Pilot Study of an Individualised Early Postpartum Intervention to Increase Physical Activity in Women with Previous Gestational Diabetes

Optimal strategies to prevent progression towards overt diabetes in women with recent gestational diabetes remain ill defined. We report a pilot study of a convenient, home based exercise program with telephone support, suited to the early post-partum period. Twenty eight women with recent gestational diabetes were enrolled at six weeks post-partum into a 12 week randomised controlled trial of Usual Care (n = 13) versus Supported Care (individualised exercise program with regular telephone support; n = 15). Baseline characteristics (Mean ± SD) were: Age  33 ± 4  years; Weight 80 ± 20 kg and Body Mass Index (BMI) 30.0 ± 9.7 kg/m2. The primary outcome, planned physical activity {Median (Range)}, increased by 60 (0–540) mins/week in the SC group versus 0 (0–580) mins/week in the UC group (P = 0.234). Walking was the predominant physical activity. Body weight, BMI, waist circumference, % body fat, fasting glucose and insulin did not change significantly over time in either group. This intervention designed to increase physical activity in post-partum women with previous gestational diabetes proved feasible. However, no measurable improvement in metabolic or biometric parameters was observed over a three month period

LPP3 mediates self-generation of chemotactic LPA gradients by melanoma cells

Melanoma cells steer out of tumours using self-generated lysophosphatidic acid (LPA) gradients. The cells break down LPA, which is present at high levels around the tumours, creating a dynamic gradient that is low in the tumour and high outside. They then also migrate up this gradient, creating a complex and evolving outward chemotactic stimulus. Here we introduce a new assay for self-generated chemotaxis, and show that raising LPA levels causes a delay in migration rather than loss of chemotactic efficiency. Knockdown of the lipid phosphatase LPP3 - but not its homologues LPP1 or LPP2 - diminishes the cell's ability to break down LPA. This is specific for chemotactically active LPAs, such as the 18:1 and 20:4 species. Inhibition of autotaxin-mediated LPA production does not diminish outward chemotaxis, but loss of LPP3-mediated LPA breakdown blocks it. Similarly, in both 2D and 3D invasion assays, knockdown of LPP3 diminishes melanoma cells' ability to invade. Our results demonstrate that LPP3 is the key enzyme in melanoma cells' breakdown of LPA, and confirm the importance of attractant breakdown in LPA-mediated cell steering

N-WASP control of LPAR1 trafficking establishes response to self-generated LPA gradients to promote pancreatic cancer cell metastasis

Pancreatic ductal adenocarcinoma is one of the most invasive and metastatic cancers and has a dismal 5-year survival rate. We show that N-WASP drives pancreatic cancer metastasis, with roles in both chemotaxis and matrix remodeling. lysophosphatidic acid, a signaling lipid abundant in blood and ascites fluid, is both a mitogen and chemoattractant for cancer cells. Pancreatic cancer cells break lysophosphatidic acid down as they respond to it, setting up a self-generated gradient driving tumor egress. N-WASP-depleted cells do not recognize lysophosphatidic acid gradients, leading to altered RhoA activation, decreased contractility and traction forces, and reduced metastasis. We describe a signaling loop whereby N-WASP and the endocytic adapter SNX18 promote lysophosphatidic acid-induced RhoA-mediated contractility and force generation by controlling lysophosphatidic acid receptor recycling and preventing degradation. This chemotactic loop drives collagen remodeling, tumor invasion, and metastasis and could be an important target against pancreatic cancer spread

Amputation-induced reactive oxygen species are required for successful Xenopus tadpole tail regeneration.

Understanding the molecular mechanisms that promote successful tissue regeneration is critical for continued advancements in regenerative medicine. Vertebrate amphibian tadpoles of the species Xenopus laevis and Xenopus tropicalis have remarkable abilities to regenerate their tails following amputation, through the coordinated activity of numerous growth factor signalling pathways, including the Wnt, Fgf, Bmp, Notch and TGF-β pathways. Little is known, however, about the events that act upstream of these signalling pathways following injury. Here, we show that Xenopus tadpole tail amputation induces a sustained production of reactive oxygen species (ROS) during tail regeneration. Lowering ROS levels, using pharmacological or genetic approaches, reduces the level of cell proliferation and impairs tail regeneration. Genetic rescue experiments restored both ROS production and the initiation of the regenerative response. Sustained increased ROS levels are required for Wnt/β-catenin signalling and the activation of one of its main downstream targets, fgf20 (ref. 7), which, in turn, is essential for proper tail regeneration. These findings demonstrate that injury-induced ROS production is an important regulator of tissue regeneration

Deciphering the role of LPA and pseudopod machinery during melanoma chemotaxis

In this thesis, I have applied a complementary and alternative understanding of melanoma chemotaxis by incorporating the role of LPA and through a pseudopod-centred approach. I have demonstrated that pseudopods are self organising actin entities that undergo mainly bifurcation (splitting) from preexisting protrusions rather than through synthesis of de novo pseudopods for melanoma cell chemotaxis. This observation was also extended to mouse melanoblast migration in vivo. These superior split pseudopods influence cell steering by alignment, size and lifetime regulation, and biases retraction. In non-metastatic cells, they are no longer able to form stable split pseudopods in response to external stimuli. LPA signaling is also established as vital for the stability of split pseudopods. Hence, in the event of LPAR1 perturbation, metastatic cells formed more actin protrusions but they adopted pseudopod morphologies similar to the non-metastatic lines. The role of Rac, Ras, Paxillin and Ezrin in split pseudopod regulation was also explored in this thesis. Finally, the increased stability of split pseudopods acting through LPA signalling could emerge as a signature of metastatic cells

Health-enhancing physical activity behaviour and related factors in postpartum women with recent gestational diabetes mellitus

This is one of the first studies to explore known preventive behaviours for type 2 diabetes (T2DM) among women with recent gestational diabetes (GDM), and the first to do so in a representative population sample. The aim of this study was to describe the prevalence of health-enhancing physical activity (PA) and explore its association with psychosocial and sociodemographic factors, in postnatal women with recent GDM. Cross-sectional telephone surveys were conducted among Queensland women with a recent history (≥6 months and ≤3 years since diagnosis) of GDM (N = 331), which included measures on PA behaviour, social support and self-efficacy for regular PA. The prevalence of health-enhancing PA among women with recent GDM was 37.2%. In multivariate analysis, both social support (OR = 1.06, 95% CI 1.03–1.09) and self-efficacy (OR = 1.04, 95% CI 1.004–1.07) were significantly associated with health-enhancing PA. The findings from this study demonstrate the need for postnatal follow-up to increase PA levels in women with recent GDM as this may reduce the risk of developing type 2 diabetes (T2DM) in this at-risk population. Strategies that address social support and self-efficacy for PA may be effective in increasing health-enhancing PA among women with recent GDM