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Biomedical subjects

Hong Cheng

Publications and source records attributed to Hong Cheng.

At least 19 recordsLinked to original sources
PubMed2026

The Soifua Manuia reference panel with 2,570 Samoan haplotypes improves genotype imputation quality among Samoans.

Genotype imputation is fundamental to association studies, and yet even gold standard panels like TOPMed are limited in the populations for which they yield good imputation. Specifically, Pacific Islanders are poorly represented in extant panels. To address this, we used whole-genome sequencing from 1,285 Samoan individuals combined with 1000 Genomes Project (1KGP) individuals to construct an imputation reference panel that better represents Pacific Islander, specifically Samoan, genetic variation. Here we show that this panel yielded up to two times more well-imputed (r2 ≥ 0.80) variants than TOPMed-R3 and 1KGP and was enriched for moderate and high impact variants. There was improved imputation accuracy across the minor allele frequency (MAF) spectrum; accuracy (r2) was greater for population-specific variants (high fixation index, FST) and those from larger haplotypes (high LD score). However, the gain in accuracy over TOPMed-R3 was largest for small haplotypes, reflecting the Samoan panel's ability to capture variation not well tagged by other panels.

Haplotypes↗
PubMed2026

Efficacy and safety of ferric citrate tablets in Chinese patients with hyperphosphatemia undergoing maintenance hemodialysis: a multicenter, randomized, open-label, active-controlled, phase III trial.

BACKGROUND: This study aimed to evaluate the efficacy and safety of ferric citrate tablets in Chinese patients with hyperphosphatemia undergoing maintenance hemodialysis (MHD). METHODS: In this phase III, multicenter, randomized, open-label, non-inferiority trial, patients with hyperphosphatemia on maintenance hemodialysis were randomly assigned to receive either ferric citrate or sevelamer carbonate tablets for 12 weeks. The primary endpoint was the change in serum phosphorus levels from baseline to week 12, with a non-inferiority margin of 0.32 mmol/L. Secondary endpoints included changes in serum calcium, intact parathyroid hormone, and safety assessments. RESULTS: A total of 239 patients were randomized to the ferric citrate group (n = 119) or the sevelamer carbonate group (n = 120). The mean change in serum phosphorus levels was -0.70 ± 0.50 mmol/L in the ferric citrate group and -0.61 ± 0.59 mmol/L in the sevelamer carbonate group (least squares mean difference, -0.09 mmol/L; 95% CI, -0.24 to 0.05 mmol/L; non-inferiority margin, 0.32 mmol/L). No significant inter-group differences were found in the percentage of patients achieving target phosphorus levels (49.09% vs. 48.28%, p = 0.902). Ferric citrate significantly improved iron-related parameters and hemoglobin levels. Most treatment-emergent adverse events were mild, with gastrointestinal disorders being the most common. CONCLUSIONS: Ferric citrate tablets were non-inferior to sevelamer carbonate in reducing serum phosphorus levels in hyperphosphatemia patients on maintenance hemodialysis, with the added benefit of improving iron-related anemia and a favorable safety profile.

Adult↗
PubMed2026

Variant harmonization critically determines polygenic score transferability for lipid traits in Samoan populations.

Dyslipidemia is a significant risk factor for cardiovascular disease (CVD), the leading cause of death in Samoa. Polygenic scores (PGSs) for lipid traits offer promise for improved CVD risk prediction; however, their performance in Pacific Islander populations-comprising only 0.002% of genome-wide association study (GWAS) participants as of 2024-remains unknown. We evaluated the transferability of multi-ancestry PGS for LDL cholesterol (LDL-C), HDL cholesterol (HDL-C), triglycerides (TGs), and total cholesterol (TC) in 4,342 Samoan adults across five cohorts spanning 1990-2010. PGSs from Graham et al. and Kanoni et al. multi-ancestry meta-analyses were harmonized with genome-wide imputed genotypes using a Samoan-specific reference panel, and performance was assessed via incremental R2 from linear mixed models with bootstrapped confidence intervals. HDL-C showed the highest performance (incremental R2 5.0%-15.0%), followed by TC (5.0%-10.7%), LDL-C (5.7%-8.6%), and TG (3.5%-7.0%). Critically, meaningful LDL-C performance was achieved only with the genome-wide PRS-CS score (99.6%-99.7% variant matching), while a curated pruning-and-thresholding score achieved ∼9% matching and near-zero performance. These findings establish systematic lipid PGS benchmarks in Samoans, demonstrating meaningful transferability when genome-wide variant coverage is ensured, and highlight variant harmonization as a critical precondition for PGS deployment in underrepresented populations.

