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- ItemDelivery of melarsoprol using folate-targeted PEGylated cyclodextrin-based nanoparticles for hepatocellular carcinoma(Elsevier B.V., 2023-03-20) Li, Ya-Nan; Shi, Xiaoju; Sun, Dandan; Han, Shulan; Zou, Yifang; Wang, Lingzhi; Yang, Leilei; Li, Yutong; Shi, Ying; Guo, Jianfeng; O'Driscoll, Caitriona M.; National Natural Science Foundation of China; Department of Science and Technology of Jilin Province; First Hospital of Jilin University, China; Jilin University, China; Science Foundation Ireland; European Regional Development FundHepatocellular carcinoma (HCC) is the most common type of primary liver cancer, and has become one of the most lethal malignancies in the world. Although chemotherapy remains a cornerstone of cancer therapy, the number of chemotherapeutic drugs approved for HCC is low, and emerging therapeutics are needed. Melarsoprol (MEL) is an arsenic-containing drug, and has been applied in the treatment of human African trypanosomiasis at the late stage. In this study, the potential of MEL for HCC therapy was investigated for the first time using in vitro and in vivo experimental approaches. A folate-targeted polyethylene glycol-modified amphiphilic cyclodextrin nanoparticle was developed for safe, efficient and specific delivery of MEL. Consequently, the targeted nanoformulation achieved cell-specific uptake, cytotoxicity, apoptosis and migration inhibition in HCC cells. Furthermore, the targeted nanoformulation significantly prolonged the survival of mice with orthotopic tumor, without causing toxic signs. This study indicates the potential of the targeted nanoformulation as an emerging chemotherapy option for treating HCC.
- ItemLong-term safety of methylphenidate in children and adolescents with ADHD: 2-year outcomes of the Attention Deficit Hyperactivity Disorder Drugs Use Chronic Effects (ADDUCE) study(Elsevier Inc., 2023-03-20) Man, Kenneth K. C.; Häge, Alexander; Banaschewski, Tobias; Inglis, Sarah K.; Buitelaar, Jan; Carucci, Sara; Danckaerts, Marina; Dittmann, Ralf W.; Falissard, Bruno; Garas, Peter; Hollis, Chris; Konrad, Kerstin; Kovshoff, Hanna; Liddle, Elizabeth; McCarthy, Suzanne; Neubert, Antje; Nagy, Peter; Rosenthal, Eric; Sonuga-Barke, Edmund J. S.; Zuddas, Alessandro; Wong, Ian C. K.; Coghill, David; Couper, Tessa; Masi, Gabriele; Gagliano, Antonella; Lamberti, Marco; Maschietto, Dino; Costantino, Antonella; Morosini, Paola; Fazzi, Maria Elisa; Oehler, Klaus-Ulrich; Pitzer, Martina; Fegert, Jörg; Häßler, Frank; Renner, Tobias; Härtling, Fabian; Romanos, Marcel; Alfred, Adam; Roessner, Veit; Wallitza, Susanne; Uebel-von Sandersleben, Henrik; Seventh Framework ProgrammeBackground: Methylphenidate is the most frequently prescribed medication for the treatment of ADHD in children and adolescents in many countries. Although many randomised controlled trials support short-term efficacy, tolerability, and safety, data on long-term safety and tolerability are scarce. The aim of this study was to investigate the safety of methylphenidate over a 2-year period in relation to growth and development, psychiatric health, neurological health, and cardiovascular function in children and adolescents. Methods: We conducted a naturalistic, longitudinal, controlled study as part of the ADDUCE research programme in 27 European child and adolescent mental health centres in the UK, Germany, Switzerland, Italy, and Hungary. Participants aged 6–17 years were recruited into three cohorts: medication-naive ADHD patients who intended to start methylphenidate treatment (methylphenidate group), medication-naive ADHD patients who did not intend to start any ADHD medication (no-methylphenidate group), and a control group without ADHD. Children with ADHD diagnosed by a qualified clinician according to the DSM-IV criteria and, in the control group, children who scored less than 1·5 on average on the Swanson, Nolan, and Pelham IV rating scale for ADHD items, and whose hyperactivity score on the parent-rated Strengths and Difficulties Questionnaire was within the normal range (<6) were eligible for inclusion. Participants were excluded if they had previously taken any ADHD medications but remained eligible if they had previously taken or were currently taking other psychotropic drugs. The primary outcome was height velocity (height velocity SD score; estimated from at least two consecutive height measurements, and normalised with reference to the mean and SD of a population of the same age and sex). Findings: Between Feb 01, 2012, and Jan 31, 2016, 1410 participants were enrolled (756 in methylphenidate group, 391 in no-methylphenidate group, and 263 in control group). 1070 (76·3%) participants were male, 332 (23·7%) were female, and for eight gender was unknown. The average age for the cohort was 9·28 years (SD 2·78; IQR 7–11). 1312 (93·0%) of 1410 participants were White. The methylphenidate and no-methylphenidate groups differed in ADHD symptom severity and other characteristics. After controlling for the effects of these variables using propensity scores, there was little evidence of an effect on growth (24 months height velocity SD score difference –0·07 (95% CI –0·18 to 0·04; p=0·20) or increased risk of psychiatric or neurological adverse events in the methylphenidate group compared with the no-methylphenidate group. Pulse rate and systolic and diastolic blood pressure were higher in the methylphenidate group compared with the no-methylphenidate group after 24 months of treatment. No serious adverse events were reported during the study. Interpretation: Our results suggest that long-term treatment with methylphenidate for 2 years is safe. There was no evidence to support the hypothesis that methylphenidate treatment leads to reductions in growth. Methylphenidate-related pulse and blood pressure changes, although relatively small, require regular monitoring.
