A cross-sectional study of inflammatory markers as determinants of circulating kynurenines in the Lung Cancer Cohort Consortium.

Circulating concentrations of metabolites (collectively called kynurenines) in the kynurenine pathway of tryptophan metabolism increase during inflammation, particularly in response to interferon-gamma (IFN-γ). Neopterin and the kynurenine/tryptophan ratio (KTR) are IFN-γ induced inflammatory markers, and together with C-reactive protein (CRP) and kynurenines they are associated with various diseases, but comprehensive data on the strength of associations of inflammatory markers with circulating concentrations of kynurenines are lacking. We measured circulating concentrations of neopterin, CRP, tryptophan and seven kynurenines in 5314 controls from 20 cohorts in the Lung Cancer Cohort Consortium (LC3). The associations of neopterin, KTR and CRP with kynurenines were investigated using regression models. In mixed models, one standard deviation (SD) higher KTR was associated with a 0.46 SD higher quinolinic acid (QA), and 0.31 SD higher 3-hydroxykynurenine (HK). One SD higher neopterin was associated with 0.48, 0.44, 0.36 and 0.28 SD higher KTR, QA, kynurenine and HK, respectively. KTR and neopterin respectively explained 24.1% and 16.7% of the variation in QA, and 11.4% and 7.5% of HK. CRP was only weakly associated with kynurenines in regression models. In summary, QA was the metabolite that was most strongly associated with the inflammatory markers. In general, the inflammatory markers were most strongly related to metabolites located along the tryptophan-NAD axis, which may support suggestions of increased production of NAD from tryptophan during inflammation.

HDF1, a novel flowering time regulator identified in a mutant suppressing sensitivity to red light reduced 1 early flowering.

Arabidopsis SENSITIVITY TO RED LIGHT REDUCED 1 (SRR1) delays the transition from vegetative to reproductive development in noninductive conditions. A second-site suppressor screen for novel genes that overcome early flowering of srr1-1 identified a range of suppressor of srr1-1 mutants flowering later than srr1-1 in short photoperiods. Here, we focus on mutants flowering with leaf numbers intermediate between srr1-1 and Col. Ssm67 overcomes srr1-1 early flowering independently of day-length and ambient temperature. Full-genome sequencing and linkage mapping identified a causative SNP in a gene encoding a Haloacid dehalogenase superfamily protein, named HAD-FAMILY REGULATOR OF DEVELOPMENT AND FLOWERING 1 (HDF1). Both, ssm67 and hdf1-1 show increased levels of FLC, indicating that HDF1 is a novel regulator of this floral repressor. HDF1 regulates flowering largely independent of SRR1, as the effect is visible in srr1-1 and in Col, but full activity on FLC may require SRR1. Furthermore, srr1-1 has a delayed leaf initiation rate that is dependent on HDF1, suggesting that SRR1 and HDF1 act together in leaf initiation. Another mutant flowering intermediate between srr1-1 and wt, ssm15, was identified as a new allele of ARABIDOPSIS SUMO PROTEASE 1, previously implicated in the regulation of FLC stability.

Impact of sex and age on adherence to guidelines in non-small cell lung cancer management.

INTRODUCTION: Age-related disparities in non-small cell lung cancer (NSCLC) treatment are well known, but few studies have assessed the impact of sex on treatment disparities. Disparities in guideline-adherence may explain the superior survival in women with NSCLC. Therefore, we aimed to define patient- and tumor-related factors associated with non-adherence to guidelines in NSCLC management with a special focus on sex and age. PATIENTS AND METHODS: Patients with NSCLC who received first-line treatment at the Vaasa Central Hospital between 2016 and 2020 were included in the study. The primary outcome was guideline adherence, defined as adherent, undertreatment, or overtreatment considering performance status. A binary logistic regression model was used to calculate the adjusted odds ratio (aOR) for non-adherence to treatment guidelines depending on patient- and tumor-related factors. RESULTS: 321 patients were included in the study. Non-adherence was highest in ≥75-year-old women (41.3%), followed by ≥75-year-old men (32.6%), <75-year-old men (27.6%) and lowest in women <75-year-old (19.7%) (p = 0.035). Non-adherent care consisted more often of undertreatment in <75-year-old men than women (26.0% versus 12.1%) and overtreatment in <75-year-old women than men (7.6% versus 1.6%). Non-adherence was associated with stage III disease (aOR 2.21; 95% CI 1.07-4.59), poor pulmonary function (aOR 3.69, 95% CI 1.56-8.71), and Charlson Comorbidity Index 1-2 (aOR 2.09; 95% CI 1.09-4.01). CONCLUSION: Sex- and age-related disparities in guideline adherence were observed in <75-year-old men and in ≥75-year-olds. Stage III NSCLC was associated with non-adherence.

