An angiotensin system inhibitor (losartan) potentiates antitumor efficacy of cisplatin in a murine model of non-small cell lung cancer.

Objective: Previous studies have demonstrated synergistic antitumor effects of angiotensin system inhibition (ASI) combined with cisplatin therapy in pancreatic cancer. This study examines whether or not synergistic antitumor effects occur with combination ASI and cisplatin treatment in lung cancer, and whether or not ASI-induced changes in epithelial-mesenchymal transition play a role in the mechanism of this antitumor phenomenon. Methods: A set of lung cancer cell lines representing a spectrum of epithelial to mesenchymal phenotypes were identified and characterized. Response of epithelial-mesenchymal transition markers to losartan was characterized. Cell culture models of lung cancer were next treated with losartan, cisplatin, or combination of both. Markers of epithelial-mesenchymal transition or surrogates of other signaling pathways (AKT, Stat3, and programmed death-ligand), and cell viability were quantified. Findings were confirmed in both allogenic and syngeneic in vivo murine flank tumor models. Results: Losartan treatment significantly increased E-cadherin and reduced vimentin in human lung cancer cell lines. Combination treatment with losartan and cisplatin enhanced epithelial markers, reduced mesenchymal markers, inhibited promesenchymal signaling mediators, and reduced cell viability. Findings were confirmed in vivo in a murine flank tumor model with transition from mesenchymal to epithelial phenotype and reduced tumor size following combination losartan and cisplatin treatment. Conclusions: Combination losartan and cisplatin treatment attenuates the epithelial-mesenchymal transition pathway and enhances the cytotoxic effect of chemotherapy with in vitro and in vivo models of non-small cell lung cancer. This study suggests an important role for ASI therapy in the treatment of lung cancer.

Genetically Proxied Therapeutic Effect of Metformin Use, Blood Pressure, and Hypertension's Risk: a Drug Target-Based Mendelian Randomization Study.

In this work, we aim to evaluate the association of the genetically proxied effect of metformin on blood pressure (BP) and hypertension through a drug target-based Mendelian randomization (MR) analysis. Thirty-two instrumental variables for five metformin targets (i.e., AMP-activated protein kinase (AMPK), growth differentiation factor 15 (GDF15), mitochondrial glycerol 3 (MG3), mitochondrial complex I (MCI), and glucagon (GCG)) were introduced to the MR analysis on the datasets of hypertension, systolic and diastolic blood pressure (SBP and DBP). The MR analyses demonstrated that the MCI- and MG3-specific metformin's use would significantly reduce SBP, DBP, and hypertension risk. The meta-analyses showed that the genetically proxied metformin's use equivalent to a 6.75 mmol/mol reduction on HbA1c could decrease both the SBP (beta = - 1.05, P < 0.001) and DBP (beta = - 0.51, P = 0.096). Furthermore, metformin's use was also implied to reduce the hypertension risk. The MG3- and MCI-dependent metformin's effect may play key roles in the anti-hypertension function.

A patient with a Berger's space filled by silicone oil.

BACKGROUND: To report a case in which silicone oil accidentally entered Berger's space (BS) after vitrectomy and to explore the effective treatments and possible etiological mechanisms. CASE PRESENTATION: A 68-year-old male underwent vitrectomy and silicone oil injection for the treatment of retinal detachment (RD) in the right eye. Six months later, we noticed an unexpected lens-like round translucent substance located behind the posterior lens capsule and diagnosed it as BS filled by silicone oil. Subsequently, we conducted vitrectomy and the drainage of the silicone oil in BS in the second surgery. A 3-month follow-up showed significant anatomic recovery and visual recovery. CONCLUSIONS: Our case report presents a patient with silicone oil entering BS after vitrectomy and provides photographs of BS from a relatively unique perspective. Furthermore, we illustrate the surgical treatment procedure and reveal the possible etiology and prevention method of silicon oil entering BS, which will provide good insights for clinical diagnosis and treatment.