Pacific Islanders↗
PubMed2026

IGF2BP1-Mediated m⁶A Modification Stabilizes HMGA2 mRNA to Promote Intrahepatic Cholangiocarcinoma Progression.

BACKGROUND & AIMS: Intrahepatic cholangiocarcinoma (iCCA) remains a lethal malignancy with a lack of effective therapies, underscoring the critical need to identify novel therapeutic targets. The high-mobility group protein A2 (HMGA2) is an oncogenic architectural transcription factor aberrantly overexpressed in multiple cancers; yet its function and regulatory mechanisms in iCCA are poorly defined. This study aimed to elucidate the clinical significance and molecular mechanism of HMGA2 in iCCA progression. METHODS: We integrated analyses across 4 independent iCCA cohorts (The Cancer Genome Atlas, 2 Zhongshan Hospital cohorts, and our 192-patient institutional cohort). Functional investigations were conducted using iCCA cell lines and multiple mouse models, including xenograft, syngeneic, YAP/AKT-driven spontaneous iCCA, and metastasis models. RESULTS: We demonstrated that HMGA2 was significantly upregulated in iCCA, correlating with poor survival, and exhibited sexually dimorphic prognostic effects with a female-specific link to perineural invasion. Functionally, HMGA2 depletion suppressed iCCA cell proliferation, migration, in vivo tumor growth and metastasis. Mechanistically, HMGA2 expression was positively regulated by the N6-methyladenosine reader insulin-like growth factor 2 messenger RNA-binding protein 1 (IGF2BP1), which directly bound to and stabilized HMGA2 messenger RNA via its KH3-4 domains in an N6-methyladenosine-dependent manner. High IGF2BP1 expression predicted poor iCCA prognosis, was required for HMGA2-driven progression, and the axis promoted PI3K-AKT pathway activation. CONCLUSIONS: Our results reveal a critical role for the IGF2BP1-HMGA2 axis in iCCA pathogenesis, thereby highlighting its potential as a therapeutic target.

Cholangiocarcinoma↗
PubMed2006

Human mRNA export machinery recruited to the 5' end of mRNA.

Pre-mRNAs undergo splicing to remove introns, and the spliced mRNA is exported to the cytoplasm for translation. Here we investigated the mechanism for recruitment of the conserved mRNA export machinery (TREX complex) to mRNA. We show that the human TREX complex is recruited to a region near the 5' end of mRNA, with the TREX component Aly bound closest to the 5' cap. Both TREX recruitment and mRNA export require the cap, and these roles for the cap are splicing dependent. CBP80, which is bound to the cap, associates efficiently with TREX, and Aly mediates this interaction. Together, these data indicate that the CBP80-Aly interaction results in recruitment of TREX to the 5' end of mRNA, where it functions in mRNA export. As a consequence, the mRNA would be exported in a 5' to 3' direction through the nuclear pore, as observed in early electron micrographs of giant Balbiani ring mRNPs.

Exons↗
PubMed2006

Regulation of IRAK-4 kinase activity via autophosphorylation within its activation loop.

Interleukin-1 stimulation leads to the recruitment of MyD88, interleukin-1 receptor-associated kinase 1 (IRAK-1) and interleukin-1 receptor-associated kinase 4 (IRAK-4) to the IL-1 receptor. The formation of the IL-1 receptor complex triggers a series of IRAK-1 autophosphorylations, which result in activation. IRAK-4 is upstream of IRAK-1 and may act as IRAK-1 kinase to transmit the signal. To date, there is no upstream kinase reported for IRAK-4; the activation mechanism of IRAK-4 remains poorly understood. Here, for the first time, we report three autophosphorylation sites that are responsible for IRAK-4 kinase activity. LC-MS/MS analysis has identified phosphorylations at T342, T345, and S346, which reside within the activation loop. Site-directed mutants at these positions exhibit significant reductions in the catalytic activity of IRAK-4 (T342A: 57%; T345A: 66%; S346A: 50%). The absence of phosphorylation in kinase-dead IRAK-4 indicates that phosphorylations in the activation loop result from autophosphorylation rather than from phosphorylation by an upstream kinase. Finally, we demonstrate that autophosphorylation is an intramolecular event as wild-type IRAK-4 failed to transphosphorylate kinase-inactive IRAK-4. The present data indicate that the kinase activity of IRAK-4 is dependent on the autophosphorylations at T342, T345, and S346 in the activation loop.

