1. |
- Muller, D. C., et al.
(author)
-
No association between circulating concentrations of vitamin D and risk of lung cancer : an analysis in 20 prospective studies in the Lung Cancer Cohort Consortium (LC3)
- 2018
-
In: Annals of Oncology. - : Oxford University Press. - 0923-7534 .- 1569-8041. ; 29:6, s. 1468-1475
-
Journal article (peer-reviewed)abstract
- Background: There is observational evidence suggesting that high vitamin D concentrations may protect against lung cancer. To investigate this hypothesis in detail, we measured circulating vitamin D concentrations in prediagnostic blood from 20 cohorts participating in the Lung Cancer Cohort Consortium (LC3).Patients and methods: The study included 5313 lung cancer cases and 5313 controls. Blood samples for the cases were collected, on average, 5 years before lung cancer diagnosis. Controls were individually matched to the cases by cohort, sex, age, race/ethnicity, date of blood collection, and smoking status in five categories. Liquid chromatography coupled with tandem mass spectrometry was used to separately analyze 25-hydroxyvitamin D2 [25(OH)D2] and 25-hydroxyvitamin D3 [25(OH)D3] and their concentrations were combined to give an overall measure of 25(OH)D. We used conditional logistic regression to calculate odds ratios (ORs) and 95% confidence intervals (CIs) for 25(OH)D as both continuous and categorical variables.Results: Overall, no apparent association between 25(OH)D and risk of lung cancer was observed (multivariable adjusted OR for a doubling in concentration: 0.98, 95% CI: 0.91, 1.06). Similarly, we found no clear evidence of interaction by cohort, sex, age, smoking status, or histology.Conclusion: This study did not support an association between vitamin D concentrations and lung cancer risk.
|
|
2. |
|
|
3. |
|
|
4. |
- Fanidi, Anouar, et al.
(author)
-
Is high vitamin B12 status a cause of lung cancer?
- 2019
-
In: International Journal of Cancer. - : John Wiley & Sons. - 0020-7136 .- 1097-0215. ; 145:6, s. 1499-1503
-
Journal article (peer-reviewed)abstract
- Vitamin B supplementation can have side effects for human health, including cancer risk. We aimed to elucidate the role of vitamin B12 in lung cancer etiology via direct measurements of pre‐diagnostic circulating vitamin B12 concentrations in a nested case–control study, complemented with a Mendelian randomization (MR) approach in an independent case–control sample. We used pre‐diagnostic biomarker data from 5183 case–control pairs nested within 20 prospective cohorts, and genetic data from 29,266 cases and 56,450 controls. Exposures included directly measured circulating vitamin B12 in pre‐diagnostic blood samples from the nested case–control study, and 8 single nucleotide polymorphisms associated with vitamin B12 concentrations in the MR study. Our main outcome of interest was increased risk for lung cancer, overall and by histological subtype, per increase in circulating vitamin B12 concentrations. We found circulating vitamin B12 to be positively associated with overall lung cancer risk in a dose response fashion (odds ratio for a doubling in B12 [ORlog2B12] = 1.15, 95% confidence interval (95%CI) = 1.06–1.25). The MR analysis based on 8 genetic variants also indicated that genetically determined higher vitamin B12 concentrations were positively associated with overall lung cancer risk (OR per 150 pmol/L standard deviation increase in B12 [ORSD] = 1.08, 95%CI = 1.00–1.16). Considering the consistency of these two independent and complementary analyses, these findings support the hypothesis that high vitamin B12 status increases the risk of lung cancer.
|
|
5. |
- Gandin, V, et al.
(author)
-
mTORC1 and CK2 coordinate ternary and eIF4F complex assembly
- 2016
-
In: Nature communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 7, s. 11127-
-
Journal article (peer-reviewed)abstract
- Ternary complex (TC) and eIF4F complex assembly are the two major rate-limiting steps in translation initiation regulated by eIF2α phosphorylation and the mTOR/4E-BP pathway, respectively. How TC and eIF4F assembly are coordinated, however, remains largely unknown. We show that mTOR suppresses translation of mRNAs activated under short-term stress wherein TC recycling is attenuated by eIF2α phosphorylation. During acute nutrient or growth factor stimulation, mTORC1 induces eIF2β phosphorylation and recruitment of NCK1 to eIF2, decreases eIF2α phosphorylation and bolsters TC recycling. Accordingly, eIF2β mediates the effect of mTORC1 on protein synthesis and proliferation. In addition, we demonstrate a formerly undocumented role for CK2 in regulation of translation initiation, whereby CK2 stimulates phosphorylation of eIF2β and simultaneously bolsters eIF4F complex assembly via the mTORC1/4E-BP pathway. These findings imply a previously unrecognized mode of translation regulation, whereby mTORC1 and CK2 coordinate TC and eIF4F complex assembly to stimulate cell proliferation.
