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]

Is Genetic Variability in Carboxylesterase-1 and Carboxylesterase-2 Drug Metabolism an Important Component of Personalized Medicine?

Xenobiotica. 2019 Oct 11;:1-21

Authors: Laizure SC, Parker RB

Abstract
The carboxylesterase drug hydrolysis pathway has been used extensively to improve the oral availability of drugs under the assumption that the high capacity and low substrate specificity of hydrolytic enzymes would ensure rapid, complete, and consistent conversion of prodrugs to their active metabolite. However, a growing body of literature indicates that drug hydrolysis is usually catalyzed by one primary enzyme, either carboxylesterase-1 or carboxlylesterase-2, and that there is wide variability in enzyme activity affecting the metabolism of prodrugs to their active metabolites. This review identifies carboxylesterase substrates and describes our current understanding of the influence of genetic polymorphisms on substrate disposition and clinical effects. Several polymorphisms are described in the literature and included in the personalized medicine database PharmGKB, but there are no carboxylesterase genotypes referenced in Food and Drug Administration approved drug labeling. The limited validation of metabolic pathways for drugs undergoing hydrolysis, and the small number of studies evaluating genotype-drug interactions confirm that this is an emerging field of drug metabolism research. The dependence of prodrugs, many with low therapeutic indexes, on carboxylesterase-mediated hydrolysis indicate that genetic variation plays an important role in prodrug activation, and that carboxylesterase genotyping will become an important component of personalized medicine.

PMID: 31601149 [PubMed - as supplied by publisher]

Association of Genetic Variants With Response to Anti-Vascular Endothelial Growth Factor Therapy in Age-Related Macular Degeneration.

JAMA Ophthalmol. 2018 08 01;136(8):875-884

Authors: Lorés-Motta L, Riaz M, Grunin M, Corominas J, van Asten F, Pauper M, Leenders M, Richardson AJ, Muether P, Cree AJ, Griffiths HL, Pham C, Belanger MC, Meester-Smoor MA, Ali M, Heid IM, Fritsche LG, Chakravarthy U, Gale R, McKibbin M, Inglehearn CF, Schlingemann RO, Omar A, Chen J, Koenekoop RK, Fauser S, Guymer RH, Hoyng CB, de Jong EK, Lotery AJ, Mitchell P, den Hollander AI, Baird PN, Chowers I

Abstract
Importance: Visual acuity (VA) outcomes differ considerably among patients with neovascular age-related macular degeneration (nAMD) treated with anti-vascular endothelial growth factor (VEGF) drugs. Identification of pharmacogenetic associations may help clinicians understand the mechanisms underlying this variability as well as pave the way for personalized treatment in nAMD.
Objective: To identify genetic factors associated with variability in the response to anti-VEGF therapy for patients with nAMD.
Design, Setting, and Participants: In this multicenter genome-wide association study, 678 patients with nAMD with genome-wide genotyping data were included in the discovery phase; 1380 additional patients with nAMD were genotyped for selected common variants in the replication phase. All participants received 3 monthly injections of bevacizumab or ranibizumab. Clinical data were evaluated for inclusion/exclusion criteria from October 2014 to October 2015, followed by data analysis from October 2015 to February 2016. For replication cohort genotyping, clinical data collection and analysis (including meta-analysis) was performed from March 2016 to April 2017.
Main Outcomes and Measures: Change in VA after the loading dose of 3 monthly anti-VEGF injections compared with baseline.
Results: Of the 2058 included patients, 1210 (58.8%) were women, and the mean (SD) age across all cohorts was 78 (7.4) years. Patients included in the discovery cohort and most of the patients in the replication cohorts were of European descent. The mean (SD) baseline VA was 51.3 (20.3) Early Treatment Diabetic Retinopathy Study (ETDRS) score letters, and the mean (SD) change in VA after the loading dose of 3 monthly injections was a gain of 5.1 (13.9) ETDRS score letters (ie, 1-line gain). Genome-wide single-variant analyses of common variants revealed 5 independent loci that reached a P value less than 10 × 10-5. After replication and meta-analysis of the lead variants, rs12138564 located in the CCT3 gene remained nominally associated with a better treatment outcome (ETDRS letter gain, 1.7; β, 0.034; SE, 0.008; P = 1.38 × 10-5). Genome-wide gene-based optimal unified sequence kernel association test of rare variants showed genome-wide significant associations for the C10orf88 (P = 4.22 × 10-7) and UNC93B1 (P = 6.09 × 10-7) genes, in both cases leading to a worse treatment outcome. Patients carrying rare variants in the C10orf88 and UNC93B1 genes lost a mean (SD) VA of 30.6 (17.4) ETDRS score letters (ie, loss of 6.09 lines) and 26.5 (13.8) ETDRS score letters (ie, loss of 5.29 lines), respectively, after 3 months of anti-VEGF treatment.
Conclusions and Relevance: We propose that there is a limited contribution of common genetic variants to variability in nAMD treatment response. Our results suggest that rare protein-altering variants in the C10orf88 and UNC93B1 genes are associated with a worse response to anti-VEGF therapy in patients with nAMD, but these results require further validation in other cohorts.

