Front Psychiatry. 2021 Apr 12;12:643609. doi: 10.3389/fpsyt.2021.643609. eCollection 2021.

ABSTRACT

The bidirectional relationship between depression and chronic pain is well-recognized, but their clinical management remains challenging. Here we characterize the shared risk factors and outcomes for their comorbidity in the Australian Genetics of Depression cohort study (N = 13,839). Participants completed online questionnaires about chronic pain, psychiatric symptoms, comorbidities, treatment response and general health. Logistic regression models were used to examine the relationship between chronic pain and clinical and demographic factors. Cumulative linked logistic regressions assessed the effect of chronic pain on treatment response for 10 different antidepressants. Chronic pain was associated with an increased risk of depression (OR = 1.86 [1.37-2.54]), recent suicide attempt (OR = 1.88 [1.14-3.09]), higher use of tobacco (OR = 1.05 [1.02-1.09]) and misuse of painkillers (e.g., opioids; OR = 1.31 [1.06-1.62]). Participants with comorbid chronic pain and depression reported fewer functional benefits from antidepressant use and lower benefits from sertraline (OR = 0.75 [0.68-0.83]), escitalopram (OR = 0.75 [0.67-0.85]) and venlafaxine (OR = 0.78 [0.68-0.88]) when compared to participants without chronic pain. Furthermore, participants taking sertraline (OR = 0.45 [0.30-0.67]), escitalopram (OR = 0.45 [0.27-0.74]) and citalopram (OR = 0.32 [0.15-0.67]) specifically for chronic pain (among other indications) reported lower benefits compared to other participants taking these same medications but not for chronic pain. These findings reveal novel insights into the complex relationship between chronic pain and depression. Treatment response analyses indicate differential effectiveness between particular antidepressants and poorer functional outcomes for these comorbid conditions. Further examination is warranted in targeted interventional clinical trials, which also include neuroimaging genetics and pharmacogenomics protocols. This work will advance the delineation of disease risk indicators and novel aetiological pathways for therapeutic intervention in comorbid pain and depression as well as other psychiatric comorbidities.

PMID:33912086 | PMC:PMC8072020 | DOI:10.3389/fpsyt.2021.643609

Front Pharmacol. 2021 Apr 12;12:646836. doi: 10.3389/fphar.2021.646836. eCollection 2021.

ABSTRACT

Technological advances in science over the past century have paved the way for remedial treatment outcomes in various diseases. Pharmacogenomic predispositions, the emergence of multidrug resistance, medication and formulation errors contribute significantly to patient mortality. The concept of "personalized" or "precision" medicines provides a window to addressing these issues and hence reducing mortality. The emergence of three-dimensional printing of medicines over the past decades has generated interests in therapeutics and dispensing, whereby the provisions of personalized medicines can be built within the framework of producing medicines at dispensaries or pharmacies. This plan is a good replacement of the fit-for-all modality in conventional therapeutics, where clinicians are constrained to prescribe pre-formulated dose units available on the market. However, three-dimension printing of personalized medicines faces several hurdles, but these are not insurmountable. In this review, we explore the relevance of personalized medicines in therapeutics and how three-dimensional printing makes a good fit in current gaps within conventional therapeutics in order to secure an effective implementation of personalized medicines. We also explore the deployment of three-dimensional printing of personalized medicines based on practical, legal and regulatory provisions.

PMID:33912058 | PMC:PMC8072378 | DOI:10.3389/fphar.2021.646836

Front Pharmacol. 2021 Apr 12;12:630658. doi: 10.3389/fphar.2021.630658. eCollection 2021.

