Pharmacogenomics. 2021 Nov 24. doi: 10.2217/pgs-2021-0126. Online ahead of print.

ABSTRACT

Aim: Phenytoin (PHT) is a common anticonvulsant agent known for inducing severe cutaneous adverse reactions (SCARs). HLA-B*15:02 as a risk factor of PHT-induced SCARs was reported in numerous studies with inconsistent results. This meta-analysis aimed to establish pooling evidence of this association. Materials & methods: Pooled odds ratios (ORs) with 95% CIs were estimated using a random-effects model. Results: A total of 11 studies on 1389 patients, were included for the analyses. There was a significant association between HLA-B*15:02 and PHT-induced SCAR (pooled OR = 2.29, 95% CI: 1.25-4.19, p = 0.008). Furthermore, there was a significant association regarding Stevens-Johnson syndrome/toxic epidermal necrolysis (OR = 3.63, 95% CI: 2.15-6.13, p < 0.001) but no association regarding drug reaction with eosinophilia and systemic symptom. Conclusion: The results supported the recommendations of HLA-B*15:02 screening before treatment with PHT.

PMID:34816768 | DOI:10.2217/pgs-2021-0126

Heliyon. 2021 Nov 9;7(11):e08353. doi: 10.1016/j.heliyon.2021.e08353. eCollection 2021 Nov.

ABSTRACT

The growing interest in the possibilities of modulating macrophages in inflammatory diseases with therapeutic purpose has prompted the development of new approaches for the treatment of periodontitis. This randomized add-on open preliminary clinical study evaluated the short-term effects of L-arginine or L-ornithine as an adjuvant to scaling and root planing (SRP) in patients with chronic periodontitis.

MATERIALS AND METHODS: Seventy-five periodontitis patients were recruited and monitored clinically and immunologically at baseline (before SRP) and 30 ± 5 days after SRP. All patients were assigned by stratified randomization to SRP (SRP only, n = 25), Arg (SRP + L-arginine, n = 25) or Control (SRP + L-ornithine, n = 25) Group. The medicines were used according to available instructions for 10 and 15 days, respectively. During the study, all patients were on a stable diet, without changing their rations and regiments. As immunological monitoring immunohistochemical study of CD68+ and CD163 + single positive gingival macrophages for 5 patients per group in the same time-point was conducted. The data were statistically analyzed.

RESULTS: Reduction of periodontal pocket depth (PPD) and bleeding on probing (BoP) was observed in all groups, with significant between-group differences for BoP in the Arg Group (p < 0.0001) at 30 days. The SRP and Arg groups demonstrated nonsignificantly increased density of CD68+ and CD163 + cells. The Orn Group showed an increase in the density of CD68+ and CD163 + macrophages at intragroup (p = 0.0066 and p < 0.0001) and between-group levels (p = 0.001 and p < 0.0001), and these changes corresponded to clinical PPD and BoP reduction. In the Arg and Orn groups at 30 days, CD163 + macrophages significantly predominated over CD68+ (p = 0.013, p < 0.0001).

CONCLUSION: The use of L-arginine and L-ornithine as an adjunct to SRP promotes additional limited immunological benefit in the treatment of periodontitis. Metabolic stimulation with L-ornithine, but not L-arginine, is preferable for CD163+ Mφs subpopulation in periodontitis-affected gingiva.

PMID:34816043 | PMC:PMC8593455 | DOI:10.1016/j.heliyon.2021.e08353

Exp Ther Med. 2022 Jan;23(1):12. doi: 10.3892/etm.2021.10934. Epub 2021 Oct 28.

