Molecular pathway analysis associates alterations in obesity related genes and antipsychotic-induced weight gain.

Acta Neuropsychiatr. 2019 Oct 17;:1-21

Authors: Corfitsen HT, Krantz B, Larsen A, Drago A

Abstract
OBJECTIVE: Antipsychotics often induce excessive weight gain. We hypothesized that individuals with genetic variations related to known obesity-risk genes have an increased risk of excessive antipsychotic-induced weight gain. This hypothesis was tested in a subset of the CATIE trial data-set.
METHODS: The CATIE trial compared effects and side effects of five different antipsychotics through an 18 month period. Based on the maximum weight gain recorded, excessive weight gain was defined as >7% weight-gain. Cytoscape and GeneMania were instrumental in composing a molecular pathway from eight selected genes linked to obesity. Genetic information on a total of 495.172 SNPs were available from 765 (556 males) individuals. Enrichment test was conducted through reactomePA and Bioconductor. A permutation test was performed, testing the generated pathway against 105 permutated pathways (p</=0.05). In addition a standard GWAS-analysis was performed.
RESULT: GWAS analysis did not detect significant differences related to excessive weight gain. The pathway generated contained 28 genes. A total of 2067 SNPs were significantly expressed (p<0.01) within this pathway when comparing excessive weight gainers to the rest of the sample. Affected genes included PPARG and PCSK1 not previously related to treatment-induced weight gain.
CONCLUSIONS: The molecular pathway composed from high-risk obesity genes, was shown to overlap with genetics of patients who gained > 7% weight gain during the CATIE trial. This suggests that genes related to obesity, composes a pathway of increased risk of excessive antipsychotic-induced weight gain. Further independent analyses are warranted that may confirm or clarify the possible reasoning behind.

PMID: 31619305 [PubMed - as supplied by publisher]

MicroRNAs as a Potential Quality Measurement Tool of Platelet Concentrate Stored in Blood Banks-A Review.

Cells. 2019 Oct 15;8(10):

Authors: Maués JHDS, Aquino Moreira-Nunes CF, Rodriguez Burbano RM

Abstract
BACKGROUND: Platelet concentrate (PC) is one of the main products used in a therapeutic transfusion. This blood component requires special storage at blood banks, however, even under good storage conditions, modifications or degradations may occur and are known as platelet storage lesions.
METHODS: This research was performed on scientific citation databases PubMed/Medline, ScienceDirect, and Web of Science, for publications containing platelet storage lesions. The results obtained mainly reveal the clinical applicability of miRNAs as biomarkers of storage injury and as useful tools for a problem affecting public and private health, the lack of PC bags in countries with few blood donors. The major studies listed in this review identified miRNAs associated with important platelet functions that are relevant in clinical practice as quality biomarkers of PC, such as miR-223, miR-126, miR-10a, miR-150, miR-16, miR-21, miR-326, miR-495, let-7b, let-7c, let-7e, miR-107, miR-10b, miR-145, miR-155, miR-17, miR-191, miR-197, miR-200b, miR-24, miR-331, miR-376. These miRNAs can be used in blood banks to identify platelet injury in PC bags.
CONCLUSION: The studies described in this review relate the functions of miRNAs with molecular mechanisms that result in functional platelet differences, such as apoptosis. Thus, miRNA profiles can be used to measure the quality of storage PC for more than 5 days, identify bags with platelet injury, and distinguish those with functional platelets.

PMID: 31618890 [PubMed - in process]

Response.

AANA J. 2018 06;86(3):30

Authors: Aroke E

PMID: 31612852 [PubMed - indexed for MEDLINE]

Design and rational for the precision medicine guided treatment for cancer pain pragmatic clinical trial.

