Front Artif Intell. 2023 May 2;6:1166426. doi: 10.3389/frai.2023.1166426. eCollection 2023.

NO ABSTRACT

PMID:37205297 | PMC:PMC10185910 | DOI:10.3389/frai.2023.1166426

Br J Clin Pharmacol. 2023 May 18. doi: 10.1111/bcp.15792. Online ahead of print.

ABSTRACT

AIM: Quantify identifiable sources of variability, including key pharmacogenetic variants in oxypurinol pharmacokinetics and their pharmacodynamic effect on serum urate.

METHODS: Hmong participants (n=34) received 100 mg allopurinol twice daily for 7 days followed by 150 mg allopurinol twice daily for 7 days. A sequential population pharmacokinetic pharmacodynamics (PKPD) analysis with non-linear mixed-effects modeling was performed. Allopurinol maintenance dose to achieve target SU was simulated based on the final PKPD model.

RESULTS: A one-compartment model with first order absorption and elimination best described the oxypurinol concentration-time data. Inhibitory of SU by oxypurinol was described with a direct inhibitory Emax model using steady-state oxypurinol concentrations. Fat-free body mass, estimated creatinine clearance and SLC22A12 rs505802 genotype (0.32 per T allele, 95%CI 0.13, 0.55) were found to predict differences in oxypurinol clearance. Oxypurinol concentration required to inhibit 50% of xanthine dehydrogenase activity was affected by PDZK1 rs12129861 genotype (-0.27 per A allele, 95%CI -0.38, -0.13). Most individuals with both PDZK1 rs12129861 AA and SLC22A12 rs505802 CC genotypes achieve target SU (with at least 75% success rate) with allopurinol below the maximum dose, regardless of renal function and body mass. In contrast, individuals with both PDZK1 rs12129861 GG and SLC22A12 rs505802 TT genotypes would require more than the maximum dose, thus selecting alternative medications.

CONCLUSION: The proposed allopurinol dosing guide uses individuals' fat-free mass, renal function, and SLC22A12 rs505802 and PDZK1 rs12129861 genotypes to achieve target SU.

PMID:37202871 | DOI:10.1111/bcp.15792

J Pediatr. 2023 May 16:113489. doi: 10.1016/j.jpeds.2023.113489. Online ahead of print.

ABSTRACT

OBJECTIVE: To evaluate the use of drugs with pharmacogenomic (PGx) guidelines from the Clinical Pharmacogenetics Implementation Consortium (CPIC) in early childhood.

STUDY DESIGN: A retrospective observational study of neonatal intensive care (NICU) patients admitted between 2005 - 2018 with at least one subsequent hospitalization at or after 5 years of age was performed to determine PGx-drug exposure. Data regarding hospitalizations, drug exposures, gestational age, birth weight, and congenital anomalies and/or a primary genetic diagnosis were collected. Incidence of PGx-drug and drug class exposures was determined and patient specific factors predictive of exposure were investigated.

RESULTS: During the study, 19,195 patients received NICU care and 4,196 (22%) met study inclusion; 67% received 1-2, 28% 3-4, and 5% 5 or more PGx-drugs in early childhood. Preterm gestation, low birth weight (<2,500 grams), and the presence of any congenital anomalies and/or a primary genetic diagnosis were statistically significant predictors of CPIC drug exposures (p<0.01, p<0.01, p<0.01, respectively).

CONCLUSION: Preemptive PGx testing in NICU patients could have a significant impact on medical management, during the NICU stay and throughout early childhood.

PMID:37201679 | DOI:10.1016/j.jpeds.2023.113489

J Epidemiol Glob Health. 2023 May 18. doi: 10.1007/s44197-023-00113-4. Online ahead of print.

ABSTRACT

BACKGROUND: Cardiovascular diseases (CVDs) are considered a leading cause of death worldwide. Allelic variation in the CYP2C19 gene leads to a dysfunctional enzyme, and patients with this loss-of-function allele will have an impaired clopidogrel metabolism, which eventually results in major adverse cardiovascular events (MACE). Ischemic heart disease patients (n = 102) who underwent percutaneous cardiac intervention (PCI) followed by clopidogrel were enrolled in the present study.

