Infectious respiratory pathogens among patients with acute exacerbation of idiopathic pulmonary fibrosis during the coronavirus disease 2019 pandemic in Japan.

BACKGROUND: Few studies have investigated the prevalence of pathogens in patients with acute exacerbation of idiopathic pulmonary fibrosis (AE-IPF), specifically, the interactions between respiratory pathogens and AE-IPF during the coronavirus disease 2019 (COVID-19) pandemic. OBJECTIVES: We aimed to analyze pathogens in patients with AE-IPF between September 2020 and December 2022. METHODS: This retrospective observational study was conducted at our hospital between September 2020 and December 2022. In patients with AE-IPF, pre-hospitalization polymerase chain reaction (PCR) tests for respiratory pathogens, including severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), were performed using multiplex PCR or Smart Gene assay with nasopharyngeal swab specimens. Microbiological assays, including Gram staining, sputum cultures, blood cultures, and urinary antigen tests for Streptococcus pneumoniae and Legionella pneumophila, were also performed. RESULTS: Forty-nine patients with AE-IPF were included. The median age was 75 years old and 42 (86 %) were male. Only one of the 49 patients (2 %) was positive for SARS-CoV-2. Two of 28 patients (7 %) were positive for human rhinovirus/enterovirus. No bacteria were detected in sputum culture, blood culture, or urinary antigen tests. CONCLUSIONS: The detection frequency of SARS-CoV-2 infection in patients with AE-IPF was lower than that of human rhinovirus/enterovirus. Continuous analysis for the presence of pathogens is necessary for appropriate infection control because respiratory viruses may increase as the coronavirus pandemic subsides.

Difficulty differentiating primary mediastinal classical Hodgkin lymphoma from inflammatory myofibroblastic tumor: A case report.

A 20-year-old Japanese man visited our hospital because an enlarged mediastinal shadow had been detected on chest x-ray. Chest computed tomography revealed a large mediastinal mass with multiple lymph node enlargement, pericardial effusion, and bilateral pleural effusion. He was diagnosed with inflammatory myofibroblastic tumor (IMT) based on a thoracoscopic tumor biopsy. Initial corticosteroid and celecoxib treatment was only partially effective; therefore, additional tumor rebiopsy and left axillary lymph node biopsy were performed. Based on the findings, the patient was rediagnosed with classical Hodgkin lymphoma (CHL). To date, there has only been one report of a case initially diagnosed as IMT and rediagnosed as CHL, as in our case, and only three reports of malignant lymphoma mimicking IMT. When IMT is suspected based on pathological findings and subsequently with treatment failure, possible CHL and performing rebiopsy should be considered.

Caspase-4 has a role in cell division in epithelial cells through actin depolymerization.

In addition to its role in pyroptosis and inflammatory cytokine maturation, caspase-4 (CASP4) also contributes to the fusion of phagosomes with lysosomes and cell migration. However, its role in cell division remains elusive. In this study, we demonstrate that CASP4 is indispensable for proper cell division in epithelial cells. Knockout of CASP4 (CASP4 KO) in HepG2 cells led to delayed cell proliferation, increased cell size, and increased multinucleation. In mitosis, CASP4 KO cells showed multipolar spindles, asymmetric spindle positioning, and chromosome segregation errors, ultimately increasing DNA content and chromosome number. We also found that phalloidin, a marker of filamentous actin, increased in CASP4 KO cells owing to suppressed actin depolymerization. Moreover, the levels of actin polymerization-related proteins, including Rho-associated protein kinase1 (ROCK1), LIM kinase1 (LIMK1), and phosphorylated cofilin, significantly increased in CASP4 KO cells. These results suggest that CASP4 contributes to proper cell division through actin depolymerization.

Acute pneumonitis caused by oral intake of incense.

Incense is typically burned for use, with bronchitis and pneumonia reported as potential side effects. Physicians should be cautious as inappropriate oral ingestion of incense can lead to acute pneumonitis.

FilGAP, a GAP for Rac1, down-regulates invadopodia formation in breast cancer cells.

