Cancers (Basel). 2024 Feb 29;16(5):995. doi: 10.3390/cancers16050995.

ABSTRACT

This study investigated the health economic evaluations of predictive biomarker testing in solid tumours treated with immune checkpoint inhibitors (ICIs). Searching PubMed, EMBASE, and Web of Science from June 2010 to February 2022, 58 relevant articles were reviewed out of the 730 screened. The focus was predominantly on non-small cell lung cancer (NSCLC) (65%) and other solid tumours (40%). Among the NSCLC studies, 21 out of 35 demonstrated cost-effectiveness, notably for pembrolizumab as first-line treatment when preceded by PD-L1 assessment, cost-effective at a threshold of $100,000/QALY compared to the standard of care. However, for bladder, cervical, and triple-negative breast cancers (TNBCs), no economic evaluations met the affordability threshold of $100,000/QALY. Overall, the review highlights a certain degree of uncertainty about the cost-effectiveness of ICI. In particular, we found PD-L1 expression associated with ICI treatment to be a cost-effective strategy, particularly in NSCLC, urothelial, and renal cell carcinoma. The findings suggest the potential value of predictive biomarker testing, specifically with pembrolizumab in NSCLC, while indicating challenges in achieving cost-effectiveness for certain other solid tumours.

PMID:38473355 | DOI:10.3390/cancers16050995

Foods. 2024 Feb 27;13(5):723. doi: 10.3390/foods13050723.

ABSTRACT

Instant rice congee (IRC) fortified with functional ingredients is designed for supplementation in nourishing the elderly. In this study, collagen peptide and curcumin were fortified in IRC to improve antioxidant and protein content. Different cooking methods were used to prepare rice congee in order to retain the nutritional content of instant fortified rice congee (IFRC). The effect of cooking methods on IFRC were investigated in this study using field emission scanning electron microscopy (FESEM) and Fourier transform infrared spectroscopy (FTIR). As for cooking methods, the steaming method (IFRC-S) exhibited the highest total phenolic content (TPC) at 36.13 ± 5.63 mg GAE/g sample; a ferric reducing antioxidant power (FRAP) value of 6.39 ± 0.24 mg TE/g sample and protein content at 52.20 ± 6.48%. There were no significant differences (p > 0.05) in the texture analysis of hardness, cohesiveness and viscosity between the different cooking methods. However, the boiling method (IFRC-B) showed the highest adhesiveness, at -58.78 ± 11.55 g/s. IFRC with different cooking methods also had no significant differences (p > 0.05) in bulk density, volume expansion and the water absorption index. In sensory analysis, it was found that there were no significant differences (p > 0.05) detected in attribute colour, odour, taste, texture and overall acceptability between each cooking method. This study is particularly useful for gaining a preliminary understanding of the development of IRC focused on the elderly.

PMID:38472836 | DOI:10.3390/foods13050723

BMJ Open Diabetes Res Care. 2024 Mar 12;12(2):e003769. doi: 10.1136/bmjdrc-2023-003769.

ABSTRACT

INTRODUCTION: Genetic variants contribute to differential responses to non-insulin antidiabetic drugs (NIADs), and consequently to variable plasma glucose control. Optimal control of plasma glucose is paramount to minimizing type 2 diabetes-related long-term complications. India's distinct genetic architecture and its exploding burden of type 2 diabetes warrants a population-specific survey of NIAD-associated pharmacogenetic (PGx) variants. The recent availability of large-scale whole genomes from the Indian population provides a unique opportunity to generate a population-specific map of NIAD-associated PGx variants.

RESEARCH DESIGN AND METHODS: We mined 1029 Indian whole genomes for PGx variants, drug-drug interaction (DDI) and drug-drug-gene interactions (DDGI) associated with 44 NIADs. Population-wise allele frequencies were estimated and compared using Fisher's exact test.

RESULTS: Overall, we found 76 known and 52 predicted deleterious common PGx variants associated with response to type 2 diabetes therapy among Indians. We report remarkable interethnic differences in the relative cumulative counts of decreased and increased response-associated alleles across NIAD classes. Indians and South Asians showed a significant excess of decreased metformin response-associated alleles compared with other global populations. Network analysis of shared PGx genes predicts high DDI risk during coadministration of NIADs with other metabolic disease drugs. We also predict an increased CYP2C19-mediated DDGI risk for CYP3A4/3A5-metabolized NIADs, saxagliptin, linagliptin and glyburide when coadministered with proton-pump inhibitors (PPIs).

