JACC Case Rep. 2023 Dec 6;27:102110. doi: 10.1016/j.jaccas.2023.102110. eCollection 2023 Dec 6.

ABSTRACT

A 32-week fetus with tachycardia and bradycardia, diagnosed with torsades de pointes, atrioventricular block, and sinus bradycardia due to a de novo KCNH2 mutation was successfully managed by a cardio-obstetrical team. Maternal/fetal pharmacogenomic testing resulted in appropriate drug dosing without toxicity and delivery of a term infant in sinus rhythm.

PMID:38094730 | PMC:PMC10715977 | DOI:10.1016/j.jaccas.2023.102110

J Pediatr Pharmacol Ther. 2023;28(8):680-686. doi: 10.5863/1551-6776-28.8.680. Epub 2023 Dec 12.

NO ABSTRACT

PMID:38094679 | PMC:PMC10715381 | DOI:10.5863/1551-6776-28.8.680

J Am Coll Cardiol. 2023 Dec 19;82(25):2350-2473. doi: 10.1016/j.jacc.2023.11.007.

NO ABSTRACT

PMID:38092509 | DOI:10.1016/j.jacc.2023.11.007

Bioinformatics. 2023 Dec 13:btad722. doi: 10.1093/bioinformatics/btad722. Online ahead of print.

ABSTRACT

MOTIVATION: The steady increment of Whole Genome/Exome sequencing and the development of novel NGS-based gene panels requires continuous testing and validation of variant calling pipelines and the detection of sequencing-related issues to be maintained up-to-date and feasible for the clinical settings. State of the art tools are reliable when used to compute standard performance metrics. However, the need for an automated software to discriminate between bioinformatic and sequencing issues and to optimize variant calling parameters remains unmet.The aim of the current work is to present RecallME, a bioinformatic suite that tracks down difficult-to-detect variants as insertions and deletions in highly repetitive regions, thus providing the maximum reachable recall for both single nucleotide variants and small insertion and deletions and to precisely guide the user in the pipeline optimization process.

AVAILABILITY: Source code is freely available under MIT license at https://github.com/mazzalab-ieo/recallme RecallME web application is available at https://translational-oncology-lab.shinyapps.io/recallme/ To use RecallME, users must obtain a license for ANNOVAR by themselves.

SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

PMID:38092052 | DOI:10.1093/bioinformatics/btad722

Front Genet. 2023 Nov 28;14:1308738. doi: 10.3389/fgene.2023.1308738. eCollection 2023.

ABSTRACT

Genomic and personalized medicine implementation efforts have largely centered on specialty care in tertiary health systems. There are few examples of fully integrated care systems that span the healthcare continuum. In 2014, NorthShore University HealthSystem launched the Center for Personalized Medicine to catalyze the delivery of personalized medicine. Successful implementation required the development of a scalable family history collection tool, the Genetic and Wellness Assessment (GWA) and Breast Health Assessment (BHA) tools; integrated pharmacogenomics programming; educational programming; electronic medical record integration; and robust clinical decision support tools. To date, more than 225,000 patients have been screened for increased hereditary conditions, such as cancer risk, through these tools in primary care. More than 35,000 patients completed clinical genetic testing following GWA or BHA completion. An innovative program trained more than 100 primary care providers in genomic medicine, activated with clinical decision support and access to patient genetic counseling services and digital healthcare tools. The development of a novel bioinformatics platform (FLYPE) enabled the incorporation of genomics data into electronic medical records. To date, over 4,000 patients have been identified to have a pathogenic or likely pathogenic variant in a gene with medical management implications. Over 33,000 patients have clinical pharmacogenomics data incorporated into the electronic health record supported by clinical decision support tools. This manuscript describes the evolution, strategy, and successful multispecialty partnerships aligned with health system leadership that enabled the implementation of a comprehensive personalized medicine program with measurable patient outcomes through a genomics-enabled learning health system model that utilizes implementation science frameworks.

PMID:38090148 | PMC:PMC10713750 | DOI:10.3389/fgene.2023.1308738

MedEdPublish (2016). 2018 Mar 22;7:66. doi: 10.15694/mep.2018.0000066.1. eCollection 2018.

