Pharmaceuticals (Basel). 2021 Mar 2;14(3):205. doi: 10.3390/ph14030205.

ABSTRACT

Osteoarthritis is the most common musculoskeletal progressive disease, with the knee as the most commonly affected joint in the human body. While several new medications are still under research, many symptomatic therapy options, such as analgesics (opioid and non-opioid), nonsteroid anti-inflammatory drugs, symptomatic slow-acting drugs in osteoarthritis, and preparations for topical administration, are being used, with a diverse clinical response and inconsistent conclusions across various professional societies guidelines. The concept of pharmacogenomic-guided therapy, which lies on principles of the right medication for the right patient in the right dose at the right time, can significantly increase the patient's response to symptom relief therapy in knee osteoarthritis. Corticosteroid intra-articular injections and hyaluronic acid injections provoke numerous discussions and disagreements among different guidelines, even though they are currently used in daily clinical practice. Biological options, such as platelet-rich plasma and mesenchymal stem cell injections, have shown good results in the treatment of osteoarthritis symptoms, greatly increasing the patient's quality of life, especially when combined with other therapeutic options. Non-inclusion of the latter therapies in the guidelines, and their inconsistent stance on numerous therapy options, requires larger and well-designed studies to examine the true effects of these therapies and update the existing guidelines.

PMID:33801304 | DOI:10.3390/ph14030205

J Pers Med. 2021 Mar 11;11(3):194. doi: 10.3390/jpm11030194.

ABSTRACT

Estrogen sulfotransferase (SULT1E1) is a phase II enzyme that sulfates estrogens to inactivate them and regulate their homeostasis. This enzyme is also involved in the sulfation of thyroid hormones and several marketed medicines. Though the profound action of SULT1E1 in molecular/pathological biology has been extensively studied, its genetic variants and functional studies have been comparatively rarely studied. Genetic variants of this gene are associated with some diseases, especially sex-hormone-related cancers. Comprehending the role and polymorphisms of SULT1E1 is crucial to developing and integrating its clinical relevance; therefore, this study gathered and reviewed various literature studies to outline several aspects of the function, molecular regulation, and polymorphisms of SULT1E1.

PMID:33799763 | DOI:10.3390/jpm11030194

Cancers (Basel). 2021 Mar 11;13(6):1219. doi: 10.3390/cancers13061219.

ABSTRACT

Patients with breast cancer often receive many drugs to manage the cancer, side effects associated with cancer treatment, and co-morbidities (i.e., polypharmacy). Drug-drug and drug-gene interactions contribute to the risk of adverse events (AEs), which could lead to non-adherence and reduced efficacy. Here we investigated several well-characterized inherited (germline) pharmacogenetic (PGx) targets in 225 patients with breast cancer. All relevant clinical, pharmaceutical, and PGx diplotype data were aggregated into a single unifying informatics platform to enable an exploratory analysis of the cohort and to evaluate pharmacy ordering patterns. Of the drugs recorded, there were 38 for which high levels of evidence for clinical actionability with PGx was available from the US FDA and/or the Clinical Pharmacogenetics Implementation Consortium (CPIC). These data were associated with 10 pharmacogenes: DPYD, CYP2C9, CYP2C19, CYP2D6, CYP3A5, CYP4F2, G6PD, MT-RNR1, SLCO1B1, and VKORC1. All patients were taking at least one of the 38 drugs and had inherited at least one actionable PGx variant that would have informed prescribing decisions if this information had been available pre-emptively. The non-cancer drugs with PGx implications that were common (prescribed to at least one-third of patients) included anti-depressants, anti-infectives, non-steroidal anti-inflammatory drugs, opioids, and proton pump inhibitors. Based on these results, we conclude that pre-emptive PGx testing may benefit patients with breast cancer by informing drug and dose selection to maximize efficacy and minimize AEs.

PMID:33799547 | DOI:10.3390/cancers13061219

Forensic Sci Int Genet. 2021 Mar 26;53:102510. doi: 10.1016/j.fsigen.2021.102510. Online ahead of print.

