Unraveling the copper-death connection: Decoding COVID-19's immune landscape through advanced bioinformatics and machine learning approaches.

This study aims to analyze Coronavirus Disease 2019 (COVID-19)-associated copper-death genes using the Gene Expression Omnibus (GEO) dataset and machine learning, exploring their immune microenvironment correlation and underlying mechanisms. Utilizing GEO, we analyzed the GSE217948 dataset with control samples. Differential expression analysis identified 16 differentially expressed copper-death genes, and Cell type Identification By Estimating Relative Subsets Of RNA Transcripts (CIBERSORT) quantified immune cell infiltration. Gene classification yielded two copper-death clusters, with Weighted Gene Co-expression Network Analysis (WGCNA) identifying key module genes. Machine learning models (random forest, Support Vector Machine (SVM), Generalized Linear Model (GLM), eXtreme Gradient Boosting (XGBoost)) selected 6 feature genes validated by the GSE213313 dataset. Ferredoxin 1 (FDX1) emerged as the top gene, corroborated by Area Under the Curve (AUC) analysis. Gene Set Enrichment Analysis (GSEA) and Gene Set Variation Analysis (GSVA) revealed enriched pathways in T cell receptor, natural killer cytotoxicity, and Peroxisome Proliferator-Activated Receptor (PPAR). We uncovered differentially expressed copper-death genes and immune infiltration differences, notably CD8 T cells and M0 macrophages. Clustering identified modules with potential implications for COVID-19. Machine learning models effectively predicted COVID-19 risk, with FDX1's pivotal role validated. FDX1's high expression was associated with immune pathways, suggesting its role in COVID-19 pathogenesis. This comprehensive approach elucidated COVID-19-related copper-death genes, their immune context, and risk prediction potential. FDX1's connection to immune pathways offers insights into COVID-19 mechanisms and therapy.

Serum exosomal m6A demethylase FTO promotes gefitinib resistance in non-small cell lung cancer by up-regulating FLRT3, PTGIS and SIRPα expression.

This study investigates the molecular mechanism of FTO m6A demethylase in non-small cell lung cancer (NSCLC) and gefitinib resistance using GEO and TCGA databases. Differentially expressed genes (DEGs) were screened from RNA-seq data sets of serum exosomes of gefitinib-resistant NSCLC patients in the GEO database and the NSCLC data set in the GEPIA2 database. From this analysis, FTO m6A demethylase was found to be significantly upregulated in the serum exosomes of gefitinib-resistant NSCLC patients. To identify downstream genes affected by FTO m6A demethylase, weighted correlation network analysis and differential expression analysis were performed, resulting in the identification of three key downstream genes (FLRT3, PTGIS, and SIRPA). Using these genes, the authors constructed a prognostic risk assessment model. Patients with high-risk scores exhibited a significantly worse prognosis. The model could predict the prognosis of NSCLC with high accuracy measured by AUC values of 0.588, 0.608, and 0.603 at 1, 3, and 5 years respectively. Furthermore, m6A sites were found in FLRT3, PTGIS, and SIRPA genes, and FTO was significantly positively correlated with the expression of these downstream genes. Overall, FTO m6A demethylase promotes gefitinib resistance in NSCLC patients by upregulating downstream FLRT3, PTGIS, and SIRPA expression, with these three downstream genes serving as strong prognostic indicators.

Validation of different personalized risk models of chemotherapy-induced nausea and vomiting: results of a randomized, double-blind, phase III trial of fosaprepitant for cancer patients treated with high-dose cisplatin.

