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Objective Anxiety is common among patients attending an initial oncology consultation. The objective of this trial was to test if an enhanced compassion video emailed to patients prior to their initial oncology consultation reduces anxiety compared with being sent an information-only introduction video.Methods and analysis We conducted a randomised control trial at a single university-based cancer centre between May 2021 and October 2023. We enrolled adult patients scheduled for an initial cancer consultation. Subjects underwent simple 1:1 randomisation to receive either a standard introduction video or an enhanced compassion video via email. Investigators and subjects were blinded to allocation. The primary outcome was degree of anxiety on arrival to the initial oncology consultation, measured using the Hospital Anxiety and Depression scale (HADS).Results Of 1005 subjects randomised to the standard video and 1038 to the enhanced compassion video, 183 and 179 subjects completed the HADS-anxiety in each group, respectively. Only 25% reported watching their assigned video. There was no difference in degree of anxiety between the standard or compassion video groups using intention to treat analysis (median (IQR) 7 (4–10) vs 7 (4–10), p value=0.473)) or per-protocol analysis (limited to subjects who reported watching the video) (median (IQR) 7 (4–10) (n=45) vs 7 (5–10) (n=46), p value=0.997).Conclusion Receiving an enhanced compassion video did not reduce anxiety compared with a standard introduction video. Given 25% of subjects reported watching their assigned video, future research should focus on identifying interventions at the point-of-care to reduce anxiety.Trial registration number NCT04503681.

Venezuelan equine encephalitis virus (VEEV) is a neurotropic arbovirus that is highly infectious as an aerosol and can result in an encephalitic phenotype in infected individuals. VEEV infections are known to be associated with robust inflammation that eventually contributes to neurodegenerative phenotypes. In this study, we utilize the TC-83 strain of VEEV, which is known to induce the expression of IL-6, IL-8, and other pro-inflammatory cytokines. We had previously demonstrated that TC-83 infection resulted in changes in mitochondrial function, eventually resulting in mitophagy. In this manuscript, we provide data that links upstream mitochondrial dysfunction with downstream pro-inflammatory cytokine production in the context of microglia and astrocytoma cells. We also provide data on the role of bystander cells, which significantly contribute to the overall inflammatory load. Use of a mitochondrial-targeted antioxidant, mitoquinone mesylate, greatly reduced the inflammatory cytokine load and ameliorated bystander cell inflammatory responses more significantly than a broad-spectrum anti-inflammatory compound (BAY 11–7082). Our data suggest that the inflammatory mediators, especially IL-1β, may prime naïve cells to infection and lead to increased infection rates in microglial and astrocytoma cells. Cumulatively, our data suggest that the interplay between mitochondrial dysfunction and inflammatory events elicited in a neuronal microenvironment during a TC-83 infection may contribute to the spread of infection.

Venezuelan equine encephalitis virus (VEEV) is an arbovirus that is associated with robust inflammation that contributes to neurodegenerative phenotypes. In addition to triggering central nervous system (CNS) inflammation, VEEV will also induce mitochondrial dysfunction, resulting in increased cellular apoptosis. In this study, we utilize the TC-83 strain of VEEV to determine the role of mitochondrial oxidative stress in mediating inflammation elicited by murine brain microglial cells. Using an in vitro model, we show that murine microglia are susceptible to TC-83 infection, and that these cells undergo mitochondrial stress as the result of infection. We also indicate that bystander microglia contribute more significantly to the overall inflammatory load than directly infected microglia. Use of a mitochondrial targeted antioxidant, mitoquinone mesylate, greatly reduced the pro-inflammatory cytokines released by both direct infected and bystander microglia. Our data suggest that release of interleukin-1β, a key instigator of neuroinflammation during VEEV infection, may be the direct result of accumulating mitochondrial stress. This data improves our understanding inflammation elicited by murine microglia and will aid in the development of more accurate in vitro and in vivo murine model of VEEV-induced neuroinflammation.

