Transforming Growth Factor-β Induces Interleukin-6 Secretion from Human Ligamentum Flavum–Derived Cells through Partial Activation of p38 and p44/42 Mitogen-Activated Protein Kinases

Goto Yuta,Kato Kenji,Yagi Kiyoshi,Kawaguchi Yohei,Yonezu Hiroki,Koshimae Tomoko,Waguri-Nagaya Yuko,Murakami Hideki,Suzuki Nobuyuki 대한척추외과학회 2023 Asian Spine Journal Vol.17 No.6

Study Design: This experimental study was performed using human ligamentum flavum–derived cells (HFCs).Purpose: To investigate the intracellular signaling mechanism of interleukin-6 (IL-6) secretion in transforming growth factor-β (TGF- β)-stimulated HFCs.Overview of Literature: Lumbar spinal stenosis (LSS) is a prevalent disease among the elderly, characterized by debilitating pain in the lower extremities. Although the number of patients with LSS has increased in recent years, the underlying pathomechanism remains unclear. Clinical examinations typically rely on magnetic resonance imaging to diagnose patients, revealing ligamentum flavum hypertrophy. Some studies have suggested an association between ligamentum flavum hypertrophy and inflammation/fibrosis, and expression of TGF-β and IL-6 has been observed in surgically obtained ligamentum flavum samples. However, direct evidence linking TGF-β and IL-6 expression in HFCs is lacking.Methods: HFCs were obtained from patients with LSS who had undergone decompression surgery. The cells were stimulated with TGF-β and pretreated with either the p38 mitogen-activated protein (MAP) kinase inhibitor SB203580 or the p44/42 MAP kinase inhibitor FR180204. IL-6 secretion in the cell culture medium and IL-6 messenger RNA (mRNA) expression levels were analyzed using an enzyme-linked immunoassay and real-time polymerase chain reaction, respectively.Results: TGF-β administration resulted in a dose- and time-dependent stimulation of IL-6 release. Treatment with SB203580 and FR180204 markedly suppressed TGF-β–induced IL-6 secretion from HFCs. Moreover, these inhibitors suppressed IL-6 mRNA expression in response to TGF-β stimulation.Conclusions: Our findings indicate that TGF-β induces IL-6 protein secretion and gene expression in HFCs through the activation of p38 or p44/42 MAP kinases. These results suggest a potential association between IL-6–mediated inflammatory response and tissue hypertrophy in LSS, and we provide insights into molecular targets for therapeutic interventions targeting LSS-related inflammation through our analysis of the MAP kinase pathway using HFCs.

A Case of a Meningeal Carcinomatosis of the Internal Auditory Meatus Treated as Sudden Deafness

Fumiyuki Goto,Miki Arai,Takeshi Wakabayashi,Tomoko Otomo,Ryoto Nagai,Shuujiro Minami,Takanobu Shimada,Masato Fujii 대한평형의학회 2015 Research in Vestibular Science Vol.14 No.4

We describe a case of meningeal carcinomatosis of the internal auditory meatus presenting as sudden deafness accompanied by dizziness. A 54-year-old woman complained of acute right-side hearing loss in October 2014. The pure tone audiometry test revealed right-side hearing loss of 47.5 dB. She was treated with oral steroids. Her hearing as well as her symptoms of dizziness worsened and she was admitted for further examination. Her right and left-side hearing had worsened to 105.0 dB and 47.5 dB, respectively. A magnetic resonance imaging scan of the head revealed bilateral enhancement of the internal auditory canal and multiple brain metastases. The chest radiograph revealed a mass in the left lung. Adenocarcinoma of the lung was diagnosed. Lumbar puncture yielded no evidence of carcinoma cells in the cerebrospinal fluid, but an increased number of lymphocytes was confirmed. A diagnosis of multiple brain metastases and leptomeningeal metastasis from the adenocarcinoma of the lung was considered. Whole-brain radiation therapy (30 Gr/10 fractions) was administered. Progressive bilateral hearing loss is a rare first manifestation of meningeal carcinomatosis. It is quite important to consider the possibility of this condition when patients present with sudden deafness.Res Vestib Sci 2015;14(4):139-142

A Case of Intractable Suspected Perilymph Fistula with Severe Depression

Fumiyuki Goto,Naoki Oishi,Tomoko Tsutsumi,Kaoru Ogawa 대한신경정신의학회 2014 PSYCHIATRY INVESTIGATION Vol.11 No.4

A 68-year-old woman presented dizziness whenever she put her finger into the right ear and also complained of water-streaming tinnitus, which indicated she would have been suffering from perilymph fistula. An exploratory tympanotomy was conducted. Leakage of perilymph from the round window was suspected, although the cochlin-tomoprotein (CTP) results were negative. After the procedure, the patient’s finger-induced dizziness, tinnitus, and vertigo spells disappeared completely. However, her dizzy symptom did not improve. The patient also complained of general fatigue, weight loss, and insomnia, which led us to suspect comorbid depression. Antidepressants and vestibular rehabilitation treatment resulted in a significant improvement in her dizziness. Although it is not apparent whether the patient had a perilymph fistula, this case demonstrates the importance of evaluating not only physical symptoms but also psychological comorbidity, especially when the physical symptoms are intractable despite treatment.