METHODS: The genetic variations in the CYP2C19 gene were identified using the TaqMan chemistry-based qPCR technique. Patients were followed up for 1 year to monitor MACE, and the correlations between the allelic variations in CYP2C19 and MACE were recorded.

RESULTS: During the follow-up, we reported 64 patients without MACE (29 with unstable angina (UA), 8 with myocadiac infarction (MI), 1 patient with non-STEMI, and 1 patient with ischemic dilated cardiomyopathy (IDC)). Genotyping of CYP2C19 in the patients who underwent PCI and were treated with clopidogrel revealed that 50 patients (49%) were normal metabolizers for clopidogrel with genotype CYP2C19*1/*1 and 52 patients (51%) were abnormal metabolizers, with genotypes CYP2C19*1/*2 (n = 15), CYP2C19*1/*3 (n = 1), CYP2C19*1/*17 (n = 35), and CYP2C19*2/*17 (n = 1). Demographic data indicated that age and residency were significantly associated with abnormal clopidogrel metabolism. Moreover, diabetes, hypertension, and cigarette smoking were significantly associated with the abnormal metabolism of clopidogrel. These data shed light on the inter-ethnic variation in metabolizing clopidogrel based on the CYP2C19 allelic distribution.

CONCLUSION: This study, along with other studies that address genotype variation of clopidogrel-metabolizing enzymes, might pave the way for further understanding of the pharmacogenetic background of CVD-related drugs.

PMID:37202608 | DOI:10.1007/s44197-023-00113-4

Front Pharmacol. 2023 May 2;14:1130548. doi: 10.3389/fphar.2023.1130548. eCollection 2023.

ABSTRACT

Methotrexate is an immunosuppressant and chemotherapeutic agent used in the treatment of a range of autoimmune disorders and cancers. Its main serious adverse effects, bone marrow suppression and gastrointestinal complications, arise from its antimetabolite effect. Nevertheless, hepatotoxicity and nephrotoxicity are two widely described adverse effects of methotrexate. Its hepatotoxicity has been studied mainly in the low-dose, chronic setting, where patients are at risk of fibrosis/cirrhosis. Studies of acute hepatoxicity of high dose methotrexate, such as during chemotherapy, are scarce. We present the case of a 14-year-old patient who received high-dose methotrexate and subsequently developed acute fulminant liver failure and acute kidney injury. Genotyping of MTHFR (Methylene tetrahydrofolate reductase gene), ABCB1 (codes for P-glycoprotein, intestinal transport and biliary excretion), ABCG2 (codes for BCRP, intestinal transporter and renal excretion) and SLCO1B1 (codes for OATP1B1, hepatic transporter) identified variants in all the genes analysed that predicted a reduced rate of methotrexate elimination and thus may have contributed to the clinical situation of the patient. Precision medicine involving pharmacogenomic testing could potentially avoid such adverse drug effects.

PMID:37201023 | PMC:PMC10185764 | DOI:10.3389/fphar.2023.1130548

Turk J Phys Med Rehabil. 2022 Aug 2;69(1):23-30. doi: 10.5606/tftrd.2023.9418. eCollection 2023 Mar.

ABSTRACT

OBJECTIVES: This study was conducted to investigate the effects of combined progressive resistance training (PRT) and functional electrical stimulation-evoked leg cycling exercise (FES-LCE) on isometric peak torque and muscle volume in individuals with incomplete spinal cord injury.

PATIENTS AND METHODS: In the single-blind, randomized controlled trial performed between April 2015 and August 2016, 28 participants were randomized between two exercise interventions (FES-LCE+PRT and FES-LCE alone), and training was conducted over 12 weeks. The isometric muscle peak torque and muscle volume for both lower limbs were measured at the baseline and after 6 and 12 weeks. Linear mixed-model analysis of variance was performed to test the effects of FES-LCE+PRT versus FES-LCE on each outcome measure over time via an intention-to-treat analysis.

