ASpedia-R: a package to retrieve junction-incorporating features and knowledge-based functions of human alternative splicing events.

Motivation: Alternative splicing (AS) is a key regulatory mechanism that confers genetic diversity and phenotypic plasticity of human. The exons and their flanking regions include comprehensive junction-incorporating sequence features like splicing factor-binding sites and protein domains. These elements involve in exon usage and finally contribute to isoform-specific biological functions. Splicing-associated sequence features are involved in the multilayered regulation encompassing DNA and proteins. However, most analysis applications have investigated limited sequence features, like protein domains. It is insufficient to explain the comprehensive cause and effect of exon-specific biological processes. Results: With the advent of RNA-seq technology, global AS event analysis has deduced more precise results. As accumulating analysis results, it could be a challenge to identify multi-omics sequence features for AS events. Therefore, application to investigate multi-omics sequence features is useful to scan critical evidence. ASpedia-R is an R package to interrogate junction-incorporating sequence features for human genes. Our database collected the heterogeneous profile encompassed from DNA to protein. Additionally, knowledge-based splicing genes were collected using text-mining to test the association with specific pathway terms. Our package retrieves AS events for high-throughput data analysis results via AS event ID converter. Finally, result profile could be visualized and saved to multiple formats: sequence feature result table, genome track figure, protein-protein interaction network, and gene set enrichment test result table. Our package is a convenient tool to understand global regulation mechanisms by splicing. Availability and implementation: The package source code is freely available to non-commercial users at https://github.com/ncc-bioinfo/ASpedia-R.

Drug Response of Patient-Derived Lung Cancer Cells Predicts Clinical Outcomes of Targeted Therapy.

Intratumor heterogeneity leads to different responses to targeted therapies, even within patients whose tumors harbor identical driver oncogenes. This study examined clinical outcomes according to a patient-derived cell (PDC)-based drug sensitivity test in lung cancer patients treated with targeted therapies. From 487 lung cancers, 397 PDCs were established with a success rate of 82%. In 139 PDCs from advanced non-small-cell lung cancer (NSCLC) patients receiving targeted therapies, the standardized area under the curve (AUC) values for the drugs was significantly correlated with their tumor response (p = 0.002). Among 59 chemo-naive EGFR/ALK-positive NSCLC patients, the PDC non-responders showed a significantly inferior response rate (RR) and progression-free survival (PFS) for the targeted drugs than the PDC responders (RR, 25% vs. 78%, p = 0.011; median PFS, 3.4 months [95% confidence interval (CI), 2.8-4.1] vs. 11.8 months [95% CI, 6.5-17.0], p < 0.001). Of 25 EGFR-positive NSCLC patients re-challenged with EGFR inhibitors, the PDC responder showed a higher RR than the PDC non-responder (42% vs. 15%). Four patients with wild-type EGFR or uncommon EGFR-mutant NSCLC were treated with EGFR inhibitors based on their favorable PDC response to EGFR inhibitors, and two patients showed dramatic responses. Therefore, the PDC-based drug sensitivity test results were significantly associated with clinical outcomes in patients with EGFR- or ALK-positive NSCLC. It may be helpful for predicting individual heterogenous clinical outcomes beyond genomic alterations.

Efficacy and Safety of High Density LED Irradiation Therapy for Patients With Hand Osteoarthritis: A Single-Center Clinical Study.

OBJECTIVE: To assess the safety and effectiveness of high-density light-emitting diode (LED) irradiation therapy in patients with hand osteoarthritis (OA) and compare the pre- and post-intervention symptoms. METHODS: Twenty-three patients with hand OA underwent eight sessions of high-density LED irradiation therapy directed at the five most painful areas in the finger joints. Each session lasted for 18 minutes; and the sessions were conducted twice a week, for 4 weeks. We evaluated the degree of pain using the visual analogue scale, ring size, and passive range of motion (flexion+extension) for two most painful joints from the baseline to post-therapy (weeks 4 and 6). RESULTS: High-density LED irradiation therapy significantly reduced the pain posttreatment compared with that observed at the baseline (p<0.001). Although improvements were observed in ring size and joint range of motion at 4 and 6 weeks, they were not statistically significant (p>0.05). No adverse events were observed. CONCLUSION: We examined the safety and effectiveness of high-density LED irradiation therapy in reducing pain and hand swelling and improving joint mobility in patients with hand OA. These results suggest that high-density LED irradiation therapy has the potential to be an important strategy for managing hand OA.