CONCLUSIONS: Indians and South Asians have a distinct PGx profile for antidiabetes drugs, marked by an excess of poor treatment response-associated alleles for various NIAD classes. This suggests the possibility of a population-specific reduced drug response in atleast some NIADs. In addition, our findings provide an actionable resource for accelerating future diabetes PGx studies in Indians and South Asians and reconsidering NIAD dosing guidelines to ensure maximum efficacy and safety in the population.

PMID:38471670 | PMC:PMC10936492 | DOI:10.1136/bmjdrc-2023-003769

J Control Release. 2024 Mar 10:S0168-3659(24)00163-9. doi: 10.1016/j.jconrel.2024.03.011. Online ahead of print.

ABSTRACT

Scramblase Xkr8 regulates the externalization of phosphatidylserine (PS) during apoptosis and holds a pivotal role in fostering tumor immunosuppression. Targeting Xkr8 in conjunction with chemotherapy demonstrated a novel avenue for amplifying antitumor immune response and overcoming chemo-immune resistance. Here we further evaluated this strategy by using a clinically relevant orthotopic model and elucidated the mechanism through in-depth single-cell RNA sequencing (scRNA-seq). We found that Xkr8 knockdown exhibited the potential to lead to immunogenic cell death (ICD) by impeding the normal clearance of apoptotic cells. Co-delivery of Xkr8 small interference RNA (siRNA) and chemo prodrug FuOXP showed remarkable therapeutic efficacy in an orthotopic pancreatic tumor model with an increase of proliferative NK cells and activated macrophages infiltration in the tumor microenvironment (TME). Single-cell trajectory analysis further unveiled that tumor infiltrating CD8+ T cells are differentiated favorably to cytotoxic over exhausted phenotype after combination treatment. Our study sheds new light on the impact of Xkr8 knockdown on TME and solidifies the rationale of combining Xkr8 knockdown with chemotherapy to treat various types of cancers.

PMID:38471639 | DOI:10.1016/j.jconrel.2024.03.011

Drug Metab Dispos. 2024 Mar 11:DMD-AR-2024-001697. doi: 10.1124/dmd.124.001697. Online ahead of print.

ABSTRACT

Bupropion is used for treating depression, obesity, seasonal affective disorder, and for smoking cessation. Bupropion is commonly-prescribed, but has complex pharmacokinetics and interindividual variability in metabolism and bioactivation may influence therapeutic response, tolerability and safety. Bupropion is extensively and stereoselectively metabolized, the metabolites are pharmacologically active, and allelic variation in CYP2B6 affects clinical hydroxylation of single-dose bupropion. Genetic effects on stereoselective disposition of steady-state bupropion are not known. In this preplanned secondary analysis of a prospective, randomized, double-blinded, crossover study which compared brand and generic bupropion XL 300 mg drug products, we measured steady-state enantiomeric plasma and urine parent bupropion and primary and secondary metabolite concentrations. This investigation evaluated the influence of genetic polymorphisms in CYP2B6, CYP2C19, and P450 oxidoreductase on the disposition of Valeant Pharmaceuticals Wellbutrin brand bupropion in 67 participants with major depressive disorder. We found that hydroxylation of both bupropion enantiomers was lower in carriers of the CYP2B6*6 allele and in carriers of the CYP2B6 516G>T variant, with correspondingly greater bupropion and lesser hydroxybupropion plasma concentrations. Hydroxylation was 25-50% lower in CYP2B6*6 carriers and one-third to one-half less in 516T carriers. Hydroxylation of the bupropion enantiomers was comparably affected by CYP2B6 variants. CYP2C19 polymorphisms did not influence bupropion plasma concentrations or hydroxybupropion formation but did influence the minor pathway of 4'-hydroxylation of bupropion and primary metabolites. P450 oxidoreductase variants did not influence bupropion disposition. Results show that CYP2B6 genetic variants affect steady-state metabolism and bioactivation of Valeant brand bupropion, which may influence therapeutic outcomes. Significance Statement Bupropion, used for depression, obesity, and smoking cessation, undergoes metabolic bioactivation, with incompletely elucidated interindividual variability. We evaluated CYP2B6, CYP2C19 and P450 oxidoreductase genetic variants and steady-state bupropion and metabolite enantiomers disposition. Both enantiomers hydroxylation was lower in CYP2B6*6 and CYP2B6 516G>T carriers, with greater bupropion and lesser hydroxybupropion plasma concentrations. CYP2C19 polymorphisms did not affect bupropion or hydroxybupropion but did influence minor 4'-hydroxylation of bupropion and primary metabolites. CYP2B6 variants affect steady-state bupropion bioactivation, which may influence therapeutic outcomes.

