Personalised medicine-the potential yet realised.

BJOG. 2018 02;125(3):351

Authors: O'Brien JM

PMID: 28771934 [PubMed - indexed for MEDLINE]

[Pharmacogenetics, tobacco, alcohol and its effect on the risk development cancer].

Rev Chil Pediatr. 2018 Aug;89(4):432-440

Authors: Roco Á, Cerda B, Cayún JP, Lavanderos A, Rubilar JC, Cerro R, Acevedo C, Cáceres D, Varela N, Quiñones LA

Abstract
Cancer is the second leading cause of death in the world, causing 8.8 million deaths in 2015 according to the World Health Organization (WHO). Risk factors for cancer include smoking and alcohol con sumption. In Chile, 33.6% of the population and 21.2% of young people smokes. Alcohol consump tion in the Chilean population is 74.5% and 12.2% in young people. Among the physiological factors that influence the development of cancer, the genetic factor plays a relevant role. It has been shown that the presence of genetic polymorphisms that alter the ability of the body to eliminate contami nants increase the risk of developing cancer. The same applies to polymorphisms that prevent DNA repair due to damage caused by environmental pollutants such as cigarette smoke. The objective of this review is to analyze the state of the art of the relationship between pharmacogenetics, smoking, and alcohol consumption as risk factors for the development of cancer. In conclusion, the results suggest that the presence of polymorphisms that alter the function of biotransformation enzymes phase I (CYP1A1, CYP1E1) and phase II (GST), as well as polymorphisms in DNA repair enzymes (ERCC1 / ERCC2), increase the risk of cancer induced by smoking and alcohol consumption. This association is important considering that smoking and drinking alcohol are highly prevalent among the Chilean population.

PMID: 30571815 [PubMed - in process]

Pharmacogenomic Profiling of ADME Gene Variants: Current Challenges and Validation Perspectives.

High Throughput. 2018 Dec 18;7(4):

Authors: Arbitrio M, Martino MTD, Scionti F, Barbieri V, Pensabene L, Tagliaferri P

Abstract
In the past decades, many efforts have been made to individualize medical treatments, taking into account molecular profiles and the individual genetic background. The development of molecularly targeted drugs and immunotherapy have revolutionized medical treatments but the inter-patient variability in the anti-tumor drug pharmacokinetics (PK) and pharmacodynamics can be explained, at least in part, by genetic variations in genes encoding drug metabolizing enzymes and transporters (ADME) or in genes encoding drug receptors. Here, we focus on high-throughput technologies applied for PK screening for the identification of predictive biomarkers of efficacy or toxicity in cancer treatment, whose application in clinical practice could promote personalized treatments tailored on individual's genetic make-up. Pharmacogenomic tools have been implemented and the clinical utility of pharmacogenetic screening could increase safety in patients for the identification of drug metabolism-related biomarkers for a personalized medicine. Although pharmacogenomic studies were performed in adult cohorts, pharmacogenetic pediatric research has yielded promising results. Additionally, we discuss the current challenges and theoretical bases for the implementation of pharmacogenetic tests for translation in the clinical practice taking into account that pharmacogenomics platforms are discovery oriented and must open the way for the setting of robust tests suitable for daily practice.

PMID: 30567415 [PubMed]

Role of miRNAs in treatment response and toxicity of childhood acute lymphoblastic leukemia.

Pharmacogenomics. 2018 03;19(4):361-373

Authors: Umerez M, Garcia-Obregon S, Martin-Guerrero I, Astigarraga I, Gutierrez-Camino A, Garcia-Orad A

Abstract
Childhood acute lymphoblastic leukemia survival rates have increased remarkably during last decades due, in part, to intensive treatment protocols. However, therapy resistance and toxicity are still two important barriers to survival. In this context, pharmacoepigenetics arises as a tool to identify new predictive markers, required to guide clinicians on risk stratification and dose individualization. The present study reviews current evidence about miRNA implication on childhood acute lymphoblastic leukemia therapy resistance and toxicity. A total of 12 studies analyzing differential miRNA expression in relation to drug resistance and six studies exploring the association between miRNAs-related SNPs and drug-induced toxicities were identified. We pointed out to miR-125b together with miR-99a and/or miR-100 overexpression as markers of vincristine resistance and rs2114358 in mir-1206 as mucositis marker as the most promising results.

