A method for predicting drugs that can boost the efficacy of immune checkpoint blockade.

Combination therapy is a promising therapeutic strategy to enhance the efficacy of immune checkpoint blockade (ICB); however, predicting drugs for effective combination is challenging. Here we developed a general data-driven method called CM-Drug for screening compounds that can boost ICB treatment efficacy based on core and minor gene sets identified between responsive and nonresponsive samples in ICB therapy. The CM-Drug method was validated using melanoma and lung cancer mouse models, with combined therapeutic efficacy demonstrated in eight of nine predicted compounds. Among these compounds, taltirelin had the strongest synergistic effect. Mechanistic analysis and experimental verification demonstrated that taltirelin can stimulate CD8+ T cells and is mediated by the induction of thyroid-stimulating hormone. This study provides an effective and general method for predicting and evaluating drugs for combination therapy and identifies candidate compounds for future ICB combination therapy.

Role of a novel circRNA-CGNL1 in regulating pancreatic cancer progression via NUDT4-HDAC4-RUNX2-GAMT-mediated apoptosis.

BACKGROUND: Pancreatic cancer (PC) is an extremely malignant tumor with low survival rate. Effective biomarkers and therapeutic targets for PC are lacking. The roles of circular RNAs (circRNAs) in cancers have been explored in various studies, however more work is needed to understand the functional roles of specific circRNAs. In this study, we explore the specific role and mechanism of circ_0035435 (termed circCGNL1) in PC. METHODS: qRT-PCR analysis was performed to detect circCGNL1 expression, indicating circCGNL1 had low expression in PC cells and tissues. The function of circCGNL1 in PC progression was examined both in vitro and in vivo. circCGNL1-interacting proteins were identified by performing RNA pulldown, co-immunoprecipitation, GST-pulldown, and dual-luciferase reporter assays. RESULTS: Overexpressing circCGNL1 inhibited PC proliferation via promoting apoptosis. CircCGNL1 interacted with phosphatase nudix hydrolase 4 (NUDT4) to promote histone deacetylase 4 (HDAC4) dephosphorylation and subsequent HDAC4 nuclear translocation. Intranuclear HDAC4 mediated RUNX Family Transcription Factor 2 (RUNX2) deacetylation and thereby accelerating RUNX2 degradation. The transcription factor, RUNX2, inhibited guanidinoacetate N-methyltransferase (GAMT) expression. GAMT was further verified to induce PC cell apoptosis via AMPK-AKT-Bad signaling pathway. CONCLUSIONS: We discovered that circCGNL1 can interact with NUDT4 to enhance NUDT4-dependent HDAC4 dephosphorylation, subsequently activating HDAC4-RUNX2-GAMT-mediated apoptosis to suppress PC cell growth. These findings suggest new therapeutic targets for PC.

Improving the Sensitivity and Linear Range of Photoionization Ion Mobility Spectrometry via Confining the Ion Recombination and Space Charge Effects Assisted by Theoretical Modeling.

Photoionization (PI) is an efficient ionization source for ion mobility spectrometry (IMS) and mass spectrometry. Its hyphenation with IMS (PI-IMS) has been employed in various on-site analysis scenarios targeting a wide range of compounds. However, the signal intensity and linear dynamic range of PI-IMS at ambient pressure usually do not follow the Beer-Lambert law predictions, and the factors causing that negative deviation remain unclear. In this work, a variable pressure PI-IMS system was developed to examine the ion loss effects from factors like ion recombination and space charge by varying its working pressure from 1 to 0.1 bar. Assisted by theoretical modeling, it was found that ion recombination could contribute up to 90% of signal intensity loss for ambient pressure PI-IMS setups. Lowering the pressure and increasing the electric field in PI-IMS helped suppress the ion recombination process and thus an optimal pressure Poptimal appeared for best signal intensity, despite the decreased net ion number density and the increased space charge effect. A simplified theoretical equation taking ion recombination as the primary ion loss factor was derived to link Poptimal with analyte concentration and electric field in PI-IMS, enabling a swift optimization of the PI-IMS performance. For example, compared to ambient pressure, PI-IMS at a Poptimal of 0.4 bar provided a signal intensity increment of more than 400% for 0.716 ppmv toluene and also expanded the linear dynamic range by more than two times. Revealing factors influencing the PI-IMS response would also benefit the applications of other chemical ionization sources in IMS or mass spectrometry (MS).

