http://hdl.handle.net/11343/159 Mon, 16 Sep 2019 05:30:14 GMT 2019-09-16T05:30:14Z http://hdl.handle.net/11343/227642 Tissue-Dependent Tumor Microenvironments and Their impact on immunotherapy Responses Oliver, AJ; Lau, PKH; Unsworth, AS; Loi, S; Darcy, PK; Kershaw, MH; Slaney, CY Recent advances in cancer immunology have led to a better understanding of the role of the tumor microenvironment (TME) in tumor initiation, progression, and metastasis. Tumors can occur at many locations within the body and coevolution between malignant tumor cells and non-malignant cells sculpts the TME at these sites. It has become increasingly clear that there are specific differences of the TMEs at different anatomical locations, and these tissue-specific TMEs regulate tumor growth, determine metastatic progression, and impact on the outcome of therapy responses. Herein, we review the scientific advances in understanding tissue-specific TMEs, discuss their impact on immunotherapeutic response, and assess the current clinical knowledge in this emerging field. A deeper understanding of the tissue-specific TME will help to develop effective immunotherapies against tumors and their metastases and assist in predicting clinical outcomes. Wed, 31 Jan 2018 00:00:00 GMT http://hdl.handle.net/11343/227642 2018-01-31T00:00:00Z http://hdl.handle.net/11343/227641 Response of subchondral bone and articular cartilage to joint surface incongruity: an equine osteochondral defect model Thomas, Megan Elizabeth Many diseases and injuries of synovial joints result in a focal loss of articular surface congruity. These conditions are known to lead to degenerative changes within the affected joint and subsequent osteoarthritis (OA). Incongruity due to loss of articular cartilage is also a feature of OA itself. However there is little work specifically investigating how the tissues of a synovial joint respond to loss of congruity. The aim of this study was to observe how articular cartilage and subchondral bone (SCB) respond to a focal loss of surface congruity using an equine model. It was hypothesised that the degree of remodelling and bone volume of SCB is dependent on local loading of the overlying joint surface and that intact cartilage would respond to changes in local surface pressure in a way that attempts to restore congruity. An osteochondral defect was created in one surface of the midcarpal joint of six adult horses. Two weeks post-operatively the animals began an eight-week treadmill training program. Following this, osteochondral samples were collected from the site of the defect and immediately adjacent to it in the radial carpal bone (Cr), and from the unloaded site directly opposing the defect and a loaded site immediately adjacent to this in the third carpal bone (C3). Control samples were collected from equivalent sites in the sham-operated contralateral limb and from un-operated, untrained control animals. Undemineralised samples were imaged with microCT and backscattered scanning electron microscopy (BSEM) and stained with Masson’s Goldner trichrome to measure cartilage thickness and osteoid. Decalcified cryosections were stained for TRAP to identify osteoclasts. Cartilage was examined with routine histology and differential interference contrast microscopy. In SCB immediately below the Cr lesion in treated joints bone volume fraction (BV/TV) was 32% lower and bone formation and erosion were markedly increased, whereas in the deeper bone formation was increased, erosion activity became less prominent and BV/TV did not change. In the unloaded region of C3 opposing the defect in treated joints the hyaline cartilage (HC) was 50% thicker, while SCB displayed a mild increase in remodelling activity with a net decrease in BV/TV of 5.3%. In the loaded region adjacent to the lesion in Cr HC was 30% thinner in treated joints while there was no change in SCB parameters. At the loaded site of C3 the HC thickness was unchanged while the calcified cartilage in treated joints was 40% thicker than in controls. In the underlying SCB in treated joints there was a mild reduction in remodelling activity and unchanged BV/TV. In this equine osteochondral defect model the articular cartilage and SCB of adult synovial joints responded in a focal manner to changes in joint surface congruity. Local unloading due to a loss of surface contact resulted in thickened HC and, in the underlying SCB, increased remodelling activity and loss of bone volume. Focally increased loading resulted in thickened calcified cartilage and decreased SCB bone remodelling activity. These focal responses may play a role in normal joint homeostasis and in the pathogenesis of OA. © 2019 Megan Elizabeth Thomas Tue, 01 Jan 2019 00:00:00 GMT http://hdl.handle.net/11343/227641 2019-01-01T00:00:00Z http://hdl.handle.net/11343/227640 Plain packaging of tobacco products: the logical next step for tobacco control policy in India Yadav, A; Nazar, GP; Rawal, T; Arora, M; Webster, P; Grills, N India implemented larger 85% pictorial health warnings on all tobacco products from 1 April 2016. However, to remove the last bit of glamour and attraction from the tobacco packs, it must now embrace plain packaging. Plain packaging prevents tobacco packs from carrying the tobacco industry brand imagery as mobile billboards. Postimplementation of larger 85% pictorial health warnings on all tobacco products, this analysis was undertaken to assess the feasibility of plain packaging as the next logical tobacco control policy measure in India. As part of this analysis, the research team reviewed the available literature on legal and policy challenges to plain packaging as a tobacco control policy initiative for India. Literature from 2010 to 2016 in English language was reviewed, which reveals that, India has taken several preparatory steps implemented by other countries like Australia and the UK that have introduced plain packaging, for example, stronger smoke-free laws, ban on tobacco advertising, promotion and sponsorship, increase in taxes and a report from civil society task force on plain packaging. The trade and investment agreements signed by India are also within the international trade norms relating to public health. A Private Member's Bill on plain packaging is also pending in the Parliament of India. Other potential challenges against such policy decision, for example, freedom of trade, right to property, violation of competition law and other laws including consumer protection laws, were found unsubstantiated by the research team. Plain packaging is the next logical step for tobacco control policy in India. Sat, 01 Sep 2018 00:00:00 GMT http://hdl.handle.net/11343/227640 2018-09-01T00:00:00Z http://hdl.handle.net/11343/227639 Transcriptomic diversification along the monocyte-macrophage continuum. Butcher, Suzanne Kathryn Current models of innate immune responses describe hard wired, gene-centric signalling networks, with limited capacity to define the molecular mechanisms underpinning transcriptomic diversity. It is well established that a transcriptional spectrum of responses accompanies acute macrophage activation, however it is unclear whether this spectrum originates in monocytes and to what extent it continues throughout reinfection. The contribution of molecular mechanisms such as enhancers and alternative transcription start sites is also undetermined. Given the critical roles that myeloid cells play in directing acute infection and priming adaptive immunity, it is important the regulation of their responses be understood. This thesis employed bioinformatic analysis of Cap Analysis Gene Expression (CAGE) and microarray data to describe transcriptional diversity along the monocyte-macrophage continuum. Using CAGE to map transcription start sites for capped RNAs, this thesis has shown that pathogen-specific transcriptional diversification commences early in monocyte infection (Chapters Three and Four) and continues throughout acute macrophage infection (Chapter Five). Transcriptomic diversity during acute infection was the product of kinetic and pathogen-specific engagement of distinct transcription start sites. Engagement of multiple transcription start sites drove responsiveness by regulating expression amplitude in functionally focused inflammatory gene sets and diversifying secondary response networks via expression of distinct protein isoforms. Chapter Six extended these studies of acute infection, demonstrating that transcriptional phenotypes continue to diversify during reinfection. These findings highlight the importance of studying innate immune responses at the isoform level and prompt the need to revise current models of innate immune signalling, such that monocyte-macrophage biology should no longer be modelled as a series of static states, but rather, as a continually evolving continuum. © 2019 Suzanne Kathryn Butcher Tue, 01 Jan 2019 00:00:00 GMT http://hdl.handle.net/11343/227639 2019-01-01T00:00:00Z