Cannabis Cannabinoid Res. 2024 Aug 26. doi: 10.1089/can.2024.0028. Online ahead of print.

ABSTRACT

Background: The chronic effects of cannabidiol (CBD) supplementation on factors that could impact the quality of life (anxiety, sleeping quality, memory, etc.) are poorly explored. Hence, the aim of this study was to establish whether chronic CBD supplementation will improve self-reported outcomes related to quality of life. Methods: In this randomized crossover trial, 64 patients with primary hypertension were assigned to receive CBD (225-450 mg) for 5 weeks followed by 5 weeks of placebo or vice versa, with a 2-week washout in-between the two. Self-reported outcomes were assessed using short form-36 (SF-36), Pittsburgh sleep quality index (PSQI), Epworth sleepiness scale (ESS), memory complaint questionnaire (MAC-Q), and state-trait anxiety inventory (STAI). Results: Five-week administration of CBD, but not of placebo, resulted in improvement of ESS score (F = 6.738, p = 0.011), as well as fatigue/vitality (ΔCBD = 5.0, p < 0.001) and psychological well-being dimensions of SF-36 (ΔCBD = 7.4, p = 0.039). No overall benefit of CBD on quality of life was noted (p = 0.674). No changes were seen in total scores of MAC-Q, PSQI, or STAI (p = 0.151, p = 0.862, p = 0.702, respectively). No significant correlations were found between plasma CBD concentrations and any of the scores. Conclusions: Chronic CBD administration reduced excessive daytime sleepiness, despite the fact that no change was observed in self-reported quality of sleep. Furthermore, self-reported fatigue and psychological well-being dimensions of quality of life also improved following chronic CBD use.

PMID:39187263 | DOI:10.1089/can.2024.0028

J Affect Disord. 2024 Aug 24:S0165-0327(24)01388-0. doi: 10.1016/j.jad.2024.08.154. Online ahead of print.

ABSTRACT

BACKGROUND: Major depressive disorder (MDD) represents a sizable economic burden in Spain. Pharmacogenetic (PGx) screening to guide the choice of antidepressant medication (ADM) in MDD patients yields higher response and remission rates, which could reduce both healthcare and indirect costs.

METHODS: We built a cost-effectiveness probabilistic Markov model with microsimulation using Tree Age Pro 2022, simulating a patient cohort from the SNHS starting ADM for MDD, and comparing PGx screening before starting ADM versus no screening (No PGx). We carried out a probabilistic sensitivity analysis using the Monte Carlo simulation with microsimulation, set for 1000 iterations and 1000 microsimulation trials, both from societal and healthcare provider perspectives, for a time horizon of 3 years.

RESULTS: From a societal perspective, the model estimated a mean cost of 3172.85€ and effectiveness of 2.64 quality-adjusted life years (QALYs) for the No PGx strategy, and a mean cost of 1687.02€ and effectiveness of 2.84 QALYs for the PGx strategy. The mean ICER was -7820.56 €/QALY. From a healthcare provider perspective (no indirect costs considered), the mean cost was 662.62€ for the No PGx strategy, and 446.60€ for the PGx strategy. The mean ICER was -1130.16 €/QALY.

LIMITATIONS: The heterogeneity of input data from the literature, the need for assumptions of homogeneous distribution of variables and events across population and time, and the inherent limitations of cost-effectiveness analysis should be considered. The model omits combined therapies (ADMs with mood stabilizers, antipsychotics, cognitive behavioral therapy…).

CONCLUSIONS: PGx screening in MDD prior to ADM start is a dominant strategy in the SNHS.

PMID:39187185 | DOI:10.1016/j.jad.2024.08.154

Gene. 2024 Aug 24:148890. doi: 10.1016/j.gene.2024.148890. Online ahead of print.