PMID: 29469670 [PubMed - indexed for MEDLINE]

BCL11A and MDR1 expressions have prognostic impact in patients with acute myeloid leukemia treated with chemotherapy.

Pharmacogenomics. 2018 03;19(4):343-348

Authors: Xutao G, PengCheng S, Yin L, Huijuan D, Yan W, Haiqing Z, Bing X

Abstract
Acute myeloid leukemia (AML) is a heterogeneous malignant disease. Many different genetic factors can affect a patient's clinical outcome.
AIM: The aim of this study was to assess the expression of BCL11A and MDR1 in AML patients, and its relation to clinical outcome.
MATERIALS & METHODS: We grouped the 142 patients by the levels of BCL11A and MDR1 and identified three different subgroups: high BCL11A and high MDR1 (n = 47), low BCL11A and low MDR1 (n = 47) and high BCL11A alone or high MDR1 alone (n = 48).
RESULTS: The results showed that AML patients with high BCL11A and MDR1 expression had the lowest complete remission and highest relapse rate. The median overall survival of the high BCL11A and high MDR1 group was the shortest among the three groups. With regards to overall survival, there were also significant differences among the groups (p < 0.001).
CONCLUSION: High BCL11A and MDR1 expression was associated with a poor response to chemotherapy, and identified a subset of AML patients with a very poor prognosis.

PMID: 29469608 [PubMed - indexed for MEDLINE]

Detection of a rare CYP3A4 variant in a transplant patient characterized by a tacrolimus poor metabolizer phenotype.

Pharmacogenomics. 2018 03;19(4):305-310

Authors: Lloberas N, Hesselink DA, van Schaik RH, Grinyò JM, Colom H, Gelder TV, Elens L

Abstract
A validated CYP3A genotype classification system allows clustering patients into poor, intermediate and extensive metabolizer phenotypes. However, substantial overlap exists between the clusters. A rare CYP3A4 allele, named CYP3A4*20 (rs67666821), has been specifically described in the Spanish population. The authors investigated the relevance of CYP3A4*20 testing to see if the above-mentioned metabolic CYP3A classification system can be improved. In a cohort of 204 kidney transplant recipients, one male patient carrying a CYP3A4*20 allele was detected. This patient was receiving very low doses of tacrolimus to maintain therapeutic levels from day 7 onward when compared with the majority of the patients. These data suggest that this patient should be regarded as a CYP3A-poor metabolizer.

PMID: 29469606 [PubMed - indexed for MEDLINE]

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Acceptability of Electronic Visits for Return of Research Results in the Mayo Clinic Biobank.

Mayo Clin Proc Innov Qual Outcomes. 2018 Dec;2(4):352-358

Authors: Olson JE, Ryu E, Lyke KJ, Bielinski SJ, Winkler EM, Hathcock MA, Bublitz JT, Takahashi PY, Cerhan JR

Abstract
Objective: To understand patient characteristics related to acceptability of returning individual research results via various modalities, focusing on electronic visits (e-visits).
Patients and Methods: Twelve hundred participants from the Mayo Clinic Biobank were selected using a stratified random sampling approach based on sex, age, and education level. Mailed surveys ascertained return of results preferences for 2 disease vignettes (cystic fibrosis and hereditary breast cancer) and a pharmacogenomics vignette. The study was conducted from October 1, 2013, through March 31, 2014.
Results: In all, 685 patients (57%) responded, and 60% reported liking e-visits, although the option of receiving results in an office visit was liked most frequently. Multivariable logistic models showed that the odds of liking the use of e-visits for returning results for cystic fibrosis and hereditary breast cancer were higher among those with higher education and better genetic knowledge and among those not living in proximity to the Mayo Clinic (Rochester, Minnesota). Level of genetic knowledge was not considerably associated with accepting e-visits, whereas education level remained important. For all vignettes, those who are divorced were less likely to accept e-visits.
Conclusion: Researchers are faced with a difficult challenge of returning results with a method that is both acceptable to recipients and logistically feasible. This study implies that the use of e-visits may be a viable option for return of results to stratify the chasm between in-person genetic counseling and online portal receipt of results.

PMID: 30560237 [PubMed]

Gene expression changes in lymphoblastoid cell lines and primary B cells by dexamethasone.

