Diagnostic Value of GDF10 for the Tumorigenesis and Immune Infiltration in Lung Squamous Cell Carcinoma.

OBJECTIVE: Lung squamous cell carcinoma (LUSC) is associated with a low survival rate. Evidence suggests that bone morphogenetic proteins (BMPs) and their receptors (BMPRs) play crucial roles in tumorigenesis and progression. However, a comprehensive analysis of their role in LUSC is lacking. Our study aimed to explore the relationship between BMPs/BMPRs expression levels and the tumorigenesis and prognosis of LUSC. METHODS: The "R/Limma" package was utilized to analyze the differential expression characteristics of BMPs/BMPRs in LUSC, using data from TCGA, GTEx, and GEO databases. Concurrently, the "survminer" packages were employed to investigate their prognostic value and correlation with clinical features in LUSC. The core gene associated with LUSC progression was further explored through weighted gene correlation network analysis (WGCNA). LASSO analysis was conducted to construct a prognostic risk model for LUSC. Clinical specimens were examined by immunohistochemical analysis to confirm the diagnostic value in LUSC. Furthermore, based on the tumor immune estimation resource database and tumor-immune system interaction database, the role of the core gene in the tumor microenvironment of LUSC was explored. RESULTS: GDF10 had a significant correlation only with the pathological T stage of LUSC, and the protein expression level of GDF10 decreased with the tumorigenesis of LUSC. A prognostic risk model was constructed with GDF10 as the core gene and 5 hub genes (HRASLS, HIST1H2BH, FLRT3, CHEK2, and ALPL) for LUSC. GDF10 showed a significant positive correlation with immune cell infiltration and immune checkpoint expression. CONCLUSION: GDF10 might serve as a diagnostic biomarker reflecting the tumorigenesis of LUSC and regulating the tumor immune microenvironment to guide more effective treatment for LUSC.

Identification and validation of DPY30 as a prognostic biomarker and tumor immune microenvironment infiltration characterization in esophageal cancer.

Esophageal cancer (ESCA) is a lethal malignancy and is associated with the alterations of various genes and epigenetic modifications. The protein dpy-30 homolog (DPY30) is a core member of histone H3K4 methylation catalase and its dysfunction is associated with the occurrence and development of cancer. Therefore, the present study investigated the role of DPY30 in ESCA and evaluated the association between the expression of DPY30, the clinicopathological characteristics of ESCA and the tumor immune microenvironment. It conducted a comprehensive analysis of DPY30 in patients with ESCA using The Cancer Genome Atlas (TCGA) database and clinical tissue microarray specimens of ESCA. Immunohistochemistry was performed to assess the expression levels of DPY30 in tissues. Receiver operating curve analysis, Kaplan-Meier survival analysis and Cox regression analysis were performed to identify the diagnostic and prognostic value of DPY30. Gene Set Enrichment Analysis, protein-protein interaction network and Estimation of Stromal and Immune cells in Malignant Tumor tissues using the Expression data were used to screen DPY30-associated genes and evaluate the immune score of the TCGA samples. The results demonstrated that the expression of mRNA and protein levels of DPY30 were significantly upregulated in tumor tissues compared with normal tissue samples. The expression of DPY30 was closely associated with the poor prognosis of patients with ESCA. The present study also found that DPY30 expression and the pathological characteristics of ESCA were significantly correlated. Additionally, the expression of DPY30 demonstrated a significant positive correlation with various immune cells infiltration. The results suggested that DPY30 might influence tumor immune infiltration. In conclusion, the findings suggested that DPY30 might be a potential prognostic biomarker and an immunotherapeutic target in ESCA.

Downregulation of T-cell cytotoxic marker IL18R1 promotes cancer proliferation and migration and is associated with dismal prognosis and immunity in lung squamous cell carcinoma.