ABSTRACT

Genetic disposition can cause variation in oxycodone pharmacokinetic characteristics and decrease or increase the expected clinical response. In forensic medicine, determination of cause of death or assessing time between drug intake and death can be facilitated by knowledge of parent and metabolite concentrations. In this study, the aim was to investigate if CYP2D6 genotyping can facilitate interpretation by investigating the frequency of the four CYP2D6 phenotypes, poor metabolizer, intermediate metabolizer, extensive metabolizer, and ultra-rapid metabolizer in postmortem cases, and to study if the CYP2D6 activity was associated with a certain cause of death, concentration, or metabolic ratio. Cases positive for oxycodone in femoral blood (n = 174) were genotyped by pyrosequencing for CYP2D6*3, *4, and *6 and concentrations of oxycodone, noroxycodone, oxymorphone, and noroxymorphone were determined by LC-MS/MS (LLOQ 0.005 µg/g). Digital droplet PCR was used to determine the copy number variation for CYP2D6*5. Cases were categorized by cause of death. It was found that poor and intermediate CYP2D6 metabolizers had significantly higher oxycodone and noroxycodone concentrations compared to extensive and ultra-rapid metabolizers. CYP2D6 phenotype were equally distributed between cause of death groups, showing that no phenotype was overrepresented in any of the cause of death groups. We also found that the concentration ratio between oxymorphone and oxycodone depended on the CYP2D6 activity when death was unrelated to intoxication. In general, a low metabolite to parent ratio indicate an acute intake. By using receiver operating characteristic (ROC) analysis, we conclude that an oxymorphone/oxycodone ratio lower than 0.075 has a high sensitivity for separating intoxications with oxycodone from other intoxications and non-intoxications. However, the phenotype needs to be known to reach a high specificity. Therefore, the ratio should not be used as a biomarker on its own to distinguish between different causes of death but needs to be complemented by genotyping.

PMID:33799050 | DOI:10.1016/j.fsigen.2021.102510

J Invest Dermatol. 2021 Mar 30:S0022-202X(21)01125-8. doi: 10.1016/j.jid.2021.03.014. Online ahead of print.

ABSTRACT

HLA-B*13:01 is associated with dapsone (DDS)-induced hypersensitivity and it has been shown that CD4+ and CD8+ T cells are activated by DDS and its nitroso metabolite (DDS-NO). However, there is a need to define the importance of the HLA association in the disease pathogenesis. Thus, DDS and DDS-NO-specific CD8+ T cell clones (TCC) were generated from hypersensitive patients expressing HLA-B*13:01 and assessed for phenotype and function, HLA-allele restriction, and killing of target cells. CD8+ TCC were stimulated to proliferate and secrete effector molecules when exposed to DDS and/or DDS-NO. DDS-responsive and several DDS-NO-responsive TCC expressing a variety of TCR sequences displayed HLA class-I-restriction, with the drug(metabolite) interacting with multiple HLA-B alleles. However, activation of certain DDS-NO-responsive CD8+ TCC was inhibited with HLA-class-II block, with DDS-NO binding to HLA-DQB1*05:01. These TCC were of different origin, but expressed TCRs displaying the same amino acid sequences. They were activated via a hapten pathway, displayed a CD45RO, CD28, PD-1 and CTLA-4 surface molecules, secreted the same panel of effector molecules as HLA class-I-restricted TCC, but displayed a lower capacity to lyse target cells. To conclude, DDS and DDS-NO interact with a number of HLA molecules to activate CD8+ TCC, with HLA class-II-restricted CD8+ TCC that display hybrid CD4/CD8 features also contributing to the promiscuous immune response that develops in patients.

PMID:33798536 | DOI:10.1016/j.jid.2021.03.014

Am J Hum Genet. 2021 Apr 1;108(4):535-548. doi: 10.1016/j.ajhg.2021.03.003.

