Breast Cancer (Auckl). 2024 Nov 27;18:11782234241285411. doi: 10.1177/11782234241285411. eCollection 2024.

ABSTRACT

BACKGROUND: Breast cancer remains the most common invasive cancer in women worldwide. Triple-negative breast cancer (TNBC) is an aggressive subtype with limited treatment options. Trastuzumab (Tz) is typically used to treat HER2-positive breast cancers, but its potential in TNBC is unclear.

OBJECTIVES: To investigate the effects of trastuzumab on cell viability, apoptosis, cell cycle progression, and gene expression in TNBC cell lines compared with HER2-positive and normal cell lines.

DESIGN: This is an in vitro experimental pre-clinical study using cultured cancer cell lines.

METHODS: MDA-MB-231 and 4T1 (TNBC), MCF-7 (HER2-positive), and HSF (normal) cell lines were treated with 20 μg/mL trastuzumab for 24 hours. Cell viability was assessed by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, apoptosis by flow cytometry, cell cycle progression by DNA content analysis, and gene expression by qPCR.

RESULTS: Trastuzumab significantly reduced cell viability and induced apoptosis in TNBC cell lines, comparable to effects in HER2-positive MCF-7 cells. Cell cycle analysis revealed G2/M phase arrest in TNBC cells. Gene expression analysis showed upregulation of ERBB2, NOTCH1, EGFR, PIK3CA, and PTEN in MDA-MB-231 cells, while 4T1 cells exhibited downregulation of most genes except NOTCH1.

CONCLUSION: This study provides initial evidence for trastuzumab's potential therapeutic effects in TNBC, despite low HER2 expression. The observed cytotoxicity, apoptosis induction, and cell cycle modulation in TNBC cells warrant further investigation into trastuzumab's mechanisms of action in HER2-negative contexts and its potential repurposing for TNBC treatment.

PMID:39611037 | PMC:PMC11603482 | DOI:10.1177/11782234241285411

J Diabetes Metab Disord. 2024 Sep 23;23(2):2279-2287. doi: 10.1007/s40200-024-01495-3. eCollection 2024 Dec.

ABSTRACT

OBJECTIVES: The efficacy and safety of drug treatments vary widely due to genetic variations. Pharmacogenomics investigates the impact of genetic variations on patient drug response. This research investigates the frequency of UGT1A1 genetic variations in the Iranian population, comparing them with global data to provide insights into the pharmacogenomic approach in the Iranian population.

METHODS: The study was conducted using the data of the Bushehr Elderly Health (BEH) program, a population-based cohort study of the elderly population aged ≥ 60 years. Genotyping of three UGT1A1 variant alleles (UGT1A1*6, UGT1A1*27, and UGT1A1*80) was performed on a group of 2730 elderly Iranian participants with the Infinium Global Screening Array.

RESULTS: The genotyping analysis revealed significant differences compared to major global populations that were addressed in the gnomAD database. UGT1A1*80 was found at a high frequency (32.34%), and followed by UGT1A1*6 (0.76%) and UGT1A1*27 (0.018) at a low frequency in the Iranian group.

CONCLUSIONS: The UGT1A1*80 was the more prevalent allele between investigated alleles in the present study which can be considered as an important allele for pharmacogenomic testing.

PMID:39610552 | PMC:PMC11599689 | DOI:10.1007/s40200-024-01495-3

JAMA Neurol. 2024 Nov 29. doi: 10.1001/jamaneurol.2024.4487. Online ahead of print.

ABSTRACT

IMPORTANCE: Typical cysteine-altering NOTCH3 (NOTCH3cys) variants are highly prevalent (approximately 1 in 300 individuals) and are associated with a broad spectrum of small vessel disease (SVD), ranging from early-onset stroke and dementia (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy [CADASIL]) to nonpenetrance. A staging system that captures the full NOTCH3-SVD severity spectrum is needed and currently lacking.

OBJECTIVE: To design a simple disease severity staging system that captures the broad clinicoradiological NOTCH3-SVD severity spectrum.