PMID:38467432 | DOI:10.1124/dmd.124.001697

Biochim Biophys Acta Gen Subj. 2024 Mar 9:130595. doi: 10.1016/j.bbagen.2024.130595. Online ahead of print.

ABSTRACT

Cytochrome P450 mediated substrate metabolism is generally characterized by the formation of reactive intermediates. In vitro and in vivo reaction uncoupling, results in the accumulation and dissociation of reactive intermediates, leading to increased ROS formation. The susceptibility towards uncoupling and altered metabolic activity is partly modulated by pharmacogenomic alleles resulting in amino acid substitutions. A large variability in the prevalence of these alleles has been demonstrated in CYP2B6, with some being predominantly unique to African populations. The aim of this study is to characterize the uncoupling potential of recombinant CYP2B6*1, CYP2B6*6 and CYP2B6*34 metabolism of specific substrates. Therefore, functional effects of these alterations on enzyme activity were determined by quantification of bupropion, efavirenz and ketamine biotransformation using HPLC-MS/MS. Determination of H2O2 levels was performed by the AmplexRed/ horseradish peroxidase assay. Our studies of the amino acid substitutions Q172H, K262R and R487S revealed an exclusive use of the peroxide shunt for the metabolism of bupropion and ketamine by CYP2B6.K262R. Ketamine was also identified as a trigger for the peroxide shunt in CYP2B6*1 and all variants. Concurrently, ketamine acted as an uncoupler for all enzymes. We further showed that the expressed CYP2B6*34 allele results in the highest H2O2 formation. We therefore conclude that the reaction uncoupling and peroxide shunt are directly linked and can be substrate specifically induced with K262R carriers being most likely able to use the peroxide shunt and R487S carrier being most prone to reaction uncoupling. This elucidates the functional diversity of pharmacogenomic in drug metabolism and safety.

PMID:38467309 | DOI:10.1016/j.bbagen.2024.130595

Eur J Clin Pharmacol. 2024 Mar 11. doi: 10.1007/s00228-024-03657-x. Online ahead of print.

ABSTRACT

PURPOSE: In order to explore clinical pharmacology and therapeutics (CPT) teaching and practices across continental Europe, the European Association of Clinical Pharmacology and Therapeutics (EACPT) made a survey in 2022 amongst its 27 affiliated societies.

METHODS: The survey was made available online to EACPT representatives, and 47 filled-in questionnaires were received from 25 countries (one to five per country), representing all geographic areas of Europe.

RESULTS: Clinical pharmacologists (CPs) spend 25%, 30%, 15%, and 25% of their time in teaching, hospital activities, committees, and research, respectively, with large variations across and within countries. CPT courses are given at Schools of Medicine in all the countries except one, mostly organized and taught by medical doctors (MDs). In Central, Western, and Southern Europe, the teachers may have medicine or pharmacy training. Therapeutic drug monitoring and pharmacovigilance were the hospital activities most frequently reported, and clinical/forensic toxicology, rounds of visits, and pharmacogenetics the least. Two-thirds of the panel think CPs should be MDs. However, the transversal nature of CPT was underlined, with patients/diseases and drugs as gravity centres, thus calling for the complementary skills of MDs and PharmDs. Besides, most respondents reported that clinical pharmacists in their country are involved in rounds of visits, pharmacovigilance, TDM, and/or pharmacogenetic testing and that collaborations with them would be beneficial.

CONCLUSION: CPT comes with a plurality of backgrounds and activities, all required to embrace the different pathologies and the whole lifecycle of medicinal products, but all of them being rarely performed in any given country. The willingness to use common CPT teaching material and prescribing exams at the European level is a good sign of increasing harmonisation of our discipline Europewide.

PMID:38466425 | DOI:10.1007/s00228-024-03657-x

Pharmacogenet Genomics. 2024 Mar 11. doi: 10.1097/FPC.0000000000000527. Online ahead of print.

ABSTRACT

OBJECTIVE: We aim to develop a personalized dosing tool for tricyclic antidepressants (TCAs) that integrates CYP2D6 and CYP2C19 gene variants and their effects while also considering the polypharmacy effect.

