Percutaneous Coronary Intervention (PCI) Reprograms Circulating Extracellular Vesicles from ACS Patients Impairing Their Cardio-Protective Properties

Extracellular vesicles (EVs) are promising therapeutic tools in the treatment of cardiovascular disorders. We have recently shown that EVs from patients with Acute Coronary Syndrome (ACS) undergoing sham pre-conditioning, before percutaneous coronary intervention (PCI) were cardio-protective, while EVs from patients experiencing remote ischemic pre-conditioning (RIPC) failed to induce protection against ischemia/reperfusion Injury (IRI). No data on EVs from ACS patients recovered after PCI are currently available. Therefore, we herein investigated the cardio-protective properties of EVs, collected after PCI from the same patients. EVs recovered from 30 patients randomly assigned (1:1) to RIPC (EV-RIPC) or sham procedures (EV-naive) ({"type":"clinical-trial","attrs":{"text":"NCT02195726","term_id":"NCT02195726"}}NCT02195726) were characterized by TEM, FACS and Western blot analysis and evaluated for their mRNA content. The impact of EVs on hypoxia/reoxygenation damage and IRI, as well as the cardio-protective signaling pathways, were investigated in vitro (HMEC-1 + H9c2 co-culture) and ex vivo (isolated rat heart). Both EV-naive and EV-RIPC failed to drive cardio-protection both in vitro and ex vivo. Consistently, EV treatment failed to activate the canonical cardio-protective pathways. Specifically, PCI reduced the EV-naive Dusp6 mRNA content, found to be crucial for their cardio-protective action, and upregulated some stress- and cell-cycle-related genes in EV-RIPC. We provide the first evidence that in ACS patients, PCI reprograms the EV cargo, impairing EV-naive cardio-protective properties without improving EV-RIPC functional capability.     

Scleroderma-like Impairment in the Network of Telocytes/CD34+ Stromal Cells in the Experimental Mouse Model of Bleomycin-Induced Dermal Fibrosis

Considerable evidence accumulated over the past decade supports that telocytes (TCs)/CD34⁺ stromal cells represent an exclusive type of interstitial cells identifiable by transmission electron microscopy (TEM) or immunohistochemistry in various organs of the human body, including the skin. By means of their characteristic cellular extensions (telopodes), dermal TCs are arranged in networks intermingled with a multitude of neighboring cells and, hence, they are thought to contribute to skin homeostasis through both intercellular contacts and releasing extracellular vesicles. In this context, fibrotic skin lesions from patients with systemic sclerosis (SSc, scleroderma) appear to be characterized by a disruption of the dermal network of TCs, which has been ascribed to either cell degenerative processes or possible transformation into profibrotic myofibroblasts. In the present study, we utilized the well-established mouse model of bleomycin-induced scleroderma to gain further insights into the TC alterations found in cutaneous fibrosis. CD34 immunofluorescence revealed a severe impairment in the dermal network of TCs/CD34⁺ stromal cells in bleomycin-treated mice. CD31/CD34 double immunofluorescence confirmed that CD31⁻/CD34⁺ TC counts were greatly reduced in the skin of bleomycin-treated mice compared with control mice. Ultrastructural signs of TC injury were detected in the skin of bleomycin-treated mice by TEM. The analyses of skin samples from mice treated with bleomycin for different times by either TEM or double immunostaining and immunoblotting for the CD34/α-SMA antigens collectively suggested that, although a few TCs may transition to α-SMA⁺ myofibroblasts in the early disease stage, most of these cells rather undergo degeneration, and then are lost. Taken together, our data demonstrate that TC changes in the skin of bleomycin-treated mice mimic very closely those observed in human SSc skin, which makes this experimental model a suitable tool to (i) unravel the pathological mechanisms underlying TC damage and (ii) clarify the possible contribution of the TC loss to the development/progression of dermal fibrosis. In perspective, these findings may have important implications in the field of skin regenerative medicine.     