DESIGN, SETTING, AND PARTICIPANTS: A cohort study was performed in which the NOTCH3-SVD severity staging system was developed using a discovery cohort (2019-2020) and validated in independent international CADASIL cohorts (1999-2023) and the UK Biobank. Clinical and imaging data were collected from participants originating from 23 international CADASIL cohorts and from the UK Biobank. Eligibility criteria were presence of a NOTCH3cys variant, availability of brain magnetic resonance imaging, and modified Rankin Scale score. The discovery cohort consisted of 195 NOTCH3cys-positive cases from families with CADASIL; the validation set included 1713 NOTCH3cys-positive cases from 15 countries. The UK Biobank cohort consisted of 101 NOTCH3cys-positive individuals. Data from 2-year (2019-2023) and 18-year (1999-2017) follow-up studies were also analyzed. Data analysis was performed from July 2023 to August 2024.

MAIN OUTCOMES AND MEASURES: Percentage of cases following the sequence of events of the NOTCH3-SVD stages, and the association between the stages and ischemic stroke, intracerebral hemorrhage, global cognition, processing speed, brain volume, brain microstructural damage, and serum neurofilament light chain (NfL) level.

RESULTS: The NOTCH3-SVD staging system encompasses 9 disease stages or substages, ranging from stage 0 (premanifest stage) to stage 4B (end stage). Of all 1908 cases, which included 195 in the discovery cohort (mean [SD] age, 52.4 [12.2] years) and 1713 in the validation cohorts (mean [SD] age, 53.1 [13.0] years), 1789 (94%) followed the sequence of events defined by the NOTCH3-SVD staging system. The NOTCH3-SVD stages were associated with neuroimaging outcomes in the NOTCH3cys-positive cases in the CADASIL cohorts and in the UK Biobank and with cognitive outcomes and serum NfL level in cases from the CADASIL cohorts. The NOTCH3-SVD staging system captured disease progression and was associated with 18-year survival.

CONCLUSIONS AND RELEVANCE: The NOTCH3-SVD staging system captures the full disease spectrum, from asymptomatic individuals with a NOTCH3cys variant to patients with end-stage disease. The NOTCH3-SVD staging system is a simple but effective tool for uniform disease staging in the clinic and in research.

PMID:39610302 | DOI:10.1001/jamaneurol.2024.4487

Genetics. 2024 Nov 28:iyae170. doi: 10.1093/genetics/iyae170. Online ahead of print.

ABSTRACT

The glucose-6-phosphate dehydrogenase (G6PD) enzyme protects red blood cells against oxidative damage. Individuals with G6PD-impairing polymorphisms are at risk of hemolytic anemia from oxidative stressors. Prevention of G6PD deficiency-related hemolytic anemia is achievable by identifying affected individuals through G6PD genetic testing. However, accurately predicting the clinical consequence of G6PD variants is limited by over 800 G6PD variants which remain of uncertain significance (VUS). There also remains inconsistency in which deficiency-causing variants are included in genetic testing arrays: many institutions only test c.202G > A, though dozens of other variants can cause G6PD deficiency. Here, we improve G6PD genotype interpretations using the All of Us Research Program data and a yeast functional assay. We confirm that G6PD coding variants are the main contributor to decreased G6PD activity and that 13% of individuals in the All of Us data with deficiency-causing variants would be missed by only genotyping for c.202G > A. We expand clinical interpretation for G6PD VUS, reporting that c.595A > G ("Dagua" or "Açores") and the novel variant c.430C > G reduce activity sufficiently to lead to G6PD deficiency. We also provide evidence that 5 missense VUS are unlikely to lead to G6PD deficiency, and we applied the new World Health Organization (WHO) guidelines to recommend classifying 2 synonymous variants as WHO Class C. In total, we provide new or updated clinical interpretations for 9 G6PD variants. We anticipate these results will improve the accuracy, and prompt increased use, of G6PD genetic tests through a more complete clinical interpretation of G6PD variants.

PMID:39607789 | DOI:10.1093/genetics/iyae170

J Clin Endocrinol Metab. 2024 Nov 28:dgae833. doi: 10.1210/clinem/dgae833. Online ahead of print.

