Technol Cancer Res Treat. 2022 Jan-Dec;21:15330338221123109. doi: 10.1177/15330338221123109.

ABSTRACT

Objectives: The TNFAIP8 gene family and TNFAIP2 gene are inextricably linked to an elevated risk of cancer development. This systemic review and meta-analysis seeks to establish the relationship between TNFAIP8 (rs11064, rs1045241, rs1045242, and rs3813308), TNFAIP8L1 (rs1060555), and TNFAIP2 (rs710100 and rs8126) polymorphisms with the risk of cancer. Methods and Materials: A systematic search of multiple databases from January 2022 to April 2022 was used to identify relevant studies. Odds ratios (ORs) with corresponding 95% CI and p-value were calculated to assess the association. Bonferroni correction was performed to correct p-values. Trial sequential analysis (TSA) and in-silico messenger RNA expression were also performed. Review Manager 5.4 software was used for performing this meta-analysis. Results: This study comprised 6909 cancer patients and 7087 healthy participants from 14 studies. Four genetic models of rs11064 (codominant 2 [COD2]: OR = 2.30, p = 7.83 × 10-5; codominant 3 [COD3]: OR = 2.10, p = .0006; recessive model [RM]: OR = 2.24, p = .0001; AC: OR = 1.47, p = .037), two genetic models of rs1045241 (codominant 1 [COD1]: OR = 1.27, p = .009; overdominant model [ODM]: OR = 1.24, p = .018), four genetic models of rs1045242 (COD1: OR = 1.52, p = .005; dominant model (DM): OR = 1.56, p = .002; OD: OR = 1.48, p = .008; AC: OR = 1.48, p = .002), and three genetic models of rs8126 (COD2: OR = 1.41, p = .0005; COD3: OR = 1.44, p = .0002; RM: OR = 1.43, p = .0001) were statistically linked to cancer risk. Only one genetic model of rs1060555 polymorphism showed a significant protective association with cancer (COD2: OR = 0.80, p = .048). The outcomes of TSA also validated the findings of the meta-analysis. Conclusion: This study summarizes that rs11064, rs1045241, and rs1045242 polymorphisms of TNFAIP8 gene and rs8126 polymorphism of TNFAIP2 gene are significantly linked with the risk of cancer development. This meta-analysis was registered at INPLASY (registration number: INPLASY202270073).

PMID:36254562 | DOI:10.1177/15330338221123109

Ther Drug Monit. 2022 Oct 11. doi: 10.1097/FTD.0000000000001043. Online ahead of print.

ABSTRACT

BACKGROUND: Though atorvastatin (ATV) is well-tolerated, patients may report muscle complaints. These are difficult to predict owing to high inter-individual variability. Such side effects are linked to intramuscular accumulation of ATV. This study aimed to investigate the relative role of transporters expressed in muscle tissue in promoting or limiting drug access to cells. The impact of common single nucleotide polymorphisms (SNPs) in SLCO2B1 coding for OATP2B1 and ABCC1 coding for MRP1 on ATV transport was also evaluated.

METHODS: HEK293 cells were stably transfected with plasmids containing cDNA encoding wild-type or variant SLCO2B1 and/or ABCC1 to generate single and double stable transfectant HEK293 recombinant models overexpressing variant or wild-type OATP2B1 (influx) and/or MRP1 (efflux) proteins. Variant plasmids were generated by site-directed mutagenesis. Expression analyses were performed to validate recombinant models. Accumulation and efflux experiments were performed at different concentrations. ATV was quantified by LC-MS/MS, and kinetic parameters were compared between single and double HEK-transfectants expressing wild-type and variant proteins.

RESULTS: The results confirm the involvement of OATP2B1 and MRP1 in ATV cellular transport as it was demonstrated that intracellular accumulation of ATV was boosted by OATP2B1 overexpression whereas ATV accumulation was decreased by MRP1 overexpression. In double-transfectants, it was observed that increased ATV intracellular accumulation driven by OATP2B1 influx was partially counteracted by MRP1 efflux. The c.935G>A SNP in SLCO2B1 was associated with decreased ATV OATP2B1-mediated influx, whereas the c.2012G>T SNP in ABCC1 appeared to increase MRP1 efflux activity against ATV.

