DHA-induced stress response in human colon cancer cells – Focus on oxidative stress and autophagy

ABSTRACTPolyunsaturated fatty acids (PUFAs) are important constituents of the diet and health benefits of omega-3/n−3 PUFAs, especially eicosapentaenoic acid (EPA, 20:5 n−3) and docosahexaenoic acid (DHA, 22:6 n−3) have been well documented in relation to several diseases. Increasing evidence suggests that n−3 PUFAs may have anticancer activity and improve the effect of conventional cancer therapy. The mechanisms behind these effects are still unclear and need to be elucidated.We have examined the DHA-induced stress response in two human colon cancer cell lines, SW620 and Caco-2. SW620 cells are growth-inhibited at early time points by DHA, while the growth of Caco-2 cells almost remains unaffected by the same treatment. Gene expression analysis of SW620 cells treated with DHA revealed changes at early time points; transcripts involved in oxidative stress and autophagy were among the first to be differentially expressed. We find that oxidative stress is induced in both cell lines, although at different time points and to different extent. DHA induced nuclear translocation of the oxidative stress sensor NFE2L2 in both cell lines, indicating an induction of an anti-oxidative response. However, vitamin E did not counteract ROS-production or the translocation of NFE2L2 to the nucleus. Neither vitamin E nor the antioxidants butylated hydoxyanisole (BHA) and butylated hydoxytoluene (BHT) did affect the growth inhibition in SW620 cells after DHA-treatment. Also, siRNA-mediated down-regulation of NFE2L2 did not sensitize SW620 and Caco-2 cells to DHA. These results indicate that oxidative stress response is not the cause of DHA-induced cytotoxicity in SW620 cells.Using biochemical and imaging based functional assays, we found a low basal level of autophagy and no increase in autophagic flux after adding DHA to the SW620 cells. However, Caco-2 cells displayed a higher level of autophagy, both in the absence and presence of DHA. Inhibition of autophagy by siRNA mediated knock down of ATG5 and ATG7 sensitized both SW620 and Caco-2 cells to DHA. Stimulation of autophagy by rapamycin in SW620 and Caco-2 cells resulted in decreased DHA-sensitivity and inhibition of autophagy in Caco-2 cells by chloroquine resulted in increased DHA-sensitivity.These results suggest that autophagy is important for the DHA sensitivity of colon cancer cells and imply possible therapeutic effects of this fatty acid against cancer cells with low autophagy

Transforming the sheep and goat industry through dispersed community based breeding and centralized management

Transforming the sheep and goat industry through dispersed community-based breeding and centralized management. Presentation at 30th ESAP Conference. September 15-17th

Evidence based assessment of scalability of agricultural technologies: The case of improved food legumes and small ruminant market sheds

United States Agency for International Developmen

Insights on Lymphedema Self-Care Knowledge and Practice in Filariasis and Podoconiosis-Endemic Communities in Bangladesh and Ethiopia

Lymphedema is a life-long sequelae to several neglected tropical diseases (NTD). In Bangladesh the main cause is lymphatic filariasis (LF) and Ethiopia is endemic for both LF and podoconiosis. The World Health Organization (WHO) recommends daily self-care including meticulous washing and drying of affected skin and attention to entry lesions, limb exercises and elevation. Adherence to this regime reduces secondary infections which cause disabling episodes of acute dermato-lymphangitis (ADL). Self-care practices must be integrated into family life, supported by community and monitored by health staff; however, little is known about the influence of personal and socio-demographic factors on adherence. People affected by lymphedema (n=272), adult caregivers (n=272), and health workers (n=68) in Bangladesh and Ethiopia were trained in lymphedema management according to WHO recommendations. Surveys on the causes and management of lymphedema were collected at baseline and 24-weeks, and patients completed a daily journal of self-care activities and symptoms. At baseline knowledge on causes and management of lymphedema was greater among health workers (&amp;gt;70%) than patients and caregivers (&amp;lt;20%) in both countries, and there were significant between-country differences in patient reported use of limb washing (Bangladesh = 7.7%. Ethiopia = 51.1%, p = 0.001). At 24-weeks knowledge on lymphedema causes and management had increased significantly among patients and caregivers, there was &amp;lt;70% adherence to limb washing and exercises, but lesser use of limb elevation in both countries. A range of patient characteristics were associated with significant variation in self-care, except for limb washing. Performance of fewer leg exercises was significantly associated with increased age or severe lymphedema in Bangladesh, and with being female or in paid work in Ethiopia. Patient journals recorded ADL symptoms and working days lost due to lymphedema more frequently than were reported by recall during the 24-week survey. Core elements of lymphedema self-care education, training and monitoring are the same for multiple etiologies. This creates opportunities for cross-cutting implementation of integrated service delivery across several skin NTDs. Sustainability will depend on community level ownership and research on factors affecting adherence to lymphedema self-care are urgently needed.</jats:p

