Translating pharmacogenomics into clinical decisions: do not let the perfect be the enemy of the good.

Hum Genomics. 2019 Aug 27;13(1):39

Authors: Krebs K, Milani L

Abstract
The field of pharmacogenomics (PGx) is gradually shifting from the reactive testing of single genes toward the proactive testing of multiple genes to improve treatment outcomes, reduce adverse events, and decrease the burden of unnecessary costs for healthcare systems. Despite the progress in the field of pharmacogenomics, its implementation into routine care has been slow due to several barriers. However, in recent years, the number of studies on the implementation of PGx has increased, all providing a wealth of knowledge on different solutions for overcoming the obstacles that have been emphasized over the past years. This review focuses on some of the challenges faced by these initiatives, the solutions and different approaches for testing that they suggest, and the evidence that they provide regarding the benefits of preemptive PGx testing.

PMID: 31455423 [PubMed - in process]

Dissecting genetic factors affecting phenylephrine infusion rates during anesthesia: a genome-wide association study employing EHR data.

BMC Med. 2019 Aug 28;17(1):168

Authors: Zhang Y, Poler SM, Li J, Abedi V, Pendergrass SA, Williams MS, Lee MTM

Abstract
BACKGROUND: The alpha-adrenergic agonist phenylephrine is often used to treat hypotension during anesthesia. In clinical situations, low blood pressure may require prompt intervention by intravenous bolus or infusion. Differences in responsiveness to phenylephrine treatment are commonly observed in clinical practice. Candidate gene studies indicate genetic variants may contribute to this variable response.
METHODS: Pharmacological and physiological data were retrospectively extracted from routine clinical anesthetic records. Response to phenylephrine boluses could not be reliably assessed, so infusion rates were used for analysis. Unsupervised k-means clustering was conducted on clean data containing 4130 patients based on phenylephrine infusion rate and blood pressure parameters, to identify potential phenotypic subtypes. Genome-wide association studies (GWAS) were performed against average infusion rates in two cohorts: phase I (n = 1205) and phase II (n = 329). Top genetic variants identified from the meta-analysis were further examined to see if they could differentiate subgroups identified by k-means clustering.
RESULTS: Three subgroups of patients with different response to phenylephrine were clustered and characterized: resistant (high infusion rate yet low mean systolic blood pressure (SBP)), intermediate (low infusion rate and low SBP), and sensitive (low infusion rate with high SBP). Differences among clusters were tabulated to assess for possible confounding influences. Comorbidity hierarchical clustering showed the resistant group had a higher prevalence of confounding factors than the intermediate and sensitive groups although overall prevalence is below 6%. Three loci with P < 1 × 10-6 were associated with phenylephrine infusion rate. Only rs11572377 with P = 6.09 × 10-7, a 3'UTR variant of EDN2, encoding a secretory vasoconstricting peptide, could significantly differentiate resistant from sensitive groups (P = 0.015 and 0.018 for phase I and phase II) or resistant from pooled sensitive and intermediate groups (P = 0.047 and 0.018).
CONCLUSIONS: Retrospective analysis of electronic anesthetic records data coupled with the genetic data identified genetic variants contributing to variable sensitivity to phenylephrine infusion during anesthesia. Although the identified top gene, EDN2, has robust biological relevance to vasoconstriction by binding to endothelin type A (ETA) receptors on arterial smooth muscle cells, further functional as well as replication studies are necessary to confirm this association.

PMID: 31455332 [PubMed - in process]

Pharmacogenetics and Depression: A Critical Perspective.

