Transcriptomic and Proteomic Profiling of Human Mesenchymal Stem Cell Derived from Umbilical Cord in the Study of Preterm Birth.

Proteomics Clin Appl. 2019 Sep 14;:e1900024

Authors: Chien CW, Lo YS, Wu HY, Hsuan Y, Lin CK, Chen YJ, Lin W, Han CL

Abstract
OBJECTIVE: Mesenchymal stem cells (MSCs) hold great therapeutic potential in morbidities associated with preterm birth. However, the molecular expressions of hMSCs in preterm birth infants have not been systematically evaluated. In this study, we presented the dual-omics analyses of umbilical cord (UC) derived hMSCs to identify the dysregulated cellular functions.
MATERIALS AND METHODS: The UC-MSCs were collected from 10 full-term and 8 preterm birth infants for microarray and iTRAQ-based proteome profiling.
RESULTS: The integrative analysis of dual-omics data discovered 5,615 commonly identified genes/proteins of which 29 genes/proteins showed consistent up- or down-regulation in preterm birth. The Gene Ontology analysis revealed that dysregulation of mitochondrial translation and cellular response to oxidative stress were mainly enriched in 290 differential expression proteins (DEPs) while the 412 differential expression genes (DEGs) were majorly involved in single-organism biosynthetic process, cellular response to stress, and mitotic cell cycle in preterm birth. Besides, we identified a 13-protein module involving CUL2 and CUL3, which plays an important role in cullin-RING-based ubiquitin ligase complex, as potential mechanism for preterm birth.
CONCLUSION: The dual-omics data not only provided new insights to the molecular mechanism but also to identify panel of candidate markers associated with preterm birth. This article is protected by copyright. All rights reserved.

PMID: 31520560 [PubMed - as supplied by publisher]

Precision Medicine: Lessons Learned From Implementation of a Pharmacogenetics-Based Patient Care Program in a Real-World Setting.

Clin Pharmacol Ther. 2019 Sep 13;:

Authors: Kim RB

PMID: 31520405 [PubMed - as supplied by publisher]

Differential Dynamics Underlying the Gln27Glu Population Variant of the β2-Adrenergic Receptor.

J Membr Biol. 2019 Sep 13;:

Authors: Bhosale S, Nikte SV, Sengupta D, Joshi M

Abstract
The β2-adrenergic receptor (β2AR) is a membrane-bound G-protein-coupled receptor and an important drug target for asthma. Clinical studies report that the population variant Gln27Glu is associated with a differential response to common asthma drugs, such as albuterol, isoproterenol and terbutaline. Interestingly, the 27th amino acid is positioned on the N-terminal region that is the most flexible and consequently the least studied part of the receptor. In this study, we probe the molecular origin of the differential drug binding by performing structural modeling and simulations of the wild-type (Gln) and variant (Glu) receptors followed by ensemble docking with the ligands, albuterol, isoproterenol and terbutaline. In line with clinical studies, the ligands were observed to interact preferentially with the Glu variant. Our results indicate that the Glu residue at the 27th position perturbs the network of electrostatic interactions that connects the N-terminal region to the binding site in the wild-type receptor. As a result, the Glu variant is observed to bind better to the three ligands tested in this study. Our study provides a structural basis to explain the variable drug response associated with the 27th position polymorphism in the β2AR and is a starting step to identify genotype-specific therapeutics.

PMID: 31520159 [PubMed - as supplied by publisher]

Characterization of Telomerase (hTERT) in Solid and Hematopoietic Cancer Cell Lines Reveals Different Expression Patterns.

