An interactive deep learning-based approach reveals mitochondrial cristae topologies.

The convolution of membranes called cristae is a critical structural and functional feature of mitochondria. Crista structure is highly diverse between different cell types, reflecting their role in metabolic adaptation. However, their precise three-dimensional (3D) arrangement requires volumetric analysis of serial electron microscopy and has therefore been limiting for unbiased quantitative assessment. Here, we developed a novel, publicly available, deep learning (DL)-based image analysis platform called Python-based human-in-the-loop workflow (PHILOW) implemented with a human-in-the-loop (HITL) algorithm. Analysis of dense, large, and isotropic volumes of focused ion beam-scanning electron microscopy (FIB-SEM) using PHILOW reveals the complex 3D nanostructure of both inner and outer mitochondrial membranes and provides deep, quantitative, structural features of cristae in a large number of individual mitochondria. This nanometer-scale analysis in micrometer-scale cellular contexts uncovers fundamental parameters of cristae, such as total surface area, orientation, tubular/lamellar cristae ratio, and crista junction density in individual mitochondria. Unbiased clustering analysis of our structural data unraveled a new function for the dynamin-related GTPase Optic Atrophy 1 (OPA1) in regulating the balance between lamellar versus tubular cristae subdomains.

Association Between Patient Preference for Inhaler Medications and Asthma Outcomes.

Purpose: Asthma guidelines recommend considering the patient preference to optimize medication choices. Patient preference for inhaler medication may affect asthma outcomes, but evidence regarding this is lacking. This study investigated the associations between patient preference for inhaler medications and asthma outcomes. Patients and Methods: A multicenter questionnaire survey was conducted among 351 adult patients with asthma treated with regular inhaled corticosteroids. Agreement between patients' preferences and current medication was evaluated using two questions: matched preference was defined as patients answering that the current inhaler medication was the most preferred treatment and they were satisfied with it. Mismatched preference was defined as when patients reported that the current inhaler medication was not the most preferred treatment and/or they were not satisfied with it. We investigated the factors associated with patient preference for asthma inhaler medications. Results: In total, 269 (76.6%) patients were classified into the matched preference group and 82 (23.4%) patients into the mismatched preference group. Multivariate analyses showed that matched preference was independently associated with higher asthma control test scores (P<0.001), fewer exacerbations (P=0.009), less regular oral corticosteroid use (P=0.009), and better inhaler adherence (P=0.006) than the mismatched preference group. In subgroup analysis, younger age was associated with matched preference in patients using dry powder inhalers but not in those using pressurized metered dose inhalers. Conclusion: The use of preference-matched inhaler medication was associated with better asthma outcomes. Evaluation of patients' preference for inhaler medication might provide useful information for individualized treatment with asthma inhaler medications.

IL-18 binding protein can be a prognostic biomarker for idiopathic pulmonary fibrosis.

Idiopathic pulmonary fibrosis is a chronic, fibrosing interstitial pneumonia that presents with various clinical courses and progression ranging from rapid to slow. To identify novel biomarkers that can support the diagnosis and/or prognostic prediction of idiopathic pulmonary fibrosis, we performed gene expression analysis, and the mRNA of interleukin-18 binding protein was increasingly expressed in patients with idiopathic pulmonary fibrosis compared with healthy controls. Therefore, we hypothesized that the interleukin-18 binding protein can serve as a diagnostic and/or prognostic biomarker for idiopathic pulmonary fibrosis. We investigated the expression of interleukin-18 binding protein in lung tissue, bronchoalveolar lavage fluid, and serum. Additionally, the correlation between interleukin-18 binding protein expression levels and the extent of fibrosis was investigated using mouse models of lung fibrosis induced by subcutaneous bleomycin injections. Serum interleukin-18 binding protein levels were significantly higher in idiopathic pulmonary fibrosis patients (5.06 ng/mL, interquartile range [IQR]: 4.20-6.35) than in healthy volunteers (3.31 ng/mL, IQR: 2.84-3.99) (p < 0.001). Multivariate logistic regression models revealed that the correlation between serum interleukin-18 binding protein levels and idiopathic pulmonary fibrosis was statistically independent after adjustment for age, sex, and smoking status. Multivariate Cox proportional hazard models revealed that serum interleukin-18 binding protein levels were predictive of idiopathic pulmonary fibrosis disease prognosis independent of other covariate factors (hazard ratio: 1.655, 95% confidence interval: 1.224-2.237, p = 0.001). We also demonstrated a significant positive correlation between lung hydroxyproline expression levels and interleukin-18 binding protein levels in bronchoalveolar lavage fluid from bleomycin-treated mice (Spearman r = 0.509, p = 0.004). These results indicate the utility of interleukin-18 binding protein as a novel prognostic biomarker for idiopathic pulmonary fibrosis.

