Publications by authors named "Shigehisa Aoki"

76 Publications

Cytological Appearances of Ovarian Seromucinous Borderline Tumor in Ascites: Presentation of 2 Cases.

Acta Cytol 2021 20;65(5):440-447. Epub 2021 Jul 20.

Department of Pathology, Saga University Hospital, Saga, Japan.

Background: Seromucinous borderline tumor (SMBT) is a rare neoplasm which was newly defined in the 2014 WHO classification. Although the clinical and histopathological characteristics of SMBT have been well described, its cytological characteristics have not. We recently experienced 2 cases of SMBT which were defined by cytological findings of ascites.

Case Presentation: Case 1 was a 65-year-old Japanese woman. Preoperative imaging studies revealed abundant ascites and a cystic tumor, with a solid component measuring 13 cm on the left ovary. Radical surgery was performed during the intraoperative diagnosis of ovarian borderline tumor, made by histological examinations of frozen tumor sections. The cytological smears of preoperatively and intraoperatively collected ascites showed many atypical cells resembling reactive mesothelial cells. Alcian-blue staining of cell block sections revealed intracytoplasmic mucin, and the results of immunohistochemistry were consistent with SMBT. The final pathological diagnosis of tumor was SMBT. Case 2 was a 28-year-old Japanese woman. Preoperative imaging studies revealed a small amount of ascites and cystic tumors with solid components in the bilateral ovaries. She initially underwent fertility preservation surgery. SMBT was suspected by cytological examination of smears of intraoperatively collected ascites and the findings of cell block. She underwent additional radical surgery based on a final pathological diagnosis of SMBT.

Conclusion: In our experience, the tumor cells of SMBT in ascites mimicked reactive mesothelial cells. The nuclear atypia of SMBTs was intermediate between that of reactive mesothelial cells and serous carcinoma. The immunohistochemistry and mucin staining using cell block were very helpful for facilitating the cytodiagnosis of SMBT.
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http://dx.doi.org/10.1159/000517313DOI Listing
September 2021

Active behavior of triple-negative breast cancer with adipose tissue invasion: a single center and retrospective review.

BMC Cancer 2021 Apr 20;21(1):434. Epub 2021 Apr 20.

Department of Urology (Chair of the Board of Directors), Seisyukai Social Medical Corporation, Fukuoka, Japan.

Background: Interactions between adipocyte and breast cancer (BC) cells have yet to be fully elucidated. Here we investigated the prognostic impact of marginal adipose tissue invasion in both luminal breast cancer (HR+/HER2-) and triple-negative breast cancer (TNBC) (HR-/HER2-).

Methods: A total of 735 patients with early-stage invasive BC (1999-2014) were retrospectively registered. Median length of patient follow-up was 8.9 years. Survival curves were calculated using a Kaplan-Meier cumulative survival plot. The prognostic difference between two groups were assessed by the univariate Cox-proportional hazard regression model.

Results: Patients with adipose tissue invasion (n = 614) had a significantly poorer prognosis than those without adipose tissue invasion (n = 121) in overall survival (OS) (hazard ratio, 2.1; 95% Confidence interval [CI], 1.1 to 4.0; P = 0.025). While a poorer prognosis was observed in TNBC (n = 137) than in luminal BC patients (n = 496) (hazard ratio, 0.45; 95% CI, 0.30 to 0.68, P < 0.001), this aggressive nature of TNBC was noted in node-positive disease (hazard ratio, 0.3; 95% CI, 0.18 to 0.5, P < 0.001) but not in node-negative disease (hazard ratio, 0.78; 95% CI, 0.39 to 1.55, P = 0.472), and also noted in adipose tissue invasion-positive patients (hazard ratio, 0.4; 95% CI, 0.26 to 0.6, P < 0.001) but not in adipose tissue invasion-negative patients (hazard ratio, 0.73; 95% CI, 0.16 to 3.24, P = 0.675). In addition, although patients suffering from TNBC with adipose tissue invasion had a poorer outcome than those without adipose tissue invasion (hazard ratio, 3.63; 95% CI, 1.11 to 11.84; P = 0.033), the difference was not observed in luminal BC (hazard ratio, 1.75; 95% CI, 0.64 to 4.82; P = 0.277).

Conclusions: Adipose tissue invasion was correlated with poor survival in TNBC. Cancer cell invasion into local fat may be a first step on cancer progression and systemic disease in TNBC.
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http://dx.doi.org/10.1186/s12885-021-08147-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8056529PMC
April 2021

Collagen Vitrigel Membrane-Coated Nylon Line Prevents Stenosis After Conization of the Cervix Uteri.

Tissue Eng Part A 2021 Jun 1. Epub 2021 Jun 1.

Department of Pathology and Microbiology, Faculty of Medicine, Saga University, Saga, Japan.

Cervical stenosis is a postoperative complication of conization for uterine cervical malignancy, but a standard method of preventing this complication has yet to be established. Collagen vitrigel is a collagen-based biomaterial that has antifibrotic and epithelization promoting actions. We evaluated the antistenotic effect of an indwelling collagen vitrigel membrane-coated nylon line (CVNL) after cervical conization in rabbits. In one group of rabbits, a CVNL was placed in the cervical canal after conization. In another group, a nylon line without a collagen coating was placed in the cervical canal after conization. The control group underwent cervical conization without placement of a device. The control (conization alone) and nylon (conization plus indwelling nylon line) groups exhibited cervical swelling. Rabbits in the CVNL group (cervical conization plus indwelling CVNL in the xerogel state) had a normal cervical surface. The cervical canal in the control group was enlarged and showed cystic changes attributed to cervical stenosis. The nylon group exhibited a trend toward cervical canal dilatation. In the CVNL group, the cervical canal was normal and did not show cystic dilatation. Fibrosis occurred to a lesser degree in the nylon group than in the control group, and the CVNL group exhibited minimal interstitial fibrosis. The control and nylon groups showed increased numbers of myofibroblasts in the regenerated cervix, but few myofibroblasts were observed in the CVNL group. Abundant collagen type III was observed in regenerated cervical tissue in the control and nylon groups but not in the CVNL group. The number of proliferative mesenchymal cells in the regenerated cervix was lowest in the CVNL group. The expressions of connective tissue growth factor (CTGF, a regulator of fibroblast growth and extracellular matrix secretion), extracellular signal-regulated protein kinases 1 and 2, and c-Jun N-terminal kinase (which are involved in the induction of CTGF by transforming growth factor-β) were lower in the CVNL group than in the control or nylon groups. This study describes an indwelling CVNL that prevents cervical stenosis and cystic changes after conization. These effects were likely mediated by inhibition of fibrosis, myofibroblast emergence, CTGF expression, and collagen type III deposition in regenerating cervix. Impact statement Collagen vitrigel is a high-density collagen material that promotes epithelization, inhibits fibrosis, and suppresses inflammation in regenerating tissue. We evaluated whether a collagen vitrigel membrane-coated nylon line would prevent cervical stenosis after conization in the rabbit. We found that an indwelling collagen vitrigel membrane-coated nylon line prevented cervical canal stenosis and cystic changes after cervical conization by inhibiting fibrosis, myofibroblast emergence, connective tissue growth factor expression, and collagen type III deposition in the regenerating cervix. Our device has potential as a new method of preventing cervical canal fibrosis and stenosis after conization for cervical cancer.
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http://dx.doi.org/10.1089/ten.TEA.2020.0374DOI Listing
June 2021