Pharmacogenet Genomics. 2018 Dec 15;:

Authors: Park HW, Dahlin A, Qiu W, Tantisira KG

Abstract
BACKGROUND: Human Epstein-Barr virus-transformed lymphoblastoid cell lines (LCLs) have been thought to be a useful model system for pharmacogenomics studies. The purpose of this study was to determine the effect of Epstein-Barr virus transformation on gene expression changes by dexamethasone (Dex) in LCLs and primary B cells (PBCs) derived from the same individuals.
PATIENTS AND METHODS: We prepared LCLs and purified PBCs from the same six male donors participating in the Childhood Asthma Management Program clinical trial, and compared mRNA profiles after 6 h incubation with Dex (10 mol/l) or sham buffer. We assessed differential expression and put the list of differentially expressed genes into the web interface of ConsensusPathDB to find the pathway-level interpretation of our genes specified. As a supplementary analysis, we looked at the expression of the Dex-regulated (inducing or repressing) genes in treatment-naive PBCs and LCLs (pre-Dex treatment) from the GSE30916 dataset.
RESULTS: By hierarchical clustering, we found clustering of probes by cell types but not by individuals irrespective of Dex treatment. We observed that the Dex-regulated genes significantly overlapped in PBCs and LCLs. In addition, the expression of these genes showed significant correlations between treatment-naive PBCs and LCLs. Common genes showing significantly decreased expressions by the Dex treatment in both cells were enriched in immune responses and proinflammatory signaling pathways.
CONCLUSION: Taken together, these results suggest the uses of LCLs are representative of the primary biologic effects of corticosteroids treatment.

PMID: 30562215 [PubMed - as supplied by publisher]

Pharmacogenomics Education Improves Pharmacy Student Perceptions of Their Abilities and Roles in Its Use.

Am J Pharm Educ. 2018 Nov;82(9):6424

Authors: Marcinak R, Paris M, Kinney SRM

Abstract
Objective. To assess whether a required first-year course, Principles in Genetics and Pharmacogenomics, and integration into subsequent courses affected pharmacy students' perceptions of pharmacogenomics. Methods. A survey was distributed to Professional Year (PY) 1 students during the first and last weeks of the course from 2014 to 2016. A follow-up survey was distributed to PY2, PY3, and PY4 students. Results. Respondents consistently agreed that pharmacogenomics is clinically relevant. After the course, PY1 students are more comfortable in their knowledge and role in the application of pharmacogenomics. Although their comfort reverts to some degree, PY2-PY4 students believe that they should be able to apply pharmacogenomics clinically. Most PY2-PY4 students indicate that later courses review pharmacogenomics. Conclusion. A required course in genetics and pharmacogenomics can promote a perception that pharmacists should have knowledge of, and be involved in the use of genetic information clinically. Inclusion of pharmacogenomic concepts in subsequent curricular components may help in maintaining these perceptions.

PMID: 30559496 [PubMed - in process]

Aloe Genus Plants: From Farm to Food Applications and Phytopharmacotherapy.

Int J Mol Sci. 2018 Sep 19;19(9):

Authors: Salehi B, Albayrak S, Antolak H, Kręgiel D, Pawlikowska E, Sharifi-Rad M, Uprety Y, Tsouh Fokou PV, Yousef Z, Amiruddin Zakaria Z, Varoni EM, Sharopov F, Martins N, Iriti M, Sharifi-Rad J

Abstract
Aloe genus plants, distributed in Old World, are widely known and have been used for centuries as topical and oral therapeutic agents due to their health, beauty, medicinal, and skin care properties. Among the well-investigated Aloe species are A. arborescens, A. barbadensis, A. ferox, and A. vera. Today, they account among the most economically important medicinal plants and are commonly used in primary health treatment, where they play a pivotal role in the treatment of various types of diseases via the modulation of biochemical and molecular pathways, besides being a rich source of valuable phytochemicals. In the present review, we summarized the recent advances in botany, phytochemical composition, ethnobotanical uses, food preservation, and the preclinical and clinical efficacy of Aloe plants. These data will be helpful to provide future directions for the industrial and medicinal use of Aloe plants.

PMID: 30235891 [PubMed - indexed for MEDLINE]

Organic Anion Transporting Polypeptide 2B1 - More than a Glass-Full of Drug Interactions.