ABSTRACT

Long non-coding RNA (lncRNA) H19 is associated with proliferation, invasion and metastasis in numerous types of cancer. H19 lncRNA has been demonstrated to be an estrogen-inducible gene, the expression of which is significantly increased in tamoxifen (TAM)-resistant MCF-7 breast cancer cells. The aim of the present study was to investigate the role and molecular mechanism of lncRNA H19 in the development of TAM resistance. TAM-resistant MCF-7 (MCF-7R) cells were developed by the treatment of wild-type MCF-7 cells with 4-hydroxytamoxifen. Analysis of H19 expression in the cells indicated that upregulation of H19 contributed to the resistance of the MCF-7R cell line. Furthermore, when H19 was knocked down in the MCF-7R cells, the sensitivity to 4-hydroxytamoxifen was markedly restored. The results further demonstrated that N-acetyltransferase 1 (NAT1) may serve an important role in TAM-resistant cells, as NAT1 expression was notably downregulated in the MCF-7R cells but significantly elevated following the knockdown of H19. In addition, lower expression of NAT1 and higher expression of H19 were indicated to be associated with poor prognosis in patients with breast cancer treated with TAM. The results of bisulfite genomic sequencing PCR analysis indicated that the methylation rate of NAT1 in MCF-7R cells was significantly higher compared with that in MCF-7 cells, while the methylation rate of NAT1 in TAM-resistant cells transfected with small interfering RNA against H19 was significantly lower than that in the corresponding untransfected cells. Therefore, the present study suggests that the H19 gene regulates NAT1 expression in TAM-resistant cells via the mediation of NAT1 promoter methylation.

PMID:34815764 | PMC:PMC8593873 | DOI:10.3892/etm.2021.10934

Mol Cancer Ther. 2021 Nov 23:molcanther.MCT-21-0136-A.2021. doi: 10.1158/1535-7163.MCT-21-0136. Online ahead of print.

ABSTRACT

The innate immune agonist STING (STimulator of INterferon Genes) binds its natural ligand 2'3'-cGAMP (cyclic guanosine-adenosine monophosphate) and initiates type I interferon production. This promotes systemic antigen-specific CD8+ T-cell priming that eventually provides potent anti-tumor activity. To exploit this mechanism, we synthesized a novel STING agonist, MSA-1, that activates both mouse and human STING with higher in vitro potency than cGAMP. Following intratumoral (IT) administration of MSA-1 to a panel of syngeneic mouse tumors on immune-competent mice, cytokine upregulation and its exposure were detected in plasma, other tissues, injected tumors, and noninjected tumors. This was accompanied by effective anti-tumor activity. Mechanistic studies in immune-deficient mice suggested that anti-tumor activity of IT-dosed STING agonists is in part due to necrosis and/or innate immune responses such as tumor necrosis factor α (TNF-α) activity, but development of a robust adaptive anti-tumor immunity is necessary for complete tumor elimination. Combination with PD-1 blockade in anti-PD-1-resistant murine models demonstrated that MSA-1 may synergize with checkpoint inhibitors but can also provide superior tumor control as a single agent. We show for the first time that potent cyclic dinucleotides can promote a rapid and stronger induction of the same genes eventually regulated by PD-1 blockade. This may have contributed to the relatively early tumor control observed with MSA-1. Taken together, these data strongly support the development of STING agonists as therapy for patients with aggressive tumors that are partially responsive or nonresponsive to single-agent anti-PD-1 treatment by enhancing the anti-PD-1 immune profile.

PMID:34815361 | DOI:10.1158/1535-7163.MCT-21-0136

Trials. 2021 Nov 23;22(1):831. doi: 10.1186/s13063-021-05752-1.

ABSTRACT

BACKGROUND: Remdesivir is a novel broad-spectrum antiviral therapeutic with activity against several viruses that cause emerging infectious diseases. The purpose of this study is to explore how commonly utilized antiretroviral therapy (tenofovir disoproxil fumarate/lamivudine [TDF/3TC] and atazanavir/ritonavir [ATV/r]) influence plasma and intracellular concentrations of remdesivir.

METHODS: This is an open-label, randomized, fixed sequence single intravenous dosing study to assess pharmacokinetic interactions between remdesivir and TDF/3TC (Study A, crossover design) or TDF/3TC plus ATV/r (Study B). Healthy volunteers satisfying study entry criteria will be enrolled in the study and randomized to either Study A; N=16 (Sequence 1 or Sequence 2) or Study B; N=8. Participants will receive standard adult doses of antiretroviral therapy for 7 days and a single 200mg remdesivir infusion administered over 60 min. Pharmacokinetic blood sampling will be performed relative to the start of remdesivir infusion; predose (before the start of remdesivir infusion) and 30 min after the start of remdesivir infusion. Additional blood samples will be taken at 2, 4, 6, 12, and 24 h after the end of remdesivir infusion.

