The protein phosphatase PC1 dephosphorylates and deactivates CatC to negatively regulate H2O2 homeostasis and salt tolerance in rice.

Catalase (CAT) is often phosphorylated and activated by protein kinases to maintain hydrogen peroxide (H2O2) homeostasis and protect cells against stresses, but whether and how CAT is switched off by protein phosphatases remains inconclusive. Here, we identified a manganese (Mn2+)-dependent protein phosphatase, which we named PHOSPHATASE OF CATALASE 1 (PC1), from rice (Oryza sativa L.) that negatively regulates salt and oxidative stress tolerance. PC1 specifically dephosphorylates CatC at Ser-9 to inhibit its tetramerization and thus activity in the peroxisome. PC1 overexpressing lines exhibited hypersensitivity to salt and oxidative stresses with a lower phospho-serine level of CATs. Phosphatase activity and seminal root growth assays indicated that PC1 promotes growth and plays a vital role during the transition from salt stress to normal growth conditions. Our findings demonstrate that PC1 acts as a molecular switch to dephosphorylate and deactivate CatC and negatively regulate H2O2 homeostasis and salt tolerance in rice. Moreover, knockout of PC1 not only improved H2O2-scavenging capacity and salt tolerance but also limited rice grain yield loss under salt stress conditions. Together, these results shed light on the mechanisms that switch off CAT and provide a strategy for breeding highly salt-tolerant rice.

The OsMYC2-JA feedback loop regulates diurnal flower-opening time via cell wall loosening in rice.

Diurnal flower-opening time (DFOT), the time of spikelet opening during the day, is an important trait for hybrid rice (Oryza sativa L.) seed production. Hybrids between indica and japonica rice varieties have strong heterosis, but the parental lines usually have different, nonoverlapping DFOTs. This reduces the success of hybrid seed production in crosses between indica and japonica subspecies, thus hindering the utilization of indica and japonica inter-subspecies heterosis. However, little is known about the molecular mechanisms regulating DFOT in rice. Here, we obtained japonica rice lines with a DFOT 1.5 h earlier than the wild type by overexpressing OsMYC2, a gene encoding a key transcription factor in the jasmonate (JA) signaling pathway. OsMYC2 is activated by JA signaling and directly regulates the transcription of genes related to JA biosynthesis and cell wall metabolism. Overexpressing OsMYC2 led to significantly increased JA contents and decreased cellulose and hemicellulose contents in lodicule cells, as well as the softening of lodicule cell walls. This may facilitate the swelling of lodicules, resulting in early diurnal flower-opening. These results suggest that the OsMYC2-JA feedback loop regulates DFOT in rice via cell wall remodeling. These findings shed light on the understanding of regulatory mechanism of the DFOT of plants, which should promote the development of indica and japonica varieties suitable for hybrid rice breeding.

Photoinduced Nonvolatile Resistive Switching Behavior in Oxygen-Doped MoS2 for a Neuromorphic Vision System.

Controlling resistance by external fields provides fascinating opportunities for the development of novel devices and circuits, such as temperature-field-induced superconductors, magnetic-field-triggered giant magnetoresistance devices, and electric-field-operated flash memories. In this work, we demonstrate a light-triggered nonvolatile resistive switching behavior in oxygen-doped MoS2. The two-terminal devices exhibit stable light-modulated resistive switching characteristics and optically tunable synaptic properties with an on/off ratio of up to 104. The integrated device with crossbar architecture enables simultaneous image sensing, preprocessing, and storage in a single device, thereby increasing the training efficiency and recognition rate of image recognition tasks. This work presents a novel pathway to develop the next generation of light-controlled memory and artificial vision systems for neuromorphic computing.

Enhanced sensitivity and durability in photodetector of Ag/nanocellulose/Si via plasma-assisted synthesis.

