Int J Mol Sci. 2023 Aug 30;24(17):13452. doi: 10.3390/ijms241713452.

ABSTRACT

We aimed to analyse whether patients with ischaemic stroke (IS) occurring within eight days after the onset of COVID-19 (IS-COV) are associated with a specific aetiology of IS. We used SUPERGNOVA to identify genome regions that correlate between the IS-COV cohort (73 IS-COV cases vs. 701 population controls) and different aetiological subtypes. Polygenic risk scores (PRSs) for each subtype were generated and tested in the IS-COV cohort using PRSice-2 and PLINK to find genetic associations. Both analyses used the IS-COV cohort and GWAS from MEGASTROKE (67,162 stroke patients vs. 454,450 population controls), GIGASTROKE (110,182 vs. 1,503,898), and the NINDS Stroke Genetics Network (16,851 vs. 32,473). Three genomic regions were associated (p-value < 0.05) with large artery atherosclerosis (LAA) and cardioembolic stroke (CES). We found four loci targeting the genes PITX2 (rs10033464, IS-COV beta = 0.04, p-value = 2.3 × 10-2, se = 0.02), previously associated with CES, HS6ST1 (rs4662630, IS-COV beta = -0.04, p-value = 1.3 × 10-3, se = 0.01), TMEM132E (rs12941838 IS-COV beta = 0.05, p-value = 3.6 × 10-4, se = 0.01), and RFFL (rs797989 IS-COV beta = 0.03, p-value = 1.0 × 10-2, se = 0.01). A statistically significant PRS was observed for LAA. Our results suggest that IS-COV cases are genetically similar to LAA and CES subtypes. Larger cohorts are needed to assess if the genetic factors in IS-COV cases are shared with the general population or specific to viral infection.

PMID:37686257 | DOI:10.3390/ijms241713452

Int J Mol Sci. 2023 Aug 27;24(17):13284. doi: 10.3390/ijms241713284.

ABSTRACT

Dihydropyrimidine dehydrogenase (DPYD) is the rate-limiting enzyme involved in the metabolism of fluoropyrimidine-based chemotherapy. However, single-nucleotide variants (SNVs) in DPYD only partially explain fluoropyrimidine-induced toxicity. The expression of DPYD has previously been shown to be regulated by microRNA-27a (miR-27a) and a common miR-27a SNV (rs895819) has been associated with an increased risk of toxicity in patients harboring a DPYD variant who received standard fluoropyrimidine dosing. We investigated if the miR-27a rs895819 SNV was associated with toxicity in DPYD wildtype patients and carriers of DPYD variants who received a reduced dose. The regulation of DPYD using miR-27a was investigated in HepG2 cells utilizing a miR-27a mimic. miR-27a overexpression decreased DPYD mRNA expression compared to control cells (p < 0.0001). In a cohort of patients that received pre-emptive DPYD genotyping, 45 patients had a DPYD variant and 180 were wildtype. Patients heterozygous for rs895819 had an increased risk of toxicity, which was seen in both patients who were wildtype for DPYD variants (OR (95%CI) = 1.99 (1.00-3.99)) and DPYD variant carriers (OR (95%CI) = 8.10 (1.16-86.21)). Therefore, miR-27a rs895819 may be a clinically relevant predictor of fluoropyrimidine-associated toxicities. Furthermore, toxicity was more profound in DPYD variant carriers, even after DPYD genotype-guided dose reduction. This suggests that patients may benefit from miR-27a genotyping to guide fluoropyrimidine dosing.

PMID:37686089 | DOI:10.3390/ijms241713284

Int J Mol Sci. 2023 Aug 23;24(17):13095. doi: 10.3390/ijms241713095.

ABSTRACT

Aortic stenosis (AS) is the most prevalent primary valve lesion demanding intervention. Two main treatment options are surgical aortic valve replacement or transcatheter aortic valve implantation. There is an unmet need for biomarkers that could predict treatment outcomes and become a helpful tool in guiding Heart Team in the decision-making process. Micro-ribonucleic acids (microRNAs/miRs) have emerged as potential biomarkers thoroughly studied in recent years. In this review, we aimed to summarize the current knowledge about the role of miRNAs in AS based on human subject research. Much research investigating miRNAs' role in AS has been conducted so far. We included 32 original human subject research relevant to the discussed field. Most of the presented miRNAs were studied only by a single research group. Nevertheless, several miRNAs appeared more than once, sometimes with high consistency between different studies but sometimes with apparent discrepancies. The molecular aspects of diseases are doubtlessly exciting and provide invaluable insights into the pathophysiology. Nevertheless, translating these findings, regarding biomarkers such as miRNAs, into clinical practice requires much effort, time, and further research with a focus on validating existing evidence.

