Haplotype structure defines effects of common DPYD variants c.85T>C (rs1801265) and c.496A>G (rs2297595) on DPD activity: implication for 5-fluorouracil toxicity.

Br J Clin Pharmacol. 2021 Jan 24;:

Authors: Hamzic S, Schärer D, Offer S, Meulendijks D, Nakas C, Diasio R, Fontana S, Wehrli M, Schürch S, Amstutz U, Largiadèr CR

Abstract
AIM: The aim of this study was to identify risk variants and haplotypes that impair dihydropyrimidine dehydrogenase (DPD) activity and are, therefore, candidate risk variants for severe toxicity to 5-fluorouracil (5-FU) chemotherapy.
METHOD: Plasma dihydrouracil/uracil (UH2 /U) ratios were measured as a population marker for DPD activity in a total of 1'382 subjects from four independent studies. Genotype and haplotype correlations with UH2 /U ratios were assessed.
RESULTS: Significantly lower UH2 /U ratios (panova <2e-16) were observed in carriers of the four well-studied 5-FU toxicity risk variants with mean differences (MD) of -43.7% for DPYD-c.1905+1G>A (rs3918290), -46.0% for DPYD-c.1679T>G (rs55886062), -37.1%, for DPYD-c.2846A>T (rs67376798), and -13.2% for DPYD-c.1129-5923C>G (rs75017182). An additional variant, DPYD c.496A>G (rs2297595), was also associated with lower UH2 /U ratios (p<0.0001, MD: -12.6%). A haplotype analysis was performed for variants in linkage disequilibrium (LD) with c.496A>G, which consisted of the common variant c.85T>C (rs1801265) and the risk variant c.1129-5923C>G. Both haplotypes carrying c.496A>G were associated with decreased UH2 /U ratios (H3, p=0.003, MD: -9.6%; H5, p=0.002, MD: -16.9%). A haplotype carrying only the variant c.85T>C (H2) was associated with elevated ratios (p=0.004, MD: +8.6%).
CONCLUSION: Based on our data, DPYD-c.496A>G is a strong candidate risk allele for 5-FU toxicity. Our data suggest that DPYD-c.85T>C might be protective; however, the deleterious impacts of the linked alleles c.496A>G and c.1129-5923C>G likely limit this effect in patients. The possible protective effect of c.85T>C and LD with c.496A>G and c.1129-5923C>G may have hampered prior association studies and should be considered in future clinical studies.

PMID: 33491253 [PubMed - as supplied by publisher]

Integrating Liquid Biopsy and Radiomics to Monitor Clonal Heterogeneity of EGFR-Positive Non-Small Cell Lung Cancer.

Front Oncol. 2020;10:593831

Authors: Cucchiara F, Del Re M, Valleggi S, Romei C, Petrini I, Lucchesi M, Crucitta S, Rofi E, De Liperi A, Chella A, Russo A, Danesi R

Abstract
Background: EGFR-positive Non-small Cell Lung Cancer (NSCLC) is a dynamic entity and tumor progression and resistance to tyrosine kinase inhibitors (TKIs) arise from the accumulation, over time and across different disease sites, of subclonal genetic mutations. For instance, the occurrence of EGFR T790M is associated with resistance to gefitinib, erlotinib, and afatinib, while EGFR C797S causes osimertinib to lose activity. Sensitive technologies as radiomics and liquid biopsy have great potential to monitor tumor heterogeneity since they are both minimally invasive, easy to perform, and can be repeated over patient's follow-up, enabling the extraction of valuable information. Yet, to date, there are no reported cases associating liquid biopsy and radiomics during treatment.
Case presentation: In this case series, seven patients with metastatic EGFR-positive NSCLC have been monitored during target therapy. Plasma-derived cell free DNA (cfDNA) was analyzed by a digital droplet PCR (ddPCR), while radiomic analyses were performed using the validated LifeX® software on computed tomography (CT)-images. The dynamics of EGFR mutations in cfDNA was compared with that of radiomic features. Then, for each EGFR mutation, a radiomic signature was defines as the sum of the most predictive features, weighted by their corresponding regression coefficients for the least absolute shrinkage and selection operator (LASSO) model. The receiver operating characteristic (ROC) curves were computed to estimate their diagnostic performance. The signatures achieved promising performance on predicting the presence of EGFR mutations (R2 = 0.447, p <0.001 EGFR activating mutations R2 = 0.301, p = 0.003 for T790M; and R2 = 0.354, p = 0.001 for activating plus resistance mutations), confirmed by ROC analysis.
Conclusion: To our knowledge, these are the first cases to highlight a potentially promising strategy to detect clonal heterogeneity and ultimately identify patients at risk of progression during treatment. Together, radiomics and liquid biopsy could detect the appearance of new mutations and therefore suggest new therapeutic management.

