Publishing type：Research paper (scientific journal)   Publisher：Springer Science and Business Media LLC  

Abstract

Background

Epstein–Barr virus (EBV) is associated with the pathogenesis of a variety of malignancies, most notably lymphomas. Especially in the background of immunodeficiency, such as primary immunodeficiency disorder (PID) and post-transplant lymphoproliferative disorder (PTLD), the role of EBV might be crucial. PIDs are rare heterogeneous diseases affecting the development and/or the function of the innate and adaptive immune system. Malignancy is the second-highest cause of death after infection, and lymphoma accounts for about half of malignancies. The most frequently reported lymphoma type is diffuse large B-cell lymphoma (DLBCL) and the incidence of T-cell lymphoma is rare. PTLDs are also rare serious lymphoid and/or plasmacytic proliferative disorders that occur after undergoing solid organ or hematopoietic stem cell transplantation (HSCT). In the context of HSCT, most reported PTLDs have occurred in patients who received allogenic HSCT, but only a few cases have been reported in autologous HSCT (AutoHSCT) recipients.

Case presentation

A 53-year-old female patient initially presented with enlargement of the left cervical lymph nodes and was diagnosed with EBV-positive DLBCL. She was treated with R-CHOP, R-ACES, and AutoHSCT and went into remission. Four years later, computed tomography results revealed multiple lung nodules and abnormal infiltration, and sustained and progressing hypogammaglobulinemia was observed. The pathological specimen of video-assisted thoracoscopic surgical lung biopsy demonstrated extensive invasion of lymphocytes with notable granuloma findings. Flow cytometric immunophenotyping analysis showed that lymphocytes were positive for CD3 and CD5; especially, CD3 was expressed in the cytoplasm. Southern blot analysis revealed rearrangements of the T-cell receptor Cβ1 gene. She was diagnosed with peripheral T-cell lymphoma, not otherwise specified, accompanied by notable granulomatous lesions.

Conclusion

Here, as a unique case of metachronous B-cell and T-cell lymphoma, we report a rare case of T-cell lymphoma that mainly affected the lungs with the presentation of notable granulomatous findings following AutoHSCT for EBV-positive DLBCL at the age of 53 years. These lung lesions of granulomatous T-cell lymphoma could be related to the underlying primary immunodeficiency background associated with sustained hypogammaglobulinemia.

DOI： 10.1186/s13000-020-01038-3

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Rheumatoid arthritis (RA)-associated interstitial lung disease (ILD), a primary cause of mortality in patients with RA, has limited treatment options. A previously established RA model in D1CC transgenic mice aberrantly expressed major histocompatibility complex class II genes in joints, developing collagen II-induced polyarthritis and anti-cyclic citrullinated peptide antibodies and interstitial pneumonitis, similar to those in humans. Molecular hydrogen (H2 ) is an efficient antioxidant that permeates cell membranes and alleviates the reactive oxygen species-induced injury implicated in RA pathogenesis. We used D1CC mice to analyse chronic lung fibrosis development and evaluate H2 treatment effects. We injected D1CC mice with type II collagen and supplied them with H2 -rich or control water until analysis. Increased serum surfactant protein D values and lung densities images were observed 10 months after injection. Inflammation was patchy within the perilymphatic stromal area, with increased 8-hydroxy-2'-deoxyguanosine-positive cell numbers and tumour necrosis factor-α, BAX, transforming growth factor-β, interleukin-6 and soluble collagen levels in the lungs. Inflammatory and fibrotic changes developed diffusely within the perilymphatic stromal area, as observed in humans. H2 treatment decreased these effects in the lungs. Thus, this model is valuable for studying the effects of H2 treatment and chronic interstitial pneumonia pathophysiology in humans. H2 appears to protect against RA-ILD by alleviating oxidative stress.

DOI： 10.1111/jcmm.14603

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Elsevier Inc  

DOI： 10.1016/j.ehpc.2018.06.003

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Elsevier Inc  

DOI： 10.1016/j.ehpc.2018.04.002

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：W B SAUNDERS CO-ELSEVIER INC  

The occurrence of osteoclast-like giant cells (OLGCs) in uterine leiomyosarcomas (LMSs) is a rare phenomenon. The nature of OLGCs and the significance of their accumulation in these tumors are poorly understood. Recent studies revealed that the formation of osteoclasts requires a specific cytokine, receptor activator of nuclear factor kappa B ligand (RANKL), in bone. In this study, we investigated the expression of RANKL in 2 cases of uterine LMS with OLGCs by means of immunohistochemistry and compared the extent of RANKL expression with that in conventional uterine LMSs and leiomyomas by using real-time reverse-transcription quantitative polymerase chain reaction. Our cases of uterine LMS with OLGCs showed markedly high expression of RANKL messenger RNA with clear RANKL immunoreactivity compared with messenger RNA expression and immunoreactivity of conventional uterine LMSs and leiomyomas. These findings suggest that the tumors producing RANKL may account for accumulation of OLGCs in tumor tissue because of RANKL-related osteoclastogenesis. (C) 2015 Elsevier Inc. All rights reserved.

DOI： 10.1016/j.humpath.2015.04.018

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：NATURE PUBLISHING GROUP  

Survivin, an inhibitor of apoptosis, regulates cell division and is a potential target for anticancer drugs because many cancers express high survivin levels. However, whether survivin would be toxic to human lung cells and tissues has not been determined. This report clarified the involvement of survivin in acute lung injury. We used immunohistochemical analysis, immunoelectron microscopy, and real-time reverse transcription-quantitative polymerase chain reaction to study survivin expression and localization in injured mouse and human lungs. We also used cultured human lung epithelial cells (BEAS-2B and A549) to study survivin cytoprotection. Nuclei and cytoplasm of epithelial cells in day 3 and day 7 models of bleomycin-injured lung showed survivin-positive results, which is consistent with upregulated survivin nnRNA expression. These nuclei also evidenced double positive findings for proliferating cell nuclear antigen and survivin. Day 7 models had similar Smac/DIABLO-positive and survivin-positive cell distributions. The cytoplasm and nuclei of epithelial cells in lesions with diffuse alveolar damage manifested strong survivin-positive findings. Bleomycin stimulation in both epithelial cell lines upregulated expression of survivin and apoptosis-related molecules. Suppression of survivin expression with small interfering RNA rendered human lung epithelial cells susceptible to bleomycin-induced damage, with markedly upregulated activation of caspase-3, caspase-7, poly (ADP-ribose) polymerase, and lactate dehydrogenase activity and an increased number of dead cells compared with mock small interfering RNA-treated cells. Overexpression of survivin via transfection resulted in these epithelial cells being resistant to bleomycin-induced cell damage, with reduced activation of apoptosis-related molecules and lactate dehydrogenase activity and fewer dead cells compared with results for mock-transfected cells. Survivin, acting at the epithelial cell level that depends partly on apoptosis inhibition, is therefore a key mediator of cytoprotection in acute lung injury. Understanding the precise role of survivin in normal lung cells is required for the development of therapeutic survivin.

DOI： 10.1038/labinvest.2013.103

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The mucin-rich variant of salivary duct carcinoma (mSDC) is a rare type of salivary duct carcinoma. mSDC usually has both conventional SDC and mucinous adenocarcinoma-like areas. This article describes a first case of mSDC in which 95% of the tumor consisted of a mucinous area without no solid conventional SDC, so that the tumor mimicked mucinous adenocarcinoma. A 55-year-old man was evaluated for a 14 mm mass in the left submandibular gland. The tumor showed that floating tumor nests in a prominent mucinous lake. Some floating tumor nests had focal cribriform pattern with comedo necrosis, and all tumor cells had immunoreactivity for androgen receptor, gross cystic disease fluid protein 15, and Her-2/neu. A diagnosis of mSDC was rendered. mSDC with prominent mucinous component sometimes resembles mucinous adenocarcinoma. Identifying specific histological and immunohistochemical features of floating tumor nests in the mucinous area are important for the diagnosis.

