A parsimonious score with a free web tool for predicting disability after an ischemic stroke: the Parsifal Score.

J Neurol. 2020 May 26;:

Authors: Muiño E, Bustamante A, Rodriguez-Campello A, Gallego-Fabrega C, Ois A, Carrera C, Cullell N, Torres-Aguila N, Cárcel-Márquez J, Rubiera M, Molina CA, Cuadrado-Godia E, Giralt-Steinhauer E, Jiménez-Conde J, Montaner J, Fernández-Cadenas I, Roquer J

Abstract
BACKGROUND: Most of the models to predict prognosis after an ischemic stroke include complex mathematical equations or too many variables, making them difficult to use in the daily clinic. We want to predict disability 3 months after an ischemic stroke in an independent patient not receiving recanalization treatment within the first 24 h, using a minimum set of variables and an easy tool to facilitate its implementation. As a secondary aim, we calculated the capacity of the score to predict an excellent/devastating outcome and mortality.
METHODS: Eight hundred and forty-four patients were evaluated. A multivariable ordinal logistic regression was used to obtain the score. The Modified Rankin Scale (mRS) was used to estimate disability at the third month. The results were replicated in another independent cohort (378 patients). The "polr" function of R was used to perform the regression, stratifying the sample into seven groups with different cutoffs (from mRS 0 to 6).
RESULTS: The Parsifal score was generated with: age, previous mRS, initial NIHSS, glycemia on admission, and dyslipidemia. This score predicts disability with an accuracy of 80-76% (discovery-replication cohorts). It has an AUC of 0.86 in the discovery and replication cohort. The specificity was 90-80% (discovery-replication cohorts); while, the sensitivity was 64-74% (discovery-replication cohorts). The prediction of an excellent or devastating outcome, as well as mortality, obtained good discrimination with AUC > 0.80.
CONCLUSIONS: The Parsifal Score is a model that predicts disability at the third month, with only five variables, with good discrimination and calibration, and being replicated in an independent cohort.

PMID: 32458199 [PubMed - as supplied by publisher]

Determinants of stakeholders' intention to adopt pharmacogenomic.

Pharmacogenomics J. 2020 May 27;:

Authors: Mustapa MAC, Amin L, Mahadi Z

Abstract
Pharmacogenomics (PGx) testing, which aims to identify the genes that affect our responses to drugs, has been favoured by healthcare professionals as a means of maximising drug efficacy and improving the safety and cost-effectiveness of healthcare. Support from the public is needed to determine the successful development of this technology and its implementation in society. Therefore, the objective of this paper was to analyse factors that influence stakeholders' intentions to adopt pharmacogenomic testing in Malaysia. A validated instrument was administered through face-to-face interviews with a total of 421 adult respondents who were stratified according to 2 stakeholder groups: healthcare providers (n = 221) and patients/family members (n = 200). The data were then analysed using SPSS® version 24 software and the advanced multivariate statistical approach of Partial Least Square (PLS) path modelling in order to analyse the complex relationships among variables. Results of the studies indicated that the Malaysian stakeholders had a high amount of trust in the key players (mean score of 5.31), perceived high benefits (mean score of 5.53) and claimed to have high intentions of adopting PGx (mean score of 5.39). The majority of the predictors have significant direct relationships with the intention to adopt PGx, with the exception of moral concerns. Perceived benefits appeared to be the most important direct predictor of the intention to adopt PGx testing (ß = 0.371, P < 0.001) followed by trust in the key players (ß = 0.312, P < 0.001), engagement (ß = 0.272, P < 0.001) and religiosity (ß = 0.133, P < 0.01). In addition, perceived risks also had a direct negative association with the intention to adopt PGx (ß = -0.096, P < 0.05). At the same time, the perceived benefits also served as a mediator for all the other factors except risk. The results provide insights into the multidimensional nature of the determinants of the intention to adopt PGx testing in Malaysia. Although the results showed that the stakeholders in Malaysia were very positive towards PGx testing, they were also cautious about it. The predictors identified in this study can serve as indicators for social acceptance of PGx testing to facilitate the clinical research and implementation of PGx.

PMID: 32457399 [PubMed - as supplied by publisher]

Attenuation of doxorubicin-induced cardiotoxicity by cryptotanshinone detected through association analysis of transcriptomic profiling and KEGG pathway.