Enhancing the Performance of Tyndall-Powell Gate Ion Mobility Spectrometry by Combining Ion Enrichment, Discrimination Reduction, and Temporal Compression into a Single Gating Process.

The broad applications of ion mobility spectrometry (IMS) demand good sensitivity and resolving power for ion species with different reduced mobilities (K0). In this work, a new Tyndall-Powell gate (TPG) gating method for combining ion enrichment, mobility discrimination reduction, and temporal compression into a single gating process is proposed to improve IMS analysis performance. The two-parallel-grid structure and well-confined gate region of the TPG make it convenient to spatiotemporally vary the electric fields within and around the gate region. Under the new gating method, a potential wave is applied on TPG grid 1 to enrich ions within the ionization region adjacent to the TPG during the gate-closed state; meanwhile, a potential wave is applied on TPG grid 2 to enhance mobility discrimination reduction and temporal compression simultaneously during the gate-open state. For triethyl phosphate (TEP) and dimethyl methylphosphonate mixtures, product ion peaks within K0 of 1.9 to 1.1 cm2/V·s exhibit a 19-fold increase in ion current compared to the traditional TPG gating method, while maintaining a resolving power of 85. The estimated limit of detection for the TEP dimer is lowered from 8 ppb to 135 ppt. The new gating method can be applied to other TPG-based IMS systems to enhance their performance in analyzing complex samples.

A co-adaptive duality-aware framework for biomedical relation extraction.

MOTIVATION: Biomedical relation extraction is a vital task for electronic health record mining and biomedical knowledge base construction. Previous work often adopts pipeline methods or joint methods to extract subject, relation, and object while ignoring the interaction of subject-object entity pair and relation within the triplet structure. However, we observe that entity pair and relation within a triplet are highly related, which motivates us to build a framework to extract triplets that can capture the rich interactions among the elements in a triplet. RESULTS: We propose a novel co-adaptive biomedical relation extraction framework based on a duality-aware mechanism. This framework is designed as a bidirectional extraction structure that fully takes interdependence into account in the duality-aware extraction process of subject-object entity pair and relation. Based on the framework, we design a co-adaptive training strategy and a co-adaptive tuning algorithm as collaborative optimization methods between modules to promote better mining framework performance gain. The experiments on two public datasets show that our method achieves the best F1 among all state-of-the-art baselines and provides strong performance gain on complex scenarios of various overlapping patterns, multiple triplets, and cross-sentence triplets. AVAILABILITY AND IMPLEMENTATION: Code is available at https://github.com/11101028/CADA-BioRE.

In Situ Synthesis of NH2-MIL-53-Al/PAN Nanofibers for Removal Co(II) through an Electrospinning Process.

In this study, researchers developed a novel composite material called NH2-MIL-53-Al/PAN, which consists of metal-organic frameworks (MOFs) grown on electrospun PAN nanofibers (NFs). The successful formation of the composite was confirmed by X-ray diffraction (XRD) and Fourier transform infrared (FTIR), and the hydrophilicity of NH2-MIL-53-Al/PAN was demonstrated by the water contact angle (WCA). Batch experiments were conducted to investigate the adsorption performance of Co(II) under different conditions. The maximum adsorption capacity reached 58.72 mg/g, and almost 95% of the adsorption was achieved within the first 6 h. The adsorption process was found to be spontaneous and endothermic and followed the pseudo-second-order kinetics and Langmuir models. Chemisorption and molecular layer adsorption are the main mechanisms of adsorption, and X-ray photoelectron spectroscopy (XPS) analysis further reveals that the interaction between the adsorbent and cobalt is a coordination interaction. In this study, NH2-MIL-53-Al was grown in situ on PAN to ensure effective loading of MOFs and prevent agglomeration during the NF mixing process. This approach successfully addressed the challenge of exposing active sites within the embedded MOF crystals. Additionally, it overcame the difficulty of recycling traditional MOF adsorbents. As a result, the exceptional performance of MOF NFs offers a promising solution for the efficient removal of cobalt-containing wastewater.

Model-based dosing optimization and therapeutic drug monitoring practices of teicoplanin in patients with complicated or non-complicated methicillin-resistant staphylococcus aureus infection.