ABSTRACT

Genome sequencing is enabling precision medicine-tailoring treatment to the unique constellation of variants in an individual's genome. The impact of recurrent pathogenic variants is often understood, however there is a long tail of rare genetic variants that are uncharacterized. The problem of uncharacterized rare variation is especially acute when it occurs in genes of known clinical importance with functionally consequential variants and associated mechanisms. Variants of uncertain significance (VUSs) in these genes are discovered at a rate that outpaces current ability to classify them with databases of previous cases, experimental evaluation, and computational predictors. Clinicians are thus left without guidance about the significance of variants that may have actionable consequences. Computational prediction of the impact of rare genetic variation is increasingly becoming an important capability. In this paper, we review the technical and ethical challenges of interpreting the function of rare variants in two settings: inborn errors of metabolism in newborns and pharmacogenomics. We propose a framework for a genomic learning healthcare system with an initial focus on early-onset treatable disease in newborns and actionable pharmacogenomics. We argue that (1) a genomic learning healthcare system must allow for continuous collection and assessment of rare variants, (2) emerging machine learning methods will enable algorithms to predict the clinical impact of rare variants on protein function, and (3) ethical considerations must inform the construction and deployment of all rare-variation triage strategies, particularly with respect to health disparities arising from unbalanced ancestry representation.

PMID:33798442 | DOI:10.1016/j.ajhg.2021.03.003

Bipolar Disord. 2021 Apr 2. doi: 10.1111/bdi.13078. Online ahead of print.

ABSTRACT

BACKGROUND: Lithium is regarded as a first line treatment for bipolar disorder (BD), but partial response and non-response commonly occurs. There exists a need to identify lithium non-responders prior to initiating treatment. The Pharmacogenomics of Bipolar Disorder (PGBD) Study was designed to identify predictors of lithium response.

METHODS: The PGBD Study was an eleven site prospective trial of lithium treatment in bipolar 1 disorder. Subjects were stabilized on lithium monotherapy over four months and gradually discontinued from all other psychotropic medications. After ensuring a sustained clinical remission (defined by a score of ≤3 on the CGI for four weeks) had been achieved, subjects were followed for up to two years to monitor clinical response. Cox proportional hazard models were used to examine the relationship between clinical measures and time until failure to remit or relapse.

RESULTS: A total of 345 individuals were enrolled into the study and included in the analysis. Of these, 101 subjects failed to remit or relapsed, 88 achieved remission and continued to study completion, and 156 were terminated from the study for other reasons. Significant clinical predictors of treatment failure (p<0.05) included baseline anxiety symptoms, functional impairments, negative life events and lifetime clinical features such as a history of migraine, suicidal ideation/attempts, and mixed episodes, as well as a chronic course of illness.

CONCLUSIONS: In this PGBD Study of lithium response, several clinical features were found to be associated with failure to respond to lithium. Future validation is needed to confirm these clinical predictors of treatment failure and their use clinically to distinguish who will do well on lithium before starting pharmacotherapy.

PMID:33797828 | DOI:10.1111/bdi.13078

Trop Biomed. 2021 Mar 1;38(1):187-204. doi: 10.47665/tb.38.1.018.