Cellular and physical microenvironments regulate the aggressiveness and sunitinib chemosensitivity of clear cell renal cell carcinoma.

J Pathol 2021 May 19;254(1):46-56. Epub 2021 Feb 19.

Division of Pathology, Department of Pathology and Microbiology, Faculty of Medicine, Saga University, Saga, Japan.

Renal cell carcinoma (RCC) is the most predominant type of kidney cancer in adults and is responsible for approximately 85% of clinical cases. The tumor-specific microenvironment includes both cellular and physical factors, and it regulates the homeostasis and function of cancer cells. Perirenal adipose tissue and tumor-associated macrophages are the major cellular components of the RCC microenvironment. The RCC microvasculature network generates interstitial fluid flow, which is the movement of fluid through the extracellular compartments of tissues. This fluid flow is a specific physical characteristic of the microenvironment of RCC. We hypothesized that there may be an interaction between the cellular and physical microenvironments and that these two factors may play an important role in regulating the behavior of RCC. To elucidate the effects of adipose tissue, macrophages, and fluid flow stimulation on RCC and to investigate the relationships between these factors, we used a collagen gel culture method to generate cancer-stroma interactions and a gyratory shaker to create fluid flow stimulation. Adipose-related cells, monocytes, and fluid flow influenced the proliferative potential and invasive capacity of RCC cells. Extracellular signal-regulated kinase and p38 signaling were regulated either synergistically or independently by both fluid flow and cellular interactions between RCC and adipose tissue fragments or macrophages. Fluid flow stimulation synergistically enhanced the anti-proliferative effect of sunitinib on RCC cells, but macrophages abolished the synergistic anti-proliferative effect related to fluid flow stimulation. In conclusion, we established a reconstructed model to investigate the cellular and physical microenvironments of RCC in vitro. Our alternative culture model may provide a promising tool for further therapeutic investigations into many types of cancer. © 2021 The Authors. The Journal of Pathology published by John Wiley & Sons, Ltd. on behalf of The Pathological Society of Great Britain and Ireland.
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http://dx.doi.org/10.1002/path.5630DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8248239PMC
May 2021

Concomitant Nephrotic Syndrome with Diffuse Large B-cell Lymphoma: A Case Report.

Tohoku J Exp Med 2020 10;252(2):153-157

Division of Hematology, Respiratory Medicine and Oncology, Department of Internal Medicine, Faculty of Medicine, Saga University.

Membranous nephropathy (MN) is a common glomerular disease that is characterized by diffuse thickening of the glomerular basement membrane, and a common cause of nephrotic syndrome (NS). MN is often accompanied with malignant disease; The solid tumors are commonly associated with MN, whereas hematological malignancies are rarely found in patients with MN. A 68-year-old man with a history of diabetes mellitus visited a hospital with a chief complaint of general fatigue. He was previously not diagnosed with any complications of diabetes. Computed tomography revealed a pancreatic tumor, and the pathological findings of the biopsied tumor revealed the tumor was diffuse large B-cell lymphoma (DLBCL). Concurrently, he developed severe proteinuria, hypoalbuminemia, systemic edema and hyperlipidemia, consistent with the diagnosis of NS. The biopsied renal specimen revealed minute spike lesions of glomerular basement membrane, and abnormal lymphocytes infiltrated in the kidney interstitially. Anti-glomerular basement membrane antibody, proteinase-3-/myeloperoxidase antineutrophil cytoplasmic antibody and hepatitis B antigenemia, are absent in the patient. Serum anti-phospholipase A2 receptor (PLA2R) antibody (marker for primary MN) was not detected. A diagnosis of secondary MN induced by DLBCL was made. He received rituximab containing chemotherapy for DLBCL, resulting in amelioration of both DLBCL and MN. We report the rare case of a patient co-existing NS and DLBCL. DLBCL might be pathogenesis of NS; the findings are supported by the presence of MN, an underlying malignancy (DLBCL), and the lack of anti-PLA2R antibodies. Although further investigation is warranted, our case suggests that DLBCL is a possible cause of secondary MN.
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http://dx.doi.org/10.1620/tjem.252.153DOI Listing
October 2020

Development of a tunable method to generate various three-dimensional microstructures by replenishing macromolecules such as extracellular matrix components and polysaccharides.

Sci Rep 2020 04 16;10(1):6567. Epub 2020 Apr 16.

Graduate School of Nanobioscience, Yokohama City University, Yokohama, Japan.

Multicellular spheroids (spheroids) are expected to be a promising approach to mimic in vivo organ functions and cell microenvironments. However, conventional spheroids do not fully consider the existence of extracellular matrices (ECMs). In this study, we developed a tunable method for replenishing macromolecules, including ECM components and polysaccharides, into spheroids without compromising cell viability by injecting a microvolume cell suspension into a high density of methylcellulose dissolved in the culture medium. Adjusting the ECM concentration in the cell suspension enabled the generation of different three-dimensional microstructures, such as "ECM gel capsules", which contained individually separated cells, and "ECM-loaded spheroids", which had thin ECM layers between cells. ECM-loaded spheroids with a 30-fold dilution of Matrigel (0.3 mg/ml) showed significantly higher albumin secretion than control spheroids composed of Hep G2 or HuH-7 cells. Additionally, the expression levels of major CYP genes were decreased in ECM gel capsules with undiluted Matrigel (9 mg/ml) compared to those in control spheroids. However, 0.3 mg/ml Matrigel did not disrupt gene expression. Furthermore, cell polarity associated with tight junction proteins (ZO-1 and Claudin-1) and the transporter protein MRP2 was markedly induced by using 0.3 mg/ml Matrigel. Thus, high-performance three-dimensional tissues fabricated by this method are applicable to increasing the efficiency of drug screening and to regenerative medicine.
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http://dx.doi.org/10.1038/s41598-020-63621-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7162899PMC
April 2020

Low-Dose Phosphodiesterase III Inhibitor Reduces the Vascular Amyloid Burden in Amyloid-β Protein Precursor Transgenic Mice.