BACKGROUND: Highly emetogenic chemotherapy induces emesis in cancer patients without prophylaxis. The purpose of this study was to evaluate the efficacy and safety of a fosaprepitant-based triple antiemetic regimen for the prevention of chemotherapy-induced nausea and vomiting (CINV) in patients with solid malignant tumors, determine risk factors and externally validate different personalized risk models for CINV. METHODS: This phase III trial was designed to test the non-inferiority of fosaprepitant toward aprepitant in cancer patients who were to receive the first cycle of single-day cisplatin chemotherapy. The primary endpoint was complete response (CR) during the overall phase (OP) with a non-inferiority margin of 10.0%. Logistic regression models were used to assess the risk factors of CR and no nausea. To validate the personalized risk models, the accuracy of the risk scoring systems was determined by measuring the specificity, sensitivity and area under the receiver operating characteristic (ROC) curve (AUC), while the predictive accuracy of the nomogram was measured using concordance index (C-index). RESULTS: A total of 720 patients were randomly assigned. CR during the OP in the fosaprepitant group was not inferior to that in the aprepitant group (78.1% vs. 77.7%, P = 0.765) with a between-group difference of 0.4% (95% CI, -5.7% to 6.6%). Female sex, higher cisplatin dose (≥ 70 mg/m2 ), no history of drinking and larger body surface area (BSA) were significantly associated with nausea. The AUC for the acute and delayed CINV risk indexes was 0.68 (95% CI: 0.66-0.71) and 0.66 (95% CI: 0.61-0.70), respectively, and the C-index for nomogram CINV prediction was 0.59 (95% CI, 0.54-0.64). Using appropriate cutoff points, the three models could stratify patients with high- or low-risk CINV. No nausea and CR rate were significantly higher in the low-risk group than in the high-risk group (P < 0.001). CONCLUSIONS: Fosaprepitant-based triple prophylaxis demonstrated non-inferior control for preventing CINV in patients treated with cisplatin-base chemotherapy. Female cancer patients without a history of alcohol consumption, with larger BSA and received high-dose cisplatin might be more vulnerable to CINV. Three personalized prediction models were well-validated and could be used to optimize antiemetic therapy for individual patients.

Analytical design and experiment of radial inductive displacement sensor with full-bridge structure for magnetic bearings.

In magnetic bearing systems, the air gap between the stator and the rotor is generally measured with an eddy current displacement sensor. However, the inductive displacement sensor (IDS) is a preferred choice due to its structural consistency with magnetic bearings, which contributes to a compact system design. While most of the reported IDS research studies are based on three-dimensional finite element method (3D FEM) simulation and the IDS of such studies is designed with a half-bridge structure, in this paper, a higher sensitivity IDS with a full-bridge structure is proposed. To optimize the response of the sensor, an accurate theoretical analysis method is presented for the sensor based on the Schwarz-Christoffel transformation, which is used for compensating fringe effects of sensor inductance. Compared to traditional 3D FEM simulation, fast sensor design and optimization can be achieved with the proposed method. Experimental results agree well with theoretical predictions. The sensitivity of the proposed sensor is nearly 15.5 mV/µm, and the displacement resolution is better than 1 µm.

Chemotherapy in idiopathic pulmonary fibrosis and small-cell lung cancer with poor lung function.

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a chronic interstitial lung disease with unclear pathogenesis. IPF is considered as a risk factor for lung cancer. Compared to other lung cancers, small-cell lung cancer (SCLC) has a lower incidence, but has a more aggressive course. Patients with IPF and SCLC have a lower survival rate, more difficult treatment, and poorer prognosis. CASE PRESENTATION: Case 1 was of a 66-year-old man with IPF for 5 years, who was admitted to our hospital for dyspnea. Case 2 was of a 68-year-old woman, who presented with chest pains, cough, and dyspnea. Both patients had extremely poor lung function. High-resolution computed tomography and pathology revealed that both patients had IPF and SCLC. Chemotherapy comprising nedaplatin (80 mg/m2) and etoposide (100 mg for 5 days) was initiated for both patients. Antifibrotic agents were continued during the chemotherapeutic regimen. Both patients showed improvement in their condition after treatment. CONCLUSION: The favorable outcomes in these 2 cases suggests that chemotherapy is worth considering in the management of patients having SCLC and IPF with poor lung function.

Severe pneumonia in adults caused by Tropheryma whipplei and Candida sp. infection: a 2019 case series.