Pharmacol Ther. 2018 Dec 14;:

Authors: McFeely SJ, Wu L, Ritchie TK, Unadkat J

Abstract
The importance of uptake transporters in determining drug disposition is increasingly appreciated. While the focus of regulatory agencies worldwide has been on the hepatic organic anion transporting polypeptides (OATPs) 1B1 and 1B3, there is another isoform of the OATP sub-family, OATP2B1, which should be considered equally relevant. Unlike the other members of the OATP sub-family, OATP2B1 is expressed in multiple organs in humans, including in the intestine and the liver. Similar to other OATPs, OATP2B1 mediates the hepatic and intestinal uptake of many drugs and endogenous compounds. The importance of OATP2B1 in the disposition of many drugs is highlighted by the growing recognition of its role in significant in vivo drug-drug or food-drug interactions. The dramatic changes in drug exposure attributable to inhibition of OATP2B1 highlight the importance of developing a better understanding of the clinical role of OATP2B1. This review aims to provide a thorough summary of the current understanding of the pharmacogenetics, regulation, expression and abundance of OATP2B1 in humans, as well as its clinical relevance in drug-drug and food-drug interactions.

PMID: 30557631 [PubMed - as supplied by publisher]

Pharmacogenetics and Psychiatric Care: A Review and Commentary.

J Ment Health Clin Psychol. 2018;2(2):17-24

Authors: Butler MG

PMID: 30556062 [PubMed]

Pharmacogenetics and Practice: Tailoring Prescribing for Safety and Effectiveness.

J Nurse Pract. 2018 Nov-Dec;14(10):697-704.e1

Authors: Fulton CR, Swart M, De Luca T, Liu SN, Collins KS, Desta Z, Gufford BT, Eadon MT

PMID: 30555285 [PubMed]

Disubstituted 4-Chloro-3-nitrophenylthiourea Derivatives: Antimicrobial and Cytotoxic Studies.

Molecules. 2018 Sep 21;23(10):

Authors: Bielenica A, Sanna G, Madeddu S, Giliberti G, Stefańska J, Kozioł AE, Savchenko O, Strzyga-Łach P, Chrzanowska A, Kubiak-Tomaszewska G, Struga M

Abstract
4-Chloro-3-nitrophenylthioureas 1⁻30 were synthesized and tested for their antimicrobial and cytotoxic activities. Compounds exhibited high to moderate antistaphylococcal activity against both standard and clinical strains (MIC values 2⁻64 μg/mL). Among them derivatives with electron-donating alkyl substituents at the phenyl ring were the most promising. Moreover, compounds 1⁻6 and 8⁻19 were cytotoxic against MT-4 cells and various other cell lines derived from human hematological tumors (CC50 ≤ 10 μM). The influence of derivatives 11, 13 and 25 on viability, mortality and the growth rate of immortalized human keratinocytes (HaCaT) was observed.

PMID: 30248936 [PubMed - indexed for MEDLINE]

Identification of susceptibility pathways for the role of chromosome 15q25.1 in modifying lung cancer risk.

Nat Commun. 2018 08 13;9(1):3221

Authors: Ji X, Bossé Y, Landi MT, Gui J, Xiao X, Qian D, Joubert P, Lamontagne M, Li Y, Gorlov I, de Biasi M, Han Y, Gorlova O, Hung RJ, Wu X, McKay J, Zong X, Carreras-Torres R, Christiani DC, Caporaso N, Johansson M, Liu G, Bojesen SE, Le Marchand L, Albanes D, Bickeböller H, Aldrich MC, Bush WS, Tardon A, Rennert G, Chen C, Teare MD, Field JK, Kiemeney LA, Lazarus P, Haugen A, Lam S, Schabath MB, Andrew AS, Shen H, Hong YC, Yuan JM, Bertazzi PA, Pesatori AC, Ye Y, Diao N, Su L, Zhang R, Brhane Y, Leighl N, Johansen JS, Mellemgaard A, Saliba W, Haiman C, Wilkens L, Fernandez-Somoano A, Fernandez-Tardon G, van der Heijden EHFM, Kim JH, Dai J, Hu Z, Davies MPA, Marcus MW, Brunnström H, Manjer J, Melander O, Muller DC, Overvad K, Trichopoulou A, Tumino R, Doherty J, Goodman GE, Cox A, Taylor F, Woll P, Brüske I, Manz J, Muley T, Risch A, Rosenberger A, Grankvist K, Johansson M, Shepherd F, Tsao MS, Arnold SM, Haura EB, Bolca C, Holcatova I, Janout V, Kontic M, Lissowska J, Mukeria A, Ognjanovic S, Orlowski TM, Scelo G, Swiatkowska B, Zaridze D, Bakke P, Skaug V, Zienolddiny S, Duell EJ, Butler LM, Koh WP, Gao YT, Houlston R, McLaughlin J, Stevens V, Nickle DC, Obeidat M, Timens W, Zhu B, Song L, Artigas MS, Tobin MD, Wain LV, Gu F, Byun J, Kamal A, Zhu D, Tyndale RF, Wei WQ, Chanock S, Brennan P, Amos CI