Contemp Clin Trials. 2018 05;68:7-13

Authors: Mosley SA, Hicks JK, Portman DG, Donovan KA, Gopalan P, Schmit J, Starr J, Silver N, Gong Y, Langaee T, Clare-Salzler M, Starostik P, Chang YD, Rajasekhara S, Smith JE, Soares HP, George TJ, McLeod HL, Cavallari LH

Abstract
INTRODUCTION: Pain is one of the most burdensome symptoms associated with cancer and its treatment, and opioids are the cornerstone of pain management. Opioid therapy is empirically selected, and patients often require adjustments in therapy to effectively alleviate pain or ameliorate adverse drug effects that interfere with quality of life. There are data suggesting CYP2D6 genotype may contribute to inter-patient variability in response to opioids through its effects on opioid metabolism. Therefore, we aim to determine if CYP2D6 genotype-guided opioid prescribing results in greater reductions in pain and symptom severity and interference with daily living compared to a conventional prescribing approach in patients with cancer.
METHODS: Patients with solid tumors with metastasis and a self-reported pain score ≥ 4/10 are eligible for enrollment and randomized to a genotype-guided or conventional pain management strategy. For patients in the genotype-guided arm, CYP2D6 genotype information is integrated into opioid prescribing decisions. Patients are asked to complete questionnaires regarding their pain, symptoms, and quality of life at baseline and 2, 4, 6, and 8 weeks after enrollment. The primary endpoint is differential change in pain severity by treatment strategy (genotype-guided versus conventional pain management). Secondary endpoints include change in pain and symptom interference with daily living.
CONCLUSION: Pharmacogenetic-guided opioid selection for cancer pain management has potential clinical utility, but current evidence is limited to retrospective and observational studies. Precision Medicine Guided Treatment for Cancer Pain is a pragmatic clinical trial that seeks to determine the utility of CYP2D6 genotype-guided opioid prescribing in patients with cancer.

PMID: 29535047 [PubMed - indexed for MEDLINE]

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pharmacogenomics

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pharmacogenomics

These pubmed results were generated on 2019/10/17

PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

Targeting the Versatile Wnt/β-Catenin Pathway in Cancer Biology and Therapeutics: From Concept to Actionable Strategy.

OMICS. 2019 Oct 15;:

Authors: Dzobo K, Thomford NE, Senthebane DA

Abstract
This expert review offers a critical synthesis of the latest insights and approaches at targeting the Wnt/β-catenin pathway in various cancers such as colorectal cancer, melanoma, leukemia, and breast and lung cancers. Notably, from organogenesis to cancer, the Wnt/β-catenin signaling displays varied and highly versatile biological functions in animals, with virtually all tissues requiring the Wnt/β-catenin signaling in one way or the other. Aberrant expression of the members of the Wnt/β-catenin has been implicated in many pathological conditions, particularly in human cancers. Mutations in the Wnt/β-catenin pathway genes have been noted in diverse cancers. Biochemical and genetic data support the idea that inhibition of Wnt/β-catenin signaling is beneficial in cancer therapeutics. The interaction of this important pathway with other signaling systems is also noteworthy, but remains as an area for further research and discovery. In addition, formation of different complexes by components of the Wnt/β-catenin pathway and the precise roles of these complexes in the cytoplasmic milieu are yet to be fully elucidated. This article highlights the latest medical technologies in imaging, single-cell omics, use of artificial intelligence (e.g., machine learning techniques), genome sequencing, quantum computing, molecular docking, and computational softwares in modeling interactions between molecules and predicting protein-protein and compound-protein interactions pertinent to the biology and therapeutic value of the Wnt/β-catenin signaling pathway. We discuss these emerging technologies in relationship to what is currently needed to move from concept to actionable strategies in translating the Wnt/β-catenin laboratory discoveries to Wnt-targeted cancer therapies and diagnostics in the clinic.

PMID: 31613700 [PubMed - as supplied by publisher]

Analysis of galanin receptor GALR2 in multiple sclerosis.

Pharmacogenomics J. 2019 Oct 14;:

Authors: Encarnacion M, Bernales CQ, Traboulsee AL, Sadovnick AD, Vilariño-Güell C

PMID: 31611593 [PubMed - as supplied by publisher]

Folyl polyglutamate synthethase (FPGS) gene polymorphisms may influence methotrexate adverse events in South Indian Tamil Rheumatoid Arthritis patients.