ABSTRACT

AIMS: Central insulin has been shown to regulate eating behavior and cognitive processes in a sex-specific manner. Besides memory, the hippocampus is pivotal in the control of appetite. However, how insulin interacts with the hippocampal food cue response and the role of sex hormones in this context remain unclear.

METHODS: Using fMRI, we evaluated task-based functional connectivity (FC) of the hippocampus during food cue presentation in 60 participants (age: 21-69; 30 women) after intranasal insulin or placebo administration, in a randomized within-subject design. In an exploratory analysis, we investigated whether hippocampal FC after intranasal insulin administration is related to estradiol and progesterone levels during the follicular and luteal phase of the menstrual cycle in 13 premenopausal women (age: 20-28).

RESULTS: Intranasal insulin increased hippocampal FC with the prefrontal cortex compared to placebo, regardless of sex. This correlated with stronger reduction in subjective feeling of hunger and food craving. Moreover, we observed an interaction between sex and nasal spray condition with higher hippocampal FC to the calcarine gyrus after insulin compared to placebo in men, while women showed a lower response. In premenopausal women, the centrally mediated effect of insulin on hippocampus to calcarine gyrus FC negatively correlated with the estradiol/progesterone ratio in the luteal phase.

CONCLUSIONS: Central insulin influences hippocampal FC to regions vital for inhibitory control during high-caloric food cue presentation, implying a potential role of the hippocampal network in modulating insulin's anorexic effects. The observed sex differences between the hippocampus and visual cortex might be influenced by sex hormone action.

PMID:39607733 | DOI:10.1210/clinem/dgae833

Expert Opin Drug Metab Toxicol. 2024 Nov 28:1-16. doi: 10.1080/17425255.2024.2432664. Online ahead of print.

ABSTRACT

INTRODUCTION: Confusion regarding methadone metabolism exists, hampering optimal clinical use. A systematic review was conducted to assess the impacts of cytochrome P450 (CYP) genetic polymorphisms on methadone outcomes.

METHODS: MEDLINE, EMBASE, Web of Science, PsycINFO, and CENTRAL were searched to identify studies reporting methadone dose-adjusted plasma concentrations, clearance, maintenance dose, or treatment response in relation to CYP polymorphisms in humans. ROBINS-I was used to evaluate risk of bias in included studies. Each outcome was synthesized for each CYP using the ratio of means or odds ratio as the effect size measure.

RESULTS: Ten, two, fourteen, and five studies were included in the meta-analyses of the concentration, clearance, dose, and treatment response, respectively. The CYP2B6 c.516 G>T variant was robustly associated with (S)-methadone concentrations (GT+TTvs.GG: ratio of means (RoM) 1.40, p < 0.01) and clearance (GT+TTvs.GG: RoM 0.65, p < 0.01) but less with (R)- or (R,S)-methadone. The CYP2B6 variant also affected methadone dose for opioid use disorder (GT+TTvs.GG: RoM 0.93, p = 0.04). CYP2C19, CYP2C9, CYP2D6, and CYP3A5 polymorphisms did not influence any of the assessed outcomes.

CONCLUSIONS: CYP2B6 genetics had statistically significant impacts on (S)-methadone and less so on (R)-methadone exposure and clearance and was statistically significantly but not clinically meaningfully associated with dose requirements.

PMID:39607043 | DOI:10.1080/17425255.2024.2432664

Ulster Med J. 2024 Nov;93(3):111-118. Epub 2024 Nov 26.

