78 results on '"Inaguma S"'
Search Results
2. Determining Infected Aortic Aneurysm Treatment Using Focused Detection of Helicobacter cinaedi
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Saito Jien, Rimbara Emiko, Inaguma Shingo, Hasegawa Chihiro, Kamiya Shinji, Mizuno Akihiro, Sone Yoshiaki, Ogawa Tatsuhito, Numata Yukihide, Takahashi Satoru, and Asano Miki
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Helicobacter cinaedi ,bacteria ,antimicrobial treatment ,infections ,aortic aneurysm ,arteriosclerosis ,Medicine ,Infectious and parasitic diseases ,RC109-216 - Abstract
We detected Helicobacter cinaedi in 4 of 10 patients with infected aortic aneurysms diagnosed using blood or tissue culture in Aichi, Japan, during September 2017–January 2021. Infected aortic aneurysms caused by H. cinaedi had a higher detection rate and better results after treatment than previously reported, without recurrent infection.
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- 2022
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3. GLI1 facilitates the migration and invasion of pancreatic cancer cells through MUC5AC-mediated attenuation of E-cadherin
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Inaguma, S, primary, Kasai, K, additional, and Ikeda, H, additional
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- 2010
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4. Down-regulation of Lsm1 is involved in human prostate cancer progression
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Takahashi, S, primary, Suzuki, S, additional, Inaguma, S, additional, Cho, Y-M, additional, Ikeda, Y, additional, Hayashi, N, additional, Inoue, T, additional, Sugimura, Y, additional, Nishiyama, N, additional, Fujita, T, additional, Ushijima, T, additional, and Shirai, T, additional
- Published
- 2002
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5. COLONIC ADENOCARCINOMAS HARBORING NTRK FUSION GENES: A CLINICOPATHOLOGIC AND MOLECULAR GENETIC STUDY OF 16 CASES AND REVIEW OF THE LITERATURE
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Paweł Kita, Sebastian Goertz, Leszek Teresiński, Janusz Ryś, Małgorzata Kołos, Maciej Kaczorowski, Massimo Milione, Krzysztof Okoń, Caj Haglund, Wojciech Biernat, Michal Pyzlak, Anna Guttmejer-Nasierowska, Arndt Hartmann, Artur Kowalik, Małgorzata Chłopek, Shingo Inaguma, Joanna Szpor, Agnieszka Hałoń, Giovanni Centonze, Jarosław Wejman, Magdalena Dubova, Ondrej Daum, Michal Michal, Jennifer Lamoureux, Justyna Szumiło, Abbas Agaimy, Blazej Szostak, Jerzy Lasota, Jason Christiansen, Ewa Chmielik, Ireneusz Dziuba, Rafał Pęksa, Ari Ristimäki, Piotr Waloszczyk, Anna Felisiak-Goląbek, Ewa Iżycka-Świeszewska, Bartosz Wasąg, Markku Miettinen, Stanisław Góźdź, Vincenzo Canzonieri, Wojciech Wesołowski, Janusz Kopczyński, Lasota, J., Chlopek, M., Lamoureux, J., Christiansen, J., Kowalik, A., Wasag, B., Felisiak-Golabek, A., Agaimy, A., Biernat, W., Canzonieri, V., Centonze, G., Chmielik, E., Daum, O., Dubova, M., Dziuba, I., Goertz, S., Gozdz, S., Guttmejer-Nasierowska, A., Haglund, C., Halon, A., Hartmann, A., Inaguma, S., Izycka-Swieszewska, E., Kaczorowski, M., Kita, P., Kolos, M., Kopczynski, J., Michal, M., Milione, M., Okon, K., Peksa, R., Pyzlak, M., Ristimaki, A., Rys, J., Szostak, B., Szpor, J., Szumilo, J., Teresinski, L., Waloszczyk, P., Wejman, J., Wesolowski, W., and Miettinen, M.
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0301 basic medicine ,Male ,Oncogene Proteins, Fusion ,Colorectal cancer ,NTRK1 ,Fusion gene ,0302 clinical medicine ,hemic and lymphatic diseases ,80 and over ,Anaplastic lymphoma kinase ,fusion genes ,Oncogene Proteins ,Aged, 80 and over ,Colonic Neoplasm ,Tumor ,Membrane Glycoproteins ,biology ,Middle Aged ,Immunohistochemistry ,3. Good health ,Receptor Protein-Tyrosine Kinase ,Gene Expression Regulation, Neoplastic ,fusion gene ,030220 oncology & carcinogenesis ,trkA ,trkB ,Colonic Neoplasms ,trkC ,Female ,Membrane Glycoprotein ,Anatomy ,2 and 3 ,Human ,Receptor ,Adenocarcinoma ,Article ,Pathology and Forensic Medicine ,Follow-Up Studie ,03 medical and health sciences ,colorectal carcinoma ,medicine ,Carcinoma ,Biomarkers, Tumor ,PTEN ,Humans ,Receptor, trkB ,Oncogene Fusion ,Receptor, trkC ,Receptor, trkA ,Fusion ,immunohistochemistry ,next-generation sequencing ,NTRK1, 2 and 3 ,TRK expression ,Aged ,Follow-Up Studies ,Neoplasm Staging ,Receptor Protein-Tyrosine Kinases ,Neoplastic ,Microsatellite instability ,Gene rearrangement ,medicine.disease ,030104 developmental biology ,Gene Expression Regulation ,Cancer research ,biology.protein ,Surgery ,Biomarkers - Abstract
This study determined the frequency and the clinicopathologic and genetic features of colorectal carcinomas driven by oncogenic fusions of the anaplastic lymphoma kinase gene (ALK). Of the 8150 screened tumors, 12 (0.15%) were immunohistochemically ALK-positive with D5F3 antibody. These cancers harbored CAD-ALK (n=1), DIAPH2-ALK (n=2), EML4-ALK (n=2), LOC101929227-ALK (n=1), SLMAP-ALK (n=1), SPTBN1-ALK (n=4), and STRN-ALK (n=1) fusions, as detected by an RNA-based next-generation sequencing assay. ALK fusion carcinomas were diagnosed mostly in older patients with a 9:3 female predominance (median age: 72 y). All tumors, except a rectal one, occurred in the right colon. Most tumors were stage T3 (n=7) or T4 (n=3). Local lymph node and distant metastases were seen at presentation in 9 and 2 patients. These tumors showed moderate (n=6) or poor (n=3) glandular differentiation, solid medullary growth pattern (n=2), and pure mucinous morphology (n=1). DNA mismatch repair-deficient phenotype was identified in 10 cases. Tumor-infiltrating lymphocytes were prominent in 9 carcinomas. In 4 carcinomas, tumor cells showed strong, focal (n=3), or diffuse programmed death-ligand 1 immunoreactivity. CDX2 expression and loss of CK20 and MUC2 expression were frequent. CK7 was expressed in 5 tumors. Four patients died of disease within 3 years, and 7 were alive with follow-up ranging from 1 to 8 years. No mutations in BRAF, RAS, and in genes encoding components of PI3K-AKT/MTOR pathway were identified. However, 1 tumor had a loss-of-function PTEN mutation. Aberration of p53 signaling, TP53 mutations, and/or nuclear accumulation of p53 protein was seen in 9 cases. ALK fusion colorectal carcinomas are a distinct and rare subtype of colorectal cancers displaying some features of mismatch repair-deficient tumors.
- Published
- 2020
6. Use of SATB2 and CDX2 Immunohistochemistry to Characterize and Diagnose Colorectal Cancer.
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Kato S, Koshino A, Lasota J, Komura M, Wang C, Ebi M, Ogasawara N, Kojima K, Tsuzuki T, Kasai K, Takahashi S, Miettinen M, Kasugai K, and Inaguma S
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- Humans, Female, Male, Middle Aged, Aged, Biomarkers, Tumor metabolism, Biomarkers, Tumor genetics, Adult, Aged, 80 and over, Keratin-20 metabolism, Keratin-20 genetics, CDX2 Transcription Factor metabolism, Colorectal Neoplasms diagnosis, Colorectal Neoplasms metabolism, Colorectal Neoplasms pathology, Matrix Attachment Region Binding Proteins metabolism, Matrix Attachment Region Binding Proteins genetics, Immunohistochemistry, Transcription Factors metabolism
- Abstract
SATB2 has been reported to be highly specific for lower gastrointestinal tract tumors. On the basis of its ileum-colon conversion effects, which involve the activation of colonic genes in cooperation with CDX2 and HNF4A, we hypothesized that SATB2 and CDX2 might define the characteristics of colorectal cancers (CRCs). In the present study, the clinicopathologic and immunohistochemical characteristics of 269 CRCs were analyzed according to SATB2 and CDX2 expression. CRCs with SATB2- and/or CDX2- phenotypes showed associations with poorly differentiated histotypes ( P <0.00001), mucus production ( P =0.0019), and mismatch repair-deficient phenotypes ( P <0.00001). SATB2-/CDX2- CRCs were significantly associated with CK20-negativity, with or without CK7 expression ( P <0.00001), as well as with MUC5AC-positivity ( P <0.00001), and CD10-negativity ( P =0.00047). Negativity for SATB2 or CDX2 was associated with the expression of PD-L1 in both all CRC ( P <0.00001) and mismatch repair-proficient CRC ( P =0.000091). Multivariate Cox hazard regression analysis identified negativity for SATB2 and/or CDX2 as potential independent risk factors for patients with CRC. Regarding the diagnostic utility of SATB2, all of the 44 CRC metastases could be diagnosed as colorectal in origin if the immunohistochemical phenotypes (including CK7, CK20, and p53) of the primary lesions and patient history were considered. Among the other 684 tumors, we were unable to distinguish a case of CK7-/CK20+/CDX2+/SATB2+ ovarian mucinous cystadenocarcinoma from metastatic CRC without the patient history and clinical information., Competing Interests: The authors declare no conflict of interest., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)
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- 2024
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7. The role of DPYD and the effects of DPYD suppressor luteolin combined with 5-FU in pancreatic cancer.
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Kato H, Sato M, Naiki-Ito A, Inaguma S, Sano M, Komura M, Nagayasu Y, Xiaochen K, Kato A, Matsuo Y, Ijichi H, and Takahashi S
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- Animals, Humans, Mice, Cell Line, Tumor, Drug Resistance, Neoplasm, Antineoplastic Combined Chemotherapy Protocols pharmacology, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Gene Expression Regulation, Neoplastic drug effects, Mice, Nude, Neoplasm Invasiveness, Fluorouracil pharmacology, Fluorouracil therapeutic use, Dihydrouracil Dehydrogenase (NADP) genetics, Dihydrouracil Dehydrogenase (NADP) metabolism, Pancreatic Neoplasms drug therapy, Pancreatic Neoplasms genetics, Pancreatic Neoplasms pathology, Pancreatic Neoplasms metabolism, Carcinoma, Pancreatic Ductal drug therapy, Carcinoma, Pancreatic Ductal pathology, Carcinoma, Pancreatic Ductal genetics, Carcinoma, Pancreatic Ductal metabolism, Luteolin pharmacology, Luteolin therapeutic use, Xenograft Model Antitumor Assays, Cell Proliferation drug effects
- Abstract
Background: Despite advances in the treatment of cancer, pancreatic ductal adenocarcinoma (PDAC) remains highly lethal due to the lack of effective therapies. Our previous study showed that Luteolin (Lut), a flavonoid, suppressed pancreatocarcinogenesis and reduced the expression of dihydropyrimidine dehydrogenase (DPYD), an enzyme that degrades pyrimidines such as 5-fluorouracil (5-FU), in PDACs. In this study, we investigated the role of DPYD and evaluated the therapeutic potential of combining 5-FU with Lut in PDACs., Methods and Results: PDAC cells overexpressing DPYD showed increased proliferation, and invasiveness, adding to the resistance to 5-FU. The xenograft tumors of DPYD-overexpressing PDAC cells also exhibit enhanced growth and invasion compared to the control xenograft tumors. RNA-seq analysis of the DPYD-overexpressing PDAC xenograft tumors revealed an upregulation of genes associated with metallopeptidase activity-MMP9 and MEP1A. Furthermore, the overexpression of MEP1A in PDAC was associated with invasion. Next, we investigated the combined effects of Lut, a DPYD suppressor, and 5-FU on DPYD-overexpressing xenograft tumors and PDAC of Pdx1-Cre; LSL-KrasG12D/+; Trp53flox/flox(KPPC) mice. Neither single administration of 5-FU nor Lut showed significant inhibitory effects; however, the combined administration of 5-FU and Lut exhibited a significant tumor-suppressive effect in both the xenograft tumors and KPPC models., Conclusion: We have elucidated that DPYD expression contributes to proliferation, invasiveness, and 5-FU resistance, in PDACs. The combination therapy of Lut and 5-FU holds the potential for enhanced efficacy against PDACs., (© 2024 The Author(s). Cancer Medicine published by John Wiley & Sons Ltd.)
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- 2024
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8. Characterisation of colorectal cancer by hierarchical clustering analyses for five stroma-related markers.
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Ito S, Koshino A, Wang C, Otani T, Komura M, Ueki A, Kato S, Takahashi H, Ebi M, Ogasawara N, Tsuzuki T, Kasai K, Kasugai K, Takiguchi S, Takahashi S, and Inaguma S
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- Humans, Male, Female, Aged, Middle Aged, Cluster Analysis, Immunohistochemistry, Tumor Microenvironment, Prognosis, Membrane Glycoproteins analysis, Membrane Glycoproteins metabolism, Stromal Cells pathology, Stromal Cells metabolism, Decorin analysis, Decorin metabolism, Adult, Aged, 80 and over, Kaplan-Meier Estimate, Colorectal Neoplasms pathology, Colorectal Neoplasms mortality, Colorectal Neoplasms metabolism, Biomarkers, Tumor analysis, Cancer-Associated Fibroblasts pathology, Cancer-Associated Fibroblasts metabolism
- Abstract
Evidence for the tumour-supporting capacities of the tumour stroma has accumulated rapidly in colorectal cancer (CRC). Tumour stroma is composed of heterogeneous cells and components including cancer-associated fibroblasts (CAFs), small vessels, immune cells, and extracellular matrix proteins. The present study examined the characteristics of CAFs and collagen, major components of cancer stroma, by immunohistochemistry and Sirius red staining. The expression status of five independent CAF-related or stromal markers, decorin (DCN), fibroblast activation protein (FAP), podoplanin (PDPN), alpha-smooth muscle actin (ACTA2), and collagen, and their association with clinicopathological features and clinical outcomes were analysed. Patients with DCN-high tumours had a significantly worse 5-year survival rate (57.3% versus 79.0%; p = 0.044). Furthermore, hierarchical clustering analyses for these five markers identified three groups that showed specific characteristics: a solid group (cancer cell-rich, DCN
Low PDPNLow ); a PDPN-dominant group (DCNMid PDPNHigh ); and a DCN-dominant group (DCNHigh PDPNLow ), with a significant association with patient survival (p = 0.0085). Cox proportional hazards model identified the PDPN-dominant group (hazard ratio = 0.50, 95% CI = 0.26-0.96, p = 0.037) as a potential favourable factor compared with the DCN-dominant group. Of note, DCN-dominant tumours showed the most advanced pT stage and contained the lowest number of CD8+ and FOXP3+ immune cells. This study has revealed that immunohistochemistry and special staining of five stromal factors with hierarchical clustering analyses could be used for the prognostication of patients with CRC. Cancer stroma-targeting therapies may be candidate treatments for patients with CRC., (© 2024 The Author(s). The Journal of Pathology: Clinical Research published by The Pathological Society of Great Britain and Ireland and John Wiley & Sons Ltd.)- Published
- 2024
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9. Simultaneous Expression of CD70 and POSTN in Cancer-Associated Fibroblasts Predicts Worse Survival of Colorectal Cancer Patients.
