Despite recent therapeutic advances, multiple myeloma (MM) is still an incurable neoplasia due to intrinsic or acquired resistance to therapy. Myeloma cell localization in the bone marrow milieu allows direct interactions between tumor cells and nontumor bone marrow cells which promote neoplastic cell growth, survival, bone disease, acquisition of drug resistance and consequent relapse. Twenty percent of MM patients are at high-risk of treatment failure as defined by tumor markers or presentation as plasma cell leukemia. Cumulative evidences indicate a key role of Notch signaling in multiple myeloma onset and progression. Unlike other Notchrelated malignancies, where the majority of patients carry gain-of-function mutations in Notch pathway members, in MM cell Notch signaling is aberrantly activated due to an increased expression of Notch receptors and ligands; notably, this also results in the activation of Notch signaling in surrounding stromal cells which contributes to myeloma cell proliferation, survival and migration, as well as to bone disease and intrinsic and acquired pharmacological resistance. Here we review the last findings on the mechanisms and the effects of Notch signaling dysregulation in MM and provide a rationale for a therapeutic strategy aiming at inhibiting Notch signaling, along with a complete overview on the currently available Notch-directed approaches.

OBJECTIVES We examined the incidence, the impact of subsequent cerebrovascular events and the clinical or procedural predictors of leaflet thrombosis (LT) in patients undergoing transcatheter aortic valve implantation (TAVI). METHODS MEDLINE/PubMed was systematically screened for studies reporting on LT in TAVI patients. Incidence [both clinical and subclinical, i.e. detected with computed tomography (CT)] of LT was the primary end point of the study. Predictors of LT evaluated at multivariable analysis and impact of LT on stroke were the secondary ones. RESULTS Eighteen studies encompassing 11 124 patients evaluating incidence of LT were included. Pooled incidence of LT was 0.43% per month [5.16% per year, 95% confidence interval (CI) 0.21–0.72, I2 = 98%]. Pooled incidence of subclinical LT was 1.36% per month (16.32% per year, 95% CI 0.71–2.19, I2 = 94%). Clinical LT was less frequent (0.04% per month, 0.48% per year, 95% CI 0.00–0.19, I2 = 93%). LT increased the risk of stroke [odds ratio (OR) 4.21, 95% CI 1.27–13.98], and was more frequent in patients with a valve diameter of 28-mm (OR 2.89: 1.55–5.8), for balloon-expandable (OR 8: 2.1–9.7) or after valve-in-valve procedures (OR 17.1: 3.1–84.9). Oral anticoagulation therapy reduced the risk of LT (OR 0.43, 95% CI: 0.22–0.84, I2 = 64%), as well as the mean transvalvular gradient. CONCLUSIONS LT represents an infrequent event after TAVI, despite increasing risk of stroke. Given its full reversal with warfarin, in high-risk patients (those with valve-in-valve procedures, balloon expandable or large-sized devices), a protocol which includes a control CT appears reasonable.

Notch signaling plays an important role in several cellular functions including growth, differentiation, cell fate determination and stemness. Increased Notch activity has been linked to several types of cancers. Activation of Notch signaling is triggered by the interaction of Notch receptors (Notch1-4) with 5 different ligands (Jagged1-2 and Dll1-3-4) expressed on the neighbouring cells. Currently, indirect approaches to inhibit Notch signalling are based on the inhibition of the key step of Notch activation catalyzed by the γ-Secretase and thereby affect several different γ-Secretase substrates; conversely direct strategies get advantage of antibody-based drugs. The evidence that Jagged-mediated Notch activation plays a key role in cancer cell biology and the interplay with the surrounding microenvironment prompted us to develop a strategy to directly inhibit Notch activation by uncoupling its interaction with the Jagged, using an unprecedented approach based on small molecules. We set-up a screening strategy based on: protein::protein docking of crystallographic structures of Notch1 with Jagged1; comparative modelling of the Notch2:Jagged2 complex, based on the Notch1::Jagged1 complex; in silico high-throughput screening directed to Notch2 interaction surface of a virtual chemical library containing a large variety of molecules commercially available. The predicted pharmacological activity of the selected compounds was validated in vitro by a gene reporter and a viability assay. This approach led to the successful identification of two candidates with different anti-proliferative potency and efficacy. This represents the first step towards the rational identification of candidate molecules for the development of entirely novel drugs directed to inhibit Notch signaling in cancer.

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Nanoparticles with active-targeting and stimuli-responsive behavior are a promising class of engineered materials able to recognize the site of cancer disease, targeting the drug release and limiting side effects in the healthy organs. In this work, new dual pH/redox-responsive nanoparticles with affinity for folate receptors were prepared by the combination of two amphiphilic dextran (DEX) derivatives. DEXFA conjugate was obtained by covalent coupling of the polysaccharide with folic acid (FA), whereas DEXssPEGCOOH derived from a reductive amination step of DEX was followed by condensation with polyethylene glycol 600. After self-assembling, nanoparticles with a mean size of 50 nm, able to be destabilized in acidic pH and reducing media, were obtained. Doxorubicin was loaded during the self-assembling process, and the release experiments showed the ability of the proposed system to modulate the drug release in response to different pH and redox conditions. Finally, the viability and uptake experiments on healthy (MCF-10A) and metastatic cancer (MDA-MB-231) cells proved the potential applicability of the proposed system as a new drug vector in cancer therapy.