Anticancer Res. 2019 Sep;39(9):4743-4748

Authors: DE Holanda LS, Mesquita FP, DE Moraes-Filho MO, DE Moraes MEA, Montenegro RC, DE Sousa Portilho AJ, Moreira-Nunes CA

Abstract
BACKGROUND/AIM: Overexpression of human telomerase reverse transcriptase (hTERT) allows disordered proliferation and immortality of malignant cells, which has been of interest for the development of targeted therapies. The present study aimed to characterize hTERT gene expression in a series of cancer cell lines.
MATERIALS AND METHODS: Leukemia cell lines K-562, its vincristine-resistant derivative K-562-Lucena1 and daunorubicin-resistant derivative FEPS; gastric adenocarcinoma lines AGP01, ACP02 and ACP03; melanoma SK-Mel-103 cells; and MN01 and MRC5, two non-neoplastic cell lines were analyzed by real-time polymerase chain reaction in order to evaluate hTERT gene expression.
RESULTS: In leukemia cells, hTERT gene expression was significantly increased only in K-562 (p<0.05) and K-562-Lucena1 (p<0.001) when compared to the calibrator MRC5. For solid tumor types, only ACP03 presented a significant hTERT gene expression when compared to ACP02 (p<0.05). hTERT gene expression in K-562 and K-562-L ucena was significantly increased (p<0.05 to p<0.001) compared to all other cell lines except ACP03.
CONCLUSION: In leukemia cell lines, hTERT gene overexpression was shown to be a potential target for pharmacological assays for drugs aiming to inhibit telomerase activity and control cell proliferation in oncohematological diseases.

PMID: 31519574 [PubMed - in process]

PLEKHS1: A new molecular marker predicting risk of progression of non-muscle-invasive bladder cancer.

Oncol Lett. 2019 Oct;18(4):3471-3480

Authors: Pignot G, Le Goux C, Vacher S, Schnitzler A, Radvanyi F, Allory Y, Lallemand F, Delongchamps NB, Zerbib M, Terris B, Damotte D, Bieche I

Abstract
Promoter mutations of pleckstrin homology domain-containing S1 (PLEKHS1) are frequent in several cancer types. To evaluate the DNA mutations, the mRNA expression and prognostic value of PLEKHS1 was evaluated in bladder cancer. We investigated DNA mutations and mRNA expression of PLEKHS1 in a first series of 154 bladder tumors [71 non-muscle-invasive bladder cancer (NMIBC) and 83 muscle-invasive bladder cancers (MIBC)] from patients who underwent transurethral bladder resection or radical cystectomy between 2001 and 2006, and 20 normal bladder samples. Results were then validated in a second series of 181 bladder tumors (91 NMIBC and 90 MIBC). All patients have signed an informed consent form. DNA mutations were analysed by high-resolution melt analysis and sanger sequencing. The mRNA expression was measured by real-time reverse-transcriptase quantitative PCR. The results of the molecular analysis were compared with survival data. PLEKHS1 mutations occurred in 25.0 and 32.2% of NMIBC and MIBC, respectively in the first series. These results were confirmed in the second series (33.0 and 37.8% of NMIBC and MIBC, respectively). In MIBC, DNA mutations were significantly more frequent with the basal than non-basal phenotype (61.5 vs. 27.1%; P=0.0025). The PLEKHS1 mRNA level was increased in 22.5 and 27.7% of NMIBC and MIBC tumors but was not associated with DNA mutations. In NMIBC, PLEKHS1 mRNA overexpression was significantly associated with progression to muscle-invasive disease (P=0.0069) and remained an independent prognostic factor on multivariate analysis (P=0.034). DNA mutations of PLEKHS1 occurred in one-third of bladder tumors and was frequent in the basal MIBC phenotype. PLEKHS1 mRNA overexpression may be an independent prognostic factor of progression-free survival in NMIBC.

PMID: 31516565 [PubMed]

A Novel PCR-RFLP Method for Detection of POR*28 Polymorphism and its Genotype/Allele Frequencies in a Turkish Population.