Psychiatry Investig. 2019 Aug 29;:

Authors: Corponi F, Fabbri C, Serretti A

Abstract
Depression leads the higher personal and socio-economical burden within psychiatric disorders. Despite the fact that over 40 antidepressants (ADs) are available, suboptimal response still poses a major challenge and is thought to be partially a result of genetic variation. Pharmacogenetics studies the effects of genetic variants on treatment outcomes with the aim of providing tailored treatments, thereby maximizing efficacy and tolerability. After two decades of pharmacogenetic research, variants in genes coding for the cytochromes involved in ADs metabolism (CYP2D6 and CYP2C19) are now considered biomarkers with sufficient scientific support for clinical application, despite the lack of conclusive cost/effectiveness evidence. The effect of variants in genes modulating ADs mechanisms of action (pharmacodynamics) is still controversial, because of the much higher complexity of ADs pharmacodynamics compared to ADs metabolism. Considerable progress has been made since the era of candidate gene studies: the genomic revolution has made possible to assess genetic variance on an unprecedented scale, throughout the whole genome, and to analyze the cumulative effect of different variants. The results have revealed key information on the biological mechanisms mediating ADs effect and identified hypothetical new pharmacological targets. They also paved the way for future availability of polygenic pharmacogenetic panels to predict treatment outcome, which are expected to explain much higher variance in ADs response compared to CYP2D6 and CYP2C19 only. As the demand and availability of AD pharmacogenetic testing is projected to increase, it is important for clinicians to keep abreast of this evolving area to facilitate informed discussions with their patients.

PMID: 31455064 [PubMed - as supplied by publisher]

Improved Cancer Immunochemotherapy via Optimal Co-delivery of Chemotherapeutic and Immunomodulatory Agents.

Mol Pharm. 2018 11 05;15(11):5162-5173

Authors: Chen Y, Sun J, Huang Y, Lu B, Li S

Abstract
It is highly demanded and still a big challenge to develop an effective formulation for immunochemotherapy against advanced tumors. We have previously reported a PEG-NLG-based immunostimulatory nanocarrier (PEG2k-Fmoc-NLG919) for co-delivery of an IDO1 inhibitor (NLG919) and a chemotherapeutic agent (paclitaxel, PTX). Although antitumor immune responses were enhanced with a PTX-loaded nanocarrier, the accumulation of myeloid-derived suppressor cells (MDSCs) was also significantly increased, which may limit the overall efficacy of therapy. In the present work, we developed an improved dual-functional nanocarrier (PEG5k-Fmoc-NLG2) to co-load PTX and sunitinib (SUN, a multitarget receptor tyrosine kinase inhibitor) for improved cancer immunochemotherapy. We found that the recruited MDSCs negatively impacted the overall antitumor activity of the PTX-loaded PEG-NLG nanocarrier. Mechanistic study suggests that this is likely attributed to the PTX-mediated induction of a number of chemokines that are involved in the recruitment of MDSCs. We have further shown that the induction of these chemokines was drastically blocked by SUN. Co-delivery of PTX and SUN via the PEG5k-Fmoc-NLG9192 nanocarrier led to a further improvement in the therapeutic efficacy with a concomitant reduction in MDSCs.

PMID: 30222360 [PubMed - indexed for MEDLINE]

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Domain selective labeling for NMR studies of multidomain proteins by domain ligation using highly active sortase A.

Biochim Biophys Acta Gen Subj. 2019 Aug 23;:129419

Authors: Aizu T, Suzuki T, Kido A, Nagai K, Kobayashi A, Sugiura R, Ito Y, Mishima M

Abstract
Structural study of multidomain proteins using NMR is an emerging issue for understanding biological functions. To this end, domain-specific labeling is expected to be a key technology for facilitating the NMR-assignment process and for collecting distance information via spin labeling. To obtain domain-specific labeled samples, use of sortase A as a protein ligation tool is a viable approach. Sortase A enables ligation of separately expressed proteins (domains) through the Leu-Pro-X-Thr-Gly linker. However, the ligation reaction mediated by sortase A is not efficient. Poor yield and long reaction times hamper large-scale preparation using sortase A. Here we report the application of highly active sortases to NMR analyses. Optimal yields can be achieved within several hours when the ligation reaction are mediated by highly active sortases at 4 °C. We propose that this protocol can contribute to structural analyses of multidomain proteins by NMR.

