Tuberous Sclerosis Complex (TSC) is a neurodevelopmental disorder caused by mutations in TSC1 or TSC2, which encode proteins that negatively regulate mTOR complex 1 (mTORC1). TSC is associated with ...significant cognitive, psychiatric, and behavioral problems, collectively termed TSC-Associated Neuropsychiatric Disorders (TAND), and the cell types responsible for these manifestations are largely unknown. Here we use cell type-specific Tsc1 deletion to test whether dopamine neurons, which modulate cognitive, motivational, and affective behaviors, are involved in TAND. We show that loss of Tsc1 and constitutive activation of mTORC1 in dopamine neurons causes somatodendritic hypertrophy, reduces intrinsic excitability, alters axon terminal structure, and impairs striatal dopamine release. These perturbations lead to a selective deficit in cognitive flexibility, preventable by genetic reduction of the mTOR-binding protein Raptor. Our results establish a critical role for Tsc1-mTORC1 signaling in setting the functional properties of dopamine neurons, and indicate that dopaminergic dysfunction may contribute to cognitive inflexibility in TSC.
Meningioma is the most common primary intracranial tumor, but the molecular drivers of aggressive meningioma are incompletely understood. Using 280 human meningioma samples and RNA sequencing, ...immunohistochemistry, whole-exome sequencing, DNA methylation arrays, and targeted gene expression profiling, we comprehensively define the molecular profile of aggressive meningioma. Transcriptomic analyses identify FOXM1 as a key transcription factor for meningioma proliferation and a marker of poor clinical outcomes. Consistently, we discover genomic and epigenomic factors associated with FOXM1 activation in aggressive meningiomas. Finally, we define a FOXM1/Wnt signaling axis in meningioma that is associated with a mitotic gene expression program, poor clinical outcomes, and proliferation of primary meningioma cells. In summary, we find that multiple molecular mechanisms converge on a FOXM1/Wnt signaling axis in aggressive meningioma.
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•Genomic, epigenomic, and transcriptomic factors identify meningioma molecular subgroups•FOXM1 expression delineates aggressive meningiomas across molecular subgroups•FOXM1/Wnt signaling is associated with mitotic gene expression in aggressive meningioma•FOXM1 signaling drives primary meningioma cell proliferation
Using multiplatform molecular profiling, Vasudevan et al. comprehensively define the molecular profile of aggressive meningioma. They identify genomic, epigenomic, and transcriptomic mechanisms that converge on a FOXM1/Wnt signaling axis in aggressive meningioma that is associated with meningioma cell proliferation and is a marker of poor clinical outcomes across molecular subgroups.
Abstract
BACKGROUND: Risk factors for pre- and postoperative seizures in supratentorial meningiomas are understudied compared to other brain tumors.
OBJECTIVE: To report seizure frequency and ...identify factors associated with pre- and postoperative seizures in a large single-center population study of patients undergoing resection of supratentorial meningioma.
METHODS: Retrospective chart review of 1033 subjects undergoing resection of supratentorial meningioma at the author's institution (1991-2014). Multivariate regression was used to identify variables significantly associated with pre- and postoperative seizures.
RESULTS: Preoperative seizures occurred in 234 (22.7%) subjects. At 5 years postoperative, probability of seizure freedom was 89.9% among subjects without preoperative seizures and 62.2% with preoperative seizures. Multivariate analysis identified the following predictors of preoperative seizures: presence of ≥1 cm peritumoral edema (odds ratio OR: 4.45, 2.55-8.50), nonskull base tumor location (OR: 2.13, 1.26-3.67), greater age (OR per unit increase: 1.03, 1.01-1.05), while presenting symptom of headache (OR: 0.50, 0.29-0.84) or cranial nerve deficit (OR: 0.36, 0.17-0.71) decreased odds of preoperative seizures. Postoperative seizures after discharge were associated with preoperative seizures (OR: 5.70, 2.57-13.13), in-hospital seizure (OR: 4.31, 1.28-13.67), and among patients without preoperative seizure, occurrence of medical or surgical complications (OR 3.39, 1.09-9.48). Perioperative anti-epileptic drug use was not associated with decreased incidence of postoperative seizures.
CONCLUSIONS: Nonskull base supratentorial meningiomas with surrounding edema have the highest risk for preoperative seizure. Long-term follow-up showing persistent seizures in meningioma patients with preoperative seizures raises the possibility that these patients may benefit from electrocorticographic mapping of adjacent cortex and resection of noneloquent, epileptically active cortex.