Curr Drug Metab. 2019 Sep 13;:

Authors: Ozdemir F, Oz MD, Suzen HS

Abstract
BACKGROUND: The Cytochrome P450 (CYP) enzymes are involved in the metabolism of many endogenous and exogenous substances. They need electrons for their activity. CYP mediated oxidation reactions require cytochrome oxidoreductase (POR) as an electron donor. A common genetic variation identified in the coding region of POR gene (POR*28) leads to an alteration in POR activity by causing amino acid change. The current study aimed to determine the allele and genotype frequencies of POR*28 in a healthy Turkish population by using a novel genotyping assay.
METHODS: A novel PCR-RFLP assay was developed for the detection of POR*28 (rs1057868) polymorphism and the obtained frequencies were compared with the data established in various ethnic groups.
RESULTS: Genotypic analysis revealed that of 209 healthy, unrelated individuals tested for POR*28 polymorphism, 55.5% of the studied subjects were homozygous for the CC genotype, 34.9% were heterozygous for the CT genotype and 9.6% were homozygous for the TT genotype. The allele frequencies were 0.73 (C) and 0.27 (T). The present results were in accordance with Hardy- Weinberg equilibrium. The distribution of POR*28 allele varies between populations. The frequency of the T allele among members of the Turkish population was similar to frequencies in Caucasian populations but was lower than in Japanese and Chinese populations.
CONCLUSIONS: In this study, a novel method was developed, which could be applied easily in every laboratory for the genotyping of POR *28 polymorphism. The developed genotyping method and documented allele frequencies may have a potential in understanding and predicting the variations in drug response/adverse reactions in pharmacotherapy and susceptibility to diseases in POR-mediated metabolism reactions.

PMID: 31518218 [PubMed - as supplied by publisher]

Comparison of Tacrolimus Starting Doses Based on CYP3A5 Phenotype or Genotype in Kidney Transplant Recipients.

Prog Transplant. 2019 Sep 12;:1526924819873905

Authors: Largeau B, Guellec CB, Longuet H, Lesne P, Bouvarel A, Préteseille L, Marquet P, Halimi JM, Büchler M, Gatault P, Noble J

Abstract
BACKGROUND: Selection of expected phenotypes (ie, expressers/non-expressers) is currently used in CYP3A5*3 genotype-based tacrolimus dosing. The authors assessed whether a dosing regimen based on the 3 CYP3A5 genotypes may reduce the occurrence of inadequate exposure.
METHODS: Tacrolimus whole blood trough levels (C 0) were retrieved from a retrospective cohort of 100 kidney transplant recipients treated with a starting dose of 0.15 (non-expressers) or 0.30 (expressers) mg/kg/d. The authors evaluated the occurrence of overexposures (12 < C 0 < 20 ng/mL) or toxic concentrations (C 0 ≥ 20 ng/mL). These results were used to set up a new strategy based on the 3 distinct CYP3A5 genotypes, which relevance was evaluated in a prospective cohort of 107 patients.
RESULTS: In the retrospective cohort, non-expressers exhibited frequent overexposure (63.6%) or toxic C 0 (20.8%). Among expressers, none of the homozygous *1 carriers exhibited overexposure contrary to 25% of the heterozygotes. Based on these results, new tacrolimus starting doses were set at 0.10, 0.20, and 0.30 mg/kg/d for CYP3A5*3/*3, CYP3A5*1/*3, and CYP3A5*1/*1 genotypes, respectively. Tacrolimus overexposure was reduced in the CYP3A5*3/*3 group (63.6% vs 40%, P = .0038). None of the heterozygous patients exhibited toxic tacrolimus C 0. Clinical outcomes were not different between the 2 periods, whatever the genotype. Our results indicate that the best tacrolimus exposure was obtained for doses of 0.10, 0.20, and 0.20 mg/kg/d for CYP3A5*3/3, CYP3A5*1/*3, and CYP3A5*1/*1, respectively.
CONCLUSIONS: Our results confirm that selecting tacrolimus dosing regimen according to the expected phenotype is appropriate, but that lower than currently recommended doses may be preferable.

PMID: 31514576 [PubMed - as supplied by publisher]

Early Tacrolimus Concentrations After Lung Transplant are Predicted by Combined Clinical and Genetic Factors and Associated with Acute Kidney Injury.

