Int J Mol Sci. 2022 May 5;23(9):5164. doi: 10.3390/ijms23095164.

ABSTRACT

The molecular mechanisms of telomerase reverse transcriptase (TERT) upregulation in breast cancer (BC) are complex. We compared genetic variability within TERT and telomere length with the clinical data of patients with BC. Additionally, we assessed the expression of the TERT, MYC, TP53 and SP1 genes in BC patients and in BC organoids (3D cell cultures obtained from breast cancer tissues). We observed the same correlation in the blood of BC patients and in BC organoids between the expression of TERT and TP53. Only in BC patients was a correlation found between the expression of the TERT and MYC genes and between TP53 and MYC. We found associations between TERT genotypes (rs2735940 and rs10069690) and TP53 expression and telomere length. BC patients with the TT genotype rs2735940 have a shorter telomere length, but patients with A allele rs10069690 have a longer telomere length. BC patients with a short allele VNTR-MNS16A showed higher expression of the SP1 and had a longer telomere. Our results bring new insight into the regulation of TERT, MYC, TP53 and SP1 gene expression related to TERT genetic variability and telomere length. Our study also showed for the first time a similar relationship in the expression of the above genes in BC patients and in BC organoids. These findings suggest that TERT genetic variability, expression and telomere length might be useful biomarkers for BC, but their prognostic value may vary depending on the clinical parameters of BC patients and tumor aggressiveness.

PMID:35563554 | DOI:10.3390/ijms23095164

Int J Mol Sci. 2022 Apr 30;23(9):5022. doi: 10.3390/ijms23095022.

ABSTRACT

The treatment of hypercholesterolemia is mainly based on statins. However, the response to pharmacological therapy shows high inter-individual variability, resulting in variable effects in both lipid lowering and risk reduction. Thus, a better understanding of the lipid-lowering mechanisms and response variability at the molecular level is required. Previously, we demonstrated a deregulation of the microRNA expression profile in HepG2 cells treated for 24 h with atorvastatin, using a microarray platform. In the present study, we evaluated the expression of hsa-miR-17-5p, hsa-miR-20a-5p and hsa-miR-106a-5p in hypercholesterolemic patients before and after atorvastatin treatment and in HepG2 cells treated for 24 h with atorvastatin The miRNA hsa-mir-20a-5p was repressed after atorvastatin treatment in hypercholesteremic subjects and in HepG2 cells in culture. Repression of hsa-mir-20a-5p increased LDLR gene and protein expression in HepG2 cells, while hsa-mir-20a-5p overexpression reduced LDLR gene and protein expression.

PMID:35563413 | DOI:10.3390/ijms23095022

Eur Neuropsychopharmacol. 2022 May 10;59:68-81. doi: 10.1016/j.euroneuro.2022.04.007. Online ahead of print.

ABSTRACT

Several data indicate that the success of pharmacological treatment in major depressive disorder (MDD) is still unsatisfactory. The reasons for the low response and remission rates are multiple and depend on environmental and biological factors intrinsic to the disease and drug treatments. Pharmacogenetic (PG) tests have the potential to increase efficacy predicting outcome and to reduce antidepressant discontinuation due to side effects. Several studies investigated the utility of PG tests for antidepressants in MDD with interesting but contrasting results. To date most of them are observational studies with no comparator group, and few are randomized controlled trials (RCTs). The aim of this review is to provide an evaluation of the state of art on clinical methodologic features of RCTs with PG tests for antidepressant drugs in MDD, offering suggestions and favoring new insights that could be useful in the implementation of future trials. Several limitations concerning study design, generalization of results, duration of trials, patients group studied, and cost-effectiveness ratio were found, and a number of barriers have been noted in the adoption of PG tests into clinical practice. Despite some preliminary positive results, there is the need for larger and longer-term RCT studies, with the goal to capture the real impact of PG tests, also with stratified analysis concerning MDD features in terms of severity and antidepressant treatment failures in different ethnicity cohorts.

PMID:35561539 | DOI:10.1016/j.euroneuro.2022.04.007

Clin Pharmacol Ther. 2022 May 13. doi: 10.1002/cpt.2643. Online ahead of print.

