Genome-wide association studies of lung cancer reported in populations of European background have identified three regions on chromosomes 5p15.33, 6p21.33, and 15q25 that have achieved genome-wide significance with p-values of 10⁻⁷ or lower. These studies have been performed primarily in cigarette smokers, raising the possibility that the observed associations could be related to tobacco use, lung carcinogenesis, or both. Since most women in Asia do not smoke, we conducted a genome-wide association study of lung adenocarcinoma in never-smoking females (584 cases, 585 controls) among Han Chinese in Taiwan and found that the most significant association was for rs2736100 on chromosome 5p15.33 (p = 1.30×10⁻¹¹). This finding was independently replicated in seven studies from East Asia totaling 1,164 lung adenocarcinomas and 1,736 controls (p = 5.38×10⁻¹¹). A pooled analysis achieved genome-wide significance for rs2736100. This SNP marker localizes to the CLPTM1L-TERT locus on chromosome 5p15.33 (p = 2.60×10⁻²⁰, allelic risk = 1.54, 95% Confidence Interval (CI) 1.41–1.68). Risks for heterozygote and homozygote carriers of the minor allele were 1.62 (95% CI; 1.40–1.87), and 2.35 (95% CI: 1.95–2.83), respectively. In summary, our results show that genetic variation in the CLPTM1L-TERT locus of chromosome 5p15.33 is directly associated with the risk of lung cancer, most notably adenocarcinoma. Worldwide, approximately 15% of lung cancer cases occur among nonsmokers. Genome-wide association studies (GWAS) of lung cancer conducted in populations of European background have identified three regions on chromosomes 5, 6, and 15 that harbor genetic variants that confer risk for lung cancer. Prior studies were conducted primarily in cigarette smokers, raising the possibility that the associations could be related to tobacco use, lung carcinogenesis, or both. A GWAS of lung cancer among never-smokers is an optimal setting to discover effects that are independent of smoking. Since most women in Asia do not smoke, we conducted a GWAS of lung adenocarcinoma among never-smoking females (584 cases, 585 controls) in Taiwan, and observed a region on chromosome 5 significantly associated with risk for lung cancer in never-smoking women. The finding was independently replicated in seven studies from East Asia totaling 1,164 lung adenocarcinomas and 1,736 controls. To our knowledge, this study is the first reported GWAS of lung cancer in East Asian women, and together with the replication studies represents the largest genetic association study in this population. The findings provide insight into the genetic contribution of common variants to lung carcinogenesis.

Background: Metabolic reconstructions (MRs) are common denominators in systems biology and represent biochemical, genetic, and genomic (BiGG) knowledge-bases for target organisms by capturing currently available information in a consistent, structured manner. Salmonella enterica subspecies I serovar Typhimurium is a human pathogen, causes various diseases and its increasing antibiotic resistance poses a public health problem. Results: Here, we describe a community-driven effort, in which more than 20 experts in S. Typhimurium biology and systems biology collaborated to reconcile and expand the S. Typhimurium BiGG knowledge-base. The consensus MR was obtained starting from two independently developed MRs for S. Typhimurium. Key results of this reconstruction jamboree include i) development and implementation of a community-based workflow for MR annotation and reconciliation; ii) incorporation of thermodynamic information; and iii) use of the consensus MR to identify potential multi-target drug therapy approaches. Conclusion: Taken together, with the growing number of parallel MRs a structured, community-driven approach will be necessary to maximize quality while increasing adoption of MRs in experimental design and interpretation.

Klebsiella pneumoniae is a Gram-negative bacterium of the family Enterobacteriaceae that possesses diverse metabolic capabilities: many strains are leading causes of hospital-acquired infections that are often refractory to multiple antibiotics, yet other strains are metabolically engineered and used for production of commercially valuable chemicals. To study its metabolism, we constructed a genome-scale metabolic model ( i YL1228) for strain MGH 78578, experimentally determined its biomass composition, experimentally determined its ability to grow on a broad range of carbon, nitrogen, phosphorus and sulfur sources, and assessed the ability of the model to accurately simulate growth versus no growth on these substrates. The model contains 1,228 genes encoding 1,188 enzymes that catalyze 1,970 reactions and accurately simulates growth on 84% of the substrates tested. Furthermore, quantitative comparison of growth rates between the model and experimental data for nine of the substrates also showed good agreement. The genome-scale metabolic reconstruction for K. pneumoniae presented here thus provides an experimentally validated in silico platform for further studies of this important industrial and biomedical organism.

