The importance of plasma apolipoprotein E concentration in addition to its common polymorphism on inter-individual variation in lipid levels: results from Apo Europe

The ApoEurope group, collaborating centres, and their associated investigators: Portugal: Unidade de Química Clínica, Instituto Nacional de Saúde, Lisboa: Maria do Carmo Martins, Maria Odete Rodrigues, Maria Isabel Albergaria, Maria Liseta AlpendreInterindividual variation in the concentration of plasma lipids which are associated with coronary artery disease (CAD) risk is determined by a combination of genetic and environmental factors. This study investigates the effects of apoE genotype and plasma concentration on cholesterol and triglycerides (TG) levels in subjects from five countries: Finland, France, Northern Ireland, Portugal, and Spain. Age and sex significantly influenced serum cholesterol, TG and apoE concentrations. The age effect differs in males and females. The allele frequencies of the apoE gene, one of the most widely studied CAD susceptibility genes, were determined: the epsilon2 allele frequency and the apoE concentration showed a north-south increasing gradient while the epsilon4 allele frequency showed the reverse. ApoE plays an important role in lipid metabolism. Total cholesterol and TG concentrations were significantly dependent on apoE genotype in both sexes. These differences in lipids between genotypes were more pronounced when plasma apoE concentrations were taken into account

Human papillomavirus, high-grade intraepithelial neoplasia and killer immunoglogulin-like receptors: a Western Australian cohort study

Background: Human papillomavirus (HPV) is the causative agent in cervical cancer and HPV genotypes 16 and 18 cause the majority of these cancers. Natural killer (NK) cells destroy virally infected and tumour cells via killer immunoglobulin-like receptors (KIR) that recognize decreased MHC class I expression. These NK cells may contribute to clearance of HPV infected and/or dysplastic cells, however since KIR controls NK cell activity, KIR gene variation may determine outcome of infection.Methods: KIR gene frequencies were compared between 147 patients with a history of high-grade cervical intraepithelial neoplasia (CIN) and a control population of 187, to determine if any KIR genes are associated with high-grade CIN. In addition a comparison was also made between cases of high grade CIN derived from 30 patients infected with HPV 16/18 and 29 patients infected with non-16/18 HPV to determine if KIR variation contributes to the disproportional carcinogenesis derived from HPV 16/18 infection.Results: High-grade CIN was weakly associated with the absence of KIR2DL2 and KIR2DS2 (p = 0.046 and 0.049 respectively, OR 0.6; 95% CI 0.4 – 0.9) but this association was lost after correction for multi-gene statistical analysis.No difference in KIR gene frequencies was found between high-grade CIN caused by HPV 16/18 and non-16/18.Conclusion: No strong association between KIR genes, high-grade CIN and HPV genotype was found in the Western Australian population

Mesothelioma tumor cells modulate dendritic cell lipid content, phenotype and function

Dendritic cells (DCs) play an important role in the generation of anti-cancer immune responses, however there is evidence that DCs in cancer patients are dysfunctional. Lipid accumulation driven by tumor-derived factors has recently been shown to contribute to DC dysfunction in several human cancers, but has not yet been examined in mesothelioma. This study investigated if mesothelioma tumor cells and/or their secreted factors promote increases in DC lipid content and modulate DC function. Human monocyte-derived DCs (MoDCs) were exposed to human mesothelioma tumor cells and tumor-derived factors in the presence or absence of lipoproteins. The data showed that immature MoDCs exposed to mesothelioma cells or factors contained increased lipid levels relative to control DCs. Lipid accumulation was associated with reduced antigen processing ability (measured using a DQ OVA assay), upregulation of the co-stimulatory molecule, CD86, and production of the tolerogenic cytokine, IL-10. Increases in DC lipid content were further enhanced by co-exposure to mesothelioma-derived factors and triglyceride-rich lipoproteins, but not low-density lipoproteins. In vivo studies using a murine mesothelioma model showed that the lipid content of tumor-infiltrating CD4<sup>+</sup>CD8a<sup>-</sup> DCs, CD4<sup>-</sup>CD8a<sup>-</sup> DCs and plasmacytoid DCs increased with tumor progression. Moreover, increasing tumor burden was associated with reduced proliferation of tumor-antigen-specific CD8<sup>+</sup> T cells in tumor-draining lymph nodes. This study shows that mesothelioma promotes DC lipid acquisition, which is associated with altered activation status and reduced capacity to process and present antigens, which may impair the ability of DCs to generate effective anti mesothelioma T cell responses