Clin Pharmacol Ther. 2019 Sep 12;:

Authors: Miano TA, Flesch JD, Feng R, Forker CM, Brown M, Oyster M, Kalman L, Rushefski M, Cantu E, Porteus M, Yang W, Russel Localio Jd A, Diamond JM, Christie JD, Shashaty MGS

Abstract
Tacrolimus exhibits unpredictable pharmacokinetics after lung transplant, partly explained by CYP-enzyme polymorphisms. However, whether exposure variability during the immediate post-operative period affects outcomes is unknown, and pharmacogenetic dosing may be limited by residual pharmacokinetic variability. We estimated adjusted associations between early post-operative tacrolimus concentrations and acute kidney injury (AKI) and acute cellular rejection (ACR), and identified clinical and pharmacogenetic factors that explain post-operative tacrolimus concentration variability in 484 lung transplant patients. Increasing tacrolimus concentration was associated with higher AKI risk: HR 1.54, (95%CI 1.20-1.96) per 5-mg/dL, and increasing AKI severity (OR 1.29 (1.04-1.60) per 5-mg/dL, but not ACR: HR 1.02 (95%CI 0.73-1.42). A model with clinical and pharmacogenetic factors explained 42% of concentration variance compared to 19% for pharmacogenetic factors only. Early tacrolimus exposure was independently associated with AKI after lung transplantation, but not ACR. Clinical factors accounted for substantial residual tacrolimus concentration variability not explained by CYP-enzyme polymorphisms.

PMID: 31513279 [PubMed - as supplied by publisher]

Pharmacogenetics in the clinical analysis laboratory: clinical practice, research, and drug development pipeline.

Expert Opin Drug Metab Toxicol. 2019 Sep 12;:1-15

Authors: Miscio G, Paroni G, Bisceglia P, Gravina C, Urbano M, Lozupone M, Piccininni C, Prisciandaro M, Ciavarella G, Daniele A, Bellomo A, Panza F, Di Mauro L, Greco A, Seripa D

Abstract
Introduction: Over the last decade, the spread of next-generation sequencing technology along with the rising cost in health management in national health systems has led to widespread use/abuse of pharmacogenetic tests (PGx) in the practice of many clinical disciplines. However, given their clinical significance, it is important to standardize these tests for having an interaction with the clinical analysis laboratory (CAL), in which a PGx service can meet these requirements. Areas covered: A diagnostic test must meet the criteria of reproducibility and validity for its utility in the clinical routine. This present review mainly describes the utility of introducing PGx tests in the CAL routine to produce correct results useful for setting up personalized drug treatments. Expert opinion: With a PGx service, CALs can provide the right tool to help clinicians to make better choices about different categories of drugs and their dosage and to manage the economic impact both in hospital-based settings and in National Health Services, throughout electronic health records. Advances in PGx also allow a new approach for pharmaceutical companies in order to improve drug development and clinical trials. As a result, CALs can achieve a powerful source of epidemiological, clinical, and research findings from PGx tests.

PMID: 31512953 [PubMed - as supplied by publisher]

Examination of a New Delivery Approach for Oral Cannabidiol in Healthy Subjects: A Randomized, Double-Blinded, Placebo-Controlled Pharmacokinetics Study.

Adv Ther. 2019 Sep 12;:

Authors: Patrician A, Versic-Bratincevic M, Mijacika T, Banic I, Marendic M, Sutlović D, Dujić Ž, Ainslie PN

Abstract
INTRODUCTION: Therapeutic effects of cannabidiol (CBD) in specialized populations continue to emerge. Despite supra-physiological dosing being shown to be tolerable in various pathologies, optimization of CBD absorption has obvious benefits for general health and recreational usage. Our objectives were to: (1) to investigate a joint pharmacokinetic-physiological time course of multiple recreational-equivalent (< 100 mg) dosages of oral CBD in young healthy adults and (2) evaluate a newly developed technology (TurboCBD™) for the enhanced delivery of CBD.
METHODS: In a double-blinded, placebo-controlled, cross-over design, 12 participants received placebo, generic 45 or 90 mg of CBD, or TurboCBD™ delivery technology capsules on five separate occasions.
RESULTS: Although there were no differences in the 45 mg conditions, circulating CBD levels were higher with the TurboCBD™ 90 mg group at both 90 (+ 86%) and 120 (+ 65%) min compared with the 90 mg control (p < 0.05). Total area under the curve tended to be higher with TurboCBD™ 90 mg compared with 90 mg (10,865 ± 6322 ng ml-1 vs. 7114 ± 2978 ng ml-1; p = 0.088). Only the TurboCBD™ 90 mg dose was elevated greater than placebo at 30 min (p = 0.017) and remained elevated at 4 h (p = 0.002).
CONCLUSION: Consistent with higher bioavailability, TurboCBD™ 90 mg at the peak CBD concentration was associated with an increase in cerebral perfusion and slight reduction in blood pressure compared with baseline and the 90 mg control. Further studies are needed to establish the mechanisms of action of this technology and to explore the therapeutic potential of acute and chronic dosing on more at-risk populations.
FUNDING: Lexaria Bioscience Corp.
TRIAL REGISTRATION: ClinicalTrials.gov identifier, NCT03295903.

