I. |
Interaction of radiation with matter
- Definition of ionizing radiation, free radicals, and radical damage
- Direct and indirect action of radiation, numbers, and types of DNA
lesions
- Consequences of unrepaired DNA DSB
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II. |
Molecular and cellular damage and repair
- Molecular mechanisms of DNA damage
- Assays for measuring DNA damage and repair
- Single lethal hits, accumulated damage, and multiple damaged
sites
- Molecular mechanisms of DNA repair
- Repair of base damage, single-strand and double-strand breaks
- DSB repair: Homologous recombination and non-homologous end
joining
- Molecular mechanisms of DNA DSB damage recognition and damage
signaling to initiate repair
- Cellular recovery
- Repair at the cellular level
- Sublethal damage repair
- Dose-rate effects and repair
- Dose-fractionation effects and repair
- Chromosome and chromatid damage
- Assays for measuring chromosome damage – Giemsa to FISH
- Dose-response relationships
- Use of peripheral blood lymphocytes in in vivo dosimetry
- Human genetic diseases that affect DNA repair, fragility, and
radiosensitivity
- Stable and unstable chromatid and chromosome aberrations
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III. |
Cellular responses to radiation
- Mechanisms of cell death
- Mechanisms and major characteristics of pathways of
radiation-induced apoptosis, necrosis, autophagy, and
senescence
- Mitotic-linked cell death and chromosome aberrations
- Cell division post-radiation and time to clonogen death
- Cell and tissue survival assays: measurement of response
- In vitro clonogenic assays – effects of dose and dose rate
- In vivo clonogenic assays – bone marrow stem cell assays,
jejunal crypt stem cell assay, skin clones, and kidney tubules
- Models of cell survival
- Random nature of cell killing and Poisson statistics
- Single hit, multitarget models of cell survival – survival
curve descriptors
- Linear-quadratic models: definition of α/β ratio
- Calculations of cell survival with dose and dose rate
- Shapes of the dose-response curves for early and late
responding tissues
- isoeffect curves and impact of changing fraction size and
number on survival and LQ parameters
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IV. |
Linear energy transfer (LET) and oxygen effect
- Linear energy transfer
- Definition of LET and quality of radiation
- RBE defined
- RBE as a function of LET in cells and tissues
- Effect on RBE on change in fractionation
- Oxygen Effect
- Definition of OER
- Dose or dose per fraction effects
- OER vs LET
- Impact of O2 concentration
- Mechanisms of oxygen effect
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V. |
Tumor biology and microenvironment
- Solid tumor assay systems
- Concept of xenograft and syngeneic tumor models
- Assay of tumor response to treatment– growth delay
- TCD50 tumor control assay
- Tumor microenvironment
- Characteristics of tumor vasculature and microenvironment;
effect of radiation on them
- How tumor microenvironment can regulate tumor growth and
vasculature
- Angiogenesis and neovasculogenesis
- Clinical consequence and relevance of hypoxia in tumors and
tumor progressions
- Reoxygenation after irradiation
- Cellular and molecular responses to hypoxia and
hypoxia-induced signal transduction
- Cellular composition of tumors
- Immune microenvironment and role of inflammation
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VI. |
Cancer biology
- Cell and tissue kinetics
- Methods to assess cell cycle kinetics
- Proteins involved in cell cycle control and checkpoint
initiation (e.g., CDKs, cyclins, CDK inhibitors)
- Phases of cell cycle and radiation sensitivity
- Cell cycle arrest and redistribution after irradiation
- Molecular signaling
- Main signaling pathways and critical proteins involved (e.g.,
PI3K/AKT, RAS/ERK, TGF-β, Wnt, Notch, NFkB)
- Receptors/ligand (e.g., EGFR, VEGFR, c-MET, HER2,
FGFR,ALK)
- Kinases
- Definition of kinases (e.g., STKs, TKs/RTKs, DSKs)
- Common kinases in cancer (e.g., ATM, ATR, Chk1, Chk2,
PI3K, MAPK) and corresponding phosphatases (e.g.,
PTEN)
- Molecular signaling pathways activated by IR
- Transcription factors involved in cancer regulation (e.g.,MYC,
TP53 and associated proteins)
- Cell death pathways and main associated players
- Intrinsic vs extrinsic apoptosis (caspases)
- BCL-2 family member proteins (pro- vs anti-apoptotic)
- Mechanisms of cancer development
- Hallmarks of cancer and how they could affect 4/5 Rs of
radiobiology
