The effect of age on alpha rhythms in the human brain derived from source localized resting-state electroencephalography.

With increasing age, peak alpha frequency (PAF) is slowed, and alpha power is reduced during resting-states with eyes closed. These age-related changes are evident across the whole scalp but remained unclear at the source level. The purpose of this study was to determine whether age impacts the power and frequency of the dominant alpha rhythm equally across source generators or whether the impact of age varies across sources. A total of 28 young adults and 26 elderly adults were recruited. High-density EEG was recorded for 10 mins with eyes closed. Single dipoles for each independent component were localized and clustered based on their anatomical label, resulting in 36 clusters. Meta-analyses were then conducted to assess effect sizes for PAF and power at PAF for all 36 clusters. Subgroup analyses were then implemented for frontal, sensorimotor, parietal, temporal, and occipital regions. The results of the meta-analyses showed that the elderly group exhibited slower PAF and less power at PAF compared to the young group. Subgroup analyses revealed age effects on PAF in parietal (g = 0.38), temporal (g = 0.65), and occipital regions (g = 1.04), with the largest effects observed in occipital regions. For power at PAF, age effects were observed in sensorimotor (g = 0.84) and parietal regions (g = 0.80), with the sensorimotor region showing the largest effect. Our findings show that age-related slowing and attenuation of the alpha rhythm manifests differentially across cortical regions, with sensorimotor and occipital regions most susceptible to age effects.

Lower individual alpha frequency in individuals with chronic low back pain and fear of movement.

ABSTRACT: Significant progress has been made in linking measures of individual alpha frequency (IAF) and pain. A lower IAF has been associated with chronic neuropathic pain and with an increased sensitivity to pain in healthy young adults. However, the translation of these findings to chronic low back pain (cLBP) are sparse and inconsistent. To address this limitation, we assessed IAFs in a cohort of 70 individuals with cLBP, implemented 3 different IAF calculations, and separated cLBP subjects based on psychological variables. We hypothesized that a higher fear movement in cLBP is associated with a lower IAF at rest. A total of 10 minutes of resting data were collected from 128 electroencephalography channels. Our results offer 3 novel contributions to the literature. First, the high fear group had a significantly lower peak alpha frequency. The high fear group also reported higher pain and higher disability. Second, we calculated individual alpha frequency using 3 different but established methods; the effect of fear on individual alpha frequency was robust across all methods. Third, fear of movement, pain intensity, and disability highly correlated with each other and together significantly predicted IAF. Our findings are the first to show that individuals with cLBP and high fear have a lower peak alpha frequency.

The effect of chronic low back pain on postural control during quiet standing: A meta-analysis.

Low back pain (LBP) has been associated with altered body sway during quiet standing, but the pattern of results is inconsistent. The purpose of this meta-analysis is to examine the effects of vision (eyes open, eyes closed) and changing the support surface (foam surface, firm surface) on postural sway during quiet standing in individuals with chronic LBP (cLBP). Five electronic databases were searched on March 27th, 2022. Of 2,856, 16 studies (n = 663) were included. Across all conditions, we found a positive and medium effect size (g = 0.77 [0.50, 1.04]) that represented greater body sway in individuals with cLBP. Subgroup analyses revealed medium effects during eyes open conditions (firm surface: g = 0.60 [0.33, 0.87]; foam surface: g = 0.68 [0.38, 0.97]), and large effects during eyes closed conditions (firm surface: g = 0.97 [0.60, 1.35]; foam surface: g = 0.89 [0.28, 1.51]). We quantified effects of self-reported pain and found a moderate effect during eyes closed plus firm surface conditions (Q = 3.28; p = 0.070). We conclude that cLBP is associated with increased postural sway, with largest effect sizes evident when vision is removed and when self-reported pain intensity is higher.

Surmounting Withdrawal to Initiate Fast Treatment with Naltrexone (SWIFT): A stepped wedge hybrid type 1 effectiveness-implementation study.