Selective Inhibition of β-Catenin/Co-Activator Cyclic AMP Response Element-Binding Protein-Dependent Signaling Prevents the Emergence of Hapten-Induced Atopic Dermatitis-Like Dermatitis

( Haruna Matsuda-hirose ),( Tomoko Yamate ),( Mizuki Goto ),( Akira Katoh ),( Hiroyuki Kouji ),( Yuya Yamamoto ),( Takashi Sakai ),( Naoto Uemura ),( Takashi Kobayashi ),( Yutaka Hatano ) 대한피부과학회 2019 Annals of Dermatology Vol.31 No.6

Background: The canonical Wnt/β-catenin signaling pathway is a fundamental regulatory system involved in various biological events. ICG-001 selectively blocks the interaction of β-catenin with its transcriptional co-activator cyclic AMP response element-binding protein (CBP). Recent studies have provided convincing evidence of the inhibitory effects of ICG-001 on Wnt-driven disease models, such as organ fibrosis, cancer, acute lymphoblastic leukemia, and asthma. However, the effects of ICG-001 in atopic dermatitis (AD) have not been investigated. Objective: To investigate whether β-catenin/CBP-dependent signaling was contributed in the pathogenesis of AD and ICG-001 could be a therapeutic agent for AD. Methods: We examined the effects of ICG-001 in an AD-like murine model generated by repeated topical application of the hapten, oxazolone (Ox). ICG-001 or vehicle alone was injected intraperitoneally every day during the development of AD-like dermatitis arising from once-daily Ox treatment. Results: Ox-induced AD-like dermatitis characterized by increases in transepidermal water loss, epidermal thickness, dermal thickness accompanied by increased myofibroblast and mast cell counts, and serum levels of thymic stromal lymphopoietin and thymus and activation- regulated chemokine, and decreases in stratum corneum hydration, were virtually normalized by the treatment with ICG-001. Elevated serum levels of periostin tended to be downregulated, without statistical significance. Conclusion: These results suggest that β-catenin/CBP-dependent signaling might be involved in the pathogenesis of AD and could be a therapeutic target. (Ann Dermatol 31(6) 631∼639, 2019)

Clear cell histology as a poor prognostic factor for advanced epithelial ovarian cancer: a single institutional case series through central pathologic review

Morikazu Miyamoto,Masashi Takano,Tomoko Goto,Masafumi Kato,Naoki Sasaki,Hitoshi Tsuda,Kenichi Furuya 대한부인종양학회 2013 Journal of Gynecologic Oncology Vol.24 No.1

Objective: Compared with serous adenocarcinoma (SAC), clear cell carcinoma (CCC) often shows chemo-resistance, which would potentially lead to a poor prognosis. On the other hand, there have been arguments over prognoses of CCC and SAC disease. In the present study, multivariate analysis to compare prognosis of CCC patients with that of SAC was aimed for the patients selected from central pathologic review. Methods: Between 1984 and 2009, a total of 500 ovarian cancer patients were treated at our university hospital. Among them,111 patients with CCC and 199 patients with SAC were identified through central pathological review. Overall survival and progression-free survival were compared using Kaplan-Meier method, and prognostic factors were investigated by multiple regression analyses. Results: Median age was 52 years for CCC and 55 years for SAC (p=0.03). The ratio of stage I patients were significantly higher in CCC compared with SAC (55% vs. 13%, p<0.01). Among evaluable cases, response rate was significantly lower in CCC than that in SAC (32% vs. 78%, p<0.01). No significant differences of progression-free survival and overall survival were observed in stage I patients; however, prognoses of CCC were significantly poorer than those of SAC in advanced-stage disease. In stage II-IV patients, not only residual tumors and clinical stages, but also clear cell histology were identified as predictors for poor prognosis. Conclusion: Clear cell histology was identified as a prognostic factor for advanced-stage ovarian cancers. Histologic subtypes should be considered in further clinical studies, especially for advanced epithelial ovarian cancers.