Pharmacogenomics J. 2019 Oct 14;:

Authors: Muralidharan N, Sundaram R, Kodidela S, Chengappa KG, Mariaselvam CM, Misra DP, Negi VS

Abstract
The aim of the study was to look for the association of FPGS 2752 G > A (rs1544105), FPGS 1994 A > G (rs10106), and GGH 452 C > T (rs 11545078), GGH -401C > T (rs 3758149) gene polymorphisms with methotrexate (MTX) treatment response and MTX-induced adverse events in South Indian Tamil patients with rheumatoid arthritis (RA). Further the influence of these gene polymorphisms on MTX polyglutamate levels was analyzed. A total of 330 patients with RA were investigated. FPGS gene polymorphisms were analyzed by TaqMan 5'nuclease assay and GGH gene polymorphisms were analyzed by PCR-RFLP. Methotrexate polyglutamates (nmol/L of packed erythrocytes) were measured by liquid chromatography mass spectrometry (LCMS/MS) method. We found that the heterozygous genotype of FPGS rs1544105 [p = 0.02, OR 1.93, 95% CI (1.15-3.35)] and FPGS rs10106 AG genotype [p = 0.01, OR 2.11, 95% CI (1.20-3.71)] were associated with MTX adverse events. FPGS rs1544105 and GGH -401C > T SNPs influenced the polyglutamate levels. None of the investigated SNPs seems to be associated with MTX treatment outcome.

PMID: 31611592 [PubMed - as supplied by publisher]

A GALNT14 rs9679162 genotype-guided therapeutic strategy for advanced hepatocellular carcinoma: systemic or hepatic arterial infusion chemotherapy.

Pharmacogenomics J. 2019 Oct 14;:

Authors: Lin CC, Hsu CW, Chen YC, Chang ML, Liang KH, Lai MW, Lin CL, Chien RN, Lin KH, Yeh CT

Abstract
Although targeted agents are recommended as the first-line treatments for advanced hepatocellular carcinoma (aHCC), systemic chemotherapy or hepatic arterial infusion chemotherapy (HAIC) are still being used in Asian countries. Beside economic considerations, it was found that targeted drugs could not significantly prolong overall survival in aHCC patients with distant metastasis. In addition, chemotherapy could achieve complete response in a small proportion of patients. Here, we aimed to investigate whether combination of three previously identified single nucleotide polymorphism (SNP) predictors (GALNT14-rs9679162, WWOX-rs13338697, and rs6025211) could guide our choice between systemic chemotherapy, HAIC, and targeted agents in aHCC patients. A cohort of 237 real-world aHCC patients (171 receiving systemic chemotherapy followed by various anticancer treatments including sorafenib; 66 receiving HAIC) were included for outcome analysis. By combining the three SNP markers with or without addition of two clinical criteria (tumor diameter <8 cm, neutrophils <80%), small groups of patients were found to harbor high complete response rates to systemic chemotherapy (35.3% if the 3-SNP signature alone matched; 60.0% if clinical criteria also matched). Subsequent sorafenib treatment for chemotherapy non-responders was associated with longer overall survival (P < 0.001). In HAIC-treated patients, GALNT14-rs9679162 genotype "GG" was associated with longer overall survival (P = 0.019, median survival > 10.5 months). In conclusion, pre-test for the 3-SNP signature in aHCC patients could identify potential systemic chemotherapy or HAIC responders. Chemotherapy non-responders still benefited from subsequent sorafenib treatment. Accordingly, we propose a roadmap for aHCC patients when chemotherapy or HAIC is to be used.

PMID: 31611591 [PubMed - as supplied by publisher]

Effect of ABCB1 genetic polymorphisms on the transport of rivaroxaban in HEK293 recombinant cell lines.