ABSTRACT

Malaria infection still remains as one of the most prominent parasitic diseases afflicting mankind in tropical and subtropical regions. The severity of malaria infection has often been associated to exuberant host immune inflammatory responses that could possibly lead to severe immunopathological conditions and subsequent death of host tissues. Activin A is a protein belonging to the transforming growth factor-beta (TGF-β) family that regulates multiple physiological processes and pathological-associated diseases. The biological roles of activin A have been associated with manipulation of inflammation-related processes and modulation of host immune responses. This implies that activin A protein could play a role in malaria pathogenesis since malaria infection has been closely linked to severe immune responses leading to death, However, the actual in vivo role of activin A in malaria infection remains elusive. Hence, this study was undertaken to investigate the involvement of activin A in malaria infection as well as to assess the modulating effects of activin A on the cytokine releases (TNF-α, IFN-γ and IL-10) and histopathological changes in major affected organs (kidney, liver, lung, brain and spleen) in malarial mice infected with Plasmodium berghei ANKA. Our results showed that the concentrations of plasma activin A were significantly increased in malarial mice throughout the study periods. Also. the systemic activin A level was positively correlated with malaria parasitemia. This indicates that activin A could play a role in malaria pathogenesis and malaria parasitemia development. Plasma TNF-α, IFN-γ and IL-10 cytokine levels were significantly increased in malarial mice at day-5 post infection, suggesting that these cytokines attributed to severe malaria pathogenesis. Histopathological features such as sequestration of parasitized red blood cells (pRBCs) and hemozoin formation were amongst the most common pathological conditions observed in tissues of major affected organs (kidney, liver, lung, brain and spleen) in malarial mice. Neutralization of activin A production via recombinant mouse activin RIIA Fc chimera (rmActivin RIIA Fc chimera) had significantly reduced the parasitemia levels in malarial mice. The release of TNF-α cytokine was significantly reduced as well as the sequestration of parasitized pRBCs and hemozoin formation in major affected organs in malarial mice were also alleviated following inhibition of activin A production. Overall, this preliminary study suggests that activin A could play an immune modulation role in malaria pathogenesis through modulation of TNF-α release that benefits host from severe pathological destructions provoked by intensified inflammatory responses. Further studies are warranted to elucidate the precise mechanism of immune modulation mediated by activin A and its associated immune-modulation mediators in regulating the inflammatory responses elicited during the course of malaria infection.

PMID:33797545 | DOI:10.47665/tb.38.1.018

Oncoimmunology. 2021 Mar 18;10(1):1896643. doi: 10.1080/2162402X.2021.1896643.

ABSTRACT

Prostaglandin E2 (PGE2), an arachidonic acid pathway metabolite produced by cyclooxygenase (COX)-1/2, has been shown to impair anti-tumor immunity through engagement with one or more E-type prostanoid receptors (EP1-4). Specific targeting of EP receptors, as opposed to COX-1/2 inhibition, has been proposed to achieve preferential antagonism of PGE2-mediated immune suppression. Here we describe the anti-tumor activity of MF-766, a potent and highly selective small-molecule inhibitor of the EP4 receptor. EP4 inhibition by MF-766 synergistically improved the efficacy of anti-programmed cell death protein 1 (PD-1) therapy in CT26 and EMT6 syngeneic tumor mouse models. Multiparameter flow cytometry analysis revealed that treatment with MF-766 promoted the infiltration of CD8+ T cells, natural killer (NK) cells and conventional dendritic cells (cDCs), induced M1-like macrophage reprogramming, and reduced granulocytic myeloid-derived suppressor cells (MDSC) in the tumor microenvironment (TME). In vitro experiments demonstrated that MF-766 restored PGE2-mediated inhibition of lipopolysaccharide (LPS)-induced tumor necrosis factor (TNF)-α production in THP-1 cells and human blood, and PGE2-mediated inhibition of interleukin (IL)-2-induced interferon (IFN)-γ production in human NK cells. MF-766 reversed the inhibition of IFN-γ in CD8+ T-cells by PGE2 and impaired suppression of CD8+ T-cells induced by myeloid-derived suppressor cells (MDSC)/PGE2. In translational studies using primary human tumors, MF-766 enhanced anti-CD3-stimulated IFN-γ, IL-2, and TNF-α production in primary histoculture and synergized with pembrolizumab in a PGE2 high TME. Our studies demonstrate that the combination of EP4 blockade with anti-PD-1 therapy enhances antitumor activity by differentially modulating myeloid cell, NK cell, cDC and T-cell infiltration profiles.

PMID:33796403 | PMC:PMC7993229 | DOI:10.1080/2162402X.2021.1896643

Circ Genom Precis Med. 2021 Apr 2:CIRCGEN121003219. doi: 10.1161/CIRCGEN.121.003219. Online ahead of print.

