Genetic variation and cognitive dysfunction in opioid-treated patients with cancer

Background and purpose The effects of single‐nucleotide polymorphisms (SNP s) on the cognitive function of opioid‐treated patients with cancer until now have not been explored, but they could potentially be related to poor functioning. This study aimed at identifying associations between SNP s of candidate genes, high opioid dose, and cognitive dysfunction. Methods Cross‐sectional multicenter study (European Pharmacogenetic Opioid Study, 2005–2008); 1586 patients; 113 SNP s from 41 genes. Inclusion criteria: cancer, age ≥18 year, opioid treatment, and available genetic data. Cognitive assessment by Mini‐Mental State Examination (MMSE ). Analyses: SNP s were rejected if violation of Hardy–Weinberg equilibrium (P < 0.0005), or minor allele frequency <5%; patients were randomly divided into discovery sample (2/3 for screening) and validation sample (1/3 for confirmatory test); false discovery rate of 10% for determining associations (Benjamini–Hochberg method). Co‐dominant, dominant, and recessive models were analyzed by Kruskal–Wallis and Mann–Whitney tests. Results In the co‐dominant model significant associations (P < 0.05) between MMSE scores and SNP s in the HTR 3E , TACR 1 , and IL 6 were observed in the discovery sample, but the replication in the validation sample did not confirm it. Associations between MMSE scores among patients receiving ≥400 mg morphine equivalent dose/day and SNP s in TNFRSF 1B , TLR 5 , HTR 2A , and ADRA 2A were observed, but they could not be confirmed in the validation sample. After correction for multiple testing, no SNP s were significant in the discovery sample. Dominant and recessive models also did not confirm significant associations. Conclusions The findings did not support influence of those SNP s analyzed to explain cognitive dysfunction in opioid‐treated patients with cancer

The N-Terminally Truncated µ3 and µ3-Like Opioid Receptors Are Transcribed from a Novel Promoter Upstream of Exon 2 in the Human OPRM1 Gene

The human µ opioid receptor gene, OPRM1, produces a multitude of alternatively spliced transcripts encoding full-length or truncated receptor variants with distinct pharmacological properties. The majority of these transcripts are transcribed from the main promoter upstream of exon 1, or from alternate promoters associated with exons 11 and 13. Two distinct transcripts encoding six transmembrane domain (6TM) hMOR receptors, µ3 and µ3-like, have been reported, both starting with the first nucleotide in exon 2. However, no mechanism explaining their initiation at exon 2 has been presented. Here we have used RT-PCR with RNA from human brain tissues to demonstrate that the µ3 and µ3-like transcripts contain nucleotide sequences from the intron 1-exon 2 boundary and are transcribed from a novel promoter located upstream of exon 2. Reporter gene assays confirmed the ability of the novel promoter to drive transcription in human cells, albeit at low levels. We also report the identification of a “full-length” seven transmembrane domain (7TM) version of µ3, hMOR-1A2, which also contains exon 1, and a novel transcript, hMOR-1Y2, with the potential to encode the previously reported hMOR-1Y receptor, but with exon Y spliced to exon 4 instead of exon 5 as in hMOR-1Y. Heterologous expression of GFP-tagged hMOR variants in HEK 293 cells showed that both 6TM receptors were retained in the intracellular compartment and were unresponsive to exogenous opioid exposure as assessed by their ability to redistribute or affect cellular cAMP production, or to promote intracellular Ca2+ release. Co-staining with an antibody specific for endoplasmic reticulum (ER) indicated that the µ3-like receptor was retained at the ER after synthesis. 7TM receptors hMOR-1A2 and hMOR-1Y2 resided in the plasma membrane, and were responsive to opioids. Notably, hMOR-1A2 exhibits novel functional properties in that it did not internalize in response to the opioid peptide [D-Ala2, N-Me-Phe4, Gly-ol5]enkephalin (DAMGO).© 2013 Andersen et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited

Health care providers underestimate symptom intensities of cancer patients: A multicenter European study

