Brief Bioinform. 2024 Jan 22;25(2):bbae088. doi: 10.1093/bib/bbae088.

ABSTRACT

Pharmacogenomics aims to provide personalized therapy to patients based on their genetic variability. However, accurate prediction of cancer drug response (CDR) is challenging due to genetic heterogeneity. Since clinical data are limited, most studies predicting drug response use preclinical data to train models. However, such models might not be generalizable to external clinical data due to differences between the preclinical and clinical datasets. In this study, a Precision Medicine Prediction using an Adversarial Network for Cancer Drug Response (PANCDR) model is proposed. PANCDR consists of two sub-models, an adversarial model and a CDR prediction model. The adversarial model reduces the gap between the preclinical and clinical datasets, while the CDR prediction model extracts features and predicts responses. PANCDR was trained using both preclinical data and unlabeled clinical data. Subsequently, it was tested on external clinical data, including The Cancer Genome Atlas and brain tumor patients. PANCDR outperformed other machine learning models in predicting external test data. Our results demonstrate the robustness of PANCDR and its potential in precision medicine by recommending patient-specific drug candidates. The PANCDR codes and data are available at https://github.com/DMCB-GIST/PANCDR.

PMID:38487849 | DOI:10.1093/bib/bbae088

Acta Pharm Sin B. 2024 Mar;14(3):1241-1256. doi: 10.1016/j.apsb.2023.12.006. Epub 2023 Dec 16.

ABSTRACT

Sulfation is a crucial and prevalent conjugation reaction involved in cellular processes and mammalian physiology. 3'-Phosphoadenosine 5'-phosphosulfate (PAPS) synthase 2 (PAPSS2) is the primary enzyme to generate the universal sulfonate donor PAPS. The involvement of PAPSS2-mediated sulfation in adenomatous polyposis coli (APC) mutation-promoted colonic carcinogenesis has not been reported. Here, we showed that the expression of PAPSS2 was decreased in human colon tumors along with cancer stages, and the lower expression of PAPSS2 was correlated with poor prognosis in advanced colon cancer. Gut epithelial-specific heterozygous Apc deficient and Papss2-knockout (ApcΔgut-HetPapss2Δgut) mice were created, and the phenotypes were compared to the spontaneous intestinal tumorigenesis of ApcΔgut-Het mice. ApcΔgut-HetPapss2Δgut mice were more sensitive to gut tumorigenesis, which was mechanistically accounted for by the activation of Wnt/β-catenin signaling pathway due to the suppression of chondroitin sulfation and inhibition of the farnesoid X receptor (FXR)-transducin-like enhancer of split 3 (TLE3) gene regulatory axis. Chondroitin sulfate supplementation in ApcΔgut-HetPapss2Δgut mice alleviated intestinal tumorigenesis. In summary, we have uncovered the protective role of PAPSS2-mediated chondroitin sulfation and bile acids-FXR-TLE3 activation in the prevention of gut carcinogenesis via the antagonization of Wnt/β-catenin signaling. Chondroitin sulfate may be explored as a therapeutic agent for Papss2 deficiency-associated colonic carcinogenesis.

PMID:38487006 | PMC:PMC10935170 | DOI:10.1016/j.apsb.2023.12.006

Pharmacogenomics J. 2024 Mar 14;24(2):8. doi: 10.1038/s41397-024-00327-0.

ABSTRACT

BACKGROUND: Tibetan medicine Gaoyuan'an capsule (GYAC) is widely used to prevent pulmonary edema at high altitude, but the specific mechanism has not been explored. In this study, we analyzed the mechanism of GYAC in hypoxia tolerance, and provided a new idea for the prevention and treatment of altitude disease.

METHODS: The effective components and corresponding targets of GYAC were screened out by the Chinese herbal medicine network database, and the key targets of hypoxia tolerance were retrieved by Genecards, OMIM and PubMed database. Cytoscape 3.7.2 was used to construct GYAC ingredient-target-hypoxia tolerance-related target network. GO function annotation and KEGG enrichment analysis were performed to predict the pathways in which target genes may be involved, and molecular docking was used to verify the binding ability of the compound to target genes. In vitro, the above results were further verified by molecular experiment.

