Differences in the prognostic role of age, extent of resection and tumor grade between astrocytoma IDHmt and oligodendroglioma: a single center cohort study.

PURPOSE: IDH-mutant glioma are classified as oligodendroglioma or astrocytoma on the basis of 1p19q-codeletion. Whether prognostic factors are similar between these tumor types is not well understood. EXPERIMENTAL DESIGN: Retrospective cohort study. Molecular characterization was performed with targeted next-generation sequencing. Tumor volumes were calculated using semi-automatic 3D segmentation on all pre- and postoperative MRI-scans. Overall survival was assessed with Cox proportional hazards model. RESULTS: 383 patients with newly diagnosed IDH-mutant glioma were followed-up for a median of 7.2 years. Grade 3 and grade 4 patients had significantly lower Karnofsky performance, with tumors having more contrast-enhancement. Patients also received more aggressive post-surgery treatment. Postoperative tumor volume is significantly and independently associated with survival (HR per cm3 1.19, 95% CI 1.03 - 1.39) in IDH-mutant glioma. Separate analysis of oligodendroglioma and astrocytoma showed a significant association of postoperative tumor volume in astrocytoma, but not in oligodendroglioma. Higher age and histological tumor grade were associated with worse survival in patients with oligodendroglioma, but not with astrocytoma. CONCLUSIONS: Our data support an initial strategy of extensive resection in both oligodendroglioma and astrocytoma patients. Other important prognostic factors differ between these tumor types, urging researchers and clinicians to keep treating these tumors as separate entities.

SARS-CoV-2 delta variant in African lions (Panthera leo) and humans at Utah's Hogle Zoo, USA, 2021-22.

AIMS: We conducted a One Health investigation to assess the source and transmission dynamics of SARS-CoV-2 infection in African lions (Panthera leo) at Utah's Hogle Zoo in Salt Lake City from October 2021 to February 2022. METHODS AND RESULTS: Following observation of respiratory illness in the lions, zoo staff collected pooled faecal samples and individual nasal swabs from four lions. All specimens tested positive for SARS-CoV-2 by reverse transcription-polymerase chain reaction (RT-PCR). The resulting investigation included: lion observation; RT-PCR testing of lion faeces every 1-7 days; RT-PCR testing of lion respiratory specimens every 2-3 weeks; staff interviews and RT-PCR testing; whole-genome sequencing of viruses from lions and staff; and comparison with existing SARS-CoV-2 human community surveillance sequences. In addition to all five lions, three staff displayed respiratory symptoms. All lions recovered and no hospitalizations or deaths were reported among staff. Three staff reported close contact with the lions in the 10 days before lion illness onset, one of whom developed symptoms and tested positive for SARS-CoV-2 on days 3 and 4, respectively, after lion illness onset. The other two did not report symptoms or test positive. Two staff who did not have close contact with the lions were symptomatic and tested positive on days 5 and 8, respectively, after lion illness onset. We detected SARS-CoV-2 RNA in lion faeces for 33 days and in lion respiratory specimens for 14 weeks after illness onset. The viruses from lions were genetically highly related to those from staff and two contemporaneous surveillance specimens from Salt Lake County; all were delta variants (AY.44). CONCLUSIONS: We did not determine the sources of these infections, although human-to-lion transmission likely occurred. The observed period of respiratory shedding was longer than in previously documented SARS-CoV-2 infections in large felids, indicating the need to further assess duration and potential implications of shedding.

Surgical treatment for insular gliomas. A systematic review and meta-analysis on behalf of the EANS neuro-oncology section.

