The ability of bystander CD8 T cells to rapidly exert effector functions may contribute to the resistance of virus-infected individuals to superinfections. Despite these rapid effector functions, the proliferation of TCR-stimulated bystander CD8 T cells was markedly inhibited. This reduced proliferation was found not to be a defect in antigen presentation, but was a T cell intrinsic defect in initiating division. Thus, bystander CD8 T cells were also susceptible to virus-induced immune suppression.
It is also likely that virus-specific CD8 T cells that are not activated until later in the response, so-called latecomer CD8 T cells, may also be susceptible to immune enhancement and suppression. Thus, latecomer CD8 T cells would be able to rapidly exert effector functions at the expense of proliferation. Taken together, we propose that during an immune response, due to spatial and temporal gradients of antigen and inflammation, it is likely that a combination of heterogeneous T cells with different signal strengths and sequences of exposure from cytokines and peptide-MHC constitute the total T cell response to pathogens.
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Thomas, Audrey. "Effet sur le microenvironnement tumoral d’une modulation pharmacologique du stress oxydant." Thesis, Paris 5, 2012. http://www.theses.fr/2012PA05T086/document.
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Les Formes réactives de l’oxygène (FRO) ont un rôle bien établi dans l’oncogénèse en augmentant les capacités de prolifération et d’invasion des cellules tumorales. Mais les FRO exercent aussi un effet important sur le microenvironnement tumoral, en particulier en participant à l’échappement des tumeurs au système immunitaire. Une modulation pharmacologique de l’équilibre oxydo-réductif tumoral est donc susceptible d’influencer la progression tumorale. Il a été montré que l’induction pharmacologique d’un stress oxydant dans les cellules tumorales peut induire un effet cytotoxique mais ses effets sur le microenvironnement sont moins bien connus. L’objectif de nos travaux était d’étudier l’effet d’une modulation du stress oxydant sur les cellules immunitaires du microenvironnement tumoral et in fine de préciser les conséquences potentielles sur la progression tumorale. L’arsenic trioxyde (As2O3), inducteur de FRO, présentait à faible dose, dénuée d’effet cytotoxique direct sur les cellules malignes, un effet antitumoral dans un modèle de cancer colique murin. Cet effet était lié à une déplétion sélective en lymphocytes T régulateurs (Tregs) et était médié par la génération d’anions superoxyde (O2°-) et de monoxyde d’azote (NO), eux même responsables de la formation de peroxynitrite. Les Tregs présentaient un niveau basal de FRO plus élevé que les autres populations lymphocytaires, qui pourrait expliquer leur plus grande sensibilité à un surcroît de stress oxydant induit par l’As2O3. Un cytotoxique antitumoral, la vinorelbine, s’est également montré capable d’exercer un effet sur le microenvironnement tumoral. Par co-cultures, nous avons montré que la vinorelbine induisait un effet bystander toxique sur les cellules immunitaires effectrices voisines des cellules tumorales. In vivo, le prétraitement par vinorelbine de cellules malignes implantées à la souris était responsable d’une perte de la réactivité anti-tumorale des cellules mono-nuclées. Cet effet était dépendant de la production d’O2°- et de NO par les cellules malignes. Un modulateur du stress oxydant, le mangafodipir, inhibait cet effet, permettant ainsi de restaurer la réponse immunitaire antitumorale locale. Notre travail a donc permis de mettre en évidence que des modulateurs du stress oxydant peuvent agir sur le microenvironnement, et spécialement sur les cellules immunitaires. Ils pourraient être utilisés en clinique pour restaurer la réponse immunitaire antitumorale. Une meilleure compréhension du rôle du stress oxydant dans la défaillance de l’immunité antitumorale est nécessaireSeveral reports have demonstrated the involvement of reactive oxygen species (ROS) in carcinogenesis, through promotion of cancer cell proliferation and invasion. But ROS could also have consequences on non cancerous cells which are part of the tumor microenvironment, such as immune cells. Therefore, a pharmacological modulation of oxidative stress can induce a cytotoxic effect on tumor cells but its consequences on microenvironment are unknown. The aim of our studies was to evaluate the effects of a pharmacological modulation of oxidative stress on immune cells from the tumor microenvironment. At low dose, Arsenic trioxide (As203), an oxidative stress modulator, was shown to exert antitumor effects in colon tumor-bearing mice. We observed that this effect was related to As203-induced regulatory T cells (Tregs) -selective depletion in vitro and in vivo and was mediated by oxidative and nitrosative bursts. The differential effect of As203 on Tregs versus other CD4 cells was related to difference in the cells’redox status. We also observed that vinorelbine, an anticancer agent, could interfere with the antitumor immune response. We showed that vinorelbine could alter the function of immune cells surrounding tumor cells by a bystander toxic effect against tumor effector cells. In vivo experiment in A549 tumor bearing nude mice showed that adoptive transfer of A549 immune splenocytes was not able to delay tumor growth when vinorelbine-pretreated A549 cells were used for immunization. This effect was mediated by ROS and was inhibited by an oxidative stress modulator, mangafodipir, which restored antitumor immune function. Therefore, our work showed that oxidative stress modulators can influence tumor microenvironment and more specifically, immune cells. They could be used to restore antitumor immune response
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Loui, Kenny. "Stand By Me: The Effects of a Police Anti-Bullying Presentation on South Korean High School Students' Attitudes About Bullying and Willingness to Intervene." NSUWorks, 2017. http://nsuworks.nova.edu/cahss_jhs_etd/5.
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Upon assuming the presidency of the Republic of Korea in 2013, Park Geun-hye announced her administration’s priority to address the country’s “Four Social Evils”—sexual violence, domestic violence, school bullying, and unsafe food products. As part of this initiative, the ROK national government urged police officers to implement anti-bullying campaigns and curb school violence. This study examined the effects of Stand By Me: Bullying Prevention and Bystander Empowerment, an anti-bullying presentation conducted by a ROK police officer for an audience of South Korean high school students in spring 2016. The study employed a nonequivalent groups design with a designated treatment group and comparison group, but was limited to a posttest survey only. The focus of the study was whether a police-administered bullying prevention presentation had an effect on Korean high school students’ attitudes toward bullying and their willingness to intervene to stop bullying, and was examined using independent-samples t tests and Mann-Whitney U tests. The relationship between moral approval of bullying and bystander intervention willingness was also examined, as well as the relationships between other key variables and bystander intervention willingness. These relationships were examined via regression analysis. The study yielded statistically significant findings indicating that students who were administered the Stand By Me presentation were less likely to support bullying and more likely to be willing to intervene in bullying incidents compared to students who did not participate in the presentation. Moral approval of bullying had only a minor impact on bystander intervention willingness, whereas perceived peer support, self-esteem, and informal social control had a greater influence on students’ inclination to intervene. Due to the limited scope of this project, it is recommended that future studies and evaluations conducted on Stand By Me and other anti-bullying programs in South Korea utilize more rigorous research designs that incorporate pretesting and random assignment. Nevertheless, given the paucity of empirical research on police anti-bullying initiatives in the ROK, one of the overarching goals of this study is to encourage further dialogue on preventing bullying, one of the endemic ‘social evils’ plaguing today’s youth, in South Korea and around the world, and the appropriate role of law enforcement in this arena.
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長谷川, 好規, 和良 今泉, 憲生 高木, 博史 下元, 和久 岩田, 篤. 渡辺, 英雄 坂, and 薫. 下方. "薬剤感受性遺伝子導入による肺癌遺伝子治療へのアプローチ : Bystander Effectの検討." 日本肺癌学会, 1994. http://hdl.handle.net/2237/11052.
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David, Taynah Ibrahim Picolo. "Construção e caracterização de vetores adenovirais portadores do cDNA para interferon-beta humano." Universidade de São Paulo, 2017. http://www.teses.usp.br/teses/disponiveis/5/5155/tde-11052017-142613/.
