Summary The unfolded protein response (UPR) is linked to metabolic dysfunction, yet it is not known how ER disruption might influence metabolic pathways. Using a multilayered genetic approach, we find that mice with genetic ablations of either ER stress sensing pathways (ATF6α, eIF2α, IRE1α), or of ER quality control (p58IPK), share a common dysregulated response to ER stress that includes the development of microvesicular steatosis. The rescue of ER protein processing capacity by the combined action of UPR pathways during stress prevents the suppression of a subset of metabolic transcription factors that regulate lipid homeostasis. This suppression occurs in part by unresolved ER stress perpetuating expression of the transcriptional repressor CHOP. As a consequence, metabolic gene expression networks are directly responsive to ER homeostasis. These results reveal an unanticipated direct link between ER homeostasis and the transcriptional regulation of metabolism and suggest mechanisms by which ER stress might underlie microvesicular steatosis.

Intracranial mesenchymal tumors with FET‐CREB fusions are a recently described group of neoplasms in children and young adults characterized by fusion of a FET family gene (usually EWSR1, but rarely FUS) to a CREB family transcription factor (ATF1, CREB1, or CREM), and have been variously termed intracranial angiomatoid fibrous histiocytoma or intracranial myxoid mesenchymal tumor. The clinical outcomes, histologic features, and genomic landscape are not well defined. Here, we studied 20 patients with intracranial mesenchymal tumors proven to harbor FET‐CREB fusion by next‐generation sequencing (NGS). The 16 female and four male patients had a median age of 14 years (range 4–70). Tumors were uniformly extra‐axial or intraventricular and located at the cerebral convexities (n = 7), falx (2), lateral ventricles (4), tentorium (2), cerebellopontine angle (4), and spinal cord (1). NGS demonstrated that eight tumors harbored EWSR1‐ATF1 fusion, seven had EWSR1‐CREB1, four had EWSR1‐CREM, and one had FUS‐CREM. Tumors were uniformly well circumscribed and typically contrast enhancing with solid and cystic growth. Tumors with EWSR1‐CREB1 fusions more often featured stellate/spindle cell morphology, mucin‐rich stroma, and hemangioma‐like vasculature compared to tumors with EWSR1‐ATF1 fusions that most often featured sheets of epithelioid cells with mucin‐poor collagenous stroma. These tumors demonstrated polyphenotypic immunoprofiles with frequent positivity for desmin, EMA, CD99, MUC4, and synaptophysin, but absence of SSTR2A, myogenin, and HMB45 expression. There was a propensity for local recurrence with a median progression‐free survival of 12 months and a median overall survival of greater than 60 months, with three patients succumbing to disease (all with EWSR1‐ATF1 fusions). In combination with prior case series, this study provides further insight into intracranial mesenchymal tumors with FET‐CREB fusion, which represent a distinct group of CNS tumors encompassing both intracranial myxoid mesenchymal tumor and angiomatoid fibrous histiocytoma‐like neoplasms.

High-grade neuroepithelial tumor with BCOR exon 15 internal tandem duplication (HGNET BCOR ex15 ITD) is a recently proposed tumor entity of the central nervous system (CNS) with a distinct methylation profile and characteristic genetic alteration. The complete spectrum of histologic features, accompanying genetic alterations, clinical outcomes, and optimal treatment for this new tumor entity are largely unknown. Here, we performed a comprehensive assessment of 10 new cases of HGNET BCOR ex15 ITD. The tumors mostly occurred in young children and were located in the cerebral or cerebellar hemispheres. On imaging all tumors were large, well-circumscribed, heterogeneous masses with variable enhancement and reduced diffusion. They were histologically characterized by predominantly solid growth, glioma-like fibrillarity, perivascular pseudorosettes, and palisading necrosis, but absence of microvascular proliferation. They demonstrated sparse to absent GFAP expression, no synaptophysin expression, variable OLIG2 and NeuN positivity, and diffuse strong BCOR nuclear positivity. While BCOR exon 15 internal tandem duplication was the solitary pathogenic alteration identified in six cases, four cases contained additional alterations including CDKN2A/B homozygous deletion, TERT amplification or promoter hotspot mutation, and damaging mutations in TP53, BCORL1, EP300, SMARCA2 and STAG2. While the limited clinical followup in prior reports had indicated a uniformly dismal prognosis for this tumor entity, this cohort includes multiple long-term survivors. Our study further supports inclusion of HGNET BCOR ex15 ITD as a distinct CNS tumor entity and expands the known clinicopathologic, radiographic, and genetic features.Brain Pathology 30 (2020) 46-62