Investigation of Potential Crucial Genes and Key Pathways in Keratoconus: An Analysis of Gene Expression Omnibus Data.

Keratoconus is one of the most common causes leading to visual impairment in young adult population. The pathogenesis of keratoconus remains poorly understood. The aim of this study was to identify the potential key genes and pathways associated with keratoconus and to further analyze its molecular mechanism. Two RNA-sequencing datasets of keratoconus and paired normal corneal tissues from the Gene Expression Omnibus database were obtained. Differentially expressed genes (DEGs) were identified, and the Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses were conducted. The protein-protein interaction (PPI) network of the DEGs was established, and the hub genes and significant gene modules of PPI were further constructed. Lastly, the GO and KEGG analyses of the hub gene were performed. In total, 548 common DEGs were identified. GO enrichment analysis showed that the DEGs were primarily associated with regulation of cell adhesion, the response to molecule of bacterial origin, lipopolysaccharide and biotic stimulus, collagen-containing extracellular matrix, extracellular matrix, and structure organization. KEGG pathway analysis showed that these DEGs were mainly involved in the TNF signaling pathway, IL-17 signaling pathway, Rheumatoid arthritis, Cytokine-cytokine receptor interaction. The PPI network was constructed with 146 nodes and 276 edges, and 3 significant modules are selected. Finally, top 10 hub genes were identified from the PPI network. The results revealed that extracellular matrix remodeling and immune inflammatory response could be the key links of keratoconus, TNF, IL6, IL1A, IL1B, CCL3, MMP3, MMP9, MMP1, and TGFB1 may be potential crucial genes, and TNF signaling pathway and IL-17 signaling pathway were the potential pathways accounting for pathogenesis and development of keratoconus.

Mendelian Randomization Analysis Reveals No Causal Relationship Between Plasma α-Synuclein and Parkinson's Disease.

So far, the studies exploring plasma α-synuclein as a biomarker of Parkinson's disease (PD) have provided contradictory results. Here, we first employed the Mendelian randomization (MR) approach to elucidate their potential causal relationship. Five genetic instrumental variables of plasma α-synuclein were acquired from two publicly available datasets. Three independent genome-wide association studies of PD were used as outcome cohorts (PD cohorts 1, 2, and 3). Two-sample MR analyses were conducted using inverse-variance weighted (IVW), MR-Egger, weighted median, simple mode, and leave-one-out methods. Though the IVW approach demonstrated positive plasma α-synuclein effect on the PD risk in three outcome cohorts (OR = 1.134, 1.164, and 1.189, respectively), the P values were all larger than 0.05. The conclusions were robust under complementary sensitivity analyses. Our results did not support the causal relationship between plasma α-synuclein and PD.

Identification of Key Genes and Molecular Pathways in Keratoconus: Integrating Text Mining and Bioinformatics Analysis.

Purpose: To identify the potential key genes and molecular pathways associated with keratoconus and allergic disease. Methods: The pubmed2ensembl database was used to identify the text mining genes (TMGs) collectively involved in keratoconus and allergic disease. The GeneCodis program was used to perform the Gene Ontology (GO) biological process and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis of TMGs. The protein-protein interaction (PPI) network of the TMGs was established by STRING; the significant gene modules and hub genes of PPI were further performed using the Cytoscape software. The DAVID database was used to perform the GO and KEGG analyses of the significant module. Results: In total, 98 TMGs collectively involved in keratoconus and allergic disease were identified. 19 enriched biological processes including 71 genes and 25 enriched KEGG pathways including 59 genes were obtained. A TMG PPI network was constructed, and 51 genes/nodes were identified with 110 edges; 3 most significant modules and 12 hub genes were chosen from the PPIs. GO enrichment analysis showed that the TMGs were primarily associated with collagen catabolic process, extracellular matrix organization and disassembly, cell adhesion and migration, collagen-containing extracellular matrix, extracellular matrix, and structure organization. KEGG pathway analysis showed that these DEGs were mainly involved in the IL-17 signaling pathway, inflammatory bowel disease, rheumatoid arthritis, allograft rejection, T cell receptor signaling pathway, cytokine-cytokine receptor interaction, and TNF signaling pathway. Conclusions: The results revealed that IL10, IL6, MMP9, MMP1, HGF, VEGFA, MMP3, MMP2, TGFB1, IL4, IL2, and IFNG were potential key genes involved in keratoconus. IL-17 signaling pathway was the potential pathways accounting for pathogenesis and development of keratoconus.

