The persistent dynamic secrets of senescence

While the beneficial versus detrimental implications of the senescence-associated secretome remain an issue of debate, time-resolved analyses of its composition, regulatory mechanisms and functional consequences have been largely missing. The dynamic activity of NOTCH is now shown to direct two distinct senescence phenotypes, by first promoting a pro-senescent TGF-{beta}1-dependent secretome, followed by a second wave of pro-inflammatory, senescence-clearing cytokines

Total quality management practices, competitive strategies and financial performance: the case of the Palestinian industrial SMEs

"This is an Accepted Manuscript of an article published by Taylor & Francis in Total Quality Management and Business Excellence on 19 Aug 2013, available online: http://wwww.tandfonline.com/10.1080/14783363.2013.824714."The purpose of this paper is to examine the relationship between Total Quality Management (TQM) practices, competitive strategies - cost leadership and differentiation- and firm performance in the Palestinian economy. Within this study total quality management has been conceptualized as soft and hard practices, in congruence with the literature. An empirical analysis based upon an extensive validation process was applied to refine TQM, competitive strategies and financial performance scales. Data were collected through surveying 202 in Palestinian industrial small and medium enterprises (SMEs). Structural Equation Modeling was carried out to test the anticipated relationships. Results derived from this study show that TQM practices have indirect, positive and significant relationship with financial performance through competitive strategies. In addition, a direct, positive and significant relationship between competitive strategies and financial performance was observed. Results derived from this study might help managers to implement TQM practices in order to effectively allocate resources and improve financial performance

The cerebral cavernous malformation 3 gene is necessary for senescence induction.

Mutations in cerebral cavernous malformation 3 gene are known to result in development of vascular malformations and have recently been proposed to also give rise to meningiomas. We report in this study that lack of CCM3 unexpectedly impairs the senescence response of cells, and this is related to the inability of CCM3-deficient cells to induce the C/EBPβ transcription factor and implement the senescence-associated secretory phenotype. Induction of C/EBPβ and cytokines is also impaired in the absence of CCM3 in response to cytokines in nonsenescent cells, pointing to it being a primary defect and not secondary to impaired senescence. CCM3-deficient cells also have a defect in autophagy at late passages of culture, and this defect is also not dependent on impaired senescence, as it is evident in immortal cells after nutrient starvation. Further, these two defects may be related, as enforcing autophagy in CCM3-deficient late passage cells increases C/EBPβ cytokine expression. These results broaden our knowledge on the mechanisms by which CCM3 deficiency results in disease and open new avenues of research into both CCM3 and senescence biology

CBX7 and miR-9 are part of an autoregulatory loop controlling p16(INK) (4a).

Polycomb repressive complexes (PRC1 and PRC2) are epigenetic regulators that act in coordination to influence multiple cellular processes including pluripotency, differentiation, cancer and senescence. The role of PRCs in senescence can be mostly explained by their ability to repress the INK4/ARF locus. CBX7 is one of five mammalian orthologues of Drosophila Polycomb that forms part of PRC1. Despite the relevance of CBX7 for regulating senescence and pluripotency, we have a limited understanding of how the expression of CBX7 is regulated. Here we report that the miR-9 family of microRNAs (miRNAS) downregulates the expression of CBX7. In turn, CBX7 represses miR-9-1 and miR-9-2 as part of a regulatory negative feedback loop. The miR-9/CBX7 feedback loop is a regulatory module contributing to induction of the cyclin-dependent kinase inhibitor (CDKI) p16(INK4a) during senescence. The ability of the miR-9 family to regulate senescence could have implications for understanding the role of miR-9 in cancer and aging

Tnfa Signaling Through Tnfr2 Protects Skin Against Oxidative Stress-Induced Inflammation