ABSTRACT

Oprm1, the gene encoding the μ-opioid receptor, has multiple reported transcripts, with a variable 3' region and many alternative sequences encoding the C-terminus of the protein. The functional implications of this variability remain mostly unexplored, though a recurring notion is that it could be exploited by developing selective ligands with improved clinical profiles. Here, we comprehensively examined Oprm1 transcriptional variants in the murine central nervous system, using long-read RNAseq as well as spatial and single-cell transcriptomics. The results were validated with RNAscope in situ hybridization. We found a mismatch between transcripts annotated in the mouse genome (GRCm38/mm10) and the RNA-seq results. Sequencing data indicated that the primary Oprm1 transcript has a 3' terminus located on chr10:6,860,027, which is ∼ 9.5 kilobases downstream of the longest annotated exon 4 end. Long-read sequencing confirmed that the final Oprm1 exon included a 10.2 kilobase long 3' untranslated region, and the presence of the long variant was unambiguously confirmed using RNAscope in situ hybridization in the thalamus, striatum, cortex and spinal cord. Conversely, expression of the Oprm1 reference transcript or alternative transcripts of the Oprm1 gene was absent or close to the detection limit. Thus, the primary transcript of the Oprm1 mouse gene is a variant with a long 3' untranslated region, which is homologous to the human OPRM1 primary transcript and encodes the same conserved C-terminal amino acid sequence.

PMID:39187136 | DOI:10.1016/j.gene.2024.148890

Cureus. 2024 Jul 24;16(7):e65279. doi: 10.7759/cureus.65279. eCollection 2024 Jul.

ABSTRACT

Some patients with schizophrenia fail to respond to standard antipsychotics and are considered treatment-resistant. In these cases, clozapine is the only antipsychotic with proven efficacy, but its use is complicated by severe adverse effects, complex monitoring requirements, and non-response. Variation within the CYP450 enzymes CYP1A2, CYP2D6, CYP3A4, and CYP2C19 has been linked to the differential metabolism of antipsychotics. Testing for CYP450 single nucleotide polymorphisms may be a useful predictor of treatment resistance and could inform pharmacogenetic recommendations to identify potential treatment non-responders. Nonetheless, it remains uncertain whether differential antipsychotic metabolism is directly related to treatment efficacy. This comprehensive narrative review endeavours to delve into the molecular and genetic basis of schizophrenia, and discuss the current treatments available. In particular, we aim to examine the aetiology of treatment resistance in schizophrenia through available literature and discuss current challenges within the field.

PMID:39184784 | PMC:PMC11343069 | DOI:10.7759/cureus.65279

Res Sq [Preprint]. 2024 Aug 13:rs.3.rs-4656461. doi: 10.21203/rs.3.rs-4656461/v1.

ABSTRACT

Underrepresented populations' participation in clinical trials remains limited, and the potential impact of genomic variants on drug metabolism remains elusive. This study aimed to assess the pharmacokinetics (PK) and pharmacogenomics (PGx) of ribociclib in self-identified Black women with hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (HER2) advanced breast cancer. LEANORA (NCT04657679) was a prospective, observational, multicenter cohort study involving 14 Black women. PK and PGx were evaluated using tandem mass spectrometry and PharmacoScan™ microarray (including CYP3A5*3 , *6 , and *7 ). CYP3A5 phenotypes varied among participants: 7 poor metabolizers (PM), 6 intermediate metabolizers (IM), and one normal metabolizer (NM). The area-under-the-curve did not significantly differ between PMs (39,230 hr*ng/mL) and IM/NMs (43,546 hr*ng/mL; p = 0.38). The incidence of adverse events (AEs) was also similar. We found no association between CYP3A5 genotype and ribociclib exposure. Continued efforts are needed to include diverse populations in clinical trials to ensure equitable treatment outcomes.

PMID:39184092 | PMC:PMC11343304 | DOI:10.21203/rs.3.rs-4656461/v1

Radiol Med. 2024 Aug 25. doi: 10.1007/s11547-024-01865-0. Online ahead of print.

ABSTRACT

INTRODUCTION: While thermal ablation is now a standard treatment option for oligometastatic colorectal cancer patients, selecting those who will benefit most from locoregional therapies remains challenging. This proof-of-concept study is the first to assess the feasibility of routine testing of ctDNA before and after thermal ablation with curative intent, analyzed by next-generation sequencing (NGS) and methylation specific digital droplet PCR (ddPCR). Our prospective study primary objective was to assess the prognostic value of ctDNA before thermal ablation.

METHODS: This single-center prospective study from November 2021 to June 2022 included colorectal cancer patients referred for curative-intent thermal ablation. Cell-free DNA was tested at different time points by next-generation sequencing and detection of WIF1 and NPY genes hypermethylation using ddPCR. The ctDNA was considered positive if either a tumor mutation or hypermethylation was detected; recurrence-free survival was used as the primary endpoint.