Aging (Albany NY). 2020 May 26;12:

Authors: Li L, Wu B, Zhao Q, Li J, Han Y, Fan X, Dong J, Li P

Abstract
OBJECTIVE: The cardiotoxicity of doxorubicin (DOX) reduces the quality of life and prognosis of cancer patients, and therefore its clinical application has been largely restricted. This study aimed to assess the effects of cryptotanshione (CPT) on DOX-induced rat cardiac insufficiency.
RESULTS: CPT treatment significantly suppressed apoptosis in vitro. The oral administration of CPT significantly improved cardiac function in the rat model, reduced collagen production and suppressed apoptosis and the production of reactive oxygen species in the heart tissue. Transcriptomic profiling and its relevant bioinformatics analysis showed that CPT suppressed doxorubicin-induced cardiotoxicity by inhibiting p53 signaling pathway.
CONCLUSION: Transcriptomic profiling and bioinformatics analysis can be used to evaluate the cardio-protective effect of CPT through inactivating p53 signaling pathway in the doxorubicin-mediated myocardial damage model.
METHODS: F-actin staining and flow cytometry were used to assess the effects of CPT on cardiomyocytes. In vivo, echocardiography and hemodynamic evaluation were used to assess the effects of CPT on the cardiac dysfunction in rats. Furthermore, transcriptomic profiling and bioinformatics analysis, as well as western blot analysis, were used to determine that CPT induced changes in the signaling pathways in the model.

PMID: 32457254 [PubMed - as supplied by publisher]

Identification of Candidate Genes Associated with Breast Cancer Prognosis.

DNA Cell Biol. 2020 May 22;:

Authors: Xu YH, Deng JL, Wang LP, Zhang HB, Tang L, Huang Y, Tang J, Wang SM, Wang G

Abstract
Breast cancer (BC) is the most malignant tumor in women. The molecular mechanisms underlying tumorigenesis still need to be further elucidated. It is necessary to investigate novel candidate genes involved in breast cancer progression and prognosis. In this study, we commit to explore candidate genes that associate with prognosis and therapy in BC by a comprehensive bioinformatic analysis. Four GEO datasets (GSE5764, GSE7904, GSE20711, and GSE29431) and the BC-related transcriptome data in TCGA database were downloaded and used to identify the differently expressed genes (DEGs). The function of DEGs was analyzed by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways enrichment analysis. The protein-protein interaction (PPI) network of DEGs was constructed to identify hub genes. Prognostic candidate genes were identified through survival analysis. In addition, potential therapeutic targets were identified by constructed gene-drug interaction network through Comparative Toxicogenomics Database. A total of 547 DEGs (302 up and 245 down) were identified. Three core-subnetwork and 25 hub genes were identified in PPI network. Seven genes (namely COL12A1, QPRT, MRPL13, KRT14, KRT15, LAMB3, and MYBPC1) were identified as crucial prognostic candidate genes, which significantly associated with breast cancer overall survival. Furthermore, two representative candidate genes (COL12A1 and LAMB3) were optionally chosen for verification by reverse transcription and quantitative real-time polymerase chain reaction (RT-PCR). What's more, the gene-drugs interaction analysis indicates several antitumor drugs that could affect the expression of these prognostic markers, such as doxorubicin, cisplatin, and tamoxifen. These results identified seven crucial candidate genes that may serve as prognosis biomarkers and novel therapeutic targets of breast cancer, which may facilitate further understanding the molecular pathogenesis and providing potential therapeutic strategies for BC.

PMID: 32456464 [PubMed - as supplied by publisher]

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pharmacogenomics

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11 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

pharmacogenomics

These pubmed results were generated on 2020/05/27

PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

Analysis of association of ADORA2A and ADORA3 polymorphisms genotypes/haplotypes with efficacy and toxicity of methotrexate in patients with Rheumatoid arthritis.

