Page 17 - 2014 Printable Abstract Book
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samples / week, and even national and international laboratory networks are expected to have
throughputs of at best a few thousand samples / week. While good enough for small-scale events, these
numbers would be inadequate if, for example, a major city were targeted. In this Topical Review, we will
consider the background to various possible large scale radiological events, as well as the various advances
that have been made in the past few years towards seriously high throughput biodosimetry.
TR5. SIRTUINS, AGING AND THE RADIATION RESPONSE
(TR501) Sirtuins, Aging and the Radiation Response. David Gius, Northwestern University, Chicago, IL
It has become increasingly clear that IR-induced production of ROS, and the subsequently altered
cellular metabolism, play a role in IR-induced genomic instability and tumorigenesis. In addition, the
mitochondria are among the pivotal organelles that generate ROS as well as determine how mammalian
cells respond to IR exposure. The response to oxidative stress is of importance since ROS have been
implicated as causative agents in several degenerative diseases, as well as in genomic instability, aging
and cancer. MnSOD is critical for the cellular ROS detoxification that is necessary for aerobic respiration,
and loss of function results in increased cellular oxidative stress. Malignancies originating from diverse
tissue types often exhibit dysregulated and/or decreased MnSOD activity, suggesting that loss of MnSOD
establishes a cell damage and tumor-permissive phenotype. MnSOD has also been shown to play a role in
IR-induced tumor cell death as well as in protecting normal tissues from IR-induced damage in murine
models. We have recently shown that SIRT3, the primary mitochondrial deacetylase, directs MnSOD
detoxification activity by deacetylating lysines 68 and 122. We also have shown that: (1) cells lacking Sirt3
in vitro and in vivo exhibit an IR-induced damage-permissive phenotype; (2) MnSOD deacetylation and
-/-
detoxification activity are induced by IR in the livers of wild-type, but not Sirt3 mice; (3) MnSOD K68/122
are SIRT3 targets induced by several agents that are known to activate sirtuins; and (4) MnSOD
deacetylation mutants prevent in vitro transformation from IR.
TR6. RADIOBIOLOGY OF SBRT
2
1
1
1
(TR601) Radiobiology of SBRT/SRS. Chang W. Song ; Robert Griffin ; Inhwan Park ; Susanta Hui ;
1
1
1
1
Chinsoo Cho ; Kathy Dusenbery ; and Paul Sperduto University of Minnesota, Minneapolis, MN and
2
University of Arkansas, Little Rock, AR
In treating various tumors with stereotactic body radiation therapy (SBRT) or stereotactic
radiosurgery (SRS), target tumors are exposed to 30-60 Gy in 1-5 fractions or 15-25 Gy in a single fraction,
respectively. Accumulating evidences clearly demonstrate that SBRT and SRS are far more effective than
would be expected on the classical l radiation survival curves of tumor cells in vivo. It has been known that
the immature tumor capillaries, which are composed of single layer of endothelial cells with incomplete
basement membrane, are rather vulnerable to ionizing radiation and that irradiation of tumors with
higher than 10 Gy in a single dose causes marked vascular damages. We have previously reported that
the radiation-induced vascular damages and the consequential deterioration of intratumor
microenvironment lead to secondary tumor cell death. Our recent studies with human tumor xenografts
and mouse tumor model confirmed our previous observations that high dose per fraction radiation
induces secondly cell death by causing vascular damage. There have also been suggestions that SBRT and
15 | P a g e
throughputs of at best a few thousand samples / week. While good enough for small-scale events, these
numbers would be inadequate if, for example, a major city were targeted. In this Topical Review, we will
consider the background to various possible large scale radiological events, as well as the various advances
that have been made in the past few years towards seriously high throughput biodosimetry.
TR5. SIRTUINS, AGING AND THE RADIATION RESPONSE
(TR501) Sirtuins, Aging and the Radiation Response. David Gius, Northwestern University, Chicago, IL
It has become increasingly clear that IR-induced production of ROS, and the subsequently altered
cellular metabolism, play a role in IR-induced genomic instability and tumorigenesis. In addition, the
mitochondria are among the pivotal organelles that generate ROS as well as determine how mammalian
cells respond to IR exposure. The response to oxidative stress is of importance since ROS have been
implicated as causative agents in several degenerative diseases, as well as in genomic instability, aging
and cancer. MnSOD is critical for the cellular ROS detoxification that is necessary for aerobic respiration,
and loss of function results in increased cellular oxidative stress. Malignancies originating from diverse
tissue types often exhibit dysregulated and/or decreased MnSOD activity, suggesting that loss of MnSOD
establishes a cell damage and tumor-permissive phenotype. MnSOD has also been shown to play a role in
IR-induced tumor cell death as well as in protecting normal tissues from IR-induced damage in murine
models. We have recently shown that SIRT3, the primary mitochondrial deacetylase, directs MnSOD
detoxification activity by deacetylating lysines 68 and 122. We also have shown that: (1) cells lacking Sirt3
in vitro and in vivo exhibit an IR-induced damage-permissive phenotype; (2) MnSOD deacetylation and
-/-
detoxification activity are induced by IR in the livers of wild-type, but not Sirt3 mice; (3) MnSOD K68/122
are SIRT3 targets induced by several agents that are known to activate sirtuins; and (4) MnSOD
deacetylation mutants prevent in vitro transformation from IR.
TR6. RADIOBIOLOGY OF SBRT
2
1
1
1
(TR601) Radiobiology of SBRT/SRS. Chang W. Song ; Robert Griffin ; Inhwan Park ; Susanta Hui ;
1
1
1
1
Chinsoo Cho ; Kathy Dusenbery ; and Paul Sperduto University of Minnesota, Minneapolis, MN and
2
University of Arkansas, Little Rock, AR
In treating various tumors with stereotactic body radiation therapy (SBRT) or stereotactic
radiosurgery (SRS), target tumors are exposed to 30-60 Gy in 1-5 fractions or 15-25 Gy in a single fraction,
respectively. Accumulating evidences clearly demonstrate that SBRT and SRS are far more effective than
would be expected on the classical l radiation survival curves of tumor cells in vivo. It has been known that
the immature tumor capillaries, which are composed of single layer of endothelial cells with incomplete
basement membrane, are rather vulnerable to ionizing radiation and that irradiation of tumors with
higher than 10 Gy in a single dose causes marked vascular damages. We have previously reported that
the radiation-induced vascular damages and the consequential deterioration of intratumor
microenvironment lead to secondary tumor cell death. Our recent studies with human tumor xenografts
and mouse tumor model confirmed our previous observations that high dose per fraction radiation
induces secondly cell death by causing vascular damage. There have also been suggestions that SBRT and
15 | P a g e
