Phenylethanolamine N-methyltransferase gene polymorphisms associate with crisis pain in sickle cell disease patients.

Pharmacogenomics. 2020 Mar 12;:

Authors: Sadhu N, Jhun EH, Posen A, Yao Y, He Y, Molokie RE, Wilkie DJ, Wang ZJ

Abstract
Aim: Phenylethanolamine N-methyltransferase (PNMT) catalyzes the conversion of sympathetic neurotransmitter norepinephrine to epinephrine. We examined the association of PNMT polymorphisms with acute and chronic pain in sickle cell disease (SCD). Methods: Utilization of emergency care owing to painful crisis was used as a marker for acute pain in 131 patients with SCD. Results: rs876493 A allele, rs2934965 T allele and rs2941523 G allele were significantly associated with decreased utilization (p ≤ 0.05). rs876493 A allele showed association with utilization in females (p = 0.003), not males (p = 0.803). rs2934965 T allele and rs2941523 G allele were predicted to cause loss of putative transcription factor binding sites. This is the first report of the association of PNMT polymorphisms with acute crisis pain in SCD. Together with our previous findings in catechol-o-methyltransferase, polymorphisms in catecholamine metabolizing enzymes appear to primarily influence acute pain in SCD.

PMID: 32162598 [PubMed - as supplied by publisher]

Reverse Vaccinology and Its Applications.

Methods Mol Biol. 2020;2131:1-16

Authors: Kanampalliwar AM

Abstract
The application of the fields of pharmacogenomics and pharmacogenetics to vaccine design, profoundly combined with bioinformatics, has been recently termed "vaccinomics." The enormous amount of information generated by whole genome sequencing projects and the rise of bioinformatics has triggered the birth of a new era of vaccine research and development, leading to a "third generation" of vaccines, which are based on the application of vaccinomics science to vaccinology. The first example of such an approach is reverse vaccinology. Reverse vaccinology reduces the period of vaccine target detection and evaluation to 1-2 years. This approach targets the genomic sequence and predicts those antigens that are most likely to be vaccine candidates. This approach allows not only the identification of all the antigens obtained by the previous methods but also the discovery of new antigens that work on a totally different paradigm. Hence this method helps in the discovery of novel mechanisms of immune intervention. Epitope-based immune-derived vaccines (IDV) are generally considered to be safe when compared to other vectored or attenuated live vaccines. Epitope-based IDV may also provide essential T-cell help for antibody-directed vaccines. Such vaccines may have a significant advantage over earlier vaccine design approaches, as the cautious assortment of the components may diminish.

PMID: 32162247 [PubMed - in process]

Covalent Modification and Regulation of the Nuclear Receptor Nurr1 by a Dopamine Metabolite.

Cell Chem Biol. 2019 05 16;26(5):674-685.e6

Authors: Bruning JM, Wang Y, Oltrabella F, Tian B, Kholodar SA, Liu H, Bhattacharya P, Guo S, Holton JM, Fletterick RJ, Jacobson MP, England PM

Abstract
Nurr1, a nuclear receptor essential for the development, maintenance, and survival of midbrain dopaminergic neurons, is a potential therapeutic target for Parkinson's disease, a neurological disorder characterized by the degeneration of these same neurons. Efforts to identify Nurr1 agonists have been hampered by the recognition that it lacks several classic regulatory elements of nuclear receptor function, including the canonical ligand-binding pocket. Here we report that the dopamine metabolite 5,6-dihydroxyindole (DHI) binds directly to and modulates the activity of Nurr1. Using biophysical assays and X-ray crystallography, we show that DHI binds to the ligand-binding domain within a non-canonical pocket, forming a covalent adduct with Cys566. In cultured cells and zebrafish, DHI stimulates Nurr1 activity, including the transcription of target genes underlying dopamine homeostasis. These findings suggest avenues for developing synthetic Nurr1 ligands to ameliorate the symptoms and progression of Parkinson's disease.

PMID: 30853418 [PubMed - indexed for MEDLINE]

Mid-life predictors of late-life depressive symptoms; determining risk factors spanning two decades in the Women's Heathy Ageing Project.