PMID: 29852030 [PubMed - indexed for MEDLINE]

The Brain-Placental Axis: Therapeutic and Pharmacological Relevancy to Pregnancy.

Pharmacol Res. 2019 Oct 07;:104468

Authors: Behura SK, Dhakal P, Kelleher AM, Balboula A, Patterson A, Spencer TE

Abstract
The placenta plays a critical role in mammalian reproduction. Although it is a transient organ, its function is indispensable to communication between the mother and fetus, and supply of nutrients and oxygen to the growing fetus. During pregnancy, the placenta is vulnerable to various intrinsic and extrinsic conditions which can result in increased risk of fetal neurodevelopmental disorders as well as fetal death. The placenta controls the neuroendocrine secretion in the brain as a means of adaptive processes to safeguard the fetus from adverse programs, to optimize fetal development and other physiological changes necessary for reproductive success. Although a wealth of information is available on neuroendocrine functions in pregnancy, they are largely limited to the regulation of hypothalamus-pituitary-adrenal/gonad (HPA/ HPG) axis, particularly the oxytocin and prolactin system. There is a major gap in knowledge on systems-level functional interaction between the brain and placenta. In this review, we aim to outline the current state of knowledge about the brain-placental axis with description of the functional interactions between the placenta and the maternal and fetal brain. While describing the brain-placental interactions, a special emphasis has been given on the therapeutics and pharmacology of the placental receptors to neuroligands expressed in the brain during gestation. As a key feature of this review, we outline the prospects of integrated pharmacogenomics, single-cell sequencing and organ-on-chip systems to foster priority areas in this field of research. Finally, we remark on the application of precision genomics approaches to study the brain-placental axis in order to accelerate personalized medicine and therapeutics to treat placental and fetal brain disorders.

PMID: 31600597 [PubMed - as supplied by publisher]

HLA-DQA1*05 Carriage Associated With Development of Anti-Drug Antibodies to Infliximab and Adalimumab in Patients With Crohn's Disease.

Gastroenterology. 2019 Oct 05;:

Authors: Sazonovs A, Kennedy NA, Moutsianas L, Heap GA, Rice DL, Reppell M, Bewshea CM, Chanchlani N, Walker GJ, Perry MH, McDonald TJ, Lees CW, Cummings JRF, Parkes M, Mansfield JC, Barrett JC, McGovern D, Goodhand JR, Anderson CA, Ahmad T, PANTS consortium

