Novel epigenetic target therapy for prostate cancer: a preclinical study.

Epigenetic events are critical contributors to the pathogenesis of cancer, and targeting epigenetic mechanisms represents a novel strategy in anticancer therapy. Classic demethylating agents, such as 5-Aza-29-deoxycytidine (Decitabine), hold the potential for reprograming somatic cancer cells demonstrating high therapeutic efficacy in haematological malignancies. On the other hand, epigenetic treatment of solid tumours often gives rise to undesired cytotoxic side effects. Appropriate delivery systems able to enrich Decitabine at the site of action and improve its bioavailability would reduce the incidence of toxicity on healthy tissues. In this work we provide preclinical evidences of a safe, versatile and efficient targeted epigenetic therapy to treat hormone sensitive (LNCap) and hormone refractory (DU145) prostate cancers. A novel Decitabine formulation, based on the use of engineered erythrocyte (Erythro-Magneto-Hemagglutinin Virosomes, EMHVs) drug delivery system (DDS) carrying this drug, has been refined. Inside the EMHVs, the drug was shielded from the environment and phosphorylated in its active form. The novel magnetic EMHV DDS, endowed with fusogenic protein, improved the stability of the carried drug and exhibited a high efficiency in confining its delivery at the site of action in vivo by applying an external static magnetic field. Here we show that Decitabine loaded into EMHVs induces a significant tumour mass reduction in prostate cancer xenograft models at a concentration, which is seven hundred times lower than the therapeutic dose, suggesting an improved pharmacokinetics/pharmacodynamics of drug. These results are relevant for and discussed in light of developing personalised autologous therapies and innovative clinical approach for the treatment of solid tumours

Molecular and functional characterization of human bone marrow adipocytes

n/

SARS-CoV-2 pre-exposure prophylaxis with tixagevimab/cilgavimab (AZD7442) provides protection in inborn errors of immunity with antibody defects: a real-world experience

Background: Preventive strategies against severe COVID-19 in Inborn Errors of Immunity (IEI) include bivalent vaccines, treatment with SARS-CoV-2 monoclonal antibodies (mAbs), early antiviral therapies, and pre-exposure prophylaxis (PrEP). Objective: To assess the effectiveness of the PrEP with tixagevimab/cilgavimab (AZD7442) in IEI with primary antibody defects during the COVID-19 Omicron wave. Methods: A six-month prospective study evaluated the SARS-CoV-2 infection rate and the COVID-19 severity in the AZD7442 group, in the no-AZD7442 group, and in a group of patients with a recent SARS-CoV-2 infection (< three months). Spike-specific IgG levels were measured at regular intervals. Results: Six out of thirty-three patients (18%) and 54/170 patients (32%) became infected in the AZD7442 group and in the no-AZD7442 group, respectively. Within 90 days post-administration, the AZD7442 group was 85% less likely to be infected and 82% less likely to have a symptomatic disease than the no-AZD7442 group. This effect was lost thereafter. In the entire cohort, no mortality/hospitalisation was observed. The control group of 35 recently infected patients was 88% and 92% less likely to be infected than the AZD7442 and no-AZD7442 groups. Serum anti-Spike IgG reached the highest peak seven days post-AZD7442 PrEP then decreased, remaining over 1000 BAU/mL 180 days thereafter. Conclusion: In patients with IEI and antibody defects, AZD7442 prophylaxis had a transient protective effect, possibly lost possibly because of the appearance of new variants. However, PrEP with newer mAbs might still represent a feasible preventive strategy in the future in this population

ClimateFish: A Collaborative Database to Track the Abundance of Selected Coastal Fish Species as Candidate Indicators of Climate Change in the Mediterranean Sea

Under the effects of global warming, many animals and plants are undergoing rapid distribution shifts. These changes can be particularly rapid in marine fishes, and many species have responded markedly to recent increases in sea temperature. ClimateFish is an open-access database, which collates abundance data for 7 Mediterranean indigenous and 8 non-indigenous fishes, proposed as candidate indicators of climate change. These species have been selected by a network of Mediterranean scientists based on their wide distribution, responsiveness to temperature conditions and easy identification. Data are periodically collected according to a standard visual census protocol in four different depth layers. At present, the database collates data on a total number of 101'771 observed individuals belonging to the 15 target species. Counts were realized along 3142 transects carried out in 7 Mediterranean countries between 2009 and 2021. This database, associated with climate data, offers new opportunities to investigate spatiotemporal effects of climate change and to test the effectiveness of each selected indicator. Data are available at https://doi.org/10.17882/86784.The Mediterranean ClimateFish initiative was initially conceived by the international basin wide monitoring program CIESM Tropical Signals (funded by the Albert II of Monaco Foundation) and subsequently supported by the Interreg Med Programme (Projects: MPA-ADAPT, grant number 1MED15_3.2_M2_337 and MPA Engage, grant number 5MED18_3.2_M23_007), 85% co funded by the European Regional Development Fund

Long-term strain oscillations related to the hydrological interaction between aquifers in intra-mountain basins: A case study from Apennines chain (Italy)