Meningiomas are the most common primary intracranial tumors. There are no effective medical therapies for meningioma patients, and new treatments have been encumbered by limited understanding of ...meningioma biology. Here, we use DNA methylation profiling on 565 meningiomas integrated with genetic, transcriptomic, biochemical, proteomic and single-cell approaches to show meningiomas are composed of three DNA methylation groups with distinct clinical outcomes, biological drivers and therapeutic vulnerabilities. Merlin-intact meningiomas (34%) have the best outcomes and are distinguished by NF2/Merlin regulation of susceptibility to cytotoxic therapy. Immune-enriched meningiomas (38%) have intermediate outcomes and are distinguished by immune infiltration, HLA expression and lymphatic vessels. Hypermitotic meningiomas (28%) have the worst outcomes and are distinguished by convergent genetic and epigenetic mechanisms driving the cell cycle and resistance to cytotoxic therapy. To translate these findings into clinical practice, we show cytostatic cell cycle inhibitors attenuate meningioma growth in cell culture, organoids, xenografts and patients.
Managing for RADical ecosystem change Lynch, Abigail J; Thompson, Laura M; Beever, Erik A ...
Frontiers in ecology and the environment,
10/2021, Letnik:
19, Številka:
8
Journal Article
Recenzirano
Odprti dostop
Ecosystem transformation involves the emergence of persistent ecological or social–ecological systems that diverge, dramatically and irreversibly, from prior ecosystem structure and function. Such ...transformations are occurring at increasing rates across the planet in response to changes in climate, land use, and other factors. Consequently, a dynamic view of ecosystem processes that accommodates rapid, irreversible change will be critical for effectively conserving fish, wildlife, and other natural resources, and maintaining ecosystem services. However, managing ecosystems toward states with novel structure and function is an inherently unpredictable and difficult task. Managers navigating ecosystem transformation can benefit from considering broader objectives, beyond a traditional focus on resisting ecosystem change, by also considering whether accepting inevitable change or directing it along some desirable pathway is more feasible (that is, practical and appropriate) under some circumstances (the RAD framework). By explicitly acknowledging transformation and implementing an iterative RAD approach, natural resource managers can be deliberate and strategic in addressing profound ecosystem change.
In this study, we identify clinical, radiographic, and histopathologic prognosticators of overall, early, and post-median recurrence in World Health Organization (WHO) grade I meningiomas. We also ...determine a clinically relevant cutoff for MIB-1 to identify patients at high risk for recurrence.
A retrospective review of WHO grade I meningioma patients with available MIB-1 index data who underwent treatment at our institution from 2007 to 2017 was performed. Univariate and multivariate analyses, and recursive partitioning analysis (RPA), were used to identify risk factors for overall, early (within 24 months), and post-median (>24 months post-treatment) recurrence.
A total of 239 patients were included. The mean age was 60.0 years, and 69.5% of patients were female. The average follow-up was 41.1 months. All patients received surgery and 2 patients each received either adjuvant radiotherapy (2/239) or gamma knife treatment (2/239). The incidence of recurrence was 10.9% (26/239 patients), with an average time to recurrence of 33.2 months (6-105 months). Posterior fossa tumor location (
= 0.004), MIB-1 staining (
= 0.008), nuclear atypia (
= 0.003), and STR (
< 0.001) were independently associated with an increased risk of recurrence on cox-regression analysis. RPA for overall recurrence highlighted extent of resection, and after gross total resection (GTR), a MIB-1 index cutoff of 4.5% as key prognostic factors for recurrence. Patients with a GTR and MIB-1 >4.5% had a similar incidence of recurrence as those with STR (18.8 vs. 18.6%). Variables independently associated with early recurrence on binary logistic regression modeling included STR (
= 0.002) and nuclear atypia (
= 0.019). RPA confirmed STR as associated with early recurrence.
STR, posterior fossa location, nuclear atypia, and elevated MIB-1 index are prognostic factors for WHO grade I meningioma recurrence. Moreover, MIB-1 index >4.5% is prognostic for recurrence in patients with GTR. Verification of our findings in larger, multi-institutional studies could enable risk stratification and recommendations for adjuvant radiotherapy following resection of WHO grade I meningiomas.
SA2RAGE: A new sequence for fast B1+-mapping Eggenschwiler, Florent; Kober, Tobias; Magill, Arthur W. ...
