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Key Points Learning and memory rely on activity-dependent changes in the strength of central glutamatergic synapses (synaptic plasticity). Synaptic plasticity can be bidirectional and depends on the patterning of incoming synaptic activity. Loss of synaptic plasticity causes an inability to learn. AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid)-type glutamate receptors (AMPARs), together with kinetically slower NMDA ( N -methyl- D -aspartate) receptors (NMDARs), are important transducers of fast synaptic transmission in glutamatergic synapses and are often the target of cellular signalling pathways responsible for regulating synaptic strength during plasticity. Long-term potentiation (LTP) and long-term depression (LTD) are two important forms of bidirectional synaptic plasticity which, while different in molecular mechanisms, can coexist in the same synapse. Depending on the brain region, the origin of LTP and LTD can be presynaptic or postsynaptic. In the CA1 area of the hippocampus, LTP and LTD are predominantly postsynaptic, require Ca 2+ influx through NMDARs and are associated with changes in properties and trafficking of synaptic AMPARs. Hippocampal LTP is complex in nature and represents an interaction of different signalling components, including kinases and phosphatases, scaffolding proteins, AMPARs and receptor-interacting proteins, cytoskeletal proteins and local dendritic protein synthesis. These signalling and structural components are functionally interconnected. AMPARs can be composed of several subunits in different brain regions and during different stages of development. In the mature brain, glutamate receptor 2 (GluR2) subunits have a particularly crucial role in determining many functional properties of AMPARs. Subunit composition of synaptic AMPARs regarding GluR2-lacking or GluR2-containing AMPARs can be dynamically altered by synaptic activity and substantially contribute to synaptic strength during different forms of postsynaptic plasticity. Phosphorylation of AMPARs in their C-termini is crucial for the properties of these receptors and their trafficking to synapses. Translocation of signalling molecules, especially calcium/calmodulin-dependent protein kinase II (CaMKII), to active synapses has an essential role in their activity-dependent strengthening during hippocampal LTP. Small G-proteins are critically involved in trafficking of AMPARs and in structural reorganization of synaptic spines associated with plasticity. CaMKs could have a key role in coupling Ca 2+ influxes to the activity of small G-proteins. Local dendritic protein synthesis is controlled by synaptic activity in different forms of synaptic plasticity. For example, the GluR1 subunit of AMPARs can be synthesized in the dendritic shaft and spines, and contributes to changes in properties of synaptic AMPARs during LTP and homeostatic synaptic plasticity. Plasticity at central glutamatergic synapses is central to learning and memory and involves alterations in the functional properties and trafficking of synaptic AMPA receptors. The authors provide insights into AMPA receptor regulation and subsequent changes in synaptic strength. Activity-dependent changes in the strength of excitatory synapses are a cellular mechanism for the plasticity of neuronal networks that is widely recognized to underlie cognitive functions such as learning and memory. AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid)-type glutamate receptors (AMPARs) are the main transducers of rapid excitatory transmission in the mammalian CNS, and recent discoveries indicate that the mechanisms which regulate AMPARs are more complex than previously thought. This review focuses on recent evidence that alterations to AMPAR functional properties are coupled to their trafficking, cytoskeletal dynamics and local protein synthesis. These relationships offer new insights into the regulation of AMPARs and synaptic strength by cellular signalling.

