Pharmacogenomics
Antidepressant-Associated Treatment Emergent Mania: A Meta-Analysis to Guide Risk Modeling Pharmacogenomic Targets of Potential Clinical Value
J Clin Psychopharmacol. 2023 Aug 16. doi: 10.1097/JCP.0000000000001747. Online ahead of print.
ABSTRACT
BACKGROUND: The purpose of this study was to review the association between the SLC6A4 5-HTTLPR polymorphism and antidepressant (AD)-associated treatment emergent mania (TEM) in bipolar disorder alongside starting a discussion on the merits of developing risk stratification models to guide when not to provide AD treatment for bipolar depression.
METHODS: Studies that examined the association between clinical and genetic risk factors, specifically monoaminergic transporter genetic variation, and TEM were identified. A meta-analysis was performed using the odds ratio to estimate the effect size under the Der-Simonian and Laird model.
RESULTS: Seven studies, referencing the SLC6A4 5-HTTLPR polymorphism and TEM (total N = 1578; TEM+ =594, TEM- = 984), of 142 identified articles were included. The time duration between the start of the AD to emergence of TEM ranged from 4 to 12 weeks. There was a nominally significant association between the s allele of the 5-HTTLPR polymorphism and TEM (odds ratio, 1.434; 95% confidence interval, 1.001-2.055; P = 0.0493; I2 = 52%). No studies have investigated norepinephrine or dopamine transporters.
CONCLUSION: Although the serotonin transporter genetic variation is commercially available in pharmacogenomic decision support tools, greater efforts, more broadly, should focus on complete genome-wide approaches to determine genetic variants that may contribute to TEM. Moreover, these data are exemplary to the merits of developing risk stratification models, which include both clinical and biological risk factors, to guide when not to use ADs in bipolar disorder. Future studies will need to validate new risk models that best inform the development of personalized medicine best practices treating bipolar depression.
PMID:37584607 | DOI:10.1097/JCP.0000000000001747
Correction: Cisplatin resistance can be curtailed by blunting Bnip3-mediated mitochondrial autophagy
Cell Death Dis. 2023 Aug 15;14(8):521. doi: 10.1038/s41419-023-05901-1.
NO ABSTRACT
PMID:37582906 | DOI:10.1038/s41419-023-05901-1
Identification of risk factors for adverse drug reactions in a pharmacovigilance database
Pharmacoepidemiol Drug Saf. 2023 Aug 14. doi: 10.1002/pds.5679. Online ahead of print.
ABSTRACT
INTRODUCTION: In addition to identifying new safety signals, pharmacovigilance databases could be used to identify potential risk factors for adverse drug reactions (ADRs).
OBJECTIVE: To evaluate whether data mining in a pharmacovigilance database can be used to identify known and possible novel risk factors for ADRs, for use in pharmacovigilance practice.
METHOD: Exploratory data mining was performed within the Swedish national database of spontaneously reported ADRs. Bleeding associated with direct oral anticoagulants (DOACs)-rivaroxaban, apixaban, edoxaban, and dabigatran-was used as a test model. We compared demographics, drug treatment, and clinical features between cases with bleeding (N = 965) and controls who had experienced other serious ADRs to DOACs (N = 511). Statistical analysis was performed by unadjusted and age adjusted logistic regression models, and the random forest based machine-learning method Boruta.
RESULTS: In the logistic regression, 13 factors were significantly more common among cases of bleeding compared with controls. Eleven were labelled or previously proposed risk factors. Cardiac arrhythmia (e.g., atrial fibrillation), hypertension, mental impairment disorders (e.g., dementia), renal and urinary tract procedures, gastrointestinal ulceration and perforation, and interacting drugs remained significant after adjustment for age. In the Boruta analysis, high age, arrhythmia, hypertension, cardiac failure, thromboembolism, and pharmacodynamically interacting drugs had a larger than random association with the outcome. High age, cardiac arrhythmia, hypertension, cardiac failure, and pharmacodynamically interacting drugs had odds ratios for bleeding above one, while thromboembolism had an odds ratio below one.
CONCLUSIONS: We demonstrated that data mining within a pharmacovigilance database identifies known risk factors for DOAC bleeding, and potential risk factors such as dementia and atrial fibrillation. We propose that the method could be used in pharmacovigilance for identification of potential ADR risk factors that merit further evaluation.
PMID:37580910 | DOI:10.1002/pds.5679
Oral and nasal provocation test in chicken egg allergy-case report
Allergy Asthma Clin Immunol. 2023 Aug 14;19(1):70. doi: 10.1186/s13223-023-00829-9.
