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Glioblastoma is a fast‐growing and aggressive form of brain cancer. Even with maximal treatment, patients show a low median survival and are often subjected to a high recurrence incidence. The currently available treatments require multimodal management, including maximal safe surgical resection, followed by radiation and chemotherapy. Because of the infiltrative glioblastoma nature, intraoperative differentiation of cancer tissue from normal brain parenchyma is very challenging, and this accounts for the low rate of complete tumor resection. For these reasons, clinicians have increasingly used various intraoperative adjuncts to improve surgical results, such as fluorescent agents. However, most of the existing fluorophores show several limitations such as poor selectivity, photostability, photosensitization and high costs. This could limit their application to successfully improve glioblastoma resection. In the present perspective, we highlight the possibility to develop next‐generation fluorescent tools able to more selectively label cancer cells during surgical resection. [ABSTRACT FROM AUTHOR]

Glioblastoma (GBM) cancer stem cells (GSCs) contribute to GBM's origin, recurrence, and resistance to treatment. However, the understanding of how mRNA expression patterns of GBM subtypes are reflected at global proteome level in GSCs is limited. To characterize protein expression in GSCs, we performed in‐depth proteogenomic analysis of patient‐derived GSCs by RNA‐sequencing and mass‐spectrometry. We quantified > 10 000 proteins in two independent GSC panels and propose a GSC‐associated proteomic signature characterizing two distinct phenotypic conditions; one defined by proteins upregulated in proneural and classical GSCs (GPC‐like), and another by proteins upregulated in mesenchymal GSCs (GM‐like). The GM‐like protein set in GBM tissue was associated with necrosis, recurrence, and worse overall survival. Through proteogenomics, we discovered 252 non‐canonical peptides in the GSCs, i.e., protein sequences that are variant or derive from genome regions previously considered non‐protein‐coding, including variants of the heterogeneous ribonucleoproteins implicated in RNA splicing. In summary, GSCs express two protein sets that have an inverse association with clinical outcomes in GBM. The discovery of non‐canonical protein sequences questions existing gene models and pinpoints new protein targets for research in GBM. [ABSTRACT FROM AUTHOR]

Femtosecond laser writing is a powerful technique that allows rapid and cost‐effective fabrication of photonic integrated circuits with unique 3D geometries. In particular, the possibility to reconfigure such devices by thermo‐optic phase shifters represents a paramount feature, exploited to produce adaptive and programmable circuits. However, the scalability is strongly limited by the flaws of current thermal phase shifters, which require hundreds of milliwatts to operate and exhibit large thermal crosstalk. In this work, thermally‐insulating 3D microstructures are exploited to decrease the power needed to induce a 2π phase shift down to 37 mW and to reduce the crosstalk to a few percent. Further improvement is demonstrated when operating in vacuum, with sub‐milliwatt power dissipation and negligible crosstalk. These results pave the way toward the demonstration of complex programmable integrated photonic circuits fabricated by femtosecond laser writing, thus opening exciting perspectives in integrated quantum photonics. [ABSTRACT FROM AUTHOR]

This study aimed to assess ex vivo the accuracy of cone‐beam computed tomography (CBCT), as compared to operative microscope, for evaluating pulp chamber size. A total of forty teeth were extracted for periodontal reasons and a horizontal section was done at the most apical level of the cement–enamel junction. The pulp chamber was photographed using a digital camera connected to an optical microscope. Then, the tooth was scanned with CBCT and the horizontal slide matching the anatomical section of pulp chamber was digitally stored. The pulp chamber section area was measured through image analysis software. The two methods provided similar results, either for monoradicular (P = 0.14) or multiradicular teeth (P = 0.93). Correlation was statistically significant (P < 0.0001), being the coefficient r = 0.89 and 0.94 for monoradicular and multiradicular teeth, respectively. Conclusively, CBCT is suitable for pulp chamber morphology evaluation. However, it has limitations in detecting the anatomical variability of small branches in root canal system. [ABSTRACT FROM AUTHOR]

