Numb Isoforms Deregulation in Medulloblastoma and Role of p66 Isoform in Cancer and Neural Stem Cells

Numb is an intracellular protein with multiple functions. The two prevalent isoforms, Numb p66 and Numb p72, are regulators of differentiation and proliferation in neuronal development. Additionally, Numb functions as cell fate determinant of stem cells and cancer stem cells and its abnormal expression has been described in several types of cancer. Involvement of deregulated Numb expression has been described in the malignant childhood brain tumor medulloblastoma, while Numb isoforms in these tumors and in cancer stem-like cells derived from them, have not been studied to date. Here we show that medulloblastoma stem-like cells and cerebellar neuronal stem cells (NSCs) express Numb p66 where its expression tampers stemness features. Furthermore, medulloblastoma samples evaluated in this study express decreased levels of Numb p66 while overexpressed Numb p72 compared with normal tissues. Our results uncover different roles for the two major Numb isoforms examined in medulloblastoma and a critical role for Numb p66 in regulating stem-like cells and NSCs maintenance

FSTL5 expression is a marker of Group C metastatic medulloblastomas

INTRODUCTION: Medulloblastoma (MB) is the most commonmalignant brain tumor in children. Four different molecular subgroups are recognized, which differ in gene expression, genomic aberrations, histology, demographics and survival:WNT and SHH groups, having specific mutations in the homonymous pathway, and groups C and D having several genetic alternations not specific to a single pathway. The gene for follistatin-like protein 5, FSTL5, is overexpressed in nonSHH/nonWNT MBs poorly characterized. Highexpression of FSTL5 is significantly associated with reduced event-free and overall survival in non-WNT/non-SHHMBs. The major aim of this project is to study the FSTL5 expression level in pediatric MBs with metastasis at the onset. METHOD: We investigated the protein expression of biomarkers involved in metastatic pathways by IHC and FSTL5 expression level by RT-PCR in 26 metastatic MBs samples and correlated these data with the outcomes by Kaplan-Meier statistic analysis. RESULTS: 83% of Group C MBs showed high level of FSTL5 while none of these presented down-expression. Low-expression level of FSTL5 was find in 60% of SHH MBs and none showed over-expression. Kaplan-Meier test revealed that, in our cohort, highexpression ofFSTL5didnot correlatewithworse outcomewhile lowexpression of FSTL5 was associated with good prognosis and the co-presence of FSTL5 with other biomarkers correlated with poorer prognosis. CONCLUSION: FSTL5 is a marker of Group C in medulloblastomas with metastasis at the onset and the results highlighted decreased FSTL5 expression as a marker of good prognosis. Group C MBs have characteristic molecular features that confirm the poorest outcome also inMBs with metastasis at the onset

In Memory of Valeria Manetto (1953–1995)

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Application of the EGM Method to a LED-Based Spotlight: A Constrained Pseudo-Optimization Design Process Based on the Analysis of the Local Entropy Generation Maps

In this paper, the entropy generation minimization (EGM) method is applied to an industrial heat transfer problem: the forced convective cooling of a LED-based spotlight. The design specification calls for eighteen diodes arranged on a circular copper plate of 35 mm diameter. Every diode dissipates 3 W and the maximum allowedtemperature of the plate is 80 °C. The cooling relies on the forced convection driven by a jet of air impinging on the plate. An initial complex geometry of plate fins is presented and analyzed with a commercial CFD code that computes the entropy generation rate. A pseudo-optimization process is carried out via a successive series of design modifications based on a careful analysis of the entropy generation maps. One of the advantages of the EGM method is that the rationale behind each step of the design process can be justified on a physical basis. It is found that the best performance is attained when the fins are periodically spaced in the radial direction

Intramedullary gangliogliomas: histopathologic and molecular features of 25 cases

Gangliogliomas are uncommon glioneuronal tumors, which usually arise in the cerebral hemispheres and occasionally in the brain stem. Gangliogliomas occurring in the spinal cord are extremely rare. In this study, we analyzed the clinical, histopathologic, and molecular features of 25 spinal gangliogliomas. The cases included in our series affected mostly children and young adults (15 males and 10 females; mean age, 20 years; median age, 14 years; age range, 1-72 years) and were predominantly localized in the cervical and thoracic spine. From the clinical point of view (detailed follow-up available for 9 pediatric cases; mean follow-up: 2 years 10 months; range, 3 months to 5 years 10 months), most patients showed stable disease after subtotal resection. Radiotherapy was rarely used as adjuvant treatment. Histologically, gangliogliomas (WHO grade I) (21 cases) showed features largely similar to their supratentorial counterparts. Anaplastic gangliogliomas (World Health Organization grade III) (4 cases) showed features of anaplasia (including high cellularity and increased mitotic and proliferation activity). From a molecular point of view, only 2 tumors (2/19, 11%) harbored a BRAFV600E mutation. In conclusion, although spinal gangliogliomas display histologic and clinical features similar to their supratentorial counterparts, they show a relatively low frequency of BRAFV600E mutations, alteration otherwise common in hemispheric and brain stem gangliogliomas