Immunotherapy can improve the survival of patients with advanced lung squamous cell carcinoma (LUSC). T cytotoxic cells are one of the main members of the immune microenvironment. Herein, we aimed to identify the roles of T-cell cytotoxic markers interleukin 18 (IL18) receptor 1 (IL18R1) in the LUSC progression using bioinformatics, clinical tissue specimen, and cell experiment. We assessed the association between the IL18R1 expression and immune infiltration and IL18R1-related competing RNA network. The IL18R1 expression was downregulated in the LUSC tissues. The IL18R1 expression downregulation was associated with diagnosis and short overall survival and disease-specific survival, and it was also an independent risk factor for dismal survival time in LUSC. IL18R1-related nomograms predicted the survival time of patients with LUSC. IL18R1 overexpression inhibited the proliferation, migration, and invasion of LUSC cells. The IL18R1 expression was significantly associated with the microenvironment (stromal, immune, and estimate scores), immune cells (such as the T cells, cytotoxic cells, CD8 T cells), and immune cell markers (such as the CD8A, PD-1, and CTLA4) in LUSC. AC091563.1 and RBPMS-AS1 downregulation was positively associated with the IL18R1 expression, negatively associated with the miR-128-3p expression, and associated with short disease-specific survival and progression in LUSC. In conclusion, IL18R1 was significantly downregulated and associated with the prognosis and immune microenvironment. IL18R1 overexpression inhibits the growth and migration of cancer cells in LUSC. Furthermore, AC091563.1 and RBPMS-AS1 might compete with IL18R1 to bind miR-128-3p for participating in LUSC progression. These results showed that IL18R1 is a biomarker for evaluating the prognosis of patients with LUSC.

Enhancing Enzyme Activity by the Modulation of Covalent Interactions in the Confined Channels of Covalent Organic Frameworks.

Controllable regulations on the enzyme conformation to optimize catalytic performance are highly desired for the immobilized biocatalysts yet remain challenging. Covalent organic frameworks (COFs) possess confined channels with finely tunable pore environment, offering a promising platform for enzyme encapsulation. Herein, we covalently immobilized the cytochrome c (Cyt c) in the size-matched channels of COFs with different contents of anchoring site, and significant enhancement of the stability and activity (≈600 % relative activity compared with free enzyme) can be realized by optimizing the covalent interactions. Structural analyses on the immobilized Cyt c suggest that covalent bonding could induce conformational perturbation resulting in more accessible active sites. The effectiveness of the covalent interaction modulation together with the tailorable confined channels of COFs offers promise to develop high-performance biocatalysts.

microRNA-21-5p from M2 macrophage-derived extracellular vesicles promotes the differentiation and activity of pancreatic cancer stem cells by mediating KLF3.

AIM: Given the fact that tumor-associated macrophage-derived extracellular vesicles (EVs) are attributable to tumor aggressiveness, this research intends to decode the mechanism of M2 macrophage-derived EVs in the differentiation and activities of pancreatic cancer (PaCa) stem cells via delivering microRNA (miR)-21-5p. METHODS: Polarized M2 macrophages were induced, from which EVs were collected and identified. miR-21-5p expression in M2 macrophage-derived EVs was tested. After cell sorting, CD24+CD44+EpCAM+ stem cells were co-cultured with M2 macrophages, in which miR-21-5p was upregulated or downregulated. The effects of M2 macrophage-derived EVs and miR-21-5p on Nanog/octamer-binding transcription factor 4 (Oct4) expression, sphere formation, colony formation, invasion and migration capacities, apoptosis, and in vivo tumorigenic ability were examined. Krüppel-like factor 3 (KLF3) expression and its interaction with miR-21-5p were determined. RESULTS: M2 macrophage-derived EVs promoted PaCa stem cell differentiation and activities. miR-21a-5p was upregulated in M2 macrophage-derived EVs. miR-21a-5p downregulation in M2 macrophage-derived EVs inhibited Nanog/Oct4 expression and impaired sphere-forming, colony-forming, invasion, migration, and anti-apoptosis abilities of PaCa stem cells in vitro and tumorigenic ability in vivo. miR-21-5p targeted KLF3 to mediate the differentiation and activities of PaCa stem cells, and KLF3 was downregulated in PaCa stem cells. CONCLUSION: This work explains that M2 macrophage-derived exosomal miR-21a-5p stimulates differentiation and activity of PaCa stem cells via targeting KLF3, paving a novel way for attenuating PaCa stemness.

MiRNA-122 Promotes Ischemia-Reperfusion Injury after Lung Transplantation via the Toll-like Receptor Signaling Pathway.