Womens Midlife Health. 2020;6:2

Authors: Campbell KE, Gorelik A, Szoeke CE, Dennerstein L

Abstract
Background: Data available from longitudinal studies of adequate duration to explore midlife risk factors for late life higher depressive symptom scores in women is lacking. This study examines midlife (mean ages 50 years and 60 years) predictors of late life (mean age 70 years) depressive symptom scores to enrich our understanding of the role of changing risk factors across the lifespan.
Methods: This investigation was an assessment of the long-term impact of lifestyle and health variables on depressive symptoms. Data were drawn from an epidemiological prospective study of women's healthy ageing spanning two decades. Variables included assessment of mood, demographics, physical health, smoking status, attitudes towards ageing and menopause, alcohol consumption and employment. Analysis was conducted to determine the set of strongest predictors assessed in 1992 (mean age 50 years) and in 2002 (mean age 60 years) in relation to higher CESD-SF scores measured in 2012 (mean aged 70 years (n = 249)). A cross-sectional analysis determining concurrent associations at mean age 70 years was also conducted.
Results: An increase in positive mood at 50 and 60 years was associated with a 0.3 (95% CI 0.1-0.5) and 0.4 (95%CI 0.1-0.8) point reduction in CESD score at 70 years respectively. An increase in Hassles score at age 50 was associated with a 0.18-point increase in CESD (95% CI 0.01-0.05) 20 years later. However, no relationship was observed between Hassles score at 60 and CESD 10 years later. Analysis of concurrent risk factors demonstrated that bothersome symptom frequency and higher anxiety were associated with higher depressive symptom scores when women were 70 years.
Conclusion: Low levels of positive mood were consistently associated with depressive symptoms scores 10 and 20 years later, suggesting clinical interventions aimed at improving positive affect may be particularly useful across the midlife.

PMID: 32158547 [PubMed]

Read-through transcripts in lung: germline genetic regulation and correlation with the expression of other genes.

Carcinogenesis. 2020 Mar 11;:

Authors: Maspero D, Dassano A, Pintarelli G, Noci S, De Cecco L, Incarbone M, Tosi D, Santambrogio L, Dragani TA, Colombo F

Abstract
Transcripts originating from the transcriptional read through of two adjacent, similarly oriented genes have been identified in normal and neoplastic tissues, but their functional role and the mechanisms that regulate their expression are mostly unknown. Here we investigated whether the expression of read-through transcripts previously identified in the non-involved lung tissue of lung adenocarcinoma patients was genetically regulated. Data on genome-wide SNV genotypes and expression levels of 10 read-through transcripts in 201 samples of lung tissue were combined to identify expression quantitative trait loci (eQTLs). Then, to identify genes whose expression levels correlated with the 10 read-through transcripts, we used whole transcriptome profiles available for 154 patients. For eight read-though transcripts, we identified 60 eQTLs (FDR<0.05), including 17 cis-eQTLs and 43 trans-eQTLs. These eQTLs did not maintain their behavior on the "parental" genes involved in the read-through transcriptional event. The expression levels of seven read-through transcripts were found to correlate with the expression of other genes: CHIA-PIFO and CTSC-RAB38 correlated with CHIA and RAB38, respectively, while five other read-through transcripts correlated with 43 unique non-parental transcripts; thus offering indications about the molecular processes in which these chimeric transcripts may be involved. We confirmed nine eQTLs (for four transcripts) in the non-involved lung tissue from an independent series of 188 lung adenocarcinoma patients. Therefore, this study indicates that the expression of four read-through transcripts in normal lung tissue is under germline genetic regulation, and that this regulation is independent of that of the genes involved in the read-through event.

PMID: 32157280 [PubMed - as supplied by publisher]

ABCA1/ABCB1 Ratio Determines Chemo- and Immune-Sensitivity in Human Osteosarcoma.