DOI： 10.1016/j.oooo.2013.01.002

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Language：Japanese   Publisher：日本医科大学医学会  

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Nonalcoholic steatohepatitis (NASH) is one of the life-threatening hepatic diseases
however, its pathogenesis is still unknown. To evaluate the causative role of hyperlipidaemia and high-fat diet, we compared C57BL/6 mice with inherited hyperlipidaemic model mice (LDLR-/- mice and ApoE -/- mice) fed a normal or a high-fat diet. LDLR-/- and ApoE-/- mice fed the normal diet showed significantly higher serum cholesterol level than that of C57BL/6 mice fed the high-fat diet. These mice, however, have shown neither significant elevation of serum alanine transaminase (ALT) level nor histopathologic features of steatohepatitis. High-fat diet groups of all three strains showed histopathological characteristics of steatohepatitis with elevated serum ALT levels and high expression of macrophage scavenger receptor MARCO mRNA in the liver. Semi-quantitative endotoxin analysis showed an elevated serum endotoxin level in the portal vein but not in the vena cava in ApoE-/- mice fed the high-fat diet. These results indicate that long-term feeding of a high-fat diet induces NASH, whereas hyperlipidaemia alone is not enough to induce NASH. Liver-restricted induction of MARCO in mice with high-fat diet and portal endotoxaemia in ApoE -/- mice fed the high-fat diet suggest the possible involvement of endotoxin in the pathogenesis of NASH.

DOI： 10.1111/j.0959-9673.2004.00401.x

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DOI： 10.1038/s42003-024-06183-9

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Publishing type：Research paper (scientific journal)   Publisher：Medical Association of Nippon Medical School  

DOI： 10.1272/jnms.jnms.2023_90-504

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BACKGROUND: To investigate the impact of Perirenal fat stranding (PRFS) on progression after radical nephroureterectomy (RNU) for renal pelvic urothelial carcinoma (RPUC) without hydronephrosis and to reveal the pathological findings of PRFS. METHODS: Clinicopathological data, including computed tomography (CT) findings of the ipsilateral PRFS, were collected from the medical records of 56 patients treated with RNU for RPUC without hydronephrosis between 2011 and 2021 at our institution. PRFS on CT was classified as either low or high PRFS. The impact of PRFS on progression-free survival (PFS) after RNU was analyzed using the Kaplan-Meier method and log-rank test. In addition, specimens including sufficient perirenal fat from patients with low and with high PRFS were pathologically analyzed. Immunohistochemical analysis of CD68, CD163, CD3, and CD20 was also performed. RESULTS: Of the 56 patients, 31(55.4%) and 25 (44.6%) patients were classified as having low and high PRFS, respectively. Within a median follow-up of 40.6 months postoperatively, 11 (19.6%) patients showed disease progression. The Kaplan-Meier method and log-rank test revealed that patients with high PRFS had significantly lower PFS rates than those with low PRFS (3-year PFS 69.8% vs 93.3%; p = 0.0393). Pathological analysis revealed that high PRFS specimens (n = 3 patients) contained more fibrous strictures in perirenal fat than low PRFS specimens (n = 3 patients). In addition, M2 macrophages (CD163 +) infiltrating fibrous tissue in perirenal area were observed in all patients with high PRFS group. CONCLUSIONS: PRFS of RPUC without hydronephrosis consists of collagenous fibers with M2 macrophages. The presence of ipsilateral high PRFS might be a preoperative risk factor for progression after RNU for RPUC patients without hydronephrosis. Prospective studies with large cohorts are required in the future.

DOI： 10.1007/s12672-023-00741-z

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Publishing type：Research paper (scientific journal)   Publisher：Wiley  

Aim

To clarify the clinicopathological characteristics and role of periglomerular angiogenesis in IgA nephropathy.

Methods and Results

The renal biopsy specimens of 114 patients with IgA nephropathy were examined. Among them, 46 (40%) showed periglomerular angiogenesis around the glomeruli. CD34 and α‐smooth muscle actin (α‐SMA) staining in serial sections revealed that these vessels contained CD34+ α‐SMA+ microarterioles along with CD34+ α‐SMA− capillaries. We termed these “periglomerular microvessels (PGMVs)”. Patients with PGMVs (PGMV group) had clinically and histologically more severe disease than those without PGMVs (non‐PGMV group) at the time of biopsy. Even after adjusting for age, there were significant differences in the degree of proteinuria and estimated glomerular filtration rate reduction between the PGMV and non‐PGMV groups. The PGMV group showed a higher incidence of segmental and global glomerulosclerosis and crescentic lesions than the non‐PGMV group (P < 0.01). Here, PGMVs were undetectable in the acute and active inflammation phase, but were observed in the acute to chronic or chronic glomerular remodelling phase. PGMVs mainly developed around glomerular adherent lesions to the Bowman's capsule with small or minimal glomerular sclerotic lesions. Conversely, they were rarely observed in segmental sclerosis areas.

Conclusion

The PGMV group is clinically and pathologically more severe than the non‐PGMV group; however, they were undetectable in segmental sclerosis with mesangial matrix accumulation. PGMVs might occur after acute/active glomerular lesions, suggesting that PGMVs may inhibit segmental glomerulosclerosis progression and could be a marker for good repair response after acute/active glomerular injury in severe IgA nephropathy cases.

DOI： 10.1111/his.14997

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BACKGROUND: Immune checkpoint inhibitors (ICIs) have provided significant benefits in cancer treatment, but they could develop immune-related adverse events (irAE). ICI-associated renal adverse effects are rare and tubulointerstitial nephritis (TIN) is the most common in the renal irAE. However, only a few case reports of renal vasculitis associated with ICI have been reported. In addition, the characteristics of infiltrating inflammatory cells of ICI-associated TIN and renal vasculitis have been uncertain. CASE PRESENTATION: A 65-year-old man received immune checkpoint inhibitors (ICIs), anti-CTLA-4 (cytotoxic T-lymphocyte-associated protein 4) and anti-PD-1 (programmed cell death 1) antibodies for aggravated metastatic malignant melanoma. About 1 week after the second administration of nivolumab and ipilimumab, acute kidney injury developed. A renal biopsy was performed that showed TIN and non-necrotizing granulomatous vasculitis in interlobular arteries. Massive CD3+ T cells and CD163+ macrophages infiltrated both tubulointerstitium and interlobular arteries. Many infiltrating cells tested positive for Ki-67 and PD-1 ligand (PD-L1), but negative for PD-1. In CD3+ T cells, CD8+ T cells were predominantly infiltrated, and these cells were positive for Granzyme B (GrB) and cytotoxic granule TIA-1, but negative for CD25, indicating antigen-independent activated CD8+ T cells. Infiltration of CD4+ T cells was noted without obvious CD4+ CD25+ regulatory T (Treg) cells. His renal dysfunction recovered within 2 months of treatment with prednisolone in addition to discontinuation of nivolumab and ipilimumab. CONCLUSIONS: We herein reported a case of ICI-related TIN and renal granulomatous vasculitis with infiltration of massive antigen-independent activated CD8+ T cells and CD163+ macrophages, and none or few CD4+ CD25+ Treg cells. These infiltrating cells might be a characteristic of the development of renal irAE.

