Investigating Multiple Candidate Genes and Nutrients in the Folate Metabolism Pathway to Detect Genetic and Nutritional Risk Factors for Lung Cancer

Purpose: Folate metabolism, with its importance to DNA repair, provides a promising region for genetic investigation of lung cancer risk. This project investigates genes (MTHFR, MTR, MTRR, CBS, SHMT1, TYMS), folate metabolism related nutrients (B vitamins, methionine, choline, and betaine) and their gene-nutrient interactions. Methods: We analyzed 115 tag single nucleotide polymorphisms (SNPs) and 15 nutrients from 1239 and 1692 non-Hispanic white, histologically-confirmed lung cancer cases and controls, respectively, using stochastic search variable selection (a Bayesian model averaging approach). Analyses were stratified by current, former, and never smoking status. Results: Rs6893114 in MTRR (odds ratio [OR] = 2.10; 95% credible interval [CI]: 1.20–3.48) and alcohol (drinkers vs. non-drinkers, OR = 0.48; 95% CI: 0.26–0.84) were associated with lung cancer risk in current smokers. Rs13170530 in MTRR (OR = 1.70; 95% CI: 1.10–2.87) and two SNP*nutrient interactions [betaine*rs2658161 (OR = 0.42; 95% CI: 0.19–0.88) and betaine*rs16948305 (OR = 0.54; 95% CI: 0.30–0.91)] were associated with lung cancer risk in former smokers. SNPs in MTRR (rs13162612; OR = 0.25; 95% CI: 0.11–0.58; rs10512948; OR = 0.61; 95% CI: 0.41–0.90; rs2924471; OR = 3.31; 95% CI: 1.66–6.59), and MTHFR (rs9651118; OR = 0.63; 95% CI: 0.43–0.95) and three SNP*nutrient interactions (choline*rs10475407; OR = 1.62; 95% CI: 1.11–2.42; choline*rs11134290; OR = 0.51; 95% CI: 0.27–0.92; and riboflavin*rs8767412; OR = 0.40; 95% CI: 0.15–0.95) were associated with lung cancer risk in never smokers. Conclusions: This study identified possible nutrient and genetic factors related to folate metabolism associated with lung cancer risk, which could potentially lead to nutritional interventions tailored by smoking status to reduce lung cancer risk

Differential Regulation of Lipoprotein and Hepatitis C Virus Secretion by Rab1b

Secretory cells produce diverse cargoes, yet how they regulate concomitant secretory traffic remains insufficiently explored. Rab GTPases control intracellular vesicular transport. To map secretion pathways, we generated a library of lentivirus-expressed dominant-negative Rab mutants and used it in a large-scale screen to identify regulators of hepatic lipoprotein secretion. We identified several candidate pathways, including those mediated by Rab11 and Rab8. Surprisingly, inhibition of Rab1b, the major regulator of transport from the endoplasmic reticulum to the Golgi, differently affected the secretion of the very-low-density lipoprotein components ApoE and ApoB100, despite their final association on mature secreted lipoprotein particles. Since hepatitis C virus (HCV) incorporates ApoE and ApoB100 into its virus particle, we also investigated infectious HCV secretion and show that its regulation by Rab1b mirrors that of ApoB100. These observations reveal differential regulation of hepatocyte secretion by Rab1b and advance our understanding of lipoprotein assembly and lipoprotein and HCV secretion

Genetic Variants in Inflammation-Related Genes Are Associated with Radiation-Induced Toxicity Following Treatment for Non-Small Cell Lung Cancer

Treatment of non-small cell lung cancer (NSCLC) with radiotherapy or chemoradiotherapy is often accompanied by the development of esophagitis and pneumonitis. Identifying patients who might be at increased risk for normal tissue toxicity would help in determination of the optimal radiation dose to avoid these events. We profiled 59 single nucleotide polymorphisms (SNPs) from 37 inflammation-related genes in 173 NSCLC patients with stage IIIA/IIIB (dry) disease who were treated with definitive radiation or chemoradiation. For esophagitis risk, nine SNPs were associated with a 1.5- to 4-fold increase in risk, including three PTGS2 (COX2) variants: rs20417 (HR:1.93, 95% CI:1.10–3.39), rs5275 (HR:1.58, 95% CI:1.09–2.27), and rs689470 (HR:3.38, 95% CI:1.09–10.49). Significantly increased risk of pneumonitis was observed for patients with genetic variation in the proinflammatory genes IL1A, IL8, TNF, TNFRSF1B, and MIF. In contrast, NOS3:rs1799983 displayed a protective effect with a 45% reduction in pneumonitis risk (HR:0.55, 95% CI:0.31–0.96). Pneumonitis risk was also modulated by polymorphisms in anti-inflammatory genes, including genetic variation in IL13. rs20541 and rs180925 each resulted in increased risk (HR:2.95, 95% CI:1.14–7.63 and HR:3.23, 95% CI:1.03–10.18, respectively). The cumulative effect of these SNPs on risk was dose-dependent, as evidenced by a significantly increased risk of either toxicity with an increasing number of risk genotypes (P<0.001). These results suggest that genetic variations among inflammation pathway genes may modulate the development of radiation-induced toxicity and, ultimately, help in identifying patients who are at an increased likelihood for such events