ABSTRACT

The role of membrane transporters on pharmacokinetics (PK), drug-drug interactions (DDIs), pharmacodynamics (PD), and toxicity of drugs has been broadly recognized. However, our knowledge of modulation of transporter expression and/or function in diseased patient population or specific populations such as pediatrics or pregnancy is still emerging. This white paper highlights recent advances in studying the changes in transporter expression and activity in various diseases (i.e., renal and hepatic impairment, cancer) and some specific populations (i.e., pediatrics and pregnancy) with the focus on clinical implications. Proposed alterations in transporter abundance and/or activity in diseased and specific populations are based on 1) quantitative transporter proteomic data and relative abundance in specific populations versus healthy adults, 2) clinical PK, and emerging transporter biomarker and/or pharmacogenomic data, and 3) physiologically based pharmacokinetic (PBPK) modeling and simulation. The potential for altered PK, PD and toxicity in these populations needs to be considered for drugs and their active metabolites in which transporter-mediated uptake/efflux is a major contributor to their absorption, distribution, and elimination pathways and/or associated DDI risk. In addition to best practices, this white paper discusses current challenges and knowledge gaps to study and quantitatively predict the effects of modulation in transporter activity in these populations, together with the perspectives from the International Transporter Consortium (ITC) on future directions.

PMID:35561140 | DOI:10.1002/cpt.2643

Front Pediatr. 2022 Apr 26;10:842480. doi: 10.3389/fped.2022.842480. eCollection 2022.

ABSTRACT

As unlicensed or off-label drugs are frequently prescribed in children, the European Pediatric Regulation came into force in 2007 to improve the safe use of medicinal products in the pediatric population. This present report analyzes the pediatric research trials over 23 years in a clinical research center dedicated to children and the impact of regulation. The database of trial characteristics from 1998 to 2020 was analyzed. We also searched for differences between two periods (1998-2006 and 2007-2020) and between institutional and industrial sponsors during the whole period (1998-2020). A total of 379 pediatric trials were initiated at our center, corresponding to inclusion of 7955 subjects and 19448 on-site patient visits. The trials were predominantly drug evaluation trials (n = 278, 73%), sponsored by industries (n = 216, 57%) or government/non-profit institutions (n = 163, 43%). All age groups and most subspecialties were concerned. We noted an important and regular increase in the number of trials conducted over the years, with an increased number of multinational, industrially sponsored trials. Based on the data presented, areas of improvement are discussed: (1) following ethical and regulatory approval depending on the sponsor, the mean time needed for administrative and financial agreement, validation of trial procedures allowing trial initiation at the level of the center was 6.3 and 6.5 months (periods 1 and 2, respectively) and should be reduced, (2) availability of expert research teams remain insufficient, time dedicated to research attributed to physicians should be organized and recognition of research nurses is required. The positive impact of the European Pediatric Regulation highlights the need to increase the availability of trained research teams, organized within identified multicenter international pediatric research networks.

PMID:35560985 | PMC:PMC9086591 | DOI:10.3389/fped.2022.842480

FASEB J. 2022 May;36 Suppl 1. doi: 10.1096/fasebj.2022.36.S1.R2048.

ABSTRACT

Phenobarbital (PB), a widely used anti-epileptic drug, is known to upregulate the expression of numerous drug-metabolizing enzymes and transporters in the liver primarily via activation of the constitutive androstane receptor (CAR, NR1I3). The solute carrier family 13 member 5 (SLC13A5), a sodium-coupled citrate transporter, plays an important role in intracellular citrate homeostasis that is associated with a number of metabolic syndromes and neurological disorders. Here, we show that PB markedly elevates the expression of SLC13A5 through a pregnane X receptor (PXR)-dependent but CAR-independent signaling pathway. In human primary hepatocytes, the mRNA and protein expression of SLC13A5 was robustly induced by PB treatment, while genetic knockdown or pharmacological inhibition of PXR significantly attenuated this induction. Utilizing genetically modified HepaRG cells, we found that PB induces SLC13A5 expression in both wild type (WT) and CAR-knockout HepaRG cells, whereas such induction was fully abolished in the PXR-knockout HepaRG cells. Mechanistically, we identified and functionally characterized three enhancer modules located upstream of the transcription start site or introns of the SLC13A5 gene that are associated with the regulation of PXR-mediated SLC13A5 induction. Moreover, metformin, a deactivator of PXR, dramatically suppressed PB-mediated induction of hepatic SLC13A5 as well as its activation of the SLC13A5 luciferase reporter activity via PXR. Collectively, these data reveal PB as a potent inducer of SLC13A5 through the activation of PXR but not CAR in human primary hepatocytes.

PMID:35560665 | DOI:10.1096/fasebj.2022.36.S1.R2048

FASEB J. 2022 May;36 Suppl 1. doi: 10.1096/fasebj.2022.36.S1.R2020.

