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高異型度漿液性癌における、卵管前癌病変のp53, CD44v9, Ki-67の免疫組織化学的発現態度
Get PDFPelvic high-grade serous carcinoma (HGSC) has been postulated to arise via a stepwise accumulation of (epi)genetic alterations from normal epithelium to secretory cell outgrowth (SCOUT), p53 signature, and serous tubal intraepithelial carcinoma (STIC) to invasive HGSC. The aim of this study is to investigate alterations in p53 and CD44v9 expression and the status of Ki-67 labeling index in a series of fallopian tube lesions of HGSC patients. A total of 45 specimens were analyzed in 16 patients with HGSC, and their lesions were categorized as follows: morphologically normal fallopian tube epithelium (FTE, n=6 samples), SCOUT (n=5), p53 signature (n=4), dormant STIC (n=8), active STIC (n=6), and HGSC (n=16). Morphologic features and immunohistochemical expression patterns of the p53 protein, CD44v9 protein, and Ki-67 antigen were blindly evaluated by 2 pathologists. Increased nuclear p53 protein accumulation was observed in p53 signature, dormant STIC, active STIC and HGSC compared with normal FTE and SCOUT (P<0.001). Immunohistochemistry scores of CD44v9 protein expression were significantly higher in normal FTE, SCOUT, and p53 signature than in dormant STIC, active STIC, and HGSC (P<0.001). Both active STIC and HGSC had significantly higher Ki-67 labeling indices than normal FTE, SCOUT, p53 signature and dormant STIC (P<0.001). CD44v9 loss contributes to the stepwise progression of p53 signature to dormant STIC. In conclusion, p53 mutation followed by CD44v9 loss may be involved in the evolution of STIC, which may confer positive clonal selection with a growth and survival advantage.博士（医学）・甲第830号・令和4年3月15日Copyright © 2021 by the International Society of Gynecological Pathologists.This article has been accepted for publication in International journal of gynecological pathology, 2021 following
peer review, and the Version of Record can be accessed online at http://dx.doi.org/10.1097/PGP.0000000000000738.発行元が定める登録猶予期間終了の後、本文を登録予定（2022.09
血清可溶性 OX40 値は薬剤性過敏症症候群の診断および予後予測の指標となりうる。
Get PDFBackground: Drug-induced hypersensitivity syndrome/drug reaction with eosinophilia and systemic symptoms (DIHS/DRESS) is a severe adverse drug reaction commonly associated with the reactivation of human herpesvirus 6 (HHV-6). There are currently no adequate biomarkers for the early diagnosis and detection of DIHS/DRESS. Notably, OX40 (CD134) has an important role in allergic inflammation and functions as a cellular receptor for HHV-6 entry. We previously reported that the membrane-bound form of OX40 in CD4⁺ T cells was upregulated in DIHS/DRESS. Objective: We sought to investigate the clinical significance of serum soluble OX40 (sOX40) in DIHS/DRESS. Methods: Serum sOX40 levels in patients with DIHS/DRESS (n = 39), maculopapular exanthema/erythema multiforme (n = 17), Stevens-Johnson syndrome/toxic epidermal necrolysis (n = 13), or autoimmune bullous diseases (n = 5), and levels in healthy volunteers (n = 5) were examined by enzyme-linked immunosorbent assay. Copy numbers of HHV-6, HHV-7, and cytomegalovirus in peripheral blood mononuclear cells were quantified using real-time PCR. Results: Serum sOX40 levels in patients with DIHS/DRESS in the acute stage were elevated in parallel with high OX40 expression on CD4⁺ T cells. Serum sOX40 levels were significantly positively correlated with disease severity and serum levels of thymus and activation-regulated chemokine, IL-5, and IL-10. Human herpesvirus 6-positive patients had higher sOX40 levels than did HHV-6-negative patients, and serum sOX40 levels were correlated with HHV-6 DNA loads. Conclusions: Serum sOX40 levels can be a useful diagnostic marker for DIHS/DRESS that reflect disease severity. Elevated serum sOX40 levels also predict HHV-6 reactivation in patients with DIHS/DRESS.博士（医学）・甲第834号・令和4年3月15日Copyright © 2021 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved
内側楔状開大式高位脛骨骨切り術後の3次元T1ρ-mappingを用いた軟骨定量評価
Get PDFPurpose: To evaluate the recently developed three-dimensional (3D) T1ρ-mapping technique for the quantitative evaluation of cartilage changes after open-wedge high tibial osteotomy (OWHTO).