Int J Mol Sci 2020 Mar 26;21(7). Epub 2020 Mar 26.

Division of Neurology, Department of Internal Medicine, Saga University Faculty of Medicine, Saga 849-8501, Japan.

A previous study reported that relatively high-dose cilostazol (0.3%) promoted the drainage of cerebrovascular amyloid-β (Aβ) protein in Aβ Precursor Protein (APP) transgenic mice overexpressing vasculotropic Aβ. We investigated whether lower-dose cilostazol can decrease micro-hemorrhages and Aβ deposition in the brain using APP transgenic mice. At baseline, 14-month-old female Tg2576 mice were randomly assigned to a control group (vehicle), aspirin group (0.01% aspirin), or cilostazol group (0.01% cilostazol). The severity of cerebral micro-hemorrhages (i.e., number), area of senile plaque, and severity of vascular amyloid burden (quantified with cerebral amyloid angiopathy (CAA) score (=number of Aβ-positive vessels × severity of amyloid burden of Aβ-positive vessels) were evaluated in the brain of mice aged 15 and 21-23 months. At 15 months, no differences were shown in each pathological change among the three groups. At 21-23 months, there were no differences in the severity of cerebral micro-hemorrhages or area of senile plaque among the three groups. However, the CAA score was significantly lower in the cilostazol compared to the control group ( = 0.046, Mann-Whitney test), although no difference was seen between the control and aspirin group. Our study showed that lower-dose cilostazol could reduce the vascular amyloid burden without increasing cerebral micro-hemorrhages in APP transgenic mice.
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http://dx.doi.org/10.3390/ijms21072295DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7177305PMC
March 2020

Terminal deoxynucleotidyl transferase (TdT) negative early T cell precursor acute lymphoblastic leukemia (ETP-ALL) with spontaneous acute kidney injury.

Ann Hematol 2020 Apr 5;99(4):885-886. Epub 2020 Feb 5.

Division of Hematology, Respiratory Medicine and Oncology, Department of Internal Medicine, Faculty of Medicine, Saga University, 5-1-1 Nabeshima, Saga, 849-8501, Japan.

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http://dx.doi.org/10.1007/s00277-020-03943-5DOI Listing
April 2020

Mesenchymal cells and fluid flow stimulation synergistically regulate the kinetics of corneal epithelial cells at the air-liquid interface.

Graefes Arch Clin Exp Ophthalmol 2019 Sep 18;257(9):1915-1924. Epub 2019 Jul 18.

Department of Pathology and Microbiology, Faculty of Medicine, Saga University, 5-1-1 Nabeshima, Saga, 849-8501, Japan.

Purpose: In vivo microenvironments are critical to tissue homeostasis and wound healing, and the cornea is regulated by a specific microenvironment complex that consists of cell-cell interactions, air-liquid interfaces, and fluid flow stimulation. In this study, we aimed to clarify the effects of and the correlations among these three component factors on the cell kinetics of corneal epithelial cells.

Methods: Human corneal epithelial-transformed (HCE-T) cells were cocultured with either primary rat corneal fibroblasts or NIH 3T3 fibroblasts. We employed a double-dish culture method to create an air-liquid interface and a gyratory shaker to create fluid flow stimulation. Morphometric and protein expression analyses were performed for the HCE-T cells.

Results: Both the primary rat fibroblasts and the NIH 3T3 cells promoted HCE-T cell proliferation, and the presence of fluid flow synergistically enhanced this effect and inhibited the apoptosis of HCE-T cells. Moreover, fluid flow enhanced the emergence of myofibroblasts when cocultured with primary rat fibroblasts or NIH 3T3 cells. Extracellular signal-regulated kinase and p38 signaling were regulated either synergistically or independently by both fluid flow and cellular interaction between the HCE-T and NIH 3T3 cells.

Conclusion: The cell-cell interaction and fluid flow stimulation in the air-liquid interface synergistically or independently regulated the behavior of HCE-T cells. Fluid flow accelerated the phenotypic change from corneal fibroblasts and NIH 3T3 cells to myofibroblasts. Elucidation of the multicomponent interplay in this microenvironment will be critical to the homeostasis and regeneration of the cornea and other ocular tissues.
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http://dx.doi.org/10.1007/s00417-019-04422-yDOI Listing
September 2019

Development of a collagen-like peptide polymer via end-to-end disulfide cross-linking and its application as a biomaterial.

Acta Biomater 2019 08 11;94:361-371. Epub 2019 Jun 11.

Department of Chemistry and Biochemistry, School of Advanced Science and Engineering, Waseda University, Tokyo 169-8555, Japan. Electronic address:

Collagen is the most abundant protein in the animal kingdom and has a unique triple-helical structure. It not only provides mechanical strength to tissues, but also performs specific biological functions as a multifaceted signaling molecule. Animal-derived collagen is therefore widely used as a biocompatible material in vitro and in vivo. In this study, we developed a novel peptide-based material that mimicked both the polymeric properties and a selected biological function of native collagen. This material was prepared by end-to-end multiple disulfide cross-linking of chemically synthesized triple-helical peptides. The peptide polymer showed a gel-forming property, and receptor-specific cell binding was observed in vitro by incorporating a peptide harboring an integrin α2β1-binding sequence. Furthermore, cell signaling activity and biodegradability were tunable according to the polymer contents. The results demonstrated the potential of this material as a designer collagen. STATEMENT OF SIGNIFICANCE: Collagen is a useful biomaterial with the gel-forming property. It also exhibits various biological activities through the interaction of specific amino acid sequences displayed on the triple helix with functional biomacromolecules. Here we report a novel synthetic material, artificial collagen, by end-to-end cross-linking of chemically synthesized collagen-like triple-helical peptides. The material allows independent regulation of polymer properties, i.e. gel stiffness, and sequence-specific bioactivities by altering peptide compositions. This material can also be variously shaped, for example, thin films with high transparency. In addition, it has low inflamatogenic properties and tunable biodegradability in vivo.
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http://dx.doi.org/10.1016/j.actbio.2019.06.010DOI Listing
August 2019

A high-density collagen xerogel thread prevents the progression of peritoneal fibrosis.