PMID: 31449838 [PubMed - as supplied by publisher]

Identification of predictive genetic signatures of Cytarabine responsiveness using a 3D acute myeloid leukaemia model.

J Cell Mol Med. 2019 Aug 26;:

Authors: Xu H, Muise ES, Javaid S, Chen L, Cristescu R, Mansueto MS, Follmer N, Cho J, Kerr K, Altura R, Machacek M, Nicholson B, Addona G, Kariv I, Chen H

Abstract
This study reports the establishment of a bone marrow mononuclear cell (BMMC) 3D culture model and the application of this model to define sensitivity and resistance biomarkers of acute myeloid leukaemia (AML) patient bone marrow samples in response to Cytarabine (Ara-C) treatment. By mimicking physiological bone marrow microenvironment, the growth conditions were optimized by using frozen BMMCs derived from healthy donors. Healthy BMMCs are capable of differentiating into major hematopoietic lineages and various types of stromal cells in this platform. Cryopreserved BMMC samples from 49 AML patients were characterized for ex vivo growth and sensitivity to Ara-C. RNA sequencing was performed for 3D and 2D cultures to determine differential gene expression patterns. Specific genetic mutations and/or gene expression signatures associated with the ability of the ex vivo expansion and response to Ara-C were elucidated by whole-exome and RNA sequencing. Data analysis identified unique gene expression signatures and novel genetic mutations associated with sensitivity to Ara-C treatment of proliferating AML specimens and can be used as predictive therapeutic biomarkers to determine the optimal treatment regimens. Furthermore, these data demonstrate the translational value of this ex vivo platform which should be widely applicable to evaluate other therapies in AML.

PMID: 31449347 [PubMed - as supplied by publisher]

EXPLORATORY ANALYSIS OF RARE AND NOVEL VARIANTS IN MEXICAN PATIENTS DIAGNOSED WITH SCHIZOPHRENIA AND DEMENTIA.

Rev Invest Clin. 2019;71(4):246-254

Authors: Martínez-Magaña JJ, Genís-Mendoza AD, González-Covarrubias V, Jiménez-Guenchi J, Galindo-Chávez AG, Roche-Bergua A, Castañeda-González C, Lanzagorta N, Soberón X, Nicolini H

Abstract
Background: Schizophrenia (SCZ) and dementia, often related, are two of the most common neuropsychiatric diseases; epidemiological studies have shown that SCZ patients present a 2-fold increased risk for dementia compared to non-schizophrenic individuals. We explored the presence of rare and novel damaging gene variants in patients diagnosed with late-onset dementia of Alzheimer's type (DAT) or SCZ.
Methods: We included 7 DAT and 12 SCZ patients and performed high-depth targeted sequencing of 184 genes.
Results: We found novel and rare damaging variants in 18 genes in these Mexican patients. Carriers of these variants showed extreme phenotypes, including, treatment-resistant SCZ or cognitive decline. Furthermore, we found a variation on ABCC1 as a possible link between psychosis and cognitive impairment.
Discussion: As an exploratory analysis, we report some interesting variations that should be corroborated in larger sample size studies.

PMID: 31448785 [PubMed - in process]

Orthostatic hypotension and dementia incidence: links and implications.

Neuropsychiatr Dis Treat. 2019;15:2181-2194

Authors: Robertson AD, Udow SJ, Espay AJ, Merola A, Camicioli R, Lang AE, Masellis M

Abstract
Orthostatic hypotension (OH) is a common condition, particularly in patients with α-synucleinopathies such as Parkinson's disease, and has a significant impact on activities of daily living and quality of life. Recent data suggest an association with cognitive impairment. Herein, we review the evidence that OH increases the odds of incident mild cognitive impairment and dementia. Potential mechanisms underlying the putative relationship are discussed, including cerebral hypoperfusion, supine hypertension, white matter hyperintensities, and neurodegeneration. Finally, we highlight the challenges with respect to treatment and the negative impact on the quality of life and long-term prognosis presented by the coexistence of OH and dementia. Large population-based studies have reported that OH is associated with about a 20% increased risk of dementia in the general population, while smaller cohort studies suggest an even greater effect in patients with α-synucleinopathies (3- to 7-fold higher than controls). Ultimately, OH exposure is difficult to quantify, predominantly limited to pressure regulation during a one-time orthostatic challenge, and the causative association with dementia may turn out to be bidirectional, especially in α-synucleinopathies. Early diagnosis and treatment of OH may improve long-term prognosis.

