Hybrid formation is a fundamental process in normal development and tissue homeostasis, while the presence and the biological role of hybrids between tumor-associated macrophages (TAMs) and ...glioblastoma (GBM) cells remain elusive. In this study, we observed that TAM-GBM cell hybrids existed in human GBM specimens as demonstrated by co-expression of glioma biomarkers (GFAP, IDH1R132H and PDGFRA) and macrophage biomarkers (CD68 and CD14). Furthermore, TAM-GBM cell hybrids could also be found in C57BL/6 mice orthotopically inoculated with mouse GBM cells labeled with RFP and after co-culture of bone marrow-derived macrophages from GFP-expressed mice with RFP-labeled GBM cells. The hybrids underwent nuclear reprogramming with unique gene expression profile as compared to parental cells. Moreover, glioma invasion-associated genes were enriched in the hybrids that possessed higher invasiveness, and more hybrids in the invasive margin of GBM were observed as compared to GBM core area. Our data demonstrate the presence of TAM-GBM cell hybrids that enhance GBM invasion. With a better understanding of TAM-GBM cell hybrids, new therapeutic strategies targeting GBM will be developed to treat GBM patients.
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•Hybrids formed by TAMs and tumor cells exist in GBM.•TAM-GBM cell hybrids bear nuclear reprogramming with unique gene expression profile.•TAM-GBM cell hybrids contribute to GBM invasion.
The endosymbiont Wolbachia manipulates host reproduction by several strategies, one of the most important of which is cytoplasmic incompatibility (CI). CI can be rescued when Wolbachia‐infected males ...mate with females infected with the same Wolbachia strain. However, the potential rescue mechanism of CI in the small brown planthopper Laodelphax striatellus is unclear. In this study, comparative transcriptome analysis was applied to explore the effect of Wolbachia on L. striatellus eggs. A total of 1387 differentially expressed genes were identified. RNA interference of 7 Wolbachia‐upregulated key planthopper genes reduced egg reproduction, suggesting that Wolbachia might improve fecundity in L. striatellus by affecting these 7 genes. Suppressing the expression of another upregulated gene, NDUFA8 (encoding NADH dehydrogenase ubiquinone 1 α subcomplex subunit 8‐like) by RNA interference significantly increased the mortality of early embryos without affecting the number of deposited eggs. Wolbachia infection upregulated the mRNA level of NDUFA8, and dsNDUFA8 treatment of Wolbachia‐infected females recreated CI‐like symptoms, suggesting that NDUFA8 is associated with the rescue phenotype. Because all L. striatellus populations worldwide are infected with Wolbachia, NDUFA8 is a potential pest control target.
Wolbachia infection upregulates the mRNA level of NDUFA8, and dsNDUFA8 treatment of Wolbachia‐infected females recreated cytoplasmic incompatibility‐like symptoms, suggesting that NDUFA8 is associated with the rescue phenotype.
The Wnt/β-catenin pathway is critical to maintaining cell fate decisions. Recent study showed that liquid–liquid-phase separation (LLPS) of Axin organized the β-catenin destruction complex ...condensates in a normal cellular state. Mutations inactivating the APC gene are found in approximately 80% of all human colorectal cancer (CRC). However, the molecular mechanism of the formation of β-catenin destruction complex condensates organized by Axin phase separation and how APC mutations impact the condensates are still unclear. Here, we report that the β-catenin destruction complex, which is constructed by Axin, was assembled condensates via a phase separation process in CRC cells. The key role of wild-type APC is to stabilize destruction complex condensates. Surprisingly, truncated APC did not affect the formation of condensates, and GSK 3β and CK1α were unsuccessfully recruited, preventing β-catenin phosphorylation and resulting in accumulation in the cytoplasm of CRCs. Besides, we propose that the phase separation ability of Axin participates in the nucleus translocation of β-catenin and be incorporated and concentrated into transcriptional condensates, affecting the transcriptional activity of Wnt signaling pathway.
DNA methylation is an important epigenetic change in carcinogenesis. However, the function and mechanism of DNA methylation dysregulation in nasopharyngeal carcinoma (NPC) is still largely unclear. ...Our previous genome-wide microarray data showed that NFAT1 is one of the most hypermethylated transcription factor genes in NPC tissues. Here, we found that NFAT1 hypermethylation contributes to its down-regulation in NPC. NFAT1 overexpression inhibited cell migration, invasion, and epithelial-mesenchymal transition in vitro and tumor metastasis in vivo. We further established that the tumor suppressor effect of NFAT1 is mediated by its inactivation of ITGA6 transcription. Our findings suggest the significance of activating NFAT1/ITGA6 signaling in aggressive NPC, defining a novel critical signaling mechanism that drives NPC invasion and metastasis and providing a novel target for future personalized therapy.