BACKGROUND: Extended-release injectable naltrexone (XR-NTX) is an effective treatment for opioid use disorder (OUD), but initiation remains a barrier to implementation. Standard practice requires a 10- to 15-day inpatient admission prior to XR-NTX initiation and involves a methadone or buprenorphine taper followed by a 7- to 10-day washout, as recommended in the Prescribing Information for XR-NTX. A 5- to 7-day rapid induction approach was developed that utilizes low-dose oral naltrexone and non-opioid medications. METHODS: The CTN-0097 Surmounting Withdrawal to Initiate Fast Treatment with Naltrexone (SWIFT) study was a hybrid type I effectiveness-implementation trial that compared the effectiveness of the standard procedure (SP) to the rapid procedure (RP) for XR-NTX initiation across six community inpatient addiction treatment units, and evaluated the implementation process. Sites were randomized to RP every 14 weeks in an optimized stepped wedge design. Participants (target recruitment = 450) received the procedure (SP or RP) that the site was implementing at time of admission. The hypothesis was RP will be non-inferior to SP on proportion of inpatients who receive XR-NTX, with a shorter admission time for RP. Superiority testing of RP was planned if the null hypothesis of inferiority of RP to SP was rejected. DISCUSSION: If RP for XR-NTX initiation is shown to be effective, the shorter inpatient stay could make XR-NTX more feasible and have an important public health impact expanding access to OUD pharmacotherapy. Further, a better understanding of facilitators and barriers to RP implementation can help with future translatability and uptake to other community programs. TRIAL REGISTRATION: NCT04762537 Registered February 21, 2021.

Neurophysiology of movement inhibition during full body reaching.

Our current understanding of response inhibition comes from go/no-go studies that draw conclusions based on the overt movement of single limbs (i.e., a single finger pushing a button). In general, go/no-go paradigms have found that an individual's ability to correctly inhibit the motor system is indicative of a healthy central nervous system. However, measuring inhibition by an overt behavioral response may lack the sensitivity to conclude whether the motor system is completely inhibited. Therefore, our goal was to use behavioral and neurophysiological measures to investigate inhibition of the motor system during a full-body reaching task. When directly comparing neurophysiological and behavioral measures, we found that neurophysiological measures were associated with a greater number of errors during no-go trials and faster onset times during go trials. Further analyses revealed a negative correlation between errors and onset times, such that the muscles that activated the earliest during go trials also had the greatest number of errors during no-go trials. Together, our observations show that the absence of an overt behavioral response does not always translate to total inhibition of the motor system.

DAPLE orchestrates apical actomyosin assembly from junctional polarity complexes.

Establishment of apicobasal polarity and the organization of the cytoskeleton must operate coordinately to ensure proper epithelial cell shape and function. However, the precise molecular mechanisms by which polarity complexes directly instruct the cytoskeletal machinery to determine cell shape are poorly understood. Here, we define a mechanism by which the PAR polarity complex (PAR3-PAR6-aPKC) at apical cell junctions leads to efficient assembly of the apical actomyosin network to maintain epithelial cell morphology. We found that the PAR polarity complex recruits the protein DAPLE to apical cell junctions, which in turn triggers a two-pronged mechanism that converges upon assembly of apical actomyosin. More specifically, DAPLE directly recruits the actin-stabilizing protein CD2AP to apical junctions and, concomitantly, activates heterotrimeric G protein signaling in a GPCR-independent manner to favor RhoA-myosin activation. These observations establish DAPLE as a direct molecular link between junctional polarity complexes and the formation of apical cytoskeletal assemblies that support epithelial cell shape.

The cell adhesion molecule TMIGD1 binds to moesin and regulates tubulin acetylation and cell migration.

