Expression and functional properties of selected miRNAs in human cancer tissue and cancer cell lines

MicroRNAs (miRNAs) are small non-coding RNAs (ncRNAs) involved in the regulation of gene expression, and they are often seen dysregulated in cancer. For this reason, it is of great scientific interest to study these ncRNAs to better understand their distribution in human tissues and their mode of function. Based on a comprehensive miRNA microarray from 108 breast cancers in the Norwegian Woman and Cancer Study and 44 healthy controls, this thesis sought to investigate tissue expression and functional properties of the miRNA cluster miR-143/145 in breast- and lung cancer tissues and cell lines, as well as miR-126 in breast cancer (BC) tissue and cell lines. Our analysis found the miR-143/145 cluster to be downregulated in tumor samples from both breast and lung, as well as in their corresponding cancer cell lines. The transfection of miR-143 into a number of cancer cell lines from both breast and lung, promoted proliferation in some, whilst having opposite or no effect in others. In contrast, all cell lines suffered inhibition in both proliferation and migration when transfected to miR-145. In BC tissue, expression of miR-143 and miR-145 was lower in malignant compared to benign breast tissue, and lower in the more aggressive tumors. Interestingly, miR-145 was mainly expressed in the myoepithelial cells of benign breast tissue, and at the subcellular level located to the nuclei. In lung cancer tissue, expression of the miR-143/145 cluster was found to correlate with expression of several sex steroid hormone receptors. Also, stromal expression of miR-143 was an independent positive prognostic factor in female patients, whereas stromal expression of miR-145 was associated with improved disease specific survival for male patients. Both miR-126-3p and its passenger strand, miR-126-5p, was verified as downregulated in BCs as well as in all tested BC cell lines. The passenger strand had a strong proliferation promoting effect in the most aggressive BC cell line, whilst having the opposite effect in the other cell lines. The introduction of miR-126-3p resulted in decreased proliferation and invasion in all BC cell lines. In BC tissue, expression of miR-126-5p was significantly higher in high grade tumors, and both miR-126 strands were downregulated in lymph node positive BCs when compared to tumors with no nodal involvement. This thesis depicts interesting findings, and ads new knowledge into function, expression and distribution of a selected few miRNAs in breast- and lung cancer. Their duplicitous properties described throughout this work, contributes new insight into their complex mode of action, and is likely to gain more attention in the future

Fate of diluted bitumen spilled in the coastal waters of British Columbia, Canada.

Abstract There is public concern about the behaviour of spilled diluted bitumen (dilbit) in marine and estuarine waters. We provide a preliminary assessment of the results of laboratory experiments and models, in the context of environmental conditions in the coastal waters of British Columbia. Most dilbit spilled within this region would likely float at the surface and be transported to shore by winds and currents. Fresh dilbit is too light to sink in coastal waters. Highly weathered dilbit could sink where salinity is less than 14, typically only near river mouths and in the top 1–3 m of fjords after heavy rainfall. Subsurface plumes of weathered dilbit could re-emerge at the surface. Sinking oil-particle aggregates are unlikely to form in coastal waters. However, dilbit could be entrained below the surface by wave mixing during storms and to depths of 150 m by coherent mixing in the Haro Strait tidal convergence zone

Tracking resource and policy impact in Uganda : Incorporating millennium development goals & indicators and poverty reduction strategy paper monitoring across sector

This report, prepared by Uganda Bureau of Statistics and Statistics Norway, demonstrates how the effects of allocations of resources in Uganda within the health, education and water and sanitation sectors might be monitored. The information presented aims at allowing the reader to follow resource allocation from policy decisions towards human welfare and poverty reduction. Using indicators from the Uganda Poverty Eradication Action Program and the Millennium Development goals, the report provides information for policy makers in Uganda and elsewhere. Available data show different trends in the three sectors. Five main recommendations are presented: 1) Consider establishing a database and publish yearly reports for tracking resource and policy impact at the national level, 2) Coordinating definitions, indicators and the statistical system, 3) Strengthening capacity within line ministries to develop indicators for performance in all sectors, 4) Improving the system of data compilation on the district - and not only regional - level and 5) Improving the compilation of data on private expenditures

Rethinking Nursing Care: An Ethnographic Approach to Nurse-Patient Interaction in the Context of a HIV Prevention Programme in Rural Tanzania.

