Search

Abstract Background p130 Crk-associated substrate (p130CAS; also known as BCAR1) is a scaffold protein that modulates many essential cellular processes such as cell adhesion, proliferation, survival, cell migration, and intracellular signaling. p130Cas has been shown to be highly expressed in a variety of human cancers of epithelial origin. However, few data are available regarding the role of p130Cas during normal epithelial development and homeostasis. Methods To this end, we have generated a genetically modified mouse in which p130Cas protein was specifically ablated in the epidermal tissue. Results By using this murine model, we show that p130Cas loss results in increased cell proliferation and reduction of cell adhesion to extracellular matrix. In addition, epidermal deletion of p130Cas protein leads to premature expression of “late” epidermal differentiation markers, altered membrane E-cadherin/catenin proteins localization and aberrant tyrosine phosphorylation of E-cadherin/catenin complexes. Interestingly, these alterations in adhesive properties in absence of p130Cas correlate with abnormalities in progenitor cells balance resulting in the amplification of a more committed cell population. Conclusion Altogether, these results provide evidence that p130Cas is an important regulator of epidermal cell fate and homeostasis.

Background: The main drawback of BRAF/MEK inhibitors (BRAF/MEKi)-based targeted therapy in the management of BRAF-mutated cutaneous metastatic melanoma (MM) is the development of therapeutic resistance. We aimed to assess in this context the role of mTORC2, a signaling complex defined by the presence of the essential RICTOR subunit, regarded as an oncogenic driver in several tumor types, including MM. Methods: After analyzing The Cancer Genome Atlas MM patients' database to explore both overall survival and molecular signatures as a function of intra-tumor RICTOR levels, we investigated the effects of RICTOR downregulation in BRAFV600E MM cell lines on their response to BRAF/MEKi. We performed proteomic screening to identify proteins modulated by changes in RICTOR expression, and Seahorse analysis to evaluate the effects of RICTOR depletion on mitochondrial respiration. The combination of BRAFi with drugs targeting proteins and processes emerged in the proteomic screening was carried out on RICTOR-deficient cells in vitro and in a xenograft setting in vivo. Results: Low RICTOR levels in BRAF-mutated MM correlate with a worse clinical outcome. Gene Set Enrichment Analysis of low-RICTOR tumors display gene signatures suggestive of activation of the mitochondrial Electron Transport Chain (ETC) energy production. RICTOR-deficient BRAFV600E cells are intrinsically tolerant to BRAF/MEKi and anticipate the onset of resistance to BRAFi upon prolonged drug exposure. Moreover, in drug-naïve cells we observed a decline in RICTOR expression shortly after BRAFi exposure. In RICTOR-depleted cells, both mitochondrial respiration and expression of nicotinamide phosphoribosyltransferase (NAMPT) are enhanced, and their pharmacological inhibition restores sensitivity to BRAFi. Conclusions: Our work unveils an unforeseen tumor-suppressing role for mTORC2 in the early adaptation phase of BRAFV600E melanoma cells to targeted therapy and identifies the NAMPT-ETC axis as a potential therapeutic vulnerability of low RICTOR tumors. Importantly, our findings indicate that the evaluation of intra-tumor RICTOR levels has a prognostic value in metastatic melanoma and may help to guide therapeutic strategies in a personalized manner. [ABSTRACT FROM AUTHOR]

Different attentional foci may modify muscle activation during exercises. Our aim was to determine if it is possible to selectively activate the pectoralis major or triceps brachii muscles according to specific verbal instructions provided during the bench press exercise. 13 resistance-trained males (25.6±5.4 yrs, 182.7±9.1 cm, 86.4±9.7 kg) underwent an electromyographic signals acquisition of the sternocostal head (SP), clavicular head of the pectoralis major (CP), the anterior deltoid (AD), and the long head of the triceps brachii (LT) during bench press exercise. Participants performed one non-instructed set (NIS) of 4 repetitions at 50% 1-RM and one non-instructed set (NIS) of 4 repetitions at 80% 1-RM. Four additional sets of 4 repetitions at 50% and 80% 1-RM were randomly performed with verbal instructions to isolate the chest muscles (chest instructed set, CIS) or to isolate the triceps muscles (triceps instructed set, TIS). Participants showed significantly higher LT activation during TIS compared to NIS both at 50% (p=0.0199) and 80% 1-RM (p=0.0061) respectively. TIS elicited a significant (p=0.0250) higher activation of LT compared to CIS. Our results suggest that verbal instructions seem to be effective for increasing activity of the triceps brachii but not the pectoralis major during the bench press.