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Komura M, Wang C, Ito S, Kato S, Ueki A, Ebi M, Ogasawara N, Tsuzuki T, Kasai K, Kasugai K, Takiguchi S, Takahashi S, and Inaguma S
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- Humans, Fibroblasts metabolism, Immunohistochemistry, Cell Proliferation, Cell Adhesion Molecules metabolism, CD27 Ligand metabolism, Cancer-Associated Fibroblasts metabolism, Colorectal Neoplasms pathology
- Abstract
Colorectal cancer (CRC) is one of the most common gastrointestinal cancers worldwide, with high morbidity and mortality rates. The evidence for the tumor-supporting capacities of cancer-associated fibroblasts (CAFs) that modulate cancer cell proliferation, invasion, metastasis, and tumor immunity, including in CRC, has been attracting attention. The present study examined the expression status of CD70 and POSTN in CRC and analyzed their association with clinicopathological features and clinical outcomes. In the present study, in total 15% (40/269) and 44% (119/269) of cases exhibited CD70 and POSTN expression on CAFs, respectively. Co-expression of CD70 and POSTN was detected in 8% (21/269) of patients. Fluorescent immunohistochemistry identified the co-expression of CD70 and POSTN with FAP and PDPN, respectively. ACTA2 was not co-expressed with CD70 or POSTN in CRC CAFs. CRC with CD70+/POSTN+ status in CAFs was significantly associated with distant organ metastasis ( p = 0.0020) or incomplete resection status ( p = 0.0011). CD70+/POSTN+ status tended to associate with advanced pT stage ( p = 0.032) or peritoneal metastasis ( p = 0.0059). Multivariate Cox hazards regression analysis identified CD70+/POSTN+ status in CAFs [hazard ratio (HR) = 3.78] as a potential independent risk factor. In vitro experiments revealed the activated phenotypes of colonic fibroblasts induced by CD70 and POSTN, while migration and invasion assays identified enhanced migration and invasion of CRC cells co-cultured with CD70- and POSTN-expressing colonic fibroblasts. On the basis of our observations, CD70 and POSTN immunohistochemistry can be used in the prognostication of CRC patients. CRC CAFs may be a promising target in the treatment of CRC patients.
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- 2024
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10. Clinical Impact of Proton Pump Inhibitor and Potassium-Competitive Acid Blocker for Predicting the Curability of Endoscopic Resection in Ulcerative Early Gastric Cancer.
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Uno K, Shimura T, Inaguma S, Kuroyanagi K, Nishigaki R, Kanno T, Sasaki M, Fukusada S, Sugimura N, Mizuno Y, Nukui T, Kojima Y, Tanaka M, Ozeki K, Kubota E, Takahashi S, and Kataoka H
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- Humans, Male, Female, Retrospective Studies, Middle Aged, Aged, Gastric Mucosa pathology, Gastric Mucosa surgery, Gastric Mucosa diagnostic imaging, Treatment Outcome, Gastroscopy methods, Adult, Neoplasm Invasiveness, Aged, 80 and over, Early Detection of Cancer methods, Stomach Neoplasms surgery, Stomach Neoplasms pathology, Stomach Neoplasms drug therapy, Proton Pump Inhibitors therapeutic use, Proton Pump Inhibitors administration & dosage, Endoscopic Mucosal Resection methods, Stomach Ulcer drug therapy, Stomach Ulcer etiology, Stomach Ulcer pathology, Stomach Ulcer diagnosis
- Abstract
Introduction: Endoscopic diagnosis is essential for predicting the curability of early gastric cancer (EGC; R0 resection) before treatment, but the relationship between ulcerative lesions and clinical outcomes remains unclear. We aimed to investigate the effect of proton pump inhibitor (PPI) or potassium-competitive acid blocker (P-CAB) on the morphological changes of ulcerative EGCs and its relevance to the clinical outcomes., Methods: Altogether, 143 patients with differentiated ulcerative EGC that were resected by endoscopic submucosal dissection were retrospectively identified and divided into the following two cohorts depending on their PPI/P-CAB administration status: PPI/P-CAB (n = 76) and non-PPI/P-CAB (n = 67) cohorts. Furthermore, in each cohort, the patients were further divided into the improved and unimproved subgroups based on the ulcerative changes., Results: In the PPI/P-CAB cohort, the deep submucosal invasion and lymphovascular invasion rates were significantly higher in the unimproved subgroup than in the improved subgroup, resulting in a significantly lower R0 resection rate. Contrarily, no significant differences were found between the two subgroups in the non-PPI/P-CAB cohort. The significance of PPI/P-CAB administration was observed only in the ulcerative EGCs with open-type atrophy (R0 resection rate; improved vs. unimproved, 90.9% vs. 48.0%, p = 0.001). When the finding of improved ulcer with PPI/P-CAB administration was used as the indication of endoscopic resection in ulcerative EGCs with open-type atrophy, high sensitivity (78.9%) and accuracy (76.3%) rates for the curability were observed, which were higher than those of conventional endoscopic diagnosis alone (p = 0.021)., Conclusion: PPI or P-CAB administration might contribute to the potential selection of ulcerative EGCs, enabling endoscopic curative resection., (© 2024 S. Karger AG, Basel.)
- Published
- 2024
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11. Characterization of Pleural Mesothelioma by Hierarchical Clustering Analyses Using Immune Cells within Tumor Microenvironment.
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Inaguma S, Wang C, Ito S, Ueki A, Lasota J, Czapiewski P, Langfort R, Rys J, Szpor J, Waloszczyk P, Okoń K, Biernat W, Takiguchi S, Schrump DS, Miettinen M, and Takahashi S
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- Humans, Male, Female, Middle Aged, Aged, Cluster Analysis, Mesothelioma immunology, Mesothelioma pathology, Adult, Mesothelioma, Malignant immunology, Mesothelioma, Malignant pathology, Aged, 80 and over, Prognosis, Immunohistochemistry, Tumor Microenvironment immunology, Pleural Neoplasms immunology, Pleural Neoplasms pathology, Lymphocytes, Tumor-Infiltrating immunology, Biomarkers, Tumor
- Abstract
Introduction: Over the past decade, classifications using immune cell infiltration have been applied to many types of tumors; however, mesotheliomas have been less frequently evaluated., Methods: In this study, 60 well-characterized pleural mesotheliomas (PMs) were evaluated immunohistochemically for the characteristics of immune cells within tumor microenvironment (TME) using 10 immunohistochemical markers: CD3, CD4, CD8, CD56, CD68, CD163, FOXP3, CD27, PD-1, and TIM-3. For further characterization of PMs, hierarchical clustering analyses using these 10 markers were performed., Results: Among the immune cell markers, CD3 (p < 0.0001), CD4 (p = 0.0016), CD8 (p = 0.00094), CD163+ (p = 0.042), and FOXP3+ (p = 0.025) were significantly associated with an unfavorable clinical outcome. Immune checkpoint receptor expressions on tumor-infiltrating lymphocytes such as PD-1 (p = 0.050), CD27 (p = 0.014), and TIM-3 (p = 0.0098) were also associated with unfavorable survival. Hierarchical clustering analyses identified three groups showing specific characteristics and significant associations with patient survival (p = 0.016): the highest number of immune cells (ICHigh); the lowest number of immune cells, especially CD8+ and CD163+ cells (ICLow); and intermediate number of immune cells (ICInt). ICHigh tumors showed significantly higher expression of PD-L1 (p = 0.00038). Cox proportional hazard model identified ICHigh [hazard ratio (HR) = 2.90] and ICInt (HR = 2.97) as potential risk factors compared with ICLow. Tumor CD47 (HR = 2.36), tumor CD70 (HR = 3.04), and tumor PD-L1 (HR = 3.21) expressions were also identified as potential risk factors for PM patients., Conclusion: Our findings indicate immune checkpoint and/or immune cell-targeting therapies against CD70-CD27 and/or CD47-SIRPA axes may be applied for PM patients in combination with PD-L1-PD-1 targeting therapies in accordance with their tumor immune microenvironment characteristics., (© 2024 S. Karger AG, Basel.)
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- 2024
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12. Characterization of colorectal cancer by hierarchical clustering analyses of five immune cell markers.
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Ito S, Koshino A, Komura M, Kato S, Otani T, Wang C, Ueki A, Takahashi H, Ebi M, Ogasawara N, Tsuzuki T, Kasai K, Kasugai K, Takiguchi S, Takahashi S, and Inaguma S
- Subjects
- Humans, CD47 Antigen, B7-H1 Antigen metabolism, Programmed Cell Death 1 Receptor metabolism, Biomarkers, Tumor analysis, Tumor Microenvironment, Colorectal Neoplasms pathology
- Abstract
The present study analyzed the expression of five independent immunohistochemical markers, CD4, CD8, CD66b, CD68, and CD163, on immune cells within the colorectal cancer (CRC) tumor microenvironment (TME). Using hierarchical clustering, patients were successfully classified according to significant associations with clinicopathological features and/or survival. Patients with mismatch repair-proficient (pMMR) CRC were categorized into four groups with survival differences (p = 0.0084): CD4
Low , CD4High , MΦHigh , and CD8Low . MΦHigh tumors showed significantly higher expression of CD47 (p < 0.0001), a phagocytosis checkpoint molecule. These tumors contained significantly greater numbers of PD-1+ (p < 0.0001), TIM-3+ (p < 0.0001), and SIRPA+ (p < 0.0001) immune cells. Notably, 10% of the patients with pMMR CRC expressed PD-L1 (CD274) on tumor cells with significantly worse survival (p = 0.00064). The Cox proportional hazards model identified MΦHigh (hazard ratio [HR] = 2.02, 95%, p = 0.032), CD8Low (HR = 2.45, p = 0.011), and tumor PD-L1 expression (HR = 2.74, p = 0.0061) as potential risk factors. PD-L1-PD-1 and/or CD47-SIRPA axes targeting immune checkpoint therapies might be considered for patients with pMMR CRC according to their tumor cells and tumor immune microenvironment characteristics., (© 2023 Japanese Society of Pathology and John Wiley & Sons Australia, Ltd.)- Published
- 2024
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13. Successful treatment with enfortumab-vedotin of metastatic signet ring cell cancer expressing nectin-4 and originating from the bladder.
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Aoki M, Naiki T, Naiki-Ito A, Morikawa T, Matsuyama N, Torii K, Kato T, Maruyama T, Inaguma S, and Yasui T
- Abstract
Introduction: As an aggressive adenocarcinoma phenotype, primary signet ring cell carcinoma of the urinary bladder is an extremely rare variant. The prognosis of metastatic signet ring cell carcinoma of the urinary bladder is extremely poor and the clinical course for its specific pathogenesis remains unelucidated., Case Presentation: A 64-year-old Japanese male patient was diagnosed with invasive urothelial carcinoma with glandular differentiation of a signet ring cell-type with pT4aN0M0, and he was eventually diagnosed with metastatic signet ring cell carcinoma of the urinary bladder. He was initially responsive to systemic combination induction chemotherapy of S-1 and cisplatin followed by avelumab switch maintenance therapy; however, signet ring cell carcinoma of the urinary bladder relapse occurred in the pathological findings of a biopsy from the right thigh. Immunohistochemical analysis of this specimen identified strong positive staining for nectin-4 and, following enfortumab-vedotin treatment, the patient showed a good response., Conclusion: We thus describe a rare case of metastatic signet ring cell carcinoma of the urinary bladder with nectin-4 expression diagnosed by a biopsy of a metastatic site., Competing Interests: The authors declare no conflict of interest., (© 2023 The Authors. IJU Case Reports published by John Wiley & Sons Australia, Ltd on behalf of Japanese Urological Association.)
- Published
- 2023
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14. CD70 and PD-L1 (CD274) co-expression predicts poor clinical outcomes in patients with pleural mesothelioma.
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Inaguma S, Ueki A, Lasota J, Komura M, Sheema AN, Czapiewski P, Langfort R, Rys J, Szpor J, Waloszczyk P, Okoń K, Biernat W, Schrump DS, Hassan R, Miettinen M, and Takahashi S
- Subjects
- Humans, Programmed Cell Death 1 Receptor, B7-H1 Antigen genetics, Forkhead Transcription Factors, Tumor Microenvironment, CD27 Ligand genetics, Lung Neoplasms pathology, Mesothelioma, Malignant, Mesothelioma drug therapy, Mesothelioma pathology, Pleural Neoplasms
- Abstract
Diffuse pleural mesothelioma (PM) is a highly aggressive tumour typically associated with short survival. Recently, the effectiveness of first-line immune checkpoint inhibitors in patients with unresectable PM was reported. CD70-CD27 signalling plays a co-stimulatory role in promoting T cell expansion and differentiation through the nuclear factor κB (NF-κB) pathway. Conversely, the PD-L1 (CD274)-PD-1 (PDCD1) pathway is crucial for the modulation of immune responses in normal conditions. Nevertheless, pathological activation of both the CD70-CD27 and PD-L1-PD-1 pathways by aberrantly expressed CD70 and PD-L1 participates in the immune evasion of tumour cells. In this study, 171 well-characterised PMs including epithelioid (n = 144), biphasic (n = 15), and sarcomatoid (n = 12) histotypes were evaluated immunohistochemically for CD70, PD-L1, and immune cell markers such as CD3, CD4, CD8, CD56, PD-1, FOXP3, CD68, and CD163. Eight percent (14/171) of mesotheliomas simultaneously expressed CD70 and PD-L1 on the tumour cell membrane. PMs co-expressing CD70 and PD-L1 contained significantly higher numbers of CD8+ (p = 0.0016), FOXP3+ (p = 0.00075), and CD163+ (p = 0.0011) immune cells within their microenvironments. Overall survival was significantly decreased in the cohort of patients with PM co-expressing CD70 and PD-L1 (p < 0.0001). In vitro experiments revealed that PD-L1 and CD70 additively enhanced the motility and invasiveness of PM cells. In contrast, PM cell proliferation was suppressed by PD-L1. PD-L1 enhanced mesenchymal phenotypes such as N-cadherin up-regulation. Collectively, these findings suggest that CD70 and PD-L1 both enhance the malignant phenotypes of PM and diminish anti-tumour immune responses. Based on our observations, combination therapy targeting these signalling pathways might be useful in patients with PM., (© 2023 The Authors. The Journal of Pathology: Clinical Research published by The Pathological Society of Great Britain and Ireland and John Wiley & Sons Ltd.)
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- 2023
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15. Stromal POSTN Enhances Motility of Both Cancer and Stromal Cells and Predicts Poor Survival in Colorectal Cancer.
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Ueki A, Komura M, Koshino A, Wang C, Nagao K, Homochi M, Tsukada Y, Ebi M, Ogasawara N, Tsuzuki T, Kasai K, Kasugai K, Takahashi S, and Inaguma S
- Abstract
Evidence for the tumor-supporting capacities of cancer-associated fibroblasts (CAFs) has rapidly been accumulating. To uncover clinicopathological importance of periostin (POSTN) expression in colorectal cancer (CRC), the present study immunohistochemically examined its expression status. Furthermore, to reveal its mechanisms involved, molecular experiments were performed. In CRC tissues, 44% of the cases (119/269) exhibited POSTN expression in the CAFs. In contrast, CRC cells expressed POSTN at almost undetectable levels. Survival analyses identified that patients with POSTN-positive CRC had a significantly worse 5-year survival rate (63.2% vs. 81.2%; p = 0.011). Univariate analyses revealed that POSTN positivity was associated with peritoneal ( p = 0.0031) and distant organ metastasis ( p < 0.001). Furthermore, immunohistochemical analyses identified a significant association between POSTN and p53 complete loss status in CRC cells. Decorin and fibroblast activation protein expression in CAFs was also associated with POSTN. POSTN significantly enhanced the migration of both CRC cells and fibroblasts with FAK and AKT or STAT3 activation, and co-culture assays demonstrated the communication between CRC cells and fibroblasts, which enhanced STAT3 activation in fibroblasts. On the basis of our results, we speculated that stromal POSTN accelerated metastasis via stromal remodeling capacity and activated the migration of both tumor and stromal cells.