Cells. 2020 Mar 06;9(3):

Authors: Belisario DC, Akman M, Godel M, Campani V, Patrizio MP, Scotti L, Hattinger CM, De Rosa G, Donadelli M, Serra M, Kopecka J, Riganti C

Abstract
The ATP Binding Cassette transporter B1 (ABCB1) induces chemoresistance in osteosarcoma, because it effluxes doxorubicin, reducing the intracellular accumulation, toxicity, and immunogenic cell death induced by the drug. The ATP Binding Cassette transporter A1 (ABCA1) effluxes isopentenyl pyrophosphate (IPP), a strong activator of anti-tumor Vγ9Vδ2 T-cells. Recruiting this population may represent an alternative strategy to rescue doxorubicin efficacy in ABCB1-expressing osteosarcoma. In this work, we analyzed how ABCA1 and ABCB1 are regulated in osteosarcoma, and if increasing the ABCA1-dependent activation of Vγ9Vδ2 T-cells could be an effective strategy against ABCB1-expressing osteosarcoma. We used 2D-cultured doxorubicin-sensitive human U-2OS and Saos-2 cells, their doxorubicin-resistant sublines (U-2OS/DX580 and Saos-2/DX580), and 3D cultures of U-2OS and Saos-2 cells. DX580-sublines and 3D cultures had higher levels of ABCB1 and higher resistance to doxorubicin than parental cells. Surprisingly, they had reduced ABCA1 levels, IPP efflux, and Vγ9Vδ2 T-cell-induced killing. In these chemo-immune-resistant cells, the Ras/Akt/mTOR axis inhibits the ABCA1-transcription induced by Liver X Receptor α (LXRα); Ras/ERK1/2/HIF-1α axis up-regulates ABCB1. Targeting the farnesylation of Ras with self-assembling nanoparticles encapsulating zoledronic acid (NZ) simultaneously inhibited both axes. In humanized mice, NZ reduced the growth of chemo-immune-resistant osteosarcomas, increased intratumor necro-apoptosis, and ABCA1/ABCB1 ratio and Vγ9Vδ2 T-cell infiltration. We suggest that the ABCB1highABCA1low phenotype is indicative of chemo-immune-resistance. We propose aminobisphosphonates as new chemo-immune-sensitizing tools against drug-resistant osteosarcomas.

PMID: 32155954 [PubMed - in process]

Pharmacodynamics of current and emerging PD-1 and PD-L1 inhibitors for the treatment of non-small cell lung cancer.

Expert Opin Drug Metab Toxicol. 2020 Feb;16(2):87-96

Authors: Rocco D, Malapelle U, Del Re M, Della Gravara L, Pepe F, Danesi R, Troncone G, Gridelli C

Abstract
Introduction: As of today, one of the cornerstones of NSCLC treatment is represented by Immune Checkpoint Inhibitors (ICI) treatment in the form of anti-PD-1/PD-L1 monoclonal antibodies. However, apart from currently approved, recommended and employed agents (nivolumab, pembrolizumab, atezolizumab, durvalumab), several new agents are currently under development and investigation both in monotherapy and in combinational settings.Areas covered: This paper aims to discuss both the current state of the art and the most interesting emerging PD-1 and PD-L1 inhibitors and their present and future role in metastatic NSCLC treatment.Expert opinion: Great scientific interest lies in combinational settings, involving both already developed FDA and EMA approved and not approved agents and anti-PD-1 and PD-L1 inhibitors, that will certainly provide data about pharmacodynamic and clinical properties of these associations, enhancing our understanding of ICIs and cancer immunotherapy. Moreover, new potential predictive biomarkers are much needed, especially considering the less decisive role of PD-L1 in treatment algorithms involving chemo-immune combinations and the current lack of other validated predictive biomarkers.

PMID: 31978315 [PubMed - indexed for MEDLINE]

Associations Between Prediagnostic Concentrations of Circulating Sex Steroid Hormones and Esophageal/Gastric Cardia Adenocarcinoma Among Men.

