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Pyrolysis is a fundamental step in thermochemical processes of biomass materials, so a suitable kinetic model is an essential tool to predict the evolution of the resulting products of reaction. However, many difficulties arise in modeling this process step due to the very high number of the involved reactions. In this work, a new double-Gaussian distributed activation energy model was applied in fitting the experimental data of olive residue pyrolysis obtained by thermogravimetric analysis. 2-DAEM formulation considers two sets of parallel reactions occurring and sharing the same pre-exponential factor, but shows different distributions of the activation energy, described by two separate Gaussian distributions that, in turn, grasp the two pyrolysis steps with a high accuracy. Since it is well known that in fitting all the kinetic parameters the pre-exponential factor results highly correlated with the activation energy, the former parameter was separately estimated as a linear combination of the values obtained for the three main biomass components, cellulose, hemicellulose and lignin. [ABSTRACT FROM AUTHOR]

Children with Down syndrome (DS) have increased susceptibility to infections and a high frequency of leukemia and autoimmune disorders, suggesting that immunodeficiency and immune dysfunction are integral parts of the syndrome. A reduction in B-cell numbers has been reported, associated with moderate immunodeficiency and normal immunoglobulin levels. Here, we compared B-cell populations of 19 children with DS with those in healthy age-matched controls. We found that all steps of peripheral B-cell development are altered in DS, with a more severe defect during the later stages of B-cell development. Transitional and mature-naïve B-cell numbers are reduced by 50% whereas switched memory B cells represent 10-15% of the numbers in age-matched controls. Serum IgM levels were slightly reduced, but all other immunoglobulin isotypes were in the normal range. The frequency of switched memory B cells specific for vaccine antigens was significantly lower in affected children than in their equivalently vaccinated siblings. In vitro switched memory B cells of patients with DS have an increased ability to differentiate into antibody-forming cells in response to TLR9 signals. Tailored vaccination schedules increasing the number of switched memory B cells may improve protection and reduce the risk of death from infection in DS. [ABSTRACT FROM AUTHOR]

Background: Cathepsins represent a group of proteases involved in determining the metastatic potential of cancer cells. Among these are cysteinyl- (e.g. cathepsin B and cathepsin L) and aspartyl-proteases (e.g. cathepsin D), normally present inside the lysosomes as inactive proenzymes. Once released in the extracellular space, cathepsins contribute to metastatic potential by facilitating cell migration and invasiveness. Results: In the present work we first evaluated, by in vitro procedures, the role of cathepsins B, L and D, in the remodeling, spreading and invasiveness of eight different cell lines: four primary and four metastatic melanoma cell lines. Among these, we considered two cell lines derived from a primary cutaneous melanoma and from a supraclavicular lymph node metastasis of the same patient. To this purpose, the effects of specific chemical inhibitors of these proteases, i.e. CA-074 and CA-074Me for cathepsin B, Cathepsin inhibitor II for cathepsin L, and Pepstatin A for cathepsin D, were evaluated. In addition, we also analyzed the effects of the biological inhibitors of these cathepsins, i.e. specific antibodies, on cell invasiveness. We found that i) cathepsin B, but not cathepsins L and D, was highly expressed at the surface of metastatic but not of primary melanoma cell lines and that ii) CA- 074, or specific antibodies to cathepsin B, hindered metastatic cell spreading and dissemination, whereas neither chemical nor biological inhibitors of cathepsins D and L had significant effects. Accordingly, in vivo studies, i.e. in murine xenografts, demonstrated that CA-074 significantly reduced human melanoma growth and the number of artificial lung metastases. Conclusions: These results suggest a reappraisal of the use of cathepsin B inhibitors (either chemical or biological) as innovative strategy in the management of metastatic melanoma disease. [ABSTRACT FROM AUTHOR]