Position-sensitive detectors (PSDs) based on the lateral photovoltaic effect (LPE) are widely used for precision displacement and angle measurement. However, high temperatures can lead to the thermal decomposition or oxidation of nanomaterials frequently utilized in PSDs, and can ultimately affect the performance. In this study, we present a PSD based on Ag/nanocellulose/Si that maintains a maximum sensitivity of 416.52 mV/mm, even at elevated temperatures. By encapsulating nanosilver in a nanocellulose matrix, the device demonstrates excellent stability and performance over a wide temperature range from 300 to 450 K. Its performance can be comparable to that of room temperature PSDs. An approach that uses nanometals to regulate optical absorption and the local electric field overcomes carrier recombination due to nanocellulose, enabling a breakthrough in sensitivity for organic PSDs. The results indicate that the LPE in this structure is dominated by local surface plasmon resonance, presenting opportunities for expanding optoelectronics in high-temperature industrial environments and monitoring applications. The proposed PSD offers a simple, fast, and cost-effective solution for real-time laser beam monitoring, and its high-temperature stability makes it ideal for a wide range of industrial applications.

Relationship between serum CHIP levels with cardiovascular disease in maintenance haemodialysis patients.

Many preclinical studies reported that the carboxyl terminus of Hsp70-interacting protein (CHIP) has cardiovascular protective effects. This study was designed to explore whether CHIP is related with cardiovascular disease (CVD) in maintanence haemodialysis (MHD) patients. 217 MHD patients and 150 healthy controls were recruited, serum CHIP concentration and clinical characteristics were measured. MHD patients were followed-up for 36 months and their cardiovascular events (CVEs) and survival conditions were recorded. Here, the data shows that serum CHIP concentrations in MHD patients were lower than those in healthy controls (31.69 ± 18.2 pg/mL vs 84.53 ± 22.1 pg/mL, p < 0.05). CHIP negatively correlated with age, C-reactive protein, B-type brain natriuretic peptide, phosphorus, parathyroid hormone, carotid intima-media thickness (CIMT) and left ventricular septal thickness (LVSTd), whereas it positively associated with albumin, haemoglobin, creatinine, Kt/V and ejection fraction (p < 0.05, respectively). Partial correlation and multiple linear regression analysis verified the negative relationship between CHIP with CIMT or LVSTd (p < 0.05, respectively). Using quartile method and Kaplan-Meier survival function, it indetified that the lower serum CHIP concentration predicted risk of CVEs, CVD and all-cause death (p < 0.001). Cox regression analysis manifested CHIP was negatively associated with CVEs (HR = 0.914, 95%CI 0.880-0.950, p < 0.001), CVD mortality (HR = 0.747, 95%CI 0.651-0.857, p < 0.001) and all-cause death (HR = 0.769, 95%CI 0.696-0.850, p < 0.001). In conclusion, the data of this study revealed that serum CHIP level is significantly correlated with multiple risk factors of CVD and may be one of the predictors of CVD risk and death in MHD patients.

Engineering of rice varieties with enhanced resistances to both blast and bacterial blight diseases via CRISPR/Cas9.

Rice blast and bacterial blight represent two of major diseases having devastating impact on the yield of rice in most rice-growing countries. Developments of resistant cultivars are the most economic and effective strategy to control these diseases. Here, we used CRISPR/Cas9-mediated gene editing to rapidly install mutations in three known broad-spectrum blast-resistant genes, Bsr-d1, Pi21 and ERF922, in an indica thermosensitive genic male sterile (TGMS) rice line Longke638S (LK638S). We obtained transgene-free homozygous single or triple mutants in T1 generations. While all single and triple mutants showed increased resistance to rice blast compared with wild type, the erf922 mutants displayed the strongest blast resistance similar with triple mutants. Surprisingly, we found that Pi21 or ERF922 single mutants conferred enhanced resistance to most of tested bacterial blight. Both resistances in mutants were attribute to the up-regulation of SA- and JA-pathway associated genes. Moreover, phenotypic analysis of these single mutants in paddy fields revealed that there were no trade-offs between resistances and main agricultural traits. Together, our study provides a rapid and effective way to generate rice varieties with resistance to both rice blast and bacterial blight.

A coordinate positioning puncture method under robot-assisted CT-guidance: phantom and animal experiments.

