Tamoxifen and the Rafoxifene analog LY117018: their effects on arachidonic acid release from cells in culture and on prostaglandin I(2 )production by rat liver cells

BACKGROUND: Tamoxifen is being used successfully to treat breast cancer. However, tamoxifen also increases the risk of developing endometrial cancer in postmenopausal women. Raloxifene also decreases breast cancer in women at high risk and may have a lower risk at developing cancer of the uterus. Tamoxifen has been shown to stimulate arachidonic acid release from rat liver cells. I have postulated that arachidonic acid release from cells may be associated with cancer chemoprevention. METHODS: Rat liver, rat glial, human colon carcinoma and human breast carcinoma cells were labelled with [(3)H] arachidonic acid. The release of the radiolabel from these cells during incubation with tamoxifen and the raloxifene analog LY117018 was measured. The prostaglandin I(2 )produced during incubation of the rat liver cells with μM concentrations of tamoxifen and the raloxifene analog was quantitatively estimated. RESULTS: Tamoxifen is about 5 times more effective than LY117018 at releasing arachidonic acid from all the cells tested. In rat liver cells only tamoxifen stimulates basal prostaglandin I(2 )production and that induced by lactacystin and 12-O-tetradecanoyl-phorbol-13-acetate. LY117018, however, blocks the tamoxifen stimulated prostaglandin production. The stimulated prostaglandin I(2 )production is rapid and not affected either by preincubation of the cells with actinomycin or by incubation with the estrogen antagonist ICI-182,780. CONCLUSIONS: Tamoxifen and the raloxifene analog, LY117018, may prevent estrogen-independent as well as estrogen-dependent breast cancer by stimulating phospholipase activity and initiating arachidonic acid release. The release of arachidonic acid and/or molecular reactions that accompany that release may initiate pathways that prevent tumor growth. Oxygenation of the intracellularly released arachidonic acid and its metabolic products may mediate some of the pharmacological actions of tamoxifen and raloxifene

Entrepreneurial sons, patriarchy and the Colonels' experiment in Thessaly, rural Greece

Existing studies within the field of institutional entrepreneurship explore how entrepreneurs influence change in economic institutions. This paper turns the attention of scholarly inquiry on the antecedents of deinstitutionalization and more specifically, the influence of entrepreneurship in shaping social institutions such as patriarchy. The paper draws from the findings of ethnographic work in two Greek lowland village communities during the military Dictatorship (1967–1974). Paradoxically this era associated with the spread of mechanization, cheap credit, revaluation of labour and clear means-ends relations, signalled entrepreneurial sons’ individuated dissent and activism who were now able to question the Patriarch’s authority, recognize opportunities and act as unintentional agents of deinstitutionalization. A ‘different’ model of institutional change is presented here, where politics intersects with entrepreneurs, in changing social institutions. This model discusses the external drivers of institutional atrophy and how handling dissensus (and its varieties over historical time) is instrumental in enabling institutional entrepreneurship

Sustained favorable long-term outcome in the treatment of schizophrenia: a 3-year prospective observational study

<p>Abstract</p> <p>Background</p> <p>This study of chronically ill patients with schizophrenia aimed to identify patients who achieve sustained favorable long-term outcome - when the outcome incorporates severity of symptoms, level of functioning, and use of acute care services - and to identify the best baseline predictors of achieving this sustained favorable long-term outcome.</p> <p>Methods</p> <p>Using data from the United States Schizophrenia Care and Assessment Program (US-SCAP) (N = 2327), a large 3-year prospective, multisite, observational study of individuals treated for schizophrenia in the US, a hierarchical cluster analysis was performed to group patients based upon baseline symptom severity. Symptom severity was assessed using the Positive and Negative Syndrome Scale (PANSS) scores, level of functioning, and use of acute care services. Level of functioning reflected patient-reported productivity and clinician-rated occupational role functioning. Use of acute care services reflected self-reported psychiatric hospitalization and emergency service use. Change of health state was determined over the 3-year period. A patient was classified as having a sustained favorable long-term outcome if their health state values had the closest distance to the defined "best baseline cluster" at each point over the length of the study. Stepwise logistic regression was used to determine baseline predictors of sustained favorable long-term outcome.</p> <p>Results</p> <p>At baseline, 5 distinct health state clusters were identified, ranging from "best" to "worst." Of 1635 patients with sufficient data, only 157 (10%) experienced sustained favorable long-term outcome during the 2-years postbaseline. The baseline predictors associated with sustained favorable long-term outcome included better quality of life, more daily activities, patient-reported clearer thinking from medication, better global functioning, being employed, not being a victim of a crime, not having received individual therapy, and not having received help with shopping and leisure activities.</p> <p>Conclusions</p> <p>Only a small percentage of patients achieved sustained favorable long-term outcome in this study, suggesting there continues to be a great need for improvement in the treatment of schizophrenia. Findings suggest that clinicians could make early projections of health states and identify those patients more likely to achieve favorable long-term outcomes enabling early therapeutic interventions to enhance benefits for patients.</p