BACKGROUND: The cell adhesion molecule transmembrane and immunoglobulin (Ig) domain containing1 (TMIGD1) is a novel tumor suppressor that plays important roles in regulating cell-cell adhesion, cell proliferation and cell cycle. However, the mechanisms of TMIGD1 signaling are not yet fully elucidated. RESULTS: TMIGD1 binds to the ERM family proteins moesin and ezrin, and an evolutionarily conserved RRKK motif on the carboxyl terminus of TMIGD1 mediates the interaction of TMIGD1 with the N-terminal ERM domains of moesin and ezrin. TMIGD1 governs the apical localization of moesin and ezrin, as the loss of TMIGD1 in mice altered apical localization of moesin and ezrin in epithelial cells. In cell culture, TMIGD1 inhibited moesin-induced filopodia-like protrusions and cell migration. More importantly, TMIGD1 stimulated the Lysine (K40) acetylation of α-tubulin and promoted mitotic spindle organization and CRISPR/Cas9-mediated knockout of moesin impaired the TMIGD1-mediated acetylation of α-tubulin and filamentous (F)-actin organization. CONCLUSIONS: TMIGD1 binds to moesin and ezrin, and regulates their cellular localization. Moesin plays critical roles in TMIGD1-dependent acetylation of α-tubulin, mitotic spindle organization and cell migration. Our findings offer a molecular framework for understanding the complex functional interplay between TMIGD1 and the ERM family proteins in the regulation of cell adhesion and mitotic spindle assembly, and have wide-ranging implications in physiological and pathological processes such as cancer progression.

Recent Advances in Glioma Therapy: Combining Vascular Normalization and Immune Checkpoint Blockade.

Glioblastoma (GBM) accounts for more than 50% of all primary malignancies of the brain. Current standard treatment regimen for GBM includes maximal surgical resection followed by radiation and adjuvant chemotherapy. However, due to the heterogeneity of the tumor cells, tumor recurrence is often inevitable. The prognosis of patients with glioma is, thus, dismal. Glioma is a highly angiogenic tumor yet immunologically cold. As such, evolving studies have focused on designing strategies that specifically target the tyrosine kinase receptors of angiokines and encourage immune infiltration. Recent promising results from immunotherapies on other cancer types have prompted further investigations of this therapy in GBM. In this article, we reviewed the pathological angiogenesis and immune reactivity in glioma, as well as its target for drug development, and we discussed future directions in glioma therapy.

Ecological Momentary Assessment: A Field Evaluation of Subjective Ratings of Speech in Noise.

PURPOSE: As hearing rehabilitation research evolves to include both retrospective and momentary assessment outcome measures, it is important to understand how in-the-moment contextual factors influence subjective ratings. We aimed to determine, over a 4-week period of participants responding to ecological momentary assessments (EMAs) in their own environments, whether: (1) participants will complete surveys in speech-in-noise listening situations; (2) ratings of speech in noise change in a predictable manner as the acoustic conditions change; and (3) EMAs provide patient insights beyond those provided from retrospective ratings. DESIGN: Fourteen adults aged 26 to 86 years with at least 6 months of hearing aid experience were recruited for an 8-week crossover field trial (4 weeks wearing hearing aids with no EMA; 4 weeks wearing hearing aids with EMA). Participants were fitted with hearing aids and provided with a streamer and a smartphone with an app that analyzed the acoustic signal from the hearing aids and alerted the participant to respond to a survey when predetermined acoustic conditions were detected. Participants were prompted to complete brief surveys up to 9 times/day that contained establishing questions, quality ratings, and items assessing perceived benefit, residual activity limitation, and satisfaction. Participants also completed retrospective questionnaires at intake and after each 4-week field trial. RESULTS: Participants completed an average of 4.4 surveys per day. The quality ratings changed as the acoustics changed: Ratings of intelligibility were lower for 10 dB signal-to-noise ratio (SNR) than 20 dB SNR (p = 0.006); ratings of noisiness were higher for 10 dB SNR than 20 dB SNR (p = 0.001) and higher for 65 dB SPL than 50 dB SPL (p < 0.001); ratings of effort were higher for 65 dB SPL than 50 dB SPL (p = 0.004); ratings of loudness were higher for 65 dB SPL than 50 dB SPL (p = 0.001). Descriptive analysis of satisfaction, benefit, and residual activity limitation responses showed that the momentary surveys provided more detail about individual variability across acoustic conditions than the retrospective questions. CONCLUSIONS: Participants completed more than 99% of the triggered surveys, demonstrating high compliance. Because the quality ratings generally changed in the hypothesized direction, it is concluded that the participants provided valid responses. The greater variability in responses with EMA than retrospective questionnaires demonstrates its potential utility as a clinical tool for exploring hearing aid outcomes in real-world environments.

