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This paper outlines the initial development of a novel magnetohydrodynamic (MHD) plasma control sys- tem which aims at mitigating shock-induced heating and the radio-frequency communication blackout typically encountered during (re-)entry into planetary atmospheres. An international consortium com- prising universities, SMEs, research institutions, and industry has been formed in order to develop this technology within the MEESST project. The latter is funded by the Future and Emerging Technologies (FET) program of the European Commission’s Horizon 2020 scheme (grant no. 899298). Atmospheric en- try imposes one of the harshest environments which a spacecraft can experience. The combination of hypersonic velocities and the rapid compression of atmospheric particles by the spacecraft leads to high- enthalpy, partially ionised gases forming around the vehicle. This inhibits radio communications and in- duces high thermal loads on the spacecraft surface. For the former problem, spacecraft can sometimes rely on satellite constellations for communicating through the plasma wake and therefore preventing the blackout. On the other hand, expensive, heavy, and non-reusable thermal protection systems (TPS) are needed to dissipate the severe thermal loads. Such TPS can represent up to 30% of an entry vehicles weight, and especially for manned missions they can reduce the cost- efficiency by sacrificing payload mass. Such systems are also prone to failure, putting the lives of astronauts at risk. The use of electro- magnetic fields to exploit MHD principles has long been considered as an attractive solution for tackling the problems described above. By pushing the boundary layer of the ionized gas layer away from the spacecraft, the thermal loads can be reduced, while also opening a magnetic window for radio com- munications and mitigating the blackout phenomenon. The application of this MHD-enabled system has previously not been demonstrated in realistic conditions due to the required large magnetic fields (on the order of Tesla or more), which for conventional technologies would demand exceptionally heavy and power-hungry electromagnets. High-temperature superconductors (HTS) have reached a level of industrial maturity sufficient for them to act as a key enabling technology for this application. Thanks to superior current densities, HTS coils can offer the necessary low weight and compactness required for space ap- plications, with the ability to generate the strong magnetic fields needed for entry purposes. This paper provides an overview of the MEESST project, including its goals, methodology and some preliminary de- sign considerations. ispartof: The Journal of Space Safety Engineering vol:10 issue:1 pages:27-34 status: published

Objectives Cerebral hyaline protoplasmic astrocytopathy (HPA) is a clinicopathologic entity characterized by eosinophilic cytoplasmic inclusions within astrocytes. It has been observed in a subset of patients with early-onset epilepsy, brain malformations, and developmental delay. The exact association of this entity with epilepsy is still unknown. This report, with its review of the literature, aims to summarize HPA features to raise awareness regarding this entity. Methods We report on 2 HPA cases and critically review the literature. Results Approximately 42 cases of HPA have been reported, including the 2 cases presented here, consisting of 23 female and 19 male patients. Patient age ranged from 3 to 39 years. All patients had early-onset seizures (3-20 months of age), ranging from partial to generalized, that were refractory despite treatment with antiepileptic drugs. Postoperative follow-up intervals ranged from 2 to 93 months, and the clinical outcome was graded according to the Engel classification, showing variable results. Conclusions Clinicians should consider HPA in differential diagnosis in patients with intractable seizures, especially when they are associated with developmental delay and brain malformations. Increasing awareness of this entity among pathologists may promote better understanding of this condition as well as better diagnosis and treatment for these patients.

During the atmospheric entry phase at hypersonic speed, the radio communication from/to a space vehicle can be disrupted due to the formation of a plasma sheath within the surrounding flow field. In order to characterize such communication blackout phases, this work presents a numerical methodology combining Computational Fluid Dynamic (CFD) simulations of ionized chemically reacting entry flows by means of Computational Object-Oriented Libraries for Fluid Dynamics (COOLFluiD) and a ray tracing analysis by means of the newly developed BlackOut RAy Tracer (BORAT). The latter is based on the numerical solution of the 3D Eikonal system of equations, offering a fast, efficient and accurate method to analyse the interaction between electromagnetic signals and weakly ionised plasmas. The proposed methodology, and BORAT in particular, is first verified on popular benchmark cases and then used to analyse the European Space Agency (ESA) 2016 ExoMars Schiaparelli entry flight into Martian environment. The corresponding results demonstrate the validity of the proposed ray tracing approach for predicting communication blackout, where signals emitted from the on-board antenna undergo reflection and refraction from the plasma surrounding the entry vehicle, and the advantage of a 3D approach for analysing real flight configuration. ispartof: Computer Physics Communications vol:286 status: published

Presentation at the Congress on "Safety and quality of milk and dairy products. Technical and legal aspects" organized by the Veterinary Medicine Association of the province of Salerno, held in Battipaglia (SA), Italy,on the 14 of April2023

Increasing fuel and electricity prices create high pressure to develop efficient external aerodynamics of road cars. At the same time, development cycles are getting shorter to meet changing customer preferences while physical testing capacities remain limited, creating a pressing need for fast and accurate turbulence models to predict aerodynamic performance.This paper introduces and discusses different turbulence modelling approaches beyond the well-known and established models used today in the industry. The RANS Lag Elliptic Blending (Lag EB) k − ϵ model, which enables highly accurate steady-state RANS, was chosen as the baseline approach. As a medium fidelity approach Scale-Resolving Hybrid (SRH) model was utilized, which modifies a RANS base model to produce a smooth transition between URANS and LES behavior. The Wall-Modelled LES (WMLES) method was chosen for high fidelity simulations.To validate the presented models, a detailed set of experimental data from the 3rd Automotive CFD Prediction Workshop was utilized. Simulations were run on the grid provided for the workshop; in addition, a reviewed volume mesh was utilized. The numerical results of the aforementioned turbulence models are discussed against experimental results of the DrivAer baseline case and its variant with front wheel deflectors. In addition to force coefficients, flow field visualizations are available, providing additional insights.The simulations show an excellent agreement for the Lag EB runs with the experimental data for the baseline model in terms of drag prediction. Scale-resolving simulations require appropriate numerical set-up for accurate drag prediction. The impact of the front wheel deflector on drag is consistently predicted by all three methods.

Introduzione al volume.

