ABSTRACT
The secreted proteins of human body fluid have the potential to be used as biomarkers for diseases. These biomarkers can be used for early diagnosis and risk prediction of diseases, so the study of secreted proteins of human body fluid has great application value. In recent years, the deep-learning-based transformer language model has transferred from the field of natural language processing (NLP) to the field of proteomics, leading to the development of protein language models (PLMs) for protein sequence representation. Here, we propose a deep learning framework called ESM Predict Secreted Proteins (ESMSec) to predict three types of proteins secreted in human body fluid. The ESMSec is based on the ESM2 model and attention architecture. Specifically, the protein sequence data are firstly put into the ESM2 model to extract the feature information from the last hidden layer, and all the input proteins are encoded into a fixed 1000 × 480 matrix. Secondly, multi-head attention with a fully connected neural network is employed as the classifier to perform binary classification according to whether they are secreted into each body fluid. Our experiment utilized three human body fluids that are important and ubiquitous markers. Experimental results show that ESMSec achieved average accuracy of 0.8486, 0.8358, and 0.8325 on the testing datasets for plasma, cerebrospinal fluid (CSF), and seminal fluid, which on average outperform the state-of-the-art (SOTA) methods. The outstanding performance results of ESMSec demonstrate that the ESM can improve the prediction performance of the model and has great potential to screen the secretion information of human body fluid proteins.
Subject(s)
Body Fluids , Humans , Body Fluids/metabolism , Body Fluids/chemistry , Biomarkers , Deep Learning , Natural Language Processing , Proteomics/methods , Proteins/metabolism , Neural Networks, Computer , Computational Biology/methodsABSTRACT
With the rapid development of communication technology and detection technology, it is difficult for devices operating in a single spectrum to meet the application requirements of device integration and miniaturization, resulting in the exploration of multi-spectrum compatible devices. However, the functional design of different spectra is often contradictory and difficult to be compatible. In this work, a transparent slit circular metasurface with a high filling ratio is proposed to achieve the compatibility of microwave, infrared and visible light. In the microwave, based on the Pancharatnam-Berry phase theory, the continuous amplitude and binary phase can be customized only by rotating the slit angle to achieve an Airy beam function at 8-12â GHz. In the infrared, the mean infrared emissivity is reduced to 0.3 at 3-14â µm by maintaining high conductive filling ratio, and in visible light, based on the transparency of materials, the mean transmittance can achieve 50% at 400-800â nm. All the results can verify the multi-spectral compatibility performance, which can also verify the validity of our design method. Importantly, the multi-spectral compatible metasurface contributes an option for multifunctional integration, which can be further applied in communication, camouflage, and other fields.
ABSTRACT
Thrombolytic enzymes constitute a class of proteases with antithrombotic functions. Derived from natural products and abundant in nature, certain thrombolytic enzymes, such as urokinase, earthworm kinase, and streptokinase, have been widely used in the clinical treatment of vascular embolic diseases. Fly maggots, characterized by their easy growth and low cost, are a traditional Chinese medicine recorded in the Compendium of Materia Medica. These maggots can also be used as raw material for the extraction and preparation of thrombolytic enzymes (maggot kinase). In this review, we assembled global research reports on natural thrombolytic enzymes through a literature search and reviewed the functions and structures of natural thrombolytic enzymes to provide a reference for natural thrombophilic drug screening and development.