A Component Content Measurement Method Modified Using Indirect Hard Modeling for Polymer Blends Based on Raman Spectroscopy.

Raman spectroscopy has been proven to be useful for the component content measurement of polymer blends. However, the soft modeling methods commonly used in quantitative analysis of Raman spectroscopy require a large number of training samples, resulting in a waste of materials and time. This work adopted a modified indirect hard modeling (IHM) method to measure the component content of polymer blends based on Raman spectroscopy. The Raman spectra of polypropylene (PP)/polystyrene (PS) blends with different component content were collected and resolved into the sum of multiple Voigt peak functions. For a large number of peak parameters, the two-dimensional correlation spectroscopy was used to screen out the characteristic Voigt peaks highly correlated with component content to reduce the parameter dimensions and build the parameterized spectral models. The spectral model of the blend was expressed as the weighted sum of the pure component spectral models, during which the parameters of the pure component models were adjusted within a range. According to the relationship between the weight and content of the pure component, a linear regression model for component content prediction was established. The coefficient of determination (R2)/root mean squared error of the IHM component content prediction model was 0.9931/0.4367 wt%. Besides, two popular soft modeling methods, partial least squares and artificial neural network, were compared with the IHM method, which showed that the IHM model had higher prediction accuracy with fewer training samples.

Identification of Prognostic Model Based on Immune-Related LncRNAs in Stage I-III Non-Small Cell Lung Cancer.

BACKGROUND: Long non-coding RNAs (lncRNAs) participate in the regulation of immune response and carcinogenesis, shaping tumor immune microenvironment, which could be utilized in the construction of prognostic signatures for non-small cell lung cancer (NSCLC) as supplements. METHODS: Data of patients with stage I-III NSCLC was downloaded from online databases. The least absolute shrinkage and selection operator was used to construct a lncRNA-based prognostic model. Differences in tumor immune microenvironments and pathways were explored for high-risk and low-risk groups, stratified by the model. We explored the potential association between the model and immunotherapy by the tumor immune dysfunction and exclusion algorithm. RESULTS: Our study extracted 15 immune-related lncRNAs to construct a prognostic model. Survival analysis suggested better survival probability in low-risk group in training and validation cohorts. The combination of tumor, node, and metastasis staging systems with immune-related lncRNA signatures presented higher prognostic efficacy than tumor, node, and metastasis staging systems. Single sample gene set enrichment analysis showed higher infiltration abundance in the low-risk group, including B cells (p<0.001), activated CD8+ T cells (p<0.01), CD4+ T cells (p<0.001), activated dendritic cells (p<0.01), and CD56+ Natural killer cells (p<0.01). Low-risk patients had significantly higher immune scores and estimated scores from the ESTIMATE algorithm. The predicted proportion of responders to immunotherapy was higher in the low-risk group. Critical pathways in the model were enriched in immune response and cytoskeleton. CONCLUSIONS: Our immune-related lncRNA model could describe the immune contexture of tumor microenvironments and facilitate clinical therapeutic strategies by improving the prognostic efficacy of traditional tumor staging systems.

Evaluation of a Three-Marker Panel for the Detection of Uveal Melanoma Metastases: A Single-Center Retrospective Analysis.

