Comprehensive landscape of m6A regulator-related gene patterns and tumor microenvironment infiltration characterization in gastric cancer.

The epigenetic regulation of N6-methyladenosine (m6A) has attracted considerable interest in tumor research, but the potential roles of m6A regulator-related genes, remain largely unknown within the context of gastric cancer (GC) and tumor microenvironment (TME). Here, a comprehensive strategy of data mining and computational biology utilizing multiple datasets based on 28 m6A regulators (including novel anti-readers) was employed to identify m6A regulator-related genes and patterns and elucidate their underlying mechanisms in GC. Subsequently, a scoring system was constructed to evaluate individual prognosis and immunotherapy response. Three distinct m6A regulator-related patterns were identified through the unsupervised clustering of 56 m6A regulator-related genes (all significantly associated with GC prognosis). TME characterization revealed that these patterns highly corresponded to immune-inflamed, immune-excluded, and immune-desert phenotypes, and their TME characteristics were highly consistent with different clinical outcomes and biological processes. Additionally, an m6A-related scoring system was developed to quantify the m6A modification pattern of individual samples. Low scores indicated high survival rates and high levels of immune activation, whereas high scores indicated stromal activation and tumor malignancy. Furthermore, the m6A-related scores were correlated with tumor mutation loads and various clinical traits, including molecular or histological subtypes and clinical stage or grade, and the score had predictive values across all digestive system tumors and even in all tumor types. Notably, a low score was linked to improved responses to anti-PD-1/L1 and anti-CTLA4 immunotherapy in three independent cohorts. This study has expanded the important role of m6A regulator-related genes in shaping TME diversity and clinical/biological traits of GC. The developed scoring system could help develop more effective immunotherapy strategies and personalized treatment guidance.

Implementation of cytochrome c proteins and carbon nanotubes hybrids in bioelectrodes towards bioelectrochemical systems applications.

Multiheme cytochrome c (Cyt c) can function as a redox protein on electrode to accomplish bioelectrocatalysis. However, the direct electron transfer (DET) between the redox site of Cyt c and electrode is low due to the large coupling distance. A close proximity or a connection pathway from the deeply buried active site to the protein surface can be established by modifying the electrode with carbon nanotubes (CNTs) to improve the DET. Therefore, the isolated Cyt c has been assembled or casted with CNTs by various processes to form Cyt c-CNTs bioelectrodes that can be further applied to biosensing and bioanalysis. These strategies can be transplanted to the fabrication of biofilm-CNTs based electrodes by complexing the out membrane (OM) Cyt c of natural electricigen with CNTs to realize the application of the electrochemical properties of "in vivo" Cyt c to bioelectrochemical systems (BESs). This review intends to highlight the preparation strategies of bioelectrodes that have been well studied in electrochemical biosensors and improving approaches of the DET from the CNTs surface to Cyt c in their hybrids. The efficient fabrication processes of the biofilm-CNTs based electrodes that can be considered as "in vivo" Cyt c-CNTs based electrodes for BES designs are also summarized, aiming to provide an inspiration source and a reference to the related studies of BES downstream.

Simulation and Optimization of Surface Gas Injection Systems for Underground Gas Storage.

With the rapid development and popularization of sensing technology and information technology, the demand for intelligence in the oil and gas industry and gas storage has increased. The optimized operation of surface engineering is an important part of intelligence. To master the operation law of the surface engineering of gas storage, improve the production management level, and reduce the cost of gas injection, we investigated the simulation and optimization of a surface gas injection system for practical underground gas storage. We propose calculation formulas for gas injection well pressure separately according to the ideal gas equation of state, the van der Waals equation, and the R-K equation and verify them using actual data. By comparing the calculation error of the data and the complexities for both the equation and the calculation process, we finally choose the formula derived from the ideal gas equation of state as the constraint condition for our research. Moreover, we model the surface gas injection system by using the Aspen HYSYS simulation software. From the variation in the compressor power, we determine that the equalizing pressure injection pattern is the optimal injection pattern and the optimal number of injection wells is three. In addition, we examine the relationship between injection flow and well pressure with injection time under the optimal injection pattern. Finally, we obtain the functional formula of well pressure and injection flow with injection time. The results can provide not only a basis for the gas injection decision making of production systems but also a basic guarantee for the digital transformation and intelligent operation of enterprises.

