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"Liu, X."
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SP1-induced upregulation of the long noncoding RNA TINCR regulates cell proliferation and apoptosis by affecting KLF2 mRNA stability in gastric cancer
The long noncoding RNA
TINCR
shows aberrant expression in human squamous carcinomas. However, its expression and function in gastric cancer remain unclear. We report that
TINCR
is strongly upregulated in human gastric carcinoma (GC), where it was found to contribute to oncogenesis and cancer progression. We also revealed that
TINCR
overexpression is induced by nuclear transcription factor SP1. Silencing
TINCR
expression inhibited cell proliferation, colony formation, tumorigenicity and apoptosis promotion, whereas
TINCR
overexpression promoted cell growth, as documented in the SGC7901 and BGC823 cell lines. Mechanistic analyses indicated that
TINCR
could bind to STAU1 (staufen1) protein, and influence
KLF2
mRNA stability and expression, then KLF2 regulated cyclin-dependent kinase genes
CDKN1A/P21
and
CDKN2B/P15
transcription and expression, thereby affecting the proliferation and apoptosis of GC cells. Together, our findings suggest that
TINCR
contributes to the oncogenic potential of GC and may constitute a potential therapeutic target in this disease.
Journal Article
Formation and evolution mechanism of regional haze: a case study in the megacity Beijing, China
The main objective of this study is to investigate the formation and evolution mechanism of the regional haze in megacity Beijing by analyzing the process of a severe haze that occurred 20–27 September 2011. Mass concentration and size distribution of aerosol particles as well as aerosol optical properties were concurrently measured at the Beijing urban atmospheric environment monitoring station. Gaseous pollutants (SO2, NO-NO2-NOx, O3, CO) and meteorological parameters (wind speed, wind direction, and relative humidity) were simultaneously monitored. Meanwhile, aerosol spatial distribution and the height of planetary boundary layer (PBL) were retrieved from the signal of satellite and LIDAR (light detection and ranging). Concentrations of NO, NO2, SO2, O3, and CO observed during 23–27 September had exceeded the national ambient air quality standards for residents. The mass concentration of PM2.5 gradually accumulated during the measurement and reached at 220 μg m−3 on 26 September, and the corresponding atmospheric visibility was only 1.1 km. The daily averaged AOD in Beijing increased from ~ 0.16 at λ = 500 nm on 22 September and reached ~ 3.5 on 26 September. The key factors that affected the formation and evolution of this haze episode were stable anti-cyclone synoptic conditions at the surface, decreasing of the height of PBL, heavy pollution emissions from urban area, number and size evolution of aerosols, and hygroscopic growth for aerosol scattering. This case study may provide valuable information for the public to recognize the formation mechanism of the regional haze event over the megacity, which is also useful for the government to adopt scientific approach to forecast and eliminate the occurrence of regional haze in China.
Journal Article
Targeting MET and AXL overcomes resistance to sunitinib therapy in renal cell carcinoma
Antiangiogenic therapy resistance occurs frequently in patients with metastatic renal cell carcinoma (RCC). The purpose of this study was to understand the mechanism of resistance to sunitinib, an antiangiogenic small molecule, and to exploit this mechanism therapeutically. We hypothesized that sunitinib-induced upregulation of the prometastatic MET and AXL receptors is associated with resistance to sunitinib and with more aggressive tumor behavior. In the present study, tissue microarrays containing sunitinib-treated and untreated RCC tissues were stained with MET and AXL antibodies. The low malignant RCC cell line 786-O was chronically treated with sunitinib and assayed for AXL, MET, epithelial–mesenchymal transition (EMT) protein expression and activation. Co-culture experiments were used to examine the effect of sunitinib pretreatment on endothelial cell growth. The effects of AXL and MET were evaluated in various cell-based models by short hairpin RNA or inhibition by cabozantinib, the multi-tyrosine kinases inhibitor that targets vascular endothelial growth factor receptor, MET and AXL. Xenograft mouse models tested the ability of cabozantinib to rescue sunitinib resistance. We demonstrated that increased AXL and MET expression was associated with inferior clinical outcome in patients. Chronic sunitinib treatment of RCC cell lines activated both AXL and MET, induced EMT-associated gene expression changes, including upregulation of Snail and β-catenin, and increased cell migration and invasion. Pretreatment with sunitinib enhanced angiogenesis in 786-0/human umbilical vein endothelial cell co-culture models. The suppression of AXL or MET expression and the inhibition of AXL and MET activation using cabozantinib both impaired chronic sunitinib treatment-induced prometastatic behavior in cell culture and rescued acquired resistance to sunitinib in xenograft models. In summary, chronic sunitinib treatment induces the activation of AXL and MET signaling and promotes prometastatic behavior and angiogenesis. The inhibition of AXL and MET activity may overcome resistance induced by prolonged sunitinib therapy in metastatic RCC.