ABSTRACT

Background: Breast cancer (BRCA) and prostate cancer (PRCA) are the most commonly diagnosed cancer types in Latin American women and men, respectively. Although in recent years large-scale efforts from international consortia have focused on improving precision oncology, a better understanding of genomic features of BRCA and PRCA in developing regions and racial/ethnic minority populations is still required. Methods: To fill in this gap, we performed integrated in silico analyses to elucidate oncogenic variants from BRCA and PRCA driver genes; to calculate their deleteriousness scores and allele frequencies from seven human populations worldwide, including Latinos; and to propose the most effective therapeutic strategies based on precision oncology. Results: We analyzed 339,100 variants belonging to 99 BRCA and 82 PRCA driver genes and identified 18,512 and 15,648 known/predicted oncogenic variants, respectively. Regarding known oncogenic variants, we prioritized the most frequent and deleterious variants of BRCA (n = 230) and PRCA (n = 167) from Latino, African, Ashkenazi Jewish, East Asian, South Asian, European Finnish, and European non-Finnish populations, to incorporate them into pharmacogenomics testing. Lastly, we identified which oncogenic variants may shape the response to anti-cancer therapies, detailing the current status of pharmacogenomics guidelines and clinical trials involved in BRCA and PRCA cancer driver proteins. Conclusion: It is imperative to unify efforts where developing countries might invest in obtaining databases of genomic profiles of their populations, and developed countries might incorporate racial/ethnic minority populations in future clinical trials and cancer researches with the overall objective of fomenting pharmacogenomics in clinical practice and public health policies.

PMID:33912047 | PMC:PMC8072346 | DOI:10.3389/fphar.2021.630658

Saudi J Biol Sci. 2021 Apr;28(4):2352-2359. doi: 10.1016/j.sjbs.2021.01.030. Epub 2021 Jan 26.

ABSTRACT

The incidence of Acanthamoeba keratitis has been increasing since the previous decades, especially among contact lens users. This infection is majorly caused by the use of ineffective contact lens disinfecting solution. Thus, this study was conducted to evaluate the in vitro effects of multi-purpose disinfecting solutions (MPDS) against Acanthamoeba trophozoites and cysts. Acanthamoeba genotype T4 isolated from contact lens paraphernalia and an environmental strains were propagated for trophozoite or cyst-containing culture and adjusted in final concentration of 1 × 105 cells/ml. Amoebicidal and cysticidal assays were conducted by incubating trophozoites and cysts with OPTI-FREE® Express®, ReNu® Fresh™, Complete® Multi-Purpose Solution and AVIZOR Unica® Sensitive according to the manufacturer's minimum recommended disinfectant time (MMRDT) for up to 12 h at 30 ⁰C. Trypan blue hemocytometer-based microscopic counts determined amoebicidal and cysticidal effects. The viability of Acanthamoeba trophozoites and cysts was confirmed by re-inoculated them in the 1.5% non-nutrient agar plates. It was found that none of the MPDS showed amoebicidal and cysticidal effects during the MMRDT. However, OPTI-FREE® Express® demonstrated a significant differences in average cell reduction for both stages within MMRDT. When subjected to 12 h exposure, both OPTI-FREE® Express® and ReNu® Fresh™ led to significant reduction in the number of trophozoite and cyst cells. Notably, Complete® Multi-Purpose Solution and AVIZOR Unica® Sensitive did appreciably improve the solution effectiveness towards trophozoite cells when incubated for 12 h. All MPDS were largely ineffective, with 100% survival of all isolates at MMRDT, while OPTI-FREE® Express® showed limited amoebicidal activity against the contact lens paraphernalia isolate, however, it was more against the environmental strains after 12 h incubation time. The commercially available MPDS employed in this research offered minimal effectiveness against the protozoa despite the contact time. Improvement or development of new solution should consider the adjustment of the appropriate disinfectant concentration, adequate exposure time or the incorporation of novel chemical elements, which are effective against Acanthamoeba for accelerated disinfecting and more reduction of potential exposure of contact lens users to Acanthamoeba keratitis.

PMID:33911949 | PMC:PMC8071914 | DOI:10.1016/j.sjbs.2021.01.030

Expert Opin Pharmacother. 2021 Apr 28. doi: 10.1080/14656566.2021.1921736. Online ahead of print.

ABSTRACT

INTRODUCTION: Clinically important depressive symptoms that occur in adults over age 60 are often termed late-life depression (LLD). LLD poses challenges for treating clinicians in both detection and treatment. Antidepressants are the most common first line treatment approach. Older adults are at an increased risk of adverse effects because of polypharmacy.

AREAS COVERED: This article summarizes the challenges and approaches when using pharmacotherapy in LLD with a focus on newer data that have become available during the last five years. While no new antidepressants have become available during this period, a review of the literature summarizes advances in the knowledge on the adverse effect associated with various antidepressants and on the potential contribution of pharmacogenetics tools when prescribing antidepressants to older patients.