Abstract
Genome-wide association studies (GWAS) identified the chromosome 15q25.1 locus as a leading susceptibility region for lung cancer. However, the pathogenic pathways, through which susceptibility SNPs within chromosome 15q25.1 affects lung cancer risk, have not been explored. We analyzed three cohorts with GWAS data consisting 42,901 individuals and lung expression quantitative trait loci (eQTL) data on 409 individuals to identify and validate the underlying pathways and to investigate the combined effect of genes from the identified susceptibility pathways. The KEGG neuroactive ligand receptor interaction pathway, two Reactome pathways, and 22 Gene Ontology terms were identified and replicated to be significantly associated with lung cancer risk, with P values less than 0.05 and FDR less than 0.1. Functional annotation of eQTL analysis results showed that the neuroactive ligand receptor interaction pathway and gated channel activity were involved in lung cancer risk. These pathways provide important insights for the etiology of lung cancer.

PMID: 30104567 [PubMed - indexed for MEDLINE]

Effect of ABCB1 C3435T Polymorphism on Pharmacokinetics of Antipsychotics and Antidepressants.

Basic Clin Pharmacol Toxicol. 2018 Oct;123(4):474-485

Authors: Saiz-Rodríguez M, Belmonte C, Román M, Ochoa D, Jiang-Zheng C, Koller D, Mejía G, Zubiaur P, Wojnicz A, Abad-Santos F

Abstract
P-glycoprotein, encoded by ABCB1, is an ATP-dependent drug efflux pump which exports substances outside the cell. Some studies described connections between C3435T polymorphism T allele and lower P-glycoprotein expression; therefore, homozygous T/T could show higher plasma levels. Our aim was to evaluate the effect of C3435T on pharmacokinetics of 4 antipsychotics (olanzapine, quetiapine, risperidone and aripiprazole) and 4 antidepressants (trazodone, sertraline, agomelatine and citalopram). The study included 473 healthy volunteers receiving a single oral dose of one of these drugs, genotyped by real-time PCR. Multivariate analysis was performed to adjust the effect of sex and genotype of the main cytochrome P450 enzymes. C3435T polymorphism had an effect on olanzapine pharmacokinetics, as T/T individuals showed lower clearance and volume of distribution. T/T individuals showed lower T1/2 of 9-OH-risperidone, but this difference disappeared after multivariate correction. T/T homozygous individuals showed lower dehydro-aripiprazole and trazodone area under the concentration-time curve, along with lower half-life and higher clearance of trazodone. C/T genotype was associated to higher citalopram maximum concentration. C3435T had no effect on quetiapine, sertraline or agomelatine pharmacokinetics. C3435T can affect the elimination of some drugs in different ways. Regarding risperidone, trazodone and dehydro-aripiprazole, we observed enhanced elimination while it was reduced in olanzapine and citalopram. However, in quetiapine, aripiprazole, sertraline and agomelatine, no changes were detected. These results suggest that P-glycoprotein polymorphisms could affect CNS drugs disposition, but the genetic factor that alters its activity is still unknown. This fact leads to consider the analysis of ABCB1 haplotypes instead of individual variants.

PMID: 29723928 [PubMed - indexed for MEDLINE]

The association between BDNF Val66Met polymorphism and emotional symptoms after mild traumatic brain injury.

