Corrigendum: Exploring the bi-directional relationship and shared genes between depression and stroke via NHANES and bioinformatic analysis.

[This corrects the article DOI: 10.3389/fgene.2023.1004457.].

Investigating Causal Effects of Hematologic Traits on Lung Cancer: A Mendelian Randomization Study.

BACKGROUND: Observational studies have suggested blood cell counts may act as predictors of cancer. It is not known whether these hematologic traits are causally associated with lung cancer. METHODS: Two-sample bidirectional univariable Mendelian randomization (MR) and multivariable MR (MVMR) were performed to investigate the causal association between hematologic traits and the overall risk of lung cancer and three histologic subtypes [lung adenocarcinoma, squamous cell lung cancer, and small cell lung cancer (SCLC)]. The instrumental variables of 23 hematologic traits were strictly selected from large-scale genome-wide association studies. Inverse-variance weighted method and five extra methods were used to obtain robust causal estimates. RESULTS: We found evidence that genetically influenced higher hematocrit [OR, 0.845; 95% confidence interval (CI), 0.783-0.913; P = 1.68 × 10-5] and hemoglobin concentration (OR, 0.868; 95% CI, 0.804-0.938; P = 3.20 × 10-4) and reticulocyte count (OR, 0.923; 95% CI, 0.872-0.976; P = 5.19 × 10-3) decreased lung carcinoma risk, especially in ever smokers. MVMR further identified hematocrit independently of smoking as an independent predictor. Subgroup analysis showed that a higher plateletcrit level increased the risk of small cell lung carcinoma (OR, 1.288; 95% CI, 1.126-1.474; P = 2.25 × 10-4). CONCLUSIONS: Genetically driven higher levels of reticulocyte count and hematocrit decreased lung cancer risk. Higher plateletcrit had an adverse effect on SCLC. Hematologic traits may act as low-cost factors for lung cancer risk stratification. IMPACT: Further studies are required to elucidate the potential mechanisms underlying the dysregulation of homeostasis related to hematologic traits, such as subclinical inflammation.

Exploring the bi-directional relationship and shared genes between depression and stroke via NHANES and bioinformatic analysis.

Background: Stroke and depression are the two most common causes of disability worldwide. Growing evidence suggests a bi-directional relationship between stroke and depression, whereas the molecular mechanisms underlying stroke and depression are not well understood. The objectives of this study were to identify hub genes and biological pathways related to the pathogenesis of ischemic stroke (IS) and major depressive disorder (MDD) and to evaluate the infiltration of immune cells in both disorders. Methods: Participants from the United States National Health and Nutritional Examination Survey (NHANES) 2005-2018 were included to evaluate the association between stroke and MDD. Two differentially expressed genes (DEGs) sets extracted from GSE98793 and GSE16561 datasets were intersected to generate common DEGs, which were further screened out in cytoHubba to identify hub genes. GO, KEGG, Metascape, GeneMANIA, NetworkAnalyst, and DGIdb were used for functional enrichment, pathway analysis, regulatory network analysis, and candidate drugs analysis. ssGSEA algorithm was used to analyze the immune infiltration. Results: Among the 29706 participants from NHANES 2005-2018, stroke was significantly associated with MDD (OR = 2.79,95% CI:2.26-3.43, p < 0.0001). A total of 41 common upregulated genes and eight common downregulated genes were finally identified between IS and MDD. Enrichment analysis revealed that the shared genes were mainly involved in immune response and immune-related pathways. A protein-protein interaction (PPI) was constructed, from which ten (CD163, AEG1, IRAK3, S100A12, HP, PGLYRP1, CEACAM8, MPO, LCN2, and DEFA4) were screened. In addition, gene-miRNAs, transcription factor-gene interactions, and protein-drug interactions coregulatory networks with hub genes were also identified. Finally, we observed that the innate immunity was activated while acquired immunity was suppressed in both disorders. Conclusion: We successfully identified the ten hub shared genes linking the IS and MDD and constructed the regulatory networks for them that could serve as novel targeted therapy for the comorbidities.

Overexpression of Wnt7b antagonizes the inhibitory effect of dexamethasone on osteoblastogenesis of ST2 cells.