PMID:37685901 | DOI:10.3390/ijms241713095

NPJ Genom Med. 2023 Sep 8;8(1):24. doi: 10.1038/s41525-023-00371-y.

ABSTRACT

Genetic variants in drug targets and genes encoding factors involved in drug absorption, distribution, metabolism and excretion (ADME) can have pronounced impacts on drug pharmacokinetics, response, and toxicity. While the landscape of genetic variability at the level of single nucleotide variants (SNVs) has been extensively studied in these pharmacogenetic loci, their structural variation is only poorly understood. Thus, we systematically analyzed the genetic structural variability across 908 pharmacogenes (344 ADME genes and 564 drug targets) based on publicly available whole genome sequencing data from 10,847 unrelated individuals. Overall, we extracted 14,984 distinct structural variants (SVs) ranging in size from 50 bp to 106 Mb. Each individual harbored on average 10.3 and 1.5 SVs with putative functional effects that affected the coding regions of ADME genes and drug targets, respectively. In addition, by cross-referencing pharmacogenomic SVs with experimentally determined binding data of 224 transcription factors across 130 cell types, we identified 1276 non-coding SVs that overlapped with gene regulatory elements. Based on these data, we estimate that non-coding structural variants account for 22% of the genetically encoded pharmacogenomic variability. Combined, these analyses provide the first comprehensive map of structural variability across pharmacogenes, derive estimates for the functional impact of non-coding SVs and incentivize the incorporation of structural genomic data into personalized drug response predictions.

PMID:37684227 | DOI:10.1038/s41525-023-00371-y

J Reprod Immunol. 2023 Aug 25;160:104139. doi: 10.1016/j.jri.2023.104139. Online ahead of print.

ABSTRACT

Racial disparities exist in the prevalence of preeclampsia (PE), with women of African ancestry suffering the highest rates of morbidity and mortality. Genetic changes may play a role in the preponderance of PE among women of African ancestry. This review discusses 30 genes with variants that have been studied in PE in women of African ancestry. These studies found that a single gene is not responsible for PE susceptibility as 13 genes have been implicated. These genes subserve endothelial, immune, hemodynamic, homeostatic, thrombophilic, oxidative stress, and lipid metabolic pathways. Notably, maternal-fetal gene interactions also contribute to the susceptibility of the disease. For instance, the maternal KIR AA genotype and paternally inherited fetal HLA-C2 genotype confer risk for developing PE. Additionally, genetic changes such as epigenetic modulation of expression of the MTHFR gene through DNA methylation is also associated with the occurrence of PE. In contrast, some genes such as the KIR B centromeric region protect against development of PE in some women. The soluble fms-like tyrosine kinase 1 (sFlt-1) contributes to the development of PE and is a potential novel therapeutic option for targeted gene silencing of anti-angiogenic sFLT-1 gene. Additionally, NOS3 gene is an important target for pharmacogenomics because it is responsible for the production of endothelial nitric oxide. In conclusion, maternal genetic and epigenetic variants confer susceptibility to PE, indicating the need for further studies to develop a screening tool incorporating maternal genetic variants to identify women at high risk for PE and offer them a preventive therapy.

PMID:37683532 | DOI:10.1016/j.jri.2023.104139

J Clin Psychopharmacol. 2023 Sep-Oct 01;43(5):428-433. doi: 10.1097/JCP.0000000000001747.

ABSTRACT

BACKGROUND: The purpose of this study was to review the association between the SLC6A4 5-HTTLPR polymorphism and antidepressant (AD)-associated treatment emergent mania (TEM) in bipolar disorder alongside starting a discussion on the merits of developing risk stratification models to guide when not to provide AD treatment for bipolar depression.

METHODS: Studies that examined the association between clinical and genetic risk factors, specifically monoaminergic transporter genetic variation, and TEM were identified. A meta-analysis was performed using the odds ratio to estimate the effect size under the Der-Simonian and Laird model.

