medRxiv. 2023 Oct 2:2023.09.29.23296372. doi: 10.1101/2023.09.29.23296372. Preprint.

ABSTRACT

BACKGROUND: High on-treatment platelet reactivity (HTPR) with clopidogrel is predictive of ischemic events in adults with coronary artery disease. Despite strong data suggesting HTPR varies with ethnicity, including clinical and genetic variables, no genome-wide association study (GWAS) of clopidogrel response has been performed among Caribbean Hispanics. This study aimed to identify genetic predictors of HTPR in a cohort of Caribbean Hispanic cardiovascular patients from Puerto Rico.

METHODS: Local Ancestry inference (LAI) and traditional GWASs were performed on a cohort of 511 clopidogrel-treated patients, stratified based on their P2Y12 reaction units (PRU) into responders and non-responders (HTPR).

RESULTS: The LAI GWAS identified variants within the CYP2C19 region associated with HTPR, predominantly driven by individuals of European ancestry and absent in those with native ancestry. Incorporating local ancestry adjustment notably enhanced our ability to detect associations. While no loci reached traditional GWAS significance, three variants showed suggestive significance at chromosomes 3, 14 and 22 (OSBPL10 rs1376606, DERL3 rs5030613, and RGS6 rs9323567). In addition, a variant in the UNC5C gene on chromosome 4 was associated with an increased risk of HTPR. These findings were not identified in other cohorts, highlighting the unique genetic landscape of Caribbean Hispanics.

CONCLUSION: This is the first GWAS of clopidogrel response in Hispanics, confirming the relevance of the CYP2C19 cluster, particularly among those with European ancestry, and also identifying novel markers in a diverse patient population. Further studies are warranted to replicate our findings in other diverse cohorts and meta-analyses.

PMID:37873439 | PMC:PMC10593031 | DOI:10.1101/2023.09.29.23296372

Pharmacogenomics. 2023 Oct 23. doi: 10.2217/pgs-2023-0140. Online ahead of print.

ABSTRACT

Aim: Tuberous sclerosis complex (TSC) is a rare disease that produces multisystemic disorders. Everolimus (EVR) is the only immunosuppressive drug approved to control the symptoms and progression of the disease. The aim was to evaluate the genotype-phenotype association to improve the pediatric TSC pharmacotherapeutic outcome. Patients & methods: Ten pediatric TSC patients were recruited. Concomitant treatment and main metabolic enzymes and transporter coding gene variants of EVR were analyzed. Results: Significant associations were found between CYP3A4*22 allele and concomitant treatment with valproic acid (CYP3A4-inhibitor) with a poor metabolizer phenotype and the presence of pneumonia. Conclusion: This is the first pharmacogenetic study of EVR in pediatric TSC patients. The authors propose to consider concomitant treatment and pharmacogenetics due to their multifactorial status.

PMID:37869874 | DOI:10.2217/pgs-2023-0140

Wellcome Open Res. 2023 Apr 24;8:183. doi: 10.12688/wellcomeopenres.19202.1. eCollection 2023.

ABSTRACT

Background: People who have experienced a stroke are at high risk of recurrent strokes. Clopidogrel is prescribed to people who have had a non-cardioembolic stroke. There is evidence that clopidogrel is not effective for patients with CYP2C19 loss-of-function alleles. Pharmacogenetic testing is a potential strategy to identify such patients and guide prescription of appropriate antiplatelet treatment. This study aimed to provide an early estimate of the cost-effectiveness of using a point-of-care pharmacogenetic CYP2C19 test in the UK National Health System. Methods: A decision-analytic model comprising a linked decision tree and Markov model were created in R comparing pharmacogenetic testing with current prescribing practice. In the pharmacogenetic testing arm, patients identified to have one of three loss-of-function alleles were prescribed modified-release dipyridamole and aspirin or aspirin alone. Indicative data were sourced from reviews of the literature supported by expert consultation to select the most appropriate value for the input parameters. The healthcare costs (£;2021) and quality adjusted life years resulting from each strategy were estimated and the incremental cost-effectiveness of testing calculated. Deterministic threshold analysis and probabilistic sensitivity analysis (PSA) was conducted to account for uncertainty in the parameter estimates. Results: The pharmacogenetic testing strategy generated 0.107 additional QALYs per patient tested and saved £512. Pharmacogenetic testing dominated current prescribing practice. The results were robust to extreme changes in key input variables. The PSA suggested that there was a 77% chance that pharmacogenetic testing would be cost-effective with a 62% chance it is cost-saving. Conclusions: A point-of-care pharmacogenetic test to guide prescription of clopidogrel for people who have experienced a stroke has the potential to provide a significant health gain by preventing secondary strokes and may save resources in the health system. This early economic analysis has also informed the direction for future research.

