HAGE, a cancer/testis antigen expressed at the protein level in a variety of cancers

The search for novel tumour antigens that are either uniquely expressed or over-expressed in a wide variety of tumours is still ongoing. Because of their expression in a broad spectrum of cancers and limited expression in normal tissues, cancer/testis antigens are considered to be potentially reliable targets for immunotherapy of cancer in general. The helicase antigen HAGE has been identified as a cancer/testis antigen. However, little is known about its expression in normal and cancer tissues. Using a newly developed antibody against HAGE, specific staining of its expression by immunohistochemistry was validated and optimised on murine tumours transfected to express the HAGE protein. The antibody was subsequently used to determine HAGE expression in normal human and cancer tissue microarrays. HAGE protein expression was confirmed in 75% (12/16) of carcinomas as compared to normal tissues, which either did not express HAGE at all or expressed HAGE at very low levels with the exception of testis. Interestingly, discrepancies were also found between mRNA analysis by real time quantitative PCR (RT-qPCR) and protein analysis by immunohistochemistry, emphasising the need to validate the expression of cancer/testis antigens at the protein level prior to the development of new vaccine strategies. HAGE is therefore proposed to be a valid candidate for designing a broad spectrum vaccine against cancer

The development of the Meaning in Life Index (MILI) and its relationship with personality and religious behaviours and beliefs among UK undergraduate students

The scales available for assessing meaning in life appear to be confounded with several related constructs, including purpose in life, satisfaction with life, and goal-directed behaviour. The Meaning in Life Index (MILI), a new instrument devised as a specific measure of meaning in life, was developed from responses to a pool of 22 items rated by a sample of 501 undergraduate students in Wales. The nine-item scale demonstrated sufficient face validity, internal consistency, and scale reliability to commend the instrument for future use. With respect to personality, the MILI scores were most strongly predicted by neuroticism (negatively), and less strongly by extraversion (positively) and psychoticism (negatively). With respect to several religious behavioural variables, those who attended church at least weekly returned significantly higher MILI scores than those who attended church less frequently. Intrinsic religiosity was the only orientation to be significantly associated with the MILI scale scores, although the magnitude of the association was smaller than anticipated. These results suggest that meaning in life is associated more strongly with individual differences in personality than with specific religious behaviours and attitudes. The implications of these results are discussed in terms of individual's personal values and attitudes that might underlie their experience of a meaning in life

Evaluating the taxa that provide shared pollination services across multiple crops and regions

Many pollinator species visit multiple crops in multiple regions, yet we know little about their pollination service provisioning at local and regional scales. We investigated the floral visitors (n = 13,200), their effectiveness (n = 1718 single visits) and response to landscape composition across three crops avocado, mango and macadamia within a single growing region (1 year), a single crop (3 years) and across different growing regions in multiple years. In total, eight wild visitor groups were shared across all three crops. The network was dominated by three pollinators, two bees (Apis mellifera and Tetragonula spp.) and a fly, Stomorhina discolor. The visitation network for the three crops was relatively generalised but with the addition of pollen deposition data, specialisation increased. Sixteen managed and wild taxa were consistently present across three years in avocado, yet their contribution to annual network structure varied. Node specialisation (d’) analyses indicated many individual orchard sites across each of the networks were significantly more specialised compared to that predicted by null models, suggesting the presence of site-specific factors driving these patterns. Identifying the taxa shared across multiple crops, regions and years will facilitate the development of specific pollinator management strategies to optimize crop pollination services in horticultural systems

HAGE (DDX43) is a biomarker for poor prognosis and a predictor of chemotherapy response in breast cancer

Background: HAGE protein is a known immunogenic cancer-specific antigen. Methods: The biological, prognostic and predictive values of HAGE expression was studied using immunohistochemistry in three cohorts of patients with BC (n=2147): early primary (EP-BC; n=1676); primary oestrogen receptor-negative (PER-BC; n=275) treated with adjuvant anthracycline-combination therapies (Adjuvant-ACT); and primary locally advanced disease (PLA-BC) who received neo-adjuvant anthracycline-combination therapies (Neo-adjuvant-ACT; n=196). The relationship between HAGE expression and the tumour-infiltrating lymphocytes (TILs) in matched prechemotherapy and postchemotherapy samples were investigated. Results: Eight percent of patients with EP-BC exhibited high HAGE expression (HAGEþ) and was associated with aggressive clinico-pathological features (Ps<0.01). Furthermore, HAGEþexpression was associated with poor prognosis in both univariate and multivariate analysis (Ps<0.001). Patients with HAGE+ did not benefit from hormonal therapy in high-risk ER-positive disease. HAGE+ and TILs were found to be independent predictors for pathological complete response to neoadjuvant-ACT; P<0.001. A statistically significant loss of HAGE expression following neoadjuvant-ACT was found (P=0.000001), and progression-free survival was worse in those patients who had HAGE+ residual disease (P=0.0003). Conclusions: This is the first report to show HAGE to be a potential prognostic marker and a predictor of response to ACT in patients with BC