Introduction: The appropriate surgical management of insular gliomas is controversial. Management strategies vary considerably between centers. Research question: To provide robust resection, functional and epilepsy outcome figures, study growth patterns and tumor classification paradigms, analyze surgical approaches, mapping/monitoring strategies, surgery for insular glioblastoma, as well as molecular findings, and to identify open questions for future research. Material and methods: On behalf of the EANS Neuro-oncology Section we performed a systematic review and meta-analysis (using a random-effects model) of the more current (2000-2023) literature in accordance with the PRISMA guidelines. Results: The pooled postoperative motor and speech deficit rates were 6.8% and 3.6%. There was a 79.6% chance for postoperative epilepsy control. The postoperative KPI was 80-100 in 83.5% of cases. Functional monitoring/mapping paradigms (which may include awake craniotomies) seem mandatory. (Additional) awake surgery may result in slightly better functional but also worse resection outcomes. Transcortical approaches may carry a lesser rate of (motor) deficits than transsylvian surgeries. Discussion and conclusions: This paper provides an inclusive overview and analysis of current surgical management of insular gliomas. Risks and complication rates in experienced centers do not necessarily compare unfavorably with the results of routine neuro-oncological procedures. Limitations of the current literature prominently include a lack of standardized outcome reporting. Questions and issues that warrant more attention include surgery for insular glioblastomas and how to classify the various growth patterns of insular gliomas.

SUPRAMAX-study: supramaximal resection versus maximal resection for glioblastoma patients: study protocol for an international multicentre prospective cohort study (ENCRAM 2201).

INTRODUCTION: A greater extent of resection of the contrast-enhancing (CE) tumour part has been associated with improved outcomes in glioblastoma. Recent results suggest that resection of the non-contrast-enhancing (NCE) part might yield even better survival outcomes (supramaximal resection, SMR). Therefore, this study evaluates the efficacy and safety of SMR with and without mapping techniques in high-grade glioma (HGG) patients in terms of survival, functional, neurological, cognitive and quality of life outcomes. Furthermore, it evaluates which patients benefit the most from SMR, and how they could be identified preoperatively. METHODS AND ANALYSIS: This study is an international, multicentre, prospective, two-arm cohort study of observational nature. Consecutive glioblastoma patients will be operated with SMR or maximal resection at a 1:1 ratio. Primary endpoints are (1) overall survival and (2) proportion of patients with National Institute of Health Stroke Scale deterioration at 6 weeks, 3 months and 6 months postoperatively. Secondary endpoints are (1) residual CE and NCE tumour volume on postoperative T1-contrast and FLAIR (Fluid-attenuated inversion recovery) MRI scans; (2) progression-free survival; (3) receipt of adjuvant therapy with chemotherapy and radiotherapy; and (4) quality of life at 6 weeks, 3 months and 6 months postoperatively. The total duration of the study is 5 years. Patient inclusion is 4 years, follow-up is 1 year. ETHICS AND DISSEMINATION: The study has been approved by the Medical Ethics Committee (METC Zuid-West Holland/Erasmus Medical Center; MEC-2020-0812). The results will be published in peer-reviewed academic journals and disseminated to patient organisations and media.

Immunogenic cell death in cancer: targeting necroptosis to induce antitumour immunity.

Most metastatic cancers remain incurable due to the emergence of apoptosis-resistant clones, fuelled by intratumour heterogeneity and tumour evolution. To improve treatment, therapies should not only kill cancer cells but also activate the immune system against the tumour to eliminate any residual cancer cells that survive treatment. While current cancer therapies rely heavily on apoptosis - a largely immunologically silent form of cell death - there is growing interest in harnessing immunogenic forms of cell death such as necroptosis. Unlike apoptosis, necroptosis generates second messengers that act on immune cells in the tumour microenvironment, alerting them of danger. This lytic form of cell death optimizes the provision of antigens and adjuvanticity for immune cells, potentially boosting anticancer treatment approaches by combining cellular suicide and immune response approaches. In this Review, we discuss the mechanisms of necroptosis and how it activates antigen-presenting cells, drives cross-priming of CD8+ T cells and induces antitumour immune responses. We also examine the opportunities and potential drawbacks of such strategies for exposing cancer cells to immunological attacks.

Modeling Heartland virus disease in mice and therapeutic intervention with 4'-fluorouridine.