PMID: 33489892 [PubMed]

Relevance of Immune Infiltration and Clinical Outcomes in Pancreatic Ductal Adenocarcinoma Subtypes.

Front Oncol. 2020;10:575264

Authors: Liu R, Liao YZ, Zhang W, Zhou HH

Abstract
Purpose: Pancreatic ductal adenocarcinoma (PDAC) is a lethal cancer with high heterogeneity and dismal survival rates. Tumor immune microenvironment plays a critical role in sensitive to chemotherapy and prognosis. Herein, we determined the relevance of the composition of tumor-infiltrating immune cells to clinical outcomes in PDACs, and we evaluated these effects by molecular subtype.
Experimental Design: Data of 1,274 samples from publically available datasets were collected. Molecular subtypes were predicted with support vector machine. Twenty-two subsets of immune cells were estimated with CIBERSORTx. The associations between each cell subset and overall survival (OS), relapse free survival (RFS), and complete response (CR) to chemotherapy were evaluated, modelling cellular proportions as quartiles.
Results: An immune-related cluster was identified with unsupervised hierarchical clustering of hallmark pathways. Of the immune cells investigated, M0 macrophages emerged as closely associated with worse OS (HR =1.23, 95% CI = 1.15-1.31, p=1.57×10-9) and RFS (HR = 1.14, 95% CI =1.04-1.25, p=2.93×10-3), regardless of molecular subtypes. The CD8+ T cells conferred favorable survival. The neutrophils conferred poor OS overall (HR=1.17, 95% CI=1.10-1.23, p=1.74×10-7) and within the classical subtype. In the basal-like subtype, activated mast cells were associated with worse OS. Consensus clustering revealed six immune subgroups with distinct survival patterns and CR rates. The higher expression of PD1 was associated with better OS.
Conclusions: The immune cellular composition infiltrate in PDAC are likely to have effects on prognosis. Further exploration of the cellular immune response has the potential to identify candidates for immunotherapy.

PMID: 33489882 [PubMed]

Precision Medicine in Childhood Asthma: Omic Studies of Treatment Response.

Int J Mol Sci. 2020 Apr 21;21(8):

Authors: Perez-Garcia J, Herrera-Luis E, Lorenzo-Diaz F, González M, Sardón O, Villar J, Pino-Yanes M

Abstract
Asthma is a heterogeneous and multifactorial respiratory disease with an important impact on childhood. Difficult-to-treat asthma is not uncommon among children, and it causes a high burden to the patient, caregivers, and society. This review aims to summarize the recent findings on pediatric asthma treatment response revealed by different omic approaches conducted in 2018-2019. A total of 13 studies were performed during this period to assess the role of genomics, epigenomics, transcriptomics, metabolomics, and the microbiome in the response to short-acting beta agonists, inhaled corticosteroids, and leukotriene receptor antagonists. These studies have identified novel associations of genetic markers, epigenetic modifications, metabolites, bacteria, and molecular mechanisms involved in asthma treatment response. This knowledge will allow us establishing molecular biomarkers that could be integrated with clinical information to improve the management of children with asthma.

PMID: 32326339 [PubMed - indexed for MEDLINE]

Serum insulin-like factor 3 quantification by LC-MS/MS in male patients with hypogonadotropic hypogonadism and Klinefelter syndrome.