CONCLUSIONS: Intracellular ATV accumulation is regulated by OATP2B1 and MRP1 transporters, whose functionality is modulated by natural genetic variants. This is significant, as it may play a role in ATV muscle side-effect susceptibility.

PMID:36253893 | DOI:10.1097/FTD.0000000000001043

Hum Genomics. 2022 Oct 17;16(1):45. doi: 10.1186/s40246-022-00418-8.

ABSTRACT

BACKGROUND: It has been suggested that bipolar disorder (BD) is associated with clinical and biological features of accelerated aging. In our previous studies, we showed that long-term lithium treatment was correlated with longer leukocyte telomere length (LTL) in BD patients. A recent study explored the role of TL in BD using patients-derived lymphoblastoid cell lines (LCLs), showing that baseline TL was shorter in BD compared to controls and that lithium in vitro increased TL but only in BD. Here, we used the same cell system (LCLs) to explore if a 7-day treatment protocol with lithium chloride (LiCl) 1 mM was able to highlight differences in TL between BD patients clinically responders (Li-R; n = 15) or non-responders (Li-NR; n = 15) to lithium, and if BD differed from non-psychiatric controls (HC; n = 15).

RESULTS: There was no difference in TL between BD patients and HC. Moreover, LiCl did not influence TL in the overall sample, and there was no difference between diagnostic or clinical response groups. Likewise, LiCl did not affect TL in neural precursor cells from healthy donors.

CONCLUSIONS: Our findings suggest that a 7-day lithium treatment protocol and the use of LCLs might not represent a suitable approach to deepen our understanding on the role of altered telomere dynamics in BD as previously suggested by studies in vivo.

PMID:36253798 | DOI:10.1186/s40246-022-00418-8

J Sci Med Sport. 2022 Oct 12:S1440-2440(22)00438-8. doi: 10.1016/j.jsams.2022.10.004. Online ahead of print.

ABSTRACT

OBJECTIVES: To determine the number of training days lost due to COVID-19 and vaccination against COVID-19 in elite athletes.

DESIGN: Retrospective cohort study.

METHODS: The questionnaire on the impact of vaccination and COVID-19 on training plans was filled out by 1073 elite Polish athletes who underwent routine medical screening between September and December 2021.

RESULTS: COVID-19 was diagnosed in 421 subjects (39 %), of whom 26 % were asymptomatic. On the 10-point scale, <1 % of athletes had perceived severity of the disease above 8, whereas for 64 % it was 4 or below. Vaccination against COVID-19 was administered in 820 athletes (76 %), and adverse events were observed more frequently after the first dose than the second (69 % vs. 47 %). Influence on training (modified or lost) was declared by 369 of 421 (88 %) COVID-19 athletes, and by 226 of 820 vaccinated athletes (28 %). During the observation period, the average number of lost training days was 8.1 for COVID-19 and 2.6 for vaccination (p < 0.001). The cumulative number of person-days lost due to COVID-19 was 1041 versus 295 after vaccination thus, the average loss ratio was 1041/1073 = 0.97 vs. 295/820 = 0.36, respectively, p < 0.01.

CONCLUSIONS: Athletes have a considerable loss of training days due to COVID-19. Vaccination against COVID-19 causes significantly smaller and predictable loss. This supports the inclusion of vaccination into prevention policies for athletes whenever they are available.

PMID:36253224 | DOI:10.1016/j.jsams.2022.10.004

Brief Bioinform. 2022 Oct 17:bbac433. doi: 10.1093/bib/bbac433. Online ahead of print.