EXPERT OPINION: During the past five years, most of the literature relevant to the pharmacotherapy of MDD in older patients has focused on adverse effects. In particular, the effects of antidepressants on cognition and bone are emerging as important areas for clinical attention and further investigation. There is also an emerging literature on the potential role of pharmacogenetic testing in patients with MDD, though recommendations for use in older adults await larger studies that demonstrate its cost-effectiveness.

PMID:33910422 | DOI:10.1080/14656566.2021.1921736

Pharmacogenomics. 2021 Apr 29. doi: 10.2217/pgs-2020-0191. Online ahead of print.

ABSTRACT

Aim: A case-control study was conducted in Filipino patients to determine the association between HLA alleles and carbamazepine-induced Stevens-Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN). Materials & methods: A retrospective review of medical records and data collection were performed. A total of 10 carbamazepine-induced SJS/TEN cases and 40 tolerant controls were recruited. Genomic DNA extracted from saliva samples was genotyped. Statistical analysis was done. Results: The HLA-B75 serotype (p = 0.003; odds ratio [OR] = 13.8; 95% CI = 2.5-76.8), HLA-B*15:21 (p = 0.041; OR = 4.7; 95% CI = 1.1-20.8) and HLA-A*24:07 (p = 0.032; OR = 6; 95% CI = 1.2-30.7) were significantly associated with carbamazepine-induced SJS/TEN. Conclusion: The HLA-B75 serotype, HLA-B*15:21 or HLA-A*24:07 may be used for pharmacogenetic screening prior to prescribing carbamazepine in Filipinos.

PMID:33910375 | DOI:10.2217/pgs-2020-0191

Pharmgenomics Pers Med. 2021 Apr 19;14:459-467. doi: 10.2147/PGPM.S289480. eCollection 2021.

ABSTRACT

PURPOSE: The search for predictors of antidepressant response is gaining increasing attention, with epigenetic markers attracting a great deal of interest. We performed a genome-wide study assessing baseline differences in DNA methylation between Responders and Non-Responders.

PATIENTS AND METHODS: Twenty-two children and adolescents, receiving fluoxetine treatment for the first time, were classified as Responders or Non-Responders according to CGI-I score after 8 weeks of fluoxetine treatment. Genome-wide DNA methylation was profiled using the Illumina Infinium MethylationEPIC BeadChip Kit and analyzed using the Chip Analysis Methylation Pipeline (ChAMP).

RESULTS: We identified 21 CpG sites significantly (FDR<0.05) associated with fluoxetine response that showed meaningful differences (Δβ> ±0.2) in methylation level between Responders and Non-Responders. Two genes, RHOJ (Ras Homolog Family Member J) and OR2L13 (Olfactory Receptor family 2 subfamily L member 13), presented more than one significant CpG sites.

CONCLUSION: Our findings provide new insights into the molecular mechanisms underlying the complex phenotype of antidepressant response, indicating that methylation at specific genes could be a promising biomarker that needs further replication in large cohorts.

PMID:33907441 | PMC:PMC8064712 | DOI:10.2147/PGPM.S289480

Medicine (Baltimore). 2021 Apr 30;100(17):e25243. doi: 10.1097/MD.0000000000025243.

ABSTRACT

Anemia is a common complication in patients with renal failure. While erythropoietin is commonly used to treat anemia, some patients exhibit a poor response to erythropoietin. Since store-operated calcium channel (SOC) signaling is one of the erythropoietin activated pathways, we aimed to investigate the association between the genetic polymorphisms of SOC signaling pathway and erythropoietin resistance in patients with renal failure.Four tagging single nucleotide polymorphisms in STIM1 and five in ORAI1 were selected in this study. Genotyping was performed with the TaqMan Allelic Discrimination assay and the association of individual tagging single nucleotide polymorphisms with erythropoietin resistance was analyzed by multivariable adjusted random intercepts model.194 patients were enrolled in this study. The mean age of participants is 68 years, and 56% were men. The mean erythropoietin resistance index was 9.04 ± 4.51 U/Kg/week/g/dL. We found that patients with the AA genotype of rs1561876 in STIM1, and the CC or CT genotypes of rs6486795 in ORAI1, were associated with increased risk of erythropoietin resistance. Functional annotation of expression quantitative trait loci revealed that the AA genotype of rs1561876 in STIM1 has a relatively lower expression of ribonucleotide reductase catalytic subunit M1 in skeletal muscle, while the CC genotype of rs6486795 in ORAI1 has a relatively higher expression of ORAI1 in the whole blood and thyroid.Overall, we demonstrate a significant association between erythropoietin resistance and genetic polymorphisms of STIM1 and ORAI1. Annotation prediction revealed the importance of SOC-mediated calcium signaling for erythropoietin resistance.