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- 2023
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16. Alterations in key signaling pathways in sinonasal tract melanoma. A molecular genetics and immunohistochemical study of 90 cases and comprehensive review of the literature.
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Chłopek M, Lasota J, Thompson LDR, Szczepaniak M, Kuźniacka A, Hińcza K, Kubicka K, Kaczorowski M, Newford M, Liu Y, Agaimy A, Biernat W, Durzyńska M, Dziuba I, Hartmann A, Inaguma S, Iżycka-Świeszewska E, Kato H, Kopczyński J, Michal M, Michal M, Pęksa R, Prochorec-Sobieszek M, Starzyńska A, Takahashi S, Wasąg B, Kowalik A, and Miettinen M
- Subjects
- Male, Female, Humans, Aged, Proto-Oncogene Proteins B-raf genetics, In Situ Hybridization, Fluorescence, Mutation, Signal Transduction, Class I Phosphatidylinositol 3-Kinases genetics, TOR Serine-Threonine Kinases genetics, RNA, Molecular Biology, DNA Mutational Analysis, Melanoma genetics, Melanoma pathology, Paranasal Sinus Neoplasms genetics, Paranasal Sinus Neoplasms pathology, Paranasal Sinuses pathology
- Abstract
Sinonasal mucosal melanoma is a rare tumor arising within the nasal cavity, paranasal sinuses, or nasopharynx (sinonasal tract). This study evaluated 90 cases diagnosed in 29 males and 61 females with median age 68 years. Most tumors involved the nasal cavity and had an epithelioid morphology. Spectrum of research techniques used in this analysis includes targeted-DNA and -RNA next-generation sequencing, Sanger sequencing, fluorescence in situ hybridization and immunohistochemistry. Sinonasal melanomas were commonly driven by RAS (38/90, 42%), especially NRAS (n = 36) mutations and rarely (4/90, 4%) displayed BRAF pathogenic variants. BRAF/RAS mutants were more frequent among paranasal sinuses (10/14, 71%) than nasal (26/64, 41%) tumors. BRAF/RAS-wild type tumors occasionally harbored alterations of the key components and regulators of Ras-MAPK signaling pathway: NF1 mutations (1/17, 6%) or NF1 locus deletions (1/25, 4%), SPRED1 (3/25, 12%), PIK3CA (3/50, 6%), PTEN (4/50, 8%) and mTOR (1/50, 2%) mutations. These mutations often occurred in a mutually exclusive manner. In several tumors some of which were NRAS mutants, TP53 was deleted (6/48, 13%) and/or mutated (5/90, 6%). Variable nuclear accumulation of TP53, mirrored by elevated nuclear MDM2 expression was seen in >50% of cases. Furthermore, sinonasal melanomas (n = 7) including RAS/BRAF-wild type tumors (n = 5) harbored alterations of the key components and regulators of canonical WNT-pathway: APC (4/90, 4%), CTNNB1 (3/90, 3%) and AMER1 (1/90, 1%). Both, TERT promoter mutations (5/53, 9%) and fusions (2/40, 5%) were identified. The latter occurred in BRAF/RAS-wild type tumors. No oncogenic fusion gene transcripts previously reported in cutaneous melanomas were detected. Eight tumors including 7 BRAF/RAS-wild type cases expressed ADCK4::NUMBL cis-fusion transcripts. In summary, this study documented mutational activation of NRAS and other key components and regulators of Ras-MAPK signaling pathway such as SPRED1 in a majority of sinonasal melanomas., (© 2022. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)
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- 2022
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17. The Complete Loss of p53 Expression Uniquely Predicts Worse Prognosis in Colorectal Cancer.
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Nagao K, Koshino A, Sugimura-Nagata A, Nagano A, Komura M, Ueki A, Ebi M, Ogasawara N, Tsuzuki T, Kasai K, Takahashi S, Kasugai K, and Inaguma S
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- Activated-Leukocyte Cell Adhesion Molecule metabolism, Biomarkers, Tumor genetics, Biomarkers, Tumor metabolism, DNA Mismatch Repair, Female, Humans, Immunohistochemistry, Tumor Suppressor Protein p53 genetics, Colorectal Neoplasms pathology, Tumor Suppressor Protein p53 metabolism
- Abstract
p53 immunohistochemistry is considered an accurate surrogate marker reflecting the underlying TP53 mutation status and has utility in tumor diagnostics. In the present study, 269 primary CRCs were immunohistochemically evaluated for p53 expression to assess its utility in diagnostic pathology and prognostication. p53 expression was wild-type in 59 cases (23%), overexpressed in 143 cases (55%), completely lost in 50 cases (19%), and cytoplasmic in 10 cases (4%). p53 immunoreactivity was associated with tumor size (p = 0.0056), mucus production (p = 0.0015), and mismatch repair (MMR) system status (p < 0.0001). Furthermore, among CRCs with wild-type p53 expression, a significantly higher number of cases had decreased CDX2 than those with p53 overexpression (p = 0.012) or complete p53 loss (p = 0.043). In contrast, among CRCs with p53 overexpression, there were significantly fewer ALCAM-positive cases than p53 wild-type cases (p = 0.0045). However, no significant association was detected between p53 immunoreactivity and the “stem-like” immunophenotype defined by CDX2 downregulation and ALCAM-positivity. Multivariate Cox hazards regression analysis identified tubular-forming histology (hazard ratio [HR] = 0.17, p < 0.0001), younger age (HR = 0.52, p = 0.021), and female sex (HR = 0.55, p = 0.046) as potential favorable factors. The analysis also revealed complete p53 loss (HR = 2.16, p = 0.0087), incomplete resection (HR = 2.65, p = 0.0068), and peritoneal metastasis (HR = 5.32, p < 0.0001) as potential independent risk factors for patients with CRC. The sub-cohort survival analyses classified according to chemotherapy after surgery revealed that CRC patients with wild-type p53 expression tended to have better survival than those with overexpression or complete loss after chemotherapy. Thus, immunohistochemistry for p53 could be used for the prognostication and chemotherapy target selection of patients with CRC.
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- 2022
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18. SPATA18 Expression Predicts Favorable Clinical Outcome in Colorectal Cancer.
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Sugimura-Nagata A, Koshino A, Nagao K, Nagano A, Komura M, Ueki A, Ebi M, Ogasawara N, Tsuzuki T, Kasai K, Takahashi S, Kasugai K, and Inaguma S
- Subjects
- Aged, Biomarkers, Tumor genetics, Biomarkers, Tumor metabolism, Humans, Immunohistochemistry, Lymphatic Metastasis, Male, Mutation, Colorectal Neoplasms pathology, Mitochondrial Proteins metabolism, Tumor Suppressor Protein p53 genetics, Tumor Suppressor Protein p53 metabolism
- Abstract
Dysregulation of mitochondrial quality control has been reported to be associated with cancer and degenerative diseases. SPATA18 (spermatogenesis-associated 18, also known as Mieap) encodes a p53-inducible protein that can induce lysosome-like organelles within mitochondria that eliminate oxidized mitochondrial proteins and has tumor suppressor functions in mitochondrial quality control. In the present study, 268 primary colorectal cancers (CRCs) were evaluated immunohistochemically for SPATA18 expression to assess its predictive utility and its association with cellular proliferation activity. Furthermore, the association with p53 immunoreactivity, a surrogate marker for TP53 mutation, was analyzed. Non-neoplastic colonic mucosa showed cytoplasmic SPATA18 expression. Seventy-two percent of the lesions (193/268) displayed high SPATA18 expression in the cytoplasm of CRC cells. Univariate analyses revealed significant associations between SPATA18 expression and tumor size (p < 0.0001), histological differentiation (p = 0.0017), and lymph node metastasis (p = 0.00039). The log-rank test revealed that patients with SPATA18-high CRCs had significantly better survival than SPATA18-low patients (p < 0.0001). Multivariate Cox hazards regression analysis identified tubular-forming histology (hazard ratio [HR] = 0.25), age < 70 years (HR = 0.50), and SPATA18-high (HR = 0.55) as potential favorable factors. Lymph node metastasis (HR = 1.98) and peritoneal metastasis (HR = 5.45) were cited as potential independent risk factors. Cellular proliferation activity was significantly higher in SPATA18-high tumors. However, no significant correlation was detected between SPATA18 expression and p53 immunoreactivity or KRAS/BRAF mutation status. On the basis of our observations, SPATA18 immunohistochemistry can be used in the prognostication of CRC patients.
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- 2022
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19. The Risk Analyses of Lymph Node Metastasis and Recurrence for Submucosal Invasive Colorectal Cancer: Novel Criteria to Skip Completion Surgery.
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Ozeki T, Shimura T, Ozeki T, Ebi M, Iwasaki H, Kato H, Inaguma S, Okuda Y, Katano T, Nishie H, Takahashi S, and Kataoka H
- Abstract
(1) Background: Additional surgical resection after endoscopic resection (ER) is recommended for patients with submucosal invasive colorectal cancer (pT1 CRC) who have risk factors for lymph node metastasis (LNM) (high-risk pT1 CRC). This study aimed to identify risk factors for LNM and metastatic recurrence and to determine the low-risk population for whom additional surgery can be omitted among high-risk pT1 CRCs. (2) Methods: We retrospectively identified 404 patients with pT1 CRC who underwent ER or surgery, and patients were divided into three groups: low-risk ( n = 79); high-risk pT1 with ER ( n = 40); and high-risk with surgery ( n = 285). We also enrolled another 64 patients with high-risk pT1 CRC in an independent validation cohort. (3) Results: In the high-risk with surgery group, LNM was seen in 11.2%, and vascular and lymphatic invasions were significantly independent risk factors for LNM on multivariate analysis. No LNMs were observed in pT1 CRCs with a negative vertical margin and SM invasion depth ≤2000 µm that had no other risk factors except for budding. Five patients developed metastatic recurrence in the high-risk with surgery group, and rectal cancer and undifferentiated histology were significantly independent risk factors for poor relapse-free survival. No LNM or recurrent cases were seen in high-risk pT1 CRCs that met these criteria: differentiated adenocarcinoma, no lymphovascular invasion, colon cancer, SM invasion depth ≤2000 μm, and a negative vertical margin, which were validated in an independent validation cohort. (4) Conclusions: Completion surgery may be skipped for high-risk pT1 CRCs that meet our proposed criteria.
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- 2022
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20. PBK Enhances Cellular Proliferation With Histone H3 Phosphorylation and Suppresses Migration and Invasion With CDH1 Stabilization in Colorectal Cancer.
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Koshino A, Nagano A, Ota A, Hyodo T, Ueki A, Komura M, Sugimura-Nagata A, Ebi M, Ogasawara N, Kasai K, Hosokawa Y, Kasugai K, Takahashi S, and Inaguma S
- Abstract
Colorectal cancer (CRC) is one of the most frequent gastrointestinal malignancies with high morbidity and mortality rates. Several biological markers for the prognostication of patient outcome of CRCs are available. Recently, our group identified two favorable factors for the survival of CRC patients: PDZ-binding kinase (PBK) and phospho-histone H3 (PHH3). Both showed a significant inverse association to pT stage. The aim of this study was to uncover the mechanism through which these cellular proliferation-associated protein expressions lead to favorable clinical outcome in CRC patients. We first confirmed co-expression of PBK and PHH3 in CRC cells. Further investigation showed that aberrantly expressed PBK up-regulated the cellular proliferation of CRC cells with accumulation of PHH3. The PBK inhibitor OTS514 suppressed cellular proliferation of CRC cells through down-regulation of PHH3 and induction of apoptosis. In vitro studies revealed that PBK suppressed the migration and invasion of CRC cells with suppression of Wnt/β-catenin signaling and CDH1 stabilization. Exogeneous PBK up-regulated the phosphorylated CDH1 at S840, S846, and S847 residues in cultured cells. Recombinant PBK directly phosphorylated HH3; however, it failed to phosphorylate CDH1 directly in vitro . The present study demonstrated the association of two markers PBK and PHH3 in CRC. We further identified one of the potential mechanisms by which higher expression of these cellular proliferation-associated proteins leads to the better survival of CRC patients, which likely involves PBK-mediated suppression of the migration and invasion of CRC cells. Our findings suggest that PBK-targeting therapeutics may be useful for the treatment of CRC patients with PBK-expressing tumors., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Koshino, Nagano, Ota, Hyodo, Ueki, Komura, Sugimura-Nagata, Ebi, Ogasawara, Kasai, Hosokawa, Kasugai, Takahashi and Inaguma.)
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- 2022
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21. Lactoferrin Prevents Hepatic Injury and Fibrosis via the Inhibition of NF-κB Signaling in a Rat Non-Alcoholic Steatohepatitis Model.
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Aoyama Y, Naiki-Ito A, Xiaochen K, Komura M, Kato H, Nagayasu Y, Inaguma S, Tsuda H, Tomita M, Matsuo Y, Takiguchi S, and Takahashi S
- Subjects
- Animals, Anticarcinogenic Agents pharmacology, Carcinogenesis drug effects, Carcinoma, Hepatocellular drug therapy, Connexins metabolism, Cytokines metabolism, Dimethylnitrosamine adverse effects, Fibrosis prevention & control, Lactoferrin administration & dosage, Liver injuries, Liver Neoplasms drug therapy, Male, Non-alcoholic Fatty Liver Disease metabolism, Rats, Transforming Growth Factor beta1 metabolism, Tumor Necrosis Factor-alpha metabolism, Gap Junction beta-1 Protein, Lactoferrin pharmacology, Liver Cirrhosis prevention & control, NF-kappa B metabolism, Non-alcoholic Fatty Liver Disease drug therapy
- Abstract
Non-alcoholic steatohepatitis (NASH) can cause liver cirrhosis and hepatocellular carcinoma (HCC), with cases increasing worldwide. To reduce the incidence of liver cirrhosis and HCC, NASH is targeted for the development of treatments, along with viral hepatitis and alcoholic hepatitis. Lactoferrin (LF) has antioxidant, anti-cancer, and anti-inflammatory activities. However, whether LF affects NASH and fibrosis remains unelucidated. We aimed to clarify the chemopreventive effect of LF on NASH progression. We used a NASH model with metabolic syndrome established using connexin 32 (Cx32) dominant negative transgenic (Cx32ΔTg) rats. Cx32ΔTg rats (7 weeks old) were fed a high-fat diet and intraperitoneally injected with dimethylnitrosamine (DMN). Rats were divided into three groups for LF treatment at 0, 100, or 500 mg/kg/day for 17 weeks. Lactoferrin significantly protected steatosis and lobular inflammation in Cx32ΔTg rat livers and attenuated bridging fibrosis or liver cirrhosis induced by DMN. By quantitative RT-PCR, LF significantly down-regulated inflammatory ( Tnf-α , Il-6 , Il-18 , and Il-1β ) and fibrosis-related ( Tgf-β1 , Timp2 , and Col1a1 ) cytokine mRNAs. Phosphorylated nuclear factor (NF)-κB protein decreased in response to LF, while phosphorylated JNK protein was unaffected. These results indicate that LF might act as a chemopreventive agent to prevent hepatic injury, inflammation, and fibrosis in NASH via NF-κB inactivation.