Human airway epithelial cells are the principal target of human rhinovirus (HRV), a common cold pathogen that triggers the majority of asthma exacerbations. The objectives of this study were 1) to evaluate an in vitro air liquid interface cultured human airway epithelial cell model for HRV infection, and 2) to identify gene expression patterns associated with asthma intrinsically and/or after HRV infection using this model.Air-liquid interface (ALI) human airway epithelial cell cultures were prepared from 6 asthmatic and 6 non-asthmatic donors. The effects of rhinovirus RV-A16 on ALI cultures were compared. Genome-wide gene expression changes in ALI cultures following HRV infection at 24 hours post exposure were further analyzed using RNA-seq technology. Cellular gene expression and cytokine/chemokine secretion were further evaluated by qPCR and a Luminex-based protein assay, respectively.ALI cultures were readily infected by HRV. RNA-seq analysis of HRV infected ALI cultures identified sets of genes associated with asthma specific viral responses. These genes are related to inflammatory pathways, epithelial structure and remodeling and cilium assembly and function, including those described previously (e.g. CCL5, CXCL10 and CX3CL1, MUC5AC, CDHR3), and novel ones that were identified for the first time in this study (e.g. CCRL1).ALI-cultured human airway epithelial cells challenged with HRV are a useful translational model for the study of HRV-induced responses in airway epithelial cells, given that gene expression profile using this model largely recapitulates some important patterns of gene responses in patients during clinical HRV infection. Furthermore, our data emphasize that both abnormal airway epithelial structure and inflammatory signaling are two important asthma signatures, which can be further exacerbated by HRV infection.

Many viruses have been implicated in utilizing or modulating the Ubiquitin Proteasome System (UPS) to enhance viral multiplication and/or to sustain a persistent infection. The mosquito-borne Venezuelan equine encephalitis virus (VEEV) belongs to the Togaviridae family and is an important biodefense pathogen and select agent. There are currently no approved vaccines or therapies for VEEV infections; therefore, it is imperative to identify novel targets for therapeutic development. We hypothesized that a functional UPS is required for efficient VEEV multiplication. We have shown that at non-toxic concentrations Bortezomib, a FDA-approved inhibitor of the proteasome, proved to be a potent inhibitor of VEEV multiplication in the human astrocytoma cell line U87MG. Bortezomib inhibited the virulent Trinidad donkey (TrD) strain and the attenuated TC-83 strain of VEEV. Additional studies with virulent strains of Eastern equine encephalitis virus (EEEV) and Western equine encephalitis virus (WEEV) demonstrated that Bortezomib is a broad spectrum inhibitor of the New World alphaviruses. Time-of-addition assays showed that Bortezomib was an effective inhibitor of viral multiplication even when the drug was introduced many hours post exposure to the virus. Mass spectrometry analyses indicated that the VEEV capsid protein is ubiquitinated in infected cells, which was validated by confocal microscopy and immunoprecipitation assays. Subsequent studies revealed that capsid is ubiquitinated on K48 during early stages of infection which was affected by Bortezomib treatment. This study will aid future investigations in identifying host proteins as potential broad spectrum therapeutic targets for treating alphavirus infections.

The circumsporozoite protein (CSP) of Plasmodium falciparum is a major surface protein, which forms a dense coat on the sporozoite's surface. Preclinical research on CSP and clinical evaluation of a CSP fragment-based RTS, S/AS01 vaccine have demonstrated a modest degree of protection against P. falciparum, mediated in part by humoral immunity and in part by cell-mediated immunity. Given the partial protective efficacy of the RTS, S/AS01 vaccine in a recent Phase 3 trial, further improvement of CSP-based vaccines is crucial. In this report, we describe the preclinical development of a full-length, recombinant CSP (rCSP)-based vaccine candidate against P. falciparum malaria suitable for current Good Manufacturing Practice (cGMP) production. Utilizing a novel high-throughput Pseudomonas fluorescens expression platform, we demonstrated greater efficacy of full-length rCSP as compared to N-terminally truncated versions, rapidly down-selected a promising lead vaccine candidate, and developed a high-yield purification process to express immunologically active, intact antigen for clinical trial material production. The rCSP, when formulated with various adjuvants, induced antigen-specific antibody responses as measured by enzyme-linked immunosorbent assay (ELISA) and immunofluorescence assay (IFA), as well as CD4+ T-cell responses as determined by ELISpot. The adjuvanted rCSP vaccine conferred protection in mice when challenged with transgenic P. berghei sporozoites containing the P. falciparum repeat region of CSP. Furthermore, heterologous prime/boost regimens with adjuvanted rCSP and an adenovirus type 35-vectored CSP (Ad35CS) showed modest improvements in eliciting CSP-specific T-cell responses and anti-malarial protection, depending on the order of vaccine delivery. Collectively, these data support the importance of further clinical development of adjuvanted rCSP, either as a stand-alone product or as one of the components in a heterologous prime/boost strategy, ultimately acting as an effective vaccine candidate for the mitigation of P. falciparum-induced malaria.