RESULTS: Twenty-three participants (18 males, 5 females; mean age: 33.4±9.7 years; range 21 to 50 years) completed study (10 in the FES-LCE+PRT group, and 13 in the FES-LCE group). The 12-week pre-and posttraining change for left hamstrings' muscle peak torque in the FES-LCE+PRT group (mean difference=4.5±7.9 Nm, 45% change, p<0.05) was consistently higher than that in the FES-LCE group (mean difference=2.4±10.3 Nm, 4% change; p<0.018). The improvement in the right quadriceps muscle's peak torque of the FES-LCE+PRT group (mean difference=19±7.6 Nm, 31% change, p<0.05) was more significant compared to the FES-LCE group. The left muscle volume showed a remarkable increase after 12 weeks in the FES-LCE+PRT group (mean difference=0.3±9.3 L, 7% change, p<0.05).

CONCLUSION: The combination of PRT and FES-LCE was better in improving lower limb muscle strength and volume in chronic incomplete individuals with spinal cord injury.

PMID:37201013 | PMC:PMC10186013 | DOI:10.5606/tftrd.2023.9418

Brief Bioinform. 2023 May 17:bbad181. doi: 10.1093/bib/bbad181. Online ahead of print.

ABSTRACT

Polygenic risk score (PRS) has been recently developed for predicting complex traits and drug responses. It remains unknown whether multi-trait PRS (mtPRS) methods, by integrating information from multiple genetically correlated traits, can improve prediction accuracy and power for PRS analysis compared with single-trait PRS (stPRS) methods. In this paper, we first review commonly used mtPRS methods and find that they do not directly model the underlying genetic correlations among traits, which has been shown to be useful in guiding multi-trait association analysis in the literature. To overcome this limitation, we propose a mtPRS-PCA method to combine PRSs from multiple traits with weights obtained from performing principal component analysis (PCA) on the genetic correlation matrix. To accommodate various genetic architectures covering different effect directions, signal sparseness and across-trait correlation structures, we further propose an omnibus mtPRS method (mtPRS-O) by combining P values from mtPRS-PCA, mtPRS-ML (mtPRS based on machine learning) and stPRSs using Cauchy Combination Test. Our extensive simulation studies show that mtPRS-PCA outperforms other mtPRS methods in both disease and pharmacogenomics (PGx) genome-wide association studies (GWAS) contexts when traits are similarly correlated, with dense signal effects and in similar effect directions, and mtPRS-O is consistently superior to most other methods due to its robustness under various genetic architectures. We further apply mtPRS-PCA, mtPRS-O and other methods to PGx GWAS data from a randomized clinical trial in the cardiovascular domain and demonstrate performance improvement of mtPRS-PCA in both prediction accuracy and patient stratification as well as the robustness of mtPRS-O in PRS association test.

PMID:37200155 | DOI:10.1093/bib/bbad181

Naunyn Schmiedebergs Arch Pharmacol. 2023 May 18. doi: 10.1007/s00210-023-02525-2. Online ahead of print.

ABSTRACT

The link between human leukocyte antigen (HLA) alleles and carbamazepine-induced cutaneous, respiratory, and gastrointestinal adverse drug reactions (ADR) has created a window of opportunity for preventing certain forms of cutaneous adverse drug reactions (cADRs); however, there is not enough data to make pharmacogenomic recommendations that can be implemented globally. The aim of this study is to assess and document carbamazepine-induced adverse reactions among prescribed Saudi/non-Saudi patients. A retrospective chart review was performed for patients who received carbamazepine (CBZ) in the period between 2016 and 2020, in the Kingdom of Saudi Arabia. Data were gathered and descriptive statistical analyses were performed on the data for the study sample. Comparisons were made using the chi-square test or independent samples' t-test. Statistical significance was considered at p < .05. All statistical analyses were performed using IBM SPSS 21.0 (Armonk, NY; IBM Corp). Results from multivariate logistic regression analyses showed that higher likelihood of carbamazepine-induced adverse reactions was significantly associated with younger age, OR = 0.82, 95% CI (0.74, 0.90); p < 0.001. Patients who were prescribed CBZ for reasons other than epilepsy or seizures were significantly more likely to develop carbamazepine-induced adverse reactions (epilepsy vs. other; OR = 0.63, p = 0.013; seizures vs. other; OR = 0.59, p = 0.018). Gender or medication duration were not related to carbamazepine-induced adverse reactions (p > 0.05). The findings of this study are comparable with those of other studies assessing carbamazepine-associated adverse reactions in children and adults. Recommendations include genetic prescreening, educating patients and parents on the possibility of adverse reactions, and routine laboratory monitoring.

