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.

Amplifying dual-visible-light photoswitching in aqueous media via confinement promoted triplet-triplet energy transfer.

Achieving visible-light photochromism is a long-term goal of chemists keen to exploit the opportunities of molecular photoswitches in multi-disciplinary research studies. Triplet-sensitization offers a flexible approach to building diverse visible-light photoswitches using existing photochromic scaffolds, circumventing the need for sophisticated molecular design and synthesis. Unfortunately, distance-dependence and environment-sensitivity of triplet-excited species remain as key challenges that severely impair sensitization efficiency and limit their practical availability. We present herein a nature-inspired nanoconfinement strategy in which a triplet-sensitized visible-light photoswitch/sensitizer system is assembled into nanoconfined micelles (d ∼ 40 nm). A ca. 10-fold efficiency increase of triplet-triplet energy transfer for photochromism as well as an amplified fluorescence on/off contrast upon bi-directional visible-light excitation (470/560 nm) was achieved in full aqueous media. By virtue of this, the hybrid photoswitchable system is successfully applied for both flash information encryption and multiple dynamic cell imaging assays, further proving its versatility in materials and life science.

Pretreatment mortality risk prediction model in patients with polymyositis/dermatomyositis-associated interstitial lung disease.

OBJECTIVES: Risk prediction for patients with polymyositis/dermatomyositis-associated interstitial lung disease (PM/DM-ILD) is challenging due to heterogeneity in the disease course. We aimed to develop a mortality risk prediction model for PM/DM-ILD. METHODS: This prognostic study analysed patients with PM/DM-ILD admitted to Nanjing Drum Hospital from 2016 to 2021. The primary outcome was mortality within 1 year. We used a least absolute shrinkage and selection operator (LASSO) logistic regression model to identify predictive laboratory indicators. These indicators were used to create a laboratory risk score, and we developed a mortality risk prediction model by incorporating clinical factors. The evaluation of model performance encompassed discrimination, calibration, clinical utility and practical application for risk prediction and prognosis. RESULTS: Overall, 418 patients with PM/DM-ILD were enrolled and randomly divided into development (n=282) and validation (n=136) cohorts. LASSO logistic regression identified four optimal features in the development cohort, forming a laboratory risk score: C reactive protein, lactate dehydrogenase, CD3+CD4+ T cell counts and PO2/FiO2. The final prediction model integrated age, arthralgia, anti-melanoma differentiation-associated gene 5 antibody status, high-resolution CT pattern and the laboratory risk score. The prediction model exhibited robust discrimination (area under the receiver operating characteristic: 0.869, 95% CI 0.811 to 0.910), excellent calibration and valuable clinical utility. Patients were categorised into three risk groups with distinct mortality rates. The internal validation, sensitivity analyses and comparative assessments against previous models further confirmed the robustness of the prediction model. CONCLUSIONS: We developed and validated an evidence-based mortality risk prediction model with simple, readily accessible clinical variables in patients with PM/DM-ILD, which may inform clinical decision-making.

Prognostic factors of fungal infection in anti-melanoma differentiation-associated gene 5 antibody-positive associated interstitial lung disease.

