CXCL16/CXCR6 axis drives microglia/macrophages phenotype in physiological conditions and plays a crucial role in glioma

Microglia are patrolling cells that sense changes in the brain microenvironment and respond acquiring distinct phenotypes that can be either beneficial or detrimental for brain homeostasis. Anti-inflammatory microglia release soluble factors that might promote brain repair; however, in glioma, anti-inflammatory microglia dampen immune response and promote a brain microenvironment that foster tumor growth and invasion. The chemokine CXCL16 is expressed in the brain, where it is neuroprotective against brain ischemia, and it has been found to be over-expressed in glioblastoma (GBM). Considering that CXCL16 specific receptor CXCR6 is diffusely expressed in the brain including in microglia cells, we wanted to investigate the role of CXCL16 in the modulation of microglia cell activity and phenotype, and in the progression of glioma. Here we report that CXCL16 drives microglia polarization toward an anti-inflammatory phenotype, also restraining microglia polarization toward an inflammatory phenotype upon LPS and IFN? stimulation. In the context of glioma, we demonstrate that CXCL16 released by tumor cells is determinant in promoting glioma associated microglia/macrophages (GAMs) modulation toward an anti-inflammatory/pro-tumor phenotype, and that cxcr6ko mice, orthotopically implanted into the brain with GL261 glioma cells,survive longer compared to wild-type mice. We also describe that CXCL16/CXCR6 signaling acts directly on mouse glioma cells, as well as human primary GBM cells, promoting tumor cell growth, migration and invasion. All together these data suggest that CXCL16 signaling could represent a good target to modulate microglia phenotype in order to restrain inflammation or to limit glioma progression

Orthogonal Joint Sparse NMF for Microarray Data Analysis

The 3D microarrays, generally known as gene-sample-time microarrays, couple the information on different time points collected by 2D microarrays that measure gene expression levels among different samples. Their analysis is useful in several biomedical applications, like monitoring dose or drug treatment responses of patients over time in pharmacogenomics studies. Many statistical and data analysis tools have been used to extract useful information. In particular, nonnegative matrix factorization (NMF), with its natural nonnegativity constraints, has demonstrated its ability to extract from 2D microarrays relevant information on specific genes involved in the particular biological process. In this paper, we propose a new NMF model, namely Orthogonal Joint Sparse NMF, to extract relevant information from 3D microarrays containing the time evolution of a 2D microarray, by adding additional constraints to enforce important biological proprieties useful for further biological analysis. We develop multiplicative updates rules that decrease the objective function monotonically, and compare our approach to state-of-the-art NMF algorithms on both synthetic and real data sets

Correlation between oesophageal acid exposure and dyspeptic symptoms in patients with nonerosive reflux disease.

Oesophageal acidification induces dyspeptic symptoms in healthy individuals. This study aimed to evaluate the correlation between oesophageal acid exposure and dyspeptic symptoms in patients with nonerosive reflux disease. METHODS: A total of 68 patients with dominant symptoms of heartburn, negative upper gastrointestinal endoscopy and concomitant dyspeptic symptoms participated in the study. The severity of dyspepsia and reflux-related symptoms was evaluated, and 24-h gastro-oesophageal pH-monitoring study was performed in all patients at baseline and after 4 weeks of therapy with esomeprazole 40 mg. RESULTS: Oesophageal basal acid exposure was pathological in 43 patients and normal in 25 patients, with a similar prevalence and severity of individual dyspeptic symptoms in the two groups. A significant correlation between reflux and dyspepsia scores was observed in the subgroup of patients with normal, but not in those with abnormal pHmetry (r=0.4, P=0.04 and r=0.2 P=0.07, respectively). After esomeprazole, a reduction in severity of dyspepsia (>or=50% with respect to baseline) was observed, independent of improvement of reflux-associated symptoms. Improvement in dyspepsia was, however, similar in patients with normal and abnormal basal acid exposure (14/25 vs. 33/43, respectively, P=NS). CONCLUSION: Dyspeptic symptoms coexist in a subset of nonerosive reflux disease patients, but prevalence and severity of the symptoms seems to be independent of oesophageal acid exposure

The glycoside oleandrin reduces glioma growth with direct and indirect effects on tumor cells