DOI： 10.1186/s12882-023-03091-8

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DOI： 10.1038/s41390-022-02332-0

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Publishing type：Research paper (scientific journal)   Publisher：SAGE Publications  

Low-vacuum scanning electron microscopy (LV-SEM) is a powerful tool that allows to observe light microscopic specimens with periodic acid-silver methenamine (PAM) staining at a higher magnification, simply by removing the coverslip. However, it is not suitable for observation of immunohistochemistry (IHC) using 3,3′-diaminobenzidine (DAB) due to insufficient backscattered electron image. Traditional heavy metal enhancement techniques for DAB in IHC, (1) osmium tetroxide and iron, (2) cobalt, (3) methenamine silver (Ag), (4) gold chloride (Gold), and (5) both Ag and Gold (Ag + Gold), were examined by LV-SEM. Tissue specimens from Thy1.1 glomerulonephritis rat kidney stained with α-smooth muscle actin and visualized with DAB were enhanced by each of these enhancement methods. We found, in light microscopic and LV-SEM, that the enhancement with Ag, Gold, or Ag + Gold had better intensity and contrast than others. At a higher magnification, Ag + Gold enhancement showed high intensity and low background, although only Ag or Gold enhancement had nonspecific background. Even after observation by LV-SEM, the quality of specimens was maintained after remounting the coverslip. It was also confirmed that Ag + Gold enhancement could be useful for IHC using clinical human renal biopsy. These findings indicate that Ag + Gold provided an adequate enhancement in IHC for both LM and LV SEM observation.

DOI： 10.1369/00221554221102996

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BACKGROUND: Low-vacuum scanning electron microscopy (LV-SEM) is applied to diagnostic renal pathology. METHODS: To demonstrate the usefulness of LV-SEM and to clarify the optimal conditions of pathology samples, we investigated the alterations of glomerular basement membrane (GBM) and podocytes in control and experimental active Heymann nephritis (AHN) rats by LV-SEM. RESULTS: On week 15 following induction of AHN, spike formation on GBM with diffuse deposition of IgG and C3 developed. Using LV-SEM, diffuse crater-like protrusions were clearly noted three-dimensionally (3D) on surface of GBM in the same specimens of light microscopy (LM) and immunofluorescence (IF) studies only after removal coverslips or further adding periodic acid-silver methenamine (PAM) staining. These 3D ultrastructural findings of GBM surface could be detected in PAM-stained specimens by LV-SEM, although true GBM surface findings could not be obtained in acellular glomeruli, because some subepithelial deposits remained on surface of GBM. Adequate thickness was 1.5-5 μm for 10% formalin-fixed paraffin-embedded (FFPE) and 5-10 μm for the unfixed frozen sections. The foot processes and their effacement of podocytes could be observed by LV-SEM using 10%FFPE specimens with platinum blue (Pt-blue) staining or double staining of PAM and Pt-blue. These findings were obtained more large areas in 2.5% glutaraldehyde-fixed paraffin-embedded (2.5%GFPE) specimens. CONCLUSION: Our findings suggest that LV-SEM is a useful assessment tool for evaluating the alterations of GBM and podocytes in renal pathology using routine LM and IF specimens, as well as 2.5%GFPE specimens.

DOI： 10.1007/s10157-021-02147-z

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We report the case of an 80 year-old woman who developed bilateral lower extremity purpura and renal impairment with proteinuria a few days after a transient fever (day 0). High levels of both anti-streptolysin-O antibody (ASO) and anti-streptokinase antibody (ASK), as well as low levels of coagulation factor XIII in serum were noted. Skin biopsy was performed and showed a leukocytoclastic vasculitis with deposition of IgA and C3 in the cutaneous small vessels, indicating IgA vasculitis in the skin. After initiation of oral prednisolone, the skin lesions showed significant improvement. However, renal function and proteinuria gradually worsened from day 12. Kidney biopsy was performed on day 29, which demonstrated a necrotizing and crescentic glomerulonephritis with mesangial deposition of IgA and C3. In addition, the deposition of galactose-deficient IgA1 (Gd-IgA1) was positive on glomeruli and cutaneous small vessels, indicating that the purpura and glomerulonephritis both shared the same Gd-IgA1-related pathogenesis. In addition, the association between the acute streptococcal infection and the IgA vasculitis was confirmed by the deposition of nephritis-associated plasmin receptor (NAPlr) in glomeruli. The patient was treated with steroid pulse and intravenous cyclophosphamide, in addition to the oral prednisolone treatment. Renal function and proteinuria gradually improved, but did not completely recover, as is typically seen with courses of IgA vasculitis in the elderly. In this case, the streptococcal infectionrelated IgA vasculitis was confirmed pathologically by the deposition of both NAPlr and Gd-IgA1 in glomeruli, as well as Gd-IgA1 in the cutaneous small vessels.

DOI： 10.1007/s13730-022-00684-4

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DOI： 10.1007/s13730-021-00676-w

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Publishing type：Research paper (scientific journal)   Publisher：Medical Association of Nippon Medical School  

DOI： 10.1272/jnms.jnms.2021_88-609

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DOI： 10.1007/s10157-021-02076-x

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Publishing type：Research paper (scientific journal)   Publisher：S. Karger AG  

Background: Focal segmental glomerulosclerosis (FSGS) is a clinicopathological syndrome characterized by nephrotic-range proteinuria with high incidence of progression to end-stage renal disease (ESRD). In primary FSGS, 40–60% of patients develop ESRD within 10–20 years. Summary: Recurrence of FSGS after kidney transplantation is frequent and is associated with poor allograft survival. The risk factors for recurrent FSGS include onset of FSGS during childhood, rapid progression of primary FSGS to ESRD, history of recurrent FSGS in previous allograft, and diffuse mesangial hypercellularity or collapsing variant of FSGS in the native kidney. The early histological findings of recurrent FSGS consist of unremarkable glomerular changes on light microscopy but significant podocyte effacement on electron microscopy; the loss of foot processes with eventual dropout of podocytes leads to the development of segmental lesions in the glomerulus. Experimental and clinical data suggest the existence of circulating permeability factors, such as soluble urokinase-type plasminogen activator receptor (suPAR), cardiotrophin-like cytokine factor-1 (CLCF-1), CD40 axis, and apolipoprotein A-Ib (ApoA-Ib), in the pathogenesis of recurrent FSGS. These biomarkers including circulating permeability factors may facilitate earlier diagnosis of FSGS posttransplant and may guide in the development of novel therapies that may be more effective and improve long-term outcomes in kidney transplantation. Key Messages: Several studies have suggested the possible circulating permeability factors, such as suPAR, CLCF-1, CD40 axis, and ApoA-Ib, in the pathogenesis and disease progression of FSGS and recurrent FSGS. Further studies should be performed to elucidate the true essential biomarker(s) associated with the onset and progression of FSGS as well as recurrent FSGS.

