Eradication of intracellular Francisella tularensis in THP-1 human macrophages with a novel autophagy inducing agent

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Where am I now and where do I want to be? Developing awareness of graduate attributes in pre-honours students.

There is increasing emphasis on the importance of making Graduate Attributes (GAs) explicit to students as part of their degree programme and the role of students themselves in proactively developing GAs. The aim of the present project was to encourage students to actively develop and reflect upon curricular and extra-curricular attributes at an earlier stage in their degree programme. To this end we developed and evaluated short-self-reflection exercises in second year (pre-honours) psychology practical classes which asked students to reflect on their curricular and extra-curricular activities and on how the practical skills gained from these activities are linked to graduate attributes.  Activities were followed by careers workshops focused on gaining confidence in communicating graduate attributes in an interview context, and the benefits of engaging with professional networking sites. We evaluated the impact of these activities on: 1) students’ levels of self-efficacy in specific GAs before and after the in-class exercises; 2) students' confidence in presenting their GAs in an interview situation; 3) student awareness of professional networking sites.  The activities resulted in increased self- efficacy ratings after the GAS reflection, increased confidence in presenting their GAs after the careers workshops, and an increased awareness of professional networking sites. The effectiveness of these activities as a method to increase student engagement in developing their GAs will be discussed in the wider context of embedding GAs and employability in pre-honours programmes across STEM disciplines. Keywords: Graduate attributes, employability, self-efficacy, pre-honours, professional networkin

Reliability of Surgical Margin Labels Using 3D Radiographic Software

Introduction: Surgical resection is a primary treatment for head and neck cancers that improves prognosis and quality of life for patients. Margin assessment is a critical component in this process as positive margins are associated with poor clinical outcomes. However, there is a lack of consensus on how surgical margins should be labeled for accurate origin identification. The objective of this project is to determine the difference in interpretation of surgical margin labels between and within Thomas Jefferson otolaryngologists and pathologists. Methods: Adults with head and neck cancer who underwent surgical resection were identified. Pre-operative head and neck CT DICOM files were obtained, and a 3D segmentation of the tumor was generated and validated by radiology. For each surgical specimen, the pathology report designating the text-based label for each surgical margin was obtained. Study subjects include Thomas Jefferson otolaryngologists and pathologists. Each subject will identify and mark surgical margins on each segmented tumor based on the text-based label. The mean difference for each surgical margin coordinate dimension (x, y, z) will be calculated and compared between and within each group using a paired t-test. Results: Anticipated results include variation in surgical margin origin between and within Thomas Jefferson otolaryngologists and pathologists. Preliminary data indicates lack of significant inter-surgeon reliability in the x dimension (p \u3e 0.02). Discussion: This study demonstrates inconsistent surgical margin labeling interpretation, suggesting a need for optimization and standardization. An optimized protocol has the potential to improve clinical outcomes for patients with head and neck cancers

Acetalated dextran encapsulated AR-12 as a host-directed therapy to control Salmonella infection

AR-12 has been evaluated in clinical trials as an anti-cancer agent but also has demonstrated host-directed, broad-spectrum clearance of bacteria. We have previously shown that AR-12 has activity in vitro against Salmonella enterica serovar Typhimurium and Francisella species by inducing autophagy and other host immune pathways. AR-12 treatment of S. Typhimurium-infected mice resulted in a 10-fold reduction in bacterial load in the liver and spleen and an increased survival time. However, AR-12 treatment did not protect mice from death, likely due poor formulation. In the current study, AR-12 was encapsulated in a microparticulate carrier formulated from the novel degradable biopolymer acetalated dextran (Ace-DEX) and subsequently evaluated for its activity in human monocyte-derived macrophages (hMDMs). Our results show that hMDMs efficiently internalized Ace-DEX microparticles (MPs), and that encapsulation significantly reduced host cell cytotoxicity compared to unencapsulated AR-12. Efficient macrophage internalization of AR-12 loaded MPs (AR-12/MPs) was further demonstrated by autophagosome formation that was comparable to free AR-12 and resulted in enhanced clearance of intracellular Salmonella. Taken together, these studies provide support that Ace-DEX encapsulated AR-12 may be a promising new therapeutic agent to control intracellular bacterial pathogens of macrophages by targeting delivery and reducing drug toxicity

