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INTRODUCTION: Few controlled studies explore proximal femoral geometry and association with femoral neck (FN) or intertrochanteric (IT) fractures, especially among the elderly Filipino population. Previous reports, however, still reveal multiple inconsistencies. The objective of the study is to establish a possible association between radiographic hip geometry and proximal femoral fractures based on measurements taken from elderly Filipino women. MATERIALS AND METHODS: This is a cross-sectional study of 182 Filipino women ≥ 60 years old at a single institution last 2019-2020. Patients were divided into groups with femoral neck fractures (n=84), intertrochanteric fractures (n=64), and those without diagnosed hip fractures (n=34). Standard pelvic radiographs with control of hip internal rotation was done and the following radiographic parameters were compared: hip axis length (HAL), femoral neck length (FNL), neck shaft angle (NSA), horizontal offset (HO), femoral head diameter (FHD), and femoral neck diameter (FND). RESULTS: Data suggests that an increased FND increased the risk for acquiring both femoral neck (OR = 1.31, 95% CI 1.06 - 1.62; p=.011) and intertrochanteric fractures (OR: 1.22, 95% CI 1.07-2.16; p=0.018). For intertrochanteric fractures alone, a wider NSA (OR 1.27, 95% CI 1.02 - 1.58, p=0.033) and larger HO (OR 1.29, 95% CI 1.02 - 1.64, p=0.036) also increased the risk for this fracture type while a longer HAL was protective (OR 0.85, 95% CI 0.73 - 0.98, p=0.30). Other radiographic parameters and ratios revealed no association. CONCLUSION: Results show that there are certain hip geometric parameters that play a role in the risk and incidence of developing femoral neck or intertrochanteric fractures. These measurements may aid in identification of patients at risk. This study may act as a guide for future implant design and increase accuracy of hip reconstruction among elderly Filipino women.

Background: The plasma level of cystatin C is a better marker than plasma creatinine for successful aging. It has been assumed that the advantage of cystatin C is not only due to it being a better marker for glomerular filtration rate (GFR) than creatinine, but also because an inflammatory state of a patient induces a raised cystatin C level. However, the observations of an association between cystatin C level and inflammation stem from large cohort studies. The present work concerns the cystatin C levels and degree of inflammation in longitudinal studies of individual subjects without inflammation, who undergo elective surgery.Methods: Cystatin C, creatinine, and the inflammatory markers CRP, serum amyloid A (SAA), haptoglobin and orosomucoid were measured in plasma samples from 35 patients the day before elective surgery and subsequently during seven consecutive days.Results: Twenty patients had CRP-levels below 1 mg/L before surgery and low levels of the additional inflammatory markers. Surgery caused marked inflammation with high peak values of CRP and SAA on the second day after the operation. The cystatin C level did not change significantly during the observation period and did not correlate significantly with the level of any of the four inflammatory markers. The creatinine level was significantly reduced on the first postoperative day but reached the preoperative level towards the end of the observation period.Conclusion: The inflammatory status of a patient does not influence the role of cystatin C as a marker of successful aging, nor of GFR. [ABSTRACT FROM AUTHOR]

Glioblastoma presents a formidable clinical challenge because of its complex microenvironment. Here, we characterized tumor-associated foam cells (TAFs), a type of lipid droplet-loaded macrophage, in human glioblastoma. Through extensive analyses of patient tumors, together with in vitro and in vivo investigations, we found that TAFs exhibit distinct protumorigenic characteristics related to hypoxia, mesenchymal transition, angiogenesis, and impaired phagocytosis, and their presence correlates with worse outcomes for patients with glioma. We further demonstrated that TAF formation is facilitated by lipid scavenging from extracellular vesicles released by glioblastoma cells. We found that targeting key enzymes involved in lipid droplet formation, such as diacylglycerol O -acyltransferase or long-chain acyl-CoA synthetase, effectively disrupted TAF functionality. Together, these data highlight TAFs as a prominent immune cell population in glioblastoma and provide insights into their contribution to the tumor microenvironment. Disrupting lipid droplet formation to target TAFs may represent an avenue for future therapeutic development for glioblastoma.

