VEGF165b, an antiangiogenic VEGF-A isoform, binds and inhibits bevacizumab treatment in experimental colorectal carcinoma: balance of pro- and antiangiogenic VEGF-A isoforms has implications for therapy

Bevacizumab, an anti-vascular endothelial growth factor (VEGF-A) antibody, is used in metastatic colorectal carcinoma (CRC) treatment, but responses are unpredictable. Vascular endothelial growth factor is alternatively spliced to form proangiogenic VEGF165 and antiangiogenic VEGF165b. Using isoform-specific enzyme-linked immunosorbent assay and quantitative polymerase chain reaction, we found that over 90% of the VEGF in normal colonic tissue was VEGFxxxb, but there was a variable upregulation of VEGFxxx and downregulation of VEGFxxxb in paired human CRC samples. Furthermore, cultured colonic adenoma cells expressed predominantly VEGFxxxb, whereas colonic carcinoma cells expressed predominantly VEGFxxx. However, adenoma cells exposed to hypoxia switched their expression from predominantly VEGFxxxb to predominantly VEGFxxx. VEGF165b overexpression in LS174t colon cancer cells inhibited colon carcinoma growth in mouse xenograft models. Western blotting and surface plasmon resonance showed that VEGF165b bound to bevacizumab with similar affinity as VEGF165. However, although bevacizumab effectively inhibited the rapid growth of colon carcinomas expressing VEGF165, it did not affect the slower growth of tumours from colonic carcinoma cells expressing VEGF165b. Both bevacizumab and anti-VEGF165b-specific antibodies were cytotoxic to colonic epithelial cells, but less so to colonic carcinoma cells. These results show that the balance of antiangiogenic to proangiogenic isoforms switches to a variable extent in CRC, regulates tumour growth rates and affects the sensitivity of tumours to bevacizumab by competitive binding. Together with the identification of an autocrine cytoprotective role for VEGF165b in colonic epithelial cells, these results indicate that bevacizumab treatment of human CRC may depend upon this balance of VEGF isoforms

Do UK universities communicate their brands effectively through their websites?

This paper attempts to explore the effectiveness of UK universities’ websites. The area of branding in higher education has received increasing academic investigation, but little work has researched how universities demonstrate their brand promises through their websites. The quest to differentiate through branding can be challenging in the university context, however. It is argued that those institutions that have a strong distinctive image will be in a better position to face a changing future. Employing a multistage methodology, the web pages of twenty UK universities were investigated by using a combination of content and multivariable analysis. Results indicated ‘traditional values’ such as teaching and research were often well communicated in terms of online brand but ‘emotional values’ like social responsibility and the universities’ environments were less consistently communicated, despite their increased topicality. It is therefore suggested that emotional values may offer a basis for possible future online differentiation

Toward a conceptual framework of emotional relationship marketing: an examination of two UK political parties

The purpose of this paper is to review the notion of branding and evaluate its applicability to political parties. As ideological politics is in decline, branding may provide a consistent narrative where voters feel a sense of warmth and belonging. The paper aims to build an understanding of the complexity of building a political brand where a combination of image, logo, leadership, and values can all contribute to a compelling brand narrative. It investigates how competing positive and negative messages attempt to build and distort the brand identity. A critical review of bran ding, relationship marketing, and political science literature articulates the conceptual development of branding and its applicability to political parties. The success or failure of negative campaigning is due to the authenticity of a political party’s brand values — creating a coherent brand story — if there is no distance between the brand values articulated by the political party and the values their community perceives then this creates an "authentic" brand. However, if there is a gap this paper illustrates how negative campaigning can be used to build a "doppelganger brand," which undermines the credibility of the authentic political brand. The paper argues that political parties need to understand how brand stories are developed but also how they can be used to protect against negative advertising. This has implications for political marketing strategists and political parties. This paper draws together branding theory and relationship marketing and incorporates them into a framework that makes a contribution to the political marketing literature

Alternative splicing of TIA-1 in human colon cancer regulates VEGF isoform expression, angiogenesis, tumour growth and bevacizumab resistance