INTRODUCTION: It is well established that glucocorticoid-induced osteoporosis is highly associated with preosteoblast differentiation and function. This study is based on the premise that Wnt7b can promote bone formation through Wnt signalling pathway because it can stimulate preosteoblast differentiation and increase its activity. However, it is unknown whether Wnt7b can rescue the inhibited osteoblast differentiation and function caused by exogenous glucocorticoid. MATERIAL AND METHODS: In this study we used Wnt7b overexpression ST2 cells to explore whether Wnt7bcan rescue the inhibited osteoblast differentiation and function, which can provide strong proof to investigate a new drug for curing the glucocorticoid induced osteoporosis. RESULTS/CONCLUSION: We found that Wnt7b can rescue the suppressed osteoblast differentiation and function without cell viability caused by dexamethasone.

Girdin Promotes Tumorigenesis and Chemoresistance in Lung Adenocarcinoma by Interacting with PKM2.

Girdin, an Akt substrate, has been reported to promote tumorigenesis in various tumors. However, the role of Girdin in a spontaneous tumor model has not yet been explored. Here, we studied the role of Girdin in lung adenocarcinoma (LUAD) using the autochthonous mouse model and found that Girdin led to LUAD progression and chemoresistance by enhancing the Warburg effect. Mechanistically, Girdin interacted with pyruvate kinase M2 (PKM2), which played a vital role in aerobic glycolysis. Furthermore, Girdin impaired Platelet Derived Growth Factor Receptor Beta (PDGFRß) degradation, which in turn, promoted PKM2 tyrosine residue 105 (Y105) phosphorylation and inhibited PKM2 activity, subsequently promoting aerobic glycolysis in cancer cells. Taken together, our study demonstrates that Girdin is a crucial regulator of tumor growth and may be a potential therapeutic target for overcoming the resistance of LUAD cells to chemotherapy.

Suppression of DLBCL Progression by the E3 Ligase Trim35 Is Mediated by CLOCK Degradation and NK Cell Infiltration.

The majority of diffuse large B-cell lymphoma (DLBCL) patients develop relapsed or refractory disease after standard ruxolitinib, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) chemotherapy, which is partly related to a dysregulated tumor immune microenvironment. However, how the infiltration of immune cells is appropriately regulated is poorly understood. Herein, we show that the E3 ubiquitin ligase Trim35 is expressed at low levels in human DLBCL tissues. We also show that overexpression of Trim35 suppresses DLBCL cell proliferation and correlates with inferior survival in DLBCL patients. Our mechanistic study shows that Trim35 functions as an E3 ligase to mediate the ubiquitination and degradation of CLOCK, a key regulator of circadian rhythmicity. High expression of Trim35 correlates with NK cell infiltration in DLBCL, partly due to the degradation of CLOCK. Consistently, patients with high expression of CLOCK show poor overall survival. Overall, these findings suggest that Trim35 suppresses the progression of DLBCL by modulating the tumor immune microenvironment, indicating that it may be a promising diagnostic and prognostic biomarker in DLBCL.

Phase III Randomized Trial of Palonosetron and Dexamethasone With or Without Aprepitant to Prevent Nausea and Vomiting Induced by Full-dose Single-day Cisplatin-based Chemotherapy in Lung Cancer.

INTRODUCTION: This study aimed to determine the efficacy and safety of aprepitant, palonosetron, and dexamethasone to prevent chemotherapy-induced nausea and vomiting in patients with locally advanced or metastatic lung cancer receiving full-dose single-day cisplatin-based combination chemotherapy. MATERIALS AND METHODS: Patients diagnosed with locally advanced or metastatic lung cancer who received full dose single-day cisplatin-based chemotherapy were randomized (1:1) to aprepitant plus palonosetron and dexamethasone, or placebo plus palonosetron and dexamethasone. The primary endpoint was complete response of nausea and vomiting in the first cycle. The secondary endpoints were the proportion of patients with nausea and vomiting who received rescue antiemetic medication, the response of cross-over patients, and safety. RESULTS: A total of 244 patients were randomized. There was no difference between the 2 groups regarding personal characteristics. The administration of aprepitant significantly improved the complete response for vomiting in the overall period (92.6% vs. 79.93%; P < .01), but not a nausea-free response (75.4% vs. 71.3%; P > .05) in the first cycle. The percentage of patients who received rescue antiemetic medication was decreased for the aprepitant group (14.8% vs. 37.1%; P < .001). Patients who did not use aprepitant and suffered with nausea and vomiting in cycle 1 were crossed over to the aprepitant group (N = 32), and the rate of nausea and vomiting in cycle 2 was decreased to 37.5% (P < .05) and 25% (P < .05), respectively. There were no drug-related adverse effects. CONCLUSIONS: Aprepitant plus palonosetron and dexamethasone proved to be effective and well-tolerated in preventing chemotherapy-induced nausea and vomiting after administration of full-dose single-day cisplatin-based combination chemotherapy.