Mitochondria-associated ER stress evokes immunogenic cell death through the ROS-PERK-eIF2α pathway under PTT/CDT combined therapy.

Chemodynamic therapy (CDT) can effectively induce immunogenic cell death (ICD) in tumours and is thus a promising strategy for boosting the efficacy of immunotherapy. However, the mechanism by which CDT enhances ICD and lowers ICD efficiency is unknown and this restricts its clinical application. In this study, a second near-infrared (NIR-II) window irradiation-triggered hydrogen peroxide (H2O2) self-supplying nanocomposite ((Cu2Se-CaO2)@LA) was constructed. The modified lauric acid was melted by the heat energy of the NIR-II irradiation, to expose the CaO2 nanoparticles, and they then reacted with water to produce H2O2 and Ca2+. H2O2 was then converted to hydroxyl radicals by the photothermal-enhanced CDT process of the Cu2Se nanocubes. Notably, the CDT and Ca2+ overload was found to induce sequential damage to the mitochondria and endoplasmic reticulum (ER), which upregulated the PERK-mediated eIF2α phosphorylation pathway and caused subsequent ICD. NIR-II irradiation of the (Cu2Se-CaO2)@LA also increased reactive oxygen species (ROS) formation and this was sufficient to increase dendritic cell maturation, attracting cytotoxic T lymphocytes, and suppressing tumour growth in vivo. Overall, we demonstrated that an enhanced CDT strategy under NIR-II exposure and H2O2 self-supply can induce extensive ICD by inducing mitochondria-associated ER stress, which represents a highly effective and promising strategy for ICD amplification and tumour immunotherapy. STATEMENT OF SIGNIFICANCE: In this study, a second near-infrared window (NIR-II) irradiation-triggered and H2O2 self-supplying nanocomposite (named (Cu2Se-CaO2)@LA) was constructed and tested both in vitro and in vivo. These nanoparticles demonstrated promising antitumor activity as designed. Mechanistically, the nanoparticles could damage mitochondria and upregulate the PERK-mediated eIF2αphosphorylation pathway, further causing endoplasmic reticulum stress, and inducing immunogenic cell death through dendritic cell maturation and cytotoxic T lymphocyte recruitment augmented activity. This system represents a highly effective and promising strategy for enhancing tumor immunotherapy and provides new insights for future studies and design refinements.

Icaritin-loaded PLGA nanoparticles activate immunogenic cell death and facilitate tumor recruitment in mice with gastric cancer.

This study aimed to explore the anti-tumor effect of icaritin loading poly (lactic-co-glycolic acid) nanoparticles (refer to PLGA@Icaritin NPs) on gastric cancer (GC) cells. Transmission Electron Microscope (TEM), size distribution, zeta potential, drug-loading capability, and other physicochemical characteristics of PLGA@Icaritin NPs were carried out. Furthermore, flow cytometry, confocal laser scanning microscope (CLSM), Cell Counting Kit-8 (CCK-8), Transwell, Elisa assay and Balb/c mice were applied to explore the cellular uptake, anti-proliferation, anti-metastasis, immune response activation effects, and related anti-tumor mechanism of PLGA@Icaritin NPs in vitro and in vivo. PLGA@Icaritin NPs showed spherical shape, with appropriate particle sizes and well drug loading and releasing capacities. Flow cytometry and CLSM results indicated that PLGA@Icaritin could efficiently enter into GC cells. CCK-8 proved that PLGA@Icaritin NPs dramatically suppressed cell growth, induced Lactic dehydrogenase (LDH) leakage, arrested more GC cells at G2 phase, and inhibited the invasion and metastasis of GC cells, compared to free icaritin. In addition, PLGA@Icaritin could help generate dozens of reactive oxygen species (ROS) within GC cells, following by significant mitochondrial membrane potentials (MMPs) loss and excessive production of oxidative-mitochondrial DNA (Ox-mitoDNA). Since that, Ox-mitoDNA further activated the releasing of damage associated molecular pattern molecules (DAMPs), and finally led to immunogenic cell death (ICD). Our in vivo data also elaborated that PLGA@Icaritin exerted a powerful inhibitory effect (∼80%), compared to free icaritin (∼60%). Most importantly, our results demonstrated that PLGA@Icaritin could activate the anti-tumor immunity via recruitment of infiltrating CD4+ cells, CD8+ T cells and increased secretion of cytokine immune factors, including interferon-γ (IFN-γ) tumor necrosis factor-α (TNF-α) and interleukin-1 (IL-1).++ Our findings validate that the successful design of PLGA@Icaritin, which can effectively active ICD and facilitate tumor recruitment in GC through inducing mitoDNA oxidative damage.

