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Astroblastoma is a rare glial neoplasm arising more frequently in young, predominantly female, patients and with unclear clinical behavior and outcome. The diagnostic molecular alteration is the rearrangement of meningioma 1 (MN1) gene.However, little is known about the specific mechanism of tumor development driven by such genetic change. microRNAs (miRNAs) are important gene expression regulators with strong implications in several biological processes. In this study we investigated the microRNAs’ expression and regulation in MN1 altered neoplasms. We collected a cohort of 14 formalin-fixed, paraffin-embedded (FFPE) tumor samples histologically defined classified as astroblastoma. The DNA methylation analysis showed that only 8 cases harbored the MN1 rearrangement characteristic of astroblastoma. The 8 MN1 altered tumors were analyzed for their expression pattern of miRNAs by Nanostring technology. Thirty-nine deregulated miRNAs were found in the 8 astroblastomas compared to normal brain tissue. In order to understand the underlying mechanisms of the miRNAs aberrant expression, we first investigated the methylation status of themicroRNA promoters. Thirty-two out 39 deregulated miRNA resulted epigenetically regulated. with methylation status coherent with microRNA expression in 14/32 miRNAs.. Secondly, we investigated the hypothesis of a genomic alteration as a reason for the abnormal expression of the remaining 18/32 deregulated miRNAs by analyzing the Copy Number Variation (CNV) of tumor samples. but no alteration was found on miRNAs chromosome loci. Finally, we identified validated targets of the 32 deregulated miRNAs and uncovered biological processes putatively correlated to miRNA target genes, clinically and pathologically relevant in MN1-altered astroblastomas. Our findings shed light on the biology of this rare disease with potential implications on prognostic markers and therapy.

Additional file 1: Figure S1. Overview of the methodological workflow of the study for the identification of miR-1248 as a progression risk stratification biomarker in pLGGs. Figure S2. Progression free survival (PFS) data for pLGG patients of cohorts I and II (p-value

As a relevant element of novelty, the fifth CNS WHO Classification highlights the distinctive pathobiology underlying gliomas arising primarily in children by recognizing for the first time the families of paediatric-type diffuse gliomas, both high-grade and low-grade. This review will focus on the family of paediatric-type diffuse high-grade gliomas, which includes four tumour types: 1) Diffuse midline glioma H3 K27-altered; 2) Diffuse hemispheric glioma H3 G34-mutant; 3) Diffuse paediatric-type high-grade glioma H3-wildtype and IDH-wildtype; and 4) Infant-type hemispheric glioma. The essential and desirable diagnostic criteria as well as the entities entering in the differential will be discussed for each tumour type. A special focus will be given on the issues encountered in the daily practice, especially regarding the diagnosis of the diffuse paediatric-type high-grade glioma H3-wildtype and IDH-wildtype. The advantages and the limits of the multiple molecular tests which may be utilised to define the entities of this tumour family will be evaluated in each diagnostic context.

Pediatric high-grade gliomas represent a heterogeneous group of tumors with a wide variety of molecular features. We performed whole exome sequencing and methylation profiling on matched primary and recurrent tumors from four pediatric patients with hemispheric high-grade gliomas. Genetic analysis showed the presence of some variants shared between primary and recurrent tumors, along with other variants exclusive of primary or recurrent tumors. NSD1 variants, all novel and not previously reported, were present at high frequency in our series (100%) and were all shared between the samples, independently of primary or recurrence. For every variant, in silico prediction tools estimated a high probability of altering protein function. The novel NSD1 variant (c.5924T > A; p.Leu1975His) was present in one in four cases at recurrence, and in two in four cases at primary. The novel NSD1 variant (c.5993T > A; p.Met1998Lys) was present in one in four cases both at primary and recurrence, and in one in four cases only at primary. The presence of NSD1 mutations only at recurrence may suggest that they can be sub-clonal, while the presence in both primary and recurrence implies that they can also represent early and stable events. Furthermore, their presence only in primary, but not in recurrent tumors, suggest that NSD1 mutations may also be influenced by treatment.

Background: In 2015, an unprecedented epidemic of microcephaly occurred in Brazil. Preliminary observations suggested involvement of cofactors in the etiopathology of Zika virus associated microcephaly. Bovine viral diarrhea virus (BVDV) was identified in fetal samples with microcephaly, originating in the state of Paraíba, and two virus sequences, obtained from the amniotic fluid collected from mothers with babies affected by Zika and microcephaly, have been characterized as two different species of BVDV, types 1 and 2. Aim: The involvement of BVDV as co-factor in the etiopathogenesis of Zika virus associated microcephaly was explored. Methods: A serological screening using an ELISA test was undertaken to detect antibodies against BVDV among patients referred to the Central laboratory of Natal, Rio Grande do Norte, encompassing microcephalic babies and their mothers, mothers and pregnant not associated with microcephaly and general patients as control group. Results: Two samples were positive, out of 382 tested, (0.52%). No specific relation with birth-defects could be established. Conclusion: The study might suggest serological evidence of the circulation of BVDV in humans. Further studies and application of improved diagnostic tests adapted to humans are necessary to clarify the epidemiological extent and impact of BVDV.