While care has been described as the essence of nursing, it is generally agreed that care is a complex phenomenon that remains elusive. Literature reviews highlight the centrality of nurse-patient interactions in shaping care. In sub-Saharan Africa, where there is a critical shortage of health workers, nurses remain the core of the health workforce, but the quality of the patient care they provide has been questioned. OBJECTIVE: The study explored how care is shaped, expressed and experienced in nurses' everyday communication among HIV positive women in Tanzania. STUDY CONTEXT: Data were collected through a prevention of mother-to-child transmission of HIV programme with a comprehensive community component conducted by a church-run hospital in rural Tanzania. The population is largely agro-pastoral, the formal educational level is low and poverty is rampant. METHODS: An ethnographic approach was employed. Nurses and women enrolled in the prevention of mother-to-child transmission of HIV programme were followed closely over a period of nine months in order to explore their encounters and interactions. FINDINGS AND DISCUSSION: The way care is shaped, expressed and experienced is not globally uniform, and the expectations of what quality care involves differ between settings. In this study the expectations of nurses' instructions and authority, combined with nurses' personal engagement were experienced as caring interactions. The findings from this study demonstrate that the quality of nursing care needs to be explored within the specific historical, socio-cultural context in which it is practised

Transcription factor PAX6 as a novel prognostic factor and putative tumour suppressor in non-small cell lung cancer

Source at https://doi.org/10.1038/s41598-018-23417-z. Licensed CC BY-NC-ND 4.0.Lung cancer is the leading cause of cancer deaths. Novel predictive biomarkers are needed to improve treatment selection and more accurate prognostication. PAX6 is a transcription factor with a proposed tumour suppressor function. Immunohistochemical staining was performed on tissue microarrays from 335 non-small cell lung cancer (NSCLC) patients for PAX6. Multivariate analyses of clinico-pathological variables and disease-specific survival (DSS) was carried out, and phenotypic changes of two NSCLC cell lines with knockdown of PAX6 were characterized. While PAX6 expression was only associated with a trend of better disease-specific survival (DSS) (p = 0.10), the pN+ subgroup (N = 103) showed significant correlation between high PAX6 expression and longer DSS (p = 0.022). Median survival for pN + patients with high PAX6 expression was 127.4 months, versus 22.9 months for patients with low PAX6 expression. In NCI-H661 cells, knockdown of PAX6 strongly activated serum-stimulated migration. In NCI-H460 cells, PAX6 knockdown activated anchorage-independent growth. We did not observe any significant effect of PAX6 on proliferation in either of cell lines. Our findings strongly support the proposition of PAX6 as a valid and positive prognostic marker in NSCLC in node-positive patients. There is a need for further studies, which should provide mechanistical explanation for the role of PAX6 in NSCLC

The Impact of HAART on the Respiratory Complications of HIV Infection: Longitudinal Trends in the MACS and WIHS Cohorts

Objective: To review the incidence of respiratory conditions and their effect on mortality in HIV-infected and uninfected individuals prior to and during the era of highly active antiretroviral therapy (HAART). Design: Two large observational cohorts of HIV-infected and HIV-uninfected men (Multicenter AIDS Cohort Study [MACS]) and women (Women's Interagency HIV Study [WIHS]), followed since 1984 and 1994, respectively. Methods: Adjusted odds or hazards ratios for incident respiratory infections or non-infectious respiratory diagnoses, respectively, in HIV-infected compared to HIV-uninfected individuals in both the pre-HAART (MACS only) and HAART eras; and adjusted Cox proportional hazard ratios for mortality in HIV-infected persons with lung disease during the HAART era. Results: Compared to HIV-uninfected participants, HIV-infected individuals had more incident respiratory infections both pre-HAART (MACS, odds ratio [adjusted-OR], 2.4; 95% confidence interval [CI], 2.2-2.7; p<0.001) and after HAART availability (MACS, adjusted-OR, 1.5; 95%CI 1.3-1.7; p<0.001; WIHS adjusted-OR, 2.2; 95%CI 1.8-2.7; p<0.001). Chronic obstructive pulmonary disease was more common in MACS HIV-infected vs. HIV-uninfected participants pre-HAART (hazard ratio [adjusted-HR] 2.9; 95%CI, 1.02-8.4; p = 0.046). After HAART availability, non-infectious lung diseases were not significantly more common in HIV-infected participants in either MACS or WIHS participants. HIV-infected participants in the HAART era with respiratory infections had an increased risk of death compared to those without infections (MACS adjusted-HR, 1.5; 95%CI, 1.3-1.7; p<0.001; WIHS adjusted-HR, 1.9; 95%CI, 1.5-2.4; p<0.001). Conclusion: HIV infection remained a significant risk for infectious respiratory diseases after the introduction of HAART, and infectious respiratory diseases were associated with an increased risk of mortality. © 2013 Gingo et al

A multi-decade record of high quality fCO2 data in version 3 of the Surface Ocean CO2 Atlas (SOCAT)