Underactuated USV path following mechanism based on the cascade method.

The path following control under disturbance was studied for an underactuated unmanned surface vehicle (USV) subject to the rudder angle and velocity constraints. For this reason, a variable look-ahead integral line-of-sight (LOS) guidance law was designed on the basis of the disturbance estimation and compensation, and a cascade path following control system was created following the heading control law based on the model prediction. Firstly, the guidance law was designed using the USV three-degree-of-freedom (DOF) motion model and the LOS method, while the tracking error state was introduced to design the real-time estimation of disturbance observer and compensate for the influence of ocean current. Moreover, the stability of the system was analyzed. Secondly, sufficient attention was paid to the rudder angle and velocity constraints and the influence of system delay and other factors in the process of path following when the heading control law was designed with the USV motion response model and the model predictive control (MPC). The moving horizon optimization strategy was adopted to achieve better dynamic performance, effectively overcome the influence of model and environmental uncertainties, and further prove the stability of the control law. Thirdly, a simulation experiment was carried out to verify the effectiveness and advancement of the proposed algorithm. Fourthly, the "Sturgeon 03" USV was used in the lake test of the proposed control algorithm to prove its feasibility in the engineering practices.

Resveratrol-modified mesoporous silica nanoparticle for tumor-targeted therapy of gastric cancer.

Resveratrol (Res) has been shown to exhibit anti-cancer properties in gastric cancer. However, its clinical application is limited by its poor pharmacokinetics, stability, and low solubility. Hence, this study aimed to explore and verify a better delivery system for gastric cancer therapy. Using transmission electron microscopy, Fourier transform infrared (FTIR) spectroscopy, and ultraviolet (UV) spectrometry, we observed the shape and encapsulation of resveratrol-modified mesoporous silica nanoparticles (MSN-Res) that were synthesized by chemical methods. To explore the anti-cancer effects of these MSN-Res in vivo and in vitro, we established AGS and HGC-27 tumor-bearing mouse models. Meanwhile, the proliferation of gastric cancer cells in vitro and in vivo was assessed by Cell Counting Kit-8, EdU, and Ki-67 immunohistochemical staining methods, while cellular apoptosis, and invasion and migration were detected by TdT-mediated dUTP nick end labeling (TUNEL) and Transwell assays, respectively. FTIR and UV results showed that we successfully synthesized and loaded drugs. Safety evaluation experiments showed that neither MSN-SH nor MSN-Res had toxic effects on the normal tissues of animals. Moreover, in vitro experiments revealed that MSN-Res significantly inhibited the proliferation, invasion, and migration of gastric cancer cells. Furthermore, TUNEL assay showed that MSN-Res promoted apoptosis in gastric cancer. These results were confirmed by the nude mouse tumorigenesis experiment. In conclusion, we demonstrated that MSN-Res showed better inhibitory effect on the development of gastric cancer than Res alone, indicating that MSN-Res could be a promising drug delivery system for gastric cancer treatment.

Circular RNA hsa_circ_0110389 promotes gastric cancer progression through upregulating SORT1 via sponging miR-127-5p and miR-136-5p.