Cortical dynamics of movement-evoked pain in chronic low back pain.

KEY POINTS: Cortical activity underlying movement-evoked pain is not well understood, despite being a key symptom of chronic musculoskeletal pain. We combined high-density electroencephalography with a full-body reaching protocol in a virtual reality environment to assess cortical activity during movement-evoked pain in chronic low back pain. Movement-evoked pain in individuals with chronic low back pain was associated with longer reaction times, delayed peak velocity and greater movement variability. Movement-evoked pain was associated with attenuated disinhibition in prefrontal motor areas, as evidenced by an attenuated reduction in beta power in the premotor cortex and supplementary motor area. ABSTRACT: Although experimental pain alters neural activity in the cortex, evidence of changes in neural activity in individuals with chronic low back pain (cLBP) remains scarce and results are inconsistent. One of the challenges in studying cLBP is that the clinical pain fluctuates over time and often changes during movement. The goal of the present study was to address this challenge by recording high-density electroencephalography (HD-EEG) data during a full-body reaching task to understand neural activity during movement-evoked pain. HD-EEG data were analysed using independent component analyses, source localization and measure projection analyses to compare neural oscillations between individuals with cLBP who experienced movement-evoked pain and pain-free controls. We report two novel findings. First, movement-evoked pain in individuals with cLBP was associated with longer reaction times, delayed peak velocity and greater movement variability. Second, movement-evoked pain was associated with an attenuated reduction in beta power in the premotor cortex and supplementary motor area. Our observations move the field forward by revealing attenuated disinhibition in prefrontal motor areas during movement-evoked pain in cLBP.

Transmembrane and Immunoglobulin Domain Containing 1, a Putative Tumor Suppressor, Induces G2/M Cell Cycle Checkpoint Arrest in Colon Cancer Cells.

Colorectal cancer (CRC) is a leading nonfamilial cause of cancer mortality among men and women. Although various genetic and epigenetic mechanisms have been identified, the full molecular mechanisms deriving CRC tumorigenesis are not fully understood. This study demonstrates that cell adhesion molecule transmembrane and immunoglobulin domain containing 1 (TMIGD1) are highly expressed in mouse and human normal intestinal epithelial cells. TMIGD1 knockout mice were developed, and the loss of TMIGD1 in mice was shown to result in the development of adenomas in small intestine and colon. In addition, the loss of TMIGD1 significantly impaired intestinal epithelium brush border membrane, junctional polarity, and maturation. Mechanistically, TMIGD1 inhibits tumor cell proliferation and cell migration, arrests cell cycle at the G2/M phase, and induces expression of p21CIP1 (cyclin-dependent kinase inhibitor 1), and p27KIP1 (cyclin-dependent kinase inhibitor 1B) expression, key cell cycle inhibitor proteins involved in the regulation of the cell cycle. Moreover, TMIGD1 is shown to be progressively down-regulated in sporadic human CRC, and its downregulation correlates with poor overall survival. The findings herein identify TMIGD1 as a novel tumor suppressor gene and provide new insights into the pathogenesis of colorectal cancer and a novel potential therapeutic target.

A Novel Method to Understand Neural Oscillations During Full-Body Reaching: A Combined EEG and 3D Virtual Reality Study.

Virtual reality (VR) can be used to create environments that are not possible in the real-world. Producing movements in VR holds enormous promise for rehabilitation and offers a platform from which to understand the neural control of movement. However, no study has examined the impact of a 3D fully immersive head-mounted display (HMD) VR system on the integrity of neural data. We assessed the quality of 64-channel EEG data with and without HMD VR during rest and during a full-body reaching task. We compared resting EEG while subjects completed three conditions: No HMD (EEG-only), HMD powered off (VR-off), and HMD powered on (VR-on). Within the same session, EEG were collected while subjects completed full-body reaching movements in two conditions (EEG-only, VR-on). During rest, no significant differences in data quality and power spectrum were observed between EEG-only, VR-off, and VR-on conditions. During reaching movements, the proportion of components attributed to the brain was greater in the EEG-only condition compared to the VR-on condition. Despite this difference, neural oscillations in source space were not significantly different between conditions, with both conditions associated with decreases in alpha and beta power in sensorimotor cortex during movements. Our findings demonstrate that the integrity of EEG data can be maintained while individuals execute full-body reaching movements within an immersive 3D VR environment. Clinical impact: Integrating VR and EEG is a viable approach to understanding the cortical processes of movement. Simultaneously recording movement and brain activity in combination with VR provides the foundation for neurobiologically informed rehabilitation therapies.

