Expert Opin Drug Discov. 2022 Feb 6:1-15. doi: 10.1080/17460441.2022.2033724. Online ahead of print.

NO ABSTRACT

PMID:35129021 | DOI:10.1080/17460441.2022.2033724

J Adv Res. 2021 Jun 12;36:265-276. doi: 10.1016/j.jare.2021.06.009. eCollection 2022 Feb.

ABSTRACT

INTRODUCTION: Colorectal cancer (CRC) is a common malignant tumor with a high global incidence, metastasis rate and low cure rate. Changes in lipid metabolism-related genes can affect the occurrence and development of CRC, and may be a potential therapeutic target for CRC. Therefore, starting from lipid metabolism-related genes to find natural medicines for tumor treatment may become a new direction in CRC research.

OBJECTIVES: This study aimed to investigate the effect of PLA2G16, a key gene involved in lipid metabolism, on the biological function of CRC, and whether the anti-CRC effect of GCK is related to PLA2G16.

METHODS: To explore the role of PLA2G16 in CRC in vitro and in vivo, we performed cell proliferation, migration, invasion and nude mice tumorigenesis assays. As for the mechanism, we designed RNA-seq analysis and verified by western blotting and immunofluorescence experiments. Subsequently, we found the anti-CRC effect of GCK is related to PLA2G16 through western blotting and rescue experiments.

RESULTS: We showed that PLA2G16 was significantly higher in CRC tissues than the adjacent normal appearing tissues, and high PLA2G16 expression correlates with unfavorable prognosis of CRC patients. Further, PLA2G16 promoted the malignant progression of CRC by inhibiting the Hippo signaling pathway determined by RNA-seq analysis, and GCK exerted anti-CRC effects by inhibiting the protein expression of PLA2G16 in vitro and in vivo.

CONCLUSION: Our results suggested that PLA2G16 promote the malignant progression of CRC by inhibiting the Hippo signaling pathway and the anti-CRC effect of GCK is through inhibiting the protein expression of PLA2G16.

PMID:35127176 | PMC:PMC8799872 | DOI:10.1016/j.jare.2021.06.009

Front Pharmacol. 2022 Jan 21;12:779497. doi: 10.3389/fphar.2021.779497. eCollection 2021.

ABSTRACT

Hydroxyurea has long been used for the treatment of sickle cell anemia (SCA), and its clinical effectiveness is related to the induction of fetal hemoglobin (HbF), a major modifier of SCA phenotypes. However, there is substantial variability in response to hydroxyurea among patients with SCA. While some patients show an increase in HbF levels and an ameliorated clinical condition under low doses of hydroxyurea, other patients present a poor effect or even develop toxicity. However, the effects of genetic polymorphisms on increasing HbF levels in response to hydroxyurea in patients with SCA (Hb SS) have been less explored. Therefore, we performed a systematic review to assess whether single-nucleotide polymorphisms (SNPs) affect HbF levels in patients with SCA treated with hydroxyurea. Moreover, we performed pathway analysis using the set of genes with SNPs found to be associated with changes in HbF levels in response to hydroxyurea among the included studies. The systematic literature search was conducted on Medline/PubMed, EMBASE, Cochrane Central Register of Controlled Trials, Cumulative Index to Nursing and Allied Health Literature (CINAHL), Scopus, and Web of Science. Seven cohort studies were included following our inclusion and exclusion criteria. From the 728 genetic polymorphisms examined in the included studies, 50 different SNPs of 17 genes were found to be associated with HbF changes in patients with SCA treated with hydroxyurea, which are known to affect baseline HbF but are not restricted to them. Enrichment analysis of this gene set revealed reactome pathways with the lowest adjusted p-values and highest combined scores related to VEGF ligand-receptor interactions (R-HSA-194313; R-HSA-195399) and the urea cycle (R-HSA-70635). Pharmacogenetic studies of response to hydroxyurea therapy in patients with SCA are still scarce and markedly heterogeneous regarding candidate genes and SNPs examined for association with HbF changes and outcomes, suggesting that further studies are needed. The reviewed findings highlighted that similar to baseline HbF, changes in HbF levels upon hydroxyurea therapy are likely to be regulated by multiple loci. There is evidence that SNPs in intron 2 of BCL11A affect HbF changes in response to hydroxyurea therapy, a potential application that might improve the clinical management of SCA. Systematic Review Registration: (https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=208790).

PMID:35126118 | PMC:PMC8814522 | DOI:10.3389/fphar.2021.779497

Lancet Gastroenterol Hepatol. 2022 Feb 3:S2468-1253(22)00005-X. doi: 10.1016/S2468-1253(22)00005-X. Online ahead of print.

