Replication study of polymorphisms associated with response to methotrexate in patients with rheumatoid arthritis.

Sci Rep. 2018 05 09;8(1):7342

Authors: López-Rodríguez R, Ferreiro-Iglesias A, Lima A, Bernardes M, Pawlik A, Paradowska-Gorycka A, Świerkot J, Slezak R, Dolžan V, González-Álvaro I, Narváez J, Cáliz R, Pérez-Pampín E, Mera-Varela A, Vidal-Bralo L, Acuña Ochoa JG, Conde C, Gómez-Reino JJ, González A

Abstract
About 70 genetic studies have already addressed the need of biomarkers to predict the response of patients with rheumatoid arthritis (RA) to methotrexate (MTX) treatment. However, no genetic biomarker has yet been sufficiently validated. Here, we aimed to replicate a selection of 25 SNPs in the largest collection of patients up to date, which consisted of 915 patients treated with MTX. The change in disease activity (measured as ΔDAS28) from baseline was considered the primary outcome. In addition, response according to widely used criteria (EULAR) was taken as secondary outcome. We considered consistency between outcomes, P values accounting for the number of SNPs, and independence from potential confounders for interpretation of the results. Only the rs1801394 SNP in MTRR fulfilled the high association standards. Its minor allele was associated with less improvement than the major allele according to ΔDAS28 (p = 0.0016), and EULAR response (p = 0.004), with independence of sex, age, baseline DAS28, smoking, seropositivity, concomitant corticosteroid use or previous treatments. In addition, previous evidence suggests the association of this SNP with response to MTX in another autoimmune disease, juvenile idiopathic arthritis, and with high intracellular folate levels, which could contribute to poor response.

PMID: 29743634 [PubMed - indexed for MEDLINE]

Clinical Utility of Pharmacogene Panel-Based Testing in Patients Undergoing Percutaneous Coronary Intervention (PCI).

Clin Transl Sci. 2019 Nov 23;:

Authors: El Rouby N, Alrwisan A, Langaee T, Lipori G, Angiolillo DJ, Franchi F, Riva A, Elsey A, Johnson JA, Cavallari LH, Winterstein AG

Abstract
We aimed to estimate the utility of panel-based pharmacogenetic testing of patients undergoing percutaneous coronary intervention (PCI). Utilization of Clinical Pharmacogenetic Implementation Consortium (CPIC) level A/B drugs after PCI was estimated in a national sample of IBM MarketScan beneficiaries. Genotype data from University of Florida (UF) PCI patients (n=211) were used to project genotype-guided opportunities among MarketScan beneficiaries with at least one- (N=105,547) and five-(N=12,462) years of follow up data. The actual incidence of genotype-guided prescribing opportunities was determined among UF patients. In MarketScan, 50.0% (52,799/105,547) over one year and 68.0% (8,473/12,462) over five years had ≥ one CPIC A/B drug besides antiplatelet therapy prescribed, with a projected incidence of genotype-guided prescribing opportunities of 39% at one year and 52% at five years. Genotype-guided prescribing opportunities occurred in 32% of UF patients. Projected and actual incidence of genotype-guided opportunities among two cohorts support the utility of panel-based testing among PCI patients.

PMID: 31758664 [PubMed - as supplied by publisher]

Alternative polyadenylation of ABC-transporters of the C-family (ABCC1, ABCC2, ABCC3) and implications on post-transcriptional micro-RNA regulation.

Mol Pharmacol. 2019 Nov 22;:

Authors: Bruhn O, Lindsay M, Wiebel F, Kaehler M, Nagel I, Bohm R, Roder C, Cascorbi I