PURPOSE: To evaluate the accuracy of the robot-assisted computed tomography (CT)-guided coordinate positioning puncture method by phantom and animal experiments. MATERIAL AND METHODS: In the phantom experiment, seven robot-assisted punctures were made to evaluate the accuracy of the method. In the animal experiment, 18 punctures (nine robotic and nine manual) were made in the livers of nine rabbits. The indicators, such as needle-tract length, angle deviation, puncture accuracy, number of scans required, and radiation exposure dose were compared between manual and robotic punctures. The paired-samples t-test was used for analysis. RESULTS: In the phantom experiment, the mean accuracy of seven punctures was 2.67 mm. In the animal experiment, there was no significant difference in needle-tract length (32.58 mm vs. 34.04 mm, p = .606), angle deviation (17.21° vs. 21.23° p = .557) and puncture accuracy (8.42 vs. 8.77 mm, p = .851) between the two groups. However, the number CT scans required (2.44 vs. 3.33, p = .002), and the radiation exposure dose (772.98 vs. 1077.89 mGy/cm, p = .003) were lower in the robot group than in the manual group. CONCLUSIONS: The coordinate positioning puncture method under robot-assisted CT-guidance can reach an accuracy that is comparable to that of the traditional manual CT-guided puncture method and with fewer CT scanning times accompanied with a lower radiation dosage.

Downregulated ZNF132 predicts unfavorable outcomes in breast Cancer via Hypermethylation modification.

BACKGROUND: An important mechanism that promoter methylation-mediated gene silencing for gene inactivation is identified in human tumorigenesis. Methylated genes have been found in breast cancer (BC) and beneficial biomarkers for early diagnosis. Prognostic assessment of breast cancer remain little known. Zinc finger protein 132 (ZNF132) is downregulated by promoter methylation in prostate cancer and esophageal squamous cell carcinoma. However, no study provides information on the status of ZNF132, analyzes diagnosis and prognostic significance of ZNF132 in BC. METHODS: In the present study, the expression of ZNF132 mRNA and protein level was determined based on the Cancer Genome Atlas (TCGA) RNA-Seq database and clinical samples analysis and multiple cancer cell lines verification. P rognostic significance of ZNF132 in BC was assessed using the Kaplan-Meier plotter. Molecular mechanisms exploration of ZNF132 in BC was performed using the multiple bioinformatic tools. Hypermethylated status of ZNF132 in BC cell lines was confirmed via Methylation specific polymerase chain reaction (MSP) analysis. RESULTS: The expression of ZNF132 both the mRNA and protein levels was downregulated in BC tissues. These results were obtained based on TCGA database and clinical sample analysis. Survival analysis from the Kaplan-Meier plotter revealed that the lower level of ZNF132 was associated with a shorter Relapse Free Survival (RFS) time. Receiver operating characteristic curve (ROC) of 0.887 confirmed ZNF132 had powerful sensitivity and specificity to distinguish between BC and adjacent normal tissues. Bioinformatic analysis showed that 6% ((58/960)) alterations of ZNF132 were identified from cBioPortal. ZNF132 participated in multiple biological pathways based on the Gene Set Enrichment Analysis (GSEA) database including the regulation of cell cycle and glycolysis. Finally, MSP analysis demonstrated that ZNF132 was hypermethylated in a panel of breast cancer cell lines and 5-aza-2'-deoxycytidine (5-Aza-dC) treatment restored ZNF132 expression in partial cell lines. CONCLUSIONS: Results revealed that hypermethylation of ZNF132 contributed to its downregulated expression and could be identified as a new diagnostic and prognostic marker in BC.

Prognostic biomarkers and therapeutic targets in oral squamous cell carcinoma: a study based on cross-database analysis.

BACKGROUND: Oral squamous cell carcinoma (OSCC) is a malignant cancer, the survival rate of patients is disappointing. Therefore, it is necessary to identify the driven-genes and prognostic biomarkers in OSCC. METHODS: Four Gene Expression Omnibus (GEO) datasets were integratedly analyzed using bioinformatics approaches, including identification of differentially expressed genes (DEGs), GO and KEGG analysis, construction of protein-protein interaction (PPI) network, selection of hub genes, analysis of prognostic information and genetic alterations of hub genes. ONCOMINE, The Cancer Genome Atlas (TCGA) and Human Protein Atlas databases were used to evaluate the expression and prognostic value of hub genes. Tumor immunity was assessed to investigate the functions of hub genes. Finally, Cox regression model was performed to construct a multiple-gene prognostic signature. RESULTS: Totally 261 genes were found to be dysregulated. 10 genes were considered to be the hub genes. The Kaplan-Meier analysis showed that upregulated SPP1, FN1, CXCL8, BIRC5, PLAUR, and AURKA were related to poor outcomes in OSCC patients. FOXM1 and TPX2 were considered as the potential immunotherapeutic targets with future clinical significance. Moreover, we constructed a nine-gene signature (TEX101, DSG2, SCG5, ADA, BOC, SCARA5, FST, SOCS1, and STC2), which can be utilized to predict prognosis of OSCC patients effectively. CONCLUSION: These findings may provide new clues for exploring the molecular mechanisms and targeted therapy in OSCC. The hub genes and risk gene signature are helpful to the personalized treatment and prognostic judgement.