|
|
6. |
|
|
7. |
- Boucher, L. M., et al.
(author)
-
Expanding conceptualizations of harm reduction: results from a qualitative community-based participatory research study with people who inject drugs
- 2017
-
In: Harm Reduction Journal. - : Springer Science and Business Media LLC. - 1477-7517. ; 14
-
Journal article (peer-reviewed)abstract
- Background: The perspectives of people who use drugs are critical in understanding why people choose to reduce harm in relation to drug use, what practices are considered or preferred in conceptualizations of harm reduction, and which environmental factors interfere with or support the use of harm reduction strategies. This study explores how people who inject drugs (PWID) think about harm reduction and considers the critical imperative of equity in health and social services delivery for this community. Methods: This community-based participatory research study was conducted in a Canadian urban centre. Using a peer-based recruitment and interviewing strategy, semi-structured qualitative interviews were conducted by and with PWID. The Vidaview Life Story Board, an innovative tool where interviewers and participant co-construct a visual "life-scape" using a board, markers, and customized picture magnets, was used to facilitate the interviews. The topics explored included injection drug use and harm reduction histories, facilitators and barriers to using harm reduction strategies, and suggestions for improving services and supports. Results: Twenty-three interviews with PWID (14 men and 9 women) were analysed, with a median age of 50. Results highlighted an expanded conceptualization of harm reduction from the perspectives of PWID, including motivations for adopting harm reduction strategies and a description of harm reduction practices that went beyond conventional health-focused concerns. The most common personal practices that PWID used included working toward moderation, employing various cognitive strategies, and engaging in community activities. The importance of social or peer support and improving self-efficacy was also evident. Further, there was a call for less rigid eligibility criteria and procedures in health and social services, and the need to more adequately address the stigmatization of drug users. Conclusions: These findings demonstrated that PWID incorporate many personal harm reduction practices in their daily lives to improve their well-being, and these practices highlight the importance of agency, self-care, and community building. Health and social services are needed to better support these practices because the many socio-structural barriers this community faces often interfere with harm reduction efforts. Finally, "one size does not fit all" when it comes to harm reduction, and more personalized or de-medicalized conceptualizations are recommended.
|
|
8. |
- Files, DC, et al.
(author)
-
I-SPY COVID adaptive platform trial for COVID-19 acute respiratory failure: rationale, design and operations
- 2022
-
In: BMJ open. - : BMJ. - 2044-6055. ; 12:6, s. e060664-
-
Journal article (peer-reviewed)abstract
- The COVID-19 pandemic brought an urgent need to discover novel effective therapeutics for patients hospitalised with severe COVID-19. The Investigation of Serial studies to Predict Your Therapeutic Response with Imaging And moLecular Analysis (ISPY COVID-19 trial) was designed and implemented in early 2020 to evaluate investigational agents rapidly and simultaneously on a phase 2 adaptive platform. This manuscript outlines the design, rationale, implementation and challenges of the ISPY COVID-19 trial during the first phase of trial activity from April 2020 until December 2021.Methods and analysisThe ISPY COVID-19 Trial is a multicentre open-label phase 2 platform trial in the USA designed to evaluate therapeutics that may have a large effect on improving outcomes from severe COVID-19. The ISPY COVID-19 Trial network includes academic and community hospitals with significant geographical diversity across the country. Enrolled patients are randomised to receive one of up to four investigational agents or a control and are evaluated for a family of two primary outcomes—time to recovery and mortality. The statistical design uses a Bayesian model with ‘stopping’ and ‘graduation’ criteria designed to efficiently discard ineffective therapies and graduate promising agents for definitive efficacy trials. Each investigational agent arm enrols to a maximum of 125 patients per arm and is compared with concurrent controls. As of December 2021, 11 investigational agent arms had been activated, and 8 arms were complete. Enrolment and adaptation of the trial design are ongoing.Ethics and disseminationISPY COVID-19 operates under a central institutional review board via Wake Forest School of Medicine IRB00066805. Data generated from this trial will be reported in peer-reviewed medical journals.Trial registration numberNCT04488081.
|
|
9. |
- Huang, Joyce Y., et al.
