Integrin trafficking, including internalization, recycling, and lysosomal degradation, is crucial for the regulation of cellular functions. Exosomes, nano‐sized extracellular vesicles, are believed ...to play important roles in intercellular communications. This study demonstrates that exosomes released from human macrophages negatively regulate endothelial cell migration through control of integrin trafficking. Macrophage‐derived exosomes promote internalization of integrin β1 in primary HUVECs. The internalized integrin β1 persistently accumulates in the perinuclear region and is not recycled back to the plasma membrane. Experimental results indicate that macrophage‐derived exosomes stimulate trafficking of internalized integrin β1 to lysosomal compartments with a corresponding decrease in the integrin destined for recycling endosomes, resulting in proteolytic degradation of the integrin. Moreover, ubiquitination of HUVEC integrin β1 is enhanced by the exosomes, and exosome‐mediated integrin degradation is blocked by bafilomycin A, a lysosomal degradation inhibitor. Macrophage‐derived exosomes were also shown to effectively suppress collagen‐induced activation of the mitogen‐activated protein kinase/extracellular signal‐regulated kinase signaling pathway and HUVEC migration, which are both dependent on integrin β1. These observations provide new insight into the functional significance of exosomes in the regulation of integrin trafficking.
Spheno-orbital meningiomas (SOMs) are complicated tumors that involve multiple structures at initial presentation, such as the orbit, temporalis muscle, sphenoidal bone, cavernous sinus, and temporal ...or infratemporal fossa. The infiltrative growth and complexity of this type of meningioma make total resection impossible. In this study, the authors evaluated the surgical outcome of the endoscopic transorbital approach (eTOA) for SOM. In addition, they identified optimal indications for the use of eTOA and analyzed the feasibility of this approach as a minimally invasive surgery for SOMs of varying types and locations at presentation.
Between September 2016 and December 2019, the authors performed eTOA in 41 patients with SOM with or without orbital involvement at 3 independent tertiary institutions. The authors evaluated the surgical outcomes of eTOA for SOM and investigated several factors that affect the outcome, such as tumor volume, tumor location, and the presence of lateral orbitotomy. Gross-total resection (GTR) was defined as complete resection of the tumor or intended subtotal resection except the cavernous sinus. This study was undertaken as a multicenter project (006) of the Korean Society of Endoscopic Neurosurgery (KOSEN-006).
There were 41 patients (5 men and 36 women) with a median age of 52.0 years (range 24-73 years). Twenty-one patients had tumors that involved the orbital structure, while 14 patients had tumors that presented at the sphenoidal bone along with other structures, such as the cavernous sinus, temporal fossa, and infratemporal fossa. Fifteen patients had the globulous type of tumor and 26 patients had the en plaque type. Overall, GTR was achieved in 21 of 41 patients (51.2%), and complications included CSF leaks in 2 patients and wound complications in 2 patients. Multiple logistic regression analysis showed that the en plaque type of tumor, absence of lateral orbital rim osteotomy, involvement of the temporal floor or infratemporal fossa, and involvement of the orbit and medial one-third of the greater sphenoidal wing were closely associated with lower GTR rates (p < 0.05). Multivariate analysis revealed that the en plaque type of tumor and the absence of lateral orbital rim osteotomy were significant predictors for lower GTR rate.
The en plaque type of SOM remains a challenge despite advances in technique such as minimally invasive surgery. Overall, clinical outcome of eTOA for SOM was comparable to the transcranial surgery. To achieve GTR, eTOA is recommended, with additional lateral orbital rim osteotomy for globulous-type tumors, without involving the floor of the temporal and infratemporal fossa.
Energy, structure, and charge are fundamental quantities characterizing a molecule. Whereas the energy flow and structure change in chemical reactions are experimentally characterized, determining ...the atomic charges of a molecule in solution has been elusive, even for a triatomic molecule such as triiodide ion, I
. Moreover, it remains to be answered how the charge distribution is coupled to the molecular geometry; which I-I bond, if two I-I bonds are unequal, dissociates depending on the electronic state. Here, femtosecond anisotropic x-ray solution scattering allows us to provide the following answers in addition to the overall rich structural dynamics. The analysis unravels that the negative charge of I
is highly localized on the terminal iodine atom forming the longer bond with the central iodine atom, and the shorter I-I bond dissociates in the excited state, whereas the longer one in the ground state. We anticipate that this work may open a new avenue for studying the atomic charge distribution of molecules in solution and taking advantage of orientational information in anisotropic scattering data for solution-phase structural dynamics.
