研究者詳細 - 横井　暁

論文 - 横井　暁

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Spatial exosome analysis using cellulose nanofiber sheets reveals the location heterogeneity of extracellular vesicles 国際誌

Yokoi, A; Yoshida, K; Koga, H; Kitagawa, M; Nagao, Y; Iida, M; Kawaguchi, S; Zhang, M; Nakayama, J; Yamamoto, Y; Baba, Y; Kajiyama, H; Yasui, T

NATURE COMMUNICATIONS 14 巻 ( 1 ) 頁： 6915 - 6915 2023年11月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Nature Communications

Extracellular vesicles (EVs), including exosomes, are recognized as promising functional targets involved in disease mechanisms. However, the intravital heterogeneity of EVs remains unclear, and the general limitation for analyzing EVs is the need for a certain volume of biofluids. Here, we present cellulose nanofiber (CNF) sheets to resolve these issues. We show that CNF sheets capture and preserve EVs from ~10 μL of biofluid and enable the analysis of bioactive molecules inside EVs. By attaching CNF sheets to moistened organs, we collect EVs in trace amounts of ascites, which is sufficient to perform small RNA sequence analyses. In an ovarian cancer mouse model, we demonstrate that CNF sheets enable the detection of cancer-associated miRNAs from the very early phase when mice did not have apparent ascites, and that EVs from different locations have unique miRNA profiles. By performing CNF sheet analyses in patients, we identify further location-based differences in EV miRNA profiles, with profiles reflecting disease conditions. We conduct spatial exosome analyses using CNF sheets to reveal that ascites EVs from cancer patients exhibit location-dependent heterogeneity. This technique could provide insights into EV biology and suggests a clinical strategy contributing to cancer diagnosis, staging evaluation, and therapy planning.

DOI： 10.1038/s41467-023-42593-9

Identifying high-grade serous ovarian carcinoma-specific extracellular vesicles by polyketone-coated nanowires 国際誌

Yokoi, A; Ukai, M; Yasui, T; Inokuma, Y; Hyeon-Deuk, K; Matsuzaki, J; Yoshida, K; Kitagawa, M; Chattrairat, K; Iida, M; Shimada, T; Manabe, Y; Chang, IY; Asano-Inami, E; Koya, Y; Nawa, A; Nakamura, K; Kiyono, T; Kato, T; Hirakawa, A; Yoshioka, Y; Ochiya, T; Hasegawa, T; Baba, Y; Yamamoto, Y; Kajiyama, H

SCIENCE ADVANCES 9 巻 ( 27 ) 頁： eade6958 2023年7月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Science Advances

Cancer cell-derived extracellular vesicles (EVs) have unique protein profiles, making them promising targets as disease biomarkers. High-grade serous ovarian carcinoma (HGSOC) is the deadly subtype of epithelial ovarian cancer, and we aimed to identify HGSOC-specific membrane proteins. Small EVs (sEVs) and medium/large EVs (m/lEVs) from cell lines or patient serum and ascites were analyzed by LC-MS/MS, revealing that both EV subtypes had unique proteomic characteristics. Multivalidation steps identified FRα, Claudin-3, and TACSTD2 as HGSOC-specific sEV proteins, but m/lEV-associated candidates were not identified. In addition, for using a simple-to-use microfluidic device for EV isolation, polyketone-coated nanowires (pNWs) were developed, which efficiently purify sEVs from biofluids. Multiplexed array assays of sEVs isolated by pNW showed specific detectability in cancer patients and predicted clinical status. In summary, the HGSOC-specific marker detection by pNW are a promising platform as clinical biomarkers, and these insights provide detailed proteomic aspects of diverse EVs in HGSOC patients.

DOI： 10.1126/sciadv.ade6958

Exosomes and extracellular vesicles: Rethinking the essential values in cancer biology 査読有り国際誌

Yokoi, A; Ochiya, T

SEMINARS IN CANCER BIOLOGY 74 巻頁： 79 - 91 2021年9月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Seminars in Cancer Biology

Extracellular vesicles (EVs) such as exosomes are released by all living cells and contain diverse bioactive molecules, including nucleic acids, proteins, lipids, and metabolites. Accumulating evidence of EV-related functions has revealed that these tiny vesicles can mediate specific cell-to-cell communication. Within the tumor microenvironment, diverse cells are actively interacting with their surroundings via EVs facilitating tumor malignancy by regulating malignant cascades including angiogenesis, immune modulation, and metastasis. This review summarizes the recent studies of fundamental understandings of EVs from the aspect of EV heterogeneity and highlights the role of EVs in the various steps from oncogenic to metastatic processes. The recognition of EV subtypes is necessary to identify which pathways can be affected by EVs and which subtypes can be targeted in therapeutic approaches or liquid biopsies.

DOI： 10.1016/j.semcancer.2021.03.032

Mechanisms of nuclear content loading to exosomes. 査読有り国際誌

Yokoi A, Villar-Prados A, Oliphint PA, Zhang J, Song X, De Hoff P, Morey R, Liu J, Roszik J, Clise-Dwyer K, Burks JK, O'Halloran TJ, Laurent LC, Sood AK

Science advances 5 巻 ( 11 ) 頁： eaax8849 2019年11月

Integrated extracellular microRNA profiling for ovarian cancer screening 査読有り国際誌

Yokoi, A; Matsuzaki, J; Yamamoto, Y; Yoneoka, Y; Takahashi, K; Shimizu, H; Uehara, T; Ishikawa, M; Ikeda, S; Sonoda, T; Kawauchi, J; Takizawa, S; Aoki, Y; Niida, S; Sakamoto, H; Kato, K; Kato, T; Ochiya, T

NATURE COMMUNICATIONS 9 巻 ( 1 ) 頁： 4319 - 4319 2018年10月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Nature Communications

A major obstacle to improving prognoses in ovarian cancer is the lack of effective screening methods for early detection. Circulating microRNAs (miRNAs) have been recognized as promising biomarkers that could lead to clinical applications. Here, to develop an optimal detection method, we use microarrays to obtain comprehensive miRNA profiles from 4046 serum samples, including 428 patients with ovarian tumors. A diagnostic model based on expression levels of ten miRNAs is constructed in the discovery set. Validation in an independent cohort reveals that the model is very accurate (sensitivity, 0.99; specificity, 1.00), and the diagnostic accuracy is maintained even in early-stage ovarian cancers. Furthermore, we construct two additional models, each using 9–10 serum miRNAs, aimed at discriminating ovarian cancers from the other types of solid tumors or benign ovarian tumors. Our findings provide robust evidence that the serum miRNA profile represents a promising diagnostic biomarker for ovarian cancer.

DOI： 10.1038/s41467-018-06434-4

Malignant extracellular vesicles carrying <i>MMP1</i> mRNA facilitate peritoneal dissemination in ovarian cancer 査読有り国際誌

Yokoi, A; Yoshioka, Y; Yamamoto, Y; Ishikawa, M; Ikeda, S; Kato, T; Kiyono, T; Takeshita, F; Kajiyama, H; Kikkawa, F; Ochiya, T

NATURE COMMUNICATIONS 8 巻頁： 14470 - 14470 2017年3月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Nature Communications

Advanced ovarian cancers are highly metastatic due to frequent peritoneal dissemination, resulting in dismal prognosis. Here we report the functions of cancer-derived extracellular vesicles (EVs), which are emerging as important mediators of tumour metastasis. The EVs from highly metastatic cells strongly induce metastatic behaviour in moderately metastatic tumours. Notably, the cancer EVs efficiently induce apoptotic cell death in human mesothelial cells in vitro and in vivo, thus resulting in the destruction of the peritoneal mesothelium barrier. Whole transcriptome analysis shows that MMP1 is significantly elevated in mesothelial cells treated with highly metastatic cancer EVs and intact MMP1 mRNAs are selectively packaged in the EVs. Importantly, MMP1 expression in ovarian cancer is tightly correlated with a poor prognosis. Moreover, MMP1 mRNA-carrying EVs exist in the ascites of cancer patients and these EVs also induce apoptosis in mesothelial cells. Our findings elucidate a previously unknown mechanism of peritoneal dissemination via EVs.

DOI： 10.1038/ncomms14470

Serum miRNA as a predictive biomarker for ovarian reserve after endometrioma-cystectomy 国際誌

Yabuki, A; Muraoka, A; Osuka, S; Yokoi, A; Yoshida, K; Kitagawa, M; Bayasura; Sonehara, R; Miyake, N; Nakanishi, N; Nakamura, T; Iwase, A; Kajiyama, H

REPRODUCTIVE BIOLOGY 24 巻 ( 1 ) 頁： 100821 - 100821 2024年3月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Reproductive Biology

Ovarian endometrioma (OE) is a common gynecological disease that is often treated with surgery and hormonal treatment. However, ovarian cystectomy can impair the ovarian reserve (OR). Previously, we showed that perioperative administration of dienogest (DNG) is an effective option for OR preservation. However, there were differences in the extent of OR preservation among patients following perioperative DNG treatment. In the current study, we performed a global examination of serum microRNAs (miRNAs) to identify accurate biomarkers that predict post-operative restoration of OR following perioperative DNG treatment. We also sought to identify specific miRNAs related to the anti-Müllerian hormone (AMH). miRNA sequencing was performed on serum samples obtained from twenty-seven patients who received perioperative DNG treatment. Candidate miRNAs were selected by comparing patients whose ORs were restored postoperatively (responder group, n = 7) with those whose ORs were not (non-responder group, n = 7). miR-370–3p and miR-1307–3p were significantly upregulated in the responder group, whereas miR-27b-3p was upregulated in the non-responder group. The pretreatment value of each miRNA could predict DNG responsiveness for OR following ovarian cystectomy (area under the curve [AUC] > 0.8). The quantitative polymerase chain reaction (qPCR) revealed only miR-1307–3p was found to be significantly upregulated in the responder group (P < 0.05). In addition, we identified miR-139–3p, miR-140–3p, and miR-629–5p as AMH-associated miRNAs. The transition of AMH showed a correlation with miR-139–3p (P < 0.05, r = −0.76). The miRNAs identified herein represent potential serum biomarkers of clinical value in predicting OR prior to DNG treatment.

DOI： 10.1016/j.repbio.2023.100821

Small extracellular vesicles in follicular fluids for predicting reproductive outcomes in assisted reproductive technology 国際誌

Muraoka, A; Yokoi, A; Yoshida, K; Kitagawa, M; Asano-Inami, E; Murakami, M; Bayasula; Miyake, N; Nakanishi, N; Nakamura, T; Osuka, S; Iwase, A; Kajiyama, H

COMMUNICATIONS MEDICINE 4 巻 ( 1 ) 頁： 33 - 33 2024年2月

Uterine leiomyosarcoma cell-derived extracellular vesicles induce the formation of cancer-associated fibroblasts. 国際誌

Nagao Y, Yokoi A, Yoshida K, Kitagawa M, Asano-Inami E, Kato T, Ishikawa M, Yamamoto Y, Kajiyama H

Biochimica et biophysica acta. Molecular basis of disease 1870 巻 ( 4 ) 頁： 167103 - 167103 2024年2月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Biochimica et Biophysica Acta - Molecular Basis of Disease

Objective: Uterine leiomyosarcoma (ULMS) is a rare malignant tumor, which is aggressive, and has a poor prognosis even during its early stages. Extracellular vesicles (EVs) carry cargo, such as microRNAs (miRNAs), which are involved in intercellular communication in the tumor microenvironment and other processes. Because there are no studies on EV-related miRNAs in ULMS, we identified EV-related miRNAs in ULMS and examined their function. Methods: Small EVs (sEVs) and medium/large EVs (m/lEVs) were extracted from ULMS cells by ultracentrifugation and their basic characteristics were evaluated. Then, small RNA sequencing was done to obtain EV-related miRNA profiles. Next, miRNA expression levels in sera and tissues of ULMS patients were compared with those of myoma patients. Results: miR-654-3p and miR-369-3p were indicated to be highly expressed in both sera and tissues of ULMS patients. These two miRNAs are also highly expressed in ULMS cell lines and ULMS-derived EVs. Some cancer-associated fibroblast (CAF) markers were increased when fibroblasts were treated with ULMS-derived EVs. Furthermore, fibroblasts took up EVs derived from ULMS as determined by confocal laser microscopy. In addition, the transfection of the two candidate miRNAs into fibroblasts significantly increased some CAF markers, particularly ACTA2. Conclusion: miR-654-3p and miR-369-3p are highly expressed in ULMS-derived EVs, indicating that these EV-related miRNAs induce the formation of cancer-associated fibroblasts.

DOI： 10.1016/j.bbadis.2024.167103

An update of oncologic and obstetric outcomes of radical trachelectomy for early-stage cervical cancer: The need for further minimally invasive treatment 国際誌

Tamauchi, S; Iyoshi, S; Yoshihara, M; Yoshida, K; Ikeda, Y; Shimizu, Y; Yokoi, A; Niimi, K; Yoshikawa, N; Kajiyama, H

JOURNAL OF OBSTETRICS AND GYNAECOLOGY RESEARCH 50 巻 ( 2 ) 頁： 175 - 181 2024年2月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Journal of Obstetrics and Gynaecology Research

Aims: To investigate the oncologic and obstetric outcomes of radical trachelectomy (RT) in patients with early-stage cervical cancer and to evaluate the potential role of fertility-preserving treatments in improving pregnancy outcomes while oncologic status is stable. Methods: In this single-institution study, we analyzed the oncologic and obstetric outcomes of 67 patients with early-stage cervical cancer who underwent RT at Nagoya University Hospital. Results: The cancer recurrence rate (6.0%) and the mortality rate (1.5%) were comparable with those of previous studies. Of the 46 patients who attempted to conceive after RT, 19 (41.3%) became pregnant, and 16 gave birth. Of these 37.5% delivered at term, and delivery at less than 28 weeks of gestation occurred in 31.3% of pregnancies. Conclusions: RT is a viable treatment option for selected patients with early-stage cervical cancer. However, the use of less invasive techniques, such as conization/simple trachelectomy and pelvic lymph node dissection, may improve pregnancy outcomes while oncologic status is stable.

DOI： 10.1111/jog.15824

Minimal information for studies of extracellular vesicles (MISEV2023): From basic to advanced approaches 国際誌

Welsh J.A., Goberdhan D.C.I., O’Driscoll L., Buzas E.I., Blenkiron C., Bussolati B., Cai H., Di Vizio D., Driedonks T.A.P., Erdbrügger U., Falcon-Perez J.M., Fu Q.L., Hill A.F., Lenassi M., Lim S.K., Mahoney M.ỹ.G., Mohanty S., Möller A., Nieuwland R., Ochiya T., Sahoo S., Torrecilhas A.C., Zheng L., Zijlstra A., Abuelreich S., Bagabas R., Bergese P., Bridges E.M., Brucale M., Burger D., Carney R.P., Cocucci E., Crescitelli R., Hanser E., Harris A.L., Haughey N.J., Hendrix A., Ivanov A.R., Jovanovic-Talisman T., Kruh-Garcia N.A., Faustino V.K.L., Kyburz D., Lässer C., Lennon K.M., Lötvall J., Maddox A.L., Martens-Uzunova E.S., Mizenko R.R., Newman L.A., Ridolfi A., Rohde E., Rojalin T., Rowland A., Saftics A., Sandau U.S., Saugstad J.A., Shekari F., Swift S., Ter-Ovanesyan D., Tosar J.P., Useckaite Z., Valle F., Varga Z., van der Pol E., van Herwijnen M.J.C., Wauben M.H.M., Wehman A.M., Williams S., Zendrini A., Zimmerman A.J., Théry C., Witwer K.W., Ahmad S., Ahmed D.A.K., Ahmed S.H., Aikawa E., Akbar N., Akiyoshi K., Al-Adra D.P., Al-Masawa M.E., Albanese M., Alberro A., Alcaraz M.J., Alexander-Brett J., Alexander K.L., Ali N., Alibhai F.J., Allelein S., Allenby M.C., Almeida F., de Almeida L.P., Almousa S.W., Altan-Bonnet N., Altei W.F., Alvarez-Llamas G., Alvarez C.L., An H.J., Anand K., Andaloussi S.E.L., Anderson J.D.

