The A2B adenosine receptor modulates the epithelial- mesenchymal transition through the balance of cAMP/PKA and MAPK/ERK pathway activation in human epithelial lung cells

The epithelial-mesenchymal transition (EMT) is a complex process in which cell phenotype switches from the epithelial to mesenchymal one. The deregulations of this process have been related with the occurrence of different diseases such as lung cancer and fibrosis. In the last decade, several efforts have been devoted in understanding the mechanisms that trigger and sustain this transition process. Adenosine is a purinergic signaling molecule that has been involved in the onset and progression of chronic lung diseases and cancer through the A2Badenosine receptor subtype activation, too. However, the relationship between A2BAR and EMT has not been investigated, yet. Herein, the A2BAR characterization was carried out in human epithelial lung cells. Moreover, the effects of receptor activation on EMT were investigated in the absence and presence of transforming growth factor-beta (TGF-β1), which has been known to promote the transition. The A2BAR activation alone decreased and increased the expression of epithelial markers (E-cadherin) and the mesenchymal one (Vimentin, N-cadherin), respectively, nevertheless a complete EMT was not observed. Surprisingly, the receptor activation counteracted the EMT induced by TGF-β1. Several intracellular pathways regulate the EMT: high levels of cAMP and ERK1/2 phosphorylation has been demonstrated to counteract and promote the transition, respectively. The A2BAR stimulation was able to modulated these two pathways, cAMP/PKA and MAPK/ERK, shifting the fine balance toward activation or inhibition of EMT. In fact, using a selective PKA inhibitor, which blocks the cAMP pathway, the A2BAR-mediated EMT promotion were exacerbated, and conversely the selective inhibition of MAPK/ERK counteracted the receptor-induced transition. These results highlighted the A2BAR as one of the receptors involved in the modulation of EMT process. Nevertheless, its activation is not enough to trigger a complete transition, its ability to affect different intracellular pathways could represent a mechanism at the basis of EMT maintenance/inhibition based on the extracellular microenvironment. Despite further investigations are needed, herein for the first time the A2BAR has been related to the EMT process, and therefore to the different EMT-related pathologies

X-ray spectroscopy of the z=6.4 quasar J1148+5251

We present the 78-ks Chandra observations of the $z=6.4$ quasar SDSS J1148+5251. The source is clearly detected in the energy range 0.3-7 keV with 42 counts (with a significance $\gtrsim9\sigma$). The X-ray spectrum is best-fitted by a power-law with photon index $\Gamma=1.9$ absorbed by a gas column density of $\rm N_{\rm H}=2.0^{+2.0}_{-1.5}\times10^{23}\,\rm cm^{-2}$. We measure an intrinsic luminosity at 2-10 keV and 10-40 keV equal to $\sim 1.5\times 10^{45}~\rm erg~s^{-1}$, comparable with luminous local and intermediate-redshift quasar properties. Moreover, the X-ray to optical power-law slope value ($\alpha_{\rm OX}=-1.76\pm 0.14$) of J1148 is consistent with the one found in quasars with similar rest-frame 2500 \AA ~luminosity ($L_{\rm 2500}\sim 10^{32}~\rm erg~s^{-1}$\AA$^{-1}$). Then we use Chandra data to test a physically motivated model that computes the intrinsic X-ray flux emitted by a quasar starting from the properties of the powering black hole and assuming that X-ray emission is attenuated by intervening, metal-rich ($Z\geq \rm Z_{\odot}$) molecular clouds distributed on $\sim$kpc scales in the host galaxy. Our analysis favors a black hole mass $M_{\rm BH} \sim 3\times 10^9 \rm M_\odot$ and a molecular hydrogen mass $M_{\rm H_2}\sim 2\times 10^{10} \rm M_\odot$, in good agreement with estimates obtained from previous studies. We finally discuss strengths and limits of our analysis.Comment: 9 pages, 3 figures, 1 table, MNRAS in pres

Citron Kinase Deficiency Leads to Chromosomal Instability and TP53-Sensitive Microcephaly