Abstract
ABC-transporters represent a large group of efflux pumps being strongly involved in the pharmacokinetics of various drugs as well as of nutrient distribution. It was recently shown that miRNAs may significantly alter their expression as proven e.g. for miR-379 and ABCC2. However, alternative mRNA polyadenylation may result in expression of 3'-untranslated regions (3'-UTRs) with varying lengths. Thus, length variants may result in presence or absence of miRNA binding sites for regulatory micro-RNAs with consequences on posttranscriptional control. In the present study, we report on 3'-UTR variants of ABCC1, ABCC2, and ABCC3 mRNA. Applying in vitro luciferase reporter gene assays, we show that expression of short ABCC2 3'-UTR variants leads to a significant loss of miR-379/ABCC2 interaction and subsequent upregulation of ABCC2 expression. Further, we show that expression of ABCC2 3'-UTR lengths varies significantly between human healthy tissues, but is not directly correlated to the respective protein level in vivo. Concluding, presence of altered 3'-UTR lengths in ABC-transporters could lead to functional consequences with regards to posttranscriptional gene expression potentially regulated by alternative polyadenylation. Hence, 3'-UTR length variability may be considered as a further mechanism contributing to variability of ABCC transporter expression and subsequent drug variation in drug response. SIGNIFICANCE STATEMENT: microRNA binding to the 3-UTR plays an important role in control of ABC-transporter mRNA degradation and translation into proteins. We disclosed various 3-UTR length variants of ABCC1, C2 and C3 mRNA partly with loss of mRNA seed regions leading to varying and tissue-dependent interaction with miRNAs as proven by reporter gene assays. Alternative 3-UTR length may contribute to variable ABCC-transporter expression and potentially explains inconsistent findings in microRNA studies.

PMID: 31757862 [PubMed - as supplied by publisher]

High content phenotypic screening identifies serotonin receptor modulators with selective activity upon breast cancer cell cycle and cytokine signaling pathways.

Bioorg Med Chem. 2019 Nov 09;:115209

Authors: Warchal SJ, Dawson JC, Shepherd E, Munro AF, Hughes RE, Makda A, Carragher NO

Abstract
Heterogeneity in disease mechanisms between genetically distinct patients contributes to high attrition rates in late stage clinical drug development. New personalized medicine strategies aim to identify predictive biomarkers which stratify patients most likely to respond to a particular therapy. However, for complex multifactorial diseases not characterized by a single genetic driver, empirical approaches to identifying predictive biomarkers and the most promising therapies for personalized medicine are required. In vitro pharmacogenomics seeks to correlate in vitro drug sensitivity testing across panels of genetically distinct cell models with genomic, gene expression or proteomic data to identify predictive biomarkers of drug response. However, the vast majority of in vitro pharmacogenomic studies performed to date are limited to dose-response screening upon a single viability assay endpoint. In this article we describe the application of multiparametric high content phenotypic screening and the theta comparative cell scoring method to quantify and rank compound hits, screened at a single concentration, which induce a broad variety of divergent phenotypic responses between distinct breast cancer cell lines. High content screening followed by transcriptomic pathway analysis identified serotonin receptor modulators which display selective activity upon breast cancer cell cycle and cytokine signaling pathways correlating with inhibition of cell growth and survival. These methods describe a new evidence-led approach to rapidly identify compounds which display distinct response between different cell types. The results presented also warrant further investigation of the selective activity of serotonin receptor modulators upon breast cancer cell growth and survival as a potential drug repurposing opportunity.

PMID: 31757681 [PubMed - as supplied by publisher]

Genomics Testing and Personalized Medicine in the Preoperative Setting.

Surg Oncol Clin N Am. 2020 Jan;29(1):73-86

Authors: Gabriel RA, Burton BN, Urman RD, Waterman RS

Abstract
Pharmacogenomics (PGx) is the study of how individuals' personal genotypes may affect their responses to various pharmacologic agents. The application of PGx principles in perioperative medicine is fairly novel. Challenges in executing PGx programs into health care systems include physician buy-in and integration into usual clinical workflow, including the electronic health record. This article discusses the current evidence highlighting the potential of PGx with various drug categories (including opioids, nonopioid analgesics, sedatives, β-blockers, antiemetics, and anticoagulants) used in the perioperative process and the challenges of integrating PGx into a health care system and relevant workflows.

PMID: 31757315 [PubMed - in process]

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Genetic Study of Severe Prolonged Lymphopenia in Multiple Sclerosis Patients Treated With Dimethyl Fumarate.