OBJECTIVE: To investigate the potential risk factors for mortality in fungal infection in anti-melanoma differentiation-associated gene 5 antibody-positive associated interstitial lung disease (MDA5-ILD). METHODS: Patients diagnosed with MDA5-ILD from April 2017 to November 2022 were included. The demographic data, laboratory examinations, therapeutic and follow-up information were recorded. Fungal infection diagnosis was established based on a combinations of host factors, clinical features and mycologic evidences. High-dose corticosteroid therapy was defined as the initial corticosteroid doses > 240mg/d. The primary endpoint was mortality. Potential factors for fungal infection occurrence and prognostic factors were analyzed using logistic regression analysis and Cox proportional hazards regression. RESULTS: In total, 121 patients with MDA5-ILD were included. During follow-up, 41 (33.9%) patients had suffered fungal infection and 39.0% (16/41) of whom had ever received high-dose corticosteroid therapy. The median interval from corticosteroid use to the occurrence of fungal infection was 29 (10-48) days. The mean survival time of patients with fungal infection was 234.32 ± 464.76 days. The mortality in MDA5-ILD with fungal infection was 85.4% (35/41), which was significantly higher than those without (85.4% VS 56.3%, P < 0.001). High-dose corticosteroid therapy (P = 0.049) was independent risk factor for fungal infection occurrence. Decreased serum albumin level (P = 0.024) and high-dose corticosteroid therapy (P = 0.008) were both associated with increased mortality in MDA5-ILD patients with fungal infection. CONCLUSION: Fungal infection is associated with an increased mortality in MDA5-ILD. The serum albumin level and corticosteroid dose should be taken into consideration when treating MDA5-ILD. Key Points • This study showed fungal infection is associated with an increased mortality in MDA5-ILD. In MDA5-ILD patients with fungal infection, the presence of decreased serum albumin level and high-dose corticosteroid therapy were identified as predictors for mortality.

Effect of high-dose intravenous methylprednisolone pulse (IVMP) therapy in the survival of patients with anti-melanoma differentiation-associated gene 5-related rapidly progressive interstitial lung disease: a retrospective analysis.

OBJECTIVES: To assess the impacts of high-dose intravenous methylprednisolone pulse (IVMP) therapy in survival and the occurrences of treatment-related infection of patients with anti-melanoma differentiation-associated gene 5 antibody-related rapidly progressive interstitial lung disease (MDA5-RPILD). METHODS: Patients with MDA5-RPILD from June 2017 to August 2022 in our hospital were retrospectively reviewed. IVMP therapy was defined as intravenous methylprednisolone (mPSL) 0.5g/day for 3 consecutive days during hospitalization or 7 days prior to admission and patients were divided into IVMP group and non-IVMP group based on who had ever received IVMP therapy. All-cause mortality and the incidence of adverse events during treatment were compared between the two groups. RESULTS: Sixty-four patients with MDA5-RPILD were enrolled. Among them, twenty-three (35.9%) patients had ever received IVMP therapy. The overall mortality was comparable between IVMP and non-IVMP group (IVMP group: 22/23, 95.7% vs. non-IVMP group: 38/41, 92.7%, p=0.11). And the incidence of treatment-related infections was also close (IVMP group: 21/23, 91.3% vs. non-IVMP group: 32/41, 78.0%, p=0.30). After adjustment for gender, age, smoking history, duration from symptom onset to diagnosis, and combination with steroid-sparing agent treatment, the Cox proportional hazards model showed that IVMP therapy was not associated with an improved survival (adjusted HR 1.10; 95% CI 0.57-2.13; p=0.77). CONCLUSION: Our study showed that the survival benefits and adverse events were comparable between IVMP-treated and untreated MDA5-RPILD patients. Future prospective trials are needed to investigate the optimal treatment regimen in MDA5-RPILD. Key Points • This observational study found that IVMP therapy may be not associated with an improved outcome in patients with MDA5-RPILD. • Treatment-related infections are common; however, the incidence of treatment-related infections had no difference between IVMP and non-IVMP group.

High prevalence of pneumocystis pneumonia in interstitial lung disease: a retrospective study.