DISCUSSION: This study will characterize the pharmacokinetics of remdesivir from a typical African population in whom clinical use is anticipated. Furthermore, this study will deliver pharmacokinetic datasets for remdesivir drug concentrations and demographic characteristics which could support pharmacometric approaches for simulation of remdesivir treatment regimens in patients concurrently using tenofovir/lamivudine and/or atazanavir/ritonavir.

TRIAL REGISTRATION: ClinicalTrials.gov NCT04385719 . Registered 13 May 2020.

PMID:34814933 | DOI:10.1186/s13063-021-05752-1

J Obstet Gynaecol Res. 2021 Nov 23. doi: 10.1111/jog.15105. Online ahead of print.

ABSTRACT

OBJECTIVE(S): This prospective observational cohort study aimed to evaluate whether women with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection during the first trimester of pregnancy are at higher risk of adverse obstetric and neonatal outcomes compared to negative patients.

STUDY DESIGN: Seromolecular testing for SARS-CoV-2 was performed at 12, 16, 21 weeks, and at delivery; the cohort was then subdivided into a first-trimester SARS-CoV-2-positive (case) group and a SARS-CoV-2-negative (control) group. The primary outcome was a composite adverse obstetric outcome, defined as the presence of either abortion, preterm delivery, preterm prelabor rupture of membranes, preeclampsia, intrauterine growth restriction, stillbirth; and a composite measure of adverse neonatal events, including either 1- and 5-min Apgar score ≤ 7, neonatal intensive care unit admission and congenital birth defects. Maternal symptoms and antibody titer were secondarily assessed.

RESULTS: A total of 17 of 164 women tested positive for SARS-CoV-2 (10.3%) in the first trimester. One SARS-CoV-2-positive patient who gave birth at another hospital was excluded. Composite adverse obstetric outcome was observed in 6.2% (1/16) SARS-CoV-2-positive and 10.5% (11/105) SARS-CoV-2-negative women; composite adverse neonatal outcome in 12.5% (2/16) and 7.6% (8/105), respectively. In the newborns of women who had developed IgG antibodies, the same antibodies were detected in arterial cord blood and the nasopharyngeal swab tested negative for SARS-CoV-2. No maternal pneumonia or hospital admission due to coronavirus disease-19 were recorded.

CONCLUSION: Asymptomatic or mildly symptomatic women during the first trimester of pregnancy did not experience significantly more adverse events than SARS-CoV-2-negative women.

PMID:34814234 | DOI:10.1111/jog.15105

Biomed Pharmacother. 2021 Nov 20;145:112436. doi: 10.1016/j.biopha.2021.112436. Online ahead of print.

ABSTRACT

Disruption or loss of oligodendrocytes (OLs) and myelin has devastating effects on CNS function and integrity, which occur in diverse neurological disorders, including Multiple Sclerosis (MS), Alzheimer's disease and neuropsychiatric disorders. Hence, there is a need to develop new therapies that promote oligodendrocyte regeneration and myelin repair. A promising approach is drug repurposing, but most agents have potentially contrasting biological actions depending on the cellular context and their dose-dependent effects on intracellular pathways. Here, we have used a combined systems biology and neurobiological approach to identify compounds that exert positive and negative effects on oligodendroglia, depending on concentration. Notably, next generation pharmacogenomic analysis identified the PI3K/Akt modulator LY294002 as the most highly ranked small molecule with both pro- and anti-oligodendroglial concentration-dependent effects. We validated these in silico findings using multidisciplinary approaches to reveal a profoundly bipartite effect of LY294002 on the generation of OPCs and their differentiation into myelinating oligodendrocytes in both postnatal and adult contexts. Finally, we employed transcriptional profiling and signalling pathway activity assays to determine cell-specific mechanisms of action of LY294002 on oligodendrocytes and resolve optimal in vivo conditions required to promote myelin repair. These results demonstrate the power of multidisciplinary strategies in determining the therapeutic potential of small molecules in neurodegenerative disorders.