Episodic memory formation in unrestricted viewing.

The brain systems of episodic memory and oculomotor control are tightly linked, suggesting a crucial role of eye movements in memory. But little is known about the neural mechanisms of memory formation across eye movements in unrestricted viewing behavior. Here, we leverage simultaneous eye tracking and EEG recording to examine episodic memory formation in free viewing. Participants memorized multi-element events while their EEG and eye movements were concurrently recorded. Each event comprised elements from three categories (face, object, place), with two exemplars from each category, in different locations on the screen. A subsequent associative memory test assessed participants' memory for the between-category associations that specified each event. We used a deconvolution approach to overcome the problem of overlapping EEG responses to sequential saccades in free viewing. Brain activity was time-locked to the fixation onsets, and we examined EEG power in the theta and alpha frequency bands, the putative oscillatory correlates of episodic encoding mechanisms. Three modulations of fixation-related EEG predicted high subsequent memory performance: (1) theta increase at fixations after between-category gaze transitions, (2) theta and alpha increase at fixations after within-element gaze transitions, (3) alpha decrease at fixations after between-exemplar gaze transitions. Thus, event encoding with unrestricted viewing behavior was characterized by three neural mechanisms, manifested in fixation-locked theta and alpha EEG activity that rapidly turned on and off during the unfolding eye movement sequences. These three distinct neural mechanisms may be the essential building blocks that subserve the buildup of coherent episodic memories during unrestricted viewing behavior.

Design and methodological considerations for biomarker discovery and validation in the Integrative Analysis of Lung Cancer Etiology and Risk (INTEGRAL) Program.

The Integrative Analysis of Lung Cancer Etiology and Risk (INTEGRAL) program is an NCI-funded initiative with an objective to develop tools to optimize low-dose CT (LDCT) lung cancer screening. Here, we describe the rationale and design for the Risk Biomarker and Nodule Malignancy projects within INTEGRAL. The overarching goal of these projects is to systematically investigate circulating protein markers to include on a panel for use (i) pre-LDCT, to identify people likely to benefit from screening, and (ii) post-LDCT, to differentiate benign versus malignant nodules. To identify informative proteins, the Risk Biomarker project measured 1161 proteins in a nested-case control study within 2 prospective cohorts (n = 252 lung cancer cases and 252 controls) and replicated associations for a subset of proteins in 4 cohorts (n = 479 cases and 479 controls). Eligible participants had a current or former history of smoking and cases were diagnosed up to 3 years following blood draw. The Nodule Malignancy project measured 1078 proteins among participants with a heavy smoking history within four LDCT screening studies (n = 425 cases diagnosed up to 5 years following blood draw, 430 benign-nodule controls, and 398 nodule-free controls). The INTEGRAL panel will enable absolute quantification of 21 proteins. We will evaluate its performance in the Risk Biomarker project using a case-cohort study including 14 cohorts (n = 1696 cases and 2926 subcohort representatives), and in the Nodule Malignancy project within five LDCT screening studies (n = 675 cases, 680 benign-nodule controls, and 648 nodule-free controls). Future progress to advance lung cancer early detection biomarkers will require carefully designed validation, translational, and comparative studies.

Increased levels of microRNA-320 in blood serum and plasma is associated with imminent and advanced lung cancer.

Lung cancer (LC) incidence is increasing globally and altered levels of microRNAs (miRNAs) in blood may contribute to identification of individuals with LC. We identified miRNAs differentially expressed in peripheral blood at LC diagnosis and evaluated, in pre-diagnostic blood specimens, how long before diagnosis expression changes in such candidate miRNAs could be detected. We identified upregulated candidate miRNAs in plasma specimens from a hospital-based study sample of 128 patients with confirmed LC and 62 individuals with suspected but confirmed negative LC (FalsePos). We then evaluated the expression of candidate miRNAs in pre-diagnostic plasma or serum specimens of 360 future LC cases and 375 matched controls. There were 1663 miRNAs detected in diagnostic specimens, nine of which met our criteria for candidate miRNAs. Higher expression of three candidates, miR-320b, 320c, and 320d, was associated with poor survival, independent of LC stage and subtype. Moreover, miR-320c and miR-320d expression was higher in pre-diagnostic specimens collected within 2 years of LC diagnosis. Our results indicated that elevated levels of miR-320c and miR-320d may be early indications of imminent and advanced LC.

