Inhibition of angiogenesis and suppression of colorectal cancer metastatic to the liver using the Sleeping Beauty Transposon System

<p>Abstract</p> <p>Background</p> <p>Metastatic colon cancer is one of the leading causes of cancer-related death worldwide, with disease progression and metastatic spread being closely associated with angiogenesis. We investigated whether an antiangiogenic gene transfer approach using the <it>Sleeping Beauty </it>(SB) transposon system could be used to inhibit growth of colorectal tumors metastatic to the liver.</p> <p>Results</p> <p>Liver CT26 tumor-bearing mice were hydrodynamically injected with different doses of a plasmid containing a transposon encoding an angiostatin-endostatin fusion gene (Statin AE) along with varying amounts of SB transposase-encoding plasmid. Animals that were injected with a low dose (10 μg) of Statin AE transposon plasmid showed a significant decrease in tumor formation only when co-injected with SB transposase-encoding plasmid, while for animals injected with a higher dose (25 μg) of Statin AE transposon, co-injection of SB transposase-encoding plasmid did not significantly affect tumor load. For animals injected with 10 μg Statin AE transposon plasmid, the number of tumor nodules was inversely proportional to the amount of co-injected SB plasmid. Suppression of metastases was further evident in histological analyses, in which untreated animals showed higher levels of tumor cell proliferation and tumor vascularization than animals treated with low dose transposon plasmid.</p> <p>Conclusion</p> <p>These results demonstrate that hepatic colorectal metastases can be reduced using antiangiogenic transposons, and provide evidence for the importance of the transposition process in mediating suppression of these tumors.</p

Mitochondrial redox studies of oxidative stress in kidneys from diabetic mice

Chronic hyperglycemia during diabetes leads to increased production of reactive oxygen species (ROS) and increased oxidative stress (OS). Here we investigated whether changes in the metabolic state can be used as a marker of OS progression in kidneys. We examined redox states of kidneys from diabetic mice, Akita/+ and Akita/+;TSP1–/– mice (Akita mice lacking thrombospondin-1, TSP1) with increasing duration of diabetes. OS as measured by mitochondrial redox ratio (NADH/FAD) was detectable shortly after the onset of diabetes and further increased with the duration of diabetes. Thus, cryo fluorescence redox imaging was used as a quantitative marker of OS progression in kidneys from diabetic mice and demonstrated that alterations in the oxidative state of kidneys occur during the early stages of diabetes

A contingency analysis of precarious organizational temporariness

This paper extends our current understanding of organizational temporariness. The life of a temporary British trade union branch established to recruit Eastern European migrant workers reveals ‘precarious temporariness’, which is less predictable than the ‘planned temporariness’ typically portrayed in the literature. This different type of temporariness was associated with four key contingencies affecting the branch: dispersed governance, bottom-up initiatives, uncertain resourcing, and an effectuation logic. Analysis of the case extends our existing understanding of organizational temporariness and points to an extension of existing theorizing by highlighting the contingent nature of temporariness. The broader managerial implication of the findings is that for projects facing contingencies of the kind studied, the conventional linear approach of target setting and performance management will be less effective than an ongoing process of communication and consultation

Politics at the Cutting Edge: Intergovernmental Policy Innovation in the Affordable Care Act

In the eight years since the passage of the Patient Protection and Affordable Care Act (ACA), state governments have remained critical sites of contention over the law. Intense partisan conflict over ACA implementation has raised questions about traditional theories of intergovernmental relations, which posit that federal–state cooperation depends largely on policy design. Yet, few studies have examined how partisanship, as well as other important factors, shape state policy innovations under the ACA. This article examines the ACA’s State Innovation Models (SIM) initiative. SIM is specifically geared towards incentivizing states to experiment with new models of payment and delivery that can improve health outcomes and/or reduce health-care costs. Drawing on a combination of quantitative and qualitative evidence, we find that states’ participation in SIM is shaped by partisanship, administrative capacity, and state policy legacies. Our findings have implications for future efforts at intergovernmental health reforms

Enhancing treatment decision-making: pilot study of a treatment decision aid in stage IV non-small cell lung cancer