Chronic jaw pain attenuates neural oscillations during motor-evoked pain.

Motor- and pain-related processes separately induce a reduction in alpha and beta power. When movement and pain occur simultaneously but are independent of each other, the effects on alpha and beta power are additive. It is not clear whether this additive effect is evident during motor-evoked pain in individuals with chronic pain. We combined highdensity electroencephalography (EEG) with a paradigm in which motor-evoked pain was induced during a jaw force task. Participants with chronic jaw pain and pain-free controls produced jaw force at 2% and 15% of their maximum voluntary contraction. The chronic jaw pain group showed exacerbated motor-evoked pain as force amplitude increased and showed increased motor variability and motor error irrespective of force amplitude. The chronic jaw pain group had an attenuated decrease in power in alpha and lower-beta frequencies in the occipital cortex during the anticipation and experience of motor-evoked pain. Rather than being additive, motor-evoked pain attenuated the modulation of alpha and beta power, and this was most evident in occipital cortex. Our findings provide the first evidence of changes in neural oscillations in the cortex during motor-evoked jaw pain.

Cortical Oscillations in Cervical Dystonia and Dystonic Tremor.

Dystonia involves sustained or repetitive muscle contractions, affects different skeletal muscles, and may be associated with tremor. Few studies have investigated if cortical pathophysiology is impaired even when dystonic muscles are not directly engaged and during the presence of dystonic tremor (DT). Here, we recorded high-density electroencephalography and time-locked behavioral data in 2 cohorts of patients and controls during the performance of head movements, upper limb movements, and grip force. Patients with cervical dystonia had reduced movement-related desynchronization in the alpha and beta bands in the bilateral sensorimotor cortex during head turning movements, produced by dystonic muscles. Reduced desynchronization in the upper beta band in the ipsilateral motor and bilateral sensorimotor cortex was found during upper limb planar movements, produced by non-dystonic muscles. In a precision grip task, patients with DT had reduced movement-related desynchronization in the alpha and beta bands in the bilateral sensorimotor cortex. We observed a general pattern of abnormal sensorimotor cortical desynchronization that was present across the head and upper limb motor tasks, in patients with and without DT when compared with controls. Our findings suggest that abnormal cortical desynchronization is a general feature of dystonia that should be a target of pharmacological and other therapeutic interventions.

Cell adhesion molecule IGPR-1 activates AMPK connecting cell adhesion to autophagy.

Autophagy plays critical roles in the maintenance of endothelial cells in response to cellular stress caused by blood flow. There is growing evidence that both cell adhesion and cell detachment can modulate autophagy, but the mechanisms responsible for this regulation remain unclear. Immunoglobulin and proline-rich receptor-1 (IGPR-1) is a cell adhesion molecule that regulates angiogenesis and endothelial barrier function. In this study, using various biochemical and cellular assays, we demonstrate that IGPR-1 is activated by autophagy-inducing stimuli, such as amino acid starvation, nutrient deprivation, rapamycin, and lipopolysaccharide. Manipulating the IκB kinase ß activity coupled with in vivo and in vitro kinase assays demonstrated that IκB kinase ß is a key serine/threonine kinase activated by autophagy stimuli and that it catalyzes phosphorylation of IGPR-1 at Ser220 The subsequent activation of IGPR-1, in turn, stimulates phosphorylation of AMP-activated protein kinase, which leads to phosphorylation of the major pro-autophagy proteins ULK1 and Beclin-1 (BECN1), increased LC3-II levels, and accumulation of LC3 punctum. Thus, our data demonstrate that IGPR-1 is activated by autophagy-inducing stimuli and in response regulates autophagy, connecting cell adhesion to autophagy. These findings may have important significance for autophagy-driven pathologies such cardiovascular diseases and cancer and suggest that IGPR-1 may serve as a promising therapeutic target.