ABSTRACT

We live in an unprecedented time in oncology. We have accumulated samples and cases in cohorts larger and more complex than ever before. New technologies are available for quantifying solid or liquid samples at the molecular level. At the same time, we are now equipped with the computational power necessary to handle this enormous amount of quantitative data. Computational models are widely used helping us to substantiate and interpret data. Under the label of systems and precision medicine, we are putting all these developments together to improve and personalize the therapy of cancer. In this review, we use melanoma as a paradigm to present the successful application of these technologies but also to discuss possible future developments in patient care linked to them. Melanoma is a paradigmatic case for disruptive improvements in therapies, with a considerable number of metastatic melanoma patients benefiting from novel therapies. Nevertheless, a large proportion of patients does not respond to therapy or suffers from adverse events. Melanoma is an ideal case study to deploy advanced technologies not only due to the medical need but also to some intrinsic features of melanoma as a disease and the skin as an organ. From the perspective of data acquisition, the skin is the ideal organ due to its accessibility and suitability for many kinds of advanced imaging techniques. We put special emphasis on the necessity of computational strategies to integrate multiple sources of quantitative data describing the tumour at different scales and levels.

PMID:36252807 | DOI:10.1093/bib/bbac433

Front Pharmacol. 2022 Sep 30;13:981874. doi: 10.3389/fphar.2022.981874. eCollection 2022.

ABSTRACT

Preparations from Hippophaë rhamnoides L. (sea buckthorn) have been traditionally used in the treatment of skin and digestive disorders, such as gastritis, gastric and duodenal ulcers, uterine erosions, as well as oral, rectal, and vaginal mucositis, in particular in the Himalayan and Eurasian regions. An influence of an aqueous extract from the fruits of H. rhamnoides (HR) on leakage of lipopolysaccharide (LPS) from Escherichia coli through gut epithelium developed from the human colorectal adenocarcinoma (Caco-2) monolayer in vitro and glucose transporter 2 (GLUT2) translocation were the principal objectives of the study. Additionally, the effect of HR on the production of pro- and anti-inflammatory cytokines (interleukins: IL-8, IL-1β, IL-10, IL-6; tumor necrosis factor: TNF-α) by the Caco-2 cell line, human neutrophils (PMN), and peripheral blood mononuclear cells (PBMC) was evaluated. The concentration of LPS on the apical and basolateral sides of the Caco-2 monolayer was evaluated with a Limulus Amebocyte Lysate (LAL) assay. GLUT2 translocation was evaluated using an immunostaining assay, whereas secretion of cytokines by cell cultures was established with an enzyme-linked immunosorbent (ELISA) assay. HR (500 μg/ml) significantly inhibited LPS leakage through epithelial monolayer in vitro in comparison with non-treated control. The treatment of Caco-2 cells with HR (50-100 μg/ml) showed GLUT2 expression similar to the non-treated control. HR decreased the secretion of most pro-inflammatory cytokines in all tested models. HR might prevent low-grade chronic inflammation caused by metabolic endotoxemia through the prevention of the absorption of LPS and decrease of chemotactic factors released by immune and epithelial cells, which support its use in metabolic disorders in traditional medicine.

PMID:36249809 | PMC:PMC9561609 | DOI:10.3389/fphar.2022.981874

Front Genet. 2022 Sep 29;13:940661. doi: 10.3389/fgene.2022.940661. eCollection 2022.

ABSTRACT

The use of antiretrovirals (ARVs) as oral, topical, or long-acting pre-exposure prophylaxis (PrEP) has emerged as a promising strategy for HIV prevention. Clinical trials testing Truvada® [tenofovir disoproxil fumarate (TDF)/tenofovir (TFV) and emtricitabine (FTC)] as oral or topical PrEP in African women showed mixed results in preventing HIV infections. Since oral and topical PrEP effectiveness is dependent on adequate drug delivery and availability to sites of HIV infection such as the blood and female genital tract (FGT); host biological factors such as drug transporters have been implicated as key regulators of PrEP. Drug transporter expression levels and function have been identified as critical determinants of PrEP efficacy by regulating PrEP pharmacokinetics across various cells and tissues of the blood, renal tissues, FGT mucosal tissues and other immune cells targeted by HIV. In addition, biological factors such as genetic polymorphisms and genital inflammation also influence drug transporter expression levels and functionality. In this review, drug transporters and biological factors modulating drug transporter disposition are used to explain discrepancies observed in PrEP clinical trials. This review also provides insight at a pharmacological level of how these factors further increase the susceptibility of the FGT to HIV infections, subsequently contributing to ineffective PrEP interventions in African women.

