Page 32 - 2014 Printable Abstract Book
P. 32
(S104) Irradiation toxicity and cognition: Are we hyper-focused on the hippocampus? Ann M. Peiffer,
Wake Forest School of Medicine, Winston-Salem, NC
Brain tumor survivors exhibit three common and not necessarily dissociable symptom clusters-
physical (fatigue and decreased performance of activities of daily living), mood (anger, anxiety, confusion,
and depression), and cognitive (difficulty concentrating, reading, remembering, and word finding). These
symptoms can be defined relative to treatment as acute/early or delayed. Early effects (within 6 months
of therapy) can resolve on their own accord and do not predict the occurrence of delayed effects (>6
months after therapy) that tend to worsen in severity and incidence as time after treatment increases.
Translating this human condition into model animal systems requires diligence, continual refinement and
a strict adherence to an operational definition of the condition to be tested.
Cognition is an emergent property of an ever changing brain that responds as a complex small-world
network to attack first by cancer and then to treatments intended to obliterate the cancer yet spare
normal tissue. Of late, the major translational research focus for irradiation toxicity and cognitive
protection has been the hippocampus. As the “gateway of memory”, the hippocampus plays a role in the
formation and retrieval of episodic memory, although it does not function in isolation from the rest of the
cortical network to accomplish this task. This presentation will discuss the different forms of memory in
relation to the cortical network providing the function and in the context of several recent treatment trials
(e.g., RTOG 0933, CCCWFU 91105 and RTOG 0614). Comparisons between model animal systems of
irradiation toxicity of normal brain tissue in rodents and non-human primates will be made to human
brain tumor survivors. Several alternative mechanisms will be explored beyond the hippocampus as a
source for the cognitive impairments suffered in brain tumor survivors that may prove useful as targets
for evaluation in model animal systems.
S02 NEW FINDINGS IN DNA REPAIR
Ionizing radiation introduces oxidative DNA damages that include a wide variety of base damage and
single and double strand breaks. Initiation of base excision repair requires the recognition of damage by
a DNA glycosylase. In this symposium, new information about how DNA glycosylases find base damage
will be discussed from experiments imaging quantum dot labeled DNA glycosylases searching for damage
on DNA. Ape1 cleaves at abasic sites produced by DNA glycosylases and is capable of generating double
strand breaks (DSBs) from closely opposed abasic sites. Evidence will be presented demonstrating that
Ape1 can convert abasic sites generated by Ogg1 into DSBs following treatment of cells with high linear
energy transfer radiation. The small DNA fragments that are produced by Ape1 can inhibit non-
homologous end-joining (NHEJ) by Ku binding to the many DNA ends generated. Inhibiting NHEJ initiation
will also be considered from the point of using prokaryote Ku to compete with eukaryote Ku for the DNA
ends of DSBs, and preventing strand break repair by inhibiting polynucleotide kinase/phosphatase (PNKP)
to radiosensitize cells will also be discussed. Novel work will therefore be presented in this symposium on
the mechanisms of base excision repair and DNA repair inhibition.
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Wake Forest School of Medicine, Winston-Salem, NC
Brain tumor survivors exhibit three common and not necessarily dissociable symptom clusters-
physical (fatigue and decreased performance of activities of daily living), mood (anger, anxiety, confusion,
and depression), and cognitive (difficulty concentrating, reading, remembering, and word finding). These
symptoms can be defined relative to treatment as acute/early or delayed. Early effects (within 6 months
of therapy) can resolve on their own accord and do not predict the occurrence of delayed effects (>6
months after therapy) that tend to worsen in severity and incidence as time after treatment increases.
Translating this human condition into model animal systems requires diligence, continual refinement and
a strict adherence to an operational definition of the condition to be tested.
Cognition is an emergent property of an ever changing brain that responds as a complex small-world
network to attack first by cancer and then to treatments intended to obliterate the cancer yet spare
normal tissue. Of late, the major translational research focus for irradiation toxicity and cognitive
protection has been the hippocampus. As the “gateway of memory”, the hippocampus plays a role in the
formation and retrieval of episodic memory, although it does not function in isolation from the rest of the
cortical network to accomplish this task. This presentation will discuss the different forms of memory in
relation to the cortical network providing the function and in the context of several recent treatment trials
(e.g., RTOG 0933, CCCWFU 91105 and RTOG 0614). Comparisons between model animal systems of
irradiation toxicity of normal brain tissue in rodents and non-human primates will be made to human
brain tumor survivors. Several alternative mechanisms will be explored beyond the hippocampus as a
source for the cognitive impairments suffered in brain tumor survivors that may prove useful as targets
for evaluation in model animal systems.
S02 NEW FINDINGS IN DNA REPAIR
Ionizing radiation introduces oxidative DNA damages that include a wide variety of base damage and
single and double strand breaks. Initiation of base excision repair requires the recognition of damage by
a DNA glycosylase. In this symposium, new information about how DNA glycosylases find base damage
will be discussed from experiments imaging quantum dot labeled DNA glycosylases searching for damage
on DNA. Ape1 cleaves at abasic sites produced by DNA glycosylases and is capable of generating double
strand breaks (DSBs) from closely opposed abasic sites. Evidence will be presented demonstrating that
Ape1 can convert abasic sites generated by Ogg1 into DSBs following treatment of cells with high linear
energy transfer radiation. The small DNA fragments that are produced by Ape1 can inhibit non-
homologous end-joining (NHEJ) by Ku binding to the many DNA ends generated. Inhibiting NHEJ initiation
will also be considered from the point of using prokaryote Ku to compete with eukaryote Ku for the DNA
ends of DSBs, and preventing strand break repair by inhibiting polynucleotide kinase/phosphatase (PNKP)
to radiosensitize cells will also be discussed. Novel work will therefore be presented in this symposium on
the mechanisms of base excision repair and DNA repair inhibition.
30 | P a g e