Sci Rep. 2018 Jul 12;8(1):10514

Authors: Sennesael AL, Panin N, Vancraeynest C, Pochet L, Spinewine A, Haufroid V, Elens L

Abstract
Direct oral anticoagulants (DOAC) are substrates for the ABCB1 transporter (also called P-glycoprotein), an active efflux pump. ABCB1 polymorphisms have been previously reported to influence the pharmacokinetics of several drugs such as immunosuppressants and tyrosine kinase inhibitors. Recently, in vivo studies have suggested that genetic variants might contribute to the inter-individual variability in DOAC plasma concentrations. Therefore, we evaluated the in vitro effect of the most common coding ABCB1 single nucleotide polymorphisms (SNP), 1236 C > T-2677G > T-3435C > T, and the coding ABCB1 1199 G > A SNP on the transport activity towards rivaroxaban. HEK293 cells were transfected to overexpress the ABCB1 wild-type (1236C-2677G-3435C, 1199 G) or variant proteins (1236C-2677G-3435T, 1236T-2677T-3435T or 1199 A). ABCB1 expression decreased the intracellular accumulation of rivaroxaban, when compared to control cells. This confirms the involvement of ABCB1 in the active transport of rivaroxaban. However, the ABCB1 1236 C > T-2677G > T-3435C > T and 1199 G > A SNPs had no significant influence on the intracellular accumulation of rivaroxaban when compared to the wild-type protein. These results suggest that the ABCB1 coding SNPs investigated in the present study are unlikely to contribute to the inter-individual variability in rivaroxaban plasma concentrations.

PMID: 30002384 [PubMed - indexed for MEDLINE]

Genetic prediction profile for adalimumab response in Slovenian Crohn's disease patients.

Z Gastroenterol. 2019 Oct;57(10):1218-1225

Authors: Gorenjak M, Repnik K, Jezernik G, Jurgec S, Skok P, Potočnik U

Abstract
INTRODUCTION:  Response to anti-TNF therapy is crucial for life expectancy and life quality in patients with severe Crohn's disease. We investigated if a previously reported gene expression profile predictive for infliximab response could be also applied to adalimumab response in an independent cohort.
METHODS:  Forty-seven Slovene Crohn's disease patients indicated for adalimumab therapy were enrolled in the study. Inflamed and non-inflamed colon biopsy samples were obtained during routine colonoscopy prior to adalimumab treatment. Response to adalimumab was measured with IBDQ. Gene expression in inflamed and non-inflamed colon biopsy samples was measured with RT-qPCR. Genotypes were extracted from previously available genotype data. Statistical analysis was performed with SPSS software. The R package e1071 was used to train bootstrap aggregated support vector machines (SVM).
RESULTS:  SVM prediction model analysis was used to analyze pooled, non-inflamed, and inflamed colon tissue datasets using IBDQ response after 4, 12, 20 and 30 weeks of adalimumab treatment. The bagging approach was used in an endeavor to obtain 100 % accuracy using 10 × 100 or 100 × 100 iterations. Average adalimumab response prediction accuracy is 75.5 % for pooled samples, 90.5 % for inflamed samples, and 100 % for non-inflamed samples. Moreover, models trained on selected SNPs from analyzed genes had an average accuracy of 92.8 %, confirming the involvement of genetic regions mapping the reported genes. Finally, using combined gene expression and SNP data we observed 100 % adalimumab response prediction accuracy for pooled, inflamed, and non-inflamed datasets.
DISCUSSION:  Our study supports the reported genetic anti-TNF response profile and extends it for adalimumab prediction.

PMID: 31610585 [PubMed - in process]

Disease associated polymorphisms within the conserved ECR1 enhancer differentially regulate the tissue specific activity of the cannabinoid-1 receptor gene promoter; implications for cannabinoid pharmacogenetics.

Hum Mutat. 2019 Oct 14;:

Authors: Hay EA, Cowie P, McEwan AR, Ross R, Pertwee RG, MacKenzie A

Abstract
Cannabinoid receptor-1 (CB1) represents a potential drug target against conditions that include obesity and substance abuse. However, drug trials targeting CB1 (encoded by the CNR1 gene) have been compromised by differences in patient response. Towards addressing the hypothesis that genetic changes within the regulatory regions controlling CNR1 expression contribute to these differences, we characterised the effects of disease associated allelic variation within a conserved regulatory sequence (ECR1) in CNR1 intron 2 that had previously been shown to modulate cannabinoid response, alcohol intake and anxiety-like behaviour. We used primary cell analysis of reporters carrying different allelic variants of the human ECR1 and found that human specific C-allele variants of ECR1 (ECR1(C)) drove higher levels of CNR1prom activity in primary hippocampal cells than did the ancestral T-allele and demonstrated a differential response to CB1 agonism. We further demonstrate a role for the AP-1 transcription factor in driving higher ECR1(C) activity and evidence that the ancestral t-allele variant of ECR1 interacted with higher affinity with the insulator binding factor CTCF. The cell-specific approaches used in our study represent an important step in gaining a mechanistic understanding the roles of non-coding polymorphic variation in disease and in the increasingly important field of cannabinoid pharmacogenetics. This article is protected by copyright. All rights reserved.

PMID: 31608546 [PubMed - as supplied by publisher]

[Beta-blockers : myths and facts].

Rev Med Suisse. 2019 Sep 04;15(661):1566-1571

Authors: Gay Des Combes Gliven P, Girod G, Petignat PA, Gobin N

Abstract
Beta-blockers are very commonly drugs used in clinical practice, but whose mechanisms and clinical impacts are not always well understood, especially in certain specific clinical situations. This article proposes a review of some pharmacology notions over the different generations of β-blockers, as well as a review of indications and side effects in particular clinical situations, such as COPD, portal hypertension with esophageal varices and erectile dysfunction. Finally, an overview of response variability of these treatments is discussed from a genetic point of view.

PMID: 31496190 [PubMed - indexed for MEDLINE]

Pharmacokinetics and safety of fluconazole and micafungin in neonates with systemic candidiasis: a randomized, open-label clinical trial.

Br J Clin Pharmacol. 2018 09;84(9):1989-1999

Authors: Leroux S, Jacqz-Aigrain E, Elie V, Legrand F, Barin-Le Guellec C, Aurich B, Biran V, Dusang B, Goudjil S, Coopman S, Garcia Sanchez R, Zhao W, Manzoni P, FP7 TINN (Treat Infections in NeoNates) consortium

Abstract
AIMS: The pharmacokinetics (PK) of fluconazole and micafungin differ in neonates compared with children and adults. Dosing instructions in product labels appear to be inconsistent with the emerging scientific evidence. Limited information is available on the safety profile of these agents in neonates. Our objective was to study the population PK and safety of both drugs, randomly administered in neonates with suspected or confirmed systemic candidiasis.
METHODS: Neonates were randomized 1:1 to fluconazole (loading dose 25 mg kg-1 ; maintenance dose 12 mg kg-1 day-1 or 20 mg kg-1 day-1 , respectively, for infants <30 weeks or ≥30 weeks' corrected gestational age) or micafungin (loading dose 15 mg kg-1 day-1 ; maintenance dose 10 mg kg-1 day-1 ). PK samples were taken on treatment days 1 and 5. Population parameters were determined using NONMEM and Monte Carlo simulations performed to reach predefined targets. Clinical and laboratory data, and adverse events were collected up to 36 weeks' corrected gestational age or hospital discharge.
RESULTS: Thirty-six neonates were enrolled. The median (range) gestational age was 28.2 (24.1-40.1) and 26.8 (23.5-40.0) weeks for fluconazole and micafungin, respectively. Based on 163 PK samples, the median population clearance (l h-1 kg-1 ) and volume of distribution (l kg-1 ) for fluconazole were: 0.015 [95% confidence interval (CI) 0.008, 0.039] and 0.913, and for micafungin were: 0.020 (95% CI 0.010, 0.023) and 0.354 (95% CI 0.225, 0.482), respectively. The loading dose was well tolerated. No adverse events associated with micafungin or fluconazole were reported.
CONCLUSION: Based on Monte Carlo simulations, a loading dose for fluconazole and dosing higher than recommended for both drugs are required to increase the area under the plasma drug concentration-time curve target attainment rate in neonates.

PMID: 29744900 [PubMed - indexed for MEDLINE]

Stage-specific Effects of Bioactive Lipids on Human iPSC Cardiac Differentiation and Cardiomyocyte Proliferation.