Abstract
BACKGROUND & AIMS: Anti-tumor necrosis factor (anti-TNF) therapies are the most widely used biologic drugs for treating immune-mediated diseases, but repeated administration can induce the formation of anti-drug antibodies. The ability to identify patients at increased risk for development of anti-drug antibodies would facilitate selection of therapy and use of preventative strategies.
METHODS: We performed a genome-wide association study to identify variants associated with time to development of anti-drug antibodies in a discovery cohort of 1240 biologic-naïve patients with Crohn's disease starting infliximab or adalimumab therapy. Immunogenicity was defined as an anti-drug antibody titer ≥10 AU/ml in a drug-tolerant ELISA assay. Significant association signals were confirmed in a replication cohort of 178 patients with inflammatory bowel disease.
RESULTS: The HLA-DQA1*05 allele, carried by approximately 40% of Europeans, significantly increased the rate of immunogenicity (hazard ratio [HR], 1.90; 95% CI, 1.60-2.25; P=5.88×10-13). The highest rates of immunogenicity, 92% at 1 year, were observed in patients treated with infliximab monotherapy who carried HLA-DQA1*05; conversely the lowest rates of immunogenicity, 10% at 1 year, were observed in patients treated with adalimumab combination therapy who did not carry HLA-DQA1*05. We confirmed this finding in the replication cohort (HR, 2.00; 95% CI, 1.35-2.98; P=6.60×10-4). This association was consistent for patients treated with adalimumab (HR, 1.89; 95% CI, 1.32-2.70) or infliximab (HR, 1.92; 95% CI, 1.57-2.33), and for patients treated with anti-TNF therapy alone (HR, 1.75; 95% CI, 1.37-2.22) or in combination with an immunomodulator (HR, 2.01; 95% CI, 1.57-2.58).
CONCLUSIONS: In an observational study, we found a genome-wide significant association between HLA-DQA1*05 and the development of antibodies against anti-TNF agents. A randomized controlled biomarker trial is required to determine whether pretreatment testing for HLA-DQA1*05 improves patient outcomes by helping physicians select anti-TNF and combination therapies. ClinicalTrials.gov no: NCT03088449.

PMID: 31600487 [PubMed - as supplied by publisher]

Differential DNA methylation correlates with response to methotrexate in rheumatoid arthritis.

Rheumatology (Oxford). 2019 Oct 10;:

Authors: Nair N, Plant D, Verstappen SM, Isaacs JD, Morgan AW, Hyrich KL, Barton A, Wilson AG

Abstract
OBJECTIVES: Identifying blood-based biomarkers that predict treatment response in RA is a clinical priority. We investigated differential DNA methylation as a candidate biomarker of response for the first-line drug used in RA, MTX.
METHODS: DNA methylation was measured in DNA samples from individuals recruited to the Rheumatoid Arthritis Medication Study. Differentially methylated positions were compared between whole blood samples collected at baseline and at 4 weeks from patients who, by 6 months, had a good (n = 34) or poor response (n = 34) to MTX using linear modelling, adjusting for gender, age, cell composition, baseline 28-joint disease activity score (DAS28) and smoking status. Analyses also compared methylation with changes in DAS28 and changes in swollen joint count and tender joint count, and changes in CRP over the initial 6 months after MTX commencement. Differentially methylated positions showing significant differences with any response parameter were tested using pyrosequencing in an independent group of 100 patients from the Rheumatoid Arthritis Medication Study.
RESULTS: In the discovery group, two CpG sites showed methylation changes at 4 weeks associated with clinical EULAR response by 6 months. Significant changes in methylation for three differentially methylated positions associated with change in tender joint counts, three with change in swollen joint count and a further four with change in CRP. Of the 12 CpGs, four showed replicated association in an independent dataset of samples from the Rheumatoid Arthritis Medication Study.
CONCLUSION: These data represent an advance on current practice by contributing to a personalized medicine strategy allowing an escalation or change in therapy as early as 4 weeks.

PMID: 31598719 [PubMed - as supplied by publisher]

Reporting of offspring data in diabetes, HIV infection and hypertension trials during pregnancy: a systematic review.