RESULTS: We found that GYAC can improve hypoxia tolerance by regulating various target genes, including IL6, IFNG, etc. The main regulatory pathways were HIF-1 signaling pathway. Molecular docking showed that the affinity between luteolin and target genes (IL6, IFNG) were better. In vitro, we observed that hypoxia can inhibit cell viability and promote apoptosis of H9C2 cell. And hypoxia can promote the expression of LDH. After the addition of luteolin, the decrease of cell viability, the increase of cell apoptosis, LDH release and the decrease of mitochondrial membrane potential were inhibited. Besides, inflammatory related factors (IL-6, IL-10, IL-2, IFNG and VEGFA) expression were also inhibited hypoxic cell models.

CONCLUSIONS: The results of network pharmacology and molecular docking showed that luteolin, a monomeric component of GYAC, played a role in hypoxia tolerance through a variety of target genes, such as IL6, IFNG. What's more, we have discovered that luteolin can reduce the inflammatory response in cardiac myocytes, thereby alleviating mitochondrial damage, and ultimately enhancing the hypoxia tolerance of H9C2 cardiomyocytes.

PMID:38485921 | DOI:10.1038/s41397-024-00327-0

Comput Biol Med. 2024 Mar 7;172:108253. doi: 10.1016/j.compbiomed.2024.108253. Online ahead of print.

ABSTRACT

BACKGROUND: The morphological attributes could serve as pivotal indicators precipitating early recurrence and dismal overall survival in hepatocellular carcinoma (HCC), and quantifying morphological features may better stratify the prognosis of HCC.

OBJECTIVE: To develop a radiomics approach based on 3D tumor morphology features for predicting the prognosis of HCC and identifying differentially expressed genes related to morphology to guide HCC treatment.

MATERIALS AND METHODS: Retrospective study of 357 HCC patients. Radiomic features were extracted from MRI tumor regions; 14 morphology-related features predicted early HCC recurrence and patient stratification via LASSO-Cox modeling. Overall survival (OS) and recurrence-free survival (RFS) were analyzed. RNA sequencing from the Cancer Imaging Archive (TCIA) examined drug sensitivity and stratified HCC using morphological immunity genes, validating recurrence and prognosis.

RESULTS: Patients were split into training (n = 225), test (n = 132), and 50 TCIA dataset cohorts. Two features (Maximum2DdiameterColumn, Sphericity) in Cox regression stratified patients into high/low-risk Morphological Radiological Score (Morph-RS) groups. Significant OS and RFS were seen across all sets. Differentially expressed genes focused on T cell receptor signaling; low-risk group had higher T cells (P = 0.039), B cells (P = 0.041), NK cells (P = 0.018). SN-38, GSK2126458 might treat high-risk morphology. Morphology-immune genes stratified HCC, showing significant RFS/OS differences.

CONCLUSION: Tumor Morph-RS effectively stratifies HCC patients' recurrence and prognosis. Limited immune infiltration seen in Morph-RS high-risk groups signifies the potential of employing tumor morphology as a potent visual biomarker for diagnosing and managing HCC.

PMID:38484698 | DOI:10.1016/j.compbiomed.2024.108253

Nurse Educ Today. 2024 Mar 7;137:106153. doi: 10.1016/j.nedt.2024.106153. Online ahead of print.

ABSTRACT

BACKGROUND: Pharmacogenomics is the bioscience investigating how genes affect medication responses. Nurses are instrumental in medication safety. Pharmacogenomics is slowly being integrated into healthcare, and knowledge and understanding of it is now pertinent to nursing practice.

PURPOSE: This paper aims to map the scholarly literature on pharmacogenomics in relation to nurses.

METHODS: A scoping review was conducted in four databases: CINAHL, Embase (Ovid), ProQuest Health and Medicine and PubMed using the search terms pharmacogenomic*, pharmacogenetic*, PGx*, and nurs*, resulting in 263 articles of which 77 articles met the inclusion criteria.

FINDINGS: Most articles (85 %, n = 65) were non-empirical and 12 presented empirical data (15 %, n = 12). The articles were USA-centric (81 %, n = 62) and represented a broad range of nursing specialties.