J Natl Cancer Inst. 2019 01 01;111(1):34-41

Authors: Petrick JL, Hyland PL, Caron P, Falk RT, Pfeiffer RM, Dawsey SM, Abnet CC, Taylor PR, Weinstein SJ, Albanes D, Freedman ND, Gapstur SM, Bradwin G, Guillemette C, Campbell PT, Cook MB

Abstract
Background: Esophageal adenocarcinoma (EA) and gastric cardia adenocarcinoma (GCA) are characterized by a strong male predominance. Concentrations of sex steroid hormones have been hypothesized to explain this sex disparity. However, no prospective population-based study has examined sex steroid hormones in relation to EA/GCA risk. Thus, we investigated whether prediagnostic circulating sex steroid hormone concentrations were associated with EA/GCA in a nested case-control study drawn from participants in three prospective cohort studies.
Methods: Using gas chromatography-mass spectrometry (GC-MS) and electrochemiluminescence immunoassay, we quantitated sex steroid hormones and sex hormone binding globulin, respectively, in serum from 259 EA/GCA male case participants and 259 matched male control participants from the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial, Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study, and Cancer Prevention Study II Nutrition Cohort. Multivariable conditional logistic regression was used to calculate odds ratios (ORs) and 95% confidence intervals (CIs) for associations between circulating hormones and EA/GCA risk. All statistical tests were two-sided.
Results: Higher concentrations of dehydroepiandrosterone (DHEA) were associated with a 38% decreased risk of EA/GCA (OR per unit increase in log2 DHEA = 0.62, 95% CI = 0.47 to 0.82, Ptrend = .001). Higher estradiol concentrations were associated with a 34% reduced risk of EA/GCA (OR = 0.66, 95% CI = 0.45 to 0.98, Ptrend = .05), and the association with free estradiol was similar. No other associations between baseline hormone concentrations and future EA/GCA risk were observed.
Conclusions: This study provides the first evidence that higher concentrations of circulating DHEA, estradiol, and free estradiol may be associated with lower risks of EA/GCA in men.

PMID: 29788475 [PubMed - indexed for MEDLINE]

Prediction of exposure-driven myelotoxicity of continuous infusion 5-fluorouracil by a semi-physiological pharmacokinetic-pharmacodynamic model in gastrointestinal cancer patients.

Cancer Chemother Pharmacol. 2020 Mar 09;:

Authors: Arshad U, Ploylearmsaeng SA, Karlsson MO, Doroshyenko O, Langer D, Schömig E, Kunze S, Güner SA, Skripnichenko R, Ullah S, Jaehde U, Fuhr U, Jetter A, Taubert M

Abstract
PURPOSE: To describe 5-fluorouracil (5FU) pharmacokinetics, myelotoxicity and respective covariates using a simultaneous nonlinear mixed effect modelling approach.
METHODS: Thirty patients with gastrointestinal cancer received 5FU 650 or 1000 mg/m2/day as 5-day continuous venous infusion (14 of whom also received cisplatin 20 mg/m2/day). 5FU and 5-fluoro-5,6-dihydrouracil (5FUH2) plasma concentrations were described by a pharmacokinetic model using NONMEM. Absolute leukocyte counts were described by a semi-mechanistic myelosuppression model. Covariate relationships were evaluated to explain the possible sources of variability in 5FU pharmacokinetics and pharmacodynamics.
RESULTS: Total clearance of 5FU correlated with body surface area (BSA). Population estimate for total clearance was 249 L/h. Clearances of 5FU and 5FUH2 fractionally changed by 77%/m2 difference from the median BSA. 5FU central and peripheral volumes of distribution were 5.56 L and 28.5 L, respectively. Estimated 5FUH2 clearance and volume of distribution were 121 L/h and 96.7 L, respectively. Baseline leukocyte count of 6.86 × 109/L, as well as mean leukocyte transit time of 281 h accounting for time delay between proliferating and circulating cells, was estimated. The relationship between 5FU plasma concentrations and absolute leukocyte count was found to be linear. A higher degree of myelosuppression was attributed to combination therapy (slope = 2.82 L/mg) with cisplatin as compared to 5FU monotherapy (slope = 1.17 L/mg).
CONCLUSIONS: BSA should be taken into account for predicting 5FU exposure. Myelosuppression was influenced by 5FU exposure and concomitant administration of cisplatin.

