A polo-like kinase inhibitor identified by computational repositioning attenuates pulmonary fibrosis.

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a fatal fibrotic lung disease with few effective therapeutic options. Recently, drug repositioning, which involves identifying novel therapeutic potentials for existing drugs, has been popularized as a new approach for the development of novel therapeutic reagents. However, this approach has not yet been fully utilized in the field of pulmonary fibrosis. METHODS: The present study identified novel therapeutic options for pulmonary fibrosis using a systematic computational approach for drug repositioning based on integration of public gene expression signatures of drug and diseases (in silico screening approach). RESULTS: Among the top compounds predicted to be therapeutic for IPF by the in silico approach, we selected BI2536, a polo-like kinase (PLK) 1/2 inhibitor, as a candidate for treating pulmonary fibrosis using an in silico analysis. However, BI2536 accelerated mortality and weight loss rate in an experimental mouse model of pulmonary fibrosis. Because immunofluorescence staining revealed that PLK1 expression was dominant in myofibroblasts while PLK2 expression was dominant in lung epithelial cells, we next focused on the anti-fibrotic effect of the selective PLK1 inhibitor GSK461364. Consequently, GSK461364 attenuated pulmonary fibrosis with acceptable mortality and weight loss in mice. CONCLUSIONS: These findings suggest that targeting PLK1 may be a novel therapeutic approach for pulmonary fibrosis by inhibiting lung fibroblast proliferation without affecting lung epithelial cells. In addition, while in silico screening is useful, it is essential to fully determine the biological activities of candidates by wet-lab validation studies.

Characteristics of chest high-resolution computed tomography in patients with anti-aminoacyl-tRNA synthetase antibody-positive interstitial lung disease.

BACKGROUND AND AIM: Anti-aminoacyl-tRNA synthetase (ARS) antibodies form a condition called Antisynthetase syndrome (ASSD). While interstitial lung disease (ILD) is a particularly frequent manifestation of ASSD and is closely associated with morbidity and mortality, few studies have been conducted on its characteristics on high-resolution computed tomography (HRCT). In this study, we clarified the HRCT findings in patients with anti-ARS antibody-positive ILD (ARS-ILD).  Methods: The HRCT findings at the time of the ILD diagnosis in 24 ARS-ILD patients were retrospectively evaluated by 2 pulmonologists and one radiologist. We also assessed the clinical symptoms, physical examination findings, and laboratory data including the type of anti-ARS antibodies. For a further analysis, the data of patients were divided into two groups: the polymyositis (PM)/dermatomyositis (DM) group and the non-PM/DM group. RESULTS: The ratio of men to women was almost 1:1. The median age at the time of the diagnosis was 53 years old. Anti-glycyl (anti-EJ) and anti-histidyl (anti-Jo-1) antibodies were more common than others. An analysis of the HRCT patterns of 23 ARS-ILD patients showed that the most common pattern was the nonspecific interstitial pneumonia (NSIP) pattern. The second most common pattern was the usual interstitial pneumonia (UIP) pattern. Between the PM/DM and non-PM/DM groups, no clear trends were noted in the age, sex ratio, proportion of HRCT patterns, or type of anti-ARS antibodies. CONCLUSIONS: This retrospective study demonstrated that ARS-ILD patients, regardless of myositis symptoms, most often showed the NSIP pattern on HRCT, as previously reported. However, unlike previous reports, the UIP pattern on HRCT was not rare.

A novel BRD4 degrader, ARV-825, attenuates lung fibrosis through senolysis and antifibrotic effect.