RESULTS: Seven studies, referencing the SLC6A4 5-HTTLPR polymorphism and TEM (total N = 1578; TEM+ =594, TEM- = 984), of 142 identified articles were included. The time duration between the start of the AD to emergence of TEM ranged from 4 to 12 weeks. There was a nominally significant association between the s allele of the 5-HTTLPR polymorphism and TEM (odds ratio, 1.434; 95% confidence interval, 1.001-2.055; P = 0.0493; I2 = 52%). No studies have investigated norepinephrine or dopamine transporters.

CONCLUSION: Although the serotonin transporter genetic variation is commercially available in pharmacogenomic decision support tools, greater efforts, more broadly, should focus on complete genome-wide approaches to determine genetic variants that may contribute to TEM. Moreover, these data are exemplary to the merits of developing risk stratification models, which include both clinical and biological risk factors, to guide when not to use ADs in bipolar disorder. Future studies will need to validate new risk models that best inform the development of personalized medicine best practices treating bipolar depression.

PMID:37683232 | DOI:10.1097/JCP.0000000000001747

J Med Toxicol. 2023 Sep 8. doi: 10.1007/s13181-023-00966-y. Online ahead of print.

ABSTRACT

INTRODUCTION: Chronic tricyclic antidepressant toxicity is rarely described in children. Symptoms include confusion, ataxia, and seizures. Toxicity may result from dosing error, CYP2C19 and CYP2D6 genetic variability, and drug-drug interactions. Chronic doxepin toxicity has not been previously reported in children. Doxepin is prescribed for insomnia and depression, with a maximum off-label dose of 3 mg/kg in children. We present a case of chronic doxepin toxicity mimicking epilepsy in a child attributable to three potential factors: supratherapeutic dosing, pharmacogenomic variability, and drug-drug interactions.

CASE REPORT: A 10-year-old boy with insomnia, diagnosed with epilepsy 6 months prior, presented to an emergency department with confusion, ataxia, and increasing seizure frequency. He was prescribed doxepin for insomnia and four antiepileptics for seizures. After admission, he had two seizures and remained confused. EKGs showed QRS prolongation, suggesting doxepin toxicity. Doxepin-nordoxepin combined serum concentration was 1419 ng/mL (therapeutic 100-300 ng/mL), confirming doxepin toxicity. Outpatient records showed onset of confusion and seizures as doxepin dose was gradually uptitrated to 300 mg nightly (4.41 mg/kg). Symptoms worsened following addition of clobazam (CYP2D6 inhibitor) and topiramate (CYP2C19 inhibitor). Following doxepin discontinuation, all symptoms resolved. CYP2D6 testing showed intermediate metabolizer phenotype (CYP2D6*1/*4; activity score = 1.0; copy number = 2.0). No seizures have occurred in more than one year since doxepin discontinuation.

DISCUSSION: Caution must be exercised when prescribing doxepin. Pharmacogenomics, dose, drug-drug interactions, and age should be considered. Chronic toxicity should be contemplated in patients taking doxepin without acute overdose who present with persistent neurologic abnormalities including seizure.

PMID:37682427 | DOI:10.1007/s13181-023-00966-y

Front Cell Infect Microbiol. 2023 Aug 23;13:1181516. doi: 10.3389/fcimb.2023.1181516. eCollection 2023.

ABSTRACT

INTRODUCTION: One of the promising leads for the rapid discovery of alternative antimicrobial agents is to repurpose other drugs, such as nonsteroidal anti-inflammatory agents (NSAIDs) for fighting bacterial infections and antimicrobial resistance.

METHODS: A series of new carbazole derivatives based on the readily available anti-inflammatory drug carprofen has been obtained by nitration, halogenation and N-alkylation of carprofen and its esters. The structures of these carbazole compounds were assigned by NMR and IR spectroscopy. Regioselective electrophilic substitution by nitration and halogenation at the carbazole ring was assigned from H NMR spectra. The single crystal X-ray structures of two representative derivatives obtained by dibromination of carprofen, were also determined. The total antioxidant capacity (TAC) was measured using the DPPH method. The antimicrobial activity assay was performed using quantitative methods, allowing establishment of the minimal inhibitory/bactericidal/biofilm eradication concentrations (MIC/MBC/MBEC) on Gram-positive (Staphylococcus aureus, Enterococcus faecalis) and Gram-negative (Escherichia coli, Pseudomonas aeruginosa) strains. Computational assays have been performed to assess the drug- and lead-likeness, pharmacokinetics (ADME-Tox) and pharmacogenomics profiles.