Mutations in citron (CIT), leading to loss or inactivation of the citron kinase protein (CITK), cause primary microcephaly in humans and rodents, associated with cytokinesis failure and apoptosis in neural progenitors. We show that CITK loss induces DNA damage accumulation and chromosomal instability in both mammals and Drosophila. CITK-deficient cells display "spontaneous" DNA damage, increased sensitivity to ionizing radiation, and defective recovery from radiation-induced DNA lesions. In CITK-deficient cells, DNA double-strand breaks increase independently of cytokinesis failure. Recruitment of RAD51 to DNA damage foci is compromised by CITK loss, and CITK physically interacts with RAD51, suggesting an involvement of CITK in homologous recombination. Consistent with this scenario, in doubly CitK and Trp53 mutant mice, neural progenitor cell death is dramatically reduced; moreover, clinical and neuroanatomical phenotypes are remarkably improved. Our results underscore a crucial role of CIT in the maintenance of genomic integrity during brain development

Cost-effectiveness of intravitreal therapy in Age-Related Macular Degeneration

Age-related macular degeneration (AMD) is still referred to as the leading cause of severe and irreversible visual loss world-wide. Advances in medical research have identified vascular endothelial growth factor (VEGF) as an important pathophysiological player in neovascular AMD and intraocular inhibition of VEGF as one of the most efficient therapies. Anti-VEGFs currently used to treat AMD included a monoclonal antibody (bevacizumab), an antibody fragments (ranibizumab), a fusion protein (aflibercept), and an aptamer (pegaptanib). The wide introduction of anti-VEGF therapy has led to an improvement in the prognosis of patients affected by AMD, with a consequent effects on the burden of care due to highly priced drugs, increasing patient numbers, and long-term disease chronicity. Aim of this review is to present an overview of available therapeutic strategies in AMD in term of clinical efficacy and economic sustainability

Baseline SD-OCT characteristics of diabetic macular oedema patterns can predict morphological features and timing of recurrence in patients treated with dexamethasone intravitreal implants

n/

Ultrastructural changes of the intestinal mucosa in Non-Celiac Gluten Sensitivity patients could represent an early indicator of cellular stress

Non-Celiac Gluten Sensitivity (NCGS) is a wide-spreading syndrome and an emerging problem in clinical practice linked to the increase of gluten content in some populations diet. It is characterized by intestinal and/or extra intestinal symptoms that improve or disappear after removing gluten from diet in non-celiac or non-wheat allergic patients [1]. In order to perform and support a precise and early diagnosis, as others recently suggested [2], the aim of this work was to analyze in detail ultrastructural features of the duodenal mucosa. Biopsy specimens were obtained from 10 patients who underwent gastrointestinal endoscopy for a diagnostic check-up at the Department of Gastroenterology of the University of Chieti and prepared for electron microscopy. Semithin sections were blindly observed but only biopsies showing well-shaped intestinal villi were selected for the ultrastructural study, observed with a ZEISS EM109 equipped with a Gatan videocamera. We analyzed: 1) brush border, 2) epithelial cell cytoplasm, 3) cellular junctions and 4) the villus connective axis with respect to inflammatory cell number and vascular alterations, evaluating amount and localization of cellular damages. Interestingly, only 3 of these biopsies, obtained from subjects in which clinical history and diagnosis was uncertain, presented fine spot damage in the epithelium from intestinal villi with an apparently normal morphology. Some epithelial cells showed sever distress such as heterochromatic and nuclei not-round shaped, dilated endoplasmic reticulum, increased number of mitochondria and a messy brush border thinned and reduced in width. Numerous damaged cellular junctions and remarkable basal detachment of cell plasma membranes were observed. These findings pave the way to a deepen characterization of intestinal mucosa from NCGS patients to identify, by means of electron microscopy, potential morphological and functional markers of NCGS. This work was supported by MIUR funds granted to R. Di Pietro and L. Centurione in 2014 and 2015

Targeting COPZ1 non-oncogene addiction counteracts the viability of thyroid tumor cells