CONCLUSION: The majority of scholarly literature on nurses and pharmacogenomics is narrative reviews. Further empirical research is warranted to investigate nurses' current knowledge levels and potential involvement with pharmacogenomics in clinical practice.

PMID:38484442 | DOI:10.1016/j.nedt.2024.106153

Drug Saf. 2024 Mar 14. doi: 10.1007/s40264-024-01416-6. Online ahead of print.

ABSTRACT

Rare diseases have become an increasingly important public health priority due to their collective prevalence and often life-threatening nature. Incentive programs, such as the Orphan Drug Act have been introduced to increase the development of rare disease therapeutics. While the approval of these therapeutics requires supportive data from stringent pre-market studies, these data lack the ability to describe the causes of treatment response heterogeneity, leading to medications often being more harmful or less effective than predicted. If a Goal Line were to be used to describe the multifactorial continuum of phenotypic variations occurring in response to a medication, the 'Goal Posts', or the two defining points of this continuum, would be (1) Super-Response, or an extraordinary therapeutic effect; and (2) Serious Harm. Investigation of the pharmacogenomics behind these two extreme phenotypes can potentially lead to the development of new therapeutics, help inform rational use criteria in drug policy, and improve the understanding of underlying disease pathophysiology. In the context of rare diseases where cohort sizes are smaller than ideal, 'small data' and 'big data' approaches to data collection and analysis should be combined to produce the most robust results. This paper presents the importance of studying drug response in parallel to other research initiatives in rare diseases, as well as the need for international collaboration in the area of rare disease pharmacogenomics.

PMID:38483768 | DOI:10.1007/s40264-024-01416-6

Adv Sci (Weinh). 2024 Mar 14:e2307940. doi: 10.1002/advs.202307940. Online ahead of print.

ABSTRACT

PARP inhibitors (PARPi)-based synthetic lethal therapy demonstrates limited efficacy for most cancer types that are homologous recombination (HR) proficient. To potentiate the PARPi application, a nanocarrier based on 5-azacytidine (AZA)-conjugated polymer (PAZA) for the codelivery of AZA and a PARP inhibitor, BMN673 (BMN) is developed. AZA conjugation significantly decreased the nanoparticle (NP) size and increased BMN loading. Molecular dynamics simulation and experimental validations shed mechanistic insights into the self-assembly of effective NPs. The small PAZA NPs demonstrated higher efficiency of tumor targeting and penetration than larger NPs, which is mediated by a new mechanism of active targeting that involves the recruitment of fibronectin from serum proteins following systemic administration of PAZA NPs. Furthermore, it is found that PAZA carrier sensitize the HR-proficient nonsmall cell lung cancer (NSCLC) to BMN, a combination therapy that is more effective at a lower AZA/BMN dosage. To investigate the underlying mechanism, the tumor immune microenvironment and various gene expressions by RNAseq are explored. Moreover, the BMN/PAZA combination increased the immunogenicity and synergized with PD-1 antibody in improving the overall therapeutic effect in an orthotopic model of lung cancer (LLC).

PMID:38482976 | DOI:10.1002/advs.202307940

Clin Pharmacol Ther. 2024 Mar 14. doi: 10.1002/cpt.3254. Online ahead of print.

ABSTRACT

Inflammation decreases the activity of cytochrome P450 3A (CYP3A). Nucleotide-binding oligomerization domain (NOD)-like receptor family pyrin domain containing 3 (NLRP3) is responsible for regulating the inflammatory response, and its genetic polymorphisms have been linked to inflammatory diseases such as asthma. However, there have been few studies on the effect of NLRP3 on CYP3A activity. We aimed to investigate the association between polymorphisms in the NLRP3 gene and plasma 4β-hydroxycholesterol (4βOHC), an endogenous marker of CYP3A activity, in patients with asthma. In this observational study including 152 adult asthma patients, we analyzed 10 NLRP3 gene single-nucleotide polymorphisms (SNPs). Plasma 4βOHC levels were measured by liquid chromatography-tandem mass spectrometry (LC-MS/MS). The results showed that five SNPs were associated with significantly lower plasma 4βOHC concentrations. Among these SNPs, rs3806265, rs4612666, rs1539019, and rs10733112 contributed to a significant increase in plasma IL-6 concentrations. Moreover, a multivariate regression model showed that the rs3806265 TT, rs4612666 CC, rs1539019 AA, and rs10733112 TT genotypes were significant factors for decreased plasma 4βOHC, even after including patient background factors and CYP3A5*3 (rs776746) gene polymorphisms as covariates. These results were also observed when plasma 4βOHC concentrations were corrected for cholesterol levels. We conclude that NLRP3 gene polymorphisms are involved in increasing plasma IL-6 concentrations and decreasing plasma 4βOHC concentrations in patients with asthma. Therefore, NLRP3 gene polymorphisms may be a predictive marker of CYP3A activity in inflammatory diseases such as asthma.

