Pregnane × Receptor (PXR) expression in colorectal cancer cells restricts irinotecan chemosensitivity through enhanced SN-38 glucuronidation

<p>Abstract</p> <p>Background</p> <p>Clinical efficacy of chemotherapy in colorectal cancer is subjected to broad inter-individual variations leading to the inability to predict outcome and toxicity. The topoisomerase I inhibitor irinotecan (CPT-11) is worldwide approved for the treatment of metastatic colorectal cancer and undergoes extensive peripheral and tumoral metabolism. PXR is a xenoreceptor activated by many drugs and environmental compounds regulating the expression of drug metabolism and transport genes in detoxification organs such as liver and gastrointestinal tract. Considering the metabolic pathway of irinotecan and the tissue distribution of Pregnane × Receptor (PXR), we hypothesized that PXR could play a key role in colon cancer cell response to irinotecan.</p> <p>Results</p> <p>PXR mRNA expression was quantified by RT-quantitative PCR in a panel of 14 colon tumor samples and their matched normal tissues. PXR expression was modulated in human colorectal cancer cells LS174T, SW480 and SW620 by transfection and siRNA strategies. Cellular response to irinotecan and its active metabolic SN38 was assessed by cell viability assays, HPLC metabolic profiles and mRNA quantification of PXR target genes. We showed that PXR was strongly expressed in colon tumor samples and displayed a great variability of expression. Expression of hPXR in human colorectal cancer cells led to a marked chemoresistance to the active metabolite SN38 correlated with PXR expression level. Metabolic profiles of SN38 showed a strong enhancement of SN38 glucuronidation to the inactive SN38G metabolite in PXR-expressing cells, correlated with an increase of UDPglucuronosyl transferases UGT1A1, UGT1A9 and UGT1A10 mRNAs. Inhibition of PXR expression by lentivirus-mediated shRNA, led to SN38 chemoresistance reversion concomitantly to a decrease of UGT1A1 expression and SN38 glucuronidation. Similarly, PXR mRNA expression levels correlated to UGT1A subfamily expression in human colon tumor biopsies.</p> <p>Conclusion</p> <p>Our results demonstrate that tumoral metabolism of SN38 is affected by PXR and point to potential therapeutic significance of PXR quantification in the prediction of irinotecan response. Furthermore, our observations are pharmacologically relevant since many patients suffering from cancer diseases are often exposed to co-medications, food additives or herbal supplements able to activate PXR. A substantial part of the variability observed among patients might be caused by such interactions</p

Study of the CAR (NR1I3) and PXR (NR1I2) : identification of a new CAR target gene (SPOT14) and a new PXR isoform (PXR-small) in human hepatocyte

CAR (Constitutive Androstane Receptor, NR1I3) et PXR (Pregnane X Receptor, NR1I2) sont deux récepteurs nucléaires dédiés à la reconna issance et à l'élimination de molécules lipophiles potentiellement toxiques pour l'organisme. Ces facteurs de transcription peuvent être activés par des ligands d'origines et de structures diverses (médicaments, polluants environnementaux, produits de l'alimentation et de phytothérapies). L'activation de ces récepteurs entraîne l'expression des gènes majeurs de la fonction de détoxication entéro-hépatique (CYP450, transférases, transporteurs) permettant l'élimination de ces toxiques. Dans ce travail, nous avons dans un premier temps 1) montré que CAR contrôle l'expression de Spot14, une protéine pro-lipogénique, et 2) nous avons identifié une nouvelle isoforme de PXR (PXR-small) codant uniquement pour le domaine de liaison des ligands de PXR. Nous avons pu déterminer les origines de transcription par 5'-RACE PCR et montrer que PXR-small représente environ 10% de l'ensemble des transcrits de PXR dans le tissu hépatique sain par une approche de PCR qua ntitative. Nous avons pu détecter sa présence par western-blot sur des extraits de protéines nucléaires issus de tissus hépatiques et de lignées cellulaires hépatiques. Par des expériences de gel retard, nous avons observé que cette nouvelle isoforme tronquée, qui ne code que pour le LBD de PXR, ne peut pas se lier à l'ADN. Des expériences de gènes rapporteurs suggèrent que cette isoforme se comporte comme un dominant négatif de PXR. Enfin, la présence d'un ilot CpG situé juste en amont de PXR-small suggère que cette nouvelle isoforme pourrait être régulée épigénétiquement par méthylation, notamment dans les cellules tumorales.CAR (Constitutive Androstane Receptor, NR1I3) and PXR (Pregnane X Receptor, NR1I2) are two nuclear receptors devoted to the recognition and elimination of lipohilic molecules potentially toxic to the body.These transcription factors can be activated by ligands of different origins and structures (drugs, environmental pollutants, food products and herbal medicine...). The activation of these receptors leads to the expression of major genes of the detoxification process (CYP450, transferases, transporters) leading to the elimination of these toxics. In this work, we 1) showed that Spot14, a pro-lipogenic protein, is a target gene of CAR, then 2) we identified a novel isoform of PXR (PXR-small), coding only the ligand binding domain of PXR. By using 5'-RACE PXR, we established the origins of transcription of PXR-small and by quantitative PCR we observed that PXR-small represents about 10% of all PXR transcripts in human liver. By using western blo t, we detect its presence on nuclear protein extracts from liver tissues and hepatic cell lines. In Electromobility shift essays experiments, we observed that PXR-small cannot bind to DNA, while reporter essay experiments suggest that this isoform acts as a dominant negative of PXR. Finally, the presence of a CpG island just upstream of PXR-small suggests that this novel isoform might be regulated epigenetically by methylation, more particularly in tumor cells

