α-Tocopheryl succinate inhibits angiogenesis by disrupting paracrine FGF2 signalling

AbstractMalignant mesothelioma (MM) cells enhanced proliferation of endothelial cells (ECs) as well as their angiogenesis in vitro by secretion of fibroblast growth factor-2 (FGF2). This effect was suppressed by pre-treating MM cells with α-tocopheryl succinate (α-TOS), which inhibited FGF2 secretion by inducing mitochondria-dependent generation of reactive oxygen species. The role of FGF2 was confirmed by its down-regulation by treating MM cells with siRNA, abolishing EC proliferation and wound healing enhancement afforded by MM cells. We conclude that α-TOS disrupts angiogenesis mediated by MM cells by inhibiting FGF2 paracrine signalling

Drugs that Kill Cancer Stem-like Cells

The hallmarks of cancer include processes like self-sufficiency for growth signals, insensitivity to growth-inhibitory (anti-growth) signals, evasion of programmed cell death (apoptosis), unlimited replicative potential, sustained angiogenesis, and tissue invasion and metastasis (Hanahan & Weinberg, 2000). Recent research dictates that these definitions, while valid, ought to be enriched. That is, we should also consider tumours as a heterogeneous ‘collection of cancer cells’ with a hierarchy. This ‘hierarchical hypothesis’ tells us that tumours contain a minute (sometimes very small) sub-set of cells with distinct properties from the bulk of the tumour mass (D’Amour & Gage, 2002; Visvader & Lindeman, 2008; Visvader, 2009). These cells feature certain characteristics inherent to stem cells, including the capacity of self-renewal, asymmetric division and differentiation. They have also a very high propensity to form tumours. Therefore these cells are referred to as cancer stem cells (CSC) or cancer stem-like cells or, better, tumour-initiating cells (TICs). The terminology, while not too important, may be misleading though, since the term ‘cancer stem cells’ implies that we are dealing with true stem cells, which is not possible to reconcile with at this stage, perhaps even more so, since the origin of CSCs is not exactly known.Griffith Health, School of Medical ScienceFull Tex

The Alternative Complement Pathways Seems to be a UVA Sensor that Leads to Systemic Immunosuppression

UV wavebands in sunlight are immunomodulatory. About half the amount of UVA within a minimum erythemal dose of sunlight is systemically immunosuppressive, whereas higher doses protect from UVB immunosuppression in mice. We have earlier shown that these responses to UVA are genetically restricted, as they occur in C57BL/6 but not in Balb/c mice. We used gene set enrichment analysis of microarray data and real-time reverse transcriptase (RT)-PCR confirmation to determine the molecular mechanisms associated with UVA immunomodulation. We found upregulation of mRNA for the alternative complement pathway. The core-enriched genes complement component 3, properdin, and complement factor B were all activated by the immunosuppressive dose of UVA only in UVA-responsive C57BL/6 but not in unresponsive BALB/c mice. This therefore matched the genetic restriction and dose responsiveness of UVA immunosuppression. The immune-protective higher UVA dose prevented UVB from downregulating chemokine receptor 7 and IL-12B, and decreased IL-10, supporting the earlier identification of IL-12 and IL-10 in high-dose UVA protection from UVB immunosuppression. Our study has identified activation of the alternative complement pathway as a trigger of UVA-induced systemic immunosuppression and suggests that this pathway is likely to be an important sensor of UVA-induced damage to the skin

Point prevalence of non-melanoma and melanoma skin cancers in Australian surfers and swimmers in Southeast Queensland and Northern New South Wales

