Influence de la radiosensibilité individuelle sur les réponses biologiques à des rayonnements ionisants l'estimation de la dose et le rôle de maintenance des telomeres

Exposure to ionizing radiation (IR), from both natural and man-made sources, is an inevitable part of modern life. It is well established that there are considerable inter-individual variations in sensitivity to IR among healthy individuals and cancer patients. However, the mechanisms involved in the heterogeneity of biological responses to IR are not well understood, and a reliable biodosimetric and clinical approach to measure and rank radiosensitivity remains to be established. In this thesis, we study the extent and impact of individual radiosensitivity in healthy individuals in the contexts of emergency dosimetry and radiotherapy, and we explore the roles of telomeres in the prediction of individual radiosensitivity and long-term human health risks following IR exposure (specifically, cardiovascular diseases and/or cancer). First, in the context of dosimetry in the event of an emergency situation (when rapid dose estimates of each individual in an irradiated population are needed), we demonstrate that the impact of individual radiosensitivity can be negligible using global cellular measurements of γH2AX fluorescence via flow cytometry in human fibroblasts and lymphocytes at 4 hours post-irradiation; this method could be an effective and rapid biodosimetry tool that can aid in the medical triage of irradiated individuals in an emergency setting based on individual levels of exposure. Second, we study the extent and influence of individual radiosensitivity on the induction of chromosomal aberrations following a routinely administered dose of 2 Gy during conventional fractionated photon radiotherapy (γ-rays) in lymphocytes of healthy individuals. For these analyses, we define individual radiosensitivity based on the frequency of IR-induced DNA double strand breaks (DSBs), which were calculated from the scoring of chromosomal aberrations visualized with telomere/centromere-fluorescence in situ hybridization (TC-FISH). This TC-FISH staining of metaphasic chromosomes enhances the “gold standard technique” of biodosimetry (the dicentric chromosome assay) with the visualization of telomeres and centromeres and thereby provides improved simplicity and sensitivity to the classical cytogenetic assay. We also compare individual radiosensitivity following γ-irradiation to that following carbon irradiation, an up-and-coming ion species currently being used in heavy ion radiotherapy. We provide dose response curves for both γ- and carbon irradiations based on the calculated frequency of IR-induced DNA DSBs at a range of doses, and estimate the relative biological effectiveness (RBE) of carbon irradiation relative to γ-irradiation. We then estimate the RBE of a third type of IR also frequently used in heavy ion radiotherapy (proton beams) in comparison to γ-irradiation, and compare individual radiosensitivity to each of these three types of IR with different IR energies. Third, we evaluate the roles of telomeres and telomere maintenance in the prediction of individual radiosensitivity; we find that inherent mean telomere length in combination with the IR-induced change in mean telomere length may be a strong predictor of individual radiosensitivity. Finally, we show how telomeres could be linked to long-term health risks following IR exposure: we demonstrate that telomere shortening could be a new prognostic factor for cardiovascular disease following radiotherapy, and discuss how telomeres could be key players in the process of radiation-induced carcinogenesis. In conclusion, we deliberate the relationships between telomere maintenance, radiation effects, and individual radiosensitivity, and propose a model of how telomeres could play crucial roles in the development of cardiovascular diseases and the process of IR-induced carcinogenesis.L'exposition