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PubMed | University of Rome La Sapienza, University of Groningen and Irccs Gb Bietti Foundation
Type: Journal Article | Journal: International journal of oncology | Year: 2016

Clinical trials using antiangiogenic drugs revealed their potential against cancer. Unfortunately, a large percentage of patients does not yet benefit from this therapeutic approach highlighting the need of diagnostic tools to non-invasively evaluate and monitor response to therapy. It would also allow to predict which kind of patient will likely benefit of antiangiogenic therapy. Reasons for treatment failure might be due to a low expression of the drug targets or prevalence of other pathways. Molecular imaging has been therefore explored as a diagnostic technique of choice. Since the vascular endothelial growth factor (VEGF/VEGFR) pathway is the main responsible of tumor angiogenesis, several new drugs targeting either the soluble ligand or its receptor to inhibit signaling leading to tumor regression could be involved. Up today, it is difficult to determine VEGF or VEGFR local levels and their non-invasive measurement in tumors might give insight into the available target for VEGF/VEGFR-dependent antiangiogenic therapies, allowing therapy decision making and monitoring of response.

PubMed | University of Rome La Sapienza, University of Groningen and Irccs Gb Bietti Foundation
Type: Journal Article | Journal: International journal of oncology | Year: 2016

Following the publication of this article, after having re-examined our manuscript, we noted an error in the acknowledgements section, as regards the funding of our study. The correct version of acknowledgements section is shown below: Acknowledgements This study was supported by the Ministry of Health and Fondazione Roma and by NOBILE S.p.A. Thanks are also due to REGIONE LAZIO Prot. FILAS-RU-2014 - 1020 (E.A.). [the original article was published in the International Journal of Oncology 49: 437-447, 2016; DOI: 10.3892/ijo.2016.3553].

Balzamino B.O.,Irccs Gb Bietti Foundation | Biamonte F.,Catholic University of the Sacred Heart | Esposito G.,Irccs Gb Bietti Foundation | Marino R.,Biomedical University of Rome | And 3 more authors.
International Journal of Cell Biology | Year: 2014

Both Reelin and Nerve Growth Factor (NGF) exert crucial roles in retinal development. Retinogenesis is severely impaired in E-reeler mice, a model of Reelin deficiency showing specific Green Fluorescent Protein expression in Rod Bipolar Cells (RBCs). Since no data are available on Reelin and NGF cross-talk, NGF and trkANGFR/ p75NTR expression was investigated in retinas from E-reeler versus control mice, by confocal microscopy, Western blotting, and real time PCR analysis. A scattered increase of NGF protein was observed in the Ganglion Cell Layer and more pronounced in the Inner Nuclear Layer (INL). A selective increase of p75NTR was detected in most of RBCs and in other cell subtypes of INL. On the contrary, a slight trend towards a decrease was detected for trkANGFR, albeit not significant. Confocal data were validated by Western blot and real time PCR. Finally, the decreased trkANGFR/ p75NTR ratio, representative of p75NTR increase, significantly correlated with E-reeler versus E-control. These data indicate that NGF-trkANGFR/ p75NTR is affected in E-reeler retina and that p75NTR might represent the main NGF receptor involved in the process. This first NGF-trkANGFR/ p75NTR characterization suggests that E-reeler might be suitable for exploring Reelin-NGF cross-talk, representing an additional information source in those pathologies characterized by retinal degeneration. © 2014 Bijorn Omar Balzamino et al.

Micera A.,Irccs Gb Bietti Foundation | Puxeddu I.,Hebrew University of Jerusalem | Balzamino B.O.,Irccs Gb Bietti Foundation | Bonini S.,Biomedical University of Rome | Levi-Schaffer F.,Hebrew University of Jerusalem
PLoS ONE | Year: 2012

In the conjunctiva, repeated or prolonged exposure to injury leads to tissue remodeling and fibrosis associated with dryness, lost of corneal transparency and defect of ocular function. At the site of injury, fibroblasts (FB) migrate and differentiate into myofibroblasts (myoFB), contributing to the healing process together with other cell types, cytokines and growth factors. While the physiological deletion of MyoFB is necessary to successfully end the healing process, myoFB prolonged survival characterizes the pathological process of fibrosis. The reason for myoFB persistence is poorly understood. Nerve Growth Factor (NGF), often increased in inflamed stromal conjunctiva, may represent an important molecule both in many inflammatory processes characterized by tissue remodeling and in promoting wound-healing and well-balanced repair in humans. NGF effects are mediated by the specific expression of the NGF neurotrophic tyrosine kinase receptor type 1 (trkANGFR) and/or the pan-neurotrophin glycoprotein receptor (p75NTR). Therefore, a conjunctival myoFB model (TGFβ1-induced myoFB) was developed and characterized for cell viability/proliferation as well as αSMA, p75NTR and trkANGFR expression. MyoFB were exposed to acute and chronic NGF treatment and examined for their p75NTR/trkANGFR, αSMA/TGFβ1 expression, and apoptosis. Both NGF treatments significantly increased the expression of p75NTR, associated with a deregulation of both αSMA/TGFβ1 genes. Acute and chronic NGF exposures induced apoptosis in p75NTR expressing myoFB, an effect counteracted by the specific trkANGFR and/or p75NTR inhibitors. Focused single p75NTR and double trkANGFR/p75NTR knocking-down experiments highlighted the role of p75NTR in NGF-induced apoptosis. Our current data indicate that NGF is able to trigger in vitro myoFB apoptosis, mainly via p75NTR. The trkANGFR/p75NTR ratio in favor of p75NTR characterizes this process. Due to the lack of effective pharmacological agents for balanced tissue repairs, these new findings suggest that NGF might be a suitable therapeutic tool in conditions with impaired tissue healing. © 2012 Micera et al.