METHODS: The study first adopted a scoring system that assigns weights to each genetic variant. A formula was then developed to compute the effect of both genes' variants on drug dosing. The output of the formula was assessed by a comparison with the clinical pharmacogenetics implementation consortium recommendation. The study also accounts for the effect of the co-administration of inhibitors and inducers on drug metabolism. Accordingly, a user-friendly tool, Clinical Dosing Tool ver.2, was created to assist clinicians in dosing patients on TCAs.

RESULTS: The study provides a comprehensive list of all alleles with corresponding activity values and phenotypes for both enzymes. The tool calculated an updated area under the curve ratio that utilizes the effects of both enzymes' variants for dose adjustment. The tool provided a more accurate individualized dosing that also integrates the polypharmacy effect.

CONCLUSION: To the best of our knowledge, the literature misses such a tool that provides a numerical adjusted dose based on continuous numerical activity scores for the considered patients' alleles and phenoconversion.

PMID:38465522 | DOI:10.1097/FPC.0000000000000527

Clin Kidney J. 2024 Feb 21;17(3):sfae043. doi: 10.1093/ckj/sfae043. eCollection 2024 Mar.

ABSTRACT

Clinical genetics is increasingly recognized as an important area within nephrology care. Clinicians require awareness of genetic kidney disease to recognize clinical phenotypes, consider use of genomics to aid diagnosis, and inform treatment decisions. Understanding the broad spectrum of clinical phenotypes and principles of genomic sequencing is becoming increasingly required in clinical nephrology, with nephrologists requiring education and support to achieve meaningful patient outcomes. Establishment of effective clinical resources, multi-disciplinary teams and education is important to increase application of genomics in clinical care, for the benefit of patients and their families. Novel applications of genomics in chronic kidney disease include pharmacogenomics and clinical translation of polygenic risk scores. This review explores established and emerging impacts and utility of genomics in kidney disease.

PMID:38464959 | PMC:PMC10921391 | DOI:10.1093/ckj/sfae043

EPMA J. 2024 Feb 22;15(1):135-148. doi: 10.1007/s13167-024-00353-9. eCollection 2024 Mar.

ABSTRACT

Multidisciplinary team from three universities based in the "Centro" Region of Portugal developed diverse approaches as parts of a project dedicated to enhancing and expanding Predictive, Preventive, and Personalized Medicine (3PM) in the Region. In a sense, outcomes acted as a proof-of-concept, in that they demonstrated the feasibility, but also the relevance of the approaches. The accomplishments comprise defining a new regional strategy for implementing 3PM within the Region, training of human resources in genomic sequencing, and generating good practices handbooks dedicated to diagnostic testing via next-generation sequencing, to legal and ethical concerns, and to knowledge transfer and entrepreneurship, aimed at increasing literacy on 3PM approaches. Further approaches also included support for entrepreneurship development and start-ups, and diverse and relevant initiatives aimed at increasing literacy relevant to 3PM. Efforts to enhance literacy encompassed citizens across the board, from patients and high school students to health professionals and health students. This focus on empowerment through literacy involved a variety of initiatives, including the creation of an illustrated book on genomics and the production of two theater plays centered on genetics. Additionally, authors stressed that genomic tools are relevant, but they are not the only resources 3PM is based on. Thus, they defend that other initiatives intended to enable citizens to take 3PM should include multi-omics and, having in mind the socio-economic burden of chronic diseases, suboptimal health status approaches in the 3PM framework should also be considered, in order to anticipate medical intervention in the subclinical phase.

SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s13167-024-00353-9.

PMID:38463621 | PMC:PMC10923757 | DOI:10.1007/s13167-024-00353-9

Clin Exp Allergy. 2024 Mar 10. doi: 10.1111/cea.14470. Online ahead of print.

NO ABSTRACT

PMID:38462790 | DOI:10.1111/cea.14470

Life Sci. 2024 Mar 7:122547. doi: 10.1016/j.lfs.2024.122547. Online ahead of print.