Increasing studies have found that circular RNAs (circRNAs) are aberrantly expressed and play important roles in the occurrence and development of human cancers. However, the function of circRNAs on environmental carcinogen-induced gastric cancer (GC) progression remains poorly elucidated. In the present study, hsa_circ_0110389 was identified as a novel upregulated circRNA in malignant-transformed GC cells through RNA-seq, and subsequent quantitative real-time PCR verified that hsa_circ_0110389 was significantly increased in GC tissues and cells. High hsa_circ_0110389 expression associates with advanced stages of GC and predicts poor prognosis. Knockdown and overexpression assays demonstrated that hsa_circ_0110389 regulates proliferation, migration, and invasion of GC cells in vitro. In addition, hsa_circ_0110389 was identified to sponge both miR-127-5p and miR-136-5p and SORT1 was validated as a direct target of miR-127-5p and miR-136-5p through multiple mechanism assays; moreover, hsa_circ_0110389 sponged miR-127-5p/miR-136-5p to upregulate SORT1 expression and hsa_circ_0110389 promoted GC progression through the miR-127-5p/miR-136-5p-SORT1 pathway. Finally, hsa_circ_0110389 knockdown suppressed GC growth in vivo. Taken together, our findings firstly identify the role of hsa_circ_0110389 in GC progression, which is through miR-127-5p/miR-136-5p-SORT1 pathway, and our study provides novel insight for the identification of diagnostic/prognostic biomarkers and therapeutic targets for GC.

Identification of circRNA-miRNA-mRNA networks contributes to explore underlying pathogenesis and therapy strategy of gastric cancer.

BACKGROUND: Circular RNAs (circRNAs) are a new class of noncoding RNAs that have gained increased attention in human tumor research. However, the identification and function of circRNAs are largely unknown in the context of gastric cancer (GC). This study aims to identify novel circRNAs and determine their action networks in GC. METHODS: A comprehensive strategy of data mining, reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and computational biology were conducted to discover novel circRNAs and to explore their potential mechanisms in GC. Promising therapeutic drugs for GC were determined by connectivity map (CMap) analysis. RESULTS: Six overlapped differentially expressed circRNAs (DECs) were screened from selected microarray and RNA-Seq datasets of GC, and the six DECs were then validated by sanger sequencing and RNase R treatment. Subsequent RT-qPCR analysis of GC samples confirmed decreased expressions of the six DECs (hsa_circ_0000390, hsa_circ_0000615, hsa_circ_0001438, hsa_circ_0002190, hsa_circ_0002449 and hsa_circ_0003120), all of which accumulated preferentially in the cytoplasm. MiRNA binding sites and AGO2 occupation of the six circRNAs were predicted using online databases, and circRNA-miRNA interactions including the six circRNAs and 33 miRNAs were determined. Then, 5320 target genes of the above 33 miRNAs and 1492 differently expressed genes (DEGs) from The Cancer Genome Atlas (TCGA) database were identified. After intersecting the miRNA target genes and the 889 downregulated DEGs, 320 overlapped target genes were acquired. The Kyoto Encyclopedia of Genes and Genomes enrichment analysis indicated that these target genes were related to two critical tumor-associated signaling pathways. A protein-protein interaction network with the 320 target genes was constructed using STRING, and fifteen hubgenes (ATF3, BTG2, DUSP1, EGR1, FGF2, FOSB, GNAO1, GNAI1, GNAZ, GNG7, ITPR1, ITPKB, JUND, NR4A3, PRKCB) in the network were identified. Finally, bioactive chemicals (including vorinostat, trichostatin A and astemizole) based on the fifteen hubgenes were identifed as therapeutic agents for GC through the CMap analysis. CONCLUSIONS: This study provides a novel insight for further exploration of the pathogenesis and therapy of GC from the circRNA-miRNA-mRNA network perspective.

Circular RNA hsa_circ_0001829 promotes gastric cancer progression through miR-155-5p/SMAD2 axis.

BACKGROUND: Accumulating evidences have shown that circular RNAs (circRNAs) play important roles in regulating the pathogenesis of cancer. However, the role of circRNAs in gastric cancer (GC) remains largely unclear. METHODS: In this study, we identified a novel upregulated circRNA, hsa_circ_0001829, in chemically induced malignant transformed human gastric epithelial cells using RNA-seq. Subsequent qRT-PCR and ISH assays were performed to detect the expression level of hsa_circ_0001829 in GC cell lines and tissues. Functional roles of hsa_circ_0001829 in GC were then explored by loss- and gain-of- function assays. Bioinformatic prediction and luciferase assay were used to investigate potential mechanisms of hsa_circ_0001829. Finally, the mice xenograft and metastasis models were constructed to assess the function of hsa_circ_0001829 in vivo. RESULTS: We found that hsa_circ_0001829 was significantly upregulated in GC tissues and cell lines. Loss- and gain-of- function assays showed that hsa_circ_0001829 promotes GC cells proliferation, migration and invasion, and the affected cell cycle progression and apoptosis rates may account for the effect of hsa_circ_0001829 on GC proliferation. In addition, bioinformatic prediction and luciferase assay showed that hsa_circ_0001829 acts as a molecular sponge for miR-155-5p and that SMAD2 was a target gene of miR-155-5p; moreover, hsa_circ_0001829 sponges miR-155-5p to regulate SMAD2 expression and hsa_circ_0001829 promotes GC progression through the miR-155-5p-SMAD2 pathway. Finally, suppression of hsa_circ_0001829 expression inhibited tumor growth and aggressiveness in vivo. CONCLUSION: Taken together, our findings firstly demonstrated a novel oncogenic role of hsa_circ_0001829 in GC progression through miR-155-5p-SMAD2 axis, and our study may offer novel biomarkers and therapeutic targets for GC.