WWP2 regulates proliferation of gastric cancer cells in a PTEN-dependent manner.

WW domain containing E3 Ub-protein ligase 2 (WWP2) plays an important role in tumor progression as an E3 ligase of PTEN. Here, we investigated the role of WWP2 in gastric cancer (GC). We found that WWP2 is overexpressed in GC tissues, which is closely related to poor prognosis of GC patients. Using a WWP2-shRNA lentivirus expressing system, we established WWP2 stable-knockdown GC cell lines and found that knockdown of WWP2 inhibits the proliferation of GC cells both in vitro and in vivo. Also, WWP2 silencing induced the up-regulation of PTEN protein level and down-regulation of AKT phosphorylation level. We further investigated the role of PTEN in this regulating process by performing rescue assay and found that PTEN is essential for WWP2-mediated regulation of GC cells proliferation. Taken together, our results demonstrated that WWP2 promotes proliferation of GC cells by downregulating PTEN, which may provide new therapeutic targets for GC.

Rhodium-catalyzed reductive carbonylation of aryl iodides to arylaldehydes with syngas.

The reductive carbonylation of aryl iodides to aryl aldehydes possesses broad application prospects. We present an efficient and facile Rh-based catalytic system composed of the commercially available Rh salt RhCl3·3H2O, PPh3 as phosphine ligand, and Et3N as the base, for the synthesis of arylaldehydes via the reductive carbonylation of aryl iodides with CO and H2 under relatively mild conditions with a broad substrate range affording the products in good to excellent yields. Systematic investigations were carried out to study the experimental parameters. We explored the optimal ratio of Rh salt and PPh3 ligand, substrate scope, carbonyl source and hydrogen source, and the reaction mechanism. Particularly, a scaled-up experiment indicated that the catalytic method could find valuable applications in industrial productions. The low gas pressure, cheap ligand and low metal dosage could significantly improve the practicability in both chemical researches and industrial applications.

GAD1 Encodes a Secreted Peptide That Regulates Grain Number, Grain Length, and Awn Development in Rice Domestication.

Cultivated rice (Oryza sativa) was domesticated from wild rice (Oryza rufipogon), which typically displays fewer grains per panicle and longer grains than cultivated rice. In addition, wild rice has long awns, whereas cultivated rice has short awns or lacks them altogether. These changes represent critical events in rice domestication. Here, we identified a major gene, GRAIN NUMBER, GRAIN LENGTH AND AWN DEVELOPMENT1 (GAD1), that regulates those critical changes during rice domestication. GAD1 is located on chromosome 8 and is predicted to encode a small secretary signal peptide belonging to the EPIDERMAL PATTERNING FACTOR-LIKE family. A frame-shift insertion in gad1 destroyed the conserved cysteine residues of the peptide, resulting in a loss of function, and causing the increased number of grains per panicle, shorter grains, and awnless phenotype characteristic of cultivated rice. Our findings provide a useful paradigm for revealing functions of peptide signal molecules in plant development and helps elucidate the molecular basis of rice domestication.

Identification of hub genes and therapeutic drugs in esophageal squamous cell carcinoma based on integrated bioinformatics strategy.