Endocrine. 2021 Jan 22;:

Authors: Johannsen TH, Ljubicic ML, Young J, Trabado S, Petersen JH, Linneberg A, Albrethsen J, Juul A

Abstract
PURPOSE: Insulin-like factor 3 (INSL3) is an emerging testicular marker, yet larger studies elucidating the clinical role of INSL3 in patients with hypogonadism are lacking. The aim was to describe serum INSL3 concentrations analyzed by LC-MS/MS methodology in males with hypogonadotropic hypogonadism (HH) and Klinefelter syndrome (KS).
METHODS: This was a combined study from two tertiary centers in Denmark and France analyzing INSL3 concentrations by LC-MS/MS. In total, 103 patients with HH and 82 patients with KS were grouped into treated (HH: n = 96; KS: n = 71) or untreated (HH: n = 7; KS: n = 11). Treatment modalities included testosterone and hCG. Serum concentrations and standard deviation (SD) scores of INSL3, total testosterone, and LH according to age and treatment were evaluated.
RESULTS: In both HH and KS, INSL3 concentrations were low. In HH, INSL3 was low regardless of treatment, except for some hCG-treated patients with normal concentrations. In untreated HH, testosterone was low, while normal to high in most testosterone- and hCG-treated patients. In untreated KS, INSL3 and testosterone concentrations were low to normal, while in testosterone-treated KS, serum INSL3 was low in most patients. INSL3 SD scores were significantly lower in untreated HH than in untreated KS (p = 0.01).
CONCLUSIONS: The dichotomy between lower INSL3 and higher testosterone concentrations, particularly observed in hCG-treated patients with HH, confirms that INSL3 is a different marker of Leydig cell function than testosterone. However, the clinical application of INSL3 in males with hypogonadism remains unclear.

PMID: 33483888 [PubMed - as supplied by publisher]

Transcriptome network analyses in human coronavirus infections suggest a rational use of immunomodulatory drugs for COVID19 therapy.

Genomics. 2021 Jan 19;:

Authors: Wong HS, Guo CL, Lin GH, Lee KY, Okada Y, Chang WC

Abstract
The recent outbreak of coronavirus disease 2019 (COVID-19) by SARS-CoV-2 has led to uptodate 24.3 M cases and 0.8 M deaths. It is thus in urgent need to rationalize potential therapeutic targets against the progression of diseases. An effective, feasible way is to use the pre-existing ΔORF6 mutant of SARS-CoV as a surrogate for SARS-CoV-2, since both lack the moiety responsible for interferon antagonistic effects. By analyzing temporal profiles of upregulated genes in ΔORF6-infected Calu-3 cells, we prioritized 55 genes and 238 ligands to reposition currently available medications for COVID-19 therapy. Eight of them are already in clinical trials. Of particular importance is the emergence of immune checkpoint inhibitors targeting PD-L1 that have not been used in COVID-19 treatment. We also pinpointed 16 drug groups from the Anatomical Therapeutic Chemical classification system, with the potential to mitigate symptoms of SARS-CoV-2 infection and thus to be repositioned for COVID-19 therapy.

PMID: 33482326 [PubMed - as supplied by publisher]

Optimized RNA-targeting CRISPR/Cas13d technology outperforms shRNA in identifying functional circRNAs.

Genome Biol. 2021 Jan 21;22(1):41

Authors: Zhang Y, Nguyen TM, Zhang XO, Wang L, Phan T, Clohessy JG, Pandolfi PP

Abstract
Short hairpin RNAs (shRNAs) are used to deplete circRNAs by targeting back-splicing junction (BSJ) sites. However, frequent discrepancies exist between shRNA-mediated circRNA knockdown and the corresponding biological effect, querying their robustness. By leveraging CRISPR/Cas13d tool and optimizing the strategy for designing single-guide RNAs against circRNA BSJ sites, we markedly enhance specificity of circRNA silencing. This specificity is validated in parallel screenings by shRNA and CRISPR/Cas13d libraries. Using a CRISPR/Cas13d screening library targeting > 2500 human hepatocellular carcinoma-related circRNAs, we subsequently identify a subset of sorafenib-resistant circRNAs. Thus, CRISPR/Cas13d represents an effective approach for high-throughput study of functional circRNAs.