RESULTS AND DISCUSSION: The crystal X-ray structures of 3,8-dibromocarprofen and its methyl ester have revealed significant differences in their supramolecular assemblies. The most active antioxidant compound was 1i, bearing one chlorine and two bromine atoms, as well as the CO2Me group. Among the tested derivatives, 1h bearing one chlorine and two bromine atoms has exhibited the widest antibacterial spectrum and the most intensive inhibitory activity, especially against the Gram-positive strains, in planktonic and biofilm growth state. The compounds 1a (bearing one chlorine, one NO2 and one CO2Me group) and 1i (bearing one chlorine, two bromine atoms and a CO2Me group) exhibited the best antibiofilm activity in the case of the P. aeruginosa strain. Moreover, these compounds comply with the drug-likeness rules, have good oral bioavailability and are not carcinogenic or mutagenic. The results demonstrate that these new carbazole derivatives have a molecular profile which deserves to be explored further for the development of novel antibacterial and antibiofilm agents.

PMID:37680749 | PMC:PMC10482414 | DOI:10.3389/fcimb.2023.1181516

Front Genet. 2023 Aug 23;14:1249003. doi: 10.3389/fgene.2023.1249003. eCollection 2023.

ABSTRACT

Introduction: This manuscript reports on a pilot program focused on implementing pharmacogenetic testing within the framework of an employer-sponsored medical plan at University of Florida (UF) Health. The aim was to understand the challenges associated with program implementation and to gather insights into patient attitudes towards PGx testing. Methods: The pilot program adopted a partially preemptive approach, targeting patients on current prescriptions for medications with relevant gene-drug associations. Patients were contacted via phone or through the MyChart system and offered pharmacogenetic testing with no additional direct costs. Results: Of 244 eligible patients, 110 agreed to participate. However, only 61 returned the mailed DNA collection kits. Among these, 89% had at least one potentially actionable genotype-based phenotype. Post-test follow-up revealed that while the majority viewed the process positively, 71% preferred a consultation with a pharmacogenetic specialist for better understanding of their results. Barriers to implementation ranged from fatigue with the healthcare system to a lack of understanding of the pharmacogenetic testing and concerns about privacy and potential misuse of genetic data. Conclusion: The findings underscore the need for clearer patient education on pharmacogenetic results and suggest the importance of the role of pharmacogenetic-trained pharmacists in delivering this education. They also highlight issues with relying on incomplete or inaccurate medication lists in patients' electronic health record. The implementation revealed less obvious challenges, the understanding of which could be beneficial for the success of future preemptive pharmacogenetic implementation programs. The insights from the pilot program served to bridge the information gap between patients, providers, and pharmacogenetic -specialists, with the ultimate goal of improving patient care.

PMID:37680199 | PMC:PMC10482099 | DOI:10.3389/fgene.2023.1249003

J Pharmacol Exp Ther. 2023 Sep 7:JPET-MR-2023-001651. doi: 10.1124/jpet.123.001651. Online ahead of print.

ABSTRACT

Awareness of drug interactions involving opioids is critical for patient treatment as they are common therapeutics used in numerous care settings including both chronic and disease related pain. Not only do opioids have narrow therapeutic indexes and are extensively used, but they have the potential to cause severe toxicity. Opioids are the classical pain treatment for patients who suffer from moderate to severe pain. More importantly, opioids are often prescribed in combination with multiple other drugs, especially in patient populations who typically are prescribed a large drug regimen. This review focuses on the current knowledge of common opioid drug-drug interactions (DDI), focusing specifically on hydrocodone, oxycodone, and morphine DDI. The DDI covered in this review include pharmacokinetic DDI arising from enzyme inhibition or induction, primarily due to inhibition of cytochrome p450 enzymes (CYPs). However, opioids such as morphine are metabolized by uridine-5'-diphosphoglucuronosyltransferases (UGTs), principally UGT2B7, and this is another important pathway for opioid-drug interactions. This review also covers several pharmacodynamic DDI studies as well as the basics of CYP and UGT metabolism including detailed opioid metabolism and the potential involvement of metabolizing enzyme gene variation in DDI. Based upon the current literature, further care is needed to fully investigate and describe the DDI potential with opioids in pain and related disease settings to improve clinical outcomes for patients. Significance Statement A review of the literature focusing on drug-drug interactions involving opioids is important because they can be toxic and potentially lethal, occurring through pharmacodynamic interactions as well as pharmacokinetic interactions occurring through inhibition or induction of drug metabolism.

