Exploring the causal effect between lipid-modifying drugs and idiopathic pulmonary fibrosis: a drug-target Mendelian randomization study.

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a respiratory disorder of obscure etiology and limited treatment options, possibly linked to dysregulation in lipid metabolism. While several observational studies suggest that lipid-lowering agents may decrease the risk of IPF, the evidence is inconsistent. The present Mendelian randomization (MR) study aims to determine the association between circulating lipid traits and IPF and to assess the potential influence of lipid-modifying medications for IPF. METHODS: Summary statistics of 5 lipid traits (high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, triglyceride, apolipoprotein A, and apolipoprotein B) and IPF were sourced from the UK Biobank and FinnGen Project Round 10. The study's focus on lipid-regulatory genes encompassed PCSK9, NPC1L1, ABCG5, ABCG8, HMGCR, APOB, LDLR, CETP, ANGPTL3, APOC3, LPL, and PPARA. The primary effect estimates were determined using the inverse-variance-weighted method, with additional analyses employing the contamination mixture method, robust adjusted profile score, the weighted median, weighted mode methods, and MR-Egger. Summary-data-based Mendelian randomization (SMR) was used to confirm significant lipid-modifying drug targets, leveraging data on expressed quantitative trait loci in relevant tissues. Sensitivity analyses included assessments of heterogeneity, horizontal pleiotropy, and leave-one-out methods. RESULTS: There was no significant effect of blood lipid traits on IPF risk (all P＞0.05). Drug-target MR analysis indicated that genetic mimicry for inhibitor of NPC1L1, PCSK9, ABCG5, ABCG8, and APOC3 were associated with increased IPF risks, with odds ratios (ORs) and 95% confidence intervals (CIs) as follows: 2.74 (1.05-7.12, P = 0.039), 1.36 (1.02-1.82, P = 0.037), 1.66 (1.12-2.45, P = 0.011), 1.68 (1.14-2.48, P = 0.009), and 1.42 (1.20-1.67, P = 3.17×10-5), respectively. The SMR method identified a significant association between PCSK9 gene expression in whole blood and reduced IPF risk (OR = 0.71, 95% CI: 0.50-0.99, P = 0.043). Sensitivity analyses showed no evidence of bias. CONCLUSIONS: Serum lipid traits did not significantly affect the risk of idiopathic pulmonary fibrosis. Drug targets MR studies examining 12 lipid-modifying drugs indicated that PCSK9 inhibitors could dramatically increase IPF risk, a mechanism that may differ from their lipid-lowering actions and thus warrants further investigation.

Simultaneous occurrence of invasive pulmonary aspergillosis and diffuse large B-cell lymphoma: case report and literature review.

BACKGROUND: Patients with lymphoma are at risk for developing pulmonary opportunistic infections due to immunocompromise. However, clinical reports of concurrent lymphoma and opportunistic infection at presentation are rare and often confined to single cases. A delayed diagnosis of either opportunistic infection or lymphoma usually occurs in this complex situation. Here, we report such a case and analyse 18 similar cases searched in the PubMed database to deepen clinicians' understanding. CASE PRESENTATION: A 48-year-old man presented with a 3-month history of fever, cough and emaciation. High-resolution computed tomography revealed bilateral cavitating lesions of different sizes. Aspergillus fumigatus complex was identified from a bronchoalveolar lavage fluid culture. However, antifungal treatment combined with multiple rounds of antibacterial therapy was unsuccessful, and the patient's lung lesions continued to deteriorate. Multiple puncture biopsies finally confirmed the coexistence of diffuse large B-cell lymphoma. Despite the initiation of combination chemotherapy, the patient died of progressive respiratory failure. CONCLUSIONS: Synchronous pulmonary lymphoma and simultaneous opportunistic infection is rare and usually lacks specific clinical and imaging manifestations. Lymphoma should be considered as part of the differential diagnosis of patients with an opportunistic infection when treatment fails or other symptoms are present that could be considered "atypical" for the condition. Tissue biopsy is the gold standard, and multiple biopsies are essential for making the final diagnosis and should be performed upon early suspicion.

Downregulation of CPA4 inhibits non small-cell lung cancer growth by suppressing the AKT/c-MYC pathway.

Carboxypeptidase A4 (CPA4) is a member of the metallocarboxypeptidase family. A previous study indicated that CPA4 may participate in the modulation of peptide hormone activity and hormone-regulated tissue growth and differentiation. However, the role of CPA4 in lung tumorigenesis remains unclear. Our study revealed that CPA4 expression was higher in both lung cancer cells and tumor tissues. We performed 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide assays, colony-formation assays, and Cellomics ArrayScan Infinity analysis to demonstrate that CPA4 knockdown inhibited non small-cell lung cancer (NSCLC) cell proliferation. Conversely, ectopic expression of CPA4 enhanced lung cancer cell proliferation. Consistent with these observations, we generated xenograft tumor models to confirm that CPA4 downregulation suppressed NSCLC cell growth. Mechanistically, we revealed that CPA4 downregulation may induce apoptosis and G1-S arrest by suppressing the protein kinase B/c-MYC pathway. These results suggest that CPA4 has an oncogenic effect on lung cancer growth. Taken together, we identified a novel gene in lung cancer that might provide a basis for new therapeutic targets.