Summary 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.

In December 2019, a novel severe acute respiratory syndrome (SARS) from a new coronavirus (SARS-CoV-2) was recognized in the city of Wuhan, China. Rapidly, it became an epidemic in China and has now spread throughout the world reaching pandemic proportions. High mortality rates characterize SARS-CoV-2 disease (COVID-19), which mainly affects the elderly, causing unrestrained cytokines-storm and subsequent pulmonary shutdown, also suspected micro thromboembolism events. At the present time, no specific and dedicated treatments, nor approved vaccines, are available, though very promising data come from the use of anti-inflammatory, anti-malaria, and anti-coagulant drugs. In addition, it seems that males are more susceptible to SARS-CoV-2 than females, with males 65% more likely to die from the infection than females. Data from the World Health Organization (WHO) and Chinese scientists show that of all cases about 1.7% of women who contract the virus will die compared with 2.8% of men, and data from Hong Kong hospitals state that 32% of male and 15% of female COVID-19 patients required intensive care or died. On the other hand, the long-term fallout of coronavirus may be worse for women than for men due to social and psychosocial reasons. Regardless of sex- or gender-biased data obtained from WHO and those gathered from sometimes controversial scientific journals, some central points should be considered. Firstly, SARS-CoV-2 has a strong interaction with the human ACE2 receptor, which plays an essential role in cell entry together with transmembrane serine protease 2 (TMPRSS2); it is interesting to note that the ACE2 gene lays on the X-chromosome, thus allowing females to be potentially heterozygous and differently assorted compared to men who are definitely hemizygous. Secondly, the higher ACE2 expression rate in females, though controversial, might ascribe them the worst prognosis, in contrast with worldwide epidemiological data. Finally, several genes involved in inflammation are located on the X-chromosome, which also contains high number of immune-related genes responsible for innate and adaptive immune responses to infection. Other genes, out from the RAS-pathway, might directly or indirectly impact on the ACE1/ACE2 balance by influencing its main actors (e.g., ABO locus, SRY, SOX3, ADAM17). Unexpectedly, the higher levels of ACE2 or ACE1/ACE2 rebalancing might improve the outcome of COVID-19 in both sexes by reducing inflammation, thrombosis, and death. Moreover, X-heterozygous females might also activate a mosaic advantage and show more pronounced sex-related differences resulting in a sex dimorphism, further favoring them in counteracting the progression of the SARS-CoV-2 infection.

Background-TRAIL protein is expressed in the medial smooth cell layer of aorta and pulmonary artery, whereas endothelial cells express all TRAIL receptors (TRAIL-Rs). Methods and Results-The role of TRAIL/TRAIL-Rs in vascular biology was investigated in primary human umbilical vein endothelial cells (HUVECs) and aortic endothelial cells, which showed comparable surface expression of death (TRAIL-R1 and -R2) and decoy (TRAIL-R3 and -R4) TRAIL-Rs. TRAIL activated the protein kinase Akt in HUVECs, as assessed by Western blot for phospho-Akt. Moreover, experiments performed with a pharmacological inhibitor of the phosphatidylinositol 3-kinase/Akt pathway (LY294002) or a dominant-negative Akt (K179M) demonstrated that TRAIL significantly protected HUVECs from apoptosis induced by trophic withdrawal via Akt and that inhibition of Akt sensitized HUVECs to TRAIL-induced caspase-dependent apoptosis. TRAIL also stimulated the ERK1/2 but not the p38 or the JNK pathways and induced a significant increase in endothelial cell proliferation in an ERK-dependent manner. Conversely, TRAIL did not activate NF-B or affect the surface expression of the inflammatory markers E-selectin, intercellular adhesion molecule-1, and vascular cell adhesion molecule-1. Conclusions-The

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Cyclooxygenase (COX)-1 or -2 and prostaglandin (PG) synthases catalyze the formation of various PGs and thromboxane (TX) A 2. We have investigated the expression and activity of COX-1 and -2 during human megakaryocytopoiesis. We analyzed megakaryocytes from bone marrow biopsies and derived from thrombopoietin-treated CD34 ؉ hemopoietic progenitor cells in culture. Platelets were obtained from healthy donors and patients with high platelet regeneration because of immune thrombocytopenia or peripheral blood stem cell transplantation. By immunocytochemistry, COX-1 was observed in CD34 ؉ cells and in megakaryocytes at each stage of maturation, whereas COX-2 was induced after 6 days of culture, and remained detectable in mature megakaryocytes. CD34 ؉ cells synthesized more PGE 2 than TXB2 (214 ؎ 50 vs. 30 ؎ 10 pg͞10 6 cells), whereas the reverse was true in mature megakaryocytes (TXB 2 8,440 ؎ 2,500 vs. PGE 2 906 ؎ 161 pg͞10 6 cells). By immunostaining, COX-2 was observed in <10% of circulating platelets from healthy controls, whereas up to 60% of COX-2-positive platelets were found in patients. A selective COX-2 inhibitor reduced platelet production of both PGE 2 and TXB2 to a significantly greater extent in patients than in healthy subjects. Finally, we found that COX-2 and the inducible PGE-synthase were coexpressed in mature megakaryocytes and in platelets. We conclude that both COX-isoforms contribute to prostanoid formation during human megakaryocytopoiesis and that COX-2-derived PGE 2 and TXA2 may play an unrecognized role in inflammatory and hemostatic responses in clinical syndromes associated with high platelet turnover.