Made by hand

Although the mainstream animation industry has adopted digital production methods, the attraction of laborious hand-made methods for making animation persists in the independent sector. The chapter considers how ‘craftivist’ opposition to mechanical, technological and digital techniques is validated in this community of practice through ideas that haptic knowledge by skilled physical labour and an exploration of materiality, autographic mark-making and imperfection (Wabi-sabi) are guarantors of authenticity and individuality that can only be carried out by hand. Why is this? What ideas and assumptions can be seen to underpin the notions of craft and crafting? Tracing connections between craft and activism since the Industrial Revolution, this chapter critically reflects on discourses of craft and the handmade through reference to Ruskin (1851), Morris (1892), Hobsbawm (2000), Thompson (1980), Benjamin (1935), Krauss (2000) and Takahashi (2005). Whereas the experimental animation community privileges analogue, handmade processes that appear to oppose and critique commercial animation production, building upon Warburton (2016) and Frayling (2017) it is argued here that this approach is underpinned by nostalgia and often faked. What looks like a hand-painted animation could actually be a simulation that was ‘painted’ in a software package: a pastiche of manual labour. Aesthetics alone do not guarantee that a work of art opposes the mainstream. Instead of recycling the past to create ‘artistic’ animation, it is argued in the conclusion that contemporary practitioners can equally investigate issues of labour and materiality through digital tools and virtual materials such as in the ‘ugly’ CGI animation of Nikita Daikur (2017)

Enhanced prediction of breast cancer prognosis by evaluating expression of p53 and prostate-specific antigen in combination

p53 gene mutation is the most common genetic alteration in neoplastic diseases, including breast cancer, for which p53 alteration may indicate poor prognosis. Recent clinical evidence suggests that prostate-specific antigen (PSA) expression may identify breast cancer patients with favourable outcome. Assessment of p53 and PSA in combination, potentially offering improved prediction, has not yet been performed. Extracts from 952 primary breast carcinomas were assayed for PSA and p53 by quantitative enzyme-linked immunosorbent assays (ELISAs) developed by the authors. Concentrations of each marker were classified as negative or positive on the basis of median and 30th percentile cut-off points for p53 and PSA respectively. Patients followed for a median of 6 years having different combinations of negative or positive status for PSA and p53 were compared with respect to the relative risks (RRs) for relapse and death by Cox proportional hazards regression analysis, in which an interaction term was also evaluated, and with respect to disease-free survival (DFS) and overall survival (OS) probabilities by Kaplan–Meier plots and log-rank tests. Multivariate models were adjusted for oestrogen and progesterone receptor status, nodal status, patient age, tumour size, DNA ploidy, S phase fraction and receipt of chemotherapy. Interactions were not found between the status of PSA and p53 in the Cox models, in which PSA-negativity (RR = 1.47, P = 0.020 for DFS, and RR = 1.49, P = 0.023 for OS) and p53-positivity (RR = 1.46, P = 0.017 for DFS, and RR = 1.41, P = 0.033 for OS) were individually associated with prognosis. Evaluation of a combined three-level variable revealed that PSA(–)/p53(+) patients had significantly higher risks for relapse (RR = 2.13, P < 0.001) and death (RR = 2.08, P = 0.001) than PSA(+)/p53(–) patients, and that patients positive or negative for both markers had intermediate risks for the outcome events in the same multivariate analysis (RR = 1.45 for both DFS and OS). The results of our study demonstrate that the assessment of combined PSA and p53 expression status by ELISAs, easily applicable to breast tumour extracts prepared for steroid hormone receptor analyses, may stratify breast cancer patients into groups differing by relapse and death risks of greater magnitude than offered by the assessment of either p53 or PSA alone. © 1999 Cancer Research Campaig