PMID: 33478577 [PubMed - in process]

TBC1D16 predicts chemosensitivity and prognosis in adult acute myeloid leukemia (AML) patients.

Eur J Pharmacol. 2021 Jan 18;:173894

Authors: Liu H, Chen P, Yang YL, Zhu KW, Wang T, Tang L, Liu YL, Cao S, Zhou G, Zeng H, Zhao XL, Zhang W, Chen XP

Abstract
Acute myeloid leukemia (AML) is a hematopoietic disease with poor survival. Chemotherapy resistance is one of the determinant factors influencing AML prognosis. To identify genes possibly affecting the drug responses in AML, the Illumina Infinium MethylationEPIC (850K) was used to screen for differential DNA methylation loci between patients achieved complete remission (CR) or not (non-CR) after induction therapy in 37 AML patients. Then, 32 differentially methylated sites (DMS) were selected for replication in another 86 AML patients by next-generation sequencing. Nine sites including cg03988660, cg16804603, cg18166936, cg11308319, cg09095403, cg18493214, cg01443536, cg16030878 and cg10143426 were replicated. Analysis of the Gene Expression Omnibus (GEO) database showed that mRNA expression of TBC1D16 and HDAC4 was associated with AML prognosis. Methylation level of the cg16030878 in TBC1D16 3'-UTR correlated positively with TBC1D16 mRNA expression in samples both in the TCGA database and clinically collected in the study. Both higher cg16030878 methylation and higher TBC1D16 mRNA expression were associated with increased risk of non-CR and worse overall survival (OS) in AML patients. In AML cells, knockdown of TBC1D16 decreased cell proliferation and ERK phosphorylation levels, as well as increased sensitivity to mitoxantrone and decitabine indicated by IC50. In patients with combined use of decitabine, those patients with CR showed significantly lower TBC1D16 mRNA expression. On the contrary, knockdown of TBC1D16 resulted in decreased sensitivity to cytarabine in U937 cells. Our findings implicated that TBC1D16 is a potential predictor for chemical sensitivity and prognosis in adult AML patients.

PMID: 33476656 [PubMed - as supplied by publisher]

Use of Pharmacogenomics to Guide Proton Pump Inhibitor Therapy in Clinical Practice.

Dig Dis Sci. 2021 Jan 21;:

Authors: Harris DM, Stancampiano FF, Burton MC, Moyer AM, Schuh MJ, Valery JR, Bi Y

Abstract
Prescribing the right medication, at the right dose, to the right patient is the goal of every physician. Pharmacogenomic information is an emerging tool that can be used to deliver precision medicine. In this review, we discuss the pharmacogenomics of available PPIs, racial differences of CYP2C19 and how PPI pharmacogenomics affects the treatment of common gastrointestinal diseases. We also provide practical guidance on when to order pharmacogenomic testing, which test to order, and how to modify treatment based on published guidelines.

PMID: 33475867 [PubMed - as supplied by publisher]

Integrating pharmacogenetic testing via medication therapy management in an outpatient family medicine clinic.

Pharmacogenomics. 2021 Jan 20;:

Authors: Brown JT, MacDonald D, Yapel A, Luczak T, Hanson A, Stenehjem DD

Abstract
Introduction: Pharmacogenetic (PGx) implementation has lagged behind the development of drug/gene pair guidelines. Materials & methods: This was a prospective study assessing the integration of PGx through medication therapy management in an outpatient clinic. Variables collected included patient diagnosis, current medications, failed or discontinued medications, PGx results/recommendations, turnaround time and pre/post clinical ratings. Results: A total of 91 participants completed study procedures with an average enrollment of approximately one consult per week. Participants were referred for testing primarily for guidance for current and future medications. The average number of recommendations per participant was 0.93. Conclusion: Integrating PGx testing into medication therapy management is feasible with PGx results available in under a week resulting in clinical recommendations in over half of patients tested.