ABSTRACT

This article was migrated. The article was marked as recommended. The Association of American Medical Colleges and the American Association of Colleges of Pharmacy with leaders of other health professions formed the Interprofessional Education Collaborative (IPEC) in 2009. Interprofessional education (IPE) is now a component of accreditation standards for academic programs in both medicine and pharmacy. While geographically separated, the Medical College of Georgia (Augusta University) and the College of Pharmacy (University of Georgia) have over 40 year history of collaboration but never intentionally added joint curricular offerings.To address IPE competencies, we developed and evaluated a medicine pharmacy collaborative exercise. Specifically, to compare the attitudes and perception toward interprofessional education and practice of students from two disciplines. An observational cross sectional study with 208 third year medical (M3) students and 108 third year pharmacy (P3) students was conducted in two consecutive academic years. Groups consisted of 6-8 M3 and 3-4 P3 students from all campuses across the state. The M3 student was to choose a patient they had seen who was taking at least 3 prescription medications. Objectives for students were to discuss the case (medications, side effects, cost, pharmacogenetics, drug-drug interactions, and cost effectiveness). A report of M3-P3 findings was to be submitted for grading by the Pharmacy faculty. Once the exercises were completed surveys were distributed and the de-identified data was analyzed in relation to IPEC competencies. The study was conducted in one academic year and 316 responses were obtained. Within medical students 48.2 % agreed and 21.2 % strongly agreed to consult with Pharm D in the future. Perception of leadership in the groups was shifted more toward pharmacy students (56.5% vs. 27.4%, p<0.0001). Students confidence in working with other professionals was improved more for pharmacy students than medical students (50.0% in P3 and 30.2% in M3 p =0.0014). Communication skills improved more in P3 than M3 (48.2% in P3 and 28.3% in M3, p=0.0043). More research is needed on equal adoption of IPE by medical and pharmacy students. Emphasis should be made on equal state of training (theory vs. clinical) on both sides with focus on working as a team and value of each team member. More direct involvement in patient care is needed with both M3 and P3 having face to face contact with patients and each other.

PMID:38089216 | PMC:PMC10712014 | DOI:10.15694/mep.2018.0000066.1

Front Pharmacol. 2023 Nov 28;14:1275238. doi: 10.3389/fphar.2023.1275238. eCollection 2023.

ABSTRACT

Introduction: The standard treatment for head and neck squamous cell carcinoma (HNSCC) is cisplatin chemoradiotherapy. One of the main treatment adverse reactions is nephrotoxicity, for which there is currently no adequate specific and sensitive biomarker. Thus, this study aimed to evaluate the use of microRNAs (miRNAs) as renal biomarker candidates. Methods: This was a retrospective cohort study. Nephrotoxicity was assessed through blood samples collected before and 5 days (D5) after chemotherapy. MiRNAs were extracted from urine samples collected at baseline and D5, and RNA sequencing identified miRNAs differentially expressed between participants with and without cisplatin-induced nephrotoxicity. Results: A total of 49 participants were included (n = 49). A significant difference was seen between the two groups for traditional renal markers (serum creatinine and creatinine clearance) and for the acute kidney injury (AKI) categories. Among the six miRNAs evaluated as biomarkers, four were upregulated (hsa-miR-6729-5p, hsa-miR-1238-5p, hsa-miR-4706, and hsa-miR-4322) and two were downregulated (hsa-miR-6805-5p and hsa-miR-21-5p), but only hsa-miR-6805-5p had a significant difference (p < 0.0001). Its receiver operating characteristic curve revealed excellent specificity (0.920) for its expression fluctuation assessment, while its absolute expression in D5 showed greater sensitivity (0.792). Conclusion: So, the integrated use of these two parameters seems to be an interesting approach for AKI.

PMID:38089043 | PMC:PMC10713822 | DOI:10.3389/fphar.2023.1275238

Chem Biodivers. 2023 Dec 13:e202301840. doi: 10.1002/cbdv.202301840. Online ahead of print.