PMID: 31512143 [PubMed - as supplied by publisher]

Heart Failure in the Era of Precision Medicine: A Scientific Statement From the American Heart Association.

Circ Genom Precis Med. 2019 Sep 12;:HCG0000000000000058

Authors: Cresci S, Pereira NL, Ahmad F, Byku M, de Las Fuentes L, Lanfear DE, Reilly CM, Owens AT, Wolf MJ, American Heart Association Council on Genomic and Precision Medicine; Council on Cardiovascular and Stroke Nursing; and Council on Quality of Care and Outcomes Research

Abstract
One of 5 people will develop heart failure over his or her lifetime. Early diagnosis and better understanding of the pathophysiology of this disease are critical to optimal treatment. The "omics"-genomics, pharmacogenomics, epigenomics, proteomics, metabolomics, and microbiomics- of heart failure represent rapidly expanding fields of science that have, to date, not been integrated into a single body of work. The goals of this statement are to provide a comprehensive overview of the current state of these omics as they relate to the development and progression of heart failure and to consider the current and potential future applications of these data for precision medicine with respect to prevention, diagnosis, and therapy.

PMID: 31510778 [PubMed - as supplied by publisher]

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

pharmacogenomics

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20 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 2019/09/12

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12 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 2019/09/11

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12 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 2019/09/10

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.

Inflammatory pathway interactions and cancer multidrug resistance regulation.

Life Sci. 2019 Sep 05;:116825

Authors: Mirzaei SA, Dinmohammadi F, Alizadeh A, Elahian F

Abstract
Multidrug resistances against chemotherapeutics are among the major challenges related to cancer treatment. Recent studies have demonstrated that different conditions may tune the expression and activity of MDR transporters. For instance, inflammation occurs through a complex cytological process and chemical reactions in the most tumor microenvironment; it can play a critical role in cancer development and is capable of altering the expression and function of MDR transporters. Cytokines, interleukins, and prostaglandins are potent inflammatory mediators that can modulate the expression of MDRs at transcriptional and post-transcriptional levels in the most human cancer cells and tissues and potentially contribute to balance bioavailability of chemotherapeutic agents. Since cancer cases are usually accompanied by inflammatory responses, glucocorticoids and NSAIDs are the primary useful combination chemotherapies in a variety of cancer treatment protocols. In addition to the anti-inflammatory activities of these agents, they exert diverse modulatory effects on MDR-mediated drug resistance via specific mechanisms. Several factors, including cell and MDR-protein types, pharmacokinetics, and pharmacogenetics, mainly influence the regulatory mechanisms. Uncovering the networks between inflammation and multidrug resistance will be clinically helpful in the treatment of malignant cancers and decreasing the cancer mortality rates.

PMID: 31494169 [PubMed - as supplied by publisher]

Inter-Individual Variation in CYP3A Activity Influences Lapatinib Bioactivation.