PMID:37199768 | DOI:10.1007/s00210-023-02525-2

AIDS. 2023 May 12. doi: 10.1097/QAD.0000000000003598. Online ahead of print.

ABSTRACT

OBJECTIVE: Our study aimed to assess the impact of pharmacogenomic panel testing in persons living with HIV (PWH).

DESIGN: Prospective, observational intervention assessment.

METHODS: One hundred PWH were provided a comprehensive pharmacogenomic panel during routine care visits within the HIV specialty clinic of a large academic medical center. The panel determined the presence of specific genetic variants that could predict response or toxicity to commonly prescribed antiretroviral therapy (ART) and non-ART medications. An HIV specialty pharmacist reviewed the results with participants and the care team. The pharmacist (1) recommended clinically actionable interventions based on the participants current drug therapy, (2) assessed for genetic explanations for prior medication failures, adverse effects, or intolerances, and (3) advised on potential future clinically actionable care interventions based on individual genetic phenotypes.

RESULTS: Ninety-six participants (median age 53y, 74% white, 84% male, 89% viral load <50 copies/ml) completed panel testing yielding 682 clinically relevant pharmacogenomic results (133 major, 549 mild-moderate). Ninety participants (89 on ART) completed follow-up visits with 65 (72%) receiving clinical recommendations based on current medication profiles. Of the 105 clinical recommendations, 70% advised additional monitoring for efficacy or toxicity, and 10% advised alteration of drug therapy. Panel results offered explanation for prior ART inefficacy in 1 participant and ART intolerance in 29%. Genetic explanation for non-ART toxicity was seen in 21% of participants, with genetic contributors to inefficacy of non-ART therapy identified in 39% of participants.

CONCLUSIONS: Preliminary data in a small cohort of PWH demonstrates benefit of routine pharmacogenomic panel testing.

PMID:37199600 | DOI:10.1097/QAD.0000000000003598

Ital J Pediatr. 2023 May 18;49(1):57. doi: 10.1186/s13052-023-01469-w.

ABSTRACT

BACKGROUND: Tacrolimus is the backbone drug in kidney transplantation. Single nucleotide polymorphism of Multidrug resistant 1 gene can affect tacrolimus metabolism consequently it can affect tacrolimus trough level and incidence of acute rejection. The aim of this study is to investigate the impact of Multidrug resistant 1 gene, C3435T and G2677T Single nucleotide polymorphisms on tacrolimus pharmacokinetics and on the risk of acute rejection in pediatric kidney transplant recipients.

METHODS: Typing of Multidrug resistant 1 gene, C3435T and G2677T gene polymorphism was done using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) for 83 pediatric kidney transplant recipients and 80 matched healthy controls.

RESULTS: In Multidrug resistant 1 gene (C3435T), CC, CT genotypes and C allele were significantly associated with risk of acute rejection when compared to none acute rejection group (P = 0.008, 0.001 and 0.01 respectively). The required tacrolimus doses to achieve trough level were significantly higher among CC than CT than TT genotypes through the 1st 6 months after kidney transplantation. While, in Multidrug resistant 1 gene (G2677T), GT, TT genotypes and T allele were associated with acute rejection when compared to none acute rejection (P = 0.023, 0.033 and 0.028 respectively). The required tacrolimus doses to achieve trough level were significantly higher among TT than GT than GG genotypes through the 1st 6 months after kidney transplantation.

CONCLUSION: The C allele, CC and CT genotypes of Multidrug resistant 1 gene (C3435T) and the T allele, GT and TT genotypes of Multidrug resistant 1 gene (G2677T) gene polymorphism may be risk factors for acute rejection and this can be attributed to their effect on tacrolimus pharmacokinetics. Tacrolimus therapy may be tailored according to the recipient genotype for better outcome.

PMID:37198710 | PMC:PMC10193607 | DOI:10.1186/s13052-023-01469-w

Mol Psychiatry. 2023 May 18. doi: 10.1038/s41380-023-02089-w. Online ahead of print.

