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Search indexed NASA NTRS and DOE OSTI research on propulsion, heat transfer, battery materials and energy systems. Follow report and document links to the original sources.

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At least 217 records · Page 12
All sourcesNASA NTRSDOE OSTI
DOE OSTI2024

Advances in statistical methods for cancer surveillance research: an age-period-cohort perspective

Background: Analysis of Lexis diagrams (population-based cancer incidence and mortality rates indexed by age group and calendar period) requires specialized statistical methods. However, existing methods have limitations that can now be overcome using new approaches. Methods: We assembled a “toolbox” of novel methods to identify trends and patterns by age group, calendar period, and birth cohort. We evaluated operating characteristics across 152 cancer incidence Lexis diagrams compiled from United States (US) Surveillance, Epidemiology and End Results Program data for 21 leading cancers in men and women in four race and ethnicity groups (the “cancer incidence panel”). Results: Nonparametric singular values adaptive kernel filtration (SIFT) decreased the estimated root mean squared error by 90% across the cancer incidence panel. A novel method for semi-parametric age-period-cohort analysis (SAGE) provided optimally smoothed estimates of age-period-cohort (APC) estimable functions and stabilized estimates of lack-of-fit (LOF). SAGE identified statistically significant birth cohort effects across the entire cancer panel; LOF had little impact. As illustrated for colon cancer, newly developed methods for comparative age-period-cohort analysis can elucidate cancer heterogeneity that would otherwise be difficult or impossible to discern using standard methods. Conclusions: Cancer surveillance researchers can now identify fine-scale temporal signals with unprecedented accuracy and elucidate cancer heterogeneity with unprecedented specificity. Birth cohort effects are ubiquitous modulators of cancer incidence in the US. The novel methods described here can advance cancer surveillance research.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2013

Cancer cachexia decreases specific force and accelerates fatigue in limb muscle

Highlights: •C-26 cancer cachexia causes a significant decrease in limb muscle absolute force. •C-26 cancer cachexia causes a significant decrease in limb muscle specific force. •C-26 cancer cachexia decreases fatigue resistance in the soleus muscle. •C-26 cancer cachexia prolongs time to peak twitch tension in limb muscle. •C-26 cancer cachexia prolongs one half twitch relaxation time in limb muscle. -- Abstract: Cancer cachexia is a complex metabolic syndrome that is characterized by the loss of skeletal muscle mass and weakness, which compromises physical function, reduces quality of life, and ultimately can lead to mortality. Experimental models of cancer cachexia have recapitulated this skeletal muscle atrophy and consequent decline in muscle force generating capacity. However, more recently, we provided evidence that during severe cancer cachexia muscle weakness in the diaphragm muscle cannot be entirely accounted for by the muscle atrophy. This indicates that muscle weakness is not just a consequence of muscle atrophy but that there is also significant contractile dysfunction. The current study aimed to determine whether contractile dysfunction is also present in limb muscles during severe Colon-26 (C26) carcinoma cachexia by studying the glycolytic extensor digitorum longus (EDL) muscle and the oxidative soleus muscle, which has an activity pattern that more closely resembles the diaphragm. Severe C-26 cancer cachexia caused significant muscle fiber atrophy and a reduction in maximum absolute force in both the EDL and soleus muscles. However, normalization to muscle cross sectional area further demonstrated a 13% decrease in maximum isometric specific force in the EDL and an even greater decrease (17%) in maximum isometric specific force in the soleus. Time to peak tension and half relaxation time were also significantly slowed in both the EDL and the solei from C-26 mice compared to controls. Since, in addition to postural control, the oxidative soleus is also important for normal locomotion, we further performed a fatigue trial in the soleus and found that the decrease in relative force was greater and more rapid in solei from C-26 mice compared to controls. These data demonstrate that severe cancer cachexia causes profound muscle weakness that is not entirely explained by the muscle atrophy. In addition, cancer cachexia decreases the fatigue resistance of the soleus muscle, a postural muscle typically resistant to fatigue. Thus, specifically targeting contractile dysfunction represents an additional means to counter muscle weakness in cancer cachexia, in addition to targeting the prevention of muscle atrophy.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2023

