Shared biomarkers and mechanisms in idiopathic pulmonary fibrosis and non-small cell lung cancer.

BACKGROUND: Epidemiological evidence has indicated the occurrence of idiopathic pulmonary fibrosis (IPF) with coexisting lung cancer is not a coincidence. The pathogenic mechanisms shared between IPF and non-small cell lung cancer (NSCLC) at the transcriptional level remain elusive and need to be further elucidated. METHODS: IPF and NSCLC datasets of expression profiles were obtained from the GEO database. Firstly, to detect the shared dysregulated genes positively correlated with both IPF and NSCLC, differentially expressed analysis and WGCNA analysis were carried out. Functional enrichment and the construction of protein-protein network were employed to reveal pathogenic mechanisms related to two diseases mediated by the shared dysregulated genes. Then, the LASSO regression was adopted for screening critical candidate biomarkers for two disorders. Moreover, ROC curves were applied to evaluate the diagnostic value of the candidate biomarkers in both IPF and NSCLC. RESULTS: The 20 shared dysregulated genes positively correlated with both IPF and NSCLC were identified after intersecting differentially expressed analysis and WGCNA analysis. Functional enrichment revealed the 20 shared genes mostly enriched in extracellular region, which is critical in the organization of extracellular matrix. The protein-protein networks unrevealed the interaction of the 11 shared genes involving in collagen deposition and the connection between PYCR1 with PSAT1. PSAT1, PYCR1, COL10A1 and KIAA1683 were screened by the LASSO regression. ROC curves comprising area under the curve (AUC) verified the potential diagnostic value of PSAT1 and COL10A1 in both IPF and NSCLC. CONCLUSIONS: We revealed dysregulated extracellular matrix through aberrant expression of the relevant genes, which provided further understanding for the common molecular mechanisms predisposing the occurrence of both IPF and NSCLC.

An observational study of clinical recurrence in patients with interstitial lung disease related to the antisynthetase syndrome.

OBJECTIVE: To describe the clinical characteristics and risk factors of clinical recurrence in interstitial lung disease related to antisynthetase syndrome (ARS-ILD). METHODS: Patients diagnosed as ARS-ILD in Nanjing Drum Tower Hospital between January 2015 and November 2020 were retrospectively analyzed. Clinical information and treatment course were reviewed. The primary endpoint was the disease recurrence, and the secondary point was mortality. Univariate and multivariable Cox regression analyses were performed to identify risk factors for recurrence. RESULTS: Totally, 132 patients with ARS-ILD received immunomodulation treatment from diagnosis. During follow-ups, sixty-nine patients showed recurrence, with a recurrency rate yielding 52.3%. The median duration from treatment initiation to recurrence was 11 (5-18) months. The median tapering course in the recurrence group was 8 (3-12.5) months, which was significantly shorter than the 16 (10-32) months in the no-recurrence group (p < 0.001). Fifty-eight patients experienced recurrence when the glucocorticoids (GC) dose dropped to 10 (9.375-15) mg/day. Twelve patients discontinued GC with a median treatment course of 11.5 (8-16.75) months, and 11 patients developed recurrence after discontinuing GC for 3 (1-4) months. Twelve patients died, with a mortality rate of 9.1%, and recurrence was not associated with increased mortality. The adjusted multivariate analysis showed that age, increased serum lactate dehydrogenase (LDH) level, relatively shorter tapering duration, and inappropriate GC discontinuation were associated with recurrence. CONCLUSION: Recurrence of ARS-ILD was common during medication intensity reduction. Age, LDH, medication tapering duration, and discontinuation were risk factors for recurrence. Further efforts to reduce recurrence should take into consideration of these factors. Key Points • Recurrence is observed commonly with a recurrency rate 52.3% in patients with interstitial lung disease related to antisynthetase syndrome (ARS-ILD) when glucocorticoids (GC) tapering or discontinuation. • Age, increased serum lactate dehydrogenase (LDH) level, medication tapering duration, and GC discontinuation were identified to be significantly associated with the recurrence of ARS-ILD.

A Retrospective Analysis of Outcome in Melanoma Differentiation-Associated Gene 5-Related Interstitial Lung Disease Treated with Tofacitinib or Tacrolimus.