DOI： 10.1159/000510748

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Vibrio cholerae produced-Cholix toxin (Cholix) is a cytotoxin that ADP-ribosylates eukaryotic elongation factor 2, inhibiting protein synthesis, and inducing apoptosis. Here, we identified prohibitin (PHB) 1 and 2 as novel Cholix-interacting membrane proteins in immortalised human hepatocytes and HepG2 cells by Cholix immunoprecipitation assays. The expression level of PHB1 was decreased by Cholix after a 12hr incubation. Cholix-induced poly (ADP-ribose) polymerase (PARP) cleavage was significantly enhanced in PHB (PHB1 or PHB2) knockdown cells. In contrast, transiently overexpressed PHB in hepatocytes attenuated Cholix-induced Bax/Bak conformational changes and PARP cleavage. In addition, Cholix-induced reactive oxygen species production and accumulation of fragmented mitochondria were enhanced in PHB-knockdown cells. Furthermore, Cholix induced activation of Rho-associated coiled coil-containing protein kinase 1 (ROCK1), which was enhanced in PHB-knockdown cells, followed by actin filament depolymerisation and accumulation of tubulin in the blebbing cells. Inhibition of ROCK1 by siRNA or its inhibitor suppressed Cholix-induced PARP cleavage and reactive oxygen species generation. Our findings identify PHB as a new protein that interacts with Cholix and is involved in Cholix-induced mitochondrial dysfunction and cytoskeletal rearrangement by ROCK1 activation during apoptosis.

DOI： 10.1111/cmi.13033

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Although inhibition of epidermal growth factor receptor (EGFR)-mediated cell signaling by the EGFR tyrosine kinase inhibitor gefitinib is highly effective against advanced non-small cell lung cancer, this drug might promote severe acute interstitial pneumonia. We previously reported that molecular hydrogen (H2) acts as a therapeutic and preventive anti-oxidant. Here, we show that treatment with H2 effectively protects the lungs of mice from severe damage caused by oral administration of gefitinib after intraperitoneal injection of naphthalene, the toxicity of which is related to oxidative stress. Drinking H2-rich water ad libitum mitigated naphthalene/gefitinib-induced weight loss and significantly improved survival, which was associated with a decrease in lung inflammation and inflammatory cytokines in the bronchoalveolar lavage fluid. Naphthalene decreased glutathione in the lung, increased malondialdehyde in the plasma, and increased 4-hydroxy-2-nonenal production in airway cells, all of which were mitigated by H2-rich water, indicating that the H2-rich water reverses cellular damage to the bronchial wall caused by oxidative stress. Finally, treatment with H2 did not interfere with the anti-tumor effects of gefitinib on a lung cancer cell line in vitro or on tumor-bearing mice in vivo. These results indicate that H2-rich water has the potential to improve quality of life during gefitinib therapy by mitigating lung injury without impairing anti-tumor activity.

DOI： 10.1038/s41374-019-0187-z

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Although mammalian target of rapamycin inhibitors (mTORi) are used to treat various malignancies, they frequently induce active alveolitis and dyslipidemia. Abnormal lipid metabolism affects alveolar surfactant function and results in pulmonary disorders; however, the pathophysiology of lung injury and its relationship with lipid metabolism remain unknown. We investigated the relationship between lipid metabolism and alveolar epithelial injury, focusing on peroxisome proliferator-activated receptor-γ (PPAR-γ) as a lipid stress-related factor in mTORi-induced lung injury. We clinicopathologically examined three patients with mTORi-induced lung injury. We constructed an mTORi injury mouse model using temsirolimus in mice (30 mg/kg/day), with the vehicle control and bleomycin injury groups. We also constructed a cultured alveolar epithelial cell injury model using temsirolimus (0-40 μM) in the mouse lung epithelial cell line MLE-12 and performed analysis with or without pioglitazone (PPAR-γ agonist) treatment. All three patients had dyslipidemia and lung lesions of hyperplastic pneumocytes with foamy and enlarged changes. In the mouse model, temsirolimus induced significantly higher levels of total cholesterol and free fatty acids in serum and higher levels of surfactant protein D in serum and BAL fluid with an increase in inflammatory cytokines in the lung compared to control. Temsirolimus also induced hyperplastic foamy pneumocytes with increased lipid-associated spots and larger round electron-lucent bodies compared to the control or bleomycin groups in microscopic analyses. Multiple lipid-associated spots within the cytoplasm were also induced by temsirolimus administration in MLE-12 cells. Temsirolimus downregulated PPAR-γ expression in mouse lung and MLE-12 cells but upregulated cleaved caspase-3 in MLE-12 cells. Pioglitazone blocked the upregulated cleaved caspase-3 expression in MLE-12 cells. The pathogenesis of mTORi-induced lung disease may be involved in alveolar epithelial injury, via lipid metabolic stress associated with downregulated PPAR-γ expression. Focusing on the relationship between lipid metabolic stress and alveolar epithelial injury represents a potentially novel approach to the study of pulmonary damage.

DOI： 10.1038/s41374-018-0158-9

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BACKGROUND: Thin basement membrane nephropathy (TBMN) is diagnosed by diffuse thinning of the glomerular basement membrane (GBM) without any clinical and pathologic findings of Alport syndrome and the other renal diseases. TBMN is characterized clinically by benign familial hematuria but rarely develops into end-stage renal disease. METHODS: In 27 cases of biopsy-proven TBMN, we evaluated the pathologic characteristics of TBMN, and examined the correlation between these pathologic characterizations and renal dysfunction. RESULTS: All patients had hematuria, and 21 patients (77.8%) had proteinuria. In six patients (28.6%) who were more than 50 years of age, the estimated glomerular filtration rate (eGFR) decreased from G3a to G4 in the chronic kidney disease stage. Pathologically, an irregular decrease in intensity of type IV collagen α5(IV) chain was seen in GBM, and irregular thinning with diffuse rough etched images was observed on the GBM surface with several sizes of holes by low-vacuum scanning electron microscopy. The glomerular morphology of TBMN was characterized by an increased number of small glomerular capillaries with an increased extracellular matrix (ECM). These characteristic morphologic alterations were evident from a young age in patients with TBMN, but were not correlated directly with the decrease of eGFR, the degree of hematuria, and proteinuria. The decrease of eGFR in patients with TBMN who were more than 50 years of age might be primarily mediated by arteriolosclerosis-associated glomerulosclerosis and interstitial fibrosis. CONCLUSION: Characteristic pathological glomerular findings and GBM alterations occurred from a young age but were not associated directly with renal impairment in biopsy-proven TBMN.

DOI： 10.1007/s10157-018-01687-1

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Naftopidil, an α-1 adrenoceptor antagonist with few adverse effects, is prescribed for prostate hyperplasia. Naftopidil inhibits prostate fibroblast proliferation; however, its effects on lung fibroblasts and fibrosis remain largely unknown. Two normal and one idiopathic pulmonary fibrosis human lung fibroblast lines were cultured with various naftopidil concentrations with or without phenoxybenzamine, an irreversible α-1 adrenoceptor inhibitor. We examined the incorporation of 5-bromo-2'-deoxyuridine into DNA and lactic acid dehydrogenase release by enzyme-linked immunosorbent assay, cell cycle analysis by flow cytometry, scratch wound-healing assay, and mRNA expressions of type IV collagen and α-smooth muscle actin by polymerase chain reaction. Effects of naftopidil on bleomycin-induced lung fibrosis in mice were evaluated using histology, micro-computed tomography, and surfactant protein-D levels in serum. Naftopidil, dose-dependently but independently of phenoxybenzamine, inhibited 5-bromo-2'-deoxyuridine incorporation in lung fibroblasts. Naftopidil induced G1 cell cycle arrest, but lactic acid dehydrogenase release and migration ability of lung fibroblasts were unaffected. Naftopidil decreased mRNA expressions of type IV collagen and α-smooth muscle actin in one normal lung fibroblast line. Histological and micro-computed tomography examination revealed that naftopidil attenuated lung fibrosis and decreased serum surfactant protein-D levels in bleomycin-induced lung fibrosis in mice. In conclusion, naftopidil may have therapeutic effects on lung fibrosis.