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- 2021
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22. PBK expression predicts favorable survival in colorectal cancer patients.
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Nagano-Matsuo A, Inoue S, Koshino A, Ota A, Nakao K, Komura M, Kato H, Naiki-Ito A, Watanabe K, Nagayasu Y, Hosokawa Y, Takiguchi S, Kasugai K, Kasai K, Inaguma S, and Takahashi S
- Subjects
- Aged, Aged, 80 and over, Antineoplastic Agents pharmacology, Apoptosis drug effects, Biomarkers, Tumor antagonists & inhibitors, Caco-2 Cells, Cell Proliferation drug effects, Colorectal Neoplasms mortality, Colorectal Neoplasms pathology, Colorectal Neoplasms therapy, Extracellular Signal-Regulated MAP Kinases metabolism, Female, HCT116 Cells, Humans, Immunohistochemistry, Male, Middle Aged, Mitogen-Activated Protein Kinase Kinases antagonists & inhibitors, Neoplasm Staging, Phosphorylation, Protein Kinase Inhibitors pharmacology, Quinolones pharmacology, Risk Assessment, Risk Factors, Thiophenes pharmacology, Time Factors, Treatment Outcome, Biomarkers, Tumor metabolism, Colorectal Neoplasms enzymology, Mitogen-Activated Protein Kinase Kinases metabolism
- Abstract
Colorectal cancer (CRC) is one of the most common gastrointestinal cancers worldwide with high morbidity and mortality rates. The discovery of small molecule anticancer reagents has significantly affected cancer therapy. However, the anticancer effects of these therapies are not sufficient to completely cure CRC. PDZ-binding kinase (PBK) was initially identified as a mitotic kinase for mitogen-activated protein kinase and is involved in cytokinesis and spermatogenesis. Aberrant expression of PBK has been reported to be closely associated with malignant phenotypes of many cancers and/or patient survival. However, the expression of PBK and its association to patient survival in CRC have not been fully elucidated. In the present study, 269 primary CRCs were evaluated immunohistochemically for PBK expression to assess its ability as a prognostic factor. CRC tumor cells variably expressed PBK (range, 0-100%; median, 32%) in the nucleus and cytoplasm. Univariate analyses identified a significant inverse correlation between PBK expression and pT stage (P<0.0001). Furthermore, patients carrying CRC with higher PBK expression showed significantly favorable survival (P=0.0094). Multivariate Cox proportional hazards regression analysis revealed high PBK expression (HR, 0.52; P=0.015) as one of the potential favorable factors for CRC patients. PBK expression showed significant correlation to Ki-67 labeling indices (ρ=0.488, P<0.0001). In vitro, the PBK inhibitor OTS514 suppressed cellular proliferation of CRC cells with PBK expression through downregulation of P-ERK and induction of apoptosis. These results suggest that PBK-targeting therapeutics may be useful for the treatment of PBK-expressing CRC patients., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH, DE part of Springer Nature.)
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- 2021
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23. DPYD, down-regulated by the potentially chemopreventive agent luteolin, interacts with STAT3 in pancreatic cancer.
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Kato H, Naiki-Ito A, Suzuki S, Inaguma S, Komura M, Nakao K, Naiki T, Kachi K, Kato A, Matsuo Y, and Takahashi S
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- Aged, Animals, Apoptosis, Carcinoma, Pancreatic Ductal metabolism, Carcinoma, Pancreatic Ductal pathology, Cell Proliferation, Cricetinae, Female, Humans, Male, Mice, Pancreatic Neoplasms metabolism, Pancreatic Neoplasms pathology, Prognosis, STAT3 Transcription Factor genetics, Survival Rate, Tumor Cells, Cultured, Xenograft Model Antitumor Assays, Carcinoma, Pancreatic Ductal drug therapy, Dihydrouracil Dehydrogenase (NADP) antagonists & inhibitors, Gene Expression Regulation, Neoplastic drug effects, Luteolin pharmacology, Pancreatic Neoplasms drug therapy, STAT3 Transcription Factor metabolism
- Abstract
The 5-year survival rate of pancreatic ductal carcinoma (PDAC) patients is <10% despite progress in clinical medicine. Strategies to prevent the development of PDAC are urgently required. The flavonoids Luteolin (Lut) and hesperetin (Hes) may be cancer-chemopreventive, but effects on pancreatic carcinogenesis in vivo have not been studied. Here, the chemopreventive effects of Lut and Hes on pancreatic carcinogenesis are assessed in the BOP-induced hamster PDAC model. Lut but not Hes suppressed proliferation of pancreatic intraepithelial neoplasia (PanIN) and reduced the incidence and multiplicity of PDAC in this model. Lut also inhibited the proliferation of hamster and human pancreatic cancer cells in vitro. Multi-blot and microarray assays revealed decreased phosphorylated STAT3 (pSTAT3) and dihydropyrimidine dehydrogenase (DPYD) on Lut exposure. To explore the relationship between DPYD and STAT3 activity, the former was silenced by RNAi or overexpressed using expression vectors, and the latter was inactivated by small molecule inhibitors or stimulated by IL6 in human PDAC cells. DPYD knock-down decreased, and overexpression increased, pSTAT3 and cell proliferation. DPYD expression was decreased by inactivation of STAT3 and increased by its activation. The frequency of pSTAT3-positive cells and DPYD expression was significantly correlated and was decreased in parallel by Lut in the hamster PDAC model. Finally, immunohistochemical analysis in 73 cases of human PDAC demonstrated that DPYD expression was positively correlated with the Ki-67 labeling index, and high expression was associated with poor prognosis. These results indicate that Lut is a promising chemopreventive agent for PDAC, targeting a novel STAT3-DPYD pathway., (© The Author(s) 2021. Published by Oxford University Press.)
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- 2021
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24. Anti-Allergic Drug Suppressed Pancreatic Carcinogenesis via Down-Regulation of Cellular Proliferation.
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Kachi K, Kato H, Naiki-Ito A, Komura M, Nagano-Matsuo A, Naitoh I, Hayashi K, Kataoka H, Inaguma S, and Takahashi S
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- Animals, Carcinogens toxicity, Cricetinae, Humans, Male, Pancreatic Neoplasms metabolism, Pancreatic Neoplasms pathology, Tumor Cells, Cultured, Acetates pharmacology, Anti-Asthmatic Agents pharmacology, Cell Proliferation, Cyclopropanes pharmacology, Leukotriene D4 metabolism, Nitrosamines toxicity, Pancreatic Neoplasms drug therapy, Quinolines pharmacology, Receptors, Leukotriene metabolism, Sulfides pharmacology
- Abstract
Pancreatic cancer is a fatal disease, and thus its chemoprevention is an important issue. Based on the recent report that patients with allergic diseases have a low risk for pancreatic cancer, we examined the potential chemopreventive effect of anti-allergic agents using a hamster pancreatic carcinogenesis model. Among the three anti-allergic drugs administered, montelukast showed a tendency to suppress the incidence of pancreatic cancer. Further animal study revealed a significantly decreased incidence of pancreatic cancer in the high-dose montelukast group compared with controls. The development of the pancreatic intraepithelial neoplasia lesions was also significantly suppressed. The Ki-67 labeling index was significantly lower in pancreatic carcinomas in the high-dose montelukast group than in controls. In vitro experiments revealed that montelukast suppressed proliferation of pancreatic cancer cells in a dose-dependent manner with decreased expression of phospho-ERK1/2. Montelukast induced G1 phase arrest. Conversely, leukotriene D
4 (LTD4 ), an agonist of CYSLTR1, increased cellular proliferation of pancreatic cancer cells with an accumulation of phospho-ERK1/2. In our cohort, pancreatic ductal adenocarcinoma patients with high CYSLTR1 expression showed a significantly unfavorable clinical outcome compared with those with low expression. Our results indicate that montelukast exerts a chemopreventive effect on pancreatic cancer via the LTD4 -CYSLTR1 axis and has potential for treatment of pancreatic carcinogenesis.- Published
- 2021
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25. Suppressive Effect and Molecular Mechanism of Houttuynia cordata Thunb. Extract against Prostate Carcinogenesis and Castration-Resistant Prostate Cancer.
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Subhawa S, Naiki-Ito A, Kato H, Naiki T, Komura M, Nagano-Matsuo A, Yeewa R, Inaguma S, Chewonarin T, Banjerdpongchai R, and Takahashi S
- Abstract
Houttuynia cordata Thunb. (HCT) is a well-known Asian medicinal plant with biological activities used in the treatment of many diseases including cancer. This study investigated the effects of HCT extract and its ethyl acetate fraction (EA) on prostate carcinogenesis and castration-resistant prostate cancer (CRPC). HCT and EA induced apoptosis in androgen-sensitive prostate cancer cells (LNCaP) and CRPC cells (PCai1) through activation of caspases, down-regulation of androgen receptor, and inactivation of AKT/ERK/MAPK signaling. Rutin was found to be a major component in HCT (44.00 ± 5.61 mg/g) and EA (81.34 ± 5.21 mg/g) in a previous study. Rutin had similar effects to HCT/EA on LNCaP cells and was considered to be one of the active compounds. Moreover, HCT/EA inhibited cell migration and epithelial-mesenchymal transition phenotypes via STAT3/Snail/Twist pathways in LNCaP cells. The consumption of 1% HCT-mixed diet significantly decreased the incidence of adenocarcinoma in the lateral prostate lobe of the Transgenic rat for adenocarcinoma of prostate model. Similarly, tumor growth of PCai1 xenografts was significantly suppressed by 1% HCT treatment. HCT also induced caspase-dependent apoptosis via AKT inactivation in both in vivo models. Together, the results of in vitro and in vivo studies indicate that HCT has inhibitory effects against prostate carcinogenesis and CRPC. This plant therefore should receive more attention as a source for the future development of non-toxic chemopreventive agents against various cancers.
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- 2021
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26. High phospho-histone H3 expression uniquely predicts favorable survival among four markers of cellular proliferation in colorectal cancer.
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Koshino A, Inoue S, Sugimura-Nagata A, Nishiyama T, Murakami H, Ito H, Riku M, Inoko A, Ebi M, Ogasawara N, Tsuzuki T, Kasugai K, Kasai K, and Inaguma S
- Subjects
- Aged, Aged, 80 and over, Cell Proliferation, Female, Histones analysis, Humans, Immunohistochemistry, Ki-67 Antigen analysis, Male, Middle Aged, Prognosis, Biomarkers, Tumor analysis, Colorectal Neoplasms diagnosis, Colorectal Neoplasms pathology
- Abstract
Colorectal cancer (CRC) is one of the most frequent gastrointestinal cancers worldwide, with high morbidity and mortality rates. Despite numerous attempts to identify prognostic markers for the CRC patients, the significance of the association of cellular proliferation markers with survival is controversial. Here we used immunohistochemistry to detect four markers of cellular proliferation expressed in primary CRC tissue specimens (n = 269) to assess their potential to serve as prognostic factors. CRC cells variably expressed phospho-histone H3 (PHH3) (range, 0-76 per high-powered field (HPF); median, 7 per HPF), cyclin A (CCNA) (range, 11.3-73.7%; median, 32%), geminin (GMNN) (range, 7.8-82.0%; median, 37.1%), and marker of proliferation Ki-67 (MKI67) (range, 4.9-96.6%; median, 49.6%). Among them, patients with PHH3-high (≥7 per HPF) tumors uniquely experienced significantly longer 5-year survival than those with PHH3-low (≤6 per HPF) (81.8% vs. 65.5%; P = 0.0047). Multivariable Cox hazards regression analysis identified PHH3-high (hazard ratio, 0.54; 95% confidence interval, 0.31-0.92; P = 0.025) as potential favorable factors. PHH3 levels inversely associated with pT stage (P < 0.0001) and were significantly and inversely associated with tumor diameter (ρ = -0.314, P < 0.0001). These findings support the use of PHH3 immunohistochemistry for predicting the prognoses of patients with CRC., (© 2021 Japanese Society of Pathology and John Wiley & Sons Australia, Ltd.)
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- 2021
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27. Expression and Prognostic Significance of CD47-SIRPA Macrophage Checkpoint Molecules in Colorectal Cancer.
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Sugimura-Nagata A, Koshino A, Inoue S, Matsuo-Nagano A, Komura M, Riku M, Ito H, Inoko A, Murakami H, Ebi M, Ogasawara N, Tsuzuki T, Takahashi S, Kasugai K, Kasai K, and Inaguma S
- Subjects
- Aged, Aged, 80 and over, Antigens, CD metabolism, Antigens, Differentiation, Myelomonocytic metabolism, Biomarkers, Tumor metabolism, Colorectal Neoplasms metabolism, Colorectal Neoplasms surgery, Female, Humans, Intestinal Mucosa metabolism, Intestinal Mucosa pathology, Macrophages metabolism, Macrophages pathology, Male, Middle Aged, Prognosis, Receptors, Cell Surface metabolism, Survival Analysis, Antigens, Differentiation metabolism, CD47 Antigen metabolism, Colorectal Neoplasms mortality, Colorectal Neoplasms pathology, Receptors, Immunologic metabolism
- Abstract
Despite the confirmed anti-cancer effects of T-cell immune checkpoint inhibitors, in colorectal cancer (CRC) they are only effective in a small subset of patients with microsatellite-unstable tumors. Thus, therapeutics targeting other types of CRCs or tumors refractory to T-cell checkpoint inhibitors are desired. The binding of aberrantly expressed CD47 on tumor cells to signal regulatory protein-alpha (SIRPA) on macrophages allows tumor cells to evade immune destruction. Based on these observations, drugs targeting the macrophage checkpoint have been developed with the expectation of anti-cancer effects against T-cell immune checkpoint inhibitor-refractory tumors. In the present study, 269 primary CRCs were evaluated immunohistochemically for CD47, SIRPA, CD68, and CD163 expression to assess their predictive utility and the applicability of CD47-SIRPA axis-modulating drugs. Thirty-five percent of the lesions (95/269) displayed CD47 expression on the cytomembrane of CRC cells. CRCs contained various numbers of tumor-associated immune cells (TAIs) with SIRPA, CD68, or CD163 expression. The log-rank test revealed that patients with CD47-positive CRCs had significantly worse survival than CD47-negative patients. Multivariate Cox hazards regression analysis identified tubular-forming histology (hazard ratio (R) = 0.23), age < 70 years (HR = 0.48), and high SIRPA-positive TAI counts (HR = 0.55) as potential favorable factors. High tumor CD47 expression (HR = 1.75), lymph node metastasis (HR = 2.26), and peritoneal metastasis (HR = 5.80) were cited as potential independent risk factors. Based on our observations, CD47-SIRPA pathway-modulating therapies may be effective in patients with CRC.
- Published
- 2021
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28. A novel model of non-alcoholic steatohepatitis with fibrosis and carcinogenesis in connexin 32 dominant-negative transgenic rats.