BACKGROUND: Esophageal squamous cell carcinoma (ESCC) is one of leading malignant cancers of gastrointestinal tract worldwide. Until now, the involved mechanisms during the development of ESCC are largely unknown. This study aims to explore the driven-genes and biological pathways in ESCC. METHODS: mRNA expression datasets of GSE29001, GSE20347, GSE100942, and GSE38129, containing 63 pairs of ESCC and non-tumor tissues data, were integrated and deeply analyzed. The bioinformatics approaches include identification of differentially expressed genes (DEGs) and hub genes, gene ontology (GO) terms analysis and biological pathway enrichment analysis, construction and analysis of protein-protein interaction (PPI) network, and miRNA-gene network construction. Subsequently, GEPIA2 database and qPCR assay were utilized to validate the expression of hub genes. DGIdb database was performed to search the candidate drugs for ESCC. RESULTS: Finally, 120 upregulated and 26 downregulated DEGs were identified. The functional enrichment of DEGs in ESCC were mainly correlated with cell cycle, DNA replication, deleted in colorectal cancer (DCC) mediated attractive signaling pathway, and Netrin-1 signaling pathway. The PPI network was constructed using STRING software with 146 nodes and 2392 edges. The most significant three modules in PPI were filtered and analyzed. Totally ten genes were selected and considered as the hub genes and nuclear division cycle 80 (NDC80) was closely related to the survival of ESCC patients. DGIdb database predicted 33 small molecules as the possible drugs for treating ESCC. CONCLUSIONS: In summary, the data may provide new insights into ESCC pathogenesis and treatments. The candidate drugs may improve the efficiency of personalized therapy in future.

Spent Lithium-Ion Batteries Derived Co3O4 for Electrocatalytic Polyethylene Terephthalate Plastic Recycling.

Spent lithium-ion batteries (LIBs) are an essential secondary resource containing valuable metal elements. Transforming spent LIBs into efficient catalysts through a simple process presents a promising strategy to address both metal resource scarcity and clean energy challenges. Herein, a deep eutectic solvent-assisted synthesis of Co3O4 material from spent LIBs is proposed. The obtained Co3O4 material possesses efficient and stable electrocatalytic activity for converting raw polyethylene terephthalate (PET) bottles into high-purity formic acid and terephthalic acid products under ambient conditions. As expected, the Co3O4 catalyst exhibits a high FE of 92 % with a concentration of produced potassium formate of 23.6 mM under alkaline conditions. This study presents a waste-treating-waste strategy for the simultaneous recovery of spent LIBs and PET waste in a greener manner.

Association of physical performance with cognitive impairment in middle-aged to older haemodialysis patients: a multicentre cross-sectional observational study.

OBJECTIVE: To determine the prevalence of cognitive impairment (CI) among middle-aged to older patients receiving maintenance haemodialysis (MHD) and to investigate the potential association between CI and physical performance. METHODS: This cross-sectional observational study enrolled participants aged 55-85 years who received MHD. Cognitive status was assessed using the Mini Mental State Examination (MMSE). Physical performance was measured by hand grip strength, the Timed Up and Go Test (TUGT) and the 4-m walking speed. Sociodemographic, clinical and laboratory parameters were recorded for each patient. RESULTS: The study included 592 patients (363 males); and of these, 126 (21.3%) were diagnosed with CI. Compared with patients with normal cognitive function, those with CI were significantly older and had significantly longer dialysis duration, lower educational level, higher Malnutrition Inflammation Score, higher depression and higher Charlson Comorbidity Index score. After adjustment for covariates, multiple regression analysis suggested that grip strength (odds ratio [OR] = 0.959, 95% confidence interval [CI] = 0.924, 0.996) and 4-m walking speed (OR = 0.161, 95% CI = 0.070, 0.368) were protective factors. TUGT (OR = 1.037, 95%CI = 1.003, 1.071) was a risk factor. CONCLUSION: Physical performance was correlated with CI and might be a significant indicator for the early identification of CI in middle-aged to older MHD patients.

Receptor-Like Cytoplasmic Kinase STK Confers Salt Tolerance in Rice.

BACKGROUND: Soil salinization is a major abiotic environmental stress factor threatening crop production throughout the world. Salt stress drastically affects the growth, development, and grain yield of rice (Oryza sativa L.), and the improvement of rice tolerance to salt stress is a desirable approach for meeting increasing food demand. Receptor-like cytoplasmic kinases (RLCKs) play essential roles in plant growth, development and responses to environmental stresses. However, little is known about their functions in salt stress. Previous reports have demonstrated that overexpression of an RLCK gene SALT TOLERANCE KINASE (STK) enhances salt tolerance in rice, and that STK may regulate the expression of GST (Glutathione S-transferase) genes. RESULTS: The expression of STK was rapidly induced by ABA. STK was highest expressed in the stem at the heading stage. STK was localized at the plasma membrane. Overexpression of STK in rice increased tolerance to salt stress and oxidative stress by increasing ROS scavenging ability and ABA sensitivity. In contrast, CRISPR/Cas9-mediated knockout of STK increased the sensitivity of rice to salt stress and oxidative stress. Transcriptome sequencing analysis suggested that STK increased the expression of GST genes (LOC_Os03g17480, LOC_Os10g38140 and LOC_Os10g38710) under salt stress. Reverse transcription quantitative PCR (RT-qPCR) suggested that four stress-related genes may be regulated by STK including OsABAR1, Os3BGlu6, OSBZ8 and OsSIK1. CONCLUSIONS: These findings suggest that STK plays a positive regulatory role in salt stress tolerance by inducing antioxidant defense and associated with the ABA signaling pathway in rice.