BACKGROUND: Isocitrate dehydrogenase (IDH) wildtype (wt) grade II gliomas are a rare and heterogeneous entity. Survival and prognostic factors are poorly defined. METHODS: We searched retrospectively all patients diagnosed with diffuse World Health Organization (WHO) grades II and III gliomas at our center (1989–2020). RESULTS: Out of 517 grade II gliomas, 47 were “diffuse astrocytomas, IDHwt.” Tumors frequently had fronto-temporo-insular location (28/47, 60%) and infiltrative behavior. We found telomerase reverse transcriptase (TERT) promoter mutations (23/45, 51%), whole chromosome 7 gains (10/37, 27%), whole chromosome 10 losses (10/41, 24%), and EGFR amplifications (4/43, 9%), but no TP53 mutations (0/22, 0%). Median overall survival (OS) was 59 months (vs 19 mo for IDHwt grade III gliomas) (P < 0.0001). Twenty-nine patients (29/43, 67%) met the definition of molecular glioblastoma according to cIMPACT-NOW update 3. Median OS in this subset was 42 months, which was shorter compared with patients with IDHwt grade II gliomas not meeting this definition (median OS: 57 mo), but substantially longer compared with IDHwt grade III gliomas meeting the definition for molecular glioblastoma (median OS: 17 mo, P < 0.0001). Most patients with IDHwt grade II gliomas met cIMPACT criteria because of isolated TERT promoter mutations (16/26, 62%), which were not predictive of poor outcome (median OS: 88 mo). Actionable targets, including 5 gene fusions involving FGFR3, were found in 7 patients (24%). CONCLUSIONS: Our findings highlight the importance of histological grading and molecular profiling for the prognostic stratification of IDHwt gliomas and suggest some caution when assimilating IDHwt grade II gliomas to molecular glioblastomas, especially those with isolated TERT promoter mutation.

The essay contains some remarks on the consequences of the constitutional reforms of 1999-2001, that introduce the direct elections of the Presidents. as to the «constitutional» organisation of the Regions, In doing so both the effects of the reforms on the relations between the President and the Regional Assemblies and the consequences of the new rules on the evolution of the regional political systems are taken into account. In its second part the essay focuses, also from an historical perspective, on the position of the Regional Law in the system of the sources of the law, and its role in shaping the regional autonomy.

We report on a case of EWSR1-PATZ1 rearranged brain tumor occurring in a 17 month-old child, originally interpreted as an infantile glioblastoma. Our case shows important analogies with the 2 previously reported cases, including the intraventricular location, the histologic appearance (pushing borders, oligodendrocyte-like morphology, rich vascular network) and the glioneural immunophenotype, supporting the role of these features as relevant clues to the diagnosis. On the other hand, our case displays unique characteristics, i.e. the onset in an infant, the presence of a focal high-grade component and the leptomeningeal dissemination, pointing to the importance of considering this entity in the differential diagnosis of an infantile glial/glioneural tumor.

To investigate the presence of Cyclospora cayetanensis, Toxoplasma gondii and Echinococcus spp. in fresh produce sold in Italy, 324 locally produced 'ready-to-eat' (RTE) mixed-salad packages belonging to three brands and 324 berries packages (blueberries and blackberries imported from Peru and Mexico, respectively, and raspberries grown in Italy) were purchased at retail. Nine individual packages from each of the six types of fresh produce were collected monthly for one year, and with the same produce pooled, this resulted in a total of 72 pools for the whole year. Using microscopy (FLOTAC), a Cyclospora-like oocyst was detected in a blueberry sample and a taeniid egg was detected in a RTE-salad sample. Molecular tools confirmed these to be C. cayetanensis and Echinococcus multilocularis, respectively. Toxoplasma gondii was not detected in any of the samples. This study shows for the first time in Europe that imported berries on the Italian market may be contaminated with C. cayetanensis and RTE salads grown in Italy with E. multilocularis. The results indicate a new epidemiological scenario and highlight that current management of fresh produce, locally produced or imported, does not ensure products are free from parasite contamination.

Esame della prima decisione con la quale la Corte costituzionale ha sospeso l'efficacia di una legge regionale (in materia di contenimento della pandemia) in attesa della pronuncia di merito.

Background Only few data are available on treatment-associated behavior of distinct rare CNS embryonal tumor entities previously treated as “CNS-primitive neuroectodermal tumors” (CNS-PNET). Respective data on specific entities, including CNS neuroblastoma, FOXR2 activated (CNS NB-FOXR2), and embryonal tumors with multilayered rosettes (ETMR) are needed for development of differentiated treatment strategies. Methods Within this retrospective, international study, tumor samples of clinically well-annotated patients with the original diagnosis of CNS-PNET were analyzed using DNA methylation arrays (n = 307). Additional cases (n = 66) with DNA methylation pattern of CNS NB-FOXR2 were included irrespective of initial histological diagnosis. Pooled clinical data (n = 292) were descriptively analyzed. Results DNA methylation profiling of “CNS-PNET” classified 58 (19%) cases as ETMR, 57 (19%) as high-grade glioma (HGG), 36 (12%) as CNS NB-FOXR2, and 89(29%) cases were classified into 18 other entities. Sixty-seven (22%) cases did not show DNA methylation patterns similar to established CNS tumor reference classes. Best treatment results were achieved for CNS NB-FOXR2 patients (5-year PFS: 63% ± 7%, OS: 85% ± 5%, n = 63), with 35/42 progression-free survivors after upfront craniospinal irradiation (CSI) and chemotherapy. The worst outcome was seen for ETMR and HGG patients with 5-year PFS of 18% ± 6% and 22% ± 7%, and 5-year OS of 24% ± 6% and 25% ± 7%, respectively. Conclusion The historically reported poor outcome of CNS-PNET patients becomes highly variable when tumors are molecularly classified based on DNA methylation profiling. Patients with CNS NB-FOXR2 responded well to current treatments and a standard-risk CSI-based regimen may be prospectively evaluated. The poor outcome of ETMR across applied treatment strategies substantiates the necessity for evaluation of novel treatments.

