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UNLABELLED: Patients with H3K27M-mutant diffuse midline glioma (DMG) have no proven effective therapies. ONC201 has recently demonstrated efficacy in these patients, but the mechanism behind this finding remains unknown. We assessed clinical outcomes, tumor sequencing, and tissue/cerebrospinal fluid (CSF) correlate samples from patients treated in two completed multisite clinical studies. Patients treated with ONC201 following initial radiation but prior to recurrence demonstrated a median overall survival of 21.7 months, whereas those treated after recurrence had a median overall survival of 9.3 months. Radiographic response was associated with increased expression of key tricarboxylic acid cycle-related genes in baseline tumor sequencing. ONC201 treatment increased 2-hydroxyglutarate levels in cultured H3K27M-DMG cells and patient CSF samples. This corresponded with increases in repressive H3K27me3 in vitro and in human tumors accompanied by epigenetic downregulation of cell cycle regulation and neuroglial differentiation genes. Overall, ONC201 demonstrates efficacy in H3K27M-DMG by disrupting integrated metabolic and epigenetic pathways and reversing pathognomonic H3K27me3 reduction. SIGNIFICANCE: The clinical, radiographic, and molecular analyses included in this study demonstrate the efficacy of ONC201 in H3K27M-mutant DMG and support ONC201 as the first monotherapy to improve outcomes in H3K27M-mutant DMG beyond radiation. Mechanistically, ONC201 disrupts integrated metabolic and epigenetic pathways and reverses pathognomonic H3K27me3 reduction. This article is featured in Selected Articles from This Issue, p. 2293.

Abstract A novel histomolecular tumor of the central nervous system (CNS), the “diffuse glioneuronal tumor with oligodendroglioma-like features and nuclear clusters (DGONC),” has recently been identified, based on a distinct DNA methylation profile and has been added to the 2021 World Health Organization Classification of CNS Tumors. This glioneuronal tumor mainly affects the supratentorial area in children and recurrently presents with a monosomy of chromosome 14. Herein, we report the case of a DNA-methylation based diagnosis of DGONC having atypical features, such as pseudo-rosettes and the absence of a chromosome 14 monosomy, thus rendering its diagnosis very challenging. Because of the wide variety of morphologies harbored by DGONC, a large range of differential diagnoses may be hypothesized from benign to malignant. Interestingly, the current case, like one previously reported, exhibited a co-expression of OLIG2, synaptophysin and SOX10, without GFAP immunopositivity. This particular immunophenotype seems to be a good indicator for a DGONC diagnosis. The classification of DGONC amongst glioneuronal or embryonal tumors is still debated. The clinical (a pediatric supratentorial tumor), morphological (from a benign oligodendroglioma-like tumor with microcalcifications and possible neuropil-like islands to a malignant embryonal tumor with a possible spongioblastic pattern), and immunohistochemical (co-expression of OLIG2 and synaptophsyin) profiles resemble CNS, neuroblastoma, FOXR2-activated and may potentially bring them together in a future classification. Further comprehensive studies are needed to conclude the cellular origin of DGONC and its prognosis.

Abstract The rapid transformation of sensory inputs into meaningful neural representations is critical to adaptive human behaviour. While non-invasive neuroimaging methods are the de-facto method for investigating neural representations, they remain expensive, not widely available, time-consuming, and restrictive. Here we show that movement trajectories can be used to measure emerging neural representations with fine temporal resolution. By combining online computer mouse-tracking and publicly available neuroimaging data via representational similarity analysis (RSA), we show that movement trajectories track the unfolding of stimulus- and category-wise neural representations along key dimensions of the human visual system. We demonstrate that time-resolved representational structures derived from movement trajectories overlap with those derived from M/EEG (albeit delayed) and those derived from fMRI in functionally-relevant brain areas. Our findings highlight the richness of movement trajectories and the power of the RSA framework to reveal and compare their information content, opening new avenues to better understand human perception.

Abstract A novel methylation class, “neuroepithelial tumor, with PLAGL1 fusion” (NET-PLAGL1), has recently been described, based on epigenetic features, as a supratentorial pediatric brain tumor with recurrent histopathological features suggesting an ependymal differentiation. Because of the recent identification of this neoplastic entity, few histopathological, radiological and clinical data are available. Herein, we present a detailed series of nine cases of PLAGL1-fused supratentorial tumors, reclassified from a series of supratentorial ependymomas, non-ZFTA/non-YAP1 fusion-positive and subependymomas of the young. This study included extensive clinical, radiological, histopathological, ultrastructural, immunohistochemical, genetic and epigenetic (DNA methylation profiling) data for characterization. An important aim of this work was to evaluate the sensitivity and specificity of a novel fluorescent in situ hybridization (FISH) targeting the PLAGL1 gene. Using histopathology, immunohistochemistry and electron microscopy, we confirmed the ependymal differentiation of this new neoplastic entity. Indeed, the cases histopathologically presented as “mixed subependymomas-ependymomas” with well-circumscribed tumors exhibiting a diffuse immunoreactivity for GFAP, without expression of Olig2 or SOX10. Ultrastructurally, they also harbored features reminiscent of ependymal differentiation, such as cilia. Different gene partners were fused with PLAGL1: FOXO1, EWSR1 and for the first time MAML2. The PLAGL1 FISH presented a 100% sensitivity and specificity according to RNA sequencing and DNA methylation profiling results. This cohort of supratentorial PLAGL1-fused tumors highlights: 1/ the ependymal cell origin of this new neoplastic entity; 2/ benefit of looking for a PLAGL1 fusion in supratentorial cases of non-ZFTA/non-YAP1 ependymomas; and 3/ the usefulness of PLAGL1 FISH.