BACKGROUND: Whipple's disease is a chronic infectious disease caused by the Gram-positive bacterium Tropheryma whipplei (TW), which not only affects the gastrointestinal tract and causes malabsorption of nutrients, but several other systems, such as the cardiovascular system, central nervous system, the joints, and the vascular system, can also be simultaneously involved. The aim of this report was to be able to alert the clinician to severe pneumonia caused by TW combined with Candida sp. CASE PRESENTATION: The case study was conducted on patients in September and November 2019. After routine examination and treatment, the results were not satisfactory. A bronchoalveolar lavage (BAL) using metagenomics next-generation sequencing was conducted on two adults who presented with fever, cough, and progressive dyspnea and who had no history of gastrointestinal symptoms, immunodeficiency diseases, or use of immunosuppressive agents. TW and Candida sp. were detected in in BAL. CONCLUSIONS: This is a report of life-threatening pneumonia caused by TW combined with Candida sp. in a Chinese population.

Primary pulmonary diffuse large B-cell lymphoma with multiple ground-glass nodules as the primary manifestation: A case report.

INTRODUCTION: Primary pulmonary lymphoma (PPL) is a rare extranodal lymphoma. Only 5% to 20% of patients suffering from PPL have diffuse large ß-cell lymphoma (DLBCL), and their chest computed tomography (CT) findings show single- or double-lung patchy or flocculated shadows, isolated or multifocal nodules, or masses. In this research paper, we report an older woman having multiple ground-glass nodules, who was eventually diagnosed with primary pulmonary diffuse large ß-cell lymphoma (PPDLBCL). PATIENT CONCERNS: A 69-year-old woman suffering from cough was admitted to the Second Hospital of Jilin University. DIAGNOSES: A chest CT scan showed multiple ground-glass nodules. She had received 2 weeks of antibiotic treatment, but the multiple ground-glass nodules were still present. Lung biopsy was performed by tracheoscopy, which showed non-Hodgkin diffuse large ß-cell lymphoma. INTERVENTIONS: The patient received R-CHOP-21 chemotherapy. OUTCOMES: The multiple ground-glass nodules were absorbed. CONCLUSION: The current study shows that spotting multiple ground-glass nodules in the lungs is a clear indication of the presence of PPDLBCL. It is important to spread awareness of PPDLBCL, which needs timely diagnosis and management.

Risk Factors for Acute Exacerbation of Chronic Obstructive Pulmonary Disease in Industrial Regions of China: A Multicenter Cross-Sectional Study.

Background: The exacerbation of chronic obstructive pulmonary disease (COPD) seriously affects the patient's quality of life and prognosis. This multicenter cross-sectional study investigated the characteristics of stable COPD and risk factors for acute exacerbation of COPD (AECOPD) in patients in Changchun, Jilin Province, China. Methods: The study included 400 outpatients admitted to four secondary hospitals and four tertiary hospitals in Jilin Province from March 2018 to March 2019. Data on the general condition of stable COPD patients, patient self-management, COPD Assessment Test (CAT) scores, number of acute exacerbations in the past 12 months, and medications received during the study period were collected using a questionnaire. Results: Sociodemographic characteristics and clinical data were obtained from 306 patients, and drug prescription data were obtained from 329 patients. Pearson correlation analysis revealed that CAT scores were positively correlated with the number of acute exacerbations. Age, education level, smoking history, disease duration, number of comorbidities, and the presence of ischemic heart disease (IHD) were associated with AECOPD. Moreover, the level of education, disease duration, and the presence of IHD were independent risk factors for AECOPD. Poor compliance due to the lack of understanding of the disease and the high cost of treatment is a risk factor for AECOPD. In addition, increased air pollution in industrial cities and vitamin D deficiency are closely related to AECOPD. Conclusion: Low education level, long disease duration, and the presence of IHD may promote the exacerbation and poor control of COPD in patients in Jilin Province.

Relationship of chest CT score with clinical characteristics of 108 patients hospitalized with COVID-19 in Wuhan, China.