(author)
-
Circulating markers of cellular immune activation in prediagnostic blood sample and lung cancer risk in the Lung Cancer Cohort Consortium (LC3)
- 2020
-
In: International Journal of Cancer. - : John Wiley & Sons. - 0020-7136 .- 1097-0215. ; 146:9, s. 2394-2405
-
Journal article (peer-reviewed)abstract
- Cell-mediated immune suppression may play an important role in lung carcinogenesis. We investigated the associations for circulating levels of tryptophan, kynurenine, kynurenine:tryptophan ratio (KTR), quinolinic acid (QA) and neopterin as markers of immune regulation and inflammation with lung cancer risk in 5,364 smoking-matched case-control pairs from 20 prospective cohorts included in the international Lung Cancer Cohort Consortium. All biomarkers were quantified by mass spectrometry-based methods in serum/plasma samples collected on average 6 years before lung cancer diagnosis. Odds ratios (ORs) and 95% confidence intervals (CIs) for lung cancer associated with individual biomarkers were calculated using conditional logistic regression with adjustment for circulating cotinine. Compared to the lowest quintile, the highest quintiles of kynurenine, KTR, QA and neopterin were associated with a 20-30% higher risk, and tryptophan with a 15% lower risk of lung cancer (all p(trend) < 0.05). The strongest associations were seen for current smokers, where the adjusted ORs (95% CIs) of lung cancer for the highest quintile of KTR, QA and neopterin were 1.42 (1.15-1.75), 1.42 (1.14-1.76) and 1.45 (1.13-1.86), respectively. A stronger association was also seen for KTR and QA with risk of lung squamous cell carcinoma followed by adenocarcinoma, and for lung cancer diagnosed within the first 2 years after blood draw. This study demonstrated that components of the tryptophan-kynurenine pathway with immunomodulatory effects are associated with risk of lung cancer overall, especially for current smokers. Further research is needed to evaluate the role of these biomarkers in lung carcinogenesis and progression.
|
|
10. |
- Guida, Florence, et al.
(author)
-
The blood metabolome of incident kidney cancer: A case-control study nested within the MetKid consortium
- 2021
-
In: PLoS Medicine. - : Public Library of Science (PLOS). - 1549-1277 .- 1549-1676. ; 18:9
-
Journal article (peer-reviewed)abstract
- Background: Excess bodyweight and related metabolic perturbations have been implicated in kidney cancer aetiology, but the specific molecular mechanisms underlying these relationships are poorly understood. In this study, we sought to identify circulating metabolites that predispose kidney cancer and to evaluate the extent to which they are influenced by body mass index (BMI).Methods and findings: We assessed the association between circulating levels of 1,416 metabolites and incident kidney cancer using pre-diagnostic blood samples from up to 1,305 kidney cancer case–control pairs from 5 prospective cohort studies. Cases were diagnosed on average 8 years after blood collection. We found 25 metabolites robustly associated with kidney cancer risk. In particular, 14 glycerophospholipids (GPLs) were inversely associated with risk, including 8 phosphatidylcholines (PCs) and 2 plasmalogens. The PC with the strongest association was PC ae C34:3 with an odds ratio (OR) for 1 standard deviation (SD) increment of 0.75 (95% confidence interval [CI]: 0.68 to 0.83, p = 2.6 × 10−8). In contrast, 4 amino acids, including glutamate (OR for 1 SD = 1.39, 95% CI: 1.20 to 1.60, p = 1.6 × 10−5), were positively associated with risk. Adjusting for BMI partly attenuated the risk association for some—but not all—metabolites, whereas other known risk factors of kidney cancer, such as smoking and alcohol consumption, had minimal impact on the observed associations. A mendelian randomisation (MR) analysis of the influence of BMI on the blood metabolome highlighted that some metabolites associated with kidney cancer risk are influenced by BMI. Specifically, elevated BMI appeared to decrease levels of several GPLs that were also found inversely associated with kidney cancer risk (e.g., −0.17 SD change [ßBMI] in 1-(1-enyl-palmitoyl)-2-linoleoyl-GPC (P-16:0/18:2) levels per SD change in BMI, p = 3.4 × 10−5). BMI was also associated with increased levels of glutamate (ßBMI: 0.12, p = 1.5 × 10−3). While our results were robust across the participating studies, they were limited to study participants of European descent, and it will, therefore, be important to evaluate if our findings can be generalised to populations with different genetic backgrounds.Conclusions: This study suggests a potentially important role of the blood metabolome in kidney cancer aetiology by highlighting a wide range of metabolites associated with the risk of developing kidney cancer and the extent to which changes in levels of these metabolites are driven by BMI - the principal modifiable risk factor of kidney cancer.