PMID: 31447560 [PubMed]

Dextromethorphan and memantine after ketamine analgesia: a randomized control trial.

Drug Des Devel Ther. 2019;13:2677-2688

Authors: Martin E, Sorel M, Morel V, Marcaillou F, Picard P, Delage N, Tiberghien F, Crosmary MC, Najjar M, Colamarino R, Créach C, Lietar B, Brumauld de Montgazon G, Margot-Duclot A, Loriot MA, Narjoz C, Lambert C, Pereira B, Pickering G

Abstract
Purpose: Intravenous ketamine is often prescribed in severe neuropathic pain. Oral N-methyl-D-aspartate receptor (NMDAR) antagonists might prolong pain relief, reducing the frequency of ketamine infusions and hospital admissions. This clinical trial aimed at assessing whether oral dextromethorphan or memantine might prolong pain relief after intravenous ketamine.
Patients and methods: A multicenter randomized controlled clinical trial included 60 patients after ketamine infusion for refractory neuropathic pain. Dextromethorphan (90 mg/day), memantine (20 mg/day) or placebo was given for 12 weeks (n=20 each) after ketamine infusion. The primary endpoint was pain intensity at one month. Secondary endpoints included pain, sleep, anxiety, depression, cognitive function and quality of life evaluations up to 12 weeks.
Results: At 1 month, dextromethorphan maintained ketamine pain relief (Numeric Pain Scale: 4.01±1.87 to 4.05±2.61, p=0.53) and diminished pain paroxysms (p=0.03) while pain intensity increased significantly with memantine and placebo (p=0.04). At 3 months, pain remained lower than at inclusion (p=0.001) and was not significantly different in the three groups. Significant benefits were observed on cognitive-affective domains and quality of life for dextromethorphan and memantine (p<0.05).
Conclusions: Oral dextromethorphan given after ketamine infusion extends pain relief during one month and could help patients to better cope with pain. Future studies should include larger populations stratified on pharmacogenetics screening. Optimization of an oral drug that could extend ketamine antihyperalgesia, with fewer hospital admissions, remains a prime challenge in refractory neuropathic pain.

PMID: 31447547 [PubMed - in process]

17p12 Influences Hematoma Volume and Outcome in Spontaneous Intracerebral Hemorrhage.

Stroke. 2018 07;49(7):1618-1625

Authors: Marini S, Devan WJ, Radmanesh F, Miyares L, Poterba T, Hansen BM, Norrving B, Jimenez-Conde J, Giralt-Steinhauer E, Elosua R, Cuadrado-Godia E, Soriano C, Roquer J, Kourkoulis CE, Ayres AM, Schwab K, Tirschwell DL, Selim M, Brown DL, Silliman SL, Worrall BB, Meschia JF, Kidwell CS, Montaner J, Fernandez-Cadenas I, Delgado P, Greenberg SM, Lindgren A, Matouk C, Sheth KN, Woo D, Anderson CD, Rosand J, Falcone GJ, International Stroke Genetics Consortium

