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Large-scale molecular profiling studies in recent years have shown that central nervous system (CNS) tumors display a much greater heterogeneity in terms of molecularly distinct entities, cellular origins and genetic drivers than anticipated from histological assessment. DNA methylation profiling has emerged as a useful tool for robust tumor classification, providing new insights into these heterogeneous molecular classes. This is particularly true for rare CNS tumors with a broad morphological spectrum, which are not possible to assign as separate entities based on histological similarity alone. Here, we describe a molecularly distinct subset of predominantly pediatric CNS neoplasms (n = 60) that harbor PATZ1 fusions. The original histological diagnoses of these tumors covered a wide spectrum of tumor types and malignancy grades. While the single most common diagnosis was glioblastoma (GBM), clinical data of the PATZ1-fused tumors showed a better prognosis than typical GBM, despite frequent relapses. RNA sequencing revealed recurrent MN1:PATZ1 or EWSR1:PATZ1 fusions related to (often extensive) copy number variations on chromosome 22, where PATZ1 and the two fusion partners are located. These fusions have individually been reported in a number of glial/glioneuronal tumors, as well as extracranial sarcomas. We show here that they are more common than previously acknowledged, and together define a biologically distinct CNS tumor type with high expression of neural development markers such as PAX2, GATA2 and IGF2. Drug screening performed on the MN1:PATZ1 fusion-bearing KS-1 brain tumor cell line revealed preliminary candidates for further study. In summary, PATZ1 fusions define a molecular class of histologically polyphenotypic neuroepithelial tumors, which show an intermediate prognosis under current treatment regimens. © 2021, The Author(s).

A case of a thirty-nine year old woman with cerebral cavernous angiomas who developed anaemia and thrombocytopenia secondary to diffuse liver angiosarcoma is reported. This unique association of liver angiosarcoma and cerebral cavernous angiomas may suggest that this tumour may potentially develop from benign vascular lesions. Hematologic abnormalities in angiosarcomas are moreover reviewed based on recent literature search.

Mouse hepatitis virus, stra in A59 (MHVA59), is a coronav irus that triggers in susceptible mice a wide va riety of pathologies, including hepatitis, thymus in vo luti o n, B lymph ocy te po lyc lona l ac ti va tio n a nd , after intra-cerebral inocul ation, transient demye lination. One recepto r that med iates entry of the virus into ta rget ce lls has bee n ide nti fied: it is a g lycopro te in of the ca rc inoembryo nic a ntige n fa mil y, ca ll ed Bgpl a . Th e ava il abi lit y of a ntibo di es recogni z ing th is mo lecul e permits the analysis of its ce llular expression and of the re lationship between receptor expression and pathology induced by the virus. Bgpl a is fo und on epitheli al and e ndo th e li a l ce lls as we ll as o n B lymph ocy tes a nd macrophages. In the live r, Bgpl a expression correlates we ll with infect ion of hepatocytes and endothelia l cells, leading to the deve lopment of hepatitis. However, other ce lls ex pressing this molecul e, such as centra l nervous system endo the lia l cells, are not in fec ted by the virus. T his o bserva ti o n may exp la in how th e bl ood-b ra in barri er prevents d issemi natio n of MHV-AS9 from the general circu lation into the brain. Thymi c atrophy results fro m a pop tosis of imm a tur e do ubl e-positi ve T lymphocy tes w hi c h mi g ht be ca use d in d irectl y by in fec tion of a small propo rtio n of thymus epitheli al ce lls that express Bgp I a ra ther than by in fec tio n of T cells th at do no t express th e rece ptor. Fin all y, po lyc lo na l ac ti va ti o n of B lym phocy tes, lead in g to in c rease d secre tio n of anti bodies of the IgG2a isotype, involves a cascade of events, including cy tokine secre tion, that may result from the interaction of MHV-A59 with B cells and macrophages that express Bgpl a. Therefore, aft er v iral in fec ti o n , ce llul a r exp ressio n of Bg p la may have d iffe re nt res ults: ce ll lysis; a lt e ra ti o n of ce llul a r functions th at may lead to indirect dea th of other ce ll ty pes, or resistance to in fec tion.

Neurosarcoidosis is a diagnostic challenge, especially in the absence of systemic involvement, even when cerebral biopsies show noncaseating granulomas. We report a patient with a pineal germinoma associated with a extensive peri- and intra- tumoural granulomatous reaction, who was first diagnosed as possible neurosarcoïdosis. A second patient was initially considered as suffering from Multiple Sclerosis. Brain biopsy showed typical granulomas and gallium scintigraphy revealed other locations of the disease. Unfortunately, he developed a severe, steroid-induced, epidural lipomatosis at the Th3-Th8 levels and died unexpectedly after surgical decompression. Granulomatous inflammation in a tissue obtained by biopsy from a midline lesion should be always considered for the differential diagnosis of germinoma. Corticosteroid-sparing immunosuppressant drugs should be used early in neurosarcoïdosis.