The PTPN2/PTPN1 inhibitor ABBV-CLS-484 unleashes potent anti-tumour immunity

Immune checkpoint blockade is effective for some patients with cancer, but most are refractory to current immunotherapies and new approaches are needed to overcome resistance. The protein tyrosine phosphatases PTPN2 and PTPN1 are central regulators of inflammation, and their genetic deletion in either tumour cells or immune cells promotes anti-tumour immunity. However, phosphatases are challenging drug targets; in particular, the active site has been considered undruggable. Here we present the discovery and characterization of ABBV-CLS-484 (AC484), a first-in-class, orally bioavailable, potent PTPN2 and PTPN1 active-site inhibitor. AC484 treatment in vitro amplifies the response to interferon and promotes the activation and function of several immune cell subsets. In mouse models of cancer resistant to PD-1 blockade, AC484 monotherapy generates potent anti-tumour immunity. We show that AC484 inflames the tumour microenvironment and promotes natural killer cell and CD8 + T cell function by enhancing JAK–STAT signalling and reducing T cell dysfunction. Inhibitors of PTPN2 and PTPN1 offer a promising new strategy for cancer immunotherapy and are currently being evaluated in patients with advanced solid tumours (ClinicalTrials.gov identifier NCT04777994). More broadly, our study shows that small-molecule inhibitors of key intracellular immune regulators can achieve efficacy comparable to or exceeding that of antibody-based immune checkpoint blockade in preclinical models. Finally, to our knowledge, AC484 represents the first active-site phosphatase inhibitor to enter clinical evaluation for cancer immunotherapy and may pave the way for additional therapeutics that target this important class of enzymes.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2022

A scalable, open-source implementation of a large-scale mechanistic model for single cell proliferation and death signaling

Mechanistic models of how single cells respond to different perturbations can help integrate disparate big data sets or predict response to varied drug combinations. However, the construction and simulation of such models have proved challenging. Here, we developed a python-based model creation and simulation pipeline that converts a few structured text files into an SBML standard and is high-performance- and cloud-computing ready. We applied this pipeline to our large-scale, mechanistic pan-cancer signaling model (named SPARCED) and demonstrate it by adding an IFNγ pathway submodel. We then investigated whether a putative crosstalk mechanism could be consistent with experimental observations from the LINCS MCF10A Data Cube that IFNγ acts as an anti-proliferative factor. The analyses suggested this observation can be explained by IFNγ-induced SOCS1 sequestering activated EGF receptors. This work forms a foundational recipe for increased mechanistic model-based data integration on a single-cell level, an important building block for clinically-predictive mechanistic models.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2015

Natural products induce a G protein-mediated calcium pathway activating p53 in cancer cells

Paclitaxel, etoposide, vincristine and doxorubicin are examples of natural products being used as chemotherapeutics but with adverse side effects that limit their therapeutic window. Natural products derived from plants and having low toxicity, such as quercetin, resveratrol, epigallocatechin gallate and piceatannol, have been shown to inhibit tumor cell growth both in vitro and in pre-clinical models of cancer, but their mechanisms of action have not been fully elucidated, thus restricting their use as prototypes for developing synthetic analogs with improved anti-cancer properties. We and others have demonstrated that one of the earliest and consistent events upon exposure of tumor cells to these less toxic natural products is a rise in cytoplasmic calcium, activating several pro-apoptotic pathways. We describe here a G protein/inositol 1,4,5-trisphosphate pathway (InsP3) in MDA-MB-231 human breast cancer cells that mediates between these less toxic natural products and the release of calcium from the endoplasmic reticulum. Further, we demonstrate that this elevation of intracellular calcium modulates p53 activity and the subsequent transcription of several pro-apoptotic genes encoding PIG8, CD95, PIDD, TP53INP, RRM2B, Noxa, p21 and PUMA. We conclude from our findings that less toxic natural products likely bind to a G protein coupled receptor that activates a G protein-mediated and calcium-dependent pathway resulting selectively in tumor cell death. - Highlights: • Natural products having low toxicity increase cytoplasmic calcium in cancer cells. • A G-protein/IP{sub 3} pathway mediates the release of calcium from the ER. • The elevation of intracellular calcium modulates p53 activity. • p53 and other Ca{sup 2+}-dependent pro-apoptotic pathways inhibit cancer cell growth.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