OBJECTIVE: MiRNAs have been recently implicated in the pathogenesis of ischemia-reperfusion (IR) injury. This study aimed to investigate the miRNA expression profiles in the early stages after lung transplantation (LT) and to study the involvement of the Toll-like receptor (TLR) signaling pathway in lung IR injury following LT. METHODS: We established the left LT model in mice and selected the miRNA-122 as a research target. The mice were injected with a miRNA-122-specific inhibitor, following which pathological changes in the lung tissue were studied using different lung injury indicators. In addition, we performed deep sequencing of transplanted lung tissues to identify differentially expressed (DE) miRNAs and their target genes. These target genes were used to further perform gene ontology (GO) enrichment analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis. RESULTS: A total of 12 DE miRNAs were selected, and 2476 target genes were identified. The GO enrichment analysis predicted 6063 terms, and the KEGG analysis predicted 1554 biological pathways. Compared with the control group, inhibiting the expression of miRNA-122 significantly reduced the lung injury and lung wet/dry ratio (P<0.05). In addition, the activity of myeloperoxidase and the expression levels of tumor necrosis factor-alpha and TLR2/4 were decreased (P<0.05); whereas the expression of interleukin-10 was increased (P<0.05). Furthermore, the inhibition of miRNA-122 suppressed the IR injury-induced activation of the TLR signaling pathway. CONCLUSION: Our findings showed the differential expression of several miRNAs in the early inflammatory response following LT. Of these, miRNA-122 promoted IR injury following LT, whereas its inhibition prevented IR injury in a TLR-dependent manner.

Hydrophilicity gradient in covalent organic frameworks for membrane distillation.

Desalination can help to alleviate the fresh-water crisis facing the world. Thermally driven membrane distillation is a promising way to purify water from a variety of saline and polluted sources by utilizing low-grade heat. However, membrane distillation membranes suffer from limited permeance and wetting owing to the lack of precise structural control. Here, we report a strategy to fabricate membrane distillation membranes composed of vertically aligned channels with a hydrophilicity gradient by engineering defects in covalent organic framework films by the removal of imine bonds. Such functional variation in individual channels enables a selective water transport pathway and a precise liquid-vapour phase change interface. In addition to having anti-fouling and anti-wetting capability, the covalent organic framework membrane on a supporting layer shows a flux of 600 l m-2 h-1 with 85 °C feed at 16 kPa absolute pressure, which is nearly triple that of the state-of-the-art membrane distillation membrane for desalination. Our results may promote the development of gradient membranes for molecular sieving.

Monocytes promote pyroptosis of endothelial cells during lung ischemia-reperfusion via IL-1R/NF-κB/NLRP3 signaling.

In our previous study, we observed that donor pulmonary intravascular nonclassical monocytes play a major role in early PGF, but the specific mechanism remained unclear. In this study, we investigated the mechanistic role of monocytes in inducing pyroptosis of human pulmonary microvascular endothelial cells (HPMECs) during IRI. A murine hilar ligation model of IRI was utilized whereby left lungs underwent 1 h of ischemia and 23 h of reperfusion. Monocyte depletion by intraperitoneal clodronate-liposome treatment on pulmonary edema and pyroptosis activation were determined. In vitro experiments, we performed the co-culture experiments under hypoxia-reoxygenation (H/R) conditions to mimic the IRI environment. We monitored the expression of NLRP3, caspase-1 and IL-1ß in co-cultures of monocytes (U937 cells) and HPMECs under H/R conditions. NLRP3, IL-1ß and IL-1R siRNA knockdown, caspase-1 and NF-κB pathway inhibitors were employed to elucidate the mechanism modulating HPMEC pyroptosis during H/R. Treatment of mice with clodronate-liposome attenuated IR-induced pulmonary edema, cytokine production and pyroptosis activation. In vitro, NLRP3 knockdown in monocytes reduced caspase-1 and IL-1ß secretion in co-cultures of monocytes and HPMECs. Reduced HPMEC pyroptosis was also observed either containing HPMECs with genetically engineered IL-1R knockdown or in co-culture treated with a Triplotide inhibitor that disrupts NF-κB signaling. Monocytes play a vital role in the development of transplant-associated ischemia-reperfusion injury. A potential role is that monocytes secrete IL-1ß to induce HPMEC pyroptosis via the IL-1R/NF-κB/NLRP3 pathway.