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O melanoma representa menos de 5% de todos os cânceres de pele, porém, quando em estádio metastático possui prognóstico ruim. Entretanto, o genótipo dos melanomas pode prover uma oportunidade para intervenção terapêutica pelo fato de 90% dos casos de melanoma possuem p53 selvagem e grande parte destes possuem deleção na região cromossômica codificadora de interferon beta. Em prévios estudos, desenvolvemos o vetor adenoviral AdRGD-PG que fornece expressão do transgene em resposta à p53 através do promotor PG e ainda o tripeptídeo RGD, que possibilita que o adenovírus transduza uma maior gama de células pela alteração de seu mecanismo de entrada. Temos utilizado este vetor para entrega da versão murina de interferon beta em modelos de terapia gênica e imunoterapia de melanoma murino, revelando uma significativa habilidade do interferon beta em inibir a proliferação celular in vitro e in vivo e promover resposta imune antitumoral. No presente trabalho, os esforços se aplicam em adaptar essa estratégia em modelo de melanoma humano para observar se a mesma interação é encontrada. O vetor AdRGD-PGhIbeta, portador do cDNA de interferon beta humano (hIbeta) foi construído e expressão do transgene observada após transdução das linhagens estabelecidas de melanoma humano SK-MEL-05 e SK-MEL-147 (ambas p53 selvagem). Foi observado um robusto efeito antitumoral in vitro onde transferência de hIbeta promoveu acumulo de células hipodiploides (mais que 80% da população celular 96 horas após transdução) e evidências de morte por apoptose (exposição de fosfatidilserina e atividade de caspases 3/7) em ambas as linhagens. Nas duas linhagens, o efeito bystander foi demonstrado quando a presença de poucas células transduzidas (ex., 10%) foi suficiente para promover o acumulo significativo de células hipodiploides (mais que 40% neste exemplo). Em modelo de terapia gênica in situ utilizando células SK-MEL-147, também foi observado forte efeito antitumoral da hIbeta com total remissão do tumor de todos os animais tratados sem recidiva durante noventa dias. A presença de hIbeta na circulação dos animais foi confirmada 48h após o tratamento com AdRGD-PG hbeta mas presente em somente dois de sete animais 90 dias após o tratamento, sugerindo que o tratamento inicial e não um efeito off target foi responsável pela resposta. Com a finalidade de investigar efeitos colaterais do sequestro do vetor adenoviral pelo fígado, observamos a concentração circulante das enzimas aminotransferase de aspartate e aminotransferase de alanine (AST e ALT, respectivamente), que se mostrou não alterada quando comparadas entre animais que receberam injeção do vetor tratamento, vetor controle e solução salina. Com nossos resultados concluímos que vetores adenovirais carreando interferon-beta humano são capazes de transduzir a linhagem de melanoma SK-MEL-147 in vitro e in vivo, promovendo efeito bystander e remissão tumoral sem indução de efeitos adversosMelanoma represents less than 5% of all cases of skin cancer, although, when metastatic, prognosis is dire. However, the genotype of melanomas might provide an opportunity for therapeutic intervention since 90% of melanoma cases possess wild-type p53 and a great portion of these possess deletion of the chromosomal region encoding interferon beta. In previous studies, we developed the adenoviral vector AdRGD-PG that supplies expression of the transgene in response to p53 through the PG promoter and that utilizes the RGD tripeptide, allowing the adenovirus to transduce a wider range of cells due to the alterated mechanism of entrance. We have used this vector to deliver the murine version of interferon beta in murine models of melanoma gene therapy and immunotherapy, revealing a significant ability of interferon beta to inhibit cellular proliferation in vitro and in vivo and promote an anti-tumor immune response. In the present project, we aimed to adapt this strategy for a human melanoma model in order to reveal if the same impact will be observed. The AdRGD-PGhIbeta vector encoding the human interferon beta (hIbeta) cDNA was constructed and expression of the transgene confirmed after transduction of the established human melanoma cell lines SK-MEL-05 and SK-MEL-147 (both wild-type p53). A striking anti-tumor effect was observed in vitro where the transfer of hIbeta promoted an accumulation of hypodiploid cells (over 80% of the cellular population 96 hours after transduction) and evidence of death by apoptosis (exposure of phosphatidylserine and activity of caspases 3/7) in both cell lines. In these cell lines, a bystander effect was demonstrated when the presence of few transduced cells (ex., 10%) was enough to promote significant accumulation of hypodiploid cells (over 40% in this example). In a model of in situ gene therapy using SK-MEL-147 cells, hIbeta induced a strong anti-tumor effect including total tumor remission in all treated animals without relapse during ninety days. The presence of hIbeta in the circulation of the animals was confirmed 48h after treatment with AdRGD-PGhIbeta, but was present in only two of the seven animals 90 days post-treatment, suggesting that the initial treatment, not off target effects, was responsible for the response. With the goal of investigating collateral effects of adenoviral sequestration by the liver, we assayed the circulating concentration of aspartate aminotransferase and alanine aminotransferase (AST and ALT, respectively), which showed no alteration when compared with animals that received the treatment with a control vector or saline solution. We conclude that our adenoviral vector carrying human interferon-beta is capable of transducing the human melanoma cell line SK-MEL-147 in vitro and in vivo, promoting a bystander effect and tumor remission without inducing adverse effects
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Fisher, Mark. "Intra and extracellular responses to DNA damage." Thesis, Queensland University of Technology, 2021. https://eprints.qut.edu.au/214106/1/Mark_Fisher_Thesis.pdf.
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Tapper, Amanda, and Madelene Olsson. "Våld i nära relationer : En kvantitativ utvärderingsstudie av projektet "Våga Hjälpa!"." Thesis, Högskolan Dalarna, Socialt arbete, 2016. http://urn.kb.se/resolve?urn=urn:nbn:se:du-20984.
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Victims of domestic violence (DV) are growing, still the number of cases reported isn't. In Rättvik only half the amount of cases are reported compared to two years ago. Rättvik is working to reduce DV by starting the project "Våga Hjälpa!". The purpose of this study was to use a quantitative approach to examine if the project is known in Rättvik. The study's based on a survey with a 27% response rate. The analysis was made by SPSS and interpreted on the basis of conformity, the bystander effect and the Theory of Planned Behaviour. Results show that the majority haven't been in contact with DV and that the knowledge of how to act is evenly spread. The study concludes with an objective evalution of "Våga Hjälpa!" where our study results are related to the project objectives. The evaluation partly shows a fullfilled result but also some improvement opportunities.Allt fler blir offer för våld i nära relationer, trots detta ökar inte anmälda relationsvåldsbrott. I Rättviks kommun ser man idag en halvering av anmälda våldsbrott i jämförelse med två år tillbaka. Kommunen arbetar aktivt för att minska relationsvåldsbrott och har startat projektet "Våga hjälpa!". Syftet med denna studie var att med en kvantitativ ansats undersöka i vilken utsträckning projektet "Våga Hjälpa!" är känt bland Rättviks invånare. Studien bygger på en enkätundersökning med en svarsfrekvens på 27%. Analysen av materialet har gjorts genom SPSS för att sedan tolkas utifrån konformitet, åskådareffekten samt Theory of Planned Behaviour. Resultatet av studien visar att majoriteten av respondenterna inte kommit i kontakt med relationsvåld samt en jämn spridning avseende kunskap om hur man ska agera. Studien avslutas med en målutvärdering av "Våga Hjälpa!" där resultatet av vår studie relateras till projektets mål. Denna utvärdering påvisar delvis ett uppfyllt resultat men även vissa förbättringsmöjligheter.
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Murphy, Megan J. "Sexual Assault-specific Bystander Behavior: Accounting for Opportunity in a Prospective Analysis of the Effects of Individual, Social Norms, and Situational Variables." Ohio University / OhioLINK, 2014. http://rave.ohiolink.edu/etdc/view?acc_num=ohiou1389008840.
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Zerweck, Alf. "Bystander-Effekt des Peroxynitrit und der toxische Effekt von Cu(II)-SOD." [S.l.] : [s.n.], 2002. http://www.freidok.uni-freiburg.de/volltexte/579.
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Whiteside, James Roy. "Persistent genomic instability and bystander effects induced by ultraviolet radiation." Thesis, Lancaster University, 2006. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.444640.
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Ladjohounlou, Riad. "Contribution des effets ciblés et non ciblés en radioimmunothérapie alpha et Auger de carcinoses péritonéales." Thesis, Montpellier, 2016. http://www.theses.fr/2016MONTT037/document.
