Impact of genotype on EPA and DHA status and responsiveness to increased intakes

At a population level, cardioprotective and cognitive actions of the fish oil (FO) derived long-chain n-3 polyunsaturated fatty acids (LC n-3 PUFAs) eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) have been extensively demonstrated. In addition to dietary intake, which is limited for many individuals, EPA and DHA status is dependent on the efficiency of their biosynthesis from α-linolenic acid. Gender and common gene variants have been identified as influencing the rate-limiting desaturase and elongase enzymes. Response to a particular intake or status is also highly heterogeneous and likely influenced by genetic variants which impacts on EPA and DHA metabolism and tissue partitioning, transcription factor activity, or physiological end-point regulation. Here available literature relating genotype to tissue LC n-3 PUFA status and response to FO intervention is considered. It is concluded that the available evidence is relatively limited, with much of the variability unexplained, though APOE and FADS genotypes are emerging as being important. Although numerous genotype × LC-n3 PUFA × phenotype associations have been described, few have been confirmed in independent studies. A more comprehensive understanding of the genetic, physiological and behavioural modulators of EPA and DHA status and response to intervention is needed to allow refinement of current dietary LC n-3 PUFA recommendations and stratification of advice to ‘vulnerable’ and responsive subgroups

Three-year tracking of fatty acid composition of plasma phospholipids in healthy children

Objectives: The fatty acid composition of plasma phospholipids reflects the dietary fatty acid intake as well as endogenous turnover. We aimed at investigating the potential tracking of plasma phospholipid fatty acid composition in children that participated in a prospective cohort study. Methods: 26 healthy children participated in a longitudinal study on health risks and had been enrolled after birth. All children were born at term with birth weights appropriate for gestational age. Follow-up took place at ages 24, 36 and 60 months. At each time point a 24-hour dietary recall was obtained, anthropometric parameters were measured and a blood sample for phospholipid fatty acid analysis was taken. Results: Dietary intake of saturated (SFA), monounsaturated (MUFA) and polyunsaturated (PUFA) fatty acids at the three time points were not correlated. We found lower values for plasma MUFA and the MUFA/SFA ratio at 60 months compared to 24 months. In contrast, total PUFA, total n-6 and n-6 long-chain polyunsaturated fatty acids (LC-PUFA) were higher at 60 months. Significant averaged correlation coefficients (average of Pearson's R for 24 versus 36 months and 36 versus 60 months) were found for n-6 LC-PUFA (r = 0.67), n-6/n-3 LC-PUFA ratio (r = 0.59) and arachidonic acid/linoleic acid ratio (r = 0.64). Partial tracking was found for the docosahexaenoic acid/alpha-linolenic acid ratio (r = 0.33). Body mass index and sum of skinfolds Z-scores were similar in the three evaluations. Conclusions: A significant tracking of n-6 LC-PUFA, n-6 LC-PUFA/n-3 LC-PUFA ratio, arachidonic acid/ linoleic acid ratio and docosahexaenoic acid/alpha-linolenic acid ratio may reflect an influence of individual endogenous fatty acid metabolism on plasma concentrations of some, but not all, fatty acids. Copyright (c) 2007 S. Karger AG, Basel

Exploring the association of diary product intake with the fatty acids C15:0 and C17:0 measured from dried blood spots in a multi-population cohort: findings from the Food4Me study

Scope: The use of biomarkers in the objective assessment of dietary intake is a high priority in nutrition research. The aim of this study was to examine pentadecanoic acid (C15:0) and heptadecanoic acid (C17:0) as biomarkers of dairy foods intake. Methods and results: The data used in the present study were obtained as part of the Food4me Study. Estimates of C15:0 and C17:0 from dried blood spots and intakes of dairy from an FFQ were obtained from participants (n=1,180) across 7 countries. Regression analyses were used to explore associations of biomarkers with dairy intake levels and receiver operating characteristic (ROC) analyses were used to evaluate the fatty acids. Significant positive associations were found between C15:0 and total intakes of high-fat dairy products. C15:0 showed good ability to distinguish between low and high consumers of high-fat dairy products. Conclusion: C15:0 can be used as a biomarker of high-fat dairy intake and of specific high-fat dairy products. Both C15:0 and C17:0 performed poorly for total dairy intake highlighting the need for caution when using these in epidemiological studies