AIMS: This study aims to establish a population pharmacokinetic (PK) model of teicoplanin in Chinese adult patients to evaluate the dosing regimen in the label sheet and optimize it. METHODS: Nonlinear mixed-effects modelling was used to estimate PK parameters. Monte Carlo simulations were used to evaluate the attainment of various dosing regimens in achieving the target trough concentrations in patients with normal or decreased renal function. RESULTS: A total of 115 patients were enrolled in this retrospective study. Creatinine clearance (CrCL) and albumin (ALB) were identified as covariates on the clearance of teicoplanin. For the treatment of non-complicated methicillin-resistant Staphylococcus aureus (MRSA) infections in patients with normal renal function and serum ALB concentration, the recommended dosing regimen was 600 mg q12h with five administrations as the loading dose followed by 600 mg qd as the maintenance dose; for the treatment of serious and/or complicated MRSA infections, the recommended dosing regimen was 800 mg q12h with five administrations as the loading dose followed by 800 mg qd as the maintenance dose. It is worth noting that both the loading and maintenance doses ought to be modified based on the patient's renal function and serum ALB concentration. In addition, trough concentrations of teicoplanin were significantly increased every other week. CONCLUSIONS: Both loading dosing and maintenance dosing regimens were recommended to be adjusted according to patient's renal function and serum ALB concentration. In addition, it is necessary to perform follow-up therapeutic drug monitoring of teicoplanin at least once every week.

Robust Cooperative Fault-Tolerant Control for Uncertain Multi-Agent Systems Subject to Actuator Faults.

This article investigates the robust cooperative fault-tolerant control problem of multi-agent systems subject to mismatched uncertainties and actuator faults. During the design process of the intermediate variable estimator, there is no need to satisfy fault estimation matching conditions, and this overcomes a crucial constraint of traditional observers and estimators. The feedback term of the designed estimator contains the centralized estimation errors and the distributed estimation errors of the agent, and this further improves the design freedom of the proposed estimator. A novel fault-tolerant control protocol is designed based on the fault estimation information. In this work, the bounds of the fault and its derivatives are unknown, and the considered method is applicable to both directed and undirected multi-agent systems. Furthermore, the parameters of the estimator are determined through the resolution of a linear matrix inequality (LMI), which is decoupled by employing coordinate transformation and Schur decomposition. Lastly, a numerical simulation result is used to demonstrate the effectiveness of the proposed method.

[Cloning and functional analysis of flavanone synthase â ¡ from Dendrobium huoshanense].

Flavonoid C-glycosides are a class of natural products that are widely involved in plant defense responses and have diverse pharmacological activities. They are also important active ingredients of Dendrobium huoshanense. Flavanone synthase Ⅱ has been proven to be a key enzyme in the synthesis pathway of flavonoid C-glycosides in plants, and their catalytic product 2-hydroxyflavanone is the precursor compound for the synthesis of various reported flavonoid C-glycosides. In this study, based on the reported amino acid sequence of flavanone synthase Ⅱ, a flavanone synthase Ⅱ gene(DhuFNSⅡ) was screened and verified from the constructed D. huoshanense genome localization database. Functional validation of the enzyme showed that it could in vitro catalyze naringenin and pinocembrin to produce apigenin and chrysin, respectively. The open reading frame(ORF) of DhuFNSⅡ was 1 644 bp in length, encoding 547 amino acids. Subcellular localization showed that the protein was localized on the endoplasmic reticulum. RT-qPCR results showed that DhuFNSⅡ had the highest expression in stems, followed by leaves and roots. The expression levels of DhuFNSⅡ and other target genes in various tissues of D. huoshanense were significantly up-regulated after four kinds of abiotic stresses commonly encountered in the growth process, but the extent of up-regulation varied among treatment groups, with drought and cold stress having more significant effects on gene expression levels. Through the identification and functional analysis of DhuFNSⅡ, this study is expected to contribute to the elucidation of the molecular mechanism of the formation of quality metabolites of D. huoshanense, flavonoid C-glycosides, and provide a reference for its quality formation and scientific cultivation.

Distinct invasive patterns in situ between estrogen receptor-positive and triple-negative breast cancer through the intraductal tracking of carbon nanoparticles.