Atypical teratoid/rhabdoid tumor (AT/RT) is a highly aggressive embryonal CNS neoplasm, characterized by inactivation of SMARCB1 (INI1) or rarely of SMARCA4 (BRG1). While it is predominantly a childhood tumor, AT/RT is rare in adults.We provide a comprehensive systematic review of literature with meta-analysis; 92 adult cases were found from 74 articles. We additionally present 4 cases of adult AT/RTs (age ranging from 19 to 29 years), located to cerebellum in 2 cases, to ponto-cerebellar angle in 1 case and to spinal cord in the remaining case.Microscopic features of our 4 cases showed a highly cellular tumor with rhabdoid morphology and high mitotic activity. All tumor cells lacked nuclear SMARCB1/INI1 protein expression. In case no. 3 we also performed methylation profiling which clustered the tumor with pediatric AT/RT-MYC subgroup. Prognosis remains poor in both pediatric and adult population with a median overall survival of 11 months. Our review demonstrated median overall survival of 15 months among the adult populations. However, consistent with a recent review, adult AT/RT seems to have highly variable prognosis and some patients reach long term survival with 22.9% of 5-year survival without evidence of disease and mean follow up time of 35.9 months (SD = 36.5). 27.1% of dissemination was also reported among the adult population.Adult AT/RTs predominantly arise in female patients and in supratentorial location. Midline structures, including the sellar region, are the most affected sites, especially among females aged40 years. Male gender is more prevalent between the age of 18 and 40 years and more frequently associated with non-midline tumors. Factors significantly associated with better prognosis are patient's age ( 40 years), combined radio-chemotherapy adjuvant approach and Ki-67 score 40%.

An extended version of the synthetic eddy method for generation of synthetic turbulence has been developed via a source term formulation and implemented in the open-source cross-platform solver PyFR. The method caters for the full space-dependent anisotropy of the target turbulent length scales, and it is agnostic of the space and time discretization of the underlying solver, which can be incompressible or compressible. Moreover, the method does not require each solution point to communicate with nearest neighbors; thus, it is well suited for modern, massively parallel, high-order unstructured codes which support mixed and possibly curved elements. The method has been applied to two test cases: incompressible plane channel flow at Reτ 180 and compressible flow over an SD7003 aerofoil at Re 66;000, Ma 0.2, and α 4 deg. The channel flow case was run on three topologically different meshes composed of hexahedra, prisms, and a combination of prisms and tetrahedra, respectively. Almost identical results have been obtained on the three meshes. Results also show that taking into account the anisotropy of the turbulent length scales can reduce the development length. For the SD7003 aerofoil case, the injection of synthetic turbulence improves agreement between numerical and experimental results.

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Medulloblastoma is the most frequent malignant childhood brain tumor with a high morbidity. Identification of new therapeutic targets would be instrumental in improving patient outcomes. We evaluated the expression of the tumor-associated antigen PRAME in biopsies from 60 patients with medulloblastoma. PRAME expression was detectable in 82% of tissues independent of molecular and histopathologic subgroups. High PRAME expression also correlated with worse overall survival. We next investigated the relevance of PRAME as a target for immunotherapy. Medulloblastoma cells were targeted using genetically modified T cells with a PRAME-specific TCR (SLL TCR T cells). SLL TCR T cells efficiently killed medulloblastoma HLA-A*02+ DAOY cells as well as primary HLA-A*02+ medulloblastoma cells. Moreover, SLL TCR T cells controlled tumor growth in an orthotopic mouse model of medulloblastoma. To prevent unexpected T-cell–related toxicity, an inducible caspase-9 (iC9) gene was introduced in frame with the SLL TCR; this safety switch triggered prompt elimination of genetically modified T cells. Altogether, these data indicate that T cells genetically modified with a high-affinity, PRAME-specific TCR and iC9 may represent a promising innovative approach for treating patients with HLA-A*02+ medulloblastoma.Significance: These findings identify PRAME as a medulloblastoma tumor-associated antigen that can be targeted using genetically modified T cells. Cancer Res; 78(12); 3337–49. ©2018 AACR.

BackgroundAccurate identification of brain tumour molecular subgroups is increasingly important. We aimed to establish the most accurate and reproducible ependymoma subgroup biomarker detection techniques, across 147 cases from International Society of Pediatric Oncology (SIOP) Ependymoma II trial participants, enrolled in the pan-European “Biomarkers of Ependymoma in Children and Adolescents (BIOMECA)” study.MethodsAcross six European BIOMECA laboratories we evaluated epigenetic profiling (DNA methylation array); immunohistochemistry (IHC) for nuclear p65-RELA, H3K27me3, and Tenascin-C; copy number analysis via FISH and MLPA (1q,CDKN2A), and MIP and DNA methylation array (genome-wide copy number evaluation); analysis ofZFTA-andYAP1-fusions by RT-PCR and sequencing, Nanostring and break-apart FISH.ResultsDNA Methylation profiling classified 65.3% (n=96/147) of cases as EPN-PFA and 15% (n=22/147) as ST-ZFTA fusion-positive. Immunohistochemical loss of H3K27me3 was a reproducible and accurate surrogate marker for EPN-PFA (sensitivity 99-100% across three centres). IHC for p65-RELA, FISH, and RNA-based analyses effectively identifiedZFTA-andYAP1-fused supratentorial ependymomas. Detection of 1q gain using FISH exhibited only 57% inter-centre concordance and low sensitivity and specificity whilst MIP, MLPA and DNA methylation-based approaches demonstrated greater accuracy.ConclusionsWe confirm, in a prospective trial cohort, that H3K27me3 immunohistochemistry is a robust EPN-PFA biomarker. Tenascin-C should be abandoned as a PFA marker. DNA methylation and MIP arrays are effective tools for copy number analysis of 1q gain, 6q andCDKN2Aloss whilst FISH is inadequate. Fusion detection was successful, but rare novel fusions need more extensive technologies. Finally, we propose test sets to guide future diagnostic approaches.Key pointsWe evaluated and cross-validated ependymoma biomarkers in a large prospective clinical trial cohort.Accurate biomarker evaluation is critical to the success of clinical trials and patient care.We propose core and core+biomarker test sets for future molecular stratification.Importance of the StudyHigh-risk paediatric ependymoma has a poor prognosis and is devastating at relapse. Molecularly defined ependymoma types need to be accurately and reliably linked to biomarkers to predict clinical outcomes and design clinical trials. Here, we evaluated and cross-validated ependymoma biomarkers in a large prospective clinical trial cohort highlighting the importance of systematic evaluation of different methods. We provide evidence to guide test selection to support the molecular stratification of paediatric ependymoma and deliver insights into the rationalisation of biomarkers for use in resource-limited settings.