BACKGROUND: In December 2019, the outbreak of a disease subsequently termed COVID-19 occurred in Wuhan, China. The number of cases increased rapidly and spread to six continents. However, there is limited information on the chest computed tomography (CT) results of affected patients. Chest CT can assess the severity of COVID-19 and has sufficient sensitivity to assess changes in response to glucocorticoid therapy. OBJECTIVE: Analyze COVID-19 patients to determine the relationships of clinical characteristics, chest CT score, and levels of inflammatory mediators. METHODS: This retrospective, single-center case series of 108 consecutive hospitalized patients with confirmed COVID-19 at Tongji Hospital, Tongji Medical College of HUST (Wuhan, China) examined patients admitted from January 28 to February 20, 2020. Patient demographics, comorbidities, clinical findings, chest CT results, and CT scores of affected lung parenchyma were recorded. The relationships between chest CT score with levels of systemic inflammatory mediators were determined. RESULTS: All patients exhibited signs of significant systemic inflammation, including increased levels of C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), procalcitonin, chest CT score, and a decreased lymphocyte (LY) count. Chest CT score had positive associations with white blood cell (WBC) count, CRP, ESR, procalcitonin, and abnormal coagulation function, and a negative association with LY count. Treatment with a glucocorticoid increased the LY count, reduced the CT score and CRP level, and improved coagulation function. CONCLUSIONS: COVID-19 infection is characterized by a systemic inflammatory response that affects the lungs, blood, digestive system, and circulatory systems. The chest CT score is a good indicator of the extent of systemic inflammation. Glucocorticoid treatment appears to reduce systemic inflammation in these patients.

A rare cause of sudden chest pain and dyspnea: A CARE-compliant case report of Chilaiditi syndrome.

RATIONALE: Chilaiditi syndrome is a rare disorder characterized by a broad spectrum of (gastro-intestinal) symptoms caused by interposition of a segment of bowel between the liver and the diaphragm. Most cases present with abdominal symptoms and the morbidity tend to increase with age. PATIENT CONCERNS: Here we present a rare case of Chilaiditi syndrome. An elderly postmenopausal woman developed unresolved postoperative respiratory symptoms and chest pain. Chest auscultation revealed considerable attenuation of respiratory sounds. She showed postoperative increase in D-dimer level and sudden onset of dyspnea. DIAGNOSES: Considering the presence of atelectasis in the middle and lower lobes of the right lung, bedside fiberoptic bronchoscopy was performed immediately to rule out bronchial phlegm embolism. However, no phlegm embolism was found in the left lung, and a small amount of yellow-white mucus was seen in the upper lobe of the right lung. Due to external pressure, the lumen of the middle and lower lobes of the right lung was obviously narrowed. INTERVENTIONS: The patient was placed in a semi-sitting position and a tube was passed through the anus to decompress the intestinal cavity; in addition, she received potassium supplementation. OUTCOMES: The patient's symptoms improved markedly. Chest and semi-supine abdominal plain radiographs showed enhanced lung markings, shadows in the left lower lung lobes, elevation of the right diaphragm, and small amount of pneumoperitoneum. The patient recovered after 5 days of continuous treatment and was discharged. LESSONS: Emergency computed tomographic pulmonary angiography may facilitate the diagnosis of Chilaiditi syndrome, especially in the postoperative setting. Occurrence of Chilaiditi syndrome in this patient was likely associated with surgical factors. Appropriate investigations and clear identification of etiology are essential for successful treatment.

Vanillin protects lipopolysaccharide-induced acute lung injury by inhibiting ERK1/2, p38 and NF-κB pathway.

Aim: Thus far, the anti-inflammatory effect of vanillin in acute lung injury (ALI) has not been studied. This study aimed to investigate the effect of vanillin in lipopolysaccharide (LPS)-induced ALI. Results & methodology: Our study detected the anti-inflammatory effects of vanillin by ELISA and western blot, respectively. Pretreatment of mice with vanillin significantly attenuated LPS-stimulated lung histopathological changes, myeloperoxidase activity and expression levels of proinflammatory cytokines by inhibiting the phosphorylation activities of ERK1/2, p38, AKT and NF-κB p65. In addition, vanillin inhibited LPS-induced TNF-α and IL-6 expression in RAW264.7 cells via ERK1/2, p38 and NF-κB signaling. Conclusion: Vanillin can inhibit macrophage activation and lung inflammation, which suggests new insights for clinical treatment of ALI.