RESULTS: The study enrolled 15 patients, and a total of 60 samples were analyzed. The median follow-up after ablation was 316 days, and median recurrence-free survival was 250 days. CtDNA was positive for 33% of the samples collected during the first 24 h. The hazard ratio for progression according to the presence of baseline circulating tumor DNA was estimated at 0.14 (CI 95%: 0.03-0.65, p = 0.019). The dynamics are provided, and patients with no recurrence were all negative at H24 for ctDNA.

DISCUSSION: This study shows the feasibility of routine testing of ctDNA before and after thermal ablation with curative intent. We report that circulating tumor DNA is detectable in patients with low tumor burden using 2 techniques. This study emphasizes the potential of ctDNA for discerning patients who are likely to benefit from thermal ablation from those who may not, which could shape future referrals. The dynamics of ctDNA before and after ablation shed light on the need for further research and larger studies.

PMID:39183242 | DOI:10.1007/s11547-024-01865-0

J Mol Diagn. 2024 Aug 23:S1525-1578(24)00183-1. doi: 10.1016/j.jmoldx.2024.07.005. Online ahead of print.

ABSTRACT

Thiopurine 6-mercaptopurine (6-MP) is metabolized by thiopurine methyl transferase (TPMT). TPMT genetic variation results in some individuals having reduced or absent TPMT enzyme activity. If these individuals take a full thiopurine dose, life-threatening adverse events can occur. Testing identifies patients with reduced or absent TPMT activity and is recommended prior to initiation of therapy. The TPMT*8 allele, defined by c.644G>A (p.Arg215His), is common among individuals of African ancestry (∼2.3% minor allele frequency), but is not included in genotyping recommendations due to its uncertain function. Here, a clinical TPMT enzyme activity assay was used to assess TPMT activity in red blood cells from 982 patients, including those with *1/*8 (n=22), *3A/*8 (n=1), and *3C/*8 (n=1) TPMT diplotypes. The average 6-MMP production (primary TPMT product measured clinically) was 3.08 ± 0.16 nmol/mL/hr for *1/*8 individuals, compared to 3.77 ± 0.03 nmol/mL/hr for normal metabolizers (p=0.0001) and 2.39 ± 0.06 nmol 6-MMP/mL/hr for intermediate metabolizers (p<0.0001). Individuals with a TPMT*1/*8 diplotype demonstrated reduced 6-MP metabolism between that of normal metabolizers and intermediate metabolizers, suggesting that TPMT*8 is a reduced function allele.

PMID:39182670 | DOI:10.1016/j.jmoldx.2024.07.005

BMJ Mil Health. 2024 Aug 24:e002721. doi: 10.1136/military-2024-002721. Online ahead of print.

ABSTRACT

Proteins control individual patient's response to pharmaceutical medication, be they receptors, transporters or enzymes. These proteins are under the control of genes. The study of these genes and the interplay between multiple genes is pharmacogenomics, with individual genes being termed pharmacogenes. The greatest understanding of pharmacogenetics is of the drug metabolising enzymes, the cytochrome P450s. Almost the entire UK population is likely to have at least one genetic variant that controls these P450s and thus the phenotype for metabolic competence. This means two patients receiving the same medication and dose may have very different responses, from adverse reaction to being ineffective. An individual military person's response to medications can be predicted from their pharmacogenetics, as an example; the response to the commonly prescribed 'pain killers', codeine, tramadol, hydrocodone or oxycodone. These opioids are metabolised into their active forms by the cytochrome 2D6. Four phenotypes classify an individual's metabolic competency: ultra-rapid, extensive, intermediate or poor. A poor metaboliser is at risk of ineffective pain relief from one of the opioids listed, whereas an ultra-rapid metaboliser is at risk of overexposure and subsequent dependency or abuse. In white European populations, the prevalence of the phenotypes is well known and may be used to guide prescribing; however, in other populations such as Nepalese or Pacific Islander the distribution of these phenotypes is unknown. Genotyping provides a framework for the precise treatment of patients and cost-effective use of medication for the UK Armed Forces, as well as potentially providing equity for minority groups.