ABSTRACT

Resistance to antimicrobial drugs has been considered a public health problem. Likewise, the increasing resistance of cancer cells to drugs currently used in therapy has also become a problem. Therefore, the research and development of synthetic peptides bring a new perspective on the emergence of new drugs for treating this resistance since bioinformatics provides a means to optimize these molecules and save time and costs in research. Peptides have several mechanisms of action, such as forming pores on the cell membrane and inhibiting protein synthesis. Some studies report the use of antimicrobial peptides with the potential for action against cancer cells, suggesting a repositioning of antimicrobial peptides to fight back cancer resistance. There is an alteration in the microenvironment, making its net charge negative for the survival and growth of cancer cells. The changes in glycoproteins favor the membrane to have a more negative charge, favoring the interaction between the cells and the peptide, thus making possible the repositioning of these antimicrobial peptides against cancer. Here, we will discuss the mechanism of action, targets and effects of peptides, comparison between microbial and cancer cells, and proteomic changes caused by the interaction of peptides and cells.

PMID:38088493 | DOI:10.1002/cbdv.202301840

Expert Rev Clin Pharmacol. 2023 Dec 13. doi: 10.1080/17512433.2023.2293999. Online ahead of print.

ABSTRACT

INTRODUCTION: The implementation of pharmacogenetic analysis within clinical trials faces methodological, ethical, and regulatory challenges, as well as tackling the difficulty in obtaining actionable information with a sufficient level of evidence to enable its integration into routine clinical practice.

AREAS COVERED: we discuss the current status of pharmacogenetics integration in clinical trials, underscore the associated challenges, and make some suggestions on the aspects to address in any clinical trial including a pharmacogenetic evaluation. We conducted a literature review, thoroughly reviewed the applicable regulations and available guidelines, and assessed the application dossiers submitted for evaluation to the Ethics committee of Hospital La Paz (Madrid, Spain) to extract information related to inclusion of pharmacogenetics evaluations.

EXPERT OPINION: The integration of pharmacogenetics into clinical trials is becoming increasingly common. However, several regulatory, methodological and ethical aspects involved are insufficiently addressed. There is a need for specific and transparent guidelines that establish unified and compliant criteria for methodology, proper handling of samples in compliance with regulations, and the protection of data privacy and confidentiality. Participants should receive complete and appropriate information regarding the purpose, handling, storage, and transfer of their samples and data, and should have the right to decide about their processing.

PMID:38088171 | DOI:10.1080/17512433.2023.2293999

Clin Pharmacol Ther. 2023 Dec 13. doi: 10.1002/cpt.3115. Online ahead of print.

NO ABSTRACT

PMID:38087986 | DOI:10.1002/cpt.3115

J Med Biochem. 2023 Oct 27;42(4):675-684. doi: 10.5937/jomb0-43154.

ABSTRACT

BACKGROUND: Besides good glycemic control, also control of lipid levels can effectively prevent or delay late type 2 diabetes (T2D) complications. As apolipoprotein E (APOE) and paraoxonase 1 (PON1) were shown to suppress atherosclerosis, we investigated the associations of common functional PON1 and APOE polymorphisms with plasma lipid levels and the risk for late complications in T2D patients.

METHODS: Our retrospective genetic association study included 181 T2D patients genotyped for PON1 rs622, PON1 rs854560, APOE rs429358 and APOE rs7412.

PMID:38084238 | PMC:PMC10710788 | DOI:10.5937/jomb0-43154

BMC Genomics. 2023 Dec 11;24(1):761. doi: 10.1186/s12864-023-09869-2.

ABSTRACT

BACKGROUND: While product of the myostatin gene (MSTN) is an important factor influencing muscle growth, which is well confirmed in nonhuman species, it has not been clearly confirmed whether MSTN expression influences interindividual differences in skeletal muscle mass, affects posttraining changes, or plays a role in the age-related loss of muscle mass and function in humans. Although the inconclusive results are usually explained by ethnic differences and the low frequency of some alleles, it is possible that the role of receptors (ACVR2A and ACVR2B) that affect the biological activity of myostatin is crucial. Therefore, we investigated the sequences of the MSTN, ACVR2A, and ACVR2B genes and determined the interaction between allelic variants and athletic performance and competition level in the Caucasian population. One hundred-two athletes were recruited for the sequencing study, and whole-genome sequencing (WGS) was performed. Second, 330 athletes and 365 controls were included, and real-time PCR was performed.