Oleandrin is a glycoside that inhibits the ubiquitous enzyme Na(+)/K(+)-ATPase. In addition to its known effects on cardiac muscle, recent in vitro and in vivo evidence highlighted its potential for anticancer properties. Here, we evaluated for the first time the effect of oleandrin on brain tumors. To this aim, mice were transplanted with human or murine glioma and analyzed for tumor progression upon oleandrin treatment. In both systems, oleandrin impaired glioma development, reduced tumor size, and inhibited cell proliferation. We demonstrated that oleandrin does the following: (1) enhances the brain-derived neurotrophic factor (BDNF) level in the brain; (2) reduces both microglia/macrophage infiltration and CD68 immunoreactivity in the tumor mass; (3) decreases astrogliosis in peritumoral area; and (4) reduces glioma cell infiltration in healthy parenchyma. In BDNF-deficient mice (bdnftm1Jae/J) and in glioma cells silenced for TrkB receptor expression, oleandrin was not effective, indicating a crucial role for BDNF in oleandrin's protective and antitumor functions. In addition, we found that oleandrin increases survival of temozolomide-treated mice. These results encourage the development of oleandrin as possible coadjuvant agent in clinical trials of glioma treatment.SIGNIFICANCE STATEMENT In this work, we paved the road for a new therapeutic approach for the treatment of brain tumors, demonstrating the potential of using the cardioactive glycoside oleandrin as a coadjuvant drug to standard chemotherapeutics such as temozolomide. In murine models of glioma, we demonstrated that oleandrin significantly increased mouse survival and reduced tumor growth both directly on tumor cells and indirectly by promoting an antitumor brain microenvironment with a key protective role played by the neurotrophin brain-derived neurotrophic factor

Clinical validation of eye vergence as an objective marker for diagnosis of ADHD in children

Objective: ADHD youth show poor oculomotor control. Recent research shows that attention-related eye vergence is weak in ADHD children. Method: To validate vergence as a marker to classify ADHD, we assessed the modulation in the angle of vergence of children (n = 43) previously diagnosed with ADHD while performing an attention task and compared the results with age-matched clinical controls (n = 19) and healthy peers (n = 30). Results: We observed strong vergence responses in healthy participants and weak vergence in the clinical controls. ADHD children showed no significant vergence responses. Machine-learning models classified ADHD patients (n = 21) from healthy controls (n = 21) with an accuracy of 96.3% (false positive [FP]: 5.12%; false negative [FN]: 0%; area under the curve [AUC]: 0.99) and ADHD children (n = 11) from clinical controls (n = 14) with an accuracy of 85.7% (FP: 4.5%; FN: 19.2%, AUC: 0.90). Conclusion: In combination with an attention task, vergence responses can be used as an objective marker to detect ADHD in children.Peer ReviewedPostprint (author's final draft

Risultati preliminari della campagna oceanografica CAFE_07 – Leg 3 nei Golfi di Napoli e Pozzuoli, Mar Tirreno Orientale

Vengono presentati i risultati preliminari della campagna oceanografica CAFE_07 - Leg 3, svoltasi nei Golfi di Napoli e Pozzuoli, nel Gennaio 2008, a bordo della Nave Oceanografica (N/O) URANIA del CNR. Lo scopo della campagna è stato l’acquisizione di profili sismici multicanale di elevata risoluzione dedicati allo studio stratigrafico-strutturale degli apparati vulcanici affioranti e sepolti nell’offshore Napoletano, ed il rilievo batimetrico di dettaglio dell’area sommersa. I dati raccolti sono consistiti in circa 800 km di profili sismici a riflessione multicanale di alta risoluzione, con acquisizione sismica simultanea da due sorgenti GI-gun operanti con potenza e frequenze differenti,mediante due cavi idrofonici. Durante la navigazione sono stati anche acquisiti profili sismici a riflessione monocanale di altissima risoluzione (sub-bottom CHIRP) e dati batimetrici mediante ecoscandaglio multifascio (multibeam). Il grid di acquisizione sismica multicanale è consistito in alcuni profili lunghi attraverso il Golfo di Napoli e da una fitta griglia di profili più corti, con interasse di circa 150 m, allo scopo di ottenere una copertura sismica quasi 3-D del Golfo di Pozzuoli. Questo set di dati costituisce una parte delle indagini di dettaglio richieste per la stesura di una proposta di perforazione del settore sommerso dei Campi Flegrei da sottomettere all’Integrated Ocean Drilling Program (IODP) ed è di supporto alla realizzazione di un progetto di perforazione profonda dei Campi Flegrei presentato all’International Continental Drilling Program (ICDP). We present the preliminary results of the oceanographic cruise CAFE_07 – Leg 3, conducted in the Napoli and Pozzuoli Bays in January 2008, on board of the Research Vessel (R/V) URANIA of the CNR. The aim of the cruise was the acquisition of high resolution multi-channel seismic profiles to understand the stratigraphic-structural setting of the Pozzuoli Bay area, with specific reference to the major offshore volcanic features, as well as the acquisition of bathymetric data on the seafloor morphology of the Bay. About 800 km of seismic profiles were acquired simultaneously by two acquisition systems, each characterized by different seismic source and streamer configuration, operating at different frequency ranges. Moreover shallow high resolution seismic reflection profiles (sub-bottom CHIRP) and multibeam echo-sounder bathymetry data have been recorded. The seismic grid consisted in a number of assistant profiles acquired over the Bay of Naples, along with a dense network of profiles with average distance of about 150 m between navigation routes, in order to obtain a quasi 3-D seismic coverage of the Pozzuoli Bay. This data set represents a part of the requirements for on-site detailed investigations (“site survey”) that are necessary for the development of an Integrated Ocean Drilling Program (IODP) proposal dedicated to the offshore drilling of the Campi Flegrei and is a relevant complement in the site survey of an ongoing project that has been submitted to the International Continental Drilling Program (ICDP)

