Publications by authors named "Mikael Johansson"

195 Publications

Transitioning to a high volume centre for Whipple pancreaticoduodenectomy in Western Australia: a single centre experience.

ANZ J Surg 2021 Nov 18. Epub 2021 Nov 18.

Department of General Surgery, Sir Charles Gairdner Hospital, Perth, Western Australia, Australia.

Background: Pancreaticoduodenectomy (PD) is a curative resection for peri-ampullary tumours associated with high rates of peri-operative mortality and morbidity. The global trend is towards the establishment of high volume centres to reduce this. Australia faces geographical and population distribution challenges. Western Australia has centralized PD to two centres and we present the results of our institution in transitioning to a high volume centre.

Methods: This was a prospective database of all PDs performed at our institution from 1 January 2005 to 2 April 2020. Mortality outcomes included peri-operative, 30 day and 90 day mortality. Complications, readmission and reinterventions at 90 days were recorded. The annual volume exceeded 20 from 2015. Outcomes prior to this were compared to characterize the transition to a high volume centre.

Results: One hundred and twenty eight PDs were performed in Period 1 (1 January 2005-31 December 2014) and 170 in the high volume Period 2 (1 January 2015-2 April 2020). There was a non-statistically significant reduction in 90 day mortality in Period 2 (4.69% versus 1.18%, p = 0.06). There was a reduction in clinically significant post-operative pancreatic fistulas (31.25% versus 11.76%, p < 0.05), delayed gastric emptying (39.84% versus 22.35%, p < 0.05) and transfusion requirements (56.25% versus 17.65%, p < 0.05). Severe complications (Clavien-Dindo III or greater) were reduced (30.47% versus 18.24%, p < 0.05).

Conclusion: Since establishing a high volume service, there was a reduction in post-operative complications and 90 day mortality. This is in line with outcomes from international centres and demonstrates the improvements that can be made.
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http://dx.doi.org/10.1111/ans.17367DOI Listing
November 2021

The Perennial Clock Is an Essential Timer for Seasonal Growth Events and Cold Hardiness.

Methods Mol Biol 2022 ;2398:227-242

Department of Plant Physiology, Umeå Plant Science Centre, Umeå University, Umeå, Sweden.

Over the last several decades, changes in global temperatures have led to changes in local environments affecting the growth conditions for many species. This is a trend that makes it even more important to understand how plants respond to local variations and seasonal changes in climate.To detect daily and seasonal changes as well as acute stress factors such as cold and drought, plants rely on a circadian clock. This chapter introduces the current knowledge and literature about the setup and function of the circadian clock in various tree and perennial species, with a focus on the Populus genus.
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http://dx.doi.org/10.1007/978-1-0716-1912-4_18DOI Listing
January 2022

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

Methods Mol Biol 2022 ;2398:215-226

Department of Plant Physiology, Umeå Plant Science Centre, Umeå University, Umeå, Sweden.

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.
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http://dx.doi.org/10.1007/978-1-0716-1912-4_17DOI Listing
January 2022

Magnetically induced ring currents in naphthalene-fused heteroporphyrinoids.

Phys Chem Chem Phys 2021 Aug;23(31):16629-16634

University of Helsinki, Department of Chemistry, Faculty of Science, P.O. Box 55 (A.I. Virtanens Plats 1), FI-00014 Helsinki, Finland.

The magnetically induced current density of an intriguing naphthalene-fused heteroporphyrin has been studied, using the quantum-chemical, gauge-including magnetically induced currents (GIMIC) method. The ring-current strengths and current-density pathways for the heteroporphyrin, its Pd complex, and the analogous quinoline-fused heteroporphyrin provide detailed information about their aromatic properties. The three porphyrinoids have similar current-density pathways and are almost as aromatic as free-base porphyrin. Notably, we show that the global ring current makes a branch at three specific points. Thus, the global current is composed of a total of eight pathways that include 22 π-electrons, with no contributions from 18-electron pathways.
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http://dx.doi.org/10.1039/d1cp02381kDOI Listing
August 2021

Halogenation at the Phenylalanine Residue of Monomethyl Auristatin F Leads to a Favorable / Equilibrium and Retained Cytotoxicity.

Mol Pharm 2021 08 23;18(8):3125-3131. Epub 2021 Jul 23.

Department of Chemistry, University of Helsinki, P.O. Box 55, A. I. Virtasen aukio 1, FI-00014 Helsinki, Finland.

Halogenation can be utilized for the purposes of labeling and molecular imaging, providing a means to, e.g., follow drug distribution in an organism through positron emission tomography (PET) or study the molecular recognition events unfolding by nuclear magnetic resonance (NMR) spectroscopy. For cancer therapeutics, where often highly toxic substances are employed, it is of importance to be able to track the distribution of the drugs and their metabolites in order to ensure minimal side effects. Labeling should ideally have a negligible disruptive effect on the efficacy of a given drug. Using a combination of NMR spectroscopy and cytotoxicity assays, we identify a site susceptible to halogenation in monomethyl auristatin F (MMAF), a widely used cytotoxic agent in the antibody-drug conjugate (ADC) family of cancer drugs, and study the effects of fluorination and chlorination on the physiological solution structure of the auristatins and their cytotoxicity. We find that the cytotoxicity of the parent drug is retained, while the conformational equilibrium is shifted significantly toward the biologically active isomer, simultaneously decreasing the concentration of the inactive and potentially disruptive isomer by up to 50%. Our results may serve as a base for the future assembly of a multifunctional toolkit for the assessment of linker technologies and exploring bystander effects from the warhead perspective in auristatin-derived ADCs.
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http://dx.doi.org/10.1021/acs.molpharmaceut.1c00342DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8397390PMC
August 2021

Epidemiology of 40 blood biomarkers of one-carbon metabolism, vitamin status, inflammation, and renal and endothelial function among cancer-free older adults.

