I. |
Interaction of Radiation with Biological Systems (++) |
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Definition of ionizing radiation Types of ionizing and non-ionizing radiation Definition of LET and quality of ionizing radiation Generation of free radicals Direct and indirect action of ionizing radiation |
II. |
Molecular Mechanisms of DNA Damage (+) |
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Assays for DNA damage |
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neutral and alkaline elution, pulsed field electrophoresis, comet, plasmid-based assay |
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Types of DNA lesions and numbers per cell/Gy Multiply damaged sites Single lethal hits and accumulated damage (inter- and intra-track) Role of oxygen in the generation of damage Role of LET and radiation quality |
III. |
Molecular Mechanisms of DNA Repair (+++) |
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Different types of DNA repair mechanisms Mechanisms involved in repair of base damage and DNA single strand breaks Mechanisms involved in repair of double strand breaks |
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Homologous recombination Non-homologous end joining |
IV. |
Chromosome and Chromatid Damage (++) |
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Assays |
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Conventional smears, banding, comparative genomic hybridization (CGH) and FISH |
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Dose response relationships Use of peripheral blood lymphocytes in in vivo dosimetry Stable and unstable chromatid and chromosome aberrations Human genetic diseases that affect DNA repair, fragility, and radiosensitivity |
V. |
Mechanisms of Cell Death (+++) |
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Apoptotic death |
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Developmental and stress induced Morphological and biochemical features of apoptosis Molecular pathways leading to apoptosis Radiation-induced apoptosis in normal tissues and tumors |
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Necrotic death |
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Morphological, pathological, and biochemical features of necrosis |
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Mitotic death following irradiation |
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Types of mitotic death - mitotic catastrophe vs. apoptosis Cell division post-radiation and time to clonogenic cell death |
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Radiation-induced senescence |
VI. |
Cell and Tissue Survival Assays (+) |
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In vitro clonogenic assays |
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Calculation of plating efficiency and surviving fraction |
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In vivo clonogenic assays |
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Bone marrow stem cell assays, jejunal crypt stem cell assay, skin clones, kidney tubules |
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Functional endpoints |
VII. |
Models of Cell Survival (+++) |
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Random nature of cell killing and Poisson statistics Doses for inactivation of viruses, bacteria, and eukaryotic cells after irradiation Single hit, multi-target models of cell survival Two component models Linear quadratic model Calculations of cell survival with dose Effects of dose, dose rate, cell type |
VIII. |
Modifiers of Cell Survival: Linear Energy Transfer (+) |
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Definition of RBE RBE as a function of LET Effect of LET on cell survival Endpoint dependence of RBE Effects of dose, dose rate, cell type |
IX. |
Modifiers of Cell Survival: Oxygen Effect (++) |
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Definition of OER Effect of dose, dose rate, cell type OER as a function of LET Impact of O2 concentration Time scale of oxygen effect Mechanisms of oxygen effect |
X. |
Modifiers of Cell Survival: Repair (++) |
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Sub-lethal damage repair Potentially lethal damage repair Half-time of repair Effects of dose, dose rate, and cell type Effect of dose fractionation Effect of LET Effects of oxygen/hypoxia |
XI. |
Solid Tumor Assay Systems (+) |
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50 limiting dilution assay Tumor regrowth assay TCD50 tumor control assay Lung colony assay In vitro/in vivo assay Monolayers vs. 3-D spheroid cultures |
XII. |
Tumor Microenvironment (+++) |
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Tumor vasculature Angiogenesis Hypoxia in tumors |
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Measurement of hypoxia Transient and chronic hypoxia |
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Reoxygenation following irradiation Relevance of hypoxia in radiation therapy Hypoxia as a factor in tumor progression Hypoxia-induced signal transduction Cellular composition of tumors |
XIII. |
Cell and Tissue Kinetics (+++) |
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Cell cycle |
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Measurement of cell cycle parameters by 3H-thymidine Measurement by flow cytometry, DNA staining and BrdU |
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Cell cycle synchronization techniques and uses Effect of cell cycle phase on radiosensitivity Cell cycle arrest and redistribution following irradiation Cell cycle checkpoints, cyclins, cyclin dependent kinase inhibitors Tissue kinetics |
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Stem, progenitor, differentiated cells Growth fraction Cell loss factor Volume doubling times Tpot |
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Growth kinetics of clinical and experimental tumors |
XIV. |
Molecular Signaling (++) |
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Receptor/ligand interactions Phosphorylation/dephosphorylation reactions Transcriptional activation Radiation-induced gene expression |
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Gene expression profiling Proteomics |
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Radiation-induced signals |
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DNA damage response Non-DNA damage responses |
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Cell survival and death pathways |
XV. |
Cancer (+++) |
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Cancer as a Genetic Disease Oncogenes Tumor suppressor genes Telomeric changes in cancer Epigenetic changes in cancer |