ABSTRACT

Rats are a major model for studying complex disease mechanisms, behavioral phenotypes, environmental factors, and for drug development and discovery. Inbred rat strains control for genetic background and allow for repeated, reproducible molecular, cellular, and whole animal phenotyping. Genetic susceptibility to disease, sensitivity to environmental elements, and pharmacogenomics are critical components of the concepts of precision medicine. The Hybrid Rat Diversity Program (HRDP) is a resource that combines the power of genetic stability within strains, power for genomic mapping strategies, and strength in an animal model that mirrors many human disease traits. The HRDP was designed to include 96 inbred rat strains with genomic and physiological diversity to maximize power to detect specific genetic loci associated with complex traits while maximizing the genetic diversity among strains. The 96 strain panel consists of 33 genetically diverse inbred strains and two panels of recombinant inbred panels: FEXL/LEXF (33 strains, Japan) and HXB/BXH (30 strains, Czech Republic). Embryo resuscitation and breeding is well underway at the Medical College of Wisconsin (MCW) with 55 strains available. Whole genome sequencing for 54 of the 96 strains is complete, having been generated on am Illumina NovaSeq S4 to achieve 30X coverage. An additional 14 related substrains have been sequenced. Liver and brain transcriptome analysis is underway through PhenoGen (http://phenogen.ucdenver.edu) at the University of Colorado. Genomic, phenotype, and strain information will be made available through the Hybrid Rat Diversity Panel portal at the Rat Genome Database (http://rgd.mcw.edu). The HRDP will provide a genetically stable population of rat strains with fully sequenced genomes, transcriptomes for brain and liver, and general phenotypic characterization to be used for systems genetic studies and fine mapping of complex traits.

PMID:35560431 | DOI:10.1096/fasebj.2022.36.S1.R2020

Front Cell Dev Biol. 2022 Apr 26;10:909619. doi: 10.3389/fcell.2022.909619. eCollection 2022.

NO ABSTRACT

PMID:35557953 | PMC:PMC9087560 | DOI:10.3389/fcell.2022.909619

FASEB J. 2022 May;36 Suppl 1. doi: 10.1096/fasebj.2022.36.S1.R5265.

ABSTRACT

Miscarriage is a condition that affects 10%-15% of all clinically recognized pregnancies, most of which occur in the first trimester. Approximately 50% of first-trimester miscarriages result from fetal chromosome abnormalities. Conventional karyotyping analysis is limited due to unsuccessful culture fetal tissue and poor chromosome quality. Chromosomal microarray analysis (CMA) provides a significant increase in test success rate and incremental diagnostic yield in early pregnancy loss, using fetal DNA. We aimed to estimate detection of pathogenic Copy Number Variants (CNVs) and variants of uncertain significance (VOUS) in early pregnancy losses. Moreover we integrate cytogenomic findings performing Whole Exome Sequencing (WES) in order to elucidate the genetic associations of gene variants clinically significant for the viability of a conceptus. We collected product of conception (POC) samples (n= 33), managed in our genetic unit between February 1, 2020, and July 31, 2021. Fetal tissue samples were obtained after informed consent from females of average age 37 years old, who experienced spontaneous pregnancy losses (□<20 weeks) (70%), medical abortion (9%) and miscarriage after assisted reproductive treatment (21%). In the 97% of cases, the cytogenomic and/or molecular analysis were performed and concluded with an informative results (n= 32) useful for couple counseling. To avoid risk of maternal cell contamination and to define sex chromosomes, before CMA, QF-PCR was performed. As aspected, autosomal trisomies are shown to be the most frequent anomalies (42%) associated with first-trimester miscarriage, followed by monosomy X (3%). 2 CNVs, are detected (6%): 1 pathogenic de novo deletion associated with monosomy 1pter and 1 duplication with uncertain clinical significance in region 7q21.13, segregated from healthy father. In this sample, we performed WES in order to understand the possible genetic cause of major malformations detected by ultrasound exploration. A missense variant in ITF80 gene was detected. The encoded protein is essential for the development and maintenance of primary cilia, but a single variant, inherited from father, is not enough to conclude the diagnosis. In another case, with a fetal peculiar clinical picture, the WES analysis performed, showed a compound heterozygosity in the CC2D2A gene, associated with Meckel syndrome, an autosomal recessive ciliopathy. Ciliopathies are an expanding disease spectrum that have been associated with over 40 genes to date. In this case, the genetic diagnosis allow us to determine the cause of miscarriage with a major impact on the future couple reproductive plans and prenatal care in future pregnancies. This study demonstrates that the DNA-based CMA technology overcomes many of the limitations of routine cytogenetic analysis of POC samples and, in selected cases, integration with WES analysis increase diagnostic rate and recurrence-risk for subsequent pregnancies can be also determined.