Abstract
BACKGROUND AND PURPOSE: Hematoma volume is an important determinant of clinical outcome in spontaneous intracerebral hemorrhage (ICH). We performed a genome-wide association study (GWAS) of hematoma volume with the aim of identifying novel biological pathways involved in the pathophysiology of primary brain injury in ICH.
METHODS: We conducted a 2-stage (discovery and replication) case-only genome-wide association study in patients with ICH of European ancestry. We utilized the admission head computed tomography to calculate hematoma volume via semiautomated computer-assisted technique. After quality control and imputation, 7 million genetic variants were available for association testing with ICH volume, which was performed separately in lobar and nonlobar ICH cases using linear regression. Signals with P<5×10-8 were pursued in replication and tested for association with admission Glasgow coma scale and 3-month post-ICH dichotomized (0-2 versus 3-6) modified Rankin Scale using ordinal and logistic regression, respectively.
RESULTS: The discovery phase included 394 ICH cases (228 lobar and 166 nonlobar) and identified 2 susceptibility loci: a genomic region on 22q13 encompassing PARVB (top single-nucleotide polymorphism rs9614326: β, 1.84; SE, 0.32; P=4.4×10-8) for lobar ICH volume and an intergenic region overlying numerous copy number variants on 17p12 (top single-nucleotide polymorphism rs11655160: β, 0.95; SE, 0.17; P=4.3×10-8) for nonlobar ICH volume. The replication included 240 ICH cases (71 lobar and 169 nonlobar) and corroborated the association for 17p12 (P=0.04; meta-analysis P=2.5×10-9; heterogeneity, P=0.16) but not for 22q13 (P=0.49). In multivariable analysis, rs11655160 was also associated with lower admission Glasgow coma scale (odds ratio, 0.17; P=0.004) and increased risk of poor 3-month modified Rankin Scale (odds ratio, 1.94; P=0.045).
CONCLUSIONS: We identified 17p12 as a novel susceptibility risk locus for hematoma volume, clinical severity, and functional outcome in nonlobar ICH. Replication in other ethnicities and follow-up translational studies are needed to elucidate the mechanism mediating the observed association.

PMID: 29915124 [PubMed - indexed for MEDLINE]

Clopidogrel but Not Prasugrel Significantly Inhibits the CYP2C8-Mediated Metabolism of Montelukast in Humans.

Clin Pharmacol Ther. 2018 09;104(3):495-504

Authors: Itkonen MK, Tornio A, Filppula AM, Neuvonen M, Neuvonen PJ, Niemi M, Backman JT

Abstract
The oxidation of montelukast is mainly mediated by cytochrome P450 (CYP) 2C8, but other mechanisms may contribute to its disposition. In healthy volunteers, we investigated the effects of two widely used P2Y12 inhibitors on montelukast pharmacokinetics. Clopidogrel (300 mg on day 1 and 75 mg on day 2) increased the area under the plasma concentration-time curve (AUC) of montelukast 2.0-fold (90% confidence interval (CI) 1.72-2.28, P < 0.001) and decreased the M6:montelukast AUC0-7h ratio to 45% of control (90% CI 40-50%, P < 0.001). Prasugrel (60 mg on day 1 and 10 mg on day 2) had no clinically meaningful effect on montelukast pharmacokinetics. Our results imply that clopidogrel is at least a moderate inhibitor of CYP2C8, but prasugrel is not a clinically relevant CYP2C8 inhibitor. The different interaction potentials of clopidogrel and prasugrel are important to consider when antiplatelet therapy is planned for patients at risk for polypharmacy with CYP2C8 substrates.

PMID: 29171020 [PubMed - indexed for MEDLINE]

The PPM1F gene moderates the association between PTSD and cortical thickness.

J Affect Disord. 2019 Aug 19;259:201-209

Authors: Sullivan DR, Morrison FG, Wolf EJ, Logue MW, Fortier CB, Salat DH, Fonda JR, Stone A, Schichman S, Milberg W, McGlinchey R, Miller MW

