CARATTERIZZAZIONE ACUSTICA DI NANOBOLLE LIPIDICHE

Vengono riportate misure riguardo l’efficienza di scattering di nanobolle lipidiche con diametro medio di 200 nm contenenti tetradecafluoroesano; le misure, effettuate con la tecnica pulse-echo, rivelano un’attenuazione dipendente dalla concentrazione in soluzione delle nanobolle con valori che, per una concentrazione del 35% di nanobolle in hepes, raggiungono, a 14 MHz, il valore di circa 6 dB/cm. Tale valore è confrontabile con le attenuazioni prodotte da agenti di contrasto commercialmente disponibili come, ad esempio, il SonoVue®. È stata inoltre utilizzata una tecnica fotoacustica per la valutazione dell’efficacia di intrappolamento del gas all’interno delle nanobolle, riscontrando, anche in questo caso, valori simili a quelli misurati nel SonoVue®

Surfactants, nanomedicines and nanocarriers: a critical evaluation on clinical trials

Advances, perspectives and innovation in drug delivery have increased in recent years; however, there is limited information available regarding the actual presence of surfactants, nanomed-icines and nanocarriers in investigational medicinal products submitted as part of a request for authorization of clinical trials, particularly for those authorized in the European Economic Area. We retrieve, analyze and report data available at the Clinical Trial Office of the Italian Medicines Agency (AIFA), increasing the transparency and availability of relevant information. An analysis of quality documentation submitted along with clinical trials authorized by the AIFA in 2018 was carried out, focusing on the key terms “surfactant”, “nanomedicine” and “nanocarrier”. Results suggest potential indications and inputs for further reflection and actions for regulators to actively and safely drive innovation from a regulatory perspective and to transpose upcoming evolution of clinical trials within a strong regulatory framework

Decoration of nanovesicles with pH (low) insertion peptide (pHLIP) for targeted delivery

Acidity at surface of cancer cells is a hallmark of tumor microenvironments, which does not depend on tumor perfusion, thus it may serve as a general biomarker for targeting tumor cells. We used the pH (low) insertion peptide (pHLIP) for decoration of liposomes and niosomes. pHLIP senses pH at the surface of cancer cells and inserts into the membrane of targeted cells, and brings nanomaterial to close proximity of cellular membrane. DMPC liposomes and Tween 20 or Span 20 niosomes with and without pHLIP in their coating were fully characterized in order to obtain fundamental understanding on nanocarrier features and facilitate the rational design of acidity sensitive nanovectors. The samples stability over time and in presence of serum was demonstrated. The size, ζ-potential, and morphology of nanovectors, as well as their ability to entrap a hydrophilic probe and modulate its release were investigated. pHLIP decorated vesicles could be useful to obtain a prolonged (modified) release of biological active substances for targeting tumors and other acidic diseased tissues

Smart magnetic nanovesicles for theranostic application: Preparation and characterization

Nanomedicines are submicrometer-sized carrier materials designed to improve the biodistribution of systemically administered (chemo)therapeutic agents. By delivering pharmacologically active agents more effectively and more selectively to the pathological site nanomedicines aim to improve the balance between the efficacy and the toxicity of systemic (chemo)therapeutic administrations. Nanomedicine formulations have also been used for imaging applications and, in recent years, for theranostic approaches, that is, for systems and strategies in which disease diagnosis and therapy are combined. On the one hand, “classical” drug delivery systems are being co-loaded with both drugs and contrast agents. Actually, nanomaterials with an intrinsic ability to be used for imaging purposes, such as iron-oxide–based magnetic nanoparticles (MNPs), are increasingly being loaded with drugs or alone for combining disease diagnosis and therapy. In this study, non-ionic surfactant vesicles loaded with lipophilic and hydrophilic MNPs have been prepared. Vesicles have been characterized in terms of dimensions, ζ-potential, time stability, bilayer characteristics and overall iron content. The encouraging obtained results confirm that Tween 20 and Span 20 vesicles could be promising carriers for the delivery of hydrophilic and lipophilic MNPs, respectively, thereby prompting various opportunities for the development of suitable theranostic strategies. The analyzed formulations confirm the importance of surfactant chemical-physical characteristics in entrapping the MNPs of different polarity, highlighting the high versatility of niosomal bilayer and structure; property that make them so appealing among drug delivery nanocarriers

RIP1-HAT1-SirT complex identification and targeting in treatment and prevention of cancer

Purpose: Alteration in cell death is a hallmark of cancer. A functional role regulating survival, apoptosis, and necroptosis has been attributed to RIP1/3 complexes.Experimental Design: We have investigated the role of RIP1 and the effects of MC2494 in cell death induction, using different methods as flow cytometry, transcriptome analysis, immunoprecipitation, enzymatic assays, transfections, mutagenesis, and in vivo studies with different mice models.Results: Here, we show that RIP1 is highly expressed in cancer, and we define a novel RIP1/3-SIRT1/2-HAT1/4 complex. Mass spectrometry identified five acetylations in the kinase and death domain of RIP1. The novel characterized pan-SIRT inhibitor, MC2494, increases RIP1 acetylation at two additional sites in the death domain. Mutagenesis of the acetylated lysine decreases RIP1-dependent cell death, suggesting a role for acetylation of the RIP1 complex in cell death modulation. Accordingly, MC2494 displays tumor-selective potential in vitro, in leukemic blasts ex vivo, and in vivo in both xenograft and allograft cancer models. Mechanistically, MC2494 induces bona fide tumor-restricted acetylated RIP1/caspase-8-mediated apoptosis. Excitingly, MC2494 displays tumor-preventive activity by blocking 7,12-dimethylbenz(α)anthracene-induced mammary gland hyperproliferation in vivoConclusions: These preventive features might prove useful in patients who may benefit from a recurrence-preventive approach with low toxicity during follow-up phases and in cases of established cancer predisposition. Thus, targeting the newly identified RIP1 complex may represent an attractive novel paradigm in cancer treatment and prevention