RESULTS: The sequence analysis revealed two polymorphisms relatively common in the athlete cohort, and the alternate allele showed overrepresentation in athletes: MSTN rs11333758 and ACVR2A rs3764955. Regarding the polymorphic site MSTN rs11333758, there was a significant overrepresentation of the -/- genotype in all high-elite and mixed-sport high-elite athletes. Carriers of the ACVR2A rs3764955 CC and GG genotypes were more likely to be elite and high-elite athletes. In addition, carriers of the CC genotype were more likely to be in the mixed-sport subelite group. The gene‒gene interaction analysis revealed that mixed-sport high elite athletes showed significant underrepresentation of the ACVR2A rs3764955 GC - MSTN rs11333758 AA genotype combination. In the same group, we observed a significant overrepresentation of the ACVR2A rs3764955 GC - MSTN rs11333758 -/- and the ACVR2A rs3764955 CC - MSTN rs11333758 -/- genotype combinations.

CONCLUSIONS: We showed that the specific genotypes of the MSTN rs11333758 and ACVR2A rs3764955, either individually or in gene‒gene combination, are significantly associated with athletes' competition level in the Polish population, especially in the mixed-sports athlete group. Thus, although further research is required, these polymorphisms, alone or in combination with other polymorphisms, are among the numerous candidates that could explain individual variations in muscle phenotypes.

PMID:38082252 | DOI:10.1186/s12864-023-09869-2

J Arthroplasty. 2023 Dec 9:S0883-5403(23)01203-2. doi: 10.1016/j.arth.2023.12.011. Online ahead of print.

ABSTRACT

BACKGROUND: This prospective, observational study was designed to assess the phenotype variation of the genes associated with pain and opioid use following total knee arthroplasty in comparison to psycho-social elements.

METHODS: Preoperative demographic data and Patient-Reported Outcomes Measurement Information System (PROMIS)-43 scores were obtained on 305 elective total knee arthroplasty patients. Patient visual analog scale (VAS) pain scores and opioid use were extracted from the hospital record. Following discharge, participants completed a daily log of VAS pain score, and medications used over 30 days. Pharmacogenomic testing was performed for three genes, CYP2D6, COMT, and OPRM1, which are involved in the opioid pathway and pain modulation.

RESULTS: Other than increased pain seen in the COMT high activity group while in the hospital, none of the phenotype variations of the three genes were significantly associated with the participants' pain or opioid use. The PROMIS-43 domains of pain interference and anxiety were significantly associated with pain and opioid use using multiple logistic regression.

CONCLUSION: Pharmacogenomic testing in this study was not predictive of pain and opioid use following total knee arthroplasty compared with psycho-social variables.

PMID:38081553 | DOI:10.1016/j.arth.2023.12.011

Eur J Clin Pharmacol. 2023 Dec 11. doi: 10.1007/s00228-023-03598-x. Online ahead of print.

ABSTRACT

PURPOSE: Personalized pharmacotherapy, including for the pediatric population, provides optimal treatment and has emerged as a major trend owing to advanced drug therapeutics and diversified drug selection. However, it is essential to understand the growth and developmental characteristics of this population to provide appropriate drug therapy. In recent years, clinical pharmacogenetics has accumulated knowledge in pediatric pharmacotherapy, and guidelines from professional organizations, such as the Clinical Pharmacogenetics Implementation Consortium, can be consulted to determine the efficacy of specific drugs and the risk of adverse effects. However, the existence of a large knowledge gap hinders the use of these findings in clinical practice.

METHODS: We provide a narrative review of the knowledge gaps in pharmacokinetics (PK) and pharmacodynamics (PD) in the pediatric population, focusing on the differences from the perspective of growth and developmental characteristics. In addition, we explored PK/PD in relation to pediatric clinical pharmacogenetics.

RESULTS: The lack of direct and indirect biomarkers for more accurate assessment of the effects of drug administration limits the current knowledge of PD. In addition, incorporating pharmacogenetic insights as pivotal covariates is indispensable in this comprehensive synthesis for precision therapy; therefore, we have provided recommendations regarding the current status and challenges of personalized pediatric pharmacotherapy. The integration of clinical pharmacogenetics with the health care system and institution of educational programs for health care providers is necessary for its safe and effective implementation. A comprehensive understanding of the physiological and genetic complexities of the pediatric population will facilitate the development of effective and personalized pharmacotherapeutic strategies.

