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]

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 2021/01/20

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.

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]

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 2021/01/16

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.

Impact of Previous Genetic Counseling and Objective Numeracy on Accurate Interpretation of a Pharmacogenetics Test Report.

Public Health Genomics. 2021 Jan 14;:1-7

Authors: Drelles K, Pilarski R, Manickam K, Shoben AB, Toland AE

Abstract
INTRODUCTION: Pharmacogenetic (PGx) testing can be useful for providing information about a patient's drug response by increasing drug efficacy and decreasing the incidence of adverse drug events. While PGx tests were previously only offered to patients under healthcare provider supervision, they are now available as direct to consumer (DTC) tests. This study aimed to assess how accurately individuals from the general population were able to interpret a sample PGx test report and if accuracy differed based on individuals' numeracy or prior genetic counseling (GC).
METHODS: We surveyed 293 individuals from the general population, ascertained through ResearchMatch. The survey included questions about PGx test interpretation, numeracy, and genetic literacy.
RESULTS: In our cohort, numeracy level impacted PGx result interpretation, with those of high numeracy performing statistically significantly better on both the table format and graphical format (p value = 0.002 and p value <0.001, respectively) and genetic knowledge questions (p value <0.001) than those with low/average numeracy. In addition, previous GC did not impact test interpretation or genetic knowledge, but the number of individuals with prior GC was small (n = 26).
DISCUSSION/CONCLUSION: We found that numeracy had a significant impact on correct interpretation of PGx test reports. Because many individuals in the USA have low numeracy levels, it is extremely important that patients do not make their own medication management decision based on the test results and that they consult with their physicians about their PGx testing. The importance of consultation and discussion with providers about results should be emphasized on the test report.

PMID: 33445171 [PubMed - as supplied by publisher]

Effect of Hydrolyzable Tannins on Glucose-Transporter Expression and Their Bioavailability in Pig Small-Intestinal 3D Cell Model.

Molecules. 2021 Jan 11;26(2):

Authors: Brus M, Frangež R, Gorenjak M, Kotnik P, Knez Ž, Škorjanc D

Abstract
Intestinal transepithelial transport of glucose is mediated by glucose transporters, and affects postprandial blood-glucose levels. This study investigates the effect of wood extracts rich in hydrolyzable tannins (HTs) that originated from sweet chestnut (Castanea sativa Mill.) and oak (Quercus petraea) on the expression of glucose transporter genes and the uptake of glucose and HT constituents in a 3D porcine-small-intestine epithelial-cell model. The viability of epithelial cells CLAB and PSI exposed to different HTs was determined using alamarBlue®. qPCR was used to analyze the gene expression of SGLT1, GLUT2, GLUT4, and POLR2A. Glucose uptake was confirmed by assay, and LC-MS/ MS was used for the analysis of HT bioavailability. HTs at 37 µg/mL were found to adversely affect cell viability and downregulate POLR2A expression. HT from wood extract Tanex at concentrations of 4 µg/mL upregulated the expression of GLUT2, as well as glucose uptake at 1 µg/mL. The time-dependent passage of gallic acid through enterocytes was influenced by all wood extracts compared to gallic acid itself as a control. These results suggest that HTs could modulate glucose uptake and gallic acid passage in the 3D cell model.

PMID: 33440878 [PubMed - in process]

Pharmacogenetics of Direct Oral Anticoagulants: A Systematic Review.

J Pers Med. 2021 Jan 11;11(1):

Authors: Raymond J, Imbert L, Cousin T, Duflot T, Varin R, Wils J, Lamoureux F

Abstract
Dabigatran, rivaroxaban, apixaban, edoxaban, and betrixaban are direct oral anticoagulants (DOACs). Their inter-individual variability in pharmacodynamics and pharmacokinetics (transport and metabolism) is high, and could result from genetic polymorphisms. As recommended by the French Network of Pharmacogenetics (RNPGx), the management of some treatments in cardiovascular diseases (as antiplatelet agents, oral vitamin K antagonists, and statins) can rely on genetic testing in order to improve healthcare by reducing therapeutic resistance or toxicity. This paper is a review of association studies between single nucleotide polymorphisms (SNPs) and systemic exposure variation of DOACs. Most of the results presented here have a lot to do with some SNPs of CES1 (rs2244613, rs8192935, and rs71647871) and ABCB1 (rs1128503, rs2032582, rs1045642, and rs4148738) genes, and dabigatran, rivaroxaban, and apixaban. Regarding edoxaban and betrixaban, as well as SNPs in the CYP3A4 and CYP3A5 genes, literature is scarce, and further studies are needed.