Bovine viral diarrhea virus (BVDV) and classical swine fever virus (CSFV) are members of the genus Pestivirus that cause disease in wild and domestic animals and are responsible for extensive economic losses of livestock and biological industry. BVDV is also a significant laboratory contaminant. Currently, no effective antiviral therapeutics are available to control their infection. Ginsenosides, as major pharmacological ingredients in the plants of ginseng, have various biological activities. In the present work, the antiviral activity of 9 ginsenosides and 3 other saponins from Araliaceae plants was investigated against Pestivirus. Ginsenoside Rb2 and Rb3 showed low cytotoxicity and obvious antiviral effect. They were able to inhibit the replication and proliferation of BVDV and CSFV. In addition, our results suggest that the possible antiviral mechanism of Rb2 might be related to its ability to affect the translation of these viruses. Obtained results suggest that ginsenoside Rb2 and Rb3 have a potential for effective treatment against Pestivirus infection.

Simple Summary Castration is used to improve the management of buffalo calves and their meat quality. Despite the growing interest in livestock welfare, water buffaloes have not been studied as frequently as other species. General anaesthesia produces complete unconsciousness, insensitivity to pain and muscle relaxation. The quality and safety of general anaesthesia may be improved using sedatives prior to the induction of general anaesthesia. The aim of this study was to evaluate the effect of two different intramuscular doses of xylazine for premedication, followed by ketamine induction, in water buffalo calves undergoing isoflurane maintenance anaesthesia for routine castration surgery. Based on the results obtained, we can conclude that both protocols are safe for buffalo castration, but the higher dose protocol is recommended for buffalo orchiectomy. Abstract Castration is one of the most frequently performed surgical procedures in livestock. All methods of castration are associated with a significant degree of pain, affecting the patients’ welfare. Limited information on species-specific protocols in buffaloes is available. Considering the importance of this species and the scarcity of reports available, the objective of this study was to evaluate the effects of two different intramuscular doses of xylazine for premedication in water buffalo calves undergoing isoflurane maintenance anaesthesia for routine castration surgery. Twenty clinically healthy male water buffaloes undergoing bilateral orchiectomy were randomly assigned to two groups of 10 animals each: Group 1 was premedicated with xylazine 0.1 mg/kg bw i.m. and Group 2 was premedicated with xylazine 0.15 mg/kg bw i.m. Anaesthesia was induced by ketamine (2 mg/kg bw i.v.) and maintained with isoflurane-oxygen-air in both groups. The HR, RR, presence/absence of ataxia, sedation, depth of anaesthesia, muscle relaxation status, response to acoustic and tactile stimuli, eyelid reflex, extent of salivation and stimulus were evaluated every 5 min. Both protocols provided consistent sedation and were safe. Faster and more satisfactory sedation was recorded when xylazine was administered at 0.15 mg/kg bw i.m., leading us to recommend this dose for buffalo orchiectomy.

Background and Objective: Pediatric guidelines on celiac disease (CD) state that children with anti-transglutaminase antibodies (TGAs) &gt, ×10 upper limit of normal (ULN) may avoid endoscopy and biopsy. We aimed to evaluate whether these criteria may be suitable for villous atrophy diagnosis in CD adults. Materials and Methods: We retrospectively enrolled patients with CD aged &gt, 18 years. TGAs were expressed as xULN. Duodenal lesions were classified as atrophic or non-atrophic according to Marsh-Oberhuber. Fisher’s exact and t-test were used for variables comparison. Receiver operating characteristics (ROC) curve analysis was performed with estimation of area under the curve (AUC), sensitivity, specificity, and positive and negative predictive value (PPV/NPV). Results: One hundred and twenty-one patients were recruited. Sixty patients (49.6%) had TGA &gt, ×10 ULN, and 93 (76.8%) had villous atrophy. The cut-off of &gt, ×10 ULN had sensitivity = 53.7%, specificity = 64.3%, PPV = 83.3%, and NPV = 29.5% to predict atrophy. Therefore, considering pediatric criteria, in 50 (41.3%) patients, biopsy could have been avoided. Patient subgroup with atrophy had higher TGA levels despite being not significant (37.2 ± 15.3 vs. 8.0 ± 1.3 ULN, p = 0.06). In adults, a slightly better diagnostic performance was obtained using a cut-off of TGA &gt, ×6.2 ULN (sensitivity = 57.1%, specificity = 65.6%, and AUC = 0.62). Conclusions: Despite our confirmation that villous atrophy is linked to high TGA levels, CD and atrophy diagnosis based only on serology is not reliable in adults.

