Bone Marrow Transplant. 2023 Dec 21. doi: 10.1038/s41409-023-02166-2. Online ahead of print.

NO ABSTRACT

PMID:38129515 | DOI:10.1038/s41409-023-02166-2

Leukemia. 2023 Dec 21. doi: 10.1038/s41375-023-02109-2. Online ahead of print.

ABSTRACT

Membrane transporters are important determinants of drug bioavailability. Their expression and activity affect the intracellular drug concentration in leukemic cells impacting response to therapy. Pharmacogenomics represents genetic markers that reflect allele arrangement of genes encoding drug transporters associated with treatment response. In previous work, we identified SNP rs460089 located in the promotor of SLC22A4 gene encoding imatinib transporter OCTN1 as influential on response of patients with chronic myeloid leukemia treated with imatinib. Patients with rs460089-GC pharmacogenotype had significantly superior response to first-line imatinib treatment compared to patients with rs460089-GG. This study investigated whether pharmacogenotypes of rs460089 are associated with sustainability of treatment-free remission (TFR) in patients from the EUROpean Stop Kinase Inhibitor (EURO-SKI) trial. In the learning sample, 176 patients showed a significantly higher 6-month probability of molecular relapse free survival (MRFS) in patients with GC genotype (73%, 95% CI: 60-82%) compared to patients with GG (51%, 95% CI: 41-61%). Also over time, patients with GC genotype had significantly higher MRFS probabilities compared with patients with GG (HR: 0.474, 95% CI: 0.280-0.802, p = 0.0054). Both results were validated with data on 93 patients from the Polish STOP imatinib study. In multiple regression models, in addition to the investigated genotype, duration of TKI therapy (EURO-SKI trial) and duration of deep molecular response (Polish study) were identified as independent prognostic factors. The SNP rs460089 was found as an independent predictor of TFR.

PMID:38129513 | DOI:10.1038/s41375-023-02109-2

Pharmacogenomics. 2023 Dec 21. doi: 10.2217/pgs-2023-0199. Online ahead of print.

ABSTRACT

We explore the relationship between epigenetic aging and drug metabolism. We review current evidence for changes in drug metabolism in normal aging, followed by a description of how epigenetic modifications associated with age can regulate the expression and functionality of genes. In particular, we focus on the role of epigenome-wide studies of human and mouse liver in understanding these age-related processes with respect to xenobiotic processing. We highlight genes encoding drug metabolizing enzymes and transporters revealed to be affected by epigenetic aging in these studies. We conclude that substantial evidence exists for epigenetic aging impacting drug metabolism and transport genes, but more work is needed. We further highlight the promise of pharmacoepigenetics applied to enhancing drug safety in older adults.

PMID:38126340 | DOI:10.2217/pgs-2023-0199

Pharmacogenomics. 2023 Dec 21. doi: 10.2217/pgs-2023-0207. Online ahead of print.

ABSTRACT

Aim: Associations between gene variants and opioid net effect are unclear. We conducted an exploratory pharmacogenetic analysis of 35 gene variants and opioid response in advanced cancer. Patients & methods: This multi-center prospective cohort study included clinical data, questionnaires (pain and adverse effects) and DNA (blood). Negative binomial regression and logistic regression were used. Results: Within 54 participants, eight statistically significant associations (p = 0.002-0.038) were observed between gene variants and opioid dose, pain scores or adverse effects, the majority being within the neuroimmune TLR4 pathway (IL1B [rs1143634], IL2 [rs2069762], IL6 [rs1800795], BDNF [rs6265]) and ARRB2 pathway (ARRB2 [rs3786047], DRD2 [rs6275]). Conclusion: Neuroimmune pathway genes may contribute to differences in opioid response in cancer and may be included in future similar studies.

PMID:38126330 | DOI:10.2217/pgs-2023-0207

Sci Rep. 2023 Dec 20;13(1):22759. doi: 10.1038/s41598-023-50211-3.