PMID:38482940 | DOI:10.1002/cpt.3254

Curr Drug Metab. 2024 Mar 12. doi: 10.2174/0113892002289753240305062601. Online ahead of print.

ABSTRACT

BACKGROUND: The use of herbal medicines is on the rise throughout the world due to their perceived safety profile. However, incidences of herb-drug, herb-herb and herb-food interactions considering safety aspects have opened new arenas for discussion.

OBJECTIVE: The current study aims to provide comprehensive insights into the various types of herb interactions, the mechanisms involved, their assessment, and historical developments, keeping herbal safety at the central point of discussion.

METHODS: The authors undertook a focused/targeted literature review and collected data from various databases, including Science Direct, Wiley Online Library, Springer, PubMed, and Google Scholar. Conventional literature on herbal remedies, such as those by the WHO and other international or national organizations.

RESULTS: The article considered reviewing the regulations, interaction mechanisms, and detection of herb-herb, herb-drug and herb-food interactions in commonly used yet vital plants, including Glycyrrhiza glabra, Mentha piperita, Aloe barbadensis, Zingiber officinale, Gingko biloba, Withania somnifera, etc. The study found that healthcare professionals worry about patients not informing them about their herbal prescriptions (primarily used with conventional treatment), which can cause herb-drug/herb-food/herb-herb interactions. These interactions were caused by altered pharmacodynamic and pharmacokinetic processes, which might be explained using in-vivo, in-vitro, in-silico, pharmacogenomics, and pharmacogenetics. Nutrivigilance may be the greatest method to monitor herb-food interactions, but its adoption is limited worldwide.

CONCLUSION: This article can serve as a lead for clinicians, guiding them regarding herb-drug, herb-food, and herb-herb interactions induced by commonly consumed plant species. Patients may also be counseled to avoid conventional drugs, botanicals, and foods with a restricted therapeutic window.

PMID:38482621 | DOI:10.2174/0113892002289753240305062601

Balkan J Med Genet. 2024 Mar 12;26(2):35-40. doi: 10.2478/bjmg-2023-0023. eCollection 2023 Dec.

ABSTRACT

Clopidogrel, is a standard treatment in the prevention of major adverse cardiovascular events (MACE) in patients with coronary artery disease (CAD). Clopidogrel response is highly variable, mainly due to the presence of polymorphisms in the genes involved in drug metabolism. The aim of this study was to evaluate the association between the presence of the ABCB1 C3435T and CYP2C19*2 polymorphism and the clinical outcome in patients with CAD treated with clopidogrel. A total of 96 patients with CAD were included in the study. Genomic DNA from peripheral blood was extracted from all patients with standard phenol/chloroform protocol. The genotyping was performed by Real-Time PCR using TagMan assays. The frequency of the reduced-function allele, in both genes, was higher in patients with negative outcome (36.36% vs 21.15%). A negative clinical outcome and an increased risk for MACE was observed in patients with concomitant inheritance of the CYP2C19 *1/*2 and ABCB1 CT genotype vs patients with other genotypes (22.73% vs 9.62%; OR 3.455; 95% CI= [0.936-12.743], p=0.05722. A trend towards higher risk of MACE was also noted in carriers of the CYP2C19*1/*1 and ABCB1 CC/CT genotype. Our results support the data on the association of the CYP2C19 *2 alone, or in combination with the ABCB1 C polymorphism with the increased risk of MACE. The results also indicate that the presence of ABCB1 C343T polymorphism might be potentially considered as independent predictor of MACE in patients on clopidogrel. However, these results are preliminary and should be confirmed on a larger number of patients.