ABSTRACT

BACKGROUND: The effects that therapies for inflammatory bowel disease (IBD) have on immune responses to SARS-CoV-2 vaccination are not yet fully known. Therefore, we sought to determine whether COVID-19 vaccine-induced antibody responses were altered in patients with IBD on commonly used immunosuppressive drugs.

METHODS: In this multicentre, prospective, case-control study (VIP), we recruited adults with IBD treated with one of six different immunosuppressive treatment regimens (thiopurines, infliximab, a thiopurine plus infliximab, ustekinumab, vedolizumab, or tofacitinib) and healthy control participants from nine centres in the UK. Eligible participants were aged 18 years or older and had received two doses of COVID-19 vaccines (either ChAdOx1 nCoV-19 [Oxford-AstraZeneca], BNT162b2 [Pfizer-BioNTech], or mRNA1273 [Moderna]) 6-12 weeks apart (according to scheduling adopted in the UK). We measured antibody responses 53-92 days after a second vaccine dose using the Roche Elecsys Anti-SARS-CoV-2 spike electrochemiluminescence immunoassay. The primary outcome was anti-SARS-CoV-2 spike protein antibody concentrations in participants without previous SARS-CoV-2 infection, adjusted by age and vaccine type, and was analysed by use of multivariable linear regression models. This study is registered in the ISRCTN Registry, ISRCTN13495664, and is ongoing.

FINDINGS: Between May 31 and Nov 24, 2021, we recruited 483 participants, including patients with IBD being treated with thiopurines (n=78), infliximab (n=63), a thiopurine plus infliximab (n=72), ustekinumab (n=57), vedolizumab (n=62), or tofacitinib (n=30), and 121 healthy controls. We included 370 participants without evidence of previous infection in our primary analysis. Geometric mean anti-SARS-CoV-2 spike protein antibody concentrations were significantly lower in patients treated with infliximab (156·8 U/mL [geometric SD 5·7]; p<0·0001), infliximab plus thiopurine (111·1 U/mL [5·7]; p<0·0001), or tofacitinib (429·5 U/mL [3·1]; p=0·0012) compared with controls (1578·3 U/mL [3·7]). There were no significant differences in antibody concentrations between patients treated with thiopurine monotherapy (1019·8 U/mL [4·3]; p=0·74), ustekinumab (582·4 U/mL [4·6]; p=0·11), or vedolizumab (954·0 U/mL [4·1]; p=0·50) and healthy controls. In multivariable modelling, lower anti-SARS-CoV-2 spike protein antibody concentrations were independently associated with infliximab (geometric mean ratio 0·12, 95% CI 0·08-0·17; p<0·0001) and tofacitinib (0·43, 0·23-0·81; p=0·0095), but not with ustekinumab (0·69, 0·41-1·19; p=0·18), thiopurines (0·89, 0·64-1·24; p=0·50), or vedolizumab (1·16, 0·74-1·83; p=0·51). mRNA vaccines (3·68, 2·80-4·84; p<0·0001; vs adenovirus vector vaccines) were independently associated with higher antibody concentrations and older age per decade (0·79, 0·72-0·87; p<0·0001) with lower antibody concentrations.

INTERPRETATION: For patients with IBD, the immunogenicity of COVID-19 vaccines varies according to immunosuppressive drug exposure, and is attenuated in recipients of infliximab, infliximab plus thiopurines, and tofacitinib. Scheduling of third primary, or booster, doses could be personalised on the basis of an individual's treatment, and patients taking anti-tumour necrosis factor and tofacitinib should be prioritised.

FUNDING: Pfizer.

PMID:35123676 | DOI:10.1016/S2468-1253(22)00005-X

Cancer Treat Res Commun. 2022 Feb 1;31:100528. doi: 10.1016/j.ctarc.2022.100528. Online ahead of print.

ABSTRACT

Clinical responses to anticancer therapies in advanced soft tissue sarcoma (STS) are unfortunately limited to a small subset of patients. Much of the inter-individual variability in treatment efficacy and risk of toxicities is as result of polymorphisms in genes encoding proteins involved in drug pharmacokinetics and pharmacodynamics. Therefore, the detection of pharmacogenomics (PGx) biomarkers that might predict drug response and toxicity can be useful to explain the genetic basis for the differences in treatment efficacy and toxicity among STS patients. PGx markers are frequently located in transporters, drug-metabolizing enzyme genes, drug targets, or HLA alleles. Along this line, genetic variability harbouring in the germline genome of the patients can influence systemic pharmacokinetics and pharmacodynamics of the treatments, acting as predictive biomarkers for drug-induced toxicity and treatment efficacy. By linking drug activity to the functional complexity of cancer genomes, also systematic pharmacogenomic profiling in cancer cell lines and primary STS samples represents area of active investigation that could eventually lead to enhanced efficacy and offer a powerful biomarker discovery platform to optimize current treatments and improve the knowledge about the individual's drug response in STS patients into the clinical practice.