- ItemMajor structure-activity relationships of resolvins, protectins, maresins and their analogues(Future Science Ltd, 2022-11-30) Daly, Kevin; O'Sullivan, Killian; O'Sullivan, Timothy P.Resolvins, protectins and maresins are a series of polyunsaturated fatty acid-derived molecules which play important roles in the resolution of inflammation. They are termed specialized proresolving mediators and facilitate a return to homeostasis following an inflammatory response. These molecules are currently the focus of intensive investigation, primarily for their ability to suppress inflammation in chronic disease states. Researchers have employed different synthetic approaches to assess whether various structural modifications of these compounds could provide access to future therapeutics. This review summarizes the modifications made thus far and focuses on the key structure-activity relationships which have been uncovered for resolvins, protectins, maresins and their analogues.
- ItemCoping strategies of healthcare professional students for stress incurred during their studies: a literature review(Taylor & Francis, 2022-01-12) Fitzgibbon, Kate; Murphy, Kevin D.Background: Stress in healthcare professional students is well-documented, however coping strategies and their relationship with stress has not been comprehensively reviewed. It is necessary for students to use positive coping strategies to effectively reduce stress levels. Aims: The aim of this review is to identify coping strategies of healthcare professional students and their consequences. Methods: Studies conducted from 2010 to 2020 on coping strategies utilised by healthcare students were reviewed. An electronic database search was performed in January 2020 of three databases CINAHL, SCOPUS and PubMed. Results: Twenty-two studies were included in this review, using a wide range of survey instruments including the Brief Coping Orientation to Problems Experienced (Brief COPE) Inventory and the Coping Behaviour Inventory Common coping strategies utilised by healthcare students include problem-focused strategies such as planning, problem-solving and active coping. Coping strategies tended to vary depending on student’s location, year of their course, gender and age. Positive coping strategies, such as problem-focused strategies, were associated with reduced stress levels and improved psychological health. Other emotion-focused coping strategies identified included acceptance, self-distraction, and optimism. Conclusions: Findings may provide direction for third-level institutions in designing interventions (such as encouraging exercise) promoting the use of positive coping strategies.
- ItemSynthesis and reactivity of dihalofuranones(Bentham Science Publishers, 2022-08-01) Lyons, Thérèse A.; Gahan, Cormac G. M.; O'Sullivan, Timothy P.; Science Foundation IrelandHalogenated furanones have been found to act as potent quorum sensing inhibitors in several bacterial species. It is believed that dihalofuranones covalently bind to the LuxS enzyme, which is necessary for autoinducer-2 synthesis. In addition to their antimicrobial activity, halogen-ated furanones also possess anti-cancer, antioxidant, and depigmentation properties. However, traditional routes to these compounds are low-yielding and capricious. The aim of this study was to investigate higher-yielding preparations of gem-dihalofuranones and compare their reactivity using Suzuki chemistry. Ramirez dibromoolefination of maleic anhydride was optimised using a variety of conditions. A similar route was investigated for the preparation of bromofluorofuranones and dichlorofuranones. The conversion of a dichlorofuranone to the corresponding iodofuranone derivatives using microwave-assisted Finkelstein chemistry was also studied. Lastly, the reactivity of the different dihalofuranones was compared by Pd-mediated coupling with phenylboronic acid. A higher-yielding, concise synthesis of dibromofuranones was developed using a modified Ramirez reaction. Additionally, a telescoped preparation of dichlorofuranone was higher yielding than previous approaches. Bromine-and iodine-substituted dihalofuranones proved more reactive than their chlorine-substituted analogues. Higher yielding routes to bromine-, fluorine-, chlorine-and iodine-containing dihalofuranones were successfully developed. Suzuki couplings of gem-dihalofuranones were found to proceed with high stereoselectivity.