ABSTRACT
It is challenging to enhance the stress-free two-way shape memory (stress-free TWSM) effect to obtain a wide range of response temperatures. Herein, a polycaprolactone (PCL)/poly(ω-pentadecalactone) (PPDL) is photocured under UV light irradiation in the solvent of 1,1,2-trichloroethane (TCA), to obtain a series of cross-linked polyesters (CPES). Controlling solvent content (SC) which is removed after the polymerization allows the yielded CPES to perform a regulatable thermodynamic and stress-free TWSM properties. High SC is beneficial to reduce the degree of chain overlap (C/C* ) of PPDL chain segments in the PCL-based CPES network, then causes the cocrystallization of PCL and PPDL and yielding an additional melting-transitions (Tm ). An enhanced stress-free TWSM is obtained in high SC samples (CPES-15-90), reflected in the attainment of a wide range of response temperature, which means a wider service temperature. The enhancement is reflected in higher reversible strain of high SC samples compared with the samples prepared with low SC when varying high trigger temperature (Thigh ). Even at high Thigh , the high SC sample still has reversible strain. Therefore, controlling SC strategy for photocuring copolyester not only provides a new preparation approach for high-performance shape memory (SM) polymers, but also offers new condensed polymer structure to explore.
Subject(s)
Polyesters , Polymers , Temperature , Solvents , Polyesters/chemistry , Polymers/chemistry , ThermodynamicsABSTRACT
OBJECTIVE: To evaluate and summarize the relevant evidence of anticoagulation and bleeding risk management in patients with extracorporeal membrane oxygenation (ECMO), and provide the evidence-based basis for the management of anticoagulation and bleeding during ECMO treatment. METHODS: According to the evidence "6S" pyramid model, all evidence on ECMO anticoagulation management and bleeding risk was searched in relevant databases, organizations and guideline websites at home and abroad. Evidence types included guidelines, expert consensus, systematic evaluation, Meta-analysis and original study. The search time limit was from May 31, 2012 to May 31, 2022. Two researchers with evidence-based research background conducted independent literature quality evaluation of the retrieved evidence, and the evidence that met the quality standards was extracted and summarized based on the opinions of industry experts. RESULTS: A total of 315 articles were retrieved, and 13 articles were included, including 3 guidelines, 6 expert consensus, and 4 Meta-analysis. A total of 27 best evidences were summarized from 7 aspects, including the selection of ECMO anticoagulation, anticoagulation in priming, anticoagulation in operation, anticoagulation monitoring, bleeding and treatment, thrombosis and treatment, and prevention and management of terminal limb ischemia. CONCLUSIONS: This study provides evidence-based basis for bleeding prevention and anticoagulant management in ECMO patients. It is recommended to selectively apply the best evidence after evaluating the clinical environmental conditions of medical institutions, so as to improve the prognosis of ECMO patients.
Subject(s)
Extracorporeal Membrane Oxygenation , Thrombosis , Humans , Extracorporeal Membrane Oxygenation/adverse effects , Blood Coagulation , Hemorrhage/etiology , Anticoagulants/adverse effects , Thrombosis/drug therapy , Thrombosis/etiology , Thrombosis/prevention & control , Retrospective StudiesABSTRACT
Apolipoprotein E (ApoE) is a member of apolipoprotein (apo) family and plays critical role in lipid metabolism. In this study, the relationship between abnormal lipid metabolism caused by ApoE-deficient and male reproduction was investigated. The effect of hyperbaric oxygen (HBO) therapy on 7-month-old ApoE-knockout male mice was assessed subsequently. Mice were randomly divided into 3 groups: control group (WT), ApoE (- / -) group (AP-CON), and ApoE (- / -) plus HBO group (AP-HBO), which received HBO treatment. We found that ApoE knockout caused a decrease in male reproductive capacity due to the reduced total sperm motility, progressive motility (PR), and lower blastocyst formation rate. HBO treatment could accelerate serum lipoprotein metabolism including LDL, T-CHO, and TG and semen quality. As a result, fertilization and blastocyst formation of AP-HBO group were higher than that of AP-CON, proving positive therapeutic effect. Mechanism exploration found that HBO treatment ameliorated the testicular microenvironment by attenuating inflammatory factor production and oxidative stress, eventually improved the sperm motility. Collectively, our study provided more evidences of HBO treatment for improving the semen quality of patients with abnormal lipid metabolism caused by ApoE-deficient.