|
|
11. |
- Keuschnig, Christoph, et al.
(author)
-
Selection processes of Arctic seasonal glacier snowpack bacterial communities
- 2023
-
In: Microbiome. - : BioMed Central (BMC). - 2049-2618. ; 11:1
-
Journal article (peer-reviewed)abstract
- BackgroundArctic snowpack microbial communities are continually subject to dynamic chemical and microbial input from the atmosphere. As such, the factors that contribute to structuring their microbial communities are complex and have yet to be completely resolved. These snowpack communities can be used to evaluate whether they fit niche-based or neutral assembly theories.MethodsWe sampled snow from 22 glacier sites on 7 glaciers across Svalbard in April during the maximum snow accumulation period and prior to the melt period to evaluate the factors that drive snowpack metataxonomy. These snowpacks were seasonal, accumulating in early winter on bare ice and firn and completely melting out in autumn. Using a Bayesian fitting strategy to evaluate Hubbell’s Unified Neutral Theory of Biodiversity at multiple sites, we tested for neutrality and defined immigration rates at different taxonomic levels. Bacterial abundance and diversity were measured and the amount of potential ice-nucleating bacteria was calculated. The chemical composition (anions, cations, organic acids) and particulate impurity load (elemental and organic carbon) of the winter and spring snowpack were also characterized. We used these data in addition to geographical information to assess possible niche-based effects on snow microbial communities using multivariate and variable partitioning analysis.ResultsWhile certain taxonomic signals were found to fit the neutral assembly model, clear evidence of niche-based selection was observed at most sites. Inorganic chemistry was not linked directly to diversity, but helped to identify predominant colonization sources and predict microbial abundance, which was tightly linked to sea spray. Organic acids were the most significant predictors of microbial diversity. At low organic acid concentrations, the snow microbial structure represented the seeding community closely, and evolved away from it at higher organic acid concentrations, with concomitant increases in bacterial numbers.ConclusionsThese results indicate that environmental selection plays a significant role in structuring snow microbial communities and that future studies should focus on activity and growth.
|
|
12. |
- Larose, Tricia L., et al.
(author)
-
Circulating cotinine concentrations and lung cancer risk in the Lung Cancer Cohort Consortium (LC3)
- 2018
-
In: International Journal of Epidemiology. - : Oxford University Press. - 0300-5771 .- 1464-3685. ; 47:6, s. 1760-1771
-
Journal article (peer-reviewed)abstract
- Background: Self-reported smoking is the principal measure used to assess lung cancer risk in epidemiological studies. We evaluated if circulating cotinine—a nicotine metabolite and biomarker of recent tobacco exposure—provides additional information on lung cancer risk.Methods: The study was conducted in the Lung Cancer Cohort Consortium (LC3) involving 20 prospective cohort studies. Pre-diagnostic serum cotinine concentrations were measured in one laboratory on 5364 lung cancer cases and 5364 individually matched controls. We used conditional logistic regression to evaluate the association between circulating cotinine and lung cancer, and assessed if cotinine provided additional risk-discriminative information compared with self-reported smoking (smoking status, smoking intensity, smoking duration), using receiver-operating characteristic (ROC) curve analysis.Results: We observed a strong positive association between cotinine and lung cancer risk for current smokers [odds ratio (OR ) per 500 nmol/L increase in cotinine (OR500): 1.39, 95% confidence interval (CI): 1.32–1.47]. Cotinine concentrations consistent with active smoking (≥115 nmol/L) were common in former smokers (cases: 14.6%; controls: 9.2%) and rare in never smokers (cases: 2.7%; controls: 0.8%). Former and never smokers with cotinine concentrations indicative of active smoking (≥115 nmol/L) also showed increased lung cancer risk. For current smokers, the risk-discriminative performance of cotinine combined with self-reported smoking (AUCintegrated: 0.69, 95% CI: 0.68–0.71) yielded a small improvement over self-reported smoking alone (AUCsmoke: 0.66, 95% CI: 0.64–0.68) (P = 1.5x10–9).Conclusions: Circulating cotinine concentrations are consistently associated with lung cancer risk for current smokers and provide additional risk-discriminative information compared with self-report smoking alone.