PMID:38482263 | PMC:PMC10932604 | DOI:10.2478/bjmg-2023-0023

Cancer Gene Ther. 2024 Mar 13. doi: 10.1038/s41417-024-00760-0. Online ahead of print.

ABSTRACT

Esophageal squamous cell carcinoma (ESCC) is one of the most common human malignancies worldwide and is associated with high morbidity and mortality. Current treatment options are limited, highlighting the need for development of novel effective agents. Here, a high-throughput drug screening (HTS) was performed using ESCC cell lines in both two- and three-dimensional culture systems to screen compounds that have anti-ESCC activity. Our screen identified romidepsin, a histone deactylase inhibitor, as a potential anti-ESCC agent. Romidepsin treatment decreased cell viability, induced apoptosis and cell cycle arrest in ESCC cell lines, and these findings were confirmed in ESCC cell line-derived xenografted (CDX) mouse models. Mechanically, romidepsin induced transcriptional upregulation of DNA damage-inducible transcript 4 (DDIT4) gene by histone hyperacetylation at its promoter region, leading to the inhibition of mammalian target of rapamycin complex 1 (mTORC1) pathway. Furthermore, romidepsin exhibited better efficacy and safety compared to the conventional therapeutic drugs in ESCC patient-derived xenografted (PDX) mouse models. These data indicate that romidepsin may be a novel option for anti-ESCC therapy.

PMID:38480975 | DOI:10.1038/s41417-024-00760-0

J Thromb Thrombolysis. 2024 Mar 13. doi: 10.1007/s11239-024-02953-8. Online ahead of print.

ABSTRACT

Genotype based personalized antiplatelet therapy in the setting of percutaneous coronary intervention (PCI) has been studied in clinical trials. Despite the demonstrated risk associated with CYP2C19 loss-of-function (LoF) carriage in clopidogrel-treated PCI patients, real-world implementation of genotyping for PCI has been low. The goal of the current study was to provide CYP2C19 genotype information to the interventionalist prior to the completion of the catheterization to facilitate immediate personalized antiplatelet therapy. Routine personalization of P2Y12 inhibitor therapy for PCI in a community hospital cardiac catheterization laboratory by POC genotyping with the SpartanRx system was first offered in February 2017. A best practice advisory (BPA) based on the Clinical Pharmacogenetics Implementation Consortium Guideline for CYP2C19 genotype and clopidogrel therapy was placed in the electronic health record prescription medication ordering system. By December 2019, 1,052 patients had CYP2C19 genotype testing, 429 patients underwent PCI with genotype guided antiplatelet therapy, and 250 patients underwent PCI without genotype testing and received antiplatelet therapy at the discretion of the treating physician. BPA compliance was 93. 87% of LoF allele carriers were prescribed ticagrelor or prasugrel whereas 96% of non-LoF allele carriers were prescribed clopidogrel. The genotyping results were available within 1 h and made immediately available for decision making by the interventional cardiologist. POC CYP2C19 genotyping is feasible in a community hospital catheterization laboratory and is associated with high rate of best practice compliance.Clinical Trial Registration: https://clinicaltrials.gov/ct2/show/NCT03040622.

PMID:38480590 | DOI:10.1007/s11239-024-02953-8

Expert Opin Drug Metab Toxicol. 2024 Mar 13. doi: 10.1080/17425255.2024.2330666. Online ahead of print.

ABSTRACT

INTRODUCTION: Pharmacokinetic parameters assessment is a critical aspect of drug discovery and development, yet challenges persist due to limited training data. Despite advancements in machine learning and in-silico predictions, scarcity of data hampers accurate prediction of drug candidates' pharmacokinetic properties.