Subject(s)
Hyperbaric Oxygenation , Male , Mice , Animals , Testis , Mice, Knockout , Semen Analysis , Semen , Sperm Motility , Inflammation/therapy , Oxidative Stress , Apolipoproteins E/genetics , Spermatozoa , ApolipoproteinsABSTRACT
The age-related decay in oocyte quality contributes to the gradual decline in fertility and the final occurrence of natural sterility. In this study, we aimed to investigate the effects of the hyperbaric oxygen treatment (HBOT) on oocyte quality in aging mouse oocyte. Eight- and forty-week-old female C57BL/6 J mice were treated with HBO for 10 days, and the quality of oocytes was analyzed. The results revealed that HBOT improved the age-related serum AMH levels. While compared with untreated aged mice, HBOT showed reduced follicular apoptosis and improved oocyte maturation, fertilization, and blastocyst formation in aged mice. HBO triggered changes in the microRNA expression in the ovaries of aged mice. In this study, 27 DEGs were identified in the HBOT mouse ovarian tissues, of which 9 were upregulated and 18 were downregulated. Notably, KEGG analysis revealed that these genes involved in different biological processes differed significantly in the ovary. Among these, the PI3K-Akt signaling was the most prominent pathway that controlled the recruitment and growth of primordial follicles. The calcium signaling pathway was found to be involved during the peri-implantation period. These results suggest that HBOT can be applied to improve the quality of oocytes, and it could be a potential clinical application to improve the fertility of aged female.
Subject(s)
Hyperbaric Oxygenation , Animals , Female , Mice , Oxygen , Phosphatidylinositol 3-Kinases/metabolism , Mice, Inbred C57BL , Oocytes/metabolism , FertilityABSTRACT
Background and objectives: The objective of this study is to investigate the outcomes of concurrent platinum-based chemoradiation therapy (CCRT), laparoscopic nerve-sparing ultra-radical hysterectomy (LNSURH), and open radical hysterectomy (ORH) on patients with locally advanced cervical carcinoma (LACC). Methods: A single-center retrospective study was conducted on LACC patients who received CCRT, ORH, or LNSURH from January 2011 to December 2019. Data on age, tumor size, overall survival (OS), disease-free survival (DFS), and early and late morbidities were collected. After 24 months of treatment, patients were asked a series of questions about their urinary, bowel, and sexual activities. Early morbidities were defined as those occurring during or within a month of treatment, whereas late morbidities and complications were defined as those occurring a month after treatment. The postoperative complications were classified with reference to the Clavien-Dindo classification (CD) system. Results: The Kaplan-Meier curves revealed no significant differences in OS and DFS among the three groups (P = 0.106 for DFS and P = 0.190 for OS). The rates of early complications in the CCRT group were comparable with those in the operated groups (P = 0.46). However, late complications were significantly lower in the ORH and LNSURH groups relative to those in the CCRT group. The scores of urinary and bowel functions were restored to the pretreatment state, although the sexual function scores were not satisfactory. Conclusions: The treatments of CCRT, ORH, and LNSURH can be considered options for patients with LACC, as their OS and DFS showed no significant difference. In addition, LNSURH exhibited a lower incidence of late complications and high sexual function scores.
ABSTRACT
MOTIVATION: The capability to predict the potential drug binding affinity against a protein target has always been a fundamental challenge in silico drug discovery. The traditional experiments in vitro and in vivo are costly and time-consuming which need to search over large compound space. Recent years have witnessed significant success on deep learning-based models for drug-target binding affinity prediction task. RESULTS: Following the recent success of the Transformer model, we propose a multigranularity protein-ligand interaction (MGPLI) model, which adopts the Transformer encoders to represent the character-level features and fragment-level features, modeling the possible interaction between residues and atoms or their segments. In addition, we use the convolutional neural network to extract higher-level features based on transformer encoder outputs and a highway layer to fuse the protein and drug features. We evaluate MGPLI on different protein-ligand interaction datasets and show the improvement of prediction performance compared to state-of-the-art baselines. AVAILABILITY AND IMPLEMENTATION: The model scripts are available at https://github.com/IILab-Resource/MGDTA.git.