PMID:35557144 | DOI:10.1096/fasebj.2022.36.S1.R5265

FASEB J. 2022 May;36 Suppl 1. doi: 10.1096/fasebj.2022.36.S1.0R295.

ABSTRACT

BACKGROUND: Evidence suggests that race is often misrepresented in undergraduate medical school curricula, particularly in the basic sciences. Incorrect discussion of race as a biological construct has long been present and is not only inaccurate but also prevents discussion of structural racism, sociopolitical and historical implications of health inequities. Although there has been increasing attention and awareness of racial bias in different areas of medical curricula like pathology and epidemiology, little has been shared about potential bias or race misrepresentation in pharmacology education.

METHODS: As part of our institutional effort to promote anti-racism curricula, pharmacology educators at the University of Illinois College of Medicine have reviewed the learning objectives, instructional materials, assessments, and required textbooks of the pharmacology curriculum used in the academic year 2018-2020. All the curricular and assessment databases along with digital copies of required pharmacology textbooks were searched for keywords like 'African American', 'black', 'Caucasian', 'white', 'Hispanic, 'Latino, 'Asian, 'Chinese, 'European, 'native', 'race', and 'ethnic'. All search results were reviewed to determine if race was appropriately mentioned with context, as a social construct, or if race was adequately representing the ancestry or with combined race/ethnicity. Based on the findings, revisions were carried out in the instructional materials and assessment in the academic year 2020-2021. The first- and second-year medical students were surveyed in each course to comment on any perceived potential bias in instructional materials and assessment items.

RESULTS: Misrepresentation of race was identified in 9% of our pharmacology instructional materials and 1% of our assessment items. The most common areas of misrepresentation were in pharmacogenomics related concepts where the race was referenced as a risk factor for certain genetic polymorphisms. Broad racial categories like Black, Asian, and Caucasian were used in pharmacogenomics despite evidence of intrapopulation genetic variations. The second most common misrepresentation was the use of race as a biological construct where race-based medicine like isosorbide dinitrate/hydralazine (BiDil) was described or race was presented as a risk factor for a disease. Evaluation of the pharmacology textbooks revealed a similar trend. Our curriculum was revised in the academic year 2020-2021 based on the findings. The student surveys revealed no potential bias in the pharmacology curricula after the revision.

CONCLUSIONS: Misrepresentation of race appeared in some parts of the pharmacology curriculum in the preclinical years as pharmacology textbooks consistently emphasize race-based biological differences. Revisiting the curriculum with an anti-racist lens helped to mitigate the racial bias and identify an opportunity to highlight the limitation and adverse consequences of using race in research and patient care. Our study revealed that there is an opportunity to integrate a holistic understanding of health disparities in the pharmacology curricula.

PMID:35555925 | DOI:10.1096/fasebj.2022.36.S1.0R295

FASEB J. 2022 May;36 Suppl 1. doi: 10.1096/fasebj.2022.36.S1.R3082.

ABSTRACT

HYPOTHESIS: Singe nucleotide polymorphisms will be associated with differential expression of Thiopurine S-Methyltransferase (TPMT) in the liver.

METHODS: Normal human liver samples (n=288) were acquired from University of Minnesota Liver Tissue Cell Distribution System, the Cooperative Human Tissue Network, and XenoTech LCC (Lenexa, KS, USA). Absolute quantification of TPMT in liver microsomes was calculated using a DIA total protein approach (DIA-TPA). Human liver samples were genotyped using the Illumina Multi-Ethnic Global Assay (Illumina, Miami, USA).