DOI： 10.1111/jcmm.14255

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Springer Tokyo  

Background: Liquid chromatography-tandem mass spectrometry (LC-MS/MS) has recently been utilized to accurately detect the amyloid proteins of renal amyloidosis. The present study investigated the optimal procedures for analyzing samples by LCMS/MS, and the advantage of using this technique to diagnosis renal amyloidosis. Methods: To detect amyloid proteins, laser microdissected glomeruli from AL (n = 13) or AA (n = 10) renal amyloidosis patients were digested and analyzed by LCMS/MS. To determine the best procedures for analyzing samples by LCMS/MS, we examined the suitability of tissue samples, frozen or formalin-fixed paraffin-embedded (FFPE), the number of dissected glomeruli required for analysis (2, 10, or 50 glomeruli), and the amount of trypsin with or without dithiothreitol (DTT). We additionally compared the detection of amyloid proteins between immunostaining and LCMS/MS. Results: Examining 10 dissected glomeruli from FFPE sections digested with trypsin 3 µL (0.1 mg/mL) without DDT made it possible to detect amyloid protein in all 10 AA and in 10 out of 12 AL amyloidosis cases. All AA amyloidosis cases were diagnosed using immunohistochemistry for amyloid A. With immunostaining, however, there were several inconclusive immunoglobulin and/or their light chain staining noted in the AA or AL amyloidosis cases. Even so, LCMS/MS was able to accurately detect amyloid protein in renal amyloidosis. Conclusion: The use of 10 laser microdissected glomeruli (170,000–220,000 µm2) with amyloid deposition from FFPE sections digested with trypsin 3 µL (0.1 mg/mL) allowed the accurate detection of amyloid protein in AA and AL amyloidosis.

DOI： 10.1007/s10157-018-1533-y

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：W B SAUNDERS CO-ELSEVIER INC  

Crystal-storing histiocytosis (CSH) is an uncommon finding in lymphoplasmacytic disorders that presents histiocytes with abnormal intralysosomal accumulations of immunoglobulin light chains as crystals of unknown etiology. A 38-year-old woman with antiphospholipid syndrome had a surgical lung biopsy because of multiple lung mass lesions. In a right middle lobe lesion, lymphoplasmacytic cells had a monocytoid appearance, destructive lymphoepithelial lesions, and positive immunoglobulin heavy chain (IGH) gene rearrangements. A right upper lobe lesion manifested proliferating rounded histiocytes with abundant, deeply eosinophilic cytoplasm and negative IGH gene rearrangements. Electron microscopy and mass spectrometry revealed a case of pulmonary CSH: abnormal proliferation of the immunoglobulin k chain of a variable region that may be crystallized within plasma cells and histiocytes. We report a rare case of localized pulmonary CSH complicating pulmonary mucosa-associated lymphoid tissue lymphoma with multiple mass lesions. We demonstrate advances in the understanding of the pathogenesis of CSH by various analyses of these lesions. (C) 2017 Elsevier Inc. All rights reserved.

DOI： 10.1016/j.humpath.2016.10.028

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：OXFORD UNIV PRESS  

Cholix toxin (Cholix) from Vibrio cholerae is a potent virulence factor exhibiting ADP-ribosyltransferase activity on eukaryotic elongation factor 2 (eEF2) of host cells, resulting in the inhibition of protein synthesis. Administration of Cholix or its homologue Pseudomonas exotoxin A (PEA) to mice causes lethal hepatocyte damage. In this study, we demonstrate cytotoxicity of Cholix on human hepatocytes in the presence of tumor necrosis factor alpha(TNF-alpha), which has been reported to play a fatal role in PEA administered to mice. Compared with incubating HepG2 cells with Cholix alone, co-treatment with TNF-alpha and Cholix (TNF-alpha/Cholix) significantly enhanced the activation of caspases, cytochrome c release from mitochondria into cytoplasm, and poly-ADP-ribose polymerase (PARP) cleavage, while incubation with TNF-alpha alone or co-treatment with TNF-alpha/catalytically inactive Cholix did not. In the early stage of cell death, Cholix increased phosphorylation of mitogenactivated protein kinases (e. g., p38, ERK, JNK) and Akt, which was not affected by TNF-alpha alone. MAPK inhibitors (SP600125, SB20852, and U0126) suppressed PARP cleavage induced by TNF-alpha/Cholix. Protein kinase inhibitor Go6976 suppressed JNK phosphorylation and PARP cleavage by TNF-alpha/Cholix. In contrast, PKC activator PMA in the absence of TNF-a promoted Cholix-induced PARP cleavage. Reactive oxygen species (ROS) inhibitor, N-acetyl cysteine (NAC), suppressed TNF-alpha/Cholixinduced JNK and ERK phosphorylation, resulting in inhibition of PARP cleavage. These data suggest that ROS and JNK pathways are important mediators of TNF-alpha/Cholix-induced HepG2 cell death.

DOI： 10.1093/toxsci/kfx009

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Language：English   Publisher：NATURE PUBLISHING GROUP  

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Language：Japanese   Publisher：日本医科大学医学会  

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：MEDICAL ASSOC NIPPON MEDICAL SCH  

Extranodal natural killer/T-cell lymphoma (ENK/TCL) is most often in the nose or the nasopharynx but can present elsewhere. We report a rare case of ENK/TCL that presented as swelling of an upper eyelid without ocular involvement. A 76-year-old man visited our hospital with a swollen lesion of the left upper eyelid which had appeared 2 months earlier. A biopsy of the upper eyelid revealed slight perivascular and periadnexal infiltration of mononuclear cells with dermal edema. Treatment with oral prednisolone at a dosage of 20 mg/day decreased the eyelid swelling. However, 5 months later, exacerbation of the swelling and nasal congestion were observed. A second biopsy of the upper eyelid revealed a diffuse dermal infiltrate composed of mononuclear cells with an angiocentic growth pattern. Immunohistochemical studies and in situ hybridization showed natural killer-lineage antigens (CD56, granzyme B, and T-cell intracellular antigen 1) with expression of Epstein-Barr virus. These findings lead to the diagnosis of ENK/TCL. We treated the patient with radiation therapy (50 Gy) and 3 courses of a regimen including dexamethasone, carboplatin, etoposide, and ifosphamide. This case suggests that ENK/TCL can present with swelling of an upper eyelid as the primary sign of the skin lesion. Swelling of an upper eyelid should be considered in the differential diagnosis of ENK/TCL.

DOI： 10.1272/jnms.83.177

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Language：English   Publisher：W B SAUNDERS CO-ELSEVIER INC  

Differentiating low-grade lymphoma from preexisting sarcoidosis is difficult because of their pathological similarity. This article describes a case of pulmonary mucosa-associated lymphoid tissue lymphoma associated with pulmonary sarcoidosis. The patient, a 45-year-old Japanese man, presented with a 10-year history of pulmonary sarcoidosis and 5-year history of ocular sarcoidosis with histologic findings. Because only the right S3 lung nodule had gradually enlarged, partial resection was performed. Pathological study revealed noncaseous epithelioid granulomas with lymphoplasmacytic proliferation but also marked lymphoid cell proliferation with lymphoepithelial lesion findings that differed from findings of typical sarcoid lesions. Our lymphoepithelial lesion evaluation via immunohistochemistry and analysis of Ig heavy-chain gene rearrangements with assessment of Propionibacterium acnes specific antibody reactions allow us to report, for the first time, this case of pulmonary mucosa-associated lymphoid tissue lymphoma associated with pulmonary sarcoidosis in exactly the same location, which may be significant for differentiating these diseases and understanding their pathogenic association. (C) 2016 Elsevier Inc. All rights reserved.