PMID:36246609 | PMC:PMC9557974 | DOI:10.3389/fgene.2022.940661

Biol Psychiatry. 2022 Aug 5:S0006-3223(22)01449-4. doi: 10.1016/j.biopsych.2022.07.014. Online ahead of print.

ABSTRACT

BACKGROUND: Treatment-resistant schizophrenia affects approximately 30% of individuals with the disorder. Clozapine is the medication of choice in treatment-resistant schizophrenia, but optimizing administration and dose titration is complex. The identification of factors influencing clozapine prescription and response, including genetics, is of interest in a precision psychiatry framework.

METHODS: We used linear regression models accounting for demographic, pharmacological, and clinical covariates to determine whether a polygenic risk score (PRS) for schizophrenia would be associated with the highest dose recorded during clozapine treatment. Analyses were performed across 2 independent multiancestry samples of individuals from a UK patient monitoring system, CLOZUK2 (n = 3133) and CLOZUK3 (n = 909), and a European sample from a Norwegian therapeutic drug monitoring service (n = 417). In a secondary analysis merging both UK cohorts, logistic regression models were used to estimate the relationship between schizophrenia PRSs and clozapine doses classified as low, standard, or high.

RESULTS: After controlling for relevant covariates, the schizophrenia PRS was correlated with the highest clozapine dose on record for each individual across all samples: CLOZUK2 (β = 12.22, SE = 3.78, p = .001), CLOZUK3 (β = 12.73, SE = 5.99, p = .034), and the Norwegian cohort (β = 46.45, SE = 18.83, p = .014). In a secondary analysis, the schizophrenia PRS was associated with taking clozapine doses >600 mg/day (odds ratio = 1.279, p = .006).

CONCLUSIONS: The schizophrenia PRS was associated with the highest clozapine dose prescribed for an individual in records from 3 independent samples, suggesting that the genetic liability for schizophrenia might index factors associated with therapeutic decisions in cohorts of patients with treatment-resistant schizophrenia.

PMID:36244804 | DOI:10.1016/j.biopsych.2022.07.014

Metabolism. 2022 Oct 13:155333. doi: 10.1016/j.metabol.2022.155333. Online ahead of print.

NO ABSTRACT

PMID:36244415 | DOI:10.1016/j.metabol.2022.155333

Pharmacogenomics J. 2022 Oct 15. doi: 10.1038/s41397-022-00290-8. Online ahead of print.

ABSTRACT

Psoriatic arthritis (PsA) is a heterogeneous chronic musculoskeletal disease, affecting up to 30% of people with psoriasis. Research into PsA pathogenesis has led to the development of targeted therapies, including Tumor Necrosis Factor inhibitors (TNF-i). Good response is only achieved by ~60% of patients leading to 'trial and error' drug management approaches, adverse reactions and increasing healthcare costs. Robust and well-validated biomarker identification, and subsequent development of sensitive and specific assays, would facilitate the implementation of a stratified approach into clinical care. This review will summarise potential genetic biomarkers for TNF-i (adalimumab, etanercept and infliximab) response that have been reported to date. It will also comment upon the importance of managing clinical confounders when understanding drug response prediction. Variants in multiple gene regions including TNF-A, FCGR2A, TNFAIP3, TNFR1/TNFR1A/TNFRSF1A, TRAIL-R1/TNFRSF10A, FCGR3A have been reported to correlate with TNF-i response at various levels of statistical significance in patients with PsA. However, results were often from heterogenous and underpowered cohorts and none are currently implemented into clinical practice. External validation of genetic biomarkers in large, well-documented cohorts is required, and assessment of the predictive value of combining multiple genetic biomarkers with clinical measures is essential to clinically embed pharmacogenomics into PsA drug management.

PMID:36243888 | DOI:10.1038/s41397-022-00290-8

J Am Pharm Assoc (2003). 2022 Sep 9:S1544-3191(22)00303-X. doi: 10.1016/j.japh.2022.09.002. Online ahead of print.