PMID: 33470873 [PubMed - as supplied by publisher]

Review on Databases and Bioinformatic Approaches on Pharmacogenomics of Adverse Drug Reactions.

Pharmgenomics Pers Med. 2021;14:61-75

Authors: Tong H, Phan NVT, Nguyen TT, Nguyen DV, Vo NS, Le L

Abstract
Pharmacogenomics has been used effectively in studying adverse drug reactions by determining the person-specific genetic factors associated with individual response to a drug. Current approaches have revealed the significant importance of sequencing technologies and sequence analysis strategies for interpreting the contribution of genetic variation in developing adverse reactions. Advance in next generation sequencing and platform brings new opportunities in validating the genetic candidates in certain reactions, and could be used to develop the preemptive tests to predict the outcome of the variation in a personal response to a drug. With the highly accumulated available data recently, the in silico approach with data analysis and modeling plays as other important alternatives which significantly support the final decisions in the transformation from research to clinical applications such as diagnosis and treatments for various types of adverse responses.

PMID: 33469342 [PubMed]

Author Correction: Liver macrophages regulate systemic metabolism through non-inflammatory factors.

Nat Metab. 2021 Jan 19;:

Authors: Morgantini C, Jager J, Li X, Levi L, Azzimato V, Sulen A, Barreby E, Xu C, Tencerova M, Näslund E, Kumar C, Verdeguer F, Straniero S, Hultenby K, Björkström NK, Ellis E, Rydén M, Kutter C, Hurrell T, Lauschke VM, Boucher J, Tomčala A, Krejčová G, Bajgar A, Aouadi M

PMID: 33469210 [PubMed - as supplied by publisher]

Computational Functional Genomics-Based AmpliSeq™ Panel for Next-Generation Sequencing of Key Genes of Pain.

Int J Mol Sci. 2021 Jan 16;22(2):

Authors: Kringel D, Malkusch S, Kalso E, Lötsch J

Abstract
The genetic background of pain is becoming increasingly well understood, which opens up possibilities for predicting the individual risk of persistent pain and the use of tailored therapies adapted to the variant pattern of the patient's pain-relevant genes. The individual variant pattern of pain-relevant genes is accessible via next-generation sequencing, although the analysis of all "pain genes" would be expensive. Here, we report on the development of a cost-effective next generation sequencing-based pain-genotyping assay comprising the development of a customized AmpliSeq™ panel and bioinformatics approaches that condensate the genetic information of pain by identifying the most representative genes. The panel includes 29 key genes that have been shown to cover 70% of the biological functions exerted by a list of 540 so-called "pain genes" derived from transgenic mice experiments. These were supplemented by 43 additional genes that had been independently proposed as relevant for persistent pain. The functional genomics covered by the resulting 72 genes is particularly represented by mitogen-activated protein kinase of extracellular signal-regulated kinase and cytokine production and secretion. The present genotyping assay was established in 61 subjects of Caucasian ethnicity and investigates the functional role of the selected genes in the context of the known genetic architecture of pain without seeking functional associations for pain. The assay identified a total of 691 genetic variants, of which many have reports for a clinical relevance for pain or in another context. The assay is applicable for small to large-scale experimental setups at contemporary genotyping costs.

PMID: 33467215 [PubMed - in process]

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ABCB1, ABCG2, ABCC1, ABCC2 and ABCC3 drug transporter polymorphisms and their impact on drug bioavailability: what is our current understanding?

