The Role of Mechanistic Data in Dose-Response Modeling

Author(s):  
Thomas B. Starr
2021 ◽  
Vol 20 (1) ◽  
Author(s):  
Zhi-Ming MAI ◽  
Roger Kai-Cheong NGAN ◽  
Dora Lai-Wan KWONG ◽  
Wai-Tong NG ◽  
Kam-Tong Yuen ◽  
...  

Abstract Background The role of dietary fiber intake on risk of nasopharyngeal carcinoma (NPC) remains unclear. We examined the associations of dietary fiber intake on the risk of NPC adjusting for a comprehensive list of potential confounders. Methods Using data from a multicenter case-control study, we included 815 histologically confirmed NPC incident cases and 1502 controls in Hong Kong, China recruited in 2014–2017. Odds ratios (ORs) of NPC (cases vs controls) for dietary fiber intake from different sources at different life periods (age 13–18, age 19–30, and 10 years before recruitment) were evaluated using unconditional logistic regression, adjusting for sex, age, socioeconomic status, smoking and drinking status, occupational hazards, family history of cancer, salted fish, and total energy intake in Model 1, Epstein-Barr virus viral capsid antigen serological status in Model 2, and duration of sun exposure and circulating 25-hydroxyvitamin D in Model 3. Results Higher intake of total dietary fiber 10 years before recruitment was significantly associated with decreased NPC risk, with demonstrable dose-response relationship (P-values for trend = 0.001, 0.020 and 0.024 in Models 1–3, respectively). The adjusted ORs (95% CI) in the highest versus the lowest quartile were 0.51 (0.38–0.69) in Model 1, 0.48 (0.33–0.69) in Model 2, and 0.48 (0.33–0.70) in Model 3. However, the association was less clear after adjustment of other potential confounders (e.g. EBV) in the two younger periods (age of 13–18 and 19–30 years). Risks of NPC were significantly lower for dietary fiber intake from fresh vegetables and fruits and soybean products over all three periods, with dose-response relationships observed in all Models (P-values for trend for age 13–18, age 19–30 and 10 years before recruitment were, respectively, 0.002, 0.009 and 0.001 for Model1; 0.020, 0.031 and 0.003 for Model 2; and 0.022, 0.037 and 0.004 for Model 3). No clear association of NPC risk with dietary fiber intake from preserved vegetables, fruits and condiments was observed. Conclusion Our study has shown the protective role of dietary fiber from fresh food items in NPC risk, but no association for total dietary fiber intake was observed, probably because total intake also included intake of preserved food. Further studies with detailed dietary information and in prospective settings are needed to confirm this finding, and to explore the possible underlying biological mechanisms.


Teratology ◽  
1993 ◽  
Vol 47 (3) ◽  
pp. 175-188 ◽  
Author(s):  
John M. Rogers ◽  
M. Leonard Mole ◽  
Neil Chernoff ◽  
Brenda D. Barbee ◽  
Christine I. Turner ◽  
...  

1980 ◽  
Vol 190 (2) ◽  
pp. 333-339 ◽  
Author(s):  
M C W Minchin

1. Protoveratrine A increased the release of gamma-amino[3H]butyrate from small slices of rat cerebral cortex. This effect increased with increasing protoveratrine concentration, reaching a maximum at 100 microM. 2. Removal of Ca2+ from the superfusing medium did not change the increase in release due to 10 microM-protoveratrine; however, the Ca2+ antagonists, compound D-600, La3+, Mn2+, Mg2+ and also high Ca2+ concentration inhibited the effect of the alkaloid, as did procaine. 3. Protoveratrine A increased the uptake of 22Na+ into the slices with a similar dose-response curve to that found for gamma-aminobutyrate release. For the most part, the substances that inhibited protoveratrine-stimulated gamma-aminobutyrate release also inhibited 22Na+ uptake, although the correlation was not perfect. 4. Although extracellular Ca2+ is not required for protoveratrine-induced gamma-aminobutyrate release, an increase in Na+ influx that is susceptible to inhibition by some Ca2+ antagonists does appear to be associated with this phenomenon. However, the possibility remains that changes in the free intracellular Ca2+ concentration may be important for transmitter release induced by depolarizing veratrum alkaloids.


1987 ◽  
Vol 63 (6) ◽  
pp. 2380-2387 ◽  
Author(s):  
P. K. Weathersby ◽  
B. L. Hart ◽  
E. T. Flynn ◽  
W. F. Walker

In the calculation of decompression schedules, it is commonly assumed that only the inert gas needs to be considered; all inspired O2 is ignored. Animal experiments have shown that high O2 can increase risk of serious decompression sickness (DCS). A trial was performed to assess the relative risks of O2 and N2 in human no-decompression dives. Controlled dives (477) of 30- to 240-min duration were performed with subjects breathing mixtures with low (0.21–0.38 ATA) or high (1.0–1.5 ATA) Po2. Depths were chosen by a sequential dose-response format. Only 11 cases of DCS and 18 cases of marginal symptoms were recorded despite exceeding the presently accepted no-decompression limits by greater than 20%. Analysis by maximum likelihood showed a shallow dose-response curve for increasing depth. O2 was estimated to have zero influence on DCS risk, although data variability still allows a slight chance that O2 could be 40% as effective as N2 in producing a risk of DCS. Consideration of only inert gases is thus justified in calculating human decompression tables.


2007 ◽  
Vol 18 (5) ◽  
pp. 515-525
Author(s):  
Munni Begum ◽  
Pranab K. Sen

2019 ◽  
Author(s):  
Othman Soufan ◽  
Jessica Ewald ◽  
Charles Viau ◽  
Doug Crump ◽  
Markus Hecker ◽  
...  

There is growing interest within regulatory agencies and toxicological research communities to develop, test, and apply new approaches, such as toxicogenomics, to more efficiently evaluate chemical hazards. Given the complexity of analyzing thousands of genes simultaneously, there is a need to identify reduced gene sets.Though several gene sets have been defined for toxicological applications, few of these were purposefully derived using toxicogenomics data. Here, we developed and applied a systematic approach to identify 1000 genes (called Toxicogenomics-1000 or T1000) highly responsive to chemical exposures. First, a co-expression network of 11,210genes was built by leveraging microarray data from the Open TG-GATEs program. This network was then re-weighted based on prior knowledge of their biological (KEGG, MSigDB) and toxicological (CTD) relevance. Finally, weighted correlation network analysis was applied to identify 258 gene clusters. T1000 was defined by selecting genes from each cluster that were most associated with outcome measures. For model evaluation, we compared the performance of T1000 to that of other gene sets (L1000, S1500, Genes selected by Limma, and random set) using two external datasets. Additionally, a smaller (T384) and a larger version (T1500) of T1000 were used for dose-response modeling to test the effect of gene set size. Our findings demonstrated that the T1000 gene set is predictive of apical outcomes across a range of conditions (e.g.,in vitroand in vivo, dose-response, multiple species, tissues, and chemicals), and generally performs as well, or better than other gene sets available.


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