Magnetic resonance in medicine,
June 2012, Letnik:
67, Številka:
6
Journal Article
To reduce unwanted variation in the passage speed of DNA through solid-state nanopores, we demonstrate nanoscale preconfinement of translocating molecules using an ultrathin nanoporous silicon ...nitride membrane separated from a single sensing nanopore by a nanoscale cavity. We present comprehensive experimental and simulation results demonstrating that the presence of an integrated nanofilter within nanoscale distances of the sensing pore eliminates the dependence of molecular passage time distributions on pore size, revealing a global minimum in the coefficient of variation of the passage time. These results provide experimental verification that the inter- and intramolecular passage time variation depends on the conformational entropy of each molecule prior to translocation. Furthermore, we show that the observed consistently narrower passage time distributions enables a more reliable DNA length separation independent of pore size and stability. We also demonstrate that the composite nanofilter/nanopore devices can be configured to suppress the frequency of folded translocations, ensuring single-file passage of captured DNA molecules. By greatly increasing the rate at which usable data can be collected, these unique attributes will offer significant practical advantages to many solid-state nanopore-based sensing schemes, including sequencing, genomic mapping, and barcoded target detection.
Purpose
To develop a framework for 3D sodium (23Na) MR fingerprinting (MRF), based on irreducible spherical tensor operators with tailored flip angle (FA) pattern and time‐efficient data acquisition ...for simultaneous quantification of T1, T2l∗, T2s∗, and T2∗ in addition to ΔB0.
Methods
23Na‐MRF was implemented in a 3D sequence and irreducible spherical tensor operators were exploited in the simulations. Furthermore, the Cramér Rao lower bound was used to optimize the flip angle pattern. A combination of single and double echo readouts was implemented to increase the readout efficiency. A study was conducted to compare results in a multicompartment phantom acquired with MRF and reference methods. Finally, the relaxation times in the human brain were measured in four healthy volunteers.
Results
Phantom experiments revealed a mean difference of 1.0% between relaxation times acquired with MRF and results determined with the reference methods. Simultaneous quantification of the longitudinal and transverse relaxation times in the human brain was possible within 32 min using 3D 23Na‐MRF with a nominal resolution of (5 mm)3. In vivo measurements in four volunteers yielded average relaxation times of: T1,brain = (35.0 ± 3.2) ms, T2l,brain∗ = (29.3 ± 3.8) ms and T2s,brain∗ = (5.5 ± 1.3) ms in brain tissue, whereas T1,CSF = (61.9 ± 2.8) ms and T2,CSF∗ = (46.3 ± 4.5) ms was found in cerebrospinal fluid.
Conclusion
The feasibility of in vivo 3D relaxometric sodium mapping within roughly ½ h is demonstrated using MRF in the human brain, moving sodium relaxometric mapping toward clinically relevant measurement times.
Determination of the etiology of primary aldosteronism remains a diagnostic challenge. The most common types of primary aldosteronism are bilateral adrenal hyperplasia (BAH), aldosterone-producing ...adenomas (APA), and primary adrenal hyperplasia. Computed tomography (CT) and adrenal vein sampling (AVS) are the primary modalities used to differentiate these subtypes. The purpose of this study was to compare AVS and CT imaging of the adrenal glands in patients with hyperaldosteronism in whom CT imaging was normal or in whom focal unilateral or bilateral adrenal abnormalities were detected. The diagnosis of primary aldosteronism was made in 62 patients based on an elevated plasma aldosterone to PRA ratio and an elevated urinary aldosterone excretion rate. Thirty-eight patients had CT imaging and successful bilateral adrenal vein sampling and were included in the final analysis. AVS was considered the gold standard in determining the specific subtype of primary aldosteronism. There were 15 patients with APA, 21 patients with BAH, and 2 patients with primary adrenal hyperplasia. Plasma aldosterone was significantly higher in patients with APA (46.3 +/- 8.5 ng/dL; 1284 +/- 235 pmol/L) than in those with BAH (29.3 +/- 2.4 ng/dL; 813 +/- 11 pmol/L; P < 0.05). Plasma potassium was significantly lower in patients with APA (3.1 +/- 0.1 mmol/L) than in patients with BAH (3.5 +/- 0.1 mmol/L; P < 0.02). There was considerable overlap in the other biochemical indices (e.g. PRA and urinary aldosterone) in patients with the different subtypes. In patients with APA proven by AVS, eight had concordant findings with CT imaging, four had discordant findings, and three had normal CT imaging. In patients with BAH proven by AVS, four had concordant findings with CT imaging, eight had discordant findings, and nine had normal CT imaging. Compared with AVS, CT imaging was either inaccurate or provided no additional information in 68% of the patients with primary aldosteronism. We conclude that adrenal CT imaging is not a reliable method to differentiate primary aldosteronism. Adrenal vein sampling is essential to establish the correct diagnosis of primary aldosteronism.
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