A SPLICS reporter reveals -synuclein regulation of lysosome-mitochondria contacts which affects TFEB nuclear translocation

Mitochondrial and lysosomal activities are crucial to maintain cellular homeostasis: optimal coordination is achieved at their membrane contact sites where distinct protein machineries regulate organelle network dynamics, ions and metabolites exchange. Here we describe a genetically encoded SPLICS reporter for short- and long- juxtapositions between mitochondria and lysosomes. We report the existence of narrow and wide lysosome-mitochondria contacts differently modulated by mitophagy, autophagy and genetic manipulation of tethering factors. The overexpression of α-synuclein (α-syn) reduces the apposition of mitochondria/lysosomes membranes and affects their privileged Ca²⁺ transfer, impinging on TFEB nuclear translocation. We observe enhanced TFEB nuclear translocation in α-syn-overexpressing cells. We propose that α-syn, by interfering with mitochondria/lysosomes tethering impacts on local Ca²⁺ regulated pathways, among which TFEB mediated signaling, and in turn mitochondrial and lysosomal function. Defects in mitochondria and lysosome represent a common hallmark of neurodegenerative diseases: targeting their communication could open therapeutic avenues

Enteroscopy in children and adults with inflammatory bowel disease

Inflammatory bowel disease (IBD) includes Crohn's disease (CD), ulcerative colitis and unclassified entities. CD commonly involves the terminal ileum and colon but at the time of diagnosis it can be confined to the small bowel (SB) in about 30% of the patients, especially in the young ones. Management of isolated SB-CD can be challenging and objective evaluation of the SB mucosa is essential in differentiating CD from other enteropathies to achieve therapeutic decisions and to plan the follow-up. The introduction of cross-sectional imaging techniques and capsule endoscopy (CE) have significantly expanded the ability to diagnose SB diseases providing a non-invasive test for the visualization of the entire SB mucosa. The main CE limitations are the low specificity, the lack of therapeutic capabilities and the impossibility to take biopsies. Device assisted enteroscopy (DAE) enables histological confirmation when traditional endoscopy, capsule endoscopy and cross-sectional imaging are inconclusive and also allows therapeutic interventions such as balloon stricture dilation, intralesional steroid injection, capsule retrieval and more recently stent insertion. In the current review we will discuss technical aspect, indications and safety profile of DAE in children and adults with IBD

CXCL16/CXCR6 Axis Drives Microglia/Macrophages Phenotype in Physiological Conditions and Plays a Crucial Role in Glioma

Microglia are patrolling cells that sense changes in the brain microenvironment and respond acquiring distinct phenotypes that can be either beneficial or detrimental for brain homeostasis. Anti-inflammatory microglia release soluble factors that might promote brain repair; however, in glioma, anti-inflammatory microglia dampen immune response and promote a brain microenvironment that foster tumor growth and invasion. The chemokine CXCL16 is expressed in the brain, where it is neuroprotective against brain ischemia, and it has been found to be over-expressed in glioblastoma (GBM). Considering that CXCL16 specific receptor CXCR6 is diffusely expressed in the brain including in microglia cells, we wanted to investigate the role of CXCL16 in the modulation of microglia cell activity and phenotype, and in the progression of glioma. Here we report that CXCL16 drives microglia polarization toward an anti-inflammatory phenotype, also restraining microglia polarization toward an inflammatory phenotype upon LPS and IFNγ stimulation. In the context of glioma, we demonstrate that CXCL16 released by tumor cells is determinant in promoting glioma associated microglia/macrophages (GAMs) modulation toward an anti-inflammatory/pro-tumor phenotype, and that cxcr6ko mice, orthotopically implanted into the brain with GL261 glioma cells,survive longer compared to wild-type mice. We also describe that CXCL16/CXCR6 signaling acts directly on mouse glioma cells, as well as human primary GBM cells, promoting tumor cell growth, migration and invasion. All together these data suggest that CXCL16 signaling could represent a good target to modulate microglia phenotype in order to restrain inflammation or to limit glioma progression

