Targeting DNA topoisomerase IIα ( TOP2A ) in the hypoxic tumour microenvironment using unidirectional hypoxia‐activated prodrugs ( uHAPs )

The hypoxic tumour microenvironment (hTME), arising from inadequate and chaotic vascularity, can present a major obstacle for the treatment of solid tumours. Hypoxic tumour cells compromise responses to treatment since they can generate resistance to radiotherapy, chemotherapy and immunotherapy. The hTME impairs the delivery of a range of anti-cancer drugs, creates routes for metastasis and exerts selection pressures for aggressive phenotypes; these changes potentially occur within an immunosuppressed environment. Therapeutic strategies aimed at the hTME include targeting the molecular changes associated with hypoxia. An alternative approach is to exploit the prevailing lack of oxygen as a principle for the selective activation of prodrugs to target cellular components within the hTME. This review focuses on the design concepts and rationale for the use of unidirectional Hypoxia-Activated Prodrugs (uHAPs) to target the hTME as exemplified by the uHAPs AQ4N and OCT1002. These agents undergo irreversible reduction in a hypoxic environment to active forms that target DNA topoisomerase IIα (TOP2A). This nuclear enzyme is essential for cell division and is a recognised chemotherapeutic target. An activated uHAP interacts with the enzyme-DNA complex to induce DNA damage, cell cycle arrest and tumour cell death. uHAPs are designed to overcome the shortcomings of conventional HAPs and offer unique pharmacodynamic properties for effective targeting of TOP2A in the hTME. uHAP therapy in combination with standard of care treatments has the potential to enhance outcomes by co-addressing the therapeutic challenge presented by the hTME

Remote Teaching of Publication-Quality, Single-Case Graphs in Microsoft Excel

Microsoft Excel is ubiquitous, cost-effective, and can be used to create publication-quality single-case design graphs. We systematically replicated the GraphPad Prism video tutorial by Mitteer et al. (2018) to teach 24 master\u27s students to create multiple-baseline graphs using Excel 2016. Students\u27 mean accuracy on the multiple-baseline graph was 25% in pretraining, 86% with the video tutorial, and 96% with the review checklist. Next, students used the same video tutorial to create multielement and reversal graphs. Students\u27 mean accuracy on the multielement graph was 93% with video tutorial and 94% with review checklist, and accuracy on the reversal graph was 82% with video tutorial and 94% with review checklist. Students reported moderate to high satisfaction with both training components. The results support scientist-practitioners using the video tutorial and review checklists to create three common graphs using Excel 2016, Excel 2019, and Excel Office 365

The design, delivery and evaluation of ‘Human Perspectives VR’: An immersive educational programme designed to raise awareness of contributory factors for a traumatic childbirth experience and PTSD

Background A traumatic childbirth experience affects ~30% of women each year, with negative impacts on maternal, infant, and family wellbeing. Women classified as vulnerable or marginalised are those more likely to experience a psychologically traumatising birth. A key contributory factor for a traumatic childbirth experience is women’s relationships with maternity care providers. Aims To develop, design and evaluate an immersive educational programme for maternity care providers to raise awareness of traumatic childbirth experiences amongst vulnerable groups, and ultimately to improve women’s experiences of childbirth. Methods A critical pedagogical approach that utilised virtual reality (VR) underpinned the design and development of the educational programme. This involved: a) collecting vulnerable/disadvantaged women’s experiences of birth via interviews; b) analysing data collected to identify key hotspots for traumatic experiences within interpersonal patient – provider relationships to develop a script; c) filming the script with professional actors creating a first person perspective via VR technology; d) using existing literature to inform the theoretical and reflective aspects of the programme; e) conducting an evaluation of the education programme using pre-and post-evaluation questionnaires and a follow-up focus group. Findings Human Perspective VR was very well received. Participants considered the content to have enhanced their reflective practice and increased their knowledge base regarding contributory factors associated with a traumatic childbirth experience. A need for further work to implement learning into practice was highlighted. Conclusion While further research is needed to evaluate the impact of the programme, Human Perspective VR programme offers an innovative approach to reflective education and to enhance participants’ care practices

Targeting Hypoxic Prostate Tumors Using the Novel Hypoxia-Activated Prodrug OCT1002 Inhibits Expression of Genes Associated with Malignant Progression

