Use of the Post-Insertion Technique to Insert Peptide Ligands into Pre-Formed Stealth Liposomes with Retention of Binding Activity and Cytotoxicity

Purpose: Simple methods for the large-scale manufacture of ligand-targeted liposomes will be needed if clinical trials are to proceed. We tested a recently developed technology for inserting peptide ligands into preformed Stealth liposomes. Antagonist G-targeted liposomes (PLG) were prepared and loaded with doxorubicin and their cellular association and cytotoxicity were evaluated using the human small cell lung cancer H69 cell line

Riparian plant biodiversity reduces stream channel migration rates in three rivers in Michigan, U.S.A.

Recent work has shown that the biodiversity of organisms can influence geophysical processes such as the transport of streambed sediments and the erosion of soils. Yet most of this work has been conducted in smallâ scale fluvial system mimics, demonstrating a clear need to investigate the relationship between biodiversity and erosion in natural systems. We conducted an observational field study across 3 rivers in forested watersheds in northern Michigan, U.S.A., quantifying streambank retreat rates using aerial photos and measuring riparian plant community biodiversity and abundance. We hypothesized that more diverse riparian plant communities would produce greater woody plant stem density and basal area, which in turn would reduce erosion rates of streambanks due to increased root production. We used structural equation modelling to compare causal networks using plant biodiversity metrics to predict streambank migration rate indirectly through effects on plant abundance, as well as models that used migration rate to predict plant abundance indirectly through effects on plant biodiversity. Although structural equation models explained both causal pathways successfully, models using biodiversity to predict migration rate were a better fit to data than models that used migration rate to predict plant biodiversity and abundance. The best performing models suggested plant biodiversity was indirectly negatively correlated with erosion rate (average standardized path coefficient = â 0.22), after accounting for environmental differences between sites. This work adds to a growing body of evidence indicating that biodiversity can modify geophysical processes, demonstrating the need to explicitly account for biological variation when considering ecogeomorphic feedbacks.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/144301/1/eco1972_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/144301/2/eco1972.pd

Checkpoint inhibition of origin firing prevents DNA topological stress.

A universal feature of DNA damage and replication stress in eukaryotes is the activation of a checkpoint-kinase response. In S-phase, the checkpoint inhibits replication initiation, yet the function of this global block to origin firing remains unknown. To establish the physiological roles of this arm of the checkpoint, we analyzed separation of function mutants in the budding yeast Saccharomyces cerevisiae that allow global origin firing upon replication stress, despite an otherwise normal checkpoint response. Using genetic screens, we show that lack of the checkpoint-block to origin firing results in a dependence on pathways required for the resolution of topological problems. Failure to inhibit replication initiation indeed causes increased DNA catenation, resulting in DNA damage and chromosome loss. We further show that such topological stress is not only a consequence of a failed checkpoint response but also occurs in an unperturbed S-phase when too many origins fire simultaneously. Together we reveal that the role of limiting the number of replication initiation events is to prevent DNA topological problems, which may be relevant for the treatment of cancer with both topoisomerase and checkpoint inhibitors

STepped exercise program for patients with knee OsteoArthritis (STEP-KOA): protocol for a randomized controlled trial

Background: Physical therapy (PT) and other exercise-based interventions are core components of care for knee osteoarthritis (OA), but both are underutilized, and some patients have limited access to PT services. This clinical trial is examining a STepped Exercise Program for patients with Knee OsteoArthritis (STEP-KOA). This model of care can help to tailor exercise-based interventions to patient needs and also conserve higher resource services (such as PT) for patients who do not make clinically relevant improvements after receiving less costly interventions. Methods / Design: Step-KOA is a randomized trial of 345 patients with symptomatic knee OA from two Department of Veterans Affairs sites. Participants are randomized to STEP-KOA and Arthritis Education (AE) Control groups with a 2:1 ratio, respectively. STEP-KOA begins with 3 months of access to an internet-based exercise program (Step 1). Participants not meeting response criteria for clinically meaningful improvement in pain and function after Step 1 progress to Step 2, which involves bi-weekly physical activity coaching calls for 3 months. Participants not meeting response criteria after Step 2 progress to in-person PT visits (Step 3). Outcomes will be assessed at baseline, 3, 6 and 9 months (primary outcome time point). The primary outcome is the Western Ontario and McMasters Universities Osteoarthritis Index (WOMAC), and secondary outcomes are objective measures of physical function. Linear mixed models will compare outcomes between the STEP-KOA and AE control groups at follow-up. We will also evaluate patient characteristics associated with treatment response and conduct a cost-effectiveness analysis of STEP-KOA. Discussion: STEP-KOA is a novel, efficient and patient-centered approach to delivering exercise-based interventions to patients with knee OA, one of the most prevalent and disabling health conditions. This trial will provide information on the effectiveness of STEP-KOA as a novel potential model of care for treatment of OA