Journal of Extracellular Vesicles 13 巻 ( 2 ) 頁： e12404 2024年2月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Journal of Extracellular Vesicles

Extracellular vesicles (EVs), through their complex cargo, can reflect the state of their cell of origin and change the functions and phenotypes of other cells. These features indicate strong biomarker and therapeutic potential and have generated broad interest, as evidenced by the steady year-on-year increase in the numbers of scientific publications about EVs. Important advances have been made in EV metrology and in understanding and applying EV biology. However, hurdles remain to realising the potential of EVs in domains ranging from basic biology to clinical applications due to challenges in EV nomenclature, separation from non-vesicular extracellular particles, characterisation and functional studies. To address the challenges and opportunities in this rapidly evolving field, the International Society for Extracellular Vesicles (ISEV) updates its ‘Minimal Information for Studies of Extracellular Vesicles’, which was first published in 2014 and then in 2018 as MISEV2014 and MISEV2018, respectively. The goal of the current document, MISEV2023, is to provide researchers with an updated snapshot of available approaches and their advantages and limitations for production, separation and characterisation of EVs from multiple sources, including cell culture, body fluids and solid tissues. In addition to presenting the latest state of the art in basic principles of EV research, this document also covers advanced techniques and approaches that are currently expanding the boundaries of the field. MISEV2023 also includes new sections on EV release and uptake and a brief discussion of in vivo approaches to study EVs. Compiling feedback from ISEV expert task forces and more than 1000 researchers, this document conveys the current state of EV research to facilitate robust scientific discoveries and move the field forward even more rapidly.

DOI： 10.1002/jev2.12404

Effect of radical trachelectomy on ovarian reserve: A single-institute prospective study 国際誌

Nakagawa, A; Tamauchi, S; Sato, M; Yoshihara, M; Yokoi, A; Shimizu, Y; Ikeda, Y; Yoshikawa, N; Niimi, K; Osuka, S; Kajiyama, H

JOURNAL OF OBSTETRICS AND GYNAECOLOGY RESEARCH 50 巻 ( 2 ) 頁： 212 - 217 2024年2月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Journal of Obstetrics and Gynaecology Research

Aim: Reduced responses to controlled ovarian stimulation (COS) after radical trachelectomy (RT) have been previously reported. We aimed to assess the effect of RT on ovarian reserve by measuring anti-Müllerian hormone (AMH) levels before and after the procedure in this prospective study. Methods: We included 12 patients who underwent RT between September 2019 and December 2021 in this study. Serum AMH levels were measured preoperatively, 1 month postoperatively, and 6 months postoperatively. Differences in the AMH levels were assessed using a paired t-test. Results: The median age of the patients was 30.6 years, and the median follow-up time was 30.1 months. AMH levels at 1 and 6 months postoperatively did not show a consistent trend. At 1 month postoperatively, the average AMH level decreased insignificantly but returned to preoperative levels at 6 months. The differences in AMH levels before and after RT were insignificant. Conclusion: Our findings indicate that RT did not affect ovarian reserve as measured by AMH levels. However, the relationship between unchanged ovarian reserve and reduced response to COS remains unclear. Further research with larger sample sizes and additional measures of ovarian function is needed to corroborate these results and investigate the long-term effects of RT on ovarian reserve. Understanding these mechanisms will help guide surgical practices and provide patients with valuable information about their reproductive outcomes after RT.

DOI： 10.1111/jog.15828

Emerging bacterial factors for understanding pathogenesis of endometriosis 国際誌

Muraoka, A; Yokoi, A; Kajiyama, H

ISCIENCE 27 巻 ( 1 ) 頁： 108739 - 108739 2024年1月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：iScience

The pathogenesis of endometriosis is a complex process, and recent research has introduced novel hypotheses in this field. This review summarizes recent studies on the pathogenesis of endometriosis. We focused on several classical hypotheses, as well as their interactions with the microenvironment of hormonal dependence and immunosuppression. Furthermore, we highlighted the emergence of bacterial factors associated with endometriosis. Recent advances in next-generation sequencing (NGS) have revealed the presence and detailed distribution of these bacteria as well as the involvement of specific bacteria in pathogenesis. These factors alter the microenvironment in the early stages of endometriosis development, leading to lesion formation. Understanding the mechanisms underlying the early development of endometriosis from a new perspective would be helpful for the development of novel therapeutic agents for endometriosis.

DOI： 10.1016/j.isci.2023.108739

Mean platelet volume as a potential biomarker for survival outcomes in ovarian clear cell carcinoma

Yoshikawa, N; Matsukawa, T; Hattori, S; Iyoshi, S; Yoshida, K; Yoshihara, M; Tamauchi, S; Shimizu, Y; Ikeda, Y; Yokoi, A; Niimi, K; Kawai, M; Kajiyama, H

INTERNATIONAL JOURNAL OF CLINICAL ONCOLOGY 28 巻 ( 12 ) 頁： 1680 - 1689 2023年12月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：International Journal of Clinical Oncology

Objective: This study aimed to explore the prognostic value of mean platelet volume (MPV) in patients with ovarian clear cell carcinoma (OCCC) and evaluate the predictive performance of a random forest model incorporating MPV and other key clinicopathological factors. Methods: A total of 204 patients with OCCC treated between January 2004 and December 2019 were retrospectively analyzed. Clinicopathological characteristics and preoperative laboratory data were collected, and survival outcomes were evaluated using the Kaplan–Meier method and Cox proportional hazards models. An optimal MPV cutoff was determined by receiver operating characteristic (ROC) curve analysis. A random forest model was then constructed using the identified independent prognostic factors, and its predictive performance was evaluated. Results: The ROC analysis identified 9.3 fL as the MPV cutoff value for predicting 2-year survival. The MPV-low group had lower 5-year overall survival and progression-free survival rates than the MPV-high group (p = 0.003 and p = 0.034, respectively). High MPV emerged as an independent prognostic factor (p = 0.006). The random forest model, incorporating the FIGO stage, residual tumors, peritoneal cytology, and MPV, demonstrated robust predictive performance (area under the curve: 0.905). Conclusion: MPV is a promising prognostic indicator in OCCC. Lower MPV correlated with worse survival rates, advocating its potential utility in refining patient management strategies. The commendable predictive performance of the random forest model, integrating MPV and other significant prognostic factors, suggests a pathway toward enhanced survival prediction, thereby warranting further research.

DOI： 10.1007/s10147-023-02417-8

Establishment and characterization of a non-gestational choriocarcinoma patient-derived xenograft model 国際誌

Oda, Y; Niimi, K; Yoshida, K; Tamauchi, S; Yokoi, A; Yasui, Y; Nishiko, Y; Shibata, M; Shimizu, Y; Yoshihara, M; Ikeda, Y; Yoshikawa, N; Nishino, K; Yamamoto, E; Kajiyama, H

BMC CANCER 23 巻 ( 1 ) 頁： 1103 - 1103 2023年11月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：BMC Cancer

Background: Non-gestational choriocarcinoma (NGC) is a rare subtype of malignant germ cell tumour and there is no consensus on its treatment. The lack of suitable preclinical models for NGC is a challenge in drug discovery research. Patient-derived xenograft (PDX) models recapitulate the tumour microenvironment of the original cancer tissue. Therefore, they have received considerable attention for studies on rare cancer. Here, we aimed to establish a PDX model from a patient with recurrent NGC. Methods: Fresh NGC tumour tissue was immediately transplanted into a severely immune-deficient mouse (NOD.Cg-Prkdc scid 1l2rg tm1Wjl/SzJ) and maintained for more than three in vivo passages. Subsequently, we evaluated the molecular characteristics of the PDX model using immunohistochemistry, polymerase chain reaction, and RNA sequencing. Moreover, the PDX tumours were transplanted into BALB/c nude mice, and we evaluated their sensitivity for cisplatin and methotrexate. Results: The PDX tumour maintained the morphological features of NGC. Moreover, Immunohistochemistry revealed that the human chorionic gonadotropin, cytokeratin 7, and EpCAM expression levels were similar to those in the primary tumour. Furthermore, serum human chorionic gonadotropin levels were elevated in both the primary tumour and the PDX models. Additionally, using PCR analysis with species-specific primers, we confirmed that the PDX tumour contained human genes and was derived from human tissue. Moreover, the gene expression profile of the NGC was compared with that of epithelial ovarian cancer samples and cell lines, and 568 dysregulated genes in the NGC were extracted. The expression of the dysregulated genes in PDX was significantly correlated with that in the primary tumour (R2 = 0.873, P < 0.001). Finally, we demonstrated that the PDX tumour was sensitive to cisplatin and methotrexate; therefore, its clinical response to the agents was similar to that of the primary tumour. Conclusions: We successfully established a PDX model of NGC, to the best of our knowledge, for the first time. The established PDX retained the molecular and transcriptome characteristics of the primary tumour and can be used to predict drug effects. It may facilitate further research and the development of novel therapeutic agents for NGC.

DOI： 10.1186/s12885-023-11626-3

9-oxo-ODAs suppresses the proliferation of human cervical cancer cells through the inhibition of CDKs and HPV oncoproteins 国際誌

Mogi, K; Koya, Y; Yoshihara, M; Sugiyama, M; Miki, R; Miyamoto, E; Fujimoto, H; Kitami, K; Iyoshi, S; Tano, S; Uno, K; Tamauchi, S; Yokoi, A; Shimizu, Y; Ikeda, Y; Yoshikawa, N; Niimi, K; Yamakita, Y; Tomita, H; Shibata, K; Nawa, A; Tomoda, Y; Kajiyama, H

SCIENTIFIC REPORTS 13 巻 ( 1 ) 頁： 19208 - 19208 2023年11月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Scientific Reports

Mucosal human papillomavirus (HPV) subtypes 16 and 18 are causative agents of cervical cancer, a leading cause of cancer-related deaths among women worldwide. In Japan, eggplant calyx is a folk remedy used to treat common warts. 9-oxo-(10E,12E)-octadecadienoic acid, isolated from eggplant calyx, may have antitumor effects. This study investigated the antitumor effects of 9-oxo-(10E, 12Z)-octadecadienoic acid and 9-oxo-(10E,12E)-octadecadienoic acid (9-oxo-ODAs) on human cervical cancer cells. 9-oxo-ODAs suppressed the proliferation of human cervical cancer cell lines (HeLa, and SiHa) in a concentration-dependent manner (IC50 = 25–50 µM). FCM analysis revealed that 9-oxo-ODAs induced apoptosis. Transcriptome, proteomics, and enrichment analyses revealed that treatment with 9-oxo-ODAs significantly altered the cell cycle and p53 pathways and decreased cyclin-dependent kinase 1 (CDK1) protein expression. Real-time PCR analysis demonstrated that 9-oxo-ODAs reduced CDK1 mRNA expression in a concentration-dependent manner. In vitro, 9-oxo-ODAs reduced the HPV oncoprotein expression. In ex vivo human cervical cancer tissues, 9-oxo-ODAs decreased CDK1 expression and increased cleaved caspase 3, an apoptosis marker. Further, 9-oxo-ODAs showed the potential to suppressed metastatic formation and growth of cervical cancer in vivo. These findings suggest that 9-oxo-ODAs induce cell cycle arrest and apoptosis in HPV-positive human cervical cancer cells, and this process involves CDK1. Consequently, 9-oxo-ODAs may be potential therapeutic agents for cervical cancer.

DOI： 10.1038/s41598-023-44365-3

Small Extracellular Vesicles from adipose-derived stem cells suppress cell proliferation by delivering the let-7 family of microRNAs in ovarian cancer 国際誌

Suzuki, H; Yokoi, A; Uno, K; Yoshida, K; Kitagawa, M; Asano-Inami, E; Matsuo, S; Nagao, Y; Suzuki, K; Nakamura, K; Yoshihara, M; Tamauchi, S; Shimizu, Y; Ikeda, Y; Yoshikawa, N; Kajiyama, H; Yamamoto, Y

BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS 680 巻頁： 211 - 219 2023年11月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Biochemical and Biophysical Research Communications

Introduction: Ovarian cancer is the leading cause of death among women with gynecological cancer, and novel treatment options are urgently needed. Extracellular vesicles (EVs), including exosomes, may be one of the most promising therapeutic tools for various diseases. In this study, we aimed to investigate the therapeutic effects of adipose-derived stem cell-derived EVs (ADSC-EVs) on ovarian cancer cell lines. Materials and methods: ADSCs and the ovarian cancer cell lines SKOV3 and OV90 were used for analysis. ADSC-EVs were isolated through ultracentrifugation and validated using a cryotransmission electron microscope, nanoparticle tracking analysis, and western blotting. Then, the effect of ADSC-EVs on ovarian cancer cells was investigated using IncuCyte and microRNA sequencing. Moreover, the potential functions of miRNAs were evaluated by gain-of function analysis and in silico analysis. Results: ADSC-EVs suppressed SKOV3 and OV90 cell proliferation. In particular, small EVs (sEVs) from ADSCs exhibited a stronger antitumor effect than ADSC-medium/large EVs (m/lEVs). Comparison of the miRNA profiles between ADSC-sEVs and ADSC-m/lEVs, along with downstream pathway analysis, suggested the involvement of the let-7 family. Overexpression of hsa-let-7b-5p and hsa-let-7e-5p significantly suppressed the proliferation of SKOV3 cells. In silico analysis revealed that four potential target genes of hsa-let-7b-5p and hsa-let-7e-5p were significantly associated with the prognoses of the patients. Conclusion: ADSC-sEVs had a stronger antitumor effect than ADSC-m/lEVs. Hsa-let-7b-5p and hsa-let-7e-5p, which are highly abundant in ADSC-sEVs, suppressed cell proliferation. These findings may open up new possibilities for therapeutic approaches using ADSC-sEVs.