AREAS COVERED: The study highlights current developments in human pharmacokinetic prediction, talks about attempts to apply synthetic approaches for molecular design, and searches several databases, including Scopus, PubMed, Web of Science, and Google Scholar. The article stresses importance of rigorous analysis of machine learning model performance in assessing progress and explores molecular modeling (MM) techniques, descriptors, and mathematical approaches.Transitioning to clinical drug development, article highlights AI (Artificial Intelligence) based computer models optimizing trial design, patient selection, dosing strategies, and biomarker identification. In-silico models, including molecular interactomes and virtual patients, predict drug performance across diverse profiles, underlining the need to align model results with clinical studies for reliability. Specialized training for human specialists in navigating predictive models is deemed critical. Pharmacogenomics, integral to personalized medicine, utilizes predictive modeling to anticipate patient responses, contributing to more efficient healthcare system. Challenges in realizing potential of predictive modeling, including ethical considerations and data privacy concerns, are acknowledged.

EXPERT OPINION: AI models are crucial in drug development, optimizing trials, patient selection, dosing, and biomarker identification and hold promise for streamlining clinical investigations.

PMID:38480460 | DOI:10.1080/17425255.2024.2330666

Pediatr Neonatol. 2024 Mar 3:S1875-9572(24)00020-2. doi: 10.1016/j.pedneo.2024.02.003. Online ahead of print.

ABSTRACT

Glucose-6-phosphate dehydrogenase (G6PD) deficiency and variants of the UDP-glucuronosyltransferase 1A1 (UGT1A1) gene are the most common genetic causes of neonatal unconjugated hyperbilirubinemia (NUH). In this review, we searched PubMed for articles on the genetic causes of NUH published before December 31, 2022, and analyzed the data. On the basis of the results, we reached eight conclusions: (1) 37 mutations of the G6PD gene are associated with NUH; (2) the clinical manifestation of G6PD deficiency depends not only on ethnicity but also on the molecular mechanisms underlying the deficiency (and thus its severity); (3) of mutations in the UGT1A1 gene, homozygous c.-53A(TA)6TAA > A(TA)7TAA is the main cause of NUH in Caucasians and Africans, whereas homozygous c.211G > A is the main genetic cause of NUH in East Asians; (4) in Indonesian neonates, homozygous c.-3279T > G is the most common cause of NUH development, and neither c.-53 A(TA)6TAA > A(TA)7TAA nor c.211G > A causes it; (5) in breast-fed East Asian neonates, the TA7 repeat variant of the UGT1A1 gene protects against the development of NUH; (6) G6PD deficiency combined with homozygous c.211G > A variation of the UGT1A1 gene increases the risk of severe NUH; (7) in Pakistani and Caucasian patients with Crigler-Najjar syndrome type 2 (CN-2), point mutations of the UGT1A1 gene are widely distributed and frequently occur with variation at nucleotide -53, whereas in Asian patients with CN-2, compound homozygous variations in the coding region are frequently observed; and (8) records of G6PD deficiency and UGT1A1 variation status for a neonate offer useful pharmacogenomic information that can aid long-term care. These results indicate that timely diagnosis of NUH through molecular tests is crucial and that early initiation of treatment for the neonates and educational programs for their parents improves outcomes.

PMID:38480019 | DOI:10.1016/j.pedneo.2024.02.003

Ann Rheum Dis. 2024 Mar 13:ard-2023-224945. doi: 10.1136/ard-2023-224945. Online ahead of print.

ABSTRACT

OBJECTIVES: Osteoarthritis is a complex disease with a huge public health burden. Genome-wide association studies (GWAS) have identified hundreds of osteoarthritis-associated sequence variants, but the effector genes underpinning these signals remain largely elusive. Understanding chromosome organisation in three-dimensional (3D) space is essential for identifying long-range contacts between distant genomic features (e.g., between genes and regulatory elements), in a tissue-specific manner. Here, we generate the first whole genome chromosome conformation analysis (Hi-C) map of primary osteoarthritis chondrocytes and identify novel candidate effector genes for the disease.

METHODS: Primary chondrocytes collected from 8 patients with knee osteoarthritis underwent Hi-C analysis to link chromosomal structure to genomic sequence. The identified loops were then combined with osteoarthritis GWAS results and epigenomic data from primary knee osteoarthritis chondrocytes to identify variants involved in gene regulation via enhancer-promoter interactions.

