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Project Title:  NSCOR: NASA Specialized Center of Research on Carcinogenesis Reduce
Images: icon  Fiscal Year: FY 2021 
Division: Human Research 
Research Discipline/Element:
HRP SR:Space Radiation
Start Date: 06/01/2015  
End Date: 05/31/2022  
Task Last Updated: 07/23/2021 
Download report in PDF pdf
Principal Investigator/Affiliation:   Weil, Michael  Ph.D. / Colorado State University 
Address:  Department of Environmental & Radiological Health Sciences 
1618 Campus Delivery 
Fort Collins , CO 80521-2807 
Email: michael.weil@colostate.edu 
Phone: 970-491-5902  
Congressional District:
Web:  
Organization Type: UNIVERSITY 
Organization Name: Colorado State University 
Joint Agency:  
Comments:  
Co-Investigator(s)
Affiliation: 
Borak, Thomas  Ph.D. Colorado State University 
Emmett, Mark  Ph.D. University Of Texas, Galveston 
Hwang, Tae Hyun  Ph.D. University of Texas Southwestern Medical Center at Dallas 
Ray, F. Andrew  Ph.D. Colorado State University 
Bacher, Jeff  Ph.D. Promega Corporation 
Halberg, Richard  Ph.D. University of Wisconsin, Madison 
Raber, Jacob  Ph.D. Oregon Health & Science University 
Story, Michael  Ph.D. University of Texas Southwestern Medical Center at Dallas 
Ullrich, Robert  Ph.D. University of Texas, Galveston 
Brandl, Alexander  Ph.D. Colorado State University 
Key Personnel Changes / Previous PI: April 2020 report: Dr. Thamm has completed his role on the NSCOR. April 2019 report: Dr. Robert L Ullrich has transitioned from NSCOR Co-Director to Consultant ; Dr. Michael D. Story now serves as the Co-Director.
Project Information: Grant/Contract No. NNX15AK13G 
Responsible Center: NASA JSC 
Grant Monitor: Elgart, Robin  
Center Contact: 281-244-0596 (o)/832-221-4576 (m) 
shona.elgart@nasa.gov 
Solicitation / Funding Source: 2013-14 HERO NNJ13ZSA002N-NSCOR Radiation 
Grant/Contract No.: NNX15AK13G 
Project Type: GROUND 
Flight Program:  
TechPort: No 
No. of Post Docs:
No. of PhD Candidates:
No. of Master's Candidates:  
No. of Bachelor's Candidates:
No. of PhD Degrees:
No. of Master's Degrees:
No. of Bachelor's Degrees:
Human Research Program Elements: (1) SR:Space Radiation
Human Research Program Risks: (1) Cancer:Risk of Radiation Carcinogenesis
(2) CVD:Risk of Spaceflight Induced Cardiovascular Disease (IRP Rev L)
(3) HFBP Bmed:Risk of Adverse Cognitive or Behavioral Conditions and Psychiatric Disorders (IRP Rev J)
Human Research Program Gaps: (1) BMed-102:Given exposures to spaceflight hazards (space radiation, isolation), how do we identify individual susceptibility, monitor molecular/biomarkers and acceptable thresholds, and validate behavioral health and CNS/neurological/neuropsychological performance measures and domains of relevance to exploration class missions? (IRP Rev L)
(2) BMed-107:What are the long-term changes and risks to astronaut health post-mission that, when using a continuity of care model, helps retrospectively identify and understand individual susceptibility (e.g., hereditary, dose, thresholds) to mitigate adverse CNS, cognitive, and behavioral health changes resulting from long-duration exploration missions, promoting the behavioral health of current and future crews? (IRP Rev L)
(3) Cancer-102:Determine the role of radiation quality on carcinogenesis and shared biology with other degenerative diseases (IRP Rev L)
(4) Cancer-201:Determine the role of dose-rate in space radiation-induced carcinogenesis (IRP Rev L)
(5) Cancer-301:Determine the tissue-specific contributions to overall space radiation carcinogenic risk and whether there are sex-specific dependencies (IRP Rev L)
(6) Cancer-302:Identify tissue-specific surrogate end-points for space radiation induced pre-malignancy and shared biology with other degenerative diseases (IRP Rev L)
(7) Cancer-401:Identify biomarkers for estimating individual susceptibility, risk assessment, and health monitoring (IRP Rev L)
Flight Assignment/Project Notes: NOTE: End date changed to 5/31/2022 per NSSC information (Ed., 3/3/2020)

Task Description: The proposed Carcinogenesis NASA Specialized Center of Research (NSCOR) addresses several key questions for the assessment of radiation risk. The NSCOR consists of four interrelated projects. Project 1 is a biomarker discovery study using integrative “omics” approaches over multiple levels of biological organization and involving multiple species. Biomarkers predictive of the outcomes of HZE (high energy) ion exposures can be used to extrapolate findings in mice to other species, including humans, that are most relevant to NASA’s exploratory missions. The biomarkers are also critical for understanding underlying carcinogenic mechanisms, early disease detection, and subsequent countermeasure development. Project 2 investigates qualitative differences in tumor progression and metastasis between HZE ion- and gamma ray-induced tumors. Project 3 examines the critical question of risk from protracted exposures to high LET (linear energy transfer) radiation at low doses and dose rates. To estimate the carcinogenic effects of these scenarios, we will use chronic exposures to high LET associated neutron radiation as a surrogate for conditions of space-relevant fluence rates and total doses. Project 4 utilizes the resources (irradiated mice and “omics” results) generated in the first three projects to study the neurobehavioral consequences of HZE ion and neutron exposures and whether they are related to tumorigenesis-related outcome measures and predicted by the same or distinct biomarkers.

Two addenda were added to the NSCOR in the April 2017 – March 2018 reporting period. The first was designed to determine if a low dose aspirin regimen could be an effective countermeasure to high LET radiation-induced hepatocellular carcinoma. Two exposure conditions are included, and acute exposure to 0.2 Gy 300 MeV 28Si ions and a chronic exposure to 0.4 Gy of 252Cf neutrons. The second was designed to compare fractioned exposures to a simulated GCR (galactic cosmic radiation) beam to an acute exposure for the induction of hepatocellular carcinoma.

Research Impact/Earth Benefits: Accurately determining the cancer risk from high energy, charged particle radiation exposure is of great importance for designing human spaceflight missions, but it is becoming increasingly important for cancer radiotherapy as well. Radiation oncology appears poised to transition to charged particle radiotherapy in the form of proton therapy and carbon ion therapy. However, one of the risks of treating cancer with charged particle radiation is that the treatment itself can result in a new cancers, known as a second malignant neoplasms (SMN) (commonly used photon radiotherapy also increases SMN risk). The radiotherapy equipment and the patient treatment plans are designed to minimize SMN, but the models to predict risks from various exposures rest on some of the same assumptions about how charged particle radiation causes cancer that are being tested in this NSCOR grant. The results obtained in this program can be used to improve the design of treatment protocols and thus reduce the risks of SMN in radiotherapy patients.

Task Progress & Bibliography Information FY2021 
Task Progress: In Project 1, we found significant overlap of circulating miRNA markers associated with hepatocellular carcinoma (HCC) in humans and mice which supports the feasibility of using the C3H mouse model to develop markers for human disease. Our results from assaying these circulating miRNA markers in a precancerous stage of radiation-induced HCC suggest that they can be used to monitor potential cancer risk during or after spaceflight. Furthermore, they may also be used to monitor high risk individuals for HCC. The integrated transcriptome analysis of mouse HCC samples suggests that high-LET and low-LET radiation induced different molecular subtypes of HCC. These can be correlated with distinct subtypes of human HCCs that have significant differences in clinical outcome. These results have been accepted for publication in Scientific Reports (Ed. note 7/25/21: now published--see Bibliography for Ding et al.).

In Project 2, we found no evidence that high LET radiation exposure leads to enhanced metastatic potential in ether of the two model systems tested. However, we did identify serum biomarkers for preclinical detection of hepatocellular carcinoma. These results have been published online in the International Journal of Radiation Biology (see Bibliography section for Udho et al.).

In Project 3, we calculated survival data for C3H male and BALB/c female mice that received acute exposures to 0.4 Gy of neutrons and compared those results to mice of the same strain and sex irradiated with 0.4 Gy of neutrons at low dose rate (1mGy/day). Acute exposure led to considerable life shortening in female BALB/c mice with a small improvement in survival if the same dose is delivered at low dose rate. In male C3H mice there is also considerable life shortening from the acute exposure, but low dose rate sparing is substantial. Whether the greater detrimental effect of the low dose rate exposure in BALB/c female mice compared to male C3H mice is due to the strain difference or the sex difference is unknown. Note that these results are for overall survival out to 800 days of age; histopathology review of the tumors that arose in these groups is in progress.

In Project 4, Drs. Raber, Emmett, and computational expert Jessica Minnier focused on analyzing the lipid data sets which had been recompiled with a s/n of 5:1. Drs. Emmett and Yu (University of Texas Medical Branch-UTMB) then assigned lipid i.d.s to the significant m/z values identified by computational analysis. Further correlations were made between the behavioral data (Dr. Raber), the miRNA data (Dr. Story), and the lipid data (Dr. Emmett). At this point, biological correlations between all data sets were assigned. The results were reported in the manuscript entitled: "Associations between lipids in selected brain regions, plasma miRNA, and behavioral and cognitive measures following 28Si ion irradiation," which has been published online in Scientific Reports (see Bibliography section for Minnier et al.).

Two Addenda were in progress during the period covered by this report: a study of low dose aspirin as a radiation countermeasure and a comparison of the effects of acute exposure and fractionated exposure to GCRsim. We observed no difference in survival between male C3H mice that received acute GCRsim exposures and those that received fractionated exposures.

Bibliography Type: Description: (Last Updated: 07/25/2021)  Show Cumulative Bibliography Listing
 