DOI： 10.1016/j.bbrc.2023.09.022

The sarcopenia index measured using the lumbar paraspinal muscle is associated with prognosis in endometrial cancer 国際誌

Uno, K; Yoshikawa, N; Kitami, K; Mori, S; Shibata, T; Iyoshi, S; Fujimoto, H; Mogi, K; Yoshihara, M; Tamauchi, S; Ikeda, Y; Yokoi, A; Kato, K; Hoshiba, T; Oguchi, H; Kajiyama, H

JAPANESE JOURNAL OF CLINICAL ONCOLOGY 53 巻 ( 10 ) 頁： 942 - 949 2023年10月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Japanese Journal of Clinical Oncology

Objective: The number of type-II endometrial cancer patients has been increasing and the prognosis is not favorable. We aim to investigate whether sarcopenia index in any of several different muscles could serve as a novel biomarker of prognosis in patients with type-II endometrial cancer. Methods: We retrospectively investigated a total of 194 patients at four hospitals. Ninety patients were treated as derivation set and the other 104 patients as validation set. Using preoperative computed tomography images, we measured the horizontal cross-sectional area at the third lumbar spine level: the (i) psoas major, (ii) iliac and (iii) paraspinal muscle. The clinical information including recurrence-free survival and overall survival were retrospectively collected. These results were validated with external data sets of three hospitals. Results: The median values of the sarcopenia index (cm2/m2) ± standard deviation with the first data of 90 patients using the psoas, iliac and paraspinal muscle were 3.4 ± 1.0, 1.7 ± 0.6 and 12.6 ± 3.2, respectively. In univariate analyses, the sarcopenia indexes measured using the psoas or paraspinal muscle were associated with recurrence-free survival and overall survival. On the other hand, in multivariate analyses, only the sarcopenia index using paraspinal muscle was significantly related to recurrence-free survival (hazard ratio = 3.78, 95% confidence intervals = 1.29-5.97, P = 0.009) and overall survival (hazard ratio = 3.13, 95% confidence interval = 1.18-8.26, P = 0.022). Paraspinal sarcopenia index was also related to overall survival (hazard ratio = 3.74, 95% confidence interval = 1.31-10.72, P = 0.014) even in patients with advanced stage. Serum albumin was significantly correlated with the sarcopenia index (P = 0.012). Within the analysis of the validation set, sarcopenia index using paraspinal muscle was related to recurrence-free survival (hazard ratio = 2.06, P = 0.045) in multivariate analysis and recurrence-free survival (P = 0.009) in patients with advanced stage. Conclusions: The sarcopenia index using the paraspinal muscle, not psoas, could be a suitable index to predict recurrence-free survival and overall survival in patients with type-II endometrial cancer even in advanced stage.

DOI： 10.1093/jjco/hyad086

Interleukin-17A stimulation induces alterations in Microglial microRNA expression profiles 国際誌

Iitani, Y; Miki, R; Imai, K; Fuma, K; Ushida, T; Tano, S; Yoshida, K; Yokoi, A; Kajiyama, H; Kotani, T

PEDIATRIC RESEARCH 95 巻 ( 1 ) 頁： 167 - 173 2023年9月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Pediatric Research

Background: Increased maternal interleukin (IL)-17A and activated microglia are pivotal factors contributing to the pathological phenotypes of maternal immune activation (MIA), developing neurodevelopmental disorders in offspring. This study aimed to determine whether IL-17A affects the microglial microRNA (miRNA) profiles. Methods: The miRNA expression profiles of primary cultured microglia stimulated with recombinant IL-17A were examined comprehensively using miRNA sequencing and validated through qRT-PCR. The expressions of miRNAs target genes identified using bioinformatics, were investigated in microglia transfected with mimic miRNA. The target gene’s expression was also examined in the fetal brains of the MIA mouse model induced by maternal lipopolysaccharide (LPS) administration. Results: Primary cultured microglia expressed the IL-17A receptor and increased proinflammatory cytokines and nitric oxide synthase 2 upon treatment with IL-17A. Among the three miRNAs with |log2FC | >1, only mmu-miR-206-3p expression was significantly up-regulated by IL-17A. Transfection with the mmu-miR-206-3p mimic resulted in a significant decrease in the expression of Hdac4 and Igf1, target genes of mmu-miR-206-3p. Hdac4 expression also significantly decreased in the LPS-induced MIA model. Conclusions: IL-17A affected microglial miRNA profiles with upregulated mmu-miR-206-3p. These findings suggest that targeting the IL-17A/mmu-miR-206-3p pathway may be a new strategy for predicting MIA-related neurodevelopmental deficits and providing preventive interventions. Impact: Despite the growing evidence of interleukin (IL)-17A and microglia in the pathology of maternal immune activation (MIA), the downstream of IL-17A in microglia is not fully known.IL-17A altered microRNA profiles and upregulated the mmu-miR-206-3p expression in microglia. The mmu-miR-206-3p reduced autism spectrum disorder (ASD) related gene expressions, Hdac4 and Igf1.The Hdac4 expression was also reduced in the brain of MIA offspring.The hsa-miR-206 sequence is consistent with that of mmu-miR-206-3p.This study may provide clues to pathological mechanisms leading to predictions and interventions for ASD children born to mothers with IL-17A-related disorders.

DOI： 10.1038/s41390-023-02825-6

DDIT4 Facilitates Lymph Node Metastasis via the Activation of NF-kB Pathway and Epithelial-Mesenchymal Transition 国際誌

Lin, XX; Yoshikawa, N; Liu, WT; Matsukawa, T; Nakamura, K; Yoshihara, M; Koya, Y; Sugiyama, M; Tamauchi, S; Ikeda, Y; Yokoi, A; Shimizu, Y; Kajiyama, H

REPRODUCTIVE SCIENCES 30 巻 ( 9 ) 頁： 2829 - 2841 2023年9月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Reproductive Sciences

This study was aimed to identify a novel metastasis-promoting molecule and elucidate its functional and prognostic roles in cervical cancer. DDIT4 (DNA-damage-inducible transcript 4), a hypoxia-inducible gene, was identified by analyzing multiple microarray databases. The correlation between DDIT4 expression in immunohistochemistry and clinicopathological characteristics in the public database and our cohort was evaluated by statistical analysis. Transwell® assay and wound-healing assay to determine cell migration and invasion were performed. DDIT4 was knocked down using siRNA or lentiviral vectors. The potential downstream pathways of DDIT4 were explored and verified by a gene set enrichment analysis and western blotting. The in vivo metastatic capability was determined with the use of an intraperitoneal injection mouse model. In the analysis of the public database and our cohort, DDIT4 high expression was significantly related to short overall survival and lymph node metastasis in patients with early-stage cervical cancer. The knockdown of DDIT4 attenuated the migration and invasion activity of tumor cells in vitro and reduced the expression of epithelial–mesenchymal transition (EMT)-related proteins and the NF-κB pathway in cervical cancer cells. DDIT4 also promoted tumor progression in the mouse model. Our results indicate that DDIT4 can be a prognostic indicator in cervical cancer and promote lymph node metastasis, augmenting malignancy via the EMT and NF-kB pathways.

DOI： 10.1007/s43032-023-01230-y

Downregulating vaccinia-related kinase 1 by luteolin suppresses ovarian cancer cell proliferation by activating the p53 signaling pathway 国際誌

Chang, X; Tamauchi, S; Yoshida, K; Yoshihara, M; Yokoi, A; Shimizu, Y; Ikeda, Y; Yoshikawa, N; Kiyono, T; Yamamoto, Y; Kajiyama, H

GYNECOLOGIC ONCOLOGY 173 巻頁： 31 - 40 2023年6月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Gynecologic Oncology

Objectives: Ovarian cancer constitutes one of the most common causes of cancer-related deaths, and preventing chemotherapy resistance and recurrence in patients with ovarian cancer remains a challenge. Herein, we aimed to identify the effect of luteolin, a novel therapeutic agent targeting vaccinia-related kinase 1 (VRK1), on high-grade serous ovarian cancer (HGSOC). Methods: Phosphokinase array, RNA sequencing, and cell cycle and apoptosis assays were conducted to determine the underlying mechanism of the effect of luteolin on HGSOC cells. The anticancer effects of oral and intraperitoneal luteolin administration were assessed in patient-derived xenograft models via several methods, including the assessment of tumor size and immunohistochemistry of phospho-p53, phosphor-HistoneH3 and cleaved caspase 3. Results: Luteolin reduced HGSOC cell proliferation and increased apoptosis and cell cycle arrest at G2/M. Compared with controls, several genes were dysregulated in luteolin-treated cells, and luteolin activated the p53 signaling pathway. The human phosphokinase array revealed distinct p53 upregulation in luteolin-treated cells, as confirmed by p53 phosphorylation at ser15 and ser46 using western blot analysis. In patient-derived xenograft models, oral or intraperitoneal luteolin administration substantially suppressed tumor growth. Moreover, combination treatment involving luteolin and cisplatin inhibited tumor cell proliferation, especially in cisplatin-resistant HGSOC cell lines. Conclusions: Luteolin demonstrated considerable anticancer effect on HGSOC cells, reduced VRK1 expression, and activated the p53 signaling pathway, thereby inducing apoptosis and cell cycle arrest in G2/M and inhibiting cell proliferation. Furthermore, luteolin exhibited a synergistic effect with cisplatin both in vivo and in vitro. Thus, luteolin can be considered a promising cotreatment option for HGSOC.

DOI： 10.1016/j.ygyno.2023.04.003

Downregulation of miR-10b-5p facilitates the proliferation of uterine leiomyosarcoma cells: A microRNA sequencing-based approach 査読有り

Yoshida, K; Yokoi, A; Kitagawa, M; Sugiyama, M; Yamamoto, T; Nakayama, J; Yoshida, H; Kato, T; Kajiyama, H; Yamamoto, Y

ONCOLOGY REPORTS 49 巻 ( 5 ) 2023年5月

担当区分：責任著者記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Oncology Reports

Uterine leiomyosarcoma (ULMS) is one of the most aggressive gynecological malignancies. In addition, the molecular background of ULMS has not been fully elucidated due to its low incidence. Therefore, no effective treatment strategies have been established based on its molecular back- ground. The present study aimed to investigate the roles of microRNAs (miRNAs/miRs) in the development of ULMS. Comprehensive miRNA sequencing was performed using six ULMS and three myoma samples, and revealed 53 and 11 significantly upregulated and downregulated miRNAs, respectively. One of the most abundant miRNAs in myoma samples was miR-10b-5p. The mean normalized read count of miR-10b-5p was 93,650 reads in myoma, but only 27,903 reads in ULMS. Subsequently, to investigate the roles of miR-10b-5p, gain-of-function analysis was performed using SK-UT-1 and SK-LMS-1 cell lines. The overexpression of miR-10b-5p suppressed cell proliferation and reduced the number of colonies. Moreover, miR-10b-5p increased the number of cells in the G1 phase. In conclusion, tumor-suppressive miR-10b-5p was significantly downregulated in ULMS compared with in myoma; thus, miR-10b-5p may serve a specific role in sarcoma progression.

DOI： 10.3892/or.2023.8523

Preoperative serum microRNAs as potential prognostic biomarkers in ovarian clear cell carcinoma 査読有り国際誌

Suzuki, K; Yokoi, A; Yoshida, K; Kato, T; Ochiya, T; Yamamoto, Y; Kajiyama, H

JOURNAL OF GYNECOLOGIC ONCOLOGY 34 巻 ( 3 ) 頁： e34 - 3310 2023年5月

担当区分：責任著者記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Journal of Gynecologic Oncology

Objective: Ovarian clear cell carcinoma (OCCC) is a subtype of epithelial ovarian carcinoma with poor prognosis. However, no effective biomarkers have been established for predicting unfavorable events, including recurrence and poor prognoses. Serum microRNAs (miRNAs) have been increasingly reported to be useful in predicting a patient’s condition and have been recognized as a potentially less-invasive source for liquid biopsy in cancer. Therefore, this study aimed to evaluate serum miRNA profiles from patients with OCCC and to establish biomarker for predicting the prognoses. Methods: The GSE106817, which included preoperative serum miRNA profiles of patients with ovarian tumors, was used, and clinical information was investigated. In all, 66 patients with OCCC were included, excluding those with other histological subtypes or insufficient prognostic information. Moreover, miRNA profiles of OCCC tissues were also examined. Results: The median follow-up period was 64.3 (8.0–153.3) months. Based on multivariable Cox regression analyses and the expression of miRNAs in OCCC tissues, miR-150-3p, miR-3195, and miR-7704 were selected as miRNA candidates associated with both progression-free survival (PFS) and overall survival (OS). Then, the prognostic index was calculated based on expression values of 3 serum miRNAs. Kaplan-Meier survival analysis indicated that the prognostic index was significantly predictive of PFS and OS (p=0.004 and p=0.012, respectively). Conclusion: Preoperative serum miRNA profiles of miR-150-3p, miR-3195, and miR-7704 can be used to potentially predict the prognosis of patients with OCCC.

DOI： 10.3802/jgo.2023.34.e34

The association of UBAP2L and G3BP1 mediated by small nucleolar RNA is essential for stress granule formation 査読有り国際誌

Asano-Inami, E; Yokoi, A; Sugiyama, M; Hyodo, T; Hamaguchi, T; Kajiyama, H

COMMUNICATIONS BIOLOGY 6 巻 ( 1 ) 頁： 415 - 415 2023年4月

担当区分：責任著者記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Communications Biology

Stress granules (SGs) are dynamic, non-membranous structures composed of non-translating mRNAs and various proteins and play critical roles in cell survival under stressed conditions. Extensive proteomics analyses have been performed to identify proteins in SGs; however, the molecular functions of these components in SG formation remain unclear. In this report, we show that ubiquitin-associated protein 2-like (UBAP2L) is a crucial component of SGs. UBAP2L localized to SGs in response to various stresses, and its depletion significantly suppressed SG organization. Proteomics and RNA sequencing analyses found that UBAP2L formed a protein-RNA complex with Ras-GTP-activating protein SH3 domain binding protein 1 (G3BP1) and small nucleolar RNAs (snoRNAs). In vitro binding analysis demonstrated that snoRNAs were required for UBAP2L association with G3BP1. In addition, decreased expression of snoRNAs reduced the interaction between UBAP2L and G3BP1 and suppressed SG formation. Our results reveal a critical role of SG component, the UBAP2L/snoRNA/G3BP1 protein-RNA complex, and provide new insights into the regulation of SG assembly.

DOI： 10.1038/s42003-023-04754-w

Novel therapeutic strategies targeting UCP2 in uterine leiomyosarcoma 査読有り国際誌

Nagao, Y; Yokoi, A; Yoshida, K; Sugiyama, M; Watanabe, E; Nakamura, K; Kitagawa, M; Asano-Inami, E; Koya, Y; Yoshihara, M; Tamauchi, S; Shimizu, Y; Ikeda, Y; Yoshikawa, N; Kato, T; Yamamoto, Y; Kajiyama, H

PHARMACOLOGICAL RESEARCH 189 巻頁： 106693 - 106693 2023年3月

担当区分：責任著者記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Pharmacological Research

Uterine leiomyosarcoma (ULMS) is a malignant stromal tumor arising from the myometrium with a poor prognosis and very limited response to current chemotherapy. This study aimed to identify novel targets for ULMS through a three-step screening process using a chemical library consisting of 1271 Food and Drug Administration-approved drugs. First, we evaluated their inhibitory effects on ULMS cells and identified four candidates: proscillaridin A, lanatoside C, floxuridine, and digoxin. Then, we subcutaneously or orthotopically transplanted SK-UT-1 cells into mice to establish mouse models. In vivo analyses showed that proscillaridin A and lanatoside C exerted a superior antitumor effect. The results of mRNA sequencing showed that uncoupling protein 2 (UCP2) was suppressed in the sirtuin signaling pathway, increasing reactive oxygen species (ROS) and inducing cell death. Moreover, the downregulation of UCP2 induced ROS and suppressed ULMS cell growth. Furthermore, analyses using clinical samples showed that UCP2 expression was significantly upregulated in ULMS tissues than in myoma tissues both at the RNA and protein levels. These findings suggested that UCP2 is a potential therapeutic target and can contribute to the development of novel therapeutic strategies in patients with ULMS.