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Naiki-Ito A, Kato H, Naiki T, Yeewa R, Aoyama Y, Nagayasu Y, Suzuki S, Inaguma S, and Takahashi S
- Subjects
- Animals, Cell Transformation, Neoplastic genetics, Cell Transformation, Neoplastic pathology, Connexins genetics, Cytokines metabolism, Diet, High-Fat, Dimethylnitrosamine, Disease Progression, Inflammation Mediators metabolism, Insulin Resistance, JNK Mitogen-Activated Protein Kinases metabolism, Liver pathology, Liver Cirrhosis, Experimental genetics, Liver Cirrhosis, Experimental metabolism, Liver Cirrhosis, Experimental pathology, Liver Neoplasms, Experimental genetics, Liver Neoplasms, Experimental metabolism, Liver Neoplasms, Experimental pathology, Male, NF-kappa B metabolism, Non-alcoholic Fatty Liver Disease genetics, Non-alcoholic Fatty Liver Disease metabolism, Non-alcoholic Fatty Liver Disease pathology, Rats, Transgenic, Signal Transduction, Gap Junction beta-1 Protein, Cell Transformation, Neoplastic metabolism, Connexins metabolism, Liver metabolism, Liver Cirrhosis, Experimental etiology, Liver Neoplasms, Experimental etiology, Non-alcoholic Fatty Liver Disease etiology
- Abstract
Non-alcoholic steatohepatitis (NASH) is a recognized risk factor for liver fibrosis and malignancies, and is associated with features of metabolic syndrome, such as obesity and insulin resistance (IR). We previously demonstrated that the disturbance of connexin 32 (Cx32), a gap junctional protein of hepatocytes, exacerbated NASH in Cx32 dominant-negative transgenic (Cx32ΔTg) rats fed methionine choline-deficient diet (MCDD). MCDD is well-established means of inducing NASH in rodents; however, the Cx32ΔTg-MCDD NASH model does not reproduce obesity and IR. In this study, we aimed to establish an improved NASH model. Eight-week-old male Cx32ΔTg and wild-type (Wt) rats received a high-fat diet (HFD) with dimethylnitrosamine (DMN) for 12 weeks. The HFD with DMN led to gains in body, liver, and visceral fat weights in both genotypes. IR was significantly greater in Cx32ΔTg than in Wt rats. Elevation of serum hepatic enzymes (AST, ALT), inflammatory cytokine expressions (Tnfα, Il-6, Tgf-β1, Il-1β, Timp2, and Col1a1), steatohepatitis, and fibrosis were significantly greater in Cx32ΔTg as compared with Wt rats. Regarding carcinogenesis, the number and area of glutathione S-transferase placental form (GST-P)-positive preneoplastic hepatic foci were significantly increased in Cx32ΔTg versus Wt rats. Moreover, activation of NF-κB and JNK contributed to the progression of NASH in Cx32ΔTg rats. These results suggest that Cx32 dysfunction promoted the progression of NASH, metabolic syndrome, and carcinogenesis. Therefore, the novel Cx32ΔTg-HFD-DMN NASH model may be a rapid and useful tool for evaluating the progression of NASH.
- Published
- 2020
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29. The standard form of CD44 as a marker for invasion of encapsulated papillary carcinoma of the breast.
- Author
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Kato H, Naiki-Ito A, Yamada T, Suzuki S, Yamashita Y, Inaguma S, Kondo N, Wanifuchi-Endo Y, Toyama T, and Takahashi S
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- Aged, Aged, 80 and over, Antigens, CD metabolism, Antigens, Differentiation, Myelomonocytic metabolism, Breast metabolism, Carcinoma in Situ metabolism, Carcinoma in Situ pathology, Carcinoma, Papillary diagnosis, Female, Humans, Immunohistochemistry methods, Middle Aged, Receptors, Cell Surface metabolism, Biomarkers, Tumor analysis, Breast pathology, Breast Neoplasms metabolism, Carcinoma, Papillary pathology, Hyaluronan Receptors metabolism
- Abstract
Encapsulated papillary carcinoma (EPC), a rare variant of papillary carcinoma of the breast, is regarded as a transition form between carcinoma in situ and invasive carcinoma. Here, we tried to identify differences in immunohistochemical phenotype between 10 EPCs with invasive properties (EPC with invasion) and 17 non-invasive EPCs (EPC). We immunohistochemically assessed the expression of hormone receptors, matrix metalloproteinase (MMP) 2 and MMP9, vascular endothelial growth factor (VEGF), CD31, and D2-40, markers of tumor-associated macrophages (CD163, CD206), Ki-67 and stem cell markers (CD44 and CD24). The frequency of MMP9-positive cases and the number of tumor-associated macrophages infiltrating into the fibrous capsule were significantly higher in EPC with invasion than in EPC. The expression of the standard form of CD44 (CD44s) was significantly stronger in EPC with invasion than in EPC (P = 0.0036) and was correlated with MMP2 expression and M2-like macrophage infiltration. A multivariate logistic model analysis showed that CD44s expression in tumor cell and infiltration of CD163 positive macrophage in EPC capsule showed an independent odds ratio for invasion of EPC. Thus, CD44s may be a potential marker predicting invasive potential of EPC and could play an important role in progression to the invasive phase of EPC., (© 2020 Japanese Society of Pathology and John Wiley & Sons Australia, Ltd.)
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- 2020
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30. Colorectal Adenocarcinomas Harboring ALK Fusion Genes: A Clinicopathologic and Molecular Genetic Study of 12 Cases and Review of the Literature.
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Lasota J, Chłopek M, Wasąg B, Kowalik A, Christiansen J, Lamoureux J, Kuźniacka A, Felisiak-Gołąbek A, Liu Y, Reyes TAR, Saha R, Agaimy A, Behenska K, Biernat W, Cattaneo L, Centonze G, Daum O, Daumova M, Domagała P, Dziuba I, Geppert CE, Góźdź S, Nasierowska-Guttmejer A, Hałoń A, Hartmann A, Inaguma S, Iżycka-Świeszewska E, Kaczorowski M, Kołos M, Kopczyński J, Michal M, Milione M, Okoń K, Pęksa R, Pyzlak M, Ryś J, Waloszczyk P, Wejman J, and Miettinen M
- Subjects
- Adenocarcinoma chemistry, Adenocarcinoma secondary, Adenocarcinoma therapy, Aged, Biomarkers, Tumor analysis, Colorectal Neoplasms chemistry, Colorectal Neoplasms pathology, Colorectal Neoplasms therapy, DNA Mutational Analysis, Europe, Female, Genetic Predisposition to Disease, Humans, Immunohistochemistry, In Situ Hybridization, Fluorescence, Japan, Lymphatic Metastasis, Male, Mutation, Neoplasm Staging, Phenotype, Treatment Outcome, United States, Adenocarcinoma genetics, Anaplastic Lymphoma Kinase genetics, Biomarkers, Tumor genetics, Colorectal Neoplasms genetics, Gene Fusion, Gene Rearrangement
- Abstract
This study determined the frequency and the clinicopathologic and genetic features of colorectal carcinomas driven by oncogenic fusions of the anaplastic lymphoma kinase gene (ALK). Of the 8150 screened tumors, 12 (0.15%) were immunohistochemically ALK-positive with D5F3 antibody. These cancers harbored CAD-ALK (n=1), DIAPH2-ALK (n=2), EML4-ALK (n=2), LOC101929227-ALK (n=1), SLMAP-ALK (n=1), SPTBN1-ALK (n=4), and STRN-ALK (n=1) fusions, as detected by an RNA-based next-generation sequencing assay. ALK fusion carcinomas were diagnosed mostly in older patients with a 9:3 female predominance (median age: 72 y). All tumors, except a rectal one, occurred in the right colon. Most tumors were stage T3 (n=7) or T4 (n=3). Local lymph node and distant metastases were seen at presentation in 9 and 2 patients. These tumors showed moderate (n=6) or poor (n=3) glandular differentiation, solid medullary growth pattern (n=2), and pure mucinous morphology (n=1). DNA mismatch repair-deficient phenotype was identified in 10 cases. Tumor-infiltrating lymphocytes were prominent in 9 carcinomas. In 4 carcinomas, tumor cells showed strong, focal (n=3), or diffuse programmed death-ligand 1 immunoreactivity. CDX2 expression and loss of CK20 and MUC2 expression were frequent. CK7 was expressed in 5 tumors. Four patients died of disease within 3 years, and 7 were alive with follow-up ranging from 1 to 8 years. No mutations in BRAF, RAS, and in genes encoding components of PI3K-AKT/MTOR pathway were identified. However, 1 tumor had a loss-of-function PTEN mutation. Aberration of p53 signaling, TP53 mutations, and/or nuclear accumulation of p53 protein was seen in 9 cases. ALK fusion colorectal carcinomas are a distinct and rare subtype of colorectal cancers displaying some features of mismatch repair-deficient tumors.
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- 2020
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31. Recruitment of miR-8080 by luteolin inhibits androgen receptor splice variant 7 expression in castration-resistant prostate cancer.
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Naiki-Ito A, Naiki T, Kato H, Iida K, Etani T, Nagayasu Y, Suzuki S, Yamashita Y, Inaguma S, Onishi M, Tanaka Y, Yasui T, and Takahashi S
- Subjects
- Androgen Receptor Antagonists therapeutic use, Animals, Antioxidants therapeutic use, Apoptosis drug effects, Carcinogenesis drug effects, Caspase 3 metabolism, Caspase 7 metabolism, Cell Line, Tumor, Chemoprevention, Humans, Luteolin therapeutic use, Male, Mice, Mice, Nude, MicroRNAs genetics, Neovascularization, Pathologic drug therapy, Prostatic Neoplasms, Castration-Resistant prevention & control, Protein Isoforms antagonists & inhibitors, Rats, Rats, Sprague-Dawley, Rats, Transgenic, Receptors, Androgen genetics, Xenograft Model Antitumor Assays, Androgen Receptor Antagonists pharmacology, Antioxidants pharmacology, Luteolin pharmacology, MicroRNAs metabolism, Prostatic Neoplasms, Castration-Resistant drug therapy, Receptors, Androgen metabolism
- Abstract
A need exists for seeking effective treatments for castration-resistant prostate cancer (CRPC) in response to its emergence following androgen deprivation therapy as a major clinical problem. In the present study, we investigated the chemopreventive and chemotherapeutic potential of luteolin, a flavonoid with antioxidative properties, on prostate cancer, including CRPC. Luteolin inhibited the progression of rat prostate carcinogenesis by induction of apoptosis in a transgenic rat for adenocarcinoma of prostate (TRAP) model. Luteolin decreased cell proliferation in a dose-dependent manner and induced apoptosis with the activation of caspases 3 and 7 in both rat (PCai1, established from a TRAP prostate tumor) and human (22Rv1) CRPC cells. Dietary luteolin also suppressed tumor growth via an increase in apoptosis and inhibition of angiogenesis in PCai1 and 22Rv1 xenografts implanted in castrated nude mice. We also focused on androgen receptor splice variant 7 (AR-V7), which contributes to cell proliferation and therapeutic resistance in CRPC. Luteolin dramatically suppressed AR-V7 protein expression in 22Rv1 cells in vitro and ex vivo. Microarray analysis identified MiR-8080, which contains a possible target sequence for AR-V7 3'-UTR, as a gene upregulated by luteolin. MiR-8080 transfection decreased the AR-V7 expression level and the induction of apoptosis in 22Rv1 cells. Furthermore, miR-8080 knockdown canceled luteolin decreasing AR-V7 and the cell growth of 22Rv1. MiR-8080 induced by luteolin intake enhanced the therapeutic effect of enzalutamide on 22Rv1 xenografts under castration conditions. These results indicate luteolin inhibits CRPC by AR-V7 suppression through miR-8080, highlighting luteolin and miR-8080 as promising therapeutic agents for this disease., (© The Author(s) 2019. Published by Oxford University Press.)
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- 2020
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32. Novel Interleukin-6 Inducible Gene PDZ-Binding Kinase Promotes Tumor Growth of Multiple Myeloma Cells.
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Ota A, Hanamura I, Karnan S, Inaguma S, Takei N, Lam VQ, Mizuno S, Kanasugi J, Wahiduzzaman M, Rahman ML, Hyodo T, Konishi H, Tsuzuki S, Ikeda H, Takami A, and Hosokawa Y
- Subjects
- Amino Acid Substitution, Animals, Apoptosis, Cell Line, Tumor, Cell Proliferation drug effects, Disease Models, Animal, Dose-Response Relationship, Drug, Female, Gene Editing, Gene Expression Profiling, Gene Knockdown Techniques, Genetic Loci, Humans, Mice, Mitogen-Activated Protein Kinase Kinases antagonists & inhibitors, Mitogen-Activated Protein Kinase Kinases metabolism, Multiple Myeloma mortality, Multiple Myeloma pathology, Phosphorylation, Prognosis, Protein Kinase Inhibitors pharmacology, STAT3 Transcription Factor, Transcriptome, Gene Expression Regulation, Enzymologic, Gene Expression Regulation, Neoplastic, Interleukin-6 metabolism, Mitogen-Activated Protein Kinase Kinases genetics, Multiple Myeloma genetics, Multiple Myeloma metabolism
- Abstract
[Figure: see text] Multiple myeloma (MM) remains an intractable hematological malignancy, despite recent advances in anti-MM drugs. Here, we show that role of PDZ binding kinase (PBK) in MM tumor growth. We identified that interleukin-6 (IL-6) readily increases PBK expression. Kaplan-Meier analysis showed that the MM patients with higher expression of PBK have a significant shorter survival time compared with those with moderate/lower expression of PBK. Knockout of PBK dramatically suppressed in vivo tumor growth in MM cells, while genome editing of PBK changing from asparagine to serine substitution (rs3779620) slightly suppresses the tumor formation. Mechanistically, loss of PBK increased the number of apoptotic cells with concomitant decrease in the phosphorylation level of Stat3 as well as caspase activities. A novel PBK inhibitor OTS514 significantly decreased KMS-11-derived tumor growth. These findings highlight the novel oncogenic role of PBK in tumor growth of myeloma, and it might be a novel therapeutic target for the treatment of patients with MM.
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- 2020
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33. Diffuse mesothelin expression leads to worse prognosis through enhanced cellular proliferation in colorectal cancer.
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Inoue S, Tsunoda T, Riku M, Ito H, Inoko A, Murakami H, Ebi M, Ogasawara N, Pastan I, Kasugai K, Kasai K, Ikeda H, and Inaguma S
- Abstract
Mesothelin (MSLN) is a glycophosphatidylinositol (GPI)-linked cell surface protein that is highly expressed in several types of malignant tumor, including malignant pleural mesothelioma, ovarian cancer and pancreatic adenocarcinoma. Recently, a comprehensive immunohistochemical study using MN-1 monoclonal antibody identified a significant number of colorectal tumors in which MSLN was expressed. However, the clinicopathological profiles and survival of patients with MSLN-positive colorectal cancer have not been fully analyzed. In the current study, the expression of MSLN in 270 primary and 44 metastatic colorectal tumors was immunohistochemically analyzed to determine the clinical usefulness of MSLN immunohistochemistry and to identify potential candidates for future anti-MSLN therapy. In vitro experiments using colon cancer cell lines were performed to investigate the biological significance of MSLN expression in tumors. The results of univariate analyses identified a significant correlation between MSLN expression and females (P=0.0042). Furthermore, an inverse correlation between MSLN expression and solid/sheet-like proliferation (P=0.014) was also revealed. Additionally, overall survival was significantly shorter in patients with diffuse luminal/membranous expression of MSLN (P=0.018). Multivariable Cox hazards regression analysis revealed diffuse MSLN expression (hazard ratio, 2.26; 95% confidence interval, 1.04-4.91; P=0.039) as a potential risk factor. When comparing primary CRCs and the metastasis of each, a weakly positive correlation was identified for MSLN positivity (% positive cells; R=0.484; P<0.0001). The in vitro experiments revealed a positive role for MSLN in colon cancer cell proliferation. Thus, MSLN immunohistochemistry may be useful in the prognostication of patients with CRC. The results demonstrated that significant numbers of patients with MSLN-positive CRC exhibiting metastasis could be targeted by anti-MSLN therapies., (Copyright: © Inoue et al.)
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- 2020
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34. Indispensable role of STIL in the regulation of cancer cell motility through the lamellipodial accumulation of ARHGEF7-PAK1 complex.