While communication is an essential part of life, it is not always easy and effortless. This is especially true when talking with someone in a noisy environment. Although communicating in noise is often the rule rather than the exception, very little research has investigated the behavioral processes individuals might use to minimize miscommunication when listening becomes challenged. Here we explored synergistic speech and movement processes that 22 pairs of adults used to hear and be heard when (mis)communicating in noise. The results revealed intricate dynamics both with respect to acoustic optimization of the speech produced and heard, as well as how individuals modulate interpersonal distance and behavioral coordination patterns.

Hyperscanning, which enables the recording of brain activity from multiple individuals simultaneously, has been increasingly used to investigate the neuropsychological processes underpinning social interaction. Previous hyperscanning research has primarily focused on interbrain synchrony, demonstrating an enhanced alignment of brain waves across individuals during social interaction. However, using EEG hyperscanning simulations, we here show that interbrain synchrony has low sensitivity to information alignment across people. Surprisingly, interbrain synchrony remains largely unchanged despite manipulating whether two individuals are seeing same or different things at the same time. Furthermore, we show that hyperscanning recordings do contain indices of interpersonal information alignment and that they can be captured using representational analyses. These findings highlight major limitations of current hyperscanning research and offer a promising alternative for investigating interactive minds.

Aberrations in nuclear size and shape are commonly used to identify cancerous tissue. However, it remains unclear whether the disturbed nuclear structure directly contributes to the cancer pathology or is merely a consequence of other events occurring during tumorigenesis. Here, we show that highly invasive and proliferative breast cancer cells frequently exhibit Akt-driven lower expression of the nuclear envelope proteins lamin A/C, leading to increased nuclear deformability that permits enhanced cell migration through confined environments that mimic interstitial spaces encountered during metastasis. Importantly, increasing lamin A/C expression in highly invasive breast cancer cells reflected gene expression changes characteristic of human breast tumors with higher LMNA expression, and specifically affected pathways related to cell-ECM interactions, cell metabolism, and PI3K/Akt signaling. Further supporting an important role of lamins in breast cancer metastasis, analysis of lamin levels in human breast tumors revealed a significant association between lower lamin A levels, Akt signaling, and decreased disease-free survival. These findings suggest that downregulation of lamin A/C in breast cancer cells may influence both cellular physical properties and biochemical signaling to promote metastatic progression.

Abstract Erythroblastic sarcoma (ES) (previously called chloroma or granulocytic sarcoma) are rare hematological neoplams characterized by the proliferation of myeloid blasts at extramedullary sites, and primarily involve the skin and soft tissue of middle-aged adults. ES may be concomitant with or secondary to myeloid neoplasms (mostly acute myeloid leukemia (AML)) or in isolated cases (de novo) without infiltration of the bone marrow by blasts. ES share cytogenetic and molecular abnormalities with AML, including RUNX1T1 fusions. Some of these alterations seem to be correlated with particular sites of involvement. Herein, we report an isolated erythroblastic sarcoma with NFIA::RUNX1T1 located in the central nervous system (CNS) of a 3-year-old boy. Recently, two pediatric cases of CNS MS with complete molecular characterization have been documented. Like the current case, they concerned infants (2 and 3 years-old) presenting a brain tumor (pineal involvement) with leptomeningeal dissemination. Both cases also harbored a NFIA::RUNX1T3 fusion. ES constitutes a diagnostic challenge for neuropathologists because it does not express differentiation markers such as CD45, and may express CD99 which could be confused with CNS Ewing sarcoma. CD43 is the earliest pan-hematopoietic marker and CD45 is not expressed by erythroid lineage cells. E-cadherin (also a marker of erythroid precursors) and CD117 (expressed on the surface of erythroid lineage cells) constitute other immunhistochemical hallmarks of ES. The prognosis of patients with ES is similar to that of other patients with AML but de novo forms seem to have a poorer prognosis, like the current case. To conclude, pediatric ES with NFIA::RUNX1T1/3 fusions seem to have a tropism for the CNS and thus constitute a potential pitfall for neuropathologists. Due to the absence of circulating blasts and a DNA-methylation signature, the diagnosis must currently be made by highlighting the translocation and expression of erythroid markers.