DOI： 10.1016/j.phrs.2023.106693

Drug library screening identifies histone deacetylase inhibition as a novel therapeutic strategy for choriocarcinoma 査読有り国際誌

Watanabe, E; Yokoi, A; Yoshida, K; Sugiyama, M; Kitagawa, M; Nishino, K; Yamamoto, E; Niimi, K; Yamamoto, Y; Kajiyama, H

CANCER MEDICINE 12 巻 ( 4 ) 頁： 4543 - 4556 2023年2月

担当区分：責任著者記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Cancer Medicine

Background: Choriocarcinoma is a rare and aggressive gynecological malignancy. The standard treatment is systemic chemotherapy as choriocarcinoma exhibits high chemosensitivity. However, refractory choriocarcinoma exhibits chemoresistance; thus, the prognosis remains very poor. This study aimed to identify novel therapeutic agents for choriocarcinoma by utilizing a drug repositioning strategy. Methods: Three choriocarcinoma cell lines (JAR, JEG-3, and BeWo) and a human extravillous trophoblast cell line (HTR-8/SVneo) were used for the analyses. The growth inhibitory effects of 1,271 FDA-approved compounds were evaluated in vitro screening assays and selected drugs were tested in tumor-bearing mice. Functional analyses of drug effects were performed based on RNA sequencing. Results: Muti-step screening identified vorinostat, camptothecin (S, +), topotecan, proscillaridin A, and digoxin as exhibiting an anti-cancer effect in choriocarcinoma cells. Vorinostat, a histone deacetylase inhibitor, was selected as a promising candidate for validation and the IC50 values for choriocarcinoma cells were approximately 1 μM. RNA sequencing and subsequent pathway analysis revealed that the ferroptosis pathway was likely implicated, and key ferroptosis-related genes (i.e., GPX4, NRF2, and SLC3A2) were downregulated following vorinostat treatment. Furthermore, vorinostat repressed tumor growth and downregulated the expression of GPX4 and NRF2 in JAR cell-bearing mice model. Conclusion: Vorinostat, a clinically approved drug for the treatment of advanced primary cutaneous T-cell lymphoma, showed a remarkable anticancer effect both in vitro and in vivo by regulating the expression of ferroptosis-related genes. Therefore, vorinostat may be an effective therapeutic candidate for patients with choriocarcinoma.

DOI： 10.1002/cam4.5243

Tumor suppressive miRNAs in small extracellular vesicles derived from ADSCs shows anti-tumor capacity in ovarian cancer

Suzuki, H; Yokoi, A; Uekusa, R; Kitagawa, M; Yoshida, K; Uno, K; Kajiyama, H

CANCER SCIENCE 114 巻頁： 1374 - 1374 2023年2月

Preoperative serum microRNAs as potential prognostic biomarkers in ovarian clear cell carcinoma

Suzuki, K; Yokoi, A; Yoshida, K; Kato, T; Ochiya, T; Yamamoto, Y; Kajiyama, H

CANCER SCIENCE 114 巻頁： 1986 - 1986 2023年2月

Novel exosome analyses for micro volume ascites in ovarian cancer dissemination

Yokoi, A; Yasui, T; Yoshida, K; Kitagawa, M; Kajiyama, H

CANCER SCIENCE 114 巻頁： 20 - 20 2023年2月

Notch signaling can be a new therapeutic target for advanced ovarian cancer

Sugiyama, M; Yoshihara, M; Koya, Y; Kitami, K; Uno, K; Iyoshi, S; Mogi, K; Yokoi, A; Nakamura, K; Nawa, A; Kajiyama, H

CANCER SCIENCE 114 巻頁： 2065 - 2065 2023年2月

Identifying Copy Number Variations in Extracellular Vesicles as a Novel Biomarker of High Grade Serous Ovarian Carcinoma

Uekusa, R; Yokoi, A; Kitagawa, M; Yoshida, K; Yoshihara, M; Tamauchi, S; Niimi, K; Matsuzaki, J; Yamamoto, Y; Kajiyama, H

CANCER SCIENCE 114 巻頁： 1063 - 1063 2023年2月

Aberrant activation of cell cycle-related kinases as novel therapeutic targets for uterine leiomyosarcoma

Yoshida, K; Yokoi, A; Kato, T; Kajiyama, H; Yamamoto, Y

CANCER SCIENCE 114 巻頁： 1457 - 1457 2023年2月

Aberrant activation of cell cycle-related kinases as novel therapeutic targets for uterine leiomyosarcoma

Yoshida, K; Yokoi, A; Kato, T; Kajiyama, H; Yamamoto, Y

CANCER SCIENCE 114 巻頁： 913 - 913 2023年2月

Development of mortality prediction models for infants with isolated, left-sided congenital diaphragmatic hernia before and after birth

Yoneda Kota, Amari Shoichiro, Mikami Masashi, Uchida Keiichi, Yokoi Akiko, Okawada Manabu, Furukawa Taizo, Toyoshima Katsuaki, Inamura Noboru, Okazaki Tadaharu, Yamoto Masaya, Masumoto Kouji, Terui Keita, Okuyama Hiroomi, Hayakawa Masahiro, Taguchi Tomoaki, Usui Noriaki, Isayama Tetsuya

PEDIATRIC PULMONOLOGY 58 巻 ( 1 ) 頁： 152 - 160 2023年1月

記述言語：英語出版者・発行元：Pediatric Pulmonology

Background: Mortality prediction of congenital diaphragmatic hernia (CDH) is essential for developing treatment strategies, including fetal therapy. Several researchers have reported prognostic factors for this rare but life-threatening condition; however, the optimal combination of prognostic factors remains to be elucidated. Objectives: This study aimed to develop the most discriminative prenatal and postnatal models to predict the mortality of infants with an isolated left-sided CDH. Methods: This multi-institutional retrospective cohort study included infants with CDH born at 15 tertiary hospitals of the Japanese CDH Study Group between 2011 and 2016. We developed multivariable logistic models with every possible combination of predictors and identified models with the highest cross-validated area under the receiver operating characteristic curve (AUC) for prenatal and postnatal predictions. Results: Among 302 eligible infants, 44 died before discharge. The prenatal mortality prediction model was based on the observed/expected lung area to head circumference ratio (O/E LHR), liver herniation, and stomach herniation (AUC, 0.830). The postnatal mortality prediction model was based on O/E LHR, liver herniation, and the lowest oxygenation index (AUC, 0.944). Conclusion: Our models can facilitate the prenatal and postnatal mortality prediction of infants with isolated left-sided CDH.

DOI： 10.1002/ppul.26172

The prognostic significance of DDIT4 in endometrial cancer 国際誌

Yoshikawa, N; Yoshida, K; Liu, WT; Matsukawa, T; Hattori, S; Yoshihara, M; Tamauchi, S; Ikeda, Y; Yokoi, A; Shimizu, Y; Niimi, K; Kajiyama, H

CANCER BIOMARKERS 37 巻 ( 4 ) 頁： 217 - 225 2023年

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Cancer Biomarkers

BACKGROUND: Despite extensive research on endometrial cancer and tumor hypoxic microenvironment, there are no reports exploring the role of DDIT4 in endometrial cancer. OBJECTIVE: This study aimed to elucidate the significance of DDIT4, as a prognostic biomarker for endometrial cancer by immunohistochemical staining and statistical analysis. METHODS: Four endometrial cancer cells were cultured under normoxia and hypoxia, and the differentially expressed genes were examined using RNA-seq. Immunohistochemical staining for DDIT4 and HIF1A was performed in 86 patients with type II endometrial cancer treated at our hospital, and their correlation with other clinicopathological factors and the prognostic role was analyzed using statistical methods. RESULTS: The expression analysis of hypoxia-inducible genes using four types of endometrial cancer cells revealed that DDIT4 was among the 28 genes that were upregulated in all cells. Based on our results of immunohistochemistry of DDIT4 expression in endometrial cancer tissues, univariate and multivariate analyses based on COX regression analysis showed that high DDIT4 expression significantly correlated to favorable prognosis in both progression-free survival and overall survival. Limited to recurrent cases, metastasis to only lymph nodes was significantly related to high DDIT4 expression, whereas metastasis to other parenchymal organs was significantly dominant in patients with low DDIT4 expression. CONCLUSIONS: The expression of DDIT4 enables to predict survival and recurrence in type II endometrial cancer.

DOI： 10.3233/CBM-220368

Prenatal predictors of mortality in fetuses with congenital diaphragmatic hernia: a systematic review and meta-analysis

Masahata Kazunori, Yamoto Masaya, Umeda Satoshi, Nagata Kouji, Terui Keita, Fujii Makoto, Shiraishi Masayuki, Hayakawa Masahiro, Amari Shoichiro, Masumoto Kouji, Okazaki Tadaharu, Inamura Noboru, Toyoshima Katsuaki, Koike Yuki, Furukawa Taizo, Yazaki Yuta, Yokoi Akiko, Endo Masayuki, Tazuke Yuko, Okuyama Hiroomi, Usui Noriaki

PEDIATRIC SURGERY INTERNATIONAL 38 巻 ( 12 ) 頁： 1745 - 1757 2022年12月

記述言語：英語出版者・発行元：Pediatric Surgery International

Purpose: This study aimed to evaluate prenatal predictors of mortality in fetuses with congenital diaphragmatic hernia (CDH). Methods: A systematic literature search was performed to identify relevant observational studies that evaluated the ability of lung-to-head ratio (LHR), observed-to-expected LHR (o/e-LHR), observed-to-expected total fetal lung volume (o/e-TFLV), lung-to-thorax transverse area ratio (L/T ratio), intrathoracic herniation of the liver and the stomach, and side of diaphragmatic hernia, using a threshold for the prediction of mortality in fetuses with CDH. Study quality was assessed using the QUADAS-2 tool. Hierarchical summary receiver operating characteristic curves were constructed. Results: A total of 50 articles were included in this meta-analysis. The QUADAS-2 tool identified a high risk of bias in more than one domain scored in all parameters. Among those parameters, the diagnostic odds ratio of mortality with o/e-LHR < 25%, o/e-TFLV < 25%, and L/T ratio < 0.08 were 11.98 [95% confidence interval (CI) 4.65–30.89], 11.14 (95% CI 5.19–23.89), and 10.28 (95% CI 3.38–31.31), respectively. The predictive values for mortality were similar between the presence of liver herniation and retrocardiac fetal stomach position. Conclusions: This systematic review suggests that o/e-LHR, o/e-TFLV, and L/T ratio are equally good predictors of neonatal mortality in fetuses with isolated CDH.

DOI： 10.1007/s00383-022-05232-w

Hypoalbuminemia for the prediction of survival in patients with stage IVB cervical cancer 国際誌

Yoshikawa, N; Yoshihara, M; Tamauchi, S; Ikeda, Y; Yokoi, A; Kajiyama, H

PLOS ONE 17 巻 ( 9 ) 頁： e0273876 2022年9月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：PLoS ONE

We evaluated the prognostic significance of malnutrition in patients with metastatic cervical cancer. In this study, we retrospectively analyzed the cases of 43 patients with stage IVB (FIGO2018) cervical cancer treated at our institute from December 2004 to December 2017. We determined the correlation between clinicopathological characteristics and survival by performing univariate and multivariate analyses. The serum albumin value at diagnosis was used as an index of malnutrition. The median follow-up period was 16.4 months (range, 0.9–91.4 months). On Kaplan-Meier analysis, the 1- and 2-year overall survival (OS) rates for all patients were 61.6% and 48.6%, respectively. The optimal serum albumin for predicting 1-year survival was 3.3 g/dL, as determined by the receiver operating characteristic curve to maximize the area under the curve. The OS of the patients with albumin >3.3 g/ dL (n = 28) was significantly better than that of the patients with albumin ≤3.3 g/dL (n = 15) (p = 0.004). The univariate and multivariate analyses revealed that pretreatment serum albumin and mode of primary treatment were significantly associated with survival in patients with stage IVB cervical cancer. Hypoalbuminemia was an unfavorable prognostic factor for patients with metastatic cervical cancer.

DOI： 10.1371/journal.pone.0273876

卵巣がん細胞外小胞の機能解析と臨床応用へ向けた基盤研究

横井暁

日本婦人科腫瘍学会雑誌 40 巻 ( 3 ) 頁： 159 - 166 2022年7月

Survival benefits of retroperitoneal lymphadenectomy for optimally-resected advanced ovarian high-grade serous carcinoma: a multi-institutional retrospective study 査読有り国際誌

Ikeda, Y; Yoshihara, M; Tamauchi, S; Yokoi, A; Yoshikawa, N; Kajiyama, H

JOURNAL OF GYNECOLOGIC ONCOLOGY 33 巻 ( 4 ) 頁： e40 2022年7月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Journal of Gynecologic Oncology

Objective: The survival benefits of retroperitoneal lymphadenectomy (RLNA) for epithelial ovarian cancer (EOC) remain controversial because clinical behaviors differ among subtypes. The purpose of the present study was to clarify whether RLNA increases the survival rate of advanced high-grade serous carcinoma (HGSC). Methods: This was a retrospective cohort analysis of 3,227 patients with EOC treated between 1986 and 2017 at 14 institutions. Among them, 335 patients with stage IIB-IV HGSC who underwent optimal cytoreduction (residual tumor of <1 cm) were included. Patients were divided into the RLNA group (n=170) and non-RLNA group (n=165). All pathological slides were assessed based on a central pathological review. Oncologic outcomes were compared between the two groups in the original and weighted cohorts adjusted with the inverse probability of treatment weighting. Results: The median observation period was 49.8 (0.5–241.5) months. Overall, 219 (65%) out of 335 patients had recurrence or progression, while 146 (44%) died of the disease. In the original cohort, RLNA was a significant prognostic factor for longer progression-free survival (PFS) (hazard ratio [HR]=0.741; 95% confidence interval [CI]=0.558–0.985) and overall survival (OS) (HR=0.652; 95% CI=0.459–0.927). In the weighted cohort in which all variables were well balanced as standardized differences decreased, RLNA was also a significant prognostic factor for more favorable oncologic outcomes (PFS, adjusted HR=0.742; 95% CI=0.613–0.899) and OS, adjusted HR=0.620; 95% CI=0.488–0.787). Conclusion: The present study demonstrated that RLNA for stage III-IV HGSC with no residual tumor after primary debulking surgery contributed to better oncologic outcomes.

