Expression and role of RIP140/NRIP1 in chronic lymphocytic leukemia

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Response to ‘Pharmacy‐based interdisciplinary intervention for patients with chronic heart failure: results of the PHARM‐CHF randomized controlled trial’

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: Vitamine B6 et cancer

International audienceVitamin B6 is well-known for its role as a cofactor in many enzymatic reactions and recently, several epidemiological studies have highlighted the importance of this vitamin as a protective agent against various cancers: elevated vitamin B6 plasma levels were associated with a lower risk of colorectal cancer development, for example. In vivo studies have shown that vitamin B6 decreased cell proliferation and enhanced the immune response. At the cellular level, antioxidant, pro-apoptotic and anti-angiogenic effects have been identified. At the molecular level, vitamin B6 is able to inhibit the transactivation potential of various nuclear receptors. Interestingly, a recent paper has described the conjugation of vitamin B6 to RIP140 (receptor interacting protein of 140 kDa), a protein that acts as a transcriptional corepressor of nuclear receptors. This post-translational modification increases the transcriptional repression of RIP140 and regulates its subcellular localization and its ability to interact with different protein partners. Finally, vitamin B6 is involved in the methyl donor cycle ant thus, some of the antitumor properties of vitamin B6 may involve an indirect effect on the level of DNA or histone methylation. All of these mechanistic and clinical data justify further studies to decipher the mechanism of action of vitamin B6 and its clinical interest in combination with molecules typically used in chemotherapy or hormonal therapy

Dialogue between estrogen receptor and E2F signaling pathways: The transcriptional coregulator RIP140 at the crossroads

International audienceEstrogen receptors and E2F transcription factors are the key players of two nuclear signaling pathways which exert a major role in oncogenesis, particularly in the mammary gland. Different levels of dialogue between these two pathways have been deciphered and deregulation of the E2F pathway has been shown to impact the response of breast cancer cells to endocrine therapies. The present review focuses on the transcriptional coregulator RIP140/NRIP1 which is involved in several regulatory feed-back loops and inhibitory cross-talks between different nuclear signaling pathways. RIP140 regulates the transactivation potential of estrogen receptors and E2Fs and is also a direct transcriptional target of these transcription factors. Published data highlight the complex regulation of RIP140 expression at the transcriptional level and its potential role in transcription cross-talks. Indeed, a subtle regulation of RIP140 expression levels has important consequences on other transcription networks targeted by this coregulator. Another level of regulation implies titration mechanisms by which activation of a pathway leads to sequestration of the RIP140 protein and thus impinges other gene regulatory circuitries. Altogether, RIP140 occupies a place of choice in the dialogue between nuclear receptors and E2Fs, which could be highly relevant in various human pathologies such as cancer or metabolic diseases

The emerging role of the transcriptional coregulator RIP140 in solid tumors

International audienceRIP140 is a transcriptional coregulator (also known as NRIP1) which plays very important physiological roles by finely tuning the activity of a large number of transcription factors. Noticeably, the RIP140 gene has been shown to be involved in the regulation of energy expenditure, in mammary gland development and intestinal homeostasis as well as in behavior and cognition. RIP140 is also involved in the regulation of various oncogenic signaling pathways and participates in the development and progression of solid tumors. This short review aims to summarize the role of this transcription factor on nuclear estrogen receptors, E2F and Wnt signaling pathways based on recent observations focusing on breast, ovary, liver and colon tumors

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

Collaboration between cardiologist and clinical pharmacist on prescription quality: What is the potential clinical impact for cardiology patients?