ABSTRACT

Treatment of anemia in patients with chronic kidney disease (CKD) with recombinant human erythropoietin (rHuEPO) can be disrupted by a severe complication, anti-rHuEPO-induced pure red cell aplasia (PRCA). Specific HLA genotypes may have played a role in the high incidence of PRCA in Thai patients (1.7/1,000 patient years vs. 0.03/10,000 patient years in Caucasians). We conducted a case-control study in 157 CKD patients with anti-rHuEPO-induced PRCA and 56 controls. The HLA typing was determined by sequencing using a highly accurate multiplex single-molecule, real-time, long-read sequencing platform. Four analytical models were deployed: Model 1 (additive: accounts for the number of alleles), Model 2 (dominant: accounts for only the presence or absence of alleles), Model 3 (adjusted additive with rHuEPO types) and Model 4 (adjusted dominant with rHuEPO types). HLA-B*46:01:01:01 and DRB1*09:01:02:01 were found to be independent risk markers for anti-rHuEPO-induced PRCA in all models [OR (95%CI), p-values for B*46:01:01:01: 4.58 (1.55-13.51), 0.006; 4.63 (1.56-13.75), 0.006; 5.72 (1.67-19.67), 0.006; and 5.81 (1.68-20.09), 0.005; for DRB1*09:01:02:01: 3.99 (1.28-12.49), 0.017, 4.50 (1.32-15.40), 0.016, 3.42 (1.09-10.74), 0.035, and 3.75 (1.08-13.07), 0.038, in Models 1-4, respectively. HLA-B*46:01:01:01 and DRB1*09:01:02:01 are susceptible alleles for anti-rHuEPO-induced PRCA. These findings support the role of HLA genotyping in helping to monitor patients receiving rHuEPO treatment.

PMID:38123661 | DOI:10.1038/s41598-023-50211-3

Ann Rheum Dis. 2023 Dec 20:ard-2023-224990. doi: 10.1136/ard-2023-224990. Online ahead of print.

ABSTRACT

INTRODUCTION: Paget's disease of bone (PDB) frequently presents at an advanced stage with irreversible skeletal damage. Clinical outcomes might be improved by earlier diagnosis and prophylactic treatment.

METHODS: We randomised 222 individuals at increased risk of PDB because of pathogenic SQSTM1 variants to receive 5 mg zoledronic acid (ZA) or placebo. The primary outcome was new bone lesions assessed by radionuclide bone scan. Secondary outcomes included change in existing lesions, biochemical markers of bone turnover and skeletal events related to PDB.

RESULTS: The median duration of follow-up was 84 months (range 0-127) and 180 participants (81%) completed the study. At baseline, 9 (8.1%) of the ZA group had PDB lesions vs 12 (10.8%) of the placebo group. Two of the placebo group developed new lesions versus none in the ZA group (OR 0.41, 95% CI 0.00 to 3.43, p=0.25). Eight of the placebo group had a poor outcome (lesions which were new, unchanged or progressing) compared with none of the ZA group (OR 0.08, 95% CI 0.00 to 0.42, p=0.003). At the study end, 1 participant in the ZA group had lesions compared with 11 in the placebo group. Biochemical markers of bone turnover were significantly reduced in the ZA group. One participant allocated to placebo required rescue therapy with ZA because of symptomatic disease. The number and severity of adverse events did not differ between groups.

CONCLUSIONS: Genetic testing for pathogenic SQSTM1 variants coupled with intervention with ZA is well tolerated and has favourable effects on the progression of early PDB.

TRIAL REGISTRATION NUMBER: ISRCTN11616770.

PMID:38123339 | DOI:10.1136/ard-2023-224990

Cancer Treat Rev. 2023 Dec 14;123:102672. doi: 10.1016/j.ctrv.2023.102672. Online ahead of print.