BACKGROUND: Interstitial lung disease (ILD) is a new risk category for pneumocystis pneumonia (PCP) with a high mortality rate. The definite diagnostic criteria of PCP in ILD patients have not been established until now. The aims of this study were to identify potential risk factors of PCP in patients with ILD, and to evaluate the performance of metagenomic next-generation sequencing (mNGS), CD4 + T cell count, (1-3)-ß-D-Glucan (BG) and lactate dehydrogenase (LDH) in the diagnosis of PCP in ILD patients. METHODS: This is a retrospective, single-center, case-control study. ILD patients who underwent mNGS from December 2018 to December 2022 were included in the study. Based on the diagnosis criteria of PCP, these patients were divided into PCP-ILD and non-PCP-ILD groups. The potential risk factors for PCP occurrence in ILD patients were analysed via logistic regression. The diagnostic efficacy of mNGS was compared with serological biomarkers. RESULTS: 92 patients with ILD were enrolled, 31 of which had a definite PCP and were assigned to the PCP-ILD group while 61 were to the non-PCP-ILD group. The infection rate of PJ in ILD patients was 33.7% (31/92). The history of glucocorticoid therapy, CD4 + T cell count, BG level and traction bronchiectasis on HRCT were associated with PCP occurrence in ILD patients. LDH level did not reach statistical significance in the logistic regression analysis. mNGS was confirmed as the most accurate test for PCP diagnosis in ILD patients. CONCLUSION: ILD is a new risk group of PCP with high PCP prevalence. Clinicians should pay close attention to the occurrence of PCP in ILD patients who possess the risk factors of previous glucocorticoid therapy, decreased CD4 + T cell count, increased BG level and absence of traction bronchiectasis on HRCT. mNGS showed the most excellent performance for PCP diagnosis in ILD patients. Peripheral blood CD4 + T cell count and BG level are alternative diagnostic methods for PCP in ILD patients. However, the diagnostic value of serum LDH level was limited in ILD patients.

ZLN005 improves the protective effect of mitochondrial function on alveolar epithelial cell aging by upregulating PGC-1α.

Background: Idiopathic pulmonary fibrosis (IPF) is a chronic and fatal pulmonary interstitial disease that usually occurs in the elderly. The senescence of alveolar epithelial cells (AECs) is an important mechanism of IPF. The AECs of patients with IPF have lower expression of peroxisome proliferator-activated receptor-γ coactivator-1 alpha (PGC-1α), which has been shown to play an important role in maintaining mitochondrial morphology and energy metabolism. This study sought to explore the mechanism by which ZLN005 improves mitochondrial function by upregulating PGC-1α to protect AECs from aging. Methods: Western blot was used to detect the expression of PGC-1α, mitochondrial synthesis protein nuclear respiratory factor-1 (NRF-1), and p21WAF1 in the lung tissue of the IPF patients and the mice with bleomycin (BLM)-induced pulmonary fibrosis. A549 cells and mice AEC2 cells were treated with hydrogen peroxide (H2O2) to construct cell senescence models. Cell senescence was detected by senescence-associated beta-galactosidase staining. The mitochondrial respiratory function was measured, including the adenosine triphosphate (ATP) generation, reactive oxygen species (ROS) level, changes in cell membrane potential, and energy metabolism. Using lentivirus as a vector and using gene editing technology to over express (upPGC-1α) and knockdown PGC-1α (shPGC-1α) in the A549 cells. The PGC-1α agonist ZLN005 was used to pretreat the A549 and shPGC-1α A549 cells, and cell aging and mitochondrial respiratory function were observed. Results: The Western blot and immunofluorescence assays showed that the expression of PGC-1α and NRF-1 was decreased in the lung tissues of the IPF patients and BLM-induced mice pulmonary fibrosis model, while the expression of p21WAF1 was increased. The results of the immunofluorescence and mitochondrial function experiments also indicated that the expression of PGC-1α and mitochondrial synthesis protein NRF-1 were decreased in the senescent cells. Further, the mitochondrial morphology was abnormal and the mitochondrial function was impaired. PGC-1α was involved in the AEC senescence by regulating mitochondrial morphology and function. Treatment with the agonist of PGC-1α (i.e., ZLN005) blocked the H2O2-induced cell senescence by enhancing the expression of PGC-1α. Conclusions: These results provide preliminary insights into the potential clinical application of ZLN005 as a novel therapeutic agent for the treatment of IPF.

Establishment and Validation of Models for the Risk of Multi-Drug Resistant Bacteria Infection and Prognosis in Elderly Patients with Pulmonary Infection: A Multicenter Retrospective Study.