PMID:39181566 | DOI:10.1136/military-2024-002721

Clin Gastroenterol Hepatol. 2024 Aug 22:S1542-3565(24)00766-3. doi: 10.1016/j.cgh.2024.07.032. Online ahead of print.

ABSTRACT

BACKGROUND AND AIMS: The prevalence of inflammatory bowel disease (IBD) among Hispanic/Latine communities is increasing. Pharmacogenomic studies reveal genetic markers that influence treatment decisions. The aim of our study was to examine the frequency and impact of genetic polymorphisms on thiopurine-associated leukopenia (NUDT15, TPMT) and anti-TNF immunogenicity (HLA-DQA1*05) in a cohort of Hispanic patients of diverse ancestral backgrounds.

METHODS: We performed a multicenter, retrospective cohort study comprised of 2225 Hispanic participants. We measured the frequency of variation affecting drug response in NUDT15, TPMT, and HLA-DQA1*05, their ancestral origin (European, African, or Amerindian), and the rate of development of myelosuppression and immunogenicity to thiopurines and anti-TNFs, respectively, in exposed patients.

RESULTS: NUDT15 and TPMT variants were rare, except for rs116855232 in NUDT15 which was common only in alleles of Amerindian origin. All NUDT15 variant alleles were inherited on an Amerindian haplotype, and among the Amerindian allele subset, the variant frequency of NUDT15*4 (rs147390019) was a remarkable 23% in patients with leukopenia but only 3% in patients without leukopenia. HLA-DQA1*05 and its European tagging variant rs2097432 were common in alleles from all ancestral origins and demonstrated association with immunogenicity to anti-TNFs. However, rs2097432 was only correlated with HLA-DQA1*05 in the European allele subset.

CONCLUSION: These findings indicate that NUDT15 testing should become standard clinical practice before prescribing thiopurines in individuals with Amerindian ancestry, including Hispanic individuals. Additionally, rs2097432 should not be used as a surrogate for HLA-DQA1*05 testing for diverse populations. Ultimately, incorporating ancestry in personalized therapeutic approaches is important for treatment of Hispanic patients with IBD.

PMID:39181428 | DOI:10.1016/j.cgh.2024.07.032

J Am Med Inform Assoc. 2024 Aug 24:ocae227. doi: 10.1093/jamia/ocae227. Online ahead of print.

ABSTRACT

BACKGROUND: Hypertension (HTN) remains a significant public health concern and the primary modifiable risk factor for cardiovascular disease, which is the leading cause of death in the United States. We applied our validated HTN computable phenotypes within the All of Us Research Program to uncover prevalence and characteristics of HTN and apparent treatment-resistant hypertension (aTRH) in United States.

METHODS: Within the All of Us Researcher Workbench, we built a retrospective cohort (January 1, 2008-July 1, 2023), identifying all adults with available age data, at least one blood pressure (BP) measurement, prescribed at least one antihypertensive medication, and with at least one SNOMED "Essential hypertension" diagnosis code.

RESULTS: We identified 99 461 participants with HTN who met the eligibility criteria. Following the application of our computable phenotypes, an overall population of 81 462 were further categorized to aTRH (14.4%), stable-controlled HTN (SCH) (39.5%), and Other HTN (46.1%). Compared to participants with SCH, participants with aTRH were older, more likely to be of Black or African American race, had higher levels of social deprivation, and a heightened prevalence of comorbidities such as hyperlipidemia and diabetes. Heart failure, chronic kidney disease, and diabetes were the comorbidities most strongly associated with aTRH. β-blockers were the most prescribed antihypertensive medication. At index date, the overall BP control rate was 62%.

DISCUSSION AND CONCLUSION: All of Us provides a unique opportunity to characterize HTN in the United States. Consistent findings from this study with our prior research highlight the interoperability of our computable phenotypes.

PMID:39181122 | DOI:10.1093/jamia/ocae227

J Am Med Inform Assoc. 2024 Aug 24:ocae232. doi: 10.1093/jamia/ocae232. Online ahead of print.

ABSTRACT

OBJECTIVE: This paper presents the novel BioASQ Synergy research process which aims to facilitate the interaction between biomedical experts and automated question answering systems.