Invadopodia are protrusive structures that mediate the extracellular matrix (ECM) degradation required for tumor invasion and metastasis. Rho small GTPases regulate invadopodia formation, but the molecular mechanisms of how Rho small GTPase activities are regulated at the invadopodia remain unclear. Here we have identified FilGAP, a GTPase-activating protein (GAP) for Rac1, as a negative regulator of invadopodia formation in tumor cells. Depletion of FilGAP in breast cancer cells increased ECM degradation and conversely, overexpression of FilGAP decreased it. FilGAP depletion promoted the formation of invadopodia with ECM degradation. In addition, FilGAP depletion and Rac1 overexpression increased the emergence of invadopodia induced by epidermal growth factor, whereas FilGAP overexpression suppressed it. Overexpression of GAP-deficient FilGAP mutant enhanced invadopodia emergence as well as FilGAP depletion. The pleckstrin-homology (PH) domain of FilGAP binds phosphatidylinositol 3,4-bisphosphate [PI(3,4)P2], which is distributed on membranes of the invadopodia. FilGAP localized to invadopodia in breast cancer cells on the ECM, but FilGAP mutant lacking PI(3,4)P2-binding showed low localization. Similarly, the decrease of PI(3,4)P2 production reduced the FilGAP localization. Our results suggest that FilGAP localizes to invadopodia through its PH domain binding to PI(3,4)P2 and down-regulates invadopodia formation by inactivating Rac1, inhibiting ECM degradation in invasive tumor cells.Key words: invadopodia, breast carcinoma, Rac1, FilGAP, PI(3,4)P2.

Hyper-progressive disease after immune checkpoint inhibitor in SMARCA4-deficient small-cell lung carcinoma.

SMARCA4 (switch/sucrose non-fermentable-related, matrix-associated, actin-dependent regulator of chromatin, subfamily A, member 4)-deficient thoracic tumours have shown poor prognosis in clinical settings. Although the optimal treatment for SMARCA4-deficient thoracic tumours remains unclear, existing studies indicate a favourable response of these tumours to immune checkpoint inhibitors (ICIs). However, there are no reports of fatality in SMARCA4-deficient small-cell lung carcinoma (SCLC) with hyper-progressive disease (HPD) upon treatment with ICIs. Herein, we report a patient with SMARCA4-deficient SCLC who had HPD after the first ICI treatment. A 35-year-old man was treated with nivolumab, subsequent to cytotoxic chemotherapy. A week after nivolumab initiation, chest computed tomography revealed marked increase in pleural effusion in the right lung and chest wall dissemination of the tumour, which concur with the definition of HPD. This is the first study to report the occurrence of HPD after treatment with ICIs in a patient with SMARCA4-deficient SCLC. Analysis of additional data is necessary to determine the optimal treatment for these patients.

Pseudoaneurysm after total arch replacement mimicking malignant lymphadenopathy.

Pseudoaneurysm should be considered in the differential diagnosis when the computed tomography (CT) findings show a mediastinal mass in patients with a history of cardiovascular surgery even if such surgery occurred over two decades previously.

Quantitative analysis of endobronchial ultrasound elastography in computed tomography-negative mediastinal and hilar lymph nodes.