Abstract
BACKGROUND: Evidence suggests that single nucleotide polymorphisms (SNPs) in genes involved in serotonergic signaling and stress response pathways moderate associations between PTSD and cortical thickness. This study examined a genetic regulator of these pathways, the PPM1F gene, which has also been implicated in mechanisms of stress responding and is differentially expressed in individuals with comorbid PTSD and depression compared to controls.
METHODS: Drawing from a sample of 240 white non-Hispanic trauma-exposed veterans, we tested 18 SNPs spanning the PPM1F gene for association with PTSD and cortical thickness.
RESULTS: Analyses revealed six PPM1F SNPs that moderated associations between PTSD symptom severity and cortical thickness of bilateral superior frontal and orbitofrontal regions as well as the right pars triangularis (all corrected p's < 0.05) such that greater PTSD severity was related to reduced cortical thickness as a function of genotype. A whole-cortex vertex-wise analysis using the most associated SNP (rs9610608) revealed this effect to be localized to a cluster in the right superior frontal gyrus (cluster-corrected p < 0.02).
LIMITATIONS: Limitations of this study include the small sample size and that the sample was all-white, non-Hispanic predominately male veterans.
CONCLUSIONS: These results extend prior work linking PPM1F to PTSD and suggest that variants in this gene may have bearing on the neural integrity of the prefrontal cortex (PFC).

PMID: 31446381 [PubMed - as supplied by publisher]

Pharmacogenetics of medication-related osteonecrosis of the jaw: a systematic review and meta-analysis.

Int J Oral Maxillofac Surg. 2019 Aug 21;:

Authors: Guo Z, Cui W, Que L, Li C, Tang X, Liu J

Abstract
Medication-related osteonecrosis of the jaw (MRONJ) is a severe complication that can develop in patients treated with anti-resorptive drugs. Although the pathogenesis of MRONJ is still unclear, genetic factors have a demonstrated important role. Thus, the aim of this study was to perform a systematic review on the pharmacogenetics of MRONJ. Studies published until March 2019 were retrieved from eight databases and were selected by two independent reviewers. Evidence on several genetic polymorphisms was summarized and a meta-analysis was conducted when possible. Fourteen studies involving 1515 participants were eligible for systematic review. For CYP2C8 rs1934951, no significant difference was observed between the MRONJ and non-MRONJ groups (odds ratio (OR) 2.04, 95% confidence interval (CI) 0.88-4.73, P=0.09). However, a subgroup analysis based on only multiple myeloma status showed a positive association (OR 3.64, 95% CI 1.29-10.30, P=0.01). PPARG rs1152003 was not differently distributed between groups (OR 0.25, 95% CI 0.01-9.92, P=0.46). Also, VEGF rs3025039 was found to be correlated with the occurrence of MRONJ (OR 0.35, 95% CI 0.15-0.82, P=0.02). CYP2C8 rs1934951 (in multiple myeloma patients) and VEGF rs3025039 are associated with the development of MRONJ in patients treated with bisphosphonates. The results are promising and call for new trials with a larger sample to further explore this growing field.

PMID: 31445964 [PubMed - as supplied by publisher]

Disruption of an enhancer associated with addictive behaviour within the cannabinoid receptor-1 gene suggests a possible role in alcohol intake, cannabinoid response and anxiety-related behaviour.

Psychoneuroendocrinology. 2019 Aug 13;109:104407

Authors: Hay EA, McEwan A, Wilson D, Barrett P, D'Agostino G, Pertwee RG, MacKenzie A

Abstract
The cannabinoid-1 receptor (CB1) plays a critical role in a number of biological processes including nutrient intake, addiction and anxiety-related behaviour. Numerous studies have shown that expression of the gene encoding CB1 (CNR1) is highly dynamic with changes in the tissue specific expression of CNR1 associated with brain homeostasis and disease progression. However, little is known of the mechanisms regulating this dynamic expression. To gain a better understanding of the genomic mechanisms modulating the expression of CNR1 in health and disease we characterised the role of a highly conserved regulatory sequence (ECR1) in CNR1 intron 2 that contained a polymorphism in linkage disequilibrium with disease associated SNPs. We used CRISPR/CAS9 technology to disrupt ECR1 within the mouse genome. Disruption of ECR1 significantly reduced CNR1 expression in the hippocampus but not in the hypothalamus. These mice also displayed an altered sex-specific anxiety-related behavioural profile (open field test), reduced ethanol intake and a reduced hypothermic response following CB1 agonism. However, no significant changes in feeding patterns were detected. These data suggest that, whilst not all of the expression of CNR1 is modulated by ECR1, this highly conserved enhancer is required for appropriate physiological responses to a number of stimuli. The combination of comparative genomics and CRISPR/CAS9 disruption used in our study to determine the functional effects of genetic and epigenetic changes on the activity of tissue-specific regulatory elements at the CNR1 locus represent an important first step in gaining a mechanistic understanding of cannabinoid regulatory pharmacogenetics.