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L’efficacité d’une radioimmunothérapie (RIT) peut impliquer la coexistence des effets ciblés et des effets dit « non ciblés ». Les effets ciblés regroupent les effets biologiques observés dans les cellules ou tissus traversés par les particules ionisantes alors que les effets non-ciblés (ou bystander) sont observés dans des cellules qui n’ont pas été irradiées mais qui sont au proche voisinage des cellules exposées. Nous avons au cours de cette étude évalué in vitro et in vivo, la contribution des effets ciblés et non ciblés dans l’efficacité obtenue lors de la RIT alpha (212Pb, 213Bi) et de la RIT Auger (125I). Les effets ciblés ont été mesurés in vitro sur les cellules irradiées (cellules donneuses) alors que les effets bystander sont mesurés sur les cellules non irradiées (cellules receveuses) par une méthode de transfert de milieu. Elle consiste, à traiter les cellules receveuses dans un milieu de culture pré-incubé pendant 2h avec les cellules donneuses. Nos résultats montrent que la contribution des effets ciblés est nettement plus importante qu’en RIT alpha qu’Auger. En RIT alpha, on observe que les lésions de l’ADN (foci 53BP1et γ-H2AX) pourraient être différenciées en lésions complexes (sites multilésés = observation de gros foci) ou simples lésions (petit foci). Par contre en RIT Auger, ce sont les effets non ciblés qui prédominent sur les effets ciblés. L’utilisation d’inhibiteurs pharmacologiques des ROS montre l’implication du stress oxydatif dans ces effets non ciblés observés en RIT alpha et Auger. Ces effets non ciblés ont été observés également in vivo sur des souris athymiques porteuses de carcinoses péritonéales de petites tailles ; démontrant ainsi leur contribution dans l’efficacité thérapeutique finale observée après la RIT alpha et Auger. L’ensemble de ces résultats indiquent que même si des lésions de l’ADN sont produites après irradiation, que les effets non ciblés pourraient aussi contribuer à l’efficacité thérapeutique finale observée avec les anticorps couplés aux émetteurs de particules alpha ou d’électrons Auger. Ces résultats sont particulièrement intéressants pour la thérapie ciblée car les vecteurs utilisés n’ont pas souvent accès à l’ensemble des cellules constituant la tumeurWe investigated in vitro and in vivo the relative contribution of targeted and non-targeted effects in the therapeutic efficacy against tumors of antibodies radiolabeled with alpha particle (212Pb, 213Bi) or Auger electron (125I) emitters. Targeted effects occurs in cells directly crossed by ionising particles while non-targeted effects are measured in cells neighbouring irradiated cells. Targeted effects were measured in vitro in cells exposed to antibodies radiolabeled with alpha or Auger emitters (donor cells) while non-targeted effects were investigated in recipient cells. Recipient cells consisted of cells not exposed to radiolabeled-mAbs, but grown in medium previously incubated for 2h with donor cells. We showed that the relative contribution of targeted effects versus non-targeted effects was higher during alpha RIT than Auger RIT. Alpha particles produced 53BP1 and gamma-H2AX foci in donor cells that could be differentiated in large, medium and small foci, while only small foci were observed in recipient cells. We assumed that large foci would correspond to locally multiply damage sites in DNA. Conversely, Auger RIT led predominantly to non-targeted effects compared with targeted effects. Use of radical scavengers showed that oxidative stress was involved in non-targeted effects. In vivo, we showed in athymic nude mice bearing tumor xenograft that non-targeted effects were also involved and participated to therapeutic efficacy of radiolabeled antibodies. These results indicate that although producing single DNA lesion, non-targeted effects can contribute to the therapeutic efficacy of mAbs radiolabeled with alpha particle or Auger electron emitters. These findings are particularly relevant for targeted therapy in which vectors cannot gain access to every tumor cell
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Blyth, Benjamin John, and benjamin blyth@flinders edu au. "Development and use of an adoptive transfer method for detecting radiation-induced bystander effects in vivo." Flinders University. School of Medicine, 2009. http://catalogue.flinders.edu.au./local/adt/public/adt-SFU20091008.150317.
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Ionising radiation can cause damage to DNA that can result in gene mutations contributing to carcinogenesis. Radiation-protection policy currently estimates cancer risks from exposures to radiation in terms of excess risk per unit dose. At very low radiation dose-rates, where not all cells are absorbing radiation energy, this formula carries the inherent assumption that risk is limited to those cells receiving direct energy depositions. Numerous studies have now called this assumption into question. Such low dose-rates are in the relevant range that the public receives from natural background and man-made sources, and, if this fundamental assumption proves unfounded, current estimations of radiation-induced cancer risk at low doses will be incorrect. Accurate predictions of stochastic cancer risks from low-dose radiation exposures are crucial to evaluating the safety of radiation-based technologies for industry, power generation and the increasing use of radiation for medical diagnostic and screening purposes.
This thesis explores phenomena known as radiation-induced bystander effects. The term bystander effects, as used here, describes biological responses to ionising radiation (hitherto observed in vitro) in cells not directly traversed by an ionising track, due to intercellular signals received from neighbouring cells that did receive energy depositions. This study aimed to determine whether radiation effects are communicated between irradiated and unirradiated cells in vivo, and if so, whether this effect alters current estimations of cancer risk following low-dose radiation exposures. In order to answer these questions, an in vivo experimental system for studying bystander effects in mice was developed. The method was based on the adoptive transfer of irradiated splenocytes into unirradiated hosts with simultaneous identification of irradiated donor cells, and biological endpoints in unirradiated bystander cells in situ using fluorescence microscopy and image analysis.
Splenocytes from donor mice were radiolabelled with 3H-thymidine or received an acute X-ray dose. The irradiated donor cells, labelled with a fluorescent probe, were then adoptively transferred into unirradiated recipient mice via the tail vein, whilst control mice received sham-irradiated donor cells. A proportion of the cells lodged in the recipient mouse spleens where they remained for a period before the tissues were cryopreserved. The locations of donor cells were identified in frozen spleen sections by the fluorescent probe, and the levels of apoptosis and proliferation were simultaneously evaluated in situ in the surrounding unirradiated bystander cells using fluorescence-based assays. Transgenic pKZ1 recipient mice were also used to quantify chromosomal inversions in bystander cells. Since three-dimensional spatial relationships were preserved, responses could be measured in the local area surrounding irradiated cells as well as further afield. Following the development of the irradiated-cell adoptive transfer protocol and validation of the sensitivity and reproducibility of the biological assays in situ, a series of experiments was performed. In the initial experiments, 500,000 radiolabelled cells (0.33 mBq.cell-1) were injected into recipient mice and the spleen tissues were isolated 22 h later. No changes in apoptosis or proliferation were detected in local bystander spleen cells or throughout the spleen, compared to mice receiving sham-radiolabelled donor cells. In subsequent experiments, the effects of a number of experimental conditions were explored including the injection of tenfold more donor cells, analysis of spleen tissues after three days lodging in vivo, radiolabelling of donor cells with 100-fold higher 3H dose-rate and irradiation of donor cells ex vivo with 0.1 or 1 Gy X-rays. In each case, no changes in apoptosis or proliferation were observed.
The in vivo method described here was designed to simulate the conditions of a bystander scenario from low dose-rate exposures relevant to public radiation protection. Contrary to the many reports of bystander effects in vitro, experiments using this sensitive method for examining the in vivo responses of unirradiated cells to neighbouring low-dose irradiated cells, have so far shown no changes in bystander cells in the spleen. This adoptive transfer method is the first in vivo method for examining the effects of known irradiated cells exposed to low radiation doses at low dose-rates, on neighbouring cells in situ that are truly unirradiated. Both the irradiated and bystander cells are normal, non-transformed primary spleen cells functioning in their natural environment. This in vivo experimental system allows the examination of tens of thousands of bystander cells and has shown a remarkable sensitivity, with statistical power to rule out changes in apoptosis <10% from the control.