Method: Eleven patients with medial knee osteoarthritis and spontaneous osteonecrosis of the medial femoral condyle underwent T1ρ magnetic resonance imaging. The full-thickness cartilage of the medial femoral condyle (MFC), lateral femoral condyle, medial tibial condyle, and lateral tibial condyle, and the trochlea and patella were set as regions of interest; mean T1ρ values were calculated using two-dimensional (2D) and 3D analyses. The state of cartilage injury was evaluated using the International Cartilage Repair Society grading system (ICRS grade). T1ρ values before OWHTO and after hardware removal were compared using the Wilcoxon signed-rank test. The correlation between T1ρ values and the ICRS grade was explored using the Spearman rank correlation coefficient. Results: Cartilage repair at the MFC was observed in a high proportion of patients (82%), but 2D analysis did not reveal a significant difference after surgery at any site. In contrast, 3D analysis revealed a significant decrease in T1ρ values after surgery at the MFC (before surgery: 44.1 ms; after surgery: 38.9 ms; p = 0.016), but no significant difference at any other site. In the MFC, there was a positive correlation between 3D T1ρ values and arthroscopic findings before and after surgery (rs = 0.62, p < 0.01), which was absent from the 2D T1ρ values. Conclusions: 3D T1ρ-mapping may be an effective tool for detecting changes in cartilage quality after OWHTO.博士（医学）・甲第848号・令和4年9月28日© 2022 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY license (https://creativecommons.org/licenses/by/4.0/)
マクロファージはクロストーク機構により子宮内膜細胞を酸化ストレスから保護する
Get PDFThis aim of this study was to investigate whether macrophages protect endometriotic cells from oxidative injury and to elucidate the underlying mechanisms of any protection. Endometriotic cells cultured with or without differentiated macrophages (dTHP-1 cells) were treated with hydrogen peroxide (H2O2) or methemoglobin, a major component of hemoglobin species in endometriotic cyst fluid. Co-culture experiments, microarray analysis, screening and validation of differentially expressed genes (DEGs), cell proliferation and viability assays, and experiments using a specific inhibitor were conducted to investigate the functional cross-talk between endometriotic cells and macrophages. Microarray analysis revealed that endometriotic cells co-cultured with dTHP-1 differentially express several genes compared with monoculture. Quantitative enzyme-linked immunosorbent assay (ELISA) and Western blotting analysis identified TGF-β1 as a promising candidate gene expressed in endometriotic cells co-cultured with dTHP-1 cells. TGF-β1 stimulated the expression of heme oxygenase-1 (HO-1) in dTHP-1 cells. HO-1 expression was increased in dTHP-1 cells co-cultured with endometriotic cells compared with the dTHP-1 monoculture. Both H2O2 and methemoglobin upregulated the expression of the HO-1 protein in the dTHP-1 monoculture; moreover, co-culture with endometriotic cells further enhanced HO-1 production. The co-culture with dTHP-1 protected endometriotic cells against oxidative injury. Blockade of HO-1 abolished the protective effects of macrophages. In an oxidative stress environment, TGF-β1 produced by endometriotic cells may protect against oxidative injury through the upregulation of macrophage-derived HO-1. The cross-talk between endometriotic cells and macrophages may contribute to the progression and pathogenesis of endometriosis.博士（医学）・甲第849号・令和4年9月28日Copyright © 2022, Society for Reproductive Investigation.© 2022 Springer Nature Switzerland AG.The version of record of this article, first published in Reproductive Sciences, is available online at Publisher's website: https://doi.org/10.1007/s43032-022-00890-6
A Case Of Nivolumab-Induced Immune-Related Adverse Event In The Upper Gastrointestinal Tract In Recurrence/Metastatic Head And Neck Cancer.