Role of RNA-binding protein 5 in the diagnosis and chemotherapeutic response of lung cancer.

Lung cancer remains one of the leading causes of cancer-associated mortality in the world. Lung carcinogenesis is frequently associated with deletions or the loss of heterozygosity at the critical chromosomal region 3p21.3, where RNA-binding protein 5 (RBM5) is localized. RBM5 regulates cell growth, cell cycle progression and apoptosis in cell homeostasis. In the lungs, altered RBM5 protein expression leads to alterations in cell growth and apoptosis, with subsequent lung pathogenesis and varied responses to treatment in patients with lung cancer. Detection of RBM5 expression may be a tumor marker for diagnosis, prediction and treatment response in lung cancer, and may be developed as a potential therapeutic target for drug resistant lung cancer. This review discusses the most recent progress on the role of RBM5 in lung cancer.

Effect of Fluconazole Coadministration and CYP2C9 Genetic Polymorphism on Siponimod Pharmacokinetics in Healthy Subjects.

OBJECTIVES: The aim of this study was to assess the pharmacokinetics (PK) and safety/tolerability of siponimod in healthy subjects when coadministered with (1) the moderate cytochrome P450 (CYP) 2C9 and CYP3A inhibitor fluconazole (Study A), and (2) with three different CYP2C9 genotype variants (Study B). METHODS: Study A was an open-label, single-dose study comprising periods 1 (14 days; day 1: siponimod 4 mg) and 2 (20 days; day 1: fluconazole 200 mg twice daily; days 2-19: fluconazole 200 mg once daily; day 3: siponimod 4 mg) in healthy subjects (n = 14) with the wild-type CYP2C9 genotype (CYP2C9*1/*1). Study B was a multicentre, open-label study comprising parts 1 (day 1: siponimod 0.25 mg once daily in the CYP2C9*1/*1, CYP2C9*2/*3 and CYP2C9*3/*3 genotypes) and 2 (days 1-2: 0.25 mg once daily; day 3: 0.5 mg once daily in the CYP2C9*2/*3 and CYP2C9*3/*3 genotypes only) in healthy subjects with polymorphic variants of CYP2C9 (n = 24). Pharmacokinetic parameters were calculated using noncompartmental methods. RESULTS: In Study A, coadministration with fluconazole produced an approximately twofold increase in mean area under the curve (AUC) versus siponimod alone (from 1110 to 2160 h*ng/mL), and an increase in maximum plasma concentration (Cmax; from 31.2 to 34.0 ng/mL) and elimination half-life (T½; from 40.6 to 61.6 h). In Study B, the AUCs of siponimod were approximately two to fourfold greater in subjects with the CYP2C9*2/*3 and CYP2C9*3/*3 genotypes, with a minor increase in Cmax versus the CYP2C9*1/*1 genotype. The mean T½ was prolonged in the CYP2C9*2/*3 (51 h) and CYP2C9*3/*3 (126 h) genotypes versus the CYP2C9*1/*1 (28 h) genotype. Siponimod did not result in increased adverse events in healthy subjects in both studies. CONCLUSIONS: Changes in siponimod PK, when coadministered with fluconazole at steady-state and in subjects with different CYP2C9 genotypes, indicate that the reduced CYP2C9 enzymatic activity does not affect the absorption phase of siponimod but prolongs the elimination phase. These results confirm the relevance of CYP2C9 activity on siponimod metabolism in humans.

Myricetin attenuates LPS-induced inflammation in RAW 264.7 macrophages and mouse models.

AIM: Acute lung injury is a common clinical syndrome associated with significant morbidity. Myricetin has been demonstrated to inhibit inflammation in a variety of diseases. In this study, we aimed to investigate the protective effects of myricetin on inflammation in lipopolysaccharide-stimulated RAW 264.7 cells and lipopolysaccharide-induced lung injury model. Results/methodology: In this study, we detected the anti-inflammatory effects of myricetin by ELISA, RT-PCR and Western blot, respectively. Myricetin significantly inhibited the production of the proinflammatory cytokines in vitro and in vivo. It exerted an anti-inflammatory effect through suppressing the NF-κB p65 and AKT activation in NF-κB pathway and JNK, p-ERK and p38 in MAPK signaling pathway. CONCLUSION: Myricetin alleviated acute lung injury by inhibiting macrophage activation, and inhibited inflammation in vitro and in vivo. It may be a potential therapeutic candidate for the prevention of inflammatory diseases.