PMID:35123198 | DOI:10.1016/j.ctarc.2022.100528

J Pharm Sci. 2022 Feb 2:S0022-3549(22)00043-0. doi: 10.1016/j.xphs.2022.01.032. Online ahead of print.

ABSTRACT

Immunogenicity to biologics is often observed following dosing in human subjects during clinical trials. Both product and host specific factors may be implicated in contributing to a potential immune response. However, even if such risk factors are identified and eliminated as part of the rational quality by design approaches, the outcome in clinic can be uncertain and challenging to predict. Several tools have been employed to identify these risk factors and consequent mitigation approaches implemented prior to dosing in humans. However, the complexity of the immune system with an interplay of network of immune cells involved in driving a long- term immune response as well as patient characteristics, can make it challenging to predict the outcome in clinic. This perspective will provide an insight into recent advances in the risk assessment approaches that are utilized during preclinical stage of development of a biologic. The outputs from such tools can help to rank order and select the most optimal candidate with the least likelihood of an immune response and can further drive the development of a clinical bioanalytical and immunogenicity monitoring strategy. Such a strategy can be proactively shared with the regulators along with the proposal to streamline clinical immunogenicity and personalizing the outcome based on pharmacogenomics and other patient-related factors. This paper provides a roadmap on performing risk assessments through a systematic identification of risks and their mitigations wherever possible. Recommendations on incorporating the key components of such risk assessments as part of the new regulatory submissions are also provided. Shorter abstract Immunogenicity to biologics is common during clinical trials. Both product and host specific factors have been implicated. Several risk assessment tools can be used to identify and mitigate the risk factors responsible for immunogenicity. An insight into recent advances in the risk assessment approaches will be presented. The outputs can define a risk score and guide the clinical bioanalytical and immunogenicity monitoring strategy. A roadmap on performing risk assessments through a systematic identification of risks and their mitigations wherever possible is provided. Best practices for a risk assessment strategy and recommendations on the content for IND and the Integrated summary of Immunogenicity are also provided.

PMID:35122828 | DOI:10.1016/j.xphs.2022.01.032

Clin Transl Sci. 2022 Feb 5. doi: 10.1111/cts.13230. Online ahead of print.

ABSTRACT

Large, observational genetic studies are commonly used to identify genetic factors associated with diseases and disease-related traits. Such cohorts have not been commonly used to identify genetic predictors of drug dosing or concentrations, perhaps because of the heterogeneity in drug dosing and formulation, and the random timing of blood sampling. We hypothesized that large sample sizes relative to traditional pharmacokinetic studies would compensate for this variability and enable the identification of pharmacogenetic predictors of drug concentrations. We performed a cross-sectional, proof-of-concept association study to replicate the well-established association between metoprolol concentrations and CYP2D6 genotype-inferred metabolizer phenotypes in participants from the Montreal Heart Institute Hospital Cohort undergoing metoprolol therapy. Plasma concentrations of metoprolol and α-hydroxymetoprolol (α-OH-metoprolol) were measured in samples collected randomly regarding the previous metoprolol dose. A total of 999 individuals were included. The metoprolol daily dose ranged from 6.25 to 400 mg (mean 84.3 ± 57.1 mg). CYP2D6-inferred phenotype was significantly associated with both metoprolol and α-OH-metoprolol in unadjusted and adjusted models (all p < 10-14 ). Models for metoprolol daily dose showed consistent results. Our study suggests that randomly drawn blood samples from biobanks can serve as a new approach to discover genetic associations related to drug concentrations and dosing, with potentially broader implications for genomewide association studies on the pharmacogenomics of drug metabolism.

PMID:35122397 | DOI:10.1111/cts.13230

Drug Resist Updat. 2022 Jan 28;60:100811. doi: 10.1016/j.drup.2022.100811. Online ahead of print.