Antibiotic bedaquiline effectively targets growth, survival and tumor angiogenesis of lung cancer through suppressing energy metabolism

Highlights: • Bedaquiline targets lung cancer in vitro and in vivo. • Bedaquiline potently inhibits angiogenesis in vitro and in vivo. • Bedaquiline inhibits mitochondrial respiration and glycolysis. • Bedaquiline causes energy crisis and oxidative damage. Tumor angiogenesis plays essential roles during lung cancer progression and metastasis. Therapeutic agent that targets both tumor cell and vascular endothelial cell may achieve additional anti-tumor efficacy. We demonstrate that bedaquiline, a FDA-approved antibiotic drug, effectively targets lung cancer cells and angiogenesis. Bedaquiline dose-dependently inhibits proliferation and induces apoptosis of a panel of lung cancer cell lines regardless of subtypes and molecular heterogeneity. Bedaquiline also inhibits capillary network formation of human lung tumor associated-endothelial cell (HLT-EC) on Matrigel and its multiple functions, such as spreading, proliferation and apoptosis, even in the presence of vascular endothelial growth factor (VEGF). We further demonstrate that bedaquiline acts on lung cancer cells and HLT-EC via inhibiting mitochondrial respiration and glycolysis, leading to ATP reduction and oxidative stress. Consistently, oxidative damage on DNA, protein and lipid were detected in cells exposed to bedaquiline. Importantly, the results obtained in in vitro cell culture are reproducible in in vivo xenograft lung cancer mouse model, confirming that bedaquiline suppresses lug tumor growth and angiogenesis, and increases oxidative stress. Our findings demonstrating that energy depletion is effectively against lung tumor cells and angiogenesis. Our work also provide pre-clinical evidence to repurpose antibiotic bedaquiline for lung cancer treatment.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2016

LNTgate: How scientific misconduct by the U.S. NAS led to governments adopting LNT for cancer risk assessment

This paper provides a detailed rebuttal to the letter of Beyea (2016) which offered a series of alternative interpretations to those offered in my article in Environmental Research (Calabrese, 2015a) concerning the role of the U.S. National Academy of Sciences (NAS) Biological Effects of Atomic Radiation (BEAR) I Committee Genetics Panel in the adoption of the linear dose response model for cancer risk assessment. Significant newly uncovered evidence is presented which supports and extends the findings of Calabrese (2015a), reaffirming the conclusion that the Genetics Panel should be evaluated for scientific misconduct for deliberate misrepresentation of the research record in order to enhance an ideological agenda. This critique documents numerous factual errors along with extensive and deliberate filtering of information in the Beyea letter (2016) that leads to consistently incorrect conclusions and an invalid general perspective.