Heartland virus (HRTV) is an emerging tick-borne bandavirus that causes a febrile illness of varying severity in humans, with cases reported in eastern and midwestern regions of the United States. No vaccines or approved therapies are available to prevent or treat HRTV disease. Here, we describe the genetic changes, natural history of disease, and pathogenesis of a mouse-adapted HRTV (MA-HRTV) that is uniformly lethal in 7- to 8-week-old AG129 mice at low challenge doses. We used this model to assess the efficacy of the ribonucleoside analog, 4'-fluorouridine (EIDD-2749), and showed that once-daily oral treatment with 3 mg/kg of drug, initiated after the onset of disease, protects mice against lethal MA-HRTV challenge and reduces viral loads in blood and tissues. Our findings provide insights into HRTV virulence and pathogenesis and support further development of EIDD-2749 as a therapeutic intervention for HRTV disease. IMPORTANCE: More than 60 cases of HRTV disease spanning 14 states have been reported to the United States Centers for Disease Control and Prevention. The expanding range of the Lone Star tick that transmits HRTV, the growing population of at-risk persons living in geographic areas where the tick is abundant, and the lack of antiviral treatments or vaccines raise significant public health concerns. Here, we report the development of a new small-animal model of lethal HRTV disease to gain insight into HRTV pathogenesis and the application of this model for the preclinical development of a promising new antiviral drug candidate, EIDD-2749. Our findings shed light on how the virus causes disease and support the continued development of EIDD-2749 as a therapeutic for severe cases of HRTV infection.

The effects of acute and chronic noise trauma on stimulus-evoked activity across primary auditory cortex layers.

Exposure to intense noise environments is a major cause of sensorineural hearing loss and auditory perception disorders, such as tinnitus and hyperacusis, which may have a central origin. The effects of noise-induced hearing loss on the auditory cortex have been documented in many studies. One limitation of these studies, however, is that the effects of noise trauma have been mostly studied at the granular layer (i.e, the main cortical recipient of thalamic input), while the cortex is a very complex structure, with six different layers each having its own pattern of connectivity and role in sensory processing. The present study aims to investigate the effects of acute and chronic noise trauma on the laminar pattern of stimulus-evoked activity in the primary auditory cortex of the anesthetized guinea pig. We show that acute and chronic noise trauma are both followed by an increase in stimulus-evoked cortical responses, mostly in the granular and supragranular layers. The cortical responses are more monotonic as a function of the intensity level after noise trauma. There was minimal change, if any, in local field potential (LFP) amplitude after acute noise trauma, while LFP amplitude was enhanced after chronic noise trauma. Finally, LFP and the current source density analysis suggest that acute but more specifically chronic noise trauma is associated with the emergence of a new sink in the supragranular layer. This result suggests that supragranular layers become a major input recipient. We discuss the possible mechanisms and functional implications of these changes.NEW & NOTEWORTHY Our study shows that cortical activity is enhanced after trauma and that the sequence of cortical column activation during stimulus-evoked response is altered, i.e. the supragranular layer becomes a major input recipient. We speculate that these large cortical changes may play a key role in the auditory hypersensitivity (hyperacusis) that can be triggered after noise trauma in human subjects.

Evaluating the Predictive Value of Glioma Growth Models for Low-Grade Glioma After Tumor Resection.

Tumor growth models have the potential to model and predict the spatiotemporal evolution of glioma in individual patients. Infiltration of glioma cells is known to be faster along the white matter tracts, and therefore structural magnetic resonance imaging (MRI) and diffusion tensor imaging (DTI) can be used to inform the model. However, applying and evaluating growth models in real patient data is challenging. In this work, we propose to formulate the problem of tumor growth as a ranking problem, as opposed to a segmentation problem, and use the average precision (AP) as a performance metric. This enables an evaluation of the spatial pattern that does not require a volume cut-off value. Using the AP metric, we evaluate diffusion-proliferation models informed by structural MRI and DTI, after tumor resection. We applied the models to a unique longitudinal dataset of 14 patients with low-grade glioma (LGG), who received no treatment after surgical resection, to predict the recurrent tumor shape after tumor resection. The diffusion models informed by structural MRI and DTI showed a small but significant increase in predictive performance with respect to homogeneous isotropic diffusion, and the DTI-informed model reached the best predictive performance. We conclude there is a significant improvement in the prediction of the recurrent tumor shape when using a DTI-informed anisotropic diffusion model with respect to istropic diffusion, and that the AP is a suitable metric to evaluate these models. All code and data used in this publication are made publicly available.

Highly Pathogenic Avian Influenza A(H5N1) Virus Clade 2.3.4.4b Infections in Wild Terrestrial Mammals, United States, 2022.

