Engineering of polymeric materials and structures for innovative application of 3d micro-additive manufacturing via two-photon laser lithography

Two-photon laser lithography it’s an innovative fabrication method which is opening exciting opportunities in many fields of research, biological one as well as in nanotechnology and industry thanks to its high spatial resolution and versatility in terms of shapes achievable. This study wants to show how a synergic use of innovative and optimized materials (as for example hydrogels) and this cut-edge technology can provide inconceivable results in many different applications.openEmbargo temporaneo per motivi di segretezza e/o di proprietà dei risultati e/o informazioni sensibil

Targeting kinases with anilinopyrimidines: Discovery of N-phenyl-N'-[4-(pyrimidin-4-ylamino)phenyl]urea derivatives as selective inhibitors of class III receptor tyrosine kinase subfamily

Kinase inhibitors are attractive drugs/drug candidates for the treatment of cancer. The most recent literature has highlighted the importance of multi target kinase inhibitors, although a correct balance between specificity and non-specificity is required. In this view, the discovery of multityrosine kinase inhibitors with subfamily selectivity is a challenging goal. Herein we present the synthesis and the preliminary kinase profiling of a set of novel 4-anilinopyrimidines. Among the synthesized compounds, the N-phenyl-N\u2019-[4-(pyrimidin-4-ylamino)phenyl]urea derivatives selectively targeted some members of class III receptor tyrosine kinase family. Starting from the structure of hit compound 19 we synthesized a further compound with an improved affinity toward the class III receptor tyrosine kinase members and endowed with a promising antitumor activity both in vitro and in vivo in a murine solid tumor model. Molecular modeling simulations were used in order to rationalize the behavior of the title compounds

Biomaterials and engineered microenvironments to control YAP/TAZ-dependent cell behaviour

Mechanical signals are increasingly recognized as overarching regulators of cell behaviour, controlling stemness, organoid biology, tissue development and regeneration. Moreover, aberrant mechanotransduction is a driver of disease, including cancer, fibrosis and cardiovascular defects. A central question remains how cells compute a host of biomechanical signals into meaningful biological behaviours. Biomaterials and microfabrication technologies are essential to address this issue. Here we review a large body of evidence that connects diverse biomaterial-based systems to the functions of YAP/TAZ, two highly related mechanosensitive transcriptional regulators. YAP/TAZ orchestrate the response to a suite of engineered microenviroments, emerging as a universal control system for cells in two and three dimensions, in static or dynamic fashions, over a range of elastic and viscoelastic stimuli, from solid to fluid states. This approach may guide the rational design of technological and material-based platforms with dramatically improved functionalities and inform the generation of new biomaterials for regenerative medicine applications

Polysaccharide hydrogels for multiscale 3D printing of pullulan scaffolds

Structurally and mechanically similar to the extracellular matrix (ECM), biomimetic hydrogels offer a number of opportunities in medical applications. However, the generation of synthetic microenvironments that simulate the effects of natural tissue niches on cell growth and differentiation requires new methods to control hydrogel feature resolution, biofunctionalization and mechanical properties. Here we show how these goals can be achieved by using a pullulan-based hydrogel, engineered in composition and server as cell-adhesive hydrogel, 3D photo-printable in dimension, ranging from the macro- to the micro-scale dimensions, and of tunable mechanical properties. For this, we used absorbers that limit light penetration, achieving 3D patterning through stereolithography with feature vertical resolution of 200 μm and with overall dimension up to several millimeters. Furthermore, we report the fabrication of 3D pullulan-modified hydrogels by two-photon lithography, with sub-millimetric dimensions and minimum feature sizes down to some microns. These materials open the possibility to produce multiscale printed scaffolds that here we demonstrate to be inert for cell adhesion, but biologically compatible and easily functionalizable with cell adhesive proteins. Under these conditions, successful cell cultures were established in 2D and 3D. Keywords: Hydrogel, Biomaterials, Polysaccharide, Pullulan, 3D printing, Two photon laser lithography, Mesenchymal stromal cell

The choice of μ-vinyliminium ligand substituents is key to optimize the antiproliferative activity of related diiron complexes

Diiron vinyliminium complexes constitute a large family of organometallics displaying a promising anticancer potential. The complexes [Fe2Cp2(CO)(mu-CO){mu-eta(1):eta(3)-C(R-3)C(R-4)CN(R-1)(R-2)}]CF3SO3 (2a-c, 4a-d) were synthesized, assessed for their behavior in aqueous solutions (D2O solubility, Log P-ow, stability in D2O/Me2SO-d(6) mixture at 37 degrees C over 48 h) and investigated for their antiproliferative activity against A2780 and A2780cisR ovarian cancer cell lines and the nontumoral one Balb/3T3 clone A31. Cytotoxicity data collected for 50 vinyliminium complexes were correlated with the structural properties (i.e. the different R-1-R-4 substituents) using the partial least squares methodology. A clear positive correlation emerged between the octanol-water partition coefficient and the relative antiproliferative activity on ovarian cancer cell lines, both of which appear as uncorrelated to the cancer cell selectivity. However, the different effects played by the R-1-R-4 substituents allow tracing guidelines for the development of novel, more effective compounds. Based on these results, three additional complexes (4p-r) were designed, synthesized and biologically investigated, revealing their ability to hamper thioredoxin reductase enzyme and to induce cancer cell production of reactive oxygen species

FXR1P Limits Long-Term Memory, Long-Lasting Synaptic Potentiation, and De Novo GluA2 Translation

