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Journal of Affective Disorders Jun 2024Disrupted cellular communication, inflammatory responses and mitochondrial dysfunction are consistently observed in late-life depression (LLD). Exosomes (EXs) mediate...
BACKGROUND
Disrupted cellular communication, inflammatory responses and mitochondrial dysfunction are consistently observed in late-life depression (LLD). Exosomes (EXs) mediate cellular communication by transporting molecules, including mitochondrial DNA (EX-mtDNA), playing critical role in immunoregulation alongside tumor necrosis factor (TNF). Changes in EX-mtDNA are indicators of impaired mitochondrial function and might increase vulnerability to adverse health outcomes. Our study examined EX-mtDNA levels and integrity, exploring their associations with levels of TNF receptors I and II (TNFRI and TNFRII), and clinical outcomes in LLD.
METHODS
Ninety older adults (50 LLD and 40 controls (HC)) participated in the study. Blood was collected and exosomes were isolated using size-exclusion chromatography. DNA was extracted and EX-mtDNA levels and deletion were assessed using qPCR. Plasma TNFRI and TNFRII levels were quantified by multiplex immunoassay. Correlation analysis explored relationships between EX-mtDNA, clinical outcomes, and inflammatory markers.
RESULTS
Although no differences were observed in EX-mtDNA levels between groups, elevated levels correlated with poorer cognitive performance (r = -0.328, p = 0.002) and increased TNFRII levels (r = 0.367, p = 0.004). LLD exhibited higher deletion rates (F = 4.402, p = 0.039), with a trend remaining after adjusting for covariates (p = 0.084). Deletion correlated with poorer cognitive performance (r = -0.335, p = 0.002). No other associations were found.
LIMITATION
Cross-sectional study with a small number of participants from a specialized geriatric psychiatry treatment center.
CONCLUSION
Our findings suggest that EX-mtDNA holds promise as an indicator of cognitive outcomes in LLD. Additional research is needed to further comprehend the role of EX-mtDNA levels/integrity in LLD, paving the way for its clinical application in the future.
PubMed: 38945405
DOI: 10.1016/j.jad.2024.06.092 -
Genetics in Medicine : Official Journal... Jun 2024Elective genomic testing (EGT) is increasingly available clinically. Limited real world evidence exists about attitudes and knowledge of EGT recipients.
BACKGROUND
Elective genomic testing (EGT) is increasingly available clinically. Limited real world evidence exists about attitudes and knowledge of EGT recipients.
METHODS
After web-based education, patients who enrolled in an EGT program at a rural nonprofit healthcare system completed a survey that assessed attitudes, knowledge, and risk perceptions.
RESULTS
From August 2020 to April 2022, 5,920 patients completed the survey and received testing. Patients most frequently cited interest in learning their personal disease risks as their primary motivation. Patients most often expected results to guide medication management (74.0%), prevent future disease (70.4%), and provide information about risks to offspring (65.4%). Patients were "very concerned" most frequently about the privacy of genetic information (19.8%) and how well testing predicted disease risks (18.0%). On average, patients answered 6.7 of 11 knowledge items correctly (61.3%). They more often rated their risks for colon and breast cancers as lower rather than higher than the average person, but more often rated their risk for a heart attack as higher rather than lower than the average person (all p<0.001).
CONCLUSION
Patients pursued EGT because of the utility expectations, but often misunderstood the test's capabilities.
PubMed: 38943480
DOI: 10.1016/j.gim.2024.101200 -
Drug Metabolism and Personalized Therapy Jul 2024Apixaban, a direct oral anticoagulant, is increasingly used worldwide for the treatment and prevention of venous thromboembolism and ischemic stroke in patients with...
OBJECTIVES
Apixaban, a direct oral anticoagulant, is increasingly used worldwide for the treatment and prevention of venous thromboembolism and ischemic stroke in patients with nonvalvular atrial fibrillation (AF). Obviously, one of the ways to enhance effectiveness and safety of drug therapy is a personalized approach to therapy, which involves pharmacogenetic and pharmacokinetic tests. The study aims to investigate the effect of , and polymorphisms on the pharmacokinetics of apixaban and the risk of bleeding.
METHODS
A total of 84 patients were enrolled in this prospective observational study. All patients received apixaban 5 or 2.5 mg twice daily. Real-time polymerase chain reaction was used to evaluate single-nucleotide polymorphisms of the gene (rs1045642 and rs4148738), (rs35599367) C>T, (rs776746) A>G. A plasma trough concentration/dose (C/D) ratio was used as a pharmacokinetic index.
