Biologically based multistage modeling of radiation effects

This past year we have made substantial progress in modeling the contribution of homeostatic regulation to low-dose radiation effects and carcinogenesis. We have worked to refine and apply our multistage carcinogenesis models to explicitly incorporate cell cycle states, simple and complex damage, checkpoint delay, slow and fast repair, differentiation, and apoptosis to study the effects of low-dose ionizing radiation in mouse intestinal crypts, as well as in other tissues. We have one paper accepted for publication in ''Advances in Space Research'', and another manuscript in preparation describing this work. I also wrote a chapter describing our combined cell-cycle and multistage carcinogenesis model that will be published in a book on stochastic carcinogenesis models edited by Wei-Yuan Tan. In addition, we organized and held a workshop on ''Biologically Based Modeling of Human Health Effects of Low dose Ionizing Radiation'', July 28-29, 2005 at Fred Hutchinson Cancer Research Center in Seattle, Washington. We had over 20 participants, including Mary Helen Barcellos-Hoff as keynote speaker, talks by most of the low-dose modelers in the DOE low-dose program, experimentalists including Les Redpath (and Mary Helen), Noelle Metting from DOE, and Tony Brooks. It appears that homeostatic regulation may be central to understanding low-dose radiation phenomena. The primary effects of ionizing radiation (IR) are cell killing, delayed cell cycling, and induction of mutations. However, homeostatic regulation causes cells that are killed or damaged by IR to eventually be replaced. Cells with an initiating mutation may have a replacement advantage, leading to clonal expansion of these initiated cells. Thus we have focused particularly on modeling effects that disturb homeostatic regulation as early steps in the carcinogenic process. There are two primary considerations that support our focus on homeostatic regulation. First, a number of epidemiologic studies using multistage carcinogenesis models that incorporate the ''initiation, promotion, and malignant conversion'' paradigm of carcinogenesis are indicating that promotion of initiated cells is the most important cellular mechanism driving the shape of the age specific hazard for many types of cancer. Second, we have realized that many of the genes that are modified in early stages of the carcinogenic process contribute to one or more of four general cellular pathways that confer a promotional advantage to cells when these pathways are disrupted

Does folic acid supplementation prevent or promote colorectal cancer? Results from model-based predictions.

Folate is essential for nucleotide synthesis, DNA replication, and methyl group supply. Low-folate status has been associated with increased risks of several cancer types, suggesting a chemopreventive role of folate. However, recent findings on giving folic acid to patients with a history of colorectal polyps raise concerns about the efficacy and safety of folate supplementation and the long-term health effects of folate fortification. Results suggest that undetected precursor lesions may progress under folic acid supplementation, consistent with the role of folate role in nucleotide synthesis and cell proliferation. To better understand the possible trade-offs between the protective effects due to decreased mutation rates and possibly concomitant detrimental effects due to increased cell proliferation of folic acid, we used a biologically based mathematical model of colorectal carcinogenesis. We predict changes in cancer risk based on timing of treatment start and the potential effect of folic acid on cell proliferation and mutation rates. Changes in colorectal cancer risk in response to folic acid supplementation are likely a complex function of treatment start, duration, and effect on cell proliferation and mutations rates. Predicted colorectal cancer incidence rates under supplementation are mostly higher than rates without folic acid supplementation unless supplementation is initiated early in life (before age 20 years). To the extent to which this model predicts reality, it indicates that the effect on cancer risk when starting folic acid supplementation late in life is small, yet mostly detrimental. Experimental studies are needed to provide direct evidence for this dual role of folate in colorectal cancer and to validate and improve the model predictions

On the number of founding germ cells in humans

BACKGROUND: The number of founding germ cells (FGCs) in mammals is of fundamental significance to the fidelity of gene transmission between generations, but estimates from various methods vary widely. In this paper we obtain a new estimate for the value in humans by using a mathematical model of germ cell development that depends on available oocyte counts for adult women. RESULTS: The germline-development model derives from the assumption that oogonial proliferation in the embryonic stage starts with a founding cells at t = 0 and that the subsequent proliferation can be defined as a simple stochastic birth process. It follows that the population size X(t) at the end of germline expansion (around the 5(th )month of pregnancy in humans; t = 0.42 years) is a random variable with a negative binomial distribution. A formula based on the expectation and variance of this random variable yields a moment-based estimate of a that is insensitive to the progressive reduction in oocyte numbers due to their utilization and apoptosis at later stages of life. In addition, we describe an algorithm for computing the maximum likelihood estimation of the FGC population size (a), as well as the rates of oogonial division and loss to apoptosis. Utilizing both of these approaches to evaluate available oocyte-counting data, we have obtained an estimate of a = 2 – 3 for Homo sapiens. CONCLUSION: The estimated number of founding germ cells in humans corresponds well with values previously derived from chimerical or mosaic mouse data. These findings suggest that the large variation in oocyte numbers between individual women is consistent with a smaller founding germ cell population size than has been estimated by cytological analyses

Multiscale Estimation of Cell Kinetics

We introduce a methodology based on the Luria–Delbrück fluctuation model for estimating the cell kinetics of clonally expanding populations. In particular, this approach allows estimation of the net cell proliferation rate, the extinction coefficient and the initial (viable) population size. We present a systematic approach based on spatial partitioning, which captures the local fluctuations of the number and sizes of individual clones. However, partitioning introduces measurement error by inflating the number of clones, which is dependent on time and the degree of cell migration. We perform various in silico experiments to explore the properties of the estimators and we show that there exists a direct relationship between precision and observation time. We also explore the trade-off between the measurement error and the estimation accuracy. By exploring different scales of cellular fluctuations, from the entire population down to those of individual clones, we show that this methodology is useful for inferring important parameters in neoplastic progression