Biosynthesis of proteins – from translation to folding to export – encompasses a complex set of events that are exquisitely regulated and scrutinized to ensure the functional quality of the end products. Cells have evolved to capitalize on multiple post-translational modifications in addition to primary structure to indicate the folding status of nascent polypeptides to the chaperones and other proteins that assist in their folding and export. These modifications can also, in the case of irreversibly misfolded candidates, signal the need for dislocation and degradation. The current Review focuses on the glycoprotein quality-control (GQC) system that utilizes protein N-glycosylation and N-glycan trimming to direct nascent glycopolypeptides through the folding, export and dislocation pathways in the endoplasmic reticulum (ER). A diverse set of pathological conditions rooted in defective as well as over-vigilant ER quality-control systems have been identified, underlining its importance in human health and disease. We describe the GQC pathways and highlight disease and animal models that have been instrumental in clarifying our current understanding of these processes.

This article reviews the histologic and molecular characterization of gliomas, including the new "integrated diagnoses" of the World Health Organization Classification, 2016 edition. The entities reviewed within include diffuse gliomas (astrocytoma, oligodendroglioma, glioblastoma), as well as circumscribed and low-grade gliomas (angiocentric glioma, pilocytic astrocytoma, subependymal giant cell astrocytoma, pleomorphic xanthoastrocytoma, pilomyxoid astrocytoma, ependymoma, myxopapillary ependymoma, and subependymoma). Diagnostic, prognostic, and predictive biomarkers are discussed for each entity. We review how molecular testing for IDH1 and ATRX and detection of chromosome 1p/19q codeletion can be used to categorize glioblastomas as IDH-wildtype or IDH-mutant, and lower grade diffuse gliomas into three molecular groups that correlate better with patient outcomes than histologic subtyping. Pediatric diffuse gliomas are highlighted, including diffuse midline glioma, H3 K27M-mutant, and inherited germline mutations that predispose to pediatric gliomas. The utility of genomic profiling of certain gliomas is discussed, including identifying candidates for experimental therapies. This review is meant to be a concise summary of glioma characterization for the practicing pathologist.

Conditional targeted cell ablation is a powerful approach for investigating the pathogenesis of human diseases and in vivo cellular functions. Intermedilysin (ILY) is a cytolytic pore-forming toxin secreted by Streptococcus intermedius that lyses human cells exclusively, owing to its receptor specificity for human CD59. We generated two transgenic mouse strains that express human CD59 either on erythrocytes (strain ThCD59(RBC)) or on endothelia (strain ThCD59(END)). Intravenous injection of ILY in ThCD59(RBC) mice induced acute intravascular hemolysis, leading to reduced nitric oxide bioavailability, increased platelet activation and rapid death. In ThCD59(END) mice, ILY induced rapid endothelial damage, leading to acute death and disseminated intravascular coagulation. Additionally, we show that human serum contains ILY-specific neutralizing antibodies not found in any other animal species. Together, these results suggest that this new rapid conditional targeted ILY-mediated cell ablation technique can be used in combination with any available transgenic expression system to study the physiologic role of specific cell populations.

Data availability Scanned image files of the H&E stained slides from which representative images are presented are available for downloading and viewing at the following link: https://figshare.com/projects/ Primary_intracranial_sarcoma_with_myogenic_differentiation_and_DICER1_mutation/57704. Sequencing and methylation data files are available from the authors upon request. Terms of use and reuse: academic research for non-commercial purposes, see here for full terms. https://www.springer.com/aamterms-v1

CD59 is a membrane protein inhibitor of the membrane attack complex (MAC) of complement. Humans express only one, whereas mice express two CD59 genes. We previously reported the targeted deletion of the mCd59b gene in which absence of mCd59b together with an unintended down regulation of mCd59a caused hemolytic anemia with spontaneous platelet activation. To confirm the complement role in the hemolytic anemia caused by abrogation of mCd59 function, we have developed a mCd59a and mCd59b double knock out mice and analyzed its phenotype in complement sufficient and deficient (C3−/−). We report here that total abrogation of mCd59 function in mCd59ab−/− mice results in complement-mediated hemolytic anemia that is rescued by the deficiency of C3 in compound mCd59ab−/−/C3−/− mice.