54 ENVIRONMENTAL SCIENCES↗
DOE OSTI2022

Optimal vocabulary selection approaches for privacy-preserving deep NLP model training for information extraction and cancer epidemiology

With the use of artificial intelligence and machine learning techniques for biomedical informatics, security and privacy concerns over the data and subject identities have also become an important issue and essential research topic. Without intentional safeguards, machine learning models may find patterns and features to improve task performance that are associated with private personal information. The privacy vulnerability of deep learning models for information extraction from medical textural contents needs to be quantified since the models are exposed to private health information and personally identifiable information. The objective of the study is to quantify the privacy vulnerability of the deep learning models for natural language processing and explore a proper way of securing patients’ information to mitigate confidentiality breaches. The target model is the multitask convolutional neural network for information extraction from cancer pathology reports, where the data for training the model are from multiple state population-based cancer registries. This study proposes the following schemes to collect vocabularies from the cancer pathology reports; (a) words appearing in multiple registries, and (b) words that have higher mutual information. We performed membership inference attacks on the models in high-performance computing environments. The comparison outcomes suggest that the proposed vocabulary selection methods resulted in lower privacy vulnerability while maintaining the same level of clinical task performance.

59 BASIC BIOLOGICAL SCIENCES↗
NASA NTRS2007

Evaluating Shielding Effectiveness for Reducing Space Radiation Cancer Risks

We discuss calculations of probability distribution functions (PDF) representing uncertainties in projecting fatal cancer risk from galactic cosmic rays (GCR) and solar particle events (SPE). The PDF s are used in significance tests of the effectiveness of potential radiation shielding approaches. Uncertainties in risk coefficients determined from epidemiology data, dose and dose-rate reduction factors, quality factors, and physics models of radiation environments are considered in models of cancer risk PDF s. Competing mortality risks and functional correlations in radiation quality factor uncertainties are treated in the calculations. We show that the cancer risk uncertainty, defined as the ratio of the 95% confidence level (CL) to the point estimate is about 4-fold for lunar and Mars mission risk projections. For short-stay lunar missions (<180 d), SPE s present the most significant risk, however one that is mitigated effectively by shielding, especially for carbon composites structures with high hydrogen content. In contrast, for long duration lunar (>180 d) or Mars missions, GCR risks may exceed radiation risk limits, with 95% CL s exceeding 10% fatal risk for males and females on a Mars mission. For reducing GCR cancer risks, shielding materials are marginally effective because of the penetrating nature of GCR and secondary radiation produced in tissue by relativistic particles. At the present time, polyethylene or carbon composite shielding can not be shown to significantly reduce risk compared to aluminum shielding based on a significance test that accounts for radiobiology uncertainties in GCR risk projection.

Cucinotta, Francis A.↗
DOE OSTI2014

SU-D-18A-01: Tumor Motion Tracking with a Regional Deformable Registration Model for Four Dimensional Radiation Treatment of Lung Cancer

Purpose: To develop a tumor motion model from four-dimensional computed tomography (4DCT) of thoracic patients and demonstrate its impact on 4D radiation therapy simulation. Methods: A regional deformable image registration algorithm was introduced to extract tumor motion out of patient's breathing cycle. The gross target volume (GTV) was manually delineated on a selected phase of 4DCT and a subregion with 10mm margin supplemented to the GTV was created on the Eclipse treatment planning system (Varian Medical Systems, Palo Alto, CA). Together with 4DCT the structures were exported into an inhouse research platform. A free form B-Spline deformable registration was carried out to map the subregion to other respiratory phases. The displacement vector fields were employed to propagate GTV contours with which the center of mass (CoM) of the GTV was computed for each breathing phase of 4DCT. The resultant GTV motion and its volumetric shape are utilized to facilitate 4D treatment planning. Five lung cancer patients undergoing stereotactic body radiation therapy were enrolled and their 4DCT sets were included in the study. Results: Application of the algorithm to five thoracic patients indicates that clinically satisfactory outcomes were achievable with a spatial accuracy better than 2mm for GTV contour propagation between adjacent phases, and 3mm between opposite phases. The GTV CoM was found to be in the range of 2.0mm through 2.5cm, depending upon the tumor location. Compared to the traditional whole image based registration, the computation of the regional model was found to be an order of magnitude more efficient. Conclusion: A regional deformable registration model was implemented to extract tumor motion. It will have widespread application in 4D radiation treatment planning in the future to maximally utilize the available spatial-tempo information.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2019