Assessment of the EarlyCDT-Lung test as an early biomarker of lung cancer in ever-smokers: A retrospective nested case-control study in two prospective cohorts.

The EarlyCDT-Lung test is a blood-based autoantibody assay intended to identify high-risk individuals for low-dose computed tomography lung cancer screening. However, there is a paucity of evidence on the performance of the EarlyCDT-Lung test in ever-smokers. We conducted a nested case-control study within two prospective cohorts to evaluate the risk-discriminatory performance of the EarlyCDT-Lung test using prediagnostic blood samples from 154 future lung cancer cases and 154 matched controls. Cases were selected from those who had ever smoked and had a prediagnostic blood sample <3 years prior to diagnosis. Conditional logistic regression was used to estimate the association between EarlyCDT-Lung test results and lung cancer risk. Sensitivity and specificity of the EarlyCDT-Lung test were calculated in all subjects and subgroups based on age, smoking history, lung cancer stage, sample collection time before diagnosis and year of sample collection. The overall lung cancer odds ratios were 0.89 (95% CI: 0.34-2.30) for a moderate risk EarlyCDT-Lung test result and 1.09 (95% CI: 0.48-2.47) for a high-risk test result compared to no significant test result. The overall sensitivity was 8.4% (95% CI: 4.6-14) and overall specificity was 92% (95% CI: 87-96) when considering a high-risk result as positive. Stratified analysis indicated higher sensitivity (17%, 95% CI: 7.2-32.1) in subjects with blood drawn up to 1 year prior to diagnosis. In conclusion, our study does not support a role of the EarlyCDT-Lung test in identifying the high-risk subjects in ever-smokers for lung cancer screening in the EPIC and NSHDS cohorts.

Synthesis and In Vitro Evaluation of a Set of 6-Deoxy-6-thio-carboranyl d-Glucoconjugates Shed Light on the Substrate Specificity of the GLUT1 Transporter.

Glucose- and sodium-dependent glucose transporters (GLUTs and SGLTs) play vital roles in human biology. Of the 14 GLUTs and 12 SGLTs, the GLUT1 transporter has gained the most widespread recognition because GLUT1 is overexpressed in several cancers and is a clinically valid therapeutic target. We have been pursuing a GLUT1-targeting approach in boron neutron capture therapy (BNCT). Here, we report on surprising findings encountered with a set of 6-deoxy-6-thio-carboranyl d-glucoconjugates. In more detail, we show that even subtle structural changes in the carborane cluster, and the linker, may significantly reduce the delivery capacity of GLUT1-based boron carriers. In addition to providing new insights on the substrate specificity of this important transporter, we reach a fresh perspective on the boundaries within which a GLUT1-targeting approach in BNCT can be further refined.

Evaluation of a Clinic-based Exercise Program in Patients with Pancreatic Cancer Undergoing Non-Surgical Treatment.

INTRODUCTION: Evidence regarding the role of exercise in pancreatic cancer (PanCa) is limited and is derived exclusively under tightly controlled research conditions. This study aimed to quantify adherence, adverse events, and changes in physical and psychological outcomes in any patients with PanCa referred to undertake exercise during non-surgical treatment. METHODS: The study involved 22 patients with localised or metastatic PanCa undertaking a clinic-based exercise program during chemotherapy or chemoradiotherapy. The program included supervised aerobic and resistance exercise undertaken twice weekly for 12 weeks and a 12-week follow-up with supervised exercise optional dependent on patient preference and condition. Patients were monitored for adherence and adverse events. Objective and patient-reported outcomes were assessed at baseline, 12 and 24 weeks. RESULTS: A total of 251 sessions were attended by 19 patients over the first 12 weeks (attendance rate: 55%). Complete case analyses indicated significant (P < .05) improvements in functional ability (5.2%-17.2%), muscle strength (16.9%-25.1%), and static balance (6.8%). There were no significant changes in body composition or patient-reported outcomes except for sleep quality which deteriorated, however, at an individual level several patients had clinically relevant improvements in cancer-related fatigue and quality of life. Patients who continued with supervised exercise to week 24 largely preserved improvements in functional ability, muscle strength, and static balance. No serious adverse events resulted from the exercise program. CONCLUSIONS: Individualised, supervised aerobic and resistance exercise in a clinic-based setting appears to be safe, and may improve or maintain physical and psychological health in patients with PanCa undergoing non-surgical treatment.