ABSTRACT

Globally with over 10 million deaths per year, cancer is the most transversal disease across countries, cultures, and ethnicities, affecting both developed and developing regions. Tumorigenesis is dynamically altered by distinct events and can be lethal when untreated. Despite the innovative therapeutics available, multidrug resistance (MDR) to chemotherapy remains the major hindrance to the success of cancer therapy. The multiple mechanisms by which cancer cells evade cell death are diverse, indicating that MDR involves complex interconnected biological networks. Molecular profiling is currently able to stratify cancer into its distinct subtypes and help identify the best therapeutics, leading to "translational systems medicine". Highly specialized methodologies are generating a large amount of "omics" data - including epigenetics, genomics, transcriptomics, proteomics, metabolomics, as well as pharmacogenomics. Many of the resulting databases store data in non-standard formats, which need to be converted, interpreted, and merged into readable formats. The latest development of artificial intelligence (AI) methodologies and tools, coupled with advancements in large-scale data management and powerful graphic processing computing units, potentiate the integration of these large data sources into relevant biological networks, which will enhance our understanding of cancer MDR. In this review, we revisit common MDR mechanisms and compile a list of the most relevant "omics" public databases. We highlight examples of AI methods that are now decisively contributing to clear advances in cancer research, such as identification of new drugs from large databases and prediction of relevant drug, target, and system properties. An overview of several freely available "ready-to-use" algorithms is also provided. The described molecular scale AI algorithms and tools will undoubtedly guide important improvements in efficiency and efficacy of traditional methods of cancer diagnostics and treatment.

PMID:35121338 | DOI:10.1016/j.drup.2022.100811

J Pediatr. 2022 Feb 1:S0022-3476(22)00072-5. doi: 10.1016/j.jpeds.2022.01.041. Online ahead of print.

ABSTRACT

OBJECTIVE: To describe the ambulatory proton pump inhibitor (PPI) prescription in French children, its trends, and the impact of French (2014) and international (2018) clinical guidelines.

STUDY DESIGN: We described PPI prescription rates based on national dispensation data in French children (IQVIA's Xponent database, 2009-2019). Using a segmented linear regression, we assessed the impact of clinical guidelines on PPI prescription rates. Analyses were performed for the overall pediatric population and by age subgroups (infants<2 years old, children 2-11, adolescents 12-17).

RESULTS: During the study period, 8,060,288 pediatric PPI prescriptions were filled, with a mean PPI prescription rate of 52.5 per 1,000 inhabitants per year. Between 2009 and 2019, the PPI prescription rate increased by 41% in the overall pediatric population (+110% in infants). The PPI prescription rate showed seasonal patterns with peaks in winter. After the release of French guidelines, significant decreases in trends of prescription rates occurred overall (change in trend -0.28, 95%CI -0.34;-0.23) and across all age groups. In infants, this change in trend was not sufficient to reverse the PPI prescription rate that was still increasing over time. In children, the PPI prescription rate slightly decreased and in adolescents, it was stable. After the release of international guidelines, a significant decrease in trend occurred in adolescents only (change in trend -0.26, 95%CI -0.47; -0.04).

CONCLUSIONS: The pediatric PPI prescription rate in France was high, displayed a major increase over the last decade, mainly among infants, and was modestly affected by clinical guidelines.

PMID:35120983 | DOI:10.1016/j.jpeds.2022.01.041

Clin Transl Sci. 2022 Feb 4. doi: 10.1111/cts.13244. Online ahead of print.

ABSTRACT

The immunosuppressant drug azathioprine is associated with a 4% risk of acute pancreatitis in patients with inflammatory bowel disease. Studies have demonstrated an increased risk in carriers of HLA-DQA1*02:01 and HLA-DRB1*07:01. We investigated whether these HLA types were associated with azathioprine-induced pancreatitis also in Swedish patients with inflammatory bowel disease, and whether the type of disease affected the association. Nineteen individuals with inflammatory bowel disease who developed acute pancreatitis after initiation of azathioprine were genotyped and compared with a population control cohort (n=4891) and a control group matched for disease (n=81). HLA-DQA1*02:01 and HLA-DRB1*07:01 were in full linkage disequilibrium, and were significantly associated with acute pancreatitis both when cases were compared with population controls (OR 3.97 [95% CI 1.57-9.97], p=0.0035) and matched controls (OR 3.55 [95% CI 1.23-10.98], p=0.0275). In a disease-specific analysis, the correlation was positive in patients with Crohn's disease vs matched controls (OR 9.27 [95% CI 1.86 - 46.19], p=0.0066), but not in those with ulcerative colitis vs matched controls (OR 0.69 [95% CI 0.07 - 6.74], p=0.749). In patients with Crohn's disease, we estimated the conditional risk of carriers of HLA-DQA1*02:01-HLA-DRB1*07:01 to 7.3%, and the conditional risk of a non-carrier to 2.2%. We conclude that HLA-DQA1*02:01-HLA-DRB1*07:01 is a marker for increased risk of acute pancreatitis in individuals of Swedish genetic origin, treated with azathioprine for Crohn's disease.