PMID:33907089 | DOI:10.1097/MD.0000000000025243

OMICS. 2021 Apr 27. doi: 10.1089/omi.2021.0029. Online ahead of print.

ABSTRACT

Pharmacogenomics (PGx) education is crucial to support the effective delivery of PGx services in any health care system. We mapped the current educational environment of genomics and PGx in the United Arab Emirates (UAE) and assessed the readiness of the accredited higher education system to move forward with the implementation of PGx in the country. We employed a mixed-methods triangulated approach to map the PGx educational environment in UAE. We used two qualitative methods and one quantitative method. University curricula inspection, interviews, and questionnaires were the main resources of data. PGx was taught in 6 out of 21 accredited universities, but only for pharmacy majors. Only three out of six PGx courses were stand-alone. Majority of academia exhibited positive attitudes toward the availability and accessibility of genetic testing, with 89% agreeing that the government should invest more money into its development. Interviews with academics and, importantly, the commissioners who oversee the accreditation process of universities in UAE revealed recurrent themes that included recognizing the importance of genomic medicine and PGx and called for translational and implementational research, including recruitment of experts in the field. We recommend, as supported by our findings in this study, the creation of standardized curriculum of genomics and PGx for each health science field, using the blended teaching approach, and benchmarking internationally accredited universities to foster international collaboration and improve the education and practice of genomics in the clinic and public health systems. An 11-item genomics and PGx strategy is presented herein. Finally, the mixed-methods study design employed in this research may also serve as a model conceptual frame for other science education mapping efforts at country or multi-institutional scales in the future.

PMID:33904793 | DOI:10.1089/omi.2021.0029

Neurol India. 2021 Mar-Apr;69(2):252-259. doi: 10.4103/0028-3886.314522.

ABSTRACT

INTRODUCTION: Chronic neurological diseases are a major cause of mortality and morbidity in the world. With increasing life expectancy in the developing world, the incidence and prevalence of these diseases are predicted to rise even further. This has also contributed to an increase in disability-adjusted life years (DALYs) for noncommunicable diseases. Treatment for such diseases also poses a challenge with multiple genetic and epigenetic factors leading to a varied outcome. Personalization of treatment is one way that treatment outcome/prognosis of disease can be improved, and pharmacogenomics plays a significant role in this context.

METHODOLOGY: This article reviewed the evidence pertaining to the association of genetic and epigenetic markers with major neurological disorders like multiple sclerosis (MS), Alzheimer's disease (AD), and Parkinson's disease (PD), which are a major source of burden among neurological disorders. Types of studies included are peer-reviewed original research articles from the PubMed database (1999-2018).

RESULTS: This study compiled data regarding specific genetic and epigenetic markers with a significant correlation between the clinical diagnosis of the disease and prognosis of therapy from 65 studies. In a single platform, this review highlights the clues to some vital questions, such as why interferon beta (IFN-β) therapy fails to improve symptoms in all MS patients? why cholinesterase inhibitors fail to improve cognitive impairment in a subset of people suffering from AD? or why some individuals on levodopa (L-DOPA) for PD suffer from side-effects ranging from dyskinesia to hallucination while others do not?

CONCLUSION: This article summarizes the genetic and epigenetic factors that may either require monitoring or help in deciding future pharmacotherapy in a patient suffering from MS, AD, and PD. As the health care system develops and reaches newer heights, we expect more and more of these biomarkers to be used as pharmacotherapeutic outcome indicators.