Subject(s)
Neural Networks, Computer , Proteins , Ligands , Proteins/chemistry , Drug DiscoveryABSTRACT
Measuring the semantic similarity between Gene Ontology (GO) terms is a fundamental step in numerous functional bioinformatics applications. To fully exploit the metadata of GO terms, word embedding-based methods have been proposed recently to map GO terms to low-dimensional feature vectors. However, these representation methods commonly overlook the key information hidden in the whole GO structure and the relationship between GO terms. In this paper, we propose a novel representation model for GO terms, named GT2Vec, which jointly considers the GO graph structure obtained by graph contrastive learning and the semantic description of GO terms based on BERT encoders. Our method is evaluated on a protein similarity task on a collection of benchmark datasets. The experimental results demonstrate the effectiveness of using a joint encoding graph structure and textual node descriptors to learn vector representations for GO terms.
Subject(s)
Computational Biology , Semantics , Computational Biology/methods , Gene Ontology , MetadataABSTRACT
Pharmacokinetics/pharmacodynamics is the foundation for guiding the rational application of antibiotics in clinical practice, so it is necessary to establish quantitative methods for accurate drug concentration determination. This study aimed to develop a rapid and simple ultrahigh-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method for simultaneous quantification of 14 antibiotics (amikacin, etimicin, ceftazidime, cefepime, cefoperazone, ceftriaxone, daptomycin, latamoxef, linezolid, meropenem, biapenem, ampicillin, norvancomycin, and vancomycin) in human plasma and cerebrospinal fluid. Antibiotics were chromatographically separated on a Waters ACQUITY UPLC BEH C18 column (2.1 mm × 50 mm, 1.7 µm) via gradient elution within 3 minutes and were monitored using positive ion fitted with multiple reaction monitoring. The lower limit of quantification was 0.05-2.0 µg·mL-1. The method was verified according to the FDA bioanalysis method validation guidelines, which showed excellent accuracy (from 86.75% to 110.85%) and precision (from 0.46% to 10.97%). At last, this method was successfully applied to therapeutic drug monitoring in 113 patients under antibiotics treatment.
ABSTRACT
As a serine/threonine phosphatase, protein phosphatase 2A (PP2A) is essential in numerous physiological processes. By generating a catalytic subunit of PP2A (Ppp2ca) conditional knockout (CKO) in C57BL/6 J mice, we explored the possible mechanisms of azoospermia by focusing on meiosis initiation and spermatogenesis. The deficiency of Ppp2ca in germ cells conspicuously disturbed spermatogonial differentiation and led to pachynema arrest, accompanied by significant apoptosis in germ cells and defects in programmed double-strand break (DSB) repair. While the formation of XY body was normal, respectively. Ppp2ca-deficient spermatocytes exhibited an abnormal cohesion complex degradation of chromosome, probably contributing to cell death. Furthermore, transcriptomics analysis was conducted to prove several genes involved in spermatogenesis and exhibited transcriptional dysregulations in Ppp2ca-deficient testes. Our study demonstrates the irreplaceable role of PP2A in spermatogenesis and provides more evidences of azoospermia etiology.