PMID:35120281 | DOI:10.1111/cts.13244

J Clin Oncol. 2022 Feb 4:JCO2102377. doi: 10.1200/JCO.21.02377. Online ahead of print.

ABSTRACT

PURPOSE: Women have more adverse events (AEs) from chemotherapy than men, but few studies have investigated sex differences in immune or targeted therapies. We examined AEs by sex across different treatment domains.

METHODS: We analyzed treatment-related AEs by sex in SWOG phase II and III clinical trials conducted between 1980 and 2019, excluding sex-specific cancers. AE codes and grade were categorized using the Common Terminology Criteria for Adverse Events. Symptomatic AEs were defined as those aligned with the National Cancer Institute's Patient-Reported Outcome-Common Terminology Criteria for Adverse Events; laboratory-based or observable/measurable AEs were designated as objective (hematologic v nonhematologic). Multivariable logistic regression was used, adjusting for age, race, and disease prognosis. Thirteen symptomatic and 14 objective AE categories were examined.

RESULTS: In total, N = 23,296 patients (women, 8,838 [37.9%]; men, 14,458 [62.1%]) from 202 trials experiencing 274,688 AEs were analyzed; 17,417 received chemotherapy, 2,319 received immunotherapy, and 3,560 received targeted therapy. Overall, 64.6% (n = 15,051) experienced one or more severe (grade ≥ 3) AEs. Women had a 34% increased risk of severe AEs compared with men (odds ratio [OR] = 1.34; 95% CI, 1.27 to 1.42; P < .001), including a 49% increased risk among those receiving immunotherapy (OR = 1.49; 95% CI, 1.24 to 1.78; P < .001). Women experienced an increased risk of severe symptomatic AEs among all treatments, especially immunotherapy (OR = 1.66; 95% CI, 1.37 to 2.01; P < .001). Women receiving chemotherapy or immunotherapy experienced increased severe hematologic AE. No statistically significant sex differences in risk of nonhematologic AEs were found.

CONCLUSION: The greater severity of both symptomatic AEs and hematologic AEs in women across multiple treatment modalities indicates that broad-based sex differences exist. This could be due to differences in AE reported, pharmacogenomics of drug metabolism/disposition, total dose received, and/or adherence to therapy. Particularly large sex differences were observed for patients receiving immunotherapy, suggesting that studying AEs from these agents is a priority.

PMID:35119908 | DOI:10.1200/JCO.21.02377

Methods Mol Biol. 2022;2418:63-75. doi: 10.1007/978-1-0716-1920-9_5.

ABSTRACT

Serine 216 constitutes a protein kinase C phosphorylation motif located within the DNA binding domain of estrogen receptor α (ERα). In this chapter, we present experimental procedures confirming that mouse ERα is phosphorylated at serine 216 in peripheral blood neutrophils and in neutrophils that infiltrate the uterus, as well as the role of phosphoserine 216 in neutrophil migration. A phospho-peptide antibody (αP-S216) was utilized in Western blot, immunohistochemistry, and double immunofluorescence staining to detect this phosphorylation of an endogenous ERα. Both immunohistochemistry (with αP-S216 or neutrophil marker Ly6G antibody) and double immunofluorescence staining of mouse uterine sections prepared from C3H/HeNCrIBR females revealed that phosphorylated ERα was expressed in all infiltrating neutrophils during hormonal cycles but not in any other of the other uterine cells. Neutrophils infiltrate the uterus from the bloodstream. White blood cells (WBC) were prepared from peripheral blood of C3H/HeNCrIBR females or males and double immunostained. Blood neutrophils also expressed phosphorylated ERα but in only about 20% of cells in both sexes. Only the neutrophils expressing phosphorylated ERα spontaneously migrated in in vitro Transwell migration assays and infiltrated the uterus in mice.

PMID:35119660 | DOI:10.1007/978-1-0716-1920-9_5

Methods Mol Biol. 2022;2418:41-51. doi: 10.1007/978-1-0716-1920-9_3.