Immunotherapies with antibody-drug-conjugates (ADC) and CAR-T cells, targeted at tumor surface antigens (surfaceome), currently revolutionize clinical oncology. However, target identification warrants a better understanding of the surfaceome and how it is modulated by the tumor microenvironment. Here, we decode the surfaceome and endocytome and its remodeling by hypoxic stress in glioblastoma (GBM), the most common and aggressive brain tumor in adults. We employed a comprehensive approach for global and dynamic profiling of the surfaceome and endocytosed (endocytome) proteins and their regulation by hypoxia in patient-derived GBM cultures. We found a heterogeneous surface-endocytome profile and a divergent response to hypoxia across GBM cultures. We provide a quantitative ranking of more than 600 surface resident and endocytosed proteins, and their regulation by hypoxia, serving as a resource to the cancer research community. As proof-of-concept, the established target antigen CD44 was identified as a commonly and abundantly expressed surface protein with high endocytic activity. Among hypoxia induced proteins, we reveal CXADR, CD47, CD81, BSG, and FXYD6 as potential targets of the stressed GBM niche. We could validate these findings by immunofluorescence analyses in patient tumors and by increased expression in the hypoxic core of GBM spheroids. Selected candidates were finally confronted by treatment studies, showing their high capacity for internalization and ADC delivery. Importantly, we highlight the limited correlation between transcriptomics and proteomics, emphasizing the critical role of membrane protein enrichment strategies and quantitative mass spectrometry. Our findings provide a comprehensive understanding of the surface-endocytome and its remodeling by hypoxia in GBM as a resource for exploration of targets for immunotherapeutic approaches in GBM., (© 2024. The Author(s).)

Background: Visual acuity (VA) and visual field defects (VF) are evaluated in the preoperative management of non-functioning pituitary adenoma (NFPA). The former is less studied than the latter., Research Question: To analyze preoperative factors, including adenoma volumetry, associated with reduced VA and postoperative improvement of VA over five years after surgery., Methods: Eighty-seven patients who had primary surgery for NFPA were retrospectively reviewed. Eyes were categorized by best/worse preoperative VA. Ophthalmology review was performed before surgery, at three months, one to two years, and five years post-surgery., Results: Reduced VA in any eye was present in 55%. VA of the worse eye improved in 77% and normalized in 54%. The majority improved within three months. Additional cases with VA improvement were seen at 1-2 years after surgery. No further improvement was seen five years after surgery. Fifty percent of patients with, per definition, normal preoperative VA showed improved VA postoperatively. Tumor height above the sella in the sagittal plane was the best radiological predictor of reduced VA. Volumetry did not add to accuracy. Age, sagittal tumor height and visual field defects were risk factors of preoperative reduced VA. No predictors of postoperative recovery were identified., Conclusion: Half of patients with reduced VA recover fully. All patients, independent of age and degree of VA reduction, may improve. No predictors of recovery were found. Early improvement is common and improvement beyond two years is unlikely. The frequency of reduced VA is underestimated. The present results could be of value in pre- and postoperative counseling., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2023 The Authors.)

Neuronal loss and axonal demyelination underlie long-term functional impairments in patients affected by brain disorders such as ischemic stroke. Stem cell-based approaches reconstructing and remyelinating brain neural circuitry, leading to recovery, are highly warranted. Here, we demonstrate the in vitro and in vivo production of myelinating oligodendrocytes from a human induced pluripotent stem cell (iPSC)-derived long-term neuroepithelial stem (lt-NES) cell line, which also gives rise to neurons with the capacity to integrate into stroke-injured, adult rat cortical networks. Most importantly, the generated oligodendrocytes survive and form myelin-ensheathing human axons in the host tissue after grafting onto adult human cortical organotypic cultures. This lt-NES cell line is the first human stem cell source that, after intracerebral delivery, can repair both injured neural circuitries and demyelinated axons. Our findings provide supportive evidence for the potential future use of human iPSC-derived cell lines to promote effective clinical recovery following brain injuries., Competing Interests: Conflict of interests The authors declare no competing interests., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Introduction: Secondary tumoral parkinsonism is a rare phenomenon that develops as a direct or indirect result of brain neoplasms or related conditions., Objectives: The first objective was to explore to what extent brain neoplasms, cavernomas, cysts, paraneoplastic syndromes (PNSs), and oncological treatment methods cause parkinsonism. The second objective was to investigate the effect of dopaminergic therapy on the symptomatology in patients with tumoral parkinsonism., Methods: A systematic literature review was conducted in the databases PubMed and Embase. Search terms like "secondary parkinsonism," "astrocytoma," and "cranial irradiation" were used. Articles fulfilling inclusion criteria were included in the review., Results: Out of 316 identified articles from the defined database search strategies, 56 were included in the detailed review. The studies, which were mostly case reports, provided research concerning tumoral parkinsonism and related conditions. It was found that various types of primary brain tumors, such as astrocytoma and meningioma, and more seldom brain metastases, can cause tumoral parkinsonism. Parkinsonism secondary to PNSs, cavernomas, cysts, as well as oncological treatments was reported. Twenty-five of the 56 included studies had tried initiating dopaminergic therapy, and of these 44% reported no, 48% low to moderate, and 8% excellent effect on motor symptomatology., Conclusion: Brain neoplasms, PNSs, certain intracranial malformations, and oncological treatments can cause parkinsonism. Dopaminergic therapy has relatively benign side effects and may relieve motor and nonmotor symptomatology in patients with tumoral parkinsonism. Dopaminergic therapy, particularly levodopa, should therefore be considered in patients with tumoral parkinsonism., (© 2023 The Authors. Brain and Behavior published by Wiley Periodicals LLC.)