Articles in Peer-reviewed Journals Udho EB, Huebner SM, Albrecht DM, Matkowskyj KA, Clipson L, Hedican CA, Koth R, Snow SM, Eberhardt EL, Miller D, Van Doorn R, Gjyzeli G, Spengler EK, Storts DR, Thamm DH, Edmondson EF, Weil MM, Halberg RB, Bacher JW. "Tumor aggressiveness is independent of radiation quality in murine hepatocellular carcinoma and mammary tumor models." Int J Radiat Biol. 2021 Mar 31:1-12. Published online: 31 Mar 2021. https://doi.org/10.1080/09553002.2021.1900946 ; PMID: 33720813 , Mar-2021
Articles in Peer-reviewed Journals Minnier J, Emmett MR, Perez R, Ding LH, Barnette BL, Larios RE, Hong C, Hwang TH, Yu Y, Fallgren CM, Story MD, Weil MM, Raber J. "Associations between lipids in selected brain regions, plasma miRNA, and behavioral and cognitive measures following 28Si ion irradiation." Sci Rep. 2021 Jul 21;11(1):14899. https://doi.org/10.1038/s41598-021-93869-3 ; PMID: 34290258; PMCID: PMC8295277 , Jul-2021
Articles in Peer-reviewed Journals Ding LH, Yu Y, Edmondson EF, Weil MM, Pop LM, McCarthy M, Ullrich RL, Story MD. "Transcriptomic analysis links hepatocellular carcinoma (HCC) in HZE ion irradiated mice to a human HCC subtype with favorable outcomes." Sci Rep. 2021 Jul 7;11(1):14052. https://doi.org/10.1038/s41598-021-93467-3 ; PMID: 34234215; PMCID: PMC8263559 , Jul-2021
Articles in Peer-reviewed Journals Zimmerman B, Kundu P, Rooney WD, Raber J. "The effect of high fat diet on cerebrovascular health and pathology: A species comparative review." Molecules. 2021 Jun 4;26(11):3406. Review. https://doi.org/10.3390/molecules26113406 ; PMID: 34199898; PMCID: PMC8200075 , Jun-2021
Articles in Peer-reviewed Journals Holden S, Perez R, Hall R, Fallgren CM, Ponnaiya B, Garty G, Brenner DJ, Weil MM, Raber J. "Effects of acute and chronic exposure to a mixed field of neutrons and photons and single or fractionated simulated galactic cosmic ray exposure on behavioral and cognitive performance in mice." Radiat Res. 2021 Jul;196(1):31-9. (Online ahead of print 2021 Apr 15.) https://doi.org/10.1667/RADE-20-00228.1 ; PMID: 33857301; PMCID: PMC8297553 , Jul-2021
Articles in Peer-reviewed Journals Raber J, Fuentes Anaya A, Torres ERS, Lee J, Boutros S, Grygoryev D, Hammer A, Kasschau KD, Sharpton TJ, Turker MS, Kronenberg A. "Effects of six sequential charged particle beams on behavioral and cognitive performance in B6D2F1 female and male mice." Front Physiol. 2020 Aug 28;11:959. https://doi.org/10.3389/fphys.2020.00959 ; PMID: 32982769; PMCID: PMC7485338 , Aug-2020
Project Title:  NSCOR: NASA Specialized Center of Research on Carcinogenesis Reduce
Images: icon  Fiscal Year: FY 2020 
Division: Human Research 
Research Discipline/Element:
HRP SR:Space Radiation
Start Date: 06/01/2015  
End Date: 05/31/2022  
Task Last Updated: 10/29/2020 
Download report in PDF pdf
Principal Investigator/Affiliation:   Weil, Michael  Ph.D. / Colorado State University 
Address:  Department of Environmental & Radiological Health Sciences 
1618 Campus Delivery 
Fort Collins , CO 80521-2807 
Email: michael.weil@colostate.edu 
Phone: 970-491-5902  
Congressional District:
Web:  
Organization Type: UNIVERSITY 
Organization Name: Colorado State University 
Joint Agency:  
Comments:  
Co-Investigator(s)
Affiliation: 
Borak, Thomas  Ph.D. Colorado State University 
Emmett, Mark  Ph.D. University Of Texas, Galveston 
Hwang, Tae Hyun  Ph.D. University of Texas Southwestern Medical Center at Dallas 
Ray, F. Andrew  Ph.D. Colorado State University 
Bacher, Jeff  Ph.D. Promega Corporation 
Halberg, Richard  Ph.D. University of Wisconsin, Madison 
Raber, Jacob  Ph.D. Oregon Health & Science University 
Story, Michael  Ph.D. University of Texas Southwestern Medical Center at Dallas 
Ullrich, Robert  Ph.D. University of Texas, Galveston 
Brandl, Alexander  Colorado State University 
Key Personnel Changes / Previous PI: April 2020 report: Dr. Thamm has completed his role on the NSCOR. April 2019 report: Dr. Robert L Ullrich has transitioned from NSCOR Co-Director to Consultant ; Dr. Michael D. Story now serves as the Co-Director.
Project Information: Grant/Contract No. NNX15AK13G 
Responsible Center: NASA JSC 
Grant Monitor: Elgart, Robin  
Center Contact: 281-244-0596 (o)/832-221-4576 (m) 
shona.elgart@nasa.gov 
Solicitation / Funding Source: 2013-14 HERO NNJ13ZSA002N-NSCOR Radiation 
Grant/Contract No.: NNX15AK13G 
Project Type: GROUND 
Flight Program:  
TechPort: No 
No. of Post Docs:
No. of PhD Candidates:
No. of Master's Candidates:  
No. of Bachelor's Candidates:
No. of PhD Degrees:
No. of Master's Degrees:
No. of Bachelor's Degrees:
Human Research Program Elements: (1) SR:Space Radiation
Human Research Program Risks: (1) Cancer:Risk of Radiation Carcinogenesis
(2) CVD:Risk of Spaceflight Induced Cardiovascular Disease (IRP Rev L)
(3) HFBP Bmed:Risk of Adverse Cognitive or Behavioral Conditions and Psychiatric Disorders (IRP Rev J)
Human Research Program Gaps: (1) BMed-102:Given exposures to spaceflight hazards (space radiation, isolation), how do we identify individual susceptibility, monitor molecular/biomarkers and acceptable thresholds, and validate behavioral health and CNS/neurological/neuropsychological performance measures and domains of relevance to exploration class missions? (IRP Rev L)
(2) BMed-107:What are the long-term changes and risks to astronaut health post-mission that, when using a continuity of care model, helps retrospectively identify and understand individual susceptibility (e.g., hereditary, dose, thresholds) to mitigate adverse CNS, cognitive, and behavioral health changes resulting from long-duration exploration missions, promoting the behavioral health of current and future crews? (IRP Rev L)
(3) Cancer-102:Determine the role of radiation quality on carcinogenesis and shared biology with other degenerative diseases (IRP Rev L)
(4) Cancer-201:Determine the role of dose-rate in space radiation-induced carcinogenesis (IRP Rev L)
(5) Cancer-301:Determine the tissue-specific contributions to overall space radiation carcinogenic risk and whether there are sex-specific dependencies (IRP Rev L)
(6) Cancer-302:Identify tissue-specific surrogate end-points for space radiation induced pre-malignancy and shared biology with other degenerative diseases (IRP Rev L)
(7) Cancer-401:Identify biomarkers for estimating individual susceptibility, risk assessment, and health monitoring (IRP Rev L)
Flight Assignment/Project Notes: NOTE: End date changed to 5/31/2022 per NSSC information (Ed., 3/3/2020)

Task Description: The proposed Carcinogenesis NASA Specialized Center of Research (NSCOR) addresses several key questions for the assessment of radiation risk. The NSCOR consists of four interrelated projects. Project 1 is a biomarker discovery study using integrative “omics” approaches over multiple levels of biological organization and involving multiple species. Biomarkers predictive of the outcomes of HZE (high energy) ion exposures can be used to extrapolate findings in mice to other species, including humans, that are most relevant to NASA’s exploratory missions. The biomarkers are also critical for understanding underlying carcinogenic mechanisms, early disease detection, and subsequent countermeasure development. Project 2 investigates qualitative differences in tumor progression and metastasis between HZE ion- and gamma ray-induced tumors. Project 3 examines the critical question of risk from protracted exposures to high LET (linear energy transfer) radiation at low doses and dose rates. To estimate the carcinogenic effects of these scenarios, we will use chronic exposures to high LET associated neutron radiation as a surrogate for conditions of space-relevant fluence rates and total doses. Project 4 utilizes the resources (irradiated mice and “omics” results) generated in the first three projects to study the neurobehavioral consequences of HZE ion and neutron exposures and whether they are related to tumorigenesis-related outcome measures and predicted by the same or distinct biomarkers.

Two addenda were added to the NSCOR in the April 2017 – March 2018 reporting period. The first was designed to determine if a low dose aspirin regimen could be an effective countermeasure to high LET radiation-induced hepatocellular carcinoma. Two exposure conditions are included, and acute exposure to 0.2 Gy 300 MeV 28Si ions and a chronic exposure to 0.4 Gy of 252Cf neutrons. The second was designed to compare fractioned exposures to a simulated GCR (galactic cosmic radiation) beam to an acute exposure for the induction of hepatocellular carcinoma.

Research Impact/Earth Benefits: Accurately determining the cancer risk from high energy, charged particle radiation exposure is of great importance for designing human spaceflight missions, but it is becoming increasingly important for cancer radiotherapy as well. Radiation oncology appears poised to transition to charged particle radiotherapy in the form of proton therapy and carbon ion therapy. However, one of the risks of treating cancer with charged particle radiation is that the treatment itself can result in a new cancers, known as a second malignant neoplasms (SMN) (commonly used photon radiotherapy also increases SMN risk). The radiotherapy equipment and the patient treatment plans are designed to minimize SMN, but the models to predict risks from various exposures rest on some of the same assumptions about how charged particle radiation causes cancer that are being tested in this NSCOR grant. The results obtained in this program can be used to improve the design of treatment protocols and thus reduce the risks of SMN in radiotherapy patients.

Task Progress & Bibliography Information FY2020 
Task Progress: In Project 1, we performed next generation sequencing (NGS) to measure the levels of circulating miRNA in plasma of C3H mice that developed radiation-induced hepatocellular carcinoma (HCC) or spontaneous HCC. We have also sequenced non-tumor-bearing C3H mice as control. Our analysis indicated that a substantial number of miRNAs exhibited differences in plasma levels between tumor-bearing and non-tumor bearing groups. We compared the mouse data with 12 human HCC circulating miRNA markers published in Nature Scientific Reports, 2019 [Jin, Y., Wong, Y.S., Goh, B.K.P. et al. Circulating microRNAs as Potential Diagnostic and Prognostic Biomarkers in Hepatocellular Carcinoma. Sci Rep 9, 10464 (2019)]. Excluding 2 miRNAs that do not present in mice, we found all of the 10 miRNAs were significantly increased in HCC-bearing mice. We have also performed NGS profiling of circulating miRNA using samples that consist of time-series of irradiated F2 (C3H x BALB/c) mice that eventually developed HCC. We finished sequencing in March and the data analysis is ongoing. We expect that analysis from F2 data will validate the results of the C3H cohort and will determine whether we can identify early diagnostic markers of HCC in precancerous stage.

In Project 2, we performed comparative analysis of gene expression profiles between mouse and human HCC. The human HCC gene expression profile was obtained from The Cancer Genome Atlas (TCGA) published data in Cell. 2017 Jun 15; 169(7):1327–1341.e23. Our analysis identified subgroups of human HCC patients that resembled gene expression of high-LET radiation-induced HCC or low-LET radiation-induced / spontaneous HCC in mouse model. The high-LET HCC group showed better survival in Kaplan-Meier analysis and were enriched with more tumor-infiltrating immune cells that function as tumor suppressors when compared with other types of HCC.

We also developed and validated the C3H Afp-mCherry mouse model for HCC. This model consists of the C3H susceptible strain with the addition of an mCherry fluorescent reporter driven by the alpha fetoprotein (Afp) promoter. The reporter is designed to fluorescently label cancer cells for simple and unambiguous identification of liver tumors and metastasis. Using this mouse model, we have identified biomarkers for early detection of liver disease, many of which are also established biomarkers used for diagnosis of human liver disease (e.g., AFP and ALT). Cholesterol and albumin serum biomarkers were elevated in an HCC specific manner, a finding in humans that indicates a steatohepatitic HCC subtype. Interestingly, the vast majority of HCCs observed in the C3H Afp-mCherry congenic mice are of the steatohepatitic subtype. HCC prognosis is rather poor due to late diagnosis and poor sensitivity of current testing methods. We have shown that elevated plasma AFP is capable of identifying mice that will eventually develop HCC, at least 6 months in advance of when tumors are typically detectible in C3H mice. In combination with other biomarkers being identified in this NSCOR, there is the potential to develop a panel of biomarkers for a minimally invasive blood test to identify early stage liver disease in mice that could potentially be translatable for use in humans. Lung lesions arising in our irradiated mice are currently being examined to determine if they are metastasized from the liver. Results of these analyses will help us answer the question of whether there is an increased HCC malignancy from HZE Ions.

In Project 3, we calculated survival data for C3H male and BALB/c female mice irradiated with 252Cf neutrons at low dose rate (1mGy/day). Histopathology review on these groups is in progress.