Background: Due to the ongoing organ shortage, marginal grafts with steatosis are more frequently used in liver transplantation, leading to higher occurrences of graft dysfunction. A histological analysis is the gold standard for the quantification of liver steatosis (LS), but has its drawbacks: it is an invasive method that varies from one pathologist to another and is not available in every hospital at the time of organ procurement. This study aimed to compare non-invasive diagnostic tools to a histological analysis for the quantification of liver steatosis. Methods: Male C57BL6J mice were fed with a methioninecholine-deficient (MCD) diet for 14 days or 28 days to induce LS, and were compared to a control group of animals fed with a normal diet. The following non-invasive techniques were performed and compared to the histological quantification of liver steatosis: magnetic resonance spectroscopy (MRS), CARS microscopy, 99mTc MIBI SPECT imaging, and a new near-infrared spectrometer (NIR-SG1). Results: After 28 days on the MCD diet, an evaluation of LS showed ≥30% macrovesicular steatosis. High correlations were found between the NIR-SG1 and the blinded pathologist analysis (R2 = 0.945) (p = 0.001), and between the CARS microscopy (R2 = 0.801 (p < 0.001); MRS, R2 = 0.898 (p < 0.001)) and the blinded pathologist analysis. The ROC curve analysis showed that the area under the curve (AUC) was 1 for both the NIR-SG1 and MRS (p = 0.021 and p < 0.001, respectively), while the AUC = 0.910 for the Oil Red O stain (p < 0.001) and the AUC = 0.865 for the CARS microscopy (p < 0.001). The AUC for the 99mTc MIBI SPECT was 0.640 (p = 0.013), and this was a less discriminating technique for LS quantification. Conclusions: The best-performing non-invasive methods for LS quantification are MRS, CARS microscopy, and the NIR-SG1. The NIR-SG1 is particularly appropriate for clinical practice and needs to be validated by clinical studies on liver grafts.

Abstract During conversations people coordinate simultaneous channels of verbal and nonverbal information to hear and be heard. But the presence of background noise levels such as those found in cafes and restaurants can be a barrier to conversational success. Here, we used speech and motion-tracking to reveal the reciprocal processes people use to communicate in noisy environments. Conversations between twenty-two pairs of typical-hearing adults were elicited under different conditions of background noise, while standing or sitting around a table. With the onset of background noise, pairs rapidly adjusted their interpersonal distance and speech level, with the degree of initial change dependent on noise level and talker configuration. Following this transient phase, pairs settled into a sustaining phase in which reciprocal speech and movement-based coordination processes synergistically maintained effective communication, again with the magnitude of stability of these coordination processes covarying with noise level and talker configuration. Finally, as communication breakdowns increased at high noise levels, pairs exhibited resetting behaviors to help restore communication—decreasing interpersonal distance and/or increasing speech levels in response to communication breakdowns. Approximately 78 dB SPL defined a threshold where behavioral processes were no longer sufficient for maintaining effective conversation and communication breakdowns rapidly increased.

ABSTRACTMalaria remains a global health problem, with 247 million cases and 619,000 deaths in 2021. Diagnosis of Plasmodium species is important for administering the appropriate treatment. The gold-standard diagnosis for accurate species identification remains the thin blood smear. Nevertheless, this method is time-consuming and requires highly skilled and trained microscopists. To overcome these issues, new diagnostic tools based on deep learning are emerging. This study aimed to evaluate the performances of a real-time detection transformer (RT-DETR) object detection algorithm to discriminate Plasmodium species on thin blood smear images. The algorithm was trained and validated on a data set consisting in 24,720 images from 475 thin blood smears corresponding to 2,002,597 labels. Performances were calculated with a test data set of 4,508 images from 170 smears corresponding to 358,825 labels coming from six French university hospitals. At the patient level, the RT-DETR algorithm exhibited an overall accuracy of 79.4% (135/170) with a recall of 74% (40/54) and 81.9% (95/116) for negative and positive smears, respectively. Among Plasmodium-positive smears, the global accuracy was 82.7% (91/110) with a recall of 90% (38/42), 81.8% (18/22), and 76.1% (35/46) for P. falciparum, P. malariae, and P. ovale/vivax, respectively. The RT-DETR model achieved a World Health Organization (WHO) competence level 2 for species identification. Besides, the RT-DETR algorithm may be run in real-time on low-cost devices such as a smartphone and could be suitable for deployment in low-resource setting areas lacking microscopy experts.IMPORTANCEMalaria remains a global health problem, with 247 million cases and 619,000 deaths in 2021. Diagnosis of Plasmodium species is important for administering the appropriate treatment. The gold-standard diagnosis for accurate species identification remains the thin blood smear. Nevertheless, this method is time-consuming and requires highly skilled and trained microscopists. To overcome these issues, new diagnostic tools based on deep learning are emerging. This study aimed to evaluate the performances of a real-time detection transformer (RT-DETR) object detection algorithm to discriminate Plasmodium species on thin blood smear images. Performances were calculated with a test data set of 4,508 images from 170 smears coming from six French university hospitals. The RT-DETR model achieved a World Health Organization (WHO) competence level 2 for species identification. Besides, the RT-DETR algorithm may be run in real-time on low-cost devices and could be suitable for deployment in low-resource setting areas.