ABSTRACT

BACKGROUND: Pharmacogenomics (PGx) is an emerging field. Many drug-gene interactions are known but not yet routinely addressed in clinical practice. Therefore, there is a significant gap in care, necessitating development of implementation strategies.

OBJECTIVE: The objective of the study was to assess the impact of implementing a PGx practice model which incorporates comprehensive pharmacogenomic risk evaluation, testing and medication optimization administered by 7 PGx-certified ambulatory care pharmacists embedded across 30 primary care clinic sites.

METHODS: Pharmacogenomic services were implemented in 30 primary care clinics within the Cincinnati, Ohio area. Patients are identified for pharmacogenomic testing using a clinical decision support tool (CDST) that is fully integrated in the electronic medical record (EMR) or by provider designation (e.g., psychotropic drug failure). Pharmacogenomic testing is performed via buccal swab using standardized clinic processes. Discrete data results are returned directly into the EMR/CDST for review by PGx-certified ambulatory care pharmacists. Recommendations and prescriptive changes are then discussed and implemented as a collaborative effort between pharmacist, primary care provider, specialists, and patient.

RESULTS: A total of 422 unique interactions were assessed by the embedded ambulatory care PGx pharmacists (N = 7) during this interim analysis. About half (213) were pharmacogenomic interactions, and of these, 124 were actionable. When an intervention was actionable, 82% of the time a change in medication was recommended. The underlying reasons for recommending therapy alterations were most commonly ineffective therapy (43%), adverse drug reaction prevented (34%), or adverse drug reaction observed (13%).

CONCLUSION: Variations in drug metabolism, response, and tolerability can negatively impact patient outcomes across many disease states and treatment specialties. Incorporation of pharmacogenomic testing with accessible clinical decision support into the team-based care model allows for a truly comprehensive review and optimization of medications. Our initial analysis suggests that comprehensive PGx testing should be considered to enhance medication safety and efficacy in at-risk patients.

PMID:36243653 | DOI:10.1016/j.japh.2022.09.002

Schizophr Res. 2022 Oct 12;250:1-9. doi: 10.1016/j.schres.2022.09.009. Online ahead of print.

ABSTRACT

INTRODUCTION: Our aim was to, firstly, identify characteristics at first-episode of psychosis that are associated with later antipsychotic treatment resistance (TR) and, secondly, to develop a parsimonious prediction model for TR.

METHODS: We combined data from ten prospective, first-episode psychosis cohorts from across Europe and categorised patients as TR or non-treatment resistant (NTR) after a mean follow up of 4.18 years (s.d. = 3.20) for secondary data analysis. We identified a list of potential predictors from clinical and demographic data recorded at first-episode. These potential predictors were entered in two models: a multivariable logistic regression to identify which were independently associated with TR and a penalised logistic regression, which performed variable selection, to produce a parsimonious prediction model. This model was internally validated using a 5-fold, 50-repeat cross-validation optimism-correction.

RESULTS: Our sample consisted of N = 2216 participants of which 385 (17 %) developed TR. Younger age of psychosis onset and fewer years in education were independently associated with increased odds of developing TR. The prediction model selected 7 out of 17 variables that, when combined, could quantify the risk of being TR better than chance. These included age of onset, years in education, gender, BMI, relationship status, alcohol use, and positive symptoms. The optimism-corrected area under the curve was 0.59 (accuracy = 64 %, sensitivity = 48 %, and specificity = 76 %).

IMPLICATIONS: Our findings show that treatment resistance can be predicted, at first-episode of psychosis. Pending a model update and external validation, we demonstrate the potential value of prediction models for TR.

PMID:36242784 | DOI:10.1016/j.schres.2022.09.009

Neurology. 2022 Aug 31:10.1212/WNL.0000000000201006. doi: 10.1212/WNL.0000000000201006. Online ahead of print.

ABSTRACT

BACKGROUND AND OBJECTIVES: Current genome-wide association studies of ischemic stroke have focused primarily on late onset disease. As a complement to these studies, we sought to identifythe contribution of common genetic variants to risk of early onset ischemic stroke.