Impact of siponimod on vaccination response in a randomized, placebo-controlled study.

OBJECTIVE: To evaluate effects of siponimod on response to T-cell-dependent (influenza) and T-cell-independent (pneumococcal polysaccharide vaccine [PPV-23]) vaccinations in healthy participants. METHODS: In this double-blind, placebo-controlled, parallel-group study, each participant underwent a 7-week treatment period and received intramuscular injections of influenza and PPV-23 vaccines (day 21). Participants were randomized to 4 treatment groups (N = 30 each) and received placebo or siponimod 2 mg once daily in concomitant, interrupted, or preceding fashion. Individual response to vaccination was defined by a ≥4-fold (influenza) antibody titer increase and by a ≥2-fold increase in serotype-specific immunoglobulin (Ig) G concentrations (PPV-23) on day 28 vs baseline. Responder rates were compared using noninferiority analysis. RESULTS: Mean influenza titers were similar to placebo in the preceding and interrupted groups but lower in the concomitant group. The proportion of participants with influenza titers ≥40 four weeks after vaccination (seroprotection) was similar to placebo across all groups and antigens. In each treatment group, response criteria were met for 3 of 4 antigens including H1N1 and H3N2. A noninferior response was determined in the context of preceding treatment but not interrupted or concomitant treatment. Regarding PPV-23, approximately 90%-100% of participants exhibited a ≥2-fold increase in IgG concentrations vs baseline. Noninferior responder rates were determined for each siponimod treatment group. CONCLUSIONS: Siponimod treatment had no relevant effect on antibody response to PPV-23. European Medicines Agency response criteria were essentially met for influenza, but titers were lower on concomitant treatment. Overall, these data suggest that siponimod has limited effect on the efficacy of vaccinations with neoantigens. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that in healthy persons, siponimod had limited effect on the immune response following influenza or pneumococcal vaccinations.

Interluekin-35 in Asthma and Its Potential as an Effective Therapeutic Agent.

Interleukin- (IL-) 35 is a member of the IL-12 cytokine family and a heterodimeric protein formed by Epstein-Barr-induced gene 3 (EBI3) and IL-12p35. Emerging evidence shows that IL-35 is a key player in the regulation of cellular communication, differentiation, and inflammation. Altered IL-35 expression has been found in disease conditions such as cancer, rheumatoid arthritis, and, more recently, asthma. In cancer, IL-35 is involved in the regulation of tumorigenesis, cancer progression, and metastasis. In rheumatoid arthritis, IL-35 acts as a negative regulator of inflammation. Similarly, IL-35 also appears to suppress allergic inflammation in asthma. In an in vivo murine model of asthma, transfer of adenovirus-mediated IL-35 markedly reduced the degree of airway hyperresponsiveness (AHR) and inflammatory cell infiltration. Many studies have shown the involvement of IL-35 in a number of aspects of allergic inflammation, such as eosinophil and neutrophil recruitment as well as inhibition of inflammatory mediators of the Th2 subtype. However, the exact molecular mechanisms underlying the role of IL-35 in human asthma have yet to be fully elucidated. This review describes the current evidence regarding the role of IL-35 in the pathophysiology of asthma and evaluates the potential of IL-35 as a biomarker for airway inflammation and a therapeutic target for the treatment of asthma.

Expression of RNA-binding motif 10 is associated with advanced tumor stage and malignant behaviors of lung adenocarcinoma cancer cells.

