Pharmacogenomics. 2024 May 17:1-30. doi: 10.1080/14622416.2024.2344430. Online ahead of print.

ABSTRACT

This scoping review explores the impact of genetic polymorphisms on the pharmacokinetics and treatment responses of mycophenolic acid (MPA), an immunosuppressant. The study includes 83 articles from 1226 original studies, focusing on transplantation (n = 80) and autoimmune disorders (n = 3). Genetic variants in uridine 5'-diphospho-glucuronosyltransferase (UGT1A9, UGT1A8 and UGT2B7) and transmembrane transporters (ABCC2, SLCO1B1, SLCO1B3 and ABCB1) significantly affected MPA's pharmacokinetics and susceptibility to its adverse effect. Whereas variants in several genes including UGT1A9, UGT2B7, IMPDH1 and IMPDH2 have been associated with a higher risk of transplant rejection. However, there is a lack of studies on MPA's impact on autoimmune disorders and limited research on the Asian population. The findings underscore the need for further research on MPA's impact across different populations and diseases, particularly among other Asian ethnic groups, to advance personalized medicine in MPA therapy.

PMID:38884938 | DOI:10.1080/14622416.2024.2344430

Pharmacogenomics. 2024 May 10:1-19. doi: 10.1080/14622416.2024.2346069. Online ahead of print.

ABSTRACT

Aim: The association between cytochrome P450 (CYP) gene polymorphisms and anti-tuberculosis drug-induced hepatotoxicity (ATDH) was investigated in patients with or without pre-existing liver diseases (PLD). Materials & methods: We followed 164 tuberculosis subjects, 58 with PLD and 106 without PLD. Polymorphisms in CYP2D6, CYP2C9, CYP2C19, CYP3A4 and CYP3A5 were analyzed using the TaqMan® SNP genotyping assay. Results: The CYP3A4*18 heterozygous genotype was associated with ATDH (OR: 3.24, 95% CI: 1.06-9.86) regardless of PLD presence. Among subjects without PLD, CYP3A4*18 heterozygotes had significantly higher ATDH risk (OR: 9.10, 95% CI: 1.56-53.16). Conversely, in the PLD group, CYP3A4*18 heterozygotes had lower ATDH risk (OR: 0.21, 95% CI: 0.05-0.98). Conclusion: CYP3A4*18 genotype is linked to ATDH in tuberculosis patients, with differential effects based on PLD presence.

PMID:38884784 | DOI:10.1080/14622416.2024.2346069

Pol Arch Intern Med. 2024 Jun 10:16772. doi: 10.20452/pamw.16772. Online ahead of print.

ABSTRACT

Laboratory tests play a central role in medicine, as they help to make diagnoses, assess prognosis, risk of disease, and monitor therapies, thus contributing to 70% of all medical decisions. This cross-sectional function offers great potential for technological and organizational innovation to influence healthcare as a whole. In recent years, a variety of technologies have emerged and entered the field of medical research, or even medical care. A new generation of biosensors allows the determination of laboratory tests at the point-of-care and enables faster medical decisions. Recent devices allow for patient-centric blood sampling, which eliminates the need for painful blood draws, patient traveling, and the workload of healthcare professionals. Analytical techniques such as metabolomics, lipidomics or proteomics can identify biomarkers extremely sensitively, even down to individual cells. Pharmacogenomics allows the determination of genetic polymorphisms that predict the response to chemotherapeutic agents. Machine-learning approaches can handle large amounts of multi-layered data for diagnostic applications. However, this enormous diagnostic potential is far from being utilized and only very few applications have been implemented in clinical practice. Why is this the case? In this article, we describe the key technology fields, discuss their medical potential and obstacles to their implementation. In addition, we present a methodological framework to support researchers, clinicians and authorities in the development and implementation of novel diagnostic approaches.

PMID:38884596 | DOI:10.20452/pamw.16772

Arerugi. 2024;73(4):307-312. doi: 10.15036/arerugi.73.307.

NO ABSTRACT

PMID:38880628 | DOI:10.15036/arerugi.73.307

Clin Epigenetics. 2024 Jun 15;16(1):79. doi: 10.1186/s13148-024-01687-x.

