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Lung and liver cancers are among the most deadly types of cancer. Despite improvements in treatment over the past few decades, patient survival remains poor, underlining the need for development of targeted therapies. MicroRNAs represent a class of small RNAs, frequently deregulated in human malignancies. We now report that miR221&222 are over-expressed in aggressive non small cell lung cancer and hepatocarcinoma cells, as compared with less invasive and/or normal lung and liver cells. We show that miR-221&222, by targeting PTEN and TIMP3 tumor suppressors, induce TRAIL resistance and enhance cellular migration through the activation of the AKT pathway and metallopeptidases. Finally, we demonstrate that the MET oncogene is involved in miR-221&222 activation, through the c-Jun transcription factor.

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) exhibits biological activity on vascular cells in vitro. Rapid variation of circulating TRAIL levels occurs during acute coronary ischemia, suggesting that biological pathways involving TRAIL may be activated during ischemic heart disease. However, whether differential levels of soluble TRAIL in normal individuals are associated with adverse health outcomes has not been investigated. We tested the hypothesis that TRAIL levels predict mortality in a population based sample of community dwelling men and women.Plasma TRAIL level was measured by ELISA at baseline in 1282 adults (mean age 68 years) enrolled in the InCHIANTI study. Vital status was ascertained over the six-year follow-up.In multivariable Cox regression analysis adjusted for potential confounders including prevalent cardiovascular diseases (CVD), ankle-brachial index, electrocardiogram abnormalities, and inflammatory markers, baseline TRAIL levels were inversely related to all-cause mortality (p=0.008). In stratified analyses, the prognostic effect of TRAIL level was strong and highly significant in participants with prevalent CVD (N=321), (lowest versus highest quartile: HR 3.1; 95% CI 1.5-6.5) while it was negligible in those free of CVD (p value for the interaction term between CVD status and TRAIL levels=0.038). Similar findings were obtained when CVD mortality was considered as the outcome of interest.In older patients with CVD, low levels of TRAIL were associated with increased risk of death over a period of 6 years. Lower concentration of circulating TRAIL may be related to the clinical evolution of older adults with CVD.

The small-molecule inhibitor of murine double minute (MDM-2), Nutlin-3, induced variable apoptosis in primary acute myeloid leukemia (AML) blasts and promoted myeloid maturation of surviving cells, as demonstrated by analysis of CD11b and CD14 surface antigens and by morphologic examination. Although the best-characterized activity of Nutlin-3 is activation of the p53 pathway, Nutlin-3 induced maturation also in one AML sample characterized by p53 deletion, as well as in the p53(-/-) human myeloblastic HL-60 cell line. At the molecular level, the maturational activity of Nutlin-3 in HL-60 cells was accompanied by the induction of E2F1 transcription factor, and it was significantly counteracted by specific gene knockdown with small interfering RNA for E2F1. Moreover, Nutlin-3, as well as tumor necrosis factor (TNF) alpha, potentiated the maturational activity of recombinant TNF-related apoptosis-inducing ligand (TRAIL) in HL-60 cells. However, although TNF-alpha significantly counteracted the proapoptotic activity of TRAIL, Nutlin-3 did not interfere with the proapoptotic activity of TRAIL. Taken together, these data disclose a novel, potentially relevant therapeutic role for Nutlin-3 in the treatment of both p53 wild-type and p53(-/-) AML, possibly in association with recombinant TRAIL.

TRAIL is a member of the tumor necrosis factor superfamily that interacts with an unusually complex receptor system, comprising transmembrane (TRAIL-R1, -R2, -R3 and -R4) and soluble (osteoprotegerin) receptors. TRAIL has received considerable attention because of the finding that many cancer cell types are sensitive to TRAIL-induced apoptosis. However, increasing experimental evidence shows that TRAIL exhibits regulatory roles in various normal tissues, as well. Although the best-characterized biological activity of TRAIL is in the homeostatic regulation of the immune system, in this review we have summarized and discussed the physiological function of TRAIL and its receptors, in normal hematopoiesis and vascular physiopathology.