Glioblastoma (GBM) is the most common and lethal primary intrinsic tumour of the adult brain and evidence indicates disease progression is driven by glioma stem cells (GSCs). Extensive advances in the molecular characterization of GBM allowed classification into proneural, mesenchymal and classical subtypes, and have raised expectations these insights may predict response to targeted therapies. We utilized GBM neurospheres that display GSC characteristics and found activation of the PI3K/AKT pathway in sphere-forming cells. The PI3Kα selective inhibitor alpelisib blocked PI3K/AKT activation and inhibited spheroid growth, suggesting an essential role for the PI3Kα catalytic isoform. p110α expression was highest in the proneural subtype and this was associated with increased phosphorylation of AKT. Further, employing the GBM BioDP, we found co-expression of PIK3CA with the neuronal stem/progenitor marker NES was associated with poor prognosis in PN GBM patients, indicating a unique role for PI3Kα in PN GSCs. Alpelisib inhibited GSC neurosphere growth and these effects were more pronounced in GSCs of the PN subtype. The antineoplastic effects of alpelisib were substantially enhanced when combined with pharmacologic mTOR inhibition. These findings identify the alpha catalytic PI3K isoform as a unique therapeutic target in proneural GBM and suggest that pharmacological mTOR inhibition may sensitize GSCs to selective PI3Kα inhibition.

Baskin et al.  report that FAM126A, which is mutated in hypomyelination and congenital cataract, regulates PI4KIII, the kinase generating PtdIns(4)P. Loss of FAM126A in patients affects PI4KIIIα complex assembly and PtdIns(4)P synthesis at the plasma membrane. Genetic defects in myelin formation and maintenance cause leukodystrophies, a group of white matter diseases whose mechanistic underpinnings are poorly understood 1 , 2 . Hypomyelination and congenital cataract (HCC), one of these disorders, is caused by mutations in FAM126A , a gene of unknown function 3 . We show that FAM126A, also known as hyccin, regulates the synthesis of phosphatidylinositol 4-phosphate (PtdIns(4)P), a determinant of plasma membrane identity 4 , 5 , 6 . HCC patient fibroblasts exhibit reduced PtdIns(4)P levels. FAM126A is an intrinsic component of the plasma membrane phosphatidylinositol 4-kinase complex that comprises PI4KIIIα and its adaptors TTC7 and EFR3 (refs  5 , 7 ). A FAM126A–TTC7 co-crystal structure reveals an all-α-helical heterodimer with a large protein–protein interface and a conserved surface that may mediate binding to PI4KIIIα. Absence of FAM126A, the predominant FAM126 isoform in oligodendrocytes, destabilizes the PI4KIIIα complex in mouse brain and patient fibroblasts. We propose that HCC pathogenesis involves defects in PtdIns(4)P production in oligodendrocytes, whose specialized function requires massive plasma membrane expansion and thus generation of PtdIns(4)P and downstream phosphoinositides 8 , 9 , 10 , 11 . Our results point to a role for FAM126A in supporting myelination, an important process in development and also following acute exacerbations in multiple sclerosis 12 , 13 , 14 .

Glioblastoma multiforme is the most malignant type of primary brain tumor with a poor prognosis. These tumors consist of a heterogeneous population of malignant cells, including well-differentiated tumor cells and less differentiated cells with stem cell properties. These cancer stem cells, known as brain tumor initiating cells, likely contribute to glioma recurrence, as they are highly invasive, mobile, resistant to radiation and chemotherapy, and have the capacity to self-renew. Glioblastoma tumor cells release excitotoxic levels of glutamate, which may be a key process in the death of peritumoral neurons, formation of necrosis, local inflammation, and glioma-related seizures. Moreover, elevated glutamate levels in the tumor may act in paracrine and autocrine manner to activate glutamate receptors on glioblastoma tumor cells, resulting in proliferation and invasion. Using a previously described culturing condition that selectively promotes the growth of brain tumor initiating cells, which express the stem cell markers nestin and SOX-2, we characterize the expression of α-amino-3-hydroxy-5-methyl-4-isozolepropionic acid (AMPA)-type glutamate receptor subunits in brain tumor initiating cells derived from glioblastomas. Here we show for the first time that glioblastoma brain tumor initiating cells express high concentrations of functional calcium-permeable AMPA receptors, compared to the differentiated tumor cultures consisting of non-stem cells. Up-regulated calcium-permeable AMPA receptor expression was confirmed by immunoblotting, immunocytochemistry, and intracellular calcium imaging in response to specific agonists. Our findings raise the possibility that glutamate secretion in the GBM tumor microenvironment may stimulate brain tumor derived cancer stem cells.