PMID: 31445429 [PubMed - as supplied by publisher]

Potential role of pharmacogenomics testing in the setting of enhanced recovery pathways after surgery.

Pharmgenomics Pers Med. 2019;12:145-154

Authors: Awad H, Ahmed A, Urman RD, Stoicea N, Bergese SD

Abstract
In 2001, a group of European academic surgeons created the Enhanced Recovery After Surgery (ERAS) study group and established the first official ERAS protocol. One of the most significant challenges during ERAS implementation is variability of drugs used throughout the perioperative period. Pharmacogenomic testing (blood or saliva) results (obtained within approximately 48 hrs) provide guidelines on how to prescribe the optimal drug with the optimal dosage to each patient based on an individual's unique genetic profile. Pharmacogenomic testing of various methods of multimodal analgesia is an essential element of ERAS protocols spanning the entire perioperative period to ultimately optimize postoperative pain control. The key goal for anesthetic management in ERAS protocols is to facilitate rapid emergence by using the shortest acting agents available, thus accelerating recovery and reducing length of stay, hospital expenses, and postoperative complications. Postoperative nausea and vomiting (PONV) is an additional challenge that should be overcome to ensure an enhanced recovery and shorter length of stay with the use of antiemetics. Postoperative ileus (POI) can result in longer hospital stay with increasing susceptibility to associated morbidities along with an increase in associated hospitalization costs. Genetics-guided pharmacotherapy and its impact on clinical outcomes should be thoroughly studied for better understanding and managing drug administration in the settings of ERAS.

PMID: 31440074 [PubMed]

High Positive Correlations between ANRIL and p16-CDKN2A/p15-CDKN2B/p14-ARF Gene Cluster Overexpression in Multi-Tumor Types Suggest Deregulated Activation of an ANRIL-ARF Bidirectional Promoter.

Noncoding RNA. 2019 Aug 21;5(3):

Authors: Drak Alsibai K, Vacher S, Meseure D, Nicolas A, Lae M, Schnitzler A, Chemlali W, Cros J, Longchampt E, Cacheux W, Pignot G, Callens C, Pasmant E, Allory Y, Bieche I

Abstract
The CDKN2B-AS1 gene, also called ANRIL, is located at the human CDKN2A/B locus at 9p21.3 and transcribed by RNA polymerase II into a long non-coding RNA of 3834 bp. The CDKN2B-AS1 gene overlaps a critical region of 125 kb covering the CDKN2B gene. The CDKN2A/B locus encompasses three major tumor suppressors juxtaposed and joined into a p16-CDKN2A/p15-CDKN2B/p14-ARF gene cluster. CDKN2A encodes splice variants p16-CDKN2A and p14-ARF, and CDKN2B encodes p15-CDKN2B. ANRIL shares a bidirectional promoter with the p14-ARF gene and is transcribed from the opposite strand to the cluster. We performed an analysis of the expression level of ANRIL and tumor suppressor p16-CDKN2A, p15-CDKN2B, and p14-ARF genes using quantitative RT-PCR in a multitumor panel. We observed the overexpression of the four genes ANRIL, p16-CDKN2A, p15-CDKN2B, and p14-ARF in the great majority of the 17 different cancer types. ANRIL was upregulated in 13/17 tumors compared to normal tissues, ranging from 5% (prostate cancer) to 91% (cervix cancer), with variable expression of p16-CDKN2A, p15-CDKN2B, and p14-ARF genes. A high positive correlation was identified between levels of expression of ANRIL and the three tumor suppressors. The strongest positive association was observed with p14-ARF (p < 0.001) in all but one (lung squamous cell carcinoma) of the examined tumor types. This correlation suggests coordinated deregulated mechanisms in all cancer types through aberrant activation of a bidirectional p14-ARF/ANRIL promoter. Furthermore, significant positive correlation was unexpectedly established in prostatic carcinomas, in contradiction with previous data.