Circulating Isovalerylcarnitine and Lung Cancer Risk: Evidence from Mendelian Randomization and Prediagnostic Blood Measurements.

BACKGROUND: Tobacco exposure causes 8 of 10 lung cancers, and identifying additional risk factors is challenging due to confounding introduced by smoking in traditional observational studies. MATERIALS AND METHODS: We used Mendelian randomization (MR) to screen 207 metabolites for their role in lung cancer predisposition using independent genome-wide association studies (GWAS) of blood metabolite levels (n = 7,824) and lung cancer risk (n = 29,266 cases/56,450 controls). A nested case-control study (656 cases and 1,296 matched controls) was subsequently performed using prediagnostic blood samples to validate MR association with lung cancer incidence data from population-based cohorts (EPIC and NSHDS). RESULTS: An MR-based scan of 207 circulating metabolites for lung cancer risk identified that blood isovalerylcarnitine (IVC) was associated with a decreased odds of lung cancer after accounting for multiple testing (log10-OR = 0.43; 95% CI, 0.29-0.63). Molar measurement of IVC in prediagnostic blood found similar results (log10-OR = 0.39; 95% CI, 0.21-0.72). Results were consistent across lung cancer subtypes. CONCLUSIONS: Independent lines of evidence support an inverse association of elevated circulating IVC with lung cancer risk through a novel methodologic approach that integrates genetic and traditional epidemiology to efficiently identify novel cancer biomarkers. IMPACT: Our results find compelling evidence in favor of a protective role for a circulating metabolite, IVC, in lung cancer etiology. From the treatment of a Mendelian disease, isovaleric acidemia, we know that circulating IVC is modifiable through a restricted protein diet or glycine and L-carnatine supplementation. IVC may represent a modifiable and inversely associated biomarker for lung cancer.

Effect of adherence to treatment guidelines on overall survival in elderly non-small-cell lung cancer patients.

OBJECTIVES: Mean age at diagnosis of lung cancer is increasing with increasing age in Western populations. The present study was designed to evaluate the effect of adherence to first-line treatment guidelines on overall survival (OS) in elderly patients with non-small-cell lung cancer (NSCLC) and reasons for non-adherence to treatment guidelines. MATERIALS AND METHODS: All patients aged ≥ 65 years diagnosed with NSCLC in Ostrobothnia, Finland, during the years 2016 to 2020 were identified from hospital registries. Adherence of first-line treatment to contemporary treatment guidelines was analysed based on diagnosis, tumour stage and performance status (PS), as was the effect of adherence on OS. RESULTS: A review of hospital registries identified 238 NSCLC patients aged ≥ 65 years. Guideline adherence by stage decreased significantly with age, with 66.4% of patients aged 65 to 74 years, but only 33.3% of those aged > 80 years treated according to guidelines (p < 0.001). Other factors associated with non-adherence to guidelines included poor PS, frailty, and limited lung function. Of the patients with PS 0-2, 26.9% were under-treated according to guidelines. Reasons for under-treatment included comorbidities, decreased lung function, physician decision to reduce treatment intensity or recommend best supportive care, patient choice and PS decline before treatment initiation. Guideline adherence increased overall OS of elderly NSCLC patients in all stages. Elderly PS 2 patients appear to benefit from guideline adherence and active treatment. In contrast, active treatment did not benefit patients with PS 3-4. CONCLUSIONS: Guideline adherence was associated with increased OS in elderly NSCLC patients. Almost 10% of elderly and otherwise fit NSCLC patients were not treated according to guidelines and could have benefitted from more intensive treatment.

Diet-wide association study of 92 foods and nutrients and lung cancer risk in the European Prospective Investigation into Cancer and Nutrition study and the Netherlands Cohort Study.