ABSTRACT
INTRODUCTION: Allergy to chicken egg protein is a common form of food allergy. The most common clinical presentation includes gastrointestinal, skin, and respiratory symptoms. Differential diagnosis, including provocative tests, is critical in diagnosis.
CASE DESCRIPTION: We present a case of a 21-year-old patient with egg allergy, who underwent a double-blind food provocation test with placebo (evaluating subjective complaints from the gastrointestinal tract) and a titrated nasal provocation test using dry chicken egg content. We assessed the response of the nasal mucosa in the provocation test using the visual analogue scale (VAS), acoustic and optical rhinometry, as well as measurements of nitric oxide concentration in the exhaled air. During the provocation test, we measured the changes in the transverse section of the nasal passages, which were accompanied by subjective complaints measured with the VAS scale, using objective techniques. In the nasal provocation test with a dose of 20 µg of chicken egg protein, we observed an increase in the reactivity of the nasal mucosa and a decrease in the level of nitric oxide in the exhaled air from the upper airways (920 ppb before the provocation test and up to 867 ppb during the early stage of the allergic reaction). During the provocation tests, we recorded typical symptoms associated with the early stage of the allergic reaction; including nasal obstruction (1.2 cm), leakage of watery discharge (0.8 cm) in the food test, and itchy nose (1.1 cm) in the food test vs. the nasal test: 4.6, 2.8, and 3.5 cm, respectively.
CONCLUSIONS: The nasal mucosa provides convenient conditions for evaluation of the severity of allergy to common food allergens, including chicken egg allergens.
PMID:37580833 | DOI:10.1186/s13223-023-00829-9
Examining Whether Genetic Variants Moderate the Skeletal Effects of Selective Serotonin Reuptake Inhibitors in Older Adolescents and Young Adults
J Child Adolesc Psychopharmacol. 2023 Aug 9. doi: 10.1089/cap.2023.0007. Online ahead of print.
ABSTRACT
Objective: To examine whether serotonin (5-HT) related genetic variants moderate the effects of selective serotonin reuptake inhibitors (SSRIs) on skeletal outcomes. Methods: Trabecular bone mineral density (BMD) at the radius, lumbar spine (LS) BMD, total body less head (TBLH) bone mineral content (BMC) and markers of bone metabolism (osteocalcin, C-terminal telopeptide of type I collagen [CTX-1], and bone specific alkaline phosphatase to CTX-1 ratio) were examined in an observational study, enrolling 15- to 20-year-old participants, unmedicated or within a month of SSRI initiation. Variants in HTR1A (rs6295), HTR1B (rs6296), HTR1D (rs6300), HTR2A (rs6311 and rs6314), HTR2B (rs6736017), and the serotonin transporter intron 2 variable number tandem repeat (STin2 VNTR) were genotyped. Linear mixed-effects regression analysis examined associations between SSRI use, genetic variants, and skeletal outcomes. Results: After adjusting for relevant covariates, rs6295 CC and GC genotypes in 262 participants (60% female, mean ± SD age = 18.9 ± 1.6 years) were significantly associated with higher LS BMD compared to the GG genotype. Rs6311 GG SSRI users had greater LS BMD compared to nonusers (β = 0.18, p = <0.0001). Female SSRI users with the combination of rs6295 CC+GC and rs6311 GG genotypes had greater LS BMD than female SSRI nonusers (β = 0.29, p < 0.0001). SSRI users with the rs6295 GG genotype had higher trabecular BMD compared to nonusers (β = 3.60, p = 0.05). No significant interactions were found for TBLH BMC or bone turnover markers. After correcting for multiple comparisons, none of the results retained significance. Conclusions: In older adolescents and young adults, HTR1A (rs6295) and HTR2A (rs6311) variants may moderate the effect of SSRIs on BMD. Sex differences may exist and require further examination. Further research with larger sample sizes is needed to confirm our preliminary findings. Clinical Trial Registration: clinicaltrials.gov NCT02147184.
PMID:37579130 | DOI:10.1089/cap.2023.0007
Apoptosis and inflammatory genes variants in primary non-response to anti-TNF therapy in Crohn's disease patients
Eur J Gastroenterol Hepatol. 2023 Jul 31. doi: 10.1097/MEG.0000000000002618. Online ahead of print.