BACKGROUND: Recent studies suggest that cellular senescence is related to the pathogenesis of idiopathic pulmonary fibrosis. However, cellular senescence has yet to be targeted therapeutically in clinical practice. ARV825, a recently developed BRD4 degrader, has been reported as a novel senolytic drug. Conversely, it has also been reported that BRD4 regulates the pro-fibrotic gene expression of fibroblasts. Therefore, this study focuses on the senolytic and anti-fibrotic effects of ARV825 and evaluated these effects on lung fibrosis. METHODS: Lung fibroblasts were induced to senescence through serial passage. The expression of senescence markers and pro-fibrotic markers were determined through quantitative PCR or immunoblot analysis. Lung fibrosis was induced in mice through intratracheal administration of bleomycin. Mice treated with ARV825 underwent histological analysis of lung fibrosis using the Ashcroft score. Total lung collagen was quantified through a hydroxyproline assay. Respiratory mechanics analysis was performed using the flexiVent system. RESULTS: For senescent cells, ARV825 induced the expression of an apoptosis marker while reducing the expression of BRD4 and senescence markers. On the other hand, for early passage pre-senescent cells, ARV825 reduced the expression of collagen type 1 and α-smooth muscle actin. In an experimental mouse model of lung fibrosis, ARV825 attenuated lung fibrosis and improved lung function. Immunohistochemical staining revealed a significant decrease in the number of senescent alveolar type 2 cells in lung tissue due to ARV825 treatment. CONCLUSIONS: These results suggest that ARV825 may impact the progressive and irreversible course of fibrotic lung diseases.

Immune checkpoint inhibitor-related pneumonitis with atypical radiologic features in a patient with anti-aminoacyl-tRNA synthetase antibody.

A man with non-small-cell lung cancer who was negative for anti-nuclear antibodies was admitted for dyspnea after immune checkpoint inhibitor (ICI) administration. Computed tomography (CT) showed complexed radiologic features, including subpleural and basal predominant reticular shadow with cystic structures and peribronchovascular consolidation. Although we treated him with high-dose steroid under a diagnosis of ICI-related pneumonitis, he developed acute exacerbation of pneumonitis with progressive fibrosis and volume loss. A re-evaluation identified anti-aminoacyl-tRNA synthetase antibody in the serum collected before ICI administration. This case highlights the importance of re-evaluating pre-existing autoimmune disorders in patients who develop ICI-related pneumonitis with atypical radiologic features.

The lymphocyte-specific protein tyrosine kinase-specific inhibitor A-770041 attenuates lung fibrosis via the suppression of TGF-ß production in regulatory T-cells.

BACKGROUND: Lymphocyte-specific protein tyrosine kinase (Lck) is a member of the Src family of tyrosine kinases. The significance of Lck inhibition in lung fibrosis has not yet been fully elucidated, even though lung fibrosis is commonly preceded by inflammation caused by infiltration of T-cells expressing Lck. In this study, we examined the effect of Lck inhibition in an experimental mouse model of lung fibrosis. We also evaluated the effect of Lck inhibition on the expression of TGF-ß1, an inhibitory cytokine regulating the immune function, in regulatory T-cells (Tregs). METHODS: Lung fibrosis was induced in mice by intratracheal administration of bleomycin. A-770041, a Lck-specific inhibitor, was administrated daily by gavage. Tregs were isolated from the lung using a CD4+CD25+ Regulatory T-cell Isolation Kit. The expression of Tgfb on Tregs was examined by flow cytometry and quantitative polymerase chain reaction. The concentration of TGF-ß in bronchoalveolar lavage fluid (BALF) and cell culture supernatant from Tregs was quantified by an enzyme-linked immunosorbent assay. RESULTS: A-770041 inhibited the phosphorylation of Lck in murine lymphocytes to the same degree as nintedanib. A-770041 attenuated lung fibrosis in bleomycin-treated mice and reduced the concentration of TGF-ß in BALF. A flow-cytometry analysis showed that A-770041 reduced the number of Tregs producing TGF-ß1 in the lung. In isolated Tregs, Lck inhibition by A-770041 decreased the Tgfb mRNA level as well as the concentration of TGF-ß in the supernatant. CONCLUSIONS: These results suggest that Lck inhibition attenuated lung fibrosis by suppressing TGF-ß production in Tregs and support the role of Tregs in the pathogenesis of lung fibrosis.