PMID:37869733 | PMC:PMC10587658 | DOI:10.12688/wellcomeopenres.19202.1

Front Med (Lausanne). 2023 Oct 6;10:1271863. doi: 10.3389/fmed.2023.1271863. eCollection 2023.

ABSTRACT

INTRODUCTION: Long-term pulmonary dysfunction (L-TPD) is one of the most critical manifestations of long-COVID. This lung affection has been associated with disease severity during the acute phase and the presence of previous comorbidities, however, the clinical manifestations, the concomitant consequences and the molecular pathways supporting this clinical condition remain unknown. The aim of this study was to identify and characterize L-TPD in patients with long-COVID and elucidate the main pathways and long-term consequences attributed to this condition by analyzing clinical parameters and functional tests supported by machine learning and serum proteome profiling.

METHODS: Patients with L-TPD were classified according to the results of their computer-tomography (CT) scan and diffusing capacity of the lungs for carbon monoxide adjusted for hemoglobin (DLCOc) tests at 4 and 12-months post-infection.

RESULTS: Regarding the acute phase, our data showed that L-TPD was favored in elderly patients with hypertension or insulin resistance, supported by pathways associated with vascular inflammation and chemotaxis of phagocytes, according to computer proteomics. Then, at 4-months post-infection, clinical and functional tests revealed that L-TPD patients exhibited a restrictive lung condition, impaired aerobic capacity and reduced muscular strength. At this time point, high circulating levels of platelets and CXCL9, and an inhibited FCgamma-receptor-mediated-phagocytosis due to reduced FcγRIII (CD16) expression in CD14+ monocytes was observed in patients with L-TPD. Finally, 1-year post infection, patients with L-TPD worsened metabolic syndrome and augmented body mass index in comparison with other patient groups.

DISCUSSION: Overall, our data demonstrated that CT scan and DLCOc identified patients with L-TPD after COVID-19. This condition was associated with vascular inflammation and impair phagocytosis of virus-antibody immune complexes by reduced FcγRIII expression. In addition, we conclude that COVID-19 survivors required a personalized follow-up and adequate intervention to reduce long-term sequelae and the appearance of further metabolic diseases.

PMID:37869162 | PMC:PMC10590130 | DOI:10.3389/fmed.2023.1271863

Cureus. 2023 Sep 19;15(9):e45575. doi: 10.7759/cureus.45575. eCollection 2023 Sep.

ABSTRACT

Diabetic kidney disease (DKD) is a significant complication of diabetes that requires innovative interventions to address its increasing impact. Precision medicine is a rapidly emerging paradigm that shows excellent promise in tailoring therapeutic strategies to the unique profiles of individual patients. This abstract examines the potential of precision medicine in managing DKD. It explores the genetic and molecular foundations, identifies biomarkers for risk assessment, provides insights into pharmacogenomics, and discusses targeted therapies. Integrating omics data and data analytics provides a comprehensive landscape for making informed decisions. The abstract highlights the difficulties encountered during the clinical implementation process, the ethical factors to be considered, and the importance of involving patients. In addition, it showcases case studies that demonstrate the effectiveness of precision-based interventions. As the field progresses, the abstract anticipates a future characterized by the integration of artificial intelligence in diagnostics and treatment. It highlights the significant impact that precision medicine can have in revolutionizing the provision of care for DKD.

