Proteomic Analysis of Ovarian Cancer Cells Reveals Dynamic Processes of Protein Secretion and Shedding of Extra-Cellular Domains

Background: Elucidation of the repertoire of secreted and cell surface proteins of tumor cells is relevant to molecular diagnostics, tumor imaging and targeted therapies. We have characterized the cell surface proteome and the proteins released into the extra-cellular milieu of three ovarian cancer cell lines, CaOV3, OVCAR3 and ES2 and of ovarian tumor cells enriched from ascites fluid. Methodology and Findings: To differentiate proteins released into the media from protein constituents of media utilized for culture, cells were grown in the presence of [ 13 C]-labeled lysine. A biotinylation-based approach was used to capture cell surface associated proteins. Our general experimental strategy consisted of fractionation of proteins from individual compartments followed by proteolytic digestion and LC-MS/MS analysis. In total, some 6,400 proteins were identified with high confidence across all specimens and fractions. Conclusions and Significance: Protein profiles of the cell lines had substantial similarity to the profiles of human ovarian cancer cells from ascites fluid and included protein markers known to be associated with ovarian cancer. Proteomic analysis indicated extensive shedding from extra-cellular domains of proteins expressed on the cell surface, and remarkably high secretion rates for some proteins (nanograms per million cells per hour). Cell surface and secreted proteins identified by indept

Differences in Regional Brain Activation Patterns Assessed by Functional Magnetic Resonance Imaging in Patients with Systemic Lupus Erythematosus Stratified by Disease Duration

The mediators of tissue damage in systemic lupus erythematosus (SLE) such as antibodies, cytokines and activated immune cells have direct access to most organs in the body but must penetrate the blood-brain barrier (BBB) to gain access to brain tissue. We hypothesized that compromise of the BBB occurs episodically such that the brain will acquire tissue damage slowly and not at the same rate as other organs. On the basis of these assumptions, we wished to determine if duration of disease correlated with brain injury, as measured with functional magnetic resonance imaging (fMRI), and if this was independent of degree of tissue damage in other organs. We investigated differences in brain activation patterns using fMRI in 13 SLE patients stratified by disease duration of ≤2 years (short-term [ST]) or ≥10 years (long-term [LT]). Two fMRI paradigms were selected to measure working memory and emotional response (fearful faces task). Performance in the working memory task was significantly better in the ST group for one and two shape recall; however, both groups did poorly with three shape recall. Imaging studies demonstrated significantly increased cortical activation in the ST group in regions associated with cognition during the two shape retention phase of the working memory task (P < 0.001) and increased amygdala (P < 0.05) and superior parietal (P < 0.01) activation in response to the fearful faces paradigm. In conclusion, analysis of activation patterns stratified by performance accuracy, differences in co-morbid disease, corticosteroid doses or disease activity suggests that these observed differences are attributable to SLE effects on the central nervous system exclusive of vascular disease or other confounding influences. Our hypothesis is further supported by the lack of correlation between regional brain abnormalities on fMRI and the Systemic Lupus International Collaborating Clinics (SLICC) damage index

The burden and trend of diseases and their risk factors in Australia, 1990–2019: a systematic analysis for the Global Burden of Disease Study 2019

Background: A comprehensive understanding of temporal trends in the disease burden in Australia is lacking, and these trends are required to inform health service planning and improve population health. We explored the burden and trends of diseases and their risk factors in Australia from 1990 to 2019 through a comprehensive analysis of the Global Burden of Disease Study (GBD) 2019. Methods: In this systematic analysis for GBD 2019, we estimated all-cause mortality using the standardised GBD methodology. Data sources included primarily vital registration systems with additional data from sample registrations, censuses, surveys, surveillance, registries, and verbal autopsies. A composite measure of health loss caused by fatal and non-fatal disease burden (disability-adjusted life-years [DALYs]) was calculated as the sum of years of life lost (YLLs) and years of life lived with disability (YLDs). Comparisons between Australia and 14 other high-income countries were made. Findings: Life expectancy at birth in Australia improved from 77·0 years (95% uncertainty interval [UI] 76·9–77·1) in 1990 to 82·9 years (82·7–83·1) in 2019. Between 1990 and 2019, the age-standardised death rate decreased from 637·7 deaths (95% UI 634·1–641·3) to 389·2 deaths (381·4–397·6) per 100 000 population. In 2019, non-communicable diseases remained the major cause of mortality in Australia, accounting for 90·9% (95% UI 90·4–91·9) of total deaths, followed by injuries (5·7%, 5·3–6·1) and communicable, maternal, neonatal, and nutritional diseases (3·3%, 2·9–3·7). Ischaemic heart disease, self-harm, tracheal, bronchus, and lung cancer, stroke, and colorectal cancer were the leading causes of YLLs. The leading causes of YLDs were low back pain, depressive disorders, other musculoskeletal diseases, falls, and anxiety disorders. The leading risk factors for DALYs were high BMI, smoking, high blood pressure, high fasting plasma glucose, and drug use. Between 1990 and 2019, all-cause DALYs decreased by 24·6% (95% UI 21·5–28·1). Relative to similar countries, Australia's ranking improved for age-standardised death rates and life expectancy at birth but not for YLDs and YLLs between 1990 and 2019. Interpretation: An important challenge for Australia is to address the health needs of people with non-communicable diseases. The health systems must be prepared to address the increasing demands of non-communicable diseases and ageing. Funding: Bill &amp; Melinda Gates Foundation.</p