Sci Rep 2021 07 5;11(1):13805. Epub 2021 Jul 5.

Duke - NUS Medical School, Singapore, Singapore.

Imbalances of blood biomarkers are associated with disease, and biomarkers may also vary non-pathologically across population groups. We described variation in concentrations of biomarkers of one-carbon metabolism, vitamin status, inflammation including tryptophan metabolism, and endothelial and renal function among cancer-free older adults. We analyzed 5167 cancer-free controls aged 40-80 years from 20 cohorts in the Lung Cancer Cohort Consortium (LC3). Centralized biochemical analyses of 40 biomarkers in plasma or serum were performed. We fit multivariable linear mixed effects models to quantify variation in standardized biomarker log-concentrations across four factors: age, sex, smoking status, and body mass index (BMI). Differences in most biomarkers across most factors were small, with 93% (186/200) of analyses showing an estimated difference lower than 0.25 standard-deviations, although most were statistically significant due to large sample size. The largest difference was for creatinine by sex, which was - 0.91 standard-deviations lower in women than men (95%CI - 0.98; - 0.84). The largest difference by age was for total cysteine (0.40 standard-deviation increase per 10-year increase, 95%CI 0.36; 0.43), and by BMI was for C-reactive protein (0.38 standard-deviation increase per 5-kg/m increase, 95%CI 0.34; 0.41). For 31 of 40 markers, the mean difference between current and never smokers was larger than between former and never smokers. A statistically significant (p < 0.05) association with time since smoking cessation was observed for 8 markers, including C-reactive protein, kynurenine, choline, and total homocysteine. We conclude that most blood biomarkers show small variations across demographic characteristics. Patterns by smoking status point to normalization of multiple physiological processes after smoking cessation.
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http://dx.doi.org/10.1038/s41598-021-93214-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8257595PMC
July 2021

Feasibility and efficacy of a multicomponent exercise medicine programme in patients with pancreatic cancer undergoing neoadjuvant therapy (the EXPAN trial): study protocol of a dual-centre, two-armed phase I randomised controlled trial.

BMJ Open Gastroenterol 2021 06;8(1)

Exercise Medicine Research Institute, Edith Cowan University, Joondalup, Western Australia, Australia.

Introduction: Exercise is emerging as a therapy in oncology for its physical and psychosocial benefits and potential effects on chemotherapy tolerability and efficacy. However, evidence from randomised controlled trials (RCTs) supporting exercise in patients with borderline resectable or locally advanced pancreatic cancer (PanCa) undergoing neoadjuvant therapy (NAT) are lacking.

Methods And Analysis: The EXPAN trial is a dual-centre, two-armed, phase I RCT. Forty patients with borderline resectable or locally advanced PanCa undergoing NAT will be randomised equally to an exercise intervention group (individualised exercise+standard NAT) or a usual care control group (standard NAT). The exercise intervention will be supervised and consist of moderate to vigorous intensity resistance and aerobic-based training undertaken two times a week for 45-60 min per session for a maximum period of 6 months. The primary outcome is feasibility. Secondary outcomes are patient-related and treatment-related endpoints, objectively measured physical function, body composition, psychological health and quality of life. Assessments will be conducted at baseline, prior to potential alteration of treatment (~4 months postbaseline), at completion of the intervention (maximum 6 months postbaseline) and 3-month and 6-month postintervention (maximum 9 and 12 months postbaseline).

Ethics And Dissemination: The EXPAN trial has been approved by Edith Cowan University (reference no.: 2020-02011-LUO), Sir Charles Gairdner Hospital (reference no.: RGS 03956) and St John of God Subiaco Hospital (reference no.: 1726). The study results will be presented at national/international conferences and submitted for publications in peer-reviewed journals.

Trial Registration Number: ACTRN12620001081909.
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http://dx.doi.org/10.1136/bmjgast-2021-000642DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8186755PMC
June 2021

Risk of primary lung cancer after adjuvant radiotherapy in breast cancer-a large population-based study.

NPJ Breast Cancer 2021 Jun 1;7(1):71. Epub 2021 Jun 1.

Department of Surgical and Perioperative Sciences, Umeå University, Umeå, Sweden.

Adjuvant radiotherapy (RT) for breast cancer (BC) has been associated with an increased risk of later radiation-induced lung cancer (LC). We examined the risk of primary LC in a population-based cohort of 52300 women treated for BC during 1992 to 2012, and 253796 age-matched women without BC. Cumulative incidence of LC was calculated by the Kaplan-Meier method, and the risk of LC after BC treatment was estimated by Cox proportional hazards regression analyses. Women with BC receiving RT had a higher cumulative incidence of LC compared to women with BC not receiving RT and women without BC. This became apparent 5 years after RT and increased with longer follow-up. Women with BC receiving RT had a Hazard ratio of 1.59 (95% confidence interval 1.37-1.84) for LC compared to women without BC. RT techniques that lower the incidental lung doses, e.g breathing adaption techniques, may lower this risk.
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http://dx.doi.org/10.1038/s41523-021-00280-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8169889PMC
June 2021

Genome-wide association meta-analysis identifies pleiotropic risk loci for aerodigestive squamous cell cancers.

PLoS Genet 2021 03 5;17(3):e1009254. Epub 2021 Mar 5.

University of Salzburg, Department of Biosciences and Cancer Cluster Salzburg, Salzburg, Austria.