PMID:37868402 | PMC:PMC10587911 | DOI:10.7759/cureus.45575

Sci Rep. 2023 Oct 21;13(1):18022. doi: 10.1038/s41598-023-45347-1.

ABSTRACT

Drug designing is high-priced and time taking process with low success rate. To overcome this obligation, computational drug repositioning technique is being promptly used to predict the possible therapeutic effects of FDA approved drugs against multiple diseases. In this computational study, protein modeling, shape-based screening, molecular docking, pharmacogenomics, and molecular dynamic simulation approaches have been utilized to retrieve the FDA approved drugs against AD. The predicted MADD protein structure was designed by homology modeling and characterized through different computational resources. Donepezil and galantamine were implanted as standard drugs and drugs were screened out based on structural similarities. Furthermore, these drugs were evaluated and based on binding energy (Kcal/mol) profiles against MADD through PyRx tool. Moreover, pharmacogenomics analysis showed good possible associations with AD mediated genes and confirmed through detail literature survey. The best 6 drug (darifenacin, astemizole, tubocurarine, elacridar, sertindole and tariquidar) further docked and analyzed their interaction behavior through hydrogen binding. Finally, MD simulation study were carried out on these drugs and evaluated their stability behavior by generating root mean square deviation and fluctuations (RMSD/F), radius of gyration (Rg) and soluble accessible surface area (SASA) graphs. Taken together, darifenacin, astemizole, tubocurarine, elacridar, sertindole and tariquidar displayed good lead like profile as compared with standard and can be used as possible therapeutic agent in the treatment of AD after in-vitro and in-vivo assessment.

PMID:37865690 | DOI:10.1038/s41598-023-45347-1

Crit Rev Oncol Hematol. 2023 Oct 18:104185. doi: 10.1016/j.critrevonc.2023.104185. Online ahead of print.

ABSTRACT

INTRODUCTION: About 30-50% of stage IV HER2+ breast cancers (BC) will present brain metastases (BMs). Their management is based on both local treatment and systemic therapy. Despite therapeutic advances, BMs still impact on survival and quality of life and the development of more effective systemic therapies represents an unmet clinical need.

MATERIALS AND METHODS: A thorough analysis of the published literature including ongoing clinical trials has been performed, investigating concepts spanning from the pathophysiology of tumor microenvironment to clinical considerations with the aim to summarize the current and future locoregional and systemic strategies.

RESULTS: Different trials have investigated monotherapies and combination treatments, highlighting how the blood-brain barrier (BBB) represents a major problem hindering diffusion and consequently efficacy of such options. Trastuzumab has long been the mainstay of systemic therapy and over the last two decades other HER2-targeted agents including lapatinib, pertuzumab, and trastuzumab emtansine, as well as more recently neratinib, tucatinib, and trastuzumab deruxtecan, have been introduced in clinical practice after showing promising results in randomized controlled trials.

CONCLUSIONS: We ultimately propose an evidence-based treatment algorithm for clinicians treating HER2+ BCs patients with BMs.

PMID:37863404 | DOI:10.1016/j.critrevonc.2023.104185

OMICS. 2023 Oct;27(10):474-482. doi: 10.1089/omi.2023.0153.

ABSTRACT

Pharmacists play a pivotal role in pharmacogenomic (PGx) implementation in clinical practice, and their university education is considered a strong driver in holding favorable intentions toward PGx adoption. Using a survey developed based on the Theory of Planned Behavior (TPB), this study aimed to evaluate the determinants of senior pharmacy students' intentions to pursue postgraduate training in PGx and personalized medicine (PM), and with an eye to propose interventions to inform pharmacy students' career choices in the field. Students manifested considerably favorable attitudes toward PGx clinical practice and had acquired a relatively satisfactory level of knowledge. However, they conceded of having a hardly moderate level of confidence in PGx clinical application, and claimed to be moderately satisfied with their PGx training. Interestingly, students alleged to have a relatively limited interest to pursue postgraduate training studies in PGx and PM. Gender was a key and significant demographic moderator of the students' intentions to pursue postgraduate training in PGx and PM. We found that the students' attitudes exerted a strong positive impact on intentions for future PGx training, while self-confidence and training satisfaction had a moderate positive effect, respectively. We propose a set of key interventions that include, inter alia, the update of existing pharmacy curricula and the promotion of interdisciplinary collaborations with other health professionals, to reinforce the pharmacists' role in PM and PGx implementation in clinical practice. To the best of our knowledge, this is the first study using the TPB to identify the role of certain factors such as gender, attitudes, self-confidence, and training satisfaction on the final-year pharmacy undergraduate students' intentions to pursue PGx-related postgraduate studies in the future.