METHODS: We performed a meta-analysis of genome-wide association studies of early onset stroke (EOS), ages 18-59, using individual level data or summary statistics in 16,730 cases and 599,237 non-stroke controls obtained across 48 different studies. We further compared effect sizes at associated loci between EOS and late onset stroke (LOS) and compared polygenic risk scores for venous thromboembolism between EOS and LOS.

RESULTS: We observed genome-wide significant associations of EOS with two variants in ABO, a known stroke locus. These variants tag blood subgroups O1 and A1, and the effect sizes of both variants were significantly larger in EOS compared to LOS. The odds ratio (OR) for rs529565, tagging O1, 0.88 (95% CI: 0.85-0.91) in EOS vs 0.96 (95% CI: 0.92-1.00) in LOS, and the OR for rs635634, tagging A1, was 1.16 (1.11-1.21) for EOS vs 1.05 (0.99-1.11) in LOS; p-values for interaction = 0.001 and 0.005, respectively. Using polygenic risk scores, we observed that greater genetic risk for venous thromboembolism, another prothrombotic condition, was more strongly associated with EOS compared to LOS (p=0.008).

DISCUSSION: The ABO locus, genetically predicted blood group A, and higher genetic propensity for venous thrombosis are more strongly associated with EOS than with LOS, supporting a stronger role of prothrombotic factors in EOS.

PMID:36240095 | DOI:10.1212/WNL.0000000000201006

J Community Genet. 2022 Oct 14. doi: 10.1007/s12687-022-00613-z. Online ahead of print.

ABSTRACT

Direct-to-consumer genetic testing (DTC GT) diagnostic tools do not entail referral through a healthcare provider and are used by consumers to screen for genetic health risk, pharmacogenomics, and predisposition to certain diseases and to learn more about ancestry. The purpose of this study was to describe the content of DTC DNA online news articles - specifically to characterize how rising concerns related to consumer privacy, medical advancements, and bioethics are covered in online news as access to these testing kits continues to grow. One hundred news articles identified on Google News using the search term "direct to consumer DNA testing" were coded for pre-determined content categories. Only 34.0% of news articles were created by healthcare professionals. Only 10.0% of online news articles mentioned testing confidentiality and privacy protection. Articles that mentioned > 5 commercial DTC DNA products more often discussed how DTC DNA testing provides personalized information about health and link to family disease risk and other traits (85.7% vs. 61.1%, p = 0.02), can lead to the location of family members or ancestors (78.6% vs. 55.63%, p = 0.03), and that the testing results housed in DNA databases can be utilized by law enforcement to track suspects or their relatives (32.1% vs. 9.7%, p = 0.01). Articles that mentioned ≤ 5 commercial DTC DNA products failed to mention that there exists a potential for data breaches (75.0% vs. 53.6%, p = 0.04). Online news articles should adequately inform consumers regarding the benefits and risks of DTC GT tests to facilitate informed decision-making.

PMID:36239910 | DOI:10.1007/s12687-022-00613-z

Pharmacogenomics. 2022 Oct 14. doi: 10.2217/pgs-2022-0133. Online ahead of print.

NO ABSTRACT

PMID:36239145 | DOI:10.2217/pgs-2022-0133

Front Pharmacol. 2022 Sep 21;13:978141. doi: 10.3389/fphar.2022.978141. eCollection 2022.