PMID:38078929 | DOI:10.1007/s00228-023-03598-x

Psychopharmacol Bull. 2023 Dec 4;53(4):8-14.

ABSTRACT

To date, haloperidol has been widely used to treat patients with acute alcoholic hallucinosis. There is strong evidence that haloperidol therapy is commonly associated with adverse drug reactions (ADRs). The 392A > G polymorphism of the CYP3A4*1B gene (rs2740574) is known to affect the metabolism rates of haloperidol; hence it correlates with both therapy efficacy and safety parameters.

OBJECTIVE: The study objective was to investigate the effect of 392A > G polymorphism of the CYP3A4*1B gene (rs2740574) on the efficacy and safety profiles of haloperidol in patients with acute alcoholic hallucinosis.

METHODS: This study enrolled 100 male patients suffering from acute alcoholic hallucinosis (mean age 41.4 ± 14.4 years). The efficacy profile of haloperidol was assessed using the PANSS (Positive and Negative Syndrome Scale) validated psychometric scale. The safety profile of therapy was assessed with the UKU Side-Effect Rating Scale and the SAS (Simpson-Angus Scale for Extrapyramidal Symptoms) scale. Genotyping was performed using the real-time polymerase chain reaction (Real-time PCR).

RESULTS: There were no statistically significant results for the efficacy rates (dynamics of the PANSS score: AA genotype -14.00 [-16.00; -12.00], AG genotype -13.00 [-14.00; -10.50], p = 0.306). Similarly, there was no statistically significant difference in the safety profiles (dynamics of the UKU score: AA genotype - 9.00 [7.00; 13.00], AG genotype - 8.50 [7.25; 10.50], p = 0.620; dynamics of the SAS score: AA genotype -12.00 [10.00; 16.75], AG genotype - 10.00 [10.00; 12.25], p = 0.321).

CONCLUSION: The study demonstrated that the 392A > G polymorphism of the CYP3A4*1B gene (rs2740574) in patients with acute alcoholic hallucinosis does not affect the efficacy and safety rates of haloperidol therapy.

PMID:38076668 | PMC:PMC10698852

Psychopharmacol Bull. 2023 Dec 4;53(4):15-22.

ABSTRACT

Haloperidol is currently used in addictology for the treatment of acute psychotic disorders, including acute alcoholic hallucinosis. The use of haloperidol is often accompanied by the occurrence of adverse drug reactions (ADRs). There is evidence that CYP2D6 isoenzyme is involved in the biotransformation of haloperidol.

AIM: The study aimed to evaluate the relationship of 1846G > A polymorphism of the CYP2D6 gene to the equilibrium concentration levels of haloperidol in patients with acute alcoholic hallucinosis.

MATERIAL AND METHODS: The study was conducted on 100 male patients with acute alcoholic hallucinosis (mean age 41.4 ± 14.4 years). The efficacy profile was evaluated using the PANSS (Positive and Negative Syndrome Scale) scale. The safety of therapy was assessed using the UKU Side-Effect Rating Scale and the SAS (Simpson-Angus Scale for Extrapyramidal Symptoms) scale. Genotyping was performed using the real-time polymerase chain reaction (Real-time PCR). Equilibrium plasma concentration levels of haloperidol were investigated using the high-performance liquid chromatography with mass spectrometry (HPLC with MS/MS).

RESULTS: No statistically significant results were obtained during the therapy efficacy assessment (dynamics of the PANSS score: GG genotype (-13.00 [-16.00; -16.00; -11.00]), GA genotype (-15.00 [-16.75; -13.00], p = 0.728). There was a statistically significant difference in safety assessment scores (dynamics of the UKU score: GG genotype (8.00 [7.00; 10.00]), GA genotype (15.00 [9.25; 18.00], p < 0.001); dynamics of the SAS score: GG genotype (11.00 [9.00; 14.00]), GA genotype (14.50 [12.00; 18.00], p < 0.001). The pharmacokinetic study results showed a statistically significant difference: GG (3.13 [2.32; 3.95]), GA (3.89 [2.92; 5.26], p = 0.010). Thus, a study conducted on a group of 100 patients with acute alcoholic hallucinosis demonstrated an association between the 1846G > A polymorphism of the CYP2D6 gene (rs3892097) and the safety profile of haloperidol therapy. We also revealed the presence of statistically significant difference in the equilibrium concentration levels of haloperidol in patients with the GG and AG genotypes.