Given that the transition from ductal carcinoma in situ (DCIS) to invasive breast cancer (BC) is crucial during the BC progression, the mechanism involved in the invasion transition behind triple-negative breast cancer (TNBC) and estrogen receptor-positive (ER-positive) subtype has remained elusive. This article detected distinct invasion patterns of BC cells between the ER-positive and TNBC using intraductal murine models with intraductal administration of carbon nanoparticles (CNPs). First, the feasibility of the utility of CNPs as a tracer was proved. The area ratio of CNPs and tumor cells invading the stroma at the late stage was found significantly higher than that in the early stage in MNU-induced ER-positive BC. However, opposite results were obtained in the triple-negative model. Consequently, we proposed that the ER-positive phenotype cells behave differently between different stages during tumor progression while there is no such difference in the invasion process of TNBC cells. The analysis regarding the duct integrity along with immunohistochemical characteristics further explained the distinct invasion features between the ER-positive and triple-negative subtypes. Last, the relationship between the duct thickness and the duct integrity suggested that ER-positive tumors gradually increased in size within the lumen before the invasion. Overall, this study suggested the different invasion characteristics of ER-positive BC and TNBC in vivo.

Manipulation of Ion Conversion in Dichloromethane-Enhanced Vacuum Ultraviolet Photoionization Mass Spectrometry of Oxygenated Volatile Organic Compounds.

The ion conversion processes in CH2Cl2-enhanced vacuum ultraviolet photoionization of oxygenated volatile organic compounds (OVOCs) have been systematically studied by regulating the pressure, humidity, and reaction time in the ionization source of a time-of-flight mass spectrometer. As the ionization source pressure increased from 100 to 1100 Pa, the main characteristic ions changed from CH2Cl+ to CH2Cl+(H2O), CH2OH+, and C2H4OH+ and then to the hydrated hydronium ions H3O+(H2O)n (n = 1, 2, 3). The total ion current (TIC) almost remained unchanged even if the humidity increased from 44 to 3120 ppmv, indicating interconversion between ions through ion-molecule reactions. The intensity of protonated methanol/ethanol (sample S) ion was almost linearly correlated with the intensity of H3O+(H2O)n, which pointed to the proton transfer reaction (PTR) mechanism. The reaction time was regulated by the electric field strength in the ionization region. The intensity variation trends of different ions with the reaction time indicated that a series of step-by-step ion-molecule reactions occurred in the ionization source, i.e., the primary ion CH2Cl+ reacted with H2O and converted to the intermediate product ions CH2OH+ and C2H4OH+, which then further reacted with H2O and led to the production of H3O+, and finally, the protonated sample ion SH+ was obtained through PTR with H3O+, as the ion-molecule reactions progressed. This study provides valuable insights into understanding the formation mechanism of some unexpected intermediate product ions and hydrated hydronium ions in dopant-enhanced VUV photoionization and also helps to optimize experimental conditions to enhance the sensitivity of OVOCs.

Systems pharmacology: a combination strategy for improving efficacy of PD-1/PD-L1 blockade.

Targeting tumor microenvironment (TME), such as immune checkpoint blockade (ICB), has achieved increased overall response rates in many advanced cancers, such as non-small cell lung cancer (NSCLC), however, only in a fraction of patients. To improve the overall and durable response rates, combining other therapeutics, such as natural products, with ICB therapy is under investigation. Unfortunately, due to the lack of systematic methods to characterize the relationship between TME and ICB, development of rational immune-combination therapy is a critical challenge. Here, we proposed a systems pharmacology strategy to identify resistance regulators of PD-1/PD-L1 blockade and develop its combinatorial drug by integrating multidimensional omics and pharmacological methods. First, a high-resolution TME cell atlas was inferred from bulk sequencing data by referring to a high-resolution single-cell data and was used to predict potential resistance regulators of PD-1/PD-L1 blockade through TME stratification analysis. Second, to explore the drug targeting the resistance regulator, we carried out the large-scale target fishing and the network analysis between multi-target drug and the resistance regulator. Finally, we predicted and verified that oxymatrine significantly enhances the infiltration of CD8+ T cells into TME and is a powerful combination agent to enhance the therapeutic effect of anti-PD-L1 in a mouse model of lung adenocarcinoma. Overall, the systems pharmacology strategy offers a paradigm to identify combinatorial drugs for ICB therapy with a systems biology perspective of drug-target-pathway-TME phenotype-ICB combination.