RESULTS: After accounting for population stratification, genome-wide association study (GWAS) analysis was conducted on 243 human liver samples. There were 30 genetic variants, all located on chromosome 6, that passed our genome-wide threshold (P < 5.0 x 10-8 ) after Bonferroni correction. Further GWAS analysis conditioning on rs1142345 (TPMT*3C/TPMT*3A), the strongest signal within the dataset and a known nonfunctional TPMT allele, showed no other independent signals. The presumed homozygous wild-type TPMT subjects had a 1.97-fold higher expression of TPMT than the TPMT*3A heterozygotes (0.1056 pmol/mg ± 0.0289 pmol/mg vs. 0.0536 pmol/mg ± 0.0143 pmol/mg, p-value: 8.4e-14 ). When comparing TPMT expression by ancestry, European ancestry donors (n= 214) had significantly higher expression than African ancestry donors (n= 34) when removing TPMT*3A carriers (0.1085 pmol/mg ± 0.0260 pmol/mg vs. 0.0860 pmol/mg ± 0.0416 pmol/mg, p-value: 0.004.

CONCLUSION: For the first time, we quantified absolute TPMT protein expression in the liver using a liquid chromatography tandem mass spectrometry based DIA-TPA proteomics approach and conducted a GWAS to identify genetic variants affecting hepatic TPMT protein expression. The only independent genetic signal from the GWAS was from the TPMT*3A haplotype, which is comprised of two nonsynonymous SNPs rs1800460 and rs1142345. Previous in vitrostudies investigating the effect of common polymorphisms on TPMT expression in COS-1 cells demonstrated that TPMT*3A is almost a complete loss of detectable TPMT due to its rapid degradation rate.1 This is in line with our expression data, where heterozygous carriers of TPMT*3A had about half the amount of TPMT as wild-type subjects. We also discovered that donors with African ancestry had significantly less TPMT expression than donors with European ancestry after removing samples that had known TPMT polymorphisms (TPMT*3A/*3B/*3C). A previous study reported patients of Afro-Caribbean ancestry had significantly lower TPMT activity than those of European or South Asian descent.2 Future studies need to be conducted to determine if the difference in TPMT expression by ancestry is due to genetic polymorphisms or other factors.

REFERENCES: 1. Ujiie, S., Sasaki, T., Mizugaki, M., Ishikawa, M. & Hiratsuka, M. Functional characterization of 23 allelic variants of thiopurine S-methyltransferase gene (TPMT*2 - *24). Pharmacogenet. Genomics 18, 887-893 (2008). 2. Cooper, S. C., Ford, L. T., Berg, J. D. & Lewis, M. J. Ethnic variation of thiopurine S-methyltransferase activity: a large, prospective population study. Pharmacogenomics 9, 303-309 (2008).

PMID:35554672 | DOI:10.1096/fasebj.2022.36.S1.R3082

FASEB J. 2022 May;36 Suppl 1. doi: 10.1096/fasebj.2022.36.S1.R4280.

ABSTRACT

PharmGKB is a user-friendly online pharmacogenomics database that annotates clinical guidelines for optimizing drug therapy based on patient genotypes. The majority of guidelines in PharmGKB are based on the interindividual variability in cytochrome P450 (CYP) enzymes responsible for metabolizing drugs. By individualizing patient therapy according to CYP genotypes, there is potential to improve pharmacotherapy outcomes and minimize the risk of adverse events. Although there is growing interest amongst educators and students to integrate pharmacogenetic content into health science curricula, there is a lack of educational resources that teach students how to utilize resources such as PharmGKB to inform clinical decision making. The purpose of this study was to assess and disseminate a case-based interactive lesson on pharmacogenetic-based drug dosing principles that uses PharmGKB. Seventy-one high school students participated in a two-hour Zoom session as part of a four-day Toxicology, Health, and Environmental Disease Program. The lesson was divided into a didactic lecture on pharmacogenetics followed by a group-based analysis of hypothetical case scenarios. Case questions focused on genetic variation in CYP enzymes in the context of different clinical scenarios. Examples included the use of codeine for analgesia (CYP2D6) and clopidogrel for stroke prevention (CYP2C19). Assessment of student understanding was measured by percent gain in correct answers between pre- and post-lesson polling questions. The first question focused on pharmacology concepts while the last two focused on genetics concepts. Students had high pre-test scores on the pharmacology question having learned these concepts earlier in the program. For the additional two questions, there was a positive gain (42%) demonstrating an increase in knowledge during the lesson. Seventy-eight percent of students would be 'extremely likely' or 'very likely' to recommend this activity. We propose that an interactive, group-based activity can be used to teach basic principles of pharmacogenetics and empower students and educators to effectively use online drug resources.

PMID:35553966 | DOI:10.1096/fasebj.2022.36.S1.R4280

FASEB J. 2022 May;36 Suppl 1. doi: 10.1096/fasebj.2022.36.S1.0R546.