Purpose: The aim of this study was to establish risk prediction and prognosis models for multidrug-resistant bacterial infections (MDRB) in elderly patients with pulmonary infections in a multicenter setting. Patients and Methods: This study is a retrospective cohort analysis in Anhui province of China. Data dimension reduction and feature selection were performed using the lasso regression model. Multifactorial regression analysis to identify risk factors associated with MDRB infection and prognosis. The relevant risks of each patient in the prognostic training cohort were scored based on prognostic independent risk factors. Subsequently, patients were classified into high-risk and low-risk groups, and survival differences were compared between them. Finally, models were established based on independent risk factors for infection, risk groups, and independent prognostic factors, and were presented on nomograms. The predictive accuracy of the model was assessed using corresponding external validation set data. Results: The study cohort comprised 994 elderly patients with pulmonary infection. Multivariate analysis revealed that endotracheal intubation, previous antibiotic use beyond 2 weeks, and concurrent respiratory failure or cerebrovascular disease were independent risk factors associated with the incidence of MDRB infection. Cox regression analysis identified respiratory failure, malnutrition, an APACHE II score of at least 20, and higher blood creatinine levels as independent prognostic risk factors. The models were validated using an external validation dataset from multiple centers, which demonstrated good diagnostic ability and a good fit with a fair benefit. Conclusion: In conclusion, our study provides an appropriate and generalisable assessment of risk factors affecting infection and prognosis in patients with MDRB, contributing to improved early identification of patients at higher risk of infection and death, and appropriately guiding clinical management.

Elevated serum mitochondrial DNA levels were associated with the progression and mortality in idiopathic pulmonary fibrosis.

Circulating mitochondrial DNA (mtDNA) was implicated in idiopathic pulmonary fibrosis (IPF), but the association between circulating mtDNA levels with clinical parameters in IPF was unclear. In this study, we investigate the relationship between serum mtDNA levels with the progression and mortality of IPF. Eighty-three patients with clinical diagnoses of IPF and fifty-three healthy controls were enrolled. Clinical data were collected and IPF patients were classified as stable disease (SD) and progressive disease (PD) based on the diagnostic criteria. Serum mtDNA levels were measured by real-time quantitative PCR and were compared between the two groups. Associations of the mtDNA levels with pulmonary function data and clinical parameters were assessed. Cox regression was performed to access the association between serum mtDNA levels with mortality in IPF. The serum mtDNA levels were significantly higher in IPF patients compared to those in healthy controls (P < 0.001), and further higher in patients with PD than those with SD (P < 0.001). Serum mtDNA levels were significantly inverse correlated with carbon monoxide diffusing capacity percent predicted (DLCO% predicted) (P = 0.030) and serum albumin levels (P = 0.008). During follow-up, 36 patients (43.4 %) died with a median survival of 46.00 (IQR: 25.00-69.75) months. Multivariate analysis showed that higher serum mtDNA levels were a significant predictor of mortality in IPF. In conclusion, elevated serum mtDNA levels were associated with the progression and mortality of IPF, which provided new insights that mitochondrial metabolism might have a potential role in the pathogenesis of IPF.

Lipid metabolism in idiopathic pulmonary fibrosis: From pathogenesis to therapy.

Idiopathic pulmonary fibrosis (IPF) is a chronic irreversible interstitial lung disease characterized by a progressive decline in lung function. The etiology of IPF is unknown, which poses a significant challenge to the treatment of IPF. Recent studies have identified a strong association between lipid metabolism and the development of IPF. Qualitative and quantitative analysis of small molecule metabolites using lipidomics reveals that lipid metabolic reprogramming plays a role in the pathogenesis of IPF. Lipids such as fatty acids, cholesterol, arachidonic acid metabolites, and phospholipids are involved in the onset and progression of IPF by inducing endoplasmic reticulum stress, promoting cell apoptosis, and enhancing the expression of pro-fibrotic biomarkers. Therefore, targeting lipid metabolism can provide a promising therapeutic strategy for pulmonary fibrosis. This review focuses on lipid metabolism in the pathogenesis of pulmonary fibrosis.