Hypoxia-induced lncRNA CASC9 enhances glycolysis and the epithelial-mesenchymal transition of pancreatic cancer by a positive feedback loop with AKT/HIF-1α signaling.

Increasing evidence indicates the dysregulations and pivotal roles of lncRNAs in the development and progression of various cancers, including pancreatic cancer. Enhanced glycolytic flux and epithelial-to-mesenchymal transition (EMT) have been considered as important factors in driving the malignance of pancreatic cancer. Here, we sought to evaluate the biological role and involved mechanism of lncRNA CASC9 (CASC9) in pancreatic cancer. Our present study showed that CASC9 was upregulated in various pancreatic cancer cell lines. Loss- and gain-of function of CASC9 demonstrated its critical roles in promoting the glycolysis and EMT phenotypes of pancreatic cancer. Moreover, knockdown of CASC9 inhibited the tumorigenicity and metastasis in vivo. Additionally, our findings showed that hypoxia induced the expression of CASC9 and enhanced the binding of HIF-1α to its promoter. We also demonstrated that the positive feedback loop of CASC9 and the AKT/HIF-1α signaling cascade partially mediated this biological process. Altogether, our results suggest that CASC9 promotes the glycolysis and EMT of pancreatic cancer by a positive feedback loop with AKT/HIF-1α signaling, which is synergistically enhanced by the tumor hypoxic niche. Our study will provide potential therapeutic targets for treating pancreatic cancer.

Analysis of risk factors for antiepileptic drug-induced adverse psychotropic effects in Chinese outpatients with epilepsy.

Antiepileptic drugs (AEDs) have adverse psychotropic effects (APEs). To explore the risk factors for AED-induced APEs, we compared Chinese outpatients with epilepsy with and without AED-induced APEs. We reviewed the medical data of outpatients with epilepsy enrolled in the Epilepsy Long-term Follow Up Registry Study (ELFURS) between January 1, 2003 and December 31, 2015. Data on demographics, comorbidities, variables related to epilepsy, AED use, and APEs were collected. APEs were determined by experienced epileptologists based on the definition of "adverse drug reaction (ADR)" proposed by the World Health Organization (WHO) in 1972, and the causality relationship between APEs and suspected medications was assessed based on the WHO-UMC scale. APEs included effects on memory, sleep, behavior, mood, psychotic symptoms, and others in this study. We divided the study population into patients with and without AED-induced APEs and then compared the differences between the two groups using univariate and multivariate methods. A total of 3074 eligible patients were included in this study (1001 patients with AED-induced APEs and 2073 patients without AED-induced APEs). Of all APEs, the effects on memory and sleep were most pronounced. The results show that the female sex (odds ratio [OR] 1.242, 95% confidence interval [CI] 1.055-1.463), psychotic disorder comorbidities (OR 1.815, 95% CI 1.159-2.841), polytherapy with AEDs (OR 1.400, 95% CI 1.061-1.847), and the duration of epilepsy (OR 1.010, 95% CI 1.000-1.020) are significant nondrug risk factors for AED-induced APEs. Recognizing risk factors for APEs may help determine optimal treatment strategies for epilepsy.

Examining the use of allopurinol: Perspectives from recent drug injury relief applications.

BACKGROUND/PURPOSE: Previous studies have reported that the indication and starting dose of allopurinol may be associated with the incidence of hypersensitive reactions. As allopurinol-related severe cutaneous adverse reactions (SCARs) constitute a significant proportion of drug injury relief applications in Taiwan, this study sought to examine allopurinol use and related adverse reactions through an analysis of recent drug injury relief applications. METHODS: Allopurinol-related drug injury relief applications from 1999 to 2016 were collected, and descriptive statistical methods were used to analyze recent applications dating from 2011 to 2016. RESULTS: A total of 174 allopurinol-related drug injury relief applications were submitted between 2011 and 2016, with the majority involving cases over the age of 65 (75.3%; mean age of all cases was 69.2). Most allopurinol-related drug injuries concerned the skin (173 out of 174 cases, 99.4%). The majority of cases had other co-morbidities such as cardiovascular disease/hypertension (86.2%), chronic kidney disease (58.6%), or diabetes (46.6%). Over 70% of cases initiated allopurinol at a dose of 100 mg/day or less. Analysis revealed that the greatest number of cases (44.6%) occurred in those with an estimated glomerular filtration rate (eGFR) between 15 and 60 mL/min/1.73 m2 and who initiated allopurinol at a dose of 100 mg/day. CONCLUSION: Old age and renal dysfunction are key risk factors for allopurinol hypersensitivity. When considering allopurinol for elderly patients with impaired kidney function, a full risk-benefit assessment, dosage adjustments, and careful monitoring may be warranted.