Lenvatinib-induced Interstitial Pneumonia in a Patient with Hepatocellular Carcinoma.

Lenvatinib is a multi-targeted tyrosine kinase inhibitor available for the treatment of unresectable hepatocellular carcinoma (HCC). We herein report an 84-year-old-man with interstitial pneumonia caused by lenvatinib. Four months after the start of lenvatinib administration for HCC, chest computed tomography revealed bilateral ground-glass opacity. However, he continued to take lenvatinib for four more months until he complained of dyspnea on exertion. This is a case of lenvatinib-induced interstitial pneumonia that progressed relatively slowly with a long asymptomatic period despite the appearance of pneumonia on image findings.

Distinct improvement of pulmonary function, ground-glass opacity, hypoxia and physical findings in an idiopathic pulmonary fibrosis patient after pirfenidone treatment : a case report with a review of the literature.

Background : Pirfenidone (PFD), an anti-fibrosis drug for idiopathic pulmonary fibrosis (IPF), suppresses disease progression and delays decline of forced vital capacity. However, this drug rarely makes marked improvement of pulmonary function, chest high-resolution computed tomography (HRCT) findings and hypoxia. Case presentation : A 59 year-old-man, who was a former smoker and had a history of alcoholic liver cirrhosis, developed exertional dyspnea and was referred to our hospital. HRCT showed honeycomb changes with surrounding ground-glass opacity (GGO) in a predominantly basal and subpleural distribution. He was diagnosed with IPF and the treatment with PFD was started. At 16 months after the start of treatment, the predicted forced vital capacity value markedly improved from 82.9% to 98.6%. His resting-state partial pressure of arterial oxygen while breathing room air increased from a minimum of 54.7 mmHg (at 2 months treatment) to 72.5 mmHg. The GGO observed at diagnosis disappeared in HRCT. But after 32 months of treatment, his general condition got worse gradually, and he died from chronic progression of IPF after 48 months of treatment. Conclusion : Our case suggests that a complication of chronic liver disease and the existence of GGO may be characteristics of super-responder to PFD treatment for IPF patients. J. Med. Invest. 67 : 358-361, August, 2020.

Primary Pleural Melanoma: A Case Report and Literature Review.

Primary pleural melanoma is an extremely rare neoplasm, and to the best of our knowledge, there have been only 8 case reports of this condition in the English literature. We herein report a rare case in which the cytological and immunocytochemical analyses of pleural fluid and ultrasonography (US)-guided biopsy of a pleural lesion were useful for the diagnosis primary pleural melanoma. This case highlights the importance of careful physical examinations, cytomorphologic and immunocytochemical analyses of pleural fluid, as well as the utility of US-guided biopsy of the pleural lesions in the diagnosis of primary pleural melanoma.

Repetitive saliva swallowing test and water swallowing test may identify a COPD phenotype at high risk of exacerbation.

INTRODUCTION: Patients with chronic obstructive pulmonary disease (COPD) are known to present with dysphagia from an early stage. Dysphagia leads to swallowing-related complications, in turn leading to COPD exacerbation. Dysphagia screening is recommended; however little is known of its utility in detecting a COPD phenotype at risk for exacerbation. The simple swallowing provocation test (SSPT), considered to be a standard screening test, requires specific equipment, physician skill and patient discomfort. OBJECTIVES: The aim of this study was to find an easier and less invasive measure to screen for dysphagia in patients with COPD. METHODS: We retrospectively reviewed patients with COPD who were screened for dysphagia [Repetitive saliva swallowing test (RSST), water swallowing test (WST), SSPT and a questionnaire] from June to November 2016. The patients were classified into two groups according to the presence of COPD exacerbation in the past 3 years (ie, exacerbation and non-exacerbation group), and the dysphagia screening results were compared between the groups. RESULTS: Of the 80 cases included, 42 had 1 or more exacerbations in the past 3 years (exacerbation group), and 38 had none (non-exacerbation group). Statistically significant differences between the groups were observed in the RSST, and vocal change in the WST (P < 0.05). There were no significant differences between the groups in the results of SSPT, COPD stage and other clinical status. CONCLUSIONS: Compared to the SSPT, RSST and WST may be more appropriate screening methods in patients with COPD. A prospective study is necessary for further assessment.

