177 research outputs found

    Preclinical Evaluation of Novel All-in-one Formulations of 5-Fluorouracil and Folinic Acid with Reduced Toxicity Profiles - Supplementary Data

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    Objectives: 5-Fluorouracil (5-FU) in combination with its synergistic biomodulator folinic acid maintains a pivotal position in cancer chemotherapy. However, clinical limitations persist with the administration of these drugs in combination including phlebitis and catheter blockages, which are associated with reduced efficacy and/or quality of life for patients. We have previously reported novel all-in-one, pH neutral, parenteral 5-FU and folinic acid formulations (termed Fluorodex) incorporating beta-cyclodextrins. Fluorodex maintains potency while overcoming the accepted incompatibility of 5-FU and folinic acid.Methods: We performed toxicological, pharmacokinetic and biodistribution, and efficacy evaluations of Fluorodex compared to 5-FU:folinic acid using several administration routes and schedules in two rodent models. These were compared to dose-matched sequential administration of 5-FU:folinic acid.Results: Fluorodex showed bioequivalence to 5-FU:folinic acid as assessed by tissue distribution and pharmacokinetics of 5-FU, but was generally better tolerated as determined by weight loss, hematological and other clinical parameters. Compared to 5-FU:folinic acid, Fluorodex was also associated with reduced phlebitis using a rabbit ear vein model. Furthermore, equivalent to enhanced efficacy of Fluorodex compared to 5-FU:folinic acid against human carcinoma tumour models in mice was observed.Conclusions: These novel all-in-one formulations represent a superior injectable form of 5- FU that allows co-delivery of folinic acid. This should translate to improved patient tolerability with potential for enhanced efficacy

    Gawky is a component of cytoplasmic mRNA processing bodies required for early Drosophila development

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    In mammalian cells, the GW182 protein localizes to cytoplasmic bodies implicated in the regulation of messenger RNA (mRNA) stability, translation, and the RNA interference pathway. Many of these functions have also been assigned to analogous yeast cytoplasmic mRNA processing bodies. We have characterized the single Drosophila melanogaster homologue of the human GW182 protein family, which we have named Gawky (GW). Drosophila GW localizes to punctate, cytoplasmic foci in an RNA-dependent manner. Drosophila GW bodies (GWBs) appear to function analogously to human GWBs, as human GW182 colocalizes with GW when expressed in Drosophila cells. The RNA-induced silencing complex component Argonaute2 and orthologues of LSm4 and Xrn1 (Pacman) associated with 5′–3′ mRNA degradation localize to some GWBs. Reducing GW activity by mutation or antibody injection during syncytial embryo development leads to abnormal nuclear divisions, demonstrating an early requirement for GWB-mediated cytoplasmic mRNA regulation. This suggests that gw represents a previously unknown member of a small group of genes that need to be expressed zygotically during early embryo development

    Probing Molecular Shape. 1. Conformational Studies of 5-Hydroxyhexahydropyrimidine and Related Compounds

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    Understanding the factors that determine molecular shape enables scientists to begin to understand and tailor molecular properties and reactivity. Many biomolecules and bioactive compounds contain aliphatic heterocyclic rings whose conformations play a major role in their biological activity. The interplay of a number of factors, both steric and electronic, is examined for 5-hydroxyhexahydropyrimidine (1) and related compounds with use of spectroscopy and molecular modeling

    Probing Molecular Shape. 1. Conformational Studies of 5-Hydroxyhexahydropyrimidine and Related Compounds

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    Understanding the factors that determine molecular shape enables scientists to begin to understand and tailor molecular properties and reactivity. Many biomolecules and bioactive compounds contain aliphatic heterocyclic rings whose conformations play a major role in their biological activity. The interplay of a number of factors, both steric and electronic, is examined for 5-hydroxyhexahydropyrimidine (1) and related compounds with use of spectroscopy and molecular modeling

    Recruitment, Retention, and Future Direction for a Heart Health Education and Risk Reduction Intervention Led by Community Health Workers in an African American Majority City

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    Heart disease is a leading cause of death for African Americans. A community-academic partnership cross-trained community health workers to engage African American adults in a 6-month heart health education and risk reduction intervention. We conducted a one-group feasibility study using a one group (pre-posttest) design. A total of 100 adults were recruited from 27 zip codes in an African American majority city through community-based organizations (46%), churches (36%), and home visits (12%). Ninety-six percent were African American; 55% were female, 39% were male, and 6% were transgender. Their mean age was 44.6 years (SD=15.9). Ninety-two percent had health insurance. Seventy-six percent of participants averaged blood pressure (BP) readings\u3e130/80 mmHg. Eleven percent of participants had a 30% or higher probability of developing cardiovascular disease in the next 10 years. Six-month follow-up was completed with 96% of participants. There were statistically significant increases in knowledge and in perception of personal risk for heart disease. However, slightly more participants (n=77, 80.2%) had BP\u3e130/80 mmHg. The Community Advisory Group recommended expanding the intervention to 12 months and incorporating telehealth with home BP monitoring. Limited intervention duration did not meet longer term objectives such as better control of high BP and sharing risk reduction planning with primary care providers

    Curating Nasa's Future Extraterrestrial Sample Collections: the Role of Advanced Curation