Background: The complement system seems to influence cancer pathophysiology. The primary aim of this study was to explore complement components associated with the classical pathway (CP) of the complement system in peripheral blood from patients with IDH-wild-type (IDH-wt) glioblastoma., Methods: Patients undergoing primary surgery due to glioblastoma in the years 2019-2021 were prospectively included in the present study. Blood samples were collected prior to surgery, and analyzed with regard to CP complement components, as well as standard coagulation tests., Results: In total, 40 patients with IDH-wt glioblastomas were included. C1q was reduced in 44% of the cases compared to the reference interval. C1r was reduced in 61% of the analyzed samples. Both C1q and C1r are parts of the initial steps of the classical complement activation pathway, which, however, was not correspondingly altered. Activated pro-thromboplastin time (APTT) was shorter in 82% of the analyzed samples compared to the reference interval. APTT was shorter in those with reduced C1q and C1r levels. C1q is an important link between the innate and acquired immunity, and C1q and C1r also interact with the coagulation system. Patients who displayed reduced levels of both C1q and C1r preoperatively had a significantly shorter overall survival compared with the rest of the cohort., Conclusions: Our findings demonstrate that there are alterations in C1q and C1r concentrations in peripheral blood from patients with IDH1-wt glioblastoma compared with the normal population. Patients who displayed reduced C1q and C1r levels had a significantly shorter survival., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Dynamic glucose-enhanced (DGE) MRI is used to study the signal intensity time course (tissue response curve) after D-glucose injection. D-glucose has potential as a biodegradable alternative or complement to gadolinium-based contrast agents, with DGE being comparable with dynamic contrast-enhanced (DCE) MRI. However, the tissue uptake kinetics as well as the detection methods of DGE differ from DCE MRI, and it is relevant to compare these techniques in terms of spatiotemporal enhancement patterns. This study aims to develop a DGE analysis method based on tissue response curve shapes, and to investigate whether DGE MRI provides similar or complementary information to DCE MRI. Eleven patients with suspected gliomas were studied. Tissue response curves were measured for DGE and DCE MRI at 7 T and the area under the curve (AUC) was assessed. Seven types of response curve shapes were postulated and subsequently identified by deep learning to create color-coded "curve maps" showing the spatial distribution of different curve types. DGE AUC values were significantly higher in lesions than in normal tissue (p < 0.007). Furthermore, the distribution of curve types differed between lesions and normal tissue for both DGE and DCE. The DGE and DCE response curves in a 6-min postinjection time interval were classified as the same curve type in 20% of the lesion voxels, which increased to 29% when a 12-min DGE time interval was considered. While both DGE and DCE tissue response curve-shape analysis enabled differentiation of lesions from normal brain tissue in humans, their enhancements were neither temporally identical nor confined entirely to the same regions. Curve maps can provide accessible and intuitive information about the shape of DGE response curves, which is expected to be useful in the continued work towards the interpretation of DGE uptake curves in terms of D-glucose delivery, transport, and metabolism., (© 2022 The Authors. NMR in Biomedicine published by John Wiley & Sons Ltd.)

A significant problem in diffusion MRI (dMRI) is the lack of understanding regarding which microstructural features account for the variability in the diffusion tensor imaging (DTI) parameters observed in meningioma tumors. A common assumption is that mean diffusivity (MD) and fractional anisotropy (FA) from DTI are inversely proportional to cell density and proportional to tissue anisotropy, respectively. Although these associations have been established across a wide range of tumors, they have been challenged for interpreting within-tumor variations where several additional microstructural features have been suggested as contributing to MD and FA. To facilitate the investigation of the biological underpinnings of DTI parameters, we performed ex-vivo DTI at 200 µm isotropic resolution on sixteen excised meningioma tumor samples. The samples exhibit a variety of microstructural features because the dataset includes meningiomas of six different meningioma types and two different grades. Diffusion-weighted signal (DWI) maps, DWI maps averaged over all directions for given b-value, signal intensities without diffusion encoding (S 0 ) as well as DTI parameters: MD, FA, in-plane FA (FA IP ), axial diffusivity (AD) and radial diffusivity (RD), were coregistered to Hematoxylin & Eosin- (H&E) and Elastica van Gieson-stained (EVG) histological sections by a non-linear landmark-based approach. Here, we provide DWI signal and DTI maps coregistered to histology sections and describe the pipeline for processing the raw DTI data and the coregistration. The raw, processed, and coregistered data are hosted by Analytic Imaging Diagnostics Arena (AIDA) data hub registry, and software tools for processing are provided via GitHub. We hope that data can be used in research and education concerning the link between the meningioma microstructure and parameters obtained by DTI., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2023 The Author(s).)