SIX1 amplification modulates stemness and tumorigenesis in breast cancer.

BACKGROUND: Sine oculis homeobox homolog 1 (SIX1) is a transcription factor that has recently been identified as a crucial regulator of embryonic development and tumorigenesis. SIX1 is upregulated in different types of tumors, including breast cancer. However, the role and mechanism of SIX1 upregulation in breast cancer carcinogenesis remains uncertain. METHODS: In this study, we utilized various databases such as UALCAN, TCGA, STRING, and Kaplan-Meier Plotter to investigate the mRNA expression, prognosis, transcriptional profile changes, signal pathway rewiring, and interaction with cancer stem cells of SIX1 in breast cancer. We also conducted both in vitro and in vivo experiments to validate its positive regulation effect on breast cancer stem cells. RESULTS: Our findings demonstrated that the expression of SIX1 varies among different subtypes of breast cancer and that it upregulates breast cancer grading and lymph node metastasis. Besides, SIX1 participates in the rewiring of several cancer signaling pathways, including estrogen, WNT, MAPK, and other pathways, and interacts with cancer stem cells. SIX1 showed a significant positive correlation with breast cancer stem cell markers such as ALDH1A1, EPCAM, ITGB1, and SOX2. Moreover, our in vitro and in vivo experiments confirmed that SIX1 can promote the increase in the proportion of stem cells and tumor progression. CONCLUSIONS: Altogether, our results suggest that SIX1 plays an essential regulatory role in breast cancer's occurrence, and its amplification can be utilized as a diagnostic and prognostic predictor. The interaction between SIX1 and cancer stem cells may play a critical role in regulating breast cancer's initiation and metastasis.

Physiological Responses of Methanosarcina barkeri under Ammonia Stress at the Molecular Level: The Unignorable Lipid Reprogramming.

Acetotrophic methanogens' dysfunction in anaerobic digestion under ammonia pressure has been widely concerned. Lipids, the main cytomembrane structural biomolecules, normally play indispensable roles in guaranteeing cell functionality. However, no studies explored the effects of high ammonia on acetotrophic methanogens' lipids. Here, a high-throughput lipidomic interrogation deciphered lipid reprogramming in representative acetoclastic methanogen (Methanosarcina barkeri) upon high ammonia exposure. The results showed that high ammonia conspicuously reduced polyunsaturated lipids and longer-chain lipids, while accumulating lipids with shorter chains and/or more saturation. Also, the correlation network analysis visualized some sphingolipids as the most active participant in lipid-lipid communications, implying that the ammonia-induced enrichment in these sphingolipids triggered other lipid changes. In addition, we discovered the decreased integrity, elevated permeability, depolarization, and diminished fluidity of lipid-supported membranes under ammonia restraint, verifying the noxious ramifications of lipid abnormalities. Additional analysis revealed that high ammonia destabilized the structure of extracellular polymeric substances (EPSs) capable of protecting lipids, e.g., declining α-helix/(ß-sheet + random coil) and 3-turn helix ratios. Furthermore, the abiotic impairment of critical EPS bonds, including C-OH, C═O-NH-, and S-S, and the biotic downregulation of functional proteins involved in transcription, translation, and EPS building blocks' supply were unraveled under ammonia stress and implied as the crucial mechanisms for EPS reshaping.

Biogenic ferrihydrite-humin coprecipitate as an electron donor for the enhancement of microbial denitrification by Pseudomonas stutzeri.

