Inhibitors of the Fanconi Anaemia pathway as potential antitumour agents for ovarian cancer

The Fanconi anaemia (FA) pathway is an important mechanism for cellular DNA damage repair, which functions to remove toxic DNA interstrand crosslinks. This is particularly relevant in the context of ovarian and other cancers which rely extensively on interstrand cross-link generating platinum chemotherapy as standard of care treatment. These cancers often respond well to initial treatment, but reoccur with resistant disease and upregulation of DNA damage repair pathways. The FA pathway is therefore of great interest as a target for therapies that aim to improve the efficacy of platinum chemotherapies, and reverse tumour resistance to these. In this review, we discuss recent advances in understanding the mechanism of interstrand cross-link repair by the FA pathway, and the potential of the component parts as targets for therapeutic agents. We then focus on the current state of play of inhibitor development, covering both the characterisation of broad spectrum inhibitors and high throughput screening approaches to identify novel small molecule inhibitors. We also consider synthetic lethality between the FA pathway and other DNA damage repair pathways as a therapeutic approach

Professor Andrew David Hamilton Wyllie – Biographical Memoir

Andrew Wyllie graduated from Aberdeen University, becoming an academic pathologist in Aberdeen, Edinburgh and Cambridge. He was the co-discoverer of apoptotic cell death having observed single cells dying following carcinogen exposure. Together with Alastair Currie and John Kerr, he realised the profound importance of this novel mode of cell death that showed a distinctive series of morphological changes, which he first described as a new cell death process. Wyllie and Currie introduced the term “apoptosis” for this cell death process in a seminal paper in 1972. Another landmark discovery was of chromatin fragmentation in apoptosis, due to activation of an endogenous endonuclease that caused internucleosomal DNA cleavage (“chromatin laddering”), which was the first biochemical mechanism of apoptosis. He further characterised chromatin fragmentation in the 1980s, followed by investigations of cell surface changes to produce “eat-me” signals to trigger rapid phagocytosis of the apoptotic cells and bodies, intracellular calcium ion signalling, caspase activation and other mechanisms of apoptosis. His cancer research helped identify the location of APC and generated his demonstration that apoptosis was regulated by oncogenes, MYC and RAS, and tumour suppressor genes, such as TP53. He showed how apoptosis occurred in response to DNA damage and was a key process influencing both carcinogenesis and tumour growth. Andrew made a major scientific observation that changed the understanding of how cells die in health and disease, although it took time for the scientific establishment to understand its fundamental importance. Andrew Wyllie is widely known as the ‘Father of Apoptosis’

The quantity-quality transition in Asia

Societies in which fertility is falling and human capital investment per child increasing are experiencing a “quantity-quality transition.” Such transitions imply, over the long term, both slower rates of labor force growth and higher levels of human capital per worker. They are fundamental to economic development. Yet, these transitions are neither automatic or self-propelling. Their momentum depends on competing forces acting at both the family and the macroeconomic levels; the balance can easily tip against further transition. Family decisions about schooling are largely motivated by its private economic returns. These returns are determined in labor markets, and here the logic of supply and demand applies. When families decide to invest more deeply in their children, they collectively produce right-ward shifts in the supply of educated young labor. If other things are held fixed, the rate of return to schooling should then fall, and this, in turn, should dampen parental enthusiasm for further educational investments. Reductions in the rate of return should also weaken the case for continued reductions in fertility. Unless they are counterbalanced by other forces, such negative feedbacks would tend to bring a quantity-quality transition to a halt. The aim of this paper is to explore both the negative and positive feedbacks that have affected the quantity-quality transition in Asia. We assemble the leading hypotheses and evidence on the macroeconomic forces, both domestic and international, that could influence returns to schooling. We also examine family factors, giving particular attention to the intergenerational links that seem to have maintained the momentum of the Asian transition. Our conclusion is that negative feedbacks associated with increases in the relative supplies of educated labor have been largely offset by beneficial macroeconomic change (resulting from increases in the stock of physical capital, substantial technological change, and trade) and by powerful family-level effects that, over the generations, have continued to propel the transition

Portland Roasting Company: Farm Friendly Direct

This case describes the issues and dilemmas facing a company in their efforts to differentiate their product through a social sustainability programme. Over the years, the company has built a strong reputation with their sustainability efforts, particularly amongst their peers in the specialty coffee industry. There is some question as to whether this reputation has been visible to consumers and if consumers see the value-proposition. The case covers the history of coffee, the specialty coffee industry, the supply chain and roles of different participants, and the competitive landscape. Furthermore, most of the competitive eco-labels and certification schemes are discussed. The reader is asked to decide the appropriate method for conveying the company’s social sustainability efforts to the marketplace and beyond that, to consider how one might measure and monitor social programs in the developing world. The case is designed to highlight decisions related to marketing and operations strategy, pros and cons of certification, and particularly social sustainability versus the other aspects of sustainability

Activation of K-RAS by co-mutation of codons 19 and 20 is transforming.

The K-RAS oncogene is widely mutated in human cancers. Activating mutations in K-RAS give rise to constitutive signalling through the MAPK/ERK and PI3K/AKT pathways promoting increased cell division, reduced apoptosis and transformation. The majority of activating mutations in K-RAS are located in codons 12 and 13. In a human colorectal cancer we identified a novel K-RAS co-mutation that altered codons 19 and 20 resulting in transitions at both codons (L19F/T20A) in the same allele. Using focus forming transformation assays in vitro , we showed that co-mutation of L19F/T20A in K-RAS demonstrated intermediate transforming ability that was greater than that of individual L19F and T20A mutants, but less than that of G12D and G12V K-RAS mutants. This demonstrated the synergistic effects of co-mutation of codons 19 and 20 and illustrated that co-mutation of these codons is functionally significant.RIGHTS : This article is licensed under the BioMed Central licence at http://www.biomedcentral.com/about/license which is similar to the 'Creative Commons Attribution Licence'. In brief you may : copy, distribute, and display the work; make derivative works; or make commercial use of the work - under the following conditions: the original author must be given credit; for any reuse or distribution, it must be made clear to others what the license terms of this work are