Alterations of immune response of non-small lung cancer with azacytidine

Innovative therapies are needed for advanced Non-Small Cell Lung Cancer (NSCLC). We have undertaken a genomics based, hypothesis driving, approach to query an emerging potential that epigenetic therapy may sensitize to immune checkpoint therapy targeting PD-L1/PD-1 interaction. NSCLC cell lines were treated with the DNA hypomethylating agent azacytidine (AZA - Vidaza) and genes and pathways altered were mapped by genome-wide expression and DNA methylation analyses. AZA-induced pathways were analyzed in The Cancer Genome Atlas (TCGA) project by mapping the derived gene signatures in hundreds of lung adeno (LUAD) and squamous cell carcinoma (LUSC) samples. AZA up-regulates genes and pathways related to both innate and adaptive immunity and genes related to immune evasion in a several NSCLC lines. DNA hypermethylation and low expression of IRF7, an interferon transcription factor, tracks with this signature particularly in LUSC. In concert with these events, AZA up-regulates PD-L1 transcripts and protein, a key ligand-mediator of immune tolerance. Analysis of TCGA samples demonstrates that a significant proportion of primary NSCLC have low expression of AZA-induced immune genes, including PD-L1. We hypothesize that epigenetic therapy combined with blockade of immune checkpoints - in particular the PD-1/PD-L1 pathway - may augment response of NSCLC by shifting the balance between immune activation and immune inhibition, particularly in a subset of NSCLC with low expression of these pathways. Our studies define a biomarker strategy for response in a recently initiated trial to examine the potential of epigenetic therapy to sensitize patients with NSCLC to PD-1 immune checkpoint blockade

Circulating and Dietary Omega‐3 and Omega‐6 Polyunsaturated Fatty Acids and Incidence of CVD in the Multi‐Ethnic Study of Atherosclerosis

Background: Dietary guidelines support intake of polyunsaturated fatty acids (PUFAs) in fish and vegetable oils. However, some controversy remains about benefits of PUFAs, and most prior studies have relied on self‐reported dietary assessment in relatively homogeneous populations. Methods and Results: In a multiethnic cohort of 2837 US adults (whites, Hispanics, African Americans, Chinese Americans), plasma phospholipid PUFAs were measured at baseline (2000–2002) using gas chromatography and dietary PUFAs estimated using a food frequency questionnaire. Incident cardiovascular disease (CVD) events (including coronary heart disease and stroke; n=189) were prospectively identified through 2010 during 19 778 person‐years of follow‐up. In multivariable‐adjusted Cox models, circulating n‐3 eicosapentaenoic acid and docosahexaenoic acid were inversely associated with incident CVD, with extreme‐quartile hazard ratios (95% CIs) of 0.49 for eicosapentaenoic acid (0.30 to 0.79; Ptrend=0.01) and 0.39 for docosahexaenoic acid (0.22 to 0.67; Ptrend<0.001). n‐3 Docosapentaenoic acid (DPA) was inversely associated with CVD in whites and Chinese, but not in other race/ethnicities (P‐interaction=0.01). No significant associations with CVD were observed for circulating n‐3 alpha‐linolenic acid or n‐6 PUFA (linoleic acid, arachidonic acid). Associations with CVD of self‐reported dietary PUFA were consistent with those of the PUFA biomarkers. All associations were similar across racial‐ethnic groups, except those of docosapentaenoic acid. Conclusions: Both dietary and circulating eicosapentaenoic acid and docosahexaenoic acid, but not alpha‐linolenic acid or n‐6 PUFA, were inversely associated with CVD incidence. These findings suggest that increased consumption of n‐3 PUFA from seafood may prevent CVD development in a multiethnic population

Decitabine impact on the endocytosis regulator RhoA, the folate carriers RFC1 and FOLR1, and the glucose transporter GLUT4 in human tumors.