PMID:34813998 | DOI:10.1016/j.biopha.2021.112436

Crit Rev Oncol Hematol. 2021 Nov 20:103525. doi: 10.1016/j.critrevonc.2021.103525. Online ahead of print.

ABSTRACT

AIMS: The KWAY project aims to investigate the economic sustainability of the up-front NGS technologies adoption in the analysis of clinically relevant molecular alterations in NSCLC patients.

METHODS: The diagnostic workflow and the related sustained costs of five Italian referral centers were assessed in four different evolving scenarios were analyzed. For each scenario, two alternative testing strategies were evaluated: the Maximized Standard strategy and the Maximized NGS strategy.

RESULTS: For each center, the robustness of obtained results was verified through a deterministic sensitivity analysis, observing the variation of total costs based on a variation of ±20 % of the input parameters and ensuring that results would present a consistent behavior compared to the original ones.

CONCLUSIONS: our project, highlighted that the adoption of NGS allows to save personnel time dedicated to testing activities and to reduce the overall cost of testing per patient.

PMID:34813925 | DOI:10.1016/j.critrevonc.2021.103525

Chem Biol Interact. 2021 Nov 20:109747. doi: 10.1016/j.cbi.2021.109747. Online ahead of print.

ABSTRACT

Our recent study demonstrated eIF3a loss contributes to vemurafenib resistance in melanoma by activating ERK. However, overexpression of eIF3a in the clinic is not feasible to produce vemurafenib re-sensitization, and ERK inhibitors combined with vemurafenib still exhibit limited effectiveness in the treatment of melanoma. Here, using the human receptor tyrosine kinase phosphorylation antibody array, we observed that silencing eIF3a could activate BMX, a tyrosine kinase. The BMX inhibitor CHMFL-BMX-078 could significantly suppress proliferation and induce cell cycle arrest in vemurafenib resistant melanoma cell line A375 (A375R), however, it was hypotoxic in immortal keratinocytes, melanoma cells, and other solid cancer cells such as glioma and breast cancer cells. Furthermore, the combined treatment of CHMFL-BMX-078 and vemurafenib synergistically reduced cell viability and restored the sensitivity of resistant cells to vemurafenib. The reversal of the resistant phenotype by CHMFL-BMX-078 was associated with the AKT signaling pathway, as co-treatment with the AKT activator SC-79 or up-regulation of AKT attenuated the anti-proliferation effect of CHMFL-BMX-078 and vemurafenib. Lastly, we demonstrated that CHMFL-BMX-078 could significantly enhance vemurafenib efficacy in a xenograft model of A375R cells without producing additive toxicity. In conclusion, these findings reveal that the BMX inhibitor CHMFL-BMX-078 may reverse vemurafenib resistance in melanoma by suppressing the AKT signaling pathway, implying that CHMFL-BMX-078 may be a promising compound for overcoming vemurafenib resistance.

PMID:34813779 | DOI:10.1016/j.cbi.2021.109747

Obes Surg. 2021 Nov 23. doi: 10.1007/s11695-021-05789-w. Online ahead of print.

ABSTRACT

PURPOSE: Fatty acids (FA), particularly polyunsaturated (PUFA) ones, are involved in the regulation of glycemic control, lipid metabolism, and inflammation. The aim of the study was to assess patient FA profile in relation to obesity, lipid and carbohydrate metabolism disturbances, and weight loss.

MATERIALS AND METHODS: The studied group consisted of 51 patients with extreme obesity, 23 of whom achieved radical weight reduction within 1 year after a laparoscopic sleeve gastrectomy (LSG). FA levels were determined using gas chromatography with flame ionization detection.

RESULTS: Patients with extreme obesity and higher serum PUFA content have lower serum levels of SFA and MUFA (especially myristic, palmitic, lignoceric acids and palmitoleic, oleic acids), as well as lower triglyceride and higher HDL-cholesterol concentrations and it was not influenced by CEPT Taq1B variant. At baseline, the fatty acid profile of patients with type II diabetes differ from patients with dyslipidemia. In patients who had lost weight, significantly lower levels of selected saturated FA and major trans-fatty acid, elaidic, were found. Moreover, the proportion of PUFA was increased.