WHO grade II and III meningiomas are more invasive than grade I malignancies and determine patients' shorter overall survival. Their tendency to recur after treatment has represented an important therapeutic challenge because of the limited treatment strategies at recurrence. Angiogenesis and mechanistic target of rapamycin (mTOR) activation are two of the main features of higher grade meningiomas, determining invasiveness and tendency to relapse. While these options prove promising, available clinical data on mTOR inhibitors' efficacy are somewhat limited.We report a case of a 25-year-old female patient diagnosed with a right parasagittal occipital anaplastic meningioma (grade III WHO) in 2013. The patient underwent multiple treatments and, in 2019, a further recurrence occurred. The patient reported an mTOR mutation, and it is for this reason that the MTB approved treatment with everolimus and bevacizumab. Therapy was administered in May 2019, and partial response and prolonged disease control was obtained in November 2021, when progression took place. The patient's death occurred in March 2022.This case report provides evidence on the efficacy of mTOR inhibitors as a treatment option in recurrent meningiomas. Furthermore, it highlights the importance of performing a molecular analysis as a preliminary step towards targeting the mTOR pathway.

Presentation at the School of Veterinary Medicine of the Faculty of Agriculture, Morioka, Iwate, Japan,on the 22 of May 2019

We compared GABAergic function and neuronal excitability in the hippocampal tissue of seven sporadic MTLE patients with a patient carrying a SCN1A loss‐of‐function mutation. All had excellent outcome from anterior temporal lobectomy, and neuropathological study always showed characteristic hippocampal sclerosis (Hs). Compared to MTLE patients, there was a more severe impairment of GABAergic transmission, due to the lower GABAergic activity related to the NaV1.1 loss‐of‐function, in addition to the typical GABA‐current rundown, a hallmark of sporadic MTLE. Our results give evidence that a pharmacological rescuing of the GABAergic dysfunction may represent a promising strategy for the treatment of these patients.

Considerazioni sulle conseguenze dell'attuazione del Recovery Plan in Italia sull'organizzazione e sul funzionamento della pubblica amministrazione.

Conversazione sulla disciplina del diritto regionale in Italia.

Il contributo ha ad oggetto alcune criticità nei processi di attuazione del PNRR, che riguardano tanto il versante della “forma di governo” regionale e statale, quanto la ripartizione di competenze tra istituzioni centrali e autonomie regionali. Di questi temi il saggio si occupa alla luce degli adempimenti dei Consigli regionali in sede di c.d. “sessioni europee” dei Consigli.

Medulloblastoma with extensive nodularity (MBEN) are cerebellar tumors with two histologically distinct compartments and varying disease course. In some children MBEN progresses, while others show spontaneous differentiation into more benign tumors. However, the mechanisms that control the tug-of-war between proliferation and differentiation are not well understood. Here, we dissected this process with a multi-modal single cell transcriptome analysis. We found that the internodular MBEN compartment comprised proliferating early cerebellar granular neuronal precursors (CGNP)-like tumor cells as well as stromal, vascular, and immune cells. In contrast, the nodular compartment consisted of postmitotic, neuronally differentiated MBEN cells. Both compartments were connected through an intermediate cell stage of actively migrating CGNPs. Furthermore, astrocyte-like tumor cells were identified that had branched off the main CGNP developmental trajectory. Cells with an astroglial phenotype were found in close proximity to migrating, late CGNP-like and postmitotic neuronally differentiated cells. Our study reveals how the spatial tissue organization is linked to the developmental trajectory of proliferating tumor cells through a migrating precursor stage into differentiated tumor cells with a more benign phenotype. We anticipate that our framework for integrating single nucleus RNA-sequencing and spatial transcriptomics will help to uncover intercompartmental interactions also in other cancers with varying histology.

This works presents the development of a three-dimensional solver for the numerical analysis of the communication blackout encountered in atmospheric entry flights. The proposed methodology is based on computational fluid dynamic (CFD) simulation in combination with a ray tracing numerical technique. The ray tracing algorithm is based on the implementation of the Eikonal system of equation, a fast, efficient and accurate method to analyse interaction of electromagnetic signals and weakly ionised plasmas. The proposed methodology is applied to the atmospheric entry of the ExoMars capsule in Martian environemnt and shows the capability of a three-dimensional approach to analyse real flight configuration. Results demonstrate the validity of the proposed ray tracing approach for the analysis of communication blackout, where signals emitted from the on-board antenna undergo reflection and refraction from the plasma surrounding the entry vehicle. ispartof: pages:1-13 ispartof: ICCFD11 PROCEEDINGS vol:https://www.iccfd.org/iccfd11/proceedings.html pages:1-13 ispartof: Eleventh International Conference on Computational Fluid Dynamics (ICCFD11) location:Maui, HI, USA date:11 Jul - 15 Jul 2022 status: published

At the international level, it is necessary to apply urban health strategies that can integrate concrete actions to protect and promote health in urban and architectural planning. In cities, thequot;urban faunaquot; mostly consists of synanthropic birds (sparrows, starlings, swallows, martins, jackdaws, crows, hawks, gulls, pigeons) that have adapted to a continuous relationship with humans. These animals enrich the ecological network of biodiversity but also pose health problems. The most successful avian colonizers are pigeons (Columba livia), which proliferate due to the abundance of food available to them and the absence of predators. Pigeons may harbor several organisms that are pathogenic for humans, and among these the role of Dermanyssus gallinae should not be underestimated. In the absence of their preferred pigeon host, these mites will move from the nest to windowsills and window frames from which they attack humans. The Authors show that modern architectural design features in towns can favor the establishment and proliferation of pigeons, contributing to the public health risk for dermanyssosis or other diseases related to these birds. They describe an outbreak of dermanyssosis due to incorrect or unsuitable structural interventions, and highlight the need of re-thinking urban architectural choices in order to safeguard public health.

