Necrotizing enterocolitis (NEC) is a severe gastrointestinal disease of the premature infant. One of the most important long-term complications observed in children who survive NEC early in life is ...the development of profound neurological impairments. However, the pathways leading to NEC-associated neurological impairments remain unknown, thus limiting the development of prevention strategies. We have recently shown that NEC development is dependent on the expression of the lipopolysaccharide receptor Toll-like receptor 4 (TLR4) on the intestinal epithelium, whose activation by bacteria in the newborn gut leads to mucosal inflammation. Here, we hypothesized that damage-induced production of TLR4 endogenous ligands in the intestine might lead to activation of microglial cells in the brain and promote cognitive impairments. We identified a gut-brain signaling axis in an NEC mouse model in which activation of intestinal TLR4 signaling led to release of high-mobility group box 1 in the intestine that, in turn, promoted microglial activation in the brain and neurological dysfunction. We further demonstrated that an orally administered dendrimer-based nanotherapeutic approach to targeting activated microglia could prevent NEC-associated neurological dysfunction in neonatal mice. These findings shed light on the molecular pathways leading to the development of NEC-associated brain injury, provide a rationale for early removal of diseased intestine in NEC, and indicate the potential of targeted therapies that protect the developing brain in the treatment of NEC in early childhood.
Malignant peripheral nerve sheath tumor (MPNST) is an aggressive soft tissue sarcoma for which the only effective therapy is surgery. In 2016, an international meeting entitled "MPNST State of the ...Science: Outlining a Research Agenda for the Future" was convened to establish short- and long-term research priorities. Key recommendations included the: 1) development of standardized, cost-efficient fluorodeoxyglucose positron emission tomography and whole-body magnetic resonance imaging guidelines to evaluate masses concerning for MPNST; 2) development of better understanding and histologic criteria for the transformation of a plexiform neurofibroma to MPNST; 3) establishment of a centralized database to collect genetic, genomic, histologic, immunohistochemical, molecular, radiographic, treatment, and related clinical data from MPNST subspecialty centers in a standardized manner; 4) creation of accurate mouse models to study the plexiform neurofibroma-to-MPNST transition, MPNST metastasis, and drug resistance; 5) use of trial designs that minimize regulatory requirements, maximize availability to patients, consider novel secondary end points, and study patients with newly diagnosed disease. Lastly, in order to minimize delays in developing novel therapies and promote the most efficient use of research resources and patient samples, data sharing should be incentivized.
A major component of cells in tenosynovial giant cell tumor (TGCT) consists of bystander macrophages responding to CSF1 that is overproduced by a small number of neoplastic cells with a chromosomal ...translocation involving the CSF1 gene. An autocrine loop was postulated where the neoplastic cells would be stimulated through CSF1R expressed on their surface. Here, we use single-cell RNA sequencing (scRNA-seq) to investigate cellular interactions in TGCT.
A total of 18,788 single cells from three TGCT and two giant cell tumor of bone (GCTB) samples underwent scRNA-seq. The three TGCTs were additionally analyzed using long-read RNA sequencing. Immunofluorescence and IHC for a range of markers were used to validate and extend the scRNA-seq findings.
Two recurrent neoplastic cell populations were identified in TGCT that are highly similar to nonneoplastic synoviocytes. We identified GFPT2 as a marker that highlights the neoplastic cells in TCGT. We show that the neoplastic cells themselves do not express CSF1R. We identified overlapping MAB features between the giant cells in TGCT and GCTB.
The neoplastic cells in TGCT are highly similar to nonneoplastic synoviocytes. The lack of CSF1R on the neoplastic cells indicates they may be unaffected by current therapies. High expression of GFPT2 in the neoplastic cells is associated with activation of the YAP1/TAZ pathway. In addition, we identified expression of the platelet-derived growth factor receptor in the neoplastic cells. These findings suggest two additional pathways to target in this tumor.
Metallic Na is a promising anode for rechargeable batteries, however, it is plagued by an unstable solid electrolyte interphase (SEI) and Na dendrites. Herein, a robust anion‐derived SEI is ...constructed on Na anode in a high‐concentration 1,2‐dimethoxyethane (DME) based electrolyte with a cosolvent hydrofluoroether, which effectively restrains Na dendrite growth. The hydrofluoroether can tune the solvation configuration of the electrolyte from three‐dimensional network aggregates to solvent–cation–anion clusters, enabling more anions to enter and reinforce the inner solvation sheath and their stepwise decomposition. The gradient inorganic‐rich SEI leads to a reduced energy barrier of Na+ migration and enhanced interfacial kinetics. These render the Na||Na3V2(PO4)3 battery with an excellent rate capability of 79.9 mAh g−1 at 24 C and a high capacity retention of 94.2 % after 6000 cycles at 2 C. This highlights the modulation of the electrode–electrolyte interphase chemistry for advanced batteries.
A gradient inorganic‐rich interphase is constructed on Na surface in a high‐concentration ether‐based electrolyte with a cosolvent hydrofluoroether. It leads to a configuration of solvent–cation–anion clusters for a reinforced inner solvation sheath. The derived interphase results in a reduced energy barrier for Na+ migration and fast interfacial kinetics, and hence excellent electrochemical performance.