We evaluated the use of a part-task simulator with 3D and haptic feedback as a training tool for a common neurosurgical procedure--placement of thoracic pedicle screws. To evaluate the learning retention of thoracic pedicle screw placement on a high-performance augmented reality and haptic technology workstation. Fifty-one fellows and residents performed thoracic pedicle screw placement on the simulator. The virtual screws were drilled into a virtual patient's thoracic spine derived from a computed tomography data set of a real patient. With a 12.5% failure rate, a 2-proportion z test yielded P = .08. For performance accuracy, an aggregate Euclidean distance deviation from entry landmark on the pedicle and a similar deviation from the target landmark in the vertebral body yielded P = .04 from a 2-sample t test in which the rejected null hypothesis assumes no improvement in performance accuracy from the practice to the test sessions, and the alternative hypothesis assumes an improvement. The performance accuracy on the simulator was comparable to the accuracy reported in literature on recent retrospective evaluation of such placements. The failure rates indicated a minor drop from practice to test sessions, and also indicated a trend (P = .08) toward learning retention resulting in improvement from practice to test sessions. The performance accuracy showed a 15% mean score improvement and more than a 50% reduction in standard deviation from practice to test. It showed evidence (P = .04) of performance accuracy improvement from practice to test session.

Mechanisms of invasion in glioblastoma (GBM) relate to differential expression of proteins conferring increased motility and penetration of the extracellular matrix. CD97 is a member of the epidermal growth factor seven-span transmembrane family of adhesion G-protein coupled receptors. These proteins facilitate mobility of leukocytes into tissue. In this study we show that CD97 is expressed in glioma, has functional effects on invasion, and is associated with poor overall survival. Glioma cell lines and low passage primary cultures were analyzed. Functional significance was assessed by transient knockdown using siRNA targeting CD97 or a non-target control sequence. Invasion was assessed 48 hours after siRNA-mediated knockdown using a Matrigel-coated invasion chamber. Migration was quantified using a scratch assay over 12 hours. Proliferation was measured 24 and 48 hours after confirmed protein knockdown. GBM cell lines and primary cultures were found to express CD97. Knockdown of CD97 decreased invasion and migration in GBM cell lines, with no difference in proliferation. Gene-expression based Kaplan-Meier analysis was performed using The Cancer Genome Atlas, demonstrating an inverse relationship between CD97 expression and survival. GBMs expressing high levels of CD97 were associated with decreased survival compared to those with low CD97 (p = 0.007). CD97 promotes invasion and migration in GBM, but has no effect on tumor proliferation. This phenotype may explain the discrepancy in survival between high and low CD97-expressing tumors. This data provides impetus for further studies to determine its viability as a therapeutic target in the treatment of GBM.

Resistance to immune checkpoint inhibitors (ICIs) represents a major challenge for the effective treatment of non-small cell lung cancer (NSCLC). Tumor heterogeneity has been identified as an important mechanism of treatment resistance in cancer and has been increasingly implicated in ICI resistance. The diversity and clonality of tumor neoantigens, which represent the target epitopes for tumor-specific immune cells, have been shown to impact the efficacy of immunotherapy. Advances in genomic techniques have further enhanced our understanding of clonal landscapes within NSCLC and their evolution in response to therapy. In this review, we examine the role of tumor heterogeneity during immune surveillance in NSCLC and highlight its spatial and temporal evolution as revealed by modern technologies. We explore additional sources of heterogeneity, including epigenetic and metabolic factors, that have come under greater scrutiny as potential mediators of the immune response. We finally discuss the implications of tumor heterogeneity on the efficacy of ICIs and highlight potential strategies for overcoming therapeutic resistance.