aux rayonnements ionisants est une composante inévitable de la vie moderne. Il est bien établi qu'il existe une grande variabilité inter-individuelle de la radiosensibilité chez les individus sains et chez des patients atteints de cancer. Cependant, les mécanismes impliqués dans l'hétérogénéité des réponses biologiques radio-induites ne sont pas encore bien compris, et une approche biologique permettant d’établir de façon fiable le niveau de radiosensibilité reste à développer. Dans cette thèse, nous avons étudié l'ampleur et l'impact de la radiosensibilité individuelle chez les individus sains dans les contextes de dosimétrie d'urgence et de radiothérapie. Nous avons également examiné les différents rôles des télomères dans la prédiction de la radiosensibilité individuelle et des risques pour la santé humaine à long terme (spécifiquement, en ce qui concerne les maladies cardiovasculaires et/ou les cancers) après irradiation. Tout d'abord, dans le contexte de la dosimétrie dans le cas d'une situation d'urgence (lorsqu’il est nécessaire d’estimer rapidement la dose d’irradiation reçu par un individu), nous avons démontré que l'impact de la radiosensibilité individuelle peut être négligeable en utilisant des mesures globales de fluorescence de γH2AX via cytométrie en flux dans des fibroblastes humains et des lymphocytes à 4 heures après exposition ; cette méthode peut être un outil de biodosimétrie efficace et rapide qui peut aider au tri des personnes irradiées dans une situation d'urgence basées sur les niveaux individuels d'exposition. Dans un second temps, nous avons étudié l'ampleur et l'influence de la radiosensibilité individuelle sur l'induction d'aberrations chromosomiques après une irradiation de 2 Gy de rayons γ, correspondant à une fraction de radiothérapie conventionnelle, dans les lymphocytes d'individus sains. Pour ces analyses, nous définissons la radiosensibilité individuelle par rapport à la fréquence des cassures double-brin (CDB) radio-induite, qui ont été calculées à partir de la quantification des aberrations chromosomiques visualisées par hybridation in situ des télomères et centromères (TC-FISH). Ce marquage améliore et simplifie la technique « gold standard » de dosimétrie biologique (la quantification des chromosomes dicentriques). Nous avons également estimé la radiosensibilité individuelle à l’irradiation carbone, ions lourds utilisés en radiothérapie, et l'efficacité biologique relative (EBR) des ions carbone par rapport à une irradiation γ. Nous avons fourni des courbes dose-réponse pour ces deux types d’irradiations en fonction de la fréquence des CDB radio-induite par exposition à une gamme de doses. De plus, nous avons estimé l'EBR d'un troisième type de rayonnement également utilisé en radiothérapie d'ions lourds (protons) par rapport à une irradiation γ, et nous avons comparé la radiosensibilité individuelle de ces trois types d'irradiation avec énergies différentes. Ensuite, nous avons évalué les rôles des télomères et de leur maintien pour la prédiction de la radiosensibilité individuelle. Nous avons constaté que la longueur moyenne des télomères, en combinaison avec leurs modifications radio-induites, peuvent être un bon prédicteur de la radiosensibilité individuelle. Enfin, nous avons montré comment les télomères pourraient être liés à des risques sanitaires à long terme après une irradiation: nous avons démontré que le raccourcissement des télomères pouvait être un nouveau facteur de prédiction de maladies cardiovasculaires après radiothérapie, et nous avons discuté par la suite, les télomères comme des acteurs clés dans le processus de cancérogenèse radio-induite. En conclusion, nous proposons un modèle présentant la façon dont les télomères pourraient jouer un rôle crucial dans ces deux pathologies radio-induite, et nous délibérons des relations entre le maintien des télomères, les effets biologiques radio-induites, et la radiosensibilité individuelle