In Project 4, BALB/c and C3H female and male mice and their F2 hybrid progeny were irradiated with 28Si ions (350 MeV/n, 0.2 Gy) and tested for behavioral and cognitive performance 1, 6, and 12 months following irradiation. The plasma of the mice was collected for analysis of miRNA levels. Select, pertinent brain regions were dissected for lipidomics analyses and analyses of levels of select biomarkers shown to be sensitive to effects of space radiation in previous studies. We analyzed the relationships between behavioral and cognitive measures, plasma miRNAs, lipid in pertinent brain regions, and biomarkers in brain sensitive to effects of radiation in previous studies. A manuscript with these data is currently being finalized.

The miRNA expression patterns developed in Project 1 have been applied to the endpoints for cognitive function being developed in Project 4. There are numerous miRNA, already identified as associated with a number of psychologic disturbances, fear for example, whose expression is altered in mice responding to different cognitive stimuli. These data are being analyzed now.

Raw lipid data sets collected on the brain samples provided by Dr. Raber have been recompiled with a s/n of 5:1. These files were sent to Dr. Raber’s group on 3/5/2020 and his computational mathematician (Jessica Minnier) is analyzing the data now. When complete we will correlate to the lipid i.d.s and determine biological significance correlated to the behavioral data.

Two Addenda were in progress during the period covered by this report: a study of low dose aspirin as a radiation countermeasure and a comparison of the effects of acute exposure and fractionated exposure to GCRsim. We saw no difference in either survival or tumor-free survival for mice on a low dose aspirin regimen during and following acute 28Si ion exposure. A similar study of aspirin efficacy against low dose rate neutron exposure is in progress.

Major Milestones (April 2019 – March 2020)

- A new mouse model for HCC has been developed and validated for studying HCC. 264 F1 and 264 C3H Afp-mCherry congenic male and female mice have been irradiated and blood samples collected at 3 to 6 month intervals and liver and lung tissues at terminal collections (21 to 24 months post irradiation).

- We have shown that the new mouse model containing the mCherry reporter for labeling cancer cells allows for unambiguous identification of liver tumors and metastases.

- Plasma and tumor biomarkers have been identified that detect liver disease can predict the development of HCC before any visible sign of a tumor using simple blood tests.

- Low dose rate (1 mGy/day) neutron irradiation leads to dose dependent life shortening in female mice.

- A low dose aspirin regimen dose not improve overall survival or tumor-free survival following acute 28Si ion exposure.

- Plasma miRNAs that distinguish between tumor-bearing and non-tumor mice have been identified.

Bibliography Type: Description: (Last Updated: 07/25/2021)  Show Cumulative Bibliography Listing
 
Abstracts for Journals and Proceedings Weil MM, Ullrich RL, Ding L, Emmett MR, Yu Y, Bacher JS, Halberg R Raber, J, Ray FA, Thamm D, Borak TB, Story MC. "Carcinogenesis NSCOR: Overview." Oral Presentation at: 2020 NASA Human Research Program Investigators’ Workshop, Galveston, TX, January 27-30, 2020.

Meeting program. 2020 NASA Human Research Program Investigators’ Workshop, Galveston, TX, January 27-30, 2020. , Jan-2020

Abstracts for Journals and Proceedings Borak TB, Weil MM. "Chronic Neutron Radiation Exposure." Oral presentation at the 35th Annual Meeting of the American Society for Gravitational and Space Research, Denver, CO, November 20-23, 2019.

Meeting program. 35th Annual Meeting of the American Society for Gravitational and Space Research, Denver, CO, November 20-23, 2019. , Nov-2019

Abstracts for Journals and Proceedings Udho E. "Carcinogenesis NSCOR: Biomarkers of Radiation Damage and Liver Disease in a New Mouse Model." Oral presentation at the 2020 NASA Human Research Program Investigators’ Workshop, Galveston, TX, January 27-30, 2020.

Meeting program. 2020 NASA Human Research Program Investigators’ Workshop, Galveston, TX, January 27-30, 2020. , Jan-2020

Abstracts for Journals and Proceedings Raber J, Perez R, Fallgren C, Emmett M, Bartnette B, Ullrich R, Ding L, Bacher J, Udo E, Hallberg R, Ray A, Borak T, Story M, Weil M. "Carcinogenesis NSCOR: Neurobehavioral Characterization, Biomarkers and Countermeasures." Oral presentation at the 2020 NASA Human Research Program Investigators’ Workshop, Galveston, TX, January 27-30, 2020.

Meeting program. 2020 NASA Human Research Program Investigators’ Workshop, Galveston, TX, January 27-30, 2020. , Jan-2020

Abstracts for Journals and Proceedings Raber J, Perez R, Glaeser B, Rockwell K, Sterett J, Nawarong N, Lenarczyk M, Olsen CM, Baker J. "Effects of mixed beam irradiation in the presence and absence of hindlimb unloading on behavioral and cognitive performance in WAG rats." Oral presentation at the 2020 NASA Human Research Program Investigators’ Workshop, Galveston, TX, January 27-30, 2020.

Meeting program. 2020 NASA Human Research Program Investigators’ Workshop, Galveston, TX, January 27-30, 2020. , Jan-2020

Abstracts for Journals and Proceedings Emmett M, Yu Y, Barnette B, Watson Z, Ullrich R, Weil M. "Lipid profiling of liver and serum from C3H and BALB/C mice irradiated with 28Si." Poster presented at the 2020 NASA Human Research Program Investigators’ Workshop, Galveston, TX, January 27-30, 2020.

Meeting program. 2020 NASA Human Research Program Investigators’ Workshop, Galveston, TX, January 27-30, 2020. , Jan-2020

Abstracts for Journals and Proceedings Weber Boutros S, Perez RE, Lee JS, Raber J. "Amifostine as a potential countermeasure against cognitive injury induced by space radiation. " Poster presented at the 2020 NASA Human Research Program Investigators’ Workshop, Galveston, TX, January 27-30, 2020.

Meeting program. 2020 NASA Human Research Program Investigators’ Workshop, Galveston, TX, January 27-30, 2020. , Jan-2020

Abstracts for Journals and Proceedings Weil MM, Borak TB, Emmett MR, Bacher JW, Raber J, Yu Y, Halberg R, Ding L, Story MD. "An overview of the NASA Specialized Center of Research on Carcinogenesis." Poster presented at the 65th Annual Meeting of the Radiation Research Society, San Diego, CA, November 3-6, 2019.

Meeting program. 65th Annual Meeting of the Radiation Research Society, San Diego, CA, November 3-6, 2019. , Nov-2019

Articles in Peer-reviewed Journals Perez RE, Younger S, Bertheau E, Fallgren CM, Weil MM, Raber J. "Effects of chronic exposure to a mixed field of neutrons and photons on behavioral and cognitive performance in mice." Behav Brain Res. 2020 Feb 3;379:112377. Epub 2019 Nov 22. https://doi.org/10.1016/j.bbr.2019.112377 ; PMID: 31765722 , Feb-2020
Articles in Peer-reviewed Journals Borak TB, Heilbronn LH, Krumland N, Weil MM. "Design and dosimetry of a facility to study health effects following exposures to fission neutrons at low dose rates for long durations." Int J Radiat Biol. 2019 Nov 14:1-14. Published online: 14 Nov 2019. https://doi.org/10.1080/09553002.2019.1688884 ; PMID: 31687872 , Nov-2019
Articles in Peer-reviewed Journals Raber J, Arzy S, Bertolus JB, Depue B, Haas HE, Hofmann SG, Kangas M, Kensinger E, Lowry CA, Marusak HA, Minnier J, Mouly AM, Mühlberger A, Norrholm SD, Peltonen K, Pinna G, Rabinak C, Shiban Y, Soreq H, van der Kooij MA, Lowe L, Weingast LT, Yamashita P, Boutros SW. "Current understanding of fear learning and memory in humans and animal models and the value of a linguistic approach for analyzing fear learning and memory in humans." Neurosci Biobehav Rev. 2019 Oct;105:136-77. Epub 2019 Apr 7. https://doi.org/10.1016/j.neubiorev.2019.03.015 ; PMID: 30970272 , Oct-2019
Articles in Peer-reviewed Journals Stefanova E, Dubljevic O, Herbert C, Fairfield B, Schroeter ML, Stern ER, Urben S, Derntl B, Wiebking C, Brown C, Drach-Zahavy A, Kathrin Loeffler LA, Albrecht F, Palumbo R, Boutros SW, Raber J, Lowe L. "Anticipatory feelings: Neural correlates and linguistic markers." Neurosci Biobehav Rev. 2020 Jun;113:308-24. https://doi.org/10.1016/j.neubiorev.2020.02.015 ; PMID: 32061891 , Jun-2020
Articles in Peer-reviewed Journals Torres ERS, Hall R, Bobe G, Choi J, Impey S, Pelz C, Lindner JR, Stevens JF, Raber J. "Integrated metabolomics-DNA methylation analysis reveals significant long-term tissue-dependent directional alterations in aminoacyl-tRNA biosynthesis in the left ventricle of the heart and hippocampus following proton irradiation." Front Mol Biosci. 2019 Sep 10;6:77. https://doi.org/10.3389/fmolb.2019.00077 ; PMID: 31552266; PMCID: PMC6746933 , Sep-2019
Articles in Peer-reviewed Journals Edmondson EF, Gatti DM, Ray FA, Garcia EL, Fallgren CM, Kamstock DA, Weil MM. "Genomic mapping in outbred mice reveals overlap in genetic susceptibility for HZE ion- and γ -ray-induced tumors." Sci Adv. 2020 Apr 15;6(16):eaax5940. https://doi.org/10.1126/sciadv.aax5940 ; PMID: 32494593; PMCID: PMC7159905 , Apr-2020
Articles in Peer-reviewed Journals Acharya MM, Baulch JE, Klein PM, Baddour AAD, Apodaca LA, Kramar EA, Alikhani L, Garcia C Jr, Angulo MC, Batra RS, Fallgren CM, Borak TB, Stark CEL, Wood MA, Britten RA, Soltesz I, Limoli CL. "New concerns for neurocognitive function during deep space exposures to chronic, low dose rate, neutron radiation." eNeuro. 2019 Aug 22;6(4):ENEURO.0094-19.2019. https://doi.org/10.1523/ENEURO.0094-19.2019 ; PMID: 31383727; PMCID: PMC6709229 , Aug-2019
Articles in Peer-reviewed Journals Cornforth MN, Anur P, Wang N, Robinson E, Ray FA, Bedford JS, Loucas BD, Williams ES, Peto M, Spellman P, Kollipara R, Kittler R, Gray JW, Bailey SM. "Molecular cytogenetics guides massively parallel sequencing of a radiation-induced chromosome translocation in human cells." Radiat Res. 2018 Jul;190(1):88-97. https://doi.org/10.1667/RR15053.1 ; PubMed PMID: 29749794; PubMed Central PMCID: PMC6055522 , Jul-2018
Project Title:  NSCOR: NASA Specialized Center of Research on Carcinogenesis Reduce
Images: icon  Fiscal Year: FY 2019 
Division: Human Research 
Research Discipline/Element:
HRP SR:Space Radiation
Start Date: 06/01/2015  
End Date: 05/30/2020  
Task Last Updated: 04/08/2019 
Download report in PDF pdf
Principal Investigator/Affiliation:   Weil, Michael  Ph.D. / Colorado State University 
Address:  Department of Environmental & Radiological Health Sciences 
1618 Campus Delivery 
Fort Collins , CO 80521-2807 
Email: michael.weil@colostate.edu 
Phone: 970-491-5902  
Congressional District:
Web:  
Organization Type: UNIVERSITY 
Organization Name: Colorado State University 
Joint Agency:  
Comments:  
Co-Investigator(s)
Affiliation: 
Borak, Thomas  Ph.D. Colorado State University 
Emmett, Mark  Ph.D. University Of Texas, Galveston 
Hwang, Tae Hyun  Ph.D. University of Texas Southwestern Medical Center at Dallas 
Liber, Howard  Ph.D. Colorado State University 
Ray, F. Andrew  Ph.D. Colorado State University 
Thamm, Douglas  V.M.D. Colorado State University 
Bacher, Jeff  Ph.D. Promega Corporation 
Halberg, Richard  Ph.D. University of Wisconsin, Madison 
Raber, Jacob  Ph.D. Oregon Health & Science University 
Story, Michael  Ph.D. University of Texas Southwestern Medical Center at Dallas 
Ullrich, Robert  Ph.D. University of Texas, Galveston 
Key Personnel Changes / Previous PI: April 2019 report: Dr. Robert L Ullrich has transitioned from NSCOR Co-Director to Consultant ; Dr. Michael D. Story now serves as the Co-Director.
Project Information: Grant/Contract No. NNX15AK13G 
Responsible Center: NASA JSC 
Grant Monitor: Simonsen, Lisa  
Center Contact:  
lisa.c.simonsen@nasa.gov 
Solicitation / Funding Source: 2013-14 HERO NNJ13ZSA002N-NSCOR Radiation 
Grant/Contract No.: NNX15AK13G 
Project Type: GROUND 
Flight Program:  
TechPort: No 
No. of Post Docs:
No. of PhD Candidates:
No. of Master's Candidates:  
No. of Bachelor's Candidates:
No. of PhD Degrees:
No. of Master's Degrees:
No. of Bachelor's Degrees:
Human Research Program Elements: (1) SR:Space Radiation
Human Research Program Risks: (1) Cancer:Risk of Radiation Carcinogenesis
(2) CVD:Risk of Spaceflight Induced Cardiovascular Disease (IRP Rev L)
(3) HFBP Bmed:Risk of Adverse Cognitive or Behavioral Conditions and Psychiatric Disorders (IRP Rev J)
Human Research Program Gaps: (1) BMed-102:Given exposures to spaceflight hazards (space radiation, isolation), how do we identify individual susceptibility, monitor molecular/biomarkers and acceptable thresholds, and validate behavioral health and CNS/neurological/neuropsychological performance measures and domains of relevance to exploration class missions? (IRP Rev L)
(2) BMed-107:What are the long-term changes and risks to astronaut health post-mission that, when using a continuity of care model, helps retrospectively identify and understand individual susceptibility (e.g., hereditary, dose, thresholds) to mitigate adverse CNS, cognitive, and behavioral health changes resulting from long-duration exploration missions, promoting the behavioral health of current and future crews? (IRP Rev L)
(3) Cancer-102:Determine the role of radiation quality on carcinogenesis and shared biology with other degenerative diseases (IRP Rev L)
(4) Cancer-201:Determine the role of dose-rate in space radiation-induced carcinogenesis (IRP Rev L)
(5) Cancer-301:Determine the tissue-specific contributions to overall space radiation carcinogenic risk and whether there are sex-specific dependencies (IRP Rev L)
(6) Cancer-302:Identify tissue-specific surrogate end-points for space radiation induced pre-malignancy and shared biology with other degenerative diseases (IRP Rev L)
(7) Cancer-401:Identify biomarkers for estimating individual susceptibility, risk assessment, and health monitoring (IRP Rev L)
Task Description: The proposed Carcinogenesis NASA Specialized Center of Research (NSCOR) addresses several key questions for the assessment of radiation risk. The NSCOR consists of four interrelated projects. Project 1 is a biomarker discovery study using integrative “omics” approaches over multiple levels of biological organization and involving multiple species. Biomarkers predictive of the outcomes of HZE (high energy) ion exposures can be used to extrapolate findings in mice to other species, including humans, that are most relevant to NASA’s exploratory missions. The biomarkers are also critical for understanding underlying carcinogenic mechanisms, early disease detection, and subsequent countermeasure development. Project 2 investigates qualitative differences in tumor progression and metastasis between HZE ion- and gamma ray-induced tumors. Project 3 examines the critical question of risk from protracted exposures to high LET (linear energy transfer) radiation at low doses and dose rates. To estimate the carcinogenic effects of these scenarios, we will use chronic exposures to high LET associated neutron radiation as a surrogate for conditions of space-relevant fluence rates and total doses. Project 4 utilizes the resources (irradiated mice and “omics” results) generated in the first three projects to study the neurobehavioral consequences of HZE ion and neutron exposures and whether they are related to tumorigenesis-related outcome measures and predicted by the same or distinct biomarkers.