ABSTRACT

BACKGROUND: As new treatment options for patients with higher-risk myelodysplastic syndromes are emerging, identification of prognostic markers for hypomethylating agent (HMA) treatment and understanding mechanisms of their delayed and short-term responses are essential. Early fetal hemoglobin (HbF) induction has been suggested as a prognostic indicator for decitabine-treated patients. Although epigenetic mechanisms are assumed, responding patients' epigenomes have not been thoroughly examined. We aimed to clarify HbF kinetics and prognostic value for azacytidine treated patients, as well as the epigenetic landscape that might influence HbF re-expression and its clinical relevance.

RESULTS: Serial HbF measurements by high-performance liquid chromatography (n = 20) showed induction of HbF only among responders (p = 0.030). Moreover, HbF increase immediately after the first azacytidine cycle demonstrated prognostic value for progression-free survival (PFS) (p = 0.032, HR = 0.19, CI 0.24-1.63). Changes in methylation patterns were revealed with methylated DNA genome-wide sequencing analysis (n = 7) for FOG-1, RCOR-1, ZBTB7A and genes of the NuRD-complex components. Targeted pyrosequencing methodology (n = 28) revealed a strong inverse correlation between the degree of γ-globin gene (HBG2) promoter methylation and baseline HbF levels (p = 0.003, rs = - 0.663). A potential epigenetic mechanism of HbF re-expression in azacytidine responders was enlightened by targeted methylation analysis, through hypomethylation of site -53 of HBG2 promoter (p = 0.039, rs = - 0.504), which corresponds to MBD2-NuRD binding site, and to hypermethylation of the CpG326 island of ZBTB7A (p = 0.05, rs = 0.482), a known HbF repressor. These changes were associated to blast cell clearance (pHBG2 = 0.011, rs = 0.480/pZBTB7A = 0.026, rs = 0.427) and showed prognostic value for PFS (pZBTB7A = 0.037, HR = 1.14, CI 0.34-3.8).

CONCLUSIONS: Early HbF induction is featured as an accessible prognostic indicator for HMA treatment and the proposed potential epigenetic mechanism of HbF re-expression in azacytidine responders includes hypomethylation of the γ-globin gene promoter region and hypermethylation of the CpG326 island of ZBTB7A. The association of these methylation patterns with blast clearance and their prognostic value for PFS paves the way to discuss in-depth azacytidine epigenetic mechanism of action.

PMID:38879530 | DOI:10.1186/s13148-024-01687-x

Eur J Pharm Sci. 2024 Jun 13:106830. doi: 10.1016/j.ejps.2024.106830. Online ahead of print.

ABSTRACT

Dual antiplatelet therapy with aspirin and clopidogrel has reduced ischemic vascular events significantly. Genetics influence, especially those in clopidogrel pharmacokinetic-relevant genes partially accounts for interindividual pharmacodynamic variability of clopidogrel. However, most studies have concentrated on the genetic variations in introns, exons, or promoters of the candidate genes, and the association between genetic variations in 3'-UTR in clopidogrel pharmacokinetic-relevant genes and clopidogrel response is unknown. In our study, ten different algorithms were applied to pick potential miRNAs targeting the clopidogrel pharmacokinetic-relevant genes. Furthermore, the correlation between miRNA expression profiles and mRNA expression of corresponding clopidogrel pharmacokinetic-relevant genes were analyzed. Through comprehensive analysis, including bioinformatics prediction and correlation analysis of miRNA and mRNA expression profiles, miR-218-5p and miR-506-5p were supposed to regulate the expression of PON1 via binding with its 3'-UTR. Moreover, PON1 rs854551 and rs854552 were located in miRNA recognizing sequences and may serve as potential miRSNPs possibly affecting PON1 expression. The rs854552 polymorphism was genotyped and platelet reactivity index (PRI) indicative of clopidogrel response was measured in 341 Chinese coronary artery disease (CAD) patients 24h after administration of 300 mg clopidogrel. Our results showed that PON1 rs854552 had a significant influence on PRI in CAD patients, especially in patients with CYP2C19 extensive metabolic phenotype. In conclusion, PON1 rs854552 polymorphisms may affect clopidogrel response. Bioinformatics prediction followed by functional validation could aid in decoding the contribution of unexplained variations in the 3'-UTR in drug-metabolizing enzymes on clopidogrel response.

PMID:38878906 | DOI:10.1016/j.ejps.2024.106830

Eur J Surg Oncol. 2024 Jun 5;50(9):108468. doi: 10.1016/j.ejso.2024.108468. Online ahead of print.