DOI： 10.1016/j.humpath.2015.12.019

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Language：English   Publisher：AMER THORACIC SOC  

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：E-CENTURY PUBLISHING CORP  

Early fibrotic lesions are thought to be one of the initial findings of lung fibrogenesis in idiopathic interstitial pneumonias, but little is known about their properties. Canstatin is an endogenous angiogenesis inhibitor derived from the C-terminal globular non-collagenous domain of the alpha 2 chain of type IV collagen, and type IV collagen is deposited in early fibrotic lesions without neovascularization in usual interstitial pneumonia (UIP). We used immunohistochemical methods to study expression of canstatin in lung specimens from patients with UIP or organizing pneumonia (OP). We analyzed the expression and function of canstatin in cultured lung fibroblasts by Western blotting and a Boyden chamber migration assay. We found expression of canstatin in early fibrotic lesions of UIP but not OP. Lung fibroblasts showed enhanced expression of canstatin after being stimulated with transforming growth factor-beta 1. Recombinant canstatin inhibited migration of not only endothelial cells but also lung fibroblasts. These results suggest that fibroblasts in early fibrotic lesions of UIP, which express canstatin, have less ability to migrate than fibroblasts in OP lesions, which do not express canstatin. Thus, canstatin in early fibrotic lesions of UIP contributes to persistent fibrogenesis and is likely involved in its refractory nature, including migration of intralesional fibroblasts.

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：NATURE PUBLISHING GROUP  

Early fibrotic lesions are thought to be the initial findings of fibrogenesis in idiopathic interstitial pneumonias, but little is known about their properties. Type IV collagen comprises six gene products, alpha 1-alpha 6, and although it is known as a major basement membrane component, its abnormal deposition is seen in fibrotic lesions of certain organs. We studied the expression of type I and III collagen and all a chains of type IV collagen in lung specimens from patients with usual interstitial pneumonia (UIP) or organizing pneumonia (OP) via immunohistochemistry. With cultured lung fibroblasts, we analyzed the expression and function of all a chains of type IV collagen via immunohistochemistry, western blotting, real-time quantitative PCR, and a Boyden chamber migration assay after the knockdown of alpha 1 and alpha 2 chains. Although we observed type I and III collagens in early fibrotic lesions of both UIP and OP, we found type IV collagen, especially alpha 1 and alpha 2 chains, in early fibrotic lesions of UIP but not OP. Fibroblasts enhanced the expression of alpha 1 and alpha 2 chains of type IV collagen after transforming growth factor-beta 1 stimulation. Small interfering RNA against alpha 1 and alpha 2 chains increased fibroblast migration, with upregulated phosphorylation of focal adhesion kinase (FAK), and adding medium containing fibroblast-produced alpha 1 and alpha 2 chains reduced the increased levels of fibroblast migration and phosphorylation of FAK. Fibroblasts in OP were positive for phosphorylated FAK but fibroblasts in UIP were not. These results suggest that fibroblasts in UIP with type IV collagen deposition, especially alpha 1 and alpha 2 chains, have less ability to migrate from early fibrotic lesions than fibroblasts in OP without type IV collagen deposition. Thus, type IV collagen deposition in early fibrotic lesions of UIP may be implicated in refractory pathophysiology including migration of lesion fibroblasts via a FAK pathway.

DOI： 10.1038/labinvest.2015.66

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：BIOMED CENTRAL LTD  

Background: To investigate associations between dual-specificity tyrosine phosphorylation-regulated kinase 2 (DYRK2) expression and survival in T1 high-grade or T2 bladder cancer patients treated with neoadjuvant chemotherapy.
Methods: The cohort under investigation comprised 44 patients who underwent neoadjuvant chemotherapy for pT1 high-grade or pT2N0M0 bladder cancer at our institution between 2002 and 2011. Immunohistochemical analysis was used to determine expression of DYRK2 in bladder cancer specimens obtained by transurethral resection before chemotherapy. Relationships between DYRK2 expression and both response to chemotherapy and survival in these patients were analyzed.
Results: DYRK2 expression was positive in 21 of 44 patients (47.7 %) and negative in 23 patients (52.3 %). In total, 20 of 21 DYRK2-positive cases showed complete response to neoadjuvant chemotherapy, whereas 11 of 23 DYRK2-negative cases did not show complete response. Sensitivity and specificity were 62.5 % and 91.7 %, respectively (P = 0.0018). In addition, disease-specific survival rate was significantly higher for DYRK2-positive patients than for DYRK2-negative patients (P = 0.017). In multivariate analysis, DYRK2 expression level was identified as an independent prognostic factor for disease-specific survival (P = 0.029). We also showed that DYRK2 mRNA expression was significantly higher in DYRK2-positive samples by immunohistochemistry than DYRK2-negative samples (P = 0.040).
Conclusions: DYRK2 expression level may predict the efficacy of neoadjuvant chemotherapy for T1 high-grade and T2 bladder cancer.

DOI： 10.1186/s12894-015-0040-7

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Language：Japanese   Publisher：日本医科大学医学会  

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DOI： 10.1038/labinvest.2015.66

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Language：English   Publisher：ELSEVIER SCIENCE INC  

DOI： 10.1016/j.juro.2014.02.851

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Background: Neoadjuvant chemotherapy has been shown to have benefit in T1 high-grade or T2 bladder cancer. However, neoadjuvant chemotherapy fails in some patients. Careful patient selection for neoadjuvant chemotherapy is therefore needed. Several reports show that Snail is associated with resistance to chemotherapy. We hypothesized that Snail expression could predict survival in T1 high-grade and T2 bladder cancer patients treated with neoadjuvant chemotherapy.
Methods: The participants were 44 patients with T1 high-grade and T2 bladder cancer receiving neoadjuvant chemotherapy. Immunohistochemical analysis was used to determine Snail expression in specimens of bladder cancer obtained by transurethral resection before neoadjuvant chemotherapy. The relationships between Snail expression and patients' outcomes were analyzed.
Results: Snail expression was positive in 15 of the 44 patients (34.1%) and negative in 29 (65.9%). Disease-free survival was significantly shorter for the Snail-positive group than for the Snail-negative group (p = 0.014). In addition, disease-specific survival was also significantly shorter for the Snail-positive group than for the Snail-negative group (p = 0.039). In multivariate analysis, Snail expression level was identified as an independent prognostic factor for disease-specific survival (p = 0.020).
Conclusions: The results indicate that Snail expression may predict poor outcome in T1 high-grade and T2 bladder cancer patients treated with neoadjuvant chemotherapy.

DOI： 10.1186/1471-2490-13-73

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Language：Japanese   Publisher：日本医科大学医学会  

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：WILEY  

Of the idiopathic interstitial pneumonias (IIPs), usual interstitial pneumonia (UIP) and diffuse alveolar damage (DAD) usually have poor prognoses. The prognoses of cryptogenic organizing pneumonia (COP) and nonspecific interstitial pneumonia (NSIP) are usually more favorable. Although several reports have described neovascularization in COP and UIP, this aspect of UIP has not been compared with NSIP. In this study, we evaluated neovascularization in intra-alveolar fibrotic lesion of cases of fibrosing NSIP (f-NSIP) (n = 26) and UIP (n = 25). In the f-NSIP group, a considerable degree of neovascularization was observed compared to the UIP group and bud type intra-alveolar fibrosis showed a greater degree of neovascularization compared to the mural-incorporation and obliterative types of intra-alveolar fibrosis. Real-time reverse transcription polymerase chain reaction revealed a significantly greater expression of VEGF-A mRNA in f-NSIP than in UIP. The expression of matrix metalloproteinase-2 (MMP-2) mRNA also showed significantly higher in f-NSIP than UIP. The greater VEGF-A and MMP-2 expression may play a role in the pathogenesis of neovascularization in early intra-alveolar fibrotic lesions in f-NSIP.