Program assessment of efforts to improve the quality of postpartum counselling in health centers in Morogoro region, Tanzania

BACKGROUND: The postpartum period represents a critical window where many maternal and child deaths occur. We assess the quality of postpartum care (PPC) as well as efforts to improve service delivery through additional training and supervision in Health Centers (HCs) in Morogoro Region, Tanzania. METHODS: Program implementers purposively selected nine program HCs for assessment with another nine HCs in the region remaining as comparison sites in a non-randomized program evaluation. PPC quality was assessed by examining structural inputs; provider and client profiles; processes (PNC counselling) and outcomes (patient knowledge) through direct observations of equipment, supplies and infrastructure (n = 18) and PPC counselling (n = 45); client exit interviews (n = 41); a provider survey (n = 62); and in-depth provider interviews (n = 10). RESULTS: While physical infrastructure, equipment and supplies were comparable across study sites (with water and electricity limitations), program areas had better availability of drugs and commodities. Overall, provider availability was also similar across study sites, with 63% of HCs following staffing norms, 17% of Reproductive and Child Health (RCH) providers absent and 14% of those providing PPC being unqualified to do so. In the program area, a median of 4 of 10 RCH providers received training. Despite training and supervisory inputs to program area HCs, provider and client knowledge of PPC was low and the content of PPC counseling provided limited to 3 of 80 PPC messages in over half the consultations observed. Among women attending PPC, 29 (71%) had delivered in a health facility and sought care a median of 13 days after delivery. Barriers to PPC care seeking included perceptions that PPC was of limited benefit to women and was primarily about child health, geographic distance, gaps in the continuity of care, and harsh facility treatment. CONCLUSIONS: Program training and supervision activities had a modest effect on the quality of PPC. To achieve broader transformation in PPC quality, client perceptions about the value of PPC need to be changed; the content of recommended PPC messages reviewed along with the location for PPC services; gaps in the availability of human resources addressed; and increased provider-client contact encouraged

Routine health management information system data in Ethiopia: consistency, trends, and challenges.

Background: Ethiopia is investing in the routine Health Management Information System. Improved routine data are needed for decision-making in the health sector. Objective: To analyse the quality of the routine Health Management Information System data and triangulate with other sources, such as the Demographic and Health Surveys. Methods: We analysed national Health Management Information System data on 19 indicators of maternal health, neonatal survival, immunization, child nutrition, malaria, and tuberculosis over the 2012-2018 time period. The analyses were conducted by 38 analysts from the Ministry of Health, Ethiopia, and two government agencies who participated in the Operational Research and Coaching for Analysts (ORCA) project between June 2018 and June 2020. Using a World Health Organization Data Quality Review toolkit, we assessed indicator definitions, completeness, internal consistency over time and between related indicators, and external consistency compared with other data sources. Results: Several services reported coverage of above 100%. For many indicators, denominators were based on poor-quality population data estimates. Data on individual vaccinations had relatively good internal consistency. In contrast, there was low external consistency for data on fully vaccinated children, with the routine Health Management Information System showing 89% coverage but the Demographic and Health Survey estimate at 39%. Maternal health indicators displayed increasing coverage over time. Indicators on child nutrition, malaria, and tuberculosis were less consistent. Data on neonatal mortality were incomplete and operationalised as mortality on day 0-6. Our comparisons with survey and population projections indicated that one in eight early neonatal deaths were reported in the routine Health Management Information System. Data quality varied between regions. Conclusions: The quality of routine data gathered in the health system needs further attention. We suggest regular triangulation with data from other sources. We recommend addressing the denominator issues, reducing the complexity of indicators, and aligning indicators to international definitions