PMID: 32152679 [PubMed - as supplied by publisher]

Invited Perspective on Pharmacogenetics in Late-Life Depression.

Am J Geriatr Psychiatry. 2020 Feb 13;:

Authors: Bigos KL

PMID: 32151554 [PubMed - as supplied by publisher]

Using Human Genetics to Drive Drug Discovery: A Perspective.

Am J Kidney Dis. 2019 07;74(1):111-119

Authors: Fox CS

Abstract
The probability of success of developing medicines to treat human disease can be improved by leveraging human genetics. Different types of genetic data and techniques, including genome-wide association, whole-exome sequencing, and whole-genome sequencing, can be used to gain insight into human disease. Layering different types of genetic evidence from Mendelian disease, coding variants, and common variation can bolster support for a genetic target. Human knockouts offer the potential to perform reverse genetic screens in humans to identify physiologically relevant targets. Other components of a good genetic target include protective loss-of-function mutations, some degree of known biology, tractability, and a clean on-target safety profile. In addition to using human genetics to inspire new drug programs, phenome-wide association studies can be used to identify alternative indications or repurposing opportunities. This information can be combined into a 5-step approach for selecting a genetic target for validation, which is presented in detail in this review. Finally, current challenges in leveraging human genetics are highlighted, including the difficulties translating certain types of genetic data, relatively small number of bona fide disease-associated coding rare variants, and current sample sizes of large well-curated biobanks linked to comprehensive genetic information.

PMID: 30898364 [PubMed - indexed for MEDLINE]

Genotype and Phenotype Concordance for Pharmacogenetic Tests Through Proficiency Survey Testing: An Update.

Arch Pathol Lab Med. 2020 Mar 09;:

Authors: Moyer AM, McMillin GA, Long TA, Gandhi MJ, Mao R, Smock KJ, Halley JG, Weck KE

Abstract
CONTEXT.—: As pharmacogenetic testing is incorporated into routine care, it is essential for laboratories to provide accurate and consistent results. Certified laboratories must successfully complete proficiency testing.
OBJECTIVES.—: To understand and examine trends in participation and performance of laboratories participating in the College of American Pathologists pharmacogenetic proficiency testing surveys.
DESIGN.—: Results from College of American Pathologists pharmacogenetic proficiency testing challenges from 2012 through 2017 were reviewed for concordance with expected genotype and phenotype for each sample (intended responses).
RESULTS.—: Laboratories correctly reported results for 96.7% to 100% of samples with no variants. Excluding CYP2D6, laboratories correctly detected and reported variant alleles for each gene (93.7%-99.2% correct). CYP2D6 showed lower concordance, with 83.1% of laboratories reporting the intended genotype across all samples; however, in many cases, the laboratories that did not report a variant allele did not test for that allele. Among laboratories reporting the intended genotype, most successfully reported the intended phenotype (85.9%-99.0%).
CONCLUSIONS.—: Although laboratories are generally performing well, there is room for additional improvement, particularly for challenging genes, such as CYP2D6. Efforts in the field of pharmacogenomics to recommend alleles that should be included in clinical tests, identify reference materials, and standardize translation from genotype to phenotype may address some of the remaining variability in results.

PMID: 32150456 [PubMed - as supplied by publisher]

Synonymous mutation rs2515641 affects CYP2E1 mRNA and protein expression and susceptibility to drug-induced liver injury.

Pharmacogenomics. 2020 Mar 09;:

Authors: Chen K, Guo R, Wei C

Abstract
Aim: To evaluate whether the synonymous mutant rs2515641 could affect Cytochrome P450 2E1 (CYP2E1) expression and the response to acetaminophen (APAP) or triptolide (TP) treatment. Materials & methods: HepG2 cells were transfected with lentiviral vector containing either CYP2E1-1263C or CYP2E1-1263T. Some of these recombinant cells were then treated with APAP or TP. CYP2E1 gene expression was detected by PCR and western blot. Results: CYP2E1 gene expression decreased significantly both in mRNA and protein level after rs2515641 mutation, indicating that this polymorphism can affect both transcription and translation. Furthermore, rs2515641 mutation dramatically changes the response of CYP2E1 expression to APAP or TP treatment. Conclusion: Rs2515641 significantly changes CYP2E1 expression and function, which would be expected to affect drug disposition and response.