Biomater Sci 2018 Dec;7(1):125-138

Department of Pathology and Microbiology, Faculty of Medicine, Saga University, Saga, Japan.

Peritoneal fibrosis is often provoked by peritoneal dialysis and is an essential precursor condition to the development of encapsulating peritoneal sclerosis. This study aimed to determine the efficacy of a high-density collagen xerogel thread (CXT) for the prevention of peritoneal fibrosis. Female ICR mice received intraperitoneal injections of chlorhexidine gluconate (CG) every other day to induce peritoneal fibrosis. For evaluation, the insertion of CXT or infusion of atelocollagen gel into the peritoneal cavity was conducted on the day before CG injection. For comparison, no collagen treatment after CG injection, and abdominal puncture without CG injection were also performed. Peritoneal fibrosis and inflammation were significantly suppressed by CXT for a long period. CXT prevented mesothelial epithelial-mesenchymal transition, myofibroblast emergence, and inflammatory cell invasion in the peritonitis tissue. In the early phase, atelocollagen gel modulated the expression of the fibrosis-associated protein transforming growth factor (TGF)-β, connective tissue growth factor (CTGF), and CD105 in the peritoneum under CG-induced inflammation, while CXT did not. In contrast, CXT regulated the expression of CTGF and CD105 in the late phase and maintained antimicrobial protein REG3G at the same level as the Sham group in the early and late phases. Although the precise mechanism remains to be clarified, these findings suggest that CXT may have the potential to be developed as a simple therapeutic device to prevent peritoneal fibrosis, a severe complication in patients undergoing long-term peritoneal dialysis.
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http://dx.doi.org/10.1039/c8bm00536bDOI Listing
December 2018

Cancer-adipose tissue interaction and fluid flow synergistically modulate cell kinetics, HER2 expression, and trastuzumab efficacy in gastric cancer.

Gastric Cancer 2018 11 25;21(6):946-955. Epub 2018 Apr 25.

Department of Pathology and Microbiology, Faculty of Medicine, Saga University, 5-1-1 Nabeshima, Saga, Saga, 849-8501, Japan.

Background: Early local tumor invasion in gastric cancer results in likely encounters between cancer cells and submucosal and subserosal adipose tissue, but these interactions remain to be clarified. Microenvironmental mechanical forces, such as fluid flow, are known to modulate normal cell kinetics, but the effects of fluid flow on gastric cancer cells are poorly understood. We analyzed the cell kinetics and chemosensitivity in gastric cancer using a simple in vitro model that simultaneously replicated the cancer-adipocyte interaction and physical microenvironment.

Methods: Gastric cancer cells (MKN7 and MKN74) were seeded on rat adipose tissue fragment-embedded discs or collagen discs alone. To generate fluid flow, samples were placed on a rotatory shaker in a CO incubator. Proliferation, apoptosis, invasion, and motility-related molecules were analyzed by morphometry and immunostaining. Proteins were evaluated by western blot analysis. Chemosensitivity was investigated by trastuzumab treatment.

Results: Adipose tissue and fluid flow had a positive synergistic effect on the proliferative potential and invasive capacity of gastric cancer cells, and adipose tissue inhibited apoptosis in these cells. Adipose tissue upregulated ERK1/2 signaling in gastric cancer cells, but downregulated p38 signaling. Notably, adipose tissue and fluid flow promoted membranous and cytoplasmic HER2 expression and modulated chemosensitivity to trastuzumab in gastric cancer cells.

Conclusion: We have demonstrated that cancer-adipocyte interaction and physical microenvironment mutually modulate gastric cancer cell kinetics. Further elucidation of the microenvironmental regulation in gastric cancer will be very important for the development of strategies involving molecular targeted therapy.
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http://dx.doi.org/10.1007/s10120-018-0829-7DOI Listing
November 2018

High-density collagen patch prevents stricture after endoscopic circumferential submucosal dissection of the esophagus: a porcine model.

Gastrointest Endosc 2017 May 15;85(5):1076-1085. Epub 2016 Oct 15.

Department of Pathology and Microbiology, Faculty of Medicine, Saga University, Saga, Japan.

Background And Aims: Extensive excision of the esophageal mucosa by endoscopic submucosal dissection (ESD) frequently evokes a luminal stricture. This study aimed to determine the efficacy of a high-density collagen patch for the prevention of esophageal stricture in extensive ESD.

Methods: Six pigs underwent circumferential esophageal ESD under general anesthesia. In 3 pigs, artificial ulcers were covered by 2 collagen patches. The other 3 pigs underwent circumferential ESD only.

Results: The 2 collagen patches were settled onto the ulcer surface using a general endoscope and instruments. The collagen patch-treated group showed significantly better patency rates on both the oral and anal sides of the wound area compared with the control group at day 14. The mucosal re-epithelization ratio was significantly promoted, and the extent of mucosal inflammation and fibrosis was significantly decreased with the collagen patch treatment in the wound area. The frequency of cells positive α-smooth muscle actin was significantly reduced in the collagen patch-treated group compared with the control group.

Conclusions: We have established a high-density collagen device that can reduce the esophageal stricture associated with extensive ESD. This easy-to-handle device would be useful during superficial esophageal cancer treatment by ESD.
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http://dx.doi.org/10.1016/j.gie.2016.10.012DOI Listing
May 2017

Effects of a cell-free method using collagen vitrigel incorporating TGF-β1 on articular cartilage repair in a rabbit osteochondral defect model.

J Biomed Mater Res B Appl Biomater 2017 Nov 12;105(8):2592-2602. Epub 2016 Oct 12.

Department of Orthopaedic Surgery, Tokyo Women's Medical University, 8-1 Kawada-cho, Shinjuku-ku, Tokyo, 162-8666, Japan.