Increased serum levels of sCD40L were associated with rapidly progressive interstitial lung disease in idiopathic inflammatory myopathies.

OBJECTIVES: Whether coagulopathy exists in development of idiopathic inflammatory myopathies associated rapidly progressive interstitial lung disease (IIMs-RPILD) is unclear. In this study, we aimed to investigate soluble CD40 ligand and D-dimer levels in RPILD patients. METHODS: Patients with IIMs-ILD were enrolled and classified as RPILD and stable-ILD group. Clinical data, laboratory examinations including coagulation-associated parameters and the myositis antibodies status, chest high-resolution computed tomography (HRCT) findings and treatment regimens were collected and serum levels of sCD40L were detected by ELISA. Univariable and adjusted multivariable cox regression were performed to identify risk factors for 6-month mortality, and further to select predictors for establishing predictive model for RPILD. RESULTS: Eighty patients with IIMs-ILD were enrolled and 34 of them were diagnosed as RPILD while 46 as stable-ILD. Multivariable cox regression showed that albumin<32.4 g/L and sCD40L<1658.55 pg/ml were independent risk factors of short-term mortality in RPILD. A SMAD model consisting of serum sCD40L>1054 pg/ml, anti-MDA5 positivity, albumin<32.4 g/L and D-dimer>0.865 mg/L were generated. The odds for RPILD with SMAD score of 0, 1, 2, 3 and 4 were 0, 26.9%, 66.7%, 91.7% and 100%. The 6-month survival stratified by mild (SMAD score 0), moderate (SMAD score 1 and 2) and severe group (SMAD score 3 and 4) were 100%, 79.5% and 20%, respectively. CONCLUSIONS: We established a predictive model for IIMs-RPILD, which provided a clue that coagulopathy might exist in IIMs-RPILD and could help to better treat patients with RPILD. This model awaits further validations.

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.

Blocking Caspase-1/Gsdmd and Caspase-3/-8/Gsdme pyroptotic pathways rescues silicosis in mice.

Millions of patients suffer from silicosis, but it remains an uncurable disease due to its unclear pathogenic mechanisms. Though the Nlrp3 inflammasome is involved in silicosis pathogenesis, inhibition of its classic downstream factors, Caspase-1 and Gsdmd, fails to block pyroptosis and cytokine release. To clarify the molecular mechanism of silicosis pathogenesis for new therapy, we examined samples from silicosis patients and genetic mouse models. We discovered an alternative pyroptotic pathway which requires cleavage of Gsdme by Caspases-3/8 in addition to Caspase-1/Gsdmd. Consistently, Gsdmd-/-Gsdme-/- mice showed markedly attenuated silicosis pathology, and Gsdmd-/-Gsdme-/- macrophages were resistant to silica-induced pyroptosis. Furthermore, we found that in addition to Caspase 1, Caspase-8 cleaved IL-1ß in silicosis, explaining why Caspase-1-/- mice also suffered from silicosis. Finally, we found that inhibitors of Caspase-1, -3, -8 or an FDA approved drug, dimethyl fumarate, could dramatically alleviate silicosis pathology through blocking cleavage of Gsdmd and Gsdme. This study highlights that Caspase-1/Gsdmd and Caspase-3/8/Gsdme-dependent pyroptosis is essential for the development of silicosis, implicating new potential targets and drug for silicosis treatment.

Mental health and chest CT scores mediate the relationship between COVID-19 vaccination status and seroconversion time: A cross-sectional observational study in B.1.617.2 (Delta) infection patients.