PMID:37861714 | DOI:10.1089/omi.2023.0153

AIDS. 2023 Oct 20. doi: 10.1097/QAD.0000000000003764. Online ahead of print.

ABSTRACT

OBJECTIVE: Concentrations of tenofovir diphosphate (TFV-DP) and lamivudine triphosphate (3TC-TP) in cells are correlates of medication adherence and antiviral activity. However, studies have yet to characterize the simultaneous relationship between TFV-DP and 3TC-TP concentrations with human immunodeficiency virus (HIV) and hepatitis B virus (HBV) suppression.

METHODS: Individuals with HIV/HBV coinfection on tenofovir disoproxil fumarate (TDF)-containing antiretroviral therapy (ART) were enrolled. Peripheral blood mononuclear cells (PBMCs) and dried blood spots (DBS) samples were collected and steady-state TFV-DP and 3TC-TP concentrations quantified using validated methods. The relationship between patient factors, TFV-DP and 3TC-TP concentrations in PBMCs and DBS with HBV and HIV viral suppression were examined.

RESULTS: Of 138 participants on TDF-containing ART for a median duration (range) of 6 (0.75-15) years, the median age was 43 years and 64% were female. Overall, 128 (92.8%) and 129 (93.5%) had suppressed HIV and HBV viral loads, respectively. Of the 128 participants with suppressed HIV, 122 (95.3%) had suppressed HBV. Self-reported ART adherence, recent change to dolutegravir-based ART, TFV-DP and 3TC-TP concentrations in PBMCs and DBS were associated with HIV RNA suppression, while HBe antigen positivity, HIV suppression and TFV-DP concentrations in DBS were associated with HBV DNA suppression (including six persons with HBV non-suppression and HIV suppression).

CONCLUSIONS: Long-term TDF/3TC-conatining ART was highly efficacious in individuals with HIV/HBV coinfection. Higher TFV-DP concentrations were predictive of suppression for both viruses. Persistent HBV viremia on TDF/3TC-containg ART requires additional research, but may represent poor adherence and the need for adherence interventions or novel antivirals.

PMID:37861682 | DOI:10.1097/QAD.0000000000003764

Medicine (Baltimore). 2023 Oct 20;102(42):e35595. doi: 10.1097/MD.0000000000035595.

ABSTRACT

Whey-acidic-protein (WAP) four-disulfide core domain protein 3 (WFDC3) is one of the WAP family proteins. This protein family is associated with the development of solid tumors and affects the tumor immunological microenvironment. However, the prognostic value of WFDC3 in pancreatic adenocarcinoma (PAAD) and its effect on the tumor immune microenvironment is yet to be clarified. The Cancer Genome Atlas database and Genotype-Tissue Expression database were used to analyze the differential expression of WFDC3 between the tumor and adjacent tissues. The clinical significance of WFDC3 was analyzed in The Cancer Genome Atlas and International Cancer Genome Consortium database using WFDC3 transcripts and clinical information. In order to elucidate the underlying mechanisms, gene set enrichment analysis was conducted to determine potential activated pathways. Immune score evaluation and publicly available pharmacogenomics database [the Genomics of Drug Sensitivity in Cancer] were utilized to quantify immune cell infiltration and the effect on chemotherapeutic drug sensitivity. WFDC3 levels were higher in PAAD tissues than in normal pancreatic tissues. High levels of WFDC3 expression progressively increased as PAAD tumor stages progressed. Patients with elevated WFDC3 expression showed a poor prognosis. The gene set enrichment analysis analysis revealed that glutamate, arginine, and proline, and histidine metabolism levels were elevated in patients with a high WFDC3 expression phenotype. B, CD4+ T, and CD8+ T cell infiltration was diminished in PAAD tissues with elevated WFDC3 expression. According to pharmacogenomics, PAAD tissues with high WFDC3 expression are susceptible to gemcitabine. WFDC3 is highly expressed in PAAD, and patients with a high level of WFDC3 expression have a shorter overall survival time, indicating a poorer prognosis. High expression of WFDC3 may lead to the development of PAAD by affecting the amino acid metabolism and the tumor immunological microenvironment. WFDC3 may serve as a potential diagnostic and prognostic biomarker for PAAD patients.