Purpose Salivary gland (SG) tissue and derived neoplasms may occur in the sellar region. As the current literature is mostly limited to case reports, the puzzling case of an inflammatory SG removed by transsphenoidal surgery (TS) and mimicking a prolactinoma prompted us to perform the first systematic review of these unusual conditions. Methods A systematic literature search was conducted according to the PRISMA guidelines. Forty-four individual cases—non-neoplastic enlarged salivary glands (NNESG, n = 15), primary benign (n = 7) and malignant (n = 8) ectopic salivary tumours (ST) and sellar metastasis from eutopic primary ST (n = 14)—were suitable for the analysis of clinical, radiological and pathological characteristics. Therapeutic outcome was reviewed as a secondary endpoint. Results All cases were diagnosed after surgery. NNESG commonly affected young and/or female patients, typically leading to headaches and hyperprolactinemia and originating close to the neurohypophysis. Submucosal SG should be excluded before concluding to an intrasellar NNESG after TS. No gender or age predominance was found for primary ectopic ST, which present as large tumors, with histological phenotypes similar to common ST. Hypopituitarism and diabetes insipidus were more frequent in ST than in NNESG. NNESG and benign ectopic ST rarely recur. Malignant ectopic ST should be distinguished from secondary localizations of eutopic ST reaching the sella by contiguity or metastatic spread; both share a frequent unfavorable outcome. Conclusion Sellar neoplasms derived from SG are rare but misleading conditions and pituitary dysfunction is likely to be more common than currently reported. Appropriate pathological evaluation and multidisciplinary approach are required.

Ready-to-eat (RTE) salads and berries are increasingly consumed in industrialized countries. These products can be contaminated by pathogenic parasites that have been responsible for foodborne outbreaks worldwide. In Italy, there are few data on contamination of RTE salads and berries with parasite transmission stages and this requires more-in-depth investigations. To estimate the prevalence of contamination with Cryptosporidium spp. and Giardia duodenalis in these fresh products, a total of 324 packages of local RTE mixed salads - belonging to three different industrial brands - and 324 packages of berries - blueberries from Peru, blackberries from Mexico, raspberries from Italy - were bought from supermarkets located in the Provinces of Bari and Foggia, Apulia, Italy. A pool size of nine packages was chosen and a total of 72 pools were processed in the whole year. After washing, the pellets were examined by microscopy (FLOTAC) and tested using conventional simplex PCR, targeting Cryptosporidium spp., Giardia duodenalis, and Entamoeba spp., and sequencing. Several Cryptosporidium species and Giardia duodenalis assemblages, some of which are of potential zoonotic relevance, as well as Entamoeba spp., were identified in both matrices. By microscopy, Giardia-like cysts in local raspberries and Entamoeba-like cysts in imported blueberries were detected. Giardia duodenalis (Assemblages A, B and E) and Entamoeba histolytica were molecularly confirmed with overall prevalences of 4.6% (95% C.I. 3.0-6.8) and 1% (95% C.I. 0.3-2.1), respectively. Molecular methods identified Cryptosporidium ryanae, Cryptosporidium bovis, Cryptosporidium xiaoi, and Cryptosporidium ubiquitum in both matrices, with a prevalence of 5.1% (95% C.I. 3.3-7.3). A distinct seasonality in prevalence was observed for G. duodenalis, with most positives occurring in spring, whereas Cryptosporidium showed no significant seasonal variations. These results highlight that inadequate management of fresh produce, both locally produced and imported, along the food chain may have the potential for consequences on human health.

Gliomas represent about 80% of primary brain tumours and about 30% of malignant ones, which today don’t have a resolution therapy because of their variability. A valid model for the study of new personalized therapies can be represented by primary cultures from patient’s tumour biopsies. In this study we consider 12 novel cell lines established from patients’ gliomas and immunohistochemically and molecularly characterized according to the newly updated 2016 CNS Tumour WHO classification. Eight of these lines were glioblastoma cells, two grade III glioma cells (anaplastic astrocytoma and oligo astrocytoma) and two low grade glioma cells (grade II astrocytoma and oligodendroglioma). All cell lines were analysed by immunohistochemistry for specific glioma markers, respectively VIMENTIN, GFAP, IDH1R132, and ATRX. The methylation status of the MGMT gene promoter was also determined in all lines. The comparison of the immunohistochemical characteristics and of the MGMT methylation status of the lines with the tissues of origin shows that the cells in culture maintain the same characteristics. Human cancer cell lines represent a support in the knowledge of tumour biology and in drug discovery through its facile experimental manipulation. NCT 04180046.

Embryonal tumors are a heterogenous group of neoplasms mostly defined by recurrent genetic driver events. They have been, previously, broadly classified as either medulloblastoma or supratentorial primitive neuroectodermal tumors (PNETs). However, the application of DNA methylation/gene expression profiling in large series of neoplasms histologically defined as PNET, revealed tumors, which showed genetic events associated with glial tumors. These findings led to the definitive removal of the term "PNET" in the 2016 World Health Organization (WHO) classification of CNS tumors. Moreover, further studies on a large scale of methylation profiling have allowed the identification of new molecular-defined entities and have largely influenced the 5

Accurate pathological diagnosis is crucial for optimal management of patients with cancer. For the approximately 100 known tumour types of the central nervous system, standardization of the diagnostic process has been shown to be particularly challenging - with substantial inter-observer variability in the histopathological diagnosis of many tumour types. Here we present a comprehensive approach for the DNA methylation-based classification of central nervous system tumours across all entities and age groups, and demonstrate its application in a routine diagnostic setting. We show that the availability of this method may have a substantial impact on diagnostic precision compared to standard methods, resulting in a change of diagnosis in up to 12% of prospective cases. For broader accessibility, we have designed a free online classifier tool, the use of which does not require any additional onsite data processing. Our results provide a blueprint for the generation of machine-learning-based tumour classifiers across other cancer entities, with the potential to fundamentally transform tumour pathology.