ABSTRACT

The integration of genomic medicine within mainstream patient care promises advances in healthcare and potential benefits for disease prediction and personalised treatment approaches. This paper explores the challenges of integrating genomic medicine within the UK's National Health Service (NHS) and potential solutions for alignment with the NHS's proposed long-term plan and Genome UK strategy. Critical challenges and knowledge gaps have been identified, including a referral-dependent system, unclear eligibility criteria, lack of policies and guidelines, gaps in clinical genomic competence, genomic sequencing costs, equity issues for genomic testing access across the UK, and data management and patient privacy concerns. Proposed solutions and future directions include extending genetic test ordering authority to include mainstream clinicians and establishing unambiguous eligibility criteria, policies and guidelines through a developing trained workforce and appropriate patient engagement. Moreover, expanded Whole Genome Sequencing (WGS) and pharmacogenomic testing approaches through up-scaling genomic sequencing capacity and standardising genetic testing across the UK will lower consumable costs. Leveraging artificial intelligence (AI) and data warehousing approaches will improve data management, particularly in the context of integration within electronic health records. In summary, the successful integration of genomic medicine within mainstream patient care holds transformative potential for healthcare provision. By recognising the challenges identified and embracing the proposed solutions, healthcare systems can revolutionise patient outcomes, advancing precision medicine and shaping the future of genomic-driven healthcare.

PMID:39606143 | PMC:PMC11591220

J Pharm Policy Pract. 2024 Nov 26;17(1):2429785. doi: 10.1080/20523211.2024.2429785. eCollection 2024.

ABSTRACT

INTRODUCTION: Pharmacogenomics implementation in clinical practice is anticipated to improve our understanding of individual variations in drug response and optimise the safety and efficacy of drug therapy. We aimed to assess the knowledge, perceptions, and readiness of physicians, pharmacists, and nurses in Qatar regarding the implementation of clinical pharmacogenomics.

METHODS: A mixed-method study with an explanatory sequential design was conducted. Phase I was the quantitative phase which involved sending an online survey to physicians, pharmacists, and nurses. Phase II was the qualitative phase which involved conducting focus group discussions.

RESULTS: A total of 802 responses were collected, with a response rate of 20%. Only 15.4% of participants had previous pharmacogenomics-related training. The median knowledge score for healthcare professionals was 4 out of 10 denoting low level of knowledge. However, compared to other professions, pharmacists had a higher knowledge score (p-value <0.001) and Doctor of Pharmacy (PharmD) holders scored higher than BSc holders (p-value <0.001). Despite the low level of knowledge, perceptions of healthcare professionals were positive. In addition, the majority believed knowledge of pharmacogenomics is necessary and that counselling patients on pharmacogenomics requires specialised training pharmacogenomic principles in practice. The main themes extracted from the focus group discussions were knowledge, outcome expectations, preparedness, facilitators, barriers, public education, and implementation planning. Regarding readiness, most healthcare professionals reported that they are not currently confident in applying.

CONCLUSIONS: Healthcare providers have a low level of knowledge of pharmacogenomics. Despite this, the majority have positive perceptions towards its implementation in practice. Compared to other professionals, pharmacists with a PharmD degree scored higher in the knowledge assessment. Most healthcare providers report low confidence regarding the readiness for the implementation of pharmacogenomics and report a lack of knowledge, specialised training, and clinical guidelines as barriers.

PMID:39605985 | PMC:PMC11600515 | DOI:10.1080/20523211.2024.2429785

Sci Rep. 2024 Nov 27;14(1):29511. doi: 10.1038/s41598-024-79965-0.

ABSTRACT

Nevirapine (NVP) and Efavirenz (EFV) can cause antiretroviral drug-induced liver injury (ARVDILI). The objectives of this study were to summarize and analyze existing data on pharmacogenomics associated with nonnucleoside reverse transcriptase inhibitors drug-induced liver injury using systematic review and meta-analysis. This study systematically searched the relevant studies regarding pharmacogenes related to ARVDILI from online databases. Genes-encoding proteins were further analyzed using the STRING program to determine the protein-protein interactions (PPI). CYP2B6 polymorphisms were further meta-analyzed. Seventeen genes have been shown to be significantly associated with ARVDILI. Illustration from STRING analysis, CYP2B6, CYP1A1, and CYP2D6 enzymes have been recognized as central proteins linked to all other analyzed proteins. Meta-analysis illustrated that CYP2B6 *1/*6 (OR = 1.83; 95% CI: 1.15-2.90; P = 0.01), *6/*6 (OR = 2.48; 95% CI: 1.28-4.79; P = 0.007), and *1/*6 plus *6/*6 (OR = 1.94; 95% CI: 1.24-3.01; P = 0.003) were associated with risks of EFV-induced liver injury. Moreover, CYP2B6 *1/*6 (OR = 0.44; 95% CI: 0.22-0.91; P = 0.03) and a group combining individuals with either *1/*6 or *6/*6 (OR = 0.42; 95% CI: 0.21-0.84; P = 0.01) were associated with reduced risks of NVP-induced liver injury. This meta-analysis revealed an association between CYP2B6 genetic polymorphism and susceptibility to ARVDILI.