Willingness to Participate in HIV Vaccine Trials among Men Who Have Sex with Men in Chennai and Mumbai, India: A Social Ecological Approach

BACKGROUND: Recruitment of low- and middle-income country volunteers from most-at-risk populations in HIV vaccine trials is essential to vaccine development. In India, men who have sex with men (MSM) are at disproportionately high risk for HIV infection and an important population for trial recruitment. Investigations of willingness to participate (WTP) in HIV vaccine trials have focused predominantly on individual-level determinants. We explored multi-level factors associated with WTP among MSM in India. METHODS: We conducted 12 focus groups (n = 68) with low socioeconomic MSM in Chennai and Mumbai, and 14 key informant interviews with MSM community leaders and service providers. Focus groups/interviews were recorded, transcribed and translated into English. Two bilingual investigators conducted thematic analysis using line-by-line coding and a constant comparative method, with member-checking by community representatives. RESULTS: Factors associated with WTP were evidenced across the social ecology of MSM–social-structural: poverty, HIV-, sexual- and gender non-conformity stigma, institutionalized discrimination and government sponsorship of trials; community-level: endorsement by MSM community leaders and organizations, and fear of within-group discrimination; interpersonal: anticipated family discord, partner rejection, having financially-dependent family members and disclosure of same-sex sexuality; and individual-level: HIV vaccine trial knowledge and misconceptions, safety concerns, altruism and preventive misconception. CONCLUSION: Pervasive familial, community and social-structural factors characteristic of the Indian sociocultural context may complicate individual-focused approaches to WTP and thereby constrain the effectiveness of interventions to support recruitment and retention in HIV vaccine trials. Interventions to reduce stigma and discrimination against MSM and people living with HIV, capacity-building of MSM community organizations and transparent communications tailored to the knowledge and educational level of local communities may support meaningful engagement of MSM in HIV vaccine trials. Vigilance in providing fair but not excessive compensation and healthcare benefits and in mitigating preventive misconception are warranted to support ethical conduct of trials among MSM in India

Nutrient regulation of ß-cell function: what do islet cell/animal studies tell us?

Diabetes mellitus is widely recognised as one of the most serious metabolic diseases worldwide, and its incidence in Asian countries is growing at an alarming rate. Type 2 diabetes (T2DM) is closely associated with age, sedentary lifestyle and poor diet. In T2DM, ß-cell dysfunction will occur before hyperglycaemia develops. Excessive levels of glucose, lipid and various inflammatory factors interact at the level of the pancreatic islet to promote ß-cell dysfunction. Pancreatic ß-cell lines have been widely utilised since the early 1980s and have contributed a large volume of important information regarding molecular, metabolic and genetic mechanisms that regulate insulin secretion. The purpose of this review is to describe the origin and characteristics of the most commonly used ß-cell lines and their contribution to discovery of fundamental regulatory processes that control insulin production and release. Pancreatic islets obtained from rodents as well as other animals have additionally provided information on the architecture and three-dimensional design of this endocrine tissue that allows precise regulation of hormone release. Understanding the nature of failure of physiologic and metabolic processes leading to insufficient insulin release and subsequent diabetes has allowed development of novel anti-diabetic therapeutics, now in common use, worldwide.European Journal of Clinical Nutrition advance online publication, 19 April 2017; doi:10.1038/ejcn.2017.49