We studied the ability of collagen vitrigel material to repair cartilage in vivo when used alone or with transforming growth factor-β (TGF-β). We measured the time course and quantity of TGF-β1 released from the collagen vitrigel in vitro to quantify the controlled release of TGF-β1. Over 14 days, 0.91 ng of TGF-β was released from the collagen vitrigel. Osteochondral defects were made in the femoral trochlear groove in 36 Japanese white rabbits, which were divided into three groups: untreated group (group A), collagen vitrigel-implanted group (group B), and TGF-β1-incorporated collagen vitrigel-implanted group (group C). The weight distribution ratio between the affected and unaffected limbs served as an indicator of pain. Animals were sacrificed at 4 and 12 weeks after surgery, and their tissues were assessed histologically. The weight distribution ratio increased in all groups and did not differ significantly between groups at 12 weeks. Group A needed 6 weeks to attain maximum improvement, and groups B and C showed near-maximum improvement at 4 and 2 weeks, respectively. The International Cartilage Repair Society II score improved significantly in group C relative to the other groups. These findings suggest that sustained, slow release of TGF-β caused early pain mitigation and cartilage repair. © 2016 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 105B: 2592-2602, 2017.
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http://dx.doi.org/10.1002/jbm.b.33792DOI Listing
November 2017

Progress in cell culture systems for pathological research.

Pathol Int 2016 Oct 31;66(10):554-562. Epub 2016 Jul 31.

Department of Pathology and Microbiology, Faculty of Medicine, Saga University, Saga, Japan.

Cell culture is a well-established standard technique and a fundamental tool in biology and medicine. Establishment of a novel culture method by meeting various challenges can sometimes open up new fields of cell biology and medicine. An artificial microenvironment for cultured cells is made up of complicated factors, including cytokines, scaffold material type, cell-cell interactions, and physical stress. To replicate the tissue architecture, cell-cell interactions, and specific physical microenvironment, we previously demonstrated the effectiveness of a three-dimensional culture system, and further established two simple culture systems: air-liquid interface (ALI) and fluid flow stress (FFS). A three-dimensional collagen gel culture system can replicate cell-cell interactions in vitro. As skin is constantly exposed to air, the ALI system closely mimicked the skin microenvironment and maintained the homeostasis of the epidermis and dermis. The ALI culture system also revealed the possibility of skin regeneration through ectopic mesenchymal cell involvement. Fluid streaming and shear stress were recently demonstrated to constitute the critical microenvironment for various cell types. The FFS system demonstrated that fluid streaming induced epithelial-mesenchymal transition of mesothelial cells, leading to peritoneal fibrosis. Our novel culture systems will hopefully open up new fields of regenerative medicine and pathological research.
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http://dx.doi.org/10.1111/pin.12443DOI Listing
October 2016

Differential effects of adipose tissue stromal cells on the apoptosis, growth and invasion of bladder urothelial carcinoma between the superficial and invasive types.

Int J Urol 2016 06 28;23(6):510-9. Epub 2016 Mar 28.

Department of Pathology and Biodefense, Faculty of Medicine, Saga University, Saga, Japan.

Objectives: To clarify the interaction between adipose tissue stromal cells and bladder cancer cells.

Methods: Superficial (RT4) and invasive (EJ) urothelial carcinoma cells were cultured on adipose tissue stromal cell-embedded or non-embedded collagen gel. Cells were analyzed by immunohistochemistry, western blot and real-time reverse transcription polymerase chain reaction.

Results: Adipose tissue stromal cells inhibited growth of RT4, while they promoted the apoptosis. In contrast, adipose tissue stromal cells promoted growth of EJ, but they did not affect the apoptosis. Adipose tissue stromal cells slightly promoted expression of mitogen-activated protein kinase cascade in RT4 and EJ. Adipose tissue stromal cells promoted display of the molecular-targeted agent human epidermal growth factor receptor-2 in only RT4. In turn, RT4 and EJ enhanced α-smooth muscle actin (myofibroblast marker) and S-100 protein (adipocyte marker) expression of adipose tissue stromal cells, respectively.

Conclusions: These findings suggest that: (i) adipose tissue stromal cells might suppress the progression of superficial-type cancer, whereas they might promote that of invasive type; (ii) adipose tissue stromal cell-activated mitogen-activated protein kinase pathway might play differential roles in both types of bladder cancer; (iii) human epidermal growth factor receptor-2 could represent a critical therapeutic agent for the superficial type under adipose tissue stromal cells-cancer interaction; and (iv) superficial bladder cancer might promote myofibroblast differentiation of adipose tissue stromal cells as a cancer-associate phenotype, whereas invasive bladder cancer might promote their adipocyte differentiation.
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http://dx.doi.org/10.1111/iju.13086DOI Listing
June 2016

Interaction between Esophageal Squamous Cell Carcinoma and Adipose Tissue in Vitro.

Am J Pathol 2016 05 4;186(5):1180-94. Epub 2016 Mar 4.

Department of Pathology and Microbiology, Faculty of Medicine, Saga University, Saga, Japan. Electronic address:

Esophageal squamous cell carcinoma (ESCC) develops within the squamous epithelial layer and invades the submucosa to the subadventitia that has adipose tissue (AT). AT seems critical to ESCC progression, but the underlying mechanism is unknown. We aimed to address the association between ESCC and AT in vitro. ESCC cells were cultured on rat or human subcutaneous AT-embedded or -non-embedded collagen gel. AT promoted the growth of ESCC cells and inhibited their apoptosis. AT promoted the expression of the squamous differentiation marker involucrin in ESCC cells. AT accelerated the expression of invasion-related factors in poorly differentiated ESCC cells only. AT promoted the expression of phosphorylated-insulin-like growth factor-1 receptor in ESCC cells, whereas it inhibited that of the human epidermal growth factor receptor 2. Insulin-like growth factor-1, but not leptin, adiponectin, or resistin, promoted and inhibited the growth and apoptosis of ESCC cells, respectively. In turn, ESCC cells decreased the production of these adipokines in AT and the number of preadipocytes and mesenchymal stem cell-like cells, which developed from AT. These results suggest that i) AT may influence the progression of ESCC with increased growth or invasion and decreased apoptosis through insulin-like growth factor-1/insulin-like growth factor-1 receptor signaling, ii) AT may affect human epidermal growth factor receptor 2-targeted therapy; and iii) the cancer cells may affect adipokine production in AT.
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http://dx.doi.org/10.1016/j.ajpath.2016.01.003DOI Listing
May 2016

Fabrication of bone marrow-like tissue from dispersed-state bone marrow cells.

Regen Ther 2016 Mar 1;3:32-37. Epub 2016 Mar 1.

Graduate School of Nanobioscience, Yokohama City University, 22-2 Seto, Kanazawa-ku, Yokohama 236-0027, Japan.