Subject(s)
Azoospermia , Protein Phosphatase 2 , Spermatocytes , Animals , Male , Mice , Azoospermia/genetics , Catalytic Domain , Meiosis , Meiotic Prophase I , Mice, Inbred C57BL , Mice, Knockout , Protein Phosphatase 2/genetics , Protein Phosphatase 2/metabolism , Spermatocytes/metabolism , Spermatogenesis/geneticsABSTRACT
BACKGROUND: Because responses of patients with cancer to immunotherapy can vary in success, effective biomarkers are urgently needed for predicting clinical response with anti-PD-1 treatment. We aimed to evaluate the IL-5 and IFN-γ level with the response of anti-PD-1 blockade in non-small-cell lung cancer (NSCLC) and gastric cancer (GC). METHODS: Metastatic NSCLC and GC patients treated with anti-PD-1 monoclonal antibody were studied. Blood samples were taken before PD-1 McAb treatment, after the first cycle treatment, and during efficacy evaluation. The association between IL-5 and IFN-γ levels and clinical response were analyzed by the nonparametric Wilcoxon matched-pairs ranked tests. The progression-free survival (PFS) time was obtained by imaging evaluation and telephone follow-up of all the patients. Kaplan-Meier and the log rank test were used to plot the survival curve. RESULTS: IL-5 and IFN-γ levels were detected in the peripheral blood of 40 NSCLC and 35 GC patients who have received anti-PD-1 treatment. In effective group, IL-5 and IFN-γ levels at best response points significantly decreased (P < 0.001) compared with pretherapeutic levels in NSCLC and GC patients with lymph node or distant metastasis. Compared with pretherapeutic levels, IL-5 and IFN-γ levels largely increased as the tumor progresses (P < 0.01). Higher IL-5 and IFN-γ levels before treatment indicated shorter progression-free survival in patients with NSCLC metastasis (P = 0.007, P = 0.0111). Moreover, their levels also accurately reflected the pseudoprogression of two NSCLC patients to anti-PD-1 treatment. CONCLUSIONS: Our results suggested that serum IL-5 and IFN-γ levels could be an effective indicator for predicting clinical efficacy and survival with anti-PD-1 blockade in NSCLC and GC patients.
Subject(s)
Antibodies, Monoclonal, Humanized/therapeutic use , Carcinoma, Non-Small-Cell Lung/drug therapy , Carcinoma/drug therapy , Immune Checkpoint Inhibitors/therapeutic use , Interferon-gamma/blood , Interleukin-5/blood , Stomach Neoplasms/drug therapy , Adult , Aged , Aged, 80 and over , Biomarkers, Tumor/blood , Carcinoma/blood , Carcinoma/mortality , Carcinoma, Non-Small-Cell Lung/blood , Carcinoma, Non-Small-Cell Lung/mortality , Clinical Decision Rules , Female , Follow-Up Studies , Humans , Immunotherapy , Male , Middle Aged , Stomach Neoplasms/blood , Stomach Neoplasms/mortality , Survival Analysis , Treatment OutcomeABSTRACT
Vitamin D (VD) is not only associated with bone growth and development, but is also closely associated with numerous other pathological conditions. The present study aimed to investigate the effect of microRNA (miRNA/miR)378d on ovarian granulosa cells by regulating the round spermatid basic protein 1 (Rsbn1) in the absence of VD. The abnormal expression of miRNAs in ovarian tissues of the VDdeficient mouse was analyzed using transcriptome sequencing. miR378d, glucose transporter 4 (Glut4) and aromatase (Cyp19a) expression levels were examined via reverse transcriptionquantitative (RTq)PCR and western blotting. The expression levels of Rsbn1, Glut4 and Cyp19a were detected in transfected mouse ovarian granulosa cells. The targeting regulation between miR378d and Rsbn1 was verified using double reporter gene assay and functional rescue experiments. Among the 672 miRNAs that were differentially expressed, cluster analysis revealed that 17 were significantly upregulated and 16 were significantly downregulated. Moreover, miR378d showed significant upregulation, which was further verified via RTqPCR. It was identified that the protein expression level of Rsbn1 was significantly downregulated. Furthermore, Glut4 mRNA expression was significantly decreased in the mimic group but markedly increased in the inhibitor group. By contrast, the mRNA expression levels of Rsbn1 and Cyp19a did not demonstrate any significant difference. The western blotting results indicated that the protein expression levels of Rsbn1 and Glut4 were decreased and increased, respectively, while Cyp19a did not show any significant change. In addition, the double reporter gene experiments confirmed that Rsbn1 was the target gene of miR378d. Collectively, the present results demonstrated that miR378d was abnormally overexpressed in the ovarian tissues of the VDdeficient mice, and that miR378d could inhibit Glut4 production by targeting Rsbn1, which may lead to insulin resistance.