Cruciferous Vegetables and Risk of Cancers of the Gastrointestinal Tract

Cancers of the oropharyngeal tissues, oesophagus, stomach and colorectum are amongst the most common causes of death from cancer throughout the world. Higher consumption of fruits and vegetables is thought to be protective, and cruciferous vegetables are of particular interest because of their unique role as a source of biologically active glucosinolate breakdown products. A literature review of primary studies and meta‐analyses indicates that higher consumption of cruciferous vegetables probably reduces the risk of colorectal and gastric cancers by approximately 8% and 19% respectively. Some studies support the hypothesis that the protective effect against colorectal cancer is modified by genetic polymorphisms of genes regulating the expression of enzymes of the glutathione S‐transferase family, but due to contradictory findings the evidence is currently inconclusive. Despite these promising findings, future epidemiological research on the protective effects of cruciferous plants will depend critically upon accurate measurement of dietary exposure, both to the vegetables themselves, and to their active constituents. The development of sensitive chemical assays has facilitated the measurement of urinary excretion of isothiocyanate metabolites as an objective biomarker of intake, but sampling strategies need to be optimised in order to assess long‐term exposures at the population level

Improved Limits on Millicharged Particles Using the ArgoNeuT Experiment at Fermilab

A search for millicharged particles, a simple extension of the standard model, has been performed with the ArgoNeuT detector exposed to the Neutrinos at the Main Injector beam at Fermilab. The ArgoNeuT Liquid Argon Time Projection Chamber detector enables a search for millicharged particles through the detection of visible electron recoils. We search for an event signature with two soft hits (MeV-scale energy depositions) aligned with the upstream target. For an exposure of the detector of $1.0$ $\times$ $10^{20}$ protons on target, one candidate event has been observed, compatible with the expected background. This search is sensitive to millicharged particles with charges between $10^{-3}e$ and $10^{-1}e$ and with masses in the range from $0.1$ GeV to $3$ GeV. This measurement provides leading constraints on millicharged particles in this large unexplored parameter space region.Comment: Version accepted by PR

First Measurement of Electron Neutrino Scattering Cross Section on Argon

We report the first electron neutrino cross section measurements on argon, based on data collected by the ArgoNeuT experiment running in the GeV-scale NuMI beamline at Fermilab. A flux-averaged $\nu_e + \overline{\nu}_e$ total and a lepton angle differential cross section are extracted using 13 $\nu_e$ and $\overline{\nu}_e$ events identified with fully-automated selection and reconstruction. We employ electromagnetic-induced shower characterization and analysis tools developed to identify $\nu_e/\overline{\nu}_e$-like events among complex interaction topologies present in ArgoNeuT data ($\langle E_{\bar{\nu}_e} \rangle = 4.3$ GeV and $\langle E_{\nu_e} \rangle = 10.5$ GeV). The techniques are widely applicable to searches for electron-flavor appearance at short- and long-baseline using liquid argon time projection chamber technology. Notably, the data-driven studies of GeV-scale $\nu_e/\overline{\nu}_e$ interactions presented in this Letter probe an energy regime relevant for future DUNE oscillation physics.Comment: added acknowledgement

The Influence of Geometry on the Vibronic Spectra of Quantum Aggregates

A study is presented of the localisation of excitonic states on extended molecular aggregates composed of identical monomers arising, not from disorder due to statistical energy shifts of the monomers, induced by environmental interactions (Anderson localisation), but rather simply due to changes in the orientation and geometrical arrangement of the transition dipoles. It is shown further that such small changes nevertheless can have a drastic effect on the shape of the vibronic spectrum of the aggregate. The vibronic spectra are calculated using the "coherent exciton scattering" (CES) approximation whose derivation we generalise to be applicable to aggregates of arbitrary size and geometry