We describe the pathology of natural infection with highly pathogenic avian influenza A(H5N1) virus of Eurasian lineage Goose/Guangdong clade 2.3.4.4b in 67 wild terrestrial mammals throughout the United States during April 1‒July 21, 2022. Affected mammals include 50 red foxes (Vulpes vulpes), 6 striped skunks (Mephitis mephitis), 4 raccoons (Procyon lotor), 2 bobcats (Lynx rufus), 2 Virginia opossums (Didelphis virginiana), 1 coyote (Canis latrans), 1 fisher (Pekania pennanti), and 1 gray fox (Urocyon cinereoargenteus). Infected mammals showed primarily neurologic signs. Necrotizing meningoencephalitis, interstitial pneumonia, and myocardial necrosis were the most common lesions; however, species variations in lesion distribution were observed. Genotype analysis of sequences from 48 animals indicates that these cases represent spillover infections from wild birds.

Poly(ADP-ribose) Polyremase-1 (PARP-1) Inhibition: A Promising Therapeutic Strategy for ETS-Expressing Tumours.

ETS transcription factors are a highly conserved family of proteins involved in the progression of many cancers, such as breast and prostate carcinomas, Ewing's sarcoma, and leukaemias. This significant involvement can be explained by their roles at all stages of carcinogenesis progression. Generally, their expression in tumours is associated with a poor prognosis and an aggressive phenotype. Until now, no efficient therapeutic strategy had emerged to specifically target ETS-expressing tumours. Nevertheless, there is evidence that pharmacological inhibition of poly(ADP-ribose) polymerase-1 (PARP-1), a key DNA repair enzyme, specifically sensitises ETS-expressing cancer cells to DNA damage and limits tumour progression by leading some of the cancer cells to death. These effects result from a strong interplay between ETS transcription factors and the PARP-1 enzyme. This review summarises the existing knowledge of this molecular interaction and discusses the promising therapeutic applications.

The Analogy between Tinnitus and Chronic Pain: A Phenomenological Approach.

Tinnitus is an auditory sensation without external acoustic stimulation or significance, which may be lived as an unpleasant experience and impact the subject's quality of life. Tinnitus loudness, which is generally low, bears no relation to distress. Factors other than psychoacoustic (such as psychological factors) are therefore implicated in the way tinnitus is experienced. The aim of this article is to attempt to understand how tinnitus can, like chronic pain, generate a 'crisis' in the process of existence, which may go as far as the collapse of the subject. The main idea put forward in the present article is that tinnitus may be compared to the phenomenon of pain from the point of view of the way it is experienced. Although the analogy between tinnitus and pain has often been made in the literature, it has been limited to a parallel concerning putative physiopathological mechanisms and has never really been explored in depth from the phenomenological point of view. Tinnitus is comparable to pain inasmuch as it is felt, not perceived: it springs up (without intention or exploration), abolishes the distance between the subject and the sensation (there is only a subject and no object), and has nothing to say about the world. Like pain, tinnitus is formless and abnormal and can alter the normal order of the world with maximum intensity. Finally, tinnitus and pain enclose the subject within the limits of the body, which then becomes in excess. Tinnitus may be a source of suffering, which affects not only the body but a person's very existence and, in particular, its deployment in time. Plans are thus abolished, so time is no longer 'secreted', it is enclosed in an eternal present. If the crisis triggered by tinnitus is not resolved, the subject may buckle and collapse (depression) when their resources for resisting are depleted. The path may be long and winding from the moment when tinnitus emerges to when it assaults existence and its eventual integration into a new existential norm where tinnitus is no longer a source of disturbance.

Sympathetic components in left and right human cervical vagus nerve: implications for vagus nerve stimulation.

