Tumorigenic proteins upregulated in the MYCN-amplified IMR-32 human neuroblastoma cells promote proliferation and migration.

Childhood neuroblastoma is one of the most common types of extra-cranial cancer affecting children with a clinical spectrum ranging from spontaneous regression to malignant and fatal progression. In order to improve the clinical outcomes of children with high-risk neuroblastoma, it is crucial to understand the tumorigenic mechanisms that govern its malignant behaviors. MYCN proto-oncogene, bHLH transcription factor (MYCN) amplification has been implicated in the malignant, treatment-evasive nature of aggressive, high-risk neuroblastoma. In this study, we used a SILAC approach to compare the proteomic signatures of MYCN-amplified IMR-32 and non-MYCN-amplified SK-N-SH human neuroblastoma cells. Tumorigenic proteins, including fatty-acid binding protein 5 (FABP5), L1-cell adhesion molecule (L1-CAM), baculoviral IAP repeat containing 5 [BIRC5 (survivin)] and high mobility group protein A1 (HMGA1) were found to be significantly upregulated in the IMR-32 compared to the SK-N-SH cells and mapped to highly tumorigenic pathways including, MYC, MYCN, microtubule associated protein Tau (MAPT), E2F transcription factor 1 (E2F1), sterol regulatory element binding transcription factor 1 or 2 (SREBF1/2), hypoxia-inducible factor 1α (HIF-1α), Sp1 transcription factor (SP1) and amyloid precursor protein (APP). The transcriptional knockdown (KD) of MYCN, HMGA1, FABP5 and L1-CAM significantly abrogated the proliferation of the IMR-32 cells at 48 h post transfection. The early apoptotic rates were significantly higher in the IMR-32 cells in which FABP5 and MYCN were knocked down, whereas cellular migration was significantly abrogated with FABP5 and HMGA1 KD compared to the controls. Of note, L1-CAM, HMGA1 and FABP5 KD concomitantly downregulated MYCN protein expression and MYCN KD concomitantly downregulated L1-CAM, HMGA1 and FABP5 protein expression, while survivin protein expression was significantly downregulated by MYCN, HMGA1 and FABP5 KD. In addition, combined L1-CAM and FABP5 KD led to the concomitant downregulation of HMGA1 protein expression. On the whole, our data indicate that this inter-play between MYCN and the highly tumorigenic proteins which are upregulated in the malignant IMR-32 cells may be fueling their aggressive behavior, thereby signifying the importance of combination, multi-modality targeted therapy to eradicate this deadly childhood cancer

Critères d'évaluation de l'efficacité des traitements de fond dans la sclérose en plaques

PARIS-BIUP (751062107) / SudocSudocFranceF

Management of acute COPD exacerbations in France: A qualitative survey in a private practice setting.

BackgroundThe current prevalence of chronic obstructive pulmonary disease (COPD) in France is estimated to be 2.6 million and is predicted to increase to 2.8 million by 2025. Presently, there is a lack of data on COPD management within the private healthcare setting. The aim of this study was to investigate the management of COPD exacerbations by pulmonologists within private practices in France.MethodsA prospective, online, qualitative survey was distributed to private practice pulmonologists in France. The survey covered all aspects of COPD management from diagnosis and therapeutic management, to secondary prevention and organization of care. Survey responses were collected between 27 January 2018 and 18 June 2018 and all data were summarized descriptively.ResultsThe survey had a response rate of 20.6%, with 116 out of 563 pulmonologists providing responses. Overall, 87.4% of respondents stated that the management of COPD represented over 15% of their total clinical activity. Most respondents indicated that they work closely with general practitioners and a large multidisciplinary team to manage patients with numerous comorbidities. Following a COPD exacerbation, the majority of respondents (78.4%) were in favor of using respiratory-connected devices (class 2a-connected medical device according to the French HAS classification and available on medical prescription) to assist with patient follow-up at home.ConclusionsCOPD management forms part of the core clinical activity for pulmonologists within the private practice setting in France. Patients with COPD generally have multiple comorbidities and are managed by a multidisciplinary team in line with French guidelines. The use of respiratory-connected devices was highlighted as an important new strategy for improving patient care following a COPD exacerbation

Insights from Social Media on the Patient Experience of Living With Rare Eosinophil-Driven Diseases.