CONCLUSION: In extreme obesity, higher PUFA exert their favorable effects on serum lipids. Significant weight reduction after the bariatric surgery is associated with beneficial changes in the fatty acid profile.

PMID:34813039 | DOI:10.1007/s11695-021-05789-w

J Med Chem. 2021 Nov 23. doi: 10.1021/acs.jmedchem.1c01547. Online ahead of print.

ABSTRACT

To fight COVID-19, much effort has been directed toward in vitro drug repurposing. Here, we investigate the impact of colloidal aggregation, a common screening artifact, in these repurposing campaigns. We tested 56 drugs reported as active in biochemical assays for aggregation by dynamic light scattering and by detergent-based enzyme counter screening; 19 formed colloids at concentrations similar to their literature IC50's, and another 14 were problematic. From a common repurposing library, we further selected another 15 drugs that had physical properties resembling known aggregators, finding that six aggregated at micromolar concentrations. This study suggests not only that many of the drugs repurposed for SARS-CoV-2 in biochemical assays are artifacts but that, more generally, at screening-relevant concentrations, even drugs can act artifactually via colloidal aggregation. Rapid detection of these artifacts will allow the community to focus on those molecules that genuinely have potential for treating COVID-19.

PMID:34812616 | DOI:10.1021/acs.jmedchem.1c01547

Transl Psychiatry. 2021 Nov 22;11(1):596. doi: 10.1038/s41398-021-01717-9.

ABSTRACT

Many antidepressants, atomoxetine, and several antipsychotics are metabolized by the cytochrome P450 enzymes CYP2D6 and CYP2C19, and guidelines for prescribers based on genetic variants exist. Although some laboratories offer such testing, there is no consensus regarding validated methodology for clinical genotyping of CYP2D6 and CYP2C19. The aim of this paper was to cross-validate multiple technologies for genotyping CYP2D6 and CYP2C19 against each other, and to contribute to feasibility for clinical implementation by providing an enhanced range of assay options, customizable automated translation of data into haplotypes, and a workflow algorithm. AmpliChip CYP450 and some TaqMan single nucleotide variant (SNV) and copy number variant (CNV) data in the Genome-based therapeutic drugs for depression (GENDEP) study were used to select 95 samples (out of 853) to represent as broad a range of CYP2D6 and CYP2C19 genotypes as possible. These 95 included a larger range of CYP2D6 hybrid configurations than have previously been reported using inter-technology data. Genotyping techniques employed were: further TaqMan CNV and SNV assays, xTAGv3 Luminex CYP2D6 and CYP2C19, PharmacoScan, the Ion AmpliSeq Pharmacogenomics Panel, and, for samples with CYP2D6 hybrid configurations, long-range polymerase chain reactions (L-PCRs) with Sanger sequencing and Luminex. Agena MassARRAY was also used for CYP2C19. This study has led to the development of a broader range of TaqMan SNV assays, haplotype phasing methodology with TaqMan adaptable for other technologies, a multiplex genotyping method for efficient identification of some hybrid haplotypes, a customizable automated translation of SNV and CNV data into haplotypes, and a clinical workflow algorithm.

PMID:34811360 | DOI:10.1038/s41398-021-01717-9

Front Pharmacol. 2021 Nov 5;12:750433. doi: 10.3389/fphar.2021.750433. eCollection 2021.

ABSTRACT

Tacrolimus (TAC) is a first-choice immunosuppressant for solid organ transplantation, characterized by high potential for drug-drug interactions, significant inter- and intra-patient variability, and narrow therapeutic index. Therapeutic drug monitoring (TDM) of TAC concentrations in whole blood (WB) is capable of reducing the incidence of adverse events. Since TAC acts within lymphocytes, its monitoring in peripheral blood mononuclear cells (PBMC) may represent a valid future alternative for TDM. Nevertheless, TAC intracellular concentrations and their variability are poorly described, particularly in the pediatric context. Therefore, our aim was describing TAC concentrations in WB and PBMC and their variability in a cohort of pediatric patients undergoing constant immunosuppressive maintenance therapy, after liver transplantation. TAC intra-PBMCs quantification was performed through a validated UHPLC-MS/MS assay over a period of 2-3 months. There were 27 patients included in this study. No significant TAC changes in intracellular concentrations were observed (p = 0.710), with a median percent change of -0.1% (IQR -22.4%-+46.9%) between timings: this intra-individual variability was similar to the one in WB, -2.9% (IQR -29.4-+42.1; p = 0.902). Among different patients, TAC weight-adjusted dose and age appeared to be significant predictors of TAC concentrations in WB and PBMC. Intra-individual seasonal variation of TAC concentrations in WB, but not in PBMC, have been observed. These data show that the intra-individual variability in TAC intracellular exposure is comparable to the one observed in WB. This opens the way for further studies aiming at the identification of therapeutic ranges for TAC intra-PBMC concentrations.