Cellular FLIP (c-FLIP) is an enzymatically inactive paralogue of caspase-8 and as such can block death receptor-induced apoptosis. However, independent of death receptors, c-FLIP-Long (c-FLIPL) can heterodimerize with and activate caspase-8. This is critical for promoting the growth and survival of T lymphocytes as well as the regulation of the RIG-I helicase pathway for type I interferon production in response to viral infections. Truncated forms of FLIP also exist in mammalian cells (c-FLIPS) and certain viruses (v-FLIP), which lack the C-terminal domain that activates caspase-8. Thus, the ratio of c-FLIPL to these short forms of FLIP may greatly influence the outcome of an immune response. We examined this model in mice transgenically expressing c-FLIPS in T cells during infection with Coxsackievirus B3 (CVB3). In contrast to our earlier findings of reduced myocarditis and mortality with CVB3 infection of c-FLIPL-transgenic mice, c-FLIPS-transgenic mice were highly sensitive to CVB3 infection as manifested by increased cardiac virus titers, myocarditis score, and mortality compared to wild-type C57BL/6 mice. This observation was paralleled by a reduction in serum levels of IL-10 and IFN-α in CVB3-infected c-FLIPS mice. In vitro infection of c-FLIPS T cells with CVB3 confirmed these results. Furthermore, molecular studies revealed that following infection of cells with CVB3, c-FLIPL associates with mitochondrial antiviral signaling protein (MAVS), increases caspase-8 activity and type I IFN production, and reduces viral replication, whereas c-FLIPS promotes the opposite phenotype.

The inability of targeted BRAF inhibitors to produce long-lasting improvement in the clinical outcome of melanoma highlights a need to identify additional approaches to inhibit melanoma growth. Recent studies have shown that activation of the Wnt/β-catenin pathway decreases tumor growth and cooperates with ERK/MAPK pathway inhibitors to promote apoptosis in melanoma. Therefore, the identification of Wnt/β-catenin regulators may advance the development of new approaches to treat this disease. In order to move towards this goal we performed a large scale small-interfering RNA (siRNA) screen for regulators of β-catenin activated reporter activity in human HT1080 fibrosarcoma cells. Integrating large scale siRNA screen data with phosphoproteomic data and bioinformatics enrichment identified a protein, FAM129B, as a potential regulator of Wnt/β-catenin signaling. Functionally, we demonstrated that siRNA-mediated knockdown of FAM129B in A375 and A2058 melanoma cell lines inhibits WNT3A-mediated activation of a β-catenin-responsive luciferase reporter and inhibits expression of the endogenous Wnt/β-catenin target gene, AXIN2. We also demonstrate that FAM129B knockdown inhibits apoptosis in melanoma cells treated with WNT3A. These experiments support a role for FAM129B in linking Wnt/β-catenin signaling to apoptosis in melanoma.

This article is a "companion" piece to a more general discussion in the preceding article, Brian ROBERTS' (2011) "Photographic Portraits: Narrative and Memory". Here the attempt is to enhance current attention to visual materials by exploring a particular interpretive approach to the photographic portrait—self-image—images taken of us by ourselves or taken by others (portraits taken by friends or relatives, or by professionals), alone or as part of a group. The article is autobiographical in focus; it explores how we "look" at personal photographs and associate them with memories of our past, our current experience, and the future. It uses as examples two school photographs taken in 1956-8 of me (the author) aged six to eight years old and applies a form of analysis employing "time perspectives" and a range of associated concepts. Two narratives are given: first, a commentary on the two school photographs and my childhood development (e.g. physical, intellectual) between six to eight years old, and second, my current outlook and activities and how they connect with the memories raised by the photographs. URN: http://nbn-resolving.de/urn:nbn:de:0114-fqs1102252