Squamous cell carcinomas (SqCC) of the aerodigestive tract have similar etiological risk factors. Although genetic risk variants for individual cancers have been identified, an agnostic, genome-wide search for shared genetic susceptibility has not been performed. To identify novel and pleotropic SqCC risk variants, we performed a meta-analysis of GWAS data on lung SqCC (LuSqCC), oro/pharyngeal SqCC (OSqCC), laryngeal SqCC (LaSqCC) and esophageal SqCC (ESqCC) cancers, totaling 13,887 cases and 61,961 controls of European ancestry. We identified one novel genome-wide significant (Pmeta<5x10-8) aerodigestive SqCC susceptibility loci in the 2q33.1 region (rs56321285, TMEM273). Additionally, three previously unknown loci reached suggestive significance (Pmeta<5x10-7): 1q32.1 (rs12133735, near MDM4), 5q31.2 (rs13181561, TMEM173) and 19p13.11 (rs61494113, ABHD8). Multiple previously identified loci for aerodigestive SqCC also showed evidence of pleiotropy in at least another SqCC site, these include: 4q23 (ADH1B), 6p21.33 (STK19), 6p21.32 (HLA-DQB1), 9p21.33 (CDKN2B-AS1) and 13q13.1(BRCA2). Gene-based association and gene set enrichment identified a set of 48 SqCC-related genes rel to DNA damage and epigenetic regulation pathways. Our study highlights the importance of cross-cancer analyses to identify pleiotropic risk loci of histology-related cancers arising at distinct anatomical sites.
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http://dx.doi.org/10.1371/journal.pgen.1009254DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7968735PMC
March 2021

Prospective Identification of Elevated Circulating CDCP1 in Patients Years before Onset of Lung Cancer.

Cancer Res 2021 07 11;81(13):3738-3748. Epub 2021 Feb 11.

MRC Centre for Environment and Health, Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, United Kingdom.

Increasing evidence points to a role for inflammation in lung carcinogenesis. A small number of circulating inflammatory proteins have been identified as showing elevated levels prior to lung cancer diagnosis, indicating the potential for prospective circulating protein concentration as a marker of early carcinogenesis. To identify novel markers of lung cancer risk, we measured a panel of 92 circulating inflammatory proteins in 648 prediagnostic blood samples from two prospective cohorts in Italy and Norway (women only). To preserve the comparability of results and protect against confounding factors, the main statistical analyses were conducted in women from both studies, with replication sought in men (Italian participants). Univariate and penalized regression models revealed for the first time higher blood levels of CDCP1 protein in cases that went on to develop lung cancer compared with controls, irrespective of time to diagnosis, smoking habits, and gender. This association was validated in an additional 450 samples. Associations were stronger for future cases of adenocarcinoma where CDCP1 showed better explanatory performance. Integrative analyses combining gene expression and protein levels of CDCP1 measured in the same individuals suggested a link between CDCP1 and the expression of transcripts of LRRN3 and SEM1. Enrichment analyses indicated a potential role for CDCP1 in pathways related to cell adhesion and mobility, such as the WNT/β-catenin pathway. Overall, this study identifies lung cancer-related dysregulation of CDCP1 expression years before diagnosis. SIGNIFICANCE: Prospective proteomics analyses reveal an association between increased levels of circulating CDCP1 and lung carcinogenesis irrespective of smoking and years before diagnosis, and integrating gene expression indicates potential underlying mechanisms..
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http://dx.doi.org/10.1158/0008-5472.CAN-20-3454DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7611235PMC
July 2021

Strategic retrieval prevents memory interference: The temporal dynamics of retrieval orientation.

Neuropsychologia 2021 04 5;154:107776. Epub 2021 Feb 5.

Department of Psychology, Lund University, Sweden.

Resolving interference between overlapping memories is crucial to remember the past. This study tests the novel prediction that orienting search focus benefits goal-relevant retrieval by reducing competition from unwanted memories. In a modified retrieval-practice paradigm, participants encoded word-pairs in one of two encoding tasks. Critically, to evaluate whether this retrieval orientation (RO) reduces memory interference, target and competitor memories were always related to different encoding tasks. At retrieval, instructions were provided for half of the blocks with the intention to bias remembering towards items encoded with one of the ROs. Behavioural data show that adopting an RO improved target accessibility, strengthened the testing effect, and reduced retrieval-induced forgetting (RIF) of competitors. Specifically, RIF - typically attributed to inhibitory control of memory interference - was prominent when no retrieval orientation (NRO) instruction was provided. Furthermore, a neural correlate of RO was calculated by training a linear discriminant analysis (LDA) to discriminate the electroencephalographic (EEG) spatial brain patterns correspondent to the two ROs over the time course of selective retrieval. RO was characterised by increases in the theta and decreases in the beta frequency band, evident both before and after category-cue onset. While the pre-cue RO reinstatement effect predicted both immediate retrieval-practice success and later target accessibility, the post-cue effect predicted disengagement of inhibitory control, such that participants showing a stronger RO reinstatement effect showed lower levels of RIF. These data suggest that strategically orienting search focus during retrieval both increases target memory accessibility and reduces memory interference, which consequently protects related memories from inhibition and later forgetting. Furthermore, they also highlight the roles of theta and beta oscillations in establishing and maintaining a task-relevant bias towards target memory representations during competitive memory retrieval.
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http://dx.doi.org/10.1016/j.neuropsychologia.2021.107776DOI Listing
April 2021

Exploring the Biochemical Foundations of a Successful GLUT1-Targeting Strategy to BNCT: Chemical Synthesis and Evaluation of the Entire Positional Isomer Library of -Carboranylmethyl-Bearing Glucoconjugates.

Mol Pharm 2021 01 1;18(1):285-304. Epub 2020 Dec 1.

Department of Chemistry, University of Helsinki, P.O. Box 55, FI-00014 Helsinki, Finland.