It is unclear whether diet, and in particular certain foods or nutrients, are associated with lung cancer risk. We assessed associations of 92 dietary factors with lung cancer risk in 327 790 participants in the European Prospective Investigation into Cancer and Nutrition (EPIC). Cox regression yielded adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) per SD higher intake/day of each food/nutrient. Correction for multiple comparisons was performed using the false discovery rate and identified associations were evaluated in the Netherlands Cohort Study (NLCS). In EPIC, 2420 incident lung cancer cases were identified during a median of 15 years of follow-up. Higher intakes of fibre (HR per 1 SD higher intake/day = 0.91, 95% CI 0.87-0.96), fruit (HR = 0.91, 95% CI 0.86-0.96) and vitamin C (HR = 0.91, 95% CI 0.86-0.96) were associated with a lower risk of lung cancer, whereas offal (HR = 1.08, 95% CI 1.03-1.14), retinol (HR = 1.06, 95% CI 1.03-1.10) and beer/cider (HR = 1.04, 95% CI 1.02-1.07) intakes were positively associated with lung cancer risk. Associations did not differ by sex and there was less evidence for associations among never smokers. None of the six associations with overall lung cancer risk identified in EPIC were replicated in the NLCS (2861 cases), however in analyses of histological subtypes, inverse associations of fruit and vitamin C with squamous cell carcinoma were replicated in the NLCS. Overall, there is little evidence that intakes of specific foods and nutrients play a major role in primary lung cancer risk, but fruit and vitamin C intakes seem to be inversely associated with squamous cell lung cancer.

Eye-movement replay supports episodic remembering.

When we bring to mind something we have seen before, our eyes spontaneously unfold in a sequential pattern strikingly similar to that made during the original encounter, even in the absence of supporting visual input. Oculomotor movements of the eye may then serve the opposite purpose of acquiring new visual information; they may serve as self-generated cues, pointing to stored memories. Over 50 years ago Donald Hebb, the forefather of cognitive neuroscience, posited that such a sequential replay of eye movements supports our ability to mentally recreate visuospatial relations during episodic remembering. However, direct evidence for this influential claim is lacking. Here we isolate the sequential properties of spontaneous eye movements during encoding and retrieval in a pure recall memory task and capture their encoding-retrieval overlap. Critically, we show that the fidelity with which a series of consecutive eye movements from initial encoding is sequentially retained during subsequent retrieval predicts the quality of the recalled memory. Our findings provide direct evidence that such scanpaths are replayed to assemble and reconstruct spatio-temporal relations as we remember and further suggest that distinct scanpath properties differentially contribute depending on the nature of the goal-relevant memory.

A Large-Scale Genome-Wide Gene-Gene Interaction Study of Lung Cancer Susceptibility in Europeans With a Trans-Ethnic Validation in Asians.

INTRODUCTION: Although genome-wide association studies have been conducted to investigate genetic variation of lung tumorigenesis, little is known about gene-gene (G × G) interactions that may influence the risk of non-small cell lung cancer (NSCLC). METHODS: Leveraging a total of 445,221 European-descent participants from the International Lung Cancer Consortium OncoArray project, Transdisciplinary Research in Cancer of the Lung and UK Biobank, we performed a large-scale genome-wide G × G interaction study on European NSCLC risk by a series of analyses. First, we used BiForce to evaluate and rank more than 58 billion G × G interactions from 340,958 single-nucleotide polymorphisms (SNPs). Then, the top interactions were further tested by demographically adjusted logistic regression models. Finally, we used the selected interactions to build lung cancer screening models of NSCLC, separately, for never and ever smokers. RESULTS: With the Bonferroni correction, we identified eight statistically significant pairs of SNPs, which predominantly appeared in the 6p21.32 and 5p15.33 regions (e.g., rs521828C6orf10 and rs204999PRRT1, ORinteraction = 1.17, p = 6.57 × 10-13; rs3135369BTNL2 and rs2858859HLA-DQA1, ORinteraction = 1.17, p = 2.43 × 10-13; rs2858859HLA-DQA1 and rs9275572HLA-DQA2, ORinteraction = 1.15, p = 2.84 × 10-13; rs2853668TERT and rs62329694CLPTM1L, ORinteraction = 0.73, p = 2.70 × 10-13). Notably, even with much genetic heterogeneity across ethnicities, three pairs of SNPs in the 6p21.32 region identified from the European-ancestry population remained significant among an Asian population from the Nanjing Medical University Global Screening Array project (rs521828C6orf10 and rs204999PRRT1, ORinteraction = 1.13, p = 0.008; rs3135369BTNL2 and rs2858859HLA-DQA1, ORinteraction = 1.11, p = 5.23 × 10-4; rs3135369BTNL2 and rs9271300HLA-DQA1, ORinteraction = 0.89, p = 0.006). The interaction-empowered polygenetic risk score that integrated classical polygenetic risk score and G × G information score was remarkable in lung cancer risk stratification. CONCLUSIONS: Important G × G interactions were identified and enriched in the 5p15.33 and 6p21.32 regions, which may enhance lung cancer screening models.