The Surface Ocean CO2 Atlas (SOCAT) is a synthesis of quality-controlled fCO2 (fugacity of carbon dioxide) values for the global surface oceans and coastal seas with regular updates. Version 3 of SOCAT has 14.7 million fCO2 values from 3646 data sets covering the years 1957 to 2014. This latest version has an additional 4.6 million fCO2 values relative to version 2 and extends the record from 2011 to 2014. Version 3 also significantly increases the data availability for 2005 to 2013. SOCAT has an average of approximately 1.2 million surface water fCO2 values per year for the years 2006 to 2012. Quality and documentation of the data has improved. A new feature is the data set quality control (QC) flag of E for data from alternative sensors and platforms. The accuracy of surface water fCO2 has been defined for all data set QC flags. Automated range checking has been carried out for all data sets during their upload into SOCAT. The upgrade of the interactive Data Set Viewer (previously known as the Cruise Data Viewer) allows better interrogation of the SOCAT data collection and rapid creation of high-quality figures for scientific presentations. Automated data upload has been launched for version 4 and will enable more frequent SOCAT releases in the future. High-profile scientific applications of SOCAT include quantification of the ocean sink for atmospheric carbon dioxide and its long-term variation, detection of ocean acidification, as well as evaluation of coupled-climate and ocean-only biogeochemical models. Users of SOCAT data products are urged to acknowledge the contribution of data providers, as stated in the SOCAT Fair Data Use Statement. This ESSD (Earth System Science Data) “living data” publication documents the methods and data sets used for the assembly of this new version of the SOCAT data collection and compares these with those used for earlier versions of the data collection (Pfeil et al., 2013; Sabine et al., 2013; Bakker et al., 2014). Individual data set files, included in the synthesis product, can be downloaded here: doi:10.1594/PANGAEA.849770. The gridded products are available here: doi:10.3334/CDIAC/OTG.SOCAT_V3_GRID

Reversing Melanoma Cross-Resistance to BRAF and MEK Inhibitors by Co-Targeting the AKT/mTOR Pathway

The sustained clinical activity of the BRAF inhibitor vemurafenib (PLX4032/RG7204) in patients with BRAF(V600) mutant melanoma is limited primarily by the development of acquired resistance leading to tumor progression. Clinical trials are in progress using MEK inhibitors following disease progression in patients receiving BRAF inhibitors. However, the PI3K/AKT pathway can also induce resistance to the inhibitors of MAPK pathway.The sensitivity to vemurafenib or the MEK inhibitor AZD6244 was tested in sensitive and resistant human melanoma cell lines exploring differences in activation-associated phosphorylation levels of major signaling molecules, leading to the testing of co-inhibition of the AKT/mTOR pathway genetically and pharmacologically. There was a high degree of cross-resistance to vemurafenib and AZD6244, except in two vemurafenib-resistant cell lines that acquired a secondary mutation in NRAS. In other cell lines, acquired resistance to both drugs was associated with persistence or increase in activity of AKT pathway. siRNA-mediated gene silencing and combination therapy with an AKT inhibitor or rapamycin partially or completely reversed the resistance.Primary and acquired resistance to vemurafenib in these in vitro models results in frequent cross resistance to MEK inhibitors, except when the resistance is the result of a secondary NRAS mutation. Resistance to BRAF or MEK inhibitors is associated with the induction or persistence of activity within the AKT pathway in the presence of these drugs. This resistance can be potentially reversed by the combination of a RAF or MEK inhibitor with an AKT or mTOR inhibitor. These combinations should be available for clinical testing in patients progressing on BRAF inhibitors

Contributions of mean and shape of blood pressure distribution to worldwide trends and variations in raised blood pressure: A pooled analysis of 1018 population-based measurement studies with 88.6 million participants

© The Author(s) 2018. Background: Change in the prevalence of raised blood pressure could be due to both shifts in the entire distribution of blood pressure (representing the combined effects of public health interventions and secular trends) and changes in its high-blood-pressure tail (representing successful clinical interventions to control blood pressure in the hypertensive population). Our aim was to quantify the contributions of these two phenomena to the worldwide trends in the prevalence of raised blood pressure. Methods: We pooled 1018 population-based studies with blood pressure measurements on 88.6 million participants from 1985 to 2016. We first calculated mean systolic blood pressure (SBP), mean diastolic blood pressure (DBP) and prevalence of raised blood pressure by sex and 10-year age group from 20-29 years to 70-79 years in each study, taking into account complex survey design and survey sample weights, where relevant. We used a linear mixed effect model to quantify the association between (probittransformed) prevalence of raised blood pressure and age-group- and sex-specific mean blood pressure. We calculated the contributions of change in mean SBP and DBP, and of change in the prevalence-mean association, to the change in prevalence of raised blood pressure. Results: In 2005-16, at the same level of population mean SBP and DBP, men and women in South Asia and in Central Asia, the Middle East and North Africa would have the highest prevalence of raised blood pressure, and men and women in the highincome Asia Pacific and high-income Western regions would have the lowest. In most region-sex-age groups where the prevalence of raised blood pressure declined, one half or more of the decline was due to the decline in mean blood pressure. Where prevalence of raised blood pressure has increased, the change was entirely driven by increasing mean blood pressure, offset partly by the change in the prevalence-mean association. Conclusions: Change in mean blood pressure is the main driver of the worldwide change in the prevalence of raised blood pressure, but change in the high-blood-pressure tail of the distribution has also contributed to the change in prevalence, especially in older age groups