Optimized CVD production of CNT-based nanohybrids by Taguchi robust design

Taguchi's robust design method is for the first time employed to optimize many aspects of the production of nanohybrids based on C nanotubes by iron-catalyzed chemical vapor deposition in i-C4H10 + H2 atmosphere. By analyzing the outcomes of the catalytic process in terms of selectivity, carbon yield, purity and crystalline arrangement of the hybrid-forming nanotubes, the influence is ranked of the following parameters: synthesis temperature (500-700 degrees C), support material (alumina, magnesia or sodium-exchanged montmorillonite), calcination- (450-750 degrees C) and reduction-(500-700 degrees C) temperatures of the 15 wt% Fe-catalyst. In the experiments initially performed for this purpose, the growth process had, on average, scarce selectivity (2 in a scale 1-5) and poor yield (130 wt%); carbonaceous deposits exhibited unsatisfactory graphitization degree (Raman D/G intensity ratio > 1.5) and contained large amounts of metal impurities (14 wt%) and amorphous carbon (5 wt%). The indications emerging from Taguchi approach to the process optimization are critically examined. The experimental conditions chosen for carrying out test experiments allow achieving excellent selectivity (5) or large yield (760 wt%), hybrids with well-graphitized nanotubes (D/G intensity ratio < 0.6), nearly free of metallic (0.3 wt%) or amorphous (0.4 wt%) inclusions, with consequent possibility of satisfying the different requisites that the specific application to be addressed may require.     

Acoustic emission technique for online monitoring during cold forging of steel components: a promising approach for online crack detection in metal forming processes

The acoustic emission technique is a very promising non-destructive and online capable approach for the detection of damage events in metal forming processes. The feasibility of using this testing method for online monitoring of cold forging processes of the case hardening steel 1.7321 (20MoCr4) was experimentally proven. In this paper, exemplary upsetting tests under varying test conditions were continuously monitored to analyze the relationship between cracking and resulting AE as well as to determine ideal AE measuring parameters. Finally, the critical forming stage of an industrial cold forging process for manufacturing of drive bevel gears is examined by applying acoustic emission technique. Cracking and tool wear were detected by analyzing the distribution of the AE parameters energy, hits and amplitude over the forming process.     

Modulatory Effects of Polyphenols on Apoptosis Induction: Relevance for Cancer Prevention

Polyphenols, occurring in fruit and vegetables, wine, tea, extra virgin olive oil, chocolate and other cocoa products, have been demonstrated to have clear antioxidant properties in vitro, and many of their biological actions have been attributed to their intrinsic reducing capabilities. However, it has become clear that, in complex biological systems, polyphenols exhibit several additional properties which are yet poorly understood. Apoptosis is a genetically controlled and evolutionarily conserved form of cell death of critical importance for the normal embryonic development and for the maintenance of tissue homeostasis in the adult organism. The malfunction of the death machinery may play a primary role in various pathological processes, since too little or too much apoptosis can lead to proliferative or degenerative diseases, respectively. Cancer cells are characterized by a deregulated proliferation, and/or an inability to undergo programmed cell death. A large body of evidence indicates that polyphenols can exert chemopreventive effects towards different organ specific cancers, affecting the overall process of carcinogenesis by several mechanisms: inhibition of DNA synthesis, modulation of ROS production, regulation of cell cycle arrest, modulation of survival/proliferation pathways. In addition, polyphenols can directly influence different points of the apoptotic process, and/or the expression of regulatory proteins. Although the bulk of data has been obtained in in vitro systems, a number of clinical studies suggesting a preventive and therapeutic effectiveness of polyphenols in vivo is available. However, a deeper knowledge of the underlying mechanisms responsible for the modulation of apoptosis by polyphenols, and their real effectiveness, is necessary in order to propose them as potential chemopreventive and chemotherapeutic candidates for cancer treatment.     

Synthesis and analysis of multi-walled carbon nanotubes/oxides hybrid materials for polymer composite applications

Nanotubes-based nanocomposites to be used as polymer reinforcing/flame-retardant additives are synthesized by decomposition of isobutane at 600 °C. Catalytic chemical vapor deposition (CCVD) is carried out over 17 wt%Fe-catalysts supported on various oxides (Al₂O₃, MgO, CaO, SrO or BaO) reduced at 600 °C. Catalysts utilized and carbonaceous deposits obtained are systematically characterized by the use of several analysis techniques, in order to investigate the influence of catalyst specifics on reaction yield, selectivity and characteristics (crystallinity and purity) of the grown nanotubes. The results show that the support greatly influences the catalyst performance. The lack of metallic iron renders Fe/SrO- and Fe/BaO-catalysts inactive. Fe/Al₂O₃ catalysts exhibit the highest catalytic activity, but give rise to scarce selectivity and large metallic impurity contents. Contrarily, using Fe/MgO and Fe/CaO catalysts leads to lower yields, but allows reducing impurities and remarkably improving selectivity and nanotube crystallinity.     

