Improving treatment of glioblastoma: new insights in targeting cancer stem cells effectively

Glioblastoma is the most common primary malignant brain tumour in the adult population. Despite multimodality treatment with surgery, radiotherapy and chemotherapy, outcomes are very poor, with less than 15% of patients alive after two years. Increasing evidence suggests that glioblastoma stem cells (GSCs) are likely to play an important role in the biology of this disease and are involved in treatment resistance and tumour recurrence following standard therapy. My thesis aims to address two main aspects of this research area: 1) optimization of methods to evaluate treatment responses of GSCs and their differentiated counterparts (non-GSCs), with a particular focus on a tissue culture model that resembles more closely the tumoral niche; 2) characterization of cell division and centrosome cycle of GSCs, investigating possible differences between these cells and non-GSCs, that would allow the identification of targets for new therapeutic strategies against glioblastomas. In the first part of my project, I optimized a clonogenic survival assay, to compare sensitivity of GSCs and non-GSCs to various treatments, and I developed the use of a 3-dimentional tissue culture system, that allows analysis of features and radiation responses of these two subpopulations in the presence of specific microenvironmental factors from the tumoral niche. In the second part, I show that GSCs display mitotic spindle abnormalities more frequently than non-GSCs and that they have distinctive features with regards to the centrosome cycle. I also demonstrate that GSCs are more sensitive than non-GSCs to subtle changes in Aurora kinase A activity, which result in a rapid increase in polyploidy and subsequently in senescence, with a consistent reduction in clonogenic survival. Based on these findings, I propose that kinases involved in the centrosome cycle need to be explored as a novel strategy to target GSCs effectively and improve outcomes of glioblastoma patients

A review of the role of ultrasound biomicroscopy in glaucoma associated with rare diseases of the anterior segment

Ultrasound biomicroscopy is a non-invasive imaging technique, which allows high-resolution evaluation of the anatomical features of the anterior segment of the eye regardless of optical media transparency. This technique provides diagnostically significant information in vivo for the cornea, anterior chamber, chamber angle, iris, posterior chamber, zonules, ciliary body, and lens, and is of great value in assessment of the mechanisms of glaucoma onset. The purpose of this paper is to review the use of ultrasound biomicroscopy in the diagnosis and management of rare diseases of the anterior segment such as mesodermal dysgenesis of the neural crest, iridocorneal endothelial syndrome, phakomatoses, and metabolic disorders

Pharmacogenetics of type 2 diabetes mellitus, the route toward tailored medicine

Type 2 diabetes mellitus (T2DM) is a chronic disease that has reached the levels of a global epidemic. In order to achieve optimal glucose control, it is often necessary to rely on combination therapy of multiple drugs or insulin because uncontrolled glucose levels result in T2DM progression and enhanced risk of complications and mortality. Several antihyperglycemic agents have been developed over time, and T2DM pharmacotherapy should be prescribed based on suitability for the individual patient's characteristics. Pharmacogenetics is the branch of genetics that investigates how our genome influences individual responses to drugs, therapeutic outcomes, and incidence of adverse effects. In this review, we evaluated the pharmacogenetic evidences currently available in the literature, and we identified the top informative genetic variants associated with response to the most common anti-diabetic drugs: metformin, DPP-4 inhibitors/GLP1R agonists, thiazolidinediones, and sulfonylureas/meglitinides. Overall, we found 40 polymorphisms for each drug class in a total of 71 loci, and we examined the possibility of encouraging genetic screening of these variants/loci in order to critically implement decision-making about the therapeutic approach through precision medicine strategies. It is possible then to anticipate that when the clinical practice will take advantage of the genetic information of the diabetic patients, this will provide a useful resource for the prevention of T2DM progression, enabling the identification of the precise drug that is most likely to be effective and safe for each patient and the reduction of the economic impact on a global scale

Ultrabiomicroscopy anterior segment evaluation of ocular contusive trauma caused by pressurized bottled drink caps. a case report