Rosette-forming glioneuronal tumor (RGNT) is a rare brain neoplasm that primarily affects young adults. Although alterations affecting the mitogen-activated protein kinase (MAPK) and phosphoinositide 3-kinase (PI3K) signaling pathway have been associated with this low-grade entity, comprehensive molecular investigations of RGNT in larger series have not been performed to date, and an integrated view of their genetic and epigenetic profiles is still lacking. Here we describe a genome-wide DNA methylation and targeted sequencing-based characterization of a molecularly distinct class of tumors (n = 30), initially identified through genome-wide DNA methylation screening among a cohort of > 30,000 tumors, of which most were diagnosed histologically as RGNT. FGFR1 hotspot mutations were observed in all tumors analyzed, with co-occurrence of PIK3CA mutations in about two-thirds of the cases (63%). Additional loss-of-function mutations in the tumor suppressor gene NF1 were detected in a subset of cases (33%). Notably, in contrast to most other low-grade gliomas, these tumors often displayed co-occurrence of two or even all three of these mutations. Our data highlight that molecularly defined RGNTs are characterized by highly recurrent combined genetic alterations affecting both MAPK and PI3K signaling pathways. Thus, these two pathways appear to synergistically interact in the formation of RGNT, and offer potential therapeutic targets for this disease.

Two cases of cutaneous myiasis diagnosed in 2018 in Emilia‐Romagna region (northern Italy) were reported. The first one, described in a domestic cat Felis silvestris catus L. (Carnivora: Felidae) and caused by Calliphora vicina Robineau‐Desvoidy (Diptera: Calliphoridae), was the first one of this type ever reported in Italy in cats. The second one was described in a domestic dog Canis lupus familiaris L. (Carnivora: Canidae) and caused by Lucilia sericata (Meigen) (Diptera: Calliphoridae) and was unusual because it occurred in absence of lesions. An extensive literature search on cutaneous myiasis in these two domestic animal species was performed in order to draw attention to predisposing conditions and risk factors., The first case of cutaneous myiasis by Calliphora vicina (Diptera: Calliphoridae) in a domestic cat Felis silvestris catus (Carnivora: Felidae) in Italy was reported. An unusual case of cutaneous myiasis in a domestic dog Canis lupus familiaris (Carnivora: Canidae) caused by Lucilia sericata (Diptera: Calliphoridae) was also reported. The predisposing conditions and risk factors of the cutaneous myiasis in cats and dogs were also discussed.

The poultry red mite, Dermanyssus gallinae, is a worldwide threat to egg production and animal and human welfare. This mite is also a potential vector for several significant diseases. EU regulation that forbids the use of conventional cages for egg-laying hens may favour the growth of D. gallinae, a species known to thrive in more complex housing systems. Current control measures emphasize the use of chemical acaricides, which may have limited efficacy on D. gallinae considering its temporary blood-feeding behaviour. In integrated pest management (IPM), two or more compatible measures targeting physical, environmental, and/or biological aspects could be judiciously combined to enhance the effectiveness against D. gallinae infestation. To inform current and future IPM for D. gallinae, a compatibility matrix is proposed to guide the selection of control measures for field application.

Background A prospective 2002–2014 study stratified 160 patients by resection extent and histological grade, reporting results in 2016. We re-analyzed the series after a median of 119 months, adding retrospectively patients’ molecular features. Methods Follow-up of all patients was updated. DNA copy number analysis and gene-fusion detection could be completed for 94/160 patients, methylation classification for 68. Results Progression-free survival (PFS) and overall survival (OS) at 5/10 years were 66/58%, and 80/73%. Ten patients had late relapses (range 66–126 mo), surviving after relapse no longer than those relapsing earlier (0–5 y). On multivariable analysis a better PFS was associated with grade II tumor and complete surgery at diagnosis and/or at radiotherapy; female sex and complete resection showed a positive association with OS. Posterior fossa (PF) tumors scoring ≥0.80 on DNA methylation analysis were classified as PFA (n = 41) and PFB (n = 9). PFB patients had better PFS and OS. Eighteen/32 supratentorial tumors were classified as RELA, and 3 as other molecular entities (anaplastic PXA, LGG MYB, HGNET). RELA had no prognostic impact. Patients with 1q gain or cyclin-dependent kinase inhibitor 2A (CDKN2A) loss had worse outcomes, included significantly more patients >3 years old (P = 0.050) and cases of dissemination at relapse (P = 0.007). Conclusions Previously described prognostic factors were confirmed at 10-year follow-up. Late relapses occurred in 6.2% of patients. Specific molecular features may affect outcome: PFB patients had a very good prognosis; 1q gain and CDKN2A loss were associated with dissemination. To draw reliable conclusions, modern ependymoma trials need to combine diagnostics with molecular risk stratification and long-term follow-up.

Background: Classical swine fever virus (CSFV), species member of the family Flaviviridae, is generally considered restricted to domestic and wild suids. The circulation of CFSV has been detected in cattle herds in China and India. Natural infection appeared associated with clinical signs in some cases.Aim: The secondary structures of the internal ribosome entry site in the 5ʹ untranslated region (UTR) were used for the genomic characterization of bovine strains.Methods: Sequences have been compared to the representative CSFV strains isolated from pigs, vaccines, and contaminants from porcine cell lines and an ovine strain isolated in Spain.Results: The observed sequences from cattle showed a genetic relatedness with live-attenuated vaccine strains used in pigs. Sequence characteristics of the Chinese strain S171 are genetically distant from the previously reported CSFV genotypes, suggesting a new outgroup in the species, described for the first time, and named CSFV-d. Other Chinese strains were genetically closely related to CSFV genotype a2 (Alfort type) pig strains. Indian strains, reported from the states of Tamil Nadu and Meghalaya, were genetically closely related to CSFV genotype a1 (Brescia type) and a5 pig strains, respectively.Conclusion: These preliminary observations are new and relevant in countries, where CSFV control and eradication strategies are applied. Keywords: Cattle, Classical swine fever virus, Pestivirus, Secondary structure.