Purpose: Glioblastoma (GBM) is the most common primary malignant brain tumor in adults. Despite the best available treatment, prognosis remains poor. Current standard therapy consists of surgical removal of the tumor followed by radiotherapy and chemotherapy with the alkylating agent temozolomide (TMZ). Experimental studies suggest that antisecretory factor (AF), an endogenous protein with proposed antisecretory and anti-inflammatory properties, may potentiate the effect of TMZ and alleviate cerebral edema. Salovum is an egg yolk powder enriched for AF and is classified as a medical food in the European Union. In this pilot study, we evaluate the safety and feasibility of add-on Salovum in GBM patients., Methods: Eight patients with newly diagnosed, histologically confirmed GBM were prescribed Salovum during concomitant radiochemotherapy. Safety was determined by the number of treatment-related adverse events. Feasibility was determined by the number of patients who completed the full prescribed Salovum treatment., Results: No serious treatment-related adverse events were observed. Out of 8 included patients, 2 did not complete the full treatment. Only one of the dropouts was due to issues directly related to Salovum, which were nausea and loss of appetite. Median survival was 23 months., Conclusions: We conclude that Salovum is safe to use as an add-on treatment for GBM. In terms of feasibility, adherence to the treatment regimen requires a determined and independent patient as the large doses prescribed may cause nausea and loss of appetite., Trial Registration: ClinicalTrials.gov NCT04116138. Registered on 04/10/2019., (© 2023. The Author(s).)

Direct cellular reprogramming has recently gained attention of cancer researchers for the possibility to convert undifferentiated cancer cells into more differentiated, postmitotic cell types. While a few studies have attempted reprogramming of glioblastoma (GBM) cells toward a neuronal fate, this approach has not yet been used to induce differentiation into other lineages and in vivo data on reduction in tumorigenicity are limited. Here, we employ cellular reprogramming to induce astrocytic differentiation as a therapeutic approach in GBM. To this end, we overexpressed key transcriptional regulators of astroglial development in human GBM and GBM stem cell lines. Treated cells undergo a remarkable shift in structure, acquiring an astrocyte-like morphology with star-shaped bodies and radial branched processes. Differentiated cells express typical glial markers and show a marked decrease in their proliferative state. In addition, forced differentiation induces astrocytic functions such as induced calcium transients and ability to respond to inflammatory stimuli. Most importantly, forced differentiation substantially reduces tumorigenicity of GBM cells in an in vivo xenotransplantation model. The current study capitalizes on cellular plasticity with a novel application in cancer. We take advantage of the similarity between neural developmental processes and cancer hierarchy to mitigate, if not completely abolish, the malignant nature of tumor cells and pave the way for new intervention strategies., (©2022 The Authors; Published by the American Association for Cancer Research.)

Background: Mean diffusivity (MD) and fractional anisotropy (FA) from diffusion MRI (dMRI) have been associated with cell density and tissue anisotropy across tumors, but it is unknown whether these associations persist at the microscopic level., Purpose: To quantify the degree to which cell density and anisotropy, as determined from histology, account for the intra-tumor variability of MD and FA in meningioma tumors. Furthermore, to clarify whether other histological features account for additional intra-tumor variability of dMRI parameters., Materials and Methods: We performed ex-vivo dMRI at 200 μm isotropic resolution and histological imaging of 16 excised meningioma tumor samples. Diffusion tensor imaging (DTI) was used to map MD and FA, as well as the in-plane FA (FA IP ). Histology images were analyzed in terms of cell nuclei density (CD) and structure anisotropy (SA; obtained from structure tensor analysis) and were used separately in a regression analysis to predict MD and FA IP , respectively. A convolutional neural network (CNN) was also trained to predict the dMRI parameters from histology patches. The association between MRI and histology was analyzed in terms of out-of-sample (R 2 OS ) on the intra-tumor level and within-sample R 2 across tumors. Regions where the dMRI parameters were poorly predicted from histology were analyzed to identify features apart from CD and SA that could influence MD and FA IP , respectively., Results: Cell density assessed by histology poorly explained intra-tumor variability of MD at the mesoscopic level (200 μm), as median R 2 OS  = 0.04 (interquartile range 0.01-0.26). Structure anisotropy explained more of the variation in FA IP (median R 2 OS  = 0.31, 0.20-0.42). Samples with low R 2 OS for FA IP exhibited low variations throughout the samples and thus low explainable variability, however, this was not the case for MD. Across tumors, CD and SA were clearly associated with MD (R 2  = 0.60) and FA IP (R 2  = 0.81), respectively. In 37% of the samples (6 out of 16), cell density did not explain intra-tumor variability of MD when compared to the degree explained by the CNN. Tumor vascularization, psammoma bodies, microcysts, and tissue cohesivity were associated with bias in MD prediction based solely on CD. Our results support that FA IP is high in the presence of elongated and aligned cell structures, but low otherwise., Conclusion: Cell density and structure anisotropy account for variability in MD and FA IP across tumors but cell density does not explain MD variations within the tumor, which means that low or high values of MD locally may not always reflect high or low tumor cell density. Features beyond cell density need to be considered when interpreting MD., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Published by Elsevier Inc.)