Arch Dis Child Fetal Neonatal Ed. 2019 Oct 09;:

Authors: Aurich B, Martin-Montoya T, Zhang D, Jacqz-Aigrain E

Abstract
BACKGROUND: Clinical trials are conducted during pregnancy to evaluate benefits and risks of medicines for mother and child. The safety of maternal treatments is a key issue for healthcare professionals and parents.
OBJECTIVE: To analyse offspring data reported in clinical trials in pregnant women with diabetes, HIV infection or hypertension (three of the most common diseases in women of childbearing potential) and either treated prior to pregnancy for these chronic diseases or diagnosed and treated during pregnancy.
METHODS: PubMed and Embase (1 January 1997 to 31 December 2017) were searched for drug trials in pregnant women with diabetes, HIV infection or hypertension. Titles and abstracts were screened, followed by a full-text review of eligible articles. Inclusion criteria were interventional clinical trials in pregnant women treated with medication and full text in English. Trial characteristics, maternal and offspring data were extracted. Data were summarised by disease and study. Twelve key items were considered for the offspring.
RESULTS: Overall, 196 articles reporting 132 clinical trials (diabetes n=55; HIV n=59; hypertension n=18) were included. Key offspring data were frequently not reported, for example, number of births (diabetes: 22/55, 40%; HIV: 14/59, 24%; hypertension: 10/18, 56%). Congenital malformations were often not reported with sufficient detail (diabetes: 40/55, 73%; HIV: 39/59, 66%; hypertension: 17/18, 94%). Similar observations were made for other key items (eg, fetal losses, neonatal deaths).
CONCLUSION: Under-reporting of key data for the offspring was frequent in publications of clinical trials in pregnant women with diabetes, HIV infection or hypertension making the assessment of the benefit-risk ratio of treatment options during pregnancy difficult.
TRIAL REGISTRATION NUMBER: CRD42017057024.

PMID: 31597728 [PubMed - as supplied by publisher]

Molecular basis for the sensitivity of TRP channels to polyunsaturated fatty acids.

Naunyn Schmiedebergs Arch Pharmacol. 2018 08;391(8):833-846

Authors: Riehle M, Tsvetkov D, Gohlke BO, Preissner R, Harteneck C, Gollasch M, Nürnberg B

Abstract
Transient receptor potential (TRP) channels represent a superfamily of unselective cation channels that are subdivided into seven subfamilies based on their sequence homology and differences in gating and functional properties. Little is known about the molecular mechanisms of TRP channel regulation, particularly of the "canonical" TRP (TRPC) subfamily and their activation by polyunsaturated fatty acids (PUFAs). Here, we analyzed the structure-function relationship of Drosophila fruit fly TRPC channels. The primary aim was to uncover the molecular basis of PUFA sensitivity of Drosophila TRP-like (TRPL) and TRPgamma channels. Amino acid (aa) sequence alignment of the three Drosophila TRPC channels revealed 50 aa residues highly conserved in PUFA-sensitive TRPL and TRPgamma channels but not in the PUFA-insensitive TRP channel. Substitution of respective aa in TRPL by corresponding aa of TRP identified 18 residues that are necessary for PUFA-mediated activation of TRPL. Most aa positions are located within a stretch comprising transmembrane domains S2-S4, whereas six aa positions have been assigned to the proximal cytosolic C-terminus. Interestingly, residues I465 and S471 are required for activation by 5,8,11,14-eicosatetraynoic acid (ETYA) but not 5,8,11-eicosatriynoic acid (ETI). As proof of concept, we generated a PUFA-sensitive TRP channel by exchanging the corresponding aa from TRPL to TRP. Our study demonstrates a specific aa pattern in the transmembrane domains S2-S4 and the proximal C-terminus essential for TRP channel activation by PUFAs.

PMID: 29736621 [PubMed - indexed for MEDLINE]

Obviously Nine Believers: Actionable Germline Genetic Variants for Pre-Emptive Pharmacogenetic Testing.