ABSTRACT

Antibody-drug conjugates (ADCs) represent a novel class of molecules composed of a recombinant monoclonal antibody targeted to a specific cell surface antigen, conjugated to a cytotoxic agent through a cleavable or non-cleavable synthetic linker. The rationale behind the development of ADCs is to overcome the limitations of conventional chemotherapy, such as the narrow therapeutic window and the emergence of resistance mechanisms. ADCs had already revolutionized the treatment algorithm of HER2-positive breast cancer. Currently, emergent non-HER2 targeted ADCs are gaining momentum, with special focus on triple-negative disease therapeutic landscape. Sacituzumab govitecan (SG) is an ADC consisting of a humanized monoclonal antibody hRS7 targeting trophoblast cell surface antigen 2 (Trop2), linked to the topoisomerase I inhibitor SN-38 by a hydrolysable linker. It currently stands as the only non-HER2 targeted ADC that already received approval for the treatment of unresectable locally advanced or metastatic triple negative breast cancer (TNBC) in patients who had received two or more prior systemic therapies, with at least one for advanced disease. The purpose of these review is to analyze the available evidence regarding ADCs in TNBC, alongside with providing an overview on the ongoing and future research horizons in this field.

PMID:38118302 | DOI:10.1016/j.ctrv.2023.102672

Genome Biol. 2023 Dec 18;24(1):291. doi: 10.1186/s13059-023-03138-x.

ABSTRACT

Spatial omics technologies can help identify spatially organized biological processes, but existing computational approaches often overlook structural dependencies in the data. Here, we introduce Smoother, a unified framework that integrates positional information into non-spatial models via modular priors and losses. In simulated and real datasets, Smoother enables accurate data imputation, cell-type deconvolution, and dimensionality reduction with remarkable efficiency. In colorectal cancer, Smoother-guided deconvolution reveals plasma cell and fibroblast subtype localizations linked to tumor microenvironment restructuring. Additionally, joint modeling of spatial and single-cell human prostate data with Smoother allows for spatial mapping of reference populations with significantly reduced ambiguity.

PMID:38110959 | PMC:PMC10726548 | DOI:10.1186/s13059-023-03138-x

Pharmacogenomics. 2023 Dec 19. doi: 10.2217/pgs-2023-0228. Online ahead of print.

NO ABSTRACT

PMID:38112072 | DOI:10.2217/pgs-2023-0228

Endocr Metab Immune Disord Drug Targets. 2023 Dec 18. doi: 10.2174/0118715303271934231211085226. Online ahead of print.

ABSTRACT

INTRODUCTION: Single Nucleotide Polymorphisms (SNPs) are used as drug susceptibility biomarkers in metabolic diseases. Alterations in the gene encoding triggers the enzyme flavin monooxygenase 3 (FMO3), involved in the Sulindac metabolization, which also is responsible for the inherited metabolic disorder. Trimethylaminuria (TMAu, OMIM: 602079). DPYD gene variants are associated with the enzyme dihydropyrimidine dehydrogenase deficiency (DPD; OMIM: 274270). This autosomal recessive metabolic disorder, ultimately leads to the inability to metabolize fluoropyrimidines, which causes severe toxicity in individuals treated with these drugs.

METHODS: Variants in genes responsible for the expression of enzymes that encode transporters or receptors involved in the metabolization pathways of certain drugs may condition the individuals response to certain drugs, compromising the therapeutic response and clinical prognosis. Thus the sequencing and identification of variants become relevant, not only gain knowledge on effects of these variants' on disease causality but also in terms of its side effects resulting from the coding enzymes responsible for drug metabolization.

RESULTS: It was found that patients with the c.472G>A (p.Glu158Lys) and c.923A>G (p.Glu308Gly) polymorphisms, in homozygosity, in FMO3 gene did not develop polyps, thus have a protective effect in the treatment of Familial Adenomatous Polyposis (PAF). However, in the case of the DPYD gene, c.1905+1G>A (IVS14+1G>A), c.1679T>G (p.Ile560Ser), c.2846A>T (p.Asp949Val) e c.1236G>A/HapB3 variants can be lethal in cancer patients indicated for fluoropyrimidine-based chemotherapy.

