Relationship between drug targets and drug-signature networks: a network-based genome-wide landscape.

Drugs produce pharmaceutical and adverse effects that arise from the complex relationship between drug targets and signatures; by considering such relationships, we can begin to understand the cellular mechanisms of drugs. In this study, we selected 463 genes from the DSigDB database corresponding to targets and signatures for 382 FDA-approved drugs with both protein binding information for a drug-target score (KDTN, i.e., the degree to which the protein encoded by the gene binds to a number of drugs) and microarray signature information for a drug-sensitive score (KDSN, i.e., the degree to which gene expression is stimulated by the drug). Accordingly, we constructed two drug-gene bipartite network models, a drug-target network and drug-signature network, which were merged into a multidimensional model. Analysis revealed that the KDTN and KDSN were in mutually exclusive and reciprocal relationships in terms of their biological network structure and gene function. A symmetric balance between the KDTN and KDSN of genes facilitates the possibility of therapeutic drug effects in whole genome. These results provide new insights into the relationship between drugs and genes, specifically drug targets and drug signatures.

Personalized Prediction of Kidney Function Decline and Network Analysis of the Risk Factors after Kidney Transplantation Using Nationwide Cohort Data.

We developed a machine-learning-based model that could predict a decrease in one-year graft function after kidney transplantation, and investigated the risk factors of the decreased function. A total of 4317 cases were included from the Korean Organ Transplant Registry (2014−2019). An XGBoost model was trained to predict the recipient's one-year estimated glomerular filtration rate (eGFR) below 45 mL/min/1.73 m2 using 112 pre- and peri-transplantation variables. The network of model factors was drawn using inter-factor partial correlations and the statistical significance of each factor. The model with seven features achieved an area under the curve of 0.82, sensitivity of 0.73, and specificity of 0.79. The model prediction was associated with five-year graft and rejection-free survival. Post-transplantation hospitalization >25 days and eGFR ≥ 88.0 were the prominent risk and preventive factors, respectively. Donor age and post-transplantation eGFR < 59.8 were connected to multiple risk factors on the network. Therefore, careful donor−recipient matching in older donors, and avoiding pre-transplantation risk factors, would reduce the risk of graft dysfunction. The model might improve long-term graft outcomes by supporting early detection of graft dysfunction, and proactive risk factor control.

Evaluation of dry eye subtypes and characteristics using conventional assessments and dynamic tear interferometry.

BACKGROUND/AIMS: To evaluate subtypes and characteristics of dry eye (DE) using conventional tests and dynamic tear interferometry, and to investigate determinants of disease severity in each DE subtype. METHODS: 309 patients diagnosed with DE and 69 healthy controls were prospectively enrolled. All eyes were evaluated using Ocular Surface Disease Index (OSDI), Schirmer's test I (ST1) and Meibomian gland dysfunction (MGD) grade were analysed. The tear interferometric pattern and lipid layer thickness were determined using DR-1α and LipiView II, respectively. RESULTS: Dynamic interferometric analysis revealed 56.6% of patients with DE exhibited Jupiter patterns, indicative of aqueous-deficiency, while 43.4% exhibited crystal patterns, indicative of lipid deficiency. These findings were in accordance with classification based on ST1 scores and MGD grade. Conventional assessment indicated 286 patients exhibited evidence of evaporative DE (EDE) due to MGD, while only 11 exhibited signs of pure aqueous-deficient DE (pure ADDE, only ST1 ≤5 mm). Interestingly, of 286 patients with EDE, 144 were categorised into the mixed-ADDE/EDE group, in which ST1 was identified as a strong negative determinant of OSDI. In contrast, 72.2% of patients with mixed-ADDE/EDE exhibited Jupiter patterns (Jupiter mixed), while 27.8% exhibited crystal patterns (crystal mixed). OSDI values were significantly higher in the crystal-mixed group than in the Jupiter mixed, in which OSDI scores were independently associated with ST1 values only. CONCLUSIONS: Our findings indicate that majority of EDE patients also exhibit aqueous deficiency, which can aggravate symptoms even in patients with lipid-deficient mixed-ADDE/EDE. Conventional assessments should be combined with interferometric tear analysis to determine the most appropriate treatment for each DE patient.

Epidemiological Characterization of a Directed and Weighted Disease Network Using Data From a Cohort of One Million Patients: Network Analysis.

BACKGROUND: In the past 20 years, various methods have been introduced to construct disease networks. However, established disease networks have not been clinically useful to date because of differences among demographic factors, as well as the temporal order and intensity among disease-disease associations. OBJECTIVE: This study sought to investigate the overall patterns of the associations among diseases; network properties, such as clustering, degree, and strength; and the relationship between the structure of disease networks and demographic factors. METHODS: We used National Health Insurance Service-National Sample Cohort (NHIS-NSC) data from the Republic of Korea, which included the time series insurance information of 1 million out of 50 million Korean (approximately 2%) patients obtained between 2002 and 2013. After setting the observation and outcome periods, we selected only 520 common Korean Classification of Disease, sixth revision codes that were the most prevalent diagnoses, making up approximately 80% of the cases, for statistical validity. Using these data, we constructed a directional and weighted temporal network that considered both demographic factors and network properties. RESULTS: Our disease network contained 294 nodes and 3085 edges, a relative risk value of more than 4, and a false discovery rate-adjusted P value of <.001. Interestingly, our network presented four large clusters. Analysis of the network topology revealed a stronger correlation between in-strength and out-strength than between in-degree and out-degree. Further, the mean age of each disease population was related to the position along the regression line of the out/in-strength plot. Conversely, clustering analysis suggested that our network boasted four large clusters with different sex, age, and disease categories. CONCLUSIONS: We constructed a directional and weighted disease network visualizing demographic factors. Our proposed disease network model is expected to be a valuable tool for use by early clinical researchers seeking to explore the relationships among diseases in the future.