The Student Movement Volume 107 Issue 22: Fulfilled: AU Presents a Story of Redemption

HUMANS Speaking Up With Women, Interviewed by: Grace No What is it Like to Work at the Athletics Department?, Interviewed by: Grace No What is Title IX?. Interviewed by: Caryn Cruz ARTS & ENTERTAINMENT Currently: Foreign Film, Solana Campbell Fulfilled: A Musical of Redemption, Aiko J. Ayala Rios NEWS KASA Banquet, Interviewed by: Anna Pak Watchmen A Capella Concert: Unstoppable: A Journey Through Self-Discovery , Gloria Oh IDEAS Charge It!, Alexander Navarro Feminism is for Everybody. Yes-Even You, Dude!, Reagan McCain Tick Tock... for TikTok?, Abby Shim PULSE Dorm Delicacies, Melissa Moore How Have We Grown?, Abraham Bravo What Do We Wish We Did?, Abraham Bravo LAST WORD Take It From Me , SM Section Editorshttps://digitalcommons.andrews.edu/sm-107/1021/thumbnail.jp

The Student Movement Volume 107 Issue 13: We\u27ve Got the Spirit: Students Celebrate Dr. Luxton

HUMANS Best of Bon Appetit, Nora Martin Interview with the Dean of Lamson and Meier Halls, Interviewed by: Grace No The Joy of Japan, Interviewed by: Gloria Oh ARTS & ENTERTAINMENT A Creation Adventure, Nathaniel Reid Currently: Velma, Solana Campbell Suite Dreams for Sweet Dreams, Skylor Stark Where do I Find God? Part II, Anonymous NEWS AUSA Celebrates 100 Years of Student-Led Action, Andrew Francis Response to A House Divided Story, Christon Arthur, Provost Where\u27s the Harm in True Crime?. Abigail Kim IDEAS Redefining Free Agency in Sports, Andrew Francis Flying Cars of 2030, Rachel Ingram-Clay The Spooky Nature of Our Physical World, Alexander Navarro The State of AI, Abby Shim PULSE Debunking Myths Surrounding J.N. Andrews Honors Program, Gloria Oh Our Dear AU: A Spirit Week Tour, Lexie Dunham Romance and Reading, Gloria Oh LAST WORD An Ode to Tea, Alexander J. Hesshttps://digitalcommons.andrews.edu/sm-107/1012/thumbnail.jp

The Student Movement Volume 108 Issue 5: From Pumpkin Spice to Sinigang: Falling Into Filipino Heritage Month

HUMANS AU SILA: Meet Darius Bridges, Lauren Kim Dawson Par: AUAFIA President, Chef, and Techie, Grace No Meet the Majors! Majors that Make UP Andrews University, Reagan McCain ARTS & ENTERTAINMENT Art Through Language: An Introduction to Andrews University\u27s Language Program, Amelia Stefanscu Ever After : The Best Fairytale Adaptation, Lexie Dunham Harana: The Filipino Serenade Poetry and Incarnation : A Study of Poetry by Craig van Rooyen, Amelia Stefanescu NEWS KASA Kicks Off with Korean School, Gio Lee Philosophy Professor Gives Lecture on the History of Creationism, Andrew Francis The AU Career Fair, Nathaniel Miller IDEAS AU Gathering in Dissent: the Polarization of Thursday Assemblies, Bella Hamman Is Economic Disaster an American Norm?, Nate Miller Jack O\u27Paganism?, Erin Beers Taylor Swift and Travis Kelce: Why Are Celebrity Relationships So Interesting?, Corinna Bevier PULSE Bachelor In Andrews, Brooklyn Anderson Filipino Food Favorites, Caitlin Adap Relaxing, Educating, And Dull?, Anna Rybachek The Flavors of Fall, Lexie Dunham LAST WORD The True Meaning of Courage, Abby Shimhttps://digitalcommons.andrews.edu/sm-108/1004/thumbnail.jp

The Student Movement Volume 107 Issue 3: Running Home: Andrews Alumni Return to Campus

HUMANS Meet Meryen Gonzalez, AUSA Religious VP, Interviewed by: Caryn Cruz Seasons of Change: Alumni Weekend 2022, Grace No Summer Mission Trip Interview with Nick Bishop, Interviewed by: Gloria Oh ARTS & ENTERTAINMENT Alumni Homecoming Gala, Wambui Karanja Currently..., Solana Campbell Hispanic Heritage Month : Highlighting the Beauty of Hispanic Crativity, Amelia Stefanescu Get Up and Go to Iceland, Jonathon Woolford-Hunt NEWS Alumni Take a Win at Saturday Night Game, Alannah Tjhatra Bradley Harvest Run Interview with Andrews Students, Interviewed by: Gloria Oh Hispanic Heritage Month-Mosaico: Colorism and Racism, Taznir Smalling, with additions by Terika Williams IDEAS Ezra Miller and The Flash , Marcel Mattox Greyhound Therapy and Forced Relocation, Valerie Akinyi The New Era of Standardized Testing, Abby Shim PULSE Andrews Celebrates the Opening of New Career Center, Reagan McCain Hispanic Heritage Month: How to Celebrate, Melissa Moore Tips for Relaxing on Campus, Wambui Karanja What Comes First is a Question, Part I, Desmond H. Murray LAST WORD Marvel\u27s Storytelling: Why We Need to Ask for Better, Alannah Tjhatrahttps://digitalcommons.andrews.edu/sm-107/1002/thumbnail.jp

The Student Movement Volume 107 Issue 18: Ain\u27t I A Woman? : AU Students Reflect on the Feminist Movement