PMID:34803692 | PMC:PMC8602893 | DOI:10.3389/fphar.2021.750433

Pharmgenomics Pers Med. 2021 Nov 13;14:1441-1455. doi: 10.2147/PGPM.S329787. eCollection 2021.

ABSTRACT

Type 2 diabetes mellitus (T2DM) is the most common form of diabetes, and is rising in incidence with widespread prevalence. Multiple gene variants are associated with glucose homeostasis, complex T2DM pathogenesis, and its complications. Exploring more effective therapeutic strategies for patients with diabetes is crucial. Pharmacogenomics has made precision medicine possible by allowing for individualized drug therapy based on a patient's genetic and genomic information. T2DM is treated with various classes of oral hypoglycemic agents, such as biguanides, sulfonylureas, thiazolidinediones, meglitinides, DPP4 inhibitors, SGLT2 inhibitors, α-glucosidase inhibitors, and GLP1 analogues, which exhibit various pharmacogenetic variants. Although genomic interventions in monogenic diabetes have been implemented in clinical practice, they are still in the early stages for complex polygenic disorders, such as T2DM. Precision DM medicine has the potential to be effective in personalized therapy for those suffering from various forms of DM, such as T2DM. With recent developments in genetic techniques, the application of candidate-gene studies, large-scale genotyping investigations, genome-wide association studies, and "multiomics" studies has begun to produce results that may lead to changes in clinical practice. Enhanced knowledge of the genetic architecture of T2DM presents a bigger translational potential. This review summarizes the genetics and pathophysiology of T2DM, candidate-gene approaches, genome-wide association studies, personalized medicine, clinical relevance of pharmacogenetic variants associated with oral hypoglycemic agents, and paths toward personalized diabetology.

PMID:34803393 | PMC:PMC8598203 | DOI:10.2147/PGPM.S329787

Tuberculosis (Edinb). 2021 Oct 8;131:102138. doi: 10.1016/j.tube.2021.102138. Online ahead of print.

ABSTRACT

The clinical utility of blood transcriptomic biosignatures for the treatment monitoring and outcome prediction of tuberculosis (TB) remains limited. In this study, we aimed to discover and validate biomarkers for pulmonary TB treatment monitoring and outcome prediction based on kinetic responses of gene expression during treatment. In particular, differentially expressed genes (DEGs) were identified by time-series comparison. Subsequently, DEGs with the monotonic expression alterations during the treatment were selected. Ten consistently down-regulated genes (CD274, KIF1B, IL15, TLR1, TLR5, FCGR1A, GBP1, NOD2, GBP2, EGF) exhibited significant potential in treatment monitoring, demonstrated via biological and technical validation. Additionally, the biosignature showed potential in predicting the cured versus relapsed patients. Furthermore, the biosignature could be utilized for TB diagnosis, latent tuberculosis infection/active TB differential diagnosis, and risk of progression to active TB. Benchmarking analysis of the 10-gene biosignature with other biosignatures showed equivalent performance in tested data sets. In conclusion, we established a 10-gene transcriptomic biosignature that represents the kinetic responses of TB treatment. Subsequent studies are warranted to validate, refine and translate the biosignature into a precise assay to assist clinical decisions in a broad spectrum of TB management.

PMID:34801869 | DOI:10.1016/j.tube.2021.102138

Environ Pollut. 2021 Nov 18:118542. doi: 10.1016/j.envpol.2021.118542. Online ahead of print.

