A Genome-wide Association Study of Lung Cancer Identifies a Region of Chromosome 5p15 Associated with Risk for Adenocarcinoma

Three genetic loci for lung cancer risk have been identified by genome-wide association studies (GWAS), but inherited susceptibility to specific histologic types of lung cancer is not well established. We conducted a GWAS of lung cancer and its major histologic types, genotyping 515,922 single-nucleotide polymorphisms (SNPs) in 5739 lung cancer cases and 5848 controls from one population-based case-control study and three cohort studies. Results were combined with summary data from ten additional studies, for a total of 13,300 cases and 19,666 controls of European descent. Four studies also provided histology data for replication, resulting in 3333 adenocarcinomas (AD), 2589 squamous cell carcinomas (SQ), and 1418 small cell carcinomas (SC). In analyses by histology, rs2736100 (TERT), on chromosome 5p15.33, was associated with risk of adenocarcinoma (odds ratio [OR] = 1.23, 95% confidence interval [CI] = 1.13–1.33, p = 3.02 × 10⁻⁷), but not with other histologic types (OR = 1.01, p = 0.84 and OR = 1.00, p = 0.93 for SQ and SC, respectively). This finding was confirmed in each replication study and overall meta-analysis (OR = 1.24, 95% CI = 1.17–1.31, p = 3.74 × 10⁻¹⁴ for AD; OR = 0.99, p = 0.69 and OR = 0.97, p = 0.48 for SQ and SC, respectively). Other previously reported association signals on 15q25 and 6p21 were also refined, but no additional loci reached genome-wide significance. In conclusion, a lung cancer GWAS identified a distinct hereditary contribution to adenocarcinoma.     

Gene mapping in the wild with SNPs: guidelines and future directions

One of the biggest challenges facing evolutionary biologists is to identify and understand loci that explain fitness variation in natural populations. This review describes how genetic (linkage) mapping with single nucleotide polymorphism (SNP) markers can lead to great progress in this area. Strategies for SNP discovery and SNP genotyping are described and an overview of how to model SNP genotype information in mapping studies is presented. Finally, the opportunity afforded by new generation sequencing and typing technologies to map fitness genes by genome-wide association studies is discussed.     

Chronic Obstructive Pulmonary Disease and Altered Risk of Lung Cancer in a Population-Based Case-Control Study

Background

Chronic obstructive pulmonary disease (COPD) has been consistently associated with increased risk of lung cancer. However, previous studies have had limited ability to determine whether the association is due to smoking.

Methodology/Principal Findings

The Environment And Genetics in Lung cancer Etiology (EAGLE) population-based case-control study recruited 2100 cases and 2120 controls, of whom 1934 cases and 2108 controls reported about diagnosis of chronic bronchitis, emphysema, COPD (chronic bronchitis and/or emphysema), or asthma more than 1 year before enrollment. We estimated odds ratios (OR) and 95% confidence intervals (CI) using logistic regression. After adjustment for smoking, other previous lung diseases, and study design variables, lung cancer risk was elevated among individuals with a history of chronic bronchitis (OR = 2.0, 95% CI = 1.5–2.5), emphysema (OR = 1.9, 95% CI = 1.4–2.8), or COPD (OR = 2.5, 95% CI = 2.0–3.1). Among current smokers, association between chronic bronchitis and lung cancer was strongest among lighter smokers. Asthma was associated with a decreased risk of lung cancer in males (OR = 0.48, 95% CI = 0.30–0.78).

Conclusions/Significance

These results suggest that the associations of personal history of chronic bronchitis, emphysema, and COPD with increased risk of lung cancer are not entirely due to smoking. Inflammatory processes may both contribute to COPD and be important for lung carcinogenesis.     

Altered Resting State in Diabetic Neuropathic Pain

Background

The spontaneous component of neuropathic pain (NP) has not been explored sufficiently with neuroimaging techniques, given the difficulty to coax out the brain components that sustain background ongoing pain. Here, we address for the first time the correlates of this component in an fMRI study of a group of eight patients suffering from diabetic neuropathic pain and eight healthy control subjects. Specifically, we studied the functional connectivity that is associated with spontaneous neuropathic pain with spatial independent component analysis (sICA).