Transmembrane protein 92 performs a tumor-promoting function in breast carcinoma by contributing to the cell growth, invasion, migration and epithelial-mesenchymal transition.

OBJECTIVE: We try to examine the role of transmembrane protein 92 (TMEM92) in the progression of breast carcinoma (BC) and assess its prognostic value. Moreover, the effects of TMEM92 on BC cell phenotypes was explored. METHODS: The levels of TMEM92 in BC tissues were evaluated using bioinformatics analysis according to the Oncomine and The Cancer Genome Atlas databases. mRNA levels of TMEM92 in BC cells were measured by qRT-PCR. Kaplan-Meier methods together with log-rank tests were used to conduct survival analysis, and chi-square tests were employed to assess the relationship between TMEM92 levels and clinicopathological parameters. Cox regression analysis was carried out to identify the independent prognosticators. Small interference RNA targeted to TMEM92 and plasmid vectors pcDNA3.1-TMEM92 were respectively used to silence and over-express TMEM92. Protein levels of molecules in this study were tested by western blot. Cell viability, invasiveness and motility of BC cells were determined by cell counting kit 8, clone formation assay and Transwell assay, appropriately. RESULTS: The data showed that TMEM92 was upregulated in BC tissues or cells in comparison with control. High expression of TMEM92 was notably correlated with stage and metastasis, and led to a poor overall survival. Moreover, cox multivariate analysis model demonstrated that TMEM92 can be seen as an independent prognostic factor. Functional experiments demonstrated that downregulation of TMEM92 showed a significantly inhibitory effect on MDA-MB-231 cell viability, invasiveness and motility, whereas overexpression of TMEM92 could promote the changes of these phenotypes. Furthermore, western blot analysis revealed that depletion of TMEM92 inactivated the epithelial-mesenchymal transition (EMT) process with raised E-cadherin protein levels, while declined N-cadherin, Vimentin and Snail levels. However, enhancement of TMEM92 showed the opposite outcomes on these EMT-related markers. CONCLUSION: TMEM92 had an independent prognostic value for BC patients, and might act as an oncogene to facilitate tumor cells growth, invasiveness and motility by modulating the EMT relative proteins.

First record of tribe Laenini (Coleoptera, Tenebrionidae, Lagriinae) from Shanghai, with description of a new species of the genus Laena Dejean.

Laena hongqiao sp. n. is described from Shanghai. This discovery expands the provincial distribution of the huge tenebrionid genus Laena in mainland China, and enriches the knowledge of the species diversity in Shanghai. A key modified from Schawaller 2008 and Wei Ren 2018 is provided to include this new species.

Association of FGFR2 and PI3KCA genetic variants with the risk of breast cancer in a Chinese population.

PURPOSE: Genome-wide association studies have found plenty of single nucleotide polymorphisms (SNPs) which are associated with breast cancer risk. SNPs in FGFR2 are mostly identified. However, the association between PI3KCA SNP and breast cancer risk remains largely unknown. The aim of this study was to investigate the significance of FGFR2 and PI3KCA genetic variants in breast cancer and their association with prognosis. METHODS: We performed genotyping of 328 breast cancer patients and 389 healthy controls. Then, we evaluated the associations of FGFR2 rs1219648 and PI3KCA rs6443624 with the susceptibility and clinicopathological features of breast cancer. Kaplan-Meier curve with log-rank test was performed to determine the prognostic values of FGFR2 rs1219648 and PI3KCA rs6443624. RESULTS: The results indicated that genotype frequencies of rs1219648 and rs6443624 were significantly different between breast cancer patients and healthy controls. Furthermore, PI3KCA rs6443624 A carriers and FGFR2 rs1219648 G carriers more frequently had advanced stages and shorter survival times. CONCLUSION: The SNPs of FGFR2 rs1219648 and PI3KCA rs6443624 may contribute to the identification of breast cancer patients at risk of more aggressive disease and may be potential prognostic factors in breast cancer in a Chinese population.