Front Genet. 2019;10:1039

Authors: Sangurdekar D, Sun C, McLaughlin H, Ayling-Rouse K, Allaire NE, Penny MA, Bronson PG

Abstract
In delayed-release dimethyl fumarate (DMF)-treated patients, absolute lymphocyte count (ALC) often declines in the first year and stabilizes thereafter; early declines have been associated with development of severe prolonged lymphopenia (SPL). Prolonged moderate or severe lymphopenia is a known risk factor for progressive multifocal leukoencephalopathy (PML); DMF-associated PML is very rare. It is unknown whether genetic predictors of SPL secondary to DMF treatment exist. We aimed to identify genetic predictors of reduced white blood cell (WBC) counts in DMF-treated multiple sclerosis (MS) patients. Genotyping (N = 1,258) and blood transcriptional profiling (N = 1,133) were performed on MS patients from DEFINE/CONFIRM. ALCs were categorized as: SPL, < 500 cells/µL for ≥6 months; moderate prolonged lymphopenia (MPL), < 800 cells/µL for ≥6 months, excluding SPL; mildly reduced lymphocytes, < 910 cells/µL at any point, excluding SPL and MPL; no lymphopenia, ≥910 cells/µL. Genome-wide association, HLA, and cross-sectional gene expression studies were performed. No common variants, HLA alleles, or expression profiles clinically useful for predicting SPL or MPL were identified. There was no overlap between genetic peaks and genetic loci known to be associated with WBC. Gene expression profiles were not associated with lymphopenia status. A classification model including gene expression features was not more predictive of lymphopenia status than standard covariates. There were no genetic predictors of SPL (or MPL) secondary to DMF treatment. Our results support ALC monitoring during DMF treatment as the most effective way to identify patients at risk of SPL.

PMID: 31749835 [PubMed]

Biflorin inhibits the proliferation of gastric cancer cells by decreasing MYC expression.

Toxicol In Vitro. 2019 Nov 18;:104735

Authors: Barbosa-Jobim GS, Costa-Lira É, Ralph ACL, Gregório L, Lemos TLG, Burbano RR, Calcagno DQ, Smith MAC, Montenegro RC, Vasconcellos MC

Abstract
Gastric cancer is the third leading cause of cancer-related death worldwide. To evaluate the anticancer potential and molecular mechanism of biflorin, a prenyl-ortho-naphthoquinone obtained from Capraria biflora L. roots, we used ACP02, a gastric cancer cell line established from a primary diffuse gastric adenocarcinoma. In this study, biflorin was shown to be a potent cytotoxic agent against ACP02 by Alamar Blue and Trypan Blue assays. Morphological analysis indicated cell death with features of necrosis. Furthermore, a decrease in colony formation, migration and invasion of ACP02 cells was observed after treatment with biflorin (1.0, 2.5 and 5.0 μM). Regarding the underlying molecular mechanism of biflorin in ACP02 cells, we observed a decrease in MYC expression and telomere length using FISH. Our findings suggest a novel molecular target of biflorin in ACP02 cells, which may be a significant therapeutic approach for gastric cancer management.

PMID: 31751609 [PubMed - as supplied by publisher]

The Patient-Centered Future of Clinical Pharmacology.

Clin Pharmacol Ther. 2019 Nov 21;:

Authors: Shahin MH, Abdel-Rahman S, Hartman D, Johnson JA, Mitchell DY, Reynolds KS, Wagner JA, Morrissey KM

PMID: 31751490 [PubMed - as supplied by publisher]

Pharmacogenetics and therapeutic drug monitoring of fluoxetine in a real-world setting: A PK/PD analysis of the influence of (non-)genetic factors.

Exp Clin Psychopharmacol. 2019 Nov 21;:

Authors: Magalhães P, Alves G, Fortuna A, Llerena A, Falcão A, Clinical Collaborators of the GnG-PK/PD-AD Study