A three-dimensional (3D) bone marrow (BM) culture system may facilitate research into the molecular mechanisms involved in hematopoiesis and BM diseases. However, because >90% of BM cells are composed of non-adherent blood cells, it is difficult to organize the dispersed BM cells into 3D multicellular spheroids using conventional aggregation methods such as hanging drop, and rotary shaking culture. The objective of this study was to reproduce BM-like tissue. We reported successful formation of BM aggregates using a 3% methylcellulose (MC) medium. This medium could aggregate even non-adherent materials. In MC medium, BM cells formed tissue-like aggregates within 24 h. Although the cell density of the BM-like tissue is slightly low, sections of the organoids resembled those of intact BM tissue. Cells of the BM-like tissue were approximately 70% viable after 7 days in culture. Staining for CD68, PDGFRα, and CXCL12 indicated that the BM-like tissue contained macrophages, and mesenchymal cells including CXCL12-abundant reticular cells. These results indicated that the method using MC medium effectively reconstitutes the BM-like tissue.
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http://dx.doi.org/10.1016/j.reth.2016.01.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6581803PMC
March 2016

Induction of hepatic tissues in multicellular spheroids composed of murine fetal hepatic cells and embedded hydrogel beads.

Regen Ther 2016 Mar 1;3:7-10. Epub 2016 Mar 1.

Graduate School of Nanobioscience, Yokohama City University, 22-2 Seto, Kanazawa-ku, Yokohama 236-0027, Japan.

Introduction: Three-dimensional (3D) multicellular spheroids are useful tools for simulation of cellular functions . However, it is difficult to culture certain epithelial cell types under 3D spheroid conditions because these cells cannot resist autonomous cell death, triggered by disordered cell polarity. The objective of this study was to find a method that enables spheroid culture of such epithelial cells utilizing hydrogel beads without cell death.

Methods: We used murine E14.5 fetal hepatic cells for the spheroid composition because they are sensitive to disorganized structures. Spheroids were formed by injecting 1-μl fresh medium containing 1000 fetal hepatic cells and the same number of alginate hydrogel beads (20 μm in diameter) into a 3% methylcellulose medium in the presence of dexamethasone and oncostatin M to induce hepatic differentiation. After 7 days of culture, microstructures were observed using hematoxylin and eosin staining and immunostaining using anti-CK8/18 antibody. Albumin secretion rate was determined by the enzyme-linked immunosorbent assay method. In addition, polarity-related proteins, E-cadherin, ezrin, and MRP2 were observed with immunostaining.

Results: Control spheroids without the use of alginate hydrogel beads showed extensive internal lack of epithelial hepatic cells. The spheroids containing alginate hydrogel beads exhibited sheet- or cord-like structures of epithelial hepatic cells, and it was clear that cell death of epithelial cells had been prevented. Albumin secretion data also supported the improvement of epithelial hepatic cell viability when alginate hydrogel beads were used. Localization of polarity-related proteins indicated the partial reconstitution of cell polarity in the spheroids using alginate hydrogel beads.

Conclusion: Based on these data, we concluded that the application of alginate hydrogel beads was effective in improving the epithelial hepatic cell culture of multicellular spheroids.
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http://dx.doi.org/10.1016/j.reth.2016.01.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6581965PMC
March 2016

The HUS1B promoter is hypomethylated in the placentas of low-birth-weight infants.

Gene 2016 Jun 18;583(2):141-146. Epub 2016 Feb 18.

Division of Molecular Genetics & Epigenetics, Department of Biomolecular Sciences, Faculty of Medicine, Saga University, Saga, Japan. Electronic address:

Aberrant DNA methylation is associated with a range of human disorders. To identify differences in DNA methylation of gene promoters between placentas of low-birth-weight (LBW) and normal-birth-weight (NBW) infants, we screened 8091 genes for aberrant methylation in placentas using microarray-based integrated analysis of methylation by isoschizomers (MIAMI). Seven candidate genes for hypomethylation in the placentas of LBW infants were selected. Among these candidates, COBRA analyses suggested that the HUS1B gene was hypomethylated in some of the placentas. Quantitative methylation analyses by bisulfite-pyrosequencing indicated that the promoter region of the gene was hypomethylated in three of the 86 placentas analyzed. The HUS1B promoter was highly methylated in two cell lines derived from trophoblastic cells. Gene expression increased when the promoter was demethylated by 5Aza-dC treatment. This suggests that hypomethylation of HUS1B alters gene expression in the placenta and that this dysregulated gene expression may contribute to the pathogenesis of LBW by affecting placental functions involved in fetal growth.
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http://dx.doi.org/10.1016/j.gene.2016.02.025DOI Listing
June 2016

Calcification around the Struts of a Sirolimus-eluting Stent Approximately 16 Months after Implantation in an Autopsy Case.

Intern Med 2016 15;55(4):353-8. Epub 2016 Feb 15.

Department of Cardiovascular Medicine, Nagasaki University Graduate School of Biomedical Sciences, Japan.

Drug-eluting stents (DES) are widely used for the treatment of coronary artery disease, and a sirolimus-eluting stent (SES; Cypher) was the first DES introduced into clinical practice. Although pathological reactions of coronary arteries to SES have been described in autopsy cases, there are few reports regarding calcification of the coronary arteries after SES implantation. The present report describes the findings of an autopsy conducted 16 months after SES implantation that showed remarkable persistent calcification. In addition, previously reported pertinent pathological findings are also described.
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http://dx.doi.org/10.2169/internalmedicine.55.4799DOI Listing
August 2016

Interaction between thyrocytes and adipose tissue in vitro.

Pathol Int 2016 Mar 26;66(3):148-157. Epub 2016 Jan 26.

Department of Pathology & Microbiology, Faculty of Medicine, Saga University, Saga, Japan.