ABSTRACT

BACKGROUND: Despite modern systemic chemotherapy, survival remains poor for patients with advanced isolated peritoneal metastases from the gastrointestinal tract. We aimed to assess the safety and efficacy of pressurized intraperitoneal aerosol chemotherapy (PIPAC) with oxaliplatin.

PATIENTS AND METHODS: We conducted a phase 1/2, open label, non-comparative, dose escalation and expansion trial of PIPAC with oxaliplatin in patients with a peritoneal cancer index (PCI) of more than 5, 13 and 15 for respectively a gastric, small bowel and colorectal primary cancer, and who had received at least three months of systemic chemotherapy. PIPAC cycle lengths were 4-6 weeks with systemic chemotherapy allowed 15 days after each PIPAC. PCI and oxaliplatin tumor concentration were assessed every PIPAC cycle. The main endpoints were tolerability, tumor response, and survival.

RESULTS: Between 2017 and 2020, 34 patients were enrolled in three centers, in this phase 1/2 study, of whom 25 were evaluable at the recommended dose determined in the phase I trial (90 mg/m2 plus systemic 5-FU). Before inclusion, patients received a median of 2 [1-4] chemotherapy lines and had a median PCI of 22.5 [7-29]. At this dose, the safety profile showed acceptable tolerability. Eight patients (32 %) had grade 3/4 treatment-related adverse events. Minor (grade 1/2) adverse events were mainly abdominal pain (n = 19, 76 %) and nausea (n = 16, 64 %). Median PFS was 6.1 months and median OS was 13 months.

CONCLUSION: In patients with advanced and refractory peritoneal metastasis, PFS of 6.1 months is encouraging. A prospective randomized phase II study is required.

PMID:38878757 | DOI:10.1016/j.ejso.2024.108468

J Exp Clin Cancer Res. 2024 Jun 14;43(1):166. doi: 10.1186/s13046-024-03087-8.

ABSTRACT

BACKGROUND: Breast cancer (BC) is a complex disease, showing heterogeneity in the genetic background, molecular subtype, and treatment algorithm. Historically, treatment strategies have been directed towards cancer cells, but these are not the unique components of the tumor bulk, where a key role is played by the tumor microenvironment (TME), whose better understanding could be crucial to obtain better outcomes.

METHODS: We evaluated mitochondrial transfer (MT) by co-culturing Adipose stem cells with different Breast cancer cells (BCCs), through MitoTracker assay, Mitoception, confocal and immunofluorescence analyses. MT inhibitors were used to confirm the MT by Tunneling Nano Tubes (TNTs). MT effect on multi-drug resistance (MDR) was assessed using Doxorubicin assay and ABC transporter evaluation. In addition, ATP production was measured by Oxygen Consumption rates (OCR) and Immunoblot analysis.

RESULTS: We found that MT occurs via Tunneling Nano Tubes (TNTs) and can be blocked by actin polymerization inhibitors. Furthermore, in hybrid co-cultures between ASCs and patient-derived organoids we found a massive MT. Breast Cancer cells (BCCs) with ASCs derived mitochondria (ADM) showed a reduced HIF-1α expression in hypoxic conditions, with an increased ATP production driving ABC transporters-mediated multi-drug resistance (MDR), linked to oxidative phosphorylation metabolism rewiring.

CONCLUSIONS: We provide a proof-of-concept of the occurrence of Mitochondrial Transfer (MT) from Adipose Stem Cells (ASCs) to BC models. Blocking MT from ASCs to BCCs could be a new effective therapeutic strategy for BC treatment.

PMID:38877575 | PMC:PMC11177397 | DOI:10.1186/s13046-024-03087-8

Therapie. 2024 Jun 5:S0040-5957(24)00068-4. doi: 10.1016/j.therap.2024.05.006. Online ahead of print.