Pharmacogenomics J. 2020 May 24;:

Authors: Grk M, Milic V, Dolzan V, Maksimovic N, Damnjanovic T, Pjevic MD, Pesic M, Novakovic I, Jekic B

Abstract
Adenosine receptors ADORA2A and ADORA3 are part of the adenosine-mediated antiinflammatory pathway and are overexpressed in patients with Rheumatoid arthritis (RA). Methotrexate (MTX) antiinflammatory effects are partially mediated via increased release of adenosine into extracellular space. Polymorphisms in ADORA2A and ADORA3 genes may have an impact on the efficacy and toxicity of MTX in RA patients. The study included 127 RA patients. Treatment efficacy was estimated using the changes in Disease activity score (DAS28) after 6 months of MTX monotherapy, according to EULAR response criteria. Patients with good and moderate response were classified as "responders", and with a poor response as "nonresponders". Adverse effects were collected during the follow-up period. Genotyping for polymorphisms within ADORA2A gene (rs2298383, rs2236624, rs5751876, rs17004921) and ADORA3 gene (rs2298191, rs1544223, rs3393) was performed using the KASPar assays. Among patients 112 (88.19%) were responders (18.8% good, 81.2% moderate). We observed no association between analyzed genotypes or alleles and MTX response by EULAR criteria but carriers of ADORA2A rs17004921 T allele (CT + TT) had a higher DAS28 decrease after 6 months of treatment than patients with CC genotype (p = 0.013). Adverse effects were reported in 31 patients (24.41%). Bone erosions were present in 82 (64.6%) patients. Haplotype block was observed among all 3 analyzed polymorphisms within ADORA3 gene and TAA haplotype was associated with bone erosions (29% vs 15.6%, p = 0.023) and hepatotoxicity (51.3% vs 21.6%, p = 0.013). According to our study, ADORA3 TAA haplotype may be associated with bone erosions and hepatotoxicity in RA patients treated with MTX.

PMID: 32448869 [PubMed - as supplied by publisher]

Prevalence and risk factors of Strongyloides stercoralis infection among Orang Asli schoolchildren: new insights into the epidemiology, transmission and diagnosis of strongyloidiasis in Malaysia.

Parasitology. 2019 10;146(12):1602-1614

Authors: Al-Mekhlafi HM, Nasr NA, Lim YAL, Elyana FN, Sady H, Atroosh WM, Dawaki S, Anuar TS, Noordin R, Mahmud R

Abstract
This cross-sectional study aimed to determine the prevalence and risk factors of S. stercoralis infection among 1142 Orang Asli primary schoolchildren in six different states of Peninsular Malaysia. Fecal samples were examined using direct smear, formalin-ether sedimentation (FES), agar plate culture (APC) and PCR techniques. Overall, 15.8% of the children were found to be infected with S. stercoralis. The prevalence was 0.2, 1.3, 15.2 and 13.7% by direct smear, FES, APC and PCR, respectively. Multivariate analysis showed that an age of >10 years, being male, belonging to a Proto-Malay tribe, belonging to the Senoi tribe, indiscriminate defecation, using an unimproved water source for drinking water and not wearing shoes when outside were the significant risk factors of infection among these children. In conclusion, we provide new evidence on the occurrence of S. stercoralis in Malaysia to show that there is a relatively high prevalence of infection among Orang Asli schoolchildren. Therefore, the use of specific methods for detecting S. stercoralis should be considered when screening these children for intestinal parasites. Moreover, prevention and control measures specific to S. stercoralis should be integrated into the intestinal parasitic infections control programme in Malaysia.

PMID: 31303180 [PubMed - indexed for MEDLINE]

Correction for multiple testing in candidate-gene methylation studies.

Epigenomics. 2019 07;11(9):1089-1105

Authors: Zhou Z, Lunetta KL, Smith AK, Wolf EJ, Stone A, Schichman SA, McGlinchey RE, Milberg WP, Miller MW, Logue MW

Abstract
Aim: We compared the performance of multiple testing corrections for candidate gene methylation studies, namely Sidak (accurate Bonferroni), false-discovery rate and three adjustments that incorporate the correlation between CpGs: extreme tail theory (ETT), Gao et al. (GEA), and Li and Ji methods. Materials & methods: The experiment-wide type 1 error rate was examined in simulations based on Illumina EPIC and 450K data. Results: For high-correlation genes, Sidak and false-discovery rate corrections were conservative while the Li and Ji method was liberal. The GEA method tended to be conservative unless a threshold parameter was adjusted. The ETT yielded an appropriate type 1 error rate. Conclusion: For genes with substantial correlation across measured CpGs, GEA and ETT can appropriately correct for multiple testing in candidate gene methylation studies.