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    The Astromaterials Acquisition and Curation Office at NASA Johnson Space Center (JSC) (henceforth referred to herein as NASA Curation Office) is responsible for curating all of NASA's extraterrestrial samples. Under the governing document, NASA Policy Directive (NPD) 7100.10F "Curation of Extraterrestrial Materials," JSC is charged with "The curation of all extraterrestrial material under NASA control, including future NASA missions." The Directive goes on to define Curation as including "...documentation, preservation, preparation, and distribution of samples for re-search, education, and public outreach." Here we describe some of the ongoing efforts to ensure that the future activities of the NASA Curation Office are working towards a state of maximum proficiency

    Peer-led walking programme to increase physical activity in inactive 60- to 70-year-olds: Walk with Me pilot RCT

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    Background Levels of physical activity decline with age. Some of the most disadvantaged individuals in society, such as those with a lower rather than a higher socioeconomic position, are also the most inactive. Peer-led physical activity interventions may offer a model to increase physical activity in these older adults and thus help reduce associated health inequalities. This study aims to develop and test the feasibility of a peer-led, multicomponent physical activity intervention in socioeconomically disadvantaged community-dwelling older adults. Objectives The study aimed to develop a peer-led intervention through a rapid review of previous peer-led interventions and interviews with members of the target population. A proposed protocol to evaluate its effectiveness was tested in a pilot randomised controlled trial (RCT). Design A rapid review of the literature and the pilot study informed the intervention design; a pilot RCT included a process evaluation of intervention delivery. Setting Socioeconomically disadvantaged communities in the South Eastern Health and Social Care Trust and the Northern Health and Social Care Trust in Northern Ireland. Participants Fifty adults aged 60–70 years, with low levels of physical activity, living in socioeconomically disadvantaged communities, recruited though community organisations and general practices. Interventions ‘Walk with Me’ is a 12-week peer-led walking intervention based on social cognitive theory. Participants met weekly with peer mentors. During the initial period (weeks 1–4), each intervention group participant wore a pedometer and set weekly step goals with their mentor’s support. During weeks 5–8 participants and mentors met regularly to walk and discuss step goals and barriers to increasing physical activity. In the final phase (weeks 9–12), participants and mentors continued to set step goals and planned activities to maintain their activity levels beyond the intervention period. The control group received only an information booklet on active ageing. Main outcome measures Rates of recruitment, retention of participants and completeness of the primary outcome [moderate- and vigorous-intensity physical activity measured using an ActiGraph GT3X+ accelerometer (ActiGraph, LLC, Pensacola, FL, USA) at baseline, 12 weeks (post intervention) and 6 months]; acceptability assessed through interviews with participants and mentors. Results The study planned to recruit 60 participants. In fact, 50 eligible individuals participated, of whom 66% (33/50) were female and 80% (40/50) were recruited from general practices. At 6 months, 86% (43/50) attended for review, 93% (40/43) of whom returned valid accelerometer data. Intervention fidelity was assessed by using weekly step diaries, which were completed by both mentors and participants for all 12 weeks, and checklists for the level of delivery of intervention components, which was high for the first 3 weeks (range 49–83%). However, the rate of return of checklists by both mentors and participants diminished thereafter. Outcome data indicate that a sample size of 214 is required for a definitive trial. Limitations The sample was predominantly female and somewhat active. Conclusions The ‘Walk with Me’ intervention is acceptable to a socioeconomically disadvantaged community of older adults and a definitive RCT to evaluate its effectiveness is feasible. Some modifications are required to ensure fidelity of intervention delivery is optimised. Future research needs to identify methods to recruit males and less active older adults into physical activity interventions

    Association of Accelerometry-Measured Physical Activity and Cardiovascular Events in Mobility-Limited Older Adults: The LIFE (Lifestyle Interventions and Independence for Elders) Study.

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    BACKGROUND:Data are sparse regarding the value of physical activity (PA) surveillance among older adults-particularly among those with mobility limitations. The objective of this study was to examine longitudinal associations between objectively measured daily PA and the incidence of cardiovascular events among older adults in the LIFE (Lifestyle Interventions and Independence for Elders) study. METHODS AND RESULTS:Cardiovascular events were adjudicated based on medical records review, and cardiovascular risk factors were controlled for in the analysis. Home-based activity data were collected by hip-worn accelerometers at baseline and at 6, 12, and 24 months postrandomization to either a physical activity or health education intervention. LIFE study participants (n=1590; age 78.9±5.2 [SD] years; 67.2% women) at baseline had an 11% lower incidence of experiencing a subsequent cardiovascular event per 500 steps taken per day based on activity data (hazard ratio, 0.89; 95% confidence interval, 0.84-0.96; P=0.001). At baseline, every 30 minutes spent performing activities ≥500 counts per minute (hazard ratio, 0.75; confidence interval, 0.65-0.89 [P=0.001]) were also associated with a lower incidence of cardiovascular events. Throughout follow-up (6, 12, and 24 months), both the number of steps per day (per 500 steps; hazard ratio, 0.90, confidence interval, 0.85-0.96 [P=0.001]) and duration of activity ≥500 counts per minute (per 30 minutes; hazard ratio, 0.76; confidence interval, 0.63-0.90 [P=0.002]) were significantly associated with lower cardiovascular event rates. CONCLUSIONS:Objective measurements of physical activity via accelerometry were associated with cardiovascular events among older adults with limited mobility (summary score >10 on the Short Physical Performance Battery) both using baseline and longitudinal data. CLINICAL TRIAL REGISTRATION:URL: http://www.clinicaltrials.gov. Unique identifier: NCT01072500
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