BACKGROUND: Surfing and swimming are two popular outdoor aquatic activities in Australia with an estimated 2.7 million surfers and three million swimmers; however, these activities are associated with intermittent exposure to ultraviolet radiation. Our aim was to determine the point prevalence of pre-skin cancer (actinic keratosis (PSC)), non-melanoma (NMSC) and melanoma skin cancers (MSC) in Australian surfers and swimmers. METHODS: This cross-sectional study involved Australian surfers who completed a survey that included physiological demographics, aquatic activity-specific demographics, history of skin cancer followed by screening. RESULTS: A total of 171 surfers (n = 116) and swimmers (n = 55) participated in the study. Both groups were identified as having a history of skin cancer (surfers 41.4%, swimmers 36.4%) and a family history of skin cancer (surfers 52.6%, swimmers 43.6%). The majority of both groups reported using a high percentage of a chemical or physical skin cancer prevention strategy (surfers 100%, Swimmers 92.7%, P = 0.003). Significantly more surfers were identified with a skin cancer of any type vs. swimmers (50% vs. 27.3%; OR 2.67; P = 0.005) with most the common skin cancer being PSC (44.7% vs. 11.3%, P = 0.076) followed by basal cell carcinoma (BCC) (24.2% vs. 7.6%, P = 0.068). There was a total of seven MSC identified in surfers and swimmers (4.6% vs. 0.8%, respectively, P = 0.137). Most skin cancers in surfers were located on the face (28.0%) followed by the arm and back (12.1% each), whereas in swimmers, the majority of skin cancers were identified on the face (17.3%), followed by the arm and lower leg (15.4% each). The highest number of melanomas were identified in surfers (n = 6) and mainly located on the face (n = 2) and back (n = 2). There was a single melanoma identified on the back in a swimmer. With the groups combined, the majority (42.9%) of melanomas were identified on the back in participants, followed by the face (28.6%). Rates per 100,000 of NMSC and MSC in surfers and swimmers (respectively) were BCC (11,206 vs. 14,545), squamous cell carcinoma (SCC) in situ (13,793 vs. 12,727), SCC (1,724 vs. 3,636) and MSC (5,172 vs. 1,818). When compared to the general Australian population, surfers and swimmers had higher odds ratios (OR), which included BCCs (OR 7.3 and 9.4, respectively), SCCs (OR 1.7 and 3.5, respectively) and MSC (OR 96.7 and 18.8, respectively). CONCLUSION: Surfers and swimmers had consistently higher rates of PSC, NMSC and MSC than the general Australian population. Point prevalence of MSC (groups combined) was 76-fold higher than the general Australian population. These findings highlight the clinical importance of regular skin cancer screenings in individuals who surf or swim for early detection and treatment of skin cancer. Additionally, these aquatic enthusiasts should be advised of the benefits of sun protection strategies such as chemical and physical barriers to reduce the likelihood of developing skin cancer

Implementation of artificial intelligence for the detection of cutaneous melanoma within a primary care setting: prevalence and types of skin cancer in outdoor enthusiasts

Background There is enthusiasm for implementing artificial intelligence (AI) to assist clinicians detect skin cancer. Performance metrics of AI from dermoscopic images have been promising, with studies documenting sensitivity and specificity values equal to or superior to specialists for the detection of malignant melanomas (MM). Early detection rates would particularly benefit Australia, which has the worlds highest incidence of MM per capita. The detection of skin cancer may be delayed due to late screening or the inherent difficulty in diagnosing early skin cancers which often have a paucity of clinical features and may blend into sun damaged skin. Individuals who participate in outdoor sports and recreation experience high levels of intermittent ultraviolet radiation (UVR), which is associated with the development of skin cancer, including MM. This research aimed to assess the prevalence of skin cancer in individuals who regularly participate in activities outdoors and to report the performance parameters of a commercially available AI-powered software to assess the predictive risk of MM development. Methods Cross-sectional study design incorporating a survey, total body skin cancer screening and AI-embedded software capable of predictive scoring of queried MM. Results A total of 423 participants consisting of surfers (n = 108), swimmers (n = 60) and walkers/runners (n = 255) participated. Point prevalence for MM was highest for surfers (6.48%), followed by walkers/runners (4.3%) and swimmers (3.33%) respectively. When compared to the general Australian population, surfers had the highest odds ratio (OR) for MM (OR 119.8), followed by walkers/runners (OR 79.74), and swimmers (OR 61.61) rounded out the populations. Surfers and swimmers reported comparatively lower lifetime hours of sun exposure (5,594 and 5,686, respectively) but more significant amounts of activity within peak ultraviolet index compared with walkers/runners (9,554 h). A total of 48 suspicious pigmented lesions made up of histopathology-confirmed MM (n = 15) and benign lesions (n = 33) were identified. The performance of the AI from this clinical population was found to have a sensitivity of 53.33%, specificity of 54.44% and accuracy of 54.17%. Conclusions Rates of both keratinocyte carcinomas and MM were notably higher in aquatic and land-based enthusiasts compared to the general Australian population. These findings further highlight the clinical importance of sun-safe protection measures and regular skin screening in individuals who spend significant time outdoors. The use of AI in the early identification of MM is promising. However, the lower-than-expected performance metrics of the AI software used in this study indicated reservations should be held before recommending this particular version of this AI software as a reliable adjunct for clinicians in skin imaging diagnostics in patients with potentially sun damaged skin