Abstract
This work presents the GnG-PK/PD-AD study-a pharmacokinetics/pharmacodynamics (PK/PD) analysis of the impact of genetic and nongenetic factors on the treatment with the antidepressant fluoxetine (FLU)-with a focus on potential biomarkers. Seventy-nine depressed patients treated with FLU were recruited and clinically characterized in the scope of the study. Clinical outcomes, including remission and antidepressant adverse effects were assessed by means of the Hamilton Depression Rating Scale and the Antidepressant Side-Effect Checklist, respectively. Patients were submitted to therapeutic drug monitoring of FLU and norfluoxetine and genotyping of the CYP2C9, CYP2C19, CYP2D6, and ABCB1 genes. A multivariate analysis was used to evaluate the impact of genetic and nongenetic factors on the drug plasma concentrations and clinical outcomes and to identify potential biomarkers. Genetically determined CYP2D6 activity was found to be a predictor of FLU and norfluoxetine concentrations (p < .05). In turn, genetic and nongenetic factors related to CYP2D6 and P-glycoprotein were found as potential biomarkers of the clinical outcomes of FLU (p < .05). Specifically, the potential of the CYP2D6 to be inhibited by drug-induced phenoconversion was associated with a higher severity of depression (p < .05). Moreover, ABCB1 TTT-haplotype was favorable to better clinical outcomes with FLU (higher likelihood of remission and lower severity of adverse effects; p < .05). The potential of the P-glycoprotein to be inhibited by drug-induced phenoconversion was also related to a worse tolerability profile (higher severity and number of adverse effects; p < .05). Lastly, the presence of nervous system comorbidities was associated with a higher severity of adverse effects and aging and the female gender with a higher severity of depression and lower probability of remission (p < .05). (PsycINFO Database Record (c) 2019 APA, all rights reserved).

PMID: 31750687 [PubMed - as supplied by publisher]

Isolation and characterization of the first Slovenian human triple-negative breast cancer cell line.

Breast J. 2019 Nov 20;:

Authors: Skok K, Gradišnik L, Čelešnik H, Potočnik U, Kavalar R, Takač I, Maver U

PMID: 31749235 [PubMed - as supplied by publisher]

Identifying genetic variants underlying medication-induced osteonecrosis of the jaw in cancer and osteoporosis: a case control study.

J Transl Med. 2019 Nov 20;17(1):381

Authors: Lee KH, Kim SH, Kim CH, Min BJ, Kim GJ, Lim Y, Kim HS, Ahn KM, Kim JH

Abstract
BACKGROUND: Bisphosphonate-induced osteonecrosis of the jaw (BRONJ) presents with a typical pattern of jaw necrosis in patients who have been prescribed bisphosphonates (BPs) and other antiangiogenetic drugs to treat osteoporosis or bone-related complications of cancer.
METHODS: This study divided 38 patients with BRONJ into two groups according to the prescribing causes: cancer (n = 13) and osteoporosis (n = 25), and underwent whole exome sequencing and compared them with normal controls (n = 90). To identify candidate genes and variants, we conducted three analyses: a traditional genetic model, gene-wise variant score burden, and rare-variant analysis methods.
RESULTS: The stop-gain mutation (rs117889746) of the PZP gene in the BRONJ cancer group was significantly identified in the additive trend model analysis. In the cancer group, ARIDS, HEBP1, LTBP1, and PLVAP were identified as candidate genes. In the osteoporosis group, VEGFA, DFFA, and FAM193A genes showed a significant association. No significant genes were identified in the rare-variant analysis pipeline. Biologically accountable functions related to BRONJ occurrence-angiogenesis-related signaling (VEGFA and PLVAP genes), TGF-β signaling (LTBP1 and PZP genes), heme toxicity (HEBP1) and osteoblast maturation (ARIDS)-were shown in candidate genes.
CONCLUSION: This study showed that the candidate causative genes contributing to the development of BRONJ differ according to the BP dose and background disease.

PMID: 31747953 [PubMed - in process]

CD147 Is a Promising Target of Tumor Progression and a Prognostic Biomarker.

Cancers (Basel). 2019 Nov 16;11(11):

Authors: Landras A, Reger de Moura C, Jouenne F, Lebbe C, Menashi S, Mourah S

Abstract
Microenvironment plays a crucial role in tumor development and progression. Cancer cells modulate the tumor microenvironment, which also contribute to resistance to therapy. Identifying biomarkers involved in tumorigenesis and cancer progression represents a great challenge for cancer diagnosis and therapeutic strategy development. CD147 is a glycoprotein involved in the regulation of the tumor microenvironment and cancer progression by several mechanisms-in particular, by the control of glycolysis and also by its well-known ability to induce proteinases leading to matrix degradation, tumor cell invasion, metastasis and angiogenesis. Accumulating evidence has demonstrated the role of CD147 expression in tumor progression and prognosis, suggesting it as a relevant tumor biomarker for cancer diagnosis and prognosis, as well as validating its potential as a promising therapeutic target in cancers.