ABSTRACT

Hepatic stellate cells (HSCs) play central roles in liver disease pathogenesis, spanning steatosis to cirrhosis and hepatocellular carcinoma. These cells, located in the liver's sinusoidal space of Disse, transition from a quiescent, vitamin A-rich state to an activated, myofibroblast-like phenotype in response to liver injury. This activation results from a complex interplay of cytokines, growth factors, and oxidative stress, leading to excessive collagen deposition and liver fibrosis, a hallmark of chronic liver diseases. Recently, HSCs have gained recognition for their dynamic, multifaceted roles in liver health and disease. Attention has shifted toward their involvement in various liver conditions, including acute liver injury, alcoholic and non-alcoholic fatty liver disease, and liver regeneration. This review aims to explore diverse functions of HSCs in these acute or chronic liver pathologies, with a focus on their roles beyond fibrogenesis. HSCs exhibit a wide range of actions, including lipid storage, immunomodulation, and interactions with other hepatic and extrahepatic cells, making them pivotal in the hepatic microenvironment. Understanding HSC involvement in the progression of liver diseases can offer novel insights into pathogenic mechanisms and guide targeted therapeutic strategies for various liver conditions.

PMID:38460810 | DOI:10.1016/j.lfs.2024.122547

J Law Med. 2023 Dec;30(4):884-898.

ABSTRACT

The mapping and sequencing of the human genome at the turn of the new millennium marks a pivotal reassessment of genomic science in its potential to replace traditional "one-size-fits-all" medicine with a personalised approach. The use of racial proxies in the development of pharmacogenomic products risks conflating genetics with race under the guise of alleviating health disparities. This article argues that the current genomic approaches to realising personalised medicine do not deliver on the promise for optimised health for all and may result in irreversible harm, including psychological, social and medical harm, to racial minority groups. In light of recent epigenetic findings, the article provides a reconceptualisation of the genome and race, which is necessary to understand enduring racial disparities and the cumulative effects of racial discrimination. It then addresses the need for regulatory oversight of the approval of race-based pharmacogenomic products.

PMID:38459879

Orphanet J Rare Dis. 2024 Mar 8;19(1):106. doi: 10.1186/s13023-024-03118-9.

ABSTRACT

Tuberous sclerosis complex (TSC) is a rare inherited disease with the potential to affect virtually every organ system. Clinical presentation is age- and partly sex-dependent and varies broadly with respect to disease manifestations including treatment-refractory epilepsy, intellectual disability and TSC-associated neuropsychiatric disorders, chronic kidney disease or progressive lung function decline. Given the complexity of this disease, multidisciplinary care in specialized TSC centres is recommended. We aimed to elucidate the state of knowledge of patients/caregivers and physicians on individual disease manifestations. We further examined whether the association to a TSC centre has an impact on the comprehensive consideration of potential disease manifestations. Therefore, a survey was performed in a cohort of German TSC patients and their physicians. Complete information was available for 94 patients with a median age of 18 years [range 1-55] and a sex distribution of 53.2% (male): 48.8% (female). Using almost identical questionnaires for patients/caregivers and their respective physician, there was a good correlation for disease assessments associated with relevant morbidity and mortality like epilepsy, renal angiomyolipoma, cardiac rhabdomyomas or intellectual disability. Correlation was moderate for several neuropsychiatric disorders and only poor for hypomelanotic macules, dental pits or retinal achromic patches. Estimation of overall disease severity using a numeric rating scale correlated highly significantly (Pearson correlation coefficient = 0.767; p < 0.001) between patients/caregivers and physicians. In general, physicians more likely quoted items as 'unknown' than patients (822 answers vs. 435 answers in the respective groups). Questionnaires completed by physicians who were associated with a specialized TSC centre declared a significantly lower proportion of items as unknown (mean 8.7% vs. 20.5%; p < 0.001). These findings indicate that patients treated by specialized TSC centres seem to obtain a more comprehensive surveillance. Furthermore, it shows that there were reasonable surveillance strategies in general and sufficient patient/caregiver interaction and education in the examined cohort. However, for the most prominent disease characteristics there was a good awareness within both the patients/caregivers and the physicians group.

PMID:38459571 | DOI:10.1186/s13023-024-03118-9

Curr Pharm Teach Learn. 2024 Mar 7:S1877-1297(24)00037-6. doi: 10.1016/j.cptl.2024.02.006. Online ahead of print.

ABSTRACT

BACKGROUND AND PURPOSE: The Pharmacy Innovation Experience and Research (PIER) program aims to provide student pharmacists with co-curricular experiences that augment their essential soft skill training while recruiting underrepresented minority (URM) high school and undergraduate students to the pharmacy profession. The goal of the PIER mentoring program is to enhance the leadership, professionalism, teaching, and cultural sensitivity skills of student pharmacists through their participation in the program.