TNFα overexpression has been associated with several chronic inflammatory diseases, including psoriasis, lichen planus, rheumatoid arthritis, and inflammatory bowel disease. Paradoxically, numerous studies have reported new-onset psoriasis and lichen planus following TNFα antagonist therapy. Here, we show that genetic inhibition of Tnfa and Tnfr2 in zebrafish results in the mobilization of neutrophils to the skin. Using combinations of fluorescent reporter transgenes, fluorescence microscopy, and flow cytometry, we identified the local production of dual oxidase 1 (Duox1)-derived H2O2 by Tnfa- and Tnfr2-deficient keratinocytes as a trigger for the activation of the master inflammation transcription factor NF-κB, which then promotes the induction of genes encoding pro-inflammatory molecules. In addition, pharmacological inhibition of Duox1 completely abrogated skin inflammation, placing Duox1-derived H2O2 upstream of this positive feedback inflammatory loop. Strikingly, DUOX1 was drastically induced in the skin lesions of psoriasis and lichen planus patients. These results reveal a crucial role for TNFα/TNFR2 axis in the protection of the skin against DUOX1-mediated oxidative stress and could establish new therapeutic targets for skin inflammatory disorders

Obstructed defaecation syndrome: European consensus guidelines on the surgical management.

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Mediterranean spotted fever: clinical and laboratory characteristics of 415 Sicilian children

BACKGROUND: Mediterranean spotted fever (MSF) is an acute febrile, zoonotic disease caused by Rickettsia conorii and transmitted to humans by the brown dogtick Rhipicephalus sanguineus. Nearly four hundred cases are reported every year (mainly from June to September) on the Italian island of Sicily. The aim of the study was to analyze the clinical and laboratory characteristics of patients with MSF and the efficacy of the drugs administered. METHODS: Our study was carried out on 415 children with MSF, during the period January 1997 – December 2004, at the "G. Di Cristina" Children's hospital in Palermo, Sicily, Italy. On admission patients' clinical history, physical and laboratory examination and indirect immunofluorescence antibody test (IFAT) for Rickettsia conorii were performed. Diagnosis was considered confirmed if the patients had an MSF diagnostic score greater than or equal to 25 according to the Raoult's scoring system. All patients were treated with chloramphenicol or with macrolides (clarithromycin or azithromycin). RESULTS: Fever, rash and tache noire were present in 386 (93%), 392 (94.5%) and 263 (63.4%) cases respectively. Eighteen (4.6%) children showed atypical exanthema. Chloramphenicol and newer macrolides all appeared to be effective and safe therapies. CONCLUSION: Clinical features of 415 children with MSF were similar to those reported by other authors except for a lower incidence of headache, arthralgia and myalgia and a higher frequency of epato-splenomegaly. Concerning therapy, clarithromycin can be considered a valid alternative therapy to tetracyclines or chloramphenicol especially for children aged < eight years

Co-Transplantation of Adipose Tissue-Derived Stromal Cells and Olfactory Ensheathing Cells for Spinal Cord Injury Repair

Patients suffering from spinal cord injury (SCI) still have a dismal prognosis. Despite all the efforts developed in this area, currently there are no effective treatments. Therefore, cell therapies have been proposed as a viable alternative to the current treatments used. Adipose tissue-derived stromal cells (ASCs) and olfactory ensheathing cells (OECs) have been used with promising results in different models of SCI, namely due to the regenerative properties of the secretome of the first, and the guidance capability of the second. Using an in vitro model of axonal growth, the dorsal root ganglia explants, we demonstrated that OECs induce neurite outgrowth mainly through cell-cell interactions, while ASCs' effects are strongly mediated by the release of paracrine factors. A proteomic analysis of ASCs' secretome revealed the presence of proteins involved in VEGF, PI3K, and Cadherin signaling pathways, which may be responsible for the effects observed. Then, the cotransplantation of ASCs and OECs showed to improve motor deficits of SCI-rats. Particular parameters of movement such as stepping, coordination, and toe clearance were improved in rats that received the transplant of cells, in comparison to nontreated rats. A histological analysis of the spinal cord tissues revealed that transplantation of ASCs and OECs had a major effect on the reduction of inflammatory cells close the lesion site. A slight reduction of astrogliosis was also evident. Overall, the results obtained with the present work indicate that the cotransplantation of ASCs and OECs brings important functional benefits to the injured spinal cord. Stem Cells 2018;36:696-708.This article is a result of the project (NORTE-01-0145-FEDER-000013), supported by Norte Portugal Regional Operational Programme (NORTE 2020), under the PORTUGAL 2020 Partnership Agreement, through the European Regional Development Fund (ERDF); Cofinanciado pelo Programa Operacional Regional do Norte (ON.2 SR&TD Integrated Program – NORTE-07-0124-FEDER- 000021), ao abrigo do Quadro de Referência Estrategico Nacional (QREN), através do Fundo Europeu de Desenvolvimento Regional (FEDER); Projeto Estrategico – LA 26 – 2011–2012 and Projeto Estratégico – LA 26 – 2013-2014 cofinan- ciado por fundos nacionais, através da Fundação para a Ciência e a Tecnologia (PEst-C/SAU/LA0026/2011; PEst-C/SAU/LA0026/2013), e pelo Fundo Europeu de DesenvolvimentoRegional (FEDER), através do COMPETE (FCOMP-01-0124- FEDER-022724; FCOMP-01-0124-FEDER-037298 ). Support also from PTDC/NEU-SCC/7051/2014; POCI-01-0145-FEDER-007440; PTDC/NEU-NMC/0205/2012; UID/NEU/04539/2013; The National Mass Spectrometry Network (RNEM) (REDE/1506/ REM/2005). This work has been funded by FEDER funds, through the Competitiveness Factors Operational Programme (COMPETE), and by National funds, through the Foundation for Science and Technology (FCT), under the scope of the pro- ject POCI-01-0145-FEDER-0070info:eu-repo/semantics/publishedVersio