Boron neutron capture therapy (BNCT) is a noninvasive binary therapeutic modality applicable to the treatment of cancers. While BNCT offers a tumor-targeting selectivity that is difficult to match by other means, the last obstacles preventing the full harness of this potential come in the form of the suboptimal boron delivery strategies presently used in the clinics. To address these challenges, we have developed delivery agents that target the glucose transporter GLUT1. Here, we present the chemical synthesis of a number of -carboranylmethyl-substituted glucoconjugates and the biological assessment of all positional isomers. Altogether, the study provides protocols for the synthesis and structural characterization of such glucoconjugates and insights into their essential properties, for example, cytotoxicity, GLUT1-affinity, metabolism, and boron delivery capacity. In addition to solidifying the biochemical foundations of a successful GLUT1-targeting approach to BNCT, we identify the most promising modification sites in d-glucose, which are critical in order to further develop this strategy toward clinical use.
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http://dx.doi.org/10.1021/acs.molpharmaceut.0c00917DOI Listing
January 2021

Core-Satellite Gold Nanoparticle Complexes Grown by Inert Gas-Phase Condensation.

J Phys Chem C Nanomater Interfaces 2020 Nov 21;124(44):24441-24450. Epub 2020 Oct 21.

Materials Science Factory, Instituto de Ciencia de Materiales de Madrid (ICMM-CSIC), Sor Juana Inés de la Cruz 3, 28049 Cantoblanco, Madrid, Spain.

Spontaneous growth of complexes consisted of a number of individual nanoparticles in a controlled manner, particularly in demanding environments of gas-phase synthesis, is a fascinating opportunity for numerous potential applications. Here, we report the formation of such core-satellite gold nanoparticle structures grown by magnetron sputtering inert gas condensation. Combining high-resolution scanning transmission electron microscopy and computational simulations, we reveal the adhesive and screening role of HO molecules in formation of stable complexes consisted of one nanoparticle surrounded by smaller satellites. A single layer of HO molecules, condensed between large and small gold nanoparticles, stabilizes positioning of nanoparticles with respect to one another during milliseconds of the synthesis time. The lack of isolated small gold nanoparticles on the substrate is explained by Brownian motion that is significantly broader for small-size particles. It is inferred that HO as an admixture in the inert gas condensation opens up possibilities of controlling the final configuration of the different noble metal nanoparticles.
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http://dx.doi.org/10.1021/acs.jpcc.0c07346DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7662783PMC
November 2020

Integration of multiomic annotation data to prioritize and characterize inflammation and immune-related risk variants in squamous cell lung cancer.

Genet Epidemiol 2021 02 14;45(1):99-114. Epub 2020 Sep 14.

Faculty of Medical Sciences, Radboud University Medical Center, Nijmegen, The Netherlands.

Clinical trial results have recently demonstrated that inhibiting inflammation by targeting the interleukin-1β pathway can offer a significant reduction in lung cancer incidence and mortality, highlighting a pressing and unmet need to understand the benefits of inflammation-focused lung cancer therapies at the genetic level. While numerous genome-wide association studies (GWAS) have explored the genetic etiology of lung cancer, there remains a large gap between the type of information that may be gleaned from an association study and the depth of understanding necessary to explain and drive translational findings. Thus, in this study we jointly model and integrate extensive multiomics data sources, utilizing a total of 40 genome-wide functional annotations that augment previously published results from the International Lung Cancer Consortium (ILCCO) GWAS, to prioritize and characterize single nucleotide polymorphisms (SNPs) that increase risk of squamous cell lung cancer through the inflammatory and immune responses. Our work bridges the gap between correlative analysis and translational follow-up research, refining GWAS association measures in an interpretable and systematic manner. In particular, reanalysis of the ILCCO data highlights the impact of highly associated SNPs from nuclear factor-κB signaling pathway genes as well as major histocompatibility complex mediated variation in immune responses. One consequence of prioritizing likely functional SNPs is the pruning of variants that might be selected for follow-up work by over an order of magnitude, from potentially tens of thousands to hundreds. The strategies we introduce provide informative and interpretable approaches for incorporating extensive genome-wide annotation data in analysis of genetic association studies.
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http://dx.doi.org/10.1002/gepi.22358DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7855632PMC
February 2021

Causal relationships between body mass index, smoking and lung cancer: Univariable and multivariable Mendelian randomization.

Int J Cancer 2021 03 23;148(5):1077-1086. Epub 2020 Sep 23.

The National Institute of Occupational Health (STAMI), Oslo, Norway.

At the time of cancer diagnosis, body mass index (BMI) is inversely correlated with lung cancer risk, which may reflect reverse causality and confounding due to smoking behavior. We used two-sample univariable and multivariable Mendelian randomization (MR) to estimate causal relationships of BMI and smoking behaviors on lung cancer and histological subtypes based on an aggregated genome-wide association studies (GWASs) analysis of lung cancer in 29 266 cases and 56 450 controls. We observed a positive causal effect for high BMI on occurrence of small-cell lung cancer (odds ratio (OR) = 1.60, 95% confidence interval (CI) = 1.24-2.06, P = 2.70 × 10 ). After adjustment of smoking behaviors using multivariable Mendelian randomization (MVMR), a direct causal effect on small cell lung cancer (OR = 1.28, 95% CI = 1.06-1.55, P = .011), and an inverse effect on lung adenocarcinoma (OR = 0.86, 95% CI = 0.77-0.96, P = .008) were observed. A weak increased risk of lung squamous cell carcinoma was observed for higher BMI in univariable Mendelian randomization (UVMR) analysis (OR = 1.19, 95% CI = 1.01-1.40, P = .036), but this effect disappeared after adjustment of smoking (OR = 1.02, 95% CI = 0.90-1.16, P = .746). These results highlight the histology-specific impact of BMI on lung carcinogenesis and imply mediator role of smoking behaviors in the association between BMI and lung cancer.
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http://dx.doi.org/10.1002/ijc.33292DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7845289PMC
March 2021

Comprehensive functional annotation of susceptibility variants identifies genetic heterogeneity between lung adenocarcinoma and squamous cell carcinoma.

Front Med 2021 Apr 5;15(2):275-291. Epub 2020 Sep 5.

National Institute of Occupational Health (STAMI), Oslo, Pb 5330, Norway.