Amino Acid Sequence↗
PubMed2006

[Influence of resistance of Helicobacter pylori to antibiotics on the Helicobacter pylori eradication regimens].

OBJECTIVE: To investigate the influence of resistance of Helicobacter pylori (H. pylori) to antibiotics on the efficacy of lansoprazole triple therapy for H. pylori eradication. METHODS: 157 patients, 102 males and 55 females, aged 42.7 (18 - 70), with upper abdominal symptoms, 59 with chronic gastritis and 98 with peptic ulcer, underwent gastroendoscopy 157 H. pylori strains were isolated from the gastric biopsy specimens of these patients and cultured. Minimal inhibitory concentrations of 3 antibiotics (metronidazole and clarithromycin) were determined by E-test. The 157 patients were treated by triple therapies, including lansoprazole, metronidazole, and clarithromycin for 7 days. Reexamination was done at least 4 weeks after the therapy. RESULTS: The resistance rates of H. pylori to metronidazole and clarithromycin were 45.9% (72/157) and 18.5% (29/157) respectively. The reexamination showed an eradication rate of H. pylori of 61.8% (97/157). The eradication rates of the metronidazole-sensitive and resistant strains were 89.4% (76/85) and 29.2% (21/72) respectively (P < 0.01), and the eradication rates of the clarithromycin-sensitive and resistant strains were 72.7% (93/128) and 16.0% (4/29) respectively (P < 0.01). Presence of a gastroduodenal ulcer, age and gender did not differ significantly between the eradicated and non-eradicated groups (all P > 0.05). CONCLUSION: Resistance of H. pylori to antibiotics is the most important cause of the failure of H. pylori eradication.

Adolescent↗
PubMed2006

1,3-Butadiene and leukemia among synthetic rubber industry workers: exposure-response relationships.

Previous research updated the mortality experience of North American synthetic rubber industry workers during the period 1944-1998, determined if leukemia and other cancers were associated with several employment factors and carried out Poisson regression analysis to examine exposure-response associations between estimated exposure to 1,3-butadiene (BD) or other chemicals and cancer. The present study used Cox regression procedures to examine further the exposure-response relationship between several unlagged and lagged, continuous, time-dependent BD exposure indices (BD parts per million (ppm)-years, the total number of exposures to BD concentrations >100 ppm ("peaks") and average intensity of BD) and leukemia, lymphoid neoplasms and myeloid neoplasms. All three BD exposure indices were associated positively with leukemia. Using continuous, untransformed BD ppm-years the regression coefficient (beta) from an analysis that controlled only for age was 2.9 x 10(-4) (p<0.01); the regression coefficient adjusted for all covariates (age, year of birth, race, plant, years since hire and dimethyldithiocarbamate) was similar in magnitude (beta=3.0 x 10(-4), p=0.04). Lagging exposure had minimal impact on the results for leukemia for any of the three BD exposure indices. In models that controlled only for age, lymphoid neoplasms were associated with BD ppm-years and myeloid neoplasms, with BD peaks, but neither trend was statistically significant after adjusting for multiple covariates. The present results support the presence of a causal relationship between high cumulative exposure and high intensity of exposure to BD and leukemia.

Butadienes↗
PubMed2006

Validation of 1,3-butadiene exposure estimates for workers at a synthetic rubber plant.