Subject(s)
Glucose Transporter Type 4/genetics , Homeodomain Proteins/genetics , MicroRNAs/genetics , Seminal Plasma Proteins/genetics , Vitamin D Deficiency/genetics , Animals , Female , Granulosa Cells/metabolism , Granulosa Cells/pathology , Humans , Insulin Resistance/genetics , Mice , Polycystic Ovary Syndrome/genetics , Polycystic Ovary Syndrome/metabolism , Polycystic Ovary Syndrome/pathology , Signal Transduction/genetics , Vitamin D/genetics , Vitamin D/metabolism , Vitamin D Deficiency/pathologyABSTRACT
BACKGROUND: To determine the phenotype, molecular characterisation and risk factors of postoperative meningitis induced by Extended-spectrum ß-lactamase (ESBL)-producing Enterobacteriaceae (EPE) in China. METHODS: We performed a multi-centre comparative cohort study of postoperative meningitis patients infected with Enterobacteriaceae in 4 neurosurgical centres in China from January 2014 to December 2019. Phenotype and molecular characteristics of the isolates were reviewed and tested, and independent risk factors of the EPE meningitis were evaluated by binary logistic regression. RESULTS: In total, 220 Enterobacteriaceae include 78 EPE were available in this study. 85.6% (67/78) ESBL-related genes were tested, and blaSHV (14.9%) and blaSHV + blaTEM + blaCTX-M-9 (20.9%) were found to be the most frequent mono and combined ESBL-related genes harboured by Enterobacteriaceae. On binary logistic analysis, craniotomy (OR. 2.583, 95% C.I. 1.274-5.235, P = 0.008) and malignancy (OR. 2.406, 95% C.I. 1.299-4.456, P = 0.005) were the associated independent risk factors to meningitis induced by EPE. CONCLUSIONS: To the best of our knowledge, this is the largest series focusing on risk factors of EPE meningitis which has been conducted in China. Craniotomy and malignancy were independent risk factors for EPE meningitis. The risk factors identified may be further utilized in clinical practice and research to avoid and reduce the mortality in future.
Subject(s)
Enterobacteriaceae Infections/epidemiology , Enterobacteriaceae/isolation & purification , Meningitis, Bacterial/epidemiology , beta-Lactamases/metabolism , Adult , China/epidemiology , Cohort Studies , Enterobacteriaceae/genetics , Enterobacteriaceae/metabolism , Enterobacteriaceae Infections/cerebrospinal fluid , Enterobacteriaceae Infections/microbiology , Female , Humans , Male , Meningitis, Bacterial/cerebrospinal fluid , Meningitis, Bacterial/microbiology , Phenotype , Polymerase Chain Reaction , Postoperative Complications/cerebrospinal fluid , Postoperative Complications/epidemiology , Postoperative Complications/microbiology , Retrospective Studies , Risk FactorsABSTRACT
BACKGROUND: In polycystic ovary syndrome (PCOS), ovarian physiology is tightly linked to the metabolic disturbances observed in this disease. Vitamin D (VD) plays an important role in the regulation of ovulatory dysfunction and can influence genes involved in steroidogenesis in granulosa cells (GCs). However, its role in the proliferation and apoptosis of ovarian GCs is unclear. The present study aimed to investigate the role of microRNA-196-5p (miR-196b-5p) in the hormone synthesis, proliferation, and apoptosis of ovarian GCs. METHODS: The abnormal expression of miRNAs in ovarian tissues of VD-deficient mice was analyzed using transcriptome sequencing. The direct target of miR-196b-5p was predict and confirmed by bioinformatics analysis and the dual-luciferase reporter assay. Reverse transcription-quantitative PCR (RT-qPCR) was used to detect the levels of miR-196b-5p, cell proliferation was detected via the CCK8 assay, and cell apoptosis and reactive oxygen species (ROS) were measured via flow cytometry. The levels of radixin (RDX), leucine rich repeat containing 17 (LRRC17), aromatase (CYP19A1), and glucose transporter 4 (GLUT4) were detected by performing RT-qPCR or western blot. RESULTS: We found that miR-196b-5p was significantly downregulated among the 672 miRNAs that were differentially expressed (DE) in VD-deficient mice. In addition, the results demonstrated that downregulated expression of miR-196b-5p significantly increased the level of RDX and LRRC17, and reduced expression of miR-196b-5p significantly promoted ovarian GC apoptosis and inhibited cell proliferation. Downregulated expression of miR-196b-5p promoted cellular ROS production and inhibited sex hormone production and glucose uptake. Transfection with miR-196b-5p mimics significantly increased the expression of CYP19A1 and GLUT4 and decreased the RDX and LRRC17 levels in ovarian GCs. CONCLUSIONS: This study shows that miR-196b-5p can regulate the oxidative stress (OS), glucose uptake, and steroid production pathway of GCs, thus promoting follicular development and maturation. This is a step towards a feasible treatment for PCOS.