Dysregulation of long noncoding RNAs (lncRNAs) contributes to tumorigenesis by modulating specific cancer-related pathways, but the roles of N6-methyladenosine (m6A)-enriched lncRNAs and underlying ...mechanisms remain elusive in nasopharyngeal carcinoma (NPC). Here, we reanalyzed the previous genome-wide analysis of lncRNA profiles in 18 pairs of NPC and normal tissues as well as in ten paired samples from NPC with or without post-treatment metastases. We discerned that an oncogenic m6A-enriched lncRNA, LINC00839, which was substantially upregulated in NPC and correlated with poor clinical prognosis, promoted NPC growth and metastasis both in vitro and in vivo. Mechanistically, by using RNA pull-down assay combined with mass spectrometry, we found that LINC00839 interacted directly with the transcription factor, TATA-box binding protein associated factor (TAF15). Besides, chromatin immunoprecipitation and dual-luciferase report assays demonstrated that LINC00839 coordinated the recruitment of TAF15 to the promoter region of amine oxidase copper-containing 1 (AOC1), which encodes a secreted glycoprotein playing vital roles in various cancers, thereby activating AOC1 transcription in trans. In this study, potential effects of AOC1 in NPC progression were first proposed. Moreover, ectopic expression of AOC1 partially rescued the inhibitory effect of downregulation of LINC00839 in NPC. Furthermore, we showed that silencing vir-like m6A methyltransferase-associated (VIRMA) and insulin-like growth factor 2 mRNA-binding proteins 1 (IGF2BP1) attenuated the expression level and RNA stability of LINC00839 in an m6A-dependent manner. Taken together, our study unveils a novel oncogenic VIRMA/IGF2BP1–LINC00839–TAF15–AOC1 axis and highlights the significance and prognostic value of LINC00839 expression in NPC carcinogenesis.
Aims
The aim of this study was to investigate the tumor microenvironment immune types (TMIT) based on tumor cell programmed cell death ligand 1 (PD‐L1) expression and tumor‐infiltrating lymphocytes ...(TILs) distribution and whether distinct TMIT subtypes (TMIT I, PD‐L1high/TILhigh; TMIT II, PD‐L1low/TILlow; TMIT III, PD‐L1high/TILlow; and TMIT IV, PD‐L1low/TILhigh) differentially affect clinical outcomes of patients with lung adenocarcinoma (LAC) and squamous cell carcinoma (SCC).
Methods and results
Immunohistochemistry (IHC) was applied to evaluate the expression of PD‐L1 and the spatial distribution of programmed cell death 1 (PD‐1) and CD8 TILs on the surgically resected specimens from 205 cases of LAC and 149 cases of SCC. PD‐1 and CD8 TILs were more frequently distributed in SCC than those in LAC, regardless of their infiltrating in the tumor islets or stroma. The density of TILs was a poor prognostic factor in LAC but a favorable one in SCC. PD‐L1 levels and its clinical prognostic significance differed in LAC vs SCC. LAC patients with TMIT III and SCC patients with TMIT I had the longest survival, respectively (P = .0197 and .0049). Moreover, TMIT stratification based on tumor cell PD‐L1 expression and stromal CD8+ TILs could be considered as an independent prognostic factor of SCC patients' survival as determined by both univariate and multivariate analysis.
Conclusion
Our study indicates that different type of TMIT provides its specific microenvironment with diverse impact on survival of LAC and SCC patients and highlights the importance of the integrative assessment of PD‐L1 status and TILs' spatial distribution to predict patients' prognosis.
Our study indicates that different type of TMIT provides its specific microenvironment with diverse impact on survival of lung adenocarcinoma and squamous cell carcinoma patients and highlights the importance of the integrative assessment of programmed cell death ligand 1 status and tumor‐infiltrating lymphocytes' spatial distribution to predict patients' prognosis.
Plastic phenotype convention between glioma stem cells (GSCs) and non-stem tumor cells (NSTCs) significantly fuels glioblastoma heterogeneity that causes therapeutic failure. Recent progressions ...indicate that glucose metabolic reprogramming could drive cell fates. However, the metabolic pattern of GSCs and NSTCs and its association with tumor cell phenotypes remain largely unknown. Here we found that GSCs were more glycolytic than NSTCs, and voltage-dependent anion channel 2 (VDAC2), a mitochondrial membrane protein, was critical for metabolic switching between GSCs and NSTCs to affect their phenotypes. VDAC2 was highly expressed in NSTCs relative to GSCs and coupled a glycolytic rate-limiting enzyme platelet-type of phosphofructokinase (PFKP) on mitochondrion to inhibit PFKP-mediated glycolysis required for GSC maintenance. Disruption of VDAC2 induced dedifferentiation of NSTCs to acquire GSC features, including the enhanced self-renewal, preferential expression of GSC markers, and increased tumorigenicity. Inversely, enforced expression ofVDAC2 impaired the self-renewal and highly tumorigenic properties of GSCs. PFK inhibitor clotrimazole compromised the effect of VDAC2 disruption on glycolytic reprogramming and GSC phenotypic transition. Clinically, VDAC2 expression inversely correlated with glioma grades (Immunohistochemical staining scores of VDAC2 were 4.7 ± 2.8, 3.2 ± 1.9, and 1.9 ± 1.9 for grade II, grade III, and IV, respectively, p < 0.05 for all) and the patients with high expression of VDAC2 had longer overall survival than those with low expression of VDAC2 (p = 0.0008). In conclusion, we demonstrate that VDAC2 is a new glycolytic regulator controlling the phenotype transition between glioma stem cells and non-stem cells and may serves as a new prognostic indicator and a potential therapeutic target for glioma patients.