RESULTS: We identified 345 genetic variants residing within chromatin loop anchors that are associated with 77 osteoarthritis GWAS signals. Ten of these variants reside directly in enhancer regions of 10 newly described active enhancer-promoter loops, identified with multiomics analysis of publicly available chromatin immunoprecipitation sequencing (ChIP-seq) and assay for transposase-accessible chromatin using sequencing (ATAC-seq) data from primary knee chondrocyte cells, pointing to two new candidate effector genes SPRY4 and PAPPA (pregnancy-associated plasma protein A) as well as further support for the gene SLC44A2 known to be involved in osteoarthritis. For example, PAPPA is directly associated with the turnover of insulin-like growth factor 1 (IGF-1) proteins, and IGF-1 is an important factor in the repair of damaged chondrocytes.

CONCLUSIONS: We have constructed the first Hi-C map of primary human chondrocytes and have made it available as a resource for the scientific community. By integrating 3D genomics with large-scale genetic association and epigenetic data, we identify novel candidate effector genes for osteoarthritis, which enhance our understanding of disease and can serve as putative high-value novel drug targets.

PMID:38479789 | DOI:10.1136/ard-2023-224945

Gynecol Oncol. 2024 Mar 12;183:9-14. doi: 10.1016/j.ygyno.2024.03.001. Online ahead of print.

ABSTRACT

OBJECTIVES: The aim of this prospective study was to compare perioperative opioid use in women by status of CYP2D6, a highly polymorphic pharmacogene relevant to opioid metabolism.

METHODS: Patients undergoing laparotomy were prospectively recruited and provided a preoperative saliva swab for a pharmacogenomic (PGx) gene panel. Postoperative opioid usage and pain scores were evaluated via chart review and a phone survey. Pharmacogenes known to be relevant to opioid metabolism were genotyped, and opioid metabolizing activity predicted by CYP2D6 genotyping. Patient and procedural factors were compared using Fisher's exact and Kruskal-Wallis tests.

RESULTS: The 96 enrolled patients were classified as ultra-rapid (N = 3, 3%), normal (58, 60%), intermediate (27, 28%), and poor (8, 8%) opioid metabolizers. There was no difference in surgical complexity across CYP2D6 categories (p = 0.61). Morphine Milligram Equivalents (MME) consumed during the first 24 h after peri-operative suite exit were significantly different between groups: ultrarapid metabolizers had the highest median MME (75, IQR 45-88) compared to the other three groups (normal metabolizers 23 [8-45], intermediate metabolizers 48 [20-63], poor metabolizers 31 [12-53], p = 0.03). Opioid requirements were clinically greater in ultrarapid metabolizers during the second 24 h and last 24 h but were statistically similar (p = 0.07). There was no difference in MME prescribed at discharge (p = 0.22) or patient satisfaction with pain control (p = 0.64) between groups.

CONCLUSIONS: A positive association existed between increased CYP2D6 activity and in-hospital opioid requirements, especially in the first 24 h after surgery. This provides important information to further individualize opioid prescriptions for patients undergoing laparotomy for gynecologic pathology.

PMID:38479169 | DOI:10.1016/j.ygyno.2024.03.001

PLoS One. 2024 Mar 13;19(3):e0296779. doi: 10.1371/journal.pone.0296779. eCollection 2024.

ABSTRACT

The mitotic spindle is the bipolar, microtubule-based structure that segregates chromosomes at each cell division. Aberrant spindles are frequently observed in cancer cells, but how oncogenic transformation affects spindle mechanics and function, particularly in the mechanical context of solid tumors, remains poorly understood. Here, we constitutively overexpress the oncogene cyclin D1 in human MCF10A cells to probe its effects on spindle architecture and response to compressive force. We find that cyclin D1 overexpression increases the incidence of spindles with extra poles, centrioles, and chromosomes. However, it also protects spindle poles from fracturing under compressive force, a deleterious outcome linked to multipolar cell divisions. Our findings suggest that cyclin D1 overexpression may adapt cells to increased compressive stress, possibly contributing to its prevalence in cancers such as breast cancer by allowing continued proliferation in mechanically challenging environments.

