Integrative analysis reveals early epigenetic alterations in high-grade serous ovarian carcinomas

Machino Hidenori,Dozen Ai,Konaka Mariko,Komatsu Masaaki,Nakamura Kohei,Ikawa Noriko,Shozu Kanto,Asada Ken,Kaneko Syuzo,Yoshida Hiroshi,Kato Tomoyasu,Nakayama Kentaro,Saloura Vassiliki,Kyo Satoru,Hamam 생화학분자생물학회 2023 Experimental and molecular medicine Vol.55 No.-

High-grade serous ovarian carcinoma (HGSOC) is the most lethal gynecological malignancy. To date, the profiles of gene mutations and copy number alterations in HGSOC have been well characterized. However, the patterns of epigenetic alterations and transcription factor dysregulation in HGSOC have not yet been fully elucidated. In this study, we performed integrative omics analyses of a series of stepwise HGSOC model cells originating from human fallopian tube secretory epithelial cells (HFTSECs) to investigate early epigenetic alterations in HGSOC tumorigenesis. Assay for transposase-accessible chromatin using sequencing (ATAC-seq), chromatin immunoprecipitation sequencing (ChIP-seq), and RNA sequencing (RNA-seq) methods were used to analyze HGSOC samples. Additionally, protein expression changes in target genes were confirmed using normal HFTSECs, serous tubal intraepithelial carcinomas (STICs), and HGSOC tissues. Transcription factor motif analysis revealed that the DNA-binding activity of the AP-1 complex and GATA family proteins was dysregulated during early tumorigenesis. The protein expression levels of JUN and FOSL2 were increased, and those of GATA6 and DAB2 were decreased in STIC lesions, which were associated with epithelial-mesenchymal transition (EMT) and proteasome downregulation. The genomic region around the FRA16D site, containing a cadherin cluster region, was epigenetically suppressed by oncogenic signaling. Proteasome inhibition caused the upregulation of chemokine genes, which may facilitate immune evasion during HGSOC tumorigenesis. Importantly, MEK inhibitor treatment reversed these oncogenic alterations, indicating its clinical effectiveness in a subgroup of patients with HGSOC. This result suggests that MEK inhibitor therapy may be an effective treatment option for chemotherapy-resistant HGSOC.

Isolated tumor cells and micrometastases in regional lymph nodes in stage I to II endometrial cancer

Yukiharu Todo,Hidenori Kato,Kazuhira Okamoto,Shinichiro Minobe,Katsushige Yamashiro,Noriaki Sakuragi 대한부인종양학회 2016 Journal of Gynecologic Oncology Vol.27 No.1

Objective: The aim of this study was to clarify the clinical significance of isolated tumor cells (ITCs) or micrometastasis (MM) in regional lymph nodes in patients with International Federation of Gynecology and Obstetrics (FIGO) stage I to II endometrial cancer. Methods: In this study, a series of 63 patients with FIGO stage I to II were included, who had at least one of the following risk factors for recurrence: G3 endometrioid/serous/clear cell adenocarcinomas, deep myometrial invasion, cervical involvement, lympho-vascular space invasion, and positive peritoneal cytology. These cases were classified as intermediate-risk endometrial cancer. Ultrastaging by multiple slicing, staining with hematoxylin and eosin and cytokeratin, and microscopic examination was performed on regional lymph nodes that had been diagnosed as negative for metastases. Results: Among 61 patients in whom paraffin-embedded block was available, ITC/MM was identified in nine patients (14.8%). Deep myometrial invasion was significantly associated with ITC/MM (p=0.028). ITC/MM was an independent risk factor for extrapelvic recurrence (hazard ratio, 17.9; 95% confidence interval [CI], 1.4 to 232.2). The 8-year overall survival (OS) and recurrence-free survival (RFS) rates were more than 20% lower in the ITC/MM group than in the node-negative group (OS, 71.4% vs. 91.9%; RFS, 55.6% vs. 84.0%), which were statistically not significant (OS, p=0.074; RFS, p=0.066). Time to recurrence tended to be longer in the ITC/MM group than in the node-negative group (median, 49 months vs. 16.5 months; p=0.080). Conclusions: It remains unclear whether ITC/MM have an adverse influence on prognosis of intermediate-risk endometrial cancer. A multicenter cooperative study is needed to clarify the clinical significance of ITC/MM.