Although genome-wide association studies have identified more than eighty genetic variants associated with non-small cell lung cancer (NSCLC) risk, biological mechanisms of these variants remain largely unknown. By integrating a large-scale genotype data of 15 581 lung adenocarcinoma (AD) cases, 8350 squamous cell carcinoma (SqCC) cases, and 27 355 controls, as well as multiple transcriptome and epigenomic databases, we conducted histology-specific meta-analyses and functional annotations of both reported and novel susceptibility variants. We identified 3064 credible risk variants for NSCLC, which were overrepresented in enhancer-like and promoter-like histone modification peaks as well as DNase I hypersensitive sites. Transcription factor enrichment analysis revealed that USF1 was AD-specific while CREB1 was SqCC-specific. Functional annotation and gene-based analysis implicated 894 target genes, including 274 specifics for AD and 123 for SqCC, which were overrepresented in somatic driver genes (ER = 1.95, P = 0.005). Pathway enrichment analysis and Gene-Set Enrichment Analysis revealed that AD genes were primarily involved in immune-related pathways, while SqCC genes were homologous recombination deficiency related. Our results illustrate the molecular basis of both well-studied and new susceptibility loci of NSCLC, providing not only novel insights into the genetic heterogeneity between AD and SqCC but also a set of plausible gene targets for post-GWAS functional experiments.
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http://dx.doi.org/10.1007/s11684-020-0779-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8374896PMC
April 2021

Addressing the Biochemical Foundations of a Glucose-Based "Trojan Horse"-Strategy to Boron Neutron Capture Therapy: From Chemical Synthesis to Assessment.

Mol Pharm 2020 10 2;17(10):3885-3899. Epub 2020 Sep 2.

Department of Chemistry, University of Helsinki, Finland, P.O. Box 55, FI-00014 Helsinki, Finland.

Boron neutron capture therapy (BNCT) for cancer is on the rise worldwide due to recent developments of in-hospital neutron accelerators which are expected to revolutionize patient treatments. There is an urgent need for improved boron delivery agents, and herein we have focused on studying the biochemical foundations upon which a successful GLUT1-targeting strategy to BNCT could be based. By combining synthesis and molecular modeling with affinity and cytotoxicity studies, we unravel the mechanisms behind the considerable potential of appropriately designed glucoconjugates as boron delivery agents for BNCT. In addition to addressing the biochemical premises of the approach in detail, we report on a hit glucoconjugate which displays good cytocompatibility, aqueous solubility, high transporter affinity, and, crucially, an exceptional boron delivery capacity in the assessment thereby pointing toward the significant potential embedded in this approach.
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http://dx.doi.org/10.1021/acs.molpharmaceut.0c00630DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7539299PMC
October 2020

A gene expression-based single sample predictor of lung adenocarcinoma molecular subtype and prognosis.

Int J Cancer 2021 01 12;148(1):238-251. Epub 2020 Aug 12.

Division of Oncology and Pathology, Department of Clinical Sciences Lund, Lund University, Medicon Village, Lund, Sweden.

Disease recurrence in surgically treated lung adenocarcinoma (AC) remains high. New approaches for risk stratification beyond tumor stage are needed. Gene expression-based AC subtypes such as the Cancer Genome Atlas Network (TCGA) terminal-respiratory unit (TRU), proximal-inflammatory (PI) and proximal-proliferative (PP) subtypes have been associated with prognosis, but show methodological limitations for robust clinical use. We aimed to derive a platform independent single sample predictor (SSP) for molecular subtype assignment and risk stratification that could function in a clinical setting. Two-class (TRU/nonTRU=SSP2) and three-class (TRU/PP/PI=SSP3) SSPs using the AIMS algorithm were trained in 1655 ACs (n = 9659 genes) from public repositories vs TCGA centroid subtypes. Validation and survival analysis were performed in 977 patients using overall survival (OS) and distant metastasis-free survival (DMFS) as endpoints. In the validation cohort, SSP2 and SSP3 showed accuracies of 0.85 and 0.81, respectively. SSPs captured relevant biology previously associated with the TCGA subtypes and were associated with prognosis. In survival analysis, OS and DMFS for cases discordantly classified between TCGA and SSP2 favored the SSP2 classification. In resected Stage I patients, SSP2 identified TRU-cases with better OS (hazard ratio [HR] = 0.30; 95% confidence interval [CI] = 0.18-0.49) and DMFS (TRU HR = 0.52; 95% CI = 0.33-0.83) independent of age, Stage IA/IB and gender. SSP2 was transformed into a NanoString nCounter assay and tested in 44 Stage I patients using RNA from formalin-fixed tissue, providing prognostic stratification (relapse-free interval, HR = 3.2; 95% CI = 1.2-8.8). In conclusion, gene expression-based SSPs can provide molecular subtype and independent prognostic information in early-stage lung ACs. SSPs may overcome critical limitations in the applicability of gene signatures in lung cancer.
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http://dx.doi.org/10.1002/ijc.33242DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7689824PMC
January 2021

Great apes selectively retrieve relevant memories to guide action.

Sci Rep 2020 07 28;10(1):12603. Epub 2020 Jul 28.

Department of Philosophy and Cognitive Science, Lund University, Lund, Sweden.

Memory allows us to draw on past experiences to inform behaviour in the present. However, memories rarely match the situation at hand exactly, and new situations regularly trigger multiple related memories where only some are relevant to act upon. The flexibility of human memory systems is largely attributed to the ability to disregard irrelevant, but salient, memories in favour of relevant ones. This is considered an expression of an executive function responsible for suppressing irrelevant memories, associated with the prefrontal cortex. It is unclear to what extent animals have access to this ability. Here, we demonstrate, in a series of tool-use tasks designed to evoke conflicting memories, that chimpanzees and an orangutan suffer from this conflict but overcome it in favour of a more relevant memory. Such mnemonic flexibility is among the most advanced expressions of executive function shown in animals to date and might explain several behaviours related to tool-use, innovation, planning and more.
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http://dx.doi.org/10.1038/s41598-020-69607-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7387339PMC
July 2020

Intratumoral retrograde microdialysis treatment of high-grade glioma with cisplatin.