PMID: 33440670 [PubMed]

Component resolved diagnosis by recombinant allergens in patients with allergies to inhalants.

J Biol Regul Homeost Agents. 2020 Sep-Oct,;34(5):1729-1737

Authors: Di Spigna G, Ladogana P, Covelli B, Ricciardone M, Salzano S, Spalletti Cernia D, Mormile I, Varriale G, Catapano O, Spadaro G, Mormile M, Postiglione L

Abstract
Molecular characterization of IgE reactivity of specific individual components of allergenic extracts is now possible due to the technology of recombinant allergens derived from studies of molecular biology of allergic pathology. The identification of the immunoreactivity to single allergenic components in allergic subjects allows to specifically define her/his allergic profile and obtain the so-termed Component Resolved Diagnosis (CRD). Molecular allergens can be classified into those that induce the respiratory allergic reactivity and those that identify the food-related allergic pathology. It is also essential to identify those molecular allergens whose immunoreactivity is able to connect the two clinical conditions: respiratory symptoms and food allergy symptoms. The present study was conducted on 50 patients with a clinical history of hypersensitivity to pollen and/or allergy and positivity to Skin Prick Test. The sera were analyzed in our laboratories and the panel of recombinant allergens was applied in the case of positivity of the specific IgE. Of the 50 patients enrolled, 31 were selected as positive to 4 main pan-allergen Bet v1, Par j2, Art v1 and Phl p1; among these, 14 subjects showed one allergen-specific IgE towards natural extracts of tested foods even in absence of clinical history. CRD allows for an increased accuracy in allergy diagnosis and prognosis and plays an important role in: a) resolving genuine vs cross-reactive sensitization in poly-sensitized patients, b) assessing, in selected cases, the risk of severe, systemic vs mild, local reactions in food allergy, and c) identifying patients and triggering allergens for specific immunotherapy (ITS). In light of our results, we believe that the transition from a diagnostic based on the use of allergenic extracts to another one based on the use of single allergenic molecules that is able to define the specific allergenic profile of each patient, seems to be able to revolutionize the allergy diagnosis.

PMID: 33143407 [PubMed - indexed for MEDLINE]

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 2021/01/14

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.

Characterization of CYP2D6 drugs as substrates of human organic cation transporters (OCTs) and multidrug and toxin extrusion proteins (MATEs).

Br J Pharmacol. 2021 Jan 12;:

Authors: Neul C, Hofmann U, Schaeffeler E, Winter S, Klein K, Giacomini KM, Eichelbaum M, Schwab M, Nies AT

Abstract
BACKGROUND AND PURPOSE: The metabolic activity of cytochrome P450 (CYP) 2D6 is highly variable and CYP2D6 genotypes insufficiently explain the extensive and intermediate metabolic phenotypes, thus limiting the prediction of drug response and/or adverse drug reactions. Since CYP2D6 prototypic substrates are positively charged, the aim of this study was to evaluate the organic cation membrane transporters (OCTs) and multidrug and toxin extrusion proteins (MATEs) as potential contributors to the variability of CYP2D6 hydroxylation of the CYP2D6 drugs debrisoquine, dextromethorphan, diphenhydramine, perhexiline and sparteine.
EXPERIMENTAL APPROACH: OCT1/SLC22A1-, OCT2/SLC22A2-, OCT3/SLC22A3-, MATE1/SLC47A1- and MATE2K/SLC47A2-overexpressing cell lines were used to investigate the transport of the selected agents. Individuals from a study cohort, well-defined with respect to CYP2D6 genotype and sparteine pharmacokinetics, were genotyped for the common OCT1 variants rs12208357 (OCT1-R61C), rs34130495 (OCT1-G401S), rs202220802 (OCT1-Met420del), rs34059508 (OCT1-G465R), OCT2 variant rs316019 (OCT2-A270S) and MATE1 variant rs2289669. Sparteine pharmacokinetics was stratified according to CYP2D6 and OCT1, OCT2 or MATE1 genotype.
KEY RESULTS: OCTs and MATE1 transport sparteine and debrisoquine with high affinity in vitro, but OCT- and MATE1-dependent transport of dextromethorphan, diphenhydramine and perhexiline was not detected. Sparteine and debrisoquine transport in vitro depends on OCT1 genotype, however, sparteine pharmacokinetics is independent from OCT1 genotype.
CONCLUSIONS AND IMPLICATIONS: Some, but not all drugs, that are substrates of CYP2D6 are also substrates of OCTs and MATE1 suggesting that the enzyme and transporters have overlapping specificities. Variability in sparteine hydroxylation in extensive and intermediate metabolizers cannot be explained by OCT1 genetic variants indicating presence of other factors. Dose-dependent toxicities of dextromethorphan, diphenhydramine and perhexiline appear to be independent from OCTs and MATEs.