Needle-Free Delivery of Acetalated Dextran-Encapsulated AR-12 Protects Mice from Francisella tularensis Lethal Challenge

ABSTRACT Francisella tularensis causes tularemia and is a potential biothreat. Given the limited antibiotics for treating tularemia and the possible use of antibiotic-resistant strains as a biowarfare agent, new antibacterial agents are needed. AR-12 is an FDA-approved investigational new drug (IND) compound that induces autophagy and has shown host-directed, broad-spectrum activity in vitro against Salmonella enterica serovar Typhimurium and F. tularensis . We have shown that AR-12 encapsulated within acetalated dextran (Ace-DEX) microparticles (AR-12/MPs) significantly reduces host cell cytotoxicity compared to that with free AR-12, while retaining the ability to control S. Typhimurium within infected human macrophages. In the present study, the toxicity and efficacy of AR-12/MPs in controlling virulent type A F. tularensis SchuS4 infection were examined in vitro and in vivo . No significant toxicity of blank MPs or AR-12/MPs was observed in lung histology sections when the formulations were given intranasally to uninfected mice. In histology sections from the lungs of intranasally infected mice treated with the formulations, increased macrophage infiltration was observed for AR-12/MPs, with or without suboptimal gentamicin treatment, but not for blank MPs, soluble AR-12, or suboptimal gentamicin alone. AR-12/MPs dramatically reduced the burden of F. tularensis in infected human macrophages, in a manner similar to that of free AR-12. However, in vivo , AR-12/MPs significantly enhanced the survival of F. tularensis SchuS4-infected mice compared to that seen with free AR-12. In combination with suboptimal gentamicin treatment, AR-12/MPs further improved the survival of F. tularensis SchuS4-infected mice. These studies provide support for Ace-DEX-encapsulated AR-12 as a promising new therapeutic agent for tularemia

RapidPlan Hippocampal Sparing Whole Brain Model Version 2-How far can we reduce the dose?

Whole-brain radiotherapy has been the standard palliative treatment for patients with brain metastases due to its effectiveness, availability, and ease of administration. Recent clinical trials have shown that limiting radiation dose to the hippocampus is associated with decreased cognitive toxicity. In this study, we updated an existing Knowledge Based Planning model to further reduce dose to the hippocampus and improve other dosimetric plan quality characteristics. Forty-two clinical cases were contoured according to guidelines. A new dosimetric scorecard was created as an objective measure for plan quality. The new Hippocampal Sparing Whole Brain Version 2 (HSWBv2) model adopted a complex recursive training process and was validated with five additional cases. HSWBv2 treatment plans were generated on the Varian Halcyo

Overcoming barriers to engaging socio-economically disadvantaged populations in CHD primary prevention: a qualitative study

<p><b>Background:</b> Preventative medicine has become increasingly important in efforts to reduce the burden of chronic disease in industrialised countries. However, interventions that fail to recruit socio-economically representative samples may widen existing health inequalities. This paper explores the barriers and facilitators to engaging a socio-economically disadvantaged (SED) population in primary prevention for coronary heart disease (CHD).</p> <p><b>Methods:</b> The primary prevention element of Have a Heart Paisley (HaHP) offered risk screening to all eligible individuals. The programme employed two approaches to engaging with the community: a) a social marketing campaign and b) a community development project adopting primarily face-to-face canvassing. Individuals living in areas of SED were under-recruited via the social marketing approach, but successfully recruited via face-to-face canvassing. This paper reports on focus group discussions with participants, exploring their perceptions about and experiences of both approaches.</p> <p><b>Results:</b> Various reasons were identified for low uptake of risk screening amongst individuals living in areas of high SED in response to the social marketing campaign and a number of ways in which the face-to-face canvassing approach overcame these barriers were identified. These have been categorised into four main themes: (1) processes of engagement; (2) issues of understanding; (3) design of the screening service and (4) the priority accorded to screening. The most immediate barriers to recruitment were the invitation letter, which often failed to reach its target, and the general distrust of postal correspondence. In contrast, participants were positive about the face-to-face canvassing approach. Participants expressed a lack of knowledge and understanding about CHD and their risk of developing it and felt there was a lack of clarity in the information provided in the mailing in terms of the process and value of screening. In contrast, direct face-to-face contact meant that outreach workers could explain what to expect. Participants felt that the procedure for uptake of screening was demanding and inflexible, but that the drop-in sessions employed by the community development project had a major impact on recruitment and retention.</p> <p><b>Conclusion:</b> Socio-economically disadvantaged individuals can be hard-to-reach; engagement requires strategies tailored to the needs of the target population rather than a population-wide approach.</p&gt