EZH2-H3K27me3-mediated silencing of mir-139-5p inhibits cellular senescence in hepatocellular carcinoma by activating TOP2A.

BACKGROUND: Epigenetic alterations play an important role in hepatocellular carcinoma (HCC) development. Enhancer of zeste homolog 2 (EZH2) is a well-known epigenetic modifier that functions as an oncogene in tumors by promoting the H3K27me3-mediated transcriptional repression of tumor suppressor genes. "Senescent cells" has been proposed as a possible core component of the hallmarks of cancer conceptualization. Induction of cell senescence and targeted elimination of these senescent tumor cells are new strategies for tumor therapy. However, the role of EZH2 in regulating cellular senescence remains poorly understood. METHODS: Bioinformatics analyses suggested that EZH2 and DNA topoisomerase II alpha (TOP2A) are coexpressed in tumors, including HCC. Kyoto Encyclopedia of Genes and Genome (KEGG) pathway enrichment analyses and gene set enrichment analyses (GSEA) suggests a correlation of EZH2 and TOP2A expression with cellular senescence in HCC. MicroRNA (miRNA) inhibitor and mimics, siRNA, PLKO-shRNA, and plenti6.3-miR-139 were used to upregulate or downregulate the expression of target genes. CCK8, EdU, clone formation, and senescence-associated ß-galactosidase (SA-ß-gal) staining assays were performed to assess cell proliferation and cellular senescence phenotypes. Dual-luciferase reporter and chromatin immunoprecipitation assays were performed to investigate the targeted binding and inhibition of TOP2A 3' untranslated region (UTR) by miR-139-5p and the DNA enrichment of miR139-5p by EZH2 and H3K27me3. BALB/c nude mice were used to establish a xenograft tumor model and verify the phenotypes upon EZH2 and TOP2A silencing and miR-139 overexpression in vivo. In addition, tissue microarrays were used to analyze the expression patterns and correlations among EZH2, TOP2A, and miR-139-5p expression in HCC. RESULTS: Bioinformatics analysis revealed that EZH2 and TOP2A are coexpressed in HCC. In vitro gain- and loss-of-function experiments showed that inhibition of EZH2 and TOP2A induces cellular senescence and inhibits proliferation of HCC cells. In vivo tumorigenesis assays indicated that EZH2 and TOP2A knockdown inhibits tumorigenesis by inducing cellular senescence. Mechanistically, EZH2 promotes TOP2A expression by regulating the H3K27me3-mediated epigenetic silencing of miR-139-5p. TOP2A is a direct target of miR-139-5p, and inhibition of miR-139-5p can reverse the promotion by EZH2 of TOP2A expression. The overexpression of miR-139-5p induces cellular senescence and inhibits proliferation of HCC cells both in vitro and in vivo. Clinically, expression of EZH2 and TOP2A are higher in HCC tissues than in normal tissues, and this high coexpression indicates a worse outcome of patients with HCC. Moreover, expression of EZH2 and TOP2A is significantly correlated with tumor differentiation grade, tumor invasion, and TNM stage in HCC. miR-139-5p expression is lower in HCC tumors than in normal tissues and is correlated with better prognosis of HCC patients. CONCLUSIONS: Our study revealed the role of the EZH2/miR-139-5p/TOP2A axis in regulating cellular senescence and cell proliferation in HCC, enriching the molecular mechanisms of EZH2-mediated epigenetic regulation in HCC. Therefore, our results provide insight into the therapeutic potential of targeting EZH2 to induce cellular senescence and then destroy senescent cells for HCC.

Targeting the E3 ligase NEDD4 as a novel therapeutic strategy for IGF1 signal pathway-driven gastric cancer.