Purpose: To understand the role of hypoxia in prostate tumor progression and to evaluate the ability of the novel unidirectional hypoxia-activated prodrug OCT1002 to enhance the antitumor effect of bicalutamide. Experimental Design: The effect of OCT1002 on prostate cancer cells (LNCaP, 22Rv1, and PC3) was measured in normoxia and hypoxia in vitro. In vivo, tumor growth and lung metastases were measured in mice treated with bicalutamide, OCT1002, or a combination. Dorsal skin fold chambers were used to image tumor vasculature in vivo. Longitudinal gene expression changes in tumors were analyzed using PCR. Results: Reduction of OCT1002 to its active form (OCT1001) decreased prostate cancer cell viability. In LNCaP-luc spheroids, OCT1002 caused increased apoptosis and decreased clonogenicity. In vivo, treatment with OCT1002 alone, or with bicalutamide, showed significantly greater tumor growth control and reduced lung metastases compared with controls. Reestablishment of the tumor microvasculature following bicalutamide-induced vascular collapse is inhibited by OCT1002. Significantly, the upregulation of RUNX2 and its targets caused by bicalutamide alone was blocked by OCT1002. Conclusions: OCT1002 selectively targets hypoxic tumor cells and enhances the antitumor efficacy of bicalutamide. Furthermore, bicalutamide caused changes in gene expression, which indicated progression to a more malignant genotype; OCT1002 blocked these effects, emphasizing that more attention should be attached to understanding genetic changes that may occur during treatment. Early targeting of hypoxic cells with OCT1002 can provide a means of inhibiting prostate tumor growth and malignant progression. This is of importance for the design and refinement of existing androgen-deprivation regimens in the clinic

Indicators of pulmonary exacerbation in cystic fibrosis: A Delphi survey of patients and health professionals

Background: There is uncertainty about the most important indicators of pulmonary exacerbations in CF. Methods: Two parallel Delphi surveys in 13 CF centres (UK and Ireland). Delphi 1: 31 adults with CF, ≥ one exacerbation over 12 months. Delphi 2: 38 CF health professionals. Rounds 1 and 2 participants rated their level of agreement with statements relating to indicators of exacerbation; Round 3 participants rated the importance of statements which were subsequently placed in rank order. Results: Objective measurements were of higher importance to health professionals. Feelings of increased debility were rated most important by adults with CF. Conclusions: There were clear differences in perspectives between the two groups as to the most important indicators of an exacerbation. This highlights that CF health professionals should take more cognisance of specific signs and symptoms reported by adults with CF, especially since these may be a precursor to an exacerbation

The unidirectional hypoxia-activated prodrug OCT1002 inhibits growth and vascular development in castrate-resistant prostate tumors

Background OCT1002 is a unidirectional hypoxia-activated prodrug (uHAP) OCT1002 that can target hypoxic tumor cells. Hypoxia is a common feature in prostate tumors and is known to drive disease progression and metastasis. It is, therefore, a rational therapeutic strategy to directly target hypoxic tumor cells in an attempt to improve treatment for this disease. Here we tested OCT1002 alone and in combination with standard-of-care agents in hypoxic models of castrate-resistant prostate cancer (CRPC). Methods The effect of OCT1002 on tumor growth and vasculature was measured using murine PC3 xenograft and dorsal skin fold (DSF) window chamber models. The effects of abiraterone, docetaxel, and cabazitaxel, both singly and in combination with OCT1002, were also compared. Results The hypoxia-targeting ability of OCT1002 effectively controls PC3 tumor growth. The effect was evident for at least 42 days after exposure to a single dose (30 mg/kg) and was comparable to, or better than, drugs currently used in the clinic. In DSF experiments OCT1002 caused vascular collapse in the PC3 tumors and inhibited the revascularization seen in controls. In this model OCT1002 also enhanced the anti-tumor effects of abiraterone, cabazitaxel, and docetaxel; an effect which was accompanied by a more prolonged reduction in tumor vasculature density. Conclusions These studies provide the first evidence that OCT1002 can be an effective agent in treating hypoxic, castrate-resistant prostate tumors, either singly or in combination with established chemotherapeutics for prostate cancer

What outcomes are important to patients with mild cognitive impairment or Alzheimer's disease, their caregivers, and health-care professionals? A systematic review

Introduction: Clinical trials involving patients with Alzheimer’s disease (AD) continue to try to identify disease-modifying treatments. Although trials are designed to meet regulatory and registration requirements, many do not measure outcomes of the disease most relevant to key stakeholders. Methods: A systematic review sought research that elicited information from people with AD, their caregivers, and health-care professionals on which outcomes of the disease were important. Studies published in any language between 2008 and 2017 were included. Results: Participants in 34 studies described 32 outcomes of AD. These included clinical (memory, mental health), practical (ability to undertake activities of daily living, access to health information), and personal (desire for patient autonomy, maintenance of identity) outcomes of the disease. Discussion: Evidence elicited directly from the people most affected by AD reveals a range of disease outcomes that are relevant to them but are not commonly captured in clinical trials of new treatments.</br