CONCLUSION: Knowledge on the drug mechanisms will affect the therapeutic response of patients treated with a given drug. Thus, pharmacogenetics is an essential tool in personalized medicine, since molecular studies allows the clinician to predict the probability of efficacy and toxicity of certain drugs, resulting higher efficiency in individualizing treatment and also improving the safety of the patient. From a personalized medicine perspective, the study of the characteristics of the drug and its metabolization site, the genes involved in the encoding of enzymes responsible for its metabolization will be of great interest.

PMID:38111112 | DOI:10.2174/0118715303271934231211085226

medRxiv. 2023 Dec 7:2023.12.05.23299140. doi: 10.1101/2023.12.05.23299140. Preprint.

ABSTRACT

Clopidogrel, an anti-platelet drug, used to prevent thrombosis after percutaneous coronary intervention. Clopidogrel resistance results in recurring ischemic episodes, with African Americans suffering disproportionately. The aim of this study was to identify biomarkers of clopidogrel resistance in African American patients. We conducted a genome-wide association study, including local ancestry adjustment, in 141 African Americans on clopidogrel to identify associations with high on-treatment platelet reactivity (HTPR). We validated genome-wide and suggestive hits in an independent cohort of African American clopidogrel patients (N = 823) from the Million Veteran's Program (MVP) along with in vitro functional follow up. We performed differential gene expression (DGE) analysis in whole blood with functional follow-up in MEG-01 cells. We identified rs7807369, within thrombospondin 7A (THSD7A), as significantly associated with increasing risk of HTPR (p = 4.56 × 10-9). Higher THSD7A expression was associated with HTPR in an independent gene expression cohort of clopidogrel treated patients (p = 0.004) and supported by increased gene expression on THSD7A in primary human endothelial cells carrying the risk haplotype. Two SNPs (rs1149515 and rs191786) were validated in the MVP cohort. DGE analysis identified an association with decreased LAIR1 expression to HTPR. LAIR1 knockdown in a MEG-01 cells resulted in increased expression of SYK and AKT1, suggesting an inhibitory role of LAIR1 in the Glycoprotein VI pathway. Notably, the CYP2C19 variants showed no association with clopidogrel response in the discovery or MVP cohorts. In summary, these finding suggest that other variants outside of CYP2C19 star alleles play an important role in clopidogrel response in African Americans.

PMID:38106031 | PMC:PMC10723512 | DOI:10.1101/2023.12.05.23299140

Front Pharmacol. 2023 Dec 1;14:1286494. doi: 10.3389/fphar.2023.1286494. eCollection 2023.

ABSTRACT

Hypertension remains a significant health burden worldwide, re-emphasizing the outstanding need for more effective and safer antihypertensive therapeutic approaches. Genetic variation contributes significantly to interindividual variability in treatment response and adverse events, suggesting pharmacogenomics as a major approach to optimize such therapy. This review examines the molecular mechanisms underlying antihypertensives-associated adverse events and surveys existing research on pharmacogenomic biomarkers associated with these events. The current literature revealed limited conclusive evidence supporting the use of genetic variants as reliable indicators of antihypertensive adverse events. However, several noteworthy associations have emerged, such as 1) the role of ACE variants in increasing the risk of multiple adverse events, 2) the bradykinin pathway's involvement in cough induced by ACE inhibitors, and 3) the impact of CYP2D6 variants on metoprolol-induced bradycardia. Nonetheless, challenges persist in identifying biomarkers for adverse events across different antihypertensive classes, sometimes due to the rarity of certain events, such as ACE inhibitors-induced angioedema. We also highlight the main limitations of previous studies that warrant attention, including using a targeted gene approach with a limited number of tested variants, small sample sizes, and design issues such as overlooking doses or the time between starting treatment and the onset of adverse events. Addressing these challenges requires collaborative efforts and the integration of technological advancements, such as next-generation sequencing, which can significantly enhance research outcomes and provide the needed evidence. Furthermore, the potential combination of genomic biomarker identification and machine learning is a promising approach for tailoring antihypertensive therapy to individual patients, thereby mitigating the risk of developing adverse events. In conclusion, a deeper understanding of the mechanisms and the pharmacogenomics of adverse events in antihypertensive therapy will likely pave the way for more personalized treatment strategies to improve patient outcomes.