HUMANS Interview with the WEAAU President, Interviewed by: Grace No What is Feminism to You?, Interviewed by: Caryn Cruz What\u27s Your Major?, Interviewed by: Nora Martin ARTS & ENTERTAINMENT Currently: The Idol, Solana Campbell Faculty Art Exhibition, Ysabelle Fernando Music Seniors: A Day in the Life, Aiko J. Ayala Rios Through the Paintings, Kaela McFadden NEWS Empowering our Neighbors: Interview with H.E.L.P. Program Director Carlisle Suttton, Isabella Koh John Wesley Taylor V Elected to be the Next Andrews University President Students Open the Month with Cultural Showcase, Andrew Francis The Agora at AU: A Conversation on Police Brutality, Solana Campbell What\u27s Going on East Palestine, Ohio?, Julia Randall IDEAS The Biblical Bechdel: How Much are Women Represented in the Bible?, Bella Hamann The Murder of Abby Choi: A Spotlight on Relationship Violence Against Women, Abby Shim PULSE Nilah Mataafa: An End to Period Poverty, Interviewed by: Chris Ngugi Remember the Ladies! : The Female Perspective on Women\u27s History Month, Amelia Stefanescu The Aerial Workout You\u27ve Never Heard Of, Melissa Moore LAST WORD Perfect Imperfections, Shania Wattshttps://digitalcommons.andrews.edu/sm-107/1017/thumbnail.jp

The Student Movement Volume 108 Issue 7: Not Throwing Away Our Shot: Honoring Hamilton\u27s Legacy

HUMANS An Arboretum of Beauty, Anneliese Tessalee Serving with All She\u27s Got: Natalia\u27s Mission Experience in the Dominican Republic, Nick Bishop WAUS Fall Fundraiser, Grace No ARTS & ENTERTAINMENT Art: A Window Into Another Reality, Madison Vath Filipino Art Through Filipino Eyes: Celebrating A Culture, Amelia Stefanescu Free-Falling Into Autumn : A Fall Playlist, Amelia Stefanescu Upcoming Events in the Art Department, Katrina Johnson What to do about Inhospitality?: A Review of Mitski\u27s Newest Album, Reagan McCain NEWS Andrews Autumn Conference Promotes Peaceful Scientific Discourse, Andrew Francis Honors Goes to Hamilton, Melissa Moore Unraveling the Historical Threads: The SDA Church\u27s Journey with the Trinity, Brendan Oh IDEAS Cats or Dogs?, Abby Shim Exploring Student Perspectives on Jewelry, Reagan Westerman Israeli- Gaza, the Split of Public Opinion, United Nations Resolutions and What We Can Do, Robert Zhang PULSE Everything Happens For A Reason , Nicole Compton-Gray Moral Conflict: What is the Right Thing to Do?, Katie Davis Productivity & Success, Anna Rybachek Social Media and the College Student: A Useful Tool or a Destructive Spiral?, Rodney Bell II LAST WORD To Be Loved and to Love, Wambui Karanjahttps://digitalcommons.andrews.edu/sm-108/1006/thumbnail.jp

The Student Movement Volume 107, Issue 9: Power (Outage) to the People: Students Frolic in Winter Wonderland

HUMANS Interview with the Speech Pathology Club, Interviewed by: Gloria Oh Meet The Chiefs of The Twin Cities, Nicholas C. Gunn Meet the Student Graduate Liaison of AUGSA, Natasha Richards, Interviewed by: Kavya Mohanram What Are AU Students Thankful For?, Interviewed by: Grace No ARTS & ENTERTAINMENT Anthony León Wins Placido Domingo\u27s Operailia 2022, Aiko J. Ayala Rios Currently..., Solana Campbell Thanks for Making Me Laugh: My Top Ten Thanksgiving Sitcom Episodes, Bella Hamann Top Gun Maverick: A SuperSonic Sequel, Leo Martins NEWS Honors Church: Lessons and Carols, Terika Williams Prime Minister after Prime Minister, Abigail Kim The Seatless Delegate: An Unfulfilled Promise to the Cherokee Nation, Julia Randall Innovation & Entrepreneurship: The Sole Full Winner of the Shark Tank Competition, Yoel Kim IDEAS A Reflect ion on Body Image, Elizabeth Getahun The Frenzy of Fast Fashion, Abby Shim The Scoop on Introverts: What Extroverts Need to Know, Isabelle Martinez To Bee or not to Bee: The Importance, Causes, and Impact of Bee Disappearance, Alexander Navarro PULSE All About AU Engage, Lexie Dunham Thoughts on Daylight Savings, Gloria Oh Thanksgiving and Our Heritage, Zothile Sibanda LAST WORD Romanticizing the Past, Alannah Tjhatrahttps://digitalcommons.andrews.edu/sm-107/1008/thumbnail.jp