Exenatide once weekly versus placebo in Parkinson's disease: a randomised, double-blind, placebo-controlled trial

BACKGROUND: Exenatide, a glucagon-like peptide-1 (GLP-1) receptor agonist, has neuroprotective effects in preclinical models of Parkinson's disease. We investigated whether these effects would be apparent in a clinical trial. METHODS: In this single-centre, randomised, double-blind, placebo-controlled trial, patients with moderate Parkinson's disease were randomly assigned (1:1) to receive subcutaneous injections of exenatide 2 mg or placebo once weekly for 48 weeks in addition to their regular medication, followed by a 12-week washout period. Eligible patients were aged 25-75 years, had idiopathic Parkinson's disease as measured by Queen Square Brain Bank criteria, were on dopaminergic treatment with wearing-off effects, and were at Hoehn and Yahr stage 2·5 or less when on treatment. Randomisation was by web-based randomisation with a two strata block design according to disease severity. Patients and investigators were masked to treatment allocation. The primary outcome was the adjusted difference in the Movement Disorders Society Unified Parkinson's Disease Rating Scale (MDS-UPDRS) motor subscale (part 3) in the practically defined off-medication state at 60 weeks. All efficacy analyses were based on a modified intention-to-treat principle, which included all patients who completed any post-randomisation follow-up assessments. The study is registered at ClinicalTrials.gov (NCT01971242) and is completed. FINDINGS: Between June 18, 2014, and March 13, 2015, 62 patients were enrolled and randomly assigned, 32 to exenatide and 30 to placebo. Our primary analysis included 31 patients in the exenatide group and 29 patients in the placebo group. At 60 weeks, off-medication scores on part 3 of the MDS-UPDRS had improved by 1·0 points (95% CI -2·6 to 0·7) in the exenatide group and worsened by 2·1 points (-0·6 to 4·8) in the placebo group, an adjusted mean difference of -3·5 points (-6·7 to -0·3; p=0·0318). Injection site reactions and gastrointestinal symptoms were common adverse events in both groups. Six serious adverse events occurred in the exenatide group and two in the placebo group, although none in either group were judged to be related to the study interventions. INTERPRETATION: Exenatide had positive effects on practically defined off-medication motor scores in Parkinson's disease, which were sustained beyond the period of exposure. Whether exenatide affects the underlying disease pathophysiology or simply induces long-lasting symptomatic effects is uncertain. Exenatide represents a major new avenue for investigation in Parkinson's disease, and effects on everyday symptoms should be examined in longer-term trials. FUNDING: Michael J Fox Foundation for Parkinson's Research

A three-drug nanoscale drug delivery system designed for preferential lymphatic uptake for the treatment of metastatic melanoma

Metastatic melanoma has a high mortality rate due to lymphatic progression of the disease. Current treatment is surgery followed by radiation and intravenous chemotherapy. However, drawbacks for current chemotherapeutics lie in the fact that they develop resistance and do not achieve therapeutic concentrations in the lymphatic system. We hypothesize that a three-drug nanoscale drug delivery system, tailored for lymphatic uptake, administered subcutaneously, will have decreased drug resistance and therefore offer better therapeutic outcomes. We prepared and characterized nanoparticles (NPs) with docetaxel, everolimus, and LY294002 in polyethyleneglycol-block-poly(ε-caprolactone) (PEG-PCL) polymer with different charge distributions by modifying the ratio of anionic and neutral end groups on the PEG block. These NPs are similarly sized (~48nm), with neutral, partially charged, or fully charged surface. The NPs are able to load ~2mg/mL of each drug and are stable for 24h. The NPs are assessed for safety and efficacy in two transgenic metastatic melanoma mouse models. All the NPs were safe in both models based on general appearance, weight changes, death, and blood biochemical analyses. The partially charged NPs are most effective in decreasing the number of melanocytes at both the proximal (sentinel) lymph node (LN) and the distal LN from the injection site. The neutral NPs are efficacious at the proximal LN, while the fully charged NPs have no effect on either LNs. Thus, our data indicates that the NP surface charge and lymphatic efficacy are closely tied to each other and the partially charged NPs have the highest potential in treating metastatic melanoma