ABSTRACT

Genome-wide association studies (GWAS) of Alzheimer's disease are predominantly carried out in European ancestry individuals despite the known variation in genetic architecture and disease prevalence across global populations. We leveraged published GWAS summary statistics from European, East Asian, and African American populations, and an additional GWAS from a Caribbean Hispanic population using previously reported genotype data to perform the largest multi-ancestry GWAS meta-analysis of Alzheimer's disease and related dementias to date. This method allowed us to identify two independent novel disease-associated loci on chromosome 3. We also leveraged diverse haplotype structures to fine-map nine loci with a posterior probability >0.8 and globally assessed the heterogeneity of known risk factors across populations. Additionally, we compared the generalizability of multi-ancestry- and single-ancestry-derived polygenic risk scores in a three-way admixed Colombian population. Our findings highlight the importance of multi-ancestry representation in uncovering and understanding putative factors that contribute to risk of Alzheimer's disease and related dementias.

PMID:37198259 | DOI:10.1038/s41380-023-02089-w

Annu Rev Biomed Data Sci. 2023 May 17. doi: 10.1146/annurev-biodatasci-102022-120818. Online ahead of print.

ABSTRACT

Despite monumental advances in molecular technology to generate genome sequence data at scale, there is still a considerable proportion of heritability in most complex diseases that remains unexplained. Because many of the discoveries have been single-nucleotide variants with small to moderate effects on disease, the functional implication of many of the variants is still unknown and, thus, we have limited new drug targets and therapeutics. We, and many others, posit that one primary factor that has limited our ability to identify novel drug targets from genome-wide association studies may be due to gene interactions (epistasis), gene-environment interactions, network/pathway effects, or multiomic relationships. We propose that many of these complex models explain much of the underlying genetic architecture of complex disease. In this review, we discuss the evidence from multiple research avenues, ranging from pairs of alleles to multiomic integration studies and pharmacogenomics, that supports the need for further investigation of gene interactions (or epistasis) in genetic and genomic studies of human disease. Our goal is to catalog the mounting evidence for epistasis in genetic studies and the connections between genetic interactions and human health and disease that could enable precision medicine of the future. Expected final online publication date for the Annual Review of Biomedical Data Science, Volume 6 is August 2023. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

PMID:37196359 | DOI:10.1146/annurev-biodatasci-102022-120818

Adv Exp Med Biol. 2023;1413:265-272. doi: 10.1007/978-3-031-26625-6_13.

ABSTRACT

Traditionally, animal models have been used for recapitulating human physiology and for studying the pathological basis of many diseases affecting humankind. Indeed, over the centuries, animal models helped advance our understanding of the biology and pathology of drug therapy for humans. However, with the advent of genomics and pharmacogenomics, we now know that conventional models cannot accurately capture the pathological conditions and biological processes in humans, although humans share many physiological and anatomical features with many animals [1-3]. Species to species variation have raised concerns about the validity and suitability of animal models for studying human conditions. Over the past decade, the development and advances in microfabrication and biomaterials have spurred the growth in micro-engineered tissue and organ models (organs-on-a-chip, OoC) as alternatives to animal and cellular models [4]. This state-of-the-art technology has been used to emulate human physiology for investigating multitudes of cellular and biomolecular processes implicated in the pathological basis of disease (Fig. 13.1) [4]. Because of their tremendous potential, OoC-based models have been listed as one of the top 10 emerging technologies in the 2016 World Economic Forum [2].

PMID:37195535 | DOI:10.1007/978-3-031-26625-6_13

Handb Exp Pharmacol. 2023 May 18. doi: 10.1007/164_2023_654. Online ahead of print.

ABSTRACT

Precision medicine uses innovative approaches to improve disease prevention and treatment outcomes by taking into account people's genetic backgrounds, environments, and lifestyles. Treatment of depression is particularly challenging, given that 30-50% of patients do not respond adequately to antidepressants, while those who respond may experience unpleasant adverse drug reactions (ADRs) that decrease their quality of life and compliance. This chapter aims to present the available scientific data that focus on the impact of genetic variants on the efficacy and toxicity of antidepressants. We compiled data from candidate gene and genome-wide association studies that investigated associations between pharmacodynamic and pharmacokinetic genes and response to antidepressants regarding symptom improvement and ADRs. We also summarized the existing pharmacogenetic-based treatment guidelines for antidepressants, used to guide the selection of the right antidepressant and its dose based on the patient's genetic profile, aiming to achieve maximum efficacy and minimum toxicity. Finally, we reviewed the clinical implementation of pharmacogenomics studies focusing on patients on antidepressants. The available data demonstrate that precision medicine can increase the efficacy of antidepressants and reduce the occurrence of ADRs and ultimately improve patients' quality of life.