PMID: 33434947 [PubMed - as supplied by publisher]

Race specific comparisons of antihypertensive and metabolic effects of hydrochlorothiazide and chlorthalidone.

Am J Med. 2021 Jan 09;:

Authors: Chekka LMS, Chapman AB, Gums JG, Cooper-DeHoff RM, Johnson DADPDJA

Abstract
BACKGROUND: Chlorthalidone is recommended over hydrochlorothiazide (HCTZ) as the preferred thiazide, but the supporting evidence is not robust at routinely used doses, or in whites versus blacks, in whom differences in response to thiazides are well known. We compare the efficacy and safety of HCTZ and chlorthalidone as first-line therapies for white and black hypertensive patients.
METHODS: We compared treatment related outcomes between the HCTZ arm (12.5mg for 2-3 weeks; 25mg for additional 6 weeks) of the Pharmacogenomic Evaluation of Antihypertensive Responses (PEAR, n=376) and chlorthalidone arm (15mg for 2 weeks; 25mg for additional 6 weeks) of PEAR-2 (n=326) clinical trials, in 17-65 year-old mild-moderate uncomplicated hypertensive whites and blacks.
RESULTS: Mean systolic/diastolic blood pressure (SBP/DBP) reduction with HCTZ vs chlorthalidone: 8±8/4±5 vs 12±9/7±5 mmHg in whites (p<10-6 SBP and DBP); 12±10/7±6 vs 15±10/9±6 in blacks (p=0.008 SBP, p=0.054 DBP). Treatment with HCTZ vs CTD in whites resulted in significantly fewer patients acheiving target-BP (<140/90 mmHg) (44% vs 57%, p=0.018) or clinical response rate (≥10 mmHg DBP reduction); and significantly higher non-response rate (<6 mmHg DBP reduction); but no significant differences in rates among blacks (e.g. target-BP rate: 56% vs 63%, p=0.31). Chlorthalidone treatment led to significantly lower rates of hypokalemia and hyperuricemia in whites and blacks, vs HCTZ, and significantly lower odds of requiring potassium supplementation among blacks (OR=0.16, 95% CI=0.07-0.37, p=3.4e-7).
CONCLUSION: Compared to HCTZ, chlorthalidone showed greater blood pressure lowering and adverse metabolic effects in whites, but similar blood pressure lowering and greater adverse effects in blacks; suggesting the recent guideline recommendations to choose chlorthalidone over HCTZ may not be warranted in blacks.

PMID: 33434556 [PubMed - as supplied by publisher]

Nonadherence to inhaled corticosteroids: A characteristic of the pediatric obese-asthma phenotype?

Pediatr Pulmonol. 2021 Jan 12;:

Authors: Orriëns LB, Vijverberg SJH, Maitland-van der Zee AH, Longo C

Abstract
BACKGROUND: Children with excess weight and asthma tend to respond less well to inhaled corticosteroids (ICS) than children with normal weight, potentially resulting in nonadherence to ICS.
OBJECTIVES: To assess whether excess weight (body mass index ≥85th percentile) was associated with general, unintentional, and intentional nonadherence to ICS in children with asthma.
METHODS: We analyzed data from 566 children aged 4-13 years with asthma, who used ICS as maintenance therapy, from the cross-sectional Pharmacogenetics of Asthma medication in Children: Medication with Anti-inflammatory effects study. General nonadherence was measured objectively with the proportion of days covered (<50%) and subjectively with the parent-reported Medication Adherence Rating Scale (MARS <21) reflecting parent-reported nonadherent behavior. Unintentional and intentional nonadherence were defined as forgetting to take medication and deliberately changing or skipping doses, respectively, from specific items of the MARS. We performed logistic regression analyses, stratifying estimates by asthma severity and age group.
RESULTS: Excess weight was associated with a trend towards increased odds of parent-reported nonadherent behavior (odds ratio [OR]: 1.54; 95% confidence interval [CI]: 0.84-2.81) and objectively measured general nonadherence, but only in moderate-to-severe asthma (OR: 1.71; 95% CI: 0.84-3.48). The odds of intentional, but not unintentional, nonadherence seemed to be greater in children with excess weight than normal weight (OR: 1.94; 95% CI: 0.94-4.01), and the association appeared to be stronger in younger (OR: 2.17; 95% CI 1.00-4.73) versus older children (OR: 1.18; 95% CI: 0.36-3.94).
CONCLUSIONS: Excess weight was associated with general nonadherence to ICS, but only in children with moderate-to-severe asthma, and nonadherent behavior, which seemed to be intentional.