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e.g hypermethylation |
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Multi-step nature of carcinogenesis Repair genes in carcinogenesis The metastatic process Molecular profiling and staging of cancer |
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Gene expression profiling Proteomics |
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Signaling abnormalities in cancer Effects of signaling abnormalities on radiation responses Prognostic significance of tumor characteristics Therapeutic targets and strategies for intervention |
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Monoclonals, small molecule inhibitors, gene therapy |
XVI. |
Total Body Irradiation (++) |
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Prodromal radiation syndrome Cerebrovascular syndrome Gastrointestinal syndrome Hematopoietic syndrome Mean lethal dose and dose/time responses Immunological effects Assessment and treatment of radiation accidents or terrorism Bone marrow transplantation |
XVII. |
Clinically Relevant Normal Tissue Responses to Radiation (+++) |
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Responses in skin, oral mucosa, oropharyngeal and esophageal mucous membranes, salivary glands, bone marrow, lymphoid tissues, bone and cartilage, lung, kidney, testis, ovary, eye, central and peripheral nervous tissues Scoring systems for tissue injury |
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LENT and SOMA |
XVIII. |
Mechanisms of Normal Tissue Radiation Responses (+++) |
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Differences between slowly and rapidly proliferating tissues Molecular and cellular responses in slowly and rapidly proliferating tissues |
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Cytokines and growth factors Regeneration Remembered dose Functional subunits |
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Mechanisms underlying clinical symptoms |
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Latency Inflammatory changes Cell killing Radiation fibrosis Vascular damage Volume effects |
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Pharmacological modification of normal tissue responses |
XIX. |
Therapeutic Ratio (+++) |
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Tumor control probability (TCP) curves |
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Calculation of TCP Factors affecting shape and slope of TCP curves Influence of tumor repopulation/regeneration on TCP |
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Normal tissue complication probability (NTCP) curves |
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Influence of normal tissue regeneration on responses |
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Response of subclinical disease Causes of treatment failure Factors determining tissue tolerance |
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Normal tissue volume effects Dose-volume histogram analysis |
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Effect of adjuvant or combined treatments on therapeutic ratio |
XX. |
Time, Dose, Fractionation (+++) |
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The 4 R's of fractionation The radiobiological rationale behind dose fractionation The effect of tissue type on the response to dose fractionation Effect of tissue/tumor types on a/b ratios Quantitation of multifraction survival curves BED and isoeffect dose calculations |
XXI. |
Brachytherapy (+) |
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Dose rate effects (HDR and LDR) Choice of isotopes Interstitial and intracavitary use Radiolabeled antibodies BED and Isoeffective dose calculations |
XXII. |
Radiobiological aspects of alternative dose delivery systems (+) |
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Protons, high LET sources, BNCT Stereotactic radiosurgery/radiotherapy, IMRT, IORtd class="spacing"ose distributions and dose heterogeneity |
XXIII. |
Chemotherapeutic agents and radiation therapy (+++) |
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Classes of agents Mechanisms of action The oxygen effect in chemotherapy Multiple drug resistance Interactions of chemotherapeutic agents with radiation therapy (chemoradiation therapy) |
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Photodynamic therapy |
XXIV. |
Radiosensitizers, Bioreductive drugs, Radioprotectors (++) |
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Tumor radiosensensitization |
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Halogenated pyrimidines, nitroimidazoles |
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Hypoxic cell cytotoxins |
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tirapazamine |
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Normal tissue radioprotection |
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Mechanisms of action, sulfhydryl compounds, WR series, dose reduction factor (DRF) |
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Biological response modifiers |
XXV. |
Hyperthermia (+) |
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Delivery modalities Cellular response to heat Heat shock proteins Thermotolerance Response of tumors and normal tissues to heat Combination with radiation therapy |
XXVI. |
Radiation Carcinogenesis (++) |
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Initiation, promotion, progression Dose response for radiation-induced cancers Importance of age at exposure and time since exposure Malignancies in prenatally exposed children Second tumors in radiation therapy patients Effects of chemotherapy on incidence Risk estimates in humans Calculations based on risk estimates |
XXVII. |
Heritable Effects of Radiation (+) |
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Single gene mutation Chromosome aberrations Relative vs. absolute mutation risk Doubling dose Heritable effects in humans Risk estimates for hereditable effects |
XXVIII. |
Radiation Effects in the Developing Embryo (+) |
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Intrauterine death Congenital abnormalities and neonatal death Microcephaly, mental retardation Growth retardation Dose, dose rate, and stage in gestation Human experience of pregnant women exposed to therapeutic dose |
XXIX. |
Radiation Protection (++) |
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General philosophy Stochastic and deterministic effects Effective dose - relative weighting factors Equivalent dose - tissue weighting factor Committed dose Collective exposure dose Dose limits for occupational and public exposure ICRP and NCRP |