Following the reduction in levels of exposure to benzene over the last few decades, the cancer risk of refuelers currently represents an occupational hygiene issue potentially underestimated by employers and workers themselves. Based on the literature data, the occurrence of adverse effects of neoplastic nature can not actually be excluded in this professional category, since it is not possible to define a threshold dose. In the period 2016 - 2019, an extensive focused campaign of labour inspections was conducted in the province of Bari by the OSH inspection services of the Health Local Authority in order to verify the compliance with the legislation on the workers' protection from carcinogenic agents at fuel stations. In particular, the obligations referring risk assessment, workplace hygiene, environmental monitoring, personal protective equipment (PPE), health surveillance, biological monitoring and recording of exposure to carcinogens were verified. Although these obligations were documentarily fulfilled by almost all the 162 plants inspected in the province of Bari, several critical issues were found in the approach to carcinogenic risk, including, more frequently, the lack of suitable changing rooms with relative lockers for clothing, the scarce use of gloves when dispensing fuel, the absence or incompleteness of the carcinogenic risk assessment documents, the failed or incorrect execution of biological monitoring. Data of the environmental monitoring carried out by the companies confirm that the current exposures to benzene of fuel distributors are considerably below the limit values set by the Italian legislation. The most frequently used biological exposure indicator was trans, trans-muconic urinary acid (TTMA-U). In order to reduce as much as possible the health risks for refuelers, it is needed that employers, workers and occupational physicians pay more attention to their respective duties, ensuring corrective or ameliorative interventions focused on assessment of the risk of carcinogens, supply and use of PPE, design of workplaces, health surveillance and biological monitoring of workers. The poor value of the end-of-shift TTMA-U as a biological indicator of exposure to low-dose benzene is also confirmed.A seguito della riduzione dei livelli di esposizione a benzene nel corso degli ultimi decenni, il rischio cancerogeno degli addetti al rifornimento di carburante rappresenta oggi un problema di igiene del lavoro potenzialmente sottovalutato dai datori di lavoro e dagli stessi lavoratori. I dati di letteratura non consentono peraltro di escludere la possibilità di effetti avversi di natura neoplastica in tale categoria professionale, non essendo possibile definire una dose soglia. Nel periodo 2016 - 2019, sul territorio della provincia di Bari, è stato condotto da parte dei competenti Organi di Vigilanza un esteso piano mirato di vigilanza atto a verificare il rispetto della normativa in materia di protezione dei lavoratori da agenti cancerogeni presso gli impianti di distribuzione carburante per autotrazione. Sono stati verificati in particolare gli obblighi in materia di valutazione dei rischi, igiene dei luoghi di lavoro, monitoraggio ambientale, dispositivi di protezione individuali (DPI), sorveglianza sanitaria, monitoraggio biologico, registri di esposizione ad agenti cancerogeni. Sebbene tali obblighi siano risultati assolti dal punto di vista documentale dalla quasi totalità dei 162 impianti ispezionati nella provincia di Bari, diverse criticità sono state riscontrate nell’approccio al rischio cancerogeno, tra le quali, con maggiore frequenza,la mancanza di idonei locali ad uso spogliatoio con relativi armadietti per gli indumenti, lo scarso impiego di guanti in fase di erogazione carburante, la assenza o incompletezza dei documenti di valutazione del rischio cancerogeno, la mancata o errata esecuzione del monitoraggio biologico. Gli esiti dei monitoraggi ambientali effettuati dalle aziende confermano che le attuali esposizioni a benzene degli addetti alla distribuzione di carburante sono notevolmente al di sotto dei valori limite fissati dalla normativa italiana. L’indicatore biologico di esposizione più frequentemente utilizzato è risultato l’acido trans, trans-muconico urinario (TTMA-U). Al fine di contribuire a ridurre il più possibile i rischi per la salute per gli addetti al rifornimento di carburante, è necessaria da parte dei datori di lavoro, dei lavoratori e dei Medici competenti una maggiore attenzione ai rispettivi obblighi, con interventi correttivi o migliorativi mirati alle attività di valutazione del rischio da agenti cancerogeni, fornitura ed utilizzo dei DPI, progettazione dei luoghi di lavoro, sorveglianza sanitaria e monitoraggio biologico. Si conferma inoltre lo scarso valore del TTMA-U di fine turno quale indicatore biologico di esposizione a benzene in caso di bassi livelli espositivi.

The authors would like to inform you that Professor Gianspero's second affiliation, IRCCS Neuromed, Pozzilli (Is), Italy, was omitted from the article in error. The authors would like to apologise for this omission.

Poultry red mites (Dermanyssus gallinae) are primarily ectoparasites of laying hens but also parasitize synanthropic birds in urban contexts. This mite can occasionally attack mammals, including humans, and cause mild to severe dermatitis. Attacks by zoonotic Mesostigmata mites are currently an increasing but still neglected problem of urban life. The authors present two cases of dermanyssosis involving two health workers at a hospital, linked to air conditioning outdoor units colonized by pigeons. Videos that describe the environmental contamination by D. gallinae and show where the infestation originated are presented. In addition, the authors update the literature of all urban cases, which, to date, reports over 240 clinical cases, mostly in private homes but also in public buildings. Dermatitis due to these mites is often unrecognized and, therefore, misdiagnosed. This report describes how the two cases herein reported were rapidly resolved thanks to the close cooperation between veterinary parasitologists and allergologists. It is crucial to raise awareness of the problem among general practitioners and specialists. In addition, the authors suggest a reconsideration of urban architectural choices that increase the public health risk posed by dermanyssosis and other diseases related to synanthropic birds.

AIMS: We report a cohort of YCMB cases homogeneously treated with HDCT in two Italian institutions, and the prognostic impact of histology and genetics retrospectively evaluated. METHODS: All YCMB (aged≤3 years) treated with upfront HDCT in the period 1998-2019 were included, reclassified according to the WHO2021 classification of CNS tumours. Mutational status ofPTCH1, SUFU, and TP53 was analysed in selected cases. Histology and genetics were correlated with survival, secondary tumours(STs), and cancer predisposition syndromes(CPSs). RESULTS: Fifty-three patients were enrolled (62.3% male), median age 2.2 years. 21 had classic(CMB), 15 desmoplastic/nodular(DMB), 11 MBEN and 6 large-cell/anaplastic(AMB/LCMB) medulloblastoma. Metastases were present in 18. Genomic pattern showed SHH-TP53wt in 29 cases, non-WNT/non-SHH in 22; 2 were SHH-TP53mut. Induction chemotherapy (VCR/HDMTX, HDVP16, VCR/HDCTX and HDCARBO) was followed by 2-3 HDCT courses; irradiation reserved to cases with metastatic disease and/or residual tumours. 22 patients never received irradiation. SHH-TP53wt cases had significantly less metastasis (p=0.002), while non-WNT/non-SHH received more often irradiation (p