PURPOSE: This investigation assessed the validity of estimates of exposure to 1,3-butadiene (BD) developed for a plant included in a study of mortality among synthetic rubber industry workers. The estimates were developed without using historical measurement data and have not been validated previously. METHODS: Personal BD measurements came from an exposure-monitoring program initiated in 1977. For each job, we computed the year-specific difference between the BD estimate and the mean of BD measurements. We also computed rank correlation coefficients and calculated the mean, across all measurements, of the difference between the estimate and the measurement. RESULTS: The mean BD concentration was 5.2 ppm for 4978 measurements and 4.7 ppm for the corresponding estimates. The mean difference between estimates and measurements was -0.50 ppm (standard deviation, 26.5 ppm) overall and ranged from -227.9 to +27.0 ppm among all 306 job/year combinations. Estimates were correlated with measurements for all 306 combinations (rank correlation coefficient, r=0.45, p<0.0001), for 82 combinations pertaining to jobs that were well-defined by a specific set of tasks and typically found in styrene-BD rubber (SBR) plants (r=0.81, p<0.0001), for 70 combinations pertaining to jobs that were well-defined but not typical (r=0.29, p=0.01) and for 92 combinations pertaining to poorly-defined jobs typically found in SBR plants (r=0.56, <0.0001). Estimates were not correlated with measurements for poorly defined jobs not typically found in SBR plants (r=0.01, p=0.93). For well-defined typical SBR jobs with measurement means that were over 7.0 ppm, estimates were consistently lower than measurements. CONCLUSIONS: Possible reasons for differences between estimates and measurements included faulty assumptions used in developing BD estimates, unstable or nonrepresentive measurements and errors in linking measurement data to the job-exposure matrix. Exposure misclassification may have been more severe for subjects from the validation study plant than for subjects from other plants in the mortality study. BD estimates for typical SBR jobs, which comprise most operations at all but one of the plants in the mortality study, appeared to be useful for ranking workers by cumulative exposure. Uncertainty analyses would enhance the utility of the BD exposure estimates for quantitative risk assessment.

Butadienes↗
PubMed2006

In vivo function of the orphan nuclear receptor NR2E3 in establishing photoreceptor identity during mammalian retinal development.

Rod and cone photoreceptors in mammalian retina are generated from common pool(s) of neuroepithelial progenitors. NRL, CRX and NR2E3 are key transcriptional regulators that control photoreceptor differentiation. Mutations in NR2E3, a rod-specific orphan nuclear receptor, lead to loss of rods, increased density of S-cones and supernormal S-cone-mediated vision in humans. To better understand its in vivo function, NR2E3 was expressed ectopically in the Nrl-/- retina, where post-mitotic precursors fated to be rods develop into functional S-cones similar to the human NR2E3 disease. Expression of NR2E3 in the Nrl-/- retina completely suppressed cone differentiation and resulted in morphologically rod-like photoreceptors, which were however not functional. Gene profiling of FACS-purified photoreceptors confirmed the role of NR2E3 as a strong suppressor of cone genes but an activator of only a subset of rod genes (including rhodopsin) in vivo. Ectopic expression of NR2E3 in cone precursors and differentiating S-cones of wild-type retina also generated rod-like cells. The dual regulatory function of NR2E3 was not dependent upon the presence of NRL and/or CRX, but on the timing and level of its expression. Our studies reveal a critical role of NR2E3 in establishing functional specificity of NRL-expressing photoreceptor precursors during retinal neurogenesis.

Animals↗
PubMed2006

Identification of a regulatory autophosphorylation site in the serine-threonine kinase RIP2.

Receptor-interacting protein 2 (RIP2) is a serine-threonine kinase that mediates signaling for many receptors of the innate and adaptive immune systems. Toll like receptors (TLR) are an important component of the innate immune response. Stimulation of RIP2-deficient cells with ligands for TLR 2, 3 and 4 results in impaired cytokine production and decreased activation of NF-kB and MAP kinases compared to wild-type cells. Stimulation of TLR 4 with its ligand lipopolysaccaride (LPS) leads to the activation of RIP2 kinase activity and its autophosphorylation. Here we identify serine residue 176 as a site of autophosphorylation using a combination of mass spectrometry and mutational analysis. Mutation of S176 to alanine not only abolishes autophosphorylation of RIP2 but also significantly decreases its catalytic activity. A phospho-specific anti-S176 antibody detects wild-type RIP2 but not kinase-dead RIP2 or the RIP2 S176A mutant. Endogenous RIP2 in THP-1 cells and mouse bone marrow derived macrophages can be detected by the phospho-RIP2 (S176) antibody only after stimulation with LPS suggesting that the antibody recognizes activated RIP2. In summary, our results indicate that S176 is a regulatory autophosphorylation site for RIP2 and that S176 phosphorylation can be used to monitor the activation state of RIP2.

Amino Acid Sequence↗
PubMed2006

In-frame deletion in a novel centrosomal/ciliary protein CEP290/NPHP6 perturbs its interaction with RPGR and results in early-onset retinal degeneration in the rd16 mouse.