In glioma patients, high levels of glutamate can cause brain edema and seizures. GLAST, a glutamate–aspartate transporter expressed by astrocytes with a role in glutamate uptake, is highly expressed on the plasma membrane of glioblastoma (GBM) cells, and its expression significantly correlates with shortened patient survival. Here, it was demonstrated that inhibition of GLAST expression limited the progression and invasion of GBM xenografts. Magnetic resonance spectroscopy was used to measure glutamate in GLAST‐expressing gliomas showing that these tumors exhibit increased glutamate concentration compared to GLAST‐depleted glioma. Despite their GLAST expression, GBM stem‐like cells (GSCs) released rather than taking up glutamate due to their lack of Na+/K+‐ATPase. Overexpression of Na+/K+‐ATPase in these cells restored glutamate uptake and induced apoptosis. The therapeutic relevance of targeting GLAST in gliomas was assessed using the inhibitor UCPH‐101. In glioma‐bearing mice, a single intratumoral injection of UCPH‐101 significantly increased survival by decreasing GLAST expression and inducing apoptosis. Thus, GLAST has a novel role in GBM that appears to have crucial relevance in glutamate trafficking and may thus be a new therapeutic target. What's new? Increased expression of the cystine/glutamate antiporter xCT is associated with glutamate‐promoted glioblastoma (GBM) invasion into surrounding brain tissue. In this study, GLAST, an astrocyte transporter physiologically devoted to glutamate uptake, was also found to serve a role in GBM aggressiveness. GLAST was highly expressed in GBM specimens and, in association with Na+/K+/ATPase downregulation, exhibited impaired glutamate uptake, resulting in elevated extracellular glutamate levels and GMB cell protection against apoptosis. GLAST inhibition, by contrast, decreased extracellular glutamate, increased GBM cell apoptosis, and prolonged survival in glioma‐bearing mice. The findings provide preliminary background for translational research of GLAST inhibitors. [ABSTRACT FROM AUTHOR]

Abstract: Aim: To evaluate retrospectively the prevalence of vertical root fractures (VRFs) in a cohort of patients during apical surgery and the factors possibly associated with VRF. Methodology: The sample consisted of 944 root filled teeth belonging to 768 patients (49.3% males and 50.7% females; mean age 43.5 ± 11.2 years, range 22–68 years), consecutively referred for endodontic surgery over a six‐year period. All patients underwent a clinical assessment of their signs and symptoms. Periapical radiographs of teeth that were candidates for endodontic surgery were taken. Sixty‐eight teeth with VRF were identified. Vertical root fractures were identified in pre‐surgical screenings in 32 cases (47.1%), and these did not undergo surgery. Another 36 cases of VRF were noted during the intervention for root‐end resection. The influence of posts, post type, tooth type, periodontal probing defects, spontaneous pain, sinus tract and follow‐up duration was assessed using a logistic regression analysis. Results: Vertical root fractures occurred significantly more frequently (P < 0.001) when a post was present (61 VRF out of 377 teeth with post, prevalence 16.2%) than in teeth without a post (1.2%). Threaded posts and cast posts were significantly more involved in VRF than fibre, silica or carbide posts (P < 0.001). Most fractures (80.9%) occurred 1–5 years after root canal treatment. Sinus tracts, probing defects and spontaneous pain were significantly more associated with VRF cases than with nonfractured teeth. Conclusions: In the present group of teeth, the major risk for VRF was represented by posts retained by actively engaging the canal via mechanical design (thread) or by frictional fit (cast). [ABSTRACT FROM AUTHOR]

Glioblastoma is a highly heterogeneous aggressive primary brain tumor, with the glioma stem-like cells ( GSC) being more sensitive to cytotoxic lymphocyte-mediated killing than glioma differentiated cells ( GDC). However, the mechanism behind this higher sensitivity is unclear. Here, we found that the mitochondrial morphology of GSCs modulates the ER-mitochondria contacts that regulate the surface expression of sialylated glycans and their recognition by cytotoxic T lymphocytes and natural killer cells. GSCs displayed diminished ER-mitochondria contacts compared to GDCs. Forced ER-mitochondria contacts in GSCs increased their cell surface expression of sialylated glycans and reduced their susceptibility to cytotoxic lymphocytes. Therefore, mitochondrial morphology and dynamism dictate the ER-mitochondria contacts in order to regulate the surface expression of certain glycans and thus play a role in GSC recognition and elimination by immune effector cells. Targeting the mitochondrial morphology, dynamism, and contacts with the ER could be an innovative strategy to deplete the cancer stem cell compartment to successfully treat glioblastoma. [ABSTRACT FROM AUTHOR]