Background and Purpose: Nociplastic pain due to central sensitization (CS) is common in people suffering from chronic pain, but no clinical practice guideline is available in rehabilitative settings for patients' management. The aim of this study is to achieve expert consensus on physiotherapy competencies in the management of people with nociplastic pain and suspected CS mechanisms. Methods: A web‐based Delphi process was employed. Experts in the rehabilitation field were recruited following pre‐defined eligibility criteria. Following completion of three Delphi rounds, the final list of competencies was generated. Results: In all, 23 participants were recruited. They all completed Round 1 (23/23, 100%), twenty Round 2 and Round 3 (20/23, 87%). Following Round 1, seven areas were identified by the panel as crucial for CS physiotherapy management; 19 competencies out of 40 reached the consensus between experts, and nine additional competencies were added to Round 2 following literary review. Round 2 identified the agreement for all the 29 competencies. During Round 3, all the experts confirmed the final list generated through the consensus process. Discussion: An agreement between experts was found for the final list of competencies that a physiotherapist should implement every time it approaches people with suspected CS mechanisms. Further research is needed to support the clinical utility of our findings and their applicability in daily practice. [ABSTRACT FROM AUTHOR]

A novel stimuli-responsive strategy against the irreversible fouling of porous materials and surfaces is presented herein. This is based on the molecular design of catalytic pore walls that foster a chemo-mechanical, self-cleaning behavior under neutral pH and mild conditions of pressure and temperature. This approach builds on bioinspired remediation mechanisms involving natural catalase enzymes for H2O2 dismutation and endogenous oxygen production. It is thus demonstrated that a very efficient antifouling activity is observed when the material pores are armed with oxygen evolving catalysts that are known to liberate nascent oxygen gas when exposed to H2O2 as chemical trigger. To this aim, the catalase-like behavior of the tetra-ruthenium substituted polyoxometalate (Ru4(SiW10)2), has been exploited for in-pore oxygen evolution so to induce an active fluid mixing and the displacement of foulant particles. The present study includes the fabrication of hybrid polymeric films with porous architecture embedding Ru4(SiW10)2 as artificial catalase to guarantee the material self-defense against pore occlusion and oxidative damage with aqueous H2O2 as mild chemical effector. The self-catalytic 'in-pore' remediation is readily applied to various materials/interfaces with porous texture and high surface area with the aim to provide long-lasting functional performances. [ABSTRACT FROM AUTHOR]

Four ruthenium(II) N-heterocyclic dicarbene complexes of general formula [Ru{MeIm(CH2) nImMe}2(RCN)2][PF6]2 ( 1: n = 1, R = Me; 2: n = 1, R = Ph; 3: n = 2, R = Me; 4: n = 2, R = Ph; MeIm = 3-methylimidazol-2-yliden-1-yl) have been synthesised by transmetalation of the dicarbene ligand from a dicarbene silver complex with [RuCl2(COD)] x (COD = 1,5-cyclooctadiene) or [RuCl2( p-cymene)]2 as ruthenium precursors. The relative position of the coordinated nitrile molecules ( cis or trans) depends on the group that links the two carbene moieties: the dicarbene with the methylene bridge affords the trans isomer, whereas the cis complex is obtained with the ethylene bridge. The lability of coordinated nitriles towards entering nucleophiles, in particular, cyclohexyl and tert-butyl isocyanide, has been carefully checked, and the corresponding substitution complexes [Ru{MeIm(CH2) nImMe}2(RNC)2][PF6]2 ( 6: n = 1, R = Cy; 7: n = 2, R = Cy; 8: n = 2, R = tBu) have been synthesised. The trans complexes are more inert than the cis ones, and benzonitrile is a better leaving group than acetonitrile; these characteristics allow a proper tuning of the coordination set and the stereoelectronic properties of these dicarbene ruthenium complexes. The X-ray crystal structures of 1 and 7 have also been determined. [ABSTRACT FROM AUTHOR]