Eosinophilic granulomatosis with polyangiitis (EGPA) and hypereosinophilic syndrome (HES) are driven by persistently high eosinophil numbers, causing damage to tissues and organs. As rare diseases, they are often underappreciated by healthcare professionals. Using a social listening analysis, we collected patient and caregiver comments relating to EGPA and HES made on online social platforms between 1 January 2019 and 31 May 2020, in English, French, and German. Results were classified into key areas of interest. In total, 746 comments with consent to publish were collected mentioning EGPA, and 39 were identified mentioning HES. The most common theme was sharing of personal experiences (EGPA: 77%; HES: 100%). Diagnosis, including diagnosis delays and misdiagnosis, was mentioned in 33% of comments for EGPA, and 82% for HES. Other common themes included seeking and giving advice, symptoms, and treatments. These insights highlight the views and unmet needs of people living with EGPA and HES. Further work should improve disease awareness and effective communications among healthcare professionals and patients with these conditions.info:eu-repo/semantics/publishe

Stereoselective Rearrangement of (Trifluoromethyl)prolinols to Enantioenriched 3‑Substituted 2‑(Trifluoromethyl)piperidines

3-Substituted 2-(trifluoromethyl)­piperidines <b>B</b> were synthesized by ring expansion of (trifluoromethyl)­prolinols <b>A</b>, which were obtained from l-proline via an aziridinium intermediate <b>C</b>. The ring opening of the (trifluoromethyl)­aziridinium intermediate by different nucleophiles is regio- and diastereoselective

Efficacy and safety of once-daily fluticasone furoate/vilanterol (FF/VI) versus twice-daily inhaled corticosteroids/long-acting β2-agonists (ICS/LABA) in patients with uncontrolled asthma: An open-label, randomized, controlled trial

International audienc

Genotypic Resistance Analysis of the Virological Response to Fosamprenavir-Ritonavir in Protease Inhibitor-Experienced Patients in CONTEXT and TRIAD Clinical Trials▿

The aim of this study was to identify human immunodeficiency virus (HIV) protease mutations associated with virological response (VR) to fosamprenavir-ritonavir (FPV/r) in 113 protease inhibitor (PI)-experienced patients randomized in both CONTEXT and TRIAD clinical trials and receiving the same dose (700/100 mg twice daily) of FPV/r. The impact of each protease mutation on the VR to FPV/r, defined as the decrease in HIV RNA at week 12, was investigated with nonparametric analyses. A step-by-step procedure was done using a Jonckheere-Terpstra (JT) test that retains the group of mutations most strongly associated with the VR. Mutations at the following 14 codons were associated with a reduced VR to FPV/r: 10, 15, 33, 46, 54, 60, 62, 63, 72, 73, 82, 84, 89, and 90. The JT procedure led to selecting the CONTEXT/TRIAD genotypic set of mutations, I15V, M46I/L, I54L/M/V, D60E, L63P/T, and I84V, as providing the strongest association with the VR (P = 1.45 × 10−11). In the nine patients with zero mutations within this set, the median decrease in HIV RNA was −2.63 log copies/ml, and was −2.22 (n = 45), −1.50 (n = 26), −0.58 (n = 23), −0.47 (n = 6), −0.13 (n = 3), and 0.04 (n = 1) log copies/ml in those with one, two, three, four, five, and six mutations, respectively. This study identified six mutations associated with VR to FPV/r. Some of these mutations are shared with the current FPV/r Agence Nationale de Recherches sur le SIDA (ANRS) resistance score, which has been cross-validated in the CONTEXT/TRIAD data set, suggesting that the current ANRS FPV/r score is a useful tool for the prediction of VR to FPV/r in PI-experienced patients

Insights from Social Media on the Patient Experience of Living With Rare Eosinophil-Driven Diseases

Eosinophilic granulomatosis with polyangiitis (EGPA) and hypereosinophilic syndrome (HES) are driven by persistently high eosinophil numbers, causing damage to tissues and organs. As rare diseases, they are often underappreciated by healthcare professionals. Using a social listening analysis, we collected patient and caregiver comments relating to EGPA and HES made on online social platforms between 1 January 2019 and 31 May 2020, in English, French, and German. Results were classified into key areas of interest. In total, 746 comments with consent to publish were collected mentioning EGPA, and 39 were identified mentioning HES. The most common theme was sharing of personal experiences (EGPA: 77%; HES: 100%). Diagnosis, including diagnosis delays and misdiagnosis, was mentioned in 33% of comments for EGPA, and 82% for HES. Other common themes included seeking and giving advice, symptoms, and treatments. These insights highlight the views and unmet needs of people living with EGPA and HES. Further work should improve disease awareness and effective communications among healthcare professionals and patients with these conditions