Centrosome- and cilia-associated proteins play crucial roles in establishing polarity and regulating intracellular transport in post-mitotic cells. Using genetic mapping and positional candidate strategy, we have identified an in-frame deletion in a novel centrosomal protein CEP290 (also called NPHP6), leading to early-onset retinal degeneration in a newly identified mouse mutant, rd16. We demonstrate that CEP290 localizes primarily to centrosomes of dividing cells and to the connecting cilium of retinal photoreceptors. We show that, in the retina, CEP290 associates with several microtubule-based transport proteins including RPGR, which is mutated in approximately 15% of patients with retinitis pigmentosa. A truncated CEP290 protein (DeltaCEP290) is detected in the rd16 retina, but in considerably reduced amounts; however, the mutant protein exhibits stronger association with specific RPGR isoform(s). Immunogold labeling studies demonstrate the redistribution of RPGR and of phototransduction proteins in the photoreceptors of rd16 retina. Our findings suggest a critical function for CEP290 in ciliary transport and provide insights into the mechanism of early-onset photoreceptor degeneration.

Animals↗
PubMed2006

A selective small molecule IkappaB Kinase beta inhibitor blocks nuclear factor kappaB-mediated inflammatory responses in human fibroblast-like synoviocytes, chondrocytes, and mast cells.

IkappaB kinase (IKK) beta is essential for inflammatory cytokine-induced activation of nuclear factor kappaB (NF-kappaB). NF-kappaB plays a pivotal role in the function of major cell types that contribute to the pathophysiological process of rheumatoid arthritis (RA). Here, we report the mechanism and the effect of the IKKbeta inhibitor N-(6-chloro-7-methoxy-9H-beta-carbolin-8-yl)-2-methylnicotinamide (ML120B), a beta-carboline derivative, on NF-kappaB signaling and gene activation in RA-relevant cell systems. ML120B is a potent, selective, reversible, and ATP-competitive inhibitor of IKKbeta with an IC50 of 60 nM when evaluated in an IkappaBalpha kinase complex assay. ML120B does not inhibit other IKK isoforms or a panel of other kinases. ML120B concentration-dependently inhibits tumor necrosis factor alpha (TNFalpha)-stimulated NF-kappaB signaling via inhibition of IkappaBalpha phosphorylation, degradation, and NF-kappaB translocation into the nucleus. For the first time, we have demonstrated that in human fibroblast-like synoviocytes, TNFalpha- or interleukin (IL)-1beta-induced monocyte chemoattractant protein-1 regulated on activation, normal T cell expressed and secreted and production is IKKbeta-dependent. In addition, for the first time, we have demonstrated that lipopolysaccharide- or peptidoglycan-induced cytokine production in human cord blood-derived mast cells is IKKbeta-dependent. In addition, in human chondrocytes, ML120B inhibited IL-1beta-induced matrix metalloproteinase production with an IC50 of approximately 1 microM. ML120B also blocked IL-1beta-induced prostaglandin E2 production. In summary, ML120B blocked numerous NF-kappaB-regulated cell responses that are involved in inflammation and destructive processes in the RA joint. Our findings support the evaluation of IKKbeta inhibitors as anti-inflammatory agents for the treatment of RA.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed2006

Targeting of GFP to newborn rods by Nrl promoter and temporal expression profiling of flow-sorted photoreceptors.

The Maf-family transcription factor Nrl is a key regulator of photoreceptor differentiation in mammals. Ablation of the Nrl gene in mice leads to functional cones at the expense of rods. We show that a 2.5-kb Nrl promoter segment directs the expression of enhanced GFP specifically to rod photoreceptors and the pineal gland of transgenic mice. GFP is detected shortly after terminal cell division, corresponding to the timing of rod genesis revealed by birthdating studies. In Nrl-/- retinas, the GFP+ photoreceptors express S-opsin, consistent with the transformation of rod precursors into cones. We report the gene profiles of freshly isolated flow-sorted GFP+ photoreceptors from wild-type and Nrl-/- retinas at five distinct developmental stages. Our results provide a framework for establishing gene regulatory networks that lead to mature functional photoreceptors from postmitotic precursors. Differentially expressed rod and cone genes are excellent candidates for retinopathies.

Animals↗
PubMed2006

Structural characterization of an equilibrium unfolding intermediate in cytochrome c.