SummaryTranslational control of mRNAs allows for rapid and selective changes in synaptic protein expression that are required for long-lasting plasticity and memory formation in the brain. Fragile X Related Protein 1 (FXR1P) is an RNA-binding protein that controls mRNA translation in nonneuronal cells and colocalizes with translational machinery in neurons. However, its neuronal mRNA targets and role in the brain are unknown. Here, we demonstrate that removal of FXR1P from the forebrain of postnatal mice selectively enhances long-term storage of spatial memories, hippocampal late-phase long-term potentiation (L-LTP), and de novo GluA2 synthesis. Furthermore, FXR1P binds specifically to the 5′ UTR of GluA2 mRNA to repress translation and limit the amount of GluA2 that is incorporated at potentiated synapses. This study uncovers a mechanism for regulating long-lasting synaptic plasticity and spatial memory formation and reveals an unexpected divergent role of FXR1P among Fragile X proteins in brain plasticity

Reprogramming normal cells into tumour precursors requires ECM stiffness and oncogene-mediated changes of cell mechanical properties

Defining the interplay between the genetic events and microenvironmental contexts necessary to initiate tumorigenesis in normal cells is a central endeavour in cancer biology. We found that receptor tyrosine kinase (RTK)–Ras oncogenes reprogram normal, freshly explanted primary mouse and human cells into tumour precursors, in a process requiring increased force transmission between oncogene-expressing cells and their surrounding extracellular matrix. Microenvironments approximating the normal softness of healthy tissues, or blunting cellular mechanotransduction, prevent oncogene-mediated cell reprogramming and tumour emergence. However, RTK–Ras oncogenes empower a disproportional cellular response to the mechanical properties of the cell’s environment, such that when cells experience even subtle supra-physiological extracellular-matrix rigidity they are converted into tumour-initiating cells. These regulations rely on YAP/TAZ mechanotransduction, and YAP/TAZ target genes account for a large fraction of the transcriptional responses downstream of oncogenic signalling. This work lays the groundwork for exploiting oncogenic mechanosignalling as a vulnerability at the onset of tumorigenesis, including tumour prevention strategies

Genome-wide meta-analysis associates HLA-DQA1/DRB1 and LPA and lifestyle factors with human longevity

Genomic analysis of longevity offers the potential to illuminate the biology of human aging. Here, using genome-wide association meta-analysis of 606,059 parents' survival, we discover two regions associated with longevity (HLA-DQA1/DRB1 and LPA). We also validate previous suggestions that APOE, CHRNA3/5, CDKN2A/B, SH2B3 and FOXO3A influence longevity. Next we show that giving up smoking, educational attainment, openness to new experience and high-density lipoprotein (HDL) cholesterol levels are most positively genetically correlated with lifespan while susceptibility to coronary artery disease (CAD), cigarettes smoked per day, lung cancer, insulin resistance and body fat are most negatively correlated. We suggest that the effect of education on lifespan is principally mediated through smoking while the effect of obesity appears to act via CAD. Using instrumental variables, we suggest that an increase of one body mass index unit reduces lifespan by 7 months while 1 year of education adds 11 months to expected lifespan.Variability in human longevity is genetically influenced. Using genetic data of parental lifespan, the authors identify associations at HLA-DQA/DRB1 and LPA and find that genetic variants that increase educational attainment have a positive effect on lifespan whereas increasing BMI negatively affects lifespan

Genome-wide meta-analysis associates HLA-DQA1/DRB1 and LPA and lifestyle factors with human longevity

Genomic analysis of longevity offers the potential to illuminate the biology of human aging. Here, using genome-wide association meta-analysis of 606,059 parents' survival, we discover two regions associated with longevity (HLA-DQA1/DRB1 and LPA). We also validate previous suggestions that APOE, CHRNA3/5, CDKN2A/B, SH2B3 and FOXO3A influence longevity. Next we show that giving up smoking, educational attainment, openness to new experience and high-density lipoprotein (HDL) cholesterol levels are most positively genetically correlated with lifespan while susceptibility to coronary artery disease (CAD), cigarettes smoked per day, lung cancer, insulin resistance and body fat are most negatively correlated. We suggest that the effect of education on lifespan is principally mediated through smoking while the effect of obesity appears to act via CAD. Using instrumental variables, we suggest that an increase of one body mass index unit reduces lifespan by 7 months while 1 year of education adds 11 months to expected lifespan

Genome-wide meta-analysis associates HLA-DQA1/DRB1 and LPA and lifestyle factors with human longevity

Genomic analysis of longevity offers the potential to illuminate the biology of human aging. Here, using genome-wide association meta-analysis of 606,059 parents' survival, we discover two regions associated with longevity (HLA-DQA1/DRB1 and LPA). We also validate previous suggestions that APOE, CHRNA3/5, CDKN2A/B, SH2B3 and FOXO3A influence longevity. Next we show that giving up smoking, educational attainment, openness to new experience and high-density lipoprotein (HDL) cholesterol levels are most positively genetically correlated with lifespan while susceptibility to coronary artery disease (CAD), cigarettes smoked per day, lung cancer, insulin resistance and body fat are most negatively correlated. We suggest that the effect of education on lifespan is principally mediated through smoking while the effect of obesity appears to act via CAD. Using instrumental variables, we suggest that an increase of one body mass index unit reduces lifespan by 7 months while 1 year of education adds 11 months to expected lifespan.Variability in human longevity is genetically influenced. Using genetic data of parental lifespan, the authors identify associations at HLA-DQA/DRB1 and LPA and find that genetic variants that increase educational attainment have a positive effect on lifespan whereas increasing BMI negatively affects lifespan