Deficiencies in DNA repair pathways, including mismatch repair (MMR), have been linked to higher tumor mutation burden and improved response to immune checkpoint inhibitors. However, the significance of MMR mutations in lung cancer has not been well characterized, and the relevance of other processes, including homologous recombination (HR) and polymerase epsilon (POLE) activity, remains unclear. Here, we analyzed a dataset of lung squamous cell carcinoma samples from The Cancer Genome Atlas. Variants in DNA repair genes were associated with increased tumor mutation and neoantigen burden, which in turn were linked with greater tumor infiltration by activated T cells. The subset of tumors with DNA repair gene variants but without T cell infiltration exhibited upregulation of TGF-β and Wnt pathway genes, and a combined score incorporating these genes and DNA repair status accurately predicted immune cell infiltration. Finally, high neoantigen burden was positively associated with genes related to cytolytic activity and immune checkpoints. These findings provide evidence that DNA repair pathway defects and immunomodulatory genes together lead to specific immunophenotypes in lung squamous cell carcinoma and could potentially serve as biomarkers for immunotherapy.

Minimally invasive sacroiliac joint fusion (SIJF) has become an increasingly accepted surgical option for chronic sacroiliac (SI) joint dysfunction, a prevalent cause of unremitting low back/buttock pain. The objective of this study was to report clinical and functional outcomes of SIJF using triangular titanium implants (TTI) in the treatment of chronic SI joint dysfunction due to degenerative sacroiliitis or sacroiliac joint (SIJ) disruption at 3 years postoperatively. A total of 103 subjects with SIJ dysfunction at 12 centers were treated with TTI in two prospective clinical trials (NCT01640353 and NCT01681004) and enrolled in this long-term follow-up study (NCT02270203). Subjects were evaluated in study clinics at study start and again at 3, 4, and 5 years. Mean (SD) preoperative SIJ pain score was 81.5, and mean preoperative Oswestry Disability Index (ODI) was 56.3. At 3 years, mean pain SIJ pain score decreased to 26.2 (a 55-point improvement from baseline, <0.0001). At 3 years, mean ODI was 28.2 (a 28-point improvement from baseline, <0.0001). In all, 82% of subjects were very satisfied with the procedure at 3 years. EuroQol-5D (EQ-5D) time trade-off index improved by 0.30 points ( <0.0001). No adverse events definitely related to the study device or procedure were reported; one subject underwent revision surgery at year 3.7. SIJ pain contralateral to the originally treated side occurred in 15 subjects of whom four underwent contralateral SIJF. The proportion of subjects who were employed outside the home full- or part-time at 3 years decreased somewhat from baseline ( =0.1814), and the proportion of subjects who would have the procedure again was lower at 3 years compared to earlier time points. In long-term (3-year) follow-up, minimally invasive trans-iliac SIJF with TTI was associated with improved pain, disability, and quality of life with relatively high satisfaction rates. Level II. SIJF with TTI.

Non-small-cell lung cancer (NSCLC) remains one of the leading causes of death worldwide. While NSCLCs possess antigens that can potentially elicit T cell responses, defective tumor antigen presentation and T cell activation hinder host anti-tumor immune responses. The NSCLC tumor microenvironment (TME) is composed of cellular and soluble mediators that can promote or combat tumor growth. The composition of the TME plays a critical role in promoting tumorigenesis and dictating anti-tumor immune responses to immunotherapy. Dendritic cells (DCs) are critical immune cells that activate anti-tumor T cell responses and sustain effector responses. DC vaccination is a promising cellular immunotherapy that has the potential to facilitate anti-tumor immune responses and transform the composition of the NSCLC TME via tumor antigen presentation and cell–cell communication. Here, we will review the features of the NSCLC TME with an emphasis on the immune cell phenotypes that directly interact with DCs. Additionally, we will summarize the major preclinical and clinical approaches for DC vaccine generation and examine how effective DC vaccination can transform the NSCLC TME toward a state of sustained anti-tumor immune signaling.