Expert Opin Drug Metab Toxicol. 2021 Jan 17;:

Authors: Bruckmueller H, Cascorbi I

Abstract
INTRODUCTION: Interindividual differences in drug response are a frequent clinical challenge partly due to variation in pharmacokinetics. ATP-binding cassette (ABC) transporters are crucial determinants of drug disposition. They are subject of gene regulation and drug-interaction; however, it is still under debate to which extend genetic variants in these transporters contribute to interindividual variability in bioavailability for a wide range of drugs.
AREAS COVERED: This review discusses the current literature on the impact of genetic variants in ABCB1, ABCG2 as well as ABCC1, ABCC2 and ABCC3 on pharmacokinetics and drug response. The aim was to evaluate if results from recent studies would increase the evidence for potential clinically relevant pharmacogenetic effects.
EXPERT OPINION: : Although enormous efforts have been made to investigate the effects of ABC transporter genotypes on drug pharmacokinetics and response, the majority of studies showed only weak if any associations. Despite few unique results, studies mostly failed to confirm earlier findings or still remained inconsistent. The impact of genetic variants on drug bioavailability is only minor and other factors regulating the transporter expression and function seem to be more critical. In our opinion, the findings on the so far investigated genetic variants in ABC efflux transporters are not suitable as predictive biomarkers.

PMID: 33459081 [PubMed - as supplied by publisher]

Influence of dopamine, noradrenaline, and serotonin transporters on the pharmacogenetics of Atremorine in Parkinson's disease.

Drug Dev Res. 2021 Jan 17;:

Authors: Cacabelos R, Carrera I, Martínez O, Naidoo V, Cacabelos N, Aliev G, Carril JC

Abstract
Atremorine is a potent dopamine (DA) enhancer obtained by nondenaturing biotechnological processes from a genetic species of Vicia faba. Atremorine affects the neuronal dopaminergic system by acting as a neuroprotective agent against Parkinson's disease (PD). PD patients (N = 127) responded to a single dose of Atremorine (5 g, p.o.) 1 h after administration in a sex-, time-, dose-, and genotype-dependent fashion. Drug-free patients (N = 81) showed an increase in DA levels from 12.14 ± 0.34 pg/ml to 6463.21 ± 1306.90 pg/ml; and patients chronically treated with anti-PD drugs (N = 46) showed an increase in DA levels from 1321.53 ± 389.94 pg/ml to 16,028.54 ± 4783.98 pg/ml, indicating that Atremorine potentiates the dopaminergic effect of conventional anti-PD drugs. The variability in Atremorine-induced DA response is strongly attributable to pharmacogenetic factors. Polymorphic variants in pathogenic, mechanistic, metabolic, transporter, and pleiotropic genes influence the DA response to Atremorine. Genetic variation in the DA (SLC6A3; rs460000), noradrenaline (NA) (SLC6A2; rs12708954, rs3785143, rs5569), and serotonin (5-HT) transporter (SLC6A4; rs2020934, rs2020936, rs4251417, rs6354) genes exert a genotype-dependent Atremorine-induced DA response in PD, with potential impact on the DA-related pharmacogenetic outcome and minimum effects on NA and 5-HT levels.

PMID: 33458869 [PubMed - as supplied by publisher]

Pharmacogenomics based precision medicine in gastroesophageal cancers: way to move forward?

Oncoscience. 2020 Nov;7(11-12):81-82

Authors: Shah S, Mukherjee S

PMID: 33457448 [PubMed]

Loss of a water-mediated network results in reduced agonist affinity in a β2-adrenergic receptor clinical variant.

Biochim Biophys Acta Proteins Proteom. 2021 Jan 13;:140605

Authors: Nikte SV, Sonar K, Tandale A, Joshi M, Sengupta D

Abstract
The β2-adrenergic receptor (β2AR) is a member of the G protein-coupled receptor (GPCR) family that is an important drug target for asthma and COPD. Clinical studies coupled with biochemical data have identified a critical receptor variant, Thr164Ile, to have a reduced response to agonist-based therapy, although the molecular mechanism underlying this seemingly "non-deleterious" substitution is not clear. Here, we couple molecular dynamics simulations with network analysis and free-energy calculations to identify the molecular determinants underlying the differential drug response. We are able to identify hydration sites in the transmembrane domain that are essential to maintain the integrity of the binding site but are absent in the variant. The loss of these hydration sites in the variant correlates with perturbations in the intra-protein interaction network and rearrangements in the orthosteric ligand binding site. In conjunction, we observe an altered binding and reduced free energy of a series of agonists, in line with experimental trends. Our work identifies a functional allosteric pathway connected by specific hydration sites in β2AR that has not been reported before and provides insight into water-mediated networks in GPCRs in general. Overall, the work is one of the first step towards developing variant-specific potent and selective agonists.

