Investigating Chemotherapeutic Resistance: Why is Glioblastoma So Deadly?

Glioblastoma multiforme (GBM), a malignancy of the glioblast stem cells of the brain, is one of the most aggressive and untreated forms of brain cancer. When an individual is diagnosed with GBM, depending on the location of the tumor, there are three treatment options including surgery, radiation, chemotherapy or the combination of these treatments. Many patients choose chemotherapy, however most GBM cases show little to no response to Temozolomide (TMZ), which is a common chemotherapy drug used for this type of cancer. In some recent studies, researchers have noticed an elevated amount or over production of an enzyme, Inosine 5\u27-monophosphate dehydrogenase (IMPDH). This enzyme 31 helps with DNA repair but in many GBM cases, due to its over production, it repairs at such a fast rate it does not allow TMZ to terminate the cancerous tumors. In our research we have been investigating whether the chemotherapeutic agent causes the increase in expression directly or whether it is a unique property of this cell type. Future directions involve: determining a molecular pathway that could lead to IMPDH expression at such high levels under chemotherapeutic stress and whether co-administering IMPDH inhibitors with TMZ can improve prognosis for those suffering from GBM.https://openriver.winona.edu/urc2019/1023/thumbnail.jp

Constraints on Late Time Violations of the Equivalence Principle in the Dark Sector

If dark energy is dynamical due to the evolution of a scalar field, then in general it is expected that the scalar is coupled to matter. While couplings to the standard model particles are highly constrained by local experiments, bounds on couplings to dark matter (DM) are only obtained from cosmological observations and they are consequently weaker. It has recently been pointed out that the coupling itself can become non-zero only at the time of dark energy domination, due to the evolution of dark energy itself, leading to a violation of the equivalence principle (EP) in the dark sector at late times. In this paper we study a specific model and show that such late-time violations of the EP in the DM sector are not strongly constrained by the evolution of the cosmological background and by observables in the linear regime (e.g. from the cosmic microwave background radiation). A study of perturbations in non-linear regime is necessary to constrain late--time violations of the equivalence principle much more strongly.Comment: 8 pages, 4 figures, 2 tables. Typos corrected, references added. Comparison to model in which initial field value sits at the minimum has been added. Version to be submitted to journa

Using parent metaphors for learning about the neonatal care experience: an interpretive perspective

© 2019 The Author(s). The final, definitive version of this paper has been published in Journal of Child Health Care by Sage Publications Ltd. All rights reserved. It is available at: https://doi.org/10.1177/1367493519875853.This study focuses on how metaphors are used by parents who have had a premature baby to describe their neonatal care experience and how these can contribute to empathic learning of health professionals. In health, metaphors are commonly used to communicate and explain difficult topics. When patients tell their story, metaphor can be a means of expression from which we can learn about their experience of illness or hospitalisation. Limited research exits on how metaphor can improve our understanding of parent’s emotional experience in neonatal care and subsequently inform education in this field. Employing narrative inquiry within an interpretive, constructivist paradigm, 20 narrative interviews with 23 parents of premature babies were analysed using a process of metaphor identification. Findings revealed common metaphors used to describe experience. Metaphor clusters used by parents in order of frequency were journeying, altered reality, darkness, breaking, connections, fighting, salvation and being on the edge. Parents widely used compelling and emotive metaphors to describe and express both difficult and challenging times as well as progression forward. Metaphors serve as a powerful way for health professionals to learn about the emotional experiences of parents and potentially enhance their empathic understanding.Peer reviewe

Optimization of an Air Core Dual Halbach Array Axial Flux Rim Drive for Electric Aircraft

The anticipated development of the on-demand-mobility (ODM) market has accelerated the development of electric aircraft. Most proposed electric aircraft have propulsion systems that consist of fans directly driven by electric motors. The lower complexity of these propulsion systems opens the door to more custom propulsion system designs that are tailored to a given aircraft and its mission. This paper represents initial steps in the development of an electric propulsion system design code. A proof of concept version of the code is presented. The proof of concept version of the code is for the design of an axial flux rim driven propulsion system. NASA's all electric aircraft X-57, is used as a case study for this design code. The results of this case study are used to discuss the feasibility and potential benefits of using an axial flux rim driven propulsor on X-57. The final result of the case study shows a potential 4km increase in range over the current design

Toward understanding the structure of Amot’s ACCH Domain

poster abstractAmots are a family of adaptor proteins widely involved in cell signaling and lipid binding. Amot80 has been linked to cellular proliferation in breast cancer via the VEGF and MAPK signaling pathways, while Amot130 and AmotL1 have been linked to cellular inhibition via the HIPPO signaling pathway. Amot family members also have a characteristic lipid-binding domain – named the ACCH Domain for its predicted coil-coil structure – that has the ability to selectively target phosphoinositols followed by deformation of the membrane. Understanding the structure-function relationship of this domain may provide options to modulate these signaling pathways, directly affecting cellular differentiation, proliferation, and migration. Extensive crystallization attempts for this domain have failed, leading to a bioinformatics and biophysics-combined approach. Using SAXS, data for the globular structure of Amot80 has been generated and analyzed. Additionally, the threading programs ITASSER and LOMETS were used to develop 20 computational theoretical models. By fitting the computational models to the SAXS data, potential ACCH domain models were generated, and then scored based on accuracy of fit via C-score, TMScore, and RMSD values. This 3D model can then be used to discover how Amot interacts with lipids and further the understanding of Amot’s role in the cancer-signaling cascade