PMID:39604537 | DOI:10.1038/s41598-024-79965-0

JACC Cardiovasc Interv. 2024 Nov 25;17(22):2639-2663. doi: 10.1016/j.jcin.2024.08.027.

ABSTRACT

Current evidence indicates that dual antiplatelet therapy with aspirin plus a P2Y12 inhibitor is essential for the prevention of thrombotic events after percutaneous coronary interventions. However, dual antiplatelet therapy is associated with increased bleeding which may outweigh the benefits. This has set the foundations for customizing antiplatelet treatments to the individual patient. However, bleeding and ischemic risks are often present in the same patient, making it difficult to achieve this balance. The fact that oral P2Y12 inhibitors (clopidogrel, prasugrel, and ticagrelor) have diverse pharmacodynamic profiles that affect clinical outcomes supports the rationale for using platelet function and genetic testing to individualize antiplatelet treatment regimens. Indeed, up to one-third of patients treated with clopidogrel, but a minority of those treated with prasugrel or ticagrelor, exhibit high residual platelet reactivity resulting in an increased thrombotic risk. On the other hand, prasugrel and ticagrelor are frequently associated with low platelet reactivity and increased bleeding risk compared with clopidogrel without providing any additional reduction in ischemic events compared with patients who adequately respond to clopidogrel. The use of platelet function and genetic testing may allow for a guided selection of oral P2Y12 inhibitors. However, the nonuniform results of randomized controlled trials have led guidelines to provide limited recommendations on the implementation of these tests in patients undergoing percutaneous coronary intervention. In light of recent advancements in the field, this consensus document by a panel of international experts fills in the guideline gap by providing updates on the latest evidence in the field as well as recommendations for clinical practice.

PMID:39603778 | DOI:10.1016/j.jcin.2024.08.027

J Mol Diagn. 2024 Dec;26(12):1038-1041. doi: 10.1016/j.jmoldx.2024.06.013.

NO ABSTRACT

PMID:39603753 | DOI:10.1016/j.jmoldx.2024.06.013

Drug Discov Today. 2024 Nov 25:104252. doi: 10.1016/j.drudis.2024.104252. Online ahead of print.

ABSTRACT

Despite being challenging, elucidating the systematic control mechanisms of multifactorial drug responses is crucial for pharmacogenomic research. We describe a new form of statistical mechanics to reconstruct informative, dynamic, omnidirectional, and personalized networks (idopNetworks), which cover all pharmacogenomic factors and their interconnections, interdependence, and mechanistic roles. IdopNetworks can characterize how cell-cell crosstalk is mediated by genes and proteins to shape body-drug interactions and identify key roadmaps of information flow and propagation for determining drug efficacy and toxicity. We argue that idopNetworks could potentially provide insight into the genomic machinery of drug responses and provide scientific guidance for the design of drugs whose potency is maximized at lower doses.

PMID:39603519 | DOI:10.1016/j.drudis.2024.104252

Molecules. 2024 Nov 16;29(22):5407. doi: 10.3390/molecules29225407.