PMID:37195310 | DOI:10.1007/164_2023_654

Per Med. 2023 May 17. doi: 10.2217/pme-2022-0126. Online ahead of print.

ABSTRACT

Studies report an association between the expression of HLA alleles and lamotrigine (LTG)-induced Stevens-Johnson syndrome (SJS). This systematic review and meta-analysis evaluates the association between HLA alleles and LTG-induced SJS in different populations. Two alleles, HLA-B*0702 and HLA-C*0702, were deemed to be protective; five alleles, HLA-B*1502, HLA-B*4403, HLA-A*2402, CYP2C19*2 and HLA-B*38, may play a role in LTG-induced SJS, for which only data studying HLA-B*1502 could be extracted. The pooled odds ratio of 2.88, 95% CI of 1.60-5.17 and p-value of 0.0004 establish the presence of HLA-B*1502 as a major risk factor for the development of LTG-induced SJS/TEN. Although multiple alleles that may play a role in the development of LTG-induced SJS/TEN were identified, the expression of the risk alleles may be ancestry-specific, and genetic screening is warranted for preventing this life-threatening adverse drug reaction.

PMID:37194923 | DOI:10.2217/pme-2022-0126

Cell Insight. 2023 Feb 1;2(2):100080. doi: 10.1016/j.cellin.2023.100080. eCollection 2023 Apr.

ABSTRACT

CRISPR-Cas12a based one-pot detection system has been used in nucleic acid detection and diagnosis. However, it is not sensitive enough to distinguish single nucleotide polymorphisms (SNP), which has greatly restricted its application. To overcome these limitations, we engineered a LbCas12a variant with enhanced sensitivity against SNP, named seCas12a (sensitive Cas12a). SeCas12a-based one-pot SNP detection system is a versatile platform that could use both canonical and non-canonical PAM, and was almost not limited by mutation types to distinguish SNPs located between position 1 to 17. The use of truncated crRNA further improved SNP specificity of seCas12a. Mechanistically, we found only when the cis-cleavage was at low level between 0.01min-1 and 0.0006 min-1, a good signal-to-noise ratio can be achieved in one-pot test. SeCas12a-based one-pot SNP detection system was applied to detect pharmacogenomic SNPs in human clinical samples. Of thirteen donors tested in two different SNPs, the seCas12a mediated one-pot system could faithfully detect the SNPs in 30 min with 100% accuracy.

PMID:37193068 | PMC:PMC10134196 | DOI:10.1016/j.cellin.2023.100080

Cell Mol Gastroenterol Hepatol. 2023 May 14:S2352-345X(23)00066-8. doi: 10.1016/j.jcmgh.2023.05.003. Online ahead of print.

ABSTRACT

BACKGROUND & AIMS: Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer deaths in the United States. Tyrosine sulfation, catalyzed by the tyrosylprotein sulfotransferase 2 (TPST2), is a post-translational modification essential for protein-protein interactions and cellular functions. SLC35B2 is a key transporter that transports the universal sulfate donor 3'-phosphoadenosine 5'-phosphosulfate (PAPS) into the Golgi apparatus where the protein sulfation occurs. The goal of this study is to determine whether and how SLC35B2-TPST2 axis of tyrosine sulfation plays a role in PDAC.

METHODS: Gene expression was analyzed in PDAC patients and mice. Human PDAC MIA PaCa-2 and PANC-1 cells were used for in vitro studies. TPST2 deficient MIA PaCa-2 cells were generated to assess xenograft tumor growth in vivo. Mouse PDAC cells derived from the KrasLSL-G12D/+;Tp53L/+;Pdx1-Cre (KPC) mice were used to generate Tpst2 KO KPC cells to evaluate tumor growth and metastasis in vivo.