BACKGROUND: Endobronchial ultrasound (EBUS) elastography assists in the differentiation of benign and malignant lymph nodes (LNs) during transbronchial needle aspiration (TBNA). However, previous studies have not compared B-mode sonographic images (BSIs) and EBUS elastography images (EEIs) with final pathological diagnoses in radiologically normal-sized (computed tomography [CT]-negative) LNs. METHODS: Consecutive patients with CT-negative LNs, who received EBUS-TBNA, were retrospectively reviewed. Images of BSIs and EEIs of each LN were stored and independently evaluated. EEIs were assessed by calculating the stiffness area ratio (SAR, blue/overall areas). The receiver operating characteristic curve was used to calculate the cutoff value for the SAR. Diagnostic test parameters were evaluated for each EBUS finding. RESULTS: A total of 132 patients (149 LNs) were enrolled, and the median SAR of malignant LNs was significantly higher than that of benign LNs (0.58 vs. 0.32, P < 0.001). At the SAR cutoff of 0.41, the sensitivity, specificity, positive predictive value, negative predictive value (NPV), and diagnostic accuracy rate (DAR) of elastography were 88.2%, 80.2%, 78.9%, 89.0%, and 83.9%, respectively. The logistic regression analysis showed that elastography was the strongest predictor of malignancy (odds ratio, 18.5; 95% confidence interval [CI]: 6.48-52.6; P < 0.001). The highest NPV (96.6%) was achieved with a combination of BSIs and EEIs. CONCLUSIONS: EBUS elastography predicted malignant LNs with a high DAR and NPV in CT-negative LNs. The NPV was highest when EEIs were combined with BSIs. Therefore, the combined evaluation of CT-negative LNs using EEIs and BSIs may help bronchoscopists perform EBUS-TBNA more efficiently. KEY POINTS: SIGNIFICANT FINDINGS OF THE STUDY: Endobronchial ultrasound elastography accurately predicted malignancy with a high diagnostic accuracy rate and negative predictive value in radiologically normal-sized lymph nodes. The additional use of B-mode sonographic features resulted in a higher negative predictive value. WHAT THIS STUDY ADDS: Endobronchial ultrasound elastography can guide the accurate collection of specimens with transbronchial needle aspiration, even in radiologically normal-sized lymph nodes. It can also readily distinguish benign and malignant lymph nodes, thus avoiding unnecessary punctures.

[Evaluation of the Influence of the Experience and Training of EBUS-TBNA on Diagnostic Rate and Safety].

Endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) has been widely used in Japan. The guidelines of the American College of Chest Physicians has recommended that EBUS-TBNA should be performed by well-trained operators who can perform highly accurate procedures, but the indicators of the degree of experience and training are unclear. In our department, physicians who do not have enough experience perform EBUS-TBNA under the supervision of bronchoscopic instructors who have EBUS-TBNA techniques (Board Certified Member of the Japan Society for Respiratory Endoscopy) after guidance and training in EBUS-TBNA using a simulator as an operator and helper. In order to evaluate the influence of the experience and training of EBUS-TBNA on diagnostic accuracy and safety, we retrospectively compared the diagnostic accuracy and safety of EBUS-TBNA performed by physicians within one year of experience of EBUS-TBNA and those performed by physicians with more than one year of experience. A total of 111 cases (148 lesions) who were eventually diagnosed as having primary lung cancer and underwent EBUS-TBNA in our department between April 2014 and January 2016 were divided into two groups. Group A (43 cases, 57 lesions) was examined by third-year doctors within one year of experience of EBUS-TBNA, and group B (68 cases, 91 lesions) was examined by doctors with four or more years of experience and with more than one year of experience of EBUS-TBNA. Diagnostic rate, examination time, and complications were evaluated. There were no significant differences between the two groups in the diagnostic rate (A, 89.5% vs. B, 90.1%, P = 1.0) or examination time (A, 27 min vs. B, 23 min, P = 0.149), and no complications were observed in either group. This study suggests that even less-experienced physicians may safely perform EBUS-TBNA as well as moderately-experienced physicians with more than 1 year experience of EBUS-TBNA with similar diagnostic rates when proper training and supervision are supplied.

[A Case of Left Upper Lobe Lung Cancer Successfully Diagnosed by Transesophageal Endoscopic Ultrasound with Bronchoscope-Guided Fine Needle Aspiration Alone].