A hot corona is suggested to be above the standard thin disk. The anisotropy of hard X-ray emission in radio-quiet active galactic nuclei implies that the corona is not static and probably moves ...outwards like winds. We perform two-dimensional magnetohydrodynamical simulations to study the outflowing corona driven by magnetic field and radiation force. In our simulations, as the initial state and the boundary condition at the disk surface, the corona temperature is set to 109 K inside a 10 Schwarzschild radius (rs), while the corona temperature is set to 107 K outside 10 rs. We employ a weak poloidal magnetic field as the initial magnetic field. A collimated outflow and a wide-angle ordered outflow are observed in our simulations. The collimated outflow is around the rotational axis and has a bulk velocity of ∼0.03-0.3c (c is speed of light) at 90 rs, while their mass outflow rate is very low. The collimated outflow is a weak jet. The wide-angle ordered outflow is distributed at middle and high latitudes and moves outwards with a velocity of 102-104 km s−1. The outflow velocity depends on the disk luminosity. The gas around the disk surface is turbulent, especially outside of 10 rs. The other properties of outflows are discussed in detail.
Objective To explore the effect of a health (E)-coach chronic disease management model on the rehabilitation behaviour management of patients with arteriosclerosis obliterans (ASO). Methods The ...E-coach chronic disease management model was constructed based on a literature review and expert interviews. The effect of the E-coach model on patients with ASO during hospitalisation was analysed by comparing the compliance rates of blood glucose control, blood pressure control, drug compliance, ankle-brachial index, 6-min walking test (6MWT) and pain-free walking distance (PFWD) scores between the E-coach and control groups. Results In total, 212 patients with ASO were included in this study. After the intervention, the blood pressure compliance rate (44.8% vs. 65.7%) and blood glucose compliance rate (48.6% vs. 66.8%) were higher in the E-coach group than in the control group (p < 0.05). After intervention, compared with the control group, the patients in the E-coach group had better drug compliance (6.8 + or - 1.9 vs. 7.9 + or - 1.0), and the difference was statistically significant (p < 0.05). The scores for the 6MWT (329.19 + or - 5.58 vs. 353.00 + or - 9.76; 412.65 + or - 12.59 vs. 499.16 + or - 18.43) and PFWD (219.15 + or - 11.96 vs. 225.36 + or - 16.13; 331.62 + or - 51.36 vs. 369.42 + or - 75.71) tests were significantly higher in the E-coach group than in the control group at 1 and 6 months after intervention (p < 0.05). Conclusion The E-coach chronic disease management model can effectively improve the control rates of blood glucose and blood pressure and the behaviour management of patients with ASO and is thus worthy of clinical reference. Keywords: Chronic disease management mode, Health coaching technology, Continuous nursing, Arteriosclerosis obliterans
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, ODKLJ, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK, VSZLJ
Postzygotic reproductive isolation, which results in the irreversible divergence of species, is commonly accompanied by hybrid sterility, necrosis/weakness, or lethality in the F
or other offspring ...generations. Here we show that the loss of function of HWS1 and HWS2, a couple of duplicated paralogs, together confer complete interspecific incompatibility between Asian and African rice. Both of these non-Mendelian determinants encode the putative Esa1-associated factor 6 (EAF6) protein, which functions as a characteristic subunit of the histone H4 acetyltransferase complex regulating transcriptional activation via genome-wide histone modification. The proliferating tapetum and inappropriate polar nuclei arrangement cause defective pollen and seeds in F
hybrid offspring due to the recombinant HWS1/2-mediated misregulation of vitamin (biotin and thiamine) metabolism and lipid synthesis. Evolutionary analysis of HWS1/2 suggests that this gene pair has undergone incomplete lineage sorting (ILS) and multiple gene duplication events during speciation. Our findings have not only uncovered a pair of speciation genes that control hybrid breakdown but also illustrate a passive mechanism that could be scaled up and used in the guidance and optimization of hybrid breeding applications for distant hybridization.
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