The polycomb repressive complex 2 (PRC2) exerts oncogenic effects in many tumour types. However, loss-of-function mutations in PRC2 components occur in a subset of haematopoietic malignancies, ...suggesting that this complex plays a dichotomous and poorly understood role in cancer. Here we provide genomic, cellular, and mouse modelling data demonstrating that the polycomb group gene SUZ12 functions as tumour suppressor in PNS tumours, high-grade gliomas and melanomas by cooperating with mutations in NF1. NF1 encodes a Ras GTPase-activating protein (RasGAP) and its loss drives cancer by activating Ras. We show that SUZ12 loss potentiates the effects of NF1 mutations by amplifying Ras-driven transcription through effects on chromatin. Importantly, however, SUZ12 inactivation also triggers an epigenetic switch that sensitizes these cancers to bromodomain inhibitors. Collectively, these studies not only reveal an unexpected connection between the PRC2 complex, NF1 and Ras, but also identify a promising epigenetic-based therapeutic strategy that may be exploited for a variety of cancers.
High‐capacity sodium (Na) anodes suffer from dendrite growth due to the high reactivity, which can be overcome through inducing a stable NaF‐rich solid electrolyte interphase (SEI). Herein, we ...propose an additive strategy for realizing the anion‐enriched structure of Na+ solvation to obtain a NaF‐rich SEI. The electron‐withdrawing acetyl group in 4‐acetylpyridine (4‐APD) increases the coordination number of PF6− in the Na+ solvation sheath to facilitate PF6− to decompose into NaF. Thus, the NaF‐rich SEI with high mechanical stability and interfacial energy is formed to repress the growth of Na dendrites. With the 4‐APD‐contained electrolyte, the symmetric Na||Na cells show excellent cycling performance over 360 h at 1.0 mA cm−2. Meanwhile, excellent stability is also achieved for Na||Na3V2(PO4)2O2F full cells with high Coulombic efficiency (97 %) and capacity retention (91 %) after 200 cycles.
Owing to the anion‐enriched effect induced by 4‐acetylpyridine (4‐APD) additive, more PF6− could enter the inner Na+ solvation sheath to be decomposed into NaF on the Na anode surface, which could effectively repress the Na dendrite growth and boost the cycling performance of Na‐metal batteries.
The myelin sheath wraps large axons in both the CNS and the PNS, and is a key determinant of efficient axonal function and health. Myelin is targeted in a series of diseases, notably multiple ...sclerosis (MS). In MS, demyelination is associated with progressive axonal damage, which determines the level of patient disability. The few treatments that are available for combating myelin damage in MS and related disorders, which largely comprise anti-inflammatory drugs, only show limited efficacy in subsets of patients. More-effective treatment of myelin disorders will probably be accomplished by early intervention with combinatorial therapies that target inflammation and other processes-for example, signaling pathways that promote remyelination. Indeed, evidence suggests that such pathways might be impaired in pathology and, hence, contribute to the failure of remyelination in such diseases. In this article, we review the molecular basis of signaling pathways that regulate myelination in the CNS and PNS, with a focus on signals that affect differentiation of myelinating glia. We also discuss factors such as extracellular molecules that act as modulators of these pathways. Finally, we consider the few preclinical and clinical trials of agents that augment this signaling.
Although complex inflammatory-like alterations are observed around the amyloid plaques of Alzheimer’s disease (AD), little is known about the molecular changes and cellular interactions that ...characterize this response. We investigate here, in an AD mouse model, the transcriptional changes occurring in tissue domains in a 100-μm diameter around amyloid plaques using spatial transcriptomics. We demonstrate early alterations in a gene co-expression network enriched for myelin and oligodendrocyte genes (OLIGs), whereas a multicellular gene co-expression network of plaque-induced genes (PIGs) involving the complement system, oxidative stress, lysosomes, and inflammation is prominent in the later phase of the disease. We confirm the majority of the observed alterations at the cellular level using in situ sequencing on mouse and human brain sections. Genome-wide spatial transcriptomics analysis provides an unprecedented approach to untangle the dysregulated cellular network in the vicinity of pathogenic hallmarks of AD and other brain diseases.
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•Spatial transcriptomics identifies a plaque-induced gene (PIG) network•Spatial transcriptomics identifies an oligodendrocyte gene (OLIG) response in AD•In situ sequencing in mouse and human confirms these responses at single-cell level•PIG and OLIG responses are conserved over different neurodegenerative diseases
A combination of spatial transcriptomics and in situ sequencing on mouse and human brain demonstrates multicellular gene co-expression networks in Alzheimer’s disease, two of which are induced by accumulating amyloid plaques. A plaque-induced gene (PIG) network mainly involving micro- and astroglia and an oligodendrocyte gene (OLIG) and myelination response are identified.
Malignant peripheral nerve sheath tumors Gupta, Gaurav; Mammis, Antonios; Maniker, Allen
Neurosurgery clinics of North America,
10/2008, Letnik:
19, Številka:
4
Journal Article
Recenzirano
Malignant peripheral nerve sheath tumors (MPNSTs) are a rare variety of soft tissue sarcoma of ectomesenchymal origin. MPNSTs arise from major or minor peripheral nerve branches or sheaths of ...peripheral nerve fibers and are derived from Schwann cells or pluripotent cells of neural crest origin. Arthur Purdy Stout played a pivotal role in the development of our current understanding of the pathogenesis of peripheral nerve sheath tumors by identifying the Schwann cell as the major contributor to the formation of benign and malignant neoplasms of the nerve sheath. Although this fact remains essentially true, the cell of origin of the MPNST remains elusive and has not yet conclusively been identified. Some have suggested these tumors may have multiple cell line origins. In the present review, MPNSTs and their epidemiology, diagnosis, management, and treatment are discussed.
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