Immune-related adverse events caused by treatment with pembrolizumab in a patient with lung cancer who infected influenza virus.

A 67-year-old man with stage IV B lung adenocarcinoma was treated with pembrolizumab. The patient was admitted to the hospital because of influenza on the day of the second cycle of pembrolizumab treatment. He was diagnosed with pneumonia and was treated with antiviral drugs and steroids. However, the patient eventually died. In this case, treatment with immune checkpoint inhibitors might have affected the immune response caused by influenza virus infection, that might have caused lung injury, which is an immune-related adverse event (irAE). Hence, it is important that, caution should be taken to prevent transmission of viral infection, and Therefore, it is important to prevent viral infections, but caution should also be paid to the possibility that infections may cause irAEs in patients with lung cancer.

Isolation and characterization of aerobic microorganisms with cellulolytic activity in the gut of endogeic earthworms

The ability of earthworms to decompose lignocellulose involves the assistance of microorganisms in their digestive system. While many studies have revealed a diverse microbiota in the earthworm gut, including aerobic and anaerobic microorganisms, it remains unclear which of these species contribute to lignocellulose digestion. In this study, aerobic microorganisms with cellulolytic activity isolated from the gut of two endogeic earthworms, Amynthas heteropoda (Megascolecidae) and Eisenia fetida (Lumbricidae) were isolated by solid culture of gut homogenates using filter paper as a carbon source. A total of 48 strains, including four bacterial and four fungal genera, were isolated from two earthworm species. Characterization of these strains using enzyme assays showed that the most representative ones had exocellulase and xylanase activities, while some had weak laccase activity. These findings suggest that earthworms digest lignocellulose by exploiting microbial exocellulase and xylanase besides their own endocellulase. Phylogenetic analysis showed that among the cellulolytic isolates in both earthworm species Burkholderia and Chaetomium were the dominant bacterial and fungal members (AU)

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Isolation and characterization of aerobic microorganisms with cellulolytic activity in the gut of endogeic earthworms.

The ability of earthworms to decompose lignocellulose involves the assistance of microorganisms in their digestive system. While many studies have revealed a diverse microbiota in the earthworm gut, including aerobic and anaerobic microorganisms, it remains unclear which of these species contribute to lignocellulose digestion. In this study, aerobic microorganisms with cellulolytic activity isolated from the gut of two endogeic earthworms, Amynthas heteropoda (Megascolecidae) and Eisenia fetida (Lumbricidae) were isolated by solid culture of gut homogenates using filter paper as a carbon source. A total of 48 strains, including four bacterial and four fungal genera, were isolated from two earthworm species. Characterization of these strains using enzyme assays showed that the most representative ones had exocellulase and xylanase activities, while some had weak laccase activity. These findings suggest that earthworms digest lignocellulose by exploiting microbial exocellulase and xylanase besides their own endocellulase. Phylogenetic analysis showed that among the cellulolytic isolates in both earthworm species Burkholderia and Chaetomium were the dominant bacterial and fungal members.

Notch induces myofibroblast differentiation of alveolar epithelial cells via transforming growth factor-{beta}-Smad3 pathway.

Notch is an ancient cell-signaling system that regulates the specification of cell fate. This study examined the role of Notch in the epithelial-mesenchymal transition (EMT) and myofibroblast differentiation of cultured RLE-6TN cells (i.e., rat alveolar epithelial cells). The activation of Notch, either by ectopic expression of the Notch intracellular domain or by the co-culture of RLE-6TN cells with L-Jagged1 cells, induces the expression of smooth muscle α-actin (SMA) and other mesenchymal marker genes (collagen I and vimentin), and reduces the expression of epithelial marker genes (E-cadherin, occludin, and zonula occludens-1). The pharmacologic inhibition of the endogenous Notch signal significantly inhibited the transforming growth factor-ß (TGF-ß)-induced expression of SMA. Cell migratory capacity was increased by Notch. Luciferase assays revealed that the CC(A/T)(6)GG (CArG) box and the TGF-ß control element (TCE) are required for Notch-induced SMA gene transcription. DNA microarray analysis revealed that members of the TGF-ß family as well as Jagged1 were induced in RLE-6TN cells by Notch. Western blot analysis showed that Notch induced the phosphorylation of Smad3, and the TGF-ß receptor type I/activin receptor-like kinase 5 (ALK5) kinase inhibitor SB431542 markedly reduced the Notch-induced expression of SMA. Enzyme-linked immunosorbent assays confirmed the production of TGF-ß1 from RLE-6TN cells by Notch. Immunohistochemistry of a bleomycin-induced model of pulmonary fibrosis and lung specimens from patients with idiopathic interstitial pneumonias showed that Notch was strongly expressed in myofibroblasts, identified as SMA-positive cells. These data indicate that Notch induces myofibroblast differentiation through a TGF-ß-Smad3 pathway that activates SMA gene transcription in a CArG-dependent and TCE-dependent manner in alveolar epithelial cells. Our data also imply that Notch induces the EMT phenotype, with increased migratory behavior in pulmonary fibrosis.