The relevance of in vitro bystander findings is unclear. Many reported bystander effects are more analogous to the systemic communication of abscopal effects from highly irradiated tissues. Disagreement between experimental systems and difficulty in reproducing key results between laboratories further complicate the translation of bystander data in vitro to human risk-estimation. The radiation protection community has expressed its need for in vivo validation of the bystander phenomenon before it can be included into the appraisal of carcinogenic risk. This adoptive transfer method is now available to study a range of bystander endpoints and potential signalling mechanisms in vivo, and provides a way to translate the wealth of data previously collected in vitro into findings directly relevant to human risk-estimation.
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Lagnado, Anthony Benjamin Sylvain. "The role of neutrophils in telomere induced senescence via bystander effects." Thesis, University of Newcastle upon Tyne, 2017. http://hdl.handle.net/10443/3901.
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Senescence is classically defined as a state of permanent cell-cycle arrest. Senescence can occur in response to various stresses, which have been shown to act mainly through the activation of a DNA damage response (DDR). Senescence is characterised not solely by a cell-cycle arrest but also by increased production of Reactive Oxygen Species (ROS) and the development of a Senescence-Associated Secretory Phenotype (SASP). SASP components include growth factors, cytokines, chemokines and immune modulators and have been shown to contribute to senescence in an autocrine manner but also impact on the tissue microenvironment trough paracrine effects. Several studies have linked the SASP with immune surveillance suggesting that Natural Killer cells, monocytes and T lymphocytes CD4+ can effectively eliminate senescent cells. However, the interaction between neutrophils (the first innate immune responders to infection or injury) and cellular senescence has not yet been investigated. In this thesis, I have shown that neutrophils induce premature senescence in human fibroblasts in a telomere-dependent manner. My data indicates that hydrogen peroxide released by neutrophils damages telomeric DNA, thereby accelerating the rate of telomere shortening and contributing to the early onset of senescence. Consistently, pre-treatment with the antioxidant enzyme catalase, prevents neutrophil-induced telomere shortening and premature senescence. In addition, overexpression of the catalytic subunit of telomerase (hTERT), which maintains telomere length in cultured fibroblasts, is able to bypass neutrophil-induced premature senescence. In accordance with my in vitro results, I have shown that following acute liver injury (using CCl4) which is characterised by neutrophil infiltration, mouse hepatocytes show increased markers of telomere dysfunction, which can be prevented by neutralisation of neutrophils. Importantly, I have found that during the ageing process or after injection with lipopolysaccharide (LPS), mouse livers experience increased neutrophil infiltrations which positively correlate with markers of telomere-dysfunction. Finally, I have shown that senescent cells secrete factors which act as a neutrophil chemoattractant and that neutrophils preferentially induce cell-death in senescent cells but not young cells. These data suggest for the first time that neutrophils play an important role in the immune clearance of senescent cells. viii Altogether, my data propose that neutrophils act as a double-edged sword: on one hand, they can induce senescence by accelerating telomere shortening; on the other hand, they can be recruited to sites where senescent cells are present and accelerate their specific clearance.
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Benouchan, Malika. "Développement d'approches in vitro et in vivo, pour le ciblage de l'angiogenèse tumorale par thérapie génique à l'aide du gène suicide codant pour la nitroreductase d'Escherichia Coli." Paris 13, 2005. http://www.theses.fr/2005PA132031.
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La thérapie anti-angiogénique représente une stratégie pertinente pour le ciblage indirect des tumeurs. La stratégie des gènes suicides, utilisée dans nos travaux, associe le gène codant pour la nitroreductase d'Escherichia Coli (ntr) à une pro-drogue, le dinitrobenzamide CB1954. Cette pro-drogue sera métabolisée par l'enzyme NTR et des co-facteurs cellulaires, en un composé hautement cytotoxique. Une particularité de ce système est l'existence d'un effet de proximité ou effet bystander, qui va permettre une propagation des effets toxiques de la pro-drogue aux cellules environnantes non transfectées. L'ensemble de nos résultats démontre l'efficacité du système ntr/CB1954 pour induire un effet cytotoxique sur les cellules endothéliales in vitro. Nous avons pu également mettre en évidence le mode d'action du système, qui induit une apotose. Enfin, les résultats obtenus sur des cultures en trois dimensions nous suggèrent l'intervention d'un effet bystander, à travers la diffusion de la toxicité à partir des cellules endothétiales transfectées vers les cellules tumorales non transfectées suite au traitement par le CB1954. Dans la seconde partie de nos travaux, nous avons pu isoler deux clones celluleires ntr+ et démontrer la sensibilité de ces clones in vitro pour de la pro-drogue. Puis nous avons testé le clone qui a montré la plus grande sensibilité in vitro, sur des souris nude. Nous avons constaté une efficacité de la pro-drogue in vivo qui agit soit en augmentant la survie des souris lorsque les cellules ntr+ sont co-injectées avec des cellules de mélanome murin, B16-F10, soit en diminuant la croissance des tumeurs lorsque ces cellules sont injectées par voie intratumorale dans des souris porteuses de mélanomes. L'ensemble de ces résultats montre l'efficacité de la stratégie des gènes suicides et plus particulièrement du système ntr/CB1954 pour le ciblage des cellules endothéliales afin d'induire la destruction des cellules tumorales grâce à la diffusion d'un effet bystanderThe anti-angiogegenic therapy represents a relevant strategy for the indiect targeting of the tumors. The strategy of the suicides genes, used in our work, associates the gene coding for the nitroreductase of Escherichia Coli (ntr) with a pro-drug, the CB1954 dinitrobenzamide. This pro-drug will be metabolized by the enzyme NTR and the cellular co-factors, into a highly cytotoxic compound. A characteristic of this system is the existence of a bystander effect, which will allow a propagation of the toxic effects of the pro-drug to the non transfected surounding cells. Our results show the effectiveness of the ntr/CB1954 system to induce a cytotoxic effect on the endothelial cells in vitro. We also could highlight the mode of action of the system, which induces an apoptosis. Lastly, the results obtenained on three dimentional cultures suggest us the intervention of a bystander effect, through the diffusion of toxicity from ntr+ endothelial cells to the ntr+ tumor cells following the treatment by CB1954. In the second part of our work, we have isolated two ntr+ clones and showed the sensivity of these clones in vitro for the pro-drug. Then, we tested the clone showing the geatest in vito sensitivity, on nude mice. We noted an effectiveness of the pro-drug in vivo which acts by increasing the survival of the mice when the cells ntr+ are co-injected with the cells of murine melanoma, B16-F10, by decreasing the growth of the tumors when these cells are injected intratumoraly in mice carrying melanoma. These results shows the effectiveness of the strategy of the suicide genes and more particularly of the ntr/CB1954 system for thetargeting of the endothelial cells in order to induce the destruction of the tumor cells thanks to the diffusion of a bystander effect
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Anzenberg, Vered. "LET dependence of radiation-induced bystander effects using human prostate tumor cells." Thesis, Massachusetts Institute of Technology, 2008. http://hdl.handle.net/1721.1/44795.
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Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Nuclear Science and Engineering, 2008."June 2008."
Includes bibliographical references (leaves 133-140).
In the past fifteen years, evidence provided by many independent research groups have indicated higher numbers of cells exhibiting damage than expected based on the number of cells traversed by the radiation. This phenomenon has been coined as the "bystander effect". The purpose of this study was to characterize the ability of irradiated tumor cells to induce bystander effects in co-cultured cells. Human DU-145 prostate carcinoma cells were grown on a 1.4 [mu]m-thick mylar membrane in specially constructed cell culture dishes for irradiation with alpha particles (average energy 3.14 MeV) from a 241Am source, or in 6-well plates for irradiation with 250 kVp x-rays at 25°C. In parallel experiments, the tumor cells were incubated at 4°C for one hour prior to irradiation and irradiated on ice to test the nature of the bystander signal. Bystander cells were placed into the medium above the irradiated DU-145 and were co-incubated for a length of time. The bystander effect endpoints measured in either DU-145 tumor cells or in normal primary AGO1522 fibroblasts were micronucleus (MN) formation, [gamma]-H2AX double strand break repair foci, and survival fraction. A 1.5-2.0-fold increase in MN formation was observed in both DU-145 and AG01522 bystander cells after either alpha particle or xray irradiation of the DU-145 target cells. A 1.5-fold [gamma]-H2AX bystander increase and a survival fraction reduction to 80% were only detected in AGO1522 cells, and only after xray irradiation of target DU-145 cells. Alpha particle irradiation of the target DU-145 cells produced neither [gamma]-H2AX foci nor survival fraction bystander effect in either cell line. Lowering the temperature to 4°C during the irradiation of the DU-145 tumor cells, with either x-rays or alpha particles, eliminated both the MN formation and the decreased survival fraction bystander effects in the co-cultured AG01522 fibroblasts.