Glial cell line-derived neurotrophic factor (GDNF) has been shown to counteract seizures when overexpressed or delivered into the brain in various animal models of epileptogenesis or chronic epilepsy. The mechanisms underlying this effect have not been investigated. We here demonstrate for the first time that GDNF enhances GABAergic inhibitory drive onto mouse pyramidal neurons by modulating postsynaptic GABA A receptors, particularly in perisomatic inhibitory synapses, by GFRα1 mediated activation of the Ret receptor pathway. Other GDNF receptors, such as NCAM or Syndecan3, are not contributing to this effect. We observed similar alterations by GDNF in human hippocampal slices resected from epilepsy patients. These data indicate that GDNF may exert its seizure-suppressant action by enhancing GABAergic inhibitory transmission in the hippocampal network, thus counteracting the increased excitability of the epileptic brain. This new knowledge can contribute to the development of novel, more precise treatment strategies based on a GDNF gene therapy approach.

Glioblastoma (GBM) is the most common and most aggressive primary brain tumor in adults. Glioma stem like cells (GSC) represent the highest cellular hierarchy in GBM and have a determining role in tumor growth, recurrence and patient prognosis. However, a better definition of GSC subpopulations, especially at the surgical resection margin, is warranted for improved oncological treatment options. The present study interrogated cells expressing CD105 (CD105 + ) specifically within the tumor front and the pre-invasive niche as a potential GSC subpopulation. GBM primary cell lines were generated from patients (n = 18) and CD105 + cells were isolated and assessed for stem-like characteristics. In vitro, CD105 + cells proliferated and enriched in serum-containing medium but not in serum-free conditions. CD105 + cells were characterized by Nestin + , Vimentin + and SOX2 - , clearly distinguishing them from SOX2 + GCS. GBM CD105 + cells differentiated into osteocytes and adipocytes but not chondrocytes. Exome sequencing revealed that GBM CD105 + cells matched 83% of somatic mutations in the Cancer cell line encyclopedia, indicating a malignant phenotype and in vivo xenotransplantation assays verified their tumorigenic potential. Cytokine assays showed that immunosuppressive and protumorigenic cytokines such as IL6, IL8, CCL2, CXCL-1 were produced by CD105 + cells. Finally, screening for 88 clinical drugs revealed that GBM CD105 + cells are resistant to most chemotherapeutics except Doxorubicin, Idarubicin, Fludarabine and ABT-751. Our study provides a rationale for targeting tumoral CD105 + cells in order to reshape the tumor microenvironment and block GBM progression., (© 2022. The Author(s).)

Background: Chemo- and radiotherapy (RT) is standard treatment for patients with high-grade glioma, but may cause side-effects on the patient's cognitive function., Aim: Use of diffusion tensor imaging (DTI) to investigate the longitudinal changes in normal-appearing brain tissue in glioblastoma patients undergoing modern arc-based RT with volumetric modulated arc therapy (VMAT) or helical tomotherapy., Materials and Methods: The study included 27 patients newly diagnosed with glioblastoma and planned for VMAT or tomotherapy. All subjects underwent magnetic resonance imaging at the start of RT and at week 3, 6, 15, and 26. Fourteen subjects were additionally imaged at week 52. The DTI data were co-registered to the dose distribution maps. Longitudinal changes in fractional anisotropy (FA), mean diffusivity (MD), radial diffusivity (RD), and axial diffusivity (AD) were assessed in the corpus callosum, the centrum semiovale, the hippocampus, and the amygdala., Results: Significant longitudinal changes in FA, MD, and RD were mainly found in the corpus callosum. In the other examined brain structures, only sparse and transient changes were seen. No consistent correlations were found between biodose, age, or gender and changes in DTI parameters., Conclusion: Longitudinal changes in MD, FA, and RD were observed but only in a limited number of brain structures and the changes were smaller than expected from literature. The results suggest that modern, arc-based RT may have less negative effect on normal-appearing parts of the brain tissue up to 12 months after radiotherapy.