A 58-year-old Japanese woman with fever and cough visited A hospital. Her chest X-ray and CT showed a tumor attached to the mediastinum in the left upper lobe with mediastinal lymphadenopathy (#4R). After an introduction from A hospital to our hospital, endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) for the mediastinal lymphadenopathy and a simultaneous approach to the mass lesion in the left upper lobe were performed. In spite of twice aspiration by EBUS-TBNA for mediastinal lymphadenopathy, we failed to obtain enough specimens, and, as the mass lesion in the left upper lobe was invisible in the endobronchial ultrasound, we could not approach it. Then using the same ultrasound bronchoscope, we subsequently performed a transesophageal endoscopic ultrasound with bronchoscope-guided fine needle aspiration (EUS-B-FNA) to the mass lesion in the left upper lobe twice, with the result that sufficient tissues were obtained. Then we changed from the ultrasound bronchoscope to a normal bronchoscope and we performed brushing and transbronchial lung biopsy for the left upper lobe mass lesion. Pathological results revealed that only the specimens obtained by EUS-B-FNA were diagnostic for adenocarcinoma; the other specimens obtained using EBUS-TBNA and normal bronchoscope failed to be diagnostic. EUS-B-FNA in combination with EBUS-TBNA has been recommended for the diagnosis of mediastinal and near-mediastinal lesions in the guidelines of the American College of Chest Physicians in 2013, but EUS-B-FNA has not been widely used in Japan. As shown in our present patient who was successfully diagnosed as having lung cancer by EUS-B-FNA alone, respiratory physicians should be aware of being skillful at performing EUS-B-FNA to accurately and effectively approach target lesions.

Hard Metal Lung Disease with Favorable Response to Corticosteroid Treatment: A Case Report and Literature Review.

Hard metal lung disease (HMLD) is a pneumoconiosis caused by occupational exposure to hard metals such as tungsten carbide and cobalt, but the treatment strategies for HMLD have not been well established. A 68-year-old Japanese man with occupational history as a grinder of hard metals for 18 years referred to our hospital because of dry cough and dyspnea. A chest computed tomography (CT) on admission revealed centrilobular micronodules, ground-glass opacities, and reticular opacities in the peripheral zone of both lungs. Mineralogic analyses of lung tissues detected components of hard metals, such as tungsten, titanium and iron, and the same metals were also detected in the sample of the dust of his workplace. Thus, the patient was diagnosed as having HMLD based on occupational exposure history and radiologic and mineralogic analyses of the lung. Corticosteroid therapy was initiated, which resulted in partial improvements in his symptoms, radiological and pulmonary functional findings. In a review of the 18 case reports of HMLD treated with corticosteroids, including our case, the majority of patients (77.8%) showed favorable responses to corticosteroid treatment. Furthermore, the presence of fibrotic changes, such as reticular opacity, in radiological examinations was associated with the resistance to corticosteroids. In conclusion, the majority of patients with HMLD are expected to favorable response to corticosteroid treatment, whereas chest CT findings such as fibrotic changes may be predictive of the resistance of corticosteroid treatment. Lastly, proper prevention of hard metal exposure is most important as the first step.

Identification of a Novel Bone Marrow Cell-Derived Accelerator of Fibrotic Liver Regeneration Through Mobilization of Hepatic Progenitor Cells in Mice.

Granulocyte colony stimulating factor (G-CSF) has been reported to ameliorate impaired liver function in patients with advanced liver diseases through mobilization and proliferation of hepatic progenitor cells (HPCs). However, the underlying mechanisms remain unknown. We previously showed that G-CSF treatment increased the number of bone marrow (BM)-derived cells migrating to the fibrotic liver following repeated carbon tetrachloride (CCl4 ) injections into mice. In this study, we identified opioid growth factor receptor-like 1 (OGFRL1) as a novel BM cell-derived accelerator of fibrotic liver regeneration in response to G-CSF treatment. Endogenous Ogfrl1 was highly expressed in the hematopoietic organs such as the BM and spleen, whereas the liver contained a relatively small amount of Ogfrl1 mRNA. Among the peripheral blood cells, monocytes were the major sources of OGFRL1. Endogenous Ogfrl1 expression in both the peripheral blood monocytes and the liver was decreased following repeated CCl4 injections. An intrasplenic injection of cells overexpressing OGFRL1 into CCl4 -treated fibrotic mice increased the number of HPC and stimulated proliferation of hepatic parenchymal cells after partial resection of the fibrotic liver. Furthermore, overexpression of OGFRL1 in cultured HPC accelerated their differentiation as estimated by increased expression of liver-specific genes such as hepatocyte nuclear factor 4α, cytochrome P450, and fatty acid binding protein 1, although it did not affect the colony forming ability of HPC. These results indicate a critical role of OGFRL1 in the mobilization and differentiation of HPC in the fibrotic liver, and administration of OGFRL1-expressing cells may serve as a potential regenerative therapy for advanced liver fibrosis. Stem Cells 2019;37:89-101.