This study assessed RNA-binding motif 10 expression in lung adenocarcinoma tissues and examined the role and mechanism of RNA-binding motif 10 in the regulation of lung adenocarcinoma malignancy. Lung adenocarcinoma and corresponding adjacent non-tumor lung tissues from 41 patients were subjected to reverse transcription-polymerase chain reaction and Western blot assessment to detect RNA-binding motif 10 expression. Recombinant lentivirus carrying RNA-binding motif 10 complementary DNA was used to infect lung adenocarcinoma cell lines, A549 and H1299 cells. Complementary DNA microarray was used to profile RNA-binding motif 10-regulated genes. Levels of RNA-binding motif 10 messenger RNA and protein were significantly lower in lung adenocarcinoma tissues than those in paired non-tumor tissues (p < 0.001). Reduced RNA-binding motif 10 expression was found to be associated with an advanced tumor stage. RNA-binding motif 10 overexpression inhibited viability and colony formation capacity of lung adenocarcinoma cell lines and induced cell-cycle arrest at G0/G1 phase in A549 cells and at S phase in H1299 cells. Complementary DNA microarray analysis identified 304 upregulated and 386 downregulated genes induced by RNA-binding motif 10 overexpression, which may be involved in cancer, focal adhesion, peroxisome proliferator-activated receptor-regulated gene pathway, cytokine-cytokine receptor interaction, mitogen-activated protein kinase signaling, complement and coagulation cascades, platelet amyloid precursor protein pathway, extracellular matrix-receptor interaction, and small cell lung cancer-related genes. Expression of FGF2, EGFR, WNT5A, NF-κB, and RAP1A was downregulated, whereas expression of AKT2, BIRC3, and JUN was upregulated. RNA-binding motif 10 messenger RNA and protein were reduced in lung adenocarcinoma tissues, and RNA-binding motif 10 overexpression inhibited lung adenocarcinoma cancer cell malignant behavior in vitro. Molecularly, RNA-binding motif 10 regulates many gene pathways involving in the tumor development or progression.

Pharmacokinetics and safety of indacaterol and glycopyrronium (IND/GLY) following repeated once daily inhalation from a fixed-dose combination in healthy Chinese subjects
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OBJECTIVE: Indacaterol/glycopyrronium (IND/GLY) is a once-daily fixed-dose combination of two long-acting bronchodilators: indacaterol 110 µg (long-acting ß2-adrenergic agonist, LABA) and glycopyrronium 50 µg (long-acting muscarinic antagonist, LAMA). This study assessed the pharmacokinetics of IND/GLY 110/50 µg following multiple once-daily inhaled administrations in healthy Chinese subjects. METHODS: This was a single-centre, open-label, multiple-dose study of inhaled IND/GLY delivered via the Breezhaler® device. Pharmacokinetic samples were collected on day 1 after first dose, on days 5, 7, 10, and 12 (predose (trough)) and on day 14 (steady state) after last dose for pharmacokinetic analysis using non-compartmental analysis. RESULTS: Both IND and GLY were absorbed rapidly after inhalation of IND/GLY (tmax: IND, 15 minutes; GLY, 5 minutes). Accumulation through systemic exposure of both IND and GLY from day 1 to day 14 was observed (mean accumulation ratio (Racc) of AUC0-24h (day 14/day 1): IND, 3.02; GLY 2.94; estimated accumulation ratio of Cmax: IND 1.56; GLY 1.33). Mean effective half-life (t1/2,acc) was 41.3 h and 40.0 h for IND and GLY, respectively. Pharmacokinetic steady states were reached after 12 and 10 days of daily dosing for IND and GLY, respectively. There was one mild adverse event (AE) not related to the study drug. No discontinuations due to treatment related AEs/SAEs (adverse event/serious adverse event) were reported. CONCLUSIONS: In healthy Chinese subjects, multiple once-daily inhaled doses of IND/GLY 110/50 µg were rapidly absorbed and were safe and well tolerated. The comparison of systemic exposure data following inhalation of IND/GLY 110/50 µg in Chinese vs. the non-Chinese populations did not indicate any clinically relevant differences across ethnicities.
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Pharmacokinetics, safety, and tolerability of siponimod (BAF312) in subjects with different levels of hepatic impairment: a single-dose, open-label, parallel-group study
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OBJECTIVE: To assess the pharmacokinetics (PK), safety, and tolerability of siponimod and major metabolites in subjects with mild, moderate, and severe hepatic impairment (HI) compared with demographically-matched healthy subjects (HS). METHODS: This open-label, parallel-group study enrolled 40 subjects (each HI group, n = 8; HS group, n = 16). A staged design was employed starting with the enrollment of subjects with mild HI, followed by those with moderate and severe HI. All subjects received single oral doses of 0.25 mg siponimod on day 1; PK and safety data were collected during the 21-day follow-up. RESULTS: All subjects had similar baseline characteristics and completed the study. No significant differences were observed in the plasma exposure of siponimod in mild, moderate, and severe HI groups vs. HS: Cmax changed by 16%, -13%, and -16%; AUC by 5%, -13%, and 15%, respectively. The unbound siponimod PK parameters vs. HS were similar in the mild HI, and increased in the moderate (Cmax, 15%; AUC, 17%) and severe HI groups (Cmax, 11%; AUC, 50%). Exposure of M3 and M5 also showed 2- to 5-fold increase, particularly in the moderate and severe HI groups vs HS. There were no clinically-relevant safety findings. CONCLUSIONS: Single oral doses of 0.25 mg siponimod were well tolerated, and HI did not significantly alter exposure to siponimod. Increase in the M3 and M5 metabolites requires further evaluation. These results do not warrant any dose adjustments of siponimod in subjects with HI.
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Overexpression of RBM5 induces autophagy in human lung adenocarcinoma cells.