Mechanisms of Sensitivity and Resistance of Primary Effusion Lymphoma to Dimethyl Fumarate (DMF)

PEL is a rare B cell lymphoma associated with KSHV that mainly arises in immune-deficient individuals. The search for new drugs to treat this cancer is still ongoing given its aggressiveness and the poor response to chemotherapies. In this study, we found that DMF, a drug known for its anti-inflammatory properties which is registered for the treatment of psoriasis and relapsing–remitting MS, could be a promising therapeutic strategy against PEL. Indeed, although some mechanisms of resistance were induced, DMF activated NRF2, reduced ROS and inhibited the phosphorylation of STAT3 and the release of the pro-inflammatory and immune suppressive cytokines IL-6 and IL-10, which are known to sustain PEL survival. Interestingly, we observed that DMF displayed a stronger cytotoxic effect against fresh PEL cells in comparison to PEL cell lines, due to the activation of ERK1/2 and autophagy in the latter cells. This finding further encourages the possibility of using DMF for the treatment of PEL.     

Large-scale production of high-quality multi-walled carbon nanotubes: Role of precursor gas and of Fe-catalyst support

The crucial role of precursor gas (PG) and of catalyst support (CS) in the growth of multi-walled C nanotubes (MWCNTs) by iron-catalysed chemical vapour deposition (CVD) is evidenced. This is accomplished by comparing structural and morphological properties of MWCNTs synthesised by the use of different PGs (ethane and isobutane) and CSs (silica and alumina). The results of analyses, carried out on catalysts and C deposits by scanning electron microscopy (SEM), high-resolution transmission electron microscopy (HRTEM), Raman spectroscopy (RS), thermo-gravimetry (TG) and X-ray diffraction (XRD), demonstrate that Al₂O₃-supported catalysts are more efficient than SiO₂-supported ones in decomposing hydrocarbons. The use of i-C₄H₁₀ as PG allows reducing Fe-encapsulation and improving yield (Y_C) and selectivity, so as the large-scale production (Y_C > 900 wt.%) of high-quality nanotubes can be operated even at moderate reaction temperature (600 °C) after proper calibration of Fe-load (29 wt.%) and catalyst reduction temperature (500 °C).     

Edge-defined metric buckling of temperature-responsive hydrogel ribbons and rings

We report the temperature-responsive buckling of ribbon-like hydrogel thin films based on photo-crosslinkable copolymers of poly(N-isopropyl acrylamide) (PNIPAM) with pendent benzophenone units. Due to the finite resolution of the photo-lithographic patterning method—here dominated by the convergence of light from the illumination source—nominally homogeneous layers are always surrounded by a more highly swelling border with a lateral size scale similar to the film thickness. As one of the in-plane dimensions of the gel sheet is reduced to only several times its thickness, this edge effect serves as a sufficiently large imperfection to drive buckling of the otherwise metrically flat ribbon. Due to the symmetric geometry, the resulting geometry has essentially constant curvature of the mid-line of the ribbon, with a radius of curvature defined by its thickness and width. In this manner, we prepare thermally responsive overcurved rings that buckle into more highly coiled configurations as they swell, due to the mismatch in metric curvature relative to the geometric shape of the object. We consider the conditions for unfrustrated coiling of both circular and polygonal rings in terms of the number of self-crossings made upon wrapping the surface of a sphere, and demonstrate the fabrication of ‘self-cinching unknots’, i.e. coiled ribbons that can fasten themselves onto other objects upon deswelling, due to topological constraints.     

Internal multiple-scattering hole-enhanced Raman spectroscopy: improved backscattering Fourier transform Raman sampling in pharmaceutical tablets utilizing cylindrical-conical holes

The benefits of Raman signal enhancement and improved measurement precision are demonstrated using 180° backscattering Fourier transform Raman (FT-Raman) spectroscopy from drilled cylindrical-conical holes within pharmaceutical tablet cores. Multiple scattering of the incident laser light within the holes results in an increased Raman signal due to the larger Raman sampling volume. This is important for overcoming typical sub-sampling issues encountered when employing FT-Raman backscattering of heterogeneous pharmaceutical tablets. Hole depth and diameter were found to be important experimental parameters and were optimized to yield the greatest signal enhancement. The FT-Raman spectra collected using backscattering from cylindrical-conical holes is compared to typical 180° backscattering from flat surfaces using tablet cores of Excedrin? and Vivarin?. Raman chemical images are used to establish a representative sampling area. We observe a three- to five-fold increase in the Raman intensity and a two-fold improvement in the measurement precision when sampling from cylindrical-conical holes rather than classic backscattering from flat tablet cores. Self-absorption effects on analyte band ratios are negligible in the fingerprint region but are more significant at the higher near-infrared (NIR) absorbances found in the C-H/O-H/-N-H stretching region. The sampling technique will facilitate developing quantitative FT-Raman methods for application to pharmaceutical tablets using the fingerprint spectral region.