Global, regional, and national cancer incidence, mortality, years of life lost, years lived with disability, and disability-Adjusted life-years for 29 cancer groups, 1990 to 2017 : A systematic analysis for the global burden of disease study

Importance: Cancer and other noncommunicable diseases (NCDs) are now widely recognized as a threat to global development. The latest United Nations high-level meeting on NCDs reaffirmed this observation and also highlighted the slow progress in meeting the 2011 Political Declaration on the Prevention and Control of Noncommunicable Diseases and the third Sustainable Development Goal. Lack of situational analyses, priority setting, and budgeting have been identified as major obstacles in achieving these goals. All of these have in common that they require information on the local cancer epidemiology. The Global Burden of Disease (GBD) study is uniquely poised to provide these crucial data. Objective: To describe cancer burden for 29 cancer groups in 195 countries from 1990 through 2017 to provide data needed for cancer control planning. Evidence Review: We used the GBD study estimation methods to describe cancer incidence, mortality, years lived with disability, years of life lost, and disability-Adjusted life-years (DALYs). Results are presented at the national level as well as by Socio-demographic Index (SDI), a composite indicator of income, educational attainment, and total fertility rate. We also analyzed the influence of the epidemiological vs the demographic transition on cancer incidence. Findings: In 2017, there were 24.5 million incident cancer cases worldwide (16.8 million without nonmelanoma skin cancer [NMSC]) and 9.6 million cancer deaths. The majority of cancer DALYs came from years of life lost (97%), and only 3% came from years lived with disability. The odds of developing cancer were the lowest in the low SDI quintile (1 in 7) and the highest in the high SDI quintile (1 in 2) for both sexes. In 2017, the most common incident cancers in men were NMSC (4.3 million incident cases); tracheal, bronchus, and lung (TBL) cancer (1.5 million incident cases); and prostate cancer (1.3 million incident cases). The most common causes of cancer deaths and DALYs for men were TBL cancer (1.3 million deaths and 28.4 million DALYs), liver cancer (572000 deaths and 15.2 million DALYs), and stomach cancer (542000 deaths and 12.2 million DALYs). For women in 2017, the most common incident cancers were NMSC (3.3 million incident cases), breast cancer (1.9 million incident cases), and colorectal cancer (819000 incident cases). The leading causes of cancer deaths and DALYs for women were breast cancer (601000 deaths and 17.4 million DALYs), TBL cancer (596000 deaths and 12.6 million DALYs), and colorectal cancer (414000 deaths and 8.3 million DALYs). Conclusions and Relevance: The national epidemiological profiles of cancer burden in the GBD study show large heterogeneities, which are a reflection of different exposures to risk factors, economic settings, lifestyles, and access to care and screening. The GBD study can be used by policy makers and other stakeholders to develop and improve national and local cancer control in order to achieve the global targets and improve equity in cancer care. © 2019 American Medical Association. All rights reserved.Peer reviewe

Global burden of 288 causes of death and life expectancy decomposition in 204 countries and territories and 811 subnational locations, 1990–2021: a systematic analysis for the Global Burden of Disease Study 2021