ABSTRACT

CYP3As are important drug-metabolizing enzymes in the liver. The causes for large inter-person variability in CYP3A expression/activity remain poorly understood. DNA methylation broadly regulates gene expression and the developmental transition from fetal CYP3A7 to adult CYP3A4, and CpG methylation upstream of the CYP3A4 promoter is associated with its expression. However, because non-promoter CYP3A regulatory regions remain largely uncharacterized, how DNA methylation influences CYP3A expression has yet to be fully explored. We recently identified a distal regulatory region (DRR) that controls the expression of CYP3A4, CYP3A5, and CYP3A7. Here, we investigated the relationship between CYP3A expression and the methylation status of 16 CpG sites within the DRR in 70 liver samples. We found significant associations between DRR methylation and the expression of CYP3A5 and CYP3A7 but not CYP3A4, indicating differential CYP3A regulation by the DRR. Also, we observed a dynamic reduction in DRR DNA methylation during the differentiation of induced pluripotent stem cells to hepatocytes, which correlated with increased CYP3A expression. We then evaluated the relative contribution of genetic variants, TFs, and DRR DNA methylation on CYP3A expression in liver samples. Our results reinforce the DRR as a CYP3A regulator and suggest that DNA methylation may impact CYP3A-mediated drug metabolism.

PMID:39598796 | DOI:10.3390/molecules29225407

Pharmaceutics. 2024 Oct 31;16(11):1407. doi: 10.3390/pharmaceutics16111407.

ABSTRACT

Given the high prevalence of breast cancer and the diverse genetic backgrounds of patients, a growing body of research emphasizes the importance of pharmacogenetic-based pharmacokinetic analysis in optimizing treatment outcomes. The treatment of breast cancer involves multiple drugs whose metabolism and efficacy are influenced by individual genetic variations. Genetic polymorphisms in drug-metabolizing enzymes and transport proteins are crucial in the regulation of pharmacokinetics. Our review aims to investigate the opportunities and challenges of pharmacogenomic-based pharmacokinetic analysis as a precision medicine tool in breast cancer management.

PMID:39598531 | DOI:10.3390/pharmaceutics16111407

Pharmaceutics. 2024 Oct 30;16(11):1399. doi: 10.3390/pharmaceutics16111399.

ABSTRACT

Background/Objectives: Research on pharmacogenetic variability in response to prescribed drugs and across ethnic groups is essential for personalized medicine, particularly in admixed and unstudied populations. For the first time, this study examines CYP2D6, CYP2C9, and CYP2C19 alleles and genotypes in 197 healthy volunteers from the Dominican Republic, as part of the RIBEF-CEIBA collaborative network. Methods: The analysis focuses on the participants' tri-hybrid genomic ancestry, with CYP alleles determined by real-time PCR and molecular ancestry inferred using 90 AIMs. Linear regression was used to associate ancestry components with CYP frequencies. Results: The average ancestry was 23.8% European, 42.6% Native American, and 33.6% African, the latter being higher than in most Latin American populations. Native American ancestry was also higher than expected. Predicted phenotype frequencies based on genotypes were 4.2% poor metabolizers (gPMs) and 3.6% ultrarapid metabolizers (gUMs) for CYP2D6, as well as 3% gPMs, 22.8% rapid metabolizers (gRMs), and 1.5% gUMs for CYP2C19. No gPM individuals were observed for CYP2C9. Certain alleles associated with decreased CYP2D6 activity (*17 and *29) and increased CYP2C19 activity (*17 and gUMs) were positively linked with African ancestry and negatively with Native American ancestry. Rare CYP2C9 alleles (*5 and *6) with clinical relevance were additionally found. Conclusions: These findings build on previous results from the RIBEF-CEIBA collaborative network, demonstrating differences in allele frequencies of CYP2D6, CYP2C9, and CYP2C19 in relation to genomic ancestry. In summary, ethnicity must be considered in the development of pharmacogenetic guidelines for clinical application, research, and regulation to avoid widening the biotechnology gap and to allow Personalized Medicine to reach the entire world population.

PMID:39598523 | DOI:10.3390/pharmaceutics16111399

Genes (Basel). 2024 Nov 20;15(11):1491. doi: 10.3390/genes15111491.