CONCLUSION: It can be concluded that patients with the GA genotype have a higher risk of ADRs compared to patients carrying the GG genotype. It is shown that 1846G > A polymorphism of the CYP2D6 gene (rs3892097) has a statistically significant effect on the equilibrium concentration levels of haloperidol.

PMID:38076663 | PMC:PMC10698856

Front Pharmacol. 2023 Nov 23;14:1280099. doi: 10.3389/fphar.2023.1280099. eCollection 2023.

ABSTRACT

Introduction: Target therapy for cancer cell mutation has brought attention to several challenges in clinical applications, including limited therapeutic targets, less patient benefits, and susceptibility to acquired due to their clear biological mechanisms and high specificity in targeting cancers with specific mutations. However, the identification of truly lethal synthetic lethal therapeutic targets for cancer cells remains uncommon, primarily due to compensatory mechanisms. Methods: In our pursuit of core therapeutic targets (CTTs) that exhibit extensive synthetic lethality in cancer and the corresponding potential drugs, we have developed a machine-learning model that utilizes multiple levels and dimensions of cancer characterization. This is achieved through the consideration of the transcriptional and post-transcriptional regulation of cancer-specific genes and the construction of a model that integrates statistics and machine learning. The model incorporates statistics such as Wilcoxon and Pearson, as well as random forest. Through WGCNA and network analysis, we identify hub genes in the SL network that serve as CTTs. Additionally, we establish regulatory networks for non-coding RNA (ncRNA) and drug-target interactions. Results: Our model has uncovered 7277 potential SL interactions, while WGCNA has identified 13 gene modules. Through network analysis, we have identified 30 CTTs with the highest degree in these modules. Based on these CTTs, we have constructed networks for ncRNA regulation and drug targets. Furthermore, by applying the same process to lung cancer and renal cell carcinoma, we have identified corresponding CTTs and potential therapeutic drugs. We have also analyzed common therapeutic targets among all three cancers. Discussion: The results of our study have broad applicability across various dimensions and histological data, as our model identifies potential therapeutic targets by learning multidimensional complex features from known synthetic lethal gene pairs. The incorporation of statistical screening and network analysis further enhances the confidence in these potential targets. Our approach provides novel theoretical insights and methodological support for the identification of CTTs and drugs in diverse types of cancer.

PMID:38074121 | PMC:PMC10701285 | DOI:10.3389/fphar.2023.1280099

Front Pharmacol. 2023 Nov 22;14:1294873. doi: 10.3389/fphar.2023.1294873. eCollection 2023.

ABSTRACT

Introduction: Methotrexate (MTX) is one of the most important drugs included in the first-line protocols to treat high-grade osteosarcoma (HGOS). Although several polymorphisms have been reported to be associated with drug response or MTX-related toxicity in pharmacogenetic studies, their role in the development of MTX resistance in HGOS is still unclear. Methods: Therefore, in this study, 22 single nucleotide polymorphisms (SNPs) in 4 genes of the folate metabolism, 7 MTX transporter genes, and 2 SNPs of the tumor protein p53 (TP53) gene were investigated using a custom multimodal-targeted next-generation sequencing (mmNGS) approach in 8 MTX-resistant and 12 MTX-sensitive human HGOS cell lines. The panel was validated by TaqMan genotyping assays. Results: High instability of TP53 rs1642785 was observed in all U-2OS/MTX variants. Allele changes of the solute carrier family 19 member 1/replication factor C subunit 1 (SLC19A1, previously known as RFC1) and rs1051266 were identified in all Saos-2/MTX-resistant variants in both DNA- and RNA- derived libraries compared to the parental Saos-2 cell line. Allele changes of methylenetetrahydrofolate reductase (MTHFR) rs1801133 were identified only in the RNA-derived libraries of the two U2OS variants with the highest MTX resistance level. Significantly upregulated gene expression associated with the development of MTX resistance was revealed for dihydrofolate reductase (DHFR) whereas SLC19A1 was downregulated. In addition, a fusion transcript of DHFR (ex4) and MutS Homolog 3 (MSH3) (ex9) was identified in the RNA libraries derived from the two U-2OS variants with the highest MTX resistance level. Conclusion: This innovative mmNGS approach enabled the simultaneous exploration of SNPs at DNA and RNA levels in human HGOS cell lines, providing evidence of the functional involvement of allele changes associated with the development of MTX resistance.