PMID: 32149563 [PubMed - as supplied by publisher]

Is milder psychological stress responsible for more severe erectile dysfunction?

Andrologia. 2020 Mar 09;:e13550

Authors: Liao ZC, Li XC, Tang YX, Li DJ, Tang ZY

Abstract
China is a sexually conservative country compared with Western countries. To evaluate the psychological characteristics of Chinese erectile dysfunction (ED) patients, we conducted a cross-sectional study of 153 ED outpatients. Patients were interviewed with the Structured Interview on Erectile Dysfunction (SIEDY) for pathogenic quantification. ED was measured by International Index of Erectile Function (IIEF). Depression and anxiety were evaluated with 9-item Patient Health Questionnaire (PHQ-9) and 7-item Generalised Anxiety Disorder Scale (GAD-7) respectively. Most patients (74.5%) were <40 years old. IIEF-5 were significantly correlated with SIEDY scale 3 (r = .16, p = .040) and GAD-7 (p = .15, p = .033). The SIEDY scale 1 increased with age, but the IIEF-5, SIEDY scale 3, PHQ-9 and GAD-7 decreased with age. A negative correlation was observed between ED and psychological stress, which conflicts with many Western-country studies. Younger patients were characterised by milder ED but more psychological stress, while older patients were characterised by worse ED but less psychological stress. Which may be responsible for the conflicting result. Meanwhile, the much younger age distribution among Chinese ED outpatients may indicate that quite a few older ED patients (≥40 years) in China do not seek outpatient service which should merit more attention.

PMID: 32149423 [PubMed - as supplied by publisher]

Ginseng berry polysaccharides on inflammation-associated colon cancer: inhibiting T-cell differentiation, promoting apoptosis, and enhancing the effects of 5-fluorouracil.

J Ginseng Res. 2020 Mar;44(2):282-290

Authors: Wang CZ, Hou L, Wan JY, Yao H, Yuan J, Zeng J, Park CW, Kim SH, Seo DB, Shin KS, Zhang CF, Chen L, Zhang QH, Liu Z, Sava-Segal C, Yuan CS

Abstract
Background: Ginseng is a commonly used herbal medicine in treating various medical conditions. Chronic gut inflammation is a recognized factor for the development of colorectal cancer (CRC). In this project, Asian ginseng berry polysaccharide preparations were used to assess their effects on CRC and related immune regulation mechanisms.
Methods: Ginseng berry polysaccharide extract (GBPE) and purified ginseng berry polysaccharide portion (GBPP) were used to evaluate their activities on human HCT-116 and HT-29 CRC cell proliferation. Interleukin-8 secretion analysis was performed on HT-29 cells. Naive CD4 cell isolation and T-helper cell differentiation were performed and determined using flow cytometry for Th1 and Treg in addition to cell cycle and apoptotic investigation.
Results: GBPE and GBPP significantly inhibited interleukin-8 secretion and cancer cell proliferation, inhibited CD4+IFN-γ+ cell (Th1) differentiation, and decreased CD4+FoxP3+ cell (Treg) differentiation. Compared to the GBPE, GBPP showed more potent antiinflammatory activities on the malignant cells. This is consistent with the observation that GBPP can also inhibit Th1-cell differentiation better, suggesting that it has an important role in antiinflammation, whereas Treg cells hinder the body's immune response against malignancies. Supported by cell cycle and apoptosis data, GBPE and GBPP, at various degrees, remarkably enhanced the anticancer activities of 5-fluorouracil.
Conclusion: Data from this project suggested that Asian ginseng berry potentially has clinical utility in managing enteric inflammation and suppressing CRC through immunomodulation mechanisms.