PMID:33904433 | DOI:10.4103/0028-3886.314522

AAPS J. 2021 Apr 26;23(3):58. doi: 10.1208/s12248-021-00583-z.

ABSTRACT

Hepatic clearance may be uptake rate limited by organic anion transporting polypeptides (OATPs) and organic cation transporter 1 (OCT1). While comparison of OATP activity has been investigated across species, little has been reported for OCT1. Additionally, while data on interspecies transporter expression in the liver exist, quantitative comparison of these transporters in multiple tissues is lacking. In the current research, the pharmacokinetics of OCT1 substrates (sumatriptan and metformin) were assessed in Oct knockout rats for comparison with previous Oct1/2-/- mice data and OCT1 pharmacogenetics in humans. Effect of OCT1 inhibitors verapamil and erlotinib on OCT1 substrate liver partitioning was also evaluated in rats. Expression of 18 transporters, including Oatps and Octs, in 9 tissues from mice and rats was quantitated using nanoLC/MS-MS, along with uptake transporters in hepatocytes from 5 species. Interspecies differences in OCT1 activity were further evaluated via uptake of OCT1 substrates in hepatocytes with corresponding in vivo liver partitioning in rodents and monkey. In Oct1-/- rats, sumatriptan hepatic clearance and liver partitioning decreased; however, metformin pharmacokinetics were unaffected. OCT1 inhibitor coadministration decreased sumatriptan liver partitioning. In rodents, Oatp expression was highest in the liver, although comparable expression of Oatps in other tissues was determined. Expression of Octs was highest in the kidney, with liver Oct1 expression comparably lower than Oatps. Liver partitioning of OCT1 substrates was lower in rodents than in monkey, in agreement with the highest OCT1 expression and uptake of OCT1 substrates in monkey hepatocytes. Species-dependent OCT1 activity requires consideration when translating preclinical data to the clinic.

PMID:33903987 | DOI:10.1208/s12248-021-00583-z

Sci Rep. 2021 Apr 26;11(1):9000. doi: 10.1038/s41598-021-88365-7.

ABSTRACT

The intracellular penetration of darunavir, a second-generation HIV protease inhibitor, is limited by the activity of the efflux P-glycoprotein (ABCB1). ABCB1 expression and/or activity levels can vary between individuals due to genetic polymorphisms including the c.1199G>A, c.1236C>T, c.2677G>T and c.3435C>T variants, which could in part explain why the pharmacokinetics of darunavir are so variable from one individual to another. While a few clinical studies have failed to demonstrate an influence of these polymorphisms on darunavir pharmacokinetics, drug-drug interactions and methodological limitations may have prevented them from revealing the true influence of ABCB1 variants. In this work, we report on the intracellular accumulation of darunavir in recombinant HEK293 cell lines expressing wild-type ABCB1 or one of several variants: ABCB1 1199A, ABCB1 3435T, and ABCB1 1236T/2677T/3435T. We demonstrate that while ABCB1 expression limits intracellular accumulation of darunavir, there is no significant difference in efflux activity between cells expressing wild-type ABCB1 and those that express any of the studied variants.

PMID:33903659 | DOI:10.1038/s41598-021-88365-7

Gut. 2021 Apr 26:gutjnl-2021-324789. doi: 10.1136/gutjnl-2021-324789. Online ahead of print.

ABSTRACT

OBJECTIVE: Delayed second dose SARS-CoV-2 vaccination trades maximal effectiveness for a lower level of immunity across more of the population. We investigated whether patients with inflammatory bowel disease treated with infliximab have attenuated serological responses to a single dose of a SARS-CoV-2 vaccine.

DESIGN: Antibody responses and seroconversion rates in infliximab-treated patients (n=865) were compared with a cohort treated with vedolizumab (n=428), a gut-selective anti-integrin α4β7 monoclonal antibody. Our primary outcome was anti-SARS-CoV-2 spike (S) antibody concentrations, measured using the Elecsys anti-SARS-CoV-2 spike (S) antibody assay 3-10 weeks after vaccination, in patients without evidence of prior infection. Secondary outcomes were seroconversion rates (defined by a cut-off of 15 U/mL), and antibody responses following past infection or a second dose of the BNT162b2 vaccine.