Principal Findings

Functional connectivity analyses revealed a cortical network consisting of two anti-correlated patterns: one includes the left fusiform gyrus, the left lingual gyrus, the left inferior temporal gyrus, the right inferior occipital gyrus, the dorsal anterior cingulate cortex bilaterally, the pre and postcentral gyrus bilaterally, in which its activity is correlated negatively with pain and positively with the controls; the other includes the left precuneus, dorsolateral prefrontal, frontopolar cortex (both bilaterally), right superior frontal gyrus, left inferior frontal gyrus, thalami, both insulae, inferior parietal lobuli, right mammillary body, and a small area in the left brainstem, in which its activity is correlated positively with pain and negatively with the controls. Furthermore, a power spectra analyses revealed group differences in the frequency bands wherein the sICA signal was decomposed: patients'' spectra are shifted towards higher frequencies.

Conclusion

In conclusion, we have characterized here for the first time a functional network of brain areas that mark the spontaneous component of NP. Pain is the result of aberrant default mode functional connectivity.     

Modulation of Caspase Activity Regulates Skeletal Muscle Regeneration and Function in Response to Vasopressin and Tumor Necrosis Factor

Muscle homeostasis involves de novo myogenesis, as observed in conditions of acute or chronic muscle damage. Tumor Necrosis Factor (TNF) triggers skeletal muscle wasting in several pathological conditions and inhibits muscle regeneration. We show that intramuscular treatment with the myogenic factor Arg⁸-vasopressin (AVP) enhanced skeletal muscle regeneration and rescued the inhibitory effects of TNF on muscle regeneration. The functional analysis of regenerating muscle performance following TNF or AVP treatments revealed that these factors exerted opposite effects on muscle function. Principal component analysis showed that TNF and AVP mainly affect muscle tetanic force and fatigue. Importantly, AVP counteracted the effects of TNF on muscle function when delivered in combination with the latter. Muscle regeneration is, at least in part, regulated by caspase activation, and AVP abrogated TNF-dependent caspase activation. The contrasting effects of AVP and TNF in vivo are recapitulated in myogenic cell cultures, which express both PW1, a caspase activator, and Hsp70, a caspase inhibitor. We identified PW1 as a potential Hsp70 partner by screening for proteins interacting with PW1. Hsp70 and PW1 co-immunoprecipitated and co-localized in muscle cells. In vivo Hsp70 protein level was upregulated by AVP, and Hsp70 overexpression counteracted the TNF block of muscle regeneration. Our results show that AVP counteracts the effects of TNF through cross-talk at the Hsp70 level. Therefore, muscle regeneration, both in the absence and in the presence of cytokines may be enhanced by increasing Hsp70 expression.     

ATP and MO25α Regulate the Conformational State of the STRADα Pseudokinase and Activation of the LKB1 Tumour Suppressor

Pseudokinases lack essential residues for kinase activity, yet are emerging as important regulators of signal transduction networks. The pseudokinase STRAD activates the LKB1 tumour suppressor by forming a heterotrimeric complex with LKB1 and the scaffolding protein MO25. Here, we describe the structure of STRADα in complex with MO25α. The structure reveals an intricate web of interactions between STRADα and MO25α involving the αC-helix of STRADα, reminiscent of the mechanism by which CDK2 interacts with cyclin A. Surprisingly, STRADα binds ATP and displays a closed conformation and an ordered activation loop, typical of active protein kinases. Inactivity is accounted for by nonconservative substitution of almost all essential catalytic residues. We demonstrate that binding of ATP enhances the affinity of STRADα for MO25α, and conversely, binding of MO25α promotes interaction of STRADα with ATP. Mutagenesis studies reveal that association of STRADα with either ATP or MO25α is essential for LKB1 activation. We conclude that ATP and MO25α cooperate to maintain STRADα in an “active” closed conformation required for LKB1 activation. It has recently been demonstrated that a mutation in human STRADα that truncates a C-terminal region of the pseudokinase domain leads to the polyhydramnios, megalencephaly, symptomatic epilepsy (PMSE) syndrome. We demonstrate this mutation destabilizes STRADα and prevents association with LKB1. In summary, our findings describe one of the first structures of a genuinely inactive pseudokinase. The ability of STRADα to activate LKB1 is dependent on a closed “active” conformation, aided by ATP and MO25α binding. Thus, the function of STRADα is mediated through an active kinase conformation rather than kinase activity. It is possible that other pseudokinases exert their function through nucleotide binding and active conformations.     

Are fentanyl and remifentanil safe opioids for rat brain mitochondrial bioenergetics?