PMID: 33434419 [PubMed - as supplied by publisher]

LncRNA linc00312 suppresses radiotherapy resistance by targeting DNA-PKcs and impairing DNA damage repair in nasopharyngeal carcinoma.

Cell Death Dis. 2021 Jan 04;12(1):69

Authors: Guo Z, Wang YH, Xu H, Yuan CS, Zhou HH, Huang WH, Wang H, Zhang W

Abstract
Radioresistance is the main obstacle in the clinical management of nasopharyngeal carcinoma (NPC). linc00312 is deregulated in a number of human cancers, including NPC. However, the detailed functions and underlying mechanisms of linc00312 in regulating radiosensitivity of NPC remains unknown. In this study, cox regression analysis was used to assess the association between linc00312 and NPC patients' survival after radiotherapy. Our results reveal that linc00312 is significantly down-regulated in NPC tissues and patients with higher expression of linc00312 are significantly associated with longer overall survival and better short-term radiotherapy efficacy. Overexpression of linc00312 could increase the sensitivity of NPC cells to ionizing radiation, as indicated by clonogenic survival assay, comet assay, and flow cytometry. Mechanistically, RNA pull down and RNA immunoprecipitation were performed to investigate the binding proteins of linc00312. linc00312 directly binds to DNA-PKcs, hinders the recruitment of DNA-PKcs to Ku80, and inhibits phosphorylation of AKT-DNA-PKcs axis, therefore inhibiting the DNA damage signal sensation and transduction in the NHEJ repair pathway. In addition, linc00312 impairs DNA repair and cell cycle control by suppressing MRN-ATM-CHK2 signal and ATR-CHK1 signal. In summary, we identified DNA-PKcs as the binding protein of linc00312 and revealed a novel mechanism of linc00312 in the DNA damage response, providing evidence for a potential therapeutic strategy in NPC.

PMID: 33431817 [PubMed - in process]

Epithelial-Mesenchymal Transition and MicroRNAs in Colorectal Cancer Chemoresistance to FOLFOX.

Pharmaceutics. 2021 Jan 08;13(1):

Authors: Escalante PI, Quiñones LA, Contreras HR

Abstract
The FOLFOX scheme, based on the association of 5-fluorouracil and oxaliplatin, is the most frequently indicated chemotherapy scheme for patients diagnosed with metastatic colorectal cancer. Nevertheless, development of chemoresistance is one of the major challenges associated with this disease. It has been reported that epithelial-mesenchymal transition (EMT) is implicated in microRNA-driven modulation of tumor cells response to 5-fluorouracil and oxaliplatin. Moreover, from pharmacogenomic research, it is known that overexpression of genes encoding dihydropyrimidine dehydrogenase (DPYD), thymidylate synthase (TYMS), methylenetetrahydrofolate reductase (MTHFR), the DNA repair enzymes ERCC1, ERCC2, and XRCC1, and the phase 2 enzyme GSTP1 impair the response to FOLFOX. It has been observed that EMT is associated with overexpression of DPYD, TYMS, ERCC1, and GSTP1. In this review, we investigated the role of miRNAs as EMT promotors in tumor cells, and its potential effect on the upregulation of DPYD, TYMS, MTHFR, ERCC1, ERCC2, XRCC1, and GSTP1 expression, which would lead to resistance of CRC tumor cells to 5-fluorouracil and oxaliplatin. This constitutes a potential mechanism of epigenetic regulation involved in late-onset of acquired resistance in mCRC patients under FOLFOX chemotherapy. Expression of these biomarker microRNAs could serve as tools for personalized medicine, and as potential therapeutic targets in the future.

PMID: 33429840 [PubMed]