Drug Metab Dispos. 2019 Sep 06;:

Authors: Bissada JE, Truong V, Abouda AA, Wines KJ, Crouch RD, Jackson KD

Abstract
Lapatinib is a dual tyrosine kinase inhibitor associated with rare but potentially severe idiosyncratic hepatotoxicity. We have previously shown that cytochromes P450 (CYP) 3A4 and CYP3A5 quantitatively contribute to lapatinib bioactivation leading to formation of a reactive, potentially toxic quinoneimine. CYP3A5 is highly polymorphic; however, the impact of CYP3A5 polymorphism on lapatinib metabolism has not been fully established. The goal of this study was to determine the effect of CYP3A5 genotype and individual variation in CYP3A activity on the metabolic activation of lapatinib using human-relevant in vitro systems. Lapatinib metabolism was examined using CYP3A5-genotyped human liver microsomes and cryopreserved human hepatocytes. CYP3A and CYP3A5-selective activities were measured in liver tissues using probe substrates midazolam and T-5 (T-1032), respectively, to evaluate the correlation between enzymatic activity and lapatinib metabolite formation. Drug metabolites were measured by HPLC - tandem mass spectrometry. Further, the relative contributions of CYP3A4 and CYP3A5 to lapatinib O-debenzylation were estimated using selective chemical inhibitors of CYP3A. The results from this study demonstrated that lapatinib O-debenzylation and quinoneimine-GSH conjugate formation were highly correlated with hepatic CYP3A activity, as measured by midazolam 1'-hydroxylation. CYP3A4 played a dominant role in lapatinib bioactivation in all liver tissues evaluated. The CYP3A5 contribution to lapatinib bioactivation varied by individual donor and was dependent on CYP3A5 genotype and activity. CYP3A5 contributed approximately 20-42% to lapatinib O-debenzylation in livers from CYP3A5 expressers. These findings indicate that individual CYP3A activity, not CYP3A5 genotype alone, is a key determinant of lapatinib bioactivation and likely influences exposure to reactive metabolites. SIGNIFICANCE STATEMENT: This is the first study to examine the effect of CYP3A5 genotype, total CYP3A activity, and CYP3A5-selective activity on lapatinib bioactivation in individual human liver tissues. The results of this investigation indicate that lapatinib bioactivation via oxidative O-debenzylation is highly correlated with total hepatic CYP3A activity, and not CYP3A5 genotype alone. These findings provide insight into the individual factors, namely CYP3A activity, that may affect individual exposure to reactive, potentially toxic metabolites of lapatinib.

PMID: 31492693 [PubMed - as supplied by publisher]

14 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 2019/09/07

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.

14 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 2019/09/07

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.

Lethal toxicities after capecitabine intake in a previously 5-FU-treated patient: why dose matters with dihydropryimidine dehydrogenase deficiency.

Pharmacogenomics. 2019 Aug;20(13):931-938

Authors: Gbeto CC, Quaranta S, Mari R, Fanciullino R, Roche C, Nahon S, Solas C, Ouafik L, Lacarelle B, Allegre T, Ciccolini J

Abstract
Dihydropryimidine dehydrogenase (DPD) deficiency is a pharmacogenetic syndrome associated with severe or lethal toxicities with oral capecitabine. Usually, patients with history of 5-FU-based therapy with no signs for life-threatening toxicities are considered as not DPD-deficient individuals who can be safely treated next with capecitabine if required. Here we describe the case of a woman originally treated with standard FEC100 protocol for metastatic breast cancer with little severe toxicities but grade-3 mucosities that were quickly resolved by symptomatic treatment. When switched to capecitabine + vinorelbine combo, extremely severe toxicities with fatal outcome were unexpectedly observed. Pharmacogenetic investigations were performed on cytidine deaminase and DPYD, and showed that this patient was heterozygous for the 2846A>T mutation on the DPYD gene. DPD phenotyping (i.e., uracil plasma levels >250 ng/ml, dihydrouracil/uracil ratio <0.5) confirmed that this patient was profoundly DPD deficient. Differences in fluoropyrimidine dosing between FEC100 (i.e., 500 mg/m2 5-FU) and capecitabine (i.e., 2250 mg daily) could explain why initial 5-FU-based protocol did not lead to life-threatening toxicities, whereas capecitabine rapidly triggered toxic death. Overall, this case report suggests that any toxicity, even when not life threatening, should be considered as a warning signal for possible underlying profound DPD deficiency syndrome, especially with low-dose protocols.

PMID: 31486738 [PubMed - in process]