RESULTS: Geometric mean (SD) anti-SARS-CoV-2 antibody concentrations were lower in patients treated with infliximab than vedolizumab, following BNT162b2 (6.0 U/mL (5.9) vs 28.8 U/mL (5.4) p<0.0001) and ChAdOx1 nCoV-19 (4.7 U/mL (4.9)) vs 13.8 U/mL (5.9) p<0.0001) vaccines. In our multivariable models, antibody concentrations were lower in infliximab-treated compared with vedolizumab-treated patients who received the BNT162b2 (fold change (FC) 0.29 (95% CI 0.21 to 0.40), p<0.0001) and ChAdOx1 nCoV-19 (FC 0.39 (95% CI 0.30 to 0.51), p<0.0001) vaccines. In both models, age ≥60 years, immunomodulator use, Crohn's disease and smoking were associated with lower, while non-white ethnicity was associated with higher, anti-SARS-CoV-2 antibody concentrations. Seroconversion rates after a single dose of either vaccine were higher in patients with prior SARS-CoV-2 infection and after two doses of BNT162b2 vaccine.

CONCLUSION: Infliximab is associated with attenuated immunogenicity to a single dose of the BNT162b2 and ChAdOx1 nCoV-19 SARS-CoV-2 vaccines. Vaccination after SARS-CoV-2 infection, or a second dose of vaccine, led to seroconversion in most patients. Delayed second dosing should be avoided in patients treated with infliximab.

TRIAL REGISTRATION NUMBER: ISRCTN45176516.

PMID:33903149 | DOI:10.1136/gutjnl-2021-324789

Stroke. 2021 Apr 27:STROKEAHA120033041. doi: 10.1161/STROKEAHA.120.033041. Online ahead of print.

ABSTRACT

BACKGROUND AND PURPOSE: MMP (matrix metalloproteinase) levels have been widely associated with ischemic stroke risk and poststroke outcome. However, their role as a risk factor or as a subeffect because of ischemia is uncertain.

METHODS: We performed a literature search of genome-wide studies that evaluate serum/plasma levels of MMPs. We used a 2-sample Mendelian randomization approach to evaluate the causality of MMP levels on ischemic stroke risk or poststroke outcome, using 2 cohorts: MEGASTROKE (n=440 328) and GODs (n=1791).

RESULTS: Genome-wide association studies of MMP-1, MMP-8, and MMP-12 plasma/serum levels were evaluated. A significant association, which was also robust in the sensitivity analysis, was found with all ischemic strokes: MMP-12 (odds ratio=0.90 [95% CI, 0.86-0.94]; q value=7.43×10-5), and with subtypes of stroke, large-artery atherosclerosis: MMP-1 (odds ratio=0.95 [95% CI, 0.92-0.98]; q value=0.01) and MMP-12 (odds ratio=0.71 [95% CI, 0.65-0.77]; q value=5.11×10-14); small-vessel occlusion: MMP-8 (odds ratio=1.24 [95% CI, 1.06-1.45]; q value=0.03). No associations were found in relation to stroke outcome.

CONCLUSIONS: Our study suggests a causal link between lower serum levels of MMP-12 and the risk of ischemic stroke, lower serum levels of MMP-1 and MMP-12 and the risk of large-artery stroke and higher serum levels of MMP-8 and the risk of lacunar stroke.

PMID:33902302 | DOI:10.1161/STROKEAHA.120.033041

Pharmacol Ther. 2021 Apr 23:107861. doi: 10.1016/j.pharmthera.2021.107861. Online ahead of print.

ABSTRACT

Adequate food intake and relative abundance of dietary nutrients have undisputed effects on the brain function. There is now substantial evidence that dietary nutrition aids in the prevention and remediation of neurologic symptoms in diverse pathological conditions. The newly described influences of dietary factors on the alterations of mitochondrial dysfunction, epigenetic modification and neuroinflammation are important mechanisms that are responsible for the action of nutrients on the brain health. In this review, we discuss the state of evidence supporting that distinct dietary interventions including dietary supplement and dietary restriction have the ability to tackle neurological disorders using Alzheimer's disease, Parkinson's disease, stroke, epilepsy, traumatic brain injury, amyotrophic lateral sclerosis, Huntington's disease and multiple sclerosis as examples. Additionally, it is also highlighting that diverse potential mechanisms such as metabolic control, epigenetic modification, neuroinflammation and gut-brain axis are of utmost importance for nutrient supply to the risk of neurologic condition and therapeutic response. Finally, we also highlight the novel concept that dietary nutrient intervention reshapes metabolism-epigenetics-immunity cycle to remediate brain dysfunction. Targeting metabolism-epigenetics-immunity network will delineate a new blueprint for combating neurological weaknesses.