Background: Nitric oxide-releasing nonsteroidal antiinflammatory drugs (NO-NSAIDs) are reported to be safer than NSAIDs because of their lower gastric toxicity. We compared the effect of a novel NO-releasing derivate, NCX 4040, with that of aspirin and its denitrated analog, NCX 4042, in in vitro and in vivo human colon cancer models and investigated the mechanisms of action underlying its antitumor activity. Methods: In vitro cytotoxicity was evaluated on a panel of colon cancer lines (LoVo, LoVo Dx, WiDr and LRWZ) by sulforhodamine B assay. Cell cycle perturbations and apoptosis were evaluated by flow cytometry. Protein expression was detected by Western blot. In the in vivo experiments, tumor-bearing mice were treated with NCX 4040, five times a week, for six consecutive weeks. Results: In the in vitro studies, aspirin and NCX 4042 did not induce an effect on any of the cell lines, whereas NCX 4040 produced a marked cytostatic dose-related effect, indicating a pivotal role of the -NO2 group. Furthermore, in LoVo and LRWZ cell lines, we observed caspase-9 and - 3-mediated apoptosis, whereas no apoptotic effect was observed after drug exposure in WiDr or LoVo Dx cell lines. In in vivo studies, both NCX 4040 and its parental compound were administered per os. NCX 4040 induced a 40% reduction in tumor weight. Conversely, aspirin did not influence tumor growth at all. Conclusions: NCX 4040, but not its parental compound, aspirin, showed an in vitro and in vivo antiproliferative activity, indicating its potential usefulness to treat colon cancer. [ABSTRACT FROM AUTHOR]

Chimeric antigen receptor (CAR) T-cell therapy has been shown to be dramatically effective in the treatment of B-cell malignancies. However, there are still substantial obstacles to overcome, before similar responses can be achieved in patients with solid tumors. We evaluated both in vitro and in a preclinical murine model the efficacy of different 2nd and 3rd generation CAR constructs targeting GD2, a disial-ganglioside expressed on the surface of neuroblastoma (NB) tumor cells. In order to address potential safety concerns regarding clinical application, an inducible safety switch, namely inducible Caspase-9 (iC9), was also included in the vector constructs. Our data indicate that a 3rd generation CAR incorporating CD28.4-1BB costimulatory domains is associated with improved anti-tumor efficacy as compared with a CAR incorporating the combination of CD28.OX40 domains. We demonstrate that the choice of 4-1BB signaling results into significant amelioration of several CAR T-cell characteristics, including: 1) T-cell exhaustion, 2) basal T-cell activation, 3) in vivo tumor control and 4) T-cell persistence. The fine-tuning of T-cell culture conditions obtained using IL7 and IL15 was found to be synergic with the CAR.GD2 design in increasing the anti-tumor activity of CAR T cells. We also demonstrate that activation of the suicide gene iC9, included in our construct without significantly impairing neither CAR expression nor anti-tumor activity, leads to a prompt induction of apoptosis of GD2.CAR T cells. Altogether, these findings are instrumental in optimizing the function of CAR T-cell products to be employed in the treatment of children with NB. [ABSTRACT FROM AUTHOR]

• Fenton process allowed to achieve a TOC removal of the sludge larger than 50 %. • A mass-transfer kinetic model was developed and tested for the data interpretation. • The scale-up of the process was applied considering a flow-sensitive flow. • A simplified process flow diagram of the process was proposed and discussed. The aim of this work was to propose a mass-transfer model and scale-up procedure of the Fenton process of organic pollutants present in sludge produced in a municipal wastewater treatment plant. The sludge was collected at the end of anaerobic stabilization, sedimentation and filter press thickening and was firstly characterized by measuring the Total Organic Carbon on the whole sludge and on the liquid phase, the Chemical Oxygen Demand on the liquid phase, the viscosity, the pH, the Cu and Fe concentration and the water content. The optimal water content for the subsequent Fenton process was assessed basing on preliminary pumpability tests, and on Fenton process performances. The analysis of Fenton process was performed by evaluating, at 24 h, the optimal Fe(II) and hydrogen peroxide concentration with respect to the initial total organic content of whole sludge and of sludge liquid phase, as well as to the chemical oxygen demand of sludge liquid phase: the optimal parameters were H 2 O 2 /total organic carbon = 1.6 g/g, added Fe(II)/H 2 O 2 = 0.1 g/g, water content = 75 %, through which a chemical oxygen demand and total organic carbon removal efficiency of 72 and 52 %, respectively, was achieved. Kinetic tests were carried out in a batch stirred tank reactor and the results were interpreted in light of a comprehensive mass transfer model to obtain suitable kinetic parameters necessary for reactor design and scale-up. Finally, a simplified process flow diagram was also proposed. Basing on the obtained results, a first real scale-up of the lab-scale reactors could be performed adopting optimal operating parameter values found in the present study, using axial-flow impeller and maintaining constant the Re number. [ABSTRACT FROM AUTHOR]