PubMed | University College London, Biomedical University of Rome and Irccs Gb Bietti Foundation
Type: | Journal: BioMed research international | Year: 2016

Vernal keratoconjunctivitis (VKC) is a chronic recurrent bilateral inflammation of the conjunctiva associated with atopy. Several inflammatory and tissue remodeling factors contribute to VKC disease. The aim is to provide a chip-based protein analysis in tears from patients suffering from quiescent or active VKC.This study cohort included 16 consecutive patients with VKC and 10 controls. Participants were subjected to clinical assessment of ocular surface and tear sampling. Total protein quantification, total protein sketch, and protein array (sixty protein candidates) were evaluated.An overall increased Fluorescent Intensity expression was observed in VKC arrays. Particularly, IL1, IL15, IL21, Eotaxin2, TACE, MIP1, MIP3, NCAM1, ICAM2, NGF, NT4, BDNF, FGF, SCF, MMP1, and MMP2 were increased in quiescent VKC. Of those candidates, only IL1, IL15, IL21, NGF, SCF, MMP2, Eotaxin2, TACE, MIP1, MIP3, NCAM1, and ICAM2 were increased in both active and quiescent VKC. Finally, NT4, FGF, and MMP1 were highly increased in active VKC.A distinct protein tear-print characterizes VKC activity, confirming some previously reported factors and highlighting some new candidates common to quiescent and active states. Those candidates expressed in quiescent VKC might be considered as predictive indicators of VKC reactivation and/or exacerbation out-of-season.

PubMed | Instituto Of Ricerche Farmacologiche Mario Negri, San Giovanni Hospital Complex, St Martino Hospital, University of Rome Tor Vergata and 2 more.
Type: Journal Article | Journal: Advances in therapy | Year: 2016

Primary open angle glaucoma (POAG) is a progressive optic neuropathy characterized by impaired aqueous outflow and extensive remodeling in the trabecular meshwork (TM). The aim of this study was to characterize and compare the expression patterns of selected proteins belonging to the tissue remodeling, inflammation and growth factor pathways in ex vivo glaucomatous and post-mortem TMs using protein-array analysis.TM specimens were collected from 63 white subjects, including 40 patients with glaucoma and 23 controls. Forty POAG TMs were collected at the time of surgery and 23 post-mortem specimens were from non-glaucomatous donor sclerocorneal tissues. Protein profiles were evaluated using a chip-based array consisting of 60 literature-selected antibodies.A different expression of some factors was observed in POAG TMs with respect to post-mortem specimens, either in abundance (interleukin [IL]10, IL6, IL5, IL7, IL12, IL3, macrophage inflammatory protein [MIP]1/, vascular endothelial growth factor [VEGF], transforming growth factor beta 1 [TGF1], soluble tumor necrosis factor receptor I [sTNFRI]) or in scarcity (IL16, IL18, intercellular adhesion molecule 3 [ICAM3], matrix metalloproteinase-7 [MMP7], tissue inhibitor of metalloproteinase 1 [TIMP1]). MMP2, MMP7, TGF1, and VEGF expressions were confirmed by Western blot, zymography, and polymerase chain reaction. No difference in protein profile expression was detected between glaucomatous subtypes.The analysis of this small TM population highlighted some proteins linked to POAG, some previously reported and others of new detection (IL7, MIPs, sTNFRI). A larger POAG population is required to select promising disease-associated biomarker candidates.This study was partially supported by the Fondazione Roma, the Italian Ministry of Health and the National 5xMille 2010 tax donation to IRCCS-G.B. Bietti Foundation.