PMID: 31240951 [PubMed - indexed for MEDLINE]

Immune Profiling of Thyroid Carcinomas Suggests the Existence of Two Major Phenotypes: An ATC-Like and a PDTC-Like.

J Clin Endocrinol Metab. 2019 08 01;104(8):3557-3575

Authors: Giannini R, Moretti S, Ugolini C, Macerola E, Menicali E, Nucci N, Morelli S, Colella R, Mandarano M, Sidoni A, Panfili M, Basolo F, Puxeddu E

Abstract
OBJECTIVES: The understanding of the mechanisms underlying thyroid cancer immune escape can lead to the identification of new molecular targets and/or efficacy biomarkers. For this purpose, we performed immune expression profiling in thyroid cancers to obtain a comprehensive view on immune mechanisms activated during cancer progression.
METHODS: The study was conducted retrospectively in 25 papillary thyroid carcinomas (PTCs), 14 poorly differentiated thyroid carcinomas (PDTC), 13 anaplastic thyroid carcinomas (ATCs), and 7 normal thyroid (NT) tissue samples. Gene expression profiling was obtained on RNA samples using the Nanostring platform and its nCounter PanCancer Immune Profiling Panel.
RESULTS: Gene expression comparison of ATC, PTC, and PDTC vs NT showed high number of regulated genes in cancer samples. In detail, immune-related gene sets were significantly upregulated (ATC > PTC > > PDTC). Most ATC and approximately half of PTC showed a microenvironment infiltrated by macrophages and T-cells with CD8+ effector phenotype, part of which appeared to be functionally exhausted. Conversely, most PDTC, as NT samples, as the remaining part of PTC, displayed a poor or absent infiltration by immune cells. Interestingly, an upregulation of inhibitory immune checkpoint mediators, including PDL1, PDL2, PD1, LAG-3, TIM-3, PVR, and TIGIT, could be detected in ATC and PTC.
CONCLUSIONS: These data indicated the existence of two major immune phenotypes in thyroid carcinoma: an ATC-like one, including hot and altered-immunosuppressed tumors and a PDTC-like one, including altered-excluded and cold tumors. Confirmation of the findings in locally advanced or metastatic cancer tissues is expected to have important immunotherapeutic implications.

PMID: 30882858 [PubMed - indexed for MEDLINE]

State of the Art of Genetic Testing for Patients With Autism: A Practical Guide for Clinicians.

Semin Pediatr Neurol. 2020 Jul;34:100804

Authors: Kreiman BL, Boles RG

Abstract
The explosion in knowledge, technology, and clinical capabilities regarding genetics and genetic testing has expanded greatly in recent years, and these gains have rapidly been applied to individuals with autism spectrum disorder (ASD). However, most clinicians are unaware or confused in regards to whom to test, what tests to order, and how testing might alter management and improve outcomes. This review will address these issues. Research shows that ASD is highly genetic, and while monogenic cases are common, most patients have multiple genes interacting in disease pathogenesis. However, as genetics dictates disease risk, not outcomes, this does not exclude environmental factors. Clinically actionable genetics test results can be found across the phenotypically-heterogeneous ASD spectrum; thus recommendations are to test everyone. As ASD is also highly genetically heterogeneous, testing should address a wide range of variant types, including both large (historically detected by microarray) and small (detected by sequencing), at least across all genes (exome). Additional specialized testing important in ASD diagnostics includes fragile X, mitochondrial DNA, and pharmacogenetics; the latter often informative for which drug to order, at which dose. Recently, whole genome sequencing has emerged as a favorite since all of the above testing, and more, can be performed at a lower total cost than individual test orders. Trio (child plus parents) sequencing is often indicated, especially in more "severe" cases in order to find new (de novo) variants not present in either parent. Additionally, Angelman syndrome testing should be considered in appropriate cases. Current testing provides a precise diagnosis in many cases with ASD. Beyond diagnosis, genetic testing can oftentimes help elucidate potentially treatable risk factors that predispose the individual patient to develop disease. In this clinician's experience (RGB), this information leads to improved outcomes in as many as one-half of cases. Clinical improvement can occur in common associated ASD symptoms (attention, behavior, and anxiety) and/or in general systemtic symptoms (nausea, fatigue, pain), as demonstrated in brief case reports. Practical guidance is provided regarding assisting clinicians to choose the appropriate test(s) and laboratory, as well as how to get testing paid for. Recent cost reductions now allow for most families to benefit from genetic testing.