Loss of MINAR2 impairs motor function and causes Parkinson's disease-like symptoms in mice.

Parkinson's disease is the second most common human neurodegenerative disease. Motor control impairment represents a key clinical hallmark and primary clinical symptom of the disease, which is further characterized by the progressive loss of dopaminergic neurons in the substantia nigra pars compacta and the accumulation of α-synuclein aggregations. We have identified major intrinsically disordered NOTCH2-associated receptor 2 encoded by KIAA1024L, a previously uncharacterized protein that is highly conserved in humans and other species. In this study, we demonstrate that major intrinsically disordered NOTCH2-associated receptor 2 expression is significantly down-regulated in the frontal lobe brain of patients with Lewy body dementia. Major intrinsically disordered NOTCH2-associated receptor 2 is predominantly expressed in brain tissue and is particularly prominent in the midbrain. Major intrinsically disordered NOTCH2-associated receptor 2 interacts with neurogenic locus notch homologue protein 2 and is localized at the endoplasmic reticulum compartments. We generated major intrinsically disordered NOTCH2-associated receptor 2 knockout mouse and demonstrated that the loss of major intrinsically disordered NOTCH2-associated receptor 2 in mouse results in severe motor deficits such as rigidity and bradykinesia, gait abnormalities, reduced spontaneous locomotor and exploratory behaviour, symptoms that are highly similar to those observed in human Parkinson's spectrum disorders. Analysis of the major intrinsically disordered NOTCH2-associated receptor 2 knockout mice brain revealed significant anomalies in neuronal function and appearance including the loss of tyrosine hydroxylase-positive neurons in the pars compacta, which was accompanied by an up-regulation in α-synuclein protein expression. Taken together, these data demonstrate a previously unknown function for major intrinsically disordered NOTCH2-associated receptor 2 in the pathogenesis of Parkinson's spectrum disorders.

Altered neural oscillations within and between sensorimotor cortex and parietal cortex in chronic jaw pain.

Pain perception is associated with priming of the motor system and the orienting of attention in healthy adults. These processes correspond with decreases in alpha and beta power in the sensorimotor and parietal cortices. The goal of the present study was to determine whether these findings extend to individuals with chronic pain. Individuals with chronic jaw pain and pain-free controls anticipated and experienced a low pain or a moderate pain-eliciting heat stimulus. Although stimuli were calibrated for each subject, stimulus temperature was not different between groups. High-density EEG data were collected during the anticipation and heat stimulation periods and were analyzed using independent component analyses, EEG source localization, and measure projection analyses. Direct directed transfer function was also estimated to identify frequency specific effective connectivity between regions. Between group differences were most evident during the heat stimulation period. We report three novel findings. First, the chronic jaw pain group had a relative increase in alpha and beta power and a relative decrease in theta and gamma power in sensorimotor cortex. Second, the chronic jaw pain group had a relative increase in power in the alpha and beta bands in parietal cortex. Third, the chronic jaw pain group had less connectivity strength in the beta and gamma bands between sensorimotor cortex and parietal cortex. Our findings show that the effect of chronic pain attenuates rather than magnifies neural responses to heat stimuli. We interpret these findings in the context of system-level changes in intrinsic sensorimotor and attentional circuits in chronic pain.

The cell adhesion molecule IGPR-1 is activated by and regulates responses of endothelial cells to shear stress.

Vascular endothelial cells respond to blood flow-induced shear stress. However, the mechanisms through which endothelial cells transduce mechanical signals to cellular responses remain poorly understood. In this report, using tensile-force assays, immunofluorescence and atomic force microscopy, we demonstrate that immunoglobulin and proline-rich receptor-1 (IGPR-1) responds to mechanical stimulation and increases the stiffness of endothelial cells. We observed that IGPR-1 is activated by shear stress and tensile force and that flow shear stress-mediated IGPR-1 activation modulates remodeling of endothelial cells. We found that under static conditions, IGPR-1 is present at the cell-cell contacts; however, under shear stress, it redistributes along the cell borders into the flow direction. IGPR-1 activation stimulated actin stress fiber assembly and cross-linking with vinculin. Moreover, we noted that IGPR-1 stabilizes cell-cell junctions of endothelial cells as determined by staining of cells with ZO1. Mechanistically, shear stress stimulated activation of AKT Ser/Thr kinase 1 (AKT1), leading to phosphorylation of IGPR-1 at Ser-220. Inhibition of this phosphorylation prevented shear stress-induced actin fiber assembly and endothelial cell remodeling. Our findings indicate that IGPR-1 is an important player in endothelial cell mechanosensing, insights that have important implications for the pathogenesis of common maladies, including ischemic heart diseases and inflammation.