Natural History of Chronic Intestinal Pseudo-obstruction and Need for Palliative Care

Kosuke Tanaka,Hidenori Ohkubo,Atsushi Yamamoto,Kota Takahashi,Yuki Kasai,Anna Ozaki,Michihiro Iwaki,Takashi Kobayashi,Tsutomu Yoshihara,Noboru Misawa,Akiko Fuyuki,Shingo Kato,Takuma Higurashi,Kunihiro 대한소화기 기능성질환∙운동학회 2023 Journal of Neurogastroenterology and Motility (JNM Vol.29 No.3

Background/AimsNatural history of chronic intestinal pseudo-obstruction (CIPO), a rare disease characterized by episodes of non-mechanical obstruction, is unclear in adults. This study evaluates the clinical course of CIPO and palliative care needs of patients. MethodsFrom October 2010 to September 2021, 74 patients who underwent cine MRI and had a definitive diagnosis of CIPO were prospectively included. We investigated disease etiology and outcomes, age at onset, nutritional status at consultation (body mass index and serum albumin), hydrogen breath test results, and total parenteral nutrition (TPN) during the disease course. ResultsForty-seven patients (64%) were women, with a mean age of 44 years at onset and 49 years at diagnosis. Primary CIPO was observed in 48 patients (65%). Secondary CIPO was observed in 26 cases (35%), of whom 18 (69%) had scleroderma. The mean body mass index, serum albumin level, and hydrogen breath test positivity rate were 17 kg/m2, 3.8 mg/dL, and 60%, respectively. TPN and invasive decompression therapy were required by 23 (31%) and 18 (24%) patients, respectively. Intestinal sterilization was performed in 51 (69%) patients and was effective in 33 (65%); of these, 28 (85%) were taking metronidazole. Seven (9%) patients used opioids. There were 9 deaths (12%), including 5 (56%) from infection and 2 (22%) from suicide. Of the deaths, 6 (67%) and 4 (44%) underwent TPN management and decompression therapy, respectively. Fifty-one patients (69%) wanted palliative care. ConclusionCIPO is a rare, severe, and under-recognized disease. Standardization of treatment strategies, including palliative care and psychiatric interventions, is desired.

Structural Analysis of Species in NbCI₅-EMIC Room-Temperature Molten Salt with Raman Spectroscopic Measurement and Ab Initio Molecular Orbital Calculation

Koura, Nobuyuki,Matsuzawa, Hidenori,Kato, Tomoki,Idemoto, Yasushi,Matsumoto, Futoshi The Korean Electrochemical Society 2002 한국전기화학회지 Vol.5 No.4

The structure of species formed in $NbCI_5-I-ethyl-3-methylimidazolium$ chloride (EMIC) room-temperature molten salt (RTMS) was examined with the Raman spectroscopic measurement and ab initio molecular orbital calculation. The equilibrium structures of $NbCl_5,\;NbCl_6^-,\;Nb_2CI_{10},\;Nb_2CI_{11}^-,\;Nb_3CI_6^-,\;NbCI_6^--EMI^+\;(in\;which\;NbCI_6^-$ anion approaches $EMI^+$ cation with strong interaction) and $Nb_2CI_{11}^--EMI^+$ were obtained with the HF/LANL2DZ level of calculation. The harmonic frequencies at each equilibrium structure were compared with Raman spectra. The harmonic frequencies of $NbCI_6^--EMI^+,\; Nb_2CI_{11}^--EMI^+,\;and\;Nb_2CI_{10}$ were in good agreement with the Raman spectra of RTMS melts. In the $NbCI_5-EMIC RTMS$, the main species were $NbCI_6^-\;and\;EMI^+$. In the $NbCl_5-EMIC$ RTMS added $NbCl_5\;over\;50mol\%$, small amount of $Nb_2CI_{11}^-\;and\; Nb_2CI_{10}$ were also formed. The structures of anions and cation in the RTMS distorted from free ions with Coulomb force.

A2E, a pigment of the lipofuscin of retinal pigment epithelial cells, is an endogenous ligand for retinoic acid receptor.

Iriyama, Aya,Fujiki, Ryoji,Inoue, Yuji,Takahashi, Hidenori,Tamaki, Yasuhiro,Takezawa, Shinichiro,Takeyama, Kenichi,Jang, Woo-Dong,Kato, Shigeaki,Yanagi, Yasuo American Society for Biochemistry and Molecular Bi 2008 The Journal of biological chemistry Vol.283 No.18

<P>Lipofuscin contains fluorophores, which represent a biomarker for cellular aging. Although it remains unsubstantiated clinically, experimental results support that the accumulation of lipofuscin is related to an increased risk of choroidal neovascularization due to age-related macular degeneration, a leading cause of legal blindness. Here, we report that a major lipofuscin component, A2E, activates the retinoic acid receptor (RAR). In vitro experiments using luciferase reporter assay, competitional binding assay, analysis of target genes, and chromatin immunoprecipitation (ChIP) assay strongly suggest that A2E is a bona fide ligand for RAR and induces sustained activation of RAR target genes. A2E-induced vascular endothelial growth factor (VEGF) expression in a human retinal pigment epithelial cell line (ARPE-19) and RAR antagonist blocked the up-regulation of VEGF. The conditioned medium of A2E-treated ARPE-19 cells induced tube formation in human umbilical vascular endothelial cells, which was blocked by the RAR antagonist and anti-VEGF antibody. These results suggest that A2E accumulation results in the phenotypic alteration of retinal pigment epithelial cells, predisposing the environment to choroidal neovascularization development. This is mediated through the agonistic function of A2E, at least in part. The results of this study provide a novel potential therapeutic target for this incurable condition.</P>