PMID: 31438464 [PubMed]

Pharmacogenetics of anxiety disorders.

Neurosci Lett. 2019 Aug 20;:134443

Authors: McGowan OO

Abstract
Anxiety disorders are common and disabling conditions the treatment of which remains a challenge. While different groups of medication are available for their treatment, a substantial proportion of patients remain refractory to pharmacotherapy. The reason for this variation in the individual response to treatment has yet to be understood; however genetic factors have been shown to play an important role. Up to now there have been limited publications about pharmacogenetics of anxiety disorders, compared to studies in depression. Published studies are focused on pharmacogenetics of antidepressants rather than being disease specific. This review summarizes pharmacogenetic findings related to the anxiolytic treatment response and their possible functional mechanisms. This inevitably focuses on genes involved in the pharmacodynamics of the medications used, along with some genes implicated in the disease process, as well as briefly mentioning genetic factors associated with psychotherapeutic response.

PMID: 31442515 [PubMed - as supplied by publisher]

ACAT1 as a therapeutic target and its genetic relationship with Alzheimer's disease.

Curr Alzheimer Res. 2019 Aug 23;:

Authors: Rubio JSA, Cedillo TJ

Abstract
BACKGROUND: Alzheimer´s disease (AD) is a chronic and progressive disease which impacts caregivers, families and societies physically, psychologically and economically. Currently available drugs can only improve cognitive symptoms, have no impact on progression and are not curative, so identifying and studying new drug targets is important. There are evidence that indicate disturbances in cholesterol homeostasis can be related with AD pathology, especially the compartmentation of intracellular cholesterol and cytoplasmic cholesterol esters formed by acyl-CoA: cholesterol acyltransferase 1 (ACAT1) can be implicated in the regulation of amyloid beta (Aβ) peptide, involved in AD. Blocking ACAT1 activity, beneficial effects are obtained, so it has been suggested that ACAT1 can be a potential new therapeutic target. The present review discusses the role of cholesterol homeostasis in AD pathology, especially with ACAT inhibitors, and how they have been raised as a therapeutic approach. In addition, the genetic relationship of ACAT and AD is discussed.
CONCLUSION: Although there are several lines of evidence from cell-based and animal studies that suggest that ACAT inhibition is an effective way of reducing cerebral Aβ, there is still an information gap in terms of mechanisms and concerns to cover before passing to the next level. Additionally, an area of interest that may be useful in understanding AD to subsequently propose new therapeutic approaches is pharmacogenetics; however, there is still a lot of missing information in this area.

PMID: 31441726 [PubMed - as supplied by publisher]

Novel natural myricetin with AIE and ESIPT characteristics for selective detection and imaging of superoxide anions in vitro and in vivo.

Chem Commun (Camb). 2019 Aug 23;:

Authors: Long R, Tang C, Xu J, Li T, Tong C, Guo Y, Shi S, Wang D

Abstract
A novel AIE probe with ESIPT characteristics, myricetin, has been easily purified from vine tea for reversible, selective and sensitive targeting of O2˙- in turn-on mode. Its AIE nanocrystals exhibit large Stokes shift, high photostability, excellent biocompatibility, and low cytotoxicity for endogenous O2˙- detection and imaging in vitro and in vivo.

PMID: 31441468 [PubMed - as supplied by publisher]