PMID:38108069 | PMC:PMC10722273 | DOI:10.3389/fphar.2023.1286494

Saudi Dent J. 2023 Dec;35(8):929-938. doi: 10.1016/j.sdentj.2023.07.016. Epub 2023 Jul 23.

ABSTRACT

BACKGROUND: The growing interest in the possibilities of macrophages modulation with therapeutic purposes promotes new approaches for periodontitis treatment.

AIM: The aim of this randomized controlled open clinical study was to evaluate the early clinical and immunological effects of the long-course azithromycin as an adjunct to scaling and root planing in periodontitis.

METHODS: 50 patients (with stage I-III, grade A/B periodontitis) and 22 periodontally healthy volunteers as the reference group were recruited. Following scaling and root planing (SRP), the patients were randomly assigned to one of two treatment modalities: SRP only (n = 25) and adjunct azithromycin (Az) treatment (n = 25). The patients were monitored at baseline, and 30 ± 5 days after therapy. Clinical attachment loss (CAL), periodontal probing depth (PPD) and bleeding on probing (BoP) were evaluated. Secondary outcome measures included mean changes in single-positive CD68 + and CD163 + macrophages (Mφs) density and ratio, evaluated by immunohistochemistry, and IL1-β, IL-6, IL-10, TGF-β levels, detected by ELISA.

RESULTS: At 1 month both groups showed significant improvements of CAL, PPD and BoP, without significant added benefit in terms of CAL, PPD and BoP of Az. But Az increased the density of CD68 + and CD163 + Mφs (P < 0.0001), decreased the CD68+/CD163 + ratio (P = 0.043), decreased IL-1β (P < 0.01), IL-6 (P < 0.001) levels, and increased IL-10 (P < 0.0001) and TGF-β (P < 0.001) levels compared to SRP and periodontitis at baseline.

CONCLUSION: The long course of Az demonstrated modulation of CD68 + and CD163 + Mφs towards M2 polarization, which may play a significant role in achieving favorable long-term treatment outcomes. ClinicalTrials.gov.

PMID:38107046 | PMC:PMC10724361 | DOI:10.1016/j.sdentj.2023.07.016

Adv Lab Med. 2023 Oct 11;4(4):341-352. doi: 10.1515/almed-2023-0123. eCollection 2023 Dec.

ABSTRACT

BACKGROUND: Statins are one of the most prescribed medications in developed countries as the treatment of choice for reducing cholesterol and preventing cardiovascular diseases. However, a large proportion of patients experience adverse drug reactions, especially myotoxicity. Among the factors that influence the diversity of response, pharmacogenetics emerges as a relevant factor of influence in inter-individual differences in response to statins and can be useful in the prevention of adverse drug effects.

CONTENT: A systematic review was performed of current knowledge of the influence of pharmacogenetics on the occurrence and prevention of statin-associated adverse reactions and clinical benefits of preemptive pharmacogenetics testing.

SUMMARY: Genetic variants SLCO1B1 (rs4149056) for all statins; ABCG2 (rs2231142) for rosuvastatin; or CYP2C9 (rs1799853 and rs1057910) for fluvastatin are associated with an increase in muscle-related adverse effects and poor treatment adherence. Besides, various inhibitors of these transporters and biotransformation enzymes increase the systemic exposure of statins, thereby favoring the occurrence of adverse drug reactions.