ABSTRACT

Estrogen receptor α (ERα) conserves a phosphorylation motif at Serine 216. This site constitutes a protein kinase C phosphorylation motif located within the DNA binding domain (DBD) of ERα. The liver plays a critical role in the regulation of metabolism of various xenobiotics, fatty acids, and cholesterol or endogenous compounds. Moreover, numerous metabolizing enzymes are mainly expressed in the liver. In this chapter, we describe several practical experimental procedures confirming that mouse ERα is phosphorylated at serine 216 in livers upon phenobarbital (PB) treatment. Also, this phosphorylation regulates the expression of estrogen sulfotransferase gene (SULT1E1) which has an important role to sulfate and inactivate estrogen. In response to PB, the conserved motif within the DBD activates the Sult1e1 gene. When this motif was mutated, the activation of Sult1e1 was suppressed significantly. This chapter also describes the use of a phospho-peptide antibody (αP-S216) in the chromatin immunoprecipitation (ChIP) assay, and the co-immunoprecipitation (Co-IP) assay visualized by Western blot analysis.

PMID:35119658 | DOI:10.1007/978-1-0716-1920-9_3

Per Med. 2022 Feb 4. doi: 10.2217/pme-2021-0022. Online ahead of print.

ABSTRACT

Background: The research considers the impact of genotype-inferred variability on blood levels of amitriptyline and its main metabolites, as may be moderated by phenocopying. Patients & methods: CYP2D6 and CYP2C19 genotypes, and serum concentrations of amitriptyline, nortriptyline and hydroxymetabolites, were determined in 33 outpatients. Co-medications were reviewed to identify CYP inhibition risk. Results: CYP2C19 metabolizer status explained interpatient variation in nortriptyline to amitriptyline concentration ratios. The hydroxymetabolite to parent ratios increased with higher CYP2D6 activity scores and lower CYP2D6 inhibition risk. In patients at high CYP2D6 inhibition risk, the amitriptyline + nortriptyline concentration was, on average, 52% above the higher end of expected ranges. Conclusion: Practical construal of pharmacogenetics and drug interactions tantamount to aberrant metabolism can facilitate patient-tailored use of the established drug.

PMID:35118877 | DOI:10.2217/pme-2021-0022

Clin Transl Sci. 2022 Feb 3. doi: 10.1111/cts.13243. Online ahead of print.

ABSTRACT

TPMT and NUDT15 variants explain less than 25% of azathioprine-associated myelotoxicity. There are 25 additional genes in the thiopurine pathway that could also contribute to azathioprine myelotoxicity. We hypothesized that among TPMT and NUDT15 normal metabolizers, a score combining the genetically predicted expression of other proteins in the thiopurine pathway would be associated with a higher risk for azathioprine discontinuation due to myelotoxicity. We conducted a retrospective cohort study of new users of azathioprine who were normal TPMT and NUDT15 metabolizers. In 1201 White patients receiving azathioprine for an inflammatory disease, we used relaxed LASSO regression to select genes that built a score for discontinuing azathioprine due to myelotoxicity. The score incorporated the predicted expression of AOX1 and NME1. Patients in the highest score tertile had a higher risk of discontinuing azathioprine compared to those in the lowest tertile [HR=2.15 (95% C.I.1.11-4.19, p=0.024)]. Results remained significant after adjusting for a propensity score including sex, tertile of calendar year at initial dose, initial dose, age at baseline, indication, prior TPMT testing, and the first 10 principal components of the genetic data [HR=2.11 (95% C.I. 1.08-4.13), p=0.030]. We validated the results in a cohort (N=517 non-White patients and those receiving azathioprine to prevent transplant rejection) that included all other patients receiving azathioprine (HR=2.00 (95% C.I. 1.09-3.65), p=0.024). In conclusion, among patients who were TPMT and NUDT15 normal metabolizers, a score combining the predicted expression of AOX1 and NME1 was associated with an increased risk for discontinuing azathioprine due to myelotoxicity.

PMID:35118815 | DOI:10.1111/cts.13243

Neurooncol Adv. 2021 Dec 31;4(1):vdab192. doi: 10.1093/noajnl/vdab192. eCollection 2022 Jan-Dec.

ABSTRACT

BACKGROUND: Poor prognosis of glioblastoma patients and the extensive heterogeneity of glioblastoma at both the molecular and cellular level necessitates developing novel individualized treatment modalities via genomics-driven approaches.