PMID:37861515 | DOI:10.1097/MD.0000000000035595

Seizure. 2023 Oct 6:S1059-1311(23)00269-8. doi: 10.1016/j.seizure.2023.10.004. Online ahead of print.

ABSTRACT

PURPOSE: The objective of this study is to evaluate the association between genetic polymorphisms and the concentration to dose ratio of topiramate in children with epilepsy.

METHODS: A cohort of 163 pediatric patients with epilepsy receiving topiramate therapy were enrolled. The ultra-performance liquid chromatography-tandem mass spectrometry method was employed to measure the trough plasma concentration of topiramate at steady-state. These concentrations were normalized by dividing them by the ratio of total daily dose to body weight, yielding the concentration to dose ratio (CDR) of topiramate. MassArray system identified 30 single nucleotide polymorphisms associated with the pharmacokinetics and pharmacodynamics of topiramate. The CDR values were logarithmic transformed (lnCDR) for normal distribution. The association between the identified genetic polymorphisms and lnCDR was assessed using the PLINK software, employing linear regression analysis with adjustments by epilepsy types, estimated glomerular filtration rate, alanine aminotransferase, valproic acid, phenobarbital, and oxcarbazepine.

RESULTS: Variant rs4148324 (UGT1A1/3/4/5/6/7/8/9/10, BETA = 0.182, P = 0.010) was significantly associated with lnCDR of topiramate. Patients carrying the G allele exhibited higher normalized topiramate plasma concentrations. No other significant associations were found.

CONCLUSIONS: In pediatric patients receiving topiramate therapy, rs4148324 was associated with normalized topiramate plasma concentration. Further studies are warranted to validate and confirm the findings.

PMID:37858371 | DOI:10.1016/j.seizure.2023.10.004

Biomed Pharmacother. 2023 Oct 17;168:115706. doi: 10.1016/j.biopha.2023.115706. Online ahead of print.

ABSTRACT

Azathioprine is commonly used as an immunosuppressive antimetabolite in the treatment of acute lymphoblastic leukemia, autoimmune disorders (such as Crohn's disease and rheumatoid arthritis), and in patients receiving organ transplants. Thiopurine-S-methyltransferase (TPMT) is a cytoplasmic trans-methylase catalyzing the S-methylation of thiopurines. The active metabolites obtained from thiopurines are hydrolyzed into inactive forms by the Nudix hydrolase 15 (NUDT15). The TPMT*2 (defined by rs1800462), *3A (defined by rs1800460 and rs1142345), *3B (defined by rs1800460), *3C (defined by rs1142345), *6 (defined by rs75543815), and NUDT15 rs116855232 genetic variant have been associated, with the highest level of evidence, with the response to azathioprine, and, the approved drug label for azathioprine and main pharmacogenetic dosing guidelines recommend starting with reduced initial doses in TPMT intermediate metabolizer (IM) patients and considering an alternative treatment in TPMT poor metabolizer (PM) patients. This study aims to assess the clinical impact of azathioprine dose tailoring based on TPMT genotyping studying the azathioprine toxicity and efficacy, treatment starts, and dose adjustments during follow-up, comparing TPMT IM/PM and normal metabolizer (NM) patients. It also studied the association of NUDT15 rs116855232 with response to azathioprine in patients receiving a tailored treatment based on TPMT and characterized the TMPT and NUDT15 studied variants in our population. Results show that azathioprine dose reduction in TPMT IM patients (TPMT*1/*2, *1/*3A, or *1/*3C genotypes) is related to lower toxicity events compared to TPMT NM (TPMT *1/*1 genotype), and lower azathioprine dose adjustments during follow-up without showing differences in the efficacy. The results support the hypothesis of existing other genetic variants affecting azathioprine toxicity.