Acta Neurochir (Wien) 2020 12 14;162(12):3043-3053. Epub 2020 Jul 14.

Deparment of Clinical Sciences, Neuroscience Unit, Umeå University, 90185, Umeå, Sweden.

Purpose: This study evaluates the application of a microdialysis technique for interstitial chemotherapy using cisplatin in high-grade glioma.

Method: An in vitro study demonstrated that cisplatin can be administered through retrograde microdialysis and defined the recovery for cisplatin. In a subsequent phase I study, 1-4 microdialysis catheters were implanted in tumor tissue, brain adjacent to tumor (BAT) tissue, and subcutaneous tissue in 10 patients with recurrent high-grade glioma. Cisplatin was administered continuously in daily doses between 0.3 and 3.9 mg for 4 to12 days. Microdialysis samples were continuously collected and analyzed for glucose metabolites, glutamate, glycerol, and cisplatin concentrations. Treatment tolerability was evaluated through clinical monitoring. Quality of life was assessed using the EORTC-QLQ-C30 questionnaire for up to 3 months after treatment.

Results: This in vitro study showed that cisplatin could be administrated with a recovery of 41-97%, depending on flowrate, type of catheter, and cisplatin concentration. During the treatment, patients were exposed to a total dose of 1.2-36.8 mg cisplatin. The concentration of cisplatin in BAT, serum, and subcutaneous tissue was close to detection level in all but two patients. A transient neurologic deterioration due to edema was commonly observed, but no systemic side effects were recorded. After onset of treatment, concentrations of glutamate and glycerol were significantly increased in tumor tissue but not in BAT, with a peak after 3 days, and consistent for the rest of the treatment. Five of the patients survived between 153 and 492 days after treatment.

Conclusion: This phase I study demonstrates that retrograde microdialysis can be used to administer cisplatin interstitially into high-grade glioma tissue. A high cytotoxicity was detected in tumor tissue, but not in the surrounding brain. Retrograde microdialysis appears to be a clinically useful method for intratumoral drug administration in high-grade glioma.
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http://dx.doi.org/10.1007/s00701-020-04488-2DOI Listing
December 2020

A daytime nap does not increase mnemonic discrimination ability.

J Sleep Res 2021 06 18;30(3):e13128. Epub 2020 Jun 18.

Department of Psychology, Lund University, Lund, Sweden.

It has been proposed that sleep readies the brain for novel learning, and previous work has shown that sleep loss impairs the ability to encode new memories. In the present study, we examined if a daytime nap would increase mnemonic discrimination (MD) performance. MD is the ability to differentiate between memories that are similar but not identical. Participants performed the Mnemonic Similarity Task (MST) twice, once in the morning and once in the afternoon. The goal of this task is to distinguish stimuli that have been seen before from novel stimuli that are similar but not identical. After the morning MST, participants were randomly allocated into either a sleep or a wake group. The sleep group had a 2-hr nap opportunity, whereas the wake group spent a similar amount of time passively resting. All participants then performed a second MST in the afternoon with a novel set of images. Results did not show any support for increased MD ability after a nap. There was, however, a correlation showing that an increase in sleepiness between sessions predicted a decrease in MD performance. Future work must systematically examine how strong sleep manipulations that are needed for sleep to have an effect on encoding ability, as well as which kind of memory tasks that are sensitive to sleep manipulations. More knowledge about the relationship between sleep and the ability to differentiate similar memories from each other is important because impaired MD ability has previously been reported in various groups in which sleep disturbances are also common.
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http://dx.doi.org/10.1111/jsr.13128DOI Listing
June 2021

Mnemonic discrimination of object and context is differentially associated with mental health.

Neurobiol Learn Mem 2020 09 10;173:107268. Epub 2020 Jun 10.

Department of Psychology, Lund University, Lund, Sweden. Electronic address:

Episodic memories are formed by hippocampal binding of the "what" and "where" features of everyday events. The hippocampus minimizes interference between related similar episodic memories by pattern separation. Stress and psychopathology are associated with lowered pattern separation. While current behavioral paradigms typically use correct rejections of single object or context lures rather than composite stimuli, it is not known if object and context pattern separation differentially associate with mental health. We reasoned that an object-in-context paradigm would be more sensitive to mental health state than current implementations, given increased task demands. We found that non-clinical depression and anxiety symptom severity were associated with reduced lure rejection for both object and context and that only the object domain was associated with a concomitant increase in lure overgeneralization. Therefore, we argue that reduced lure rejection and increased overgeneralization must not be conflated. Although our object-in-context paradigm was not more sensitive to variation in mental health, we show that lure rejection and overgeneralization rate in one domain (e.g. object) was affected by the status of the other domain (e.g. context target versus lure). Finally, as several metrics of pattern separation exist in the literature, we evaluated the association of different metrics with mental health.
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http://dx.doi.org/10.1016/j.nlm.2020.107268DOI Listing
September 2020

Protein-altering germline mutations implicate novel genes related to lung cancer development.

Nat Commun 2020 05 11;11(1):2220. Epub 2020 May 11.

Radboud University Medical Center, Radboud Institute for Health Sciences, Nijmegen, The Netherlands.