PMID:38478555 | DOI:10.1371/journal.pone.0296779

J Psychopharmacol. 2024 Mar 13:2698811241238284. doi: 10.1177/02698811241238284. Online ahead of print.

ABSTRACT

BACKGROUND: Converging lines of evidence indicate that ketamine is a rapid antidepressant for individuals with treatment-resistant depression. Hitherto, no reliable a priori predictors of ketamine response have been reported. Pharmacogenetic biomarkers have yielded mixed results regarding potential candidate genes associated with ketamine's biochemistry as reliable predictors of response.

AIMS: No studies have examined the effects of Val66Met and CYP2B6 genotypes on patients receiving repeated infusions of intravenous ketamine.

METHODS: In all, 85 participants with major depressive disorder who had previously received four infusions of intravenous ketamine were recruited to the foregoing study. Buccal swabs were collected and genotype variants across the Val66Met and CYP2B6 genes were analyzed. A repeated measures mixed linear model was used to assess change in depressive symptoms, suicidality, and anxiety, correcting for sex and age. Multiple regression was run to determine whether these genetic markers were associated with treatment efficacy for depressive severity, suicidal ideation, anxiolytic response, and degree of dissociation to intravenous ketamine.

RESULTS: Participants experienced significant overall reductions in depression, suicide, and anxiety. Overall, 25% met the response criteria and 15% met the remission criteria. However, Val66Met and CYP2B6 did not significantly predict changes in symptoms of depression, suicide, anxiety, or average dissociation.

CONCLUSIONS: This study contributes to the growing literature that ketamine efficacy is unlikely to be predicted by single genes, and a pleiotropic approach may likely be necessary for developing reliable predictors of clinical benefits.

PMID:38477185 | DOI:10.1177/02698811241238284

Adv Sci (Weinh). 2024 Mar 13:e2307921. doi: 10.1002/advs.202307921. Online ahead of print.

ABSTRACT

Additive manufacturing (AM) is widely recognized as a versatile tool for achieving complex geometries and customized functionalities in designed materials. However, the challenge lies in selecting an appropriate AM method that simultaneously realizes desired microstructures and macroscopic geometrical designs in a single sample. This study presents a direct ink writing method for 3D printing intricate, high-fidelity macroscopic cellulose aerogel forms. The resulting aerogels exhibit tunable anisotropic mechanical and thermal characteristics by incorporating fibers of different length scales into the hydrogel inks. The alignment of nanofibers significantly enhances mechanical strength and thermal resistance, leading to higher thermal conductivities in the longitudinal direction (65 mW m-1 K-1 ) compared to the transverse direction (24 mW m-1 K-1 ). Moreover, the rehydration of printed cellulose aerogels for biomedical applications preserves their high surface area (≈300 m2 g-1 ) while significantly improving mechanical properties in the transverse direction. These printed cellulose aerogels demonstrate excellent cellular viability (>90% for NIH/3T3 fibroblasts) and exhibit robust antibacterial activity through in situ-grown silver nanoparticles.

PMID:38477181 | DOI:10.1002/advs.202307921

Clin Transl Sci. 2024 Mar;17(3):e13761. doi: 10.1111/cts.13761.

ABSTRACT

Tamoxifen, a selective estrogen receptor modulator, is used to treat hormone receptor-positive breast cancer. Tamoxifen acts as a prodrug, with its primary therapeutic effect mediated by its principal metabolite, endoxifen. However, tamoxifen has complex pharmacokinetics involving several drug-metabolizing enzymes and transporters influencing its disposition. Genes encoding enzymes involved in tamoxifen disposition exhibit genetic polymorphisms which vary widely across world populations. This review highlights the lack of data on tamoxifen pharmacogenetics among African populations. Gaps in data are described in this study with the purpose that future research can address this dearth of research on the pharmacogenetics of tamoxifen among African breast cancer patients. Initiatives such as the African Pharmacogenomics Network (APN) are crucial in promoting comprehensive pharmacogenetics studies to pinpoint important variants in pharmacogenes that could be used to reduce toxicity and improve efficacy.

PMID:38476074 | DOI:10.1111/cts.13761