Blood-based B-cell activating factor (BAFF), growth differentiation factor-15 (GDF-15) and osteopontin (OPN) have been identified to be promising biomarkers for the metastases of uveal melanoma (UM). This study intended to assess their kinetics and to evaluate their significance as a three-marker panel. A group of 36 UM patients with and 137 patients without metastases were included in the study. Their plasma OPN levels were measured by ELISA; serum BAFF and GDF-15 levels were determined with a Luminex MAGPIX system. Receiver operating characteristic (ROC) analysis was performed to calculate the cutoff values of the three markers for identifying the patients with metastases. The ability to identify patients with metastases was compared between the single markers and the combination as a three-marker panel. By using the Student's t-test, we also investigated the kinetic changes of the levels of BAFF, GDF-15 and OPN across six periods (i.e., 0-6 months, 6-12 months, 12-18 months, 18-24 months, >24 months and post-metastasis) before the imaging diagnosis of metastases. By maximizing the Youden's index, the serum GDF-15 level of 1209 pg/mL and the plasma OPN level of 92 ng/mL were identified to have the best performance for distinguishing the metastatic patients from non-metastatic patients. The three-marker panel offered a better performance in distinguishing patients with metastases, with an area under the curve of 0.802, than any single biomarker. Increasing trends of the levels of three biomarkers were observed in the two-year period before the imaging diagnosis of metastases. The combined panel of BAFF, GDF-15 and OPN might be a utilizable implementation for the detection of UM metastases. In the bioinformatics study with two external datasets, the high expression of gene BAFF and GDF-15 in primary UM tissues was identified to be associated with poor overall survival rates. As the current work is a single-center retrospective study, more well-designed prospective investigations employing larger cohorts are urgently needed to validate our findings.

Exploring the role of BAFF as biomarker in the detection of uveal melanoma metastases.

PURPOSE: While B-cell activating factor (BAFF) was identified to promote the invasion in other malignancies, its role in the progression of uveal melanoma (UM) still remains unexplored. Here, we analysed the serum level of BAFF in UM patients with regard to its significance as biomarker for the metastases. METHODS: In this retrospective study, serum BAFF levels in 173 UM patients (36 with metastases and 137 without), and 23 healthy controls were measured with a multiplexed sandwich ELISA system and then correlated with clinicopathological characteristics such as primary tumor size, tumor location, histological cell type, sex, cancer stage, cytogenetic alterations of chromosome 3, and the metastatic burden. Immunohistochemical staining of 50 UM tissue specimens was also performed to evaluate the expression of BAFF and its receptors BAFF-R and TACI. RESULTS: The metastatic patients were identified to have significantly higher serum BAFF levels (mean ± SD, 1520.8 ± 1182.1 pg/ml) than those without metastases (950.4 ± 494.6 pg/ml) and controls (810.3 ± 140.5 pg/ml). While no distinctions were detected with regard to tumor location, histological cell type, gender, and monosomy 3, the patients in cancer stages II, III, and IV displayed higher serum BAFF levels than those in stage I. The serum BAFF level was significantly correlated with the metastatic burden. The serum BAFF level of 1120 pg/ml was identified to have the best performance for distinguishing the metastatic patients from non-metastatic patients. In the kinetic study, we noticed that 20.8% of the analysed patients already demonstrated elevated serum BAFF concentrations before the clinical diagnosis of metastases. Positive BAFF staining was detected in the cytoplasm of single tumor cells (in 13 specimens), macrophages (in 12 specimens), and tumor-infiltrating lymphocytes (TILs) (in 13 specimens). The expressions of BAFF-R and TACI were also observed in 17 and 36 of the 50 tested UM specimens, respectively. CONCLUSIONS: Our study first suggests that BAFF might be a promising serum marker for the detection of UM metastases.

Homologous recombination repair rathway and RAD54L in early-stage lung adenocarcinoma.