Although the denaturant-induced unfolding transition of cytochrome c was initially thought to be a cooperative process, recent spectroscopic studies have shown deviations from two-state behavior consistent with accumulation of an equilibrium intermediate. However, little is known about the structural and thermodynamic properties of this state, and whether it is stabilized by the presence of non-native heme ligands. We monitored the reversible denaturant-induced unfolding equilibrium of oxidized horse cytochrome c using various spectroscopic probes, including fluorescence, near and far-UV CD, heme absorbance bands in the Soret, visible and near-IR regions of the spectrum, as well as 2D NMR. Global fitting techniques were used for a quantitative interpretation of the results in terms of a three-state model, which enabled us to determine the intrinsic spectroscopic properties of the intermediate. A well-populated intermediate was observed in equilibrium experiments at pH 5 using either guanidine-HCl or urea as a denaturant, both for wild-type cytochrome c as well as an H33N mutant chosen to prevent formation of non-native His-heme ligation. For a more detailed structural characterization of the intermediate, we used 2D 1H-15N correlation spectroscopy to follow the changes in peak intensity for individual backbone amide groups. The equilibrium state observed in our optical and NMR studies contains many native-like structural features, including a well-structured alpha-helical sub-domain, a short Trp59-heme distance and solvent-shielded heme environment, but lacks the native Met80 sulfur-iron linkage and shows major perturbations in side-chain packing and other tertiary interactions. These structural properties are reminiscent of the A-state of cytochrome c, a compact denatured form found under acidic high-salt conditions, as well as a kinetic intermediate populated at a late stage of folding. The denaturant-induced intermediate also resembles alkaline forms of cytochrome c with altered heme ligation, suggesting that disruption of the native methionine ligand favors accumulation of structurally analogous states both in the presence and absence of non-native ligands.

Amino Acid Substitution↗
PubMed2006

Distribution of signal transducer and activator of transcription 6 gene G2964A polymorphism in Chinese patients with ulcerative colitis.

BACKGROUND AND AIMS: The signal transducer and activator of transcription 6 (STAT6) gene is located on chromosome 12q13.3-14.1 just within the IBD2 region and is a key transcription factor involved in interleukin (IL)-4 and IL-13-mediated Th2 response. The aim of the present study was to determine distribution of the STAT6 gene polymorphism in Chinese patients with ulcerative colitis. METHODS: The G2964A polymorphism in the 3' untranslated region of the STAT6 gene was studied in 84 unrelated Chinese patients with ulcerative colitis and 176 healthy controls by PCR and the amplification created restriction site method. The results were then compared with those from a Dutch study published previously. RESULT: Significant differences in genotype and allele frequencies of the STAT6 G2964A polymorphism were not found between patients with ulcerative colitis and healthy controls. Subgroups of the patients with ulcerative colitis classified according to the age at onset, sex and location of disease did not differ significantly in the distribution of this polymorphism. However, the genotypes (P < 0.0001, chi-squared = 75.332) and allele frequencies (P < 0.0001, odds ratio = 4.298, 95% confidence interval = 3.070-6.018) were significantly different between the Chinese and Dutch populations. CONCLUSION: The STAT6 G2964A polymorphism is not involved in the genetic susceptibility to ulcerative colitis in Chinese patients.

Adult↗
PubMed2006

TCDD exposure-response analysis and risk assessment.

We examined the relation between cancer mortality and time-dependent cumulative exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) estimated from a concentration- and age-dependent kinetic model of elimination, and we estimated incremental cancer risks at age 75. Data from the National Institute for Occupational Safety and Health study of 3,538 workers with occupational exposure to TCDD were analyzed using standardized mortality ratios and Cox regression procedures. Analyses adjusted for potential confounding by age, year of birth, and race and considered exposure lag periods of 0, 10, or 15 years. Other potential confounders including smoking and other occupational exposures were evaluated indirectly. To explore the influence of extreme values of cumulative TCDD ppt-years, we restricted the analysis to observations with exposure below the 95th percentile or used logarithmic (ln) transformed exposure values. We applied penalized smoothing splines to examine variation in the exposure-response relation across the exposure range. TCDD was not statistically significantly associated with cancer mortality using the full data set, regardless of the lag period. When we restricted the analysis to observations with exposure below the 95th percentile, TCDD was associated positively with cancer mortality, particularly when a 15-year lag was applied (untransformed exposure data: regression coefficient , standard error (s.e.) = 1.4 x 10(-6), p < 0.05; ln-transformed exposure data: , s.e. = 2.9 x 10(-2), p < 0.05). The estimated incremental lifetime risk of mortality at age 75 from all cancers was about 6 to more than 10 times lower than previous estimates derived from this cohort using exposure models that did not consider the age and concentration dependence of TCDD elimination.

Aged↗