Static stress drop as determined from geodetic strain rates and statistical seismicity

Two critical items in the energetic budget of a seismic province are the strain rate, which is measured geodetically on the Earth’s surface, and the yearly number of earthquakes exceeding a given magnitude. Our study is based on one of the most complete and recent seismic catalogs of Italian earthquakes and on the strain rate map implied by a multi-year velocity solution for permanent GPS stations. For 36 homogeneous seismic zones, we used the appropriate Gutenberg Richter relation based on the seismicity catalog to estimate a seismic strain rate, which is the strain rate associated with the mechanical work due to a co-seismic displacement. The volume storing most of the elastic energy is associated with the long-term deformation of each seismic zone, and therefore, the seismic strain rate is inversely proportional to the static stress drop. The GPS-derived strain rate for each seismic zone limits the corresponding seismic strain rate, and an upper bound for the average stress drop is estimated. These results demonstrated that the implied regional static stress drop ranged from 0.1 to 5.7 MPa for catalog earthquakes in the moment magnitude range [4.5–7.3]. These results for stress drop are independent of the “a” and “b” regional parameters and heat flow but are very sensitive to the assumed maximum magnitude of a seismic province. The data do not rule out the hypothesis that the stress drop positively correlates with the time elapsed after the largest earthquake recorded in each seismic zone

Angiosarcoma of the breast: a new therapeutic approach?

Introduction Angiosarcomas are highly malignant endothelial cell tumors with poor prognosis. These can be due to breast cancer itself or to subsequent therapeutic modalities. No evidence-based guidelines exist concerning the ideal treatment of angiosarcomas. Presentation of the case We report the case of a 76-year-old woman who developed an exuberant and aggressive post radiation angiosarcoma of the breast and discuss different aspects of therapy for this disease. A total left mastectomy was performed, followed by a right mastectomy. The lesions into the chest wall, and multiple abdominal skin nodules were treated with local Electrochemotherapy (ECT) with intravenous bleomicin. Discussion No evidence-based guidelines exist concerning the ideal treatment of angiosarcomas. Electrochemotherapy (ECT) is an efficient palliative treatment of cutaneous and subcutaneous tumor nodules. It consists of the combination of a cytotoxic drug and electroporation, using appropriate electrical parameters; destabilization of the membrane is reversible, ensuring a high survival of permeabilized cells and the delivery of non-permeant molecules inside the cell. Conclusion Due to the rarity of the disease, prospective studies concerning adjuvant or neoadjuvant therapy are limited and no evidence-based guidelines exist. The response to chemotherapy seems to be poor. Treatment with ECT in addition to systemic chemotherapy achieves a complete response in all the lesions and improving patient body image perception

Corrigendum to “Effects of therapeutic hypothermia on the gut microbiota and metabolome of infants suffering hypoxic-ischemic encephalopathy at birth” [Int. J. Biochem. Cell Biol. 93 (December) (2017), 110-118]

peer-reviewedCorrigendum Refers to: Watkins, C., Murphy, K., Yen, S., Carafa, I., Dempsey, E., O’Shea, C., Vercoe, E., Ross, R., Stanton, C. and Ryan, C. (2017). Effects of therapeutic hypothermia on the gut microbiota and metabolome of infants suffering hypoxic-ischemic encephalopathy at birth. The International Journal of Biochemistry & Cell Biology, [online] 93, pp.110-118. Available at: https://doi.org/10.1016/j.biocel.2017.08.01

The new low-toxic histone deacetylase inhibitor S-(2) induces apoptosis in various acute myeloid leukemia cells

Histone deacetylase inhibitors (HDACi) induce tumour cell cycle arrest and/or apoptosis, and some of them are currently used in cancer therapy. Recently, we described a series of powerful HDACi characterized by a 1,4-benzodiazepine (BDZ) ring hybridized with a linear alkyl chain bearing a hydroxamate function as Zn(++)-chelating group. Here, we explored the anti-leukaemic properties of three novel hybrids, namely the chiral compounds (S)-2 and (R)-2, and their non-chiral analogue 4, which were first comparatively tested in promyelocytic NB4 cells. (S)-2 and partially 4– but not (R)-2 – caused G0/G1 cell-cycle arrest by up-regulating cyclin G2 and p21 expression and down-regulating cyclin D2 expression, and also apoptosis as assessed by cell morphology and cytofluorimetric assay, histone H2AX phosphorylation and PARP cleavage. Notably, these events were partly prevented by an anti-oxidant. Moreover, novel HDACi prompted p53 and α-tubulin acetylation and, consistently, inhibited HDAC1 and 6 activity. The rank order of potency was (S)-2 > 4 > (R)-2, reflecting that of other biological assays and addressing (S)-2 as the most effective compound capable of triggering apoptosis in various acute myeloid leukaemia (AML) cell lines and blasts from patients with different AML subtypes. Importantly, (S)-2 was safe in mice (up to 150 mg/kg/week) as determined by liver, spleen, kidney and bone marrow histopathology; and displayed negligible affinity for peripheral/central BDZ-receptors. Overall, the BDZ-hydroxamate (S)-2 showed to be a low-toxic HDACi with powerful anti-proliferative and pro-apototic activities towards different cultured and primary AML cells, and therefore of clinical interest to support conventional anti-leukaemic therapy