ABSTRACT

Following the neutral results of the dal-OUTCOMES trial, a genome-wide study identified the rs1967309 variant in the adenylate cyclase type 9 (ADCY9) gene on chromosome 16 as being associated with the risk of future cardiovascular events only in subjects taking dalcetrapib, a CETP (cholesterol ester transfer protein) modulator. Homozygotes for the minor A allele (AA) were protected from recurrent cardiovascular events when treated with dalcetrapib, while homozygotes for the major G allele (GG) had increased risk. Here, we present the current state of knowledge regarding the impact of rs1967309 in ADCY9 on clinical observations and biomarkers in dalcetrapib trials and the effects of mouse ADCY9 gene inactivation on cardiovascular physiology. Finally, we present our current model of the interaction between dalcetrapib and ADCY9 gene variants in the arterial wall macrophage, based on the intracellular role of CETP in the transfer of complex lipids from endoplasmic reticulum membranes to lipid droplets. Briefly, the concept is that dalcetrapib would inhibit CETP-mediated transfer of cholesteryl esters, resulting in a progressive inhibition of cholesteryl ester synthesis and free cholesterol accumulation in the endoplasmic reticulum. Reduced ADCY9 activity, by paradoxically leading to higher cyclic AMP levels and in turn increased cellular cholesterol efflux, could impart cardiovascular protection in rs1967309 AA patients. The ongoing dal-GenE trial recruited 6145 patients with the protective AA genotype and will provide a definitive answer to whether dalcetrapib will be protective in this population.

PMID:33794646 | DOI:10.1161/CIRCGEN.121.003219

Crit Rev Oncol Hematol. 2021 Mar 29:103312. doi: 10.1016/j.critrevonc.2021.103312. Online ahead of print.

ABSTRACT

Methotrexate (MTX), an important chemotherapeutic agent, is often accompanied with mucositis. The occurrence and severity are unpredictable and show large interindividual variability. In this study, we review and meta-analyze previously studied genetic variants in relation to MTX-induced mucositis. We conducted a systematic search in Medline and Embase. We included genetic association studies of MTX-induced mucositis in cancer patients. A meta-analysis was conducted for single nucleotide polymorphisms (SNPs) for which at least two studies found a statistically significant association. A total of 34 SNPs were associated with mucositis in more than one study of the 57 included studies. Two of the seven SNPs included in our meta-analysis were statistically significantly associated with mucositis: MTHFR c.677C > T (recessive, grade ≥3 vs grade 0-2, OR 2.53, 95%CI [1.48-4.32], False Discovery Rate[FDR]-corrected p-value 0.011) and MTRR c.66A > G (overdominant, grade ≥1 vs grade 0, OR 2.08, 95%CI [1.16-3.73], FDR-corrected p-value 0.042).

PMID:33794308 | DOI:10.1016/j.critrevonc.2021.103312

JCO Oncol Pract. 2021 Apr 1:OP2001072. doi: 10.1200/OP.20.01072. Online ahead of print.

NO ABSTRACT

PMID:33793308 | DOI:10.1200/OP.20.01072

Compr Physiol. 2021 Apr 1;11(2):1759-1783. doi: 10.1002/cphy.c200013.

ABSTRACT

Discovered almost simultaneously with insulin, glucagon is a pleiotropic hormone with metabolic action that goes far beyond its classical role to increase blood glucose. Albeit best known for its ability to directly act on the liver to increase de novo glucose production and to inhibit glycogen breakdown, glucagon lowers body weight by decreasing food intake and by increasing metabolic rate. Glucagon further promotes lipolysis and lipid oxidation and has positive chronotropic and inotropic effects in the heart. Interestingly, recent decades have witnessed a remarkable renaissance of glucagon's biology with the acknowledgment that glucagon has pharmacological value beyond its classical use as rescue medication to treat severe hypoglycemia. In this article, we summarize the multifaceted nature of glucagon with a special focus on its hepatic action and discuss the pharmacological potential of either agonizing or antagonizing the glucagon receptor for health and disease. © 2021 American Physiological Society. Compr Physiol 11:1759-1783, 2021.

PMID:33792899 | DOI:10.1002/cphy.c200013

Clin Pharmacol Ther. 2021 Apr 1. doi: 10.1002/cpt.2244. Online ahead of print.

