Development and Validation of a Machine Learning-Based Model Using CT Radiomics for Predicting Immune Checkpoint Inhibitor-related Pneumonitis in Patients With NSCLC Receiving Anti-PD1 Immunotherapy: A Multicenter Retrospective CaseControl Study.

RATIONALE AND OBJECTIVES: This study aimed to develop and evaluate a radiomics-based model combined with clinical and qualitative radiological (semantic feature [SF]) features to predict immune checkpoint inhibitor-related pneumonitis (CIP) in patients with non-small cell lung cancer (NSCLC) treated with programmed cell death protein 1 inhibitors. MATERIALS AND METHODS: This was a multicenter retrospective casecontrol study conducted from January 1, 2018, to December 31, 2022, at three centers. Patients with NSCLC treated with anti-PD1 were enrolled and randomly divided into two groups (7:3): training (n = 95) and validation (n = 39). Logistic regression (LR) and support vector machine (SVM) algorithms were used to transform features into the models. RESULTS: The study comprised 134 participants from three independent centers (male, 114/134, 85%; mean [±standard deviation] age, 63.92 [±7.9] years). The radiomics score (RS) models built based on the LR and SVM algorithms could accurately predict CIP (area under the receiver operating characteristics curve [AUC], 0.860 [0.780, 0.939] and 0.861 [0.781, 0.941], respectively). The AUCs for the RS-clinic-SF combined model were 0.903 (0.839, 0.967) and 0.826 (0.688, 0.964) in the training and validation cohorts, respectively. Decision curve analysis showed that the combined models achieved high clinical net benefit across the majority of the range of reasonable threshold probabilities. CONCLUSION: This study demonstrated that the combined model constructed by the identified features of RS, clinical features, and SF has the potential to precisely predict CIP. The RS-clinic-SF combined model has the potential to be used more widely as a practical tool for the noninvasive prediction of CIP to support individualized treatment planning.

Anti-TIF1 gamma-positive IPAF patient developed stage IVB lung squamous carcinoma in 1 year: a case report.

BACKGROUND: Patients with connective tissue disease, such as dermatomyositis (DM), and positive anti-TIF1γ self-antibodies are commonly diagnosed with malignant tumors as a comorbidity. The relationship between anti-TIF1γ self-antibodies and existing malignant tumors has been confirmed by several reports. However, interstitial pneumonia with autoimmune features (IPAF) cases with a positive anti-TIF1γ self-antibody developing to solid malignant tumors are rarely reported now. CASE PRESENTATION: Herein, we presented an IPAF patient with anti-TIF1γ self-antibodies. No evidence of malignant tumors was found at the initial visit. However, the patient had developed stage IVB lung squamous cell carcinoma at the 1-year follow-up review. CONCLUSIONS: Altogether, this report described a rare case of IPAF patient with anti-TIF1γ self-antibodies developed to advanced lung squamous cell carcinoma in 1 year. The present case highlights more frequent imaging examinations to identify the occurrence of malignant tumors as early as possible in IPAF patients with positive anti-TIF1γ self-antibodies.

The Degradation of Airway Epithelial Tight Junctions in Asthma Under High Airway Pressure Is Probably Mediated by Piezo-1.

Full functioning of the airway physical barrier depends on cellular integrity, which is coordinated by a series of tight junction (TJ) proteins. Due to airway spasm, edema, and mucus obstruction, positive end-expiratory alveolar pressure (also termed auto-PEEP) is a common pathophysiological phenomenon, especially in acute asthma attack. However, the influence of auto-PEEP on small airway epithelial TJs is currently unclear. We performed studies to investigate the effect of extra pressure on small airway epithelial TJs and its mechanism. The results first confirmed that a novel mechanosensitive receptor, piezo-1, was highly expressed in the airway epithelium of asthmatic mice. Extra pressure induced the degradation of occludin, ZO-1 and claudin-18 in primary human small airway epithelial cells (HSAECs), resulting in a decrease in transepithelial electrical resistance (TER) and an increase in cell layer permeability. Through in vitro investigations, we observed that exogenous pressure stimulation could elevate the intracellular calcium concentration ([Ca2+] i ) in HSAECs. Downregulation of piezo-1 with siRNA and pretreatment with BAPTA-AM or ALLN reduced the degradation of TJs and attenuated the impairment of TJ function induced by exogenous pressure. These findings indicate the critical role of piezo-1/[Ca2+] i /calpain signaling in the regulation of small airway TJs under extra pressure stimulation.

The role of the XBP-1/AGR2 signaling pathway in the regulation of airway Mucin5ac hypersecretion under hypoxia.