Therapeutic strategies directed at the tumor surfaceome (TS), including checkpoint inhibitor blocking antibodies, antibody drug conjugates (ADCs), and chimeric antigen receptor T (CAR-T) cells, provide a new armament to fight cancer. However, a remaining bottleneck is the lack of strategies to comprehensively interrogate patient tumors for potential TS targets. Here, we have developed a platform (tumor surfaceome mapping [TS-MAP]) integrated with a newly curated TS classifier (SURFME) that allows profiling of primary 3D cultures and intact patient glioma tumors with preserved tissue architecture. Moreover, TS-MAP specifically identifies proteins capable of endocytosis as tractable targets for ADCs and other modalities requiring toxic payload internalization. In high-grade gliomas that remain among the most aggressive forms of cancer, we show that cellular spatial organization (2D vs. 3D) fundamentally transforms the surfaceome and endocytome (e.g., integrins, proteoglycans, semaphorins, and cancer stem cell markers) with general implications for target screening approaches, as exemplified by an ADC targeting EGFR. The TS-MAP platform was further applied to profile the surfaceome and endocytome landscape in a cohort of freshly resected gliomas. We found a highly diverse TS repertoire between patient tumors, not directly associated with grade and histology, which highlights the need for individualized approaches. Our data provide additional layers of understanding fundamental to the future development of immunotherapy strategies, as well as procedures for proteomics-based target identification and selection. The TS-MAP platform should be widely applicable in efforts aiming at a better understanding of how to harness the TS for personalized immunotherapy., Competing Interests: Competing interest statement: K.G.d.O and M.B. have filed a patent on the use of TS-MAP for identifying cancer treatment targets., (Copyright © 2022 the Author(s). Published by PNAS.)

Background: Preoperative radiological assessment of meningioma characteristics is of value for pre- and post-operative patient management, counselling, and surgical approach., Purpose: To investigate whether tensor-valued diffusion MRI can add to the preoperative prediction of meningioma consistency, grade and type., Materials and Methods: 30 patients with intracranial meningiomas (22 WHO grade I, 8 WHO grade II) underwent MRI prior to surgery. Diffusion MRI was performed with linear and spherical b-tensors with b-values up to 2000 s/mm 2 . The data were used to estimate mean diffusivity (MD), fractional anisotropy (FA), mean kurtosis (MK) and its components-the anisotropic and isotropic kurtoses (MK A and MK I ). Meningioma consistency was estimated for 16 patients during resection based on ultrasonic aspiration intensity, ease of resection with instrumentation or suction. Grade and type were determined by histopathological analysis. The relation between consistency, grade and type and dMRI parameters was analyzed inside the tumor ("whole-tumor") and within brain tissue in the immediate periphery outside the tumor ("rim") by histogram analysis., Results: Lower 10th percentiles of MK and MK A in the whole-tumor were associated with firm consistency compared with pooled soft and variable consistency (n = 7 vs 9; U test, p = 0.02 for MK A 10 and p = 0.04 for MK 10 ) and lower 10th percentile of MD with variable against soft and firm (n = 5 vs 11; U test, p = 0.02). Higher standard deviation of MK I in the rim was associated with lower grade (n = 22 vs 8; U test, p = 0.04) and in the MK I maps we observed elevated rim-like structure that could be associated with grade. Higher median MK A and lower median MK I distinguished psammomatous type from other pooled meningioma types (n = 5 vs 25; U test; p = 0.03 for MK A 50 and p = 0.03 and p = 0.04 for MK I 50 )., Conclusion: Parameters from tensor-valued dMRI can facilitate prediction of consistency, grade and type., (Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.)

Gamma-aminobutyric acid (GABA)-releasing interneurons modulate neuronal network activity in the brain by inhibiting other neurons. The alteration or absence of these cells disrupts the balance between excitatory and inhibitory processes, leading to neurological disorders such as epilepsy. In this regard, cell-based therapy may be an alternative therapeutic approach. We generated light-sensitive human embryonic stem cell (hESC)-derived GABAergic interneurons (hdIN) and tested their functionality. After 35 days in vitro (DIV), hdINs showed electrophysiological properties and spontaneous synaptic currents comparable to mature neurons. In co-culture with human cortical neurons and after transplantation (AT) into human brain tissue resected from patients with drug-resistant epilepsy, light-activated channelrhodopsin-2 (ChR2) expressing hdINs induced postsynaptic currents in human neurons, strongly suggesting functional efferent synapse formation. These results provide a proof-of-concept that hESC-derived neurons can integrate and modulate the activity of a human host neuronal network. Therefore, this study supports the possibility of precise temporal control of network excitability by transplantation of light-sensitive interneurons., (© 2021. The Author(s).)