ABSTRACT

Liver-derived small extracellular vesicles (sEV), prepared from small sets of banked serum samples using a novel two-step protocol, were deployed as liquid biopsy to study the induction of cytochromes P450 (CYP3A4, CYP3A5, CYP2D6) and organic anion transporting polypeptides (OATP1B1 and OATP1B3) during pregnancy (non-pregnant [T0], 1st , 2nd and 3rd [T3] trimester females; N = 3 each) and after administration of rifampicin (RIF) to healthy male subjects. Proteomic analysis revealed induction (mean fold-increase, 90% confidence interval) of sEV CYP3A4 after RIF 300 mg x 7 days [3.5 (2.5-4.5), N = 4, P = 0.029] and 600 mg x 14 days [3.7 (2.1-6.0), N = 5, P = 0.018] consistent with the mean oral midazolam area under the plasma concentration time curve (AUC) ratio in the same subjects [0.28 (0.22-0.34), P <0.0001; 0.17 (0.13-0.22), P < 0.0001]. Compared to CYP3A4, liver sEV CYP3A5 protein (subjects genotyped CYP3A5*1/*3) was weakly induced (≤ 1.5-fold). It was also possible to measure liver sEV-catalysed dextromethorphan (DEX) O-demethylation to dextrorphan (DXO), correlated with sEV CYP2D6 expression (r = 0.917, P = 0.0001; N = 10) and 3hr plasma DXO-to-DEX concentration ratio (r = 0.843, P = 0.002; N = 10), and show that CYP2D6 was not induced by RIF. Non-parametric analysis of liver sEV revealed significantly higher CYP3A4 (3.2-fold; P = 0.003) and CYP2D6 (3.7-fold; P = 0.03) protein expression in T3 versus T0 females. In contrast, expression of both OATPs in liver sEV was unaltered by RIF administration and pregnancy.

PMID:33792897 | DOI:10.1002/cpt.2244

Clin Pharmacol Ther. 2021 Mar 31. doi: 10.1002/cpt.2246. Online ahead of print.

ABSTRACT

The metabolic activity of the polymorphic CYP2D6 enzyme is dependent on the CYP2D6 genotype; however, the guidelines for translating the genotype into phenotype, which are of relevance for adequate drug dose personalization, are ambiguous. In the present study, retrospective therapeutic drug monitoring data from 4,700 CYP2D6 genotyped patients treated with risperidone, venlafaxine, and/or aripiprazole were analyzed to quantify the effect of CYP2D6 genotype on the CYP2D6 metabolic activities, as measured by metabolic ratios of these substrates. The patients were categorized into diplotypes based on the presence of normal function (CYP2D6Norm), nonfunctional (CYP2D6Nonf) and decreased function (CYP2D6Decr i.e. CYP2D6*9, CYP2D6*10, and CYP2D6*41) CYP2D6 haplotypes. Significant correlations between the metabolic ratios were observed in patients (n=77-103) co-treated with risperidone and venlafaxine, risperidone and aripiprazole, or venlafaxine and aripiprazole (ρ = 0.874, 0.785, and 0.644, respectively; p<0.001 for all). Relative metabolic CYP2D6 diplotype activity was calculated based on that the metabolic ratios, where median values for CYP2D6Nonf/Nonf and CYP2D6Norm/Norm subgroups were set to 0% and 100%, respectively. The relative CYP2D6 activities were: 7.0% for CYP2D6Nonf/*41, 16.7% for CYP2D6Nonf/*9-10, 13.2% for CYP2D6*41/*41, 24.9% for CYP2D6*41/*9-10, 33.1% for CYP2D6*9-10/*9-10, 41.3% for CYP2D6Nonf/Norm, 55.0% for CYP2D6*41/Norm, 58.9% for CYP2D6*9-10/Norm, and 149.2% for CYP2D6Norm/Normx2. Compared to the CYP2D6Norm alleles, the activity scores of CYP2D6*41 and CYP2D6*9-10 alleles were estimated to be one sixth and one third, respectively. The results of this highly powered study provide a solid basis for the translation of the CYP2D6 genotype into a drug metabolic phenotype.