- Common oncogenes (e.g., HER2/neu, Ras, Myc) & tumor
suppressors (Rb, p16, p53,
BRCA1/BRCA2, APC, NF1)
- Telomeres and pathways in cancer to overcome telomere
shortening (e.g., TERT promoter mutations and alternative
lengthening of telomeres (ALT))
- Signaling abnormalities and association with treatment
response
- Cancer as a genetic disease
- Multistep nature of carcinogenesis
- Signaling abnormalities in carcinogenesis
- Prognostic and therapeutic significance of tumor
characteristics
- Cancer genetics/genomics
- Types of epigenetic regulation (e.g., DNA methylation
(DNMTs/TETs), histone modifications (e.g. HDACs/HATs),
chromatin remodelers)
- Main epigenetic alterations (e.g., CpG island methylator
phenotype [CIMP]) in cancer
- IDH1/2 mutations in glioma and AML
- TET2 mutations in AML
- Epigenetic targets in cancer (DNMTi, HDACi, IDHi, EZH2i)
- Omics approaches in cancer (next-gen sequencing/arrays) and
newer methods (ctDNA)
- Biomarkers in cancer (e.g., BCR-ABL, EGFR, ALK)
- Molecular profiling of cancer
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VII. |
Radiobiology of normal tissues
- Clinically relevant normal tissue responses to radiation
- Responses in early versus late responding tissues
- Reirradiation
- Mechanisms of normal tissue radiation responses
- Molecular and cellular responses in slowly and rapidly
proliferating tissues
- Mechanisms underlying clinical symptoms
- Tissue kinetics
- Total body irradiation
- Prodromal radiation syndrome
- Acute radiation syndromes
- Mean lethal dose and dose/time responses
- Immunological effects
- Assessment and treatment of radiation accidents
- Bone marrow transplantation
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VIII. |
Dose delivery
- Therapeutic ratio
- Tumor control probability (TCP) curves
- Normal tissue complication probability (NTCP) curves
- Causes of treatment failure
- Time, dose, and fractionation
- The four R’s of fractionation
- Radiobiological rationale behind dose fractionation
- Effect of tissue/tumor type on the response to dose
fractionation (α/β ratios)
- Quantitation of multifraction survival curves
- BED and isoeffect dose calculations
- Hypofractionation
- Brachytherapy
- Dose-rate effects (HDR and LDR)
- Choice of isotopes
- Radiolabeled antibodies and other ligands
- Radiobiological aspects of different radiation modalities
- Protons, high LET sources
- Stereotactic radiosurgery/radiotherapy, IMRT, IORT, and systemic radionuclides
- Dose distributions and dose heterogeneity
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IX. |
Combined modality therapy
- Chemotherapeutic agents and radiation therapy
- Classes of chemotherapy agents
- Mechanisms of action
- Oxygen effect on radiation therapy and chemotherapy
- Main drug resistance mechanisms (e.g., MDR genes)
- Interactions/synergism of chemotherapy with radiation therapy
- Targeted therapeutic agents
- Radiosensitizers, bioreductive drugs, and radioprotectors
- Definition of therapeutic window
- Tumor radiosensitizers (e.g., oxygen) and mimics (e.g.,
nitromidazole)
- Normal tissue radioprotectors (e.g., amifostine)
- Biological response modifiers (e.g., IL-2 and IFN)
- DNA repair inhibitors (e.g., PARPi, ATMi, ATRi, Chk1/2i)
- Immune therapeutics
- Types of immunotherapy treatments in oncology
- Monoclonal antibodies (MABs)
- Checkpoint inhibitors
- Cytokines
- Vaccines
- Adoptive cell transfer types (chimeric antigen receptors
[CARs], tumor infiltrating lymphocytes [TILs], and T cell
receptors [TCRs])
- Combination of immune therapies and radiation
- Recently published trials (e.g., PACIFIC, KEYNOTE)
- Known predictors of response/biomarkers
- Hyperthermia
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X. |
Late effects and radiation protection
- Radiation carcinogenesis
- Dose response for radiation-induced cancers
- Importance of age at exposure, time since exposure, sex, and
tissue
- Second tumors in radiation therapy patients
- Risk estimates in humans
- Heritable effects of radiation
- Relative vs absolute mutation risk
- Doubling dose
- Heritable effects in humans
- Risk estimates for hereditable effects
- Radiation effects in the developing embryo
- Dependence of abnormalities and death on dose and gestational
stage
- Microcephaly, intellectual disabilities
- Radiation protection
- Stochastic effects and tissue reactions
- Tissue and radiation weighting factors
- Equivalent dose, effective dose, committed dose
- Dose limits for occupational and public exposure
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