miniTAO/ANIR Paα SURVEY OF LOCAL LIRGs

Tateuchi, Ken,Motohara, Kentaro,Konishi, Masahiro,Takahashi, Hidenori,Kato, Natsuko,Uchimoto, Yuka K.,Toshikawa, Koji,Ohsawa, Ryou,Kitagawa, Yutaro,Yoshii, Yuzuru,Doi, Mamoru,Kohno, Kotaro,Kawara, Kim The Korean Astronomical Society 2012 天文學論叢 Vol.27 No.4

ANIR (Atacama Near InfraRed camera) is a near infrared camera for the University of Tokyo Atacama 1m telescope, installed at the summit of Co. Chajnantor (5,640 m altitude) in northern Chile. The high altitude and extremely low water vapor (PWV = 0.5 mm) of the site enable us to perform observation of hydrogen $Pa{\alpha}$ emission line at $1.8751{\mu}m$. Since its first light observation in June 2009, we have been carrying out a $Pa{\alpha}$ narrow-band imaging survey of nearby luminous infrared galaxies (LIRGs), and have obtained $Pa{\alpha}$ for 38 nearby LIRGs listed in AKARI/FIS-PSC at the velocity of recession between 2,800 km/s and 8,100 km/s. LIRGs are affected by a large amount of dust extinction ($A_V$~ 3 mag), produced by their active star formation activities. Because $Pa{\alpha}$ is the strongest hydrogen recombination line in the infrared wavelength ranges, it is a good and direct tracer of dust-enshrouded star forming regions, and enables us to probe the star formation activities in LIRGs. We find that LIRGs have two star-forming modes. The origin of the two modes probably come from differences between merging stage and/or star-forming process.

Prognostic factors for patients with cervical cancer treated with concurrent chemoradiotherapy:a retrospective analysis in a Japanese cohort

Daisuke Endo,Yukiharu Todo,Kazuhira Okamoto,Shinichiro Minobe,Hidenori Kato,Noriaki Nishiyama 대한부인종양학회 2015 Journal of Gynecologic Oncology Vol.26 No.1

Objective: Concurrent chemoradiotherapy (CCRT) is the primary treatment for locally advanced cervical cancer. We studied prognostic factors for patients treated with CCRT. Methods: We retrospectively reviewed records of 85 consecutive patients with cervical cancer who were treated with CCRT between 2002 and 2011, with external beam radiation therapy, intracavitary brachytherapy, and platinum-based chemotherapy. Survival data were analyzed with Kaplan-Meier methods and Cox proportional hazard models. Results: Of the 85 patients, 69 patients (81%) had International Federation of Gynecology and Obstetrics (FIGO) stage III/IV disease; 25 patients (29%) had pelvic lymph node enlargement (based on magnetic resonance imaging), and 64 patients (75%) achieved clinical remission following treatment. Median maximum tumor diameter was 5.5 cm. The 3- and 5-year overall survival rates were 60.3% and 55.5%, respectively. Cox regression analysis showed tumor diameter >6 cm (hazard ratio [HR], 2.3; 95% confidence interval [CI], 1.2 to 4.6), pelvic lymph node enlargement (HR, 2.2; 95% CI, 1.1 to 4.5), and distant metastasis (HR, 10.0; 95% CI, 3.7 to 27.0) were significantly and independently related to poor outcomes. Conclusion: New treatment strategies should be considered for locally advanced cervical cancers with tumors >6 cm and radiologically enlarged pelvic lymph nodes.

Pretreatment risk factors for parametrial involvement in FIGO stage IB1 cervical cancer

Hiroyuki Yamazaki,Yukiharu Todo,Kazuhira Okamoto,Katsushige Yamashiro,Hidenori Kato 대한부인종양학회 2015 Journal of Gynecologic Oncology Vol.26 No.4