Few germline mutations are known to affect lung cancer risk. We performed analyses of rare variants from 39,146 individuals of European ancestry and investigated gene expression levels in 7,773 samples. We find a large-effect association with an ATM L2307F (rs56009889) mutation in adenocarcinoma for discovery (adjusted Odds Ratio = 8.82, P = 1.18 × 10) and replication (adjusted OR = 2.93, P = 2.22 × 10) that is more pronounced in females (adjusted OR = 6.81 and 3.19 and for discovery and replication). We observe an excess loss of heterozygosity in lung tumors among ATM L2307F allele carriers. L2307F is more frequent (4%) among Ashkenazi Jewish populations. We also observe an association in discovery (adjusted OR = 2.61, P = 7.98 × 10) and replication datasets (adjusted OR = 1.55, P = 0.06) with a loss-of-function mutation, Q4X (rs150665432) of an uncharacterized gene, KIAA0930. Our findings implicate germline genetic variants in ATM with lung cancer susceptibility and suggest KIAA0930 as a novel candidate gene for lung cancer risk.
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http://dx.doi.org/10.1038/s41467-020-15905-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7214407PMC
May 2020

Association Analysis of Driver Gene-Related Genetic Variants Identified Novel Lung Cancer Susceptibility Loci with 20,871 Lung Cancer Cases and 15,971 Controls.

Cancer Epidemiol Biomarkers Prev 2020 07 10;29(7):1423-1429. Epub 2020 Apr 10.

National Institute of Occupational Health (STAMI), Oslo, Norway.

Background: A substantial proportion of cancer driver genes (CDG) are also cancer predisposition genes. However, the associations between genetic variants in lung CDGs and the susceptibility to lung cancer have rarely been investigated.

Methods: We selected expression-related single-nucleotide polymorphisms (eSNP) and nonsynonymous variants of lung CDGs, and tested their associations with lung cancer risk in two large-scale genome-wide association studies (20,871 cases and 15,971 controls of European descent). Conditional and joint association analysis was performed to identify independent risk variants. The associations of independent risk variants with somatic alterations in lung CDGs or recurrently altered pathways were investigated using data from The Cancer Genome Atlas (TCGA) project.

Results: We identified seven independent SNPs in five lung CDGs that were consistently associated with lung cancer risk in discovery ( < 0.001) and validation ( < 0.05) stages. Among these loci, rs78062588 in (1q21.3) was a new lung cancer susceptibility locus (OR = 0.86, = 1.65 × 10). Subgroup analysis by histologic types further identified nine lung CDGs. Analysis of somatic alterations found that in lung adenocarcinomas, rs78062588[C] allele ( in 1q21.3) was associated with elevated somatic copy number of (OR = 1.16, = 0.02). In lung adenocarcinomas, rs1611182 ( in 6p22.1) was associated with truncation mutations of the transcriptional misregulation in cancer pathway (OR = 0.66, = 1.76 × 10).

Conclusions: Genetic variants can regulate functions of lung CDGs and influence lung cancer susceptibility.

Impact: Our findings might help unravel biological mechanisms underlying lung cancer susceptibility.
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http://dx.doi.org/10.1158/1055-9965.EPI-19-1085DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8120681PMC
July 2020

Temporal Dynamics of Memory-guided Cognitive Control and Generalization of Control via Overlapping Associative Memories.

J Neurosci 2020 03 4;40(11):2343-2356. Epub 2020 Feb 4.

Department of Psychology, Stanford University, Stanford, California 94305.

Goal-directed behavior can benefit from proactive adjustments of cognitive control that occur in anticipation of forthcoming cognitive control demands (CCD). Predictions of forthcoming CCD are thought to depend on learning and memory in two ways: First, through direct experience, associative encoding may link previously experienced CCD to its triggering item, such that subsequent encounters with the item serve to cue retrieval of (i.e., predict) the associated CCD. Second, in the absence of direct experience, pattern completion and mnemonic integration mechanisms may allow CCD to be generalized from its associated item to other items related in memory. While extant behavioral evidence documents both types of CCD prediction, the neurocognitive mechanisms giving rise to these predictions remain largely unexplored. Here, we tested two hypotheses: (1) memory-guided predictions about CCD precede control adjustments due to the actual CCD required; and (2) generalization of CCD can be accomplished through integration mechanisms that link partially overlapping CCD-item and item-item associations in memory. Supporting these hypotheses, the temporal dynamics of theta and alpha power in human electroencephalography data ( = 43, 26 females) revealed that an associative CCD effect emerges earlier than interaction effects involving actual CCD. Furthermore, generalization of CCD from one item (X) to another item (Y) was predicted by a decrease in alpha power following the presentation of the X-Y pair. These findings advance understanding of the mechanisms underlying memory-guided adjustments of cognitive control. Cognitive control adaptively regulates information processing to align with task goals. Experience-based expectations enable adjustments of control, leading to improved performance when expectations match the actual control demand required. Using EEG, we demonstrate that memory for past cognitive control demand proactively guides the allocation of cognitive control, preceding adjustments of control triggered by the demands of the present environment. Furthermore, we demonstrate that learned cognitive control demands can be generalized through mnemonic integration processes, enabling the spread of expectations about cognitive control demands to items associated in memory. We reveal that this generalization is linked to decreased alpha oscillation in medial frontal channels. Collectively, these findings provide new insights into how memory-control interactions facilitate goal-directed behavior.
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http://dx.doi.org/10.1523/JNEUROSCI.1869-19.2020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7083282PMC
March 2020

Publisher Correction: Pupil dilation tracks the dynamics of mnemonic interference resolution.

Sci Rep 2020 Jan 10;10(1):317. Epub 2020 Jan 10.

Department of Psychology, Lund University, Lund, Sweden.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.
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http://dx.doi.org/10.1038/s41598-019-55183-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6954207PMC
January 2020

Gaze position regulates memory accessibility during competitive memory retrieval.

Cognition 2020 04 27;197:104169. Epub 2019 Dec 27.