Evaluation of integrin αvβ6 cystine knot PET tracers to detect cancer and idiopathic pulmonary fibrosis

Abstract Advances in precision molecular imaging promise to transform our ability to detect, diagnose and treat disease. Here, we describe the engineering and validation of a new cystine knot peptide (knottin) that selectively recognizes human integrin αvβ 6 with single-digit nanomolar affinity. We solve its 3D structure by NMR and x-ray crystallography and validate leads with 3 different radiolabels in pre-clinical models of cancer. We evaluate the lead tracer’s safety, biodistribution and pharmacokinetics in healthy human volunteers, and show its ability to detect multiple cancers (pancreatic, cervical and lung) in patients at two study locations. Additionally, we demonstrate that the knottin PET tracers can also detect fibrotic lung disease in idiopathic pulmonary fibrosis patients. Our results indicate that these cystine knot PET tracers may have potential utility in multiple disease states that are associated with upregulation of integrin α v β 6 .

60 APPLIED LIFE SCIENCES↗
DOE OSTI2013

A phylogenetic model for understanding the effect of gene duplication on cancer progression

As biotechnology advances rapidly, a tremendous amount of cancer genetic data has become available, providing an unprecedented opportunity for understanding the genetic mechanisms of cancer. To understand the effects of duplications and deletions on cancer progression, two genomes (normal and tumor) were sequenced from each of five stomach cancer patients in different stages (I, II, III and IV). We developed a phylogenetic model for analyzing stomach cancer data. The model assumes that duplication and deletion occur in accordance with a continuous time Markov Chain along the branches of a phylogenetic tree attached with five extended branches leading to the tumor genomes. Moreover, coalescence times of the phylogenetic tree follow a coalescence process. The simulation study suggests that the maximum likelihood approach can accurately estimate parameters in the phylogenetic model. The phylogenetic model was applied to the stomach cancer data. We found that the expected number of changes (duplication and deletion) per gene for the tumor genomes is significantly higher than that for the normal genomes. The goodness-of-fit test suggests that the phylogenetic model with constant duplication and deletion rates can adequately fit the duplication data for the normal genomes. The analysis found nine duplicated genes that are significantly associated with stomach cancer.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2017

Characterization of stem-like cells in a new astroblastoma cell line

Cell lines established from tumors are the most commonly used models in cancer research, and their use in recent years has enabled a greater understanding of the biology of cancer and the means to develop effective treatment strategies. Astroblastomas are uncommon neuroepithelial tumors of glial origin, predominantly affecting young people, mainly teenagers and children, predominantly females. To date, only a single study has reported that astroblastomas contain a large number of neural stem-like cells, which had only a partial proliferation capacity and differentiation. Our objective was to establish an astroblastoma cell line to investigate the presence of astroblastic cells and cancer stem-like cells. The migratory and invasion abilities of the cells were quantified with invasion and migration assays and compared to a glioblastoma cell line. The presence of stem cells was detected with surface-marker analysis by using flow cytometry, and measuring the differentiation ability with a differentiation assay and the self-renewal capacity with a sphere-forming assay. These characteristics may determine whether this novel cell line is a model for astroblastomas that may have stem-cell characteristics. With this novel cell line, scientists can investigate the molecular pathways underlying astroblastomas and develop new therapeutic strategies for patients with these tumors. - Highlights: • An establishment of a novel astroblastoma cell line was proposed. • The presence of astroblastic cells and cancer stem-like cells was investigated. • The molecular pathways underlying astroblastomas may be investigated. • New therapeutic strategies for patients with astroblastoma may be developed.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2016

WE-FG-BRA-11: Theranostic Platinum Nanoparticle for Radiation Sensitization in Breast Cancer Radiotherapy