Tumor recurrence following treatment is the major cause of mortality for glioblastoma multiforme (GBM) patients. Thus, insights on the evolutionary process at recurrence are critical for improved ...patient care. Here, we describe our genomic analyses of the initial and recurrent tumor specimens from each of 38 GBM patients. A substantial divergence in the landscape of driver alterations was associated with distant appearance of a recurrent tumor from the initial tumor, suggesting that the genomic profile of the initial tumor can mislead targeted therapies for the distally recurred tumor. In addition, in contrast to IDH1-mutated gliomas, IDH1-wild-type primary GBMs rarely developed hypermutation following temozolomide (TMZ) treatment, indicating low risk for TMZ-induced hypermutation for these tumors under the standard regimen.
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•Distant recurrence predicts branched evolution of the paired tumors•Distant recurrence frequently involves divergence in key GBM driver alterations•Recurrent GBMs have more aberrations in core GBM driver pathways than initial GBMs•TMZ-induced hypermutation is rare in IDH1-wild-type primary GBMs
Kim et al. find that glioblastomas recurring at distant sites have driver genetic alterations very different from those of matched initial tumors. They also show that, in contrast to IDH1-mutated tumors, IDH1-wild-type primary glioblastomas rarely develop hypermutation following temozolomide treatment.
Precision medicine in cancer proposes that genomic characterization of tumors can inform personalized targeted therapies. However, this proposition is complicated by spatial and temporal ...heterogeneity. Here we study genomic and expression profiles across 127 multisector or longitudinal specimens from 52 individuals with glioblastoma (GBM). Using bulk and single-cell data, we find that samples from the same tumor mass share genomic and expression signatures, whereas geographically separated, multifocal tumors and/or long-term recurrent tumors are seeded from different clones. Chemical screening of patient-derived glioma cells (PDCs) shows that therapeutic response is associated with genetic similarity, and multifocal tumors that are enriched with PIK3CA mutations have a heterogeneous drug-response pattern. We show that targeting truncal events is more efficacious than targeting private events in reducing the tumor burden. In summary, this work demonstrates that evolutionary inference from integrated genomic analysis in multisector biopsies can inform targeted therapeutic interventions for patients with GBM.
The endoscopic endonasal approach (EEA) and the transcranial approach (TCA) are good options for the treatment of tuberculum sellae (TS) meningiomas. The objective of this study was to identify the ...key anatomical features in TS meningiomas and compare the two surgical approaches.
The authors retrospectively reviewed clinical data in 178 patients with TS meningiomas treated at 3 institutions between January 2010 and July 2016. Patients with tumors encasing the internal carotid artery or anterior cerebral artery or involving the anterior clinoid process or cavernous sinus were excluded. Tumors were classified as high-lying or low-lying based on their location, and involvement of the optic canal was evaluated. The surgical outcomes of EEA and TCA were analyzed according to the relevant anatomical features.
During the study period, 84 patients underwent EEA and 94 patients underwent TCA. Based on preoperative MR images, 43 (24.2%) meningiomas were classified as high-lying tumors, 126 (70.8%) as low-lying, and 9 (5.0%) as nonspecific. Gross-total resection (GTR) was performed in 145 patients (81.5%); the GTR rate did not differ significantly between the EEA and TCA groups. Of 157 patients with preoperative visual disturbance, 140 had improved or stable vision postoperatively. However, 17 patients (9.6%) experienced some visual deterioration after surgery. The TCA group had a worse visual outcome than the EEA group in patients with preoperative optic canal involvement (77.6% vs 93.2%, p = 0.019), whereas there was no significant difference in visual outcome based on whether tumors were high-lying or low-lying.
The results of this study support EEA over TCA, at least with respect to visual improvement with acceptable complications, although TCA is still an effective approach for TS meningioma.
Optical Kerr effect (OKE) spectroscopy is a method that measures the time-dependent change of the birefringence induced by an optical laser pulse using another optical laser pulse and has been used ...often to study the ultrafast dynamics of molecular liquids. Here we demonstrate an alternative method, femtosecond time-resolved X-ray liquidography (fs-TRXL), where the microscopic structural motions related to the OKE response can be monitored using a different type of probe, i.e., X-ray solution scattering. By applying fs-TRXL to acetonitrile and a dye solution in acetonitrile, we demonstrate that different types of molecular motions around photoaligned molecules can be resolved selectively, even without any theoretical modeling, based on the anisotropy of two-dimensional scattering patterns and extra structural information contained in the q-space scattering data. Specifically, the dynamics of reorientational (libration and orientational diffusion) and translational (interaction-induced motion) motions are captured separately by anisotropic and isotropic scattering signals, respectively. Furthermore, the two different types of reorientational motions are distinguished from each other by their own characteristic scattering patterns and time scales. The measured time-resolved scattering signals are in excellent agreement with the simulated scattering signals based on a molecular dynamics simulation for plausible molecular configurations, providing the detailed structural description of the OKE response in liquid acetonitrile.