Cervical vagus nerve stimulation is in a great variety of clinical situations indicated as a form of treatment. It is textbook knowledge that at the cervical level the vagus nerve contains many different fiber classes. Yet, recently, several reports have shown that this nerve also may contain an additional class of potentially noradrenergic fibers, suggested to denote efferent sympathetic fibers. As such, the nature and presence of these fibers should be considered when choosing a stimulation protocol. We have studied human vagus material extracted from dissection room cadavers in order to further confirm the presence of this class of fibers, to study their origin and direction within the nerve and to determine their distribution and variability between subjects and pairs of left and right nerves of the same individual. Sections were studied with immunohistochemical techniques using antibodies against tyrosine hydroxylase (TH: presumed to indicate noradrenergic fibers), myelin basic protein and neurofilament. Our results show that at least part of the TH-positive fibers derive from the superior cervical ganglion or sympathetic trunk, do not follow a cranial but take a peripheral course through the nerve. The portion of TH-positive fibers is highly variable between individuals but also between the left and right pairs of the same individual. TH-positive fibers can distribute and wander throughout the fascicles but maintain a generally clustered appearance. The fraction of TH-positive fibers generally diminishes in the left cervical vagus nerve when moving in a caudal direction but remains more constant in the right nerve. These results may help to determine optimal stimulation parameters for cervical vagus stimulation in clinical settings.

Case report: High-resolution, intra-operative µDoppler-imaging of spinal cord hemangioblastoma.

Surgical resection of spinal cord hemangioblastomas remains a challenging endeavor: the neurosurgeon's aim to reach total tumor resections directly endangers their aim to minimize post-operative neurological deficits. The currently available tools to guide the neurosurgeon's intra-operative decision-making consist mostly of pre-operative imaging techniques such as MRI or MRA, which cannot cater to intra-operative changes in field of view. For a while now, spinal cord surgeons have adopted ultrasound and its submodalities such as Doppler and CEUS as intra-operative techniques, given their many benefits such as real-time feedback, mobility and ease of use. However, for highly vascularized lesions such as hemangioblastomas, which contain up to capillary-level microvasculature, having access to higher-resolution intra-operative vascular imaging could potentially be highly beneficial. µDoppler-imaging is a new imaging modality especially fit for high-resolution hemodynamic imaging. Over the last decade, µDoppler-imaging has emerged as a high-resolution, contrast-free sonography-based technique which relies on High-Frame-Rate (HFR)-ultrasound and subsequent Doppler processing. In contrast to conventional millimeter-scale (Doppler) ultrasound, the µDoppler technique has a higher sensitivity to detect slow flow in the entire field-of-view which allows for unprecedented visualization of blood flow down to sub-millimeter resolution. In contrast to CEUS, µDoppler is able to image high-resolution details continuously, without being contrast bolus-dependent. Previously, our team has demonstrated the use of this technique in the context of functional brain mapping during awake brain tumor resections and surgical resections of cerebral arteriovenous malformations (AVM). However, the application of µDoppler-imaging in the context of the spinal cord has remained restricted to a handful of mostly pre-clinical animal studies. Here we describe the first application of µDoppler-imaging in the case of a patient with two thoracic spinal hemangioblastomas. We demonstrate how µDoppler is able to identify intra-operatively and with high-resolution, hemodynamic features of the lesion. In contrast to pre-operative MRA, µDoppler could identify intralesional vascular details, in real-time during the surgical procedure. Additionally, we show highly detailed post-resection images of physiological human spinal cord anatomy. Finally, we discuss the necessary future steps to push µDoppler to reach actual clinical maturity.

Music to prevent deliriUm during neuroSurgerY (MUSYC): a single-centre, prospective randomised controlled trial.