OUTLOOK: The clinical preemptive testing of this pharmacogenetic panel would largely prevent the incidence of adverse drug reactions. Standardized methods should be used for the identification of adverse effects and the performance and interpretation of genotyping test results. Standardization would allow to obtain more conclusive results about the association between SLCO1B1, ABCG and CYP2C9 variants and the occurrence of adverse drug reactions. As a result, more personalized recommendations could be established for each statin.

PMID:38106499 | PMC:PMC10724874 | DOI:10.1515/almed-2023-0123

medRxiv. 2023 Dec 6:2023.12.05.23299547. doi: 10.1101/2023.12.05.23299547. Preprint.

ABSTRACT

BACKGROUND: After percutaneous coronary intervention (PCI), clopidogrel resistant patients are at an increased risk of major adverse cardiovascular and cerebrovascular events (MACCEs). We aimed to assess whether genotype-guided selection of oral antiplatelet drugs using a clinical decision support (CDS) algorithm reduces the occurrence of these ischemic events and improves outcomes among Caribbean Hispanic patients from Puerto Rico, who are underrepresented in clinical pharmacogenomic (PGx)-guided implementation studies.

METHODS: Individual platelet function testing (PRU) measures, CYP2C19 *2 and PON1 rs662 genotypes, clinical and demographic data from 8 medical facilities were included. Patients were separated into standard of care (SoC) and genotype-guided groups (150 each). Risk scores were calculated based on a previously developed CDS risk prediction algorithm designed to make actionable treatment recommendations for each patient. Alternative therapy with ticagrelor was recommended for patients with a high risk score ≥2. Statistical associations between patient time free of MACCEs and predictor variables (i.e., treatment groups, risk scores) were tested in this population using Kaplan-Meier survival analyses and Cox proportional-hazards regression models.

RESULTS: Median age of participants is 67 years; BMI: 27.8; 48% women; 14% smokers; 59% with type-2 diabetes mellitus (T2DM). Among patients with high-risk scores who were free from MACCE events 6 months after coronary stenting, genotype-driven guidance of antiplatelet therapy showed superiority over SoC in terms of reducing the incidence rate of atherothrombotic events.

CONCLUSIONS: The clinical utility of our PGx-driven CDS algorithm to reduce the incidence rate of MACCEs among post-PCI Caribbean Hispanic patients on clopidogrel was externally demonstrated.

CLINICAL TRIAL REGISTRATION UNIQUE IDENTIFIER: NCT03419325.

PMID:38106133 | PMC:PMC10723501 | DOI:10.1101/2023.12.05.23299547

bioRxiv. 2023 Dec 8:2023.12.07.570723. doi: 10.1101/2023.12.07.570723. Preprint.

ABSTRACT

Pharmacogenomics studies are attracting an increasing amount of interest from researchers in precision medicine. The advances in high-throughput experiments and multiplexed approaches allow the large-scale quantification of drug sensitivities in molecularly characterized cancer cell lines (CCLs), resulting in a number of open drug sensitivity datasets for drug biomarker discovery. However, a significant inconsistency in drug sensitivity values among these datasets has been noted. Such inconsistency indicates the presence of substantial noise, subsequently hindering downstream analyses. To address the noise in drug sensitivity data, we introduce a robust and scalable deep learning framework, Residual Thresholded Deep Matrix Factorization (RT-DMF). This method takes a single drug sensitivity data matrix as its sole input and outputs a corrected and imputed matrix. Deep Matrix Factorization (DMF) excels at uncovering subtle patterns, due to its minimal reliance on data structure assumptions. This attribute significantly boosts DMF's ability to identify complex hidden patterns among nuisance effects in the data, thereby facilitating the detection of signals that are therapeutically relevant. Furthermore, RT-DMF incorporates an iterative residual thresholding (RT) procedure, which plays a crucial role in retaining signals more likely to hold therapeutic importance. Validation using simulated datasets and real pharmacogenomics datasets demonstrates the effectiveness of our approach in correcting noise and imputing missing data in drug sensitivity datasets (open source package available at https://github.com/tomwhoooo/rtdmf ).

