Hannah Smith

Metabolic Alterations During the Growth of Tumour Spheroids

Abstract Solid tumours undergo considerable alterations in their metabolism of nutrients in order to generate sufficient energy and biomass for sustained growth and proliferation. During growth, the tumour microenvironment exerts a number of influences (e.g. hypoxia and acidity) that affect cellular biology and the flux or utilisation of fuels including glucose. The tumour spheroid model was used to characterise the utilisation of glucose and describe alterations to the activity and expression of key glycolytic enzymes during the tissue growth curve. Glucose was avidly consumed and associated with the production of lactate and an acidified medium, confirming the reliance on glycolytic pathways and a diminution of oxidative phosphorylation. The expression levels and activities of hexokinase, phosphofructokinase-1, pyruvate kinase and lactate dehydrogenase in the glycolytic pathway were measured to assess glycolytic capacity. Similar measurements were made for glucose-6-phosphate dehydrogenase, the entry point and regulatory step of the pentose-phosphate pathway (PPP) and for cytosolic malate dehydrogenase, a key link to TCA cycle intermediates. The parameters for these key enzymes were shown to undergo considerable variation during the growth curve of tumour spheroids. In addition, they revealed that the dynamic alterations were influenced by both transcriptional and posttranslational mechanisms.

ENGLISH ‘FEMINIST’ WRITINGS AND JUDITH DRAKE'S AN ESSAY IN DEFENCE OF THE FEMALE SEX (1696)

English ‘feminist’ writings of the late seventeenth century frequently united pro-woman arguments with party-political polemics. But although such texts have been discussed in terms of rationalist and contractarian philosophy, or as forerunners of modern feminist concerns, the contemporary issues which underscore them have been ignored. However, an understanding of these debates is vital to comprehending fully the motives of pro-woman writers, many of whom were more concerned with the survival of the Church of England than ameliorating the lot of seventeenth-century women. The underlying importance of party politics is exemplified in one of the greatest works of early modern ‘feminism’, Judith Drakes An essay in defence of the female sex (1696). Although Drake shared political similarities with other tory ‘feminists’, including the more celebrated Mary Astell, Drakes work differed radically from theirs over how an Anglican tory society could be maintained. Instead of stressing the necessity of teaching the tenets of Anglicanism to young women, as had her predecessors, Drake combined tory ideas with Lockean philosophy and concepts of ‘politeness’ to formulate an early Enlightenment vision of sociable, secularized, learning and the role female conversation could play in settling a society fractured by party politics.

The Effects of Severe Hypoxia on Glycolytic Flux and Enzyme Activity in a Model of Solid Tumors.

Solid tumors contend with, and adapt to, a hostile micro‐environment that includes limited availability of nutrient fuels and oxygen. The presence of hypoxia (O2 <5%) stabilizes the transcription factor Hif1 and results in numerous cellular adaptations including increased flux of glucose through glycolysis. Increasingly, more sophisticated analysis of tumor oxygenation has revealed large gradients of oxygen tension and significant regions under severe hypoxia (O2 ∼0.1%). The present investigation has demonstrated a significant increase in the glycolytic flux rate when tumor spheroids were exposed to 0.1% O2. The severe hypoxia was associated with uniform pimonidazole adduct formation and elevated levels of Hif1α and c‐Myc. This resulted in elevated expression of GLUT and MCT transporters, in addition to increased activity of PFK1 in comparison to that observed in normoxia. However, the protein expression and enzymatic capacity of HK2, G6PDH, PK, and LDH were all reduced by severe hypoxia. Clearly, the effects of exposure to severe hypoxia lead to a significantly abridged Hif1 response, yet one still able to elevate glycolytic flux and prevent loss of intermediates to anabolism. J. Cell. Biochem. 117: 1890–1901, 2016.

The Army, Provincial Urban Communities, and Loyalist Cultures in England, c. 1714-50

Professional armies were unpopular in early eighteenth century England, the professional soldier being seen as an agent of political tyranny. However, there also existed an alternative rhetoric, which portrayed him as a soldier-citizen, who fought to defend his country’s liberties. The article begins by exploring these characterizations of professional soldiers, and goes on to examine civic-military relations in English cities and towns during the reigns of George I and George II. A culture of political loyalism, focusing on the early Georgian kings, may have assisted attempts at coexistence between soldiers and citizens in communities where the inhabitants shared a commitment to the Protestant Succession with the soldiers in their midst. Polite sociability, and all that it implied, might also act as a medium for non-confrontational interaction between the urban elites and officer corps.