BACKGROUND Regular, detailed reporting on population health by underlying cause of death is fundamental for public health decision making. Cause-specific estimates of mortality and the subsequent effects on life expectancy worldwide are valuable metrics to gauge progress in reducing mortality rates. These estimates are particularly important following large-scale mortality spikes, such as the COVID-19 pandemic. When systematically analysed, mortality rates and life expectancy allow comparisons of the consequences of causes of death globally and over time, providing a nuanced understanding of the effect of these causes on global populations. METHODS The Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2021 cause-of-death analysis estimated mortality and years of life lost (YLLs) from 288 causes of death by age-sex-location-year in 204 countries and territories and 811 subnational locations for each year from 1990 until 2021. The analysis used 56 604 data sources, including data from vital registration and verbal autopsy as well as surveys, censuses, surveillance systems, and cancer registries, among others. As with previous GBD rounds, cause-specific death rates for most causes were estimated using the Cause of Death Ensemble model-a modelling tool developed for GBD to assess the out-of-sample predictive validity of different statistical models and covariate permutations and combine those results to produce cause-specific mortality estimates-with alternative strategies adapted to model causes with insufficient data, substantial changes in reporting over the study period, or unusual epidemiology. YLLs were computed as the product of the number of deaths for each cause-age-sex-location-year and the standard life expectancy at each age. As part of the modelling process, uncertainty intervals (UIs) were generated using the 2·5th and 97·5th percentiles from a 1000-draw distribution for each metric. We decomposed life expectancy by cause of death, location, and year to show cause-specific effects on life expectancy from 1990 to 2021. We also used the coefficient of variation and the fraction of population affected by 90% of deaths to highlight concentrations of mortality. Findings are reported in counts and age-standardised rates. Methodological improvements for cause-of-death estimates in GBD 2021 include the expansion of under-5-years age group to include four new age groups, enhanced methods to account for stochastic variation of sparse data, and the inclusion of COVID-19 and other pandemic-related mortality-which includes excess mortality associated with the pandemic, excluding COVID-19, lower respiratory infections, measles, malaria, and pertussis. For this analysis, 199 new country-years of vital registration cause-of-death data, 5 country-years of surveillance data, 21 country-years of verbal autopsy data, and 94 country-years of other data types were added to those used in previous GBD rounds. FINDINGS The leading causes of age-standardised deaths globally were the same in 2019 as they were in 1990; in descending order, these were, ischaemic heart disease, stroke, chronic obstructive pulmonary disease, and lower respiratory infections. In 2021, however, COVID-19 replaced stroke as the second-leading age-standardised cause of death, with 94·0 deaths (95% UI 89·2-100·0) per 100 000 population. The COVID-19 pandemic shifted the rankings of the leading five causes, lowering stroke to the third-leading and chronic obstructive pulmonary disease to the fourth-leading position. In 2021, the highest age-standardised death rates from COVID-19 occurred in sub-Saharan Africa (271·0 deaths [250·1-290·7] per 100 000 population) and Latin America and the Caribbean (195·4 deaths [182·1-211·4] per 100 000 population). The lowest age-standardised death rates from COVID-19 were in the high-income super-region (48·1 deaths [47·4-48·8] per 100 000 population) and southeast Asia, east Asia, and Oceania (23·2 deaths [16·3-37·2] per 100 000 population). Globally, life expectancy steadily improved between 1990 and 2019 for 18 of the 22 investigated causes. Decomposition of global and regional life expectancy showed the positive effect that reductions in deaths from enteric infections, lower respiratory infections, stroke, and neonatal deaths, among others have contributed to improved survival over the study period. However, a net reduction of 1·6 years occurred in global life expectancy between 2019 and 2021, primarily due to increased death rates from COVID-19 and other pandemic-related mortality. Life expectancy was highly variable between super-regions over the study period, with southeast Asia, east Asia, and Oceania gaining 8·3 years (6·7-9·9) overall, while having the smallest reduction in life expectancy due to COVID-19 (0·4 years). The largest reduction in life expectancy due to COVID-19 occurred in Latin America and the Caribbean (3·6 years). Additionally, 53 of the 288 causes of death were highly concentrated in locations with less than 50% of the global population as of 2021, and these causes of death became progressively more concentrated since 1990, when only 44 causes showed this pattern. The concentration phenomenon is discussed heuristically with respect to enteric and lower respiratory infections, malaria, HIV/AIDS, neonatal disorders, tuberculosis, and measles. INTERPRETATION Long-standing gains in life expectancy and reductions in many of the leading causes of death have been disrupted by the COVID-19 pandemic, the adverse effects of which were spread unevenly among populations. Despite the pandemic, there has been continued progress in combatting several notable causes of death, leading to improved global life expectancy over the study period. Each of the seven GBD super-regions showed an overall improvement from 1990 and 2021, obscuring the negative effect in the years of the pandemic. Additionally, our findings regarding regional variation in causes of death driving increases in life expectancy hold clear policy utility. Analyses of shifting mortality trends reveal that several causes, once widespread globally, are now increasingly concentrated geographically. These changes in mortality concentration, alongside further investigation of changing risks, interventions, and relevant policy, present an important opportunity to deepen our understanding of mortality-reduction strategies. Examining patterns in mortality concentration might reveal areas where successful public health interventions have been implemented. Translating these successes to locations where certain causes of death remain entrenched can inform policies that work to improve life expectancy for people everywhere. FUNDING Bill & Melinda Gates Foundation