No full textA 61-year-old male patient underwent partial glossectomy and right neck dissection for tongue cancer cT2N1MO. Because of the locoregional recurrence, the patient received neoadjuvant chemotherapy followed by subtotal glossectomy, neck dissection, and reconstruction. However, new locoregional lesions and distant metastasis were detected during postoperative chemotherapy. Seven courses of nivolumab were administered, but the tumor grew. Hence, the chemotherapy regimen was switched to paclitaxel and cetuximab. After eight courses of this regimen, leakage of liquid enteral nutrients around the gastrostoma began, and the patient was hospitalized urgently due to severe abdominal distension and nausea. Upper gastrointestinal endoscopy revealed edematous esophageal and gastric mucosa covered with white coating spots. Histopathological examination of the duodenal mucosa specimen showed CD8-+ natural killer (NK) T-cells infiltrating the lamina propria mucosae, which corresponded with an immune-related adverse event (irAE). Pulse steroid therapy significantly improved the findings of upper gastrointestinal endoscopy and symptoms
消化器がん細胞におけるpterostilbeneの抗幹細胞作用
Get PDFPterostilbene (PTE) is a natural sterbenoid contained in blueberries that has an antioxidant effect. In contrast, PTE also generates oxidative stress in cancer cells and provides an antitumor effect. Here, we examined the potential mechanism of this contrasting effect of PTE using three gastrointestinal cancer cell lines, namely CT26, HT29, and MKN74. PTE showed a dose-dependent inhibition of cell proliferation, sphere-forming ability, and stem cell marker expression in all three cell lines. Furthermore, the cells treated with PTE showed an increase in mitochondrial membrane potential and an increase in mitochondrial oxidative stress and lipid peroxide. Upon concurrent treatment with vitamin E, N-acetyl-L-cysteine, and PTE, the PTE-induced mitochondrial oxidative stress and growth inhibition were suppressed. These findings indicate that PTE induces oxidative stress in cancer cells, suppresses stemness, and inhibits proliferation. These antitumor effects of PTE are considered to be useful in cancer treatment.博士（医学）・甲第821号・令和4年3月15日© 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/)
ROTEMを用いた小児特発性ネフローゼ症候群患者の急性期における包括的全血凝固線溶能
Get PDFBackground: Venous thromboembolism is a rare, serious complication of idiopathic nephrotic syndrome (INS) in childhood. The mechanisms responsible for the hypercoagulable state in the acute phase of INS are poorly understood, however. This study aimed to assess overall coagulation and fibrinolytic function in pediatric patients with INS. Methods: Global coagulation and fibrinolysis were examined in whole blood samples from 22 children with initial onset INS (initial-group), 22 children with relapsed INS (relapse-group), and 15 control pediatric patients using rotational thromboelastometry (ROTEM®). In the initial-group, blood samples were obtained before (week 0) and 1-4 weeks after initiation of corticosteroid therapy. EXTEM and FIBTEM were used to assess coagulation and fibrinolysis, respectively. Clot time (CT), clot formation time (CFT), maximum clot firmness (MCF), and α-angle were determined as coagulation parameters, and lysis index at 30 and 60 min (LI30 and LI60, respectively) were assessed as fibrinolytic parameters. Results: CT was significantly shortened, and MCF and α-angle were significantly greater than controls at week 0 and week 1 both in the initial-group and the relapse-group. MCF correlated with serum albumin (r = 0.70, p < 0.001) and fibrinogen level (r = 0.68, p < 0.001). The fibrinolytic parameters (LI30 and LI60) in the initial-group were stable and higher than those in controls at all time points (p < 0.01). Conclusions: We have shown that the hypofibrinolytic defect did not improve with effective NS treatment at the early 4-week time-point. Additionally, a likely pre-thrombotic state was evident in the period before initial onset and 1 week after corticosteroid therapy in pediatric INS.博士（医学）・乙第1522号・令和4年3月15日© 2021. The Author(s), under exclusive licence to International Pediatric Nephrology Association.This version of the article has been accepted for publication, after peer review (when applicable) and is subject to Springer Nature’s AM terms of use, but is not the Version of Record and does not reflect post-acceptance improvements, or any corrections. The Version of Record is available online at: http://dx.doi.org/10.1007/s00467-021-05366-4.発行元が定める登録猶予期間終了の後、本文を登録予定（2023.01