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Ito H, Tsunoda T, Riku M, Inaguma S, Inoko A, Murakami H, Ikeda H, Matsuda M, and Kasai K
- Subjects
- Actins, Apoptosis, Biomarkers, Tumor genetics, Cell Membrane metabolism, Cell Proliferation, Cytoskeleton, Gene Expression Regulation, Neoplastic, Humans, Intracellular Signaling Peptides and Proteins genetics, Neoplasms genetics, Neoplasms metabolism, Phosphorylation, Rho Guanine Nucleotide Exchange Factors genetics, Tumor Cells, Cultured, p21-Activated Kinases genetics, Biomarkers, Tumor metabolism, Cell Movement, Intracellular Signaling Peptides and Proteins metabolism, Neoplasms pathology, Pseudopodia physiology, Rho Guanine Nucleotide Exchange Factors metabolism, p21-Activated Kinases metabolism
- Abstract
Cell motility is a tightly regulated phenomenon that supports the accurate formation of organ structure during development and homeostasis, including wound healing and inflammation. Meanwhile, cancer cells exhibit dysregulated motility, which causes spreading and invasion. The Dbl family RhoGEF ARHGEF7/β-PIX and its binding partner p21-activated kinase PAK1 are overexpressed in a variety of cancers and have been shown to be responsible for cancer cell migration. A key step in motility is the intracellular transport of ARHGEF7-PAK1 complex to the migrating front of cells, where lamellipodia protrusion and cytoskeletal remodeling efficiently occur. However, the molecular mechanisms of the intracellular transport of this complex are not fully understood. Here we revealed that SCL/TAL1-interrupting locus (STIL) is indispensable for the efficient migration of cancer cells. STIL forms a ternary complex with ARHGEF7 and PAK1 and accumulates with those proteins at the lamellipodia protrusion of motile cells. Knockdown of STIL impedes the accumulation of ARHGEF7-PAK1 complex within membrane ruffles and attenuates the phosphorylation of PAK1 substrates and cortical actin remodeling at the migrating front. Intriguingly, ARHGEF7 knockdown also diminishes STIL and PAK1 accumulation in membrane ruffles. Either STIL or ARHGEF7 knockdown impedes cell migration and Rac1 activity at the migrating front of cells. These results indicate that STIL is involved in the ARHGEF7-mediated positive-feedback activation of cytoskeletal remodeling through accumulating the ARHGEF7-PAK1 complex in lamellipodia. We conclude that its involvement is crucial for the polarized formation of Rac1-mediated leading edge, which supports the efficient migration of cancer cells.
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- 2020
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35. CD70 expression correlates with a worse prognosis in malignant pleural mesothelioma patients via immune evasion and enhanced invasiveness.
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Inaguma S, Lasota J, Czapiewski P, Langfort R, Rys J, Szpor J, Waloszczyk P, Okoń K, Biernat W, Schrump DS, Hassan R, Kasai K, Miettinen M, and Ikeda H
- Subjects
- Adult, Aged, Aged, 80 and over, Animals, Antigens, CD metabolism, Forkhead Transcription Factors metabolism, Heterografts, Humans, Kaplan-Meier Estimate, Lung Neoplasms pathology, Lymphocytes, Tumor-Infiltrating immunology, Mesothelioma pathology, Mesothelioma, Malignant, Mice, Inbred NOD, Middle Aged, Neoplasm Invasiveness, Neoplasm Transplantation, Pleural Neoplasms pathology, Prognosis, Programmed Cell Death 1 Receptor metabolism, Biomarkers, Tumor metabolism, CD27 Ligand metabolism, Lung Neoplasms immunology, Mesothelioma immunology, Pleural Neoplasms immunology, Tumor Escape immunology
- Abstract
Diffuse malignant mesothelioma of the pleura (MPM) is a highly aggressive tumour that typically is associated with short survival. CD70 and CD27 belong to the tumour necrosis factor (TNF) and the TNF receptor (TNFR) superfamily, respectively. Under physiological conditions, the tightly regulated interaction between CD70 and CD27 plays a co-stimulatory role in promoting T-cell expansion and differentiation through the NFκB pathway. Aberrantly high CD70 expression has been documented in haematological and solid malignancies in association with immune evasion in malignant cells. In this study, 172 well-characterised primary diffuse MPM tumours including epithelioid (n = 145), biphasic (n = 15), and sarcomatoid (n = 12) histotypes were evaluated immunohistochemically for CD70, CD27, CD3, CD4, CD8, CD56, PDCD1 (PD-1), and FOXP3 expression. Twenty per cent (34/172) of the mesothelioma cells expressed CD70 on the cell membrane. Overall survival was significantly decreased in the cohort of patients with CD70-expressing tumour cells (p < 0.01). Patients with MPM containing a higher number of CD3
+ (p < 0.01), CD4+ (p < 0.01), CD8+ (p < 0.01), or FOXP3+ (p < 0.01) tumour-infiltrating lymphoid cells (TILs) showed significantly worse clinical outcomes. As potential independent risk factors for MPM patients, multivariate Cox proportional hazards regression analysis revealed CD70 expression on mesothelioma cells [hazard ratio (HR) 2.25; p = 0.010], higher FOXP3+ TILs (HR 2.81; p = 0.004), and higher CD3+ TIL accumulation (HR 6.12; p < 0.001). In contrast, as a potential independent favourable factor, higher CD27+ TIL accumulation (HR 0.48; p = 0.037) was identified. In vitro experiments and an immunodeficient mouse model revealed that CD70 enhances the invasiveness of MPM cells through MET-ERK axis activation. Further analyses in syngeneic mouse models demonstrated possible roles for CD70 in immune evasion. Collectively, these findings suggest that the CD70-CD27 pathway enhances the malignant phenotypes of MPM and diminishes anti-tumor immune response in patients with these neoplasms. These markers might be useful in MPM for prognostic evaluations as well as targeted therapeutics. © 2019 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd., (© 2019 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.)- Published
- 2020
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36. Colonic Adenocarcinomas Harboring NTRK Fusion Genes: A Clinicopathologic and Molecular Genetic Study of 16 Cases and Review of the Literature.
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Lasota J, Chłopek M, Lamoureux J, Christiansen J, Kowalik A, Wasąg B, Felisiak-Gołąbek A, Agaimy A, Biernat W, Canzonieri V, Centonze G, Chmielik E, Daum O, Dubová M, Dziuba I, Goertz S, Góźdź S, Guttmejer-Nasierowska A, Haglund C, Hałoń A, Hartmann A, Inaguma S, Iżycka-Świeszewska E, Kaczorowski M, Kita P, Kołos M, Kopczyński J, Michal M, Milione M, Okoń K, Pęksa R, Pyzlak M, Ristimäki A, Ryś J, Szostak B, Szpor J, Szumiło J, Teresiński L, Waloszczyk P, Wejman J, Wesołowski W, and Miettinen M
- Subjects
- Adenocarcinoma pathology, Aged, Aged, 80 and over, Biomarkers, Tumor metabolism, Colonic Neoplasms pathology, Female, Follow-Up Studies, Gene Expression Regulation, Neoplastic, Humans, Immunohistochemistry, Male, Membrane Glycoproteins genetics, Membrane Glycoproteins metabolism, Middle Aged, Neoplasm Staging, Oncogene Fusion, Oncogene Proteins, Fusion metabolism, Receptor Protein-Tyrosine Kinases metabolism, Receptor, trkA genetics, Receptor, trkA metabolism, Receptor, trkB genetics, Receptor, trkB metabolism, Receptor, trkC genetics, Receptor, trkC metabolism, Adenocarcinoma diagnosis, Adenocarcinoma genetics, Biomarkers, Tumor genetics, Colonic Neoplasms diagnosis, Colonic Neoplasms genetics, Oncogene Proteins, Fusion genetics, Receptor Protein-Tyrosine Kinases genetics
- Abstract
This study was undertaken to determine the frequency, and the clinicopathologic and genetic features, of colon cancers driven by neurotrophic receptor tyrosine kinase (NTRK) gene fusions. Of the 7008 tumors screened for NTRK expression using a pan-Trk antibody, 16 (0.23%) had Trk immunoreactivity. ArcherDx assay detected TPM3-NTRK1 (n=9), LMNA-NTRK1 (n=3), TPR-NTRK1 (n=2) and EML4-NTRK3 (n=1) fusion transcripts in 15 cases with sufficient RNA quality. Patients were predominantly women (median age: 63 y). The tumors involved the right (n=12) and left colon unequally and were either stage T3 (n=12) or T4. Local lymph node and distant metastases were seen at presentation in 6 and 1 patients, respectively. Lymphovascular invasion was present in all cases. Histologically, tumors showed moderate to poor (n=11) differentiation with a partly or entirely solid pattern (n=5) and mucinous component (n=10), including 1 case with sheets of signet ring cells. DNA mismatch repair-deficient phenotype was seen in 13 cases. Tumor-infiltrating CD4/CD8 lymphocytes were prominent in 9 cases. Programmed death-ligand 1 positive tumor-infiltrating immune cells and focal tumor cell positivity were seen in the majority of cases. CDX2 expression and loss of CK20 and MUC2 expression were frequent. CK7 was expressed in 5 cases. No mutations in BRAF, RAS, and PIK3CA were identified. However, other genes of the PI3K-AKT/MTOR pathway were mutated. In several cases, components of Wnt/β-catenin (APC, AMER1, CTNNB1), p53, and TGFβ (ACVR2A, TGFBR2) pathways were mutated. However, no SMAD4 mutations were found. Two tumors harbored FBXW7 tumor suppressor gene mutations. NTRK fusion tumors constitute a distinct but rare subgroup of colorectal carcinomas.
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- 2020
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37. Sporadic neurofibroma of transverse colon in a patient without neurofibromatosis type 1: A case report.
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Imagami T, Sugita S, Nagasaki T, Kimura M, Ito K, and Inaguma S
- Abstract
Introduction: The occurrence of sporadic colonic neurofibroma particularly in a patient without neurofibromatosis type 1 has been rarely reported. Therefore, the clinical significance of this disease has not been fully elucidated., Presentation of Case: An 81-year-old woman with a positive fecal occult blood test result was referred to our institution for the evaluation of anemia. On colonoscopy, a 50-mm submucosal tumor-like mass was found in the hepatic flexure of the colon. Superficial biopsy and boring biopsy showed unspecific granulation tissues, and immunostaining revealed that the mesenchymal tumor was negative for CD34, c-kit, desmin, and S100 protein. The patient underwent laparoscopic right colectomy with complete mesocolic excision (CME). Pathologically, the tumor was diagnosed as neurofibroma., Discussion: Gastrointestinal neurofibromas are known to cause clinical symptoms. No colonic neurofibroma has been diagnosed before resection. Moreover, neurofibromas, particularly large lesions, reportedly undergo malignant transformation. Surgical extirpation with clear margins is the primary treatment, and laparoscopic surgery is considered acceptable for colonic neurofibroma and colon cancer., Conclusion: Based on our experience, a preoperative diagnosis was impossible for colonic neurofibroma. Laparoscopic surgery with CME is considered feasible for sporadic colonic neurofibroma., (Copyright © 2020 The Author(s). Published by Elsevier Ltd.. All rights reserved.)
- Published
- 2020
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38. CD70 expression in tumor-associated fibroblasts predicts worse survival in colorectal cancer patients.
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Inoue S, Ito H, Tsunoda T, Murakami H, Ebi M, Ogasawara N, Kasugai K, Kasai K, Ikeda H, and Inaguma S
- Subjects
- Adult, Aged, Biomarkers, Tumor analysis, Biomarkers, Tumor immunology, CD27 Ligand analysis, CD27 Ligand immunology, Colorectal Neoplasms mortality, Female, Humans, Male, Middle Aged, Tumor Necrosis Factor Receptor Superfamily, Member 7 biosynthesis, Tumor Necrosis Factor Receptor Superfamily, Member 7 immunology, CD27 Ligand biosynthesis, Cancer-Associated Fibroblasts immunology, Colorectal Neoplasms immunology, Colorectal Neoplasms pathology
- Abstract
The anticancer effects of immune checkpoint inhibitors against CTLA4 and CD274-PDCD1 axes are evident. However, these immunotherapies for colorectal cancers (CRCs) are now limited to a small subset of patients with microsatellite unstable tumors. Thus, therapeutics targeting other types of CRCs is desired. The CD70-CD27 axis plays a co-stimulatory role in promoting the expansion and differentiation of T-lymphocytes through the activation of NFκB pathway. Aberrant activation of the CD70-CD27 axis accelerates tumor cell proliferation, survival, and immune evasion of tumor cells. Based on these observations, drugs modulating the CD70-CD27 axis have been developed with expectation of anticancer effects. In the present study, 269 primary CRCs were evaluated immunohistochemically for CD70, CD27, and FOXP3 expression to assess their clinical usage and the application of CD70-CD27 axis modulating drugs. CRC tumor cells rarely (2.2%) expressed CD70. In contrast, tumor-surrounding fibroblasts showed various CD70 expressions (fCD70) in 14.9%. The logistic regression analysis revealed significant association of fCD70 expression with incomplete resection status (OR, 2.60; 95% CI, 1.10-6.13; P = 0.029). Overall survival was significantly decreased in the cohort of the patients with fCD70-positive tumor (P = 0.0078). Furthermore, significantly more CD27+ tumor-associated lymphocytes were detected within the primary CRCs without metastases (P = 0.024). Thus, the CD70-CD27 axis may have several roles in CRCs independent from their mismatch repair (MMR) system status. CD70-CD27 pathway-modulating therapies may be applied to CRC patients regardless of their tumor MMR status.
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- 2019
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39. Epithelioid variant of gastrointestinal stromal tumor harboring PDGFRA mutation and MLH1 gene alteration: A case report.
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Kobayashi M, Inaguma S, Raffeld M, Kato H, Suzuki S, Wakasugi T, Mitsui A, Kuwabara Y, Lasota J, Ikeda H, Miettinen M, and Takahashi S
- Subjects
- Amino Acid Substitution, Anoctamin-1 immunology, Epithelioid Cells pathology, Exons genetics, Female, Gastrointestinal Neoplasms drug therapy, Gastrointestinal Neoplasms genetics, Gastrointestinal Neoplasms pathology, Gastrointestinal Stromal Tumors drug therapy, Gastrointestinal Stromal Tumors genetics, Gastrointestinal Stromal Tumors pathology, Gastrointestinal Tract pathology, Humans, Middle Aged, Mutation, Neoplasm Proteins immunology, Proto-Oncogene Proteins c-kit immunology, Antineoplastic Agents therapeutic use, Gastrointestinal Neoplasms diagnostic imaging, Gastrointestinal Stromal Tumors diagnostic imaging, Imatinib Mesylate therapeutic use, MutL Protein Homolog 1 genetics, Receptor, Platelet-Derived Growth Factor alpha genetics
- Abstract
Gastrointestinal stromal tumors (GISTs) are the most important and common mesenchymal tumors of the gastrointestinal tract, especially in the stomach. GISTs are usually driven by activating mutations in either KIT or PDGFRA genes. It is known that activating gene mutations predicts, to a certain extent, not only the morphology of the tumor cells but also a response to treatment with tyrosine kinase inhibitors. Here, we present a case of an epithelioid variant of GIST harboring PDGFRA and MLH1 gene alterations in the stomach of a 55-year-old Japanese woman. The tumor of 98 mm with multiple cysts showed exophytic growth from the gastric fundus. Histopathologically, it consisted of scattered medium-sized epithelioid tumor cells in a loose myxoid background. Based on c-kit and DOG-1 immunoreactivity and a PDGFRA mutation (p.Trp559_Arg560del), the tumor was diagnosed as an epithelioid variant GIST. Interestingly, it had a gene alteration (p.Met524Ile) in the MLH1 gene of unknown pathogenicity. It was assigned to Group 3a (low risk for malignant behavior). After surgery, the patient has been on imatinib therapy and disease-free for 10 months., (© 2019 Japanese Society of Pathology and John Wiley & Sons Australia, Ltd.)