RESULTS: High expressions of SLC35B2 and TPST2 were correlated with poor PDAC patient survival. Knockdown of SLC35B2 or TPST2, or pharmacological inhibition of sulfation inhibited PDAC cell proliferation and migration in vitro. TPST2 deficient MIA PaCa-2 cells exhibited inhibited xenograft tumor growth. Orthotopic inoculation of Tpst2 KO KPC cells in mice showed inhibition of primary tumor growth, local invasion, and metastasis. Mechanistically, the integrin ITGB4 was found to be a novel substrate of TPST2. Inhibition of sulfation destabilizes ITGB4 protein, which may have accounted for the suppression of metastasis.

CONCLUSIONS: Targeting the SLC35B2-TPST2 axis of tyrosine sulfation may represent a novel approach for therapeutic intervention of PDAC.

PMID:37192689 | DOI:10.1016/j.jcmgh.2023.05.003

Curr Allergy Asthma Rep. 2023 May 16. doi: 10.1007/s11882-023-01087-w. Online ahead of print.

ABSTRACT

PURPOSE OF REVIEW: Adverse drug reactions (ADRs) are a significant cause of morbidity and mortality. The electronic health record (EHR) provides an opportunity to monitor ADRs, mainly through the utilization of drug allergy data and pharmacogenomics. This review article explores the current use of the EHR for ADR monitoring and highlights areas that require improvement.

RECENT FINDINGS: Recent research has identified several issues with using EHR for ADR monitoring. These include the lack of standardization between EHR systems, specificity in data entry options, incomplete and inaccurate documentation, and alert fatigue. These issues can limit the effectiveness of ADR monitoring and compromise patient safety. The EHR has great potential for monitoring ADR but needs significant updates to improve patient safety and optimize care. Future research should concentrate on developing standardized documentation and clinical decision support systems within EHRs. Healthcare professionals should also be educated on the significance of accurate and complete ADR monitoring.

PMID:37191903 | DOI:10.1007/s11882-023-01087-w

Expert Rev Clin Immunol. 2023 May 16. doi: 10.1080/1744666X.2023.2214363. Online ahead of print.

ABSTRACT

INTRODUCTION: Asthma is a heterogenous, multifactorial disease with multiple genetic and environmental risk factors playing a role in pathogenesis and therapeutic response. Understanding of pharmacogenetics can help with matching individualized treatments to specific genotypes of asthma to improve therapeutic outcomes especially in uncontrolled or severe asthma.

AREAS COVERED: In this review, we outline novel information about biology, pathways and mechanisms related to interindividual variability in drug response (corticosteroids, bronchodilators, leukotriene modifiers and Biologics) for childhood asthma. We discuss candidate gene, genome-wide association studies and newer omics studies including epigenomics, transcriptomics, proteomics, and metabolomics as well as integrative genomics and systems biology methods related to childhood asthma. The articles were obtained after a series of searches, last updated November 2022, using database PubMed/CINAHL DB.

EXPERT OPINION: Implementation of pharmacogenetic algorithms can improve therapeutic targeting in children with asthma, particularly with severe or uncontrolled asthma who typically have challenges in clinical management and carry considerable financial burden. Future studies focusing on potential biomarkers both clinical and pharmacogenetic can help formulate a prognostic test for asthma treatment response that would represent true bench to bedside clinical implementation.

PMID:37190963 | DOI:10.1080/1744666X.2023.2214363

Cells. 2023 Apr 19;12(8):1188. doi: 10.3390/cells12081188.

ABSTRACT

Amyotrophic lateral sclerosis is one of several chronic neurodegenerative conditions in which mitochondrial abnormalities are posited to contribute to disease progression. Therapeutic options targeting mitochondria include enhancing metabolism, suppressing reactive oxygen production and disrupting mitochondria-mediated programmed cell death pathways. Herein is reviewed mechanistic evidence supporting a meaningful pathophysiological role for the constellation of abnormal mitochondrial fusion, fission and transport, collectively designated mitochondrial dysdynamism, in ALS. Following this is a discussion on preclinical studies in ALS mice that seemingly validate the idea that normalizing mitochondrial dynamism can delay ALS by interrupting a vicious cycle of mitochondrial degeneration, leading to neuronal die-back and death. Finally, the relative benefits of suppressing mitochondrial fusion vs. enhancing mitochondrial fusion in ALS are speculated upon, and the paper concludes with the prediction that the two approaches could be additive or synergistic, although a side-by-side comparative trial may be challenging to perform.

PMID:37190097 | DOI:10.3390/cells12081188