Number and Size Distribution of Colorectal Adenomas under the Multistage Clonal Expansion Model of Cancer

Colorectal cancer (CRC) is believed to arise from mutant stem cells in colonic crypts that undergo a well-characterized progression involving benign adenoma, the precursor to invasive carcinoma. Although a number of (epi)genetic events have been identified as drivers of this process, little is known about the dynamics involved in the stage-wise progression from the first appearance of an adenoma to its ultimate conversion to malignant cancer. By the time adenomas become endoscopically detectable (i.e., are in the range of 1–2 mm in diameter), adenomas are already comprised of hundreds of thousands of cells and may have been in existence for several years if not decades. Thus, a large fraction of adenomas may actually remain undetected during endoscopic screening and, at least in principle, could give rise to cancer before they are detected. It is therefore of importance to establish what fraction of adenomas is detectable, both as a function of when the colon is screened for neoplasia and as a function of the achievable detection limit. To this end, we have derived mathematical expressions for the detectable adenoma number and size distributions based on a recently developed stochastic model of CRC. Our results and illustrations using these expressions suggest (1) that screening efficacy is critically dependent on the detection threshold and implicit knowledge of the relevant stem cell fraction in adenomas, (2) that a large fraction of non-extinct adenomas remains likely undetected assuming plausible detection thresholds and cell division rates, and (3), under a realistic description of adenoma initiation, growth and progression to CRC, the empirical prevalence of adenomas is likely inflated with lesions that are not on the pathway to cancer

Implications of Epigenetic Drift in Colorectal Neoplasia

NIH grants U01CA182940 (G.E. Luebeck, W.D. Hazelton, W.M. Grady, S.K. Madden, K. Curtius), U01CA199336 (G.E. Luebeck, W.D. Hazelton); Barts Charity grant 472-2300, London (K. Curtius) and UK Medical Research Council Rutherford fellowship (K. Curtius); and NIH grants (P30CA15704, U01CA152756, R01CA194663, R01CA220004, U54CA143862, P01CA077852),R.A.C.E. Charities, Cottrell Family Fund, R03CA165153, Listwin Family Foundation, Seattle Translational Tumor Research program, Fred Hutchinson Cancer Research Center (S.K. Madden, M. Yu, K.T. Carter, and W.M. Grady), R01CA189184 (C. Lee, C.M. Ulrich, S.K.Madden, M. Yu, K.T. Carter, and W.M. Grady), R01CA112516, R01CA114467, R01CA120523 (C.M. Ulrich, S.K. Madden, M. Yu, K.T. Carter, and W.M. Grady), Huntsman Cancer Foundation, U01 CA206110, R01CA189184 R01CA 207371 and P30CACA042014 (C.M. Ulrich). U24CA074794 (P.A. Newcomb, S.K. Madden, M. Yu, K.T. Carter, and W.M. Grady). This material is the result of work supported in part by resources from the VA Puget Sound Health Care System and the ColoCare Study

Radiofrequency Ablation of Barrett's Esophagus Reduces Esophageal Adenocarcinoma Incidence and Mortality in a Comparative Modeling Analysis

No Abstract Availabl

Optimizing Management of Patients With Barrett's Esophagus and Low-Grade or No Dysplasia Based on Comparative Modeling

Background & Aims: Endoscopic treatment is recommended for patients with Barrett's esophagus (BE) with high-grade dysplasia, yet clinical management recommendations are inconsistent for patients with BE without dysplasia (NDBE) or with low-grade dysplasia (LGD). We used a comparative modeling analysis to identify optimal management strategies for these patients. Methods: We used 3 independent population-based models to simulate cohorts of 60-year-old individuals with BE in the United States. We followed up each cohort until death without surveillance and treatment (natural disease progression), compared with 78 different strategies of management for patients with NDBE or LGD. We determined the optimal strategy using cost-effectiveness analyses, at a willingness-to-pay threshold of $100,000 per quality-adjusted life-year (QALY). Results: In the 3 models, the average cumulative incidence of esophageal adenocarcinoma was 111 cases, with costs totaling$5.7 million per 1000 men with BE. Surveillance and treatment of men with BE prevented 23% to 75% of cases of esophageal adenocarcinoma, but increased costs to $6.2 to$17.3 million per 1000 men with BE. The optimal strategy was surveillance every 3 years for men with NDBE and treatment of LGD after confirmation by repeat endoscopy (incremental cost-effectiveness ratio, $53,044/QALY). The average results for women were consistent with the results for men for LGD management, but the optimal surveillance interval for women with NDBE was 5 years (incremental cost-effectiveness ratio,$36,045/QALY). Conclusions: Based on analyses from 3 population-based models, the optimal management strategy for patient with BE and LGD is endoscopic eradication, but only after LGD is confirmed by a repeat endoscopy. The optimal strategy for patients with NDBE is endoscopic surveillance, using a 3-year interval for men and a 5-year interval for women

A Multiscale Model Evaluates Screening for Neoplasia in Barrett's Esophagus

National Cancer Institute grants U01 CA152926 (CISNET) (to EGL, JJ, and WDH) and U01 CA182940 (BG-U01) (to EGL and WDH). National Science Foundation (www.nsf.gov) under grant no. DGE-0718124 (to KC

A Molecular Clock Infers Heterogeneous Tissue Age Among Patients with Barrett's Esophagus

National Institutes of Health (www.nih.gov) and the National Cancer Institute (www.cancer.gov) under grants U01CA182940 (BG-U01) (to EGL, CJW, WDH, WMG, and KC), 5P30CA015704 (to WMG and CJW), 5U01CA152756 (to WMG and CJW), 5U54CA163060 (to AC), and NIH1P50CA150964-01A1 (to JEW