A proteomic study of human Merkel Cell Carcinoma

Merkel Cell Carcinoma (MCC) is an aggressive neuroendocrine cancer of the skin. The incidence has been quadrupled with a 5-year mortality rate of 46%, presently there is no cure for metastatic disease. Despite the contribution of Merkel cell polyomavirus, the molecular events of MCC carcinogenesis are poorly defined. To better understand MCC carcinogensis, we have performed the first quantitative proteomic comparison of formalin-fixed, paraffin-embedded (FFPE) MCC tissues using another neuroendocrine tumor (carcinoid tumor of the lung) as controls. Bioinformatic analysis of the proteomic data has revealed that MCCs carry distinct protein expression patterns. Further analysis of significantly over-expressed proteins suggested the involvement of MAPK, PI3K/Akt/mTOR, wnt, and apoptosis signaling pathways. Our previous study and that from others have shown mTOR activation in MCCs. Therefore, we have focused on two downstream molecules of the mTOR pathway, lactate dehydrogenase B (LDHB) and heterogeneous ribonucleoprotein F (hnRNPF). We confirm over-expression of LDHB and hnRNPF in two primary human MCC cell lines, 16 fresh tumors, and in the majority of 80 tissue microarray samples. Moreover, mTOR inhibition suppresses LDHB and hnRNPF expression in MCC cells. The results of the current study provide insight into MCC carcinogenesis and provide rationale for mTOR inhibition in pre-clinical studies

How robust are value judgements of health inequality aversion? Testing for framing and cognitive effects

Background: Empirical studies have found that members of the public are inequality averse and value health gains for disadvantaged groups with poor health many times more highly than gains for better off groups. However, these studies typically use abstract scenarios that involve unrealistically large reductions in health inequality, and face-to-face survey administration. It is not known how robust these findings are to more realistic scenarios or anonymous online survey administration. Methods: This study aimed to test the robustness of questionnaire estimates of inequality aversion by comparing the following: (1) small versus unrealistically large health inequality reductions; (2) population-level versus individual-level descriptions of health inequality reductions; (3) concrete versus abstract intervention scenarios; and (4) online versus face to face mode of administration. Fifty-two members of the public participated in face-to-face discussion groups, while 83 members of the public completed an online survey. Participants were given a questionnaire instrument with different scenario descriptions for eliciting aversion to social inequality in health. Results: The median respondent was inequality averse under all scenarios. Scenarios involving small rather than unrealistically large health gains made little difference in terms of inequality aversion, as did population-level rather than individual-level scenarios. However, the proportion expressing extreme inequality aversion fell 19 percentage points when considering a specific health intervention scenario rather than an abstract scenario, and was 11-21 percentage points lower among online public respondents compared to the discussion group. Conclusions: Our study suggests that both concrete scenarios and online administration reduce the proportion expressing extreme inequality aversion but still yield median responses implying substantial health inequality aversion

The Relative Importance of Clinical, Economic, Patient Values and Feasibility Criteria in Cancer Drug Reimbursement in Canada:A Revealed Preferences Analysis of Recommendations of the Pan-Canadian Oncology Drug Review 2011–2017

Background: Most Canadian provinces and territories rely on the pan-Canadian Oncology Drug Review (pCODR) to provide recommendations regarding public reimbursement of cancer drugs. The pCODR review process considers four dimensions of value—clinical benefit, economic evaluation, patient-based values and adoption feasibility—but they do not define weights for individual decision criteria or an acceptable threshold for any of the criteria. Given this implicit review process, it is of interest to understand which factors appear to carry the most weight in pCODR recommendations using a revealed preferences approach. Methods: Using publicly available decision summaries (n = 91) describing submissions and resulting recommendations 2011–2017, we extracted ten attributes that characterized each submission. Using logistic regression, we identified statistically significant attributes and estimated their relative impact in final recommendations. Results: Clinical aspects appear to carry the greatest weight in the decision to reject or not reject, along with aspects of patient value (treatments with no alternatives were less likely to be rejected). Cost effectiveness does not appear to play a role in the initial decision to reject or not reject but is critical in full versus conditional approvals. There is evidence of a maximum acceptable threshold of around $Can140,000 per quality-adjusted life-year (QALY) gained. Conclusion: A set of factors driving pCODR recommendations is identifiable, supporting the consistency of the review process. However, the implicit nature of the review process and the difficulty of extracting and interpreting some of the attribute levels used in the analysis suggests that the process may still lack full transparency

Depression and anxiety symptoms post-stroke/TIA:prevalence and associations in cross-sectional data from a regional stroke registry

BACKGROUND: Mood disorders are commonly seen in those with cerebrovascular disease. Literature to-date has tended to focus on depression and on patients with stroke, with relatively little known about post-stroke anxiety or mood disorder in those with transient ischaemic attack (TIA). We aimed to describe prevalence of depression and anxiety symptoms in stroke and TIA cohorts and to explore association with clinical and socio-demographic factors. METHODS: We used a city wide primary care stroke registry (Glasgow Local Enhanced Service for Stroke - LES). All community dwelling stroke-survivors were included. We described cross-sectional prevalence of depression and anxiety symptoms using the Hospital Anxiety and Depression Scale (HADS). Data on clinical and demographic details was collected and univariable and multivariable analyses performed to describe associations with HADS scores. We examined those with a diagnosis of 'stroke' and 'TIA' as separate cohorts. RESULTS: From 13,283 potentially eligible stroke patients in the registry, we had full HADS data on 4,079. Of the 3,584 potentially eligible TIA patients, we had full HADS data on 1,247 patients. Across the stroke cohort, 1181 (29%) had HADS anxiety scores suggestive of probable or possible anxiety; 993 (24%) for depression. For TIA patients, 361 (29%) had anxiety and 254 (21%) had depression. Independent predictors of both depression and anxiety symptoms were female sex, younger age and higher socioeconomic deprivation score (all p < 0.001). CONCLUSION: Using HADS, we found a high prevalence of anxiety and depression symptoms in a community-based cohort of patients with cerebrovascular disease