(cont.) This study demonstrates that biochemical processes in the directly-irradiated tumor cells are required for initiation of the signaling process. Low temperature during the irradiation inhibited the initiation of a bystander signal. There are also LET-dependent differences in the signal released from DU-145 human prostate carcinoma cells; and that, for some endpoints, bystander AG01522 fibroblasts and bystander DU-145 prostate carcinoma cells respond differently to the same, medium-mediated signal.
by Vered Anzenberg.
Ph.D.
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Sprague, Leslee. ""Please Stand By: Investigating the bystander effects of the oncolytic virus HSV1716"." The Ohio State University, 2018. http://rave.ohiolink.edu/etdc/view?acc_num=osu1523960439218798.
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Garcia, Rodríguez Laura. "Modulació de la comunicació intercel·lular com a estratègia per incrementar l'eficàcia de teràpies antitumorals en models de càncer de pàncrees." Doctoral thesis, Universitat Pompeu Fabra, 2008. http://hdl.handle.net/10803/7124.
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L'adenocarcinoma ductal de pàncrees és un càncer molt agressiu que actualment representa la quarta causa de mort per càncer als països occidentals. Les teràpies clàssiques, basades en la resecció quirúrgica, la radioteràpia i el tractament amb quimioteràpics com la gemcitabina, no són efectives en la gran majoria del pacients. En aquests darrers anys s'està estudiant l'aplicació de la teràpia gènica com a teràpia alternativa o adjuvant per al tractament d'aquesta neoplàsia. Una aproximació important és la que es basa en la transferència del gen de la timidina quinasa del virus Herpes simplex tipus 1 (TK) i l'administració de la pro-droga ganciclovir (GCV). Un dels atractius que presenta aquest sistema TK/GCV és que disposa d'un mecanisme amplificador de la mort cel·lular, que va més enllà d'eliminar la cèl·lula tumoral modificada genèticament amb el gen TK i que es coneix com l'efecte adjacent. S'ha proposat, que aquest efecte podria ser degut al trànsit dels metabòlits tòxics del GCV a través dels canals intercel·lulars que formen les unions gap.En aquesta tesi hem realitzat una caracterització de l'expressió de les molécules constitutives de les unions gap, les connexines, en l'adenocarcinoma de pàncrees; i hem estudiat el seu paper en l'eficàcia de dues estratègies terapèutiques basades en l'administració de compostos anàlegs de nucleòsids: el sistema suïcida TK/GCV i el quimioteràpic gemcitabina. S'ha estudiat també la possible contribució de l'E-cadherina, element clau de les unions adherents epitelials, en l'efecte citotòxic d'aquestes teràpies i amb especial èmfasi en el sistema TK/GCV.
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Neff, Andrea. "Cyberbullying on Facebook: Group composition and effects of content exposure on bystander state hostility." Thesis, University of Canterbury. Psychology, 2013. http://hdl.handle.net/10092/8652.
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This study addressed the extent to which offensive cyberbullying content exists on Facebook and the extent to which bystanders that view cyberbullying content reported increased levels of hostile affect. Experiment 1 identified 200 open Facebook groups that contained offensive cyberbullying content. Group composition, in terms of group membership and participation, and the content within the groups, in terms of the number and content of posts, were analysed for gender differences and severity of content. Results from Experiment 1 highlighted the visibility of offensive cyberbullying material that is accessible to any member of the Facebook community. Given the prevalence for such content, Experiment 2 was designed to identify the extent to which exposure to cyberbullying content on Facebook would increase levels of state hostility (i.e., hostile affect), while also examining gender differences and controlling for trait hostility. Participants were presented with Facebook screenshots that contained either offensive or neutral Facebook screenshots and were asked to respond to questionnaires via self-reporting methods. Results indicated that exposure to offensive content led to an increase in levels of state hostility, particularly in those who had previously reported higher levels of trait hostility. Taken together, these findings suggest that not only is offensive material perpetrating cyberbullying behaviour prevalent and accessible to any Facebook member, but bystanders who view offensive cyberbullying content have the tendency to respond with increased levels of hostile affect post-exposure.
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Holmström, Ida, and Katharina Jonestrand. "Att stå utanför en konflikt på arbetsplatsen : hur påverkas en utanförstående av konflikter mellan arbetskamrater?" Thesis, Högskolan i Gävle, Akademin för hälsa och arbetsliv, 2012. http://urn.kb.se/resolve?urn=urn:nbn:se:hig:diva-12228.
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Syftet med denna studie var att ta reda på hur en utanförstående upplever, påverkas av, och hanterar en konflikt mellan arbetskamrater på arbetsplatsen. En kvalitativ studie med öppna intervjuer genomfördes med åtta deltagare. Data analyserades med induktiv tematisk analys. Resultatet visade att konflikter på arbetsplatsen påverkar såväl individen, arbetsgruppen som hela arbetsplatsen negativt. Den utanförstående upplever konflikter på arbetsplatsen som påfrestande och att de på flera olika sätt påverkas negativt av dem. Hur utanförstående upplever, påverkas av och hanterar konflikter mellan arbetskamrater är framför allt beroende av konfliktens innehåll och allvar. De negativa känslorna visar sig vara starkare vid konflikter där någon upplevs bli utsatt eller illa behandlad och då ökar även viljan att ingripa i konflikten. Vid konflikter som mestadels rör arbetsfrågor uppkommer istället känslor av passivitet, många vill ta avstånd och anser att konflikten är löjlig och onödig.The purpose of this study was to find out how an bystander feels, gets influenced by, and handles a conflict among colleagues at work. A qualitative study with eight participants, using open interviews was conducted. Data were analyzed by inductive thematic analysis. The results showed that workplace conflicts affect the individual, the work group and the entire workplace negatively. Bystanders experience workplace conflicts as stressful and that they are negatively affected by them in several ways. How outsiders perceive, are affected by and deal with conflicts between colleagues depend on the content and severity of the conflict. The negative emotions appears to be stronger in conflicts where someone is considered to be victimized or treated badly and the willingness to intervene in such conflict increases. Conflicts mostly related to work issues mainly arise feelings of passivity. People often want to dissociate themselves because they consider the conflict to be ridiculous and unnecessary.
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Fullerton, Natasha Eileen. "Gene therapy and targeted radiotherapy applied to bladder and prostate cancer : examination of radiation-induced bystander effects in targeted radiotherapy." Thesis, University of Glasgow, 2006. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.438687.
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Wulf, Linda [Verfasser], Hartmut H. [Akademischer Betreuer] Holzmüller, and Jens [Gutachter] Rowold. "Three essays on spillover effects of product certifications on non-certified bystander products / Linda Wulf ; Gutachter: Jens Rowold ; Betreuer: Hartmut H. Holzmüller." Dortmund : Universitätsbibliothek Dortmund, 2018. http://d-nb.info/1162339845/34.
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Carrère, Nicolas. "Thérapie génique expérimentale du cancer du pancréas par transfert in vivo du gène du récepteur de somatostatine sst2 : caractérisation de l'effet bystander antitumoral." Toulouse 3, 2007. http://thesesups.ups-tlse.fr/136/.