DOI： 10.1111/pin.12058

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Language：English   Publisher：MEDICAL ASSOC NIPPON MEDICAL SCH  

Orthotopic liver transplantation (OLT) in rats is technically feasible and useful for the assessment of clinical liver transplantation and analysis of inflammatory liver diseases. OLT in rats was pioneered by Lee et al. in 1973 using hand-suture techniques of all vessels. This model has not been widely used due to the long operative time and technical demand. The cuff method was introduced by Kamada in 1979, and today, the Kamada technique is the one most commonly used worldwide. However, this technique does not include hepatic artery reconstruction, although this procedure is routinely performed in clinical transplantation. Nevertheless, several techniques for hepatic artery reconstruction in rat OLT have been reported recently, and our group also developed a simple splint technique from recipient right renal artery to donor celiac axis bearing the hepatic artery. In the present article, we describe the Kamada technique, as a standard surgical method for rat OLT. In addition, we also describe our splint technique for hepatic artery reconstruction. Then, we compare the features of Kamada technique and our splint technique for hepatic artery reconstruction and all other surgical techniques currently in use for rat OLT. The widespread use of the rat OLT model should help to provide full assessment of transplant immunology and the mechanism and treatment of inflammatory liver diseases. (Nippon Med Sch 2013; 80: 4-15)

DOI： 10.1272/jnms.80.4

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：KARGER  

Background/Aims: Acute kidney injury (AKI) is a common complication in advanced liver dysfunction. Our aim is to clarify the mechanisms of acute hepatic failure (AHF)-associated AKI. Methods: We examined the mechanisms of AHF-associated AKI, which is characterized by AKI in AHF and hyperbilirubinemia, following DA-to-Lewis rat liver transplantation. Results: During the progression of AHF and hyperbilirubinemia in liver graft rejection, AHF-associated AKI gradually developed by day 11. Degeneration and apoptotic cells were apparent in tubular epithelial cells with bile pigment accumulation and mitochondrial degeneration. Injury of peritubular capillaries (PTCs) was also noted with apoptotic endothelial cells, decreased expression of endothelial nitric oxide synthase, accumulation of a-smooth muscle actin+ pericytes and/or myofibroblasts, and inflammation. Angiogenic factors including vascular endothelial growth factor, angiopoietin-1, and angiopoietin-2 in the cortex were decreased on day 11. In addition, a marked reduction in the velocity of red blood cells in PTCs was evident in vivo. Conclusions: AHF-associated AKI seems to be mediated by renal tubular epithelial cell injury with bile pigment accumulation, impaired microcirculation caused by PTC endothelial cell injury with depletion of endothelial nitric oxide synthase and angiogenic factors, and by a decrease in RBC velocity and renal inflammation. Multiple mechanisms including tubular and PTC injuries and renal inflammation may be involved in the development of AHF-associated AKI. Copyright (C) 2013 S. Karger AG, Basel

DOI： 10.1159/000348567

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Language：English   Publisher：EUROPEAN RESPIRATORY SOC JOURNALS LTD  

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Language：Japanese   Publisher：The Medical Association of Nippon Medical School  

An 83-year-old man presented with supraclavicular and mediastinal lymph nodes swelling and elevated serum levels of neuron-specific enolase (NSE), pro-gastrin-releasing peptide (pro-GRP), and cytokeratin fragment (CYFRA). He underwent supraclavicular lymph node dissection. The pathological diagnosis was metastatic lymph node neuroendocrine carcinoma. The initial diagnosis was small cell lung carcinoma c-TxN3M0 III B with an unknown primary site, because fluorine-18-fluorodeoxyglucose positron emission tomography (FDG-PET) had revealed increased uptake in the neck and mediastinal lymphadenopathy, but no significant intrapulmonary uptake. However, computed tomography (CT) of the chest had detected a lesion, which was assumed to be a vessel, in the right lower lung. The patient underwent radiotherapy, and CT of the chest 1 month later revealed a partial response of the lymph nodes. However, at the same time, disease recurred in the skin adjacent to the site of supraclavicular lymph node dissection, and the lesion in the right lower lung enlarged. We suspected that this intrapulmonary lesion was the primary site. Metastasis to cervical and mediastinal lymph nodes from an unknown primary carcinoma is rare, and the primary site should be determined so that appropriate treatment can be performed. If the primary site cannot be determined with the initial examination, regular follow-up examinations with CT, magnetic resonance imaging, and FDG-PET should be performed.<br>

DOI： 10.1272/manms.8.162

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：AMER PHYSIOLOGICAL SOC  

Terasaki Y, Ohsawa I, Terasaki M, Takahashi M, Kunugi S, Dedong K, Urushiyama H, Amenomori S, Kaneko-Togashi M, Kuwahara N, Ishikawa A, Kamimura N, Ohta S, Fukuda Y. Hydrogen therapy attenuates irradiation-induced lung damage by reducing oxidative stress. Am J Physiol Lung Cell Mol Physiol 301: L415-L426, 2011. First published July 15, 2011; doi: 10.1152/ajplung.00008.2011.-Molecular hydrogen (H-2) is an efficient antioxidant that diffuses rapidly across cell membranes, reduces reactive oxygen species (ROS), such as hydroxyl radicals and peroxynitrite, and suppresses oxidative stress-induced injury in several organs. ROS have been implicated in radiation-induced damage to lungs. Because prompt elimination of irradiation-induced ROS should protect lung tissue from damaging effects of irradiation, we investigated the possibility that H-2 could serve as a radioprotector in the lung. Cells of the human lung epithelial cell line A549 received 10 Gy irradiation with or without H-2 treatment via H-2-rich PBS or medium. We studied the possible radioprotective effects of H-2 by analyzing ROS and cell damage. Also, C57BL/6J female mice received 15 Gy irradiation to the thorax. Treatment groups inhaled 3% H-2 gas and drank H-2-enriched water. We evaluated acute and late-irradiation lung damage after H-2 treatment. H-2 reduced the amount of irradiation-induced ROS in A549 cells, as shown by electron spin resonance and fluorescent indicator signals. H-2 also reduced cell damage, measured as levels of oxidative stress and apoptotic markers, and improved cell viability. Within 1 wk after whole thorax irradiation, immunohistochemistry and immunoblotting showed that H-2 treatment reduced oxidative stress and apoptosis, measures of acute damage, in the lungs of mice. At 5 mo after irradiation, chest computed tomography, Ashcroft scores, and type III collagen deposition demonstrated that H-2 treatment reduced lung fibrosis (late damage). This study thus demonstrated that H-2 treatment is valuable for protection against irradiation lung damage with no known toxicity.