Giardia and Cryptosporidium and public health: the epidemiological scenario from the Italian perspective

Giardia and Cryptosporidium spp. are protozoa that cause human and animal disease worldwide and often exhibit zoonotic transmission. This review gives ample information concerning the epidemiology of these parasites in Italy, i.e. prevalence data in humans, farm and pet animals, shellfish and aquatic environment. Moreover, it reports genotyping results obtained from different isolates, with particular emphasis on the spread of host-specific and zoonotic species/genotypes of various origin, and on molecular data that make the Italian situation different from that of other countries. Finally, possible explanations are given for the infrequent reports of Giardia and Cryptosporidium spp. outbreaks, despite widespread faecal contamination by these parasites

Transdural Spread of Glioblastoma with Endonasal Growth in a Long-Term Survivor Patient: Case Report and Literature Review.

Glioblastoma (GBM) is the most aggressive primary tumor of the central nervous system (CNS) in adults. Its growth has been always described as locally invasive. This tumor rarely penetrates dura mater and invades extracranial structures. We present a case of GBM, which occurred in a 39-year-old man, with final involvement of the nasal cavity. The patient was operated four times in three years, and a personalized adjuvant chemotherapy regimen was administered in a neo-adjuvant fashion. Histopathological features of the tumor are described. To our knowledge, there are only 9 cases reported in the literature showing this growth pattern and the last case was reported in 1998

Hyperfractionated radiotherapy and chemotherapy for chidhood ependymoma: final results of the first prospective AIEOP (Associazione Italiana di Ematologia-Oncologia pediatrica) study

Purpose: A postsurgical “stage-based” protocol for ependymoma was designed. Methods and Materials: Children were given: (1) focal hyperfractionated radiotherapy (HFRT) if with no evidence of disease (NED), or (2) 4 courses with VEC followed by HFRT for residual disease (ED). HFRT dose was 70.4 Gy (1.1 Gy/fraction b.i.d.); VEC consisted of VCR 1.5 mg/m2 1/w, VP16 100 mg/m2/day 3, CTX 3 g/m2 d 1. When feasible, second-look surgery was recommended. Results: Sixty-three consecutive children were enrolled: 46 NED, 17 ED; the tumor was infratentorial in 47 and supratentorial in 16, with spinal metastasis in 1. Of NED patients, 35 of 46 have been treated with HFRT; 8 received conventionally fractionated radiotherapy, and 3 received no treatment. Of the 17 ED patients, 9 received VEC HFRT; violations due to postsurgical morbidity were as follows: HFRT only (2), conventionally fractionated radiotherapy (3) VEC (2), and no therapy (1). Objective responses to VEC were seen in 54%; objective responses to RT were seen in 75%. Overall survival and progression-free survival at 5 years for all 63 children were 75% and 56%, respectively; for the NED subgroup, 82% and 65%; and for the ED subgroup, 61% and 35%, respectively. All histologies were centrally reviewed. At multivariate analysis, grading, age, and site proved significant for prognosis. Conclusions: HFRT, despite the high total dose adopted, did not change the prognosis of childhood ependymoma as compared to historical series: New radiotherapeutic approaches are needed to improve local control. Future ependymoma strategies should consider grading when stratifying treatment indications

Surrogate models for the prediction of the aerodynamic performance of exhaust systems

The aerodynamic performance of the exhaust system is becoming more important in the design of engines for civil aircraft applications. To increase propulsive efficiency and reduce specific fuel consumption, it is expected that future engines will operate with higher bypass ratios, lower fan pressure ratios and lower specific thrust. At these operating conditions, the net thrust and the specific fuel consumption are more sensitive to losses in the exhaust. Thus the performance of the exhaust needs to be accurately assessed as early as possible during the design process. This research investigates low-order models for the prediction of the performance of separate-jet exhaust systems, as a function of the free-stream Mach number, the fan nozzle pressure ratio and the extraction ratio (fan to core pressure ratio). In the current practice the two nozzles are typically considered in isolation and the performance is modelled as a function of their pressure ratio. It is shown that the additional degrees of freedom have a substantial impact on the metrics describing the performance of the exhaust system. These models can be employed at a preliminary design stage coupled with engine performance models, which require as input the characteristics of the exhaust system. Two engines, which are representative of current and future large turbofan architectures are studied. The low-order models investigated, generalized Kriging and radial basis functions, are constructed based on data obtained with computational fluid dynamics simulations. The data represents the characteristics of the exhaust of each engine, and they are provided for the first time for a wide operational envelope. The influence on accuracy of the type of surragate model and its settings have been quantified. Furthermore, the trade-off between the accuracy of the model and the number of samples has been identified. It is found that the exhaust performance metrics can be modelled using a low-order model with sufficient accuracy. Recommendations on the best settings of the model are also provided