Two addenda were added to the NSCOR in the April 2017 – March 2018 reporting period. The first was designed to determine if a low dose aspirin regimen could be an effective countermeasure to high LET radiation-induced hepatocellular carcinoma. Two exposure conditions are included, and acute exposure to 0.2 Gy 300 MeV 28Si ions and a chronic exposure to 0.4 Gy of 252Cf neutrons. The second was designed to compare fractioned exposures to a simulated GCR (galactic cosmic radiation) beam to an acute exposure for the induction of hepatocellular carcinoma.

Research Impact/Earth Benefits: Accurately determining the cancer risk from high energy, charged particle radiation exposure is of great importance for designing human spaceflight missions, but it is becoming increasingly important for cancer radiotherapy as well. Radiation oncology appears poised to transition to charged particle radiotherapy in the form of proton therapy and carbon ion therapy. However, one of the risks of treating cancer with charged particle radiation is that the treatment itself can result in a new cancers, known as a second malignant neoplasms (SMN) (commonly used photon radiotherapy also increases SMN risk). The radiotherapy equipment and the patient treatment plans are designed to minimize SMN, but the models to predict risks from various exposures rest on some of the same assumptions about how charged particle radiation causes cancer that are being tested in this NSCOR grant. The results obtained in this program can be used to improve the design of treatment protocols and thus reduce the risks of SMN in radiotherapy patients.

Task Progress & Bibliography Information FY2019 
Task Progress: For Project 1, we collected tissue samples of lung, liver, amygdala and hypothalamus, along with serum, plasma, and feces from the unirradiated and 28Si irradiated parental strains (BALB/c and C3H). Lipid profiling was completed on the liver, lung, amygdala, hypothalamus, and serum samples from all post-irradiation time points (1, 6, 12, and 18 months). Circulating miRNA from blood plasma was analyzed at 1, 6, and 12 months. 18 month plasma samples were not collected. Strain appears to be the largest factor in characterizing the miRNA found in blood plasma, followed by time post-irradiation. Sex is but a modest factor of variation. The presence of 87 miRNA can be partitioned into 15 clusters based upon their presence at a given time. These patterns can be used to develop predictors for hepatocellular carcinoma (HCC) risk and then applied across the F2 mice as validation.

We monitored the F2 mice until they became moribund or reached 800 days of age. All of the F2 mice have now been necropsied and any tissue lesions detected were prepared for histopathology. Histopathology has been completed on about half of these mice.

In Project 2, we completed the sample collection from the (B6C3H)F1 Tg::Apf-mCherry mice. Liver and lung tissue sections were examined by a pathologist and we have found a variety of pathologies in the liver (HCC, dysplastic nodules, hepatitis, and steatosis) and lung (peribronchial chronic inflammation and carcinoma), though no major difference among treatment groups (sham, gamma-irradiated, and silicon-irradiated) was observed. Our mouse model was validated and found to be an excellent model for detecting early alpha fetoprotein (AFP) expression in liver disease as well as for unambiguous identification of metastasis from the liver to other tissues. Among the approximately 30 measurements obtained from plasma and whole blood (liquid biopsy-accessible measurements), we have found AFP and alanine aminotransferase (ALT) to be good predictors of the presence of liver disease (sensitivity 60-70%, specificity 85-90%).

Our second cohort of mice, the C3H Tg::Afp-mCherry, which also include a pilot study with the radioprotectant PrC-210, were irradiated a tNASA Space Radiation Laboratory (NSRL) NSRL18A and we completed plasma collections at two timepoints (6 and 9 months post irradiation) for our longitudinal study.

Also ongoing in Project 2 is the genomic and epigenomic characterization of HCC tumors in C3H mice. At this juncture we have started to develop approaches that use other HCC data sets from mice based upon exposures to chemicals (7 datasets) or in genetically engineered mouse strains (4 datasets) to compare to low LET, high LET, or spontaneous tumors generated in the prior NSCOR. Furthermore, we have begun making comparisons of these mouse datasets to datasets for human HCC.

In Project 3 we completed the low dose rate neutron irradiations and performed acute neutron exposures at Columbia University. We also completed low dose neutron exposures of mice and rats for the CNS (central nervous system) NSCOR, rats for a cardiovascular effects study (Marjan Boerma, Principal Investigator-PI), and mice for an in utero effects study (Jon Steller, PI). The facility is currently being used to irradiate mice for the GI (Gastronintestinal) NSCOR (Albert Fornace, PI), and for a countermeasure addendum and an immunological effects pilot study. In Project 4, we finalized behavioral and cognitive testing of BALB/c, C3H, and F2 mice 1, 6, and 12 months following acute 28Si ion irradiation. At the three time points, plasma was collected for miRNA analyses by Dr. Story’s laboratory at UTSW (University of Texas Southwestern Medical Center) (Project 1). At the three time points, selected mice of the parental strains were sacrificed by cervical dislocation and their hypothalamus and amygdala dissected. The tissues of one hemisphere were analyzed for lipidomics by Dr. Emmett’s laboratory at UTMB (University of Texas Medical Branch at Galveston). Six lipid measures of the mice from the three time points were analyzed. From the hypothalamic and amygdaloid tissues of the other hemisphere, ELISAs were performed to assess levels of the specific biomarkers. For the parental strains, we compiled a large excel file with all the behavioral data for the open field, object recognition, and contextual and cued fear learning and morning, all the plasma miRNA data, and the lipidomics data on the six lipids. The data are currently analyzed for several manuscripts. This year, we also performed a countermeasure study with aspirin. An independent cohort of C3H male mice were tested 6 and 18 months following 28Si ion irradiation as part of an aspirin treatment study. In addition, we started to behaviorally test C3H and BALB/c mice as part of Project 3, following chronic neutron exposure. Mice were tested at 600 days of age in March of 2019. The data are currently being analyzed.

For the Addenda, we began neutron irradiation of mice for the low dose rate arm of the aspirin countermeasure study. We irradiated mice for the GSAM (Galactic Cosmic Ray Simulation and Mitigation) study in November of 2018 (NSRL-18C). 135 male C3H mice were irradiated with 0.4 Gy of simulated GCR split into 19 fractions delivered over 4 weeks. An additional 135 mice received an acute exposure of 0.4 Gy.

Major Milestones (April 2018 – March 2019)

* Lipid data completed for liver, lung and serum for all time points (1, 6, 12 and 18-momth) for Project 1.

* Completed necropsies and histopathology slide preparation for all F2 mice in Project 1.

* Completed low dose rate neutron exposures for Project 3 and performed acute neutron exposures at Columbia University.

* Provide low dose rate neutron exposures for several NASA funded investigators.

* Lipid data completed for amygdala and hypothalamus samples for all time points provided for Project 4.

* Irradiated mice at NSRL for the GSAM study.

* Began the low dose rate exposure aspirin countermeasure study.

* Completed behavioral and cognitive testing of BALB/c, CRH, and F2 mice 1, 6, and 12 months following acute 28Si ion irradiation, along with plasma miRNA, brain lipidomics on 6 lipids.