<p>Abstract</p> <p>Background</p> <p>Many patients with advanced cancer depend upon health care providers for symptom assessment. The extent of agreement between patient and provider symptom assessments and the association of agreement with demographic- and disease-related factors was examined.</p> <p>Methods</p> <p>This cross-sectional study included 1933 patient-health care provider dyads, from 11 European countries. Patients reported symptoms by using the four-point scales of the European Organization of Research and Treatment of Cancer Core Quality of Life Questionnaire (EORTC QLQ-C30) version 3, and providers used corresponding four-point categorical scales. Level of agreement was addressed at the group level (Wilcoxon Signed-Rank test), by difference scores (provider score minus patient score), at the individual level (Intraclass Correlation Coefficients, ICCs) and visually by Bland-Altman plots. Absolute numbers and chi-square tests were used to investigate the relationship between agreement and demographic-, as well as disease-related factors.</p> <p>Results</p> <p>The prevalence of symptoms assessed as moderate or severe by patients and providers, respectively, were for pain (67 vs.47%), fatigue (71 vs. 54%), generalized weakness (65 vs. 47%), anorexia (47 vs. 25%), depression (31 vs. 17%), constipation (45 vs. 30%), poor sleep (32 vs. 21%), dyspnea (30 vs. 16%), nausea (27 vs. 14%), vomiting (14 vs. 6%) and diarrhea (14 vs. 6%). Symptom scores were identical or differed by only one response category in the majority of patient-provider assessment pairs (79-93%). Providers underestimated the symptom in approximately one of ten patients and overestimated in 1% of patients. Agreement at the individual level was moderate (ICC 0.38 to 0.59). Patients with low Karnofsky Performance Status, high Mini Mental State-score, hospitalized, recently diagnosed or undergoing opioid titration were at increased risk of symptom underestimation by providers (all p < 0.001). Also, the agreement was significantly associated with drug abuse (p = 0.024), provider profession (p < 0.001), cancer diagnosis (p < 0.001) and country (p < 0.001).</p> <p>Conclusions</p> <p>Considerable numbers of health care providers underestimated symptom intensities. Clinicians in cancer care should be aware of the factors characterizing patients at risk of symptom underestimation.</p

Genetic variation in the Catechol-O-Methyltransferase (COMT) gene and morphine requirements in cancer patients with pain

<p>Abstract</p> <p>Background</p> <p>Genetic variation contributes to differences in pain sensitivity and response to different analgesics. Catecholamines are involved in the modulation of pain and are partly metabolized by the catechol-O-methyltransferase (COMT) enzyme. Genetic variability in the <it>COMT </it>gene may therefore contribute to differences in pain sensitivity and response to analgesics. It is shown that a polymorphism in the <it>COMT </it>gene, Rs4680 (Val158Met), influence pain sensitivity in human experimental pain and the efficacy for morphine in cancer pain treatment. In this study we wanted to investigate if variability in other regions in the <it>COMT </it>gene also contributes to interindividual variability in morphine efficacy.</p> <p>Results</p> <p>We genotyped 11 single nucleotide polymorphisms (SNPs) throughout the <it>COMT </it>gene, and constructed haplotypes from these 11 SNPs, which were in Hardy-Weinberg equilibrium. We compared both genotypes and haplotypes against pharmacological, demographical and patient symptoms measurements in a Caucasian cancer patient cohort (n = 197) receiving oral morphine treatment for cancer pain. There were two frequent haplotypes (34.5% and 17.8%) in our cohort. Multivariate analyses showed that patients carrying the most frequent haplotype (34.5%) needed lower morphine doses than patients not carrying the haplotype, with a reduction factor of 0.71 (p = 0.005). On the allele level, carriers of alleles for six of the SNPs show weak associations in respect to morphine dose and the alleles associated with the lowest morphine doses constitute part of the most frequent haplotype.</p> <p>Conclusion</p> <p>This study suggests that genetic variability in the <it>COMT </it>gene influence the efficacy of morphine in cancer patients with pain, and that increased understanding of this variability is reached by expanding from analyses of single SNPs to haplotype construction and analyses.</p

Genetic and Non-genetic Factors Associated With Constipation in Cancer Patients Receiving Opioids

Acknowledgments. We are grateful to all the researchers involved in The European Pharmacogenetic Opioid Study (EPOS) and to Gunnhild Jakobsen who organized the collection of data.Peer reviewedPublisher PD

Penerapan Pembelajaran Kooperatif Tipe Jigsaw Dalam Meningkatkan Motivasi Dan Hasil Belajar IPA Pada Siswa Kelas VII Semester II SMP Negeri 2 Pulokulon

Permasalahan pokok yang akan dipecahkan lewat Penelitian Tindakan Kelas ini adalah: apakah penerapan model pembelajaran kooperatif tipe jigsaw dapat meningkatkan hasil belajar IPA. Tujuannya untuk meningkatkan motivasi dan hasil belajar siswa dalam mata pelajaran IPA..Penelitian ini merupakan tindakan guru untuk memperbaiki hasil belajar siswa kelas VII SMP Negeri 2 Pulokulon Semester 2 Tahun Pelajaran 2013/2004, dan pelakunya adalah guru IPA. Penelitian dilakukan dalam 2 siklus dan meliputi 4 tahapan, yaitu perencanaan, tindakan,pengamatan dan refleksi.Hasil penelitian menunjukkan bahwa dari keseluruhan siklus yang telah dilakukan motivasi dan perolehan nilai siswa kelas VII SMP Negeri 2 Pulokulon Semester 2 Tahun Pelajaran 2013/2004 mengalami peningkatan dari satu siklus ke siklus berikutnya. Jadi secara keseluruhan siklus yang telah dilakukan, penerapan model pembelajaran kooperatif tipe jigsaw dapat meningkatkan motivasi dan hasil belajar siswa dalam mata pelajaran IPA