PMID: 31744072 [PubMed]

A Validation Study of the Remotely Administered Montreal Cognitive Assessment Tool in the Elderly Japanese Population.

Telemed J E Health. 2019 Nov 19;:

Authors: Iiboshi K, Yoshida K, Yamaoka Y, Eguchi Y, Sato D, Kishimoto M, Funaki K, Mimura M, Kishimoto T

Abstract
Background: In an aging society, neuropsychological testing using video teleconferencing (VTC) is increasingly important. Despite the potential benefit of a VTC-administered Montreal Cognitive Assessment Tool (MoCA) to detect cognitive decline, only a limited number of studies have investigated this tool's reliability. Therefore, we aimed to evaluate the reliability of VTC-administered MoCA compared with face-to-face (FTF)-administered MoCA among elderly Japanese participants. Moreover, we examined participants' satisfaction with VTC-administered MoCA. Methods: Participants ≥60 years of age with and without cognitive impairment (i.e., those with mild cognitive impairment [MCI], those with dementia, and healthy controls [HC]) were assessed with VTC- and FTF-administered MoCA at an interval of >2 weeks and <3 months. The order effect (VTC first vs. FTF first) and time effect (first vs. second testing session), as well as several covariates such as age and years of education were controlled. Intraclass correlation coefficients (ICCs) were calculated using a mixed-effects model to assess the agreement between the two (VTC- vs. FTF-administered) groups. Participants' satisfaction with VTC-administered MoCA was examined using a Likert scale asking seven questions. Results: We included 73 participants in the study (36 men; age, 76.3 ± 7.5 years). The ICC for the MoCA total score was high in the entire sample (0.85), whereas ICCs were moderate to high for the subgroups (MCI: 0.82, dementia: 0.82, and HC: 0.53). Furthermore, we found good overall participant satisfaction with VTC-administered MoCA. Discussion: VTC-administered MoCA appears viable as an alternative to FTF-administered MoCA, although further replication studies with larger sample sizes are needed.

PMID: 31746697 [PubMed - as supplied by publisher]

Dutch Pharmacogenetics Working Group (DPWG) guideline for the gene-drug interaction of DPYD and fluoropyrimidines.

Eur J Hum Genet. 2019 Nov 19;:

Authors: Lunenburg CATC, van der Wouden CH, Nijenhuis M, Crommentuijn-van Rhenen MH, de Boer-Veger NJ, Buunk AM, Houwink EJF, Mulder H, Rongen GA, van Schaik RHN, van der Weide J, Wilffert B, Deneer VHM, Swen JJ, Guchelaar HJ

Abstract
Despite advances in the field of pharmacogenetics (PGx), clinical acceptance has remained limited. The Dutch Pharmacogenetics Working Group (DPWG) aims to facilitate PGx implementation by developing evidence-based pharmacogenetics guidelines to optimize pharmacotherapy. This guideline describes the starting dose optimization of three anti-cancer drugs (fluoropyrimidines: 5-fluorouracil, capecitabine and tegafur) to decrease the risk of severe, potentially fatal, toxicity (such as diarrhoea, hand-foot syndrome, mucositis or myelosuppression). Dihydropyrimidine dehydrogenase (DPD, encoded by the DPYD gene) enzyme deficiency increases risk of fluoropyrimidine-induced toxicity. The DPYD-gene activity score, determined by four DPYD variants, predicts DPD activity and can be used to optimize an individual's starting dose. The gene activity score ranges from 0 (no DPD activity) to 2 (normal DPD activity). In case it is not possible to calculate the gene activity score based on DPYD genotype, we recommend to determine the DPD activity and adjust the initial dose based on available data. For patients initiating 5-fluorouracil or capecitabine: subjects with a gene activity score of 0 are recommended to avoid systemic and cutaneous 5-fluorouracil or capecitabine; subjects with a gene activity score of 1 or 1.5 are recommended to initiate therapy with 50% the standard dose of 5-fluorouracil or capecitabine. For subjects initiating tegafur: subjects with a gene activity score of 0, 1 or 1.5 are recommended to avoid tegafur. Subjects with a gene activity score of 2 (reference) should receive a standard dose. Based on the DPWG clinical implication score, DPYD genotyping is considered "essential", therefore directing DPYD testing prior to initiating fluoropyrimidines.

