Enhancement of chemotherapy using oncolytic virotherapy: Mathematical and optimal control analysis

Oncolytic virotherapy (OV) has been emerging as a promising novel cancer treatment that may be further combined with the existing therapeutic modalities to enhance their effects. To investigate how OV could enhance chemotherapy, we propose an ODE based model describing the interactions between tumour cells, the immune response, and a treatment combination with chemotherapy and oncolytic viruses. Stability analysis of the model with constant chemotherapy treatment rates shows that without any form of treatment, a tumour would grow to its maximum size. It also demonstrates that chemotherapy alone is capable of clearing tumour cells provided that the drug efficacy is greater than the intrinsic tumour growth rate. Furthermore, OV alone may not be able to clear tumour cells from body tissue but would rather enhance chemotherapy if viruses with high viral potency are used. To assess the combined effect of OV and chemotherapy we use the forward sensitivity index to perform a sensitivity analysis, with respect to chemotherapy key parameters, of the virus basic reproductive number and the tumour endemic equilibrium. The results from this sensitivity analysis indicate the existence of a critical dose of chemotherapy above which no further significant reduction in the tumour population can be observed. Numerical simulations show that a successful combinational therapy of the chemotherapeutic drugs and viruses depends mostly on the virus burst size, infection rate, and the amount of drugs supplied. Optimal control analysis was performed, by means of Pontryagin's principle, to further refine predictions of the model with constant treatment rates by accounting for the treatment costs and sides effects.Comment: This is a preprint of a paper whose final and definite form is with 'Mathematical Biosciences and Engineering', ISSN 1551-0018 (print), ISSN 1547-1063 (online), available at [http://www.aimsciences.org/journal/1551-0018]. Submitted 27-March-2018; revised 04-July-2018; accepted for publication 10-July-201

A Tailored Systems Engineering Framework for Science and Technology Projects

As government and industry becomes subject to a wider range of technology initiatives, science and technology (S&T) research project leadership recognizes the need to incorporate more systems engineering (SE) rigor into their projects. The objective of this research is to develop a tailorable systems engineering framework for S&T project planning, execution, assessment and transition. The key deliverable is an Excel-based tool instantiating the SE framework for a wide range of S&T projects in technology development organizations. It includes a report with tailored methods based on programmatic discriminants. To develop this framework, a comprehensive understanding of SE principles is applied to several case studies across government and supporting industry-sponsored S&T activities. This research followed a six-step approach: (1) Literature Review; (2) Formulate Taxonomy; (3) Prepare Data Gathering Approach; (4) Review Case Studies; (5) Develop Tailorable SE Framework for Technology Development and Transition; and (6) Validate Framework.The framework allows S&T project leaders and engineers to customize a recommended set of SE processes, methods and tools for their specific project type, size, maturity, budget, and integration level. Recommendations for SE methods are made at a summary level, with additional details available for desired activities. References to established SE documentation is also included for further investigation of appropriate SE techniques

The narrative potential of the British Birth Cohort Studies

This paper draws attention to the narrative potential of longitudinal studies such as the British Birth Cohort Studies (BBCS), and explores the possibility of creating narrative case histories and conducting narrative analysis based on information available from the studies. The BBCS have historically adopted a quantitative research design and used structured interviews and questionnaires to collect data from large samples of individuals born in specific years. However, the longitudinal nature of these studies means that they follow the same sample of individuals from birth through childhood into adult life, and this leads to the creation of data that can be understood as a quantitative auto/biography

The provision of nutritional advice and care for cancer patients: a UK national survey of healthcare professionals.

PURPOSE: People living with and beyond cancer often experience nutrition-related issues and should receive appropriate advice on nutrition that is consistent and evidence based. The aim of this study was to investigate current practice for the provision of nutritional care by healthcare professionals (HCPs) from a UK national survey produced by the National Institute for Health Research (NIHR) Cancer and Nutrition Collaboration. METHODS: An online survey sent to professional groups and networks included questions on discussing nutrition, providing information, awareness of guidelines, confidence in providing nutritional advice, training and strategies for improving nutritional management. RESULTS: There were 610 HCPs who responded including nurses (31%), dietitians (25%), doctors (31%) and speech and language therapists (9%). The majority of HCPs discusses nutrition (94%) and provides information on nutrition (77%). However, only 39% of HCPs reported being aware of nutritional guidelines, and just 20% were completely confident in providing nutritional advice. Awareness of guidelines varied between the different professional groups with most but not all dietitians reporting the greatest awareness of guidelines and GPs the least (p = 0.001). Those HCPs with a greater awareness of guidelines had received training (p = 0.001) and were more likely to report complete confidence in providing nutritional advice (p = 0.001). CONCLUSION: Whilst HCPs discuss nutrition with cancer patients and may provide information, many lack an awareness of guidelines and confidence in providing nutritional advice. To ensure consistency of practice and improvements in patient care, there is scope for enhancing the provision of appropriate nutrition education and training