PMID: 32446438 [PubMed - as supplied by publisher]

Central nervous pathways of insulin action in the control of metabolism and food intake.

Lancet Diabetes Endocrinol. 2020 Jun;8(6):524-534

Authors: Kullmann S, Kleinridders A, Small DM, Fritsche A, Häring HU, Preissl H, Heni M

Abstract
Insulin acts on the CNS to modulate behaviour and systemic metabolism. Disturbances in brain insulin action represent a possible link between metabolic and cognitive health. Current findings from human research suggest that boosting central insulin action in the brain modulates peripheral metabolism, enhancing whole-body insulin sensitivity and suppressing endogenous glucose production. Moreover, central insulin action curbs food intake by reducing the salience of highly palatable food cues and increasing cognitive control. Animal models show that the mesocorticolimbic circuitry is finely tuned in response to insulin, driven mainly by the dopamine system. These mechanisms are impaired in people with obesity, which might increase their risk of developing type 2 diabetes and associated diseases. Overall, current findings highlight the role of insulin action in the brain and its consequences on peripheral metabolism and cognition. Hence, improving central insulin action could represent a therapeutic option for people at an increased risk of developing metabolic and cognitive diseases.

PMID: 32445739 [PubMed - as supplied by publisher]

Clinical Validation of a 106-SNV MALDI-ToF MS Pharmacogenomic Panel.

J Appl Lab Med. 2020 May 01;5(3):454-466

Authors: Williams GR, Cook L, Lewis LD, Tsongalis GJ, Nerenz RD

Abstract
BACKGROUND: Laboratorians have the opportunity to help minimize the frequency of adverse drug reactions by implementing pharmacogenomic testing and alerting care providers to possible patient/drug incompatibilities before drug treatment is initiated. Methods combining PCR with MALDI-ToF MS have allowed for sensitive, economical, and multiplexed pharmacogenomic testing results to be delivered in a timely fashion.
METHOD: This study evaluated the analytical performance of the Agena Biosciences iPLEX® PGx 74 panel and a custom iPLEX panel on a MassARRAY MALDI-TOF MS instrument in a clinical laboratory setting. Collectively, these panels evaluate 112 SNVs across 34 genes implicated in drug response. Using commercially available samples (Coriell Biorepository) and in-house extracted DNA, we determined ideal reaction conditions and assessed accuracy, precision, and robustness.
RESULTS: Following protocol optimization, the Agena PGx74 and custom panels demonstrated 100% concordance with the 1000 Genomes Project Database and clinically validated hydrolysis probe genotyping assays. 100% concordance was also observed in all assessments of assay precision when appropriate QC metrics were applied.
CONCLUSIONS: Significant development time was required to optimize sample preparation and instrumental analysis and 3 assays were removed due to inconsistent performance. Following modification of the manufacturer's protocol and instituting manual review of each assay plate, the Agena PGx74 and custom panel constitute a cost-effective, robust, and accurate method for clinical identification of 106 SNVs involved in drug response.

PMID: 32445367 [PubMed - as supplied by publisher]

Prenatal Exposure to Valproic Acid Affects Microglia and Synaptic Ultrastructure in a Brain-Region-Specific Manner in Young-Adult Male Rats: Relevance to Autism Spectrum Disorders.