MATERIALS AND METHODS: The proposed research allows systems to provide answers to emerging questions, which in turn are assessed by experts. The assessment of the experts is fed back to the systems, together with new questions. With this iteration, we aim to facilitate the incremental understanding of a developing problem and contribute to solution discovery.

RESULTS: The results suggest that the proposed approach can assist researchers to navigate available resources. The experts seem to be very satisfied with the quality of the ideal answers provided by the systems, suggesting that such systems are already useful in answering open research questions.

DISCUSSION: BioASQ Synergy aspire to provide a tool that gives the experts easy and personalised access to the latest findings in a fast growing corpus of material.

CONCLUSION: In this paper we envisioned BioASQ Synergy as a continuous dialogue between experts and systems to issue open questions. We ran an initial proof-of-concept of the approach, in order to evaluate its usefulness, both from the side of the experts, as well as from the side of the participating systems.

PMID:39180335 | DOI:10.1093/jamia/ocae232

Pharmacogenomics J. 2024 Aug 23;24(5):29. doi: 10.1038/s41397-024-00349-8.

ABSTRACT

African American (AA) kidney transplant recipients (KTRs) have poor outcomes, which may in-part be due to tacrolimus (TAC) sub-optimal immunosuppression. We previously determined the common genetic regulators of TAC pharmacokinetics in AAs which were CYP3A5 *3, *6, and *7. To identify low-frequency variants that impact TAC pharmacokinetics, we used extreme phenotype sampling and compared individuals with extreme high (n = 58) and low (n = 60) TAC troughs (N = 515 AA KTRs). Targeted next generation sequencing was conducted in these two groups. Median TAC troughs in the high group were 7.7 ng/ml compared with 6.3 ng/ml in the low group, despite lower daily doses of 5 versus 12 mg, respectively. Of 34,542 identified variants across 99 genes, 1406 variants were suggestively associated with TAC troughs in univariate models (p-value < 0.05), however none were significant after multiple testing correction. We suggest future studies investigate additional sources of TAC pharmacokinetic variability such as drug-drug-gene interactions and pharmacomicrobiome.

PMID:39179559 | DOI:10.1038/s41397-024-00349-8

Pharmacogenomics J. 2024 Aug 23;24(5):28. doi: 10.1038/s41397-024-00348-9.

NO ABSTRACT

PMID:39179533 | DOI:10.1038/s41397-024-00348-9

Am J Pathol. 2024 Aug 21:S0002-9440(24)00299-2. doi: 10.1016/j.ajpath.2024.08.003. Online ahead of print.

ABSTRACT

Casein kinase 1 epsilon (CK1ε), a member of the serine/threonine protein kinase family, is known to phosphorylate a broad range of substrates. However, its role in the development of chronic liver diseases remains elusive. This study aimed to investigate the role of CK1ε in the development and progression of metabolic dysfunction-associated steatohepatitis (MASH). Hepatocyte-specific CK1ε knockout (CK1εΔHEP) mice were generated by crossbreeding mice with floxed CK1ε alleles (CK1εfl/fl) and Cre expressing Albumin mice. Mice were fed either a Western diet (WD) or a methionine and choline-deficient (MCD) to induce MASH. CK1εΔHEP was associated with a decreased severity of WD- or MCD-induced MASH, as confirmed by reduced incidence of hepatic lesions and significantly lower levels of alanine aminotransferase, aspartate aminotransferase, and proinflammatory cytokine TNF-α. CK1εΔHEP WD-fed mice exhibited significant amelioration of total cholesterol, triglycerides and de novo lipogenic genes, indicating that CK1ε could influence lipid metabolism. CK1εΔHEP WD-fed mice showed significantly downregulated TRAF3, phosphorylated (p) TAK1, pTBK1, and pAKT levels, thereby affecting downstream MAPK signaling, indicating a potential mechanism for the observed rescue. Finally, pharmacological inhibition of CK1ε with PF670462 improved PA-induced steatohepatitis in vitro and attenuated WD-induced metabolic profile in vivo. In conclusion, CK1ε upregulates TRAF3, which in turn causes TAK1-dependent signaling, amplifies downstream MAPK signaling, modifies p-c-Jun levels, and exacerbates inflammation, all of which are factors in WD-induced MASLD.