ABSTRACT
It has been reported that the impaired cytotoxicity of natural killer (NK) cells and abnormal cytokines that are changed by the interaction between ectopic endometrial cells and immune cells is indispensable for the initiation and development of endometriosis (EMS). However, the mechanism of NK cells dysfunction in EMS remains largely unclear. Here, we found that NK cells in peritoneal fluid from women with EMS highly expressed indoleamine 2,3-dioxygenase (IDO). Furthermore, IDO+NK cells possessed lower NKp46 and NKG2D but higher IL-10 than that of IDO-NK. Co-culture with endometrial stromal cells (nESCs) from healthy control or ectopic ESCs (eESCs) from women with EMS led to a significant increase in the IDO level in NK cells from peripheral blood, particularly eESCs, and an anti-TGF-ß neutralizing antibody suppressed these effects in vitro. NK cells co-cultured with ESC more preferentially inhibited the viability of nESCs than eESCs did, and pretreating with 1-methyl-tryptophan (1-MT), an IDO inhibitor, reversed the inhibitory effect of NK cells on eESC viability. These data suggest that ESCs induce IDO+NK cells differentiation partly by TGF-ß, and that IDO further restricts the cytotoxicity of NK cells in response to eESCs, which provides a potential therapeutic strategy for EMS patients, particularly those with a high number of impaired cytotoxic IDO+NK cells.
Subject(s)
Endometriosis/immunology , Endometrium/immunology , Indoleamine-Pyrrole 2,3,-Dioxygenase/metabolism , Killer Cells, Natural/enzymology , Adult , Ascitic Fluid/immunology , Case-Control Studies , Cells, Cultured , Endometrium/cytology , Female , Humans , Middle Aged , NK Cell Lectin-Like Receptor Subfamily K/metabolism , Natural Cytotoxicity Triggering Receptor 1/metabolism , Stromal Cells/immunology , Transforming Growth Factor beta/metabolism , Young AdultABSTRACT
INTRODUCTION: Ovarian cancer is the most deadly gynecologic cancer, and the therapy is very difficult. Apatinib is a novel tyrosine kinase inhibitor targeting vascular endothelial growth factor receptor-2. At present, there are few studies or case reports on apatinib treatment for patients with ovarian cancer. CASE PRESENTATION: A 75-year-old Chinese woman had a medical history of ovarian high-grade serous papillary adenocarcinoma, who got many lines of chemotherapy and apatinib-an antiangiogenesis drug therapy. Either alone or in combination, apatinib may extend the survival time of patients with advanced ovarian cancer. CONCLUSION: Apatinib may be an option for advanced ovarian cancer after failure of chemotherapy or other targeted therapy. The role of apatinib in the treatment of advanced ovarian cancer needs further study.