OBJECTIVE: The current study aims to identify the dysregulated pathway involved in carcinogenesis and the essential survival-related dysregulated genes among this pathway in the early stage of lung adenocarcinoma (LUAD). PATIENTS AND METHODS: Data from The Cancer Genome Atlas (TCGA) including 526 tumor tissues of LUAD and 59 healthy lung tissues were analyzed to gain differentially expressed genes (DEGs). Gene ontology (GO) analysis was conducted with DAVID, while the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis of DEGs was performed, followed by gene set enrichment analysis (GSEA) methods. Survival analysis was implemented in TCGA dataset and validated in Gene Expression Omnibus (GEO) cohort GSE50081, which includes 127 patients with stage I LUAD. RESULTS: GSEA enrichment analysis suggested that homologous recombination repair (HRR) pathway was significantly enriched. Subsequent KEGG pathway enrichment analysis indicated the significant up-regulation of HRR pathway in patients with T1 stage LUAD. Retrieved in Gene database, RAD54L is involved in HRR pathway and were recognized to be significantly differentially expressed in T1 stage LUAD in our study. The survival analysis indicated that high expression of RAD54L was significantly related to worse overall survival in patients with T1 stage LUAD (TCGA cohort: HR=2.10, 95% CI [1.47-2.98], P = 0.001; GSE50081 validation cohort: HR = 2.61, 95% CI [1.51-4.52], P = 0.002). Multivariate cox regression analysis indicated that RAD54L is an independent prognostic factor in the early-stage LUAD. CONCLUSION: HRR pathway is up-regulated in LUAD, among which the expression of RAD54L was found to be significantly differentially expressed in T1 stage tumor tissue. Patients with high expression of RAD54L were associated with worse overall survival in the TCGA cohort and validation cohort. This study suggests a potential mechanism of lung cancer progression and provide a budding prognostic factor and treatment target in early-stage LUAD.

A multi-omics study on cutaneous and uveal melanoma.

AIM: To present the multi-omics landscape of cutaneous melanoma (CM) and uveal melanoma (UM) from The Cancer Genome Atlas (TCGA). METHODS: The differentially expressed genes (DEGs) between CM and UM were found and integrated into a gene ontology enrichment analysis. Besides, the differentially expressed miRNAs were also identified. We also compared the methylation level of CM with UM and identified the differentially methylated regions to integrate with the DEGs to display the relationship between the gene expression and DNA methylation. The differentially expressed transcription factors (TFs) were identified. RESULTS: Though CM had more mutational burden than UM, they shared several similarities such as the same rankings in diverse variant types. Except GNAQ and GNA11, the other top 18 mutated genes of the combined group were mostly detected in CM instead of UM. On the transcriptomic level, 4610 DEGs were found and integrated into a gene ontology enrichment analysis. We also identified 485 differentially expressed miRNAs. The methylation analysis showed that UM had a significantly higher methylation level than CM. The integration of differentially methylated regions and DEGs demonstrated that most DEGs were downregulated in UM and the hypo- and hypermethylation presented no obvious difference within these DEGs. Finally, 116 hypermethylated TFs and 114 hypomethylated TFs were identified as differentially expressed TFs in CM when compared with UM. CONCLUSION: This multi-omics study on comparing CM with UM confirms that they differ in all analyzed levels. Of notice, the results also offer new insights with implications for elucidating certain unclear problems such as the distinct role of epithelial mesenchymal transition in two melanomas, the different metastatic routes of CM and UM and the liver tropism of metastatic UM.

In-Line Monitoring the Degradation of Polypropylene under Multiple Extrusions Based on Raman Spectroscopy.