Osteosarcoma is the most common primary bone cancer and the most frequent cause of bone cancer‐related deaths in children and adolescents. Osteosarcoma cells are able to establish a crosstalk with resident bone cells leading to the formation of a deleterious vicious cycle. We hypothesized that osteosarcoma cells can release, in the bone microenvironment, transforming Extracellular Vesicles (EVs) involved in regulating bone cell proliferation and differentiation, thereby promoting tumor growth. We assessed EV production by three osteosarcoma cell lines with increasing aggressiveness in order to investigate their roles in the communication between osteosarcoma cells and normal recipient cells. Osteosarcoma‐derived EVs were used to treat the murine fibroblast cell line NIH3T3 and to study the induction of tumor‐like phenotypes. Our results showed that osteosarcoma cell lines are able to produce EVs that fuse to recipient cells, with a very high uptake efficiency. The treatment of recipient NIH3T3 with osteosarcoma‐derived EVs induced substantial biological and functional effects, as an enhanced proliferation and survival capability under starved conditions, high levels of activated survival pathways, an increased migration, adhesion, and 3D sphere formation and the acquired capability to grow in an anchorage‐independent manner. Moreover, in murine NIH3T3 we found human mRNAs of TNF‐α, IL‐6, and TGF‐β, as well as a de novo expression of murine MMP‐9 and TNF‐α following the treatment of human osteosarcoma‐derived EVs. [ABSTRACT FROM AUTHOR]

The full development of the mammalian immune system occurs after birth upon exposure to non self-antigens. The gut is the first site of bacterial colonization where it is crucial to create the appropriate microenvironment able to balance effector or tolerogenic responses to external stimuli. It is a well-established fact that at mucosal sites bacteria play a key role in developing the immune system but we ignore how colonising bacteria impact the maturation of the spleen. Here we addressed this issue. Taking advantage of the fact that milk SIgA regulates bacterial colonization of the newborn intestine, we generated immunocompetent mice born either from IgA pro-efficient or IgA deficient females. Having demonstrated that SIgA in maternal milk modulates neonatal gut microbiota by promoting an increased diversity of the colonizing species we also found that immunocompetent pups, not exposed to milk SIgA, fail to properly develop the FDC network and primary follicles in the spleen compromising the response to T-dependent antigens. The presence of a less diverse microbiota with a higher representation of pathogenic species leads to a fast replenishment of the marginal zone and the IgM plasma cell compartment of the spleen as well as IgA plasma cells in the gut. [ABSTRACT FROM AUTHOR]

The usage of disposable face mask to control the spread of COVID-19 disease has led to the alarming generation of a huge amount of plastic waste in a short span of time. On other hand, face masks are made of high-quality thermoplastic polymers that could be recovered and converted into valuable products. The aim of this study is to investigate a complementary approach for the recycling of face mask in lab-scale plants: the mechanical recycling of the filter in polypropylene (PP) and the chemical recycling of the whole face mask. For this purpose, a new designed surgical face mask was chemically and physically characterized. The results shows that the face mask was composed of 92.3 wt% high grade PP (filter), very similar to virgin PP but with a high melt volume index (MVI, 385 cm3/10 min) due to its non-woven manufacturing. The PP from face mask was mixed with recycled virgin PP in order to obtain a MVI suitable for the extrusion process and recycled as filament for 3D printing. This filament was used to print a specimen with a very similar visual quality of that printed with a commercial PP filament. Simultaneously, the whole face mask underwent a pyrolysis process to produce new feedstocks or fuels. Low-cost catalysts derived from coal fly ash (CFA) were employed to enhance the production of light hydrocarbons. In particular, the synthetized acid X zeolite (HX/CFA) improved the yield of light fractions up to 91 wt% (79 wt% for thermal pyrolysis) and the quality of the light oil with the 85% of C 6 –C 10 (55% for thermal pyrolysis). Furthermore, HX/CFA decreased the degradation temperature of PP to 384 °C versus 458 °C of thermal cracking. [Display omitted] • A complementary approach was adopted for the recycling of waste face masks. • Filament for 3D printing was extruded from a mixture of face mask and recycled PP. • Specimens 3D printed with recycled and commercial filaments have similar quality. • Thermal and catalytic pyrolysis of whole face mask yielded 60–70 wt% of light oil. • HX/CFA lowered the pyrolysis temperature and increased C 6 –C 10 in the light oil. [ABSTRACT FROM AUTHOR]