ABSTRACT

Background/Objectives:MIR27A rs895819 polymorphism has emerged as a potential additional pharmacogenomic marker of fluoropyrimidine response. Current evidence on its potential effect on miR-27a expression, which represses DPD activity, leading to DPD deficiency and increased fluoropyrimidine-associated toxicity risk, is scarce and inconsistent. We have analyzed the effect of MIR27A rs895819 polymorphism on miR-27a-3p plasma expression levels under different models of inheritance to contribute further evidence on its plausible biological role in miR-27a expression. Methods: A total of 59 individuals with no medical history of cancer were included in this study. MIR27A rs895819 genotyping and miR-27a-3p expression were analyzed by using predesigned TaqMan assays. Results: The frequency of TT, TC, and CC genotypes was present at a prevalence of 50.8%, 44.1%, and 5.1%, respectively. Individuals carrying the CC genotype presented with decreased miR-27a-3p expression (0.422 fold-change versus TT, p = 0.041; 0.461 fold-change versus TC, p = 0.064), whereas no differences were present between TT and TC individuals (1.092 fold-change, p = 0.718). miR-27a-3p expression was decreased in CC individuals under a recessive model of inheritance (0.440 fold-change, p = 0.047). No differences were found in dominant (TT vs. TC+CC, 0.845 fold-change, p = 0.471) or over dominant (TT+CC vs. TC, 0.990 fold-change, p = 0.996) models of inheritance. Conclusions:MIR27A rs895819CC genotype leads to severely reduced miR-27a-3p expression in plasma. Further study of this association is warranted in cancer patients to apply MIR27A genotyping in therapeutics to identify fluoropyrimidine-treated patients who are at a decreased risk of experiencing fluoropyrimidine-induced severe toxicity.

PMID:39596691 | DOI:10.3390/genes15111491

Genes (Basel). 2024 Oct 22;15(11):1352. doi: 10.3390/genes15111352.

ABSTRACT

Although a lack of diversity in genetic studies is an acknowledged obstacle for personalized medicine and precision public health, Latin American populations remain particularly understudied despite their heterogeneity and mixed ancestry. This gap extends to COVID-19 despite its variability in susceptibility and clinical course, where ethnic background appears to influence disease severity, with non-Europeans facing higher hospitalization rates. In addition, access to high-quality samples and data is a critical issue for personalized and precision medicine, and it has become clear that the solution lies in biobanks. The creation of the Chilean COVID-19 Biorepository reported here addresses these gaps, representing the first nationwide multicentric Chilean initiative. It operates under rigorous biobanking standards and serves as one of South America's largest COVID cohorts. A centralized harmonization strategy was chosen and included unified standard operating procedures, a sampling coding system, and biobanking staff training. Adults with confirmed SARS-CoV-2 infection provided broad informed consent. Samples were collected to preserve blood, plasma, buffy coat, and DNA. Quality controls included adherence to the standard preanalytical code, incident reporting, and DNA concentration and absorbance ratio 260/280 assessments. Detailed sociodemographic, health, medication, and preexisting condition data were gathered. In five months, 2262 participants were enrolled, pseudonymized, and sorted by disease severity. The average Amerindian ancestry considering all participant was 44.0% [SD 15.5%], and this value increased to 61.2% [SD 19.5%] among those who self-identified as Native South Americans. Notably, 279 participants self-identified with one of 12 ethnic groups. High compliance (>90%) in all assessed quality controls was achieved. Looking ahead, our team founded the COVID-19 Genomics Network (C19-GenoNet) focused on identifying genetic factors influencing SARS-CoV-2 outcomes. In conclusion, this bottom-up collaborative effort aims to promote the integration of Latin American populations into global genetic research and welcomes collaborations supporting this endeavor. Interested parties are invited to explore collaboration opportunities through our catalog, accessible online.

PMID:39596552 | DOI:10.3390/genes15111352

Biomedicines. 2024 Oct 23;12(11):2428. doi: 10.3390/biomedicines12112428.