© 2014 The Authors. The angiogenic capability of colorectal carcinomas (CRC), and their susceptibility to anti-angiogenic therapy, is determined by expression of vascular endothelial growth factor (VEGF) isoforms. The intracellular protein T-cell Intracellular Antigen (TIA-1) alters post-transcriptional RNA processing and binds VEGF-A mRNA. We therefore tested the hypothesis that TIA-1 could regulate VEGF-A isoform expression in colorectal cancers. TIA-1 and VEGF-A isoform expression was measured in colorectal cancers and cell lines. We discovered that an endogenous splice variant of TIA-1 encoding a truncated protein, short TIA-1 (sTIA-1) was expressed in CRC tissues and invasive K-Ras mutant colon cancer cells and tissues but not in adenoma cell lines. sTIA-1 was more highly expressed in CRC than in normal tissues and increased with tumour stage. Knockdown of sTIA-1 or over-expression of full length TIA-1 (flTIA-1) induced expression of the anti-angiogenic VEGF isoform VEGF-A 165 b. Whereas flTIA-1 selectively bound VEGF-A 165 mRNA and increased translation of VEGF-A 165 b, sTIA-1 prevented this binding. In nude mice, xenografted colon cancer cells over-expressing flTIA-1 formed smaller, less vascular tumours than those expressing sTIA-1, but flTIA-1 expression inhibited the effect of anti-VEGF antibodies. These results indicate that alternative splicing of an RNA binding protein can regulate isoform specific expression of VEGF providing an added layer of complexity to the angiogenic profile of colorectal cancer and their resistance to anti-angiogenic therapy

Sustainability, epistemology, ecocentric business and marketing strategy:ideology, reality and vision

This conceptual article examines the relationship between marketing and sustainability through the dual lenses of anthropocentric and ecocentric epistemology. Using the current anthropocentric epistemology and its associated dominant social paradigm, corporate ecological sustainability in commercial practice and business school research and teaching is difficult to achieve. However, adopting an ecocentric epistemology enables the development of an alternative business and marketing approach that places equal importance on nature, the planet, and ecological sustainability as the source of human and other species' well-being, as well as the source of all products and services. This article examines ecocentric, transformational business, and marketing strategies epistemologically, conceptually and practically and thereby proposes six ecocentric, transformational, strategic marketing universal premises as part of a vision of and solution to current global un-sustainability. Finally, this article outlines several opportunities for management practice and further research

‘We Call it Jail Craft’: The Erosion of the Protective Discourses Drawn on by Prison Officers Dealing with Ageing and Dying Prisoners in the Neoliberal, Carceral System

The UK prison population has doubled in the last decade, with the greatest increases among prisoners over the age of 60 years, many of whom are sex offenders imprisoned late in life for ‘historical’ offences. Occurring in a context of ‘austerity’ and the wider neoliberal project, an under-researched consequence of this increase has been the rising numbers of ‘anticipated’ prison deaths; that is, deaths that are foreseeable and that require end of life care. We focus here on ‘jail craft’; a nostalgic, multi-layered, narrative or discourse, and set of tacit practices which are drawn on by officers to manage the affective and practical challenges of working with the demands of this changed prison environment. Utilising findings from an empirical study of end of life care in prisons, we propose that the erosion of jail craft depletes protective resources and sharpens the practical consequences of neoliberal penal policies

Ovarian VEGF165b expression regulates follicular development, corpus luteum function and fertility

Angiogenesis and vascular regression are critical for the female ovulatory cycle. They enable progression and regression of follicular development, and corpora lutea formation and regression. Angiogenesis in the ovary occurs under the control of the vascular endothelial growth factor-A (VEGFA) family of proteins, which are generated as both pro-(VEGF165) and anti(VEGF165b)-angiogenic isoforms by alternative splicing. To determine the role of the VEGF165b isoforms in the ovulatory cycle, we measured VEGF165b expression in marmoset ovaries by immunohistochemistry and ELISA, and used transgenic mice over-expressing VEGF165b in the ovary. VEGF165b was expressed in the marmoset ovaries in granulosa cells and theca, and the balance of VEGF165b:VEGF165 was regulated during luteogenesis. Mice over-expressing VEGF165b in the ovary were less fertile than wild-type littermates, had reduced secondary and tertiary follicles after mating, increased atretic follicles, fewer corpora lutea and generated fewer embryos in the oviduct after mating, and these were more likely not to retain the corona radiata. These results indicate that the balance of VEGFA isoforms controls follicle progression and luteogenesis, and that control of isoform expression may regulate fertility in mammals, including in primates