ABSTRACT

Background: Precision medicine beckons new horizons for therapy geared to one's genetics, lifestyle, and environmental determinants. Molecular, pathology, and clinical diagnostics can be integrated to provide pharmaceutical care. Aims: The value and appeal of precision medicine to community pharmacists, knowledge attained, and training programmes perceived as necessary were evaluated. Methods: Over 10 months, a published questionnaire, which was also digitally accessible during the COVID-19 outbreak, was distributed by hand, via email and social media. 300 community pharmacists across 9 districts in an urban state in Malaysia, self-administered and returned completed versions (response rate 75%). Three- or five-point Likert scale and multiple-choice responses were analysed using SPSS to assess whether or not exposure through the pharmacy curricula impacted current knowledge, perception and willingness to pursue precision medicine. Results: Respondents were largely: females (N = 196, 65.3%) and practicing for up to 10 years (N = 190, 66.3%). Although knowledge levels were moderate (76%), positive perceptions were showcased (94%), and 80% were willing to integrate precision medicine into their daily practice. Although 61% did not or do not recall having had prior exposure to pharmacogenomics as part of their pharmacy school curricula, many (93%) were willing to attain knowledge by undergoing additional training. Desired training included current pharmacogenetic testing available (17%), interpretation of the test results (15%), and ethical considerations (13%). Community pharmacists who had 0.5-10 years' work experience possessed greater knowledge (μ = 1.48, CI 1.35-1.61, p = 0.017), than the pharmacists who had 21-40 years of work experience (μ = 1.28, CI 1.05-1.51, p = 0.021). Exposure to the subject during pharmacy education positively impacted the willingness to integrate precision medicine in daily practice (p = 0.035). Conclusion: Community pharmacists were receptive to and valued precision medicine. A relatively high number had prior exposure to concepts of precision medicine through the pharmacy curriculum, and were therefore willing to adopt the practice in their day-to-day provision of healthcare. With adequate training centred on bioethics, utilising pharmacogenetic testing, and interpretation of the results, community pharmacists will be equipped for the provision of precision medicine services in the foreseeable future.

PMID:36238562 | PMC:PMC9552318 | DOI:10.3389/fphar.2022.978141

Front Pharmacol. 2022 Sep 27;13:941182. doi: 10.3389/fphar.2022.941182. eCollection 2022.

ABSTRACT

Thiopurines, including thioguanine (TG), 6-mercaptopurine (6-MP), and azathioprine (AZA), are extensively used in clinical practice in children with acute lymphoblastic leukemia (ALL) and inflammatory bowel diseases. However, the common adverse effects caused by myelosuppression and hepatotoxicity limit their application. Metabolizing enzymes such as thiopurine S-methyltransferase (TPMT), nudix hydrolase 15 (NUDT15), inosine triphosphate pyrophosphohydrolase (ITPA), and drug transporters like multidrug resistance-associated protein 4 (MRP4) have been reported to mediate the metabolism and transportation of thiopurine drugs. Hence, the single nucleotide polymorphisms (SNPs) in those genes could theoretically affect the pharmacokinetics and pharmacological effects of these drugs, and might also become one of the determinants of clinical efficacy and adverse effects. Moreover, long-term clinical practices have confirmed that thiopurine-related adverse reactions are associated with the systemic concentrations of their active metabolites. In this review, we mainly summarized the pharmacogenetic studies of thiopurine drugs. We also evaluated the therapeutic drug monitoring (TDM) research studies and focused on those active metabolites, hoping to continuously improve monitoring strategies for thiopurine therapy to maximize therapeutic efficacy and minimize the adverse effects or toxicity. We proposed that tailoring thiopurine dosing based on MRP4, ITPA, NUDT15, and TMPT genotypes, defined as "MINT" panel sequencing strategy, might contribute toward improving the efficacy and safety of thiopurines. Moreover, the DNA-incorporated thioguanine nucleotide (DNA-TG) metabolite level was more suitable for red cell 6-thioguanine nucleotide (6-TGNs) monitoring, which can better predict the efficacy and safety of thiopurines. Integrating the panel "MINT" sequencing strategy with therapeutic "DNA-TG" monitoring would offer a new insight into the precision thiopurine therapy for pediatric acute lymphoblastic leukemia patients.

PMID:36238550 | PMC:PMC9552076 | DOI:10.3389/fphar.2022.941182

Nutrients. 2022 Sep 24;14(19):3963. doi: 10.3390/nu14193963.