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Une approche originale de thérapie génique du cancer du pancréas par transfert in vivo du gène du récepteur de somatostatine sst2 a été proposée. Dans deux modèles d'adénocarcinome pancréatique établis chez l'animal, il a été démontré que la réexpression de sst2 après transfert in vivo est responsable d'un effet antitumoral. Ses mécanismes, et notamment la diffusion de l'effet anti-oncogénique à l'ensemble des cellules tumorales non transfectées (effet bystander ou effet de voisinage) ont alors été caractérisés. Le transfert in vivo du gène sst2 induit la production intra-tumorale de son ligand la somatostatine, établissant ainsi une boucle autocrine inhibitrice de la prolifération cellulaire. La rupture de cette boucle autocrine par interférence ARN abolit totalement l'activité antitumorale de sst2. La densité micro-vasculaire et l'expression du facteur angiogénique vascular endothelial growth factor (VEGF) dans ces tumeurs sont fortement inhibées en réponse au transfert du gène sst2, tandis que le récepteur de somatostatine sst3 est surexprimé. Ces effets sont dépendants de la production de somatostatine par les cellules tumorales transfectées par sst2. De plus, les récepteurs de somatostatine sst1 et sst5 sont surexprimés, à l'échelle de l'ARN, au sein des tumeurs pancréatiques après transfert de sst2. Enfin, sst2 paraît sensibiliser les cellules tumorales pancréatiques à l'action cytotoxique de la gemcitabine. Le transfert du gène sst2 apparaît donc comme une alternative thérapeutique novatrice pour inhiber la progression de ce cancer. Un projet clinique de thérapie génique du cancer pancréatique chez l'homme a ainsi pu être proposéPancreatic cancer is one of the most aggressive and devastating human malignancies. The present study was conducted to determine whether in vivo sst2 gene transfer into human pancreatic tumors would impair tumor progression, and to characterize sst2 antitumoral bystander mechanisms. Sst2 administration using the synthetic vector PEI, strongly inhibited tumor progression of human pancreatic adenocarcinoma, in vivo. Sst2 gene transfer induced intratumoral production of its ligand somatostatin. Disruption of this autocrine loop by RNA interference completely reversed sst2 antitumoral activity. Microvessel density and vascular endothelial growth factor (VEGF) expression were markedly reduced in sst2-transfected tumors, whereas sst3 somatostatin receptor was upregulated. Depleting somatostatin by RNA interference completely abolished the sst2 inhibitory effect on VEGF expression and tumor angiogenesis, and sst2-induced sst3 expression in peripheral tumor vessels. We conclude that in vivo sst2 gene transfer elicited intratumoral somatostatin production and strongly impaired human pancreatic tumor growth. NK cells were not involved in this antitumoral bystander effect. VEGF and tumor vascularization were identified as novel targets for sst2-mediated antitumoral bystander effect. Sst1, sst3, and sst5 somatostatin receptors were upregulated in sst2-transfected tumors. Furthermore, sst2 gene re-expression can sensitize pancreatic cancer cells to gemcitabine. Thus, in vivo gene delivery of sst2 receptor to target the angiogenic process in pancreatic ductal adenocarcinoma might be a new therapeutic approach for treatment of pancreatic cancer in patients with unresectable disease
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Feng, Shaoyong. "C. Elegans and Microbeam Models in Bystander Effect Research." Thesis, 2013. http://hdl.handle.net/1969.1/151271.
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Radiation induced bystander effects have changed our understanding of the biological effects of ionizing radiations. The original assumption was that biological effects require direct damage to DNA. The bystander effect eliminated that requirement and has become one main stream in radiation research ever since first reported over 20 years ago.
Most bystander studies to date have been carried out by using conventional single cell in vitro systems , 2D cell array and 3D tissue samples, which are useful tools to characterize basic cellular and molecular responses. But to reveal the complexity of radiation responses and cellular communication, live animal models have many advantages. In recent years, models such as C. elegans and Zebrafish have been utilized in bystander effects research. In the Loma Linda/TAMU experiment, a L1 larva C. elegans model was devloped to study the radiation bystander effects by irradiating single intestine cell nuclei with a microbeam of protons.
Due to the stochastic nature of particle interactions with matter and changing stopping power when protons slow down, precise dosimetry in the target nucleus is a difficult problem. This research was undertaken to provide a detailed description of the energy deposition in the targeted and surrounding non-targeted cell nuclei, and to evaluate the probabilities of the non-targeted cell nucleus being irradiated. A low probability is required to exclude the possibility of radiation biological an effect in non-targeted cells is caused by scattered particles. Mathematical models of the microbeam system and the worm body were constructed in this research. Performing Monte Carlo simulations with computer code, Geant 4, this research provided dosimetry data in cell nuclei in different positions and Geant 4, this research provided dosimetry data in cell nuclei in different positions and probabilities of scattering to non-targeted cell nuclei in various microbeam collima- tor configurations. The data provided will be useful for future collimated microbeam design.
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Fernandes, Saúl Simão Monteiro. "Induction of bystander effect by different contaminants on soil oligochaetes." Master's thesis, 2019. https://hdl.handle.net/10216/125348.
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Fernandes, Saúl Simão Monteiro. "Induction of bystander effect by different contaminants on soil oligochaetes." Dissertação, 2019. https://hdl.handle.net/10216/125348.
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Silva, Paulo Francisco Lopes da. "Do senescent cells in vivo induce a bystander effect in muscle?" Master's thesis, 2016. http://hdl.handle.net/10316/34130.
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SILVA, Paulo Francisco Lopes da - Do senescent cells in vivo induce a bystander effect in muscle?. Coimbra : [s.n.], 2016. Dissertação de Mestrado.Cellular senescence is traditionally regarded as a state of irreversible cell cycle arrest elicited as a response to diverse stressors. Depending on cellular context, senescence can have beneficial or detrimental roles and it is currently known to be involved in tumor suppression and progression, tissue repair, organismal development and aging processes. In vivo, the frequency of senescent cells in certain organs can help predict lifespan and selective ablation of senescent cells was shown to postpone ageing phenotypes, showing their importance for the ageing process. The senescent phenotype can be induced by multiple stimuli and cellular contexts. These stimuli usually trigger a persistent DNA-damage response (DDR) that drives not only the irreversible loss of replicative capacity but the production and secretion of reactive oxygen species via p21-mediated signaling pathways. In addition, senescent cells develop a senescence-associated secretory phenotype (SASP). Several bioactive molecules comprising the SASP can diffuse and affect surrounding cells, suggesting that senescent cells can damage their microenvironment. Supporting this assumption, it was observed that senescent cells harboring a DDR can communicate this response to surrounding cells, leading to physiological alterations in these cells, a phenomenon termed “bystander effect”. This makes senescent cells a potential cause of age-dependent tissue functional decline. While the existence and effects of the bystander effect have been previously validated in vitro, comprehensive proof of its role in non-pathological conditions in vivo is still lacking. We present here a panel of candidate biomarkers to evaluate cellular senescence in skeletal muscle cryosections. We report age-dependent increases in frequencies of lipofuscin-containing fibers, HMGB1-negative and TAF-positive nuclei, as well as decrease in mean nuclear LB1 fluorescence. These results may prove useful to generate robust tests for identification of senescent cells within postmitotic tissues. Moreover, we show here that injection of senescent cells into skeletal muscle of young mice promotes accumulation of certain senescence biomarkers, specifically p21 and lipofuscin in adjacent, bystander muscle fibers, an effect dependent on the abundance of nearby senescent cells. Our data suggest senescent cells are capable of inducing persistent DNA damage and DDR in skeletal muscle bystander cells in vivo and engendering downstream senescence-like features in those same cells. These results may be the first line of evidence of a senescent bystander effect in postmitotic cells, in vivo. This data might contribute to understanding the reported age-related increase of senescent cells in tissues and their role in ageing/age-related pathologies, while strongly supporting a novel understanding of senescence as a dynamic phenotypic state generated and maintained by stable, self-sustainable feedback loops, driven by DDR and independent of the onset of growth arrest.