ABSTRACT

The administration of aminoglycosides can induce nephrotoxicity or ototoxicity, which can be monitored through pharmacological therapeutic drug monitoring. However, there are cases of genetic predisposition to ototoxicity related to the MT-RNR1 gene, which may occur from the first administrations. Pharmacogenetic analysis recommendations have recently been proposed by the Clinical Pharmacogenetics Implementation Consortium (CPIC). The Francophone Pharmacogenetics Network (RNPGx) provides a bibliographic synthesis of this genetic predisposition, as well as professional recommendations. The MT-RNR1 gene codes for mitochondrial 12S rRNA, which constitutes the small subunit of the mitochondrial ribosome. Three variants can be identified: the variants m.1555A>G and m.1494C>T of the MT-RNR1 gene have a 'high' level of evidence regarding the risk of ototoxicity. The variant m.1095T>C has a 'moderate' level of evidence. The search for these variants can be performed in the laboratory if the administration of aminoglycosides can be delayed after obtaining the result. However, if the treatment is urgent, there is currently no rapid test available in France (a 'point-of-care' test is authorized in Great Britain). RNPGx considers: (1) the search for the m.1555A>G, m.1494C>T variants as 'highly recommended' and the m.1095T>C variant as 'moderately recommended' before the administration of an aminoglycoside (if compatible with the medical context). It should be noted that the level of heteroplasmy detected does not modify the recommendation; (2) pharmacogenetic analysis is currently not feasible in situations of short-term aminoglycoside administration, in the absence of an available analytical solution (rapid test to be evaluated in France); (3) the retrospective analysis in case of aminoglycoside-induced ototoxicity is 'recommended'; (4) analysis of relatives is 'recommended'. Through this summary, RNPGx proposes an updated review of the MT-RNR1-aminoglycoside gene-drug pair to serve as a basis for adapting practices regarding pharmacogenetic analysis related to aminoglycoside treatment.

PMID:38876950 | DOI:10.1016/j.therap.2024.05.006

Biomed Pharmacother. 2024 Jun 13;176:116882. doi: 10.1016/j.biopha.2024.116882. Online ahead of print.

ABSTRACT

BACKGROUND: Several opioids have pharmacogenetic and drug-drug interactions which may compromise their analgesic effectiveness, but are not routinely implemented into supportive pain management. We hypothesized that CYP2D6 phenotypes and concomitant use of CYP2D6 substrates or inhibitors would correlate with opioid analgesic outcomes.

MATERIALS AND METHODS: An observational cross-sectional study was conducted with 263 adult chronic non cancer pain (CNCP) patients from a real-world pain unit under long-term CYP2D6-related opioid treatment (tramadol, hydromorphone, tapentadol or oxycodone). Metabolizer phenotype (ultrarapid [UM], normal [NM], intermediate [IM] or poor [PM]) was determined by the CYP2D6 genotype. The socio-demographic (sex, age, employment status), clinical (pain intensity and relief, neuropathic component, quality of life, disability, anxiety and depression), pharmacological (opioid doses and concomitant pharmacotherapy) and safety (adverse events) variables were recorded.

RESULTS: The whole population (66 % female, 65 (14) years old, 70 % retired and 63 % attended for low back pain) were classified as PM (5 %), IM (32 %), NM (56 %) and UM (6 %). Multiple linear and logistic regressions showed higher pain intensity and neuropathic component at younger ages when using any CYP2D6 substrate (p = 0.022) or inhibitor (p = 0.030) drug, respectively, with poorer pain relief when CYP2D6 inhibitors (p=0.030) were present.

CONCLUSION: The concomitant use of CYP2D6 substrates or inhibitors during opioid therapy for CNCP may result in lack of analgesic effectiveness. This aspect could be relevant for pharmacological decision making during CNCP management.

PMID:38876046 | DOI:10.1016/j.biopha.2024.116882

Thromb Res. 2024 Jun 6;240:109060. doi: 10.1016/j.thromres.2024.109060. Online ahead of print.

ABSTRACT

Antiplatelet therapy, the gold standard of care for patients with acute coronary syndrome (ACS) undergoing percutaneous coronary intervention (PCI), is one of the therapeutic approaches most associated with the development of adverse drug reactions (ADRs). Although numerous studies have shown that pharmacological intervention based on a limited number of high-evidence variants (primarily CYP2C19*2 and *3) can reduce the incidence of major adverse cardiovascular events (MACEs), ADRs still occur at variable rates (10.1 % in our case) despite personalized therapy. This study aimed to identify novel genetic variants associated with the endpoint of MACEs 12 months after PCI by designing and analyzing a targeted gene panel. We sequenced 244 ACS-PCI-stent patients (109 with event and 135 without event) and 99 controls without structural cardiovascular disease and performed an association analysis to search for unexpected genetic variants. No single nucleotide polymorphisms reached genomic significance after correction, but three novel variants, including ABCA1 (rs2472434), KLB (rs17618244), and ZNF335 (rs3827066), may play a role in MACEs in ACS patients. These genetic variants are involved in regulating high-density lipoprotein levels and cholesterol deposition, and as they are regulatory variants, they may affect the expression of nearby lipid metabolism-related genes. Our findings suggest new targets (both at the gene and pathway levels) that may increase susceptibility to MACEs, but further research is needed to clarify the role and impact of the identified variants before these findings can be incorporated into the therapeutic decision-making process.