Demonstration of a laserwire emittance scanner for hydrogen ion beams at CERN

A non-invasive, compact laserwire system has been developed to measure the transverse emittance of an H- beam and has been demonstrated at the new LINAC4 injector for the LHC at CERN. Light from a low power, pulsed laser source is conveyed via fibre to collide with the H- beam, a fraction of which is neutralized and then intercepted by a downstream diamond detector. Scanning the focused laser across the H- beam and measuring the distribution of the photo-neutralized particles enables the transverse emittance to be reconstructed. The vertical phase-space distribution of a 3 MeV beam during LINAC4 commissioning has been measured by the laserwire and verified with a conventional slit and grid method.Comment: 10 pages, 13 figures, to be published in Physical Review Special Topics - Accelerators and Beam

Distinct stem cells subpopulations isolated from human adipose tissue exhibit different chondrogenic and osteogenic differentiation potential

Recently adipose tissue has become a research topic also for the searching for an alternative stem cells source to use in cell based therapies such as tissue engineer. In fact Adipose Stem Cells (ASCs) exhibit an important differentiation potential for several cell lineages such as chondrogenic, osteogenic, myogenic, adipogenic and endothelial cells. ASCs populations isolated using standard methodologies (i.e., based on their adherence ability) are very heterogeneous but very few studies have analysed this aspect. Consequently, several questions are still pending, as for example, on what regard the existence/ or not of distinct ASCs subpopulations. The present study is originally aimed at isolating selected ASCs subpopulations, and to analyse their behaviour towards the heterogeneous population regarding the expression of stem cell markers and also regarding their osteogenic and chondrogenic differentiation potential. Human Adipose derived Stem Cells (hASCs) subpopulations were isolated using immunomagnetic beads coated with several different antibodies (CD29, CD44, CD49d, CD73, CD90, CD 105, Stro-1 and p75) and were characterized by Real Time RT-PCR in order to assess the expression of mesenchymal stem cells markers (CD44, CD73, Stro-1, CD105 and CD90) as well as known markers of the chondrogenic (Sox 9, Collagen II) and osteogenic lineage (Osteopontin, Osteocalcin). The obtained results underline the complexity of the ASCs population demonstrating that it is composed of several subpopulations, which express different levels of ASCs markers and exhibit distinctive differentiation potentials. Furthermore, the results obtained clearly evidence of the advantages of using selected populations in cell-based therapies, such as bone and cartilage regenerative medicine approaches.EU funded Marie Curie Actions Alea Jacta Est for a PhD fellowship. This work was carried out under the scope of the European NoE EXPERTISSUES (NMP3-CT-2004-500283)

MulTI-domain self-management in older People wiTh OstEoarthritis and multi-morbidities: protocol for the TIPTOE randomised controlled trial

Background Four out of five people living with osteoarthritis (OA) also suffer with at least one other long-term health condition. The complex interaction between OA and multiple long-term conditions (MLTCs) can result in difficulties with self-care, restricted mobility, pain, anxiety, depression and reduced quality of life. The aim of the MulTI-domain Self-management in Older People wiTh OstEoarthritis and Multi-Morbidities (TIPTOE) trial is to evaluate the clinical and cost-effectiveness of the Living Well self-management support intervention, co-designed with people living with OA, integrated into usual care, in comparison to usual care alone. Methods TIPTOE is a multi-centre, two-arm, individually randomised controlled trial where 824 individuals over 65 years old with knee and/or hip joint pain from their OA affected joint and at least one other long-term health condition will be randomised to receive either the Living Well Self-Management support intervention or usual care. Eligible participants can self-refer onto the trial via a website or be referred via NHS services across Wales and England. Those randomised to receive the Living Well support intervention will be offered up to six one-to-one coaching sessions with a TIPTOE-trained healthcare practitioner and a co-designed book. Participants will be encouraged to nominate a support person to assist them throughout the study. All participants will complete a series of self-reported outcome measures at baseline and 6- and 12-month follow-up. The primary outcome is symptoms and quality of life as assessed by the Musculoskeletal Health Questionnaire (MSK-HQ). Routine data will be used to evaluate health resource use. A mixed methods process evaluation will be conducted alongside the trial to inform future implementation should the TIPTOE intervention be found both clinically and cost-effective. An embedded ‘Study Within A Project’ (SWAP) will explore and address barriers to the inclusion of under-served patient groups (e.g. oldest old, low socioeconomic groups, ethnic groups). Discussion TIPTOE will evaluate the clinical and cost-effectiveness of a co-designed, living well personalised self-management support intervention for older individuals with knee and/or hip OA and MLTCs. The trial has been designed to maximise inclusivity and access. Trial registration ISRCTN 16024745. Registered on October 16, 2023