Adaptive capacity beyond the household: a systematic review of empirical social-ecological research

The concept of adaptive capacity has received significant attention within social-ecological and environmental change research. Within both the resilience and vulnerability literatures specifically, adaptive capacity has emerged as a fundamental concept for assessing the ability of social-ecological systems to adapt to environmental change. Although methods and indicators used to evaluate adaptive capacity are broad, the focus of existing scholarship has predominately been at the individual- and household- levels. However, the capacities necessary for humans to adapt to global environmental change are often a function of individual and societal characteristics, as well as cumulative and emergent capacities across communities and jurisdictions. In this paper, we apply a systematic literature review and co-citation analysis to investigate empirical research on adaptive capacity that focus on societal levels beyond the household. Our review demonstrates that assessments of adaptive capacity at higher societal levels are increasing in frequency, yet vary widely in approach, framing, and results; analyses focus on adaptive capacity at many different levels (e.g. community, municipality, global region), geographic locations, and cover multiple types of disturbances and their impacts across sectors. We also found that there are considerable challenges with regard to the ‘fit’ between data collected and analytical methods used in adequately capturing the cross-scale and cross-level determinants of adaptive capacity. Current approaches to assessing adaptive capacity at societal levels beyond the household tend to simply aggregate individual- or household-level data, which we argue oversimplifies and ignores the inherent interactions within and across societal levels of decision-making that shape the capacity of humans to adapt to environmental change across multiple scales. In order for future adaptive capacity research to be more practice-oriented and effectively guide policy, there is a need to develop indicators and assessments that are matched with the levels of potential policy applications

Mindfulness-Based Stress Reduction in Women with Overweight or Obesity: A Randomized Clinical Trial.

OBJECTIVE: To evaluate the feasibility and cardiometabolic effects of mindfulness-based stress reduction (MBSR) in women with overweight or obesity. METHODS: Eighty-six women with BMI ≥ 25 kg/m RESULTS: Compared to health education, the MBSR group demonstrated significantly improved mindfulness at 8 weeks (mean change from baseline, 4.5 vs. -1.0; P = 0.03) and significantly decreased perceived stress at 16 weeks (-3.6 vs. -1.3, P = 0.01). In the MBSR group, there were significant reductions in fasting glucose at 8 weeks (-8.9 mg/dL, P = 0.02) and at 16 weeks (-9.3 mg/dL, P = 0.02) compared to baseline. Fasting glucose did not significantly improve in the health education group. There were no significant changes in blood pressure, weight, or insulin resistance in the MBSR group. CONCLUSIONS: In women with overweight or obesity, MBSR significantly reduces stress and may have beneficial effects on glucose. Future studies demonstrating long-term cardiometabolic benefits of MBSR will be key for establishing MBSR as an effective tool in the management of obesity

Non-Compliance with Growth Hormone Treatment in Children Is Common and Impairs Linear Growth

BACKGROUND: GH therapy requires daily injections over many years and compliance can be difficult to sustain. As growth hormone (GH) is expensive, non-compliance is likely to lead to suboptimal growth, at considerable cost. Thus, we aimed to assess the compliance rate of children and adolescents with GH treatment in New Zealand. METHODS: This was a national survey of GH compliance, in which all children receiving government-funded GH for a four-month interval were included. Compliance was defined as ≥ 85% adherence (no more than one missed dose a week on average) to prescribed treatment. Compliance was determined based on two parameters: either the number of GH vials requested (GHreq) by the family or the number of empty GH vials returned (GHret). Data are presented as mean ± SEM. FINDINGS: 177 patients were receiving GH in the study period, aged 12.1 ± 0.6 years. The rate of returned vials, but not number of vials requested, was positively associated with HVSDS (p < 0.05), such that patients with good compliance had significantly greater linear growth over the study period (p<0.05). GHret was therefore used for subsequent analyses. 66% of patients were non-compliant, and this outcome was not affected by sex, age or clinical diagnosis. However, Maori ethnicity was associated with a lower rate of compliance. INTERPRETATION: An objective assessment of compliance such as returned vials is much more reliable than compliance based on parental or patient based information. Non-compliance with GH treatment is common, and associated with reduced linear growth. Non-compliance should be considered in all patients with apparently suboptimal response to GH treatment