DOI： 10.1152/ajplung.00008.2011

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Language：English   Publisher：AMER THORACIC SOC  

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Language：Japanese   Publisher：日本医科大学医学会  

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J-GLOBAL

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：AMER THORACIC SOC  

Rationale: Nitric oxide (NO)-induced nitrative stress of nucleic acids, as evidenced by guanine nitration, appears to be involved in inflammation-induced carcinogenesis. A high incidence of lung cancer in idiopathic pulmonary fibrosis (IPF) is the major reason for poor prognosis in patients with IPF. Objectives and Methods: We immunolhistochemically analyzed the formation and localization of 8-nitroguanine in lung tissues from control subjects, patients with IPF, and patients with lung cancer. Main Results: Immunolhistochernical analysis of control smoker and nonsmoker lungs showed weak immunoreactivity for 8-nitroguanine, mainly in cytoplasm of bronchial epithelial cells. In addition to the bronchial epithelial cells, metaplastic regenerated epithelial cells overlying dense fibrotic lesions in IPF showed strong 8-nitroguanine staining in the cytoplasm. The staining in these metaplastic cells colocalized with staining of inducible and endothelial NO synthases and 8-oxodeoxyguanosine, as evidenced by doubleimmuno-staining analysis. Confocal and immunoelectron microscopy revealed localization of 8-nitroquanine in metaplastic epithelial cytoplasm, mostly in mitochondria. Appreciable 8-nitroguanine immunostaining was also observed in both nuclei and cytoplasm of malignant epithelial cells in squamous cell carcinoma. No significant difference was found in the epithelial 8-nitroguanine formation between control smokers and nonsmokers, but much higher guanine nitration was observed in patients with IPF than in control subjects and patients with lung cancer, via a quantitative immunofluorescence image analysis. Conclusions: The present study indicates that not only oxidative stress but also nitrative stress induced by NO may participate in the pathogenesis of epithelia[ cell damage and aberrant regeneration occurring in IPF. Thus, guanine nitration may be a major risk factor for lung cancer development in IPF.

DOI： 10.1164/rccm.200510-1580OC

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Language：English   Publisher：ELSEVIER IRELAND LTD  

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Language：Japanese   Publisher：(一社)日本病理学会  

58歳男.検診の腹部エコーで骨盤内腫瘤を指摘され,骨盤部MRIで,膀胱左後方に骨盤腔を占拠する腫瘍性病変を認めたため,摘出術を施行した.腫瘍は膀胱頸周囲の軟部組織内にあり,恥骨後面と強固な癒着がみられたが,膀胱・直腸・前立腺との連続性はなかった.腫瘍は境界明瞭で,大部分充実性で,内部に大小の結節形成がみられ,辺縁は嚢胞状で,出血を一部認めたが壊死はみられなかった.腫瘍内結節部では類円形から紡錘形の比較的揃った核を有する腫瘍細胞が,アザン染色に青染する放射状のコラーゲン線維形成を伴って増殖していた.結節部周辺の腫瘍組織では細胞成分に乏しい浮腫状間質を示す部位がみられ,硝子化した血管や星芒状の核を示す腫瘍細胞が散見された.組織学的所見,免疫組織化学所見等より骨盤腔に発生したextrathoracic solitary fibrous tumorと診断した

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Other Link： https://search.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2002&ichushi_jid=J03623&link_issn=&doc_id=20020812410024&doc_link_id=%2Fcd9jjodp%2F2002%2F001903%2F024%2F0266-0268%26dl%3D0&url=http%3A%2F%2Fwww.medicalonline.jp%2Fjamas.php%3FGoodsID%3D%2Fcd9jjodp%2F2002%2F001903%2F024%2F0266-0268%26dl%3D0&type=MedicalOnline&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00004_2.gif

Language：Japanese   Publisher：(一社)日本病理学会  

80歳男.約5年前よりの右上唇腫瘤の増大を主訴とした.腫瘍は小指頭大,弾性軟,可動性良好で,上部を覆う正常粘膜とともに摘出された.粘膜下に存在する大きさ9×7mm の境界明瞭な腫瘍で,組織学的にcanalicular adenomaに特徴的な二列の円柱上皮のビーズ状配列と浮腫状の間質が認められた.腫瘍に近接した小唾液腺内にcanalicular adenomaの腫瘍細胞形態と類似した小病巣と考えられる部位を認めた.multifocal canalicular adenomaの可能性も考え,再発に注意すべきであると考えられた

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Elsevier  

DOI： 10.1016/b978-044450669-6/50005-0

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特発性肺線維症急性増悪の剖検15例で、臨床・病理を対比検討した。増悪から死亡までは3日〜6ヵ月、7例で増悪のきっかけは不明であった。全例で臨床病期に一致したDADがみられた。OP様像の目立つ症例は、血管再生不良、筋線維芽細胞化、DADへの移行像がありDADの一所見と理解されるが、同時に、特発性AIPとの類似性が示唆される。半数で、線維芽細胞巣が目立ち、IPFとして活動性が高いと判断される。(著者抄録)

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Event date： 2018.4

Language：Japanese  

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Event date： 2018.4

Language：Japanese  

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Event date： 2018.4

Language：Japanese  

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Event date： 2018.4

Language：Japanese  

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Event date： 2018.4

Language：Japanese  

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Event date： 2018.4

Language：English  

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Event date： 2017.10

Language：Japanese  

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Event date： 2017.3

Language：English  

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Event date： 2017.3

Language：Japanese  

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Event date： 2017

Language：Japanese  

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Event date： 2016.5

Language：Japanese  

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Event date： 2016.5

Language：Japanese  

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Event date： 2016.4

Language：Japanese  

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Event date： 2016.4

Language：Japanese  

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Event date： 2016.4

Language：Japanese  

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Event date： 2015.6

Language：Japanese  

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Event date： 2015.4

Language：Japanese  

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Event date： 2015.4

Language：Japanese  

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Event date： 2015.4

Language：Japanese  

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Event date： 2015.3

Language：Japanese  

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Event date： 2015.3

Language：Japanese  

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Event date： 2015.3

Language：Japanese  

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Event date： 2015.3

Language：Japanese  

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Event date： 2015.3

Language：Japanese  

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Event date： 2015.3

Language：Japanese  

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Event date： 2014.8

Language：Japanese  

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Event date： 2014.3

Language：Japanese  

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Event date： 2014.3

Language：Japanese  

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Event date： 2014.3

Language：Japanese  

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Event date： 2013.4

Language：Japanese  

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Event date： 2013.4

Language：Japanese  

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Event date： 2013.4

Language：Japanese  

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Event date： 2013.4

Language：Japanese  

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Event date： 2013.4

Language：Japanese  

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Event date： 2013

Language：Japanese  

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Event date： 2013

Language：Japanese  

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Event date： 2013

Language：Japanese  

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Event date： 2012.4

Language：Japanese  

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Event date： 2012.3

Language：Japanese  

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Event date： 2012.3

Language：Japanese  

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Event date： 2012

Language：Japanese  

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Event date： 2011.3

Language：Japanese  

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Event date： 2011.3

Language：Japanese  

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Event date： 2011.3

Language：Japanese  

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Event date： 2011.3

Language：Japanese  

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Event date： 2011.3

Language：Japanese  

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Event date： 2011.3

Language：Japanese  

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Event date： 2011

Language：Japanese  

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Event date： 2010.12

Language：Japanese  

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Event date： 2005.3

Language：Japanese  

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Event date： 2003.9

Language：Japanese  

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Event date： 2003.4

Language：Japanese  

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Event date： 2002.3

Language：Japanese  

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Event date： 2001.5

Language：Japanese  

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Event date： 2000.3

Language：Japanese  

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Venue：米子  

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Language：English   Presentation type：Poster presentation  

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Venue：仙台  

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Venue：仙台  

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Venue：東京  

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Venue：東京  

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Venue：熊本  

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Language：Japanese   Presentation type：Poster presentation  

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Language：Japanese   Presentation type：Poster presentation  

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Venue：札幌  

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Venue：東京  

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Language：Japanese   Presentation type：Poster presentation  

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Venue：仙台  

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