Senescência celular é tradicionalmente considerada como um estado de suspensão permanente do ciclo celular evocado como resposta a diversos agentes causadores de stress. Dependendo do contexto celular, o processo de senescência pode ter funções benéficas ou prejudiciais e actualmente, sabe-se estar envolvido em processos de supressão e progressão tumorais, reparação de tecidos, desenvolvimento do organismo e envelhecimento. In vivo, a frequência de células senescentes em certos órgãos pode ajudar a prever o tempo de duração de vida e a ablação seletiva de células senescentes provou ser eficaz em adiar o desenvolvimento de fenótipos de envelhecimento, demonstrando a sua importância para o processo de envelhecimento. O fenótipo senescente pode ser induzido por múltiplos estímulos e contextos celulares. Estes estímulos normalmente induzem uma “DNA-damage response” (DDR) persistente que controla não só a perda irreversível de capacidade replicativa mas também a produção e secreção de espécies reativas de oxigénio por vias de sinalização mediadas por p21. Além disso, células senescentes desenvolvem um “Senescence-Associated Secretory Phenotype” (SASP). Várias moléculas bioativas incluídas no SASP são capazes de se difundir e afetar células nas suas imediações, levando a alterações fisiológicas nestas células, um fenómeno conhecido como “bystander effect”. Tudo isto torna as células senescentes potenciais efetores do declínio funcional observado em tecidos com o avanço de idade. Apesar de a existência e os efeitos do “bystander effect” terem sido anteriormente validados in vitro, provas compreensivas do seu papel em condições não-patológicas in vivo estão ainda em falta. Apresentamos neste trabalho um painel de biomarcadores para avaliar senescência celular em criosecções de músculo esquelético. Relatamos também, aumentos nas frequências de fibras contendo lipofuscina, núcleos positivos para HMGB1 e núcleos contendo TAFs, assim como uma diminuição na fluorescência média nuclear de LB1, tudo isto em função do aumento da idade dos tecidos. Estes resultados podem vir a ser úteis para gerar testes de identificação robustos para células senescentes em tecidos pós-mitóticos. Além disso, mostramos ainda que a injeção de células senescentes em músculos esqueléticos de ratinhos jovens promove acumulação de certos marcadores de senescência, especialmente p21 e lipofuscina, em fibras musculares adjacentes, dependendo da abundância de células senescentes nas proximidades. Estes dados sugerem que células senescentes são capazes de induzir danos persistentes no DNA e uma DDR em células “bystander” de músculo esquelético in vivo e de engendrar, nessas células, o desenvolvimento de características típicas de células senescentes. Estes resultados são possivelmente as primeiras provas de um “bystander effect” senescente em células pós-mitóticas in vivo e podem contribuir para uma maior compreensão do aumento, com a idade, de células senescentes em tecidos e o seu papel no envelhecimento e patologias relacionadas. Isto suporta também uma visão do processo de senescência como um estado fenotípico dinâmico gerado e mantido por “feedback loops” estáveis e auto-sustentáveis, gerados por uma DDR independente da suspensão de proliferação celular.
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Sjostedt, Svetlana. "An in vitro investigation of the impact of radiation induced bystander effect on the therapeutic irradiation of a prostate cancer cell line." Thesis, 2013. http://hdl.handle.net/2440/81550.
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Introduction. The aim of radiotherapy, in general, is to deliver a high enough radiation dose to tumour cells to control (and stop) their growth without causing severe complications to surrounding healthy tissues. As a result, it is very important to define a precise irradiation target for radiotherapy treatment. For many years only DNA has been seen as the main target for radiation to cause cellular death in living tissues. In the last decade the fundamental dogma of radiobiology, known as the ‘target theory’, has been reviewed. The extensive experimental evidence demonstrates that not only cell nucleus but also cellular cytoplasm, membrane, and even neighbouring cells, located outside the radiation field, should be viewed as possible targets for therapeutic ionising radiation. Methodology. The research described in this thesis aims to investigate the impact of the non-targeted effects of 6MV x-rays during the radiotherapy. This thesis intends to analyse the published mathematical models which predict occurrence and magnitude of radiation induced bystander effects (RIBEs), with experimental validation of one of these models. The methodology undertaken involved: • Literature review and development of comprehensive understanding of general concepts of radiation induced bystander effects; • Establishment of a suitable experimental methodology to investigate these phenomena, in particular radiation induced additional killing, in the application to radiotherapy to PC3 human prostate epithelial adenocarcinoma cell line, including: • evaluation of biological characteristics such as population doubling time and plating efficiency; • evaluation of radiobiological characteristics such as the dose which kills half of clonogenes (D₅₀), which will be used subsequently as the prescribed dose in the dose cold spot experiment; (in the experiment investigating cell survival in the under-dosed region) • determination of suitable biological end-points (such as apoptotic cell death, reduced proliferation rate, clonogenic cell death) following radiation treatment; • design of a dose-cold spot experiment to investigate RIBE in a reduced dose region (ie receiving ~80% of the prescribed dose) in freely communicating cells and non-communicating cells; • Investigation of the extent of non-targeted effects on cell killing in a dose cold spot in human prostate PC3 cancer cell line; • Analysis of RIBE related models; • Validation of the published stochastic model that relates absorbed dose to the emission and processing of cell death signals by non-irradiated cells which included: • determination of magnitude of medium-borne signals (affecting non-targeted cells) dependence on the radiation doses received by donor cells • investigation of donor cell concentration impact on the emission of death signals predicted by the model. All cell irradiations were performed at the Royal Adelaide Hospital, Radiation Oncology Department using a 6 MV x-ray beam produced by a Varian linear accelerator (Varian, Palo Alto, CA,USA). A clinically applied nominal dose rate of 3 Gy/min was used. Each radiation treatment was performed at 100 cm from the beam focal spot with 20 x 20 cm² radiation field size. The culture dishes were placed on the top of 1.5 cm thick solid water build up sheets. To avoid irradiation through air gaps cells were treated posteriorly with gantry positioned at 180°. Custom made wax phantoms (for different flask sizes) were used in conjunction with 5 cm thick solid water slab to cover the flask to ensure full scatter conditions. Machine radiation output was routinely checked with Daily QA 3™ device (Sun Nuclear, USA) before each radiation treatment. The primary research objectives were investigated through a series of research papers. Results. The findings and results of the experiments designed and performed in the current work include: I. Biological characteristics of PC3 cell line such as plating efficiency and population doubling time were found to be 0.60, 48 hours respectively. II. The fraction of cells surviving the standard clinical daily dose of 2 Gy (SF2) typical of curative radiation protocols was found to be 0.586 (± 0.0279), while the dose that killed half of the clonogen population (D₅₀) was found to be 2.037Gy. III. Radiosensitivity of PC3 cells differs widely among laboratories - the maximum difference found was 131.58%. This cell line appeared to be very sensitive to the methods used therefore it was important to evaluate D₅₀ independently rather than relying on published data. IV. Apoptotic assay revealed no significant dose dependant early cell deaths until 96 hours after radiation exposure. Following this time the first sizable colonies can be detected by the clonogenic survival assessment. Hence cellular damage in a dose cold spot was assessed by long term survival data which includes all types of radiation induced damages. V. Cells exposed to a dose cold spot that are freely communicating versus non-communicating cells revealed significant decrease (16.2%) in cells survival presumably due to intercellular communication. Validation of the stochastic model predicting emission and processing of cell death signals in non-irradiated cells revealed significant decreases in cell survival (P<0.001) exposed to irradiated cell condition media (ICCM) derived from donor cells of various concentrations and irradiated with different doses. Dependency of the toxicity of ICCM on the cellular concentration of donor cells was fond to be significant (p<0.5) as well. Conclusion. For the given cell line under existing growing and treatment conditions the cell survival in the dose cold spot region was significantly lower when under-irradiated cells were in contact with the cells receiving 100% of the prescribed dose compared to the cellular survival obtained from the under-dosed cells, by the same amount of radiation, which were treated separately. Presumably these variations were mainly due to intercellular communication. Significant reduction in PC3 cell survival after receiving ICCM was observed. Data fitting revealed an exponential decrease in recipient cell survival with the dose received by the ICCM. However the current experiment was not able to identify the associated dose threshold for the reduction in survival from ICCM due to the saturation of the effect at the doses investigated. This can be attributed to either saturation in signal generation due to limited signal potency or saturation in recipient cell responses. It appeared that death signal emission may increase with increasing numbers of radiation hits to a certain target and with increasing number of targets able to emit death signals. However, the effect saturates when it reaches a specific value in a number of hits or in an amount of critical targets. The mechanisms behind radiation induced additional killing are not clear yet. Little is known about the types of DNA damage affecting bystander cells. The impact of RIBEs in application to novel radiotherapy treatment techniques, such as intensity modulated radiation therapy and tomotherapy, needs further investigation as they deliver highly conformal doses to tumours, but cover bigger volumes with the low doses where bystander responses are more pronounced. Incorporation of RIBEs into the research that underpins clinical radiotherapy will result in a shift beyond simple mechanistic models currently used towards a more systems-based approach. It is a difficult task to design a coherent research strategy to investigate the clinical impact of bystander phenomena, given the complex protean nature of it. Any consideration of bystander effects will challenge clinicians' preconceptions concerning the effects of radiation on tumours and normal tissues and therefore disease management.Thesis (M.Sc.(Med.Phy.)) -- University of Adelaide, School of Chemistry and Physics, 2013
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Μαρτίνου, Μαρία. "Μελέτη των ακτινοβιολογικών φαινομένων που παρατηρούνται μετά από έκθεση καρκινικών κυττάρων σε ιοντίζουσα ακτινοβολία χαμηλής δόσης. Η σημασία τους στη [sic] κλινική πράξη." Thesis, 2014. http://hdl.handle.net/10889/8532.