Basic Clin Pharmacol Toxicol. 2019 Oct 09;:

Authors: Damkier P

Abstract
A recent publication in Clinical Pharmacology and Therapeutics (CPT) by van der Wouden and colleagues on the preemptive pharmacogenomic PGx Passport, intended to optimize drug prescribing, caught my attention. 1 I believe that the overall narrative of the paper is disproportional to the supporting evidence. The Editors of CPT did not find that my comment and reflections on this paper could be prioritized. I hope that BCPT will endorse a discussion of how we, as a research community, frame and disseminate our findings.

PMID: 31597220 [PubMed - as supplied by publisher]

Use of circulating tumoral DNA to guide treatment for metastatic melanoma.

Pharmacogenomics. 2019 Oct 09;:

Authors: Herbreteau G, Charpentier S, Vallée A, Denis MG

Abstract
The management of metastatic cutaneous melanoma is conditioned by the identification of BRAF-activating mutations in tumor DNA. Tumor genotyping is usually performed on DNA extracted from tissue samples. However, these invasive samples are rarely repeated during follow-up, and their analysis requires a sample pre-treatment which may take several weeks. Circulating tumor DNA (ctDNA), released into blood by cancer cells, is a good alternative to tissue sampling. ctDNA is not subject to tumor heterogeneity, and can be analyzed rapidly, making possible the detection of mutations in emergency or in patients whose tumor cannot be sampled. ctDNA can also be analyzed repeatedly during follow-up, for postresection minimal residual disease assessment, for therapeutic response monitoring and for early relapse detection.

PMID: 31596166 [PubMed - as supplied by publisher]

Tacrolimus in adult hematopoietic stem cell transplantation.

Expert Opin Drug Metab Toxicol. 2019 Oct 09;:1-9

Authors: Gao Y, Ma J

Abstract
Introduction: Graft-versus-host disease (GVHD) is the most common complication of hematopoietic stem cell transplantation (HSCT); therefore, the prevention of GVHD is important for a successful treatment. Tacrolimus (Tac), a calcineurin inhibitor, has been widely used for the prophylaxis of GVHD in HSCT recipients. Areas covered: This review introduces phase II/III of clinical trials related with Tac's roles in the prevention of GVHD in HSCT. Furthermore, we discuss the normal ranges of Tac concentrations, pharmacogenetics, and drug interactions of Tac, as well as its side effects in adult HSCT recipients. Expert opinion: A series of studies has established the efficacy and safety of Tac alone or in combination with other agents in HSCT. However, successful administration of Tac is complicated by its narrow therapeutic window, inter-patient pharmacokinetic variability, and a spectrum of undesirable side effects. It is necessary to maintain concentrations of Tac within the desired ranges for GVHD prophylaxis. Moreover, various factors contribute to significant variability in Tac pharmacokinetics, including drug interactions and genomic variation.

PMID: 31595800 [PubMed - as supplied by publisher]

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pharmacogenomics

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pharmacogenomics

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Southeast Asian Pharmacogenomics Research Network (SEAPharm): Current Status and Perspectives.

Public Health Genomics. 2019 Oct 04;:1-8

Authors: Chumnumwat S, Lu ZH, Sukasem C, Winther MD, Capule FR, Abdul Hamid AAAT, Bhandari B, Chaikledkaew U, Chanhom N, Chantarangsu S, Charoenyingwattana A, Hang TT, Hlaing TM, Htun KS, Jittikoon J, Le L, Mahasirimongkol S, Mohamed Noor DA, Shrestha J, Suwannoi L, Tragulpiankit P, Turongkaravee S, Wattanapokayakit S, Xangsayarath P, Yuliwulandari R, Zain SM, Chantratita W

Abstract
Pharmacogenomics (PGx) is increasingly being recognized as a potential tool for improving the efficacy and safety of drug therapy. Therefore, several efforts have been undertaken globally to facilitate the implementation process of PGx into routine clinical practice. Part of these efforts include the formation of PGx working groups working on PGx research, synthesis, and dissemination of PGx data and creation of PGx implementation strategies. In Asia, the Southeast Asian Pharmacogenomics Research Network (SEAPharm) is established to enable and strengthen PGx research among the various PGx communities within but not limited to countries in SEA; with the ultimate goal to support PGx implementation in the region. From the perspective of SEAPharm member countries, there are several key elements essential for PGx implementation at the national level. They include pharmacovigilance database, PGx research, health economics research, dedicated laboratory to support PGx testing for both research and clinical use, structured PGx education, and supportive national health policy. The status of these essential elements is presented here to provide a broad picture of the readiness for PGx implementation among the SEAPharm member countries, and to strengthen the PGx research network and practice in this region.