RESULTS
The C/D ratio was higher in patients aged >80 years (F(1)=11.209, p=0.00124) and was affected by serum creatinine (>133 μmol/L, F(1)=6.7, p=0.01124). (rs1045642 and rs4148738), () and (rs35599367) polymorphisms did not show a correlation with C/D ratio of apixaban. Multivariate logistic regression analyses showed that none of the clinical or genetic factors predicted the fact of bleeding.
CONCLUSIONS
We report no significant association between gene polymorphisms (rs1045642 and rs4148738), (rs35599367) C>T, (rs776746) A>G and bleeding events on apixaban treatment. Complementing the existing criteria with pharmacogenetic and pharmacokinetics information for the patients with AF will enable further individualization of apixaban.
PubMed: 38943286
DOI: 10.1515/dmpt-2024-0013 -
Clinical and Translational Science Jul 2024Electronic health records (EHRs) contain a vast array of phenotypic data on large numbers of individuals, often collected over decades. Due to the wealth of information,... (Review)
Review
Electronic health records (EHRs) contain a vast array of phenotypic data on large numbers of individuals, often collected over decades. Due to the wealth of information, EHR data have emerged as a powerful resource to make first discoveries and identify disparities in our healthcare system. While the number of EHR-based studies has exploded in recent years, most of these studies are directed at associations with disease rather than pharmacotherapeutic outcomes, such as drug response or adverse drug reactions. This is largely due to challenges specific to deriving drug-related phenotypes from the EHR. There is great potential for EHR-based discovery in clinical pharmacology research, and there is a critical need to address specific challenges related to accurate and reproducible derivation of drug-related phenotypes from the EHR. This review provides a detailed evaluation of challenges and considerations for deriving drug-related data from EHRs. We provide an examination of EHR-based computable phenotypes and discuss cutting-edge approaches to map medication information for clinical pharmacology research, including medication-based computable phenotypes and natural language processing. We also discuss additional considerations such as data structure, heterogeneity and missing data, rare phenotypes, and diversity within the EHR. By further understanding the complexities associated with conducting clinical pharmacology research using EHR-based data, investigators will be better equipped to design thoughtful studies with more reproducible results. Progress in utilizing EHRs for clinical pharmacology research should lead to significant advances in our ability to understand differential drug response and predict adverse drug reactions.
Topics: Electronic Health Records; Humans; Pharmacology, Clinical; Phenotype; Natural Language Processing; Biomedical Research; Drug-Related Side Effects and Adverse Reactions
PubMed: 38943244
DOI: 10.1111/cts.13871 -
Scientific Reports Jun 2024Preterm born (PTB) infants are at risk for injuries related to oxidative stress. We investigated the association between antioxidant and neurodevelopmental gene...
Preterm born (PTB) infants are at risk for injuries related to oxidative stress. We investigated the association between antioxidant and neurodevelopmental gene polymorphisms and oxidative stress parameters in PTB male young adults and their term-born counterparts at rest and during exercise. Healthy young PTB (N = 22) and full-term (N = 15) males underwent graded exercise tests in normobaric normoxic (FO = 0.21) and hypoxic (FO = 0.13) conditions. CAT rs1001179 was associated with decrease in nitrites in the whole group and in PTB individuals (P = 0.017 and P = 0.043, respectively). GPX1 rs1050450 was associated with decrease in ferric reducing antioxidant power in the whole group and in full-term individuals (P = 0.017 and P = 0.021, respectively). HIF1A rs11549465 was associated with decrease in nitrotyrosine and increase in malondialdehyde (P = 0.022 and P = 0.018, respectively). NOTCH4 rs367398 was associated with increase in advanced oxidation protein products and nitrites (P = 0.002 and P = 0.004, respectively) in hypoxia. In normoxia, NOTCH4 rs367398 was associated with increase in malondialdehyde in the whole group (P = 0.043). BDNF rs6265 was associated with decreased nitrites/nitrates in the whole group and in PTB individuals (P = 0.009 and P = 0.043, respectively). Polymorphisms in investigated genes and PTB might influence oxidative stress response after exercise in normoxic or hypoxic conditions far beyond the neonatal period in young male adults.