The use and beauty of ultra-high-resolution seismic reflection imaging in Late Quaternary marine volcaniclastic settings, Bay of Naples, Italy

A Nápolyi-öbölben felvett ultra nagy felbontású egycsatornás (IKB-Seistec™) reflexiós szeizmikus szelvények korábbi geológiai és geofizikai vizsgálatok eredményeivel együtt kivételes, eddig soha nem látott felbontású szeizmikus leképezését nyújtják a Flegrei-mezők és a Somma-Vezúv felszín alá süllyedt késő-pleisztocén–holocén rétegtani felépí - tésének. A szeizmikus szelvényeken látott geometria és gravitációs magvevővel nyert üledékek adatainak összevetéséből Campania partközeli kontinentális talapzatán számos olyan üledékes és vulkáni szerkezet, valamint hidrotermális jelenség került leképezésre, melyek a legutolsó glaciális maximum (kb. 18 000 év) óta keletkeztek. A Pozzuoli-öbölben mért Seistec szelvények jól mutatják a beomlott kaldera gyűrűs vetőjét, a kb. 15 ezer éves Nápolyi Sárga Tufa (NYT) lerakódáshoz vezető kitöréskor felújuló boltozatot, és alátámasztják a deformáció későnegyedidőszaki korára és stílusára vonatkozó hipotéziseket. A szeizmikus szelvényeken látható a NYT rétegeinek töréses szerkezete, valamint hidrotermális fluidum-feláramlások és vulkáni/szubvulkáni intrúziók a gyűrűs vetők mentén. A Somma-Vezúv rétegvulkán előterében a kontinentális talapzat felett mért szeizmikus szelvények leképezték a Vezúv i.sz. 79-es kitörésekor Herculaneum városát elpusztító piroklaszt-ár tengervízbe érésekor keletkező, gravitációsan összeomló homokhullámok szerkezetét is. A Somma-Vezúv és a Pozzuoli-öböl közti, buckás felszínű Banco della Montagna területén mért szelvények és fúrómagok vulkanoklasztos diapírok sorát tárták fel. Ezeket a konszolidálatlan horzsakőből álló testeket a fluidum - feláramlás és aktív kigázosodás hatására kialakult mélybeli túlnyomás hozta fel a tengerfenékre.Very high-resolution, single channel (IKB-Seistec™) reflection seizmic profiles acquired in the Bay of Naples, com - plemented with geological and geophysical data from the literature, provide unprecedented, superb seismic imaging of the latest Pleistocene–Holocene stratigraphic architecture of the submerged sectors Campi Flegrei and Somma-Vesuvius volcanic districts. Seismic profiles were calibrated by gravity core data and document a range of depositional systems, volcanic structures and hydrothermal features that evolved after the onset of the Last Glacial Maximum (~ 18 ka BP) over the continental shelf on the Campania coastal zone. Seistec profiles from the Pozzuoli Bay yield high-resolution images of the shallow structure of the collapse caldera-ring fault — resurgent dome system associated with the eruption of the Neapolitan Yellow Tuff (NYT) (ca 15 ka) and support a working hypothesis to assess the timing and the styles of deformation of the NYT resurgent structure throughout the latest Quaternary. Seismic images also revealed the nature of the fragile deformation of strata along the NYT ring fault system and the occurrence of hydrothermal fluids and volcanic/subvolcanic intrusions ascending along the ring fault zone. Seismic data acquired over the continental shelf off the Somma-Vesuvius stratovolcano, display evidence of gravit - ational instability of wavy bedforms representing the submarine prosecution of pyroclastic flows originated from the Vesuvius during the eruption that destroyed the Roman city of Herculaneum in 79 CE. At the Banco della Montagna, a hummocky seafloor knoll located between the Somma-Vesuvius and the Pozzuoli Bay, seismic profiles and gravity core data revealed the occurrence of a field of volcaniclastic diapirs formed by the dragging and rising up of unconsolidated pumice, as a consequence of fluid overpressure at depth associated with active degassing and fluid venting at the seafloor