The role of Microenvironment in tumorigenesis. Focus on dendritic cells in human papillomavirus E6, E7-transformed keratinocytes

The inception of tumor microenvironment (TME), a complex and dynamic system constituted by different types of cells engaged by tumor and extracellular matrix surrounding cancer cells, is a way for them to elude the immune surveillance. Dendritic cells (DCs), as a sentinel, are able to recognize alteration in the microenvironment and predispose the immune system response. The relationship between cancer and virus infection is well documented. High-risk Human Papillomavirus (HR-HPV) has a well-characterized transforming property and has been associated with squamous cell carcinoma of the ano-genital and oral tracts. Transforming ability of HR-HPVs is based on the function of E6 and E7 viral oncoproteins, which interact and inactivate p53 and pRb oncosuppressors, respectively. Recently, it was demonstrated that HPV oncoproteins are also able to affect a number of microRNAs (miRNAs) regulating the expression of genes involved in proliferative control. For these reasons DC-based vaccines targeting oncogenic E6 and E7 are ideal candidates to elicit strong immune responses. Here we summarize significant data about the analysis of TME in HPV-induced tumorigenesis. We also report original results produced by cytotoxic T lymphocyte (CTL) in vitro priming against E6 and E7 HPV16 antigens, performed using human monocyte-derived dendritic cells. Dendritic cells, maturated by the exposition to necrotic or apoptotic keratinocytes expressing both oncoproteins of HPV16, show different expression levels of specific maturation markers. Evidence indicating the ability of necrotic keratinocytes to alter the microRNA profile in DCs, macrophages (MΦ) and Langerhans cells (LCs) compared to prototypical stimuli as bacterial lipopolysaccharide was also provided. We can speculate that, based on transformed cells death pathway (i.e. apoptosis versus necrosis), virus-induced immune alterations might show different results in creating an immunotolerogenic microenvironment during the carcinogenesis process

RELATION OF PULSE WAVE VELOCITY TO CONTEMPORANEOUS AND HISTORICAL BLOOD PRESSURE IN FEMALE TWINS:Arterial Stiffness and Blood Pressure

An association between blood pressure and aortic stiffness is well known, but ambiguity remains as to whether one precedes the other. This study aimed to investigate the association of aortic stiffness with contemporaneous versus historic blood pressure and direction of causality between aortic stiffening and hypertension in female twins. METHODS: Aortic stiffness, measured by carotid-femoral pulse wave velocity (PWV), and mean arterial pressure (MAP) was recorded in 2037 female TwinsUK participants (mean age: 62.4±9.7 years) at a single time point. A subset of 947 participants had repeat PWV and MAP measures (mean interval 5.5±1.7 years) with additional historic MAP (mean interval 6.6±3.3 years before baseline). RESULTS: Cross-sectional multivariable linear regression analysis confirmed PWV significantly associated with age and MAP. In longitudinal analysis, annual progression of PWV was not associated with historic MAP (standardized beta coefficient [β]=-0.02, P=0.698), weakly associated with baseline MAP (β=0.09, P=0.049) but strongly associated with progression (from baseline to most recent measurement) of MAP (β= 0.26, P<0.001). Progression of MAP associated with both baseline and progression of PWV (β=0.13, P=0.003 and β=0.24, P<0.001, respectively). CONCLUSIONS: Progression of aortic stiffness associates more strongly with contemporaneous MAP compared with historic MAP. In contrast, progression of MAP is associated with prior arterial stiffness. These findings suggest a bidirectional relationship between arterial stiffness and blood pressure, and that lowering blood pressure may prevent a cycle of arterial stiffening and hypertension

Estimating telomere length from whole genome sequence data.

Telomeres play a key role in replicative ageing and undergo age-dependent attrition in vivo. Here, we report a novel method, TelSeq, to measure average telomere length from whole genome or exome shotgun sequence data. In 260 leukocyte samples, we show that TelSeq results correlate with Southern blot measurements of the mean length of terminal restriction fragments (mTRFs) and display age-dependent attrition comparably well as mTRFs

Innate and adaptive immune traits are differentially affected by genetic and environmental factors

The diversity and activity of leukocytes is controlled by genetic and environmental influences to maintain balanced immune responses. However, the relative contribution of environmental compared with genetic factors that affect variations in immune traits is unknown. Here we analyse 23,394 immune phenotypes in 497 adult female twins. 76% of these traits show a predominantly heritable influence, whereas 24% are mostly influenced by environment. These data highlight the importance of shared childhood environmental influences such as diet, infections or microbes in shaping immune homeostasis for monocytes, B1 cells, γδ T cells and NKT cells, whereas dendritic cells, B2 cells, CD4(+) T and CD8(+) T cells are more influenced by genetics. Although leukocyte subsets are influenced by genetics and environment, adaptive immune traits are more affected by genetics, whereas innate immune traits are more affected by environment

Decreasing initial telomere length in humans intergenerationally understates age-associated telomere shortening

Telomere length shortens with aging, and short telomeres have been linked to a wide variety of pathologies. Previous studies suggested a discrepancy in age-associated telomere shortening rate estimated by cross-sectional studies versus the rate measured in longitudinal studies, indicating a potential bias in cross-sectional estimates. Intergenerational changes in initial telomere length, such as that predicted by the previously described effect of a father's age at birth of his offspring (FAB), could explain the discrepancy in shortening rate measurements. We evaluated whether changes occur in initial telomere length over multiple generations in three large datasets and identified paternal birth year (PBY) as a variable that reconciles the difference between longitudinal and cross-sectional measurements. We also clarify the association between FAB and offspring telomere length, demonstrating that this effect is substantially larger than reported in the past. These results indicate the presence of a downward secular trend in telomere length at birth over generational time with potential public health implications