ABSTRACT
Anti-TNF therapy has indeed revolutionized the treatment of Crohn's disease, leading to higher rates of response and remission in patients. However, a significant proportion of 20-40% of patients do not respond to the initial therapy, others experience a secondary loss of response with ongoing treatment. Adverse drug reactions also occur in some patients. The effectiveness of anti-TNF treatment may be influenced by genetic variability, including FCGR3A, ADAM17, TNFRSF1A, TNFRSF1B, FAS, FASL, IL1B, CASP9, and MIF genes. In this article, we provide an overview of the current knowledge and findings in the pharmacogenetics of anti-TNF drugs in CD focusing on the aspect of apoptosis and inflammatory genes variants in primary non-response. Pharmacogenetic investigations have been conducted to identify genetic markers that can predict response to anti-TNF therapy. However, large multi-center validation studies and multi-loci algorithms development are required to effectively prognose the treatment effect. The identification of predictive markers of response to anti-TNF therapy can help clinicians make informed decisions about treatment options and minimize adverse drug reactions in patients.
PMID:37577818 | DOI:10.1097/MEG.0000000000002618
SpaRx: Elucidate single-cell spatial heterogeneity of drug responses for personalized treatment
bioRxiv. 2023 Aug 6:2023.08.03.551911. doi: 10.1101/2023.08.03.551911. Preprint.
ABSTRACT
Spatial cellular heterogeneity contributes to differential drug responses in a tumor lesion and potential therapeutic resistance. Recent emerging spatial technologies such as CosMx SMI, MERSCOPE, and Xenium delineate the spatial gene expression patterns at the single cell resolution. This provides unprecedented opportunities to identify spatially localized cellular resistance and to optimize the treatment for individual patients. In this work, we present a graph-based domain adaptation model, SpaRx, to reveal the heterogeneity of spatial cellular response to drugs. SpaRx transfers the knowledge from pharmacogenomics profiles to single-cell spatial transcriptomics data, through hybrid learning with dynamic adversarial adaption. Comprehensive benchmarking demonstrates the superior and robust performance of SpaRx at different dropout rates, noise levels, and transcriptomics coverage. Further application of SpaRx to the state-of-art single-cell spatial transcriptomics data reveals that tumor cells in different locations of a tumor lesion present heterogenous sensitivity or resistance to drugs. Moreover, resistant tumor cells interact with themselves or the surrounding constituents to form an ecosystem for drug resistance. Collectively, SpaRx characterizes the spatial therapeutic variability, unveils the molecular mechanisms underpinning drug resistance, and identifies personalized drug targets and effective drug combinations.
KEY POINTS: We have developed a novel graph-based domain adaption model named SpaRx, to reveal the heterogeneity of spatial cellular response to different types of drugs, which bridges the gap between pharmacogenomics knowledgebase and single-cell spatial transcriptomics data.SpaRx is developed tailored for single-cell spatial transcriptomics data and is provided available as a ready-to-use open-source software, which demonstrates high accuracy and robust performance.SpaRx uncovers that tumor cells located in different areas within tumor lesion exhibit varying levels of sensitivity or resistance to drugs. Moreover, SpaRx reveals that tumor cells interact with themselves and the surrounding microenvironment to form an ecosystem capable of drug resistance.
PMID:37577665 | PMC:PMC10418183 | DOI:10.1101/2023.08.03.551911
Comparative Analysis of Molecular Pathogenic Mechanisms and Antiviral Development Targeting Old and New World Hantaviruses
bioRxiv. 2023 Aug 5:2023.08.04.552083. doi: 10.1101/2023.08.04.552083. Preprint.
ABSTRACT
BACKGROUND: Hantaviruses - dichotomized into New World (i.e. Andes virus, ANDV; Sin Nombre virus, SNV) and Old-World viruses (i.e. Hantaan virus, HTNV) - are zoonotic viruses transmitted from rodents to humans. Currently, no FDA-approved vaccines against hantaviruses exist. Given the recent breakthrough to human-human transmission by the ANDV, an essential step is to establish an effective pandemic preparedness infrastructure to rapidly identify cell tropism, infective potential, and effective therapeutic agents through systematic investigation.
METHODS: We established human cell model systems in lung (airway and distal lung epithelial cells), heart (pluripotent stem cell-derived (PSC-) cardiomyocytes), and brain (PSC-astrocytes) cell types and subsequently evaluated ANDV, HTNV and SNV tropisms. Transcriptomic, lipidomic and bioinformatic data analyses were performed to identify the molecular pathogenic mechanisms of viruses in different cell types. This cell-based infection system was utilized to establish a drug testing platform and pharmacogenomic comparisons.