No association between chronic musculoskeletal complaints and Val158Met polymorphism in the Catechol-O-methyltransferase gene. The HUNT study

BACKGROUND: The Catechol-O-methyltransferase (COMT) gene contains a functional polymorphism, Val158Met, that has been found to influence human pain perception. In one study fibromyalgia was less likely among those with Val/Val genotype. METHODS: In the 1995–97 Nord-Trøndelag Health Study (HUNT), the association between Val/Met polymorphism at the COMT gene and chronic musculoskeletal complaints (MSCs) was evaluated in a random sample of 3017 individuals. RESULTS: The distribution of the COMT Val158Met genotypes and alleles were similar between controls and the twelve different chronic MSCs groups. Even when the Met/Met and Val/Met genotypes were pooled, the distribution of the Val/Val genotype and other genotypes were similar between controls and the chronic MSCs groups. CONCLUSION: In this population-based study, no significant association was found between Val/Met polymorphism at the COMT gene and chronic MSCs

Assessing the role of genome-wide DNA methylation between smoking and risk of lung cancer using repeated measurements: the HUNT Study

Background - It is unclear if smoking-related DNA methylation represents a causal pathway between smoking and risk of lung cancer. We sought to identify novel smoking-related DNA methylation sites in blood, with repeated measurements, and to appraise the putative role of DNA methylation in the pathway between smoking and lung cancer development. Methods - We derived a nested case-control study from the Trøndelag Health Study (HUNT), including 140 incident patients who developed lung cancer during 2009–13 and 140 controls. We profiled 850 K DNA methylation sites (Illumina Infinium EPIC array) in DNA extracted from blood that was collected in HUNT2 (1995–97) and HUNT3 (2006–08) for the same individuals. Epigenome-wide association studies (EWAS) were performed for a detailed smoking phenotype and for lung cancer. Two-step Mendelian randomization (MR) analyses were performed to assess the potential causal effect of smoking on DNA methylation as well as of DNA methylation (13 sites as putative mediators) on risk of lung cancer. Results - The EWAS for smoking in HUNT2 identified associations at 76 DNA methylation sites (P –8), including 16 novel sites. Smoking was associated with DNA hypomethylation in a dose-response relationship among 83% of the 76 sites, which was confirmed by analyses using repeated measurements from blood that was collected at 11 years apart for the same individuals. Two-step MR analyses showed evidence for a causal effect of smoking on DNA methylation but no evidence for a causal link between DNA methylation and the risk of lung cancer. Conclusions - DNA methylation modifications in blood did not seem to represent a causal pathway linking smoking and the lung cancer risk

Depression and anxiety in relation to catechol-O-methyltransferase Val158Met genotype in the general population: The Nord-Trøndelag Health Study (HUNT)

<p>Abstract</p> <p>Background</p> <p>The catechol-O-methyltransferase (COMT) gene contains a functional polymorphism, Val158Met, which has been linked to anxiety and depression, but previous results are not conclusive. The aim of the present study was to examine the relationship between the Val158Met COMT gene polymorphism and anxiety and depression measured by the Hospital Anxiety and Depression Scale (HADS) in the general adult population.</p> <p>Methods</p> <p>In the Nord-Trøndelag Health Study (HUNT) the association between the Val158Met polymorphism and anxiety and depression was evaluated in a random sample of 5531 individuals. Two different cut off scores (≥ 8 and ≥ 11) were used to identify cases with anxiety (HADS-A) and depression (HADS-D), whereas controls had HADS-A <8 and HADS-D <8.</p> <p>Results</p> <p>The COMT genotype distribution was similar between controls and individuals in the groups with anxiety and depression using cut-off scores of ≥ 8. When utilizing the alternative cut-off score HADS-D ≥ 11, Met/Met genotype and Met allele were less common among men with depression compared to the controls (genotype: p = 0.017, allele: p = 0.006). In the multivariate analysis, adjusting for age and heart disease, depression (HADS-D ≥ 11) was less likely among men with the Met/Met genotype than among men with the Val/Val genotype (OR = 0.37, 95% CI = 0.18–0.76).</p> <p>Conclusion</p> <p>In this population-based study, no clear association between the Val158Met polymorphism and depression and anxiety was revealed. The Met/Met genotype was less likely among men with depression defined as HADS-D ≥ 11, but this may be an incidental finding.</p