MYC deregulation is common in human cancer and has a role in sustaining the aggressive cancer stem cell populations. MYC mediates a broad transcriptional response controlling normal biological programmes, but its activity is not clearly understood. We address MYC function in cancer stem cells through the inducible expression of Omomyc-a MYC-derived polypeptide interfering with MYC activity-taking as model the most lethal brain tumour, glioblastoma. Omomyc bridles the key cancer stemlike cell features and affects the tumour microenvironment, inhibiting angiogenesis. This occurs because Omomyc interferes with proper MYC localization and itself associates with the genome, with a preference for sites occupied by MYC. This is accompanied by selective repression of master transcription factors for glioblastoma stemlike cell identity such as OLIG2, POU3F2, SOX2, upregulation of effectors of tumour suppression and differentiation such as ID4, MIAT, PTEN, and modulation of the expression of micro RNAs that target molecules implicated in glioblastoma growth and invasion such as EGFR and ZEB1. Data support a novel view of MYC as a network stabilizer that strengthens the regulatory nodes of gene expression networks controlling cell phenotype and highlight Omomyc as model molecule for targeting cancer stem cells. [ABSTRACT FROM AUTHOR]

Charcot-Marie-Tooth ( CMT) neuropathies are highly heterogeneous disorders caused by mutations in more than 70 genes, with no available treatment. Thus, it is difficult to envisage a single suitable treatment for all pathogenetic mechanisms. Axonal Neuregulin 1 (Nrg1) type III drives Schwann cell myelination and determines myelin thickness by ErbB2/B3- PI3K-Akt signaling pathway activation. Nrg1 type III is inhibited by the α-secretase Tace, which negatively regulates PNS myelination. We hypothesized that modulation of Nrg1 levels and/or secretase activity may constitute a unifying treatment strategy for CMT neuropathies with focal hypermyelination as it could restore normal levels of myelination. Here we show that in vivo delivery of Niaspan, a FDA-approved drug known to enhance TACE activity, efficiently rescues myelination in the Mtmr2−/− mouse, a model of CMT4B1 with myelin outfoldings, and in the Pmp22 +/− mouse, which reproduces HNPP (hereditary neuropathy with liability to pressure palsies) with tomacula. Importantly, we also found that Niaspan reduces hypermyelination of Vim (vimentin)−/− mice, characterized by increased Nrg1 type III and Akt activation, thus corroborating the hypothesis that Niaspan treatment downregulates Nrg1 type III signaling. [ABSTRACT FROM AUTHOR]

Glioblastoma ( GBM) contains stem-like cells ( GSCs) known to be resistant to ionizing radiation and thus responsible for therapeutic failure and rapidly lethal tumor recurrence. It is known that GSC radioresistance relies on efficient activation of the DNA damage response, but the mechanisms linking this response with the stem status are still unclear. Here, we show that the MET receptor kinase, a functional marker of GSCs, is specifically expressed in a subset of radioresistant GSCs and overexpressed in human GBM recurring after radiotherapy. We elucidate that MET promotes GSC radioresistance through a novel mechanism, relying on AKT activity and leading to (i) sustained activation of Aurora kinase A, ATM kinase, and the downstream effectors of DNA repair, and (ii) phosphorylation and cytoplasmic retention of p21, which is associated with anti-apoptotic functions. We show that MET pharmacological inhibition causes DNA damage accumulation in irradiated GSCs and their depletion in vitro and in GBMs generated by GSC xenotransplantation. Preclinical evidence is thus provided that MET inhibitors can radiosensitize tumors and convert GSC-positive selection, induced by radiotherapy, into GSC eradication. [ABSTRACT FROM AUTHOR]

Introduction: Perineural scar formation is responsible for pain and loss of function after surgical procedures. Neurolysis and application of anti-adhesion gels are required to restore a gliding surface. We tested a carboxymethylcellulose (CMC) and polyethylene oxide (PEO) gel on mouse sciatic nerve to describe its safety and efficacy.Methods: Adult mice underwent a surgical procedure in which we burned the muscular bed of the sciatic nerve bilaterally (Burned group) and applied anti-adhesion gel to 1 of the nerves (Burned+gel group). After 3 weeks, we studied scar tissue by biomechanical and histological evaluation.Results: Both histological and biomechanical analysis showed that the gel reduced perineural scarring. The difference between the Burned and Burned+gel groups was statistically significant.Conclusions: CMC-PEO gel can reduce perineural scar tissue. In histological section, scar tissue was present in both groups, but in the Burned+gel group a gliding surface was identified between scar and nerve. [ABSTRACT FROM AUTHOR]