Optimisation de la prise en charge médicamenteuse dans un service de médecine (place de l interne en pharmacie de la rédaction d un système d assurance qualité aux activités de pharmacie clinique au lit du malade)

MONTPELLIER-BU Pharmacie (341722105) / SudocSudocFranceF

Patients with diabetes are at high risk of serious medication errors at hospital: Interest of clinical pharmacist intervention to improve healthcare

International audienceBACKGROUND:Medication errors (ME) are major public health issues in hospitals because of their consequences on patients' morbi-mortality. This study aims to evaluate the prevalence of ME at admission and discharge of hospitalization in diabetic and non-diabetic patients, and determine their potential clinical impact.METHOD:This prospective observational study was conducted at the Endocrinology-Diabetology-Nutrition Department. All adult patients admitted were eligible. A total of 904 patients were included, of which 671 (74.2%) with diabetes mellitus. Clinical pharmacists conducted medication reconciliation: they collected the Best Possible Medication History and then compared it with admission and discharge prescriptions to identify medication discrepancies. ME were defined as unintended medication discrepancies if corrected by the physician.RESULTS:Clinical pharmacists allowed correcting ME in 176/904 (19.5%) patients at admission and in 86/865 (9.9%) patients at discharge. More than half of ME were omissions. Diabetic patients were more affected by ME than non-diabetic patients, both at admission (22.1% vs 12.0%, p<0.001) and at discharge (11.4% vs 5.7%, p=0.01). The diabetic group also had more potentially severe and very severe ME. Diabetic patients had on average twice more medications than non-diabetic patients (8.7±4.5 vs 4.4±3.4, p<0.001). The polypharmacy associated with diabetes, but not diabetes mellitus itself, was identified as a risk factor of ME.CONCLUSIONS:The intervention of clinical pharmacists allowed correcting 378 ME in 25.8% of the cohort before they caused harm. Clinicians, pharmacists and other health care providers should therefore work together to improve patients' safety, in particular in high-risk patients such as diabetic patients

Impact of a medico-pharmaceutical follow-up and an optimized communication between hospital and community on the readmission to the emergency department for an adverse drug event: URGEIM, study protocol for a randomized controlled trial

International audienceBackground Adverse drug events (ADE) represent one of the main causes of admission to emergency department (ED). Their detection, documentation, and reporting are essential to avoid readmission. We hypothesize that a pharmacist-initiated multidisciplinary transition of care program combining ED pharmacist contribution and medications’ data transfer between inpatient and outpatient caregivers will reduce emergency visits related to ADEMethod/design This is a prospective, open-label, randomized controlled trial. The primary aim of the study is 6-month ED readmission related to the same ADE. Three hundred forty-six adult patients with an ADE detected by a binomial pharmacist-physician will be recruited from the ED of an University Hospital and will be randomized in two groups: [1] experimental group (multidisciplinary transition of care program and medications’ data transfer between inpatient and outpatient caregivers) and [2] control group (usual care). Patients will be followed up over a period of 6 months. Endpoints will be carried out blindly of the randomization arm. The primary endpoint is the rate of patients who had at least one readmission in the ED for the same reason at 6 months (data collected during a phone call with the patient and the general practitioner). Trials registered NCT03725046.Discussion The trial results will have implications for the role of the clinical pharmacist in an emergency department. If successful, the intervention could be considered for implementation across other hospitals.Trial registration ClinicalTrials.gov NCT03725046 . Registered on 30 October 201