EDUCATIONAL ACTIVITY AND SETTING: During this pilot study, student pharmacists were trained to mentor high school and undergraduate students prior to the start of PIER. Pre- and post-program surveys were used to assess the self-perceived benefit PIER had on the soft skill development of student pharmacists. Survey responses were analyzed using unpaired t-tests.

FINDINGS: There was an observed increase in self-perceived abilities among student pharmacists in mentoring (82% versus 68%), leading a team (94% versus 82%), and teaching (77% versus 64%). In post-program surveys, 90% of the students viewed their experience as useful for their career versus 71% in pre-surveys. While a high percentage felt comfortable interacting with diverse participants (90%) and knowledgeable about diversity issues in healthcare (89%), the data indicated that the PIER program did not have a quantifiable impact on their cultural sensitivity.

SUMMARY: PIER is a co-curricular program for student pharmacists that enhances self-perception of essential soft skills for their careers. Nevertheless, additional assessment of the skills gained through PIER is needed to verify competency. Other schools of pharmacy should recognize the importance of programs like PIER to both recruit URMs to pharmacy schools and provide current students with a co-curricular experience that will encourage their success.

PMID:38458840 | DOI:10.1016/j.cptl.2024.02.006

Biomark Med. 2024 Mar 8. doi: 10.2217/bmm-2023-0476. Online ahead of print.

ABSTRACT

Coronary artery disease (CAD) has a high mortality rate. Despite various therapeutic targets, non-responsiveness to drugs remains a prevalent issue. Pharmacogenomics assesses the way an individual's genetic attributes affect their likely response to drug therapy. Single-nucleotide polymorphisms play a crucial role in determining these outcomes. This review offers an overview of single-nucleotide polymorphisms investigated in clinical studies and their associations with drug response/nonresponse in the treatment of CAD. A total of 104 studies of whole sets of chromosomes and several genes were explored. A total of 161 polymorphisms exhibited associations with drug response/nonresponse in CAD across diverse ethnic populations. This pool can serve as a pharmacogenomic biomarker for predicting response to drug therapy in patients with CAD.

PMID:38456296 | DOI:10.2217/bmm-2023-0476

Postgrad Med. 2024 Mar 7. doi: 10.1080/00325481.2024.2328513. Online ahead of print.

ABSTRACT

OBJECTIVES: The factors determining the response to treatment with glucagon-like peptide-1 receptor agonists (GLP-1- RAs) have not been clarified. The present study investigated the association between polymorphisms in TCF7L2, CTRB1/2 and GLP-1 R genes and response to GLP-1 RAs regarding glycemic control and weight loss among Greek patients with type 2 diabetes mellitus (T2DM).

METHODS: Patients (n = 191) treated with GLP-1 RAs for at least 6 months were included. Participants were genotyped for TCF7L2 rs7903146 (C>T), CTRB1/2 rs7202877 (T>G) and GLP-1 R rs367543060 (C>T) polymorphisms. Clinical and laboratory parameters were measured before, 3, and 6 months after treatment initiation. The patients were classified into responders and non-responders according to specific criteria.

RESULTS: Carriers of at least one rs7903146 'T' allele and rs7202877 'G' allele presented similar glucose control and weight loss response to GLP-1 RAs with the respective homozygous wild-type genotypes [odds ratio (OR): 1.08, 95% confidence interval (CI): 0.5, 2.31, p = 0.85 and OR: 1.35, 95% CI: 0.66, 2.76, p = 0.42; OR: 1.4, 95% CI: 0.56, 3.47, p = 0.47 and OR: 1.28, 95% CI: 0.55, 2.98, p = 0.57, respectively). Regarding the GLP-1 R polymorphism, all participants were homozygous for the wild-type allele; thus, no comparisons were feasible. Female sex (p = 0.03) and lower baseline weight (p = 0.024) were associated with an improved glycemic and weight loss response, respectively.

CONCLUSION: There is no evidence suggesting a role for the variants studied in response to GLP-1 RA therapy in people with T2DM. However, specific demographic and clinical factors may be related to a better response to treatment with these agents.

PMID:38453649 | DOI:10.1080/00325481.2024.2328513

Pharmacogenomics. 2024 Mar 7. doi: 10.2217/pgs-2023-0234. Online ahead of print.