PMID: 31587001 [PubMed - as supplied by publisher]

The impact of steroids on the injured podocytes in nephrotic syndrome.

J Steroid Biochem Mol Biol. 2019 Oct 03;:105490

Authors: Hosseiniyan Khatibi SM, Ardalan M, Abediazar S, Vahed SZ

Abstract
Nephrotic syndrome (NS), a common chronic kidney disease, embraces a variety of kidney disorders. Though Glucocorticoids (GCs) are generally used in the treatment of NS, their mechanism of action is poorly understood. A plethora of evidence indicates that podocytes are considered as the main target cells for the therapeutic strategies to prevent NS. GCs regulate the transactivation and transrepression of genes in podocytes that affect their morphological and cytoskeletal features, motility, apoptosis, and survival rate. Moreover, they prevent protein leakage through the glomerular barrier membrane by affecting the synthesis, trafficking, and posttranslational modifications of slit diaphragms components, podocytes' intercellular junctions. The response to the treatment is variable among different ethnics and populations and resistance to the steroids is detected in almost 50% of adult patients. Not only do pharmacokinetics and pharmacogenetics of steroids play a role in GC resistance but also the genetic variations in one or more podocyte related genes are connected with the steroid resistance in cases with NS. The focus of this review is to explain the underlying cellular and molecular mechanisms of GCs in podocytes. Understanding the mechanisms by which the GCs and GCs receptors in podocytes regulate the gene expression network and crosstalk with other molecular pathways would guarantee an optimum therapeutic benefit of steroid treatment.

PMID: 31586640 [PubMed - as supplied by publisher]

Comparison of effects of UGT1A1*6 and UGT1A1*28 on irinotecan-induced adverse reactions in the Japanese population: analysis of the Biobank Japan Project.

J Hum Genet. 2019 Oct 04;:

Authors: Hikino K, Ozeki T, Koido M, Terao C, Kamatani Y, Murakami Y, Kubo M, Mushiroda T

Abstract
It has been reported that there are differences in effects on irinotecan-induced adverse reactions between UGT1A1*6 and UGT1A1*28. In order to compare those differences in the Japanese population, we examined the associations between UGT1A1 and irinotecan-induced adverse reactions using the BioBank Japan Project database. We genotyped UTG1A1*6 and UGT1A1*28 and conducted case-control analyses. A total of 651 patients (102 cases and 549 tolerant controls) were included in this study. The results showed that UGT1A1*6/*6 is a predictor of adverse drug reactions (ADRs) (p-value 0.00070, odds ratio 6.59, 95% confidence interval 2.33-18.6), whereas UGT1A1*6/*28 and UGT1A1*28/*28 were not. The subanalysis comprising only patients with UGT1A1*6/*6, UGT1A1*6/*28, and UGT1A1*28/*28 revealed a trend towards an increased risk of ADRs in patients with UGT1A1*6 (p-value 0.0092, odds ratio 4.39, 95% confidence interval 1.57-14.9). Multiple logistic regression analyses showed that use of platinum-based antineoplastic drugs and presence of UGT1A1*6/*6 were independent variables, significantly associated with ADRs. The diagnostic performance of a predictive model had a sensitivity of 49.0%, specificity of 70.1%, and a number needed to screen of 5.8. We concluded that UGT1A1 testing could be useful to predict irinotecan-induced ADRs, and that UTG1A1*6 rather than UGT1A1*28 contributed to ADR occurrence.

PMID: 31586129 [PubMed - as supplied by publisher]