Interaction Between Allelic Variations in Vitamin D Receptor and Retinoid X Receptor Genes on Metabolic Traits

Low vitamin D status has been shown to be a risk factor for several metabolic traits such as obesity, diabetes and cardiovascular disease. The biological actions of 1, 25-dihydroxyvitamin D, are mediated through the vitamin D receptor (VDR), which heterodimerizes with retinoid X receptor, gamma (RXRG). Hence, we examined the potential interactions between the tagging polymorphisms in the VDR (22 tag SNPs) and RXRG (23 tag SNPs) genes on metabolic outcomes such as body mass index, waist circumference, waist-hip ratio (WHR), high- and low-density lipoprotein (LDL) cholesterols, serum triglycerides, systolic and diastolic blood pressures and glycated haemoglobin in the 1958 British Birth Cohort (1958BC, up to n = 5,231). We used Multifactor- dimensionality reduction (MDR) program as a non-parametric test to examine for potential interactions between the VDR and RXRG gene polymorphisms in the 1958BC. We used the data from Northern Finland Birth Cohort 1966 (NFBC66, up to n = 5,316) and Twins UK (up to n = 3,943) to replicate our initial findings from 1958BC

Dietary influence on systolic and diastolic blood pressure in the TwinsUK cohort

Nutrition plays a key role in blood pressure (BP) regulation. Here, we examine associations between nutrient intakes and BP in a large predominantly female population-based cohort. We assessed the correlation between 45 nutrients (from food frequency questionnaires) and systolic BP/diastolic BP (SBP/DBP) in 3889 individuals from TwinsUK not on hypertensive treatments and replicated in an independent subset of monozygotic twins discordant for nutrient intake (17–242 pairs). Results from both analyses were meta-analysed. For significant nutrients, we calculated heritability using structural equation modelling. We identified and replicated 15 nutrients associated with SBP, 9 also being associated with DBP, adjusting for covariates and multiple testing. 14 of those had a heritable component (h2: 27.1–57.6%). Strong associations with SBP were observed for riboflavin (Beta(SE) = −1.49(0.38), P = 1.00 × 10−4) and tryptophan (−0.31(0.01), P = 5 × 10−4), while with DBP for alcohol (0.05(0.07), P = 1.00 × 10−4) and lactose (−0.05(0.0), P = 1.3 × 10−3). Two multivariable nutrient scores, combining independently SBP/DBP-associated nutrients, explained 22% of the variance in SBP and 13.6% of the variance in DBP. Moreover, bivariate heritability analysis suggested that nutrients and BP share some genetic influences. We confirm current understanding and extend the panel of dietary nutrients implicated in BP regulation underscoring the value of nutrient focused dietary research in preventing and managing hypertension

Immune phenotypes that are associated with subsequent COVID-19 severity inferred from post-recovery samples

Severe COVID-19 causes profound immune perturbations, but pre-infection immune signatures contributing to severe COVID-19 remain unknown. Genome-wide association studies (GWAS) identified strong associations between severe disease and several chemokine receptors and molecules from the type I interferon pathway. Here, we define immune signatures associated with severe COVID-19 using high-dimensional flow cytometry. We measure the cells of the peripheral immune system from individuals who recovered from mild, moderate, severe or critical COVID-19 and focused only on those immune signatures returning to steady-state. Individuals that suffered from severe COVID-19 show reduced frequencies of T cell, mucosal-associated invariant T cell (MAIT) and dendritic cell (DC) subsets and altered chemokine receptor expression on several subsets, such as reduced levels of CCR1 and CCR2 on monocyte subsets. Furthermore, we find reduced frequencies of type I interferon-producing plasmacytoid DCs and altered IFNAR2 expression on several myeloid cells in individuals recovered from severe COVID-19. Thus, these data identify potential immune mechanisms contributing to severe COVID-19

Integrated multiomics approach identifies calcium and integrin-binding protein-2 as a novel gene for pulse wave velocity

Background: Carotid-femoral pulse wave velocity (PWV) is an important measure of arterial stiffness, which is an independent predictor of cardiovascular morbidity and mortality. In this study, we used an integrated genetic, epigenetic and transcriptomics approach to uncover novel molecular mechanisms contributing to PWV. Methods and results: We measured PWV in 1505 healthy twins of European descendent. A genomewide association analysis was performed using standardized residual of the inverse of PWV. We identified one single-nucleotide polymorphism (rs7164338) in the calcium and integrin-binding protein-2 (CIB2) gene on chromosome 15q25.1 associated with PWV [beta = -0.359, standard error (SE) = 0.07, P = 4.8 x 10(-8)]. The same variant was also associated with increased CIB2 expression in leucocytes (beta = 0.034, SE = 0.008, P = 4.95 x 10(-5)) and skin (beta = 0.072, SE = 0.01, P = 2.35 x 10(-9)) and with hypomethylation of the gene promoter (beta = -.899, SE = 0.098, P = 3.63 x 10(-20)). Conclusion: Our data indicate that reduced methylation of the CIB2 promoter in individuals carrying rs7164338 may lead to increased CIB2 expression. Given that CIB2 is thought to regulate intracellular calcium levels, an increase in protein levels may prevent the accumulation of serum calcium and phosphate, ultimately slowing down the process of vascular calcification. This study shows the power of integrating multiple omics to discover novel cardiovascular mechanisms