The tumor microenvironment plays an essential role in supporting glioma stemness and radioresistance. Following radiotherapy, recurrent gliomas form in an irradiated microenvironment. Here we report that astrocytes, when pre-irradiated, increase stemness and survival of cocultured glioma cells. Tumor-naïve brains increased reactive astrocytes in response to radiation, and mice subjected to radiation prior to implantation of glioma cells developed more aggressive tumors. Extracellular matrix derived from irradiated astrocytes were found to be a major driver of this phenotype and astrocyte-derived transglutaminase 2 (TGM2) was identified as a promoter of glioma stemness and radioresistance. TGM2 levels increased after radiation in vivo and in recurrent human glioma, and TGM2 inhibitors abrogated glioma stemness and survival. These data suggest that irradiation of the brain results in the formation of a tumor-supportive microenvironment. Therapeutic targeting of radiation-induced, astrocyte-derived extracellular matrix proteins may enhance the efficacy of standard-of-care radiotherapy by reducing stemness in glioma. SIGNIFICANCE: These findings presented here indicate that radiotherapy can result in a tumor-supportive microenvironment, the targeting of which may be necessary to overcome tumor cell therapeutic resistance and recurrence. GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/81/8/2101/F1.large.jpg., (©2021 American Association for Cancer Research.)

Microglia, the immune sentinel of the central nervous system (CNS), are generated from yolk sac erythromyeloid progenitors that populate the developing CNS. Interestingly, a specific type of bone marrow-derived monocyte is able to express a yolk sac microglial signature and populate CNS in disease. Here we have examined human bone marrow (hBM) in an attempt to identify novel cell sources for generating microglia-like cells to use in cell-based therapies and in vitro modeling. We demonstrate that hBM stroma harbors a progenitor cell that we name stromal microglial progenitor (STR-MP). STR-MP single-cell gene analysis revealed the expression of the consensus genetic microglial signature and microglial-specific genes present in development and CNS pathologies. STR-MPs can be expanded and generate microglia-like cells in vitro, which we name stromal microglia (STR-M). STR-M cells show phagocytic ability, classically activate, and survive and phagocyte in human brain tissue. Thus, our results reveal that hBM harbors a source of microglia-like precursors that can be used in patient-centered fast derivative approaches., (© 2020 The Authors. STEM CELLS TRANSLATIONAL MEDICINE published by Wiley Periodicals LLC on behalf of AlphaMed Press.)