PMID:38875847 | DOI:10.1016/j.thromres.2024.109060

J Clin Psychiatry. 2024 Jun 10;85(2):23m15024. doi: 10.4088/JCP.23m15024.

ABSTRACT

Objective: The effectiveness of antidepressant treatment for mood disorders is often limited by either a poor response or the emergence of adverse effects. These complications often necessitate multiple drug trials. This clinical challenge intensifies during pregnancy, when medications must be selected to improve the likelihood of response and optimize reproductive outcomes. We determined the distribution of common pharmacogenetic variants, metabolizer phenotypes, past medication responses, and side effects in childbearing-aged individuals seeking treatment in a tertiary care perinatal mental health clinic.

Methods: Sixty treatment-seeking women (based on sex at birth) with DSM-5- defined bipolar disorder (n = 28) or major depressive disorder (n = 32) provided DNA samples and completed psychiatric diagnostic and severity assessments between April 2014 and December 2017. Samples were genotyped for single-nucleotide variants in drug metabolizing enzyme genes of commonly prescribed antidepressants (cytochrome P450 [CYP] 1A2, 2B6, 2C9, 2C19, 2D6, 3A4, and 3A5), and the frequency of normative metabolizer status was compared to reference populations data from Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines. The Antidepressant Treatment History Form was used to record historic medication trials and side effects.

Results: A significantly greater proportion of extensive metabolizers for CYP2B6 was observed in the study population when compared to CPIC population frequency databases in Caucasians (0.64 vs 0.43 [95% CI: 0.49-0.76]; P value = .006) and African Americans (0.71 vs 0.33 [95% CI: 0.29-0.96]; P value = .045). No significant association was found between metabolizer phenotype and the likelihood of a medication side effect.

Conclusion: Pharmacogenomic testing may have value for personalized prescribing in individuals capable of or considering pregnancy.

PMID:38874574 | DOI:10.4088/JCP.23m15024

J Am Heart Assoc. 2024 Jun 14:e033791. doi: 10.1161/JAHA.123.033791. Online ahead of print.

ABSTRACT

BACKGROUND: Cytochrome P450 2C19 (CYP2C19) intermediate and poor metabolizer patients exhibit diminished clopidogrel clinical effectiveness after percutaneous coronary intervention (PCI). However, outcome studies to date have lacked racial diversity. Thus, the impact of CYP2C19 genotype on cardiovascular outcomes in patients treated with clopidogrel who identify as Black or African American remains unclear.

METHODS AND RESULTS: Adults among 5 institutions who self-identified as Black or African American, underwent PCI and clinical CYP2C19 genotyping, and were treated with clopidogrel were included. Data were abstracted from health records. Major atherothrombotic (composite of death, myocardial infarction, ischemic stroke, stent thrombosis, or revascularization for unstable angina) and bleeding event rates within 1 year after PCI were compared across CYP2C19 metabolizer groups using multivariable Cox regression adjusted for potential confounders and baseline variables meeting a threshold of P<0.10. The population included 567 Black patients treated with clopidogrel (median age, 62 years; 46% women; 70% with an acute coronary syndrome indication for PCI). Major atherothrombotic events rates were significantly higher among clopidogrel-treated intermediate and poor metabolizers (24 of 125 [19.2%]) versus patients treated with clopidogrel without a no function allele (43 of 442 [9.7%]; 35.1 versus 15.9 events per 100 person-years; adjusted hazard ratio, 2.00 [95% CI, 1.20-3.33], P=0.008). Bleeding event rates were low overall (23 of 567 [4.1%]) and did not differ among the metabolizer groups.