A chronic disease in older adults usually runs a course that is less predictable than in younger individuals. Unexplained variations in disease incidence, prognosis, therapeutic responses, and toxicity are frequently observed among older adults. This heterogeneity poses huge challenges to the current one-size-fits-all health care systems, and calls for more personalized managements of chronic diseases in older adults. Aging is characterized by progressive deterioration of bodily functions with increasing risk of failure over time. The entire process is hierarchically organized, and progresses from intracellular events to changes at systemic and ultimately organism levels at different rates among different individuals. Aging biology exerts great influences on the development and progression of most age-related chronic diseases. Thus, aging biology could contribute to the complexity of illnesses that increase with age, and aging biomarkers possess a great potential to enable personalized health risk assessment and health care. We review evidences supporting the roles of aging biomarkers in risk assessment of prevalent age-related diseases. Frailty phenotype is an objectively measured indicator of advanced-stage aging that is characterized by organism-level dysfunction. In contrast, altered inflammation markers level signifies an earlier stage between cellular abnormalities and systems dysfunction. Results of human observational studies and randomized controlled trials indicate that these measures, albeit simple, greatly facilitate classification of older patients with cancer, chronic kidney disease, cardiovascular diseases and type 2 diabetes mellitus into groups that vary in disease incidence, prognosis and therapeutic response/toxicity. As the detailed mechanisms underlying the complex biologic process of aging are unraveled in the future, a larger array of biomarkers that correlate with biologic aging at different stages will be discovered. Following the translational research framework described in this article, these research efforts would result in innovations in disease prevention and management that address the huge unmet health needs of aging populations.

Motivation: Continual and accumulated mutations in hemagglutinin (HA) protein of influenza A virus generate novel antigenic strains that cause annual epidemics. Results: We propose a model by incorporating scoring and regression methods to predict antigenic variants. Based on collected sequences of influenza A/H3N2 viruses isolated between 1971 and 2002, our model can be used to accurately predict the antigenic variants in 1999–2004 (agreement rate = 91.67%). Twenty amino acid positions identified in our model contribute significantly to antigenic difference and are potential immunodominant positions. Contact: hsiung@nhri.org.tw Supplementary information: The supplementary information includes 62 amino acid sequences of H3N2 viruses and 277 pair-wise antigenic distances.

Few studies have examined the association between environmental phthalate exposure and children’s neurocognitive development. This longitudinal study examined cognitive function in relation to pre-and postnatal phthalate exposure in children 2–12 years old. We recruited 430 pregnant women in their third trimester in Taichung, Taiwan from 2001–2002. A total of 110, 79, 76, and 73 children were followed up at ages 2, 5, 8, and 11, respectively. We evaluated the children’s cognitive function at four different time points using the Bayley and Wechsler tests for assessing neurocognitive functions and intelligence (IQ). Urine samples were collected from mothers during pregnancy and from children at each follow-up visit. They were analyzed for seven metabolite concentrations of widely used phthalate esters. These esters included monomethyl phthalate, monoethyl phthalate, mono-butyl phthalate, mono-benzyl phthalate, and three metabolites of di(2-ethylhexyl) phthalate, namely, mono-2-ethylhexyl phthalate, mono(2-ethyl-5-hydroxyhexyl) phthalate, and mono(2-ethyl-5-oxohexyl) phthalate. We constructed a linear mixed model to examine the relationships between the phthalate metabolite concentrations and the Bayley and IQ scores. We found significant inverse associations between the children’s levels of urinary mono(2-ethyl-5-oxohexyl) phthalate and the sum of the three metabolites of di(2-ethylhexyl) phthalate and their IQ scores (β = -1.818; 95% CI: -3.061, -0.574, p = 0.004 for mono(2-ethyl-5-oxohexyl) phthalate; β = -1.575; 95% CI: -3.037, -0.113, p = 0.035 for the sum of the three metabolites) after controlling for maternal phthalate levels and potential confounders. We did not observe significant associations between maternal phthalate exposure and the children’s IQ scores. Children’s but not prenatal phthalate exposure was associated with decreased cognitive development in the young children. Large-scale prospective cohort studies are needed to confirm these findings in the future.