Pathogenic mutations in neurofibromin identifies a leucine-rich domain regulating glioma cell invasiveness.

Glioblastoma (GBM) is the most aggressive tumor of the brain. NF1, a tumor suppressor gene and RAS-GTPase, is one of the highly mutated genes in GBM. Dysregulated NF1 expression promotes cell invasion, proliferation, and tumorigenesis. Loss of NF1 expression in glioblastoma is associated with increased aggressiveness of the tumor. Here, we show that NF1-loss in patient-derived glioma cells using shRNA increases self-renewal, heightens cell invasion, and promotes mesenchymal subtype and epithelial mesenchymal transition-specific gene expression that enhances tumorigenesis. The neurofibromin protein contains at least four major domains, with the GAP-related domain being the most well-studied. In this study, we report that the leucine-rich domain (LRD) of neurofibromin inhibits invasion of human glioblastoma cells without affecting their proliferation. Moreover, under conditions tested, the NF1-LRD fails to hydrolyze Ras-GTP to Ras-GDP, suggesting that its suppressive function is independent of Ras signaling. We further demonstrate that rare variants within the NF1-LRD domain found in a subset of the patients are pathogenic and reduce NF1-LRD's invasion suppressive function. Taken together, our results show, for the first time, that NF1-LRD inhibits glioma invasion, and provides evidence of a previously unrecognized function of NF1-LRD in glioma biology.

Anti-tumour effects of all-trans retinoid acid on serous ovarian cancer.

BACKGROUND: Annexin A2 is increased in serous ovarian cancer and plays an essential role in ovarian cancer invasion and metastasis. In combination with S100A10, annexin A2 plays an important role in the plasminogen activator system regulating plasmin production. The aim of this study was to investigate the potential utility of all-trans retinoid acid (ATRA), an inhibitor of the annexin A2-S100A10 signalling pathway, as a new therapeutic against serous ovarian cancer. METHODS: In this study we determined the effects of ATRA treatment (1-5 µM) on annexin A2 and S100A10 expression, plasmin activation, and the ability of ATRA to inhibit serous ovarian cancer cell survival, motility and invasion in vitro. We also employed an ex vivo tissue explant assay to assess response to ATRA treatment in serous ovarian cancers. Cryopreserved serous ovarian cancer tissues were cultured on gelatin sponges for 72 h with ATRA (1 µM). Effects on apoptosis and proliferation were assessed by immunohistochemistry using antibodies to cleaved caspase 3 or Ki67, respectively. RESULTS: Survival of serous ovarian cancer cells (OVCAR-3, OV-90, & OAW28) was significantly decreased by ATRA treatment (1-5 µM). ATRA (1 µM) also significantly decreased proliferation (Ki67 positivity, p = 0.0034), S100A10 protein levels (p = 0.0273), and increased cell apoptosis (cleaved caspase-3 positivity, p = 0.0024) in serous ovarian cancer tissues using the ex vivo tissue explant assay. In OAW28 cells, reduced cell survival following ATRA treatment was associated with a reduction of S100A10 mRNA and protein levels, S100A10 and annexin A2 membrane localization, plasmin generation, motility and invasion. In contrast, ATRA inhibited OV-90 cell survival and invasion but did not affect plasmin activation or S100A10 and annexin A2 expression or membrane localization. CONCLUSIONS: These findings suggest that ATRA inhibits serous ovarian cancer proliferation and invasion via both S100A10 dependant and S100A10 independent mechanisms. Our results show that ATRA has promising potential as a novel therapy against serous ovarian cancer that warrants further evaluation.