ABSTRACT

Perfluorooctane sulfonic acid (PFOS) is a persistent environmental pollutant. Exposure to PFOS has been associated with abnormal fetal development. The long non-coding RNA (lncRNA) has been showed to play a role in fetal growth restriction (FGR), preeclampsia (PE) and other pregnancy complications. Whether the lncRNA contributes to PFOS-induced toxicity in the placenta remains unknown. In this study, we investigated the function of lncRNA MEG3 and its derived miR-770 in PFOS-induced placental toxicity. Pregnant mice received gavage administration of different concentrations of PFOS (0.5, 2.5, and 12.5 mg/kg/day) from GD0 to GD17, and HTR-8/SVneo cells were treated with PFOS in the concentrations of 0, 10-1, 1, 10 μM. We found that expression levels of miR-770 and its host gene MEG3 were reduced in mice placentas and HTR-8/SVneo cells with exposure of PFOS. A significant hypermethylation was observed at MEG3 promoter in placentas of mice gestational-treated with PFOS. We also confirmed that MEG3 and miR-770 overexpression alleviated the cell growth inhibition induced by PFOS. Furthermore, PTX3 (Pentraxin 3) was identified as the direct target of miR-770 and it was enhanced after PFOS exposure. In summary, our results suggested that MEG3 alleviate PFOS-induced placental cell inhibition through MEG3/miR-770/PTX3 axis.

PMID:34801623 | DOI:10.1016/j.envpol.2021.118542

J Biol Chem. 2021 Nov 18:101413. doi: 10.1016/j.jbc.2021.101413. Online ahead of print.

ABSTRACT

Naturally occurring missense variants of G protein-coupled receptors (GPCRs) with loss-of-function have been linked to metabolic disease in case studies and in animal experiments. The glucagon receptor, one such GPCR, is involved in maintaining blood glucose and amino acid homeostasis; however, loss-of-function mutations of this receptor have not been systematically characterized. Here, we observed fewer glucagon receptor missense variants than expected, as well as lower allele diversity and fewer variants with trait associations as compared to other class B1 receptors. We performed molecular pharmacological phenotyping of 38 missense variants located in the receptor extracellular domain, at the glucagon interface, or with previously suggested clinical implications. These variants were characterized in terms of cAMP accumulation to assess glucagon-induced Gɑs coupling, and of recruitment of β-arrestin-1/2. Fifteen variants were impaired in at least one of these downstream functions, with six variants affected in both cAMP accumulation and β-arrestin 1/2 recruitment. For the eight variants with decreased Gɑs signaling (D63ECDN, P86ECDS, V96ECDE, G125ECDC, R2253.30H, R3085.40W, V3686.59M, and R3787.35C) binding experiments revealed preserved glucagon affinity, although with significantly reduced binding capacity. Finally, using the UK Biobank, we found that variants with wildtype-like Gɑs signaling did not associate with metabolic phenotypes, whereas carriers of cAMP accumulation-impairing variants displayed a tendency towards increased risk of obesity and increased body mass and blood pressure. These observations are in line with the essential role of the glucagon system in metabolism and support that Gɑs is the main signaling pathway effecting the physiological roles of the glucagon receptor.

PMID:34801547 | DOI:10.1016/j.jbc.2021.101413

J Am Pharm Assoc (2003). 2021 Nov 3:S1544-3191(21)00462-3. doi: 10.1016/j.japh.2021.10.033. Online ahead of print.

ABSTRACT

BACKGROUND: Variability in individual drug response may delay time to relief of symptoms for various disease states. As pharmacogenomic (PGx) testing becomes more widespread, providers are tasked with determining when and in who PGx testing is most appropriate. The use of PGx testing in patients with depressive symptoms has shown some utility, but how this translates to a general population within a primary care setting has yet to be determined.

OBJECTIVE: The objective of this pilot study was to determine the effect of PGx testing on treatment decisions in patients with depressive symptoms in an interprofessional primary care setting.

METHODS: This was a retrospective observational study in which patients who underwent PGx testing for psychotropic medications between April 2019 and March 2021 at a private interprofessional primary care clinic were identified. Charts were reviewed to determine whether a resultant change was made to the prescribed psychotropic medication regimen based on PGx testing results. The number of antidepressants trialed before and after testing was also reviewed. Data were analyzed using descriptive statistics and t test where appropriate.