We analyze the multiyear strain cycle of a network of continuous GPS stations in the L’Aquila intra-mountain basin in Central Apennines, Italy. The basin is bounded by two aquifers (Nuria-Velino and Gran Sasso) hosted in two tectonically active mountain ranges. All stations show coherent displacements, mostly in the horizontal plane and orthogonal to the normal fault zones of the Apennine mountain range. The displacement repeats back and forth, roughly every 4–5 years with elongation up to 6 mm. The deformation occurs in the region bounded by the two aquifers and the displacement amplitude decreases with distance as predicted by two tensile sources acting in an elastic medium. We interpret this type of deformation as induced by the opening of pre-existing fractures related to two different fault systems as a response to hydrostatic pressure variations. The strain cycle follows the average multiyear rainfall cycle and foresees a dilatation phase during high rainy seasons and a contraction during drier periods. The estimated depth of the equivalent tensile sources ranges from 1.2 to 1.5 km affecting stations at distances up to 20 km away. GPS data show the cumulated movement induced by the two nearby aquifers and suggest a mutual interaction in the elastic space related to the different average annual rainfall and effective infiltration. We fit two tensile sources located along the main faults affecting the aquifers. The eastern source corresponds to the major active fault system affecting the Gran Sasso Range, while the western one includes the sub-parallel active faults of the Mt. Ocre in the Nuria-Velino Range, where carbonate rocks show a higher structural permeability and effective infiltration. These fault systems affect Jurassic-Miocene limestones and dolomites inducing parallel fracturation style of the rock matrix and favoring a strong anisotropy allowing a prevalent lateral expansion as a reaction to pore pressure variations. The recorded hydrological signal may hamper other geophysical signals in GPS time series, thus the measure of tectonic strains requires a careful mapping and modeling of major aquifers.Published1-122T. Deformazione crostale attivaJCR Journa

Synthesis and Characterization of Alginate Gel Beads with Embedded Zeolite Structures as Carriers of Hydrophobic Curcumin

Alginate-based beads containing a porous zeolite filler were developed as carriers of bioactive compounds with a hydrophobic nature, such as curcumin (Cur). Curcumin, a natural pigment extracted from the turmeric (Curcuma longa) plant, exhibits antioxidant, anti-inflammatory, anticarcinogenic, and antiviral properties. To enhance the bioavailability of the drug, curcumin needs to be encapsulated in a suitable carrier that improves its dispersibility and solubility. Commercial A-type zeolites (Z5A) were used as curcumin-binding agents and they were immobilized within the alginate gel beads by cross-linking in calcium chloride solution during an extrusion dripping process. The process parameters (alginate and CaCl2 concentrations, needle gauge, collecting distance) were optimized to fabricate beads with good sphericity factor and 1.5–1.7 mm diameter in their hydrated state. The chemical structure of the gel beads was assessed using FTIR spectroscopy, while their thermal stability was evaluated through differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA). Due to the alginate matrix, the composite Alg/ZA5-Cur beads possess pH-responsive properties. In addition, the gel beads were modified by chitosan (CS) to enhance the stability and control the degradation behavior of the gel matrix. The swelling behavior and the degradation of the beads were analyzed in physiological solutions with different pH values. Results demonstrate the stabilizing and protective effect of the chitosan coating, as well as the reinforcing effect of the zeolite filler. This makes the pH-responsive alginate gel beads good candidates for the delivery of lipophilic drugs to specific inflammatory sites

Novel Epigenetic Target Therapy for Prostate Cancer: A Preclinical Study

Epigenetic events are critical contributors to the pathogenesis of cancer, and targeting epigenetic mechanisms represents a novel strategy in anticancer therapy. Classic demethylating agents, such as 5-Aza-2′-deoxycytidine (Decitabine), hold the potential for reprograming somatic cancer cells demonstrating high therapeutic efficacy in haematological malignancies. On the other hand, epigenetic treatment of solid tumours often gives rise to undesired cytotoxic side effects. Appropriate delivery systems able to enrich Decitabine at the site of action and improve its bioavailability would reduce the incidence of toxicity on healthy tissues. In this work we provide preclinical evidences of a safe, versatile and efficient targeted epigenetic therapy to treat hormone sensitive (LNCap) and hormone refractory (DU145) prostate cancers. A novel Decitabine formulation, based on the use of engineered erythrocyte (Erythro-Magneto-Hemagglutinin Virosomes, EMHVs) drug delivery system (DDS) carrying this drug, has been refined. Inside the EMHVs, the drug was shielded from the environment and phosphorylated in its active form. The novel magnetic EMHV DDS, endowed with fusogenic protein, improved the stability of the carried drug and exhibited a high efficiency in confining its delivery at the site of action in vivo by applying an external static magnetic field. Here we show that Decitabine loaded into EMHVs induces a significant tumour mass reduction in prostate cancer xenograft models at a concentration, which is seven hundred times lower than the therapeutic dose, suggesting an improved pharmacokinetics/pharmacodynamics of drug. These results are relevant for and discussed in light of developing personalised autologous therapies and innovative clinical approach for the treatment of solid tumours

Psychopathology and personality in problematic internet users

Few studies have addressed the issue of psychopathology and personality of individuals with problematic use of internet. In this study we research psychopathological symptoms, personality traits and predictive variables associated with problematic internet use. The study was conducted on a total of 343 students from four Italian Universities using Pathological Internet Use Scale, Big Five Questionnaire, and Symptom Check List 90 Revised. According to this study 52.7% of the sample shows a problematic internet use while only 7.6% don't suffer from any symptom. More than half of subjects admits to have got into arguments with a significant other over being online, and to have missed social engagements because of online activities. Subjects with problematic internet use scored higher in psychopathological scales. Low levels of Friendliness and Emotional Stability could predict the problematic use of internet. Problematic internet use may be associated with higher psychopathology levels and personality traits