Here, we developed an unbiased, functional target-discovery platform to identify immunogenic proteins from primary non-small cell lung cancer (NSCLC) cells that had been induced to apoptosis by cisplatin (CDDP) treatment in vitro, as compared with their live counterparts. Among the multitude of proteins identified, some of them were represented as fragmented proteins in apoptotic tumor cells, and acted as non-mutated neoantigens (NM-neoAgs). Indeed, only the fragmented proteins elicited effective multi-specific CD4+ and CD8+ T cell responses, upon a chemotherapy protocol including CDDP. Importantly, these responses further increased upon anti-PD-1 therapy, and correlated with patients’ survival and decreased PD-1 expression. Cross-presentation assays showed that NM-neoAgs were unveiled in apoptotic tumor cells as the result of caspase-dependent proteolytic activity of cellular proteins. Our study demonstrates that apoptotic tumor cells generate a repertoire of immunogenic NM-neoAgs that could be potentially used for developing effective T cell-based immunotherapy across multiple cancer patients., Grimaldi and Cammarata et al. develop a proteomics-based, target discovery platform to identify immunogenic proteins specific to apoptotic tumor cells. This study highlights the importance of protein modifications in apoptotic tumor cells as a mechanism of generating immunogenic neoantigens that can be targeted for T cell-based immunotherapy.

Medulloblastoma (MB) is the most common malignant brain tumor in children and among the subtypes, Group 3 MB has the worst outcome. Here, we perform an in vivo, patient-specific screen leading to the identification of Otx2 and c-MYC as strong Group 3 MB inducers. We validated our findings in human cerebellar organoids where Otx2/c-MYC give rise to MB-like organoids harboring a DNA methylation signature that clusters with human Group 3 tumors. Furthermore, we show that SMARCA4 is able to reduce Otx2/c-MYC tumorigenic activity in vivo and in human cerebellar organoids while SMARCA4 T910M, a mutant form found in human MB patients, inhibits the wild-type protein function. Finally, treatment with Tazemetostat, a EZH2-specific inhibitor, reduces Otx2/c-MYC tumorigenesis in ex vivo culture and human cerebellar organoids. In conclusion, human cerebellar organoids can be efficiently used to understand the role of genes found altered in cancer patients and represent a reliable tool for developing personalized therapies., Group 3 medulloblastoma (MB) is considered one of the most aggressive forms of this cancer. Here, the authors show that Otx2 and c-MYC oncogenes can drive Group 3 MB formation in mouse and human cerebellar organoids while SMARCA4 overexpression or a EZH2-specific inhibitor can inhibit tumorigenesis.

Astroblastomas are neuroepithelial tumours defined by the presence of MN1 rearrangement and are typically located in the cerebral hemispheres. Rare cases of astroblastoma-like tumours carrying an EWSR1-BEND2 fusion have been recently described in the brain stem and spinal cord. We report a paediatric case of neuroepithelial astroblastoma-like tumour occurring in the spine and carrying a novel MAMLD1-BEND2 fusion. We believe that our case aligns with the rare astroblastoma-like tumours with EWSR1-BEND2 fusion, in terms of non-hemispheric location, pathology, methylation profile and activation of BEND2 transcription. Whether they may represent a distinct entity or a variant of MN1-altered astroblastoma is not clear.

Cerebellar liponeurocytoma (CL) is an unusual tumor, histologically composed of a mixture of small to medium-sized, rounded neurocytic cells and a variable lipomatous component. Although CL was originally considered as a subtype of medulloblastoma, subsequent molecular studies demonstrated that this tumor was a distinct entity, exhibiting the tumor protein p53 gene (TP53) missense mutations in 20% of cases, chromosome 17 deletion, and the absence of mutations in the adenomatous polyposis coli gene (APC), the protein patched homolog gene (PTCH), the kinase insert domain receptor gene (KDR), and the β-catenin gene (CTNNB). Apart from these molecular features, little is known about the pathogenesis and the genetic landscape of CL to date. In order to characterize the mutational landscape of CL and identify alterations that are driving tumorigenesis, we report a series of three cases, including one recurrent tumor, analysed by next-generation sequencing (NGS), which identified a total of 22 variants, of which four were missense mutations, nine were synonymous variants, and nine were located on intronic regions. In particular, DNA sequencing identified missense mutations in APC, KDR, and TP53 that could be implicated in promoting tumor progression and angiogenesis of CL. Furthermore, the NGS analysis revealed that recurrent CL did not have additional genetic changes compared with the primary tumor. Moreover, the high frequencies of detected mutations suggested that the identified alterations are germline variants. Indeed, an additional NGS on the genomic DNA obtained from one of the three patients confirmed the presence of the variants in the germline DNA. In conclusion, the obtained data support the hypothesis that CL is a distinct pathological entity that does not show specific somatic alterations driving tumorigenesis.

Diffuse midline gliomas (DMGs) originate in the thalamus, brainstem, cerebellum and spine. This entity includes tumors that infiltrate the pons, called diffuse intrinsic pontine gliomas (DIPGs), with a rapid onset and devastating neurological symptoms. Since surgical removal in DIPGs is not feasible, the purpose of this study was to profile circulating miRNA expression in DIPG patients in an effort to identify a non-invasive prognostic signature with clinical impact. Using a high-throughput platform, miRNA expression was profiled in serum samples collected at the time of MRI diagnosis and prior to radiation and/or systemic therapy from 47 patients enrolled in clinical studies, combining nimotuzumab and vinorelbine with concomitant radiation. With progression-free survival as the primary endpoint, a semi-supervised learning approach was used to identify a signature that was also tested taking overall survival as the clinical endpoint. A signature comprising 13 circulating miRNAs was identified in the training set (n = 23) as being able to stratify patients by risk of disease progression (log-rank p = 0.00014; HR = 7.99, 95% CI 2.38–26.87). When challenged in a separate validation set (n = 24), it confirmed its ability to predict progression (log-rank p = 0.00026; HR = 5.51, 95% CI 2.03–14.9). The value of our signature was also confirmed when overall survival was considered (log-rank p = 0.0021, HR = 4.12, 95% CI 1.57–10.8). We have identified and validated a prognostic marker based on the expression of 13 circulating miRNAs that can shed light on a patient’s risk of progression. This is the first demonstration of the usefulness of nucleic acids circulating in the blood as powerful, easy-to-assay molecular markers of disease status in DIPG. This study provides Class II evidence that a signature based on 13 circulating miRNAs is associated with the risk of disease progression.