Tuning the O2 Binding Affinity of Cobalt(II) Centers by Changing the Structural and Electronic Properties of the Distal Substituents on Azole-Based Chelating Ligands.

The effects of the substituents on the chelating ligands located in the secondary coordination sphere on the O2 affinity of cobalt(II) centers have been explored. The combination of facially capping tridentate tris(pyrazolyl)borates (= TpMe2,4R) and bidentate bis(imidazolyl)borates (= [B(Im N-Me)2MeX]- ; LX) yields square-pyramidal cobalt(II) complexes. The structural properties of the substituent groups X attached to the boron center of LX affect the arrangement of X in the resulting cobalt(II) complexes [CoII(TpMe2,4R)(LX)]. When the boron-attached moiety of X is a relatively bulky sp3-CH2Y group (i.e., X:Y = Me:H and nBu: nPr), the alkyl group X faces the cobalt center, whereas for isopropoxy (O iPr) and phenyl (Ph) groups, of which the boron-attached atoms are a less hindered oxygen atom and a planer sp2-carbon, respectively, the X group is arranged away from the cobalt center. This flexible behavior of LX is reflected in the O2 affinity of the cobalt(II) center, which depends on the extent to which the complex sphere is shielded by the ligands. The dependence of the cobalt(II) oxidation potential on the X substituent of LX is inconsistent with the O2 affinity. On the other hand, the electronic properties of R, which is attached to the fourth position of the pyrazolyl rings in the rigid TpMe2,4R ligand, are reflected in the electrochemical properties and O2 affinity of the cobalt center.

Characterization of Mononuclear Non-heme Iron(III)-Superoxo Complex with a Five-Azole Ligand Set.

Reaction of O2 with a high-spin mononuclear iron(II) complex supported by a five-azole donor set yields the corresponding mononuclear non-heme iron(III)-superoxo species, which was characterized by UV/Vis spectroscopy and resonance Raman spectroscopy. (1)H NMR analysis reveals diamagnetic nature of the superoxo complex arising from antiferromagnetic coupling between the spins on the low-spin iron(III) and superoxide. This superoxo species reacts with H-atom donating reagents to give a low-spin iron(III)-hydroperoxo species showing characteristic UV/Vis, resonance Raman, and EPR spectra.

Two-step synthesis of difluoromethyl-substituted 2,3-dihydrobenzoheteroles.

3-Difluoromethylated 2,3-dihydrobenzoheteroles, 2,3-dihydrobenzofurans, 2,3-dihydrobenzothiophenes, and indolines were readily synthesized from ortho-heterosubstituted bromobenzenes, 2-bromophenols, 2-bromobenzenethiols, and 2-bromoanilines, respectively, in two steps: (1) γ-selective allylic substitution of 3-bromo-3,3-difluoropropene with heteronucleophiles and (2) intramolecular radical cyclization of the resulting 3,3-difluoroallylic compounds.

Responses of Bruguiera gymnorrhiza to saltwater monitored by miniature electrodes.

We measured the voltage between two Ag/AgCl electrodes, one inserted into the seedling of the salt-tolerant plant Bruguiera gymnorrhiza and the other into the vermiculite in which the seedling was potted. Four seedlings were placed in different environments, in saltwater or pure water, with light or alternating light/dark conditions. We have found that (1) the voltage profiles showed periodical oscillatory behavior; (2) seedlings in saltwater showed higher voltage compared to the ones in pure water; (3) in the light environment, the voltage was higher compared to the one in the dark environment; (4) in the dark environment, a voltage wave was hardly observable; and (5) electrodes inserted into the propagule cortex, stem cortex, and petiole showed different voltage wave amplitudes. The voltage profiles will provide an effective way to evaluate the movement of salt water inside the salt-tolerant plant.