PMID: 31745289 [PubMed - as supplied by publisher]

Gender based differences, pharmacogenetics and adverse events in chronic pain management.

Pharmacogenomics J. 2019 Nov 20;:

Authors: Planelles B, Margarit C, Inda MD, Ballester P, Muriel J, Barrachina J, Ajo R, Esteban MD, Peiró AM

Abstract
Safety data in chronic non-cancer pain (CNCP) with long-term opioid therapy has been poorly studied and can be differently influenced by gender. Furthermore, pharmacogenetics (PGx) could possibly be used to tailor pain medication based on the individual's genetic background. The aim was to assess whether PGx applied to a pharmacovigilance system could help to improve a patient's security profile. A pharmacovigilance data recording system was conducted over 24 months, including genotyping of OPRM1 variants (opioid receptor, A118G) and COMT (enzyme that degrades catecholamines such as norepinephrine, G1947A). Pain intensity (visual analogue scale, VAS), morphine equivalent daily dose (MEDD), adverse events (AEs) and suspected adverse drug reactions (ADRs) were recorded and analysed by gender. The Ethics Committee approved the study and data were analysed with R 3.6.0 software. A total of 748 patients were recruited in the study (67% female, VAS 62 ± 29 mm, MEDD 119 ± 114 mg/day) reporting a median of 6 (3.5-9) AEs/patient. Women presented more nausea, headaches, insomnia, loss of appetite, weight change, depression and dizziness than men. Analysis by genotype demonstrated that PGx influenced the prevalence of vomiting and depression in men, dizziness in women and sexual dysfunction in both. Physicians notified 150 ADRs mostly in females (79%) related to nervous system disorders. PGx applied to a pharmacovigilance recording system provides important information to achieve a better knowledge about AEs in CNCP pharmacological therapy. OPRM1 and COMT polymorphisms were associated with AEs in CNCP patients that differed according to gender.

PMID: 31745220 [PubMed - as supplied by publisher]

Chaperone Sigma1R mediates the neuroprotective action of afobazole in the 6-OHDA model of Parkinson's disease.

Sci Rep. 2019 Nov 19;9(1):17020

Authors: Voronin MV, Kadnikov IA, Voronkov DN, Seredenin SB

Abstract
Parkinson's disease (PD) is a progressive neurodegenerative disease with limited treatment options. Therefore, the identification of therapeutic targets is urgently needed. Previous studies have shown that the ligand activation of the sigma-1 chaperone (Sigma1R) promotes neuroprotection. The multitarget drug afobazole (5-ethoxy-2-[2-(morpholino)-ethylthio]benzimidazole dihydrochloride) was shown to interact with Sigma1Rs and prevent decreases in striatal dopamine in the 6-hydroxydopamine (6-OHDA)-induced parkinsonism model. The aim of the present study was to elucidate the role of Sigma1Rs in afobazole pharmacological activity. Using ICR mice we found that administration of afobazole (2.5 mg/kg, i.p.) or selective agonist of Sigma1R PRE-084 (1.0 mg/kg, i.p.) over 14 days normalizes motor disfunction and prevents decreases in dopamine in the 6-OHDA-lesioned striatum. Afobazole administration also prevents the loss of TH + neurons in the substantia nigra. The pre-administration of selective Sigma1R antagonist BD-1047 (3.0 mg/kg, i.p.) abolishes the activity of either afobazole or PRE-084, as determined using the rotarod test and the analysis of striatal dopamine content. The current study demonstrates the contribution of Sigma1Rs in the neuroprotective effect of afobazole in the 6-OHDA model of Parkinson's disease and defines the therapeutic perspective of Sigma1R agonists in the clinic.