BACKGROUND: Gliomatosis cerebri (GC), a radiologically defined diffusely infiltrating glioma, is no longer considered a distinct entity since the 2016 WHO classification for tumors of the CNS. Due to its rarity and dismal prognosis treatment recommendations in children remain ambiguous. Using central neuroradiological review, we performed a multi-institutional, retrospective study of GC providing comprehensive radiological, clinical, and (epi)genetic characterization. RESULTS: We included 104 patients between 1-19 years. Within a median follow-up of 15.5 months (range, 2.3-138.8), 93 patients (89.4 %) had died, 4 (3.8 %) were lost to follow-up and 7 (6.8 %) were alive with stable/progressive disease. Median progression-free- (PFS) and overall survival (OS) were 8.6 months (interquartile range, 4.3-14.0) and 15.5 months (10.9-27.7), respectively. Former WHO grading correlated significantly with median OS: WHO °II: 47.8 months (25.2-55.7); WHO °III: 15.9 months (11.4-26.3); WHO °IV: 10.4 months (8.8-14.4) (p

Introduction: Medulloblastoma is the most common malignant brain tumor in children, but accounts for only 1% of brain cancers in adults. For standard-risk pediatric medulloblastoma, current therapy includes craniospinal irradiation (CSI) at reduced doses (23.4Gy) associated with chemotherapy. Whereas most same-stage adult patients are still given CSI at 36Gy, with or without chemotherapy, we report here on our use of reduced-dose CSI associated with chemotherapy for older patients. Methods: We gathered non-metastatic patients over 18years old (median age 28years, range 18–48) with minimal or no residual disease after surgery, no negative histological subtypes, treated between 1996–2018 at the Centre Léon Bérard (Lyon) and the INT (Milano). A series of 54 children with similar tumors treated in Milano was used for comparison. Results: Forty-four adults were considered (median follow-up 101months): 36 had 23.4Gy of CSI, and 8 had 30.6Gy, plus a boost to the posterior fossa/tumor bed; 43 had chemotherapy as all 54 children, who had a median 83-month follow-up. The PFS and OS were 82.2 ± 6.1% and 89 ± 5.2% at 5 years, and 78.5 ± 6.9% and 75.2 ± 7.8% at ten, not significantly different from those of the children. CSI doses higher than 23.4Gy did not influence PFS. Female adult patients tended to have a better outcome than males. Conclusion: The results obtained in our combined series are comparable with, or even better than those obtained after high CSI doses, underscoring the need to reconsider this treatment in adults.

Medulloblastoma is a highly aggressive brain tumor that typically affects children, while in adults it represents ~1% of all brain tumors. Little is known about microRNA expression profile of the rare adult medulloblastoma. The main aim of this study was to identify peculiar differences in microRNA expression between childhood and adult medulloblastoma. Medulloblastomas were profiled for microRNA expression using the Exiqon Human miRNome panel (I + II) analyzing 752 microRNAs in a training set of six adult and six childhood cases. Then, the most differentially expressed microRNAs were validated in a total of 21 adult and 19 childhood cases. Eight microRNAs (miR-196b-5p, miR-183-5p, miR-200b-3p, miR-196a-5p, miR-193a-3p, miR-29c-3p, miR-33b-5p, and miR-200a-3p) were differentially expressed in medulloblastoma of adults and children. Analysis of the validation set confirmed that miR-196b-5p and miR-200b-3p were significantly overexpressed in medulloblastoma of adults as compared with those of children. We followed an in silico approach to investigate direct targets and the pathways involved for the two microRNAs (miR-196b and miR-200b) differently expressed between adult and childhood medulloblastoma. Adult and childhood medulloblastoma have different miRNA expression profiles. In particular, the differential dysregulation of miR-196b-5p and miR-200b-3p characterizes the miRNA profile of adult medulloblastoma and suggests potential targets for novel diagnostic, prognostic, or therapeutic strategies.

Context.— Standards for pathology reporting of cancer are foundational to national and international benchmarking, epidemiology, and clinical trials, with international standards for pathology reporting of cancer being undertaken through the International Collaboration on Cancer Reporting (ICCR). Objective.— To develop standardized templates for brain tumor diagnostic pathology reporting. Design.— As a response to the 2016 updated 4th edition of the WHO (World Health Organization) Classification of Tumours of the Central Nervous System (2016 CNS WHO), an expert ICCR committee developed data sets to facilitate reporting of brain tumors that are classified histologically and molecularly by the 2016 CNS WHO; as such, this represents the first combined histologic and molecular ICCR data set, and required a novel approach with 3 highly related data sets that should be used in an integrated manner. Results.— The current article and accompanying ICCR Web site describe reporting data sets for central nervous system tumors in the hope that they provide easy-to-use and highly reproducible means to issue diagnostic reports in consort with the 2016 CNS WHO. Conclusions.— The consistent use of these templates will undoubtedly prove useful for patient care, clinical trials, epidemiologic studies, and monitoring of neuro-oncologic care around the world.

Analisi, alla luce della giurisprudenza costituzionale, del rapporto tra competenze statali e regionali in materia di tutela dell'ambiente.

Esame degli strumenti di gestione della pandemia COVID-19 con particolare riferimento ai primi mesi dell'emergenza, sul piano delle omogeneità e delle differenziazioni territoriali.

Analisi del rapporto della normativa emergenziale in rapporto al sistema delle fonti preesistenti, con particolare riguardo al rapporto tra competenze statali e regionali.