Int J Mol Sci. 2020 May 18;21(10):

Authors: Gąssowska-Dobrowolska M, Cieślik M, Czapski GA, Jęśko H, Frontczak-Baniewicz M, Gewartowska M, Dominiak A, Polowy R, Filipkowski RK, Babiec L, Adamczyk A

Abstract
Autism spectrum disorders (ASD) are a heterogeneous group of neurodevelopmental conditions categorized as synaptopathies. Environmental risk factors contribute to ASD aetiology. In particular, prenatal exposure to the anti-epileptic drug valproic acid (VPA) may increase the risk of autism. In the present study, we investigated the effect of prenatal exposure to VPA on the synaptic morphology and expression of key synaptic proteins in the hippocampus and cerebral cortex of young-adult male offspring. To characterize the VPA-induced autism model, behavioural outcomes, microglia-related neuroinflammation, and oxidative stress were analysed. Our data showed that prenatal exposure to VPA impaired communication in neonatal rats, reduced their exploratory activity, and led to anxiety-like and repetitive behaviours in the young-adult animals. VPA-induced pathological alterations in the ultrastructures of synapses accompanied by deregulation of key pre- and postsynaptic structural and functional proteins. Moreover, VPA exposure altered the redox status and expression of proinflammatory genes in a brain region-specific manner. The disruption of synaptic structure and plasticity may be the primary insult responsible for autism-related behaviour in the offspring. The vulnerability of specific synaptic proteins to the epigenetic effects of VPA may highlight the potential mechanisms by which prenatal VPA exposure generates behavioural changes.

PMID: 32443651 [PubMed - as supplied by publisher]

Exome-Wide Analysis of the DiscovEHR Cohort Reveals Novel Candidate Pharmacogenomic Variants for Clinical Pharmacogenomics.

Genes (Basel). 2020 May 18;11(5):

Authors: Pandi MT, Williams MS, van der Spek P, Koromina M, Patrinos GP

Abstract
Recent advances in next-generation sequencing technology have led to the production of an unprecedented volume of genomic data, thus further advancing our understanding of the role of genetic variation in clinical pharmacogenomics. In the present study, we used whole exome sequencing data from 50,726 participants, as derived from the DiscovEHR cohort, to identify pharmacogenomic variants of potential clinical relevance, according to their occurrence within the PharmGKB database. We further assessed the distribution of the identified rare and common pharmacogenomics variants amongst different GnomAD subpopulations. Overall, our findings show that the use of publicly available sequence data, such as the DiscovEHR dataset and GnomAD, provides an opportunity for a deeper understanding of genetic variation in pharmacogenes with direct implications in clinical pharmacogenomics.

PMID: 32443490 [PubMed - as supplied by publisher]

CYP2D6 Basic Genotyping of Patients with Chronic Pain Receiving Tramadol or Codeine. A Study in a Greek Cohort.

Pain Med. 2020 May 22;:

Authors: Batistaki C, Chrona E, Kostroglou A, Kostopanagiotou G, Gazouli M

Abstract
OBJECTIVE: To assess CYP2D6 genotype prevalence in chronic pain patients treated with tramadol or codeine.
DESIGN: Prospective cohort study.
SETTING: General hospital, pain management unit.
SUBJECTS: Patients with chronic pain, treated with codeine or tramadol.
METHODS: Patients' pain was assessed at baseline (numeric rating scale [NRS]; 0-10). Prescription of codeine or tramadol was selected randomly. The assessment of patients' response to the drug in terms of pain relief and adverse effects was performed after 24 hours. Reduction of pain intensity of >50% or an NRS <4 was considered a positive response. Patients' blood samples were collected during the first visit. Genotyping for the common variants CYP2D6 *2, *3, *4, *5, *6, *9, *10, *14, and *17 was performed, and alleles not carrying any polymorphic allele were classified as CYP2D6*1 (wild-type [wt]).
RESULTS: Seventy-six consecutive patients were studied (20 males, 56 females), aged 21-85 years. Thirty-four received tramadol and 42 codeine. The main genotypes of CYP2D6 identified were the wt/wt (35.5%), the *4/wt (17.1%), and the *6/wt (10.5%). Adverse effects were common, especially in carriers of *9/*9, *5/*5, *5/*4, and *10/*10, as well as in variants including the 4 allele (*4/*1 [38.4%] and *4/*4 [42.8%]).
CONCLUSIONS: Genotyping can facilitate personalized pain management with opioids, as specific alleles are related to decreased efficacy and adverse effects.

PMID: 32443139 [PubMed - as supplied by publisher]

Lack of concordance between EMIT assay and LC-MS/MS for Therapeutic Drug Monitoring of Mycophenolic Acid: Potential increased risk for graft rejection?