DOI： 10.3802/jgo.2022.33.e40

Long-Term Outcomes of Congenital Diaphragmatic Hernia: Report of a Multicenter Study in Japan

Yamoto Masaya, Nagata Kouji, Terui Keita, Hayakawa Masahiro, Okuyama Hiroomi, Amari Shoichiro, Yokoi Akiko, Masumoto Kouji, Okazaki Tadaharu, Inamura Noboru, Toyoshima Katsuaki, Koike Yuhki, Yazaki Yuta, Furukawa Taizo, Usui Noriaki

CHILDREN-BASEL 9 巻 ( 6 ) 2022年6月

記述言語：英語出版者・発行元：Children

Background: Treatment modalities for neonates with congenital diaphragmatic hernia (CDH) have greatly improved in recent years, with a concomitant increase in survival. However, long-term outcomes restrict the identification of optimal care pathways for CDH survivors in adolescence and adulthood. Therefore, we evaluated the long-term outcomes within the Japanese CDH Study Group (JCDHSG). Methods: Participants were born with CDH between 2006 and 2018 according to the JCDHSG. Participants were enrolled in the database at 1.5, 3, 6, and 12 years old. Follow-up items included long-term complications, operations for long-term complication, and home medical care. Results: A total of 747 patients were included in this study, with 626 survivors (83.8%) and 121 non-survivors (16.2%). At 1.5, 3, 6, and 12 years old, 45.4%, 36.5%, 34.8%, and 43.6% developed complications, and 20.1%, 14.7%, 11.5%, and 5.1% of participants required home care, respectively. Recurrence, pneumonia, pneumothorax, gastroesophageal reflux disease, and intestinal obstruction decreased with age, and thoracic deformity increased with age. Conclusions: As CDH survival rates improve, there is a need for continued research and fine-tuning of long-term care to optimize appropriate surveillance and long-term follow-up.

DOI： 10.3390/children9060856

Aberrant Activation of Cell-Cycle-Related Kinases and the Potential Therapeutic Impact of PLK1 or CHEK1 Inhibition in Uterine Leiomyosarcoma 査読有り国際誌

Yoshida, K; Yokoi, A; Yamamoto, T; Hayashi, Y; Nakayama, J; Yokoi, T; Yoshida, H; Kato, T; Kajiyama, H; Yamamoto, Y

CLINICAL CANCER RESEARCH 28 巻 ( 10 ) 頁： 2147 - 2159 2022年5月

担当区分：責任著者記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Clinical Cancer Research

Purpose: Uterine leiomyosarcoma is among the most aggressive gynecological malignancies. No effective treatment strategies have been established. This study aimed to identify novel therapeutic targets for uterine leiomyosarcoma based on transcriptome analysis and assess the preclinical efficacy of novel drug candidates. Experimental Design: Transcriptome analysis was performed using fresh-frozen samples of six uterine leiomyosarcomas and three myomas. The Ingenuity Pathway Analysis (IPA) was used to identify potential therapeutic target genes for uterine leiomyosarcoma. Afterward, our results were validated using three independent datasets, including 40 uterine leiomyosarcomas. Then, the inhibitory effects of several selective inhibitors for the candidate genes were examined using SK-UT-1, SK-LMS-1, and SKN cell lines. Results: We identified 512 considerably dysregulated genes in uterine leiomyosarcoma compared with myoma. The IPA revealed that the function of several genes, including CHEK1 and PLK1, were predicted to be activated in uterine leiomyosarcoma. Through an in vitro drug screening, PLK1 or CHEK1 inhibitors (BI-2536 or prexasertib) were found to exert a superior anticancer effect against cell lines at low nanomolar concentrations and induce cell-cycle arrest. In SK-UT-1 tumor-bearing mice, BI-2536 monotherapy remarkably suppressed tumorigenicity. Moreover, the prexasertib and cisplatin combination therapy inhibited tumor proliferation and prolonged the time to tumor progression. Conclusions: We identified upregulated expressions of PLK1 and CHEK1; their kinase activity was activated in uterine leiomyosarcoma. BI-2536 and prexasertib demonstrated a significant anticancer effect. Therefore, cell-cycle–related kinases may present a promising therapeutic strategy for the treatment of uterine leiomyosarcoma.

DOI： 10.1158/1078-0432.CCR-22-0100

Is cystectomy an option as conservative surgery for young patients with borderline ovarian tumor? A multi-institutional retrospective study 国際誌

Ikeda, Y; Yoshihara, M; Yoshikawa, N; Tamauchi, S; Yokoi, A; Nishino, K; Niimi, K; Kajiyama, H

INTERNATIONAL JOURNAL OF GYNECOLOGY & OBSTETRICS 157 巻 ( 2 ) 頁： 437 - 443 2022年5月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：International Journal of Gynecology and Obstetrics

Objective: To investigate the impact of cystectomy for borderline ovarian tumor (BOT) on tumor recurrence compared with salpingo-oophorectomy using inverse probability of treatment weighting (IPTW). Methods: A central pathologic review and a search of the medical records from 14 collaborating institutions from 1986 to 2017 identified 4708 women with a malignant ovarian neoplasm. Data for young women with Stage I BOT were extracted. To compare recurrence-free survival between the surgery groups, Cox regression analyses and the IPTW-adjusted Kaplan-Meier method were employed. Results: During a median follow-up of 62.0 (1.2–270.4) months, 10 of the 285 patients identified (3.5%) developed recurrence. In multivariate analysis, the practice of cystectomy was not a significant prognostic indicator of recurrence-free survival (hazard ratio [95% confidence interval] 1.276 [0.150–10.864]; P = 0.823). In the IPTW-adjusted cohort, the 5-year recurrence-free survival rates were 95.8% and 96.0% in patients receiving cystectomy and salpingo-oophorectomy, respectively (P = 0.378). Conclusion: If patients are selected appropriately, cystectomy in itself may not increase tumor recurrence in young women with early-stage BOT. A large-scale prospective clinical study is necessary to validate this finding.

DOI： 10.1002/ijgo.13844

Peritoneal restoration by repurposing vitamin D inhibits ovarian cancer dissemination via blockade of the TGF-β1/thrombospondin-1 axis 査読有り国際誌

Kitami, K; Yoshihara, M; Tamauchi, S; Sugiyama, M; Koya, Y; Yamakita, Y; Fujimoto, H; Iyoshi, S; Uno, K; Mogi, K; Ikeda, Y; Yokoi, A; Yoshikawa, N; Nishino, K; Niimi, K; Nawa, A; Enomoto, A; Kajiyama, H

MATRIX BIOLOGY 109 巻頁： 70 - 90 2022年5月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Matrix Biology

Ovarian cancer (OvCa), a lethal gynecological malignancy, disseminates to the peritoneum. Mesothelial cells (MCs) act as barriers in the abdominal cavity, preventing the adhesion of cancer cells. However, in patients with OvCa, they are transformed into cancer-associated mesothelial cells (CAMs) via mesenchymal transition and form a favorable microenvironment for tumors to promote metastasis. However, attempts for restoring CAMs to their original state have been limited. Here, we investigated whether inhibition of mesenchymal transition and restoration of MCs by vitamin D suppressed the OvCa dissemination in vitro and in vivo. The effect of vitamin D on the mutual association of MCs and OvCa cells was evaluated using in vitro coculture models and in vivo using a xenograft model. Vitamin D restored the CAMs, and thrombospondin-1 (component of the extracellular matrix that is clinically associated with poor prognosis and is highly expressed in peritoneally metastasized OvCa) was found to promote OvCa cell adhesion and proliferation. Mechanistically, TGF-β1 secreted from OvCa cells enhanced thrombospondin-1 expression in CAMs via Smad-dependent TGF-β signaling. Vitamin D inhibited mesenchymal transition in MCs and suppressed thrombospondin-1 expression via vitamin D receptor/Smad3 competition, contributing to the marked reduction in peritoneal dissemination in vivo. Importantly, vitamin D restored CAMs from a stabilized mesenchymal state to the epithelial state and normalized thrombospondin-1 expression in preclinical models that mimic cancerous peritonitis in vivo. MCs are key players in OvCa dissemination and peritoneal restoration and normalization of thrombospondin-1 expression by vitamin D may be a novel strategy for preventing OvCa dissemination.

DOI： 10.1016/j.matbio.2022.03.003

Is adjuvant chemotherapy necessary for young women with early-stage epithelial ovarian cancer who have undergone fertility-sparing surgery?: a multicenter retrospective analysis 査読有り国際誌

Ikeda, Y; Yoshihara, M; Yoshikawa, N; Yokoi, A; Tamauchi, S; Nishino, K; Niimi, K; Kajiyama, H

BMC WOMENS HEALTH 22 巻 ( 1 ) 頁： 80 - 80 2022年3月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：BMC Women's Health

Objective: In young patients with early-stage epithelial ovarian carcinoma (EOC) who were received fertility-sparing surgery (FSS), the role of adjuvant chemotherapy is unclear. Here, we performed a multicenter study using inverse probability of treatment weighting (IPTW) to explore the effect of chemotherapy on patients’ survival. Methods: Between 1987 and 2015, a retrospective study was carried out, including 1183 patients with stage I EOC. Among them, a total of 101 women with stage I EOC who underwent FSS were investigated, including 64 and 37 patients with or without adjuvant chemotherapy, respectively. Oncologic outcomes were compared between the two arms using original and IPTW cohorts. Results: During 62.6 months (median) of follow-up, recurrence was noted in 11 (17.2%) women in the chemotherapy arm and 6 (16.2%) patients in the observation arm. In the unweighted cohort, the 5-year overall and recurrence-free survival (OS/RFS) rates of chemotherapy and observation arms were 86.3/80.8 and 90.2/79.8%, respectively. There was no significant difference between the two groups {Log-rank: P = 0.649 (OS)/P = 0.894 (RFS)}. In the IPTW cohort after adjusting for various clinicopathologic covariates, we also failed to identify a difference in RFS/OS between the two groups {RFS (chemotherapy vs. observation), HR: 0.501 (95% CI 0.234–1.072), P = 0.075: OS (chemotherapy vs. observation), HR: 0.939 (95% CI 0.330–2.669), P = 0.905}. Conclusions: Even after adjusting clinicopathologic covariates, performing adjuvant chemotherapy may not improve the oncologic outcome in young patients who have undergone FSS.

DOI： 10.1186/s12905-022-01642-z

Significance of platinum distribution to predict platinum resistance in ovarian cancer after platinum treatment in neoadjuvant chemotherapy 査読有り国際誌

Uno, K; Yoshikawa, N; Tazaki, A; Ohnuma, S; Kitami, K; Iyoshi, S; Mogi, K; Yoshihara, M; Koya, Y; Sugiyama, M; Tamauchi, S; Ikeda, Y; Yokoi, A; Kikkawa, F; Kato, M; Kajiyama, H

SCIENTIFIC REPORTS 12 巻 ( 1 ) 頁： 4513 - 4513 2022年3月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Scientific Reports

Most patients with ovarian cancer experience recurrence and develop resistance to platinum-based agents. The diagnosis of platinum resistance based on the platinum-free interval is not always accurate and timely in clinical settings. Herein, we used laser ablation inductively coupled plasma mass spectrometry to visualize the platinum distribution in the ovarian cancer tissues at the time of interval debulking surgery after neoadjuvant chemotherapy in 27patients with advanced high-grade serous ovarian cancer. Two distinct patterns of platinum distribution were observed. Type A (n = 16): platinum accumulation at the adjacent stroma but little in the tumor; type B (n = 11): even distribution of platinum throughout the tumor and adjacent stroma. The type A patients treated post-surgery with platinum-based adjuvant chemotherapy showed significantly shorter periods of recurrence after the last platinum-based chemotherapy session (p = 0.020) and were diagnosed with “platinum-resistant recurrence”. Moreover, type A was significantly correlated with worse prognosis (p = 0.031). Post-surgery treatment with non-platinum-based chemotherapy could be effective for the patients classified as type A. Our findings indicate that the platinum resistance can be predicted prior to recurrence, based on the platinum distribution; this could contribute to the selection of more appropriate adjuvant chemotherapy, which may lead to improves prognoses.

DOI： 10.1038/s41598-022-08503-7

Adjuvant taxane plus platinum chemotherapy for stage I ovarian clear cell carcinoma with complete surgical staging: are more than three cycles necessary?

Ukai, M; Suzuki, S; Yoshihara, M; Yokoi, A; Yoshikawa, N; Kajiyama, H; Kikkawa, F

INTERNATIONAL JOURNAL OF CLINICAL ONCOLOGY 27 巻 ( 3 ) 頁： 609 - 618 2022年3月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：International Journal of Clinical Oncology

Background: Previous studies on adjuvant chemotherapy for patients with ovarian clear cell carcinoma (OCCC) have included a limited number of Asian patients with surgical stage I OCCC, despite differences in OCCC survival by race and stage. The aim of this study was to estimate the survival effect of the number of cycles of adjuvant taxane plus carboplatin chemotherapy in Asian patients with surgical stage I OCCC. Methods: We retrospectively identified 227 patients with surgical stage I OCCC at 14 institutions from 1995 to 2017. Kaplan–Meier analysis and Cox proportional hazard regression with inverse probability of treatment weighting (IPTW) adjustment were performed to evaluate overall survival (OS) and recurrence-free survival (RFS) in patients receiving ≤ 3 and 4–6 cycles of taxane plus platinum adjuvant chemotherapy. Results: Eighty-nine and 138 patients received ≤ 3 and 4–6 cycles of adjuvant chemotherapy, respectively. There was no between-group difference in OS or RFS with or without IPTW adjustment. In Cox proportional hazards analysis, 4–6 cycles of adjuvant chemotherapy were not associated with improved OS (HR 1.090; 95% CI 0.518–2.291; p = 0.821) or RFS (HR 1.144; 95% CI 0.619–2.114; p = 0.669) compared to ≤ 3 cycles, even with IPTW adjustment. Subgroup analysis in different substages of stage I OCCC showed that the number of cycles of adjuvant chemotherapy had no impact on OS or RFS. Conclusion: Three or fewer cycles of taxane plus carboplatin chemotherapy may be a reasonable treatment regime for patients with surgical staging I OCCC.