SMARCB1 inactivation is a well-established trigger event in atypical teratoid/rhabdoid tumor. Recently, a role for SMARCB1 inactivation has emerged as a mechanism of clonal evolution in other tumor types, including rare brain tumors. We describe an unusual malignant intra-axial SMARCB1-deficient spindle cell desmoplastic neoplasm, occurring in a 6-year-old child with meningioangiomatosis and a long history of seizures. Striking features of the tumor were a storiform pattern and strong CD34 expression. Undifferentiated round cell areas with isolated rhabdoid cells showing high mitotic index and focal necrosis with INI1 expression loss were present. The meningioangiomatosis component showed few chromosomal imbalances, including chromosomal 22 monosomy (where SMARCB1 maps) and gain at 6q14.3. In addition to these abnormalities, the spindle cell desmoplastic neoplasm and its dedifferentiated SMARCB1-deficient component shared several other aberrations, including homozygous deletion at 9p21.3, losses at 1p, 3p, 3q, 10p, and 13q, gains and losses at 5p and 11p. In line with INI1 loss, the dedifferentiated component showed remarkably decreased levels of SMARCB1 transcript. The residual SMARCB1 allele was wildtype. Our findings suggest progression from the meningioangiomatosis to the malignant desmoplastic neoplasm through the occurrence of complex chromosomal abnormalities, and point to functional silencing of SMARCB1 in the dedifferentiation component.

Background There is a paucity of knowledge regarding pediatric biomarkers, including the relevance of ErbB pathway aberrations in pediatric tumors. We investigated the occurrence of ErbB receptor aberrations across different pediatric malignancies, to identify patterns of ErbB dysregulation and define biomarkers suitable for patient enrichment in clinical studies. Procedure Tissue samples from 297 patients with nervous system tumors and rhabdomyosarcoma were analyzed for immunohistochemical expression or gene amplification of epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor 2 (HER2). Exploratory analyses of HER3/HER4 expression, and mRNA expression of ErbB receptors/ligands (NanoString) were performed. Assay validation followed general procedures, with additional validation to address Clinical Laboratory Improvement Amendments (CLIA) requirements. Results In most tumor types, samples with high ErbB receptor expression were found with heterogeneous distribution. We considered increased/aberrant ErbB pathway activation when greater than or equal to two EGFR/HER2 markers were simultaneously upregulated. ErbB pathway dysregulation was identified in ∼20%-30% of samples for most tumor types (medulloblastoma/primitive neuroectodermal tumors 31.1%, high-grade glioma 27.1%, neuroblastoma 22.7%, rhabdomyosarcoma 23.1%, ependymoma 18.8%), 4.2% of diffuse intrinsic pontine gliomas, and no recurrent or refractory low-grade astrocytomas. In medulloblastoma/primitive neuroectodermal tumors and neuroblastoma, this was attributed mainly to high EGFR polysomy/HER2 amplification, whereas EGFR gene amplification was observed in some high-grade glioma samples. EGFR/HER2 overexpression was most prevalent in ependymoma. Conclusions Overexpression and/or amplification of EGFR/HER2 were identified as potential enrichment biomarkers for clinical trials of ErbB-targeted drugs.

The authors wish to make the following corrections to this paper [...]

Seminal plasma (SP) of donkey stallions was evaluated using various oxidative stress parameters as well as protease and protease inhibitor activities. SP was obtained by nine donkey stallions. In addition, one donkey stallion with non-obstructive azoospermia was enrolled in this study. Free radical scavenging activity (FRSA), the ferric reducing ability of plasma (FRAP), total antioxidant capacity (TAC), and total thiol level (TTL) were highly correlated with each other and with the protease inhibitor activity. However, only FRAP, TAC, and the nitrate/nitrite concentration (NOx) were significantly correlated with sperm concentration, production, and kinetics. Protease inhibitor activity was highly correlated with sperm concentration and production; however, it did not correlate with sperm kinetics. The azoospermic stallion produced a lower amount of semen than the normospermic stallions and its SP showed a lower antioxidant activity when evaluated with FRAP, TAC, and TTL as well as a higher NOx and a lower protease inhibitor activity. In conclusion, the evaluation of SP oxidative profile by FRAP, TAC, and NOx may provide reliable information on donkey sperm quality whereas protease inhibitor activity may play a role as a marker of the sperm concentration in this species.

BACKGROUND: Considering that pediatric high-grade gliomas (HGGs) are biologically distinct from their adult counterparts, the objective of this study was to define the landscape of HGGs in adolescents and young adults (AYAs). METHODS: We performed a multicentric retrospective study of 112 AYAs from adult and pediatric Ile-de-France neurosurgical units, treated between 1998 and 2013 to analyze their clinicoradiological and histomolecular profiles. The inclusion criteria were age between 15 and 25 years, histopathological HGG diagnosis, available clinical data, and preoperative and follow-up MRI. MRI and tumoral samples were centrally reviewed. Immunohistochemistry and complementary molecular techniques such as targeted/next-generation sequencing, whole exome sequencing, and DNA-methylation analyses were performed to achieve an integrated diagnosis according to the 2016 World Health Organization (WHO) classification. RESULTS: Based on 80 documented AYA patients, HGGs constitute heterogeneous clinicopathological and molecular groups, with a predominant representation of pediatric subtypes (histone H3-mutants, 40%) but also adult subtypes (isocitrate dehydrogenase [IDH] mutants, 28%) characterized by the rarity of oligodendrogliomas, IDH mutants, and 1p/19q codeletion and the relative high frequency of “rare adult IDH mutations” (20%). H3G34-mutants (14%) represent the most specific subgroup in AYAs. In the H3K27-mutant subgroup, non-brainstem diffuse midline gliomas are more frequent (66.7%) than diffuse intrinsic pontine gliomas (23.8%), contrary to what is observed in children. We found that WHO grade has no prognostic value, but molecular subgrouping has major prognostic importance. CONCLUSIONS: HGGs in AYAs could benefit from a specific classification, driven by molecular subtyping rather than age group. Collaborative efforts are needed from pediatric and adult neuro-oncology teams to improve the management of HGGs in AYAs.