BMC Med Genet. 2018 01 22;19(1):13

Authors: Wang YJ, Chen KY, Kuo LN, Wang WC, Hsu YW, Wong HS, Lin CM, Liao KH, Zhang YF, Chiang YH, Chang WC

Abstract
BACKGROUND: Brain-derived neurotrophic factor (BDNF) is one of the most abundant neurotrophins in the adult brain, and it plays important roles in modulating synaptic plasticity and synaptogenesis. This study attempted to elucidate the role of the BDNF variant rs6265 in emotional symptoms following mild traumatic brain injury (mTBI).
METHODS: To investigate the association between BDNF Val66Met polymorphism (rs6265) and emotional symptoms in mTBI patients, we recruited 192 mTBI patients and evaluated their Beck Anxiety Inventory (BAI) and Beck Depression Inventory (BDI) scores in the first and sixth week after mTBI.
RESULTS: The patients carrying the T allele of rs6265 had significantly higher BAI scores in the first week following mTBI. In addition, the patients carrying the T allele also showed higher scores of BDI in the first week. In the gender-specific subgroup analysis, the male patients carrying the T allele of rs6265 had higher scores of both BAI and BDI in the first and sixth week. Meanwhile, female patients carrying the T allele also had significantly higher scores of BDI in the first week following mTBI.
CONCLUSIONS: This study provides evidence for the association between the BDNF variant rs6265 and emotional symptoms following mTBI.

PMID: 29357818 [PubMed - indexed for MEDLINE]

GDSCTools for mining pharmacogenomic interactions in cancer.

Bioinformatics. 2018 04 01;34(7):1226-1228

Authors: Cokelaer T, Chen E, Iorio F, Menden MP, Lightfoot H, Saez-Rodriguez J, Garnett MJ

Abstract
Motivation: Large pharmacogenomic screenings integrate heterogeneous cancer genomic datasets as well as anti-cancer drug responses on thousand human cancer cell lines. Mining this data to identify new therapies for cancer sub-populations would benefit from common data structures, modular computational biology tools and user-friendly interfaces.
Results: We have developed GDSCTools: a software aimed at the identification of clinically relevant genomic markers of drug response. The Genomics of Drug Sensitivity in Cancer (GDSC) database (www.cancerRxgene.org) integrates heterogeneous cancer genomic datasets as well as anti-cancer drug responses on a thousand cancer cell lines. Including statistical tools (analysis of variance) and predictive methods (Elastic Net), as well as common data structures, GDSCTools allows users to reproduce published results from GDSC and to implement new analytical methods. In addition, non-GDSC data resources can also be analysed since drug responses and genomic features can be encoded as CSV files.
Contact: thomas.cokelaer@pasteur.fr or saezrodriguez.rwth-aachen.de or mg12@sanger.ac.uk.
Supplementary information: Supplementary data are available at Bioinformatics online.

PMID: 29186349 [PubMed - indexed for MEDLINE]

CellMinerCDB for Integrative Cross-Database Genomics and Pharmacogenomics Analyses of Cancer Cell Lines.

iScience. 2018 Nov 30;:

Authors: Rajapakse VN, Luna A, Yamade M, Loman L, Varma S, Sunshine M, Iorio F, Sousa FG, Elloumi F, Aladjem MI, Thomas A, Sander C, Kohn KW, Benes CH, Garnett M, Reinhold WC, Pommier Y

Abstract
CellMinerCDB provides a web-based resource (https://discover.nci.nih.gov/cellminercdb/) for integrating multiple forms of pharmacological and genomic analyses, and unifying the richest cancer cell line datasets (the NCI-60, NCI-SCLC, Sanger/MGH GDSC, and Broad CCLE/CTRP). CellMinerCDB enables data queries for genomics and gene regulatory network analyses, and exploration of pharmacogenomic determinants and drug signatures. It leverages overlaps of cell lines and drugs across databases to examine reproducibility and expand pathway analyses. We illustrate the value of CellMinerCDB for elucidating gene expression determinants, such as DNA methylation and copy number variations, and highlight complexities in assessing mutational burden. We demonstrate the value of CellMinerCDB in selecting drugs with reproducible activity, expand on the dominant role of SLFN11 for drug response, and present novel response determinants and genomic signatures for topoisomerase inhibitors and schweinfurthins. We also introduce LIX1L as a gene associated with mesenchymal signature and regulation of cellular migration and invasiveness.

PMID: 30553813 [PubMed - as supplied by publisher]