Crosstalk between glial and glioblastoma cells triggers the "go-or-grow" phenotype of tumor cells

Background: Glioblastoma (GBM), the most malignant primary brain tumor, leads to poor and unpredictable clinical outcomes. Recent studies showed the tumor microenvironment has a critical role in regulating tumor growth by establishing a complex network of interactions with tumor cells. In this context, we investigated how GBM cells modulate resident glial cells, particularly their paracrine activity, and how this modulation can influence back on the malignant phenotype of GBM cells. Methods: Conditioned media (CM) of primary mouse glial cultures unexposed (unprimed) or exposed (primed) to the secretome of GL261 GBM cells were analyzed by proteomic analysis. Additionally, these CM were used in GBM cells to evaluate their impact in glioma cell viability, migration capacity and activation of tumor-related intracellular pathways. Results: The proteomic analysis revealed that the pre-exposure of glial cells to CM from GBM cells led to the upregulation of several proteins related to inflammatory response, cell adhesion and extracellular structure organization within the secretome of primed glial cells. At the functional levels, CM derived from unprimed glial cells favored an increase in GBM cell migration capacity, while CM from primed glial cells promoted cells viability. These effects on GBM cells were accompanied by activation of particular intracellular cancer-related pathways, mainly the MAPK/ERK pathway, which is a known regulator of cell proliferation. Conclusions: Together, our results suggest that glial cells can impact on the pathophysiology of GBM tumors, and that the secretome of GBM cells is able to modulate the secretome of neighboring glial cells, in a way that regulates the "go-or-grow" phenotypic switch of GBM cells.Fundação para a Ciência e Tecnologia (IF/00601/2012 to B.M.C.; IF/00111 to A.J.S; SFRH/BD/52287/2013 to A.I.O.; SFRH/BD/81495/2011 to S.I.A.; SFRH/BD/88121/2012 to J.V.C.; projects PTDC/SAU-GMG/113795/2009 to B.M.C.; PTDC/NEU-NMC/0205/2012, PTDC/NEU-SCC/7051/2014, PEst-C/SAU/LA0001/2013–2014 and UID/NEU/04539/2013 to B.M.), Liga Portuguesa Contra o Cancro (B.M.C.), Fundação Calouste Gulbenkian (B.M.C.) and Inter-University Doctoral Programme in Ageing and Chronic Disease (PhDOC; to A.I.O.). Project co-financed by Programa Operacional Regional do Norte (ON.2—O Novo Norte), Quadro de Referência Estratégico Nacional (QREN), Fundo Europeu de Desenvolvimento Regional (FEDER), Programa Operacional Factores de Competitividade (COMPETE), and by The National Mass Spectrometry Network (RNEM) under the contract REDE/1506/REM/2005info:eu-repo/semantics/publishedVersio