Background: Poor infiltration of functioning T cells renders tumors unresponsive to checkpoint-blocking immunotherapies. Here, we identified a combinatorial in situ immunomodulation strategy based on the administration of selected immunogenic drugs and immunotherapy to sensitize poorly T-cell-infiltrated neuroblastoma (NB) to the host antitumor immune response. Methods: 975A2 and 9464D NB cell lines derived from spontaneous tumors of TH-MYCN transgenic mice were employed to study drug combinations able of enhancing the antitumor immune response using in vivo and ex vivo approaches. Migration of immune cells towards drug-treated murine-derived organotypic tumor spheroids (MDOTS) were assessed by microfluidic devices. Activation status of immune cells co-cultured with drug-treated MDOTS was evaluated by flow cytometry analysis. The effect of drug treatment on the immune content of subcutaneous or orthotopic tumors was comprehensively analyzed by flow-cytometry, immunohistochemistry and multiplex immunofluorescence. The chemokine array assay was used to detect soluble factors released into the tumor microenvironment. Patient-derived organotypic tumor spheroids (PDOTS) were generated from human NB specimens. Migration and activation status of autologous immune cells to drug-treated PDOTS were performed. Results: We found that treatment with low-doses of mitoxantrone (MTX) recalled immune cells and promoted CD8+ T and NK cell activation in MDOTS when combined with TGFβ and PD-1 blockade. This combined immunotherapy strategy curbed NB growth resulting in the enrichment of a variety of both lymphoid and myeloid immune cells, especially intratumoral dendritic cells (DC) and IFNγ- and granzyme B-expressing CD8+ T cells and NK cells. A concomitant production of inflammatory chemokines involved in remodelling the tumor immune landscape was also detected. Interestingly, this treatment induced immune cell recruitment against PDOTS and activation of CD8+ T cells and NK cells. Conclusions: Combined treatment with low-dose of MTX and anti-TGFβ treatment with PD-1 blockade improves antitumor immunity by remodelling the tumor immune landscape and overcoming the immunosuppressive microenvironment of aggressive NB. [ABSTRACT FROM AUTHOR]

Abstract: Disruption of poly(ADP-ribose) polymerase (PARP) pathways by inhibitors of PARP catalytic domain has been shown to increase the anti-tumour activity of temozolomide (TMZ). Since PARP is inhibited by poly(ADP)ribosylation, herein we tested whether inhibition of poly(ADP-ribose) glycohydrolase (PARG) might enhance TMZ efficacy. The PARG inhibitor N-bis-(3-phenyl-propyl)9-oxo-fluorene-2,7-diamide (GPI 16552) was administered in combination with TMZ to mice injected subcutaneously or intracranially with B16 melanoma cells. The ability of treatment to reduce melanoma metastatic spreading and invasion of the extracellular matrix was also tested. The results indicated that combined treatment with GPI 16552 and TMZ significantly reduced melanoma growth, increased life-span of mice bearing tumour at the CNS site, and decreased the ability of melanoma cells to form lung metastases and to invade the extracellular matrix. In conclusion, PARG inhibition represents an alternative strategy to enhance TMZ efficacy against melanoma in peripheral as well as at CNS site. [Copyright &y& Elsevier]

The aim of this study was to assess whether lonidamine (LND) interferes with some steps in angiogenesis progression. We report here, for the first time, that LND inhibited angiogenic-related endothelial cell functions in a dose-dependent manner (1-50 µg/ml). In particular, LND decreased proliferation, migration, invasion, and morphogenesis on matrigel of different endothelial cell lines. Zymographic and Western blot analysis assays showed that LND treatment produced a reduction in the secretion of matrix metalloproteinase-2 and metalloproteinase-9 by endothelial cells. Vessel formation in a matrigel plug was also reduced by LND. The viability, migration, invasion, and matrix metalloproteinase production of different tumor cell lines were not affected by low doses of LND (1-10 µg/ml), whereas 50 µg/ml LND, which corresponds to the dose used in clinical management of tumors, triggered apoptosis both in endothelial and tumor cells. Together, these data demonstrate that LND is a compound that interferes with endothelial cell functions, both at low and high doses. Thus, the effect of LND on endothelial cell functions, previously undescribed, may be a significant contributor to the antitumor effect of LND observed for clinical management of solid tumors. [ABSTRACT FROM AUTHOR]