We report the case of a patient presented to the emergency department because of a contu-sive trauma from a pressurized bottled drink cap. During the visit, the patient indicated that he had been hit in his left eye by a cork while he was opening a sparkling wine bottle. He underwent a total ophthalmology examination. He had an important reduction of visual acuity, corneal swelling, Descemet’s folds, and hyphema. Therefore, we decided to perform ultrabio-microscopy (UBM) of the anterior segment to study the endothelial damage and Descemet’s membrane. UBM images confirmed the direct biomicroscopy, highlighting the damaged loca-tion

Ocriplasmin in the treatment of vitreomacular traction in a patient with central retinal vein occlusion. a case report

Aim: To investigate the efficacy of intravitreal injection of ocriplasmin (JETREA®) in the treat-ment of vitreomacular traction (VMT). Materials and Methods: An 81-year-old man with VMT associated with central retinal vein occlusion in his left eye, was treated with a single intravitreal injection of ocriplasmin (25 μg). Best corrected visual acuity (BCVA), ocular fundus, and optical coherence tomography were examined before and after treatment. Results: Complete release of VMT produced a reduction of central macular thickness, ranging from 459 to 141 μm. BCVA remained stable. Discussion and Conclusions: The use of ocriplasmin was effective in the treatment of VMT. Ocriplasmin represents a valid alternative to conventional pars plana vitrec-tomy

I graffiti preistorici paleolitici della “Zà Minica” in territorio di Torretta (Palermo)

L’autore riassume i risultati alla Zà Minica (zia Domenica) in territorio di Torretta, provincia di Palermo; dà una lista della fauna pleistocenica proveniente da uno scavo, poi si sofferma sulla scoperta di una figura di Bos primigenius graffita nella grotta. Descrive la vicina nicchia omonima, ricorda l’incisione di un cervo trafitto da zagaglie, le incisioni lineari e due soggetti dipinti già noti, si sofferma a descrivere un nuovo gruppo d’incisioni lineari. Auspica di trasmettere entusiasmo per altre ricerche e di aver notizia di nuove scoperte.The author sums up the results of research carried out at the cave of Zà Minica (aunt Domenica) in the territory of Torretta; Province of Palermo. An account of the remains of Pleistocene fauna recovered during excavation at the site is given, it is followed by a description of the engraved image of an aurochs Bos primigenius discovered on the walls of the cave. The author goes on to describe the nearby homonymous rockshelter with its rock art portraying a speared red deer, linear engravings and two figures, which had been published previously. A group of unpublished linear engravings is presented in detail. He hopes that this paper will encourage new research and discoveries

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Del lemma sono forniti etimologia, definizioni, generalità storico-architettoniche e informazioni correlate (derivazione, eventuale processo formativo, filoni tipologici, tipi distributivi e funzionali ecc.), esempi, bibliografia essenziale di riferimento

Differential sensitivity of Glioma stem cells to Aurora kinase A inhibitors: implications for stem cell mitosis and centrosome dynamics

Glioma stem-cell-like cells are considered to be responsible for treatment resistance and tumour recurrence following chemo-radiation in glioblastoma patients, but specific targets by which to kill the cancer stem cell population remain elusive. A characteristic feature of stem cells is their ability to undergo both symmetric and asymmetric cell divisions. In this study we have analysed specific features of glioma stem cell mitosis. We found that glioma stem cells appear to be highly prone to undergo aberrant cell division and polyploidization. Moreover, we discovered a pronounced change in the dynamic of mitotic centrosome maturation in these cells. Accordingly, glioma stem cell survival appeared to be strongly dependent on Aurora A activity. Unlike differentiated cells, glioma stem cells responded to moderate Aurora A inhibition with spindle defects, polyploidization and a dramatic increase in cellular senescence, and were selectively sensitive to Aurora A and Plk1 inhibitor treatment. Our study proposes inhibition of centrosomal kinases as a novel strategy to selectively target glioma stem cells