Journal Article
Acetylation-dependent regulation of PD-L1 nuclear translocation dictates the efficacy of anti-PD-1 immunotherapy
Immunotherapies that target programmed cell death protein 1 (PD-1) and its ligand PD-L1 as well as cytotoxic T-lymphocyte-associated protein 4 (CTLA4) have shown impressive clinical outcomes for multiple tumours. However, only a subset of patients achieves durable responses, suggesting that the mechanisms of the immune checkpoint pathways are not completely understood. Here, we report that PD-L1 translocates from the plasma membrane into the nucleus through interactions with components of the endocytosis and nucleocytoplasmic transport pathways, regulated by p300-mediated acetylation and HDAC2-dependent deacetylation of PD-L1. Moreover, PD-L1 deficiency leads to compromised expression of multiple immune-response-related genes. Genetically or pharmacologically modulating PD-L1 acetylation blocks its nuclear translocation, reprograms the expression of immune-response-related genes and, as a consequence, enhances the anti-tumour response to PD-1 blockade. Thus, our results reveal an acetylation-dependent regulation of PD-L1 nuclear localization that governs immune-response gene expression, and thereby advocate targeting PD-L1 translocation to enhance the efficacy of PD-1/PD-L1 blockade.Gao et al. uncover p300-induced acetylation and HDAC2-mediated deacetylation of PD-L1, which modulate its nuclear translocation to affect the expression of immune genes and the efficacy of anti-PD-1 therapy.
Journal Article
Curse of rarity for autonomous vehicles
The curse of rarity—the rarity of safety-critical events in high-dimensional variable spaces—presents significant challenges in ensuring the safety of autonomous vehicles using deep learning. Looking at it from distinct perspectives, we identify three potential approaches for addressing the issue.
The curse of rarity—the rarity of safety-critical events in high-dimensional variable spaces—presents significant challenges in ensuring the safety of autonomous vehicles using deep learning. Looking at it from distinct perspectives, the authors identify three potential approaches for addressing the issue.
Journal Article
Strain-Induced Ultrahard and Ultrastable Nanolaminated Structure in Nickel
Heavy plastic deformation may refine grains of metals and make them very strong. But the strain-induced refinement saturates at large strains, forming three-dimensional ultrafine-grained (3D UFG) structures with random orientations. Further refinement of this microstructure is limited because of the enhanced mobility of grain boundaries. Very-high-rate shear deformation with high strain gradients was applied in the top surface layer of bulk nickel, where a 2D nanometer-scale laminated structure was induced. The strongly textured nanotaminated structure (average lamellar thickness of 20 nanometers) with low-angle boundaries among the lamellae is ultrahard and ultrastable: It exhibits a hardness of 6.4 gigapascal—which is higher than any reported hardness of the UFG nickel—and a coarsening temperature of 40 kelvin above that in UFG nickel
Journal Article
TRUST4: immune repertoire reconstruction from bulk and single-cell RNA-seq data
We introduce the TRUST4 open-source algorithm for reconstruction of immune receptor repertoires in αβ/γδ T cells and B cells from RNA-sequencing (RNA-seq) data. Compared with competing methods, TRUST4 supports both FASTQ and BAM format and is faster and more sensitive in assembling longer—even full-length—receptor repertoires. TRUST4 can also call repertoire sequences from single-cell RNA-seq (scRNA-seq) data without V(D)J enrichment, and is compatible with both SMART-seq and 5′ 10x Genomics platforms.TRUST4 is a computational tool for reconstructing T-cell and B-cell receptor repertoires using bulk and single-cell RNA-seq data.
Journal Article
Predicting Anticancer Drug Responses Using a Dual-Layer Integrated Cell Line-Drug Network Model
The ability to predict the response of a cancer patient to a therapeutic agent is a major goal in modern oncology that should ultimately lead to personalized treatment. Existing approaches to predicting drug sensitivity rely primarily on profiling of cancer cell line panels that have been treated with different drugs and selecting genomic or functional genomic features to regress or classify the drug response. Here, we propose a dual-layer integrated cell line-drug network model, which uses both cell line similarity network (CSN) data and drug similarity network (DSN) data to predict the drug response of a given cell line using a weighted model. Using the Cancer Cell Line Encyclopedia (CCLE) and Cancer Genome Project (CGP) studies as benchmark datasets, our single-layer model with CSN or DSN and only a single parameter achieved a prediction performance comparable to the previously generated elastic net model. When using the dual-layer model integrating both CSN and DSN, our predicted response reached a 0.6 Pearson correlation coefficient with observed responses for most drugs, which is significantly better than the previous results using the elastic net model. We have also applied the dual-layer cell line-drug integrated network model to fill in the missing drug response values in the CGP dataset. Even though the dual-layer integrated cell line-drug network model does not specifically model mutation information, it correctly predicted that BRAF mutant cell lines would be more sensitive than BRAF wild-type cell lines to three MEK1/2 inhibitors tested.
Journal Article