PMID:33792048 | DOI:10.1002/cpt.2246

Front Pediatr. 2021 Mar 11;9:592571. doi: 10.3389/fped.2021.592571. eCollection 2021.

ABSTRACT

Hereditary or developmental neurological disorders (HNDs or DNDs) affect the quality of life and contribute to the high mortality rates among neonates. Most HNDs are incurable, and the search for new and effective treatments is hampered by challenges peculiar to the human brain, which is guarded by the near-impervious blood-brain barrier. Clustered Regularly Interspaced Short Palindromic Repeat (CRISPR), a gene-editing tool repurposed from bacterial defense systems against viruses, has been touted by some as a panacea for genetic diseases. CRISPR has expedited the research into HNDs, enabling the generation of in vitro and in vivo models to simulate the changes in human physiology caused by genetic variation. In this review, we describe the basic principles and workings of CRISPR and the modifications that have been made to broaden its applications. Then, we review important CRISPR-based studies that have opened new doors to the treatment of HNDs such as fragile X syndrome and Down syndrome. We also discuss how CRISPR can be used to generate research models to examine the effects of genetic variation and caffeine therapy on the developing brain. Several drawbacks of CRISPR may preclude its use at the clinics, particularly the vulnerability of neuronal cells to the adverse effect of gene editing, and the inefficiency of CRISPR delivery into the brain. In concluding the review, we offer some suggestions for enhancing the gene-editing efficacy of CRISPR and how it may be morphed into safe and effective therapy for HNDs and other brain disorders.

PMID:33791256 | PMC:PMC8006930 | DOI:10.3389/fped.2021.592571

Front Genet. 2021 Mar 15;12:626685. doi: 10.3389/fgene.2021.626685. eCollection 2021.

ABSTRACT

BACKGROUND: The rapid spread of personalized medicine requires professionals to manage the "omics revolution." Therefore, the genetics/genomics literacy of healthcare professionals should be in line with the continuous advances in this field, in order to implement its potential implications for diagnosis, control and treatment of diseases. The present study investigates the effectiveness of a distance learning course on genetics and genomics targeted at medical doctors.

METHODS: In the context of a project funded by the Italian Ministry of Health, we developed a distance learning course, entitled Genetics and Genomics practice. The course focused on genetic/genomics testing, pharmacogenetics and oncogenomics and was developed according to andragogical training methods (Problem-based Learning and Case-based Learning). We used a pre-test vs. post-test study design to assess knowledge improvement on a set of 10 Multiple Choice Questions (MCQs). We analyzed the proportion of correct answers for each question pre and post-test and the mean score difference stratified by gender, age, professional status and medical discipline. Moreover, the test was submitted to the participants 8 months after the conclusion of the course (follow-up), in order to assess the retained knowledge.

RESULTS: The course was completed by 1,637 Italian physicians, most of which were primary care physicians (20.8%), public health professionals (11.5%) and specialist pediatricians (10.6%). The proportion of correct answers increased in the post-test for all the MCQs. The overall mean score significantly increased, from 59.46 in the pre-test to 71.42 in the post-test (p < 0.0001). The comparison in test performance between follow-up and pre-test demonstrated an overall knowledge improvement.

CONCLUSION: Genomics literacy among healthcare professionals is essential to ensure optimal translation to healthcare delivery of research. The results of this course suggest that distance-learning training in genetic/genomics practice represents an effective method to improve physicians' knowledge in the immediate and mid-term time scale. A preprint version of this paper is available at: https://www.researchsquare.com/article/rs-10083/v1.

PMID:33790945 | PMC:PMC8005606 | DOI:10.3389/fgene.2021.626685

Int J Gen Med. 2021 Mar 25;14:1093-1100. doi: 10.2147/IJGM.S298597. eCollection 2021.