METHODS: This study leverages numerous pharmacogenomic and tissue databases to examine drug repositioning for glioblastoma. RNA-seq of glioblastoma tumor samples from The Cancer Genome Atlas (TCGA, n = 117) were compared to "normal" frontal lobe samples from Genotype-Tissue Expression Portal (GTEX, n = 120) to find differentially expressed genes (DEGs). Using compound gene expression data and drug activity data from the Library of Integrated Network-Based Cellular Signatures (LINCS, n = 66,512 compounds) CCLE (71 glioma cell lines), and Chemical European Molecular Biology Laboratory (ChEMBL) platforms, we employed a summarized reversal gene expression metric (sRGES) to "reverse" the resultant disease signature for GBM and its subtypes. A multiparametric strategy was employed to stratify compounds capable of blood-brain barrier penetrance with a favorable pharmacokinetic profile (CNS-MPO).

RESULTS: Significant correlations were identified between sRGES and drug efficacy in GBM cell lines in both ChEMBL(r = 0.37, P < .001) and Cancer Therapeutic Response Portal (CTRP) databases (r = 0.35, P < 0.001). Our multiparametric algorithm identified two classes of drugs with highest sRGES and CNS-MPO: HDAC inhibitors (vorinostat and entinostat) and topoisomerase inhibitors suitable for drug repurposing.

CONCLUSIONS: Our studies suggest that reversal of glioblastoma disease signature correlates with drug potency for various GBM subtypes. This multiparametric approach may set the foundation for an early-phase personalized -omics clinical trial for glioblastoma by effectively identifying drugs that are capable of reversing the disease signature and have favorable pharmacokinetic and safety profiles.

PMID:35118385 | PMC:PMC8807341 | DOI:10.1093/noajnl/vdab192

Ment Health Clin. 2022 Jan 21;12(1):45-48. doi: 10.9740/mhc.2022.01.045. eCollection 2022 Jan.

ABSTRACT

BACKGROUND: Clozapine levels can be influenced by many factors, including pharmacogenomic variability, pharmacokinetic drug interactions, and infection/inflammation. The concentration-to-dose ratio (C/D), a measure of a medication's rate of metabolism and clearance, may increase during an acute infection due to decreased medication metabolism and clearance.

CASE REPORT: A 56-year-old White man was restarted on clozapine and titrated up to 350 mg/d with therapeutic steady-state levels (C/D 1.11) on hospital day (HD) 69. At this time, he was also being treated for COPD exacerbation. For the next month, he continued to complain of cough, but vital signs and chest x-ray remained normal. Labs were unremarkable except for occasional leukocytosis that would resolve on repeat evaluation. A routine clozapine level drawn on HD 104, resulted on day 108 and showed clozapine toxicity with C/D 4.05, although the patient was asymptomatic. After receipt of labs on day 109, showing elevated WBC count, he was immediately sent to the emergency room where he was admitted for treatment of pneumonia. On return to the state hospital, the patient was continued on 100 mg clozapine and titrated to 200 mg/d based on low drug levels. He continued to do well on 200 mg/d clozapine with C/D averaging 1.13 (range, 0.75-1.52).

DISCUSSION: Acute infection and illness can lead to significantly increased clozapine levels and toxicity, even if symptoms of toxicity are minimal or absent. This appears to be the first report of a toxic level being the first indication of severe medical illness.

PMID:35116212 | PMC:PMC8788300 | DOI:10.9740/mhc.2022.01.045

Pharmgenomics Pers Med. 2022 Jan 25;15:45-54. doi: 10.2147/PGPM.S345038. eCollection 2022.

ABSTRACT

PURPOSE: DNA polymorphism describes the difference between individuals, groups, or ethnicities, races, etc., in terms of their DNA sequences or phenotypes as relates to drug metabolism. Using predictive genotyping of drug-metabolizing genes, we can develop individuals' drug therapies that are less toxic and more effective. The main aim of the study was to evaluate genotype-phenotype-based correlation and incidence of genetic polymorphism of efavirenz blood levels among HIV/AIDS patients of the Niger Delta population.

METHODS: A study questionnaire was designed to obtained patients' data, blood samples were obtained, plasma was separated from the serum using a centrifuge for 5 minutes at 4000 rpm for HPLC analysis, polymerase chain reaction (PCR) and restriction fragment length polymorphism (RFLP) analysis was conducted using Bsrl endonuclease enzyme to digest the PCR amplicons. Standard efavirenz was used at 0.5, 1, 2, 4, 16 mg/L to construct a calibration curve. Data were analyzed with SPSS software using chi-square test at p-value ≤0.5 and Microsoft excel 2013, while PCR and RFLP results were obtained after 1% Agarose gel electrophoresis, respectively.