PMID:33901506 | DOI:10.1016/j.pharmthera.2021.107861

Basic Clin Pharmacol Toxicol. 2021 Apr 26. doi: 10.1111/bcpt.13593. Online ahead of print.

ABSTRACT

Anthracyclines are widely used as part of chemotherapeutic regimens in paediatric oncology patients. The most serious adverse drug reaction caused by anthracycline use is cardiotoxicity, a serious condition that can lead to cardiac dysfunction and subsequent heart failure. Both clinical and genetic factors contribute to a patient's risk of experiencing anthracycline-induced cardiotoxicity. In particular, genetic variants in RARG, UGT1A6 and SLC28A3 have been consistently shown to influence an individual's risk of experiencing this reaction. By combining clinical and genetic risks, decision-making can be improved to optimize treatment and prevent potentially serious adverse drug reactions. As part of a precision medicine initiative, we used pharmacogenetic testing, focused on RARG, UGT1A6 and SLC28A3 variants, to help predict an individual's risk of experiencing anthracycline-induced cardiotoxicity. Pharmacogenetic results are currently being used in clinical decision-making to inform treatment regimen choice, anthracycline dosing and decisions to initiate cardioprotective agents. In this case series, we demonstrate examples of the impact of genetic testing and discuss its potential to allow patients to be increasingly involved in their own treatment decisions.

PMID:33900042 | DOI:10.1111/bcpt.13593

Leuk Lymphoma. 2021 Apr 26:1-12. doi: 10.1080/10428194.2021.1913140. Online ahead of print.

ABSTRACT

Methotrexate (MTX), an antimetabolite for the treatment of leukemia, could cause neutropenia and subsequently fever, which might lead to treatment delay and affect prognosis. Here, we aimed to predict neutropenia and fever related to high-dose MTX using artificial intelligence. This study included 139 pediatric patients newly diagnosed with standard- or intermediate risk B-cell acute lymphoblastic leukemia. Fifty-seven SNPs of 16 genes were genotyped. Univariate and multivariate analysis were used to select SNPs and clinical covariates for model developing. Five machine learning algorithms combined with four resampling techniques were used to build optimal predictive model. The combination of random forest with adaptive synthetic appeared to be the best model for neutropenia (sensitivity = 0.935, specificity = 0.920, AUC = 0.927) and performed best for fever (sensitivity = 0.818, specificity = 0.924, AUC = 0.870). By machine learning, we have developed and validated comprehensive models to predict the risk of neutropenia and fever. Such models may be helpful for medical oncologists in quick decision-making.

PMID:33899650 | DOI:10.1080/10428194.2021.1913140

J Transl Autoimmun. 2021 Apr 5;4:100096. doi: 10.1016/j.jtauto.2021.100096. eCollection 2021.