Springbok behaviour as affected by environmental conditions in the Kalahari

Springbok behavioural ecology in the Kalahari was examined with the use of public questionnaires and field forms. Springbok favoured grass and forbs overall more than shrubs and trees, but diet selection was influenced by time of day and season. Feeding was the most common activity and the frequency of occurrence varied during the day and between seasons. Weather and microhabitat conditions were found to have a significant effect on the feeding behaviour. Springbok fed in direct sunlight in the mornings and moved into the shade during the afternoon. More time was spent feeding in the shade during the warmer months than during the colder months, especially under northerly to northeasterly wind directions. Natural licks were commonly utilised. Herd sizes were found to increase during the cold-dry season and decrease during the hot-wet season. Springbok and blue wildebeest appeared to avoid competition by niche separation. The study showed that springbok behaviour was significantly affected by environmental conditions. These results imply that changes in climatic conditions, such as those predicted by climate change, or changes in vegetation structure due to degradation, can negatively affect springbok behaviour

Mitochondrially targeted vitamin E succinate efficiently kills breast tumour-initiating cells in a complex II-dependent manner

Background: Accumulating evidence suggests that breast cancer involves tumour-initiating cells (TICs), which play a role in initiation, metastasis, therapeutic resistance and relapse of the disease. Emerging drugs that target TICs are becoming a focus of contemporary research. Mitocans, a group of compounds that induce apoptosis of cancer cells by destabilising their mitochondria, are showing their potential in killing TICs. In this project, we investigated mitochondrially targeted vitamin E succinate (MitoVES), a recently developed mitocan, for its in vitro and in vivo efficacy against TICs.Methods: The mammosphere model of breast TICs was established by culturing murine NeuTL and human MCF7 cells as spheres. This model was verified by stem cell marker expression, tumour initiation capacity and chemotherapeutic resistance. Cell susceptibility to MitoVES was assessed and the cell death pathway investigated. In vivo efficacy was studied by grafting NeuTL TICs to form syngeneic tumours.Results: Mammospheres derived from NeuTL and MCF7 breast cancer cells were enriched in the level of stemness, and the sphere cells featured altered mitochondrial function. Sphere cultures were resistant to several established anti-cancer agents while they were susceptible to MitoVES. Killing of mammospheres was suppressed when the mitochondrial complex II, the molecular target of MitoVES, was knocked down. Importantly, MitoVES inhibited progression of syngeneic HER2(high) tumours derived from breast TICs by inducing apoptosis in tumour cells.Conclusions: These results demonstrate that using mammospheres, a plausible model for studying TICs, drugs that target mitochondria efficiently kill breast tumour-initiating cells

Validation of three Setswana measures for psychological wellbeing

Orientation: From the perspective of positive psychology, it is important to evaluate people’s strengths. There is, however, a lack of validated measures for these purposes in many of the South African official languages. As language is a medium for cultural meanings, measures of mental health should be validated in the mother tongue of the people involved. Research purpose: The aim of this study was therefore to explore the psychometric properties of Setswana versions of three measures of psychological wellbeing, namely the Sense of Coherence Scale (SOC) (the 29-item version) (Antonovsky, 1987), Satisfaction With Life Scale (SWLS) (Diener, Emmons, Larson & Griffen, 1985) and Affectometer 2 (AFM) (Kammann & Flett, 1983). Research design, approach and method: A cross-sectional survey design was implemented for this study. Questionnaires were translated, back-translated and evaluated in a research-committee approach. A stratified sample of 738 Setswana-speaking participants completed the questionnaires in randomly selected sites of the North West province of South Africa as part of the multi-disciplinary Transition and Health during Urbanisation of South Africans project. Reliability indices, means, standard deviations, ranges of scores, patterns of correlations and factor structures were established for all the scales. Main findings: The present Setswana SWLS and AFM are reliable and valid for use in this group, as is, to some extent, the SOC. The factor structures of the three scales were also consistent with the latent factor structures of the original scales. Practical implications: These validated measures are instruments for use in the clinical, community and work contexts of Setswana-speaking people