CONCLUSIONS: Black patients with CYP2C19 intermediate and poor metabolizer phenotypes who are treated with clopidogrel exhibit increased risk of adverse cardiovascular outcomes after PCI in a real-world clinical setting. Bleeding outcomes should be interpreted cautiously. Prospective studies are needed to determine whether genotype-guided use of prasugrel or ticagrelor in intermediate and poor metabolizers improves outcomes in Black patients undergoing PCI.

PMID:38874073 | DOI:10.1161/JAHA.123.033791

Clin Chem. 2024 Jun 14:hvae076. doi: 10.1093/clinchem/hvae076. Online ahead of print.

ABSTRACT

BACKGROUND: The analysis of haplotypes of variants is important for pharmacogenomics analysis and noninvasive prenatal testing for monogenic diseases. However, there is a lack of robust methods for targeted haplotyping.

METHODS: We developed digital PCR haplotype sequencing (dHapSeq) for targeted haplotyping of variants, which is a method that compartmentalizes long DNA molecules into droplets. Within one droplet, 2 target regions are PCR amplified from one template molecule, and their amplicons are fused together. The fused products are then sequenced to determine the phase relationship of the single nucleotide polymorphism (SNP) alleles. The entire haplotype of 10s of SNPs can be deduced after the phase relationship of individual SNPs are determined in a pairwise manner. We applied dHapSeq to noninvasive prenatal testing in 4 families at risk for thalassemia and utilized it to detect NUDT15 diplotypes for predicting drug tolerance in pediatric acute lymphoblastic leukemia (72 cases and 506 controls).

RESULTS: For SNPs within 40 kb, phase relation can be determined with 100% accuracy. In 7 trio families, the haplotyping results for 97 SNPs spanning 185 kb determined by dHapSeq were concordant with the results deduced from the genotypes of both parents and the fetus. In 4 thalassemia families, a 19.3-kb Southeast Asian deletion was successfully phased with 97 downstream SNPs, enabling noninvasive determination of fetal inheritance using relative haplotype dosage analysis. In the NUDT15 analysis, the variant status and phase of the variants were successfully determined in all cases and controls.

CONCLUSIONS: The dHapSeq represents a robust and scalable haplotyping approach with numerous clinical and research applications.

PMID:38873917 | DOI:10.1093/clinchem/hvae076

Food Sci Nutr. 2024 Apr 26;12(6):3863-3871. doi: 10.1002/fsn3.4042. eCollection 2024 Jun.

ABSTRACT

Metabolic Syndrome (MetS) is a constellation of risk factors including abdominal obesity, high triglycerides, low HDL cholesterol (HDL-C), elevated blood pressure, and elevated fasting glucose. In Spain, according to WHO criteria, the MetS prevalence is shown to be 32% in men and 29% in women. The role of dietary habits is one of the main therapeutic strategies for the management of MetS but the most effective dietary pattern has not been established yet. This study aimed to analyze the effect of on body composition, serum lipids, and MetS components of a high-MUFA and high-fiber diet (HMFD). A case-control study was performed considering 40 cohabiting women. Participants were randomly assigned to HMFD group or high mono-unsaturated diet (HMD) group to receive one of the two proposed dietary interventions. All data (serum lipids, blood pressure, height, weight, body composition, and waist circumference) were collected fasting at baseline, 55, 98, and 132 days. The HMFD group showed higher decrease in waist circumference than in the HMD group. LDL-C dropped in both groups. Triglycerides in the HMFD group dropped during the intervention, but once the intervention was over, they returned to baseline values. The mean systolic blood pressure was lower in HMFD group. A HMFD from a weekly consumption of processed meat (Torrezno de Soria) deeply fried in extra virgin olive oil in combination with vegetables logged in a Mediterranean diet can improve MetS risk factors in healthy overweight women.

PMID:38873480 | PMC:PMC11167160 | DOI:10.1002/fsn3.4042

Saudi Pharm J. 2024 Jul;32(7):102105. doi: 10.1016/j.jsps.2024.102105. Epub 2024 May 16.