J Pharm Biomed Anal. 2020 May 06;187:113337

Authors: De Nicolò A, Ianniello A, Benagli C, Della Bruna R, Keller F, Antonucci M, D'Avolio A, Cantù M

Abstract
Therapeutic drug monitoring (TDM) of immunosuppressive drugs is crucial in organ-transplanted patients to prevent rejection or toxic effects due to inadequate dosage. Mycophenolic acid (MPA) is a commonly used immunosuppressant in this setting. Nowadays, MPA concentrations are monitored by Enzyme Multiplied Immunoassay Technology (EMIT), and Liquid Chromatography (LC)-based techniques, particularly coupled to Tandem Mass Spectrometry (LC-MS/MS). This study evaluates the concordance between TDM results for MPA obtained through CE-IVD EMIT and LC-MS/MS assays in plasma samples. LC-MS/MS quantification was based on a commercial kit and the analytical performance in terms of accuracy was tested through external proficiency tests and inter-laboratory comparison with a home-made HPLC-UV method. Both these evaluations confirmed the reliability of the LC-MS/MS method (1.6 % and 9.0 % of bias, respectively). Conversely, the comparison between EMIT and LC-MS/MS showed overestimation by EMIT of 33.5 %. This bias resulted concentration-dependent, ranging from 46.4 % in the concentration range of 1-2 mg/L, to 21.4 % over 4 mg/L. Considering the theoretical clinical impact of this overestimation, a fraction comprised between 12.4 % and 31.4 % of samples which resulted over three different minimum effective concentration values by EMIT (no indication for dose adjustment) had discordant indications by LC-MS/MS (dose adjustment needed). Concluding, this study highlights a clinically relevant systematic overestimation of MPA concentration by EMIT, supporting the switch to LC-MS/MS techniques for TDM purpose. However, further prospective studies are needed in order to evaluate the clinical impact of switching the TDM activity from EMIT to LC-MS/MS in a larger cohort in a long period.

PMID: 32442868 [PubMed - as supplied by publisher]

Pharmacogenetic testing in psychiatric inpatients with polypharmacy is associated with decreased medication side effects but not via medication changes.

J Psychiatr Res. 2020 May 10;126:105-111

Authors: Collins AR, Kung S, Ho JT, Wright JA, Dammen KC, Johnson EK, Lapid MI, Leung JG

Abstract
In psychiatric patients, medication adverse effects are regularly attributed to psychosomatic causes. However, many psychotropic medications are metabolized by cytochrome P450 (CYP450) enzymes. In the setting of polypharmacy, the activity of these enzymes may produce unfavorable drug-drug interactions (DDI) and drug-genotype interactions (DGI) that contribute to morbidity and mortality. This study sought to estimate the risk of adverse DDI and DGI in psychiatric inpatients with polypharmacy. We assessed whether medication changes made after pharmacogenetics (PGx) testing correlated with changes in side effects and overall improvement. Adult psychiatry inpatients with polypharmacy, defined as 5 or more scheduled prescription medications, completed the 24-item Antidepressant Side Effect Checklist (ASEC) questionnaire on enrollment and underwent PGx testing. Analysis of PGx results focused on whether the CYP2D6 and CYP2C19 phenotypes were "extreme," defined as poor, poor to intermediate, or ultrarapid. Approximately 30 days after PGx results were sent to outpatient providers, patients were contacted to obtain their current medication list and ASEC and Clinical Global Impression Improvement (CGI-I) scores. A total of 80 patients were enrolled, and 52 (65%) completed follow-up. ASEC scores improved from 11.5 (±8.1) to 7.2 (±6.0) (p = 0.0009). Mean CGI-I score was 2.7 (±1.4), between "minimal" to "much improved." However, linear regression revealed that these improvements were not correlated with whether medications were changed. We concluded that the impact of drug-genotype interactions in this small sample of inpatients with polypharmacy was low, and that patient improvement was related not to PGx-guided medication changes but to other treatments during hospitalization.

PMID: 32442780 [PubMed - as supplied by publisher]

Phenotypic and functional translation of IL33 genetics in asthma.