PMID:39179201 | DOI:10.1016/j.ajpath.2024.08.003

Clin Transl Sci. 2024 Aug;17(8):e70005. doi: 10.1111/cts.70005.

ABSTRACT

Chronic pain is a prevalent condition with enormous economic burden. Opioids such as tramadol, codeine, and hydrocodone are commonly used to treat chronic pain; these drugs are activated to more potent opioid receptor agonists by the hepatic CYP2D6 enzyme. Results from clinical studies and mechanistic understandings suggest that CYP2D6-guided therapy will improve pain control and reduce adverse drug events. However, CYP2D6 is rarely used in clinical practice due in part to the demand for additional clinical trial evidence. Thus, we designed the ADOPT-PGx (A Depression and Opioid Pragmatic Trial in Pharmacogenetics) chronic pain study, a multicenter, pragmatic, randomized controlled clinical trial, to assess the effect of CYP2D6 testing on pain management. The study enrolled 1048 participants who are taking or being considered for treatment with CYP2D6-impacted opioids for their chronic pain. Participants were randomized to receive immediate or delayed (by 6 months) genotyping of CYP2D6 with clinical decision support (CDS). CDS encouraged the providers to follow the CYP2D6-guided trial recommendations. The primary study outcome is the 3-month absolute change in the composite pain intensity score assessed using Patient-Reported Outcomes Measurement Information System (PROMIS) measures. Follow-up will be completed in July 2024. Herein, we describe the design of this trial along with challenges encountered during enrollment.

PMID:39177194 | DOI:10.1111/cts.70005

Eur Heart J Open. 2024 Aug 6;4(4):oeae063. doi: 10.1093/ehjopen/oeae063. eCollection 2024 Jul.

NO ABSTRACT

PMID:39175847 | PMC:PMC11339708 | DOI:10.1093/ehjopen/oeae063

Brain. 2024 Aug 22:awae271. doi: 10.1093/brain/awae271. Online ahead of print.

ABSTRACT

It is debated whether central nervous system involvement begins during acute HIV infection in persons without meningitis/encephalitis and if specific antiretroviral drugs or combinations would be beneficial. Neurologically asymptomatic participants enrolled in a randomized and controlled study comparing three combination antiretroviral regimens (tenofovir alafenamide/emtricitabine plus dolutegravir, darunavir or both) during primary HIV infection were enrolled. Serum and cerebrospinal fluid (CSF) were collected at baseline, 12 and 48 (serum only) weeks after treatment initiation. Single Molecule Array was used to measure neurofilament light chain (NFL), total tau protein (Tau), Brain-Derived Neurotrophic Factor (BDNF), Glial Fibrillary Acidic Protein (GFAP), Ubiquitin C-terminal Hydrolase (UCH-L1). We assessed the longitudinal change in biomarkers over time as well as the change in the prevalence of serum NFL concentrations above previously published age-adjusted cut-offs (7 pg/mL if 5-18 years, 10 pg/mL if 18-51 years, 15 pg/mL if 51-61 years, 20 pg/mL if 61-70 years and 35 pg/mL if >70 years). Serum was available from 47 participants at all time points while CSF was in 13 and 7 participants (baseline/W12). We observed a significant direct serum-to-CSF correlation for NFL (rho = 0.692, p = 0.009), GFAP (rho = 0.659, p = 0.014) and BDNF (rho = 0.587, p = 0.045). Serum (rho = 0.560, p = 0.046) and CSF NFL (rho = 0.582, p = 0.037) concentrations were directly associated with CSF HIV RNA levels. We observed a significant decrease over time in serum NFL (p = 0.006) and GFAP (p = 0.006) but not in the other biomarkers. No significant difference was observed among the treatment arms. At baseline, serum and CSF age-adjusted NFL levels were above age-adjusted cut-offs in 23 (48.9%) and 4 participants (30.8%); considering serum NFL, this proportion was lower at weeks 12 (31.9%, p = 0.057) and 48 (27.7%, p = 0.13). A relevant proportion of neurologically asymptomatic participants had abnormal CSF and serum NFL levels during primary HIV infection. NFL and GFAP decreased in serum following combination antiretroviral therapy without significant differences among the treatment arms.