Sci Rep. 2018 04 26;8(1):6618

Authors: Sharma A, Zhang Y, Buikema JW, Serpooshan V, Chirikian O, Kosaric N, Churko JM, Dzilic E, Shieh A, Burridge PW, Wu JC, Wu SM

Abstract
Bioactive lipids such as sphingosine-1-phosphate (S1P) and lysophosphatidic acid (LPA) regulate diverse processes including cell proliferation, differentiation, and migration. However, their roles in cardiac differentiation and cardiomyocyte proliferation have not been explored. Using a 96-well differentiation platform for generating human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) we found that S1P and LPA can independently enhance cardiomyocyte generation when administered at an early stage of differentiation. We showed that the combined S1P and LPA treatment of undifferentiated hiPSCs resulted in increased nuclear accumulation of β-catenin, the canonical Wnt signaling pathway mediator, and synergized with CHIR99021, a glycogen synthase kinase 3 beta inhibitor, to enhance mesodermal induction and subsequent cardiac differentiation. At later stages of cardiac differentiation, the addition of S1P and LPA resulted in cell cycle initiation in hiPSC-CMs, an effect mediated through increased ERK signaling. Although the addition of S1P and LPA alone was insufficient to induce cell division, it was able to enhance β-catenin-mediated hiPSC-CM proliferation. In summary, we demonstrated a developmental stage-specific effect of bioactive lipids to enhance hiPSC-CM differentiation and proliferation via modulating the effect of canonical Wnt/β-catenin and ERK signaling. These findings may improve hiPSC-CM generation for cardiac disease modeling, precision medicine, and regenerative therapies.

PMID: 29700394 [PubMed - indexed for MEDLINE]

Comparison of dental caries in Croats from the early medieval period and the 20th century.

Arch Oral Biol. 2019 Sep 27;109:104581

Authors: Nedoklan S, Tadin A, Knezović Z, Sutlović D

Abstract
OBJECTIVE: To compare dental caries frequency in the Croatian population exhumed from two archeological periods and compare two methods: International Caries Detection and Assessment System (ICDAS) and DMFT (Decayed-Missing-Filled-Tooth) index.
MATERIALS AND METHODS: The study included 279 teeth from 69 human remains: Set I of 30 remains and 126 teeth dated from 9th to10th centuries A.D. and Set II of 39 remains and 153 teeth from the recent 20th century. Methods used for caries prevalence were ICDAS and DMFT. Tooth wear was recorded according to the Brabant index.
RESULTS: ICDAS scoring system showed significantly higher caries frequency in Set I of 64.34% and in Set II 59.47%, compared to DMFT method with 16.52% for Set I and 28.75% for Set II. Dental wear in Set I showed 73.91% and in Set II 73.15%, so no significant difference was observed.
CONCLUSIONS: Depending on the ICDAS or DMFT method used for caries detection, different results have been obtained whereby the ICDAS system has a more precise and advanced approach for caries lesions.

PMID: 31605919 [PubMed - as supplied by publisher]

Genetic predictors of long-term response and trough levels of infliximab in Crohn's disease.

Pharmacol Res. 2019 Oct 09;:104478

Authors: Salvador-Martín S, López-Cauce B, Nuñez O, Laserna-Mendieta EJ, García MI, Lobato E, Abarca-Zabalía J, Sanjurjo-Saez M, Lucendo AJ, Marín-Jiménez I, Menchén LA, López-Fernández LA