DNA‐Interacting characteristics of the archaeal Rudiviral protein SIRV2_Gp1

Whereas the infection cycles of many bacterial and eukaryotic viruses have been characterized in detail, those of archaeal viruses remain largely unexplored. Recently, studies on a few model archaeal viruses such as SIRV2 (Sulfolobus islandicus rod‐shaped virus) have revealed an unusual lysis mechanism that involves the formation of pyramidal egress structures on the host cell surface. To expand understanding of the infection cycle of SIRV2, we aimed to functionally characterize gp1, which is a SIRV2 gene with unknown function. The SIRV2_Gp1 protein is highly expressed during early stages of infection and it is the only protein that is encoded twice on the viral genome. It harbours a helix‐turn‐helix motif and was therefore hypothesized to bind DNA. The DNA‐binding behavior of SIRV2_Gp1 was characterized with electrophoretic mobility shift assays and atomic force microscopy. We provide evidence that the protein interacts with DNA and that it forms large aggregates, thereby causing extreme condensation of the DNA. Furthermore, the N‐terminal domain of the protein mediates toxicity to the viral host Sulfolobus. Our findings may lead to biotechnological applications, such as the development of a toxic peptide for the containment of pathogenic bacteria, and add to our understanding of the Rudiviral infection cycle.Publisher PDFPeer reviewe

Male frequent attenders of general practice and their help seeking preferences

Background: Low rates of health service usage by men are commonly linked to masculine values and traditional male gender roles. However, not all men conform to these stereotypical notions of masculinity, with some men choosing to attend health services on a frequent basis, for a variety of different reasons. This study draws upon the accounts of male frequent attenders of the General Practitioner's (GP) surgery, examining their help-seeking preferences and their reasons for choosing services within general practice over other sources of support. Methods: The study extends thematic analysis of interview data from the Self Care in Primary Care study (SCinPC), a large scale multi-method evaluation study of a self care programme delivered to frequent attenders of general practice. Data were collected from 34 semi-structured interviews conducted with men prior to their exposure to the intervention. Results: The ages of interviewed men ranged from 16 to 72 years, and 91% of the sample (n= 31) stated that they had a current health condition. The thematic analysis exposed diverse perspectives within male help-seeking preferences and the decision-making behind men's choice of services. The study also draws attention to the large variation in men's knowledge of available health services, particularly alternatives to general practice. Furthermore, the data revealed some men's lack of confidence in existing alternatives to general practice. Conclusions: The study highlights the complex nature of male help-seeking preferences, and provides evidence that there should be no 'one size fits all' approach to male service provision. It also provides impetus for conducting further studies into this under researched area of interest. © 2011 WPMH GmbH

Bone Morphogenetic Protein‐2 Decreases MicroRNA‐30b and MicroRNA‐30c to Promote Vascular Smooth Muscle Cell Calcification

Background: Vascular calcification resembles bone formation and involves vascular smooth muscle cell (SMC) transition to an osteoblast‐like phenotype to express Runx2, a master osteoblast transcription factor. One possible mechanism by which Runx2 protein expression is induced is downregulation of inhibitory microRNAs (miR). Methods and Results: Human coronary artery SMCs (CASMCs) treated with bone morphogenetic protein‐2 (BMP‐2; 100 ng/mL) demonstrated a 1.7‐fold (P<0.02) increase in Runx2 protein expression at 24 hours. A miR microarray and target prediction database analysis independently identified miR‐30b and miR‐30c (miR‐30b‐c) as miRs that regulate Runx2 expression. Real‐time–polymerase chain reaction confirmed that BMP‐2 decreased miR‐30b and miR‐30c expression. A luciferase reporter assay verified that both miR‐30b and miR‐30c bind to the 3′‐untranslated region of Runx2 mRNA to regulate its expression. CASMCs transfected with antagomirs to downregulate miR‐30b‐c demonstrated significantly increased Runx2, intracellular calcium deposition, and mineralization. Conversely, forced expression of miR‐30b‐c by transfection with pre–miR‐30b‐c prevented the increase in Runx2 expression and mineralization of SMCs. Calcified human coronary arteries demonstrated higher levels of BMP‐2 and lower levels of miR‐30b than did noncalcified donor coronary arteries. Conclusions: BMP‐2 downregulates miR‐30b and miR‐30c to increase Runx2 expression in CASMCs and promote mineralization. Strategies that modulate expression of miR‐30b and miR‐30c may influence vascular calcification

Thrombosis Is Reduced by Inhibition of COX-1, but Unaffected by Inhibition of COX-2, in an Acute Model of Platelet Activation in the Mouse

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