PMID:37679047 | DOI:10.1124/jpet.123.001651

J Allergy Clin Immunol. 2023 Sep 5:S0091-6749(23)01108-9. doi: 10.1016/j.jaci.2023.08.026. Online ahead of print.

ABSTRACT

BACKGROUND: Diagnosing drug-induced allergy, especially non-immediate phenotypes, is challenging. Incorrect classifications have unwanted consequences.

OBJECTIVE: We sought to evaluate the diagnostic utility of interferon-gamma enzyme-linked immunospot assay (IFN-γ ELISpot) and clinical parameters in predicting drug-induced non-immediate hypersensitivity using machine learning.

METHODS: Three hundred and ninety-three patients were recruited. A positive patch test or drug provocation test (DPT) was used to define positive drug hypersensitivity. Various clinical factors were considered in developing random forest (RF) and logistic regression (LR) models. Performances were compared against the IFN-γ ELISpot-only model.

RESULTS: Among the 102 patients who had 164 DPTs, most patients had severe cutaneous adverse reactions (35/102, 34.3%) and maculopapular exanthems (33/102, 32.4%). Common suspected drugs were anti-tuberculosis (46/164, 28.1%) and beta-lactams (42/164, 25.6%). Patients with DPT aged 52.7±20.8 years. IFN-γ ELISpot, fixed drug eruption, Naranjo categories, and NSAIDs were the most important features in all developed models. The RF and LR models had higher discriminating abilities. An IFN-γ ELISpot cut-off value of 16.0 SFC/106 PBMC achieved 94.8% specificity and 57.1% sensitivity. Depending on clinical needs, optimal cut-off values for RF and LR models can be chosen to achieve either high specificity (0.41 for 96.1% specificity, 0.52 for 97.4%, respectively) or high sensitivity (0.26 for 78.6% sensitivity, and 0.37 for 71.4%, respectively).

CONCLUSION: IFN-γ ELISpot assay was valuable in identifying culprit drugs, whether used individually or incorporated in a prediction model. Performances of RF and LR models were comparable, and additional test datasets with DPT would be helpful to validate the model further.

PMID:37678574 | DOI:10.1016/j.jaci.2023.08.026

Int Immunopharmacol. 2023 Sep 5;124(Pt A):110866. doi: 10.1016/j.intimp.2023.110866. Online ahead of print.

ABSTRACT

BACKGROUND: The purpose of the study was to develop a genotype-incorporated population pharmacokinetic (PPK) model of tacrolimus (TAC) in adults with systemic lupus erythematosus (SLE) to investigate the factors influencing TAC pharmacokinetics and to develop an individualized dosing regimen based on the model. In addition, a non-genotype-incorporated model was also established to assess its predictive performance compared to the genotype-incorporated model.

METHODS: A total of 365 trough concentrations from 133 adult SLE patients treated with TAC were collected to develop a genotype-incorporated PPK model and a non-genotype-incorporated PPK model of TAC using a nonlinear mixed-effects model (NONMEM). External validation of the two models was performed using data from an additional 29 patients. Goodness-of-fit diagnostic plots, bootstrap method, and normalized predictive distribution error test were used to validate the predictive performance and stability of the final models. The goodness-of-fit of the two final models was compared using the Akaike information criterion (AIC). The dosing regimen was optimized using Monte Carlo simulations based on the developed optimal model.

RESULTS: The typical value of the apparent clearance (CL/F) of TAC estimated in the final genotype-incorporated model was 14.3 L h-1 with inter-individual variability of 27.6%. CYP3A5 polymorphism and coadministered medication were significant factors affecting TAC-CL/F. CYP3A5 rs776746 GG genotype carriers had only 77.3% of the TAC-CL/F of AA or AG genotype carriers. Omeprazole reduced TAC-CL/F by 3.7 L h-1 when combined with TAC, while TAC-CL/F increased nonlinearly as glucocorticoid dose increased. Similar findings were demonstrated in the non-genotype-incorporated PPK model. Comparing these two models, the genotype-incorporated PPK model was superior to the non-genotype-incorporated PPK model (AIC = 643.19 vs. 657.425). Monte Carlo simulation based on the genotype-incorporated PPK model indicated that CYP3A5 rs776746 AA or AG genotype carriers required a 1/2-1 fold higher dose of TAC than GG genotype carriers to achieve the target concentration. And as the daily dose of prednisone increases, the dose of TAC required to reach the target concentration increases appropriately.