Subject(s)
Adenocarcinoma, Papillary/drug therapy , Ovarian Neoplasms/drug therapy , Pyridines/therapeutic use , Vascular Endothelial Growth Factor A/antagonists & inhibitors , Adenocarcinoma, Papillary/pathology , Aged , Antineoplastic Agents/therapeutic use , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , CA-125 Antigen/blood , Disease-Free Survival , Female , Folic Acid Antagonists/therapeutic use , Humans , Membrane Proteins/blood , Neoplasm Metastasis/drug therapy , Ovarian Neoplasms/pathology , Pemetrexed/administration & dosage , Pemetrexed/adverse effects , Pemetrexed/therapeutic use , Protein Kinase Inhibitors/therapeutic use , Pyridines/administration & dosage , Pyridines/adverse effects , Recurrence , Treatment OutcomeABSTRACT
An intravenously injectable liquid formulation of the poorly water-soluble isosteviol sodium (ISVNa) that has a great clinical potential for cardiovascular diseases was developed using the co-solvent technology. The pH and composition of the co-solvent were optimized to obtain a stable liquid formulation (termed as STVNa) based on saline at pH 10.0 containing 25% (v/v) of ethanol and 20% (v/v) of propylene glycol. STVNa was physicochemically stable upon storage for more than 3 months under various conditions. In vitro studies showed that STVNa did not induce hemolytic effects up to 9.1% (v/v) after 3 h of incubation and it was cytocompatible up to 50 µg/mL in H2C9 cells. Furthermore, STVNa showed acceptable safety and pharmacokinetic parameters comparable with those of ISVNa in saline (dissolved at 60 °C) upon i.v. injection in Wistar rats. Overall, the results demonstrated that STVNa is a promising formulation of ISVNa for clinical translation.
Subject(s)
Diterpenes, Kaurane/administration & dosage , Diterpenes, Kaurane/blood , Ethanol/chemistry , Pharmaceutical Vehicles/chemistry , Propylene Glycol/chemistry , Administration, Intravenous , Animals , Cell Line , Diterpenes, Kaurane/chemistry , Drug Compounding , Drug Stability , Ethanol/toxicity , Hemolysis/drug effects , Humans , Hydrogen-Ion Concentration , Pharmaceutical Vehicles/toxicity , Propylene Glycol/toxicity , Rats, Wistar , Solubility , Solvents/chemistry , Solvents/toxicity , Water/chemistryABSTRACT
Endometriosis (EMS) is associated with an abnormal immune response to endometrial cells, which can facilitate the implantation and proliferation of ectopic endometrial tissues. It has been reported that human endometrial stromal cells (ESCs) express interleukin (IL)15. The aim of our study was to elucidate whether or not IL15 regulates the cross talk between ESCs and natural killer (NK) cells in the endometriotic milieu and, if so, how this regulation occurs. The ESC behaviors in vitro were verified by Cell Counting Kit-8 (CCK-8), Annexin/PI, and Matrigel invasion assays, respectively. To imitate the local immune microenvironment, the co-culture system between ESCs and NK cells was constructed. The effect of IL15 on NK cells in the co-culture unit was investigated by flow cytometry (FCM). In this study, we found that ectopic endometrium from patients with EMS highly expressed IL15. Rapamycin, an autophagy inducer, decreased the level of IL15 receptors (i.e. IL15Rα and IL2Rß). IL15 inhibits apoptosis and promotes the invasiveness, viability, and proliferation of ESCs. Meanwhile, a co-culture with ESCs led to a decrease in CD16 on NK cells. In the co-culture system, IL15 treatment downregulated the levels of Granzyme B and IFN-γ in CD16(+)NK cells, NKG2D in CD56(dim)CD16(-)NK cells, and NKP44 in CD56(bright)CD16(-)NK cells. On the one hand, these results indicated that IL15 derived from ESCs directly stimulates the growth and invasion of ESCs. On the other hand, IL15 may help the immune escape of ESCs by suppressing the cytotoxic activity of NK cells in the ectopic milieu, thereby facilitating the progression of EMS.