RESULTS: ANDV showed broad tropism for all cell types assessed. HTNV replication was predominantly observed in heart and brain cells. ANDV efficiently replicated in human and mouse 3D distal lung organoids. Transcriptomic analysis showed that ANDV infection resulted in pronounced inflammatory response and downregulation of cholesterol biosynthesis pathway in lung cells. Lipidomic profiling revealed that ANDV-infected cells showed reduced level of cholesterol esters and triglycerides. Further analysis of pathway-based molecular signatures showed that, compared to SNV and HTNV, ANDV infection caused drastic lung cell injury responses. A selective drug screening identified STING agonists, nucleoside analogues and plant-derived compounds that inhibited ANDV viral infection and rescued cellular metabolism. In line with experimental results, transcriptome data shows that the least number of total and unique differentially expressed genes were identified in urolithin B- and favipiravir-treated cells, confirming the higher efficiency of these two drugs in inhibiting ANDV, resulting in host cell ability to balance gene expression to establish proper cell functioning.
CONCLUSIONS: Overall, our study describes advanced human PSC-derived model systems and systems-level transcriptomics and lipidomic data to better understand Old and New World hantaviral tropism, as well as drug candidates that can be further assessed for potential rapid deployment in the event of a pandemic.
PMID:37577539 | PMC:PMC10418258 | DOI:10.1101/2023.08.04.552083
A frequent CYP2D6 variant promotes skipping of exon 3 and reduces CYP2D6 protein expression in human liver samples
Front Pharmacol. 2023 Jul 27;14:1186540. doi: 10.3389/fphar.2023.1186540. eCollection 2023.
ABSTRACT
CYP2D6 is one of the most polymorphic drug-metabolizing enzymes in the liver. While genetic CYP2D6 variants serve as clinical biomarkers to predict CYP2D6 activity, large inter-person variability in CYP2D6 expression remains unaccounted for. Previous results suggest that there is variable expression of a CYP2D6 splice isoform with an in-frame deletion of exon 3 (CYP2D6ΔE3) encoding a protein lacking numerous active site residues. Here, using fragment analysis and RT-qPCR, we revealed that rs1058164 G (MAF = 27%-43%) is associated with increased formation of CYP2D6∆E3 in human liver samples (1.4-2.5-fold) and transfected cells. Furthermore, western blots showed that rs1058164 G was associated with a 50% decrease in full-length hepatic CYP2D6 protein expression. In addition, by studying a larger liver cohort, we confirmed our previous results that rs16947 (CYP2D6*2) reduces full-length CYP2D6 mRNA by increasing the production of an unstable splice isoform lacking exon 6 (CYP2D6ΔE6) and that the impact of CYP2D6ΔE6 is offset in carriers of the downstream enhancer variant rs5758550. The three frequent SNPs (rs1058164, rs16947, and rs5758550) form various 3-SNP-haplotypes, each with distinct CYP2D6 expression characteristics. Using an expression score (ES) system, we tested the impact of the 3-SNP-haplotype on improving the standard model to predict hepatic CYP2D6 protein expression based on genotype. A model that incorporates the 3-SNP-haplotype provided the best fit for CYP2D6 expression and also accounted for more variability in CYP2D6 protein levels (59%) than a model based on the accepted standard (36%) or one that only adds rs16947 and rs5758550 (42%). Clinical studies are needed to determine whether including the 3-SNP-haplotype alongside current standard CYP2D6 models improves the predictive value of CYP2D6 panels.
PMID:37576811 | PMC:PMC10412816 | DOI:10.3389/fphar.2023.1186540
Combined Use of Immune Checkpoint Inhibitors and Phytochemicals as a Novel Therapeutic Strategy against Cancer
J Cancer. 2023 Jul 24;14(12):2315-2328. doi: 10.7150/jca.85966. eCollection 2023.
ABSTRACT
Immune checkpoint inhibitor (ICI) therapy has dramatically changed cancer treatment, opening novel opportunities to cure malignant diseases. To date, most prevalently targeted immune checkpoints are programmed cell death protein 1 (PD-1) and cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4), with many others being under extensive investigations. However, according to available data, only a fraction of patients may respond to ICI therapy. Additionally, this therapy may cause severe adverse immune-related side effects, such as diarrhea, headache, muscle weakness, rash, hepatitis and leucopenia, although most of them are not fatal, they can affect the patient's treatment outcome and quality of life. On the other hand, growing evidence has shown that phytochemicals with anticancer effects may combine ICI therapy to augment the safety and effectiveness of the treatment against cancer while reducing the adverse side effects. In this review, we summarize the state of art in the various experiments and clinical application of ICIs plus phytochemicals, with a focus on their combined use as a novel therapeutic strategy to cure cancer.