PMID:37857254 | DOI:10.1016/j.biopha.2023.115706

Front Pharmacol. 2023 Oct 3;14:1280562. doi: 10.3389/fphar.2023.1280562. eCollection 2023.

ABSTRACT

Background: Globally, the use of amphetamines as therapeutic agents in pediatric medicine is a crucial area of concern, especially given the population's vulnerability. Methods: On 6 August 2023, a search was conducted on ClinicalTrials.gov using "amphetamine" as the keyword. Two independent examiners screened trials against set criteria, including a focus on amphetamine, completion status, an interventional approach, and included children. Ongoing or observational studies were excluded. Data extracted from the qualified trials encompassed primary objectives, participant counts, study duration, and outcomes, with the aim of analyzing children disorders treated by amphetamine. Results: On 6 August 2023, a search of the ClinicalTrials.gov database with the term "amphetamines" identified 179 clinical trials. After extensive exclusion criteria, 19 trials were ultimately selected for analysis. The predominant condition under investigation was attention deficit hyperactivity disorder (ADHD), present in 84.2% of studies. Key study characteristics included: phase 4 trials (36.8%), randomized allocation (63.2%), and the parallel intervention model (42.1%). Masking techniques varied, with no masking in 42.1% of studies, and double and quadruple masking both accounting for 21.1%. Geographically, 78.9% of the studies' participants were from the United States. Conclusion: This study highlights the notable therapeutic potential of amphetamines in pediatric ADHD populations and emphasizes the importance of recognizing potential side effects and addiction risks. As pharmacogenomics offers the prospect of personalized treatments, there is potential to increase therapeutic efficacy and decrease adverse reactions. It is vital to balance these benefits against the inherent risks, understanding the need for continued research to optimize the use of amphetamines in medicine.

PMID:37854716 | PMC:PMC10579567 | DOI:10.3389/fphar.2023.1280562

Neurol Res. 2023 Oct 19:1-8. doi: 10.1080/01616412.2023.2258042. Online ahead of print.

ABSTRACT

OBJECTIVES: Inflammatory cytokines like tumor necrosis factor-α (TNF-α), interleukin (IL)-1β, and IL-6 can cause brain injury, slow recovery, and adverse effects (ADEs) in ischemic stroke (IS) patients treated with recombinant tissue plasminogen activator (rtPA). We explored the relationship between selected polymorphisms within TNF-α, IL-1β and IL-6 genes, and post-IS outcome and ADEs in patients treated with rtPA.

METHODS: One hundred and sixty-six patients with IS treated with rtPA were included in this study. The modified Rankin Scale (mRS) was used to assess functional recovery 3 months after IS likewise thrombolytic therapy efficacy. Patients were classified into groups with favorable (0-1) or poor recovery based on their mRS score at the ninetieth day post-IS. During hospitalization, ADEs following rtPA were monitored. TNF-α-308 G/A (rs1800629), IL-1β-511 G/A (rs16944), and IL-6-174 G/C (rs1800795) polymorphisms were genotyped using Real-Time PCR. SPSS software version 22.0 was used for statistical analyses.

RESULTS: Patients with the TNF-α-308 G/A GG genotype had a higher mean NIHSS value at admission (12.75 ± 5.176) than those carrying A-allele (10.56 ± 3.979;p = 0.016). Individuals with the CC genotype of the IL-6-174 G/C polymorphism had significantly lower NIHSS scores (8.79 ± 5.053) than those with G-allele (12.06 ± 6.562) 24 hours after rtPA (p = 0.050). Patients with the GG genotype of the IL-6-174 G/C polymorphism had a significantly poorer outcome (p = 0.024; OR = 2.339; 95%CI 1.121-4.880), while patients who were G-allele carriers of the Il-6-174 G/C polymorphism and had the AA genotype of the IL-1β-511 G/A polymorphism were statistically significantly more likely to experience hemorrhagic transformation (p = 0.046; OR = 2.7273; 95%CI 1.0414-7.1426).