The IGF1 signal pathway is highly activated in some subtype of gastric cancer(GC) that exhibits poor survival and chemotherapy resistance. Although the results of clinical trials of anti-IGF1R monoclonal antibodies and IGF-1R inhibitors have been mostly disappointing in unselected cancer patients, some patients benefit from anti-IGF1R therapy in these failed studies. Therefore, it is necessary to characterize the complex IGF signaling in GC and help refine the strategies targeting the IGF1 pathway. We found that GC cell lines exhibit differential responses to the specific IGF1R inhibitor OSI906. According to the phosphorylation status of Akt upon the OSI906 treatment, we divided the GC cell lines into IGF1R-dependent and IGF1R-independent cells. Both in vitro and in vivo experiments indicate that Dox-induced knockdown of NEDD4 significantly suppresses tumor growth of IGF1R-dependent GC cells and NEDD4 overexpression promotes tumor growth of IGF1R-dependent GC cells. In contrast, the proliferation of IGF1R-independent GC cells is not affected by NEDD4 silencing and overexpression. The rescue experiments show that a PTEN-IRS1 axis is required for NEDD4-mediated regulation of Akt activation and tumor growth in GC cells. Clinically, NEDD4 is expressed higher in IGF1-high GC tissues compared with IGF1-low GC tissues and normal tissues, and the co-high expression of NEDD4 and IGF1 predicts a worse prognosis in GC patients. Taken together, our study demonstrated that NEDD4 specifically promotes proliferation of GC cells dependent on IGF1/IGF1R signaling by antagonizing the protein phosphatase activity of PTEN to IRS1, and targeting NEDD4 may be a promising therapeutic strategy for IGF1 signal pathway-driven gastric cancer.

Development and validation of a ligand-receptor pairs signature to predict outcome and provide a therapeutic strategy in gastric cancer.

BACKGROUND: An important factor in tumor development and progression is the tumor microenvironment (TME), which is heterogeneous. Previous studies have mainly investigated the expression profile and prognostic values of genes in gastric cancer (GC) at the cell population level but neglected the interactions and heterogeneity between cells. METHODS: The pattern of ligand-receptor (LR) interactions was delineated on a scRNA-seq dataset containing 44,953 cells from nine GC patients and a fourth bulk RNA-seq dataset including data from 1159 GC patients. We then constructed an LR.Score scoring model to comprehensively evaluate the influence of LR-pairs on the TME, overall survival, and immunotherapy response in GC patients from several cohorts. RESULTS: Cell communication network among 13 cell types was constructed based on the LR-pairs. We proposed a new molecular subtyping model for GC based on the LR-pairs and revealed the differences in prognosis, pathophysiologic features, mutation characteristics, function enrichment, and immunological characteristics among the three subtypes. Finally, an LR.Score model based on LR-pairs was developed and validated on several datasets. CONCLUSIONS: Based on the selected LR-pairs, we successfully constructed a novel prediction model and observed its well performance on molecular subtyping, target and pathway screening, prognosis judging, and immunotherapy response predicting.

Prognostic role and immune infiltration characteristics of EI24 in multiple cancer types.

BACKGROUND: The autophagy-associated transmembrane protein EI24 is associated with cancer growth and patient survival. We aimed to explore the prognostic role and immune infiltration characteristics of EI24 at a pan-cancer level. METHODS: We collected data from multiple databases to explore the expression and prognostic role of EI24 in various cancers. Correlations between EI24 expression and DNA methylation, RNA modification, tumor mutation burden (TMB), microsatellite instability (MSI), immune moderator, immune checkpoint-related genes, the tumor immune microenvironment, and clinicopathological characteristics were analyzed. Finally, immunohistochemistry and western blotting were performed to validate the protein levels of EI24 in different tumors. RESULTS: Differential expression of EI24 was observed in most cancer types compared to non-cancerous tissues. EI24 showed a significant association with prognosis and may represent a new indicator of prognosis in patients with cancer. In most cancers, EI24 is closely associated with tumor immunity and interacts with various immune cells. Moreover, significant correlations were observed between EI24 expression and RNA modification, TMB, MSI, immune moderators, and immune checkpoint-related genes. CONCLUSION: This study provides new insights into the functions and clinical value of EI24 in different tumors and suggests that EI24 may serve as a promising biomarker or therapeutic target for cancer management.