PMID:37576404 | PMC:PMC10414047 | DOI:10.7150/jca.85966
Psychiatric manifestations of Kleefstra syndrome: a case report
Front Psychiatry. 2023 Jul 27;14:1174195. doi: 10.3389/fpsyt.2023.1174195. eCollection 2023.
ABSTRACT
BACKGROUND: Kleefstra syndrome is a rare genetic condition, which affects at least 1 in 120,000 individuals who have a neurodevelopmental disorder, characterized by the core clinical phenotype of intellectual disability, hypotonia, severe speech delay, and distinct facial characteristics with additional clinical features including sleep disturbance, overweight, psychiatric disorders, and autism spectrum disorder. To date, a limited number of case reports of Kleefstra syndrome with psychiatric manifestations have been reported.
CASE PRESENTATION: We reported a case of a 35-year-old male diagnosed with Kleefstra syndrome, who also had diagnoses of autism spectrum disorder and moderate to severe intellectual disability. He exhibited various psychiatric manifestations, including temporarily manic-like symptoms, excessive eating/overweight, addictive/gambling behaviors, inappropriate and unsafe internet use, sleep disturbance, rigid routines, and behaviors that challenged in the form of meltdowns. These symptoms were eventually relatively successfully managed with a combination of non-pharmacological and pharmacological treatments.
CONCLUSION: To our knowledge, there is only a limited number of case reports that detail patients with Kleefstra syndrome exhibiting various psychiatric manifestations. Our report adds further knowledge to the paucity of literature and highlights the effectiveness of a combination of non-pharmacological and pharmacological treatments for behavioral/psychiatric difficulties in Kleefstra syndrome.
PMID:37575568 | PMC:PMC10416101 | DOI:10.3389/fpsyt.2023.1174195
Ex vivo Drug Sensitivity Imaging-based Platform for Primary Acute Lymphoblastic Leukemia Cells
Bio Protoc. 2023 Aug 5;13(15):e4731. doi: 10.21769/BioProtoc.4731. eCollection 2023 Aug 5.
ABSTRACT
Resistance of acute lymphoblastic leukemia (ALL) cells to chemotherapy, whether present at diagnosis or acquired during treatment, is a major cause of treatment failure. Primary ALL cells are accessible for drug sensitivity testing at the time of new diagnosis or at relapse, but there are major limitations with current methods for determining drug sensitivity ex vivo. Here, we describe a functional precision medicine method using a fluorescence imaging platform to test drug sensitivity profiles of primary ALL cells. Leukemia cells are co-cultured with mesenchymal stromal cells and tested with a panel of 40 anti-leukemia drugs to determine individual patterns of drug resistance and sensitivity ("pharmacotype"). This imaging-based pharmacotyping assay addresses the limitations of prior ex vivo drug sensitivity methods by automating data analysis to produce high-throughput data while requiring fewer cells and significantly decreasing the labor-intensive time required to conduct the assay. The integration of drug sensitivity data with genomic profiling provides a basis for rational genomics-guided precision medicine. Key features Analysis of primary acute lymphoblastic leukemia (ALL) blasts obtained at diagnosis from bone marrow aspirate or peripheral blood. Experiments are performed ex vivo with mesenchymal stromal cell co-culture and require four days to complete. This fluorescence imaging-based protocol enhances previous ex vivo drug sensitivity assays and improves efficiency by requiring fewer primary cells while increasing the number of drugs tested to 40. It takes approximately 2-3 h for sample preparation and processing and a 1.5-hour imaging time. Graphical overview.
PMID:37575398 | PMC:PMC10415213 | DOI:10.21769/BioProtoc.4731
A response to Al et al. Trials 2023;24:233
Trials. 2023 Aug 13;24(1):525. doi: 10.1186/s13063-023-07574-9.
ABSTRACT
In their recent paper, Al and colleagues (Trials 2023;24:233) argue that manipulation of the methods of recruitment using well-known techniques in order to increase enrollment can be ethically acceptable. This brief response challenges that notion as an affront to voluntariness and a devolution of the ethics of human subjects research to the "ethics" of the marketplace.
PMID:37574550 | PMC:PMC10424340 | DOI:10.1186/s13063-023-07574-9
Hinge-like paper-based dual-channel enzyme-free ratiometric fluorescent microfluidic platform for simultaneous visual detection of carbaryl and glyphosate
Food Chem. 2023 Aug 11;431:137127. doi: 10.1016/j.foodchem.2023.137127. Online ahead of print.