What’s past (and present) is prologue : interactions between justice levels and trajectories predicting behavioral reciprocity

Much of organizational justice research has tended to take a static approach, linking employees’ contemporaneous justice levels to outcomes of interest. In the present study, we tested a dynamic model emphasizing the interactive influences of both justice levels and trajectories for predicting behavioral social exchange outcomes. Specifically, our model posited both main effects and interactions between present justice levels and past justice changes over time in predicting helping behavior and voluntary turnover behavior. Data over four yearly measurement periods from 4,348 employees of a banking organization generally supported the notion that justice trajectories interact with absolute levels to predict both outcomes. Together, the findings highlight how employees invoke present fairness evaluations within the context of past fairness trends—rather than either in isolation—to inform decisions about behaviorally reciprocating at work

VEGF-A165b is an endogenous neuroprotective splice isoform of vascular endothelial growth factor A in vivo and in vitro

Vascular endothelial growth factor (VEGF) A is generated as two isoform families by alternative RNA splicing, represented by VEGF-A165a and VEGF-A165b. These isoforms have opposing actions on vascular permeability, angiogenesis, and vasodilatation. The proangiogenic VEGF-A165a isoform is neuroprotective in hippocampal, dorsal root ganglia, and retinal neurons, but its propermeability, vasodilatatory, and angiogenic properties limit its therapeutic usefulness. In contrast, a neuroprotective effect of endogenous VEGF-A165b on neurons would be advantageous for neurodegenerative pathologies. Endogenous expression of human and rat VEGF-A165b was detected in hippocampal and cortical neurons. VEGF-A165b formed a significant proportion of total VEGF-A in rat brain. Recombinant human VEGF-A165b exerted neuroprotective effects in response to multiple insults, including glutamatergic excitotoxicity in hippocampal neurons, chemotherapy-induced cytotoxicity of dorsal root ganglion neurons, and retinal ganglion cells (RGCs) in rat retinal ischemia-reperfusion injury in vivo. Neuroprotection was dependent on VEGFR2 and MEK1/2 activation but not on p38 or phosphatidylinositol 3-kinase activation. Recombinant human VEGF-A165b is a neuroprotective agent that effectively protects both peripheral and central neurons in vivo and in vitro through VEGFR2, MEK1/2, and inhibition of caspase-3 induction. VEGF-A165b may be therapeutically useful for pathologies that involve neuronal damage, including hippocampal neurodegeneration, glaucoma diabetic retinopathy, and peripheral neuropathy. The endogenous nature of VEGF-A165b expression suggests that non-isoform-specific inhibition of VEGF-A (for antiangiogenic reasons) may be damaging to retinal and sensory neurons

Expression of VEGFxxxb, the inhibitory isoforms of VEGF, in malignant melanoma

Malignant melanoma is the most lethal of the skin cancers and the UK incidence is rising faster than that of any other cancer. Angiogenesis – the growth of new vessels from preexisting vasculature – is an absolute requirement for tumour survival and progression beyond a few hundred microns in diameter. We previously described a class of anti-angiogenic isoforms of VEGF, VEGFxxxb, that inhibit tumour growth in animal models, and are downregulated in some cancers, but have not been investigated in melanoma. To determine whether VEGFxxxb expression was altered in melanoma, PCR and immunohistochemistry of archived human tumour samples were used. In normal epidermis and in a proportion of melanoma samples, VEGFxxxb staining was seen. Some melanomas had much weaker staining. Subsequent examination revealed that expression was significantly reduced in primary melanoma samples (both horizontal and vertical growth phases) from patients who subsequently developed tumour metastasis compared with those who did not (analysis of variance (ANOVA) P<0.001 metastatic vs nonmetastatic), irrespective of tumour thickness, while the surrounding epidermis showed no difference in expression. Staining for total VEGF expression showed staining in metastatic and nonmetastatic melanomas, and normal epidermis. An absence of VEGFxxxb expression appears to predict metastatic spread in patients with primary melanoma. These results suggest that there is a switch in splicing as part of the metastatic process, from anti-angiogenic to pro-angiogenic VEGF isoforms. This may form part of a wider metastatic splicing phenotype