PMID: 31745133 [PubMed - in process]

Pregnancy and CYP3A5 Genotype Affect Day 7 Plasma Lumefantrine Concentrations.

Drug Metab Dispos. 2019 Dec;47(12):1415-1424

Authors: Mutagonda RF, Minzi OMS, Massawe SN, Asghar M, Färnert A, Kamuhabwa AAR, Aklillu E

Abstract
Pregnancy and pharmacogenetics variation alter drug disposition and treatment outcome. The objective of this study was to investigate the effect of pregnancy and pharmacogenetics variation on day 7 lumefantrine (LF) plasma concentration and therapeutic responses in malaria-infected women treated with artemether-lumefantrine (ALu) in Tanzania. A total of 277 (205 pregnant and 72 nonpregnant) women with uncomplicated Plasmodium falciparum malaria were enrolled. Patients were treated with ALu and followed up for 28 days. CYP3A4, CYP3A5, and ABCB1 genotyping were done. Day 7 plasma LF concentration and the polymerase chain reaction (PCR) - corrected adequate clinical and parasitological response (ACPR) at day 28 were determined. The mean day 7 plasma LF concentrations were significantly lower in pregnant women than nonpregnant women [geometric mean ratio = 1.40; 95% confidence interval (CI) of geometric mean ratio (1.119-1.1745), P < 0.003]. Pregnancy, low body weight, and CYP3A5*1/*1 genotype were significantly associated with low day 7 LF plasma concentration (P < 0.01). PCR-corrected ACPR was 93% (95% CI = 89.4-96.6) in pregnant women and 95.7% (95% CI = 90.7-100) in nonpregnant women. Patients with lower day 7 LF concentration had a high risk of treatment failure (mean 652 vs. 232 ng/ml, P < 0.001). In conclusion, pregnancy, low body weight, and CYP3A5*1 allele are significant predictors of low day 7 LF plasma exposure. In turn, lower day 7 LF concentration is associated with a higher risk of recrudescence. SIGNIFICANCE STATEMENT: This study reports a number of factors contributing to the lower day 7 lumefantrine (LF) concentration in women, which includes pregnancy, body weight, and CYP3A5*1/*1 genotype. It also shows that day 7 LF concentration is a main predictor of malaria treatment. These findings highlight the need to look into artemether-LF dosage adjustment in pregnant women so as to be able to maintain adequate drug concentration, which is required to reduce treatment failure rates in pregnant women.

PMID: 31744845 [PubMed - in process]

Pharma-Oncogenomics in the Era of Personal Genomics: A Quick Guide to Online Resources and Tools.

Adv Exp Med Biol. 2019;1168:103-115

Authors: Joshi RP, Steiner DF, Konnick EQ, Suarez CJ

Abstract
The past two decades have seen unprecedented advances in the field of oncogenomics. The ongoing characterization of neoplastic tissues through genomic techniques has transformed many aspects of cancer research, diagnosis, and treatment. However, identifying sequence variants with biological and clinical significance is a challenging endeavor. In order to accomplish this task, variants must be annotated and interpreted using various online resources. Data on protein structure, functional prediction, variant frequency in relevant populations, and multiple other factors have been compiled in useful databases for this purpose. Thus, understanding the available online resources for the annotation and interpretation of sequence variants is critical to aid molecular pathologists and researchers working in this space.

PMID: 31713167 [PubMed - indexed for MEDLINE]

Issues and Ethical Considerations in Pharmaco-oncogenomics.

Adv Exp Med Biol. 2019;1168:91-101

Authors: Morgan G

Abstract
The rapid advancements of treatment modalities and vast amounts of information being generated through novel technologies, paint the picture of a very promising future, one that will allow for a more efficient and precise DNA sequencing and potentially more tailored cancer therapies for patients. However, with all these advances we must address the ethical and legal considerations each one of these technologies will raise. This is a necessity in order for advancement, not to stand in the way of science and development, but as a safeguard in protecting humanity and our personal genetic information.

PMID: 31713166 [PubMed - indexed for MEDLINE]