RESULTS: Phenotypic results showed that the participants had different efavirenz plasma concentrations. Six subjects (12%) had efavirenz plasma levels below 0.10 mg/L, considered ultra-rapid metabolizers (UMs), 22 (44%) 0.10 mg/L to 0.90 mg/L, classified as extensive metabolizers (EMs), 19 (38%) had 1.0 to 3.9 mg/L and were noted as intermediate metabolizers (IM), while 3 (6%) subjects showed efavirenz plasma levels from 4.0 mg/L to 6.0 mg/L, categorized as poor metabolizers (PM). RFLP results showed more than half of the population (56%) with a homozygous wild-type gene with CYP2B6*1*1 allele, 38% were CYP2B6*1*6 (heterozygous mutant) allele and 6% had homozygous mutant gene (CYP2B6*6*6 allele). Out of the 15 male subjects among the 50 patients that participated in the study, 8% were UM, 12% EM, 14% IM while no PM was observed, on the contrary, out of the 35 females participated in the study, 4% were observed as UM, 32% EM, 24% IM, while 6% were PM.

CONCLUSION: There was no significant difference (p ≤ 0.05) between genotype and phenotype data for CYP2B6 polymorphism, among the HIV/AIDS patients that participated in this study. Genetic polymorphism of the CYP2B6 gene is prevalent among HIV/AIDs patients in the Niger Delta ethnic population on efavirenz-based HAART treatment, as the population having homozygous mutant gene or PM are >1% (6%).

PMID:35115810 | PMC:PMC8800862 | DOI:10.2147/PGPM.S345038

Nat Commun. 2022 Feb 3;13(1):675. doi: 10.1038/s41467-022-28273-0.

ABSTRACT

Alzheimer's Disease (AD) is a neurodegenerative disorder that is still not fully understood. Sex modifies AD vulnerability, but the reasons for this are largely unknown. We utilize two independent electronic medical record (EMR) systems across 44,288 patients to perform deep clinical phenotyping and network analysis to gain insight into clinical characteristics and sex-specific clinical associations in AD. Embeddings and network representation of patient diagnoses demonstrate greater comorbidity interactions in AD in comparison to matched controls. Enrichment analysis identifies multiple known and new diagnostic, medication, and lab result associations across the whole cohort and in a sex-stratified analysis. With this data-driven method of phenotyping, we can represent AD complexity and generate hypotheses of clinical factors that can be followed-up for further diagnostic and predictive analyses, mechanistic understanding, or drug repurposing and therapeutic approaches.

PMID:35115528 | DOI:10.1038/s41467-022-28273-0

J Formos Med Assoc. 2022 Jan 31:S0929-6646(22)00033-X. doi: 10.1016/j.jfma.2022.01.013. Online ahead of print.

ABSTRACT

BACKGROUND/PURPOSE: Pharmacogenetics is a potential driver of the "East Asian paradox," in which East Asian acute coronary syndrome (ACS) patients receiving dual antiplatelet therapy (DAPT) with clopidogrel following percutaneous coronary intervention (PCI) demonstrate higher levels of platelet reactivity on treatment than Western patients, yet have lower ischemic risk and higher bleeding risk at comparable doses. However, the impact of pharmacogenetics, particularly regarding CYP2C19 genotype, on the pharmacodynamics of P2Y12 inhibitors has not been extensively studied in Taiwanese ACS patients as yet.

METHODS: CYP2C19 genotyping and pharmacogenetic analysis was conducted on 102 subjects from the Switch Study, a multicenter, single-arm, open-label intervention study that examined the effects on platelet activity and clinical outcomes of switching from clopidogrel (75 mg daily) to low-dose prasugrel (3.75 mg daily) for maintenance DAPT after PCI in 203 Taiwanese ACS patients.

RESULTS: Genotyping results revealed that 43.1% were CYP2C19 extensive metabolizers (EM), while 56.9% were reduced metabolizers (RM). After switching to prasugrel, mean P2Y12 reaction units (PRU) values were significantly reduced in both EM and RM populations, while the proportion of high on-treatment platelet reactivity (HPR) patients significantly declined in RM patients. No increase in bleeding risk after switching was observed during follow-up. Multivariate analysis indicated that for RM patients, low estimated glomerular filtration rate (eGFR) and low hemoglobin were associated with greater HPR risk on clopidogrel, but not after switching to prasugrel.

CONCLUSION: Switching to low-dose prasugrel from clopidogrel reduced mean PRU levels and proportion of HPR patients, with more significant reduction in RM patients.

PMID:35115197 | DOI:10.1016/j.jfma.2022.01.013