Fentanyl and remifentanil are potent opioid widely used in routine anesthesia procedures. This study evaluates and compares the effects of fentanyl/remifentanil in isolated brain mitochondria bioenergetic status. Fentanyl and remifentanil in clinical concentrations does not interfere with rat brain isolated mitochondria. Do not withstand, fentanyl concentrations >4 μg/mL, induces an impairment of the respiratory chain characterized by a decrease in respiratory control ratio, state 3 and uncoupled respiration. Additionally, membrane potential collapses and ADP/O were reduced. Remifentanil follows the same profile but with effects at higher concentrations (>10 μg/mL). High concentrations of fentanyl and remifentanil interfere with mitochondrial electron chain (complexes III, IV) and on mitochondrial phosphorylation unit (complex V). Mitochondrial permeability transition pore was not induced by both fentanyl and remifentanil in tested concentrations. These data provide the first indication that fentanyl and remifentanil (μg/mL range) alters mitochondrial metabolism. Fentanyl showed a stronger inhibitory effect on mitochondrial bioenergetics.     

Patterns and controls of the variability of radiation use efficiency and primary productivity across terrestrial ecosystems

Aim The controls of gross radiation use efficiency (RUE), the ratio between gross primary productivity (GPP) and the radiation intercepted by terrestrial vegetation, and its spatial and temporal variation are not yet fully understood. Our objectives were to analyse and synthesize the spatial variability of GPP and the spatial and temporal variability of RUE and its climatic controls for a wide range of vegetation types. Location A global range of sites from tundra to rain forest. Methods We analysed a global dataset on photosynthetic uptake and climatic variables from 35 eddy covariance (EC) flux sites spanning between 100 and 2200 mm mean annual rainfall and between ?13 and 26°C mean annual temperature. RUE was calculated from the data provided by EC flux sites and remote sensing (MODIS). Results Rainfall and actual evapotranspiration (AET) positively influenced the spatial variation of annual GPP, whereas temperature only influenced the GPP of forests. Annual and maximum RUE were also positively controlled primarily by annual rainfall. The main control parameters of the growth season variation of gross RUE varied for each ecosystem type. Overall, the ratio between actual and potential evapotranspiration and a surrogate for the energy balance explained a greater proportion of the seasonal variation of RUE than the vapour pressure deficit (VPD), AET and precipitation. Temperature was important for determining the intra‐annual variability of the RUE at the coldest energy‐limited sites. Main conclusions Our analysis supports the idea that the annual functioning of vegetation that is adapted to its local environment is more constrained by water availability than by temperature. The spatial variability of annual and maximum RUE can be largely explained by annual precipitation, more than by vegetation type. The intra‐annual variation of RUE was mainly linked to the energy balance and water availability along the climatic gradient. Furthermore, we showed that intra‐annual variation of gross RUE is only weakly influenced by VPD and temperature, contrary to what is frequently assumed. Our results provide a better understanding of the spatial and temporal controls of the RUE and thus could lead to a better estimation of ecosystem carbon fixation and better modelling.     

Automatic fermentation control based on a real-time in situ SIRE biosensor regulated glucose feed

Monitoring and regulation of fermentations is of a paramount industrial and academic importance in order to keep conditions optimal during the entire process. Established techniques employed today include HPLC and spectrophotometry, which both have the disadvantage that broth samples have to be drawn from the fermentor and that they often require sample pre-treatment. The objectives of this study was to design and evaluate a software controlled automatic real-time SIRE biosensor connected to a glucose feed solution pump for in situ based monitoring and regulation of the glucose concentration during a yeast fermentation process. The maximal frequency for the measuring-regulation cycles was 30/h. A 10 mM mean glucose concentration level was successfully maintained within +/-0.013 mM during 60 min fermentations at various concentrations of yeast (10, 20, 40 and 80g/l). The on/off-regulator used caused some expected fluctuations (oscillations) of the glucose concentration around the mean value (+/-0.12 mM at 10 g/l, +/-0.26 mM at 20 g/l, +/-0.51 mM at 40 g/l, and +/-0.99 mM at 80 g/l). A 7-h fermentation process (10 mM glucose and 20 g/l yeast) was successfully monitored and regulated. The obtained measuring data were found to be 8.5-22.9% lower than data obtained with a commercially available spectrophotometric kit. The difference increased linearly (-0.26 mM/h), during the fermentation process and indicated that some clogging of the in situ positioned probe occurred. The speed and the automatisation adaptability of the presented device suggest advantages compared to established techniques.