DOI： 10.1007/s10147-021-02075-8

その他リンク： https://link.springer.com/article/10.1007/s10147-021-02075-8/fulltext.html

Adipose-mesothelial crosstalk regulates peritoneal tumor microenvironment and accelerates metastasis of ovarian cancer

Mogi, K; Yoshihara, M; Uno, K; Iyoshi, S; Kitami, K; Sugiyama, M; Koya, Y; Tamauchi, S; Yokoi, A; Yoshikawa, N; Nawa, A; Kajiyama, H

CANCER SCIENCE 113 巻頁： 735 - 735 2022年2月

Vitamin D inhibits mesothelial-mesenchymal-transition accelerating peritoneal dissemination in ovarian cancer via THBS1

Kitami, K; Yoshihara, M; Sugiyama, M; Koya, Y; Yamakita, Y; Iyoshi, S; Uno, K; Mogi, K; Tamauchi, S; Yokoi, A; Yoshikawa, N; Nishino, K; Niimi, K; Nawa, A; Kajiyama, H

CANCER SCIENCE 113 巻頁： 729 - 729 2022年2月

Prognostic impact of extracellular miRNAs in patients with high-grade serous ovarian carcinoma

Yoshida, K; Yokoi, A; Matsuzaki, J; Kato, T; Ochiya, T; Kajiyama, H; Yamamoto, Y

CANCER SCIENCE 113 巻頁： 1788 - 1788 2022年2月

Notch signaling contributes to drug resistance acquisition through metabolic alteration in advanced ovarian cancer

Sugiyama, M; Yoshihara, M; Koya, Y; Kitami, K; Uno, K; Iyoshi, S; Mogi, K; Yokoi, A; Nawa, A; Kajiyama, H

CANCER SCIENCE 113 巻頁： 1280 - 1280 2022年2月

Drug repositioning screening for an inhibitor of EV secretion in ovarian cancer cells

Yoshioka, Y; Yokoi, A; Ochiya, T

CANCER SCIENCE 113 巻頁： 1410 - 1410 2022年2月

Discovering novel therapeutic agents for uterine leiomyosarcoma

Nagao, Y; Yokoi, A; Yoshida, K; Watanabe, E; Yoshihara, M; Tamauchi, S; Yoshikawa, N; Yamamoto, Y; Kato, T; Kajiyama, H

CANCER SCIENCE 113 巻頁： 1181 - 1181 2022年2月

Chemical library-based drug repositioning strategy for choriocarcinoma therapy

Watanabe, E; Yokoi, A; Yoshida, K; Yamamoto, Y; Nishino, K; Niimi, K; Kajiyama, H

CANCER SCIENCE 113 巻頁： 1501 - 1501 2022年2月

Anti-tumor capacity of specific contents in small extracellular vesicles derived from ADSCs in ovarian cancer

Yokoi, A; Yoshida, K; Uno, K; Kajiyama, H

CANCER SCIENCE 113 巻頁： 1408 - 1408 2022年2月

バルトリン腺癌との鑑別に難渋したクローン病合併痔瘻癌の1例

松井真実, 新美薫, 吉原雅人, 玉内学志, 横井暁, 池田芳紀, 芳川修久, 西野公博, 梶山広明

日本婦人科腫瘍学会雑誌 40 巻 ( 1 ) 頁： 10 - 16 2022年1月

記述言語：日本語出版者・発行元：公益社団法人日本婦人科腫瘍学会

<p>外陰部腺癌は稀であり，腟前庭後部の病変はバルトリン腺原発と考えやすい．今回クローン病罹患中の外陰部腺癌が，術後に痔瘻癌と判明した症例を経験したので報告する．症例は48歳の女性で，クローン病で内科的治療を継続していた．前医を受診する6カ月前に左腟前庭部に腫瘤が出現し前医を受診した．生検でadenocarcinomaと診断された．腸管由来の可能性も示唆されたため，上下部消化管内視鏡精査を行ったが悪性腫瘍を認めず，バルトリン腺癌疑いで当院を紹介受診した．初診時，左バルトリン腺領域に4 cm大，その腹側の陰核左側に1.5 cm大の腫瘤を認めた．CT検査で両側鼠径リンパ節の軽度腫大を認めた．2週間後に単純外陰切除術，両側鼠径リンパ節生検を施行した．病理診断は中分化腺癌であり，大腸粘膜上皮と腺癌との連続性が確認できたため痔瘻癌と診断した．切除断端は左腟壁深部剥離面が陽性であり，両側鼠径リンパ節にも転移を認めた．前手術から3カ月後に外科にてロボット支援腹腔鏡下腹会陰式直腸切断術，腟会陰切除術，大腸ストーマ造設術，鼠径リンパ節郭清術を施行され，現在化学療法（CAPOX療法）を行っている．外陰部は痔瘻が発生する場所として矛盾しないため，クローン病既往の外陰部腺癌は痔瘻由来の可能性を積極的に考慮し，術前に痔瘻の精査を十分に行う必要がある．</p>

DOI： 10.57291/jsgo.40.1_10

Integrative transcriptomics analysis for uterine leiomyosarcoma identifies aberrant activation of cell cycle-dependent kinases and their potential therapeutic significance.

Kosuke Yoshida, Akira Yokoi, Tomofumi Yamamoto, Yusuke Hayashi, Jun Nakayama, Tsuyoshi Yokoi, Hiroshi Yoshida, Tomoyasu Kato, Hiroaki Kajiyama, Yusuke Yamamoto

2022年1月

出版者・発行元：Cold Spring Harbor Laboratory

Purpose: Uterine leiomyosarcoma is among the most aggressive gynecological malignancies. No effective treatment strategies have been established. This study aimed to identify novel therapeutic targets for uterine leiomyosarcoma based on transcriptome analysis and assess the preclinical efficacy of novel drug candidates.
Experimental Design: Transcriptome analysis was carried out using fresh-frozen samples of six uterine leiomyosarcomas and three myomas. The Ingenuity Pathway Analysis was then used to identify potential therapeutic target genes for uterine leiomyosarcoma. Moreover, our results were validated using three independent datasets, including 40 uterine leiomyosarcomas. Then, the inhibitory effects of several selective inhibitors for the candidate genes were examined using the SK-UT-1, SK-LMS-1, and SKN cell lines.
Results: We identified 512 considerably dysregulated genes in uterine leiomyosarcoma compared with myoma. The Ingenuity Pathway Analysis showed that the function of several genes, including CHEK1 and PLK1, were predicted to be activated in uterine leiomyosarcoma. Through an in vitro drug screening, PLK1 or CHEK1 inhibitors (BI 2536 or prexasertib) were found to exert a superior anti-cancer effect against cell lines at low nanomolar concentrations and induced cell cycle arrest. In SK-UT-1 tumor-bearing mice, BI 2536 monotherapy demonstrated a marked tumor regression. Moreover, the prexasertib and cisplatin combination therapy also reduced tumorigenicity and prolonged survival.
Conclusion: We identified the upregulated expression of PLK1 and CHEK1; their kinase activity was considered to be activated in uterine leiomyosarcoma. BI 2536 and prexasertib demonstrate a significant anti-cancer effect; thus, cell cycle-related kinases may represent a promising therapeutic strategy for treating uterine leiomyosarcoma.

DOI： 10.1101/2022.01.06.22268775

Clinical effects of cervical conization with positive margins in cervical cancer 査読有り国際誌

Nagao, Y; Yokoi, A; Yoshida, K; Sumi, M; Yoshihara, M; Tamauchi, S; Ikeda, Y; Yoshikawa, N; Nishino, K; Niimi, K; Kajiyama, H

SCIENTIFIC REPORTS 11 巻 ( 1 ) 頁： 23288 - 23288 2021年12月

担当区分：責任著者記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Scientific Reports

Radical surgery after cervical conization is a common approach for the treatment of cervical cancer. In some cases, disease progression is observed after positive margins at conization, but the effect of conization on disease progression remains unclear. Thus, the aim of this study was to investigate the clinical outcomes of positive margins at conization in cervical cancer. A total of 101 patients who underwent cervical conization before radical hysterectomy and pelvic lymph node dissection were considered eligible by reviewing medical records. The association between the positive margins and patient outcomes, including subsequent lymph node metastasis, was evaluated. The rate of lymphovascular space invasion (LVSI) positivity at radical surgery was significantly higher in patients with positive margins (p = 0.017) than in those with negative margins, although there was no significant difference in the rate of pelvic lymph node metastasis (p = 0.155). Moreover, there was no significant difference in the overall survival or progression-free survival between the two groups (p = 0.332 and 0.200, respectively). A positive margin at conization presented no significant prognostic disadvantage; thus, diagnostic conization is one of the most suitable treatment options for early-stage cervical cancer that is difficult to accurately assess.

DOI： 10.1038/s41598-021-02635-y

Extracellular microRNA profiling for prognostic prediction in patients with high-grade serous ovarian carcinoma 査読有り国際誌

Yoshida, K; Yokoi, A; Matsuzaki, J; Kato, T; Ochiya, T; Kajiyama, H; Yamamoto, Y

CANCER SCIENCE 112 巻 ( 12 ) 頁： 4977 - 4986 2021年12月

担当区分：責任著者記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Cancer Science

High-grade serous ovarian carcinoma is a leading cause of death in female patients worldwide. MicroRNAs (miRNAs) are stable noncoding RNAs in the peripheral blood that reflect a patient’s condition, and therefore, they have received substantial attention as noninvasive biomarkers in various diseases. We previously reported the usefulness of serum miRNAs as diagnostic biomarkers. Here, we investigated the prognostic impact of the serum miRNA profile. We used the GSE106817 dataset, which included preoperative miRNA profiles of patients with ovarian malignancies. Excluding patients with other malignancy or insufficient prognostic information, we included 175 patients with high-grade serous ovarian carcinoma. All patients except four underwent surgery and received chemotherapy as initial treatment. The median follow-up period was 54.6 months (range, 3.5-144.1 months). Univariate Cox regression analysis revealed that higher levels of miR-187-5p and miR-6870-5p were associated with both poorer progression-free survival (PFS) and overall survival (OS), and miR-1908-5p, miR-6727-5p, and miR-6850-5p were poor prognostic indicators of PFS. The OS and PFS prognostic indices were then calculated using the expression values of three prognostic miRNAs. Multivariate Cox regression analysis showed that both indices were significantly independent poor prognostic factors (hazard ratio for OS and PFS, 2.343 [P =.015] and 2.357 [P =.005], respectively). In conclusion, circulating miRNA profiles can potentially provide information to predict the prognosis of patients with high-grade serous ovarian carcinoma. Therefore, there is a strong demand for early clinical application of circulating miRNAs as noninvasive biomarkers.

DOI： 10.1111/cas.15154

その他リンク： https://onlinelibrary.wiley.com/doi/full-xml/10.1111/cas.15154

CD63-mediated cloaking of VEGF in small extracellular vesicles contributes to anti-VEGF therapy resistance. 国際誌

Ma S, Mangala LS, Hu W, Bayaktar E, Yokoi A, Hu W, Pradeep S, Lee S, Piehowski PD, Villar-Prados A, Wu SY, McGuire MH, Lara OD, Rodriguez-Aguayo C, LaFargue CJ, Jennings NB, Rodland KD, Liu T, Kundra V, Ram PT, Ramakrishnan S, Lopez-Berestein G, Coleman RL, Sood AK

Cell reports 36 巻 ( 7 ) 頁： 109549 - 109549 2021年8月

Metabolome analysis reveals a diversity of cancer tissues in advanced epithelial ovarian cancer 国際誌

Yoshida, K; Yoshikawa, N; Kitami, K; Tamauchi, S; Ikeda, Y; Yokoi, A; Nishino, K; Niimi, K; Kajiyama, H

CANCER CELL INTERNATIONAL 21 巻 ( 1 ) 頁： 314 - 314 2021年6月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Cancer Cell International

Background: Epithelial ovarian cancer remains one of the leading causes of cancer deaths among women worldwide, and advanced epithelial ovarian cancer frequently metastasizes to the omentum. The characteristics of metastatic cancer may differ from those of primary ovarian cancer and reflect the unique omental microenvironment. This study investigated metabolomic differences in epithelial ovarian cancers. Methods: Patients with advanced epithelial ovarian cancer were eligible for this study. Five patients underwent surgery and resection of paired primary ovarian and omental metastatic cancer at Nagoya University. Metabolome analysis was performed in these paired cancer and metastatic cancer tissues through a facility service (C-SCOPE) at Human Metabolome Technologies, Inc. The concentrations of 116 compounds were measured by CE-TOFMS and CE-QqQMS, and 30 metabolic parameters were calculated. For statistical analyses, Welch’s t-test was used for comparisons between two independent groups. Results: Metabolite profiles were all different, which reflects diversity among these cancer tissues. Of the measured compounds, urea was the only metabolite that was significantly decreased in omental metastatic cancers compared with the primary cancers (p = 0.031). Moreover, in omental metastatic cancers, the pentose phosphate pathway was more dominant than glycolysis. Furthermore, in some cases, lactic acids in omental metastatic cancers were markedly decreased compared with primary cancers. With regard to histological subtype, the total levels of amino acids, especially the percentage of glutamine, were significantly enriched in serous carcinomas compared with nonserous carcinomas (p = 0.004 and p = 0.001). Moreover, the reduced forms of glutathione and polyamines were also more abundant in serous carcinomas than in nonserous carcinomas (p = 0.025 and 0.048). Conclusions: The metabolite profiles differed depending on tumor location and histological subtype. Metabolome analysis may be a useful tool for identifying cancer diagnostic and prognostic markers.

DOI： 10.1186/s12935-021-02014-7

Significance of Concurrent Chemoradiotherapy as Primary Treatment in Patients with Metastatic Cervical Cancer 査読有り国際誌

Hattori, S; Yoshikawa, N; Mogi, K; Yoshida, K; Yoshihara, M; Tamauchi, S; Ikeda, Y; Yokoi, A; Nishino, K; Niimi, K; Suzuki, S; Kajiyama, H

CURRENT ONCOLOGY 28 巻 ( 3 ) 頁： 1663 - 1672 2021年6月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Current Oncology

(1) This study investigated the prognostic impact of tumor size in patients with metastatic cervical cancer. (2) Methods: Seventy-three cervical cancer patients in our institute were stratified into two groups based on distant metastasis: para-aortic lymph node metastasis alone (IIIC2) or spread to distant visceral organs with or without para-aortic lymph node metastasis (IVB) to identify primary tumor size and concurrent chemoradiotherapy. (3) Results: The overall survival (OS) for patients with a tumor >6.9 cm in size was significantly poorer than that for patients with a tumor ≤6.9 cm in the IVB group (p = 0.0028); the corresponding five-year OS rates in patients with a tumor ≤6.9 and >6.9 cm were 53.3% and 13.4%, respectively. In the multivariate analysis, tumor size and primary treatment were significantly associated with survival in metastatic cervical cancer. (4) Conclusions: Tumor size ≤6.9 cm and concurrent chemoradiotherapy as the primary treatment were favorable prognostic factors for patients with metastatic cervical cancer.

DOI： 10.3390/curroncol28030155

ChrXq27.3 miRNA cluster functions in cancer development 査読有り国際誌

Yoshida, K; Yokoi, A; Yamamoto, Y; Kajiyama, H

JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH 40 巻 ( 1 ) 頁： 112 - 112 2021年3月

担当区分：責任著者記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Journal of Experimental and Clinical Cancer Research

MicroRNAs (miRNAs) regulate the expression of their target genes post-transcriptionally; thus, they are deeply involved in fundamental biological processes. miRNA clusters contain two or more miRNA-encoding genes, and these miRNAs are usually coexpressed due to common expression mechanisms. Therefore, miRNA clusters are effective modulators of biological pathways by the members coordinately regulating their multiple target genes, and an miRNA cluster located on the X chromosome q27.3 region has received much attention in cancer research recently. In this review, we discuss the novel findings of the chrXq27.3 miRNA cluster in various types of cancer. The chrXq27.3 miRNA cluster contains 30 mature miRNAs synthesized from 22 miRNA-encoding genes in an ~ 1.3-Mb region. The expressions of these miRNAs are usually negligible in many normal tissues, with the male reproductive system being an exception. In cancer tissues, each miRNA is dysregulated, compared with in adjacent normal tissues. The miRNA-encoding genes are not uniformly distributed in the region, and they are further divided into two groups (the miR-506-514 and miR-888-892 groups) according to their location on the genome. Most of the miRNAs in the former group are tumor-suppressive miRNAs that are further downregulated in various cancers compared with normal tissues. miR-506-3p in particular is the most well-known miRNA in this cluster, and it has various tumor-suppressive functions associated with the epithelial–mesenchymal transition, proliferation, and drug resistance. Moreover, other miRNAs, such as miR-508-3p and miR-509-3p, have similar tumor-suppressive effects. Hence, the expression of these miRNAs is clinically favorable as prognostic factors in various cancers. However, the functions of the latter group are less understood. In the latter group, miR-888-5p displays oncogenic functions, whereas miR-892b is tumor suppressive. Therefore, the functions of the miR-888–892 group are considered to be cell type- or tissue-specific. In conclusion, the chrXq27.3 miRNA cluster is a critical regulator of cancer progression, and the miRNAs themselves, their regulatory mechanisms, and their target genes might be promising therapeutic targets.