International audienceObjectives: The aim of this study was to determine the effect of pharmacists’ interventions (PI) on the potential clinical impact of medication errors, including the lack of therapeutic optimisation of patients with cardiologic diseases, such as heart failure and acute coronary syndrome).Methods: This was an observational, prospective study conducted in the cardiology department of a French university hospital centre for a duration of 9 months. All prescriptions were analysed and PI were registered for clinical rating by pharmacists and cardiologist.Results: A total of 532 PI cases were recorded in 339 patients, with a mean of 1.57 (±1.04) PI. The PI acceptance rate was 98.1%. “Dose adjustment” and “introduction therapy” were the most common interventions and represented 38.0% and 32.9%, respectively, of all PI. Statins were the most frequently involved drugs (18.1%), followed by ACE (Angiotensin Converting Enzyme) inhibitors (10.9%) and antiplatelet agents (9.3%). Moreover, 13.8% of PI potentially avoided a severe or very severe clinical impact (n = 71) and 38.6% had a significant impact altering the quality of life (n = 198). There was no significant difference between the average score performed by the clinical pharmacist included in the cardiology team and the one obtained by the cardiologist (P = .797). In contrast, a significant difference was observed for the average score established by the pharmacist localised in central pharmacy versus the rating of the cardiologist (P < .001).Conclusions: The collaboration between clinical pharmacists and cardiologists in the medical units seems to be beneficial to the quality of prescriptions, including the implementation of recommendations. The good rate of PI acceptance and the similar rating with the cardiologist show that there is a change in perspective of the pharmacist, being closer to the clinical realit

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

Medication Errors at Hospital Admission and Discharge

International audienceOBJECTIVE:First, the aim of the study was to assess the prevalence, characteristics, and severity of unintended medication discrepancies (UMDs) and medication errors (MEs) at admission and discharge of hospitalization. Second, the aim of the study was to identify clinical and hospitalization factors associated with risk of UMDs as well as characteristics of the medication reconciliation process associated with UMDs detection.METHODS:This prospective observational study included all adult patients admitted from 2013 to 2015 in the Endocrinology-Diabetology-Nutrition Department of Montpellier Hospital, France. Clinical pharmacists conducted medication reconciliation by collecting the best possible medication history from different sources and comparing it with admission and discharge prescriptions to identify discrepancies. Unintended medication discrepancies corrected by the physician were considered as MEs. Risk factors of UMDs were identified with logistic regression.RESULTS:Of 904 patients included, 266 (29.4%) had at least one UMD, at admission or at discharge. In total, 378 (98.2%) of 385 UMDs were considered to be MEs. Most MEs were omissions (59.3%). Medication errors were serious or very serious in 36% of patients and had potentially moderate severity in almost 40% of patients. The risk of UMDs increased constantly with the number of treatments (P < 0.001). Thyroid (adjusted odds ratio [OR] = 1.79, 95% CI = 1.12-2.86) and infectious diseases (adjusted OR = 1.80, 95% CI = 1.17-2.78) were associated with UMDs risk at admission. The best type of source for the detection of UMDs was the general practitioner or nurse (OR = 2.64, 95% CI = 1.51-4.63).CONCLUSIONS:Unintended medication discrepancies are frequent at hospital and depend on intrinsic clinical parameters but also on practice of medication reconciliation process, such as number and type of sources used

Receptor-interacting protein 140 is a repressor of the androgen receptor activity.: AR repression by RIP140

International audienceThe androgen receptor (AR) is a ligand-activated transcription factor that controls growth and survival of prostate cancer cells. In the present study, we investigated the regulation of AR activity by the receptor-interacting protein 140 (RIP140). We first showed that RIP140 could be coimmunoprecipitated with the receptor when coexpressed in 293T cells. This interaction appeared physiologically relevant because chromatin immunoprecipitation assays revealed that, under R1881 treatment, RIP140 could be recruited to the prostate-specific antigen encoding gene in LNCaP cells. In vitro glutathione S-transferase pull-down assays provided evidence that the carboxy-terminal domain of AR could interact with different regions of RIP140. By means of fluorescent proteins, we demonstrated that ligand-activated AR was not only able to translocate to the nucleus but also to relocate RIP140 from very structured nuclear foci to a diffuse pattern. Overexpression of RIP140 strongly repressed AR-dependent transactivation by preferentially targeting the ligand binding domain-dependent activity. Moreover, disruption of RIP140 expression induced AR overactivation, thus revealing RIP140 as a strong AR repressor. We analyzed its mechanism of transrepression and first demonstrated that different regions of RIP140 could mediate AR-dependent repression. We then showed that the carboxy-terminal end of RIP140 could reverse transcriptional intermediary factor 2-dependent overactivation of AR. The use of mutants of RIP140 allowed us to suggest that C-terminal binding protein played no role in RIP140-dependent inhibition of AR activity, whereas histone deacetylases partly regulated that transrepression. Finally, we provided evidence for a stimulation of RIP140 mRNA expression in LNCaP cells under androgen treatment, further emphasizing the role of RIP140 in androgen signaling