RESULTS: A total of 78 patients were included in the study. A total of 42 patients (53.8%) experienced a change to their antidepressant regimen after PGx testing. The most frequent change identified was the addition of another antidepressant (50%). This was followed by switching the antidepressant and then by an increase in dose of the prescribed antidepressant. No difference between the number of antidepressants trialed before and after testing was identified.

CONCLUSION: PGx testing in an interprofessional primary care setting leads to a medication change in most patients in this study. Based on the changes identified, testing may be most useful in those beginning treatment with an antidepressant or in those who experience an inadequate response to their prescribed regimen.

PMID:34801407 | DOI:10.1016/j.japh.2021.10.033

Mol Psychiatry. 2021 Nov 19. doi: 10.1038/s41380-021-01383-9. Online ahead of print.

ABSTRACT

Schizophrenia has a multifactorial etiology, involving a polygenic architecture. The potential benefit of whole genome sequencing (WGS) in schizophrenia and other psychotic disorders is not well studied. We investigated the yield of clinical WGS analysis in 251 families with a proband diagnosed with schizophrenia (N = 190), schizoaffective disorder (N = 49), or other conditions involving psychosis (N = 48). Participants were recruited in Israel and USA, mainly of Jewish, Arab, and other European ancestries. Trio (parents and proband) WGS was performed for 228 families (90.8%); in the other families, WGS included parents and at least two affected siblings. In the secondary analyses, we evaluated the contribution of rare variant enrichment in particular gene sets, and calculated polygenic risk score (PRS) for schizophrenia. For the primary outcome, diagnostic rate was 6.4%; we found clinically significant, single nucleotide variants (SNVs) or small insertions or deletions (indels) in 14 probands (5.6%), and copy number variants (CNVs) in 2 (0.8%). Significant enrichment of rare loss-of-function variants was observed in a gene set of top schizophrenia candidate genes in affected individuals, compared with population controls (N = 6,840). The PRS for schizophrenia was significantly increased in the affected individuals group, compared to their unaffected relatives. Last, we were also able to provide pharmacogenomics information based on CYP2D6 genotype data for most participants, and determine their antipsychotic metabolizer status. In conclusion, our findings suggest that WGS may have a role in the setting of both research and genetic counseling for individuals with schizophrenia and other psychotic disorders and their families.

PMID:34799694 | DOI:10.1038/s41380-021-01383-9

Curr Pharm Teach Learn. 2021 Nov;13(11):1438-1444. doi: 10.1016/j.cptl.2021.09.047. Epub 2021 Sep 25.

ABSTRACT

INTRODUCTION: With community pharmacy transitioning from a fee-for-service model to a value-based care focus, the desired skills of pharmacist graduates is an evolving paradigm. As active stakeholders in community practice, pharmacist preceptors are in a unique position to compare the ever-changing dichotomy between pharmacy practice and training. Examining preceptors' assessments of these essential contemporary practice skills may provide useful insights.

METHODS: A survey was emailed to all regional, active college of pharmacy community advanced pharmacy practice experiences preceptors. Participating preceptors were given 30 days to complete the online survey. Weekly reminders were provided.

RESULTS: Of the 168 preceptors invited to participate, 42 (25%) completed the survey. Descriptive analysis compared preceptors' perceptions of transformative services vs. their relative implementation in practice. This revealed service areas such as health screenings that were proportionate in their prevalence of offering and perception as contemporary. In contrast, services such as pharmacogenomic testing were more widely perceived as contemporary compared to their low prevalence as an offering. Participants showed broad consensus in the importance of most skills listed in the survey, predominantly indicating these skills were either "very important" or "extremely important." Only a few specific skills areas were identified that showed less consensus, with a minority of respondents specifying that these skills were of less importance.

CONCLUSIONS: Preceptor surveys may offer insights on the progression of community practice curricula. Continued monitoring of changes in service parameters over time may reveal trends in practice transformation, identifying service areas being more widely adopted.

PMID:34799056 | DOI:10.1016/j.cptl.2021.09.047