The interplay between glioma stem cells (GSCs) and the tumor microenvironment plays crucial roles in promoting malignant growth of glioblastoma (GBM), the most lethal brain tumor. However, the ...molecular mechanisms underlying this crosstalk are incompletely understood. Here, we show that GSCs secrete the Wnt-induced signaling protein 1 (WISP1) to facilitate a pro-tumor microenvironment by promoting the survival of both GSCs and tumor-associated macrophages (TAMs). WISP1 is preferentially expressed and secreted by GSCs. Silencing WISP1 markedly disrupts GSC maintenance, reduces tumor-supportive TAMs (M2), and potently inhibits GBM growth. WISP1 signals through Integrin α6β1-Akt to maintain GSCs by an autocrine mechanism and M2 TAMs through a paracrine manner. Importantly, inhibition of Wnt/β-catenin-WISP1 signaling by carnosic acid (CA) suppresses GBM tumor growth. Collectively, these data demonstrate that WISP1 plays critical roles in maintaining GSCs and tumor-supportive TAMs in GBM, indicating that targeting Wnt/β-catenin-WISP1 signaling may effectively improve GBM treatment and the patient survival.
In order to achieve efficient particle packing, minimizing the space of occupation and maximizing the strength of packing, it is important to understand the best methods of fill and the effects of ...various particle properties, including particle shape. In this study, the packing behavior of cylindrical particles is studied via both Discrete Element Method (DEM) simulations and complementary experiments. The effects of coefficient of friction, coefficient of restitution, drop height, fill height, packing method, deposition intensity (number of particles deposited per second), container size, surface roughness, and Young's modulus are investigated. In addition, two methods of packing density analysis from DEM simulations - a center of particle method and a top grid analysis method - are introduced. It is found that the packing density increases with fill height, container diameter, coefficient of restitution and drop height and decreases with coefficient of friction, surface roughness and Young's modulus. Different packing methods are explored, and it is found that the most efficient packing scheme is to pouring particles over the whole cross-section with low deposition intensity and at a variable drop height. Finally, DEM simulation predictions for particle packing of cylinders show good agreement with experimental measurements.
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•Highest packing density at variable drop height, low deposition intensity•Packing density increases with coefficient of restitution and drop height.•Packing density decreases with friction coefficient and surface roughness.•Two new methods of packing density analysis for DEM simulations are introduced.•Hertz-Mindlin over-predicts packing density unless rolling friction is included.
Tumor hypoxia is associated with poor patient survival and is a characteristic of glioblastoma. Notch signaling is implicated in maintaining glioma stem-like cells (GSCs) within the hypoxic niche, ...although the molecular mechanisms linking hypoxia to Notch activation have not been clearly delineated. Here we show that Vasorin is a critical link between hypoxia and Notch signaling in GSCs. Vasorin is preferentially induced in GSCs by a HIF1α/STAT3 co-activator complex and stabilizes Notch1 protein at the cell membrane. This interaction prevents Numb from binding Notch1, rescuing it from Numb-mediated lysosomal degradation. Thus, Vasorin acts as a switch to augment Notch signaling under hypoxic conditions. Vasorin promotes tumor growth and reduces survival in mouse models of glioblastoma, and its expression correlates with increased aggression of human gliomas. These findings provide mechanistic insights into how hypoxia promotes Notch signaling in glioma and identify Vasorin as a potential therapeutic target.
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•Vasorin maintains glioma stem-like cells (GSCs) in the hypoxic niche•HIF1α/STAT3 co-activator complex induces Vasorin expression selectively in GSCs•Vasorin binds to and regulates membranous Notch1 turnover•Vasorin expression correlates with glioma aggressiveness
Man et al. show that hypoxia preferentially augments Notch signaling in glioma stem-like cells by inducing the HIF1/STAT3 target gene Vasorin. Vasorin functions as a competitive inhibitor of Numb to reduce Notch turnover, augmenting Notch signaling under hypoxic stress.