CONCLUSION: GG genotype of the IL-6-174 G/C polymorphism is associated with poor recovery after IS treated with rtPA therapy.

PMID:37853768 | DOI:10.1080/01616412.2023.2258042

Schizophrenia (Heidelb). 2023 Oct 18;9(1):74. doi: 10.1038/s41537-023-00404-6.

ABSTRACT

Clozapine is effective at reducing symptoms of treatment-resistant schizophrenia, but it can also induce several adverse outcomes including neutropenia and agranulocytosis. We used linear mixed-effect models and structural equation modelling to determine whether pharmacokinetic and genetic variables influence absolute neutrophil count in a longitudinal UK-based sample of clozapine users not currently experiencing neutropenia (N = 811). Increased daily clozapine dose was associated with elevated neutrophil count, amounting to a 133 cells/mm3 rise per standard deviation increase in clozapine dose. One-third of the total effect of clozapine dose was mediated by plasma clozapine and norclozapine levels, which themselves demonstrated opposing, independent associations with absolute neutrophil count. Finally, CYP1A2 pharmacogenomic activity score was associated with absolute neutrophil count, supporting lower neutrophil levels in CYP1A2 poor metabolisers during clozapine use. This information may facilitate identifying at-risk patients and then introducing preventative interventions or individualised pharmacovigilance procedures to help mitigate these adverse haematological reactions.

PMID:37853043 | DOI:10.1038/s41537-023-00404-6

Mol Cell Biochem. 2023 Oct 18. doi: 10.1007/s11010-023-04873-2. Online ahead of print.

ABSTRACT

Cell death is a fundamental physiological process in all living organisms. Processes such as embryonic development, organ formation, tissue growth, organismal immunity, and drug response are accompanied by cell death. In recent years with the development of electron microscopy as well as biological techniques, especially the discovery of novel death modes such as ferroptosis, cuprotosis, alkaliptosis, oxeiptosis, and disulfidptosis, researchers have been promoted to have a deeper understanding of cell death modes. In this systematic review, we examined the current understanding of modes of cell death, including the recently discovered novel death modes. Our analysis highlights the common and unique pathways of these death modes, as well as their impact on surrounding cells and the organism as a whole. Our aim was to provide a comprehensive overview of the current state of research on cell death, with a focus on identifying gaps in our knowledge and opportunities for future investigation. We also presented a new insight for macroscopic intracellular survival patterns, namely that intracellular molecular homeostasis is central to the balance of different cell death modes, and this viewpoint can be well justified by the signaling crosstalk of different death modes. These concepts can facilitate the future research about cell death in clinical diagnosis, drug development, and therapeutic modalities.

PMID:37851176 | DOI:10.1007/s11010-023-04873-2

Front Microbiol. 2023 Oct 2;14:1276928. doi: 10.3389/fmicb.2023.1276928. eCollection 2023.

ABSTRACT

Cyclodepsipeptides are a large family of peptide-related natural products consisting of hydroxy and amino acids linked by amide and ester bonds. A number of cyclodepsipeptides have been isolated and characterized from fungi and bacteria. Most of them showed antitumor, antifungal, antiviral, antimalarial, and antitrypanosomal properties. Herein, this review summarizes the recent literatures (2010-2022) on the progress of cyclodepsipeptides from fungi and bacteria except for those of marine origin, in order to enrich our knowledge about their structural features and biological sources.

PMID:37849925 | PMC:PMC10577210 | DOI:10.3389/fmicb.2023.1276928

Aging (Albany NY). 2023 Oct 16;15. doi: 10.18632/aging.205128. Online ahead of print.