Wound Healing and Mucin Gene Expression of Human Corneal Epithelial Cells Treated with Deproteinized Extract of Calf Blood.

Purpose: The function of Solcoseryl in the corneal epithelium has not been fully examined. Here, we investigated the roles of Solcoseryl in the regulation of gene expression and corneal epithelial cell (CEC) activity.Materials and Methods: The effect of Solcoseryl on CEC activity was analyzed through cell migration, adhesion, proliferation, and wound healing assays. Analysis of gene expression was conducted via western blotting and quantitative reverse transcription polymerase chain reaction (PCR).Results: The results demonstrated that Solcoseryl increased the adhesion, migration, proliferation, and wound healing of CECs. Analysis of gene expression showed that Solcoseryl-stimulated CECs exhibited increased expression of mucin family genes, such as MUC1, -5AC, -7, and -16. Solcoseryl also increased the activities of the intracellular signaling molecules AKT, FAK, ERK, and Src in CECs. Using pharmacologic inhibitors of ERK and AKT, we showed that the expression of mucin genes by Solcoseryl is mediated by the activation of ERK and AKT signaling.Conclusions: Our findings demonstrate that Solcoseryl may contribute to the wound healing of CECs by enhancing their migration, adhesion, and proliferation. Additionally, our results suggest that Solcoseryl has a protective effect on ocular surfaces due to its induction of the expression of mucin genes in CECs. These findings suggest that Solcoseryl is a useful therapeutic target for patients with corneal wounds.

Serologic Markers Are Associated With Ocular Staining Score in Primary Sjögren Syndrome.

PURPOSE: To investigate the relationship between serologic markers and dry eye severity in subjects with primary Sjögren syndrome (SS). METHODS: This study evaluated 64 patients diagnosed with primary SS according to the 2012 Sjögren's International Collaborative Clinical Alliance (SICCA) classification criteria. Serum anti-Ro/SSA, anti-La/SSB, rheumatoid factor (RF), and antinuclear antibody (ANA) levels, Ocular Surface Disease Index (OSDI), Schirmer I test values, tear film breakup time, and SICCA ocular staining score (OSS) were determined. RESULTS: The conjunctival staining scores were 3.3 ± 1.9, 3.6 ± 2.0, 3.4 ± 1.9, and 3.5 ± 1.9 in the positive anti-Ro (≥25 EU), positive anti-La (≥25 EU), positive RF (≥20 IU/mL), and positive ANA (≥1:320) group, respectively. Subjects with positive anti-Ro, anti-La, RF, or ANA had significantly higher conjunctival staining scores compared with those with negative levels (P < 0.05). The total OSS in the positive ANA group was 5.5 ± 3.0, which was significantly higher than the total OSS (3.4 ± 2.1) in the negative ANA group (P = 0.005). Serum RF and ANA levels had strong correlations with conjunctival staining scores and the total OSS but not with corneal staining scores (r = 0.53, P < 0.001 and r = 0.382, P = 0.002). Other ocular parameters (OSDI, Schirmer I test values, and tear film breakup time) did not differ by the serologic marker level. Interestingly, the OSDI was positively correlated with the corneal staining score and total OSS (r = 0.646, P < 0.001 and r = 0.476, P < 0.001). CONCLUSIONS: Serum RF and ANA levels are associated with conjunctival staining scores and the total OSS according to the SICCA OSS in primary SS.

Effects of AG490 on lens epithelial cell death induced by H(2)O(2).

PURPOSE: To evaluate the influence of H(2)O(2) on lens epithelial cells (LECs) and to determine the effect of the Janus kinase (JAK) inhibitor AG490 and the mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) kinase (MEK) inhibitor U0126 on LEC death after H(2)O(2) exposure. METHODS: Human lens epithelial (HLE) B-3 cells were cultured. Cells were treated for 45 min with H2O2 and signal transducers and activators transcription (STAT) 3, JAK2, and ERK1/2 phosphorylation were surveyed by Western blot analysis. After pretreatment with either 40 microM AG490 or 25 microM U0126, LECs were exposed to H(2)O(2). LEC death was evaluated by microscopy and flow cytometry. RESULTS: H(2)O(2) induced phosphorylation of Tyr-705 STAT3, JAK2, and ERK1/2 in LECs. In cells pretreated with both AG490 and U0126, phosphorylation of Tyr-705 STAT3, JAK2, and ERK1/2 was suppressed. Microscopic findings, however, showed that only AG490 noticeably enhanced cell survival, and flow cytometry showed that cell necrosis decreased to 4.05% after pretreatment with 40 microM AG490. CONCLUSIONS: AG490 may prevent H(2)O(2)-induced LEC death by blocking an unknown necrosis pathway. Further investigation is required to characterize that pathway.