PMID: 32148410 [PubMed]

Pharmacokinetic and pharmacodynamic considerations of general anesthesia in pediatric subjects.

Expert Opin Drug Metab Toxicol. 2020 Mar 09;:

Authors: Anderson BJ, Morse JD, Hannam JA, Cortinez LI

Abstract
Introduction: Pharmacokinetic-pharmacodynamic (PKPD) modelling in pediatric anesthesia has proved beneficial for children. The target concentration strategy uses PKPD information for dose determination. Models have also quantified exposure-response relationships, improved understanding of developmental pharmacokinetics, rationalized dose prescription, provided insight into the importance of covariate information, explained drug interactions and driven decision making and learning during drug developmentAreas covered: The prime PKPD consideration is parameter estimation and quantification of variability. The main sources of variability in children are age (maturation) and weight (size). Unaccounted variability due to obesity, genetic influences, and organ dysfunction remains poorly described. Model use is mostly confined to pharmacokinetics, partly because anesthesia effect models in the young are imprecise. Pharmacodynamic models often ignore placebo and nocebo effects that can have powerful influence in young children. Circadian rhythms may have influence on anesthesia effects. The use of effect interaction models has proven useful in adult anesthesia but interactions remain inadequately explored in children. Exploration of these covariates and their variability holds potential to better individualize treatmentExpert opinion: The ability to model drugs using computer-based technology in anaesthesia is well established. However, data required to individualize treatment using these programs remain lacking. Target concentration intervention strategies remain incomplete because covariate information that might better predict individualization of dose is absent. Age and size are valuable covariates, but incorporation of other covariates will reduce unknown variability. Pharmacogenomics appears a valuable area for investigation for pharmacodynamics and pharmacodynamics. Phenotype rather than genotype requires focus for pharmacokinetics. The ability to readily measure drug serum concentration will enable titration to effect. However, effect measures in the very young are imprecise. While neuromuscular monitoring is satisfactory, depth of anaesthesia EEG interpretation is inadequate. Assessment of the analgesic component of anesthesia is crude.

PMID: 32148110 [PubMed - as supplied by publisher]

A role for vitamin D and omega-3 fatty acids in major depression? An exploration using genomics.

Transl Psychiatry. 2019 09 05;9(1):219

Authors: Milaneschi Y, Peyrot WJ, Nivard MG, Mbarek H, Boomsma DI, W J H Penninx B

Abstract
Trials testing the effect of vitamin D or omega-3 polyunsaturated fatty acid (n3-PUFA) supplementation on major depressive disorder (MDD) reported conflicting findings. These trials were inspired by epidemiological evidence suggesting an inverse association of circulating 25-hydroxyvitamin D (25-OH-D) and n3-PUFA levels with MDD. Observational associations may emerge from unresolved confounding, shared genetic risk, or direct causal relationships. We explored the nature of these associations exploiting data and statistical tools from genomics. Results from genome-wide association studies on 25-OH-D (N = 79 366), n3-PUFA (N = 24 925), and MDD (135 458 cases, 344 901 controls) were applied to individual-level data (>2000 subjects with measures of genotype, DSM-IV (Diagnostic and Statistical Manual of Mental Disorders, 4th edition) lifetime MDD diagnoses and circulating 25-OH-D and n3-PUFA) and summary-level data analyses. Shared genetic risk between traits was tested by polygenic risk scores (PRS). Two-sample Mendelian Randomization (2SMR) analyses tested the potential bidirectional causality between traits. In individual-level data analyses, PRS were associated with the phenotype of the same trait (PRS 25-OH-D p = 1.4e - 20, PRS n3-PUFA p = 9.3e - 6, PRS MDD p = 1.4e - 4), but not with the other phenotypes, suggesting a lack of shared genetic effects. In summary-level data analyses, 2SMR analyses provided no evidence of a causal role on MDD of 25-OH-D (p = 0.50) or n3-PUFA (p = 0.16), or for a causal role of MDD on 25-OH-D (p = 0.25) or n3-PUFA (p = 0.66). Applying genomics tools indicated that shared genetic risk or direct causality between 25-OH-D, n3-PUFA, and MDD is unlikely: unresolved confounding may explain the associations reported in observational studies. These findings represent a cautionary tale for testing supplementation of these compounds in preventing or treating MDD.