PMID: 33453412 [PubMed - as supplied by publisher]

Avoiding tacrolimus under- and overexposure with a dosing algorithm for renal transplant recipients: a single arm prospective intervention trial.

Clin Pharmacol Ther. 2021 Jan 15;:

Authors: Francke MI, Andrews LM, Le HL, van de Wetering J, Clahsen-van Groningen MC, van Gelder T, van Schaik RHN, van der Holt B, de Winter BCM, Hesselink DA

Abstract
Bodyweight-based tacrolimus dosing followed by therapeutic drug monitoring is standard clinical care after renal transplantation. However, after transplantation, a meagre 38% of patients is on target at first steady state and it can take up to three weeks to reach the target tacrolimus pre-dose concentration (C0 ). Tacrolimus under- and overexposure is associated with an increased risk of rejection and drug-related toxicity, respectively. To minimize sub- and supra-therapeutic tacrolimus exposure in the immediate post-transplant phase, a previously-developed dosing algorithm to predict an individual's tacrolimus starting dose was tested prospectively. In this single-arm, prospective, therapeutic intervention trial, 60 de novo kidney transplant recipients received a tacrolimus starting dose based on a dosing algorithm instead of a standard, bodyweight-based dose. The algorithm included cytochrome P450 (CYP) 3A4 and 3A5 genotype, body surface area and age as covariates. The target tacrolimus C0 , measured for the first time at day 3, was 7.5-12.5 ng/mL. Between 23 February 2019 and 07 July 2020, 60 patients were included. One patient was excluded because of a protocol violation. On day three post-transplantation, 34 out of 59 patients (58%; 90%-CI 47% to 68%) had a tacrolimus C0 within the therapeutic range. Markedly sub-therapeutic (<5.0 ng/mL) and supra-therapeutic (>20 ng/mL) tacrolimus concentrations were observed in 7% and 3% of the patients, respectively. Biopsy-proven acute rejection occurred in three patients (5%). In conclusion, algorithm-based tacrolimus dosing leads to the achievement of the tacrolimus target C0 in as many as 58% of the patients on day three after kidney transplantation.

PMID: 33452682 [PubMed - as supplied by publisher]

The Human Immunopeptidome Project: A Roadmap to Predict and Treat Immune Diseases.

Mol Cell Proteomics. 2020 Jan;19(1):31-49

Authors: Vizcaíno JA, Kubiniok P, Kovalchik KA, Ma Q, Duquette JD, Mongrain I, Deutsch EW, Peters B, Sette A, Sirois I, Caron E

Abstract
The science that investigates the ensembles of all peptides associated to human leukocyte antigen (HLA) molecules is termed "immunopeptidomics" and is typically driven by mass spectrometry (MS) technologies. Recent advances in MS technologies, neoantigen discovery and cancer immunotherapy have catalyzed the launch of the Human Immunopeptidome Project (HIPP) with the goal of providing a complete map of the human immunopeptidome and making the technology so robust that it will be available in every clinic. Here, we provide a long-term perspective of the field and we use this framework to explore how we think the completion of the HIPP will truly impact the society in the future. In this context, we introduce the concept of immunopeptidome-wide association studies (IWAS). We highlight the importance of large cohort studies for the future and how applying quantitative immunopeptidomics at population scale may provide a new look at individual predisposition to common immune diseases as well as responsiveness to vaccines and immunotherapies. Through this vision, we aim to provide a fresh view of the field to stimulate new discussions within the community, and present what we see as the key challenges for the future for unlocking the full potential of immunopeptidomics in this era of precision medicine.

PMID: 33451557 [PubMed - as supplied by publisher]