Transgenic mice overexpressing the interleukin 9 gene were generated to study the biological activity of this cytokine in vivo. Although no major histological or morphological modifications of the lymphoid system were observed in most animals, approximately 7% of transgenic mice developed thymic lymphomas at the age of 3-9 months. The tumor cells, which were clonal, with unique T cell rearrangements, were double positive for the expression of CD4 and CD8. The need for additional transforming events, suggested by the low incidence of spontaneous tumors, was further indicated by the high susceptibility of the transgenic animals to injections of low doses of N-methyl-N-nitrosourea, a chemical carcinogen with a thymic tropism. Expression of interleukin 9 was required for optimal tumor growth in vivo, as one of the tumors studied, which had lost the transgene, was much more efficiently transplanted into transgenic than in normal mice. Moreover, the in vitro proliferative activity of interleukin 9 on cell lines derived from such transgene-negative tumors suggests that an autocrine loop mediates the proliferation of these cells in vivo. Taken together, these results indicate that dysregulated IL-9 expression could be involved in the development of some T cell malignancies.

International audience; BACKGROUND: Deregulation of cholesterol metabolism represents a hallmark of prostate cancer (PCa) and promotes its development. OBJECTIVE: To compare cholesterol metabolism on individual paired normal and tumour prostate tissues obtained from patients with PCa. DESIGN, SETTING, AND PARTICIPANTS: Between 2008 and 2012, normal and tumour paired tissue samples were collected from radical prostatectomy specimens from a cohort of 69 patients treated for localised PCa. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Tumour and normal tissues were subjected to gene analysis, sterol measurement, and immunohistochemistry. The Wilcoxon paired test and Spearman test were applied for comparison and correlation analyses, respectively. Principal component analysis was also carried out to investigate relationships between quantitative variables. RESULTS AND LIMITATIONS: Overall, cholesterol concentrations were not significantly different between tissue pairs. However, tumour samples were significantly associated with downregulated de novo cholesterol synthesis, but exhibited 54.7% overexpression of SCARB1 that could increase high-density lipoprotein uptake in PCa. Tumour tissues showed different trafficking of available cholesterol, with significantly lower ACAT1, and an altered efflux via APOE. Furthermore, cholesterol metabolism in tumour tissues was characterised by higher accumulation of 7alpha-hydroxycholesterol (OHC), 7betaOHC, and 7-ketosterol, and a lower level of 27OHC. CONCLUSIONS: Focusing on individually paired prostate tissues, our results highlighted several differences between normal and tumour samples linked to a metabolic shift in cholesterol flux. PCa samples exhibited a specific tissue signature characterised by higher SCARB1 expression, higher accumulation of OHC species, and clear downregulation of de novo cholesterol synthesis. PATIENT SUMMARY: Comparing normal and tumour tissues from the same prostates, our study identified a set of alterations in prostate cancer samples in terms of their use of cholesterol. These included higher cholesterol uptake, accumulation of oxidised cholesterol derivatives, and autonomous cellular production of cholesterol. Together, these data provide promising clinical targets to fight prostate cancer.

Conformational diseases result from cellular dysfunctions induced by aberrant aggregation of proteins. They are caused either by excess of secretion of a normal protein, or more frequently, by mutation in a protein, as in prion diseases. Recently, one of them, familial encephalopathy with neuroserpin inclusion bodies (FENIB, OMIM #604218), an autosomal dominant dementia, was recognized. It is caused by mutations in PI12 (proteinase inhibitor 12, SERPINI1 or neuroserpin, OMIM #602445), a neuron-specific serine proteinase inhibitor (serpin).1,2 Neuroserpin was first identified in culture medium of chicken axons, then in human neurons.3 It plays roles in synapses and vessel permeability, and is known to be associated with learning, memory, and behavior. It belongs to the serpin super-family, members of which display at least 30% amino acid sequence homology with their archetype, alpha-1-antitrypsin. Mutated neuroserpin progressively polymerizes in neuronal endoplasmic reticulum, inducing cognitive impairment and sometimes myoclonic epilepsy. Neuropathology is characterized by neuronal intra-cytoplasmic rounded inclusions, homogeneously pale to intensely pink with eosin, and PAS positive after diastase treatment (Collins bodies). Four different mutations have been described in six families affected by FENIB: two in exon 2 (S49P and S52R) and two in exon 9 (H338R and G392E). Known mutations in serpins are localized in the mobile regions of the molecule (exon 2 and 9). They result in proteins …