ZEITLUPE Promotes ABA-Induced Stomatal Closure in Arabidopsis and Populus.

Plants balance water availability with gas exchange and photosynthesis by controlling stomatal aperture. This control is regulated in part by the circadian clock, but it remains unclear how signalling pathways of daily rhythms are integrated into stress responses. The serine/threonine protein kinase OPEN STOMATA 1 (OST1) contributes to the regulation of stomatal closure via activation of S-type anion channels. OST1 also mediates gene regulation in response to ABA/drought stress. We show that ZEITLUPE (ZTL), a blue light photoreceptor and clock component, also regulates ABA-induced stomatal closure in Arabidopsis thaliana, establishing a link between clock and ABA-signalling pathways. ZTL sustains expression of OST1 and ABA-signalling genes. Stomatal closure in response to ABA is reduced in ztl mutants, which maintain wider stomatal apertures and show higher rates of gas exchange and water loss than wild-type plants. Detached rosette leaf assays revealed a stronger water loss phenotype in ztl-3, ost1-3 double mutants, indicating that ZTL and OST1 contributed synergistically to the control of stomatal aperture. Experimental studies of Populus sp., revealed that ZTL regulated the circadian clock and stomata, indicating ZTL function was similar in these trees and Arabidopsis. PSEUDO-RESPONSE REGULATOR 5 (PRR5), a known target of ZTL, affects ABA-induced responses, including stomatal regulation. Like ZTL, PRR5 interacted physically with OST1 and contributed to the integration of ABA responses with circadian clock signalling. This suggests a novel mechanism whereby the PRR proteins-which are expressed from dawn to dusk-interact with OST1 to mediate ABA-dependent plant responses to reduce water loss in time of stress.

Drivers' Performance in Non-critical Take-Overs From an Automated Driving System-An On-Road Study.

OBJECTIVE: The objective of this semi-controlled study was to investigate drivers' performance when resuming control from an Automated Driving System (ADS), simulated through the Wizard of Oz method, in real traffic. BACKGROUND: Research on take-overs has primarily focused on urgent scenarios. This article aims to shift the focus to non-critical take-overs from a system operating in congested traffic situations. METHOD: Twenty drivers drove a selected route in rush-hour traffic in the San Francisco Bay Area, CA, USA. During the drive, the ADS became available when predetermined availability conditions were fulfilled. When the system was active, the drivers were free to engage in non-driving related activities. RESULTS: The results show that drivers' transition time goes down with exposure, making it reasonable to assume that some experience is required to regain control with comfort and ease. The novel analysis of after-effects of automated driving on manual driving performance implies that the after-effects were close to negligible. Observational data indicate that, with exposure, a majority of the participants started to engage in non-driving related activities to some extent, but it is unclear how the activities influenced the take-over performance. CONCLUSION: The results indicate that drivers need repeated exposure to take-overs to be able to fully resume manual control with ease. APPLICATION: Take-over signals (e.g., visuals, sounds, and haptics) should be carefully designed to avoid startle effects and the human-machine interface should provide clear guidance on the required take-over actions.

Genome-wide interaction analysis identified low-frequency variants with sex disparity in lung cancer risk.

Differences by sex in lung cancer incidence and mortality have been reported which cannot be fully explained by sex differences in smoking behavior, implying existence of genetic and molecular basis for sex disparity in lung cancer development. However, the information about sex dimorphism in lung cancer risk is quite limited despite the great success in lung cancer association studies. By adopting a stringent two-stage analysis strategy, we performed a genome-wide gene-sex interaction analysis using genotypes from a lung cancer cohort including ~ 47 000 individuals with European ancestry. Three low-frequency variants (minor allele frequency < 0.05), rs17662871 [odds ratio (OR) = 0.71, P = 4.29×10-8); rs79942605 (OR = 2.17, P = 2.81×10-8) and rs208908 (OR = 0.70, P = 4.54×10-8) were identified with different risk effect of lung cancer between men and women. Further expression quantitative trait loci and functional annotation analysis suggested rs208908 affects lung cancer risk through differential regulation of Coxsackie virus and adenovirus receptor gene expression in lung tissues between men and women. Our study is one of the first studies to provide novel insights about the genetic and molecular basis for sex disparity in lung cancer development.