ABSTRACT

BACKGROUND: (-)-∆ 9-Tetrahydrocannabinol (THC) is the most abundant psychoactive compound in marijuana. With legalization of marijuana, its use has increased including by pregnant women. The latter raises concerns of fetal toxicity which is likely driven by fetal THC exposure. Interestingly, in the catheterized maternal-fetal macaque model, fetal THC exposure is lower than its corresponding maternal exposure (fetal/maternal AUC0-inf ratio of 0.37). This difference is supported by sparse human THC umbilical vein/maternal plasma concentrations at term. The most likely explanation for these observations is that THC is effluxed by P-glycoprotein (P-gp) which is highly expressed in the human placenta. THC oral pharmacokinetics studies in P-gp knock-out mice support the hypothesis that P-gp can transport THC. Therefore, the objective of our study was to investigate if THC is effluxed in human placentae by estimating the maternal to fetal clearance (m-f-CL) and fetal to maternal clearance (f-m-CL) using the dual cotyledon, dual perfusion, placenta model.

METHODS: Term placentae were utilized from uncomplicated, unlabored, cesarean deliveries with no known history of tobacco or drug use. Two cotyledons from each placenta were perfused at physiological rates (m: 10 mL/min; f: 4 mL/min) for 2-4 hours in a single-pass mode with oxygenated HBSS buffer containing 0.2% BSA, 2000 U/L sodium heparin and 5 mg/mL gentamicin. To determine m-f CL, the maternal perfusate also contained 5 μM THC, a P-gp transporter probe (1 or 10 μM saquinavir), and a passive diffusion probe (20 μg/mL antipyrine) and effluent from the fetal vein and intervillous space were collected at multiple timepoints. To determine f-m-CL, the fetal perfusate of the second cotyledon contained the aforementioned drugs. All perfusions were conducted with (n = 7) and without (n = 5) a pan efflux transporter inhibitor, 4 μM valspodar. THC concentrations in the effluent were quantified using LC-MS/MS. THC CL indices, i.e. m-f-CL and f-m-CL, normalized to the corresponding antipyrine CL, were compared in the absence and presence of valspodar.

RESULTS: THC m-f-CL index, 0.40 ± 0.15, was not significantly different from the f-m-CL index, 0.54 ± 0.13 (p = 0.31; two-tailed Wilcoxon signed rank test), suggesting that THC passively diffuses across the placental barrier. Surprisingly, in the presence of valspodar, THC m-f-CL index, 0.24 ± 0.14, was significantly lower than the corresponding f-m-CL index, 0.44 ± 0.14 (p = 0.016; two-tailed Wilcoxon signed rank test). The reason for this difference is unknown.

CONCLUSIONS: Because THC passively crosses the human placenta, changes in activity of placental transporters (e.g. drugs that inhibit/induce placental transporters or pharmacogenetics) should not alter fetal THC exposure. Further, mechanisms other than P-gp efflux (e.g. binding to placental tissue) need to be explored to explain the fetal and maternal THC exposure of less than unity detailed in the introduction.

PMID:35553017 | DOI:10.1096/fasebj.2022.36.S1.0R546

FASEB J. 2022 May;36 Suppl 1. doi: 10.1096/fasebj.2022.36.S1.R6046.

ABSTRACT

OBJECTIVE: Social determinants of health, including race, ethnicity, and gender, represent important factors in health care delivery and patient outcomes, and contribute to health disparities. Pharmacology, as an integrated discipline, lies at the nexus between foundational science and clinical practice, providing a platform for educators to discuss the impact of social determinants on patient outcomes. Our goal is to create a framework that provides guidance for topics in pharmacotherapeutics for educators, learners, and providers to use in promoting antiracism in medical curricula.

METHODS: Through iterative discussions, we developed a conceptual framework that includes topics taught across medical schools, such as drug metabolism, pharmacogenomics, adverse drug reactions, prescribing guidelines, factors affecting medication adherence, pain management, and therapeutic outcomes. Under each topic, we describe how social constructs such as race, ethnicity, and gender can impact pharmacology and therapeutic outcomes.

RESULTS: Literature reports show that some topics in pharmacology education have already established cultural competency and should be adopted widely by all pharmacology educators, e.g., using more appropriate terminology for drug reactions such as vancomycin-infusion reaction. Other topics are less established, so a more nuanced discussion with students is required. Society guidelines for managing diseases such as hypertension include prescribing recommendations based on race, with which learners are expected to be familiar as they enter clinical training but are actively being debated. Similarly, inter-ethnic differences in drug metabolism are often reported as a function of genetic polymorphisms without considering non-genetic factors.