A sensitive and specific polymerase chain reaction method for the detection of human herpesvirus 6 (HHV-6) DNA in serum or plasma has been developed. In total, 157 human serum or plasma samples were studied. HHV-6 DNA was detected in 6 (85.7%) of 7 children with exanthem subitum, 3 (23.1%) of 13 bone marrow transplant (BMT) recipients, 4 (22.2%) of 18 human immunodeficiency virus (HIV)-infected patients, 1 (2.6%) of 39 patients with chronic fatigue syndrome, and none of 37 healthy adults. In the HHV-6-positive BMT recipients, HHV-6 plasma DNA was transiently detected during episodes of fever and respiratory infection. In children with exanthem subitum and in 1 HIV-infected patient, the HHV-6 strains were characterized as variant B, whereas variant A was detected in all other patients. Detection of viral DNA in serum or plasma is a marker of active infection that can be used to investigate the role of HHV-6 in human disease.

The two murine double minute (MDM) family members MDM2 and MDMX are at the center of an intense clinical assessment as molecular target for the management of cancer. Indeed, the two proteins act as regulators of P53, a well-known key controller of the cell cycle regulation and cell proliferation that, when altered, plays a direct role on cancer development and progression. Several evidence demonstrated that functional aberrations of P53 in tumors are in most cases the consequence of alterations on the MDM2 and MDMX regulatory proteins, in particular in patients with hematological malignancies where TP53 shows a relatively low frequency of mutation while MDM2 and MDMX are frequently found amplified/overexpressed. The pharmacological targeting of these two P53-regulators in order to restore or increase P53 expression and activity represents therefore a strategy for cancer therapy. From the discovery of the Nutlins in 2004, several compounds have been developed and reported with the ability of targeting the P53-MDM2/X axis by inhibiting MDM2 and/or MDMX. From natural compounds up to small molecules and stapled peptides, these MDM2/X pharmacological inhibitors have been extensively studied, revealing different biological features and different rate of efficacy when tested in in vitro and in vivo experimental tumor models. The data/evidence coming from the preclinical experimentation have allowed the identification of the most promising molecules and the setting of clinical studies for their evaluation as monotherapy or in therapeutic combination with conventional chemotherapy or with innovative therapeutic protocols in different tumor settings. Preliminary results have been recently published reporting data about safety, tolerability, potential side effects, and efficacy of such therapeutic approaches. In this light, the aim of this review is to give an updated overview about the state of the art of the clinical evaluation of MDM2/X inhibitor compounds with a special attention to hematological malignancies and to the potential for the management of pediatric cancers.

Aberrant expression of microRNAs (miRNAs) has been associated with clinical outcome in patients with chronic lymphocytic leukemia (CLL). To identify a powerful and easily assessable miRNA bio-marker of prognosis and survival, we performed quantitative reverse-transcription polymerase chain reaction (qRT-PCR) profiling in 104 CLL patients with a welldefined chromosome 17p status, and we validated our findings with miRNA microarray data from an independent cohort of 80 patients. We found that miR-15a, miR-21, miR-34a, miR-155, and miR-181b were differentially expressed between CLLs with chromosome 17p deletion and CLLs with normal 17p and normal karyotype, and that miR-181b was downregulated in therapy-refractory cases. miR-21 expression levels were significantly higher in patients with poor prognosis and predicted overall survival (OS), and miR-181b expression levels significantly predicted treatment-free survival. We developed a 21FK score (miR-21 qRT-PCR, fluorescence in situ hybridization, Karyotype) to stratify patients according to OS and found that patients with a low score had a significantly longer OS time. When we evaluated the relative power of the 21FK score with the most used prognostic factors, the score was the most significant in both CLL cohorts. We conclude that the 21FK score represents a useful tool for distinguishing between good-prognosis and poor-prognosis CLL patients. (Blood. 2010;116(6):945-952)