The adoptive transfer of autologous T cells engineered to express a chimeric antigen receptor (CAR) has emerged as a promising cancer therapy. Despite impressive clinical efficacy, the general ...application of current CAR–T-cell therapy is limited by serious treatment-related toxicities. One approach to improve the safety of CAR-T cells involves making their activation and proliferation dependent upon adaptor molecules that mediate formation of the immunological synapse between the target cancer cell and T-cell. Here, we describe the design and synthesis of structurally defined semisynthetic adaptors we refer to as “switch” molecules, in which anti-CD19 and anti-CD22 antibody fragments are site-specifically modified with FITC using genetically encoded noncanonical amino acids. This approach allows the precise control over the geometry and stoichiometry of complex formation between CD19- or CD22-expressing cancer cells and a “universal” anti-FITC–directed CAR-T cell. Optimization of this CAR–switch combination results in potent, dose-dependent in vivo antitumor activity in xenograft models. The advantage of being able to titrate CAR–T-cell in vivo activity was further evidenced by reduced in vivo toxicity and the elimination of persistent B-cell aplasia in immune-competent mice. The ability to control CAR-T cell and cancer cell interactions using intermediate switch molecules may expand the scope of engineered T-cell therapy to solid tumors, as well as indications beyond cancer therapy.
Four severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants predominated in the United States since 2021. Understanding disease severity related to different SARS-CoV-2 variants ...remains limited.
Viral genome analysis was performed on SARS-CoV-2 clinical isolates circulating March 2021 through March 2022 in Cleveland, Ohio. Major variants were correlated with disease severity and patient outcomes.
In total 2779 patients identified with either Alpha (n 1153), Gamma (n 122), Delta (n 808), or Omicron variants (n 696) were selected for analysis. No difference in frequency of hospitalization, intensive care unit (ICU) admission, and death were found among Alpha, Gamma, and Delta variants. However, patients with Omicron infection were significantly less likely to be admitted to the hospital, require oxygen, or admission to the ICU (2 12.8, P .001; 2 21.6, P .002; 2 9.6, P .01, respectively). In patients whose vaccination status was known, a substantial number had breakthrough infections with Delta or Omicron variants (218/808 26.9 and 513/696 73.7, respectively). In breakthrough infections, hospitalization rate was similar regardless of variant by multivariate analysis. No difference in disease severity was identified between Omicron subvariants BA.1 and BA.2.
Disease severity associated with Alpha, Gamma, and Delta variants is comparable while Omicron infections are significantly less severe. Breakthrough disease is significantly more common in patients with Omicron infection.
PbTiO3-based compounds are well-known ferroelectrics that exhibit a negative thermal expansion more or less in the tetragonal phase. The mechanism of negative thermal expansion has been studied by ...high-temperature neutron powder diffraction performed on two representative compounds, 0.7PbTiO3–0.3BiFeO3 and 0.7PbTiO3–0.3Bi(Zn1/2Ti1/2)O3, whose negative thermal expansion is contrarily enhanced and weakened, respectively. With increasing temperature up to the Curie temperature, the spontaneous polarization displacement of Pb/Bi (δz Pb/Bi) is weakened in 0.7PbTiO3–0.3BiFeO3 but well-maintained in 0.7PbTiO3–0.3Bi(Zn1/2Ti1/2)O3. There is an apparent correlation between tetragonality (c/a) and spontaneous polarization. Direct experimental evidence indicates that the spontaneous polarization originating from Pb/Bi–O hybridization is strongly associated with the negative thermal expansion. This mechanism can be used as a guide for the future design of negative thermal expansion of phase-transforming oxides.
Aging is the primary risk factor for cognitive decline, an emerging health threat to aging societies worldwide. Whether anti-aging factors such as klotho can counteract cognitive decline is unknown. ...We show that a lifespan-extending variant of the human KLOTHO gene, KL-VS, is associated with enhanced cognition in heterozygous carriers. Because this allele increased klotho levels in serum, we analyzed transgenic mice with systemic overexpression of klotho. They performed better than controls in multiple tests of learning and memory. Elevating klotho in mice also enhanced long-term potentiation, a form of synaptic plasticity, and enriched synaptic GluN2B, an N-methyl-D-aspartate receptor (NMDAR) subunit with key functions in learning and memory. Blockade of GluN2B abolished klotho-mediated effects. Surprisingly, klotho effects were evident also in young mice and did not correlate with age in humans, suggesting independence from the aging process. Augmenting klotho or its effects may enhance cognition and counteract cognitive deficits at different life stages.
