FAK activity sustains intrinsic and acquired ovarian cancer resistance to platinum chemotherapy.

Gene copy number alterations, tumor cell stemness, and the development of platinum chemotherapy resistance contribute to high-grade serous ovarian cancer (HGSOC) recurrence. Stem phenotypes involving Wnt-β-catenin, aldehyde dehydrogenase activities, intrinsic platinum resistance, and tumorsphere formation are here associated with spontaneous gains in Kras, Myc and FAK (KMF) genes in a new aggressive murine model of ovarian cancer. Adhesion-independent FAK signaling sustained KMF and human tumorsphere proliferation as well as resistance to cisplatin cytotoxicity. Platinum-resistant tumorspheres can acquire a dependence on FAK for growth. Accordingly, increased FAK tyrosine phosphorylation was observed within HGSOC patient tumors surviving neo-adjuvant chemotherapy. Combining a FAK inhibitor with platinum overcame chemoresistance and triggered cell apoptosis. FAK transcriptomic analyses across knockout and reconstituted cells identified 135 targets, elevated in HGSOC, that were regulated by FAK activity and β-catenin including Myc, pluripotency and DNA repair genes. These studies reveal an oncogenic FAK signaling role supporting chemoresistance

Age group, location or pedagogue: factors affecting parental choice of kindergartens in Hungary

Hungary has experienced significant political, economic, demographic and social changes since the end of Soviet domination in the 1990s. The gradual move towards liberal-democracy has been accompanied by growing emphasis on individualism, choice and diversity. Universal kindergarten provision for 5-6 year olds is a long established feature of the Hungarian education system, but little is known about parental choice (Török, 2004). A case study (Yin, 2004) of factors influencing parental choice and satisfaction was undertaken in one Hungarian town. This was based on a survey of 251 parents of children attending both mixed-age and same-age groups across 12 kindergartens. Parents suggested that the most important influences were geographical location and the individual pedagogue(s). Given that traditionally each pedagogue follows ‘their’ cohort from kindergarten entry to primary school, their influence appears heightened. Although generally satisfied with their chosen arrangement, parents from same-age groups expressed significantly more confidence and satisfaction, particularly in relation to cognitive development and preparation for school. Parents appear less convinced about the trend towards mixed-age groups and questions are raised about sufficiency of evidence of their benefits in a Hungarian context and the driving factors behind change

Coexpression of Nuclear Receptors and Histone Methylation Modifying Genes in the Testis: Implications for Endocrine Disruptor Modes of Action

BACKGROUND: Endocrine disruptor chemicals elicit adverse health effects by perturbing nuclear receptor signalling systems. It has been speculated that these compounds may also perturb epigenetic mechanisms and thus contribute to the early origin of adult onset disease. We hypothesised that histone methylation may be a component of the epigenome that is susceptible to perturbation. We used coexpression analysis of publicly available data to investigate the combinatorial actions of nuclear receptors and genes involved in histone methylation in normal testis and when faced with endocrine disruptor compounds. METHODOLOGY/PRINCIPAL FINDINGS: The expression patterns of a set of genes were profiled across testis tissue in human, rat and mouse, plus control and exposed samples from four toxicity experiments in the rat. Our results indicate that histone methylation events are a more general component of nuclear receptor mediated transcriptional regulation in the testis than previously appreciated. Coexpression patterns support the role of a gatekeeper mechanism involving the histone methylation modifiers Kdm1, Prdm2, and Ehmt1 and indicate that this mechanism is a common determinant of transcriptional integrity for genes critical to diverse physiological endpoints relevant to endocrine disruption. Coexpression patterns following exposure to vinclozolin and dibutyl phthalate suggest that coactivity of the demethylase Kdm1 in particular warrants further investigation in relation to endocrine disruptor mode of action. CONCLUSIONS/SIGNIFICANCE: This study provides proof of concept that a bioinformatics approach that profiles genes related to a specific hypothesis across multiple biological settings can provide powerful insight into coregulatory activity that would be difficult to discern at an individual experiment level or by traditional differential expression analysis methods

ethics and/or Ethics in qualitative social research: negotiating a path around and between the two