Background: The coronavirus disease (COVID-19) pandemic, which has been ongoing for more than 2 years, has become one of the largest public health issues. Vaccination against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is one of the most important interventions to mitigate the COVID-19 pandemic. Our objective is to investigate the relationship between vaccination status and time to seroconversion. Methods: We conducted a cross-sectional observational study during the SARS-CoV-2 B.1.617.2 outbreak in Jiangsu, China. Participants who infected with the B.1.617.2 variant were enrolled. Cognitive performance, quality of life, emotional state, chest computed tomography (CT) score and seroconversion time were evaluated for each participant. Statistical analyses were performed using one-way ANOVA, univariate and multivariate regression analyses, Pearson correlation, and mediation analysis. Results: A total of 91 patients were included in the analysis, of whom 37.3, 25.3, and 37.3% were unvaccinated, partially vaccinated, and fully vaccinated, respectively. Quality of life was impaired in 30.7% of patients, especially for mental component summary (MCS) score. Vaccination status, subjective cognitive decline, and depression were risk factors for quality-of-life impairment. The chest CT score mediated the relationship of vaccination status with the MCS score, and the MCS score mediated the relationship of the chest CT score with time to seroconversion. Conclusion: Full immunization course with an inactivated vaccine effectively lowered the chest CT score and improved quality of life in hospitalized patients. Vaccination status could influence time to seroconversion by affecting CT score and MCS score indirectly. Our study emphasizes the importance of continuous efforts in encouraging a full vaccination course.

Prediction model for the pretreatment evaluation of mortality risk in anti-melanoma differentiation-associated gene 5 antibody-positive dermatomyositis with interstitial lung disease.

Background: Anti-melanoma differentiation-associated gene 5 antibody-positive dermatomyositis with interstitial lung disease (anti-MDA5 DM-ILD) is a disease with high mortality. We sought to develop an effective and convenient prediction tool to estimate mortality risk in patients with anti-MDA5 DM-ILD and inform clinical decision-making early. Methods: This prognostic study included Asian patients with anti-MDA5 DM-ILD hospitalized at the Nanjing Drum Hospital from December 2016 to December 2020. Candidate laboratory indicators were retrospectively collected. Patients hospitalized from 2016 to 2018 were used as the discovery cohort and applied to identify the optimal predictive features using a least absolute shrinkage and selection operator (LASSO) logistic regression model. A risk score was determined based on these features and used to construct the mortality risk prediction model in combination with clinical characteristics. Results were verified in a temporal validation comprising patients treated between 2019 and 2020. The primary outcome was mortality risk within one year. The secondary outcome was overall survival. The prediction model's performance was assessed in terms of discrimination, calibration, and clinical usefulness. Results: This study included 127 patients, (72 men [56.7%]; median age, 54 years [interquartile range, 48-63 years], split into discovery (n = 87, 70%) and temporal validation (n=37, 30%) cohorts. Five optimal features were selected by LASSO logistic regression in the discovery cohort (n = 87) and used to construct a risk score, including lymphocyte counts, CD3+CD4+ T-cell counts, cytokeratin 19 fragment (CYFRA21-1), oxygenation index, and anti-Ro52 antibody. The retained predictive variables in the final prediction model were age, Heliotrope, fever, and risk score, and the most predictive factor was the risk score. The prediction model showed good discrimination (AUC: 0.915, 95% CI: 0.846-0.957), good calibration (Hosmer-Lemeshow test, P = 0.506; Brier score, 0.12), and fair clinical usefulness in the discovery cohort. The results were verified among patients in the temporal validation cohort (n = 38). We successfully divided patients into three risk groups with very different mortality rates according to the predictive score in both the discovery and validation cohorts (Cochran-Armitage test for trend, P < 0.001). Conclusions: We developed and validated a mortality risk prediction tool with good discrimination and calibration for Asian patients with anti-MDA5 DM-ILD. This tool can offer individualized mortality risk estimation and inform clinical decision-making.

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.

Soluble ST2 in serum predicts the prognosis of idiopathic pulmonary fibrosis: a retrospective study.