Purpose: We have developed a novel receptor-targeted theranostic platinum nanoparticle (HER-PtNP) for enhanced radiation sensitization in HER2-positive breast cancer radiation treatment. This study aims to evaluate receptor-targeting specificity, and radiation sensitization of the nanoparticle. Methods: The platinum nanoparticle (PtNP) was synthesized with the diameter of 2nm, and capped with cysteine. The nanoparticle was tagged with a fluorescent dye (cy5) for the fluoresence detection, and conjuated with HER2/3 targeted protein (HerPBK10) for HER2-targeting specificity. We evaluated the theranostic features using in vitro breast cancer cell models: HER2-positive BT-474, and HER2-negative MDA-MB-231. The HER2-targeting specificity was evaluated using immunofluorescence and confocal microscopy. For each cell line, three sets of samples, including non-stained control, fluorescence stained PtNP-cy5 treated, and HER-PtNP treated, were imaged by confocal microscopy. Two breast cancer cell lineages were incubated with PtNP and HER-PtNP at 10 µg/mL, and then irradiated with X-rays for 2 Gy dose at 50 kVp. A colonogenic assay was used to determine cellular survival fractions by immediately reseeding 300 cells after irradiation in growth media and allowing colonies to grow for 2 weeks. Results: The results of confocal images show that no apparent nanoparticle cellular uptake was observed in the HER2-(MDA-MB-231) cells with 1% for PtNP-cy5 and 0.5% for HER-PtNP. Similarly no apparent PtNP-cy5 uptake (<1%) for BT474 cells was observed. However, there was significant HER-PtNP uptake (73%) for the HER2+(BT474) cells. The clonogenic assay showed that BT474 cells treated with HER-PtNP had significantly lower survival compared to those treated with PtNP (32% vs 81%, p=0.01). However, no significant radiosensitivity enhancement was observed for MDA-MB-231 cell treated with PtNP and HER-PtNP (89% vs 92%, p=0.78). Conclusion: Our studies suggest that the HER2-targeted platinum nanoparticle has excellent receptor targeting specificity and enhanced radiation sensitization compared to nanoparticle alone, suggesting potential for clinical applications in breast cancer radiotherapy.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2014

N-methylhemeanthidine chloride, a novel Amaryllidaceae alkaloid, inhibits pancreatic cancer cell proliferation via down-regulating AKT activation

We previously reported the isolation of a novel Amaryllidaceae alkaloid, N-methylhemeanthidine chloride (NMHC), from Zephyranthes candida, which exhibits potent cytotoxicity in a spectrum of tumor cells. However, the mechanism of action remains unclear. Using multiple cell lines derived from human pancreatic cancer, one of the most mortal and refractory human malignancies, we further studied the NMHC-mediated cytotoxicity and found that it induced drastic cytotoxicity in pancreatic cancer cells whereas an insignificant effect on a noncancerous cell line. The NMHC-mediated growth inhibition was more severe than the first-line chemotherapeutic agent gemcitabine, leading to cell cycle arrest, apoptotic death and decreased glycolysis. NMHC exerted its function through down-regulating AKT activation, and the ectopic expression of activated AKT rescued the growth inhibition. Consistently, NMHC injections in a pancreatic cancer xenograft model manifested the anti-tumor effect in vivo. Engrafted tumor cells underwent AKT attenuation and apoptotic death upon treatments. As such, we here demonstrate the AKT inhibition may be one of the mechanisms by which NMHC decreases tumor cell survival rate in vitro and in vivo. Our data thereby suggest that NMHC holds great promise as a potent chemotherapeutic agent against pancreatic cancer and sheds new light on obtaining such agents from natural products toward therapeutic purposes. - Highlights: • N-methylhemeanthidine chloride (NMHC) is a novel Amaryllidaceae alkaloid. • NMHC exhibits potent anti-neoplastic activity. • NMHC leads to cell cycle arrest, apoptotic death and decreased metabolism. • NMHC down-regulates the AKT signaling pathway.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

Structure-Based Optimization of a Novel Class of Aldehyde Dehydrogenase 1A (ALDH1A) Subfamily-Selective Inhibitors as Potential Adjuncts to Ovarian Cancer Chemotherapy