Topics: Humans; Oxidative Stress; Male; Hypoxia; Antioxidants; Polymorphism, Single Nucleotide; Young Adult; Infant, Newborn; Glutathione Peroxidase GPX1; Hypoxia-Inducible Factor 1, alpha Subunit; Catalase; Adult; Glutathione Peroxidase; Infant, Premature; Nitrites; Malondialdehyde; Tyrosine; Premature Birth
PubMed: 38942829
DOI: 10.1038/s41598-024-65647-4 -
JACC. Advances Sep 2023
PubMed: 38939475
DOI: 10.1016/j.jacadv.2023.100572 -
Toxicology Mechanisms and Methods Jun 2024Cyclosporine A (CsA) has shown efficacy against immunity-related diseases despite its toxicity in various organs, including the liver, emphasizing the need to elucidate...
Cyclosporine A (CsA) has shown efficacy against immunity-related diseases despite its toxicity in various organs, including the liver, emphasizing the need to elucidate its underlying hepatotoxicity mechanism. This study aimed to capture the alterations in genome-wide expression over time and the subsequent perturbations of corresponding pathways across species. Six data from humans, mice, and rats, including animal liver tissue, human liver microtissues, and two liver cell lines exposed to CsA toxic dose, were used. The microtissue exposed to CsA for 10 d was analyzed to obtain dynamically differentially expressed genes (DEGs). Single-time points data at 1, 3, 5, 7, and 28 d of different species were used to provide additional evidence. Using liver microtissue-based longitudinal design, DEGs that were consistently up- or down-regulated over time were captured, and the well-known mechanism involved in CsA toxicity was elucidated. Thirty DEGs that consistently changed in longitudinal data were also altered in 28-d rat in-house data with concordant expression. Some genes (e.g. , , ) showed good concordance with identified DEGs in 1-d and 7-d mouse data. Pathway analysis revealed up-regulations of protein processing, asparagine N-linked glycosylation, and cargo concentration in the endoplasmic reticulum. Furthermore, the down-regulations of pathways related to biological oxidations and metabolite and lipid metabolism were elucidated. These pathways were also enriched in single-time-point data and conserved across species, implying their biological significance and generalizability. Overall, the human organoids-based longitudinal design coupled with cross-species validation provides temporal molecular change tracking, aiding mechanistic elucidation and biologically relevant biomarker discovery.
PubMed: 38937256
DOI: 10.1080/15376516.2024.2371894 -
Journal of Cystic Fibrosis : Official... Jun 2024With advancements in CF drug development, people with cystic fibrosis (PwCF) now take a median of seven medications daily, increasing treatment complexity, risk of drug...
BACKGROUND
With advancements in CF drug development, people with cystic fibrosis (PwCF) now take a median of seven medications daily, increasing treatment complexity, risk of drug therapy problems (DTPs), and interference with treatment goals. Given that some of these DTPs can be prevented with preemptive pharmacogenetic testing, the overall goal of this study was to test the clinical utility of a multi-gene pharmacogenetics (PGx) panel in potentially reducing DTPs in PwCF.
METHODS
A population based retrospective study of patients with CF was conducted at the University of Utah Health Care System. The patients were genotyped for CYP450 enzymes using a pharmacogenomic assay, and their drug utilization information was obtained retrospectively. This pharmacogenomic information was combined with clinical guidelines to predict the number of actionable PGx interventions in this patient cohort.
RESULTS
A total of 52 patients were included in this study. In the patient sample, a minimum of one order of actionable PGx medication was observed in 75 % of the cases. Results revealed that 4.2 treatment modifications per 10 patients can be enabled with the help of a PGx intervention in this patient population. Additionally, our findings suggest that polymorphisms in CYP2D6 and CYP2C19 are most likely to be the primary contributors to DTP's within PwCF.
CONCLUSION
This study provides evidence that the PGx panel has the potential to help alleviate the clinical burden of DTPs in PwCF and can assist in informing pharmacotherapy recommendations. Future research should validate these findings and evaluate which subgroups of PwCF would most benefit from pharmacogenetic testing.
PubMed: 38937211
DOI: 10.1016/j.jcf.2024.06.006 -
In Vivo (Athens, Greece) 2024Acute myeloid leukemia (AML) is a myeloproliferative neoplasm marked by abnormal clonal expansion of hematopoietic progenitor cells, displaying karyotypic aberrations...