CONCLUSIONS: We have developed a conceptual framework for promoting antiracism in pharmacology education by categorizing topics based on those where cultural competencies are clearly established and those where a more nuanced discussion is required with learners, as well as identifying and reducing bias in assessment. These are generalizable across health professions in which pharmacology education is a discipline in the curriculum.

PMID:35552881 | DOI:10.1096/fasebj.2022.36.S1.R6046

J Clin Psychiatry. 2022 May 9;83(4):21m14110. doi: 10.4088/JCP.21m14110.

ABSTRACT

Background: Atypical antipsychotics can induce metabolic side effects, but whether they are dose-dependent remains unclear.

Objective: To assess the effect of risperidone and/or paliperidone dosing on weight gain and blood lipids, glucose, and blood pressure alterations.

Methods: Data for 438 patients taking risperidone and/or its metabolite (paliperidone) for up to 1 year were obtained between 2007 and 2018 from a longitudinal study monitoring metabolic parameters.

Results: For each milligram increase in dose, we observed a weight increase of 0.16% at 1 month of treatment (P = .002) and increases of 0.29%, 0.21%, and 0.25% at 3, 6, and 12 months of treatment, respectively (P < .001 for each). Moreover, dose increases of 1 mg raised the risk of a ≥ 5% weight gain after 1 month (OR = 1.18; P = .012), a strong predictor of important weight gain in the long term. When we split the cohort into age categories, the dose had an effect on weight change after 3 months of treatment (up to 1.63%, P = .008) among adolescents (age ≤ 17 years), at 3 (0.13%, P = .013) and 12 (0.13%, P = .036) months among adults (age > 17 and < 65 years), and at each timepoint (up to 1.58%, P < .001) among older patients (age ≥ 65 years). In the whole cohort, for each additional milligram we observed a 0.05 mmol/L increase in total cholesterol (P = .018) and a 0.04 mmol/L increase in LDL cholesterol (P = .011) after 1 year.

Conclusions: Although of small amplitude, these results show an effect of daily risperidone dose on weight gain and blood cholesterol levels. Particular attention should be given to the decision of increasing the drug dose, and minimum effective dosages should be preferred.

PMID:35551499 | DOI:10.4088/JCP.21m14110

Nat Genet. 2022 May 12. doi: 10.1038/s41588-022-01058-3. Online ahead of print.

ABSTRACT

We assembled an ancestrally diverse collection of genome-wide association studies (GWAS) of type 2 diabetes (T2D) in 180,834 affected individuals and 1,159,055 controls (48.9% non-European descent) through the Diabetes Meta-Analysis of Trans-Ethnic association studies (DIAMANTE) Consortium. Multi-ancestry GWAS meta-analysis identified 237 loci attaining stringent genome-wide significance (P < 5 × 10-9), which were delineated to 338 distinct association signals. Fine-mapping of these signals was enhanced by the increased sample size and expanded population diversity of the multi-ancestry meta-analysis, which localized 54.4% of T2D associations to a single variant with >50% posterior probability. This improved fine-mapping enabled systematic assessment of candidate causal genes and molecular mechanisms through which T2D associations are mediated, laying the foundations for functional investigations. Multi-ancestry genetic risk scores enhanced transferability of T2D prediction across diverse populations. Our study provides a step toward more effective clinical translation of T2D GWAS to improve global health for all, irrespective of genetic background.

PMID:35551307 | DOI:10.1038/s41588-022-01058-3

Comput Methods Programs Biomed. 2022 Apr 26;221:106839. doi: 10.1016/j.cmpb.2022.106839. Online ahead of print.

ABSTRACT

BACKGROUND AND OBJECTIVE: Platinum-induced nephrotoxicity is a severe and unexpected adverse drug reaction that could lead to treatment failure in non-small cell lung cancer patients. Better prediction and management of this nephrotoxicity can increase patient survival. Our study aimed to build up and compare the best machine learning models with clinical and genomic features to predict platinum-induced nephrotoxicity in non-small cell lung cancer patients.

METHODS: Clinical and genomic data of patients undergoing platinum chemotherapy at Wan Fang Hospital were collected after they were recruited. Twelve models were established by artificial neural network, logistic regression, random forest, and support vector machine with integrated, clinical, and genomic modes. Grid search and genetic algorithm were applied to construct the fine-tuned model with the best combination of predictive hyperparameters and features. Accuracy, precision, recall, F1 score, and area under the receiver operating characteristic curve were calculated to compare the performance of the 12 models.