OBJECTIVES: Delirium is a serious complication following neurosurgical procedures. We hypothesise that the beneficial effect of music on a combination of delirium-eliciting factors might reduce delirium incidence following neurosurgery and subsequently improve clinical outcomes. DESIGN: Prospective randomised controlled trial. SETTING: Single centre, conducted at the neurosurgical department of the Erasmus Medical Center, Rotterdam, the Netherlands. PARTICIPANTS: Adult patients undergoing craniotomy were eligible. INTERVENTIONS: Patients in the intervention group received preferred recorded music before, during and after the operation until day 3 after surgery. Patients in the control group were treated according to standard of clinical care. PRIMARY AND SECONDARY OUTCOME MEASURES: Primary outcome was presence or absence of postoperative delirium within the first 5 postoperative days measured with the Delirium Observation Screening Scale (DOSS) and, in case of a daily mean score of 3 or higher, a psychiatric evaluation with the latest Diagnostic and Statistical Manual of Mental Disorders (DSM-5) criteria. Secondary outcomes included anxiety, heart rate variability (HRV), depth of anaesthesia, delirium severity and duration, postoperative complications, length of stay and location of discharge. RESULTS: We enrolled 189 patients (music=95, control=94) from July 2020 through September 2021. Delirium, as assessed by the DOSS, was less common in the music (n=11, 11.6%) than in the control group (n=21, 22.3%, OR:0.49, p=0.048). However, after DSM-5 confirmation, differences in delirium were not significant (4.2% vs 7.4%, OR:0.47, p=0.342). Moreover, music increased the HRV (root mean square of successive differences between normal heartbeats, p=0.012). All other secondary outcomes were not different between groups. CONCLUSION: Our results support the efficacy of music in reducing the incidence of delirium after craniotomy, as found with DOSS but not after DSM-5 confirmation, substantiated by the effect of music on preoperative autonomic tone. Delirium screening tools should be validated and the long-term implications should be evaluated after craniotomy. TRIAL REGISTRATION NUMBER: Trialregister.nl: NL8503 and ClinicalTrials.gov: NCT04649450.

Offset responses in primary auditory cortex are enhanced after notched noise stimulation.

Sensory "aftereffects" are a subgroup of sensory illusions that can be defined as an illusory phenomenon triggered after prolonged exposure to a given sensory inducer. These phenomena are interesting because they can provide insights into the mechanisms of perception. In auditory modality, there is a special interest in the so-called "Zwicker tone" (ZT), an auditory aftereffect triggered after the presentation of a notched noise (NN, broadband noise with a missing frequency band). The ZT has been considered a plausible model of a specific tinnitus subtype since it presents some key characteristics in common with tinnitus. Indeed, both the tinnitus percept and ZT can be triggered by a relative "sensory deprivation," and their pitch corresponds to the frequency region that has been sensory deprived. The effects of a NN presentation on the central auditory system are still barely investigated, and the mechanisms of the ZT are elusive. In this study, we analyzed the laminar structure of the neural activity in the primary cortex of anesthetized and awake guinea pigs during and after white noise (WN) and NN stimulation. We found significantly increased offset responses, in terms of both spiking activity and local field potential amplitude, after NN compared with WN presentation. The offset responses were circumscribed to the granular and upper infragranular layers (input layers) and were maximal when the neuron's best frequency was within or near the missing frequency band. The mechanisms of the offset response and its putative link with the ZT are discussed.NEW & NOTEWORTHY Notched noise (white noise with embedded spectral gap) causes significant excitatory offset responses in the auditory cortex of awake and anesthetized guinea pigs. The largest offset responses were located in the infragranular/granular layers, and current source density analysis revealed that offset responses were associated with an early current sink localized in the upper infragranular layers. We discuss the possibility that the offset responses might be associated with an auditory phantom percept (Zwicker tone).

Transcriptomic analysis of lung development in wildtype and CFTR-/- sheep suggests an early inflammatory signature in the CF distal lung.

The precise molecular events initiating human lung disease are often poorly characterized. Investigating prenatal events that may underlie lung disease in later life is challenging in man, but insights from the well-characterized sheep model of lung development are valuable. Here, we determine the transcriptomic signature of lung development in wild-type sheep (WT) and use a sheep model of cystic fibrosis (CF) to characterize disease associated changes in gene expression through the pseudoglandular, canalicular, saccular, and alveolar stages of lung growth and differentiation. Using gene ontology process enrichment analysis of differentially expressed genes at each developmental time point, we define changes in biological processes (BP) in proximal and distal lung from WT or CF animals. We also compare divergent BP in WT and CF animals at each time point. Next, we establish the developmental profile of key genes encoding components of ion transport and innate immunity that are pivotal in CF lung disease and validate transcriptomic data by RT-qPCR. Consistent with the known pro-inflammatory phenotype of the CF lung after birth, we observe upregulation of inflammatory response processes in the CF sheep distal lung during the saccular stage of prenatal development. These data suggest early commencement of therapeutic regimens may be beneficial.