ABSTRACT

The present study investigates the clinical relevance of glycolytic factors, specifically PGAM1, in the tumor microenvironment of kidney renal clear cell carcinoma (KIRC). Despite the established role of glycolytic metabolism in cancer pathophysiology, the prognostic implications and key targets in KIRC remain elusive. We analyzed GEO and TCGA datasets to identify DEGs in KIRC and studied their relationship with immune gene expression, survival, tumor stage, gene mutations, and infiltrating immune cells. We explored Pgam1 gene expression in different kidney regions using spatial transcriptomics after mouse kidney injury analysis. Single-cell RNA-sequencing was used to assess the association of PGAM1 with immune cells. Findings were validated with tumor specimens from 60 KIRC patients, correlating PGAM1 expression with clinicopathological features and prognosis using bioinformatics and immunohistochemistry. We demonstrated the expression of central gene regulators in renal cancer in relation to genetic variants, deletions, and tumor microenvironment. Mutations in these hub genes were positively associated with distinct immune cells in six different immune datasets and played a crucial role in immune cell infiltration in KIRC. Single-cell RNA-sequencing revealed that elevated PGAM1 was associated with immune cell infiltration, specifically macrophages. Furthermore, pharmacogenomic analysis of renal cancer cell lines indicated that inactivation of PGAM1 was associated with increased sensitivity to specific small-molecule drugs. Altered PGAM1 in KIRC is associated with disease progression and immune microenvironment. It has diagnostic and prognostic implications, indicating its potential in precision medicine and drug screening.

PMID:37847178 | DOI:10.18632/aging.205128

Clin Pharmacol Ther. 2023 Oct 17. doi: 10.1002/cpt.3077. Online ahead of print.

ABSTRACT

Clinical use of tacrolimus, an essential immunosuppressant following transplantation, is complexified by its high pharmacokinetic variability. The gut microbiota gains growing interest but limited investigations have evaluated its contribution to tacrolimus pharmacokinetics. Here, we explore the associations between the gut microbiota composition and tacrolimus pharmacokinetics. In this pilot cross-sectional study (Clinicaltrial.gov NCT04360031), we recruited 93 CYP3A5 non-expressers stabilized kidney transplant patients. Gut microbiota composition was characterized by 16S rRNA gene sequencing, tacrolimus pharmacokinetic parameters were computed, and additional demographical and medical covariates were collected. Associations between pharmacokinetic parameters or diabetic status and the gut microbiota composition, as reflected by α- and β-diversity metrics, were evaluated. Patients with higher tacrolimus AUC/(dose/kg) had higher bacterial richness, and tacrolimus pharmacokinetic parameters were associated with specific bacterial taxa (e.g., Bilophila) and amplicon sequence variant (ASV) (e.g., ASV 1508 and ASV 1982 [Veillonella/unclassified Sporomusaceae]; ASV 664 [unclassified Oscillospiraceae]). Building a multiple linear regression model showed that ASV 1508 (co-abundant with ASV 1982) and ASV 664 explained respectively 16.0% and 4.6% of the inter-individual variability in tacrolimus AUC/(dose/kg) in CYP3A5 non-expressers patients, when adjusting for haematocrit and age. Anaerostipes relative abundance was decreased in diabetic patients. Altogether, this pilot study revealed unprecedented links between the gut microbiota composition and diversity and tacrolimus pharmacokinetics in stable kidney transplant patients. It supports the relevance of studying the gut microbiota as an important contributor to tacrolimus pharmacokinetic variability. Elucidating the causal relationship will offer new perspectives to predict tacrolimus inter- and intra-pharmacokinetic variability.

PMID:37846607 | DOI:10.1002/cpt.3077

Pharmacogenomics. 2023 Oct 17. doi: 10.2217/pgs-2023-0187. Online ahead of print.

ABSTRACT

Tweetable abstract Accurate variant interpretation has become a key bottleneck for the translation of an individual's pharmacogenome into actionable recommendations. We recommend an integrated use of multiplexed assays, structure-based predictions and biobank data to develop more accurate effect predictors.

PMID:37846582 | DOI:10.2217/pgs-2023-0187