Coexisting TIF1γ-positive Primary Pulmonary Lymphoepithelioma-like Carcinoma and Anti-TIF1γ Antibody-positive Dermatomyositis.

Anti-transcriptional intermediary factor 1γ (anti-TIF1γ) antibody-positive dermatomyositis (DM) is strongly associated with cancer, although the mechanism of action is still unclear. We herein describe the first known case of an 80-year-old woman diagnosed with TIF1γ-positive primary pulmonary lymphoepithelioma-like carcinoma (LELC) coexisting with anti-TIF1γ antibody-positive DM. The diagnosis of LELC can only be made by a surgical lung biopsy, and not by a computed tomography-guided biopsy, because of heavy lymphocytic infiltration. This instructive case reaffirmed the importance of active screening for malignancy in patients with anti-TIF1γ antibody-positive DM. Interestingly, the results also suggested that the strong relationship which exists between anti-TIF1γ antibody-positive DM and cancer is potentially caused by tumor-derived TIF1γ.

Albumin-globulin ratio is a predictive biomarker of antitumor effect of anti-PD-1 antibody in patients with non-small cell lung cancer.

BACKGROUND: Anti-programmed cell death receptor (PD)-1 antibody treatment results in better prognosis than standard chemotherapy in patients with non-small cell lung cancer (NSCLC), especially those with high PD-ligand 1 (PD-L1) expression. However, several studies have reported a lack of antitumor effect of PD-1 antibody, even in patients with high PD-L1 expression. Therefore, reliable predictors of treatment response are urgently needed. The albumin-globulin ratio (AGR) is associated with prognosis in several cancers. We aimed to determine whether AGR is a predictive biomarker of anti-PD-1 antibody response in patients with NSCLC. PATIENTS AND METHODS: Seventy-four NSCLC patients treated with anti-PD-1 antibody were retrospectively enrolled. Patients with driver mutations were excluded. RESULTS: The mean AGR was significantly higher in the disease control (DC) group than in the progressive disease (PD) group (p < 0.001). Receiver operating characteristic curve analysis revealed an AGR cutoff value for dividing patients into the DC or PD groups of 1.17. Multivariate logistic regression analysis showed that a high AGR (≥1.17, cutoff value) was an independent predictor of DC (p = 0.001). Progression-free survival (PFS) and overall survival (OS) were significantly longer in the high-AGR group than in the low-AGR group (p = 0.008, p = 0.002, respectively). Multivariate Cox regression analysis of PFS and OS showed that high AGR was an independent prognostic factor (p = 0.020, p < 0.001, respectively). CONCLUSION: Pretreatment serum AGR may be a useful predictor for DC and prognostic factor of anti-PD-1 antibody in patients with NSCLC. The clinical utility of AGR still needs to be confirmed in a prospective analysis.

Pre-existing interstitial lung abnormalities are risk factors for immune checkpoint inhibitor-induced interstitial lung disease in non-small cell lung cancer.

BACKGROUND: Approximately 5% of non-small cell lung cancer (NSCLC) patients develop immune checkpoint inhibitor (ICI)-induced interstitial lung disease (ICI-ILD), 10% of whom die. However, there are no established risk factors for its occurrence. Interstitial lung abnormalities (ILA) are areas of increased lung density on lung computed tomography (CT) in individuals with no known ILD. This study retrospectively investigated whether any patient characteristics, including ILA, were risk factors for ICI-ILD in patients with NSCLC. METHODS: NSCLC patients who received anti-programmed death (PD)-1 antibody treatment at our hospital between September 2015 and December 2017 were enrolled. Information on patient characteristics before anti-PD-1 antibody administration, including chest CT findings and laboratory data, were obtained. RESULTS: Among 83 enrolled patients, the incidence of ICI-ILD was 16.9% (14/83). All ICI-ILD cases developed by the third line of treatment. The incidence of ICI-ILD was significantly higher in patients with pre-existing ILA than that in those without (p = 0.007). Furthermore, patients with ground glass attenuation (GGA) in ILA had a higher incidence of ICI-ILD than that in those without (p < 0.001). In univariate logistic analysis, ILA were significant risk factors for ICI-ILD (p = 0.005). Multivariate logistic analysis revealed that only GGA in ILA was a significant risk factor for ICI-ILD (p < 0.001). CONCLUSIONS: Pre-existing ILA are risk factors for ICI-ILD and GGA in ILA is an independent risk factor for ICI-ILD. Therefore, we should be more aware of the development of ICI-ILD in patients with ILA, especially those with GGA.