Adipose tissue (AT)-thyrocyte interaction is largely unknown. Here we described the interaction in a co-culture system, in which thyrocytes were cultured on AT fragment (ATF)-embedded collagen gel, using electron microscopy, immunocytochemistry, real-time reverse transcription-polymerase chain reaction (RT-PCR) and enzyme-linked immunosorbent assay (ELISA). ATFs promoted the hypertrophy, polarization and lipid accumulation of thyrocytes. ATFs did not affect the growth of thyroyctes, and inhibited their apoptosis. ATFs increased the protein expression of thyroglobulin (Tg) and paired box gene 8 (PAX8) in thyrocytes. In turn, thyrocytes decreased the concentration of leptin and adiponectin, and increased the expression of these mRNAs in ATFs. Thyrotropin (TSH) enhanced the ATF-induced nuclear hypertrophy and Tg protein expression in thyrocytes, while TSH enhanced the thyrocyte-induced expression of leptin and adiponectin mRNAs in ATFs. Finally, leptin promoted the hypertrophy and Tg protein expression in thyrocytes. TSH enhanced these leptin-induced effects. The data indicate an active interaction between thyrocytes and AT, suggesting that (i) ATFs may serve to regulate the morphology, survival and differentiation of thyrocytes probably through lipid accumulation partly in a TSH-synergistic way; (ii) thyrocytes may affect adipokine production from ATFs in a TSH-independent manner; and (3) leptin may be related to the hypertrophy and differentiation of thyrocytes in a TSH-synergistic way.
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http://dx.doi.org/10.1111/pin.12387DOI Listing
March 2016

Cytokeratin immunohistochemistry improves interobserver variability between unskilled pathologists in the evaluation of tumor budding in T1 colorectal cancer.

Pathol Int 2016 Feb 11;66(2):75-82. Epub 2016 Jan 11.

Departments of Pathology & Microbiology, Faculty of Medicine, Saga University, Saga, Japan.

Tumor budding is a major risk factor for T1 colorectal cancer. Quality control of the pathological diagnosis of budding is crucial, irrespective of the pathologist's experience. This study examines the interobserver variability according to pathologists' experience and evaluates the influence of cytokeratin (CK) immunostaining in the assessment of budding. Hematoxylin-eosin (HE) and CK-immunostained slides of 40 cases with T1 primary colorectal cancer were examined. Budding grades were individually evaluated by 12 pathologists who we categorized into three groups by their experience (expert, with >10 years of experience (n = 4), senior, with 5-10 years (n = 4), and junior, < 5 years (n = 4)). The results revealed a tendency for the more experienced pathologists to assign higher budding grades compared to the less-experienced pathologists. In the junior group, the interobserver variability obtained with HE slides was poor, but it was markedly improved in the evaluation using CK-immunostained slides. The benefit of CK immunostaining was only slight in the expert group. CK immunostaining would be useful when a pathologist is not experienced enough or does not have enough confidence in the assessment of budding.
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http://dx.doi.org/10.1111/pin.12374DOI Listing
February 2016

Fluid dwell impact induces peritoneal fibrosis in the peritoneal cavity reconstructed in vitro.

J Artif Organs 2016 Mar 30;19(1):87-96. Epub 2015 Aug 30.

Department of Pathology and Microbiology, Faculty of Medicine, Saga University, 5-1-1 Nabeshima, Saga, 849-8501, Japan.

Peritoneal fluid dwell impacts the peritoneum by creating an abnormal physiological microenvironment. Little is known about the precise effects of fluid dwell on the peritoneum, and no adequate in vitro models to analyze the impact of fluid dwell have been established. In this study, we developed a peritoneal fluid dwell model combined with an artificial peritoneal cavity and fluid stirring generation system to clarify the effects of different dwelling solutions on the peritoneum over time. To replicate the peritoneal cavity, we devised a reconstructed peritoneal cavity utilizing a mesothelial layer, endothelial layer, and collagen membrane chamber. The reconstructed peritoneal cavity was infused with Dulbecco's modified Eagle's medium, saline, lactated Ringer's solution or peritoneal dialysis solution with repeated 4-h dwells for 10 or 20 consecutive days. The above-described solutions induced epithelial-mesenchymal transition (EMT) and hyperplasia of mesothelial cells. All solution types modulated nitric oxide synthase activities in mesothelial and endothelial cells and nitric oxide concentrations in dwelling solutions. Inhibition of nitric oxide synthase activity acted synergistically on mesothelial EMT and hyperplasia. The present findings suggest that solutions infused into the peritoneal cavity are likely to affect nitric oxide production in the peritoneum and promote peritoneal fibrosis. Our newly devised peritoneal cavity model should be a promising tool for understanding peritoneal cellular kinetics and homeostasis.
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http://dx.doi.org/10.1007/s10047-015-0864-7DOI Listing
March 2016

A new cell-free bandage-type artificial skin for cutaneous wounds.

Wound Repair Regen 2015 Nov-Dec;23(6):819-29. Epub 2015 Jul 14.

Department of Pathology and Microbiology, Faculty of Medicine, Saga University, Saga, Japan.

Engineered skin substitutes are widely used in skin wound management. However, no currently available products satisfy all the criteria of usability in emergency situations, easy handling, and minimal scar formation. To overcome these shortcomings, we designed a cell-free bandage-type artificial skin, named "VitriBand" (VB), using adhesive film dressing, silicone-coated polyethylene terephthalate film, and collagen xerogel membrane defined as a dried collagen vitrigel membrane without free water. We analyzed its advantages over in-line products by comparing VB with hydrocolloid dressing and collagen sponge. For evaluation, mice inflicted with full-thickness skin defects were treated with VB, hydrocolloid dressing, and collagen sponge. A plastic film group treated only with adhesive film dressing and silicone-coated polyethylene terephthalate film, and a no treatment group were also compared. VB promoted epithelization while inhibiting the emergence of myofibroblasts and inflammation in the regenerating tissue more effectively than the plastic film, hydrocolloid dressing, and collagen sponge products. We have succeeded in establishing a cell-free bandage-type artificial skin that could serve as a promising first-line medical biomaterial for emergency treatment of skin injuries in various medical situations.
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http://dx.doi.org/10.1111/wrr.12321DOI Listing
October 2016

Experimental pulmonary fibrosis in rats with chronic gastric acid reflux esophagitis.

Auris Nasus Larynx 2015 Oct 8;42(5):382-4. Epub 2015 Apr 8.

Department of Otolaryngology, Head & Neck Surgery, Faculty of Medicine, Saga University, 5-1-1 Nabeshima, Saga 849 8501, Japan.

Objective: To elucidate the association between gastric acid reflux and respiratory diseases by studying the histological changes of the lower airway in rats with chronic acid reflux esophagitis.

Methods: An experimental rat model of chronic acid reflux esophagitis was surgically created. The lower airways of these rats were histologically observed for more than 50 weeks.

Results: Although there were no histological changes which induced gastric acid reflux at 10 weeks after surgery, thickening of the basal laminae and the proliferation of the collagenous fibers were observed in the alveolar epithelium at 20 weeks after surgery. At 50 weeks after surgery, the collagenous fibers obliterated the pulmonary alveoli and bronchial lumen. These findings observed in the GERD rats are similar to the pathological findings of human pulmonary fibrosis.