We developed a decision aid (DA) for patients with metastatic non-small cell lung cancer (NSCLC), to better inform patients of their prognosis and treatment options, and facilitate involvement in decision-making. In a pilot study, 20 patients with metastatic NSCLC attending outpatient clinics at a major cancer centre, who had already made a treatment decision, reviewed acceptability of the DA. The median age of the patients was 61 years (range 37–77 years), 35% were male, 20% had a university education, and most (75%) had English as a first language. Most had received chemotherapy, with 65% currently on treatment. Patients were not anxious at baseline and had clear understanding of the goals and toxicity of chemotherapy in advanced NSCLC. After reviewing the DA, patients' anxiety decreased slightly (P=0.04) and knowledge scores improved by 25% (P<0.001). Most improvements in understanding were of prognosis with and without chemotherapy, although patients still believed advanced NSCLC to be curable. Patients rated the DA highly with respect to information clarity, usefulness and were positive about its use in practice, although 40% found the prognostic information slightly upsetting. The DA for advanced NSCLC is feasible, acceptable to patients and improves understanding of advanced NSCLC without increasing patient anxiety

Lineage diversification and historical demography of a montane bird Garrulax elliotii - implications for the Pleistocene evolutionary history of the eastern Himalayas

<p>Abstract</p> <p>Background</p> <p>Pleistocene climate fluctuations have shaped the patterns of genetic diversity observed in many extant species. In montane habitats, species' ranges may have expanded and contracted along an altitudinal gradient in response to environmental fluctuations leading to alternating periods of genetic isolation and connectivity. Because species' responses to climate change are influenced by interactions between species-specific characteristics and local topography, diversification pattern differs between species and locations. The eastern Himalayas is one of the world's most prominent mountain ranges. Its complex topography and environmental heterogeneity present an ideal system in which to study how climatic changes during Pleistocene have influenced species distributions, genetic diversification, and demography. The Elliot's laughing thrush (<it>Garrulax elliotii</it>) is largely restricted to high-elevation shrublands in eastern Himalayas. We used mitochondrial DNA and microsatellites to investigate how genetic diversity in this species was affected by Pleistocene glaciations.</p> <p>Results</p> <p>Mitochondrial data detected two partially sympatric north-eastern and southern lineages. Microsatellite data, however, identified three distinct lineages congruent with the geographically separated southern, northern and eastern eco-subregions of the eastern Himalayas. Geographic breaks occur in steep mountains and deep valleys of the Kangding-Muli-Baoxin Divide. Divergence time estimates and coalescent simulations indicate that lineage diversification occurred on two different geographic and temporal scales; recent divergence, associated with geographic isolation into individual subregions, and historical divergence, associated with displacement into multiple refugia. Despite long-term isolation, genetic admixture among these subregional populations was observed, indicating historic periods of connectivity. The demographic history of <it>Garrulax elliotii </it>shows continuous population growth since late Pleistocene (about 0.125 mya).</p> <p>Conclusion</p> <p>While altitude-associated isolation is typical of many species in other montane regions, our results suggest that eco-subregions in the eastern Himalayas exhibiting island-like characteristics appear to have determined the diversification of <it>Garrulax elliotii</it>. During the Pleistocene, these populations became isolated on subregions during interglacial periods but were connected when these expanded to low altitude during cooler periods. The resultant genetic admixture of lineages might obscure pattern of genetic variation. Our results provide new insights into sky island diversification in a previously unstudied region, and further demonstrate that Pleistocene climatic changes can have profound effects on lineage diversification and demography in montane species.</p

Macrophages in Breast Cancer: Do Involution Macrophages Account for the Poor Prognosis of Pregnancy-Associated Breast Cancer?

Macrophage influx is associated with negative outcomes for women with breast cancer and has been demonstrated to be required for metastasis of mammary tumors in mouse models. Pregnancy-associated breast cancer is characterized by particularly poor outcomes, however the reasons remain obscure. Recently, post-pregnancy mammary involution has been characterized as having a wound healing signature. We have proposed the involution-hypothesis, which states that the wound healing microenvironment of the involuting gland is tumor promotional. Macrophage influx is one of the prominent features of the involuting gland, identifying the macrophage a potential instigator of tumor progression and a novel target for breast cancer treatment and prevention