PMID: 31488809 [PubMed - indexed for MEDLINE]

Genetically Determined Risk of Depression and Functional Outcome After Ischemic Stroke.

Stroke. 2019 08;50(8):2219-2222

Authors: Gill D, James NE, Monori G, Lorentzen E, Fernandez-Cadenas I, Lemmens R, Thijs V, Rost NS, Scott R, Hankey GJ, Lindgren A, Jern C, Maguire JM, International Stroke Genetics Consortium and the GISCOME Network

Abstract
Background and Purpose- Psychosocial factors can have implications for ischemic stroke risk and recovery. This study investigated the effect of genetically determined risk of depression on these outcomes using the Mendelian randomization (MR) framework. Methods- Genetic instruments for risk of depression were identified in a discovery genome-wide association study of 246 363 cases and 561 190 controls and further replicated in a separate population of 474 574 cases and 1 032 579 controls. Corresponding genetic association estimates for risk of ischemic stroke were taken from 60 341 cases and 454 450 controls, with those for functional outcome 3 months after ischemic stroke taken from an analysis of 6021 patients. Following statistical power calculation, inverse-variance weighted MR was performed to pool estimates across different instruments. The Cochran Q heterogeneity test, weighted median MR, and MR pleiotropy residual sum and outlier were used to explore possible bias relating to inclusion of pleiotropic variants. Results- There was no MR evidence for an effect of genetically determined risk of depression on ischemic stroke risk. Although suffering low statistical power, the main inverse-variance weighted MR analysis was suggestive of a detrimental effect of genetically determined risk of depression on functional outcome after ischemic stroke (odds ratio of poor outcome [modified Rankin Scale, ≥3] per 1-SD increase in genetically determined risk of depression, 1.81; 95% CI, 0.98-3.35; P=0.06). There was no evidence of heterogeneity between MR estimates produced by different instruments (Q P=0.26). Comparable MR estimates were obtained with weighted median MR (odds ratio, 2.57; 95% CI, 1.05-6.25; P=0.04) and MR pleiotropy residual sum and outlier (odds ratio, 1.81; 95% CI, 0.95-3.46; P=0.08). Conclusions- We found no MR evidence of genetically determined risk of depression affecting ischemic stroke risk but did find consistent MR evidence suggestive of a possible effect on functional outcome after ischemic stroke. Given the widespread prevalence of depression-related morbidity, these findings could have implications for prognostication and personalized rehabilitation after stroke.

PMID: 31238828 [PubMed - indexed for MEDLINE]

Key considerations for using pharmacogenomics to optimize pain management.

J Am Pharm Assoc (2003). 2020 Mar 04;:

Authors: Gammal RS, Mayes J, Caudle KE

PMID: 32146135 [PubMed - as supplied by publisher]

Pharmacogenomics for the efficacy of platinum-based chemotherapy: Old drugs, new integrated perspective.

Biomed Pharmacother. 2020 Mar 04;126:110057

Authors: Mao CX, Li M, Zhang W, Zhou HH, Yin JY, Liu ZQ

Abstract
Platinum-based chemotherapy remains the cornerstone of treatment for many malignancies. However, although therapeutic efficiency varies greatly among individuals, there is a lack of pharmacogenomic biomarkers that can be used in clinical settings to identify chemosensitive patients and allow stratification. With the development of high-throughput screening techniques and systems biology approaches, a growing body of evidence has shown that platinum resistance is a multifactorial, multi-dimensional, dynamic process incorporating genetic background, tumor evolution and gut microbes. This review critically summarizes potential pharmacogenomic biomarkers for predicting the efficacy of platinum drugs and provides a comprehensive, time-varying perspective that integrates multiple markers.

PMID: 32145590 [PubMed - as supplied by publisher]