ABSTRACT
On-site multi-pesticide residues detection is particularly urgent and challenging. Here, we fabricated an enzyme-free ratiometric fluorescent detection system in combination with a hinge-like dual-channel 3D microfluidic paper analytical device (3D μPAD) for simultaneous visual detection of carbaryl and glyphosate. Blue-emission 1-naphthol (Em. 470 nm) was hydrolyzed from carbaryl, while yellow-emission 2,3-diaminophenazine (Em. 570 nm) was produced with the aid of Cu2+ for glyphosate sensing. Inner-filter effect between 1-naphthol or 2,3-diaminophenazine and green-emission carbon dots (Em. 510 nm) realized two ratiometric fluorescent detection systems. Remarkable color variation of green-blue for carbaryl (50.00-1100 μΜ) and yellow-green for glyphosate (5.00-600 μΜ) were observed on a dual-channel 3D μPAD without crosstalk. Their detection limits were 1.11 and 0.63 μΜ, respectively. The strategy realized simultaneous visual detection of carbaryl and glyphosate in food/herbal with excellent accuracy (spiked recoveries, 91.00-107.2%), high precision (RSD ≤ 8.43%), and superior selectivity.
PMID:37573744 | DOI:10.1016/j.foodchem.2023.137127
Association between Nonfood Pre- or Probiotic Use and Cognitive Function: Results from NHANES 2011-2014
Nutrients. 2023 Jul 31;15(15):3408. doi: 10.3390/nu15153408.
ABSTRACT
In this study, we collected data from the National Health and Nutrition Examination Survey (NHANES) for the years 2011-2014. Multiple linear regression and logistic regression were used to analyse the association between nonfood pro- or prebiotic use and cognitive function among elderly Americans. To estimate the potential unobserved results, propensity score matching (PSM) was used to analyse the causal effect. Nonfood pro- or prebiotic use was analysed through the Dietary Supplement Use 30-Day Study. Cognitive function was evaluated by the Digit Symbol Substitution Test (DSST), the Animal Fluency Test (AFT), the Consortium to Establish a Registry for Alzheimer's Disease (CERAD), and a composite Z-score calculated by summing the Z-scores of three tests. Male participants who used nonfood pro- or prebiotics tended to have higher comprehensive cognitive function (sum.z) with a β-coefficient of 0.64 (95% CI: 0.08-1.19). Probiotics or prebiotics may be a protective factor against cognitive impairment in males, with an odds ratio of 0.08 (95% CI: 0.02-0.29). Furthermore, the average treatment effect for the treated (ATT) with nonfood pro- or prebiotics (0.555) on sum.z in males was statistically significant (p < 0.05). Our research revealed that nonfood pre- or probiotic use was an effective method to improve cognitive function in elderly men from the USA.
PMID:37571344 | DOI:10.3390/nu15153408
Mutational Signatures in Gastric Cancer and Their Clinical Implications
Cancers (Basel). 2023 Jul 26;15(15):3788. doi: 10.3390/cancers15153788.
ABSTRACT
Gastric cancer is characterised by high inter- and intratumour heterogeneity. The majority of patients are older than 65 years and the global burden of this disease is increasing due to the aging of the population. The disease is usually diagnosed at advanced stages, which is a consequence of nonspecific symptoms. Few improvements have been made at the level of noninvasive molecular diagnosis of sporadic gastric cancer, and therefore the mortality rate remains high. A new field of mutational signatures has emerged in the past decade with advances in the genome sequencing technology. These distinct mutational patterns in the genome, caused by exogenous and endogenous mutational processes, can be associated with tumour aetiology and disease progression, and could provide novel perception on the treatment possibilities. This review assesses the mutational signatures found in gastric cancer and summarises their potential for use in clinical setting as diagnostic or prognostic biomarkers. Associated treatment options and biomarkers already implemented in clinical use are discussed, together with those that are still being explored or are in clinical studies.
PMID:37568604 | DOI:10.3390/cancers15153788
CathAI: fully automated coronary angiography interpretation and stenosis estimation
NPJ Digit Med. 2023 Aug 11;6(1):142. doi: 10.1038/s41746-023-00880-1.