Full textAbstract:
Τα αποτελέσματα ποικίλων δόσεων ακτινών Χ στην κυτταρική απόπτωση, τον πολλαπλασιασμό, την έκφραση του υποδοχέα του επιδερμικού αυξητικού παράγοντα (EGFR) και των μεταλλοπρωτεϊνασών-2 (MMP-2), μελετήθηκαν σε δύο κυτταρικές σειρές ανθρώπινου γλοιοβλαστώματος.
Μέθοδος: Οι κυτταρικές σειρές LN18 και M059K ακτινοβολήθηκαν σε θερμοκρασία δωματίου με δόσεις κυμαινόμενες από 0,5 έως 15 Gy με τη χρήση πηγής 6 MV. Η απόπτωση μελετήθηκε με τη μέθοδο annexin V, ο πολλαπλασιασμός με τη μέθοδο MTT (methyl tetrazolium) και η έκκριση των MMP-2 με ζυμογράφημα. H καταγραφή των επιπέδων του φωσφοριωμένου EGFR έγινε με ELISA.
Αποτελέσματα: Ο κυτταρικός πολλαπλασιασμός ανεστάλη με δόσο-εξαρτώμενο τρόπο ενώ η απόπτωση αυξήθηκε σημαντικά μετά την ακτινοβολία. Σε δόσεις μικρότερες των 2 Gy δεν καταγράφηκε καμία μεταβολή στην απόπτωση και τον κυτταρικό πολλαπλασιασμό. Τα επίπεδα των MMP-2 αυξήθηκαν 48 ώρες μετά την ακτινοβόληση με δόσο-εξαρτώμενο τρόπο. Αντιθέτως, η έκφραση του EGFR αυξήθηκε σημαντικά 15 λεπτά μετά την ακτινοβόληση και κατά δόσο-εξαρτώμενο τρόπο.
Συμπέρασμα: Η ιοντίζουσα ακτινοβολία επάγει την έκφραση του EGFR και αυξάνει την έκκριση των MMP-2 γεγονός που αιτιολογεί την διηθητική και κακοήθη συμπεριφορά των γλοιωμάτων καθώς και την ανταπόκριση τους στην ιοντίζουσα ακτινοβολία.The effect of different doses of X(-)rays on apoptosis, proliferation, epidermal growth factor receptor (EGFR) and matrix metalloproteinase (MMP-2) expression was investigated in a human glioblastoma cell line. Materials and Methods: The cell line LN18 was irradiated at room temperature with doses ranging from 0.5 to 15 Gy using 6 MV X(-)rays. Apoptosis was assessed using the annexin V binding assay, proliferation by the methyl tetrazolium (MTT) assay and MMP-2 secretion with zymography. The levels of phosphorylated (pEGFR) were estimated using a commercially available ELISA kit. Results: Cell proliferation decreased in a dose-dependent manner, while apoptosis was increased after radiation. Doses below 2 Gy did not affect proliferation or apoptosis. MMP-2 levels were increased 48 h after radiation in a dose-dependent manner. In contrast, EGFR signaling was significantly activated 15 min after radiation in a dose-dependent manner. Conclusion: Ionizing radiation activates EGFR signalling and enhances MMP-2 secretion, suggesting that the molecular pathways involved may contribute to the invasiveness and malignant behaviour of glioma cells and help to explain the response of gliomas to ionizing radiation.
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Hou, Ya-Hsiue, and 侯雅雪. "Radiation-Induced Bystander Effect in Human Glioblastoma Cells and Functional Characterization of Lung Cancer Related Genes." Thesis, 2008. http://ndltd.ncl.edu.tw/handle/u6prap.
Full textAbstract:
碩士中臺科技大學
放射科學研究所
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Lung cancer, especially non-small cell lung cancer (NSCLC), is the most common cause of cancer related death worldwide. It is generally believed that lack of biomarkers of early detection or prognosis of NSCLC is the main reason that explains high mortality of this disease. In order to obtain such biomarkers, we have conducted a lung cancer cell line-based functional genomics screen, in which sox9 was a candidate biomarker. In the present study, in silico data mining and molecular biology emphasizing siRNA gene silencing technique was used to probe the functional roles of sox9 in NSCLC. Here we showed that the expression of sox9 is significantly higher in the tumor parts than in the normal parts of cells of NSCLC; mean while, its expression is also higher in patients with recurrent diseases than those without. Furthermore, silencing of sox9 expression can cause reduced viability of cells, affect the cell cycle progression through G1 or G2 phases, and change the invasion capability of cells. Microarray gene expression analysis and quantitative polymerase chain reaction (q-PCR) revealed that the genes affected by silencing of sox9 included MT2A、FTL、CASP4、FTH1、RPL35、AKAP5、JNK1 (up-regulated) and sox1、sox17、BBC3、IRS2、WNT6 (down-regulated). Many of the differentially expressed genes are involved in the signaling pathways of cell growth or proliferation. In summary, we concluded that sox9 plays important roles in the survival of NSCLC cells.
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BIAGIONI, MARTINA. "Fighting inflammation to save cones: anti-inflammatory approaches to slow down cone degeneration in a mouse model of retinitis pigmentosa." Doctoral thesis, 2019. http://hdl.handle.net/2158/1151621.
Full textAbstract:
The term Retinitis Pigmentosa (RP) defines a group of inherited dystrophies characterized by progressive degeneration of photoreceptors (PRs) and abnormalities in retinal pigment epithelium (RPE). In typical RP, primary degeneration of rods is followed by secondary death of cones. Affected individuals exhibit initial night blindness and constricted visual field, while central vision is eventually lost later, as cone cells degenerate. Unfortunately, there is no cure for RP.
An important concept of RP pathophysiology is the biological link(s) between rod and cone death in this disease, where mutations are usually rod-specific and cones, genetically intact, degenerate as a consequence of a bystander effect. To note, the main cause of clinically significant vision loss is associated with cone, rather than with rod death. Although cones represent less than 5% of all PRs in the retina of most mammals, their role on human vision is crucial and their degeneration leads to a condition of irreversible vision loss. Survival of still-functioning cones following rod death enables patients with a night-blindness disease to lead normal lives for some time (Shelley et al., 2009).
Previous studies of our laboratory and based on the rd10 mouse model of human RP demonstrated with molecular tools that inflammation emerges as a relevant component of RP, overcoming any other biological process expected to occur in this pathology. Here, we hypothesized that cones, non-primarily affected by the disease-causing mutation and long lasting with respect to rods, may suffer from side effects of such inflammatory process and finally die out. In this study, we employed a protocol of synthetic steroid administration to test the hypothesis that counteracting retinal inflammation concomitantly to the acute phase of PR degeneration may improve cone fate. Indeed, we demonstrated that systemic Dexamethasone treatment resulted in decreased inflammatory response at retinal level and this event was associated to improved cone survival and preservation of visual acuity in rd10 mice. Subsequently, we postulated that different classes of Mononuclear Phagocytes (MPs, such as microglia and monocytes-derived macrophages, primarily involved in the inflammatory response) played different roles in the chronic, noxious inflammatory response found at retinal level. The particular role of the CCL2 chemokine was assessed.
Altogether, our findings suggest a link between local retinal inflammation and worsening of cone fate, opening the perspective of slowing down retinal decay and vision loss in RP by using anti-inflammatory strategies.