Background: Idiopathic pulmonary fibrosis (IPF) is a heterogeneous and progressive fibrosing interstitial lung disease with a poor prognosis. However, there are currently no effective biomarker that can reliably predict the prognosis for IPF in clinic. The serum level of soluble suppression of tumorigenicity-2 (sST2), which is involved in the immune response, has proven to be a prognostic predictor for various diseases. Previous studies have confirmed that the immune dysfunction plays an important role in the pathogenesis of IPF and the serum sST2 concentrations in patients with IPF are elevated. However, the relationship between sST2 and the prognosis of IPF remains unknown. Methods: A total of 83 patients with IPF and 20 healthy controls from 2016 to 2021 were enrolled and demographic variables, indices of lung function testing as well as the biomarkers including the sST2 were obtained at baseline. During follow-up, the primary endpoint was defined as all-cause death and clinical deterioration. Cox hazard models and Kaplan-Meier method were used to assess the prognostic value of various indices including sST2. Results: Mean duration of follow-up was 29 months, during which 49 patients had an event, and of them, 35 patients died. The sST2 level was higher in the IPF patients compared with the healthy controls. Although the sST2 level did not directly predict all-cause death in the present study, it was proved to be an independent predictor of event-free survival. Multivariate forward stepwise model which was adjusted by age, sex, and body surface area (BSA) showed that the overexpression of sST2 increased the hazard ratio [1.005, 95% confidence interval (CI): 1.001-1.010]. A higher sST2 serum level heralded more deterioration and the poor outcomes. Moreover, the effect of sST2 on the prognosis of IPF may not necessarily involve the development of IPF-related pulmonary hypertension (PH). Conclusions: In our study, the sST2 serum level was significantly elevated and a higher serum level of sST2 predicted more deterioration and poor outcomes in patients with IPF. Thus, sST2 can serve as a valuable prognostic biomarker for the outcome of IPF. However, further multicenter clinical trials of larger sample size are needed in the future.

KLF4 regulates TERT expression in alveolar epithelial cells in pulmonary fibrosis.

Idiopathic pulmonary fibrosis (IPF) was considered as a telomere-mediated disease. TERT and TERC correlated with telomere length. Although telomerase gene mutations were associated with IPF, majority patients did not carry mutations. The mechanism by which telomerase expression was regulated in IPF are still unclear. In this study, we aimed to delineate the mechanisms that how TERT protein expression were regulated in alveolar epithelial cells (AECs) in pulmonary fibrosis. Here, we found that P16, P21 and fibrosis markers (αSMA and Collagen-I) were prominently increased in lung tissues of IPF patients and bleomycin-induced mouse models, while the expression of KLF4 and TERT were decreased in AECs. In vivo experiments, AAV-6 vectors mediated KLF4 over-expression with specific SP-C promoter was constructed. Over-expression of KLF4 in AECs could protect TERT expression and suppress the development of pulmonary fibrosis in bleomycin-induced mouse models. In the mechanism exploration of TERT regulation, KLF4 and TERT were both down-regulated in bleomycin-induced senescent MLE-12 and BEAS-2B cells. Compared with control group, small-interfering RNA targeting KLF4 significantly reduced the TERT expression and telomerase activity, while overexpression of KLF4 can increased the expression of TERT and telomerase activity in senescent AECs. Furthermore, ChIP showed that KLF4 protein could bind to the TERT promoter region in MLE-12 cells, suggesting that KLF4 could implicate in pathogenesis of lung fibrosis through regulating TERT transcription in AECs. Taken together, this study identified that KLF4 might be a promising potential target for further understanding the mechanism and developing novel strategy for the treatment of lung fibrosis in IPF.

Stepping Out of the Blue: From Visible to Near-IR Triggered Photoswitches.

Light offers unique opportunities for controlling the activity of materials and biosystems with high spatiotemporal resolution. Molecular photoswitches are chromophores that undergo reversible isomerization between different states upon irradiation with light, allowing a convenient means to control their influence over the system of interest. However, a significant limitation of classical photoswitches is the requirement to initiate the switching in one or both directions using deleterious UV light with poor tissue penetration. Red-shifted photoswitches are hence in high demand and have attracted keen recent research interest. In this Review, we highlight recent progress towards the development of visible- and NIR-activated photoswitches characterized by distinct photochromic reaction mechanisms. We hope to inspire further endeavors in this field, allowing the full potential of these tools in biotechnology and materials chemistry applications to be realized.