This article is a more general "companion" to the subsequent, Brian ROBERTS (2011) "Interpreting Photographic Portraits: Autobiography, Time Perspectives and Two School Photographs". The article seeks to add to the growing awareness of the importance of visual materials and methods in qualitative social research and to give an introduction to the "photographic self image"—self-portraits and portraits. It focuses on time and memory, including the experiential associations (in consciousness and the senses) that the self engenders, thus linking the "visual" (photographic) and "auto/biographical". The article attempts to "map" a field—the use of portraiture within social science—drawing on narrative and biographical research, on one side, and photographic portraiture, on the other. In supporting the use of photography in qualitative research it points to the need for researchers to have a greater knowledge of photographic (and art) criticism and cognisance of photographic practices. The article does not intend to give a definitive account of photographic portraiture or prescribe in detail how it may be used within social science. It is an initial overview of the development and issues within the area of photographic portraiture and an exploration of relevant methodological issues when images of individuals are employed within social science—so that "portraiture" is better understood and developed within biographical and narrative research. URN: http://nbn-resolving.de/urn:nbn:de:0114-fqs110263

This article reviews recent work applying a notion of "performance" in the study and representation of lives. It tries to clarify some of the issues involved—including the meaning of "performance"—and "performative"—the range of possible approaches (e.g., in addition to drama—other arts) and the relationship between "subjects", "researcher" and "audience". An immediate concern is the nature of the researcher—as having the necessary skills and abilities or knowledge involved in "performance" (in researching, writing, recording and representing), as engaged (to some extent) in "artistic" endeavour, and moving between a number of "roles" and social relations in "performing" with/to others (the "researched" group, audience and society). An important issue for social science in crossing or bridging the social science-arts, in taking up "performative approaches", is "What remains distinctive about the social science if it becomes involved with performance approaches?" As a source for comparison (and inspiration), some brief reference will be made to the work of KANDINSKY—who moved across disciplinary boundaries and artistic practices—as ethnographer, painter, teacher, designer, theorist and poet. Finally, perhaps, there is a deeper "turn" indicated by the "turn to performance" in the study of lives, a more "complete" portrait of the individual as an active, communicative and sensual being. URN: urn:nbn:de:0114-fqs0802588

This article examines the autobiographical and some other writings of Mamphela RAMPHELE, a former political and community activist in South Africa with reference to forms of narrative analysis. It is argued that these writings can be viewed together and compared as auto­biographical texts. This view raises a number of methodological issues concerning the degree of re-interpretation and other changes in the "re­telling" of an account in different circumstances and form. The article compares this single case with models of "political activism" where individuals orientate their lives and activities towards various social goals. Here the attempt is to link and analyse the particular case within wider analyses of political activism. The article argues that in RAMPHELE's narrative telling and retelling certain events in terms of communal rituals and boundary crossings, she has utilised a "reflective biographical template" in her life which she both returned to and re-used as she met new challenges and situations. URN: urn:nbn:de:0114-fqs0403107

The inability of targeted BRAF inhibitors to produce long-lasting improvement in the clinical outcome of melanoma highlights a need to identify additional approaches to inhibit melanoma growth. Recent studies have shown that activation of the Wnt/β-catenin pathway decreases tumor growth and cooperates with ERK/MAPK pathway inhibitors to promote apoptosis in melanoma. Therefore, the identification of Wnt/β-catenin regulators may advance the development of new approaches to treat this disease. In order to move towards this goal we performed a large scale small-interfering RNA (siRNA) screen for regulators of β-catenin activated reporter activity in human HT1080 fibrosarcoma cells. Integrating large scale siRNA screen data with phosphoproteomic data and bioinformatics enrichment identified a protein, FAM129B, as a potential regulator of Wnt/β-catenin signaling. Functionally, we demonstrated that siRNA-mediated knockdown of FAM129B in A375 and A2058 melanoma cell lines inhibits WNT3A-mediated activation of a β-catenin-responsive luciferase reporter and inhibits expression of the endogenous Wnt/β-catenin target gene, AXIN2. We also demonstrate that FAM129B knockdown inhibits apoptosis in melanoma cells treated with WNT3A. These experiments support a role for FAM129B in linking Wnt/β-catenin signaling to apoptosis in melanoma.