ABSTRACT

Psoriasis is an autoimmune disease associated with interleukins, their receptors, key transcription factors and more recently, antimicrobial peptides (AMPs). Cathelicidin LL-37 is an AMP proposed to play a fundamental role in psoriasis etiology. With our proprietary software SNPClinic v.1.0, we analyzed 203 common SNPs (MAF frequency ​> ​1%) in proximal promoters of 22 genes associated with psoriasis. These include nine genes which protein products are classic drug targets for psoriasis (TNF, IL17A, IL17B, IL17C, IL17F, IL17RA, IL12A, IL12B and IL23A). SNPClinic predictions were run with DNAseI-HUP chromatin accessibility data in eight psoriasis/epithelia-relevant cell lines from ENCODE including keratinocytes (NHEK), TH1 and TH17 lymphocytes. Results were ranked quantitatively by transcriptional relevance according to our novel Functional Impact Factor (FIF) parameter. We found six rSNPs in five genes (CAMP/cathelicidin, S100A7/psoriasin, IL17C, IL17RA and TNF) and each was confirmed as true rSNP in at least one public eQTL database including GTEx portal and ENCODE (Phase 3). Predicted regulatory SNPs in cathelicidin, IL17C and IL17RA genes may explain hyperproliferation of keratinocytes. Predicted rSNPs in psoriasin, IL17C and cathelicidin may contribute to activation and polarization of lymphocytes. Predicted rSNPs in TNF gene are concordant with the epithelium-mesenchymal transition. In spite that these results must be validated in vitro and in vivo with a functional genomics approach, we propose FOXP2, RUNX2, NR2F1, ELF1 and HESX1 transcription factors (those with the highest FIF on each gene) as novel drug targets for psoriasis. Furthermore, four out of six rSNPs uncovered by SNPClinic v.1.0 software, could also be validated in the clinic as companion diagnostics/pharmacogenetics assays for psoriasis prescribed drugs that block TNF-α (e.g. Etanercept), IL-17 (e.g. Secukinumab) and IL-17 receptor (Brodalumab).

PMID:33898962 | PMC:PMC8060581 | DOI:10.1016/j.jtauto.2021.100096

Front Cell Dev Biol. 2021 Apr 7;9:631011. doi: 10.3389/fcell.2021.631011. eCollection 2021.

ABSTRACT

One of the vital challenges for cancer diseases is efficient biomarkers monitoring formation and development are limited. Omics data integration plays a crucial role in the mining of biomarkers in the human condition. As the link between omics study on biomarkers discovery and cancer diseases is deepened, defining the principal technologies applied in the field is a must not only for the current period but also for the future. We utilize topic modeling to extract topics (or themes) as a probabilistic distribution of latent topics from the dataset. To predict the future trend of related cases, we utilize the Prophet neural network to perform a prediction correction model for existing topics. A total of 2,318 pieces of literature (from 2006 to 2020) were retrieved from MEDLINE with the query on "omics" and "cancer." Our study found 20 topics covering current research types. The topic extraction results indicate that, with the rapid development of omics data integration research, multi-omics analysis (Topic 11) and genomics of colorectal cancer (Topic 10) have more studies reported last 15 years. From the topic prediction view, research findings in multi-omics data processing and novel biomarker discovery for cancer prediction (Topic 2, 3, 10, 11) will be heavily focused in the future. From the topic visuallization and evolution trends, metabolomics of breast cancer (Topic 9), pharmacogenomics (Topic 15), genome-guided therapy regimens (Topic 16), and microRNAs target genes (Topic 17) could have more rapidly developed in the study of cancer treatment effect and recurrence prediction.

PMID:33898421 | PMC:PMC8058380 | DOI:10.3389/fcell.2021.631011

Cent Eur J Immunol. 2021;46(1):92-98. doi: 10.5114/ceji.2021.104425. Epub 2021 Mar 15.

ABSTRACT

The present study aimed to analyse and compare the distribution of MICA (rs1051792) and NKG2D/KLRK1 (rs1154831, rs1049174, rs2255336) polymorphisms in 61 Greek and 100 Polish patients with rheumatoid arthritis in relation to the presence of the HLA-DRB1 shared epitope and clinical parameters. Genotyping of selected polymorphism was performed using real-time PCR. HLA-DRB1 shared epitope alleles segregated differently in Greek and Polish patients but in both populations were detected in over 60% of cases. The rs1051792-A variant was more common among SE-positive Polish patients (p = 0.003) while the rs1049174-G allele was more frequently observed in Greeks than in Poles (p < 0.001). Moreover, among Greek patients, the rs1051792-GG homozygotes more frequently presented with anti-CCP antibodies and rheumatoid factor (RF), while carriers of the rs1049174-G variant and rs1154831-CC homozygotes were characterized by lower disease activity scores (p < 0.05 in all cases). These results imply that, in addition to the HLA-DRB1 SE alleles, MICA and NKG2D polymorphisms may also play a role in rheumatoid arthritis.

PMID:33897289 | PMC:PMC8056341 | DOI:10.5114/ceji.2021.104425