Aldehyde dehydrogenase (ALDH) activity is commonly used as a marker to identify cancer stem-like cells. The three ALDH1A isoforms have all been individually implicated in cancer stem-like cells and in chemoresistance; however, which isoform is preferentially expressed varies between cell lines. In this work, we sought to explore the structural determinants of ALDH1A isoform selectivity in a series of small-molecule inhibitors in support of research into the role of ALDH1A in cancer stem cells. An SAR campaign guided by a cocrystal structure of the HTS hit CM39 (7) with ALDH1A1 afforded first-in-class inhibitors of the ALDH1A subfamily with excellent selectivity over the homologous ALDH2 isoform. We also discovered the first reported modestly selective single isoform 1A2 and 1A3 inhibitors. Two compounds, 13g and 13h, depleted the CD133+ putative cancer stem cell pool, synergized with cisplatin, and achieved efficacious concentrations in vivo following IP administration. Compound 13h additionally synergized with cisplatin in a patient-derived ovarian cancer spheroid model.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2019

Mathematical modelling the pathway of genomic instability in lung cancer

Genomic instability plays a significant role in lung cancer. Although substantial research has been conducted using both clinical and theoretical studies, it is still a hotly debated issue to whether genomic instability is necessary or whether genomic instability precedes oncogenes activation and tumor suppressor genes inactivation for lung cancer. In response to this issue, we come up with a mathematical model incorporating effects of genomic instability to investigate the genomic instability pathway of human lung cancer. The presented model are applied to match the incidence rate data of lung cancer from the Life Span Study cohort of the atomic bomb survivors in Nagasaki and Hiroshima and the Surveillance Epidemiology and End Results registry in the United States. Model results suggest that genomic instability is necessary in the tumorigenesis of lung cancer, and genomic instability has no significant impact on the net proliferation rate of cells by statistical criteria. By comparing the results of the LSS data to those of the SEER data, we conclude that the genomic instability pathway exhibits a sensitivity to radiation exposure, more intensive in male patients.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2015

Age at exposure and attained age variations of cancer risk in the Japanese A-bomb and radiotherapy cohorts

Purpose: Phenomenological risk models for radiation-induced cancer are frequently applied to estimate the risk of radiation-induced cancers at radiotherapy doses. Such models often include the effect modification, of the main risk to radiation dose response, by age at exposure and attained age. The aim of this paper is to compare the patterns in risk effect modification by age, between models obtained from the Japanese atomic-bomb (A-bomb) survivor data and models for cancer risks previously reported for radiotherapy patients. Patterns in risk effect modification by age from the epidemiological studies of radiotherapy patients were also used to refine and extend the risk effect modification by age obtained from the A-bomb survivor data, so that more universal models can be presented here. Methods: Simple log-linear and power functions of age for the risk effect modification applied in models of the A-bomb survivor data are compared to risks from epidemiological studies of second cancers after radiotherapy. These functions of age were also refined and fitted to radiotherapy risks. The resulting age models provide a refined and extended functional dependence of risk with age at exposure and attained age especially beyond 40 and 65 yr, respectively, and provide a better representation than the currently available simple age functions. Results: It was found that the A-bomb models predict risk similarly to the outcomes of testicular cancer survivors. The survivors of Hodgkin’s disease show steeper variations of risk with both age at exposure and attained age. The extended models predict solid cancer risk increase as a function of age at exposure beyond 40 yr and the risk decrease as a function of attained age beyond 65 yr better than the simple models. Conclusions: The standard functions for risk effect modification by age, based on the A-bomb survivor data, predict second cancer risk in radiotherapy patients for ages at exposure prior to 40 yr and attained ages before 55 yr reasonably well. However, for larger ages, the refined and extended models can be applied to predict the risk as a function of age.

60 APPLIED LIFE SCIENCES↗