Abstract
INTRODUCTION: Several factors, such as trough serum anti-TNF levels, have been associated with response to therapy in Crohn's disease. However, this association is observed after initiation of treatment. Identifying DNA variants may prove useful for predicting long-term response or failure to these drugs before initiation of treatment.
OBJECTIVE: To identify genetic variants associated with long-term response to infliximab and trough levels in Crohn's disease.
PATIENTS AND METHODS: An observational, longitudinal study was conducted. We analyzed blood samples from 132 infliximab-treated patients diagnosed with Crohn's disease from 2 hospitals. We genotyped 21 polymorphisms previously related to anti-TNF response in genes involved in the NFkB-mediated inflammatory response, TNFα-signaling and cytokines regulated by NFkB, using real-time PCR. Trough infliximab levels were measured using ELISA. The association between SNPs and time-to-failure (defined as the time from the initiation of induction therapy to the date of treatment withdrawal due to a primary or secondary failure) was analyzed using log-rank test. The association between SNPs and supra-(>7 µg/mL) or infratherapeutic (<3 µg/mL) infliximab trough levels was analyzed using a linear-by-linear association chi-squared test.
RESULTS: Two SNPs in TLR2, rs1816702 and rs3804099, and 1 SNP in TNFRSF1B, rs1061624, were associated with long-term response (up to ten years follow-up) to infliximab (HR, 0.13 [95%CI, 0.02-1.00], p < 0.05; HR, 0.39 [95%CI, 0.18-0.88], p < 0.05; and HR, 0.04 [95%CI, 0.18-0.92] p > 0.05, respectively). In addition, IL6 rs10499563 C and IL10 rs1800872 A were associated with supratherapeutic trough infliximab levels; IL10 rs3024505 T was associated with infratherapeutic levels (p < 0.05).
CONCLUSION: Genotyping of the variants identified in the genes encoding TLR2, TNFRSF1B, IL6 and IL10 reported herein represent a promising tool for the identification and selection of those patients who will benefit most from infliximab.

PMID: 31605784 [PubMed - as supplied by publisher]

Drug resistance in papillary RCC: from putative mechanisms to clinical practicalities.

Nat Rev Urol. 2019 Oct 10;:

Authors: Brodziak A, Sobczuk P, Bartnik E, Fiedorowicz M, Porta C, Szczylik C, Czarnecka AM

Abstract
Papillary renal cell carcinoma (pRCC) is the second most common renal cell carcinoma (RCC) subtype and accounts for 10-15% of all RCCs. Despite clinical need, few pharmacogenomics studies in pRCC have been performed. Moreover, current research fails to adequately include pRCC laboratory models, such as the ACHN or Caki-2 pRCC cell lines. The molecular mechanisms involved in pRCC development and drug resistance are more diverse than in clear-cell RCC, in which inactivation of VHL occurs in the majority of tumours. Drug resistance to multiple therapies in pRCC occurs via genetic alteration (such as mutations resulting in abnormal receptor tyrosine kinase activation or RALBP1 inhibition), dysregulation of signalling pathways (such as GSK3β-EIF4EBP1, PI3K-AKT and the MAPK or interleukin signalling pathways), deregulation of cellular processes (such as resistance to apoptosis or epithelial-to-mesenchymal transition) and interactions between the cell and its environment (for example, through activation of matrix metalloproteinases). Improved understanding of resistance mechanisms will facilitate drug discovery and provide new effective therapies. Further studies on novel resistance biomarkers are needed to improve patient prognosis and stratification as well as drug development.

PMID: 31602010 [PubMed - as supplied by publisher]

Methotrexate Central Nervous System Toxicity Identified in a Pharmacogenomics Pharmacist Consult Patient.

Sr Care Pharm. 2019 Oct 01;34(9):595-599

Authors: Schuh MJ, Crosby S

Abstract
OBJECTIVE: To report a possible pharmacogenomics (PGx)-related, cognitive dysfunction, adverse drug reaction from methotrexate (MTX) that may be multifactorial in origin. SUMMARY: The patient subject is a 76-year-old Caucasian female of Russian ancestry suffering from rheumatoid arthritis and treated with MTX who presented to the diagnostic and consultative physician service in a medical clinic with advancing cognitive dysfunction, manifesting as memory loss, dizziness, and confusion. Components of this possible adverse drug reaction (ADR) may include ancestry, pharmacogenomics (PGx) characteristics of the patient, and a change in route of administration, among others. The case demonstrates how patients referred to a pharmacist consult service for a suspected ADR with possible PGx implications may uncover other contributory factors to the ADR. CONCLUSION: PGx testing may increase clinical pharmacist referrals to identify a PGx etiology to an ADR. However, they may also identify other non-PGx contributory factors to an ADR.

PMID: 31601292 [PubMed - in process]