ABSTRACT
Coronary angiography is the primary procedure for diagnosis and management decisions in coronary artery disease (CAD), but ad-hoc visual assessment of angiograms has high variability. Here we report a fully automated approach to interpret angiographic coronary artery stenosis from standard coronary angiograms. Using 13,843 angiographic studies from 11,972 adult patients at University of California, San Francisco (UCSF), between April 1, 2008 and December 31, 2019, we train neural networks to accomplish four sequential necessary tasks for automatic coronary artery stenosis localization and estimation. Algorithms are internally validated against criterion-standard labels for each task in hold-out test datasets. Algorithms are then externally validated in real-world angiograms from the University of Ottawa Heart Institute (UOHI) and also retrained using quantitative coronary angiography (QCA) data from the Montreal Heart Institute (MHI) core lab. The CathAI system achieves state-of-the-art performance across all tasks on unselected, real-world angiograms. Positive predictive value, sensitivity and F1 score are all ≥90% to identify projection angle and ≥93% for left/right coronary artery angiogram detection. To predict obstructive CAD stenosis (≥70%), CathAI exhibits an AUC of 0.862 (95% CI: 0.843-0.880). In UOHI external validation, CathAI achieves AUC 0.869 (95% CI: 0.830-0.907) to predict obstructive CAD. In the MHI QCA dataset, CathAI achieves an AUC of 0.775 (95%. CI: 0.594-0.955) after retraining. In conclusion, multiple purpose-built neural networks can function in sequence to accomplish automated analysis of real-world angiograms, which could increase standardization and reproducibility in angiographic coronary stenosis assessment.
PMID:37568050 | PMC:PMC10421915 | DOI:10.1038/s41746-023-00880-1
Establishment of a mathematical prediction model for voriconazole stable maintenance dose: a prospective study
Front Cell Infect Microbiol. 2023 Jul 26;13:1157944. doi: 10.3389/fcimb.2023.1157944. eCollection 2023.
ABSTRACT
BACKGROUND: In patients with invasive fungal infection (IFI), the steady-state serum trough concentration (C min) of voriconazole (VCZ) is highly variable and can lead to treatment failure (C min < 0.5 mg/L) and toxicity (C min ≥ 5.0 mg/L). However, It remains challenging to determine the ideal maintenance dose to achieve the desired C min level quickly.
AIMS: This randomized, prospective observational single-center study aimed to identify factors affecting VCZ-C min and maintenance dose and create an algorithmic model to predict the necessary maintenance dose. MeThe study enrolled 306 adult IFI patients, split into two groups: non-gene-directed (A) (where CYP2C19 phenotype is not involved in determining VCZ dose) and gene-directed (B) (where CYP2C19 phenotype is involved in determining VCZ dose).
RESULTS: Results indicated that CYP2C19 genetic polymorphisms might significantly impact VCZ loading and maintenance dose selection. CYP2C19 phenotype, C-reaction protein (CRP), and average daily dose/body weight were significant influencers on VCZ-C min, while CYP2C19 phenotype, CRP, and body weight significantly impacted VCZ maintenance dose. A feasible predictive formula for VCZ stable maintenance dose was derived from the regression equation as a maintenance dose (mg) =282.774-0.735×age (year)+2.946×body weight(Kg)-19.402×CYP2C19 phenotype (UM/RM/NM:0, IM:1, PM:2)-0.316×CRP (mg/L) (p < 0.001).
DISCUSSION: DiThis formula may serve as a valuable supplement to the Clinical Pharmacogenetics Implementation Consortium (CPIC®) guideline for CYP2C19 and VCZ therapy, especially for IFI patients with highly variable inflammatory cytokines during VCZ therapy.
PMID:37565064 | PMC:PMC10410275 | DOI:10.3389/fcimb.2023.1157944
Pharmacotherapy and pulmonary fibrosis risk after SARS-CoV-2 infection: a prospective nationwide cohort study in the United States
Lancet Reg Health Am. 2023 Aug 2;25:100566. doi: 10.1016/j.lana.2023.100566. eCollection 2023 Sep.
ABSTRACT
BACKGROUND: Pulmonary fibrosis is characterized by lung parenchymal destruction and can increase morbidity and mortality. Pulmonary fibrosis commonly occurs following hospitalization for SARS-CoV-2 infection. As there are medications that modify pulmonary fibrosis risk, we investigated whether distinct pharmacotherapies (amiodarone, cancer chemotherapy, corticosteroids, and rituximab) are associated with differences in post-COVID-19 pulmonary fibrosis incidence.