Medulloblastoma (MB) is the most common malignant childhood brain tumor. The current clinical approach consists of multimodal strategies with debilitating long-term effects and risk of tumor recurrence. Medulloblastoma stem cells (MBSCs) are a fraction of tumor cells with high proliferation potential and the capability to adapt to adverse/restrictive conditions in tumor milieu thus driving the refractoriness to conventional therapies. Recently, high basal levels of Unfolded Protein Response (UPR) molecules have been found in tumors of different tissue-origin and are correlated with poor prognosis and low patient survival. However, little is known about the role of UPR in MB. We investigated the expression and activation of UPR players in MBSCs. Human group 3 MB (G3MB) cell lines, specifically CHLA-01, D283- and D341-Med, were grown in Vitamin A and/or FBS or in stem selective medium (B27™) for 72 h before collection. Cells were fixed, stained with proper primary antibodies and images were acquired by confocal microscopy. The analysis of the transcription factors ATF-4 and CHOP revealed their elevated nuclear expression and co-localization, which resulted to be more marked in G3MB stem-like cells than in the differentiated ones. Also the ATF-6 branch was investigated, in differentiating conditions D283 and D341-Med showed a greater activation of ATF-6, represented by its nuclear localization, in respect to stem cells, while CHLA-01 did not show differences. Conversely XBP1, the transcription factor downstream IRE1 signaling, was not expressed in the three cell lines. Lastly, a Kaplan-Meier analysis on MB patients showed a worse prognosis with a shorter survival rate of patients expressing high ATF4 transcript levels. Our results reveal, even in resting conditions, preferential activation of the PERK branch in G3MB cells grown in stem-like condition suggesting that ATF-4 might be a promising therapeutic and prognostic factor to specifically target the stem compartment in aggressive MB.

Neoplastic cells acquire the ability to proliferate endlessly by maintaining telomeres via telomerase, or alternative lengthening of telomeres (ALT). The role of telomere maintenance in pituitary neuroendocrine tumors (PitNETs) has yet to be thoroughly investigated. We analyzed surgical samples of 24 adult recurrent PitNETs (including onset and relapses for 14 of them) and 12 pediatric primary PitNETs. The presence of ALT was assessed using telomere-specific fluorescence in situ hybridization, methylation of telomerase reverse transcriptase promoter (TERTp) by methylation-specific PCR, and ATRX expression by immunohistochemistry. Among the adult recurrent PitNETs, we identified 3/24 (12.5%) ALT-positive cases. ALT was present from the onset and maintained in subsequent relapses, suggesting that this mechanism occurs early in tumorigenesis and is stable during progression. ATRX loss was only seen in one ALT-positive case. Noteworthy, ALT was observed in 3 out of 5 aggressive PitNETs, including two aggressive corticotroph tumors, eventually leading to patient's death. ALT-negative tumors (87.5%) were classified according to their low (29.2%), medium (50%), and high (8.3%) telomere fluorescence intensity, with no significant differences emerging in their molecular, clinical, or pathological characteristics. TERTp methylation was found in 6/24 cases (25%), with a total concordance in methylation status between onset and recurrences, suggesting that this mechanism remains stable throughout disease progression. TERTp methylation did not influence telomere length. In the pediatric cohort of PitNETs, TERTp methylation was also observed in 4/12 cases (33.3%), but no case of ALT activation was observed. In conclusion, ALT is triggered at onset and maintained during tumor progression in a subset of adult PitNETs, suggesting that it could be used for clinical purposes, as a potential predictor of aggressive behavior.

Background More than 40% of patients with intracranial ependymoma need a salvage treatment within 5 years after diagnosis, and no standard treatment is available as yet. We report the outcome after first relapse of 64 patients treated within the 2nd AIEOP protocol. Methods We considered relapse sites and treatments, that is, various combinations of complete/incomplete surgery, if followed by standard or hypofractionated radiotherapy (RT) ± chemotherapy (CT). Molecular analyses were available for 38/64 samples obtained at first diagnosis. Of the 64 cases, 55 were suitable for subsequent analyses. Results The median follow-up was 147 months after diagnosis, 84 months after first relapse, 5-year EFS/OS were 26.2%/30.8% (median EFS/OS 13/32 months) after relapse. For patients with a local relapse (LR), the 5-year cumulative incidence of second LRs was 51.6%, with a 5-year event-specific probability of being LR-free of 40.0%. Tumor site/grade, need for shunting, age above/below 3 years, molecular subgroup at diagnosis, had no influence on outcomes. Due to variation in the RT dose/fractionation used and the subgroup sizes, it was not possible to assess the impact of the different RT modalities. Multivariable analyses identified completion of surgery, the absence of symptoms at relapse, and female sex as prognostically favorable. Tumors with a 1q gain carried a higher cumulative incidence of dissemination after first relapse. Conclusions Survival after recurrence was significantly influenced by symptoms and completeness of surgery. Only a homogeneous protocol with well-posed, randomized questions could clarify the numerous issues, orient salvage treatment, and ameliorate prognosis for this group of patients.

A clinical report of otomyiasis in a 1-year-old girl is reported. A III instar larva of Sarcophaga sp. was microscopically identified and Sarcophaga (Liopygia) argyrostoma (Diptera, Sarcophagidae) was suspected. A molecular method targeting a fragment of the cox1 gene was used to confirm the identity of the specimen. Although myiases are not frequent manifestations in otolaryngology, they should arouse the attention of doctors, social workers and parents dealing with disabled people, the elderly and children. This contribution also highlights the need of combining microscopy and molecular tools to achieve a correct and reliable identification of the specimen/s.