Purpose: Radiological assessment of primary brain neoplasms, both high (HGG) and low grade tumors (LGG), based on contrast-enhancement alone can be inaccurate. We evaluated the radiological value of amide proton transfer weighted (APTw) MRI as an imaging complement for pre-surgical radiological diagnosis of brain tumors., Methods: Twenty-six patients were evaluated prospectively; (22 males, 4 females, mean age 55 years, range 26-76 years) underwent MRI at 3T using T1-MPRAGE pre- and post-contrast administration, conventional T2w, FLAIR, and APTw imaging pre-surgically for suspected primary/secondary brain tumor. Assessment of the additional value of APTw imaging compared to conventional MRI for correct pre-surgical brain tumor diagnosis. The initial radiological pre-operative diagnosis was based on the conventional contrast-enhanced MR images. The range, minimum, maximum, and mean APTw signals were evaluated. Conventional normality testing was performed; with boxplots/outliers/skewness/kurtosis and a Shapiro-Wilk's test. Mann-Whitney U for analysis of significance for mean/max/min and range APTw signal. A logistic regression model was constructed for mean, max, range and Receiver Operating Characteristic (ROC) curves calculated for individual and combined APTw signals., Results: Conventional radiological diagnosis prior to surgery/biopsy was HGG (8 patients), LGG (12 patients), and metastasis (6 patients). Using the mean and maximum: APTw signal would have changed the pre-operative evaluation the diagnosis in 8 of 22 patients (two LGGs excluded, two METs excluded). Using a cut off value of >2.0% for mean APTw signal integral, 4 of the 12 radiologically suspected LGG would have been diagnosed as high grade glioma, which was confirmed by histopathological diagnosis. APTw mean of >2.0% and max >2.48% outperformed four separate clinical radiological assessments of tumor type, P-values = .004 and = .002, respectively., Conclusions: Using APTw-images as part of the daily clinical pre-operative radiological evaluation may improve diagnostic precision in differentiating LGGs from HGGs, with potential improvement of patient management and treatment., Competing Interests: PvZ acknowledges research support from Philips Healthcare, travel support from Philips Healthcare, paid lectures for Philips Healthcare. Also, APT technology is licensed to Philips Healthcare. The commercial vendor Siemens Healthcare provided support in the form of salaries for authors FT and BS, but did not have any additional role in the study. The specific roles of these authors are articulated in the ‘author contributions’ section. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Several neurodegenerative diseases cause loss of cortical neurons, leading to sensory, motor, and cognitive impairments. Studies in different animal models have raised the possibility that transplantation of human cortical neuronal progenitors, generated from pluripotent stem cells, might be developed into a novel therapeutic strategy for disorders affecting cerebral cortex. For example, we have shown that human long-term neuroepithelial-like stem (lt-NES) cell-derived cortical neurons, produced from induced pluripotent stem cells and transplanted into stroke-injured adult rat cortex, improve neurological deficits and establish both afferent and efferent morphological and functional connections with host cortical neurons. So far, all studies with human pluripotent stem cell-derived neurons have been carried out using xenotransplantation in animal models. Whether these neurons can integrate also into adult human brain circuitry is unknown. Here, we show that cortically fated lt-NES cells, which are able to form functional synaptic networks in cell culture, differentiate to mature, layer-specific cortical neurons when transplanted ex vivo onto organotypic cultures of adult human cortex. The grafted neurons are functional and establish both afferent and efferent synapses with adult human cortical neurons in the slices as evidenced by immuno-electron microscopy, rabies virus retrograde monosynaptic tracing, and whole-cell patch-clamp recordings. Our findings provide the first evidence that pluripotent stem cell-derived neurons can integrate into adult host neural networks also in a human-to-human grafting situation, thereby supporting their potential future clinical use to promote recovery by neuronal replacement in the patient's diseased brain., (© 2020 The Authors. STEM CELLS TRANSLATIONAL MEDICINE published by Wiley Periodicals LLC on behalf of AlphaMed Press.)

Introduction : Cognitive function is an important outcome measure in patients with brain tumor, providing information about the patient's clinical situation, treatment effects and possible progressive disease. The aim of this longitudinal study was to evaluate effects of the currently used radiation and chemotherapy treatment on cognitive function and to investigate associations between cognitive function at baseline and progression as well as overall survival. Methods : 32 patients newly diagnosed with malignant glioma were evaluated at baseline with CNS Vital Signs (CNS-VS), a computerized standardized neuropsychological test battery, prior to arc-based radiotherapy and concomitant chemotherapy with Temozolomide. CNS-VS measures the cognitive functions known to be affected in patients with brain tumor, covering nine cognitive domains. Follow-up cognitive evaluations were performed in 26 patients after 3.5 months and in 13 patients 1 year after treatment start. Results : Overall cognitive scores were lower in the studied patient cohort at baseline compared to standardized domain scores. At 3.5 months follow-up cognitive functioning was slightly decreased, but only in 1/9 cognitive domains - visual memory - where significant changes were found compared to baseline test results. Similarly, at 12 months follow-up no significant changes in cognitive test results were seen compared to baseline examination, except for a decrease in the visual memory domain. In relation to early progression, the most significant cognitive deficits were dysfunctional visual memory and low executive functioning at baseline. Low executive function at baseline correlated most significantly with shorter overall survival. Conclusion : The present study suggests that the currently used arc-based radiotherapy and chemotherapy might affect cognitive function less negatively than previously described during treatment and in the first year after treatment in malignant glioma patients. In general, a high cognitive test score at baseline was associated with longer time to progression and with longer survival.

In epilepsy patients, drug-resistant seizures often originate in one of the temporal lobes. In selected cases, when certain requirements are met, this area is surgically resected for therapeutic reasons. We kept the resected tissue slices alive in vitro for 48 h to create a platform for testing a novel treatment strategy based on neuropeptide Y (NPY) against drug-resistant epilepsy. We demonstrate that NPY exerts a significant inhibitory effect on epileptiform activity, recorded with whole-cell patch-clamp, in human hippocampal dentate gyrus. Application of NPY reduced overall number of paroxysmal depolarising shifts and action potentials. This effect was mediated by Y2 receptors, since application of selective Y2-receptor antagonist blocked the effect of NPY. This proof-of-concept finding is an important translational milestone for validating NPY-based gene therapy for targeting focal drug-resistant epilepsies, and increasing the prospects for positive outcome in potential clinical trials.