Hypoglycemia While Driving in Insulin-Treated Patients Incidence and risk factors

International audienceThis study aimed to investigate a potential daily-life concern for patients with diabetes hypoglycemia while driving by (1) estimating their incidence in insulin-treated drivers, (2) determining factors associated with their occurrence, and (3) analyzing patients' behavior regarding prevention of hypoglycemia

Decreased RNF41 expression leads to insulin resistance in skeletal muscle of obese women

International audienc

Impact of Hospitalization in an Endocrinology Department on Vaccination Coverage in People Living with Diabetes: A Real-Life Study

International audienceBackground and Objectives: Vaccination coverage is suboptimal in people living with diabetes. The objectives of this study were to determine the impact of hospitalization on vaccination coverage and the variables associated with vaccination during hospital stay. Materials and Methods: This observational study was conducted from May 2019 to December 2019 in the Endocrinology-Nutrition-Diabetes Department of the University Hospital of Montpellier, France. This department encompasses three medical units, two of which have a full-time clinical pharmacist involved in the multidisciplinary management of patients. All adult diabetic patients who completed a questionnaire about vaccines were prospectively included by a clinical pharmacist and followed until department discharge. Coverage at the time of admission for the tetanus, diphtheria, pertussis (Tdap), pneumococcal, influenza, and herpes zoster vaccines was assessed from patient interviews and/or contact with the general practitioner and/or with the community pharmacist. Multivariable logistic regression analysis was performed to identify the factors associated with a vaccination update during the hospital stay. Results: A total of 222 patients were included (mean age: 59.4 years, 68.5% type 2 diabetes). Vaccination coverage increased by 26.7% (47.3% to 59.9%), 188.0% (10.8% to 31.1%) and 8.9% (45.9% to 50.0%), respectively, for the Tdap, pneumococcal and influenza vaccines during hospital stay. Female sex, admission to a diabetes care unit with a full-time pharmacist, favorable feelings about vaccination, unknown immunization coverage for pneumococcal vaccines, and evaluation and recording of vaccine coverage at admission in the patient medical records were associated with at least one vaccination during hospital stay. Conclusions: Our real-life study highlights that hospitalization and multidisciplinary management (i.e., physician-pharmacist) may be key points in the diabetes care pathway to improve vaccination coverage, especially for patients with advanced diabetes and comorbidities (study registered on ClinicalTrials.gov, NCT04391088)

Frequency, Characteristics, and Predictive Factors of Adverse Drug Events in an Adult Emergency Department according to Age: A Cross-Sectional Study

International audienceAdverse drug events (ADEs) are a major public health concern, given their consequences in terms of morbi-mortality and associated healthcare costs. Many studies have focused on the elderly, who are considered particularly vulnerable in this respect. We aimed to determine and compare the frequency, characteristics, and predictive factors of ADEs according to age in an adult population. A prospective seven-year cross-sectional study was conducted in a university hospital emergency department. Structured medication reviews and ADE detection were performed. Patient data and ADE characteristics were collected. Descriptive statistics and logistic regression were performed in two age groups: Group 1 (age < 65 years) and 2 (age ≥ 65 years). Among the 13,653 patients included, 18.4% in Group 1 and 22.6% in Group 2 experienced an ADE. Differences were identified in terms of the ADE type (more ADEs due to noncompliance in Group 1) and ADE symptoms (greater bleeding in Group 2). In the multivariable analysis, several specific predictive factors were identified, including kidney failure and antidiabetic drug use in Group 1 and inappropriate prescription and antithrombotic treatment in Group 2. Analysis by age provided a more refined vision of ADEs as we identified distinct profiles of iatrogenesis. These results will lead to a better detection of ADEs

Évaluation de l’hémoglobine glyquée en unité d’hospitalisation : données de registre

International audienceLes variations et les taux d'HbA1c selon l'âge et la fonction rénale ne sont pas en adéquation avec les directives de la SFD. Une analyse par régression logistique permettra d'identifier des variables associées à un objectif non atteint de l'HbA1c