The cost-effectiveness of an updated theory-based online health behavior intervention for new university students: U@Uni2

Background: The transition to university marks a point where young people may be open to changing health behaviours such as smoking, exercise, diet and alcohol intake. This study aimed to estimate the cost-effectiveness of an updated online health behaviour intervention for new university students in the UK – “U@Uni2”, compared with both a control (measurement only) scenario and with the original intervention (“U@Uni1”). Methods: The economic analysis, based on a randomised controlled trial, comprised a detailed costing analysis, a within-trial cost-effectiveness analysis and long-term economic modelling. Cost-effectiveness of the U@Uni2 trial was estimated using 6-month data on costs and health-related quality of life. An individual patient simulation model was adapted for long-term economic analysis of U@Uni2. Probabilistic sensitivity analysis and value of information analysis accounted for uncertainty in model inputs and identified key parameters. Results: The U@Uni2 intervention costs £45.97 per person for full implementation, £10.43 per person for roll-out in a different institution and £3.03 per person for roll-out over five years. The U@Uni2 trial was not cost-effective because marginally fewer quality-adjusted life years (QALYs) were obtained in the intervention arm than control. However, modelled over a lifetime, U@Uni2 is estimated to produce more QALYs than control but fewer than U@Uni1, primarily due to the effect of the interventions on smoking. Roll-out of U@Uni2 is highly likely to be more cost-effective than doing nothing (ICER = £536 per QALY, 86% probability cost-effective). Decision uncertainty occurs primarily around the effectiveness of the U@Uni2 intervention and is worth up to £3.24m. Conclusions: The U@Uni2 intervention is highly likely to be cost-effective to roll-out compared with doing nothing. The results suggest that preventing uptake of smoking is the key driver of QALY gain and should be the primary target of such interventions. Trial Registration: Current Controlled Trials ISRCTN6768418

Chromosome instability and benefit from adjuvant anthracyclines in breast cancer

BACKGROUND: Duplication of the centromeric region of chromosome 17 (Ch17CEP) is associated with sensitivity to anthracyclines. An explanation may be chromosome instability (CIN); a frequent event in solid tumours associated with poor outcome. The predictive value of CIN seems to be drug dependent and CIN has been associated with both sensitivity and resistance to chemotherapy. METHODS: In this study, we used fluorescent in situ hybridisation for chromosomes 1, 7, 11, 17 and 18 to identify patients with high tumour CIN% in 322 patients recruited into the BR9601 clinical trial. RESULTS: High tumour CIN% was correlated to Ch17CEP (P=3.68e−7) and is associated with a reduced RFS (P=0.0011) and OS (P=0.04). Patients with high CIN had a decreased risk of death on E-CMF compared with CMF. CONCLUSION: CIN is of prognostic significance and may be of predictive value in determining anthracycline response, although further testing is required

Enhancer control of MicroRNA miR-155 expression in EpsteinBarr virus-infected B cells

The oncogenic microRNA miR-155 is the most frequently upregulated miRNA in Epstein-Barr virus (EBV)-positive B cell malignancies and is upregulated in other non-viral lymphomas. Both the EBV nuclear antigen 2 (EBNA2), and B cell transcription factor, interferon regulatory factor 4 (IRF4) are known to activate transcription of the host cell gene from which miR-155 is processed (miR-155HG, BIC). EBNA2 also activates IRF4 transcription indicating that EBV may upregulate miR-155 through direct and indirect mechanisms. The mechanism of transcriptional regulation of IRF4 and miR-155HG by EBNA2 however has not been defined. We demonstrate that EBNA2 can activate IRF4 and miR-155HG expression through specific upstream enhancers that are dependent on the Notch signaling transcription factor RBPJ, a known binding partner of EBNA2. We demonstrate that in addition to activation of the miR-155HG promoter, IRF4 can also activate miR-155HG via the upstream enhancer also targeted by EBNA2. Gene editing to remove the EBNA2- and IRF4-responsive miR-155HG enhancer located 60 kb upstream of miR-155HG led to reduced miR155HG expression in EBV-infected cells. Our data therefore demonstrate that specific RBPJ-dependent enhancers regulate the IRF4-miR-155 expression network and play a key role in the maintenance of miR-155 expression in EBV-infected B cells. These findings provide important insights that will improve our understanding of miR-155 control in B cell malignancies