We have recently reported that bcl-2 overexpression and hypoxia synergistically interact to modulate vascular endothelial growth factor (VEGF) and in vivo angiogenesis in tumour cells through VEGF mRNA stabilization and hypoxia-inducible factor 1-mediated transcriptional activity. Bcl-2 antisense treatment has shown promising clinical results in patients with malignant melanoma. In the present study, we demonstrated that the bcl-2/bcl-xL bispecific antisense oligonucleotide 4625 inhibits bcl-2 expression and angiogenesis in two bcl-2 overexpressing clones derived from the M14 human melanoma cell line. The antiangiogenic effect was determined in in vitro and in vivo angiogenesis assays. In particular, a reduction of hypoxia-induced VEGF secretion was observed after 4625 treatment, and the conditioned medium (CM) of bcl-2 overexpressing clones treated with 4625 and exposed to hypoxic conditions resulted in decreased endothelial cell proliferation when compared to CM of untreated control cells. In addition, we found that CM of 4625 antisense-treated bcl-2 transfectants inhibited in vivo vessel formation in matrigel plugs implanted subcutaneously in C57/B16 mice. Our findings confirm that bcl-2 plays a crucial role in melanoma angiogenesis and demonstrate for the first time that downregulation of bcl-2 by antisense treatment has potential to inhibit angiogenesis independent of its effect on cell survival. The use of 4625 in cancer therapy is suggested as an approach to facilitate simultaneously tumour cell apoptosis and inhibit tumour angiogenesis.Oncogene (2003) 22, 8441-8447. doi:10.1038/sj.onc.1206999 [ABSTRACT FROM AUTHOR]

An amendment to this paper has been published and can be accessed via the original article. [ABSTRACT FROM AUTHOR]

Catalytic hydrotreating of guaiacol as a model compound was investigated using bifunctional catalysts constituted of Ni supported on chemically modified zeolites with increased mesoporosity. In the reaction conditions, the hydrogen required for the process was generated in situ by the Zn–H 2 O redox system, which represents a promising green alternative to the use of gaseous hydrogen. The guaiacol hydrotreating conversion using as support zeolites with increased mesoporosity, is largely higher than that obtained with the original ones. The introduction of mesopores through desilication treatment with NaOH and TBAOH significantly increased the mass transfer of guaiacol and improved the accessibility of the active sites, accordingly enhancing the catalytic performance. The alkaline treatment notably increased the mesopore volume of Ni/HZSM-5 and Ni/HBeta by 5.6 and 3.8 times, respectively. Ni supported on desilicated HBeta zeolite displayed high hydrodeoxygenation and hydrodearomatization efficiencies with values of 69.37% and 62.82%, respectively. The reusability of this catalyst was investigated, showing a decrease in the performance after three consecutive runs due to the oxidation of Ni active site, coking and zinc oxide contamination. The main of guaiacol conversion products are cyclohexane, cyclohexanone, cyclohexanol, benzene and phenol. A reaction pathway of guaiacol hydrotreating using Ni-zeolites catalysts is proposed. [Display omitted] [ABSTRACT FROM AUTHOR]

Background: Hepatocellular carcinoma (HCC) is one of the most common and lethal malignant tumours worldwide. Sorafenib (SOR) is one of the most effective single-drug systemic therapy against advanced HCC, but the identification of novel combination regimens for a continued improvement in overall survival is a big challenge. Recent studies highlighted the crucial role of focal adhesion kinase (FAK) in HCC growth. The aim of this study was to investigate the antitumor effects of three different FAK inhibitors (FAKi), alone or in combination with SOR, using in vitro and in vivo models of HCC. Methods: The effect of PND1186, PF431396, TAE226 on cell viability was compared to SOR. Among them TAE226, emerging as the most effective FAKi, was tested alone or in combination with SOR using 2D/3D human HCC cell line cultures and HCC xenograft murine models. The mechanisms of action were assessed by gene/protein expression and imaging approaches, combined with high-throughput methods. Results: TAE226 was the more effective FAKi to be combined with SOR against HCC. Combined TAE226 and SOR treatment reduced HCC growth both in vitro and in vivo by affecting tumour-promoting gene expression and inducing epigenetic changes via dysregulation of FAK nuclear interactome. We characterized a novel nuclear functional interaction between FAK and the NuRD complex. TAE226-mediated FAK depletion and SOR-promoted MAPK down-modulation caused a decrease in the nuclear amount of HDAC1/2 and a consequent increase of the histone H3 lysine 27 acetylation, thus counteracting histone H3 lysine 27 trimethylation. Conclusions: Altogether, our findings provide the first evidence that TAE226 combined with SOR efficiently reduces HCC growth in vitro and in vivo. Also, our data highlight that deep analysis of FAK nuclear interactome may lead to the identification of new promising targets for HCC therapy. [ABSTRACT FROM AUTHOR]