Nitrate pollution of groundwater has become an increasingly serious environmental problem that poses a great threat to aquatic ecosystems and to human health. Previous studies have shown that solid-phase humin (HM) can act as an additional electron donor to support microbial denitrification in the bioremediation of nitrate-contaminated groundwater where electron donor is deficient. However, the electron-donating capacities of HMs vary widely. In this study, we introduced ferrihydrite and prepared ferrihydrite-humin (Fh-HM) coprecipitates via biotic means to strengthen their electron-donating capacities. The spectroscopic results showed that the crystal phase of Fh did not change after coprecipitation with HM in the presence of Shewanella oneidensis MR-1, and iron may have complexed with the organic groups of HM. The Fh-HM coprecipitate prepared with an optimal initial Fh-HM mass ratio of 14:1 enhanced the microbial denitrification of Pseudomonas stutzeri with an electron-donating capacity 2.4-fold higher than that of HM alone, and the enhancement was not caused by greater bacterial growth. The alginate bead embedding assay indicated that the oxidation pathway of Fh-HM coprecipitate was mainly through direct contact between P. stutzeri and the coprecipitate. Further analyses suggested that quinone and organic-complexed Fe were the main electron-donating fractions of the coprecipitate. The results of the column experiments demonstrated that the column filled with Fh-HM-coated quartz sand exhibited a higher denitrification rate than the one filled with quartz sand, indicating its potential for practical applications.

Assessing the influencing factors of out-of-pocket costs on tuberculosis in Sichuan Province: a cross-sectional study.

BACKGROUND: Although diagnosis and treatment services for tuberculosis (TB) are provided free of charge in most countries, direct non-medical and indirect costs due to absenteeism, also place a significant burden on patients and their families. Sichuan Province has the second highest incidence of TB in China, with an incidence of approximately 100 cases per 100 000 people. However, there are limited research on out-of-pocket expenditure (OOPE) and its influencing factors in TB patients in Sichuan Province. METHODS: A retrospective cross-sectional study was conducted on TB patients in designated medical institutions for TB in Sichuan Province from 2017-2021. A face-to-face questionnaire was conducted to obtain the information related to hospitalization of patients, and the multi-level regression model was used to analyse the factors that influence OOPE and total out-of-pocket expenditure (TOOPE) of TB patients. RESULTS: A total of 2644 patients were investigated, and 74.24% of TB patients and their families experienced catastrophic total costs due to TB. The median total cost was 9223.37 CNY (1429.98 USD), in which the median direct and indirect costs of TB patients were 10185.00 CNY (1579.07 USD) and 2400.00 CNY (372.09 USD), respectively, and indirect costs contributed to 43% of total costs. The median OOPE and TOOPE costs were 6024.00 CNY (933.95 USD) and 11890.50 CNY (1843.49 USD), respectively. OOPE and TOOPE had common influencing factors including whether the patient's family had four or more members, a history of hospitalization, combination with other types of TB, the number of visits before diagnosis, and co-occurrence with chronic disease. CONCLUSIONS: The OOPE and TOOPE for TB patients and their families in Sichuan Province are still heavy. In the long run, it is necessary to strengthen education and awareness campaigns on TB related knowledge, disseminate basic medical knowledge to the public, improve healthcare-seeking behavior, and enhance the healthcare infrastructure to improve the accuracy of TB diagnosis and reduce the significant OOPE and TOOPE faced by TB patients and their families in Sichuan Province.

Dendrobium huoshanense Polysaccharide Improves High-Fat Diet Induced Liver Injury by Regulating the Gut-Liver Axis.

Dendrobium huoshanense is an important Traditional Chinese medicine that thickens the stomach and intestines. Its active ingredient Dendrobium huoshanense polysaccharide (DHP), was revealed to relieve the symptoms of liver injury. However, its mechanism of action remains poorly understood. This study aimed to investigate the mechanism of DHP in protecting the liver. The effects of DHP on lipid levels, liver function, and intestinal barrier function were investigated in mice with high-fat diet-induced liver damage. Changes in the gut flora and their metabolites were analyzed using 16S rRNA sequencing and metabolomics. The results showed that DHP reduced lipid levels, liver injury, and intestinal permeability. DHP altered the intestinal flora structure and increased the relative abundance of Bifidobacterium animalis and Clostridium disporicum. Furthermore, fecal metabolomics revealed that DHP altered fecal metabolites and significantly increased levels of gut-derived metabolites, spermidine, and indole, which have been reported to inhibit liver injury and improve lipid metabolism and the intestinal barrier. Correlation analysis showed that spermidine and indole levels were significantly negatively correlated with liver injury-related parameters and positively correlated with the intestinal species B. animalis enriched by DHP. Overall, this study confirmed that DHP prevented liver injury by regulating intestinal microbiota dysbiosis and fecal metabolites.

Circular RNA circ_0008305 aggravates hepatocellular carcinoma growth through binding to miR-186 and inducing TMED2.