The Oregon Promise Barley Population: A tool for understanding the genetic basis of traits fundamental for barley production, malting, brewing, and distilling

The simultaneous availability of unique germplasm resources and cost-effective high-throughput genotyping allows for accelerated genome exploration and gene discovery. Our germplasm -the Oregon Promise population- is an array of 200 barley doubled haploids developed from the cross of Full Pint x Golden Promise. The spring 2-row parents have contrasting alleles at two of the dwarfing genes deployed in current varieties. The four homozygous combinations of these plant height alleles lead to contrasting phenotypes and each allele has pleiotropic effects on a range of other traits. Golden Promise is an iconic variety for malting, brewing, and distilling; Full Pint is a contributor to the craft brew Renaissance. Accordingly, the Oregon Promise will provide a valuable resource for extending current knowledge of malting and brewing genes to the frontiers of sensory assessment. The population shows transgressive segregation for adult plant resistance to stripe rust. As this disease is likely to become increasingly prevalent as a consequence of climate change, expanding the catalog of genes conferring durable resistance to this pathogen is an essential defensive breeding step. The availability of a quick-turnaround and cost effective SNP genotyping service (400+ markers) at Eureka Genomics (developed in collaboration with the James Hutton Institute) allows accelerated linkage map construction, QTL detection, and unraveling of gene interactions and pleiotropic effects based on the multi-environment, multi-trait phenotyping of the Oregon Promise population. This project is possible thanks to the tools and knowledge generated by the USDA-NIFA T-CAP project.Peer Reviewe

Developing a National Implementation Strategy to accelerate Uptake of Evidence-Based Family Caregiver Support in Us Cancer Centers

OBJECTIVE: Characterize key factors and training needs of U.S. cancer centers in implementing family caregiver support services. METHODS: Sequential explanatory mixed methods design consisting of: (1) a national survey of clinicians and administrators from Commission-on-Cancer-accredited cancer centers (N = 238) on factors and training needed for establishing new caregiver programs and (2) qualitative interviews with a subsample of survey respondents (N = 30) to elicit feedback on survey findings and the outline of an implementation strategy to facilitate implementation of evidence-based family caregiver support (the Caregiver Support Accelerator). Survey data was tabulated using descriptive statistics and transcribed interviews were analyzed using thematic analysis. RESULTS: top factors for developing new caregiver programs were that the program be: consistent with the cancer center\u27s mission and strategic plan (87%), supported by clinic leadership (86.5%) and providers and staff (85.7%), and low cost or cost effective (84.9%). top training needs were how to: train staff to implement programs (72.3%), obtain program materials (63.0%), and evaluate program outcomes (62.6%). Only 3.8% reported that no training was needed. Qualitative interviews yielded four main themes: (1) gaining leadership, clinician, and staff buy-in and support is essential; (2) cost and clinician burden are major factors to program implementation; (3) training should help with adapting and marketing programs to local context and culture; and (4) the Accelerator strategy is comprehensive and would benefit from key organizational partnerships and policy standards. CONCLUSION: Findings will be used to inform and refine the Accelerator implementation strategy to facilitate the adoption and growth of evidence-based cancer caregiver support in U.S. cancer centers