Nivolumab after Induction Chemotherapy in Previously Treated Non-Small-Cell Lung Cancer Patients with Low PD-L1 Expression.

This study aimed to investigate whether cyclophosphamide (C) and adriamycin (A) induction therapy (IT) prior to nivolumab could enhance the efficacy of nivolumab in previously treated patients with non-squamous (NSQ) non-small-cell lung cancer (NSCLC) with less than 10% programmed death-ligand 1 (PD-L1) expression. Twenty-two enrolled patients received four cycles of CA-IT every 3 weeks. Nivolumab was given 360 mg every 3 weeks from the second cycle and 480 mg every 4 weeks after four cycles of CA-IT. The median progression-free survival (PFS) and overall survival (OS) were 2.4 months and 11.6 months, respectively. Fluorescence-activated cell sorting revealed the lowest ratio of myeloid-derived suppressor cells (MDSCs) to CD8+T-cells in the responders. Proteomic analysis identified a consistent upregulation of extracellular matrix-receptor interactions and phagosome pathways in the responders. Among the differentially expressed proteins, the transferrin receptor protein (TFRC) was higher in the responders before treatment (fold change > 1.2). TFRC validation with an independent cohort showed the prognostic significance of either OS or PFS in patients with low PD-L1 expression. In summary, CA-IT did not improve nivolumab efficacy in NSQ-NSCLCs with low PD-L1 expression; however, it induced decreasing MDSC, resulting in a durable response. Higher baseline TFRC levels predicted a favorable response to nivolumab in NSCLC with low PD-L1 expression.

Patient-derived cell-based pharmacogenomic assessment to unveil underlying resistance mechanisms and novel therapeutics for advanced lung cancer.

BACKGROUND: A pharmacogenomic platform using patient-derived cells (PDCs) was established to identify the underlying resistance mechanisms and tailored treatment for patients with advanced or refractory lung cancer. METHODS: Drug sensitivity screening and multi-omics datasets were acquired from lung cancer PDCs (n = 102). Integrative analysis was performed to explore drug candidates according to genetic variants, gene expression, and clinical profiles. RESULTS: PDCs had genomic characteristics resembled with those of solid lung cancer tissues. PDC molecular subtyping classified patients into four groups: (1) inflammatory, (2) epithelial-to-mesenchymal transition (EMT)-like, (3) stemness, and (4) epithelial growth factor receptor (EGFR)-dominant. EGFR mutations of the EMT-like subtype were associated with a reduced response to EGFR-tyrosine kinase inhibitor therapy. Moreover, although RB1/TP53 mutations were significantly enriched in small-cell lung cancer (SCLC) PDCs, they were also present in non-SCLC PDCs. In contrast to its effect in the cell lines, alpelisib (a PI3K-AKT inhibitor) significantly inhibited both RB1/TP53 expression and SCLC cell growth in our PDC model. Furthermore, cell cycle inhibitors could effectively target SCLC cells. Finally, the upregulation of transforming growth factor-ß expression and the YAP/TAZ pathway was observed in osimertinib-resistant PDCs, predisposing them to the EMT-like subtype. Our platform selected XAV939 (a WNT-TNKS-ß-catenin inhibitor) for the treatment of osimertinib-resistant PDCs. Using an in vitro model, we further demonstrated that acquisition of osimertinib resistance enhances invasive characteristics and EMT, upregulates the YAP/TAZ-AXL axis, and increases the sensitivity of cancer cells to XAV939. CONCLUSIONS: Our PDC models recapitulated the molecular characteristics of lung cancer, and pharmacogenomics analysis provided plausible therapeutic candidates.