ABSTRACT

Spinal muscular atrophy (SMA) is a severe neurodegenerative disease caused by the loss of the survival motor neuron (SMN) protein, leading to degeneration of anterior motor neurons and resulting in progressive muscle weakness and atrophy. Given that SMA has a single, well-defined genetic cause, gene-targeted therapies have been developed, aiming to increase SMN production in SMA patients. The SMN protein is likely involved in the synthesis of microRNAs (miRNAs), and dysregulated miRNA expression is increasingly associated with the pathophysiology of SMA. Currently, there is a lack of reliable biomarkers to monitor SMA; therefore, the search for novel SMA biomarkers, including miRNAs, is crucial as reliable tools are needed to track disease progression, predict the response to therapy and understand the different clinical outcomes of available treatments. In this review, we compile data on miRNAs associated with SMA pathogenesis and their potential use as biomarkers. Based on current knowledge, the most frequently deregulated miRNAs between SMA patients and controls, as well as pre- and post-treatment in SMA patients, include miR-1-3p, miR-133a-3p, miR-133b, and miR-206. These findings offer promising possibilities for improving patient classification and monitoring disease progression and response to treatment. Additionally, these findings provide insights into the broader molecular mechanisms and networks of SMA that could inform the development of future therapeutic strategies.

PMID:39594995 | DOI:10.3390/biomedicines12112428

Children (Basel). 2024 Oct 30;11(11):1329. doi: 10.3390/children11111329.

ABSTRACT

The clinical outcome for children diagnosed with acute lymphoblastic leukemia is a testimony to the success of modern medicine. Over the past few decades, survival has climbed from ∼10% to >90% for certain subgroups. Yet, the outcome for those with relapsed disease is often poor, and survivors struggle with a multitude of healthcare issues, some of which are lifelong. In recent years, the advent of the widespread sequencing of tumors has made available patients with previously unrecognized subtypes of leukemia, who have the potential to benefit from the addition of targeted therapies. Indeed, the promise of precision medicine, encompassing a person's environment, genetics and lifestyle, is likely to have profound impact on further tailoring therapies that are likely to improve outcomes, diminish toxicity and ultimately pave the pathway for a healthier population.

PMID:39594904 | DOI:10.3390/children11111329

BMC Med. 2024 Nov 26;22(1):558. doi: 10.1186/s12916-024-03771-8.

ABSTRACT

BACKGROUND: The potential impact of specific food additives, common in Western diets, on the risk of developing type 2 diabetes is not well understood. This study focuses on carrageenan, a widely used food additive known to induce insulin resistance and gut inflammation in animal models, and its effects on human health.

METHODS: In a randomised, double-blind, placebo-controlled, cross-over trial conducted at a university hospital metabolic study centre, 20 males (age 27.4 ± 4.3 years, BMI 24.5 ± 2.5 kg/m2) participated. The intervention involved oral intake of carrageenan (250 mg) or placebo in the morning and in the evening and each intervention lasted 2 weeks. The primary outcome measured was insulin sensitivity (using oral glucose tolerance test [OGTT] and hyperinsulinaemic-euglycaemic clamp). Additional end-points included whole body and hepatic insulin sensitivity, MRI-measured brain inflammation and insulin resistance, intestinal permeability (via lactulose-mannitol test and plasma zonulin levels), and gut microbiome composition. Immune-cell activation and pro-inflammatory cytokine release from peripheral blood mononuclear cells were measured.

RESULTS: Overall insulin sensitivity did not show significant differences between the treatments. However, interactions between BMI and treatment were observed (OGTT-based insulin sensitivity index: p=0.04, fasting insulin resistance: p=0.01, hepatic insulin sensitivity index: p=0.04). In overweight participants, carrageenan exposure resulted in lower whole body and hepatic insulin sensitivity, a trend towards increased brain inflammation, and elevated C-reactive protein (CRP) and IL-6 levels compared to placebo. Additionally, carrageenan was associated with increased intestinal permeability. In vitro natural killer (NK-)cell activation and increased pro-inflammatory cytokine release were found after carrageenan exposure in the participant's peripheral blood mononuclear cells.

CONCLUSIONS: These findings suggest that carrageenan, a common food additive, may contribute to insulin resistance and subclinical inflammation in overweight individuals through pro-inflammatory mechanisms in the gut. Further investigation into the long-term health impacts of carrageenan and other food additives is warranted.

TRIAL REGISTRATION: NCT02629705.

PMID:39593091 | DOI:10.1186/s12916-024-03771-8