Introduction: Leucocyte telomere length (LTL) is an important determinant of telomere function and cellular replicative capacity. The aim of the present study was to examine prospectively the associations between telomere shortening (TS) and both the progression of atherosclerosis and the incidence of cardiovascular events (CVEs).Materials and Methods: Leucocyte telomere length was measured by quantitative polymerase chain reaction to determine the ratio of telomere length to single-copy gene (T/S) in 768 subjects (462 female and 306 male) enrolled in a large general population survey [the Progressione della Lesione Intimale Carotidea (PLIC study)]. Common carotid artery intima-media thickness was determined at baseline and after 6 years of follow-up, and the associations between TS and the progression of atherosclerosis and incidence of CVEs were evaluated.Results: Mean LTL was 1.25 ± 0.92 T/S (median 1.14) at baseline and 0.70 ± 0.37 T/S (median 0.70) after 6 years of follow-up. Median 6-year LTL change was -0.46 T/S [interquartile range (IQR) -0.57 to 1.06], equating to -0.078 T/S [IQR(-0.092 to 0.176)] per year. Of note, telomere lengthening occurred in 30.4% of subjects. After adjustment for classical cardiovascular disease (CVD) risk factors (age, gender, smoking, physical activity, alcohol consumption, systolic blood pressure, glucose levels, lipid profile and therapies), TS was associated with incident subclinical carotid vascular damage [hazard ratio (HR) 5.19, 95% confidence interval (CI) 1.20-22.4, P = 0.028]. Finally, subjects in whom LTL shortened over time showed an increased risk of incident CVE, compared to those in whom LTL lengthened (HR 1.69, CI 1.02-2.78, P = 0.041).Conclusion: These data indicate that TS is associated with increased risk of subclinical carotid vascular damage and increased incidence of CVEs beyond CVD risk factors in the general population, whereas LTL lengthening is protective. [ABSTRACT FROM AUTHOR]

Background Autonomic nervous system ( ANS) regulation may be altered in functional diseases, including irritable bowel syndrome ( IBS), but published data are not clear to date. The aim of the study was to analyze ANS function in IBS subjects classified by Rome III criteria and healthy controls using standardized technique. Methods ANS activity was evaluated by autoregressive spectral analysis of RR interval and systolic arterial pressure variabilities, to obtain indices of sympatho-vagal modulation of the heart and of spontaneous cardiac baroreflex ( α index). A symptom list was used to score 18 somatic complaints (score 0-180) (4 SQ). Fatigue and stress were assessed through the use of a global scoring index (0-10). Key Results We enrolled 41 IBS subjects (29 F, age 40 ± 2 years) and 42 healthy matched controls. Heart rate was higher in IBS than control subjects (69 ± 2 vs 61 ± 1; p < 0.001). The total variance of RR interval variability, and α index, were significantly lower in IBS compared to controls (1983.12 ± 384.64 ms2 vs 4184.55 ± 649.59 ms2; 18.1 ± 2 ms/mmHg vs 29 ± 3 ms/mmHg; p < 0.01). The α index results showed an inverse correlation with stress scores and somatic symptoms. Conclusions & Inferences IBS subjects display a significant reduction in α index, an established marker of cardiac baroreflex. ANS dysfunction appears to be involved in the pathophysiology of IBS and its assessment may open new perspectives for clinical management of patients suffering from IBS. [ABSTRACT FROM AUTHOR]

The increasing use of commercially available acellular dermis matrices for postmastectomy breast reconstruction seems to have simplified the surgical procedure and enhanced the outcome. These materials, generally considered to be highly safe or with only minor contraindications due to the necessary manipulation in preparatory phases, allow an easier one-phase surgical procedure, in comparison with autologous flaps, offering a high patient satisfaction. Unfortunately, the claimfor a higher rate of complications associated with irradiation at the implant site, especially when the radiation therapy was given before the reconstructive surgery, suggested a careful behaviour when this technique is preferred. However, this hypothesis was never submitted to a crucial test, and data supporting it are often discordant or incomplete. To provide a comprehensive analysis of the field, we searched and systematically reviewed papers published after year 2005 and registered clinical trials. On the basis of a meta-analysis of data, we conclude that the negative effect of the radiotherapy on the breast reconstruction seems to be evident even in the case of acellular dermis matrices aided surgery. However, more trials are needed to make solid conclusions and clarify the poor comprehension of all the factors negatively influencing outcome. [ABSTRACT FROM AUTHOR]