Summary: The transition of neural progenitors to differentiated postmitotic neurons is mainly considered irreversible in physiological conditions. In the present work, we show that Shh pathway activation through SmoM2 expression promotes postmitotic neurons dedifferentiation, re-entering in the cell cycle and originating medulloblastoma in vivo. Notably, human adult patients present inactivating mutations of the chromatin reader BRPF1 that are associated with SMO mutations and absent in pediatric and adolescent patients. Here, we found that truncated BRPF1 protein, as found in human adult patients, is able to induce medulloblastoma in adult mice upon SmoM2 activation. Indeed, postmitotic neurons re-entered the cell cycle and proliferated as a result of chromatin remodeling of neurons by BRPF1. Our model of brain cancer explains the onset of a subset of human medulloblastoma in adult individuals where granule neuron progenitors are no longer present. : Medulloblastoma is a brain tumor affecting the cerebellum of infants and adults. Aiello et al. establish a mouse model for adult onset, which allows investigation of the pathogenesis of the disease and identifies neurons as putative cells of origin. Keywords: medulloblastoma, dedifferentiation, cell-of-origin, BRPF1, super-enhancers, SHH, adult

Tea Tree oil (TTO), the essential oil from the Australian native Melaleuca alternifolia has demonstrated a variety of beneficial efficacies including antimicrobial, antifungal, antiviral and anti-inflammatory. This report discusses data obtained on the in vitro activity of TTO on human glioblastoma cells U87MG. Cell viability was examined by 2-(4,5-dimethyl-2-thiazolyl)-3,5-diphenyl-2H-tetrazolium bromide MTT assay. Growth was investigated by incubating cells with various concentrations of TTO (0.025 and 0.05 %) for 24, 48 or 72 h and daily cell count. Cell cycle and apoptosis assay were assessed by flow citometry. TTO decreased cell viability in a dose and time-dependent manner. . The cell cycle distribution showed that TTO enhanced the accumulation of the cells in G0/G1 phase. The analysis by Western blot of protein related to cell cycle (CDK2 and p27), cell apoptosis (caspase 6 and 8), necrosis (TNFR1 and RIP1) demonstrated that TTO induces U87MG growth inhibition by more synergic mechanisms: necrosis, low level apoptosis and cell cycle arrest. TTO induces also in vivo glioblastoma tumor growth inhibition in a murine subcutaneous model. Key words: Brain cancer, tea tree oil, terpinol, glioblastoma, natural drug, adjuvant chemotherapy, temozolomide, apoptosis, cell cycle.

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.

Blastocystis is a ubiquitous protozoan with a wide range of hosts. In humans, its presence has been associated with gastrointestinal disorders, although its role as a pathogen still needs to be elucidated. Until now, 17 Blastocystis subtypes (STs) have been identified, with ST1-ST4 the most commonly found in humans. Among domestic animals, the same STs reported in humans have been detected in dogs. An epidemiological survey on dog kennels was carried out to evaluate the prevalence of Blastocystis and the STs involved. Overall, 99 faecal samples were collected from the rescue shelters. Blastocystis detection was performed through conventional barcoding PCR targeting the 1800-bp SSU-rDNA, followed by sequencing and phylogenetic analysis. Blastocystis DNA was found in 21 faecal samples (21.2%), and all samples were successfully sequenced and identified as ST3 in a unique monophyletic group. The presence of Blastocystis was reported for the first time in dogs from Italy, with the identification of ST3, the subtype most commonly found in humans.

Pestiviruses are responsible for widespread diseases affecting cattle, pigs and other ruminants, presenting a wide range of clinical manifestations, with significant impact on animal production. Given the recent various reports of a relatively high number of new strains and atypical genomic variants, in the present study, ninety-seven genomic sequences from southern Italy have been evaluated applying the palindromic nucleotide substitutions method, based on 5’-UTR secondary structure alignment and computing genetic distance among strains in the internal ribosome entry site. Sequence analysis revealed a highly heterogeneous virus population, indicating the introduction of virus variants of Bovine viral diarrhea virus and Border disease virus species from foreign countries. The application of different analytical procedures was useful to avoid interpretation difficulties. Circulation of heterogeneous virus populations showed the need for more accurate epidemiological investigations and stringent veterinary controls to protect animal health and welfare.

Mediterranean mussels ( Mytilus galloprovincialis) and blue mussels ( Mytilus edulis) are among the most consumed fishery products, but they are frequent vehicles of foodborne infection worldwide. In this study, we investigated the occurrence and seasonality of zoonotic protozoans in mussels farmed or sold at retail outlets in Italy. We collected and tested 1,440 M. galloprovincialis and 180 M. edulis. Pooled samples were molecularly tested for Giardia duodenalis, Cryptosporidium spp., and Toxoplasma gondii and then sequenced. Sixty-two (45.9%; 95% confidence interval, 37.5 to 54.3%) mussel pools tested positive for one or more of the investigated pathogens. Both Mytilus species and samples from all the investigated areas harbored pathogens. Mussels were statistically more contaminated by Cryptosporidium spp., followed by T. gondii and G. duodenalis assemblage A, and M. galloprovincialis was more contaminated than M. edulis ( P < 0.01). Contamination was more likely in mussels at retail outlets ( P < 0.05) than in those from farms and in mussels collected in spring ( P < 0.01) than in other seasons. This is the first report of T. gondii found in M. galloprovincialis in Italy and in M. edulis in Europe. The detection of zoonotic protozoans in a widely consumed food source indicates the need for a more detailed microbiological risk analysis, especially considering that bivalve mollusks are often consumed raw worldwide.