RESULTS: In total, 118 patients were recruited for this study, among which 28 (23.73%) were experiencing nephrotoxicity. Machine learning models with clinical and genomic features achieved better prediction performances than clinical or genomic features alone. Artificial neural network with clinical and genomic features demonstrated the best predictive outcomes among all 12 models. The average accuracy, precision, recall, F1 score and area under the receiver operating characteristic curve of the artificial neural network with integrated mode were 0.923, 0.950, 0.713, 0.808 and 0.900, respectively.

CONCLUSIONS: Machine learning models with clinical and genomic features can be a preliminary tool for oncologists to predict platinum-induced nephrotoxicity and provide preventive strategies in advance.

PMID:35550456 | DOI:10.1016/j.cmpb.2022.106839

Front Pharmacol. 2022 Apr 25;13:886377. doi: 10.3389/fphar.2022.886377. eCollection 2022.

ABSTRACT

Adverse drug reactions (ADR) remain the major problems in healthcare. Most severe ADR are unpredictable, dose-independent and termed as type B idiosyncratic reactions. Recent pharmacogenomic studies have demonstrated the strong associations between severe ADR and genetic markers, including specific HLA alleles (e.g., HLA-B*15:02/HLA-B*57:01/HLA-A*31:01 for carbamazepine-induced severe cutaneous adverse drug reactions [SCAR], HLA-B*58:01 for allopurinol-SCAR, HLA-B*57:01 for abacavir-hypersensitivity, HLA-B*13:01 for dapsone/co-trimoxazole-induced SCAR, and HLA-A*33:01 for terbinafine-induced liver injury), drug metabolism enzymes (such as CYP2C9*3 for phenytoin-induced SCAR and missense variant of TPMT/NUDT15 for thiopurine-induced leukopenia), drug transporters (e.g., SLCO1B1 polymorphism for statin-induced myopathy), and T cell receptors (Sulfanilamide binding into the CDR3/Vα of the TCR 1.3). This mini review article aims to summarize the current knowledge of pharmacogenomics of severe ADR, and the potentially clinical use of these genetic markers for avoidance of ADR.

PMID:35548363 | PMC:PMC9081981 | DOI:10.3389/fphar.2022.886377

Curr Alzheimer Res. 2022 May 11. doi: 10.2174/1567205019666220511140955. Online ahead of print.

ABSTRACT

BACKGROUND: Alzheimer's disease (AD) is the most common form of neurodegenerative disorder. The association of BIN1, CLU and IDE genetic polymorphisms with AD risk have been evaluated overtimes that produced conflicting outcomes.

OBJECTIVE: We performed this meta-analysis to investigate the contribution of BIN1 (rs744373 and rs7561528), CLU (rs11136000 and rs9331888), and IDE (rs1887922) polymorphisms to AD risk.

METHODS: From a systemic literature search up to July 15, 2021, we included 25 studies with rs744373, 16 studies with rs7561528, 37 studies with rs11136000, 16 studies with rs9331888, and 4 studies with rs1887922. To analyze the correlation, we constructed seven genetic models that used odds ratio and 95% confidence intervals. We used RevMan 5.4 for meta-analysis.

RESULTS: Our study suggests that BIN1 rs744373 is associated with a significantly increased risk of AD in five genetic models (OR>1). Again, CLU rs11136000 showed reduced association in all genetic models (OR<1). CLU rs9331888 revealed an increased association in two models (OR>1). The IDE rs1887922 showed significantly increased risk in four models (OR>1). From subgroup analysis, a significantly increased risk of AD was observed in Caucasians and Asians for BIN1 rs744373. Again, BIN1 rs7561528 showed a significantly enhanced risk of AD only in Caucasians. CLU rs11136000 showed significantly reduced risk in Caucasians but rs9331888 showed increased risk in the same ethnicity.

CONCLUSION: Our meta-analysis confirms the association of BIN1 rs744373, CLU rs9331888 and IDE rs1887922 polymorphisms with an increased risk of AD, especially in Caucasians. Again, CLU rs11136000 is associated with reduced AD risk in the overall population and Caucasians.

PMID:35546756 | DOI:10.2174/1567205019666220511140955

Pharmacogenomics. 2022 May 12. doi: 10.2217/pgs-2022-0054. Online ahead of print.

NO ABSTRACT

PMID:35546341 | DOI:10.2217/pgs-2022-0054