NO ABSTRACT

PMID:38450459 | DOI:10.2217/pgs-2023-0234

Br J Biomed Sci. 2024 Feb 21;81:11835. doi: 10.3389/bjbs.2024.11835. eCollection 2024.

ABSTRACT

Background: Publications on the associations of genetic variants with the response to platinum-based chemotherapy (PBC) in NSCLC patients have surged over the years, but the results have been inconsistent. Here, a comprehensive meta-analysis was conducted to combine eligible studies for a more accurate assessment of the pharmacogenetics of PBC in NSCLC patients. Methods: Relevant publications were searched in PubMed, Scopus, and Web of Science databases through 15 May 2021. Inclusion criteria for eligible publications include studies that reported genotype and allele frequencies of NSCLC patients treated with PBC, delineated by their treatment response (sensitive vs. resistant). Publications on cell lines or animal models, duplicate reports, and non-primary research were excluded. Epidemiological credibility of cumulative evidence was assessed using the Newcastle-Ottawa Scale (NOS) and Venice criteria. Begg's and Egger's tests were used to assess publication bias. Cochran's Q-test and I2 test were used to calculate the odds ratio and heterogeneity value to proceed with the random effects or fixed-effects method. Venice criteria were used to assess the strength of evidence, replication methods and protection against bias in the studies. Results: A total of 121 publications comprising 29,478 subjects were included in this study, and meta-analyses were performed on 184 genetic variants. Twelve genetic variants from 10 candidate genes showed significant associations with PBC response in NSCLC patients with strong or moderate cumulative epidemiological evidence (increased risk: ERCC1 rs3212986, ERCC2 rs1799793, ERCC2 rs1052555, and CYP1A1 rs1048943; decreased risk: GSTM1 rs36631, XRCC1 rs1799782 and rs25487, XRCC3 rs861539, XPC rs77907221, ABCC2 rs717620, ABCG2 rs2231142, and CDA rs1048977). Bioinformatics analysis predicted possible damaging or deleterious effects for XRCC1 rs1799782 and possible low or medium functional impact for CYP1A1 rs1048943. Conclusion: Our results provide an up-to-date summary of the association between genetic variants and response to PBC in NSCLC patients.

PMID:38450253 | PMC:PMC10914946 | DOI:10.3389/bjbs.2024.11835

Front Neuroinform. 2024 Feb 21;17:1244336. doi: 10.3389/fninf.2023.1244336. eCollection 2023.

ABSTRACT

INTRODUCTION: Pharmacogenetics currently supports clinical decision-making on the basis of a limited number of variants in a few genes and may benefit paediatric prescribing where there is a need for more precise dosing. Integrating genomic information such as methylation into pharmacogenetic models holds the potential to improve their accuracy and consequently prescribing decisions. Cytochrome P450 2D6 (CYP2D6) is a highly polymorphic gene conventionally associated with the metabolism of commonly used drugs and endogenous substrates. We thus sought to predict epigenetic loci from single nucleotide polymorphisms (SNPs) related to CYP2D6 in children from the GUSTO cohort.

METHODS: Buffy coat DNA methylation was quantified using the Illumina Infinium Methylation EPIC beadchip. CpG sites associated with CYP2D6 were used as outcome variables in Linear Regression, Elastic Net and XGBoost models. We compared feature selection of SNPs from GWAS mQTLs, GTEx eQTLs and SNPs within 2 MB of the CYP2D6 gene and the impact of adding demographic data. The samples were split into training (75%) sets and test (25%) sets for validation. In Elastic Net model and XGBoost models, optimal hyperparameter search was done using 10-fold cross validation. Root Mean Square Error and R-squared values were obtained to investigate each models' performance. When GWAS was performed to determine SNPs associated with CpG sites, a total of 15 SNPs were identified where several SNPs appeared to influence multiple CpG sites.

RESULTS: Overall, Elastic Net models of genetic features appeared to perform marginally better than heritability estimates and substantially better than Linear Regression and XGBoost models. The addition of nongenetic features appeared to improve performance for some but not all feature sets and probes. The best feature set and Machine Learning (ML) approach differed substantially between CpG sites and a number of top variables were identified for each model.

DISCUSSION: The development of SNP-based prediction models for CYP2D6 CpG methylation in Singaporean children of varying ethnicities in this study has clinical application. With further validation, they may add to the set of tools available to improve precision medicine and pharmacogenetics-based dosing.

PMID:38449836 | PMC:PMC10915285 | DOI:10.3389/fninf.2023.1244336