The management of patients with Central Nervous System (CNS) malignancies relies on the appropriate classification of these tumors. Recently, the World Health Organization (WHO) has published new criteria underlining the importance of an accurate molecular characterization of CNS malignancies, in order to integrate the information generated by histology. Next generation sequencing (NGS) allows single step sequencing of multiple genes, generating a comprehensive and specific mutational profile of the tumor tissue. We developed a custom NGS-based multi-gene panel (Glio-DNA panel) for the identification of the correct glioma oncotype and the detection of its essential molecular aberrations. Specifically, the Glio-DNA panel targets specific genetic and chromosomal alterations involving ATRX chromatin remodeler (ATRX), cyclin dependent kinase inhibitor 2A (CDKN2A), isocitrate dehydrogenase (NADP+) 1 (IDH1) and the telomerase reverse transcriptase (TERT) promoter while also recognizing the co-deletion of 1p/19q, loss of chromosome 10 and gain of chromosome 7. Furthermore, the Glio-DNA panel also evaluates the methylation level of the O-6-methylguanine-DNA methyltransferase (MGMT) gene promoter that predicts temozolomide efficacy. As knowledge of the mutational landscape of each glioma is mandatory to define a personalized therapeutic strategy, the Glio-DNA panel also identifies alterations involving “druggable” or “actionable” genes. To test the specificity of our panel, we used two reference mutated DNAs verifying that NGS allele frequency measurement was highly accurate and sensitive. Subsequently, we performed a comparative analysis between conventional techniques - such as immunohistochemistry or fluorescence in situ hybridization - and NGS on 60 diffuse glioma samples that had been previously characterized. The comparison between conventional testing and NGS showed high concordance, suggesting that the Glio-DNA panel may replace multiple time-consuming tests. Finally, the identification of alterations involving different actionable genes matches glioma patients with potential targeted therapies available through clinical trials. In conclusion, our analysis demonstrates NGS efficacy in simultaneously detecting different genetic alterations useful for the diagnosis, prognosis and treatment of adult patients with diffuse glioma.

Atmospheric entry represents one of the most critical phases of a space mission. The safety of the expensive payload strongly depends on the spacecraft survival to the harsh conditions experienced during the hypersonic descent into the target planetary atmosphere, characterised by high thermal loads on the vehicle surface. In addition, flight at hypersonic speed generates a plasma layer around the vehicle, leading to a disruption of the communication system during the crucial terminal phase of a space mission. The formation of entry plasma prevents radio signals to be received and transmitted from spacecraft, leading to a communication blackout, which can last several minutes, endangering the whole mission and deeply affecting crew or payload safety. The current aerospace technology requires further investigations and investments to overcome these two problems, especially considering the recent renewed interest in future human missions to colonise the space system. As of today, the reduction of thermal loads on spacecraft is based on physical expensive, heavy, and non-reusable thermal protection systems (TPS). For human exploration missions, such as Mars exploration, the use of such physical TPS greatly increases the design effort and cost of the spacecraft and reduces the cost efficiency of the mission by sacrificing payload mass for such systems.Regarding communication blackout, on the other hand, spacecraft solely rely on satellite constellations to communicate through the plasma wake, partially reducing the telecommunication blackout period, but with no active system dedicated to this issue. As previously demonstrated with theoretical, experimental and numerical studies, Magnetohydrodynamics (MHD) provides a framework for tackling both issues affecting atmospheric entry: in principle, high enough electromagnetic (EM) fields can be used to reduce heat fluxes (as a consequence of modifying bow shock standoff distance and shock layer structure) and create a magnetic windowing able to mitigate the blackout. This work presents a numerical tool to analyse the effect of the application of MHD flow control systems for atmospheric entry flights. Numerical Computational Fluid Dynamics (CFD) simulations will be performed at different trajectory points for an hypersonic entry in Martian atmosphere. Different simulation of flow/electromagnetic coupling will be performed with the COOLFLuiD solver which is based on a three dimensional, finite volume, unstructured grid framework. The study will be useful for evaluating potential benefits for communication blackout in hypersonic flight with electromagnetic field imposed from an onboard device. The interaction between the electromagnetic waves and the ionised plasma around the vehicle will be analysed by the application of an optical ray tracing method. The use of an advanced blackout analysis method capable of reproducing more complex waves phenomena, such as reflection, refraction and phase modulation, has the advantage of improving the overall understanding of the complex physical phenomena involved in the blackout problem. A comparison between different configurations of MHD control at different entry conditions will be performed to asses the benefits of magnetic windowing on the communication systems. The final goal is to present a numerical methodology capable to investigate the impact of electromagnetic fields for reducing surface thermal heat loads and communication blackout, opening up promising perspectives for the future generation of spacecraft.

Background: Aggressive and metastatic PitNETs are challenging conditions. Immune checkpoint inhibitors (ICIs) are currently considered in cases resistant to temozolomide (TMZ). However, clinical experience is essentially limited to case reports, with variable outcomes. Material and Methods: The effects of ICIs on 12 aggressive/metastatic PitNETs from the literature were reviewed and analyzed according to tumor characteristics, with the additional description of a silent-Pit1 metastatic tumor responding to pembrolizumab. Results: Most cases were metastatic (10/13: 6 corticotroph, 3 lactotroph, 1 silent Pit1); 3 were aggressive (2 corticotroph, 1 lactotroph). ICIS was used either as monotherapy or in combination. At last follow-up on ICI, a complete response (CR) was present in 3 cases and a partial response (PR) in 2 cases (4/5 metastatic). One sustained stable disease (SD) was reported. Progressive disease (PD) was observed in 7 cases, 3 of them after initial SD (n = 1) or PR (n = 3), with 2 reported deaths. PDL1 expression was studied in 10 cases and was high (>95%) in 2 Pit1-derived metastatic PitNETs (1 CR and 1 remarkable PR) but absent/low (

Background Pediatric low-grade gliomas (pLGGs), particularly incompletely resected supratentorial tumours, can undergo progression after surgery. However to date, there are no predictive biomarkers for progression. Here, we aimed to identify pLGG-specific microRNA signatures and evaluate their value as a prognostic tool. Methods We identified and validated supratentorial incompletey resected pLGG-specific microRNAs in independent cohorts from four European Pediatric Neuro-Oncology Centres. Results These microRNAs demonstrated high accuracy in differentiating patients with or without progression. Specifically, incompletely resected supratentorial pLGGs with disease progression showed significantly higher miR-1248 combined with lower miR-376a-3p and miR-888-5p levels than tumours without progression. A significant (p Conclusions Altogether, we provide a novel molecular biomarker able to successfully identify pLGG patients associated with disease progression that could support the clinicians in the decision-making strategy, advancing personalized medicine.