ABSTRACT

Hecogenin (HEC) is a steroidal saponin found in many plant species and serves as a precursor for steroidal drugs. The diuretic effects of HEC and its derivative, hecogenin acetate (HA), remain largely unexplored. The present study aimed to explore the potential diuretic effects of HEC and HA compared to furosemide (FUR) and spironolactone (SPIR). Additionally, the study aimed to explore the underlying mechanism particularly focusing on aldosterone synthase gene expression. Fifty-four Sprague-Dawley rats were allocated into nine groups (Group 1-9). Group 1 (control) received the vehicle, Groups 2 received FUR 10 mg/kg, Group 3, 4, and 5 were given HEC, while Groups 6, 7 and 8 received HA i.p at doses of 5, 10, and 25 mg/kg, respectively. Group 9 received SPIR i.p at the dose of 25 mg/kg. Urine volume, diuretic index and diuretic activity were monitored at 1, 2, 3, 4, 5, 6, and 24 h post-administration. Treatment was given daily for seven days. After that, rats were sacrificed and blood was collected for serum electrolytes determination. Adrenal glands were dissected out for gene expression studies. The results revealed that HEC and HA at the administered doses significantly and dose-dependently increased urine and electrolyte excretion. These results were primarily observed at 25 mg/kg of each compound. Gene expression studies demonstrated a dose-dependent reduction in aldosterone synthase gene expression, suggesting aldosterone synthesis inhibition as a potential mechanism for their diuretic activity. Notably, HA exhibited more pronounced diuretic effects surpassing those of HEC. This enhanced diuretic activity of HA can be attributed to its stronger impact on aldosterone synthase inhibition. These findings offer valuable insights into the diuretic effects of both HEC and HA along with their underlying molecular mechanisms.

PMID:38873334 | PMC:PMC11170188 | DOI:10.1016/j.jsps.2024.102105

World J Surg Oncol. 2024 Jun 13;22(1):156. doi: 10.1186/s12957-024-03435-0.

ABSTRACT

BACKGROUND: Non-small cell lung cancer (NSCLC) is a prevalent and heterogeneous disease with significant genomic variations between the early and advanced stages. The identification of key genes and pathways driving NSCLC tumor progression is critical for improving the diagnosis and treatment outcomes of this disease.

METHODS: In this study, we conducted single-cell transcriptome analysis on 93,406 cells from 22 NSCLC patients to characterize malignant NSCLC cancer cells. Utilizing cNMF, we classified these cells into distinct modules, thus identifying the diverse molecular profiles within NSCLC. Through pseudotime analysis, we delineated temporal gene expression changes during NSCLC evolution, thus demonstrating genes associated with disease progression. Using the XGBoost model, we assessed the significance of these genes in the pseudotime trajectory. Our findings were validated by using transcriptome sequencing data from The Cancer Genome Atlas (TCGA), supplemented via LASSO regression to refine the selection of characteristic genes. Subsequently, we established a risk score model based on these genes, thus providing a potential tool for cancer risk assessment and personalized treatment strategies.

RESULTS: We used cNMF to classify malignant NSCLC cells into three functional modules, including the metabolic reprogramming module, cell cycle module, and cell stemness module, which can be used for the functional classification of malignant tumor cells in NSCLC. These findings also indicate that metabolism, the cell cycle, and tumor stemness play important driving roles in the malignant evolution of NSCLC. We integrated cNMF and XGBoost to select marker genes that are indicative of both early and advanced NSCLC stages. The expression of genes such as CHCHD2, GAPDH, and CD24 was strongly correlated with the malignant evolution of NSCLC at the single-cell data level. These genes have been validated via histological data. The risk score model that we established (represented by eight genes) was ultimately validated with GEO data.

CONCLUSION: In summary, our study contributes to the identification of temporal heterogeneous biomarkers in NSCLC, thus offering insights into disease progression mechanisms and potential therapeutic targets. The developed workflow demonstrates promise for future applications in clinical practice.

PMID:38872167 | DOI:10.1186/s12957-024-03435-0

Therapie. 2024 Jun 3:S0040-5957(24)00067-2. doi: 10.1016/j.therap.2024.05.005. Online ahead of print.

ABSTRACT

BACKGROUND: Prescribing tramadol in children raises safety concerns. In Europe, tramadol is still approved and licensed for use in children over 1-3 years of age, depending on the country. In this context, the authors report a case of a tramadol overdose in a 5-year-old-child with a medical history of homozygous sickle cell disease.

METHODS: Tramadol and M1 were quantified using liquid chromatography with a diode array detection method. CYP2D6 genotype was determined using a next generation sequencing platform (MISeq, Illumina).