Polymer degradation is a common problem in the extrusion process. In this work, Raman spectroscopy, a robust, rapid, and non-destructive tool for in-line monitoring, was utilized to in-line monitor the degradation of polypropylene (PP) under multiple extrusions. Raw spectra were pretreated by chemometrics methods to extract variations of spectra and eliminate noise. The variation of Raman intensity with the increasing number of extrusions was caused by the scission of PP chains and oxidative degradation, and the variation trend of Raman intensity indicated that long chains were more likely to be damaged by the extrusion. For the quantitative analysis of degradation, the partial least square was used to build a model to predict the degree of PP degradation measured by gel permeation chromatography (GPC). For the calibration set, the coefficient of determination (R2) and the root mean square error of cross-validation (RMSECV) were 0.9859 and 1.2676%, and for the prediction set, R2 and the root mean square error of prediction (RMSEP) were 0.9752 and 1.7228%, which demonstrated the accuracy of the proposed model. The in-line Raman spectroscopy combined with the chemometrics methods was proved to be an accurate and highly effective tool, which can monitor the degradation of polymer in real time.

Influences of personality characteristics and coping modes on anxiety in primary glaucoma patients.

AIM: To examine the influences of personality characteristics and coping modes on the anxiety of primary glaucoma patients. METHODS: A total of 200 individuals, including 50 with primary angle-closure glaucoma, 60 with primary open angle glaucoma and 90 control participants, filled out the State-Trait Anxiety Inventory, NEO Five-Factor Inventory, and Medical Coping Modes Questionnaire. Sociodemographic information was also collected. Data were analyzed via the Spearman rank correlation test and stepwise regression. RESULTS: The personality and coping variables are predictive and jointly account for a significant amount (45.3%-54.2%) of variance across the two subscales of anxiety measures. Notably, neuroticism seems to be most closely related to anxiety disturbances in glaucoma patients. The level of resignation is positively linked to anxiety scores. CONCLUSION: Some personality factors and coping modes help to predict the process of anxiety disorders in primary glaucoma patients. Recognizing the predictive role of these variables in the patients may further enrich clinical research in glaucoma and help to design more effective interventions involving both ophthalmology and psychiatry.

The 100 most influential papers about cataract surgery: a bibliometric analysis.

AIM: To identify the 100 most cited papers in cataract surgery, we performed a comprehensive bibliometric analysis basing on the literature search on the Thomson Reuters Web of Knowledge. METHODS: The number of citations, including the total citations, latest 5y citations and average citation number per year (ACY), authorship, year of publication, major topics, journal of publication, country and institution of origin of each paper were recorded and then analyzed. Pearson's correlation analysis was conducted to evaluate the correlation between the published year and the number of citations. The correlation between journal's impact factor (IF) and number of citations was assessed as well. RESULTS: The most cited paper was the classic paper done by the European Society of Cataract & Refractive Surgeons (ESCRS) group. This paper focused on the topic of endophthalmitis. Not only the most cited papers originated from the USA, but also some American institutions like Johns Hopkins University, Harvard Medical School, etc. had the most citations. Pearson's correlation analysis indicated that the latest 5y citations and ACY were significantly related with the published year (5y citations: r=0.615, P<0.001; ACY: r=0.657, P<0.001), whereas no association between the total number of citations and published year was found (r=0.045). Moreover, the IFs of journals were found to have no significant effect on the number of total citations. CONCLUSION: To our knowledge, this is the first study on the most influential papers in cataract surgery after a comprehensive research of relevant literatures. The present work may provide us concise information concerning the development history of cataract surgery over the past 66y.

Characteristics of corneal dystrophies: a review from clinical, histological and genetic perspectives.

Corneal dystrophy is a common type of hereditary corneal diseases. It includes many types, which have varied pathology, histology and clinical manifestations. Recently, the examination techniques of ophthalmology and gene sequencing advance greatly, which do benefit to our understanding of these diseases. However, many aspects remain still unknown. And due to the poor knowledge of these diseases, the results of the treatments are not satisfoctory. The purpose of this review was to summarize the clinical, histological and genetic characteristics of different types of corneal dystrophies.