This article explores the process of university Ethical Review both as lived experience and as part of institutional governance at an English university. The article uses Blackburn's distinction between ethics and Ethics (Ethics—A Very Short Introduction, Oxford University Press, Oxford, 2001) as a framework to examine the themes of ‘vulnerability’, ‘power’ and ‘relationships’. These themes are analysed closely both within the institutional and the fieldwork contexts, attempting to include the perspectives of all those involved in the research ethics process. The article does not seek to draw any definitive conclusions but rather to stimulate, and add to the iterative discussion on the process of Ethical Review within institutions. Nonetheless, it does conclude by making some suggestions concerning the way in which the lived experience of ethics could better inform the practice of institutional Ethical Review

Scientists' Warning to Humanity on Threats to Indigenous and Local Knowledge Systems

The knowledge systems and practices of Indigenous Peoples and local communities play critical roles in safeguarding the biological and cultural diversity of our planet. Globalization, government policies, capitalism, colonialism, and other rapid social-ecological changes threaten the relationships between Indigenous Peoples and local communities and their environments, thereby challenging the continuity and dynamism of Indigenous and Local Knowledge (ILK). In this article, we contribute to the “World Scientists' Warning to Humanity,” issued by the Alliance of World Scientists, by exploring opportunities for sustaining ILK systems on behalf of the future stewardship of our planet. Our warning raises the alarm about the pervasive and ubiquitous erosion of knowledge and practice and the social and ecological consequences of this erosion. While ILK systems can be adaptable and resilient, the foundations of these knowledge systems are compromised by ongoing suppression, misrepresentation, appropriation, assimilation, disconnection, and destruction of biocultural heritage. Three case studies illustrate these processes and how protecting ILK is central to biocultural conservation. We conclude with 15 recommendations that call for the recognition and support of Indigenous Peoples and local communities and their knowledge systems. Enacting these recommendations will entail a transformative and sustained shift in how ILK systems, their knowledge holders, and their multiple expressions in lands and waters are recognized, affirmed, and valued. We appeal for urgent action to support the efforts of Indigenous Peoples and local communities around the world to maintain their knowledge systems, languages, stewardship rights, ties to lands and waters, and the biocultural integrity of their territories—on which we all depend.Peer reviewe

Measurement of the cosmic ray spectrum above 4×10184{\times}10^{18} eV using inclined events detected with the Pierre Auger Observatory

A measurement of the cosmic-ray spectrum for energies exceeding $4{\times}10^{18}$ eV is presented, which is based on the analysis of showers with zenith angles greater than $60^{\circ}$ detected with the Pierre Auger Observatory between 1 January 2004 and 31 December 2013. The measured spectrum confirms a flux suppression at the highest energies. Above $5.3{\times}10^{18}$ eV, the "ankle", the flux can be described by a power law $E^{-\gamma}$ with index $\gamma=2.70 \pm 0.02 \,\text{(stat)} \pm 0.1\,\text{(sys)}$ followed by a smooth suppression region. For the energy ($E_\text{s}$) at which the spectral flux has fallen to one-half of its extrapolated value in the absence of suppression, we find $E_\text{s}=(5.12\pm0.25\,\text{(stat)}^{+1.0}_{-1.2}\,\text{(sys)}){\times}10^{19}$ eV.Comment: Replaced with published version. Added journal reference and DO

Pan-cancer Alterations of the MYC Oncogene and Its Proximal Network across the Cancer Genome Atlas

Although theMYConcogene has been implicated incancer, a systematic assessment of alterations ofMYC, related transcription factors, and co-regulatoryproteins, forming the proximal MYC network (PMN),across human cancers is lacking. Using computa-tional approaches, we define genomic and proteo-mic features associated with MYC and the PMNacross the 33 cancers of The Cancer Genome Atlas.Pan-cancer, 28% of all samples had at least one ofthe MYC paralogs amplified. In contrast, the MYCantagonists MGA and MNT were the most frequentlymutated or deleted members, proposing a roleas tumor suppressors.MYCalterations were mutu-ally exclusive withPIK3CA,PTEN,APC,orBRAFalterations, suggesting that MYC is a distinct onco-genic driver. Expression analysis revealed MYC-associated pathways in tumor subtypes, such asimmune response and growth factor signaling; chro-matin, translation, and DNA replication/repair wereconserved pan-cancer. This analysis reveals insightsinto MYC biology and is a reference for biomarkersand therapeutics for cancers with alterations ofMYC or the PMN