J Allergy Clin Immunol. 2020 May 19;:

Authors: Ketelaar ME, Portelli MA, Dijk FN, Shrine N, Faiz A, Vermeulen CJ, Xu CJ, Hankinson J, Bhaker S, Henry AP, Billington CK, Shaw DE, Johnson SR, Benest AV, Pang V, Bates D, Pogson ZEK, Fogarty A, McKeever TM, Singapuri A, Heaney L, Mansur AH, Chaudhuri R, Thomson NC, Holloway JW, Lockett GA, Howarth PH, Niven R, Simpson A, Tobin MD, Hall IP, Wain LV, Blakey JD, Brightling CE, Obeidat M, Sin DD, Nickle C, Bossé Y, Vonk JM, van den Berge M, Koppelman GH, Sayers I, Nawijn MC

Abstract
BACKGROUND: Asthma is a complex disease with multiple phenotypes that may differ in disease pathobiology and treatment response. Interleukin 33 (IL33) single nucleotide polymorphisms (SNPs) have been reproducibly associated with asthma. IL33 levels are elevated in sputum, and bronchial biopsies of asthma patients. The functional consequences of IL33 asthma SNPs remain unknown.
OBJECTIVE: We studied whether IL33 SNPs associate with asthma-related phenotypes and with IL33 expression in lung or bronchial epithelium. We investigated the effect of increased IL33 expression on human bronchial epithelial cell (HBEC) function.
METHODS: Association between IL33 SNPs (Chr9: 5,815,786-6,657,983) and asthma phenotypes (Lifelines/DAG/GASP cohorts) and between SNPs and expression (lung tissue, bronchial brushes, HBECs) was done using regression modelling. Lentiviral overexpression was used to study IL33 effects on HBECs.
RESULTS: 161 SNPs spanning the IL33 region associated with one or more asthma phenotypes after correction for multiple testing. We report one main independent signal tagged by rs992969 associating with blood eosinophil levels, asthma and eosinophilic asthma. A second, independent signal tagged by rs4008366 presented modest association with eosinophilic asthma. Neither signal associated with FEV1, FEV1/FVC, atopy, and age of asthma onset. The two IL33 signals are expression quantitative loci (eQTLs) in bronchial brushes and cultured HBECs, but not in lung tissue. IL33 overexpression in vitro resulted in reduced viability and ROS-capturing of HBECs, without influencing epithelial cell count, metabolic activity or barrier function.
CONCLUSION: We identify IL33 as an epithelial susceptibility gene for eosinophilia and asthma, provide mechanistic insight, and implicate targeting of the IL33 pathway specifically in eosinophilic asthma.

PMID: 32442646 [PubMed - as supplied by publisher]

SYNERGxDB: an integrative pharmacogenomic portal to identify synergistic drug combinations for precision oncology.

Nucleic Acids Res. 2020 May 22;:

Authors: Seo H, Tkachuk D, Ho C, Mammoliti A, Rezaie A, Madani Tonekaboni SA, Haibe-Kains B

Abstract
Drug-combination data portals have recently been introduced to mine huge amounts of pharmacological data with the aim of improving current chemotherapy strategies. However, these portals have only been investigated for isolated datasets, and molecular profiles of cancer cell lines are lacking. Here we developed a cloud-based pharmacogenomics portal called SYNERGxDB (http://SYNERGxDB.ca/) that integrates multiple high-throughput drug-combination studies with molecular and pharmacological profiles of a large panel of cancer cell lines. This portal enables the identification of synergistic drug combinations through harmonization and unified computational analysis. We integrated nine of the largest drug combination datasets from both academic groups and pharmaceutical companies, resulting in 22 507 unique drug combinations (1977 unique compounds) screened against 151 cancer cell lines. This data compendium includes metabolomics, gene expression, copy number and mutation profiles of the cancer cell lines. In addition, SYNERGxDB provides analytical tools to discover effective therapeutic combinations and predictive biomarkers across cancer, including specific types. Combining molecular and pharmacological profiles, we systematically explored the large space of univariate predictors of drug synergism. SYNERGxDB constitutes a comprehensive resource that opens new avenues of research for exploring the mechanism of action for drug synergy with the potential of identifying new treatment strategies for cancer patients.

PMID: 32442307 [PubMed - as supplied by publisher]