METHODS: We used the National COVID-19 Cohort Collaboration (N3C) Data Enclave, which aggregates and harmonizes COVID-19 data across the United States, to assess pulmonary fibrosis incidence documented at least 60 days after COVID-19 diagnosis among adults hospitalized between January 1st, 2020 and July 6th, 2022 without pre-existing pulmonary fibrosis. We used propensity scores to match pre-COVID-19 drug-exposed and unexposed cohorts (1:1) based on covariates with known influence on pulmonary fibrosis incidence, and estimated the association of drug exposure with risk for post-COVID-19 pulmonary fibrosis. Sensitivity analyses considered pulmonary fibrosis incidence documented at least 30- or 90-days post-hospitalization and pulmonary fibrosis incidence in the COVID-19-negative N3C population.
FINDINGS: Among 5,923,394 patients with COVID-19, we analyzed 452,951 hospitalized adults, among whom pulmonary fibrosis incidence was 1.1 per 100-person-years. 277,984 hospitalized adults with COVID-19 were included in our primary analysis, among whom all drug exposed cohorts were well-matched to unexposed cohorts (standardized mean differences <0.1). The post-COVID-19 pulmonary fibrosis incidence rate ratio (IRR) was 2.5 (95% CI 1.2-5.1, P = 0.01) for rituximab, 1.6 (95% CI 1.3-2.0, P < 0.0001) for chemotherapy, and 1.2 (95% CI 1.0-1.3, P = 0.02) for corticosteroids. Amiodarone exposure had no significant association with post-COVID-19 pulmonary fibrosis (IRR = 0.8, 95% CI 0.6-1.1, P = 0.24). In sensitivity analyses, pre-COVID-19 corticosteroid use was not consistently associated with post-COVID-19 pulmonary fibrosis. In the COVID-19 negative hospitalized population (n = 1,240,461), pulmonary fibrosis incidence was lower overall (0.6 per 100-person-years) and for patients exposed to all four drugs.
INTERPRETATION: Recent rituximab or cancer chemotherapy before COVID-19 infection in hospitalized patients is associated with increased risk for post-COVID-19 pulmonary fibrosis.
FUNDING: The analyses described in this publication were conducted with data or tools accessed through the NCATS N3C Data Enclave https://covid.cd2h.org and N3C Attribution & Publication Policy v1.2-2020-08-25b supported by NIHK23HL146942, NIHK08HL150291, NIHK23HL148387, NIHUL1TR002389, NCATSU24 TR002306, and a SECURED grant from the Walder Foundation/Center for Healthcare Delivery Science and Innovation, University of Chicago. WFP received a grant from the Greenwall Foundation. This research was possible because of the patients whose information is included within the data and the organizations (https://ncats.nih.gov/n3c/resources/data-contribution/data-transfer-agreement-signatories) and scientists who have contributed to the on-going development of this community resource (https://doi.org/10.1093/jamia/ocaa196).
PMID:37564420 | PMC:PMC10410516 | DOI:10.1016/j.lana.2023.100566
The Utility of Mixed-Effects Models in the Evaluation of Complex Genomic Traits In Vitro
Drug Metab Dispos. 2023 Aug 10:DMD-AR-2023-001260. doi: 10.1124/dmd.123.001260. Online ahead of print.
ABSTRACT
In pharmacogenomic studies, the use of human liver microsomes as a model system to evaluate the impact of complex genomic traits (i.e., linkage-disequilibrium patterns, coding, and non-coding variation, etc.) on efficiency of drug metabolism is challenging. To accurately predict the true effect size of genomic traits requires large richly sampled datasets representative of the study population. Moreover, the acquisition of this data can be labor-intensive if the study design or bioanalytical methods are not high throughput, and it is potentially unfeasible if the abundance of sample needed for experiments is limited. To overcome these challenges, we developed a novel strategic approach using non-linear mixed effect models (NLME) to determine enzyme kinetic parameters for individual liver specimens using sparse data. This method can facilitate evaluation of the impact of complex genomic traits on the metabolism of xenobiotics in vitro when tissue and other resources are limited. In addition to facilitating the accrual of data, it allows for rigorous testing of covariates as sources of kinetic parameter variability. In this in silico study, we present a practical application of such an approach using previously published in vitro CYP2D6 data and explore the impact of sparse sampling, and experimental error on known kinetic parameter estimates of CYP2D6 mediated formation of 4-hydroxy-atomoxetine in human liver microsomes. Significance Statement This study presents a novel NLME based framework for evaluating the impact of complex genomic traits on Michaelis-Menten parameters in vitro using sparse data. The utility of this approach extends beyond gene variant associations, including determination of covariate effects on in vitro kinetic parameters, and reduced demand for precious experimental material.
PMID:37562955 | DOI:10.1124/dmd.123.001260