* Completed behavioral testing of mice treated with aspirin as a contermeasure.

* Completed behavioral testing of C3H and BALB/c following chronic neutron exposure at 600 days of age.

Bibliography Type: Description: (Last Updated: 07/25/2021)  Show Cumulative Bibliography Listing
 
Abstracts for Journals and Proceedings Weil MM, Ullrich RL, Ding L, Emmett M, Yu Y, Bacher JS, Halberg R, Raber J, Edmondson EF, Ray FA, Thamm D, Borak T, Story MD. "Carcinogenesis NSCOR Overview and Dose-Rate Effects." 2019 NASA Human Research Program Investigators’ Workshop, Galveston, TX, January 22-25, 2019.

2019 NASA Human Research Program Investigators’ Workshop, Galveston, TX, January 22-25, 2019. , Jan-2019

Abstracts for Journals and Proceedings Weil MM. "Approaches to understanding space radiation cancer risks." Joint session at Radiation Research Society Annual Meeting and Conference on Radiation and Health Meeting. 64th Annual Meeting of the Radiation Research Society, Chicago, IL, September 23-26, 2018.

64th Annual Meeting of the Radiation Research Society, Chicago, IL, September 23-26, 2018. , Sep-2018

Abstracts for Journals and Proceedings Halberg R. "Mechanisms Underlying Increased Malignancy from Space Radiation." 2019 NASA Human Research Program Investigators’ Workshop, Galveston, TX, January 22-25, 2019.

2019 NASA Human Research Program Investigators’ Workshop, Galveston, TX, January 22-25, 2019. , Jan-2019

Abstracts for Journals and Proceedings Raber J, Turker M, Impey S. "A general space radiation synaptic signature in hippocampus following proton, 56Fe, and 28Si ion irradiation." Session; F2.2: Space Radiation Risk and Countermeasures: Physical and Biophysical Mechanisms, Modelling and Simulations. Committee on Space Research (COSPAR) 2018 42nd Scientific Assembly, Pasadena, CA, July 14-22, 2018.

Committee on Space Research (COSPAR) 2018 42nd Scientific Assembly, Pasadena, CA, July 14-22, 2018. , Jul-2018

Abstracts for Journals and Proceedings Kronenberg A, Gauny S, Gygoryev D, Fuentes Anaya A, Lee J, Torres ERS, Boutros S, Turker M, Raber J. "GCR simulation studies with human and mouse models." 2019 NASA Human Research Program Investigators’ Workshop, Galveston, TX, January 22-25, 2019.

2019 NASA Human Research Program Investigators’ Workshop, Galveston, TX, January 22-25, 2019. , Jan-2019

Abstracts for Journals and Proceedings Raber J, Perez R, Fallgren C, Emmett M, Bartnette B, Ullrich R, Ding L, Bacher J, Udo E, Halberg R, Ray A, Borak T, Story M, Weil M. "Carcinogenesis NSCOR: Neurobehavioral Characterization, Biomarkers and Countermeasures." 2019 NASA Human Research Program Investigators’ Workshop, Galveston, TX, January 22-25, 2019.

2019 NASA Human Research Program Investigators’ Workshop, Galveston, TX, January 22-25, 2019. , Jan-2019

Abstracts for Journals and Proceedings Bacher J, Udho E, Koth R, Matkowskyj K, Huebner S, Albrecht D, Newton M, Vo T, Dague K, Storts D, Weil M, Halberg R. "Hepatocellular Carcinoma: A New Mouse Model and Biomarker Identification." 2019 NASA Human Research Program Investigators’ Workshop, Galveston, TX, January 22-25, 2019.

2019 NASA Human Research Program Investigators’ Workshop, Galveston, TX, January 22-25, 2019. , Jan-2019

Abstracts for Journals and Proceedings Borak TB, Krumland N, Phillips P, Weil MM. "A Facility to Investigate Health Effects from High LET Radiation at Space-Relevant Dose Rates and Total Exposures." 2019 NASA Human Research Program Investigators’ Workshop, Galveston, TX, January 22-25, 2019.

2019 NASA Human Research Program Investigators’ Workshop, Galveston, TX, January 22-25, 2019. , Jan-2019

Abstracts for Journals and Proceedings Selemenakis P, Weber S, Raber J, Kim S, Wiese C. "How does exposure of the brain to ionizing radiation lead to cognitive injury?" 64th Annual Meeting of the Radiation Research Society, Chicago, IL, September 23-26, 2018.

64th Annual Meeting of the Radiation Research Society, Chicago, IL, September 23-26, 2018. , Sep-2018

Abstracts for Journals and Proceedings Bacher J, Udo E, Halberg R, Raber J, Perez R, Emmett MR, Ullrich RL, Ding L, Ray FA, Story MC, Weil MM. "Carcinogenesis NSCOR: Mechanisms Underlying Increase Hepatocellular Carcinoma Malignancy from Space Radiation." 2019 NASA Human Research Program Investigators’ Workshop, Galveston, TX, January 22-25, 2019.

2019 NASA Human Research Program Investigators’ Workshop, Galveston, TX, January 22-25, 2019. , Jan-2019

Abstracts for Journals and Proceedings Ray FA, Fallgren CM, Weil MM. "GSAM Project: Feasibility of an Extended Fractionation Exposure." 2019 NASA Human Research Program Investigators’ Workshop, Galveston, TX, January 22-25, 2019.

2019 NASA Human Research Program Investigators’ Workshop, Galveston, TX, January 22-25, 2019. , Jan-2019

Articles in Peer-reviewed Journals Ochola DO, Sharif R, Bedford JS, Keefe TJ, Kato TA, Fallgren CM, Demant P, Costes SV, Weil MM. "Persistence of gamma-H2AX foci in bronchial cells correlates with susceptibility to radiation associated lung cancer in mice." Radiat Res. 2019 Jan;191(1):67-75. Epub 2018 Nov 6. https://doi.org/10.1667/RR14979.1 ; PubMed PMID: 30398394 , Jan-2019
Project Title:  NSCOR: NASA Specialized Center of Research on Carcinogenesis Reduce
Images: icon  Fiscal Year: FY 2018 
Division: Human Research 
Research Discipline/Element:
HRP SR:Space Radiation
Start Date: 06/01/2015  
End Date: 05/30/2020  
Task Last Updated: 04/30/2018 
Download report in PDF pdf
Principal Investigator/Affiliation:   Weil, Michael  Ph.D. / Colorado State University 
Address:  Department of Environmental & Radiological Health Sciences 
1618 Campus Delivery 
Fort Collins , CO 80521-2807 
Email: michael.weil@colostate.edu 
Phone: 970-491-5902  
Congressional District:
Web:  
Organization Type: UNIVERSITY 
Organization Name: Colorado State University 
Joint Agency:  
Comments:  
Co-Investigator(s)
Affiliation: 
Borak, Thomas  Ph.D. Colorado State University 
Emmett, Mark  Ph.D. University Of Texas, Galveston 
Hwang, Tae Hyun  Ph.D. University of Texas Southwestern Medical Center at Dallas 
Liber, Howard  Ph.D. Colorado State University 
Ray, F. Andrew  Ph.D. Colorado State University 
Thamm, Douglas  V.M.D. Colorado State University 
Bacher, Jeff  Ph.D. Promega Corporation 
Halberg, Richard  Ph.D. University of Wisconsin, Madison 
Raber, Jacob  Ph.D. Oregon Health & Science University 
Story, Michael  Ph.D. University of Texas Southwestern Medical Center at Dallas 
Ullrich, Robert  Ph.D. University of Texas, Galveston 
Project Information: Grant/Contract No. NNX15AK13G 
Responsible Center: NASA JSC 
Grant Monitor: Simonsen, Lisa  
Center Contact:  
lisa.c.simonsen@nasa.gov 
Solicitation / Funding Source: 2013-14 HERO NNJ13ZSA002N-NSCOR Radiation 
Grant/Contract No.: NNX15AK13G 
Project Type: GROUND 
Flight Program:  
TechPort: No 
No. of Post Docs:  
No. of PhD Candidates:
No. of Master's Candidates:  
No. of Bachelor's Candidates:
No. of PhD Degrees:
No. of Master's Degrees:
No. of Bachelor's Degrees:
Human Research Program Elements: (1) SR:Space Radiation
Human Research Program Risks: (1) Cancer:Risk of Radiation Carcinogenesis
(2) CVD:Risk of Spaceflight Induced Cardiovascular Disease (IRP Rev L)
(3) HFBP Bmed:Risk of Adverse Cognitive or Behavioral Conditions and Psychiatric Disorders (IRP Rev J)
Human Research Program Gaps: (1) BMed-102:Given exposures to spaceflight hazards (space radiation, isolation), how do we identify individual susceptibility, monitor molecular/biomarkers and acceptable thresholds, and validate behavioral health and CNS/neurological/neuropsychological performance measures and domains of relevance to exploration class missions? (IRP Rev L)
(2) BMed-107:What are the long-term changes and risks to astronaut health post-mission that, when using a continuity of care model, helps retrospectively identify and understand individual susceptibility (e.g., hereditary, dose, thresholds) to mitigate adverse CNS, cognitive, and behavioral health changes resulting from long-duration exploration missions, promoting the behavioral health of current and future crews? (IRP Rev L)
(3) Cancer-102:Determine the role of radiation quality on carcinogenesis and shared biology with other degenerative diseases (IRP Rev L)
(4) Cancer-201:Determine the role of dose-rate in space radiation-induced carcinogenesis (IRP Rev L)
(5) Cancer-301:Determine the tissue-specific contributions to overall space radiation carcinogenic risk and whether there are sex-specific dependencies (IRP Rev L)
(6) Cancer-302:Identify tissue-specific surrogate end-points for space radiation induced pre-malignancy and shared biology with other degenerative diseases (IRP Rev L)
(7) Cancer-401:Identify biomarkers for estimating individual susceptibility, risk assessment, and health monitoring (IRP Rev L)
Task Description: The proposed Carcinogenesis NASA Specialized Center of Research (NSCOR) addresses several key questions for the assessment of radiation risk. The NSCOR consists of four interrelated projects. Project 1 is a biomarker discovery study using integrative “omics” approaches over multiple levels of biological organization and involving multiple species. Biomarkers predictive of the outcomes of HZE (high energy) ion exposures can be used to extrapolate findings in mice to other species, including humans, that are most relevant to NASA’s exploratory missions. The biomarkers are also critical for understanding underlying carcinogenic mechanisms, early disease detection, and subsequent countermeasure development. Project 2 investigates qualitative differences in tumor progression and metastasis between HZE ion- and gamma ray-induced tumors. Project 3 examines the critical question of risk from protracted exposures to high LET (linear energy transfer) radiation at low doses and dose rates. To estimate the carcinogenic effects of these scenarios, we will use chronic exposures to high LET associated neutron radiation as a surrogate for conditions of space-relevant fluence rates and total doses. Project 4 utilizes the resources (irradiated mice and “omics” results) generated in the first three projects to study the neurobehavioral consequences of HZE ion and neutron exposures and whether they are related to tumorigenesis-related outcome measures and predicted by the same or distinct biomarkers.

Two addenda were added to the NSCOR in the April 2017 – March 2018 reporting period. The first was designed to determine if a low dose aspirin regimen could be an effective countermeasure to high LET radiation-induced hepatocellular carcinoma. Two exposure conditions are included, and acute exposure to 0.2 Gy 300 MeV 28Si ions and a chronic exposure to 0.4 Gy of 252Cf neutrons. The second was designed to compare fractioned exposures to a simulated GCR (galactic cosmic radiation) beam to an acute exposure for the induction of hepatocellular carcinoma.