Department of Psychology, Lund University, Sweden. Electronic address:

While previous research has demonstrated that gaze position can increase the accessibility of previous memories when reconstructing the past (Johansson & Johansson, 2014), the present study tested whether such gaze behavior can assist in selecting target memories in the face of competing memories. An adapted retrieval practice paradigm was used, where participants were engaged in selective retrieval while looking at locations that overlapped with the encoding location of either the target item or the competing item. Replicating previous findings, we show that encoding-retrieval compatibility in gaze positions increases the likelihood of successful remembering. We furthermore provide novel evidence that looking at locations where competing items were encoded during retrieval practice induces forgetting of the competitors during subsequent tests of memory. Corroborating evidence from changes in pupil size suggests that such gaze induced forgetting is modulated by the increased demands to successfully resolve interference from competing memories. This study represents the first demonstration that gaze position can both up- and downregulate memory accessibility during competitive memory retrieval and offers novel insights into the underlying dynamics.
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http://dx.doi.org/10.1016/j.cognition.2019.104169DOI Listing
April 2020

Metabolic response patterns in brain microdialysis fluids and serum during interstitial cisplatin treatment of high-grade glioma.

Br J Cancer 2020 01 10;122(2):221-232. Epub 2019 Dec 10.

Department of Chemistry, Umeå University, Umeå, Sweden.

Background: High-grade gliomas are associated with poor prognosis. Tumour heterogeneity and invasiveness create challenges for effective treatment and use of systemically administrated drugs. Furthermore, lack of functional predictive response-assays based on drug efficacy complicates evaluation of early treatment responses.

Methods: We used microdialysis to deliver cisplatin into the tumour and to monitor levels of metabolic compounds present in the tumour and non-malignant brain tissue adjacent to tumour, before and during treatment. In parallel, we collected serum samples and used multivariate statistics to analyse the metabolic effects.

Results: We found distinct metabolic patterns in the extracellular fluids from tumour compared to non-malignant brain tissue, including high concentrations of a wide range of amino acids, amino acid derivatives and reduced levels of monosaccharides and purine nucleosides. We found that locoregional cisplatin delivery had a strong metabolic effect at the tumour site, resulting in substantial release of glutamic acid, phosphate, and spermidine and a reduction of cysteine levels. In addition, patients with long-time survival displayed different treatment response patterns in both tumour and serum. Longer survival was associated with low tumour levels of lactic acid, glyceric acid, ketoses, creatinine and cysteine. Patients with longer survival displayed lower serum levels of ketohexoses, fatty acid methyl esters, glycerol-3-phosphate and alpha-tocopherol, while elevated phosphate levels were seen in both tumour and serum during treatment.

Conclusion: We highlight distinct metabolic patterns associated with high-grade tumour metabolism, and responses to cytotoxic cisplatin treatment.
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http://dx.doi.org/10.1038/s41416-019-0652-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7052137PMC
January 2020

Immune-mediated ECM depletion improves tumour perfusion and payload delivery.

EMBO Mol Med 2019 12 11;11(12):e10923. Epub 2019 Nov 11.

Cancer Research Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, USA.

High extracellular matrix (ECM) content in solid cancers impairs tumour perfusion and thus access of imaging and therapeutic agents. We have devised a new approach to degrade tumour ECM, which improves uptake of circulating compounds. We target the immune-modulating cytokine, tumour necrosis factor alpha (TNFα), to tumours using a newly discovered peptide ligand referred to as CSG. This peptide binds to laminin-nidogen complexes in the ECM of mouse and human carcinomas with little or no peptide detected in normal tissues, and it selectively delivers a recombinant TNFα-CSG fusion protein to tumour ECM in tumour-bearing mice. Intravenously injected TNFα-CSG triggered robust immune cell infiltration in mouse tumours, particularly in the ECM-rich zones. The immune cell influx was accompanied by extensive ECM degradation, reduction in tumour stiffness, dilation of tumour blood vessels, improved perfusion and greater intratumoral uptake of the contrast agents gadoteridol and iron oxide nanoparticles. Suppressed tumour growth and prolonged survival of tumour-bearing mice were observed. These effects were attainable without the usually severe toxic side effects of TNFα.
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http://dx.doi.org/10.15252/emmm.201910923DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6895610PMC
December 2019

Transcriptome-wide association study reveals candidate causal genes for lung cancer.

Int J Cancer 2020 04 9;146(7):1862-1878. Epub 2019 Dec 9.

Epidemiology Division, Princess Margaret Cancer Center, Toronto, ON, Canada.

We have recently completed the largest GWAS on lung cancer including 29,266 cases and 56,450 controls of European descent. The goal of our study has been to integrate the complete GWAS results with a large-scale expression quantitative trait loci (eQTL) mapping study in human lung tissues (n = 1,038) to identify candidate causal genes for lung cancer. We performed transcriptome-wide association study (TWAS) for lung cancer overall, by histology (adenocarcinoma, squamous cell carcinoma and small cell lung cancer) and smoking subgroups (never- and ever-smokers). We performed replication analysis using lung data from the Genotype-Tissue Expression (GTEx) project. DNA damage assays were performed in human lung fibroblasts for selected TWAS genes. As expected, the main TWAS signal for all histological subtypes and ever-smokers was on chromosome 15q25. The gene most strongly associated with lung cancer at this locus using the TWAS approach was IREB2 (p = 1.09E-99), where lower predicted expression increased lung cancer risk. A new lung adenocarcinoma susceptibility locus was revealed on 9p13.3 and associated with higher predicted expression of AQP3 (p = 3.72E-6). Among the 45 previously described lung cancer GWAS loci, we mapped candidate target gene for 17 of them. The association AQP3-adenocarcinoma on 9p13.3 was replicated using GTEx (p = 6.55E-5). Consistent with the effect of risk alleles on gene expression levels, IREB2 knockdown and AQP3 overproduction promote endogenous DNA damage. These findings indicate genes whose expression in lung tissue directly influences lung cancer risk.
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http://dx.doi.org/10.1002/ijc.32771DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7008463PMC
April 2020
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