Dysregulation of circRNAs is reported to exert crucial roles in cancers, including hepatocellular carcinoma (HCC). So far, the function of circRNAs in HCC development remains poorly known. Currently, our data showed that circ_0008305 was highly elevated in HCC cell lines and 30 paired tissue samples of HCC. As evidenced, suppression of circ_0008305 repressed HCC cell growth significantly. Meanwhile, up-regulation of circ_0008305 significantly reduced HCC cell growth. Mechanistically, we displayed that circ_0008305 could bind with miR-186 by using bioinformatics analysis. miR-186 has been reported to be a crucial tumour oncogene in many cancers. In addition, we proved miR-186 was greatly decreased in HCC. The direct correlation between miR-186 and circ_0008305 was confirmed in our work. In addition, up-regulation of miR-186 obviously restrained HCC progression. Increased expression of transmembrane p24 trafficking protein 2 (TMED2) is significantly related to the unfavourable outcomes in cancer patients. At our present work, we proved that TMED2 could act as a direct target of miR-186. Mechanistically, we demonstrated that circ_0008305 up-regulated TMED2 expression by sponging miR-186, which resulted in significantly induced HCC progression in vitro and in vivo. These revealed the significant role of circ_0008305 in HCC progression, which might indicate a new perspective on circRNAs in HCC development.

Comparison of dual mTORC1/2 inhibitor AZD8055 and mTORC1 inhibitor rapamycin on the metabolism of breast cancer cells using proton nuclear magnetic resonance spectroscopy metabolomics.

Dual mTORC1/2 inhibitors may be more effective than mTORC1 inhibitor rapamycin. Nevertheless, their metabolic effects on breast cancer cells have not been reported. We compared the anti-proliferative capacity of rapamycin and a novel mTORC1/2 dual inhibitor (AZD8055) in two breast cancer cell lines (MDA-MB-231 and MDA-MB-453) and analyzed their metabolic effects using proton nuclear magnetic resonance (1H NMR) spectroscopy-based metabolomics. We found that AZD8055 more strongly inhibited breast cancer cell proliferation than rapamycin. The half-inhibitory concentration of AZD8055 in breast cancer cells was almost one-tenth that of rapamycin. We identified 22 and 23 metabolites from the 1H NMR spectra of MDA-MB-231 and MDA-MB-453 cells. The patterns of AZD8055- and rapamycin-treated breast cancer cells differed significantly; we then selected the metabolites that contributed to these differences. For inhibiting glycolysis and reducing glucose consumption, AZD8055 was likely to be more potent than rapamycin. For amino acids metabolism, although AZD8055 has a broad effect as rapamycin, their effects in degrees were not exactly the same. AZD8055 and rapamycin displayed cell-specific metabolic effects on breast cancer cells, a finding that deserves further study. These findings help fill the knowledge gap concerning dual mTORC1/2 inhibitors and provide a theoretical basis for their development.

Visual typing detection of brucellosis with a lateral flow immunoassay based on coloured latex microspheres.

AIMS: Treatment and preventive control strategies for Brucella melitensis (B. melitensis) and Brucella abortus (B. abortus) infection differ. A lateral flow immunoassay (LFIA) for the rapid typing and detection of brucellosis by using polychromatic dye-doped latex microspheres (LMs) as a labelling material was developed. METHODS AND RESULTS: This LFIA utilizes a double-antigen sandwich method in which the BP26 protein is used as the diagnostic antigen to detect brucellosis infection and the OMP31 protein is used as the identified antigen to distinguish between bovine and sheep brucellosis. Thus, people and animals infected with brucellosis can be diagnosed according to the different colours of the signals displayed on the detection lines. The results indicated that the accuracy of this assay was found to reach 98%, and the immunochromatographic test strip is highly accurate, shows good sensitivity and can facilitate typing diagnosis, among other features. CONCLUSIONS: The established LFIA can distinguish B. melitensis infection from B. abortus infection and produces results in a short period of time while retaining the advantages of LFIAs. SIGNIFICANCE AND IMPACT OF THE STUDY: This technology lays a foundation for the development of multi-disease test strips and the establishment of methods for rapid, multi-specimen quantitative detection and is thus of great importance for the development of medical diagnostic technologies.