- Published
- 2019
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40. SP174 Antibody Lacks Specificity for NRAS Q61R and Cross-Reacts With HRAS and KRAS Q61R Mutant Proteins in Malignant Melanoma.
- Author
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Felisiak-Goląbek A, Inaguma S, Kowalik A, Wasąg B, Wang ZF, Zięba S, Pięciak L, Ryś J, Kopczynski J, Sarlomo-Rikala M, Góźdź S, Lasota J, and Miettinen M
- Subjects
- Adolescent, Adult, Aged, Aged, 80 and over, Animals, Antibodies, Monoclonal chemistry, Binding Sites, Antibody, Female, Humans, Male, Melanoma genetics, Melanoma physiopathology, Middle Aged, Mutation, Proto-Oncogene Proteins p21(ras) genetics, Rats, Antibodies, Monoclonal metabolism, GTP Phosphohydrolases metabolism, Immunohistochemistry standards, Melanoma diagnosis, Membrane Proteins metabolism, Proto-Oncogene Proteins p21(ras) metabolism, Receptors, Purinergic P2 metabolism
- Abstract
HRAS, KRAS, and NRAS, highly homologous proteins, are often mutationally activated in cancer. Usually, mutations cluster in codons 12, 13, and 61 and are detected by molecular genetic testing of tumor DNA. Recently, immunohistochemistry with SP174 antibody has been introduced to detect NRAS Q61R-mutant protein. Studies on malignant melanomas showed that such an approach could be a viable alternative to molecular genetic testing. This investigation was undertaken to evaluate the value of SP174 immunohistochemistry for detection of NRAS Q61R-mutant isoform. Two hundred ninety-two malignant melanomas were evaluated using Leica Bond-Max automated immunostainer. Twenty-nine tumors (10%) showed positive immunoreactivity. NRAS codon 61 was polymerase chain reaction amplified and sequenced in 24 positive and 92 negative cases using Sanger sequencing, quantitative polymerase chain reaction, and next-generation sequencing approaches. A c.182A>G substitution leading to NRAS Q61R mutation was identified in 22 tumors. Two NRAS wild-type tumors revealed c.182A>G substitutions in HRAS and KRAS codon 61, respectively. Both mutations were detected by next-generation sequencing and independently confirmed by Sanger sequencing. None of 85 NRAS codon 61 wild-type tumors and 7 NRAS mutants other than Q61R showed immunoreactivity with SP174 antibody. Thus, SP174 antibody was 100% sensitive in detecting NRAS Q61R-mutant isoform in malignant melanoma, but not fully specific as it cross-reacted with HRAS and KRAS Q61R-mutant proteins. Therefore, molecular testing is needed to determine which RAS gene is mutated. The rarity of HRAS and KRAS Q61R mutants in malignant melanoma let previous investigations erroneously conclude that SP174 is specific for NRAS Q61R-mutant protein.
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- 2018
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41. Expression of ALCAM (CD166) and PD-L1 (CD274) independently predicts shorter survival in malignant pleural mesothelioma.
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Inaguma S, Lasota J, Wang Z, Czapiewski P, Langfort R, Rys J, Szpor J, Waloszczyk P, Okoń K, Biernat W, Ikeda H, Schrump DS, Hassan R, and Miettinen M
- Subjects
- Adult, Aged, Female, Humans, Male, Mesothelioma, Malignant, Middle Aged, Prognosis, Proportional Hazards Models, Antigens, CD biosynthesis, B7-H1 Antigen biosynthesis, Biomarkers, Tumor analysis, Cell Adhesion Molecules, Neuronal biosynthesis, Fetal Proteins biosynthesis, Lung Neoplasms pathology, Mesothelioma pathology, Pleural Neoplasms pathology
- Abstract
Diffuse malignant mesothelioma of the pleura is a highly aggressive tumor typically associated with short survival. ALCAM (CD166), a type I transmembrane protein, is a member of the immunoglobulin superfamily. In normal cells, ALCAM regulates physiological processes such as angiogenesis and immune response. In cancer, it is associated with neoplastic progression, including invasion, migration, and metastasis. Furthermore, ALCAM is considered one of the cancer stem cell markers such as ALDH1 (ALDH1A1) and SALL4. The PD-L1 (CD274)/PD-1 (PDCD1, CD279) pathway is crucial for the modulation of immune responses in normal cells. Nevertheless, pathologic activation of the PD-L1/PD-1 pathway participates in immune evasion by tumor cells. Many PD-L1-expressing tumor cells have been identified in different types of cancer, including malignant mesothelioma. In this study, 175 well-characterized primary diffuse pleural mesotheliomas, including the epithelioid (n = 148), biphasic (n = 15), and sarcomatoid (n = 12) histotypes, were evaluated immunohistochemically for cancer stem cell markers (ALCAM, ALDH1, and SALL4) and PD-L1 expression. Twenty-five percent of the mesotheliomas (43/175) expressed ALCAM, whereas ALDH1 and SALL4 positivity was seen in 1% to 2% of cases. Thirty-three percent of the analyzed tumors (57/175) contained PD-L1-positive cells. Overall survival was significantly decreased in the cohort of patients with ALCAM- or PD-L1-positive tumors (both P < .01). Furthermore, the multivariate Cox hazards regression analysis identified ALCAM and PD-L1 (both P < 0.01) as potential independent risk factors. Thus, a combination of these 2 markers might be useful for prognostication and planning the treatment of patients with malignant pleural mesothelioma., (Copyright © 2017 Elsevier Inc. All rights reserved.)
- Published
- 2018
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42. Histopathological and genotypic characterization of metastatic colorectal carcinoma with PD-L1 (CD274)-expression: Possible roles of tumour micro environmental factors for CD274 expression.
- Author
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Inaguma S, Lasota J, Felisiak-Golabek A, Kowalik A, Wang Z, Zieba S, Kalisz J, Ikeda H, and Miettinen M
- Abstract
Aberrant PD-L1 (CD274) expression has been described in different types of tumour and linked to tumour aggressiveness and a poor prognosis. In primary colorectal carcinomas (CRCs), CD274 expression was reported to be associated with mismatch repair (MMR)-deficiency, BRAF mutation, and "stem-like" immunophenotype defined by down-regulation of homeobox protein CDX2 and membranous expression of activated leukocyte cell adhesion molecule (ALCAM). However, the immunophenotype and genotype of CD274-positive metastatic CRC have not been extensively analysed. In this study, 189 CRC metastases were evaluated immunohistochemically for CD274, MMR proteins, CDX2, and ALCAM expression. Immunostaining for CD4, CD8, and FOXP3 was also performed to characterize tumour-associated immune cells. In addition, 34 arbitrarily selected lesions were genotyped using Sanger- and next-generation sequencing. Univariate analyses showed no clear association between CD274 expression and clinicopathological parameters including MMR-deficiency or "stem-like" immunophenotype after adjustment for multiple testing. Comparison of the clinicopathological profiles of CD274-positive primary and metastatic tumours revealed in the latter younger age of occurrence (60.9 ± 13.3 versus 72.6 ± 13.1 years, p = 0.001), cytoplasm-dominant CD274 expression ( p < 0.001), infrequent MMR-deficiency ( p < 0.001), and common KRAS mutations (54%, p < 0.001). In five cultured colon cancer cell lines, CD274 was expressed and modulated after exogenous exposure to IFNγ and TGF-β1. Thus, CD274 regulation mechanisms might include tumour micro environmental factors. Based on significantly different characteristics in CD274-positive metastatic and primary CRCs, evaluation of metastases should also be considered when planning immune checkpoint inhibitor therapy.
- Published
- 2017
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43. GIST Manifesting as a Retroperitoneal Tumor: Clinicopathologic Immunohistochemical, and Molecular Genetic Study of 112 Cases.
- Author
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Miettinen M, Felisiak-Golabek A, Wang Z, Inaguma S, and Lasota J
- Subjects
- Adult, Aged, Aged, 80 and over, Anoctamin-1, Biopsy, Chloride Channels analysis, Female, Gastrointestinal Stromal Tumors chemistry, Gastrointestinal Stromal Tumors genetics, Gastrointestinal Stromal Tumors pathology, Genetic Predisposition to Disease, Humans, Kaplan-Meier Estimate, Male, Middle Aged, Mitotic Index, Multivariate Analysis, Mutation, Neoplasm Proteins analysis, Phenotype, Predictive Value of Tests, Prognosis, Proportional Hazards Models, Proto-Oncogene Proteins c-kit analysis, Proto-Oncogene Proteins c-kit genetics, Receptor, Platelet-Derived Growth Factor alpha genetics, Retroperitoneal Neoplasms chemistry, Retroperitoneal Neoplasms genetics, Retroperitoneal Neoplasms pathology, Risk Factors, Succinate Dehydrogenase analysis, Survival Rate, Time Factors, Tumor Burden, Young Adult, Biomarkers, Tumor analysis, Biomarkers, Tumor genetics, DNA Mutational Analysis, Gastrointestinal Stromal Tumors diagnosis, Immunohistochemistry, Molecular Diagnostic Techniques, Retroperitoneal Neoplasms diagnosis
- Abstract
Most gastrointestinal stromal tumors (GISTs) occur in the tubular gastrointestinal (GI) tract, but some present apparently outside the GI tract. In this study, we analyzed 112 GISTs located in the retroperitoneum. These tumors occurred in 55 women and 57 men with a median age of 65 years (range: 21 to 89 y). On the basis of clinically or histologically detected connections to GI tract, 15 tumors were considered likely of gastric, 9 duodenal, and 13 of small intestinal origin. The remaining cases were categorized by location as peripancreatic (n=25), pelvic (n=11), mesenteric (n=4), and of unspecified/miscellaneous sites (n=35). The tumors varied in size 3 to 35 cm (median, 15 cm) and by mitotic rate per 5 mm, 0 to >100 (median, 10). Histologically the tumors apparently arising outside the GI tract had features of intestinal (n=41) and gastric GISTs (n=25); 9 cases had indeterminate histology. The histologic variants included spindled, epithelioid, vacuolated, nested, and myxoid potentially simulating other tumors such as liposarcoma and solitary fibrous tumor. Most GISTs were KIT-positive (106/112 cases), and the remaining 6 tumors were DOG1/Ano1-positive. Five cases showed focal nuclear positivity for MDM2. KIT mutations were detected in 42/59 cases, and PDGFRA mutations in 4/16 KIT wild-type and 3/5 of the KIT-negative tumors analyzed. One pelvic retroperitoneal GIST was succinate dehydrogenase deficient. All 79 patients were dead at last follow-up with a median survival of 14 months, with few survivals >5 years. Only operable versus inoperable tumor was a statistically favorable factor in univariate analysis (P<0.01). In multivariate analysis, mitotic rate >50/5 mm was significant for a shorter survival (hazard ratio, 5.25; 95% confidence interval, 1.65-16.8; P<0.01). Histologic and clinicopathologic similarity of extragastrointestinal retroperitoneal GISTs with GISTs of GI tract suggests their GI tract origin. Potentially overlapping features between GIST and other retroperitoneal tumors necessitate use of multiple diagnostic markers and molecular genetic studies.
- Published
- 2017
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44. Comprehensive immunohistochemical study of mesothelin (MSLN) using different monoclonal antibodies 5B2 and MN-1 in 1562 tumors with evaluation of its prognostic value in malignant pleural mesothelioma.
- Author
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Inaguma S, Wang Z, Lasota J, Onda M, Czapiewski P, Langfort R, Rys J, Szpor J, Waloszczyk P, Okoń K, Biernat W, Ikeda H, Schrump DS, Hassan R, Pastan I, and Miettinen M
- Subjects
- Antibodies, Monoclonal, Diagnosis, Differential, Gene Expression, Humans, Immunohistochemistry, Lung Neoplasms diagnosis, Lung Neoplasms genetics, Mesothelin, Mesothelioma diagnosis, Mesothelioma genetics, Mesothelioma, Malignant, Mutation, Pleural Neoplasms diagnosis, Pleural Neoplasms genetics, Prognosis, Survival Analysis, Biomarkers, Tumor, GPI-Linked Proteins metabolism, Lung Neoplasms metabolism, Lung Neoplasms mortality, Mesothelioma metabolism, Mesothelioma mortality, Pleural Neoplasms metabolism, Pleural Neoplasms mortality
- Abstract
Mesothelin (MSLN) is a glycophosphatidylinositol (GPI)-linked cell surface protein highly expressed in several types of malignant tumors sometimes in association with increased tumor aggressiveness and poor clinical outcome. In the present study, 1562 tumors were immunohistochemically analyzed for mesothelin expression using two different types of mouse monoclonal antibodies (5B2 and MN-1) to determine the clinical usefulness of mesothelin immunohistochemistry as well as to pinpoint potential targets for future anti-mesothelin therapy. Also, characterization of selected mesothelin-positive tumors was performed by immunohistochemistry and oncogene sequencing. Among the tumors analyzed, the highest frequencies of mesothelin-positivity were detected in ovarian serous carcinoma (90% in 5B2 and 94% in MN-1). Both antibodies showed frequent positivity in pancreatic adenocarcinoma (71% using 5B2 and 87% using MN-1) and malignant pleural mesothelioma (75% using 5B2 and 78% using MN-1). In malignant mesothelioma, overall survival was significantly longer in the cohort of patients with diffuse membranous expression of mesothelin (P < 0.001). Both antibodies showed positive staining in thymic carcinoma (77% in 5B2 and 59% in MN-1), however, no expression was detected in thymoma. No correlation was detected between mesothelin expression and mismatch repair system deficient phenotype or gene mutation (BRAF and RAS) status in gastrointestinal adenocarcinomas. Mesothelin immunohistochemistry may assist the differential diagnosis of thymoma vs. thymic carcinoma as well as prognostication of mesothelioma patients. Our results demonstrate that patients with solid tumors expressing mesothelin could be targeted by anti-mesothelin therapies.
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- 2017
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45. SP174, NRAS Q61R Mutant-Specific Antibody, Cross-Reacts With KRAS Q61R Mutant Protein in Colorectal Carcinoma.