Usefulness of the Endotoxin Activity Assay to Evaluate the Degree of Lung Injury

Yuichiro Sakamoto,Satoshi Inoue,Takashi Iwamura,Tomoko Yamashita,Atsushi Nakashima,Hiroyuki Koami,Toru Miike,Mayuko Yahata,Hisashi Imahase,Akiko Goto,Showgo Narumi,Miho Ohta,Chris-Kosuke Yamada 연세대학교의과대학 2014 Yonsei medical journal Vol.55 No.4

Purpose: It has been reported that the Pulse Contour Cardiac Output (PiCCO) is very useful mainly in the field of intensive care and treatment to grasp the pathophysiologicalconditions of pulmonary edema because of its capability of obtainingdata such as Pulmonary Vascular Permeability Index (PVPI) and Extra VascularLung Water (EVLW). Furthermore, a high degree of usability of various markers has been reported for better understanding of the pathological conditions in cases with septicemia. Materials and Methods: The correlation between the cardiorespiratory status based upon the PiCCO monitor (EVLW and PVPI) and inflammatorymarkers including C reactive protein, procalcitonin (PC), and EndotoxinActivity Assay (EAA) were evaluated in 11 severe cases that required treatmentwith a respirator in an intensive care unit. Results: The EAA values were significantly higher in patients with abnormal EVLW at 0.46±0.20 compared to the normal EVLW group at 0.21±0.19 (p=0.0064). In a similar fashion, patients with abnormal PVPI values tended to have higher PC levels at 18.9±21.8 comparedto normal PVPI cases at 2.4±2.2 (p=0.0676). On the other hand, PVPI was significantly higher in the abnormal EAA group at 3.55±0.48 in comparison with the normal EAA group at 1.99±0.68 (p=0.0029). The abnormal EAA group tended to have higher PVPI values than the normal EAA group. Conclusion: The EAA is a measurement method designed to estimate the activity of endotoxins in the whole blood. Our results suggest that the EAA value, which had the greatest correlationwith lung disorders diagnosed by the PiCCO monitoring, reflects inflammatoryreactions predominantly in the lungs.

Studies on Therapeutic Effects and Pathological Features of an Antithrombin Preparation in Septic Disseminated Intravascular Coagulation Patients

Yuichiro Sakamoto,Satoshi Inoue,Takashi Iwamura,Tomoko Yamashita,Atsushi Nakashima,Yoichi Nishimura,Hiroyuki Koami,Hisashi Imahase,Akiko Goto,Kosuke Chris Yamada,Kunihiro Mashiko,Hiroyuki Yokota 연세대학교의과대학 2013 Yonsei medical journal Vol.54 No.3

Purpose: Few reports have been made on the therapeutic effects as well as pathological features of an antithrombin preparation in patients diagnosed with septic disseminated intravascular coagulation (DIC) by the diagnostic criteria for acute DIC. Materials and Methods: A total of 88 sepsis patients who had received inpatient hospital care during the period from January 2000 through December 2008 were divided into two groups, an antithrombin group and a non-antithrombin group, to study the outcomes. Furthermore, the relationship between sepsis-related factors and DIC in 44 patients was studied. Results: The antithrombin group contained 34 patients, and the non-antithrombin group contained 54 patients. The outcomes were significantly better in the antithrombin group. The levels of protein C were low in DIC patients. Conclusion: Our results suggest that early administration of antithrombin might improve outcomes of septic DIC patients in the diagnostic criteria for Japanese Association for Acute Medicine acute DIC.

Comparison of respiratory muscle strength in individuals performing continuous and noncontinuous walking exercises in water after the 6-week program

Yoshihiro Yamashina,Hiroki Aoyama,Hirofumi Hori,Emiko Morita,Nami Sakagami,Tomoko Hirayama,Yosuke Yamato,Hiroto Honda,Shigeru Terada,Masahiro Goto,Kazuyuki Tabira 한국운동재활학회 2019 JER Vol.15 No.4

DNA mismatch repair-related protein loss as a prognostic factor in endometrial cancers

Masafumi Kato,Masashi Takano,Morikazu Miyamoto,Naoki Sasaki,Tomoko Goto,Hitoshi Tsuda,Kenichi Furuya 대한부인종양학회 2015 Journal of Gynecologic Oncology Vol.26 No.1

Objective: Recent investigations have revealed DNA mismatch repair (MMR) gene mutations are closely related with carcinogenesis of endometrial cancer; however the impact of MMR protein expression on prognosis is not determined. Correlations between MMR-related protein expression and clinicopathological factors of endometrial cancers are analyzed in the present study. Methods: A total of 191 endometrial cancer tissues treated between 1990 and 2007 in our hospital were enrolled. Immunoreactions for MSH2, MLH1, MSH6, and PMS2 on tissue microarray specimens and clinicopathological features were analyzed retrospectively. Results: Seventy-six cases (40%) had at least one immunohistochemical alteration in MMR proteins (MMR-deficient group). There were statistically significant differences of histology, International Federation of Gynecology and Obstetrics (FIGO) stage, and histological grade between MMR-deficient group and the other cases (MMR-retained group). Response rate of first-line chemotherapy in evaluable cases was slightly higher in MMR-deficient cases (67% vs. 44%, p=0.34). MMR-deficient cases had significantly better progression-free and overall survival (OS) compared with MMR-retained cases. Multivariate analysis revealed MMR status was an independent prognostic factor for OS in endometrial cancers. Conclusion: MMR-related proteins expression was identified as an independent prognostic factor for OS, suggesting that MMR was a key biomarker for further investigations of endometrial cancers.