Thyroid carcinoma is generally associated with good prognosis, but no effective treatments are currently available for aggressive forms not cured by standard therapy. To find novel therapeutic targets for this tumor type, we had previously performed a siRNA-based functional screening to identify genes essential for sustaining the oncogenic phenotype of thyroid tumor cells, but not required to the same extent for the viability of normal cells (non-oncogene addiction paradigm). Among those, we found the coatomer protein complex ζ1 (COPZ1) gene, which is involved in intracellular traffic, autophagy and lipid homeostasis. In this paper, we investigated the mechanisms through which COPZ1 depletion leads to thyroid tumor cell death. We showed that siRNA-mediated COPZ1 depletion causes abortive autophagy, endoplasmic reticulum stress, unfolded protein response and apoptosis. Interestingly, we observed that mouse tumor xenografts, locally treated with siRNA targeting COPZ1, showed a significant reduction of tumor growth. On the whole, we demonstrated for the first time the crucial role of COPZ1 in the viability of thyroid tumor cells, suggesting that it may be considered an attractive target for novel therapeutic approaches for thyroid cancer

Citron Kinase Deficiency Leads to Chromosomal Instability and TP53-Sensitive Microcephaly

Mutations in citron (CIT), leading to loss or inactivation of the citron kinase protein (CITK), cause primary microcephaly in humans and rodents, associated with cytokinesis failure and apoptosis in neural progenitors. We show that CITK loss induces DNA damage accumulation and chromosomal instability in both mammals and Drosophila. CITK-deficient cells display “spontaneous” DNA damage, increased sensitivity to ionizing radiation, and defective recovery from radiation-induced DNA lesions. In CITK-deficient cells, DNA double-strand breaks increase independently of cytokinesis failure. Recruitment of RAD51 to DNA damage foci is compromised by CITK loss, and CITK physically interacts with RAD51, suggesting an involvement of CITK in homologous recombination. Consistent with this scenario, in doubly CitK and Trp53 mutant mice, neural progenitor cell death is dramatically reduced; moreover, clinical and neuroanatomical phenotypes are remarkably improved. Our results underscore a crucial role of CIT in the maintenance of genomic integrity during brain development

The addition of Capsicum baccatum to Calabrian monovarietal extra virgin olive oils leads to flavoured olive oils with enhanced oxidative stability

This study aimed to evaluate the influence of Capsicum baccatum L. Aji Angelo and Bishop crown cultivars to the quality parameters of flavoured olive oils (FOOs) obtained by the addition of both fresh and dried pepper powders (1%) to Dolce di Rossano and Roggianella monovarietal extra virgin olive oils (EVOOs). First, pepper extracts were investigated for their total phenolic, flavonoid, carotenoid content as well as phenolic acids, fatty acid profile, and vitamin C and E content. In order to evaluate the impact of both fresh and dried peppers on the oxidative stability of FOOs, the Rancimat test was applied. 2,2-Azinobis(3-ethylbenzothiazoline-6-sulfonic) acid (ABTS), 2,2-diphenyl-1-picrylhydrazyl (DPPH), ?-carotene bleaching (B-CB) and ferric reducing antioxidant power (FRAP) assays were used to investigate the antioxidant potential. Bishop crown dried extracts showed the highest phenolic, carotenoid and vitamin content, whereas Aji Angelo had the highest amount of capsaicinoids. Among EVOOs, Roggianella EVOO showed the highest antioxidant activity as well as the highest induction time (39.6 h). Remarkably, FOO obtained by the addition of Bishop crown dried pepper extract to Roggianella EVOO showed a higher induction time (44.9 h) with respect to the corresponding EVOO

Humans, resources, or what else?

The literature on human resource management shows growing attention to the “personal” dimension of the subject-organization relationship, while the subjectivist contributions do not disregard the discussion on managerial implications. This ebook proposes a reflection on this apparent convergence. It discusses the internal criticism arising from the mainstream literature and the criticism originating from different disciplinary perspectives (organization, sociology of science, psychology of work, and labor law). Alternatives to the idea of human resources are proposed through the reflection on the goals of the processes of actions and decisions, the ontological reflection on the idea of man, and the epistemological reflection on the choices that allow overcoming the objectivism/subjectivism antinomy