Objective The present study was aimed at characterizing the expression and activity of cyclooxygenase (COX) isoenzymes in erythropoiesis. Methods The expression and activity of cyclooxygenase (COX) and prostaglandin (PG) synthases were investigated in: 1) erythroblasts developed in culture from human CD34 + hematopoietic progenitors, 2) erythroblasts in bone marrow specimens, and 3) peripheral erythrocytes isolated from healthy donors and from patients with a high regeneration rate of erythrocytes. Results While COX-1 protein was observed at each stage of erythroblast development, COX-2 protein was induced at later stages through a p38/MAPK-dependent pathway. Both COX isoforms were also observed in mature erythroblasts of the bone marrow. Erythroblasts developed in culture synthesized significantly more PGE 2 than TXB 2 and indomethacin delayed erythroid maturation. COX-1 and COX-2 were also observed in erythrocytes by immunostainings, although COX expression was confined to a fraction of circulating erythrocytes. Peripheral erythrocytes synthesized low but detectable amounts of PGE 2 and TXB 2 . Similarly to erythroblast progenitors, PGE 2 was the prevalent prostanoid released by erythrocytes. This biosynthetic capacity was significantly increased in erythrocytes from patients with accelerated erythropoiesis as compared to controls. Conclusions Both COX isoforms are present and enzymatically active during human erythropoiesis, although with different kinetics, and COX-derived prostanoids may play a role in erythroid maturation. Furthermore, peripheral erythrocytes retain in part the capacity of expressing COX and synthesizing prostanoids, which may contribute to the hemostatic/thrombotic response to vascular injury in different diseases, including congenital hemolytic disorders.

Background Preeclampsia is a syndrome with a heterogeneous clinical expression and is associated with long-term consequences for the mother and the newborn. Recently two major subtypes of preeclampsia the placental and maternal have been proposed. It is generally accepted that an abnormal placentation is strongly associated with IUGR, even in the absence of preeclampsia, but is less clearly documented in association with preeclampsia and normal fetal growth. The current definition of preeclampsia is a relic of the past, when the disorder was not yet well understood. Now, using trophoblastic biomarkers associated with preeclampsia, the placental component of the syndrome can be identified separately and incorporated in its definition. sTRAIL has been noted as a possible marker to identify patients at risk of developing preeclampsia because of its role in the remodeling of uterine arteries. Objective of the study To determine serum sTRAIL in patients who developed preeclampsia based on the placental contribution, to define the detection rate (DR) and the associated cut-off of sTRAIL for placental preeclampsia. Materials and methods A retrospective cross-sectional study was conducted by using a clinical database and a relative bank of biological samples stored at University Hospital S. Anna in Turin. All patients bearing a singleton pregnancy were enrolled and divided into three groups: 22 women constituted the control group (i): the study groups were constituted by 11 women with preeclampsia and AGA fetus (ii), and 24 women with preeclampsia and IUGR+ impaired uterine arteries Doppler velocimetry (iii) all patients had a blood draw between 20 and 42 weeks of gestation . Serum aliquots were obtained and subsequently stored at −70 °C. The sTRAIL concentrations were obtained at the Department of Biomedical Sciences and Advanced Therapies, University of Ferrara using an enzyme immunoassay (ELISA). Data were analyzed by a non parametric approach. A ROC curve was used to test the sTRAIL discriminant ability for identifying groups ii and iii. Results sTRAIL concentrations, after MoM, conversion (adjusted for gestational age at the blood test and BMI) were lower in the preeclamptic women with IUGR plus impaired uterine arteries Doppler when compared with those of the control group (0.80 vs. 1.00, p-value 0.042). Finally, the univariable DR for group PE+ IUGR was 46.7% at a fixed 10% of false positives. The associated MoM sTRAIL cut-off was 0.71 (p-value = 0.019) Conclusions Plasma concentrations of sTRAIL are significantly reduced in patients with preeclampsia with IUGR and impaired Doppler velocimetry of uteroplacental district (group iii), thus demonstrating how this biomarker, if validated prospectically, could be predictive of placental preeclampsia. However, the sTRAIL DR is not sufficient by itself to create a screening algorithm for preeclampsia associated with IUGR, and therefore must be integrated with other variable for improving the performance of the risk assessment.

Two isolates of human herpesvirus 7 (HHV-7) were recovered from phytohemagglutinin-activated peripheral blood mononuclear cells of a patient with chronic fatigue syndrome and of a healthy blood donor. A genetic polymorphism between the two isolates was detected by Southern blot analysis using a novel HHV-7 genomic clone (pVL8) as a probe. We developed optimized conditions for the in vitro propagation of HHV-7 by using enriched populations of activated CD4+ T lymphocytes derived from normal peripheral blood, resulting in the production of high-titered extracellular virus (>106 cell culture infectious doses/ml). Bona fide syncytia formation was documented both in normal CD4+ T lymphocytes and in the Sup-T1 CD4+ T-cell line following infection with high-titered HHV-7. To identify neutralizing antibodies to HHV-7, a syncytia-inhibition test was developed. Variable titers of syncytia-neutralizing antibodies were detected in all the human sere tested, thus confirming the high prevalence of HHV-7 in the human population.