Objective: All patients with stage IB1 cervical cancer do not need to undergo parametrectomy. Some low-risk criteria for parametrial involvement (PI) have been proposed based on pathological findings. The aim of this study was to determine pretreatment risk factors for PI in stage IB1 cervical cancer. Methods: We retrospectively reviewed 115 patients with stage IB1 cervical cancer who underwent radical hysterectomy or radical trachelectomy. Magnetic resonance imaging (MRI) was performed and serum concentrations of squamous cell carcinoma antigen (SCC-Ag) and cancer antigen 125 (CA-125) were determined in all patients before initial treatment. The following pretreatment factors were investigated: histological variant, maximum tumor diameter, tumor volume (volume index), pelvic lymph node enlargement, and serum tumor markers. Logistic regression analysis was used to select the independent risk factors for PI. Results: Eighteen of the 115 patients (15.7%) were pathologically diagnosed with PI. Multivariate analysis confirmed the following independent risk factors for PI: MRI-based tumor diameter ≥25 mm (odds ratio [OR], 9.9; 95% confidence interval [CI], 2.1 to 48.1), MRI-based volume index ≥5,000 mm3 (OR, 13.3; 95% CI, 1.4 to 125.0), and positive serum tumor markers SCC-Ag ≥1.5 ng/mL or CA-125 ≥35 U/mL (OR, 5.7; 95% CI, 1.3 to 25.1). Of 53 patients with no risk factors for PI, none had PI. Conclusion: Less radical surgery may become one of the treatment options for stage IB1 cervical cancer patients with MRIbased tumor diameter <25 mm, MRI-based volume index <5,000 mm3, and negativity for SCC-Ag and CA-125.

Incidence of metastasis in circumflex iliac nodes distal to the external iliac nodes in cervical cancer

Sho Takeshita,Yukiharu Todo,Kazuhira Okamoto,Satoko Sudo,Katsushige Yamashiro,Hidenori Kato 대한부인종양학회 2016 Journal of Gynecologic Oncology Vol.27 No.4

Objective: A causal relationship between removal of circumflex iliac nodes distal to the external iliac nodes (CINDEIN) and lower leg edema has been recently suggested. The aim of this study was to elucidate the incidence of CINDEIN metastasis in cervical cancer. Methods: A retrospective chart review was carried out for 531 patients with cervical cancer who underwent lymph node dissection between 1993 and 2014. CINDEIN metastasis was pathologically identified by microscopic investigation. After 2007, sentinel lymph node biopsy was performed selectively in patients with non-bulky cervical cancer. The sentinel node was identified using 99mTc-phytate and by scanning the pelvic cavity with a γ probe. Results: Two hundred and ninety-seven patients (55.9%) underwent CINDEIN dissection and 234 (44.1%) did not. The percentage of International Federation of Gynecology and Obstetrics stage IIb to IV (42.4% vs. 23.5%, p<0.001) was significantly higher in patients who underwent CINDEIN dissection than those who did not. CINDEIN metastasis was identified in 1.9% overall and in 3.4% of patients who underwent CINDEIN dissection. For patients with stage Ia to IIa disease, CINDEIN metastasis was identified in 0.6% overall and in 1.2% of patients who underwent CINDEIN dissection. Of 115 patients with sentinel node mapping, only one (0.9%) had CINDEIN detected as a sentinel node. In this case, the other three lymph nodes were concurrently detected as sentinel lymph nodes. Conclusion: CINDEIN dissection can be eliminated in patients with stage Ia to IIa disease. CINDEIN might not be regional lymph nodes in cervical cancer.

A prediction model of survival for patients with bone metastasis from uterine cervical cancer

Hiroko Matsumiya,Yukiharu Todo,Kazuhira Okamoto,Sho Takeshita,Hiroyuki Yamazaki,Katsushige Yamashiro,Hidenori Kato 대한부인종양학회 2016 Journal of Gynecologic Oncology Vol.27 No.6

Objective: The aim of the study was to establish a predictive model of survival period afterbone metastasis from cervical cancer. Methods: A total of 54 patients with bone metastasis from cervical cancer were included in thestudy. Data at the time of bone metastasis diagnosis, which included presence of extraskeletalmetastasis, performance status, history of any previous radiation or chemotherapy, thenumber of bone metastases, onset period, and treatment were collected. Survival data wereanalyzed using Kaplan-Meier method and Cox proportional hazards model. Results: The median survival period after diagnosis of bone metastasis was 22 weeks (5months). The 26- and 52-week survival rates after bone metastasis were 36.5% and 15.4%,respectively. Cox regression analysis showed that extraskeletal metastasis (hazard ratio [HR],6.1; 95% CI, 2.2 to 16.6), performance status of 3 to 4 (HR, 7.8; 95% CI, 3.3 to 18.2), previousradiation or chemotherapy (HR, 3.3; 95% CI, 1.4 to 7.8), multiple bone metastases (HR, 1.9;95% CI, 1.0 to 3.5), and a bone metastasis-free interval of <12 months (HR, 2.5; 95% CI, 1.2to 5.3) were significantly and independently related to poor survival. A prognostic score wascalculated by adding the number of each significant factor. The 26-week survival rates afterdiagnosis of bone metastasis were 70.1% in the group with a score ≤2, 46.7% in the groupwith a score of 3, and 12.5% in the group with a score ≥4 (p<0.001). Conclusion: This scoring system provided useful prognostic information on survival ofpatients with bone metastasis of cervical cancer.