A case of huge lymphatic and venous malformations of the mediastinum.

We herein report a case of huge lymphatic and venous malformations of the mediastinum (LVM). A 19-year-old man presented for evaluation of a mediastinal mass. On chest computed tomography, the mass demonstrated contrast enhancement and showed dilated veins draining into the superior and inferior vena cava, with multiple scattered calcifications. The lesion was enhanced heterogeneously on T1-weighted magnetic resonance imaging (MRI) and hyperintense on T2-weighted MRI. Contrast-enhanced MRI revealed that the mass was enhanced, with the multilocular part marginally enhanced. From these images, we diagnosed him with LVM. Given that an operation presented a high risk, we decided to follow him up without any treatment.

Pneumocystis jirovecii Pneumonia in an Immunocompetent Japanese Man: A Case Report and Literature Review.

We herein report the case of a 37-year-old immunocompetent man who died from Pneumocystis jirovecii pneumonia (PCP). He was initially treated for an acute exacerbation of interstitial pneumonia; however, the elevation of the patient's serum (1-3) ß-D glucan (BG) level suggested the possibility of PCP and sulfamethoxazole trimethoprim was added. A postmortem pathological examination and retrospective Grocott's methenamine silver (GMS) staining of the bronchoalveolar lavage fluid (BALF), which was obtained on the day of admission, revealed PCP. The present case suggests that it is essential to perform a BG assay and GMS staining of BALF specimens when patients show diffuse ground-glass opacity on chest computed tomography, regardless of their immune status.

"Pulmonary Actinomycosis attributable to Actinomyces meyeri presenting as cardiac tamponade: a case report".

BACKGROUND: Recently, it is reported that Actinomyces meyeri is the most common species causing actinomycosis. However, to our knowledge, there was no report about pulmonary actinomycosis attributable to A. meyeri presenting as cardiac tamponade. CASE PRESENTATION: Hereby we describe a case of pulmonary actinomycosis attributable to A. meyeri presenting as cardiac tamponade. At first, the patient was diagnosed with bacterial pericarditis with lung abscess in the left lower lung lobe and underwent pericardial drainage. Three days after the removal of the drainage tube, atrial fibrillation followed by cardiac arrest with asystole occurred and immediate cardiopulmonary resuscitation restored his circulation. Thereafter, he underwent pneumocentesis of the lung abscess and the culture grew A. meyeri. He was successfully treated with penicillin G. CONCLUSION: This is the first case of pulmonary actinomycosis attributable to A. meyeri presenting as cardiac tamponade. We believe that an increased awareness of the disease is necessary to expedite diagnosis therefore minimizing morbidity and mortality.

Peripheral T cell lymphoma not otherwise specified (PTCL-NOS) presenting as an endobronchial lesion: Case report and literature review.

Peripheral T cell lymphoma not otherwise specified (PTCL-NOS) is a rare entity of lymphoma. We herein report an even rarer case of a 68-year-old male with PTCL-NOS presenting as an endobronchial lesion, and review previously published cases in the literature. Initially, he was referred to our hospital for further investigation of the right upper lobe consolidation on chest radiograph. Computed tomography and 18F-fludeoxyglucose positron emission tomography revealed a right hilar mass with obstruction of the main bronchus and submandibular, right axillary and mediastinal lymphadenopathy. Pathological examination of the biopsy specimens from of the endobronchial lesion and subcutaneous nodule revealed PTCL-NOS. Chemotherapy was started but he finally died due to septic shock after the second-line chemotherapy.