PMID:38106027 | PMC:PMC10723412 | DOI:10.1101/2023.12.07.570723

J Thromb Haemost. 2023 Dec 14:S1538-7836(23)00870-X. doi: 10.1016/j.jtha.2023.11.027. Online ahead of print.

ABSTRACT

BACKGROUND: Thrombolytic recombinant tissue-plasminogen activator (r-tPA) treatment is the only pharmacological intervention available in the ischemic stroke acute phase. This treatment is associated with an increased risk of intracerebral hemorrhages, known as hemorrhagic transformations (HT), which worsen patient's prognosis.

OBJECTIVES: To investigate the association between genetically-determined natural hemostatic factors' levels, with increased risk of HT after r-tPA treatment.

PATIENTS/METHODS: Using genome-wide association studies data on risk of HT after r-tPA treatment, and from seven hemostatic factors (VII, VIII, von-Willebrand factor [VWF], XI, fibrinogen, plasminogen activator inhibitor-1 [PAI-1], and tissue plasminogen activator [tPA]), we performed local and global genetic correlations estimation multi-trait analyses and colocalization, and two-sample Mendelian Randomization (MR) analyses between hemostatic factors and HT.

RESULTS: Local correlations identified a genomic region on chromosome 16 with shared covariance: fibrinogen-HT, p-value=2.45×10-11. Multi-trait analysis between fibrinogen-HT revealed 3 loci that simultaneously regulate circulating levels of fibrinogen and risk of HT: rs56026866 (PLXND1), p-value=8.80×10-10, rs1421067 (CHD9), p-value=1.81×10-14, and rs34780449, near ROBO1 gene, p-value=1.64×10-08. Multi-trait analysis between VWF-HT showed a novel common association regulating VWF and risk of HT after r-tPA at rs10942300 (ZNF366), p-value=1.81×10-14. MR analysis did not find significant causal associations, although a nominal association was observed for FXI-HT (inverse variance weighted estimate [SE], 0.07[-0.29-0.00]; OR 0.87[0.75-1.00], raw-p-value=0.05).

CONCLUSIONS: We identified 4 shared loci between hemostatic factors and HT after r-tPA treatment, suggesting common regulatory mechanisms between fibrinogen and VWF levels and HT. Further research to determine a possible mediating effect of fibrinogen on HT risk are needed.

PMID:38103737 | DOI:10.1016/j.jtha.2023.11.027

Neurobiol Learn Mem. 2023 Dec 14:107880. doi: 10.1016/j.nlm.2023.107880. Online ahead of print.

ABSTRACT

Environmental enrichment (EE) is a process of brain stimulation by modifying the surroundings, for example, by changing the sensory, social, or physical conditions. Rodents have been used in such experimental strategies through exposure to diverse physical, social, and exploration conditions. The present study conducted an extensive analysis of the existing literature surrounding the impact of EE on dementia rodent models. The review emphasised the two principal aspects that are very closely related to dementia: cognitive function (learning and memory) as well as psychological factors (anxiety-related behaviours such as phobias and unrealistic worries). Also highlighted were the mechanisms involved in the rodent models of dementia showing EE effects. Two search engines, PubMed and Science Direct, were used for data collection using the following keywords: environmental enrichment, dementia, rodent model, cognitive performance, and anxiety-related behaviour. Fifty-five articles were chosen depending on the criteria for inclusion and exclusion. The rodent models with dementia demonstrated improved learning and memory in the form of hampered inflammatory responses, enhanced neuronal plasticity, and sustained neuronal activity. EE housing also prevented memory impairment through the prevention of amyloid beta (Aβ) seeding formation, an early stage of Aβ plaque formation. The rodents subjected to EE were observed to present increased exploratory activity and exert less anxiety-related behaviour, compared to those in standard housing. However, some studies have proposed that EE intervention through exercise would be too mild to counteract the anxiety-related behaviour and risk assessment behaviour deficits in the Alzheimer's disease rodent model. Future studies should be conducted on old-aged rodents and the duration of EE exposure that would elicit the greatest benefits since the existing studies have been conducted on a range of ages and EE durations. In summary, EE had a considerable effect on dementia rodent models, with the most evident being improved cognitive function.