The role of amino acid positron emission tomography (PET) in glioma grading and outcome prognostication has not yet been well established. This is particularly true in the context of the new WHO 2016 classification, which introduced a definition of glioma subtypes primarily based on molecular fingerprints. The aim of the present study was to correlate 3,4‑dihydroxy‑6‑[18F]‑fluoro-l‑phenylalanine (F-DOPA) uptake parameters with IDH mutation, 1p/19q status, and survival outcomes in patients with glioma. The study population consisted of 33 patients (17 M/16 F, mean age: 46 ± 13 years) who underwent F-DOPA PET/CT for the evaluation of tumor extent before the start of chemo or radiotherapy. The presence of IDH mutation and 1p/19q status was assessed in all the cases. Tumor volume and semiquantitative uptake parameters, namely SUVmax, tumor-to-normal brain ratio and tumor-to-normal striatum ratio, were calculated for each tumor. Imaging-derived parameters were compared between patients stratified according to molecular fingerprints, using parametric or non-parametric tests, where appropriate. The Kaplan–Meier method was used to assess differences of overall survival (OS) and progression-free survival (PFS) between groups. PET parameters were also tested as prognostic factors in univariate Cox survival regression models. There were 12 IDH-wild-type and 21 IDH-mutant patients. Stratification according to 1p/19q co-deletion resulted in 20 non-co-deleted and 13 co-deleted patients. Median follow-up time from PET/CT exam was 30.5 months (range 3.5–74 months). Semiquantitative uptake parameters did correlate neither with IDH mutation nor with 1p/19q status. Uptake was similar in low-grade and high-grade tumors, respectively. In addition, F-DOPA uptake parameters, macroscopic tumor volume, or tumor grade did not stratify OS, while a correlation between SUVmax and PFS was shown in the subgroup of astrocytomas. On the other hand, IDH mutation status and presence of 1p/19q co-deletion had a significant impact on survival outcomes. The prognostic value of IDH mutation status was also confirmed in the subgroup of patients with astrocytic tumors. F-DOPA uptake parameters do not correlate with tumor molecular and histological characteristics. The predictive value of PET-derived parameters on outcomes of survival is limited.

Dermanyssus gallinae is a haematophagous ectoparasite primarily known as a pest of domestic and wild birds. It occasionally feeds on a range of mammals, and, more importantly, is of growing concern in human medicine. This review highlights mite attacks on people working with poultry, and updates the increasing incidence of dermanyssosis in urban environments in Europe. Although several cases of dermanyssosis have been documented, there are a number of reasons why diagnosis of D. gallinae infestations in humans is likely to be underestimated. Firstly, medical specialists are not well aware of D. gallinae infestations in humans. There is also a lack of collaboration with specialists from other disciplines. The problem is compounded by misdiagnoses and by the lack of diagnostic tools. We review the literature on human dermanyssosis cases in Europe, and also provide information on the epidemiology, clinical, histo-pathological and immunological aspects of dermanyssosis. We stress the need for improved recognition of this challenging infestation in humans, and provide straightforward recommendations for health practitioners, starting with collection of the correct anamnestic information and including appropriate management methods for case recognition and resolution. Finally, we indicate the most urgent areas to be addressed by future research. RESEARCH HIGHLIGHTSDermanyssus gallinae is of growing concern in human medicine. Most physicians are not well aware of dermanyssosis in humans. Bio-epidemiological and clinical aspects of this ectoparasitosis are highlighted. Practical key actions for diagnosis and correct management of infestation in humans are provided.

Pestivirus are responsible for cosmopolitan diseases affecting cattle, pigs and other ruminants, presenting a wide range of clinical manifestations, with relevant impact on zootechnic production. Understanding genomic characteristic and virus taxonomy is fundamental in order to sustain control and prophylactic programs. Given the recent various studies reporting a relatively high number of new strains, in particular from Asian countries, in the present study, six hundred-fifty-one genomic sequences have been considered applying the palindromic nucleotide substitutions method for genotyping. Based on the secondary structure analysis of the 5’ untranslated region of RNA, sequence characteristics among Asian genomic clusters within the different Pestivirus species suggested geographic segregation and occurrence of micro-evolutive steps in the genus evolutionary history. This aspect was particularly evident in atypical sequences originated from China or Turkey, indicating risk of diffusion by animals and products trade or contamination of biological products as bovine calf serum, with potential diagnostic and control difficulties.

Despite the economic and animal welfare importance of the Poultry Red Mite Dermanyssus gallinae, its genetic structure has been studied in a scattered way so far. The prophylaxis and control of such a globally distributed ectoparasite can be significantly improved by understanding its genetic population structure (composition in species and intraspecific variants). The present study aims to establish a rigorous framework for characterizing the neutral genetic structure of D. gallinae based on a literature review combined with an integrative analysis of the data available in GenBank on population-level nucleotide sequence diversity supplemented by a new dataset. The integrative analysis was conducted on sequence data extracted from GenBank coupled with new sequences of two fragments of the mitochondrial gene encoding Cytochrome Oxidase I (CO1) as well as of an intron of the nuclear gene encoding Tropomyosin (Tpm) from several PRM populations sampled from European poultry farms. Emphasis was placed on using the mitochondrial gene encoding CO1 on which the main universal region of DNA barcoding in animals is located. The species D. gallinae sensu lato is a species complex, encompassing at least two cryptic species, i.e., not distinguishable by morphological characters: D. gallinae sensu stricto and D. gallinae L1. Only D. gallinae s.s. has been recorded among the populations sampled in poultry farms worldwide. Current knowledge suggests they are structured in three mitochondrial groups (haplogroups A, B, and C). Haplogroup A is cosmopolitan, and the other two present slightly contrasted distributions (B rather in the northern part of Europe, C most frequently found in the southern part). Recent data indicate that a dynamic geographic expansion of haplogroup C is underway in Europe. Our results also show that NUMT (nuclear mitochondrial DNA) pseudogenes have generated artifactual groups (haplogroups E and F). It is important to exclude these artifact groups from future analyses to avoid confusion. We provide an operational framework that will promote consistency in the analysis of subsequent results using the CO1 fragment and recommendations for future analyses.