Study Type - Therapy (case series) Level of Evidence 4 What's known on the subject? and What does the study add? Mesothelioma of the tunica vaginalis testis is a rare tumour. From 2000 to 2010, 13 mesothelioma of the tunica vaginalis testis cases were reported in the most populated and industrialized region in Italy. Asbestos exposure was documented in two-thirds of these cases. OBJECTIVE To describe cases of mesothelioma of the tunica vaginalis testis (MTVT) recorded in the Lombardy Mesothelioma Registry between 2000 and 2010., METHODS The Lombardy Mesothelioma Registry, established in 2000, collects data regarding all incident cases of mesothelioma of the pleura, peritoneum, pericardium and tunica vaginalis testis that have been diagnosed in the population of the Lombardy region., These data include a detailed clinical report and a complete occupational history for each MTVT patient, with the latter including details of the industrial sector involved, the patient's job, and the specific tasks performed. To address the potential for asbestos exposure outside the work environment, the residential history, lifestyle habits and hobbies of the patient, as well as job information for all subjects living with the patient, are also collected., Records were reviewed and discussed by a panel of experts., RESULTS Thirteen cases of MTVT were reported between 2000 and 2010., The age-standardized incidence rate of MTVT for the Lombardy region of Italy is 0.2 cases per million individuals/year., Asbestos exposure was documented in 8 of the 12 (67%) interviewed cases., CONCLUSIONS Asbestos exposure was associated with a higher proportion of MTVT cases than previously reported in the literature. These results confirm the aetiological role for asbestos in the pathogenesis of MTVT., The results of this study also highlight the importance of obtaining detailed occupational histories and lifestyle habits from patients, particularly by trained interviewers. [ABSTRACT FROM AUTHOR]

F. Orzan, S. Pellegatta, P. L. Poliani, F. Pisati, V. Caldera, F. Menghi, D. Kapetis, C. Marras, D. Schiffer and G. Finocchiaro (2011) Neuropathology and Applied Neurobiology 381-394 ? Proteins of the Polycomb repressive complex 2 (PRC2) are epigenetic gene silencers and are involved in tumour development. Their oncogenic function might be associated with their role in stem cell maintenance. The histone methyltransferase Enhancer of Zeste 2 ( EZH2) is a key member of PRC2 function: we have investigated its expression and function in gliomas. EZH2 expression was studied in grade II-IV gliomas and in glioma stem?like cells (GSC) by quantitative PCR and immunohistochemistry. Effects of EZH2 down?regulation were analysed by treating GSC with the histone deacetylase (HDAC) inhibitor suberoylanide hydroxamic acid (SAHA) and by shRNA. DNA microarray analysis showed that EZH2 is highly expressed in murine and human GSC. Real?time PCR on gliomas of different grade ( n?=?66) indicated that EZH2 is more expressed in glioblastoma multiforme (GBM) than in low?grade gliomas ( P?=?0.0013). This was confirmed by immunohistochemistry on an independent set of 106 gliomas. Treatment with SAHA caused significant up?regulation of PRC2 predicted target genes, GSC disruption and decreased expression of EZH2 and of the stem cell marker CD133. Inhibition of EZH2 expression by shRNA was associated with a significant decrease of glioma proliferation. The data suggest that EZH2 plays a role in glioma progression and encourage the therapeutic targeting of these malignancies by HDAC inhibitors. [ABSTRACT FROM AUTHOR]

Melanoma-associated peptides recognized by cytolytic T lymphocytes (CTL) in the context of several histocompatibility leukocyte antigens (HLA) are required for the development of specific immunotherapies. Using a transient transfection assay into COS-7 cells, we identified the gp100/pMel17 melanosomal protein as the shared antigen recognized by three independent CD8+ CTL clones in HLA-A*6801-restricted fashion. This finding was confirmed by the correlation between lack of gp100/pMel17 protein in a number of HLA-A*6801-positive melanomas and their resistance to lysis/cytokine production by the specific effectors. The gp100/pMel17 antigenic epitope was identified based on recognition of subfragments and on a computer-based prediction algorithm. Among a panel of gp100/pMel17-derived synthetic peptides only the 10-mer HTMEVTVYHR (gp100/pMel17182-191 ) induced tumor necrosis factor (TNF) release by CTL clones when pulsed on suitable target cells whereas both the 10-mer and the shorter 9-mer gp100/pMel17183-191 sensitized the same antigen-pulsed cells to lysis. In conclusion, the identification of the HTMEVTVYHR peptide will extend to HLA-A*6801 melanoma patients the possibility to exploit gp100/pMel17 melanosomal protein for experimental and clinical studies. [ABSTRACT FROM AUTHOR]

Facial lipoatrophy is one of the most difficult complication in the patients with lupus profundus. In this paper, we present a case of a 55-year-old woman affected by lupus profundus, with a grade V lipoatrophy, treated with lipofilling technique. No complications were observed and results at 12 months were stable, natural, and symmetric. [ABSTRACT FROM AUTHOR]