Research Impact/Earth Benefits: Accurately determining the cancer risk from high energy, charged particle radiation exposure is of great importance for designing human spaceflight missions, but it is becoming increasingly important for cancer radiotherapy as well. Radiation oncology appears poised to transition to charged particle radiotherapy in the form of proton therapy and carbon ion therapy. However, one of the risks of treating cancer with charged particle radiation is that the treatment itself can result in a new cancers, known as a second malignant neoplasms (SMN) (commonly used photon radiotherapy also increases SMN risk). The radiotherapy equipment and the patient treatment plans are designed to minimize SMN, but the models to predict risks from various exposures rest on some of the same assumptions about how charged particle radiation causes cancer that are being tested in this NSCOR grant. The results obtained in this program can be used to improve the design of treatment protocols and thus reduce the risks of SMN in radiotherapy patients.

Task Progress & Bibliography Information FY2018 
Task Progress: In Project 1, we collected serum, plasma, tissue samples and feces for the six and 12 month time points, and completed the gamma-H2AX assay on 32 of the fibroblast cultures established from 316 irradiated F2 mice. We found an expected and encouraging level of interindividual variance in double strand break (DSB) repair efficacies. We tested the directional genomic hybridization probes for mouse chromosomes 1 to 4 and found that they are not well suited as an exposure biomarker. We began to quantify miR-122-3p in the parental strains based on results obtained with archival samples in project 2. While the results are preliminary, we are seeing strain and sex differences in miR-122-3p levels. We are currently expanding the screening circulating miRNA profiles at various time points after radiation using molecular barcoding and next generation sequencing. The preliminary data indicated high correlation of NGS and qPCR results.

In Project 2, gene expression profiles were re-analyzed using pathologically confirmed archival samples. The analysis identified common signaling pathways in high-LET induced, low-LET induced, and spontaneous hepatocellular carcinoma (HCC). These include activation of PI3K/AKT and suppression of PTEN (phosphatase and tensin homolog deleted from chromosome 10) signaling, which are also the molecular mechanisms in human HCC. Other identified signaling pathways are highly involved in ROS (reactive oxygen species) signaling, inflammatory responses, cell proliferation, and apoptosis. Despite the common molecular pathways, a subset of genes including 815 probes emerged as a signature to separate not only tumor and non-tumor, but also radiation-type in each group. The signature does not have a statistically significant pathway enrichment. We are currently investigating the driver genes and functional impact of this signature on different types of HCC.

We completed experimental metastasis studies with MMTV-PyMT mice and continued studies with Afp-mCherry mice. In the MMTV-PyMT model, we found that high LET exposures do not increase metastatic efficacy.

Ninety Afp-mCherry mice were irradiated or sham irradiated at NASA Space Radiation Laboratory (NSRL). These mice are used to study HCC metastasis to the lung. The mice are being monitored for circulating tumor cells, and some have been sacrificed 3 months post-irradiation to detect the earliest stages of tumorigenesis using newly developed tissue clearing and optical approaches.

Project 3 involves the commissioning of a neutron irradiator in a shielded vivarium that meets the animal care requirements for long term mouse housing. Over the past year we renovated the building, calculated the activity of radioactive material required, and acquired the source and the irradiator. In Project 4, we are determining the effects of space radiation on brain function by performing neurobehavioral tests on mice exposed to simulated space radiation or neutron radiation. This year we completed the behavioral and cognitive testing at three time points following 28Si irradiation (300 MeV/n, 0.2 Gy): 1, 6, and 12 months. A striking observation was that irradiated BALB/c mice and irradiated F2 mice showed more hippocampus-contextual fear memory and a wider range in individual variability in contextual fear memory than irradiated C3H mice. The cognitive data illustrate the individual performance differences in 28Si ion-irradiated mice, especially in irradiated F2 mice and data support the potential to identify biomarkers for radiation-induced cognitive deficits. Eight mice of each treatment and sex were sacrificed and pertinent brain regions dissected for lipidomics analyses in the laboratory by Dr. Mark Emmett at University of Texas Medical Branch (UTMB). 192 samples were extracted and 191 (one sample was lost) were analyzed for comprehensive lipid composition by ultra high-resolution mass spectrometry methods. All samples were block randomized for consistency. Data analysis is in progress.

In addition, Dr. Michael Story at UTSW (University of Texas Southwestern Medical Center) is analyzing plasma miRNA in the same mice. Finally, we are assessing levels of some specific markers shown to be sensitive to effects of aging and space radiation on the brain. In addition to the study described above, an independent cohort of C3H male mice were tested 6 months following 28Si ion irradiation as part of an aspirin treatment study. The dose of aspirin used has CNS (central nervous system) effects in C3H/HeNCrl mice. This is an important finding as the dosing was based on aspirin studies in C57BL/6J mice. We are currently analyzing these data and consider testing at later time points.

For the addenda, we irradiated the mice for the acute 28Si exposure condition in the aspirin countermeasure study. The chronic neutron exposures are scheduled to begin in mid-May or early June of 2018. Work on the GCR simulator addendum is slated to begin in November of 2018 (NSRL-18C).

Bibliography Type: Description: (Last Updated: 07/25/2021)  Show Cumulative Bibliography Listing
 
Abstracts for Journals and Proceedings McGinnis GJ, Yu B, Ransom C, Guidarelli C, Thomas CR Jr, Winters-Stone K, Raber J. "E4 cancer survivors show better fall and functional status outcomes after receiving exercise interventions than non-E4 cancer survivors." Presented at the 59th Annual Meeting of the American Society for Radiology and Oncology, San Diego, CA, September 24–27, 2017.

International Journal of Radiation Oncology. 2017 Oct 1;99 (2 Suppl):E541. (Proceedings of the American Society for Radiation Oncology, September 24-27, 2017.) https://doi.org/10.1016/j.ijrobp.2017.06.1900 , Oct-2017

Abstracts for Journals and Proceedings Weil MM, Ullrich L, Ding L, Emmett M, Yu Y, Bacher JS, Halberg R, Raber J, Edmondson EF, Ray FA, Thamm DH, Liber H, Borak TB,Story MD. "NASA Specialized Center of Research on Carcinogenesis. The role of ApoE4 in cancer- and radiation-related behavioral and cognitive dysfunction." 2018 NASA Human Research Program Investigators’ Workshop, Galveston, TX, January 22-25, 2018.

2018 NASA Human Research Program Investigators’ Workshop, Galveston, TX, January 22-25, 2018. , Jan-2018

Abstracts for Journals and Proceedings Raber J, Patel E, Torres ERS, Fallgren C, Barnette BL, Weil M, Emmet MR. "Effects of 28Si ion irradiation on behavioral and cognitive performance of BALB/c and C3H mice following exposure." 2018 NASA Human Research Program Investigators’ Workshop, Galveston, TX, January 22-25, 2018.

2018 NASA Human Research Program Investigators’ Workshop, Galveston, TX, January 22-25, 2018. , Jan-2018

Abstracts for Journals and Proceedings Barnette BL, Strain SK, Lichti CF, Yu Y, Ullrich RL, Emmett MR. "Systems Biology Approach to Define the Molecular Mechanisms of Galactic Cosmic Ray Induced Hepatocellular Carcinoma." 65th Annual American Society for Mass Spectrometry Conference (ASMS), Indianapolis, IN, June 4-7, 2017.

65th Annual American Society for Mass Spectrometry Conference (ASMS), Indianapolis, IN, June 4-7, 2017. , Jun-2017

Abstracts for Journals and Proceedings Barnette BL, Nia AM, Strain SK, Lichti CF, Yu Y, Ullrich RL, Emmett MR. "29th Annual NASA Human Research Program, An Integrated Omics Approach to Define the Molecular Mechanisms of Hepatocellular Carcinoma (HCC) Induced by Low Dose, High-Energy, High charge Ions (HZE)." 2018 NASA Human Research Program Investigators’ Workshop, Galveston, TX, January 22-25, 2018.

2018 NASA Human Research Program Investigators’ Workshop, Galveston, TX, January 22-25, 2018. , Jan-2018

Articles in Peer-reviewed Journals Chernyavskiy P, Edmondson EF, Weil MM, Little MP. "High-energy particle beam and gamma radiation exposure, familial relatedness and cancer in mice." Br J Cancer. 2017 Jun 27;117(1):41-50. Epub 2017 May 23. https://doi.org/10.1038/bjc.2017.141 ; PubMed PMID: 28535153; PubMed Central PMCID: PMC5520205 , Jun-2017
Articles in Peer-reviewed Journals Yu K, Doherty AH, Genik PC, Gookin SE4, Roteliuk DM, Wojda SJ, Jiang ZS, McGee-Lawrence ME, Weil MM, Donahue SW. "Mimicking the effects of spaceflight on bone: Combined effects of disuse and chronic low-dose rate radiation exposure on bone mass in mice." Life Sci Space Res (Amst). 2017 Nov;15:62-8. Epub 2017 Aug 12. https://doi.org/10.1016/j.lssr.2017.08.004 ; PubMed PMID: 29198315 , Nov-2017
Articles in Peer-reviewed Journals McGinnis GJ, Raber J. "CNS side effects of immune checkpoint inhibitors: Preclinical models, genetics and multimodality therapy." Immunotherapy. 2017 Sep;9(11):929-41. https://doi.org/10.2217/imt-2017-0056 ; PubMed PMID: 29338610 , Sep-2017
Project Title:  NSCOR: NASA Specialized Center of Research on Carcinogenesis Reduce
Images: icon  Fiscal Year: FY 2017 
Division: Human Research 
Research Discipline/Element:
HRP SR:Space Radiation
Start Date: 06/01/2015  
End Date: 05/30/2020  
Task Last Updated: 04/03/2017 
Download report in PDF pdf
Principal Investigator/Affiliation:   Weil, Michael  Ph.D. / Colorado State University 
Address:  Department of Environmental & Radiological Health Sciences 
1618 Campus Delivery 
Fort Collins , CO 80521-2807 
Email: michael.weil@colostate.edu 
Phone: 970-491-5902  
Congressional District:
Web:  
Organization Type: UNIVERSITY 
Organization Name: Colorado State University 
Joint Agency:  
Comments:  
Co-Investigator(s)
Affiliation: 
Borak, Thomas  Ph.D. Colorado State University 
Emmett, Mark  Ph.D. University Of Texas, Galveston 
Hwang, Tae Hyun  Ph.D. University of Texas Southwestern Medical Center at Dallas 
Liber, Howard  Ph.D. Colorado State University 
Ray, F. Andrew  Ph.D. Colorado State University 
Thamm, Douglas  V.M.D. Colorado State University 
Bacher, Jeff  Ph.D. Promega Corporation 
Halberg, Richard  Ph.D. University of Wisconsin, Madison 
Raber, Jacob  Ph.D. Oregon Health & Science University 
Story, Michael  Ph.D. University of Texas Southwestern Medical Center at Dallas 
Ullrich, Robert  Ph.D. University of Texas, Galveston 
Project Information: Grant/Contract No. NNX15AK13G 
Responsible Center: NASA JSC 
Grant Monitor: Simonsen, Lisa  
Center Contact:  
lisa.c.simonsen@nasa.gov 
Solicitation / Funding Source: 2013-14 HERO NNJ13ZSA002N-NSCOR Radiation 
Grant/Contract No.: NNX15AK13G 
Project Type: GROUND 
Flight Program:  
TechPort: No 
No. of Post Docs:  
No. of PhD Candidates:
No. of Master's Candidates:
No. of Bachelor's Candidates:
No. of PhD Degrees:
No. of Master's Degrees:
No. of Bachelor's Degrees:
Human Research Program Elements: (1) SR:Space Radiation
Human Research Program Risks: (1) Cancer:Risk of Radiation Carcinogenesis
(2) CVD:Risk of Spaceflight Induced Cardiovascular Disease (IRP Rev L)
(3) HFBP Bmed:Risk of Adverse Cognitive or Behavioral Conditions and Psychiatric Disorders (IRP Rev J)
Human Research Program Gaps: (1) BMed-102:Given exposures to spaceflight hazards (space radiation, isolation), how do we identify individual susceptibility, monitor molecular/biomarkers and acceptable thresholds, and validate behavioral health and CNS/neurological/neuropsychological performance measures and domains of relevance to exploration class missions? (IRP Rev L)
(2) BMed-107:What are the long-term changes and risks to astronaut health post-mission that, when using a continuity of care model, helps retrospectively identify and understand individual susceptibility (e.g., hereditary, dose, thresholds) to mitigate adverse CNS, cognitive, and behavioral health changes resulting from long-duration exploration missions, promoting the behavioral health of current and future crews? (IRP Rev L)
(3) Cancer-102:Determine the role of radiation quality on carcinogenesis and shared biology with other degenerative diseases (IRP Rev L)
(4) Cancer-201:Determine the role of dose-rate in space radiation-induced carcinogenesis (IRP Rev L)
(5) Cancer-301:Determine the tissue-specific contributions to overall space radiation carcinogenic risk and whether there are sex-specific dependencies (IRP Rev L)
(6) Cancer-302:Identify tissue-specific surrogate end-points for space radiation induced pre-malignancy and shared biology with other degenerative diseases (IRP Rev L)
(7) Cancer-401:Identify biomarkers for estimating individual susceptibility, risk assessment, and health monitoring (IRP Rev L)
Task Description: The proposed Carcinogenesis NASA Specialized Center of Research (NSCOR) addresses several key questions for the assessment of radiation risk. The NSCOR consists of four interrelated projects. Project 1 is a biomarker discovery study using integrative “omics” approaches over multiple levels of biological organization and involving multiple species. Biomarkers predictive of the outcomes of HZE (high energy) ion exposures can be used to extrapolate findings in mice to other species, including humans, that are most relevant to NASA’s exploratory missions. The biomarkers are also critical for understanding underlying carcinogenic mechanisms, early disease detection, and subsequent countermeasure development. Project 2 investigates qualitative differences in tumor progression and metastasis between HZE ion- and gamma ray-induced tumors. Project 3 examines the critical question of risk from protracted exposures to high LET (linear energy transfer) radiation at low doses and dose rates. To estimate the carcinogenic effects of these scenarios, we will use chronic exposures to high LET associated neutron radiation as a surrogate for conditions of space-relevant fluence rates and total doses. Project 4 utilizes the resources (irradiated mice and “omics” results) generated in the first three projects to study the neurobehavioral consequences of HZE ion and neutron exposures and whether they are related to tumorigenesis-related outcome measures and predicted by the same or distinct biomarkers.