Encoding contexts are incidentally reinstated during competitive retrieval and track the temporal dynamics of memory interference.

The ability to remember an episode from our past is often hindered by competition from similar events. For example, if we want to remember the article a colleague recommended during the last lab meeting, we may need to resolve interference from other article recommendations from the same colleague. This study investigates if the contextual features specifying the encoding episodes are incidentally reinstated during competitive memory retrieval. Competition between memories was created through the AB/AC interference paradigm. Individual word-pairs were presented embedded in a slowly drifting real-word-like context. Multivariate pattern analysis (MVPA) of high temporal-resolution electroencephalographic (EEG) data was used to investigate context reactivation during memory retrieval. Behaviorally, we observed proactive (but not retroactive) interference; that is, performance for AC competitive retrieval was worse compared with a control DE noncompetitive retrieval, whereas AB retrieval did not suffer from competition. Neurally, proactive interference was accompanied by an early reinstatement of the competitor context and interference resolution was associated with the ensuing reinstatement of the target context. Together, these findings provide novel evidence showing that the encoding contexts of competing discrete events are incidentally reinstated during competitive retrieval and that such reinstatement tracks retrieval competition and subsequent interference resolution.

Gene-gene interaction of AhRwith and within the Wntcascade affects susceptibility to lung cancer.

BACKGROUND: Aberrant Wnt signalling, regulating cell development and stemness, influences the development of many cancer types. The Aryl hydrocarbon receptor (AhR) mediates tumorigenesis of environmental pollutants. Complex interaction patterns of genes assigned to AhR/Wnt-signalling were recently associated with lung cancer susceptibility. AIM: To assess the association and predictive ability of AhR/Wnt-genes with lung cancer in cases and controls of European descent. METHODS: Odds ratios (OR) were estimated for genomic variants assigned to the Wnt agonist and the antagonistic genes DKK2, DKK3, DKK4, FRZB, SFRP4 and Axin2. Logistic regression models with variable selection were trained, validated and tested to predict lung cancer, at which other previously identified SNPs that have been robustly associated with lung cancer risk could also enter the model. Furthermore, decision trees were created to investigate variant × variant interaction. All analyses were performed for overall lung cancer and for subgroups. RESULTS: No genome-wide significant association of AhR/Wnt-genes with overall lung cancer was observed, but within the subgroups of ever smokers (e.g., maker rs2722278 SFRP4; OR = 1.20; 95% CI 1.13-1.27; p = 5.6 × 10-10) and never smokers (e.g., maker rs1133683 Axin2; OR = 1.27; 95% CI 1.19-1.35; p = 1.0 × 10-12). Although predictability is poor, AhR/Wnt-variants are unexpectedly overrepresented in optimized prediction scores for overall lung cancer and for small cell lung cancer. Remarkably, the score for never-smokers contained solely two AhR/Wnt-variants. The optimal decision tree for never smokers consists of 7 AhR/Wnt-variants and only two lung cancer variants. CONCLUSIONS: The role of variants belonging to Wnt/AhR-pathways in lung cancer susceptibility may be underrated in main-effects association analysis. Complex interaction patterns in individuals of European descent have moderate predictive capacity for lung cancer or subgroups thereof, especially in never smokers.

Monitoring Seasonal Bud Set, Bud Burst, and Cold Hardiness in Populus.

Using a perennial model plant allows the study of reoccurring seasonal events in a way that is not possible using a fast-growing annual such as A. thaliana (Arabidopsis). In this study, we present a hybrid aspen (Populus tremula × P. tremuloides) as our perennial model plant. These plants can be grown in growth chambers to shorten growth periods and manipulate day length and temperature in ways that would be impossible under natural conditions. In addition, the use of growth chambers allows easy monitoring of height and diameter expansion, accelerating the collection of data from new strategies that allow evaluation of promoters or inhibitors of growth. Here, we describe how to study and quantify responses to seasonal changes (mainly using P. tremula × P. tremuloides) by measuring growth rate and key events under different photoperiodic cycles.