DOI： 10.1186/s13046-021-01910-0

Expression of the chrXq27.3 miRNA cluster in recurrent ovarian clear cell carcinoma and its impact on cisplatin resistance 査読有り国際誌

Yoshida, K; Yokoi, A; Sugiyama, M; Oda, S; Kitami, K; Tamauchi, S; Ikeda, Y; Yoshikawa, N; Nishino, K; Niimi, K; Suzuki, S; Kikkawa, F; Yokoi, T; Kajiyama, H

ONCOGENE 40 巻 ( 7 ) 頁： 1255 - 1268 2021年2月

担当区分：責任著者記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Oncogene

Ovarian clear cell carcinoma (OCCC) is a histological subtype of epithelial ovarian cancer and exhibits dismal prognosis due to chemoresistance. Moreover, only few effective therapeutic options exist for patients with recurrent OCCC, and an understanding of its molecular characteristics is essential for the development of novel therapeutic approaches. In the present study, we investigated unique MicroRNAs (miRNA) profiles in recurrent/metastatic OCCC and the role of miRNAs in cisplatin resistance. Comprehensive miRNA sequencing revealed that expression of several miRNAs, including miR-508-3p, miR-509-3p, miR-509-3-5p, and miR-514a-3p was remarkably less in recurrent cancer tissues when compared with that in paired primary cancer tissues. These miRNAs are located in the chrXq27.3 region on the genome. Moreover, its expression was negative in omental metastases in two patients with advanced OCCC. In vitro analyses revealed that overexpression of miR-509-3p and miR-509-3-5p reversed cisplatin resistance and yes-associated protein 1 (YAP1) was partially responsible for the resistance. Immunohistochemistry revealed that YAP1 expression was inversely correlated with the chrXq27.3 miRNA cluster expression. In conclusion, these findings suggest that alteration of the chrXq27.3 miRNA cluster could play a critical role in chemoresistance and miRNAs in the cluster and their target genes can be potential therapeutic targets.

DOI： 10.1038/s41388-020-01595-3

Gain-of-function p53 protein transferred via small extracellular vesicles promotes conversion of fibroblasts to a cancer-associated phenotype. 査読有り国際誌

Ma S, McGuire MH, Mangala LS, Lee S, Stur E, Hu W, Bayraktar E, Villar-Prados A, Ivan C, Wu SY, Yokoi A, Dasari SK, Jennings NB, Liu J, Lopez-Berestein G, Ram P, Sood AK

Cell reports 34 巻 ( 6 ) 頁： 108726 - 108726 2021年2月

A novel approach for liquid biopsy by using nuclear derived exosomes in ovarian cancer 査読有り国際誌

Yokoi, A

CANCER SCIENCE 112 巻頁： 986 - 986 2021年2月

The role of chrXq27.3 miRNA cluster in advanced ovarian clear cell carcinoma 査読有り国際誌

Yoshida, K; Yokoi, A; Yoshihara, M; Tamauchi, S; Yoshikawa, N; Nishino, K; Niimi, K; Kikkawa, F; Kajiyama, H

CANCER SCIENCE 112 巻頁： 291 - 291 2021年2月

Luteolin suppresses Ovarian Cancer progression via decrease the expression of VRK1 査読有り国際誌

Chang, XY; Kajiyama, H; Yoshikawa, N; Yokoi, A; Tamauchi, S; Yoshihara, M

CANCER SCIENCE 112 巻頁： 770 - 770 2021年2月

Intra-tumoral polarity induced by Notch signaling can be a novel therapeutic target for advanced ovarian cancer 査読有り国際誌

Yoshihara, M; Sugiyama, M; Koya, Y; Iyoshi, S; Kitami, K; Uno, K; Mogi, K; Tano, S; Tamauchi, S; Yokoi, A; Yoshikawa, N; Nawa, A; Kajiyama, H

CANCER SCIENCE 112 巻頁： 363 - 363 2021年2月

How do peritoneal mesothelial cells on adipose tissue attract ovarian cancer cells? 査読有り国際誌

Mogi, K; Yoshihara, M; Kitami, K; Iyoshi, S; Uno, K; Tano, S; Sugiyama, M; Koya, Y; Tamauchi, S; Yokoi, A; Yoshikawa, N; Nawa, A; Kajiyama, H

CANCER SCIENCE 112 巻頁： 341 - 341 2021年2月

Extracellular miRNAs as Predictive Biomarkers for Glypican-3-Derived Peptide Vaccine Therapy Response in Ovarian Clear Cell Carcinoma 査読有り国際誌

Ukai, M; Yokoi, A; Yoshida, K; Suzuki, S; Shibata, K; Kikkawa, F; Nakatsura, T; Kajiyama, H

CANCERS 13 巻 ( 3 ) 頁： 550 - 550 2021年2月

担当区分：責任著者記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Cancers

Ovarian clear cell carcinoma (OCCC) has been treated with surgery and chemotherapy; however, the prognosis remains poor because of chemoresistance. Therefore, immunotherapies are attracting attention, including the GPC3 peptide vaccine, which improves overall survival. However, the response rate is limited and there are no sufficient predictive biomarkers that can identify responders before treatment. Our purpose was to identify circulating serum miRNAs as predictive biomarkers for response to GPC3 peptide vaccine. Eighty-four patients in a phase II trial of a GPC3 peptide vaccine were enrolled and miRNA sequencing was performed on their serum samples. Candidate miRNAs were selected from a group of 14 patients for whom treatment was responsive and validated in an independent group of 10 patients for whom treatment was responsive. Three markedly upregulated miRNAs, miR-375-3p, miR-193a-5p, and miR-1228-5p, were identified, and the combination of those miRNAs demonstrated high value in the prediction of the response. The origin of these miRNAs was assessed by referring to OCCC tissue miRNA profiles, and they were not identified as cancer tissue-related miRNAs. Functional annotation analysis suggested that they were associated with interferon-related pathways. The miRNAs identified herein have great potential to allow the realization of liquid biopsy for predicting the immunotherapy response and precision medicine.

DOI： 10.3390/cancers13030550

Exploring the biological roles of extracellular vesicles carrying nucleic acids in ovarian cancer 査読有り国際誌

Yokoi, A

CANCER SCIENCE 112 巻頁： 204 - 204 2021年2月

Comprehensive analyses of small extracellular vesicles carrying nucleic acids in ovarian cancer 査読有り国際誌

Yokoi, A; Ochiya, T

CANCER SCIENCE 112 巻頁： 973 - 973 2021年2月

Active vitamin D inhibits mesothelial-mesenchymal-transition accelerating peritoneal dissemination in ovarian cancer 査読有り国際誌

Kitami, K; Yoshihara, M; Sugiyama, M; Koya, Y; Iyoshi, S; Uno, K; Mogi, K; Tamauchi, S; Yokoi, A; Yoshikawa, N; Nawa, A; Kajiyama, H

CANCER SCIENCE 112 巻頁： 351 - 351 2021年2月

血液マイクロRNAによる子宮肉腫と変性筋腫の術前鑑別診断

加藤友康, 横井暁, 松崎潤太郎, 山本雄介, 舘慶生, 米岡完, 清水華子, 植原貴史, 石川光也, 滝澤聡子, 青木良晃, 加藤健, 落谷孝広, 東レ株式会社新事業開発部門DNAチップG

日本婦人科腫瘍学会雑誌 39 巻 ( 1 ) 頁： 297 - 297 2021年1月

Establishment and characterization of cell lines from human endometrial epithelial and mesenchymal cells from patients with endometriosis. 査読有り国際誌

Muraoka A, Osuka S, Kiyono T, Suzuki M, Yokoi A, Murase T, Nishino K, Niimi K, Nakamura T, Goto M, Kajiyama H, Kondo Y, Kikkawa F

F&S science 1 巻 ( 2 ) 頁： 195 - 205 2020年11月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：F and S Science

Objective: To establish and characterize cell lines derived from human endometrial epithelial cells (ECs) and mesenchymal cells (MCs) from patients with and without endometriosis. Design: In vitro experimental study. Setting: University and national cancer center research institute. Patient(s): Two women with endometriosis and two women without endometriosis. Intervention(s): Sampling of endometrial ECs and MCs. Main Outcome Measure(s): Establishing immortalized endometrial ECs and MCs with quantitative reverse transcription-polymerase chain reaction (qRT-PCR), immunocytochemical analysis, and RNA sequence profiling performed to characterize the immortalized cells and a cell proliferation assay, three-dimensional culture, and assays for hormone responses performed to characterize the features of ECs. Result(s): The qRT-PCR, immunocytochemical analysis, and Western blot analysis revealed that the ECs and MCs maintained their original features. Moreover, the immortalized cells were found to retain responsiveness to sex steroid hormones. The ECs formed a gland-like structure in three-dimensional culture, indicating the maintenance of normal EC phenotypes. The RNA sequence profiling, principal component analysis, and clustering analysis showed that the gene expression patterns of the immortalized cells were different from those of cancer cells. Several signaling pathways that were statistically significantly enriched in ECs and MCs with endometriosis were revealed. Conclusion(s): We successfully obtained four paired immortalized endometrial ECs and MCs from patients with and without endometriosis. Using these cells could help identify diagnostic and therapeutic targets for endometriosis. The cell lines established in this study will thus serve as powerful experimental tools in the study of endometriosis.

DOI： 10.1016/j.xfss.2020.09.001

The clinical impact of intra- and extracellular miRNAs in ovarian cancer 査読有り国際誌

Yoshida, K; Yokoi, A; Kato, T; Ochiya, T; Yamamoto, Y

CANCER SCIENCE 111 巻 ( 10 ) 頁： 3435 - 3444 2020年10月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Cancer Science

Ovarian cancer is the most lethal gynecological cancer due to lack of early screening methods and acquired drug resistance. MicroRNAs (miRNAs) are effective post-transcriptional regulators that are transferred by extracellular vesicles, such as exosomes. Numerous studies have revealed that miRNAs are differentially expressed in epithelial ovarian cancer and act either as oncogenes or tumor suppressor genes. Cancer cells secrete exosomes containing miRNAs, which exert various effects on the components of the tumor microenvironment, including cancer-associated fibroblasts, macrophages, and adipocytes. Conversely, cancer cells also receive exosomes from these cells. As a result of cell-to-cell communication, epithelial ovarian cancer acquires a more aggressive phenotype and resistance to multiple drugs. In addition, some circulating miRNAs are protected from RNase degradation in the peripheral blood and can be potential non-invasive biomarkers. In particular, the combination of several circulating miRNAs enhances the accuracy of cancer screening. Likewise, comprehensive analyses revealed specific miRNA signatures in non-epithelial ovarian tumors and several miRNAs contributing to alterations of carcinogenic pathways. Overall, miRNAs play a crucial role in ovarian cancer progression. In this review, we discuss the emerging roles of intra- and extracellular miRNAs in ovarian cancers. In the near future, miRNAs will be practical biomarkers and computational deep learning will help in the clinical application of miRNAs. Moreover, miRNAs are potential therapeutic targets and agents, and there are ongoing clinical trials of miRNA replacement therapy. Therefore, accelerating research on miRNA might improve the prognosis of patients with ovarian cancer.

DOI： 10.1111/cas.14599

Ovarian cancer-associated mesothelial cells induce acquired platinum-resistance in peritoneal metastasis <i>via</i> the FN1/Akt signaling pathway 査読有り国際誌

Yoshihara, M; Kajiyama, H; Yokoi, A; Sugiyama, M; Koya, Y; Yamakita, Y; Liu, WT; Nakamura, K; Moriyama, Y; Yasui, H; Suzuki, S; Yamamoto, Y; Ricciardelli, C; Nawa, A; Shibata, K; Kikkawa, F

INTERNATIONAL JOURNAL OF CANCER 146 巻 ( 8 ) 頁： 2268 - 2280 2020年4月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：International Journal of Cancer

Peritoneal dissemination of ovarian cancer (OvCa) arises from the surface of the peritoneum, covered by monolayer of mesothelial cells (MCs). Given that both OvCa cells and MCs are present in the same peritoneal metastatic microenvironment, they may establish cell-to-cell crosstalk or phenotypic alterations including the acquisition of platinum-resistance in OvCa cells. Herein, we report how OvCa-associated mesothelial cells (OCAMs) induce platinum-resistance in OvCa cells through direct cell-to-cell crosstalk. We evaluated mutual associations between OvCa cells and human primary MCs with in vitro coculturing experimental models and in silico omics data analysis. The role of OCAMs was also investigated using clinical samples and in vivo mice models. Results of in vitro experiments show that mesenchymal transition is induced in OCAMs primarily by TGF-β1 stimulation. Furthermore, OCAMs influence the behavior of OvCa cells as a component of the tumor microenvironment of peritoneal metastasis. Mechanistically, OCAMs can induce decreased platinum-sensitivity in OvCa cells via induction of the FN1/Akt signaling pathway via cell-to-cell interactions. Histological analysis of OvCa peritoneal metastasis also illustrated FN1 expression in stromal cells that are supposed to originate from MCs. Further, we also confirmed the activation of Akt signaling in OvCa cells in contact with TGF-β1 stimulated peritoneum, using an in vivo mice model. Our results suggest that the tumor microenvironment, enhanced by direct cell-to-cell crosstalk between OvCa cells and OCAMs, induces acquisition of platinum-resistance in OvCa cells, which may serve as a novel therapeutic target for prevention of OvCa peritoneal dissemination.

DOI： 10.1002/ijc.32854

Prognostic impact of pelvic and para-aortic lymphadenectomy on clinically-apparent stage I primary mucinous epithelial ovarian carcinoma: a multi-institutional study with propensity score-weighted analysis 査読有り国際誌

Yoshihara, M; Kajiyama, H; Tamauchi, S; Iyoshi, S; Yokoi, A; Suzuki, S; Kawai, M; Nagasaka, T; Takahashi, K; Matsui, S; Kikkawa, F

JAPANESE JOURNAL OF CLINICAL ONCOLOGY 50 巻 ( 2 ) 頁： 145 - 151 2020年2月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Japanese Journal of Clinical Oncology

Background: The exact impact of full-staging lymphadenectomy on patients with primary mucinous epithelial ovarian carcinoma confined to the ovary is still unclear. In this study, we investigated the prognostic impact of lymphadenectomy covering both pelvic and para-aortic lymph nodes in patients with clinically-apparent stage I mucinous epithelial ovarian carcinoma, using data from multi-institutions under a central pathological review system and analyses with a propensity score-based method. Methods: We conducted a regional multi-institutional retrospective study between 1986 and 2017. Among 4730 patients with malignant ovarian tumors, a total of 186 women with mucinous epithelial ovarian carcinoma were eligible. We evaluated differences in survival outcomes between patients with both pelvic and para-aortic lymphadenectomy and those with only pelvic lymphadenectomy and/or clinical lymph node evaluation. To analyze the therapeutic effects, the baseline imbalance between patients with both pelvic and para-aortic lymphadenectomy and others was adjusted with an inverse probability of treatment weighting using propensity score involving independent clinical variables. Results: Fifty-five patients received both pelvic and para-aortic lymphadenectomy. With PS-based adjustment, both pelvic and para-aortic lymphadenectomy did not have additive effects regarding overall survival (P = 0.696) and recurrence-free survival (P = 0.978). Multivariate analysis similarly showed no significant impact of both pelvic and para-aortic lymphadenectomy on their prognosis. Conclusions: The effect of pelvic and para-aortic lymphadenectomy is limited for clinically-apparent stage I primary mucinous epithelial ovarian carcinoma as long as full peritoneal and clinical lymph node evaluations are conducted. The results of this study should be used as the basis for additional studies, including prospective trials.