Effects of Exposure Duration and Exposure Levels of Ambient Air Pollutants on the Risk of Polycystic Ovarian Syndrome: A 2015-2019 Korean Population-Based Cohort Study.

Exposure to ambient air pollution is associated with an increased risk of menstrual disorders and infertility. This study examined the relationships between the levels and duration of air pollution exposure and the risk of polycystic ovarian syndrome (PCOS) using Korean population-based cohort data (2015-2019). Real-time data on PM10, PM2.5, O3, CO, SO2, and NO2 were provided by the Korean Ministry of Environment. The average monthly air pollutant concentration from 1 January 2014 to 31 December 2018 was analyzed. To assess individual-level exposure to air pollutants, a spatial prediction model and an area-averaging approach were used. In total, 237,582 PCOS cases were analyzed. The annual age-adjusted PCOS incidence was 6.70, 8.28, 9.73, 11.58, and 11.97% from 2015-2019, respectively. The PCOS risk increased 1.29-1.32, 1.43-1.52, and 1.32-fold following exposure to the 2-year and 3-year average levels of PM2.5, O3, and NO2, respectively, compared to their 1-year average levels. The PCOS risk increased 1.75-fold (95% confidence interval: 1.66-1.85) in the fourth-quartile for the NO2 level. Increased SO2 and CO levels in the second- and third-quartiles were also associated with an increased PCOS risk. Exposure to air pollutants thus increased the risk for PCOS in the Korean population.

Vitamin C supplementation promotes mental vitality in healthy young adults: results from a cross-sectional analysis and a randomized, double-blind, placebo-controlled trial.

PURPOSE: We aimed to investigate the link of vitamin C status with vitality and psychological functions in a cross-sectional study, and examine their causal relationship through a randomized controlled trial (RCT). METHODS: We first conducted a population-based cross-sectional investigation of healthy young adults (n = 214, 20-39 years), and analyzed the associations of serum vitamin C concentrations with vitality (fatigue and attention) and mood status (stress, depression, and positive and negative affect) using Pearson's correlation and multiple linear regression analyses. Next, we performed a double-blind RCT in healthy subjects whose serum vitamin C concentrations were inadequate (< 50 µmol/L). Subjects were randomly allocated to receive 500 mg of vitamin C twice a day for 4 weeks (n = 24) or a placebo (n = 22). We assessed vitality, which included fatigue, attention, work engagement, and self-control resources, and measured mood status, including stress, depression, positive and negative affect, and anxiety. ELISA determined serum brain-derived neurotrophic factor (BDNF), and a Stroop color-word test evaluated attention capacity and processing speed. RESULTS: In the cross-sectional data, the serum vitamin C concentration was positively associated with the level of attention (r = 0.16, p = 0.02; standardized ß = 0.21, p = 0.003), while no significant associations with the levels of fatigue and mood variables being found. In the RCT, compared to the placebo, the vitamin C supplementation significantly increased attention (p = 0.03) and work absorption (p = 0.03) with distinct tendency of improvement on fatigue (p = 0.06) and comprehensive work engagement (p = 0.07). The vitamin C supplementation did not affect mood and serum concentrations of BDNF. However, in the Stroop color-word test, the subjects supplemented with vitamin C showed better performance than those in the placebo group (p = 0.04). CONCLUSION: Inadequate vitamin C status is related to a low level of mental vitality. Vitamin C supplementation effectively increased work motivation and attentional focus and contributed to better performance on cognitive tasks requiring sustained attention. TRIAL REGISTRATION NUMBER AND DATE OF REGISTRATION: Cross-sectional study: KCT0005074 (cris.nih.go.kr)/1 June, 2020 (retrospectively registered). Intervention study: KCT0004276 (cris.nih.go.kr)/4 September, 2019.