Hypoxia-inducible factor-1α mediates TGF-ß-induced PAI-1 production in alveolar macrophages in pulmonary fibrosis.

Hypoxia-inducible factor-1α (HIF-1α), a transcription factor that functions as a master regulator of oxygen homeostasis, has been implicated in fibrinogenesis. Here, we explore the role of HIF-1α in transforming growth factor-ß (TGF-ß) signaling by examining the effects of TGF-ß(1) on the expression of plasminogen activator inhibitor-1 (PAI-1). Immunohistochemistry of lung tissue from a mouse bleomycin (BLM)-induced pulmonary fibrosis model revealed that expression of HIF-1α and PAI-1 was predominantly induced in alveolar macrophages. Real-time RT-PCR and ELISA analysis showed that PAI-1 mRNA and activated PAI-1 protein level were strongly induced 7 days after BLM instillation. Stimulation of cultured mouse alveolar macrophages (MH-S cells) with TGF-ß(1) induced PAI-1 production, which was associated with HIF-1α protein accumulation. This accumulation of HIF-1α protein was inhibited by SB431542 (type I TGF-ß receptor/ALK receptor inhibitor) but not by PD98059 (MEK1 inhibitor) and SB203580 (p38 MAP kinase inhibitor). Expression of prolyl-hydroxylase domain (PHD)-2, which is essential for HIF-1α degradation, was inhibited by TGF-ß(1), and this decrease was abolished by SB431542. TGF-ß(1) induction of PAI-1 mRNA and its protein expression were significantly attenuated by HIF-1α silencing. Transcriptome analysis by cDNA microarray of MH-S cells after HIF-1α silencing uncovered several pro-fibrotic genes whose regulation by TGF-ß(1) required HIF-1α, including platelet-derived growth factor-A. Taken together, these findings expand our concept of the role of HIF-1α in pulmonary fibrosis in mediating the effects of TGF-ß(1) on the expression of the pro-fibrotic genes in activated alveolar macrophages.

[A case of sarcoidosis with hypoxia showing slight ground glass opacities on chest CT].

A 62-year-old man had had renal dysfunction and hepatosplenomegaly since 2000. In 2006, he complained of general fatigue and hemodialysis therapy was initiated because his renal function had deteriorated worse. In May 2007, he was admitted to our hospital because his general fatigue took a turn for the worse. He also had hypoxia. A chest radiograph showed no abnormal shadows. A chest computed tomography showed ground glass opacities in both lower lobes slightly. However, 67Ga-citrate scintigraph showed marked accumulation of 67Ga-citrate in the lungs, liver, spleen and kidneys. Transbronchial lung biopsy (TBLB) and bone marrow biopsy showed noncaseating epithelioid cell granulomas, and anti-PAB antibody positive cells were detected in epithelioid cell granulomas in the TBLB specimens. Therefore we diagnosed sarcoidosis. Although we could not perform renal or liver biopsy, we assumed that he had renal and liver sarcoidosis. After oral corticosteroid therapy, his symptoms and image findings improved. We report a rare case of sarcoidosis with hypoxia showing slight ground glass opacities

[Case of Wegener's granulomatosis associated with mediastinal lymphadenopathy].

A 54-year-old asymptomatic man was admitted to our hospital because his abnormal chest radiograph finding became worse. A chest radiograph and a chest computed tomography showed a mass in the right upper lobe and mediastinal lymphadenopathy. Thoracoscopic partial lung resection was performed. The specimens showed vasculitis and geographic basophilic necrosis palisading histiocytes and neutrophils. Wegener's granulomatosis was diagnosed. After resection, mediastinal lympahdenopathy was gradually improved in spite of no drug therapy. We report a rare case of Wegener's granulomatosis associated with lymphadenopathy.

[A case of anaphylactoid purpura associated with nephrosis followed by pulmonary tuberculosis].

A 54-year old man was admitted to our hospital because of high fever, productive cough and purpura in both legs in June 2005. Urinalysis showed microscopic hematuria and proteinuria. Chest radiograph showed consolidation of right upper field. Because acid-fast bacilli and polymerase chain reaction test for Mycobacterium tuberculosis were positive in bronchial lavage fluid, we made a diagnosis of pulmonary tuberculosis, and prescribed antituberculosis therapy with isoniazid, rifampicin, ethambutol and pyrazinamide. In addition, anaphylactoid purpura was diagnosed by skin biopsy. In July 2005, renal function was deteriorated and nephrosis appeared. We treated with corticosteroid in addition to antituberculosis therapy. His symptoms and renal dysfunction improved. We report a rare case of an anaphylactoid purpura following occurence of pulmonary tuberculosis.