Ewing sarcomas (ES) are highly malignant bone or soft tissue tumors. Genetically, ES are defined by balanced chromosomal EWS/ETS translocations, which give rise to chimeric proteins (EWS-ETS) that generate an oncogenic transcriptional program associated with altered epigenetic marks throughout the genome. By use of an inhibitor (JQ1) blocking BET bromodomain binding proteins (BRDs) we strikingly observed a strong down-regulation of the predominant EWS-ETS protein EWS-FLI1 in a dose dependent manner. This was further enhanced by co-treatment with an inhibitor of the PI3K pathway. Microarray analysis further revealed JQ1 treatment to block a typical ES associated expression program. The effect on this expression program was mimicked by RNA interference with BRD3 or BRD4 expression, indicating that the EWS-FLI1 mediated expression profile is at least in part mediated via such epigenetic readers. Consequently, contact dependent and independent proliferation of different ES lines was strongly inhibited. Mechanistically, treatment of ES resulted in a partial arrest of the cell cycle as well as induction of apoptosis. Tumor development was suppressed dose dependently in a xeno-transplant model in immune deficient mice, overall indicating that ES may be susceptible to treatment with epigenetic inhibitors blocking BET bromodomain activity and the associated pathognomonic EWS-ETS transcriptional program.

In this paper, a new model describing the human\ud immunodeficiency virus (HIV)-acquired immuno deficiency syndrome\ud (AIDS) epidemic spread is proposed. The improvement\ud with respect to the known models has been driven by recent\ud results obtained from historical data collection and the suggestions\ud given by the World Health Organization: the characteristics\ud of the virus diffusion, mainly by body fluids, imply the trivial\ud fact that wise behaviors of healthy subjects and fast timely recognition\ud of a new positive diagnosis should reduce the spread quite\ud fast. Therefore, the set of susceptible subjects is divided into two\ud categories: the wise people that, suitably informed, avoid dangerous\ud behaviors, and the ones that, with irresponsible acts, could\ud get the infection. The set of infected subjects is constituted by\ud people who are still not aware of being infected (and therefore\ud are responsible of the HIV spread), along with the subjects aware\ud of being infected by HIV or AIDS. Inspired by the international\ud guidelines suggestions, three controls are introduced, aiming both\ud at the prevention and at the cure: an informative campaign, a\ud test campaign, and an HIV/AIDS therapy action. Among them,\ud the core of the control effort is a fast HIV diagnosis. The equilibrium\ud points, their stability, and the influences of the introduced\ud inputs to the system behavior are studied, yielding to preliminary\ud statements for prospective works on suitable control design\ud approaches

Ewing sarcoma (ES) is the second most frequent bone cancer in childhood and is characterized by the presence of the balanced translocation t(11;22)(q24;q12) in more than 85% of cases, generating a dysregulated transcription factor EWS/FLI1. This fusion protein is an essential oncogenic component of ES development which is necessary for tumor cell maintenance and represents an attractive therapeutic target. To search for modulators of EWS/FLI1 activity we screened a library of 153 targeted compounds and identified inhibitors of the PI3K pathway to directly modulate EWS/FLI1 transcription. Surprisingly, treatment of four different ES cell lines with BEZ235 resulted in down regulation of EWS/FLI1 mRNA and protein by ∼50% with subsequent modulation of target gene expression. Analysis of the EWS/FLI1 promoter region (−2239/+67) using various deletion constructs identified two 14bp minimal elements as being important for EWS/FLI1 transcription. We identified SP1 as modulator of EWS/FLI1 gene expression and demonstrated direct binding to one of these regions in the EWS/FLI1 promoter by EMSA and ChIP experiments. These results provide the first insights on the transcriptional regulation of EWS/FLI1, an area that has not been investigated so far, and offer an additional molecular explanation for the known sensitivity of ES cell lines to PI3K inhibition.

Aim: The aim of this work was to evaluate the reliability of pSWE in assessing the stiffness of the vastus medialis muscle and of the quadriceps and patellar tendons.Material and methods: For this purpose, 18 subjects (9 males and 9 females of 57±22 years) in good clinical conditions were included in this study. pSWE examination was conducted by a unique expert operator with more than ten years of experience in musculoskeletal ultrasound. Two sets of five measurements for each muscle and tendon district were bilaterally performed at the same manner, at least fifteen minutes apart. The mean value of the measurements of each set was statistically compared with that of the other set.Results: No significant differences were found comparing the mean value of the measurements of the two sets of evaluation performed in muscle and tendon areas (vastus medialis muscle: p=0.285; quadriceps tendon: p=0.979; patellar tendon: p=0.187). The intraclass correlation coefficient was excellent for all areas (vastus medialis muscle: 0.969; quadriceps and patellar tendons: 0.995 and 0.989, respectively).Conclusion: The pSWE technique demonstrated that it was a reliable method for measuring stiffness in vastus medialis muscle and quadriceps and patellar tendon in subjects who had undergone orthopedic surgery. This opens the possibility of many applications in monitoring stiffness before and after surgery and during rehabilitation.

Neuropsychiatric systemic lupus erythematosus is a diagnostic challenge due to the multifarious neurological and psychiatric manifestations that define it but, when suspected, diagnostic imaging can give a fundamental help. The advancements and variety of neuroimaging techniques allow us to perform more and more accurate evaluations of structure, perfusion, and metabolism of the brain and to detect cerebral and spinal lesions. Moreover, vascular districts of the neck and the brain, as well as the electrical brain and peripheral muscle activity may be accurately investigated, thus giving us a wide panoramic view. Although magnetic resonance is recognized as a fundamental neuroimaging technique to reach a correct diagnosis, the juxtaposition of other diagnostic techniques has improved the possibility to make diagnoses but has also increased the confusion about deciding which of them to use and when. Our aim was to combine the number of available techniques with the need to simplify the diagnostic path. Therefore, through the construction of an algorithm from an evidence based approach, we believe we are providing some added improvements to facilitate and expedite the diagnosis of NPSLE.