ABSTRACT

Vitamin D deficiency is a global health problem that not only leads to metabolic bone disease but also to many other illnesses, most of which are associated with chronic inflammation. Thus, our aim was to investigate the safety and effectiveness of a single high dose of vitamin D3 (80,000 IU) on vitamin D status and proinflammatory cytokines such as interleukin (IL)6, IL8 and tumor necrosis factor (TNF) in healthy Saudi females. Fifty healthy females were recruited and orally supplemented with a single vitamin D3 bolus (80,000 IU). All participants donated fasting blood samples at baseline, one day and thirty days after supplementation. Serum 25-hydroxyvitamin D3 (25(OH)D3), IL6, IL8, TNF, calcium, phosphate, parathyroid hormone (PTH) and blood lipid levels were determined. Serum 25(OH)D3 significantly increased one and thirty days after supplementation when compared with baseline without causing elevation in calcium or phosphate or a decrease in PTH to abnormal levels. In contrast, the concentrations of the three representative proinflammatory cytokines decreased gradually until the end of the study period. In conclusion, a single high dose (80,000 IU) is effective in improving serum vitamin D status and reducing the concentration of the proinflammatory cytokines in a rapid and safe way in healthy females.

PMID:36235615 | DOI:10.3390/nu14193963

J Clin Med. 2022 Sep 28;11(19):5756. doi: 10.3390/jcm11195756.

ABSTRACT

Isavuconazole (ISA), a triazole antifungal agent, is licensed for the treatment of invasive aspergillosis and mucormycosis. Therapeutic drug monitoring (TDM) is a cornerstone of treatment efficacy for triazole antifungals due to their pharmacokinetic variability, except for ISA, for which the utility of TDM is still uncertain. We performed a retrospective study that aimed to assess the inter- and intra-individual variability of ISA trough concentrations (Cmin) and to identify the determinants involved in such variability. ISA Cmin measured in adult patients at the Grenoble Alpes University Hospital between January 2018 and August 2020 were retrospectively analyzed. In total, 304 ISA Cmin for 33 patients were analyzed. The median ISA Cmin was 2.8 [25th-75th percentiles: 2.0-3.7] mg/L. The inter- and intra-individual variability was 41.5% and 30.7%, respectively. Multivariate analysis showed independent covariate effects of dose (β = 0.004 ± 3.56 × 10-4, p &lt; 0.001), Aspartate aminotransférase (ASAT) (β = 0.002 ± 5.41 × 10-4, p = 0.002), and protein levels (β = 0.022 ± 0.004, p &lt; 0.001) on ISA Cmin, whereas C reactive protein levels did not show any association. This study, conducted on a large number of ISA Cmin, shows that ISA exposure exhibits variability, explained in part by the ISA dose, and ASAT and protein levels.

PMID:36233624 | DOI:10.3390/jcm11195756

Int J Mol Sci. 2022 Oct 9;23(19):11992. doi: 10.3390/ijms231911992.

ABSTRACT

Vitamin D deficiency has increased in the general population and is a public health issue. Vitamin D plays an important role in regulating the immune system, e.g., by modulating the production of inflammatory cytokines. In most countries, the recommended maximal daily dose of vitamin D3 is 4000 IU (100 µg) per day. In this study, we investigated whether a single vitamin D3 bolus can reduce the levels of the inflammatory markers interleukin (IL) 6, IL8 and tumor necrosis factor (TNF) within one month. Fifty healthy Saudi males were recruited from the local community in Jeddah city and were orally supplemented with a single dose of 80,000 IU vitamin D3. Serum samples were collected at time points 0, 1 and 30 days, and serum levels of IL6, IL8 and TNF, parathyroid hormone (PTH), 25-hydroxyvitamin D3 (25(OH)D3), triglycerides, cholesterol, calcium (Ca2+) and phosphate (PO4-) were determined. On average, the vitamin D3 bolus resulted in a significant increase in vitamin D status as well as in a significant decrease in the levels of inflammatory cytokines even one month after supplementation without changing serum Ca2+, PO4- or lipid levels. In conclusion, single high-dose vitamin D3 supplementation is safe for reducing inflammation markers and may lead to an update of current recommendations for vitamin D intake, in order to prevent critical health problems.

PMID:36233290 | DOI:10.3390/ijms231911992