Signals downstream of Akt can either favor or oppose stem cell (SC) maintenance, but how this dual role can be achieved is still undefined. Using human limbal keratinocyte stem cells (LKSCs), a SC type used in transplantation therapies for corneal regeneration, we show that Akt signaling is prominent in SC populations both in vivo and in vitro, and that Akt1 promotes while Akt2 opposes SC self-renewal. Noteworthy, loss of Akt2 signaling enhances LKSC maintenance ex vivo, whereas Akt1 depletion anticipates SC exhaustion. Mechanistically, the antagonistic functions of Akt1 and Akt2 in SC control are mainly dictated by their differential subcellular distribution, being nuclear Akt2 selectively implicated in FOXO inhibition. Akt2 downregulation favors LKSC maintenance as a result of a gain of FOXO functions, which attenuates the mechanistic target of rapamycin complex one signaling via tuberous sclerosis one gene induction, and promotes growth factor signaling through Akt1. Consistently, Akt2 deficiency also enhances limbal SCs in vivo. Thus, our findings reveal distinct roles for nuclear versus cytosolic Akt signaling in normal epithelial SC control and suggest that the selective Akt2 inhibition may provide novel pharmacological strategies for human LKSC expansion in therapeutic settings and mechanistic research. S tem C ells 2014;32:754-769 [ABSTRACT FROM AUTHOR]

Polyvinylidenefluoride (PVDF) hollow fiber membranes prepared in laboratory through the inversion phase method were characterized and used to clarify an aqueous extract from red wine lees. Steady-state permeate fluxes of 53 kg/m2h were obtained in the treatment of the aqueous extract in selected operating conditions. Suspended solids were completely retained by the hollow fiber membranes while bioactive compounds, including polyphenols, anthocyanins, and resveratrol were recovered in the permeate stream. The clarified stream was then fractionated by nanofiltration (NF). Three different commercial membranes, in flat-sheet configuration (NP010 and NP030 from Microdyn-Nadir, MPF36 from Koch Membrane Systems), were selected and tested for their productivity and selectivity towards sugars and bioactive compounds, including phenolic compounds, anthocyanins, and resveratrol. All selected membranes showed high retention towards anthocyanins (higher than 93%). Therefore, they were considered suitable to concentrate anthocyanins from clarified wine lees extracts at low temperature. On the other hand, NF permeate streams resulted enriched in phenolic compounds and resveratrol. Among the selected membranes, the MPF36 exhibited the lowest retention towards resveratrol (10%) and polyphenols (26.3%) and the best separation factor between these compounds and anthocyanins. [ABSTRACT FROM AUTHOR]

Background: p130 Crk-associated substrate (p130CAS; also known as BCAR1) is a scaffold protein that modulates many essential cellular processes such as cell adhesion, proliferation, survival, cell migration, and intracellular signaling. p130Cas has been shown to be highly expressed in a variety of human cancers of epithelial origin. However, few data are available regarding the role of p130Cas during normal epithelial development and homeostasis. Methods: To this end, we have generated a genetically modified mouse in which p130Cas protein was specifically ablated in the epidermal tissue. Results: By using this murine model, we show that p130Cas loss results in increased cell proliferation and reduction of cell adhesion to extracellular matrix. In addition, epidermal deletion of p130Cas protein leads to premature expression of "late" epidermal differentiation markers, altered membrane E-cadherin/catenin proteins localization and aberrant tyrosine phosphorylation of E-cadherin/catenin complexes. Interestingly, these alterations in adhesive properties in absence of p130Cas correlate with abnormalities in progenitor cells balance resulting in the amplification of a more committed cell population. Conclusion: Altogether, these results provide evidence that p130Cas is an important regulator of epidermal cell fate and homeostasis. [ABSTRACT FROM AUTHOR]

Polyvinylidene difluoride (PVDF) mixed matrix membranes loaded with inorganic TiO2 nanoparticles have received increasing attention in the last few years as self-cleaning membranes for possible application in wastewater treatment and seawater filtration. These novel membranes show increased hydrophilicity, stability and catalytic activity under UV-A irradiation. In this work, PVDF-TiO2 hollow fibers were prepared by employing new strategies for enhancing the stability of the TiO2 dispersion, reducing particle agglomeration and improving their distribution. The spinning conditions for producing ultrafiltration hollow fiber membranes from PVDF material and nano-TiO2 were investigated. Finally, the optimized fibers have been characterized and tested for methylene blue (MB) degradation in water and salty seawater, revealing good permeability, long-term stability under UV-A irradiation, and photo-catalytic activity in both test solutions. [ABSTRACT FROM AUTHOR]

The cover page of the journal "Advanced Materials Interfaces" is presented.