PMID:39171829 | DOI:10.1093/brain/awae271

Pharmacogenomics. 2024 Aug 22:1-10. doi: 10.1080/14622416.2024.2385289. Online ahead of print.

ABSTRACT

Aim: To evaluate the association between irinotecan safety and the UGT1A1 gene polymorphism in colorectal cancer (CRC) patients.Materials & methods: The studies were systematically searched and identified from three databases (PubMed, Embase and The Cochrane Library) until 28 February 2023. The relationships were evaluated using pooled odds ratio (OR).Results: A total of 30 studies out of 600 were included, comprising 4471 patients. UGT1A1*28 was associated with a statistically significant increase in the OR for diarrhea (OR: 1.59, 95% CI = 1.24-2.06 in the additive model; OR = 3.24, 95% CI = 2.01-5.21 in the recessive model; and OR = 1.95, 95% CI = 1.42-2.69 in the dominant model) and neutropenia (OR = 1.70, 95% CI = 1.40-2.06 in the additive model; OR = 4.10, 95%CI = 2.69-6.23 in the recessive model; and OR = 1.93, 95% CI = 1.61-2.31 in the dominant model). Subgroup analysis indicated consistent associations in both Asian and non-Asian populations. UGT1A1*6 was associated with a statistically significant elevation in the OR for diarrhea (only in the recessive model, OR = 2.42; 95% CI = 1.14-5.11) and neutropenia (across all genetic models).Conclusion: The UGT1A1*28 and UGT1A1*6 alleles might be a crucial indicator for predicting irinotecan safety in CRC.

PMID:39171626 | DOI:10.1080/14622416.2024.2385289

Curr Pharm Des. 2024 Aug 21. doi: 10.2174/0113816128324199240730093415. Online ahead of print.

ABSTRACT

BACKGROUND: Sirolimus, one of the immunosuppressive drugs administered to renal transplant recipients, is metabolized by cytochrome P450 (CYP) 3A5. Accordingly, CYP3A5 polymorphism is a genetic factor affecting sirolimus pharmacokinetics (PK). Therefore, we conducted a systematic review and meta-analysis on the association between sirolimus PK and CYP3A5*3 polymorphism.

METHODS: We searched for studies published up to 13 June 2024 from PubMed, Embase, Cochrane Library, and Web of Science. We reviewed studies on the relationship between CYP3A5*3 polymorphism and weightadjusted trough concentration/dose (C/D) ratio and dosage of sirolimus in renal transplant recipients, according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. We evaluated mean differences (MDs) and 95% confidence intervals (CIs).

RESULTS: A total of seven studies were included. The weight-adjusted C/D ratio of sirolimus was significantly higher in patients with the CYP3A5*3/*3 rather than CYP3A5*1/*1 or CYP3A5*1/*3 genotype (MD 95.27 ng/mL per mg/kg; 95% CI: 58.06, 132.47; I2 = 74%; p < 0.00001). Also, the weight-adjusted dosage of sirolimus was significantly lower in patients with the CYP3A5*3/*3 rather than CYP3A5*1/*1 or CYP3A5*1/*3 genotype (MD -2.60 × 10-3 mg/kg; 95% CI: -4.52, -0.69; I2 = 44%; p = 0.008).

CONCLUSION: Our meta-analysis showed a significant effect for the CYP3A5*3 genotype on weight-adjusted C/D ratio and dosage of sirolimus in adult renal transplant recipients.

PMID:39171589 | DOI:10.2174/0113816128324199240730093415

JACC Basic Transl Sci. 2024 Feb 28;9(7):918-934. doi: 10.1016/j.jacbts.2023.12.006. eCollection 2024 Jul.

ABSTRACT

The heritability of atrial fibrillation (AF) is well established. Over the last decade genetic architecture of AF has been unraveled by genome-wide association studies and family-based studies. However, the translation of these genetic discoveries has lagged owing to an incomplete understanding of the pathogenic mechanisms underlying the genetic variants, challenges in classifying variants of uncertain significance (VUS), and limitations of existing disease models. We review the mechanistic insight provided by basic science studies regarding AF mechanisms, recent developments in high-throughput classification of VUS, and advances in bioengineered cardiac models for developing personalized therapy for AF.

PMID:39170958 | PMC:PMC11334418 | DOI:10.1016/j.jacbts.2023.12.006