Research Impact/Earth Benefits: Accurately determining the cancer risk from high energy, charged particle radiation exposure is of great importance for designing human spaceflight missions, but it is becoming increasingly important for cancer radiotherapy as well. Radiation oncology appears poised to transition to charged particle radiotherapy in the form of proton therapy and carbon ion therapy. However, one of the risks of treating cancer with charged particle radiation is that the treatment itself can result in a new cancers, known as a second malignant neoplasms (SMN) (commonly used photon radiotherapy also increases SMN risk). The radiotherapy equipment and the patient treatment plans are designed to minimize SMN, but the models to predict risks from various exposures rest on some of the same assumptions about how charged particle radiation causes cancer that are being tested in this NSCOR grant. The results obtained in this program can be used to improve the design of treatment protocols and thus reduce the risks of SMN in radiotherapy patients.

Task Progress & Bibliography Information FY2017 
Task Progress: In Project 1, we have irradiated all of the mice for the first two aims with 28Si ions at NASA Space Radiation Laboratory (NSRL). We have collected serum, plasma, tissue samples, and feces for the one month time point, and we have established fibroblast cultures from 300 of the irradiated F2 mice. We have designed, produced, and validated directional genomic hybridization probes for mouse chromosomes 1 to 4 and begun to use the probes to screen fibroblasts from mice previously irradiated with 28Si ions. We have optimized a lipidomic screen for use with mouse samples.

In Project 2 we have reviewed the pathology on 208 cases of mouse hepatocellular carcinomas (HCC) from the previous Carcinogenesis NSCOR to allow correct classification of cases as metastatic and nonmetastatic. Each case has been assigned a histologic subtype and mitotic index, and semi-quantitatively scored for local invasion, vascular invasion, cellular pleomorphism, nuclear pleomorphism, degree of differentiation, and presence of fibrosis. We have also begun to look for mutations in the tumors by sequencing DNA from five of them (whole exome sequencing). We have detected mutations in these tumors that are also common in human HCC.

We have begun experimental metastasis studies with MMTV-PyMT and Afp-mCherry transgenic mice. MMTV-PyMT mice are a model for mammary tumor metastasis to the lungs. We have irradiated forty-four of these mice on two different strain backgrounds and followed them for mammary tumor development. We are now quantifying the extent of metastases in the mice. Viable tumors have been cryopreserved and serially transplanted for further work.

Ninety Afp-mCherry mice were irradiated or sham irradiated at NSRL. These mice are used to study HCC metastasis to the lung. The mice are being monitored for circulating tumor cells, and some have been sacrificed 3 months post-irradiation to detect the earliest stages of tumorigenesis using newly developed tissue clearing and optical approaches.

Project 3 involves the commissioning of a neutron irradiator in a shielded vivarium that meets the animal care requirements for long term mouse housing. Over the past year we renovated the building, calculated the activity of radioactive material required, and acquired the source and the irradiator.

For Project 4, we completed neurobehavioral testing for the one month time point and collected tissues from the mice that were tested.

Bibliography Type: Description: (Last Updated: 07/25/2021)  Show Cumulative Bibliography Listing
 
Abstracts for Journals and Proceedings Ullrich RL, Story MC, Ding L, Hwang TH, Emmett MR, Yu Y, Bacher JS, Hallberg R, Raber J, Edmondson EF, Ray FA, Thamm DH, Liber HL, Borak TB, Weil MM. "NASA Specialized Center of Research on Carcinogenesis." 2017 NASA Human Research Program Investigators’ Workshop, Galveston, TX, January 23-26, 2017.

2017 NASA Human Research Program Investigators’ Workshop, Galveston, TX, January 23-26, 2017. Abstract book. , Jan-2017

Abstracts for Journals and Proceedings Borak TB, Ray FA, Weil MM. "Status of the Neutron Radiation Facility at CSU." 2017 NASA Human Research Program Investigators’ Workshop, Galveston, TX, January 23-26, 2017.

2017 NASA Human Research Program Investigators’ Workshop, Galveston, TX, January 23-26, 2017. Abstract book. , Jan-2017

Abstracts for Journals and Proceedings Barnette B, Strain S, Lichti C, Yu Y, Ullrich R, Emmett M. "The application of lipidomics to the study of Heptocellular Carcinoma (HCC) Induced by low dose, high-energy, high charge ions (HZE)." 64th Conference on Mass Spectrometry and Allied Topics, San Antonio, TX, June 5-9, 2016.

64th Conference on Mass Spectrometry and Allied Topics, San Antonio, TX, June 5-9, 2016. Abstract book. , Jun-2016

Abstracts for Journals and Proceedings Weil MM. "High LET Radiation Carcinogenesis." 62nd Annual Meeting of the Radiation Research Society, Big Island, Hawaii, October 16-19, 2016.

62nd Annual Meeting of the Radiation Research Society, Big Island, Hawaii, October 16-19, 2016. Abstract book. , Oct-2016

Abstracts for Journals and Proceedings Weil MM. "Cancer Risks to Spaceflight Crews." 62nd Annual Meeting of the Radiation Research Society, Conference on Radiation and Health, Big Island, Hawaii, October 16-19, 2016.

62nd Annual Meeting of the Radiation Research Society, Big Island, Hawaii, October 16-19, 2016. Abstract book. , Oct-2016

Abstracts for Journals and Proceedings Weil MM. "Special Lecture 'Cancer Risks from Space Radiation Exposures.' " The 3rd International Symposium of Gunma University Initiative for Advanced Research, Maebashi, Japan, October 25, 2016.

The 3rd International Symposium of Gunma University Initiative for Advanced Research, Maebashi, Japan, October 25, 2016. Abstract book. , Oct-2016

Abstracts for Journals and Proceedings Raber J, Patel E, Fallgren C, Weil M. "Effects of 28Si ion irradiation on behavioral and cognitive performance of BALB/c and C3H mice one month following exposure." 2017 NASA Human Research Program Investigators’ Workshop, Galveston, TX, January 23-26, 2017.

2017 NASA Human Research Program Investigators’ Workshop, Galveston, TX, January 23-26, 2017. Abstract book. , Jan-2017

Abstracts for Journals and Proceedings Barnette B, Strain S, Lichti C, Yu Y, Ullrich R, Emmett M. "An integrated omics approach to the study of Heptocellular Carcinoma (HCC) induced by low dose, high-energy, high charge ions (HZE)." 28th Annual NASA Human Research Program Investigators’ Workshop Integrated Pathways to Mars, Galveston, TX, January 24, 2017.