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Lasota J, Kowalik A, Felisiak-Golabek A, Inaguma S, Wang ZF, Pięciak L, Zięba S, Pęksa R, Kopczynski J, Okoń K, Waloszczyk P, Gozdz S, Biernat W, and Miettinen M
- Subjects
- Base Sequence, Cohort Studies, Colorectal Neoplasms diagnosis, Colorectal Neoplasms genetics, GTP Phosphohydrolases genetics, Genetic Testing methods, High-Throughput Nucleotide Sequencing, Humans, Immunohistochemistry methods, Membrane Proteins genetics, Polymerase Chain Reaction, Proto-Oncogene Proteins p21(ras) genetics, Proto-Oncogene Proteins p21(ras) immunology, Reproducibility of Results, Sensitivity and Specificity, Sequence Analysis, DNA, Antibodies immunology, Colorectal Neoplasms immunology, Cross Reactions immunology, GTP Phosphohydrolases immunology, Membrane Proteins immunology, Mutant Proteins immunology, Mutation, Missense immunology
- Abstract
Context: - NRAS is a member of the RAS family oncoproteins implicated in cancer. Gain-of-function NRAS mutations were reported in a subset of colorectal cancers. These mutations occur at codons 12, 13, and 61 and are detected by molecular genetic testing. Recently, an antibody (clone SP174) became available to immunohistochemically pinpoint NRAS Q61R mutant protein. In malignant melanoma, NRAS Q61R mutant-specific immunohistochemistry was shown to be a valuable supplement to traditional genetic testing., Objective: - To evaluate the significance of NRAS Q61R mutant-specific immunohistochemistry in a cohort of colorectal carcinomas., Design: - A total of 1185 colorectal carcinomas were immunohistochemically evaluated with SP174 antibody. NRAS Q61R mutant-specific immunohistochemistry was validated by molecular genetic testing including Sanger sequencing, quantitative polymerase chain reaction (qPCR), and next-generation sequencing., Results: - Twelve tumors showed strong SP174 immunoreactivity. Sanger sequencing detected an identical c.182A>G substitution, causing NRAS Q61R mutation at the protein level, only in 8 SP174-positive cases. These results were confirmed by qPCR study. Subsequently, NRAS wild-type tumors with strong SP174 staining were evaluated by next-generation sequencing and revealed KRAS c.182A>G substitutions predicted to cause KRAS Q61R mutation. Review of colorectal carcinomas with known KRAS and NRAS genotype revealed that none of 62 wild-type tumors or 47 mutants other than Q61R were SP174 positive., Conclusion: - SP174 immunohistochemistry allows sensitive detection of NRAS and KRAS Q61R mutants. However, molecular genetic testing is necessary to determine specifically which RAS gene is mutated.
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- 2017
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46. A Rho-Associated Kinase Inhibitor Protects Permeability in a Cell Culture Model of Ocular Disease, and Reduces Aqueous Flare in Anterior Uveitis.
- Author
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Yamada H, Yoneda M, Inaguma S, Gosho M, Murasawa Y, Isogai Z, and Zako M
- Subjects
- Adult, Aged, Betamethasone administration & dosage, Betamethasone pharmacology, Cell Culture Techniques, Cell Membrane Permeability drug effects, Cells, Cultured, Female, Glaucoma drug therapy, Glaucoma pathology, Humans, Isoquinolines administration & dosage, Male, Middle Aged, Ocular Hypertension drug therapy, Ocular Hypertension pathology, Ophthalmic Solutions administration & dosage, Retrospective Studies, Sulfonamides administration & dosage, Uveitis, Anterior pathology, rho-Associated Kinases antagonists & inhibitors, rho-Associated Kinases metabolism, Aqueous Humor drug effects, Betamethasone analogs & derivatives, Isoquinolines pharmacology, Ophthalmic Solutions pharmacology, Protein Kinase Inhibitors pharmacology, Sulfonamides pharmacology, Uveitis, Anterior drug therapy
- Abstract
Purpose: Recent clinical and experimental studies have reported favorable results when using Rho-associated kinase (ROCK) inhibitors for ocular disease, and in cell culture. Disruption of the human, nonpigmented ciliary epithelial cells (HNPCECs) that comprise the blood-aqueous barrier (BAB) induces anterior uveitis; these cells therefore provide a useful cell model of ocular disease. In this study, we examined the effects of ROCK inhibitors in anterior uveitis and in HNPCECs., Methods: Aqueous flare values and intraocular pressures (IOPs) were determined in patients with anterior uveitis, 2 weeks after administration of ripasudil hydrochloride hydrate, a commercial ROCK inhibitor used to treat glaucoma or ocular hypertension. We also investigated the effects of Y-27632, a second ROCK inhibitor, in HNPCECs following exposure to matrix metalloproteinases (MMPs) and human tumor necrosis factor-alpha (TNF-α)., Results: Patients with anterior uveitis, glaucoma, or ocular hypertension, referred to the Aichi Medical University from February to July 2015, were enrolled. Thirty eyes from 25 outpatients were studied. Aqueous flare values and IOPs were significantly decreased 2 weeks after ripasudil hydrochloride hydrate treatment, with no adverse events. In a cultured HNPCEC monolayer, permeability was markedly increased following exposure to MMPs-1, 3, 9, and TNF-α, with these effects attenuated by exposure to Y-27632. In cultured HNPCECs, Y-27632 provoked a marked alteration in cytoskeletal morphology without a significant change in expression levels of claudin-1 and occludin., Conclusion: ROCK inhibitors may confer favorable effects in anterior uveitis, possibly due to a reorganized BAB, although the relevant mechanisms remain unclear.
- Published
- 2017
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47. Clinicopathologic profile, immunophenotype, and genotype of CD274 (PD-L1)-positive colorectal carcinomas.
- Author
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Inaguma S, Lasota J, Wang Z, Felisiak-Golabek A, Ikeda H, and Miettinen M
- Subjects
- Aged, Aged, 80 and over, Aldehyde Dehydrogenase genetics, Aldehyde Dehydrogenase metabolism, Aldehyde Dehydrogenase 1 Family, Antigens, CD genetics, Antigens, CD metabolism, B7-H1 Antigen genetics, CDX2 Transcription Factor genetics, CDX2 Transcription Factor metabolism, Carcinoma, Medullary genetics, Carcinoma, Medullary metabolism, Cell Adhesion Molecules, Neuronal genetics, Cell Adhesion Molecules, Neuronal metabolism, Colorectal Neoplasms genetics, Colorectal Neoplasms metabolism, DNA Mismatch Repair genetics, DNA Mutational Analysis, Female, Fetal Proteins genetics, Fetal Proteins metabolism, Genotype, Humans, Immunohistochemistry, Immunophenotyping, Male, Middle Aged, Mutation, Proto-Oncogene Proteins B-raf genetics, Proto-Oncogene Proteins B-raf metabolism, Retinal Dehydrogenase, Transcription Factors genetics, Transcription Factors metabolism, B7-H1 Antigen metabolism, Carcinoma, Medullary pathology, Colorectal Neoplasms pathology
- Abstract
The CD274 (PD-L1)/PDCD1 (PD-1) pathway is crucial for the modulation of immune responses and self-tolerance. Aberrantly expressed CD274 allows tumor cells to evade host immune system and is considered to be a mechanism of adaptive immune resistance. Inhibition of the CD274/PDCD1 immune checkpoint offers a promising new therapeutic strategy. Although CD274-expressing tumor cells have been identified in different types of tumors including colorectal cancer, clinicopathologic profile of these CD274-positive tumors has not been extensively studied. In this study, 454 primary colorectal carcinomas were analyzed histologically and immunohistochemically for CD274, mismatch repair (MMR) proteins, intestinal differentiation marker (CDX2), and stem cell markers (ALCAM, ALDH1A1, and SALL4). CD274-positive colorectal carcinomas (54/454 (12%)) usually (83%) involved the right or transverse colon with poorly differentiated and solid/medullary histology. On the basis of multivariate logistic regression analysis, CD274 positivity was significantly associated with poorly differentiated histotype (OR: 3.32; 95% CI: 1.46-7.51; P=0.004), MMR deficiency (OR: 10.0; 95% CI: 4.66-21.5; P<0.001), and 'stem-like' immunophenotype defined by the loss or weak expression of CDX2 and ALCAM-positivity (OR: 5.51; 95% CI: 1.66-18.3; P=0.005). Mutation analysis of 66 arbitrary selected colorectal carcinomas revealed that CD274-positive tumors usually (88%) carried the BRAF V600E mutation. Thus, colorectal carcinomas defined by CD274 positivity displayed features associated with tumors arising via the serrated neoplasia pathway. Moreover, colorectal carcinomas characterized by lack of CDX2 and prominent expression of ALCAM frequently (71%) showed CD274 positivity. This might suggest association of CD274 expression with 'stem-like' phenotype. Further evaluation of a larger cohort or experimental analyses would be needed to confirm this notion.
- Published
- 2017
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48. Expression of neural cell adhesion molecule L1 (CD171) in neuroectodermal and other tumors: An immunohistochemical study of 5155 tumors and critical evaluation of CD171 prognostic value in gastrointestinal stromal tumors.
- Author
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Inaguma S, Wang Z, Lasota JP, and Miettinen MM
- Subjects
- Adult, Aged, Aged, 80 and over, Female, Gastrointestinal Neoplasms mortality, Gastrointestinal Stromal Tumors mortality, Humans, Immunohistochemistry, Male, Middle Aged, Neuroectodermal Tumors mortality, Prognosis, Gastrointestinal Neoplasms chemistry, Gastrointestinal Stromal Tumors chemistry, Neural Cell Adhesion Molecule L1 analysis, Neuroectodermal Tumors chemistry
- Abstract
The neural cell adhesion molecule L1 (CD171) is a multidomain type 1 membrane glycoprotein of the immunoglobulin superfamily important in the nervous system development, kidney morphogenesis, and maintenance of the immune system. Recent studies reported CD171 expression being associated with adverse clinical outcome in different types of cancer and there has been a growing interest in targeting this cell membrane molecule on neoplastic cells by chimeric antigen receptor redirected T lymphocytes or specific antibodies. Nevertheless, conflicting results regarding the prognostic value of CD171 expression in renal cell carcinomas and gastrointestinal stromal tumors were published. In this study, CD171 expression was immunohistochemically analyzed in 5155 epithelial, mesenchymal, melanocytic, and lymphohematopoietic tumors to assess its utility in diagnostic pathology and to pinpoint potential targets for CD171-targeting therapy. A newly developed anti-CD171 rabbit monoclonal antibody, clone 014, was selected from the panel of commercially available CD171 antibodies. Immunohistochemistry was performed using Leica Bond Max automation and multitumor blocks containing up to 60 tumor samples. CD171 was constitutively and strongly expressed in neuroectodermal tumors such as schwannoma, neuroblastoma, and paraganglioma, whereas other mesenchymal tumors including schwannoma mimics showed only rarely CD171 positivity. Frequent CD171-expression was also detected in ovarian serous carcinoma, malignant mesothelioma, and testicular embryonal carcinoma. CD171 immunohistochemistry may have some role in immunophenotypic differential diagnosis of neurogenic tumors and pinpointing potential candidates for anti-CD171 therapy. Though, because of its rare expression and lack of predictive value, CD171 is neither a diagnostic nor prognostic marker for gastrointestinal stromal tumors.
- Published
- 2016
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49. Comprehensive Immunohistochemical Study of Programmed Cell Death Ligand 1 (PD-L1): Analysis in 5536 Cases Revealed Consistent Expression in Trophoblastic Tumors.
- Author
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Inaguma S, Wang Z, Lasota J, Sarlomo-Rikala M, McCue PA, Ikeda H, and Miettinen M
- Subjects
- B7-H1 Antigen analysis, Female, Humans, Immunohistochemistry, Pregnancy, B7-H1 Antigen biosynthesis, Biomarkers, Tumor analysis, Trophoblastic Neoplasms, Uterine Neoplasms
- Abstract
Programmed cell death 1/programmed cell death ligand (PD-1/PD-Ls) axis is crucial for the modulation of immune responses and self-tolerance. Also, aberrant PD-L1 expression on the tumor cells or tumor-associated inflammatory cells accelerates immune evasion of tumor cells. In the past decade, PD-1/PD-L immune checkpoint inhibitors were introduced to cancer treatment trials and, in some cases, showed significant anticancer effects. PD-L1 immunohistochemical staining is considered a potential predictor of clinical response to PD-1/PD-L immune checkpoint inhibitor treatment. However, immunohistochemical data on PD-L1 expression in different types of cancer especially rare entities remain incomplete. In this study, PD-L1 expression was immunohistochemically analyzed in 5536 tumors including germ cell, epithelial, mesenchymal, melanocytic/neuroectodermal, and lymphohematopoietic tumors, as well as in a set of human normal tissues including a fetus. Immunohistochemical analysis was performed with E1L3N rabbit monoclonal antibody and Leica Bond Max automation using multitumor blocks containing up to 70 tumor samples. PD-L1 was constitutively and strongly expressed in placental trophoblasts as well as choriocarcinomas and trophoblastic components of germ cell tumors. Also, the neoplastic cells of classical Hodgkin lymphoma, anaplastic large cell lymphoma, schwannoma, thymoma, and squamous cell carcinoma of various sites frequently expressed PD-L1. In gastrointestinal adenocarcinomas, PD-L1-expression was associated with EBER positivity and mismatch-repair deficiency. In addition, PD-L1 was variably expressed in non-neoplastic macrophages and dendritic cells. PD-L1 immunohistochemistry may have some role in the immunophenotypic differential diagnosis of tumors and pinpointing potential candidates for anti-PD-1/PD-L immune checkpoint therapy.
- Published
- 2016
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50. Down-regulation of the zinc-finger homeobox protein TSHZ2 releases GLI1 from the nuclear repressor complex to restore its transcriptional activity during mammary tumorigenesis.
- Author
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Riku M, Inaguma S, Ito H, Tsunoda T, Ikeda H, and Kasai K
- Subjects
- Apoptosis, Blotting, Western, Breast metabolism, Breast Neoplasms genetics, Breast Neoplasms metabolism, Carboxypeptidases genetics, Carboxypeptidases metabolism, Carcinoma, Ductal, Breast genetics, Carcinoma, Ductal, Breast metabolism, Carcinoma, Ductal, Breast pathology, Carcinoma, Intraductal, Noninfiltrating genetics, Carcinoma, Intraductal, Noninfiltrating metabolism, Carcinoma, Intraductal, Noninfiltrating pathology, Carcinoma, Lobular genetics, Carcinoma, Lobular metabolism, Carcinoma, Lobular pathology, Case-Control Studies, Cell Proliferation, Cell Transformation, Neoplastic pathology, Cells, Cultured, Female, Humans, Immunoenzyme Techniques, Immunoprecipitation, RNA, Messenger genetics, Real-Time Polymerase Chain Reaction, Receptors, CXCR4 genetics, Receptors, CXCR4 metabolism, Repressor Proteins genetics, Reverse Transcriptase Polymerase Chain Reaction, Transcriptional Activation, Zinc Finger Protein GLI1 genetics, Breast pathology, Breast Neoplasms pathology, Cell Transformation, Neoplastic genetics, Gene Expression Regulation, Neoplastic, Repressor Proteins metabolism, Zinc Finger Protein GLI1 metabolism
- Abstract
Although breast cancer is one of the most common malignancies, the molecular mechanisms underlying its development and progression are not fully understood. To identify key molecules involved, we screened publicly available microarray datasets for genes differentially expressed between breast cancers and normal mammary glands. We found that three of the genes predicted in this analysis were differentially expressed among human mammary tissues and cell lines. Of these genes, we focused on the role of the zinc-finger homeobox protein TSHZ2, which is down-regulated in breast cancer cells. We found that TSHZ2 is a nuclear protein harboring a bipartite nuclear localization signal, and we confirmed its function as a C-terminal binding protein (CtBP)-dependent transcriptional repressor. Through comprehensive screening, we identified TSHZ2-suppressing genes such as AEBP1 and CXCR4, which are conversely up-regulated by GLI1, the downstream transcription factor of Hedgehog signaling. We found that GLI1 forms a ternary complex with CtBP2 in the presence of TSHZ2 and that the transcriptional activity of GLI1 is suppressed by TSHZ2 in a CtBP-dependent manner. Indeed, knockdown of TSHZ2 increases the expression of AEBP1 and CXCR4 in TSHZ2-expressing immortalized mammary duct epithelium. Concordantly, immunohistochemical staining of mammary glands revealed that normal duct cells expresses GLI1 in the nucleus along with TSHZ2 and CtBP2, whereas invasive ductal carcinoma cells, which does not express TSHZ2, show the increase in the expression of AEBP1 and CXCR4 and in the cytoplasmic localization of GLI1. Thus, we propose that down-regulation of TSHZ2 is crucial for mammary tumorigenesis via the activation of GLI1.
- Published
- 2016
- Full Text
- View/download PDF
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