BACKGROUND: Dysfunctions in autophagy and apoptosis are closely interacted and play an important role in cancer development. RNA binding motif 5 (RBM5) is a tumor suppressor gene, which inhibits tumor cells' growth and enhances chemosensitivity through inducing apoptosis in our previous studies. In this study, we investigated the relationship between RBM5 overexpression and autophagy in human lung adenocarcinoma cells. METHODS: Human lung adenocarcinoma cancer (A549) cells were cultured in vitro and were transiently transfected with a RBM5 expressing plasmid (GV287-RBM5) or plasmid with scrambled control sequence. RBM5 expression was determined by semi-quantitative reverse transcription polymerase chain reaction (RT-PCR) and Western blot. Intracellular LC-3 I/II, Beclin-1, lysosome associated membrane protein-1 (LAMP1), Bcl-2, and NF-κB/p65 protein levels were detected by Western blot. Chemical staining with monodansylcadaverine (MDC) and acridine orange (AO) was applied to detect acidic vesicular organelles (AVOs). The ultrastructure changes were observed under transmission electron microscope (TEM). Then, transplanted tumor models of A549 cells on BALB/c nude mice were established and treated with the recombinant plasmids carried by attenuated Salmonella to induce RBM5 overexpression in tumor tissues. RBM5, LC-3, LAMP1, and Beclin1 expression was determined by immunohistochemistry staining in plasmids-treated A549 xenografts. RESULTS: Our study demonstrated that overexpression of RBM5 caused an increase in the autophagy-related proteins including LC3-I, LC3-II, LC3-II/LC3-I ratio, Beclin1, and LAMP1 in A549 cells. A large number of autophagosomes with double-membrane structure and AVOs were detected in the cytoplasm of A549 cells transfected with GV287-RBM5 at 24 h. We observed that the protein level of NF-κB/P65 was increased and the protein level of Bcl-2 decreased by RBM5 overexpression. Furthermore, treatment with an autophagy inhibitor, 3-MA, enhanced RBM5-induced cell death and chemosensitivity in A549 cells. Furthermore, we successfully established the lung adenocarcinoma animal model using A549 cells. Overexpression of RBM5 enhanced the LC-3, LAMP1, and Beclin1 expression in the A549 xenografts. CONCLUSIONS: Our findings showed for the first time that RBM5 overexpression induced autophagy in human lung adenocarcinoma cells, which might be driven by upregulation of Beclin1, NF-κB/P65, and downregulation of Bcl-2. RBM5-enhanced autophagy acts in a cytoprotective way and inhibition of autophagy may improve the anti-tumor efficacy of RBM5 in lung cancer.