In 70 healthy subjects with a large age range, the relationships between plasma tumor necrosis factor-α (TNF-α) and body composition, insulin action, and substrate oxidation were investigated. In the cross-sectional study ( n = 70), advancing age correlated with plasma TNF-α concentration ( r = 0.64, P < 0.001) and whole body glucose disposal (WBGD; r= −0.38, P < 0.01). The correlation between plasma TNF-α and age was independent of sex and body fat (BF; r = 0.31, P < 0.01). Independent of age and sex, a significant relationship between plasma TNF-α and leptin concentration ( r = 0.29, P < 0.02) was also found. After control for age, sex, BF, and waist-to-hip ratio (WHR), plasma TNF-α was still correlated with WBGD ( r = −0.33, P < 0.007). Further correction for plasma free fatty acid (FFA) concentration made the latter correlation no more significant. In a multivariate analysis, a model made by age, sex, BF, fat- free mass, WHR, and plasma TNF-α concentrations explained 69% of WBGD variability with age ( P < 0.009), BF ( P < 0.006), fat-free mass ( P < 0.005), and plasma TNF-α ( P < 0.05) significantly and independently associated with WBGD. In the longitudinal study, made with subjects at the highest tertiles of plasma TNF-α concentration ( n = 50), plasma TNF-α concentration predicted a decline in WBGD independent of age, sex, BF, WHR [relative risk (RR) = 2.0; 95% confidence intervals (CI) = 1.2–2.4]. After further adjustment for plasma fasting FFA concentration, the predictive role of fasting plasma TNF-α concentration on WBGD (RR = 1.2; CI = 0.8–1.5) was no more significant. In conclusion, our study demonstrates that plasma TNF-α concentration is significantly associated with advancing age and that it predicts the impairment in insulin action with advancing age.

Vaccines targeting pathogens are generally effective and protective because based on foreign non-self antigens which are extremely potent in eliciting an immune response. On the contrary, efficacy of therapeutic cancer vaccines is still disappointing. One of the major reasons for such poor outcome, among others, is the difficulty of identifying tumor-specific target antigens which should be unique to the tumors or, at least, overexpressed on the tumors as compared to normal cells. Indeed, this is the only option to overcome the peripheral immune tolerance and elicit a non toxic immune response. New and more potent strategies are now available to identify specific tumor-associated antigens for development of cancer vaccine approaches aiming at eliciting targeted anti-tumor cellular responses. In the last years this aspect has been addressed and many therapeutic vaccination strategies based on either whole tumor cells or specific antigens have been and are being currently evaluated in clinical trials. This review summarizes the current state of cancer vaccines, mainly focusing on antigen-specific approaches.

The chemokine system mediates acute inflammation by driving leukocyte migration to damaged or infected tissues. However, elevated expression of chemokines and their receptors can contribute to chronic inflammation and malignancy. Thus, great effort has been taken to target these molecules. The first hint of the druggability of the chemokine system was derived from the role of chemokine receptors in HIV infection. CCR5 and CXCR4 function as essential co-receptors for HIV entry, with the former accounting for most new HIV infections worldwide. Not by chance, an anti-CCR5 compound, maraviroc, was the first FDA-approved chemokine receptor-targeting drug. CCR5, by directing leukocytes to sites of inflammation and regulating their activation, also represents an important player in the inflammatory response. This function is shared with CCR2 and its selective ligand CCL2, which constitute the primary chemokine axis driving the recruitment of monocytes/ macrophages to inflammatory sites. Both receptors are indeed involved in the pathogenesis of several immune-mediated diseases, and dual CCR5/CCR2 targeting is emerging as a more efficacious strategy than targeting either receptor alone in the treatment of complex human disorders. In this review, we focus on the distinctive and complementary contributions of CCR5 and CCR2/CCL2 in HIV infection, multiple sclerosis, liver fibrosis and associated hepatocellular carcinoma. The emerging therapeutic approaches based on the inhibition of these chemokine axes are highlighted.

Abstract-Leptin, the product of the ob gene, has been shown to increase heart rate and blood pressure through a stimulation of cardiac sympathetic nervous system activity, a phenomenon also involved in the pathogenesis of left ventricular hypertrophy in hypertensives. Thus, we hypothesize that plasma leptin concentration is associated with left ventricular hypertrophy. Forty hypertensive males and 15 healthy male subjects underwent anthropometric and echocardiographic evaluations, assessment of insulin sensitivity through euglycemic glucose clamp combined with indirect calorimetry, and determination of fasting plasma leptin concentration. Fasting plasma leptin levels were higher in hypertensives than in controls (6.48Ϯ2.9 versus 4.62Ϯ1.5 ng/mL, PϽ0.05); these results were unchanged after adjustment for body mass index (PϽ0.05). In the whole group of patients (nϭ55), fasting plasma leptin concentration was correlated with body mass index (rϭ0.46, PϽ0.001) and waist/hip ratio (rϭ0.50, PϽ0.001); independent of body mass index and waist/hip ratio, fasting plasma leptin concentration was correlated (nϭ55) with whole-body glucose disposal (rϭϪ0.27, PϽ0.04), interventricular septum thickness (rϭ0.34, PϽ0.001), posterior wall thickness (rϭ0.38, PϽ0.003), and the sum of wall thicknesses (rϭ0.68, PϽ0.001). In a multivariate analysis (nϭ55), age, body mass index, fasting plasma leptin concentration, plasma Na ϩ concentration, whole-body glucose disposal, and diastolic blood pressure explained 68% of the variability of the sum of wall thicknesses with fasting plasma leptin concentration (PϽ0.03), whole body glucose disposal (PϽ0.002), and diastolic blood pressure (PϽ0.001), which were significantly and independently associated with the sum of wall thicknesses. In conclusion, our study demonstrates that fasting plasma leptin levels are associated with increased myocardial wall thickness independent of body composition and blood pressure levels in hypertensives. (Hypertension. 1999;34:1047-1052.) Key Words: leptin Ⅲ hypertension, essential Ⅲ hypertension, arterial Ⅲ insulin L eptin, the product of the ob gene, 1 is a peptide hormone produced by adipose tissue involved in body weight control through a decrease in food intake and an increase in energy expenditure. 2 Several studies have shown leptin to increase in insulin-resistant states such as obesity 3 and hypertension. 4 Nevertheless, a direct relation between plasma leptin concentration and the cardiovascular system needs to be investigated. The possibility that leptin plays a role in the cardiovascular system is strengthened by the evidence that chronic leptin infusion has been shown to increase heart rate and blood pressure through stimulation of sympathetic nervous system activity. 5,6 Interestingly, this latter phenomenon is also involved in the pathogenesis of left ventricular (LV) hypertrophy. 7,8 Thus, we hypothesize that plasma leptin concentration is associated with the presence of LV hypertrophy. To determine the accuracy of this hypothesis, we evaluated the pos...