Conclusion: In this study, we reported pathological changes in the lower airways of GERD rat models observed for more than 50 weeks. These results suggest that gastric acid reflux may be one of the pathogenic or exacerbating factors of pulmonary fibrosis.
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http://dx.doi.org/10.1016/j.anl.2015.03.005DOI Listing
October 2015

Merkel cell carcinoma with glandular differentiation admixed with sweat gland carcinoma and spindle cell carcinoma: histogenesis of merkel cell carcinoma from hair follicle stem cells.

Am J Dermatopathol 2015 Mar;37(3):e31-6

*Division of Dermatology, Department of Internal Medicine, Faculty of Medicine, Saga University, Saga, Japan; and †Department of Pathology and Microbiology, Faculty of Medicine, Saga University, Saga, Japan.

We describe a unique case of Merkel cell carcinoma (MCC) with a heterogeneous differentiation exhibiting distinct triphasic phenotypic differentiation features: small cells typical of MCC, sweat gland carcinoma (sweat gland Ca.) with possible decapitation secretion, and spindle cell carcinoma (spindle cell Ca.). The patient was an 84-year-old Japanese woman. We evaluated the present case immunohistochemically with various antibodies. The histological features showed a gradual transition from MCC to sweat gland Ca. and spindle cell Ca. For clarifying the histogenesis, immunophenotypic analysis of the 3 different components of the carcinoma was performed using hair follicle stem cell markers (eg, CK15, CK19, and CD200) that have been identified as biomarkers of human bulge cells. The triphasic components immunohistochemically shared the characteristic feature of CK19 and CD200 expression. We posit that the MCC arose from hair follicle stem cells residing within the bulge area where Merkel cells are preferentially situated. Based on our findings, we recommend adding this rare neoplasm to the expanding morphological spectrum of MCC.
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http://dx.doi.org/10.1097/DAD.0000000000000064DOI Listing
March 2015

Two cases of minor glomerular abnormalities with proteinuria disproportionate to the degree of hypoproteinemia.

CEN Case Rep 2014 Nov 14;3(2):172-177. Epub 2014 Feb 14.

Department of Internal Medicine, Saga University Faculty of Medicine, 5-1-1 Nabeshima, Saga, Saga, 849-8501, Japan.

We experienced two female cases of minor glomerular abnormalities with proteinuria disproportionate to the degree of hypoproteinemia. They did not have adequately large amounts of urine protein so as to cause nephrotic syndrome; however, we were unable to determine any cause of hypoproteinemia other than proteinuria. The renal pathology revealed foot process effacement, and hyaline droplet degeneration, suggesting urine protein hyper-reabsorption in the proximal convoluted tubule. Therefore, we thought these cases involved pathophysiological conditions, such as minimal change nephrotic syndrome. In both cases, the hypoproteinemia improved following the administration of oral prednisolone. As in past reports, it is thought that the principal causative factor of hypoalbuminemia in patients with nephrotic syndrome is a catabolic reaction after the serum albumin filtered at the glomerulus is reabsorbed in the proximal tubule. In the present two cases, it is supposed that a large amount of urine protein was filtered in the primitive urine; however, the amount of final urinary protein did not reach the nephrotic range because most of it was reabsorbed in the proximal tubule and reabsorbed in the blood after being disintegrated into amino acids by a catabolic reaction. Or we might simply observe the process before the case 1 got nephrotic syndrome and the healing process of nephrotic syndrome in the case 2.
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http://dx.doi.org/10.1007/s13730-014-0112-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5413662PMC
November 2014

Histopathology of tenosynovium in trigger fingers.

Pathol Int 2014 Jun;64(6):276-82

Department of Pathology and Microbiology, Faculty of Medicine, Saga University, Saga, Japan.

Stenosing flexor tenosynovitis, trigger finger, is a common clinical disorder causing painful locking or contracture of the involved digits, and most instances are idiopathic. This problem is generally caused by a size mismatch between the swollen flexor tendon and the thickened first annular pulley. Although hypertrophic pulleys have been histologically and ultrasonographically detected, little is known about the histopathology of the tenosynovium covering the tendons of trigger fingers. We identified chondrocytoid cells that produced hyaluronic acid in 23 (61%) fingers and hypocellular collagen matrix in 32 (84%) fingers around the tenosynovium among 38 specimens of tenosynovium from patients with trigger fingers. These chondrocytoid cells expressed the synovial B cell marker CD44, but not the chondrocyte marker S-100 protein. The incidence of these findings was much higher than that of conventional findings of synovitis, such as inflammatory infiltrate (37%), increased vascularity (37%), hyperplasia of synovial lining cells (21%), or fibrin exudation (5%). We discovered the following distinctive histopathological features of trigger finger: hyaluronic acid-producing chondrocytoid cells originated from fibroblastic synovial B cells, and a hypocellular collagen matrix surrounding the tenosynovium. Thus, an edematous extracellular matrix with active hyaluronic acid synthesis might increase pressure under the pulley and contribute to the progression of stenosis.
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http://dx.doi.org/10.1111/pin.12168DOI Listing
June 2014

Laryngeal granuloma in experimental rats with gastroesophageal reflux disease and mechanically injured vocal cord mucosa.

Ann Otol Rhinol Laryngol 2014 Apr;123(4):247-51

Department of Otolaryngology, Head & Neck Surgery, Faculty of Medicine, Saga University, Saga, Japan.

Objective: This study was undertaken to elucidate the mechanisms underlying laryngeal granuloma formation in a rat model of gastroesophageal reflux disease (GERD) with mechanically injured vocal cord mucosa.

Methods: The rat model of GERD was surgically created by tying the pyloric sphincter and ligating the transitional region between the forestomach and the glandular portion (limiting ridge). The control rats received only a midline incision. In all the animals, a plastic bar was inserted into the trachea, and moved vertically thrice in 3 seconds to cause mechanical injury of the vocal cord mucosa. The rats were sacrificed 2 weeks postsurgically, and their pharynx and larynx were observed histologically.

Results: Granulomas were observed in the vocal cord mucosa of the GERD group (3 of 5 animals); they presented a similar pathological structure to that of human laryngeal granulomas. In contrast, only abrasions and blisters were observed on the vocal cord mucosa in the control group (all 5 animals).

Conclusions: The development of laryngeal granuloma may involve both mechanical injury and gastric acid reflux.
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http://dx.doi.org/10.1177/0003489414525018DOI Listing
April 2014
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