[Effects of combined application of maize- and horsebean straws on the straws decomposition and soil nutrient contents].

A laboratory incubation experiment was conducted to study the straw decomposition and soil nutrient contents after single and combined applications of maize- and horsebean straws. With the single application of maize straw, the mineralization rates of the straw and soil organic C were lower, and the immobilization of soil mineral N sustained longest. Combined application of maize- and horsebean straws promoted the mineralization of the straws organic C and soil immobilized N. Both single and combined application of the straws increased the contents of soil microbial biomass C and N significantly. It was suggested that a combined application of gramineous and leguminous straws could promote the straws decomposition and harmonize the soil nutrient supply.

A program to enhance nursing managers' capability of operating computerized processing system.

The purpose of this program is to improve the capacities of head nurses of operating hospital information system, relevant operation of the Intranet, electronic forms, and computerized processing system through nursing information educational courses and hands-on operation. The results of questionnaires show that head nurses score averagely 4.05 on the knowledge of computerized processing system in the hospital and 3.6, the lowest, on those of schedule arrangement of nursing personnel, cashier, and accounting operation. In addition, the knowledge of the Intranet operation scored averagely 4.28 and 3.8 on the operation of electronic forms and equipment maintenance and repairing request. After collecting, analyzing, compiling information and comparing to literature review, the researchers conclude the solutions as: (1) conducting nursing information training courses to improve knowledge of head nurses on relevant computerized processing system; (2) monitoring and evaluating nursing administration to promote heads-on evaluation operation for furthering understanding of individual operation problem. After the implementation of above proposed program, head nurses score 4.99 on the knowledge of hospital information and operation of relevant intranet system and demonstrate 88% of satisfaction level indicating the importance of conducting nursing information training courses to effectively improve computer operation capacity, work efficiency, and satisfaction level.

A program to improve the electronic working environment and computer hardware.

Information technology is the inevitable product of modern society and computerized medical information provides clinic workers with more timely and instant information. Therefore, computer hardware equipment is a must to promote computerized information system. Yet, there is low satisfaction level toward the arrangement of clinical computer equipment. The purpose of this program is to improve the satisfaction level and easiness to access to e- environment and computer hardware equipment at nursing stations. Results after the improvement and rearrangement of e-environment indicated that the satisfaction level of nursing staffs has been improved by 22.4% from 41.4% to 63.8% improving the accessibility, the interactions between and among staffs and patients, and the utilization of computer equipment.

[Strategies to improve protection from glutaraldehyde in endoscopic examination].

Safety of the working environment has emerged as an important issue in recent years. Of safe work place is a prerequisite for the practice of medicine. High level disinfection by glutaraldehyde (GAD) is the usual method for sterilizing endoscopes. But GAD is highly volatile and is an irritant. Prolonged exposure to GAD in a closed unit usually causes discomfort. Our study demonstrated that the main reasons for this are: (1) nursing staff are not sufficiently familiar with GAD, (2) high GAD concentration in the air, (3) insufficient training to use the facilities and disinfectant, (4) lack of safety precautions due to large amount of GAD in examination room. In order to diminish the dangers of unavoidable exposure, the following strategies are recommended: intensify training for the handling of GAD, decrease the amount of GAD, encourage the use of individual precautions and remove fuzzy carpets, and use appropriate disinfection facilities. Many improvements can be achieved with the introduction of these measures as, this article shows. These improvements include: (1) a 100% response rate and a 97% satisfaction rate from trainees, (2) a total reduction of 150 liters of GAD per month with atmospheric GAD markedly reduced, to 0.0054 ppm, (3) reduction in reported discomforts from between 80% and 100% to 10%, (4) a protection rate of 100% compared to the previous 10% - 30%.