Src is the prototypal member of Src Family tyrosine Kinases (SFKs), a large non-receptor kinase class that controls multiple signaling pathways in animal cells. SFKs activation is necessary for the mitogenic signal from many growth factors, but also for the acquisition of migratory and invasive phenotype. Indeed, oncogenic activation of SFKs has been demonstrated to play an important role in solid cancers; promoting tumor growth and formation of distant metastases. Several drugs targeting SFKs have been developed and tested in preclinical models and many of them have successfully reached clinical use in hematologic cancers. Although in solid tumors SFKs inhibitors have consistently confirmed their ability in blocking cancer cell progression in several experimental models; their utilization in clinical trials has unveiled unexpected complications against an effective utilization in patients. In this review, we summarize basic molecular mechanisms involving SFKs in cancer spreading and metastasization; and discuss preclinical and clinical data highlighting the main challenges for their future application as therapeutic targets in solid cancer progression

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The conciliation between career and family is a relevant issue for working women, in particular during the first years of motherhood. Data about the state of the cardiac autonomic regulation in working women with preschoolers are lacking. Aim of this study was to compare the cardiac autonomic profile of female healthcare professionals with and without preschoolers via the analysis of the variability of the time distance between two consecutive R-wave peaks (RR) from standard 24-h Holter electrocardiogram (ECG). Fifty healthy active female healthcare professionals were enrolled: 25 with at least one preschooler (W_KID) and 25 without (W_NOKID). A standard Holter ECG was obtained during a regular working day. Segments of 5000 consecutive RRs were selected during daytime (DAY) and nighttime (NIGHT). Heart rate variability analysis was performed and the following parameters were considered for comparison between the two groups: mean (μRR), variance (σ2RR), and the absolute power in high frequency component (HF) of RR (HFRR) series. HFRR was considered as a marker of vagal cardiac modulation. Only µRR significantly increased from DAY to NIGHT in both groups (699 ± 88 vs 887 ± 140 ms in W_KID and 728 ± 90 vs 942 ± 166 ms in W_NOKID). Instead, σ2RR and HFRR increased from DAY to NIGHT only in W_NOKID (from 3334 ± 2153 to 4816 ± 4063 ms2 and from 356 ± 334 to 1397 ± 1629 ms2, respectively). W_KID showed lower σ2RR and HFRR during NIGHT, compared to W_NOKID (2336 ± 3170 vs 4816 ± 4063 ms2 and 556 ± 950 vs 1397 ± 1629 ms2, respectively). The perceived stress according to the visual analogue scale was similar in the two groups (4.7 ± 2.1 in W_KID, 5.7 ± 2.1 in W_NOKID). The presence of preschoolers lowered nocturnal cardiac vagal modulation in female healthcare professionals. This might represent an adaptation with a finalistic purpose, scilicet the facilitation of a prompt reaction in case of a child’s need.

DDX3X is an ATP-dependent RNA helicase that has recently attracted interest for its involvement in viral replication and oncogenic progression. Starting from hit compounds previously identified by our group, we have designed and synthesized a new series of DDX3X inhibitors that effectively blocked its helicase activity. These new compounds were able to inhibit the proliferation of cell lines from different cancer types, also in DDX3X low-expressing cancer cell lines. According to the absorption, distribution, metabolism, elimination properties, and antitumoral activity, compound BA103 was chosen to be further investigated in glioblastoma models. BA103 determined a significant reduction in the proliferation and migration of U87 and U251 cells, downregulating the oncogenic protein β-catenin. An in vivo evaluation demonstrated that BA103 was able to reach the brain and reduce the tumor growth in xenograft and orthotopic models without evident side effects. This study represents the first demonstration that DDX3X-targeted small molecules are feasible and promising drugs also in glioblastoma.

14-3-3 are regulatory proteins that through protein-protein interactions (PPI) with numerous binding partners could be involved in several human diseases, including cancer, neurodegenerative disorders, and pathogens infections. Following our research interest in the development of 14-3-3 PPI inhibitors, here we exploited the privileged 4-aminoantipyrine scaffold in the design and synthesis of some derivatives endowed with antiproliferative activity against K-562 cells, and capable of binding to recombinant 14-3-3r as evidenced by NMR spectroscopy. The binding mode was further explored by molecular modelling, while coupling confocal microscopy with intensitometric analysis showed that compound 1 was able to promote the nuclear translocation of c-Abl at low micromolar concentrations. Overall, 1 is chemically stable compared to parent 14-3-3 PPI inhibitors, and thus emerged as a confirmed hit for further development.