Oversecretion of Mucin5ac (MUC5AC), which is primarily synthesized by goblet cells and is the major gel-forming mucin, is a hallmark of various pulmonary inflammatory diseases. Hypoxia is considered a common pathophysiologic feature in various pulmonary inflammatory diseases. It has been suggested that hypoxia-inducible factor 1α (HIF-1α) acts as a key factor in hypoxia-induced MUC5AC hypersecretion; however, the exact mechanisms that maintain the stability of HIF-1α and support oversecretion by airway epithelial cells under hypoxia are still unclear. With immunohistochemistry, we found overexpression of anterior gradient 2 (AGR2) in the bronchial epithelial cells of hypoxia-treated mice. With specific shRNA transduction, AGR2 was demonstrated to be a key factor in MUC5AC hypersecretion in vitro. Additionally, co-immunoprecipitation, cell immunochemistry and confocal microscopy experiments were performed to explore the interaction between HIF-1α and AGR2 during hypoxia-induced MUC5AC hypersecretion in vitro. The results indicated increased binding and intracytoplasmic colocation of HIF-1α and AGR2. Our findings suggest that AGR2 acts as a key regulator in hypoxia-induced airway MUC5AC hypersecretion by increasing the stability of HIF-1α. Additionally, the elevated expression of AGR2 induced by hypoxia in bronchial epithelial cells likely depends on an XBP-1-associated pathway.

Saxifragifolin D attenuates phagosome maturation arrest in Mycobacterium tuberculosis-infected macrophages via an AMPK and VPS34-dependent pathway.

Saxifragifolin D (SD), a traditional Chinese medicine, is a pentacyclic triterpenoid compound first isolated from Androsace umbellata. Various plant triterpenoids have been reported to exhibit antitubercular activity. In this study, THP-1-derived macrophages were infected with an attenuated M. tuberculosis (M.tb) strain, H37Ra. Intracellular replication of M.tb was evaluated by counting the colonies after 4 weeks of incubation. The results indicated that SD treatment reduced the intracellular replication of M.tb in THP-1-derived macrophages but not in A549 cells. We performed a phagosome maturation test using confocal microscopy and found that SD treatment partially attenuated the phagosome arrest induced by M.tb infection. These effects were dependent on a VPS34-associated pathway. Immunoprecipitation assays showed that SD increased intracellular UVRAG-linked VPS34, the active VPS34 complex II. However, SD had no effect on the total VPS34 pool. Moreover, the results indicated that the SD-mediated increase in VPS34 complex II activity was mediated by an AMPK-dependent pathway. Collectively, these data indicate that SD may be a promising candidate for treatment of M.tb.

Sodium valproate sensitizes non-small lung cancer A549 cells to γδ T-cell-mediated killing through upregulating the expression of MICA.

Major histocompatibility complex (MHC) class I chain-related protein A (MICA) is involved in γδ T-cell recognition of target tumor cells. The aim of this study was to investigate the feasibility of utilization of sodium valproate (VPA), a histone deacetylase inhibitor, to sensitize non-small cell lung cancer A549 cells to γδ T-cell-mediated killing. VPA induced a dose-dependent increase in the mRNA and protein expression of MICA in A549 cells. γδ T cells showed cytotoxicity to A549 cells, which was increased by about 50% in the presence of VPA. The concomitant addition of MICA antibody significantly attenuated the VPA-mediated sensitization to γδ T-cell killing. VPA enhanced the cleavage of caspase-3 and caspase-9 in A549 cells cocultured with γδ T cells, and such enhancement was reversed by the MICA antibody. In conclusion, VPA sensitizes tumor cells to γδ T-cell-mediated cytotoxicity through the upregulation of MICA and may thus have benefits in improving γδ T-cell-based cancer immunotherapy.

The viable Mycobacterium tuberculosis H37Ra strain induces a stronger mouse macrophage response compared to the heat-inactivated H37Rv strain.

Macrophages are the target cells for Mycobacterium tuberculosis (M. tuberculosis) as well as key effector cells for clearance of this pathogen. The aim of the present study was to measure and compare the responses of mouse peritoneal macrophages following exposure to the live M. tuberculosis H37Ra and heat-inactivated H37Rv strains. In vitro phagocytosis assays indicated that the macrophages had a higher capacity to engulf the live H37Ra strain compared to the inactivated H37Rv strain. Enzyme-linked immunosorbent assay (ELISA) demonstrated that H37Ra­stimulated macrophages produced significantly increased concentrations of interleukin­12p40 (IL­12p40), tumor necrosis factor-α (TNF­α) and interferon­Î³ (IFN­Î³) compared to the untreated control cells. However, H37Rv exposure induced little to no increase in the levels of the cytokines examined. The results from ELISA were confirmed by reverse transcription-polymerase chain reaction (RT­PCR) at the mRNA level. There was a dose-dependent increase in nitric oxide (NO) and hydrogen peroxide (H2O2) production from the H37Ra­stimulated macrophages compared to the H37Rv­stimulated ones. Confocal microscopy and flow cytometric analysis indicated that the IFN­Î³­stimulated macrophages from viable H37Ra­immunized mice had an enhanced surface expression of CD40 ligand (CD40L) compared to those from inactivated H37Rv­immunized mice. Our data collectively indicate that exposure to the viable H37Ra strain induces a stronger macrophage response compared to exposure to the heat-inactivated H37Rv strain, which may be associated with the increased surface expression of CD40L in activated macrophages.