BackgroundIn 31 solid tumor patients treated with the demethylating agent decitabine, we performed tumor biopsies before and after the first cycle of decitabine and used immunohistochemistry (IHC) to assess whether decitabine increased expression of various membrane transporters. Resistance to chemotherapy may arise due to promoter methylation/downregulation of expression of transporters required for drug uptake, and decitabine can reverse resistance in vitro. The endocytosis regulator RhoA, the folate carriers FOLR1 and RFC1, and the glucose transporter GLUT4 were assessed.ResultsPre-decitabine RhoA was higher in patients who had received their last therapy &gt;3&nbsp;months previously than in patients with more recent prior therapy (P = 0.02), and varied inversely with global DNA methylation as assessed by LINE1 methylation (r = -0.58, P = 0.006). Tumor RhoA scores increased with decitabine (P = 0.03), and RFC1 also increased in patients with pre-decitabine scores ≤150 (P = 0.004). Change in LINE1 methylation with decitabine did not correlate significantly with change in IHC scores for any transporter assessed. We also assessed methylation of the RFC1 gene (alias SLC19A1). SLC19A1 methylation correlated with tumor LINE1 methylation (r = 0.45, P = 0.02). There was a small (statistically insignificant) decrease in SLC19A1 methylation with decitabine, and there was a trend towards change in SLC19A1 methylation with decitabine correlating with change in LINE1 methylation (r = 0.47, P &lt;0.15). While SLC19A1 methylation did not correlate with RFC1 scores, there was a trend towards an inverse correlation between change in SLC19A1 methylation and change in RFC1 expression (r = -0.45, P = 0.19).ConclusionsIn conclusion, after decitabine administration, there was increased expression of some (but not other) transporters that may play a role in chemotherapy uptake. Larger patient numbers will be needed to define the extent to which this increased expression is associated with changes in DNA methylation

The Roots of Collapse: Imposing Constitutional Governance

The foundational assumption of constitutional governance poses a conundrum for contemporary state-builders: a constitution heavily influenced by foreigners does not represent the views of the governed. Can a modern state-building effort foster democratic institutions when the new government reflects foreign? Nowhere was this tension more apparent than in Afghanistan, where the United States and the United Nations were heavily involved in drafting the 2004 Constitution. They shaped the process from the initial framework to the final, frenzied approval. Foreigners were engaged at both the procedural level—determining how the negotiations would occur and who would participate—and at the substantive level—providing input about particular provisions. Using judicial review as a lens through which to understand the constitution-writing process, this article shows how foreign involvement led to a final draft that failed to resolve a fundamental issue of governance: what institution had the authority to interpret the constitution. The resulting confusion contributed to an ineffective central government and, eventually, the quick downfall of the Afghan government

Human Rights Movements in the Middle East: Global Norms and Regional Particularities

(Excerpt) The Middle East is often portrayed as an outlier when it comes to human rights, but rights are an important part of the political, diplomatic, and social fabric of the region. This chapter summarises regional trends in human rights advocacy at both the international and domestic levels. Popular movements for independence, equality for women, and protections for workers have deep roots in the region. When the United Nations began to enshrine these values into law after World War II, representatives from the Middle East were at the centre of the debates. In the following two decades, human rights largely played out in the international political realm. Middle Eastern governments contributed to diplomatic efforts to shape emerging treaties and norms and often mobilised human rights rhetoric against colonialism. In the 1970s, however, the locus of human rights shifted to non-governmental organisations (NGOs) that used human rights to pressure their own governments for change. Activists created organisations promoting the rights of prisoners, leftists, Islamists, dissidents, women, and the poor. Human rights became more threatening to Middle Eastern regimes that were overwhelmingly undemocratic. States had little tolerance for institutions that could challenge them and often responded violently. Even though widespread violations continue, human rights have become an important framework across the region. Most states now address human rights concerns in response to domestic and international pressure. Rights have increasingly become the language of popular protest and were one of several ways that people articulated grievances before and during the uprisings in several Arab countries in 2011

Mobilizing Universalism: The Origins of Human Rights

Human rights law claims to be universal, setting rights apart from paradigms based on shared religion, culture, or nationality. This claim of universality was a significant factor in the proliferation of human rights NGOs in the 1970s and remains an important source of legitimacy. The universality of human rights has been challenged and contested since they were first discussed at the United Nations (UN). Today, much of the debate centers around the origins of human rights-particularly whether they arose out of Western traditions or whether they have more global roots. For too long, discussions about universality have ignored the practice of human rights in the Global South, particularly in Arab countries. Instead of searching for evidence of universality in the halls of the UN, this Article looks at how activists mobilized and produced universality through their work. Archival sources and interviews show that the turn to human rights in the Arab world was rooted in the politics of the 1970s but relied on the concept of universality as embodied in the foundational human rights documents of the 1940s and 1960s. Activists used these documents to advance conceptions of human rights that were compatible with several distinct political visions. Their work supports the claim that human rights can be universal, not because rights exist outside of politics or have diverse origins, but because they were constantly reinvented to support a range of different, sometimes contradictory, political goals