CONCLUSIONS: We developed the first pharmacogenetic-based PPK model of TAC in adult patients with SLE and proposed a dosing regimen based on glucocorticoid dose and CYP3A5 genotype according to the model, which could facilitate individualized dosing for TAC.

PMID:37678026 | DOI:10.1016/j.intimp.2023.110866

Clin J Oncol Nurs. 2023 Mar 16;27(2):129-133. doi: 10.1188/23.CJON.129-133.

ABSTRACT

The implementation of pharmacogenomics in clinical practice has increased in clinical oncology practice. Pharmacogenomic germline testing can be used to develop and prescribe safer and more effective medications and treatment.

PMID:37677833 | DOI:10.1188/23.CJON.129-133

J Antimicrob Chemother. 2023 Sep 6:dkad277. doi: 10.1093/jac/dkad277. Online ahead of print.

NO ABSTRACT

PMID:37671818 | DOI:10.1093/jac/dkad277

Korean J Med Educ. 2023 Sep;35(3):303-307. doi: 10.3946/kjme.2023.269. Epub 2023 Aug 31.

NO ABSTRACT

PMID:37670527 | DOI:10.3946/kjme.2023.269

JAAPA. 2023 Sep 1;36(9):1-6. doi: 10.1097/01.JAA.0000947084.60262.4e.

ABSTRACT

Cytochrome P450 enzyme metabolism is altered by environmental and genetic factors, which can affect the efficacy and safety of opioids. This article describes CYP polymorphisms and how pharmacogenetic testing could be used to help clinicians make safer decisions about opioid use in patients.

PMID:37668489 | DOI:10.1097/01.JAA.0000947084.60262.4e

Redox Biol. 2023 Aug 25;66:102861. doi: 10.1016/j.redox.2023.102861. Online ahead of print.

ABSTRACT

Uterine fibroids, the most common benign tumors of the myometrium in women, are characterized by abnormal extracellular matrix deposition and uterine smooth muscle cell neoplasia, with high recurrence rates. Here, we investigated the potential of the marine natural product manzamine A (Manz A), which has potent anti-cancer effects, as a treatment for uterine fibroids. Manz A inhibited leiomyoma cell proliferation in vitro and in vivo by arresting cell cycle progression and inducing caspase-mediated apoptosis. We performed target prediction analysis and identified sterol o-acyltransferases (SOATs) as potential targets of Manz A. Cholesterol esterification and lipid droplet formation were reduced by Manz A, in line with reduced SOAT expression. As a downstream target of SOAT, Manz A also prevented extracellular matrix deposition by inhibiting the β-catenin/fibronectin/metalloproteinases axis and enhanced autophagy turnover. Excessive free fatty acid accumulation by SOAT inhibition led to reactive oxygen species to impair mitochondrial oxidative phosphorylation and trigger endoplasmic reticulum stress via PERK/eIF2α/CHOP signaling. The inhibitory effect of ManzA on cell proliferation was partially restored by PERK knockdown and eliminated by tauroursodeoxycholic acid, suggesting oxidative stress plays a critical role in the mechanism of action of Manz A. These findings suggest that targeting SOATs by Manz A may be a promising therapeutic approach for uterine fibroids.

PMID:37666118 | DOI:10.1016/j.redox.2023.102861

Ann Hematol. 2023 Sep 4. doi: 10.1007/s00277-023-05431-y. Online ahead of print.

ABSTRACT

Cytarabine (Ara-C) plays an irreplaceable role in the treatment of acute myeloid leukemia (AML). However, there are significant differences in efficacy among patients. Our previous studies found that E2F1 rs3213150 polymorphism was associated with remission rate of Ara-C chemotherapy, but the specific mechanism is not clear. This study aimed to further confirm the correlation between E2F1 rs3213150 polymorphism and Ara-C resistance and prognosis in AML patients, and to provide valuable information for elucidating the molecular mechanisms involved.