2017 NASA Human Research Program Investigators’ Workshop, Galveston, TX, January 23-26, 2017. Abstract book. , Jan-2017

Project Title:  NSCOR: NASA Specialized Center of Research on Carcinogenesis Reduce
Images: icon  Fiscal Year: FY 2016 
Division: Human Research 
Research Discipline/Element:
HRP SR:Space Radiation
Start Date: 06/01/2015  
End Date: 05/30/2020  
Task Last Updated: 04/02/2016 
Download report in PDF pdf
Principal Investigator/Affiliation:   Weil, Michael  Ph.D. / Colorado State University 
Address:  Department of Environmental & Radiological Health Sciences 
1618 Campus Delivery 
Fort Collins , CO 80521-2807 
Email: michael.weil@colostate.edu 
Phone: 970-491-5902  
Congressional District:
Web:  
Organization Type: UNIVERSITY 
Organization Name: Colorado State University 
Joint Agency:  
Comments:  
Co-Investigator(s)
Affiliation: 
Borak, Thomas  Ph.D. Colorado State University 
Emmett, Mark  Ph.D. University Of Texas, Galveston 
Hwang, Tae Hyun  Ph.D. University of Texas Southwestern Medical Center at Dallas 
Liber, Howard  Ph.D. Colorado State University 
Ray, F. Andrew  Ph.D. Colorado State University 
Thamm, Douglas  V.M.D. Colorado State University 
Bacher, Jeff  Ph.D. Promega Corporation 
Halberg, Richard  Ph.D. University of Wisconsin, Madison 
Raber, Jacob  Ph.D. Oregon Health & Science University 
Story, Michael  Ph.D. University of Texas Southwestern Medical Center at Dallas 
Ullrich, Robert  Ph.D. University of Texas, Galveston 
Project Information: Grant/Contract No. NNX15AK13G 
Responsible Center: NASA JSC 
Grant Monitor: Simonsen, Lisa  
Center Contact:  
lisa.c.simonsen@nasa.gov 
Solicitation / Funding Source: 2013-14 HERO NNJ13ZSA002N-NSCOR Radiation 
Grant/Contract No.: NNX15AK13G 
Project Type: GROUND 
Flight Program:  
TechPort: No 
No. of Post Docs:
No. of PhD Candidates:  
No. of Master's Candidates:
No. of Bachelor's Candidates:
No. of PhD Degrees:
No. of Master's Degrees:
No. of Bachelor's Degrees:
Human Research Program Elements: (1) SR:Space Radiation
Human Research Program Risks: (1) Cancer:Risk of Radiation Carcinogenesis
(2) CVD:Risk of Spaceflight Induced Cardiovascular Disease (IRP Rev L)
(3) HFBP Bmed:Risk of Adverse Cognitive or Behavioral Conditions and Psychiatric Disorders (IRP Rev J)
Human Research Program Gaps: (1) BMed-102:Given exposures to spaceflight hazards (space radiation, isolation), how do we identify individual susceptibility, monitor molecular/biomarkers and acceptable thresholds, and validate behavioral health and CNS/neurological/neuropsychological performance measures and domains of relevance to exploration class missions? (IRP Rev L)
(2) BMed-107:What are the long-term changes and risks to astronaut health post-mission that, when using a continuity of care model, helps retrospectively identify and understand individual susceptibility (e.g., hereditary, dose, thresholds) to mitigate adverse CNS, cognitive, and behavioral health changes resulting from long-duration exploration missions, promoting the behavioral health of current and future crews? (IRP Rev L)
(3) Cancer-102:Determine the role of radiation quality on carcinogenesis and shared biology with other degenerative diseases (IRP Rev L)
(4) Cancer-201:Determine the role of dose-rate in space radiation-induced carcinogenesis (IRP Rev L)
(5) Cancer-301:Determine the tissue-specific contributions to overall space radiation carcinogenic risk and whether there are sex-specific dependencies (IRP Rev L)
(6) Cancer-302:Identify tissue-specific surrogate end-points for space radiation induced pre-malignancy and shared biology with other degenerative diseases (IRP Rev L)
(7) Cancer-401:Identify biomarkers for estimating individual susceptibility, risk assessment, and health monitoring (IRP Rev L)
Task Description: The proposed Carcinogenesis NASA Specialized Center of Research (NSCOR) addresses several key questions for the assessment of radiation risk. The NSCOR consists of four interrelated projects. Project 1 is a biomarker discovery study using integrative “omics” approaches over multiple levels of biological organization and involving multiple species. Biomarkers predictive of the outcomes of HZE (high energy) ion exposures can be used to extrapolate findings in mice to other species, including humans, that are most relevant to NASA’s exploratory missions. The biomarkers are also critical for understanding underlying carcinogenic mechanisms, early disease detection, and subsequent countermeasure development. Project 2 investigates qualitative differences in tumor progression and metastasis between HZE ion- and gamma ray-induced tumors. Project 3 examines the critical question of risk from protracted exposures to high LET (linear energy transfer) radiation at low doses and dose rates. To estimate the carcinogenic effects of these scenarios, we will use chronic exposures to high LET associated neutron radiation as a surrogate for conditions of space-relevant fluence rates and total doses. Project 4 utilizes the resources (irradiated mice and “omics” results) generated in the first three projects to study the neurobehavioral consequences of HZE ion and neutron exposures and whether they are related to tumorigenesis-related outcome measures and predicted by the same or distinct biomarkers.

Research Impact/Earth Benefits: Accurately determining the cancer risk from high energy, charged particle radiation exposure is of great importance for designing human spaceflight missions, but it is becoming increasingly important for cancer radiotherapy as well. Radiation oncology appears poised to transition to charged particle radiotherapy in the form of proton therapy and carbon ion therapy. However, one of the risks of treating cancer with charged particle radiation is that the treatment itself can result in a new cancers, known as a second malignant neoplasms (SMN) (commonly used photon radiotherapy also increases SMN risk). The radiotherapy equipment and the patient treatment plans are designed to minimize SMN, but the models to predict risks from various exposures rest on some of the same assumptions about how charged particle radiation causes cancer that are being tested in this NSCOR grant. The results obtained in this program can be used to improve the design of treatment protocols and thus reduce the risks of SMN in radiotherapy patients.

Task Progress & Bibliography Information FY2016 
Task Progress: This is the first year of funding, so much of the work to date has been logistical to prepare for mouse irradiations. We have arranged for beam time at NASA Space Radiation Laboratory (NSRL) in Fall 2016 and secured approval from 4 different institutions for the use of mice in the experiments. Because some of the strains of mice needed are not commercially available in sufficient numbers, we have established breeding colonies for them at Colorado State University and the University of Wisconsin.

In Project 1 we have optimized a lipidomic screen for use with mouse samples. In Project 2 we have reviewed the pathology on 210 cases of mouse hepatocellular carcinomas (HCC) and characterized them for histological features that may be relevant to their propensity to metastasize to the lung, including fibrosis, local invasion, vascular invasion, cellular and nuclear pleomorphism, tumor subtype, and mitotic index. One feature, high microvessel density, appears to be more common in metastatic HCC. We have also begun to look for mutations in the tumors by sequencing DNA from five of them (whole exome sequencing). We have detected mutations in these tumors that are also common in human HCC.

Project 3 requires us to install a neutron irradiator in a heavily shielded building that also meets the animal care requirements for long term mouse housing. We have secured a suitable building and begun the process of renovating it. We are also drawing up the specifications for the radioactive source in the neutron irradiator.

For Project 4 we have identified the neurobehavioral assays that will be most sensitive to radiation effects.

Bibliography Type: Description: (Last Updated: 07/25/2021)  Show Cumulative Bibliography Listing
 
Abstracts for Journals and Proceedings Weil MM, Ullrich RL, Story MC, Bacher JS, Ray FA, Borak TB, Liber HL, Thamm HL, Raber J, Emmett MR, Hallberg R, Hwang TH. "Carcinogenesis NSCOR." Presented at 2016 NASA Human Research Program Investigators’ Workshop, Galveston, TX, February 8-11, 2016.

2016 NASA Human Research Program Investigators’ Workshop, Galveston, TX, February 8-11, 2016. , Feb-2016

Articles in Peer-reviewed Journals Locke PA, Weil MM. "Personalized cancer risk assessments for space radiation exposures." Front Oncol. 2016 Feb 22;6:38. eCollection 2016. Review. http://dx.doi.org/10.3389/fonc.2016.00038 ; PubMed PMID: 26942127; PubMed Central PMCID: PMC4762001 , Feb-2016
Project Title:  NSCOR: NASA Specialized Center of Research on Carcinogenesis Reduce
Images: icon  Fiscal Year: FY 2015 
Division: Human Research 
Research Discipline/Element:
HRP SR:Space Radiation
Start Date: 06/01/2015  
End Date: 05/30/2020  
Task Last Updated: 08/12/2015 
Download report in PDF pdf
Principal Investigator/Affiliation:   Weil, Michael  Ph.D. / Colorado State University 
Address:  Department of Environmental & Radiological Health Sciences 
1618 Campus Delivery 
Fort Collins , CO 80521-2807 
Email: michael.weil@colostate.edu 
Phone: 970-491-5902  
Congressional District:
Web:  
Organization Type: UNIVERSITY 
Organization Name: Colorado State University 
Joint Agency:  
Comments:  
Co-Investigator(s)
Affiliation: 
Borak, Thomas  Ph.D. Colorado State University 
Emmett, Mark  Ph.D. University Of Texas, Galveston 
Hwang, Tae Hyun  Ph.D. University of Texas Southwestern Medical Center at Dallas 
Liber, Howard  Ph.D. Colorado State University 
Ray, F. Andrew  Ph.D. Colorado State University 
Thamm, Douglas  V.M.D. Colorado State University 
Bacher, Jeff  Ph.D. Promega Corporation 
Halberg, Richard  Ph.D. University of Wisconsin, Madison 
Raber, Jacob  Ph.D. Oregon Health & Science University 
Story, Michael  Ph.D. University of Texas Southwestern Medical Center at Dallas 
Ullrich, Robert  Ph.D. University of Texas, Galveston 
Project Information: Grant/Contract No. NNX15AK13G 
Responsible Center: NASA JSC 
Grant Monitor: Simonsen, Lisa  
Center Contact:  
lisa.c.simonsen@nasa.gov 
Solicitation / Funding Source: 2013-14 HERO NNJ13ZSA002N-NSCOR Radiation 
Grant/Contract No.: NNX15AK13G 
Project Type: GROUND 
Flight Program:  
TechPort: No 
No. of Post Docs:  
No. of PhD Candidates:  
No. of Master's Candidates:  
No. of Bachelor's Candidates:  
No. of PhD Degrees:  
No. of Master's Degrees:  
No. of Bachelor's Degrees:  
Human Research Program Elements: (1) SR:Space Radiation
Human Research Program Risks: (1) Cancer:Risk of Radiation Carcinogenesis
(2) CVD:Risk of Spaceflight Induced Cardiovascular Disease (IRP Rev L)
(3) HFBP Bmed:Risk of Adverse Cognitive or Behavioral Conditions and Psychiatric Disorders (IRP Rev J)
Human Research Program Gaps: (1) BMed-102:Given exposures to spaceflight hazards (space radiation, isolation), how do we identify individual susceptibility, monitor molecular/biomarkers and acceptable thresholds, and validate behavioral health and CNS/neurological/neuropsychological performance measures and domains of relevance to exploration class missions? (IRP Rev L)
(2) BMed-107:What are the long-term changes and risks to astronaut health post-mission that, when using a continuity of care model, helps retrospectively identify and understand individual susceptibility (e.g., hereditary, dose, thresholds) to mitigate adverse CNS, cognitive, and behavioral health changes resulting from long-duration exploration missions, promoting the behavioral health of current and future crews? (IRP Rev L)
(3) Cancer-102:Determine the role of radiation quality on carcinogenesis and shared biology with other degenerative diseases (IRP Rev L)
(4) Cancer-201:Determine the role of dose-rate in space radiation-induced carcinogenesis (IRP Rev L)
(5) Cancer-301:Determine the tissue-specific contributions to overall space radiation carcinogenic risk and whether there are sex-specific dependencies (IRP Rev L)
(6) Cancer-302:Identify tissue-specific surrogate end-points for space radiation induced pre-malignancy and shared biology with other degenerative diseases (IRP Rev L)
(7) Cancer-401:Identify biomarkers for estimating individual susceptibility, risk assessment, and health monitoring (IRP Rev L)
Task Description: The proposed Carcinogenesis NASA Specialized Center of Research (NSCOR) addresses several key questions for the assessment of radiation risk. The NSCOR consists of four interrelated projects. Project 1 is a biomarker discovery study using integrative “omics” approaches over multiple levels of biological organization and involving multiple species. Biomarkers predictive of the outcomes of HZE ion exposures can be used to extrapolate findings in mice to other species, including humans, that are most relevant to NASA’s exploratory missions. The biomarkers are also critical for understanding underlying carcinogenic mechanisms, early disease detection, and subsequent countermeasure development. Project 2 investigates qualitative differences in tumor progression and metastasis between HZE ion- and gamma ray-induced tumors. Project 3 examines the critical question of risk from protracted exposures to high LET (linear energy transfer) radiation at low doses and dose rates. To estimate the carcinogenic effects of these scenarios, we will use chronic exposures to high LET associated neutron radiation as a surrogate for conditions of space-relevant fluence rates and total doses. Project 4 utilizes the resources (irradiated mice and “omics” results) generated in the first three projects to study the neurobehavioral consequences of HZE ion and neutron exposures and whether they are related to tumorigenesis-related outcome measures and predicted by the same or distinct biomarkers.

Research Impact/Earth Benefits:

Task Progress & Bibliography Information FY2015 
Task Progress: New project for FY2015.

Bibliography Type: Description: (Last Updated: 07/25/2021)  Show Cumulative Bibliography Listing
 
 None in FY 2015