OBJECTIVE: The efficacy of tofacitinib (TOF) in the early diagnosis of melanoma differentiation-associated gene 5 (MDA5)-related interstitial lung disease (ILD) has been described. However, whether TOF exposure is associated with a reduced 1-year mortality rate remains undetermined. METHODS: Patients diagnosed with MDA5-ILD receiving TOF or tacrolimus (TAC) treatment were included. A Cox proportional hazards model, which was adjusted for age, sex, smoking history, anti-MDA5 antibody titers, and concurrent use of other steroid-sparing agents, was performed to compare all-cause mortality and to investigate the risk factors predicting 1-year mortality rates in the 2 treatment groups. RESULTS: During the study period, 26 patients were treated with TOF and 35 were treated with TAC. The 6-month (38.5% vs 62.9%; P = 0.03) and 1-year (44.0% vs 65.7%; P = 0.03) mortality rates in the TOF group were significantly lower than those in the TAC group. There were 13 patients diagnosed with rapidly progressive ILD (RP-ILD) in the TOF group and 22 in the TAC group. The majority of deaths occurred in patients with RP-ILD. The 6-month (76.9% vs 95.5%; P = 0.02) and 1-year (84.6% vs 100.0%; P = 0.02) mortality rates of patients with RP-ILD in the TOF group were also lower than those in the TAC group, respectively. The adjusted model showed that TOF exposure was associated with a lower risk for 1-year mortality (hazard ratio 0.44, 95% CI 0.20-0.96; P = 0.04). However, the incidence of adverse events (73.1% vs 74.3%; P > 0.99) and medication discontinuation rates (23.1% vs 14.3%; P = 0.50) in the TOF and TAC groups were similar, respectively. CONCLUSION: Our observational study showed that TOF use might have a potential effect on improving the outcomes of MDA5-ILD. Future clinical trials are needed to assess the long-term efficacy and tolerability of TOF.

Effect of glial cells on remyelination after spinal cord injury.

Remyelination plays a key role in functional recovery of axons after spinal cord injury. Glial cells are the most abundant cells in the central nervous system. When spinal cord injury occurs, many glial cells at the lesion site are immediately activated, and different cells differentially affect inflammatory reactions after injury. In this review, we aim to discuss the core role of oligodendrocyte precursor cells and crosstalk with the rest of glia and their subcategories in the remyelination process. Activated astrocytes influence proliferation, differentiation, and maturation of oligodendrocyte precursor cells, while activated microglia alter remyelination by regulating the inflammatory reaction after spinal cord injury. Understanding the interaction between oligodendrocyte precursor cells and the rest of glia is necessary when designing a therapeutic plan of remyelination after spinal cord injury.

Familial Alzheimer's disease mutations in presenilins: effects on endoplasmic reticulum calcium homeostasis and correlation with clinical phenotypes.

Mutations in presenilins 1 and 2 (PS1 and PS2) are responsible for approximately 40% of all early onset familial Alzheimer's disease (FAD) monogenic cases. Presenilins (PSs) function as the catalytic subunit of γ-secretase and support cleavage of the amyloid-ß protein precursor (AßPP). We previously discovered that PSs also function as passive endoplasmic reticulum (ER) calcium (Ca2+) leak channels and that most FAD mutations in PSs affected their ER Ca2+ leak function. To further validate the relevance of our findings to human disease, we here performed Ca2+ imaging experiments with lymphoblasts established from FAD patients. We discovered that most FAD mutations in PSs disrupted ER Ca2+ leak function and resulted in increased ER Ca2+ pool in human lymphoblasts. However, we found that a subset of PS1 FAD mutants supported ER Ca2+ leak activity, as ER Ca2+ pool was unaffected in lymphoblasts. Most of the "functional" mutations for ER Ca2+ leak were clustered in the exon 8-9 area of PSEN1 gene and segregated with the cotton wool plaques and spastic paraparesis clinical phenotype occasionally observed in PS1 FAD patients. Our findings with the "functional" and "non-functional" PS1 FAD mutants were confirmed in Ca2+ rescue experiments with PS double-knockout mouse embryonic fibroblasts. Based on the combined effects of the PS1 FAD mutations on ER Ca2+ leak and γ-secretase activities we propose a model that explains the heterogeneity observed in FAD. The proposed model has implications for understanding the pathogenesis of both familial and sporadic AD.

Direct regulation of egl-1 and of programmed cell death by the Hox protein MAB-5 and by CEH-20, a C. elegans homolog of Pbx1.

Hox genes are crucial determinants of cell fates and of body morphology of animals; mutations affecting these genes result in abnormal patterns of programmed cell death. How Hox genes regulate programmed cell death is an important and poorly understood aspect of normal development. In the nematode C. elegans, the Hox gene mab-5 is required for the programmed cell deaths of two lineally related cells generated in the P11 and P12 lineages. We show here that in the P11 lineage, a complex between MAB-5 and the Pbx homolog CEH-20 directly regulates transcription of the BH3 domain gene egl-1 to initiate programmed cell death; in the P12 lineage, mab-5 and ceh-20 apparently act indirectly to initiate programmed cell death. Direct regulation of programmed cell death may be an evolutionarily ancient and conserved function of Hox genes.