|
|
13. |
- Muller, David C., et al.
(author)
-
Circulating high sensitivity C reactive protein concentrations and risk of lung cancer : nested case-control study within Lung Cancer Cohort Consortium
- 2019
-
In: The BMJ. - : BMJ Publishing Group Ltd. - 1756-1833 .- 0959-8138. ; 364
-
Journal article (peer-reviewed)abstract
- Objectives To conduct a comprehensive analysis of prospectively measured circulating high sensitivity C reactive protein (hsCRP) concentration and risk of lung cancer overall, by smoking status (never, former, and current smokers), and histological sub-type.Design Nested case-control study.Setting 20 population based cohort studies in Asia, Europe, Australia, and the United States.Participants 5299 patients with incident lung cancer, with individually incidence density matched controls.Exposure Circulating hsCRP concentrations in prediagnostic serum or plasma samples.Main outcome measure Incident lung cancer diagnosis.Results A positive association between circulating hsCRP concentration and the risk of lung cancer for current (odds ratio associated with a doubling in hsCRP concentration 1.09, 95% confidence interval 1.05 to 1.13) and former smokers (1.09, 1.04 to 1.14) was observed, but not for never smokers (P<0.01 for interaction). This association was strong and consistent across all histological subtypes, except for adenocarcinoma, which was not strongly associated with hsCRP concentration regardless of smoking status (odds ratio for adenocarcinoma overall 0.97, 95% confidence interval 0.94 to 1.01). The association between circulating hsCRP concentration and the risk of lung cancer was strongest in the first two years of follow-up for former and current smokers. Including hsCRP concentration in a risk model, in addition to smoking based variables, did not improve risk discrimination overall, but slightly improved discrimination for cancers diagnosed in the first two years of follow-up.Conclusions Former and current smokers with higher circulating hsCRP concentrations had a higher risk of lung cancer overall. Circulating hsCRP concentration was not associated with the risk of lung adenocarcinoma. Circulating hsCRP concentration could be a prediagnostic marker of lung cancer rather than a causal risk factor.
|
|
14. |
- Parkinson, Alan J., et al.
(author)
-
Climate change and infectious diseases in the Arctic : Establishment of a circumpolar working group
- 2014
-
In: International Journal of Circumpolar Health. - : Taylor & Francis. - 1239-9736 .- 2242-3982. ; 73
-
Journal article (peer-reviewed)abstract
- The Arctic, even more so than other parts of the world, has warmed substantially over the past few decades. Temperature and humidity influence the rate of development, survival and reproduction of pathogens and thus the incidence and prevalence of many infectious diseases. Higher temperatures may also allow infected host species to survive winters in larger numbers, increase the population size and expand their habitat range. The impact of these changes on human disease in the Arctic has not been fully evaluated. There is concern that climate change may shift the geographic and temporal distribution of a range of infectious diseases. Many infectious diseases are climate sensitive, where their emergence in a region is dependent on climate-related ecological changes. Most are zoonotic diseases, and can be spread between humans and animals by arthropod vectors, water, soil, wild or domestic animals. Potentially climate-sensitive zoonotic pathogens of circumpolar concern include Brucella spp., Toxoplasma gondii, Trichinella spp., Clostridium botulinum, Francisella tularensis, Borrelia burgdorferi, Bacillus anthracis, Echinococcus spp., Leptospira spp., Giardia spp., Cryptosporida spp., Coxiella burnetti, rabies virus, West Nile virus, Hantaviruses, and tick-borne encephalitis viruses.
|
|
15. |
|
|