Basal Diet Fed to Recipient Mice Was the Driving Factor for Colitis and Colon Tumorigenesis, despite Fecal Microbiota Transfer from Mice with Severe or Mild Disease.

Consumption of the total Western diet (TWD) in mice has been shown to increase gut inflammation, promote colon tumorigenesis, and alter fecal microbiome composition when compared to mice fed a healthy diet, i.e., AIN93G (AIN). However, it is unclear whether the gut microbiome contributes directly to colitis-associated CRC in this model. The objective of this study was to determine whether dynamic fecal microbiota transfer (FMT) from donor mice fed either the AIN basal diet or the TWD would alter colitis symptoms or colitis-associated CRC in recipient mice, which were fed either the AIN diet or the TWD, using a 2 × 2 factorial experiment design. Time-matched FMT from the donor mice fed the TWD did not significantly enhance symptoms of colitis, colon epithelial inflammation, mucosal injury, or colon tumor burden in the recipient mice fed the AIN diet. Conversely, FMT from the AIN-fed donors did not impart a protective effect on the recipient mice fed the TWD. Likewise, the composition of fecal microbiomes of the recipient mice was also affected to a much greater extent by the diet they consumed than by the source of FMT. In summary, FMT from the donor mice fed either basal diet with differing colitis or tumor outcomes did not shift colitis symptoms or colon tumorigenesis in the recipient mice, regardless of the basal diet they consumed. These observations suggest that the gut microbiome may not contribute directly to the development of disease in this animal model.

Transcriptome analysis reveals tumor microenvironment changes in glioblastoma.

A better understanding of transcriptional evolution of IDH-wild-type glioblastoma may be crucial for treatment optimization. Here, we perform RNA sequencing (RNA-seq) (n = 322 test, n = 245 validation) on paired primary-recurrent glioblastoma resections of patients treated with the current standard of care. Transcriptional subtypes form an interconnected continuum in a two-dimensional space. Recurrent tumors show preferential mesenchymal progression. Over time, hallmark glioblastoma genes are not significantly altered. Instead, tumor purity decreases over time and is accompanied by co-increases in neuron and oligodendrocyte marker genes and, independently, tumor-associated macrophages. A decrease is observed in endothelial marker genes. These composition changes are confirmed by single-cell RNA-seq and immunohistochemistry. An extracellular matrix-associated gene set increases at recurrence and bulk, single-cell RNA, and immunohistochemistry indicate it is expressed mainly by pericytes. This signature is associated with significantly worse survival at recurrence. Our data demonstrate that glioblastomas evolve mainly by microenvironment (re-)organization rather than molecular evolution of tumor cells.

Functional imaging of the exposed brain.

When the brain is exposed, such as after a craniotomy in neurosurgical procedures, we are provided with the unique opportunity for real-time imaging of brain functionality. Real-time functional maps of the exposed brain are vital to ensuring safe and effective navigation during these neurosurgical procedures. However, current neurosurgical practice has yet to fully harness this potential as it pre-dominantly relies on inherently limited techniques such as electrical stimulation to provide functional feedback to guide surgical decision-making. A wealth of especially experimental imaging techniques show unique potential to improve intra-operative decision-making and neurosurgical safety, and as an added bonus, improve our fundamental neuroscientific understanding of human brain function. In this review we compare and contrast close to twenty candidate imaging techniques based on their underlying biological substrate, technical characteristics and ability to meet clinical constraints such as compatibility with surgical workflow. Our review gives insight into the interplay between technical parameters such sampling method, data rate and a technique's real-time imaging potential in the operating room. By the end of the review, the reader will understand why new, real-time volumetric imaging techniques such as functional Ultrasound (fUS) and functional Photoacoustic Computed Tomography (fPACT) hold great clinical potential for procedures in especially highly eloquent areas, despite the higher data rates involved. Finally, we will highlight the neuroscientific perspective on the exposed brain. While different neurosurgical procedures ask for different functional maps to navigate surgical territories, neuroscience potentially benefits from all these maps. In the surgical context we can uniquely combine healthy volunteer studies, lesion studies and even reversible lesion studies in in the same individual. Ultimately, individual cases will build a greater understanding of human brain function in general, which in turn will improve neurosurgeons' future navigational efforts.