Immune-mediated genetic pathways resulting in pulmonary function impairment increase lung cancer susceptibility

Impaired lung function is often caused by cigarette smoking, making it challenging to disentangle its role in lung cancer susceptibility. Investigation of the shared genetic basis of these phenotypes in the UK Biobank and International Lung Cancer Consortium (29,266 cases, 56,450 controls) shows that lung cancer is genetically correlated with reduced forced expiratory volume in one second (FEV1: r(g) = 0.098, p = 2.3 x 10(-8)) and the ratio of FEV1 to forced vital capacity (FEV1/FVC: r(g) = 0.137, p = 2.0 x 10(-12)). Mendelian randomization analyses demonstrate that reduced FEV1 increases squamous cell carcinoma risk (odds ratio (OR) = 1.51, 95% confidence intervals: 1.21-1.88), while reduced FEV1/FVC increases the risk of adenocarcinoma (OR = 1.17, 1.01-1.35) and lung cancer in never smokers (OR = 1.56, 1.05-2.30). These findings support a causal role of pulmonary impairment in lung cancer etiology. Integrative analyses reveal that pulmonary function instruments, including 73 novel variants, influence lung tissue gene expression and implicate immune-related pathways in mediating the observed effects on lung carcinogenesis

Assessing Lung Cancer Absolute Risk Trajectory Based on a Polygenic Risk Model

Lung cancer is the leading cause of cancer death globally. An improved risk stratification strategy can increase efficiency of low-dose computed tomography (LDCT) screening. Here we assessed whether individual’s genetic background has clinical utility for risk stratification in the context of LDCT screening. Based on 13,119 lung cancer patients and 10,008 controls with European ancestry in the International Lung Cancer Consortium, we constructed a polygenic risk score (PRS) via 10-fold cross-validation with regularized penalized regression. The performance of risk model integrating PRS, including calibration and ability to discriminate, was assessed using UK biobank data (N=335,931). Absolute risk was estimated based on age-specific lung cancer incidence and all-cause mortality as competing risk. To evaluate its potential clinical utility, the PRS distribution was simulated in the National Lung Screening Trial (N=50,772 participants). The lung cancer odds ratio (ORs) for individuals at the top decile of the PRS distribution versus those at bottom 10% was 2.39 (95%CI=1.92–3.00, P=1.80×10(−14)) in the validation set (trend p-value of 5.26 × 10(−20)). The OR per standard deviation of PRS increase was 1.26 (95%CI=1.20–1.32, P=9.69×10(−23)) for overall lung cancer risk in the validation set. When considering absolute risks, individuals at different PRS deciles showed differential trajectories of 5-year and cumulative absolute risk. The age reaching the LDCT screening recommendation threshold can vary by 4 to 8 years, depending on the individual’s genetic background, smoking status and family history. Collectively, these results suggest that individual’s genetic background may inform the optimal lung cancer LDCT screening strategy

Quantifying the Ultrafast and Steady-State Molecular Reduction Potential of a Plasmonic Photocatalyst

Plasmonic materials are promising photocatalysts as they are well-suited to convert light into hot carriers and heat. Hot electron transfer is suggested as the driving force in many plasmon-driven reactions. However, to date there are no direct molecular measures of the rate and yield of plasmon-to-molecule electron transfer, or energy of these electrons on the timescale of plasmon decay. Here, we use ultrafast and spectroelectrochemical surface-enhanced Raman spectroscopy to quantify electron transfer from a plasmonic substrate to adsorbed methyl viologen molecules. We observe a reduction yield of 2.4 - 3.5 % on the picosecond timescale, with plasmon-induced potentials ranging from -3.1 to -4.5 mV. Excitingly, some of these reduced species are stabilized and persist for tens of minutes. This work provides concrete metrics toward optimizing material-molecule interactions for efficient plasmon-driven photocatalysis

Continuous Wave Photon Upconversion from a Copper Selenide Nanocrystal Film

Photon upconversion is of great interest for improving the efficiency of silicon photovoltaic cells, for biological imaging, and for thermal management strategies. Currently, the vast majority of materials being developed for solar upconversion are composed of rare and expensive elemental compounds. Moving forward, the development of earth abundant, non-toxic materials that efficiently convert near infrared light into visible light would be ideal. Copper selenide-based materials meet these criteria, and are of great interest due to their unique thermoelectric and plasmonic properties. In particular, doped copper selenides (Cu2−xSe) have tunable near infrared localized surface plasmon resonances, large Seebeck coefficients, and low thermal conductivity, with a range of chemical and thermoelectric applications. Here, we observe another interesting application of this material in the upconversion of near infrared light from a silica xerogel film containing degenerately doped Cu2−xSe nanocrystals, with an onset flux of ∼ 1.96 ± 0.29 kW/cm^2 and at least 1% quantum yield. Our investigations suggest a plasmon-driven thermal mechanism likely plays a role in this upconversion process

Structure of Xanthine Oxidase-Related 4-Hydroxybenzoyl-CoA Reductase with an Additional [4Fe-4S] Cluster and an Inverted Electron Flow

AbstractThe Mo-flavo-Fe/S-dependent heterohexameric protein complex 4-hydroxybenzoyl-CoA reductase (4-HBCR, dehydroxylating) is a central enzyme of the anaerobic degradation of phenolic compounds and belongs to the xanthine oxidase (XO) family of molybdenum enzymes. Its X-ray structure was established at 1.6 Å resolution. The most pronounced difference between 4-HBCR and other structurally characterized members of the XO family is the insertion of 40 amino acids within the β subunit, which carries an additional [4Fe-4S] cluster at a distance of 16.5 Å to the isoalloxazine ring of FAD. The architecture of 4-HBCR and concomitantly performed electron transfer rate calculations suggest an inverted electron transfer chain from the donor ferredoxin via the [4Fe-4S] cluster to the Mo over a distance of 55 Å. The binding site of 4-hydroxybenzoyl-CoA is located in an 18 Å long channel lined up by several aromatic side chains around the aromatic moiety, which are proposed to shield and stabilize the postulated radical intermediates during catalysis

Toward a mechanistic understanding of plasmon-mediated photocatalysis

One of the most exciting new developments in the plasmonic nanomaterials field is the discovery of their ability to mediate a number of photocatalytic reactions. Since the initial prediction of driving chemical reactions with plasmons in the 1980s, the field has rapidly expanded in recent years, demonstrating the ability of plasmons to drive chemical reactions, such as water splitting, ammonia generation, and CO2 reduction, among many other examples. Unfortunately, the efficiencies of these processes are currently suboptimal for practical widespread applications. The limitations in recorded outputs can be linked to the current lack of a knowledge pertaining to mechanisms of the partitioning of plasmonic energy after photoexcitation. Providing a descriptive and quantitative mechanism of the processes involved in driving plasmon-induced photochemical reactions, starting at the initial plasmon excitation, followed by hot carrier generation, energy transfer, and thermal effects, is critical for the advancement of the field as a whole. Here, we provide a mechanistic perspective on plasmonic photocatalysis by reviewing select experimental approaches. We focus on spectroscopic and electrochemical techniques that provide molecular-scale information on the processes that occur in the coupled molecular-plasmonic system after photoexcitation. To conclude, we evaluate several promising techniques for future applications in elucidating the mechanism of plasmon-mediated photocatalysis