RESULTS: Tramadol and M1 were quantified in blood respectively at 5.48 and 1.32μg/mL at admission, at 0.77 and 0.35μg/mL 12hours later, and at 0.32 and 0.18μg/mL 20hours later. The patient was predicted as a CYP2D6 normal metabolizer (*35/*29).

CONCLUSION: One of the most important difficulties with the use of tramadol in children relates to its pharmacokinetic (PK) properties. Indeed, tramadol's PK is characterized by a great variability related to: (i) anatomical/physiological factors that impact the volume of distribution (Vd); (ii) CYP2D6 genetic polymorphisms. Considering such an issue is particularly relevant to prevent poisoning. In the reported case, the plasma elimination half-life was estimated at 6.3h, significantly more than those reported in 2-8 year-old children (about 3h). This discrepancy does not seem related to genetic polymorphisms but rather to the Vd. Indeed, the patient was predicted to be a CYP2D6 normal metabolizer (*35/*29). The case presented here highlights the risk associated with the tramadol use in children and emphasizes the importance of considering PK variability among this population. Such variability necessitates greater caution in prescribing tramadol in children and highlights the importance of therapeutic education for families of children treated with this painkiller.

PMID:38871543 | DOI:10.1016/j.therap.2024.05.005

Expert Rev Endocrinol Metab. 2024 Jun 13:1-16. doi: 10.1080/17446651.2024.2365785. Online ahead of print.

ABSTRACT

INTRODUCTION: Obesity is a growing public health concern affecting both children and adults. Since it involves both genetic and environmental components, the management of obesity requires both, an understanding of the underlying genetics and changes in lifestyle. The knowledge of obesity genetics will enable the possibility of precision medicine in anti-obesity medications.

AREAS COVERED: Here, we explore health complications and the prevalence of obesity. We discuss disruptions in energy balance as a symptom of obesity, examining evolutionary theories, its multi-factorial origins, and heritability. Additionally, we discuss monogenic and polygenic obesity, the converging biological pathways, potential pharmacogenomics applications, and existing anti-obesity medications - specifically focussing on the leptin-melanocortin and incretin pathways. Comparisons between childhood and adult obesity genetics are made, along with insights into structural variants, epigenetic changes, and environmental influences on epigenetic signatures.

EXPERT OPINION: With recent advancements in anti-obesity drugs, genetic studies pinpoint new targets and allow for repurposing existing drugs. This creates opportunities for genotype-informed treatment options. Also, lifestyle interventions can help in the prevention and treatment of obesity by altering the epigenetic signatures. The comparison of genetic architecture in adults and children revealed a significant overlap. However, more robust studies with diverse ethnic representation is required in childhood obesity.

PMID:38869356 | DOI:10.1080/17446651.2024.2365785

J Pharm Policy Pract. 2024 Jun 10;17(1):2354879. doi: 10.1080/20523211.2024.2354879. eCollection 2024.

ABSTRACT

BACKGROUND: Pharmacogenomics, a key component of precision medicine, aims to improve healthcare outcomes. As pharmacists play a pivotal role in this evolving field, an assessment of their preparedness to apply pharmacogenomics is imperative.

METHODS: In this cross-sectional study, a validated questionnaire (Content Validity Ratio > 0.741, p < 0.05) that demonstrated reliability (Cronbach's alpha for all scales > 0.7) gathered data on demographics, knowledge, attitudes, barriers, and confidence in pharmacogenomics among pharmacists and pharmacy students in Jordan. Statistical analysis assessed associations and their strength within the collected data and variables.

RESULTS: This study included 514 pharmacists and pharmacy students. Knowledge scores were moderate and correlated with academic level and pharmacy school attended. Most participants were open to providing pharmacogenomics testing and interpretation through pharmacy services, but the majority demonstrated concerns about potential misinterpretation of test results and the resulting patients' anxiety. Students cited limited accessibility, while pharmacists identified the lack of standardised guidelines as the main roadblock.

CONCLUSION: This study highlights the need for education to prepare pharmacists for their role in pharmacogenomics. Despite positive attitudes from pharmacists, addressing knowledge gaps, the low confidence in recommending pharmacogenomics tests, and concerns about implementation are essential.

PMID:38868176 | PMC:PMC11168213 | DOI:10.1080/20523211.2024.2354879