METHODS: Rs3213150 genotyping was performed in 922 AML patients by Sanger sequencing, and the effects of different genotypes on chemosensitivity and prognosis were analyzed by Logistic regression and Cox regression. Meanwhile, a prediction model of Ara-C chemotherapy resistance was established. The impact of rs3213150 polymorphism on E2F1 expression level was determined by luciferase reporter gene assay, and differentially expressed genes between patients with different genotypes were identified by RNA sequencing.

RESULTS: Compared with rs3213150 G allele carriers, patients with AA genotype had more obvious Ara-C resistance (41.94% vs. 27.94%, P = 0.002), shorter overall survival (529 d vs. 644 d, P = 0.008) and disease-free survival (519 d vs. 556 d, P = 0.023). Rs3213150G > A mutation resulted in decreased E2F1 expression.

CONCLUSION: E2F1 rs3213150 polymorphism influences the chemosensitivity and prognosis of Ara-C in Chinese AML patients.

PMID:37665348 | DOI:10.1007/s00277-023-05431-y

iScience. 2023 Aug 17;26(9):107627. doi: 10.1016/j.isci.2023.107627. eCollection 2023 Sep 15.

ABSTRACT

Robust and accurate survival prediction of clinical trials using high-throughput genomics data is a fundamental challenge in pharmacogenomics. Current machine learning tools often provide limited predictive performance and model interpretation in these settings. In the present study, we extend the application of REFINED-CNN from regression tasks to making survival predictions, by mapping high-dimensional RNA sequencing data into REFINED images which are conducive to CNN modeling. We show that the REFINED-CNN survival model can be easily adapted to new tasks of a similar nature (e.g., predicting on new cancer types) using transfer learning with a low number of patients. Furthermore, the model can also be interpreted both locally and globally through risk score back propagation that quantifies each feature (e.g., gene) importance in survival prediction task for the patient or cancer type of interest.

PMID:37664631 | PMC:PMC10474067 | DOI:10.1016/j.isci.2023.107627

Infect Drug Resist. 2023 Aug 28;16:5665-5680. doi: 10.2147/IDR.S418176. eCollection 2023.

ABSTRACT

PURPOSE: Sepsis is an organ dysfunction with high mortality. Early identification, diagnosis, and effective treatment of sepsis are beneficial to the survival of patients. This study aimed to find potential diagnosis and immune-related genes, and drug targets, which could provide novel diagnostic and therapeutic markers for sepsis.

PATIENTS AND METHODS: The GSE69063, GSE154918 and GSE28750 datasets were integrated to evaluate immune infiltration and identify differentially expressed genes (DEGs) and immune-related genes. Weighted gene co-expression network analysis (WGCNA) was applied to find the hub module related to immune score and sepsis. Immune-related key genes were screened out by taking interaction of DEGs, immune-related genes, and genes in hub module. Protein-protein interaction (PPI) analysis was used to further screen immune-related hub genes, followed by construction of a diagnostic model based on immune-related hub genes. Functional analysis and drug prediction of immune-related hub genes were, respectively, performed by David software and DGIdb database, followed by expression validation by reverse transcriptase polymerase chain reaction (RT-PCR).

RESULTS: Totally, 93 immune-related key genes were identified between 561 DEGs, 1793 immune-related genes and 12,459 genes in the hub module of WGCNA. Through PPI analysis, a total of 5 diagnose and immune-related hub genes were further obtained, including IL7R, IL10, CD40LG, CD28 and LCN2. Relationship pairs between these 5 genes and immune cell were identified, including LCN2/IL7R/CD28-activated dendritic cell and IL10-immature B cell. Based on pharmacogenomics, 17 candidate drugs might interact with IL 10, including CYCLOSPORINE. Six candidate drugs might interact with CD28 and 11 with CD40LG, CD40LG and CD28 were drug targets of ALDESLEUKIN. Four significantly enriched signaling pathways were identified, such as T cell receptor signaling pathway, NF-kappa B signaling pathway and JAK-STAT signaling pathway.

CONCLUSION: The 5-gene diagnostic model could be used to diagnose and guide clinical immunotherapy for sepsis.

PMID:37662976 | PMC:PMC10473429 | DOI:10.2147/IDR.S418176