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•KLOTHO variant elevates klotho levels and is associated with enhanced human cognition•Elevation of klotho in mice enhances normal cognition, independent of age•Klotho elevation leads to greater synaptic GluN2B (NMDAR subunit) levels and plasticity•GluN2B blockade abolishes klotho-mediated effects on NMDAR functions and cognition
Klotho extends lifespan. Whether aging regulators like klotho can counteract aging-related cognitive decline and promote brain health is unknown. Here, Dubal, Mucke, and colleagues demonstrate that a variant of the KLOTHO gene that increases klotho levels in the circulation is associated with better cognition in normal aging individuals. Elevating klotho in mice also enhanced cognition and synaptic plasticity, even in the young life stage, through mechanisms that involve regulation of NMDA receptors, key players in learning and memory.
Glioblastoma (GBM) is the most lethal primary brain tumor and is highly resistant to current treatments. GBM harbors glioma stem cells (GSCs) that not only initiate and maintain malignant growth but ...also promote therapeutic resistance including radioresistance. Thus, targeting GSCs is critical for overcoming the resistance to improve GBM treatment. Because the bone marrow and X-linked (BMX) nonreceptor tyrosine kinase is preferentially up-regulated in GSCs relative to nonstem tumor cells and the BMX-mediated activation of the signal transducer and activator of transcription 3 (STAT3) is required for maintaining GSC self-renewal and tumorigenic potential, pharmacological inhibition of BMX may suppress GBM growth and reduce therapeutic resistance. We demonstrate that BMX inhibition by ibrutinib potently disrupts GSCs, suppresses GBM malignant growth, and effectively combines with radiotherapy. Ibrutinib markedly disrupts the BMX-mediated STAT3 activation in GSCs but shows minimal effect on neural progenitor cells (NPCs) lacking BMX expression. Mechanistically, BMX bypasses the suppressor of cytokine signaling 3 (SOCS3)-mediated inhibition of Janus kinase 2 (JAK2), whereas NPCs dampen the JAK2-mediated STAT3 activation via the negative regulation by SOCS3, providing a molecular basis for targeting BMX by ibrutinib to specifically eliminate GSCs while preserving NPCs. Our preclinical data suggest that repurposing ibrutinib for targeting GSCs could effectively control GBM tumor growth both as monotherapy and as adjuvant with conventional therapies.
Granular materials exhibit unique secondary flow behaviors upon shearing. We demonstrate, using particle dynamics simulations, that the secondary flow patterns are controlled by a pressure exerted on ...particle bed. A threshold pressure, at which vortex flow transitions to disturbed or chaotic flow, depends on particle shape, that influences interparticle contacts and rheological performance. Our results show that the flow patterns are essentially determined by a dimensionless term combining pressure and granular temperature for all the spherical and Platonic solid‐shaped particles explored. Particle mixing is promoted by the vortex flow or disturbed flow with strong diffusion. The highest mixing rate under a specified pressure is obtained for cubic particles, due to the significant microstructural ordering near the boundaries causing a high gradient of packing density. These findings shed light on how applied pressure and particle shape affect secondary flows which is critical to the understanding and control of granular mixing.
Different cancer cell compartments often communicate through soluble factors to facilitate tumor growth. Glioma stem cells (GSCs) are a subset of tumor cells that resist standard therapy to ...contribute to disease progression. How GSCs employ a distinct secretory program to communicate with and nurture each other over the nonstem tumor cell (NSTC) population is not well defined. Here, we show that GSCs preferentially secrete Sema3C and coordinately express PlexinA2/D1 receptors to activate Rac1/nuclear factor (NF)-κB signaling in an autocrine/paracrine loop to promote their own survival. Importantly, Sema3C is not expressed in neural progenitor cells (NPCs) or NSTCs. Disruption of Sema3C induced apoptosis of GSCs, but not NPCs or NSTCs, and suppressed tumor growth in orthotopic models of glioblastoma. Introduction of activated Rac1 rescued the Sema3C knockdown phenotype in vivo. Our study supports the targeting of Sema3C to break this GSC-specific autocrine/paracrine loop in order to improve glioblastoma treatment, potentially with a high therapeutic index.
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