DOI： 10.1093/jjco/hyz163

Serum microRNA profile enables preoperative diagnosis of uterine leiomyosarcoma 査読有り国際誌

Yokoi, A; Matsuzaki, J; Yamamoto, Y; Tate, K; Yoneoka, Y; Shimizu, H; Uehara, T; Ishikawa, M; Takizawa, S; Aoki, Y; Kato, K; Kato, T; Ochiya, T

CANCER SCIENCE 110 巻 ( 12 ) 頁： 3718 - 3726 2019年12月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Cancer Science

Uterine leiomyosarcoma (ULMS) is the major subtype of uterine sarcoma (US) and contributes to uterine cancer deaths. Although preoperative diagnosis of US remains challenging, frequent application of laparoscopic surgery for benign uterine leiomyomas (ULM) requires precise exclusion of US. MicroRNAs are stably present in the bloodstream, and the application of circulating miRNAs as disease biomarkers has been recognized. In the present study, we aimed to identify diagnostic biomarkers for distinguishing US from ULM by focusing on circulating miRNAs. All serum samples were collected preoperatively between 2009 and 2017, and all cases were histopathologically diagnosed. Whole miRNA profiles were obtained using a miRNA microarray. By analyzing expression levels of the miRNAs, candidate miRNAs were selected based on diagnostic performance in discriminating US from ULM, and a diagnostic model was then constructed. A total of 90 serum samples were analyzed, and clustering analyses revealed that the profiles of ULMS were distinct from those of controls. Based on leave-one-out cross-validation, seven miRNAs were selected as biomarker candidates. Based on model construction, the optimal model consisted of two miRNAs (miR-1246 and miR-191-5p), with an area under the receiver operating characteristic curve (AUC) for identifying ULMS of 0.97 (95% confidence interval [CI], 0.91-1.00). In contrast, serum lactate dehydrogenase had an AUC of only 0.64 (95% CI, 0.34-0.94). Seven serum miRNAs with high diagnostic performance for preoperative US screening were detected, and a promising diagnostic model for ULMS was generated.

DOI： 10.1111/cas.14215

Unique miRNA profiling of squamous cell carcinoma arising from ovarian mature teratoma: comprehensive miRNA sequence analysis of its molecular background 査読有り国際誌

Yoshida, K; Yokoi, A; Kagawa, T; Oda, S; Hattori, S; Tamauchi, S; Ikeda, Y; Yoshikawa, N; Nishino, K; Utsumi, F; Niimi, K; Suzuki, S; Shibata, K; Kajiyama, H; Yokoi, T; Kikkawa, F

CARCINOGENESIS 40 巻 ( 12 ) 頁： 1435 - 1444 2019年12月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Carcinogenesis

Owing to its rarity, the carcinogenesis and molecular biological characteristics of squamous cell carcinoma arising from mature teratoma remain unclear. This study aims to elucidate the molecular background of malignant transformation from the aspects of microRNA (miRNA) profiling. We examined 7 patients with squamous cell carcinoma and 20 patients with mature teratoma and extracted their total RNA from formalin-fixed paraffin-embedded tissues. Then we prepared small RNA libraries and performed comprehensive miRNA sequencing. Heatmap and principal component analysis revealed markedly different miRNA profiling in cancer, normal ovarian and mature teratoma tissues. Then we narrowed down cancer-related miRNAs, comparing paired-cancer and normal ovaries. Comparisons of cancer and mature teratoma identified two markedly upregulated miRNAs (miR-151a-3p and miR-378a-3p) and two markedly downregulated miRNAs (miR-26a-5p and miR-99a-5p). In addition, these findings were validated in fresh cancer tissues of patient-derived xenograft (PDX) models. Moreover, several miRNAs, including miR-151a-3p and miR-378a-3p, were elevated in the murine plasma when tumor tissues were enlarged although miR-26a-5p and miR-99a-5p were not elucidated in the murine plasma. Finally, we performed target prediction and functional annotation analysis in silico and indicated that targets genes of these miRNAs markedly correlated with cancer-related pathways, including 'pathway in cancer' and 'cell cycle'. In conclusion, this is the first study on miRNA sequencing for squamous cell carcinoma arising from mature teratoma. The study identified four cancer-related miRNAs that were considered to be related to the feature of malignant transformation. Moreover, miRNAs circulating in the murine plasma of the PDX model could be novel diagnostic biomarkers.

DOI： 10.1093/carcin/bgz135

COMPREHENSIVE MIRNA SEQUENCING OF SQUAMOUS CELL CARCINOMA ARISING FROM OVARIAN MATURE TERATOMA 査読有り国際誌

Yoshida, K; Yokoi, A; Tamauchi, S; Ikeda, Y; Yoshikawa, N; Nishino, K; Niimi, K; Suzuki, S; Kajiyama, H; Kikkawa, F

INTERNATIONAL JOURNAL OF GYNECOLOGICAL CANCER 29 巻頁： A544 - A545 2019年11月

Cancer extracellular vesicles contribute to stromal heterogeneity by inducing chemokines in cancer-associated fibroblasts. 査読有り国際誌

Naito Y, Yamamoto Y, Sakamoto N, Shimomura I, Kogure A, Kumazaki M, Yokoi A, Yashiro M, Kiyono T, Yanagihara K, Takahashi RU, Hirakawa K, Yasui W, Ochiya T

Oncogene 38 巻 ( 28 ) 頁： 5566 - 5579 2019年7月

A landmark in drug discovery based on complex natural product synthesis.

Kawano S, Ito K, Yahata K, Kira K, Abe T, Akagi T, Asano M, Iso K, Sato Y, Matsuura F, Ohashi I, Matsumoto Y, Isomura M, Sasaki T, Fukuyama T, Miyashita Y, Kaburagi Y, Yokoi A, Asano O, Owa T, Kishi Y

Scientific reports 9 巻 ( 1 ) 頁： 8656 2019年6月

Drug library screen reveals benzimidazole derivatives as selective cytotoxic agents for KRAS-mutant lung cancer. 査読有り国際誌

Shimomura I, Yokoi A, Kohama I, Kumazaki M, Tada Y, Tatsumi K, Ochiya T, Yamamoto Y

Cancer letters 451 巻頁： 11 - 22 2019年6月

PAI-1 secreted from metastatic ovarian cancer cells triggers the tumor-promoting role of the mesothelium in a feedback loop to accelerate peritoneal dissemination 査読有り国際誌

Peng, Y; Kajiyama, H; Yuan, H; Nakamura, K; Yoshihara, M; Yokoi, A; Fujikake, K; Yasui, H; Yoshikawa, N; Suzuki, S; Senga, T; Shibata, K; Kikkawa, F

CANCER LETTERS 442 巻頁： 181 - 192 2019年2月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Cancer Letters

The mesothelium, covered by a continuous monolayer of mesothelial cells, is the first protective barrier against metastatic ovarian cancer. However, mesothelial cells release tumor-promoting factors that accelerate the process of peritoneal metastasis. We identified cancer-associated mesothelial cells (CAMs) that had tumor-promoting potential. Here, we found that plasminogen activator inhibitor-1 (PAI-1) induced the formation of CAMs, after which CAMs increasingly secreted the oncogenic factors interleukin-8 (IL-8) and C-X-C motif chemokine ligand 5 (CXCL5), further promoting the metastasis of ovarian cancer cells in a feedback loop. After the formation of CAMs, PAI-1 activated the nuclear factor kappa B (NFκB) pathway in the CAMs, thus transcriptionally upregulating the expression of the downstream NFκB targets IL-8 and CXCL5. Moreover, PAI-1 correlated with peritoneal metastasis in ovarian cancer patients and indicated a poor prognosis. In both ex vivo and in vivo models, after PAI-1 expression was knocked down, the metastasis of ovarian cancer cells decreased significantly. Therefore, targeting PAI-1 may provide a potential target for future therapeutics to prevent the formation of CAMs and alleviate peritoneal metastasis in ovarian cancer patients.

DOI： 10.1016/j.canlet.2018.10.027

院内助産で分娩管理を行った生殖補助医療（ART）妊婦の産後過多出血の検討

大島和美, 横井暁, 柴田幸子, 真野真紀子

日本助産学会誌 32 巻 ( 2 ) 頁： 169 - 177 2018年12月

記述言語：日本語出版者・発行元：一般社団法人日本助産学会

<p><b>目　的</b></p><p>バースセンター（以下BC）は，総合周産期母子医療センターに併設する院内助産施設である。BCでは妊娠分娩経過は正常であっても，出産後に予期せぬ多量出血を経験することがある。生殖補助医療（以下ART）妊娠は癒着胎盤のリスク因子と言われており，且つ癒着胎盤は産科危機的出血の原因となり得る。当施設ではART妊娠であっても院内助産分娩希望があれば，産科医許可のもとBCで分娩を取扱っている。本研究ではART妊娠（新鮮胚移植妊娠，融解胚移植妊娠）の産後過多出血（以下PPH）を検証し，院内助産におけるリスク評価，及び対応を検討した。</p><p><b>対象と方法</b></p><p>研究デザインは症例対照研究である。対象は2013年4月から2016年3月の調査期間中にBCで取り扱った分娩604例で，うち非ART妊娠は567例，ART妊娠は37例（新鮮胚移植9例，融解胚移植28例）であった。非ART妊娠と新鮮胚移植妊娠，融解胚移植妊娠で分娩後出血量，産褥24時間出血量，及びPPH（分娩後出血500ml以上，産褥24時間出血800ml以上）頻度の統計解析を行った。分娩後出血量，産褥24時間出血量を重回帰分析で，PPH頻度を多変量ロジスティック分析により検証した。</p><p><b>結　果</b></p><p>融解胚移植妊娠は分娩後出血量，産褥24時間出血量が非ART妊娠より有意に多く，PPHの頻度は非ART妊娠より有意に高かった。PPHのうち4例が産科危機的出血であったが，うち3例は融解胚移植のART妊婦であった。</p><p><b>結　論</b></p><p>ART妊婦の中でも融解胚移植妊娠はPPHのリスク因子になることが示唆された。融解胚移植妊娠については医師と速やかな医療連携がとれる体制の確立，及び将来的に院内助産分娩の対象から除外すべきか検討するための調査が必要と考える。</p>

DOI： 10.3418/jjam.jjam-2017-0048

Cancer-associated mesothelial cells as a potential therapeutic target in epithelial ovarian cancer 査読有り国際誌

Yoshihara, M; Kajiyama, H; Sugiyama, M; Koya, Y; Ryu, B; Yokoi, A; Yamamoto, Y; Kikkawa, F

CANCER SCIENCE 109 巻頁： 247 - 247 2018年12月

The role of extracellular RNAs in ovarian cancer 査読有り国際誌

Yokoi, A; Yoshioka, Y; Yamamoto, Y; Matsuzaki, J; Kato, T; Kato, K; Kajiyama, H; Kikkawa, F; Ochiya, T

CANCER SCIENCE 109 巻頁： 351 - 351 2018年12月

Notch signaling enhances the mutual association with epithelial ovarian cancer and mesothelial cells 査読有り国際誌

Sugiyama, M; Yoshihara, M; Koya, Y; Yokoi, A; Ryu, B; Kikkawa, F; Kajiyama, H

CANCER SCIENCE 109 巻頁： 864 - 864 2018年12月

Carcinoma-associated mesothelial cells promote dissemination and platinum resistance in epithelial ovarian cancer. 査読有り国際誌

Yoshihara, M; Kajiyama, H; Sugiyama, M; Yasui, H; Koya, Y; Yamakita, Y; Ryu, B; Yokoi, A; Yamamoto, Y; Kikkawa, F

CANCER SCIENCE 109 巻頁： 118 - 118 2018年1月

Malignant extracellular vesicles carrying MMP1 mRNA facilitate peritoneal dissemination in ovarian cancer 査読有り国際誌

Yokoi, A; Yoshioka, Y; Yamamoto, Y; Ishikawa, M; Kato, T; Kiyono, T; Kajiyama, H; Kikkawa, F; Ochiya, T

CANCER SCIENCE 109 巻頁： 29 - 29 2018年1月

既存薬ライブラリーを用いた、活性型Ras変異がんを標的とする分子標的治療の探索査読有り国際誌

下村巌, 横井暁, 山本雄介, 多田裕司, 巽浩一郎, 落谷孝広

生命科学系学会合同年次大会 2017年度巻頁： [3P - 0974] 2017年12月

A combination of circulating miRNAs for the early detection of ovarian cancer 査読有り国際誌

Yokoi, A; Yoshioka, Y; Hirakawa, A; Yamamoto, Y; Ishikawa, M; Ikeda, S; Kato, T; Niimi, K; Kajiyama, H; Kikkawa, F; Ochiya, T

ONCOTARGET 8 巻 ( 52 ) 頁： 89811 - 89823 2017年10月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Oncotarget

Ovarian cancer is the leading cause of gynecologic cancer mortality, due to the difficulty of early detection. Current screening methods lack sufficient accuracy, and it is still challenging to propose a new early detection method that improves patient outcomes with less-invasiveness. Although many studies have suggested the utility of circulating microRNAs in cancer detection, their potential for early detection remains elusive. Here, we develop novel predictive models using a combination of 8 circulating serum miRNAs. This method was able to successfully distinguish ovarian cancer patients from healthy controls (area under the curve, 0.97; sensitivity, 0.92; and specificity, 0.91) and early-stage ovarian cancer from patients with benign tumors (0.91, 0.86 and 0.83, respectively). This method also enables subtype classification in 4 types of epithelial ovarian cancer. Furthermore, it is found that most of the 8 miRNAs were packaged in extracellular vesicles, including exosomes, derived from ovarian cancer cells, and they were circulating in murine blood stream. The circulating miRNAs described in this study may serve as biomarkers for ovarian cancer patients. Early detection and subtype determination prior to surgery are crucial for clinicians to design an effective treatment strategy for each patient, as is the goal of precision medicine.

DOI： 10.18632/oncotarget.20688

血清中miRNAプロファイルによる早期卵巣がん診断バイオマーカーの開発

横井暁, 吉岡祐亮, 加藤友康, 梶山広明, 吉川史隆, 落谷孝広

日本分子腫瘍マーカー研究会誌 32 巻 ( 0 ) 頁： 27 2017年

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