PMID:38074116 | PMC:PMC10698553 | DOI:10.3389/fphar.2023.1294873

Neurogastroenterol Motil. 2023 Dec 10:e14722. doi: 10.1111/nmo.14722. Online ahead of print.

ABSTRACT

BACKGROUND: How variations predicted by pharmacogenomic testing to alter drug metabolism and therapeutic response affect outcomes for patients with disorders of gut- brain interaction is unclear.

AIMS: To assess the prevalence of pharmacogenomics-predicted drug-gene interactions and symptom outcomes for patients with disorders of gut-brain interaction.

METHODS: Patients who were treated in our clinical practice for functional dyspepsia/bowel disorder underwent pharmacogenomic testing. The change in symptoms from baseline to 6 months was compared for patients with variations in CYP2D6 and CYP2C19, which metabolize neuromodulators, and SLC6A4, which encodes the sodium- dependent serotonin transporter.

RESULTS: At baseline, 79 of 94 participants (84%) had at least one predicted major drug- gene interaction, and all 94 (100%) had at least one predicted moderate interaction. For the 44 participants who completed a survey of their symptoms at 6 months, the mean (SD) irritable bowel syndrome-symptom severity score decreased from 284 (71) at baseline to 231 (95) at 6 months (p < 0.001). Among patients taking selective serotonin reuptake inhibitors, the decrease in symptom severity (p = 0.03) and pain (p = 0.002) scores from baseline to 6 months was greater for patients with a homozygous SLC6A4 long/long genotype (n = 30) (ie, increased serotonin transporter activity) than for patients with homozygous short/short or heterozygous long/short genotypes (n = 64). Symptom outcomes were not affected by CYP2D6 or CYP2C19 variations.

CONCLUSIONS: The homozygous SLC6A4 long/long genotype confers better symptom resolution for patients with disorders of gut-brain interaction who take selective serotonin reuptake inhibitors than do the homozygous short/short or heterozygous long/short genotypes.

PMID:38072827 | DOI:10.1111/nmo.14722

Lancet Gastroenterol Hepatol. 2024 Jan;9(1):83-91. doi: 10.1016/S2468-1253(23)00270-4.

ABSTRACT

As morbidity and mortality related to potentially preventable liver diseases are on the rise globally, early detection of liver fibrosis offers a window of opportunity to prevent disease progression. Early detection of non-alcoholic fatty liver disease allows for initiation and reinforcement of guidance on bodyweight management, risk stratification for advanced liver fibrosis, and treatment optimisation of diabetes and other metabolic complications. Identification of alcohol-related liver disease provides the opportunity to support patients with detoxification and abstinence programmes. In all patient groups, identification of cirrhosis ensures that patients are enrolled in surveillance programmes for hepatocellular carcinoma and portal hypertension. When considering early detection strategies, success can be achieved from applying ad-hoc screening for liver fibrosis in established frameworks of care. Patients with type 2 diabetes are an important group to consider case findings of advanced liver fibrosis and cirrhosis, as up to 19% have advanced fibrosis (which is ten times higher than the general population) and almost 70% have non-alcoholic fatty liver disease. Additionally, patients with type 2 diabetes with alcohol use disorders have the highest proportion of liver-related morbidity of people with type 2 diabetes generally. Patients with type 2 diabetes receive an annual diabetes review as part of their routine clinical care, in which the health of many organs are considered. Yet, liver health is seldom included in this review. This Viewpoint argues that augmenting the existing risk stratification strategy with an additional liver health check provides the opportunity to detect advanced liver fibrosis, thereby opening a window for early interventions to prevent end-stage liver disease and its complications, including hepatocellular carcinoma.

PMID:38070521 | DOI:10.1016/S2468-1253(23)00270-4