ABSTRACT

INTRODUCTION: Warfarin has been in use for more than 60 years; however, it has serious side effects including major bleeding. The high interpatient variability in the required dose impacts the sensitivity and responsiveness to warfarin in different patients. This study aims to assess the influence of CDHR3, CACNAC1, and LTA gene polymorphisms on the variability of warfarin dose requirements and susceptibility to coronary heart disease in the Jordanian population.

METHODS: This study was conducted in the anti-coagulation clinic in Queen Alia Heart Institute in Amman, with 212 patients in total. Three SNPs were genotyped within CDHR3 (rs10270308), CACNAC1 (rs216013), and LTA (rs1041981) genes.

RESULTS: Our findings revealed that patients with LTA polymorphism are more prone to warfarin sensitivity than others. Furthermore, carriers of the LTA polymorphism needed a lower initial dose of warfarin and are associated with less variation in doses required to achieve target INR.

CONCLUSION: The current study could help in understanding the role of genetic variability in warfarin dosing and matching patients to different treatment options. Clinical applications of these findings for warfarin treatment may also contribute to improving the efficacy and safety of warfarin treatment in Jordanian patients with cardiovascular disease.

PMID:33790638 | PMC:PMC8006967 | DOI:10.2147/IJGM.S298597

Gut. 2021 Mar 31:gutjnl-2020-323276. doi: 10.1136/gutjnl-2020-323276. Online ahead of print.

ABSTRACT

OBJECTIVE: Oesophageal squamous cell carcinoma (OSCC), like other squamous carcinomas, harbour highly recurrent cell cycle pathway alterations, especially hyperactivation of the CCND1/CDK4/6 axis, raising the potential for use of existing CDK4/6 inhibitors in these cancers. Although CDK4/6 inhibition has shown striking success when combined with endocrine therapy in oestrogen receptor positive breast cancer, CDK4/6 inhibitor palbociclib monotherapy has not revealed evidence of efficacy to date in OSCC clinical studies. Herein, we sought to elucidate the identification of key dependencies in OSCC as a foundation for the selection of targets whose blockade could be combined with CDK4/6 inhibition.

DESIGN: We combined large-scale genomic dependency and pharmaceutical screening datasets with preclinical cell line models, to identified potential combination therapies in squamous cell cancer.

RESULTS: We identified sensitivity to inhibitors to the ERBB family of receptor kinases, results clearly extending beyond the previously described minority of tumours with EGFR amplification/dependence, specifically finding a subset of OSCCs with dual dependence on ERBB3 and ERBB2. Subsequently. we demonstrated marked efficacy of combined pan-ERBB and CDK4/6 inhibition in vitro and in vivo. Furthermore, we demonstrated that squamous lineage transcription factor KLF5 facilitated activation of ERBBs in OSCC.

CONCLUSION: These results provide clear rationale for development of combined ERBB and CDK4/6 inhibition in these cancers and raises the potential for KLF5 expression as a candidate biomarker to guide the use of these agents. These data suggested that by combining existing Food and Drug Administration (FDA)-approved agents, we have the capacity to improve therapy for OSCC and other squamous cancer.

PMID:33789967 | DOI:10.1136/gutjnl-2020-323276

Pharmacogenomics. 2021 Apr 1. doi: 10.2217/pgs-2020-0140. Online ahead of print.

ABSTRACT

Aim: This study investigated major allelic variants of CYP2D6, CYP3A4 and CYP3A5 in Egyptians, an Arabic population for which there is little information regarding these important pharmacogenes. Patients & methods: CYP2D6*2, *4, *5, *10, *41 and gene copy number variation, as well as CYP3A4*22 and CYP3A5*3 were determined with commercially available TaqMan assays in 145 healthy study participants. Results: The CYP2D6 alleles identified suggest that the prevalence of poor metabolizers is low as none were found among the 145 subjects investigated. The frequency for CYP3A5 nonexpressers was 74.5% and the CYP3A4*22 allele frequency was low at 2.0%. Conclusion: These preliminary findings indicate that pharmacogene variation in Egyptians is different from those of other Middle Eastern/Arabic populations and warrants further investigation.

PMID:33789449 | DOI:10.2217/pgs-2020-0140