Curcumin-guided nanotherapy: a lipid-based nanomedicine for targeted drug delivery in breast cancer therapy.

BACKGROUND: Delivery of anti-cancer drugs into the cancer cells or tissues by multifunctional nanocarriers may provide a new paradigm in cancer treatment. In this study, folate (FA) decorated nanostructured lipid carriers (NLCs) were constructed as nanomedicine for the delivery of curcumin (CUR). METHODS: CUR-loaded NLCs (CUR-NLCs) were prepared. FA containing polyethylene glycol (PEG)-distearoylphosphatidylethanolamine (DSPE) (FA-PEG-DSPE) was synthesized and used for the decoration of CUR-NLCs. Their particle size, zeta potential, and drug encapsulation efficiency (EE) were evaluated. In vitro cytotoxicity study FA decorated CUR-NLCs (FA-CUR-NLCs) was tested in MCF-7 human breast cancer cells (MCF-7 cells). In vivo anti-tumor efficacies of the carriers were evaluated on mice bearing breast cancer model. RESULTS: The optimum FA-CUR-NLCs formulations with the particle size of 127 nm and with a +13 mV surface charge. The growth of MCF-7 cells in vitro was obviously inhibited. FA-CUR-NLCs also displayed the best anti-tumor activity than other formulations in vivo. CONCLUSION: The results demonstrated that FA-CUR-NLCs were efficient in selective delivery to cancer cells over-expressing FA receptors (FRs). Also FA-CUR-NLCs transfer CUR to the breast cancer cells, enhance the anti-tumor capacity. Thus, FA-CUR-NLCs could prove to be a superior nanomedicine to achieve tumor therapeutic efficacy.

Bortezomib and lenalidomide as front-line therapy for multiple myeloma.

The objective of the study was to investigate the effects and safety of novel agents such as bortezomib and lenalidomide in the treatment of newly diagnosed patients with multiple myeloma. We performed a comprehensive meta-analysis of randomized controlled trials (RCTs). An initial search yielded 627 citations, of which 10 RCTs enrolling 4534 patients met the inclusion criteria. The addition of bortezomib to first-line therapy significantly prolonged overall survival (OS) (hazard ratio [HR], 0.75 [0.65, 0.87], p < 0.001). On the other hand, the addition of lenalidomide had no impact on survival (HR, 0.88 [0.65, 1.20], p = 0.42). Both lenalidomide and bortezomib consistently improved progression-free survival (PFS) compared with conventional therapy alone. The corresponding HRs were 0.65, 95% confidence interval (CI) [0.55, 0.77] (p < 0.001) for bortezomib and 0.48, 95% CI [0.42, 0.55]; (p < 0.001) for lenalidomide, respectively. Some of the increased adverse events reported were herpes zoster (relative risk [RR], 3.64 [2.23, 5.94], p < 0.001), peripheral neuropathy (RR, 3.59 [1.89, 6.83], p < 0.001) and gastrointestinal effects (RR, 2.19 [1.37, 3.50], p = 0.001) among patients receiving bortezomib, and gastrointestinal effects (RR, 2.36 [1.33, 4.17], p = 0.003) and thromboembolic events (RR, 2.55 [1.48, 4.38], p < 0.001) among patients receiving lenalidomide. Interestingly, treatment with bortezomib seemed to be associated with a lower rate of treatment related mortality (RR, 0.39 [0.18, 0.85], p = 0.02). An increased incidence of second primary cancers was observed in the lenalidomide group (RR 2.61 [1.60, 4.27], p < 0.001). In summary, bortezomib improved OS, and both lenalidomide and bortezomib consistently improved PFS of patients with newly diagnosed myeloma when it was added to standard therapy.