Bank performance and executive pay: tournament or teamwork

We investigate the relationship between the dispersion of executive pay and bank performance/valuation by examining two competing theories, the tournament theory (hierarchical wage structure) and the equity fairness theory (compressed wage structure). The key variable of executive pay dispersion is measured using a hand-collected dataset composed of 63 banks from OECD countries and 29 banks from developing countries. The dataset covers the period 2004 to 2012. By combining and modifying a translog profit function and a pay-dispersion model, we are able to address the potential problems of relying on reduced-form estimation. In our subsample of developed and civil law countries, where bank performance is measured by either Tobin’s Q or by the price-to-book ratio, the overall impact of executive pay dispersion is mostly negative, and we find supporting evidence for the equity fairness theory, except for very high levels of dispersion. There is a non-linear effect, as banks perform best when there is either very low or very high executive pay dispersion. For developing country sample banks, greater executive pay dispersion has a negative impact on bank profit. In our subsample of common law countries, however, we find no evidence of a significant impact of executive pay dispersion on bank performance. We conclude that lower executive pay dispersion, a proxy for teamwork, is mostly effective in enhancing bank performance in a significant section of sample banks, i.e., civil law and developing countries

Discovering functional modules by identifying recurrent and mutually exclusive mutational patterns in tumors

<p>Abstract</p> <p>Background</p> <p>Assays of multiple tumor samples frequently reveal recurrent genomic aberrations, including point mutations and copy-number alterations, that affect individual genes. Analyses that extend beyond single genes are often restricted to examining pathways, interactions and functional modules that are already known.</p> <p>Methods</p> <p>We present a method that identifies functional modules without any information other than patterns of recurrent and mutually exclusive aberrations (RME patterns) that arise due to positive selection for key cancer phenotypes. Our algorithm efficiently constructs and searches networks of potential interactions and identifies significant modules (RME modules) by using the algorithmic significance test.</p> <p>Results</p> <p>We apply the method to the TCGA collection of 145 glioblastoma samples, resulting in extension of known pathways and discovery of new functional modules. The method predicts a role for <it>EP300 </it>that was previously unknown in glioblastoma. We demonstrate the clinical relevance of these results by validating that expression of <it>EP300 </it>is prognostic, predicting survival independent of age at diagnosis and tumor grade.</p> <p>Conclusions</p> <p>We have developed a sensitive, simple, and fast method for automatically detecting functional modules in tumors based solely on patterns of recurrent genomic aberration. Due to its ability to analyze very large amounts of diverse data, we expect it to be increasingly useful when applied to the many tumor panels scheduled to be assayed in the near future.</p

tAnGo: a randomised phase III trial of gemcitabine in paclitaxel-containing, epirubicin/cyclophosphamide-based, adjuvant chemotherapy for early breast cancer: a prospective pulmonary, cardiac and hepatic function evaluation

tAnGo is a large randomised trial assessing the addition of gemcitabine(G) to paclitaxel(T), following epirubicin(E) and cyclophosphamide(C) in women with invasive higher risk early breast cancer. To assess the safety and tolerability of adding G, a detailed safety substudy was undertaken. A total of 135 patients had cardiac, pulmonary and hepatic function assessed at (i) randomisation, (ii) mid-chemotherapy, (iii) immediately post-chemotherapy and (iv) 6 months post-chemotherapy. Skin toxicity was assessed during radiotherapy. No differences were detected in FEV1 or FVC levels between treatment arms or time points. Diffusion capacity (TLCO) reduced during treatment (P<0.0001), with a significantly lower drop in EC-GT patients (P=0.02). Most of the reduction occurred during EC and recovered by 6-months post treatment. There was no difference in cardiac function between treatment arms. Only 11 patients had echocardiography/MUGA results change from normal to abnormal during treatment, with only five having LVEF<50%. Transient transaminitis occurred in both treatment arms with significantly more in EC-GT patients post-chemotherapy (AST P=0.03, ALT P=0.003), although the majority was low grade. There was no correlation between transaminitis and other toxicities. Both treatment regimens reported temporary reductions in pulmonary functions and transient transaminitis levels. Despite these being greater with EC-GT, both regimens appear well tolerated