PubMed | University of Rome La Sapienza, Semmelweis University and Irccs Gb Bietti Foundation
Type: Journal Article | Journal: International journal of immunopathology and pharmacology | Year: 2016

Normal human aging and diabetes are associated with a gradual decrease of cerebral flow in the brain with changes in vascular architecture. Thickening of the capillary basement membrane and microvascular fibrosis are evident in the central nervous system of elderly and diabetic patients. Current findings assign a primary role to endothelial dysfunction as a cause of basement membrane (BM) thickening, while retinal alterations are considered to be a secondary cause of either ischemia or exudation. The aim of this study was to reveal any initial retinal alterations and variations in the BM of retinal capillaries during diabetes and aging as compared to healthy controls. Moreover, we investigated the potential role of vascular endothelial growth factor (VEGF) and pro-inflammatory cytokines in diabetic retina.Transmission electron microscopy (TEM) was performed on 46 enucleated human eyes with particular attention to alterations of the retinal capillary wall and Mller glial cells. Inflammatory cytokines expression in the retina was investigated by immunohistochemistry.Our electron microscopy findings demonstrated that thickening of the BM begins primarily at the level of the glial side of the retina during aging and diabetes. The Mller cells showed numerous cytoplasmic endosomes and highly electron-dense lysosomes which surrounded the retinal capillaries. Our study is the first to present morphological evidence that Mller cells start to deposit excessive BM material in retinal capillaries during aging and diabetes. Our results confirm the induction of pro-inflammatory cytokines TNF- and IL-1 within the retina as a result of diabetes.These observations strongly suggest that inflammatory cytokines and changes in the metabolism of Mller glial cells rather than changes in of endothelial cells may play a primary role in the alteration of retinal capillaries BM during aging and diabetes.

Aloe L.,CNR Institute of Neuroscience | Rocco M.L.,CNR Institute of Neuroscience | Balzamino B.O.,Irccs Gb Bietti Foundation | Micera A.,Irccs Gb Bietti Foundation
Current Neuropharmacology | Year: 2015

Nerve growth factor (NGF) is the firstly discovered and best characterized neurotrophic factor, known to play a critical protective role in the development and survival of sympathetic, sensory and forebrain cholinergic neurons. NGF promotes neuritis outgrowth both in vivo and in vitro and nerve cell recovery after ischemic, surgical or chemical injuries. Recently, the therapeutic property of NGF has been demonstrated on human cutaneous and corneal ulcers, pressure ulcer, glaucoma, maculopathy and retinitis pigmentosa. NGF eye drops administration is well tolerated, with no detectable clinical evidence of systemic or local adverse effects. The aim of this review is to summarize these biological properties and the potential clinical development of NGF. © 2015 Bentham Science Publishers.

Aloe L.,CNR Institute of Neuroscience | Rocco M.L.,CNR Institute of Neuroscience | Balzamino B.O.,Irccs Gb Bietti Foundation | Micera A.,Irccs Gb Bietti Foundation
Journal of Experimental and Clinical Cancer Research | Year: 2016

Recent progress in the Nerve Growth Factor (NGF) research has shown that this factor acts not only outside its classical domain of the peripheral and central nervous system, but also on non-neuronal and cancer cells. This latter observation has led to divergent hypothesis about the role of NGF, its specific distribution pattern within the tissues and its implication in induction as well as progression of carcinogenesis. Moreover, other recent studies have shown that NGF has direct clinical relevance in certain human brain neuron degeneration and a number of human ocular disorders. These studies, by suggesting that NGF is involved in a plethora of physiological function in health and disease, warrant further investigation regarding the true role of NGF in carcinogenesis. Based on our long-lasting experience in the physiopathology of NGF, we aimed to review previous and recent in vivo and in vitro NGF studies on tumor cell induction, progression and arrest. Overall, these studies indicate that the only presence of NGF is unable to generate cell carcinogenesis, both in normal neuronal and non-neuronal cells/tissues. However, it cannot be excluded the possibility that the co-expression of NGF and pro-carcinogenic molecules might open to different consequence. Whether NGF plays a direct or an indirect role in cell proliferation during carcinogenesis remains to demonstrate. © 2016 The Author(s).

PubMed | University of Rome La Sapienza, University of Rome Tor Vergata and Irccs Gb Bietti Foundation
Type: Journal Article | Journal: Journal of biological regulators and homeostatic agents | Year: 2016

The aim of this paper is to study the morphology and the distribution of the monoamine oxidase enzymatic system in the optic nerve of 4 month-old Wistar (young) and 28 month-old Wistar (old) rats. The optic nerve was harvested from 20 young and old rats. The segment of optic nerve was divided longitudinally into two pieces, each 0.1 mm in length. The first piece was used for transmission electron microscopy. The second piece was stained with histochemical reaction for monoamine oxidase. The agerelated changes in the optic nerve of rats include micro-anatomical details, ultrastructure and monoamine oxidase histochemical staining. A strong decrease of the thin nerve fibers and a swelling of the thick ones can be observed in optic nerve fibers of old rats. Increased monoamine oxidase histochemical staining of the optic nerve of aged rats is well demonstrated. The increase of meningeal shealth and the decrease of thin nerve fibers of the optic nerve in old rats are well documented. Morphological, ultrastructural and histochemical changes observed in optic nerve fibers of the old rats show a close relation with aging.

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