BACKGROUND/AIM
Acute myeloid leukemia (AML) is a myeloproliferative neoplasm marked by abnormal clonal expansion of hematopoietic progenitor cells, displaying karyotypic aberrations and genetic mutations as prognostic indicators. The World Health Organization (WHO) and the European LeukemiaNet guidelines categorize BCR::ABL1 p190+ AML as high risk. This study explored the identification of the increased incidence of BCR::ABL1 p190+ in our AML population.
PATIENTS AND METHODS
This study included 96 AML patients stratified according to WHO guidelines. Subsequently, patients were screened for genetic abnormalities, such as BCR::ABL1 p 190+, PML::RARA, RUNX1::RUNX1T1, and CBFB::MYH11 by quantitative reverse transcription polymerase chain reaction (RT-qPCR) analysis.
RESULTS
Among 96 AML patients, 36 displayed BCR::ABL1 p190+, overcoming the expected global incidence. Age variations (19 to 78 years) showed no significant laboratory differences between BCR::ABL1 p190+ and non-BCR::ABL p190+ cases. The overall survival analysis revealed no statistically significant differences among the patients (p=0.786).
CONCLUSION
The analyzed population presented a higher frequency of BCR::ABL1 p190+ detection in adult AML patients when compared to what is described in the worldwide literature. Therefore, more studies are needed to establish the reason why this incidence is higher and what the best treatment approach should be in these cases.
Topics: Humans; Adult; Leukemia, Myeloid, Acute; Middle Aged; Male; Female; Fusion Proteins, bcr-abl; Aged; Prognosis; Young Adult; Mutation
PubMed: 38936913
DOI: 10.21873/invivo.13659 -
JCO Precision Oncology Jun 2024Fluoropyrimidine-related toxicity and mortality risk increases significantly in patients carrying certain genetic variants with standard dosing. We implemented... (Observational Study)
Observational Study
Real-World Impact of an In-House Dihydropyrimidine Dehydrogenase () Genotype Test on Fluoropyrimidine Dosing, Toxicities, and Hospitalizations at a Multisite Cancer Center.
PURPOSE
Fluoropyrimidine-related toxicity and mortality risk increases significantly in patients carrying certain genetic variants with standard dosing. We implemented genotyping at a multisite cancer center and evaluated its impact on dosing, toxicity, and hospitalization.
METHODS
In this prospective observational study, patients receiving (reactive) or planning to receive (pretreatment) fluoropyrimidine-based chemotherapy were genotyped for five variants as standard practice per provider discretion. The primary end point was the proportion of variant carriers receiving fluoropyrimidine modifications. Secondary end points included mean relative dose intensity, fluoropyrimidine-related grade 3+ toxicities, and hospitalizations. Fisher's exact test compared toxicity and hospitalization rates between pretreatment carriers, reactive carriers, and wild-type patients. Univariable and multivariable logistic regression identified factors associated with toxicity and hospitalization risk. Kaplan-Meier methods estimated time to event of first grade 3+ toxicity and hospitalization.
RESULTS
Of the 757 patients who received genotyping (median age 63, 54% male, 74% White, 19% Black, 88% GI malignancy), 45 (5.9%) were heterozygous carriers. Fluoropyrimidine was modified in 93% of carriers who started treatment. In 442 patients with 3-month follow-up, 64%, 31%, and 30% of reactive carriers, pretreatment carriers, and wild-type patients had grade 3+ toxicity, respectively ( = .085); 64%, 25%, and 13% were hospitalized ( < .001). Reactive carriers had 10-fold higher odds of hospitalization compared with wild-type patients ( = .001), whereas no significant difference was noted between pretreatment carriers and wild-type patients. Time-to-event of toxicity and hospitalization were significantly different between genotype groups ( < .001), with reactive carriers having the earliest onset and highest incidence.
CONCLUSION
genotyping prompted fluoropyrimidine modifications in most carriers. Pretreatment testing reduced toxicities and hospitalizations compared with reactive testing, thus normalizing the risk to that of wild-type patients, and should be considered standard practice.
Topics: Humans; Male; Female; Dihydrouracil Dehydrogenase (NADP); Middle Aged; Hospitalization; Prospective Studies; Genotype; Aged; Fluorouracil; Neoplasms; Antimetabolites, Antineoplastic; Cancer Care Facilities; Adult
PubMed: 38935897
DOI: 10.1200/PO.23.00623