PMID:38103676 | DOI:10.1016/j.nlm.2023.107880

Best Pract Res Clin Obstet Gynaecol. 2023 Nov 25;92:102437. doi: 10.1016/j.bpobgyn.2023.102437. Online ahead of print.

ABSTRACT

Preeclampsia is a pregnancy-specific disorder, and it is a leading cause of maternal and perinatal morbidity and mortality. The application of pharmacogenetics to antihypertensive agents and dose selection in women with preeclampsia is still in its infancy. No current prescribing guidelines from the clinical pharmacogenetics implementation consortium (CPIC) exist for preeclampsia. Although more studies on pharmacogenomics are underway, there is some evidence for the pharmacogenomics of preeclampsia therapies, considering both the pharmacokinetic (PK) and pharmacodynamic (PD) properties of drugs used in preeclampsia. It has been revealed that the CYP2D6*10 variant is significantly higher in women with preeclampsia who are non-responsive to labetalol compared to those who are in the responsive group. Various genetic variants of PD targets, i.e., NOS3, MMP9, MMP2, TIMP1, TIMP3, VEGF, and NAMPT, have been investigated to assess the responsiveness of antihypertensive therapies in preeclampsia management, and they indicated that certain genetic variants of MMP9, TIMP1, and NAMPT are more frequently observed in those who are non-responsive to anti-hypertensive therapies compared to those who are responsive. Further, gene-gene interactions have revealed that NAMPT, TIMP1, and MMP2 genotypes are associated with an increased risk of preeclampsia, and they are more frequently observed in the non-responsive subgroup of women with preeclampsia. The current evidence is not rigorous enough for clinical implementation; however, an institutional or regional-based retrospective analysis of audited data may help close the knowledge gap during the transitional period from a traditional approach (a "one-size-fits-all" strategy) to the pharmacogenomics of preeclampsia therapies.

PMID:38103508 | DOI:10.1016/j.bpobgyn.2023.102437

J Clin Psychopharmacol. 2024 Jan-Feb 01;44(1):49-56. doi: 10.1097/JCP.0000000000001795. Epub 2023 Nov 12.

ABSTRACT

PURPOSE/BACKGROUND: Pharmacogenetics (PGx) studies the genetic factors underlying interindividual variability in drug response. Only a few countries around the world are already using PGx testing in psychiatric clinical practice, whereas others are still far from adopting it. The main barrier to the clinical adoption of PGx testing seems to be the limited knowledge among psychiatrists regarding the clinical relevance of specific genetic variants to personalize therapies and the accessibility of PGx data. This review aims at further highlighting the importance of PGx-driven clinical decision making for psychotropic medications and raising psychiatrists' awareness of the value of PGx testing in psychiatry.

METHODS/PROCEDURES: We summarize the genes for which substantial evidence exists about the clinical utility of integrating their PGx testing in psychiatry. Specifically, we systematically describe the functional role of clinically relevant allelic variants, their frequency across different ethnic groups, and how they contribute to classify patients in relation to their capability in metabolizing psychotropic drugs.

FINDINGS/RESULTS: Briefly, clinical guidelines recommend considering PGx testing of the cytochrome class 2 C9 (CYP2C9), C19 (CYP2C19), and D6 (CYP2D6) genes and the human leukocyte antigen (HLA)-A and -B genes for several psychotropic drugs.

IMPLICATIONS/CONCLUSIONS: Extensive studies have been carried out to provide a solid rationale for the inclusion of PGx testing in psychiatry. Comprehensive clinical guidelines are readily accessible to support health care providers in tailoring the prescription of psychotropic drugs based on patient's genotype information. This approach presents a tangible opportunity to significantly improve individual responses to psychiatric medications.

PMID:38100778 | DOI:10.1097/JCP.0000000000001795